Pharmacological studies of antipsychotic drug, penfluridol. 2. General pharmacological properties]

General pharmacological properties of penfluridol (TLP-607) a long-acting antipsychotic drug, were examined in experimental animals and the following results were obtained. 1) TLP-607 produced a lowering of arterial blood pressure and bradycardia but had almost no effect on respiration and peripheral blood flow. 2) TLP-607 slightly hypertension induced by dopamine, adrenaline and noradrenaline, but had no effect on hypotension induced by acetylcholine and histamine. 3) Antagonistic actions of TLP-607 on such spasmogens as acetylcholine, histamine and barium chloride were slightly stronger than those of haloperidol and chlorpromazine. 4) TLP-607 had neither ganglionic nor neuromuscular blocking action. 5) TLP-607 had a slight or no effect in the following experiments; protection against stomach ulcer, activity of ileum and uterus in vivo and in vitro, urinary volume and electrolytes excretion, and gastro-intestinal propulsion. These results suggest that TLP-607 has no striking peripheral actions in experimental animals.     

Denzimol, a new anticonvulsant drug. II. General pharmacological activities

The paper reports on the pharmacological properties of N-[beta-[4-(beta-phenylethyl)phenyl]-beta-hydroxyethyl]imidazole hydrochloride (denzimol, Rec 15-1533), a compound endowed with anticonvulsant properties, and its possible side effects. Effects on the CNS, effects on vigilance and general motility are similar to those of phenytoin and occur at doses much above anticonvulsant levels. The drug has good in vitro antihistamine, anticholinergic and anti-5-HT activity which accounts for the effects on the gastrointestinal system e.g. inhibition of gastric secretion and motility and anti-ulcer properties. There was no significant effect on the cardiovascular system or respiration, except an interesting antiarrhythmic activity.     

Pharmacological studies on a new benzamide derivative, YM-09151-2, with potential neuroleptic properties

The electrophysiological properties and cataleptogenicity of YM-09151-2 (N-[(2RS, 3RS)-1-benzyl-2-methyl-3-pyrrolidinyl]-5-chloro-2-methoxy-4-methylaminobenzamide) were studied in the cat. This drug inhibited the EEG arousal response to electrical stimulation of the mesencephalic reticular formation with the same potency as that of haloperidol, whereas chlorpromazine revealed a more potent central depressant action. The duration of the afterdischarge induced by electrical stimulation of the amygdaloid nucleus was initially shortened and thereafter prolonged by both YM-09151-2 and haloperidol. However, YM-09151-2 was less effective than haloperidol and chlorpromazine in both augmenting the spindle bursts produced by electrical stimulation of the caudate nucleus and antagonizing the inhibitory effect of L-DOPA on the caudate spindle, indicating a smaller effect of YM-09151-2 on the extrapyramidal dopaminergic system than that of the two neuroleptic drugs. In fact, YM-09151-2 produced no cataleptic behaviour in the cat even at a dose of 5 mg/kg (s.c.), although haloperidol and chlorpromazine caused catalepsy in doses of 0.5 and 5 mg/kg (s.c.), respectively. Sulpiride, chemically related to YM-09151-2, showed much weaker central actions than YM-09151-2. The results indicate that a new benzamide, YM-09151-2, has a potent neuroleptic effect with a slight central depressant activity and that the cataleptogenicity of the compound is weaker than that of haloperidol and of chlorpromazine.     

An electroencephalographical study on timiperone, a new antipsychotic drug

This investigation was undertaken to analyze the EEG synchronizing effects of timiperone in cats. The effects of timiperone on the brain-stem reticular and hypothalamic activating system, diffuse and specific thalamic projection system, and caudate spindle were investigated by the electroencephalographic method. Timiperone produced a weak inhibition of EEG arousal response induced by electrical stimulation of the sciatic nerve almost without affecting that which was induced by stimulation of the mesencephalic reticular formation. Furthermore, timiperone suppressed the activation of neocortical EEG in response to stimulation of the posterior hypothalamus more selectively than that of limbic EEG. Neither the recruiting response to stimulation of the centro-median nucleus of the thalamus nor the augmenting response to stimulation of the ventro-postero-lateral nucleus of the thalamus was modified by timiperone. In addition, timiperone significantly potentiated the caudate spindle. The EEG effects of haloperidol were qualitatively similar to those of timiperone. These results indicate that the synchronizing effect of timiperone may be mediated by a suppression of an ascending reticular activating system and may influence the conscious levels and sleep-wakefulness cycle in cats.     

Pharmacological properties of new neuroleptic compounds.

RMI 61 140, RMI 61 144 and RMI 61 280 are newly synthetized N-[8-R-dibenzo(b,f)oxepin-10-yl]-N'-methyl-piperazine-maleates which show interesting psychopharmacologic effects. This work contains the results of a study performed with these three compounds, in order to demonstrate their neuropsycholeptic activity in comparison with chloropromazine (CPZ) and chlordiazepoxide (CPD). The inhibition of motility observed in mice shows that the compounds reduce the normal spontaneous motility as well as the muscle tone. The central-depressant activity is evidenced by increased barbiturate-induced sleep and a remarkable eyelid ptosis can also be observed. Our compounds do not show any activity on electroshock just as do CPZ and CPD. As to the antipsychotic outline, our compounds show strong reduction of lethality due to amphetamine in grouped mice and a strong antiapomorphine activity. They show also an antiaggressive effect and an inhibitory activity on avoidance behaviour much stronger than CPZ. We have also found extrapyramidal effects, as catalepsy, common to many tranquillizers of the kind of the standards used by us. As for vegetative phenomena, the compounds show hypotensive dose related action ranging from moderate to strong, probably due to an a-receptor inhibition. Adrenolytic activity against lethal doses of adrenaline, antiserotonin and antihistaminic effects, as well as other actions (hypothermia, analgesia, etc.) confirm that RMI 61 140, RMI 61 144 and RMI 61 280 are endowed with pharmacologic properties similar and more potent than those of CPZ. Studies on the metabolism of brain catecholamines show that they are similar to CPZ, although with less effect on dopamine level.     

Pharmacological properties of taglutimide, a new sedative-hypnotic drug

2-[Bicyclo(2,2,1)heptane-2-endo-3-endo-dicarboximido]-glutarimide (taglutimide, K-2004) proved to be a new sedative-hypnotic drug which did not produce any toxic effects when administered orally to mice even at a very high dosage. Central-nervous depression was demonstrated by a reduction in spontaneous motor activity, potentiation of the central-depressant effect of pentobarbital, antagonism of the central-stimulant effect of amphetamine after oral administration and by narcotic activity after i.v. administration of the drug. Furthermore, oral administration of taglutimide potentiated the analgesic action of morphine without being effective on its own. Only weak potentiation of chlorpromazine-induced catalepsy, but not of reserpine-induced catalepsy was observed after taglutimide pretreatment. The drug influenced neither motor co-ordination nor the toxicity of ethanol. Taglutimide exhibited no anticonvulsant activity with respect to maximum electroshock or strychnine-induced seizures. No effect on heart rate or blood pressure was demonstrable after taglutimide treatment in conscious dogs.     

Pharmacological properties of a new non-steroidal anti-inflammatory drug: flunoxaprofen

The anti-inflammatory, analgesic and antipyretic activities of S-(+)-2(4-fluorophenyl)-alpha-methyl-5 benzoxazole acetic acid (flunoxaprofen: Flu), a new non-steroidal anti-inflammatory drug, were compared with those of indomethacin and other non-steroidal anti-inflammatory drugs (NSAIDs) in experimental animals. Flu showed strong inhibitory activity on acute and subacute inflammation tests in rats, such as carrageenin hind paw oedema (oral: 6-25 mg/kg; rectal: 50-100 mg/kg); pellet-induced granuloma formation (5-20 mg/kg/day) and adjuvant-induced arthritis (10 mg/kg/day). Its potency was comparable with that of indomethacin (I) and higher than that of acetyl salicylic acid (ASA), ibuprofen (IBU) or phenylbutazone (P). The analgesic activity of Flu, evaluated by the hot plate method and tail pinching in mice, was slightly lower than that of I but higher than that of ASA and IBU. In pyretic rabbits Flu showed an antipyretic activity higher than that of ASA and IBU. The ability of Flu to affect platelet aggregation, mucopolysaccharide synthesis by fibroblasts and the proteolytic action of trypsin was also investigated.     

Effect of timiperone, a new antipsychotic drug, on the sleep-wakefulness cycle in cats

The effect of timiperone, a new antipsychotic drug, on the sleep-wakefulness cycle in cats was assessed by EEG, EMG and eye movement potential. Timiperone (0.03 to 0.3 mg/kg, i.p.) dose-dependently increased the slow wave sleep (SWS) time and decreased the paradoxical sleep (PS) time. Further, the onset of the first period of PS was delayed, and the number of PS phases tended to be decreased after the 0.3 mg/kg dose. These results suggest that the neurological control of the cerebral dopaminergic system might be at least in part attributable to the effect of timiperone on sleep mechanisms.     

Pharmacological properties of buprenorphine, a new analgesic agent. Part II. (author's transl)

Pharmacological properties of buprenorphine were compared with those of morphine and pentazocine. Buprenorphine scarcely showed any effects on spontaneous EEGs and sleep-wakefulness cycles. Buprenorphine tended to depress the recruiting and augmenting responses and the spindle burst, and it also inhibited the hypothalamic arousal response. Buprenorphine had weaker emetic action than morphine and protected against apomorphine-induced emesis in the same manner as morphine. Buprenorphine scarcely affected respirations, blood pressure, heart rate, blood flow, ECG, cardiac contractile force, cornary flow, and intracranial pressure. However, morphine and pentazocine caused depressed respiration, decreased blood pressure, increased blood flow and cardiac contractile force, and elevated intracranial pressure. Buprenorphine, morphine, and pentazocine did not affect bile secretion, but produced contraction of the sphincter of Oddi. Buprenorphine had very little effect on renal function, but morphine and pentazocine reduced this function to depress urine flow. Buprenorphine and morphine inhibited carrageenin-induced edema. Buprenorphine had no effect on blood histamine level, but morphine increased the concentration of histamine. These results indicate that buprenorphine has little effect on the central nervous system, respiratory and cardiovascular system, and renal function.     

Some clinical pharmacological studies with terfenadine, a new antihistamine drug.

1 A double-blind cross-over trial between placebo, chlorpheniramine, and terfenadine, a new antihistamine drug, was performed in healthy male volunteers to determine and compare their CNS and autonomic effects. 2 Terfenadine and chlorpheniramine were administered orally in therapeutic doses. 3 In objective tests of critical flicker frequency, pursuit rotor, reaction time, salivary volume and pupillary diameter, no statistically significant difference was observed between the treatments. 4 On analogue rating scales, chlorpheniramine produced a statistically significant (P less than 0.05) degree of sedation and impaired concentration as compared to placebo and terfenadine. 5 The results obtained in analogue rating scales were not normally distributed and, therefore, use of non-parametric statistical methods for analysis of such data is strongly advocated.     

General pharmacological properties of YJA20379-2, a new antiulcer agent

The general pharmacological properties of YJA20379-2 2-dimethylamino-4,5-dihydrothiazolo[4,5:3,4]pyridol[1,2-a]++ +benzoimidazole, a novel proton pump inhibitor with antiulcer activities were investigated in mice, rats, guinea pigs and rabbits. YJA20379-2 at oral doses of 50, 100 and 200 mg/kg did not affect the general behaviour, hexobarbital hypnosis and motor coordination in mice. The drug did not have analgesic or anticonvulsant action at 200 mg/kg. Locomotor activity and body temperature were not influenced at 100 mg/kg. At a concentration up to 2 x 10(-4) g/ml, YJA20379-2 did not produce any contraction or relaxation of isolated preparations, such as the rat fundus, the guinea pig ileum and the rat uterus, and did not antagonize the contractile response to several spasmogens, such as histamine, acetylcholine, serotonin and oxytocin. At dosages up to 200mg/kg p.o. YJA20379-2 did not affect the pupil size of mice. Intestinal propulsion of mice was not affected up to 200 mg/kg p.o. and the drug did not affect urinary excretion at 100 mg/kg p.o. These results indicate that at dosages up to 100 mg/kg p.o. YJA20379 was found not to affect this pharmacological profile. However, at 200 mg/kg the drug lowered body temperature and showed decreases in locomotor activity and urine volume.