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Severe infectious diseases result in an increased volume of distribution. Renal function is usually impaired, but can in fact be increased early in the course of the disease. In renally cleared drugs with a small therapeutic index a dose reduction should take place or these medications should be temporarily discontinued. Renally cleared antibiotics may be subject to subtherapeutic levels of antibiotics, especially early in the course of the disease. Diuretics and RAAS inhibitors should usually be interrupted during acute illness; bèta-blockers should be continued. Statins can usually be continued. Paracetamol can usually be prescribed. NSAIDs, however, are almost always contra-indicated. Patients with chronic use of corticosteroids should receive a stress dose. There is no evidence to support discontinuing immunosuppressants. Platelet aggregation inhibitors and directly acting oral anticoagulants are continued, whereas coumarins should be monitored vigorously or substituted for low molecular weight heparins.

In this commentary we discuss the findings of the recently published OPTiMiSE trial. In terms of design, important advantages of the trial are the naturalistic, open label set-up that allowed the authors to assess the efficacy of the sequential use of amisulpride followed by olanzapine and clozapine. In terms of results, we highlight the efficacy of amisulpride, while we disagree with the authors of OPTiMiSE when they claim clozapine should be tried in the clinic after one unsuccessful trial of amisulpride. We also show how the actual percentages of those complaining of sexual side effects during amisulpride use are higher than computed by the authors. On a general note, we suggest that whenever symptoms of patients allow it - and gradual improvement is observed - clinicians may wish to wait several weeks before considering a switch to amisulpride.

Serotonin syndrome is a medication-induced clinical syndrome, caused by an increased concentration of serotonin in the central and peripheral nervous system. An excess of serotonin can be caused by the use of one or more serotinergic substances on the one hand, or by decreased clearance of these substances on the other hand We carried out a systematic literature search to make an estimation of substances and patient-related factors that might be associated with an increased risk of serotonin syndrome. We also carried out a search for all reports of serotonin syndrome in the Lareb (Netherlands pharmacovigilance centre) database. Patient-centred medication monitoring is not yet possible because there is an almost complete lack of clinical predictors. For the time being, all that treatment providers can do to help recognise serototin syndrome on time is to be extra alert in patients belonging to risk groups (the elderly, or patients with renal or hepatic insufficiency.

An important goal in medicine is to provide patients with individualised and personalised treatment. Personalised medicine is making an important contribution.To summarise developments in the field of personalised medicine in rheumatology.We review the results so far and discuss what developments we can expect in the future.In rheumatology there have been advances in three main areas: 1. therapeutic drug monitoring (measuring medication levels and using the results as a guide for further treatment); 2. the use of biomarkers to determine which drugs should be selected or which should be stopped; 3. involvement of the patient's own observations concerning treatment options.Personalised medicine is being used increasingly in rheumatology.

OBJECTIVE: To determine the relation between tacrolimus trough levels in blood and adverse events in paediatric liver transplantation. Although therapeutic drug monitoring plays an important role in daily practice, there is no general agreement on the therapeutic window in children. DESIGN AND METHODS: A retrospective cohort study was conducted by chart review of liver transplant recipients with an age under 18 years. The main study parameter was the occurrence of adverse events in relation to trough levels of tacrolimus. These events were categorized for severity according to the Common Criteria for Adverse Events, and assessed for causality using the Naranjo scale in a multidisciplinary approach. RESULTS: Data of 22 patients were analyzed, resulting in an average of 7 adverse events per patient during follow-up. Infection and gastro-intestinal toxicity occurred most frequently. Rejection represented 4% of the total number of identified adverse events. The mean tacrolimus trough level at the time of toxicity was 10.8 μg/L and was significantly different from the trough level when no adverse event occurred (8.6 μg/L). CONCLUSION: There is a relation between tacrolimus trough level in blood and adverse events. This suggests that accurate therapeutic drug monitoring is essential for the use of tacrolimus in immunosuppressive treatment. The used regimens for tacrolimus are probably excessive and should be reconsidered using results of prospective research.

The Summary of Product Characteristics (Smpc) for psychotropic drugs includes instructions for clinical and biomarker monitoring intended to optimise effectiveness and minimise harm.br/To evaluate which monitoring instructions are given in the Smpc and to assess the applicability in clinical practice.br/The reasons and requirements for monitoring in Smpcs for psychotropic drugs were assessed and somatic parameters were distinguished from non-somatic parameters, thereby the applicability was assessed.br/An average of 3.3 instructions per drug label was found. Monitoring was primarily for safety reasons (78%). Requirement was predominantly mandatory (71%). Somatic parameters were most often mentioned (80%). Only 34% of the instructions were determined applicable.br/Monitoring instructions for psychotropic drugs are aimed at improving safe use. However, most instructions on monitoring do not provide sufficient information to be applicable in clinical practice.

OBJECTIVE To assess target attainment of busulfan exposure using a new model-based dosing regimen and therapeutic drug monitoring (TDM). Busulfan is an alkylating drug used in conditioning regimens for allogeneic haematopoietic cell transplantation (allo-HCT). Its narrow therapeutic range in combination with large interindividual variability in exposure, even after intravenous administration, necessitates dose individualization. DESIGN Prospective cohort study. METHODS All children who underwent allo-HCT in 2011 or 2012 receiving busulfan-based conditioning were included. Intravenous busulfan was administered once daily on four consecutive days and drug levels were measured on days 1 and k. For each patient a 'hypothetical' exposure (cAUC) without TDM was determined by extrapolating the AUC of day 1. The 'true' cAUC was then estimated based on pharmacokinetic data obtained on days 1-4 including TDM-based dose adjustment. Means and ranges were compared between cAUCs determined with and without TDM-based dose corrections. Also target attainment rates (cAUC 80-100 mg-h/L] were compared between 'hypothetical' and 'true' exposure. RESULTS 50 patients were included. Without TDM mean cAUC was 85.3 mg-h/L versus 96.2 mg-h/L with TDM. The range in individual cAUCs was significantly larger without TDM than with TDM IP = 0.001 ). Without TDM 34% of patients reached target cAUC and with TDM this significantly increased to 70% of patients (P = 0.0011. CONCLUSION The weight-based dosing regimen overall led to a mean busulfan exposure within the target range, yet the interindividual variation was substantial. Therefore, TDM of intravenous busulfan remains recommended and is of utmost importance to reach optimal target exposure in order to optimize HCT outcomes.

OBJECTIVE To assess target attainment of busulfan exposure using a new model-based dosing regimen and therapeutic drug monitoring (TDM). Busulfan is an alkylating drug used in conditioning regimens for allogeneic haematopoietic cell transplantation (allo-HCT). Its narrow therapeutic range in combination with large interindividual variability in exposure, even after intravenous administration, necessitates dose individualization. DESIGN Prospective cohort study. METHODS All children who underwent allo-HCT in 2011 or 2012 receiving busulfan-based conditioning were included. Intravenous busulfan was administered once daily on four consecutive days and drug levels were measured on days 1 and k. For each patient a 'hypothetical' exposure (cAUC) without TDM was determined by extrapolating the AUC of day 1. The 'true' cAUC was then estimated based on pharmacokinetic data obtained on days 1-4 including TDM-based dose adjustment. Means and ranges were compared between cAUCs determined with and without TDM-based dose corrections. Also target attainment rates (cAUC 80-100 mg-h/L] were compared between 'hypothetical' and 'true' exposure. RESULTS 50 patients were included. Without TDM mean cAUC was 85.3 mg-h/L versus 96.2 mg-h/L with TDM. The range in individual cAUCs was significantly larger without TDM than with TDM IP = 0.001 ). Without TDM 34% of patients reached target cAUC and with TDM this significantly increased to 70% of patients (P = 0.0011. CONCLUSION The weight-based dosing regimen overall led to a mean busulfan exposure within the target range, yet the interindividual variation was substantial. Therefore, TDM of intravenous busulfan remains recommended and is of utmost importance to reach optimal target exposure in order to optimize HCT outcomes.

Objective: To describe the frequency, nature, determinants and clinical relevance of prescription modifications in a Dutch community pharmacy. Design: A descriptive, retrospective study of the documented prescription modifications during dispensing in 2007. Methods: The frequency and nature of prescription modifications and their patient, drug and prescriber related determinants were assessed. To examine the clinical value of pharmacists' interventions, each prescription modification was rated from A to D (A is clinically irrelevant, D is clinically relevant with possible fatal consequences for the patient). Results: In 2007, on average, one intervention was documented per workday. Almost 50% of all interventions concerned dose corrections. Prescriptions for incidental medications, children (0-20 year) and patients with less than four other medications, had a higher chance of modification. A higher chance of prescription modifications was found in anti-infective agents for systemic use, in treatments for the central nervous system and the sensory organs. Verification and attentiveness to the prescriptions of these risk groups can reduce (serious) clinical consequences. Of all prescription modifications 86% were clinically relevant (groups B, C and D) and every ten days at least one harmful clinical incident was prevented by prescription modifications. Conclusions: Modifications of prescriptions by pharmacists vary in nature from clinically irrelevant to potentially fatal. Analysis of documented interventions in one community pharmacy allows identification of patients who are at risk and need more attention from prescribing physicians. It also shows that pharmacists' interventions have a positive impact on patients' health.

There are a number of effective but highly toxic drugs that exhibit a narrow therapheutic index and marked intersubject pharmacokinetic variability. Optimal therapy with such drugs requires therapeutic drug monitoring (TDM) in order to safely obtain the desired clinical effects. A systematic review was carried out to document the cost-effectiveness of TDM. The Cochrane database and Medline were searched. Reference lists of articles found were searched manually for relevant articles. Very few studies are performed that document the cost-effectiveness of TDM. Only for aminoglycosides it has been demonstrated that TDM is cost-effective. For the other classes of TDM drugs, its rationale has been made plausible, but cost-effectiveness has not been investigated. Since the use of many of these drugs would contain risks of underdosing or overdosing without TDM, emphasis should not be placed on its cost-effectiveness, but rather on how to use it in the most cost-effective and clinically effective manner possible.

There are a number of effective but highly toxic drugs that exhibit a narrow therapeutic index and marked intersubject pharmacokinetic variability. Optimal therapy with such drugs requires therapeutic drug monitoring (TDM) in order to safely obtain the desired clinical effects. A systematic review was carried out to document the cost-effectiveness of TDM. The Cochrane database and Medline were searched. Reference lists of articles found were searched manually for relevant articles. Very few studies are performed that document the cost-effectiveness of TDM. Only for aminoglycosides it has been demonstrated that TDM is cost-effective. For the other classes of TDM drugs, its rationale has been made plausible, but cost-effectiveness has not been investigated. Since the use of many of these drugs would contain risks of underdosing or overdosing without TDM, emphasis should not be placed on its cost-effectiveness, but rather on how to use it in the most cost-effective and clinically effective manner possible.

The importance of dose adjustments of antimicrobials based on measured concentrations in an individual ('therapeutic drug monitoring', TDM) is increasingly recognized. There are several reasons for this. First, there is a better understanding of the relationships between doses administered, concentrations achieved and effects of antimicrobials. Second, adverse events from antimicrobials and their relationship to drug concentrations are better described. Third, analytical methods to measure concentrations have become more widely available. In this article, we provide an overview of the situation of available antimicrobials in the Netherlands for which TDM is or could be indicated.

The goal of therapeutic drug monitoring (TDM) is to maximise the effect of drug therapy and to minimise toxicity. TDM is meaningful if on the one hand there is a relationship between the serum concentration of the drug and its effect and on the other hand there is no obvious relationship between dose and efficacy due to wide interindividual variability in pharmacokinetics. In case of digoxin, phenytoin, carbamazepine and valproic acid interindividual pharmacokinetics can vary to such an extent, that drug therapy should be guided by determination of serum drug levels.

Plasma levels can be used to monitor the clinical efficacy of tricyclic antidepressants (TCAs). In practice, the interpretation of plasma levels can be problematical, for several reasons: varying time-intervals between ingestion and blood sampling, the number of times per day a particular antidepressant is administered, the presence of active metabolites and the use of slow-release substances.To present realistic recommendations regarding the interpretation of plasma levels of TCA in clinical practice.We studied the relevant literature.On the basis of the literature we make the following recommendations

The use of antipsychotics can lead to the development of obesity, dyslipidemia, hypertension and hyperglycemia, risk factors for diabetes mellitus type 2 and cardiovascular diseases.To find out whether patients suffering from psychoses and schizophrenia and taking antipsychotics should be monitored systematically and periodically for the risk factors for and complications of the above-mentioned diseases.A written survey was conducted among the relatives of users of antipsychotics, relatives being members of the Ypsilon association in the Limburg region.Seventy-eight relatives (27%) returned the forms. Compared to the Dutch population, the risk factor for high blood pressure was remarkably common in the 20-30 age group. In the group of persons aged 30-40 obesity occurred surprisingly frequently; remarkably frequent too was diabetes in the 40-50 age group. At each monitoring session 27% of the users were checked on all parameters. Only 59% of the users were checked periodically.Apparently, systematic and regular monitoring of risk factors and somatic complications is currently inadequate. The regional survey therefore needs to be extended so that it covers the entire country.

OBJECTIVE To assess target attainment of busulfan exposure using a new model-based dosing regimen and therapeutic drug monitoring (TDM). Busulfan is an alkylating drug used in conditioning regimens for allogeneic haematopoietic cell transplantation (allo-HCT). Its narrow therapeutic range in combination with large interindividual variability in exposure, even after intravenous administration, necessitates dose individualization. DESIGN Prospective cohort study. METHODS All children who underwent allo-HCT in 2011 or 2012 receiving busulfan-based conditioning were included. Intravenous busulfan was administered once daily on four consecutive days and drug levels were measured on days 1 and k. For each patient a 'hypothetical' exposure (cAUC) without TDM was determined by extrapolating the AUC of day 1. The 'true' cAUC was then estimated based on pharmacokinetic data obtained on days 1-4 including TDM-based dose adjustment. Means and ranges were compared between cAUCs determined with and without TDM-based dose corrections. Also target attainment rates (cAUC 80-100 mg-h/L] were compared between 'hypothetical' and 'true' exposure. RESULTS 50 patients were included. Without TDM mean cAUC was 85.3 mg-h/L versus 96.2 mg-h/L with TDM. The range in individual cAUCs was significantly larger without TDM than with TDM IP = 0.001 ). Without TDM 34% of patients reached target cAUC and with TDM this significantly increased to 70% of patients (P = 0.0011. CONCLUSION The weight-based dosing regimen overall led to a mean busulfan exposure within the target range, yet the interindividual variation was substantial. Therefore, TDM of intravenous busulfan remains recommended and is of utmost importance to reach optimal target exposure in order to optimize HCT outcomes.

Clozapine has a narrow therapeutic range. The threshold value for plasma concentrations is 350 μg/l. If plasma concentrations exceed that value, serious side-effects can occur. An increase in plasma concentrations can occur as a result of inflammatory processes which may or may not be caused by an infection. Two cases are discussed in which the plasma concentration of clozapine increased as a result of an inflammatory reaction and signs of intoxication were observed. These developments seemed to be due to cholecystitis and bacterial pneumonia respectively. The clinical presentation and pathophysiology are discussed in relation to inflammatory processes.

Objective: To describe the frequency, nature, determinants and clinical relevance of prescription modifications in a Dutch community pharmacy. Design: A descriptive, retrospective study of the documented prescription modifications during dispensing in 2007. Methods: The frequency and nature of prescription modifications and their patient, drug and prescriber related determinants were assessed. To examine the clinical value of pharmacists' interventions, each prescription modification was rated from A to D (A is clinically irrelevant, D is clinically relevant with possible fatal consequences for the patient). Results: In 2007, on average, one intervention was documented per workday. Almost 50% of all interventions concerned dose corrections. Prescriptions for incidental medications, children (0-20 year) and patients with less than four other medications, had a higher chance of modification. A higher chance of prescription modifications was found in anti-infective agents for systemic use, in treatments for the central nervous system and the sensory organs. Verification and attentiveness to the prescriptions of these risk groups can reduce (serious) clinical consequences. Of all prescription modifications 86% were clinically relevant (groups B, C and D) and every ten days at least one harmful clinical incident was prevented by prescription modifications. Conclusions: Modifications of prescriptions by pharmacists vary in nature from clinically irrelevant to potentially fatal. Analysis of documented interventions in one community pharmacy allows identification of patients who are at risk and need more attention from prescribing physicians. It also shows that pharmacists' interventions have a positive impact on patients' health.

The cytochrome P450 iso-enzyme system plays a key role in the biotransformation of many drugs, including psychotropics. Its activity is determined by both genetic and environmental factors. The most important iso- enzymes for psychiatry in general are P450 IID6, 3A4 and 1A2. Knowledge about the involvement of these enzymes and biotransformation processes is mandatory because of the individual variability in their metabolic capacity. Regular measurement of plasmaconcentrations of (psycho)pharmacological compounds is therefore essential. In addition, the potential value of pheno- and/or genotyping has to be investigated.

Two patients, a 35-year-old woman and a 60-year-old man, developed severe neurological side effects during treatment with phenytoin: disorientation, myoclonia, hallucinations and drowsiness in the first patient and a comatose state in the second. The woman had spina bifida, a ventriculoperitoneal drain because of hydrocephalus, recurrent urinary-tract infection, and a history of status epilepticus. The man suffered from diabetic ketoacidosis complicated by epileptic convulsions. In both patients, the total phenytoin concentration in the blood was within the therapeutic range of 8-20 mg/l. However, both had low serum albumin concentrations, below 25 g/l. Low serum albumin levels are associated with increased concentrations of the free fraction of phenytoin. Toxic levels of free phenytoin were found: 4 and 8 mg/l, respectively, while the therapeutic range is 0.5-2 mg/l. The first patient recovered after treatment with phenytoin was stopped, after which she was placed on a lower dosage; the second patient died. When prescribing phenytoin to patients with hypoalbuminaemia, one should be aware of the risk of intoxication due to a high level of free phenytoin and consequently an increased risk of severe neurological side effects.

There are a number of effective but highly toxic drugs that exhibit a narrow therapheutic index and marked intersubject pharmacokinetic variability. Optimal therapy with such drugs requires therapeutic drug monitoring (TDM) in order to safely obtain the desired clinical effects. A systematic review was carried out to document the cost-effectiveness of TDM. The Cochrane database and Medline were searched. Reference lists of articles found were searched manually for relevant articles. Very few studies are performed that document the cost-effectiveness of TDM. Only for aminoglycosides it has been demonstrated that TDM is cost-effective. For the other classes of TDM drugs, its rationale has been made plausible, but cost-effectiveness has not been investigated. Since the use of many of these drugs would contain risks of underdosing or overdosing without TDM, emphasis should not be placed on its cost-effectiveness, but rather on how to use it in the most cost-effective and clinically effective manner possible.

There are a number of effective but highly toxic drugs that exhibit a narrow therapeutic index and marked intersubject pharmacokinetic variability. Optimal therapy with such drugs requires therapeutic drug monitoring (TDM) in order to safely obtain the desired clinical effects. A systematic review was carried out to document the cost-effectiveness of TDM. The Cochrane database and Medline were searched. Reference lists of articles found were searched manually for relevant articles. Very few studies are performed that document the cost-effectiveness of TDM. Only for aminoglycosides it has been demonstrated that TDM is cost-effective. For the other classes of TDM drugs, its rationale has been made plausible, but cost-effectiveness has not been investigated. Since the use of many of these drugs would contain risks of underdosing or overdosing without TDM, emphasis should not be placed on its cost-effectiveness, but rather on how to use it in the most cost-effective and clinically effective manner possible.

The goal of therapeutic drug monitoring (TDM) is to maximise the effect of drug therapy and to minimise toxicity. TDM is meaningful if on the one hand there is a relationship between the serum concentration of the drug and its effect and on the other hand there is no obvious relationship between dose and efficacy due to wide interindividual variability in pharmacokinetics. In case of digoxin, phenytoin, carbamazepine and valproic acid interindividual pharmacokinetics can vary to such an extent, that drug therapy should be guided by determination of serum drug levels.

Description of the extent and nature of polypharmacy in the elderly in general practice.Retrospective cross-sectional study.Medication and morbidity data were collected over July-December 1994 on all 2197 patientsor = 65 years registered in 3 family practices connected with the Medication and Morbidity Registration Network Groningen, the Netherlands. Special attention was paid to the simultaneous use ofor = 2 drugs duringor = 120 days in the study period ('chronic use'). Three categories of polypharmacy were distinguished: mild (2-3 drugs), moderate (4-5) and extensive (5).Forty per cent of the study group were males; 54% were 65-74 years, 34% were 75-84 years and 12% wereor = 85 years. The mean number of drugs used was 3.9 per person (SD: 3.6), of which 1.4 (SD: 1.8) chronically. Polypharmacy occurred in 35%: mild in 23%, moderate in 8% and extensive in 4%. All occurred mostly in the group between 75 and 84 years old. Cardiovascular drugs, in particular diuretics, and psycholeptics were mostly prescribed concomitantly with each other and with other drugs. The prevalence of concomitant use of drugs with potential interactions was low (3%). The indications for psycholeptic drugs were quite often not clear. Congestive heart failure, chronic obstructive pulmonary disease (COPD)/asthma and diabetes mellitus were mainly responsible for extensive polypharmacy.

The centralized European registration of drugs is characterized by relative openness, like the publication of public assessment reports. In our country the registration authorities should also be more focused on the users and become more accountable for their decisions. Then, in their daily practice, the prescriber and pharmacist can make better use of the available expertise.

In most European countries there are research institutes with responsibilities similar to those of the I.H.E. in Belgium. In English they are generally called "National Institute of Public Health". However, these Institutes are quite different from one country to another, because they are the result of general political factors as well as of the specific epidemiological context of each country. The evolution of the I.H.E., which for decades had research activities which are now the responsibility of three different political levels (Federal/Regions/Communities), has been strongly influenced by the profound institutional reforms which took place in Belgium since 1970. The accompanying difficulties and changes are described. More details are given concerning the specific tasks and responsibilities of the institute, its structure, perspectives for its future and the planned merging with the Pasteur Institute.

The task of the authorities with regard to medications starts with formulating the appropriate rules concerning clinical studies, mainly for drugs that are not yet registered, and also includes registration and reimbursement. There is, however, an important task for the authorities with regard to post-marketing activities, e.g. pharmacovigilance and drug use studies, in order to define better the value of a product, with implications for the future fate and reimbursement of a product. The authorities have also an important role in providing information to those who prescribe, deliver or use medications. Also in order to improve prescribing, the prescriber should be aware of his/her prescribing pattern. Ever more emphasis is put upon the "rational use of drugs" (use only drugs for which validated studies exist, use them in an appropriate manner and with consideration for the financial aspects) and upon "Evidence-Based Medicine" and "Evidence-Based Pharmacotherapy". For rational prescribing and use of medications based on evidence, a long term policy is needed and Belgium has in this regard still much to do.