CYP2C76-mediated species difference in drug metabolism: a comparison of pitavastatin metabolism between monkeys and humans.

The monkey is often used to predict metabolism of drugs in humans since it generally shows a metabolic pattern similar to humans. However, metabolic profiles different from humans are occasionally seen in monkeys for some drugs including pitavastatin. Recently, we have successfully identified a monkey-specific cytochrome P450 (CYP) 2C76, which possibly accounts for a species difference between monkeys and humans because of its sequence and functional uniqueness. The present study on the role of CYP2C76 and other monkey CYP2Cs in pitavastatin metabolism, as an example, has revealed that CYP2C76 is important for the metabolism of the lactone form, indicating a major role of CYP2C76 for the difference in the metabolism of pitavastatin and possibly other drugs between monkeys and humans. The current investigation on the involvement of CYP2C76 in the metabolism of other drugs is expected to reveal further the further importance of this monkey-specific drug-metabolizing enzyme.

Serial changes in cerebral blood flow and flow-metabolism uncoupling in primates with acute thromboembolic stroke.

The authors recently developed a primate thromboembolic stroke model. To characterize the primate model, the authors determined serial changes in cerebral blood flow (CBF) and the relation between CBF and cerebral metabolic rate of glucose (CMRglc) using high-resolution positron emission tomography. Thromboembolic stroke was produced in male cynomolgus monkeys (n = 4). Acute obstruction of the left middle cerebral artery was achieved by injecting an autologous blood clot into the left internal carotid artery. Cerebral blood flow was measured with [15O]H2O before and 1, 2, 4, 6, and 24 hours after embolization. CMRglc was measured with 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) 24 hours after embolization. Lesion size and location 24 hours after embolization was determined by the 2,3,5-triphenyltetrazolium chloride (TTC) staining method. The results are summarized as follows: (1) 1 hour after embolization, CBF in the temporal cortex and the basal ganglia decreased to < 40% of the contralateral values. In these regions, regarded as an ischemic core, CBF decreased further with time and CMRglc at 24 hours also decreased. Infarcted lesions as indicated by being unstained with TTC were consistently observed in these regions. (2) In the parietal cortex and several regions surrounding the ischemic core, CBF was > 40% of the contralateral values 1 hour after embolization and recovered gradually with time (ischemic penumbra). In these regions, CMRglc at 24 hours increased compared with that in the contralateral regions, indicating an uncoupling of CBF and CMRglc. No obvious TTC-unstained lesions were detected in these regions. The authors demonstrated a gradual recovery of reduced CBF, an elevated CMRglc and a CBF-CMRglc uncoupling in the penumbra regions of the primate model. Positron emission tomography investigations using this model will provide better understanding of the pathophysiology of thromboembolic stroke in humans.

Experimental thromboembolic stroke in cynomolgus monkey.

To develop an experimental model of thromboembolic stroke without intracranial surgery, an autologous blood clot was delivered to the middle cerebral artery (MCA) via the internal carotid artery in cynomolgus monkeys. Male cynomolgus monkeys, in which a chronic catheter had been earlier implanted in the left internal carotid artery, were used. The clot was flushed into the internal carotid artery under sevofluorane anesthesia. A neurologic deficit score was assigned after MCA embolization. After 24 h, cerebral infarct size and location were determined by the TTC staining method. Cerebral blood flow (CBF) was measured prior to and after MCA embolization, using positron emission tomography (PET). After embolization, long-lasting and profound extensor hypotonia of the contralateral upper and lower limbs, and mild to severe incoordination were observed. Contralateral hemiplegia was observed over the following 24 h. In gross morphologic observation of the brain, the lesions involved mostly the caudate nucleus, putamen, globus pallidus and insular cortex. CBF was maximally reduced in the left MCA territory, but not in the right MCA territory. This model is relevant to thromboembolic stroke in human in neurologic dysfunction and histopathologic brain damage.

Characterization of the high sensitivity of rabbits to the effects of TCV-116, an angiotensin II receptor antagonist.

A high incidence of maternal toxicity in rabbits characterized by uremia and death was observed when TCV-116, a novel angiotensin II subtype-1 (AT1) receptor antagonist, was orally administered to pregnant rabbits at dosage levels of 3 mg/kg/day or more. The effects of TCV-116 on blood pressure in nonpregnant or male rabbits and rats and on blood chemistry, renal circulation, and plasma renin activity in nonpregnant or male rabbits were examined to characterize the toxicity in rabbits. In a 2-week repeated dose study, most nonpregnant female rabbits receiving 3 or 100 mg/kg/day died or were sacrificed in a moribund state, indicating that toxicity could be caused independently of pregnancy. When these rabbits became moribund, marked hypotension, accompanied by increases in plasma concentrations of urea nitrogen, creatinine, and potassium, was observed, suggesting uremia. In a single-dose study, blood pressure in rabbits was decreased after administration of 10 or 100 mg/kg of TCV-116, and the hypotension was more marked and sustained than that in rats, as was the case with 30 mg/kg of enalapril. The sustained pharmacological effect in rabbits was also confirmed with regard to decreases in effective renal plasma flow and the glomerular filtration rate and increased plasma renin activity. Species differences in the hypotensive effect and mortality could not be explained by toxicokinetic data for the active metabolite of TCV-116 in various species, which supported a possibility that the differences in toxicity may be related to the species difference in sensitivity to the pharmacological effect of TCV-116. We conclude that the specific maternal toxicity of TCV-116 in rabbits may be mainly due to the higher sensitivity of rabbits to the pharmacological effects and is caused by marked and sustained hypotension resulting in the decrease in glomerular filtration rate, uremia, and death.

General pharmacological properties of the new angiotensin II receptor antagonist (+/-)-1-(cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl]-1 H-benzimidazole-7-carboxylate. Part II: Effect on cardiovascular system and renal functions.

The effects of TCV-116 ((+/-)-1-(cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-[[2'-(1 H-tetrazol-5-yl)biphenyl-4-yl] methyl]-1 H-benzimidazole-7-carboxylate, CAS 145040-37-5) on the cardiovascular system and renal function were investigated in rats, guinea pigs, and dogs. TCV-116 at doses of 3 mg/kg (i.d.) and higher markedly increased renal blood flow in anesthetized dogs. TCV-116 at 30 mg/kg (i.d.) had no effect on heart rate, left ventricular systolic pressure, its dp/dtmax, or cardiac output in anesthetized dogs. Furthermore, TCV-116 at 10 and 30 mg/kg (p.o.) had little effect on cardiac output, right atrial pressure, pulmonary artery pressure, pulmonary capillary wedge pressure or respiration in conscious dogs. In isolated guinea pig perfused heart, CV-11974 even at a dose of 0.1 mg/ heart had no effect on cardiac function. In isolated guinea-pig atria, CV-11974, the active metabolite of TCV-116, even at 10(-4) mol/l had no effect on the spontaneous beating rate of the right atria or the contractile force of electrically-paced left atria. No significant effect of TCV-116 on urinary volume or urinary excretion of sodium and potassium was observed in rats (at 30, 100 or 300 mg/kg p.o.). These findings suggest that TCV-116 exerts no any additional pharmacological effects on cardiac and respiratory functions in dogs or on renal function in rats, other than an increase in renal blood flow in anesthetized dogs thought to be due to its inhibitory effect on the renin-angiotensin system.

General pharmacological properties of the new angiotensin II receptor antagonist (+/-)-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate. Part I: Effects on central nervous system and other properties.

The effects of TCV-116 ((+/-)-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate, CAS 145040-37-5), a nonpeptide angiotensin II receptor antagonist, on the central nervous and autonomic nervous systems, isolated smooth muscle and digestive system were investigated in various experimental animals. TCV-116 at 1000 mg/kg (p.o.) produced a slight decrease in body tone in mice, but at 300 mg/kg did not affect spontaneous locomotor activity, skeletal muscle coordination, tonic extensor convulsions, pentobarbital-induced sleeping time, frequency of acetic acid-induced writhing, or body temperature in mice or rats. TCV-116 (at 300 mg/kg p.o.) did not affect the spontaneous EEG in conscious, unrestrained cats, or (at 100 mg/kg i.d.) the spinal reflex in anesthetized cats. CV-11974, the active metabolite of TCV-116, did not inhibit neuromuscular transmission in isolated rat phrenic nerve-diaphragm preparations (10(-5) mol/l and 10(-4) mol/l). In anesthetized cats, TCV-116 at 100 and 300 mg/kg (i.d.) slightly reduced the pressor response to carotid occlusion, but had no effect on the bradycardic response to stimulation of the cervical vagus nerve, contraction of the nictitating membrane induced by electrical stimulation of the cervical sympathetic preganglionic nerve, or the changes in blood pressure in response to acetylcholine, histamine, norepinephrine, or bradykinin. CV-11974 had no effect on agonist-induced contraction of guinea pig ileum. In isolated smooth muscle preparations, CV-11974 even at 10(-4) mol/l did not affect the spontaneous motility of the rabbit ileum or the rat uterus, or KCl-induced tension in guinea pig trachea. TCV-116 at 300 mg/kg (p.o.) had no significant effect on gastric emptying or intestinal transport of a semisolid meal in rats, or on gastric secretion in pylorus-ligated rats. TCV-116 (30-300 mg/kg p.o.) had no effect on carrageenin-induced paw edema in rats. The results suggest that TCV-116 exerts no notable pharmacological effects on the central nervous system, autonomic nervous system, gastrointestinal function or smooth muscle function.

Effects of the non-peptide angiotensin II receptor antagonist TCV-116 on systemic and renal hemodynamics in dogs with renal hypertension.

The effects of TCV-116, a new non-peptide angiotensin II receptor antagonist, on systemic and renal hemodynamics were studied in conscious normotensive and renal hypertensive (2-kidney, 1-clip Gold-blatt type) dogs. When orally administered at 0.03 to 1.0 mg/kg, TCV-116 inhibited the pressor response to angiotensin II in conscious normotensive dogs in a dose-dependent fashion. The IC50 and IC100 values were 0.06 mg/kg and 0.86 mg/kg, respectively. TCV-116 at doses of 0.3 mg/kg and 1.0 mg/kg dose-dependently and persistently decreased systolic and diastolic blood pressure in both dogs with acute renal (hyperreninemic) and those with chronic renal (normoreninemic) hypertension. Even a high dose of TCV-116 (10 mg/kg, p.o.) increased effective renal plasma flow without affecting blood pressure or glomerular filtration rate in normotensive dogs. Furthermore, even at this high dose, TCV-116 did not reduce effective renal plasma flow or glomerular filtration rate in dogs with renal hypertension despite marked reduction in systemic blood pressure. The angiotensin converting enzyme inhibitor enalapril (10 mg/kg, p.o.) had renal hemodynamic effects similar to those of TCV-116. These findings indicate that TCV-116 has potent hypotensive effects not only in dogs with acute renal hypertension but also in those with chronic renal hypertension, but does not appear to adversely affect renal hemodynamics.

[Rotarod method in young rats and the antidepressive effect: is the rotarod method capable of evaluating antidepressive effects?].

The possibilities of applying the rotarod method in young rats for evaluating the antidepressive effect were studied. The results were compared with those obtained by the despair test, which was also used to evaluate the antidepressive effect. The rats used in these tests had not been trained previously. In the rotarod test, antidepressant drugs such as imipramine (30 mg/kg, p.o.), desipramine (10 mg/kg, p.o.), clorgyline (10 mg/kg, p.o.), mianserin (30 mg/kg, p.o.), trazodone (10 mg/kg, p.o.) and clomipramine (30 mg/kg, p.o.) and an ACE inhibitor, enalapril (30 mg/kg, p.o.), significantly prolonged the time rats were able to remain on the rotating rod in a dose-dependent manner. Diazepam significantly reduced the duration on the rotating rod. Theophylline, caffeine and fenfluramine did not affect the duration on the rotating rod. In the despair test (forced swimming test), clorgyline, enalapril and caffeine significantly reduced the duration of immobility during the forced swimming in a dose-dependent manner. Imipramine and desipramine significantly reduced the duration of immobility during forced swimming. Trazodone and clomipramine did not affect the duration of immobility. Diazepam significantly prolonged the duration of immobility. A highly significant correlation was noted between the results obtained by the rotarod method and those obtained by the despair test. In the traction test, theophylline and caffeine significantly prolonged the duration during the traction response. However, other drugs did not affect the duration during the traction response. These results demonstrate that the rotarod method in young rats may be applicable for evaluating the antidepressive effect.

[Effect of CV-4151 on the cerebral hypoperfusion and production of thromboxane A2 following complete cerebral ischemia-reperfusion in dogs].

The effects of CV-4151 on post-ischemic brain hypoperfusion and thromboxane (Tx)A2 production in a canine model of total global brain ischemia were studied. Complete cerebral ischemia for 5 min was produced in adult mongrel dogs by temporary ligation of the venae cavae and aorta. In the non-treated group, cerebral blood flow (CBF) increased during the first 20 to 30 min post-ischemia followed by a gradual decline and then stayed below preischemic level; CBF at 2 hr after the reperfusion was significantly reduced to ca 77% of the pre-ischemic level. Water content in the cerebral cortex at 2 hr after the reperfusion in the non-treated group was 78.15 +/- 0.21%, higher than the content in the control group, 76.70 +/- 0.07%. The concentration of TxB2 in the sagittal sinus was significantly increased at 30 min post ischemia. CV-4151 (1.0 mg/kg, i.v.) almost completely inhibited the post-ischemic hypoperfusion, significantly inhibited the increase in water content and almost completely inhibited the production of TxB2 in the post-ischemic period and increased the production of 6-keto PGF1 alpha. OKY-046 (10 mg/kg, i.v.) had no significant effects on both post-ischemic hypoperfusion and increase in water content in the cerebral cortex. We conclude that CV-4151 ameliorates post-ischemic cerebral hypoperfusion and that this improvement is associated with decreased sagittal sinus levels of TxB2.

Quinones. 4. Novel eicosanoid antagonists: synthesis and pharmacological evaluation.

A new series of omega-phenyl-omega-quinonylalkanoic acids and related compounds was synthesized. The compounds were tested for their inhibitory effects on U-44069-induced contraction of the rabbit aorta. (+/- )-7-(3,5,6-Trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptanoic acid (4d) (AA-2414) with pA2 value of 8.28 was one of the most potent compounds. Compound 4d inhibited U-46619-induced contraction of the guinea pig lung (pA2 = 8.29) and U-44069-induced aggregation of the guinea pig platelet (IC50 = 3.5 x 10(-7) M). Compound 4d displaced the binding of [3H]U-46619 to guinea pig platelets (IC50 = 7.4 x 10(-9) M). Compound 4d also showed very potent inhibitory effects with an MED of 0.3 mg/kg (po) on U-46619-, LTD4-, PAF-, or IgG1-induced bronchoconstriction in guinea pigs. The enantiomers of 4d were prepared. The R-(+) isomer 8a was active in both in vitro and in vivo tests, but the S-(-) isomer 8b was much less active. We concluded that the antiasthmatic effects of 4d were based mainly on the TXA2 receptor antagonistic action. In addition, compound 4d showed potent inhibitory effects on PGD2-, PGF2 alpha-, and 11-epi-PGF2 alpha-induced contraction of the guinea pig tracheal strips. The diverse inhibitory effects might be expressed in terms of eicosanoid-antagonistic activity.

Effects of CV-3611, a new free radical scavenger, on ischemic heart failure in conscious beagle dogs.

The effects of CV-3611, a new free radical scavenger, on coronary circulation failure and infarct size after ischemia/reperfusion were studied in conscious beagle dogs. The dogs underwent occlusion of the left circumflex coronary artery for 60 min and then were reperfused for 14 days. The dogs were divided into three groups: a control group, a pre-treated group that received CV-3611 or alpha-tocopherol, and a post-treated group that received CV-3611. During occlusion, varying degrees of ventricular arrhythmia were noted; after reperfusion, the arrhythmia tended to become severe. CV-3611 at a daily dose of 10 mg/kg or 30 mg/kg and alpha-tocopherol at a daily dose of 60 mg/kg reduced the incidence of overall post-occlusion arrhythmia. Coronary blood flow in the control group was reduced to 20% of the preocclusion level at 7 days after reperfusion, whereas in the CV-3611 and alpha-tocopherol treated groups, the decreased coronary flow was remarkably suppressed. The infarct size for the CV-3611- and alpha-tocopherol-treated groups, measured at 14 days after reperfusion, was reduced by 70% when compared with the control group. Based on these observations, it is proposed that CV-3611 exerts its beneficial effects on ischemic tissue by protecting against oxygen free radical-mediated damage induced by ischemia/reperfusion.

The antiobesity action of (S)-(+)-1-(4-chlorophenylthiomethyl)-N-methylethylamine fumarate (AO-124).

The antiobesity effects of (S)-(+)-1-(4-chlorophenylthiomethyl)-N-methylethylamine fumarate (AO-124) were examined in rats and dogs. AO-124 suppressed food intake dose dependently in normal, Zucker fatty and VMH-obese rats, and beagle dogs. Its anorectic activity was not altered by pretreatment with methysergide, a serotonin receptor blocker. AO-124 also reduced the hyperphagia induced by 2-deoxy-D-glucose but not that induced by insulin, noradrenaline or muscimol, suggesting that the anoretic mechanism of AO-124 may be implicated in a glucostatic regulatory system of feeding. In addition, AO-124 decreased insulin secretion in response to an oral, but not an intravenous, glucose load. Such a suppression in insulin secretion may be explained by slow absorption of glucose from the intestine: AO-124 delayed the gastric emptying time of glucose and inhibited the active transport of glucose as observed in the everted small intestine. Two week administration of AO-124 to Zucker fatty rats resulted in a significant reduction of plasma insulin levels, body weight gain, and body lipid without exerting any changes in body protein. These findings indicate that AO-124 may be useful as an antibesity agent on the basis of its unique mechanisms of action.

Influence of cerebral cortex stimulation upon cough-like spasmodic expiratory response (SER) and cough in the cat.

In 27 pentobarbitalized cats, the influence of electrical stimulation of the cerebral cortex upon the spasmodic expiratory response (SER) was studied and compared with cortical influences on coughing induced by stimulation of the superior laryngeal nerve (sup. laryngeal N.). This cortical influence was evoked by electrical stimulation of the cortical nucleus of amygdala (Aco), and was very similar to coughing accompanying changes in emotional behavior and was depressed more effectively by psychotropics than by centrally acting antitussives like codeine. When anterior cingulate gyrus (ant. cingulate G.) or orbital gyrus (orbital G.) were stimulated simultaneously with Aco or sup. laryngeal N., weak stimulation was sufficient to inhibit SER, while stronger stimuli were needed for the suppression of cough. If the same cortical regions were stimulated after initiation of SER or cough, SER was markedly suppressed but cough little affected. Production of SER was facilitated by simultaneous stimulation of the piriform lobe (piriform L.) or olfactory tract (olfactory T.), whereas cough production was facilitated by simultaneous stimulation of the suprasylvian gyrus. These results suggest that SER and coughing are differently controlled by the cerebral cortex, and that SER is modulated by the limbic cortex, in particular, by ant. cingulate G., orbital G. and piriform L. The mechanism of modulation for SER is discussed.

Neural mechanism for production of spasmodic expiratory response like cough induced by amygdala stimulation in the cat. I. Pathways from the amygdala to the lower brain stem.

The pathways descending from the amygdala to neural structures in the lower brain stem responsible for production of spasmodic expiratory response like cough (SER), which occurred upon electrical stimulation of the cortical nucleus of amygdala (Aco), were investigated using microinjection and ablation techniques in the cat. 1) Following transection of the bilateral stria terminalis (STT), the threshold for SER production was remarkably elevated. 2) SER was suppressed by administration of procaine (20 microgram) or diazepam (5 microgram) into either side of the hypothalamic ventromedial nucleus (Hvm); furthermore, SER completely disappeared after lesion of bilateral Hvm. After lesion of the ipsilateral Hvm to the side of stimulation, the threshold for SER was obviously elevated, but SER was not affected by lesion of the contralateral Hvm. 3) After section of the substantia grisea centralis at the midcollicular level, SER disappeared. 4) Both SER and peripherally-induced coughs were depressed by codeine (10 microgram), dextromethorphan (10 microgram) or procaine (20 microgram) administered into the solitary tract nucleus (STN) or the nucleus reticularis parvocellularis. 5) SER and coughs disappeared after lesion of the bilateral STN or nucleus ambiguus (AM). These results demonstrate that most of the efferent fibers from Aco get to Hvm via STT, and further to STN and AM in the medulla.

[Pharmacological studies on expectorants (author's transl)].

Perry and Boyd's method described in 1941 appears to be the most suitable for evaluating the efficacy of expectorants. In this method, changes in volume of respiratory tract fluid (RTF) collected by postural drainage from animals breathing air kept at a constant temperature and humidity are used as criteria. We attempted to improve on the method and to establish the optimum experimental conditions for rabbits. Accordingly, an air conditioning apparatus and tracheal cannula were re-designed and basic experimental conditions essential for quantitative collection of RTF were studied. Using this method, the effects of drugs on the volume of respiratory tract fluid (VRTF) were determined. Bromhexine and emetine as expectorants increased VRTF, and the former showed far more remarkable effects. Codeine and dextromethorphan as antitussives, isoproterenol, clorprenaline and C-78 as bronchodilators decreased VTRF. On the other hand, fominoben and eprazinone as antitussives increased VRTF. Our findings with application of this new approach indicate that this method is applicable for evaluating not only the efficacy of expectorants which increase VRTF but also that of other drugs which decrease VRTF.

Antitussive activity and other related pharmacological properties of d-3-methyl-N-methylmorphinan (AT-17).

Antitussive activity and some other related pharmacological properties of d-3-methyl-N-methylmorphinan were studied. Toxic symptoms in mice and dogs were due to the CNS excitation. Acute toxicity of (AT-17) in mice was slightly (s.c.) or far (p.o.) weaker than that of codeine, but it was three times as toxic as codeine in dogs (i.v.). Antitussive efficacy was about 40% of that of codeine in dogs, whereas 77% as potent as codeine in cats. It showed no relaxing effect on the bronchial muscle of guinea pigs in either normal tone or histamine-induced spasms. It had analgesic effect 1/3 as potent as codeine in mice but it was not antagonized by levallorphan. The prolongation of hexobarbital sleeping time by AT-17 was similar extent to that by codeine. Anti-electroshock effect was half as potent as that of phenobarbital. The inhibitory effect on the transportation of intestinal contents in mice was far weaker than that of codeine. Effect on the respiratory and circulatory systems were also investigated.

On the sites of antitussive action of d-3-methyl-N-methylmorphinan (AT-17).

The sites of antitussive action of d-3-methyl-N-methylmorphinan (AT-17) were studied. It was assumed from the following results that AT-17 acts on the cough centre per se. a) When AT-17 was given by the routes leading to the brain stem such as the cerebello-medullar cistern, far smaller doses were sufficient to obtain the same effect as that by i.v. administration. b) It showed neither effect on the afferent pathway for cough reflex nor influence on pulmonary stretch receptors. c) Decerebration exerted no influence on the antitussive efficacy. d) It definitely depressed the potentials of both the recurrent and internal intercostal nerves evoked by the superior laryngeal nerve stimulation. e) Micro-injection of AT-17 into the bilateral solitary nuclei or their adjacent regions inhibited coughs induced by peripheral stimulation. f) In deafferentated and decerebrate cats, AT-17 increased the spontaneous discharges of the phrenic nerve, whereas codeine decreased them.

Pharmacological studies of 1-(o-chlorophenyl)-2-tert.-butylaminoethanol (C-78), a new bonchodilator.

The bronchodilating effects and other related pharmacological properties of 1-(o-chlorophenyl)-2-tert.-butylaminoethanol-hydrochloride (C-78) were studied in comparison with those of isoproterenol, salbutamol and clorprenaline. C-78 was found to produce a bronchodilating effect 2--10 times stronger and considerably weaker than clorprenaline and isoproterenol, respectively. However, the bronchodilating effect of C-78 was sustained more than 10 times as long as those of isoproterenol and sulbutamol and, especially on oral administration, it was much more potent. The bronchodilating effect of C-78 seems to be due to excitation of the adrenergic beta-receptor, and was antagonized by propranolol. The positive chronotropic and inotropic effects of C-78 on an isolated atrial preparation were less than 1/1000 as potent as those of isoproterenol. C-78 also decreased the tone of smooth muscle, such as the uterus, but its affinity for the bronchial muscle is much higher than for the uterus. C-78 showed strong anti-anaphylactic action and strongly promoted the tracheal ciliary movement. Anitussive effect was also demonstrated, though this was inferior to that of codeine, however, there was no influence on bronchosecretion.