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At least 1,441 records · Page 80Linked to original sources
PubMed2002

Actions of the new antimuscarinic compound Lu 25-109 on isolated human and pig detrusor.

The aim of this study was to evaluate the effects of a novel antimuscarinic agent, Lu 25-109, a partial M1 receptor agonist, and M2/M3 receptor antagonist in human and pig detrusor to establish its affinity for muscarinic receptors in human detrusor and parotid gland and to compare the results with those obtained with oxybutynin. Effects on the detrusor were determined as regards the ability to inhibit carbachol-induced contractions and contractions induced by electrical field stimulation (EFS). Radioligand binding studies were performed to assess the ability to displace quinuclidinyl benzilate (3H-QNB) from muscarinic receptors in the detrusor and parotid gland. Lu 25-109 produced a concentration-dependent rightward shift of the concentration-response curves for carbachol in both human and pig detrusor, the pK(b) values being 6.2+/-0.1 (n=6) and 5.8+/-0.3 (n=6). Corresponding values for oxybutynin were 7.9+/-0.1 (n=7) and 7.8+/-0.1 (n=6). Contractions induced by EFS in human detrusor were almost completely inhibited by 100 micromol/L Lu 25-109 (84+/-4%; n=4). In contrast, EFS-induced contractions in pig detrusor were less sensitive to Lu 25-109, resulting in a final inhibition of 32+/-6% (n=9) with the highest concentration used (100 micromol/L). This difference in effect between human and pig detrusor was not observed with oxybutynin. Radioligand binding experiments demonstrated a small difference in affinity for Lu 25-109 in the parotid gland compared with the bladder, the pKi values being 6.2+/-0.1 versus 6.5+/-0.1 (n=4). Corresponding values for oxybutynin were 8.5+/-0.1 versus 8.2+/-0.1 (n=4). The results show that Lu 25-109 competitively and effectively antagonizes carbachol-induced contractions and contractions induced by EFS in human detrusor muscle. Even if Lu 25-109 were less potent than oxybutynin, it has an effect profile that makes it of interest to test its ability to counteract bladder overactivity in humans.

Adult↗
PubMed1989

In vivo pharmacokinetics of aldose reductase inhibitors: 3-fluoro-3-deoxy-D-glucose NMR studies in rat brains.

Direct quantification of the inhibitory effects of orally administered drugs (sorbinil, cyclandelate and sulindac) on aldose reductase activities in rat brains was performed non-invasively using the 3-fluoro-3-deoxy-D-glucose (3-FDG) 19F NMR spectroscopic technique. Quantitative data obtained directly from the target organ (brain) allowed for unprecedentedly accurate analysis of drug effects in the brain in vivo. Sorbinil, a potent aldose reductase inhibitor, exhibited a classic monophasic organ response, whereas cyclandelate and sulindac showed biphasic suppression patterns. The latter indicate that there are metabolites of these drugs which possess aldose reductase inhibitory activities. The estimated potency of aldose reductase inhibition for each of the three drugs in this study was significantly discrepant from the in vitro studies indicating the complicated nature of the bioavailability of a pharmaceutical agent in vivo, especially where pharmacologically active metabolites of a given drug are involved. Our method allows for a direct quantitative assay and hence the most reliable technique for evaluating aldose reductase inhibitory activities in the target organ.

Aldehyde Reductase↗
PubMed2006

Synthesis and fungicidal activity of N-2-(3-methoxy-4-propargyloxy)phenethyl amides. Part II: anti-oomycetic mandelamides.

Novel types of anti-oomycetic compounds have been designed and prepared. The synthetic approach to these mandelamides is outlined. Biological data demonstrate their high efficacy against important plant diseases such as tomato and potato late blight (Phytophthora infestans De Bary) and grape downy mildew (Plasmopara viticola Berliner & de Toni). Structure-activity relationship studies are discussed. The new development product mandipropamid is presented.

Benzeneacetamides↗
PubMed2007

Synthesis and fungicidal activity of N-2-(3-methoxy-4-propargyloxy) phenethyl amides. Part 3: stretched and heterocyclic mandelamide oomyceticides.

Novel analogues of mandipropamid have been designed and prepared. The synthetic approach to these stretched and heterocyclic mandelamides is outlined. Biological data demonstrate their high efficacy against important plant diseases like tomato and potato late blight (Phytophthora infestans De Bary) and grape downy mildew (Plasmopara viticola Berliner & de Toni). Structure-activity relationship studies are discussed.

Amides↗
PubMed2004

Improved precision and accuracy for high-performance liquid chromatography/Fourier transform ion cyclotron resonance mass spectrometric exact mass measurement of small molecules from the simultaneous and controlled introduction of internal calibrants via a second electrospray nebuliser.

The use of a second electrospray nebuliser has proved to be highly successful for exact mass measurement during high-performance liquid chromatography/Fourier transform ion cyclotron resonance mass spectrometry (HPLC/FTICRMS). Much improved accuracy and precision of mass measurement were afforded by the introduction of the internal calibration solution, thus overcoming space charge issues due to the lack of control over relative ion abundances of the species eluting from the HPLC column. Further, issues of suppression of ionisation, observed when using a T-piece method, are addressed and this simple system has significant benefits over other more elaborate approaches providing data that compares very favourably with these other approaches. The technique is robust, flexible and transferable and can be used in conjunction with HPLC, infusion or flow injection analysis (FIA) to provide constant internal calibration signals to allow routine, accurate and precise mass measurements to be recorded.

Calibration↗
PubMed1990

Oxidative deamination of noradrenaline in human blood vessels.

Human vascular tissue (saphenous vein and uterine artery) was incubated with tritiated noradrenaline. In both vessels, oxidative deamination predominated over O-methylation. Deamination was due to the action of MAO type A and B, as well as of a semicarbazide-sensitive oxidase. Whereas DOPEG was a good index of intraneuronal deamination, NMN, DOMA and OMDA appeared to be entirely extraneuronal in origin. Extraneuronal deamination plays an important role in human vascular tissue and may contribute to the inactivation of circulating catecholamines.

Arteries↗
PubMed1991

Extraneuronal inactivation of noradrenaline in tissue culture.

Corticosterone-sensitive extraneuronal transport (uptake2) and metabolism of noradrenaline was investigated in the clonal human Caki-1 cell line. Caki-1 cells are the first experimental system for uptake2 which is based on a tissue culture technique. Previous experiments with Caki-1 cells opened the possibility of a close relationship between uptake2 and the renal transport system for organic cations (RTOC). The finding that steroids potently inhibit both uptake2 and RTOC further supports this hypothesis. Noradrenaline which has been taken up into Caki-1 cells by uptake2 is metabolized by the intracellular enzymes catechol-O-methyltransferase (COMT) and to a lesser extend by monoamineoxidase (MAO).

Adenocarcinoma↗
PubMed1987

Early intraneuronal mobilization and deamination of noradrenaline during global ischemia in the isolated perfused rat heart.

Isolated rat hearts were perfused according to the Langendorff technique and both extraneuronal uptake of noradrenaline and COMT were inhibited. The noradrenergic neurones were first prelabelled with 3H-(-)-noradrenaline (13 nmol/l). Thereafter the hearts were submitted to global ischemia (perfusion rate reduced from 5 up to 0.5 ml/min) for 60 min and subsequently reperfused for 5 min. The coronary effluent was continuously collected and analyzed for the appearance of 3H-noradrenaline and its metabolites. 1. Global ischemia was associated with an early release of 3H-noradrenaline. At reperfusion a brisk increase in the FRL of 3H-noradrenaline was observed which may indicate that, on severe restriction in coronary flow, perfusion of the tissue became heterogenous and thus partially masked the amount of 3H-noradrenaline released from the noradrenergic nerve terminals. Gradual reduction in coronary flow also progressively reduced (but did not abolish) the total formation of 3H-DOPEG. 2. The maximal efflux of 3H-noradrenaline was observed during the 1st min of reperfusion whereafter the efflux declined rapidly, indicating a wash-out of transmitter trapped in the extracellular space. The efflux of the lipophilic metabolite 3H-DOPEG, on the other hand, continuously increased during the reperfusion. This was due to both new formation and "wash-out" of 3H-DOPEG retained and/or distributed into the tissue during the period of restricted flow. 3. Neither a reduction of the extracellular calcium concentration (from 2.6 mmol/l to 0.1 mmol/l) nor the presence of the calcium entry blocker verapamil (250 nmol/l) reduced the efflux of 3H-noradrenaline seen during ischemia and reperfusion. 4. Desipramine (100 nmol/l) markedly reduced the ischemia-induced release of 3H-noradrenaline and simultaneously attenuated the formation of 3H-DOPEG. 5. A moderate reduction in the ischemia-induced mobilization of 3H-noradrenaline was seen in hearts perfused with 1 mumol/l reserpine, whereas the formation of 3H-DOPEG from such hearts was markedly higher than in corresponding controls. Only minor deviations from this pattern was observed when desipramine was present in addition to reserpine. It is concluded that a severe restriction in myocardial perfusion rate is associated with an enhanced net leakage of vesicular noradrenaline. This results in a rise of the free axoplasmic noradrenaline concentration which, in combination with an altered transmembrane sodium gradient, induces an increased local release of noradrenaline partly mediated by a calcium-independent, carrier-mediated outward transport.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

Influences of trospium chloride and oxybutynin on quantitative EEG in healthy volunteers.

Trospium chloride and oxybutynin are two antimuscarinergic agents used in the treatment of unstable bladder, urge incontinence, combined stress urge incontinence and detrusor hyperreflexia. The possibility that these two drugs produce changes in central nervous electrical activity was examined in an open, prospective, phase I study involving 12 volunteers. Quantitative evaluation of the multichannel electroencephalogram obtained from young healthy volunteers showed statistically significant decreases in alpha and beta 1 activity after oxybutynin, but not after intravenous or oral administration of trospium chloride. The biological activity of both drugs was ascertained by continuous simultaneous recording of the heart rate. A decrease in heart rate was detected after oral administration of oxybutynin, and an increase was seen after i.v. administration of trospium chloride. The results suggest that trospium chloride is less likely to produce central nervous adverse effects than to oxybutynin.

Adult↗
PubMed1994

Plasma levels of oxybutynine chloride in children.

Anticholinergic adverse-effects in children treated with conventional doses of oxybutynine led us to measure plasma oxybutynine levels in children. 18 children, aged 5 to 13 y, who required treatment with oxybutynine chloride for daytime incontinence were studied. Plasma concentrations were measured on the fifth day of a course of treatment in which the dose was adapted to the child's body weight; the dose was given twice daily at 12-hour intervals. In 10 children aged between 5 and 8 y, the mean dose was 0.1 mg.kg-1. In 8 children aged between 10 and 13 years, the mean dose was 0.15 mg.kg-1. The highest concentration was usually found between 1 and 2 h after administration. The subsequent fall in concentration was rapid and after 6 h oxybutynine was no longer measurable in 14 of the children. The concentrations found were not different from those seen in adults given equivalent doses. The results show that plasma concentrations in children were not very different from those observed in adults if the dose were adapted to the body weight of the children. No special differences in paediatric use were revealed that might explain the particular adverse-effects. The results of the study argue against the dosage regimen proposed before these adverse events were detected. They strongly favour a dose adapted to the body weight of the child, with a 12-hour interval between doses.

Adolescent↗
PubMed1987

Effect of cyclospasmol on early diabetic retinopathy.

A randomized, double-blind, placebo controlled study to investigate the long-term effect of Cyclospasmol (cyclandelate) on the abnormal permeability of the blood-retinal barrier was performed in 26 patients with insulin-dependent diabetes mellitus for at least 1 year and minimal retinopathy. Cyclospasmol 400 mg or placebo capsules were taken 4 times daily for 12 months by equal numbers in both groups. Each patient underwent a routine ophthalmoscopic examination, retinal fluorescein angiography and quantitative vitreous fluorophotometry to assess the permeability of the blood-retinal barrier just before the trial and following 6 and 12 months of therapy. Laboratory tests for determining blood and urine glucose levels and blood HbA1-levels were also carried out at these assessments. Statistically significant changes in diabetic control, in HbA1-levels or in the frequency of retinal microaneurysms could not be shown in either treatment group during the trial, nor were there any significant differences in these parameters between the two groups. Analysis of fluorophotometric data on fluorescein penetration into the left posterior vitreous demonstrated significant reductions in this parameter during the trial compared to the pretreatment level in Cyclospasmol treated diabetics. These changes in the pretreatment level after 6 and 12 months also differed significantly between the two groups. However, this statistically significant beneficial reduction in fluorescein penetration into the left posterior vitreous did not occur in the right eye in the Cyclospasmol group. In placebo treated patients a consistently deleterious trend for this parameter was observed for both eyes during the one year study.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

Anaerobic oxidation of phenylacetate and 4-hydroxyphenylacetate to benzoyl-coenzyme A and CO2 in denitrifying Pseudomonas sp. Evidence for an alpha-oxidation mechanism.

Anaerobic degradation of (4-hydroxy)phenylacetate in denitrifying Pseudomonas sp. was investigated. Evidence is presented for alpha-oxidation of the coenzyme A (CoA)-activated carboxymethyl side chain, a reaction which has not been described. The C6-C2 compounds are degraded to benzoyl-CoA and furtheron to CO2 via the following intermediates: Phenylacetyl-CoA, phenylglyoxylate, benzoyl-CoA plus CO2; 4-hydroxyphenylacetyl-CoA, 4-hydroxyphenylglyoxylate, 4-hydroxybenzoyl-CoA plus CO2, benzoyl-CoA. Trace amounts of mandelate possibly derived from mandelyl-CoA were detected during phenylacetate degradation in vitro. The reactions are catalyzed by (i) phenylacetate-CoA ligase which converts phenylacetate to phenylacetyl-CoA and by a second enzyme for 4-hydroxyphenylacetate; (ii) a (4-hydroxy)-phenylacetyl-CoA dehydrogenase system which oxidizes phenylacetyl-CoA to (4-hydroxy)phenylglyoxylate plus CoA; and (iii) (4-hydroxy)phenylglyoxylate: acceptor oxidoreductase (CoA acylating) which catalyzes the oxidative decarboxylation of (4-hydroxy)phenylglyoxylate to (4-hydroxy)benzoyl-CoA and CO2. (iv) The degradation of 4-hydroxyphenylacetate in addition requires the reductive dehydroxylation of 4-hydroxybenzoyl-CoA to benzoyl-CoA, catalyzed by 4-hydroxybenzoyl-CoA reductase (dehydroxylating). The whole cell regulation of these enzyme activities supports the proposed pathway. An ionic mechanism for anaerobic alpha-oxidation of the CoA-activated carboxymethyl side chain is proposed.

Acyl Coenzyme A↗
PubMed1991

The applicability of the measurement of urinary thioethers. A study of humans exposed to styrene during diet standardization.

The excretion of thioethers was measured in the urine of 6 volunteers, who were experimentally exposed to styrene, and 18 styrene workers. In addition, 12 clerks (non-smokers) and 12 sheet-metal workers (smokers) served as control groups. Diet was standardized during the experiments. Thioethers were measured by a spectrophotometric method. The volunteers were exposed to styrene, 210 mg/m3, for 2h at a 50-W workload. An increase in thioether excretion was observed; the largest was in the urine samples collected between 0.5 and 5 h after the end of the exposure. After 43 h the excretion of thioethers was close to the pre-exposure level (3.5 mmol/mol creatinine). About 1% of the styrene absorbed was detected as thioethers in urine, which is only about 1/10 of the conversion reported for rats. From excretion rate curves a half-life of about 11 h was calculated for styrene thioethers. The styrene workers were employed at two plants. The average exposure to styrene (time-weighted average 8 h) was estimated to be about 115 mg/m3 (smokers in plant A), 55 mg/m3 (non-smokers in plant A) and less than or equal to 10 mg/m3 (non-smokers in plant B). The excretion of thioethers in exposed workers at plant A was higher by 2-4 mmol/mol creatinine than that in non-exposed controls. In plant B, where exposure was lower, an increase in that amount of thioethers excreted in the urine by exposed workers was less pronounced, and was statistically significant only when post-shift samples were compared with pre-shift samples.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗