ORCID Profile
0000-0003-3808-7562
Current Organisations
University of Newcastle Australia
,
NHMRC Australian Centre for Cannabinoid Clinical and Research Excellence
,
University of New South Wales
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Publications
Cannabidiol for treating drug‐resistant epilepsy in children: the New South Wales experience
Publisher: AMPCo
Date: 13-08-2018
DOI: 10.5694/MJA18.00023
Abstract: To evaluate the tolerability and safety of cannabidiol for treating drug-resistant epilepsy in children, and to describe adverse events associated with such treatment. Prospective, open label cohort study. Three tertiary NSW referral centres with paediatric neurology services. First 40 children enrolled in the NSW Compassionate Access Scheme for children with drug-resistant epilepsy and uncountable daily seizures. Children received cannabidiol as an adjunct anti-epileptic drug, titrated to a maximum of 25 mg/kg/day, for up to 12 weeks. Adverse events, withdrawals, and caregiver and physician Global Impression of Change assessments were recorded at 4, 8 and 12 weeks. Seizure frequency could not be reliably recorded because of disease severity. Thirty-nine patients reported at least one adverse event many were deemed unrelated to cannabidiol treatment. The most frequent treatment-related adverse event was somnolence (15 participants), which resolved spontaneously in ten patients it was particularly frequent in patients taking higher clobazam doses. Gastrointestinal effects (nausea, vomiting, diarrhoea) were each reported by seven to nine participants. Four children were withdrawn from treatment, including one with elevated transaminase levels. The caregivers of 12 children felt the overall health of their children had much or very much improved clinicians assessed seven children as being much or very much improved. Cannabidiol as an adjunct treatment had some subjective benefit for overall health, with a manageable adverse event profile. Monitoring changes in liver function and awareness of potential drug interactions is essential. Whether the reported benefit is attributable to cannabidiol cannot be established in an open label study of participants with severe intractable epilepsy.
Developing a preclinical model of Parkinson's disease: A study of behaviour in rats with graded 6-OHDA lesions
Publisher: Elsevier BV
Date: 04-2006
DOI: 10.1016/J.BBR.2005.11.026
Abstract: Injection of increasing concentrations of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle (MFB) can be used to establish a graded model of different clinical stages of Parkinson's disease (PD). We investigated the relationship between behavioural alterations and loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). Forty female Sprague-Dawley rats were injected with either (i) 4 microg (ii) 8 microg or (iii) 16 microg 6-hydroxydopamine (6-OHDA) to mimic the preclinical, mild and advanced clinical stages of PD, respectively. Vehicle was injected in a separate control group. Behaviours analysed included postural asymmetry, balance, locomotion, sensorimotor deficits and apomorphine rotation. At post-mortem the degree of tyrosine immunoreactive dopaminergic cell (TH-ir) loss was then estimated. There was a graded and consistent trend in each of the behaviours studied with respect to cell loss between the different sized lesion groups when examined using correlation analysis (all comparisons, r > 0.8, p < 0.001). Rats with large lesions demonstrated more significant behavioural changes over 8 weeks of testing than those with intermediate and smaller lesions (group comparisons p < 0.001). PD symptomatology became overt when cell loss reached 70%, however some significant changes can be observed with as little as 40% dopaminergic cell loss. Thus, injection with increasing concentrations 6-OHDA into the MFB can produce increasing extents of cell loss and behavioural changes, which were well correlated. This graded model can be useful for testing potential neuroprotective compounds for PD.
Effect of cortical spreading depression on basal and evoked traffic in the trigeminovascular sensory system
Publisher: SAGE Publications
Date: 22-09-2011
Abstract: Aim: To use an animal model to test whether migraine pain arises peripherally or centrally. Methods: We monitored the spontaneous and evoked activity of second-order trigeminovascular neurons in rats to test whether traffic increased following a potential migraine trigger (cortical spreading depression, CSD) and by what mechanism any such change was mediated. Results: Neurons ( n = 33) responded to stimulation of the dura mater and facial skin with A-δ latencies. They were spontaneously active with a discharge rate of 6.1 ± 6.4 discharges s −1 . Injection of 10 µg lignocaine into the trigeminal ganglion produced a fully reversible reduction of the spontaneous discharge rate of neurons. Neuronal discharge rate returned to normal by 90 min. Lignocaine reduced the evoked responses of neurons to dural stimulation to 37% and to facial skin stimulation to 53% of control. Induction of CSD by cortical injection of KCl increased the spontaneous discharge rate of neurons from 2.9 to 16.3 discharges s −1 at 20 min post CSD. Injection of 10 µg lignocaine into the trigeminal ganglion at this time failed to arrest or reverse this increase. Injection of lignocaine prior to the initiation of CSD failed to prevent the subsequent development of CSD-induced increases in discharge rates. Conclusions: These results suggest that there is a continuous baseline traffic in primary trigeminovascular fibres and that CSD does not act to increase this traffic by a peripheral action alone − rather, it must produce some of its effect by a mechanism intrinsic to the central nervous system. Thus the pain of migraine may not always be the result of peripheral sensory stimulation, but may also arise by a central mechanism.
Stimulation of dural vessels excites the SI somatosensory cortex of the cat via a relay in the thalamus
Publisher: SAGE Publications
Date: 14-10-2013
Abstract: We carried out experiments in cats to determine the thalamo-cortical projection sites of trigeminovascular sensory neurons. 1) We stimulated the middle meningeal artery (MMA) with C-fibre intensity electrical shocks and made field potential recordings over the somatosensory cortical surface. 2) We then recorded neurons in the ventroposteromedial (VPM) nucleus of the thalamus in search of neurons which could be activated from the skin, MMA and superior sagittal sinus. 3) Finally, we attempted to antidromically activate the neurons found in stage 2 by stimulating the responsive cortical areas revealed in stage 1. VPM neurons received trigeminovascular input, input from the V1 facial skin and could also be activated by electrical stimulation of the somatosensory cortex. VPM neurons activated from the cortex responded with short and invariant latencies (6.7 ± 7.7 msec mean and SD). They could follow high rates of stimulation and sometimes showed collision with orthodromic action potentials. We conclude that somatosensory (SI) cortical stimulation excites trigeminovascular VPM neurons antidromically. In consequence, these VPM neurons project to the somatosensory cortex. These findings may help to explain the ability of migraineurs with headache in the trigeminal distribution to localise their pain to a particular region in this distribution.
Over the counter low-dose cannabidiol: A viewpoint from the ACRE Capacity Building Group
Publisher: SAGE Publications
Date: 03-08-2022
DOI: 10.1177/02698811211035394
Abstract: Amidst growing global acceptance of medicinal cannabinoids as a potential therapeutic interest in cannabidiol (CBD) is increasing. In Australia in 2020, a government inquiry examined the barriers that the public are experiencing in accessing medicinal cannabis. A number of recommendations to improve access were made. In response to these recommendations, the Australian therapeutics regulatory authority down-scheduled CBD from Prescription Only (Schedule 4) to Pharmacist Only (Schedule 3). As a group of early to mid-career researchers of the Australian Centre for Cannabinoid Clinical and Research Excellence (ACRE), we propose some considerations in relation to over-the-counter availability of CBD and opportunities to improve knowledge about its potential therapeutic benefits alongside its increased uptake.
Behavioural effects of a selective NMDA NR1A/2B receptor antagonist in rats with unilateral 6-OHDA+parafascicular lesions
Publisher: Elsevier BV
Date: 02-2009
DOI: 10.1016/J.BRAINRESBULL.2008.10.004
Abstract: Experimental lesions involving the parafascicular (Pf) nucleus and medial forebrain bundle (MFB) may model to some extent the pathological loss of glutamatergic neurons from the centromedian-parafascicular (CM-Pf) complex and nigral dopaminergic cell loss observed clinically at post-mortem in Parkinson's disease (PD) cases. Our study investigated whether there were alterations in symptomatology in such rats with unilateral 6-OHDA+Pf lesions after treatment with either a selective NR1A/NR2B NMDA antagonist and/or l-dopa. Rats were given dual surgery to the MFB with 6-hydroxydopamine (6-OHDA) and Pf with N-methyl-d-aspartate (NMDA). (i) An NR1A/NR2B selective NMDA antagonist (BZAD-01 10mg/kg), (ii) l-dopa (25mg/kg), (iii) BZAD-01+l-dopa (10mg/kg 25mg/kg) or (iv) vehicle solution were administered for 6 weeks, during which behavioural testing was performed. BZAD-01 improved postural asymmetry in the first month as well as apomorphine-induced rotation. The latter was also improved by l-dopa in this model. These data support the use of selective NR1/NR2B NMDA antagonists in the therapeutics of PD.
Efficacy and safety of cannabidivarin treatment of epilepsy in girls with Rett syndrome: A phase 1 clinical trial
Publisher: Wiley
Date: 20-04-2022
DOI: 10.1111/EPI.17247
Abstract: Rett syndrome (RTT), commonly caused by methyl‐CpG‐binding protein 2 ( MECP2 ) pathogenic variants, has many comorbidities. Fifty to ninety percent of children with RTT have epilepsy, which is often drug‐resistant. Cannabi arin (CBDV), a non‐hallucinogenic phytocannabinoid, has shown benefit in MECP2 animal models. This phase 1 trial assessed the safety and tolerability of CBDV in female children with RTT and drug‐resistant epilepsy, as well as the effect on mean monthly seizure frequency (MMSF), the electroencephalogram (EEG), and non‐epilepsy comorbid symptoms. Five female children with drug‐resistant epilepsy and a pathogenic MECP2 variant were enrolled. Baseline clinical and laboratory assessments, including monthly seizure frequency, were recorded. CBDV oral solution (50 mg/ml) was prescribed and titrated to 10 mg/kg/day. Data collected included pharmacokinetics, seizure type and frequency, adverse events, EEG, and responses to the Rett Syndrome Behaviour Questionnaire and Rett Syndrome Symptom Severity Index, and were compared to baseline data. All five children reached the maximum CBDV dose of 10 mg/kg/day and had a reduction in MMSF (median = 79% reduction). Three children had MMSF reduction 75%. This corresponded to an overall reduction in seizure frequency from 32 to 7.2 seizures per month. Ninety‐one percent of adverse events were mild or moderate, and none required drug withdrawal. Sixty‐two percent were judged to be unrelated to CBDV. Thirty‐one percent of adverse events were identified as possibly related, of which nearly all were mild, and the remainder were later assessed as RTT symptoms. Hypersomnolence and drooling were identified as related to CBDV. No serious adverse events reported were related to CBDV. No significant change was noted in EEG or non‐epilepsy‐related symptoms of RTT. A dose of 10 mg/kg/day of CBDV is safe and well tolerated in a pediatric RTT cohort and suggests improved seizure control in children with MECP2 ‐related RTT.
Relative Preservation of Thalamic Centromedian Nucleus in Parkinsonian Patients with Dystonia
Publisher: Wiley
Date: 04-09-2009
DOI: 10.1002/MDS.22747
Abstract: To determine whether variable thalamic degeneration in Parkinson's disease (PD) contributes to less drug responsive clinical features. Formalin-fixed thalami from longitudinally followed patients with PD and early dystonia (N = 6), early falls (N = 5) or no dystonia or falls (N = 6) and age-matched controls without neuropathology (N = 10) were serially sectioned, stained, and analyzed. Neurons in the centromedian parafascicular (CM-Pf) nucleus were quantified using the optical disector method and analysis of variance with post hoc testing used to determine variability in neurodegeneration between groups. Patients with PD were confirmed to have significant neurodegeneration in the CM-Pf complex, with no difference in the degree of neurodegeneration between patients with PD with early falls compared with patients with no history of falls or dystonia. In contrast, patients with PD with early dystonia had significantly less neurodegeneration of the CM but not the Pf than patients without this feature. Preservation of the CM in patients with PD with early dystonia would result in a relative increase in CM activity through the direct basal ganglia pathway and increased primary motor cortex activity. Overall this data provides evidence for pathway-specific neurodegeneration as an underlying feature of the clinical variability observed in patients with PD.
Related Organisations
NHMRC Australian Centre For Cannabinoid Clinical And Research Excellence
Location: Australia
South Eastern Finland University Of Applied Sciences
Location: Finland
Elsevier Ltd
Location: United Kingdom of Great Britain and Northern Ireland
Related Funding Activities
No related grants have been discovered for Linda Truong.