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Community pharmacists have many kinds of problems for demonstrating their ability and activity. One of them is to realize the professional activity. At present, I am afraid that such community professional activities might be for now confined to legal extension. I would therefore like to discuss the aspect of professional centrifugal practice in community health care system under the pharmaceutical law system. Secondly, the role of pharmacists in drug sale comprises advising and controlling medication that we call "Application Pharmacy" in which individual pharmacokinetics and susceptivities have to be considered. The Application Pharmacy will be established in the community medical health care system for new pharmacist's activity. The Application Pharmacy should be a requirement for community pharmacists and lead to a notion of "Community Pharmacy Therapeutics."].

The brain levels of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA), the synthesis rate of 5-HT and 5-HIAA, and the elimination rate of 5-HIAA in the rat offspring brain exposed to ethanol were examined. Ethanol was administered as a drinking water (group L) and in combination with 4 g/kg. p.o. of ethanol (group H) to the pregnant mothers during days 3 to 21 of gestation. There was no difference in brain 5-HT levels between control and groups L and H at 2, 3, 4 and 6-7 weeks of age. A significant decrease in brain 5-HIAA levels was observed at 3 and 6-7 weeks of age in group L and group H, respectively. In the pups of group H, the 5-HT synthesis rate and the elimination rate of 5-HIAA reduced at 4 and 6-7 weeks of age in comparison with the respective control pups. On the other hand, in the pups of group L, the 5-HT synthesis rate increased, and the 5-HIAA synthesis rate reduced at 3, 4 and 6-7 weeks of age. These results suggest that differential exposure to ethanol, such as group L and H, in the CNS during developmental period induces a differential change in the activity of serotonergic system.

The effects of constituents of an antitussive and expectorant preparation on physical dependence potential and antitussive activity of dihydrocodeine (DC) were studied. Rats were treated with DC, methylephedrine (ME), chlorpheniramine (CP), and caffeine (CA) singly or simultaneously admixed with food (DC 0.125, ME: 0.25, CP: 0.05, CA: 0.25 mg /g of food) for 7 days. Subsequently, rats were treated with naloxone (0.5 mg/kg, sc) and withdrawal signs produced were observed. Naloxone-precipitated body weight loss in DC-treated rats was suppressed by simultaneous administration of the three drugs (ME, CP and CA) or CP, which is a H1-receptor antagonist. In abrupt withdrawal, the withdrawal signs were also suppressed by CP. Moreover, tripelennamine, the same kind of H1-receptor antagonist, suppressed naloxone-precipitated withdrawal signs, but cimetidine H2-receptor antagonist, did not suppress them. These results may suggest that H1-receptor antagonists suppress the development of physical dependence on DC, and that H1-receptors play an important role in the physical dependence. On the other hand, the cough reflex was induced by electric stimulation in order to evaluate the influence of ME, CP, and CA on antitussive effect of DC in guinea pigs. ME enhanced the effect of DC. These experimental findings suggest that the constituents of the antitussive and expectorant preparation suppress the development of physical dependence on DC, though they increase the antitussive effect of DC.

We investigated the involvement of inhibitory innervation in reflex tracheal dilatation (RTD) induced by inflating the lungs in dogs. RTD was inhibited about 50% by 100 micrograms propranolol injected into the cranial thyroid artery, but was unaffected by adrenalectomy. Residual RTD under beta-blockade was abolished by sections of both the bilateral superior laryngeal nerves and spinal cord at the C1 level. These findings suggest that RTD may be mediated by adrenergic innervation and partly by nonadrenergic inhibitory innervation.

Oral administration of a hot-water extract (Folin) of bamboo grass (Sasa albomarginata MakinoShibata) significantly reduced the incidence of water-immersion and restraint stress-, ethanol-induced and indomethacin-induced gastric ulcers in rats. Histological examination of the Folin-treated gastric mucosa showed that microscopic blood clots overlaid the superficial epithelium, maintaining the cellular integrity of gastric mucosa, especially against stress ulcer. In addition, Folin suppressed the incidence of hyperaemia and a decline of acid mucopolysaccharides in the ethanol-induced ulcer. Folin suppressed a release of histamine from rat mast cells, and stabilized erythrocytes and accelerated their agglutination under acid conditions. These results suggest that a microscopic haemostatic effect of Folin reinforced by a membrane-stabilizing effect might be responsible for the prevention of the gastric lesions.

To investigate the role of bronchoconstriction in the cough reflex, we compared antitussive effects of several drugs with their ability to effect the respiratory tract (i.e. bronchodilation vs. bronchoconstriction). Antitussive activities of five drugs administered either intravenously or orally on electrically-induced cough were evaluated in the non-anesthetized dog. The antitussive activities were as follows: morphine, 0.1 mg/kg (i.v.) and 0.5 mg/kg (p.o.); codeine, 1.0, 4.0; picoperidamine, 2.0, 9.8; piclobetol, 7.6, 9.0; HH-197, 12.5, 143.0, respectively. Morphine, codeine and HH-197 caused bronchoconstriction, but picoperidamine and picrobetol caused bronchodilation. The antitussive and bronchodilatation effects of isoproterenol were abolished by propranolol. Each bronchoconstricting drug (i.e. morphine, codeine and HH-197) was administered concurrently with isoproterenol (10 mug/kg, i.v., and non-antitussive activity), and the cough reflex was observed. Compared with the single administration of each drug, respiratory resistance was decreased and the antitussive effect was increased. These results indicate a strong correlation between bronchodilatation and increased antitussive activity.

Physical dependence on narcotics is induced in laboratory animals by intermittent parenteral administration (2 approximately 3 times daily). However, inducing of dependence on pethidine has been unsuccessful using the parenteral method. Recently, it has been reported that physical dependence on pethidine can be induced by continuous infusion methods (5.6). In the present experiment, pethidine was administered to rats (n=5 approximately 6) by ingestion of pethidine-admixed food preparations (0.5 approximately 4.0 mg/g of feed). The results indicated that (a) when rats are allowed free access to two food preparations (0.5 mg/g vs. 1 mg/g of food) for 7 weeks, spontaneous intake ratios of food (1 mg/g of food) gradually increased from 15% to 30% after 3 weeks. (b) Abrupt withdrawal for 48 hr after a 10 day administration period (2 mg/g of food on day 1 approximately 3 and 4 mg/g of food on day 4 approximately 10) resulted in a loss of body weight in the next 24 hr, and the prewithdrawal level of body weight was recovered in 48 hr. (c) The time course of body weight and food intake during the first 24 hr withdrawal period demonstrated the characteristic pattern of abstinence syndrome of pethidine, viz. early onset (12 approximately 13 hr) and rapid recovery (within 48 hr), as compared to morphine withdrawal. (d) Suppression of pethidine abstinence of both a single injection of morphine (10 mg/kg, s.c.) and substitution for morphine-admixed food was also realized. (e) When levallorphan (5 mg/kg, s.c.) was administered to both pethidine and morphine dependence rats, the maximal decrease in body weight was less than that in morphine dependent rats. These data indicate that pethidine possesses about one fifth the dependence liability of morphine and the maximal abstinence syndrome appears within 24 hr after withdrawal. Conclusively, application of a drug-admixed food preparation in drug dependence tests in rats has proven to be a useful method, particularly in the case of pethidine-like drugs which rapidly disappear from the blood.

Organic semiconductor devices using electrochemically prepared poly(N-methylpyrrole) (PNP) were characterized by capacitance-voltage (C-V) measurements. A device with aluminum evaporated on the PNP behaved as a MOS (metal-oxide semiconductor) diode in vacuum. Assuming the oxide layer between the metal and the PNP to be pure Al2O3, the MOS parameters were calculated. The values obtained for depletion width W = 166 A and acceptor density NA = 1018 cm−3 in the PNP were reasonable by comparison with the previously reported values obtained by Schottky analysis. An indium/poly(p-phenylene)-1,3,4-oxadiazole (POD)/PNP diode was prepared, and C-V measurements were carried out in air. The diode behaved like an MIS (metal-insulator semiconductor) device, but the characteristics showed large variation with frequency. We have proposed a schematic model for this mechanism on the basis of the results obtained by dielectric measurements of POD and the temperature dependence of the MIS characteristics.

Antiasthmatic effect of ipratropium bromide (Sch 1000) which is a quarternary ammonium derivative of atropine was investigated in comparison with atropine in anesthetized dogs. Asthmatic responses were provoked with inhalation of Ascaris suum antigen. Sch 1000 (0.1 approximately 0.3%) and atropine (0.1 approximately 0.3%) were given by inhalation for 10 min prior to or after the antigen inhalation. Pretreatment of Sch 1000 and atropine inhibited the increase in respiratory resistance (Rrs) induced by antigen by 55 approximately 75% and 25 approximately 50%, respectively. After treatment with each drug, the enhanced Rrs was reduced by 40 approximately 55% and 35 approximately 40%, respectively. The activity of Sch 1000 was three fold stronger than that of atropine. Sch 1000 and atropine also effectively inhibited the increase in airway secretion produced by antigen, while both drugs in 0.3% solution had no effect on the normal bronchial tone and secretion. The findings suggest that vagal activity is involved in allergy related asthma and inhalations of anticholinergic drugs such as Sch 1000 show promise in the treatment of bronchial asthma.

The purpose of the present paper is to investigate the effect of combined treatment of morphine and ethanol on preference for morphine or ethanol and morphine dependence formation. Rats were treated with morphine by DAF (drug-admixed food; 0.5 and 1 mg/g food) method or subcutaneous injection (20-100 mg/kg body weight), and/or treated with ethanol solution (5 and 10 w/w %) or oral administration (2.5 g/kg body weight). There were no effects of chronic treatment of ethanol and morphine on preference for morphine and ethanol, respectively. While, preference for morphine did not increase and preference for ethanol enhanced markedly in rats chronically treated with morphine and ethanol. Effect of chronic ethanol treatment on morphine physical dependence formation in rats was evaluated by body weight loss after morphine withdrawal, and the weight loss significantly attenuated and diarrhea was suppressed in comparison with morphine alone group. These results indicated that preference for morphine and morphine physical dependence formation were reduced when rats were chronically treated with ethanol during chronic morphine treatment, and that preference for ethanol was enhanced.

The effect of long-term administration of phenobarbital (PB) or barbital for five weeks on brain aldehyde reductase (A1R) and aldehyde dehydrogenase (A1DH) activities in the rat was studied. Mitochondrial (m)-A1DH and NADH-dependent A1R activities were significantly increased over control values after five-week treatment with PB or barbital, while no significant alteration of supernatant (s)-A1DH and NADPH-dependent A1R activities was observed under the same condition. Increase in m-A1DH activity by the treatment with barbiturates was recovered to the control level, however, increased activity of NADH-dependent A1R was maintained even after the cessation of the treatment. In groups of rats pretreated with barbiturates for five weeks, no animals were induced to sleep after intracerebroventricular injection of PB, and this finding strongly suggests the decrease in sensitivity of rats to barbiturates.

The spontnaeous morphine intake ratio (M-SIR) under free access to morphine-admixed food and quinine-admixed food conditions was measured for 3 weeks in naive and morphine-experienced rats. In the case of morphine (0.5 mg/g of food) vs. quinine (0.5 mg/g of food), naive rats gradually increased M-SIR from 17% to 77%. Using a higher level of morphine- and quinine-admixed food (1 mg/g vs. 1 mg/g of food), M-SIR was more rapidly increased than that in the lower group. Thus while on the 10 approximately 60 mg/kg/day dose range, the M-SIR was gradually increased dose dependently in naive rats due mainly to the positive reinforcing properties of morphine. Morphine-experienced rats showed a significant increase in M-SIR for the first 4 days specifically as compared with naive rats. Morphine dependent rats thus obtained morphine in sufficient amounts to maintain dependent states only after the first 2 approximately 3 days. This choice behavior revealed the psychological aspects of morphine dependence in rats and the preference for morphine was also observed after withdrawal for more than 2 weeks as secondary abstinence syndrome.

Physical dependence on narcotics is induced in laboratory animals by intermittent parenteral administration (2 approximately 3 times daily). However, inducing of dependence on pethidine has been unsuccessful using the parenteral method. Recently, it has been reported that physical dependence on pethidine can be induced by continuous infusion methods (5.6). In the present experiment, pethidine was administered to rats (n=5 approximately 6) by ingestion of pethidine-admixed food preparations (0.5 approximately 4.0 mg/g of feed). The results indicated that (a) when rats are allowed free access to two food preparations (0.5 mg/g vs. 1 mg/g of food) for 7 weeks, spontaneous intake ratios of food (1 mg/g of food) gradually increased from 15% to 30% after 3 weeks. (b) Abrupt withdrawal for 48 hr after a 10 day administration period (2 mg/g of food on day 1 approximately 3 and 4 mg/g of food on day 4 approximately 10) resulted in a loss of body weight in the next 24 hr, and the prewithdrawal level of body weight was recovered in 48 hr. (c) The time course of body weight and food intake during the first 24 hr withdrawal period demonstrated the characteristic pattern of abstinence syndrome of pethidine, viz. early onset (12 approximately 13 hr) and rapid recovery (within 48 hr), as compared to morphine withdrawal. (d) Suppression of pethidine abstinence of both a single injection of morphine (10 mg/kg, s.c.) and substitution for morphine-admixed food was also realized. (e) When levallorphan (5 mg/kg, s.c.) was administered to both pethidine and morphine dependence rats, the maximal decrease in body weight was less than that in morphine dependent rats. These data indicate that pethidine possesses about one fifth the dependence liability of morphine and the maximal abstinence syndrome appears within 24 hr after withdrawal. Conclusively, application of a drug-admixed food preparation in drug dependence tests in rats has proven to be a useful method, particularly in the case of pethidine-like drugs which rapidly disappear from the blood.

Effects of some bile acids on the biliary flow, BSP output and composition (phospholipid, cholesterol, bilirubin and bile acids) were studied in dogs. Ursodeoxycholic acid (UD), chenodeoxycholic acid (CD) and dehydrocholic acid (DC) caused a dramatic increase in biliary flow and BSP output. Relative potencies of these effects were DC greater than CD greater than or equal to UD. UD increased the phospholipid, bile acids and cholesterol concentration but had little effect on bilirubin concentration. Furthermore, UD greatly increased the output of four bile components. CD slightly decreased the phospholipid, cholesterol and bilirubin concentration without the bile acids, while CD increased the output of bile components. After UD or CD administration, the bile acid of each appeared markedly in the bile, dose dependently. On the other hand, DC caused a dramatic decrease of phospholipid, cholesterol and bilirubin concentration but had little effect on bile acids concentration. Output of bile components was increased by DC the first 1 hr but decreased at 2 hr. After DC administration, 3alpha, 7alpha-dihydroxy-12keto-5beta-cholanic acid appeared in the bile while DC did not. Therefore, it is concluded that UD and CD are cholanereticas and DC is a hydrocholeretica.

The relationship between urinary excretion of sex-dependent low molecular weight proteins (LMWP) in male rats and narcotic dependence has been investigated in this study. Chronic administration of codeine (0.5 mg/g food) caused a significant decrease in urinary excretion of LMWP from the third day, without any change in urinary high molecular weight proteins. The decrease recovered to the control level after the withdrawal of codeine. Withdrawal symptoms including loss of body weight and diarrhea were observed following codeine withdrawal. In animals chronically treated with pethidine (1.0 mg/g food), however, neither changes in urinary LMWP excretion nor withdrawal symptoms were observed. These present findings suggest that the decrease in urinary excretion of sex-dependent LMWP is related to narcotic dependence in male rats, since we previously reported the decrease in urinary excreted LMWP in morphine-dependent rats.

The effects of noscapine and chlorpheniramine on physical dependence liability and antitussive activity of dihydrocodeine, a narcotic antitussive, were studied. For developing physical dependence, male Sprague-Dawley rats were treated with dihydrocodeine (DC), noscapine (N), and chlorpheniramine (CP) singly or simultaneously admixed with food (drug-admixed food method (DAF): DC: 0.125, N: 0.25, CP: 0.05 mg/g of food, for 7 days) or were intermittently medicated for 3 days at one-hour intervals through an implanted intravenous cannula (infusion method: DC: 0.5-2, N: 1-4, CP: 0.2-0.8 mg/kg x 24 times/day). Subsequently, rats were treated with naloxone (0.5 mg/kg, sc) and checked for withdrawal signs during 3 hours. Naloxone-precipitated body weight loss of DC was suppressed by simultaneous administration of N or CP. In combined group of DC, N, and CP, withdrawal signs, such as body weight loss, body shakes, and diarrhea, were more remarkably suppressed. Papaverine, the same kind of spasmolytic as N, was tested by the same schedule of DAF. Papaverine did not suppress the naloxone-precipitated withdrawal signs of DC. These results suggest that suppressive effect of N is not due to its spasmolytic action. On the other hand, the cough reflex was induced by electric stimulation in guinea pigs and the fifty percent of antitussive dose (AtD50) was estimated in order to evaluate the influence of N and CP on antitussive effect of DC. N and CP did not change the antitussive effect of DC. These results may suggest that N and CP suppress the development of physical dependence of DC without diminishing the pharmacological effects of DC.

Physical dependence on morphine-type drugs (morphine, codeine and pethidine) in mice were examined by the drug-admixed food method. Mice were treated with drug-admixed food of increasing concentration (1, 2 and 3 mg/g food) every third day for 9 days. Morphine- and codeine-treated mice showed withdrawal signs when they were given naloxone (5 mg/kg, s.c.), while pethidine-treated mice did not show the withdrawal signs. However, mice treated with pethidine-admixed food (1-6 mg/g food) for 28 days showed naloxone precipitated withdrawal signs. Thus, the data obtained with mice indicate that pethidine produces a weak physical dependence. On the other hand, codeine (40 mg/kg, s.c.) and pethidine (100 mg/kg, s.c.) administration suppressed the abrupt withdrawal signs of morphine-dependent mice that were treated with morphine-admixed food, while the withdrawal signs were completely suppressed in mice administered only 5 mg/kg morphine. These results suggest that the physical dependence liability of morphine type drugs can be predicted by the drug-admixed food method.

A single injection of barbital increased glycogen, while it decreased glucose and glucose-6-phosphate levels in the rat brain. In long barbital dosing (36 days), however, the metabolite level of carbohydrate was almost recovered to the non-treated level. At the later stage of withdrawal (24-48 hr), all metabolites examined except lactate decreased. Only lactate increased remarkably. The effect of barbital dosing and withdrawal was almost same in the three portions, i.e., the cerebral cortex, brain stem, and cerebellum. Barbital depresses the central glycometabolism, and at the dependent stage (long term barbital dosing, 36 days or more), metabolism was almost same as the control. At the later period of withdrawal, it appeared that lactate was increased because of the hypoxic condition caused by stroke. In conclusion, carbohydrate metabolism can probably serve as a sensitive measure for the development of barbital dependence and the onset of withdrawal.

In order to understand the relationship between the cough and respiratory centers in the brain stem, we investigated the effects of respiratory stimulants, pentylenetetrazol (PTZ) and nikethamide (NK), and a respiratory depressant, pentobarbital (PB)on the cough reflex. Coughs were induced in lightly anesthetized dogs by intraarterially into the vertebral artery. The rate (RR), amplitude (RA), and volume (RV) of the respiration and the number (NC) and amplitude (AC) of the cough reflex induced were used as indices. PTZ and NK, even at subthreshold doses for respiratory stimulation, enhanced the cough reflex (NC; not AC). On the other hand, PB at subthreshold doses for a respiratory depression decreased both NC and AC. The above findings suggest that respiratory stimulants generally enhance the cough reflex, and respiratory depressants reduce the cough reflex. Additionally, the thresholds for the cough responses to respiratory drugs are lower than those for the respiratory responses.

We examined the quantitative evaluation of preference for morphine by assessing the conflict behavior between positive motivation and negative motivation. The apparatus consisted of a single runway in which both the usual diet and morphine-admixed food were placed. For access to the latter, the rats were compelled to pull heavy weights which were connected to their necks. During the forced trials (only morphine-admixed food was given) and the choice trials (rats could select either food), the preference rates gradually increased and then became stable at levels of 60%. After these trials, experiments on conflict behavior were performed using several different weights. Assessment of relation between the intensity of the dependence on the drug and the degree of weight showed a good correlation. We conclude that the preference for a drug can be quantitatively measured by means of assessing conflict behavior.

Behavior of mucus glycoproteins in tracheal secretory cells after treatment with pilocarpine was investigated histologically and histochemically using the isolated canine trachea. Following pilocarpine treatment, the number of total and neutral glycoprotein-containing goblet cells was reduced concentration-dependently. The number of acid glycoprotein (AGP)-containing goblet cells was not altered with 10(-7) and 10(-6) M pilocarpine, but significantly decreased with 10(-5) and 10(-4) M pilocarpine. The thickness of the acini of submucosal glands significantly decreased, and the ratio of acinar inner diameter to tracheal wall thickness increased in 10(-5) and 10(-4) M pilocarpine. AGP content in glandular cells increased in 10(-7) and 10(-6) M pilocarpine, but markedly decreased at concentrations of 10(-5) and 10(-4) M. Pilocarpine treatment caused an increase in N-acetylhexosamine concentration in the incubation fluid. Total saccharide concentration in the incubation fluid decreased in 10(-7) and 10(-6) M pilocarpine, but was not apparently altered at concentrations of 10(-5) and 10(-4) M. These findings suggest that lower concentrations of pilocarpine stimulate synthesis of AGP in goblet and glandular cells much more preferentially than it stimulates discharge of AGP from the cells. While at higher concentrations, the AGP-discharge effect overcomes the stimulation in synthesis.

Effects of barbital and disulfiram on the metabolism of serotonin (5-HT) in vivo were studied. One hr after intracerebroventricular injection of [14C]-5-HT (3 nmoles, 0.5 muCi), the levels of the total and deaminated radioactive materials were increased in rats receiving either barbital or disulfiram, as compared to those of control rats. In addition, an additive effect was observed by a combined administration of these two drugs. The results in this paper strongly suggest that barbital and disulfiram inhibit the metabolism of 5-hydroxyindoleacetaldehyde (5-HIAAld), a first deaminated metabolite in 5-HT metabolism.

The effect of bromhexine on behaviors of lysosomal enzymes in the submucosal gland was investigated using canine tracheal slice preparations, with reference to the histochemical changes in acid glycoproteins (AGP) in the gland. Incubation of tracheal slices with 1% Triton X-100 or 0.0004-0.04% bromhexine for 30 min decreased the number of stained lysosomes in the glandular cells. The decrease in stained lysosomes after treatment with 1% Triton X-100 or 0.04% bromhexine was effectively prevented by addition of 5% lecithin. The number of glandular cells that were stained red (stain index R) in the combined alcian blue at pH 2.5 and periodic acid-Schiff procedure markedly increased by treatment with 1% Triton X-100 or 0.0004-0.04% bromhexine. In the bromhexine treated groups, there was a close correlation (r=0.932, P less than 0.01) between the increase in the number of glandular cells showing the stain index R and the decrease in the number of stained lysosomes in the cells. These findings suggest that the enzymes which are liberated from lysosomes into the cytoplasm by bromhexine may, at least in a part, be involved in the mucolytic action of the agent on AGP contained in mucus granules of the submucosal gland.

Antipsychotic agents which are considered to depressive to the central nervous system (CNS) but free of dependence liability were used in combination with barbiturates or tranquilizers to study the physical dependence liability in the so-enhanced CNS depression. In the study of physical dependence formation, when CNS depression was maintained in an enhanced stage during the continuous application of the drug combinations, the withdrawal convulsions were enhanced in both frequency and severity. In the crossphysical dependence study, two-drug combinations, i.e., phenobarbital (PhB)-chloropromazine (CPZ), PhB-diphenhydramine (DPH) and nitrazepam-chlorprothixene, and 3-drug combinations (i.e., PhB-CPZ-promethazine and PhB-CPZ-DPH were evaluated. The 2-drug combinations suppressed some of the withdrawal signs, but those at high dosages showed a tendency to aggravate the signs. The 3-drug combinations differed from the 2-drug combinations in that the suppression of withdrawal signs was synergistically enhanced and the barbital withdrawal signs were weak. In conclusion, when CNS depression with PhB was enhanced with combinations of dependence liability-free drugs the drug combinations enhanced withdrawal convulsions both in frequency and severity. The sedation enhanced by the combinations did not always parallel the suppression of barbital withdrawal.

The effects of lithium and disulfiram on the 5-hydroxytryptamine (5-HT) system and hexobarbital (HX)-induced hypnosis were studied. Treatment with lithium significantly prolonged HX hypnosis. Disulfiram, a potent inhibitor of brain aldehyde dehydrogenase, also produced a prolongation of HX hypnosis. A combination of lithium treatment for 3 days with disulfiram synergistically potentiated the HX hypnosis and reduced the brain HX levels on awakening. Furthermore, L-tryptophan loading significantly increased the HX sleeping time and reduced the brain HX level on awakening in lithium-pretreated rats, whereas it had not effect on HX hypnosis in controls rats. L-Tryptophan also potentiated HX hypnosis in disulfiram-treated rats. The combination of L-tryptophan, lithium and disulfiram caused the greatest prolongation of HX hypnosis. However, no synergism between lithium and disulfiram was observed in animals treated with lithium for 5 days. after 3 days of lithium treatment, the rate of synthesis of 5-HT was elevated, whereas it had returned to the control level after 5 days of lithium treatment. Tryptophan loading increased the rate of synthesis of 5-HT more than 2-fold in control animals. The increase in the rate of 5-HT synthesis caused by lithium was further potentiated by tryptophan loading. These results suggest that lithium and disulfiram exert their synergistic effect on HX hypnosis by acting on the 5-HT system and that an accumulation of 5-hydroxyindoleacetaldehyde, an active metabolite of 5-HT, may be responsible for the increase in the brain sensitivity to barbiturates caused by these drugs.

The effects of morphine on plasma corticosterone concentration in rats were studied using the drug-admixed food method. Morphine was mixed with the powder form of rat food in concentrations of 0.5 mg/g, 1 mg/g, and 2 mg/g of food. Plasma corticosterone concentration in rats treated with morphine-admixed food increased significantly, and the increment depended on the morphine concentration of drug-admixed food. The time course change of plasma corticosterone concentration in rats treated with morphine-admixed food (1 mg/g food) for 1 week was similar to that of non-treated rats without the concentration at 9:00. The plasma corticosterone concentration of morphine-treated rats at 9:00 was significantly increased in comparison with that of non-treated rats. Furthermore, the plasma corticosterone concentration after withdrawal in morphine-treated rats increased with time, and a significant increment in corticosterone was observed at 24 hr after the withdrawal. Naloxone, injected subcutaneously into morphine-dependent rats, significantly increased plasma corticosterone concentration. Increment of plasma corticosterone concentration in rats treated with morphine-admixed food for 3 or 4 weeks was significantly different from the non-treated group. The increment of plasma corticosterone concentration after the withdrawal was in a morphine treatment period-related manner. By these results, we suggest that tolerance to the increment action in plasma corticosterone concentration of morphine does not develop for at least 4 weeks using the drug-admixed food method, and the drug-admixed food method could induce morphine dependence without disturbance of the circadian rhythm in plasma corticosterone.

The relationship between the decrease in urinary sex-dependent low molecular weight proteins (LMWP), which exist only in the male rat, and the serum levels of some hormones were examined in this study. Castration of male rats reduced the urinary excretion of LMWP by about 50%. Replacement therapy with testosterone increased the urinary LMWP excretion. Adrenalectomy did not affect the urinary excretion of LMWP. In the adrenalectomized rat, however, corticosterone increased LMWP excretion. Therefore, it is considered that testosterone and corticosterone play a part in the urinary excretion of LMWP under physiological conditions and that the effect of testosterone is more specific than that of corticosterone. Serum concentration of testosterone and corticosterone tended to increase in comparison with the control on the 7th day after chronic treatment with morphine (0.5 mg/g food), when the urinary excretion of LMWP was significantly decreased. Furthermore, after rats were chronically administered morphine following castration or adrenalectomy, the urinary LMWP excretion was markedly decreased in the same way as found in intact animals. On the other hand, the serum thyroxine level of rats treated with morphine for 7 days was significantly lower than that of the control. Thyroxine increased dose-dependently the decreased urinary excretion of LMWP induced by morphine administration. These findings suggest that the decrease in urinary excretion of LMWP after chronic treatment with morphine may be caused by the change of serum thyroxine level via the action of morphine on the endocrine functions.

The present study was made to investigate the developmental toxicity of ethanol and several sedative-hypnotics (barbital, diazepam, phenobarbital) administered to rat pups via dams for 18 days (day 3-21 after parturition) from the relatively early postnatal stage in terms of changes in the threshold for pentetrazol (PTZ)-induced convulsion, tolerance to, and physical dependence on barbital (B). In the pups of all dosed groups, the convulsive threshold for PTZ is reduced significantly compared with that in the naive group. The sleeping time with B in phenobarbital-exposed offspring was also reduced significantly compared with that in the naive pups. No difference was however, noted in the B concentration of the brain or plasma upon awaking between these groups of pups, which proved that the phenobarbital-exposed pups had obviously acquired a functional tolerance to B. B-dependence formation and the ensuring weight loss and appearance of withdrawal signs, especially clonic-tonic convulsion, were made intense in the phenobarbital-experienced pups. From these results, it may be concluded that exposure to sedative-hypnotics from the early CNS developing stage makes a lowered state of convulsive threshold for PTZ, and therefore, tends to enhance B-withdrawal convulsion. These phenomena were discussed from the viewpoint of monoamine metabolism in the brain.

The influence of alfalfa meal on hyperlipidemia induced by dietary cholesterol was examined and changes in serum total cholesterol (TC), triglycerides (TG) and non-esterified fatty acid (NEFA) in rabbits were recorded. Serum lipid levels of groups treated with alfalfa meal (R-1) as well as those not treated (R-2) were found to be elevated. TC of R-1 was lower than that of R-2. The inhibition effect of alfalfa meal on elevation of TC was apparent to a certain extent. The inhibition effect of alfalfa meal on elevation of TG and NEFA was greater than that of TC, thus it is suggested that alfalfa meal can be successfully utilized for experiments with lipids, when the rabbit is the experimental animal of choice. Effect of riboflavine-2,3,4,5-tetranicotinate (RN-4) on changes of TC, TG and NEFA in rats fed 1% cholesterol diet was also examined. RN-4 was mixed in the diet (0.5, 0.25 and 0.125%). TG levels in groups treated with RN-4 (Rt-2, Rt-3 and Rt-4) were lower than previously observed.

The effects of brovanexine (BvX) on secretory activities of tracheal secretory cells and on behavior of mucus glycoprotein in these cells were investigated histologically and histochemically using the biopsy technique. When BvX was given at 10 or 20 mg/kg intraduodenally to anesthetized dogs, the thickness of the acini of submucosal glands (SG) and the ratio of the acinar inner diameter to the tracheal wall thickness (A1WR) markedly increased dose-dependently after 2 to 6 hr. The numbers of goblet cells (GC) and glandular cells showing a stain index BP with a combination of alcian blue (AB) at pH 2.5 or pH 1.0 and periodic acid-Schiff (PAS) were reduced dose-dependently after 1 to 6 hr, while the number of cells with a stain index R were increased. Both the BvX-induced histological changes in SG and histochemical changes in GC and SG reached a peak after 4 hr. These histological and histochemical changes were also found for the BR-227-, a metabolite of BvX, and bromhexine (BH)-treated groups. BR-227- or BH-induced histological changes were to the same degree as those induced by BvX, but BvX- or BR-227-induced histochemical changes were slighter than those induced by BH. The total number of GC stained positively with a combination of AB at pH 2.5 and PAS was unaffected by BvX or BH treatment, while BR-227 tended to decrease it. These findings suggest that BvX both has a secretagogic action selectively on SG and a mucolytic action toward acid glycoprotein in granules of secretory cells in vivo, and these actions are durable.

The experimental results on tolerance to and dependence on phenobarbital (PhB) in male, ICR mice were compared with results previously reported in the case of rats. When food admixed with 1 and 2 mg PhB/g food was administered daily for 13 consecutive days, the mice began to acquire tolerance to PhB from the 4th day or so (rotarod performance test), with little suppression being observed on days 6 or 7. These results indicate that tolerance to PhB is acquired earlier in mice than in rats. The blood and brain concentrations of PhB during the dosing period were reduced abruptly on the 3rd or 4th day, corresponding well with the time course changes in the development of tolerance shown by rotarod performance. The mice were given daily doses of PhB increasing stepwise from 0.5 and 1 mg PhB/g food to 4 mg PhB/g food, over 39 consecutive days. With this gradually increasing dose regimen, the animals maintained moderate to severe depression of CNS throughout the dosing period. The blood and brain half-life of PhB after withdrawal were 16 and 8 hr respectively. From 17 to 24 hours after withdrawal of PhB, the animals showed signs of systemic tremors, Straub-tail, hyperkinesia, wild running "rum fits" and clonic-tonic convulsions. Contrary to the findings in rats, in which there was a frequent incidence of convulsion from 17 to 48 hours after withdrawal, the duration of the characteristic signs after barbiturate withdrawal was obviously short-term. These results suggest that may be more reasonable to use rats in preference to mice as a preclinical model of dependence, especially in cross-physical dependence tests for sedative-hypnotic drugs.

The modification of cough reflex by contraction and relaxation of the peripheral airway was investigated in anesthetized dogs. For administration of the drugs directly into the peripheral airway, an arterial cannula was chronically implanted in the right bronchial artery via the right intercostal artery. The cough reflex was induced by electrical stimulation of the upper tracheal mucosa by means of an electrode-cannula. Evaluation of the cough response was made by changes in frequency and amplitude of coughs. Drug solutions were infused for 5 min at a rate of 0.17 ml/min into the right bronchial artery. Intraarterial infusion of isoproterenol, 1-3 mu g/min, reduced the amplitude, but had no effect on the frequency of coughs, while that of histamine, 3-10 mu g/min, increased the frequency and amplitude of coughs. Atropine, 100 mu g/min, caused no significant changes in amplitude and frequency, respectively. Benzonatate, 0.85 mg/min, reduced the frequency, but had no effect on the amplitude. Thus, the tonus of the peripheral airway, in particular the airway contraction, may the increase the frequency of cough reflex by lowering the threshold of the airway receptors.

A single administration of ifenprodil at the doses of 100, 200 and 400 mg/kg (p.o.), and 50 and 100 mg/kg (i.m.) produced a moderate CNS depression in rats, such as, sedation, ptosis, systemic muscle relaxation and decrease in motor activity. These symptoms appeared dose-dependently and persisted for about 4 hours following administration. In a direct physical dependence test, 5 groups of rats were fed the ifenprodil-admixed food together with drinking water ad libitum for 24 hours daily for 53 approximately 103 days (mean ifenprodil intake, 43--240 mg/kg/day), on the gradedly increased dosage schedule with a dosage level of 0.5 vs. 1 mg/g food to 4 mg/g food. In the natural withdrawal following administration, no significant withdrawal signs were observed in any group. In a substitution test either for phenobarbital or morphine, no suppression of withdrawal signs during the period of cross-administration of ifenprodil and no maintenance of dependence were observed. In a physical dependence-producing test, the rats fed ifenprodil never manifested withdrawal signs such as diarrhea, "wet shakes", sudden loss of body weight as in the levallorphan precipitation test. Ifenprodil apparently has no physical dependence liability.

In the present study, the learned behavior caused by hypothalamic electrical stimulation was examined in order to determine the effects of psychotropic drugs. Subjects were albino male rabbits with electrodes chronically implanted in the hypothalamic area. A shuttle box, which was adjusted for behavioral pharmacological estimation of drugs in rabbits, was used. A buzzer sound (85dB) and electrical stimulation of hypothalamus (100 HZ, 1 msec, 1.2-2.0V) were used as the conditional stimulation (CS) and unconditional stimulation (UCS), respectively. The same animal was trained in habituation to a buzzer sound as the CS. For avoidance conditioning in a two-compartment situation, the animal was placed in a shuttle box divided by a hurdle situated at the middle of two-compartments. After the CS was presented for 10 sec, the UCS was given. The animals were subjected to 15 conditioning trials per day. The avoidance and escape behavior model became as distinct by hypothalamic stimulation as by UCS. After termination of the experiments, extinction trials were carried out after which the animals were sacrificed, and localization of the stimulating electrodes was determined histologically.

Attempts have been made to examine the relationship between urinary excretion of sex-dependent low molecular weight proteins found only in male rats (LMWP) and morphine physical dependence. Chronic administration of morphine produced a dose-related decrease in urinary LMWP excretion, which was correlated to the intensity of withdrawal signs including body weight loss and abnormal behaviors recognized after naloxone challenge. Furthermore, a statistically high correlation was obtained between the decrease in urinary LMWP excretion and the loss of body weight precipitated by naloxone challenge. LMWP was identified immunologically in the livers, kidneys, and sera using an antibody against purified LMWP. The serum level of LMWP was increased rapidly following bilateral nephrectomy. After chronic treatment with morphine, the LMWP content in the livers, kidneys, and sera were decreased. These findings indicate that the decrease in urinary LMWP excretion induced by chronic administration of morphine can be a useful parameter to assess the development of physical dependence on narcotics on the peripheral level without requiring drug withdrawal and naloxone challenge. This decrease in urinary LMWP may be caused by the inhibition of LMWP synthesis in the liver.

Mice were given one or repeated administrations of methylmercury chloride (MMC) in an attempt to determine the sexual differences as related to toxic signs, particularly, motor incoordination and the period to evolvement of toxicity. Male and female mice were given 50.6 mg/kg of MMC (about equal to the LD50 in female mice) orally only once, and changes in general behavior and mortality were observed for the following 13 days. Another group of male and female mice was fed food containing 50 and 100 ppm of MMC for 30 days, respectively. The rotarod performance test was carried out daily during the application period, to compare the onset stages of toxic signs and motor incoordination between the groups. The mercury content of the brain was measured at 1- to 2-day intervals during the application period. When the animals were given MMC only once, the males began to die at 3 days, 7/8 of the group dying by the 7th day, while the females began to die at 8 days, with 5/8 of the group dying thereafter: there was thus an obvious sexual difference in the toxicity. When the animals were given MMC admixed with food, however, the females proved more sensitive to the compound both in onset and severity of toxic signs. The onset was seen in the females at the stage when they had ingested about half the amount of the toxic food ingested by the males. The onset and the period in days to the onset of suppressed rotarod performance both in the groups on 50 and 100 ppm were correlated to the daily intake of MMC, the total MMC intake to the onset in the 2 groups being similar. The accumulation of mercury in the brain increased linearly in both groups, with the MMC content of the brain at the onset was about 20 microgram Hg per g of brain (on the wet basis), i.e., about twice that of the human brain. The mercury content in the brain of the female mice tended to reach the toxicity threshold earlier than that in the brain of the males.

The effects of brovanexine (BvX) and BR-227 on sectetory activities of tracheal submucosal glands (SG) including behavior of mucus glycoproteins in the cells were investigated. BvX, BR-227 or bromhexine (BH) was given repeatedly at a dose of 10 or 20 mg/kg p.o. a day, to rats for 1, 3, 7 or 14 days. Then, the trachea was excised and drug effects were determined according to our histological/histochemical technique. The outer diameter of the acini of SG did not change, but the inner diameter markedly increased by the drug given for 3-14 days. The ratio of the acinar inner diameter to the tracheal wall thickness (AIWR) was increased with the 3, 7, and 14 day treatments with BvX or BR-227 at a dose of 10 mg/kg a day. On the other hand, these drugs at a dose of 20 mg/kg a day caused an increase in AIWR when drug was given for 1-14 days. BH (10 mg/kg a day)-induced increase in AIWR was shown when drug was administered for 7 and 14 days. The number of SG cells stained blue with alcian blue (pH 2.5)/periodic acid-Schiff decreased with the 1, 3, 7 and 14 day treatments, and a part of SG cells became red with the 7- and 14-day treatments. There was no significant difference in the effects among the three drugs both qualitatively and quantitatively. These findings indicate that repeated treatments with BvX and BR-227 have an effective secretagogic action on SG, and in addition, a mucolytic action toward acid glycoprotein in granules of the cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Participation of histamine H1- and H2-receptors in both asthmas, i.e. experimentally induced bronchoconstriction and bronchosecretion, with ascaris suum and histamine in anesthetized dogs was investigated. Dogs given 0.2% histamine solution or ascaris antigen (3 mg protein) by inhalation showed increases in respiratory resistance (Rrs) and respiratory rate to 2.5-5.0 fold. Airway secretion volume was also significantly increased 3-4 fold. The increase in Rrs by histamine inhalation was effectively inhibited or abolished by a histamine H1-receptor antagonist, chlorpheniramine (0.3-1 mg/kg i.v.), but not by a H2-receptor antagonist, cimetidine (1-3 mg/kg i.v.). The increase in Rrs by antigen inhalation was reduced by relatively high doses of chlorpheniramine (1-3 mg/kg i.v.), and not by cimetidine. In contrast, hypersecretion of tracheobronchial fluid in both asthmas was significantly prevented by either chlorpheniramine or cimetidine. Combinations of both antagonists abolished the hypersecretion. Atropine (2 mg/kg i.v.) significantly inhibited the occurrence of responses in both asthmas. The results suggest that histamine is involved in the allergic asthma produced by ascaris suum and that histamine directly evokes airway constriction through H1-receptors and hypersecretion of tracheobronchial fluid through H1- and H2-receptors, and, in part, indirectly activates the cholinergic pathway.

The antitussive effect of the new compound 1, 2, 3, 4a, 9b-hexahydro-8, 9b-dimethyl-4-[3-(4-methyl-piperazine-1-yl) propionamide] dibenzofuran-3-one dihydrochloride (RU-20201) was investigated in dogs and guinea pigs, including its sites of action. The antitussive effect of RU-20201 was about 1/10 as potent as that of codeine phosphate in dogs with the puncture electrode-induced cough (PEC) method and about 1/12 and 1/4 as potent as that of codeine phosphate in guinea pigs with the PEC and chemical stimulation methods, respectively. When RU-20201 was administered in a dose range of 1 to 10 mg into the vertebral artery toward the brain in lightly anesthetized dogs, no antitussive effect was observed against the coughing elicited by electrical stimulation of the central cut end of the superior laryngeal nerve. However, a stimulative effect on respiration, especially on respiratory rate occurred. The peripheral effect of RU-20201 on the cough was investigated using the in situ upper trachea perfusion preparation which allows a direct drug administration to the local site around the tracheal mucosa, this site being electrically stimulated to induce coughing. A close i.a. infusion of RU-20201 in doses of 1 and 3 mg/min into the tracheal vascular bed for 5 min inhibited the cough response elicited by mucosal stimulation. The above findings suggest that RU-20201 has a significant antitussive activity, the site of action being probably, at least, at the cough receptor level.

The effects of bromhexine on secretory activities of canine tracheal secretory cells with stimulated synthesis of acid glycoprotein (AGP) by pilocarpine 10(-6)M treatment an on behaviour of glycoprotein in these secretory cells were investigated histologically and histochemically. Following bromhexine treatment, the number of total glycoprotein-containing goblet cells (GC) remained unchanged. The numbers of AGP-containing and sulphated glycoprotein (SGP)-containing GC significantly decreased, while neutral glycoprotein (NGP)-containing GC significantly increased. The acinar inner diameter of the submucosal gland and the acinar inner diameter of this gland to wall ratio slightly increased. Thickness of the acinus and Reid index slightly decreased, concentration-dependently. AGP and SGP content in glandular cells decreased, while NGP content in these cells markedly increased. Bromhexine 10(-5) and 10(-4)M treatment resulted in increased total saccharide and protein concentrations in the incubation fluid, whereas the agent significantly decreased N-acetylhexosamine, in a concentration-dependent manner. These findings suggest that while bromhexine does not stimulate secretory activities of GC, it does slightly stimulate the activities of the submucosal glands. Bromhexine markedly dissolves AGP in the granules of these secretory cells.