[Show abstract][Hide abstract] ABSTRACT: Evaluation of noribogaine safety, pharmacokinetics and effects on opioid withdrawal in methadone-dependent patients
Paul Gluea, Michelle Lockhartb, Fred Lamc, Noelyn Hungc, C Tak Hungc, Donna Tunnicliffed, Gavin Caped, Jane Devanee, Holger Weise, John Howese and Lawrence Friedhofff
aUniversity of Otago, Dunedin, New Zealand; bUniversity of Auckland, NZ; cZenith Technology Ltd, Dunedin, NZ; dCommunity Alcohol and Drug Service, Dunedin, NZ; eDemeRx, Inc., Fort Lauderdale, Florida, USA; fPharmaceutical Special Projects Group, LLC
Introduction: The iboga alkaloids appear to have striking efficacy for treatment of substance dependence in individual and case series reports, but no blinded, controlled clinical trials have been performed. This study tested single doses of noribogaine hydrochloride (NI), an analog of ibogaine, in opioid-dependent patients.
Objectives: To evaluate the safety, tolerability, pharmacokinetics (PK) and changes in withdrawal ratings after single doses of NI or placebo (PLA) administered to opioid-dependent patients.
Methods: This was a phase 1B, randomized, double-blind, placebo-controlled, single ascending dose study in 27 patients seeking to discontinue methadone opioid substitution treatment (OST). The study was conducted in 3 cohorts each with 6 active and 3 placebo patients. NI doses were 60mg, 120mg or 180mg. 1 week prior to NI administration, methadone was replaced by oral, controlled-release morphine (6 days) followed by 1 day of oral immediate-release (IR) morphine. On the NI treatment day, a single dose of IR morphine was administered followed 2 hours later by a single blinded oral dose of NI or PLA. Patients resuming OST received morphine within 24h of blinded NI/PLA dosing, and methadone post-24h. PK blood samples were collected for 7 days following NI/PLA. Safety assessments were conducted to Day 21 (±3) following NI/PLA. Safety monitoring included: physical examinations, vital signs, serum chemistry, hematology, urinalysis, 12 lead ECGs, Holter monitoring, telemetry, oximetry, capnography, pupillometry, opioid withdrawal rating scales and mood VAS.
Results: NI was well tolerated. In addition to signs and symptoms of opioid withdrawal, the most frequent treatment-emergent adverse events were headache and nausea. Non-euphoric changes in light perception occurred at ~1h post dosing and decreased/disappeared by 2.5-3h post-dose. NI peak concentrations occurred 2-4 hours post-dose, with dose-linear increases for AUC and Cmax. The drug was slowly eliminated with t1/2 estimates of 24-30 hours across dose groups. There was a concentration-dependent increase in QTcI (0.17msec/ng/mL) and dose-dependent peak increases in QTcI of ~16msec, 28msec, and 42msec in the 60mg, 120mg, and 180mg groups, respectively. There were no changes in vital signs or safety laboratory tests. There were no statistical differences between the mean time to OST in the NI cohorts vs PLA. The 120mg cohort had the longest time to OST resumption with trend significance vs PLA. NI showed a trend to decrease total scores in the opioid withdrawal rating scales, most notably at the 120mg dose, but the study was not powered for this endpoint.
Conclusions: NI pharmacokinetic parameters in opioid-dependent patients were similar to those from a prior healthy volunteer study. NI was well tolerated. The main safety finding was a concentration-dependent increase in QTcI. QTc increases from NI continued to decline after restarting methadone. The lack of statistically significant dose-related changes in time to OST resumption could be due to the small number of patients, and possible contamination effects from co-localization of patients during the in-patient portion of the study. Future multiple-dose NI studies are planned, using dosing regimens to limit changes in QTc.
The 46th ASAM Annual Conference, Austin, Texas, USA; 04/2015
[Show abstract][Hide abstract] ABSTRACT: Conversion of ibogaine to its active metabolite noribogaine appears to be mediated primarily by CYP2D6. We compared 168 h pharmacokinetic profiles of both analytes after a single oral 20 mg dose of ibogaine in 21 healthy subjects who had been pretreated for 6 days with placebo or the CYP2D6 inhibitor paroxetine. In placebo-pretreated subjects, ibogaine was rapidly converted to noribogaine. Median peak noribogaine concentrations occurred at 4 h. Compared with placebo-pretreated subjects, paroxetine-pretreated subjects had rapid (Tmax = 1.5 h) and substantial absorption of ibogaine, with detectable levels out to 72 h, and an elimination half-life of 10.2 h. In this group, ibogaine was also rapidly converted to noribogaine with a median Tmax of 3 h. Extent of noribogaine exposure was similar in both groups. CYP2D6 phenotype was robustly correlated with ibogaine AUC0-t (r = 0.82) and Cmax (r = 0.77). Active moiety (ibogaine plus noribogaine) exposure was ∼2-fold higher in paroxetine-pretreated subjects. Single 20 mg ibogaine doses were safe and well tolerated in all subjects. The doubling of exposure to active moiety in subjects with reduced CYP2D6 activity suggests it may be prudent to genotype patients awaiting ibogaine treatment, and to at least halve the intended dose of ibogaine in CYP2D6 poor metabolizers. This article is protected by copyright. All rights reserved
The Journal of Clinical Pharmacology 02/2015; · 2.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Noribogaine is the active metabolite of the naturally occurring psychoactive substance ibogaine, and may help suppress withdrawal symptoms in opioid dependent subjects. The objectives of this Phase I study were to assess the safety, tolerability, pharmacokinetic and pharmacodynamic profile of noribogaine. In this ascending single-dose, placebo-controlled, randomised, double-blind, parallel-group study in 36 healthy drug-free male volunteers, four cohorts (n=9) received oral doses of 3, 10, 30 or 60mg or matching placebo, with intensive safety and pharmacokinetic assessments out to 216h, along with pharmacodynamic assessments sensitive to the effects of mu-opioid agonists. Noribogaine was rapidly absorbed, with peak concentrations occurring 2-3 hours after oral dosing, and showed dose-linear increases of AUC and Cmax between 3-60mg. The drug was slowly eliminated, with mean half-life estimates of 28-49 hours across dose groups. Apparent volume of distribution was high (mean 1417-3086 L across dose groups). No safety or tolerability issues were identified in any cohort. No mu-opioid agonist pharmacodynamic effects were noted in pupillometry or cold-pressor testing. Single oral doses of noribogaine 3-60mg were safe and well tolerated in healthy volunteers.
The Journal of Clinical Pharmacology 10/2014; · 2.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives. Research studies have reported impressive antidepressant effects with ketamine but significant knowledge gaps remain over the best method of administering ketamine, and the relationships between dose, antidepressant response and adverse effects. Methods. In this pilot dose-finding study, the efficacy and tolerability of ketamine given by rapid intravenous (i.v.) infusion were assessed in a double-blind, placebo-controlled, crossover design, in four subjects with treatment- resistant depression. Each subject received up to four i.v. doses of ketamine (0.1, 0.2, 0.3, 0.4 mg/kg), given over 2–5 min, 1 week apart, and one randomly inserted placebo treatment. Results. Three of four subjects achieved antidepressant response (≥ 50% decrease in Montgomery–Asberg Depression Rating Scale scores), two at the minimum 0.1 mg/kg dose, though all relapsed within a week. For two subjects, the greatest improvement occurred at the highest dose received. Rapid infusion over 2 min led to significant adverse psychotomimetic effects which also increased proportionately with ketamine dosage. Conclusions. This is the first trial to present dose–response data of ketamine efficacy and psychomimetic effects in depressed subjects. Antidepressant efficacy may be dose-related. Psychotomimetic effects were dose-related. Rapid infusion over 2 min may not be a feasible clinical approach to treatment, given poor tolerability.
The World Journal of Biological Psychiatry 06/2014; 15:579-584. · 4.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Auckland and Otago medical programmes have different methods for selecting students. This study compared postgraduate retention in New Zealand (NZ) of medical graduates from the two medical programmes, to assess whether different selection methods influenced retention. Other variables assessed included entrance category and age at graduation.
Anonymised databases were created of all graduates from the Otago Faculty of Medicine (1999-2011) and the Auckland medical programme (2000-2012). Demographic and entry category data were recorded. Retention was defined as presence on the NZ Medical Register in December 2012. Risk differences (RD) were calculated to compare retention between the two medical programmes using the Mantel-Haenszel method. The influence of medical programme entrance category on retention was also tested. The influence of covariates on retaining graduates on the register was evaluated using a multiple logistic regression model.
The postgraduate retention of graduates of the two medical programmes over 13 years was identical (Auckland 74.9%, Otago 73.6%, P=0.48). Retention of graduate and non-graduate entry students from both medical programmes was similar by 6 years after graduation. Age during medical school did not affect retention.
University of attendance had no effect on postgraduation retention of students on the NZ Medical Register, suggesting that retention is not influenced by the different student selection methods at each programme. The data presented shows that New Zealand graduates regardless of programme completed show a similar profile in terms of retention.
The New Zealand medical journal 01/2014; 127(1388):47-54.
[Show abstract][Hide abstract] ABSTRACT: Objectives:There are wide global variations in electroconvulsive therapy (ECT) use patterns. This audit reviewed patient-level ECT use patterns over 10 years at a single New Zealand clinic, including factors associated with clinical response and patterns of repeated administration.Methods:Retrospective audit of all 2003-2012 ECT and clinical file data.Results:A total of 199 patients received ECT, which was used to treat mostly affective disorders in a predominantly female, older population, generally with a single course of treatment. There were different demographics and patterns of ECT use between patients being treated for affective and psychotic disorders. Overall treatment response was high, with over 90% of patients having a full or partial response. Treatment response was not associated with diagnosis, gender, or medication use, but showed a trend in significance for greater response in elderly patients.Conclusions:ECT use patterns in Otago New Zealand are similar to those reported in Australia, USA, and UK, although yearly use rate in Otago is lower. Because of their different demographic and ECT treatment patterns, future studies should report data for patients with affective and psychotic disorders separately.
Australian and New Zealand Journal of Psychiatry 11/2013; · 3.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Voriconazole is more effective for aspergillosis infections with central nervous system involvement than other antifungal agents. The clinical efficacy of voriconazole for central nervous system infections has been attributed to its ability to cross the blood brain barrier. However, pharmacokinetic studies are limited to plasma and cerebrospinal fluid so it remains unclear how much of the drug enters the brain. Fluorinated compounds such as voriconazole can be quantified in the brain using fluorine-19 magnetic resonance spectroscopy (MRS). Twelve healthy adult males participated in a pharmacokinetic analysis of voriconazole levels in the brain and plasma. Open label voriconazole was dosed per clinical protocol with a loading dose of 400 mg every 12 hours on Day 1 followed by 200 mg every 12 hours administered orally over a 3 day period. MRS was performed before and after dosing on the third day. Voriconazole levels in the brain exceeded the minimum inhibitory concentration for Aspergillus. The brain to plasma ratio was 3.0 at steady state on Day 3 (predose) and 1.9 postdose. This study indicates that voriconazole is able to penetrate the brain tissue, which can be quantified using a non-invasive MRS technique.
Antimicrobial Agents and Chemotherapy 08/2013; · 4.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective:Narrative review of the literature on the efficacy and safety of subanaesthetic doses of ketamine for the treatment of depression.Method:Medline and PubMed databases were searched up to October 2012 using appropriate keywords.Results:The studies consistently report substantial efficacy with high response and remission rates from 4 to 72 hours (averages 77% and 43%, respectively) from single doses, though not all patients respond to ketamine. Early relapse is common. While the usual procedure involves the administration of intravenous ketamine at a dose of 0.5 mg/kg over 40 minutes, some preliminary evidence suggests other dosing regimens and routes of administration may be useful or even better. Repeated doses and maintenance pharmacological treatments have been investigated in order to prolong the antidepressant effects, with only modest success.Conclusions:Current research on the antidepressant effects of ketamine has consistently shown rapid and substantial improvement in mood in the majority of patients. However, these effects have often been found to be short-lived. Future research should focus on identifying predictors of response (e.g. clinical, genetic, pharmacokinetic, environmental), examining different dosing regimens and routes of administration, and strategies to maintain the antidepressant response.
Australian and New Zealand Journal of Psychiatry 05/2013; · 3.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background There is conjecture regarding the profile of cognitive development over time in chil-dren with Down syndrome (DS). Characterising this profile would be valuable for the planning and assessment of intervention studies. Method A systematic search of the literature from 1990 to the present was conducted to identify
Journal of Intellectual Disability Research 04/2013; 57(4):306-318. · 2.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE: Factors associated with acute admission to inpatient psychiatric wards have been difficult to replicate, possibly reflecting methodological limitations of analyzing individual variables. The objective of this analysis was to identify factors associated with hospitalization at an inpatient psychiatric unit using cluster analytic methods. METHODS: Demographic, admission and treatment data for all admissions to a single inpatient unit in 2010 were collected retrospectively. Cluster analysis was performed using Ward's method. RESULTS: The initial clustering identified a high suicidality/crisis group, which then gave two further subclusters, an internalizing one characterized by affective symptoms and an externalizing one characterized by intoxication at admission, and a population with poor medication compliance that included most cases of psychosis. These subclusters had different clinical and demographic characteristics, different rates of hospital readmission and different durations of stay. CONCLUSIONS: Cluster analysis may be a useful exploratory technique to assist in planning and developing services for adult patients needing admission to a psychiatric hospital.
[Show abstract][Hide abstract] ABSTRACT: To evaluate the proportion of patients hospitalised in an acute psychiatric ward associated with use of the synthetic cannabinoid K2, along with their clinical features.
Retrospective audit. K2 use was based on self-report.
Seventeen patients had a total of 21 admissions during between January and April 2013; this represented 13% of all admissions to the ward during this time. This was a first hospitalisation for 4 patients. Of the 13 patients with previous psychiatric hospitalisation, 9 patients had recurrences of pre-existing disorders, and 4 patients presented new psychotic symptoms. Presenting symptoms were variable, and included psychotic (paranoia, thought disorder, disorganised behaviour), affective (anxious, depressed) disturbances, and/or intense suicidal thinking/behaviour. Mean duration of admission was 8.5 days, with significantly longer durations for those presenting with psychotic symptoms (13.1 vs 4.4 days).
In this case series, use of K2 was associated with significant psychotoxicity requiring hospitalisation, and indicates substantial risk associated with use of synthetic cannabinoids.
The New Zealand medical journal 01/2013; 126(1377):18-23.
[Show abstract][Hide abstract] ABSTRACT: To examine the influence of a number of variables, including age and medical school entrance category, on postgraduate retention of New Zealand (NZ) medical graduates.
An anonymised database was created of all graduates from the Otago School of Medicine (1999-2010), with demographic and entry category data. The NZ Medical Register was checked in January 2012 to identify which graduates remained in NZ. Risk Differences (RD) were calculated to compare retention between medical school entrance categories by year of graduation using the random effects Mantel-Haenszel method. The influence of covariates on remaining on the New Zealand Medical Register was evaluated using logistic regression.
The odds of remaining on the NZ Medical Register increased by 7% for each additional year of age at graduation (Odds Ratio=1.070, 95%CI 1.038-1.113, p<0.001). Compared with students who entered medical school after a competitive first year exam, retention of students who entered after completion of a bachelor's degree was 7% higher, and 20% higher for "Other Category" (older, work experienced) students. Multiple logistic regression identified medical school entry category as the only significant predictor of higher retention.
Admission policies favouring graduate entry and "Other Category" students could contribute to increased retention of NZ medical graduates.
The New Zealand medical journal 01/2013; 126(1371):27-32.