PubMed Health⌕ Search

Biomedical subjects

G Neugebauer

Publications and source records attributed to G Neugebauer.

At least 19 recordsLinked to original sources
PubMed2002

Association between pharmacokinetics of oral ibandronate and clinical response in bone mass and bone turnover in women with postmenopausal osteoporosis.

Data from the 1-year, phase II trial of oral ibandronate for treatment of postmenopausal osteoporosis are presented (n = 180). Participants were at least 10 years past menopause and had osteopenia defined as a forearm bone mineral density at least 1.5 SD below the premenopausal mean value. Doses were 0.25, 0.50, 1.0, 2.5, or 5.0 mg daily oral ibandronate or placebo. A total of 116 women treated with ibandronate completed the study. Blood samples for pharmacokinetic analyses were drawn 20 min, 40 min, 60 min, 2 h, 4 h, and 6 h after the first and last administration of the study drug. An enzyme-linked immunosorbent assay was used to determine the concentration of ibandronic acid (BM 21.0955) in serum (Enzymun-Test System ES 600). The assay is based on streptavidine technology to fix the capture antibody to the wall of the tube. Standards were prepared for each participant using individual drug-free serum. The serum concentration-time curves of ibandronate, expressed as the area under the curve over the sampling period (AUC(0-6h)), revealed a highly significant dose-response relationship, p < 0.0001, and linear pharmacokinetic behavior. An initial half-life (T(1/2lambda1)) in serum representing distribution and early elimination was 1.3 hours. Steady-state AUC (AUC(0-6h ss)) increased by a factor of 2.5, which is consistent with an apparent elimination half-life of 32.6 h and a dosing interval of 24 h. There was an exponential association between AUC(0-6h) (ss) and the change from baseline at month 12 in the bone markers (n = 116): r = -0.37 (serum total osteocalcin), r = -0.65 (urine C-telopeptides of type I collagen), and r = -0.65 (serum C-telopeptides of type I collagen), all p < 0.0001. All bone markers were maximally depressed at values of AUC(0-6h ss) of about 3 ng h/mL. AUC(0-6h ss) furthermore revealed a logarithmic association with change from baseline at month 12 in spine BMD, r = 0.39, p < 0.0001. In conclusion, the serum concentration of ibandronate was determined validly by the enzyme-linked immunosorbent assay. The data are the first to show highly significant associations between pharmacokinetic parameters of a bisphosphonate and the clinical response in bone mass and bone turnover.

Aged↗
PubMed1999

Current clinical use of reteplase for thrombolysis. A pharmacokinetic-pharmacodynamic perspective.

Clinical evaluation of a new thrombolytic agent should start with a dose that provides adequate efficacy and has an acceptably low bleeding risk; this results in a narrow therapeutic window at the upper end of the dose-response curve. Angiographic patency of the infarct-related artery is still the clinical surrogate end-point for mortality in phase II dose-ranging studies. There is experimental and clinical evidence that the area under the concentration-time curve (AUC) for plasminogenolytic activity of a thrombolytic agent is positively correlated with patency of the infarct-related artery. Dose-ranging studies of the novel recombinant plasminogen activator reteplase in healthy volunteers enabled computation of a linear regression curve by which a clinical starting dose could be calculated for an adapted target AUC that would be clinically effective. Pharmacokinetic analysis also revealed that the half-life of reteplase is 4 times longer than that of the reference thrombolytic alteplase, thus allowing bolus injection. The suggested single bolus starting dose of 10U was supported by results from studies in a canine model of coronary thrombolysis. The feedback of insufficiently high patency rates compared with the increased efficacy of front-loaded and accelerated alteplase demanded optimisation strategies for reteplase. Animal experiments suggested that a double bolus regimen of reteplase would be preferable to doubling the single bolus dose. Pharmacokinetic modelling suggested a time interval of 30 min between the 2 bolus injections. Selection of the tested double bolus regimens was conservative and empirical. First, the previously tested single bolus of 15U was divided to 10 + 5U; secondly, the second bolus dose was increased to 10U. This strategy proved to be successful. The current dosage recommendation for reteplase is a double bolus intravenous injection of 10 + 10U, each over 2 min, 30 min apart. This produces a reduction in mortality in patients with acute myocardial infarction that is equivalent to that produced by front-loaded and accelerated infusion of alteplase.

Animals↗
PubMed1996

Systematic screening for pharmacokinetic interactions during drug development.

The possible involvement of a new chemical entity in pharmacokinetic drug interactions is an important safety issue. Not all relevant drug combinations for evaluation of the interactive potential of a new drug can be examined. Therefore, experiments should be selected to provide information which is valid not only for the interaction investigated, but which can be extrapolated to other comedications. In this respect the typical approaches currently used, including interaction studies with high risk drugs and compounds frequently given as comedication, or studies involving standard inhibitors and standard substrates are unsatisfactory. A better approach is to characterize drugs according to their effects on the underlying pharmacokinetic processes. Indeed, recent progress in understanding drug interaction mechanisms and in the development and refinement of in vitro test systems enables in many cases experiments to be designed which predict the occurrence of drug interactions. This paper illustrates systematic investigational procedures based on mechanism of interaction. Interaction mechanisms involving drug absorption, distribution, metabolism, and/or excretion are briefly summarized. Detailed proposals are derived which allow identification of the possible role of a new drug in interaction mechanisms for which valid test systems are available. Emphasis is placed on the rational selection of experiments with optimal cost-effectiveness. In vitro methods are integrated in the schemes wherever possible. In addition, it is proposed that pharmacoepidemiological screening, starting in phase II of drug development, be used to identify those relevant drug interactions missed by the mechanism-based approach. As exemplified by several recently discovered interactions it should be possible, by implementation of the proposed procedure, to avoid most serious unexpected adverse effects due to pharmacokinetic drug interactions.

Animals↗
PubMed1994

Dose-effect and pharmacokinetic-pharmacodynamic relationships of the beta 1-adrenergic receptor blocking properties of various doses of carvedilol in healthy humans.

OBJECTIVE: To evaluate the pharmacodynamic properties of carvedilol across a broad range of doses in relation to its enantiospecific kinetics and adrenergic receptor occupancies, relative to placebo and propranolol. METHODS: Twelve healthy male subjects were investigated on six separate occasions at least 1 week apart when they received either a single peroral dose of 40 mg propranolol, 12.5, 25, 50, or 100 mg carvedilol, or placebo. The subjects were extensively profiled at supine rest, and they underwent supine bicycle ergometry before and at 2, 4, 6, 9, 12, and 22 hours after dosing. At these time points blood was drawn for the high performance liquid chromatographic determination of the enantiomers of carvedilol and for the radioreceptor assay determination of alpha 1- and beta 1-adrenergic receptor binding and related concentrations. RESULTS: Carvedilol was confirmed to bind to beta 1-adrenergic receptors and (albeit to a lesser extent) to alpha 1-adrenergic receptors. Carvedilol furthermore attenuated the ergometric increase in heart rate in a closely dose-related fashion, which exemplified its beta 1-adrenergic receptor blocking effects. However, the basal efferent adrenergic drive might have been too low to show consistent alpha 1-blocking properties. The radioreceptor and enantiomer kinetics were proportional with dose. There was no indication that the overall kinetic behavior of contributing active metabolites would differ from that of the S(-)-enantiomer. On average, there was a smooth linear relationship between the ergometric treatment responses and log-transformed dose, log-transformed concentrations of the S(-)-enantiomer, and the radioreceptor assay derived beta 1-adrenergic receptor occupancies. CONCLUSION: The relative complexity of the kinetics of carvedilol (enantiospecific kinetics and dynamics, protein binding, and involvement of active metabolites) does not preclude relatively simple and straight-forward dose-effect and kinetic-dynamic relationships.

Administration, Oral↗
PubMed1992

Disposition of carvedilol enantiomers in patients with liver cirrhosis: evidence for disappearance of stereoselective first-pass extraction.

The racemic drug carvedilol exerts its antihypertensive action through vasodilation and nonselective beta-blockade. The R(+)-enantiomer has twice (31.1%) the absolute bioavailability than the S(-) form (15.1%). The pharmacokinetics of the enantiomers were investigated after intravenous (i.v.) (12.5 mg in 1 h) and p.o. (25 mg) administration of racemic carvedilol in six patients with cirrhosis of the liver according to a randomized crossover design. Although the difference between areas under the curve of R(+) and S(-) were of borderline significance after i.v. administration but significant after oral administration, no difference existed between the absolute bioavailabilities of R(+) (83.7%) and S(-) (71.3%). The enantiomer ratio is similar after i.v. (1.3) and p.o. administration (1.6). In contrast to healthy subjects, the apparent volume of distribution of S(-) is about 90% greater than that of R(+) in patients. The renal excretion of carvedilol and of one of its major metabolites, carvedilol glucuronide, also exhibited stereoselective behavior, but in opposite directions. In patients with liver cirrhosis, stereoselective metabolism of carvedilol is still operative. However, probably because of portocaval shunts, the hepatic first-pass extraction is markedly reduced, eliminating the difference in bioavailability between the two enantiomers.

Administration, Oral↗
PubMed1991

Pharmacokinetic and hemostatic properties of the recombinant plasminogen activator bm 06.022 in healthy volunteers.

In a randomized, single-blind, placebo-controlled, cross-over Phase-I study pharmacokinetic and hemostatic properties of BM 06.022 were investigated in seven healthy, male human volunteers. The novel recombinant plasminogen activator BM 06.022 consists of the kringle 2 domain and the protease domain of human t-PA and is unglycosylated due to its expression in Escherichia coli cells. Vehicle or 6 MU (= 10.4 mg) BM 06.022 was administered as a single i.v. bolus injection of 10 ml over 2 min. BM 06.022 was well tolerated. Fibrinogen levels and clotting times remained unchanged at baseline levels after 6 MU BM 06.022; plasminogen and alpha 2-antiplasmin (collected on chloromethylketone) decreased maximally to 83 +/- 1% and 64 +/- 3%, respectively, of baseline. D-dimers and fibrinogen degradation products increased to 1,006 +/- 234 ng/ml and 555 +/- 155 ng/ml, respectively, after BM 06.022. Half-life of BM 06.022-activity was 11.2 +/- 0.4 min and of antigen was 13.9 +/- 0.7 min, followed by a terminal half-life only for antigen of 173 +/- 33 min. Plasma clearance of BM 06.022 was 371 +/- 13 ml/min for activity and 183 +/- 15 ml/min for antigen. Thus, BM 06.022 is not fibrinogenolytic at 6 MU and is a fibrinolytic agent with a longer half-life than t-PA.

Adult↗
PubMed1991

Dose-ranging study of the novel recombinant plasminogen activator BM 06.022 in healthy volunteers.

The novel recombinant plasminogen activator BM 06.022 consists of the kringle 2 and protease domains of human tissue-type plasminogen activator and is unglycosylated because of its expression in Escherichia coli cells. Pharmacokinetics for activity and hemostatic effects of BM 06.022 were studied in 18 healthy male volunteers after an intravenous bolus injection over 2 minutes. BM 06.022 was administered successively at doses of 0.1125, 0.55, 2.2, 3.3, 4.4, and 5.5 MU to three volunteers. Plasma fibrinogen was unchanged; effects of BM 06.022 were observed on plasminogen only at higher doses, and dose-dependent effects were seen on alpha 2-antiplasmin and fibrin D-dimers. The concentration of plasminogen and alpha 2-antiplasmin was 87% +/- 3% and 79% +/- 3%, respectively, of baseline 2 hours after injection of 5.5 MU of BM 06.022. Fibrin D-dimers were highest with 1147 +/- 380 ng/ml at 5.5 MU of BM 06.022. The area under the activity concentration-time curve (AUC) increased dose-dependently and linearly. At 5.5 MU of BM 06.022, the AUC was 313 +/- 47 IU.hr.ml-1, the total plasma clearance was 306 +/- 40 ml/min, and the half-life was 14.4 +/- 1.1 minutes.

Adult↗
PubMed1990

Stereoselective disposition of carvedilol in man after intravenous and oral administration of the racemic compound.

The racemic compound carvedilol is a multiple-action oral antihypertensive drug that exhibits both vasodilator and non-selective beta-adrenergic blocking activities. The effects of the levorotatory S-enantiomer [S(-)-CARV] are vasodilatation and beta-blockade. The R(+)-enantiomer [R(+)-CARV] is a pure vasodilating agent. Quantitative determination of the enantiomers in human plasma by HPLC was carried out after formation of diastereoisomers with the chiral reagent 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl isothiocyanate (GITC). The pharmacokinetics of the enantiomers were studied following i.v. (12.5 mg in 1 h) and p.o. (50 mg) administration of racemic carvedilol in ten healthy male subjects according to a randomized crossover design. The AUCs of S(-)-CARV were significantly lower than those of R(+)-CARV after both i.v. and p.o. administration. The systemic clearance of the two enantiomers was significantly different, whereas half-lives and apparent distribution volumes were comparable. Following p.o. administration, the absolute bioavailability (31.1% and 15.1%, respectively) and maximal plasma concentrations of R(+)-CARV were twice those of S(-)-CARV. A similar difference was found in the half-lives. A close correlation existed between enantiomeric ratios after i.v. and after p.o. administration, demonstrating slight intraindividual variability. The preferential systemic clearance of the S(-)-enantiomer suggests stereoselective hepatic metabolism of carvedilol, becoming especially apparent after p.o. administration. The small intrasubject variability in enantiomer ratios indicates a relatively constant relation of beta-blockade to vasodilation during chronic treatment.

Administration, Oral↗
PubMed1989

Pharmacokinetics of picumast dihydrochloride and its active metabolites M1 and M2 in humans.

The pharmacokinetics of picumast dihydrochloride (3,4-dimethyl-7-[4-(4-chlorobenzyl)piperazine-1-yl]propoxycoumarin dihydrochloride) and the pharmacodynamically active metabolites M1 and M2 as well as the absolute bioavailability of picumast dihydrochloride have been studied in healthy volunteers after oral administration of the drug in doses which were considerably higher than therapeutically used. After intravenous administration of 10 mg picumast dihydrochloride a peak concentration of 182 ng/ml was achieved at the end of the 1 h infusion. Picumast dihydrochloride was extensively distributed to the tissues (Vz = 130 l) and almost exclusively eliminated by hepatic metabolism (total clearance 95 ml/min, amount of unchanged compound excreted in urine below detection limit). Median elimination half-life was 16.5 h. The absolute bioavailability reached 57%. The relative bioavailability of picumast dihydrochloride was 20% higher after a meal. After a 20 mg oral dose maximum concentrations between 129 and 284 ng/ml were achieved within 1.3 h. The elimination half-life ranged from 10-26 h. No difference existed between oral (14.5 h) and intravenous administration. The metabolites M1 and M2 in human plasma peaked at 3.4 and 4 h. With 41 h (M1) and 34 h (M2) they exhibited longer half-lives than the parent compound. So under steady state conditions the average plasma concentration of these metabolites amounted to about 68% and 40%, resp., of the unchanged drug as calculated by the ratio of the total areas. The total amount of metabolites M1 and M2 recovered in urine was 6.88% of the oral dose administered, i.e. 6.8% M1 and 0.08% M2. The renal clearance was determined as 28 and 0.5 ml/min for M1 and M2, resp.

Administration, Oral↗
PubMed1989

Study of potential kinetic interactions of picumast dihydrochloride and theophylline in vitro and after oral administration in man.

The kinetic interaction of picumast dihydrochloride (3,4-dimethyl-7-[4-(4-chlorobenzyl)piperazine-1-yl]propoxycoumarin dihydrochloride) and theophylline has been studied in vitro (displacement from protein binding) and in vivo in healthy male non-smokers after oral administration. In a randomized, three-way cross-over study, 12 subjects received at weekly intervals either separated or combined single doses of picumast dihydrochloride (10 mg) and theophylline (7 mg/kg b.w.) Picumast and its metabolites were analysed in plasma and urine up to 24 h and theophylline was assayed in plasma during the same time. Theophylline pharmacokinetic parameters like time to peak concentration, peak concentration, elimination half-life, area under the plasma concentration-time curve and oral clearance were not changed after a concomitant dose of picumast dihydrochloride. The combination of theophylline and picumast dihydrochloride revealed no significant changes in the picumast pharmacokinetic parameters t1/2, tmax and CLR. However, Cmax and AUC0-24 decreased significantly by 11% and 7%, resp. Additional theophylline administration significantly increased peak concentration of the intermediate active metabolite M2 by 23% from 7 to 8.6 ng/ml. The absorptive parameters, i.e. time to peak and peak concentration of M1 as well as the AUC calculated from 0-24 h and the renal clearance did not differ in single or combined picumast dihydrochloride administration. A supplementary in vitro study showed no change in plasma protein binding of picumast (100 ng/ml) in the presence of theophylline (20 micrograms/ml) and vice versa. In all volunteers picumast dihydrochloride proved to be safe and well tolerated and treatment was not negatively influenced by theophylline co-administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Pharmacokinetics of picumast dihydrochloride in patients with liver cirrhosis.

In a randomized parallel group design the pharmacokinetics of picumast dihydrochloride (3,4-dimethyl-7-[4-(4-chlorobenzyl)piperazine-1-yl]propoxycoumarine++ + dihydrochloride) and its active metabolites M1 and M2 were studied after intravenous or oral administration of a single dose of 10 mg picumast dihydrochloride in two groups of 8 patients with liver cirrhosis. After intravenous administration, the terminal half-life of 65 h was about 4 times longer than in healthy subjects although the total body clearance of 87 ml/min was only 7.4% lower. The 3.6-fold increase in the steady-state volume of distribution (351 l) may be due to a higher uptake by the liver and other tissues and/or to a slower re-diffusion from these tissues into the circulation. Only negligible amounts of picumast dihydrochloride appeared in the urine. Picumast dihydrochloride is almost exclusively eliminated by hepatic metabolism. After oral administration peak concentrations were reached at 1.4 h; plasma elimination half-life was considerably longer (107 h), however, without being significantly different from i.v. administration. The two patient groups differed with respect to their drug metabolizing capacity, therefore the absolute biovailability could not be established. The maximum concentration of the metabolites was reached 1.4 to 3.4 h later than Cmax of the parent drug. As compared to healthy subjects the clearance of the metabolites appeared to the reduced to a greater extent than that of the parent compound, so that under steady-state conditions in patients with liver disease these active metabolites will contribute more to the overall therapeutic effect than in normal individuals. 10.4% to 12.8% of the dose were recovered from the urine als M1.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1989

Performance of a slow-release formulation of isosorbide-5-mononitrate (ISMO retard).

From the in vitro release-rate constant of a new sustained-release (SR) preparation of 40 mg isosorbide-5-mononitrate, the concentration-time profile in healthy subjects could be excellently predicted. Therapeutically, effective concentrations of 100 ng/ml were achieved within 20 min and lasted up to a maximum of 15.6 h. The decline of concentrations below this value thereafter, guarantees the absence of tolerance development in chronic therapy. In a three-period change-over study, two other commercial SR preparations exhibited only 79% and 53% of the bioavailability of the new formulation, which was significant in both cases. Compared with literature data, the absolute bioavailability of the new form should lie in the order of at least 85%.

Adolescent↗
PubMed1988

Steady-state kinetics of bezafibrate retard in hyperlipidemic geriatric patients.

The pharmacokinetics of a slow-release formulation of bezafibrate were investigated under steady-state conditions in 19 hyperlipidemic patients between the age of 61 and 87 years and compared to the kinetics in 20 healthy volunteers (age 19-42 years). Maximum serum levels were 1.6-fold higher in the elderly, which was partly due to a diminished renal clearance caused by the reduction in renal function (CLCR 23-81 ml/min) and partly due to a decrease in extrarenal clearance (probably hydroxylation and hydrolysis). Evidence for the additional decrease in extrarenal clearance was provided by the greater decline in total drug clearance than would be anticipated from a mere reduction in glomerular filtration. Thus, dose adjustment of slow-release bezafibrate in elderly patients cannot be based merely on creatinine clearance. In general, it is recommended that bezafibrate retard is substituted by a reduced dose of normal-release bezafibrate below a creatinine clearance of 60 ml/min.

Administration, Oral↗
PubMed1988

Pharmacokinetics and metabolism of torasemide in man.

Torasemide (1-isopropyl-3-([4-(3-methyl-phenylamino)pyridine]-3- sulfonyl)urea) is a potent new loop diuretic. The pharmacokinetics, absolute bioavailability and metabolic disposition of torasemide have been studied after administration of a standard-release tablet to healthy volunteers. According to a latin square design 9 subjects received in random order single doses of either 20 mg i.v. over 1 h or 20 or 40 mg p.o. On each of the three occasions, torasemide and its metabolites were analysed in plasma and urine up to 24 h. From the results of urinary excretion and plasma AUC, the availability of torasemide from the tablet was 80% to 90%, i.e. nearly complete. The kinetics were linear with dose. The time of peak was reached at 1 h, the elimination half-life varied from 3 h to 4 h. None of the metabolites M1, M3 or M5 found in plasma exhibited a longer half-life. Only a quarter of the low systemic clearance of torasemide (41 ml/min) was accounted for by renal clearance. The distribution volume of 15.5 l was in the order of the extracellular fluid volume. The total amount of torasemide and metabolites recovered in urine was 83%, i.e. 25% torasemide, 11% M1, 3% M3 (both active), and 44% M5 (inactive). Therefore, M1 and M3 probably contribute to the diuretic action of torasemide. Since the renal clearances of the metabolites exceeded that of the parent drug, renal impairment may change their elimination kinetics.

Adult↗
PubMed1987

[From the nail/plate to the dynamic hip screw--example of a generation change in implants for para-articular femoral fractures].

In trochanteric fractures of the femur, where operative techniques are preferable to conservative treatment, a change in the choice of implants has taken place over the past years. As several comparative studies show, the traditional system of nail/plate fixation has not been completely replaced by Ender nailing in many surgical departments. The system of nail/plate is, however, losing significance in face of the increasing usage of screwing-systems (such as, for instance, DHS of AO-Dynamic Hip Screw). The possibility of compression during the operation in screwing methods is the decisive factor.

Aged↗
PubMed1987

Pharmacokinetics and bioavailability of carvedilol, a vasodilating beta-blocker.

The pharmacokinetics and absolute bioavailability of carvedilol have been studied in 20 male healthy volunteers in a randomised 4-period, cross-over trial. Carvedilol 12.5 mg was given i.v., 50 mg was administered p.o. as a suspension and 25 and 50 mg were given in a capsule formulation. For the 50 mg capsule Cmax was 66 micrograms.l-1, tmax 1.2 h, t1/2 6.4 h. The t1/2 after i.v. administration was 2.4 h, CL 589 ml/min and VZ 132 l. The absolute bioavailability was 24% (50 mg capsule). The kinetics after the 25 and 50 mg capsules were consistent with dose linearity.

Administration, Oral↗