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Biomedical subjects

Thomas Kosten

Publications and source records attributed to Thomas Kosten.

13 recordsLinked to original sources
PubMed2006

Effects of topiramate in combination with intravenous nicotine in overnight abstinent smokers.

RATIONALE: Topiramate, an anticonvulsant medication, may be effective as a treatment for alcohol and cocaine addiction. While a recent clinical study has demonstrated the potential utility of topiramate for smoking cessation in alcohol-dependent smokers, the effects of topiramate on tobacco addiction have not been systematically examined in humans. OBJECTIVES: To determine topiramate's effects on acute physiological and subjective responses to intravenous (IV) nicotine in overnight abstinent smokers. METHODS: Seven male and five female smokers participated in a double-blind, placebo-controlled, crossover study, which consisted of one adaptation and three experimental sessions. Before each session, participants were treated orally with either a single 25 or 50 mg topiramate dose or with placebo. Starting 2 h following the medication treatment, participants received an IV saline injection, followed by 0.5 and 1.0 mg/70 kg IV nicotine. RESULTS: Topiramate treatment at 50 mg, compared to 25 mg or placebo, attenuated heart rate increases induced by nicotine. Topiramate, compared to placebo, enhanced the ratings of subjective effects from nicotine including "drug strength," "good effects," "head rush," and "drug liking." Topiramate treatment did not affect performance on the Stroop test. CONCLUSIONS: These results suggest that topiramate may enhance the subjective effects of nicotine and attenuate the heart rate response to nicotine. While the exact mechanisms are unclear, enhancement of the dopaminergic system and attenuation of the noradrenergic system may mediate the topiramate's effects on the subjective and cardiovascular responses to nicotine, respectively. The utility of topiramate for smoking cessation needs to be examined further in controlled clinical trials.

Administration, Oral↗
PubMed2006

Cocaine withdrawal symptoms predict medication response in cocaine users.

The purpose of this study was to examine the influence of cocaine withdrawal symptoms on addiction severity and treatment outcomes in methadone stabilized cocaine users who participated in pharmacotherapy trials using gamma-aminobutyric acid (GABA) medications. Subjects who fulfilled DSM-IV cocaine withdrawal criteria (n = 45), compared to those who did not (n = 40), showed a greater increase in cocaine free urines in response to pharmacotherapy with GABA medications. Altogether, our results and previous studies support the clinical utility of cocaine withdrawal symptoms in predicting treatment response to medications, such that low withdrawal severity may predict better treatment response to GABA medications, while high withdrawal severity may predict better response to adrenergic blockers. This hypothesis needs to be tested in prospective clinical trials.

Cocaine↗
PubMed2006

Adrenergic blocker carvedilol attenuates the cardiovascular and aversive effects of nicotine in abstinent smokers.

The cardiovascular response to nicotine is mediated mainly by noradrenergic activation. Whether noradrenergic activation mediates other effects of nicotine has not been well documented in humans. In this study, we examined the effects of an alpha and beta-adrenergic receptor blocker: carvedilol, on cardiovascular and subjective responses to nicotine lozenge and on the ability of nicotine lozenge to suppress tobacco withdrawal symptoms in overnight abstinent smokers. Fifteen smokers, nine men and six women, participated in a double-blind, placebo-controlled, crossover study. In each of the three experimental sessions, participants were treated orally with a single 25 or 50 mg dose of carvedilol or placebo. Two hours and 10 min following the medication treatment, participants received a single 4 mg nicotine lozenge. Carvedilol treatment attenuated the nicotine-induced heart rate, systolic and diastolic blood pressure increases. Carvedilol also attenuated the self-report rating of 'bad effects' in response to nicotine. Carvedilol, alone or in combination with nicotine lozenge, did not affect tobacco withdrawal symptoms. Carvedilol treatment did not affect performance on the Stroop Test. These results support the effectiveness of carvedilol for attenuating the cardiovascular effects of nicotine. Attenuation of the rating of 'bad effects' by carvedilol suggests that noradrenergic activation may also mediate the aversive effects of nicotine.

Adrenergic Antagonists↗
PubMed2005

Effects of tiagabine in combination with intravenous nicotine in overnight abstinent smokers.

RATIONALE: Preclinical studies suggest that medications enhancing the brain gamma amino butyric acid (GABA) system attenuate the rewarding effects of stimulants including nicotine. These preclinical studies have not been followed up in systematic human studies. OBJECTIVES: This study was conducted to examine the effects of a GABAergic medication, tiagabine, on acute physiological and subjective effects of intravenous (i.v.) nicotine and on tobacco withdrawal symptoms in overnight abstinent smokers. The proposed mechanism of action for tiagabine is selective inhibition of GABA transporter type I, which leads to increases in synaptic GABA levels. METHODS: Eight male and four female smokers participated in a double-blind, placebo-controlled, crossover study. In each of three experimental sessions, participants were treated orally with a single 4- or 8-mg dose of tiagabine or placebo. Two hours following the medication treatment, participants received i.v. saline, followed 30 min later by 1.5 mg/70 kg i.v. nicotine. RESULTS: Tiagabine treatment did not affect the heart rate or blood pressure changes induced by nicotine. There was a significant treatment effect for the subjective responses to nicotine, such that tiagabine, compared to placebo, attenuated the ratings of "good effects" and "drug liking." Tiagabine treatment at 8 mg attenuated the craving for cigarettes and enhanced the cognitive performance in the Classical Stoop Tests, compared to placebo or 4 mg tiagabine condition. CONCLUSIONS: These results suggest that GABA enhancing medication tiagabine may reduce the rewarding effects of nicotine and improve cognitive performance in abstinent smokers. The utility of GABA medications for smoking cessation needs to be examined further in controlled clinical trials.

Adult↗
PubMed2005

Immunotherapy for the treatment of drug abuse.

Antibody therapy (as either active or passive immunization) is designed primarily to prevent drugs of abuse from entering the central nervous system (CNS). Antidrug antibodies reduce rush, euphoria, and drug distribution to the brain at doses that exceed the apparent binding capacity of the antibody. This is accomplished through a pharmacokinetic antagonism, which reduces the amount of drug in the brain, the rate of clearance across the blood-brain barrier, and the volume of drug distribution. Because the antibodies remain primarily in the circulatory system, they have no apparent central nervous system side effects. Active immunization with drug-protein conjugate vaccines has been tested for cocaine, heroin, methamphetamine, and nicotine in animal, with 1 cocaine and 3 nicotine vaccines in Phase 2 human trials. Passive immunization with high affinity monoclonal antibodies has been tested for cocaine, methamphetamine, nicotine, and phencyclidine (PCP) in preclinical animal models. Antibodies have 2 immediate clinical applications in drug abuse treatment: to treat drug overdose and to reduce relapse to drug use in addicted patients. The specificity of the therapies, the lack of addiction liability, minimal side effects, and long-lasting protection against drug use offer major therapeutic benefit over conventional small molecule agonists and antagonists. Immunotherapies can also be combined with other antiaddiction medications and enhance behavioral therapies. Current immunotherapies already show efficacy, but improved antigen design and antibody engineering promise highly specific and rapidly developed treatments for both existing and future addictions.

Animals↗
PubMed2005

Gender effects following repeated administration of cocaine and alcohol in humans.

RATIONALE: Use of cocaine, alcohol, and the two drugs simultaneously is common and the risk of morbidity and mortality associated with these drugs is widely reported. This double-blind, placebo-controlled, randomized study examined gender differences in response to administration of these drugs alone and in combination. METHODS: Current users of cocaine and alcohol (n = 17) who met diagnostic criteria (DSM-IV) for cocaine dependence and alcohol abuse or dependence (not physiologically dependent on alcohol) and who were not seeking treatment for substance use disorders gave voluntary, written, informed consent to participate in three drug administration sessions:1) four doses of intranasal cocaine (1 mg/kg every 30 min) with oral alcohol (1 g/kg following the initial cocaine dose and a second drink at +60 min (120 mg/kg) calculated to maintain a plasma alcohol concentration of approximately 100 mg/dL; 2)four doses of cocaine and alcohol placebo; 3) cocaine placebo and alcohol. Pharmacokinetics were obtained by serial blood sampling, physiological measurements (heart rate and blood pressure) were obtained with automated equipment, and subjective effects were assessed using visual analog scales over 480 min. RESULTS: Responses to cocaine, alcohol, and cocaine-alcohol were equivalent by gender for most measurements. Women had higher heart rates following alcohol administration (p = .02). Women consistently reported higher ratings for "Feel Good:' a measure of overall mental/physical well-being, for all study conditions, reaching statistical significance for cocaine (p = .05) and approaching significance for alcohol administration (p = .1). CONCLUSION: Women showed equivalent responses to drug administration with the exception of perception of well-being, which was significantly increased for women. These findings may have implications for differential risk for acute and chronic toxicity in women.

Administration, Intranasal↗
PubMed2003

Desipramine and contingency management for cocaine and opiate dependence in buprenorphine maintained patients.

Co-dependence on opiates and cocaine occurs in about 60% of patients entering methadone treatment and has a poor prognosis. However, we recently found that desipramine (DMI) could be combined with buprenorphine to significantly reduce combined opiate and cocaine use among these dually dependent patients. Furthermore, contingency management (CM) has been quite potent in reducing cocaine abuse during methadone maintenance. To test the efficacy of combining CM with these medications we designed a 12-week, randomized, double blind, four cell trial evaluating DMI (150 mg/day) or placebo plus CM or a non-contingent voucher control in 160 cocaine abusers maintained on buprenorphine (median 16 mg daily). Cocaine-free and combined opiate and cocaine-free urines increased more rapidly over time in those treated with either DMI or CM, and those receiving both interventions had more drug-free urines (50%) than the other three treatment groups (25-29%). Self reported opiate and cocaine use and depressive and opioid withdrawal symptoms showed no differences among the groups and symptom levels did not correlate with urine toxicology results. Lower DMI plasma levels (average 125 ng/ml) were associated with greater cocaine-free urines. DMI and CM had independent and additive effects in facilitating cocaine-free urines in buprenorphine maintained patients. The antidepressant appeared to enhance responsiveness to CM reinforcement.

Adult↗
PubMed2003

Effects of reducing contingency management values on heroin and cocaine use for buprenorphine- and desipramine-treated patients.

AIMS: During 3 months where contingency management (CM) had an escalating value for each consecutive drug-free urine (escalating CM), cocaine- and heroin-abusing patients significantly increased drug-free urines. The 'escalating CM' was eliminated during months 4-6 to assess any reduction in drug-free urines. DESIGN: Patients who completed a 3-month, randomized, double-blind, trial evaluating CM versus non-CM and desipramine (DMI) versus placebo, had an 'escalating CM' eliminated during months 4-6. The CM and non-CM groups were compared using thrice-weekly urine samples. SETTING: Out-patient buprenorphine maintenance for 6 months. PARTICIPANTS: All 75 of the 160 original study patients who completed month 3 of the clinical trial. INTERVENTION: The 'escalating CM' was eliminated for all 3 months and during months 5 and 6 the response requirement was also increased to two and then three consecutive drug-free urines in order to obtain a voucher. MEASUREMENTS: Urine toxicology for opiates and cocaine. FINDINGS: After eliminating the 'escalating CM', the CM group showed a decline in combined opioid- and cocaine-free urines. This decline within the CM group was greater in those treated with DMI than placebo. CONCLUSIONS: Buprenorphine with DMI maintained drug abstinence after eliminating the 'escalating CM', but not after increasing the response requirement, suggesting the need for more intensive psychosocial interventions during CM.

Adult↗
PubMed2002

Sensory gating and psychosis vulnerability in cocaine-dependent individuals: preliminary data.

BACKGROUND: Factors increasing vulnerability of a cocaine user to develop psychotic symptoms are unknown. Deficits in sensory gating and attention, such as those occurring in idiopathic psychosis, might represent experimentally tractable factors contributing to vulnerability to cocaine-induced paranoia. METHODS: Severity of cocaine-induced paranoid symptoms was assessed with the Cocaine Experience Questionnaire (CEQ) in 30 abstinent cocaine-dependent individuals. Sensory gating was assessed in a paired-click auditory evoked potential paradigm (S1 and S2) using the S2/S1 attenuation ratio of the P50 evoked response as the primary outcome measure. The Wender-Utah Rating Scale (WURS) for attention deficit was also administered. RESULTS: Subjects were divided into those with high CEQ scores (n = 10) and those with low CEQ scores (n = 20). The mean P50 ratios were significantly higher for the high CEQ subjects compared with the low CEQ group (F = 4.6, p <.04). The WURS did not correlate with the total CEQ but correlated with the CEQ Severity subscale, r =.432, p <.02. CONCLUSIONS: The data suggest that deficient P50 sensory gating and attention deficits may be associated with increased proneness to developing psychotic symptoms in the context of cocaine use. Further exploration of these factors seems warranted.

Adult↗
PubMedDate not supplied

Depression predicts higher rates of heroin use on desipramine with buprenorphine than with methadone.

The effect of lifetime depression was examined in a randomized clinical trial in 164 opioid- and cocaine-dependent patients who were treated with desipramine in combination with either methadone or buprenorphine. We examined treatment retention, illicit opioid and cocaine use, and depressive symptoms, and found that opioid-free urines at baseline, but not later in treatment, were greater among the depressed than non-depressed patients. Among the depressed patients, depressive symptoms at baseline, but not later in treatment, were greater in patients treated with buprenorphine than methadone. Desipramine did not reduce depressive symptoms more than placebo. Finally, the depressed patients treated with desipramine and buprenorphine showed the least improvement in opioid-free urines, while the non-depressed patients treated with desipramine and methadone had more opioid-free urines than those patients treated with placebo desipramine. Cocaine-free urines showed no association with depression. This poor outcome with desipramine and buprenorphine suggests that this medication combination is not indicated in depressed opioid-dependent patients.

Adult↗
PubMedDate not supplied

Desipramine treatment for cocaine dependence in buprenorphine- or methadone-treated patients: baseline urine results as predictor of response.

The prognostic importance of baseline urines for cocaine was examined in a randomized, placebo-controlled, twelve-week clinical trial in 165 opioid- and cocaine-dependent patients who were treated with desipramine (DMI) in combination with buprenorphine (BUP) or methadone (Meth). Patients with a cocaine-positive urine at baseline (CU+) had significantly fewer cocaine-free urines than those with a negative urine at baseline (CU-neg). The CU+ patients showed a treatment effect of DMI. This DMI effect was significant in patients maintained on BUP but not on Meth.

Adrenergic Uptake Inhibitors↗