摘要:

AbstractIn vitro and in vivo studies of the actions of various antagonists and agonists of bradykinin (BK) B1and B2receptors have been reviewed and analyzed. It seems apparent that certain B2‐antagonists, such as [Thi5,8,D‐Phe7]‐BK and D‐Arg0‐[Hyp3,Thi5,8,D‐Phe7]‐BK will serve as valuable model substances for developing new anti‐inflammatory/analgesic drugs. Further development of B1‐antagonists, based on modifications of the structure of des‐Arg9,[Leu8]‐BK, or combined B1/B2‐antagonists might be useful in controlling disease states involving chronic tissue injury an

ISSN:0272-4391    

DOI:10.1002/ddr.430160102

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

年代:1989

数据来源: WILEY

摘要:

AbstractWe evaluated the effects of oral nisoldipine with or without propranolol on exercise‐induced myocardial ischemia in conscious pigs with a coronary artery stenosis. Treadmill‐running up to 4 km/hr increased cardiac output (90%), heart rate (90%), maxLVdP/dt (80%), left ventricular systolic (15%) and end‐diastolic (13±3 mmHg) blood pressures, while systolic wall thickening (SWT) of the poststenotic left ventricular myocardium was reduced from 29%±8% to 19%±6%. Nisoldipine neither affected the systemic hemodynamic profile during exercise nor the exercise‐induced reductions in SWT. Propranolol attenuated both the positive chronotropic and inotropic effects and the deterioration of wall function caused by the treadmill exercise. Combined treatment with the two drugs resulted in a cardiovascular profile similar to propranolol during exercise, but the loss of wall function was now completely prevented. We conclude that, unlike propranolol, nisoldipine alone was not effective against the exercise‐induced myocardial ischemia but, in combination with β‐adrenoceptor antagonists, nisoldipine may further decrease the exercise‐induced reductions in SWT of the postst

ISSN:0272-4391    

DOI:10.1002/ddr.430160103

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

年代:1989

数据来源: WILEY

摘要:

AbstractThe present study was undertaken to determine whether withdrawal from chlordiazepoxide administered via a liquid diet would produce a pentylenetetrazole (PTZ)‐like stimulus. Rats were trained with food reward in a two‐lever operant task. Presses on one lever were reinforced after injections of PTZ (20 mg/kg, i.p.) and on the other lever after saline (1 ml/kg, i.p.). After rats had acquired the PTZ discrimination, training was halted, and chlordiazepoxide (240 mg/kg/day) was administered via a nutritionally balanced liquid diet to three groups of rats for 3, 4, or 6 days. Upon termination of chronic administration, withdrawal was precipitated with the benzodiazepine receptor blocker flumazenil (Ro 15‐1788) given intraperitoneally. During precipitated withdrawal, the rats selected the PTZ‐appropriate lever, indicating the presence of a PTZ‐like stimulus, and this stimulus was blocked by phenobarbital (80 mg/kg, i.p.). The percentage of rats selecting the PTZ‐appropriate lever depended on the duration of chlordiazepoxide treatment and dose of flumazenil. At 10 days after the last chlordiazepoxide dose, the rats had recovered baseline discrimination, as indicated by their selection of the saline appropriate lever following saline injections and the PTZ‐appropriate lever following PTZ. These data indicate that a subjective effect of withdrawal similar to that produced by the anxiogenic drug PTZ is present during withdrawal from oral chl

ISSN:0272-4391    

DOI:10.1002/ddr.430160104

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

年代:1989

数据来源: WILEY

摘要:

AbstractOral administration of MDL 19,301 (N‐(1,3‐dithiolan‐2‐ylidene)‐4‐hexyl‐benzenamine) inhibited rat paw edema induced by carrageenan (ED30 4.8 mg/kg) or an Arthus reaction (ED30 8.2 mg/kg p.o.). The oral dose which induced gastric ulceration in 50% of fasted rats (UD50) was greater than 1,000 mg/kg, demonstrating a more favorable therapeutic ratio than conventional nonsteroidal anti‐inflammatory agents. Its major metabolite ((MDL16,861, 4[1,3‐dithiolan‐2‐yliden)amino]‐benzeneacetic acid) was also a potent inhibitor of carrageenan paw edema (ED50 5.5 mg/kg p.o.), although it was more ulcerogenic (UD50 52 mg/kg p.o.). The anti‐inflammatory activity of MDL 19,301, but not that of MDL 16,861, was attenuated by co‐administration of an inhibitor of drug metabolism (SK&F525A 30 mg/kg i.p.). This suggests that MDL 19,301 is a prodrug of MDL 16,861 and this phenomenon would explain its lack of ulcerogenicity. Additional anti‐inflammatory properties of MDL 19,301 included inhibition of carrageenan pleurisy, adjuvant arthritis, and acetic‐acid‐induced writhing. Other pharmacological data indicate that MDL 19,301 administration results in inhibition of prostaglandin synthesis; inhibition of arachidonic‐acid‐induced, but not prostaglandin‐E2‐induced, diarrhea in mice; and inhibition of ex vivo arachidonic‐acid‐induced, but not adenosine‐diphosphate‐induced, rat platelet aggregation. MDL 19,301 and MDL 16,861 were unexpectedly weak antipyretic agents in rats. In summary, MDL 19,301 is an anti‐inflammatory, analgesic prodrug which, unlike conventional agents, is

ISSN:0272-4391    

DOI:10.1002/ddr.430160105

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

年代:1989

数据来源: WILEY

摘要:

AbstractTwo cellular model systems for the in vitro study of biochemical and pharmacological effects of new β‐adrenergic compounds were compared: the human neutrophilic polymorphonuclear leukocyte and the hamster white fat tissue adipocyte. The adipocyte β‐adrenoceptor governing the physiological response is atypical in nature, whereas neutrophils seem to have a homogeneous β2‐adrenoceptor population. Both model systems have their own advantages, but as far as pharmacological characterisation is concerned, the β2‐adrenoceptor of neutrophils is far more sensitive and this model system is an obvious choice for the comparison of, for example, isomers. The differentiation between R 67 138 and R 67 145, optical isomers of the β‐adrenoceptor antagonist nebivolol (R 67 555), is 20 times larger on neutrophils than on adipocytes. Some broader applications of both systems

ISSN:0272-4391    

DOI:10.1002/ddr.430160106

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

年代:1989

数据来源: WILEY

摘要:

AbstractThe in vivo effects of irindalone, a newly developed serotonin2(5‐HT2) antagonist, have been investigated in comparison with a series of reference compounds. Irindalone potently antagonizes the pressor response induced by 5‐HT in pithed rats, but has a 173 times weaker effect against the α1‐adrenoceptor agonist phenylephrine. Irindalone is relatively weak in rat models detecting central 5‐HT2antagonism, that is, inhibition of quipazine‐ or I‐5‐HTP plus citalopram‐induced head twitches, inhibition of I‐5‐HTP plus citalopram‐induced increases of flexor reflexes, and inhibition of the discriminative stimulus properties induced by d‐LSD. Furthermore, it displaces in vivo3H‐ketanserin binding in frontal cortex. Irindalone weakly antagonizes the flexor reflex stimulated by the α1‐adrenoceptor agonist St 587. No dopamine receptor inhibition is detected in the methylphenidate gnawing test in mice. High bioavailability is indicated by the identical ED50values obtained in the head twitch model after s.c. and p.o. administration. The activity profile of irindalone resembles that of ketanserin except in two characteristics: ketanserin has greater potency than irindalone as an antagonist in the 5‐HTP‐induced flexor reflex, but has a shorter duration of action. The effect of irindalone is stereoselective, since its opposite enantiomer Lu 21‐099 is almost inactive in the models for central and peripheral 5‐HT2receptor antagonism. Finally, the effect of repeated treatment with irindalone (18 μmol/kg, p.o., twice daily for 2 weeks) on inhibition of quipazine‐induced head twitches was studied. Two days after the last dose, the potency for inhibiting quipazine was unchanged, indicating that no tolerance to 5‐HT2receptor antagonism develops using this dose regimen. It is concluded that irindalone is a potent 5‐HT2antagonist w

ISSN:0272-4391    

DOI:10.1002/ddr.430160107

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

年代:1989

数据来源: WILEY

摘要:

AbstractSK&F 85174 is a mixed DA‐1/DA‐2 receptor agonist which is shown to inhibit sympathetic neurotransmission and cause hypotension in anesthetized animals. In this study, we have determined the regional and systemic hemodynamic effects of an intravenous infusion of SK&F 85174 (5 μg/kg/min for 5 min) in pentobarbital‐anesthetized dogs and attempted to identify the dopamine receptor subtype(s) involved in the cardiac as well as vascular effects of this compound. SK&F 85174 produced significant decreases in mean blood pressure (MBP), left ventricular pressure (LVP), left ventricular dp/dt, total peripheral resistance (TPR) and renal vascular resistance (RVR), and a significant increase in renal blood flow (RBF). There were no significant changes in heart rate, cardiac output, coronary blood flow, or coronary vascular resistance. Prior treatment with SCH 23390 (DA‐1 receptor antagonist) significantly attenuated the effects of SK&F 85174 on MBP, LVP, TPR, RBF, and RVR. In a second group of dogs S‐sulpiride (DA‐2 receptor antagonist) significantly antagonized the effects of SK&F 85174 on MBP, LVP, and dp/dt, but did not influence its effects on RBF, TPR, and RVR. These results show that (a) a decrease in total peripheral resistance and not the cardiac output accounts for the hypotensive action of SK&F 85174, (b) the renal hemodynamic effects of SK&F 85174 are mediated primarily via the activation of DA‐1 receptors, and (c) whereas DA‐1 receptors are involved primarily with the hypotensive action of this compound, it appears that activation of DA‐2 receptors also contributes

ISSN:0272-4391    

DOI:10.1002/ddr.430160108

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

年代:1989

数据来源: WILEY

摘要:

AbstractRimcazole (BW234U), a substituted carbazole compound, has been reported to be effective in treating acutely ill schizophrenic patients without significant extrapyramidal side effects. A two‐phase study was done to assess the efficacy and safety of rimcazole in the maintenance treatment of schizophrenia. Study I was a double‐blind comparison of rimcazole (50–300 mg daily) with haloperidol (5–30 mg daily) with ten stable schizophrenic outpatients. Three of six patients relapsed on rimcazole, while there were no relapses on haloperidol. One patient dropped out of each group. Extrapyramidal side effects were minimal in the rimcazole group, and two patients with tardive dyskinesia showed marked improvement in AIMS Scores. Study II was an open label trial of rimcazole using a higher maximum dose of 450 mg daily in seven schizophrenic outpatients. Four of the seven patients relapsed, at a mean of 7 weeks, one dropped out, and two patients remained stable. While the drug was generally well tolerated, both of the nonrelapsing patients developed transient elevations in liver transaminases. The small sample size in these studies prevents definitive conclusions to be drawn. There may be subgroups of schizophrenic patients who can be successfully maintained on rimcazole with less morbidity than from standard neurolepti

ISSN:0272-4391    

DOI:10.1002/ddr.430160109

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

年代:1989

数据来源: WILEY

摘要:

AbstractCompounds of various pharmacological and chemical classes were studied for their interaction with methohexital hypnosis. Rats were treated daily for 5 days with an oral dose of a test compound or solvent. On days 1, 5, and 8 methohexital was injected intraperitoneally and the duration of hypnosis was measured. Three types of interaction with methohexital hypnosis were observed. Acute prolongation of hypnosis on day 1 was the most marked effect of fluconazole (median effective dose, ED50: 8.66 mg/kg), but this occurred also with phenobarbital (ED50: 26.4 mg/kg) and diphenylhydantion (ED50: ∼ 160 mg/kg). Tolerance to prolongation, i.e., a decrease of the hypnosis time by more than 50% from day 1 to day 5, was most marked with phenobarbital (ED50: 12.6 mg/kg) and diphenylhydantion (ED50: 113 mg/kg) but was also found with fluconazole (ED50: 22.6 mg/kg). Shortened hypnosis times on day 8 occurred with phenobarbital (ED50: ∼ 40.0 mg/kg) and diphenylhydantoin (ED50: ∼ 160 mg/kg). The antimycotic itraconazole, the antidiarrheal loperamide, the thymosthenic agent ritanserin, and the antiallergics astemizole and levocabastine were devoid of interactions with methohexital. When compared with the basic activity of the tested compounds in rats, interference with methohexital hypnosis was most pronounced with phenobarbital (ratio 3.13) followed by fluconazole (ratio: 3.28) and diphenylhydantoin (ratio:

ISSN:0272-4391    

DOI:10.1002/ddr.430160110

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

年代:1989

数据来源: WILEY

ISSN:0272-4391    

DOI:10.1002/ddr.430160101

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

年代:1989

数据来源: WILEY