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Biomedical subjects

H Knauf

Publications and source records attributed to H Knauf.

At least 19 recordsLinked to original sources
PubMed1992

Bioavailability study of two different verapamil formulations.

Relative bioavailability and bioequivalence of two oral verapamil preparations were investigated (dosage 80 mg, film-coated tablets as reference, dragées as test formulation). The clinical study was performed in a 2-period-cross-over design with 16 male healthy volunteers (mean age 28.8 +/- 3 years). The active metabolite norverapamil was included in the investigation. To assess bioequivalence several pharmacokinetic characteristics (i.e. AUC(o-oo), Cmax, tmax) were taken into account. Shortest 90% confidence intervals were calculated based on parametric (ANOVA, ANOVAlog) and non-parametric (Wilcoxon, Mann-Whitney) statistical tests. A positive decision for bioequivalence was accepted if the confidence intervals did not exceed the limits of 80-120% for AUC and 70-130% for Cmax. A mean relative bioavailability of 127% for the test preparation was found. Thus, bioavailability of the dragées is marked higher than bioavailability of the film-coated tablets.

Adult↗
PubMed1992

Constant K+/Na+ excretion ratio during peak diuresis after piretanide but insignificant K+ loss during 24 hours.

The effect of piretanide on Na+ and K+ excretion and on renal haemodynamics has been studied in 14 subjects with a GFR (Inulin clearance) ranging from 140 to 2 ml.min-1. After a two day fluid and salt balance control period, oral piretanide 6 mg induced a natriuresis and kaliuresis, which was proportional to the GFR of the patients. The ratio of drug-induced K+ to Na+ excretion was always 0.13, independent of individual GFR. This was only true for the duration of the action of piretanide, tau, which was 6 h in subjects with normal GFR and 5 h in patients with impaired kidney function. Surprisingly, after tau, i.e. for 24 h after drug administration, less potassium was lost than in the pretreatment period. Neither the GFR nor the renal blood flow (PAH clearance) of the patients were affected by piretanide. In conclusion, piretanide given once a day was an effective natriuretic agent, even in end-stage renal disease, and it produced relatively little K(+)-loss when given once daily.

Adult↗
PubMed1992

Modulation of electrolyte excretion by potassium retaining diuretics.

Triamterene and amiloride belong to the potassium retaining diuretics of the cycloamidine type. These agents exert natriuretic as well as antikaliuretic effects. After administration of high doses an additional magnesium-sparing property also becomes evident. Whereas amiloride is only metabolized to a minor extent, triamterene is rapidly bio-transformed to the phase-I metabolite, hydroxytriamterene, and the phase-II metabolite, hydroxytriamterene sulphuric acid ester. This acidic phase-II metabolite is still diuretically active, but its electrolyte excretion profile is different from the parent compound: although the natriuretic properties are not altered, the potassium retention is very weak. Further studies in rats with cycloamidine derivatives of the triamterene type containing neutral, acidic or basic side chains at the phenyl moiety as well as with basic pteridine derivatives, revealed further evidence that the natriuretic, antikaliuretic and antimagnesiuretic effects can be influenced almost independently by structural variations of the parent drug. Thus, it was possible to obtain compounds predominantly increasing sodium excretion without affecting potassium or magnesium excretion. On the other hand, substances could be developed with mainly antikaliuretic effects, or compounds, which enhanced sodium and reduced magnesium excretion and did not interfere with the potassium elimination. Based on these findings, it can be concluded that distal tubular transport of sodium, potassium and magnesium may be influenced independently from each other. These renal effects of triamterene and its derivatives seem to be independent of their antiarrhythmic actions, as suggested by recent studies.

Animals↗
PubMed1991

Pharmacodynamic and kinetic considerations on diuretics as a basis for differential therapy.

Diuretics are classified according to their site of action in the nephron: loop diuretics, thiazides, and antikaliuretics. During peak diuresis the pattern of electrolyte excretion is constant and characteristic for a class of diuretics. The ratio of diuretic-induced excretion of K+ to Na+ is 0.12 for loop diuretics, 0.20 for thiazides, and -0.21 for antikaliuretics. The ratio of Ca2+ to Na+ is 0.02 for loop diuretics and 0.003 for thiazides. Mg2+ excretion follows K+ excretion in a ratio of 0.15. The natriuretic effect of a diuretic directly depends on the renal clearance of the drug and is proportionate to the number of intact nephrons. Not only loop diuretics but also thiazides and antikaliuretics were demonstrated to be effective natriuretic drugs down to end-stage renal disease. In renal failure FENa is doubled with every halfening of GFR. Loop diuretics increase FENa to a maximum of 24%, thiazides to 10-15%, and FENa is doubled by antikaliuretics. Comedication of loop diuretics with thiazides in renal failure may therefore be more effective than increasing monotherapy. In liver disease, nonrenal drug clearance is reduced the more the patient's direct bilirubin rises thus causing an increase in AUC and urinary excretion of parent drug and metabolites. Despite increased Ae, the cirrhotic patient may become resistant to diuretics as many patients with congestive heart failure or nephrotic syndrome. This is considered to be due to reduced Na+ load available at the diuretic's site of action following avid proximal Na+ reabsorption. In reduced EABV a short-term comedication of loop diuretics with carboanhydratase inhibitors is considered a more effective diuretic strategy than vigorously increasing monotherapy.

Biotransformation↗
PubMed1991

The loop diuretic torasemide in chronic renal failure. Pharmacokinetics and pharmacodynamics.

The pharmacodynamic effect of a diuretic agent is essentially dependent on its renal elimination characteristics. The influence of renal function on the pharmacodynamic and pharmacokinetic characteristics of a diuretic should therefore be considered. The results of a study with torasemide given intravenously in healthy subjects and in patients with stable chronic renal failure of various degrees are reported and discussed. After a single dose of torasemide 20mg, a marked diuresis was observed and electrolyte excretion was increased, whereas the glomerular filtration rate was unchanged. Throughout the duration of action (tau) of torasemide, drug-induced excretion of Cl-, Na+, K+, Ca++ and Mg++ was linearly related to the creatinine clearance (CLcr), and excretion of K+ and Ca++ were closely related to that of Na+ over the entire range of CLcr. Similarly, excretion of Mg++ was related to that of K+. As occurs with furosemide (frusemide), torasemide induced a kaliuresis which amounted to 12% of natriuresis. This kaliuretic effect of loop diuretics is less than that of thiazides. Beyond tau, e.g. over a 24-hour period, kaliuresis was no longer correlated with natriuresis. The extent to which a rebound effect occurred was diminished with increasing renal impairment. tau averaged 6 hours and was independent of CLcr. The mean half-life (t1/2) of torasemide was approximately 5 hours and was independent of renal function, since renal clearance accounted for only around 25% of total body clearance. In contrast to the parent drug, however, the active minor metabolite M1 and the inactive main metabolite, M5, were found to accumulate in patients with chronic renal failure.

Animals↗
PubMed1990

Gemfibrozil absorption and elimination in kidney and liver disease.

The disposition of the lipid-lowering drug gemfibrozil was studied in patients with either renal (n = 8) or hepatic disease (n = 8) and compared to those of healthy volunteers (n = 6). Gemfibrozil was determined in plasma and urine by means of a HPLC method. Urine was also analyzed for gemfibrozil conjugates. Following oral administration of 900 mg gemfibrozil, maximal plasma levels of the parent drug were 46.1 +/- 15.8 micrograms/ml, attained after 2.2 +/- 1.1 h. In chronic renal failure and in liver cirrhosis the plasma concentrations of gemfibrozil did not significantly differ from that of controls except in those patients who were co-medicated with antacids. These patients had significantly lower Cmax and AUC values. The elimination half-life of the drug was 1.5 h in controls, 2.4 h in renal failure, and 2.1 h in liver disease. In healthy volunteers, only 0.02 to 0.15% of the given dose was recovered in the urine as parent gemfibrozil, while conjugates made up 7-14%. In patients with renal failure also, only traces of parent gemfibrozil could be detected, and conjugates accounted for 0.5-9.8%. In those with liver disease, however, about 0.1-0.2% were recovered in urine as parent gemfibrozil and up to 50% as conjugates. Strikingly, the amount of excreted conjugates in the urine was positively correlated to the direct bilirubin plasma concentration.

Adult↗
PubMed1990

Prediction of diuretic mobilization of cirrhotic ascites by pretreatment fractional sodium excretion.

In a randomized prospective study the efficacy and side effects of xipamide versus the combination spironolactone/furosemide in the treatment of cirrhotic ascites were studied. Out of 27 patients four responded to a basic treatment consisting of salt and water restriction and one had to be excluded because of deterioration of kidney function. The remaining 22 patients were randomized to additional treatment with either 20 mg xipamide/day (group I) or 200 mg spironolactone/day combined with 40 mg of furosemide every other day (group II). A response to treatment during the first 4 days was seen in 7 of 11 patients of group I versus only 3 of 11 patients in group II. In the latter group 7 of 11 patients finally responded after 8 days of treatment. Responsiveness to either diuretic treatment strongly depended on pretreatment fractional Na excretion, FENa. The resistance to diuretic treatment can be predicted by a FENa less than 0.2%, and could be overcome by additional strategies known to reduce avid proximal Na reabsorption. Xipamide frequently induced hypokalemia, whereas hyperkalemia was seen following treatment with spironolactone/furosemide. Kidney function remained stable during either diuretic treatment.

Adult↗
PubMed1990

Single- and multiple-dose pharmacokinetics of R-(-)-and S-(+)-prenylamine in man.

The pharmacokinetics of S-(+)- and R-(-)-prenylamine was studied in eight healthy volunteers given single and repeated oral doses of the racemic drug. Distinct differences in various pharmacokinetic parameters were found between the S- and R-enantiomer. The maximum plasma concentrations and AUCs of the R-enantiomer exceeded those of the S-enantiomer five-fold; the apparent oral clearance of the S-form was five-times and the renal clearance three-times higher than of the R-form. Acid catalyzed hydrolysis of urine samples released more S-prenylamine, indicating stereoselective glucuronidation of unchanged prenylamine. Plasma protein binding also differed between the two enantiomers, generally with a higher unbound fraction of the S-form, whereas analysis of the bound fractions showed that prenylamine was bound to different plasma proteins with inverse stereoselectivity.

Adult↗
PubMed1990

Saluretic effect of the loop diuretic torasemide in chronic renal failure. Interdependence of electrolyte excretion.

The effects of torasemide have been studied in 7 healthy controls and 9 patients with stable chronic renal failure of various degrees. After a control period of 3 days torasemide 20 mg i.v. caused a dramatic increase in diuresis and electrolyte excretion without affecting the glomerular filtration rate. The duration of action of torasemide, tau, averaged 6 h and was independent of the creatinine clearance, CLCR. When related to tau the drug-induced excretion of Cl-, Na+, K+, Ca2+ and Mg2+ showed strong linear dependence on CLCR. Both the kaliuresis and the calciuresis during tau were tightly correlated with the natriuresis over the broad range of CLCR. Similarly, the excretion of Mg2+ was dependent on the kaliuresis. The torasemide-induced kaliuresis amounted to 12% of natriuresis, as after furosemide. The kaliuretic effect of loop diuretics is smaller than that of the thiazides. After tau, e.g. over a 24 h period, kaliuresis was not correlated with natriuresis. The magnitude of the rebound effect was diminished with increasing renal impairment.

Adult↗
PubMed1990

Pharmacokinetics of torasemide and its metabolites in healthy controls and in chronic renal failure.

The pharmacokinetics of 20 mg torasemide i.v. has been studied in 7 healthy controls and 9 patients with varying degrees of renal impairment. Torasemide had a t1/2 of about 4h which was independent of kidney function, as the nonrenal clearance of torasemide was 3-times greater than its renal clearance. The active metabolite M 1 and the main metabolite M 5 were accumulated in chronic renal failure. In contrast to liver function, therefore, kidney failure does not have an important effect on the pharmacokinetics of torasemide.

Diuretics↗
PubMed1990

Comparative enantioselective pharmacokinetic studies of celiprolol in healthy volunteers and patients with impaired renal function.

The pharmacokinetics of the beta 1-selective adrenergic antagonist (R,S)-celiprolol has been studied after oral administration of 200 mg celiprolol-HCl to 8 healthy volunteers and 8 patients with various degrees of impaired renal function. No significant difference was found between the two enantiomers in the control group or in the patients. In healthy volunteers an average of 9.8% of the dose of R-(+)-celiprolol and 9.5% of S-(-)-celiprolol was recovered unchanged in the urine. Renal impairment reduced the urinary excretion of both enantiomers to the same extent according to the severity of the uraemia, producing higher AUCs. Nevertheless, the terminal half-lives of the R- and S-enantiomers were not significantly different between the groups. Dosage reduction in patients with renal impairment does not seem to be necessary.

Administration, Oral↗
PubMed1990

Determination of short-circuit current in small tubular structures via cable analysis.

Use of cable analysis is a time-consuming maneuver. On the other hand, the advantage of the cable method consists in obtaining the Isc and Rm related to unit area without the explicit measurement of inside radius r of the tubular structure. Obviously, application of the clamping technique requires, in addition, the determination of the surface area. In summary, for small tubular structures, such as the salivary ducts of rats and rabbits, and for human experiments, cable analysis is the method of choice for the Isc determination in vivo as well as in vitro. For larger tubular structures such as the rat colon the Isc should be determined in vivo by the clamping technique described above, whereas the in vitro measurements should be done in an Ussing-type chamber. In the intermediate range of size both in vivo techniques should be applied, in which case one method may serve as a check of the other.

Animals↗
PubMed1990

Xipamide disposition in liver cirrhosis.

The pharmacokinetics of the sulfonamide-type diuretic xipamide was studied in patients with liver cirrhosis and ascites and compared with healthy control subjects. After oral administration of 40 mg xipamide, the diuretic was rapidly distributed in the blood and the ascites. The ratio of the area under the concentration-time curve (AUC) of plasma and ascitic fluid was 7:2, as was the protein content in the respective compartments. The AUC in plasma of cirrhotic patients was significantly greater than in control subjects (p less than 0.001). The most striking finding was the increase of the amount (Ae) of parent drug and main metabolite excreted into the urine (p less than 0.001). The renal clearance of xipamide was only moderately reduced in patients with liver cirrhosis. Both AUC and Ae were positively correlated to the plasma concentration of direct bilirubin of the patients (p less than 0.05). We concluded that nonrenal drug clearance in patients with liver cirrhosis was reduced as a result of the blockade of hepatobiliary excretion during cholestatic conditions.

Administration, Oral↗
PubMed1990

Sulfated bile acids inhibit Na(+)-H+ antiport in human kidney brush-border membrane vesicles.

Patients with obstructive jaundice are at a high risk for acute renal failure after surgery. Direct toxic membrane effects of bile acids or bilirubin have been discussed as possible causes. Therefore, we investigated the influence of bile acids and conjugated bilirubin on Na(+)-H+ antiport and ion permeabilities in brush-border membrane vesicles isolated from the human kidney. Brush-border membrane vesicles were prepared by Mg2+ precipitation. These were highly purified as estimated from the 14-fold enrichment in the specific activity of alanine aminopeptidase. The pH-sensitive dye acridine orange was used to study the properties of proton uptake under different conditions. The brush-border membrane vesicles from human kidney cortex exhibited Na+ and K+ conductances, which were small compared with H+ conductance. Furthermore, these membranes possess an Na(+)-H+ antiporter that is sensitive to amiloride. Various bile acids (30 microM) had no significant effect on Na(+)-H+ antiport. However, the addition of sulfated bile acids resulted in a significant inhibition (greater than 50%) of the Na(+)-H+ antiporter. A nonspecific effect of sulfated bile acids on the vesicles was excluded by the use of ionophores to determine vesicle integrity and to estimate the various ion conductances. Therefore specific inhibition of the human renal Na(+)-H+ antiporter by sulfated bile acids occurs. This could result in an impaired cellular pH regulation and might play a role in postoperative acute renal failure in patients with obstructive jaundice.

Acridine Orange↗