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G Neugebauer

Publications and source records attributed to G Neugebauer.

At least 37 records · Page 2Linked to original sources
PubMed1987

Pharmacokinetics and disposition of carvedilol in humans.

Pharmacokinetics of carvedilol (C) have been studied in healthy volunteers after a single i.v. and oral administration, and the metabolic disposition after oral administration of 14C-labeled drug. C demonstrates dose-linear behavior. The absolute bioavailability reaches 24% probably due to a first-pass effect. After a 50 mg oral dose, maximum concentrations of 66 micrograms/l are achieved within 1.2 h. C is extensively distributed to the tissues (Vz = 132 l) and eliminated primarily by hepatic metabolism (total clearance 590 ml/min, renal clearance 4 ml/min). Because of the longer half-life of 6.4 h after oral administration in contrast to 2.4 h after i.v. administration, C is assumed to be absorption dependent since no sustained-release formulation was used. The half-life of radioactivity in plasma is 39 h; 16% of C is excreted in urine in the form of metabolites and only 0.3% unchanged. The urinary metabolites consist of carvedilol glucuronide (5.2% of the dose), cleavage products of the beta-blocking side chain (2.1%), and ring-hydroxylated forms (2.9%). Sixty percent of the dose is recovered in the feces. A demethylated product of C exhibits only minor beta-blocking activity. This metabolite is detected in plasma in concentrations ten times lower than the parent compound.

Administration, Oral↗
PubMed1986

Influence of beta-blocker coadministration on the kinetics of isosorbide mononitrate and dinitrate.

The influence of beta-blocker coadministration on the kinetics of oral isosorbide-5-mononitrate (ISMN) and isosorbide dinitrate (ISDN) was studied in healthy volunteers. In the first study, 12 subjects ingested 20 mg ISMN on three occasions: in the control state, during coadministration of metipranolol (20 mg 3 times daily), or during metoprolol (100 mg twice daily). There were no significant differences among the three phases in peak serum ISMN concentration (470 ng/ml), the time of peak (0.6 h after dose), elimination half-life (4.5 h), or oral clearance (142 ml/min). In the second study, 10 subjects received 20 mg ISDN in the control state and again during coadministration of propranolol (80 mg 3 times daily). There were no differences between the two phases in peak serum ISDN concentration (20 ng/ml) or the time of peak (0.6 h). Propranolol increased, although not significantly, ISDN clearance (16.5 vs 12.3 L/min, P less than 0.1), and had no effect on total area under the curve for ISMN, the major metabolite of ISDN. Thus, therapeutic doses of these beta-blockers have a minimal influence on the kinetics of single doses of ISMN or ISDN in healthy individuals.

Adrenergic beta-Antagonists↗
PubMed1986

Single dose pharmacokinetics and effects on platelet function of the thromboxane receptor blocker BM 13.177.

The pharmacokinetics and pharmacodynamic effect on platelet activation of a single 800 mg oral dose of BM 13.177 have been investigated in 8 male volunteers. BM 13.177 disappeared from plasma with a terminal elimination half-life of 0.85 h. 52% of the dose was excreted unchanged in urine. Assuming complete absorption, total clearance was calculated to be 741.3 ml/min and renal clearance to range from 310.4 to 396.9 ml/min. The pharmacodynamic studies were performed ex vivo/in vitro in studies were performed ex vivo/in vitro in platelets stimulated either with methyl mercury chloride or with U 46619. Methyl mercury chloride is a platelet activator that requires TXA2 formation from endogenous arachidonic acid, whereas U 46619 is a stable PGH2 analogue and thromboxane mimetic at the platelet TXA2/PGH2 receptor. A close correlation between the plasma concentration-time profile of BM 13.177 and inhibition of platelet shape change or aggregation was demonstrated.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1986

Clinical pharmacologic investigations with carvedilol, a new beta-blocker with direct vasodilator activity.

Carvedilol (BM 14.190) has been shown to have beta-adrenergic blocking and vasodilating activity. By means of digital plethysmography, the threshold for vasodilation was ascertained at a dose of 2.6 mg iv infused over 1 hour. The oral threshold dose was established at about 15 mg, with a linear increase in response (r = 0.78) up to 76.5 mg. This dose increased blood flow to the forearm by reduction of arterial resistance. Although venous capacity was not changed, postural symptoms in three subjects could also be indicative of venous involvement. Carvedilol, 50 mg, reduced exercise heart rate for about 10 hours.

Administration, Oral↗
PubMed1986

The pharmacokinetic and pharmacodynamic profiles of the thromboxane A-2 receptor blocker BM 13.177.

The pharmacokinetics and pharmacodynamics of BM 13.177 were investigated in eight healthy men who received a single oral dose of 800 mg on the first day and seven equal doses in 8-hour intervals on the second to fourth days. Pharmacodynamic effects were measured ex vivo by the testing of platelet functions such as shape change, aggregation, and [3H]serotonin release. The maximum serum concentration of 6.6 or 6.7 mg/L was achieved within 1.6 hours after the first dose and within 1.5 hours after multiple doses, respectively. Afterwards, BM 13.177 was eliminated in urine with a terminal elimination t1/2 of 0.84 or 1.0 hours after single and multiple dosing, respectively. The inhibition of platelet function showed the same close correlation with the serum concentrations of BM 13.177 after single and after multiple doses. Apparently, BM 13.177 induces neither refractoriness to BM 13.177 nor desensitization of the platelet thromboxane receptor. Because BM 13.177 was also well tolerated without subjective or objective side effects, this drug appears to be useful in evaluating the clinical benefit of thromboxane receptor blockade.

Adult↗
PubMed1985

Pharmacokinetics and metabolism of isosorbide-dinitrate after intravenous and oral administration.

The bioavailabilities of a conventional and two slow release 20 mg isosorbide dinitrate (ISDN) formulations were compared after oral administration in a three way cross-over study in 8 male volunteers. In a further group of 6 male volunteers the pharmacokinetics and metabolism of ISDN were investigated after intravenous infusion of a median dose of 14.1 mg for 2.5 h. A new analytical procedure was developed for the determination of isosorbide-5-mononitrate-2-glucuronide (IS-5-MN-2-Glu) and of isosorbide (IS). Kinetic data analysis on a molar basis was performed by the program package KIN-PAK providing model independent parameters. The median elimination half-lives of ISDN, IS-5-MN, IS-2-MN and IS-5-MN-2-Glu were 0.7, 5.1, 3.2 and 2.5 h, respectively. The systemic clearance of ISDN was 3.71/min and the distribution volume 2521 (3.1 l/kg). Apart from IS-5-MN-2-Glu, with a renal clearance of 5.9 l/min which suggested substantial glucuronidation in the kidney, the renal clearances of ISDN, IS-5-MN, IS-2-MN and the corresponding amounts excreted were negligible. 27.8% of the administered ISDN was excreted as IS-5-MN-2-Glu (8.7%) and IS (19.1%). Calculations based on the two mononitrate metabolites formed from ISDN showed an incomplete recovery of 84.1%, leading to the assumption that a simultaneous denitration to IS must have occurred. The rate of denitration at each nitro group in ISDN was almost twice as high as for the same position in the corresponding mononitrate.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1985

Absolute bioavailability and bioequivalence of glibenclamide (Semi-Euglucon N).

The absolute bioavailability of HB 420 (a new pharmaceutical form of glibenclamide) was investigated in comparison with an i.v. infusion of glibenclamide and also in comparison with HB 419 (Semi-Euglucon) on a group of 10 healthy volunteers with the aid of a highly specific bioanalytical detection method. A comparison of the dose-corrected areas under the concentration-time curves yielded an absolute bioavailability of 102% for HB 420. The relative bioavailability of HB 419 to HB 420 was 73%. This resulted in a bioequivalent dosage relationship of 2.5 mg HB 419 to 1.75 mg HB 420. It could be experimentally confirmed on further 10 healthy volunteers that 1.75 mg HB 420 (identical with Semi-Euglucon N) and Semi-Euglucon (containing 2.5 mg HB 419) are bioequivalent with respect to the absorbed quantity of active agents. The differences in absorption rate between the new and the old form did not lead to relevant differences in the glucose profile and the release of insulin, so that the two forms can be regarded as being pharmacodynamically equivalent. The median for the terminal elimination half-life for glibenclamide was 1.38 hours (min. 0.65, max. 4.64 hours), the total clearance was 100 ml/min and the steady-state distribution volume was 7.3 l (0.1 l/kg). On the basis of half-life, it can be expected that the elimination of the unchanged substance will be virtually complete within 10-12 hours. During long-term therapy, however, it cannot be ruled out that in some diabetics cumulation could occur, the cause of which cannot be explained by the data presented.

Adult↗
PubMed1985

Digital pulse plethysmography--a tool for investigating vasoactive substances.

Plethysmographic investigations have been in use for at least a hundred years for the measurement of pharmacological actions in humans. Finger plethysmography was used particularly in the investigation of the vasodilating effect of organic nitrates. It has also proved valuable in determining the relative bioavailability of representatives of this class of drugs. This paper deals with personal experience in the use of this method for the investigation of older and newer organic nitrates. The apparatus that was developed to enable electronic data processing of the plethysmographic signals is described. The effects of other pharmacological interventions on finger volume pulse are also discussed, and the finger plethysmographic investigation of vasodilating substances that belong to classes of drugs other than organic nitrates is presented. The possibilities and limits of the method are discussed.

Carbazoles↗
PubMed1984

Inhibitory effects of the selective thromboxane receptor antagonist BM 13.177 on platelet aggregation, vasoconstriction and sudden death.

BM 13.177 (0.1-100 microM) produced a concentration-dependent reduction of the platelet shape change, aggregation and (3H)serotonin release induced by the stable PGH2 analogues U 46619 and U 44069 or exogenous and endogenous arachidonic acid, the latter mobilized by hydrogen peroxide or collagen. BM 13.177 (100 microM) did not inhibit the primary platelet activation by ADP, serotonin, thrombin or collagen in washed platelets or citrated PRP that had been pre-treated with ASA (acetylsalicylic acid). The formation of TXB2 triggered by 100 microM hydrogen peroxide or 10 microM arachidonic acid was not influenced by BM 13.177 (10 microM). In spiral strips of rat and rabbit aorta, BM 13.117 markedly reduced the vasoconstriction triggered by U 46619 and PGF2 alpha. BM 13.177 did not inhibit the K+-or noradrenaline-induced constriction. The concentration/response curves of the U 46619-stimulated platelet shape change and of the vasoconstriction induced by U 46619 and PGF2 alpha were shifted in parallel to the right by BM 13.177, implicating a competitive antagonism. The pAx values were about the same in these models which indicates that BM 13.177 does not differentiate between the thromboxane receptors in human platelets and rabbit aorta. In mice, BM 13.177 prevented in a dose-dependent fashion the sudden death and the symptoms of respiratory depression and shock induced by i.v. injections of U 46619 or arachidonic acid. BM 13.177 did not exert partial agonist activity in the in vitro and in the animal models.(ABSTRACT TRUNCATED AT 250 WORDS)

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1984

A cross-over study of oral and intravenous administration of theophylline in male volunteers. Absolute bioavailability of theophylline tablets.

Seven normal male volunteers each received an injection of 208 mg theophylline anhydride for 4 min, and a 185-mg single oral dose theophylline anhydride (Broncho-Afonilum) on separate occasions. The concentrations of unchanged theophylline was analyzed over a 24-h period in plasma and a 48-h period in urine after both dosage forms. A 2-compartment model was required to describe the intravenous plasma concentration-time course in all seven subjects. A 1-compartment model sufficed to account for the decay of the oral plasma concentrations in all subjects. The mean plasma t1/2 after i.v. dosing was 6.5 h (3.5-9 h), and the mean plasma t1/2 after oral doses was 5.7 h (3-12 h). The calculated total of 23% (11-70%) of the intravenous dose was excreted in urine, and the mean total excretion after the oral dose was 12% (7-19%). The absolute bioavailability of oral theophylline was 94 +/- 20%

Administration, Oral↗
PubMed1983

Beta-blocking and electrophysiological effects of propafenone in volunteers.

The chemical structure of propafenone (P) and certain experimental findings suggest that this antiarrhythmic compound could possess beta-blocking properties. To evaluate the clinical relevance of the latter cardiovascular effects of P during exercise were studied. After oral administration of P 150 and 300 mg in solution, six healthy volunteers were subjected to graded exercise. These doses of P, which are usually effective against arrhythmias, decreased exercise-induced tachycardia, whereas the systolic blood pressure was lowered but only at rest, and the diastolic pressure was slightly raised. However, taking into account dose ratio, and the intensity and duration of the reduction in exercise tachycardia, this effect of P was only about 5% at its maximum compared to propranolol and similar active beta-blocking compounds. The reduction in heart rate produced by P was not correlated with the plasma level nor did it show dose dependency, in contrast to beta-blocking agents, and also in contrast to its electrophysiological effects on the PQ interval.

Adult↗
PubMed1983

Pharmacodynamic and pharmacokinetic evaluation in man of the new sympathomimetic amezinium.

Blood pressure, ECG and plasma concentration were determined for up to 12 h following single i.v. (10 mg) and oral (20 mg) doses of amezinium (Regulton) in 8 healthy, male volunteers. The i.v. and oral doses were almost equi-active in significantly increasing systolic blood pressure (SBP) by 14.5 and 15.6 mmHg, respectively. The maximum SBP after the i.v. dose was reached after 45 min, and 105 min after oral administration. The heart rate fell reflexly. The increases in mean and diastolic blood pressures were not significant. Pulse pressure was enhanced after both i.v. and oral administration. The effect on systolic blood pressure lasted for about 4 h. There was a slight shortening of the QTc duration, which could not be explained as a drug effect. Other ECG time intervals were not altered. Multiple regression analysis showed a significant positive correlation between the log plasma concentration and the increase in SBP between 0.5 and 5 h after oral administration (r = 0.78, p less than 0.001) and between 0.75 and 5 h after i.v. administration (r = 0.83, p less than 0.001). 30 min after amezinium p.o. the mean SBP began to rise, when a plasma level of about 30 ng/ml was reached.

Adult↗
PubMed1983

A crossover study after oral and intravenous administration of theophylline in male volunteers (absolute bioavailability of Afonilum tablets).

Seven normal male volunteers received an injection of 208 mg theophylline-anhydride (Solosin) each for 4 min, and a 225-mg single oral dose (Afonilum) on separate occasions. The concentration of unchanged theophylline was analyzed over a 24-h period in plasma and over a 48-h period in urine, after both dosage forms. A two-compartment model was required to describe the i.v. plasma concentration-time course in all seven subjects. A one-compartment model sufficed to account for the decay of the oral plasma concentrations in five of the subjects. The mean plasma t 1/2 after i.v. dosing was 6.5 h (3.5-9 h), and the mean plasma t 1/2 after oral doses was 5.9 h (3-8.3 h). The calculated mean total of 23% (11-70%) of the i.v. dose was excreted in the urine, and the mean total excretion after the oral dose was 15% (7-44%). The absolute bioavailability of Afonilum was 108 +/- 11%.

Administration, Oral↗
PubMed1981

[Preoperative diagnosis of a Meckel's diverticulum (author's transl)].

The most common complications of a Meckel's diverticulum is bleeding. With the introduction of abdominal scintigraphy we have a non-invasive examination method at our disposal which enables this condition to be diagnosed with accuracy preoperatively. A relevant case is described.

Child↗
PubMed1981

Haemodynamic effects of amezinium in man.

After single i.v. (5 and 10 mg) and p.o. (10, 20 and 40 mg) administrations, 4-amino-6-methyoxy-1-phenyl-pyridazinium methyl sulfate (ameziniummetilsulfate, LU 1631, Regulton), in the following briefly called amezinium, a new antihypotensive agent, was studied by non-invasive methods for its cardiovascular action in comparison with norfenefrine (10 mg i.m. and 40 mg p.o.) and dihydroergotamine (1 mg i.m. and 4 mg p.o.) in a group of 33 volunteers. The action pattern of 10 mg amezinium i.v. consisted of a significant rise in arterial blood pressure (systolic 23%, diastolic 14%) with an increase in pulse pressure (38%) and a reflex fall in heart rate (9%). The total peripheral resistance was increased by 29%, with a moderate reduction of cardiac output (5%; n.s.) and an increase of the stroke volume (6%; n.s.). A clear positive inotropic effect was discernible by the significant reduction of heart rate, corrected preejection period (delta PEP; 13 ms), left ventricular ejection time (delta LVET; 8 ms; n.s.) and a decrease of the ratio PEP/LVET (-0.028). This pattern of action points to stimulation of vascular alpha- as well as cardiac beta 1-adrenoceptors and is in accordance with the findings from animal experiments as amezinium acts via endogenous noradrenaline. The reference substance norfenefrine exhibited purely alpha-sympathomimetic action, whereas dihydroergotamine presumably exerted venoconstrictive and central sympatholytic effects. The effects of amezinium after p.o. administration on the circulation were similar to those after i.v. administration, whereas the reference substances did not reveal any definite pharmacodynamic action when given p.o. Single administrations of the various p.o. doses of amezinium gave rise to a dose-dependent increase of the systolic blood pressure, persisting over the 180 min of the investigation period. From the dose-response relationships after parenteral and oral administration a relative enteral efficacy of 50-80% was established, which corresponds well with bioavailability data. The results show amezinium to have potent, long-lasting blood pressure increasing and positive inotropic actions in man after oral as well as parenteral administration.

2-Hydroxyphenethylamine↗
PubMed1981

Cardiovascular effects of amezinium in humans during passive upright tilt in comparison with norfenefrine and dihydroergotamine.

20 min after single i.v. administration of 10 mg 4-amino-6-methoxy-1-phenyl-pyridazinium methyl sulfate (ameziniummetilsulfate, LU 1631, Regulton), in the following briefly called amezinium, a new antihypotensive agent, was studied in comparison with 10 mg norfenefrine i.m. and 1 mg dihydroergotamine i.m. during orthostatic stress on a tilt table in a total group of 29 healthy volunteers with stable cardiovascular conditions. The study of each substance was preceded by a control tilting test. After amezinium a higher systolic blood pressure of 10 to 15 mmHg in comparison with the control test was maintained during 5 min upright tilt with both a smaller increase in the rise of heart rate and decrease in stroke volume. In comparison with control, pulse pressure was also clearly increased whereas cardiac output and total peripheral resistance were not significantly different. The increase in stroke volume in comparison with control was a result of the positive inotropic effect on the one hand, which could be seen in both a diminished prolongation of the preejection period and increase in the PEP/LVET ratio, and an increased venous return to the heart on the other hand. Systolic blood pressure and heart rate after norfenefrine were principally similar to those after amezinium, whereas the effect on stroke volume was of minor magnitude because of the absence of a positive inotropic action. Moreover, cardiac output decreased more with higher total peripheral resistance in comparison to control. Besides a slight reduction in heart rate, dihydroergotamine did not reveal any significant differences from control during orthostatic stress. At the dose studied, amezinium seemed to produce a better adaptation to passive upright tilt than the reference substances.

2-Hydroxyphenethylamine↗
PubMed1981

Absolute bioavailability of amezinium. A cross-over study after i.v. and p.o. application.

The absolute bioavailability and pharmacokinetics of 4-amino-6-methoxy-1-phenyl-pyridazinium methyl sulfate (amesiniummetilsulfate, LU 1631, Regulton), in the following briefly called amezinium, were examined following i.v. injection (10 mg) and single p.o. doses administered to eight healthy male volunteers. After i.v. injection plasma levels of amezinium were described by a tri-exponential function and the mean half-lives of the three phases were 0.08, 1.5 and 14 h, respectively. The volume of distribution at steady state ranged between 201 and 476 1. After p.o. doses of tablets, absorption of the drug obviously commenced immediately after dosing. After 0.5 h the absorption took place more rapidly and peak plasma levels between 31 and 61 ng/ml were reached after 1.2 to 2.4 h. The mean terminal half-life in plasma was 13 h after p.o. doses. 77% of the i.v. dose was excreted unchanged in the urine over 48 h; the mean excretion after the p.o. dose was 32%. Within the first 7 h the renal clearance of amezinium was considerably higher than afterwards. The mean absolute bioavailability determined by means of the area under the plasma concentration-time curve (AUC) was 53% and ranged between 40% and 74%.

Administration, Oral↗