Short- and medium-term impact of bariatric surgery on the activities of CYP2D6, CYP3A4, CYP2C9, and CYP1A2 in morbid obesity.

Morbid obesity and bariatric surgery induce anatomical, physiological and metabolic alterations that may alter the body's disposition of drugs. Current literature on this topic is limited and sometimes inconsistent. Cytochrome P450 (CYP) is a superfamily of enzymes that metabolize around 75% of all marketed drugs. The purpose of this study was to evaluate the impact of body mass index and bariatric surgery on CYP activities. Firstly, we evaluated the in vivo activity of 4 major CYP isoenzymes (CYP2D6, CYP3A4, CYP2C9, and CYP1A2) in normal weight, overweight, and morbidly obese individuals. Secondly, we assessed the short- (1 month) and medium-term (6 month) effects of the most commonly employed bariatric surgery techniques (laparoscopic sleeve gastrectomy and Roux-en-Y gastric bypass) on the activity of these enzymes. CYP3A4 activity was lower in morbidly obese individuals, compared to normal-weight controls. Interestingly, bariatric surgery normalized CYP3A4 activity. In comparison with normal-weight controls, morbidly obese individuals had higher CYP2D6 activity, which was only observed in individuals with two functional alleles for this isoenzyme. Neither body mass index nor surgery had significant effects on CYP2C9 and CYP1A2 activities. Overall, no relevant differences in CYP activities were found between surgical techniques. In conclusion, further studies should evaluate whether the observed alterations in CYP3A4 activity will require dose adjustments for CYP3A4 substrates especially in morbidly obese individuals before and after bariatric surgery.

Pharmacokinetics in Morbid Obesity: Influence of Two Bariatric Surgery Techniques on Paracetamol and Caffeine Metabolism.

PURPOSE: The purpose of the study was to study the impact of the two most common bariatric surgery techniques on paracetamol pharmacokinetics (a marker of gastric emptying) and caffeine metabolism (a marker of liver function). MATERIALS AND METHODS: In the present prospective study, we studied 24 morbid obese patients before, at 4 weeks, and 6 months after having undergone sleeve gastrectomy (n = 10) or Roux-en-Y gastric bypass (n = 14). For comparative purposes, 28 healthy controls (14 normal weights and 14 overweights) were also included in the study. RESULTS: Paracetamol pharmacokinetics was altered in the obese participants leading to lower bioavailability. Bariatric surgery resulted in faster absorption and normalized pharmacokinetic parameters, prompting an increase in paracetamol bioavailability. No differences were found between surgical procedures. In the case of caffeine, the ratio paraxanthine/caffeine did not differ between morbid obese and healthy individuals. This ratio remained unmodified after surgery, indicating that the liver function (assessed by cytochrome P450 1A2 activity) was unaffected by obesity or bariatric surgery. CONCLUSIONS: Paracetamol pharmacokinetics and caffeine plasma levels are altered in severely obese patients. The two studied bariatric surgical techniques normalize paracetamol oral bioavailability without impairing the liver function (measured by cytochrome P450 1A2 activity).

Decision-making impairment predicts 3-month hair-indexed cocaine relapse.

RATIONALE: One of the key outstanding challenges in cocaine dependence research is determining who is at risk of relapsing during treatment. OBJECTIVES: We examined whether cognitive decision-making profiles predict objectively (hair) indexed cocaine relapse at 3-month follow-up. METHODS: Thirty-three cocaine-dependent patients commencing outpatient treatment in a public clinic performed baseline decision-making assessments with the original and variant versions of the Iowa Gambling Task, and provided a 3-cm hair sample 3 months afterwards. Based on Iowa Gambling Tasks' performance cut-offs, 5 patients had intact decision-making skills, 17 patients showed impaired sensitivity to reward or punishment (impairment in one of the tasks), and 9 patients showed insensitivity to future consequences (impairment in both tasks). Based on a 0.3 ng/mg cocaine cut-off, 23 patients were classified as relapsers and 10 as non-relapsers at the 3-month follow-up. RESULTS: Eighty percent of patients with intact decision-making were abstinent at follow-up, whereas 90% of patients with insensitivity to future consequences had relapsed. The two subgroups (relapsers and non-relapsers) showed no significant differences on drug use, comorbidities, or psychosocial function, and significantly differed on verbal but not performance IQ. A regression model including decision-making scores and verbal IQ predicted abstinence status with high sensitivity (95%) and moderately high specificity (81%). CONCLUSION: These preliminary findings demonstrate that decision-making profiles are associated with cocaine relapse. Moreover, combined decision-making and IQ assessments provide optimal predictive values over stimulant relapse, yielding significant opportunities for clinical translation.

COMT val158met and 5-HTTLPR genetic polymorphisms moderate executive control in cannabis users.

The adverse effects of cannabis use on executive functions are still controversial, fostering the need for novel biomarkers able to unveil individual differences in the cognitive impact of cannabis consumption. Two common genetic polymorphisms have been linked to the neuroadaptive impact of Δ9-tetrahydrocannabinol (THC) exposure and to executive functions in animals: the catechol-O-methyltransferase (COMT) gene val158met polymorphism and the SLC6A4 gene 5-HTTLPR polymorphism. We aimed to test if these polymorphisms moderate the harmful effects of cannabis use on executive function in young cannabis users. We recruited 144 participants: 86 cannabis users and 58 non-drug user controls. Both groups were genotyped and matched for genetic makeup, sex, age, education, and IQ. We used a computerized neuropsychological battery to assess different aspects of executive functions: sustained attention (CANTAB Rapid Visual Information Processing Test, RVIP), working memory (N-back), monitoring/shifting (CANTAB ID/ED set shifting), planning (CANTAB Stockings of Cambridge, SOC), and decision-making (Iowa Gambling Task, IGT). We used general linear model-based analyses to test performance differences between cannabis users and controls as a function of genotypes. We found that: (i) daily cannabis use is not associated with executive function deficits; and (ii) COMT val158met and 5-HTTLPR polymorphisms moderate the link between cannabis use and executive performance. Cannabis users carrying the COMT val/val genotype exhibited lower accuracy of sustained attention, associated with a more strict response bias, than val/val non-users. Cannabis users carrying the COMT val allele also committed more monitoring/shifting errors than cannabis users carrying the met/met genotype. Finally, cannabis users carrying the 5-HTTLPR s/s genotype had worse IGT performance than s/s non-users. COMT and SLC6A4 genes moderate the impact of cannabis use on executive functions.

Hair analysis following chronic smoked-drugs-of-abuse exposure in adults and their toddler: a case report.

INTRODUCTION: Over the past two decades, the study of chronic cocaine and crack cocaine exposure in the pediatric population has been focused on the potential adverse effects, especially in the prenatal period and early childhood. Non-invasive biological matrices have become an essential tool for the assessment of a long-term history of drug of abuse exposure. CASE REPORT: We analyze the significance of different biomarker values in hair after chronic crack exposure in a two-year-old Caucasian girl and her parents, who are self-reported crack smokers. The level of benzoylecgonine, the principal metabolite of cocaine, was determined in segmented hair samples (0 cm to 3 cm from the scalp, and > 3 cm from the scalp) following washing to exclude external contamination. Benzoylecgonine was detectable in high concentrations in the child's hair, at 1.9 ng/mg and 7.04 ng/mg, respectively. Benzoylecgonine was also present in the maternal and paternal hair samples at 7.88 ng/mg and 6.39 ng/mg, and 13.06 ng/mg and 12.97 ng/mg, respectively. CONCLUSION: Based on the data from this case and from previously published poisoning cases, as well as on the experience of our research group, we conclude that, using similar matrices for the study of chronic drug exposure, children present with a higher cocaine concentration in hair and they experience more serious deleterious acute effects, probably due to a different and slower cocaine metabolism. Consequently, children must be not exposed to secondhand crack smoke under any circumstance.

Acute heroin intoxication in a baby chronically exposed to cocaine and heroin: a case report.

INTRODUCTION: Acute intoxication with drugs of abuse in children is often only the tip of the iceberg, actually hiding chronic exposure. Analysis using non-conventional matrices such as hair can provide long-term information about exposure to recreational drugs. CASE PRESENTATION: We report the case of a one-month-old Caucasian boy admitted to our pediatric emergency unit with respiratory distress and neurological abnormalities. A routine urine test was positive for opiates, suggesting an acute opiate ingestion. No other drugs of misuse, such as cocaine, cannabis, amphetamines or derivatives, were detected in the baby's urine. Subsequently, hair samples from the baby and the parents were collected to evaluate the possibility of chronic exposure to drug misuse by segmental analysis. Opiates and cocaine metabolites were detected in hair samples from the baby boy and his parents. CONCLUSIONS: In light of these and previous results, we recommend hair analysis in babies and children from risky environments to detect exposure to heroin and other drug misuse, which could provide the basis for specific social and health interventions.

Gas chromatography-mass spectrometry assay for the simultaneous quantification of drugs of abuse in human placenta at 12th week of gestation.

We describe the development and validation of a method for the quantification of drugs of abuse, using gas chromatography-mass spectrometry (GC/MS), in human placenta. Concentration ranges covered were 5-500 ng/g for amphetamine, methamphetamine, MDMA, methadone, cocaine, benzoylecgonine, cocaethylene, morphine, 11-nor-9-carboxy-delta-9-tetrahydrocannabinol, nicotine, and cotinine. Intra-assay and inter-assay imprecisions were less than 15.7% for lower quality control samples and less than 14.9% for medium and high quality control samples. Recovery range was 36.2-83.7%. Placenta samples were kept at -80 degrees C until analysis; analytes were stable after three freeze-thaw cycles (samples stored at -20 degrees C). This accurate and precise assay has sufficient sensitivity and specificity for the analysis of specimens collected from women who voluntarily terminated their pregnancy at 12th week of gestation. The method has proven to be robust and accurate for the quantification of the principal recreational drugs of abuse in this period of the prenatal life. This is the first report that highlights the presence of drugs of abuse during the first trimester of gestation.

Alcohol consumption is associated with high concentrations of urinary hydroxytyrosol.

BACKGROUND: Previously, we reported the presence of hydroxytyrosol in red wine and higher human urinary recovery of total hydroxytyrosol than that expected after a single red wine intake. We hypothesized that the alcohol present in wine could promote endogenous hydroxytyrosol generation. OBJECTIVE: The objective was to assess the relation between alcohol consumption and urinary hydroxytyrosol concentrations. DESIGN: This was a cross-sectional study with baseline data from a subsample of the PREvención con DIeta MEDiterránea (PREDIMED) trial, an intervention study directed at testing the efficacy of the Mediterranean diet on the primary prevention of cardiovascular disease. Participants included 1045 subjects, aged 55-80 y, who were at high cardiovascular risk. Alcohol consumption was estimated through a validated food-frequency questionnaire. Urinary hydroxytyrosol and ethyl glucuronide, a biomarker of alcohol consumption, were measured. RESULTS: Urinary ethyl glucuronide concentrations were directly related to alcohol and wine consumption (P < 0.001) as well as to urinary hydroxytyrosol in both sexes (P < 0.001). The degree of alcohol consumption was directly associated with urinary hydroxytyrosol in male alcohol consumers (P < 0.001). Multivariate logistic regression analyses showed a significant linear trend (P < 0.05) for elevated hydroxytyrosol concentrations with an increase in alcohol consumption. Intakes of >20 g (2 drinks)/d and >10 g (1 drink)/d alcohol in men and women, respectively, were associated (P < 0.05) with elevated concentrations of hydroxytyrosol. CONCLUSIONS: We report for the first time a direct association between urinary hydroxytyrosol and alcohol consumption at a population level. These findings reinforce previous work in human and animal models that examines wine as a source of hydroxytyrosol and alcohol as an indirect promoter of endogenous hydroxytyrosol generation. This trial was registered at controlled-trials.com/isrctn/ as ISRCTN 35739639.

Unsuspected exposure to cocaine in preschool children from a Mediterranean city detected by hair analysis.

We used hair testing to investigate the prevalence of unsuspected exposure to cocaine in a group of preschool children presenting to an urban pediatric emergency department without signs or symptoms suggestive of exposure. Hair samples were obtained from 90 children between 18 months and 5 years of age attending the emergency room of Hospital del Mar in Barcelona, Spain. In 85 cases, hair samples from the accompanying parent were also provided. The samples were analyzed for the presence of cocaine and benzoylecgonine by gas chromatography-mass spectrometry, which also determined opiates and amphetamines. Parental sociodemographics, possible drug history, and information on the child's features were recorded. Hair samples from 21 children (23.3%) were positive for cocaine (concentration range 0.3-5.96 ng/mg of hair) with 1 sample also positive for 3,4-methylenedioxymethamphetamine and another for opiates. In 88% of the positive cases, cocaine was also found in the hair of the accompanying parent (15 of 17 matched parent-child hair samples). Parental sociodemographics were associated neither with children's exposure to cocaine nor with somatometry of children at birth. However, the behavioral patterns with potential harmful effects for the child's health (eg, tobacco smoking, cannabis, benzodiazepines and/or antidepressants use, and shorter breast-feeding time) were significantly higher in the parents of exposed children. A statistically higher percentage of exposed children were in the lower weight percentile group compared with the nonexposed children. In the light of these results, we advocate general hair screening to disclose exposure to cocaine and other drugs of abuse in children from risky environments, which could provide the basis for specific social and health interventions.

A simple and reliable procedure for the determination of psychoactive drugs in oral fluid by gas chromatography-mass spectrometry.

A simple and reliable gas chromatography-mass spectrometry method for identifying and quantifying psychoactive drugs in oral fluid is described. Substances under investigation were: psychostimulant drugs (amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine, 3,4-methylenedioxiamphetamine, 3,4-methylenedioxy-N-ethylamphetamine, phentermine), cocaine and metabolites (benzoylecgonine, cocaethylene, and ecgonine methyl esther), cannabinoids (delta-9-tetrahydrocannabinol, 11-nor-9-carboxy-delta-9-tetrahydrocannabinol, 11-hydroxy-delta-9-tetrahydrocannabinol, cannabinol and cannabidiol), opiates (6-monoacetylmorphine, morphine and codeine), hypnotics (flurazepam, flunitrazepam, dipotassium chlorazepate, alprazolam, diazepam and oxazepam), antidepressant drugs (amitryptiline, paroxetine and sertraline), antipsychotic drugs (haloperidol, chlorpromazine and fluphenazine) chlormethiazole, loratidine, hydroxyzine, diphenhydramine, valproic acid and gabapentin. After the addition of deuterated analogues of morphine, 3,4-methylenedioxymethamphetamine, (+/-)-11-nor-9-carboxy-delta-9-tetrahydrocannabinol and clonazepam as internal standards, all the compounds were simultaneously extracted from oral fluid by solid-phase extraction procedure. Acid compounds were eluted with acetone while basic and neutral compounds with dichloromethane:isopropanol:ammonium (80:20:2, v/v/v). Chromatography was performed on a methylsilicone capillary column and analytes, derivatized with N-Methyl-N-(trimethylsilyl)trifluoroacetamide, were determined in the selected-ion-monitoring (SIM) mode. Mean recovery ranged between 44.5 and 97.7 % and quantification limit between 0.9 and 44.2 ng/ml oral fluid for the different analytes. The developed analytical methodology was applied to investigate the presence of psychoactive drugs in oral fluid from injured individuals attending the emergency room (MACIUS project).