ORCID Profile
0000-0002-3725-793X
Current Organisation
Flinders University
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Biochemistry and Cell Biology | Analytical Biochemistry | Structural Chemistry | Cell Development (Incl. Cell Division And Apoptosis) | Physical Chemistry (Incl. Structural) | Cellular Immunology | Biochemistry And Cell Biology Not Elsewhere Classified | Physiology | Genetics | Characterisation Of Macromolecules | Plant Improvement (Selection, Breeding And Genetic Engineering) | Natural Resource Management | Biochemistry and Cell Biology not elsewhere classified | Microbiology not elsewhere classified | Biophysics | Animal Physiology - Cell | Gene Expression (incl. Microarray and other genome-wide approaches) | Toxicology (Incl. Clinical Toxicology) | Basic Pharmacology | Pharmaceutical Sciences And Pharmacy | Protein Targeting And Signal Transduction | Complementary/Alternative Medicine Not Elsewhere Classified | Characterisation of Biological Macromolecules | Biological Psychology (Neuropsychology, Psychopharmacology, | Analytical Spectrometry | Medicinal and Biomolecular Chemistry | Learning, Memory, Cognition And Language | Environmental Science and Management | Sensory Processes, Perception And Performance | Sensor (Chemical And Bio-) Technology | Biologically Active Molecules | Plant Improvement (Selection, Breeding And Genetic Engineering) | Immunology | Psychology | Gene Expression | Genetic Immunology | Materials Engineering Not Elsewhere Classified | Animal Physiology—Systems | Diagnostic Applications |
ANZSRC Socio-Economic Objective (SEO)
Biological sciences | Chemical sciences | Treatments (e.g. chemicals, antibiotics) | Barley | Clinical health not specific to particular organs, diseases and conditions | Immune system and allergy | Cancer and related disorders | Expanding Knowledge in the Medical and Health Sciences | Expanding Knowledge in the Agricultural and Veterinary Sciences | Expanding Knowledge in the Biological Sciences | Wheat | Physical sciences | Reproductive system and disorders | Diagnostics | Organs, diseases and abnormal conditions not elsewhere classified | Law enforcement | Inherited diseases (incl. gene therapy) | Behavioural and cognitive sciences | Polymeric materials (e.g. paints) | Aboriginal and Torres Strait Islander heritage
Related Links
Publications
Regulation of UDP-Glucuronosyltransferases UGT2B4 and UGT2B7 by MicroRNAs in Liver Cancer Cellss
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 07-04-2017
Abstract: The transcriptional regulation of UDP-glucuronosyltransferases
Binding of SEP-363856 within TAAR1 and the 5HT(1A) receptor: implications for the design of novel antipsychotic drugs
Publisher: Springer Science and Business Media LLC
Date: 10-08-2022
DOI: 10.1038/S41380-021-01250-7
Abstract: Current medications for schizophrenia typically modulate dopaminergic neurotransmission. While affecting positive symptoms, antipsychotic drugs have little clinical effect on negative symptoms and cognitive impairment. Moreover, newer 'atypical' antipsychotic drugs also have significant metabolic adverse-effects. The recent positive clinical trial of the novel drug candidate SEP-363856, which targets non-dopamine receptors (trace amine-associated receptor and the 5HT
Hepatic nuclear receptor PPAR alpha in the koala (Phascolarctos cinereus): Cloning and molecular characterisation
Publisher: Elsevier BV
Date: 09-2007
DOI: 10.1016/J.CBPC.2007.04.013
Abstract: Peroxisome proliferator-activated receptor alpha (PPARalpha) is a member of the nuclear/steroid receptor gene superfamily that plays an essential role in fatty acid metabolism. PPARalpha modulates the expression of genes encoding peroxisomal fatty acid beta-oxidation enzymes and microsomal fatty acid hydroxylases CYP4As. We have previously reported that the obligate Eucalyptus feeder koala (Phascolarctos cinereus) exhibits a higher hepatic CYP4A activity and an absence of peroxisomal palmitoyl-CoA oxidation as compared to non-Eucalyptus feeders human, rat or wallaby. Here we describe the cloning, expression and molecular characterisation of koala hepatic PPARalpha. A full-length PPARalpha cDNA of size 1515 bp was cloned by reverse transcription-polymerase chain reaction (RT-PCR) and rapid lification of cDNA ends (RACE). The koala PPARalpha cDNA encodes a protein of 468 amino acids. Transfection of the koala PPARalpha cDNA into Cos-7 cells resulted in the expression of a protein recognised by a rabbit anti-human PPARalpha polyclonal antibody. PPARalpha immunoreactive bands of the same molecular mass were detected in nuclear extracts of koala livers. The results of this study demonstrate the presence of koala hepatic PPARalpha which shares several common features with other published PPARalphas however, it exhibits important differences in both the DNA and ligand binding domains.
Regulation of human UGT2B15 and UGT2B17 by miR-376c in prostate cancer cell liness
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 10-07-2015
Abstract: Given the prime importance of UDP-glucuronosyltransferase (UGT) 2B15 and UGT2B17 in inactivating testosterone and dihydrotestosterone, control of their expression and activity in the prostate is essential for androgen signaling homeostasis in this organ. Although several studies provide evidence of transcriptional control of UGT2B15 and UGT2B17 by various endogenous and exogenous compounds, potential post-transcriptional regulation of UGT2B15 and UGT2B17 by microRNAs (miRs) in prostate cancer cells has not been examined. The present study identified a putative miR-376c target site in the 3'-untranslated regions (UTRs) of both UGT2B15 and UGT2B17 mRNAs. In accordance with the possibility that this miRNA negatively regulates UGT2B15 and UGT2B17 expression, there is an inverse correlation in the levels of miR-376c and UGT2B15/UGT2B17 mRNAs in prostate cancer cell lines versus normal prostate tissue. In LNCaP cells, transfection of miR-376c mimics inhibited the glucuronidations of testosterone, 4-methylumbelliferone (a substrate of UGT2B15), and androsterone (a substrate of UGT2B17). miR-376c reduced both UGT2B15 and UGT2B17 mRNA and protein levels and the activity of luciferase reporters containing UGT2B15 or UGT2B17 3'-UTRs. This microRNA-mediated repression was significantly abrogated by mutating the miR-376c binding site in the 3'-UTRs of both UGTs. Collectively, these data indicate that the expression of UGT2B15 and UGT2B17 is negatively regulated by the binding of miR-376c to the 3'-UTRs of UGT2B15 and UGT2B17 in prostate cancer cells. This represents the first evidence for post-transcriptional regulation of UGT2B15 and UGT2B17 by miRNAs in prostate cancer cells and may have importance in regulating androgen receptor signaling.
Absence of type 1 11 beta-hydroxysteroid dehydrogenase enzyme in koala liver
Publisher: Elsevier BV
Date: 2002
DOI: 10.1016/S1532-0456(01)00278-2
Abstract: The 11beta-hydroxysteroid dehydrogenases (11beta-HSDs) interconvert 11beta-hydroxysteroids such as cortisol into 11-oxosteroids such as cortisone. In most mammals, 11beta-HSD 1 is expressed predominantly in the liver and is active in both the oxidative (cortisol to cortisone) and dehydrogenase (cortisone to cortisol) directions, whilst 11beta-HSD 2 is expressed predominantly in the kidney and functions as a pure oxidative enzyme. We have investigated 11beta-HSD 1 activity in the Australian koala (Phascolarctos cinereus) and have found no activity (either reductive or oxidative) in hepatic microsomes. Immunoblot analysis of koala hepatic microsomes, using an 11beta-HSD 1 antibody raised against the mouse enzyme, failed to identify immunoreactive protein. Reverse transcriptase-polymerase chain reaction (RT-PCR) of koala liver mRNA and genomic PCR using primers designed against highly conserved regions of 11beta-HSD 1 nucleotide sequences were also negative. Furthermore, Southern and Northern blot analysis of koala genomic DNA and mRNA, respectively, confirmed that the koala lacks the 11beta-HSD 1 gene and gene transcript. These results support the fact that the lack of hepatic 11beta-HSD 1 activity in the koala is due to the absence of the 11beta-HSD 1 gene, and this absence is novel among mammalian species studied to date.
Inhibition of human UDP-glucuronosyltransferase enzymes by lapatinib, pazopanib, regorafenib and sorafenib: Implications for hyperbilirubinemia
Publisher: Elsevier BV
Date: 04-2017
DOI: 10.1016/J.BCP.2017.01.002
Abstract: Kinase inhibitors (KIs) are a rapidly expanding class of drugs used primarily for the treatment of cancer. Data relating to the inhibition of UDP-glucuronosyltransferase (UGT) enzymes by KIs is sparse. However, lapatinib (LAP), pazopanib (PAZ), regorafenib (REG) and sorafenib (SOR) have been implicated in the development of hyperbilirubinemia in patients. This study aimed to characterise the role of UGT1A1 inhibition in hyperbilirubinemia and assess the broader potential of these drugs to perpetrate drug-drug interactions arising from UGT enzyme inhibition. Twelve recombinant human UGTs from subfamilies 1A and 2B were screened for inhibition by LAP, PAZ, REG and SOR. IC
Interventions targeting the prescribing and monitoring of vancomycin for hospitalized patients: a systematic review with meta-analysis
Publisher: Informa UK Limited
Date: 10-2018
DOI: 10.2147/IDR.S176519
Polymorphisms in UDP Glucuronosyltransferase Genes: Functional Consequences and Clinical Relevance
Publisher: Walter de Gruyter GmbH
Date: 18-09-2000
Abstract: As glucuronidation is a major process for the metabolism and removal of lipophilic chemicals, polymorphic variations in genes encoding the enzymes involved in this process, the UDP glucuronosyltransferases (UGT), may have a significant impact on our capacity to detoxify and eliminate drugs and toxins. Although 24 human UGT genes have been identified to date, only polymorphisms in five UGTs, viz. UGT1A1, UGT1A6, UGT2B4, UGT2B7 and UGT2B15 have been described. Polymorphisms in UGT1A1, the major bilirubin-glucuronidating form, often result in a decreased capacity to glucuronidate bilirubin, such as observed in Gilbert Syndrome and some forms of perinatal jaundice. The frequencies of in idual UGT1A1 polymorphisms show extensive variability across ethnic groups. Two variants of UGT1A6 and UGT2B4 and one variant of UGT2B7 and UGT2B15 have been identified. However, the clinical significance of these variants is unclear. More UGT polymorphisms will undoubtedly be discovered when the human genome is sequenced. However, unless the UGT in question is responsible for the exclusive metabolism of a particular drug or chemical ( e.g. UGT1A1 and bilirubin) or is the predominant or only UGT present in the cell, it is unlikely that these polymorphisms will be of major clinical significance.
Pharmacists' role in targeted cancer therapy in Australia and implications for pharmacy education
Publisher: Elsevier BV
Date: 11-2010
DOI: 10.5688/AJ7409168
Potential Novel Role of UDP Glucuronosyltransferases 2B11 and 2B28 in Crosstalk Between Androgen and Lipid Signalling
Publisher: Wiley
Date: 04-2020
Induction of UDP-glucuronosyltransferase 2B15 gene expression by the major active metabolites of tamoxifen,4-hydroxytamoxifen and endoxifen, in breast cancer cells
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 20-03-2015
Abstract: We previously reported upregulation of UGT2B15 by 17β-estradiol in breast cancer MCF7 cells via binding of the estrogen receptor α (ERα) to an estrogen response unit (ERU) in the proximal UGT2B15 promoter. In the present study, we show that this ERα-mediated upregulation was significantly reduced by two ER antagonists (fulvestrant and raloxifene) but was not affected by a third ER antagonist, 4-hydroxytamoxifen (4-OHTAM), a major active tamoxifen (TAM) metabolite. Furthermore, we found that, similar to 17β-estradiol, 4-OHTAM and endoxifen (another major active TAM metabolite) elevated UGT2B15 mRNA levels, and that this stimulation was significantly abrogated by fulvestrant. Further experiments using 4-OHTAM revealed a critical role for ERα in this regulation. Specifically knockdown of ERα expression by anti-ERα small interfering RNA reduced the 4-OHTAM-mediated induction of UGT2B15 expression 4-OHTAM activated the wild-type but not the ERU-mutated UGT2B15 promoter and chromatin immunoprecipitation assays showed increased ERα occupancy at the UGT2B15 ERU in MCF7 cells upon exposure to 4-OHTAM. Together, these data indicate that both 17β-estradiol and the antiestrogen 4-OHTAM upregulate UGT2B15 in MCF7 cells via the same ERα-signaling pathway. This is consistent with previous observations that both 17β-estradiol and TAM upregulate a common set of genes in MCF7 cells via the ER-signaling pathway. As 4-OHTAM is a UGT2B15 substrate, the upregulation of UGT2B15 by 4-OHTAM in target breast cancer cells is likely to enhance local metabolism and inactivation of 4-OHTAM within the tumor. This represents a potential mechanism that may reduce TAM therapeutic efficacy or even contribute to the development of acquired TAM resistance.
Polymorphisms and haplotypes of the udp-glucuronosyltransferase 2b7 gene promoter s
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 21-02-2014
Abstract: Identification of functional polymorphisms in the UDP-glucuronosyltransferase 2B7 (UGT2B7) gene predicting interpatient variability in the glucuronidation of drugs that are primarily metabolized by UGT2B7 has been the subject of many studies. These studies have shown linkage disequilibrium (LD) covering the region from -2 kb to 16 kb of the UGT2B7 gene. We identified three novel single-nucleotide polymorphisms (SNPs) and extended this LD in the 5'-upstream direction to cover an additional nine prevalent polymorphisms in the distal -2600- to -4000-base pair (bp) promoter. We further showed complete LD between these distal promoter SNPs and the SNP (802C>T) in exon 2 in a panel of 26 livers. Because of this LD, we showed that all of the 23 prevalent polymorphisms in the 4-kb UGT2B7 promoter are linked together, defining two major haplotypes (i.e., I and II). The addition of the minor allele of a rare polymorphism and allele exchanges between haplotypes I and II generated subhaplotypes of I and II. We demonstrated a higher promoter activity of haplotype II over haplotype I, and this higher activity was abolished by an A-to-G change at a single SNP (-900A>G). This mutation changed a consensus activating protein-1 (AP-1) site (TGAGTCA) as occurred in haplotype II to a mutated AP-1 site (TGAGTCG) as occurred in haplotype I. Finally, we showed that the previously reported Alu element resides exclusively in haplotype I and is a highly conserved CG-rich Alu Y element.
Reforming pharmaceutical education to enhance the global uptake of pharmacogenomics and personalized medicine
Publisher: Bentham Science Publishers Ltd.
Date: 08-2012
Polyandric acid A, a clerodane diterpenoid from the australian medicinal plant dodonaea polyandra, attenuates pro-inflammatory cytokine secretion in vitro and in vivo
Publisher: American Chemical Society (ACS)
Date: 08-01-2014
DOI: 10.1021/NP400704B
Abstract: Dodonaea polyandra is a medicinal plant used traditionally by the Kuuku I'yu (Northern Kaanju) indigenous people of Cape York Peninsula, Australia. The most potent of the diterpenoids previously identified from this plant, polyandric acid A (1), has been examined for inhibition of pro-inflammatory cytokine production and other inflammatory mediators using well-established acute and chronic mouse ear edema models and in vitro cellular models. Topical application of 1 significantly inhibited interleukin-1β production in mouse ear tissue in an acute model. In a chronic skin inflammation model, a marked reduction in ear thickness, associated with significant reduction in myeloperoxidase accumulation, was observed. Treatment of primary neonatal human keratinocytes with 1 followed by activation with phorbol ester/ionomycin showed a significant reduction in IL-6 secretion. The present study provides evidence that the anti-inflammatory properties of 1 are due to inhibition of pro-inflammatory cytokines associated with skin inflammation and may be useful in applications for skin inflammatory conditions including psoriasis and dermatitis.
Testosterone dehydrogenase activity in koala liver: characterisation of cofactor and steroid substrate differences
Publisher: Elsevier BV
Date: 02-2000
DOI: 10.1016/S0742-8413(99)00109-7
Abstract: We have studied the hepatic microsomal 17beta-hydroxysteroid dehydrogenase (17beta-HSD) capacity of koala (Phascolarctos cinereus) and tammar wallaby (Macropus eugenii). A detailed comparison of the activity in hepatic fractions from koala and rat was made. Hepatic microsomal NADP-supported 17beta-HSD activity was significantly higher in koala (11.64+/-3.35 nmoles/mg protein/min), (mean+/-S.D.) than in tammar wallaby liver (1.52+/-0.79 nmoles/mg protein/min). However, when NAD was utilised as cofactor the activity was similar in both marsupial species (2.83+/-2.03 nmoles/mg protein/min, koala 0.70+/-0.71 nmoles/mg protein/min, tammar wallaby). Data for rat indicated a cofactor preference for NAD rather than NADP (17.94+/-6.40 nmoles/mg protein/min, NAD 2.18+/-1.04 nmoles/mg protein/min, NADP). Michaelis-Menten parameters for the kinetics of 17beta-HSD testosterone oxidation by NADP and NAD were determined in the koala. The Km for testosterone was of the order of 10.0-24.0 microM (n = 6) irrespective of the cofactor used, whilst the Km for NADP was 0.28-0.43 microM (n = 2) and for NAD was 13.9-18.5 microM (n = 2). 17beta-estradiol was found to be an inhibitor of both NAD- and NADP- supported 17beta-HSD activity. These findings indicate that NADP-mediated, but not NAD-mediated testosterone dehydrogenation is a major pathway of steroid biotransformation in koala liver the reaction is less extensive in fractions from wallaby, human and rat. Such species-related differences in cofactor preference may contribute along with species differences in gene expression to observed rates of 17beta-HSD activity in mammals.
Transforming pharmaceutical education: A needs-based global analysis for policy development
Publisher: Elsevier BV
Date: 03-2023
Exemestane and its active metabolite 17-hydroexemestane induce UDP-glucuronosyltransferase (UGT) 2B17 expression in breast cancer cells
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 12-04-2017
Abstract: Exemestane (EXE) is an aromatase inhibitor indicated for endocrine therapy of breast cancer in postmenopausal women. The primary active metabolite of EXE, 17-hydroexemestane (17-HE), is inactivated via glucuronidation, mainly by UDP-glucuronosyltransferase 2B17 (UGT2B17). UGT2B17 also has a primary role in inactivation of endogenous androgens testosterone and dihydrotestosterone and may play an important role in regulation of breast and prostate tumor intracrinology. We recently reported that
Audit of Data Sharing by Pharmaceutical Companies for Anticancer Medicines Approved by the US Food and Drug Administration
Publisher: American Medical Association (AMA)
Date: 09-2022
DOI: 10.1001/JAMAONCOL.2022.2867
Abstract: Emerging policies drafted by the pharmaceutical industry indicate that they will transparently share clinical trial data. These data offer an unparalleled opportunity to advance evidence-based medicine and support decision-making. To evaluate the eligibility of independent, qualified researchers to access in idual participant data (IPD) from oncology trials that supported US Food and Drug Administration (FDA) approval of new anticancer medicines within the past 10 years. In this quality improvement study, a cross-sectional analysis was performed of pivotal clinical trials whose results supported FDA-approved anticancer medicines between January 1, 2011, and June 30, 2021. These trials’ results were identified from product labels. Eligibility for IPD sharing was confirmed by identification of a public listing of the trial as eligible for sharing or by receipt of a positive response from the sponsor to a standardized inquiry. The main outcome was frequency of IPD sharing eligibility. Reasons for data sharing ineligibility were requested and collated, and company-, drug-, and trial-level subgroups were evaluated and presented using χ 2 tests and forest plots. During the 10-year period examined, 115 anticancer medicines were approved by the FDA on the basis of evidence from 304 pharmaceutical industry–sponsored trials. Of these trials, 136 (45%) were eligible for IPD sharing and 168 (55%) were not. Data sharing rates differed substantially among industry sponsors, with the most common reason for not sharing trial IPD being that the collection of long-term follow-up data was still ongoing (89 of 168 trials [53%]). Of the top 10 anticancer medicines by global sales, nivolumab, pembrolizumab, and pomalidomide had the lowest eligibility rates for data sharing (& % of trials). There has been a substantial increase in IPD sharing for industry-sponsored oncology trials over the past 5 years. However, this quality improvement study found that more than 50% of queried trials for FDA-approved anticancer medicines were ineligible for IPD sharing. Data accessibility would be substantially improved if, at the time of FDA registration of a medicine, all data that support the registration were made available.
The effect of the UGT1A1*28 allele on survival after irinotecan-based chemotherapy: a collaborative meta-analysis
Publisher: Springer Science and Business Media LLC
Date: 08-04-2014
DOI: 10.1038/TPJ.2014.16
Abstract: To date, studies of irinotecan pharmacogenetics have mostly focused on the effect of the UGT1A1*28 allele on irinotecan-related toxicity. However, the clinical utility of routine UGT1A1*28 genotyping to pre-emptively adjust irinotecan dosage is dependent upon whether UGT1A1*28 also affects patient survival following irinotecan therapy. Previous observational studies evaluating the influence of UGT1A1*28 on survival have shown contradictory results. A systematic review and meta-analysis of both published and unpublished data were performed to summarize the available evidence of the relationship between the UGT1A1*28 allele and patient survival related to irinotecan therapy. Overall and progression-free survival meta-analysis data were available for 1524 patients and 1494 patients, respectively. The difference in the survival between patients of different UGT1A1*28 genotypes (homozygous, heterozygous or wild-type) who had received irinotecan was not found to be statistically significant. There was also no evidence of irinotecan dose, regimen or line of therapy having an impact on this association.
Smoking and immunotherapy efficacy in lung cancer by PDL1 subgroups: An individual participant data meta-analysis of atezolizumab clinical trials
Publisher: Elsevier BV
Date: 2022
Nuances to precision dosing strategies of targeted cancer medicines
Publisher: Wiley
Date: 13-07-2020
DOI: 10.1002/PRP2.625
Characterisation of tolbutamide hydroxylase activity in the common brushtail possum, (Trichosurus vulpecula) and koala (Phascolarctos cinereus): inhibition by the Eucalyptus terpene 1,8-cineole
Publisher: Elsevier BV
Date: 12-2000
DOI: 10.1016/S0742-8413(00)00163-8
Abstract: Plant constituents such as terpenes are major constituents of the essential oil in Eucalyptus sp. 1,8-Cineole and p-cymene (Terpenes present in high amounts in Eucalyptus leaves) are potential substrates for the CYP family of enzymes. We have investigated tolbutamide hydroxylase as a probe substrate reaction in both koala and terpene pretreated and control brushtail possum liver microsomes and examined inhibition of this reaction by Eucalyptus terpenes. The specific activity determined for tolbutamide hydroxylase in the terpene treated brushtails was significantly higher than that for the control animals (1865+/-334 nmol/mg microsomal protein per min versus 895+/-27 nmol/mg microsomal protein per min). The activity determined in koala microsomes was 8159+/-370 nmol/mg microsomal protein per min. Vmax values and Km values for the terpene treated possum, control, possum and koala were 1932-2225 nmol/mg microsomal protein per min and 0.80 0.81 mM 1406-1484 nmol/mg microsomal protein per min and 0.87-0.92 mM and 5895-6403 nmol/mg microsomal protein per min and 0.067-0.071 mM, respectively. Terpenes were examined as potential inhibitors of tolbutamide hydroxylase activity. 1,8-Cineole was found to be a competitive inhibitor for the enzyme responsible for tolbutamide hydroxylation (Ki 15 microM) in the possum. In koala liver microsomes stimulation of tolbutamide hydroxylase activity was observed when concentrations of cineole were increased. Therefore, although inhibition was observed, the type of inhibition could not be determined.
Cooperative regulation of intestinal udp-glucuronosyltransferases 1A8, -1A9, and 1A10 by CDX2 and HNF4a is mediated by a novel composite regulatory elements
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 08-03-2018
Abstract: The gastrointestinal tract expresses several UDP-glucuronosyltransferases (UGTs) that act as a first line of defense against dietary toxins and contribute to the metabolism of orally administered drugs. The expression of
Cancer and Chronic Conditions: Addressing the Problem of Multimorbidity in Cancer Patients and Survivors -- The management of polypharmacy in people with cancer and chronic conditions
Publisher: Springer Singapore
Date: 2016
Biosimilars are not (bio)generics
Publisher: Therapeutic Guidelines Limited
Date: 12-2009
Comparison of Linear and Nonlinear Classification Algorithms for the Prediction of Drug and Chemical Metabolism by Human UDP-Glucuronosyltransferase Isoforms
Publisher: American Chemical Society (ACS)
Date: 06-09-2003
DOI: 10.1021/CI034108K
Abstract: Partial least squares discriminant analysis (PLSDA), Bayesian regularized artificial neural network (BRANN), and support vector machine (SVM) methodologies were compared by their ability to classify substrates and nonsubstrates of 12 isoforms of human UDP-glucuronosyltransferase (UGT), an enzyme "superfamily" involved in the metabolism of drugs, nondrug xenobiotics, and endogenous compounds. Simple two-dimensional descriptors were used to capture chemical information. For each data set, 70% of the data were used for training, and the remainder were used to assess the generalization performance. In general, the SVM methodology was able to produce models with the best predictive performance, followed by BRANN and then PLSDA. However, a small number of data sets showed either equivalent or better predictability using PLSDA, which may indicate relatively linear relationships in these data sets. All SVM models showed predictive ability (>60% of test set predicted correctly) and five out of the 12 test sets showed excellent prediction (>80% prediction accuracy). These models represent the first use of pattern recognition methods to discriminate between substrates and nonsubstrates of human drug metabolizing enzymes and the first thorough assessment of three classification algorithms using multiple metabolic data sets.
POSSIBLE ROLE OF CYTOCHROMES P450 IN LUPUS-ERYTHEMATOSUS AND RELATED DISORDERS
Publisher: SAGE Publications
Date: 12-2016
DOI: 10.1177/096120339400300608
Abstract: Cytochromes P450 comprise a superfamily of enzymes pivotal in the metabolism of innumerable substrates of both endogenous and exogenous origin. The total number of distinct P450 genes, each encoding a different enzyme in humans, is estimated to be at least 60 and possibly several hundred. The cytochrome P450 (CYP) superfamily nomenclature system is based on ergent evolution of the genes. Most of the enzymes within gene families CYP1, CYP2, CYP3 and CYP4 appear to have evolved as the body's primary defense against the onslaught of chemicals confronted on a daily basis. Whereas P450 enzymes more than 3.5 billion years ago were undoubtedly designed as necessary components of signal transduction pathways, in the past billion years most P450 enzymes have become generally responsible for the detoxification of numerous foreign chemicals. During such oxidative metabolism, it has become increasingly apparent that these enzymes are also capable of functioning in an ambivalent manner, generating toxic intermediates. More than a dozen human P450 polymorphisms have been characterized. Genetic variability in P450 expression is therefore likely to have significant bearing on in idual susceptibility to chemical toxicity. In this review, genetic differences in human P450 expression are outlined, and their possible relationship to autoimmune disease is examined. In addition, the speculative role of P450 polymorphisms in several 'lupus-like' disorders is discussed.
Exploration of the perceptions, barriers and drivers of pharmacogenomics practice among hospital pharmacists in Adelaide, South Australia.
Publisher: Springer Science and Business Media LLC
Date: 10-09-2014
DOI: 10.1038/TPJ.2013.31
Abstract: There is little literature regarding the barriers to the uptake of pharmacogenomics (PG) in pharmacy practice, especially with respect to Australia. To date, pharmacists have seldom been engaged in discussions of these issues. This study aimed to obtain an in-depth understanding of these barriers by interviewing pharmacists in Adelaide, South Australia. Ethics approved semistructured interviews were carried out with 21 public hospital pharmacists. Analysis of the data identified themes including: confidence to engage in PG, clinician acceptance of a pharmacist PG role, and the importance of timely and relevant PG education. Interviewees thought that pharmacists could have a greater participation in PG in the future, but they questioned whether this would be possible at the moment given, among other factors, existing time and work constraints.
Commentary
Publisher: Frontiers Media SA
Date: 05-08-2021
Chemical similarities and differences among inhibitors of nitric oxide synthase, arginase and dimethylarginine dimethylaminohydrolase-1: Implications for the design of novel enzyme inhibitors modulating the nitric oxide pathway.
Publisher: Elsevier BV
Date: 10-2022
DOI: 10.1016/J.BMC.2022.116970
Abstract: Nitric oxide (NO) is a signalling molecule that controls a multitude of regulatory functions including neurotransmission, vascular tone, immune response, and angiogenesis. Regulating NO concentrations in cells using small molecules is an active area of research in the treatment of several pathologies such as cardiovascular disease, cancer, and inflammatory conditions. Small molecule-inhibition of critical NO regulatory enzymes, NO synthase (NOS), arginase, and dimethylarginine dimethyaminohydrolase-1 (DDAH1), has shown therapeutic benefits as well as limitations and is a focus of current research.In recent years, DDAH1 has been explored as a potential target to indirectly regulate NO in diseases characterized by excessive NO production. This review discusses the biological and pathophysiological role of the NO pathway, the existing inhibitors of NOS, arginase and DDAH1, and the conventional and structure-guided structure-activity relationship studies involved in their discovery. The key structural elements of amino acid-derived inhibitors responsible for selective inhibition of each enzyme, and the chemical features responsible for dual enzyme inhibition are also discussed. Finally, a synthetic scheme for developing both selective and dual inhibitors using common starting materials is provided, offering unique insights in the quest for the rational design of novel NO pathway inhibitors.
Towards integrated ADME prediction: past, present and future directions for modelling metabolism by UDP-glucuronosyltransferases
Publisher: Elsevier BV
Date: 07-2004
The MEF2 gene is essential for yeast longevity, with a dual role in cell respiration and maintenance of mitochondrial membrane potential
Publisher: Wiley
Date: 15-03-2011
DOI: 10.1016/J.FEBSLET.2011.03.022
Abstract: The Saccharomyces cerevisiae MEF2 gene is a mitochondrial protein translation factor. Formerly believed to catalyze peptide elongation, evidence now suggests its involvement in ribosome recycling. This study confirms the role of the MEF2 gene for cell respiration and further uncovers a slow growth phenotype and reduced chronological lifespan. Furthermore, in comparison with cytoplasmic ρ(0) strains, mef2Δ strains have a marked reduction of the inner mitochondrial membrane potential and mitochondria show a tendency to aggregate, suggesting an additional role for the MEF2 gene in maintenance of mitochondrial health, a role that may also be shared by other mitochondrial protein synthesis factors.
Machine Learning for Prediction of Survival Outcomes with Immune-Checkpoint Inhibitors in Urothelial Cancer
Publisher: MDPI AG
Date: 21-04-2021
Abstract: Machine learning (ML) may enhance the efficiency of developing accurate prediction models for survival, which is critical in informing disease prognosis and care planning. This study aimed to develop an ML prediction model for survival outcomes in patients with urothelial cancer-initiating atezolizumab and to compare model performances when built using an expert-selected (curated) versus an all-in list (uncurated) of variables. Gradient-boosted machine (GBM), random forest, Cox-boosted, and penalised, generalised linear models (GLM) were evaluated for predicting overall survival (OS) and progression-free survival (PFS) outcomes. C-statistic (c) was utilised to evaluate model performance. The atezolizumab cohort in IMvigor210 was used for model training, and IMvigor211 was used for external model validation. The curated list consisted of 23 pretreatment factors, while the all-in list consisted of 75. Using the best-performing model, patients were stratified into risk tertiles. Kaplan–Meier analysis was used to estimate survival probabilities. On external validation, the curated list GBM model provided slightly higher OS discrimination (c = 0.71) than that of the random forest (c = 0.70), CoxBoost (c = 0.70), and GLM (c = 0.69) models. All models were equivalent in predicting PFS (c = 0.62). Expansion to the uncurated list was associated with worse OS discrimination (GBM c = 0.70 random forest c = 0.69 CoxBoost c = 0.69, and GLM c = 0.69). In the atezolizumab IMvigor211 cohort, the curated list GBM model discriminated 1-year OS probabilities for the low-, intermediate-, and high-risk groups at 66%, 40%, and 12%, respectively. The ML model discriminated urothelial-cancer patients with distinctly different survival risks, with the GBM applied to a curated list attaining the highest performance. Expansion to an all-in approach may harm model performance.
The role of xenobiotic metabolizing enzymes in arylamine toxicity and carcinogenesis: functional and localization studies.
Publisher: Elsevier BV
Date: 05-1997
DOI: 10.1016/S0027-5107(97)00038-9
Abstract: In both animal models and humans, the first and obligatory step in the activation of arylamines is N-hydroxylation. This pathway is primarily mediated by the phase-I enzymes CYP1A1, CYP1A2 and CYP4B1. In the presence of flavonoids such as alpha-naphthoflavone and flavone, both CYP3A4 and CYP3A5 have also been shown to play a minor role in the activation of food-derived heterocyclic amines. The further activation of N-hydroxyarylamines by phase-II metabolism can involve both N, O-acetylation and N, O-sulfonation catalyzed by N-acetyltransferases (NAT1 and NAT2) and sulfotransferases, respectively. Using an array of techniques, we have been unable to detect constitutive CYP1A expression in any segments of the human gastrointestinal tract. This is in contrast to the rabbit where CYP1A1 protein was readily detectable on immunoblots in microsomes prepared from the small intestine. In humans, CYP3A3/3A4 expression was detectable in the esophagus and all segments of the small intestine. Northern blot analysis of eleven human colons showed considerable heterogeneity in CYP3A mRNA between in iduals, with the presence of two mRNA species in some subjects. Employing the technique of hybridization histochemistry (also known as in situ hybridization), CYP4B1 expression was observed in some human colons but not in the liver or the small intestine. Hybridization histochemistry studies have also demonstrated variable NAT1 and NAT2 expression in the human gastrointestinal tract. NAT1 and NAT2 mRNA expression was detected in the human liver, small intestine, colon, esophagus, bladder, ureter, stomach and lung. Using a general aryl sulfotransferase riboprobe (HAST1), we have demonstrated marked sulfotransferase expression in the human colon, small intestine, lung, stomach and liver. These studies demonstrate that considerable variability exists in the expression of enzymes involved in the activation of aromatic amines in human tissues. The significance of these results in relation to a role for heterocyclic amines in colon cancer is discussed.
The UGTome
Publisher: Elsevier BV
Date: 12-2019
DOI: 10.1016/J.PHARMTHERA.2019.107414
Abstract: The UDP glycosyltransferase (UGT) superfamily of enzymes is responsible for the metabolism and clearance of thousands of lipophilic chemicals including drugs, toxins and endogenous signaling molecules. They provide a protective interface between the organism and its chemical-rich environment, as well as controlling critical signaling pathways to maintain healthy tissue function. UGTs are associated with drug responses and interactions, as well as a wide range of diseases including cancer. The human genome contains 22 UGT genes however as befitting their exceptionally erse substrate ranges and biological activities, the output of these UGT genes is functionally ersified by multiple processes including alternative splicing, post-translational modification, homo- and hetero-oligomerization, and interactions with other proteins. All UGT genes are subject to extensive alternative splicing generating variant/truncated UGT proteins with altered functions including the capacity to dominantly modulate/inhibit cognate full-length forms. Heterotypic oligomerization of different UGTs can alter kinetic properties relative to monotypic complexes, and potentially produce novel substrate specificities. Moreover, the recently profiled interactions of UGTs with non-UGT proteins may facilitate coordination between different metabolic processes, as well as providing opportunities for UGTs to engage in novel 'moonlighting' functions. Herein we provide a detailed and comprehensive review of all known modes of UGT functional ersification and propose a UGTome model to describe the resulting expansion of metabolic capacity and its potential to modulate drug/xenobiotic responses and cell behaviours in normal and disease contexts.
Value of the Lung Immune Prognostic Index in Patients with Non-Small Cell Lung Cancer Initiating First-Line Atezolizumab Combination Therapy: Subgroup Analysis of the IMPOWER150 Trial
Publisher: MDPI AG
Date: 09-03-2021
Abstract: The lung immune prognostic index (LIPI) is proposed to differentiate prognosis and treatment benefit from immune checkpoint inhibitors (ICIs) in advanced non-small cell lung cancer (NSCLC). There is minimal information on the predictive importance with first-line, combination ICI approaches. In post-hoc analysis of IMpower150, Cox-proportional hazard analysis assessed the association between LIPI groups and overall survival (OS) rogression free survival (PFS). IMpower150 involved chemotherapy-naïve, metastatic non-squamous NSCLC participants randomized atezolizumab-carboplatin-paclitaxel (ACP), bevacizumab-carboplatin-paclitaxel (BCP), or atezolizumab-BCP (ABCP). Good (0 factors), intermediate (1 factor), and poor LIPI (2 factors) were defined via derived neutrophil-to-lymphocyte ratio , and lactate dehydrogenase upper limit of normal. Of 1148 participants, 548 had good, 479 intermediate, and 121 poor LIPI. In 385 participants randomised ABCP, a significant association between LIPI and OS (HR (95%CI): intermediate LIPI = 2.16 (1.47–3.18), poor LIPI = 5.28 (3.20–8.69), p 0.001) and PFS (HR (95%CI): intermediate LIPI = 1.47 (1.11–1.95), poor LIPI = 3.02 (2.03–4.50), p 0.001) was identified. Median OS was 24, 16, and 7 months for good, intermediate, and poor LIPI, respectively. ACP associations were similar. Relative OS treatment effect (HR 95%CI) of ABCP vs. BCP was 0.78 (0.53–1.15), 0.67 (0.49–0.91), and 0.87 (0.51–1.47) for the good, intermediate, and poor LIPI groups, respectively (P(interaction) = 0.66), with no benefit in median OS observed in the poor LIPI group. LIPI identified subgroups with significantly different survival following ABCP and ACP initiation for chemotherapy-naïve, metastatic non-squamous NSCLC. There was insufficient evidence that LIPI identifies patients unlikely to benefit from ABCP treatment.
Characterisation of CYP3A gene subfamily expression in human gastrointestinal tissues
Publisher: BMJ
Date: 02-1995
DOI: 10.1136/GUT.36.2.259
Abstract: The human CYP3A subfamily is of interest due to its multiplicity, activity toward known carcinogens, and extrahepatic expression. In situ hybridisation analysis of formalin fixed, routinely processed biopsy specimens was used to localise CYP3A mRNA in human gastrointestinal tissues from several in iduals. CYP3A mRNA is abundant in human liver and in mucosal epithelial cells of all segments of the human small intestine. RNA blot analyses showed that the mRNA species observed in most livers and in human small intestine represent CYP3A3/3A4 transcripts. This was confirmed at the protein level by immunoblot comparison of small intestine microsomes to in vitro expressed CYP3A4 and CYP3A5 proteins. In liver and small intestine, CYP3A mRNA is not uniformly distributed, with grain density highest in cells within the respective non-proliferative compartments. CYP3A mRNA was also observed in human oesophagus and colon. RNA blot analysis of multiple colons showed heterogeneity in the CYP3A mRNAs present. Two CYP3A mRNAs (CYP3A3/3A4 and CYP3A5) were detected in colon s les from several in iduals. In addition to those localisation studies, the capacity of expressed CYP3A4 and CYP3A5 to activate the dietary heterocyclic amine MeIQ in the presence of alpha-naphthoflavone was shown. These results show that there is considerable heterogeneity in the expression of the CYP3A subfamily in human gastrointestinal tissues.
Enhanced Bellmunt Risk Score for Survival Prediction in Urothelial Carcinoma Treated With Immunotherapy
Publisher: Elsevier BV
Date: 04-2022
DOI: 10.1016/J.CLGC.2021.11.010
Abstract: The discrimination performance of Bellmunt risk score for immune checkpoint inhibitor (ICI) therapy is largely unknown. This study aimed to validate and enhance discrimination of the Bellmunt score in patients with urothelial carcinoma treated with ICIs. Cox proportional hazard analysis were used to validate overall survival (OS) discrimination performance of the Bellmunt score in patients with urothelial carcinoma treated with atezolizumab in IMvigor210. The c-statistic (c) was used to evaluate the ability of C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), lactate dehydrogenase (LDH), PD-L1 gene expression level on immune cells (PD-L1 ICs), albumin, time from prior chemotherapy, and tumor site count to enhance the Bellmunt score. External validation of an enhanced Bellmunt score utilized the independent atezolizumab arm of IMvigor211. In IMvigor210, Bellmunt score displayed moderate OS discrimination (c = 0.66). Addition of CRP (one point for CRP>30 mg/L) to the Bellmunt score resulted in greatest improvement in performance (c = 0.70), followed by NLR (c = 0.69). On external validation, CRP-Bellmunt score had superior performance (OS c = 0.67, PFS c = 0.60) than original Bellmunt score (OS c = 0.64, PFS c = 0.59) with 30% of patients reclassified into a higher risk group. Patients with CRP-Bellmunt score of 0, 1, 2, or 3-plus had 1-year OS probabilities of 63%, 44%, 21%, and 15%, respectively. CRP inclusion within the Bellmunt score enhanced the ability to discriminate high risk patients misclassified using the original model. We propose that the CRP-Bellmunt score may enable improved patient stratification in ICI clinical trials and provide more accurate prognostic information for patients with urothelial carcinoma initiating ICIs.
Combination chemotherapy with cyclophosphamide, epirubicin and 5-fluorouracil causes trabecular bone loss, bone marrow cell depletion and marrow adiposity in female rats
Publisher: Springer Science and Business Media LLC
Date: 09-06-2015
DOI: 10.1007/S00774-015-0679-X
Abstract: The introduction of anthracyclines to adjuvant chemotherapy has increased survival rates among breast cancer patients. Cyclophosphamide, epirubicin and 5-fluorouracil (CEF) combination therapy is now one of the preferred regimens for treating node-positive breast cancer due to better survival with less toxicity involved. Despite the increasing use of CEF, its potential in causing adverse skeletal effects remains unclear. Using a mature female rat model mimicking the clinical setting, this study examined the effects of CEF treatment on bone and bone marrow in long bones. Following six cycles of CEF treatment (weekly intravenous injections of cyclophosphamide at 10 mg/kg, epirubicin at 2.5 mg/kg and 5-flurouracil at 10 mg/kg), a significant reduction in trabecular bone volume was observed at the metaphysis, which was associated with a reduced serum level of bone formation marker alkaline phosphatase (ALP), increased trends of osteoclast density and osteoclast area at the metaphysis, as well as an increased size of osteoclasts being formed from the bone marrow cells ex vivo. Moreover, a severe reduction of bone marrow cellularity was observed following CEF treatment, which was accompanied by an increase in marrow adipose tissue volume. This increase in marrow adiposity was associated with an expansion in adipocyte size but not in marrow adipocyte density. Overall, this study indicates that six cycles of CEF chemotherapy may induce some bone loss and severe bone marrow damage. Mechanisms for CEF-induced bone/bone marrow pathologies and potential preventive strategies warrant further investigation.
Genetic polymorphisms of UDP-glucuronosyltransferases and their functional significance
Publisher: Elsevier BV
Date: 12-2002
DOI: 10.1016/S0300-483X(02)00449-3
Abstract: UDP-Glucuronosyltransferase (UGT), the microsomal enzyme responsible for glucuronidation reactions, exists as a superfamily of enzymes. Genetic polymorphism has been described for 6 of the 16 functional human UGT genes characterised to date, namely UGT 1A1, 1A6, 1A7, 2B4, 2B7 and 2B15. Since glucuronidation is an essential pathway for the elimination of a myriad of xenobiotics and endogenous compounds, genetic polymorphism of UGT is potentially of toxicological and physiological importance. However, functional significance has only been convincingly demonstrated for genetic polymorphism of UGT1A1. Apart from impaired bilirubin glucuronidation, the mutations responsible for Gilbert syndrome also affect the elimination of a limited number of xenobiotics. It has been proposed on the basis of altered catalytic activity of mutants of UGT 1A6, 1A7 and 2B15 that genetic polymorphism of these forms may be of toxicological significance, but this is yet to be proven.
Polymorphic variations in the expression of the chemical detoxifying UDP glucuronosyltransferases
Publisher: Elsevier BV
Date: 09-2005
DOI: 10.1016/J.TAAP.2004.12.026
Abstract: The UDP glucuronosyltransferases (UGT) are expressed predominantly in the liver and gastrointestinal tract in humans. Their expression varies widely between in iduals, due in part to coding region polymorphisms that alter catalytic function and in part, to differences in the regulation of UGT genes. The latter differences are most likely the result of polymorphisms in the regulatory elements of UGT genes and in the transcription factors that bind to these elements. Several frequent polymorphisms in the promoters of UGT genes have been described however, few of these fall within critical regulatory elements and alter UGT expression. Some rare mutations alter UGT promoter activity in in vitro systems but their effect in the clinic is still to be confirmed. Several transcription factors that regulate UGT gene expression in cells of hepatic and intestinal origin have been identified. These include positive regulators of UGT gene expression such as hepatocyte nuclear factor 1 alpha (HNF1 alpha), octamer transcription factor-1 (Oct-1) and the intestine-specific transcription factor, caudal-related homeodomain protein 2 (Cdx2). Negative regulators include the Pre B cell homeobox factor (Pbx2) and its dimerization partner, Pbx regulating protein 1 (Prep1). Polymorphisms in these transcription factors may cause differences in their interaction and binding to UGT promoters. Current work describing the effects of these transcription factor polymorphisms on UGT expression will be described. Knowledge of UGT promoter elements and the proteins that bind to these elements, as well as knowledge of polymorphisms that alter their function, may aid in the prediction of an in idual's response to chemicals and in the prediction of chemical toxicities.
Cytochrome P450 Part 2: Genetics of Inter-Individual Variability
Publisher: Wiley
Date: 09-2008
DOI: 10.1002/J.2055-2335.2008.TB00845.X
Abstract: Inter‐in idual variability in drug metabolism results from the influence of a myriad of factors, such as concomitant drug therapy and genetic factors. Advances in recombinant DNA technology have enhanced our understanding of the extent of genetic variation in the cytochrome P450 (CYP) enzyme super family, thus clarifying the molecular basis of many clinically observed variations in drug response. This second article in the CYP series describes current understanding of genetic variability in the major drug metabolising CYP enzymes, nomenclature used to describe variant CYP genes, and the clinical significance of such variability.
The role and utility of measuring red blood cell methotrexate polyglutamate concentrations in inflammatory arthropathies - A systematic review
Publisher: Springer Science and Business Media LLC
Date: 18-02-2015
DOI: 10.1007/S00228-015-1819-X
Abstract: Evidence regarding the relationship between red blood cell methotrexate polyglutamate concentration and response to treatment and adverse drug reactions in patients using methotrexate for inflammatory arthropathies is complex and in some respects appears conflicting. Accordingly, we undertook a systematic analysis of available evidence to determine the clinical utility of dosing methotrexate to a target red blood cell methotrexate polyglutamate concentration. A systematic literature review was conducted to identify all studies that had reported an association between red blood cell methotrexate polyglutamate concentration and disease activity or adverse drug reactions in users of methotrexate for the treatment of rheumatoid arthritis, juvenile idiopathic arthritis or psoriatic arthritis. No randomised controlled trials were identified. Thirteen studies (ten in patients with rheumatoid arthritis and three in patients with juvenile idiopathic arthritis) were identified. All studies evaluated an association between red blood cell methotrexate polyglutamate concentration and response to treatment, and eight evaluated an association with toxicity. Eight studies identified lower disease activity with at least one higher red blood cell methotrexate polyglutamate concentration, although there was at least moderate potential for bias in all of these studies. Relatively large increases in concentration appeared to be required to produce a meaningful reduction in disease activity. Only one study identified an association between red blood cell methotrexate polyglutamate concentration and methotrexate-induced side effects, although studies were likely underpowered to detect this type of association. The manner in which data were presented in the included studies had many limitations that h ered its conclusive assessment, but red blood cell methotrexate polyglutamate concentrations appear to be a potentially useful guide to treatment in patients with inflammatory arthropathies, but the specific polyglutamate that should be monitored and how monitoring could be integrated into treat-to-target approaches should be clarified before it can be routinely implemented.
Efficacy of first-line atezolizumab combination therapy in patients with non-small cell lung cancer receiving proton pump inhibitors: post hoc analysis of IMpower150
Publisher: Springer Science and Business Media LLC
Date: 28-10-2021
Trace Amine-Associated Receptor 1 (TAAR1): Molecular and Clinical Insights for the Treatment of Schizophrenia and Related Comorbidities
Publisher: American Chemical Society (ACS)
Date: 18-02-2022
Clinical translation of predictive markers for anti-EGFR monoclonal antibody therapy in metastatic colorectal cancer
Publisher: AME Publishing Company
Date: 06-2016
A functional screen with metformin identifies microRNAs that regulate metabolism in colorectal cancer cells.
Publisher: Springer Science and Business Media LLC
Date: 21-02-2022
DOI: 10.1038/S41598-022-06587-9
Abstract: Metformin inhibits oxidative phosphorylation and can be used to dissect metabolic pathways in colorectal cancer (CRC) cells. CRC cell proliferation is inhibited by metformin in a dose dependent manner. MicroRNAs that regulate metabolism could be identified by their ability to alter the effect of metformin on CRC cell proliferation. An unbiased high throughput functional screen of a synthetic micoRNA (miRNA) library was used to identify miRNAs that impact the metformin response in CRC cells. Experimental validation of selected hits identified miRNAs that sensitize CRC cells to metformin through modulation of proliferation, apoptosis, cell-cycle and direct metabolic disruption. Among eight metformin sensitizing miRNAs identified by functional screening, miR-676-3p had both pro-apoptotic and cell cycle arrest activity in combination with metformin, whereas other miRNAs (miR-18b-5p, miR-145-3p miR-376b-5p, and miR-718) resulted primarily in cell cycle arrest when combined with metformin. Investigation of the combined effect of miRNAs and metformin on CRC cell metabolism showed that miR-18b-5p, miR-145-3p, miR-376b-5p, miR-676-3p and miR-718 affected glycolysis only, while miR-1181 only regulated CRC respiration. MicroRNAs can sensitize CRC cells to the anti-proliferative effects of metformin. Identifying relevant miRNA targets may enable the design of innovative therapeutic strategies.
Xenobiotic metabolism in Australian marsupials
Publisher: Elsevier BV
Date: 09-2009
Biosimilarity and Interchangeability: Principles and Evidence: A Systematic Review
Publisher: Springer Science and Business Media LLC
Date: 17-01-2018
Polymorphisms in the mitochondrial ribosome recycling factor EF-G2mt/MEF2 compromise cell respiratory function and increase atorvastatin toxicity
Publisher: Public Library of Science (PLoS)
Date: 14-06-2012
Baseline tumor size and survival outcomes in lung cancer patients treated with immune checkpoint inhibitors
Publisher: Elsevier BV
Date: 08-2019
DOI: 10.1053/J.SEMINONCOL.2019.10.002
Abstract: Baseline tumor size (BTS) was recently indicated as prognostic of overall survival (OS) in patients advanced melanoma treated with pembrolizumab. We review the association between BTS and OS rogression-free survival (PFS) in patients with a diagnosis of advanced non-small-cell lung cancer (NSCLC) treated with atezolizumab. Data from 1,461 patients with a diagnosis of advanced NSCLC enrolled in the OAK, POPLAR, BIRCH, and FIR trials and treated with atezolizumab were pooled and analyzed. Using Cox proportional hazards regression, we modeled the association between baseline SLD and survival outcomes. Multivariable analyses were adjusted for pretreatment ECOG PS, age, sex, race, smoking status, histology, count of prior treatments, PDL1 expression, serum LDH levels, and the presence of liver, lung, or brain lesions. On univariable and multivariable analysis, baseline sum of the longest diameters of target lesions (SLD) was identified as significantly associated with OS (hazard ratio [95% confidence interval] per decimeter: 1.64 [1.41-1.91], P < .001) and PFS (1.21 [1.07-1.38], P = .003). Median OS were 16 months versus 10 months for baseline SLD < median, versus baseline SLD ≥ median, respectively. Median PFS were 4 months versus 3 months, respectively. Large BTS was identified as an independent prognostic factor of worse OS and PFS, raising the need to evaluate atezolizumab as an earlier NSCLC treatment in future trials.
Systematic statistical comparison of comparative molecular similarity indices analysis molecular fields for computer-aided lead optimization
Publisher: American Chemical Society (ACS)
Date: 31-08-2006
DOI: 10.1021/CI600214B
Abstract: Comparative molecular similarity indices analysis (CoMSIA) is a 3D quantitative structure-activity relationship technique used to determine structural and electronic features influencing biological activity. This proves particularly useful for facilitating lead optimization projects. This study aimed to compare CoMSIA models produced using different subsets of the CoMSIA molecular fields (steric, electrostatic, hydrophobic, hydrogen-bond donor, and hydrogen-bond acceptor) in a systematic and statistically valid manner. A total of 23 data sets sourced from the literature were used to compare molecular field contribution and model predictivity using leave-one-out cross-validated R2 values. Predictive ability varied in a highly statistically significant manner depending on the set of CoMSIA molecular fields used. In general, the greater the number of CoMSIA molecular fields included in the analysis, the better the model predictivity was. There is great redundancy in the information contained in the different CoMSIA molecular fields. When all five CoMSIA molecular fields are included, the hydrophobic and electrostatic fields had the largest and the steric field the smallest contribution. Data sets were clustered into four groups on the basis of the utility of molecular field sets to generate predictive models.
Metabolic differences in colon mucosal cells.
Publisher: Elsevier BV
Date: 11-1993
DOI: 10.1016/0027-5107(93)90029-F
Abstract: The colonic expression of cytochromes P450 from the CYP1A, CYP3A and CYP4B subfamilies has been characterized in rabbit and human tissues using RNA blotting, immunoblotting, immunohistochemistry and hybridization histochemistry. These studies demonstrate negligible expression of the CYP1A subfamily in either rabbit or human colon. The CYP3A6 gene is expressed in rabbit colon although at markedly reduced levels relative to liver and small intestine. Whilst at least two CYP3A genes are expressed at the mRNA level in human colon tissue from some in iduals, no expression was demonstrated in others. Where expression was observed, this expression was continuous throughout the length of the colon. In rabbits, CYP4B1 represents a major colon P450 enzyme, expressed at levels in colon comparable to liver and small intestine. In contrast, the human CYP4B1 gene is expressed at low levels in some in iduals. These studies highlight in idual differences in the expression of cytochrome P450 enzymes of importance in procarcinogen metabolism.
Combination breast cancer chemotherapy with doxorubicin and cyclophosphamide damages bone and bone marrow in a female rat model
Publisher: Springer Science and Business Media LLC
Date: 26-05-2017
DOI: 10.1007/S10549-017-4308-3
Abstract: Anthracyclines (including doxorubicin) are still the backbone of commonly used breast cancer chemotherapy regimens. Despite increasing use of doxorubicin and cyclophosphamide (AC) combinations for treating breast cancer, their potential to cause adverse skeletal effects remains unclear. This study examined the effects of treatments with the AC regimen on bone and bone marrow in adult female rats. AC treatment for four cycles (weekly intravenous injection of 2 mg/kg doxorubicin and 20 mg/kg cyclophosphamide) resulted in a reduced volume of trabecular bone at the metaphysis, which was associated with reduced serum levels of 25-hydroxy vitamin D3 and alkaline phosphatase. Reductions in densities of osteocytes and bone lining cells were also observed. In addition, bone marrow was severely damaged, including a severe reduction in bone marrow cellularity and an increase in marrow adipocyte content. Accompanying these changes, there were increases in mRNA expression of adipogenesis regulatory genes (PPARγ and FABP4) and an inflammatory cytokine (TNFα) in metaphysis bone and bone marrow. This study indicates that AC chemotherapy may induce some bone loss, due to reduced bone formation, and bone marrow damage, due to increased marrow adiposity. Preventive strategies for preserving the bone and bone marrow microenvironment during anthracycline chemotherapy warrant further investigation.
Predictors of Long-Term Disease Control and Survival for HER2-Positive Advanced Breast Cancer Patients Treated With Pertuzumab, Trastuzumab, and Docetaxel
Publisher: Frontiers Media SA
Date: 22-08-2019
Effect of steric molecular field settings on CoMFA predictivity
Publisher: Springer Science and Business Media LLC
Date: 24-11-2008
DOI: 10.1007/S00894-007-0252-1
Abstract: Steric molecular field can be represented in a number of ways in comparative molecular field analysis (CoMFA). This study aimed to investigate whether the choice of steric molecular field settings significantly influences the predictive performance of CoMFA and, if so, which is the best. The three-dimensional quantitative structure activity relationship (3D-QSAR) models based on Lennard-Jones, indicator, parabolic and Gaussian steric fields were compared using 28 datasets taken from the literature. The analysis of the predictive ability of these models (cross validated R(2)) indicates that steric fields in which the value drops off quickly with distance (i.e. Lennard-Jones and indicator fields) tend to perform better than the Gaussian version, which has a slower and smoother decrease. Furthermore, depending on the steric field type used, the field s ling density (i.e. grid spacing) has a variable influence on the predictive ability of the models generated.
Transcriptional up-regulation of human udp-glucuronosyltransferase (UGT) 2B17 by exemestane and its active metabolite 17-hydroexemestane in breast cancer cells
Publisher: Elsevier BV
Date: 2017
Computational Prediction of the Site(s) of Metabolism and Binding Modes of Protein Kinase Inhibitors Metabolized by CYP3A4
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 22-03-2019
Abstract: Protein kinase inhibitors (KIs), which are mainly biotransformed by CYP3A4-catalyzed oxidation, represent a rapidly expanding class of drugs used primarily for the treatment of cancer. Ligand- and structure-based methods were applied here to investigate whether computational approaches may be used to predict the site(s) of metabolism (SOM) of KIs and to identify amino acids within the CYP3A4 active site involved in KI binding. A data set of the experimentally determined SOMs of 31 KIs known to undergo biotransformation by CYP3A4 was collated. The structure-based (molecular docking) approach employed three CYP3A4 X-ray crystal structures to account for structural plasticity of this enzyme. Docking pose and SOM predictivity were influenced by the X-ray crystal template used for docking and the scoring function used for ranking binding poses. The best prediction of SOM (77%) was achieved using the substrate (bromoergocryptine)-bound X-ray crystal template together with the potential of mean force score. Binding interactions of KIs with CYP3A4 active site residues were generally similar to those observed for other substrates of this enzyme. The ligand-based molecular superposition approach, using bromoergocryptine from the X-ray cocrystal structure as a template, poorly predicted (42%) the SOM of KIs, although predictivity improved to 71% when the docked conformation of sorafenib was used as the template. Among the web-based approaches examined, all web servers provided excellent predictivity, with one web server predicting the SOM of 87% of the data set molecules. Computational approaches may be used to predict the SOM of KIs, and presumably other classes of CYP3A4 substrates, but predictivity varies between methods.
Prasugrel vs. clopidogrel for cytochrome P450 2C19-genotyped subgroups: integration of the TRITON-TIMI 38 trial data
Publisher: Elsevier BV
Date: 08-2010
DOI: 10.1111/J.1538-7836.2010.03923.X
Abstract: Prasugrel is a newly marketed antiplatelet drug with improved cardiac outcomes as compared with clopidogrel for acute coronary syndromes involving percutaneous coronary intervention (PCI). Analysis of a subset of the TRITON-TIMI 38 trial demonstrated that cytochrome P450 2C19 (CYP2C19) reduced-function genotypes are associated with differential clinical responses to clopidogrel, but not prasugrel. Whether the CYP2C19 genotype has the potential to influence clinical choice of these drugs prior to PCI for in iduals with unstable angina or non-ST segment elevation myocardial infarction is currently uncertain. An exploratory, secondary analysis was undertaken to estimate the clinical benefit of prasugrel over clopidogrel in subgroups defined by CYP2C19 genotype, by integrating the published results of the genetic substudy and the overall TRITON-TIMI 38 trial. In iduals with a CYP2C19 reduced-metabolizer genotype were estimated to have a substantial reduction in the risk of the composite primary outcome (cardiovascular death, myocardial infarction, or stroke) with prasugrel as compared with clopidogrel [relative risk (RR) 0.57 95% confidence interval (CI) 0.39-0.83]. For CYP2C19 extensive metabolizers (∼70% of the population), however, the composite outcome risks with prasugrel and clopidogrel were not substantially different (RR 0.98 95% CI 0.80-1.20). Integration of the TRITON-TIMI 38 data suggests that the CYP2C19 genotype can discriminate between in iduals who receive extensive benefit from using prasugrel instead of clopidogrel, and in iduals with comparable clinical outcomes with prasugrel and clopidorel. Thus, CYP2C19 genotyping has the potential to guide the choice of antiplatelet therapy, and further research is warranted to validate this estimate.
Educating our students about pharmaceutical care for those living with cancer.
Publisher: Elsevier BV
Date: 09-2012
DOI: 10.5688/AJPE767119
Xenobiotic detoxification in Australian marsupials – An overview
Publisher: Elsevier BV
Date: 09-2009
Low adoption of pharmacogenetic testing: an exploration and explanation of the reasons in Australia
Publisher: Future Medicine Ltd
Date: 05-2007
Abstract: The research reported here sought to identify and illuminate the reasons for the low adoption of pharmacogenetic tests in Australia. The research initially established possible reasons and propositions drawn from previous studies and surveys on the problem in Europe and the literature on the adoption of innovations. A small-scale exploratory, qualitative study was undertaken in one state in Australia clinicians and other stake-holders were interviewed about their use of or support for pharmacogenetic tests. The expected, quite extensive in idual factors known to influence adoption and rejection of innovations were found to be present in the situations covered. The reasons for nonadoption that were found in previous surveys were also supported. Some other, possibly critical, reasons were also identified. The implications from this initial exploration are discussed and the prospects for the increased use of the tests proposed.
Effectiveness of the Pharmacist-Involved Multidisciplinary Management of Heart Failure to Improve Hospitalizations and Mortality Rates in 4630 Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Publisher: Elsevier BV
Date: 09-2019
DOI: 10.1016/J.CARDFAIL.2019.07.455
Abstract: There is evidence that heart failure (HF) patients who receive pharmacist care have better clinical outcomes. English-language peer-reviewed randomized controlled trials comparing the pharmacist-involved multidisciplinary intervention with usual care were included. We searched PubMed, MEDLINE, EMBASE, CINAHL, Web of Science, Scopus, and the Cochrane Library from inception through March 2017. Cochrane method for risk of bias was used to assess within and between studies. 18 RCTs (n = 4630) were included for systematic review, and 16 (n = 4447) for meta-analysis. Meta-analysis showed a significant reduction in HF hospitalizations {odds ratio (OR) 0.72 [95% confidence interval (CI) 0.55-0.93], P = .01, I2 = 39%} but no effect on HF mortality. Similarly, a significant reduction in all-cause hospitalizations [OR 0.76, 95% CI (0.60-0.96), P = .02, I2 = 52%] but no effect on all-cause mortality was revealed. The overall trend was an improvement in medication adherence. There were significant improvements in HF knowledge (P<.05), but no significant improvements were found on health care costs and self-care. The pharmacist is a vital member of a multidisciplinary team in HF management to improve clinical outcomes. There was a great deal of variability about which specific intervention is most effective in improving clinical outcomes.
Pharmacogenomics in a global world: A roadmap for Australia, prospects and challenges
Publisher: Bentham Science Publishers Ltd.
Date: 31-01-2013
Thelytokous Parthenogenesis in Unmated Queen Honeybees (Apis mellifera capensis): Central Fusion and High Recombination Rates
Publisher: Oxford University Press (OUP)
Date: 09-2008
DOI: 10.1534/GENETICS.108.090415
Abstract: The subspecies of honeybee indigenous to the Cape region of South Africa, Apis mellifera capensis, is unique because a high proportion of unmated workers can lay eggs that develop into females via thelytokous parthenogenesis involving central fusion of meiotic products. This ability allows pseudoclonal lineages of workers to establish, which are presently widespread as reproductive parasites within the honeybee populations of South Africa. Successful long-term propagation of a parthenogen requires the maintenance of heterozygosity at the sex locus, which in honeybees must be heterozygous for the expression of female traits. Thus, in successful lineages of parasitic workers, recombination events are reduced by an order of magnitude relative to meiosis in queens of other honeybee subspecies. Here we show that in unmated A. m. capensis queens treated to induce oviposition, no such reduction in recombination occurs, indicating that thelytoky and reduced recombination are not controlled by the same gene. Our virgin queens were able to lay both arrhenotokous male-producing haploid eggs and thelytokous female-producing diploid eggs at the same time, with evidence that they have some voluntary control over which kind of egg was laid. If so, they are able to influence the kind of second- ision meiosis that occurs in their eggs post partum.
Comparison datasets for benchmarking QSAR methodologies in lead optimization
Publisher: American Chemical Society (ACS)
Date: 02-07-2009
DOI: 10.1021/CI900117M
Abstract: 2D and 3D QSAR techniques are widely used in lead optimization-like processes. A compilation of 40 erse data sets is described. It is proposed that these can be used as a common benchmark s le for comparisons of QSAR methodologies, primarily in terms of predictive ability. Use of this benchmark set will be useful for both assessment of new methods and for optimization of existing methods.
Atorvastatin-induced cell toxicity in yeast is linked to disruption of protein isoprenylation
Publisher: Oxford University Press (OUP)
Date: 03-2010
DOI: 10.1111/J.1567-1364.2009.00593.X
Abstract: Statins, used to treat hypercholesterolemia, are one of the most frequently prescribed drug classes in the developed world. However, a significant proportion of users suffer symptoms of myotoxicity, and currently, the molecular mechanisms underlying myotoxicity remain ambiguous. In this study, Saccharomyces cerevisiae was exploited as a model system to gain further insight into the molecular mechanisms of atorvastatin toxicity. Atorvastatin-treated yeast cells display marked morphological deformities, have reduced cell viability and are highly vulnerable to perturbed mitochondrial function. Supplementation assays of atorvastatin-treated cells reveal that both loss of viability and mitochondrial dysfunction occur as a consequence of perturbation of the sterol synthesis pathway. This was further investigated by supplementing statin-treated cells with various metabolites of the sterol synthesis pathway that are believed to be essential for cell function. Ergosterol, coenzyme Q and a heme precursor were all ineffective in the prevention of statin-induced mitochondrial disruption and cell death. However, the addition of geranylgeranyl pyrophosphate and farnesyl pyrophosphate significantly restored cell viability, although these did not overcome petite induction. This highlights the pleiotropic nature of statin toxicity, but has established protein prenylation disruption as one of the principal mechanisms underlying statin-induced cell death in yeast.
Correlation Between Peroxisome Proliferation and Up-Regulation of Cytochrome P450 CYP4A and Peroxisomal Beta-Oxidation Fatty Acyl CoA Oxidases (AOX) in the Koala (Phascolarctos Cinereus)
Publisher: Portico
Date: 02-2010
DOI: 10.4137/GGG.S3368
Transforming Pharmaceutical Education to Accelerate the Acceptance and Implementation of Personalized Medicine
Publisher: Elsevier BV
Date: 08-2011
DOI: 10.5688/AJPE756107
Human drug-metabolizing enzyme polymorphisms: Effects on risk of toxicity and cancer
Publisher: Mary Ann Liebert Inc
Date: 04-1996
Abstract: A growing number of human genetic polymorphisms in drug-metabolizing enzymes (DMEs) are being characterized. Some of these have been shown, quite convincingly, to be correlated with risk of toxicity or cancer, whereas others presently remain equivocal. There is good evidence that the correlation is stronger in populations exposed to a variety of environmental procarcinogens perhaps 30% of DME substrates are able to be metabolically potentiated. Phase I DMEs, most of which represent cytochromes P450, metabolically activate procarcinogens to genotoxic electrophilic intermediates, and Phase II DMEs conjugate the intermediates to water-soluble derivatives, completing the detoxification cycle. It follows that genetic differences in the regulation, expression and activity of genes coding for Phase I and Phase II DMEs would be crucial factors in defining cancer susceptibility and the toxic or carcinogenic power of environmental chemicals. Not all Phase I and Phase II DMEs are implicated in detoxification previous work from this and from other laboratories has identified candidate Phase I and Phase II genes in which certain alleles are more likely to be associated with cancer susceptibility. In some cases, the allelic frequencies vary dramatically between ethnic groups. In this review, our current knowledge about polymorphisms in the following genes are updated: the aromatic hydrocarbon receptor (AHR), the CYP1A1 structural gene (which encodes aryl hydrocarbon hydroxylase activity), the CYP1A2 structural gene (arylamine oxidations), the CYP2C19 gene (S-mephenytoin 4'-hydroxylase), the CYP2D6 gene (debrisoquine hydroxylase), the CYP2E1 gene (N,N-dimethylnitrosamine N-demethylase), the null mutant for the GSTM1 gene (glutathione transferase mu), and the NAT2 gene (arylamine N-acetyltransferase). If unequivocal biomarkers of genetic susceptibility to cancer and toxicity can be developed successfully, then identification of in iduals at increased risk would be very helpful in the fields of public health and preventive medicine.
Cytochrome P450 knockout mice: new toxicological models
Publisher: Wiley
Date: 10-1998
DOI: 10.1111/J.1440-1681.1998.TB02153.X
Abstract: 1. Despite the frenetic pace of cytochrome P450 (CYP) research, important questions remain about the possible role of xenobiotic-metabolizing CYP in development and cellular homeostasis. 2. The recent experimental development of CYP null mouse lines has provided valuable new models for addressing these issues, as well as providing novel in vivo models to study the precise role of CYP in chemical-mediated toxicity. 3. The present review summarizes results from the three Cyp gene knockout mouse lines generated so far and looks at likely future directions of this research field. 4. Also discussed are null mouse lines with targeted mutations in genes encoding receptors having primary roles in Cyp gene regulation.
The obesity paradox in early and advanced HER2 positive breast cancer: pooled analysis of clinical trial data
Publisher: Springer Science and Business Media LLC
Date: 22-03-2021
DOI: 10.1038/S41523-021-00241-9
Abstract: While many studies have evaluated the relationship between BMI and breast cancer outcomes, it is unclear whether this relationship is consistent between early breast cancer (BC) and advanced BC. The study included 5099 patients with HER2 positive early BC (EBC) and 3496 with HER2 positive advanced BC (ABC). In the EBC cohort, higher BMI was associated with worse overall survival (OS) (HR [95% CI]: overweight = 1.30 [1.13–1.51] obese = 1.37 [1.14–1.64], P = 0.001), and worse disease-free survival (overweight = 1.10 [0.98–1.24] obese = 1.20 [1.04–1.39], P = 0.061). In contrast, for the ABC cohort, higher BMI was significantly associated with improved OS (overweight = 0.85 [0.76–0.96] obese = 0.82 [0.72–0.95], P = 0.014), and progression-free survival (overweight = 0.91 [0.83–1.01] obese = 0.87 [0.77–0.98], P = 0.034). In this large high-quality dataset, higher BMI was independently associated with worse survival in EBC, paradoxically in ABC higher BMI was independently associated with improved survival.
Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: a meta-analysis of randomized, controlled trials
Publisher: Elsevier BV
Date: 2015
Abstract: Monoclonal antibodies (mAbs) targeting the epidermal growth factor receptor (EGFR) prolong survival in metastatic colorectal cancer (mCRC) Kirsten rat sarcoma viral oncogene (KRAS) exon 2 wild-type tumors. Recent evidence has suggested that other RAS mutations (in exons 3 and 4 of KRAS and exons 2, 3 and 4 of a related gene, NRAS) may also be predictive of resistance. Systematic review and meta-analysis of randomized, controlled trials (RCTs) evaluating anti-EGFR mAbs that have assessed tumors for new RAS mutations. Tumors with the new RAS mutations were compared with both tumors without any RAS mutations and tumors with KRAS exon 2 mutations with respect to anti-EGFR treatment progression-free survival (PFS) and overall survival (OS) benefit. Nine RCTs comprising a total of 5948 participants evaluated for both KRAS exon 2 and new RAS mutations met the inclusion criteria. Approximately 20% of KRAS exon 2 wild-type tumors harbored one of the new RAS mutations. Tumors without any RAS mutations (either KRAS exon 2 or new RAS mutations) were found to have significantly superior anti-EGFR mAb PFS (P 0.05). Tumors harboring one of the new RAS mutations are unlikely to significantly benefit from anti-EGFR mAb therapy in mCRC.
Correlation between peroxisome proliferation and upregulation of cytochrome P450 CYP4A and peroxisomal beta-oxidation fatty acyl CoA oxidases (AOX) in the koala (Phascolarctos cinereus)
Publisher: Elsevier BV
Date: 09-2008
Localization of cytochromes P450 in human tissues: Implications for chemical toxicity
Publisher: Elsevier BV
Date: 1996
DOI: 10.1080/00313029600169783
Abstract: Cytochromes P450 comprise a remarkably erse superfamily of heme-thiolate proteins critical in the metabolism of numerous endogenous ligands and xenobiotics. Among the myriad of P450 substrates are many compounds of toxicological and pharmacological significance. The precise complement of cytochrome P450 isoforms in any given tissue may therefore be an important determinant of susceptibility to chemical-mediated toxicity. We have used a histological approach to study the distribution of in idual P450s in human and rabbit gastro-intestinal tissues. We have focused primarily on P450 enzymes of importance in the metabolism of carcinogens, namely CYP1A1, CYP1A2, CYP2E1, CYP3A4/3A5 and CYP4B1. Here we give an overview of the distribution of these enzymes in human and rabbit tissues and discuss the possible toxicological implications of the results. In addition we will discuss the value of archival human tissue specimens for histological analysis of P450 distribution.
Identification and cloning of two forms of liver peroxisomal fatty Acyl CoA Oxidase from the koala (Phascolarctos cinereus)
Publisher: Elsevier BV
Date: 05-2003
DOI: 10.1016/S0378-1119(03)00491-8
Abstract: In the present study, the cloning, expression and characterization of the rate-limiting enzyme of the peroxisomal beta-oxidation spiral, acyl CoA oxidase (AOX), from koala (Phascolarctos cinereus) liver is described. It has been previously reported that peroxisomal cyanide-insensitive palmitoyl-CoA oxidation activity was absent in koala liver [Comp. Biochem. Physiol. (C) 127 (2000) 327]. This activity is a measure of the overall peroxisomal beta-oxidation minus the final step catalysed by thiolase. Two 2039 bp koala liver AOX cDNAs, designated AOX1 and AOX2, were cloned by reverse transcription-polymerase chain reaction and rapid lification of cDNA ends. The koala AOX cDNAs encode proteins of 662 amino acids. Transfection of the koala AOX cDNAs into Cos-7 cells resulted in the expression of proteins with palmitoyl-CoA oxidase activity. The apparent K(m) values for AOX1 and AOX2 cDNA-expressed enzymes were 28 and 38 microM, respectively, which are within the range of order of magnitude reported for rat and human purified AOX enzymes (approximately 10 microM). Northern analysis, utilizing the koala AOX1 cDNA as probe, detected a more intense AOX mRNA band in the koala liver as compared to rats and humans. Southern blot analysis of liver genomic DNA s les revealed a single AOX gene fragment of less than 14 kb in koalas, rat and humans, suggesting a single AOX gene. Collectively, the results of this study suggest that the absence of peroxisomal cyanide-insensitive palmitoyl-CoA oxidation activity in the koala liver is possibly due to deficiencies of one or more enzymes downstream of acyl-CoA oxidase and/or deficiencies of mitochondrial beta-oxidation enzymes.
Cytochrome P450 part 1: Multiplicity and function
Publisher: Wiley
Date: 03-2008
DOI: 10.1002/J.2055-2335.2008.TB00798.X
Abstract: While new cytochrome P450 (CYP450) enzymes continue to be identified, it is now possible to predict with some confidence the total number of human CYP450 enzymes. This review is an update of the CYP450 superfamily of drug metabolising enzymes. It comprises a brief history of CYP450 research, outlines the standard P450 nomenclature system, and describes CYP450 multiplicity, structure and function.
Pharmacophore and quantitative structure activity relationship modelling of UDP-glucuronosyltransferase 1A1 (UGT1A1) substrates
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2002
DOI: 10.1097/00008571-200211000-00008
Abstract: UDP-glucuronosyltransferase 1A1 (UGT1A1) is a polymorphic enzyme responsible for the glucuronidation of structurally erse drugs, non-drug xenobiotics and endogenous compounds (e.g. bilirubin). Thus, definition of UGT1A1 substrate and inhibitor selectivities and binding affinities assumes importance for the identification of compounds whose elimination may be impaired in subjects with variant genotypes, and for the prediction of potentially inhibitory interactions involving xenobiotics and endogenous compounds metabolized by UGT1A1. We report the generation of two- and three-dimensional (2D and 3D) quantitative structure activity relationships (QSAR) and pharmacophore models for 23 known UGT1A1 substrates with erse structure and binding affinity. Initially, a simple procedure was developed to determine apparent inhibition constants (Ki,app) for these compounds. Eighteen substrates were subsequently used to construct models and the remaining five to validate the predictive ability of the models. Three different models were constructed: (i) three feature pharmacophore model able to predict the Ki,app on the basis of the degree to which a substrate can fit to the arrangement of 3D features (r2 = 0.87, Ki,app for all five test substrates predicted within log unit) (ii) 3D-QSAR using a 'common features' pharmacophore to align the substrates (r2 = 0.71, Ki,app for four out of five test substrates predicted within one log unit) (iii) 2D-QSAR constructed with six chemical descriptors (r2 = 0.92, Ki,app of all five test substrates predicted within one log unit). The common features pharmacophore demonstrated the importance of two hydrophobic domains separated from the glucuronidation site by 4 A and 7 A, respectively. These models, which represent the first generalized predictive models for a UGT isoform, complement each other and are an important first step towards computer based (in silico) models of UGT1A1 for high throughput prediction of metabolism.
Meta-analysis of BRAF mutation as a predictive biomarker of benefit from anti-EGFR monoclonal antibody therapy for RAS wild-type metastatic colorectal cancer
Publisher: Springer Science and Business Media LLC
Date: 19-05-2015
DOI: 10.1038/BJC.2015.173
Interventions Targeting the Prescribing and Monitoring of Vancomycin for Hospitalized Patients: A Systematic Review Protocol
Publisher: Springer Science and Business Media LLC
Date: 27-10-2017
In silico insights: Chemical and structural characteristics associated with uridine diphosphate‐glucuronosyltransferase substrate selectivity
Publisher: Wiley
Date: 11-2003
DOI: 10.1046/J.1440-1681.2003.03923.X
Abstract: 1. Undesirable absorption, distribution, metabolism, excretion properties are the cause of many drug development failures and this has led to the need to identify such problems earlier in the development process. This work highlights computational (in silico) approaches used to identify characteristics influencing the metabolism of uridine diphosphate (UDP)-glucuronosyltransferase (UGT) substrates. Uridine diphosphate-glucuronosyltransferase facilitates conjugation between glucuronic acid and a nucleophilic site within a substrate and is one of the major drug-metabolizing enzymes. 2. An understanding of the relevant structural and chemical characteristics of the ligand and the enzyme active site will lead to greater utilization of metabolically relevant structural information in drug design. However, an X-ray crystal structure of UGT is not yet available, little has been reported about important structurally or catalytically relevant amino acids and only recently has the reported substrate profile of UGT isoforms reached an interpretable level. 3. A database of all the known substrates and non-substrates for each human UGT isoform was assembled and a range of modelling approaches assessed. Currently, pharmacophore models developed using Catalyst (Accelrys, San Diego, CA, USA) indicate that substrates of the UGT1A family share two key hydrophobic regions 3 and 6-7 A from the site of glucuronidation in a well-defined spatial geometry. Furthermore, two-dimensional quantitative structure-activity relationship models show significant reliance on substrate lipophilicity and a range of other descriptors that are known to capture information relevant to ligand-protein interactions. 4. In conclusion, substrate-based modelling of UGT appears both useful and feasible, with significant potential for determining aspects of chemical structure associated with metabolism and to quantify the nature of the relationship for UGT substrates. The development of a novel, user-defined 'glucuronidation feature' for alignment was crucial to the development of pharmacophore-based UGT models.
Deregulation of the genes that are involved in drug absorption, distribution, metabolism, and excretion in hepatocellular carcinoma
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 21-12-2019
Abstract: Genes involved in drug absorption, distribution, metabolism, and excretion (ADME) are called ADME genes. Currently, 298 genes that encode phase I and II drug metabolizing enzymes, transporters, and modifiers are designated as ADME genes by the PharmaADME Consortium. ADME genes are highly expressed in the liver and their levels can be influenced by liver diseases such as hepatocellular carcinoma (HCC). In this study, we obtained RNA-sequencing and microRNA (miRNA)-sequencing data from 371 HCC patients via The Cancer Genome Atlas liver hepatocellular carcinoma project and performed ADME gene-targeted differential gene expression analysis and expression correlation analysis. Two hundred thirty-three of the 298 ADME genes (78%) were expressed in HCC. Of these genes, almost one-quarter (58 genes) were significantly downregulated, while only 6% (15) were upregulated in HCC relative to healthy liver. Moreover, one-half (14/28) of the core ADME genes (
Cytochrome P450 1: Multiplicity and function
Publisher: Wiley
Date: 04-2000
The Emergence of Pharmacogenomics
Publisher: Wiley
Date: 06-2003
Regulation of UDP-glucuronosyltransferase 2B15 by miR-331-5p in prostate cancer cells involves canonical and noncanonical target sitess
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 24-01-2018
Cloning and expression of koala (Phascolarctos cinereus) liver cytochrome P450 reductase
Publisher: Elsevier BV
Date: 07-2009
DOI: 10.1016/J.CBPC.2009.01.010
Abstract: The cloning, expression and characterization of hepatic NADPH-cytochrome P450 reductase (CPR) from koala (Phascolarctos cinereus) is described. Two 2059 bp koala liver CPR cDNAs, designated CPR1 and CPR2, were cloned by reverse transcription-polymerase chain reaction and rapid lification of cDNA ends. The koala CPR cDNAs encode proteins of 678 amino acids and share 85% amino acid sequence identity to human CPR. Transfection of the koala CPR cDNAs into Cos-7 cells resulted in the expression of proteins, which were recognized by a goat-antihuman CPR antibody. The koala CPR1 and 2 cDNA-expressed enzymes catalysed cytochrome c reductase at the rates of 4.9 +/- 0.5 and 2.6 +/- 0.4 nmol/min/mg protein (mean +/- SD, n = 3), respectively which were comparable to that of rat CPR cDNA-expressed enzyme. The apparent Km value for CPR activity in koala liver microsomes was 11.61 +/- 6.01 microM, which is consistent with that reported for rat CPR enzyme. Northern analysis detected a CPR mRNA band of approximately 2.6 kb. Southern analysis suggested a single PCR gene across species. The present study provides primary molecular data regarding koala CPR1 and CPR2 genes in this unique marsupial species.
In vitro metabolism of the anti-inflammatory clerodane diterpenoid polyandric acid A and its hydrolysis product by human liver microsomes and recombinant cytochrome P450 and UDP-glucuronosyltransferase enzymes
Publisher: Informa UK Limited
Date: 14-07-2016
DOI: 10.1080/00498254.2016.1203041
Abstract: 1. The metabolism of the anti-inflammatory diterpenoid polyandric acid A (PAA), a constituent of the Australian Aboriginal medicinal plant Dodonaea polyandra, and its de-esterified alcohol metabolite, hydrolysed polyandric acid A (PAAH) was studied in vitro using human liver microsomes (HLM) and recombinant UDP-glucuronosyltransferase (UGT) and cytochrome P450 (CYP) enzymes. 2. Hydrolysis of PAA to yield PAAH occurred upon incubation with HLM. Further incubations of PAAH with HLM in the presence of UGT and CYP cofactors resulted in significant depletion, with UGT-mediated depletion as the major pathway. 3. Reaction phenotyping utilising selective enzyme inhibitors and recombinant human UGT and CYP enzymes revealed UGT2B7 and UGT1A1, and CYP2C9 and CYP3A4 as the major enzymes involved in the metabolism of PAAH. 4. Analysis of incubations of PAAH with UDP-glucuronic acid-supplemented HLM and recombinant enzymes by UPLC/MS/MS identified three glucuronide metabolites. The metabolites were further characterised by β-glucuronidase and mild alkaline hydrolysis. The acyl glucuronide of PAAH was shown to be the major metabolite. 5. This study demonstrates the in vitro metabolism of PAA and PAAH and represents the first systematic study of the metabolism of an active constituent of an Australian Aboriginal medicinal plant.
A novel function for UDP glycosyltransferase 8: Galactosidation of bile acids
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 17-12-2015
Abstract: The human UDP glycosyltransferase (UGT) superfamily comprises four families of enzymes that catalyze the addition of sugar residues to small lipophilic chemicals. The UGT1 and UGT2 enzymes use UDP-glucuronic acid, and UGT3 enzymes use UDP-N-acetylglucosamine, UDP-glucose, and UDP-xylose to conjugate xenobiotics, including drugs and endobiotics such as metabolic byproducts, hormones, and signaling molecules. This metabolism renders the substrate more polar and more readily excreted from the body and/or functionally inactive. The fourth UGT family, called UGT8, contains only one member that, unlike other UGTs, is considered biosynthetic. UGT8 uses UDP galactose to galactosidate ceramide, a key step in the synthesis of brain sphingolipids. To date other substrates for this UGT have not been identified and there has been no suggestion that UGT8 is involved in metabolism of endo- or xenobiotics. We re-examined the functions of UGT8 and discovered that it efficiently galactosidates bile acids and drug-like bile acid analogs. UGT8 conjugates bile acids ∼60-fold more efficiently than ceramide based on in vitro assays with substrate preference deoxycholic acid > chenodeoxycholic acid > cholic acid > hyodeoxycholic acid > ursodeoxycholic acid. Activities of human and mouse UGT8 are qualitatively similar. UGT8 is expressed at significant levels in kidney and gastrointestinal tract (intestine, colon) where conjugation of bile acids is likely to be metabolically significant. We also investigate the structural determinants of UDP-galactose selectivity. Our novel findings suggest a new role for UGT8 as a modulator of bile acid homeostasis and signaling.
Cytochrome P450 3. Clinically significant drug interactions
Publisher: Wiley
Date: 08-2000
Global supply of health professionals.
Publisher: No publisher found
Date: 2014
Using granular activated carbon prepared from oil palm shell by ZnCl 2 and physical activation for methane adsorption
Publisher: Elsevier BV
Date: 11-2010
Predicting Thrombocytopenia in Patients With Breast Cancer Treated With Ado-trastuzumab Emtansine
Publisher: Elsevier BV
Date: 04-2020
DOI: 10.1016/J.CLBC.2019.10.001
Abstract: Thrombocytopenia is a common and potentially serious adverse event of ado-trastuzumab emtansine (T-DM1) use in patients with advanced breast cancer. However, the risk factors have been minimally explored. Our aim was to develop a clinical prediction model from the clinicopathologic data that would allow for quantification of the personalized risks of thrombocytopenia from T-DM1 usage. Data from 3 clinical trials, EMILIA (a study of trastuzumab emtansine versus capecitabine + lapatinib in participants with HER2 [human epidermal growth factor receptor 2]-positive locally advanced or metastatic breast cancer), TH3RESA (a study of trastuzumab emtansine in comparison with treatment of physician's choice in participants with HER2-positive breast cancer who have received at least two prior regimens of HER2-directed therapy), and MARIANNE [a study of trastuzumab emtansine (T-DM1) plus pertuzumab ertuzumab placebo versus trastuzumab (Herceptin) plus a taxane in participants with metastatic breast cancer], were pooled. Cox proportional hazard analysis was used to assess the association between the pretreatment clinicopathologic data and grade ≥ 3 thrombocytopenia occurring within the first 365 days of T-DM1 use. A multivariable clinical prediction model was developed using a backward elimination process. Of the 1620 participants, 141 (9%) had experienced grade ≥ 3 thrombocytopenia. On univariable analysis, the body mass index, race, presence of brain metastasis, platelet count, white blood cell count, and concomitant corticosteroid use were significantly associated with the occurrence of grade ≥ 3 thrombocytopenia (P 300 × 10 A clinical prediction model, defined by race and pretreatment platelet count, was able to discriminate subgroups with a significantly different risk of grade ≥ 3 thrombocytopenia after T-DM1 initiation. The model allows for improved interpretation of the personalized risks and risk/benefit ratio of T-DM1.
Measurement of cytochrome P450 activation of xenobiotics using the Ames Salmonella test.
Publisher: Elsevier
Date: 1991
Junior doctors’ preparedness to prescribe, monitor, and treat patients with the antibiotic vancomycin in an Australian teaching hospital
Publisher: Korea Health Personnel Licensing Examination Institute
Date: 07-06-2017
Abstract: Purpose: We aimed to assess the preparedness of junior doctors to use vancomycin, and to determine whether attending an educational session and being provided pocket guidelines were associated with self-reported confidence and objective knowledge. Methods: This was a 2-component cross-sectional study. A 60-minute educational session was implemented and pocket guidelines were provided. Preparedness was evaluated by a self-reported confidence survey in the early and late stages of each training year, and by continuing medical education (CME) knowledge scores. Results: Self-confidence was higher among those later in the training year (n=75) than in those earlier (n=120) in the year for all questions. In the late group, vancomycin education was associated with higher self-confidence regarding the frequency of therapeutic drug monitoring (P=0.02) and dose amendment (P=0.05) however, the confidence for initial monitoring was lower (P .05). Those with pocket guidelines were more confident treating patients with vancomycin (P .001), choosing initial (P=0.01) and maintenance doses (P .001), and knowing the monitoring frequency (P=0.03). The 85 respondents who completed the knowledge assessment scored a mean±standard deviation of 8.55±1.55 on 10 questions, and the interventions had no significant effect. Conclusion: Attending an educational session and possessing pocket guidelines were associated with preparedness, as measured by higher self-reported confidence using vancomycin. High knowledge scores were attained following CME however attending an educational session or possessing pocket guidelines did not significantly increase the knowledge scores. Our findings support providing educational sessions and pocket guidelines to increase self-confidence in prescribing vancomycin, yet also highlight the importance of evaluating content, format, and delivery when seeking to improve preparedness to use vancomycin through education.
Binding of clozapine to the GABAB receptor: clinical and structural insights
Publisher: Springer Science and Business Media LLC
Date: 13-03-2020
DOI: 10.1038/S41380-020-0709-5
Abstract: Clozapine is the gold-standard agent for treatment resistant schizophrenia but its mechanism of action remains unclear. There is emerging evidence of the potential role of the GABA
Heterogeneity and Utility of Pharmaceutical Company Sharing of Individual-Participant Data Packages.
Publisher: American Medical Association (AMA)
Date: 05-10-2023
Reply to Auclin et al. Comment on “Hopkins et al. Value of the Lung Immune Prognostic Index in Patients with Non-Small Cell Lung Cancer Initiating First-Line Atezolizumab Combination Therapy: Subgroup
Publisher: MDPI AG
Date: 27-07-2021
Abstract: We thank Auclin et al. [...]
Pharmacophore and Quantitative Structure−Activity Relationship Modeling: Complementary Approaches for the Rationalization and Prediction of UDP-Glucuronosyltransferase 1A4 Substrate Selectivity
Publisher: American Chemical Society (ACS)
Date: 04-2003
DOI: 10.1021/JM020397C
Abstract: Pharmacophore, two-dimensional (2D), and three-dimensional (3D) quantitative structure-activity relationship (QSAR) modeling techniques were used to develop and test models capable of rationalizing and predicting human UDP-glucuronosyltransferase 1A4 (UGT1A4) substrate selectivity and binding affinity (as K(m,app)). The dataset included 24 structurally erse UGT1A4 substrates, with 18 of these comprising the training set and 6 an external prediction set. A common features pharmacophore was generated with the program Catalyst after overlapping the sites of conjugation using a novel, user-defined "glucuronidation" feature. Pharmacophore-based 3D-QSAR (r(2) = 0.88) and molecular-field-based 3D-QSAR (r(2) = 0.73) models were developed using Catalyst and self-organizing molecular field analysis (SOMFA) software, respectively. In addition, a 2D-QSAR (r(2) = 0.80, CV r(2) = 0.73) was generated using partial least-squares (PLS) regression and variable selection using an unsupervised forward selection (UFS) algorithm. Both UGT1A4 pharmacophores included two hydrophobic features and the glucuronidation site. The 2D-QSAR showed the best overall predictivity and highlighted the importance of hydrophobicity (as log P) in substrate-enzyme binding.
Arginine-259 of UGT2B7 Confers UDP-Sugar Selectivity
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 02-10-2020
Circular RNAs of UDP-Glycosyltransferase (UGT) genes expand the complexity and diversity of the UGT transcriptome
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 06-04-2021
A clinical scoring tool validated with machine learning for predicting severe hand-foot syndrome from sorafenib in hepatocellular carcinoma.
Publisher: Springer Science and Business Media LLC
Date: 28-02-2022
DOI: 10.1007/S00280-022-04411-9
Abstract: Sorafenib is an effective therapy for advanced hepatocellular carcinoma (HCC). Hand–foot syndrome (HFS) is a serious adverse effect associated with sorafenib therapy. This study aimed to develop an updated clinical prediction tool that allows personalized prediction of HFS following sorafenib initiation. In idual participant data from Phase III clinical trial NCT00699374 were used in Cox proportional hazard analysis of the association between pre-treatment clinicopathological data and grade ≥ 3 HFS occurring within the first 365 days of sorafenib treatment for advanced HCC. Multivariable prediction models were developed using stepwise forward inclusion and backward deletion and internally validated using a random forest machine learning approach. Of 542 patients, 116 (21%) experienced grades ≥ 3 HFS. The prediction tool was optimally defined by sex (male vs female), haemoglobin ( 130 vs ≥ 130 g/L) and bilirubin ( 10 vs 10–20 vs ≥ 20 µmol/L). The prediction tool was able to discriminate subgroups with significantly different risks of grade ≥ 3 HFS ( P ≤ 0.001). The high (score = 3 +)-, intermediate (score = 2)- and low (score = 0–1)-risk subgroups had 40%, 27% and 14% probability of developing grade ≥ 3 HFS within the first 365 days of sorafenib treatment, respectively. A clinical prediction tool defined by female sex, high haemoglobin and low bilirubin had high discrimination for predicting HFS risk. The tool may enable improved evaluation of personalized risks of HFS for patients with advanced HCC initiating sorafenib.
Functional high-throughput screen identifies microRNAs that promote butyrate-induced death in colorectal cancer cells
Publisher: Elsevier BV
Date: 12-2022
Evaluation of demographic, clinical characteristics, and the prescribing practice of guideline-directed medical therapy among chronic heart failure outpatients in multidisciplinary clinics in a large tertiary hospital: a retrospective audit of 1186 patients from 12 years
Publisher: Research Square Platform LLC
Date: 15-09-2020
DOI: 10.21203/RS.3.RS-70812/V1
Abstract: BackgroundAdherence to guideline-directed medical therapy (GDMT) remains low particularly in elderly despite several approaches. Previous studies showed that heart failure (HF) patients who receive pharmacist-involved multidisciplinary care may have better clinical outcomes. We evaluated patient characteristics and the practice of receiving in idual GDMT in chronic HF patients who attended multidisciplinary clinics.MethodsA retrospective audit of data of chronic HF patients presenting to two multidisciplinary outpatient clinics at a tertiary hospital between March 2005 and January 2017 was performed. Data were obtained from two clinics, a Multidisciplinary Ambulatory Consulting Service (MACS) clinic which uses a pharmacist-involved model of multidisciplinary care, and a General Cardiology Heart Failure Service (GCHFS) clinic which does not have the active involvement of a pharmacist.ResultsHF with mid-range ejection fraction (HFmrEF) subjects resembled the HF with preserved ejection fraction (HFpEF) patients in terms of age, heart rate (HR), systolic blood pressure (SBP) and having higher prevalence of polypharmacy whereas resembled with the HF with reduced ejection fraction (HFrEF) for the proportion of male distribution and prevalence of ischemic heart disease (IHD). Both the clinics had similar prescribing rates of GDMT and achieved maximal tolerated doses of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARB) in HFrEF, but significantly higher prescription of ACEIs/ARBs (70.5% v. 56.2%) was found in HFpEF patients in the MACS clinic. There was significantly lower rates of β-blockers and mineralocorticoid receptor antagonists (MRAs) prescription in HFrEF and HFpEF patients in both clinics. Use of digoxin in chronic atrial fibrillation (AF) was significantly higher in HFrEF patients (82.5% v. 58.5%), but number of people anticoagulated in presence of AF and prescription of diuretics were significantly lowered in MACS clinic in HFpEF patients. Age, anemia, chronic renal failure, SBP, HR and comorbidities were the significant predictors in a multivariate binary logistic regression for the utilization of GDMT.ConclusionsOur study concludes that pharmacist is an important member of a multidisciplinary team in the management of chronic heart failure. The other roles of the pharmacist within a multidisciplinary team, including continuity of care, medication compliance and prevention of adverse reactions need further research.
A Fragment-Based Approach for the Computational Prediction of the Nonspecific Binding of Drugs to Hepatic Microsomes
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 19-08-2016
Abstract: Correction for the nonspecific binding (NSB) of drugs to liver microsomes is essential for the accurate measurement of the kinetic parameters K
Partial charge calculation method affects CoMFA QSAR prediction accuracy.
Publisher: American Chemical Society (ACS)
Date: 25-02-2009
DOI: 10.1021/CI800390M
Abstract: The 3D-QSAR method comparative molecular field analysis (CoMFA) involves the estimation of atomic partial charges as part of the process of calculating molecular electrostatic fields. Using 30 data sets from the literature the effect of using different common partial charge calculation methods on the predictivity (cross-validated R2) of CoMFA was studied. The partial charge methods ranged from the popular Gasteiger and the newer MMFF94 electronegativity equalization methods, to the more complex and computationally expensive semiempirical charges AM1, MNDO, and PM3. The MMFF94 and semiempirical MNDO, AM1, and PM3 methods for computing charges were found to result in statistically significantly more predictive CoMFA models than the Gasteiger charges. Although there was a trend toward the semiempirical charges performing better than the MMFF94 charges, the difference was not statistically significant. Thus, semiempirical partial charge calculation methods are suggested for the most predictive CoMFA models, but the MMFF94 charge calculation method is a very good alternative if semiempirical methods are not available or faster calculation speed is important.
In vivo activity of benzoyl ester clerodane diterpenoid derivatives from dodonaea polyandra
Publisher: American Chemical Society (ACS)
Date: 07-03-2011
DOI: 10.1021/NP100701S
Abstract: Four new benzoyl ester clerodane diterpenoids, 15,16-epoxy-8α-(benzoyloxy)methylcleroda-3,13(16),14-trien-18-oic acid (1), 15,16-epoxy-8α-(benzoyloxy)methyl-2α-hydroxycleroda-3,13(16),14-trien-18-oic acid (2), 15,16-epoxy-8α-(benzoyloxy)methyl-2-oxocleroda-3,13(16),14-trien-18-oic acid (3), and 15,16-epoxy-2α-benzoyloxycleroda-3,13(16),14-trien-18-oic acid (4), have been isolated from the leaves and stems of Dodonaea polyandra. The anti-inflammatory activities of compounds 1, 2, and 4 were evaluated by means of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse ear edema. Compounds 2 and 4 exhibited maximum inhibition of inflammation (70-76%) at doses of 0.22 and 0.9 μmol/ear, respectively. Modest activity (~45% inhibition) was maintained at nanomole/ear doses.
A novel approach for the simultaneous quantification of 18 small molecule kinase inhibitors in human plasma: A platform for optimised KI dosing
Publisher: Elsevier BV
Date: 10-2016
DOI: 10.1016/J.JCHROMB.2016.07.046
Abstract: Small molecule kinase inhibitors (KIs) are a rapidly expanding class of narrow therapeutic index antineoplastic drugs that exhibit substantial inter-in idual variability in exposure. This manuscript describes a novel approach for the quantification of 18 KIs in plasma, providing a platform that is unparalleled in terms of scope for the assessment of KI therapeutic drug monitoring (TDM) and facilitating pharmacokinetic studies with KIs. Following the addition of a panel of four deuterated internal standards, plasma s les were prepared by solvent precipitation with acidified methanol. Analytes were separated on a Waters ACQUITY™ T3 HSS C18 analytical column (150×2.1mm, 1.8μm particle size) by linear gradient elution, with subsequent detection by time-of-flight mass spectrometry. Time-of-flight data were collected in wide pass mode, with selected ion (pseudo-MRM) spectra extracted at the precursor m/z of analytes in ESI+ mode. The analytical performance of this approach in terms of specificity, linearity, accuracy, precision range, quantification limit and detection limit meet all criteria for an analytical platform for the quantification of drugs. This approach was developed, validated and reported in accordance with the 2015 version of the FDA guidance for industry on 'analytical procedures are methods validation for drugs and biologics' facilitating direct application as a clinical trials platform.
Prediction of severe neutropenia and diarrhoea in breast cancer patients treated with abemaciclib
Publisher: Elsevier BV
Date: 08-2021
BRAF V600E and survival benefit of anti-EGFR monoclonal antibody (mAb) therapy for metastatic colorectal cancer (mCRC): A meta-analysis
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2015
Sensitivity of CYP1A1 mRNA inducibility by dioxin is the same in Cyp1a2(+/+) wild-type and Cyp1a2(-/-) null mutant mice
Publisher: Elsevier BV
Date: 11-1997
DOI: 10.1016/S0006-2952(97)00263-3
Abstract: In mammals, the induction of experimental porphyria by halogenated aromatic hydrocarbons (HAHs) seems to be influenced by the levels of hepatic CYP1A2. The pharmacokinetics and relative rates of uptake and storage of HAHs in the liver are correlated with hepatic CYP1A2 concentrations. It is possible that these rates of HAH uptake and storage might affect the expression of other HAH-inducible genes. The differential inducibility of liver CYP1A1 mRNA by dioxin was therefore compared in Cyp1a2(+/+) wild-type mice, Cyp1a2(+/-) heterozygotes, and Cyp1a2(-/-) homozygous null mutants. Using doses of dioxin over eight orders of magnitude (from 10[-12] to 10[-4] g/kg), we could detect no differences in the sensitivity of CYP1A1 mRNA inducibility. These data indicate that the complete absence of the microsomal CYP1A2 enzyme has no measurable effect on hepatic expression of the Cyp1a1, gene, the only other known member of the mammalian CYP1A cytochrome P450 subfamily.
Development and evaluation of a topical anti-inflammatory preparation containing Dodonaea polyandra extract
Publisher: Frontiers Media SA
Date: 24-10-2015
DOI: 10.18433/J38P57
Abstract: Purpose: We have previously reported that the Australian Northern Kaanju (Kuuku I’yu) medicinal plant Dodonaea polyandra has anti-inflammatory activity. This is attributed largely to the presence of clerodane diterpenoids contained within the leaf resin. We envisaged developing a topical preparation to treat indications relating to skin inflammation. However, it was unknown whether the resin could be incorporated into a suitable dosage form while retaining the therapeutic value demonstrated in previous work. Therefore, the following study was undertaken to assess parameters of safety and efficacy for a prototype formulation containing the leaf resin extracted from D. polyandra. Methods: Using the assessment criteria of optimum appearance, tactile feeling, spreadability and odour, 78 different formulations were developed. Formulation stability was assessed using a centrifugal test with preparations displaying phase separation further modified or re-formulated. A prototype formulation containing 5% w/w plant resin was selected and subjected to in vitro release studies. This was quantified through HPLC analysis using two major bioactive diterpenoids as reference. The prototype formulation was tested for efficacy in a TPA-induced acute murine skin inflammation model as well as a 3D human skin model for irritancy/toxicity (Epiderm™). Results: The prototype resin cream was a chartreuse-coloured homogenous semisolid preparation that was readily spreadable upon contact with skin with no sensation of tackiness, residual greasiness, or irritation. The optimized cream showed no phase separation after 30 min centrifugation at 825 g. In the TPA-induced inflammation model, the resin formulation significantly reduced ear thickness and interleukin-1 beta levels in mouse ear tissue. The 5% w/w resin cream formulation showed no irritancy in a 3D human skin model. Conclusions: Our results demonstrate that bioactive resin from D. polyandra can be formulated into a stable and non-irritant semi-solid dosage form and reduce parameters of acute skin inflammation in vivo. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
The Somatic Mutation Landscape of UDP-Glycosyltransferase (UGT) Genes in Human Cancers
Publisher: MDPI AG
Date: 21-11-2022
Abstract: The human UDP-glycosyltransferase (UGTs) superfamily has a critical role in the metabolism of anticancer drugs and numerous pro/anti-cancer molecules (e.g., steroids, lipids, fatty acids, bile acids and carcinogens). Recent studies have shown wide and abundant expression of UGT genes in human cancers. However, the extent to which UGT genes acquire somatic mutations within tumors remains to be systematically investigated. In the present study, our comprehensive analysis of the somatic mutation profiles of 10,069 tumors from 33 different TCGA cancer types identified 3427 somatic mutations in UGT genes. Overall, nearly 18% (1802/10,069) of the assessed tumors had mutations in UGT genes with huge variations in mutation frequency across different cancer types, ranging from over 25% in five cancers (COAD, LUAD, LUSC, SKCM and UCSC) to less than 5% in eight cancers (LAML, MESO, PCPG, PAAD, PRAD, TGCT, THYM and UVM). All 22 UGT genes showed somatic mutations in tumors, with UGT2B4, UGT3A1 and UGT3A2 showing the largest number of mutations (289, 307 and 255 mutations, respectively). Nearly 65% (2260/3427) of the mutations were missense, frame-shift and nonsense mutations that have been predicted to code for variant UGT proteins. Furthermore, about 10% (362/3427) of the mutations occurred in non-coding regions (5′ UTR, 3′ UTR and splice sites) that may be able to alter the efficiency of translation initiation, miRNA regulation or the splicing of UGT transcripts. In conclusion, our data show widespread somatic mutations of UGT genes in human cancers that may affect the capacity of cancer cells to metabolize anticancer drugs and endobiotics that control pro/anti-cancer signaling pathways. This highlights their potential utility as biomarkers for predicting therapeutic efficacy and clinical outcomes.
Role of the pharmacist for improving self-care and outcomes in heart failure
Publisher: Springer Science and Business Media LLC
Date: 23-02-2017
DOI: 10.1007/S11897-017-0323-2
Abstract: This review highlights the current and emerging approaches for the role of the pharmacist for improving self-care and outcomes in heart failure management. Pharmacists are contributing to heart failure management in a variety of settings, including hospitals, clinics, and communities. Different interventions which may be mediated by the pharmacist include drug adherence, discharge counseling, medication reconciliation, telephone follow-up, and recommendation of evidence-based medicines. Pharmacist engagement in heart failure management has demonstrated improved drug adherence, readmission rates, medication management, self-care ability, patient satisfaction, and heart failure knowledge. Some findings are mixed, especially for readmission rates. Improved medication management was reported in nearly all studies, despite significant heterogeneity in the models of care, patient populations, and study designs. This review highlights the requirement for large randomized trials with extended follow-up to confirm the impact of the role of the pharmacist in HF self-care, particularly through multidisciplinary-based interventions.
Safety considerations of biosimilars
Publisher: Therapeutic Guidelines Limited
Date: 05-12-2016
A 10-year update to the principles for clinical trial data sharing by pharmaceutical companies: perspectives based on a decade of literature and policies
Publisher: Springer Science and Business Media LLC
Date: 23-10-2023
The expression profiles of ADME genes in human cancers and their associations with clinical outcomes
Publisher: MDPI AG
Date: 13-11-2020
Abstract: ADME genes are a group of genes that are involved in drug absorption, distribution, metabolism, and excretion (ADME). The expression profiles of ADME genes within tumours is proposed to impact on cancer patient survival however, this has not been systematically examined. In this study, our comprehensive analyses of pan-cancer datasets from the Cancer Genome Atlas (TCGA) revealed differential intratumoral expression profiles for ADME genes in 21 different cancer types. Most genes also showed high interin idual variability within cancer-specific patient cohorts. Using Kaplan-Meier plots and logrank tests, we showed that intratumoral expression levels of twenty of the thirty-two core ADME genes were associated with overall survival (OS) in these cancers. Of these genes, five showed significant association with unfavourable OS in three cancers, including SKCM (ABCC2, GSTP1), KIRC (CYP2D6, CYP2E1), PAAD (UGT2B7) sixteen showed significant associations with favourable OS in twelve cancers, including BLCA (UGT2B15), BRCA (CYP2D6), COAD (NAT1), HNSC (ABCB1), KIRC (ABCG2, CYP3A4, SLC22A2, SLC22A6), KIRP (SLC22A2), LIHC (CYP2C19, CYP2C8, CYP2C9, CYP3A5, SLC22A1), LUAD (SLC15A2), LUSC (UGT1A1), PAAD (ABCB1), SARC (ABCB1), and SKCM (ABCB1, DYPD). Overall, these data provide compelling evidence supporting ADME genes as prognostic biomarkers and potential therapeutic targets. We propose that intratumoral expression of ADME genes may impact cancer patient survival by multiple mechanisms that can include metabolizing/transporting anticancer drugs, activating anticancer drugs, and metabolizing/transporting a variety of endogenous molecules involved in metabolically fuelling cancer cells and/or controlling pro-growth signalling pathways.
Cytochrome P450 part 3: Impact of drug-drug interactions
Publisher: Wiley
Date: 03-2009
DOI: 10.1002/J.2055-2335.2009.TB00705.X
Abstract: The role of in idual hepatic cytochrome P450 (CYP) enzymes in drug metabolism and the factors that modulate CYP activity are becoming increasingly well understood. These advances have resulted in a better understanding of drug‐drug and drug‐ food interactions and an enhanced capacity to predict drug interactions that may occur with new drugs. This final article in the series describes the issues and principles that are important in identifying and assessing drug interactions that involve CYP enzymes.
Rapid Prediction of Chemical Metabolism by Human UDP-glucuronosyltransferase Isoforms Using Quantum Chemical Descriptors Derived with the Electronegativity Equalization Method
Publisher: American Chemical Society (ACS)
Date: 15-09-2004
DOI: 10.1021/JM0495529
Abstract: This study aimed to evaluate in silico models based on quantum chemical (QC) descriptors derived using the electronegativity equalization method (EEM) and to assess the use of QC properties to predict chemical metabolism by human UDP-glucuronosyltransferase (UGT) isoforms. Various EEM-derived QC molecular descriptors were calculated for known UGT substrates and nonsubstrates. Classification models were developed using support vector machine and partial least squares discriminant analysis. In general, the most predictive models were generated with the support vector machine. Combining QC and 2D descriptors (from previous work) using a consensus approach resulted in a statistically significant improvement in predictivity (to 84%) over both the QC and 2D models and the other methods of combining the descriptors. EEM-derived QC descriptors were shown to be both highly predictive and computationally efficient. It is likely that EEM-derived QC properties will be generally useful for predicting ADMET and physicochemical properties during drug discovery.
Morphological examination and quantification of hepatic peroxisomes in the koala (Phascolarctos cinereus) by electron microscopy
Publisher: Elsevier BV
Date: 09-2008
A literature review of treatment-specific clinical prediction models in patients with breast cancer
Publisher: Elsevier BV
Date: 04-2020
Defeating diabetes
Publisher: OMICS Publishing Group
Date: 10-2014
DOI: 10.2217/DMT.14.40
The UDP-Glycosyltransferase (UGT) Superfamily
Publisher: American Physiological Society
Date: 04-2019
DOI: 10.1152/PHYSREV.00058.2017
Abstract: UDP-glycosyltransferases (UGTs) catalyze the covalent addition of sugars to a broad range of lipophilic molecules. This biotransformation plays a critical role in elimination of a broad range of exogenous chemicals and by-products of endogenous metabolism, and also controls the levels and distribution of many endogenous signaling molecules. In mammals, the superfamily comprises four families: UGT1, UGT2, UGT3, and UGT8. UGT1 and UGT2 enzymes have important roles in pharmacology and toxicology including contributing to interin idual differences in drug disposition as well as to cancer risk. These UGTs are highly expressed in organs of detoxification (e.g., liver, kidney, intestine) and can be induced by pathways that sense demand for detoxification and for modulation of endobiotic signaling molecules. The functions of the UGT3 and UGT8 family enzymes have only been characterized relatively recently these enzymes show different UDP-sugar preferences to that of UGT1 and UGT2 enzymes, and to date, their contributions to drug metabolism appear to be relatively minor. This review summarizes and provides critical analysis of the current state of research into all four families of UGT enzymes. Key areas discussed include the roles of UGTs in drug metabolism, cancer risk, and regulation of signaling, as well as the transcriptional and posttranscriptional control of UGT expression and function. The latter part of this review provides an in-depth analysis of the known and predicted functions of UGT3 and UGT8 enzymes, focused on their likely roles in modulation of levels of endogenous signaling pathways.
Cytochrome P450 structure–function: insights from molecular dynamics simulations
Publisher: Informa UK Limited
Date: 10-05-2016
DOI: 10.1080/03602532.2016.1178771
Abstract: Cytochrome P450 (CYP) family 1, 2, and 3 enzymes play an essential role in the metabolic clearance and detoxification of a myriad of structurally and chemically erse drugs and non-drug xenobiotics. The in idual CYP enzymes exhibit distinct substrate and inhibitor selectivities, and hence differing patterns of inhibitory drug-drug interactions. In addition, CYP enzymes differ in terms of regulation of expression, genetic polymorphism, and environmental factors that alter activity. The availability of three-dimensional structures from X-ray crystallography have been invaluable for understanding the structural basis of the ligand selectivity of CYP enzymes. Moreover, the X-ray crystal structures demonstrate that CYP proteins exhibit marked flexibility, particularly around the active site, and the principle of ligand-induced conformational changes is now well accepted. Recent studies have demonstrated that molecular dynamics simulations (MDS) provide an additional approach for modeling the structural flexibility of CYP enzymes, both in the presence and absence of bound ligand, and understanding the functional consequences of plasticity. However, most of the MDS studies reported to date have utilized short simulation time scales, and few have validated the computationally-generated data experimentally (e.g. by site-directed mutagenesis and enzyme kinetic approaches). Although modeling approaches require further development and validation, MDS has the potential to provide a deeper understanding of CYP structure-function than is available from experimental techniques such as X-ray crystallography alone.
Integrated care in cancer: What is it, how is it used and where are the gaps? A textual narrative literature synthesis.
Publisher: Hindawi Limited
Date: 20-04-2017
DOI: 10.1111/ECC.12689
Abstract: Integrated care is an underpinning concept of contemporary health care policy proffered as a strategy to overcome the fragmentations in care encountered by people with complex care needs (Shaw et al. [2011] What is Integrated Care? An Overview of Integrated Care in the NHS). Cancer patients have potential to benefit from such policy, often having needs that extend beyond cancer. This paper seeks to understand how the concept of integrated care is used in the cancer literature. A search of leading databases was conducted for original research relating to integrated care or an integration intervention aiming to improve outcomes of cancer patients, and analysed using textual narrative synthesis. 38 papers were included, each with a focus on improving cancer-specific aspects of care enhancing the capabilities of the cancer multidisciplinary team. Of the eight studies involving integration between the cancer service and other care providers, all focused on utilising the external provider to deliver aspects of cancer care or placed them in a passive role, as survey participant, a recipient of cancer-related clinical information or as the comparator "usual care" arm. Within the cancer literature, integration is predominantly used to describe initiatives to improve cancer-related aspects of care. Less attention is given to integration initiatives that enhance coordination across levels of the healthcare system or service providers.
Knowledge and perceptions of community patients about generic medicines
Publisher: Wiley
Date: 12-2015
DOI: 10.1002/J.2055-2335.2012.TB00189.X
Abstract: Patients' knowledge and perceptions about generic medicines are extremely important for promoting generic substitution. Few studies have investigated patients' acceptance or understanding of generic medicines. To explore knowledge and perceptions of community patients about generic medicines. A self‐administered anonymous survey was completed by patients presenting at 1 of 18 community pharmacies in Adelaide, South Australia. The questionnaire comprised items on: demographics (age, gender, ethnicity, education, income, self‐rated health status), safety, efficacy, cost and value of generic medicines, and patients' willingness to use these. 503 patients completed the survey − 51% females and 49% males. 60% of patients were on more than one prescription medication. 67% of patients rarely asked for a generic medicine when their prescriptions were being filled. Around 47% of patients believed that they needed more information on the difference between generic and brand‐name medicines. Around 81% of patients knew that generic medicines were less expensive than brand‐name medicines and 51% believed generic medicines offered better value. When asked whether 'they would rather take generic medicines than brand‐name medicines' – about 30% indicated they would, 25%) would not, 40% were neutral and 5% did not provide an answer Younger patients (55 years or less) asked for generic medicines more often than older patients (over 55 years) (p 0.05). There were no other significant differences. Most patients had some knowledge about generic medicines. However, many were unsure if they preferred generic to brand‐name medicines or brand‐name to generic medicines.
CYP2C19 genotype has a greater effect on adverse cardiovascular outcomes following percutaneous coronary intervention and in Asian populations treated with clopidogrel: A meta-analysis
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2014
DOI: 10.1161/CIRCGENETICS.114.000669
Abstract: The degree to which cytochrome P450 (CYP) 2C19 genotype influences the effectiveness of clopidogrel remains uncertain because of considerable heterogeneity in results between studies and potential publication bias. Clopidogrel indication and ethnic population have been proposed to influence the effect of CYP2C19 genotype. A systematic review was undertaken up to 14 November 2013. Meta-analysis of the CYP2C19 genotype effect was stratified by the predominant clopidogrel indication (percutaneous coronary intervention [PCI] versus non-PCI) and ethnic population (white versus Asian) of each primary study. The primary analysis was restricted to studies with ≥500 participants, which comprised 24 studies and a total of 36 076 participants. The association between carriage of ≥1 CYP2C19 loss-of-function (LoF) allele and major cardiovascular outcomes differed significantly ( P .001) between studies of whites not undergoing PCI (relative risk 0.99 [95% confidence interval, 0.84–1.17] n=7043), whites undergoing PCI (1.20 [1.10–1.31] n=19,016), and Asians undergoing PCI (1.91 [1.61–2.27] n=10,017). Similar differences were identified in secondary analyses of 2 CYP2C19 LoF alleles, stent thrombosis outcomes, and studies with ≥200 participants. Minimal heterogeneity was apparent between studies of Asian populations. The reported association between CYP2C19 LoF allele carriage and major cardiovascular outcomes differs based on the ethnic population of the study and, to a lesser extent, the clopidogrel indication. This is potentially of major importance given that over 50% of Asians carry ≥1 CYP2C19 LoF alleles.
Kinase inhibitor pharmacokinetics: comprehensive summary and roadmap for addressing inter-individual variability in exposure
Publisher: Informa UK Limited
Date: 09-2016
DOI: 10.1080/17425255.2016.1229303
Abstract: Small molecule protein kinase inhibitors (KIs) are a class of drugs with complex and unconventional physiochemical and pharmacokinetic characteristics. Cytochrome P450 mediated metabolism and transporter-mediated uptake and efflux are important processes that determine KI disposition and exposure. Areas covered: We provide an overview of KI pharmacology, with a comprehensive summary of KI physiochemical and pharmacokinetic properties and description of the major sources of variability in KI pharmacokinetics focusing on common pathways involved in determining exposure. We also consider the strategies proposed to optimize KI dosing, appraise the current evidence for their use and analyze the challenges and knowledge gaps for KI dose optimization. Expert opinion: A number of strategies to optimize KI dosing have been proposed, but evidence underpinning their use is limited. The major challenge for optimized KI dosing is the development of high-quality evidence to demonstrate a significant improvement in therapeutic outcomes and /or reduction in adverse events through appropriately designed trials in a setting where the limited KI prescribing restricts capacity to undertake prospective randomized studies. If precision KI dosing can facilitate a fraction of the reported observational benefits, then substantial gains in patient outcomes will be derived in a cost-effective manner.
Lymphocytes of BRCA1 and BRCA2 germ-line mutation carriers, with or without breast cancer, are not abnormally sensitive to the chromosome damaging effect of moderate folate deficiency
Publisher: Oxford University Press (OUP)
Date: 14-09-2006
Abstract: Mutations in BRCA1 and BRCA2 genes may cause defective DNA repair and increase the risk for breast cancer. Folate deficiency is associated with increased breast cancer risk and induces chromosome abnormalities. We hypothesized that BRCA1 and BRCA2 germline mutation carriers are more sensitive to the genome damaging effect of folate deficiency compared with healthy non-carrier controls and that this sensitivity is further increased in those carriers who develop breast cancer. We tested these hypotheses in lymphocytes cultured in a medium containing 12 or 120 nM folic acid (FA) for 9 days and measured proliferative capacity and chromosomal instability using the cytokinesis-block micronucleus assay. BRCA1 and BRCA2 mutation carriers with or without breast cancer were not abnormally sensitive to FA deficiency-induced chromosome instability however, BRCA2 mutation carriers had significantly reduced cell proliferation. FA deficiency reduced cell proliferation and increased micronucleus formation significantly, accounting for 45-59% and 70-75% of the variance in these parameters compared with 0.3-8.5% and 0.2-0.3% contributed by BRCA1 or BRCA2 mutation carrier status, respectively. The results of this study suggest that moderate folate deficiency has a stronger effect on chromosomal instability than BRCA1 or BRCA2 mutations found in breast cancer families.
Hepatic microsomal enzyme activity in the koala and tammar wallaby: high 17 beta-hydroxysteroid oxidoreductase activity in koala liver microsomes
Publisher: Elsevier BV
Date: 05-1999
DOI: 10.1016/S0742-8413(99)00012-2
Abstract: We have studied the hepatic microsomal xenobiotic metabolising capacity of koala (Phascolarctos cinereus) and tammar wallaby (Macropus eugenii). Total cytochrome P450 content in hepatic microsomes from koala (0.87 +/- 0.18 nmol/mg protein, n = 4, mean (S.D.) and rat were comparable while tammar wallaby displayed reduced P450 content (0.24 +/- 0.04 nmol/mg protein). Associated microsomal activities (NADPH cytochrome P450 reductase, aminopyrine N-demethylation, aniline hydroxylation, and androstenedione 6beta- and 16alpha-hydroxylation) in koala liver were similar to or reduced relative to rat. Hepatic microsomal NADPH-supported 17beta-hydroxysteroid oxidoreductase (17beta-HSOR) activity was significantly higher in koala (9.99+/-3.08 nmol/mg protein/min) than in tammar wallaby liver (0.86 +/- 0.16 nmol/mg protein/min). However, when NADH was utilised as cofactor the activity was similar in both marsupial species (koala, 1.44 +/- 0.84 nmol/mg protein/min tammar wallaby, 1.52 +/- 0.44 nmol/mg protein/min). Michaelis-Menten parameters for the kinetics of 17beta-HSOR androstenedione reduction by NADPH and NADH were determined in the koala. The Km for androstenedione was of the order of 1.9-4 microM (n = 4) irrespective of the cofactor used, whilst the Km for NADPH was 0.04-0.05 microM (n = 2) and for NADH was 134-430 microM (n = 2). Potential inhibitors were evaluated for their effects on NADPH-mediated 17beta-HSOR activity with menadione and, to lesser extents, menthone, benzaldehyde and metyrapone eliciting significant inhibition. From detailed kinetic studies menthone was found to be an uncompetitive inhibitor of the activity in koala liver (Ki 220 microM).
Complementary and alternative medicines and dietary interventions in multiple sclerosis: What is being used in South Australia and why?
Publisher: Elsevier BV
Date: 08-2009
DOI: 10.1016/J.CTIM.2009.03.001
Abstract: To investigate the usage patterns of complementary and alternative medicines (CAMs), as well as dietary interventions, by South Australian people with multiple sclerosis (MS). Self-administered postal survey. Questionnaire mailed to recipients of the South Australian (SA) MS Society newsletter (n=1230). Patterns of CAMs use and dietary interventions, reasons for using/not using CAMs in MS, sources of CAMs information and monthly expenditure on CAMs/dietary interventions. A total of 428 surveys were returned (response rate 34.8%) of which 416 met the inclusion criteria for analysis. The majority of SA people with MS who responded reported using CAMs/dietary interventions (64.7%). Respondents with tertiary education and those with mild and moderate disease reported highest CAM use. The most frequently used CAM product categories were vitamins (81.8%), essential fatty acids (80.7%) and minerals (62.5%). Commonly used herbal products included Ginkgo biloba (18.2%) and valerian (16.4%). Popular diets were the low fat (39.8%), low/no sugar (23.8%) and gluten-free (16.4%) diets. The majority of those using CAMs/dietary interventions did so concurrently with conventional treatments (72.1%). Reasons for use included: general health and well-being to alleviate 'general' as well as specific MS symptoms such as muscle weakness, urinary or memory problems and mobility. Conventional health professionals, and friends/family, were the most common sources of information. Monthly expenditure was most commonly AUD$20-49/month. This study reports frequent use of CAM/dietary intervention amongst SA people with MS. The majority of users did so in conjunction with conventional treatments.
Incidence of vancomycin-induced red man syndrome in a women's and children's hospital
Publisher: Wiley
Date: 06-2007
DOI: 10.1002/J.2055-2335.2007.TB00033.X
Abstract: Red man syndrome (RMS) is an adverse reaction to vancomycin. Symptoms include rash, itch, hypotension, hypothermia, angioedema and respiratory distress. The incidence of RMS in the paediatric population is unclear. To estimate the incidence of RMS in a women's and children's hospital, focusing on the paediatric population, and to identify risk factors. Patients at a women's and children's hospital receiving IV vancomycin were identified during a 2‐month period and their case notes were reviewed for documented RMS symptoms. 21 patients (5 days to 24 years of age) were identified, and 37 vancomycin courses were investigated. RMS symptoms occurred in 8/21 (38%) patients and in 8/37 (22%) vancomycin courses. 4 patients experienced a rash only, mostly an itchy, urticarial rash on the face and/or limbs. 4 patients experienced RMS without a rash: 2 had hypotension 1 had bradycardia and 1 had hypothermia, hypotension and bradycardia. None of the reactions were life‐threatening, and none resulted in cessation of vancomycin. 3/4 patients who experienced a rash received antihistamines, whereas none of the 4 patients who experienced RMS without a rash received antihistamines. RMS is common and unpredictable. Cardiovascular symptoms can occur without accompanying dermatological symptoms. There may be potential for greater use of antihistamine prophylaxis and treatment for RMS.
Regulation of human UDP-glycosyltransferase (UGT) genes by miRNAs
Publisher: Informa UK Limited
Date: 11-03-2022
DOI: 10.1080/03602532.2022.2048846
Abstract: The human
The Importance of Local Chemical Structure for Chemical Metabolism by Human Uridine 5‘-Diphosphate−Glucuronosyltransferase
Publisher: American Chemical Society (ACS)
Date: 22-09-2006
DOI: 10.1021/CI600248E
Abstract: The uridine 5'-diphosphate- (UDP-)glucuronosyltransferase (UGT) family of enzymes catalyzes the conjugation of chemicals containing a suitable nucleophilic atom with glucuronic acid. Despite the importance of glucuronidation as an elimination and detoxification mechanism for drugs, environmental chemicals, and endogenous compounds, the structural features of substrates that confer isoform selectivity are poorly understood. The relationship between the local molecular structure of nucleophilic atoms of chemicals and the ability of UGT isoforms to glucuronidate the nucleophilic atoms was investigated here. The proximity of an aromatic ring to the nucleophilic atom was highly associated with a greater likelihood of glucuronidation by most UGT isoforms. Similarly, most UGT isoforms were found to have a statistically significant preference for oxygen over nitrogen as the nucleophilic atom. The converse was established only for UGT1A4. Naïve Bayes models were trained to predict the site of glucuronidation for eight UGT isoforms on the basis of the partial charge and Fukui function of the nucleophilic atom and whether an aromatic ring was attached to the nucleophilic atom. On average, the cross-validated sensitivity and specificity of the models were approximately 75-80%. For all but UGT2B7, the area under the receiver operating characteristics curve of the model was greater than 0.8, indicating strong predictive ability. A chemical ersity analysis of the currently available data indicates bias toward chemicals containing phenolic groups, and it is likely that the availability of chemical data sets with greater ersity will facilitate further insights into the structural features of substrates that confer enzyme selectivity.
Genetic polymorphisms in human drug-metabolizing enzymes: Potential uses of reverse genetics to identify genes of toxicological relevance
Publisher: Informa UK Limited
Date: 1997
DOI: 10.3109/10408449709021619
Abstract: The human mind was engaged with fundamental questions on the nature of heredity long before the study of genetics became a scientific discipline. Many traits, such as height, eye color, blood pressure, or cancer susceptibility, have been known to run in families, although the genes or combination of genes that underlie these observable characteristics remain unknown in most cases. Differences in susceptibility to environmental agents in humans are likewise determined by variations in genetic background--genetic polymorphisms. In this article, we review the current status of studies on human polymorphisms in drug-metabolizing enzymes and discuss various approaches to the analysis of genetic polymorphisms. We expect that in the near future, novel methods in genetic analysis of human populations will be likely to play a key role in the identification of genes of toxicological relevance.
Novel nine-exon AR transcripts (Exon 1/Exon 1b/ Exons 2-8) in normal and cancerous breast and prostate cells
Publisher: MDPI AG
Date: 27-12-2017
DOI: 10.3390/IJMS18010040
Micromanaging aerobic respiration and glycolysis in cancer cells
Publisher: Elsevier BV
Date: 05-2019
Impact of the UGT1A1*28 allele on response to irinotecan: a systematic review and meta-analysis
Publisher: Future Medicine Ltd
Date: 06-2012
DOI: 10.2217/PGS.12.68
Abstract: Aim: Pre-emptive irinotecan dose reduction for UGT1A1*28 homozygotes may result in reduced risk of severe neutropenia and diarrhea. However, clinical utility and cost–effectiveness are dependent upon such a dose reduction not impacting irinotecan efficacy. Whether UGT1A1*28 genotype is associated with irinotecan response therefore is an important gap in existing knowledge to inform clinical utility. Materials & methods: A systematic review and meta-analysis was performed to analyze the difference in objective response rate (ORR) between irinotecan-administered cancer patients with different UGT1A1*28 genotypes: *28/*28 (homozygous variant), *1/*28 (heterozygous variant) or *1/*1 (wild-type). The effect of irinotecan dose on the association between UGT1A1*28 and ORR was also assessed. Results: Differences in ORR for either of the genotype comparisons, *28/*28 versus *1/*1 and *1/*28 versus *1/*1, were not statistically significant. Irinotecan dose also did not impact upon ORR differences between UGT1A1 genotype groups. Conclusion: An in idual’s response to irinotecan is unlikely to be affected by UGT1A1*28 status. Original submitted 23 February 2012 Revision submitted 20 April 2012
Arid awakening: New opportunities for Australian plant natural product research
Publisher: CSIRO Publishing
Date: 2016
DOI: 10.1071/RJ16004
Abstract: The importance of plants and other natural reserves as sources for biologically important compounds, particularly for application in food and medicine, is undeniable. Herein we provide a historical context of the major scientific research programs conducted in Australia that have been aimed at discovering novel bioactive natural products from terrestrial plants. Generally speaking, the main approaches used to guide the discovery of novel bioactive compounds from natural resources have included random, ethnobotanical and chemotaxonomic strategies. Previous Australian plant natural product research c aigns appear to have lacked the use of a fourth strategy with equally high potential, namely the ecologically guided approach. In addition, many large studies have s led plant material predominantly from tropical regions of Australia, even though arid and semi-arid zones make up 70% of mainland Australia. Therefore, plants growing in arid zone environments, which are exposed to different external stressors (e.g. low rainfall, high ultraviolet exposure) compared with tropical flora, remain an untapped reservoir of potentially novel bioactive compounds. Research of Australian arid zone plants that is ecologically guided creates a new opportunity for the discovery of novel bioactive compounds from plants (and potentially other biota) for application in health care, food and agricultural industries.
The Routine Clinical use of Pharmacogenetic Tests: What it Will Require?
Publisher: Springer Science and Business Media LLC
Date: 24-02-2017
DOI: 10.1007/S11095-017-2128-0
Abstract: Pharmacogenetic testing aims to personalize drug therapy with a view to optimising drug efficacy and minimise toxicity. However, despite the potential benefits, pharmacogenetic testing is mostly confined to specialised medical areas, laboratories and centres. Widespread integration into routine clinical practice has been limited by a complex set of issues including regulatory and reimbursement frameworks, evidence of clinical utility and clinician perspectives, practices and education. Here we assess the current barriers to widespread clinical uptake and identify the key issue necessary to address to accelerate routine testing.
Xenobiotic metabolism in Australian marsupials
Publisher: Elsevier BV
Date: 03-2001
DOI: 10.1016/S1532-0456(00)00211-8
Abstract: The Australian marsupials are significant and unique Australian fauna. Xenobiotic metabolism is the process of enzymatic modification of xenobiotics, which include the chemicals, such as agricultural chemicals and natural dietary toxins, that these animals may be exposed to. Very little is known about the enzymes involved in xenobiotic metabolism in this unique group of animals. Folivore marsupials such as the koala (Phascolarctos cinereus and the brushtail possum (Trichosurus vulpecula) represent unique adaptation which has only been relatively superficially examined to date. We provide an overview of our current knowledge of marsupial xenobiotic metabolism.
Supplementation with Brazil nuts and green tea extract regulates targeted biomarkers related to colorectal cancer risk in humans
Publisher: Cambridge University Press (CUP)
Date: 07-12-2016
DOI: 10.1017/S0007114516003937
Abstract: Se and green tea have been shown in epidemiological, observational and preclinical studies to be inversely related to the risk of developing colorectal cancer (CRC). However, there are limited studies to evaluate their regulatory effects on genes roteins that relate to CRC oncogenesis in human subjects, such as selenoproteins, WNT signalling pathway, inflammation and methylation. This study examined the effects of supplementation of Se using Brazil nuts and green tea extract (GTE) capsules, alone and in combination, on targeted biomarkers. In total, thirty-two volunteers ( years of age) with plasma Se≤1·36 µmol/l were randomised to one of three treatment groups: nine to Se (approximately 48 µg/d) as six Brazil nuts, eleven to four GTE capsules (800 mg (-)-epigallocatechin-3-gallate) and twelve to a combination of Brazil nuts and GTE. Blood and rectal biopsies were obtained before and after each intervention. Plasma Se levels, rectal selenoprotein P (SePP) and β -catenin mRNA increased significantly in subjects consuming Brazil nuts alone or in combination, whereas rectal DNA methyltransferase (DNMT1) and NF- κ B mRNA were reduced significantly in subjects consuming GTE alone or in combination. None of the interventions significantly affected rectal acetylated histone H3 or Ki-67 expression at the protein level or plasma C-reactive protein. Effects of the combination of Brazil nuts and GTE did not differ from what would be expected from either agent alone. In conclusion, supplementation of Brazil nuts and/or GTE regulates targeted biomarkers related to CRC oncogenesis, specifically genes associated with selenoproteins (SePP), WNT signalling ( β -catenin), inflammation (NF- κ B) and methylation (DNMT1). Their combination does not appear to provide additional effects compared with either agent alone.
PPAR-Alpha Cloning, Expression, and Characterization
Publisher: Humana Press
Date: 27-09-2012
DOI: 10.1007/978-1-62703-155-4_2
Abstract: Peroxisome proliferator-activated receptor α (PPARα) is a member of the nuclear/steroid receptor gene superfamily that also comprises β, δ, and γ isoforms. PPARα is a ligand-activated transcription factor that plays an important role in the regulation of many genes involved in key metabolic processes. Today, PPARα has been cloned from mammalian, marsupial, and a number of marine species and its expression has been found to be relatively tissue- and species-specific. Here, we describe the methods for cloning of PPARα genes by RT-PCR and RACE approaches and related protocols for studying the expression of cloned PPARα cDNAs in mammalian cell systems.
Hepatic cytochrome P450 enzymes belonging to the CYP2C subfamily from an Australian marsupial, the koala (Phascolarctos cinereus).
Publisher: Elsevier BV
Date: 09-2008
DOI: 10.1016/J.CBPC.2008.05.020
Abstract: Cytochromes P450 (CYPs) are critically important in the oxidative metabolism of a erse array of xenobiotics and endogenous substrates. We have previously reported that the obligate Eucalyptus feeder koala (Phascolarctos cinereus) exhibits a higher hepatic CYP2C activity as compared to non-Eucalyptus feeders human or rat, with stimulation of CYP2C activity by cineole. In the present study, we examine CYP2C expression by immunohistochemistry and describe the identification and cloning of koala CYP2Cs. Utilising anti-rat CYP2C6 antibody, the expression of CYP2C was found to be uniform across the hepatic sections, being consistent with that observed in human and rat. Two 1647 and 1638 bp koala liver CYP2C complete cDNAs, designated CYP2C47 and CYP2C48 respectively, were cloned by cDNA library screening. The koala CYP2C cDNAs encode a protein of 495 amino acids. Three additional partial CYP2C sequences were also identified from the koala, indicating the multiplicity of the CYP2C subfamily in this unique marsupial species. The results of this study demonstrate the presence of koala hepatic CYP2Cs that share several common features with other published CYP2Cs however CYP2C47 and CYP2C48 contain four extra amino acid residues at the NH2-terminal, a transmembrane anchor which was reported being a fundamentally conserved structure core of all eukaryote CYP enzymes.
Cytochrome P450 CYP3A in marsupials: cloning and characterisation of the second identified CYP3A subfamily member, isoform 3A78 from koala (Phascolarctos cinereus)
Publisher: Elsevier BV
Date: 11-2011
DOI: 10.1016/J.CBPC.2011.07.007
Abstract: Cytochromes P450 (CYPs) are critically important in the oxidative metabolism of a erse array of xenobiotics and endogenous substrates. Previously, we cloned and characterised the CYP2C, CYP4A, and CYP4B gene subfamilies from marsupials and demonstrated important species-differences in both activity and tissue expression of these CYP enzymes. Recently, we isolated the Eastern grey kangaroo CYP3A70. Here we have cloned and characterised the second identified member of marsupial CYP3A gene subfamily, CYP3A78 from the koala (Phascolarctos cinereus). In addition, we have examined the gender-differences in microsomal erythromycin N-demethylation activity (a CYP3A marker) and CYP3A protein expression across test marsupial species. Significant differences in hepatic erythromycin N-demethylation activity were observed between male and female koalas, with the activity detected in female koalas being 2.5-fold higher compared to that in male koalas (p<0.01). No gender-differences were observed in tammar wallaby or Eastern grey kangaroo. Immunoblot analysis utilising anti-human CYP3A4 antibody detected immunoreactive proteins in liver microsomes from all test male and female marsupials including the koala, tammar wallaby, and Eastern grey kangaroo, with no gender-differences detected across test marsupials. A 1610 bp koala hepatic CYP3A complete cDNA, designated CYP3A78, was cloned by reverse transcription-polymerase chain reaction approaches. It displays 64% nucleotide and 57% amino acid sequence identity to the Eastern grey kangaroo CYP3A70. The CYP3A78 cDNA encodes a protein of 515 amino acids, shares approximately 68% nucleotide and 56% amino acid sequence identity to human CYP3A4, and displays high sequence similarity to other published mammalian CYP3As from human, monkey, cow, pig, dog, rat, rabbit, mouse, hamster, and guinea pig. Collectively, this study provides primary molecular data regarding koala hepatic CYP3A78 gene and enables further functional analyses of CYP3A enzymes in marsupials. Given the significant role that CYP3A enzymes play in the metabolism of both endogenous and exogenous compounds, the clone provides an important step in elucidating the metabolic capacity of marsupials.
Mir-18a inhibits CDC42 and plays a tumour suppressor role in colorectal cancer cells
Publisher: Public Library of Science (PLoS)
Date: 07-11-2014
The impact of a pilot continuing professional development module on hospital pharmacists’ preparedness to provide contemporary advice on the clinical use of vancomycin
Publisher: Springer Science and Business Media LLC
Date: 15-03-2016
Prediction of Metabolism by Cytochrome P450 2C9: Alignment and Docking Studies of a Validated Database of Substrates
Publisher: American Chemical Society (ACS)
Date: 23-07-190728635
DOI: 10.1021/JM7009793
Abstract: A validated database of 70 molecules known to undergo biotransformation by CYP2C9 was collated. The molecular alignment program ROCS was used with the query molecule flurbiprofen as a basis for predicting the correct active site orientation of the CYP2C9 database molecules. The quality of the results obtained was excellent, with 39 of the first 44 molecules (89%) sorted by ROCS combination score having alignments that accounted for the experimentally observed site of oxidation. Transposition of the first 39 correctly aligned molecules into the CYP2C9 active site yielded an average site of metabolism to iron heme distance of 5.21 A, in good agreement with previous experimental observations. Molecular docking studies were also undertaken, but the results were less successful than the ROCS-based alignment method, indicating that ligand-based approaches with chemical typing are important in the prediction of metabolism by CYP2C9.
Regulation of UDP glucuronosyltransferase 2B genes in breast cancer cells
Publisher: Elsevier BV
Date: 2018
Anti-inflammatory diterpenoids and other secondary metabolites from Dodonaea polyandra; a traditional medicine used by Kaanju people in North Eastern Australia.
Publisher: Georg Thieme Verlag KG
Date: 08-2010
DOI: 10.1055/S-002-21285
C-reactive protein provides superior prognostic accuracy than the IMDC risk model in renal cell carcinoma treated with Atezolizumab/Bevacizumab
Publisher: Frontiers Media SA
Date: 08-2022
Abstract: Immune checkpoint inhibitors (ICIs) is the main treatment option for patients with metastatic renal cell carcinoma (mRCC) however, significant heterogeneity in response is commonly observed. This study aimed to evaluate the ability of C-reactive protein (CRP) to predict overall survival (OS) and progression-free survival (PFS) in patients with mRCC treated with immunotherapy. Data from patients with mRCC treated with atezolizumab plus bevacizumab in the IMmotion150 and IMmotion151 trials were pooled. Cox proportional regression was used to model prognostic associations. The relative importance of CRP against International Metastatic RCC Database Consortium (IMDC) factors was confirmed using machine learning. CRPs were available from 527 patients (mean[range] CRP, 6.3[0.21–340]mg/L). Elevated CRP was significantly associated with worse OS (HR[95%CI], 1.71[1.54–1.90], p& .001) and PFS (1.27[1.18–1.35], p& .001). CRP was the most prognostic factor for survival within the available clinicopathological data. The prognostic performance of CRP was superior to IMDC model for OS (CRP c=0.76, IMDC c=0.67, p& .001) and PFS (CRP OS c=0.62, IMDC c=0.59, p=0.03). Predicted 2-year OS probabilities for patients with CRP values of 0.5, 5, 40, and 150 mg/L were 96%, 73%, 42%, and 23%, respectively. CRP is a powerful prognostic marker for survival, and its prognostic value was superior to the IMDC risk model. This study highlights that CRP could be implemented as stratification factor for mRCC immunotherapy trials and potentially as an easy-to-use prognostic tool in the clinic.
Marine bioactives: from energy to nutrition
Publisher: Elsevier BV
Date: 03-2022
DOI: 10.1016/J.TIBTECH.2021.08.004
Abstract: Microalgae have been evaluated as promising resource for biodiesel production, but algal biofuel production is not yet commercially viable, which reflects the high energy costs linked with cultivation, harvesting, and dewatering of algae. As crude oil processing declines, microalgae biorefineries are being considered for producing bioactives such as enzymes, proteins, omega-3 oils, pigments, recombinant products, and vitamins, to offset the costs of biofuel production. We believe that producing algal bioactives through advanced manufacturing pathways, encompassing a biorefinery approach, would be effective, profitable, and economical.
Personalized Medicine: Potential, Barriers and Contemporary Issues
Publisher: Bentham Science Publishers Ltd.
Date: 07-2012
DOI: 10.2174/138920012802138615
Abstract: Personalized medicine has gained significant attention over the last decade as technologies for understanding biological differences between in iduals have advanced dramatically. There are many potential benefits of personalized medicine including minimizing risk of drug toxicity, increasing benefit from drugs used, contributing to the sustainability of the healthcare system and facilitating drug discovery and development programs. Unfortunately there are also many barriers such as cost, complexity, high quality evidence requirements, and the need for further education that have limited the clinical translation of pharmacogenomic tests to date. Issues that need to be clarified are also considered, such as the regulatory evidence requirements for pharmacogenomic tests and the need for multiple pathways and for pharmacogenomic marker development. These issues surrounding personalized medicine are contextualized using three contemporary ex les of pharmacogenetic tests involving drug metabolising enzymes: UDP glucuronosyltransferase 1A1 and irinotecan toxicity, cytochrome P450 2C19 and clopidogrel efficacy, and cytochrome P450 2C9 and warfarin dosing.
The effect of molecular fields, lattice spacing and analysis options on CoMFA predictive ability
Publisher: Wiley
Date: 07-2009
Abstract: Comparative Molecular Field Analysis (CoMFA) is a popular Three‐Dimensional Quantitative Structure–Activity Relationship (3D‐QSAR) method. The effect of varying molecular fields [CoMFA vs. Comparative Molecular Similarity Indices Analysis (CoMSIA)], lattice spacing and analysis options on predictive performance was assessed based on cross validated R 2 values of 30 datasets taken from the literature. The CoMFA method results in statistically significantly higher cross validated R 2 values compared to CoMSIA when only steric and electrostatic fields are used. When the hydrophobic molecular field is included in the CoMSIA analysis (as is most commonly the case) the difference between CoMFA and CoMSIA is no longer statistically significant. Addition of hydrogen bond field does not improve CoMFA predictivity. Although there was a trend towards increased predictivity with decreased lattice spacing, this was not statistically significant. Altering the default filtering criteria and cut‐off values for Lennard Jones and Coulomb fields also did not generally result in a statistically significant effect on predictive performance.
Is there a role for routinely screening children with autism spectrum disorder for creatine deficiency syndrome?
Publisher: Wiley
Date: 29-06-2010
DOI: 10.1002/AUR.145
Abstract: Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that presents in the first three years of life. Currently, diagnosis of ASD is based on its behavioural manifestations, as laboratory diagnostic tests do not exist. Creatine deficiency syndrome (CDS) is one form of inborn error of metabolism where affected in iduals have similar clinical features to in iduals with ASD. Abnormal urinary creatine (CR) and guanidinoacetate (GAA) levels have been reported as biomarkers of CDS. We hypothesized that screening for abnormal levels of urinary CR and GAA in children with ASD may assist in identifying a subgroup of ASD in iduals who can be managed with dietary interventions. Morning urine s les were collected from children with and without autism and analyzed for CR and GAA levels. Results showed there was no statistically significant difference in urinary CR:creatinine and GAA:creatinine between the children with ASD and sibling or unrelated controls. In conclusion, routine screening for abnormal urinary CR and GAA could be considered in ASD diagnostic protocols however, in iduals positive for CDS are likely to be rare in an ASD cohort.
Global supply of health professionals [3]
Publisher: Massachusetts Medical Society
Date: 05-06-2014
DOI: 10.1056/NEJMC1404326
Cyp1a2(-/-) null mutant mice develop normally but show deficient drug metabolism.
Publisher: Proceedings of the National Academy of Sciences
Date: 20-02-1996
Abstract: Cytochrome P450 1A2 (CYP1A2) is a predominantly hepatic enzyme known to be important in the metabolism of numerous foreign chemicals of pharmacologic, toxicologic, and carcinogenic significance. CYP1A2 substrates include aflatoxin B1, acetaminophen, and a variety of environmental arylamines. To define better the developmental and metabolic functions of this enzyme, we developed a CYP1A2-deficient mouse line by homologous recombination in embryonic stem cells. Mice homozygous for the targeted Cyp1a2 gene, designated Cyp1a2(-/-), are completely viable and fertile histologic examination of 15-day embryos, newborn pups, and 3-week-old mice revealed no abnormalities. No CYP1A2 mRNA was detected by Northern blot analysis. Moreover, mRNA levels of Cyp1a1, the other gene in the same subfamily, appear unaffected by loss of the Cyp1a2 gene. Because the muscle relaxant zoxazolamine is a known substrate for CYP1A2, we studied the Cyp1a2(-/-) genotype by using the zoxazolamine paralysis test: the Cyp1a2(-/-) mice exhibited dramatically lengthened paralysis times relative to the Cyp1a2(+/+) wild-type animals, and the Cyp1a2(+/-) heterozygotes showed an intermediate effect. Availability of a viable and fertile CYP1A2-deficient mouse line will provide a valuable tool for researchers wishing to define the precise role of CYP1A2 in numerous metabolic and pharmacokinetic processes.
Cloning and expression of koala liver CYP4A (Phascolarctos cinereus)
Publisher: Elsevier BV
Date: 07-2006
DOI: 10.1016/J.GENE.2006.02.020
Abstract: In the present study, the cloning, expression and characterization of hepatic cytochrome P450 (CYP) CYP4A from koala (Phascolarctos cinereus), an obligate eucalyptus feeder, is described. It has been previously reported that microsomal lauric acid hydroxylase activity (a CYP4A marker) and CYP content were higher in koala liver in comparison to that in human, rat or wallaby, species that do not ingest eucalyptus leaves as food [Ngo, S., Kong, S., Kirlich, A., Mckinnon, R.A., Stupans, I., 2000. Cytochrome P450 4A, peroxisomal enzymes and nicotinamide cofactors in koala liver. Comp. Biochem. Physiol., C 127, 327-334]. A 1544 bp koala liver CYP4A cDNA, designated CYP4A15, was cloned by reverse transcription-polymerase chain reaction and rapid lification of cDNA ends. The koala CYP4A15 cDNA encodes a protein of 500 amino acids and shares 69% nucleotide and 65% amino acid sequence identity to human CYP4A11. Transfection of the koala CYP4A15 cDNA into Cos-7 cells resulted in the expression of a protein with lauric acid hydroxylase activity. The koala CYP4A15 cDNA-expressed enzyme catalysed lauric acid hydroxylation at the rates of 0.45+/-0.18 nmol/min/mg protein and 4.79+/-1.91 nmol/min/nmol CYP (mean+/-SD, n=3), which were comparable to that of rat CYP4A subfamilies. Total CYP content for koala CYP4A15-expressed protein in Cos-7 cells was 0.094+/-0.001 nmol/mg protein (mean+/-SD, n=3) with negligible CYP content in untransfected Cos-7 cells lysate. Immunoblot analysis, using a sheep anti-rat CYP4A polyclonal antibody, detected multiple CYP4A immunoreactive bands in the liver from all species studied. The koala bands were found to be fainter and less confined but appeared much broader as compared to rat, human and wallaby. Northern blot analysis, utilising the koala CYP4A15 cDNA 417 bp probe, detected a mRNA species of approximately 2.6 kb in the koala liver and a mRNA species of approximately 2.4 kb in other species studied. Relative to the intensity of the beta-actin mRNA species, much stronger CYP4A mRNA signal was detected for koala liver relative to rat and human. In Southern blot analysis of EcoR 1-digested genomic DNAs, using the same koala CYP4A15 cDNA probe, the size of CYP4A gene fragments observed for the koala and other species were different, suggested a different CYP4A gene organization across species. Collectively, this study provides primary molecular data regarding koala CYP4A15 gene. The possibility that there may be higher CYP4A15 expression in the koala liver could not be excluded.
PREMENSTRUAL-SYNDROME AND SPIRONOLACTONE
Publisher: Wiley
Date: 11-1991
DOI: 10.1111/J.1479-828X.1991.TB02824.X
Abstract: A double blind placebo controlled randomized cross over study was conducted to assess the response to spironolactone by patients suffering from 'Premenstrual Syndrome'. Somatic and neuropsychiatric symptoms were self-assessed daily and a total score was calculated for each symptom for the 14 days prior to menstruation. No significant difference was noted for the symptoms assessed on or off spironolactone. The levels of oestradiol, progesterone and prolactin showed no changes from the first to the second half of the cycle. In those patients who did respond to spironolactone, a significant difference in androgen levels from the follicular to the luteal phase of the cycle prior to treatment was demonstrated. Significant differences in androgen levels from the follicular to the luteal phase of the menstrual cycle may therefore be an important determinant in predicting those patients with premenstrual syndrome likely to respond to spironolactone therapy.
Predicting Human Drug Glucuronidation Parameters: Application of In Vitro and In Silico Modeling Approaches
Publisher: Annual Reviews
Date: 10-02-2004
DOI: 10.1146/ANNUREV.PHARMTOX.44.101802.121546
Abstract: Cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT), which both exist as enzyme “superfamilies,” are together responsible for the metabolism of most hepatically cleared drugs. There is currently intense interest in the development of techniques that permit identification of the CYP and UGT isoform(s) involved in the metabolism of a newly discovered drug, and hence prediction of factors likely to alter elimination in vivo. In addition, the quantitative scaling of kinetic parameters for a metabolic pathway assumes importance for identifying newly discovered drugs with undesirable in vivo pharmacokinetic properties. Although qualitative and quantitative in vitro–in vivo correlation based on data generated using human liver tissue or recombinant enzymes have been applied successfully to many drugs eliminated by CYP, these strategies have proved less definitive for glucuronidated compounds. Computational (in silico) modeling techniques that potentially provide a facile and economic alternative to the in vitro methods are now emerging. This review assesses the utility of in vitro and in silico approaches for the qualitative and quantitative prediction of drug glucuronidation parameters and the challenges facing the development of generalizable models.
Anti-inflammatory diterpenoids and other secondary metabolites from Dodonaea polyandra; a traditional medicine used by Kaanju people in North Eastern Australia
Publisher: Georg Thieme Verlag KG
Date: 24-08-2010
The Expression Profiles and Deregulation of UDP-Glycosyltransferase (UGT) Genes in Human Cancers and Their Association with Clinical Outcomes
Publisher: MDPI AG
Date: 06-09-2021
Abstract: The human UDP-glycosyltransferase (UGTs) superfamily has 22 functional enzymes that play a critical role in the metabolism of small lipophilic compounds, including carcinogens, drugs, steroids, lipids, fatty acids, and bile acids. The expression profiles of UGT genes in human cancers and their impact on cancer patient survival remains to be systematically investigated. In the present study, a comprehensive analysis of the RNAseq and clinical datasets of 9514 patients from 33 different TCGA (the Genome Cancer Atlas) cancers demonstrated cancer-specific UGT expression profiles with high interin idual variability among and within in idual cancers. Notably, cancers derived from drug metabolizing tissues (liver, kidney, gut, pancreas) expressed the largest number of UGT genes (COAD, KIRC, KIRP, LIHC, PAAD) six UGT genes (1A6, 1A9, 1A10, 2A3, 2B7, UGT8) showed high expression in five or more different cancers. Kaplan–Meier plots and logrank tests revealed that six UGT genes were significantly associated with increased overall survival (OS) rates [UGT1A1 (LUSC), UGT1A6 (ACC), UGT1A7 (ACC), UGT2A3 (KIRC), UGT2B15 (BLCA, SKCM)] or decreased OS rates [UGT2B15 (LGG), UGT8 (UVM)] in specific cancers. Finally, differential expression analysis of 611 patients from 12 TCGA cancers identified 16 UGT genes (1A1, 1A3, 1A6, 1A7, 1A8, 1A9, 1A10, 2A1, 2A3, 2B4, 2B7, 2B11, 2B15, 3A1, 3A2, UGT8) that were up/downregulated in at least one cancer relative to normal tissues. In conclusion, our data show widespread expression of UGT genes in cancers, highlighting the capacity for intratumoural drug metabolism through the UGT conjugation pathway. The data also suggests the potentials for specific UGT genes to serve as prognostic biomarkers or therapeutic targets in cancers.
The predictive utility of patient-reported outcomes and performance status for survival in metastatic lung cancer patients treated with chemoimmunotherapy
Publisher: AME Publishing Company
Date: 03-2022
DOI: 10.21037/TLCR-21-938
Cytochrome P450 4A, peroxisomal enzymes and nicotinamide cofactors in koala liver
Publisher: Elsevier BV
Date: 12-2000
DOI: 10.1016/S0742-8413(00)00160-2
Abstract: We have examined hepatic levels of microsomal lauric acid hydroxylase activity and cyanide-insensitive palmitoyl coenzyme A oxidative activity in koala (Phascolarctos cinereus) and tammar wallaby (Macropus eugenii) and compared our results to those determined in rat. Microsomal lauric acid hydroxylation was significantly higher in koala than in tammar wallaby or rat. However, cyanide-insensitive palmitoyl-CoA oxidation was absent in the koala. We have also determined the hepatic nicotinamide cofactors in these species. Hepatic nicotinamide-adenine dinucleotide (NAD) and the ratio of NAD/nicotinamide-adenine dinucleotide phosphate (NADP) were higher in koala than in tammar wallaby and rat liver. Reverse transcription of koala liver mRNA, followed by polymerase chain reaction using primers based on highly conserved areas in the CYP4A family led to the cloning of a partial, near full length, cDNA clone with approximately 70% nucleotide and deduced amino acid sequence identity to human CYP4A11. The CYP has been named CYP4A15.
Early Adverse Events predict Survival Outcomes in HER2-positive Advanced Breast Cancer Patients treated with Lapatinib plus Capecitabine
Publisher: Ivyspring International Publisher
Date: 2020
DOI: 10.7150/JCA.41996
Meta-analysis comparing the efficacy of anti-EGFR monoclonal antibody therapy between KRAS G13D and other KRAS mutant metastatic colorectal cancer tumours
Publisher: Elsevier BV
Date: 03-2016
DOI: 10.1016/J.EJCA.2015.11.025
Abstract: Metastatic colorectal cancer (mCRC) tumours harbouring a RAS mutation are associated with a lack of treatment benefit from anti-EGFR monoclonal antibodies (mAbs). However, observational evidence has led to speculation that mCRC patients with KRAS G13D mutant (MT) tumours may derive a benefit from treatment with anti-EGFR mAbs. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate whether the efficacy of anti-EGFR mAbs for mCRC differs between tumours harbouring a KRAS G13D mutation (KRAS G13D) and KRAS mutations other than G13D (other KRAS MT). Eight RCTs (n = 5967) met the inclusion criteria for assessment of both overall survival (OS) and progression-free survival (PFS). For other KRAS MT the hazard ratio for OS benefit with addition of anti-EGFR mAb therapy was 1.06 (95% confidence interval [CI] 0.96, 1.17), compared to 1.08 (95% CI 0.73, 1.60) for KRAS G13D [test for interaction p=0.99]. In contrast, the hazard ratio for KRAS wild-type (WT) tumours was 0.85 (95% CI 0.76, 0.95). Regarding PFS benefit with anti-EGFR mAbs, the hazard ratio was 1.07 (95% CI 0.92, 1.26) for other KRAS MT, 0.96 (95% CI 0.73, 1.27) for KRAS G13D, and 0.68 (95% CI 0.54, 0.85) for KRAS WT. Again, the test for interaction (p=0.46) demonstrated no significant difference in PFS benefit for anti-EGFR mAb therapy between KRAS G13D and other KRAS MT. This meta-analysis demonstrates no significant difference between KRAS G13D and other KRAS MT tumours in terms of treatment benefit from anti-EGFR mAbs for mCRC.
Role of CYP2A5 and 2G1 in Acetaminophen Metabolism and Toxicity in the Olfactory Mucosa of the Cyp1a2(−/−)Mouse
Publisher: Elsevier BV
Date: 06-1998
DOI: 10.1016/S0006-2952(98)00004-5
Abstract: Acetaminophen (AP) is a widely-used analgesic agent that has been linked to human liver and kidney disease with prolonged or high-dose usage. In rodents, the target organs that are affected include liver, kidney, and the olfactory mucosa. AP toxicity requires cytochrome P450(CYP)-mediated metabolic activation, and the isozymes CYP1A2, 2E1, and 3A are known to activate AP in the human. In the present study, we determined that olfactory mucosal toxicity of AP was not different between the Cyp1a2(+/+) wild-type and the Cyp1a2(-/-) knockout mouse, whereas the hepatic toxicity of AP was significantly diminished in Cyp1a2(-/-) mice. Western blots of olfactory mucosa revealed that CYP2E1 and CYP3A levels are similar between untreated Cyp1a2(+/+) and Cyp1a2(-/-) mice. Diallyl sulfide (DAS), a known inhibitor of CYP2E1 and of CYP2A10/2A11 (the rabbit orthologue of mouse CYP2A5), completely eliminated olfactory toxicity of AP in both the Cyp1a2(-/-) and wild-type mouse olfactory mucosa. We found that heterologously expressed mouse CYP2A5 and CYP2G1 enzymes (known to be present in olfactory mucosa) form 3-hydroxyacetaminophen (3-OH-AP) and 3-(glutathion-S-yl)acetaminophen (GS-AP) CYP2A5 is considerably more active than 2G1. Addition of GSH caused increases in GS-AP proportional to decreases in 3-OH-AP, suggesting that these two metabolites arise from a common precursor or are formed by way of competing pathways. We also found that both CYP2A5 and CYP2G1 are inhibitable by DAS in vitro. These studies provide strong evidence that, in addition to CYP2E1, CYP2A5 and 2G1 are important in AP bioactivation in the mouse olfactory mucosa and that CYP1A2 appears to be of minor importance for AP olfactory toxicity.
Pharmacogenomics and Personalised Medicine: Consumer Perspectives, Lessons Learned in Australia and Beyond
Publisher: Bentham Science Publishers Ltd.
Date: 05-2012
LOCALIZATION OF CYP1A1 AND CYP1A2 MESSENGER-RNA IN NORMAL HUMAN LIVER AND IN HEPATOCELLULAR-CARCINOMA BY INSITU HYBRIDIZATION
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-1991
Abstract: To better characterize the precise cellular distribution of CYP1A gene products in man, we have undertaken Northern-blot and in situ hybridization analyses of CYP1A expression in human liver. Using riboprobes transcribed from both CYP1A1 and CYP1A2 complementary DNAs to probe a series of Northern blots of 23 human liver messenger RNA s les, CYP1A1 expression was demonstrated in 11 s les and CYP1A2 expression was evident in 22 s les. The level of expression of both CYP1A enzymes in these livers demonstrated marked variability. The CYP1A1 and CYP1A2 riboprobes were then used for in situ hybridization localization of CYP1A1/1A2 messenger RNA sequences on paraffin-embedded, formalin-fixed human liver sections. These studies demonstrated that both CYP1A1 and CYP1A2 messenger RNAs are distributed nonuniformly across the human liver acinus, with levels highest in hepatocytes surrounding terminal hepatic venules and intercalated veins. Immunohistochemistry with an anti-rabbit CYP1A1 serum demonstrated a corresponding distribution for the translated CYP1A proteins. In situ hybridization analysis was also performed on sections of hepatocellular carcinoma, demonstrating a significant down-regulation in CYP1A expression. Functional studies using the activation of the food-derived heterocyclic amine MeIQ (2-amino-3,4-dimethylimadazo [4,5-f] quinoline) to a mutagen in the Ames test as an indicator of CYP1A expression confirmed this down-regulation. These results demonstrate heterogeneity of hepatic CYP1A expression both between in iduals and in different acinar zones. This variation in expression may be of significance in assessing cell specific toxicities of various drugs and carcinogens.
Generic substitution in the treatment of epilepsy: patient attitudes and perceptions
Publisher: Elsevier BV
Date: 2013
DOI: 10.1016/J.YEBEH.2012.10.032
Abstract: There have been considerable debates about bioequivalence and generic substitution of certain critical care drugs. We aimed to understand patient attitudes and perceptions about generic substitution in the treatment of epilepsy. In this pilot study, a self-administered anonymous survey was completed by 47 patients with epilepsy. The response rate by postal mail was 6.7%. More than 70% of the patients were concerned about the effectiveness of generic antiepileptic drugs, and 68% of the patients were not comfortable receiving generics to treat their epilepsy. About 87% of the patients thought that their antiepileptic drug should only be substituted with a generic with their consent, and 64% of the patients believed that substitution should only take place with the consent of their doctor. Considerable concern exists among patients about generic substitution in the treatment of epilepsy. More data regarding whether generic antiepileptic drugs are bioequivalent in clinical situations would help to address patient concerns.
Evaluation of the anti-inflammatory properties of Dodonaea polyandra, a Kaanju traditional medicine
Publisher: Elsevier BV
Date: 10-2010
DOI: 10.1016/J.JEP.2010.07.012
Abstract: Extracts of the medicinal plant species Dodonaea polyandra were investigated as part of a collegial research partnership between Northern Kaanju traditional owners represented by Chuulangun Aboriginal Corporation (centred on the Wenlock and Pascoe Rivers, Cape York Peninsula, Queensland, Australia) and university-based researchers. D. polyandra, known as "Uncha" in Kaanju language, is used in Northern Kaanju Traditional Medicine for relief from pain associated with toothache and related ailments. The species has a restricted distribution in Cape York Peninsula and there has been no previous Western scientific investigation of its pharmacology or chemistry. The current study investigates the anti-inflammatory effects of several extracts from D. polyandra. Phytochemical screening was conducted using TLC. Anti-inflammatory effects of leaf extracts were determined using an acute mouse ear oedema model induced by croton oil and 12-o-tetradecanoylphorbol-13-acetate (TPA) chemical irritants. Flavonoid and terpenoid secondary compounds were detected in leaf extracts of D. polyandra. Non-polar hexane and methylene chloride/methanol extracts showed potent inhibition of inflammation in TPA-induced mouse ear oedema by 72.12 and 79.81%, respectively, after 24 h at 0.4 mg/ear. In a mouse model of acute inflammation, this study revealed that leaf extracts of D. polyandra possess significant anti-inflammatory potential. These results contribute to a Western scientific understanding of the ethnopharmacological use of the plant in Northern Kaanju Medicine for reducing tooth-related pain.
CPPM 2013 Onward: Building a Socio-Technical GPS for Global Personalized Medicine - A Welcome to Editors-In-Chief Adrián LLerena (Spain) and Ross A. McKinnon (Australia)
Publisher: Bentham Science Publishers Ltd.
Date: 05-2013
Integrative transcriptomic network analysis of butyrate treated colorectal cancer cells
Publisher: MDPI AG
Date: 05-02-2021
Abstract: Diet-derived histone deacetylase inhibitor (HDACi), butyrate, alters global acetylation and consequently global gene expression in colorectal cancer (CRC) cells to exert its anticancer effects. Aberrant microRNA (miRNA) expression contributes to CRC development and progression. Butyrate-mediated modulation of microRNA (miRNA) expression remains under-investigated. This study employed a systems biology approach to gain a comprehensive understanding of the complex miRNA-mRNA interactions contributing to the butyrate response in CRC cells. Next-generation sequencing, gene ontology (GO) and pathway enrichment analyses were utilized to reveal the extent of butyrate-mediated gene regulation in CRC cells. Changes in cell proliferation, apoptosis, the cell cycle and gene expression induced by miRNAs and target gene knockdown in CRC cells were assessed. Butyrate induced differential expression of 113 miRNAs and 2447 protein-coding genes in HCT116 cells. Butyrate also altered transcript splicing of 1589 protein-coding genes. GO, and pathway enrichment analyses revealed the cell cycle to be a central target of the butyrate response. Two butyrate-induced miRNAs, miR-139 and miR-542, acted cooperatively with butyrate to induce apoptosis and reduce CRC cell proliferation by regulating target genes, including cell cycle-related EIF4G2 and BIRC5. EIF4G2 RNA interference mimicked the miR-139-mediated reduction in cell proliferation. The cell cycle is a critical pathway involved in the butyrate response of CRC cells. These findings reveal novel roles for miRNAs in the cell cycle-related, anticancer effects of butyrate in CRC cells.
Intergenic Splicing between Four Adjacent UGT Genes (2B15, 2B29P2, 2B17, 2B29P1) Gives Rise to Variant UGT Proteins That Inhibit Glucuronidation via Protein-Protein Interactions
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 29-06-2018
Abstract: Recent studies have investigated alternative splicing profiles of UDP-glucuronosyltransferase
Down-regulation of metabolic pathways could offset the poor prognosis conferred by co-existent diabetes mellitus in pancreatic (head) adenocarcinoma
Publisher: Wiley
Date: 13-09-2021
DOI: 10.1111/ANS.17194
Abstract: Pancreatic ductal adenocarcinoma (PDAC) patients with diabetes mellitus (DM) have poor overall survival. Underlying mechanisms have not been fully clarified. This presents an opportunity for precision‐oncology for which we systematically analysed publicly‐available PDAC transcriptome data. PDAC TCGA RNASeq data were used. Analyses were restricted to only ‘high purity’ and ‘head’ as anatomical site. Patients were characterised by: (1) Gene expression classification, and (2) Weighted gene correlation network analysis (WGCNA) to identify co‐expression patterns of genes. Newly identified gene signature subclasses of pancreatic head PDAC were associated with clinical and functional characteristics of patients. Consensus clustering identified two patient subclasses within PDAC involving pancreatic head. WGCNA identified 11 distinct networks of gene expression patterns across two sub‐classes. Class 1 patients demonstrated a significant upregulation of Module 5 and Module 6 gene expression compared to Class 2. Class 1 predominantly expressed the acinar, ductal and islet cell gene signatures. There were significantly less patients with DM in Class 1 subclass compared to Class 2 ( p 0.037). Patients with DM had significant downregulation of pathways involved in cellular metabolism, hormone secretion and paucity of islet cell markers with no reduced survival compared with non‐diabetics. A significant proportion of patients with PDAC of pancreatic head and DM exhibit downregulation of pathways involved in cellular metabolism, hormone secretion and signalling accompanied by a paucity of islet expression. Investigating the relationship between DM and gene expression profiles in patients with PDAC presents opportunities to improve overall survival in diabetics with PDAC.
Is urinary indolyl-3-acryloylglycine a biomarker for autism with gastrointestinal symptoms?
Publisher: Informa UK Limited
Date: 12-2009
DOI: 10.3109/13547500903183962
Abstract: An autism spectrum disorder (ASD) diagnosis is based on clinical behaviours as there are no validated biological diagnostic tools. Indolyl-3-acryloylglycine (IAG) is a chemical produced by gut microflora and there are conflicting reports as to whether urinary levels are elevated in children with ASD compared with controls. Urinary IAG levels in morning urine s les were statistically significantly higher in children with ASD whose caregivers reported the presence of chronic gastrointestinal (GI) disturbance than children with ASD without chronic GI disturbance. Urinary IAG, however, was not statistically significantly higher in children with ASD, compared with siblings or unrelated controls without ASD.
Antiproliferative Aporphine Alkaloids from Litsea glutinosa and Ethnopharmacological Relevance to Kuuku I’yu Traditional Medicine
Publisher: CSIRO Publishing
Date: 2015
DOI: 10.1071/CH15456
Abstract: Australian Aboriginal people have a long history of relying on plants for the treatment of various ailments and illnesses. Our ongoing collaborative research project initiated by Chuulangun Aboriginal Corporation (Cape York, Australia) has recently focussed on revealing whether Kuuku I’yu plant medicines possess anticancer-related activities and the chemistry responsible for this. Here, we present results from a study of the plant Litsea glutinosa, used traditionally for the treatment of gastrointestinal disorders. Four known aporphine alkaloids N-methylactinodaphnine (1), boldine (2), N-methyllaurotetanine (3), and isoboldine (4) were isolated by activity-guided fractionation and tested for cytotoxicity against HT29, SKMEL28, and primary human keratinocytes. Compound 1 was the most cytotoxic and this observation may be explained by the presence of a 1,2-methylenedioxy group. In silico docking revealed that a plausible mechanism for the observed cytotoxicity is the stabilization of a topoisomerase II (β) DNA–enzyme complex. The ethnopharmacological relevance of this study is discussed in the context of researching and using traditional knowledge in biomolecular discovery.
An Overview of Current Regulatory Requirements for Approval of Biosimilar Insulins
Publisher: Mary Ann Liebert Inc
Date: 07-2015
Manipulation of the gut microbiota using resistant starch is associated with protection against colitis-associated colorectal cancer in rats
Publisher: Oxford University Press (OUP)
Date: 19-02-2016
Abstract: This study evaluated whether dietary resistant starch (RS) and green tea extract (GTE), which have anti-inflammatory and anticancer properties, protect against colitis-associated colorectal cancer (CAC) using a rat model, also investigated potential mechanisms of action of these agents including their effects on the gut microbiota. Rats were fed a control diet or diets containing 10% RS, 0.5% GTE or a combination of the two (RS + GTE). CAC was initiated with 2 weekly azoxymethane (AOM) injections (10mg/kg) followed by 2% dextran sodium sulphate in drinking water for 7 days after 2 weeks on diets. Rats were killed 20 weeks after the first AOM. Colon tissues and tumours were examined for histopathology by H&E, gene rotein expression by PCR and immunohistochemistry and digesta for analyses of fermentation products and microbiota populations. RS and RS + GTE (but not GTE) diets significantly (P< 0.05) decreased tumour multiplicity and adenocarcinoma formation, relative to the control diet. Effects of RS + GTE were not different from RS alone. RS diet caused significant shifts in microbial composition/ ersity, with increases in Parabacteroides, Barnesiella, Ruminococcus, Marvinbryantia and Bifidobacterium as primary contributors to the shift. RS-containing diets increased short chain fatty acids (SCFA) and expression of the SCFA receptor GPR43 mRNA, and reduced inflammation (COX-2, NF-kB, TNF-α and IL-1β mRNA) and cell proliferation P< 0.05. GTE had no effect. This is the first study that demonstrates chemopreventive effects of RS (but not GTE) in a rodent CAC model, suggesting RS might have benefit to patients with ulcerative colitis who are at an increased risk of developing CRC.
Sustained improvement in vancomycin dosing and monitoring post-implementation of guidelines: Results of a three-year follow-up after a multifaceted intervention in an Australian teaching hospital.
Publisher: Elsevier BV
Date: 02-2017
DOI: 10.1016/J.JIAC.2017.09.010
Abstract: Despite vancomycin being in use for over half-a-century, it is still not dosed or monitored appropriately in many centers around the world. The objective of this study was to determine the effectiveness of a multifaceted intervention to implement a vancomycin dosing and monitoring guideline across multiple medical and surgical units over time. This was an observational before-and-after interventional cohort study. The pre-intervention period was August to December 2010-2011 and the post-intervention period was September to November 2012-2014. The implementation strategy comprised: face-to-face education, online continuing medical education, dissemination of pocket guideline and email reminder. Outcome measures included: appropriate prescribing of loading and maintenance doses, therapeutic drug monitoring, time to attain target range and nephrotoxicity. Post-implementation prescribing of loading doses increased (10.4%-43.6%, P=<0.001), guideline adherent first maintenance dose (44%-68.4% P = 0.04), correct dose adjustment from (53.1%-72.2%, P = 0.009). Beneficial effects pre and post-implementation were observed for adherent timing of initial concentration (43.2%-51.9%, P = 0.01), concentrations in target range (32.6%-44.1%, P = 0.001), time to target range (median 6-4 days, P=<0.001), potentially nephrotoxic concentrations (30.7%-20.9%, P=<0.001) and nephrotoxicity (10.4%-6.8%, P=<0.001). A multifaceted intervention to implement a vancomycin dosing and monitoring guideline significantly improved prescribing, monitoring, pharmacokinetic and safety outcomes for patients treated with vancomycin over an extended period. However, increased guideline adoption by clinicians is required to maximize and prolong the utility of this important agent.
Transcriptional regulation of human UDP-glucuronosyltransferase genes
Publisher: Informa UK Limited
Date: 22-10-2014
DOI: 10.3109/03602532.2014.973037
Abstract: Glucuronidation is an important metabolic pathway for many small endogenous and exogenous lipophilic compounds, including bilirubin, steroid hormones, bile acids, carcinogens and therapeutic drugs. Glucuronidation is primarily catalyzed by the UDP-glucuronosyltransferase (UGT) 1A and two subfamilies, including nine functional UGT1A enzymes (1A1, 1A3-1A10) and 10 functional UGT2 enzymes (2A1, 2A2, 2A3, 2B4, 2B7, 2B10, 2B11, 2B15, 2B17 and 2B28). Most UGTs are expressed in the liver and this expression relates to the major role of hepatic glucuronidation in systemic clearance of toxic lipophilic compounds. Hepatic glucuronidation activity protects the body from chemical insults and governs the therapeutic efficacy of drugs that are inactivated by UGTs. UGT mRNAs have also been detected in over 20 extrahepatic tissues with a unique complement of UGT mRNAs seen in almost every tissue. This extrahepatic glucuronidation activity helps to maintain homeostasis and hence regulates biological activity of endogenous molecules that are primarily inactivated by UGTs. Deciphering the molecular mechanisms underlying tissue-specific UGT expression has been the subject of a large number of studies over the last two decades. These studies have shown that the constitutive and inducible expression of UGTs is primarily regulated by tissue-specific and ligand-activated transcription factors (TFs) via their binding to cis-regulatory elements (CREs) in UGT promoters and enhancers. This review first briefly summarizes published UGT gene transcriptional studies and the experimental models and tools utilized in these studies, and then describes in detail the TFs and their respective CREs that have been identified in the promoters and/or enhancers of in idual UGT genes.
Human thiopurine methyltransferase: No evidence of activation by its substrates
Publisher: Elsevier BV
Date: 12-1997
DOI: 10.1016/S0024-3205(97)01116-8
Abstract: A HPLC assay was developed to assay baculovirus expressed human thiopurine methyltransferase activity. Using 6-mercaptopurine as substrate, the expressed thiopurine methyltransferase was found to have an apparent Km of 0.99 mM and a Vmax of 19 nmoles/mg/min. These values are in agreement with those determined using the standard radiometric assay for thiopurine methyltransferase activity. The effects of 6-thioguanine on 6-mercaptopurine metabolism were determined. 6-Thioguanine was found to be a mixed inhibitor of 6-mercaptopurine methylation.
Breaking the Silos: Integrated Care for Cancer and Chronic Conditions
Publisher: Springer Singapore
Date: 2016
Rare, seven-membered cyclic ether labdane diterpenoid from Dodonaea polyandra
Publisher: Elsevier BV
Date: 12-2012
DOI: 10.1016/J.PHYTOCHEM.2012.07.016
Abstract: Previous phytochemical studies on the leaf resin of dioecious plant species Dodonaea polyandra have identified the presence of furanoclerodane diterpenoids. As part of ongoing research on this species the chemical profile of an in idual plant displaying male flowers was investigated. Repeated chromatographic separation of a resinous extract from the leaves of the plant yielded three labdane diterpenoids, 13,17-epoxy-13-methyl-15-oxo-labda-7-ene (1), 17-hydroxy-13-methyl-labda-7,13Z-diene-15-oic acid (2) and 13-methyl-17-oxo-labda-7,13Z-diene-15-oic acid (3) and a fourth known labdane diterpenoid (4) reported as being isolated from a natural source for the first time. Structural elucidation was carried out using conventional 1D and 2D NMR and mass spectrometry together with other complementary techniques (UV and IR). The leaf extract from this in idual of D. polyandra with male flowers present displays a marked difference in the chemical composition of diterpenoids compared to previously studied extracts from the leaves of this species.
Patient-reported outcomes predict survival and adverse events following anticancer treatment initiation in advanced HER2-positive breast cancer
Publisher: Elsevier BV
Date: 06-2022
Flavonoids from the leaves and stems of Dodonaea polyandra: A Northern Kaanju medicinal plant
Publisher: Elsevier BV
Date: 10-2011
DOI: 10.1016/J.PHYTOCHEM.2011.05.006
Abstract: Three prenylated flavonoids 5,7,4'-trihydroxy-3'(3-methylbut-2-enyl)-3-methoxy flavone, 5,7-dihydroxy-3'(3-methylbut-2-enyl)-3,4'-dimethoxy flavone and 5,7,4'-trihydroxy-3',5'(3-methylbuyt-2-enyl)-3-methoxy flavone together with three other known flavonoids were isolated from the medicinal plant Dodonaea polyandra. The plant is used in the traditional medicine system of Northern Kaanju people of Cape York Peninsula, Queensland, Australia. The extracts studied have previously been found to possess anti-inflammatory activity. Successive fractionation of leaf and stem extracts by column and high performance liquid chromatography led to the isolation of these compounds. Their structures were determined using a number of spectroscopic techniques including 1D and 2D NMR and high resolution mass spectroscopy. The structural elucidation is reported herein accompanied by full ¹H and ¹³C NMR spectroscopic data. Spectroscopic data of known compounds was in agreement with that previously reported in literature.
Learning from both sides: Experiences and opportunities in the investigation of Australian aboriginal medicinal plants
Publisher: Frontiers Media SA
Date: 11-06-2013
DOI: 10.18433/J31S4Q
Abstract: With one of the oldest surviving cultures in the world, Australian Aboriginal people have developed immense knowledge about the erse Australian flora. Western scientific investigation of some Australian Aboriginal medicinal plants has demonstrated interesting pharmacological activities and chemistry, however the majority of these species have not yet been extensively examined. We argue that research that is locally initiated and driven by Indigenous traditional owners in collaboration with Western scientists has significant potential to develop new plant-based products. Locally driven medicinal plants research in which traditional owners work as researchers in collaboration with University-based colleagues in the investigation of medicines rather than “stakeholders” or “informants” is one model that may be used in characterising plants with the potential to be developed into sustainable plant-based medicinal products with commercial value. Our team has taken this approach in research located both on traditional homelands and in the laboratory. Research being conducted by the University of South Australia and Chuulangun Aboriginal Corporation has led to patent filing for protection of intellectual property associated with novel compounds and extracts with the potential for development through cosmetic, complementary medicine and pharmaceutical routes. Ongoing research is examining the commercial developmental pathways and requirements for product development in these spaces. This review will address the opportunities that might exist for working in partnership with Australian Indigenous communities, some of the scientific knowledge which has been generated so far from our work together and the lessons learnt since the inception of the collaboration between the Chuulangun Aboriginal Corporation and scientists from the University of South Australia. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
Pulmonary cytochrome P450 enzymes belonging to the CYP4B subfamily from an Australian marsupial, the tammar wallaby (Macropus eugenii)
Publisher: Elsevier BV
Date: 2011
DOI: 10.1016/J.CBPC.2010.08.006
Abstract: Cytochromes P450 (CYPs) are critically important in the oxidative metabolism of a erse array of xenobiotics and endogenous substrates. We have previously reported the cloning and characterisation of the koala CYP4A15, the first reported member of the CYP4 family from marsupials, and have demonstrated important species differences in CYP4A activity and tissue expression. In the present study, the cloning of CYP4B1 in the wallaby (Macropus eugenii) and their expression across marsupials is described. Rabbit anti-mouse CYP4B1 antibody detected immunoreactive proteins in lung and liver microsomes from all test marsupials, with relative weak signal detected from the koala, suggesting a species-specific expression. Microsomal 2-aminofluorene bio-activation (a CYP4B1 marker) in wallaby lung was comparable to that of rabbit, with significant higher activities detected in wallaby liver and kidneys compared to rabbit. A 1548bp wallaby lung CYP4B complete cDNA, designated CYP4B1, which encodes a protein of 510 amino acids and shares 72% nucleotide and 69% amino acid sequence identity to human CYP4B1, was cloned by polymerase chain reaction approaches. The results demonstrate the presence of wallaby CYP4B1 that shares several common features with other published CYP4Bs however the wallaby CYP4B1 cDNA contains four extra amino acid residues at the NH₂-terminal, a fundamentally conserved transmembrane anchor of all eukaryote CYPs.
AAPS–FIP Summary Workshop Report: Pharmacogenetics in Individualized Medicine: Methods, Regulatory, and Clinical Applications
Publisher: Springer Science and Business Media LLC
Date: 25-03-2009
Optimizing bacterial expression of catalytically active human cytochromes P450: comparison of CYP2C8 and CYP2C9
Publisher: Informa UK Limited
Date: 2004
Cytochrome P450 CYP3A in marsupials: cloning and identification of the first CYP3A subfamily member, isoform 3A70 from Eastern gray kangaroo (Macropus giganteus)
Publisher: Elsevier BV
Date: 09-2012
DOI: 10.1016/J.GENE.2012.06.024
Abstract: Australian marsupials are unique fauna that have evolved and adapted to unique environments and thus it is likely that their detoxification systems differ considerably from those of well-studied eutherian mammals. Knowledge of these processes in marsupials is therefore vital to understanding the consequences of exposure to xenobiotics. Cytochromes P450 (CYPs) are critically important in the oxidative metabolism of a erse array of both xenobiotics and endogenous substrates. In this study we have cloned and characterized CYP3A70, the first identified member of the CYP3A gene subfamily from Eastern gray kangaroo (Macropus giganteus). A 1665 base pair kangaroo hepatic CYP3A complete cDNA, designated CYP3A70, was cloned by reverse transcription-polymerase chain reaction approaches, which encodes a protein of 506 amino acids. The CYP3A70 cDNA shares approximately 71% nucleotide and 65% amino acid sequence homology to human CYP3A4 and displays high sequence similarity to other published mammalian CYP3As from human, monkey, cow, pig, dog, rat, rabbit, mouse, hamster, and guinea pig. Transfection of the CYP3A70 cDNAs into 293T cells resulted in stable cell lines expressing a CYP3A immuno-reactive protein that was recognized by a goat anti-human CYP3A4 polyclonal antibody. The anti-human CYP3A4 antibody also detected immunoreactive proteins in liver microsomes from all test marsupials, including the kangaroo, koala, wallaby, and wombat, with multiple CYP3A immunoreactive bands observed in kangaroo and wallaby tissues. Relatively, very low CYP catalytic activity was detected for the kangaroo CYP3A70 cDNA-expressed proteins (19.6 relative luminescent units/μg protein), which may be due to low protein expression levels. Collectively, this study provides primary molecular data regarding the Eastern kangaroo hepatic CYP3A70 gene and enables further functional analyses of CYP3A enzymes in marsupials.
Recent Advances in the In Silico Modelling of UDP Glucuronosyltransferase Substrates
Publisher: Bentham Science Publishers Ltd.
Date: 2008
DOI: 10.2174/138920008783331167
Abstract: UDP glucurononosyltransferases (UGT) are a superfamily of enzymes that catalyse the conjugation of a range of structurally erse drugs, environmental and endogenous chemicals with glucuronic acid. This process plays a significant role in the clearance and detoxification of many chemicals. Over the last decade the regulation and substrate profiles of UGT isoforms have been increasingly characterised. The resulting data has facilitated the prototyping of ligand based in silico models capable of predicting, and gaining insights into, binding affinity and the substrate- and regio- selectivity of glucuronidation by UGT isoforms. Pharmacophore modelling has produced particularly insightful models and quantitative structure-activity relationships based on machine learning algorithms result in accurate predictions. Simple structural chemical descriptors were found to capture much of the chemical information relevant to UGT metabolism. However, quantum chemical properties of molecules and the nucleophilic atoms in the molecule can enhance both the predictivity and chemical intuitiveness of structure-activity models. Chemical ersity analysis of known substrates has shown some bias towards chemicals with aromatic and aliphatic hydroxyl groups. Future progress in in silico development will depend on larger and more erse high quality metabolic datasets. Furthermore, improved protein structure data on UGTs will enable the application of structural modelling techniques likely leading to greater insight into the binding and reactive processes of UGT catalysed glucuronidation.
Induction of Cytochrome P450 CYP3A by St John's Wort in the Rat Liver and Intestine
Publisher: SAGE Publications
Date: 2007
DOI: 10.1177/117863370700200008
Abstract: It has been well reported that complementary medicines can significantly alter the way the body handles conventional drugs, leading to potential fatal herb-drug interactions. The aim of the present study was to investigate the molecular mechanism of drug interactions involving St John's wort (SJW) (Hypericum perforatum L), a popular herbal medicine widely used for depression, particularly examining changes in the expression of cytochrome P450 CYP3A, the most abundant drug metabolising CYP enzymes in man. Eighteen Sprague-Dawley (SD) rats were assigned randomly into 3 groups (n = 6/group): control, low dose and high dose (500 and 1000 mg/kg/day of SJW, equal to 1500 and 3000 µg/kg/day of Hypericin). Each group was treated with SJW or control preparation, by gastric gavage, for 14 consecutive days. Liver and intestinal CYP3A activity and protein and mRNA levels, from five segments of the intestine, were examined using CYP3A-dependent erythromycin N-demethylation activity assay, quantitative immuno-blotting and real-time RT-PCR. Increase in CYP3A activity and protein level by SJW was observed in some intestinal regions, with a 3.0 fold increase in liver CYP3A activity and a 10.6 fold increase in liver CYP3A1 mRNA (p 0.05) in a dose dependent manner. The results suggested that up regulation of liver CYP3A mRNA and differential induction of intestinal CYP3A play an important role in the molecular mechanism of herb-drug interactions.
Genetic polymorphisms of human UDP-glucuronosyltransferase (UGT) genes and cancer risk
Publisher: Informa UK Limited
Date: 02-01-2016
DOI: 10.3109/03602532.2015.1131292
Abstract: Identification of genetic polymorphisms that contribute to the risk of developing cancers is important for cancer prevention. The most recent human genome GRCh38/hg38 assembly (2013) reveals thousands of genetic polymorphisms in human uridine diphosphoglucuronosyltransferase (UGT) genes. Among these, a large number of polymorphisms at the UGT1A and UGT2B genes have been shown to modulate UGT gene promoter activity or enzymatic activity. Glucuronidation plays an important role in the metabolism and clearance of endogenous and exogenous carcinogenic compounds, and this reaction is primarily catalyzed by the UGT1A and UGT2B enzymes. Therefore, it has long been hypothesized that UGT polymorphisms that reduce the capacity to glucuronidate carcinogens and other types of cancer-promoting molecules (e.g. sex hormones) are associated with an increased risk of developing cancers. A large number of case-control studies have investigated this hypothesis and these studies identified numerous UGT polymorphisms in UGT1A and UGT2B genes as genetic risk factors for a wide variety of cancers, including bladder, breast, colorectal, endometrial, esophageal, head and neck, liver, lung, prostate, and thyroid. These UGT polymorphisms may be cancer causative polymorphisms, or be linked to as yet undefined causative polymorphisms, either in UGT genes or neighboring genes. This article presents a comprehensive review of these case-control studies, discusses current areas of uncertainty, and highlights future research directions in this field.
Methionine-dependence phenotype in the de novo pathway in BRCA1 and BRCA2 mutation carriers with and without breast cancer
Publisher: American Association for Cancer Research (AACR)
Date: 10-2008
DOI: 10.1158/1055-9965.EPI-08-0140
Abstract: Methionine-dependence phenotype (MDP) refers to the reduced ability of cells to proliferate when methionine is restricted and/or replaced by its immediate precursor homocysteine. MDP is a characteristic of human tumors in vivo, human tumor cell lines, and normal somatic tissue in some in iduals. It was hypothesized that MDP is a risk factor for developing breast cancer in BRCA (BRCA1 and BRCA2) germline mutation carriers. To test the hypothesis, human peripheral blood lymphocytes of BRCA carriers with and without breast cancer and healthy non-carrier relatives (controls) were cultured for 9 days in medium containing either 0.1 mmol/L l-methionine or 0.2 mmol/L d,l-homocysteine, with the ratio of viable cell growth in both types of medium after 9 days used to calculate the methionine-dependence index (MDI), a measure of MDP. We also tested whether MDP was associated with common polymorphisms in methionine metabolism. Viable cell growth, MDI, and polymorphism frequency in MTRR (A66G and C524T) and MTHFR (A1298C and A1793G) did not differ among the study groups however, MDI tended to be higher in BRCA carriers with breast cancer than those without and was significantly increased in MTHFR 677T allele carriers relative to wild-type carriers (P = 0.017). The presence of MTR A2756G mutant allele and MTHFR C677T mutant allele in carriers was associated with increased breast cancer risk [odds ration, 3.2 (P = 0.16 95% confidence interval, 0.76-13.9) and 3.9 (P = 0.09 95% confidence interval, 0.93-16.3), respectively]. The results of this study support the hypothesis that defects in methionine metabolism may be associated with breast cancer risk in BRCA carriers. (Cancer Epidemiol Biomarkers Prev 2008 (10):2565–71)
Refining the mouse chromosomal location of Cdm, the major gene associated with susceptibility to cadmium-induced testicular necrosis
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2000
DOI: 10.1097/00008571-200003000-00006
Abstract: Cadmium (Cd++) is a widespread environmental pollutant and classifed as an IARC 'Category I' human carcinogen. Cd++ can also cause severe renal toxicity and may be involved clinically in cardiovascular disease and osteoporosis. Genetic differences in sensitivity to cadmium toxicity have been noted in humans, whereas, among inbred mouse strains, unequivocal genetic data exist. Resistance to cadmium-induced testicular damage was reported in 1973 to be associated with a single major recessive gene, named Cdm, which has now been localized to mouse chromosome (Chr) 3. Using polymorphic microsatellite markers and semiquantitative histological parameters, we have corroborated the original 1973 data concerning mendelian inheritance and have further refined the region containing the Cdm gene from more than 24 cM to 0.64 cM (estimated 40-80 genes). We phenotyped 26 recombinant inbred lines generated from C57BL/6J (B6, resistant) and DBA/2J (D2, sensitive) inbred mice, and determined that the Cdm gene maps between microsatellite markers D3Mit110 and D3Mit255. Although toxicity to numerous heavy metals is well known, virtually no molecular mechanisms have yet been uncovered either in humans or laboratory animals. Identification and characterization of the mouse Cdm gene should enhance our understanding of heavy metal toxicity by identifying and characterizing, for the first time, a major mammalian gene responsible for susceptibility to diseases caused by heavy metal toxicity.
Evaluation of the prescribing practice of guideline-directed medical therapy among ambulatory chronic heart failure patients.
Publisher: Springer Science and Business Media LLC
Date: 18-02-2021
DOI: 10.1186/S12872-021-01868-Z
Abstract: Studies have demonstrated that heart failure (HF) patients who receive direct pharmacist input as part of multidisciplinary care have better clinical outcomes. This study evaluated/compared the difference in prescribing practices of guideline-directed medical therapy (GDMT) for chronic HF patients between two multidisciplinary clinics—with and without the direct involvement of a pharmacist. A retrospective audit of chronic HF patients, presenting to two multidisciplinary outpatient clinics between March 2005 and January 2017, was performed a Multidisciplinary Ambulatory Consulting Service (MACS) with an integrated pharmacist model of care and a General Cardiology Heart Failure Service (GCHFS) clinic, without the active involvement of a pharmacist. MACS clinic patients were significantly older (80 vs. 73 years, p .001), more likely to be female ( p .001), and had significantly higher systolic (123 vs. 112 mmHg, p .001) and diastolic (67 vs. 60 mmHg, p .05) blood pressures compared to the GCHF clinic patients. Moreover, the MACS clinic patients showed more polypharmacy and higher prevalence of multiple comorbidities. Both clinics had similar prescribing rates of GDMT and achieved maximal tolerated doses of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in HFrEF. However, HFpEF patients in the MACS clinic were significantly more likely to be prescribed ACEIs/ARBs (70.5% vs. 56.2%, p = 0.0314) than the GCHFS patients. Patients with both HFrEF and HFpEF (MACS clinic) were significantly less likely to be prescribed β-blockers and mineralocorticoid receptor antagonists. Use of digoxin in chronic atrial fibrillation (AF) in MACS clinic was significantly higher in HFrEF patients (82.5% vs. 58.5%, p = 0.004), but the number of people anticoagulated in presence of AF (27.1% vs. 48.0%, p = 0.002) and prescribed diuretics (84.0% vs. 94.5%, p = 0.022) were significantly lower in HFpEF patients attending the MACS clinic. Age, heart rate, systolic blood pressure (SBP), anemia, chronic renal failure, and other comorbidities were the main significant predictors of utilization of GDMT in a multivariate binary logistic regression. Lower prescription rates of some medications in the pharmacist-involved multidisciplinary team were found. Careful consideration of demographic and clinical characteristics, contraindications for use of medications, polypharmacy, and underlying comorbidities is necessary to achieve best practice.
Induction of human UDP-Glucuronosyltransferase 2B7 gene expression by cytotoxic anticancer drugs in liver cancer HepG2 Cells
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 23-02-2015
Abstract: We recently reported induction of UGT2B7 by its substrate epirubicin, a cytotoxic anthracycline anticancer drug, via activation of p53 and subsequent recruitment of p53 to the UGT2B7 promoter in hepatocellular carcinoma HepG2 cells. Using the same HepG2 model cell line, the present study assessed the possibility of a similar induction of UGT2B7 by several other cytotoxic drugs. We first demonstrated by reverse transcriptase quantitative real-time polymerase chain reaction that, as observed with epirubicin, nine cytotoxic drugs including three anthracyclines (doxorubicin, daunorubicin, and idarubicin) and six nonanthracyclines (mitomycin C, 5-fluorouracil, c tothecin, 7-ethyl-10-hydroxyc tothecin, topotecan, and etoposide) significantly increased UGT2B7 mRNA levels. To investigate a potential involvement of p53 in this induction, we conducted further experiments with four of the nine drugs (doxorubicin, daunorubicin, idarubicin, and mitomycin C). The cytotoxic drugs studied increased p53 and UGT2B7 protein levels. Knockdown of p53 expression by small interfering RNA reduced cytotoxic drug-induced UGT2B7 expression. Luciferase reporter assays showed activation of the UGT2B7 promoter by cytotoxic drugs via a previously reported p53 site. Finally, chromatin immunoprecipitation assays demonstrated p53 recruitment to the UGT2B7 p53 site upon exposure to mitomycin C, the most potent UGT2B7 inducer among the nine tested drugs. Taken together, these results provide further evidence supporting UGT2B7 as a p53 target gene. The cytotoxic drug-induced UGT2B7 activity in target liver cancer cells or possibly in normal liver cells may affect the therapeutic efficacy of co-administered cytotoxic drugs (e.g., epirubicin) and noncytotoxic drugs (e.g., morphine), which are UGT2B7 substrates.
Low-molecular-weight heparin biosimilars: potential implications for clinical practice
Publisher: Wiley
Date: 05-2014
DOI: 10.1111/IMJ.12417
Abstract: A working group of clinicians and scientists was formed to review the clinical considerations for use of low-molecular-weight heparin (LMWH) biosimilars. LMWH are biological molecules of significant complexity the full complexity of chemical structure is still to be elucidated. LMWH biosimilars are products that are biologically similar to their reference product and rely on clinical data from a reference product to establish safety and efficacy. The complex nature of LMWH molecules means that it is uncertain whether a LMWH biosimilar is chemically identical to its reference product this introduces the possibility of differences in activity and immunogenicity. The challenge for regulators and clinicians is to evaluate the level of evidence required to demonstrate that a LMWH is sufficiently similar to the reference product. The consensus opinion of the working group is that prior to clinical use a LMWH biosimilar should have proven efficacy and safety, similar to the reference product with prospective studies, which should be confirmed with a proactive post-marketing pharmacovigilance programme.
The molecular basis of dapsone activation of CYP2C9-catalyzed nonsteroidal anti-inflammatory drug oxidation
Publisher: Elsevier BV
Date: 10-2023
Effect of early adverse events resulting in ado-trastuzumab emtansine dose adjustments on survival outcomes of HER2+ advanced breast cancer patients
Publisher: Springer Science and Business Media LLC
Date: 09-08-2019
DOI: 10.1007/S10549-019-05393-8
Abstract: Ado-trastuzumab emtansine (T-DM1) treatment in HER2+ advanced breast cancer patients is generally well tolerated, but when adverse events occur dose adjustments may be required. This study evaluated the impact of early adverse events requiring T-DM1 dose interruptions or reductions on overall survival (OS) and progression-free survival (PFS) in HER2+ advanced metastatic breast cancer patients in the clinical trials EMILIA and TH3RESA. The study included 893 participants initiated on T-DM1 treatment. A landmark approach set at 4 months was used to evaluate the association between early adverse events requiring T-DM1 dose interruptions or reductions and OS/PFS. Cox proportional hazard analysis modeled the association between events requiring T-DM1 dose interruptions or reductions and OS/PFS. Associations were reported as hazard ratios with 95% confidence intervals. Adverse events requiring T-DM1 dose interruptions or reductions within the first 4 months of treatment were not significantly associated with OS (hazard ratio (HR) [95% CI]: dose interrupted = 1.15 [0.85-1.55] dose reduced = 0.75 [0.49-1.14] P = 0.214) nor PFS (hazard ratio (HR) [95% CI]: dose interrupted = 1.13 [0.87-1.48] dose reduced = 0.90 [0.62-1.31] P = 0.534). The occurrence of early adverse events requiring T-DM1 dose interruptions or reductions do not appear to be associated with altered long-term OS or PFS within a pooled analysis of data from EMILIA and TH3RESA.
Reply: Comment on ‘Meta-analysis of BRAF mutation as a predictive biomarker of benefit from anti-EGFR monoclonal-antibody therapy for RAS wild-type metastatic colorectal cancer’
Publisher: Springer Science and Business Media LLC
Date: 10-09-2015
DOI: 10.1038/BJC.2015.325
Predicting response and toxicity to immune checkpoint inhibitors using routinely available blood and clinical markers
Publisher: Springer Science and Business Media LLC
Date: 24-08-2017
DOI: 10.1038/BJC.2017.274
The effects of Eucalyptus terpenes on hepatic cytochrome P450 CYP4A, peroxisomal Acyl CoA oxidase (AOX) and peroxisome proliferator activated receptor alpha (PPARalpha) in the common brush tail possum (Trichosurus vulpecula)
Publisher: Elsevier BV
Date: 10-2003
DOI: 10.1016/S1532-0456(03)00197-2
Abstract: Eucalyptus leaves contain a high proportion of essential oils comprising of a complex mixture of monoterpenes such as 1,8-cineole, alpha-pinene, d-limonene and p-cymene. In this study, hepatic levels of microsomal lauric acid hydroxylase and peroxisomal cyanide-intensive palmitoyl coenzyme A oxidative activities were examined in livers of possums given an artificial diet consisting of the above monoterpenes for 10 days. These values were compared with those of possums fed a control diet containing only fruits and cereals. Peroxisomal cyanide-intensive palmitoyl coenzyme A oxidative activity was significantly higher in livers of treated possums relative to that of control possums (2.96+/-0.93 vs. 0.98+/-0.88 nmol/mg protein per min, P<0.01) (mean+/-S.D., n=4). A small increase in microsomal lauric acid hydroxylase activity was observed in the treated possum in comparison with the control group (4.40+/-0.85 vs. 3.60+/-0.48 nmol/mg protein per min) (mean+/-S.D., n=4). A higher NAD/ NADP ratio was observed in treated possums as compared with control possums (4.73+/-0.65 vs. 3.51+/-0.64 nmol/mg protein per min, P<0.05) (mean+/-S.D., n=4). No other statistically significant differences in pyridine nucleotide contents were found between control and treated possums. Northern blot analysis of mRNA from rat, human, terpene treated and control possum livers, using the corresponding koala cDNA probes, detected a more intense acyl CoA oxidase (AOX) mRNA band in livers of terpene fed possums. Negligible differences in the intensity of CYP4A and PPARalpha mRNA bands were observed between the two groups. These data suggest that Eucalyptus terpenes elevate hepatic AOX expression in possums.
Young-Onset Gastrointestinal Adenocarcinoma Incidence and Survival Trends in the Northern Territory, Australia, with Emphasis on Indigenous Peoples
Publisher: MDPI AG
Date: 10-06-2022
Abstract: Background and Aims: A concerning rise in incidence of young-onset cancers globally led to the examination of trends in incidence and survival of gastrointestinal (GI) adenocarcinomas in the Northern Territory (NT), Australia, over a 28-year period, with a special emphasis on Indigenous peoples. Methods: This cross-sectional analysis of a prospective longitudinal database, NT Cancer Registry (1990–2017), includes all reported cases of GI (oesophagus, gastric, small intestinal, pancreas, colon, and rectum) adenocarcinomas. Poisson regression was used to estimate incidence ratio ratios, and survival was modelled using Cox proportional hazard models separately for people aged 18–50 years and years. Results: A total of 1608 cases of GI adenocarcinoma were recorded during the time of the study. While the overall incidence in people 18–50 years remained unchanged over this time (p = 0.51), the rate in in iduals aged years decreased (IRR = 0.65 (95% CI 0.56–0.75 p 0.0001)). Incidence rates were significantly less in females years (IRR = 0.67 95% CI 0.59–0.75 p 0.0001), and their survival was significantly better (HR = 0.84 (95%CI 0.72–0.98 p 0.03)) compared to males. Overall survival across all GI subsites improved in both age cohorts, especially between 2010 and 2017 (HR = 0.45 (95%CI 0.29–0.72 p 0.0007) and HR = 0.64 (95%CI 0.52–0.78 p 0.0001), respectively) compared to 1990–1999, driven by an improvement in survival in colonic adenocarcinoma alone, as the survival remained unchanged in other GI subsites. The incidence was significantly lower in Indigenous patients compared to non-Indigenous patients, in both age cohorts (18–50 years IRR = 0.68 95% CI 0.51–0.91 p 0.009 and years IRR = 0.48 95% CI 0.40–0.57 p 0.0001). However, Indigenous patients had worse survival rates (18–50 years HR = 2.06 95% CI 1.36–3.11 p 0.0007 and years HR = 1.66 95% CI 1.32–2.08 p 0.0001). Conclusions: There is a trend towards an increased incidence of young-onset GI adenocarcinomas in the NT. Young Indigenous patients have lower incidence but worse survival across all GI subsites, highlighting significant health inequities in life expectancy. Targeted, culturally safe Indigenous community-focussed programs are needed for early detection and patient-centred management of GI adenocarcinomas.
Investigation of HTR3C mutations for association with 5HT3 receptor antagonist anti-emetic efficacy
Publisher: Future Medicine Ltd
Date: 08-2008
DOI: 10.2217/14622416.9.8.1027
Abstract: Objective: Chemotherapy-induced nausea and vomiting is a significant clinical problem. The 5HT 3 receptor antagonists are effective anti-emetic medications but approximately 30% of patients do not respond. Method: We examined the HTR3C gene, which is believed to encode a subunit of the 5HT 3 receptor, for genetic variation and association with anti-emetic efficacy in a group of 70 patients receiving cancer chemotherapy. Results: Seven novel mutations were identified three mutations resulted in amino acid substitutions, two were synonymous and two were intronic. No statistically significant associations between either isolated mutations or estimated haplotypes and anti-emetic efficacy were detected. Conclusion: The results of this investigation indicate that the genetic variants that have been identified within HTR3C do not predict response to 5HT 3 antagonists, necessitating further investigation of possible genetic determinants of 5HT 3 antagonist efficacy.
Multiple Pharmacophores for the Investigation of Human UDP-Glucuronosyltransferase Isoform Substrate Selectivity
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 22-01-2004
DOI: 10.1124/MOL.65.2.301
Possible role for clinical pharmacists in identifying pharmacogenomic interventions
Publisher: Wiley
Date: 03-2006
DOI: 10.1002/J.2055-2335.2006.TB00884.X
Abstract: In idualised drug therapy is important in contemporary pharmacy practice. Pharmacogenomics is one way of in idualising therapy to maximise efficacy and minimise toxicity, based on patients' genetic data. To assess clinical pharmacists' understanding of pharmacogenomics and their ability to identify interventions. Structured interviews were conducted with 9 clinical pharmacists, practising in a private hospital setting, to identify: level of understanding of pharmacogenomics drugs encountered that display significant inter‐patient variability and whether a literature review could confirm that dugs identified are likely to have a genetic basis for their variability. Findings of this pilot study show that although pharmacists had a negligible understanding of pharmacogenomics, they acknowledged the importance of its integration into clinical practice and the need for education. Pharmacists identified a number of drugs which displayed inter‐patient variability—the drugs were subsequently confirmed by a literature search to be affected by genetic polymorphisms. For pharmacogenomics to be successfully implemented in practice, there is a need for education of pharmacists. Pharmacists saw pharmacogenomics as a beneficial technology that could improve patient outcomes.
The Influence of Pre-Existing Beta-Blockers Use on Survival Outcomes in HER2 Positive Advanced Breast Cancer: Pooled Analysis of Clinical Trial Data
Publisher: Frontiers Media SA
Date: 14-07-2020
Impact of Histone Deacetylase Inhibitors on microRNA Expression and Cancer Therapy: A Review
Publisher: Wiley
Date: 25-08-2015
DOI: 10.1002/DDR.21268
Abstract: Chromatin-modifying drugs, such as histone deacetylase inhibitors (HDACi), have shown potential as cancer therapeutics, either alone or in combination with other therapies. HDACi have the ability to reverse aberrant epigenetic modifications associated with cancer, namely dysregulated histone acetylation. There are currently three FDA approved HDACi vorinostat, romidepsin, and panobinostat. Epigenetic modifications can regulate the expression of protein coding genes, and in addition can alter expression of microRNA (miRNA) genes. Many miRNAs play key roles in cell proliferation and apoptosis, and are commonly dysregulated in cancer states. A number of in vitro and in vivo studies have demonstrated the ability of chromatin-modifying drugs to alter miRNA expression, which may provide the basis for further investigation of miRNAs as therapeutic targets or as biomarkers of drug response. This review summarises findings from studies investigating the effects of HDACi on miRNA expression, as well as key clinical trials involving HDACi. Understanding how chromatin-modifying drugs epigenetically modulate miRNA genes provides further insight into the cellular mechanisms that deliver therapeutic responses, and may assist in refining treatment strategies.
SPECIES-SPECIFIC EXPRESSION OF CYP4B1 IN RABBIT AND HUMAN GASTROINTESTINAL TISSUES
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-1994
DOI: 10.1097/00008571-199410000-00004
Abstract: CYP4B1 is a P450 enzyme displaying tissue and species specific regulation. The rabbit CYP4B1 enzyme exhibits activity towards procarcinogenic aromatic amines. In the present study, CYP4B1 expression has been characterized in rabbit tissues using histological techniques, Northern blotting and Western blotting. Similar analyses were attempted using available human tissues. CYP4B1 mRNA and protein was demonstrated throughout the rabbit small intestine and colon. A unique 1.8 kb transcript, that is smaller than the transcript found in other tissues, was detected in rabbit stomach with a CYP4B1 specific RNA probe. No CYP4B1 protein was detected in this tissue. In rabbit liver, CYP4B1 was induced by phenobarbital primarily in zone 1 hepatocytes (periportal). In humans, CYP4B1 expression was demonstrated at low levels in human colon using in situ hybridization but not in liver or the small intestine. All rabbit gastrointestinal tissues other than stomach possess a high capacity for the activation of 2-aminofluorene compatible with CYP4B1 expression. In contrast, no activity was observed in human gastrointestinal microsomes. The present study therefore shows that CYP4B1 is an abundant P450 in the rabbit gastrointestinal tract and identifies species-specific differences in CYP4B1 expression and function.
Palliative Care Is Everyone's Business, Including Pharmacists
Publisher: Elsevier BV
Date: 03-2013
DOI: 10.5688/AJPE77221
Efficacy of atezolizumab in patients with advanced non-small cell lung cancer receiving concomitant antibiotic or proton pump inhibitor treatment: pooled analysis of five randomised control trials.: Proton pump inhibitors, antibiotics, and immunotherapies.
Publisher: Elsevier BV
Date: 06-2022
DOI: 10.1016/J.JTHO.2022.02.003
Abstract: Gut dysbiosis may reduce immune checkpoint inhibitor (ICI) efficacy. Antibiotics and proton pump inhibitors (PPIs) are commonly used drugs causing gut dysbiosis. There is limited randomized controlled trial (RCT) evidence on whether antibiotics or PPIs impact ICI benefit versus comparator treatments. This study pooled five RCTs (IMpower130, IMpower131, IMpower150, OAK, and POPLAR) evaluating atezolizumab in advanced NSCLC. Atezolizumab efficacy (hazard ratio with 95% confidence intervals) was assessed for subgroups on the basis of antibiotic and PPI use at randomization. The association between antibiotic and PPI use with pretreatment peripheral blood immunophenotype was also explored. Of 4458 participants, 285 received an antibiotic in the 30-day pretreatment and 1225 were using a PPI at treatment initiation. Overall survival efficacy of atezolizumab was similar (p[interaction] = 0.35) for antibiotic users (hazard ratio 95% confidence interval: 0.73 [0.53-0.99]) and antibiotic nonusers (0.82 [0.74-0.91]). Nevertheless, efficacy was reduced (p[interaction] = 0.003) for PPI users (1.00 [0.85-1.17]) compared with PPI nonusers (0.76 [0.69-0.83]). Findings were consistent across RCTs and for progression-free survival. PPI use was associated with 9%, 18%, and 9% lower counts of lymphocytes, CD19+, and CD16+CD56+ immune cells, respectively (p < 0·01). Reassuringly, atezolizumab efficacy did not differ for antibiotic users. Opposingly, PPI use was consistently associated with decreased atezolizumab efficacy and lower pretreatment counts of lymphocytes, CD19+, and CD16+CD56+ immune cells. Given that approximately 30% of patients with cancer use PPIs, there is an urgent need for evidence on the impacts of PPIs on other ICIs and for the development of guidelines on nonessential PPI use with ICIs.
Consumers' views of pharmacogenetics-A qualitative study
Publisher: Elsevier BV
Date: 09-2010
DOI: 10.1016/J.SAPHARM.2009.08.002
Abstract: Adverse drug reactions are recognized as a significant public health issue. Pharmacogenetics (PGx) provides a potential means of preventing some adverse drug reactions by predicting the optimal medication dose for an in idual however, PGx is rarely used in clinical practice. Thus far, there have been few studies investigating consumers' perceptions of the barriers to the implementation of PGx in clinical practice. This study explored the views of the general public regarding their current use of medications, and their experiences of side effects and opinions on PGx. Members of the general public who suffered a chronic medical condition and/or had an immediate family member with a chronic medical condition were recruited to form 5 separate focus groups (n=35). Three separate age ranges were used in the focus groups. A questioning route was developed and used in focus groups to determine participants' experiences with medication use and opinions on PGx (referred to as "Personalized Medicine"). Focus group discussions were transcribed by 2 separate investigators, and qualitative analysis, based on the framework approach, was applied to the data. Data were independently coded to identify key themes then compared both within and between focus groups. A common theme was a desire to have a holistic approach to disease diagnosis and medication selection. A wide range of views were expressed by the focus group participants. Concerns were raised regarding the current level of side effects experienced with medications. Storage and privacy of genetic information, and the costs involved, were also seen as potential barriers to implementation of PGx. PGx testing was seen as a potential positive contribution, but only if other factors were considered during the prescribing process. As participants desired a high level of information and effective communication from their health-care professionals, PGx education of clinicians and pharmacists will be essential to satisfy consumers' requirements.
Cytochrome P450 2: pharmacogenetics
Publisher: Wiley
Date: 06-2000
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