摘要:

AbstractAside from its established use as an antileprotic and anti‐inflammatory drug, dapsone is also effective in the therapy of Pneurnocystis carinii pneumonia. Unfortunately, its use is often limited by its dose‐dependent toxicity, such as methaemoglobinaemia and haemolysis; the latter condition occurs most frequently in gIucose‐6‐dehydrogenase deficient individuals. It is also responsible for occasional life‐threatening disorders such as agranulocytosis. Dapsone may undergo acetylation, but its toxicity is due to the product of its oxidative metabolism, dapsone hydroxylamine. This is generated in man by the constitutive hepatic cytochrome P450 enzyme IIIA4. Studies in the rat revealed that dapsone‐dependent methaemoglobinaemia could be greatly diminished by the co‐administration of metabolic inhibitors. In the isolated perfused rat liver, dapsone hydroxylamine levels and hence methaemoglobin formation fell significantly in the presence of cimetidine. In addition, the clearance of the parent drug was retarded, and perfusate concentrations of monoacetyl dapsone increased. The protective effect of cimetidine also reduced methaemoglobin formation in the whole rat during the chronic administration of dapsone. Incubation of dapsone in a two‐compartment in vitro system using human tissues in the presence of cimetidine or ketoconazole resulted in a decrease in methaemoglobin formation in all the human livers tested. Although cimetidine was only effective if incubated with microsomes and NADPH prior to the addition of dapsone. Administration of cimetidine (3 × 400 mg daily) to volunteers 3 days prior to and 4 days post administration of a single dose of 100 mg dapsone caused drug concentrations to increase by almost 30%. There was a marked fall in peak methaemoglobin levels and the percentage of the dose excreted in urine as dapsone hydroxylamine N‐glucuronide was reduced by almost one third. During high dose dapsone therapy it may be possible that the co‐administration of cimetidine might reduce toxicity while maint

ISSN:0272-4391    

DOI:10.1002/ddr.430250102

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractThe 5‐HT3receptor antagonist properties of the novel compound L‐683,877 (−) (2′‐(1‐methyl‐1H‐indol‐3‐yl)‐)spiro(1‐azabicyclo[2.2.2]octane‐3,5′(4′H)‐oxazole) have been characterised in vitro and in vivo. In radioligand binding studies, L‐683,877 displaced [3H]quaternized ICS 205–930 binding to membranes of rat cortex with a pKiof 8.71. L‐683,877 was essentially inactive (pKi<5) at 5‐HT1A, 5‐HT1B, 5‐HT1C, 5‐HT1D, 5‐HT2, and dopamine D1and D2binding sites. In the rat isolated vagus nerve and superior cervical ganglion (SCG) preparations, L‐683,877 antagonized 5‐HT3agonist‐induced depolarizations with apparent pKBvalues of 9.30 and 8.25, respectively. Similarly L‐683,877 antagonized the positive chronotropic effects of 5‐HT in the isolated rabbit heart preparation (apparent pKB10.10). In the anaesthetized rat, L‐683,877 (10–100 μg kg−1i.v.) antagonized the Bezold Jarisch reflex evoked by 5‐HT; at a dose of 10 μg kg−1i.v. L‐683,877 caused a twofold shift in the dose response curve. The retching and vomiting response induced in the ferret by cisplatin (10 mg kg−1i.v.), was markedly attenuated by L‐683,877 (0.1 mg kg−1i.v. and p.o.) and completely prevented by higher doses (10 mg kg−1i.v. and p.o.). These

ISSN:0272-4391    

DOI:10.1002/ddr.430250103

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractDextran metabolism was evaluated in euvolemic and hemorrhaged rabbits following administration of a 7.5%NaCl/6% Dextran‐70 (HSD) solution. Control rabbits and those bled 8 ml/kg body weight were infused i.v. with 4 ml/kg of HSD or HSD containing14C‐Dextran‐70. Blood samples were withdrawn prior to and at times up to 96 hr after HSD infusion. Peak serum dextran concentrations were about 29% higher in hemorrhaged rabbits than in controls, yet serum dextran t1/2was similar in both groups. Molecular weight (MW) distribution of dextran in serum showed a slight shift toward a MW>70,000, consistent with excretion of lower MW forms in the urine. After 96 hr concentrations of14C‐Dextran were 20‐fold higher in liver from both groups of rabbits, in comparison to spleen, lung, and kidney. In addition, dextranase activity in liver was markedly higher than in the other tissues assayed. These studies indicate that dextran infused as HSD does not associate with any protein fractions, is found only in low concentrations in tissue, and has a serum half‐life adequate to serve as a useful plasma volu

ISSN:0272-4391    

DOI:10.1002/ddr.430250104

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractAfter a period of forced exposure to cocaine, rats developed a preference for cocaine when given the choice to drink either a cocaine solution or water. The development of cocaine preference was dependent on the cocaine concentration given during choice but appeared to be independent of the presence of an cocaine withdrawal phase. The serotonin antagonist ritanserin reduced cocaine (0.1 mg/ml solution) preference and cocaine intake in a dose‐related manner. The activity of ritanserin started at doses ≥ 0.04 mg/kg when given subcutaneously once daily. Changes in test procedure did not affect the effectivity of ritanserin, although shifts in the lowest active dose were present. In the active dose range (i.e., between 0.04 and 10.00 mg/kg) ritanserin reduced cocaine intake by 29 to 53% and cocaine preference decreased by 19 to 32%. At any time during treatment, the decrease in cocaine consumption was compensated by an increase in water consumption. As a consequence, total fluid intake remained at a constant level. Body weight gain in ritanserin‐treated rats was not different from vehicle‐treated animals. In additional experiments it was shown that ritanserin neither directly interacted with the discriminative stimulus properties of cocaine nor induced a cocaine aversion. The activity of ritanserin against chronic exposure to cocaine is discussed in terms of a serotonin 5‐HT2a

ISSN:0272-4391    

DOI:10.1002/ddr.430250105

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractRats given the choice between fentanyl and water will develop a preference for fentanyl after a first period of exposure to fentanyl alone. Chronic treatment with the 5‐HT2antagonist ritanserin reduced the fentanyl intake and fentanyl preference. The effects of ritanserin were present from the first day and activity started at doses ≥0.04 mg/kg when given subcutaneously once daily. At 2.5 mg/kg ritanserin, the highest dose tested, fentanyl intake and fentanyl preference was reduced by 50 and 33%, respectively. The reductions in fentanyl intake were compensated by an increase in water drinking. At no time was there a systematic interference of ritanserin with consumatory physiological processes nor did ristanserin create aversion for fentanyl. Furthermore, ritanserin did not interact with the discriminative stimulus properties of fentanyl. In a similar experiment and in contrast to its activity on fentanyl intake, ritanserin was unable to reduce sucrose intake and sucrose preference. These results are discussed in terms of a global and specific mechanism of action of ritanserin on the need for drug reinforcement after chronic exposure to drugs of ab

ISSN:0272-4391    

DOI:10.1002/ddr.430250106

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

Abstract3‐(1,2,5,6‐Tetrahydro‐4‐pyridyl)‐5‐pyrrolo[3,2‐b]pyridone, CP‐93, 129, is a selective agonist ligand for 5‐HT1Breceptors. High affinity binding sites of [3H]CP‐93, 129 were found in rat whole brain membranes, which showed KDand Bmaxvalues similar to those for 5‐HT1Bsites labeled by [3H]5‐HT. Uptake of [3H]CP‐93, 129 in crude rat synaptosomes was also observed, which was potently inhibited by 5‐HT uptake blockers and 5‐HT but not by desipramine (NE uptake blocker) or tametraline (NE and DA uptake blocker). Because of this sensitivity to 5‐HT uptake inhibitors and the structural similarity of CP‐93, 129 to serotonin, [3H]CP‐93, 129 uptak

ISSN:0272-4391    

DOI:10.1002/ddr.430250107

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractThe discriminative stimulus effects of the novel antidepressant venlafaxine were examined in rhesus monkeys. Separate groups of monkeys discriminated either 0.56 or 1.0 mg/kg (i.g.)d‐amphetamine (N = 3) or 10 mg/kg (i.g.) pentobarbital (N = 4) from saline, in a discrete‐trials shock avoidance/escape paradigm. Ind‐amphetamine‐trained monkeys, 10–17 mg/kg venlafaxine occasioned only saline‐appropriate responding and had minimal effect on response latency in alll monkeys. The highest dose of venlafaxine tested (30 mg/kg) occasioned at least 95%d‐amphetamine‐lever responding in two of three monkeys. Following this dose, the average latency to respond after the onset of a trial increased substantially in both monkeys; in one monkey avoidance responding was disrupted and shocks were occasionally received. In the third monkey, 30 mg/kg venlafaxine occasioned only saline‐lever responding and had no effect on response latency. In pentobarbital‐trained monkeys, venlafaxine (3.0–30 mg/kg) occasioned primarily saline‐lever responding and these doses had minimal effects on response latency. In general, venlafaxine was more potent ind‐amphetamine‐trained monkeys than in pentobarbital‐trained monkeys in its effects on response latency. Drug discrimination procedures in animals have been shown to differentiate compunds in a manner that is consistent with their subjective effects. Thus, result from the present experiment suggest that venlafaxine may produce subjective effects similar tod‐amphetamine in some indi

ISSN:0272-4391    

DOI:10.1002/ddr.430250108

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

ISSN:0272-4391    

DOI:10.1002/ddr.430250101

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY