Biomedical subjects
Ernst Mutschler
Publications and source records attributed to Ernst Mutschler.
[Sequential nephron blockade].
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[Mechanism of action of xipamide and its classification as a "low ceiling diuretic". Pharmacodynamic-pharmacokinetic studies in healthy volunteers and in kidney and liver patients].
Xipamide (CAS 14293-44-8) shows structural features comparable with the thiazide- as well as the class of loop diuretics. According to earlier findings this diuretic, in contrast to the thiazides, should not decrease the glomerular filtration rate (GFR) and be effective even in patients with advanced renal failure. Therefore recently the question, which class of diuretics xipamide should be related to, has been increasingly discussed. In order to solve this issue, the diuretic effect of xipamide was assessed in healthy volunteers once without and once under strict water and salt restriction. Additionally, changes in GFR were monitored by means of measurement of the creatinine clearance. Kinetic parameters were determined in plasma and urine; further, in patients with liver cirrhosis, renal elimination kinetics of the diuretic were correlated with the concentration of direct plasma bilirubin, as a marker of cholestasis, at the beginning of a treatment with xipamide, 40 mg qd. The investigations proved that xipamide, like a typical thiazide diuretic, gives rise to a temporary decrease in GFR of about 30 %, provided the renin-angiotensin-aldosterone system of the volunteer is activated by previous salt and water restriction. Xipamide leads to an increase of K+ and Mg2+ excretion, but to a decrease of Ca2+ excretion in urine, a charactaristical feature of the thiazide-like diuretics. The correlation between Na+ excretion and drug excreted in urine over time showed a functional graph that is characteristic for a "low ceiling" thiazide diuretic. In patients with renal failure FE(Na) was increased when related to the GFR-adjusted drug excretion rate, whereas it was diminished in conditions with decreased effective circulating volume like in liver cirrhosis with ascites. It could be shown that the elimination kinetics of xipamide are determined by renal drug clearance, which proportionally decreases with GFR. In patients with liver failure, a decrease of non-renal drug clearance went along with an increase in urinary drug excretion. The amount of drug excreted in urine (Ae) proportionally increased with the concentration of the patients' direct plasma bilirubin. Thus, from a pharmacological as well as clinical point of view xipamide acts like a thiazide diuretic. As could be shown for other thiazides some time ago, xipamide is effective not only in patients with cardiovascular diseases, but also in those with advanced renal failure.
Structure-activity relationships of dimethindene derivatives as new M2-selective muscarinic receptor antagonists.
A series of 2,3-disubstituted indenes, which are analogues of the widely used histamine H(1) receptor antagonist dimethindene, have been synthesized and studied as muscarinic and histamine receptor antagonists. The affinities of these compounds for the five human muscarinic receptor subtypes (M(1)-M(5)) and for human histamine H(1) receptors were determined in radioligand binding studies using membranes from transfected Chinese hamster ovary (CHO) cells and [(3)H]N-methylscopolamine ([(3)H]NMS). The results demonstrate that the diisopropyl analogue 19 has a similar high affinity as (S)-dimethindene at M(2) receptors ((S)-dimethindene: pK(i) = 7.52; (-)-19: pK(i) = 7.37) with an improved selectivity pattern ((S)-dimethindene: M(2)/M(1) = 6-fold, M(2)/M(3) = 5-fold, M(2)/M(4) = 10-fold, M(2)/M(5) = 25-fold; (-)-19: M(2)/M(1) = 36-fold, M(2)/M(3) = 96-fold, M(2)/M(4) = 42-fold, M(2)/M(5) = 275-fold). In addition, compound (-)-19 showed 35-fold lower affinity at histamine H(1) receptors (pK(i) = 5.61) than (S)-dimethindene (pK(i) = 7.16). Another interesting compound is the fluoroethyl derivative 20 (pK(i)/M(2) = 7.49), which also exhibits a higher M(2) selectivity (M(2)/M(1) = 19-fold; M(2)/M(3) = 22-fold; M(2)/M(4) = 13-fold; M(2)/M(5) = 62-fold) than (S)-dimethindene. Unfortunately, compound 20 also shows a high affinity for histamine H(1) receptors (pK(i) = 8.14). The compound with the highest affinity for M(2) receptors (pK(i) = 7.91), the dimethylaminomethylene analogue 31, displayed only a small preference for M(2) receptors. In conclusion, compound (-)-19 might be useful to test the hypothesis that blockade of muscarinic M(2) receptors in the brain is a viable mechanism by which to produce improved cognition. This second-generation dimethindene analogue might also be the starting point for the development of M(2)-selective muscarinic antagonists useful for quantifying M(2) receptors in the central nervous system with positron emission tomography imaging.
[Living collegenin and collagen].
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Pharmacokinetics and bioavailability of denaverine hydrochloride in healthy subjects following intravenous, oral and rectal single doses.
The neurotropic-musculotropic spasmolytic agent denaverine hydrochloride is used mainly in the treatment of smooth muscle spasms of the gastrointestinal and urogenital tract. Despite its commercial availability as a solution for intravenous or intramuscular administration (ampoule) and as a suppository formulation, no pharmacokinetic data in man was available to date. Therefore, the objectives of this clinical trial were to determine the basic pharmacokinetic parameters of denaverine after intravenous administration, to assess the feasibility of using the oral route of administration and to characterise the bioavailability of the suppository formulation. To achieve this, healthy subjects received 50 mg denaverine hydrochloride intravenously, orally and rectally in aqueous solutions and rectally as suppository in an open, randomised crossover design. Total body clearance, volume of distribution at steady-state and half-life of denaverine are 5.7 ml/min per kg, 7.1 l/kg and 33.8 h, respectively. The absolute bioavailability after oral administration of an aqueous solution is 37%. First-pass metabolism leading to the formation of N-monodemethyl denaverine was found to be one reason for the incomplete bioavailability after oral administration. Rectal administration of an aqueous solution of denaverine hydrochloride resulted in a decreased rate (median of C(max) ratios: 26%, difference in median t(max) values: 1.9 h) and extent (31%) of bioavailability compared to oral administration. Using the suppository formulation led to a further reduction in rate (median of C(max) ratios: 30%, difference in median t(max) values: 3 h) and extent (42%) of bioavailability compared to the rectal solution.
GERD 2003 -- a consensus on the way ahead.
Gastroesophageal reflux disease (GERD) has in recent times become an important public health issue owing to the considerable health care resources utilized in its management, its deleterious effect on quality of life and the increasing prevalence of a relatively rare complication of reflux disease - esophageal adenocarcinoma. We review here the major current challenges in the field of reflux disease and its complications, and provide some approaches that may be useful in management. The issues to be faced include the very limited comprehension of the reasons behind the increasing prevalence of the disease, difficulties in correlating symptoms with objective data of pathological gastroesophageal reflux and the relatively unsophisticated tools we are employing to investigate the underlying pathophysiology. It is certain that the lack of well-defined and characterized methodologies to compare the effects of therapy require the development of more effective questionnaire-type analytic tools. In regard to treatment, there is little doubt that the widely prescribed proton pump inhibitors have dose-equivalent efficacy and are the most highly effective agents capable of suppressing acid, controlling many of the symptoms of GERD and healing erosions. Nevertheless, many patients continue to experience symptoms on withdrawal or at night. Pharmacological agents that can effectively increase lower esophageal sphincter pressure or promote motility are as yet unavailable. Although the introduction of laparoscopic techniques has resulted in a modest revival in surgical intervention using a variety of 'wrap-type' operations, the indications are few and the procedure is associated with a significant morbidity and even mortality especially if the expertise of the surgeon is an issue. Endoscopic techniques of regulating reflux are at this time experimental and not applicable to the general population. Intestinal metaplasia in the lower esophagus is probably very common. Whether and how to, first, screen for, and then, perform surveillance in Barrett's esophagus remains highly problematic and contentious.
Determination of triamterene and its main metabolite hydroxytriamterene sulfate in human urine by capillary electrophoresis using ultraviolet absorbance and laser-induced fluorescence detection.
Two capillary electrophoresis methods have been developed for the direct determination of triamterene and its main metabolite hydroxytriamterene sulfate in human urine. Analytes were detected using conventional UV detection as well as laser-induced fluorescence (LIF) detection with an HeCd-laser operating at a wavelength of 325 nm. The results of both detection techniques were compared. Indeed, the limit of quantification was eightfold lower using LIF detection (50 ng/ml) in comparison to UV detection (400 ng/ml). As no interference due to endogenous urine compounds was observed, direct urine analysis was feasible. Analysis was very simple and fast-one run could be performed within less than 10 min (CE-UV method) and 2.5 min (CE-LIF method), respectively. Both assays were fully validated and applied to urine samples from a human volunteer. The results of the application of the CE-LIF method to human urine samples are presented in this publication.
Pharmacodynamic studies on the angiotensin II type 1 antagonists irbesartan and candesartan based on angiotensin II dose response in humans.
The in vivo effects of two unsurmountable angiotensin II type 1 (AT1) antagonists, irbesartan (150 mg) and candesartan (8 mg), were studied in a double-blind, randomized, crossover study in 18 healthy men. The drugs' direct vascular effects were assessed as the rightward shift (dose ratio - 1) of angiotensin dose-effect curves on diastolic blood pressure (DBP). Renal and adrenal effects were assessed by plasma renin activity (PRA), aldosterone concentrations, and antagonistic concentration equivalents (n x Ki) in a radioligand rat lung receptor assay. Both drugs exerted similar substantial (> 30-fold) and long-lasting (> 2-fold 47 h after dosing) rightward shifts of the angiotensin II dose effect declining with half-lives of 15 h irbesartan and 12 h candesartan, respectively. Dose ratio - 1 versus n x Ki showed a linear relationship in Schild regression plots; both drugs increased PRA, decreased DBP, and suppressed aldosterone. The slopes of linear relationship between angiotensin antagonism (dose ratio - 1) and PRA increase were almost threefold steeper (p = 0.005) following irbesartan as compared with candesartan. The findings suggest that for the same degree of angiotensin II antagonism, irbesartan produces a greater increase in PRA than candesartan. These pharmacodynamic differences warrant further investigation and clarification.