摘要:

AbstractThis overview summarizes the results of microdialysis studies into the effects of several psychoactive drugs on extracellular serotonin (5‐HT) levels in rat brain. The effects of (+)3,4‐methylenedioxymethamphetamine (MDMA, ecstasy) were examined in the brain slice preparation for comparison with parallel electrophysiological studies of the impact of (+)‐MDMA on dorsal raphe 5‐HT neuronal firing. (+)‐MDMA induced the release of 5‐HT from slices of dorsal raphe. The release was inhibited by fluoxetine, and augmented by tryptophan pretreatment. The results support a mechanism of action whereby (+)‐MDMA inhibits 5‐HT neuronal firing by releasing 5‐HT which then acts upon somatodendritic autoreceptors. In other studies, the effects of cocaine and cocaethylene (the psychoactive metabolite of concurrent cocaine/ethanol consumption) on extracellular 5‐HT and dopamine levels in the chloral hydrate‐anesthetized rat were examined. Both the intravenous and intraperitoneal routes were examined. By intravenous route, both drugs had equivalent effect at increasing dopamine levels. Cocaine significantly increased 5‐HT levels, while cocaethylene had no impact. By intraperitoneal route, cocaethylene was able to increase 5‐HT levels, but cocaine remained more potent. Route‐dependent differences in bioavailability were evident from studies of brain levels using microdialysis. By intravenous administration, equivalent amounts of both drugs entered the brain, whereas by intraperitoneal route, levels of cocaethylene were half those of coca

ISSN:0272-4391    

DOI:10.1002/ddr.430330102

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

年代:1994

数据来源: WILEY

摘要:

AbstractThe therapeutic effects of S‐312‐d on cerebral metabolic impairment were investigated in the stroke‐prone spontaneously hypertensive rats (SHRSP) with apparent stroke symptoms. S‐312‐d was orally administered 10 mg/kg/day (25 μmol/kg/day) to the SHRSP group (SP‐312) for 3 weeks. Several stroke symptoms such as piloerection, hyperreactivity, and limb paralysis in SHRSP were markedly alleviated in SP‐312. Their body weight and food intake also increased. The hypotensive and positive chronotropic effects with S‐312‐d were recovered to pre‐drug levels at 24 h after daily administration. The increases of water, Na+and Ca2+and the decreases of K+and Mg2+in the cortex of SHRSP administered 1% gum arabic solution (SP‐cont) were significantly improved in SP‐312. The increases of glucose and lactate/pyruvate ratio in the cortex of SP‐cont were also significantly reduced in SP‐312, while the recoveries of the decreased ATP and creatine phosphate in the cortex of SP‐312 were slight. The cholinergic and monoaminergic neurotransmitters in the brain were generally decreased in SP‐cont. The decreased acetylcholine (ACh) and choline acetyltransferase activity (CAT) in the cortex of SP‐cont were significantly restored in SP‐312. In the cortex, the decreased dopamine (DA) in SP‐cont was significantly restored, while the decreased norepinephrine (NE) and 5‐hydroxytryptamine (5‐HT) in SP‐cont were only slightly recovered in SP‐312. However, the decreased NE and 5‐HT in SP‐cont showed marked recovery in the hippocampus of SP‐312. Many biochemical deteriorations in cerebral organs such as marked edema, increases of Na+and Ca+contents, and decreases of several neurotransmitters in symptomatic SHRSP, which had some characteristic symptoms of stroke, seemed to be improved by the several pharmacological effects resulting from Ca2+antagonistic effects of S‐312‐d. These data suggests that S‐312‐d can prevent the deteriorating metabolic changes in

ISSN:0272-4391    

DOI:10.1002/ddr.430330103

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

年代:1994

数据来源: WILEY

摘要:

AbstractIndorenate is a 5‐HT1Areceptor agonist with antihypertensive properties. This study was aimed to determine if indorenate, like other 5‐HT1Areceptor agonists, may also interact with α‐adrenoceptors. Therefore, the effects of indorenate and 8‐hydroxy‐2‐(di‐n‐propylamino) tetralin (8‐OH‐DPAT; which has affinity for 5‐HT1Areceptors and, to a lesser extent, for α1‐adrenoceptors) on the blood pressure of pithed rats were compared. Both compounds produced dose‐dependent increases in blood pressure; 8‐OH‐DPAT was the most potent whereas indorenate produced a higher maximum effect. Metitepine (a mixed 5‐HT1/5‐HT2receptor antagonist), but not pindolol (a β‐adrenoceptor and 5‐HT1receptor blocker), antagonized the pressor responses produced by both agonists; only the pressor effects of 8‐OH‐DPAT, however, were antagonized by prazosin (an α1‐adrenoceptor antagonist). Interestingly, ketanserin (a 5‐HT2and α1‐adrenoceptor blocker) strongly antagonized the pressor responses to indorenate whereas only a slight inhibition of 8‐OH‐DPAT responses was observed. Further, in pithed rats intravenously infused with norepinephrine (NE), 8‐OH‐DPAT, but not indorenate, produced dose‐dependent hypotensive effects and both compounds were inactive in rats infused with quipazine. In conclusion, 8‐OH‐DPAT behaved as a partial agonist at α1‐adrenoceptors whereas indorenate produced pressor effects probably due to stimulation of 5‐HT2receptors. Thus, 8‐OH‐DPAT, but not indorenate, sh

ISSN:0272-4391    

DOI:10.1002/ddr.430330104

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

年代:1994

数据来源: WILEY

摘要:

AbstractThe analgesic effects of dipyrone and morphine administered either separately or in 24 different combination were determined in the “Pain‐Induced Functional Impairment in the Rat” (PIFIR analgesic model). This allowed the detection of the profile of analgesic interaction of the various combinations. Furthermore, the optimal degree of potentiation obtained with a specific combination of the above drugs was determined by means of the “Surface of Synergistic Interaction” (SSI) of the combinations. This parameter was calculated from the total analgesic effect produced by the combination after having subtracted the analgesic effect produced by each drug alone. Over the dose‐ranges used, the analgesic activities of either dipyrone or morphine tended to be smaller than those of their respective combinations. Furthermore, 11 combinations showed various degrees of potentiation (P<0.05), while the remainder (13) exhibited additive analgesic effects. The combination of dipyrone (562 mg/kg, sc) and morphine (5.6 mg/kg, sc) produced the maximum analgesic effect. However, dipyrone (178 mg/kg) with morphine (3.2 mg/kg) produced the highest potentiation effect (P<0.001). The surface of synergistic interaction clearly showed which combination of analgesic drugs produced the highest degree of potentiation in the rat. This represents the first study to show that a specific ratio of combination of analgesic drugs can produce an optimal potentiation of their analgesic effects. These findings may have important implications for the treatment of pain. © 1994 Wil

ISSN:0272-4391    

DOI:10.1002/ddr.430330105

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

年代:1994

数据来源: WILEY

摘要:

AbstractThe thrombolytic activity of a novel modified t‐PA analog, YM866, was compared with that of recombinant t‐PA (t‐PA) in rabbits with experimental jugular vein thrombosis. Thrombus was induced in an isolated segment of the jugular vein from a mixture of whole autologous blood and thrombin. Thirty minutes after the induction of thrombus, YM866 was administered by iv bolus injection, while t‐PA was given by the same method or by a 60‐min iv infusion. Thrombi were removed 70 min after iv bolus injection or 10 min after the termination of iv infusion, and thrombus size was measured by total protein content in the isolated thrombus. Both YM866 and t‐PA exhibited dose‐dependent thrombolysis; the thrombolytic activity of YM866, however, was 4 times greater than that of t‐PA. The improved thrombolytic activity of YM866 correlated with its relatively higher antigen levels in plasma, which result from its prolonged biological half‐life. Depletion of plasma fibrinogen to less than 20% of baseline levels was observed in all groups. Template bleeding time was not significantly altered in any group. These results suggest that YM866 offers the potential for clinical use in thrombolytic therapy by iv bolus injection for patients with venous thromboembolic diseases. © 19

ISSN:0272-4391    

DOI:10.1002/ddr.430330106

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

年代:1994

数据来源: WILEY

摘要:

AbstractCL 284,846, N‐[3‐3‐cyanopyrazolo[1,5‐a]pyrimidin‐7‐yl(phenyl)]‐N‐ethylacetamide, is a novel non‐benzodiazepine sedative‐hypnotic with benzodiazepine‐like sedative effects, but with less apparent liability for accompanying undesired side effects. Three metabolites of the parent sedative‐hypnotic have been isolated and identified, a desethyl metabolite, CL 284,859, a desethyl‐5‐keto metabolite, CL 345,644, and a 5‐keto metabolite, CL 345,905. In experiments to determine the ability of these compounds to displace [3H]‐flunitrazepam from rat cortical benzodiazepine receptors, the IC50values were 205 nM for CL 284,846 compared to 4.5 nM for diazepam as a positive control, and 11 μM for CL 284,859. The other two metabolite, CL 345,644 and CL 345,905, failed to displace [3H]‐flunitrazepam. In a second experiment designed to evaluate in vivo receptor‐mediated activity, CL 284,846 (3.0 mg/kg; 9.836 μmol/kg) was established as a discriminative stimulus (DS) in rats. While CL 284,846 (0.03ndash;3.0 mg/kg; 0.098–9.836 μmol/kg) showed a doserelated increase in drug‐appropriate responding and one dose of triazolam (0.3 mg/kg; 0.875 μmol/kg) substituted as a positive control, all three metabolites (3.0–100.0 mg/kg; 10.3–341.3 μmol/kg for CL 284,859; 6.0–201.2 μmol/kg for CL 345,644; 9.3–311.5 μmol/kg for CL 345,905) failed to substitute for the DS effects of CL 284,846. These results suggest that CL 284,859, CL 345,644, and CL 345,905, the metabolites of the sedative‐hypnotic CL 284,846, have no significant neuropharmacological effects at central benzodiazepine receptors and, thus, do not contribute to the

ISSN:0272-4391    

DOI:10.1002/ddr.430330107

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

年代:1994

数据来源: WILEY

摘要:

AbstractRifampicin, an anti‐tubercular drug, at 100 mg/kg (122 μmol) body weight (daily single ip injection for 6 days) caused changes in most of the biochemical parameters of the liver and serum in rats, 24 h after the last injection. These included significant increase in the activities of hepatic γ‐glutamyl transpeptidase, acid ribonuclease, acid phosphatase and decrease in the activity of succinate dehydrogenase. The levels of RNA, total proteins, bilirubin, total lipids, phospholipids, cholesterol, lipid peroxides in liver and bilirubin in serum increased while hepatic glycogen and serum proteins decreased. At a lower dose (50 mg/kg; 61 μmol/kg) the changes were less as compared to 100 mg/kg dose. When Picroliv (12 mg/kg body weight), a standardized iridoid glycoside mixture ofPicrorhiza kurroawas administered simultaneously with rifampicin, most of the biochemical changes in liver and serum were prevented. These results indicate protective effect of Picroliv against rifampicin‐induced hepatotoxicity in rats. © 1994 Wiley

ISSN:0272-4391    

DOI:10.1002/ddr.430330108

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

年代:1994

数据来源: WILEY

摘要:

AbstractBinding affinities of purine derivatives at A3adenosine receptors in different species were compared. Binding was carried out using the novel high affinity agonist ligand [125I]AB‐MECA (3‐iodo‐4‐aminobenzyladenosine‐5′‐N‐methyluronamide) in the presence of 1.0 μM XAC (8‐[4‐[[[[(2‐aminoethyl)amino]carbonyl]methyl]oxy]phenyl]‐1,3‐dipropylxanthin), an A1‐ and A2a‐adenosine antagonist. XAC was added to eliminate binding to non‐A3receptors. In rat brain membranes [125I]AB‐MECA exhibited saturable, specific binding with a Kdof 2.28 nM and a Bmaxof 43 fmol/mg protein. The affinity of [125I]AB‐MECA at the gerbil and rabbit brain A3‐receptors was similar to the rat, suggesting that the affinity of this agonist is not highly species dependent. The affinity of various xanthine derivatives was measured in [125I]AB‐MECA competition binding assays. Gerbil and rabbit brain A3‐receptors were similar in the affinity of antagonists whose potency order in both species was: BWA522 ≥ CPX>XCC, XAC, SPX, BWA1433>theophylline. The affinities of 8‐arylxanthines at the rat, rabbit, and gerbil brain A3receptors were considerably less than the previously reported affinities at cloned sheep and human A3receptors. Species differences in agonist affinity were assessed by comparing Kivalues at cloned rat brain A3receptors expressed in CHO cells with cloned sheep and human A3receptors. Human and rat brain A3receptors were highly similar in the relative affinities of agonists, and sheep brain A3receptors were unlike either human or rat A3recepto

ISSN:0272-4391    

DOI:10.1002/ddr.430330109

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

年代:1994

数据来源: WILEY

ISSN:0272-4391    

DOI:10.1002/ddr.430330110

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

年代:1994

数据来源: WILEY

ISSN:0272-4391    

DOI:10.1002/ddr.430330101

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

年代:1994

数据来源: WILEY