Understanding the NSAID related risk of vascular events

Concern is growing about an increased risk of thrombotic events (including myocardial infarction and stroke) during the use of non-steroidal anti-inflammatory drugs (NSAIDs), in particular the so called selective cyclo-oxygenase-2 (COX 2) inhibitors. Although clinical trials give conflicting results with respect to the incidence of vascular events, increasing evidence shows that a class effect might exist for selective COX 2 inhibitors. Even before the massive introduction of selective COX 2 inhibitors, observational studies showed that the use of NSAIDs causes congestive heart failure in elderly patients.1,2 Conversely, the discontinuation of NSAIDs has also been associated with increased risk of myocardial infarction, especially in the first several weeks after stopping chronic NSAID treatment.3Many different mechanisms could explain the different effects of classic NSAIDs and selective COX 2 inhibitors in relation to thrombotic vascular events. In this review we link biochemical facts concerning NSAIDs and COX inhibitors with data from clinical trials

Dehydroepiandrosterone sulphate as a putative protective factor against tardive dyskinesia

AbstractBackgroundTardive dyskinesia (TD) is a potentially irreversible consequence of long term treatment with antipsychotic drugs which is according to a well-known theory believed to be related to oxidative stress induced neurotoxicity. Dehydroepiandrosterone (DHEA) is an endogenous antioxidant with neuroprotective activity. The biosynthesis of DHEA depends upon the activity of cytochrome P450c17α (CYP17). The gene that encodes for CYP17 has a (T34C) single nucleotide polymorphism which enhances CYP17 transcription and expression.ObjectiveTo test the hypothesis that carriership of a more active CYP17 variant would result in higher DHEA(S) levels and protect against neurotoxicity which results in orofaciolingual TD (TDof), limb-truncal TD (TDlt) or both (TDsum).MethodTardive dyskinesia was assessed cross-sectionally in 146 Caucasian psychiatric inpatients from Siberia.ResultsPatients who are carriers of the Cyp17 genotype CC have less chance of developing TD compared to patients who are carriers of the Cyp17 genotypes TC or TT (p<0.05). However, these carriers have significant lower circulating DHEAS levels compared to carriers of the Cyp17 genotypes TC and TT (p<0.05). Conversely, carriers of the CYP17 T-allele have significant elevated DHEAS levels. After correcting for gender and age no significant relationship between Cyp17 genotype CC, the T-allelle and the C-allele and the DHEAS concentration of patients was observed.ConclusionsAlthough an association between the CYP17 CC genotype and TD is indicated, our findings do not support the hypothesis that this is mediated through increased DHEA(S) levels. We believe that the relationship between this polymorphism and neuroprotective effects of steroids is more complex and cannot be elucidated without taking the posttranslational regulation of the enzyme into account

Pharmacokinetic-Pharmacodynamic Drug Interactions with Nonsteroidal Anti-Inflammatory Drugs

The nonsteroidal anti-inflammatory drugs (NSAIDs) are very commonly prescribed, especially in the elderly population. In many countries more than 10 different NSAIDs are available. As the older pyrazole compounds like phenylbutazone, oxyphenbutazone and azapropazone are most prone to pharmacokinetic interactions, the use of these compounds should be avoided where possible. Acidic NSAIDs interact with bile acid-binding resins, resulting in decreased concentrations of NSAIDs in the blood. In earlier reports it was suggested that the absorption of NSAIDs was affected by antacids and sucralfate. More recently, it was shown that there is delayed absorption of these drugs, but there is no difference in the extent of absorption. Only salicylates had their urinary secretion enhanced by antacids, which increase the urinary pH to values >7. Histamine H-2-receptor antagonists can be combined safely with NSAIDs. The concomitant administration of probenecid increased the blood concentration of NSAIDs, so an enhanced anti-inflammatory effect can be expected when these 2 drugs are combined. More importantly, NSAIDs can cause pharmacokinetic drug-drug interactions with other drugs. As can be expected, interactions with drugs that have a small therapeutic window art most likely to be of clinical significance. For example, lithium, medium to high dose methotrexate and, to a lesser extent, cyclosporin may be affected by concomitant administration of an NSAID. Aspirin (acetylsalicylic acid) and/or pyrazoles interact with oral anticoagulants, oral antihyperglycaemic agents and the anticonvulsants phenytoin and valproic acid (sodium valproate). Elevation of blood concentrations of these agents can be potentially dangerous. Similarly, NSAIDs interact with digoxin. This interaction is most likely to occur in the elderly, in neonates or in patients with renal impairment. Indomethacin can influence the blood concentrations of aminoglycosides in neonates. Unfortunately, this effect seems unpredictable, so practical therapeutic recommendations cannot be made. When NSAIDs are combined with salicylates or diflunisal, the blood concentrations of the salicylate or diflunisal may increase. However, the clinical relevance of this increase in drug concentration seems to be of minor importance. Gastrointestinal bleeding caused by NSAIDs is the most dangerous when it results from a mixed pharmacokinetic/pharmacodynamic interaction; however, patients are also at risk when pharmacodynamic interactions only are involved

Pharmacogenetics as a tool in the therapy of schizophrenia

Aim: This review summarises the present knowledge of associations between pharmacogenetics and therapeutic efficacy and side effects of antipsychotics to enable pharmacists to judge the applicability for a more tailor made therapy in patients with schizophrenia. Polymorphisms of Cytochrome P450 isoenzymes and neurotransmitter receptors involved in the efficacy and side effects of antipsychotics are highlighted in this review. Method: A search was performed in Medline and EMBASE for the period 1995 - August 2002. Also relevant references from the selected papers were incorporated. Results: Poor metabolism with respect to CYP2D6 seems to be related with more pronounced extrapyramidal symptoms and more specifically with a higher incidence of tardive dyskinesia. The C/C-genotype for CYP1A2 results in smokers in a reduction of enzyme activity, but an effect on the incidence of tardive dyskinesia is controversial. For dopamine D-2 receptors the effect of the - 141C Ins/ Del polymorphism on efficacy is not clear yet, although the Taq I polymorphism is associated with greater improvement of positive, but not negative symptoms in acute psychosis. The Gly9-allele of the dopamine D-3 receptor is associated with the response to clozapine, but in studies in which the choice of antipsychotics is not restricted, the role of this polymorphism is unclear. The reverse is applicable to the dopamine D-4.2/4.7 polymorphism. For the 5-HT2A receptor the His452Tyr polymorphism is associated with response to clozapine, the 102 T/C polymorphism leads to equivocal results. The polymorphism studied for 5-HT5A, 5-HT6, alpha(1A)- and alpha(2A)- receptors give no clear associations with the response to clozapine. The polymorphism studied of the dopamine D-2 and D-4 receptor are not related to extrapyramidal adverse effects and side effects, respectively. The 9Gly-variant of the dopamine D-3 receptor, the 102C-variant, but not the His452Tyr polymorphism of the 5-HT2A-receptor and the 23Ser-variant ( for females only) of the 5-HT2C receptor seem to increase the susceptibility to tardive dyskinesia. Weight gain induced by antipsychotics seems to be associated with the - 759C-allele of the 5-HT2C receptor. Conclusion: The results show the first careful steps toward application of pharmacogenetics in a more individualised, tailor-made, pharmacotherapy. A precondition seems to be a multifactorial approach, as can be expected for multifactorial processes