Biomedical subjects

Robert J Malcolm

Publications and source records attributed to Robert J Malcolm.

12 recordsLinked to original sources

PubMed2006

Characteristics of cocaine- and marijuana-dependent subjects presenting for medication treatment trials.

Evaluation of the characteristics of individuals presenting for substance abuse treatment can provide important information to help focus treatment services. In this study, demographic and clinical characteristics of individuals presenting for medication trials for the treatment of cocaine or marijuana dependence were compared. Marijuana-dependent subjects were generally younger than cocaine-dependent subjects, more likely to be Caucasian, and completed more years of education. Marijuana-dependent subjects also reported significantly more days using than cocaine-dependent subjects, as well as higher levels of craving. Some differences in psychiatric symptomatology were also noted, with cocaine-dependent subjects more likely to report anxiety symptoms and marijuana-dependent subjects reporting more past depressive episodes. Past and current other drug use was similar between the two groups. These results highlight the significant impairments associated with marijuana and cocaine dependence.

Adult↗

PubMed2006

An open-label trial of N-acetylcysteine for the treatment of cocaine dependence: a pilot study.

Recent preclinical studies implicate N-acetylcysteine (NAC), a cysteine prodrug, as a potential medication for preventing relapse to cocaine use; however, little is known about the safety and tolerability of NAC in cocaine-dependent subjects in an outpatient setting. This pilot study examines the safety and tolerability of 3 doses of NAC for the treatment of cocaine dependence. Twenty three treatment-seeking cocaine-dependent patients participated in a 4-week medication trial and received NAC at doses of 1200 mg/day, 2400 mg/day or 3600 mg/day. Results suggested that the three doses were well tolerated. Overall, the retention rates appeared to favor higher doses of NAC (2400 mg/day and 3600 mg/day). The majority of subjects who completed the study (n=16) either terminated use of cocaine completely or significantly reduced their use of cocaine during treatment. Overall the findings suggest that it is feasible to treat cocaine-dependent treatment seekers with N-acetylcysteine on an outpatient basis.

Acetylcysteine↗

PubMed2006

An overview of medications for the treatment of alcohol withdrawal and alcohol dependence with an emphasis on the use of older and newer anticonvulsants.

There is a growing interest in the development of new pharmacological tools for treating alcohol withdrawal and dependence. A number of anticonvulsants including valproate and carbamazepine have been shown to be safe and effective alternatives to benzodiazepines for treating alcohol withdrawal. These agents are relatively safe, are free from demonstrated abuse liability, and do not usually potentiate the psychomotor and cognitive effects of alcohol. For the treatment of alcohol dependence, there is a growing literature on the utility of medications that have neurochemical effects at opioid, serotonergic, GABAergic, and glutamate receptors. Furthermore, as a class of medication, there appears to be a growing interest in investigating the utility of novel anticonvulsants such as topiramate for the treatment of alcohol dependence.

Alcohol Deterrents↗

PubMed2006

Randomization in substance abuse clinical trials.

BACKGROUND: A well designed randomized clinical trial rates as the highest level of evidence for a particular intervention's efficacy. Randomization, a fundamental feature of clinical trials design, is a process invoking the use of probability to assign treatment interventions to patients. In general, randomization techniques pursue the goal of providing objectivity to the assignment of treatments, while at the same time balancing for treatment assignment totals and covariate distributions. Numerous randomization techniques, each with varying properties of randomness and balance, are suggested in the statistical literature. This paper reviews common randomization techniques often used in substance abuse research and an application from a National Institute on Drug Abuse (NIDA)-funded clinical trial in substance abuse is used to illustrate several choices an investigator faces when designing a clinical trial. RESULTS: Comparisons and contrasts of randomization schemes are provided with respect to deterministic and balancing properties. Specifically, Monte Carlo simulation is used to explore the balancing nature of randomization techniques for moderately sized clinical trials. Results demonstrate large treatment imbalance for complete randomization with less imbalance for the urn or adaptive scheme. The urn and adaptive randomization methods display smaller treatment imbalance as demonstrated by the low variability of treatment allocation imbalance. For all randomization schemes, covariate imbalance between treatment arms was small with little variation between adaptive schemes, stratified schemes and unstratified schemes given that sample sizes were moderate to large. CONCLUSION: We develop this paper with the goal of reminding substance abuse researchers of the broad array of randomization options available for clinical trial designs. There may be too quick a tendency for substance abuse researchers to implement the fashionable urn randomization schemes and other highly adaptive designs. In many instances, simple or blocked randomization with stratification on a major covariate or two will accomplish the same objectives as an urn or adaptive design, and it can do so with more simply implemented schedules and without the dangers of overmatching. Furthermore, the proper analysis, fully accounting for the stratified design, can be conducted.

Humans↗

PubMed2006

Pharmacokinetics of olanzapine after single-dose oral administration of standard tablet versus normal and sublingual administration of an orally disintegrating tablet in normal volunteers.

Olanzapine (OLZ) is a second-generation antipsychotic agent available in 2 solid oral dosage forms, a standard oral tablet (SOT) and an orally disintegrating tablet (ODT). This study assessed the absorption of each by different routes of administration. Secondarily, the influence of P-glycoprotein (P-gp) genotype was assessed. It was hypothesized that more rapid absorption of the OLZ ODT would occur when administered sublingually versus standard oral administration. A randomized, 3-way crossover study assessed the 5-mg OLZ formulations in healthy volunteers (n = 10). Blood was collected (0-8 hours) to assess OLZ pharmacokinetics using liquid chromatography/mass spectrometry. Both routes of ODT administration resulted in more measurable early concentrations relative to SOT. However, there were no statistically significant differences observed between any of the OLZ exposures for observed pharmacokinetic parameters (C(max), T(max), AUC(0-8h)). The homozygous TT genotype for P-gp resulted in an increased AUC of OLZ for SOT administration but not for either condition where sublingual absorption could occur.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed2005

Tiagabine reduces ethanol reward in C57BL/6 mice under acute and chronic administration regimens.

Three experiments conducted on male C57BL/6 (B6) mice examined the effects of subcutaneous injections of the GABA uptake inhibitor, tiagabine, on appetitive (lever responding) and consummatory behavior (fountain contacts) of food restricted B6 mice for 12% ethanol and water rewards (Exp-1), and for food reward (Exp-2) delivered on a fixed ratio 4 schedule of reinforcement. Effects of acute injections (1,3,6,9 mgkg) and chronic administration (6,9 mg/kg) was examined. Exp-3 examined tiagabine effects on the voluntary consumption of continuously available 12% ethanol, and on the interactive effects of tiagabine and ethanol on motor activity of non-food restricted B6 mice. Results of Exp-1 and Exp-2 indicated that tiagabine can reduce appetitive behavior for ethanol reward with no evidence of tolerance upon chronic exposure. Tiagabine doses that reduced ethanol reward had less effect on behavior maintained by either water or food, and had no effect on motor activity. In contrast to the absence of tolerance to its effect on appetitive behavior for ethanol, mice rapidly developed tolerance to tiagabine's initial reduction of the consummatory response for ethanol (Exp-1), and the intake of freely available ethanol exceeded pre-tiagabine levels after several daily injections (Exp-3). Importantly, mice developed tolerance to tiagabine's sedative effect after three daily injections and its sedation was not enhanced when combined with ethanol, an effect consistent with the lack of a tiagabine + ethanol interaction previously reported for humans. The results of the experiments suggest that in addition to reducing alcohol withdrawal symptoms, tiagabine might also reduce the potency of ethanol-conditioned cues that drive appetitive behavior for ethanol.

Alcohol Drinking↗

PubMed2005

Modafinil influences the pharmacokinetics of intravenous cocaine in healthy cocaine-dependent volunteers.

OBJECTIVE: To determine if modafinil, a putative treatment for cocaine dependence, influences the pharmacokinetics of intravenous cocaine in otherwise healthy cocaine-dependent volunteers. METHODS: Cocaine 20 or 40 mg was administered intravenously on consecutive days over 1 minute at baseline and after modafinil administration at each of two dosages of 400 and 800 mg/day for 7 days. RESULTS: Twelve subjects completed the clinical protocol. Compared with baseline, the cocaine peak plasma concentration was decreased after both the 20 and 40 mg cocaine infusions, but the reduction was only statistically significant after the 40 mg cocaine infusion (p < 0.01 after modafinil 400 mg/day; p < 0.05 after modafinil 800 mg/day). The area under the cocaine plasma concentration-time curve from 0 to 180 minutes (AUC180) was significantly decreased by modafinil administration (p < 0.01 and p < 0.001 for modafinil 400 and 800 mg/day, respectively, for the cocaine 20mg dose; p < 0.001 for the cocaine 40 mg dose at both modafinil levels). There were no significant changes in total AUC, clearance or elimination half-life of cocaine. CONCLUSION: This study did not find evidence for a harmful pharmacokinetic interaction between modafinil and cocaine. In contrast, long-term administration of modafinil significantly decreased systemic exposure to cocaine during the first 180 minutes following intravenous cocaine administration.

Administration, Oral↗

PubMed2004

Development of novel pharmacotherapies for the treatment of alcohol dependence: focus on antiepileptics.

This article represents the proceedings of a symposium, "Development of Novel Pharmacotherapies for the Treatment of Alcohol Dependence: Focus on Antiepileptics," presented at the 2003 annual meeting of the Research Society on Alcoholism in Fort Lauderdale, FL. The organizers and cochairs were Bankole A. Johnson and Robert M. Swift. The presentations were (1) Development of topiramate in the treatment of alcoholism, by Bankole A. Johnson; (2) Craving as a predictor of treatment outcome in pharmacotherapy trials for the treatment of alcoholism, by Nassima Ait-Daoud; (3) Use of biomarkers as a predictor of treatment response in treating alcoholism, by Martin A. Javors; (4) Psychotherapy to enhance compliance with pharmacotherapy in treatment trials for alcohol dependence, by Carlo C. DiClemente; (5) Synopsis of promising medications to treat alcoholism, by Robert M. Swift; and (6) New knowledge on the development of antiepileptic medications for the treatment of alcoholism, by Robert J. Malcolm, Jr.

Alcoholism↗

PubMed2004

Family-focused smoking cessation:enhanced efficacy by the addition of partner support and group therapy.

While partner support has been found to be an important factor in smoking cessation, programs with partner training have not demonstrated improved efficacy. The goal of this project was to evaluate the effectiveness of a smoking cessation treatment program that included partner support in an innovative education/therapy model similar to alcohol and drug treatment programs. Subjects included 23 smokers, 71% with a support partner. The program consisted of a smoking cessation curriculum, combined with facilitated group therapy for participants and partners, and individualized medication evaluation. Smoking abstinence was 87% at program completion and 80% at one month follow up, 100% abstinence in participants with support and 50% in participants without support (p < 0.05). Smoking Stage of Change at enrollment was: contemplation 22%, preparation 70%, and action 8%, with 87% movement toward action stage. In the present study, partner support enhanced short-term abstinence from smoking.

Adolescent↗

PubMed2003

Chiral analysis of d- and l-modafinil in human serum: application to human pharmacokinetic studies.

Modafinil is a novel stimulant approved by the FDA for use in the management of excessive sleepiness associated with narcolepsy. Utility for other indications includes attention deficit-hyperactivity disorder (ADHD), depression, and management of cocaine dependence. To investigate the pharmacokinetics of modafinil in these patients, the authors improved and validated an HPLC method to separate and quantitate the separate enantiomers of modafinil in human serum. d- and l-Modafinil and the internal standard 3,3-diphenylpropylamine were extracted from serum, separated by gradient elution on a beta-cyclodextrin column, and then detected by UV absorbance at 225 nm. The elution gradient was developed to eliminate interferences by other drugs used to manage narcolepsy, ADHD, and stimulants of abuse, and endogenous substances in human serum. Validation studies included determination of stability, selectivity, precision, accuracy, and recovery. The method was used to investigate the pharmacokinetics of d- and l-modafinil in a volunteer after receiving 400 mg twice daily of racemic modafinil for 5 days. Interday and intraday assay variability (CV) typically ranged from 3% to 4%. The limits of detection (0.01 microg/mL) and quantitation (0.5 microg/mL) were well below the concentration expected in serum from patients receiving therapeutic doses of modafinil. The method was free from interference by methylphenidate, cocaine, commonly used antidepressants, and amphetamines. An example of apparent stereoselective disposition is presented as d-modafinil was eliminated more rapidly than l-modafinil from human serum. The validation data support the use of this method for human pharmacokinetic studies of modafinil in patients with known or suspected use of common antidepressants, psychostimulants, and drugs of abuse.

Benzhydryl Compounds↗

PubMed2003

GABA systems, benzodiazepines, and substance dependence.

Alterations in the gamma-aminobutyric acid (GABA) receptor complex and GABA neurotransmission influence the reinforcing and intoxicating effects of alcohol and benzodiazepines. Chronic modulation of the GABA(A)-benzodiazepine receptor complex plays a major role in central nervous system dysregulation during alcohol abstinence. Withdrawal symptoms stem in part from a decreased GABAergic inhibitory function and an increase in glutamatergic excitatory function. GABA(A) receptors play a role in both reward and withdrawal phenomena from alcohol and sedative-hypnotics. Although less well understood, GABA(B) receptor complexes appear to play a role in inhibition of motivation and diminish relapse potential to reinforcing drugs. Evidence suggests that long-term alcohol use and concomitant serial withdrawals permanently alter GABAergic function, down-regulate benzodiazepine binding sites, and in preclinical models lead to cell death. Benzodiazepines have substantial drawbacks in the treatment of substance use-related disorders that include interactions with alcohol, rebound effects, alcohol priming, and the risk of supplanting alcohol dependency with addiction to both alcohol and benzodiazepines. Polysubstance-dependent individuals frequently self-medicate with benzodiazepines. Selective GABA agents with novel mechanisms of action have anxiolytic, anticonvulsant, and reward inhibition profiles that have potential in treating substance use and withdrawal and enhancing relapse prevention with less liability than benzodiazepines. The GABA(B) receptor agonist baclofen has promise in relapse prevention in a number of substance dependence disorders. The GABA(A) and GABA(B) pump reuptake inhibitor tiagabine has potential for managing alcohol and sedative-hypnotic withdrawal and also possibly a role in relapse prevention.

Alcohol Drinking↗

PubMed2002

Carbamazepine in the treatment of cocaine dependence: subtyping by affective disorder.

Studies investigating carbamazepine (CBZ) in the treatment of cocaine dependence have been inconsistent. In this study, cocaine-dependent individuals with (n = 57) and without (n = 82) affective disorder were compared in a 12-week, double-blind, placebo-controlled trial. Urine drug screens (UDS) and self-report of drug use were collected weekly. Affective symptoms were measured monthly. Subjects receiving CBZ attended more medication sessions (p = .03). The CBZ-treated affective group had a trend toward fewer cocaine-positive UDS (p = .08) and a significantly longer time to first cocaine use (p = .06). CBZ treatment did not have any impact on cocaine use in individuals without affective disorders.

Adolescent↗