Dried blood spot analysis for therapeutic drug monitoring of linezolid in patients with multidrug-resistant tuberculosis.

Linezolid is a promising antimicrobial agent for the treatment of multidrug-resistant tuberculosis (MDR-TB), but its use is limited by toxicity. Therapeutic drug monitoring (TDM) may help to minimize toxicity while adequate drug exposure is maintained. Conventional plasma sampling and monitoring might be hindered in many parts of the world by logistical problems that may be solved by dried blood spot (DBS) sampling. The aim of this study was to develop and validate a novel method for TDM of linezolid in MDR-TB patients using DBS sampling. Plasma, venous DBS, and capillary DBS specimens were obtained simultaneously from eight patients receiving linezolid. A DBS sampling method was developed and clinically validated by comparing DBS with plasma results using Passing-Bablok regression and Bland-Altman analysis. This study showed that DBS analysis was reproducible and robust. Accuracy and between- and within-day precision values from three validations presented as bias and coefficient of variation (CV) were less than 17.2% for the lower limit of quantification and less than 7.8% for other levels. The method showed a high recovery of approximately 95% and a low matrix effect of less than 8.7%. DBS specimens were stable at 37°C for 2 months and at 50°C for 1 week. The ratio of the concentration of linezolid in DBS samples to that in plasma was 1.2 (95% confidence interval [CI], 1.12 to 1.27). Linezolid exposure calculated from concentrations DBS samples and plasma showed good agreement. In conclusion, DBS analysis of linezolid is a promising tool to optimize linezolid treatment in MDR-TB patients. An easy sampling procedure and high sample stability may facilitate TDM, even in underdeveloped countries with limited resources and where conventional plasma sampling is not feasible.

Substantial skin disorders in psychiatric illness coincide with diabetes and addiction.

BACKGROUND: Dermatological diseases in psychiatric patients are common; however, epidemiological data on this subject are scarce and to our knowledge integral studies of dermatological disease in psychiatric inpatients are not available yet. AIM: The aim of this study was to describe the incidence of dermatological problems in psychiatric inpatients. METHOD: This study evaluates the consultations for new dermatological problems by inpatients of a general psychiatric hospital of over 700 beds during a 6-month period. RESULTS: A total of 255 patients consulted their physician because of a new dermatological problem. Diagnoses (n=360) included skin infections (32%), accidents (7%), decubitus ulcers (7%), complications of medical treatment (3%), auto mutilation (1%) and neoplasms of the skin (1%). Patients with skin infections were likely to have diabetes [odds ratio (OR)=3.6; 95% confidence interval (CI): 1.56-8.40]. Patients with decubitus ulcers were likely to have an addiction problem (OR=6.4; 95% CI: 1.46-28.00). Dermatitis was associated with affective disorder (OR=2.5; 95% CI: 1.12-5.43) but not with psychosis (OR=0.5; 95% CI: 0.23-0.90). Only a poor correlation existed between the length of hospital stay and skin problems. CONCLUSIONS: Dermatological problems are common in hospitalized psychiatric patients. Patients with diabetes mellitus are at high risk for skin infections. There are significant relationships between the psychiatric and the dermatological diagnoses. The length of the admission to a psychiatric hospital does not seem to play a major role in skin diseases.

Doctors' beliefs and knowledge on corticosteroid-induced osteoporosis: identifying barriers to improve prevention.

WHAT IS KNOWN AND OBJECTIVE: Despite the availability of effective treatments for the management of corticosteroid-induced osteoporosis (CIOP), the condition is undertreated. Our objective was to assess prescribers' knowledge and likely prescribing patterns concerning the diagnosis and treatment of CIOP. Another goal was to identify key barriers to the use of preventive therapy in patients using long-term corticosteroids. METHODS: We used a postal survey of general practitioners (GPs) and specialists in the Netherlands. The survey comprised of questions on: demographic data, perceived barriers to the use of preventive therapy for CIOP, and knowledge of diagnosis and treatment of CIOP. Case scenarios were questioned to assess practice patterns. RESULTS: Responding prescribers correctly answered an average of 55% of knowledge questions and 69% of case scenarios. Multiple questions and cases showed that knowledge on the use of bone mineral density (BMD) determination was poor. BMD was determined in patients who, according to the national osteoporosis guideline, should be treated with bisphosphonates independent of BMD. Moreover, only 18% of doctors correctly answered that the BMD cutoff in CIOP patients is a T-score of ≤-1 or ≤-1·5. Key barriers identified were: (i) GPs, significantly more than specialists, consider prescription of preventive therapy the responsibility of another doctor; (ii) discontinuation of anti-resorptive medication due to adverse effects and (iii) the reluctance to prescribe preventive therapy in patients already prescribed multiple medications. WHAT IS NEW AND CONCLUSION: Doctors did not identify many barriers to the prescribing of anti-resorptive therapies. Lack of knowledge, especially concerning use of BMD-results, likely led to the under-treatment of the presented patients.

Missense polymorphisms in three oxidative-stress enzymes (GSTP1, SOD2, and GPX1) and dyskinesias in Russian psychiatric inpatients from Siberia.

Neuronal degeneration due to oxidative stress (OS) has been proposed as a mechanism for tardive dyskinesia (TD) pathogenesis. Cellular defense mechanisms against OS may involve detoxification enzymes (e.g., glutathione peroxidase-1, GPX1; superoxide dismutase-2, SOD2 [also commonly known as MnSOD]; and glutathione S-transferase P1, GSTP1). Several pharmacogenetic studies have examined TD and OS in different ethnic groups, but not in Russians. Here we report the association between orofaciolingual (TDof) and limb-truncal dyskinesias (TDlt) and polymorphisms of GSTP1 (Ile105Val), MnSOD (Ala-9Val), and GPX1 (Pro197Leu) genes in 146 Russian inpatients from Siberia. We applied AIMS instrument to rate dyskinesias. Two-part model analyses, logistic and multivariate parametric regressions were applied to assess the effects of different variables (e.g., genotype, age, gender, and medication use). Our analyses do not suggest that Pro197Leu (GPX1) is associated with TD. However, our analyses suggest that the 105Val-allele of Ile105Val (GSTP1) may be associated with a lower risk and a severity of TDof and TDlt and that Ile105Val pharmacogenetics may be different in Slavonic Caucasians from that in American Caucasians. Furthermore, we find evidence for an association between Ala-9Val (MnSOD) and TDof, but not TDlt. Subject to further replication, our findings extend the available knowledge on the pharmacogenetics of TD and oxidative stress.

Skin disorders in chronic psychiatric illness.

BACKGROUND: Chronic psychiatric patients are prone to develop skin diseases. However, epidemiological data are scarce. OBJECTIVE: To describe the prevalence of skin complaints and dermatological disorders in residential psychiatric patients. METHODS: Ninety-one randomly chosen patients of the residential wards of a general psychiatric hospital completed a short, structured interview concerning skin disease and underwent a physical examination of the skin. RESULTS: Of the examined patients, 69% reported symptoms of skin disease in the month prior to the interview and 77% had skin disorders at physical examination. In 34 (37%) patients, skin disorders were diagnosed, which were not mentioned in the interview. Patients with diabetes had infectious skin disease more often than their fellow patients [odds ratio (OR) 10.9; 95% confidence interval (CI): 2.40-49.75]. Moreover, overweight patients had infectious skin disease more often (OR 7.4; 95% CI: 1.38-39.3). Women reported more skin complaints (OR 6.4: 95% CI: 1.67-24.2), and also had skin problems other than infection, tumours or dermatitis more frequently (OR 3.7; 95% CI: 1.34-10.14). Clozapine use was associated with benign neoplasms of the skin. The nature of this association remains unclear and merits further investigation. CONCLUSIONS: Many chronic psychiatric patients have skin problems. Clinical examination of the skin is important to discover these problems. Patients with diabetes mellitus are particularly at risk for skin infections. Because of their relationship with overweight and diabetes mellitus, atypical antipsychotics may be partly responsible for these serious complications. Only a few other relationships between psychiatric medication and specific skin problems were found.

A randomised controlled trial on the efficacy and tolerability with dose escalation of allopurinol 300-600 mg/day versus benzbromarone 100-200 mg/day in patients with gout.

OBJECTIVES: To compare the efficacy and tolerability of allopurinol 300-600 mg/day versus benzbromarone 100-200 mg/day used to attain a target serum urate concentration (sUr) < or =0.30 mmol/l (5 mg/dl). METHODS: A randomised, controlled, open-label, multicentre trial in gout patients with renal function defined as a calculated creatinine clearance > or =50 ml/min. Patients were treated with 300 mg allopurinol or 100 mg benzbromarone once a day (stage 1). If sUr < or =0.30 mmol/l was not attained after 2 months, the dose was doubled to allopurinol 300 mg twice a day or benzbromarone 200 mg once a day (stage 2). The primary end point was treatment success in either of the two stages, defined as clinical tolerability and attainment of biochemical target sUr. RESULTS: Sixty-five patients were enrolled in stage 1; 36 received allopurinol and 29 received benzbromarone. Fifty-five patients (85%) were analysed at stage 1: the success rates were 8/31 (26%) and 13/25 (52%), respectively, and the difference was -0.26 (95% CI from -0.486 to -0.005), p = 0.049. At stage 2, the success rates were 21/27 (78%) and 18/23 (78%), respectively, and the difference was -0.005 (95% CI from -0.223 to 0.220), p = 1.00. Two patients stopped receiving allopurinol and three stopped receiving benzbromarone because of adverse drug reactions. CONCLUSIONS: Increasing the allopurinol dose from 300 to 600 mg/day and the benzbromarone dose from 100 to 200 mg/day according to the target sUr produced significantly higher success rates (both 78% successful in attaining sUr < or =0.30 mmol/l). No significant differences in treatment success between benzbromarone and allopurinol were found after dose escalation. TRIAL REGISTRATION NUMBER: ISRCTN49563848).

Efficacy and tolerability of urate-lowering drugs in gout: a randomised controlled trial of benzbromarone versus probenecid after failure of allopurinol.

OBJECTIVES: To investigate the efficacy and tolerability of allopurinol as the first-choice antihyperuricaemic treatment for gout, and compare the efficacy and tolerability of benzbromarone and probenecid as second-choice treatment. METHODS: Prospective, multicentre, open-label, two-stage randomised controlled trial in gout patients with normal renal function. Enrolled patients were given 300 mg allopurinol for 2 months (stage 1). Those patients who could not tolerate allopurinol or who did not attain the target serum urate concentration (sUr) < or=0.30 mmol/l (5.0 mg/dl), which was defined as successful, were randomised to benzbromarone 200 mg/day or probenecid 2 g/day for another 2 months (stage 2). RESULTS: 96 patients were enrolled in stage 1. 82 patients (85%) were eligible for the analysis at the end of stage 1: there was a mean (SD) decrease in sUr concentration of 35 (11)% from baseline; 20 patients (24%) attained target sUr < or=0.30 mmol/l; and 9 patients (11%) stopped allopurinol because of adverse drug reactions. 62 patients were enrolled in stage 2. 27 patients received benzbromarone (3 patients not eligible for analysis) and 35 received probenecid (4 patients not eligible for analysis). Treatment with benzbromarone was successful in 22/24 patients (92%) and with probenecid in 20/31 patients (65%) (p = 0.03 compared with benzbromarone). Compared with baseline values, there was a mean (SD) decrease of sUr concentration of 64 (9)% with benzbromarone and 50 (7)% with probenecid (p<0.001). CONCLUSION: This study showed that allopurinol 300 mg/day has a poor efficacy and tolerability profile when used to attain a biochemical predefined target level of sUr < or =0.30 mmol/l, following 2 months of treatment. In stage 2, benzbromarone 200 mg/day was more effective and better tolerated than probenecid 2 g/day.

Tardive dyskinesia and DRD3, HTR2A and HTR2C gene polymorphisms in Russian psychiatric inpatients from Siberia.

BACKGROUND: Pharmacogenetics of tardive dyskinesia and dopamine D3 (DRD3), serotonin 2A (HTR2A), and 2C (HTR2C) receptors has been examined in various populations, but not in Russians. PURPOSE: To investigate the association between orofaciolingual (TDof) and limb-truncal dyskinesias (TDlt) and Ser9Gly (DRD3), -1438G>A (HTR2A), and Cys23Ser (HTR2C) polymorphisms in Russian psychiatric inpatients from Tomsk, Siberia. METHODS: In total, 146 subjects were included. Standard protocols were applied for genotyping. TDof and TDlt were assessed with AIMS items 1-4 and 5-7, respectively. Two-part model, logistic and log-normal regression analyses were applied to assess different variables (e.g., allele-carriership status, age, gender, and medication use). RESULTS: TDlt, but not TDof, exhibited an association with Ser9Gly and Cys23Ser (with 9Gly and 23Ser alleles exhibiting opposite effects). However, -1438G>A was not associated with TDof and Dlt. CONCLUSIONS: This is the first pharmacogenetic report on tardive dyskinesia in Russians. Subject to further replication, our findings extend and support the available data.

The role of dopamine D3, 5-HT2A and 5-HT2C receptor variants as pharmacogenetic determinants in tardive dyskinesia in African-Caribbean patients under chronic antipsychotic treatment: Curacao extrapyramidal syndromes study IX.

Tardive dyskinesia (TD) is associated with polymorphisms of the dopamine D(3), serotonin 2A and 2C receptors (DRD3, HTR2A and HTR2C, respectively). This study investigated the possible relationship between TD and the polymorphisms Ser9Gly (DRD3), 102T>C (HTR2A), -1438G>A(HTR2A) and Cys23Ser (HTR2C) in African-Caribbean inpatients. One hundred and twenty-six patients under chronic antipsychotic treatment were genotyped. The assessment of TD was carried out with the abnormal involuntary movement scale (AIMS). The relationships between the carriership of the least frequent alleles and the respective orofaciolingual dyskinesia (TDof) (sum of the items 1-4 of the AIMS), limb-truncal dyskinesia (TDlt) (sum of items 5-7 of the AIMS) and TD (sum of items 1-7 of the AIMS) were analyzed with ANCOVA, comparing means with age as a covariate and stratification for carriers and non-carriers of the mutations. In addition, we conducted pre-planned t-tests to compare AIMS values of carriers of the combinations of alleles versus the corresponding non-carriers. In the study population, females with 9Ser carriership exhibited higher AIMS values than non-carriers. Male subjects with 9Ser carriership in combination with 23Ser or -1438A carriership exhibited higher AIMS values. In male patients also, the combination of 23Ser and -1438A carriership increased TD. The study clearly shows that the African-Caribbean population differs from the Caucasian population with regard to the association of TD with the polymorphisms studied and suggests that the association of TD with the studied polymorphisms of the 5-HT(2C) and probably of the 5-HT(2A) receptor are the result of a changed susceptibility of the patients, independent of the action of the antipsychotics on these receptors.

Interventies na een gestructureerde medicatie-analyse door klinisch geriater en ziekenhuisapotheker bij klinisch opgenomen kwetsbare oudere patiënten.

EFFECTS OF A STRUCTURED MEDICATION REVIEW BY GERIATRICIAN AND CLINICAL PHARMACOLOGIST ON APPROPRIATENESS OF PHARMACOTHERAPY OF FRAIL ELDERLY INPATIENTS: Objective To study the results of a structured medication review of geriatric inpatients by both geriatrician and hospital pharmacist/clinical pharmacologist. Methods Patients who were present at the geriatric ward were eligible for a review of their medication and medical problems using a screening form. Recommendations and questions following these forms were subsequently discussed in the gerontopharmacologic meeting ('GFO') held every two weeks. Results In a 30 month-period 44 GFO's were held during which 184 patients were discussed. A total of 206 recommendations were made and 115 questions were asked. Of the recommended interventions,134 (65%) were accepted by the geriatrician. To stop a medication (64/206), to change the dosage of a medication (60/206) and to switch to another medication (44/206) were the types of interventions most accounted for. Conclusion Structured medication review led to a substantial number of medication changes in geriatric inpatients. Nearly two-thirds of the recommended interventions were accepted by the geriatricians. Seventy-two recommendations (35%) were not implemented due to logistic or patient-related reasons.

[Effects of a structured medication review by geriatrician and clinical pharmacologist on appropriateness of pharmacotherapy in frail elderly inpatients]. / Interventies na een gestructureerde medicatie-analyse door klinisch geriater en ziekenhuisapotheker bij klinisch opgenomen kwetsbare oudere patiënten.

OBJECTIVE: To study the results of a structured medication review of geriatric inpatients by both geriatrician and hospital pharmacist/clinical pharmacologist. METHODS: Patients who were present at the geriatric ward were eligible for a review of their medication and medical problems using a screening form. Recommendations and questions following these forms were subsequently discussed in the gerontopharmacologic meeting ('GFO') held every two weeks. RESULTS: In a 30 month-period 44 GFO's were held during which 184 patients were discussed. A total of 206 recommendations were made and 115 questions were asked. Of the recommended interventions,134 (65%) were accepted by the geriatrician. To stop a medication (64/206), to change the dosage of a medication (60/206) and to switch to another medication (44/206) were the types of interventions most accounted for. CONCLUSION: Structured medication review led to a substantial number of medication changes in geriatric inpatients. Nearly two-thirds of the recommended interventions were accepted by the geriatricians. Seventy-two recommendations (35%) were not implemented due to logistic or patient-related reasons.

Systematic review of trends in prophylaxis of corticosteroid-induced osteoporosis: the need for standard audit guidelines.

UNLABELLED: Corticosteroid-induced osteoporosis (CIOP) is currently undertreated. Systematic review of the literature revealed that the percentage of patients treated adequately is dependent on study quality. Therefore, it remains unknown whether adherence to the guidelines is really so poor. Five major quality criteria provide the standard for future studies on this scope. INTRODUCTION: It has recently been stated that the degree of prophylaxis of corticosteroid-induced osteoporosis (CIOP) is low and effort should be put into determining reasons for non-prescribing of preventive agents. The aim of this study was to identify: how many studies adequately audit the prevalent guideline; the longitudinal trends in prevention of CIOP; which patient groups appear to be most undertreated; and which intervention strategies are effective. METHODS: We performed a comprehensive search of MEDLINE and systematically recorded the outcomes and quality of published studies, using five major criteria. RESULTS: Twenty-four studies were included in the analysis. The quality of the included studies was poor (31%) or moderate (37%). There was a longitudinal increase in quality of the studies and percentage of prevention. Multivariable linear regression showed that the quality of the study was the only independent predictor of the prevention rate reported in the study. CONCLUSIONS: The results show undertreatment of CIOP might be due to insufficient quality of the studies rather than poor practice or failure to recognise the right patients. Future interventions should comply with five major quality criteria, and a multifaceted approach is required in order to make an impact on the underprescribing of CIOP prophylaxis.

A cross-sectional study of prescribing patterns in chronic psychiatric patients living in sheltered housing facilities.

OBJECTIVE: To analyze prescribing patterns of chronic psychiatric patients living in sheltered housing facilities, to identify the extent of polypharmacy and to estimate associated risks in this patient group. METHODS: In a retrospective cross-sectional study the prescription data of 323 chronic psychiatric patients (average age 48.5 years) living in sheltered housing facilities in Rotterdam, The Netherlands, were analyzed. Prescription data were obtained from pharmacy-dispensing records. RESULTS: Patients received on average 4.6 drugs (95% CI, 4.3-4.9). The most frequently prescribed drugs were as expected antipsychotics, benzodiazepines and antimuscarinic drugs. Overall 25% (n=81) of patients received two or more antipsychotic drugs. A high proportion of patients (38%, n=124) received one benzodiazepine, and 15% (n=50) received two or more benzodiazepines. CONCLUSION: Patients in our study received a worryingly high number of drugs, and a quarter of the population was subject to antipsychotic polypharmacy. This increases the risk that drug-drug interactions, adverse drug reactions and noncompliance occur. Our study indicates potentially low quality of prescribing and shows the need for reviewing and special monitoring of pharmacotherapy in this patient group.

Treatment of pregnant and non-pregnant rheumatic patients: a survey among Dutch rheumatologists.

BACKGROUND: The aim of this study was to explore, among Dutch rheumatologists, aspects such as attitude towards guidelines, pharmacotherapy and information needs in the treatment of pregnant as well as non-pregnant rheumatoid arthritis (RA) patients. METHODS: Fifteen rheumatologists from nine different hospitals were interviewed by means of a semi-structured interview. Questions addressing attitude towards guidelines, pharmacotherapy preferences and information needs with respect to the pregnant and non-pregnant patient were asked. The analysis will be based on descriptive statistics. RESULTS: Guidelines are used by almost half of the hospitals with respect to pregnant RA patients and by all hospitals for RA patients in general. With respect to pregnant women, nine respondents preferred stopping the medication as soon pregnancy is known. When treating RA patients, in general sulfasalazine and methotrexate would be drugs of first choice. Information is found in international and national books and guidelines. CONCLUSION: Dutch rheumatologists are of the view that there is sufficient information on the treatment of RA in pregnant women or women wishing to become pregnant, except for safe use of medication during pregnancy. In the future, pregnancy risk categorization should be updated and discussed regularly. This should be based on more recent literature and experience. A good monitoring system for following all young patients with a rheumatic disease should be set up as a first step to collect more information on the safe use of medication during pregnancy.

Trends in direct oral anticoagulant (DOAC) use: health benefits and patient preference.

In 2012, the Dutch Health Council published a report addressing barriers for an early and broad introduction of direct oral anticoagulants (DOACs). The report raised concerns about the lack of an antidote, adherence, lack of monitoring in the case of overdose and the increased budget impact at DOAC introduction. In the past decade, international studies have shown that DOACs can provide healthcare benefits for a large number of patients. This has led to an increase in the prescription of DOACs, as they are an effective and user-friendly alternative to vitamin K antagonists (VKAs). Unlike VKAs, DOACs do not need monitoring of the international normalized ratio due to more predictable pharmacokinetics. However, the number of prescriptions of DOACs in the Netherlands is still lagging, compared to other European countries. This article highlights the potential health gains in the Netherlands if the use of DOACs were to increase, based on current international experience.

['Red yeast rice' as a cholesterol-lowering substance?Caution is warranted]. / 'Rode gist rijst' als cholesterolverlager?

- In various non-medical publications, red yeast rice (red fermented rice, RYR) is recommended as a cholesterol-lowering substance. This supplement contains a naturally occurring statin, namely monacolin K.- Patients who wish to use RYR should be advised to only take products from reputable pharmaceutical companies. Pharmacists can provide advice on this.- Users of RYR should be alerted to the potential drug interactions and serious risks associated with its use during pregnancy.- RYR appears to be better tolerated than statins. This difference in tolerance can be traced back to the applied dosages. On average, the daily RYR dosage contains less statin than the standard dosage for statins.- The Netherlands Food and Consumer Product Safety Authority should urgently test the RYR supplements available in the Netherlands to gain more insight into the quality of said products.- Mandatory registration of RYR as an herbal medicine appears necessary to guarantee the quality of, and monacolin levels in, the products and to reduce health risks.

Optimization of vitamin K antagonist drug dose finding by replacement of the international normalized ratio by a bidirectional factor: validation of a new algorithm.

UNLABELLED: ESSENTIALS: We developed a new algorithm to optimize vitamin K antagonist dose finding. Validation was by comparing actual dosing to algorithm predictions. Predicted and actual dosing of well performing centers were highly associated. The method is promising and should be tested in a randomized trial. BACKGROUND: Oral vitamin K antagonists (VKAs) have a narrow therapeutic window and thus require frequent monitoring of its intensity by the international normalized ratio (INR). Improvement of VKA dosing defined as more time in therapeutic range (TTR) can reduce thrombotic disease and bleeding. Computerized decision support programs (CDSs) are used to optimize VKA dosing, but the effects are heterogeneous. CDSs significantly improve the proportion of time in the therapeutic INR range for initiation therapy but not the quality of anticoagulant management in an outpatient setting. One of the major problems of VKA dose finding is that the INR is a ratio and does not present linearity. We developed a new dose-finding algorithm, based on a novel bidirectional factor (BF). This BF is linear transformation of the nonlinear INR. METHODS: We compared the outcomes of the new algorithm, called BF-N, with dose finding performed at three highly ranked Dutch anticoagulation centers, using both acenocoumarol and phenprocoumon. RESULTS: The outcomes of the BF-N algorithm showed a linear correlation with VKA doses of the three centers (y = 1.001x, r(2) 0.999 for acenocoumarol and y = 0.999x, r(2) 0.999 for phenprocoumon), with a standard deviation of 3.83%. The rate of automated dosage proposals increased to 100%. CONCLUSION: The BF-N algorithm performs well in real-life settings and increases the rate of automated dosage proposals. The algorithm can be easily built into existing CDSs. Experienced staff remains necessary for complicated situations. The new algorithm needs to be evaluated in a prospective trial.

[5-HT3-antagonists as a substitute for metoclopramide and domperidone: a literature review]. / 5-HT3-receptorantagonisten als vervangers van metoclopramide en domperidon.

OBJECTIVE: To investigate whether the anti-emetics metoclopramide and domperidone can be replaced by 5-HT3-antagonists, as side effects restrict use of these dopamine antagonists. DESIGN: Systematic review. METHOD: We searched the Embase and PubMed databases for articles published in the period 1995-October 2015, in which the efficacy or side effects of metoclopramide or domperidone were compared with at least one of the 5-HT3-antagonists ondansetron, granisetron, tropisetron or palonosetron. These had to be randomised controlled clinical studies into the known indications for metoclopramide and domperidone for prevention and treatment of nausea and vomiting. Two reviewers independently selected articles based on the title and abstract, then assessed for eligibility based on the full texts. RESULTS: In total, 56 articles were included in this review. The conclusion in 51 studies was that the efficacy of 5-HT3-antagonists in nausea and vomiting is comparable or even superior to that of metoclopramide. Metoclopramide more often caused extrapyramidal side effects; 5-HT3-antagonists were more likely to cause headaches and constipation. The majority of the studies compared metoclopramide with ondansetron. None of the articles studied palonosetron, and only one study compared domperidone with a 5-HT3-antagonist. CONCLUSION: We found enough evidence to presume that metoclopramide can be replaced by 5-HT3-antagonists for preventing delayed chemotherapy-induced nausea and vomiting and for prophylaxis or treatment of postoperative nausea and vomiting. More research is needed into the other indications and into the substitutability of domperidone.

Thiopurines in inflammatory bowel disease: pharmacogenetics, therapeutic drug monitoring and clinical recommendations.

There is a growing interest in the use of thiopurines (azathioprine, 6-mercaptopurine and 6-thioguanine) for the management of inflammatory bowel disease. The genetically controlled thiopurine (S)-methyltransferase enzyme is involved in the metabolism of these agents and is hypothesised to determine the clinical response to thiopurines. Diminished activity of this enzyme decreases the methylation of thiopurines, theoretically resulting in potential overdosing, while high thiopurine (S)-methyltransferase status leads to overproduction of toxic metabolites and ineffectiveness of azathioprine and 6-mercaptopurine. In practice, controversies exist regarding the utility of standard thiopurine (S)-methyltransferase pheno- and genotyping. Current pharmacogenetic insights suggest that another enzyme system may participate in the efficacy and toxicity of thiopurines; inosine triphosphate pyrophosphatase. Other topics discussed in this review are the utilisation of therapeutic drug monitoring and the experimental use of 6-thioguanine in the treatment of inflammatory bowel disease. 6-Thioguanine has a less genetically controlled metabolism and skips genetically determined metabolic steps. On theoretical basis, 6-thioguanine might therefore have a more predictable profile than azathioprine and 6-mercaptopurine. However, the use of 6-thioguanine has been associated with an increased risk of nodular regenerative hyperplasia of the liver and veno-occlusive disease. Further research is warranted before 6-thioguanine can be considered as a treatment option for inflammatory bowel disease.

[Appropriate choice of drugs in older patients]. / De juiste keuze van geneesmiddelen bij ouderen.

Older patients use many drugs, while there is hardly any information about the effect and safety of these in elderly patients. It appears that only 56%, and 20% of the information required by the European Medicines Agency (EMA) concerning use of medication in the elderly is stated in the patient information leaflet and in the Dutch Pharmacotherapeutic Compass, respectively. The Expertise Centre PHarmacotherapy in Old Persons (Ephor) gathered all available information about drug prescribing in older patients for a number of drug groups from national and international literature, and provided prescribing advice. This information will be made available to users of the Dutch Pharmacotherapeutic Compass, for quick accessibility.