De patient bestaat niet

Rede, Uitgesproken bij aanvaarding van van het ambt van bijzonder hoogleraar met als leeropdracht klinische farmacologie aan het Erasmus MC, faculteit van de Erasmus Universiteit Rotterdam op 16 september 2011. De klinische farmacologie is de wetenschap die zich bezighoudt met het bestuderen van de toepassing van geneesmiddelen bij de mens. De basis wordt gevormd door kennis over de werkingsmechanismen van geneesmiddelen en de pathofysiologie van ziektebeelden. De klinische farmacologie verbindt als het ware de basale farmacologische principes met de klinische praktijk. Het uiteindelijke doel is het beter inzetten van geneesmiddelen bij de behandeling van patiënten, waarbij gestreefd wordt naar optimale effectiviteit en naar het beperken van bijwerkingen. De veronderstelling dat geneeskunde en farmacie hierbij gecombineerd worden is dus ook niet zo gek. Sterker nog, om de klinische farmacologie optimaal te benutten is een nauwe samenwerking tussen artsen en apothekers van groot belang

Retroperitoneal fibrosis and β-blocking agents:Is there an association?

AIM: Retroperitoneal fibrosis (RPF) is a rare chronic fibro-inflammatory disorder which may be secondary to certain drugs, including beta-blocking agents (BBAs). However, their causative role is unclear. We aimed to investigate this association. METHODS: Disproportionality analysis was carried out on cases from 1985 to October 4, 2020 in VigiBase®, the WHO pharmacovigilance database. The Bayesian-based IC025 metric and reporting odds ratio were used in order to assess the adverse event signal. We also analysed all published case reports from the literature regarding BBA-associated RPF to assess the value of suggested supportive clinical evidence. RESULTS: 1.599 individual case safety reports (ICSRs) of RPF were reported to VigiBase®, of which 132 (32%) concerned 16 different single BBA. For 12 of these agents (75%), reporting of RPF was disproportionate, indicating a potential safety signal. Line listing analysis of ICSRs showed no consistent time interval from start of BBA to RPF diagnosis (range 0,7-264 mo). Dechallenge was negative or unknown in the majority of cases (74%). In 18 published cases from the literature, time from start of BBA to RPF diagnosis varied widely (range 3-156 mo). BBA were discontinued 6 mo before (n=1) or at the time of RPF diagnosis (n=17). Most patients (84%) also received RPF specific treatment. Follow-up (FU) duration was short (median 5 mo [range 1-24 mo]) and in most cases (83%) relevant FU data were lacking. CONCLUSION: Although disproportionality analysis indicated a potential safety signal for RPF associated with BBAs, clinical evidence did not support a cause and effect relationship

Drug-drug interactions with tyrosine-kinase inhibitors:A clinical perspective

In the past decade, many tyrosine-kinase inhibitors have been introduced in oncology and haemato-oncology. Because this new class of drugs is extensively used, serious drug-drug interactions are an increasing risk. In this Review, we give a comprehensive overview of known or suspected drug-drug interactions between tyrosine-kinase inhibitors and other drugs. We discuss all haemato-oncological and oncological tyrosine-kinase inhibitors that had been approved by Aug 1, 2013, by the US Food and Drug Administration or the European Medicines Agency. Various clinically relevant drug interactions with tyrosine-kinase inhibitors have been identified. Most interactions concern altered bioavailability due to altered stomach pH, metabolism by cytochrome P450 isoenzymes, and prolongation of the QTc interval. To guarantee the safe use of tyrosine-kinase inhibitors, a drugs review for each patient is needed. This Review provides specific recommendations to guide haemato-oncologists, oncologists, and clinical pharmacists, through the process of managing drug-drug interactions during treatment with tyrosine-kinase inhibitors in daily clinical practice

Pharmacological treatment of Lambert-Eaton Myasthenic Syndrome

Lambert-Eaton myasthenic syndrome (LEMS) is a very rare antibody-mediated autoimmune disease of the neuromuscular junction. Therapy can be divided in symptomatic treatment and immunosuppressive treatment. Symptomatic treatment with amifampridine is the only therapy currently authorized for use in LEMS patients. In the Netherlands the first choice drug is amifampridine base in an extended release formulation instead of the currently authorized amifampridine phosphate. This formulation has lower costs and is possibly safer due to lower peak concentrations. Other therapy used in LEMS patients is prescribed off-label and is based on experience in patients with myasthenia gravis. In many cases pyridostigmine is added as symptomatic treatment. In almost half of patients immunosuppressive therapy is started, mostly corticosteroids with or without azathioprine. Intravenous immunoglobulins and plasma exchange are used as emergency treatment. Currently no randomized clinical trials with new therapies are ongoing or announced in patients with LEMS, although multiple new therapies for myasthenia gravis are being investigated. These future therapies can be differentiated in symptomatic and immunomodulating drugs. The immunomodulating drugs can be further differentiated in early stage drugs which target the B-cell, later stage drugs which target the circulating antibodies and targeted therapy which have a disease-specific target. Some early and later stage immunomodulating drugs show promising results in myasthenia gravis although high cost and uncertain long term safety may be limiting for incorporating these drugs in LEMS treatment guidelines. Clinical trials in LEMS patients are lacking due to the rarity of the disease and we suggest the following requirements for future trials of potential new treatments: Sufficient power by performing multicenter or n-of-1 trials when appropriate, a cross-over design to reduce the number of patients and using a LEMS-specific quantitative primary outcome measure like the 3TUG score

The influence of the diagnostic technique on the histopathological diagnosis in malignant mesothelioma

In the histopathology of malignant mesotheliomas three different types (epithelial, connective tissue and mixed type) are distinguished. Some authors believe all tumours to be of mixed type, but consider that due to inadequate sampling or small biopsies this may be missed frequently. In this study the relationship between the histopathological diagnosis and the amount of tissue examined was investigated. In a series of 124 cases of malignant pleural mesothelioma a high percentage of mixed type tumours was found (55%). In cases where the decisive diagnostic procedure had been an Abrams biopsy (the "small-specimen" technique) mixed-type histology was found in 36%. If thoracoscopy, thoracotomy or autopsy (the "large-specimen" techniques) had delivered a definite diagnosis, mixed-type histology was found in 63%. Apparently diagnosing the mixed-type variety depends on the amount of tumour tissue obtained. However, the assumption that all mesotheliomas are of mixed type cannot be confirmed