Drug concentrations in post‐mortem femoral blood compared with therapeutic concentrations in plasma

Therapeutic drug concentrations measured in plasma are of limited value as reference intervals for interpretation in post‐mortem (PM) toxicology. In this study, drug concentration distributions were studied in PM femoral venous blood from 57 903 Finnish autopsy cases representing all causes of death during an 11‐year period. Cause‐of‐death information was obtained from death certificates issued by forensic pathologists. Median, mean, and upper percentile (90th, 95th, 97.5th) concentrations were calculated for 129 drugs. To illustrate how PM median concentrations relate to established therapeutic ranges in plasma, a PM blood/plasma relationship was calculated for each drug. Males represented 75% of the subjects and showed a lower median age (55 yrs) than females (59 yrs). In 43% of these cases, blood alcohol concentration was higher than 0.2‰, and the median was 1.8‰. Sixty‐one (47%) of the 129 drugs showed a PM blood/plasma relationship of 1. For 22 drugs (17%), the relationship was <1, and for 46 drugs (35%), the relationship was >1. No marked correlation was found between the PM blood/plasma relationship and the volume of distribution (V_d). For 36 drugs, more than 10% of cases were fatal poisonings attributed to this drug as the main finding. These drug concentration distributions based on a large database provide a helpful reference not only to forensic toxicologists and pathologists but also to clinical pharmacologists in charge of interpreting drug concentrations in PM cases. © 2013 The Authors. Drug Testing and Analysis published by John Wiley & Sons, Ltd.     

Drug concentrations in post‐mortem specimens

A meta‐analysis of drug concentrations in post‐mortem specimens is presented. The analysis involved 50 commonly used drugs and their concentrations in femoral blood, other blood (such as cardiac blood), vitreous humor, muscle, liver, kidney, brain, heart, lung, spleen, and bile. A total of 10 993 analytical results from 5375 post‐mortem cases in 388 studies were gathered and the ratios of drug concentrations in tissue material to median femoral blood concentrations were calculated. Analytical results from the laboratory's own database (years 2000–2018) were also included. The results show that the variation of ratios between post‐mortem specimens and femoral blood is highly compound dependent. This database can be utilized in interpretation of toxicological results in cases where femoral blood is not available. The specimens with similar concentrations as in femoral blood were vitreous humor, muscle, and other blood, such as cardiac blood, and the highest concentrations were generally measured from liver and bile. For these reasons we suggest the following order for biological specimens to be used for a quantitative toxicological analysis in cases where femoral blood is not available: 1. other blood, 2. muscle, 3. vitreous humor, 4. brain, 5. heart, 6. spleen, 7. kidney, 8. liver, and 9. bile.     

Clinical relevance of deferasirox trough levels in β‐thalassemia patients

We evaluated the role of deferasirox therapeutic drug monitoring in order to avoid toxicity or treatment failure. Plasma concentrations, measured between two consecutive liver iron determinations, were determined at the end of dosing interval. Fifty‐four β‐thalassemic adult patients were enrolled: 50% were males; median age was 32.3 years (IQR 19.1‐41.7 years) and median body mass index was 22.25 kg/m² (IQR 20.24‐23.75 kg/m²). The mean deferasirox dose was 28.6 ± 6.3 mg/kg/d and mean plasma concentration was 17.3 ± 16.8 μg/mL. Drug levels showed lower results in males. Deferasirox concentration was significantly correlated with serum creatinine levels (P = .01) and serum ferritin (P < .0001). The assessment of deferasirox therapeutic drug monitoring could help clinicians to predict patient responses and to optimize the therapy.     

Post‐mortem determination of insulin using chemiluminescence enzyme immunoassay: preliminary results

Insulin determination in blood sampled during post‐mortem investigation has been repeatedly asserted as being of little diagnostic value due to the rapid occurrence of decompositional changes and blood haemolysis. In this study, we assessed the feasibility of insulin determination in post‐mortem serum, vitreous humour, bile, and cerebrospinal and pericardial fluids in one case of fatal insulin self‐administration and a series of 40 control cases (diabetics and non‐diabetics) using a chemiluminescence enzyme immunoassay. In the case of suicide by insulin self‐administration, insulin concentrations in pericardial fluid and bile were higher than blood clinical reference values, though lower than post‐mortem serum concentration. Insulin concentrations in vitreous (11.50 mU/L) and cerebrospinal fluid (17.30 mU/L) were lower than blood clinical reference values. Vitreous insulin concentrations in non‐diabetic control cases were lower than the estimated detection limit of the method. These preliminary results tend to confirm the usefulness of insulin determination in vitreous humour in situations of suspected fatal insulin administration. Additional findings pertaining to insulin determination in bile, pericardial, and cerebrospinal fluid would suggest that analysis performed in post‐mortem serum and injection sites could be complemented, in individual cases, by investigations carried out in alternative biological fluids. Lastly, these results would indicate that analysis with chemiluminescence enzyme immunoassay may provide suitable data, similar to analysis with liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) and immunoradiometric assay, to support the hypothesis of insulin overdose. Copyright © 2015 John Wiley & Sons, Ltd.     

Validation of a fully automated solid‐phase extraction and ultra‐high‐performance liquid chromatography–tandem mass spectrometry method for quantification of 30 pharmaceuticals and metabolites in post‐mortem blood and brain samples

In this study, we present the validation of an analytical method capable of quantifying 30 commonly encountered pharmaceuticals and metabolites in whole blood and brain tissue from forensic cases. Solid‐phase extraction was performed by a fully automated robotic system, thereby minimising manual labour and human error while increasing sample throughput, robustness, and traceability. The method was validated in blood in terms of selectivity, linear range, matrix effect, extraction recovery, process efficiency, carry‐over, stability, precision, and accuracy. Deuterated analogues of each analyte were used as internal standards, which corrected adequately for any inter‐individual variability in matrix effects on analyte accuracy and precision. The lower limit of quantification (LLOQ) spanned from 0.0008 to 0.010 mg/kg, depending on the analyte, while the upper LOQ ranged between 0.40 and 2.0 mg/kg. Thus, the linear range covered both therapeutic and toxic levels. The method showed acceptable accuracy and precision, with accuracies ranging from 80 to 118% and precision below 19% for the majority of the analytes. Linear range, matrix effect, extraction recovery, process efficiency, precision, and accuracy were also tested in brain homogenate and the results agreed with those from blood. An additional finding was that the analyte concentrations in brain samples could be quantified by calibration curves obtained from spiked blood samples with acceptable precision and accuracy when using deuterated analogues of each analyte as internal standards. This method has been successfully implemented as a routine analysis procedure for quantification of pharmaceuticals in both blood and brain tissue since 2015.     

Lamotrigine drug interactions in combination therapy and the influence of therapeutic drug monitoring on clinical outcomes in paediatric patients

The aim was to study the impact of therapeutic drug monitoring (TDM) on paediatric patients on lamotrigine therapy and the evaluation of possible drug interactions, especially in triple antiepileptic drug combinations. During the period of 2001‐2015, 1308 pre‐dose samples were taken from 430 patients <15 years of age as part of routine TDM. Drug interactions were evaluated using calculation of lamotrigine clearance. Valproic acid decreased lamotrigine clearance by 54% in bitherapy, and by 21% in triple therapy with carbamazepine. Carbamazepine increased lamotrigine clearance by 191% in bitherapy. Levetiracetam and topiramate had no effect. The upper limit of lamotrigine therapeutic range (TR) was exceeded in 2% of cases in monotherapy, and in 6%‐7% of cases in bi‐ or triple therapy. About 61% of plasma levels were found within the TR during 2001‐2005, compared to 75% and 74% during 2006‐2010 and 2011‐2015, respectively. Adverse drug reactions (ADRs) were reported in 22 cases. Higher number of supratherapeutic levels in combination therapy led to a 3‐fold increase in incidence of ADRs. Seizures occurred more often daily and monthly during 2001‐2005 and in patients with three or four antiepileptic drugs in combination. Carbamazepine only partially compensated for the inhibitory effect of valproic acid. Lamotrigine clearance in monotherapy in children is similar to adults, but in polytherapy was found higher susceptibility to induction. A significantly higher number of supratherapeutic lamotrigine levels were found in combinations with valproate. Despite poor correlation with TR, both seizure frequency and ADRs declined after the implementation of TDM.     

Enantioselective analysis of citalopram and demethylcitalopram in human whole blood by chiral LC–MS/MS and application in forensic cases

Citalopram is one of the most frequently used antidepressants in Denmark. It is marketed as a racemic mixture (50:50) of S‐ and R‐enantiomers as well as of the S‐enantiomer alone, which is the active enantiomer named escitalopram that processes the inhibitory effects. In this study, a chiral liquid chromatography–tandem mass spectrometry (LC–MS/MS) method is developed for the measurement of citalopram and demethylcitalopram enantiomers in whole blood and is applied to forensic cases. Whole blood samples (0.10 g) were extracted with butyl acetate after adjusting the pH with 2 M NaOH. The analytes were separated on a 250 × 4.6 mm Chirobiotic V, 5 μm column by isocratic elution with methanol:ammonia:acetic acid (1000:1:1) using an ultra‐high‐pressure liquid chromatography (UHPLC) system. Quantification was performed by tandem mass spectrometry (MS/MS) using multiple reaction monitoring (MRM) in the positive mode. The total chromatographic run time was 20 min. The limit of detection (LOD) and quantification (LOQ) were 0.001 and 0.005 mg/kg of all four enantiomers, respectively. Linear behaviour was obtained for all four enantiomers from LOQ to 0.50 mg/kg blood with absolute recoveries from 71 to 80%. The method showed an acceptable precision and accuracy as the obtained coefficient of variation, and bias values were ≤16% for all enantiomers. After the validation of the method, a correlation with the racemic method was assessed and found to be acceptable. Then, the method was successfully applied to authentic blood samples from forensic investigations demonstrating that escitalopram was less frequent than citalopram among all forensic cases. Copyright © 2017 John Wiley & Sons, Ltd.     

Population pharmacokinetic–pharmacodynamic modelling to describe the effects of paracetamol and N‐acetylcysteine on the international normalized ratio

Paracetamol is one of the most common pharmaceutical agents taken in self‐poisonings, and can increase the prothrombin time (PT) through liver injury, and in overdose without hepatic injury by reducing functional factor VII. PT is a measure of hepatic injury used to predict and monitor hepatotoxicity, reported as the international normalized ratio (INR). The antidote for paracetamol poisoning, N‐acetylcysteine (NAC), has been reported to have an effect on the PT. This analysis included patients from a retrospective case series, a prospective inception cohort of paracetamol and psychotropic (control) overdoses, and a cross‐over clinical trial. A population pharmacokinetic–pharmacodynamic model describing the pharmacodynamic effects of paracetamol and NAC on the INR was developed in Phoenix NLME. The dataset included 172 patients; the median age was 22 years (range 13–71 years). A one‐compartment model with first‐order input and linear disposition best described paracetamol pharmacokinetics. The population mean estimate of the concentration that induced a response halfway between the baseline and maximal pharmacological effect of paracetamol was 1302 μmol/L (242), the maximum effect of paracetamol was 0.534 (202; from baseline) and the maximum effect of NAC was 0.325 (9.03; from baseline). Both paracetamol and NAC contributed a pharmacological effect to the elevation of INR. The estimated paracetamol concentration that induced a response halfway between the baseline and maximal pharmacological effect was within the range of plasma paracetamol values studied, fivefold greater than the maximum therapeutic concentration, suggesting that an elevated INR would not be expected within the therapeutic range. Simulated 24 and 48 g paracetamol overdoses with NAC administration produced INR values (50th percentile) that reached the upper limit of, or exceeded, the reference range.     

Creatinine in urine – a method comparison

Drug screening in urine is widely applied in forensic toxicology. Contrary to blood analysis, excessive or reduced fluid intake can substantially alter the concentration of substances in urine. As a standard to detect urinary dilution, creatinine concentrations are analyzed. A sample with a concentration below 20 mg/dL is generally defined as too diluted to provide a valid result in abstinence control samples. This work investigates the potential of three different methods for the determination of creatinine concentrations in urine samples: A ZIC®‐HILIC‐based liquid chromatography–tandem mass spectrometry (LC–MS/MS) method, a spectrophotometric method on an AU 480 chemistry system, and a portable, chemical‐reaction‐based, point‐of‐care testing device were compared by measuring 200 urine samples. When comparing the two laboratory methods, LC–MS/MS and spectrophotometry, a mean difference of 3.7 ± 14 mg/dL was found, indicating that the spectrophotometric method slightly overestimates the creatinine concentration. When comparing the LC–MS/MS method with the point‐of‐care testing device, a mean concentration difference within the calibration range for POCT (>20 mg/dL (excluding 16 samples) and <500 mg/dL (excluding 4 samples)) of 21 ± 37 mg/dL was found, indicating that the point‐of‐care testing device overestimates the measured creatinine concentration. A point‐of‐care testing device as used during this study can provide valuable information for on‐site analysis. However, reported concentrations above 500 mg/dL should be further evaluated, for example by dilution of the sample. Copyright © 2017 John Wiley & Sons, Ltd.     

Analysis of phenazepam and 3‐hydroxyphenazepam in post‐mortem fluids and tissues

Phenazepam is a benzodiazepine that is predominantly used clinically in the former Soviet states but is being abused throughout the wider world. This study reports the tissue distribution and concentration of both phenazepam and 3‐hydroxyphenazepam in 29 cases quantitated by liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) in a variety of post‐mortem fluids (subclavian blood, femoral blood, cardiac blood, urine, vitreous humour) and tissues (thalamus, liver and psoas muscle). In 27 cases, the cause of death was not directly related to phenazepam (preserved (fluoride/oxalate) femoral blood phenazepam concentrations 0.007 mg/L to 0.360 mg/L (median 0.097 mg/L). In two cases, phenazepam was either a contributing factor to, or the certified cause of death (preserved (fluoride/oxalate) femoral blood 0.97 mg/L and 1.64 mg/L). The analysis of phenazepam and 3‐hydroxyphenazepam in this study suggests that they are unlikely to be subject to large post‐mortem redistribution and that there is no direct correlation between tissues/fluid and femoral blood concentrations. Preliminary investigations of phenazepam stability comparing femoral blood phenazepam concentrations in paired preserved (2.5% fluoride/oxalate) and unpreserved blood show that unpreserved samples show on average a 14% lower concentration of phenazepam and we recommend that phenazepam quantitation is carried out using preserved samples wherever possible. Copyright © 2015 John Wiley & Sons, Ltd.     

Analysis of cis and trans 3‐methylfentanyl by liquid chromatography–high resolution mass spectrometry and findings in forensic toxicology casework

3‐methylfentanyl (3‐MF), N‐(3‐methyl‐1‐phenethyl‐4‐piperidyl)‐N‐phenyl‐propanamide, has reappeared on the US illicit drug market since its disappearance after a series of overdose deaths in 1988. 3‐MF presents an analytical challenge, due to presence of cis and trans stereoisomers, each with different potencies, and ultimately very low concentrations in the blood after use. A method was developed using liquid chromatography–time‐of‐flight–mass spectrometry for the analysis of (±)‐cis‐3‐MF and (±)‐trans‐3‐MF in blood specimens after solid phase extraction. The linear dynamic range of this method was 0.1–10 ng/mL. Blood samples from 25 postmortem cases and 2 human performance case involving 3‐MF were submitted for quantitative analysis. The mean and median concentration for the (±)‐cis‐3‐MF were 0.84 ng/mL (±0.81) and 0.67 ng/mL, respectively, range 0.14–3.43 ng/mL. The resulting (±)‐trans‐3‐MF mean concentration was 0.46 ng/mL (±0.38) and the median concentration was 0.37 ng/mL with a range of 0.11–1.90 ng/mL. The resulting (±)‐cis‐3‐MF and (±)‐trans‐3‐MF concentrations were summed to give the total amount of 3‐MF present in the case with the resulting average concentration at 1.28 ng/mL (±1.16), median at 1.01 ng/mL and range 0.18–5.18. As the estimated dose of this compound is approximately 0.1 mg–0.5 mg with the resulting concentrations in the sub‐nanogram range, it is necessary for forensic toxicology laboratories to obtain instruments sensitive enough to detect these substances in driving under the influence of drugs and postmortem cases. Quantitation of 3‐MF with separation of (±)‐cis and (±)‐trans‐3‐MF provides additional detail for more specific toxicological interpretation.     

Characteristics of drugs safety signals that predict safety related product information update

Purpose

Investigation of drug safety signals is one of the major tasks in pharmacovigilance. Among many potential signals identified, only a few reflect adverse drug reactions requiring regulatory actions, such as product information (PI) update. Limited information is available regarding the signal characteristics that might predict PI update following signal evaluation. The objective of this study was to identify signal characteristics associated with PI updates following signal evaluation by the European Medicines Agency Pharmacovigilance Risk Assessment Committee during 2012 to 2016.

Methods

A comparative study was performed based on data from 172 safety signals. Characteristics of signals were extracted from the European Pharmacovigilance Issues Tracking Tool database. Multivariable logistic regression analysis was used to assess the relationship between signal characteristics and the decision to update the PI.

Results

Multivariable logistic regression analysis showed that the presence of evidence in multiple types of data sources (adjusted odds ratio [OR] 7.8 95% CI [1.5, 40.1]); mechanistic plausibility of the drug‐event association (adjusted OR 3.9 95% CI [1.9, 8.0]); seriousness of the event (adjusted OR 4.2 95% CI [1.3, 13.9]); and age of drugs ≤5 years (adjusted OR 3.9 95% CI [1.2, 12.7]) were associated with the decision to change the PI (P < 0.05).

Conclusions

This study identified 4 characteristics of drug safety signals that have shown to be associated with PI changes as outcome of signal evaluation. These characteristics may be used as criteria for selection and prioritization of potential signals that are more likely to necessitate product information updates.     

Clinical laboratory test standards for a sample of schizophrenics

The normal ranges for 15 clinical laboratory tests for a pooled sample of 325 schizophrenics, largely chronic and hospitalized, are presented. Laboratory data came from pretreatment blood samples of subjects who were all participants in clinical psychotropic drug trials conducted through the Early Clinical Drug Evaluation Unit (ECDEU) Program of the National Institute of Mental Health. Both parametric means and ranges (mean ± 2 standard deviations) and nonparametric medians and percentile ranges (2.5 and 97.5 percentiles) are reported. The results generally confirm the finding of increased variability in schizophrenic laboratory test data noted in the past. This, and implications of the method are discussed.Detailed information about the assay methods used at each laboratory is available from the authors.Occasionally the 10th and 90th percentile are utilized. However, the 2.5 and 97.5 percentile limits include 95% of the sample, which is comparable to the percent of sample included in the parametric range defined at ± 2 S.D.     

Therapeutic Drug Monitoring of Venlafaxine in an Everyday Clinical Setting: Analysis of Age,Sex and Dose Concentration Relationships

Venlafaxine is a commonly used antidepressant agent. We aimed to provide detailed information on the associations between venlafaxine dose and concentrations of venlafaxine, by patient age and sex. From a therapeutic drug monitoring (TDM) database located at Odense University Hospital, Denmark, we identified all adults for whom the treating physician had requested clinical advice on the TDM result for venlafaxine between 2002 and 2012. We identified 1077 TDM samples of venlafaxine from 334 males and 743 females (median age 45 years), and the median daily dose was 225 mg. Median plasma concentration of venlafaxine and o‐desmethylvenlafaxine (ODV) was 306 nmol/L and 861 nmol/L, respectively. The median dose‐corrected serum level for venlafaxine was 1.49 nmol/L/mg., while the dose‐corrected serum level of men and women were 1.21 nmol/L/mg and 1.60 nmol/L/mg, respectively. The dose‐corrected sum of venlafaxine and ODV was 8.91 nmol/L/mg (IQR 6.56–12.26) versus 5.52 nmol/L/mg (IQR 4.16–7.52) for patients above 64 years and below the age of 65 years, respectively. Dose‐corrected plasma concentrations of venlafaxine and ODV are increased to a clinically significant degree in patients above the age of 64, and initiation of venlafaxine therapy in the elderly should be made cautiously and supported by drug measurements.     

Urinary concentrations of AICAR and mannitol in athlete population

Both AICAR and mannitol are prohibited for use in sports, but no decisive criteria that would guide anti‐doping laboratories on data interpretation have been established so far. In an attempt to help harmonize reporting and management of analytical findings, reference population data collected for US athletes are presented. Upon analysis of 12 377 samples, mean urinary AICAR concentration was found to be 647 ± 365 ng/mL with median value of 574 ng/mL, 99th percentile at 1786 ng/mL and 99.7th percentile at 2151 ng/mL. Based on these results, we suggest that any sample with AICAR concentration greater than 2000 or 2500 ng/mL be analyzed by carbon isotope ratio mass spectrometry to establish the origin. Urinary mannitol concentrations demonstrate larger variation with the mean value of 72 ± 140 μg/mL and median at 41 μg/mL (n = 6407). While the 99.7th percentile for mannitol was measured to be 1094 μg/mL, the population data alone is not sufficient to suggest a threshold value. It is also shown that the use of mannitol as a sweetener in amounts of up to 20 g per day results in a urinary concentration of about 14 mg/mL. As only intravenous mannitol is prohibited in sports, controlled excretion studies are needed to see whether intravenous administration could in fact be discriminated from dietary intake. An important observation is that mannitol present in mg/mL quantities significantly increases urine specific gravity, which makes a widely accepted normalization approach not applicable.     

抗癫痫中成药中非法添加西药成分的血药浓度监测分析

目的：对长期服用抗癫痫中成药的患者进行血药浓度监测,查明抗癫痫中成药中非法添加的西药成分。方法：通过全自动生化分析仪,采用酶联免疫法测定中成药中添加的丙戊酸、卡马西平、苯巴比妥、苯妥英的种类及血药浓度。结果：所有服用抗癫痫中成药的患者中均检测到上述四种西药成分,其中含丙戊酸17例,血药浓度在有效范围内占23.53%;含卡马西平17例,血药浓度在有效范围内占17.65%;含苯巴比妥17例,血药浓度在有效范围内占41.18%;含苯妥英5例,血药浓度在有效范围内占60.00%。结论：本方法操作简便、准确,可快速筛查抗癫痫中成药中非法添加的西药成分,便于临床指导患者合理用药。     

Non‐Chemotherapy‐Induced Agranulocytosis Detected by a Prospective Pharmacovigilance Program in a Tertiary Hospital

We conducted a prospective evaluation of non‐chemotherapy‐induced agranulocytosis (NIA) in a tertiary hospital in Spain. Through our Prospective Pharmacovigilance Program from Laboratory Signals at Hospital, we detected agranulocytosis cases over a period of 42 consecutive months. This report estimates incidence, drug causality, clinical features and outcomes of NIA cases and assesses laboratory differences with respect to non‐NIA. We detected 1349 cases of agranulocytosis in 538 adult patients; of these, 43 cases in 40 patients were caused by non‐chemotherapy drugs. The incidence rate for 10,000 patients during the study period was 2.75 [Poisson confidence interval (CI)‐95%: 0.62–7.22]. The mean (S.D.) age was 48 (21) years. All cases were categorized as serious, because they required hospitalization (28 cases) or prolongation of hospitalization (15 cases). The outcome was recovery without sequela (39 cases), recovery with sequela (one case of toe amputation) or death (three cases, 7%). The most frequent cause of NIA was antimicrobial drugs (19 cases). The highest incidence rate per 10,000 defined daily doses was for cefepime (83.85; Poisson‐CI 95%: 67–102.89). Automatic linear modelling (n = 75, R² = 77.9%) showed a significant inverse association with platelets, alkaline phosphatase, C‐reactive protein, fibrinogen, lactate dehydrogenase; and direct association with mean corpuscular haemoglobin, and haematocrit. A generalized linear model retained platelets, total serum proteins, creatinine and haemoglobin. The findings suggest an immune‐mediated destruction or myeloid toxicity, possibly facilitated by an increase in drug exposure. There might be additional contributing factors, such as nutritional deficiencies or chronic diseases, to develop NIA after exposure to a potentially causative drug.     

Management of pharmacotherapy‐related problems in acute coronary syndrome: Role of clinical pharmacist in cardiac rehabilitation unit

Acute coronary syndrome (ACS) is one of the leading causes of mortality worldwide and negatively impacts healthcare costs, productivity and quality of life. Polymorbidity and polypharmacy predispose ACS patients to medication discrepancies between cardiologist‐prescribed medication and drug use by the patient, drug‐related problems (DRPs) and inadequate drug adherence. This study aimed to evaluate the impact of clinical pharmacist–provided services on the outcome of ACS patients. This was a prospective, randomized, controlled study on ACS patients participating in a cardiac rehabilitation programme. Forty ACS patients were randomly assigned to either control group, who received standard medical care, or intervention group, who received standard medical care plus clinical pharmacist–provided services. Services included DRP management, clinical assessment and enforcing the patient education and adherence. For both groups, the following were assessed at baseline and after 3 months: DRPs, adherence (assessed by 8‐item Morisky Adherence Questionnaire), patient's knowledge (assessed by Coronary Artery Disease Questionnaire), 36‐Short Form Health Survey (SF‐36), heart rate, systolic and diastolic blood pressure, low‐density lipoprotein (LDL), total cholesterol (TC) and fasting blood glucose (FBG). After 3 months, there was a significant difference between the intervention and control groups in the per cent change of DRPs (median: ?100 vs 5.882, P = 0.0001), patient's adherence score (median: 39.13 vs ?14.58, P = 0.0001), knowledge score (median: 30.28 vs ?5.196, P = 0.0001), SF‐36 scores, heart rate (mean: ?10.04 vs 6.791, P = 0.0001), diastolic blood pressure (mean: ?17.87 vs 10.45, P = 0.0001), systolic blood pressure (mean: ?16.22 vs 4.751, P = 0.0001), LDL (median: ?25.73 vs ?0.2538, P = 0.0071), TC (median: ?14.62 vs 4.123, P = 0.0005) and FBG (median: ?11.42 vs 5.422, P = 0.0098). Clinical pharmacists can play an important role as part of a cardiac rehabilitation team through patient education and interventions to minimize DRPs.     

Do capillary dried blood spot concentrations of gamma‐hydroxybutyric acid mirror those in venous blood? A comparative study

Gamma‐hydroxybutyric acid (GHB) is a well‐known illicit club and date‐rape drug. Dried blood spot (DBS) sampling is a promising alternative for classical venous sampling in cases of (suspected) GHB intoxication since it allows rapid sampling, which is of interest for the extensively metabolized GHB. However, there is limited data if ‐and how‐ capillary DBS concentrations correlate with venous concentrations. We conducted a comparative study in 50 patients with suspected GHB intoxication, to determine and to correlate GHB concentrations in venous DBS (vDBS) and capillary DBS (cDBS). This is the first study that evaluates in a large cohort the correlation between capillary and venous concentrations of an illicit drug in real‐life samples. Of the 50 paired samples, 7 were excluded: the vDBS concentration was below the LLOQ of 2 µg/mL in 3 cases and 4 samples were excluded after visual inspection of the DBS. Bland‐Altman analysis revealed a mean % difference of ‐2.8% between cDBS and vDBS concentrations, with the zero value included in the 95% confidence interval of the mean difference in GHB concentration. A paired sample t‐test confirmed this observation (p = 0.17). Also the requirement for incurred sample reproducibility was fulfilled: for more than two‐thirds of the samples the concentrations obtained in cDBS and those in vDBS were within 20% of their mean. Since equivalent concentrations were observed in cDBS and vDBS, blood obtained by fingerprick can be considered a valid alternative for venous blood for GHB determination. Copyright © 2015 John Wiley & Sons, Ltd.     

Drug‐resistant epilepsy and topiramate: Plasma concentration and frequency of epileptic seizures

Topiramate (TPM) is a second‐generation antiepileptic drug (AED), acting on drug‐resistant epilepsy. The aim of the study was to evaluate the influence of the dose, use of other AEDs on TPM plasma concentration (C_p), and frequency of epileptic seizures. A cross‐sectional analytical study was developed with patients aged 18‐60 years, for diagnosis of drug‐resistant epilepsy, using TPM in monotherapy or associated with other AEDs. The following variables were analyzed: age, frequency of epileptic seizures, pharmacotherapeutic regimen with its respective doses, adherence to medication treatment, and adverse events score. Thirty‐seven patients were included, 83.8% of the patients presented C_p below the therapeutic range. Multiple linear regression estimated that the increase of 1.0 mg/kg/d promoted an increase of 0.68 μg/mL in TPMC_p, while the use of inducers predicted a reduction of 2.97 μg/mL (P < .001). Multiple Poisson regression predicts that an increase of 1.0 μg/mL in TPMC_p decreased the patient's chance of presenting seizures, and patients using AED inducers were about ten times more likely to present seizures than those who do not use (P < .001). In addition, for patients using AED inducers with C_p below the therapeutic range, the mean number of seizures per month was greater than those with C_p within the therapeutic range. The prescribed dose and the use of AED inducers influence C_p of TPM, likewise the low C_p of first‐line AEDs and of the adjuvant in the treatment, TPM, as well as low TPM dose seem to affect the control of epileptic seizures.