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.

Lack of evidence for association of high altitude pulmonary edema and polymorphisms of the NO pathway.

One essential factor in the development of high altitude pulmonary edema (HAPE) is elevated pulmonary artery pressure, possibly due to a lack of nitric oxide (NO) in pulmonary vessels. NOS3 gene polymorphisms (G894T, T-786C, and CA-repeats > or =38) might be linked to decreased NO synthesis and increased susceptibility to HAPE, while the C242T polymorphism of the CYBA gene [encoding for the NAD(P)H oxidase subunit p22phox] may increase NO availability and thus convey resistance to HAPE. To test this hypothesis, we genotyped 51 mountaineers susceptible and 52 mountaineers not susceptible to HAPE.

Interaction of antiepileptic drugs with human P-glycoprotein in vitro.

About one-third of epilepsy patients are resistant to treatment with antiepileptic drugs (AEDs). This refractoriness is not fully understood, but is thought to be attributed to overexpression of multidrug transporters at the blood-brain barrier, particularly P-glycoprotein (Pgp). In certain cases pharmacoresistance can be overcome by add-on therapy, raising the question of whether the coadministered drugs act as inhibitors of Pgp.

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.

Pharmacokinetic and pharmaceutic interaction between digoxin and Cremophor RH40.

Background: The pharmacokinetics of digoxin is modulated by the efflux pump P-glycoprotein. Cremophor EL (BASF Aktiengesellschaft, Ludwigshafen, Germany) (polyoxyl 35 castor oil), a castor oil derivative used to improve the solubilization of drugs and vitamins, has been shown to inhibit this membrane transporter in vitro and in vivo. So far, no study in humans has evaluated the effect of Cremophor RH40 (BASF Aktiengesellschaft) (polyoxyl 40 hydrogenated castor oil) on P-glycoprotein.

Rapid and reliable genotyping of the C181T polymorphism in the bradykinin B2 receptor gene.

Bradykinin is not only a mediator of pain and inflammation but also a potent vasodilator and is likely to contribute to the cardioprotective effects of angiotensin-converting enzyme inhibitors. The B2 receptor (B2-R) mediating most of the inflammatory and cardiovascular effects of bradykinin represents a candidate gene likely involved in the complex genetic causes of common chronic disorders such as hypertension. The C181T polymorphism of the B2-R gene influences the potency of bradykinin and there is evidence of a possible role of this polymorphism in the development of hypertension and end-stage renal disease.

Inhibition of P-glycoprotein by newer antidepressants.

Pharmacokinetic drug-drug interactions often occur at the level of P-glycoprotein (Pgp). To study possible interactions caused by the newer antidepressants we investigated citalopram, fluoxetine, fluvoxamine, paroxetine, reboxetine, sertraline, and venlafaxine and their major metabolites desmethylcitalopram, norfluoxetine, paroxetine-metabolite (paroxetine-M), desmethylsertraline, N-desmethylvenlafaxine, and O-desmethylvenlafaxine for their ability to inhibit Pgp. Pgp inhibition was studied by a fluorometric assay using calcein-acetoxymethylester as Pgp substrate and two different cell systems: L-MDR1 cells (model for human Pgp) and primary porcine brain capillary endothelial cells (pBCECs, model for the blood-brain barrier).

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.

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.

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.

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.

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.

Local effect of transdermal isosorbide dinitrate ointment on hand vein diameter.

Objective: To assess the effect of topically applied isosorbide dinitrate (ISDN) ointment on superficial hand veins preconstricted with phenylephrine.

Methods: Using the hand vein compliance technique, venous diameter changes were measured in a double-blind, randomised, placebo-controlled cross-over trial in 12 healthy volunteers. During preconstriction with phenylephrine, placebo or ISDN ointment was administered to assess the dilator effect of transdermal ISDN.

Ritonavir increases loperamide plasma concentrations without evidence for P-glycoprotein involvement.

Background: The antidiarrheal drug loperamide is frequently used to treat ritonavir-associated diarrhea in patients with human immunodeficiency virus. The absence of marked central opioid effects has been attributed to its low bioavailability and its poor penetration of the blood-brain barrier, both of which might be altered by ritonavir, a potent P-glycoprotein and cytochrome P4503A inhibitor.

Methods: A 16-mg dose of loperamide was administered to 12 healthy male and female volunteers together with either 600 mg of ritonavir or placebo.

Risk of cataract in patients treated with statins.

Background: Studies in dogs showed that some hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) are associated with cataract when administered in excessive doses. Clinical safety data of statins regarding cataract development in humans have been of limited value so far.

Objective: To determine whether long-term use of statins is associated with an increased risk of cataract.

Drug dosage in patients with renal failure optimized by immediate concurrent feedback.

Objective: To examine the impact of immediate concurrent feedback on dose adjustment in patients with renal failure.

Design: Prospective 12-month study in patients with various degrees of renal failure, with comparison to a retrospective control group.

Setting: A 39-bed unit of a university hospital providing primary and tertiary care.

Disturbed ratio of erythrocyte and plasma S-adenosylmethionine/S-adenosylhomocysteine in peripheral arterial occlusive disease.

Altered homocysteine metabolism associated with peripheral arterial occlusive disease (PAOD) may lead to impairment of vital methylation reactions through accumulation of S-adenosylhomocysteine (AdoHcy) as well as through alteration of the ratio S-adenosylmethionine (AdoMet)/AdoHcy. We determined AdoMet, AdoHcy, their ratio, and homocysteine in plasma as well as AdoMet, AdoHcy, and their ratio in erythrocytes of 61 patients with PAOD (age 49-93) and 50 healthy controls (age 41-87). Geometric mean values of plasma homocysteine, AdoMet, and AdoHcy were significantly increased in patients compared with controls (15.

[Clinically relevant adverse drug interactions].

Drug interactions may lead to adverse drug effects or therapeutic failure. Many clinically relevant unwanted interactions are caused by a change in the activity of cytochrome P450 isoenzymes or the activity of active drug transport systems (e.g.

[Consideration of drug absorption in customizing drug therapy].

The rate and extent of drug absorption from the small intestine are related to the release of the active ingredient from a dosage form, its solubility in the liquid phase of gastrointestinal contents, and the transport of the dissolved compound or the intact dosage form from the stomach into the duodenum. With pharmaceutical preparations releasing the active compound within the stomach, and enteric-coated "micro"-formulations (micropellets), gastric emptying is possible during the interdigestive and the digestive period. Potential differences of drug absorption between fasting administration and intake during the digestive period are unpredictable, because they are related to the release characteristics of the dosage form.

[Individualized drug therapy--need for improvement].

The lack of dose adjustment to the individual needs of a patient is a major cause for the substantial difference between the efficacy of therapies established in large trials and the therapeutic results obtained in everyday practice (reduced effectiveness). In addition, these differences affect drug safety and ultimately also costs. Hence strategies to maintain good compliance and to avoid incompatibilities, drug interactions and adverse events should be applied whenever drugs are prescribed.

Effect of P-glycoprotein modulation on the clinical pharmacokinetics and adverse effects of morphine.

Aims: To investigate the effect of acute P-glycoprotein inhibition by the multidrug-resistance (MDR) modulator valspodar (SDZ PSC 833; PSC) on the pharmacokinetics, and potentially adverse pharmacodynamic effects of morphine, and its principal pharmacologically active metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G).

Methods: In a double-blind, three-way crossover study, the pharmacokinetic and potentially adverse pharmacodynamic effects (reaction time, transcutaneous PCO2, blood pressure) of morphine were compared with and without acute inhibition of P-glycoprotein by PSC. The effects of PSC alone were also evaluated.

Correlation between apolipoprotein B and endothelin-1-induced vasoconstriction in humans.

Low-density lipoprotein (LDL) concentrations have been linked to altered responses to endogenous vasodilators and vasoconstrictors. We evaluated retrospectively the relationship between LDL and vasoconstrictor (endothelin-1, phenylephrine) responsiveness of the forearm vasculature in 15 elderly healthy volunteers with apolipoprotein B and LDL levels in the normal range. In contrast to phenylephrine, changes in forearm vascular resistance induced by endothelin-1 were correlated with apolipoprotein B, LDL, and total cholesterol concentrations in women but not in men.

Inspired oxygen fraction after cardiopulmonary bypass: effects on pulmonary function with regard to endothelin-1 concentrations and venous admixture.

Twenty consecutive patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) were allocated at random to group 1 (n = 10, high inspired oxygen fraction (FIO2) after CPB), or group 2 (n = 10, moderate FIO2 after CPB). The effects of each FIO2 on arterial and mixed venous concentrations of endothelin-1 (ET-1) and its precursor, Big ET-1, were measured. Venous admixture was calculated to assess the efficiency of pulmonary gas exchange.