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Biomedical subjects

H Laufen

Publications and source records attributed to H Laufen.

At least 73 records · Page 4Linked to original sources
PubMed1986

[Comparative pharmacology of glycerol-1-nitrate and glyceryl trinitrate in various species].

The present studies yield that all 4 metabolites of glyceryl trinitrate (Nitro Mack, GTN) cause the same typical pharmacological effects as the parent substance. Continuous infusion of 4 mg/kg/min of glyceryl 1-nitrate (G-1-N) in the conscious dog results in a drop in blood pressure which is maintained for at least 20 min after stopping the infusion. Under comparable conditions the reduction in blood pressure caused by glyceryl 2-nitrate (G-2-N) (infused at 16 mg/kg/min) decreases by only 3 mmHg. The drop in blood pressure caused by a continuous infusion with GTN (8 micrograms/kg/min) disappeared 10 to 12 min after the end of the infusion. GTN is active in rat, dog and man for 15 to 30 min. Our experiments indicate that after oral administration to the rat or dog glyceryl 1,2-dinitrate (1,2-GDN) and glyceryl 1,3-dinitrate (1,2-GDN) are active for 3 h. Earlier experiments have shown that the administration of high oral doses of 1,2-GDN or 1,3-GDN (280 mg/kg) to the rat increases the time of action to 5-6 h. This is taken as indication that the dinitrates form pharmacologically active metabolites. 1,3-GDN (70 mg/kg p.o.) and 1,2-GDN (140 mg/kg p.o.) exhibited antianginal activity in the rat for 3 or 2 h, respectively. Orally administered GTN is only active for 15 min in the rat or dog. Its pharmacological activity after this time and up to 2-3 h on the rat (280 mg/kg p.o.) and on the dog (4 mg/kg p.o.) is brought about by the dinitrate metabolites (1,2-GDN, 1,3-GDN) and after this time probably only by G-1-N.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗
PubMed1986

[Hypotensive, antianginal action and pharmacokinetics of glyceryl-1-nitrate in rats and dogs].

The antianginal and hypotensive activity and the pharmacokinetic properties of glyceryl 1-nitrate (G-1-N) were examined in the rat and in the dog. The level and duration of antianginal and hypotensive activity were the same after single or repeated oral dosage of G-1-N to the anaesthetized rat. The haemodynamic activity of intravenously administered G-1-N in the anaesthetized and thoracotomized dog was dose-dependent. A bolus injection of G-1-N or glyceryl trinitrate (GTN, Nitro Mack) antagonized the cardiovascular activity of intravenously injected dihydroergotamine (DHE) in the anaesthetized and thoracotomized dog. The bioavailability of G-1-N in the rat and in the dog is practically 100%. After intravenous or oral administration to the rat the concentrations of G-1-N in the walls of the vena cava caudalis were markedly higher and in the aorta abdominalis somewhat higher than in the blood or in the other organs examined. G-1-N was eliminated more slowly from the walls of the animals veins than from the walls of the aorta abdominalis or from the blood.

Angina Pectoris↗
PubMed1986

[Comparative hemodynamics action of glycero-2-nitrate and glycerol trinitrate in various species and the pharmacokinetics of glycerol-2-nitrate in the dog].

Comparative Hemodynamic Activity of Glyceryl 2-Nitrate and Glyceryl Trinitrate in Various Species and Pharmacokinetics of Glyceryl 2-Nitrate in Dog A single dose of glyceryl 2-nitrate (G-2-N) had practically identical hypotensive and cardiovascular activity when administered intravenously or enterally to the anaesthetized rabbit, cat or dog. In all three species the hypotensive and also cardiovascular activity of G-2-N lasted much longer than that of glyceryl trinitrate (GTN, Nitro Mack). In the rabbit, cat and dog enterally active doses of GTN were 500-1000 times greater than parenterally active doses. In all species enterally administered GTN was about 8 times more active than enterally administered G-2-N. G-2-N is 100% bioavailable in the conscious dog.

Animals↗
PubMed1986

[Intracellular effects of josamycin].

Josamycin (Wilprafen) is accumulated in human polymorphonuclear leucocytes and monocytes (macrophages) by a factor of 12-20fold, in comparison with extracellular fluid. The uptake of the antibiotic by lymphocytes and erythrocytes is much less than with the two types of phagocytic cells. The distribution of 14C-josamycin was measured after lysing the polymorphonuclear leucocytes and the results confirmed that the antibiotic penetrates through the cell membrane and accumulates in the cytoplasm. The results indicate that josamycin is taken up into the cell by an active transport mechanism. It is significant for the clinical application of josamycin that the active drug is present inside the cells and can thus support the bactericidal activity of polymorphonuclear leucocytes or monocytes against intracellularly localized microorganism. This localization of the antibiotic in the two types of phagocytosing cells of the defense system could be important for the treatment of several infectious diseases.

Biological Transport, Active↗
PubMed1986

The effect of activated charcoal on the bioavailability of piroxicam in man.

The effect of single and multiple oral doses of activated charcoal (a.c.) on the plasma concentrations of piroxicam was investigated in a cross-over study in 6 healthy volunteers after oral and rectal doses of 20 mg piroxicam. 50 g a.c. swallowed 5 min after the oral administration of one capsule of piroxicam almost completely prevented the absorption of the drug. 70 g a.c. per day were given in multiple doses over the interval of 10-58 h after the oral and 2-58 h after the rectal administration of piroxicam. This treatment reduced the mean bioavailability of piroxicam by 41.7% (oral) or 48.8% (rectal), relative to the control. The apparent total clearance increased significantly (p less than 0.05) to 163.6% (oral) or 187.9% (rectal) of the control. Half-lives of elimination were reduced on the average from 40.2 h to 19.6 h after the oral dose and from 40.7 h to 21.6 hours after the rectal dose under the a.c. treatment. It is inferred from these results that piroxicam is subject to enteral circulation. A.c. appears useful as an antidote in acute intoxications from piroxicam.

Adult↗
PubMed1985

Uptake of antimicrobial agents by human polymorphonuclear leucocytes.

The uptake of the antimicrobial agents tinidazole, josamycin and penicillin G by normal human polymorphonuclear leucocytes (PMNs) was measured in vitro, using radiolabeled drugs. Extracellular concentrations corresponding to therapeutically effective serum levels of the drugs were used. Penicillin G penetrated the leucocyte membrane poorly, the ratio of the cell-associated to the extracellular concentration (C/E) being between 0.23 and 0.54. In contrast, tinidazole and josamycin were accumulated by the cells: C/E for tinidazole varied from 1.38 to 1.56 and C/E for josamycin from 3.5 to 21.4, depending on incubation times. It is inferred that these two compounds are capable of inactivating intracellular organisms and would therefore be useful for treating or preventing chronic infections caused by pathogens which survive intracellularly. The extraordinarily high accumulation of josamycin by PMNs could not easily be reversed by repeated cell washing and might be explained by the existence of an active transport mechanism.

Anti-Bacterial Agents↗
PubMed1985

[Pharmacology of isosorbide dinitrate after transdermal application].

Different organic nitrates exhibit markedly different in vitro partition coefficients, P. The lipophilic character, of which P is a measure, is the most important physico-chemical property which influences the penetration of nitrate molecules through the skin. It follows that there are several possibilities for developing formulations in which the diffusion of the molecules through the layers of the epidermis is furthered. A transdermal spray of isosorbide dinitrate (ISDN, TD Spray Iso Mack) was administered to volunteers and blood concentrations of the nitrate were measured. The results demonstrate that therapeutically effective amounts of the nitrate do in fact penetrate through the various levels of the skin. In addition pharmacokinetic measurements confirm that ISDN penetrates from the sprayed on film into the surface of the skin within 20 min and is then slowly released from the epidermis into the capillaries of the corium. An advantage of the administration of ISDN through the skin lies in the avoidance of the rapid metabolism of the drug which takes place during its first passage through the liver (first-pass effect). The protracted efficacy of the transdermal spray in the treatment of patients with coronary disease is, therefore, due to the unchanged ISDN and not, as with oral treatment, to pharmacologically active metabolites.

Administration, Topical↗
PubMed1985

The reaction between organic nitrates and sulfhydryl compounds. A possible model system for the activation of organic nitrates.

The rate of loss of the sulfhydryl group, determined with the Ellman reagent, was used to derive second order rate constants for the reaction of a series of organic nitrates with a series of sulfhydryl compounds. For the organic nitrates, increases in the rate of reaction with cysteine, in general, ran parallel both with increases in pharmacological potency (flow in the Langendorff heart) and with increases in total clearance. Cysteine was the most active sulfhydryl compound examined, which is compatible with a possible role as an important nitrate receptor. Under some conditions the rate of loss of the sulfhydryl group was much greater than the rate of formation of nitrite ion. This indicates the presence of a reaction intermediate, probably a thionitrate. It is suggested that, in vivo, a thionitrate could function as an important intermediate in the activation of guanylate cyclase.

Animals↗
PubMed1984

Overdosage of piroxicam.

A 54-year-old woman took an overdose of 1 800 mg piroxicam. She complained of nausea and abdominal pain. Endoscopy revealed multiple superficial ulcerations in the pyloric antrum and the first part of duodenum. There were no symptoms or signs from other organ system and recovery was uneventful. The highest serum concentration was 241.6 mg/l, which is about 30 times the usual therapeutic level of 5-10 mg/l.

Anti-Inflammatory Agents↗
PubMed1983

Use of isosorbide dinitrate saliva concentrations for biopharmaceutical investigations.

The concentration of isosorbide dinitrate in paired samples of plasma and mixed saliva was monitored for up to 24 hr after oral administration of 60 mg of sustained-release isosorbide dinitrate to eight healthy volunteers. Measured isosorbide dinitrate plasma concentrations were mainly in the range of 0.1-10 ng/ml. Isosorbide dinitrate was excreted into saliva resulting in a mean (+/- SD) saliva-plasma concentration ratio of 0.68 +/- 0.37. A significant correlation between concentrations of isosorbide dinitrate in saliva and plasma was found (p less than 0.01). The sustained-release properties of the administered formulation were confirmed from the concentrations of isosorbide dinitrate found in both saliva and plasma. Saliva-plasma ratios were independent of the absolute concentrations of isosorbide dinitrate but showed a slight tendency to decrease with time. The principal factor relating saliva and plasma isosorbide dinitrate concentrations appeared to be the degree of plasma protein binding of the drug.

Adolescent↗
PubMed1983

Oral absorption and disposition of isosorbide dinitrate and isosorbide mononitrates in man.

The plasma concentrations of isosorbide dinitrate (ISDN) and its two pharmacologically active metabolites isosorbide 2-mononitrate (IS-2-MN) and isosorbide 5-mononitrate (IS-5-MN) were determined after oral administration of 20 mg ISDN and 20 mg of each of the mononitrates. The mean concentration-time curve of ISDN showed a peak of 51.6 ng/ml 15 min after drug intake, and declined bi-exponentially with a terminal half-life of 36.5 min. The mean concentrations of the simultaneously measured metabolic products IS-2-MN and IS-5-MN reached a maximum of 40.5 ng/ml and 144.4 ng/ml, respectively. In contrast, after the direct ingestion of isosorbide mononitrates, peaks of 409.1 ng/ml (IS-2-MN) and 483.2 ng/ml (IS-5-MN) were observed in the corresponding mean curves. Mean half-lives of 1.72 h for IS-2-MN and 4.20 h for IS-5-MN were calculated. The mean apparent volumes of distribution were 44.5 l (IS-2-MN) and 34.4 l (IS-5-MN), suggesting that the isosorbide mononitrates are distributed throughout the whole body fluid. After ISDN administration, it was estimated that 3.0 mg IS-2-MN and 7.8 mg IS-5-MN reached the systemic circulation. This corresponds to 63% of the ISDN dose being converted to isosorbide mononitrates by metabolic processes.

Administration, Oral↗
PubMed1983

[Comparative antianginal, hemodynamic and pharmacokinetic effects of isosorbide-2-mononitrate and isosorbide dinitrate in the rat].

The effect of isosorbide 2-mononitrate (IS-2-MN) was compared with that of isosorbide dinitrate (ISDN) in rats regarding the antianginal, haemodynamic and pharmacokinetic properties. The antianginal effect of IS-2-MN in equal oral dose persisted 3 times longer in the rat than did ISDN. In the same oral dosage, the two compounds caused the equal reduction of the number of deaths after an acute myocardial infarction. The intravenous or enteral administration of a single IS-2-MN dose caused an increasingly dose-dependent reduction of the systolic and mean arterial blood pressure in anaesthetized rats. The amounts of IS-2-MN required for the purpose were identical for both kinds of application. The fall of the systolic and mean arterial blood pressure due to ISDN is approx. 22 times weaker after enteral administration than it is after intravenous application. The hypotensive effect of ISDN or IS-2-MN could be antagonized by pre-treatment of the animals with i.v. dihydroergotamine (DHE). The half-life of IS-2-MN in the rat was unchanged after increase of the oral doses. The bioavailability of IS-2-MN in the rat was 100%. 1 h after oral or intravenous administration of IS-2-MN to the rat, the concentrations in the walls of aorta abdominalis and aorta thoracica and in the walls of vena cava caudalis and vena thoracica were distinctly greater than in the blood or in the other tissues examined.

Angina Pectoris↗
PubMed1978

Improved method for the rapid determination of isosorbide dinitrate in human plasma and its application in pharmacokinetic studies.

A rapid, accurate and highly sensitive method was developed for the determination of isosorbide dinitrate in human plasma. Concentrations in the lower nanogram and subnanogram range are determined by a one-step extraction of 2 ml plasma, containing 4 ng/ml nitroglycerine as internal standard, with 5.5 ml n-pentane. The extract is subjected to gas--liquid chromatography--electron capture detection analysis. The lower limit of quantitation is 200 pg/ml, but concentrations as low as 50 pg/ml are still detectable. The method allows the quantitative determination of isosorbide dinitrate plasma levels in man following a 5 mg sublingual administration up to four hours after application.

Chromatography, Gas↗