PubMed Health⌕ Search

Biomedical subjects

R Bonn

Publications and source records attributed to R Bonn.

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

Sustained-release isosorbide mononitrate (50 mg): optimization of a once-daily dosage form for long-term treatment of angina pectoris.

A capsule formulation containing 50 mg of isosorbide mononitrate has been developed, 30% of which is in a nonsustained-release form to ensure rapid attainment of initial plasma levels. The remaining 70% is in a sustained-release form that ensures a long-lasting effect and the convenience of once-daily dosing. This formulation of sustained-release isosorbide mononitrate (Elantan LA 50 mg) provides plasma levels greater than 100 ng/ml for 17 hours after oral administration. For the remaining 7 hours, the nitrate plasma level ranges between 50 and 100 ng/ml.

Adolescent↗
PubMed1987

Pharmacokinetics of isosorbide-5-nitrate during haemodialysis and peritoneal dialysis.

The pharmacokinetics of isosorbide-5-nitrate (IS-5-N) was studied in ten patients on haemodialysis (HD) after a single oral dose of 20 mg IS-5-N, and in six patients on continuous ambulatory peritoneal dialysis (CAPD) after repeated oral doses of 3 X 20 mg IS-5-N. There was significant removal of IS-5-N from blood during HD; Cmax decreased by about 20%, AUC(0-8 h) by 30% and t1/2 by about 20% from 4.3 to 3.4 h, and plasma clearance was increased by 81 ml/min. No important loss of IS-5-N was observed in patients on CAPD.

Adult↗
PubMed1987

Metabolic fate of the thrombolytic agent benzarone in man: comparison with the rat and dog.

1. The metabolic fate of 14C-benzarone in the rat and dog has been compared to that in human subjects. An oral dose was well-absorbed in all three species. However, the 14C excretion patterns differed: humans (100 mg) excreted means of 73 and 19% dose in the urine and faeces respectively, whereas the rat (2 mg/kg) and dog (0.5 mg/kg) excreted greater than 80% in the faeces, mostly during the first 48 h. 2. Much of the faecal 14C was attributable to 14C excreted in the bile which amounted to 59% in the 7 h bile collected from an intravenously dosed dog, and a mean of 72% in the 24 h bile of orally dosed rats. Enterohepatic circulation of 14C was demonstrated in rats. 3. Total 14C in human plasma reached peak concentrations between 1-2 h and declined relatively rapidly, to about 10% of this value within 24 h. Unchanged benzarone was not detected in plasma (less than 25 ng/ml), even after a 400 mg dose, but conjugated benzarone was--accounting for about 10% of the peak concentration of 14C. In the dog, by contrast, conjugated benzarone accounted for about 50% of the peak concentration of 14C of 0.96 microgram equiv./ml at 1 h. The extent of binding of benzarone to human plasma proteins (greater than 99%; in vitro was slightly greater than that (greater than 96%) of total 14C (ex vivo, representing metabolites). 4. Examination of metabolite profiles by h.p.l.c. suggested that in the rat and dog, at least 70% absorbed dose was eliminated by direct conjugation, whereas in humans at least 70% was hydroxylated before conjugation, mainly with glucuronic acid. Hydroxylation occurred in the benzofuran ring and/or the ethyl side-chain. The principal urinary metabolite in humans was the conjugate(s) of the 1-hydroxylated ethyl side-chain derivative (mean 26% dose).

Adult↗
PubMed1987

Kinetic studies of the tissue binding tendency of the new vasodilator pildralazine.

Studies of the binding and release of the new antihypertensive drug (+/-)-1-[(6-hydrazinopyridazin-3-yl)methylamino]-2-propanol (pildralazine, PD) were performed on isolated perfused guinea pig hearts according to the Langendorff technique. Extensive binding to and accumulation in the tissue were recorded. Even after 30 min of washout considerable PD concentrations were detected both in the myocardium (900 ng/g w.w.) and the effluent (17 ng/ml = 100 ng/min). The calculation of elimination half-life yielded a nearly identical value in the myocardial tissue and the effluent. Coronary vasodilation mediated by PD ran in close parallel to the drug concentrations. As the washout of [3H]-sucrose as an extracellular space marker was half-maximal already after 1.6 min rediffusion of PD originated from tissue sites and not only by dilution of the fluid in the extracellular space. In addition the results indicated that the observed binding of PD to cell structures prevented its normally rapid chemical destruction, already evident in aqueous solutions. The back diffusion of PD from the binding and storage sites into the coronary perfusate was very slow, explaining its long-lasting biological availability and action in vivo. The release kinetics may be described by an exponential function which obeys the criterions of a first order elimination process.

Animals↗
PubMed1986

Nitrate therapy without loss of action by correct dosage.

Previous studies carried out with ISDN prove that long lasting, unfluctuating plasma concentrations--e.g. above 300 ng IS-5-N/ml--cause a severe loss of action. This could be cancelled by administration of isosorbide dinitrate (ISDN) according to a regimen in which an interval with considerably reduced nitrate levels is guaranteed. On the other hand a dosage regimen which leads to steady state plasma concentrations which fluctuate between 100 and 300 ng IS-5-N/ml (after 3 times daily 20 mg ISDN) showed no clinically significant loss of efficacy even after 4 weeks of application. Based on these findings a therapy like once daily 120 mg ISDN sustained release which guarantees plasma levels of up to 600 ng IS-5-N/ml (over the active day of the patient) with an interval of nitrate levels down to 100 ng (overnight) could be judged as efficient. As recent studies showed there is no clinically found loss of efficacy after four week application. With regard to a better compliance this regimen seemed to be the optimum.

Coronary Disease↗
PubMed1985

Metabolism and pharmacokinetics of the dihydropyridine calcium antagonist, ryosidine, in man.

The metabolic fate of [14C]ryosidine (ryodipine) has been investigated after oral administration to human subjects (by capsule), and to rats and dogs (in solution). The excretion patterns of 14C were similar for all three species: about 50% dose was excreted in urine, mainly in 24 h, but a proportion was excreted slowly, particularly by humans. Absorption in man appeared to be less than in the animal species, probably as a result of the capsule dosage form used. Mean concentrations of total 14C in human plasma reached a peak value of 0.41 microgram equiv./ml at four hours and declined biphasically thereafter (mean terminal t1/2 = 28 h). Unchanged ryosidine was only detected in plasma from two to six hours (mean t1/2 = 80 min), and never accounted for more than 5% of the plasma 14C. The extent of binding of ryosidine to the plasma proteins (in vitro) was similar (greater than 90%) to that of total 14C (in vivo; mainly metabolites). Less than 0.5% of the dose to human subjects was excreted via the kidneys as unchanged ryosidine, whereas the bulk of the extractable faecal 14C was in the form of unchanged drug and presumably represented unabsorbed material. The principal routes of biotransformation of ryosidine in all three species involved oxidative aromatization of the 1,4-dihydropyridine ring, followed by ester hydrolysis, O-dealkylation, hydroxylation of an alpha-methyl group (and lactonization) and some glucuronidation, although quantitative interspecies differences were apparent.

Administration, Oral↗
PubMed1984

Metabolic fact of 14C-isosorbide 5-mononitrate in humans.

Single oral doses of 20 mg of the carbon-14 labelled form of the antianginal drug isosorbide 5-mononitrate (5-ISMN, Elantan) were essentially completely absorbed and excreted fairly rapidly in the urine. Means of 24, 52, 78, 93 and 96% dose were excreted during 6, 12, 24, 48 and 120 h, respectively. Concentrations of 14C reached peak levels at about 1-2 h when about 86% of the 14C was associated with the parent drug, 5-ISMN (peak mean level 430 ng/ml), and the remainder mainly with the pharmacologically-inactive denitrated product isosorbide. Because the plasma (and urinary) half-life of isosorbide was longer (about 8-9 h) than that of 5-ISMN (about 4.5 h), the proportions of the former in plasma increased relative to the latter. Concentrations of 14C in whole-blood and plasma were similar, implying that 5-ISMN diffused into blood cells. Concentrations of 5-ISMN in saliva and plasma were almost identical, presumably because of the almost negligible plasma protein binding of the drug (less than 5%). At least five metabolites of 5-ISMN were detected in urine - these were isosorbide (about 37% dose), conjugated material (about 25% dose) presumably mainly 5-ISMN-glucuronide, sorbitol (about 7% dose), the parent drug 5-ISMN (about 2% dose) and two unidentified metabolites (about 7 and 4% dose, respectively). The conjugated material was excreted in the urine relatively more rapidly than the denitrated product, isosorbide.

Adult↗
PubMed1983

[The effect on biologic availability of the choice of infusion material in nitroglycerin therapy].

The loss of nitroglycerin (glycerol trinitrate (GTN), Perlinganit) when infused at various rates through polyvinyl chloride (PVC) tubing was measured against time by continuously monitoring the GTN concentrations at the outflow of the tubing using a direct photometric method. The portion of GTN loss depends on the rate of infusion; at flow rates of 3-6 ml/h, GTN losses of up to 60% may be expected. Polyethylene (PE) tubing does not show this reduction in the outflow concentration of GTN. When GTN is infused through PVC tubing, the dosage cannot be controlled and any assessment of pharmacokinetics or absolute bioavailability becomes invalid. This effect of tubing accounts for apparent losses of bioavailability of up to 50%. Other organic nitrates like isosorbide dinitrate are shown to be absorbed into PVC in a similar way. The losses increase with larger liphophilicity of the drug.

Biological Availability↗
PubMed1983

[Pharmacodynamics and pharmacokinetics of bemetizid in comparison with hydrochlorothiazide. A controlled human pharmacologic study of acute effects].

Pharmacodynamics and Pharmacokinetics of Bemetizide Compared with Hydrochlorothiazide/Controlled clinical study of acute effects Bemetizide in doses of 1, 5, 10, 20, 50 mg versus 25 mg of hydrochlorothiazide were examined in a placebo-controlled randomized single-dose study under standardized conditions in normal male volunteers. The diuretic effects of bemetizide and hydrochlorothiazide were qualitatively equal, though after higher doses bemetizide showed greater maximal, statistically significant effects on the excretion of sodium, chloride and urine volume (relative efficacy). A trend to increased elimination of potassium was detectable. Diuresis of calcium and magnesium and pH of urine were unchanged. The effects of the reference dosis of hydrochlorothiazide were constantly lower than those of higher doses of bemetizide conferring to the 24-h aliquot and the fractioned samples. The action of both substances began within 1 to 2 h after oral application exceeding 24 h. Kinetics of effects and pharmacokinetics were closely correlated. The evidence of dose-dependent kinetics for bemetizide supports the assumption, that it is absorbed incompletely in higher doses. Because of the lack of a parenteral preparation it is not possible to provide reliable information on the maximal potency of bemetizide.

Adolescent↗
PubMed1980

[Autoradiographic distribution of 14C after administering tracer-marked nitroprusside, cyanide and thiocyanate to pregnant mice and rats (author's transl)].

Doses of ca. 2--3 mg/kg of nitroprusside, cyanide and thiocyanate, tracer-marked with 14C, were applied i.v. to pregnant mice and rats. Autoradiograms of the whole animal were taken 1 min, 10 min and 60 min after administration. After administering nitroprusside two phases of the tracer pattern could be distinguished: the phase of removal of the cyanide poisoning with tracer-markings predominant in the liver and the lungs, followed by the phase of thiocyanate excretion, with tracer-markings predominantly in the stomach and urinary system. Tracer-markings in the foetuses were observed during the thiocyanate phase, but not during the cyanide phase. The therapeutic consequences are discussed.

Animals↗
PubMed1979

Counteraction of cyanide poisoning by thiosulphate when administering sodium nitroprusside as a hypotensive treatment.

A 42-year old patient received a continuous infusion of sodium nitroprusside (SNP) at a dosage rate of 600 microgram/min for approximately four days. On the third day of treatment a dangerous high level of cyanide was measured in the blood. When an additional continuous infusion of sodium thiosulphate at five times the molar concentration of the SNP was given, this cyanide level dropped over a period of 7h to one-seventh of its initial value. The thiosulphate did not reduce the effectiveness of the SNP in lowering the blood pressure.

Adult↗
PubMed1979

Kinetics of elimination of thiocyanate in 7 healthy subjects and in 8 subjects with renal failure.

The concentration of thiocyanate in the serum of eight test subjects with renal failure and seven healthy control subjects was measured, as it declined with time, after oral doses of thiocyanate or i.v. injections of nitroprusside had been administered. Additional measurements were taken, on the healthy subjects only, of the concentrations of thiocyanate in the urine, and also of the influence of an increased chloride intake on the rate of elimination of thiocyanate. For the healthy subjects an elimination half-life of between one and five days (mean c. 3 days) was found. Increasing the chloride elimination rate to approximately twice normal did not significantly speed up the rate of thiocyanate elimination. The amounts of thiocyanate which had been administered as doses reappeared almost exclusively in the urine. For the subjects with renal failure, the elimination half-life had a mean value of approximately nine days. The elimination constants were found to be proportional to the creatinine-clearance rates. The ke value at a creatinine-clearance of zero ml/min was approximately 15% of the ke value at a creatinine-clearance rate of 120 ml/min. The distribution volumes for thiocyanate were greater for the patients with renal failure than for the healthy subjects. The conclusions for therapies using nitroprusside are discussed.

Adult↗
PubMed1978

The effect of chronic administration of digitoxin on the activity of the myocardial (Na + K)-ATPase in guinea-pigs.

When guinea-pigs were treated for 24 days with digitoxin 0.3 mg/kg s.c., the activity of the (Na + K)-ATPase of the heart muscle increased by about 30% compared to controls, whereas the enzymes prepared from kidney and brain showed no significant alteration in their activity. In animal species treated with digitoxin for 1 to 5 days, no increase of enzyme activity was observed. Only after 10 to 15 days of treatment, a significant increase of the (Na + K)-ATPase activity was noted which increased no further with treatment up to 24 days. There was no significant difference in the kinetic properties of the (Na + K)-ATPase prepared from digitoxin-treated animals compared to those from control animals; the KM-values for ATP remained unchanged, and there was the same dependence of the activity on the K+-concentration and the same sensitivity towards digitoxin. As there appears to be no significant change in the specific properties of the enzyme, the increase in activity may possibly be caused by an increase in the amount of enzyme as a result of an adaptive enzyme regulation.

Adenosine Triphosphatases↗
PubMed1976

Increase in the (Na+ + K+)-ATPase activity in heart muscle after chronic treatment with digitoxin or potassium deficient diet.

In guinea pigs, administration of digitoxin (0.3 mg/kg s.c. for 7-24 days) causes an increase in activity of the (Na+ + K+)-ATPase of the heart. The plasma K+ level and the K+ content of the heart muscle of these animals remains unchanged and there is no significant alteration in the digitoxin toxicity compared to controls. In guinea pigs with potassium deficiency produced by a potassium deficient diet for 12 days, there is a related increase of the (Na+ + K+)-ATPase. The plasma K+ level of these animals is diminished while the K+ content in the heart muscle remains unchanged the toxicity of digitoxin is enhanced. In both test groups the increase in the (Na+ + K+)-ATPase activity is limited to enzymes from heart muscle, those from brain or kidney remaining unaffected. This increase in activity seems to be the result of an adaptive enzyme induction.

Adenosine Triphosphatases↗