ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1987.tb01761.x

出版商:Blackwell Publishing Ltd    

年代:1987

数据来源: WILEY

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1987.tb01710.x

出版商:Blackwell Publishing Ltd    

年代:1987

数据来源: WILEY

摘要:

Abstract:The abilities of some naturally occurring β‐carbolines (BCs), dihydro‐BCs and tetrahydro‐BCs to inhibit the specific binding of3H‐tryptamine (TA),3H‐serotonin (5‐HT) and3H‐ketanserine to rat brain membranes and to induce tremor in mice were studied. These compounds, particularly DHBCs and BCs, showed higher affinity for TA binding sites than to 5‐HT1or 5‐HT2binding sites inhibiting the former at nanomolar and the two latter ones at micromolar or high micromolar concentrations. The Kivalues for norharmane, harmaline and harmine (17, 18 and 74 nM, respectively) for TA sites indicate the highest affinity so far described for natural β‐carbolines to any receptor sites and thus may indicate their major site of action. Among the BC derivatives studied, the before mentioned harmala alkaloids were the most potent inducers of tremor in mice, although the orders of the tremorogenic potency and the binding to TA site did not correlate. It is suggested that especially the tremorigenic effect of BC derivatives is partly based on the binding to specific

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1987.tb01711.x

出版商:Blackwell Publishing Ltd    

年代:1987

数据来源: WILEY

摘要:

Abstract:The hepatocarcinogen acetamide, in single doses of 100 and 400 mg/kg b.wt., was shown to act as an initiator in a dose‐dependent fashion in rat liver using the Solt‐Farber method. Acetamide and its putative metabolite N‐hydroxy‐acetamide did not cause liver necrosis in single dose experiments. Acetamide showed no evidence for genotoxicity in tests for mutations inSalmonella typhimurium, for DNA damage in rat hepatoma cells or for DNA repair in isolated rat hepatocytes. In contrast, N‐hydroxy‐acetamide displayed genotoxic activity in all 3 test systems. Neither acetamide nor N‐hydroxy‐acetamide induced transformation of primary Syrian hamster embryo cells or gave evidence of inhibition of metabolic cooperation in V79 cells. Radiolabeled acetamide and N‐hydroxy‐acetamide were not bound covalently to proteins in the presence of various metabolic activation systems (microsomes plus NADPH or xanthine/xanthine oxidase, cytosol or cytosol plus acetyl CoA or proline plus ATP). N‐Hydroxy‐acetamide was cytotoxic to monolayers of isolated hepatocytes at concentrations above 2.5 mM. This cytotoxicity was increased after diethyl maleate treatment, but N‐hydroxy‐acetamide did not deplete cellular glutathione. A HPLC system was developed for the separation and quantification of acetamide, N‐hydroxy‐acetamide and acetic acid. No significant excretion of N‐hydroxy‐acetamide or acetic acid in the urine could be demonstrated after treatment of rats with 100 or 1,000 mg/kg b.wt. of acetamide. The underlying mechanism for the observed initia

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1987.tb01712.x

出版商:Blackwell Publishing Ltd    

年代:1987

数据来源: WILEY

摘要:

Abstract:The influence of lithium on calmodulin‐stimulated adenylate cyclase activity has been studiedin vitroand after chronic treatment. Chronic lithium treatment decreased calcium‐calmodulin‐stimulated adenylate cyclase activity in rat cortical membranes, while no effect was observed on GTP‐stimulated activity. Lithiumin vitroinhibited adenylate cyclase activity stimulated by isoprenaline, GTP or calcium‐calmodulin. Calcium‐calmodulin‐stimulated activity was more sensitive to lithium (2 mM) than isoprenaline‐ and GTP‐stimulated activities (5 mM) and activities by these agents combined. Lithium had no effect on the unstimulated enzyme activity. The inhibitory effect of lithiumin vitroon calcium‐calmodulin‐stimulated adenylate cyclase activity was antagonized by magnesium. The inhibition induced by lithiumin vitroon the GTP‐stimulated adenylate cyclase activity was increased by substituting manganese for magnesium in the assay media. Furthermore, the manganese‐stimulated activity was also reduced by lithium. The latter effect was not observed in calmodulin‐depleted membranes, but the inhibitory effect of lithium could be restored by addition of exogenous calmodulin. The present results suggest that lithium might influence the interaction of calmodulin with the enzyme and/or interfere with the divalent cation site(s) on t

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1987.tb01713.x

出版商:Blackwell Publishing Ltd    

年代:1987

数据来源: WILEY

摘要:

Abstract:The excretion routes of intact metronidazole and tinidazole were studied in rats kept in metabolism cages and cannulated for continuous bile collection. The nitroimidazoles were given intraarterially either alone or after a 5‐day pretreatment with phenobarbitone (70 mg/kg/day intravenously) or after a single dose of cimetidine (50 mg/kg intraarterially). After 30 mg/kg, 27.0% of the metronidazole dose was excreted intact in 24‐hr urine and 2.2% in bile. After tinidazole, the recoveries of the intact drug in urine and bile were 48.1% and 1.7%, respectively. After 90 mg/kg, the total recoveries of both drugs were 25‐28% smaller than after 30 mg/kg. Phenobarbitone pretreatment did not affect metronidazole levels in plasma but decreased tinidazole levels at 4 hrs. The 24‐hr recoveries of the intact nitroimidazoles in urine were significantly reduced by phenobarbitone while the 24‐hr bile recoveries were not. Cimetidine treatment enhanced both metronidazole (at 1, 2 and 3 hrs) and tinidazole (only at 1 hr) concentrations in plasma, but this shift was not reflected in the 24‐hr urine recoveries of the intact nitroimidazoles. Cimetidine doubled, however, the 24‐hr bile recovery of the intact tinidazole. The calculations of the apparent degree of metabolism, assuming no methodological losses, showed that phenobarbitone increased the metabolism of tinidazole by about 62% and that of metronidazole only by about 16%. The effect of a single dose of cimetidine w

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1987.tb01714.x

出版商:Blackwell Publishing Ltd    

年代:1987

数据来源: WILEY

摘要:

Abstract:These studies were performed to investigate the effects of MeHg on testicular function inMacaca fascicularismonkeys. In anin vivostudy involving oral treatment of adult malesMacaca fascicularismonkeys with MeHg for 20 weeks, changes in spermatozoal production, motility and morphology and in serum testosterone were followed before, during and after treatment. MeHg treatment significantly decreased% motile spermatozoa and scores for sperm speed and forward progression and increased % abnormal sperm tail forms, at sub‐neurotoxic levels. The MeHg‐induced increase in semen abnormalities was not accompanied by any significant changes in serum levels of testosterone. No consistent histological abnormalities were detected in testicular biopsies from the treated animals at the end of the treatment period. A good recovery pattern was observed for the MeHg effects on sperm motility while this was unclear for the effects on sperm morphol

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1987.tb01715.x

出版商:Blackwell Publishing Ltd    

年代:1987

数据来源: WILEY

摘要:

Abstract:The ability of various compounds to antagonise the 5‐MeODMT induced prolongations of latency and duration of postdecapitation convulsions (PDCs) were compared. The 5‐hydroxytryptamine (5‐HT) receptor antagonists, mianserin, methergoline, cinanserin and methysergide antagonised the 5‐MeODMT (0.5 to 4.0 mg/kg) induced prolongations of latency to onset of convulsions substantially and to a lesser extent the prolongation of duration. The efficacy of the 5‐HT antagonists for blocking 5‐MeODMT changes of PDCs was roughly of the order mianserin>cinanserin>methysergide>methergoline. Pirenperone, the 5‐HT2antagonist, and pimozide, the dopamine receptor antagonist did not antagonise the 5‐MeODMT induced changes. Mianserin, methergoline, cinanserin and methysergide, by themselves, prolonged the duration of PDCs but did not affect latency. Pirenperone (0.25 mg/kg) prolonged both the latency and duration of the PDCs while pimozide (0.5‐2.0 mg/kg) had no effect upon PDCs. This evidence suggests that 5‐MeODMT induced changes of PDCs are mediated via 5‐HT1receptors and thus a reliable model to combine with other measures of spinal

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1987.tb01716.x

出版商:Blackwell Publishing Ltd    

年代:1987

数据来源: WILEY

摘要:

Abstract:A pharmacological characterization of the postjunctional α‐adrenoceptors in human superficial epigastric artery and vein was performed, using several α‐adrenoceptor subtype selective agonists, and the antagonists prazosin (α1) and rauwolscine (α22). In the arteries prazosin fulfilled the criteria for a competitive antagonism in concentrations 10‐9‐10‐7M, giving a pA2‐value of 9.17 in the Schild plot. Rauwolscine in concentrations 10‐8‐10‐6M caused less pronounced but significant dextral shifts of the noradrenaline (NA) concentration‐response curves. In the veins rauwolscine behaved like a competitive antagonist (10‐‐10‐6M). The pA2‐value was 9.16. Prazosin 10‐9M displaced the NA concentration‐response curve, but higher concentrations (10‐8and 10‐7M) caused no further displacement. Prazosin reduced the Emax‐values in the veins. In the arteries the rank order of potency for the agonists was: cirazoline (α1)>NA>naphazoline (α2)>guanfacine (α2)>phenylephrine (α1). The intrinsic activities of clonidine (α2), ST 587 (α1), B‐HT 920 (α2) and B‐HT 933 (α2) were too low to allow meaningful comparisons to be made. The rank order of potency in the veins was: NA>clonidine (α2)>naphazoline (α2)>guanfacine (α2)>phenylephrine (α1)>B‐HT 920 (α2)>cirazoline (α1)>B‐HT 933 (α2). The intrinsic activity of ST 587 was low. Only two pEC50‐values could be determined for clonidine in the arteries and these were higher than the pEC50‐values for clonidine in the veins. Phenylephrine, naphazoline and guanfacine were equipotent in both types of vessel. Cirazoline was 135 times more potent and NA was 3 times less potent in the arteries than in the veins. The data suggest that the rank order of potency of subtype selective agonists cannot be used for characterization of the α‐adrenoceptors in human superficial epigastric arteries and veins. Antagonists on the other hand, give distinct satisfactory information. In the arteries α1‐adrenoceptors predominate, but a population of α2‐adrenoceptors cannot be excluded in some patients. In the veins α2‐adrenocep

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1987.tb01717.x

出版商:Blackwell Publishing Ltd    

年代:1987

数据来源: WILEY

摘要:

Abstract:Haem arginate is a new haem compound recently introduced for treatment of porphyrias. Previously haematin has been reported to increase certain hydroxylase activities in extrahepatic tissues, but even in therapeutic doses it impairs the microsomal foreign substance metabolism in the liver. Haem arginate at a dose equivalent to haem 10 mg/kg (threefold therapeutic dose) did not prolong the hexobarbital sleeping time of mice, 20 mg/kg did prolong the hexobarbital and possibly also the ethanol sleeping time. Haem arginate administered in high doses prior to oral propranolol did not alter the bioavailability of the latter. With regard to drug interactions haem arginate may be safer than haematin.

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1987.tb01718.x

出版商:Blackwell Publishing Ltd    

年代:1987

数据来源: WILEY