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Importance and objective: Self-reported caffeine consumption has been widely used in research while it may be subject to bias. We sought to investigate the associations between self-reported caffeine consumption and plasma levels of caffeine and its two main metabolites (paraxanthine and theophylline) in the community. Methods: Data from two population-based studies (SKIPOGH1 and 2 (N = 1246) and CoLaus|PsyCoLaus (N = 4461)) conducted in Switzerland were used. Self-reported caffeine consumption was assessed using questionnaires. Plasma levels of caffeine and its metabolites were quantified by ultra-high performance liquid chromatography coupled to a tandem quadrupole mass spectrometer. Results: In both studies, mean log plasma levels of caffeine and its two metabolites were over 6.48 (plasma levels = 652 ng/ml) when no caffeine consumption was reported. Subsequently, nonlinear associations between log plasma levels and self-reported caffeine consumption were observed in SKIPOGH, with a change of the slope at 3–5 cups of espresso per day in SKIPOGH1 but not SKIPOGH2. In CoLaus|PsyCoLaus, increased daily consumption of caffeinated beverages was associated with increased log plasma levels with a change of the slope at 3 cups. In both studies, declared caffeine consumption higher than 3–5 cups per day was not associated with higher plasma levels of caffeine and its metabolites. Conclusion: Self-reports of no or low caffeine consumption and consumption of more than 3–5 cups of coffee should be interpreted with caution, with possible under- or over-estimation. Quantifying plasma levels of caffeine and its metabolites may contribute to a better estimation of caffeine intake. [ABSTRACT FROM AUTHOR]

Purpose: Roux-en-Y gastric bypass (RYGB) involves alterations of the gastrointestinal tract resulting in altered absorption. Patients with obesity have a higher prevalence of depression, and antidepressants are often prescribed. Alterations caused by RYGB could modify drug bioavailability and cause potential subtherapeutic plasma concentrations, increasing the risk of depressive relapse. The aim of this study was to describe the evolution of trough drug dose-normalized antidepressant plasma concentrations before and after RYGB. Materials and Methods: This naturalistic prospective case series considers patients with trough plasma concentrations in a 1-year timeframe before and after RYGB. Only antidepressants prescribed to at least three patients were included in the present study. Results: Thirteen patients (n = 12 females, median age 44 years, median BMI before intervention = 41.3 kg/m2) were included. Two patients were treated concurrently with fluoxetine and trazodone; the remaining patients were all treated with antidepressant monotherapy. Therapeutic drug monitoring (TDM) values for duloxetine (n = 3), escitalopram (n = 4), fluoxetine (n = 4), and trazodone (n = 4) before (median 4.7 weeks) and after (median 21.3 weeks) RYGB intervention were analyzed. Compared to preintervention, median [interquartile range] decreases in dose-normalized trough plasma concentrations for duloxetine (33% [− 47; − 23]), escitalopram (43% [− 51; − 31]), fluoxetine (9% [− 20; 0.2]), and trazodone (16% [− 29; 0.3]) were observed. Conclusion: This study shows a decrease in plasma antidepressant concentrations following RYGB. TDM before and after RYGB, in addition to close monitoring of psychiatric symptomatology, may help optimize antidepressant treatment after bariatric surgery. These results also highlight the need for prospective studies assessing the clinical evidence available through TDM in these patients. [ABSTRACT FROM AUTHOR]

The impact of bariatric surgery on depression appears to be positive during the early months (the so-called honeymoon period), but depressive symptoms tend to increase 36 months post-intervention [[1]]. Another case series of 12 subjects treated with selective serotonin reuptake inhibitors (SSRI) and serotonin-noradrenaline reuptake inhibitors (SNRI) showed a decreased area under the curve (AUC) between 36 to 80% in eight patients 1 month after RYGB intervention [[6]]. In case of malabsorption, daily dosage increase, switching to liquid oral dosage forms, crushing tablets (according to the package insert), and dividing the daily dosage into several daily drug intakes are strategies that can easily be implemented. [Extracted from the article]

Purpose: The objectives of this study were (1) to estimate caffeine intake and identify the main sources of intake using a dietary questionnaire, (2) to assess 24-h urinary excretion of caffeine and its metabolites, and (3) to assess how self-reported intake estimates correlates with urinary excretion among children in Switzerland. Methods: We conducted a cross-sectional study of children between 6 and 16 years of age in one region of Switzerland. The participants filled in a dietary questionnaire and collected a 24-h urine sample. Caffeine intake was estimated with the questionnaire. Caffeine, paraxanthine, theophylline, and theobromine excretions were measured in the urine sample. Correlations between questionnaire-based intake and urinary excretion estimates were assessed using Spearman correlation coefficients. Results: Ninety-one children were included in the analysis (mean age 10.6 years; 43% female). The mean daily caffeine intake estimate derived from the diet questionnaire was 39 mg (range 0–237), corresponding, when related to body weight, to 1.2 mg/kg (range 0.0–6.3). Seven children (8%) had a caffeine intake above the upper recommended level of 3 mg/kg per day. The main sources of caffeine intake were cocoa milk (29%), chocolate (25%), soft drinks (11%), mocha yogurt (10%), tea (8%), and energy drinks (8%). The 24-h urinary excretion of caffeine was 0.3 mg (range 0.0–1.5), paraxanthine 1.4 mg (range 0.0–7.1), theophylline 0.1 mg (range 0.0–0.6), and theobromine 14.8 mg (range 0.3–59.9). The correlations between estimates of caffeine intake and the 24-h urinary excretion of caffeine was modest (ρ = 0.21, p = 0.046) and with the metabolites of caffeine were weak (ρ = 0.09–0.11, p = 0.288–0.423). Conclusions: Caffeine intake in a sample of children in a region of Switzerland was relatively low. The major sources of intake were cocoa milk, chocolate and soft drinks. Self-reported caffeine intake correlated weakly with urinary excretion of caffeine and some of its main metabolites. Trial registration number: NCT02900261. [ABSTRACT FROM AUTHOR]

Background: Amisulpride is an antipsychotic used in a wide range of doses. One of the major adverse events of amisulpride is hyperprolactinemia, and the drug might also induce body weight gain.Objective: The aims of this work were to characterize the pharmacokinetics of amisulpride in order to suggest optimal dosage regimens to achieve the reference range of trough concentrations at steady-state (Cmin,ss) and to describe the relationship between drug pharmacokinetics and prolactin and body weight data.Methods: The influence of clinical and genetic characteristics on amisulpride pharmacokinetics was quantified using a population approach. The final model was used to simulate Cmin,ss under several dosage regimens, and was combined with a direct Emax model to describe the prolactin data. The effect of model-based average amisulpride concentrations over 24 h (Cav) on weight was estimated using a linear model.Results: A one-compartment model with first-order absorption and elimination best fitted the 513 concentrations provided by 242 patients. Amisulpride clearance significantly decreased with age and increased with lean body weight (LBW). Cmin,ss was higher than the reference range in 65% of the patients aged 60 years receiving 400 mg twice daily, and in 82% of the patients aged > 75 years with a LBW of 30 kg receiving 200 mg twice daily. The pharmacokinetic/pharmacodynamic model included 101 prolactin measurements from 68 patients. The Emax parameter was 53% lower in males compared with females. Model-predicted prolactin levels were above the normal values for Cmin,ss within the reference range. Weight gain did not depend on Cav.Conclusions: Amisulpride treatment might be optimized when considering age and body weight. Hyperprolactinemia and weight gain do not depend on amisulpride concentrations. Modification of the amisulpride dosage regimen is not appropriate to reduce prolactin concentrations and alternative treatment should be considered. [ABSTRACT FROM AUTHOR]

This article provides an overview of the pharmacokinetic drug-drug interactions (DDIs) for agents prescribed for attention-deficit/hyperactivity disorder (ADHD). Polypharmacy in the treatment of patients with ADHD leads to high exposures to DDIs and possibly adverse safety outcomes. We performed a systematic search of DDI reports for ADHD agents in Embase and Medline. We also searched for agents in the pharmacological pipeline, which include (1) mazindol, molindone and viloxazine, which were previously prescribed for other indications; (2) centanafadine and AR-08, never before approved; and (3) two extracts (Polygala tenuifolia extract and the French maritime pine bark extracts). The identified literature included case reports, cross-sectional, cross-over and placebo-controlled studies of patient cohorts and healthy volunteers. The DDIs were classified as follows: ADHD agents acting as perpetrators, i.e., affecting the clearance of co-prescribed agents (victim drugs), or ADHD agents being the victim drugs, being affected by other agents. Ratios for changes in pharmacokinetic parameters before and after the DDI were used as a rough estimate of the extent of the DDI. Alcohol may increase plasma dextroamphetamine concentrations by presystemic effects. Until studies are done to orient clinicians regarding dosing changes, clinicians need to be aware of the potential for cytochrome P450 (CYP) 2D6 inhibitors to increase amphetamine levels, which is equivalent to increasing dosages. Atomoxetine is a wide therapeutic window drug. The CYP2D6 poor metabolizers who do not have CYP2D6 activity had better atomoxetine response, but also an increased risk of adverse effects. CYP2D6 inhibitors have been used to increase atomoxetine response in CYP2D6 extensive metabolizers. Guanfacine is mainly metabolized by CYP3A4, which can be induced and inhibited. The package insert recommends that in guanfacine-treated patients, after adding potent CYP3A4 inducers, the guanfacine dose should be doubled; after adding potent CYP3A4 inhibitors the guanfacine dose should be halved. Based on a phenobarbital case report and our experience with CYP3A4-metabolized antipsychotics, these correction factors may be too low. According to two case reports, carbamazepine is a clinically relevant inducer of methylphenidate (MPH). A case series study suggested that MPH may be associated with important elevations in imipramine concentrations. Due to the absence of or limitations in the data, no comments for clinicians can be provided on the pharmacokinetic DDIs for clonidine, centanafadine, mazindol, molindone, AR-08, P. tenuifolia extract and the French maritime pine bark extracts. According to currently available data, clinicians should not expect that ADHD drugs modify each other's serum concentrations. A summary table for clinicians provides our current recommendations on pharmacokinetic DDIs of ADHD agents based on our literature review and the package inserts; whenever it was possible, we provide information on serum concentrations and dose correction factors. There will be a need to periodically update these recommendations and these correction factors as new knowledge becomes available. [ABSTRACT FROM AUTHOR]

Purpose: The abstinence rate to tobacco after varenicline treatment is moderate and might be partially affected by variability in varenicline concentrations. This study aimed at characterizing the sources of variability in varenicline pharmacokinetics and to relate varenicline exposure to abstinence. Methods: The population pharmacokinetic analysis (NONMEM®) included 121 varenicline concentrations from 82 individuals and tested the influence of genetic and non-genetic characteristics on apparent clearance (CL/F) and volume of distribution (V/F). Model-based average concentrations over 24 h (Cav) were used to test the impact of varenicline exposure on the input rate (Kin) expressed as a function of the number of cigarettes per day in a turnover model of 373 expired carbon monoxide levels. Results: A one-compartment model with first-order absorption and elimination appropriately described varenicline concentrations. CL/F was 8.5 L/h (coefficient of variation, 26%), V/F was 228 L, and the absorption rate (ka) was fixed to 0.98 h−1. CL/F increased by 46% in 100-kg individuals compared to 60-kg individuals and was found to be 21% higher in UGT2B7 rs7439366 TT individuals. These covariates explained 14% and 9% of the interindividual variability in CL/F, respectively. No influence of varenicline Cav was found on Kin in addition to the number of cigarettes. Conclusions: Body weight mostly and to a smaller extent genetic polymorphisms of UGT2B7 can influence varenicline exposure. Dose adjustment based on body weight and, if available, on UGT2B7 genotype might be useful to improve clinical efficacy and tolerability of varenicline. [ABSTRACT FROM AUTHOR]

Background and Objectives: Methadone is a μ-opioid agonist widely used for the treatment of pain, and for detoxification or maintenance treatment in opioid addiction. It has been shown to exhibit large pharmacokinetic variability and concentration-QTc relationships. In this study we investigated the relative influence of genetic polymorphism and other variables on the dose concentration-QTc relationship.Patients and Methods: A population model for methadone enantiomers in 251 opioid-dependent patients was developed using non-linear mixed effect modeling (NONMEM®). Various models were tested to characterize the pharmacokinetics of (R)- and (S)-methadone and the pharmacokinetic-pharmacodynamic relationship, while including demographics, physiological conditions, co-medications, and genetic variants as covariates. Model-based simulations were performed to assess the relative increase in QTc with dose upon stratification according to genetic polymorphisms involved in methadone disposition.Results: A two-compartment model with first-order absorption and lag time provided the best model fit for (R)- and (S)-methadone pharmacokinetics. (S)-methadone clearance was influenced by cytochrome P450 (CYP) 2B6 activity, ABCB1 3435C>T, and α-1 acid glycoprotein level, while (R)-methadone clearance was influenced by CYP2B6 activity, POR*28, and CYP3A4*22. A linear model described the methadone concentration-QTc relationship, with a mean QTc increase of 9.9 ms and 19.2 ms per 1000 ng/ml of (R)- and (S)-methadone, respectively. Simulations with different methadone doses up to 240 mg/day showed that <8 % of patients presented with a QTc interval above 450 ms; however, this might reach 12 to 18 % for (R)- and (S)-methadone, respectively, in patients with a genetic status associated with a decreased methadone elimination at doses exceeding 240 mg/day.Conclusion: Risk factor assessment, electrocardiogram monitoring, and therapeutic drug monitoring are beneficial to optimize treatment in methadone patients, especially for those who have low levels despite high methadone doses, or who are at risk of overdosing. [ABSTRACT FROM AUTHOR]

Background: High interindividual variability in plasma concentrations of risperidone and its active metabolite, 9-hydroxyrisperidone, may lead to suboptimal drug concentration.Objective: Using a population pharmacokinetic approach, we aimed to characterize the genetic and non-genetic sources of variability affecting risperidone and 9-hydroxyrisperidone pharmacokinetics, and relate them to common side effects.Methods: Overall, 150 psychiatric patients (178 observations) treated with risperidone were genotyped for common polymorphisms in NR1/2, POR, PPARα, ABCB1, CYP2D6 and CYP3A genes. Plasma risperidone and 9-hydroxyrisperidone were measured, and clinical data and common clinical chemistry parameters were collected. Drug and metabolite concentrations were analyzed using non-linear mixed effect modeling (NONMEM(®)). Correlations between trough concentrations of the active moiety (risperidone plus 9-hydroxyrisperidone) and common side effects were assessed using logistic regression and linear mixed modeling.Results: The cytochrome P450 (CYP) 2D6 phenotype explained 52% of interindividual variability in risperidone pharmacokinetics. The area under the concentration-time curve (AUC) of the active moiety was found to be 28% higher in CYP2D6 poor metabolizers compared with intermediate, extensive and ultrarapid metabolizers. No other genetic markers were found to significantly affect risperidone concentrations. 9-hydroxyrisperidone elimination was decreased by 26% with doubling of age. A correlation between trough predicted concentration of the active moiety and neurologic symptoms was found (p = 0.03), suggesting that a concentration >40 ng/mL should be targeted only in cases of insufficient, or absence of, response.Conclusions: Genetic polymorphisms of CYP2D6 play an important role in risperidone, 9-hydroxyrisperidone and active moiety plasma concentration variability, which were associated with common side effects. These results highlight the importance of a personalized dosage adjustment during risperidone treatment. [ABSTRACT FROM AUTHOR]

To assess tobacco, alcohol, cannabis and benzodiazepine use in methadone maintenance treatment (MMT) as potential sources of variability in methadone pharmacokinetics. Trough plasma ( R)- and ( S)-methadone concentrations were measured on 77 Australian and 74 Swiss MMT patients with no additional medications other than benzodiazepines. Simple and multiple regression analyses were performed for the primary metric, plasma methadone concentration/dose. Cannabis and methadone dose were significantly associated with lower 24-h plasma ( R)- and ( S)-methadone concentrations/dose. The models containing these variables explained 14–16% and 17–25% of the variation in ( R)- and ( S)-methadone concentration/dose, respectively. Analysis of 61 patients using only CYP3A4 metabolised benzodiazepines showed this class to be associated with higher (R)-concentration/dose, which is consistent with a potential competitive inhibition of CYP3A4. Cannabis use and higher methadone doses in MMT could in part be a response to—or a cause of—more rapid methadone clearance. The effects of cannabis and benzodiazepines should be controlled for in future studies on methadone pharmacokinetics in MMT. [ABSTRACT FROM AUTHOR]

This article presents the results of an investigation into the enhancement of sensitivity and thermal stability of polyclonal antibody immobilized magnetoelastic biosensors. The Langmuir–Blodgett (LB) monolayer technique was employed for antibody (specific to Salmonella sp.) immobilization on rectangular shaped strip magnetoelastic sensors. Biosensor performance was investigated by exposing to graded concentrations (5 × 101–5 × 108 cfu mL−1) of Salmonella typhimurium solutions in a flow through mode. Bacterial binding to the antibody on the sensor surfaces changed the resonance parameters, and these changes were quantified by the sensor’s resonance frequency shift. An increase in the sensitivity from 159 Hz decade−1 for a 2 mm sensor to 246 Hz decade−1 for a 1 mm sensor was observed during the dose–response measurements. The stability of the biosensor was also investigated by storing the biosensor at 25, 45 and 65 °C. The binding activity of the stored biosensor was estimated by measuring the changes in resonance frequency after exposure to the bacterial solutions (109 cfu mL−1). Binding activity was also confirmed by counting bound S. typhimurium cells on the sensor surface using Scanning Electron Microscopy (SEM) micrographs. The results show that at each temperature, the binding activity of the biosensor gradually decreased over the testing period. Degradation of biosensor accelerated at higher storage temperatures. The activation energy of biosensor system degradation was determined to be 7.7 kcal mol−1. [ABSTRACT FROM AUTHOR]

Therapeutic drug monitoring (TDM) and pharmacogenetic tests play a major role in minimising adverse drug reactions and enhancing optimal therapeutic response. The response to medication varies greatly between individuals, according to genetic constitution, age, sex, co-morbidities, environmental factors including diet and lifestyle (e.g. smoking and alcohol intake), and drug-related factors such as pharmacokinetic or pharmacodynamic drug-drug interactions. Most adverse drug reactions are type A reactions, i.e. plasma-level dependent, and represent one of the major causes of hospitalisation, in some cases leading to death. However, they may be avoidable to some extent if pharmacokinetic and pharmacogenetic factors are taken into consideration.This article provides a review of the literature and describes how to apply and interpret TDM and certain pharmacogenetic tests and is illustrated by case reports. An algorithm on the use of TDM and pharmacogenetic tests to help characterise adverse drug reactions is also presented. Although, in the scientific community, differences in drug response are increasingly recognised, there is an urgent need to translate this knowledge into clinical recommendations. Databases on drug-drug interactions and the impact of pharmacogenetic polymorphisms and adverse drug reaction information systems will be helpful to guide clinicians in individualised treatment choices. [ABSTRACT FROM AUTHOR]

Rationale: A dysregulation of the hypothalamic--pituitary--adrenal (HPA) axis is a well-documented neurobiological finding in major depression. Moreover, clinically effective therapy with antidepressant drugs may normalize the HPA axis activity. Objective: The aim of this study was to test whether citalopram (R/S-CIT) affects the function of the HPA axis in patients with major depression (DSM IV). Methods: Twenty depressed patients (11 women and 9 men) were challenged with a combined dexamethasone (DEX) suppression and corticotropin-releasing hormone (CRH) stimulation test (DEX/CRH test) following a placebo week and after 2, 4, and 16 weeks of 40 mg/day R/SCIT treatment. Results: The results show a time-dependent reduction of adrenocorticotrophic hormone (ACTH) and cortisol response during the DEX/CRH test both in treatment responders and nonresponders within 16 weeks. There was a significant relationship between post-DEX baseline cortisol levels (measured before administration of CRH) and severity of depression at pretreatment baseline. Multiple linear regression analyses were performed to identify the impact of psychopathology and hormonal stress responsiveness and R/S-CIT concentrations in plasma and cerebrospinal fluid (CSF). The magnitude of decrease in cortisol responsivity from pretreatment baseline to week 4 on drug [delta-area under the curve (AUC) cortisol] was a significant predictor (p<0.0001) of the degree of symptom improvement following 16 weeks on drug (i.e., decrease in HAM-D21 total score). The model demonstrated that the interaction of CSF S-CIT concentrations and clinical improvement was the most powerful predictor of AUC cortisol responsiveness. Conclusion: The present study shows that decreased AUC cortisol was highly associated with SCIT concentrations in plasma and CSF. Therefore, our data suggest that the CSF or plasma S-CIT concentrations rather than the R/S-CIT dose should be considered as an indicator of the selective serotonergic reuptake inhibitors (SSRIs) effect on HPA axis responsiveness as measured by AUC cortisol response. [ABSTRACT FROM AUTHOR]

Objective. We investigated whether differences in pharmacokinetics of midazolam, a CYP3A probe, could be demonstrated between subjects with different CYP3A4 and CYP3A5 genotypes. Methods. Plasma concentrations of midazolam, and of total (conjugated + unconjugated) 1′OH-midazolam, and 4′OH-midazolam were measured after the oral administration of 7.5 mg or of 75 µg of midazolam in 21 healthy subjects. Results. CYP3A5*7, CYP3A4*1E, CYP3A4*2, CYP3A4*4, CYP3A4*5, CYP3A4*6, CYP3A4*8, CYP3A4*11, CYP3A4*12, CYP3A4*13, CYP3A4*17 and CYP3A4*18 alleles were not identified in the 21 subjects. CYP3A5*3, CYP3A5*6, CYP3A4*1B and CYP3A4*1F alleles were identified in 20, 1, 4 and 2 subjects, respectively. No statistically significant differences were observed for the AUCinf values between the different genotypes after the 75-µg or the 7.5-mg dose. Conclusion. Presently, CYP3A4 and CYP3A5 genotyping methods do not sufficiently reflect the inter-individual variability of CYP3A activity. [ABSTRACT FROM AUTHOR]

Objective. We investigated whether the oral administration of a low dose (75 µg) of midazolam, a CYP3A probe, can be used to measure the in vivo CYP3A activity. Methods. Plasma concentrations of midazolam, 1′OH-midazolam and 4′OH-midazolam were measured after the oral administration of 7.5 mg and 75 µg midazolam in 13 healthy subjects without medication, in four subjects pretreated for 2 days with ketoconazole (200 mg b.i.d.), a CYP3A inhibitor, and in four subjects pretreated for 4 days with rifampicin (450 mg q.d.), a CYP3A inducer. Results. After oral administration of 75 µg midazolam, the 30-min total (unconjugated + conjugated) 1′OH-midazolam/midazolam ratios measured in the groups without co-medication, with ketoconazole and with rifampicin were (mean±SD): 6.23±2.61, 0.79±0.39 and 56.1±12.4, respectively. No side effects were reported by the subjects taking this low dose of midazolam. Good correlations were observed between the 30-min total 1′OH-midazolam/midazolam ratio and midazolam clearance in the group without co-medication (r2=0.64, P<0.001) and in the three groups taken together (r2=0.91, P<0.0001). Good correlations were also observed between midazolam plasma levels and midazolam clearance, measured between 1.5 h and 4 h. Conclusion. A low oral dose of midazolam can be used to phenotype CYP3A, either by the determination of total 1′OH-midazolam/midazolam ratios at 30 min or by the determination of midazolam plasma levels between 1.5 h and 4 h after its administration. [ABSTRACT FROM AUTHOR]

Methadone is widely used for the treatment of opioid dependence. Although in most countries the drug is administered as a racemic mixture of (R)- and (S)- methadone, (R)-methadone accounts for most, if not all, of the opioid effects. Methadone can be detected in the blood 15-45 minutes after oral administration, with peak plasma concentration at 2.5-4 hours. Methadone has a mean bioavailability of around 75% (range 36-100%). Methadone is highly bound to plasma proteins, in particular to α-acid glycoprotein. Its mean free fraction is around 13%, with a 4-fold interindividual variation. Its volume of distribution is about 4 L/kg (range 2-13 L/kg). The elimination of methadone is mediated by biotransformation, followed by renal and faecal excretion. Total body clearance is about 0.095 L/min, with wide interindividual variation (range 0.02-2 L/min). Plasma concentrations of methadone decrease in a biexponential manner, with a mean value of around 22 hours (range 5-130 hours) for elimination half-life. For the active (R)-enantiomer, mean values of around 40 hours have been determined. Cytochrome P450 (CYP) 3A4 and to a lesser extent 2D6 are probably the main isoforms involved in methadone metabolism. Rifampicin (rifampin), phenobarbital, phenytoin, carbamazepine, nevirapine, and efavirenz decrease methadone blood concentrations, probably by induction of CYP3A4 activity, which can result in severe withdrawal symptoms. Inhibitors of CYP3A4, such as fluconazole, and of CYP2D6, such as paroxetine, increase methadone blood concentrations. There is an up to 17-fold interindividual variation of methadone blood concentration for a given dosage, and interindividual variability of CYP enzymes accounts for a large part of this variation. Since methadone probably also displays large interindividual variability in its pharmacodynamics, methadone treatment must be individually adapted to each patient. Because of the high morbidity and mortality associated with opioid dependence, it is of major importance that methadone is used at an effective dosage in maintenance treatment: at least 60 mg/day, but typically 80-100 mg/day. Recent studies also show that a subset of patients might benefit from methadone dosages larger than 100 mg/day, many of them because of high clearance. In clinical management, medical evaluation of objective signs and subjective symptoms is sufficient for dosage titration in most patients. However, therapeutic drug monitoring can be useful in particular situations. In the case of non-response trough plasma concentrations of 400 μg/L for (R,S)-methadone or 250 μg/L for (R)-methadone might be used as target values. [ABSTRACT FROM AUTHOR]

Presents a commentary on the blockade of the renin-angiotensin-aldosterone system (RAAS) by combining angiotensin receptor antagonist and angiotensin converting enzyme (ACE) inhibitor therapy for heart failure. Effect of blockade of angiotensin II; Metigenic actions of tissue-based RAAS; Impact of the combination therapy on diabetics.

We describe a patient with AIDS who presented with focal neurological symptoms, and who had contrast-enhancing brain lesions on MRI which demonstrated increased thallium-201 uptake on SPECT. These findings were consistent with lymphoma; however, brain biopsy established a diagnosis of progressive multifocal leukoencephalopathy (PML). To our knowledge, this is the first reported case of PML with increased thallium-201 uptake on brain SPECT. [ABSTRACT FROM AUTHOR]

This work is to investigate the on-line control of the fermentation by Arthrobacter viscosus. This species of bacteria can secrete penicillin acylase which is a key enzyme in pharmaceutical industry. The growth of more cells during the fermentation will obtain more enzyme. Both the enzyme activity and the cell growth are rather sensitive to the change of pH. Once the pH during a fermentation is not properly controlled, the decay of cells' activity will irreversibly occur. Two peristaltic pumps for supplying acidic and basic solutions, respectively, were connected for the regulation of pH. With superior ability in identification and prediction of dynamic time series, recurrent backpropagation network (RBPN), instead of conventional controllers, was used as the adaptive controller model for the fermentation with dynamic characteristics. Based on a 1-3-1 BPN, a corresponding 4-4-1 RBPN was determined. The deviation of the pH measured at current time from the set point of 7.0, denoted as Δ pH(t), was chosen as the input node of the network controller. The output node of this network controller was the predicted flow rate of the peristaltic pump for next control time interval. Such a model was operated by two phases. During the first phase, the network was set as the process model and trained by a fixed set of on-line acquired data. During the second phase, the network was stopped learning and switched to become a predictor, the predicted control action was hence obtained. The optimum sampling time was determined experimentally. To enhance the effective computation of this network, the number of training data was limited. A moving-window type of supplying training data to the network was applied for the on-line learning. The window size was also determined for each learning. With properly chosen network parameters as well as operation conditions, pH of the fermentation was thus well controlled by the RBPN controller. [ABSTRACT FROM AUTHOR]

Eight complex austenitic stainless steel alloys based on the composition Fe-13Cr-15Ni-2Mo-2Mn-0.2Ti-0.8Si-0.06C were implanted simultaneously with 400-keV B+ and 550-keV N ions and were investigated for changes in fatigue properties and surface microhardness. The nearsurface hardness of all eight alloys improved, but the fatigue life of each decreased. These findings were contrary to those obtained in an earlier study using four simple Fe-13Cr-15Ni alloys, where the dual implantation improved fatigue life by up to 250 pct. While unimplanted specimens failed by slip-band crack initiation, it was hypothesized that the dual implantation suppressed slip to the extent that fewer slip-band cracks were initiated and these were subjected to accelerated crack propagation. In addition, grain-boundary cracking was promoted, yielding a lower fatigue life. Support for this hypothesis was obtained by a study of single crystals of Fe-15Cr-15Ni, which were also implanted with B and N. The dual implantation caused a lower fatigue life due to concentration of slip along a few slip bands to relieve applied stress. Evidence of grain-boundary cracking was obtained using the four simple alloys, which were subjected to triple ion implantation with B, N, and C. The triple implantation decreased the fatigue life of the alloys and caused accelerated growth of fewer slip bands and grain-boundary cracking due to suppression of surface slip bands. This study thus shows the existence of an optimum level of strengthening when multiple ion implantation is used to improve the fatigue properties of alloys. [ABSTRACT FROM AUTHOR]

Three-dimensional, single-crystal reinforcements of TiC were produced in situ during manufacture of Ti-TiC composites. The composites, containing 40 to 50 vol pct TiC, were produced using standard casting procedures. The presence of aluminum in Ti-TiC composites showed enhanced strength without loss of ductility at room and elevated temperatures. Aluminum additions were found to solid solution strengthen the Ti matrix and increase the strength of the TiC phase. The morphology of the TiC, which was controlled by processing parameters, influenced the properties of the Ti-TiC composites investigated. Refinement of the secondary dendrite arm spacing of the three-dimensional (3-D) TiC particles was found to dramatically improve the ultimate tensile strength (UTS) and ductility of the Ti-TiC composites. [ABSTRACT FROM AUTHOR]

Helium was implanted in type 316 stainless steel, through tritium decay, to levels of 0. 18, 2. 5, 27, 105, and 256 atomic parts per million (appm). Bead-on-sheet welds were then made using the gas tungsten arc (GTA) process. Intergranular cracking occurred in the heat-affected zones (HAZs) of specimens with helium concentrations equal to or greater than 2.5 appm. No such cracking was observed in helium-free control specimens or in specimens containing the lowest helium concentration. In addition to the HAZ cracking, brittle, centerline cracking occurred in the fusion zone of specimens containing 105 and 256 appm helium. Transmission and scanning electron microscopy results indicated that both the HAZ cracking and centerline cracking in the fusion zone resulted from the stress-induced growth and coalescence of cavities initiated at helium bubbles on interfaces. For the HAZ case, the cavity growth rate is modeled and shown to predict the experimentally measured 1-second time lag between peak weld temperature and the onset of cracking. [ABSTRACT FROM AUTHOR]

In-reactor stress to rupture results in excess of 11,000 hours are reported. Stress rupture properties during in-reactor testing of AISI 316 CW were demonstrated to be greater than or equal to the unirradiated material properties. Failure strains of the pressurized tube specimens were found to be stress dependent with a minimum in failure strain occurring at 200 MPa for unirradiated tests. Higher failure strains at lower stresses resulted from a transition in crack propagation mechanisms from triple point wedge cracking to grain boundary cavitation. The triple point cracking to cavitation transition was shifted to lower stresses by irradiation. [ABSTRACT FROM AUTHOR]

The theoretically appropriate diffusion coefficients for creep in binary solid solutions are verified in Part I. Furthermore it is observed that the observed composition dependence of the steady-state creep rate for Al-Zn alloys may be described by these diffusion coefficients. Part II further examines the creep behavior of the Al-Zn system. Stress exponent and activation energy measurements indicate that a transition from climb-controlled to glide-controlled creep occurs as the Zn concentration increases. It is found that the observed creep behavior can be explained by a combination of climb and glide controlled creep processes. Glide creep is dependent on the chemical diffusivity which approaches zero at the miscibility gap composition and temperature. This causes a minimum in the creep rate at the miscibility gap composition. By using a sequential summation of a semiempirical climb equation and the Cottrell-Jaswon glide equation, the absolute magnitude of the observed creep rate can be rationalized for all compositions. The observed behavior of the stress exponent and activation energy is also predicted. [ABSTRACT FROM AUTHOR]

The article presents a study which examines the impact of phenobarbital (PB) pretreatment on the in vivo metabolism of carbaryl in rat subjects. It mentions that urine samples from the rats were treated with glusulase to check for the presence of glucuronide and sulfate metabolites of carbaryl. Results show that PB pretreatment increased the excretion of sulfate conjugates of carbaryl in urine in the rats treated with higher dose of carbaryl.