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Biomedical subjects

A Kovar

Publications and source records attributed to A Kovar.

10 recordsLinked to original sources
PubMed2006

The role of pharmacokinetics and pharmacodynamics in phosphodiesterase-5 inhibitor therapy.

Differences in clinical pharmacology of the currently marketed phosphodiesterase (PDE)5 inhibitors sildenafil, vardenafil and tadalafil are largely determined by their pharmacokinetic (PK) properties and their PDE5 inhibitory activity profile. This review outlines the basic concepts of pharmacokinetics and pharmacokinetic pharmacodynamic (PK/PD) relationships and their relevance to dose selection and applied pharmacotherapy. It is followed by a detailed comparative discussion on the pharmacokinetics and exposure-response relationship of the currently available PDE5 inhibitors, including known drug-drug interactions and dosage adjustments in special populations. The review is aimed at providing a critical assessment of the pharmacokinetics of PDE5 inhibitors, which may assist clinicians in tailoring drug and/or treatment regimens to the unique needs of each individual patient with erectile dysfunction.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2001

Clinical trial with escalating doses of the antiepidermal growth factor receptor humanized monoclonal antibody EMD 72 000 in patients with advanced squamous cell carcinoma of the larynx and hypopharynx.

In this open uncontrolled phase I study, nine patients with stage III and IV squamous cell carcinoma of the head and neck (SCCHN) were treated with five administrations of the humanized antiepidermal growth factor receptor monoclonal antibody EMD 72000 in three consecutive ascending dose groups. Loading doses of 100 mg (group I), 200 mg (group II), and 400 mg (group III) were followed by four weekly maintenance doses of half the loading doses, i.e. 50, 100, and 200 mg, respectively. Two EMD 72000 administrations were scheduled before and three after surgery. The objectives of this trial were (a) to investigate the safety and toxicity of multiple EMD 72000 doses, (b) to determine the cumulative maximum tolerated dose of EMD 72000 at dosages between 300 mg and 1,200 mg, and (c) to determine the serum pharmacokinetics of EMD 72000. In total, 102 adverse events (AEs) were reported: five of toxicity grade 3, 18 of toxicity grade 2, 66 of toxicity grade 1, and 38 of toxicity grade 0. All AEs of toxicity grade 3 were considered to be not or remotely related to EMD 72000. The most frequent study drug-related AEs were fever and a transient elevation of liver enzymes. In all patients, the time to reach peak serum concentrations (tmax) was within 1-3 h of the start of each EMD 72000 infusion. Average peak serum concentrations (Cmax) after correction for dosage appeared to be dose-independent, whereas the half-life (t1/2) showed dose dependency. In conclusion, EMD 72000 was very well tolerated in patients with advanced stage SCCHN. The pharmacokinetic data from this trial suggest the feasibility of conducting future studies with weekly doses of 200 mg EMD 72000.

Aged↗
PubMed2001

Pharmacokinetic/pharmacodynamic evaluation of the NHE inhibitor eniporide.

The aim of this study was to investigate the pharmacokinetics and pharmacodynamics of the new cardioprotective sodium/proton exchange (NHE-1) inhibitor eniporide in humans. Eniporide was administered intravenously to healthy volunteers in doses between 2.5 and 100 mg. Concentrations of parent drug and its metabolite were measured by HPLC, and the data were analyzed by noncompartmental and compartmental pharmacokinetic methods. Platelet-swelling time was determined in each subject as a biomarker to assess pharmacodynamic activity. Eniporide showed linear pharmacokinetics with an average half-life of approximately 2 hours. The mean total body clearance was 34.4 L/h. The mean volume of distribution (Vdss) was 77.5 L, and the mean residence time was 2.3 hours. An average of 43% of the dose was recovered unchanged from urine. A pharmacokinetic two-compartment model was found suitable to provide excellent curve fits of the measured plasma concentration profiles. Plasma concentrations of the major metabolite were lower than that of the parent drug. An average of 27% of the dose was found in urine as that metabolite. The effect on platelet swelling could be well characterized by a direct Emax model. The average concentration for half-maximum effect (IC50) was 12 ng/mL. Eniporide was found to have predictable linear pharmacokinetics in the investigated dose range. Platelet-swelling time was shown to be a reproducible individual biomarker for pharmacodynamic activity, with great potential for a surrogate that predicts clinical outcome, since this effect is mediated through the same mechanism of action (NHE-1 inhibition) as the desired cardioprotective activity. Pharmacokinetic/pharmacodynamic modeling allowed a first estimate of the degree of NHE inhibition in the investigated dose range.

Adolescent↗
PubMed1998

Determination of free interstitial concentrations of piperacillin-tazobactam combinations by microdialysis.

The investigation of tissue penetration and distribution of antibiotics is of great importance, since infections occur mostly in the tissues. The aim of this study was to investigate the pharmacokinetics of piperacillin and tazobactam, alone and in combination, by measuring total plasma and free interstitial concentrations, and to examine the relationship between free levels of both drugs in blood and those in the extracellular space. Piperacillin and tazobactam were administered, alone and in combination, to anaesthetized rats as a single iv bolus dose. Total plasma concentrations and free extracellular concentrations were quantified by HPLC. In-vivo microdialysis sampling was used to study the free tissue distribution patterns of both drugs. The pharmacokinetics of piperacillin and tazobactam in plasma were consistent with a two-compartment body model. Piperacillin pharmacokinetics were not influenced by co-administration of tazobactam. Tazobactam's volumes of distribution and clearance were decreased by the co-administration of piperacillin and the area under the curve was significantly increased. Comparisons between calculated free concentrations in the peripheral compartment for both drugs and measured free extracellular concentrations revealed excellent agreement. For piperacillin and tazobactam, alone and in combination, predictions of the concentration-time profiles of free drug in the peripheral compartment can be made on the basis of plasma data.

Animals↗
PubMed1997

Relationship between serum and free interstitial concentrations of cefodizime and cefpirome in muscle and subcutaneous adipose tissue of healthy volunteers measured by microdialysis.

Microdialysis is a suitable method to monitor unbound concentrations of antimicrobial drugs in the interstitial tissue space which is the site of many infections. The aim of this investigation was to examine whether free tissue levels of cefodizime (81% plasma protein binding) and cefpirome (10% plasma protein binding) in muscle and subcutaneous adipose tissue of healthy volunteers obtained by microdialysis are consistent with the extent of their respective plasma protein binding. Healthy volunteers were given cefodizine and cefpirome at a single intravenous 2-g dose in a randomized crossover design. Microdialysis probes were inserted into a medial vastus muscle and into the periumbilical subcutaneous layer. After calibration of the probe, samples of serum and microdialysis fluid were obtained and drug concentrations were measured using a microagar diffusion-bioassay. There was a reasonable agreement between plasma protein binding data and the tissue penetration of both cephalosporins (AUC0-infinity tissue, free/AUC0-infinity serum, total-ratios) into the interstitial fluid of the muscle tissue, but not for the subcutaneous tissue layer. Furthermore, the serum and tissue concentrations of both drugs were fitted to an open two-compartment body model. The measured free-tissue concentrations were compared with calculated unbound concentrations in the peripheral compartment. Good agreement was observed for the free muscle concentrations, but unbound concentrations in the subcutaneous tissue was somewhat higher (cefpirome) or lower (cefodizime) than predicted. This may be due to the different lipophilicities of the two compounds.

Adipose Tissue↗
PubMed1997

Comparison of plasma and free tissue levels of ceftriaxone in rats by microdialysis.

Ceftriaxone has a very high plasma protein binding (up to 98%) that is saturable and decreases with higher concentrations. This high protein binding results in high concentrations in plasma that are frequently related to the anti-infective activity. However, because only the free fraction of the drug is pharmacologically active and most of the infections are located in the tissues, it is more relevant to evaluate unbound concentrations in the interstitial space. Plasma and tissue pharmacokinetics of ceftriaxone in rats after single intravenous administration were investigated at two different concentrations (50 and 100 mg/kg). Both plasma and tissue samples were taken simultaneously from the same animal and analyzed by reversed-phase high-performance liquid chromatography. Free tissue levels in the thigh muscle were measured by microdialysis. The concentration in plasma is much higher than the free concentration in tissue. After determination of nonlinear protein binding by microdialysis and including these parameters in the pharmacokinetic model, it is possible to predict free concentrations in the interstitial space from plasma levels for any given dose.

Animals↗
PubMed1992

Sleep EEG effects of 3,4-methylenedioxyethamphetamine (MDE; "eve") in healthy volunteers.

3,4-methylenedioxyethamphetamine (MDE; "Eve") exerts similar psychotropic effects in humans as 3,4-methylenedioxymethamphetamine (MDMA; "Ecstasy") and is less toxic in animal studies. We conducted a double-blind, placebo-controlled, cross-over sleep electroencephalogram (EEG) study with healthy volunteers. One hundred forty milligrams of MDE or placebo were administered PO in six subjects at 11 PM. Sleep EEG was registered from 11 PM-7 AM the next morning. All subjects had a normal sleep onset latency. They all awoke 60 to 120 min after administration of MDE and stayed awake for at least 150 min (total sleep time, TST MDE < placebo and intermittent time awake MDE > placebo: p < 0.001). After again falling asleep rapid eye movement (REM) sleep was totally suppressed (REM during time in bed, TIB MDE < placebo: p < 0.001). A cyclic alternation of relatively long periods of slow wave sleep (SWS) with periods of light sleep occurred in three subjects during the second part of the night (stage 4 in second part of night MDE > placebo: p = 0.16). The effects of MDE on sleep variables largely demonstrate the stimulant, amphetamine-like properties of MDE.

3,4-Methylenedioxyamphetamine↗