The effect of a new calcium antagonist, TA3090 (clentiazem), on experimental transient focal cerebral ischemia in cats.

BACKGROUND AND PURPOSE: TA3090 (Clentiazem) has been shown to have cerebrovascular protective properties in three experimental studies. An in vivo investigation was undertaken to determine its effects on pial arteries and cerebral blood flow and its therapeutic value in transient focal cerebral ischemia. METHODS: This experiment was divided into two protocols. In the first, 200 or 400 micrograms/kg per hour TA3090 was administered continuously for 3 hours in cats without ischemic insult (n = 6 for each group). The effects on pial arteries and cerebral blood flow were estimated. In the second protocol, 400 micrograms/kg per hour TA3090 (treated group, n = 14) or physiological saline (control group, n = 10) was administered 5 minutes before 1 hour of middle cerebral artery occlusion in cats. The effects on the pial arteries and cerebral blood flow were observed continuously, followed by autoradiography for a quantitative measurement of cerebral blood flow 5 hours after middle cerebral artery recirculation. The volumes of the cerebral edema and infarct were estimated by planimetry from cerebral preparations made for histological examination. RESULTS: Pial arteries dilated by up to approximately 10% in the 400-micrograms group and 3% in the 200-micrograms group 30 minutes after administration of TA3090. Increases in cerebral blood flow of about 10% in the 400-micrograms group and 2% in the 200-micrograms group were demonstrated with laser Doppler flowmetry. In the second protocol, dilatation of pial arteries was significantly smaller during and after the ischemic insult in the treated group compared with the control group (p < 0.01). Cerebral blood flow decreased less significantly during ischemia (p < 0.01 at the end of ischemia) and increased less significantly after ischemia (p < 0.01 at the end) in the treated group compared with the control group. Autoradiography showed a more remarkable increase in cerebral blood flow due to luxury perfusion in the cerebral cortex, which was mainly perfused by the middle cerebral artery on the affected side in the control group (p < 0.01). Cerebral blood flow in the cerebral cortex, thalamus, and caudate nucleus on the contralateral side of the treated group increased by about 20% more than that of the control group (p < 0.05). Cerebral edema and infarction were much smaller in the treated group than in the control group (p < 0.01). CONCLUSIONS: 1) TA3090 dilates pial arteries and increases cerebral blood flow in normal brain regions in a dose-response fashion; 2) in ischemic regions compared with those in untreated animals, TA3090 results in a lesser reduction of cerebral blood flow during ischemia and in a lesser degree of hyperemia during reperfusion; 3) TA3090 is associated with less pial artery dilatation during ischemia, presumably due to improved collateral flow; and 4) the improved hemodynamic state with TA3090 is associated with significant reduction of cerebral edema and infarct size.

Pharmacological study of nicergoline. Effects on regional cerebral blood flows and arterial carbon dioxide and oxygen pressure and pH in rats under cyanide-induced histotoxic anoxia.

1. Effects of nicergoline (CAS 27848-84-6) and two alpha-adrenoceptor antagonists on changes in the regional frontal cortex and brainstem blood flow (rFCBF and rBSBF), as determined by the hydrogen clearance method, PaCO2, PaO2 and pHa, were studied in immobilized and ventilated rats under KCN-induced histotoxic anoxia. In the control group of rats in the early anoxic phase 3 min after the injection of a sublethal dose of KCN (3 mg/kg i.v.), rFCBF became markedly decreased, and was associated with a fall in PaCO2, a rise in PaO2 and an elevation in pHa (metabolic alkalosis); but rBSBF remained unchanged. Twenty to 30 min after KCN, the lowered PaCO2 and the raised PaO2 returned to pre-KCN levels, but pHa declined markedly (metabolic acidosis). During this recovery period, the marked increases in both rFCBF and rBSBF were produced. These anoxic changes disappeared 60 min after KCN. Nicergoline (8 and 32 micrograms/kg i.v.) improved the lowered PaCO2, the raised PaO2 and the metabolic alkalosis, and also prevented the marked decrease of rFCBF in the early anoxic phase. The drug also promoted recovery of the raised PaO2, improved the metabolic acidosis, and prevented the marked increases in rFCBF and rBSBF during the recovery period. These effects of nicergoline as well as those of dihydroergotoxine (32 and 128 micrograms/kg, i.v.) were dose-dependent. Phentolamine (128 micrograms/kg i.v.), however, did not affect the anoxic changes in rFCBF, rBSBF, or the above humoral factors after KCN.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacological effects of nicergoline and its metabolites, decomposition products and impurities in animals.

The main pharmacological effects and acute toxicity of nicergoline (NCG, ester type), its 5 metabolites [1-DN (ester type), 1-MMDL, 1-OHMMDL, MDL (ergoline-alcohol type) and 5-BNA (bromonicotinic acid)], 2 decomposition products (1-MMDL and 5-BNA) and 2 impurities [1-DN and 5-CN (ester type)] were studied in animals. In mice, the acute intraperitoneal toxicity of 1-MMDL, 1-OHMMDL and 5-CN was similar to that of NCG (LD50 197.6 mg/kg). The toxicity of 1-DN, MDL and 5-BNA was approximately 2-fold, 2- fold and one half of NCG, respectively. These substances caused no delayed death. In protective effects against KCN- and adrenaline-induced death in mice when given i.p., 1-DN and 1-MMDL were less potent than NCG, and 1-CN was similar in potency to NCG. In competitive inhibitory effects on phenylephrine-induced contraction of isolated guinea pig vas deferens, 1-DN was less potent, 1-MMDL was much less potent and 5-CN was more potent than NCG. In an inhibitory effect on collagen-induced platelet aggregation in vitro using rat platelet-rich plasma, 1-DN and 5-CN were similar in activity to NCG and 1-MMDL was less active than NCG. On the other hand, 1-OHMMDL, MDL and 5-BNA were inactive in these experiments. In experiments on gross behavior, motor function and barbital anesthesia using mice, when given i.p., 5-CN as well as NCG moderately induced depressive effects on the central nervous systems. 1-DN and 1-MMDL were less potent in the effects than NCG. In anesthetized rats, when given i.v., 1-DN and 5-CN dose-dependently caused lowering effects on blood pressure similar to NCG. 1-MMDL and 1-OHMMDL were less potent than NCG in the lowering effect. 1-DN and 5-CN moderately decreased the contractile force in the isolated guinea pig heart when given i.a. 5-CN alone decreased urine volume in rats when given i.p. and all the substances had no effect on the intestinal transit ability in mice when given i.p. These results suggest that the pharmacological effects of NCG are due to NCG per se and in part to its metabolites. As regards structure-activity relationships, NCG, 1-DN and 5-CN with an ester linkage were found to be more potent in pharmacological activities than ergoline-alcohol compounds.(ABSTRACT TRUNCATED AT 400 WORDS)

[Pharmacological study of nicergoline. (III). Effects on cerebral and peripheral circulation in animals].

Effects of nicergoline on the cerebral and peripheral circulation were compared with those of dihydroergotoxine (DHE) and papaverine (PAP) in anesthetized and/or immobilized cats. The i.a. injection of nicergoline (0.032 approximately 32 micrograms/kg), similarly to PAP, caused dose-dependent increases in intramaxillary artery (as the human intracarotid artery) blood flow (IMBF) and femoral artery blood flow, but the injection of DHE had no effect on these blood flows. The i.v. injection of nicergoline (32 approximately 128 micrograms/kg) caused a dose-dependent fall in blood pressure (BP) and a transient slight decrease in cerebral vascular resistance, but did not affect IMBF, regional cerebral blood flow (r-CBF), intracranial pressure (ICP) and heart rate (HR). The i.v. injection of DHE produced a slight fall in BP and a marked long-lasting decrease in HR, without affecting other parameters. The i.v. injection of PAP (4 mg/kg) induced marked increases in IMBF, r-CBF, ICP and HR and caused a transient fall followed by a marked elevation in BP. The p.o. administration of nicergoline (0.06 approximately 4 mg/kg) caused a dose-dependent fall in BP and selective inhibition of pressure response to adrenaline (ID50: 0.25 mg/kg). The administration of DHE produced marked inhibition of pressure responses to both adrenaline and noradrenaline, accompanied with a slight fall in BP. Furthermore, the administration of nicergoline (3 approximately 100 mg/kg) induced a dose-dependent fall in BP in SHR. These results suggest that the cerebral and peripheral circulatory effects of nicergoline may be due to direct vasodilating action and alpha-blocking action in the animals.

[Pharmacological study of nicergoline. (II). Protective effect on ischemic brain damages in animals].

Effects of nicergoline on ischemic brain damages induced by bilateral carotid arterial ligation (BCAL) in ICR-strain mice and mongolian gerbils and lipid peroxide formation (LPOF) in normal brain homogenate of rats were compared with those of dihydroergotoxine (DHE). In mice, nicergoline (16 mg/kg, i.p.) significantly reduced the cumulative mortality rate after BCAL (from 80-83% in the control to 50-55%). In gerbils, nicergoline (32 mg/kg, i.p.) significantly prolonged the mean onset time of ischemic seizure following recirculation after the 30-min BCAL (from 45.8 min in the control to 94.9 min). DHE also showed protective effects in these animals. In the ischemic brain of mice, marked decreases of creatine-P, ATP, glucose and glycogen; a remarkable increase of lactate; and elevation of L/P ratio were observed 1 to 10 min after BCAL. Nicergoline (16 mg/kg, i.p.) slightly prevented these decreases and significantly suppressed the increase of lactate and the elevation of L/P ratio 2 min after BCAL. The inhibitory action of nicergoline (20-100 microM) on LPOF is more potent than those of alpha-tocopherol and DHE. These results suggest that nicergoline may have protective effects against ischemic brain damages due to its ameliorating action on cerebral energy metabolism and partially due to its inhibitory action of LPOF.

[Pharmacological study of nicergoline. (I): Protective effect against anoxic brain damages in animals].

The protective effects of nicergoline (NCG) against anoxic brain damages in animals were compared with those of dihydroergotoxine (DHE) and phentolamine (PTA). NCG (16 mg/kg, i.p.) prolonged the survival time of mice under hypobaric hypoxia, but DHE and PTA shortened the time. NCG (1-16 mg/kg, i.p. and 16-64 mg/kg, p.o.), like DHE, dose-dependently prolonged the survival time of mice after a lethal dose of KCN (3 mg/kg, i.v.), but PTA did not. NCG (8-128 micrograms/kg, i.v.), like DHE, dose-dependently protected against disappearance of EEG of rats in histotoxic anoxia induced by a sublethal dose of KCN (1.5 mg/kg, i.v.), but PTA did not. Its protective effect was 10 times or more stronger than that of DHE. NCG (1-16 mg/kg, i.p.) dose-dependently promoted recovery from behavioral disorders and disturbance of cerebral energy metabolism of mice in histotoxic anoxia induced by a sublethal dose of KCN (1.8 mg/kg, i.v.). NCG (100 microM), like DHE, showed antagonistic action against inhibition of cerebral cytochrome oxidase activity by KCN, but PTA did not. The ED50 values of NCG, DHE and PTA for the protective effect against adrenaline-induced death in mice were 1.18, 0.27 and 0.35 mg/kg (i.p.), respectively. 7) These results suggest that NCG may show protective effects against the anoxic brain damages due to its ameliorating action on cerebral energy metabolism, mainly contributed by an activation of cerebral cytochrome oxidase, without relation to its alpha-blocking action.

[Pharmacological studies of an antipschotic agent, penfluridol. (1). The central pharmacological actions].

Neuropharmacological properties of penfluridol (TLP-607) were investigated in experimental animals and were compared with those of haloperidol and chlorpromazine. Locomotor activity of mice significantly decreased at doses of 16-32 mg/kg p.o. Like haloperidol and chlorpromazine, TLP-607 (4-16 mg/kg p.o.) demonstrated catalepsy lasting for 48-72 hr in rats. TLP-607 strongly inhibited apomorphine-induced emesis in dogs and the ED50 was 0.016 mg/kg p.o. This effect lasted for 192 hr when administered 0.04 mg/kg p.o. TLP-607 antagnonized methamphetamine-induced stereotyped behavior in rats, and the ED50 was 1.83 ng/kg p.o. TLP-607 also inhibited conditioned avoidance responses in rats, and the ED50's in the pole climbing and Sidman avoidance methods were 6.73 and 3.4 mg/kg p.o., respectively. TLP-607 neither inhibited motor coordination nor enhanced hexobarbital-induced anesthesia in mice. These results suggest that TLP-607 is a potent and long-acting antipsychotic drug which has less neurotoxic side-effects.

Effects of penfluridol and other drugs on apomorphine-induced stereotyped behavior in monkeys.

The effects of some drugs on apomorphine-induced stereotyped behavior were studied in male cynomolgus monkeys. Apomorphine produced the dose-dependent stereotyped behavior characterized mainly by continuous licking and biting, and repetitive movements of the hands, head and body in the monkeys. Penfluridol as well as haloperidol showed a clear antagonistic effect on the apomorphine-induced stereotyped behavior, while chlorpromazine was less antagonistic than haloperidol. The antagonistic effect of penfluridol lasted longer than that of haloperidol. Reserpine did not inhibit the apomorphine-induced stereotyped behavior though the drug elicited markedly the behavioral depression and alpha-methyl-p-tyrosine also did not block the stereotyped behavior. Nialamide did not depress the apomorphine-induced stereotyped behavior. In provoking the stereotyped behavior in monkeys, apomorphine probably acts directly on dopamine receptors in the extrapyramidal system, and penfluridol is suggested to act as a dopamine receptor blocker with a long action. The results indicate that protection against apomorphine-induced stereotyped behavior in monkeys may be a useful method for evaluating neuroleptic drugs.

Effects of psychotropic drugs on methamphetamine-induced behavioral excitation in grouped mice.

When 7 mice injected with methamphetamine (5 mg/kg, s.c.) were placed together into a box with a limited space maintained at 28-30 degrees C, the grouped mice showed extreme behavioral excitation consisting of 2 typical features: fighting behavior with squeak and hyperactive behavior characterized by running and jumping. The effects of various drugs tested, according to the minimal effective doses (mg/kg, p.o.) which inhibited fighting behavior and hyperactive behavior respectively, were: haloperidol, 0.1 (fighting)--0.25 (hyperactivity); clothiapine, 1 - 1; perphenazine, 1 - 1; thiothixene, 1 - 5; chlorpromazine, 5 - 10; diazepam, 5 - 100; reserpine, 100 - 100; phenoxybenzamine, 200 - 200 (no effect). Major tranquilizers except rauwolfia alkaloids completely inhibited both types of excited behavior at low doses, as compared with the taming effects of the drugs on footshock-induced fighting episodes in pairs of mice. On the other hand, minor tranquilizers suppressed only fighting behavior, showing little effect on hyperactive behavior. None of the antidepressants, adrenergic blocking agents and other drugs showed antagonism to both types of excited behavior. The results indicate that this method may be useful for the evaluation of psychotropic drug effects in grouped mice.