Biomedical subjects

Walter E Haefeli

Publications and source records attributed to Walter E Haefeli.

44 records · Page 3Linked to original sources

PubMed2004

Undeclared exposure to St. John's Wort in hospitalized patients.

AIM: The herbal medicine St. John's Wort (SJW) causes substantial decreases in the plasma concentrations of a range of co-administered drugs. Therefore, we evaluated the extent of systemic exposure to hyperforin and hypericin, two of the main constituents of SJW, in patients on admission and during hospital stay, and compared the results with known use of SJW as documented in the drug chart and detected in additional interviews. METHODS: One hundred and fifty patients aged > or = 18 years and admitted, between August 2000 and February 2002, to an internal medicine ward of a large German university hospital were included. Hyperforin and hypericin was determined in plasma by a sensitive liquid chromotography/mass spectometry (LC/MS/MS) method. To assess undeclared use of SJW the data were compared to information obtained from drug charts and from up to three interviews that had a particular focus on intake of herbal medicines and self-medication during hospitalization. RESULTS: Hyperforin was detected in 12 patients (plasma concentration on the first day of hospitalization = 12-100 ng ml(-1) in five patients and < 3 ng ml(-1) in seven), and hypericin in five patients (0.5-4.3 ng ml(-1)). Nine patients (6%) were taking/had taken SJW without the knowledge of the medical team and the pharmacist, who conducted the additional interviews, and 11 (7.3%) were taking/had taken SJW without the knowledge of the medical team alone. Seven of these patients were treated concurrently with drugs that can interact with SJW. CONCLUSIONS: Unrecognized use of SJW is frequent and may have an important influence on the effectiveness and safety of drug therapy during hospital stay.

Adult↗

PubMed2003

Highly sensitive determination of saquinavir in biological samples using liquid chromatography-tandem mass spectrometry.

A selective and sensitive method for the determination of the HIV protease inhibitor saquinavir in human plasma, saliva, and urine using liquid-liquid extraction and LC-MS-MS has been developed, validated, and applied to samples of a healthy individual. After extraction with ethyl acetate, sample extracts were chromatographed isocratically within 5 min on Kromasil RP-18. The drug was detected with tandem mass spectrometry in the selected reaction monitoring mode using an electrospray ion source and 2H(5)-saquinavir as internal standard. The limit of quantification was 0.05 ng/mL. The accuracy of the method varied between -1 and +10% (SD within-batch) and the precision ranged from +4 to +10% (SD batch-to-batch). The method is linear at least within 0.05 and 87.6 ng/mL. After a regular oral dose (600 mg) saquinavir concentrations were detectable for 48 h in plasma and were well correlated with saliva concentrations (r(2)=0.9348, mean saliva/plasma ratio 1:15.1). The method is well suited for low saquinavir concentrations in different matrices.

Chromatography, Liquid↗

PubMed2003

Impact of serum creatinine measurement error on dose adjustment in renal failure.

BACKGROUND: Doses of renally eliminated drugs should be adjusted according to kidney function to prevent adverse drug events and cost. Dose adjustment can be based on serum creatinine level, subsequent creatinine clearance estimation, and dosage calculation with consideration of the renal elimination properties of the respective compound. OBJECTIVE: Our objective was to quantify the impact and relevance of serum creatinine measurement error on dose adjustment in renal failure. METHODS: We analyzed 27914 measurements from external quality assessment surveys of 1878 German laboratories that used a kinetic alkaline picrate (69% of results) or an enzymatic method (25%) for creatinine determination. Linear models were fit for both methods combined and separately. On the basis of 95% confidence intervals (CIs) for creatinine values, 95% CIs for drug dosing were calculated. RESULTS: The 95% CI for a measured serum creatinine value was 0.80. Measured value < Reference method value < 1.28. Measured value for the kinetic alkaline picrate method and 0.87. Measured value < Reference method value < 1.21. Measured value for the enzymatic method. Applied to a data set of 6.5 million simulated patients with all possible combinations of characteristics relevant for drug dosing, the dosing error caused by serum creatinine measurement error did not exceed 25% in patients with creatinine clearance estimates lower than 50 mL/min according to the Cockcroft-Gault equation. For drugs completely eliminated by the kidneys in active form, the dosing error was up to 6-fold smaller than that which would occur if doses were not adjusted. CONCLUSION: The serum creatinine measurement error of current laboratory methods is small and is comparable to other errors influencing dose adjustment.

Aging↗

PubMed2003

Interaction of ibuprofen and probenecid with drug metabolizing enzyme phenotyping procedures using caffeine as the probe drug.

AIMS: To examine the suspected inhibitory potential of the over-the-counter (OTC) drug ibuprofen on N-acetyltransferase 2 (NAT2) in vitro and in vivo and the possible implications for phenotyping procedures using caffeine as probe drug. METHODS: We first studied the inhibitory effect of ibuprofen on NAT2 in vitro, using human liver cytosol and sulfamethazine as substrate. In vivo 15 fast and 15 slow acetylating healthy volunteers were treated with a single dose of ibuprofen (800 mg) orally and phenotyped for NAT2, CYP1A2, and xanthine oxidase (XO) with caffeine as probe drug before and during drug treatment. Because of unexpected in vivo results with ibuprofen this study was repeated in 20 healthy volunteers with probenecid, a model substrate of renal organic anion transport (OAT). For phenotyping tests a urine sample was collected 6 h after caffeine (200 mg) intake. The caffeine metabolites acetyl-6-formylamino-3-methyluracil (AFMU), 1-methylxanthine (1MX), 1-methyluric acid (1MU), and 1,7-dimethyluric acid (17MU) were quantified by HPLC, and the corresponding metabolic ratios for CYP1A2, NAT2, and XO were then calculated. Genotyping for NAT2 was performed with standard PCR-RFLP methods. RESULTS: In vitro, with human liver cytosol an inhibition by ibuprofen of the acetylation of sulfamethazine with Ki values between 2.2 and 3.1 mm was observed. Surprisingly, in vivo a significant (P < 0.001) increase of the acetyl-6-formylamino-3-methyluracil/1-methylxanthine (AFMU/1MX) urinary ratio from 0.97 +/- 0.16 to 1.08 +/- 0.18 (95% CI on the difference 0.049, 0.170) was found, indicating an apparent elevation of NAT2 activity. In contrast, no change was observed for the ratios used for XO and CYP1A2. Because an induction of NAT2 could be excluded, an interaction of ibuprofen with the tubular secretion of some of the caffeine metabolites was assumed. To prove this assumption, the in vivo study was repeated with probenecid, a model substrate of the renal OAT system. Again, a prominent elevation of the AFMU/1MX ratio from 0.97 +/- 0.21 to 1.53 +/- 0.35 was found (P < 0.002; 95% CI on the difference 0.237, 0.876), but also the XO ratio 1MU/1MX was significantly (P < 0.0001) increased from 1.34 +/- 0.09 to 2.24 +/- 0.14 (95% CI on difference 0.735, 1.059) due to a reduction of 1MX excretion. CONCLUSIONS: Substrates of OAT interact with renal excretion of caffeine metabolites and may falsify NAT2 and XO phenotyping results. Other phenotyping procedures, which are based on urinary metabolic ratios, should also be validated in this respect, especially in patients under polymedication.

Adult↗

PubMed2003

Contribution of increased oral bioavailability and reduced nonglomerular renal clearance of digoxin to the digoxin-clarithromycin interaction.

AIMS: A clinically important interaction between the cardiac glycoside digoxin and the antibiotic clarithromycin has been suggested in earlier reports. The aim of this study was to investigate the extent of the interaction and the relative contribution of different mechanisms. METHODS: In a randomized, placebo-controlled, double-blind cross-over design single oral doses of 0.75 mg digoxin with oral coadministration of placebo or 250 mg clarithromycin twice daily for 3 days were administered to 12 healthy men. Additionally, three of the subjects received single intravenous doses of 0.01 mg x kg(-1) digoxin with oral placebo or clarithromycin. Digoxin plasma and urine concentrations were determined by a highly sensitive radioimmunoassay. RESULTS: Oral coadministration of clarithromycin resulted in a 1.7-fold increase of the area under the digoxin plasma concentration-time curve [mean AUC(0,24) +/- SD 23 +/- 5.2 vs. 14 +/- 2.9 microg x L(-1) x h; 95% confidence interval (CI) on the difference 7.0, 12; P = 0.002] and in a reduction of the nonglomerular renal clearance of digoxin [mean ClRng(0, 24) +/- SD 34 +/- 39 vs. 57 +/- 41 mL min-1; 95% CI on the difference 7.2, 45; P = 0.03]. The ratios of mean digoxin plasma concentrations with and without clarithromycin were highest during the absorption period of clarithromycin. After intravenous administration digoxin AUC(0,24) increased only 1.2-fold during coadministration of clarithromycin. CONCLUSIONS: Increased oral bioavailability and reduced nonglomerular renal clearance of digoxin both contribute to the interaction between digoxin and clarithromycin, probably due to inhibition of intestinal and renal P-glycoprotein.

Administration, Oral↗

PubMed2002

Quality markers of drug information on the Internet: an evaluation of sites about St. John's wort.

PURPOSE: We aimed to evaluate websites about St. John's wort for the quality of their content, including accuracy as reflected by statement of correct indication and mentioning of interacting drugs, the presence of formal criteria as reflected by adherence to published standards for health information on the Internet, and the validity of individual formal criteria as markers of content quality. SUBJECTS AND METHODS: The Internet was searched with the metasearch engine WebFerret for sites about St. John's wort. A cross-sectional survey of a representative sample of randomly selected sites (n = 208) was performed. The main outcomes were the percentage of sites fulfilling the two criteria of content quality, the percentage of sites exhibiting eight formal criteria, and the associations between formal criteria and criteria of content quality, as determined by multivariate logistic regression analysis. RESULTS: Twenty-two percent (n = 45) of the websites correctly listed depression as the only indication for use of St. John's wort, and 22% (n = 46) identified at least one drug interaction with St. John's wort. Citing scientific publications was associated with mentioning the correct indication (odds ratio [OR] = 4.4; 95% confidence interval [CI]: 1.4 to 14) and mentioning of any interacting drug (OR = 6.0; 95% CI: 2.0 to 18). Absence of financial interest was associated with mentioning the correct indication (OR = 5.4; 95% CI: 2.2 to 14) and interacting drugs (OR = 3.1; 95% CI: 1.2 to 7.7). CONCLUSION: The content quality of sites about St. John's wort was generally poor. Our results suggest that Internet users should prefer noncommercial sites that reference the information to scientific publications when searching for drug information.

Cross-Sectional Studies↗

PubMed2002

Dose-dependent increase of saquinavir bioavailability by the pharmaceutic aid cremophor EL.

AIMS: Bioavailability of orally administered drugs depends on several factors including active excretion, e.g. by P-glycoprotein (PGP), and presystemic metabolism, e.g. by cytochrome P450 3A (CYP3A), in both gastrointestinal tract and liver. Many drugs including saquinavir are substrates of both PGP and CYP3A. It was the aim of this study to test whether the extremely low bioavailability of saquinavir can be increased dose-dependently in vivo by cremophor EL, an 'inactive' pharmaceutic aid known to inhibit PGP in vitro. METHODS: In a randomized, placebo-controlled, double-blind, four phase cross-over design single doses of oral saquinavir (Invirase, 600 mg, without food) were administered with increasing single doses of oral cremophor EL (up to 5000 mg) to eight healthy, male individuals. Saquinavir plasma concentrations were determined by LC/MS/MS up to 48 h after intake. Main outcome measures were area under the plasma concentration time curve (AUC), peak concentration (Cmax), time to reach Cmax (tmax) and terminal elimination half-life (t(1/2)). RESULTS: Cremophor EL dose-dependently increased Cmax, AUC(0,4 h), and AUC(0,infinity) of saquinavir. As compared with placebo, the increment observed after 5000 mg cremophor EL was 13-fold for both Cmax and AUC(0,4 h) and 5-fold for AUC(0,infinity). The terminal half-life and the time to reach Cmax (tmax) were unchanged. CONCLUSIONS: Cremophor EL increased the systemic availability of saquinavir without affecting its elimination suggesting that cremophor EL is not devoid of pharmacological action and acts as a modulator of the absorption process, probably by inhibiting intestinal PGP.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2002

Rapid detection of polymorphisms of the nitric oxide cascade.

NOS3 (endothelial nitric oxide (NO) synthase) and p22phox (subunit of NAD(P)H oxidase) are two genes whose products are involved in formation and degradation of NO, a ubiquitous signaling molecule largely responsible for the maintenance of normal endothelial function. The G894T polymorphism of NOS3 and the C242T polymorphism of p22phox are reportedly associated with numerous cardiovascular diseases. For each polymorphism we developed a rapid and reliable method with the hybridization probes format on the LightCycler and compared it with conventional PCR-restriction fragment length polymorphism (PCR-RFLP) analysis with regard to reliability, duration and cost. The new methods are more reliable, faster and less expensive than PCR-RFLP analysis and therefore represent a significant advantage in the detection of two candidate risk factors for cardiovascular diseases.

Alleles↗