Biomedical subjects

Walter E Haefeli

Publications and source records attributed to Walter E Haefeli.

At least 19 recordsLinked to original sources

PubMed2007

Management of potential drug interactions in community pharmacies: a questionnaire-based survey in Switzerland.

OBJECTIVE: To analyze the current drug-interaction management in Swiss community pharmacies, with a particular focus on electronic systems, and to compare the results with those expressed by German general practitioners in a recent survey. METHODS: Data were collected with a postal questionnaire which was randomly sent to 500 out of 833 community pharmacies in the German part of Switzerland. RESULTS: The response rate was 57.4%, and only 24.7% pharmacists reported that they were confronted less than daily with potential drug interactions. Use of computer software to identify potential drug interactions was widespread in community pharmacies (90.2%), and the software was the primary source of information (81.2 +/- 29.6%). The quality of the interaction software was judged sensitive (identifying all dangerous interactions) by 80.5 +/- 21.5%, but specific (identifying only relevant interactions) by only 38.3 +/- 32%. Pharmacists declared a low override rate (14%) of drug interaction alerts, although unjustified alerts were reported by 60.6 +/- 33.1%. In contrast to general practitioners, pharmacists opted less often for information on the mechanism of the interaction, and more frequently for details for dose adjustment. Both groups complained about deficient information on non-interacting alternatives. CONCLUSION: The information needs of community pharmacists differed considerably from general practitioners, and pharmacists were overwhelmed by inappropriate alerts because of a lack of specificity of their drug-interaction systems. Substantial improvement of drug-interaction software systems is thus required at least in two important aspects, the suppression of inappropriate alerts and the tailoring to the needs of the user.

Adult↗

PubMed2006

NKIM-6, a new immortalized human brain capillary endothelial cell line with conserved endothelial characteristics.

Primary human brain capillary endothelial cells (hBCECs) are available only in small quantities and have a short life span in vitro; this restricts their use as in vitro model for the blood-brain barrier (BBB). To overcome these limitations, we have established an immortalized hBCEC line (NKIM-6) by transfection with pLXSN16E6E7, which encodes the human papillomavirus type 16 E6 and E7 genes. The cell line exhibits an extended life span in vitro and retains its characteristic endothelial morphology, endothelial markers, and physiology. Likewise, as demonstrated by immunohistochemistry and reverse transcription/polymerase chain reaction (RT-PCR), NKIM-6 cells express BBB markers, and the lack of glial, neuronal, and epithelial markers confirms their endothelial origin. Moreover, with quantitative RT-PCR, we have been able to demonstrate that several ATP-binding cassette-transporters are expressed in NKIM-6 cells with a conserved expression order compared with primary hBCECs. Our results suggest that this cell line might be suitable as in vitro model for several aspects of the BBB.

ATP-Binding Cassette Transporters↗

PubMed2006

Monitoring of lopinavir and ritonavir in peripheral blood mononuclear cells, plasma, and ultrafiltrate using a selective and highly sensitive LC/MS/MS assay.

For the determination of the HIV protease inhibitors lopinavir and ritonavir in human plasma, plasma ultrafiltrate, and peripheral blood mononuclear cells (PBMCs) a highly sensitive and selective method has been developed, validated, and applied to samples of a healthy volunteer. BD Vacutainer CPT and Amicon Centriplus centrifugal filter devices were used for separation of PBMCs and for ultrafiltrate generation, respectively. After liquid/liquid-extraction extracts were chromatographed isocratically within 6 min on a Jupiter Proteo column. The drugs were quantified using 2H5-saquinavir as internal standard and electrospray tandem mass spectrometry in the selected reaction monitoring mode. Limits of quantification for both analytes were 4.0 ng/mL in plasma, 0.2 ng/mL in ultrafiltrate, and 0.1 ng/cell pellet (approximately 3 x 10(6) cells) in PBMCs. The calibration ranges were linear over more than three logs with an over-all accuracy varying between 98.7% and 111.5% and an over-all precision ranging from 6.2% to 14.0% (SD batch-to-batch). After a regular oral dose of Kaletra (400 mg lopinavir, 100 mg ritonavir) analyte concentrations were detectable over a full dosing interval in plasma, ultrafiltrate, and PBMCs. The method is well suited for monitoring of free and total plasma, and intracellular lopinavir/ritonavir concentrations in samples from clinical trials.

HIV Protease Inhibitors↗

PubMed2006

Voriconazole concentration in human aqueous humor and plasma during topical or combined topical and systemic administration for fungal keratitis.

Voriconazole (VRC) is an antifungal drug that effectively treats keratitis caused by yeasts and molds when administered orally. We retrospectively evaluated clinical outcomes and plasma and aqueous humor drug concentrations in five patients with fungal keratitis and one patient with posttraumatic endophthalmitis who were treated with VRC. VRC was administered either topically (1% eye drops every hour) or orally (400 mg twice a day). Plasma and aqueous humor samples from affected eyes were taken 12 h after oral administration or 1 h after eye drop application. The drug concentration was measured by liquid chromatography with UV or mass spectrometric detection. All six patients responded well to VRC treatment. The VRC concentration ranged from 2.93 to 3.40 mg/liter in the aqueous humor and from 3.20 to 4.20 mg/liter in the plasma after combined oral and topical treatment. Topical administration alone resulted in highly variable trough VRC concentrations of 0.61 to 3.30 mg/liter in the aqueous humor. VRC concentrations were above the MIC for Candida albicans Aspergillus fumigatus and clinical improvement was seen in all four patients with C. albicans and A. fumigatus keratitis. Combined orally and topically administered VRC resulted in aqueous humor drug concentrations of > or =2.93 mg/liter, which is above the VRC MIC for most fungi. Topical VRC treatment resulted in an aqueous humor drug concentration >0.61 mg/liter, which is above the MIC for most Candida species. The results from this small series of patients suggest that both topical and combined systemic and topical VRC therapy can be effective in treating fungal keratitis. Furthermore, the data provide preliminary support for initiation of VRC treatment with a combined topical and systemic administration until the causative fungus and its MIC are identified.

Administration, Oral↗

PubMed2006

Pharmacokinetics of a netilmicin loading dose on the first postnatal day in preterm neonates with very low gestational age.

OBJECTIVE: Pharmacokinetic parameters are important for dose adjustment of aminoglycosides, but they are highly variable in neonates. In this study the pharmacokinetics of a netilmicin loading dose was investigated on the first postnatal day in preterm neonates with very low gestational age (GA). METHODS: In an open prospective study, 20 neonates with GA between 22.9 and 32.0 weeks and suspected postnatal bacterial infection received an intravenous loading dose of 5 mg/kg netilmicin over 1 h during the first postnatal day. Netilmicin serum concentrations were determined by an enzyme multiplied immunoassay. RESULTS: The systemic clearance of netilmicin normalized to body weight (BW) was not significantly different in three GA subgroups (0.59+/- 0.02 ml/min/kg for GA <24 weeks, 0.72+/-0.14 ml/min/kg for GA 24-27 weeks, and 0.62+/-0.19 ml/min/kg for GA 27-32 weeks, P=0.123). Similar results were also obtained for serum elimination half-time and for the distribution volume normalized to BW. Multiple regression analysis showed that systemic clearance and volume of distribution (both not normalized to BW) significantly correlated with BW (P<0.0001) but not with GA. In the entire group, 20% of peak concentrations were below the target of 6 mg/l, and 63% of trough concentrations were above the target of 2 mg/l. CONCLUSION: In neonates with very low GA, the pharmacokinetic parameters of netilmicin determined after an intravenous loading dose were not dependent on GA when normalized to BW. A number of neonates did not reach targeted peak and trough netilmicin serum concentrations, suggesting that a higher loading dose and a prolonged dosing interval might enhance the effectiveness and safety of netilmicin in preterm neonates immediately after birth.

Anti-Bacterial Agents↗

PubMed2006

Potent cytochrome P450 2C19 genotype-related interaction between voriconazole and the cytochrome P450 3A4 inhibitor ritonavir.

OBJECTIVES: Cytochrome P450 (CYP) 2C19 and CYP3A4 are the major enzymes responsible for voriconazole elimination. Because the activity of CYP2C19 is under genetic control, the extent of inhibition with a CYP3A4 inhibitor was expected to be modulated by the CYP2C19 metabolizer status. This study thus assessed the effect of the potent CYP3A4 inhibitor ritonavir after short-term administration on voriconazole pharmacokinetics in extensive metabolizers (EMs) and poor metabolizers (PMs) of CYP2C19. METHODS: In a randomized, placebo-controlled crossover study, 20 healthy participants who were stratified according to CYP2C19 genotype received oral ritonavir (300 mg twice daily) or placebo for 2 days. Together with the first ritonavir or placebo dose, a single oral dose of 400 mg voriconazole was administered. Voriconazole was determined in plasma and urine by liquid chromatography-mass spectrometry, and pharmacokinetic parameters were estimated by noncompartmental analysis. RESULTS: When given alone, the apparent oral clearance of voriconazole after single oral dosing was 26%+/-16% (P > .05) lower in CYP2C19*1/*2 individuals and 66%+/-14% (P < .01) lower in CYP2C19 PMs. The addition of ritonavir caused a major reduction in voriconazole apparent oral clearance (354+/-173 mL/min versus 202+/-139 mL/min, P = .0001). This reduction occurred in all CYP2C19 genotypes (463+/-168 mL/min versus 305+/-112 mL/min [P = .023] for *1/*1, 343+/-127 mL/min versus 190+/-93 mL/min [P = .008] for *1/*2, and 158+/-54 mL/min versus 22+/-11 mL/min for *2/*2) and is probably caused by inhibition of CYP3A4-mediated voriconazole metabolism. CONCLUSIONS: Coadministration of a potent CYP3A4 inhibitor leads to a higher and prolonged exposure with voriconazole that might increase the risk of the development of adverse drug reactions on a short-term basis, particularly in CYP2C19 PM patients.

Adult↗

PubMed2006

Kinetics and dynamics of the peripheral neurokinin-1 receptor antagonist SLV317 in healthy individuals.

AIMS: To investigate the pharmacokinetics and the pharmacodynamic effects in dorsal hand veins of the neurokinin-1 receptor antagonist SLV317. METHODS: In a randomized, double-blind, placebo-controlled cross-over study 19 healthy men received a single oral dose of SLV317 or placebo. Blood samples were collected for analysis of SLV317 plasma concentrations and the inhibition of the venodilator response to substance P was evaluated using the hand vein compliance method. RESULTS: Administration of 250 mg SLV317 as an oral solution was well tolerated and resulted in mean peak plasma concentrations (+/- SEM) of 77 +/- 9 ng ml(-1) within 47 +/- 3 min; the mean half-life was 9.9 +/- 1.6 h. In hand veins preconstricted with phenylephrine, local infusion of substance P resulted in a mean venodilation of 56 +/- 8% and 49 +/- 6% (P = 0.91) before administration of SLV317 or placebo, respectively. SLV317 caused a substantial inhibition of substance P-induced venodilation, whereas placebo had no effect (P < 0.001). The maximum antagonizing effect of SLV317 averaged 95 +/- 8% and was observed after 1.47 +/- 00.24 h. Correspondingly, the mean area under the effect curve after administration of SLV317 [278 +/- 67% h(-1); 95% confidence interval (CI) 198, 358] was significantly higher compared with placebo (49 +/- 12% h(-1); 95% CI -24, 122; P < 0.001). CONCLUSIONS: This study demonstrates that the neurokinin-1 receptor antagonist SLV317 is an orally active and highly effective antagonist of substance P-induced effects in humans.

Administration, Oral↗

PubMed2005

Interaction of the mitotic kinesin Eg5 inhibitor monastrol with P-glycoprotein.

Monastrol is the first characterised small molecule inhibitor of the motor protein Eg5 involved in bipolar mitotic spindle assembly. Eg5 localises to microtubules in mitosis, but not to interphase microtubules, suggesting that Eg5 inhibitors may be useful to specifically target proliferating tumour tissue, thereby avoiding dose-limiting neuropathy observed with other antimicrotubule agents like taxanes or vinca alkaloids. Because other antimicrotubule agents fail in multidrug resistance associated with P-glycoprotein (Pgp) over-expression, we investigated the interaction of monastrol with Pgp in vitro. By means of the calcein assay (with P388/dx cells and primary porcine brain capillary endothelial cells) and confocal laser-scanning microscopy (with L-MDR1 cells) we demonstrated that monastrol is a weak inhibitor of Pgp in vitro, with f2 values being about two orders of magnitude greater than those of the well-known inhibitors verapamil and quinidine. Monastrol also induces Pgp in vitro as measured by mRNA expression in LS180 cells after incubation with monastrol. However, its effect is weak compared to rifampicin. Whilst it reveals weak inhibitory and inductive characteristics, monastrol appears to be not transported by Pgp, as indicated by the lack of difference in the antiproliferative effect of this compound in cell lines with and without over-expression of Pgp. The observed interaction profile of monastrol with Pgp is promising for the development of other more potent Eg5 inhibitors.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

A similarity measure for case based reasoning modeling with temporal abstraction based on cross-correlation.

Adverse drug events (ADEs) are a major limitation of drug safety. They are often caused by inappropriate selection of dose and the concurrent use of drugs modulating each other (drug interaction). Risk assessment and prevention strategies must therefore consider co-administered drugs, individual doses, and their timing. In a new approach we evaluated the performance of cross correlation, commonly used in signal processing, to determine similarities in patient treatments. To achieve this, patient treatments were modeled as groups of vectors representing discrete time intervals. These vectors were cross-correlated and the results evaluated to find clusters in time courses indicating similarity in treatment of different patients. To evaluate our algorithm, we then created a number of test cases. The focus of this article is on each treatment, and its pattern in time and dosage. The algorithm successfully produces a relatively low similarity score for cases that are completely different with respect to their pattern of time and dosage but high scores when they are equal (score of 0.699) or similar (score of 0.528) in their therapies, and thus succeeds in having a relatively high specificity (27/30). Such an approach might help to considerably reduce the problem of false alarms which hampers most existing alerting systems for medication errors or impending ADEs.

Adverse Drug Reaction Reporting Systems↗

PubMed2005

Fluconazole dosing in continuous veno-venous haemofiltration (CVVHF): need for a high daily dose of 800 mg.

To cover intermediate sensitive Candida glabrata in ICU patients, fluconazole plasma peak levels at least in the range of 16-32 microg/ml appear necessary for treatment. Previous studies did not reach these fluconazole levels under continuous veno-venous haemofiltration (CVVHF) with dosages of 200-600 mg fluconzole daily. In the present study, nine patients simultaneously requiring CVVHF for treatment of acute oligoanuric renal failure and antimycotic therapy of Candida septicemia received fluconazole 800 mg/day. Fluconazole plasma levels were determined to evaluate whether this dosage is adequate to reach the advised fluconazole levels. Patients were dialysed on two consecutive days with an ultrafiltration rate (UF) of 1000 ml/h or 2000 ml/h, respectively, in a randomized order. The predilution was 800 ml/h and 1800 ml/h, respectively. The treatment was tolerated without adverse effects. All patients reached plasma fluconazole concentrations between 16 and 32 microg/ml, remaining in this range for a minimum of 1 up to 24 h with a mean of 9.6 h and a UF rate of 2000 ml/h, and 15.7 h with a UF rate of 1000 ml/h. So far, there are no in vivo data on the fluconazole plasma concentrations required for effective treatment. However, our data demonstrate, that at least the fluconazole concentrations desirable on the basis of in vitro susceptibility testing can be reached in critically ill patients on CVVHF in an ICU setting. However, in these patients, 800 mg fluconazole/day are necessary to achieve fungicidal drug concentrations.

Acute Kidney Injury↗

PubMed2005

Analysis of methylene blue in human urine by capillary electrophoresis.

A capillary electrophoresis method for the determination of the dye methylene blue (tetramethylthionine, MB) in human urine depending on liquid/liquid-extraction and diode array detection has been developed, validated, and applied to samples of healthy individuals, who had been dosed with methylene blue within clinical studies. After extraction with dichloromethane and sodium hexanesulfonate, sample extracts were measured on an extended light path capillary. The dye was detected simultaneously at 292 and 592 nm using methylene violet 3 RAX as internal standard. The limit of quantification was 1.0 microg/ml. The accuracy of the method varied between -15.2 and +0.8% and the precision ranged from 2.0 to 12.0%. The method was linear at least within 1.0 and 60 microg/ml. In contrast to earlier indirect determinations no leuco methylene blue (LMB) was directly detected in urine, whereas in aqueous test solutions containing surplus amounts of ascorbic acid leuco methylene blue was well separated from MB in a single run.

Ascorbic Acid↗

PubMed2005

Modulation of endothelial and smooth muscle function by bed rest and hypoenergetic, low-fat nutrition.

Prolonged microgravity alters the regulation of the peripheral vasculature. The influence of reduced food intake, as often observed in astronauts, on vascular function is unclear. In a randomized, four-phase, crossover study, the effect of simulated microgravity (13 days of bed rest), energetic restriction (-25%, fat reduced), and their combination on endothelium-dependent and -independent vasodilation was compared with ambulatory control conditions. Using venous occlusion plethysmography, cumulative intra-arterial dose-response curves to endothelium-dependent (acetylcholine) and -independent (sodium nitroprusside) vasodilators were constructed in 10 healthy male volunteers before and on day 13 of each of the four intervention periods. Bed rest combined with normoenergetic nutrition impaired the dose-response to acetylcholine (ANOVA, P = 0.004) but not to sodium nitroprusside, whereas hypoenergetic diet under ambulatory conditions improved responses to acetylcholine (P = 0.044) and sodium nitroprusside (P < 0.001). When bed rest was combined with hypoenergetic diet, acetylcholine responses did not change. Similarly, under control conditions, no change was observed. Individual changes in the total cholesterol-to-HDL ratio were correlated with changes in endothelial and vascular smooth muscle relaxation. In conclusion, short-term bed rest impairs endothelium-dependent arterial relaxation in humans. A hypoenergetic, low-fat diet modulates serum lipids, improves endothelium-dependent and -independent relaxation, and may antagonize the unfavorable effects of simulated microgravity on endothelial function.

Adaptation, Physiological↗

PubMed2005

Information deficits in the summary of product characteristics preclude an optimal management of drug interactions: a comparison with evidence from the literature.

OBJECTIVE: To compare comprehensiveness and accuracy of drug interaction information in the German summary of product characteristics (SPC) with current evidence from the literature and to evaluate the SPC's usefulness with respect to management of drug interactions. METHODS: Information on clinically relevant drug interactions was compared between the SPC and three standard information sources on drug interactions (DRUGDEX, Hansten/Horn's Drug Interactions Analysis and Management, Stockley's Drug Interactions) according to five consecutive criteria (inclusion, appropriateness of class labelling, effect description, management recommendation, explicit dose adjustment). Using medication data of an outpatient population (n=4,949), we determined what percentage of insufficiently characterized combinations indeed occurred in outpatients treated with combination drug therapy. RESULTS: Only for 33% (192/579) of the evaluated combinations did SPCs provide drug interaction information equivalent to the evidence from the published literature. Of the clinically relevant drug interactions, 16% were completely missing and 51% were insufficiently characterized compared with standard sources. Explicit management recommendations were either missing or differed from standard sources in 18% of the evaluated pairs of compounds. Of these missing or insufficiently characterized combinations, 12% (47/387) were indeed prescribed to outpatients. Those drug combinations for which the interaction potential was not mentioned in the SPC were received by 0.6% (32/4,949) of patients, and 4% (192/4,949) of patients received combinations that had insufficiently characterized drug interactions. CONCLUSIONS: If physicians only rely on SPC information for drug interactions, adverse events due to lacking management recommendations may occur. To meet the SPCs claim of being the basis of information for health professionals on how to use medicinal products safely and effectively, information on drug interactions should be thoroughly up-dated and expanded.

Databases as Topic↗

PubMed2005

Hypoxia impairs systemic endothelial function in individuals prone to high-altitude pulmonary edema.

RATIONALE: High-altitude pulmonary edema (HAPE) is characterized by excessive pulmonary vasoconstriction and is associated with decreased concentrations of nitric oxide (NO) in the lung. OBJECTIVES: We hypothesized that individuals susceptible to HAPE (HAPE-S) would also have dysfunction of the vascular NO vasodilator pathway during hypoxia in the systemic vasculature. METHODS: During normoxia (FI(O(2)) = 0.21) and 4 hours of normobaric hypoxia (FI(O(2)) = 0.12, corresponding to an altitude of 4,500 m above sea level) endothelium-dependent and endothelium-independent vasodilator responses to intraarterial infusion of acetylcholine (ACh) and sodium nitroprusside, respectively, were measured by forearm venous occlusion plethysmography in nine HAPE-S subjects and in nine HAPE-resistant control subjects. MAIN RESULTS: Pulmonary artery systolic pressure increased from 22 +/- 3 to 33 +/- 6 mm Hg (p < 0.001) during hypoxia in control subjects, and from 25 +/- 4 to 50 +/- 9 mm Hg in HAPE-S subjects (p < 0.001). Despite similar responses during normoxia in both groups, ACh-induced changes in forearm blood flow markedly decreased during hypoxia in HAPE-S subjects (p = 0.01) but not in control subjects. The attenuated vascular response to ACh infusion during hypoxia inversely correlated with increased pulmonary artery systolic pressure (p = 0.04) and decreased plasma nitrite correlated with attenuated ACh-induced vasodilation in HAPE-S subjects (p = 0.02). CONCLUSIONS: Hypoxia markedly impairs vascular endothelial function in the systemic circulation in HAPE-S subjects due to a decreased bioavailability of NO. Impairment of the NO pathway could contribute to the enhanced hypoxic pulmonary vasoconstriction that is central to the pathogenesis of HAPE.

Acetylcholine↗

PubMed2005

Mail surveys: obsolescent model or valuable instrument in general practice research?

QUESTION UNDER STUDY: Due to low response rates mail surveys have been called into question as research instruments in general practice. The most effective actions to reduce non-response, such as financial incentives and complex follow-up procedures, are costly. We investigated whether a good response rate is achievable with a less costly survey design, and examined the effect of increased response rates due to repeated follow-ups on survey results. METHODS: In a mail survey on drug interactions among 2000 general practitioners in south-west Germany, most well-known criteria influencing response rates were met except financial incentives. A four stage design with two reminders was applied and the time course of response was recorded. Results after both reminders were calculated with 95% confidence intervals and compared with initial results using the Jonckheere-Terpstra test with correction for multiple testing. A p <0.01 was considered significant. RESULTS: Although we did not provide financial incentives we achieved a response rate of 60.8% with our survey design. The first reminder with a simple postcard was almost three times less effective than the second reminder including another copy of the questionnaire. For only two survey questions, the answers of late respondents differed significantly from those of initial respondents (p <0.01). For these two questions, cumulative results after both reminders never differed from initial results by more than 3.7%. CONCLUSION: Even if financial incentives are not affordable, good response rates can be obtained among general practitioners when surveys are meticulously planned and implemented. Potential non-response bias introduced by those general practitioners who do not answer despite numerous reminders, cannot be tested by comparing early and late respondents. Therefore, we suggest that the impact of reminders on survey results should be assessed early. If no bias can be detected one further reminder with a copy of the questionnaire might result in estimates very similar to those after numerous reminders.

Drug Interactions↗

PubMed2005

Cytochrome P450 enzyme-mediated drug metabolism at exposure to acute hypoxia (corresponding to an altitude of 4,500 m).

OBJECTIVE: To investigate the effect of acute hypoxia and concomitant changes in portal blood flow on the disposition of drugs mainly metabolized by the cytochrome P(450) enzymes (CYP) 3A4 (verapamil) and CYP1A2 (theophylline). METHODS: Twenty healthy male participants were studied on two 14-h study days in a normobaric hypoxic chamber and were allocated randomly to one of two groups receiving short infusions of either theophylline (6 mg kg (-1) body weight) or verapamil (5 mg) intravenously. According to a randomized, cross-over design, participants were once exposed to normoxia and once to hypoxia (12% oxygen corresponding to the ambient( P)O(2) at an altitude of 4,500 m above sea level). The concentrations of theophylline, 1,3-dimethyluric acid, verapamil, and norverapamil were determined in serial blood samples by means of liquid chromatography-mass spectrometry (LC/MS/MS). Portal blood flow was assessed by transabdominal duplex ultrasonography. RESULTS: Acute hypoxia did not alter the pharmacokinetics of theophylline [half-life+/-SD: 9.29+/-1.77 versus 9.39+/-1.40 (hypoxia)], 1,3-dimethyluric acid (12.9+/-4.72 versus 15.1+/-8.59), verapamil (2.00+/-0.98 versus 1.79+/-0.58), or norverapamil (7.98+/-2.94 versus 9.91+/-6.40). Individual changes of elimination half-life and changes in capillary oxygen saturation,( P)O(2), or portal vein flow were not correlated. Portal vein flow was unaffected by hypoxia. CONCLUSIONS: Acute hypoxia corresponding to hypoxia at altitudes of 4,500 m does not impair the metabolism mediated by CYP1A2 or CYP3A4. At rapid ascent to and short-term stay at altitudes up to 4,500 m, the doses of drugs metabolized by these CYPs do therefore not require dose modification, and major changes in the disposition of already administered drugs are not to be expected.

Adult↗

PubMed2005

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

OBJECTIVES: Constituents of St John's 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. METHODS: In a controlled, open-label study, single oral doses of 400 mg voriconazole were administered to 16 healthy men stratified for CYP2C19 genotype before and on day 1 and day 15 of concomitant SJW intake (300 mg LI 160 3 times daily). Plasma and urine concentrations of voriconazole were determined by liquid chromatography with mass-spectrometric detection. RESULTS: During the initial 10 hours of the first day of SJW administration, the area under the voriconazole plasma concentration-time curve was increased by 22% compared with control (15.5 +/- 6.84 h . microg/mL versus 12.7 +/- 4.16 h . microg/mL, P = .02). After 15 days of SJW intake, the area under the plasma concentration-time curve from hour 0 to infinity was reduced by 59% compared with control (9.63 +/- 6.03 h . microg/mL versus 23.5 +/- 15.6 h . microg/mL, P = .0004), with a corresponding increase in oral voriconazole clearance (CL/F) from 390 +/- 192 to 952 +/- 524 mL/min (P = .0004). The baseline CL/F of voriconazole and the absolute increase in CL/F were smaller in carriers of 1 or 2 deficient CYP2C19*2 alleles compared with wild-type individuals (P < .03). CONCLUSIONS: Coadministration of SJW leads to a short-term but clinically irrelevant increase followed by a prolonged extensive reduction in voriconazole exposure. SJW might put CYP2C19 wild-type individuals at highest risk for potential voriconazole treatment failure.

Administration, Oral↗

PubMed2005

Fluvoxamine affects sildenafil kinetics and dynamics.

Sildenafil used as oral drug treatment for erectile dysfunction is predominantly metabolized by the cytochrome P450 isozyme 3A4. The antidepressant fluvoxamine is an inhibitor of cytochrome P450 3A4. In a randomized, double-blind, placebo-controlled, crossover study, we evaluated the effects of fluvoxamine dosed to steady state on the pharmacokinetics and pharmacodynamics of sildenafil. Twelve healthy men received oral fluvoxamine or placebo for 10 days (50 mg every day on days 1-3; 100 mg every day on days 4-10). On day 11, all participants received a single, oral, open-label dose of 50 mg sildenafil, and blood samples were collected for analysis of sildenafil plasma concentrations by liquid chromatography/mass spectrometry. Concurrently, the effect of sildenafil on venodilation induced by a constant dose of sodium nitroprusside was assessed using the dorsal hand vein compliance technique. Sildenafil was well tolerated in the presence of fluvoxamine. During fluvoxamine, sildenafil exposure (area under the curve) significantly increased by 40% (P < 0.001), and its half-life increased by 19% (P = 0.034). Concurrently, sodium nitroprusside-induced venodilation was significantly augmented by 59% during fluvoxamine compared to placebo (P = 0.012). In conclusion, sildenafil kinetics are mildly affected by fluvoxamine which translates into an increase in vascular sildenafil effects. Whereas the pharmacokinetic changes do not suggest a large clinically relevant interaction, it may be prudent to consider a starting dose of 25 mg in patients concurrently treated with fluvoxamine.

Adult↗