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Biomedical subjects

G Kühne

Publications and source records attributed to G Kühne.

At least 37 records · Page 2Linked to original sources
PubMed1988

Pharmacokinetics of rolipram in the rhesus and cynomolgus monkeys, the rat and the rabbit. Studies on species differences.

1. The pharmacokinetics of rolipram were studied in rat, rabbit, rhesus monkey and cynomolgus monkey using 14C- or 3H-labelled rolipram and a radioimmunoassay for measurement of unchanged drug. 2. Rolipram was rapidly and completely absorbed after oral doses of up to 50 mg/kg. Bioavailability was 0.1% in rhesus monkey, 3.7% in cynomolgus monkey, 3.6% in rabbit, 35% in rat, and 75% in man. 3. Rolipram was able to pass the blood-brain barrier achieving concentrations in brain twice those in plasma. 4. Plasma levels of the unchanged drug declined with a similar half-life of 1-3 h in all species investigated. In the rat, there were indications for a different clearance of the two rolipram enantiomers. 5. Labelled rolipram was excreted rapidly and completely. The main route of elimination was via the urine.

Animals↗
PubMed1987

Pharmacokinetics and metabolism of mespirenone, a new aldosterone antagonist, in rat and cynomolgus monkey.

The pharmacokinetics and metabolism of mespirenone were examined in rat and cynomolgus monkey using the tritiated drug. Following i.v. administration, mespirenone exhibited a short half-life and a high plasma clearance; after oral administration the unchanged compound was not detectable. Thus, mespirenone has to be considered a pro-drug. From rat urine three metabolites were isolated by h.p.l.c. and identified by mass spectra and 1H n.m.r., all having retained the 7 alpha-sulphur substituent as a thiomethyl or a sulphinylmethyl group. The 7 alpha-thiomethyl metabolite had a half-life of six hours in rat plasma and its AUC value was 35% of that for total 3H. As this metabolite has marked anti-aldosterone activity, it is an active metabolite that contributes to the pharmacological effect of mespirenone.

Administration, Oral↗
PubMed1986

Half-lives in plasma and bioavailability of ethinylestradiol in laboratory animals.

The pharmacokinetics of 19-nor-17 alpha-pregna-1,3,5(10)-trien-20-yne-3,17-diol (ethinylestradiol, Progynon C) (EE2) has been studied after intravenous administration of 0.1 or 0.01 mg/kg and after intragastric administration of 1 mg/kg in female rats, rabbits, beagle dogs, rhesus monkeys and baboons. After intravenous administration disposition of unchanged drug in the plasma was biphasic with initial half-lives between 0.3 and 0.5 h and terminal half-lives between 2.3 and 3.0 h. Total plasma clearance was of the same magnitude as total plasma liver flow or even higher rat) indicating a rapid biotransformation of the estrogen in the liver. Systemic availability of intragastric EE2 amounted to 3% in the rat, 0.3% in the rabbit, 9% in the dog, 0.6% in rhesus monkeys and 2% in the baboon and was considerably lower than in humans (40%). Differences in the pharmacokinetics and in the systemic availability of EE2 between laboratory animals and man should be taken into account in the retrospective interpretation of pharmacological and toxicological data and in the design of new studies.

Administration, Oral↗
PubMed1983

Pharmacokinetics and biotransformation of methane sulphonanilides with anti-inflammatory activity in the rat and monkey--comparison with piroxicam.

The biotransformation of N-(6-phenoxyindan-5-yl)methansulphonamide (PMS) and of its 2',4'-difluoro derivative (DF-PMS) were studied in vitro using rat-liver homogenate followed by h.p.l.c. separation and mass-spectrometric identification of metabolites. Both sulphonamides were rapidly oxidized at positions 1 and 3. The pharmacokinetics of DF-PMS and of piroxicam were examined in the rat and monkey (Macaca fascicularis). Considerable concentrations were achieved in the plasma only by the 1-oxo metabolite of DF-PMS but not by the unchanged drug, indicating that the administered compound was a pro-drug of the active principle. 1-Oxo DF-PMS exhibited shorter half-lives, larger volumes of distribution and higher total clearance rates than piroxicam in the animal model studied.

Animals↗
PubMed1983

[Incidence of irritant dermatosis among employees of the shipbuilding industry].

Irritant dermatosis is a non-specific reactive change on the skin. In most cases it represents the summated effects induced by various agents. Not only the shortened recovery phases of the skin but also a dispositional factor are important. Such changes, which are relatively common in some vocations but are usually only slight, cannot, as a rule, be regarded as signs of illness. Nevertheless, attention should be drawn to the necessity of intensive skin care and observation of the recovery phases because the frequency of irritant dermatosis can increase with increasing length of employment.

Adolescent↗
PubMed1982

Isolation and identification of spirorenone metabolites from the monkey (Macaca fascicularis).

The plasma level of spirorenone was determined 3 h after 1, 8, 22 and 46 daily oral administrations of 20 mg/kg to two female and two male monkeys (Macaca fascicularis). A fifth animal, female, was treated with eight daily doses of tritium-labelled drug and was completely bled from the carotid vein 4 h after the last administration in order to isolate and identify plasma metabolites. After repeated daily doses of spirorenone the mean plasma level of unchanged drug was 711 +/- 213 ng/ml. In the plasma of the fifth animal four radioactively labelled compounds could be detected after extraction and subsequent HPLC separation. Mass spectrometric identification of three of the substances indicated 1,2-dihydrospirorenone, hydroxy-1,2-dihydrospirorenone and the unchanged drug itself.

Androstadienes↗
PubMed1976

[Bioavailability and pharmacokinetics of 14C-cyproterone acetate after administration as a 50-mg tablet (author's transl)].

Four male volunteers were each given a 50 mg oral dose of methylene-14C-labelled cyproterone acetate in a formulation largely identical to the commercial preparation Androcur Tablets. A further 3 volunteers were each given 10 mg of the 14C-labelled compound by intramuscular injection. Plasma samples were obtained and urine and faeces collected quantitatively from each volunteer up to 10 days post administration. 1. Absorption of the 50 mg of cyproterone acetate administered in the form of Androcur Tablets was largely complete. 2. The maximal plasma level of 400 +/- 40 ng cyproterone acetate equivalents/ml of plasma, calculated from the 14C activity, was found 3,8 +/- 0,5 hours after oral administration. By 10 hours post administration the plasma level had declined with a half-life of 7,9 +/- 2,5 hours (distribution and elimination). The fictitious distribution volume assignable to this process amounted to 140 +/- 40% of body weight. Plasma 14C-activity then decreased with a half-life of 1,8 +/- 0,2 days, which was consistent with elimination. 3. The labelled substance was almost completely extractable from plasma and could be separated by chromatography into 2 fractions of about equal size: cyproterone acetate and one metabolite. 4. Orally administered cyproterone acetate was eliminated with a half-life of 1,6 +/- 0,1 days. By 10 days post administration 33 +/- 6% of the dose had been detected in urine and 60 +/- 8% in faeces. Up to this time total elimination amounted to 93 +/- 5% of the dose. 5. After intramuscular injection of 10 mg of cyproterone acetate the half-life for absorption from the muscular depot was 7,0 +/- 0,2 hours. Between 2 and 10 days post administration there was a uniform decrease in plasma level and urinary elimination with half-life of 2,3 +/- 0,1 days and 2,1 +/- 0,2 days respectively. By the end of the trial 34 +/- 5% of the dose had been eliminated with urine and 57 +/- 6% with faeces.

Administration, Oral↗
PubMedDate not supplied

Ergonovine-induced constrictions of epicardial coronary arteries in conscious dogs: alpha-adrenoceptors are not involved.

The effect of i.v. ergonovine tartrate infusions (0.05-20 micrograms/kg/min, 12 minutes duration) on coronary arteries was studied in 14 conscious dogs instrumented to continuously measure vascular diameter by an ultrasonic dimension gauge using 10-MHz piezoelectric crystals. Ergonovine induced a biphasic coronary response: small, transient dilation during the first minutes of infusion, followed by slowly developing constriction reaching its maximum 5 to 15 minutes after the end of the infusion and persisting at this level for at least 10 minutes. The threshold dosage for significant constriction was 0.05 microgram/kg/min. A dosage of 5 micrograms/kg/min (cumulative 60 micrograms/kg, corresponding to 35 micrograms/kg ergonovine maleate) caused a decline in mean left circumflex artery diameter by 137 +/- 15 micrometers (= 4.6%) without significantly altering heart rate, plasma catecholamines or plasma renin activity. Coronary venous O2 saturation did not decline, indicating the absence of coronary resistance vessel constriction. The epicardial artery constriction was not attenuated by a vasopressin antagonist. Under adrenergic blockade (2 mg/kg phentolamine and 2 mg/kg nadolol) or under ganglionic blockade (5 mg/kg pentolinium tartrate), ergonovine (5 micrograms/kg /min) caused substantial elevation in mean arterial pressure, while the decline in coronary artery diameter was attenuated. When this increase in arterial pressure was prevented by appropriate bleeding, the ergonovine-induced coronary constriction was not diminished by adrenergic or ganglionic blockade. The serotonin antagonist methysergide (0.5 mg/kg) completely abolished the ergonovine-induced coronary artery vasomotion. It is concluded that ergonovine in dogs causes an epicardial coronary artery constriction comparable to the diffuse coronary artery narrowing in men not suffering from variant angina pectoris. These constrictions are not mediated by an adrenergic mechanism.

Adrenergic beta-Antagonists↗
PubMedDate not supplied

Antibody-magnetite nanoparticles: in vitro characterization of a potential tumor-specific contrast agent for magnetic resonance imaging.

Target-specific superparamagnetic contrast agents may allow the localization of specific tissues such as tumors by magnetic resonance imaging (MRI). In this report the preparation and in vitro characterization of tumor-specific superparamagnetic particles (SMP) are described. Particles of uniform size (9.6 +/- 0.8 nm) were prepared from an alkaline solution of ferric and ferrous ions and isolated by differential centrifugation. The resulting nanoparticle suspension is stabilized in buffer using a polypeptide coat to which a monoclonal antibody, specific to carcinoembryonic antigen (CEA), was covalently attached at the hinge region. The resulting anti-CEA SMP have a hydrodynamic radius of less than 50 nm, and specifically bind to CEA in vitro. The visualization of epitopes, present on a cell surface in very low density as expected for tumor antigens or receptors, may be achieved due to the high R2 relaxivity of 300 L mmol-1s-1 of the contrast agent described here. Furthermore, the polypeptide coat chosen provides an ideal platform for the attachment of biological modifiers needed for the reduction of the antigenicity and blood clearance rate of anti-CEA SMP.

Antibodies↗
PubMedDate not supplied

Beta-adrenergic activation of the renin-angiotensin system following alpha 2-, alpha 1-, or nonselective alpha-blockade in conscious dogs: no relation to the changes in blood pressure.

We analyzed the role of the renin-angiotensin system following alpha 2-, alpha 1-, or nonselective alpha-blockade in an intact organism in which both postsynaptic alpha-adrenoceptor types contribute to adrenergic vasoconstriction. In conscious dogs, alpha 2-blockade (0.3 mg/kg rauwolscine, n = 10) increased mean arterial pressure by 40 mm Hg, while hypotension by 8 mm Hg occurred following nonselective alpha-blockade (1.5 mg/kg phentolamine, n = 9) and by 20 mm Hg following alpha 1-blockade (1.2 mg/kg prazosin, n = 10). Plasma angiotensin II (pg/ml) rose by 103 +/- 28 (SEM), 143 +/- 48, and 58 +/- 15 following alpha 2-, nonselective alpha-, or alpha 1-blockade, respectively. While alpha 2- or nonselective alpha-blockade induced tachycardia and substantial elevations of plasma catecholamines, alpha 1-blockade did not. Beta-Blockade (2 mg/kg nadolol) attenuated the elevations of angiotensin following alpha 2- or nonselective alpha-blockade by 100 and 88%, respectively, without affecting the alpha 1-blockade-induced elevation, which is mainly mediated by the hypotension. Pretreatment with 3 mg/kg captopril reduced the pressure increase induced by alpha 2-blockade from 40 to 13 +/- 10 mm Hg and aggravated the decline in blood pressure induced by nonselective alpha-blockade from 8 to greater than 50 mm Hg. In anesthetized, spinalized dogs, both types of alpha-blockade competitively antagonized the pressor effect of the alpha 2-agonist azepexole by the same degree. It is concluded that, in the intact animal, the central and peripheral presynaptic augmentation of sympathoexcitation induced by alpha 2- or nonselective alpha-blockade leads to a strong beta-adrenergic activation of the renin-angiotensin system, independent of the concomitant changes in blood pressure. The constrictive action of the activation contributes substantially to the compensation of the vascular adrenoceptor blockade induced by nonselective or alpha 2-selective blockade in the intact organism.

Adrenergic alpha-Antagonists↗
PubMedDate not supplied

Pharmacokinetics of mepindolol sulfate in the rat, dog, and rhesus monkey. Studies on species differences.

14C-labeled mepindolol was rapidly and almost completely absorbed in the rat and dog after oral administration of 0.4 mg/kg, achieving maximum concentrations in the plasma after 1-2 hr. In the rhesus monkey, absorption was distinctly slower. Higher doses (25 mg/kg) given to rats and dogs exhibited maximum levels at 6 hr. The bioavailability of low doses was 1-2% in the rat and 40% in the dog. Plasma levels of unchanged drug declined biphasically in the dog with half-lives of 8 min and 3 hr. Excretion of radioactivity was mainly biliary in the rat. In the dog, elimination was equal in feces and urine, and in the rhesus monkey it was mainly renal. Although in the rat and rhesus monkey 14C-active compounds were completely eliminated, substantial amounts of metabolites were retained in the liver of the dog even 10 days after administration. After repeated administration, labeled substances accumulated in the dog, reaching maximum concentrations in the liver.

Animals↗