Pilot randomized double blind placebo-controlled study of dexamphetamine for cocaine dependence

Aims To establish the feasibility of conducting a placebo‐controlled clinical trial of dexamphetamine replacement therapy for cocaine dependence and to obtain preliminary data. Design Double‐blind randomized placebo‐controlled trial. Participants Thirty cocaine‐dependent injecting drug users. Intervention Subjects were assigned randomly to receive 60 mg/day dexamphetamine (n = 16) or placebo (n = 14) for 14 weeks. Measurements Immunoassay and mass spectrometric techniques were used to identify cocaine metabolites in urine. Subjects were screened using the Composite International Diagnostic Interview and DSM‐IV. The Opiate Treatment Index, Brief Symptom Inventory, Severity of Dependence Scale and visual analogue craving scales were used to collect pre‐ and post‐self‐report data. Findings Treatment retention was equivalent between groups; however, outcomes favoured the treatment group with no improvements observed in the placebo control group. The proportion of cocaine‐positive urine samples detected in the treatment group declined from 94% to 56% compared to no change in the placebo group (79% positive). While the improvements were not significant between groups, within‐group analysis revealed that the treatment group reduced self‐reported cocaine use (P = 0.02), reduced criminal activity (P = 0.04), reduced cravings (P < 0.01) and reduced severity of cocaine dependence (P < 0.01) with no within‐group improvements found in the placebo group. Conclusions A definitive evaluation of the utility of dexamphetamine in the management of cocaine dependence is feasible and warranted.     

Abnormally short activated partial thromboplastin time values are associated with increased risk of recurrence of venous thromboembolism after oral anticoagulation withdrawal

This study prospectively evaluated the relationship between activated partial thromboplastin time (aPTT) and risk of venous thromboembolism (VTE) recurrence after oral anticoagulant (OA) withdrawal in patients with a previous unprovoked VTE event. Six hundred twenty-eight patients (331 males; median age: 67 years) were followed after OA interruption (mean follow-up = 22 months). Three to four weeks from OA discontinuation patients were given a complete thrombophilic work-out, including aPTT (automated aPTT). Recurrent symptomatic VTE events (objectively documented) occurred in 71/628 (11.3%, 6.8/100 person-years) patients. The VTE recurrence rate was 17.5% and 7.5% in patients with aPTT in the lower (ratio < or =0.90) and in the upper (ratio >1.05) quartiles. The recurrence risk was more than twofold higher in patients with ratio < or =0.90 versus those of the reference category [Relative risk (RR): 2.38 (95% confidence interval (CI): 1.18-4.78)]. As expected, the increase in recurrence risk disappeared after adjustment for factor VIII, IX and XI levels [RR: 1.74 (95%CI: 0.43-2.76)]. In contrast, the risk was persistently increased in patients with a ratio < or =0.90 [RR: 2.07 (95%CI: 1.02-4.18)] after adjustment for age, gender and d-dimer level. The aPTT predictive value was independent of the presence of inherited thrombophilic alterations. In conclusion, abnormally short aPTT values are associated with a significantly increased risk of VTE recurrence.     

Effects of potential agonist-replacement therapies for stimulant dependence on inhibitory control in cocaine abusers

Two experiments were conducted to determine whether methylphenidate or modafinil, two potential pharmacotherapies for stimulant dependence, would impair inhibitory behavior in cocaine users. Eleven cocaine abusers were administered methylphenidate (0, 15, 30, and 45 mg) or modafinil (0, 150, 300, and 450 mg) across four experimental sessions. A cued go-no-go task was used to measure response execution and inhibition. Subjective and cardiovascular measures were collected. Neither methylphenidate nor modafinil impaired inhibitory control, but produced prototypical subject-rated and cardiovascular effects. The results of these studies may have implications for the use of these drugs as agonist-replacement therapies for stimulant dependence.     

Effects of Potential Agonist-Replacement Therapies for Stimulant Dependence on Inhibitory Control in Cocaine Abusers

Two experiments were conducted to determine whether methylphenidate or modafinil, two potential pharmacotherapies for stimulant dependence, would impair inhibitory behavior in cocaine users. Eleven cocaine abusers were administered methylphenidate (0, 15, 30, and 45 mg) or modafinil (0, 150, 300, and 450 mg) across four experimental sessions. A cued go–no-go task was used to measure response execution and inhibition. Subjective and cardiovascular measures were collected. Neither methylphenidate nor modafinil impaired inhibitory control, but produced prototypical subject-rated and cardiovascular effects. The results of these studies may have implications for the use of these drugs as agonist-replacement therapies for stimulant dependence.     

Assessing the cardio–cerebrovascular safety of vildagliptin: meta‐analysis of adjudicated events from a large Phase III type 2 diabetes population

Aim: To assess the cardiovascular and cerebrovascular (CCV) safety of the dipeptidyl peptidase‐IV inhibitor vildagliptin. Methods: Data were pooled from 25 Phase III studies of vildagliptin, used either as monotherapy or combination therapy, with durations of 12 weeks to ≥ 2 years. The safety of vildagliptin [50 mg qd (N = 1393) or 50 mg bid (N = 6116)] was assessed relative to a pool of all comparators [both placebo and active comparators (N = 6061)]. CCV events were adjudicated in a prospective, blinded fashion by an independent CCV adjudication committee. Meta‐analysis of confirmed CCV events was performed with Mantel–Haenszel risk ratios (RRs); categories included in the composite endpoint were acute coronary syndrome, transient ischaemic attack (with imaging evidence of infarction), stroke and CCV death. Subgroup analyses by age (< and ≥ 65 years), gender and cardiovascular (CV) risk status [high CV risk status defined as a previous history of events in the Standard MedDRA Queries of ischaemic heart disease, cardiac failure, ischaemic cerebrovascular conditions and/or embolic/thrombotic events, arterial) were also carried out. In addition, unadjusted and exposure‐adjusted incidences are presented for both the composite endpoint and its components. Results: Relative to all comparators, the RRs for the composite endpoint were < 1 for both vildagliptin 50 mg qd [RR = 0.88; 95% CI (0.37, 2.11)] and vildagliptin 50 mg bid [RR = 0.84; 95% CI (0.62, 1.14)]. The results were consistent across subgroups defined by age, gender and CV risk status, including the higher CV risk subgroups of elderly patients [RR for vildagliptin 50 mg bid vs. all comparators = 1.04; 95% CI (0.62, 1.73)], males [RR = 0.87; 95% CI (0.60, 1.24)] or patients with a high CV risk status [RR = 0.78; 95% CI (0.51, 1.19)]. The exposure‐adjusted incidences of each component of the composite endpoint for vildagliptin 50 mg bid were also lower than or similar to those of all comparators. Conclusions: In a large meta‐analysis, vildagliptin was not associated with an increased risk of adjudicated CCV events relative to all comparators in the broad population of type 2 diabetes including patients at increased risk of CCV events.     

Stimulant Use in Sports

The authors provide an overview of the topic of stimulant use in psychiatric sports medicine. They address the following areas: 1) the history of stimulant use in sports; 2) recent events related to the use of stimulants in sports, including a new stimulant used at the 1996 Olympic competition in Atlanta, GA; 3) ergogenic or ergolytic (i.e., performance-impairing) potential of several major categories of stimulants, including amphetamines, beta₂ agonists, caffeine, and cocaine; 4) review of how the brain reward circuit is affected by stimulants; 5) individual factors that induce athletes to utilize stimulants; and 6) sports organizational factors that induce athletes to use stimulants.     

Impact of obesity on long-term prognosis following acute myocardial infarction

OBJECTIVE: To evaluate the impact of obesity on mortality in patients with acute myocardial infarction. METHODS: This study comprises 6676 consecutive patients with acute myocardial infarction screened for entry into the Danish Trandolapril Cardiac Evaluation (TRACE) study. At baseline, body mass index (BMI) and waist to hip ratio (WHR) were measured. Survival status was determined after 8-10 years. RESULTS: BMI was used to divide patients into 4 groups: underweight, normal weight, overweight and obese. The normal weight group was used as reference for the other groups. WHR was divided in quartiles and the lowest quartile was used as reference for the three other quartiles. The prevalence of overweight (BMI 25-29.9 kg/m(2)) and obesity (BMI>30 kg/m(2)) were 48% and 13% in males and 31% and 13% in females. Obese patients were younger, less often smokers and more frequently suffered from diabetes and hypertension. In both men and women, there was no association between obesity assessed as BMI and mortality [men: adjusted RR=0.99 (0.85-1.14, p=0.3); women: adjusted RR=0.90 (0.74-1.10, p=0.2)]. Men with WHR in the upper quartile had an increased mortality [adjusted RR=1.21 (1.07-1.37, p<0.01)]. Increasing WHR in women showed a trend of increased mortality, although this was not significant [adjusted RR=1.13 (0.95-1.34, p=0.2)]. CONCLUSION: In patients with acute myocardial infarction overall obesity as assessed by body mass index is inversely related to mortality. However, abdominal obesity appears to be an independent predictor of all-cause mortality in men and perhaps also in women.     

The Obsessive-Compulsive Cocaine Scale (OCCS): a pilot study of a new questionnaire for assessing cocaine craving

This study aimed to develop a scale (Obsessive-Compulsive Cocaine Scale [OCCS]) for measuring cocaine craving based on the Obsessive Compulsive Drinking Scale (OCDS). We tested the scale on 116 French-speaking cocaine users. The scale was reliable (Cronbach's α= 0.93). It was significantly correlated with a visual analogue scale of craving (r = 0.641, p < .001) and discriminated between cocaine-dependant subjects (score 36 ± 11) and abusers (score 17 ± 9, p < .001). Prospective tests on a sample of 20 subjects showed that the OCCS score changed over 3 weeks of treatment and was significantly correlated with the visual analogue scale of craving (r = 0.492, p = .038). Principal component analysis identified three factors: resistance, intensity, and interference. The OCCS questionnaire could be used to repeatedly assess cocaine craving in prospective studies in cocaine addicts. (Am J Addict 2012;00:1-7).     

Association between treatment with central nervous system stimulants and Raynaud's syndrome in children: a retrospective case-control study of rheumatology patients

OBJECTIVE: To investigate whether central nervous system (CNS) stimulants used for the treatment of attention deficit hyperactivity disorder (ADHD) are associated with the development of Raynaud's syndrome (RS). METHODS: A case-control design was used for this study. All patients seen in a pediatric rheumatology practice during a 5-year period who had signs and symptoms of RS and met diagnostic criteria for RS as determined by pulse volume recording were studied as cases. Controls were randomly selected patients at the same clinic who did not have signs or symptoms of RS. They were matched to the cases for age, sex, and time of presentation. We tested for associations between various CNS medications and presence of RS. We also evaluated differences in laboratory test results between RS cases and matched controls. RESULTS: Sixty-four patients were enrolled in the study (32 cases with RS [23 female, 9 male] and 32 control patients). McNemar's test showed a significant association between the presence of RS and past or current use of ADHD stimulants (methylphenidate and dextroamphetamine) (chi(2) = 5.00, P = 0.01). The use of other CNS medications was not found to be significantly associated with RS (chi(2) = 1.33, P = 0.25 by McNemar's test). C-reactive protein levels and erythrocyte sedimentation rates were significantly higher in controls than in cases. CONCLUSION: The results of this study indicate that there is a significant association between development of RS and therapy with CNS stimulants used for the treatment of ADHD. Although this was a small study, these findings provide preliminary evidence of an adverse effect of CNS stimulant medications in patients seen in rheumatology practice.     

Is methamphetamine use associated with idiopathic pulmonary arterial hypertension?

BACKGROUND: Amphetamine, methamphetamine, and cocaine are suspected of being pulmonary hypertension risk factors based on a small number of case reports along with pharmacologic similarities to fenfluramine, a diet drug associated with pulmonary arterial hypertension (PAH). We sought to determine whether rates of stimulant use are increased in patients believed to have idiopathic PAH compared with patients with PAH and known risk factors and patients with chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: In this retrospective study, rates of stimulant use were determined for 340 patients with idiopathic PAH, PAH and known risk factors, or CTEPH seen between November 2002 and April 2004. "Stimulant" use was defined as any reported use of amphetamine, methamphetamine, or cocaine. Odds of stimulant use were calculated using a polychotomous logistic regression model. RESULTS: A history of stimulant use was found in 28.9% of patients with a diagnosis of idiopathic PAH, compared with 3.8% of patients with PAH and a known risk factor, and 4.3% of patients with CTEPH. After adjustment for differences in age, patients with idiopathic PAH were 10.14 times (95% confidence interval, 3.39 to 30.3; p < 0.0001) more likely to have used stimulants than patients with PAH and known risk factors, and 7.63 times (95% confidence interval, 2.99 to 19.5; p < 0.0001) more likely to have used stimulants than patients with CTEPH. CONCLUSIONS: Patients with idiopathic PAH are significantly more likely to have used stimulants than patients with other forms of pulmonary hypertension.     

Bromocriptine for Cocaine Dependence

On the basis of the dopamine depletion theory, bromocriptine has been tested to treat cocaine withdrawal and dependence. The authors conducted a 6-week study with 1 week of pretreatment observation and 5 weeks of a randomized, double-blind, placebo-controlled clinical trial of bromocriptine for DSM-III-R-defined cocaine dependence in methadone-maintained male patients. The bromocriptine group (n = 24) did not differ from the placebo group (n = 26) in self-reported cocaine use, proportion of positive urine toxicology samples, craving for cocaine, resistance to cocaine use, or mood symptoms between the pretreatment baseline and the last week of the clinical trial. Both groups showed significant reduction in self-reported frequency of cocaine use, resistance to craving, and mood symptoms during participation in the protocol. The results of this study are consistent with recent clinical and laboratory findings in primary cocaine users. Despite initially promising pilot studies, recent evidence does not support the efficacy of bromocriptine to reduce cocaine use or craving.     

小剂量阿司匹林对心血管病一级预防效果及安全性的系统评价

目的 系统评价小剂量阿司匹林在高危人群中一级预防心血管病的有效性和安全性.方法 计算机检索MEDLINE、EMbase、Cochrane图书馆(2008年第3期)、中国生物医学文献数据库、中国学术期刊全文数据库,同时筛检了纳入文献的参考文献.收集小剂量阿司匹林(75～150 mg)一级预防心血管病的随机对照试验(RCT),2名评价员独立评价文献质量和提取资料,并采用RevMan4.2软件对资料进行荟萃分析.结果 共纳入6个研究(TPT,HOT,PPP,WHS,POPADAD,JPAD),72 466例患者.(1)小剂量阿司匹林总的心血管事件的发生率(RR=0.85,95% CI:0.80～0.92)、卒中发生率(RR=0.87,95% CI:0.77～0.98)、非致死性卒中发生率(RR=0.81,95%CI:0.70～0.95)、短暂脑缺血发作发生率(RR=0.76,95%CI:0.64～0.90)均低于安慰剂(均P＜0.05).(2)小剂量阿司匹林非致死性心肌梗死(RR=0.89,95%CI:0.77～1.02)、心血管性死亡(RR=0.98,95% CI:0.86～1.13)、全因死亡发生率(RR=0.95,95%CI:0.88～1.02)与安慰剂比较,差异无统计学意义(P＞0.05).(3)在老年人群中分析显示,小剂量阿司匹林冠心病的发生率低于安慰剂(RR=0.81,95%CI:0.70～0.94,P＜0.01).(4)在安全性方面,与安慰剂比较,小剂量阿司匹林有出血并发症的风险(RR=1.15,95%CI:1.12～1.18,P＜0.01),而在过敏反应方面差异无统计学意义(P＞0.05).结论 小剂最阿司匹林能降低总的心血管事件、短暂脑缺血发作、卒中、非致死性卒中的发生率;对降低非致死性心肌梗死、心血管性死亡、全因死亡方面效果不明显;在老年人群中小剂量阿司匹林能降低冠心病的发牛率;长期应用无明显过敏反应,但存在出血并发症的风险.     

Comparison of amantadine and desipramine combined with psychotherapy for treatment of cocaine dependence.

We conducted a single-blind, random assignment, placebo-controlled, 12-week comparison of desipramine hydrochloride and amantadine hydrochloride as adjunctive treatments to counseling for cocaine dependence. Subjects were 54 outpatients who met DSM III-R criteria for active cocaine dependence and who completed a minimum of 2 weeks of treatment. Subjects treated with fixed doses of 200 mg/day desipramine (N = 17), 400 mg/day amantadine-placebo (N = 16), and placebo (N = 21) did not differ for lifetime cocaine use, lifetime histories of psychopathology, admission scores on psychometric assessments, and sociodemographics. All treatment groups demonstrated dramatic and persistent decreases in cocaine use, craving for cocaine, and psychiatric symptoms consequent to treatment. Although there was a trend for more dropouts by subjects taking desipramine, there were no significant differences among treatment groups regarding retention in treatment, craving for cocaine, and decreased cocaine use confirmed by urine toxicology. There was a trend for subjects treated with desipramine to maintain longer periods of cocaine abstinence. Mean plasma concentration of desipramine in a subsample of our subjects was less than that recommended for treatment of depression, thus the dosage of desipramine may have been subtherapeutic.     

Differences in Attitudes About HIV Pre-Exposure Prophylaxis Use Among Stimulant Versus Alcohol Using Men Who Have Sex with Men

Alcohol and stimulant use are independently associated with increased HIV acquisition among men who have sex with men (MSM). We assessed differences in acceptability and perceived barriers to uptake of pre-exposure prophylaxis (PrEP) among stimulant and alcohol-using MSM in Boston. From September 2012–2013, a quantitative assessment was conducted with 254 MSM respondents who reported recent condomless sex in the context of concurrent stimulant (crack/cocaine and crystal methamphetamine; n = 132) or alcohol use (n = 122). Thirteen (5.1  %) reported previous PrEP use. In multivariable models, stimulant users were more likely to be concerned that substance use would affect PrEP adherence (aRR = 2.79, 95  % CI 1.63–4.77), and were less concerned about HIV stigma as a barrier to PrEP uptake (aRR = 0.52, 95  % CI 0.30–0.90) compared to alcohol users. Barriers to PrEP uptake and adherence differ by type of substance used. Different strategies may be required for PrEP implementation among MSM who use stimulants and alcohol.     

Fluvastatin Reduces Cardiac Mortality in Patients with Coronary Heart Disease

PURPOSE: To test the effectiveness of fluvastatin, 40-80 mg, in reducing the occurrence of cardiac and all-cause mortality in patients with coronary heart disease (CHD). METHODS: Meta-analysis of all clinical trials that assessed the effects of fluvastatin in CHD patients on major adverse cardiac events (MACE) as a prespecified endpoint was performed. A pooled analysis of four studies (n = 3525) was performed on an intent-to-treat basis. Clinical endpoints were the incidence, and time to first occurrence, of MACE (cardiac death, nonfatal MI, revascularization), noncardiac death, or all-cause death. Lipid parameters were also analyzed. RESULTS: Fluvastatin treatment significantly prolonged the time to cardiac death (p = 0.0174) and the time to cardiac death or nonfatal MI (p = 0.0055) compared with placebo. Fluvastatin significantly reduced the risk of any MACE (Cox risk ratio [RR], 0.85; 95% confidence interval [CI], 0.73-0.98), cardiac death (RR, 0.53; 95% CI, 0.31-0.90), cardiac death or MI (RR, 0.66; 95% CI, 0.49-0.89), all-cause death (RR, 0.65; 95% CI, 0.45-0.94) and all-cause death or MI (RR, 0.69; 95% CI, 0.53-0.90). Fluvastatin significantly lowered total cholesterol and low-density lipoprotein cholesterol levels and was well tolerated, with no cases of rhabdomyolysis in any of the studies assessed in the meta-analysis. CONCLUSIONS: This meta-analysis demonstrates clear beneficial effects of fluvastatin on cardiac and all-cause mortality in CHD patients, and supports the use of fluvastatin to reduce the incidence of MACE in a wide range of at-risk patients.     

Heterogeneity of Stimulant Dependence: A National Drug Abuse Treatment Clinical Trials Network Study

We investigated the presence of DSM‐IV subtyping for dependence on cocaine and amphetamines (with versus without physical dependence) among outpatient stimulant users enrolled in a multisite study of the Clinical Trials Network (CTN). Three mutually exclusive groups were identified: primary cocaine users (n = 287), primary amphetamine users (n = 99), and dual users (cocaine and amphetamines; n = 29). Distinct subtypes were examined with latent class and logistic regression procedures. Cocaine users were distinct from amphetamine users in age and race/ethnicity. There were four distinct classes of primary cocaine users: non‐dependence (15%), compulsive use (14%), tolerance and compulsive use (15%), and physiological dependence (tolerance, withdrawal, and compulsive use; 56%). Three distinct classes of primary amphetamine users were identified: non‐dependence (11%), intermediate physiological dependence (31%), and physiological dependence (58%). Regardless of stimulants used, most female users were in the most severe or the physiological dependence group. These results lend support for subtyping dependence in the emerging DSM‐V.     

A double-blind,placebo-controlled study of naltrexone in the treatment of alcohol-dependence disorder: results from a multicenter clinical trial

BACKGROUND: A 12-week, multicenter, double-blind, randomized, parallel-group clinical trial to compare naltrexone and placebo was carried out to determine the efficacy, safety, and tolerability of naltrexone together with a psychosocial intervention in the treatment of alcoholism. METHODS: A total of 202 alcohol-dependent patients were assigned to 12 weeks' treatment with either naltrexone or placebo. The relapse rate was evaluated by means of intention-to-treat analyses. Alcohol consumption, craving, adverse events, and changes in the biochemical markers of heavy drinking and possible toxicity were evaluated in the 192 patients who were considered to be assessable. RESULTS: The survival function for patients who were treated with naltrexone was significantly better than that of the patients who were treated with placebo (Kaplan-Meier log rank = 4, df = 1, p < 0.05). In addition, 7.9% of patients who were treated with naltrexone relapsed as compared with 18.8% of those who received placebo [chi = 5.89, df = 2, p = 0.050]. In comparing naltrexone with placebo-treated patients, the most common adverse events were abdominal pain [8.6% vs. 1%; (chi = 6.1, df = 1, p < 0.05)] and headache [7.5% vs. 1% (chi = 5.1, df = 1, p < 0.05)]. CONCLUSIONS: Naltrexone was well-tolerated, as the rate of adverse events was low, and safe, as it did not interfere with the normalization of biochemical markers of heavy drinking or alter liver function markers. Naltrexone seemed to reduce relapse rate to heavy drinking, but we found no differences in other alcohol consumption variables between naltrexone- and placebo-treated groups. Although the naltrexone group showed a tendency to consume fewer drinks per drinking day and had a longer time to first drink, differences were not statistically significant.     

Transdermal Nicotine and Drug Craving

The authors observed the effect of transdermally administered nicotine on the drug craving of 15 patients with nicotine dependence and recent cocaine abuse. Transdermal nicotine and placebo patches were applied in a crossover, double-blind design, and outcome was assessed by visual analog scales to measure drug craving. Nicotine patches significantly reduced craving for cigarettes without affecting cigarette use. There was a nonsignificant trend for nicotine patches to reduce cocaine craving more than placebo patches.     

Effect of Fenfluramine Challenge on Cocaine Craving in Addicted Male Users

The authors studied the effects of a challenging dose of the serotonin (5-HT)-releaser/reuptake inhibitor d,l-fenfluramine (FEN) on spontaneous cocaine craving in a group of cocaine-addicted users in order to evaluate the involvement of serotonergic pathways in the modulation of craving for cocaine. Nineteen cocaine-dependent male inpatients received 60 mg of FEN or placebo (double-blind). Data were compared with those obtained in a previous study of another serotonergic probe, the partial postsynaptic agonist meta-chlorophenyl-piperazine (m-CPP). FEN significantly reduced cocaine craving and increased cortisol and prolactin when compared with placebo. When the responses to the two drugs were compared, there were no differences in the cortisol and prolactin rises, but m-CPP was a more potent inhibitor of cocaine craving than FEN. These data suggest that 5-HT releasers/reuptake inhibitors and serotonergic agents with greater postsynaptic activity should be further examined. (Am J Addict 1998; 7:142–155)