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Biomedical subjects

E Mutschler

Publications and source records attributed to E Mutschler.

At least 73 records · Page 4Linked to original sources
PubMed1996

Pharmacokinetics and drug input characteristics for a diclofenac-codeine phosphate combination following oral and rectal administration.

In a single dose cross-over study with 12 healthy male volunteers the plasma concentrations of diclofenac (CAS 15307-86-5) and codeine (CAS 76-57-3) were determined after oral and rectal application of formulations containing 50 mg of each drug. For kinetic analysis of the concentration-time profiles non-compartmental as well as compartmental procedures were used. The compartment model included two disposition compartments supplemented by a dissolution and drug absorption step. For both compounds, the AUC0-infinity values of the two treatments were similar with only a slightly higher AUC for the suppositories, which was not found to be significantly different under the employed conditions (p > 0.05). Referring to the pharmacokinetic parameters Cmax and tmax typical differences between oral and rectal formulations were observed. For the suppositories, diclofenac and codeine average peak plasma concentrations were only half as high as for the tablets, whereas the respective tmax values were doubled. The results obtained show a similar extent of diclofenac and codeine bioavailability for both administration routes, but the rate of drug input was lower for the suppositories. The total mean input time (MITtot) was found to be significantly longer for the suppositories. This seems to be caused by a slow release from the dosage form or dissolution of the drugs, which is confirmed by a longer MITtot compared to the MRTsys in most of the volunteers.

Administration, Oral↗
PubMed1996

The renin-angiotensin-aldosterone system: focus on its distinct role in arterial hypertension and its various inhibitors as a therapeutic strategy to effectively lower blood pressure.

Chronically elevated blood pressure results from pathological alterations in control systems. Current approaches to elucidate the underlying etiology strongly emphasize the (patho)physiological significance of the Renin-Angiotensin-Aldosterone System (RAAS) which interestingly interacts with the sympathetic, the cholinergic and purinergic systems. While the angiotensin-II-receptor subtype 1 (AT1), which mediates the blood-pressure-related effects of angiotensin II (All), has so far been extensively investigated, the physiological relevance of the other angiotensin-II-receptor subtypes-in particular of the AT2-receptor subtype-is about to be evolved by analysis of the various signal transduction mechanisms and by evaluation of transgenic animals, e.g. the knock-out mice, following disruption of the single A-II-receptor subtypes. Based on the clinical success of ACE inhibitors, the blockade of the Renin-Angiotensin-Aldosterone System in many different ways has been recognized as a successful strategy to effectively lower blood pressure.

Angiotensin Receptor Antagonists↗
PubMed1995

The (S)-(+)-enantiomer of dimethindene: a novel M2-selective muscarinic receptor antagonist.

The present study was designed to determine to determine the in vitro affinity profile of (R)-(-)-dimethindene and (S)-(+)-dimethindene at muscarinic receptor subtypes using both functional and binding assays. In addition, the racemate was investigated in functional studies. The functional muscarinic receptors studied were putative M1 receptors in rabbit vas deferens and rat duodenum, M2 receptors in guinea-pig left atria and rabbit vas deferens, as well as M3 receptors in guinea-pig ileum and trachea. Furthermore, the histamine H1 antagonism by (R)-(-)- and (S)-(+)-dimethindene has been examined in guinea-pig ileum. Muscarinic binding selectivity was assessed in homogenates from human neuroblastoma NB-OF 1 cells (M1), rat heart (M2), pancreas (3) and striatum (M4). The results demonstrate that (S)-(+)-dimethindene is a potent M2-selective muscarinic receptor antagonist (pA2 = 7.86/7.74; pKi = 7.78) with lower affinities for the muscarinic M1 (pA2 = 6.83/6.36; pKi = 7.08), the M3 (pA2 = 6.92/6.96; pKi = 6.70) and the M4 receptors (pKi = 7.00), respectively. The (S)-(+)-enantiomer was more potent (up to 41-fold) than the (R)-(-)-enantiomer in all muscarinic assays. In contrast, the stereoselectivity was inverse at histamine H1 receptors, the (R)-(-)-enantiomer being the eutomer (pA2 = 9.42; pA2/(S)-isomer = 7.48). In conclusion, (S)-(+)-dimethindene is a useful tool to investigate muscarinic receptor heterogeneity. In addition, this lipophilic compound might become the starting point for the development of M2-selective muscarinic receptor antagonists useful as diagnostic tools for quantifying muscarinic M2 receptors in the central nervous system with positron emission tomography imaging, and to test the hypothesis that muscarinic M2 receptor antagonists show beneficial effects in the treatment of cognitive disorders.

Animals↗
PubMed1995

A new rapid and sensitive high-performance liquid chromatographic assay for diclofenac in human plasma.

A new rapid and sensitive reversed-phase HPLC method for the routine analysis of diclofenac in human plasma is described. The method shows high selectivity, sensitivity, and reproducibility employing 4'-methoxydiclofenac as internal standard (IS) with UV-detection at 282 nm. The correlation of peak area ratios (diclofenac/IS) versus diclofenac plasma concentrations are linear between 5.0-2000 ng/ml with a detection limit of 3 ng/ml. Intra- and interday precision studies yielded coefficients of variation < 6.2% for all concentrations (range 20.0-1600 ng/ml). The method was applied for the assay of diclofenac in plasma of healthy volunteers after p.o. and rectal dosage of 50 mg diclofenac sodium and was found to be highly suitable for routine analyses.

Chromatography, High Pressure Liquid↗
PubMed1995

Regioisomeric 5(3)-aminomethyl-3(5)-phenylisoxazoles: synthesis, spectroscopic discrimination, and muscarinic activity.

The regioselective synthesis of isomeric 5(3)-aminomethyl-3(5)-phenyl isoxazoles using different methods is described. Spectroscopic data, especially mass spectrometric fragmentation, were used to identify and characterize the regioisomers. The muscarinic activity of these isoxazoles was assayed on isolated guinea-pig ileum and atria as well as on isolated rabbit vas deferens.

Animals↗
PubMed1995

Sympathetic re-innervation after heart transplantation: dual-isotope neurotransmitter scintigraphy, norepinephrine content and histological examination.

Cardiac transplantation entails surgical disruption of the sympathetic nerve fibres from their somata, resulting in sympathetic denervation. In order to investigate the occurrence of sympathetic re-innervation, neurotransmitter scintigraphy using the norepinephrine analogue iodine-123 metaiodobenzylguanidine (MIBG) was performed in 15 patients 2-69 months after transplantation. In addition, norepinephrine content and immunohistochemical reactions of antibodies to Schwann cell-associated S100 protein, to neuron-specific enolase (NSE) and to norepinephrine were examined in 34 endomyocardial biopsies of 29 patients 1-88 months after transplantation. Anterobasal 123I-MIBG uptake indicating partial sympathetic re-innervation could be shown in 40% of the scintigraphically investigated patients 37-69 months after transplantation. In immunohistochemical studies 83% of the patients investigated 1-72 months after transplantation showed nerve fibres in their biopsies but not positive reaction to norepinephrine. Significant norepinephrine content indicating re-innervation could not be detected in any biopsy. It was concluded that in spite of the lack of norepinephrine content there seemed to be immunohistological and scintigraphic evidence of sympathetic re-innervation. An explanation for this contradictory finding may be the reduced or missing norepinephrine storage ability compared to the restored uptake ability of regenerated sympathetic nerve fibres.

3-Iodobenzylguanidine↗
PubMed1995

Chronic treatment with the uncompetitive NMDA receptor antagonist memantine influences the polyamine and glycine binding sites of the NMDA receptor complex in aged rats.

Receptor binding studies on rat cortical membranes were used to characterize the NMDA receptor in aged rats (22 months) treated for 20 months with a memantine containing diet delivering 30 mg/kg/day in comparison to aged and young/adult rats treated with control-diet. Spatial memory impairing effects of (+)-MK-801 (0.16 mg/kg) in the radial maze was not altered within the course of memantine-treatment (up to 16 months). However, chronic memantine-treatment significantly increased the number of [3H]MK-801 binding sites and the affinity of [3H]glycine. A non-significant trend to such changes was also seen in aged-control rats. Glycine-dependent [3H]MK-801 binding (functional binding under non-equilibrium conditions at a fixed L-glutamate concentration) revealed that a decreased ability of glycine to stimulate channel opening in aged rats was partially attenuated by the long-term memantine treatment. Furthermore, an increased ability of spermidine to enhance [3H]MK-801 binding in aged-control rats was even more pronounced in the aged memantine-treated group. Together these findings may indicate that changes in functional receptor-channel properties during the process of aging occur prior to a detectable loss of binding sites and that memantine enhances an endogenous compensatory mechanism triggered by glutamatergic hypofunction which is suggested to take place in aging.

Aging↗
PubMed1995

Celiprolol double-peak occurrence and gastric motility: nonlinear mixed effects modeling of bioavailability data obtained in dogs.

Investigation of the underlying mechanism leading to inter- and intrasubject variations in the plasma concentration-time profiles of drugs (1) can considerably benefit rational drug therapy. The significant effect of gastric emptying on the rate and extent of celiprolol absorption and its role with respect to double-peak formation was demonstrated in the present study. In four dogs racemic celiprolol was dosed perorally in a crossover design during four different phases of the fasted-state gastric cycle and gastric motility was recorded simultaneously using a manometric measurement system. Intravenous doses were also given to obtain disposition and bioavailability parameters. The blood samples were assayed by a stereoselective HPLC method (2). The time to onset of the active phase of the gastric cycle showed an excellent correlation with the time to celiprolol peak concentration. Furthermore, bioavailability was increased when celiprolol was administered during the active phase. Double peaks were observed when the first active phase was relatively short, suggesting that a portion of the drug remained in the stomach until the next active phase. Population pharmacokinetic modeling of the data with a two-compartment open model with two lag times incorporating the motility data confirmed the effect of time to gastric emptying on the variability of the oral pharmacokinetics of celiprolol. The fasted-state motility phases determine the rate and extent of celiprolol absorption and influence the occurrence of double peaks. Peak plasma levels of celiprolol exhibit less variability if lag times, and therefore gastric emptying times, are taken into consideration.

Adrenergic beta-Antagonists↗
PubMed1995

Muscarinic acetylcholine receptors: structural basis of ligand binding and G protein coupling.

Muscarinic acetylcholine receptors (m1-m5) were studied by a combined molecular genetic/pharmacologic approach to elucidate the molecular characteristics of the ligand binding site and of the receptor domains involved in G protein coupling. Site-directed mutagenesis studies of the rat m3 muscarinic receptor suggest that the acetylcholine binding domain is formed by a series of hydrophilic amino acids located in the "upper" half of transmembrane domains (TM) III, V, VI, and VII. Moreover, we showed that mutational modification of a TM VI Asn residue (Asn507 in the rat m3 receptor sequence) which is characteristic for the muscarinic receptor family has little effect on high-affinity acetylcholine binding and receptor activation, but results in dramatic reductions in binding affinities for certain subclasses of muscarinic antagonists. The N-terminal portion of the third intracellular loop (i3) of muscarinic and other G protein-coupled receptors has been shown to play a central role in determining the G protein coupling profile of a given receptor subtype. Insertion mutagenesis studies with the rat m3 muscarinic receptor suggest that this region forms an amphiphilic alpha-helix and that the hydrophobic side of this helix represents an important G protein recognition surface. Further mutational analysis of this receptor segment showed that Tyr254 located at the N-terminus of the i3 loop of the m3 muscarinic receptor plays a key role in muscarinic receptor-induced Gq activation. The studies described here, complemented by biochemical and biophysical approaches, should eventually lead to a detailed structural model of the ligand-receptor-G protein complex.

Amino Acid Sequence↗
PubMed1995

Different binding affinities of NMDA receptor channel blockers in various brain regions--indication of NMDA receptor heterogeneity.

The N-methyl-D-aspartate (NMDA) receptor-channel complex exists in multiple forms which probably have different physiological and pharmacological properties. To further evaluate this concept of different NMDA receptor subtypes, receptor binding and autoradiographic techniques were used to study the phencyclidine (PCP) binding site of the NMDA receptor ion-channel complex. [3H]MK-801 was employed to characterize binding properties of (+)-MK-801, (-)-MK-801, phencyclidine (PCP), (+/-)-ketamine, amantadine (1-amino-adamantane) and memantine (3,5-dimethyl-1-amino-adamantane) in different brain regions. Saturation experiments on homogenized membranes revealed the existence of single classes of binding sites in cortex and cerebellum but with significant different affinities between these regions (KD/Cortex = 4.59 nM, Bmax/Cortex = 0.836 pmol/mg protein; KD/Cereb. = 25.99 nM, Bmax/Cereb. = 0.573 pmol/mg protein) suggesting that the lower affinity in cerebellum indicates another population of NMDA receptor channels. In contrast, in striatum there was clear evidence for two binding sites (KD/high = 1.43 nM, Bmax/high = 0.272 pmol/mg protein; KD/low = 12.15 nM, Bmax/low = 1.76 pmol/mg protein). Displacement studies (autoradiography and binding) revealed a lower affinity for unlabeled (+)-MK-801 in striatum which was clearly not the case for memantine. In cerebellar membranes there was a significant decrease in the affinity for both MK-801 enantiomers and PCP but not for the 1-amino-adamantanes. In contrast, all compounds showed lowered affinity in the dentate gyrus. These findings support NMDA receptor heterogeneity which may be of particular relevance for the development of subtype-selective drugs.

Animals↗
PubMed1995

New specific and sensitive HPLC-assays for ethacrynic acid and its main metabolite--the cysteine conjugate--in biological material.

A reversed-phase high-performance liquid chromatography (HPLC) method was developed and validated for the determination of the loop diuretic ethacrynic acid and its potentially active main metabolite, the ethacrynic acid-cysteine conjugate, in biological material. Simple and rapid sample preparation procedures were established using solid-phase extraction for the parent drug and direct injection after one washing step for the metabolite. HPLC separation was performed on a Spherisorb ODS II (3 microns) analytical column using isocratic elution with different mixtures of mobile phases (phosphoric acid-methanol-acetonitrile-tetrahydrofuran or triethylamine buffer-methanol, respectively). The analytes were detected by measuring the UV absorption of the eluate at 275 nm. Stability studies revealed that considerable amounts of ethacrynic acid may be released from the cysteine conjugate unless the urine samples are pH stabilized (pH 3-4). The assay provided high sensitivity with limits of quantification of 20 ng ml-1 for ethacrynic acid in plasma and urine, and 240 ng ml-1 for the cysteine conjugate in urine. All validation parameters were within the required limits. For the presented assays, the applicability to pharmacokinetic studies and routine analyses was proved.

Chromatography, High Pressure Liquid↗
PubMed1995

Noncompetitive NMDA receptor antagonists with fast open-channel blocking kinetics and strong voltage-dependency as potential therapeutic agents for Alzheimer's dementia.

There is a growing body of evidence that disturbances of glutamatergic neurotransmission may underlie the pathomechanism and cognitive deficits of Alzheimer's disease. This review describes the potential use of low affinity, noncompetitive NMDA receptor antagonists in the treatment of this disease using memantine as an example. Evidence is presented indicating that this class of compound is neuroprotective in preclinical models of subchronic glutamate toxicity without producing side effects characteristic for other classes of NMDA receptor antagonist. This is attributed to their fast blocking kinetics and strong voltage dependency. Memantine also produces symptomatological improvement of cognition in animal models. The mechanism of action of this effect is still unclear but might be related to an enhancement of AMPA receptor mediated neurotransmission. In patients with dementia syndrome of various aetiologies, memantine produces a rapid onset, clinical improvement in various symptomatological deficits.

Alzheimer Disease↗
PubMed1995

Diuretic effectiveness of hydrochlorothiazide and furosemide alone and in combination in chronic renal failure.

In the absence of formal clinical trials, the efficacy of thiazide diuretics in patients with renal impairment remains in doubt. Our study was therefore designed to evaluate the separate and combined effects of single and multiple doses of hydrochlorothiazide (HCTZ) and furosemide (FU) on the glomerular filtration rate (GFR) and electrolyte excretion in 19 patients with chronic renal insufficiency and in six normal control subjects by a randomized single-blind protocol. After establishment of a steady state of urinary electrolyte excretion, a single oral dose of HCTZ (25 mg) induced increases in the urinary excretion of Na+, K+, Cl-, Ca2+, and Mg2+ over the subsequent 12 h, which was significantly inversely related to the GFR for each electrolyte. The ratios of HCTZ-induced excretion of the different electrolytes were constant and independent of the GFR. After HCTZ, there was a double peak of Na+ excretion related to the abrupt reduction in GFR and Na+ excretion when the latter exceeded 40 mmol/h in normal subjects and 15 mmol/h in patients with advanced renal failure. The dose-response curves for HCTZ and FU were both relatively flat: doubling the dose of each produced statistically insignificant increases in sodium excretion. In contrast, when the lower doses of each were coadministered, there was a substantial and statistically significant increase in Na+ excretion. The clinical implication of these findings is that a combination of low doses of diuretics acting at different functional sites of electrolyte reabsorption in the nephron is superior in saluretic potency to increasing the dose of either diuretic alone.

Adult↗
PubMed1995

Dose-effect and kinetic-dynamic relationships of the beta-adrenoceptor blocking properties of various doses of talinolol in healthy humans.

Twelve healthy subjects were investigated on six separate occasions at least 1 week apart when they either received a single oral dose of 80 mg propranolol; 25, 50, 100, or 400 mg talinolol; or placebo (double-blinded, period-balanced six-way cross-over design). The subjects were investigated during supine rest and performed supine bicycle ergometry 0200, 0500, 0730, 1000, and 2400 h after dosing. Isoprenaline (ISO) and epinephrine (EPI) were infused intravenously (i.v.) at a constant infusion rate of 1 microgram/min for 10 min, at 0315 and 0400 h after dosing, respectively. At various timepoints, blood was drawn for the high-performance liquid chromatography (HPLC) determination of the plasma concentrations of talinolol's enantiomers and for the ex vivo in vitro determination of beta 1- and beta 2-adrenoceptor binding and related concentrations by radioreceptor assay (RRA). Talinolol was confirmed to bind to beta-adrenoceptors with moderate affinity but to act as a highly selective and efficient beta 1-adrenoceptor antagonist in terms of the relative degree and duration of its ergometric effects. At doses < or = 100 mg talinolol hardly altered the reduction of estimated vascular total peripheral resistance (TPR) in response to the intravenous infusion of ISO and EPI. Only at doses of 400 mg did talinolol more closely approximate the effects of propranolol, which lead to a loss of the vasodilatory actions of EPI ("EPI reversal"). On the average, there was a smoothly linear relationship between the ergometric treatment effects and log-transformed dose, the logtransformed concentrations of the S(-)-enantiomer measured by HPLC, and the RRA-derived estimated occupancies beta 1-adrenoceptors.

Adrenergic beta-Antagonists↗
PubMed1995

Inhibitory action of PPADS on relaxant responses to adenine nucleotides or electrical field stimulation in guinea-pig taenia coli and rat duodenum.

1. The effect of pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) on the relaxant response to adenine nucleotides was examined in the carbachol-contracted guinea-pig taenia coli and rat duodenum, two tissues possessing P2y-purinoceptors. In addition, in the taenia coli PPADS was investigated for its effect on relaxations evoked by adenosine, noradrenaline and electrical field stimulation. In order to assess the selectivity of PPADS between P2-purinoceptor blockade and ectonucleotidase activity, its influence on ATP degradation was studied in guinea-pig taenia coli. 2. The resulting rank order of potency for the adenine nucleotides in guinea-pig taenia coli was: 2-methylthio ATP >> ATP > alpha,beta-methylene ATP with the respective pD2-values 7.96 +/- 0.08 (n = 23), 6.27 +/- 0.12 (n = 21) and 5.88 +/- 0.04 (n = 24). 3. In guinea-pig taenia coli, PPADS (10-100 microM) caused a consistent dextral shift of the concentration-response curve (CRC) of 2-methylthio ATP and ATP resulting in a biphasic Schild plot. A substantial shift was only observed at 100 microM PPADS, the respective pA2-values at this particular concentration were 5.26 +/- 0.16 (n = 5) and 5.15 +/- 0.13 (n = 6). Lower concentrations of PPADS (3-30 microM) antagonized the relaxant effects to alpha,beta-methylene ATP in a surmountable manner. An extensive shift of the CRC was produced only by 30 microM PPADS (pA2 = 5.97 +/- 0.08, n = 6), and the Schild plot was again biphasic. 4. The relaxant responses to electrical field stimulation (80 V, 0.3 ms, 5 s, 0.5-16 Hz) in guinea-pigtaenia coli were concentration-dependently inhibited by PPADS (10-100 microM).5. In guinea-pig taenia coli, the potency of ATP in inducing relaxation appeared to be independent of its rate of degradation by ecto-nucleotidases, since the Km-value (366 microM) obtained in the enzyme assay was much higher than the functional EC50-value (0.45 microM) of ATP. PPADS (3-100 microM) was only weakly active in inhibiting ecto-nucleotidase activity leaving a residual activity of 81.8 +/- 5.1% at 100 microM.Enzyme inhibition by PPADS was concentration-independent and non-competitive.6. In rat duodenum, the rank order of potency was: 2-methylthio ATP >ATP> >alpha,beta-methylene ATP,the respective pD2-values being 6.98 +/- 0.04 (n = 76), 6.26 +/- 0.02 (n = 6) and 4.83 +/- 0.02 (n = 6). Among these agonists, 2-methylthio ATP displayed the lowest apparent efficacy.7. The CRC of 2-methylthio ATP in rat duodenum was shifted to the right by PPADS (10-100 microM) ina concentration-dependent manner, and Schild analysis gave a pA2-value of 5.09 +/- 0.06 (slope = 1.02,n=14).8 PPADS was without any effect on the carbachol-induced contraction in guinea-pig taenia coli or rat duodenum and on the relaxation to noradrenaline or adenosine in guinea-pig taenia coli.9 In conclusion, the antagonistic properties of PPADS at the taenia coli and rat duodenum P2y-purinoceptors were different from those recently described at the P2x-subtype: inhibition of P2y-purinoceptor-mediated responses was observed at higher concentrations (3-100 microM vs. 1-10 (30) microM).Furthermore, we conclude that in addition to the classical P2y-subtype, which is largely PPADS-resistant,the guinea-pig taenia coli may be endowed with a distinct relaxation-mediating P2-purinoceptor subtype which is sensitive to PPADS.

Adenosine↗
PubMed1995

Two different inhibitory effects of pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid on adenosine diphosphate-induced human platelet aggregation.

In the present study, the novel compound pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), which has been shown to inhibit P2x-purinoceptor-mediated contractions in smooth muscle, was investigated for its antagonistic effects on adenosine diphosphate (ADP)-induced human platelet aggregation in platelet-rich plasma (PRP) and in washed platelets, respectively. Suramin served as reference compound. In PRP, suramin (1 mmol/l) was inactive whereas PPADS (1 mmol/l) considerably reduced the extent of aggregation. In contrast, both suramin (1 mmol/l) and PPADS (500 mumol/l) markedly depressed the aggregation of washed platelets. In addition, there was a peculiarity in washed platelets: a delay of onset of platelet aggregation up to 15 min in the presence of PPADS (10-500 mumol/l) and suramin (0.1-1 mmol/l). Thus, in the present study washed platelets were more suited to detect an influence of PPADS and suramin as inhibitors of ADP-induced aggregation, and a delay of onset of aggregation was the most sensitive parameter in this regard. Comparing the effective threshold concentration of PPADS at P2x (1 mumol/l)- and the platelet P2t-purinoceptor, PPADS proves to be P2x-selective.

Adenosine Diphosphate↗