Significance of the genetic polymorphism of CYP2D6 and NAT2 in patients with inflammatory bowel diseases

BackgroundThe main types of inflammatory bowel diseases (IBD) are ulcerative colitis (UC) and Crohn's disease (CD). There is evidence that, in addition to immunological and environmental factors, genetic factors also play an important role in the pathogenesis of IBD. Determination of polymorphism of CYP2D6 and NAT2 genes encoding I and II phase enzymes of xenobiotic biotransformation may have clinical value as an indicator of individual predisposition to diseases, and also contribute to effective and safe pharmacotherapy. The aim of this study was to investigate the association between genetic polymorphism of CYP2D6 and NAT2 and the incidence of IBD, including UC and CD, among inhabitants of central Poland.MethodsThe study was performed in 258 individuals from central Poland (115 patients with IBD, including 65 patients with UC and 50 with CD; and in 143 healthy controls). The CYP2D6 genotypes of oxidation and NAT2 genotypes of acetylation were analyzed using the PCR-RFLP method.ResultsThere were no statistically significant differences in the frequency of the CYP2D6 genotypes and alleles in patients with IBD, UC and CD in comparison with the control group. The relative risk (OR) of IBD, UC and CD was higher in carriers of the allele NAT2*7 and was OR = 3.49 (p = 0.0019), OR = 3.86 (p = 0.0019), and OR = 3.02 (p = 0.0247), respectively.ConclusionsPolymorphism of the gene encoding CYP2D6 does not affect the incidence of inflammatory bowel diseases. The carriers of the NAT2*7 allele which determines slow acetylation may be more predisposed to inflammatory bowel diseases, including ulcerative colitis and Crohn's disease.     

Childhood hyperactivity-inattention symptoms and smoking in adolescence

Background:The objective of the study was to examine in both genders the link between childhood hyperactivity-inattention symptoms (HI-s) and smoking in adolescence, controlling for psychopathology, temperament and environmental risk factors.Methods:Subjects (421 males, 495 females), aged 7 to 18, were recruited in the GAZEL cohort representative of the general population and surveyed in 1991 and 1999. Parent and adolescent self-report measures were used to assess child psychopathology and smoking patterns. Logistic regression was used to assess the effects of childhood hyperactivity-inattention symptoms and other predictors on adolescent smoking.Results:In females, hyperactivity-inattention symptoms contributed independently to subsequent daily smoking (OR = 1.98, p = 0.04). In males, hyperactivity-inattention symptoms alone did not increase the risk for smoking. Conduct disorder symptoms was an important predictor in males (OR = 2.95, p < 0.01) and females (OR = 1.75, p = 0.09). The risk of adolescent smoking was significantly increased in boys with high activity level (OR = 1.70, p = 0.03) and decreased in shy girls (OR = 0.60, p = 0.02). Parental smoking increased the liability to smoking in their offspring (males: OR = 1.96, p < 0.01; females: OR = 1.63, p = 0.02).Conclusions:If replicated, these findings suggest a role for smoking prevention in girls with hyperactivity-inattention symptoms and in boys with high activity level.     

Influence of sex and CYP2D6 genotype on mirtazapine disposition, evaluated in Spanish healthy volunteers

AimsTo evaluate the influence of sex and CYP2D6 genotype on mirtazapine disposition within two bioequivalence studies in healthy volunteers.MethodsSeventy-two healthy volunteers were included in two standard 2 × 2 crossover bioequivalence trials. Subjects received a single 30-mg oral dose of each mirtazapine formulation in each study period. Plasma concentrations were measured from 0 to 96 or 120 h by a HPLC with coupled mass spectrometry validated method. CYP2D6 genotyping was available for 68 subjects that were classified into three phenotypic groups depending on the number of active gene copies: extensive/ultrarapid metabolizers (UM-EM), intermediate (IM) and poor metabolizers (PM). To evaluate the influence of sex and genotype on mirtazapine disposition we performed a linear mixed model for repeated measures. Pharmacokinetic data were log-transformed and AUC and C_max adjusted to the administered dose/weight. Factors included in the model were centre, formulation, period, sequence, sex and genotype as fixed effects, and subject nested sequence × sex × genotype as random one. A second model was also performed adding the interaction sex × genotype to the previous model.ResultsMirtazapine disposition evaluated as AUC_0–∞ is influenced by sex (p = 0.007) and CYP2D6 phenotype group (p = 0.01). Attending to the theoretical figures provided by the model, mean (95% CI) dose/weight adjusted AUC_0–∞ (ng h/ml)/(mg/kg) is 1516.62 (1411.27–1628.22) in EM/UM, 1613.63 (1482.14–1758.55) in IM and 2049.28 (1779.78–2357.24) in PM. In the case of C_max these figures also show a trend to higher values in PM, but it did not reach statistical significance. Females show a lower dose/weight adjusted AUC_0–∞: 1594.39 (1477.70–1720.28) vs. 1837.65 (1694.67–1992.70). On the contrary dose/weight adjusted C_max is higher in females than in males: 38.33 (34.79–42.28) vs. 32.66 (29.44–36.21).ConclusionsBoth CYP2D6 genotype group and sex influence the disposition of mirtazapine in healthy volunteers and confirm reported data in the literature obtained by different methods. No sex-by-genotype interaction could be detected.     

Polymorphism of CYP1A1 gene variants rs4646903 and rs1048943 relation to the incidence of cervical cancer in Chhattisgarh

Cytochrome P450 CYP1A1 is a phase 1 xenobiotic metabolizing enzyme involved in the metabolism of toxins, endogenous hormones and pharmaceutical drugs. It is therefore possible that polymorphism of CYP1A1 gene producing functional changes in the enzyme may be susceptible factors in cervical carcinogenesis. This study was aimed to look association of CYP1A1 m1 (T > C) and m2 (A > G) gene polymorphisms in Chhattisgarh population. In this case-control study, we analyzed leukocyte DNA from a total of 200 subjects form Chhattisgarh (100 cases and 100 controls). All subjects were genotyped for CYP1A1 m1 (T > C) and m2 (A > G) using PCR-RFLP with statistical analysis by using SPSS version 16.0 and VassarStats (online). Among the two gene variants rs4646903 (T > C) and rs1048943 (A > G), individuals with AG and GG genotypes of CYP1A1 m2 polymorphism have significantly higher and increased risk of cervical cancer (OR = 2.0, 95%CI = 1.04-3.84, p = 0.035; OR = 62.9, 95%CI = 3.72-1063.83, p = 0.004 respectively) and the association of CYP1A1 m1 polymorphism did not show any significant relationship with cervical cancer patients (p = 0.23). The ‘G’ allele showed strong association with the disease (p < 0.0001). Thus, CYP1A1 m2 polymorphism showed an increased risk in the population leading to cervical cancer. Our study suggested that the presence of ‘C’ allele of rs4646903 (T > C) showed no risk and ‘G’ allele of rs1048943 (A > G) might be a leading allele to cause increased cervical cancer susceptibility due to significant association of CYP1A1 m2 gene polymorphism.     

Variability in CYP2C9 allele frequency: A pilot study of its predicted impact on warfarin response among healthy South and North Indians

BackgroundWide variability exists in the frequency of pharmacogenetic markers for anticoagulant response in different populations. There is insufficient data on the prevalence of these variant genotypes in the Indian population. This study aims to determine the frequency of various genotype combinations of CYP2C9*2, *3 and VKORC1-1639G>A polymorphisms in the South and North Indians.MethodsGenotyping was carried out by PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) technique in 209 North Indians (NI) and 82 South Indians (SI). Warfarin maintenance dose was predicted for all subjects based on FDA approved genotype-based dose estimates from revised COUMADIN medication guide. Fisher exact test and χ² test were applied to compare categorical data among the SI and NI groups.ResultsIn SI and NI, the allele frequency of CYP2C9*2 was 0.006 and 0.05 (significant variation; p < 0.001); of CYP2C9*3 was 0.09 and 0.11; and of VKORC1-1639A was 0.14 and 0.19 (not significant), respectively. The variation in the frequency of combined CYP2C9/ VKORC1 genotypes revealed plausible difference in warfarin response among SI and NI. Based on the FDA approved revised dosing guidelines, significantly higher percentage of NI were likely to require intermediate dose (3–4 mg/day; p = 0.015, RR = 2.16) and were also predicted to have an increased risk of bleeding episodes and over anticoagulation (p = 0.012, RR = 1.93).ConclusionsGenotype frequency of CYP2C9 and VKORC1 SNPs is variable among the two ethno-geographically distinct Indian populations. This could translate into diverse warfarin response among the Indian population.     

Influence of ABCB1, CYP3A4*18B and CYP3A5*3 polymorphisms on cyclosporine A pharmacokinetics in bone marrow transplant recipients

The aim of this study was to retrospectively evaluate the effect of polymorphisms in the CYP3A4, CYP3A5 and ABCB1 genes on the dose-adjusted concentration and dose requirement of cyclosporine A (CsA) in Chinese recipients during the early period after bone marrow or hematopoietic stem cell transplantation. Ninety-one bone marrow transplant recipients were genotyped by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay or by direct sequencing for the C1236T, G2677T/A and C3435T polymorphisms in CYP3A4*18B, CYP3A5*3, and ABCB1, respectively. The concentration at zero before administration (C₀) and concentration at 2 h after administration (C₂) of whole blood CsA were measured by fluorescence polarization immunoassay. Dose-adjusted C₀ and C₂ were determined and compared among groups with different genotypes. Compared with CYP3A5*3/*3 individuals, CYP3A5*1/*1 subjects have a significantly lower dose-adjusted C₀ and C₂ at days 1–10 and a higher dose requirement for CsA at days 16–30 (p < 0.05). In addition, homozygotes for the ABCB1 3435T mutant have a significantly higher dose-adjusted C₀ and C₂ and a lower dose requirement compared with wildtype (p < 0.05). Similar results were also derived for carriers of the T-G-C haplotype in CYP3A5 producers compared with non-carriers (p < 0.05 and p < 0.01, respectively). In summary, the ABCB1 3435T SNP, T-G-C haplotype in CYP3A5 producers, and CYP3A5*3 SNP are all associated with differences in CsA pharmacokinetics and dose requirements during the first month after bone marrow or hematopoietic stem cell transplantation. Genetic testing can therefore help to determine initial dosage and individualize immunosuppressive therapy.     

The influence of CYP2A6 polymorphisms and cadmium on nicotine metabolism in Thai population

We investigated the influence of genetic, cadmium exposure and smoking status, on cytochrome P450-mediated nicotine metabolism (CYP2A6) in 182 Thai subjects after receiving 2 mg of nicotine gum chewing for 30 min. The urinary excretion of cotinine was normally distributed over a 2 h period (logarithmically transformed). Individuals with urinary cotinine levels in the ranges of 0.01–0.21, and 0.52–94.99 μg/2 h were categorized as poor metabolizes (PMs: 6.5%), and extensive metabolizers (EMs: 93.5%), respectively. The majority of EMs (45%) carried homozygous wild-type genotypes (CYP2A6*1A/*1A, CYP2A6*1A/*1B and CYP2A6*1B/*1B), whereas only 1% of PMs carried these genotypes. Markedly higher frequencies of EMs were also observed in all heterozygous defective genotypes including the null genotype (*4C/*4C; 1 subject).A weak but significant positive correlation was observed between total amounts of urinary cadmium excretion and total cotinine excretion over 2 h. Our study shows generally good agreement between CYP2A6 genotypes and phenotypes. Smokers accumulated about 3–4-fold higher mean total amounts of 2-h urinary cadmium excretion (127.5 ± 218.2 ng/2 h) than that of non-smokers (40.5 ± 78.4 ng/2 h). Among the smokers (n = 16), homologous wild-type genotype *1/*1 was significantly the predominant genotype (6/16) compared with other defective allele including *4C/*4C. In addition, 2 h urinary excretion of cotinine in smokers of all genotypes was significantly higher than non-smokers. The proportion of smokers who smoked more than 5 cigarettes/day was significantly higher in EMs in all CYP2A6 genotypes (n = 14) than in PMs (n = 0).     

Is Internet addiction transitory or persistent? Incidence and prospective predictors of remission of Internet addiction among Chinese secondary school students

BackgroundInternet addiction (IA) is prevalent among adolescents but it is potentially revertible. Only three Taiwan adolescent studies reported IA remission and a few related factors. We investigated incidence and predictors of remission among Hong Kong Chinese secondary school students with a 12-month longitudinal study.MethodsIA was defined as Chen Internet Addiction Scale (CIAS) score > 63. Validated measures were used to assess students' psychosocial wellbeing at baseline and follow-up.ResultsOf 1545 students with IA at baseline, 1296 (83.9%) provided matched baseline/12-month follow-up data; their data were analyzed. Incidence of remission (CIAS ≤ 63 at follow-up) was 59.29/100 person-years. Significant predictors included: 1) baseline CIAS score (ORa = .95), 2) baseline health belief model (HBM) constructs [perception of having severe IA (ORa = .34), perceived susceptibility to IA (ORa = 0.82), perceived barrier (ORa = 0.95), cue to action from parents (ORa = 0.82), and self-efficacy for reducing Internet use (ORa = 1.13)], and 3) baseline psychosocial health measures [self-esteem (ORa = 1.03), severe depression (ORa = 0.72) and social anxiety (ORa = 0.96)] and their changes over time [depression (ORa = .95), anxiety (ORa = .94), loneliness (ORa = .93), self-esteem (ORa = 1.07), positive affect (ORa = 1.10) and family support (ORa = 1.03)]. Two-thirds (64.3%) of the remission group presented reduced CIAS score > 1.5 SD, and recorded larger improvements in psychosocial status over time than the non-remission group.ConclusionWithout noticeable interventions, incidence of remission was high and related to improvements in psychosocial health. Most of the HBM constructs, and baseline/changes in psychosocial measures predicted remission. Interventions to increase remission should modify these factors.     

Review of prescription medications in home-based older adults with stroke: A pilot study

BackgroundPharmacological intervention for comorbid management and stroke prevention may increase polypharmacy, inappropriately prescribed drugs (IPDs), and potential drug-drug interactions (PDDIs) among older adults with a history of stroke.ObjectiveThe objective of this study was to determine prevalence and incidence of polypharmacy, IPDs, and PDDIs in a cohort of home-based older adults with self-reported stroke living in New York and Florida.MethodsUsing a cross-sectional design, we determined the prevalence of PDDIs in 191 older adults with a history of stroke. We quantified the odds of PDDIs using bivariate logistic regression. Using a 3-year retrospective longitudinal design, we determined the relative risk (RR) of PDDIs in 41 new cases (New York) with polypharmacy and IPD. The independent variables were polypharmacy and IPDs, and the dependent variable was PDDIs.ResultsSubjects from Florida were older, had higher frequencies of some medical conditions, and used more medications, but the prevalence rates of PDDIs showed similar trends for the 2 states: 60% (New York) and 86% (Florida). The 3 strongest predictors of PDDIs in New York were polypharmacy (≥4 drugs) (odds ratio [OR] = 10.3; 95% confidence interval [CI] = 3.8-27.8); IPDs (OR = 8.4; 95% CI = 2.7-25.5); and having a heart condition (OR = 6.0; 95% CI = 1.6-22.8). The logistic model yielded one predictor for PDDIs in Florida: polypharmacy (≥4 drugs) (OR = 9.7; 95% CI = 1.4-65.4). The 3-year RR for PDDIs (New York) was 1.8 (95% CI = 1.2-2.8) from polypharmacy and 2.1 (95% CI = 1.3-3.3) from IPDs.ConclusionsAlthough this research is exploratory and used a small convenience sample, the estimates obtained suggest consideration of prospective hypothesis testing using a larger database and a greater number of subjects using more recent medications. Prospective examination of developing drug-drug interactions in this way will enhance the generalizability of these findings. This study shows similarities in the prevalence rates between 2 historical cohorts in 2 states, thereby suggesting plausibility of findings.     

Awareness of legal blood alcohol concentration limits amongst respondents of a national roadside survey for alcohol and traffic behaviours in Brazil

BackgroundIn Brazil the legal blood alcohol content (BAC) allowed for driving was changed to zero in 2008. If the BAC found is above 0.6 g/L, drivers may be arrested. However, there are limited data on drivers’ awareness of such limits.MethodsDrivers from 27 major metropolitan areas (n = 3397) were randomly asked to participate in roadside survey from 12 a.m. to 12 p.m. on Fridays and Saturdays. They were breathalized by highway patrol officers, and after consent interviewers collected data on drinking behaviours, knowledge about the law, and breath tests results.ResultsThe mean age was 37.3 ± 11.3 years; 94.3% were male and 26.5% had some college education. When asked about the BAC that could result in arrest, 34.5% of the subjects claimed to know it. However, only 23.5% (8.1% of the total sample) provided correct answers. Factors associated with the right answers were: male gender (p = 0.04; OR = 2.08; CI = 1.01–4.27); higher education (p < 0.0001); negative BAC or self-report of driving under the influence (DUI) (p = 0.02); higher family income (p = 0.01) and non-professional driving (p = 0.041). Age was not statistically different between groups. After multivariate analysis, male gender (p = 0.002), higher education (p < 0.0001) and negative BAC or DUI (p = 0.046) remained in the model.ConclusionsThe knowledge that BAC levels over 0.6 g/L may result in arrest is sparse amongst Brazilian drivers, notably amongst women, the less educated and those who drink and drive. Educational programmes targeted at those specific groups may be necessary in order to increase awareness about the legal BAC limit and its consequences.     

Tobacco consumption and spontaneous quitting at the first trimester of pregnancy

IntroductionThe purpose of this study was to examine the association between pregnant women's socio-demographic characteristics, smoking-related variables and psychological symptoms (anxiety and depression) and both tobacco consumption and spontaneous quitting at the first trimester of pregnancy. In particular, we wished to examine the contribution of depressive symptoms to tobacco consumption and spontaneous quitting, while controlling for anxiety symptoms, socio-demographic and smoking-related variables.MethodsThe sample was comprised of 901 Spanish pregnant women. Assessment included an ad hoc questionnaire with socio-demographic and tobacco consumption information, the Edinburg Postnatal Depression Scale (EPDS), and The State-Anxiety Inventory (STAI-S). Two multiple logistic regression analyses were performed, respectively to predict tobacco consumption and to predict spontaneous quitting.ResultsHaving a partner who smokes (OR = 5.578), not having a college education (OR = 2.803), higher scores on the EPDS (OR = 1.073) and higher scores on the STAI-S (OR = 1.027) increase the probability of continuing smoking. Being primiparous (OR = 2.463), having a college education (OR = 2.141), smoking fewer cigarettes before pregnancy (OR = 1.175), and lower scores on the STAI-S (OR = 1.045) increase the probability of spontaneously quitting smoking at the first trimester of pregnancy.ConclusionsDepressive symptoms were a predictor of tobacco consumption but not of spontaneous quitting; spontaneous quitting was better predicted by anxiety symptoms. These findings support recommendations that women with depressive symptoms are at risk for smoking during pregnancy and highlight that anxious symptoms should be targeted in interventions for smoking cessation during pregnancy.     

Frequency of common CYP3A5 gene variants in healthy Polish newborn infants

Cytochrome P450 monooxygenases catalyze the metabolism of approximately 40-60% of widely used drugs with a A6986G CYP3A5 polymorphism determining expresser (A6986, *1) and reduced- expresser (*3) variants with modified drug metabolism activity. In this report, the allele frequency of CYP3A5 *1 and *3 (A6986 or G6986, respectively) was analyzed by the PCR-RFLP technique in a cohort of 200 Polish newborns from the West Pomeranian region. Of the studied group, 1% (n = 2/200) proved homozygous for the CYP3A5*1 allele, 89% (n=178/200) for the *3 allele, and 10% (n = 20/200) were heterozygous for *1/*3.Similar frequencies were found in other Caucasian European populations. This study provides basic genetic data related to the metabolism of drugs, with a narrow therapeutic window in a Polish population.     

Association between corneal temperature and mental status of treatment-resistant schizophrenia inpatients

IntroductionPreliminary point-prevalent data suggest that drug-free schizophrenia patients may exhibit increased body/corneal temperature, that antipsychotic drugs (APDs) may decrease body/core temperature and that patients' mental status might be associated with their body/corneal temperature. Hence, we hypothesized that treatment-resistant psychotic APD-treated schizophrenia patients' mental status may correlate with their corneal temperature during a continuous 6-week period.MethodsCorneal temperature of 12 treatment-resistant schizophrenia inpatients and 16 healthy volunteers was evaluated 2–3 times a week during 6 consecutive weeks using a flir thermal imaging camera.ResultsA significant and substantial correlation was found between inpatients' mean weekly Positive and Negative Syndrome Scale (PANSS)'s total scores and their mean weekly corneal temperature during the 6-week study period (r = 0.82; n = 6 weeks; p = 0.043). There was no significant difference in mean 6-week corneal temperature between the patient group and the healthy subjects (34.25 ± 0.64 °C vs. 34.39 ± 0.69 °C, respectively; t = 1.127, df = 131, p = 0.26).ConclusionsThis study indicates that treatment-resistant overtly psychotic schizophrenia inpatients' mental status (as assessed by the PANSS) correlates with their corneal temperature. The relevance of these phenomena to the pathophysiology of schizophrenia, the biological mechanism underlying corneal temperature alterations and the possible role of temperature-modulating drugs (neuroleptics or non-neuroleptics) on schizophrenic psychosis merits further large-scale investigation in both medicated- and drug-free schizophrenia patients compared to matched controls.     

The effectiveness of outreach case management in re-enrolling discharged methadone patients

BackgroundHeroin dependence is a chronic relapsing disease often requiring multiple treatment experiences. Despite this knowledge, few methadone programs follow-up with discharged patients who frequently continue to engage in risky behaviors. The aim of this project was to evaluate the effectiveness of outreach case management for post-discharged methadone patients.MethodsAt 90 days post-discharge 128 active out of treatment heroin users were randomly assigned to receive either a passive referral (PR) for drug treatment (n = 52) or were provided with 6 weeks of outreach case management (OCM), an intervention designed to help motivate and coach patients to re-enter treatment (n = 76).ResultsAt 6 months post-baseline 29% of the OCM participants had successfully re-enrolled in drug treatment compared to 8% of the PR participants (χ² = 7.6, d.f. = 1, p = 0.006). A logistic regression analysis showed that OCM participants were nearly six times more likely than PR participants to re-engage in MMT (OR = 5.8, CI = 1.6–20.8, p = 0.008). Moreover, OCM subjects had fewer opiate and cocaine positive urines at the 6-month follow-up compared to PR subjects.ConclusionsThe findings highlight the importance of engaging former patients in treatment and actively assisting in treatment re-entry. OCM is a simple approach to reduce the number of out-of-treatment drug users, although availability of treatment funding limits enrollment opportunities.     

The inhibition of major human hepatic cytochrome P450 enzymes by 18 pesticides: Comparison of the N-in-one and single substrate approaches

In the present study on human hepatic microsomes, the N-in-one assay with ten probe substrates for nine cytochrome-P450 enzymes (CYPs) was compared with the single substrate assays to investigate pesticides–CYP interactions. CYP inhibition was measured by liquid chromatography–tandem mass spectrometry (LC/MS–MS). As illustrated by the initial screening at 100 μM concentration of 18 pesticides, CYPs are more sensitive to organophosphates (OPs) than to other pesticide groups. Chlorpyrifos and fenitrothion were most effective in inhibiting CYP1A1/2, and CYP2B6. Profenofos was also inhibitory towards multiple CYPs. Pyrethroids, e.g. deltamethrin, fenvalerate and lambda-cyhalothrin, potently inhibited CYP2D6. CYP3A4 activity was moderately inhibited by fenvalerate and potently by alpha-cypermethrin. The correlations between IC₅₀ values obtained from the N-in-one and single substrate approaches were highly significant for CYP2Cs (r² = 0.94), CYP3A4, omeprazole-sulfoxidation, (r² = 0.89), followed by CYP1A2 and CYP2B6 (r² = 0.82), and CYP2D6 (r² = 0.80). In contrast no correlation was observed with CYP2E1 and CYP3A4 (midazolam-1′-hydroxylation). The N-in-one screening assay seems useful and reliable for most CYP activities when a comprehensive and quick evaluation of potential interactions with CYPs is needed. However, at the present moment, it does not enable discrimination on the basis of mechanism of inhibition. A strict comparison between single and N-in-one assays is a prerequisite for more extensive routine use.     

The prototypic pharmacogenetic drug debrisoquine is a substrate of the genetically polymorphic organic cation transporter OCT1

Debrisoquine is a probe drug for in vivo phenotyping of human CYP2D6 metabolic activity. However, debrisoquine is positively charged under physiological conditions and it is unclear how it enters the hepatocytes to undergo CYP2D6 metabolism. We analysed whether debrisoquine is a substrate of the hepatic organic cation transporter OCT1 and whether drug–drug interactions at OCT1, or polymorphisms in OCT1 gene, affect debrisoquine uptake.Debrisoquine showed low carrier-independent membrane permeability (P_e of 0.01 × 10^?6 cm/s in artificial PAMPA membranes) and strongly inhibited the uptake of the model OCT1 substrate MPP⁺ (IC₅₀ of 6.2 ± 0.8 μM). Debrisoquine uptake was significantly increased in HEK293 cells overexpressing OCT1 compared to control cells. The OCT1-mediated uptake of debrisoquine followed Michaelis–Menten kinetics (K_M of 5.9 ± 1.5 μM and V_max of 41.9 ± 4.5 pmol/min/mg protein) and was inhibited by known OCT1 inhibitors and by commonly used drugs. OCT1-mediated debrisoquine uptake was reduced or missing in cells expressing loss-of-function OCT1 isoforms. Deletion of Met420 or substitution of Arg61Cys or Gly401Ser reduced V_max by 48, 63 and 91%, respectively, but did not affect the K_M. The OCT1 isoforms carrying Cys88Arg or Gly465Arg substitutions completely lacked OCT1-mediated debrisoquine uptake.In conclusion, debrisoquine is a substrate of OCT1 and has the potential to be used as a phenotyping marker for OCT1 activity. Moreover, variations in debrisoquine metabolic phenotypes and their associations with diseases may be due not only to genetic variations CYP2D6, but also in OCT1.     

Psychiatric disorders,suicidal ideation,and sexually transmitted infections among post-deployment veterans who utilize digital social media for sexual partner seeking

IntroductionDigital social media platforms represent outlets through which individuals may find partners for sexual encounters. Using a sample of US post-deployment military veterans, the current study evaluated the prevalence of digital sex seeking as well as clinical correlates of psychopathology, suicidal ideation, and sexually transmitted infections (STIs).MethodsUsing data from a baseline telephone interview and follow-up internet-based survey, we examined the prevalence of sexual partnering via digital social media platforms in a national sample of 283 US combat veterans.ResultsAmong veterans, 35.5% of men and 8.5% of women reported having used digital social media to meet someone for sex. Individuals who reported having used digital social media to find sexual partners (DSMSP+) as compared to those who did not (DSMSP-) were more likely to be young, male, and in the Marine Corps. After adjusting for sociodemographic variables, DSMSP+ status was associated with post-traumatic stress disorder (OR = 2.26, p = 0.01), insomnia (OR = 1.99, p = 0.02), depression (OR = 1.95, p = 0.03), hypersexuality (OR = 6.16, p < 0.001), suicidal ideation (OR = 3.24, p = 0.04), and treatment for an STI (OR = 1.98, p = 0.04).ConclusionAmong US post-deployment military veterans, DSMSP+ behaviors were prevalent, particularly among men. The association between DSMSP+ behaviors and PTSD, insomnia, depression, hypersexuality, suicidal ideation, and STIs suggest that veterans who engage in DSMSP+ behaviors should be particularly thoroughly screened and evaluated for these psychiatric concerns and counseled on the benefits of safe sexual practices.     

Effect of antidepressant drugs on cytochrome P450 2C11 (CYP2C11) in rat liver

BackgroundRat CYP2C11 (besides CYP2C6) can be regarded as a functional counterpart of human CYP2C9. The aim of the present study was to investigate the influence of classic and novel antidepressant drugs on the activity of CYP2C11, measured as a rate of testosterone 2α- and 16α-hydroxylation.MethodsThe reaction was studied in control liver microsomes in the presence of antidepressants, as well as in microsomes from rats treated intraperitoneally (ip) with pharmacological doses of the tested drugs (imipramine, amitriptyline, clomipramine, nefazodone – 10 mg/kg ip; desipramine, fluoxetine, sertraline - 5 mg/kg ip; mirtazapine - 3 mg/kg ip) for one day or two weeks (twice a day), in the absence of antidepressants in vitro.ResultsThe investigated antidepressant drugs added to control liver microsomes produced certain inhibitory effects on CYP2C11 activity, which were moderate (sertraline, nefazodone and clomipramine: K_i = 39, 56 and 66 μM, respectively), modest (fluoxetine and amitriptyline: K_i = 98 and 108 μM, respectively) or weak (imipramine and desipramine: K_i = 191 and 212 μM, respectively). Mirtazapine had no inhibitory effect on CYP2C11 activity. One-day exposure of rats to the antidepressant drugs did not significantly change the activity of CYP2C11 in liver microsomes; however, imipramine, desipramine and fluoxetine showed a tendency to diminish the activity of CYP2C11. Of the antidepressants studied, only desipramine and fluoxetine administered chronically elevated CYP2C11 activity; those effects were positively correlated with the observed increases in the enzyme protein level.ConclusionThree different mechanisms of the antidepressants-CYP2C11 interaction are postulated: 1) a direct inhibition of CYP2C11 shown in vitro by nefazodone, SSRIs and TADs; 2) in vivo inhibition of CYP2C11 produced by one-day treatment with imipramine, desipramine and fluoxetine, which suggests inactivation of the enzyme by reactive metabolites; 3) in vivo induction of CYP2C11 produced by chronic treatment with desipramine and fluoxetine, which suggests their influence on enzyme regulation.     

Effects of alcohol and cigarette use on the initiation,reinitiation, and persistence of cannabis use from adolescence to emerging adulthood

ObjectiveAdolescent cannabis use has been associated with several negative outcomes. A previous study on an adult sample found alcohol and cigarette use to be associated with three cannabis use stages: initiation, reinitiation, and persistence, which represent distinct periods of use regarding progression and severity. Yet, the risk factors associated with these important stages have never been examined in a longitudinal study spanning adolescence to emerging adulthood.MethodsUsing longitudinal data from Add Health Waves 1–3, 1775 nonusers, 200 prior users, and 384 current users of cannabis were identified who were at risk of cannabis use initiation, reinitiation, and persistence, respectively. Three logistic regressions were conducted to examine the effects of prior cigarette and alcohol use on the three cannabis use stages, controlling for sociodemographic factors.ResultsEarly onset of cigarette use (OR = 2.04, p = 0.006) and higher alcohol use frequency (OR = 1.40, p < 0.001) were associated with cannabis use initiation. Greater cigarette use quantity was associated with a lower likelihood of reinitiation of cannabis use (OR = 0.58, p = 0.02). Increased cannabis use frequency (OR = 1.72, p = 0.006) and higher alcohol use frequency (OR = 1.32, p = 0.048) were associated with persistence of cannabis use. Sociodemographic factors such as household income, sex, and being older adolescents were associated with different cannabis use stages.ConclusionsPrior cigarette and alcohol use affect the risk of initiation, reinitiation, and persistence of cannabis use. The specific risk factors vary across different cannabis use stages. Interventions to prevent adolescent cannabis use should recognize these different risk factors and tailor to the stages of cannabis use.