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Objective: Digoxin is monitored because of its narrow range of therapeutic doses and risk of toxicity. Thus, we aimed to evaluate the effect of different blood collection tubes on digoxin levels and its stability. Methods: Samples from 30 volunteers who received digoxin therapy were collected in 5 different tubes: no additive and gel-free glass tube (Z-tube) (reference tube), clot-activator tubes containing gel (Vacusera), clot-activator tubes containing gel (serum separator tube), barrier-free lithium heparinized tube (LiH), and new lithium heparinized tube with a barrier (Barricor). Digoxin levels in tubes were analyzed at 0 and 48 hours (h). Results: No statistical difference was found between 0 and 48 h results in other tubes, except for LiH, and the difference in LiH was also not clinically significant. Digoxin levels in other tubes were not statistically different according to the reference tube, except for Barricor. The digoxin level in Barricor was clinically significantly higher than that in the reference tube. Although a strong correlation was found in the digoxin level between Barricor and Z-tubes, a proportional increase in digoxin level in Barricor was determined. Conclusion: The digoxin levels in the tubes may be used interchangeably, except for Barricor. The reliability and accuracy of digoxin levels may be increased by the identification of a new therapeutic range for Barricor. [ABSTRACT FROM AUTHOR]

Aims Despite pharmacokinetic monitoring of calcineurin inhibitors, the long-term outcome after transplantation (Tx) is still hampered by the side effects of these drugs. The aim of the present study was to characterize nuclear factor of activated T cells (NFAT)-regulated gene expression as a potential pharmacodynamic biomarker for further individualization of tacrolimus (Tac) therapy. Methods In 29 renal allograft recipients, samples were drawn once pre-Tx, and before and 1.5 h after Tac dosing at approximately 1 week, 6 weeks and 1 year post-Tx. Tac concentrations were measured by immunoassay, while the expression of genes encoding NFAT-regulated cytokines [interleukin 2 ( IL2), interferon gamma ( IFNG), colony stimulating factor 2 ( CSF2)] and cytochrome P450 3A5 ( CYP3A5) genotyping were determined by real-time polymerase chain reaction. Results The cytokine response after Tac dosing varied up to 46-fold between patients and changed significantly with time post-engraftment. Tac concentrations 1.5 h postdose (C1.5) >15 μg l-1 were associated with strong cytokine inhibition and residual gene expression (RGE) ≤10%, while lower Tac C1.5 resulted in more variable responses (RGE 2.5-68.7%). Patients with ongoing subclinical acute rejection ( n = 5) demonstrated limited cytokine inhibition (RGE 39.7-72.6%), while patients with polyoma virus viraemia ( n = 3) had relatively strong inhibition of cytokines (RGE 2.5-32.5%). By contrast, there was no association between Tac exposure and rejection or viraemia. Conclusions The findings of our study support the potential of NFAT-regulated gene expression measurements as a pharmacodynamic tool for additional monitoring of Tac therapy, especially in the context of overimmunosuppression and viraemia. [ABSTRACT FROM AUTHOR]

The purpose was to investigate pharmacokinetic variability of valproic acid ( VPA) in women of childbearing age by therapeutic drug monitoring ( TDM) data to elucidate the variable relationship between dose and serum concentrations with the ultimate aim of facilitating safer use of VPA. Anonymized retrospective data from the TDM database (2006-2015) at the National Center for Epilepsy in Norway were used. Trough total concentrations of VPA at assumed steady state in women aged 14-46 years were analyzed. Data from 643 nonpregnant women of childbearing age (mean age = 27 years) were included. Mean dose and serum concentration of VPA were 968 (standard deviation [ SD] = 453) mg/day and 411 ( SD = 138) μmol/L, respectively, and 59% used polytherapy. The pharmacokinetic variability in serum concentration/dose (C/D) ratios between women was extensive. For doses <700 mg/day (n = 202; 32%; 150-625 mg/day), mean serum concentration was 336 μmol/L and variability in C/D ratio was 10-fold. The variability decreased with increasing dose to eightfold (≥700 to <1,500 mg/day, n = 358) and fourfold (≥1,500 mg/day, n = 96). This study demonstrates the extensive pharmacokinetic variability of VPA among women of childbearing age, which is most pronounced at low doses. In future studies, serum concentrations of VPA, rather than dosage, should be used as a guide for exposure of VPA and possible risks of teratogenicity to evaluate safety aspects of VPA in women. [ABSTRACT FROM AUTHOR]

An external evaluation of phenobarbital population pharmacokinetic model described by Marsot et al. was performed in pediatric intensive care unit. Model evaluation is an important issue for dose adjustment. This external evaluation should allow confirming the proposed dosage adaptation and extending these recommendations to the entire intensive care pediatric population. External evaluation of phenobarbital published population pharmacokinetic model of Marsot et al. was realized in a new retrospective dataset of 35 patients hospitalized in a pediatric intensive care unit. The published population pharmacokinetic model was implemented in nonmem 7.3. Predictive performance was assessed by quantifying bias and inaccuracy of model prediction. Normalized prediction distribution errors ( NPDE) and visual predictive check ( VPC) were also evaluated. A total of 35 infants were studied with a mean age of 33.5 weeks (range: 12 days-16 years) and a mean weight of 12.6 kg (range: 2.7-70.0 kg). The model predicted the observed phenobarbital concentrations with a reasonable bias and inaccuracy. The median prediction error was 3.03% (95% CI: −8.52 to 58.12%), and the median absolute prediction error was 26.20% (95% CI: 13.07-75.59%). No trends in NPDE and VPC were observed. The model previously proposed by Marsot et al. in neonates hospitalized in intensive care unit was externally validated for IV infusion administration. The model-based dosing regimen was extended in all pediatric intensive care unit to optimize treatment. Due to inter- and intravariability in pharmacokinetic model, this dosing regimen should be combined with therapeutic drug monitoring. [ABSTRACT FROM AUTHOR]

Aim The aim of the present study was to provide an insight into the characteristics and follow-up of postmarketing studies of medicines that were conditionally authorized in the European Union (EU). Methods We compiled a list of all postmarketing studies attached as specific obligations to the licence of medicines that were granted conditional marketing authorization from January 2006 to April 2014. Studies were characterized based on their objective, design, status upon marketing authorization (MA) and due data set by authorities. They were linked to online study registrations (, ENCePP) to determine completion date. We described and associated characteristics of studies and medicines, and determined whether studies were completed on time. Results A total of 59 postmarketing studies were requested for 21 conditionally authorized medicines. Most studies had an interventional study design (73%), were ongoing upon MA (61%) and aimed to provide additional data on efficacy (45%). Interventional studies were more often ongoing and providing efficacy data, while observational and other studies were more often new and providing safety data. Frequent grounds for requesting postmarketing studies were 'long-term follow-up' and 'increase data on subpopulations'. Of the 34 studies eligible for follow-up analysis, 26 (76%) were completed and 17 (50%) completed on time. Actual completion time took a median (interquartile range) of 274 (−121 to 556) days longer than expected. Conclusions Our results indicated that most postmarketing studies attached to a conditional marketing authorization were eventually completed but that half were completed with a substantial delay. The observations suggest caution when broadening the use of postmarketing studies for resolving uncertainties about benefits and risks after MA. [ABSTRACT FROM AUTHOR]

Background: Therapeutic drug monitoring (TDM) of infliximab (IFX, Remicade®) can aid to optimize therapy efficacy. Many assays are available for this purpose. However, a reference standard is lacking. Therefore, we evaluated the analytical performance, agreement and clinically relevant differences of three commercially available IFX ELISA kits on an automated processing system. Methods: The kits of Theradiag (Lisa Tracker Infliximab), Progenika (Promonitor IFX) and apDia (Infliximab ELISA) were implemented on an automated processing system. Imprecision was determined by triplicate measurements of patient samples on five days. Agreement was evaluated by analysis of 30 patient samples and four spiked samples by the selected ELISA kits and the in-house IFX ELISA of Sanquin Diagnostics (Amsterdam, The Netherlands). Therapeutic consequences were evaluated by dividing patients into four treatment groups using cut-off levels of 1, 3 and 7 µg/mL and determining assay concordance. Results: Within-run and between-run imprecision were acceptable (≤ 12% and ≤ 17%, respectively) within the quantification range of the selected ELISA kits. The apDia assay had the best precision and agreement to target values. Statistically significant differences were found between all assays except between Sanquin Diagnostics and the Lisa Tracker assay. The Promonitor assay measured the lowest IFX concentrations, the apDia assay the highest. When patients were classified in four treatment categories, 70% concordance was achieved. Conclusions: Although all assays are suitable for TDM, significant differences were observed in both imprecision and agreement. Therapeutic consequences were acceptable when patients were divided in treatment categories, but this could be improved by assay standardization. [ABSTRACT FROM AUTHOR]

Background: Preventable adverse events of medication are an important cause of hospital admissions in the developed world, in which non-steroidal anti-inflammatory drugs (NSAIDs) and renin-angiotensin system (RAS-) inhibitors are frequently involved. NSAIDs and RAS-inhibitors are also often used in Ghana. The purpose of this study is to assess whether biochemical monitoring in patients on RAS-inhibitors, and co-administration of gastro protective agents (GPAs) in patients on NSAIDs, is done properly in Ghana. Material and methods: Two retrospective cross-sectional studies were carried out at the Agogo Presbyterian Hospital, Ghana, in 2013. In 114 out-and inpatients who are on NSAIDs, the risk for gastrointestinal side effects and the frequency of co-administration of GPAs were determined. In 301 outpatients who are on RAS-inhibitors, the risk for renal dysfunction and the frequency of biochemical monitoring were determined. Fisher's exact test was used to determine the statistical strength. Results: Co-administration of GPAs was done in 1.8% of patients on NSAIDs. Serum creatinine and potassium monitoring within one month after initiation of treatment with RAS-inhibitors were performed in 6.3% and 3.7%, respectively. Risk factors were neither associated with prescription of a GPA in patients on NSAIDs (p=0.134), nor in performing biochemical monitoring in patients on RAS-inhibitors (p=0.219 for creatinine, p=0.062 for potassium). Conclusions: Biochemical monitoring in patients on RAS-inhibitors and use of GPAs in patients on NSAIDs is poorly performed at the Agogo Presbyterian Hospital in Ghana. Improving the already existing Ghanaian guidelines, especially those for RAS-inhibitors, and encouraging their widespread use among prescribers should be pursued. [ABSTRACT FROM AUTHOR]

Background: Although therapeutic drug monitoring (TDM) for antibiotics in critically ill patients is recommended by expert panels, no commercial tests are available for most antibiotics. Therefore, we previously developed a multianalyte method for the quantification of piperacillin, tazobactam, cefepime, meropenem, ciprofloxacin and linezolid in serum. However, limited stability data were available, and the relevant studies did not address the coefficients of variation of the methods applied, which may be important for verifying the storage dependency of the observed effects. Here we aimed to evaluate the storage effects of antibiotics by applying a novel evaluation protocol. Methods: Serum-based test samples were aliquoted and stored at room temperature, 4 °C, -20 °C or -80 °C for up to 180 days. Using an innovative evaluation protocol (considering the coefficient of variation, p-value, and criterion of monotony of observed changes), we assessed whether relevant changes (defined as ≥ 15% in comparison with baseline) were storage dependent (defined as substantial changes). Results: Storage at -80 °C for up to 180 days did not lead to substantial changes for any analyte. In contrast, storage at -20 °C induced substantial decreases after ≥ 7 days for piperacillin, tazobactam, cefepime and meropenem; after 90 days at -20 °C, only ≤ 23% of the initial concentrations were found for these parameters. No substantial changes were observed for linezolid and ciprofloxacin at any storage condition. All of the observed substantial changes were monotonic decreases. Conclusions: We recommend a storage temperature of -80 °C for β-lactam antibiotics. The applied evaluation protocol yielded conclusive results and may be generally useful for stability studies. [ABSTRACT FROM AUTHOR]

Traditional antibiotic dosing was not designed for today's escalating antibiotic resistance, lack of novel antibiotics and growing complexity in patient populations. Dosing that ensures optimal antibiotic exposures should be considered essential to increase the likelihood of effective patient treatment. Given the variability in these exposures across different patients, a 'one-dose-fits-all' approach is increasingly problematic. Therapeutic drug monitoring (TDM) of the β-lactams, the most widely used antibiotic class, is underutilized in certain populations. Clinical experience with β-lactam TDM remains relatively scarce. Patients most likely to benefit from such an intervention include the critically ill, the obese, the elderly and those with cystic fibrosis. Most centres actively performing β-lactam TDM target a minimum 100% of the time during the dosing interval that the free (unbound) concentration of antibiotic exceeds the MIC of the pathogen (100% fT>MIC), which is higher than a traditional target supported by in vitro data. Ideally, isolated pathogens should undergo MIC testing along with TDM on a regular basis, allowing clinicians to address the triad of bug, drug and patient ('mug') in equal measure. [ABSTRACT FROM AUTHOR]

Background: The non-vitamin K antagonist oral anticoagulants (NOACs) apixaban, dabigatran, and rivaroxaban are being administered in fixed doses without routine monitoring of anticoagulant activities. Despite this key advantage over vitamin K antagonists (VKAs), assessment of anticoagulant intensities is required in various clinical circumstances. We developed a multi-analyte approach for mass spectrometric analysis of NOACs in human plasma. Methods: Plasma samples were precipitated with acetonitrile. Separation was achieved by liquid chromatography using a C18 column and a gradient elution within a run time of 2.5 min. Positive electrospray ionization was used and ion transitions monitored by a triple quadrupole mass spectrometer. Stable-isotope-labeled analogues of analytes were employed as internal standards for quantitative analysis. Certified external quality control samples were obtained for external validation. Results: For all analytes, linearity could be demonstrated over the concentration range of 1-500 µg/L (R²>0.999), and the calculated limits of quantification were <1 µg/L. Results for inter- and intra-day assay precision and true-ness were obtained using internal quality control samples and remained within the acceptance criterion of ±15%. External quality control samples were measured at the specified nominal values with inter- and intra-day precisions <14%. Matrix effects were fully compensated by co-eluting internal standards, which in turn did not relevantly influence ionization efficiency. Conclusions: The method enables rapid and reliable simultaneous determination of NOAC concentrations in human plasma. It was successfully introduced into clinical practice; a case with rivaroxaban overdose is presented to exemplify the method's applicability. [ABSTRACT FROM AUTHOR]

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Objective(s): Dispersive liquid-liquid microextraction coupled with gas chromatography (GC)-flame ionization detector was developed for the determination of valproic acid (VPA) in human plasma. Materials and Methods: Using a syringe, a mixture of suitable extraction solvent (40 µl chloroform) and disperser (1 ml acetone) was quickly added to 10 ml of diluted plasma sample containing VPA (pH, 1.0; concentration of NaCl, 4% (w/v)), resulting in a cloudy solution. After centrifugation (6000 rpm for 6 min)), an aliquot (1 µl) of the sedimented organic phase was removed using a 1-µl GC microsyringe and injected into the GC system for analysis. One vvariable at a time optimization method was used to study various parameters affecting the extraction efficiency of target analyte. Then, the developed method was fully validated for its accuracy, preecision, recovery, stability, and robustness. Results: Under the optimum extraction conditions, good linearity range was obtained for the calibration graph, with correlation coefficient higher than 0.998. Limm it of detection and lower limit of quantitation were 3.2 and 6 μg/ml, respectively. The relative standard deviations of intra and inter-day analysis of examined compound were less than 11.5%. The relative recoveries were found in the range of 97 to 107.5%. Finally, the validated method was successfully applied to the analysis of VPA in patient sample. Conclusion: The preesented method has acceptable levels of precision, accuracy and relative recovery and could be used for therapeutic drug monitoring of VPA in human plasma. [ABSTRACT FROM AUTHOR]

Objectives: TB is currently the second cause of death among patients affected with infectious diseases. Quantification of drug levels in plasma and in cells where Mycobacterium tuberculosis persists and grows may be useful in understanding the appropriateness of dosage regimens. We report a new and fully validated chro-matographic method to quantify first-line antituberculars in plasma and PBMCs. The method was used for plasma and cell quantification of antituberculars in patients undergoing treatment with standard oral therapy. Methods: Ethambutol, isoniazid, pyrazinamide and rifampicin were extracted from plasma and PBMCs using two separate and optimized procedures; analysis was performed using UPLC coupled with a mass-mass detector system (UPLC-MS-MS). Antitubercular levels in patients were assayed at the end of the dosing interval (Ctrough) and 2 h post-dose (Cmax). Results: The method was accurate and precise. Recovery and the matrix effect were reproducible. While rifampicin intracellular concentrations were similar to plasma values (median intra-PBMC Cmax=7503 ng/mL versus median plasma Cmax = 6505 ng/mL), isoniazid and pyrazinamide intracellular concentrations were lower than plasma values (median intra-PBMC Cmax=12 ng/mL versus median plasma Cmax = 3258 ng/mL for isoniazid and median intra-PBMC Cmax = 2364 ng/mL versus median plasma Cmax = 26988 ng/mL for pyrazinamide) and ethambutol intracellular concentrations were significantly higher than plasma values (median intra-PBMC Cmax = 73334 ng/mL versus median plasma Cmax = 2244 ng/mL). Conclusions: The method was suitable for both therapeutic drug monitoring and for pharmacokinetic analysis. Should the clinical usefulness of measuring antitubercular drug intracellular concentrations be confirmed, this method could be useful to enhance the clinical application of intra-PBMC evaluation. [ABSTRACT FROM AUTHOR]

The article discusses a study which examined the medicine prescription practices of the medical officers and medicine dispensing practices of the pharmacists in primary health centres in Karnataka, India. Topics covered include the prescription indicators measured in the study such as the average number of medicines per prescription, the calculation of the Index of Rational Drug Prescribing and the overuse of injection.

Background & objectives: Information available on drug consumption is inadequate in most low and middle income countries. This systematic review was conducted to analyse published work on drug utilization research/studies (DUR) in the SEARO region of WHO for study objectives, methodology, results and recommendations and to identify the need for improving DUR and the use of the ATC/DDD system. Methods: A literature search for DUR was carried out in biomedical databases (PubMed, Scirus, Scopus and Google Scholar) up to May 2012. Publications were selected if those were in the English language, describing DUR or prescription practices, and study conducted in the WHO-SEARO countries. Results: A total of 318 publications were included in the review. Of these, 67 per cent were from India and 13 per cent were from Thailand. Majority of the publications were hospital based; only 16 per cent were community based. The ATC/DDD system was used in only 20 per cent of the publications, of which 73 per cent publications used DDD indicators. Several publications focused on antibiotics (31%). Publications that recommended the need for a policy or intervention to improve prescription practices/rational drug use amounted to 35 per cent. Interpretation & conclusions: Drug utilization studies using ATC/DDD system need to be promoted and carried out on an ongoing basis. DUR is important for rational use of drugs. Its relevance to policy making and resource allocation needs to be emphasized. [ABSTRACT FROM AUTHOR]

Background: This study aimed to develop a clinically acceptable method of therapeutic drug monitoring (TDM) for olanzapine and risperidone and to evaluate the feasibility of its implementation. Method: A non-randomised study of inpatients from five Mental Health Trusts was conducted, with a clinical interview at the time of TDM and a subsequent 6-week follow-up review of clinical notes. The TDM intervention comprised: (a) a venous blood sample taken 12 hours post-dose, 7–10 days after drug initiation, and (b) rapid results feedback, with interpretation algorithm guidance. Results: Thirty-two participants provided samples (19 prescribed olanzapine, 13 risperidone). Twenty-six participants remained on the target drug at study end, with seven experiencing a dose change, for whom only four of the TDM results were confirmed as having been checked. Mean dose increased for olanzapine (0.9 mg/day, range 0–10) and decreased for risperidone (-0.3 mg/day, range -4–3). Conclusion: TDM can be implemented as part of routine clinical practice for both drugs. However, the lack of robust supporting evidence for or against antipsychotic TDM has probably led to a lack of enthusiasm for and interest in the results. Nevertheless, the advent of less invasive measures and the targeting of patients who might be more likely to benefit may facilitate uptake. [ABSTRACT FROM AUTHOR]

The use of small scale renewable sorbent material for automated solid phase extraction of multi-residue pharmaceuticals in environmental samples exploiting the sequential injection analysis-bead injection with direct coupling to liquid chromatography-electrospray ionization tandem mass spectrometry (SIA-BI-μSPE-LC-ESI-MS/MS) is presented to determine beta-blockers, namely atenolol, sotalol, pindolol, acebutolol, timolol, metoprolol, labetalol, carazolol, propranolol and betaxolol. These compounds yielded the same product ions, therefore were affected in terms of quantification when flow injection analysis-mass spectrometry (FIA-MS) was used. Thus, analytes and matrix present in the sample travel together into the ionization source which can seriously affect the ionization efficiency and analyte signals due to monitoring over a short time period. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

In the field of LC-MS, reversed phase liquid chromatography is the predominant method of choice for the separation of prohibited substances from various classes in sports drug testing. However, highly polar and charged compounds still represent a challenging task in liquid chromatography due to their difficult chromatographic behavior using reversed phase materials. A very promising approach for the separation of hydrophilic compounds is hydrophilic interaction liquid chromatography (HILIC). Despite its great potential and versatile advantages for the separation of highly polar compounds, HILIC is up to now not very common in doping analysis, although most manufacturers offer a variety of HILIC columns in their portfolio. In this study, a novel multi-target approach based on HILIC high resolution/high accuracy mass spectrometry is presented to screen for various polar stimulants, stimulant sulfo-conjugates, glycerol, AICAR, ethyl glucuronide, morphine-3-glucuronide, and myo-inositol trispyrophosphate after direct injection of diluted urine specimens. The usage of an effective online sample cleanup and a zwitterionic HILIC analytical column in combination with a new generation Hybrid Quadrupol-Orbitrap® mass spectrometer enabled the detection of highly polar analytes without any time-consuming hydrolysis or further purification steps, far below the required detection limits. The methodology was fully validated for qualitative and quantitative (AICAR, glycerol) purposes considering the parameters specificity; robustness (rRT < 2.0 %); linearity ( R > 0.99); intra- and inter-day precision at low, medium, and high concentration levels (CV < 20 %); limit of detection (stimulants and stimulant sulfo-conjugates < 10 ng/mL; norfenefrine; octopamine < 30 ng/mL; AICAR < 10 ng/mL; glycerol 100 μg/mL; ETG < 100 ng/mL); accuracy (AICAR 103.8-105.5 %, glycerol 85.1-98.3 % at three concentration levels) and ion suppression/enhancement effects. [ABSTRACT FROM AUTHOR]

We performed high-dose loading (12 mg/kg every 12 h for 48 h; 4 doses total) of teicoplanin (TEIC) in patients with severe methicillin-resistant Staphylococcus aureus (MRSA) infections, with the goal of achieving target serum concentration (TEICc) ≥15 mg/l within 48 h of starting administration. The safety and effectiveness of the fixed, early-stage administration method were evaluated across a range of kidney dysfunction severity levels. TEIC high-dose loading was administered to 106 patients with MRSA infection from February 2010 to February 2013. After high-dose loading, maintenance doses based on therapeutic drug monitoring (TDM) of TEICc were administered via 30-min intravenous drips, every 24 h. Subjects were divided into 4 groups based on kidney function and renal replacement therapy (RRT) status for safety and effectiveness evaluation: group 1 (G1) did not undergo RRT and exhibited creatinine clearance (Ccr; ml/min/m 2 ) >50, group 2 (G2) exhibited Ccr ≤50, group 3 (G3) underwent continuous RRT (CRRT), and group 4 (G4) underwent intermittent RRT (IRRT). TEICc was measured after 24, 48, 72, and 144 h, immediately before TEIC administration. Target TEICc was reached in all groups, and bacteriological effectiveness and utility were high in G1, G2, and G3. The maximum TEICc (≥28.0 mg/l) and serum albumin (≤1.84 g/dl) were associated with organ toxicity. Fixed high-dose loading of TEIC achieved the target therapeutic range (≥15 mg/l) within 48 h of the start of administration regardless of kidney dysfunction, and exhibited sufficient utility. [ABSTRACT FROM AUTHOR]

Consumer reporting of adverse drug reactions (ADRs) has existed in several countries for decades, but throughout Europe the role of consumers as a source of information on ADRs has not been fully accepted until recently. In Europe, The Netherlands and Sweden were among the first countries to implement consumer reporting well before it was mandated by law throughout the EU. Consumer reporting is an integral part of the spontaneous reporting systems in both The Netherlands and Sweden, with yearly numbers of reports constantly increasing. Consumer reporting forms and handling procedures are essentially the same as for healthcare professional reporting; the message in the reports, not the type of messenger, is what is of importance. Studies have established the significant contribution of consumer reporting to ADR signal detection. Combining all reports regardless of reporter type is recommended since it yields the largest critical mass of reports for signal detection. Examples of signals where consumer reports have been of crucial importance for signal detection are electric shock-like sensations associated with the use of duloxetine, and persistent sexual dysfunction after discontinuation of selective serotonin reuptake inhibitors. An example of consumer reporting significantly strengthening a detected signal is Pandemrix (influenza H1N1 vaccine)-induced narcolepsy. Raising public awareness of ADR reporting is important, but time- and resource-consuming. The minimum effort taken should be to passively inform consumers, e.g. via stakeholders' homepages and via drug product information leaflets. Another possibility of reaching out to this target group could be through co-operation with other (non-government) organizations. Information from consumer reports may give a new perspective on ADRs via the consumers' unfiltered experiences. Consumers' views may change the way the benefit-harm balance of drugs is perceived and assessed today, and, being the ultimate users of drugs, consumers could have a relevant influence in the regulatory decision-making processes for drugs. All stakeholders in pharmacovigilance should embrace this new valuable source of information. [ABSTRACT FROM AUTHOR]

The Monitoring Medicines project (MM), funded by the FP-7 EU framework, was carried out between 2009 and 2013 by a consortium of 11 partners. The objectives were to support and strengthen consumer reporting of adverse drug reactions (ADRs); expand the role and scope of national pharmacovigilance centres concerning medication errors; promote improved use of pharmacovigilance data; and develop methods to complement spontaneous reporting. The work was organised into four themes: patient reporting; medication errors; drug dependence, counterfeit and substandard medicines and clinical risk estimation; and active and targeted spontaneous pharmacovigilance. MM differed from some other major pharmacovigilance initiatives by having participants from developing countries in Asia and Africa and in leaning towards public health and communicable diseases. MM brought together stakeholders including WHO, drug regulators, pharmacovigilance centres, consumers, public health and disease specialists and patient safety networks. Resources and methodologies developed directly by, or with support from, MM include electronic systems/tools for consumer ADR reporting and cohort event monitoring; publication by WHO of handbooks on consumer reporting, medication errors and pharmacovigilance for TB medicines; methodologies for detecting drug dependence and substandard or counterfeit medicines in ADR databases; and a database on HIV treatment risks with a risk assessment tool. MM enabled stakeholders to achieve more than if they had worked alone in pursuit of patient safety. [ABSTRACT FROM AUTHOR]

Background and Objective: Antiretroviral drugs have well-documented evidence-based favorable benefit-risk ratios. Although various studies have investigated and characterized the safety profile of antiretroviral medicines, there are a limited number of studies evaluating the safety of first-line antiretroviral therapy (ART) in patients with a specific co-morbidity. A cohort event monitoring (CEM) study of the safety and effectiveness of antiretroviral medicines in a target population that has a significant level of co-morbidities (chronic infectious diseases, peripheral blood cytopenias) was implemented. The aim was to evaluate the safety profile of the highly active ART (HAART) in the target population and subpopulations with risk factors, to optimize the monitoring and decision-making procedure for subgroups of patients with specific types of co-morbidity, and to implement a more vigilant approach to therapy management in risk groups of patients. Methods: Prospective observational CEM was implemented among HAART-naïve HIV-positive patients at four clinical sites from December 2012. Eligible patients were those starting first-line HAART. Close medical supervision of all enrolled patients, with regular clinical and laboratory monitoring, was provided by healthcare professionals within 1 year after commencement of therapy. Standardized forms were used for data collection on initial and subsequent visits. All objective or subjective deviations in condition (events) were assessed for a causal relationship with ART, and for severity, seriousness, reversibility, preventability, and pre-existing risk factors in the case of adverse drug reactions (ADRs). Results: A total of 518 HAART-naïve HIV-positive patients were enrolled in the CEM study. Of these patients, 65 % (337) experienced one or several ADRs related to one or more components of HAART. Most of the ADRs reported were non-serious, expected, common (very common), transient (correctable), or reversible. The most common were hematotoxic, hepatotoxic, and neurotoxic adverse reactions. In several cases, some types of toxicities, associated with zidovudine, efavirenz, and nevirapine, had a high level of severity, necessitating hospitalization and drug regimen or single-agent substitution. Severe cases of hematological, hepatobiliary, and psychiatric toxicities were associated with pre-existing risk factors. Conclusion: CEM is an effective tool for safety and effectiveness monitoring and could be successfully implemented for intensive study of important safety issues and for overcoming knowledge gaps regarding safety. In order to achieve a favorable benefit-risk ratio for HAART in the specific sections of the population with pre-existing risk factors for development of ART toxicities, more vigilant consideration and careful assessment before therapy is commenced and further regular monitoring of key laboratory parameters is required. [ABSTRACT FROM AUTHOR]

Background: Pharmacovigilance centres (PVCs) in the World Health Organization (WHO) Programme for International Drug Monitoring have demonstrated their ability to detect preventable adverse drug reactions (ADRs) in their databases. In this field, there is no gold-standard method for detecting medication errors and evaluating ADR preventability. Therefore, we developed, from existing tools, a preventability assessment method: the 'P Method' (PM). Objective: To present the PM and to evaluate its inter-rater reliability. Methods: The PM includes 20 explicit criteria for assessing ADR preventability. This approach is based on identification of any potentially preventable risk factor that increases the likelihood of ADR occurrence. The outcome of the preventability assessment results in one of three possible scores: 'preventable', 'non-preventable' or 'not assessable'. The PM was tested in a multicentre study involving nine national PVCs. Two experienced reviewers at each participating PVC independently analysed the preventability of 183 ADRs, applying the PM. Results: The overall agreement between all reviewers for assessment of ADR preventability was 'fair', with a kappa value of 0.27 [95 % confidence interval (CI) 0.21-0.40]. The level of agreement between reviewer pairs ranged from 'slight', with a kappa value of 0.12 (95 % CI −0.03 to 0.27), to 'substantial', with a kappa value of 0.69 (95 % CI 0.48-0.89). Conclusion: The analysis of the agreements and disagreements between reviewers highlighted where improvements might be made. Given that no standard assessment tool exists in the WHO Programme, the transparency of the assessment process in this method provides a substantial basis for further development and for support in signalling possible preventability. [ABSTRACT FROM AUTHOR]

Background: Recent studies have demonstrated highly variable blood concentrations of piperacillin, tazobactam, cefepime, meropenem, ciprofloxacin and linezolid in critically ill patients with a high incidence of sub-therapeutic levels. Consequently, therapeutic drug monitoring (TDM) of these antibiotics has to be considered, requiring robust and reliable routine analytical methods. The aim of the present work was to develop and validate a multi-analyte ultra high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method for the simultaneous quantification of the above mentioned antibiotics. Methods: Sample preparation included a manual protein precipitation step followed by two-dimensional ultra high performance liquid chromatography (2D-UHPLC). Corresponding stable isotope-labeled substances were used as internal standards for all of the analytes, with the exception of tazobactam. The injected sample volume was 7 μL. The run time was 5.0 min. Results: Inaccuracy was ≤8% and imprecision coefficient of variation (CV) was <9% for all analytes. Only minor matrix effects and negligible carry-over was observed. The method was found to be robust during the validation period. Conclusions: We were able to develop a reliable 2D-UHPLC-MS/MS method addressing analytes with highly heterogeneous physico-chemical properties. The novel assay may be an efficient tool for an optimized process workflow in clinical laboratories for important antibiotics in regards to TDM. [ABSTRACT FROM AUTHOR]

Context: Phenytoin (PHT) is one of the frontrunner drugs used as monotherapy in the management of epilepsy. It is also one of the most common drugs causing adverse drug reactions (ADRs). The aim of this study was to study the relationship between serum PHT levels and the age, gender, dosage and genetic polymorphisms in a North Indian population. This knowledge will help in devising drug dosage schedules in various sub-groups of patients as well as in reducing its ADRs. Materials and Methods: A retrospective analysis of data of 6224 patients from 1998 to 2009 receiving PHT alone for greater than (>) 4 weeks was performed. Patients suspected of being non-compliant, being overdosed or having a hepatic or renal disorder were excluded from the study. Two thousand eight hundred and eighty-eight patients fulfilling the inclusion criteria were divided into three groups: children (1-18 years), adults (19-60 years) and elderly (>60 years). Results: There was a male preponderance (80%) in all the groups. A significant difference was found in the mean dose between children and adults as well as between children and elderly (P = 0.00). Also, there was a significant difference in the mean concentration and dose ratio between children and adults (P = 0.00). However, a negative correlation was observed between the daily dose and dose ratio (r = -0.36, P = 0.00) that was highest (r = -0.58, P = 0.00) in the elderly. There was a significant gender difference in the mean dose in both children (P = 0.03) and adults (P = 0.00), whereas the mean concentration differed in adults only. Every fifth patient was an intermediate metabolizer (IM) (CYP2C9*1/*3) and showed higher steady state drug levels (>17 mg/L) compared with extensive metabolizers (EMs) (<12 mg/L). The genetic difference between IM and EM was more prevalent in the dose ratio at maintenance dose, with a mean ± SD of 4.041 ± 1.288 mg/L/mg/kg in nine patients carrying the CYP2C9*1/*3 genotype compared with 2.145 ± 0.817 mg/L/mg/kg in 26 patients carrying the CYP2C9*1/*1 genotype (P = 0.00). Conclusion: North Indian female children and male adults frequently attain a higher serum concentration with the same dose when compared to the other groups. Absence of poor metabolizers may be responsible for a lower number of cases exhibiting toxicity in our population; however, this needs elucidation in a larger number of patients. [ABSTRACT FROM AUTHOR]

Background: Therapeutic drug monitoring (TDM) of antiepileptic drugs is widely used in clinical practice to optimise therapy, but it is limited by technical problems and cost considerations. The aim of the present study was: 1) to validate a chromatographic method for the concomitant determination of levetiracetam, lamotrigine, ethosuximide, felbamate, rufinamide, zonisamide and monohydroxycarbamazepine; 2) to develop it for dried plasma spot (DPS) assessing its reliability against the classical determination from plasma; and 3) test its clinical application. Methods: Extraction of plasma samples and DPS was done by simple precipitation. Chromatographic analysis was performed using high performance liquid chromatography with ultraviolet detection. After validation, both methods were applied for the quantification of plasma samples from patients on antiepileptic therapy. Results: Mean inter- and intra-day accuracy and precision were  < 15% for all compounds both in plasma and in DPS samples. DPS samples were considered stable under tested conditions. Measurements between plasma and DPS samples appeared related (p < 0.0001). BlandAltman analysis revealed accordance in lamotrigine values with mean overestimation of concentration for DPS sample of 2.8%. Also for monohydroxycarbamazepine data the agreement was acceptable (mean overestimation of 9.2%). For levetiracetam mean difference was 7.6%, while for ethosuximide mean percentage difference was 20.6%. Conclusions: The developed methods simplify TDM of antiepileptic drugs. This is particularly relevant for the method on dried spot sample devices because it facilitates further sample handling, stability and shipments making the management of therapies in epileptic patients easier also in hospitals devoid of a dedicated laboratory. [ABSTRACT FROM AUTHOR]

Since the late 1990s, the number of opioid analgesic overdose deaths has quadrupled in the United States of America (from 4 030 deaths in 1999 to 16 651 in 2010). The objectives of this article are to provide an overview of the problem of prescription drug overdose in the United States and to discuss actions that could help reduce the problem, with particular attention to the characteristics of prescription drug monitoring programs (PDMPs). These programs consist of state-level databases that monitor controlled substances. The information compiled in the databases is at the disposal of authorized persons (e.g., physicians, pharmacists, and other health-care providers) and may be used only for professional purposes. Suppliers can use such information to prevent interaction with other drugs or therapeutic duplication, or to identify drug-search behavior. Law enforcement agencies can use these programs to identify improper drug prescription or dispensing patterns, or drug diversion. [ABSTRACT FROM AUTHOR]

Patients treated with adalimumab (ADL) can induce anti-ADL antibodies (AAA) formation that is associated with low drug levels and clinical non-response. But, in the majority of the assays, the measurement of AAA is hampered by the presence of the drug itself. In support of immunogenicity assessment in clinical samples with subtherapeutic ADL levels, we proved acid pre-treatment for AAA detection with the Promonitor-enzyme-linked immunosorbent assay (ELISA). Were measured AAA after acidification in 32 serum samples with a subtherapeutic ADL trough level. ADL and AAA concentrations were measured by ELISA (Promonitor). The impact of drug concentration on AAA recovery (with or without acidification) was also evaluated by mixing known amounts of ADL (0.25, 0.5 and 1 mg/L) and AAA (100, 200, 300 and 400 AU/mL) from clinical samples in pooled serum. The drug significantly inhibited the detection of AAA in untreated samples. And progressively higher levels of ADL cause increasing inhibition of signal. Acid pre-treatment carried a significant increase in assay response, particularly at lower free ADL concentrations. AAA were detected in the 53 % of the samples after acid dissociation. In seven patients, the positive AAA after dissociation was detected in the first monitoring of ADL and five patients were positive 3 months later for AAA with the standard assay. Monitoring AAA using acid dissociation in patients with subtherapeutic circulating level of ADL could detect precocious problems of bioavailability, assess the immunogenicity of ADL and may be used to optimise dose regimens, thereby preventing prolonged use of inadequate therapy and guide change of treatment. [ABSTRACT FROM AUTHOR]

Objectives The rate of accumulation of atazanavir and ritonavir within cells is still debated due to methodological limitations. Our aim was to measure peripheral blood mononuclear cell (PBMC) concentrations of atazanavir and ritonavir and investigate whether single-nucleotide polymorphisms of OATP, ABCB1, CYP3A4 and PXR genes are involved in intracellular drug penetration. Methods HIV-positive patients administered 300 mg of atazanavir/100 mg of ritonavir were enrolled. Blood sampling was performed at the end of the dosing interval (Ctrough). PBMC-associated and plasma atazanavir and ritonavir concentrations were measured by validated HPLC coupled with a single mass detector (HPLC–MS) and HPLC–photodiode array (PDA) methods, respectively. Cell count and mean cellular volume were determined using a Coulter counter. Genotyping was conducted using real-time PCR. Results Thirty-five patients were enrolled. Median atazanavir and ritonavir intracellular concentrations were 1844 and 716 ng/mL, respectively. Median plasma concentrations were 645 ng/mL for atazanavir and 75 ng/mL for ritonavir, while median intracellular/plasma concentration ratios were 2.4 and 9.2, respectively. Median ritonavir intracellular concentrations were higher for OATP1B1 521 T→C TC or CC carriers and for PXR 44477 A→G AG or GG carriers. Atazanavir intracellular/plasma concentration ratios were higher in patients GG for the ABCB1 2677 G→T single-nucleotide polymorphism (SNP) compared with GT and TT groups. Conclusions Our study showed a higher intracellular ritonavir accumulation than previously reported. Ritonavir intracellular concentrations were associated with OATP1B1 521 and PXR 44477 SNPs while intracellular atazanavir exposure was associated with the ABCB1 2677 SNP. Further clinical studies are necessary in order to confirm these data. [ABSTRACT FROM PUBLISHER]

Objectives Since 2007 the Dutch Association for Quality Assessment in Therapeutic Drug Monitoring (KKGT) has organized an international interlaboratory proficiency testing (PT) programme for measurement of antifungal drugs in plasma. We describe the 5 year results of the laboratories' performance. Methods Twice a year, laboratories received a set of blind plasma samples containing low or high concentrations of fluconazole, itraconazole, hydroxyitraconazole, posaconazole, voriconazole and flucytosine. Participating laboratories were asked to report their results within 6 weeks after dispatch and provide details of their analytical methods. Results deviating >20% from the weighed-in concentration were considered inaccurate. Four-way ANOVA was performed to assess the effect of antifungal drug measured, concentration, analytical method and performing laboratory on the absolute inaccuracy. In 2012, a questionnaire based on the CLSI guidelines was dispatched with the request to provide input on sources of error. Results Fifty-seven laboratories (13 countries) reported 2251 results (287 fluconazole, 451 itraconazole, 348 hydroxyitraconazole, 402 posaconazole, 652 voriconazole and 111 flucytosine) in 5 years. Analyses were performed using HPLC (55.0%), LC-MS(/MS) (43.4%), UPLC (1.4%) or GC-MS (0.2%). Overall, 432 (19.2%) analyses were inaccurate. The performing laboratory was the only factor clearly associated with inaccuracies. The questionnaire results indicated that laboratories encounter significant problems analysing low concentrations (15.4% of all inaccuracies). Conclusions Results of the PT programme suggest that one out of five measurements is inaccurate. The performing laboratory is the main determinant of inaccuracy, suggesting that internal quality assurance is pivotal in preventing inaccuracies, irrespective of the antifungal drug measured, concentration and analytical equipment. [ABSTRACT FROM PUBLISHER]

Background. Therapeutic drug monitoring (TDM) of the antiepileptic drug valproic acid (VPA) is recommended in patients with multiple drug therapy or with concomitant disabilities to ensure treatment efficacy and avoid adverse reactions in both adults and children. The use of sampling techniques compatible with home sampling, such as dried blood spot sampling could potentially facilitate this for patients. Aim. To assess the usefulness of a bioanalytical method for quantification of VPA in dried blood spots. Materials and methods. Quantification was based on liquid chromatography-mass spectrometry (LC-MS), both for the DBS method and the plasma-based reference method. Results. The method was validated in the range 10-1200 μmol/L. Total imprecision ranged from 4.9-8.9 (%CV) and accuracy was within ± 14%. Conclusion. The validated method has potential for evaluation in therapeutic drug monitoring in combination with home sampling of DBS. The impact of spot size can be controlled through acceptance criteria and hematocrit in the range 30-60% can be accepted in sampling. Comparison of VPA levels between plasma and whole blood cannot be done without considering the blood-plasma ratio. [ABSTRACT FROM AUTHOR]

Aims To investigate the suitability of newly developed Becton Dickinson Vacutainer rapid serum tube (RST) for therapeutic drug monitoring of antibiotics and anticonvulsants. Methods Two pools of citrated whole blood were created by spiking high and low concentrations of gentamicin, vancomycin, phenytoin, lamotrigine and carbamazepine. After recalcification with 15 mmol/L calcium chloride, spiked whole blood was added into four different Becton Dickinson blood collection tubes: RST, serum separator tube, red top tube and polyethylene plain tube. Serum aliquots were collected at baseline (0 h), 2 h, 24 h, day 3 and day 7. Drug concentrations were measured in batch by HPLC and the Architect c8000. Results Gentamicin and vancomycin concentrations were stable up to 7 days in all 4 blood collection tubes. Anticonvulsants results for the RST were stable and did not deviate substantially from those of the red top and plain tubes, and demonstrated better performance than the serum separator tubes that showed significant (=10% bias, p<0.05) decrease in phenytoin and carbamazepine levels after 3 days of storage. Conclusions The RST provides acceptable drug stability over the course of 7 days for gentamicin, vancomycin, phenytoin and lamotrigine and over 3 days for carbamazepine. [ABSTRACT FROM AUTHOR]

In October 2011 the Task Force Therapeutic Drug Monitoring of the Association for Neuropsychopharmacology and Pharmacopsychiatry (AGNP) published an update (Pharmacopsychiatry 2011, 44: 195-235) of the first version of the consensus paper on therapeutic drug monitoring (TDM) published in 2004. This article summarizes the essential statements to make them accessible to a wider readership in German speaking countries. [ABSTRACT FROM AUTHOR]

Objectives: To examine situations that prompt pharmacists to access a prescription drug monitoring program (PDMP) database and management of opioid abuse/addiction; assess pharmacists' actions when abuse is suspected; and describe pharmacists' tasks when dispensing controlled substance prescriptions (CSPs) and their related continuing pharmacy education (CPE). Design: Cross-sectional mail survey of 1,000 randomly selected pharmacists. Setting: Texas from February 2012 to April 2012. Participants: 1,000 Texas community pharmacists. intervention: Mail survey instrument. Main outcome measures: Prompts to use a PDMP and pharmacists' views, actions, and related CPE programs Results: The usable response rate was 26.2%. Pharmacists were more supportive of mandated PDMP use by physicians than by pharmacists (mean ± SD 4.1 ± 1.2 versus 3.2 ± 1.5; P <0.001), based on a 5-point Likert scale (1, strongly disagree, to 5, strongly agree). Most pharmacists would be prompted to use a PDMP if the prescription contains mistakes (68.1%) or the patient requests an early refill (66.3%). Bivariate statistics showed that men pharmacists, those with BSPharm degrees, and pharmacists ≥50 years of age reported a greater number of CPE hours related to prescription opioid abuse and pain management. An analysis of variance showed that pharmacy owners reported significantly more (P <0.05) CPE compared with manager and staff pharmacists. Conclusion: Older pharmacists with a BSPharm degree may be more willing to provide counseling to patients with opioid addiction based on their work experience and additional CPE related to controlled substances. As PDMP use becomes more prevalent, pharmacists should be prepared to interact and counsel patients identified with aberrant controlled prescription drug use and properly deliver pain management care. Additionally, schools of pharmacy curricula must prepare new pharmacists to prevent abuse and diversion, as well as intervene when aberrant use is identified. [ABSTRACT FROM AUTHOR]

The introduction of monoclonal antibody therapy directed against tumor necrosis factor-α revolutionized the modern management of patients with IBD. In spite of this, a proportion of patients do not initially respond to this therapy or, of those that do, some lose response with time. The mechanisms for loss of response include immunogenicity leading to increased drug clearance. In this regard, a growing body of evidence has demonstrated a relationship between circulating drug Levels, anti-drug antibodies, and clinical outcomes. This article addresses these issues in the context of therapeutic drug monitoring and aims to give the treating clinician a platform upon which to make clinical decisions to guide management of loss of response. [ABSTRACT FROM AUTHOR]

Introduction: Post-marketing activities to continuously assess new drugs have been actively driven around the world. In Japan, post-marketing surveillance (PMS) studies have commonly been performed to assess the safety and efficacy of new drugs in the clinical setting, in tandem with the safety reporting system. However, to date, little has been reported on the usefulness and role of the PMS study. Objective: We conducted research to investigate the implications and utility of the safety information obtained from PMS studies, characteristics of the PMS studies, and how the safety and efficacy information obtained by a new drug's PMS program contributes to timely label changes. Methods: Re-examination reports for 150 products were reviewed, along with their PMS study data and information obtained from the safety reporting system (e.g., spontaneous reports by healthcare professionals, adverse drug reaction reports, and foreign reports from the marketing authorization holders). The evidence source for each safety-/efficacy-related label change was reviewed. Results: For all 150 products, it was confirmed that at least one PMS study had been conducted during the product's re-examination period. In total, 302 PMS studies were performed, which included approximately 490,000 patients for safety analyses in the PMS studies. All 302 PMS studies were conducted as observational studies without a comparator arm. Of the products, 8.7 % (13/150) had a safety-related label change as a result of a PMS study, whereas 68.0 % (102/150) had a label change as a result of the safety reporting system. Conclusion: Commonly, one or two PMS studies are conducted, with an observational study design, during the re-examination period. There were few PMS studies targeting special populations, particularly geriatric, renal impairment and liver impairment patients. A major evidence source for safety-related label changes for new drugs in Japan is the safety reporting system, and safety-related label changes resulting from PMS studies are not frequent. [ABSTRACT FROM AUTHOR]

Objectives: Use of a local calibrator has been recommended for standardization of the international normalized ratio (INR) and international sensitivity index (ISI). We investigated the performance of two commercial local calibrators for warfarin monitoring and determined the significance of liver-specific INR. Methods: ISI values were determined using the World Health Organization (WHO) method and two commercial local calibrators. Liver-specific ISI was determined using plasma samples from patients with liver cirrhosis and normal controls. Results: In warfarin monitoring, the two local ISIs determined by the two local calibrators showed better consistency than uncorrected ISI, although they were inferior to the ISIs calibrated using the WHO method. Alternative calibration using calibration plasma from patients with liver cirrhosis instead of warfarinized plasma reduced the INR variability. Conclusions: Local ISI determined by a commercial local calibrator improved INR standardization among thromboplastins. The alternative ISI calibration using liver-specific calibration plasma is expected to reduce INR variability for the evaluation of liver function. [ABSTRACT FROM AUTHOR]

Background Methotrexate ( MTX) is a risky medication requiring careful attention to dosing and monitoring. Dosing and monitoring practices are not well characterized. Aims The aim of this study was to assess variation in the dosing and monitoring of methotrexate among Iranian dermatologists. Methods A questionnaire was administered to forty experts in psoriasis concerning the use of MTX. Results Among the 39 responding dermatologists (15 women, 24 men), 54% saw fewer than 10 psoriatic patients per week, 23% 10-20 patients, and 23% more than 20 patients. About half of the dermatologists treat their patients with an initial MTX dose of <7.5 mg/week (range 5-17.5 mg/week), an average dose of <10 mg/week (range 5-25 mg/week), and a maximum dose of <20 mg/week (range 7.5ٲ-50 mg/week) with 71.8% prescribing the medication orally and 28.2% intramuscularly. Subcutaneous injection was preferred by none of the dermatologists as a usual route of administration. Nearly 5% of the dermatologists believe that liver biopsy should be performed prior to treatment with MTX in all patients, and another 5% consider this procedure prior to treatment only in patients with risk factors. About 44 and 33% of the dermatologists do the liver biopsy after 1.0-1.5 g and 3.54 g total cumulative doses, respectively. Conclusion After more than a half century, there are still noticeable controversies on the manner of using MTX in treating psoriasis among Iranian dermatologists. A national guideline may help standardize treatment practices. [ABSTRACT FROM AUTHOR]

Purpose: There is variability in the pharmacokinetics (PK) of antibiotics (AB) in critically ill patients. Therapeutic drug monitoring (TDM) could overcome this variability and increase PK target attainment. The objective of this study was to analyse the effect of a dose-adaption strategy based on daily TDM on target attainment. Methods: This was a prospective, partially blinded, and randomised controlled trial in patients with normal kidney function treated with meropenem (MEM) or piperacillin/tazobactam (PTZ). The intervention group underwent daily TDM, with dose adjustment when necessary. The predefined PK/pharmacodynamic (PK/PD) target was 100 % fT [percentage of time during a dosing interval that the free ( f) drug concentration exceeded 4 times the MIC]. The control group received conventional treatment. The primary endpoint was the proportion of patients that reached 100 % fT and 100 % fT at 72 h. Results: Forty-one patients (median age 56 years) were included in the study. Pneumonia was the primary infectious diagnosis. At baseline, 100 % fT was achieved in 21 % of the PTZ patients and in none of the MEM patients; 100 % fT was achieved in 71 % of the PTZ patients and 46 % of the MEM patients. Of the patients in the intervention group, 76 % needed dose adaptation, and five required an additional increase. At 72 h, target attainment rates for 100 % fT and 100 % fT were higher in the intervention group: 58 vs. 16 %, p = 0.007 and 95 vs. 68 %, p = 0.045, respectively. Conclusions: Among critically ill patients with normal kidney function, a strategy of dose adaptation based on daily TDM led to an increase in PK/PD target attainment compared to conventional dosing. [ABSTRACT FROM AUTHOR]

Objective: In an attempt to reduce high levels of traffic crashes, a new legislation was approved in Brazil in 2008. This study aimed to assess behavioral change among drivers who had drunk at alcohol outlets (AO) after implementation of the law. Method: A three-stage probability sampling survey was conducted in Porto Alegre, state of Rio Grande do Sul, Brazil. Individuals seen leaving AOs after drinking were approached (n=3,018). Selected drivers (n=683) answered a structured interview, were breathalyzed, and had saliva specimens collected for drug screening. Results: Overall, 60.3% (SE 4.5) of drivers reported they did not change their behavior. Among those who reported behavioral changes, most reported drinking less as their main strategy toward safer driving behavior. Variables independently associated with behavior change included having drunk at a high outlet density area (odds ratio [OR] 1.7 [1.1-2.8]) and having a favorable opinion about the law (OR 4.3 [2.1-8.9]). Conclusions: Our findings suggest that awareness of the law has not been enough to promote behavioral change. As most drivers had a favorable opinion of the law and this variable was found to be the strongest predictor of behavior change, efforts to better integrate education and enforcement seem to be pivotal and might be well received by the population. [ABSTRACT FROM AUTHOR]

This study aims to examine the vancomycin initial dosing and the resultant trough level in paediatric patients. In this retrospective observational study, all therapeutic drug monitoring (TDM) records of paediatric patients admitted to Sabah Women and Children Hospital (SWACH) from January 2011 to September 2013 were reviewed and 116 patients without renal disease were included in the study. Of the total, 38.8% were neonates, 32.8% were infants and 28.4% were children. The majority of the patients were intensive care patients (69.0%) and the most common clinical indication for vancomycin was sepsis (44.8%). The four initial dosing regimens identified were 40 mg/kg/day (38.8%), 30 mg/kg/day (31.0%), 60 mg/kg/day (25.0%) and 45 mg/kg/day (5.2%). The distribution of initial dosing regimen was significantly different between the three age groups (p<0.001). The proportion of those who achieved the target therapeutic range (10--20 mg/L) was 39.7% whereas the proportions of those who were in sub-therapeutic range (<10 mg/L) and supra-therapeutic range (>20 mg/L) were 43.1% and 17.2% respectively. The distribution of trough level was significantly different between those who received ≤40 mg/kg/day and those who received >40 mg/kg/day (p=0.007). The proportions of those who achieved the target therapeutic range (10-20 mg/L) in the 2 dosing groups were 30.9% and 60.0% respectively. In conclusion, the study showed that the initial dosing of >40 mg/kg/day is more likely to achieve the target therapeutic range (10-20 mg/L) compared to the initial dosing of ≤40 mg/kg/day. [ABSTRACT FROM AUTHOR]

Therapeutic drug monitoring (TDM) requires timely results in order to be clinically helpful. Such assays, when carried out using mass spectrometry-based methods, typically involve a batched sample approach with multipoint calibration. Isotopic internal calibration offers the possibility of open-access mass spectrometric analysis with consequent shortening of turnaround times. We measured plasma clozapine and N-desmethylclozapine (norclozapine) concentrations in (1) external quality assessment (EQA) samples ( N = 22) and (2) patient samples ( N = 100) using liquid chromatography-tandem mass spectrometry with isotopic internal calibration (ICAL-LC-MS/MS). Analyte concentrations were calculated from graphs of the response of three internal calibrators (clozapine-D 4, norclozapine-D 8, and clozapine-D 8) against concentration. Precision (% RSD) and accuracy (% nominal concentrations) for the ICAL-LC-MS/MS method were <5 % and 104–112 %, respectively for both analytes. There was excellent agreement with consensus mean and with ‘spiked’ values on analysis of the EQA samples ( R2 = 0.98 and 0.97, respectively, inclusive of clozapine and norclozapine results). In the patient samples, comparison against traditionally calibrated HPLC-UV and LC-MS/MS methods showed excellent agreement ( R2 = 0.97 or better) with small albeit significant mean differences (<0.041 and <0.042 mg/L for clozapine and norclozapine, respectively). These differences probably reflect discrepancies in the in-house preparation of calibrators and/or interference in the UV method. Internal calibration offers a novel and attractive alternative to traditionally calibrated batch analysis in analytical toxicology. The method described has been validated for use in the high-throughput TDM of clozapine and norclozapine, and allows for (1) same-day reporting of results and (2) significant cost savings. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Regular immunosuppressant drug monitoring is important for maintaining the drug concentrations of organ recipients within the therapeutic range. The standardized liquid chromatography-tandem mass spectrometry (LC-TMS) technique has been used for the accurate analysis of immunosuppressive drugs. In the present study, the performance of the recently developed high-throughput, rapid ultra-performance liquid chromatography combined with tandem mass spectrometry (UPLC-TMS) method was validated for the simultaneous measurement of cyclosporin A and tacrolimus in whole blood. The method of measuring cyclosporin A and tacrolimus using UPLC-TMS was established and the precision, limit of detection (LOD), limit of quantitation (LOQ) and matrix effect were validated. In addition, the performance of UPLC-TMS was compared with that of a chemiluminescence immunoassay (CLIA) in >3,400 clinical specimens. The UPLC-TMS revealed a within-run and between-run precision of <8% and showed a bias of <5%. The LOD and LOQ were 2.0 and 2.5 ng/ml for cyclosporin A, and 0.3 and 0.4 ng/ ml for tacrolimus, respectively. Interference from the matrix was not observed. The CLIA measurements of cyclosporin A and tacrolimus showed correlations corresponding with the formulae: Concentration(CLIA) = 1.18 x UPLC-TMS - 5.85; [95% CI: proportional, 1.16-1.19; constant, -6.86-(-4.81)] and Concentration(CLIA) = 1.14 x UPLC-TMS - 0.38; [(95% CI: proportional, 1.13-1.14; constant, -0.35-(-0.43)], respectively. The majority of results were higher for the immunoassay than for the UPLC-TMS. The newly developed rapid UPLC-TMS method was suitable for use with a large therapeutic concentration range of the analyzed immunosuppressive drugs. Sample preparation was simple and it was possible to detect several immunosuppressants simultaneously, thus significantly lowering the cost of analysis. In conclusion, this method may contribute to improved accuracy and may be preferred to immunoassays for the routine clinical measurement of immunosuppressive drug concentrations in whole blood. [ABSTRACT FROM AUTHOR]

Background: Oral anticoagulation therapy with warfarin is used to prevent and to treat venous and arterial thrombosis and embolism. Its narrow therapeutic index should be monitored carefully in order to reach the desired outcomes. Objective: This study aims to evaluate the clinical pharmacist-led in-patient warfarin's knowledge education program and to assess a follow-up efficacy in a Chinese tertiary referral teaching hospital. Design and Setting: A cross-sectional and observational study was conducted at the Affiliated Hospital of Medical College of Nanjing University, a 1460-bed tertiary referral teaching hospital in Nanjing. Materials and Methods: One-on-one interview questionnaire was conducted among 47 Chinese patients who had undergone prosthetic valve replacement. Before the patient education program's implemented, at discharge time and 3 months, 6-9 months and 12 months after surgery were considered as time points. A previously validated 17-item questionnaire was used to measure the patient's knowledge level of warfarin and to assess and evaluate a follow-up efficacy of this patient education program run by a clinical pharmacist. Knowledge scores were compared using the Student's t-test or one-way analysis of variance. Main Outcome Measure: Patients' knowledge on the warfarin education program and warfarin knowledge score, drug therapy problems or bleeding complication events associated to warfarin therapy and evaluation of clinical pharmacist's service provided. Results: Patients mean age was 47.68 ± 9.70 years (range 23-67). The higher education strata had significantly higher warfarin knowledge scores (P < 0.05). In terms of hospital stay post-surgery, compared with other groups, patients with an average of 11-14 days, were found significantly and statically higher knowledgeable in warfarin (P < 0.05). The clinical pharmacist' service was found very satisfying f(80.85%). Conclusion: Chinese patients on warfarin therapy should benefit from periodic educational efforts reinforcing key medication safety information. Patient education is not a once-off procedure. A complete patient education program run by a clinical pharmacist in a Cardio-thoracic ward can considerably improve and enhance to reduce the hospital stays and significantly enlighten the role of the patient education in adherence to therapy. [ABSTRACT FROM AUTHOR]

Study Objective To evaluate the incidence of posaconazole serum levels below 700 μg/L, the rate of breakthrough infections during posaconazole prophylaxis, and factors influencing posaconazole exposure in daily clinical practice. Design Prospective observational study and review of the literature. Setting Hematology and oncology department in a tertiary care academic medical center. Patients A total of 31 patients with hematologic diseases: 27 received posaconazole prophylaxis and 4 received posaconazole therapy. Measurements and Main Results We analyzed 187 posaconazole serum levels from 31 patients (median of five posaconazole levels per patient; range 1-16). The analyses revealed that 80 of 187 levels (43%) were below 700 μg/L, and 68% of patients were found to have at least one measured level below this threshold. Breakthrough invasive fungal infections categorized as probable or possible infections occurred in 4 of 27 patients (15%) receiving the drug as prophylaxis. A multivariate analysis, accounting for repeated measurements per patient, revealed that age (p=0.02) and mucositis (p=0.04) were associated with significantly reduced posaconazole serum levels. A review of the current literature on posaconazole therapeutic drug monitoring data from real-world studies is presented as an overview table, highlighting the frequency of patients with inadequate posaconazole exposure and heterogeneity of factors influencing posaconazole levels. Conclusion Therapeutic drug monitoring of posaconazole is an important tool of therapy optimization because oral posaconazole suspension shows unreliable absorption rates and exposure. [ABSTRACT FROM AUTHOR]

Objectives Therapeutic drug monitoring (TDM) of anti-tuberculosis (TB) drugs is beneficial for patients responding slowly to treatment and those with multidrug-resistant TB. We used ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) to develop a rapid method for simultaneously measuring the blood concentrations of nine second-line anti-TB drugs: streptomycin, kanamycin, clarithromycin, cycloserine, moxifloxacin, levofloxacin, para-aminosalicylic acid, prothionamide and linezolid. Methods Serum samples were extracted with acidified methanol and neutralized with NaOH. A Waters Acquity HSS T3 column and gradients of ammonium formate and acetonitrile in 0.1% formic acid were used for UPLC separation. Drug concentrations were determined by multiple reaction monitoring in positive ion mode, and assay performance was evaluated. We applied this method to TDM, analysing random serum samples from 85 patients treated with second-line drugs. Results Sample preparation using acidified methanol extraction followed by neutralization yielded good recovery and ionization efficiency, with chromatographic separation achieved within 3 min per sample. Within-run and between-run precisions were 1.7%–7.5% and 1.7%–12.4%, respectively, at concentrations representing low and high levels for the nine drugs. Lower limits of detection and quantification were 0.025–0.5 and 0.25–5.0 μg/mL, respectively. Linearity was acceptable at five concentrations for each drug. No ion suppression was observed at the retention time for most compounds, except for streptomycin, kanamycin and cycloserine, which were eluted close to the void volume of the column. In a limited pilot study, all quantifiable human samples had values within the validated assay ranges. Conclusions The performance of our MS/MS detection technique was generally acceptable. The method provided rapid, sensitive and reproducible quantification of nine second-line anti-TB drugs and should facilitate drug monitoring during treatment. [ABSTRACT FROM PUBLISHER]

Objective: To compare the completeness of medication and blood pressure monitoring among patients requesting medication refills through the pharmacist-managed medication refill and laboratory monitoring program (MRLMP) versus usual care. Design: Quasiexperimental study. Setting: Kaiser Permanente Colorado between November 2011 and June 2012. Patients: Patients requesting chronic medication prescription refills. Intervention: Community pharmacists managed the refill authorization request (RAR) process at the intervention site. For each RAR, the pharmacist reviewed patient medication monitoring needs and ordered laboratory test(s) or a clinic visit, as needed, before approval. Main outcome measures: For medications due for laboratory or blood pressure monitoring at the time of the RAR, the 1-month rate of attaining complete monitoring was compared between groups. Pharmacist, primary care physician (PCP), and patient satisfaction and PCP time saved also were compared. Results: 3,797 RARs for MRLMP-eligible medications were approved in the month following MRLMP implementation in the intervention and control clinics. The intervention and control groups converted 49% and 29% of medications due for laboratory monitoring (P < 0.001) and 56% and 33% of those due for blood pressure monitoring, respectively (P = 0.020). The intervention group PCPs were more likely than control group PCPs to report being "very satisfied" with the RAR process (80% vs. 27%, P = 0.015) and spent fewer minutes per day on refill requests (mean 17 vs. 23, P = 0.049). The intervention group pharmacists reported higher job satisfaction (mean index score 22 vs. 18, P = 0.024), and intervention group patients reported higher satisfaction with the "readiness" of their prescription when they came to pick it up (91% vs. 80%, P = 0.004). Conclusion: A pharmacist-managed MRLMP resulted in improved process-related outcomes. Future studies should assess clinical outcomes. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the timing of therapeutic drug monitoring (TDM) in patients with impaired renal function treated with once-daily administration of vancomycin (VCM). Once-daily administration was selected for patients whose creatinine clearance (C) was <80 ml/min. TDM was conducted on day 3 or on day 4. Adult patients whose VCM dosage was not altered according to initial C and for whom subsequent follow-up TDM was performed within 1 week were entered into the study. Patients whose renal function deteriorated at follow-up TDM were excluded. One hundred sixty-five patients were eligible for analysis. Among patients with once-daily dosing, relative increases of C at follow-up TDM compared with initial TDM were 34.5 ± 39.2 % in TDM on day 3 and 16.6 ± 20.6 % in TDM on day 4 ( P = 0.016). In contrast, there was no significant difference in the relative increase of C between TDM on days 3 and 4 (26.1 ± 39.6 vs. 18.4 ± 25.6 %, P = 0.551) in the twice-daily regimen. On multivariate analysis, TDM on day 3 alone (odds ratio, 4.93; 95 % confidence interval, 1.71-14.2) was selected as an independent risk factor associated with a relative increase of C by >30 % in the once-daily regimen. Steady-state VCM serum concentration was not achieved on day 3 in the once-daily regimen in patients with impaired renal function, and TDM on day 3 caused underestimation of C. [ABSTRACT FROM AUTHOR]

Objectives Hyperbilirubinaemia is a frequent complication of atazanavir-containing antiretroviral therapy and its severity is related to UDP-glucuronosyl transferase (UGT) 1A1*28 polymorphism. The aim of this study was to evaluate the safety and outcome of unboosted atazanavir-containing regimens based on the genetic constitution. Methods Fifty-one HIV-1-infected patients on boosted atazanavir were prospectively enrolled in the study. Twenty-five patients with a UGT1A1*28 allele switched to 400 mg of unboosted atazanavir. Results At baseline, UGT1A1 heterozygous and homozygous patients had significantly higher bilirubin levels than wild-type (P = 0.012 and P < 0.001, respectively). After ritonavir removal, a reduction was observed in total bilirubin (from 4.09 to 1.82 mg/dL; P < 0.001), γ-glutamyl transpeptidase (P = 0.015), triglycerides (P = 0.03) and total cholesterol (P = 0.05). No significant changes in CD4 T cell count and no increases in viral load were observed 12 months after unboosting. Plasma drug monitoring after ritonavir removal revealed the presence of therapeutic atazanavir concentrations in all patients except one with poor therapy adherence. Conclusions UGT1A1*28 is significantly related to hyperbilirubinaemia in HIV-1 patients receiving atazanavir. Genotyping before the initiation of antiretroviral therapy can reduce the emergence of severe hyperbilirubinaemia. Unboosted atazanavir-containing therapy is safe and efficacious in patients with an undetectable viral load with a UGT1A1*28 polymorphism, allowing the use of atazanavir in patients otherwise likely unable to receive it. [ABSTRACT FROM PUBLISHER]

The article presents a report on the users of Amphetamine in Western Australia from 1999 till 2009, from the study of the Drug Use Monitoring in Australia (DUMA) project. According to the 2010 National Drug Strategy Household Survey (NDSHS), 7 percent of 14 years and older Australians had 'ever' used amphetamines/methamphetamines. The article presents the comparison of the profile of amphetamine users with those of the non-users. It further provides implications to the government and community organizations for the growing knowledge on amphetamine use.