摘要:

Abstract:5‐HT3receptors have an exclusive neuronal location and evidence is presented of their involvement in behaviour. 5‐HT3receptor antagonists such as ondansetron, tropisetron and zacopride have provided the critical pharmacological tools to reveal a potent and efficacious ability to regulate disturbed behaviour. Thus the 5‐HT3receptor antagonists will restore to normal rodent and primate behaviour disturbed by increasing limbic dopamine function, aversive situations, cognitive impairments and drug abuse. The remarkable feature of their action is a failure to modify normal behaviour. This unique pharmacological signature has ensured a wide interest in the potential role of the 5‐HT3receptor antagonists in the treatment of schizophrenia, anxiety, age related memory impairment and the problems of withdrawal from drugs of abuse. The preclinical data and preliminary clinical observations are pr

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00570.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:Incubation of the tricyclic antidepressant desmethylimpramine (DMI) with rat liver or brain microsomes in the presence of NADPH or t‐butyl‐hydroperoxide (TBH) revealed different regiospecificities in the hydroxylation reactions between the tissues. In brain preparations 10‐OH‐DMI was formed in reactions supported by NADPH or TBH, whereas in the latter case also an unidentified metabolite could be detected. Inclusion of exogenous NADPH‐cytochrome P450 reductase in the brain preparations caused a 10‐fold higher rate of 10‐hydroxylation but no 2‐OH‐DMI could be detected. By contrast, liver microsomal preparations in the presence of NADPH catalyzed formation of both 2‐ and 10‐OH‐DMI, whereas only 10‐OH‐DMI was formed in TBH‐supported reactions. The results indicate that antidepressant drugs can be metabolized in brain with different stereospe

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00571.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:The disposition of14C‐labelled hexachlorobenzene (HCB) and 2,4′,5‐trichlorobiphenyl (triCB) was studied in cod (Gadus morhua) and rainbow trout (Oncorhynchus mykiss). For both compounds tape section autoradiography revealed substantial amounts of radiolabeled material in the central nervous system (CNS) of cod, whereas only traces of radioactivity were observed in the CNS of rainbow trout. Furthermore, an enrichment of radiolabeled compound in the cerebrospinal fluid (CSF) was observed in the cod, whereas no radioactivity could be detected in the CSF of rainbow trout. According to autoradiography, the CNS of cod dosed with HCB contained the parent compound, whereas the major part of radioactivity in CSF was due to HCB metabolites. Thin‐layer chromatography of extracts from cod dosed with triCB showed the presence of parent compound in the CNS, whereas part of the radioactivity in the CSF was due to triCB metabolites. The activities of cytochrome P‐450 and UDP‐glucuronosyltransferase in the CNS of cod and rainbow trout were determined in microsomal and mitochondrial fractions. Both species expressed activities which were in the same order of magnitude as those reported for the corresponding fractions from rat brain. Incubation of triCB with cod brain mitochondria and microsomes resulted in the formation of two polar metabolites. It is suggested that cod may be more vulnerable than raindow trout regarding neurotoxicological effects of HCB, triCB and related environmental

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00572.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:Central and peripheral α2‐adrenoceptors, including those of the gastrointestinal tract, have been indicated as a toxicity target of formamidine pesticides in mammals. In this study, the inhibitory effect of chlordimeform on twitch contractions from electrically‐stimulated longitudinal muscle‐myenteric plexus preparations (LMMPs) of the guinea‐pig ileum was found to be resistant to the action of the α2‐adrenoceptor antagonist idazoxan. This drug was also ineffective on chlordimeform‐induced inhibition of peristalsis recorded in whole ileal segments. As expected, idazoxan antagonized the inhibitory effect of the α2‐adrenoceptor agonist clonidine on twitch contractions and peristaltic activity. Chlordimeform reduced the amplitude of direct mechanical responses to a variety of spasmogens such as acetylcholine, histamine and substance P, suggesting a muscular site of action. Moreover, in Ca2+‐free, K+‐depolarized LMMPs, chlordimeform inhibited submaximal contractions caused by addition of exogenous calcium, through an action apparently similar to that of the Ca2+entry blocker nifedipine. Both chlordimeform‐ and nifedipine‐induced inhibition of calcium contractions were reversed by the calcium channel activator BAY K 8644. This compound also partially prevented the inhibitory action of chlordimeform on peristaltic activity. On the whole, these results indicate that chlordimeform‐induced depression of motor activity in the guinea‐pig ileum is, at least in part, related to inhibition of transmembrane Ca2+fluxes responsible f

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00573.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:The effects of nickel (Ni) on hepatic monooxygenase activities (aniline 4‐hydroxylase, AH; ethylmorphine N‐demethylase. EMND; aminopyrine N‐demethylase, AMND), cytochrome P‐450, cytochrome b5, microsomal haem and reduced glutathione (GSH) levels, and glutathione S‐transferase (GST) activities toward several substrates (1, chloro‐2‐4‐dinitrobenzene, CDNB; 1,2 dichloro‐4‐nitrobenzene, DCNB; ethacrynic acid, EAA) in mice, rats and guinea‐pigs were studied. Ni (59.50 mg NiCl2· 6H2O/kg. subcutaneously) was administered to the animals 16 hr prior to sacrifice. Ni significantly inhibited AH, EMND, AMND activities, and decreased cytochrome P‐450, cytochrome b5(except in the livers of rats), and microsomal haem levels in the livers of all the animal species examined. However, the depressions were more profound in livers of mice than in those of the other two species. The hepatic GSH level was significantly inhibited in mice whereas no alteration was observed in rats. In guinea‐pigs, the hepatic GSH level was significantly increased by Ni. The hepatic GST activity toward the substrate CDNB was significantly depressed in mice, unaltered in rats and significantly increased in guinea‐pigs by Ni. The hepatic GST activity toward DCNB was significantly inhibited in mice whereas no significant alteration was observed in rats. In guinea‐pigs, Ni caused significant increase in hepatic GST activity for DCNB. However, hepatic GST activity toward EAA was significantly inhibited in mice whereas significantly increased in rats and guinea‐pigs. These results seem to indicate that i) there exists quantitative, but not qualitative, differences among the hepatic monooxygenases of rodents in response to Ni, mice being more sensitive than rats and guinea‐pigs, ii) the influence of Ni on hepatic GSH level varies depending on the animal species and iii) the hepatic GSTs of rodents

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00574.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:The behavioural and neuropathological effects of both systemic and intrahippocampal injections of paraquat dichloride (1,1′‐dimethyl 4,4‐bipyridinium dichloride) were studied in rats.Paraquat(0.1–1.0 μmol) injected into the dorsal hippocampus, produced limbic motor seizures within a few minutes of injection followed by neuronal damage in the CA1 and CA3 pyramidal cell layers, pyriform cortex, dentate granule cell layer and in the hilus fascia dentata at 24 hr (n = 9 rats). A smaller dose of paraquat (10 nmol) was ineffective. The effects of intrahippocampal injections of paraquat (1 μmol) were prevented by administering it together with atropine (50 nmol; n = 6 rats) or by giving it 60 min. after MK 801 (0.3 mg · kg‐1intraperitoneally). Systemic injections of paraquat (20‐100 mg · kg‐1) also produced forelimb clonus and rearing in 10 out of 15 animals. Neuronal cell death was found 24 hr later in 9 of these rats and was restricted to the pyriform cortex, the brain region with the highest concentrations of paraquat. Atropine (150 mg · kg‐1intraperitoneally given 60 min. previously) completely prevented the motor seizures but cell death still occurred in 2 of the 6 animals tested. In conclusion, both systemic and intrahippocampal injections of paraquat produced behavioural excitation accompanied 24 hr later by brain damage and antagonist studies suggested involvement of muscarinic and NMDA receptors in the

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00575.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:Eighty‐two strains of bacteria (Neisseria meningitidis, Haemophilus influenzae, Enterobacteriaceae, Streptococcus pneumoniae, group B streptococci andListeria monocytogenes) were examined for theirin vitrosusceptibility to eight drugs, seven neuroleptics (perphenazine, fluphenazine, cis(Z)‐clopenthixol, haloperidol, clozapine, clebopride and SCH 23390), and the neuroleptically inactive trans(E)‐clopenthixol. The phenothiazines and the thioxanthenes were, on the whole, the most active drugs when measured, the IC5050for each group of bacteria being 7.4 to 84 mg/1 (with the exception of the activity against the enterobacteriaceae). The antibacterial potency of clozapine, which has an atypical neuroleptic profile, was between 50 and 140 mg/1. Haloperidol also showed an antibacterial activity in the concentration range 35‐140 mg/1. The selective D1antagonist, SCH 23390 and the selective D2antagonist, clebopride, inhibited only few of the bacteria in the concentration range inves

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00576.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:A study was made of the effects of certain inhibitors of transport systems on the actions of four cadmium (Cd) complexing N,N‐disubstituted dithiocarbamates (DTCs) in mobilizing murine renal and hepatic Cdin vivo.Probenecid, the prototypical antagonist of organic anion transport in the kidney, when given 1 hr prior to each DTC, sharply suppressed the DTC‐induced reduction of renal Cd but was virtually without effect on mobilization of Cd from liver. Sulfinpyrazone, which blocks tubular reabsorption of uric acid and also inhibits transport of a variety of organic acids, inhibited markedly the mobilization of both renal and hepatic Cd by DTCs. Phlorizin, an inhibitor of tubular sugar reabsorption, did not affect the Cd mobilizing actions of DTCs in any consistent fashion. We propose that the high degree of selectivity of DTCs in mobilizing renal and hepatic Cd is dependent, at least in part, upon active transport of DTCs into these tissues via the organic anion transport systems. This report presents the first evidence that compounds of the (R)2NCSS class may gain access to intracellular space by an active, carrier‐mediated pr

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00577.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00578.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY