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Biomedical subjects

Walter E Haefeli

Publications and source records attributed to Walter E Haefeli.

At least 37 records · Page 2Linked to original sources
PubMed2005

In vitro assessment of methylene blue on chloroquine-sensitive and -resistant Plasmodium falciparum strains reveals synergistic action with artemisinins.

Methylene blue (MB) represents a promising antimalarial drug candidate for combination therapies against drug-resistant parasite strains. To support and facilitate the application of MB in future field trials, we studied its antiparasitic effects in vitro. MB is active against all blood stages of both chloroquine (CQ)-sensitive and CQ-resistant P. falciparum strains with 50% inhibitory concentration (IC50) values in the lower nanomolar range. Ring stages showed the highest susceptibility. As demonstrated by high-performance liquid chromatography-tandem mass spectrometry on different cell culture compartments, MB is accumulated in malarial parasites. In drug combination assays, MB was found to be antagonistic with CQ and other quinoline antimalarials like piperaquine and amodiaquine; with mefloquine and quinine, MB showed additive effects. In contrast, we observed synergistic effects of MB with artemisinin, artesunate, and artemether for all tested parasite strains. Artemisinin/MB combination concentration ratios of 3:1 were found to be advantageous, demonstrating that the combination of artemisinin with a smaller amount of MB can be recommended for reaching maximal therapeutic effects. Our in vitro data indicate that combinations of MB with artemisinin and related endoperoxides might be a promising option for treating drug-resistant malaria and should be studied in future field trials. Resistance development under this drug combination is unlikely to occur.

Animals↗
PubMed2005

Drug interactions and risk of acute bleeding leading to hospitalisation or death in patients with chronic atrial fibrillation treated with warfarin.

Although drug interactions with warfarin are an important cause of excessive anticoagulation, their impact on the risk of serious bleeding is unknown. We therefore performed a cohort study and a nested case-control analysis to determine the risk of serious bleeding in 4152 patients (aged 40-84 years) with nonvalvular atrial fibrillation (AF) taking long-term warfarin (> 3 months). The study population was drawn from the UK General Practice Research Database. More than half (58%) of eligible patients used potentially interacting drugs during continuous warfarin treatment. Among 45 identified cases of incident idiopathic bleeds (resulting in hospitalisation within 30 days or death within 7 days) and 143 matched controls, more cases than controls took > or = 1 potentially interacting drug within the preceding 30 days (62.2% vs. 35.7%) and used > 4 drugs (polypharmacy) within the preceding 90 days (80.0% vs. 66.4%). Conditional logistic regression analysis yielded an odds ratio (OR) of 3.4 (95% confidence interval [CI]: 1.4-8.5) for the risk of serious bleeding in patients treated with warfarin and > or = 1 drugs potentially increasing the effect of warfarin vs. warfarin alone adjusted for polypharmacy, diabetes, hypertension, heart failure, and thyroid disease; the adjusted OR for the combined use of warfarin and aspirin vs. warfarin alone was 4.5 (95% CI: 1.1-18.1). We conclude that concurrent use of potentially interacting drugs with warfarin is associated with a 3 to 4.5-fold increased risk of serious bleeding in long-term warfarin users.

Adult↗
PubMed2004

Simultaneous determination of hypericin and hyperforin in human plasma with liquid chromatography-tandem mass spectrometry.

A selective and sensitive method for the simultaneous determination of hypericin and hyperforin--the two main active ingredients of St. John's Wort (SJW) extract--in human plasma depending on liquid/liquid-extraction and LC/MS/MS detection has been developed, validated after specifying the stability of the photosensitive hypericin in plasma samples during light exposure and applied to samples of a patient. After extraction with ethyl acetate/n-hexane in the darkness, sample extracts were chromatographed isocratically within 6 min on a Kromasil RP-18 column. The analytes were detected with tandem mass spectrometry in the selected reaction monitoring mode using an electrospray ion source. The limit of quantification was 0.05 ng/mL for hypericin and 0.035 ng/mL for hyperforin. The accuracy of the method varied between 101.9 and 114.2% and the precision ranged from 4.7 to 15.4% (S.D., batch-to-batch) for both analytes. The method was linear at least between 0.05 and 10 ng/mL for hypericin and between 0.035 and 100 ng/mL for hyperforin. Using this method hypericin and hyperforin were determined successfully in a patient over seven days following discontinuation of exposure with therapeutic doses of St. John's Wort extract.

Aged↗
PubMed2004

In vitro and ex vivo evidence for modulation of P-glycoprotein activity by progestins.

The well known gender-related differences in drug action may partly be explained by changes in activity and expression of drug metabolising enzymes, but also by modulation of active drug transport systems (e.g. P-glycoprotein, Pgp) by sexual steroids, which is yet not well investigated. Because many women are using hormones (e.g. as oral contraceptives) we investigated the influence of different synthetic progestins on Pgp activity. Pgp inhibition of progesterone, medroxyprogesterone, chlormadinone, cyproterone, levonorgestrel, norethisterone, desogestrel, and norgestimate was measured in vitro in two Pgp over-expressing cell lines (L-MDR1, P388/dx cells) and the corresponding parental cell lines by means of calcein assay, and ex vivo in human peripheral blood mononuclear cells (PBMCs) by rhodamine123 efflux. For most progestins tested, concentrations needed to double baseline fluorescence (f2) in L-MDR1 cells were similar to that of the potent Pgp inhibitor quinidine, whereas levonorgestrel and norethisterone did not reach f2. The results in P388/dx cells essentially confirmed our findings in L-MDR1 cells. Additionally, Pgp inhibitory activity of all progestins tested was also shown ex vivo in PBMCs. The potent Pgp inhibition by several synthetic progestins in vitro and ex vivo suggests that such an interaction might be clinically relevant despite generally low plasma concentrations of progestins. The results may be of particular importance for Pgp substrates, such as protease inhibitors and chemotherapeutic agents, for which intracellular concentrations are critical.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Dose individualisation in patients with renal insufficiency: does drug labelling support optimal management?

OBJECTIVE: An important information source for pharmacotherapy in populations at risk is drug labelling. We compared the recommendations for patients with renal insufficiency included in German drug labellings with evidence from the literature. METHODS: From the 120 drugs with the highest turnover in a large university hospital, all drugs with pharmacokinetics independent of renal function (n=48) and those with substantial accumulation in renal failure (n=28) were identified. For both groups of compounds, pharmacokinetic and pharmacodynamic aspects relevant for dose individualisation in those with renal insufficiency were extracted from the literature and compared with the information given in the German drug labelling. RESULTS: Over half of the labellings (15 of 26) of non-accumulating drugs without renal adverse drug reactions contained no dose recommendation for patients with renal insufficiency. The labelling of nephrotoxic compounds that do not accumulate included more frequently a recommendation to adapt the dose or to monitor than the labelling of drugs without nephrotoxic potential (15 of 22 versus 5 of 26, P=0.002). For over half of accumulating drugs (16 of 28), the dose given in the labelling depends primarily on creatinine clearance. The ratio between the labelling dose and the dose based on the pharmacokinetic concept to achieve identical plasma concentrations (Q0 concept) differed widely (0.4-2). CONCLUSIONS: When renal failure had no impact on dosing, information was often missing. Such information is however important to differentiate, whether no dose adaptation is necessary or no information is available. If dose adjustment is required, application of a uniform concept is desirable.

Creatinine↗
PubMed2004

Pharmacokinetic interaction of chloroquine and methylene blue combination against malaria.

OBJECTIVE: The combination of chloroquine and methylene blue is potentially effective for the treatment of chloroquine-resistant malaria caused by Plasmodium falciparum. The aim of this study was to investigate whether methylene blue influences the pharmacokinetics of chloroquine. METHODS: In a randomized, placebo-controlled, parallel group design, a 3-day course of therapeutic oral doses of chloroquine (total 2.5 g in male, 1.875 g in female participants) with oral co-administration of placebo or 130 mg methylene blue twice daily for 3 days was administered to 24 healthy individuals. Chloroquine, desethylchloroquine, and methylene blue concentrations were determined by means of HPLC/UV or LC/MS/MS assays in whole blood, plasma, and urine for 28 days after the last dose. RESULTS: During methylene blue exposure, the area under the chloroquine whole blood concentration-time curve normalized to body weight (AUC(0-24 h)/BW) yielded a trend of reduction (249+/-98.2 h mug l(-1) kg(-1) versus 315+/-65.0 h mug l(-1) kg(-1), P=0.06). The AUC(0-24 h)/BW of desethylchloroquine was reduced by 35% (104+/-40.3 h mug l(-1) kg(-1) versus 159+/-66.6 h mug l(-1) kg(-1), P=0.03), whereas the metabolic ratio between chloroquine and desethylchloroquine remained unchanged (2.25+/-0.49 versus 1.95+/-0.42, P=0.17). The renal clearance of chloroquine and the ratio between chloroquine in whole blood and plasma remained unchanged (P>0.1). CONCLUSION: Oral co-administration of methylene blue appears to result in a small reduction of chloroquine exposure which is not expected to be clinically relevant and thus represents no concern for further development as an anti-malarial combination.

Administration, Oral↗
PubMed2004

Requirements for a successful implementation of drug interaction information systems in general practice: results of a questionnaire survey in Germany.

OBJECTIVE: To determine drug interaction information requirements in general practice with respect to both content and mode of presentation. METHODS: In a mail survey among 2,000 general practitioners in south-west Germany, we collected information on risk evaluation of drug interactions and combinations of concern, usage of and satisfaction with the current information sources, desirable content and mode of future presentation and demographic variables. Categorical variables were compared using chi2 test. Trends were analysed with Cochran-Armitage test and determinants of literature usage with logistic regression. RESULTS: Response rate was 60.8%. The majority of general practitioners considered drug interactions a risk factor in prescribing (88.6%). For 18.2% of the drug combinations most frequently indicated as interacting, there was no published evidence of a clinically relevant interaction. More than half of the participants were dissatisfied with the information on severity, mechanism, and dose adjustment currently available in their sources. In particular, non-interacting alternatives were thought to be lacking (86.9%). Users of drug interaction software more frequently retrieved drug interaction information than non-users [odds ratio (OR) 1.95; 95% confidence intervals (CI) 1.50, 2.52], but only 28.6% of general practitioners had access to such systems. There was a significant trend towards electronic sources among younger physicians, but at present, 41.7% of general practitioners favour printed sources, and 8.8% would refuse to use electronic sources. CONCLUSION: General practitioners wish for more informative support on drug interactions, especially concerning management. Despite a trend towards electronic information sources, printed documents are presently still required to reach all prescribers.

Adverse Drug Reaction Reporting Systems↗
PubMed2004

High prevalence of unknown co-medication in hospitalised patients.

OBJECTIVE: Co-medication unknown to the treating physician, including self-medication, may compromise drug safety by increasing the risk of duplicate therapy, drug interactions and adverse drug reactions that are not recognised as such. The aim of the current study was to estimate exposure to unknown co-medication during hospitalisation by performing an analytical screening for a broad range of drugs and drug classes in urine of patients admitted to a general internal medicine ward. METHODS: Urine samples of 44 patients were analysed with REMEDiHS (high-performance liquid chromatography) and six different immunoassays. Positive results were compared with drug history and documented drug prescription. If appropriate, gas chromatographic-mass spectrometric confirmatory analyses were performed on drugs classified at least once as possible unknown co-medication. RESULTS: Nine (20%) of the patients tested positive for a compound detected by two independent analytical methods and 18 (41%) for a compound detected by at least one analytical method. Unknown co-medication consisted mostly of analgesics, benzodiazepines or ranitidine. CONCLUSION: At least one in five patients exhibits at least once during hospitalisation exposure to drugs not documented in the patient record, which may compromise patient safety.

Adult↗
PubMed2004

A drug database model as a central element for computer-supported dose adjustment within a CPOE system.

The incidence of adverse drug reactions may be decreased by computerized physician order entry (CPOE) with decision support. The authors describe the development of a drug database model for computer-supported dose adjustment within a CPOE system. The following two core elements were included: (1) To allow electronic dose and volume calculation, the relation between strength (e.g., 5 mg/1 mL) and prescribed unit (e.g., 1 ampoule containing 2 mL) must be available in coded form. (2) The site of action along with the parent active ingredient, i.e., the pure drug without salt or ester, is necessary for linkage to knowledge bases. All complex examples of drugs that were examined could be described by the data model. With the ultimate goal of increasing prescribing effectiveness and quality the authors developed a drug database model for inclusion in a CPOE system, which allows dose calculations and may be coupled to decision support systems.

Databases, Factual↗
PubMed2004

Autosomal-dominant hypertension with type E brachydactyly is caused by rearrangement on the short arm of chromosome 12.

We are studying a Turkish family with autosomal-dominant hypertension and brachydactyly; affected persons die of stroke before 50 years of age. With interphase fluorescence in situ hybridization, we found a chromosome 12p deletion, reinsertion, and inversion in affected persons. This finding suggested that the hypertension could be caused by one or more of 3 genes, the ATP-dependent potassium channel Kir6.1, its regulator the sulfonyl urea receptor SUR2, and the phosphodiesterase PDE3A. We further studied 6 affected and 4 nonaffected persons. Buttocks biopsies were done, small vessels were tested on a myograph, and mRNA was extracted. We performed forearm blood flow studies with intrabrachial artery diazoxide, isoproterenol, and milrinone infusions. Systemic pharmacological testing was done with intravenous diazoxide, nitroprusside, and isoproterenol. PDE3A mRNA was high in vessels from 3 affected subjects, but not high in 3 others. The vessels responded similarly to forskolin, with or without glibenclamide, and to cromakalim. However, there was a suggestion that the dilatation after milrinone might be exaggerated. The forearm infusion studies showed no differences in the responses to diazoxide, isoproterenol, or milrinone. Systemically, affected persons showed a greater blood pressure response to diazoxide and nitroprusside, and a greater heart rate response to isoproterenol than nonaffected persons. The results shed doubt on Kir6.1 and SUR2. The differences in PDE3A expression and responses may be the result of hypertension rather than the cause. Although our 3 candidate genes are no longer likely, the rearrangement we describe greatly enhances the perspectives of this project.

Arteries↗
PubMed2004

Acute hyperhomocysteinemia decreases NO bioavailability in healthy adults.

Hyperhomocysteinemia is associated with decreased vascular reactivity and increased cardiovascular morbidity. Oxidative stress and reduced NO bioavailability have been proposed as a mechanism for the adverse effects of chronically elevated plasma homocysteine levels. Recent studies suggest that acute elevations of plasma homocysteine may also impair endothelial function and vasodilation, however, the mechanism is not clear. In the present study, we investigated whether moderate hyperhomocysteinemia after methionine loading decreases NO bioavailability, increases oxidative stress, and impairs receptor-mediated NO-dependent venodilation in healthy adults. After oral methionine loading (0.1g/kg), mean homocysteine concentrations increased 3.2-fold, from 6.9 +/- 0.5 to 27.8 +/- 1.9 micromol/l (n = 16), whereas plasma NO(x) concentrations, an indicator of NO release, were decreased by 12% compared to placebo treatment (P = 0.005). Vitamin E levels in freshly isolated low density lipoprotein (LDL), a sensitive marker of LDL oxidation, and LDL lipid (hydro)peroxide levels were unchanged after methionine loading. Endothelium-dependent venodilation induced by bradykinin was reduced by 18% during hyperhomocysteinemia (P = 0.06). Taken together our data suggest that the reduced NO bioavailability was likely due to decreased NO synthesis and release rather than to NO destruction by oxidative stress.

Adult↗
PubMed2004

Substantial pharmacokinetic interaction between digoxin and ritonavir in healthy volunteers.

BACKGROUND: Ritonavir is a potent in vitro inhibitor of several cytochrome P450 isozymes and ABC transporters including the efflux pump P-glycoprotein (P-gp). This study assessed the effect of repetitive ritonavir administration on digoxin distribution and total and renal digoxin clearance as a marker for P-gp activity in vivo. METHODS: In a randomized, placebo-controlled crossover study, 12 healthy male participants received oral ritonavir (300 mg twice daily) for 11 days. With the assumption that ritonavir steady state had been reached, 0.5 mg digoxin was given intravenously on day 3. Digoxin concentrations were determined in plasma and urine by radioimmunoassay, and plasma ritonavir concentrations were determined by liquid chromatography-tandem mass spectrometry. Digoxin kinetics was estimated by compartmental and noncompartmental analyses, by use of the area under the plasma concentration-time curve, and the corresponding digoxin amount excreted into urine was used for digoxin clearance calculations. RESULTS: Ritonavir significantly (P <.01) increased digoxin area under the plasma concentration-time curve from time 0 to infinity by 86% and its volume of distribution by 77% and decreased nonrenal and renal digoxin clearance by 48% and 35%, respectively. Digoxin terminal half-life in plasma increased by 156% (P <.01). CONCLUSION: This inhibition of renal digoxin clearance is likely caused by ritonavir inhibition of P-gp. Its extent is considerable and similar to the effect of other potent P-gp inhibitors on digoxin disposition such as quinidine. These findings may, therefore, indicate that the pharmacokinetics of P-gp substrates sharing the renal tubular elimination pathway will be affected when combined with therapeutic doses of ritonavir in antiretroviral treatment regimens. In addition and contrarily to quinidine, these data indicate that ritonavir promotes digoxin distribution in the body.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Drug interactions in primary care: impact of a new algorithm on risk determination.

BACKGROUND: If managed adequately, many drug interactions do not result in clinical manifestations. Earlier studies may have overestimated the risk arising from drug interactions because they usually reported interaction frequencies and the severity of potential outcomes irrespective of their manageability. OBJECTIVE: Our objective was to estimate the risk associated with drug interactions in a large population when not only the severity of possible clinical events but also measures of their prevention (manageability, modulating factors) are considered. METHODS: We evaluated all drug pairs concurrently prescribed to 9481 adults aged 50 to 75 years who participated in a health-screening examination. Drug interactions were evaluated by use of an algorithm with 4 decision layers (severity, manageability, risk/benefit assessment, and patient-related risk factors), and this risk evaluation was compared with the conventional evaluation solely on the basis of severity. RESULTS: More than 52% of the patients received combination therapy. Interaction information was available in a standard source (DRUGDEX; Thomson MICROMEDEX, Greenwood Village, Colo) for only 1029 of all 13,672 individual prescribed drug pairs. Of the drug pairs, 881 (6.4%) were identified as interacting. Of these 881 interactions, 132 (15.0%) were of major severity but 101 of 132 (76.5%) were considered manageable. Only 31 (23.5%) of 132 major interactions (ie, 31/881 [3.5% of all interacting pairs]) offered no management options and should thus be avoided. CONCLUSION: For many commonly prescribed drug pairs, explicit drug interaction information is currently not available in DRUGDEX. For major interactions with published evidence, the overwhelming majority were manageable, and therefore risk estimates only based on the severity of potential outcomes will grossly overestimate the risk associated with such combinations.

Aged↗
PubMed2004

Quality of drug information on the World Wide Web and strategies to improve pages with poor information quality. An intervention study on pages about sildenafil.

AIMS: The generally poor quality of health information on the world wide web (WWW) has caused preventable adverse outcomes. Quality management of information on the internet is therefore critical given its widespread use. In order to develop strategies for the safe use of drugs, we scored general and content quality of pages about sildenafil and performed an intervention to improve their quality. METHODS: The internet was searched with Yahoo and AltaVista for pages about sildenafil and 303 pages were included. For assessment of content quality a score based on accuracy and completeness of essential drug information was assigned. For assessment of general quality, four criteria were evaluated and their association with high content quality was determined by multivariate logistic regression analysis. The pages were randomly allocated to either control or intervention group. Evaluation took place before, as well as 7 and 22 weeks after an intervention which consisted of two letters with individualized feedback information on the respective page which were sent electronically to the address mentioned on the page. RESULTS: Providing references to scientific publications or prescribing information was significantly associated with high content quality (odds ratio: 8.2, 95% CI 3.2, 20.5). The intervention had no influence on general or content quality. CONCLUSIONS: To prevent adverse outcomes caused by misinformation on the WWW individualized feedback to the address mentioned on the page was ineffective. It is currently probably the most straight-forward approach to inform lay persons about indicators of high information quality, i.e. the provision of references.

Contraindications↗
PubMed2004

Oral contraception does not alter single dose saquinavir pharmacokinetics in women.

AIMS: Women experience more adverse drug reactions (ADR) to antiretroviral therapy than men. This may be attributed to higher plasma concentrations of protease inhibitors due to pharmacokinetic interactions with hormonal preparations. Thus, in the present study we aimed to investigate the influence of oral contraceptives (OC) on the pharmacokinetics of the protease inhibitor saquinavir. METHODS: Saquinavir was administered in a hard gelatin capsule formulation (Invirase) to rule out confounding by pharmaceutical aids of the more frequently used soft gelatin capsule. After an overnight fast, eight healthy female participants ingested a single oral dose of 600 mg saquinavir immediately before and after the 19th dose of a combined, low dose OC (0.03 mg ethinylestradiol, 0.075 mg gestodene) in a prospective, fixed sequence study design. The first saquinavir application was scheduled on day 1, 2, or 3 of the individual menstrual cycle. Plasma concentrations of saquinavir and relative concentrations of its M2&M3-hydroxy metabolites were determined by LC/MS/MS for 48 h. RESULTS: Intake of OC resulted in a significant decrease in morning serum concentrations (before intake of OC, compared to day 19 of OC therapy) of 17beta-estradiol by -23.4 pg ml-1 (57%, 95%CI: -76% to -37.4%); progesterone by -0.25 ng ml-1 (33%, 95%CI: -45.3% to -21.5%); follicle-stimulating hormone by -4.06 U l-1 (82%, 95%CI: -96.5% to -67.7%); and luteinizing hormone by -3.49 U l-1 (74%, 95%CI: -93 to -54.6%). Conversely, sexual hormone binding globulin serum concentrations increased by 83.6 nmol l-1 (205%, 95%CI: 32.2% to 377%). Pharmacokinetic parameters of saquinavir (AUC, Cmax, tmax, t1/2, CLR) were not affected by OC, nor was the relative metabolic ratio of saquinavir/M2&M3-hydroxy saquinavir. Furthermore, there was no association of serum hormone concentrations or MDR1-polymorphisms (C3435T and G2677T) with pharmacokinetic parameters of saquinavir. CONCLUSIONS: There was no effect of OC on saquinavir pharmacokinetics. Thus, pharmacokinetic interactions of synthetic sexual steroids with saquinavir are not likely to account for the increased ADR to antiretroviral therapy seen in women.

Adult↗
PubMed2004

Endothelial venodilator response in carriers of genetic polymorphisms involved in NO synthesis and degradation.

AIMS: Polymorphisms of the NOSIII gene and of the CYBA gene have been associated with a number of pathological conditions such as arterial hypertension, coronary artery disease, and myocardial infarction. Because endothelium-dependent vasodilation is impaired in these disorders, we hypothesized that polymorphisms of NOSIII or CYBA might modulate endothelial function of venous capacitance vessels already before cardiovascular disease becomes overt. METHODS: Endothelium-dependent and -independent venodilation was assessed by measuring local vascular responses to bradykinin and sodium nitroprusside in the dorsal hand vein after preconstriction with phenylephrine in 72 healthy male Caucasians after careful exclusion of cardiovascular risk factors. Genotyping was performed for polymorphisms of the NOSIII gene (T-786C, G894T, (CA)(n)) and the CYBA gene (C242T). RESULTS: Genotype distribution for each polymorphism followed the Hardy-Weinberg equilibrium. In all studied single nucleotide polymorphisms no significant difference between the respective genotypes and the venodilator response to either sodium nitroprusside or bradykinin was observed, and the number of CA repeat copies was not related to the venodilator response to bradykinin. Mean venodilation induced by bradykinin 50 ng min(-1) (+/-SEM) for homozygote carriers of the single nucleotide polymorphisms was 48.9 +/- 8.5% venodilation (G894T; wild type: 49.8 +/- 6.9), 50.3 +/- 11.0% venodilation (T-786C; wild type: 42.6 +/- 5.2), and 30.4 +/- 9.1% venodilation (C242T; wild type: 49.2 +/- 6.0), respectively. CONCLUSIONS: This study suggests that the studied polymorphisms of NOSIII and CYBA do not significantly modulate endothelium-dependent venodilation in individuals without vascular risk factors.

Bradykinin↗