The effect of acute tryptophan depletion on mood and impulsivity in polydrug ecstasy users

Rationale

Several studies suggest users of 3,4-methylenedioxymethamphetamine (ecstasy) have low levels of serotonin. Low serotonin may make them susceptible to lowered mood.

Objective

This work aims to study the acute effects on mood and impulsivity of lowering serotonin levels with acute tryptophan depletion in polydrug ecstasy users and to determine whether effects were different in men and women.

Methods

In a double-blind cross-over study, participants who had used ecstasy at least 25 times (n?=?13) and nonuser controls (n?=?17) received a tryptophan-deficient amino acid mixture and a control amino acid mixture containing tryptophan, at least 1 week apart. Mood was measured using the profile of mood states, and impulsivity was measured with the Go/No-Go task.

Results

The main result shows that a lowering of mood after acute tryptophan depletion occurred only in female polydrug ecstasy users (n?=?7), relative to controls (n?=?9). Results from the Go/No-Go task suggested that impulsivity was not increased by acute tryptophan depletion in polydrug ecstasy users.

Limitation

The group sizes were small, when males and females were considered separately.

Conclusions

Women polydrug ecstasy users appear to be more susceptible than men to the effects of lowered serotonin levels. If use of ecstasy alone or in conjunction with other drugs causes progressive damage of serotonin neurons, women polydrug ecstasy users may become susceptible to clinical depression.     

Role of Drug Efflux and Uptake Transporters in Atazanavir Intestinal Permeability and Drug-Drug Interactions

Purpose

To investigate the role of membrane-associated drug transporters in regulating the intestinal absorption of the HIV-1 protease inhibitor, atazanavir, and assess the potential contribution of these transporters in clinical interactions of atazanavir with other protease inhibitors and tenofovir disoproxil fumarate (TDF).

Methods

Intestinal permeability of atazanavir was investigated in vitro, using the Caco-2 cell line system grown on Transwell inserts, and in situ, by single-pass perfusion of rat intestinal segments, jejunum and ileum, in the absence or presence of standard transporter inhibitors or antiretroviral drugs.

Results

Atazanavir accumulation by Caco-2 cells was susceptible to inhibition by P-glycoprotein and organic anion transporting polypeptide (OATP) family inhibitors and several antiretroviral drugs (protease inhibitors, TDF). The secretory flux of atazanavir (basolateral-to-apical P_app) was 11.7-fold higher than its absorptive flux. This efflux ratio was reduced to 1.5–1.7 in the presence of P-glycoprotein inhibitors or ritonavir. P-glycoprotein inhibition also resulted in 1.5–2.5-fold increase in atazanavir absorption in situ. Co-administration of TDF, however, reduced atazanavir intestinal permeability by 13–49%, similar to the effect observed clinically.

Conclusions

Drug transporters such as P-glycoprotein and OATPs regulate intestinal permeability of atazanavir and may contribute to its poor oral bioavailability and drug-drug interactions with other protease inhibitors and TDF.     

Superstitious conditioning as a model of delusion formation following chronic but not acute ketamine in humans

Background

Ketamine has previously been shown to induce delusion-like or referential beliefs, both acutely in healthy volunteers and naturalistically among nonintoxicated users of the drug. Delusions are theoretically underpinned by increased superstitious conditioning or the erroneous reinforcement of random events.

Materials and methods

Using a novel and objectively measured superstitious conditioning task, experiment 1 assessed healthy volunteers before and during placebo (n?=?16), low-dose (n?=?15), and high-dose ketamine (n?=?16) under randomized and double-blind conditions. Experiment 2 used the same task to compare ketamine users (n?=?18), polydrug controls (n?=?19), and nondrug-using controls (n?=?17).

Results

In experiment 1, ketamine produced dose-dependent psychotomimetic effects but did not cause changes in superstitious conditioning. Experiment 2 found increased levels of superstitious conditioning among ketamine users compared to polydrug and nondrug-using controls, respectively, as evidenced by both objective task responses and subjective beliefs following the task.

Conclusions

Results indicate that chronic but not acute exposure to ketamine may increase the propensity to adopt superstitious conditioning. These findings are discussed in terms of acute and chronic ketamine models of delusion-like belief formation in schizophrenia.     

Interaction of ambrisentan with clarithromycin and its modulation by polymorphic SLCO1B1

Purpose

We assessed the effect of cytochrome P450 (CYP) 3A4 and the OATP1B1 inhibitor clarithromycin on ambrisentan steady-state kinetics and its relationship to the SLCO1B1*15 haplotype in healthy volunteers.

Methods

In this open-label, monocenter, one-sequence crossover clinical trial ten male healthy participants were stratified according to CYP2C19 and SLCO1B1 (encoding for OATP1B1) genotype into two groups: group 1 (n?=?6), with CYP2C19*1/*1 (extensive metabolizer, EM) and SLCO1B1 wild-type; group 2 (n?=?4), with CYP2C19 EM and homozygous (n?=?3) or heterozygous for SLCO1B1*15 (n?=?1). The participants were administered a once-daily oral dose of 5 mg ambrisentan on study days 1 and days 3–14 and twice-daily oral doses of 500 mg clarithromycin on study days 11–14. To monitor CYP3A activity 3 mg midazolam was given orally 1 day before the first ambrisentan administration and on days 1, 10, and 14 of ambrisentan treatment. Ambrisentan plasma kinetics was assessed on days 1 (single dose), 10 (steady-state), and 14 (CYP3A4/OATP1B1 inhibition by clarithromycin).

Results

Consistent with the expectation that ambrisentan does not induce its own metabolism, ambrisentan exposure and peak concentration (C_max) were similar after the first dose and at steady-state. Clarithromycin increased the area under the plasma concentration-time curve of ambrisentan by 41 % and C_max by 27 % (n?=?10, both p?<?0.05). No contribution of SLCO1B1*15 to the extent of this interaction was observed.

Conclusions

Clarithromycin increased ambrisentan exposure to a similar extent to ketoconazole, namely, clinically minor and likely irrelevant.     

Cigarette craving and withdrawal symptoms during temporary abstinence and the effect of nicotine gum

Rationale

It is widely believed that nicotine withdrawal symptoms appear within a few hours of stopping smoking, but few data exist documenting their emergence in naturalistic settings. In several countries, nicotine replacement products are licensed for relief of withdrawal symptoms during temporary abstinence, but again, there are no data supporting this from naturalistic settings.

Objectives

To examine the emergence of cigarette craving and withdrawal symptoms during temporary abstinence in a naturalistic setting while using either nicotine or placebo gum.

Methods

Double-blind, randomised, placebo-controlled study in which 132 dependent smokers abstained for 6 h with the assistance of either nicotine (2 mg, n?=?42 or 4 mg, n?=?24) or placebo (n?=?66) gum while travelling on a non-smoking train. Outcome measures were ratings of craving and mood withdrawal symptoms prior to treatment and at regular intervals during abstinence.

Results

In a multivariate analysis of all symptoms, there was no interaction between treatment and time [F(21,110)?=?1.28, p?=?0.20, $ \eta_{\mathrm{p}}^2 $ ?=?0.20] nor an effect of treatment [F(7,124)?=?0.45, p?=?0.87, $ \eta_{\mathrm{p}}^2 $ ?=?0.03]. There was an effect of time [F(21,110)?=?11.59, p?<?0.001, $ \eta_{\mathrm{p}}^2 $ ?=?0.69) and univariate analyses revealed that the majority of symptoms increased linearly throughout the period of abstinence with detectable onsets typically between the first 60 and 180 min of abstinence.

Conclusions

Smokers who temporarily abstain in naturalistic settings experience craving and withdrawal symptoms that emerge linearly over the first 6 h of abstinence. Changes in craving and several mood withdrawal symptoms can be detected within the first 3 h. Nicotine gum may not have an acute effect on the development of these symptoms.     

Adverse drug reactions: Analysis of spontaneous reporting system in Europe in 2007–2009

Purpose

Spontaneous reporting systems in European countries are crucial for collecting adverse drug reaction (ADR) reports. The aim of this study was to evaluate reporting activity among countries and their strategy to increase the number of reports. We also established the best measure for assessment quantity of reports.

Methods

This was a retrospective observational study based on questionnaires and annual reports. The most reliable measure of reporting was determined by Spearman correlation coefficients.

Results

Data collected in spontaneous reporting systems in 26 European countries were analysed. In 2007, 2008 and 2009, the average value of reports per year per million inhabitants based on the safety databases of countries was 208, 236, 286, respectively; in comparison, that of EudraVigilance was 311, 453 and 435, respectively. Twelve countries reached a significant level for signal detection of ADRs in 2009. The population-based reporting ratio (PBRR) was correlated to the total expenditure on health (ρ?=?0.499, p?=?0.023, n?=?21), public expenditure on health (ρ?=?0.477, p?=?0.035, n?=?20), density of physicians (ρ?=?0.336, p?=?0.136, n?=?21) and expenditure on pharmaceuticals (ρ?=?0.365, p?=?0.114, n?=?20). Strategies of regulatory authorities to increase reporting were determined.

Conclusions

The results of this study make several noteworthy contributions regarding national spontaneous reporting systems. The relevance of the PBRR for the measurement reporting activity is clearly supported by the current findings. This study also shows that there is a general trend towards increased reporting activity. This is maintained by regional centres and encouragement of reporting. A further study would be helpful to assess the effectiveness of reporting systems at both the national and European level.     

Automatic approach bias towards smoking cues is present in smokers but not in ex-smokers

Rationale

Drug-addicted individuals show automatic approach tendencies towards drug-related cues, i.e., an approach bias (ApB). Nevertheless, little is known about ApB in tobacco smokers and about the presence of ApB after smoking abstinence.

Objectives

We investigated ApB to smoking cues in heavy tobacco smokers versus never-smokers and studied its relation to smoking characteristics and craving. Second, we compared ApBs of heavy smokers with biases of abstinent heavy smokers.

Method

A group of current heavy smokers (n?=?24), ex-smokers who were abstinent for at least 5 years (n?=?20), and never-smokers (n?=?20) took part in the experiment. An indirect smoking approach avoidance task was performed, in which participants were required to respond to pictures of smoking and neutral cues by pulling (approach) or pushing (avoid) on a joystick, according to the content-irrelevant format of the picture (landscape or portrait). Craving scores were examined using the Questionnaire of Smoking Urges.

Results

Heavy smokers showed an ApB for smoking cues compared to ex-smokers and never-smokers, which correlated positively to craving scores. There were no group differences in ApB scores for ex-smokers and never-smokers.

Conclusion

These results suggest that ApBs for smoking cues are present in heavy smokers and decrease after long-term successful smoking cessation.     

Neonatal phencyclidine administration and post-weaning social isolation as a dual-hit model of ‘schizophrenia-like’ behaviour in the rat

Rationale

Schizophrenia is a debilitating disorder comprising positive, negative and cognitive deficits with a poorly defined neurobiological aetiology; therefore, animal models with greater translational reliability are essential to develop improved therapies.

Objectives

This study combines two developmental challenges in rats, neonatal phencyclidine (PCP) injection and subsequent rearing in social isolation from weaning, to attempt to produce more robust behavioural deficits with greater translational relevance to schizophrenia than either challenge alone.

Methods

Forty-two male Lister-hooded rat pups received the N-methyl-d-aspartate (NMDA) receptor antagonist, phencyclidine (PCP, 10 mg/kg, s.c.), or vehicle on post-natal day (PND) 7, 9 and 11 and were weaned on PND 23 into group housing (saline-treated n?=?11 or PCP-treated n?=?10) or isolation (saline n?=?10 or PCP n?=?11). Six weeks post-weaning, novelty- and PCP-induced (3.2 mg/kg) locomotor activity, novel object discrimination, prepulse inhibition of acoustic startle and contextual memory in a conditioned emotion response (CER) were recorded.

Results

Isolation rearing alone significantly elevated baseline locomotor activity and induced visual recognition memory impairment in novel object discrimination. Neonatal PCP treatment did not induce locomotor sensitisation to a subsequent acute PCP injection, but it impaired prepulse inhibition when combined with isolation rearing. CER freezing behaviour was significantly reduced by isolation rearing but an even greater effect occurred when combined with neonatal PCP treatment.

Conclusions

Neonatal PCP and isolation rearing both produce behavioural deficits in adult rats, but combined treatment caused a wider range of more severe cognitive impairments, providing a more comprehensive preclinical model to determine the neurobiological aetiology of schizophrenia than either treatment alone.     

Pharmacokinetics of gemcitabine in non-small-cell lung cancer patients: impact of the 79A>C cytidine deaminase polymorphism

Objective

To study the impact of the 79A>C polymorphism in the cytidine deaminase (CDA) gene on the pharmacokinetics of gemcitabine and its metabolite 2′,2′-difluorodeoxyuridine (dFdU) in non-small-cell lung cancer (NSCLC) patients.

Patients and methods

Patients (n?=?20) received gemcitabine 1,125 mg/m² as a 30 min i.v. infusion as part of treatment for NSCLC. Plasma samples were collected during 0–6 h after gemcitabine administration. Gemcitabine and dFdU were quantified by high performance liquid chromatography with ultraviolet detection. The CDA 79A>C genotype was determined with PCR and DNA sequencing.

Results

Gemcitabine was rapidly cleared from plasma and undetectable after 3 h. The allele frequency of the 79A>C polymorphism was 0.40. Diplotypes were distributed as A/A n?=?8, A/C n?=?8 ,and C/C n?=?4. No significant differences were found between the different CDA genotypes and gemcitabine or dFdU AUC, clearance, or half-life.

Conclusion

The 79A>C polymorphism in the CDA gene does not have a major consistent and signficant impact on gemcitabine pharmacokinetics.     

Alterations to global but not local motion processing in long-term ecstasy (MDMA) users

Rationale

Growing evidence indicates that the main psychoactive ingredient in the illegal drug “ecstasy” (methylendioxymethamphetamine) causes reduced activity in the serotonin and gamma-aminobutyric acid (GABA) systems in humans. On the basis of substantial serotonin input to the occipital lobe, recent research investigated visual processing in long-term users and found a larger magnitude of the tilt aftereffect, interpreted to reflect broadened orientation tuning bandwidths. Further research found higher orientation discrimination thresholds and reduced long-range interactions in the primary visual area of ecstasy users.

Objectives

The aim of the present research was to investigate whether serotonin-mediated V1 visual processing deficits in ecstasy users extend to motion processing mechanisms.

Method

Forty-five participants (21 controls, 24 drug users) completed two psychophysical studies: A direction discrimination study directly measured local motion processing in V1, while a motion coherence task tested global motion processing in area V5/MT.

Results

“Primary” ecstasy users (n?=?18), those without substantial polydrug use, had significantly lower global motion thresholds than controls [p?=?0.027, Cohen’s d?=?0.78 (large)], indicating increased sensitivity to global motion stimuli, but no difference in local motion processing (p?=?0.365).

Conclusion

These results extend on previous research investigating the long-term effects of illicit drugs on visual processing. Two possible explanations are explored: defuse attentional processes may be facilitating spatial pooling of motion signals in users. Alternatively, it may be that a GABA-mediated disruption to V5/MT processing is reducing spatial suppression and therefore improving global motion perception in ecstasy users.     

Yohimbine administration and cue-reactivity in cocaine-dependent individuals

Rationale

Preclinical studies suggest that stress potentiates cue-induced cocaine seeking and that this effect is more pronounced in females. These findings have not been characterized in clinical populations.

Objectives

The objectives of this study were to examine the impact a pharmacological stressor, alpha-2 adrenergic receptor antagonist yohimbine, on the subjective, endocrine, and physiologic responses to drug-paired cues cocaine-dependent men and women.

Methods

In a double-blind placebo-controlled cross-over study, cocaine-dependent men (n?=?32), cocaine-dependent women (n?=?30), control men (n?=?32), and control women (n?=?25) received either yohimbine or placebo prior to two cocaine cue exposure sessions.

Results

Yohimbine increased ratings of anxiety both before (p?p?=?0.035) cues, and the post-cue increase in anxiety was more pronounced in women (p?=?0.001). Yohimbine also significantly increased craving, compared with placebo (p?p?=?0.006). Yohimbine also increased salivary cortisol (p?p?=?0.003) levels, regardless of diagnostic group. Women had a significantly greater heart rate response following yohimbine as compared with men (p?Conclusions Stress may increase the salience of cocaine cues for cocaine-dependent women as compared with men. This suggests gender differences in vulnerability to craving and relapse under stressful conditions.     

Risperidone, QTc interval prolongation, and torsade de pointes: a systematic review of case reports

Rationale

A recent publication asserted that even low-dose risperidone may induce corrected QT (QTc) interval prolongation up to 500 ms without drug-induced I_Kr blockade. We seek to better understand the complexity of any link between risperidone-induced/associated QTc interval prolongation and torsade de pointes (TdP).

Objectives

The objective of this study is to systematically analyze all available case reports of risperidone, QTc interval prolongation, and/or TdP.

Method

We identify case reports using PubMed, Medline, EMBASE, and Cochrane.

Results

Of the 15 cases found, nine were adult women (ages 31, 33, 34, 37, 47, “elderly”, 77, 84, and 87 years) and one was a teenager. There were four men (ages 28, 29, 29, and 46 years) and one preadolescent boy. Besides risperidone administration or overdose, traditional risk factors for QTc interval prolongation and TdP included female sex (n?=?10), older age (n?=?4), heart disease (n?=?3), hypokalemia (n?=?2), bradycardia (n?=?1), liver disease (n?=?1), QTc interval prolonging drugs other than risperidone (n?=?8), and metabolic inhibitors (n?=?2). TdP occurred in four cases. Six patients died, and three deaths were probably related to TdP.

Conclusion

Risperidone (when properly prescribed in patients free of other risk factors for QTc interval prolongation and TdP) is a relatively safe drug. Conventional statistics can neither predict the individual patient who will experience TdP nor determine the relationship of drug dose to QTc interval prolongation and TdP. Narrative medicine using a case report format appears to be an alternative and valuable additional approach to advance our understanding of this relationship and to reduce risks.     

Effect of d-amphetamine on emotion-potentiated startle in healthy humans: implications for psychopathy and antisocial behaviour

Rationale

An emerging literature associates increased dopaminergic neurotransmission with altered brain response to aversive stimuli in humans. The direction of the effect of dopamine on aversive motivation, however, remains unclear, with some studies reporting increased and others decreased amygdala activation to aversive stimuli following the administration of dopamine agonists. Potentiation of the startle response by aversive foreground stimuli provides an objective and directional measure of emotional reactivity and is considered useful as an index of the emotional effects of different drugs.

Objective

We investigated the effects of two doses of d-amphetamine (5 and 10 mg), compared to placebo, for the first time to our knowledge, using the affect–startle paradigm.

Method

The study employed a between-subjects, double-blind design, with three conditions: 0 mg (placebo), and 5 and 10 mg d-amphetamine (initially n?=?20/group; final sample: n?=?18, placebo; n?=?18, 5 mg; n?=?16, 10 mg). After drug/placebo administration, startle responses (eyeblinks) to intermittent noise probes were measured during viewing of pleasant, neutral and unpleasant images. Participants’ general and specific impulsivity and fear-related personality traits were also assessed.

Results

The three groups were comparable on personality traits. Only the placebo group showed significant startle potentiation by unpleasant, relative to neutral, images; this effect was absent in both 5- and 10-mg d-amphetamine groups (i.e. the same effect of d-amphetamine observed at different doses in different people).

Conclusions

Our findings demonstrate a reduced aversive emotional response under d-amphetamine and may help to account for the known link between the use of psychostimulant drugs and antisocial behaviour.     

Brain RGS4 and RGS10 protein expression in schizophrenia and depression. Effect of drug treatment

Rationale

Regulator of G-protein signaling (RGS) proteins, RGS4 and RGS10, may be involved in the pathophysiology of schizophrenia. RGS4 has attracted special interest since the reports of genetic association between SNPs in RGS4 and schizophrenia. However, there is no information about the subcellular distribution of RGS4 and RGS10 proteins in psychiatric disorders.

Objectives

Plasma membrane RGS4 and cytosolic RGS10 protein immunoreactivity in prefrontal cortex from schizophrenic subjects (n?=?25), non-diagnosed suicides (n?=?13), and control subjects (n?=?35), matched by age, gender, and postmortem delay, was analyzed by western blot. A second group of depressed subjects (n?=?25) and control subjects (n?=?25) was evaluated. The effect of the antipsychotic or antidepressant treatments was also assessed.

Results

No significant differences in plasma membrane RGS4 and cytosolic RGS10 protein expression were observed between schizophrenic subjects, non-diagnosed suicides, and control subjects. However, RGS4 immunoreactivity was significantly higher (Δ?=?33?±?10 %, p?<?0.05) in the antipsychotic-treated subgroup (n?=?12) than in the antipsychotic-free subgroup (n?=?13). Immunodensities of plasma membrane RGS4 and cytosolic RGS10 proteins did not differ between depressed and matched control subjects.

Conclusions

Expression of RGS4 and RGS10 proteins at their predominant subcellular location was studied in the postmortem brain of subjects with psychiatric disorders. The results suggest unaltered membrane RGS4 and cytosolic RGS10 proteins levels in schizophrenia and major depression. Antipsychotic treatment seems to increase membrane RGS4 immunoreactivity. Further studies are needed to elucidate RGS4 and RGS10 functional status.     

The effects of varenicline on attention and inhibitory control among treatment-seeking smokers

Rationale

Varenicline represents a new class of smoking cessation aids that has different mechanisms of action that are unique from bupropion or nicotine replacement therapies. An improved understanding of these mechanisms may lead to greater treatment success in quitting smoking.

Objectives

We examined the effects of steady-state varenicline on attention and inhibitory control among adult treatment-seeking smokers.

Methods

Adult smokers enrolled in a randomized clinical trial received either 4 weeks of pre-quit varenicline (n?=?31) or 3 weeks of placebo (n?=?26) followed by 1 week of standard varenicline treatment. Participants in the present work completed cognitive assessments at a baseline session (prior to treatment) and again 3 weeks later (during active treatment). At both sessions, participants completed the stop signal task to assess both lapses in attention and inhibitory control.

Results

Analyses indicated that varenicline improved lapses in attention compared to placebo. There were no significant differences observed between groups at either session for inhibitory control.

Conclusions

The present study demonstrated that varenicline improves lapses in attention among treatment-seeking smokers preparing to make a quit attempt. These findings suggest that the domain of attention may be a good candidate for larger studies of the role of improved cognition in understanding the mechanisms of varenicline treatment for smoking cessation.     

Drug-induced immune thrombocytopaenia: results from the Berlin Case–Control Surveillance Study

Purpose

Drug-induced immune thrombocytopaenia is a rare, serious condition that can be triggered by numerous medications. To characterize the spectrum of drugs associated with immune thrombocytopaenia (ITP) in the Berlin Case–Control Surveillance Study (FAKOS).

Methods

Adult hospitalized patients with new onset idiopathic, secondary or drug-induced acute ITP and hospital control patients were ascertained by active surveillance in 50 Berlin hospitals (>180 clinical departments) between 2000 and 2009. Drug exposures were obtained in a personal interview. Chronic cases were excluded in a follow-up after 6 or more months. A standardized causality assessment was conducted for each ITP patient to assess possible drug aetiology. Drug risks were quantified in a case–control design with unconditional logistic regression analysis.

Results

Ninety out of 169 validated cases of acute ITP were assessed as being at least possibly drug-related (n?=?85 different drugs overall, n?=?30 drugs with certain or probable causality). Drugs involved in ≥2 cases with a probable or certain relationship were tirofiban (n?=?10 cases), abciximab (n?=?4), trimethoprim/sulphamethoxazole (n?=?4), influenza vaccine (n?=?3), and citalopram (n?=?2). Pneumococcal and poliomyelitis vaccine were assessed as probably causing ITP in one case each. In the case–control analyses, significantly increased risks were observed for tirofiban, abciximab, trimethoprim/sulphamethoxazole, gentamicin, triamterene/hydrochlorothiazide, drospirenone/ethinylestradiol, and influenza vaccination.

Conclusions

Our study confirms known ITP risks for glycoprotein IIb/IIIa receptor antagonists and sulphonamides and generates signals for several other drugs and vaccines. New onset of ITP should not only direct attention to drugs as possible aetiological agents, but also to vaccines that are known to cause autoimmune phenomena.     

CYP2A6 genetic variation and dexmedetomidine disposition

Purpose

There is a large interindividual variability in dexmedetomidine dose requirements for sedation of patients in intensive care units (ICU). Cytochrome P450 2A6 (CYP2A6) mediates an important route of dexmedetomidine metabolism, and genetic variation in CYP2A6 affects the clearance of other substrate drugs. We examined whether CYP2A6 genotypes affect dexmedetomidine disposition.

Methods

In 43 critically ill ICU patients receiving dexmedetomidine infusions adjusted to achieve the desired level of sedation, we determined a median of five plasma dexmedetomidine concentrations each. Forty subjects were genotyped for five common CYP2A6 alleles and grouped into normal (n?=?33), intermediate (n?=?5), and slow metabolizers (n?=?2).

Results

Using a Bayesian hierarchical nonlinear mixture model, estimated dexmedetomidine clearance was 49.1?L/h (posterior mean; 95% credible interval 41.4–57.6?L/h). There were no significant differences in dexmedetomidine clearance among normal, intermediate, and slow CYP2A6 metabolizer groups.

Conclusion

Genetic variation in CYP2A6 does not appear to be an important determinant of dexmedetomidine clearance in ICU patients.     

Effect of ABCB1 polymorphisms and atorvastatin on sitagliptin pharmacokinetics in healthy volunteers

Objectives

The objectives of this study were to determine if ABCB1 polymorphisms are associated with interindividual variability in sitagliptin pharmacokinetics and if atorvastatin alters the pharmacokinetic disposition of sitagliptin in healthy volunteers.

Methods

In this open-label, randomized, two-phase crossover study, healthy volunteers were prospectively stratified according to ABCB1 1236/2677/3435 diplotype (n?=?9, CGC/CGC; n?=?10, CGC/TTT; n?=?10, TTT/TTT). In one phase, participants received a single 100 mg dose of sitagliptin; in the other phase, participants received 40 mg of atorvastatin for 5 days, with a single 100 mg dose of sitagliptin administered on day 5. A 24-h pharmacokinetic study followed each sitagliptin dose, and the study phases were separated by a 14-day washout period.

Results

Sitagliptin pharmacokinetic parameters did not differ significantly between ABCB1 CGC/CGC, CGC/TTT, and TTT/TTT diplotype groups during the monotherapy phase. Atorvastatin administration did not significantly affect sitagliptin pharmacokinetics, with geometric mean ratios (90 % confidence intervals) for sitagliptin maximum plasma concentration, plasma concentration–time curve from zero to infinity, renal clearance, and fraction of sitagliptin excreted unchanged in the urine of 0.93 (0.86–1.01), 0.96 (0.91–1.01), 1.02 (0.93–1.12), and 0.98 (0.90–1.06), respectively.

Conclusions

ABCB1 CGC/CGC, CGC/TTT, and TTT/TTT diplotypes did not influence sitagliptin pharmacokinetics in healthy volunteers. Furthermore, atorvastatin had no effect on the pharmacokinetics of sitagliptin in the setting of ABCB1 CGC/CGC, CGC/TTT, and TTT/TTT diplotypes.     

Altruism in time: social temporal discounting differentiates smokers from problem drinkers

Rationale

Recent studies on reinforcer valuation in social situations have informed research on mental illness. Social temporal discounting may be a way to examine effects of social context on the devaluation of delayed reinforcers. In prior research with non-drug-using groups, we demonstrated that individuals discount delayed rewards less rapidly (i.e., value the future more) for a group of which they are a member than they do for themselves alone.

Objectives

The current study examined how cigarette smoking and level of alcohol use relate to rates of delay and social temporal discounting.

Methods

In this study, we used crowd-sourcing technology to contact a large number of individuals (N?=?796). Some of these individuals were hazardous-to-harmful drinkers (n?=?269), whereas others were non-problem drinkers (n?=?523); some were smokers (n?=?182), whereas others were nonsmokers (n?=?614). Delay discounting questionnaires for individual rewards (me now, me later) and for group rewards (we now, we later; me now, we later) were used to measure individuals’ discounting rates across various social contexts.

Results

Our analyses found that smokers discounted delayed rewards more rapidly than controls under all conditions. However, hazardous-to-harmful drinkers discounted delayed rewards significantly more rapidly than the non-problem drinkers under the individual condition, but not under the social conditions.

Conclusions

This finding suggests that the use of different abused drugs may be associated with excessive discounting in the individual condition and has selective effects when discounting for a group in the social conditions.