David Owen

A Comparison of the Pharmacokinetics and Pulmonary Lymphatic Exposure of a Generation 4 PEGylated Dendrimer Following Intravenous and Aerosol Administration to Rats and Sheep

Publisher: Springer Science and Business Media LLC

Date: 20-10-2015

DOI: 10.1007/S11095-015-1806-Z

Abstract: Cancer metastasis to pulmonary lymph nodes dictates the need to deliver chemotherapeutic and diagnostic agents to the lung and associated lymph nodes. Drug conjugation to dendrimer-based delivery systems has the potential to reduce toxicity, enhance lung retention and promote lymphatic distribution in rats. The current study therefore evaluated the pharmacokinetics and lung lymphatic exposure of a PEGylated dendrimer following inhaled administration. Plasma pharmacokinetics and disposition of a 22 kDa PEGylated dendrimer were compared after aerosol administration to rats and sheep. Lung-derived lymph could not be s led in rats and so lymphatic transport of the dendrimer from the lung was assessed in sheep. Higher plasma concentrations were achieved when dendrimer was administered to the lungs of rats as a liquid instillation when compared to an aerosol. Plasma pharmacokinetics were similar between sheep and rats, although some differences in disposition patterns were evident. Unexpectedly, less than 0.5% of the aerosol dose was recovered in pulmonary lymph. The data suggest that rats provide a relevant model for assessing the pharmacokinetics of inhaled macromolecules prior to evaluation in larger animals, but that the pulmonary lymphatics are unlikely to play a major role in the absorption of nanocarriers from the lungs.

Synthesis and evaluation of galactofuranosyl N,N-dialkyl sulfenamides and sulfonamides as antimycobacterial agents

Publisher: Elsevier BV

Date: 04-2007

DOI: 10.1016/J.BMCL.2007.01.068

Abstract: The recent emergence of clinically oppressive superbugs, some with resistance to nearly all frontline drug therapies, has challenged our ability to combat such infectious organisms as Mycobacterium tuberculosis, the causative agent of tuberculosis (TB). Our medicinal chemistry program targeting this pathogen has identified several potent galactofuranose-based in vitro inhibitors of mycobacterial growth. The most potent compound, the Galf N,N-didecyl sulfenamide 8d, displayed anti-mycobacterial activity (MIC) of 1 microg/mL in a cell based assay against a representative strain of Mycobacterium smegmatis.

Doxorubicin-Conjugated PEGylated Dendrimers Show Similar Tumoricidal Activity but Lower Systemic Toxicity When Compared to PEGylated Liposome and Solution Formulations in Mouse and Rat Tumor Models

Publisher: American Chemical Society (ACS)

Date: 27-01-2012

DOI: 10.1021/MP200522D

Abstract: PEGylated polylysine dendrimers show promise as novel drug delivery systems with the potential to direct site specific deposition patterns and to reduce toxicity at nontarget sites. Here the activity and toxicity profiles of a generation 5 polylysine dendrimer with 50% surface conjugation of PEG1100 and 50% surface conjugation of doxorubicin (via an acid labile 4-hydrazinosulfonyl benzoic acid linker) have been compared in a Walker 256 rat tumor model and a human MDA-MB231 xenograft in mice. A direct comparison was also made to a PEGylated liposomal formulation of doxorubicin and a doxorubicin solution. In both rat and mouse breast cancer models, the dendrimer formulation gave equivalent antitumor efficacy when compared to the liposomal or solution doxorubicin formulations and administration of all three doxorubicin formulations resulted in a significant reduction (>75%) in tumor growth in both models at doses ranging from 2 to 10 mg/kg doxorubicin equivalents. The dendrimer formulation, however, was better tolerated by both rats and mice, and approximately 2-fold higher doses were required to induce similar levels of toxicity (as assessed by organ weight, peripheral white cell counts, body weight and survival curves) when compared to administration of the doxorubicin solution or PEGylated liposomal doxorubicin. In rats the appearance of palmar plantar erythematosis (PPE), or hand foot syndrome, was also less evident after administration of dendrimer doxorubicin when compared to the liposome. Finally, even after administration to mice at 2-fold higher doses, dendrimer-doxorubicin resulted in a reduced incidence of cardiotoxicity when compared with a simple solution formulation of doxorubicin. The data suggest that dendrimer-based doxorubicin formulations may provide advantage over solution and liposomal formulations of doxorubicin via a reduction in systemic toxicity.

Phosphoisoprenoid Binding Specificity of Geranylgeranyltransferase Type II

Publisher: American Chemical Society (ACS)

Date: 02-09-2000

DOI: 10.1021/BI000835M

Abstract: Geranylgeranyltransferase type II (GGTase-II) modifies small monomeric GTPases of the Rab family by attaching geranylgeranyl moieties onto two cysteines of their C-terminus. We investigated to what extent GGTase-II discriminates between its native substrate geranylgeranyl pyrophosphate (GGpp) and other phosphoisoprenoids, including farnesyl pyrophosphate (Fpp). On the basis of a novel fluorescent assay, we demonstrated that GGpp binds to GGTase-II with an affinity of 8 +/- 4 nM, while Fpp is bound less strongly (K(d) = 60 +/- 8 nM). Analysis of the binding kinetics of four different phosphoisoprenoids indicated that in all cases association is rapid, with rate constants in the range of 0.15 nM(-1) s(-1). In contrast, the dissociation rates differed greatly, depending on the phosphoisoprenoid used, with weak binding substrates generally displaying an increased rate of dissociation. The affinity of GGpp and Fpp for GGTase-II was also determined in the presence of the Rab7-REP-1 complex. The affinity for GGpp was essentially unaffected by the presence of the complex Fpp on the other hand bound less strongly to the GGTase-II under these conditions, resulting in a K(d) of 260 +/- 60 nM. In vitro prenylation experiments were used to establish that Fpp not only does bind to GGTase-II but also is transferred with an observed rate constant of 0.082 s(-1) which is very similar to that of GGpp. The implications of the low level of discrimination by GGTase-II for the in vivo specificity of the enzyme and the use of farnesyltransferase inhibitors in anti-cancer therapy are discussed.

Total Synthesis of (–)-Episilvestrol and (–)-Silvestrol

Publisher: Wiley

Date: 04-10-2007

DOI: 10.1002/ANIE.200702700

Doxorubicin Conjugation and Drug Linker Chemistry Alter the Intravenous and Pulmonary Pharmacokinetics of a PEGylated Generation 4 Polylysine Dendrimer in Rats

Publisher: Elsevier BV

Date: 09-2018

DOI: 10.1016/J.XPHS.2018.05.013

Abstract: PEGylated polylysine dendrimers have demonstrated potential as inhalable drug delivery systems that can improve the treatment of lung cancers. Their treatment potential may be enhanced by developing constructs that display prolonged lung retention, together with good systemic absorption, the capacity to passively target lung tumors from the blood and highly selective, yet rapid liberation in the tumor microenvironment. This study sought to characterize how the nature of cathepsin B-cleavable peptide linkers, used to conjugate doxorubicin (Dox) to a PEGylated (PEG570) G4 polylysine dendrimer, affects drug liberation kinetics and intravenous and pulmonary pharmacokinetics in rats. The construct bearing a self-emolative diglycolic acid-V-Citrulline linker exhibited faster Dox release kinetics compared to constructs bearing self-emolative diglycolic acid-glycine-leucine-phenylalanine-glycine (GLFG), or non-self-emolative glutaric acid-GLFG linkers. The V-Citrulline construct exhibited slower plasma clearance, but faster absorption from the lungs than a GLFG construct, although mucociliary clearance and urinary elimination were unchanged. Dox-conjugation enhanced localization in the bronchoalveolar lavage fluid compared to lung tissue, suggesting that projection of Dox from the dendrimer surface reduced tissue uptake. These data show that the linker chemistry employed to conjugate drugs to PEGylated carriers can affect drug release profiles and systemic and lung disposition.

Protocol for process evaluation of a randomised controlled trial of family-led rehabilitation post stroke (ATTEND) in India

Publisher: BMJ

Date: 09-2016

DOI: 10.1136/BMJOPEN-2016-012027

Abstract: We are undertaking a randomised controlled trial (fAmily led rehabiliTaTion aftEr stroke in INDia, ATTEND) evaluating training a family carer to enable maximal rehabilitation of patients with stroke-related disability as a potentially affordable, culturally acceptable and effective intervention for use in India. A process evaluation is needed to understand how and why this complex intervention may be effective, and to capture important barriers and facilitators to its implementation. We describe the protocol for our process evaluation to encourage the development of in-process evaluation methodology and transparency in reporting. The realist and RE-AIM (Reach, Effectiveness, Adoption, Implementation and Maintenance) frameworks informed the design. Mixed methods include semistructured interviews with health providers, patients and their carers, analysis of quantitative process data describing fidelity and dose of intervention, observations of trial set up and implementation, and the analysis of the cost data from the patients and their families perspective and programme budgets. These qualitative and quantitative data will be analysed iteratively prior to knowing the quantitative outcomes of the trial, and then triangulated with the results from the primary outcome evaluation. The process evaluation has received ethical approval for all sites in India. In low-income and middle-income countries, the available human capital can form an approach to reducing the evidence practice gap, compared with the high cost alternatives available in established market economies. This process evaluation will provide insights into how such a programme can be implemented in practice and brought to scale. Through local stakeholder engagement and dissemination of findings globally we hope to build on patient-centred, cost-effective and sustainable models of stroke rehabilitation. CTRI/2013/04/003557.

Trial of pregabalin in acute and chronic sciatica

Publisher: Massachusetts Medical Society

Date: 23-03-2017

DOI: 10.1056/NEJMOA1614292

2,5-Dithiacyclopentylideneketene and ethenedithione, S:C:C:S, generated by flash vacuum pyrolysis

Publisher: American Chemical Society (ACS)

Date: 04-1991

DOI: 10.1021/JA00008A048

Cost-effectiveness of a text message programme for the prevention of recurrent cardiovascular events

Publisher: BMJ

Date: 24-02-2017

DOI: 10.1136/HEARTJNL-2016-310195

Abstract: To estimate the cost-effectiveness of Tobacco, Exercise and Diet Messages (TEXT ME), a text message-based intervention that provides advice, motivation, information and support to improve health-related behaviours. A lifetime Markov model was used to estimate major vascular events (myocardial infarctions and strokes) avoided, quality-adjusted life years (QALYs) gained, costs to the health system and the incremental cost per QALY gained. The model was informed by data from a randomised controlled trial of TEXT ME, with evidence from systematic reviews and meta-analyses used to estimate the effects of changes in risk factors on the risk of major vascular events. Expected costs and health outcomes were estimated with uncertainty surrounding these characterised using probabilistic sensitivity analysis and a number of scenario analyses. For a target population of 50 000 patients with documented coronary heart disease, the intervention is expected to lead to 563 fewer myocardial infarctions, 361 fewer strokes and 1143 additional QALYs. TEXT ME is expected to lead to an overall saving of $10.56 million for the health system over the patients' lifetimes. The intervention can therefore be considered cost-saving and health-improving. Neither parameter nor structural uncertainty had a significant impact on the conclusion that TEXT ME is cost-effective. The provision of TEXT ME is predicted to lead to better health outcomes and an overall saving in costs for the health system. anzctr.org.au identifier: ACTRN12611000161921.

A comparison of changes to doxorubicin pharmacokinetics, antitumor activity, and toxicity mediated by PEGylated dendrimer and PEGylated liposome drug delivery systems

Publisher: Elsevier BV

Date: 2012

DOI: 10.1016/J.NANO.2011.05.013

Abstract: The pharmacokinetics, biodistribution, and antitumor efficacy of three doxorubicin formulations (doxorubicin in saline, conjugated to a polylysine dendrimer, and encapsulated within a stealth liposome) were investigated in Walker 256 tumor-bearing rats. Liposomal and dendrimer-based delivery systems resulted in more prolonged plasma exposure of total doxorubicin when compared to administration of doxorubicin in saline, although concentrations of free doxorubicin remained low in both cases. Biodistribution profiles revealed enhanced accumulation of dendrimer- and liposome-associated doxorubicin in tumors when compared to doxorubicin alone, although all three doxorubicin formulations reduced tumor growth to a similar extent. Markers of systemic toxicity (spleen weight, white blood cell counts, body weight, and cardiotoxicity) were more pronounced in rats that received doxorubicin and liposomal doxorubicin when compared to dendrimer-doxorubicin. The data provide preliminary evidence that dendrimer-doxorubicin displays similar antitumor efficacy to PEGylated liposomal doxorubicin, but with lower systemic toxicity (resulting from reduced drug exposure to nontarget organs). In this manuscript, three different doxorubicin preparations are compared and preliminary evidence suggests that dendrimer-doxorubicin displays similar antitumor efficacy to PEGylated liposomal doxorubicin, but with lower systemic toxicity.

Making guidelines for economic evaluations relevant to public health in Australia

Publisher: Elsevier BV

Date: 04-2017

DOI: 10.1111/1753-6405.12601

Does tax-based health financing offer protection from financial catastrophe? Findings from a household economic impact survey of ischaemic heart disease in Malaysia

Publisher: Oxford University Press (OUP)

Date: 26-12-2016

DOI: 10.1093/INTHEALTH/IHW054

Abstract: Malaysia is an upper-middle income country with a tax-based health financing system. Health care is relatively affordable, and safety nets are provided for the needy. The objectives of this study were to determine the out-of-pocket health spending, proportion of catastrophic health spending (out-of-pocket spending >40% of non-food expenditure), economic hardship and financial coping strategies among patients with ischaemic heart disease (IHD) in Malaysia under the present health financing system. A cross-sectional study was conducted at the National Heart Institute of Malaysia involving 503 patients who were hospitalized during the year prior to the survey. The mean annual out-of-pocket health spending for IHD was MYR3045 (at the time US$761). Almost 16% (79/503) suffered from catastrophic health spending (out-of-pocket health spending ≥40% of household non-food expenditures), 29.2% (147/503) were unable to pay for medical bills, 25.0% (126/503) withdrew savings to help meet living expenses, 16.5% (83/503) reduced their monthly food consumption, 12.5% (63/503) were unable to pay utility bills and 9.0% (45/503) borrowed money to help meet living expenses. Overall, the economic impact of IHD on patients in Malaysia was considerable and the prospect of economic hardship likely to persist over the years due to the long-standing nature of IHD. The findings highlight the need to evaluate the present health financing system in Malaysia and to expand its safety net coverage for vulnerable patients.

PrevenTing Falls in a high-risk, vision-impaired population through specialist ORientation and Mobility services: protocol for the PlaTFORM randomised trial

Publisher: BMJ

Date: 13-02-2017

DOI: 10.1136/INJURYPREV-2016-042301

Abstract: Older people with vision impairment have significant ongoing morbidity, including risk of falls, but are neglected in fall prevention programmes. PlaTFORM is a pragmatic evaluation of the Lifestyle-integrated Functional Exercise fall prevention programme for older people with vision impairment or blindness (v-LiFE). Implementation and scalability issues will also be investigated. PlaTFORM is a single-blinded, randomised trial designed to evaluate the v-LiFE programme compared with usual care. Primary outcomes are fall rate over 12 months, measured using prospective monthly fall calendars, and function and participation assessed by the Late-Life Function and Disability Instrument (Late-Life FDI) Function component. The secondary outcome is rate of falls requiring medical care. Activity-normalised fall rate will be estimated using accelerometer-measured physical activity data. EuroQol 5-dimension 5-level questionnaire will measure quality of life and impact of falls. Health record linkage will estimate resource use associated with falls. v-LiFE cost-effectiveness will be determined compared with usual care. 500 participants (250 per group) can provide 90% power to detect a significant between-group difference in fall rates 588 will be recruited to allow for drop-out. Falls per person-year and Late-Life FDI will be compared between groups. PlaTFORM will determine if falls can be prevented among older people with vision loss through a home-based exercise programme. v-LiFE embeds balance and strength training within everyday activities with the aim of preventing falls. The study will also determine whether the programme can be effectively delivered by personnel who provide Orientation and Mobility training for people with vision impairment. ACTRN12616001186448p.

3-epi-GA63, antheridiogen in Anemia phyllitidis

Publisher: Elsevier BV

Date: 04-1995

DOI: 10.1016/0031-9422(94)00834-G

Synthesis and biological evaluation of galactofuranosyl alkyl thioglycosides as inhibitors of mycobacteria

Publisher: Elsevier BV

Date: 09-2007

DOI: 10.1016/J.CARRES.2007.04.027

Abstract: As part of our research interest directed toward the development of antimycobacterial agents, we have investigated compounds based on galactofuranose (Galf), an essential cell wall component of mycobacteria. The objective of this study was to explore structure activity relationships of Galf thioglycosides with straight chain and branched aglycons. Acylated Galf 9-heptadecyl thioglycoside was prepared by Lewis acid-catalyzed thioglycosidation of 1,2,3,5,6-penta-O-acyl-D-galactofuranose with 9-heptadecanethiol, and subsequently converted to the corresponding sulfone using m-CPBA. Both Galf 9-heptadecyl thioglycoside and sulfone displayed in vitro inhibition (MIC) of the growth of Mycobacterium smegmatis below 5 microg/mL, while Galf 1-octyl thioglycoside gave no inhibition at or below 32 microg/mL.

Subcutaneous delivery of a dendrimer-BH3 mimetic improves lymphatic uptake and survival in lymphoma

Publisher: Elsevier BV

Date: 08-2022

DOI: 10.1016/J.JCONREL.2022.05.041

Abstract: As a malignant tumour of lymphatic origin, B-cell lymphoma represents a significant challenge for drug delivery, where effective therapies must access malignant cells in the blood, organs and lymphatics while avoiding off-target toxicity. Subcutaneous (SC) administration of nanomedicines allows preferential access to both the lymphatic and blood systems and may therefore provide a route to enhanced drug exposure to lymphomas. Here we examine the impact of SC dosing on lymphatic exposure, pharmacokinetics (PK), and efficacy of AZD0466, a small molecule dual Bcl-2/Bcl-xL inhibitor conjugated to a 'DEP®' G5 poly-l-lysine dendrimer. PK studies reveal that the plasma half-life of the dendrimer-drug conjugate is 8-times longer than that of drug alone, providing evidence of slow release from the circulating dendrimer nanocarrier. The SC dosed construct also shows preferential lymphatic transport, with over 50% of the bioavailable dose recovered in thoracic lymph. Increases in dose (up to 400 mg/kg) are well tolerated after SC administration and studies in a model of disseminated lymphoma in mice show that high dose SC treatment outperforms IV administration using doses that lead to similar total plasma exposure (lower peak concentrations but extended exposure after SC). These data show that the DEP® dendrimer can act as a circulating drug depot accessing both the lymphatic and blood circulatory systems. SC administration improves lymphatic exposure and facilitates higher dose administration due to improved tolerability. Higher dose SC administration also results in improved efficacy, suggesting that drug delivery systems that access both plasma and lymph hold significant potential for the treatment of haematological cancers where lymphatic and extranodal dissemination are poor prognostic factors.

Identification of GA113, GA114, GA115 and GA116 and further novel gibberellins in Raphanus sativus

Publisher: Elsevier BV

Date: 06-1998

DOI: 10.1016/S0031-9422(98)00035-1

To Close the Gap we need to identify the best (and worst) buys in Indigenous health

Publisher: Elsevier BV

Date: 06-2017

DOI: 10.1111/1753-6405.12612

Capping Methotrexate α-Carboxyl Groups Enhances Systemic Exposure and Retains the Cytotoxicity of Drug Conjugated PEGylated Polylysine Dendrimers

Publisher: American Chemical Society (ACS)

Date: 21-01-2011

DOI: 10.1021/MP1001872

Abstract: A generation 5 PEGylated (PEG 1100) polylysine dendrimer, conjugated via a stable amide linker to OtBu protected methotrexate (MTX), was previously shown to have a circulatory half-life of 2 days and to target solid tumors in both rats and mice. Here, we show that deprotection of MTX and substitution of the stable linker with a matrix metalloproteinase (MMP) 2 and 9 cleavable linker (PVGLIG) dramatically increased plasma clearance and promoted deposition in the liver and spleen (50-80% of the dose recovered in the liver 3 days post dose). Similar rapid clearance was also seen using a scrambled peptide suggesting that clearance was not dependent on the cleavable nature of the linker. Surprisingly, dendrimers where OtBu capped MTX was linked to the dendrimer surface via the hexapeptide linker showed equivalent in vitro cytotoxicity against HT1080 cells when compared to the uncapped dendrimer and also retained the long circulating characteristics of the stable constructs. The OtBu capped MTX conjugated dendrimer was subsequently shown to significantly reduce tumor growth in HT1080 tumor bearing mice compared to control. In contrast the equivalent dendrimer comprising uncapped MTX conjugated to the dendrimer via the same hexapeptide linker did not reduce tumor growth, presumably reflecting very rapid clearance of the construct. The results are consistent with the suggestion that protection of the α-carboxyl group of methotrexate may be used to improve the circulatory half-life and reduce the liver accumulation of similar MTX-conjugated dendrimers, while still retaining antitumor activity in vivo.

System-wide analysis of health financing equity in Cambodia: a study protocol

Publisher: BMJ

Date: 2017

DOI: 10.1136/BMJGH-2016-000153

Methotrexate-conjugated PEGylated dendrimers show differential patterns of deposition and activity in tumor-burdened lymph nodes after intravenous and subcutaneous administration in rats

Publisher: American Chemical Society (ACS)

Date: 25-02-1100

DOI: 10.1021/MP500531E

Abstract: The current study sought to explore whether the subcutaneous administration of lymph targeted dendrimers, conjugated with a model chemotherapeutic (methotrexate, MTX), was able to enhance anticancer activity against lymph node metastases. The lymphatic pharmacokinetics and antitumor activity of PEGylated polylysine dendrimers conjugated to MTX [D-MTX(OH)] via a tumor-labile hexapeptide linker was examined in rats and compared to a similar system where MTX was α-carboxyl O-tert-butylated [D-MTX(OtBu)]. The latter has previously been shown to exhibit longer plasma circulation times. D-MTX(OtBu) was well absorbed from the subcutaneous injection site via the lymph, and 3 to 4%/g of the dose was retained by sentinel lymph nodes. In contrast, D-MTX(OH) showed limited absorption from the subcutaneous injection site, but absorption was almost exclusively via the lymph. The retention of D-MTX(OH) by sentinel lymph nodes was also significantly elevated (approximately 30% dose/g). MTX alone was not absorbed into the lymph. All dendrimers displayed lower lymph node targeting after intravenous administration. Despite significant differences in the lymph node retention of D-MTX(OH) and D-MTX(OtBu) after subcutaneous and intravenous administration, the growth of lymph node metastases was similarly inhibited. In contrast, the administration of MTX alone did not significantly reduce lymph node tumor growth. Subcutaneous administration of drug-conjugated dendrimers therefore provides an opportunity to improve drug deposition in downstream tumor-burdened lymph nodes. In this case, however, increased lymph node biodistribution did not correlate well with antitumor activity, possibly suggesting constrained drug release at the site of action.

Synthesis and confirmation of structure for a new gibberellin, 2β-hydroxy-GA12 (GA110), from spinach and oil palm

Publisher: Elsevier BV

Date: 02-1998

DOI: 10.1016/S0031-9422(97)00577-3

Abstract: The identity of a new gibberellin (GA) in spinach and oil palm sap has been confirmed as 2 beta-hydroxy-GA12 (GA110) by comparisons of GC-mass spectral data obtained for the trimethylsilyl ether methyl ester derivatives with those of a synthetic s le prepared by means of a 24 step sequence from gibberellic acid 2 beta-hydroxy-GA24 was also prepared. Experimental details for the latter part of the syntheses are described.

Peptide conjugates as tools for the study of biological signal transduction

Publisher: Elsevier BV

Date: 02-1999

DOI: 10.1016/S0968-0896(98)00204-1

Abstract: Today, many biological phenomena are being investigated and understood in molecular detail, and organic chemistry is increasingly being directed towards biological phenomena. This review is intended to highlight this interplay of organic chemistry and biology, using biological signal transduction as an ex le. Lipo-, glyco-, phospho- and nucleoproteins play key roles in the processes whereby chemical signals are passed across cell membranes and further to the cell nucleus. For the study of the biological phenomena associated with these protein conjugates, structurally well-defined peptides containing the characteristic linkage region of the peptide backbone with the lipid, the carbohydrate or the phosphoric acid ester can provide valuable tools. The multi-functionality and pronounced acid- and base-lability of such compounds renders their synthesis a formidable challenge to conventional organic synthesis. However, the recent development of enzymatic protecting groups, provides one of the central techniques which, when coupled with classic chemical synthesis, can provide access to these complex and sensitive biologically relevant peptide conjugates under particularly mild conditions and with high selectivity.

Enantioselective inhibition of squalene synthase by aziridine analogues of presqualene diphosphate

Publisher: American Chemical Society (ACS)

Date: 15-06-2010

DOI: 10.1021/JO100718Z

Lymphatic transport and lymph node targeting of methotrexate-conjugated PEGylated dendrimers are enhanced by reducing the length of the drug linker or masking interactions with the injection site

Publisher: Elsevier BV

Date: 11-2017

DOI: 10.1016/J.NANO.2017.08.003

Abstract: Drug conjugation to dendrimer-based delivery systems has been shown to enhance delivery to the lymphatic system after subcutaneous administration. Dendrimer interaction with components of the interstitium at the injection site, however, may prevent drainage from the injection site. The current study sought to vary the length of a linker employed to conjugate methotrexate (MTX) to a PEGylated dendrimer, in an attempt to reduce MTX interaction with interstitial binding sites and enhance lymphatic drainage. Dendrimers with shorter linkers resulted in higher lymphatic drainage, presumably via shielding of interaction sites by the PEG mantle, but were not retained in lymph nodes. Improved drainage of dendrimers with longer linkers was achieved through coadministration with dextran to mask interactions at the injection site while maintaining retention within the node. Enhanced drug exposure to the lymph node has the potential to enhance the treatment of lymph-node resident cancer metastases.

Structure determination and synthesis of a new gibberellin, GA99, from spinach plants: 2β-hydroxy-GA19

Publisher: Elsevier BV

Date: 1996

DOI: 10.1016/0040-4039(95)02252-X

Preferences for the emergency department or alternatives for older people in aged care: A discrete choice experiment

Publisher: Oxford University Press (OUP)

Date: 10-09-2017

DOI: 10.1093/AGEING/AFW163

Abstract: To estimate the effect of factors that influence decisions to transfer residents of aged care facilities to an emergency department (ED) for acute medical emergencies. A discrete choice experiment with residents (N = 149), the relatives of residents (N = 137) and staff members (N = 128) of aged care facilities. Aged care facilities in three Australian states. Using random parameter logit models, parameter estimates and odds ratios were estimated, and resultant utility functions for ED and alternate care were constructed. All attributes (including waiting time, complication rates, symptom relief and time spent alone) significantly influence choice for accessing acute care. There is a strong overall preference for ED care (odds ratio 1.73, 95% confidence interval 1.57–1.92), but this varies by clinical scenario, being the strongest for pneumonia and weakest for wrist fracture. Relatives of residents were less tolerant of reductions in care quality than staff members or residents themselves. Underlying preference for ED transfer of aged care facility residents in acute medical emergencies is strong and independent of commonly used quality of care measures.

Identification of endogenous gibberellins in strawberry, including the novel gibberellins GA123, GA124 and GA125

Publisher: Elsevier BV

Date: 12-2000

DOI: 10.1016/S0031-9422(00)00237-5

Abstract: Extracts of carboxylic acids from immature fruits of strawberry (Fragaria x ananassa Duch. cv. Elsanta) were analysed for gibberellins by combined gas chromatography-mass spectrometry. The following previously characterised gibberellins were identified by comparison of their mass spectra and Kovats retention indices (KRIs) with those of standards or published data: GA1, GA3, GA5, GA8, GA12, GA17, GA19, GA20, GA29, GA44, GA48, GA49, GA53, GA77, GA97, GA111 and GA112. Evidence for endogenous 1-epi GA61 (GA119) and 11alpha-OH-GA12 was also obtained. In addition, a number of putative GAs were detected. Of these, three were shown to be 12alpha-hydroxy-GA53, 12alpha-hydroxy-GA44, and 12alpha-hydroxy-GA19 by comparison with authentic compounds prepared by rational synthesis, and have been allocated the descriptors GA123, GA124 and GA125, respectively.

Reducing Dendrimer Generation and PEG Chain Length Increases Drug Release and Promotes Anticancer Activity of PEGylated Polylysine Dendrimers Conjugated with Doxorubicin via a Cathepsin-Cleavable Peptide Linker

Publisher: American Chemical Society (ACS)

Date: 14-08-2018

DOI: 10.1021/ACS.MOLPHARMACEUT.8B00581

Abstract: PEGylation typically improves the systemic exposure and tumor biodistribution of polymeric drug delivery systems, but may also restrict enzyme access to peptide-based drug linkers. The impact of dendrimer generation (G4 vs G5) and PEG length (570 vs 1100 Da) on the pharmacokinetics, tumor biodistribution, drug release kinetics, and anticancer activity of a series of PEGylated polylysine dendrimers conjugated with doxorubicin via a cathepsin-B cleavable valine-citrulline linker was therefore investigated in rodents. Although the smallest G4 PEG570 dendrimer showed the most efficient cathepsin-mediated doxorubicin release, systemic exposure and tumor uptake were limited. The largest G5 PEG1100 dendrimer showed good tumor uptake and retention but restricted drug liberation and therefore limited anticancer activity. Superior anticancer activity was achieved using an intermediate sized dendrimer that showed better drug release kinetics, systemic exposure, tumor uptake, and retention. The data suggest that balancing PEG molecular weight and dendrimer size is critical when designing chemotherapeutic dendrimers.

In depth characterization of physicochemical critical quality attributes of a clinical drug-dendrimer conjugate

Publisher: Elsevier BV

Date: 04-2023

DOI: 10.1016/J.IJPHARM.2023.122905

The household economic burden for acute coronary syndrome survivors in Australia

Publisher: Springer Science and Business Media LLC

Date: 08-11-2016

DOI: 10.1186/S12913-016-1887-3

Chemo-Enzymatic Synthesis of Fluorescent Rab 7 Proteins: Tools to Study Vesicular Trafficking in Cells

Publisher: Wiley

Date: 15-02-1999

DOI: 10.1002/(SICI)1521-3773(19990215)38:4<509::AID-ANIE509>3.0.CO;2-3

Statistical analysis plan for the family-led rehabilitation after stroke in India (ATTEND) trial: A multicenter randomized controlled trial of a new model of stroke rehabilitation compared to usual ca

Publisher: SAGE Publications

Date: 22-10-2016

DOI: 10.1177/1747493016674956

Abstract: In low- and middle-income countries, few patients receive organized rehabilitation after stroke, yet the burden of chronic diseases such as stroke is increasing in these countries. Affordable models of effective rehabilitation could have a major impact. The ATTEND trial is evaluating a family-led caregiver delivered rehabilitation program after stroke. To publish the detailed statistical analysis plan for the ATTEND trial prior to trial unblinding. Based upon the published registration and protocol, the blinded steering committee and management team, led by the trial statistician, have developed a statistical analysis plan. The plan has been informed by the chosen outcome measures, the data collection forms and knowledge of key baseline data. The resulting statistical analysis plan is consistent with best practice and will allow open and transparent reporting. Publication of the trial statistical analysis plan reduces potential bias in trial reporting, and clearly outlines pre-specified analyses. India CTRI/2013/04/003557 Australian New Zealand Clinical Trials Registry ACTRN1261000078752 Universal Trial Number U1111-1138-6707.

Total Synthesis of the Potent Anticancer Aglaia Metabolites (−)-Silvestrol and (−)-Episilvestrol and the Active Analogue (−)-4′-Desmethoxyepisilvestrol

Publisher: American Chemical Society (ACS)

Date: 13-01-2009

DOI: 10.1021/JA808402E

Abstract: Total synthesis of the anticancer 1,4-dioxane containing natural products silvestrol (1) and episilvestrol (2) is described by an approach based on the proposed biosynthesis of these novel compounds. The key steps included an oxidative rearrangement of the protected d-glucose derivative 11 to afford the 1,4-dioxane 12, which could be elaborated to the coupling partner 5 and a photochemical [3 + 2]-cycloadditon between the 3-hydroxyflavone 27 and methyl cinnamate followed by base-induced alpha-ketol rearrangement and reduction to give the cyclopentabenzofuran core 33. The core (-)-6 and 1,4-dioxane fragment 5 were united by a highly stereoselective Mitsunobu coupling with the modified azodicarboxylate DMEAD to afford the axial coupled product 36. Deprotection then gave episilvestrol (2). Silvestrol (1) was synthesized by a coupling between core (-)-6 and the dioxane 44 followed by deprotection. Compound 1 was also synthesized from episilvestrol (2) by a Mitsunobu inversion. In addition, the analogue 4'-desmethoxyepisilvestrol (46) was synthesized via the same route. It was found that 46 and episilvestrol 2 displayed an unexpected concentration-dependent chemical shift variation for the nonexchangeable dioxane protons. Synthetic compounds 1, 2, 38, 46, and 54 were tested against cancer cells lines, and it was found that the stereochemistry of the core was critical for activity. Synthetic analogue 4'-desmethoxyepisilvestrol (46) was also active against lung and colon cancer cell lines.

Information, regulation and coordination: realist analysis of the efforts of community health committees to limit informal health care providers in Nigeria

Publisher: Springer Science and Business Media LLC

Date: 14-11-2016

DOI: 10.1186/S13561-016-0131-5

Multisite prospective investigation of psychological outcomes following cataract surgery in Vietnam

Publisher: BMJ

Date: 2017

DOI: 10.1136/BMJGH-2016-000162

Synthesis of gibberellin GA53 and its (17,17-D2)derivative

Publisher: CSIRO Publishing

Date: 1996

DOI: 10.1071/CH9960249

Abstract: Gibberellin GA53 (1) has been prepared by a modified Wolff- Kishner reduction of gibberellin GA19 protected as its 13-methoxymethyl ether (11). Careful regulation of the temperature at c. 174� is necessary, otherwise migration of the 16-ene function into the endocyclic 15-ene position occurs to an increasing extent at higher temperatures. The methodology was also extended to the preparation of the (17,17-D2)derivative (20).

A convenient synthesis of C-galactofuranosylic compounds (C-galactofuranosides)

Publisher: Elsevier BV

Date: 11-2002

DOI: 10.1016/S0008-6215(02)00133-7

Abstract: Galactofuranose sugar units are essential for the production of the cell coat of many pathogenic microorganisms. This sugar is not found in mammals, and so compounds that may interfere with the biosynthetic processing of this sugar unit provide interesting targets for drug design. This paper describes the use of a cyanation reaction for the production of a one-carbon extension of a galactofuranosylic unit at C-1, giving 2,5-anhydro-3,4,6,7-tetra-O-benzoyl-D-glycero-L-manno-heptononitrile. A procedure for the efficient hydrolysis of the introduced nitrile group to produce the methyl ester is reported, along with procedures for the synthesis of both the corresponding alpha,beta-unsaturated, and 3-deoxy ester derivatives.

An integrated general practice and pharmacy-based intervention to promote the use of appropriate preventive medications among individuals at high cardiovascular disease risk: Protocol for a cluster randomized controlled trial

Publisher: Springer Science and Business Media LLC

Date: 12-2016

DOI: 10.1186/S13012-016-0488-1

Analysis of out-of-pocket costs associated with hospitalised injuries in Vietnam

Publisher: BMJ

Date: 02-2017

DOI: 10.1136/BMJGH-2016-000082

Pulmonary administration of a doxorubicin-conjugated dendrimer enhances drug exposure to lung metastases and improves cancer therapy

Publisher: Elsevier BV

Date: 06-2014

DOI: 10.1016/J.JCONREL.2014.03.012

Abstract: Direct administration of chemotherapeutic drugs to the lungs significantly enhances drug exposure to lung resident cancers and may improve chemotherapy when compared to intravenous administration. Direct inhalation of uncomplexed or unencapsulated cytotoxic drugs, however, leads to bolus release and unacceptable lung toxicity. Here, we explored the utility of a 56kDa PEGylated polylysine dendrimer, conjugated to doxorubicin, to promote the controlled and prolonged exposure of lung-resident cancers to cytotoxic drug. After intratracheal instillation to rats, approximately 60% of the dendrimer was rapidly removed from the lungs (within 24h) via mucociliary clearance and absorption into the blood. This was followed by a slower clearance phase that reflected both absorption from the lungs (bioavailability 10-13%) and biodegradation of the dendrimer scaffold. After 7days, approximately 15% of the dose remained in the lungs. A syngeneic rat model of lung metastasised breast cancer was subsequently employed to compare the anticancer activity of the dendrimer with a doxorubicin solution formulation after intravenous and pulmonary administration. Twice weekly intratracheal instillation of the dendrimer led to a >95% reduction in lung tumour burden after 2weeks in comparison to IV administration of doxorubicin solution which reduced lung tumour burden by only 30-50%. Intratracheal instillation of an equivalent dose of doxorubicin solution led to extensive lung-related toxicity and death withinseveral days of a single dose. The data suggest that PEGylated dendrimers have potential as inhalable drug delivery systems to promote the prolonged exposure of lung-resident cancers to chemotherapeutic drugs and to improve anti-cancer activity.

Creating a new investment pool for innovative health systems research.

Publisher: CSIRO Publishing

Date: 2017

DOI: 10.1071/AH15230

Abstract: Recent trends in health research funding towards ‘safe bets’ is discouraging investment into the development of health systems interventions and choking off a vital area of policy-relevant research. This paper argues that to encourage investment into innovative and perceivably riskier health systems research, researchers need to create more attractive business cases by exploring alternative approaches to the design and evaluation of health system interventions. At the same time, the creation of dedicated funding opportunities to support this work, as well as for relevant early career researchers, is needed.

Synthesis and evaluation of aziridine analogues of presqualene diphosphate as squalene synthase inhibitors

Publisher: American Chemical Society (ACS)

Date: 19-12-1999

DOI: 10.1021/JO981833Z

The Course and Impact of Poststroke Insomnia in Stroke Survivors Aged 18 to 65 Years: Results from the Psychosocial Outcomes In StrokE (POISE) Study

Publisher: S. Karger AG

Date: 03-02-2017

DOI: 10.1159/000455751

Abstract: b i Background: /i /b Insomnia symptoms are common in the population and have negative psychosocial and functional sequelae. There are no prospective studies of the course of such symptoms and their impact, if any, in stroke survivors. This prospective cohort study investigated insomnia after stroke in working-age adults and evaluated its impact on psychological and functional outcomes over the subsequent year. b i Methods: /i /b We prospectively recruited 441 young (& #x3c years) consecutive stroke survivors from 20 public hospitals in the New South Wales Stroke Service network. Participants were assessed by self-report and interview at 28 days, 6 months, and 12 months after stroke. Insomnia was defined using a common epidemiological measure of sleep disturbance and daytime consequences. Depression, anxiety, disability, and return to work were assessed through standardized measures. b i Results: /i /b The point prevalence of insomnia at each time point in the year after stroke was stable at 30–37% and more common in females. Fifty-eight (16%) of all participants reported “chronic” insomnia, with symptoms at both baseline and 6 months later. At 12 months, this group was more likely to be depressed (OR 6.75, 95% CI 2.78–16.4), anxious (OR 3.31, 95% CI 1.54–7.09), disabled (OR 3.60, 95% CI 2.07–6.25), and not have returned to work, compared to those without insomnia over the same period. b i Conclusions: /i /b Chronic insomnia has a negative effect on disability and return to work 1 year after stroke even after adjusting for demographic, psychiatric, and disability factors. Identifying and appropriately targeting insomnia through known effective treatments may improve functional outcomes after stroke.

Synthesis and confirmation of structure of three 13,15β-dihydroxy C-20 gibberellins, GA100, GA101 and GA102, isolated from the seeds of Helianthus annuus L

Publisher: Elsevier BV

Date: 07-1996

DOI: 10.1016/0031-9422(96)00045-3

Identification of three C20-gibberellins: GA97 (2β-hydroxy-GA53), GA98 (2β-hydroxy-GA44) and GA99 (2β-hydroxy-GA19)

Publisher: Elsevier BV

Date: 09-1996

DOI: 10.1016/0031-9422(96)00251-8

Abstract: Three new C20-gibberellins, GA97 (2 beta-hydroxy-GA53), GA98 (2 beta-hydroxy-GA44) and GA99 (2 beta-hydroxy-GA19), have all been isolated from spinach, GA97 also from tomato root cultures and pea pods, and GA98 from maize pollen. The structures of these compounds were established by GC-mass spectrometric comparisons of the trimethylsilylated methyl esters with authentic s les prepared from gibberellic acid (GA3).

Design and optimisation of dendrimer-conjugated Bcl-2/xL inhibitor, AZD0466, with improved therapeutic index for cancer therapy

Publisher: Springer Science and Business Media LLC

Date: 25-01-2021

DOI: 10.1038/S42003-020-01631-8

Abstract: Dual Bcl-2/Bcl-x L inhibitors are expected to deliver therapeutic benefit in many haematological and solid malignancies, however, their use is limited by tolerability issues. AZD4320, a potent dual Bcl-2/Bcl-x L inhibitor, has shown good efficacy however had dose limiting cardiovascular toxicity in preclinical species, coupled with challenging physicochemical properties, which prevented its clinical development. Here, we describe the design and development of AZD0466, a drug-dendrimer conjugate, where AZD4320 is chemically conjugated to a PEGylated poly-lysine dendrimer. Mathematical modelling was employed to determine the optimal release rate of the drug from the dendrimer for maximal therapeutic index in terms of preclinical anti-tumour efficacy and cardiovascular tolerability. The optimised candidate is shown to be efficacious and better tolerated in preclinical models compared with AZD4320 alone. The AZD4320-dendrimer conjugate (AZD0466) identified, through mathematical modelling, has resulted in an improved therapeutic index and thus enabled progression of this promising dual Bcl-2/Bcl-x L inhibitor into clinical development.

A one-pot synthesis of novel N,N-dialkyl-S-glycosylsulfenamides

Publisher: Elsevier BV

Date: 09-2000

DOI: 10.1016/S0008-6215(00)00110-5

Abstract: An efficient new entry into N,N-dialkyl-S-glycosylsulfenamides is reported. The reaction of bis-activated alkyl halides in the presence of a secondary amine base with glycosylic S-acetyl derivatives (1-S-acetyl-1-thioaldoses or 2-S-acetyl-2-thioketoses) results in the formation of novel carbohydrate sulfonamides. These new carbohydrate-based sulfonamides may provide useful derivatives with biological activity, as well as provide reactive carbohydrate sulfonylating agents.

Characterisation and tumour targeting of PEGylated polylysine dendrimers bearing doxorubicin via a pH labile linker

Publisher: Elsevier BV

Date: 06-2011

DOI: 10.1016/J.JCONREL.2011.02.005

Abstract: Polylysine dendrimers have potential as biodegradable vectors for the delivery of cytotoxic drugs to solid tumours. Here, the cytotoxicity, drug release and tumour targeting properties of Generation 5 PEGylated polylysine dendrimers comprising an outer generation of l-lysine or succinimyldipropyldiamine (SPN) and containing doxorubicin (DOX) linked through an acid labile 4-(hydrazinosulfonyl) benzoic acid (HSBA) linker have been characterised. Less than 10% of the DOX load was released from LYS or SPN dendrimers in pH 7.4 buffer over 3 days. In contrast approximately 100% release was evident at pH 5. The DOX-conjugated dendrimers also retained similar cytotoxic properties to free DOX in in vitro cell culture studies (presumably as a result of in situ liberation of free DOX). The clearance patterns of the DOX conjugated SPN and all-lysine dendrimers were similar to the equivalent non-DOX conjugated systems, however the SPN dendrimers showed reduced metabolic lability and increased uptake into RES organs when compared to the equivalent all-lysine dendrimers. In vivo assessment of the DOX-conjugated, PEGylated polylysine dendrimers (both SPN and LYS constructs) in rats bearing Walker 256 tumours revealed higher uptake into tumour tissue when compared with control tissue such as muscle (~8 fold) and heart (~3 fold). The data suggest that polylysine dendrimers containing DOX conjugated via an acid labile HSBA linker may provide a mechanism to target the delivery of DOX to tumours.

Family-led rehabilitation after stroke in India (ATTEND): a randomised controlled trial

Publisher: Elsevier BV

Date: 08-2017

DOI: 10.1016/S0140-6736(17)31447-2

Synthesis of 12-hydroxy C20-gibberellins

Publisher: Elsevier BV

Date: 02-1997

DOI: 10.1016/S0040-4020(96)01109-X

Process evaluations for large clinical trials involving complex interventions

Publisher: Springer Science and Business Media LLC

Date: 11-2017

DOI: 10.1038/SC.2017.107

Cerylid Biosciences

Location: Australia

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University Of Queensland

Location: No location found

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University Of Utah

Location: United States of America

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Mimotopes Pty Ltd.

Location: Australia

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Australian National University

Location: Australia

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University Of Queensland

Location: Australia

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Karlsruher Institut Für Technologie Fakultät Für Wirtschaftswissenschaften

Location: Germany

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Starpharma (Australia)

Location: Australia

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Monash University Faculty Of Pharmacy And Pharmaceutical Sciences

Location: Australia

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Griffith University Institute For Glycomics

Location: Australia

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Controlling The Spatial Distribution Of Targeting Ligands On Dendrimer Surfaces As A Means Of Dictating Cellular Recognition And Fate

Start Date: 2014

End Date: 2017

Funder: Australian Research Council

A Structure-based Design Approach To Maximising Targeting Interactions

Start Date: 2020

End Date: 2023

Funder: Australian Research Council

ARC Research Hub For Advanced Manufacture Of Targeted Radiopharmaceuticals

Start Date: 2022

End Date: 2026

Funder: Australian Research Council

(Designing Dendrimer-based Lymphatic Drug Vectors As Improved Treatments For Metastatic Cancer)

Start Date: 2010

End Date: 2013

Funder: Australian Research Council

Linkage Projects - Grant ID: LP100200500

Start Date: 2011

End Date: 2014

Amount: $410,000.00

Funder: Australian Research Council

Linkage Projects - Grant ID: LP130100672

Start Date: 2014

End Date: 12-2017

Amount: $547,863.00

Funder: Australian Research Council

Linkage Projects - Grant ID: LP200100540

Start Date: 07-2020

End Date: 12-2023

Amount: $433,000.00

Funder: Australian Research Council

Industrial Transformation Research Hubs - Grant ID: IH220100017

Start Date: 09-2023

End Date: 09-2028

Amount: $4,808,669.00

Funder: Australian Research Council