An experiment was conducted in an attempt to determine the effect of arsenic on body weight, brain weight and brain chemical composition in suckling rats. Four hundred and ninety-nine young rats from Wistar albino mothers in a closed colony (TAMURA, 1950) were grouped into four according to the treatment given. Group I served as control. Rats in Group II were treated with As₂O₃ 1.5 mg/kg, those in Group III 15 mg/kg and those in Group IV arsenic compounds (corresponding 15 mg/kg of As₂O₃) for 7 to 21 days after birth. Measurements were recorded for 3 to 15 weeks. The mortality of groups I and II was approximately 10%. while that of groups III and IV was approximately 50%. Regarding body weight, brain weight and brain chemical composition of provision of the same, there was no significant difference between controls and the arsenic treated males and females under conditions Oriental feed diet and powdered milk.

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Although the pigment leakage method is one of the most conventional for determining vascular permeability, accuracy in macroscopic measurement of the diameter of the stained area with an arbitary scale leaves much to be desired. We developed a simple and beneficial method for quantitative assay using a densitometer (Chromatoscanner CS-900). Guinea pigs weighing 300-350 g were used. Formalin as a phlogistic, in a dose of 2.3 ?? 37mg was injected intradermally in the shaved skin of the back, and 15mg/kg of pontamine blue was then given into the femoral vein. One hour after the injection the animals were sacrificed and the skin of the back, which was stained by the leaked pigment, was stripped off and allowed to adhere to a wooden plate for 24 hours. Reflection and a zig-zag scanning technique were used to measure the volume of the leaked pigment. There was a liner relationship between the dose of formalin and the integrated values. A dose-dependent relation-ship was also obtained when histamine, serotonin, kallikrein and bradykinin were used as phlogistics. Representative anti-inflammatory drugs such as aspirin, hydrocortisone, oxyphenbutazone, benzydamine, diclofenac sodium, sodium salicylate and aminopyrine depressed the leakage due to formalin. Depression of leakage by aspirin in a dose of 400 mg/kg was the most remarkable. Pigment leakage elicited by histamine, serotonin, kallikrein and bradykinin was examined on the same individual animal. Aspirin more than the other agents depressed the leakages due to bradykinin and kallikrein. Hydrocortisone and oxyphenbutazone depressed the leakage due to bradykinin, serotonin and histamine, but enhanced that due to kallikrein. The results obtained were consistent with those of a previous study and as this method is simple and more reliable, it is applicable for assay of anti-inflammatory compounds.

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The mortality of ddK mice treated with 40 mg/kg i.p. of methamphetamine (MA) was 85% in grouped conditions (10 mice in a cage) and 3% in individually isolated conditions. This mortality was not altered by the social environments even when other mice in the cage were not treated with MA. The mortality of mice individually isolated in cages with transparent walls was significantly higher than that of completely isolated mice. Almost all neuroleptics dose-dependently antagonized the MA toxicity in grouped mice, in small doses. The antagonizing activity of clozapine was somewhat weak, and sulpiride potentiated MA toxicity. Phentolamine and propranolol antagonized the MA toxicity at higher doses than neuroleptics. Reserpine and tetrabenazine previously given to mice remarkably antagonized the MA toxicity. H44/68 (a tyrosine hydroxylase inhibitor) had a considerable effect in antagonizing the MA toxicity, but diethyldithiocarbamate, U-14, 624 and FLA 63 (dopamine-β-hydroxylase inhibitors) prevented the MA toxicity to a lesser extent than did H44/68. Apomorphine had no effect on the MA toxicity. The present data show that the MA toxicity in grouped mice (the increase in mortality) was enhanced by the presence of other mice, and suggest that the norepinephrine neurons play an important role in promoting the MA toxicity. Neuroleptics antagonize MA toxicity probably by blocking α-receptors in the central nervous system.

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In isolated dog heart, Theo-Esberiven 0.1 mg, which contains 12 mg proxyphylline, 2.5 mg rutin and 5 mg Melilotus extract, and proxyphylline (12 mg) increased coronary blood flow (CBF) and was associated with increased heart rate (HR) and myocardial contractile force (MCF). The effect of Theo-Esberiven on CBF was about 1.7 times higher than that of proxyphylline. Theo-Esberiven did not significantly affect myocardial oxygen consumption (QO₂) and redox potential (ΔEh), while proxyphylline aggravated myocardial metabolisms, as determined from these parameters. Esberiven 0.1 ml, which contains 2.5 mg rutin and 5 mg Melilotus extract, slightly but significantly increased CBF and decreased QO₂ and ΔEh without changing HR and MCF. In situ, intra-coronary injection of either Theo-Esberiven or proxyphylline resulted in a dose-dependent increase in left circumflex coronary flow (LCCF). The effect of Esberiven on LCCF was much less and was slight at the higher doses. Intravenous injection of Theo-Esberiven (0.1 ml/kg) increased LCCF. Besides this change, marked fall in blood pressure and tachycardia were induced by both Theo-Esberiven and proxyphylline without the change in dP/dt_max. Esberiven by the same route led to the decrease in blood pressure associated with HR and dP/dt_max. These results indicate that Theo-Esberiven may be appropriately prescribed for ischemic heart diseases.

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The digestant effects of a new digestive capsule, excelase containing sanactase, proctase, meicelase, olipase-2S and pancreatic digestive enzyme TA, were investigated in vivo. Jejunectomy and pancreato-jejunectomy were performed to cause an artificial disturbance of gastro-intestinal digestion and absorption in Beagle dogs. Absorption of protein and fat was measured using chromic oxide as an indicator. Excelase (3 capsules/dog/ day) was given orally to Beagle dogs 1 week after each operation for 7 weeks. Changes in body weight and absorption of protein and fat were observed during the administration. The decrease in body weight of dogs treated with excelase fully recovered, however, that of controls remained even 8 weeks after the surgery. Absorption of protein and fat in the groups of dogs treated with excelase was greatly improved as compared with controls.. The digestant effects of excelase on percent absorption of protein and fat were more manifest in pancreato-jejunectomized dogs than in jejunectomized dogs. These results indicate that excelase is effective for gastro-intestinal disturbances of digestion and absorption. The digestant effects of excelase on starch, protein and cellulose were also investigated in vitro using a gastro-intestinal model.

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Caffeine (10 or 20 mM)-induced isometric contraction of guinea pig taenia coli showed two successively occurring phasic contractions (I and II) followed by a low sustained tension. Half-time of tension decay in II was 4 ?? 6 times longer than in I. The contraction occasionally showed only a single phasic contraction, of which tension, however, decayed showing two half-times as in two phasic contractions. In the presence of procaine 0.1 ?? 0.5 mM, DNP 0.03 ?? 0.1 mM or Mn²⁺ 0.5 ?? 1.0 mM, II was entirely abolished whereas I was partially inhibited and such were confirmed by analyzing the time course of tension decay. Maximal tension of I decreased in parallel with lowering the external Na while II was enhanced with 50 ?? 100 mM Na and inhibited by further withdrawal of Na. I and II showed the same Ca-dependecy with respect to the inhibition by Ca deficiency and to the time course of recovery from Ca-free state. Refractoriness tocaffeine after preceding caffeine-contraction also showed little difference between I and II. Sustained tension by caffeine was dependent on Ca in the same manner as tonic K-contracture. Increase in ⁴⁵Ca uptake with 40 mM K was completely inhibited by 10 mM caffeine while cellular Ca content in the presence of high K markedly increased with caffeine indicating the decrease in Ca exchangeability. The above results indicate that caffeine induced contraction consists of two phasic contractions of which EC-coupling Ca is released from two different cellular sites, and that the phasic contractions are followed by a sustained low tension caused by an increased Ca influx. In the presence of high K, caffeine abolishes the increase in Ca influx by high K and sequesters the sarcoplasmic free Ca resulting in the relaxation of K-contracture.

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We studied the drug-induced spectra of hemoglobin and cytochrome c using aniline, aminopyrine, hydrocortisone and prednisolone. The difference spectrum of methemoglobin induced by aniline or aminopyrine was similar to type II, and that of oxidized cytochrome c induced by aniline was similar to type I. Characteristic spectral change occurred with addition of hydrocortisone or prednisolone to each of methemoglobin, oxyhemoglobin and carboxyhemoglobin, and by addition of each drug to deoxyhemoglobin, respectively. Other spectral changes were attributed to oxidation-reduction reactions between the drugs and the hemoproteins. Each of the reduced forms of hemoglobin showed a higher affinity to aniline and aminopyrine than did methemoglobin. Each of the reduced forms of hemoglobin or reduced cytochrome c showed a higher affinity to aminopyrine than to aniline. It is interesting that not only cytochrome P-450, a hydrophobic hemoprotein, but also hemoglobin and cytochrome c, hydrophilic hemoproteins, showed the drug-induced difference spectra. These results suggest direct interactions between drugs and hemoproteins. Oxyhemoglobin had a lower affinity to drugs in hemolysate than in the buffer only.

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Wada et al. found a hyperbolic curve in the Lineweaver-Burk plots of the drug-metabolizing activity and competitive inhibition of steroid hormones to drugs, and suggested that several enzymes acting on different sites of various steroid hormone molecules might metabolize drugs without having specificities for hydroxylation sites. Recently, several cytochrome P-450s were separated and purified from liver microsomes. We studied the relation between the drug-metabolizing activities and multiplicity of cytochrome P-450 with the pH curve and the Lineweaver-Burk plots. Phenobarbital and methylcholanthrene-treatment had remarkable effects on the pH curve of aniline hydroxylation by mouse liver microsomes. Addition of cortisol inhibited aniline hydroxylation by liver microsomes from phenobarbital-treated mice more effectively at higher pH range and the pH curve was similar to that seen for normal mice. Haugen and Coon separated preparations [A] [B] and [C] with hydroxylapatite chromatography and we obtained [Aú] (eluted by 100 mM K-phosphate buffer, pH 7.4) between [A] (50 mM) and [B] (300 mM). The preparation [A´] had the same absorption maximum (451 nm) of reduced CO complex as [A], but Km and pH curve for [A´] were similar to those for [B]. Each separated preparation of cytochrome P-450 showed a hyperbolic curve in Lineweaver-Burk plots and a different pH curve from each other.

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Gibson and Pollock recently reported that metyrapone, a relatively specific 11-B-hydroxylase inhibitor, abolished the pronounced fall in body weight which was observed during morphine withdrawal. The present study was carried out in an attempt to confirm their observation and, in addition, to assess whether or not such an effect might be related to the adrenal effect of metyrapone. In male SD strain rats treated with morphine-admixed food for 7 days, abstinence syndrome such as dramatic decreases in body weight and food intake as well as diarrhea appeared when morphine-admixed food was substituted by a regular diet. The abstinence syndrome by morphine withdrawal in animals treated with a combination of morphine and metyrapone for 7 days was significantly mild. Metyrapone also inhibited the abstinence syndrome which occurred when levallorphan was given. However, metyrapone itself did not affect the body weight and the food intake of normal rats. In morphine dependent rats which were subjected to adrenalectomy prior to morphine treatment, a similar abstinence syndrome following morphine withdrawal appeared, and an inhibition of the syndrome by a combination of morphine and metyrapone was also observed, as was seen in animals with the intact adrenals. On the other hand, we found using the hot plate method that metyrapone did not suppress the morphine analgesia in normal rats, but rather enhanced it. These results indicate that metyrapone inhibits morphine abstinence syndrome specifically, without inhibiting the analgesic effect of morphine and also that the inhibition of the abstinence syndrome by metyrapone is due to an effect other than that of metyrapone on the adrenal function.

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The effects of drug administration on the dams (F₀) and their offspring (F₁), particularly on the central nervous and reproductive functions of F₁, were studied by oral administration of pentazocine HCl to rats during the perinatal and postnatal periods. No significant differences were observed between administered and control rats regarding body weight changes and food intake during perinatal and postnatal periods in F₀ at all dosages, but temporary salivation was observed in the 200 and 100 mg/kg groups, and decline of spontaneous activity and respiratory rate, disappearance of righting reflex, clonic convulsion were observed in some of the 200 mg/kg group. No significant differences were observed regarding litter size, birth rate, state and timing of differentiation as postnatal development, sex maturity, reproductive function in F₁, although some groups were slightly inferior in body weight at birth and during the nursing period. Furthermore, no differences were observed in respect to the nervous functions of balance, exercise and psychotic related activity in the openfield test.

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In previous literature, we reported that the rats, whose dams had been administered pentazocine HCl 200 mg/kg/day during the perinatal and postnatal periods, showed no differences between control rats in the physiological function and psychotic activity tests. Brain tissues of the rats were observed histologically herein to confirm the result of previous tests. Abnormal findings such as deficits, undevelopment and metamorphosis, in the shape, size and configuration of nerve cells, myelin sheaths and vessels in consecutive transverse sections stained by Nissl and Klüver-Barrera method were not evident on examination under light microscope, and in cell bodies, dendrites, axons, myelin sheaths, synaptic complexes of nerve cell, neuroglia and vessels in the cerebral cortex, under electron microscope. The lack of abnormal findings in the histological observation of brain tissues supports the result of previously conducted physiological function and psychotic activity tests in which no significant differences were found between treated and control rats. Pentazocine HCl had no effect on the brain tissues of rat offspring from dams administered the drug during perinatal and postnatal periods.

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The present study was undertaken to compare the antihypertensive effects of β-blocking agents and to clarify the relations between antihypertensive effects and β-blocking actions. In this study, blood pressure was measured by a direct cannulation of the abdominal aorta. Subcutaneous administration of carteolol and pindolol caused a significant fall in mean blood pressure in both normotensive and spontaneously hypertensive rats, whereas propranolol produced a rise in blood pressure. Maximum fall in blood pressure was observed 3 ?? 7 hr after the administration of carteolol and pindolol. In order to determine the β-blocking action, changes in heart rate and blood pressure in response to isoproterenol (3 μg/kg i.v.) were observed during the experiment. β-Blocking action was found as early as 1 hr after subcutaneous administration. Carteolol showed the most effective blocking action throughout the experiment. Although β-blocking agents lowered the blood pressure in this experiment, there was no apparent parallel between antihypertensive effects and β-blocking action on the cardiac function.

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Effects of loperamide on diarrhea induced by castor oil and prostaglandin E₁ were investigated in rats and mice and compared with those of narcotic analgesics, atropine, mecamylamine and local anesthetics. The followingresults were obtained. Loperamide markedly suppressed the appearance of diarrhea induced by oral administration of castor oil in rats and the ED50 values for 1 and 2 hr protection was 0.082 and 0.42 mg/kg p.o., respectively. Loperamide markedly suppressed the appearance of diarrhea induced by i.v. administration of prostaglandin E₁ and the ED50 value for 2 hr protection was 0.24 mg/kg p.o. in rats. The ID120 min value of loperamide which was calculated on the basis of the dose producing a 20% or more inhibition of the charcoal transport in the small intestine for 120 min was 0.8 mg/kg p.o. in mice and this activity was 9.2 times more potent than that of morphine. The analgesic ED50 value (Haffner's method) and LD50 value of loperamide was 149 and 249 mg/kg p.o., respectively. These results suggest that loperamide has a potent anti-diarrheal activity and specificity to the gastrointestinal tract and inhibits the effect of prostaglandin E₁ and ricinoleic acid on the intestinal tract in rats.

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Effects of loperamide on peristalsis in the guinea pig intestines were investigated in comparison with those of morphine and atropine. The following results were obtained. The ejection of intraluminal fluid produced by the peristaltic contraction of the isolated ileum was suppressed by loperamide at a concentration of 10^-8 or 2 × 10-^-8 g/ml. Peristalsis in the intestinal loop of anesthetized guinea pigs was inhibited by i.v. administration of loperamide at a dose of 0.03 mg/kg. Morphine (0.03 mg/kg i.v.) and atropine (0.05 mg/kg i.v.) also inhibited the peristaltic contraction. The effect of loperamide continued longer than that of morphine. Peristalsis in the colonic loop of anesthetized guinea pigs was inhibited by i.v. administration of loperamide at a dose of 0.01 or 0.03 mg/kg. Morphine (0.1 mg/kg i.v.) and atropine (0.03 mg/kg ix.) also inhibited the peristaltic contraction of the colonic loop. Loperamide (0.01 or 0.03 mg/kg i.v.) and morphine (0.1 mg/ kg i.v.) caused a slight and temporary increase of resting level of intraluminal pressure with inhibition of peristalsis in the colonic loop. These results suggest that loperamide suppresses the peristaltic contraction caused by distension of the intestinal lumen.

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