Ingeborg Walter-Sack

Elevated plasma concentrations of homocysteine in antiepileptic drug treatment.

Summary: Purpose: Homocysteine is an experimental convulsant and an established risk factor in atherosclerosis. A nuritional deficiency of vitamin B6, vitamin B12, or folate leads to increased homocysteine plasma concentrations. During treatment with carbamazepine (CBZ), phenytoin, or phenobarbital, a deficiency in these vitamins is common. The objective of the study was to test the hypothesis that antiepileptic drug (AED) treatment is associated with increased homocysteine plasma concentrations.

Opposite effects of short‐term and long‐term St John's wort intake on voriconazole pharmacokinetics

Constituents of St Johns wort (SJW) in vivo induce the cytochrome P450 (CYP) isozymes 3A4, 2C9, and 2C19 but in vitro were shown to inhibit them. This study investigates both short‐ and long‐term effects of SJW on the antifungal voriconazole, which is metabolized by these enzymes.

CYP2C19 genotype is a major factor contributing to the highly variable pharmacokinetics of voriconazole.

In vitro data on the metabolism of the antifungal voriconazole suggest that its pharmacokinetics might be influenced by the activity of CYP2C19, CYP2C9, and CYP3A. To elucidate the genetic influence of polymorphic enzymes on voriconazole metabolism, the authors pooled the pharmacokinetic data from 2 interaction studies in which 35 participants were enrolled according to their CYP2C19 genotype to receive a single 400‐mg oral dose of voriconazole. Nine participants were homozygous for CYP2C19*1/*1, 8 heterozygous for *1/*17, 11 heterozygous for*1/*2, 2 heterozygous for *2/*17, 4 homozygous for *2/*2, and 1 with a double mutation CYP2C19*2/*2*17. Nine (heterozygous) individuals were carriers of the CYP2C9*2 or *3 variant alleles. Twenty‐five participants did not express the CYP3A5 isozyme (*3/*3), whereas in 5 individuals, the *1/*3 combination was present (active enzyme). In addition, the CYP2D6 genotype and 2 variants of the drug transporter MDR1 (C3435T and G2677T) were determined. Multiple regression analysis of voriconazole apparent oral clearance revealed that 49% of its variance can be explained solely by the CYP2C19 polymorphism (P < .0001). Including the other polymorphisms into the regression model did not show any significant contribution. The number of variant CYP2C19 alleles therefore explains a substantial part of the wide variability of voriconazole pharmacokinetics, whereas the presence of functional CYP3A5 and the CYP2C9 genotype had no significant impact on voriconazole exposure. Some minor contribution results from the MDR1 C3435T genotype.

Methylene blue for malaria in Africa: results from a dose-finding study in combination with chloroquine

The development of safe, effective and affordable drug combinations against malaria in Africa is a public health priority. Methylene blue (MB) has a similar mode of action as chloroquine (CQ) and has moreover been shown to selectively inhibit the Plasmodium falciparum glutathione reductase. In 2004, an uncontrolled dose-finding study on the combination MB-CQ was performed in 435 young children with uncomplicated falciparum malaria in Burkina Faso (CQ monotherapy had a > 50% clinical failure rate in this area in 2003). Three serious adverse events (SAE) occurred of which one was probably attributable to the study medication. In the per protocol safety analysis, there were no dose specific effects. The overall clinical and parasitological failure rates by day 14 were 10% [95% CI (7.5%, 14.0%)] and 24% [95% CI (19.4%, 28.3%)], respectively. MB appears to have efficacy against malaria, but the combination of CQ-MB is clearly not effective in the treatment of malaria in Africa.

Safety of the methylene blue plus chloroquine combination in the treatment of uncomplicated falciparum malaria in young children of Burkina Faso [ISRCTN27290841]

BackgroundSafe, effective and affordable drug combinations against falciparum malaria are urgently needed for the poor populations in malaria endemic countries. Methylene blue (MB) combined with chloroquine (CQ) has been considered as one promising new regimen.ObjectivesThe primary objective of this study was to evaluate the safety of CQ-MB in African children with uncomplicated falciparum malaria. Secondary objectives were to assess the efficacy and the acceptance of CQ-MB in a rural population of West Africa.MethodsIn this hospital-based randomized controlled trial, 226 children (6–59 months) with uncomplicated falciparum malaria were treated in Burkina Faso. The children were 4:1 randomized to CQ-MB (n = 181; 25 mg/kg CQ and 12 mg/kg MB over three days) or CQ (n = 45; 25 mg/kg over three days) respectively. The primary outcome was the incidence of severe haemolysis or other serious adverse events (SAEs). Efficacy outcomes were defined according to the WHO 2003 classification system. Patients were hospitalized for four days and followed up until day 14.ResultsNo differences in the incidence of SAEs and other adverse events were observed between children treated with CQ-MB (including 24 cases of G6PD deficiency) compared to children treated with CQ. There was no case of severe haemolysis and also no significant difference in mean haemoglobin between study groups. Treatment failure rates were 53.7% (95% CI [37.4%; 69.3%]) in the CQ group compared to 44.0% (95% CI [36.3%; 51.9%]) in the CQ-MB group.ConclusionMB is safe for the treatment of uncomplicated falciparum malaria, even in G6PD deficient African children. However, the efficacy of the CQ-MB combination has not been sufficient at the MB dose used in this study. Future studies need to assess the efficacy of MB at higher doses and in combination with appropriate partner drugs.

Elevated plasma concentrations of lipoprotein(a) in medicated epileptic patients

Abstract Lipoprotein(a) [Lp(a)] has been identified as an independent risk factor for vascular diseases. There are no data on Lp(a) levels in patients on long-term medication with carbamazepine, phenytoin, phenobarbital, or valproate. To investigate the effects of such treatment on Lp(a) levels and common carotid artery intima media thickness we studied 51 epileptic outpatients on long-term antiepileptic medication and 51 age- and sex-matched controls. Lp(a) levels above 45 mg/dl were found in 11 of 50 patients, but in only 4 of 51 controls (P<0.05). The mean serum concentration of Lp(a) was 33.0±7.0 mg/dl in patients and 16.9±2.7 mg/dl in controls (P<0.05). Epileptic patients also had a thicker intima media of the common carotid artery (0.79±0.04 mm) than controls (0.69±0.02 mm, P<0.05) as measured by B-mode ultrasonography. Our results suggest an untoward effect of long-term antiepileptic medication on Lp(a) serum concentrations. Elevated Lp(a) levels might be a risk factor for arteriosclerosis in epileptic patients.

Safety of the combination of chloroquine and methylene blue in healthy adult men with G6PD deficiency from rural Burkina Faso

New drug combinations against falciparum malaria which are both effective and affordable for Sub‐Saharan African populations are urgently needed. The combination of the well‐known drugs chloroquine (CQ) and methylene blue (MB) is such a promising new regimen. However, there is some concern that MB could cause development of haemolysis in patients with glucose‐6‐phosphate dehydrogenase (G6PD) deficiency, a condition which is prevalent in malaria‐endemic regions. Against this background, 74 G6PD‐deficient but otherwise healthy adult men were given a 3‐day oral regimen of a total of 1500 mg CQ and 780 mg MB in the District Hospital of Nouna in north‐western Burkina Faso. Haemolysis did not occur, haemoglobin levels remained stable or even rose in the study participants, and the drug regimen was well tolerated. Therefore, standard dosages of MB appear to be safe in G6PD‐deficient African populations with predominantly class III G6PD deficiency.

Quantification of cationic anti-malaria agent methylene blue in different human biological matrices using cation exchange chromatography coupled to tandem mass spectrometry

Selective and sensitive methods for the determination of the cationic dye and anti-malarial methylene blue in human liquid whole blood, dried whole blood (paper spot), and plasma depending on protein precipitation and cation exchange chromatography coupled to electrospray ionisation (ESI) tandem mass spectrometry (MS/MS) have been developed, validated according to FDA standards, and applied to samples of healthy individuals and malaria patients within clinical studies. Acidic protein precipitation with acetonitrile and trifluoroacetic acid was used for liquid whole blood and plasma. For the extraction of methylene blue from paper spots aqueous acetonitrile was used. Sample extracts were chromatographed on a mixed mode column (cation exchange/reversed phase, Uptisphere MM1) using an aqueous ammonium acetate/acetonitrile gradient. Methylene blue was quantified with MS/MS in the selected reaction monitoring mode using ESI and methylene violet 3RAX as internal standard. Depending on the sample volume (whole blood and plasma 250 microL, and 100 microL on paper spots) the method was linear at least within 75 and 10,000 ng/mL and the limit of quantification in all matrices was 75 ng/mL. Batch-to-batch accuracies of the whole blood, plasma, and paper spot methods varied between -4.5 and +6.6%, -3.7 and +7.5%, and -5.8 and +11.1%, respectively, with corresponding precision ranging from 3.8 to 11.8% CV. After a single oral dose (500 mg) methylene blue concentrations were detectable for 72 h in plasma. The methods were applied within clinical studies to samples from healthy individuals and malaria patients from Burkina Faso.

Efficacy of methylene blue monotherapy in semi-immune adults with uncomplicated falciparum malaria: a controlled trial in Burkina Faso

Objective  To assess the efficacy of methylene blue (MB) monotherapy in semi‐immune adults with uncomplicated malaria in Burkina Faso.

Successful strategy to improve the specificity of electronic statin?drug interaction alerts

PurposeA considerable weakness of current clinical decision support systems managing drug–drug interactions (DDI) is the high incidence of inappropriate alerts. Because DDI-induced, dose-dependent adverse events can be prevented by dosage adjustment, corresponding DDI alerts should only be issued if dosages exceed safe limits. We have designed a logical framework for a DDI alert-system that considers prescribed dosage and retrospectively evaluates the impact on the frequency of statin–drug interaction alerts.MethodsUpper statin dose limits were extracted from the drug label (SPC) (20 statin-drug combinations) or clinical trials specifying the extent of the pharmacokinetic interaction (43 statin–drug combinations). We retrospectively assessed electronic DDI alerts and compared the number of standard alerts to alerts that took dosage into account.ResultsFrom among 2457 electronic prescriptions, we identified 73 high-risk statin–drug pairs. Of these, SPC dosage information classified 19 warnings as inappropriate. Data from pharmacokinetic trials took quantitative dosage information more often into consideration and classified 40 warnings as inappropriate. This is a significant reduction in the number of alerts by 55% compared to SPC-based information (26%; p < 0.001).ConclusionThis retrospective study of pharmacokinetic statin interactions demonstrates that more than half of the DDI alerts that presented in a clinical decision support system were inappropriate if DDI-specific upper dose limits are not considered.