Band 26, Heft 2

No abstract available

The thienopyridine, clopidogrel bisulfate (clopidogrel), is the most widely prescribed antiplatelet therapy in the world. Clopidogrel, alone or in conjunction with aspirin as part of a dual antiplatelet therapy regimen, is the standard of care for reducing ischemic events in patients with acute coronary syndrome, recent myocardial infarction, recent stroke, or established peripheral artery disease. Initially approved for use in 1997, the label was updated by both the USA Food and Drug Administration and the European Medicines Agency in 2009 to include information regarding cytochrome P450 (CYP) genotype status and concomitant proton pump inhibitor use. Labeling warns of reduced effectiveness in those with impaired CYP2C19 function and to avoid concomitant clopidogrel use with drugs that are strong or moderate CYP2C19 inhibitors, such as omeprazole. The interpretation of this warning and the implementation in clinical practice is not without controversy. The following review provides a summary of the published evidence regarding CYP2C19 function, both genotype status and drug inhibition from concomitant proton pump inhibitors use, and response to clopidogrel.

Herbal usage remains popular as an alternative or complementary form of treatment, especially in Africa. However, the misconception that herbal remedies are safe due to their “natural” origins jeopardizes human safety, as many different interactions can occur with concomitant use with other pharmaceuticals on top of potential inherent toxicity. Cytochrome P450 enzymes are highly polymorphic, and pose a problem for pharmaceutical drug tailoring to meet an individual’s specific metabolic activity. The influence of herbal remedies further complicates this. The plants included in this review have been mainly researched for determining their effect on cytochrome P450 enzymes and P-glycoprotein drug transporters. Usage of herbal remedies, such as Hypoxis hemerocallidea , Sutherlandia frutescens and Harpagophytum procumbens is popular in Africa. The literature suggests that there is a potential for drug-herb interactions, which could occur through alterations in metabolism and transportation of drugs. Research has primarily been conducted in vitro, whereas in vivo data are lacking. Research concerning the effect of African herbals on drug metabolism should also be approached, as specific plants are especially popular in conjunction with certain treatments. Although these interactions can be beneficial, the harm they pose is just as great.

Stroke is a major human health problem without efficient available therapeutics. Ischemic brain injury can induce cell death as well as upregulation of endogenous adaptive mechanisms depending on the severity and duration of hypoxia, and the activity of transcription factors, such as hypoxia inducible factor 1-α (HIF-1α). HIF-1α induces gene expression as multidrug resistance ( MDR-1 ) gene associated with drug-refractory phenotype, as well as erythropoietin (Epo) and erythropoietin receptor (Epo-R) associated with O 2 supply. The spontaneous stimulation of the Epo/Epo-R system is not enough for brain protection. Therefore, administration of exogenous recombinant human Epo (rHu-Epo) was suggested as an alternative therapy in stroke. In several experimental models of brain hypoxia, Epo and Epo variants, including rHu-Epo, showed neuroprotective effects. Intranasal administration of these Epo-compounds can reach the central nervous system and protect the brain against ischemia, avoiding hematopoietic effects. However, it has been reported that high expression of Epo-R in neurons must be available to be activated by Epo. According to these considerations, intranasal delivery of rHu-Epo could be an interesting approach in the treatment of cerebral hypoxias avoiding both (i) adverse peripheral effects of treatment with Epo in stroke, and (ii) the pharmacoresistant phenotype depending on MDR-1 expression.

Background: The objective of this study is to predict morphine clearance in children (preterm neonates to 10-month-old infants) by maturation models that include age and weight and to compare the predictive performance of morphine maturation models with simple allometric models. Methods : Age, weight, and morphine clearance data were obtained from the literature. A maturation model (n=60) for morphine was developed using data from preterm and term neonates to 5-year-old children. The allometric models were developed using the same data as the maturation model. The predictive performance of the models was tested in 88 children of different age groups. Results : The maturation and allometric models predicted morphine clearance in children with the same degree of accuracy or error. Out of 88 subjects, the prediction error of 50% or less was observed in slightly >60% of the subjects. Almost 40% of the subjects showed a prediction error >50%, 20% of which showed an error ≥100%. Although both the maturation and allometric models provided a good prediction of morphine clearance in many children, they were less accurate for many others. Conclusions : High intersubject variability in morphine clearance probably led to less than adequate performance of the models. However, there could be many drugs for which intersubject variability in clearance might not be as high as morphine clearance and in those situations these models could perform reasonably well.

We present the case of an 82-year-old man admitted to our hospital for muscle weakness. He was under simvastatin 20 mg per day and was given pulse itraconazole therapy 8 days before the onset of symptoms for onychomycosis. He developed severe rhabdomyolysis inducing an acute renal failure necessitating renal replacement therapy. He eventually fully recovered. Given the possible concurrent use of simvastatin and itraconazole, awareness of this potential interaction is clinically important.

The binding of nateglinide (NA) enantiomers with human plasma (HP), human serum albumin (HSA) and bovine serum albumin (BSA) was investigated. The protein binding was studied over a drug concentration range of 5–100 μM at a protein concentration of 600 μM. Unbound drug concentrations were determined by direct chiral liquid chromatography using chiralcel OJ-RH column. At therapeutic drug concentrations, the protein binding of each enantiomer was >98%. The results showed that the binding of NA enantiomers was stereoselective, mutually competitive and non-linear. The binding characteristics were, however, opposite for the two most important plasma binding proteins. Opposite stereo-selectivity was observed between BSA and HSA while stereo-selectivity was identical between HSA and HP. Scatchard analysis was used to illustrate the different binding affinities of NA enantiomers to BSA, HSA and HP. The interaction between enantiomers observed in HP and serum albumins was confirmed as a competitive type interaction at the high affinity site. Scatchard analysis was used to illustrate the different binding affinities of NA enantiomers to BSA, HSA and HP.