摘要:

Abstract:Of the known biochemical actions of caffeine, only inhibition of adenosine receptors occurs at concentrations achieved during normal human consumption of the drug. Under normal physiological conditions, adenosine is present in sufficient concentrations to activate A1and A2areceptors. Via actions on A, receptors, adenosine decreases neuronal firing and the release of neurotransmitters. The exact mechanisms are not known, but several possibilities are discussed. Via actions on A2areceptors, adenosine ‐ and hence caffeine ‐ can influence dopaminergic neurotransmission. Caffeine can induce rapid changes in gene expression and, somewhat later, marked adaptive changes. These include antiepileptic and neuroprotective changes. Thus, caffeine has a number of central effects directly or indirectly related to adenosine receptors. Some of these are potentially useful, and drug development based on the actions of caffeine should be interest

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1995.tb00111.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

Abstract:A protease inhibitor, gabexate (ethyl‐p‐6‐guanidinohexanoyloxy benzoate), was found to have an antimuscarinic action in muscle strips of the guinea‐pig gastric fundus. Gabexate reversibly inhibited carbachol‐induced contractions in the presence of prostaglandin synthesis inhibitors (indomethacin or meclofenamate) with a pA2of 5.66 for the circular and 5.25 for the longitudinal muscle. The effect was not affected by tetrodotoxin. Gabexate also inhibited contractions produced by prostaglandin E2(PGE2) (21.7 ± 7.3% with 30 μM, n = 12). The inhibition was markedly potentiated by anticholinesterase, diisopropyl fluorophosphate, but converted to contraction by atropine. In the absence of PGE2, gabexate produced no mechanical response on its own even after atropine application. Treatment with hemicholinium, an acetylcholine synthesis inhibitor, also converted the relaxant effect of gabexate, applied during PGE2‐induced contraction, to contraction. Gabexate also inhibited contracture induced by 30 mM K+weakly (13 ± 2% with 30 μM, n=5). This relaxation was abolished by atropine, without converting to contraction. PGE2and excess K+are likely to release acetylcholine from nerve fibres. These results suggest that the inhibitory effect of gabexate is mainly due to the muscarinic receptor blocking action. In addition, gabexate has a potentiating action on the prostaglandin‐in

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1995.tb00112.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

Abstract:Male pigmented rats (n=36) were exposed to toluene and/or ethanol (1000 p.p.m. toluene in the inhaled air 21 hr/day, and 5.7‐8.0% ethanol in the drinking water continuously) during 8 weeks. Electrophysiological recordings were made 1 week after the exposure. Auditory sensitivity (auditory brainstem response) was reduced only after exposures including toluene. At 20 kHz, ethanol antagonized toluene‐induced loss of auditory sensitivity (P<0.05). Flash evoked potentials were not affected in any group. In peripheral nerve, exposures containing ethanol were followed by increased amplitudes of nerve and muscle action potentials. Exposures including toluene were followed by an increase in liquid consumpt

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1995.tb00113.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

Abstract:Exposure of the cyclodiene insecticide heptachlor at 1/8 and 1/4 LD50to male and female albino rats before mating affected fertility in both sexes. A decrease in implantations, serum oestrogen and progesterone levels and increase in resorptions in the females was observed. However, no histological changes were observed except for few atretic follicles in the treated females. In males, a dose‐dependent significant decrease in the sperm count and coagulating gland fructose levels was observed, with marginal degeneration of seminiferous tubules. These results are indicative of the prenatal toxicity of heptachlor in male and female rat

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1995.tb00114.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

Abstract:In the commercially available intravenous formulation of Cyclosporin A (Sandimmun®), polyoxyethylated castor oil (Cremophor®EL) is used as a solubilizing agent. We have recently reported that the acute nephrotoxic effect of this preparation was alleviated by replacing Cremophor®EL with a soybean oil‐based fat emulsion in a rat model. To further explore the potential of fat emulsions as carriers for cyclosporin A, data on the in vivo pharmacokinetics and tissue distribution are required. In this study in pigs, the pharmacokinetics of soybean oil‐cyclosporin A was compared to that of Sandimmun®. The two formulations seemed bioequivalent, as there were no significant differences in the systemic clearances, volumes of distribution or elimination half‐lives. Moreover, the tissue distributions of soybean oil‐cyclosporin A and Sandimmun® were compared in rats. These studies also included two additional lipid‐based carriers: one based on iodized ester of poppy seed oil and the other on a liposomal preparation. The tissue distributions were found to be similar regardless of the carriers used. Fat emulsion carriers seem to offer possibilities for preparing better tolerated intravenous formulations of cyclosporin A while maintaining the same characteristics concerning pharmacokinetics and tissu

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1995.tb00115.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

Abstract:Brain serotonergic, noradrenergic and GABAergic mechanisms are all involved in the regulation of conflict behaviour, and the GABAA/benzodiazepine receptor complex may play the most central role in this context. Since facilitation of GABAergic inhibitory transmission produces anticonflict effects, it has been suggested that antagonism of excitatory inputs may serve the same cause, and, indeed, blockade of excitatory neurotransmission mediated via N‐methyl‐D‐aspartate (NMDA), receptors, produces anticonflict effects. In the present study, using a modified Vogel's rat conflict model, we have investigated whether the anticonflict effect of the non‐competitive NMDA antagonist MK‐801 can be linked to NMDA receptor blockade, and if stimulation of these receptors instead produces proconflict effects. The tentative involvement of noradrenergic, serotonergic or GABAergic effects in the MK‐801‐induced anticonflict effect was also studied. MK‐801 produced a dose‐dependent and specific anticonflict effect (maximal effect after 0.05 mg/kg, intraperitoneally,–90 min.). This anticonflict action was completely counteracted by NMDA in a dose (0.125 μg, intracerebroventricularly) not affecting behaviourper se. The highest dose tested of NMDA alone (0.5 μg) tended to produce a proconflict effect, but this action may be unspecific due to concomitant drug‐induced motor‐inhibition. Neither bicuculline and picrotoxin, antagonists at the GABAA/benzodiazepine receptor complex, nor the adrenoceptor antagonists propranolol and prazosin significantly altered the MK‐801‐induced anticonflict effect, whereas L‐5‐HTP (50 mg/kg, intraperitoneally, after inhibition of peripheral decarboxylation with benzerazide) completely abolished the anticonflict effect of MK‐801. The results indicate that the anticonflict effect of MK‐801 is primarily mediated by antagonism of NMDA receptors, and that brain 5‐HT syst

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1995.tb00116.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

Abstract:The effects of eight aminoglycoside antibiotics, gentamicin, neomycin B, ribostamycin, dibekacin B, kanamycin A, streptomycin, tobramycin and amikacin, and two non‐aminoglycoside antibiotics, tetracycline and ampicillin, on cholinergic autonomic nervous transmission were studied using isolated guinea‐pig ileum preparation. The aminoglycoside antibiotics blocked the transmurally elicited twitches of the ileum in a concentration‐dependent manner. The blocking effect of aminoglycosides was biphasic, i.e., an initial reduction followed by a spontaneous partial recovery. Dibekacin was the most potent parasympathetic inhibitor, followed by neomycin B, tetracycline, gentamicin, streptomycin, kanamycin A, tobramycin, ribostamycin, and amikacin. Ampicillin had no blocking effect. The tested antibiotics did not affect acetylcholine (ACh)‐induced contraction of the ileum, except for high concentrations of neomycin B, gentamicin, and streptomycin. The three antibiotics shifted the dose‐response curves for ACh to the right without affecting the maximal contraction. Naloxon, yohimbine, hexamethonium and choline chloride failed to eliminate the blocking effect of the antibiotics on twitches of the ileum induced by transmural stimulation. However, increase of the extracellular Ca ion concentration virtually abolished the blockade. Dibekacin blocked the evoked but not the spontaneous release of ACh and shifted the dose‐response curve of CaCl2‐dependent transmurally elicited contractions of the ileum to the right. These results suggest that the site for the block of aminoglycosides is mainly the cholinergic nerve terminal, where they reduce the available Ca ions required for the r

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1995.tb00117.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

Abstract:The metabolism of acetate at concentrations of 1, 2.5, 5 and 10 mM was investigated in freshly isolated hepatocytes from 48 hr fasted, female rats in the absence and presence of 10 mM ethanol. The maximal capacity for acetate metabolism was 0.85 μmol/(108cells · min). Ethanol caused a 20% decrease in the apparent Vmaxfor acetate metabolism and an increase in the apparent Km for acetate from 3.0 to 4.6 mM. At physiological concentration of acetate (~ 1 mM) and in the absence of an inhibitory effect of ethanol, the capacity for acetate metabolism was 15–20% of the rate of acetate formation from ethanol and the inhibitory effect of ethanol further reduced it to 10–15%. The results thus explain the well‐known but hitherto not understood fact that only a small fraction of acetate produced in the liver during ethanol oxidation is further metabolized by the liver, while the majority is exported for oxidation in other tissues. Finally, a new method for calculation of liver acetate uptake in the presence of ethanol is pr

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1995.tb00118.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

Abstract:In vitrodata suggest that the serotonin receptor subtype 4 (5‐HT4) mediate part of the serotonin (5‐HT)‐induced intestinal secretion. This study elucidates the involvement of the intestinal 5‐HT4receptor subtype and the anti‐diarrhoeal therapeutic potentials of tropisetron and octreotide in 5‐HT‐induced intestinal hypersecretionin vivo.The effects of intraluminal 5‐HT, 5‐methoxytryptamine, and tropisetron (ICS 205‐930), and subcutaneous octreotide (SMS 201‐995) on fluid hypersecretion (accumulation) was studied in tied‐off loops in pig jejunum. 5‐HT, 5‐methoxytryptamine (5‐HT4agonist), and tropisetron (5‐HT3/5‐HT4antagonist) all induced a dose‐dependent hypersecretion. Low doses of tropisetron reduced, while high doses of tropisetron enhanced the 5‐HT and 5‐methoxytryptamine responses. Taking into account the hypersecretory effect by itself, tropisetron seemed to completely block the hypersecretory effects of 5‐HT and 5‐methoxytryptamine. Finally, octreotide reduced the hypersecretory effect of 5‐HT, maximally by 30%. These results suggest the involvement of the intestinal 5‐HT4receptor subtype in 5‐HT‐induced hypersecretion in pig jejunumin vivo.Furthermore, this study demonstrates a potential therapeutic value for octreotide

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1995.tb00119.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

Abstract:The characteristics of the binding of3H‐proadifen to rat liver membranes were studied and compared to those of3H‐cocaine. It was found that3H‐proadifen was bound reversibly with high affinity (KD=1.8 ± 0.5 nM) and large capacity (Bmax=2010 ± 340 pmol/g wet tissue) to liver membranes. The corresponding values for the3H‐cocaine binding were 3.5 nM and 1000 pmol/g wet tissue. The binding of3H‐proadifen was mainly localised to the microsomal fraction. The number of binding sites was not increased by treatment of rats with phenobarbitone. With 1 μM CdCl2in the incubation buffer it was possible to differentiate between two3H‐cocaine binding sites with Kd values of 1.6 and 7.7 nM and Bmaxvalues of 280 and 940 pmol/g wet liver tissue. S‐(‐)‐Alaproclate inhibited the binding of3H‐proadifen and3H‐cocaine with high affinity (IC50=2.2 nM and 0.4 nM, respectively). The R‐enantiomer was 100 to 300 times less potent. Cocaine inhibited the binding of3H‐proadifen (IC50= 10 nM) and proadifen that of3H‐cocaine (IC50= 1 nM). There was a high correlation coefficient (rr=0.972; P<0.01; n=12) in the Spearman rank test between the inhibitory potencies of compounds examined in both systems. Besides some potent alaproclate analogues a couple of compounds had moderately high affinity (IC50= 100–500 nM): chloroquine, phenoxybenzamine, amitriptyline, ajmaline, remoxipride, imipramine and (‐)‐alaprenolol. CdCl2, ZnCl2and CuCl2inhibited the binding of both ligands with low Hill coefficients, indicating heterogeneous binding sites. The inhibition curve of Cd2+on the cocaine binding was biphasic with a high affinity part around 50 nM and a low affinity part at 15 μM. The similarity of the characteristics of the binding of these ligands with that of3H‐alaproclate is discussed. It is suggested that all three compounds bind to the same sites, although additional bi

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1995.tb00120.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY