ABSTRACT
BACKGROUND: Methamphetamine dependence is a significant public health concern without any approved medications for treatment. We evaluated ibudilast, a nonselective phosphodiesterase inhibitor, to assess the safety and tolerability during intravenous methamphetamine administration. We conducted a randomized, double-blind, placebo-controlled, within-subjects crossover clinical trial. METHODS: Participants received ibudilast (20 mg twice daily followed by 50 mg twice daily) and placebo, with order determined by randomization, and then underwent intravenous methamphetamine challenges (15 and 30 mg). We monitored cardiovascular effects, methamphetamine pharmacokinetics, and reported adverse events. RESULTS: Ibudilast treatment had similar rates of adverse events compared with placebo, and there was no significant augmentation of cardiovascular effects of methamphetamine. Pharmacokinetic analysis revealed no clinically significant change in maximum concentration or half-life of methamphetamine with ibudilast. CONCLUSIONS: Methamphetamine administration during ibudilast treatment was well tolerated without additive cardiovascular effects or serious adverse events, providing initial safety data to pursue ibudilast's effectiveness for the treatment of methamphetamine dependence.
Subject(s)
Amphetamine-Related Disorders/drug therapy , Central Nervous System Stimulants , Methamphetamine , Outcome Assessment, Health Care , Phosphodiesterase Inhibitors/pharmacology , Pyridines/pharmacology , Administration, Intravenous , Adult , Central Nervous System Stimulants/administration & dosage , Central Nervous System Stimulants/adverse effects , Central Nervous System Stimulants/pharmacokinetics , Central Nervous System Stimulants/pharmacology , Cross-Over Studies , Double-Blind Method , Female , Humans , Male , Methamphetamine/administration & dosage , Methamphetamine/adverse effects , Methamphetamine/pharmacokinetics , Methamphetamine/pharmacology , Middle Aged , Phosphodiesterase Inhibitors/administration & dosage , Phosphodiesterase Inhibitors/adverse effects , Pyridines/administration & dosage , Pyridines/adverse effectsABSTRACT
INTRODUCTION AND AIMS: Cigarette smoking occurs frequently among individuals with methamphetamine (MA) dependence. Preclinical and clinical evidence has suggested that the common co-abuse of MA and cigarettes represents a pharmacologically meaningful pattern. METHODS: The present study is a secondary analysis of a randomised, placebo-controlled trial of bupropion treatment for MA dependence (bupropion n = 36; placebo n = 37). A hierarchical logistic modelling approach assessed the efficacy of bupropion for reducing MA use separately among smokers and non-smokers. Among smokers, relations between cigarettes smoked and MA use were assessed. RESULTS: Smoking status did not affect treatment responsiveness in either the bupropion condition or the placebo condition. In the placebo condition, increased cigarette use was associated with an increased probability of MA use during the same time period. This effect was not observed in the bupropion condition. DISCUSSION AND CONCLUSIONS: Initial smoking status did not impact treatment outcomes. Among smokers, results suggest that bupropion may dissociate cigarette and MA use. The effect was modest and a precise pharmacological mechanism remains elusive. Cholinergic systems may be relevant for MA use outcomes. Future studies should continue to assess the role of smoking in MA treatment outcomes.
Subject(s)
Amphetamine-Related Disorders/epidemiology , Amphetamine-Related Disorders/psychology , Methamphetamine , Smoking Cessation/methods , Smoking/epidemiology , Smoking/psychology , Adult , Amphetamine-Related Disorders/drug therapy , Bupropion/therapeutic use , Cognitive Behavioral Therapy/methods , Double-Blind Method , Female , Humans , Male , Smoking/drug therapy , Treatment OutcomeABSTRACT
We observed a 46, XY infant with atrophy of the optic nerve, complex congenital heart disease including a double outlet right ventricle, hypoplasia of the right pulmonary artery and lung, eventration of the diaphragm, and ambiguous genitalia. The baby died of cardiac arrhythmias at 204 days. The pattern of malformations was compatible with pulmonary tract and pulmonary artery, agonadism, omphalocele, diaphragmatic defect, and dextrocardia (PAGOD) syndrome. The condition may resemble the malformation complex associated with developmental deficiency of vitamin A or retinoic acid, as described in animal models.
Subject(s)
Abnormalities, Multiple/pathology , Heart Defects, Congenital/pathology , Lung/abnormalities , Optic Nerve/abnormalities , Abnormalities, Multiple/genetics , Animals , Diaphragm/abnormalities , Disease Models, Animal , Fatal Outcome , Genitalia, Male/abnormalities , Humans , Infant , Male , Syndrome , Vitamin A Deficiency/congenitalABSTRACT
BACKGROUND: QTc interval prolongation can occur as a result of treatment with both conventional and novel antipsychotic medications and is of clinical concern because of its association with the potentially fatal ventricular arrhythmia, torsade de pointes. METHODS: One case is described in which a patient with schizophrenia, who was being treated for dyslipidemia, developed a prolonged QTc interval while taking quetiapine and lovastatin. RESULTS: QTc returned to baseline when the lovastatin dose was reduced. CONCLUSIONS: QTc prolongation associated with antipsychotic medication occurs in a dose-dependent manner. We therefore hypothesize that the addition of lovastatin caused an increase in plasma quetiapine levels through competitive inhibition of the cytochrome P(450) (CYP) isoenzyme 3A4. Our case highlights the potential for a drug interaction between quetiapine and lovastatin leading to QTc prolongation during the management of dysipidemia in patients with schizophrenia.
