Hemoglobin and cytochrome P-450 have in common heme structure (i.e. protoporphyrin IX), binding ability to molecular oxygen or carbon monoxide and enzyme-like activity (i.e. aniline hydroxylation; J.B.C. 251 3442, 1976). We have already reported the interactions between hemoglobin and several drugs, aminopyrine, aniline and steroid hormones, as determined from the spectral changes of hemoglobin. Similar results were obtained with many other drugs. Difference spectra of methemoglobin induced by most chemicals tested had a trough at 40 ?? 403 nm and a peak at 420 ?? 430 nm. Methanol and ethanol formed a peak at 403 nm and a trough at 420 nm. Difference spectra of oxyhemoglobin induced by most chemicals tested had a peak at 400 ?? 403 nm and a trough at 420 nm. Each of steroid hormones and amino acids tested induced a characteristic spectral change of methemoglobin or oxyhemoglobin. The effect of drug-administration on oxygen affinity of hemoglobin was then examined. We measured oxygen half saturation pressure (P₅₀) using whole blood or purified hemoglobin. Addition of meclofenoxate HCl, PAS-Na and IHMS to purified hemoglobin solution increased P₅₀. Whole blood samples, before and one hour after drug-administration, from 33 inpatients, 13 outpatients and 20 normal subjects (not on drug-administration) were used to determine ΔP₅₀ (after minus before the administration). Values of ΔP₅₀ of 12 outpatients were within normal range (-0.5 ?? +0.5 mmHg). Those of 14 inpatients, however, were distributed out of range. The determination of ΔP₅₀ may be useful as a screening test for inappropriate drug-administration.

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Mice were immunized with sheep red blood cells (SRBC) at day 0, and hemagglutinin (HA) titer of the serum, hemolytic plaque forming cells (HPFC) in the spleen cells and rosette forming cells (RFC) in both the spleen and thymus cells were assayed at day 5. The immune responses in the mice immunized with 1 ×10⁸ SRBC intravenously were not affected by Y-12, 141 given orally for 5 days (0 ?? 4 days) at doses of 30 ?? 100 mg/kg, but were suppressed by cyclophosphamide (10 ?? 30 mg/kg p.o.) and D-penicillamine (100 mg/kg p.o.). The treatment of the mice with levamisole (1 ?? 30 mg/kg p.o.) resulted in the increase of RFC number in the spleen. Levamisole increased the number of RFC in the mice immunized with 5 ×10⁶ ?? 10⁸ SRBC. On the other hand, Y-12, 141 (10 ?? 30 mg/kg p.o.) increased spleen RFC number in the mice immunized with 5 ?? 10 × 10⁶ SRBC. Y-12, 141 and levamisole given orally on day 0, 1 or 2 increased spleen RFC number in the mice immunized with 5 ×10⁶ SRBC. D-Penicillamine given orally for 3 days (-2 ?? 0 days) also potentiated spleen rosette formation. The decreased number of RFC in the spleen and thymus by cyclophosphamide given orally in a dose of 20 mg/kg was restored by the treatment with Y-12, 141 (3 ?? 30 mg/kg) and levamisole (1 ?? 30 mg/kg). In addition, these agents suppressed 19S HA titer, and elevated 7S HA titer in the cyclophosphamide-treated mice. Prednisolone given orally in a dose of 30 mg/kg also decreased the number of RFC in the spleen. This decrease was restored by the treatment with Y-12, 141 and levamisole. These findings suggest that Y-12, 141 has a capacity to potentiate the immune response in mice immunized with low doses of SRBC and to restore the decrease of immune response caused by immunosuppressive drugs such as cyclophosphamide and prednisolone.

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The ganglionic blocking effects of the secondary and tertiary amines, mecamylamine and pempidine, on the spinal reflex of cats of both sexes were investigated. These blocking effects were then compared with findings in the quaternary ammonium compounds such as tetraethylammonium (TEA) and decamethonium (CIO). Mecamylamine (5 mg/kg) and pempidine (1 mg/kg) inhibited spinal reflex potentials such as the monosynaptic reflex (MSR), the polysynaptic reflex (PSR) and the dorsal root reflex (DRR). Maximal inhibition occurred 40 min after intravenous administration these drugs. In the case of mecamylamine, the inhibited potentials recovered gradually after reaching the maximum inhibition. However, the inhibitory effect of pempidine was prolonged, and recovery of the potentials did not occur for 60 min or longer. Although 10 mg/kg of CIO and 0.025 mg/kg of nicotine transiently inhibited the MSR and PSR, these compounds had no effect on the DRR. TEA produced prolonged inhibition of the MSR and PSR, and slightly enhanced the DRR. These results demonstrated the differences in DRR responses to secondary and tertiary amines, and quaternary ammoniums.

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We investigated the effects of various parasympathetic drugs on the head-twitch response (HTR), as induced by intracerebroventricular (i.c.v.) administration of tyramine in mice pretreated with safrazine, a monoamine oxidase inhibitor. Intraperitoneal administration of neostigmine, methacholine, carbamylcholine, methylatropine or hexamethonium did not alter the HTR induced by tyramine. The i.c.v. infusion of acetylcholine, physostigmine, nicotine, carbamylcholine or atropine slightly inhibited the tyramine-response. The i.c.v. infusion of pilocarpine, methacholine, mechamylamine, hexamethonium or tetraethylammonium resulted in a slight or significant potentiation of the HTR. These results suggest that the HTR induced by tyramine is accelerated by mechanisms related to muscarinic receptors within the central nervous system and that the tyramine-response is suppressed by mechanisms related to nicotinic receptors.

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The behavioral and electroencephalographic effects of alprazolam and its metabolites were investigated in mice, rats and rabbits, and compared with the data on diazepam, lorazepam and nitrazepam. Locomotor activity of mice in an open-field situation was increased with smaller doses of alprazolam and nitrazepam but not with diazepam and lorazepam. Alprazolam increased the hyperactivity induced by methamphetamine in mice. The anticonflict effects of alprazolam in rats were more potent than those of diazepam and lorazepam. In suppressing hyperemotionality and muricide of olfactory bulbectomized rats, alprazolam was more potent than diazepam and fairly equal to that of lorazepam. Muricide of raphe-lesioned rats was markedly inhibited by alprazolam. Mescaline-induced head-twitches in mice were more markedly increased with alprazolam than with nitrazepam and diazepam. Alprazolam, diazepam and lorazepam prevented both maximal electroshock and pentetrazol convulsions in mice. Alprazolam was more potent than diazepam and lorazepam in potentiating thiopental, ether and ethanol anesthesia in mice. In the impaired rotarod performance, alprazolam was more potent than diazepam and lorazepam in mice, but was much less potent than lorazepam in rats. In conscious rabbits with chronically implanted electrodes, alprazolam induced a drowsy EEG pattern and depressed the EEG arousal response not only to auditory stimulation but also to mesencephalic reticular stimulation. The EEG effect of alprazolam was approx. twice that of diazepam. The pharmacological activity of α-hydroxyalprazolam was approx. one third that of alprazolam. However, 5-chloro-2-(3-hydromethyl-5methyl-4H-l, 2, 4-triazolo-4-yl) benzophenone showed no pharmacological activity. These results indicate that alprazolam possesses pharmacologic properties characteristic to benzodiazepines and that the activity is more potent than diazepam. In addition, alprazolarn seems to have a specific effect on the central serotonergic mechanisms.

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Effects of 4'-ethyl-2-methyl-3-piperidinopropiophenone hydrochloride (EMPP) on experimental rigidities in rats and spinal cord activities in cats were studied. EMPP in a dose range of 1.25 ?? 10 mg/kg i.v. reduced EMG spikes of the intercollicular decerebrate rigidity and anemic decerebrate rigidity in rats. In α-chloralose anesthetized cats, EMPP in a dose range of 2.5 ?? 10 mg/kg i.v. caused a dose-related inhibition of the flexor reflex without any effect on the patellar reflex. In spinal cats, 2.5 ?? 10 mg/kg of EMPP caused a dose-related inhibition of the flexor reflex but the potency was less than that in anesthetized cats. Oral administration of EMPP 100 ?? 200 mg/kg produced a selective inhibition of the flexor reflex and the effect was twice as potent as tolperisone and chlormezanone. On the other hand, EMPP at 2.5 ?? 10 mg/kg i.v. which had little effect on the patellar reflex inhibited both monosynaptic and polysynaptic reflex potentials recorded from the ventral root to the same extent and also depressed dorsal root reflex potential recorded from the dorsal root in spinal cats. EMPP reduced the frequency of spontaneous γ-motoneurone discharges in spinal cats, but had no appreciable effect on GIa discharges from muscle spindle of the triceps surae muscle. These results indicate that EMPP reduces α- and γ-efferent activities and that EMPP exerts a marked inhibitory effect on spinal cord activities acting on the spinal cord and supraspinal structures.

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Effects of cis-N-(1-benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4-methylaminobenzamide (YM-091512), a newly synthesized psychotropic agent, on avoidance responses in rats under a Sidman-type avoidance situation (R-3=30 sec, S-S=5 sec) and a discriminated-type avoidance situation (ITI=25 see, CS duration =5 see) were investigated. The results were compared with the findings obtained in the case of YM-08050, YM-08051 and sulpiride, benzamide derivatives having similar chemical structures as YM-09151-2, and with the effects of chlorpromazine and haloperidol. After administration of YM-09151-2 (0.0025-0.01 mg/kg s.c. or 0.2-1.6 mg/kg p.o.), we observed a dose-related suppression of the avoidance responses, which attained to the maximum at 2-3 hr and persisted for about 24 hr. The average avoidance-suppressing and anti-amphetamine effects during the 2 hr session were in the order of YM-09151-2, YM-08050, haloperidol, YM-08051, chlorpromazine and sulpiride, when these agents were given s.c. Here, the avoidance-suppressing effects of YM-09151-2 were estimated to be 94-137 times as potent as those of chlorpromazine, and 4-37 times as those of haloperidol. After p.o. administration, the suppressing effects on the Sidman-type avoidance response were in the order of YM-08050, YM-08051, haloperidol, YM-09151-2, chlorpromazine and sulpiride, and on the discriminated-type one in the order of YM-08050, YM-09151-2, haloperidol, YM-08051, chlorpromazine and sulpiride. The present results suggest that YM-09151-2 has a more potent avoidance-suppressing effect when it is administered s.c., while the effect is as potent as that of haloperidol when given p.o. The effect appears rapidly and persists for about 24 hr after either s.c. or p.o. administration.

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The pharmacological profile of Ro 12-0068 as a new anti-inflammatory agent has been established in 9 different animal models and was compared with the profiles of 10 reference drugs. In adjuvant arthritis, scald-related edema and bradykinin-induced capillary permeability tests, the inhibitory potency of Ro 12-0068 was greater than findings in the case of diclofenac sodium which was the most potent agent available, while Ro 12-0068 exerted a stronger inhibitory effect on granuloma formation than did indomethacin. Anti-inflammatory potency of Ro 12-0068 in other models was equivalent to that of piroxicam. Ro 12-0068 was categorized as a potent anti-inflammatory agent and was grouped with diclofenac sodium, indomethacin and piroxicam, as compared to rather weak agents such as naproxen, carprofen, phenylbutazone, flufenamic, mefenamic, and acetylsalicylic acids. In fasting rats, ulcerogenicity of Ro 12-0068 in the gastric glandular and duodenal portions was weaker than that of indomethacin, appeared to be less than that of piroxicam and was equivalent to that of diclofenac sodium. Induction of fecal occult bleeding in dogs was markedly greater in case of indomethacin and piroxicam than with Ro 12-0068, within few days after oral treatment. Ro 12-0068 and piroxicam had much the same inhibitory effect on prostaglandin synthesis of inflammatory tissues and exudates from gastro-intestinal tissues. Nevertheless, therapeutic indices of Ro 12-0068 in rats were larger than those of piroxicam, in all models, and those of indomethacin in most cases. These results strongly suggest that Ro 12-0068 is a potent anti-inflammatory agent and that the occurrences of related gastro-intestinal disturbances are fewer.

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Bronchodilator effects of diltiazem were investigated in the isolated guinea pig tracheal chain and in the anesthetized cat. Interaction of diltiazem with isoproterenol (iso) was also examined. Diltiazem (10^-4g/ml) relaxed by 70% the tracheal chain contracted by histamine, 10^-5g/ml. This effect of diltiazem was not affected by pretreatment with propranolol, 3×10^-8g/ml. Diltiazem (400 μg/kg, i.v.) diminished by 20% the elevation of intratracheal pressure induced by serotonin aerosol, the effect of which lasted for approximately 20 min. On the other hand, diltiazem (10^-5g/ml) produced no influence on the iso-induced relaxation of the guinea pig trachea. In the anesthetized dog, diltiazem (20 μg/kg/min, i.v.) did not affect the iso-induced bronchodilation when histamine was used as a spasmogen, while the positive chronotropic action of iso was diminished. On the contrary, propranolol (30 μg/kg, i.v.) potentiated the bronchoconstrictor effect of histamine and suppressed both the bronchodilating and positive chronotropic actions of iso. Thus, the effects of diltiazem differed from those of propranolol. In summary, diltiazem showed bronchodilation both in vitro and in vivo, although the activity was not so potent. With regard to the iso-induced bronchodilation, diltiazem had no effect at a dose which diminished the positive chronotropic action of iso.

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