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Biomedical subjects

U Moser

Publications and source records attributed to U Moser.

At least 73 records · Page 4Linked to original sources
PubMed1989

A double-blind randomised multicentre study with tenoxicam, piroxicam and diclofenac sodium retard in the treatment of ambulant patients with osteoarthritis and extra-articular rheumatism.

In a randomised, double-blind comparative study involving a total of 1,630 out-patients, tenoxicam (a new non-steroidal anti-inflammatory drug belonging to the oxicam group), piroxicam and diclofenac retard were tested for their efficacy and tolerability in the treatment of osteoarthritis (OA) and extra-articular rheumatism (EAR). Single doses of 20 mg tenoxicam, 20 mg piroxicam or 100 mg diclofenac sodium retard were administered daily. Tenoxicam was found to be as effective as piroxicam and diclofenac sodium retard in the treatment of degenerative and extra-articular rheumatic disorders of the musculo-skeletal system. When baseline values were compared with values obtained at all subsequent examinations, all evaluation parameters for all three substances showed improvement. In analyses of the frequency, degree of severity and type of undesired effects, tenoxicam proved to be superior to the reference drugs. This was particularly evident from an improved gastrointestinal and central nervous system (CNS) tolerance and a lower rate of withdrawal from treatment. Tenoxicam has a favourable risk/benefit ratio and can be recommended for the treatment of chronic pain due to inflammation resulting from degenerative and extra-articular rheumatic disorders of the musculoskeletal system.

Aged↗
PubMed1989

Pharmacology of hexahydro-difenidol, hexahydro-sila-difenidol and related selective muscarinic antagonists.

A series of hexahydro-difenidol (HHD) and hexahydro-sila-difenidol (HHSiD) analogues modified in the amino group, the phenyl ring and in the alkylene chain were investigated for their binding and functional properties at muscarinic M1, M2 and M3 receptors. Novel muscarinic receptor antagonists were obtained which exhibited different receptor selectivity profiles from the parent compounds HHD and HHSiD (M1 congruent to M3 greater than M2), e.g. HHD and HHSiD methiodides, M1 greater than M2 congruent to M3; p-fluoro-HHSiD, M3 greater than M1 greater than M2; trans-hexbutenol, M1 greater than M3 greater than M2; and (s)-p-fluoro-hexbutinol, M3 greater than M2 congruent to M1. Stereoselectivity ratios [(R)/(S)] for the enantiomers of HHD, hexbutinol and p-fluoro-hexbutinol were highest at M1, intermediate at M3 and lowest at M2 receptors.

Animals↗
PubMed1988

Stereoselectivity of the enantiomers of trihexyphenidyl and its methiodide at muscarinic receptor subtypes.

High stereoselectivity was observed for the enantiomers of trihexyphenidyl and trihexyphenidyl methiodide at muscarinic M1-receptors in field-stimulated rabbit vas deferens and at M2 alpha- and M2 beta-receptors in guinea-pig atrium and ileum, respectively. Considerably higher affinities (up to 1700-fold) were found for the (R)-(-)-enantiomers. The stereochemical demands made by the muscarinic receptor subtypes were most stringent at the M1-receptors. The (R)-(-)-enantiomers were found to be potent M1-selective antagonists (pA2 = 10.1/10.6). They showed a 91- and 45-fold selectivity for M1- over M2 alpha-receptors, respectively.

Animals↗
PubMed1988

[Characteristics of hereditary colorectal carcinoma without pre-existing polyposis].

The report presents two families with inherited predisposition to colorectal carcinoma without preexisting polyposis coli. In these families the disease is characterized by early onset and tumor localization in the right side colon. Screening colonoscopy should be started early. Families of this kind are of greatest value for genetic marker studies.

Adenocarcinoma↗
PubMed1988

Effects of alpha-tocopherol, its carboxylic acid chromane compound and two novel antioxidant isoflavanones on prostaglandin H synthase activity and autodeactivation.

The natural antioxidant alpha-tocopherol has repeatedly been described to inhibit platelet aggregation and thromboxane formation, whereas its influence on prostaglandin H synthase in vivo and in vitro is a matter of controversy. In the present study the effects of different antioxidative compounds on ram vesicular gland microsomal prostaglandin H synthase activity were investigated in vitro: d,l-alpha-tocopherol, its carboxylic acid chromane compound (Trolox), phytol, alpha-tocopherol-acetate and two novel antioxidative isoflavanones, obtained by methylation and/or hydrogenation of naturally occurring isoflavones from fermented soybeans (6,7-dihydroxy-4'-methoxyisoflavanone and 6,7,4'-trihydroxyisoflavanone). Alpha-tocopherol, -acetate and phytol revealed no significant influence on the enzyme activity when applied in concentrations up to 1 mM. Trolox (100-1000 mu mumol/l) and the two isoflavanones (5-50 and 10-100 mumol/l) dose-dependently augmented the initial rate of oxygen consumption and the total oxygen uptake during prostaglandin H synthase incubation with arachidonic acid (AA). In parallel, these compounds increased the formation of prostaglandin E2 and F2 alpha from 14C-labelled AA, and they markedly protected the prostaglandin H synthase from rapid autodeactivation as revealed by repetitive application of AA in small doses. We suggest that these compounds serve as cosubstrates to which the oxidizing equivalents are transferred which arise during the hydroperoxidase reaction of the enzyme.

Animals↗
PubMed1988

Methoctramine selectively blocks cardiac muscarinic M2 receptors in vivo.

The antimuscarinic effects of methoctramine (N, N'-bis[6-[(2-methoxybenzyl)amino]hexyl]-1, 8-octanediamine tetrahydrochloride), a polymethylene tetraamine endowed with high cardioselectivity in vitro, were assessed in two in vivo preparations. Methoctramine (300 micrograms/kg i.v.) strongly inhibited the methacholine- and muscarine-induced bradycardia in the anaesthetized an pithed rat, respectively. The same dose of methoctramine did not significantly affect the depressor action of methacholine in the anaesthetized rat mediated by vascular M2 receptors. Furthermore, even high doses of methoctramine (up to 1 mg/kg i.v.) did not reduce the ganglionic M1 receptor-mediated tachycardia and pressor response to muscarine or McN-A-343 in the pithed rat. These data suggest that methoctramine while showing high affinity for cardiac M2 alpha receptors has rather low affinity for ganglionic M1 and vascular M2 receptors. This in vivo study thus provides further evidence to support the view that methoctramine is a potent and highly selective antagonist of cardiac M2 alpha receptors.

Animals↗
PubMed1988

Different binding properties of muscarinic M2-receptor subtypes for agonists and antagonists in porcine gastric smooth muscle and mucosa.

The hypothesis that muscarinic receptors on smooth muscle differ from those in epithelial glands was tested by comparing the properties of muscarinic binding sites in porcine fundic smooth muscle with those in mucosal membranes. The binding of agonists and of antagonists was assessed by displacement of [3H]N-methylscopolamine. Pirenzepine (M1-antagonist) labeled low-affinity binding sites in smooth muscle (KD = 229 nM) and in mucosa (KD = 124 nM) consistent with the presence of M2 sites. Carbachol interacted with a high-affinity (KD = 164 nM) and a low-affinity (KD = 18.2 microM) state of binding sites in smooth muscle. Guanyl 5'-yl-imidodiphosphate converted all sites to the low-affinity state. N-ethylmaleimide pretreatment increased the affinity of carbachol and the proportion of high-affinity sites. In clear contrast, only low-affinity sites of carbachol were detectable in mucosa (KD = 17 microM) that were not modulated by N-ethylmaleimide or guanyl 5'-yl-imidodiphosphate. The cardioselective antagonist AF-DX 116 displayed low affinity to mucosal binding sites (KD = 3.4 microM), whereas its affinity to smooth muscle was 503 nM. The antagonist hexahydro-sila-difenidol had a very high affinity (KD = 2.9 nM) to mucosal receptors, whereas its affinity to smooth muscle sites was 88 nM. These data show that muscarinic M2 binding sites in mucosa and smooth muscle can be distinguished by both agonist and antagonist binding experiments, and suggest the existence of different subtypes of M2-binding sites in these tissues.

Animals↗
PubMed1988

Integrated plasma and synovial fluid pharmacokinetics of tenoxicam in patients with rheumatoid arthritis and osteoarthritis: factors determining the synovial fluid/plasma distribution ratio.

Single oral doses of 40 mg of the nonsteroidal antiinflammatory drug, tenoxicam, were given to four patients (three with rheumatoid arthritis, one with osteoarthritis). The concentrations of the drug in synovial fluid and plasma were measured by a specific high-performance liquid chromatography method. The unbound fractions of the drug in both fluids were determined at pH 7.4 and 37 degrees C by equilibrium dialysis. The possible influence of the pH on the protein binding was also assessed. The total concentration time curves in plasma and synovial fluid were fitted to linear oral 1 and 2 compartment body models with an additional synovial fluid compartment connected to the central compartment. The unbound fractions of drug in synovial fluid and plasma were on average 0.015 and 0.011, respectively: not significantly different from each other. The protein binding of tenoxicam was pH dependent with increased free fractions at pH values less than 7.4. The average peak concentrations of tenoxicam in plasma and synovial fluid were 4.3 and 1.4 micrograms/ml, respectively. The mean ratio of the areas under the total concentration time curves in synovial fluid and plasma was 0.42, which corresponded to the steady state of equilibrium ratio of the total drug concentrations in the two body fluids. Two hypotheses were tested: hypothesis I assuming that equilibration across the synovial tissue takes place between the unbound, unionized tenoxicam molecules; hypothesis II assuming that equilibration across the synovial tissue is established between the unbound (unionized + ionized) tenoxicam molecules. Based on the available evidence hypothesis II was rejected.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1988

L-ascorbic acid modulates 5-lipoxygenase activity in human polymorphonuclear leukocytes.

Leukotriene B4 (LTB4), a metabolite of the arachidonic acid pathway mediated by 5-lipoxygenase, is released by stimulated polymorphonuclear neutrophils (PMNL) and has been postulated to be an important mediator of the inflammatory response. Extracellular L-ascorbate at concentrations in the range of 0.5-5.0 mM effectively inhibits the biosynthesis of LTB4 and 5-hydroxyeicosatetraenoic acid (5-HETE) stimulated by the calcium ionophore A 23187. The ionophore-activated LTB4 production is reduced after incubation of PMNL with opsonized zymosan as a phagocytic stimulus. Extracellular L-ascorbate at concentrations above 0.1 mM reverses the zymosan-induced deactivation of 5-lipoxygenase, resulting in significantly higher LTB4 and 5-HETE yields. The inhibitory effect of zymosan preincubation on LTB4 production is independent of calcium or free arachidonic acid in the incubation medium. Interaction of L-ascorbate with the catabolism of LTB4 was excluded by measuring the trihydroxy metabolites which were unchanged. Furthermore, the formation of glutathione derivatives of leukotriene A4 can be excluded due to the lack of glutathione transferase activity in PMNL. In order to link the intracellular function of L-ascorbate with the serum level, the ascorbate uptake has been studied in more detail. The L-ascorbate transport into PMNL is stereospecific and can best be described by kinetics consisting of a saturation part, Km and Vmax being 39 microM and 0.28 nmol/10(8) cells.min, respectively, plus passive diffusion, the diffusion coefficient P being 1.75 microliter/10(8) cells.min. Furthermore, the uptake is inhibited by the isomers D-ascorbic acid and D-erythorbic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

Arachidonate 5-Lipoxygenase↗
PubMed1987

Stimulation of ganglionic muscarinic M1 receptors by a series of tertiary arecaidine and isoarecaidine esters in the pithed rat.

The cardiovascular effects of a series of tertiary esters of arecaidine (1-methyl-1,2,5,6-tetrahydro-3-carboxy-pyridine) and isoarecaidine (1-methyl-1,2,5,6-tetrahydro-4-carboxy-pyridine) were investigated in the pithed rat. For some esters (e.g. arecoline, arecaidine propargyl ester, isoarecoline) a prominent elevation in mean arterial pressure and heart rate was observed following an initial short-lasting and atropine-sensitive depressor response and bradycardia (dose range: 0.1-10 mumol/kg i.v.). The increase in blood pressure and heart rate was not affected by pretreatment with mecamylamine (0.5 and 5 mg/kg i.v.), but could be totally blocked by N-methylatropine (500 micrograms/kg i.v.). Furthermore, the M1 receptor antagonist pirenzepine (300 micrograms/kg i.v.) selectively antagonized these stimulatory cardiovascular responses, indicating that these effects are due to an activation of muscarinic M1 receptors in sympathetic ganglia. As tertiary arecaidine and isoarecaidine esters easily penetrate the blood-brain barrier, they might also stimulate central M1 receptors and thus become lead compounds in the search for an effective drug treatment of Alzheimer's disease.

Animals↗
PubMed1987

[Doppler sonography assessment of blood flow velocity in the ascending aorta. Problems and possible solutions].

Irregularities of the transvascular distribution of blood flow within the human ascending aorta have been documented by means of 16 Doppler gates positioned along one scanline of a sector scanner. The velocity profiles recorded from ten healthy adults, ten patients suffering from hypertrophic obstructive cardiomyopathy, ten patients suffering from hypertrophic nonobstructive cardiomyopathy, and ten patients with severe aortic insufficiency exhibited nonuniformities which varied not only from individual to individual but also between the groups and depending on the phase of the cardiac cycle. These variations prevent any local measurement from being representative for the instantaneous mean velocity in all cases. A reliable mean should therefore be determined by simultaneously taking into account all velocities within the vascular cross-section. A computer simulation in order to indicate a potential solution to this problem demonstrates that an annular array transducer can be excited in such a manner that it produces a homogeneous ultrasound beam of a transverse area a hundred times larger than the one obtained in the conventional maximally focussed mode.

Aorta, Thoracic↗
PubMed1986

The role of ascorbic acid in carcinogenesis.

Vitamin C is an essential nutrient whose protective role in carcinogenesis has been discussed for more than 50 years. Epidemiologic studies suggest that the consumption of vitamin C-rich foods is associated with a lower risk of cancers of the esophagus and stomach. The observation that cancer patients have low leukocyte vitamin C levels led to therapeutic trials the results of which are controversial; the hypothesis that vitamin C acts like a drug must be questioned. On the other hand, ascorbic acid interacts with various tumor-inducing compounds, such as the precursors of N-nitroso compounds, to prevent the formation of tumors. Experiments with animals and cell cultures indicate that ascorbic acid can interfere with the metabolism of tumor promoters. It has also been postulated that ascorbic acid helps to prevent cancer by enhancing cellular immunity. In general, evidence suggests that vitamin C can inhibit the formation of some carcinogens.

Animals↗
PubMed1986

Muscarinic ganglionic stimulants: conformationally restrained analogues related to [4-[[N-(3-chlorophenyl)carbamoyl]oxy]-2-butynyl]trimethylammonium chloride.

The synthesis of a series of tertiary and quaternary cyclic analogues (isoarecolinol, dihydroisoarecolinol, arecolinol, and 3-pyrroline-3-carbinol derivatives) of [4-[[N-(3-chlorophenyl)carbamoyl]oxy]-2-butynyl]trimethylammonium chloride (McN-A-343) (1), a selective stimulant of muscarinic receptors in sympathetic ganglia (so-called M1 receptors), is reported. The compounds 3-10 were tested for muscarinic ganglion-stimulating activity by recording blood pressure responses in pithed rats. All tertiary compounds tested had no ganglion-stimulating activity. Among the series of quaternary derivatives, only the isoarecolinol analogues 4a and 4b showed considerable ganglion-stimulating effects, whereas the dihydroisoarecolinol (8), the arecolinol (6a, 6b), and the 3-pyrroline-3-carbinol derivatives (10) were much less potent. Our experiments therefore demonstrate that in this series a quaternary nitrogen atom, unsaturation at C2 of the ammonium side chain, and a certain spatial arrangement of the ammonium and the phenylcarbamate groups are essential for potent M1-receptor stimulating activity.

Animals↗
PubMed1986

Effect of functional stimulation on ascorbate content in phagocytes under physiological and pathological conditions.

Neutrophil polymorphonuclear leucocytes and macrophages contain 10-40 times increased intracellular ascorbate concentrations compared to plasma. A slight decrease of ascorbate content could be observed in total white blood cells and in monocytes upon stimulation with opsonized zymosan. These decreases were more pronounced in peritoneal and alveolar macrophages from rats. In patients with rheumatoid disease whose phagocytes are exposed to a constant challenge, significantly lowered intracellular ascorbate contents were found in neutrophils and mononuclear cells. Surgical and thermal trauma in rats depressed intracellular ascorbate levels in peritoneal macrophages. These results are indicative of an essential role ascorbic acid plays in phagocytic cells.

Animals↗
PubMed1984

A comparison of the antimuscarinic effects of pirenzepine and N-methylatropine on ganglionic and vascular muscarinic receptors in the rat.

The antimuscarinic properties of pirenzepine and N-methylatropine were evaluated in two intact preparations by measuring A) the inhibition of increase in mean arterial pressure evoked by McN-A-343 in pithed rats through activation of ganglionic muscarinic receptors and B) the inhibition of fall in arterial pressure evoked by methacholine in anaesthetized rats through activation of vascular muscarinic receptors. To characterize the antimuscarinic potencies of pirenzepine and N-methylatropine, for both antagonists doses were calculated that produce a 10-fold shift to the right of the dose-response curves for A) the pressor response to McN-A-343 (i.v. administration) in pithed rats (D10-p.r.) and B) for the depressor effect to methacholine (i.v. administration) in anaesthetized rats (D10-an.r.), respectively. Whereas N-methylatropine was virtually equieffective in blocking both muscarinic responses (D10-an.r./D10-p.r. approximately equal to 1), pirenzepine, however, was considerably more potent at ganglionic than at vascular muscarinic receptors (D10-an.r./D10-p.r. approximately equal to 16). These data confirm the existence of excitatory ganglionic muscarinic receptors with high affinity for pirenzepine (M1) and provide evidence for the presence of M2 receptors - receptors which show a low sensitivity to pirenzepine - on vascular smooth muscle cells. To further characterize the anticholinergic properties of pirenzepine, its effect on the pressor response to DMPP, a nicotinic ganglionic stimulant, was investigated in pithed rats. A high dose of pirenzepine (1.13 mumol/kg), given i.v., did not affect nicotinic ganglionic transmission.

Animals↗