CYP2C19 and CYP2J2 genotypes predict praziquantel plasma exposure among Ethiopian school-aged children.

Metabolism of praziquantel (PZQ), a racemic mixture and the only drug approved to treat S. mansoni infection, is mediated by genetically polymorphic enzymes. Periodic school-based mass drug administration (MDA) with PZQ is the core intervention to control schistosomiasis. However data on the impact of pharmacogenetic variation, nutrition, and infection status on plasma PZQ exposure is scarce. We investigated genetic and non-genetic factors influencing PZQ plasma concentration and its metabolic ratios (trans-4-OH-PZQ/PZQ and cis-4-OH-PZQ/PZQ). Four hundred forty-six school children aged 7-15 years from four primary schools in southern Ethiopia who received albendazole and PZQ preventive chemotherapy through MDA campaign were enrolled. Genotyping for common functional variants of CYP3A4 (*1B), CYP3A5 (*3, *6), CYP2C19 (*2, *3, *17), CYP2C9 (*2, *3), and CYP2J2*7 was performed. Plasma concentrations of PZQ, trans-4-OH-PZQ, and cis-4-OH-PZQ were quantified using UPLCMS/MS. Carriers of CYP2C19 defective variant alleles (*2 and *3) had significantly higher mean PZQ plasma concentration than CYP2C19*1/*1 or *17 carriers (p = 0.005). CYP2C19*1/*1 and CYP2C19*17 carriers had higher trans-4-OH-PZQ/PZQ and cis-4-OH-PZQ/PZQ metabolic ratios compared with CYP2C19*2 or *3 carriers (p < 0.001). CYP2J2*7 carriers had lower mean PZQ plasma concentration (p = 0.05) and higher trans-4-OH-PZQ/PZQ and cis-4-OH-PZQ/PZQ metabolic ratios. Male participants had significantly higher PZQ concentration (p = 0.006) and lower metabolic ratios (p = 0.001) than females. There was no significant effect of stunting, wasting, S. mansoni or soil-transmitted helminth infections, CYP3A4, CYP3A5, or CYP2C9 genotypes on plasma PZQ or its metabolic ratios. In conclusion, sex, CYP2C19 and CYP2J2 genotypes significantly predict PZQ plasma exposure among Ethiopian children. The impact of CYP2C19 and CYP2J2 genotypes on praziquantel treatment outcomes requires further investigation.

Lived experiences of closeness to a person using Anabolic androgenic steroids a next of kin perspective.

PURPOSE: Anabolic androgenic steroids (AAS) are used for their aesthetic and performance-enhancing effects and are associated with physical and psychological side effects. Behavioural changes/side effects as mood swings, aggressiveness, depression, potency problems, anxiety, and emotional coldness have been reported by next of kin to people using AAS. METHODS: This phenomenological study is based on the reflective lifeworld research approach. Interviews were conducted with twelve next of kin about their experiences of living close to persons using AAS. RESULTS: Next of kin to persons using AAS are particularly vulnerable because they experience little opportunity to influence their situation. Their given and safe context is lost, and their lives are circumscribed by feelings of insecurity, fear, powerlessness, and grief. Feelings of loneliness develop when their problems are not noticed by others and support is lacking from family and society. CONCLUSIONS: Our research adds important knowledge on how the use of AAS affects next of kin. Understanding is required to approach the lifeworld of next of kin with flexibility and empathy in their difficulties and vulnerability. Healthcare professionals and other concerned professions need to be aware of next of kin existential needs to be able to meet and support them in their life situation.

Pharmacological Risk Assessment Among Older Patients with Polypharmacy Using the Clinical Decision Support System Janusmed Risk Profile: A Cross-Sectional Register Study.

BACKGROUND: Polypharmacy in older people is steadily increasing and a combination of many medicines may result in adverse effects, especially if the medicines interact pharmacodynamically. Examples are additive or synergistic effects increasing the risk of falls, haemorrhage, serotonin syndrome and torsade de pointes. The clinical decision support system Janusmed Risk Profile has been developed to find such risks based on a patients' medication list. OBJECTIVES: The main aim of this retrospective register-based study was to study what pharmacodynamic risks older patients (aged 65 years or older) on polypharmacy (defined as using five or more medicines) are exposed to. Second, we studied if the introduction of the Janusmed Risk Profile in the main electronic health record system in Region Stockholm influenced the proportion of patients prescribed combinations that increase the risk for the nine adverse-effect categories defined (anticholinergic effects, haemorrhage, constipation, orthostatism, QT prolongation, renal toxicity, sedation, seizures and serotonin syndrome). METHODS: Data on all prescription medicines to individuals aged 65 years or older, and with at least five concomitant medicines were retrieved and analysed for the risk categories in the Janusmed Risk Profile. The proportions of patients with a high/moderate risk during a 4-month period before (period 1) and after (period 2) the introduction were compared. RESULTS: A total of 127,719 patients in period 1 (November 2016-February 2017), and 131,458 patients in period 2 (November 2017-February 2018) were included in the study. The proportion of patients with a high or moderate risk for each of the nine properties (anticholinergic effects, haemorrhage, constipation, orthostatism, QT prolongation, renal toxicity, sedation, seizures and serotonergic effects) were 10.9, 34.7, 32.8, 33.6, 17.2, 0.7, 15.4, 0.5 and 2.4%, respectively, in period 1 and 10.4, 35.5, 32.8, 33.3, 10.8, 0.71, 14.9, 0.5 and 2.3% in period 2. The changes for sedation and QT prolongation were statistically significant, with the most pronounced decrease for QT prolongation from 17.2 to 10.8% (p < 0.001). When analysing patients at a high risk, the decrease was significant for haemorrhage, orthostatism, QT prolongation and sedation. CONCLUSIONS: Older people are exposed to combinations of medications that increase the risk for potentially severe adverse effects. Prescribers seem to respond especially to warnings for QT prolongation, presented in the Janusmed Risk Profile implemented in the electronic health record system.

Plasma concentrations of methylphenidate enantiomers in adults with ADHD and substance use disorder, with focus on high doses and relationship to carboxylesterase activity.

Scarce data are available on methylphenidate (MPH) plasma concentrations reached after doses higher than 180 mg. The interindividual and intraindividual variability in the exposure of MPH and ritalinic acid (RA) enantiomers was examined in 28 patients with ADHD and substance use disorders, with MPH daily doses between 30 and 600 mg (median 160 mg). MPH and RA plasma concentrations were analysed with an enantioselective LC-MS/MS method. d-MPH plasma concentration/dose varied 25-fold between subjects but was reasonably stable within an individual. Twelve subjects had quantifiable l-MPH plasma concentrations, which accounted for up to 48% of the total MPH plasma concentration. The less active l-MPH enantiomer could, in individuals with low carboxylesterase 1 (CES1) activity, contribute significantly to the total MPH plasma drug concentration and hamper the estimation of the exposure to the more active d-MPH enantiomer. However, the high correlation between the total (d + l) RA/MPH metabolic ratio and the d-RA/d-MPH metabolic ratio (rs  = 0.94) indicates that the ratio based on non-enantioselective analysis could be used as a marker of CES1 activity. Whether this holds true for subjects with aberrant metabolism due to genetic variants or during concomitant treatment with inhibitors or inducers of the enzyme remains to be studied.

Women's Experiences of Using Anabolic Androgenic Steroids.

Anabolic androgenic steroids are used by women to increase their muscle mass and because of their performance-enhancing effects. Despite permanent/high risk of side effects, knowledge is inadequate. Our aim has been to deepen understanding about women's use of anabolic androgenic steroids. This phenomenological study is based on the reflective lifeworld research (RLR) approach. Lifeworld interviews were conducted with 12 women, aged 21-56 years, about their experiences of using anabolic steroids. The results show that women experience a sense of pride when they successfully achieve their goals. This is the driving force, triggering tension between suffering and success. Our research adds important knowledge from a reflective lifeworld perspective and shows that women's use of anabolic androgenic steroids is a complex phenomenon. Understanding and knowledge are important in order to be able to meet and support women in their fears and difficulties.

Men´s experiences of using anabolic androgenic steroids.

Purpose: Anabolic androgenic steroids (AAS) are used by men for their aesthetic and performance-enhancing effects and are associated with risk for side effects. Our research aims to deepen knowledge and understanding of men´s experiences of using AAS.Method: This phenomenological study is based on the reflective lifeworld research approach. Lifeworld interviews were conducted with twelve men about their experiences of using AAS.Results: By using AAS, men strive towards a muscular, strong and athletic ideal. Self-imposed demands, self-discipline and performance accelerate male physical development. The perfect male body ideal thus attained is fragile from both an existential and a biological perspective. The perfect self-image can easily be shattered by adversity. A man's very existence may be jeopardized if the use of AAS is revealed to others or if the body is let down by illness.Conclusions: Men´s use of AAS is a complex phenomenon. It partly concerns a traditional view of masculinity that is reflected in the community. It requires both broad and deep knowledge and understanding to be able to meet men using AAS in their problems and vulnerability; a meeting that is hampered by their low trust in healthcare, and by the fact that AAS are illegal.

CYP2D6-inhibiting drugs and risk of fall injuries after newly initiated antidepressant and antipsychotic therapy in a Swedish, register-based case-crossover study.

Drug-drug interactions have been shown to affect the risk of fall injuries when opioids are used concomitantly with drugs inhibiting the cytochrome P450 2D6 (CYP2D6) enzyme in a previous pharmacoepidemiological study. The aim of this study was to determine whether CYP2D6-inhibiting drugs reinforce the risk of fall injuries when used concomitantly with antidepressants or antipsychotics. We identified all 252,704 adults with a first fall injury leading to hospitalisation from the National Patient Register in Sweden 2006-2013. Data on dispensed drugs was linked from the Swedish Prescribed Drug Register. We applied a case-crossover design to analyse newly dispensed (28 days preceding the fall injury, preceded by a 12-week washout period) antidepressants and antipsychotics, respectively, in relation to risk of a fall injury and according to concomitant use of CYP2D6-inhibiting drugs. Newly dispensed drugs were assessed correspondingly in a control period of equal length, 28 days prior to the 12-week washout period. Overall, the risk of fall injury was increased after newly initiated antidepressant and antipsychotic treatment. For antidepressants, concomitant CYP2D6 inhibitor use further elevated the risk estimates compared to non-use, most pronounced for the groups selective serotonin reuptake inhibitors (sertraline excluded) [OR = 1.47 (95% CI 1.19-1.80) vs. OR = 1.19 (95% CI 1.13-1.26)], and tricyclic antidepressants [OR = 1.71 (95% CI 1.17-2.51) vs. 1.27 (95% CI 1.11-1.47)] as well as for sertraline [OR = 1.61 (95% CI 1.05-2.38) vs. 1.12 (95% CI 1.00-1.26)]. For antipsychotics, the risk of fall injury was not altered by concomitant use of CYP2D6-inhibiting drugs. In conclusion, concomitant use of CYP2D6 inhibiting drugs tends to further increase the risk of fall injury in newly initiated antidepressant treatment, but not in antipsychotic treatment.

A Summary of Online Enquiries Submitted to Anti-doping Hotline 2005-2018.

Anabolic Androgenic Steroid (AAS) abuse in the society is considered a health problem and has been associated with cardiovascular toxicity, endocrine disruption, as well as psychiatric symptoms such as aggression and cognitive dysfunction. Men and women abusing AAS, as well as persons in close relationship to AAS abusers, may encounter concerns. Subsequently, the Anti-Doping Hotline was formed 1993 to answers questions about doping in the society. Here we have reviewed 7,123 enquiries posted on the Anti-Doping Hotline website between 2005 and 2018 to see what type of questions were raised. Most questions (n = 2,924) involved AAS, 60% from abusers themselves, and 17% from a person close to an AAS abusers. Only 2.3% of the questions concerned AAS abusing women. Of the AAS specific questions most were from persons who sought personal advice regarding risks and side effects. Notably, the AAS abusers themselves were concerned about somatic side effects (e.g., gynecomastia) and problems related to the AAS injection. The persons in close relationship to an AAS abusers on the other hand, expressed concerns about psychiatric changes including mood swings and aggressivity. In addition to AAS, 26 and 13% of the questions involved dietary supplements and other doping substances, respectively. A gradual decrease of questions regarding ephedrine was noted, whereas the numbers of SARMs related questions increased during this time. Our results show that there is a continuous need to provide medical, nursing, and social support and counseling to AAS abusers and their next of kin.

Guiding principles for the use of knowledge bases and real-world data in clinical decision support systems: report by an international expert workshop at Karolinska Institutet.

INTRODUCTION: Technical and logical breakthroughs have provided new opportunities in medicine to use knowledge bases and large-scale clinical data (real-world) at point-of-care as part of a learning healthcare system to diminish the knowledge-practice gap. AREAS COVERED: The article is based on presentations, discussions and recommendations from an international scientific workshop. Value, research needs and funding avenues of knowledge bases and access to real-world data as well as transparency and incorporation of patient perspectives are discussed. EXPERT OPINION: Evidence-based, publicly funded, well-structured and curated knowledge bases are of global importance. They ought to be considered as a public responsibility requiring transparency and handling of conflicts of interest. Information has to be made accessible for clinical decision support systems (CDSS) for healthcare staff and patients. Access to rich and real-world data is essential for a learning health care ecosystem and can be augmented by data on patient-reported outcomes and preferences. This field can progress by the establishment of an international policy group for developing a best practice guideline on the development, maintenance, governance, evaluation principles and financing of open-source knowledge bases and handling of real-world data.

Male Anabolic Androgenic Steroid Users with Personality Disorders Report More Aggressive Feelings, Suicidal Thoughts, and Criminality.

Background and objectives: Anabolic androgenic steroids (AAS) are mainly used for aesthetic and performance-enhancing reasons. Their use is a growing public health problem and concern for society because of their adverse effects. The primary aim of this study was to identify psychiatric and personality disorders and to measure anxiety and depression in AAS users. Materials and Methods: Fifty-six males who actively contacted the Anti-Doping Hot-Line and wished to stop using AAS were included. Structured Clinical Interviews Diagnosis-I and -II were used to diagnose psychiatric and personality disorders. The Brief Scale for Anxiety and Montgomery Asberg Depression Rating Scale (subscales from the Comprehensive Psychopathological Rating Scale) were used to measure changes in anxiety and depression. Structured Clinical Interviews Diagnosis-I and -II were performed at one time point. Anxiety and depression were measured at inclusion and after six months. Urine samples were collected for an analysis of AAS and drugs of abuse. Results: All participants reported some adverse effects that they associated with AAS use. In total, 56% and 52% of the cohort fulfilled the criteria for Structured Clinical Interviews Diagnosis-I and -II diagnoses, respectively. A significantly increased risk of reporting aggressive feelings/behaviors (Odds Ratio (OR) = 4.9; Confidence Interval (CI) 0.99-25, p = 0.04), suicidal thoughts/attempts (OR = 4.6, CI 95; 0.99-21, p = 0.04) and criminality (OR = 6.5, CI 1-39, p = 0.03) was found among individuals with AAS use fulfilling the criteria for personality disorders compared with those without such AAS use. The Brief Scale for Anxiety score decreased from the median of 15 at inclusion to 10 at the follow-up visit six months later (p = 0.01, n = 19). Conclusions: Our findings indicate that among individuals with AAS use, those with a personality disorder report more aggressive behaviors, suicidal thoughts/suicidal attempts, and criminality than those without a personality disorder.

Studies of athlete biological passport biomarkers and clinical parameters in male and female users of anabolic androgenic steroids and other doping agents.

The use of anabolic androgenic steroids (AAS) and other performance enhancing substances can change over time, so there is a need to constantly update what substances are used and can be detected. Six women and 30 men anabolic androgenic steroid users were recruited who filled out an anonymous questionnaire about their use of performance enhancing substances during the past year. Sampling took place on a single occasion and included blood and urine collection. Our aim was to identify which doping agents can be detected in men and women self-reporting AAS use. The first choice of substances differed between men (testosterone) and women (oxandrolone). The use of growth hormones was reported among men (10%) and women (50%). Growth hormone releasing factors/secretagogs were reported by about ~ 20% in both genders. Nandrolone was the most frequently detected anabolic androgenic steroid even in those who did not report use in the past year. Of the current male testosterone users, 82% exhibited testosterone/epitestosterone (T/E) ratios of > 4. Men with current testosterone use displayed 4-fold and 6-fold higher median T/E, respectively, when compared with recent and previous testosterone users (P = 0.0001). Dermal testosterone use in women (n = 2) was not associated with a T/E ratio of > 4, but with supra-physiological total serum testosterone concentrations. Changes in gonadotropins and hematological parameters were associated with the time of the last anabolic androgenic steroid intake in men, whereas in women these biomarkers were within the normal range. This highlights gender specific differences and indicates the need for additional biomarkers in female athletes.

Pharmacokinetics of methylphenidate and ritalinic acid in plasma correlations with exhaled breath and oral fluid in healthy volunteers.

PURPOSE: The primary aim of this study was to explore the potential of alternative sampling matrices for methylphenidate by assessing the correlations between dl-threo-methylphenidate and dl-threo-ritalinic acid concentrations in exhaled breath and oral fluid with those in plasma, in repeated samples collected after a single oral dose of methylphenidate. The secondary aim was to study the enantioselective pharmacokinetics of methylphenidate in plasma, with a focus on interindividual variability in the metabolism of methylphenidate to ritalinic acid. METHODS: Twelve healthy volunteers received a single oral dose of dl-threo-methylphenidate (Ritalin® capsules, 20 mg). Venous blood samples were collected for 24 h, and plasma analyzed for threo-enantiomers of methylphenidate and ritalinic acid with LC-MS/MS. Repeated sampling of exhaled breath, using a particle filter device, and of non-stimulated oral fluid, using a felt pad device, was also performed. Exhaled breath and oral fluid were analyzed with a non-enantioselective LC-MS/MS method for dl-threo-methylphenidate and dl-threo-ritalinic acid. RESULTS: In all subjects, d-threo-methylphenidate was detectable in plasma for at least 15 h after the dose with a biphasic profile. l-threo-Methylphenidate was measurable in only five subjects and in most cases in low concentrations. However, one female subject displayed a biphasic concentration-time profile for l-threo-methylphenidate. This subject also had the highest d-threo-methylphenidate AUC (191 ng*h/mL versus 32-119 ng*h/mL in the other subjects). d-threo-Ritalinic acid concentrations were on average 25-fold higher (range 6-126) than the corresponding d-threo-methylphenidate concentrations. Single-time point plasma concentration ratios between d-threo-ritalinic acid and d-threo-methylphenidate 1.5-12 h after dose correlated highly (r = 0.88-0.98) with the d-threo-ritalinic acid AUC/d-threo-methylphenidate AUC ratio. In eleven subjects, dl-threo-methylphenidate in oral fluid mirrored the biphasic profile of methylphenidate (sum of d- and l-threo-enantiomers) in plasma, but the concentrations in oral fluid were on average 1.8 times higher than in plasma. dl-threo-Methylphenidate was detected in exhaled breath in all subjects, but there was no consistent concentration-time pattern. CONCLUSIONS: In some subjects, the pharmacologically less active l-threo-enantiomer may contribute to the total plasma methylphenidate concentrations. Monitoring methylphenidate concentrations without enantiomeric determination carries the risk of missing such subjects, which might affect how the plasma concentrations of methylphenidate are interpreted and used for clinical decision making. The use of exhaled breath and oral fluid to assess medication adherence to MPH in patients with ADHD warrants further studies.

Methylphenidate effects on processing speed in a clinical sample of adults with ADHD and substance use disorder: a pilot study.

BACKGROUND: Substance use disorders (SUDs) are common comorbidities of Attention Deficit Hyperactivity Disorder (ADHD). The most commonly prescribed medication for ADHD is methylphenidate. The clinical response to methylphenidate may be monitored against DSM-5 symptomatology, rating scales or interviews. AIMS: To evaluate the use of perceptual and cognitive processing speed measures to monitor methylphenidate effects in adults with ADHD and SUD. METHODS: A Quick Test of Cognitive Speed (AQT) monitored perceptual and cognitive processing speed in 28 adults with ADHD and SUD on treatment with methylphenidate before and after the morning dose. RESULTS: Twenty-six patients responded on AQT after the morning dose of methylphenidate. One-way ANOVA indicated significant treatment effects for color, form, and color-form combination naming, but not for shift cost values. Before the morning dose of methylphenidate, 92% were identified by cutoff time criteria for longer-than-normal processing times. After the morning dose of methylphenidate, 65% obtained color and form measures in the normal range for age peers. Only 35% obtained color-form processing measures in the normal range. Inter-individual response variability before medication intake was considerably larger than previously reported in studies of adults with ADHD only. CONCLUSION: Proportionally, fewer adults with ADHD and SUD exhibited normalization of processing speed than previously observed for adults with ADHD without SUD. A potential clinical implication of the present study is that the AQT test may be used as a tool for dose-adjustment of central stimulants in the treatment of adults with ADHD and SUD.

Drug abuse screening with exhaled breath and oral fluid in adults with substance use disorder.

In the treatment of substance use disorder, regular laboratory-based testing has the dual purpose of monitoring compliance with the prescribed medication and abstention from medically non-motivated substances (ie, drug abuse screening). The principal specimen for testing is urine, but collection of urine has some disadvantages, for example being more time-consuming and more intrusive compared to other matrices. There is also the risk of adulteration. This project compared exhaled breath and oral fluid as alternative matrices for drug abuse screening in patients with substance use disorder. All 51 subjects included in the study were enrolled at the Drug Addiction Emergency Unit in Stockholm. Exhaled breath, oral fluid, and urine samples were collected together with a self-report. Of all 117 self-reported drug intakes during the previous week, 72% were confirmed in urine, 73% in oral fluid and 39% in exhaled breath. In 31% of the subjects, additional substances other than those self-reported were detected analytically. For substance abuse screening, urine had the highest detection rate for buprenorphine, cannabis, and benzodiazepines, while oral fluid had the highest detection rate for amphetamines and methadone. Exhaled breath showed the highest detection rate of all matrices for cocaine. To identify significant differences in detection rates between the matrices future studies with larger sampling sizes are needed. Both oral fluid and exhaled breath are viable alternative specimens to urine, depending on the circumstances and purpose of the testing.

Correlation Between Serum Concentrations of N-Desmethylclozapine and Granulocyte Levels in Patients with Schizophrenia: A Retrospective Observational Study.

BACKGROUND: Clozapine is restricted to use in patients with treatment-refractory schizophrenia due to the risk of a serious drop in absolute neutrophil granulocyte count (ANC). The formation of reactive, unstable metabolites (adducts) has been suggested as a mechanism of clozapine-induced granulocyte decline. These adducts are not detectable in vivo, but stable clozapine metabolites could potentially be indirect pharmacokinetic measures of adduct formation. OBJECTIVE: The present retrospective observational study investigated the correlation between concentrations of N-desmethylclozapine, the major stable clozapine metabolite, and ANC in a real-life population of clozapine-treated patients. METHODS: Patients were included from a therapeutic drug monitoring service at the Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway, between March 2005 and December 2015. Information about clozapine and N-desmethylclozapine steady-state trough concentrations, as well as accompanying measurements of ANC, were collected from the laboratory database. Correlations of serum concentrations of N-desmethylclozapine and clozapine (and their respective ratios) with ANC were investigated by linear mixed-model analysis. RESULTS: Overall, 129 patients with 855 measurements of clozapine/N-desmethylclozapine concentrations and ANC (range 0.9-19 × 109 cells/L, median 4.6) were included. Concentrations of N-desmethylclozapine, but not clozapine, correlated significantly and positively with ANC (estimated model slope 0.0011 × 109 cells/L/nM; p = 0.002), and the N-desmethylclozapine/clozapine ratio also positively correlated with ANC (p = 0.040). CONCLUSIONS: N-Desmethylclozapine level and ANC significantly correlated in this real-life population of schizophrenia patients. The positive correlation, which was also present for the metabolic ratio, might reflect reduced clozapine availability for the formation of reactive metabolites potentially affecting granulocyte level. However, as our findings were based on ANC mainly within the reference range, this hypothesis should be studied further in clozapine-treated patients with neutropenia or agranulocytosis.

Genetic variants in CYP2B6 and CYP2A6 explain interindividual variation in efavirenz plasma concentrations of HIV-infected children with diverse ethnic origin.

BACKGROUND: Approximately 2.6 million children live with HIV globally, and efavirenz (EFV) is one of the most widely used antiretroviral agents for HIV treatment in children and adults. There are concerns about the appropriateness of current EFV dosing and it has been discussed whether EFV dosing should be adapted according to genotype in children as suggested for adults. AIM: To investigate if pediatric EFV dosing should be guided by genetic variation in drug metabolizing enzymes rather than by body weight. METHOD: EFV plasma concentrations measured for clinical purposes from all children less than 18 years old at Karolinska University Hospital, Stockholm, Sweden, treated with EFV were collected retrospectively. They were genotyped for eleven polymorphisms in genes coding for drug-metabolizing enzymes and P-glycoprotein, of potential importance for EFV disposition. Data on country of origin, sex, age, weight, HIV RNA, viral resistance patterns, CD4 cells, adherence to treatment, subjective health status and adverse events were collected from their medical records. RESULTS: Thirty-six patients and 182 (mean 5 samples/patient) EFV plasma concentration measurements from children of African, Asian and Latin American origin were included. EFV plasma concentration varied 21-fold between measurements (n = 182) (0.85-19.3 mg/L) and 9-fold measured as mean EFV plasma concentration across the subjects (1.55-13.4 mg/L). A multivariate mixed-effects restricted maximum likelihood regression model, including multiple gene polymorphisms, identified CYP2B6*6 T/T (p < 0.0005), CYP2B6*11 G/G (p < 0.0005), CYP2A6*9 A/C (p = 0.001) genotypes, age at treatment initiation (p = 0.002) and time from treatment initiation (p < 0.0005) as independent factors significantly related to loge concentration/(dose/weight). The contribution of the model to the intra- and interindividual variation were 6 and 75%, respectively (Bryk/Raudenbush R-squared level). CONCLUSION: Genetic polymorphisms in CYP2B6 and CYP2A6 explained a significant proportion of variability in EFV plasma concentration in HIV-infected children in a multi-ethnic outpatient clinic. Knowledge about individual variants in key drug metabolizing enzyme genes could improve clinical safety and genotype directed dosing could achieve more predictable EFV plasma concentrations in HIV-infected children.

Recruitment to doping and help-seeking behavior of eight female AAS users.

BACKGROUND: Doping with anabolic androgenic steroids in sports has now developed to a widespread use of these agents among young people outside the sport. This is of major concern to the society. The purpose of the use is mainly for aesthetic reasons and is seen as a male phenomenon. But use also occurs in women where the knowledge is scarce. Our aim was to identify the pattern of doping agents in eight female cases and compare them with similar data from men. METHODS: Eight female users were recruited through Anti-Doping Hot-Line, a national telephone counseling service on doping issues during the years 1998-2004. The use was confirmed with urine doping analysis at the Doping Laboratory. The characteristic of use, co-use of narcotics/other doping agents, exercise pattern, adverse-side effects, family history and reason to begin was evaluated. RESULTS: The women used on average 1.9 different anabolic androgenic steroids and clenbuterol preparations. Ephedrine and growth hormone were co-used in five and one of the women, respectively. Three women reported co-use of narcotics (cannabis and cocaine). The average duration of anabolic agent use before contacting health care was 58 weeks (range 7-104). Side effects for anabolic androgenic steroids (n = 5) included voice changes, clitoral enlargement, body hair growth, whereas women using clenbuterol (n = 2) reported tachycardia and depression. All women except one had a man in close relationship encouraging them to begin with the doping agents. CONCLUSIONS: The use of doping agents in our eight women was different from that in male users. The women used less doping agents and were more prone to contact the health care, at an earlier stage, probably due to the adverse effects. The co-use with ephedrine, growth hormone and cannabis appeared to be in the same range as in men. This is the first study showing that a man in close relationship may motivate a woman to use anabolic agents.