Evaluation of the dopamine ?-hydroxylase (D?H) inhibitor nepicastat in participants who meet criteria for cocaine use disorder.
ABSTRACT: In the present study, we tested the hypothesis that the potent and selective dopamine-?-hydroxylase (D?H) inhibitor nepicastat would have minimal effects on cardiovascular and pharmacokinetic parameters associated with cocaine administration and would reduce the positive subjective effects produced by cocaine. We conducted a double-blind, placebo-controlled, inpatient study of oral nepicastat (0, 80 and 160mg) concurrent with intravenous (IV) cocaine (0, 10, 20 and 40mg) in non-treatment seeking participants who metcriteria for cocaine use disorder. Safety analyses revealed that nepicastat was well-tolerated and there were no differences in adverse events observed after nepicastat plus cocaine vs. cocaine alone. In addition, the pharmacokinetic properties of cocaine administration were not altered by nepicastat treatment. Cocaine-induced cardiovascular and subjective effects were evaluated for completers in the cohort randomized to nepicastat (n=13) using a within-subjects statistical analysis strategy. Specifically, the cardiovascular and subjective effects of cocaine were assessed in the presence of placebo (0mg), 80mg of nepicastat or 160mg of nepicastat on study Days 4, 8 and 12, respectively. Analyses revealed a main effect of nepicastat to reduce several cocaine-induced positive subjective effects. Taken together, these data indicate that nepicastat is safe when co-administered with cocaine and may suppress its positive subjective effects, and may be viable as a pharmacotherapy for treatment of cocaine use disorder.
Project description:Inhibitors of dopamine ?-hydroxylase (DBH), the enzyme that converts dopamine (DA) to norepinephrine (NE) in noradrenergic cells, have shown promise for the treatment of cocaine abuse disorders. However, the mechanisms underlying the beneficial effects of these compounds have not been fully elucidated. We used the drug discrimination paradigm to determine the impact of DBH inhibitors on the interoceptive stimulus properties of cocaine. Sprague-Dawley rats were trained to discriminate cocaine (5.6 mg/kg) from saline using a multicomponent, food-reinforced discrimination procedure. On test days, subjects were pretreated with the nonselective DBH inhibitor disulfiram (0-100.0 mg/kg i.p.) or the selective DBH inhibitor nepicastat (0-56.0 mg/kg i.p.) 2 hours prior to a test session either alone or in combination with cumulatively administered cocaine (0-5.6 mg/kg i.p.). Neither disulfiram nor nepicastat substituted for the cocaine stimulus when tested up to doses that nonspecifically reduced responding. However, in combination studies, pretreatment with either disulfiram or nepicastat produced leftward shifts in the cocaine dose-response function and also conferred cocaine-like stimulus effects to the selective NE transporter inhibitor, reboxetine (0.3-5.6 mg/kg i.p.). These results indicate that pharmacological inhibition of DBH does not produce cocaine-like interoceptive stimulus effects alone, but functionally enhances the interoceptive stimulus effects of cocaine, possibly due to facilitated increases in DA released from noradrenergic terminals. These findings suggest that DBH inhibitors have low abuse liability and provide support to clinical reports that some subjective effects produced by cocaine, particularly aversive effects, are enhanced after DBH inhibition.
Project description:INTRODUCTION:Disulfiram has been claimed to be useful in cocaine addiction therapy, its efficacy being attributed to dopamine-beta-hydroxylase (DBH) inhibition. Our previous results indicate that disulfiram and the selective DBH inhibitor nepicastat increase extracellular dopamine (DA) in the rat medial prefrontal cortex (mPFC), and markedly potentiated cocaine-induced increase. Concomitantly, in rats with cocaine self-administration history, cocaine-seeking behavior induced by drug priming was prevented, probably through overstimulation of D1 receptors due to the DA increase. The present research was aimed at studying the neurochemical mechanisms originating the enhanced DA release. METHODS:Noradrenergic system ablation was attained by intracerebroventricular (i.c.v.) administration of the neurotoxin anti-DBH-saporin (aDBH-sap). DA, noradrenaline (NA), and DOPAC were assessed by HPLC after ex vivo tissue extraction or in vivo microdialysis. Control and denervated rats were subjected to microdialysis in the mPFC and caudate nucleus to evaluate the effect of nepicastat-cocaine combination on extracellular DA levels and their regulation by ?2-adrenoceptors. RESULTS:Fifteen days after neurotoxin or its vehicle administration, tissue and extracellular NA were reduced to less than 2% the control value, while extracellular DA was increased by approximately 100%. In control rats, nepicastat given alone and in combination with cocaine increased extracellular DA by about 250% and 1100%, respectively. In denervated rats, nepicastat slightly affected extracellular DA, while in combination with cocaine increased extracellular DA by 250%. No differences were found in the caudate nucleus. Clonidine almost totally reversed the extracellular DA elevation produced by nepicastat-cocaine combination, while it was ineffective in denervated rats. CONCLUSIONS:This research shows that the increase of extracellular DA produced by nepicastat alone or in combination with cocaine was prevented by noradrenergic denervation. The results indicate that nepicastat enhances DA release from noradrenergic terminals supposedly by removing NA from ?2-autoreceptors. In addition to the inhibition of DA uptake, the latter mechanism may explain the synergistic effect of cocaine on nepicastat-induced DA release.
Project description:No pharmacotherapies are approved for the treatment of cocaine use disorders (CUD). Behavioral treatments for CUD are efficacious for some individuals, but recovery rates from CUD remain low. Cognitive impairments in CUD have been linked with poorer clinical outcomes. Cognitive enhancing pharmacotherapies have been proposed as promising treatments for CUD. Atomoxetine, a norepinephrine transporter inhibitor, shows potential as a treatment for CUD based on its efficacy as a cognitive enhancer in other clinical populations and impact on addictive processes in preclinical and human laboratory studies. In this randomized, double-blind, crossover study, abstinent individuals with CUD (N=39) received placebo, 40 and 80mg atomoxetine, over three sessions. Measures of attention, response inhibition and working memory; subjective medication effects and mood; and cardiovascular effects were collected. Analyses assessed acute, dose-dependent effects of atomoxetine. In addition, preliminary analyses investigating the modulation of atomoxetine dose effects by sex were performed. Atomoxetine increased heart rate and blood pressure, was rated as having positive and negative subjective drug effects, and had only modest effects on mood and cognitive enhancement.
Project description:Methamphetamine (METH) potently activates the sympathetic nervous system (SNS) by increasing central and peripheral norepinephrine (NE). Salivary ?-amylase (sAA) is a biomarker of SNS activation that correlates with plasma NE levels. The purpose of this study was to determine the impact of METH on sAA activity and whether changes in sAA activity were correlated with subjective effects ratings.Non-treatment seeking METH-dependent volunteers (N=8) participated in this within-subjects laboratory-based study. Volunteers received randomly administered intravenous METH (0mg, 30 mg) and sAA activity, cardiovascular measures and subjective ratings were assessed at baseline (-15 min) and five post-METH time points (10, 20, 30, 45, and 60 min).METH (30 mg) increased sAA activity over time. sAA activity significantly correlated with diastolic blood pressure following 0mg METH and systolic blood pressure following 30 mg METH. Subjective ratings (ANY EFFECT, HIGH, GOOD, STIMULATED, LIKE, WLLING TO PAY) highly correlated with sAA over five post-METH time points (N=40; r's=0.543-0.684, p's<0.001). Age, body mass index and METH amount received on a mg/kg basis were significantly associated with sAA activity. Multiple linear regression analysis indicated sAA activity remained a significant predictor of subjective ratings following METH after controlling for these factors.The NE peripheral biomarker sAA activity is associated with METH's subjective effects.
Project description:There is currently no anti-fibrotic drug therapy available to treat hepatitis C virus (HCV) cirrhosis. The aim of this study was to assess the safety, tolerability, and anti-fibrotic effect of PRI-724, a small-molecule modulator of Wnt signaling, in patients with HCV cirrhosis.In this single-center, open-label, phase 1 trial, we sequentially enrolled patients with HCV cirrhosis who were classified as Child-Pugh (CP) class A or B. PRI-724 was administered as a continuous intravenous infusion of 10, 40, or 160mg/m2/day for six cycles of 1week on and 1week off. The primary endpoints were frequency and severity of adverse events. The secondary endpoint was efficacy of PRI-724 in treating cirrhosis based on CP score and liver biopsy. This study is registered with ClinicalTrials.gov (no. NCT02195440).Between Sept 3, 2014 and May 2, 2016, 14 patients were enrolled: CP class A:B, 6:8; median age, 62 (range: 43 to 74) years; male:female, 10:4. Twelve of the 14 patients completed six cycles of treatment; one was withdrawn from the study due to possible study drug-related liver injury (grade 3) in the 160mg/m2/day dose cohort and one withdrew for personal reasons. Serious adverse events occurred in three patients [21% (3/14)], one of which was possibly related to PRI-724. The most common adverse events were nausea [29% (4/14)] and fatigue [21% (3/14)]. After PRI-724 administration, the CP scores worsened by 1 point in two patients in the 10mg/m2/day cohort, improved in three patients at 1, 1, and 2 points in the 40mg/m2/day cohort, and improved in one patient by 3 points in the 160mg/m2/day cohort. The histology activity index scores of the liver tissue improved in two patients and exacerbated in two patients in the 10mg/m2/day cohort, and improved in one patient in the 40mg/m2/day cohort.This study showed that administration of 10 or 40mg/m2/day intravenous PRI-724 over 12weeks was well-tolerated by patients with HCV cirrhosis; however, liver injury as a possible related serious adverse event was observed in the 160mg/m2/day cohort.AMED.
Project description:INTRODUCTION:Atorvastatin-80mg/day and Rosuvastatin-40mg/day are the commonest high-dose statin (3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors) regimes for post-PCI (Percutaneous Coronary Interventions) patients to lower (by ?50%) blood low-density-lipoprotein cholesterol (LDL-C). Dearth of conclusive evidence from developing world, regarding overall safety, tolerability and comparative effectiveness (outcome/safety/tolerability/endothelial inflammation control) of Rosuvastatin over Atorvastatin in high-dose, given its higher cost, called for an overall and comparative assessment among post-PCI patients in a tertiary cardiac-care hospital of Kolkata, India. METHODS:A record-based non-concurrent cohort study was conducted involving 942 post-PCI patients, aged 18-75 years, on high-dose statin for three months and followed up for ?one year. Those on Atorvastatin-80mg (n = 321) and Rosuvastatin-40mg (n = 621) were compared regarding outcome (death/non-fatal myocardial infarction: MI/repeated hospitalization/target-vessel revascularisation/control of LDL and high-sensitivity C-reactive protein: hsCRP), safety (transaminitis/myopathy/myalgia/myositis/rhabdomyolysis), tolerability (gastroesophageal reflux disease: GERD/gastritis) and inflammation control adjusting for socio-demographics, tobacco-use, medications and comorbidities using SAS-9.4. RESULTS:Groups varied minimally regarding distribution of age/gender/tobacco-use/medication/comorbidity/baseline (pre-PCI) LDL and hs-CRP level. During one-year post-PCI follow up, none died. One acute MI and two target vessel revascularizations occurred per group. Repeated hospitalization for angina/stroke was 2.18% in Atorvastatin group vs. 2.90% in Rosuvastatin group. At three-months follow up, GERD/Gastritis (2.18% vs 4.83%), uncontrolled hs-CRP (22.74% vs 31.08%) and overall non-tolerability (4.67% vs. 8.21%) were lower for Atorvastatin group. Multiple logistic regression did show that compared to Atorvastatin-80mg, Rosuvastatin-40mg regime had poorer control of hs-CRP (A3OR = 1.45,p = 0.0202), higher (A3OR = 2.07) adverse effects, poorer safety profile (A3OR = 1.23), higher GERD/Gastritis (A3OR = 1.50) and poorer overall tolerability (A3OR = 1.50). CONCLUSION:Post-PCI high dose statins were effective, safe and well-tolerated. High dose Rosuvastatin as compared to high dose Atorvastatin were similar in their clinical efficacy. Patients treated with Atrovastatin had significantly lower number of patients with hs-CRP (high-sensitivity C-reactive protein)/C-reactive protein (CRP) level beyond comparable safe limit and relatively better tolerated as opposed to Rosuvastatin-40mg.Thus given the lower price, Atorvastatin 80mg/day appeared to be more cost-effective. A head-to-head cost-effectiveness as well as efficacy trial may be the need of the hour.
Project description:Inconsistent findings from four observational studies suggest that the risk of acute kidney injury (AKI) may increase with increasing statin dose or potency, but none of the studies took statin-related severe muscle injury, including rhabdomyolysis, into account. We undertook a nationwide nested case-control study in New Zealand to examine the risk of AKI without concurrent serious muscle injury according to simvastatin dose in two cohorts: people without a history of renal disease and people with non-dialysis dependent chronic kidney disease.A total of 334,710 people aged ? 18 years without a history of renal disease (cohort 1) and 5,437 with non-dialysis dependent chronic kidney disease (cohort 2) who initiated simvastatin therapy between 1 January 2006 and 31 December 2013 were identified using national pharmaceutical dispensing and hospital discharge data. Patients who developed AKI without concurrent serious muscle injury during follow-up (cases) were ascertained using hospital discharge and mortality data (n = 931 from cohort 1, n = 160 from cohort 2). Up to 10 controls per case, matched by date of birth, sex, and cohort entry date were randomly selected from the relevant cohort using risk set sampling.Relative to current use of 20mg simvastatin daily, the adjusted odds ratios and 95% confidence intervals (95% CI) in cohort 1 for current use of 40mg and 80mg were 0.9 (95% CI 0.7-1.2) and 1.3 (95% CI 0.7-2.3), respectively. The adjusted odds ratio for 40mg in cohort 2 was 1.1 (95% CI 0.7-1.9); the numbers taking 80mg were very small and the confidence interval was correspondingly wide.The findings of this study suggest that a relationship between statin dose and AKI may not exist independent of serious muscle injury.
Project description:Disrupted glutamate homeostasis is thought to contribute to cocaine-use disorder, in particular, by enhancing the incentive salience of cocaine stimuli. n-Acetylcysteine might be useful in cocaine-use disorder by normalizing glutamate function. In prior studies, n-acetylcysteine blocked the reinstatement of cocaine seeking in laboratory animals and reduced the salience of cocaine stimuli and delayed relapse in humans.The present study determined the ability of maintenance on n-acetylcysteine (0 or 2400mg/day, counterbalanced) to reduce the incentive salience of cocaine stimuli, as measured by an attentional bias task, and attenuate intranasal cocaine self-administration (0, 30, and 60mg). Fourteen individuals (N=14) who met criteria for cocaine abuse or dependence completed this within-subjects, double-blind, crossover-design study.Cocaine-cue attentional bias was greatest following administration of 0mg cocaine during placebo maintenance, and was attenuated by n-acetylcysteine. Cocaine maintained responding during placebo and n-acetylcysteine maintenance, but the reinforcing effects of cocaine were significantly attenuated across both maintenance conditions in participants maintained on n-acetylcysteine first compared to participants maintained on placebo first.These results collectively suggest that a reduction in the incentive salience of cocaine-related stimuli during n-acetylcysteine maintenance may be accompanied by reductions in cocaine self-administration. These results are in agreement with, and link, prior preclinical and clinical trial results suggesting that n-acetylcysteine might be useful for preventing cocaine relapse by attenuating the incentive salience of cocaine cues.
Project description:BACKGROUND:Subjective effects of cocaine are mediated primarily by dopamine (DA) transporter (DAT) blockade. The present study assessed the hypothesis that different DAT conformational equilibria regulate differences in cocaine-like subjective effects and extracellular DA induced by diverse DA-uptake inhibitors (DUIs). METHODS:The relationship between cocaine-like subjective effects and stimulation of mesolimbic DA levels by standard DUIs (cocaine, methylphenidate, WIN35,428) and atypical DUIs (benztropine analogs: AHN1-055, AHN2-005, JHW007) was investigated using cocaine discrimination and DA microdialysis procedures in rats. RESULTS:All drugs stimulated DA levels with different maxima and time courses. Standard DUIs, which preferentially bind outward-facing DAT conformations, fully substituted for cocaine, consistently producing cocaine-like subjective effects at DA levels of 100-125% over basal values, regardless of dose or pretreatment time. The atypical DUIs, with DAT binding minimally affected by DAT conformation, produced inconsistent cocaine-like subjective effects. Full effects were obtained, if at all, only at a few doses and pretreatment times and at DA levels 600-700% greater than basal values. Importantly, the linear, time-independent, relationship between cocaine-like subjective effects and DA stimulation obtained with standard DUIs was not obtained with the atypical DUIs. CONCLUSIONS:These results suggest a time-related desensitization process underlying the reduced cocaine subjective effects of atypical DUIs that may be differentially induced by the binding modalities identified using molecular approaches. Since the DAT is the target of several drugs for treating neuropsychiatric disorders, such as attention-deficit/hyperactivity disorder, these results help to identify safe and effective medications with minimal cocaine-like subjective effects that contribute to abuse liability.
Project description:BACKGROUND:3,4-methylenedioxypyrovalerone (MDPV) toxicity includes intense neurological and cardiovascular events. We examined MDPV-induced cardiovascular, temperature, and locomotor effects following escalating and repeated MDPV administration in adult male and female Sprague-Dawley rats and compared these effects to cocaine in male rats. METHODS:Telemetry devices were surgically implanted to allow continuous measurement of cardiovascular, temperature, and locomotor activity over a 22?h period after dosing. Rats were administered increasing intraperitoneal (IP) MDPV doses (1-5.6?mg/kg) every other day, followed two days later by a binge regimen of four injections of 3?mg/kg MDPV at 2?h intervals. MDPV serum concentrations were measured by LC-MS/MS. Cocaine (3-30?mg/kg) and four injections of 30?mg/kg IP were administered to male rats for comparison with male MDPV data. RESULTS:The duration of MDPV cardiovascular effects was significantly greater (p?<?0.05) in male rats than female rats at 3-5.6?mg/kg. The ED50 for MDPV-induced locomotor was significantly lower in males (2.4?±?0.3) than females (3.4?±?0.2). Males showed significantly greater variability in MDPV serum concentrations than females after binge dosing. MDPV produced five-fold more potent cardiovascular effects than cocaine in male rats. MDPV did not alter thermoregulation in either sex, but cocaine binge administration decreased temperature. CONCLUSION:Effects of MDPV on temperature were not significantly different between sexes. MDPV-induced cardiovascular and locomotor effects in males lasted significantly longer and were more potent than in females. These differences appeared to be related to pharmacokinetic factors leading to greater variance in MDPV serum concentrations in males.