Recreational drug use: patterns from a South Wales self-report survey

This study aimed to examine patterns of illicit recreational drug use, alcohol consumption, and smoking in a community-based population sample. A postal questionnaire survey was conducted of people who were selected at random from the Electoral registers of Cardiff and Merthyr Tydfil. Twelve percent of respondents reported illicit recreational drug use in the last year, and 7% in the last month. Among respondents aged under 25 years, 34% (39% of males and 31% of females) had used illicit drugs in the last year, and 19% (23% of males and 17% of females) in the last month. Twenty-one percent of respondents smoked (20% of males and 22% of females). Twenty-seven percent of respondents reported drinking more alcohol than currently recommended sensible limits (36% of males and 21% of females). Among respondents aged under 25 years, 53% of men and 38% of women drank over these limits. Illicit drug use was associated with heavy alcohol consumption and, in particular, with smoking. Smoking and heavy alcohol consumption combined was most strongly associated with illicit drug use. Rates of illicit recreational drug use were higher than have previously been reported for Wales. Illicit drug use and smoking varied with age, sex, work status and geographical location, whereas heavy alcohol consumption varied with age, sex and work status, but not geographical location. Both smoking and alcohol consumption were associated with illicit drug use, with smokers who were also heavy drinkers being those most likely to report illicit drug use.     

Pharmacokinetic characteristics of ritonavir, zidovudine, lamivudine, and stavudine in children with human immunodeficiency virus infection

STUDY OBJECTIVE: To evaluate and describe the parameters and characteristics of different drug regimens in children infected with human immunodeficiency virus (HIV). DESIGN: Randomized, open-label, multicenter study. SETTING: Pediatric HIV research clinics in the United States and Puerto Rico. PATIENTS: Twenty-one HIV-infected children, aged 3-14 years, who were clinically stable and treated with the same antiretroviral therapy for 16 weeks or longer. INTERVENTION: In step 1, children were randomized to receive one of three treatment regimens: zidovudine plus lamivudine, ritonavir plus zidovudine and lamivudine, or ritonavir plus stavudine. Patients originally assigned to the zidovudine plus lamivudine group in step 1 were eligible to progress to step 2 if their HIV RNA values at week 12, 24, or 36 were 10,000 copies/ml or greater but 100,000 copies/ml or less. In step 2 they received a regimen of ritonavir plus stavudine and nevirapine. MEASUREMENTS AND MAIN RESULTS: Seven children were randomized to each of the three treatment regimens. Concentrations of the agents were quantitated at steady state after observed doses, and the pharmacokinetic parameters were determined. Nevirapine concentrations were not determined. One child was excluded from analysis because pharmacokinetic parameters could not be estimated. Ritonavir oral clearance was slower in the pooled cohort of children who received stavudine compared with zidovudine and lamivudine. Stavudine oral clearance was marginally faster when combined with ritonavir and nevirapine compared with only ritonavir. CONCLUSION: Therapy for HIV is complex, and pharmacodynamic data indicate that relationships exist between systemic concentrations of antiretroviral drugs and virologic response. Careful drug interaction studies have not been conducted for all treatment regimens, and it will not be surprising if unexpected interactions are found. Pharmacokinetic studies to address these considerations should be viewed as a fundamental component of antiretroviral drug development, as they represent a tool to improve pharmacotherapy for HIV-infected children.     

Reward drive and rash impulsiveness as dimensions of impulsivity: implications for substance misuse

One of the primary personality dimensions or traits that has consistently been linked to substance abuse is impulsivity. However, impulsivity is not a homogenous construct and although many of the measures of impulsivity are correlated, the most recent review of published factor analytic studies has proposed two independent dimensions of impulsivity: reward sensitivity, reflecting one of the primary dimension of J. A. Gray's personality theory, and rash impulsiveness. These two facets of impulsivity derived from the field of personality research parallel recent developments in the neurosciences where changes in the incentive value of rewarding substances has been linked to alterations in neural substrates involved in reward seeking and with a diminished capacity to inhibit behavior due to chronic drug exposure. In this paper, we propose a model that integrates the findings from research into individual differences with recent models of neural substrates implicated in the development of substance misuse.     

Heterogeneity in phenotypes based on smoking status in the Great Lakes Smoker Sibling Registry

We investigated whether 52 same-sex sibling pairs discordant for ever-smoking differed on psychiatric cofactors, alcohol and caffeine use, and responses to initial exposure to smoking. Ever-smokers scored significantly higher on measures of novelty seeking, depression, and childhood ADHD, and on alcohol dependence, alcohol intake, and caffeine intake. They reported significantly more pleasurable experiences, dizziness, "buzz," and relaxation upon initial exposure to smoking and significantly fewer displeasurable sensations, nausea, and cough than did nicotine-exposed, never-smoking siblings. Ever-smokers had significantly fewer years of education than their never-smoking siblings, suggesting that the concentration of smokers in lower socioeconomic strata may be partly due to downward mobility among smokers, possibly because of the observed elevation in psychiatric cofactors, which may interfere with academic performance. These findings are consistent with differences previously identified in unrelated ever- and never-smokers. Because same-sex siblings typically share a large set of common environments during childhood, our findings could be due either to genetic differences among siblings and/or (excepting educational level and responses to early exposure) to differences in adult environments.     

The unique regulation of brain cytochrome P450 2 (CYP2) family enzymes by drugs and genetics

Cytochrome P450 (CYP) enzymes in the brain may have a role in the activation or inactivation of centrally acting drugs, in the metabolism of endogenous compounds, and in the generation of damaging toxic metabolites and/or oxygen stress. CYPs are distributed unevenly among brain regions, and are found in neurons, glial cells and at the blood-brain interface. They have been observed in mitochondrial membranes, in neuronal processes and in the plasma membrane, as well as in endoplastic reticulum. Brain CYPs are inducible by many common hepatic inducers, however many compounds affect liver and brain CYP expression differently, and some CYPs which are constitutively expressed in liver are inducible in brain. CYP induction is isozyme-, brain region-, cell type- and inducer-specific. While it is unlikely that brain CYPs contribute to overall clearance of xenobiotics, their punctate, region- and cell-specific expression suggests that CNS CYPs may create micro-environments in the brain with differing drug and metabolite levels (not detected or predicted by plasma drug monitoring). Coupled with the sensitivity of CNS CYPs to induction, this may in part account for inter-individual variation in response to centrally acting drugs and neurotoxins, and may have implications for individual variation in receptor adaptation and cross-tolerance to different drugs. In addition, genetic variation in brain CYPs, depending on the type of polymorphism (structural versus regulatory), will alter enzyme activity. These aspects of brain CYP expression regulation and genetic influences are illustrated in this review using mRNA, protein, and enzyme activity data for CYP2D1/6, CYP2E1 and CYP2B1/6 in rat and human brain. The role of CYP-mediated metabolism in the brain, a highly heterogeneous and complex organ, is a new and relatively unexplored field of scientific enquiry. It holds promise for furthering our undestanding of inter-individual variability in response to centrally acting drugs as well as risk for neurological diseases and pathogies.     

Relative bioavailability of different buprenorphine formulations under chronic dosing conditions

BACKGROUND: Buprenorphine is an approved medication for the treatment of opioid dependence. Three sublingual formulations have been used at various times during its development-a solution containing alcohol, tablets containing buprenorphine alone, and tablets containing buprenorphine plus naloxone. This study compared the relative buprenorphine bioavailability of these different formulations. METHODS: Outpatient volunteers (N = 10) were maintained for 14 days of daily administration on each formulation; the dose of buprenorphine (8 mg) was constant across formulations. Blood samples were collected and tested for buprenorphine and norbuprenorphine concentrations after 7 and 14 days maintenance on each formulation. Serial samples were collected before and for 6 h after a daily dose of each formulation. RESULTS: Peak buprenorphine concentrations (C(max)) and area under the curve (AUC) for the 6h interval (AUC(0-6)) were highest for the solution and lowest for buprenorphine alone tablets; values for combination tablets were more similar to those for solution. Differences between formulations were less pronounced at day 14 than day 7. There was considerable between-subject variability in concentrations produced. CONCLUSIONS: These results suggest there may be greater bioavailability of buprenorphine/naloxone versus buprenorphine alone tablets, and that the bioavailability of buprenorphine from the former is very similar to that seen with solution after 2 weeks of stabilization on each formulation.     

Open-label trial of an injection depot formulation of buprenorphine in opioid detoxification

Buprenorphine, a partial mu-opioid agonist, has been shown effective for treatment of opioid dependence but also has some abuse potential. A novel formulation of buprenorphine, using a polymer microcapsule depot sustained-release technology, has been developed which may offer effective treatment of opioid dependence while also minimizing risks of patient noncompliance and illicit diversion. This open-label, first-in-human study evaluated the safety and pharmacokinetics of a single-dose buprenorphine depot in physically dependent opioid abusers. The present study also examined the efficacy of depot buprenorphine in suppressing symptoms of opioid withdrawal, attenuating the effects of exogenous opioid challenge, and providing clinical detoxification. Five opioid-dependent volunteers each received a single subcutaneous depot injection containing 58 mg of buprenorphine and were assessed for at least four weeks for signs and symptoms of opioid withdrawal, first residentially and then as outpatients. Depot buprenorphine appeared to provide effective relief from opioid withdrawal, with no participant requiring additional medication for withdrawal relief following depot administration. The depot was safe and well-tolerated, with no significant side effects, signs of intoxication, or respiratory depression. In the opioid challenge sessions, depot buprenorphine appeared to produce substantial opioid blockade that persisted for 6 weeks post-depot administration. Results from the present study suggest that depot buprenorphine offers significant promise for enhancing the delivery of effective opioid agonist treatment while minimizing risk for abuse of the medication.     

The impact of motivational interviewing on substance abuse treatment retention: a randomized control trial of women involved with child welfare

Previous studies have supported the efficacy of Motivational Interviewing (MI) in increasing treatment engagement and retention among people with substance abuse disorders. However, few studies have assessed the impact of MI with coerced populations, particularly women referred to drug abuse treatment by child welfare due to prenatal drug use. Seventy-one such women who used drugs during pregnancy were randomly assigned to either receive three MI sessions or to watch two educational videos and participate in a home visit. Treatment retention group attendance and random urine analysis results were evaluated in these women during the first 8 weeks of treatment. No differences were found between the two conditions on these variables. Possible reasons for these negative findings are discussed, as are ideas for future research with coerced populations.     

Cochlear activation at low sound intensities by a fluid pathway

In order to assess the mechanisms responsible for cochlear activation at low sound intensities, a semi-circular canal was fenestrated in fat sand rats, and in other experiments a hole was made in the bone over the scala vestibuli of the first turn of the guinea-pig cochlea. Such holes, which expose the cochlear fluids to air, provide a sound pathway out of the cochlea which is of lower impedance than that through the round window. This should attenuate the pressure difference across the cochlear partition and thereby reduce the driving force for the base-to-apex traveling wave along the basilar membrane. The thresholds of the auditory nerve brainstem evoked responses (ABR) and of the cochlear microphonic potentials were not affected in the fenestration experiments. In addition, holes in the scala vestibuli of the first turn did not cause ABR threshold elevations. These results contribute further evidence that at low sound intensities the outer hair cells are probably not activated by a base-to-apex traveling wave along the basilar membrane. Instead it is possible that they are excited directly by the alternating condensation/rarefaction fluid pressures induced by the vibrations of the stapes footplate. The activated outer hair cells would then cause the localized basilar membrane movement.     

Ex vivo reversal of chemoresistance by tariquidar (XR9576)

The expression of P-glycoprotein (P-gp) has been demonstrated to confer resistance to several anticancer drugs, including anthracyclines, taxanes and vinca alkaloids. Tariquidar is a novel inhibitor of P-gp that has been shown to reverse resistance to cytotoxic drugs in tumor cell lines and mouse xenografts. We have used an ATP-based chemosensitivity assay (ATP-TCA) to compare the activity of cytotoxic drugs in combination with tariquidar against a variety of solid tumors (n = 37). The expression of P-gp was determined in a subset of solid tumor samples by immunohistochemistry (n = 16). Resistance was seen in 20 of 37 (54%) tumors tested with doxorubicin, in 27 of 34 (79%) samples tested with paclitaxel and 17 of 31 (55%) with vinorelbine. Tariquidar alone showed no activity over a wide range of concentrations up to 2 microM (n = 14). The median IC90s for doxorubicin, paclitaxel and vinorelbine, alone were 2.57, 27.4 and 15.5 microM. These decreased to 1.67 (p<0.0005), 20.6 (p<0.05) and 9.5 microM (p<0.001), respectively, in combination with tariquidar. Tariquidar also significantly decreased resistance in 14 of 20 (70%), six of 27 (22%) and six of 17 (35%) samples tested with doxorubicin, paclitaxel and vinorelbine, respectively. Immunohistochemical staining for P-gp was positive in nine of 16 (56%) samples and in all of these cases addition of tariquidar improved the activity of the cytotoxic. The results show that tariquidar is able to decrease resistance in a number of solid tumors resistant to cytotoxic drugs known to be P-gp substrates. These data support the introduction of tariquidar in combination with chemotherapy to clinical trials of patients expressing P-gp.