[The proposal for community pharmacist activity from a viewpoint of science history].

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."].

Sex differences in physical dependence on pentobarbital in four inbred strains of rats.

1. In Lewis (LEW), Fischer 344 (F344), Spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) rats, pentobarbital (PB)-induced sleep time was much longer in female than in male rats. 2. At the time of awakening, brain levels of PB were significantly higher in the female F344 than in the male rats, but there was no sex differences in other strains. 3. Each strain of rats was treated with PB-admixed food for 47 days. There were significant sex differences in mean drug intake of the SHR and LEW strains, but not the WKY and F344 strains during the final concentration. 4. Only female rats exhibited moderate to severe motor impairment by PB. 5. After PB treatment ended, various signs of PB withdrawal occurred in female, but not male, rats. These marked sex differences were observed in all four inbred strains. 6. The sex differences in physical dependence on PB may be due mainly to differences in rates of drug metabolism for the LEW, SHR and WKY rats, and to differences in CNS sensitivity for the F344 rats.

Developmental changes in serotonergic neurons by maternal ethanol consumption in the rat offspring.

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 on and antitussive activity of dihydrocodeine].

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.

Inhibitory modulation of the reflex tracheal constriction induced by afferent vagal stimulation.

Afferent cervical vagal electrical stimulation caused a reflex tracheal constriction. Atropine changed the tracheal constriction into a tracheal dilatation that was almost inhibited by propranolol. In the hypertonic trachea with 5-hydroxytryptamine, a reflex dilatation following a constriction was observed by afferent vagal stimulation. The reflex dilatation was inhibited about 50% by propranolol and was abolished by hexamethonium. These results suggest that the adrenergic and nonadrenergic inhibitory innervations may mediate the reflex tracheal dilatation, especially in a hypertonic tracheal condition.

Preference for cocaine by the weight pulling method in rats.

The purpose of the present study is to show the efficiency of the weight pulling method in evaluating quantitatively the positive reinforcing effect of cocaine. Rats were trained to pull the weight in order to eat the drug-admixed food (DAF). The experiments began with the preexposure of the drug through the repetition of CFF schedule. The schedule consisted of one choice trial (C) between the intake of normal food and DAF followed by two consecutive forced trials (F), in which the rats were forced to take the DAF only. The study consisted of Experiment I, where cocaine concentration in DAF was varied while the period of cocaine preexposure was kept constant and Experiment II, where the period of preexposure was varied while the cocaine concentration was kept constant. Results show that the reinforcing effect of cocaine was dependent on cocaine intake. On the other hand, the reinforcing effect of cocaine was independent of cocaine preexposure period. The effect of cocaine on the drug-seeking behavior was evident on the first day of cocaine exposure. It is concluded that the weight pulling method is sufficient to evaluate quantitatively the reinforcing effects of cocaine in rats, and this method may be useful for the prediction of dependence potential in man.

Involvement of inhibitory innervation in reflex tracheal dilatation induced by lung inflation.

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.

Preferences for opioids by the weight pulling method in rats.

The preference for morphine and codeine was studied by means of the antagonistic conflict behavior between the positive drive of drug intake and the negative drive of weight pulling in rats. An apparatus was developed in which rats were compelled to pull the weight for the intake of drug-admixed food. The experiments began with the preadministration of the drug through the repetition of CFF schedule. The schedule consisted of one choice trial between the intake of normal food and drug-admixed food followed by two consecutive forced trials, in which the rats were forced to take the drug-admixed food only. In the test trial, the findings were that the rats which had already shown a drug seeking behavior toward morphine or codeine pulled weight to take each drug and that the reinforcing effects of these drugs on the drug seeking behavior depended on the treatment period of these drugs. The reinforcing effect of codeine was weaker than one of morphine. It is suggested that the reinforcing effects of these opioids can be evaluated quantitatively by the weight pulling method in rats.

Histo-chemical studies on the anti-ulcer effect of bamboo grass in rats.

Oral administration of a hot-water extract (Folin) of bamboo grass (Sasa albomarginata Makino & Shibata) 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.

Induction of physical dependence on pentobarbital by new infusion method in the rat.

1. A new intermittent intravenous infusion method was developed for the induction of tolerance to and physical dependence on pentobarbital in rats. 2. Female and male rats were injected with pentobarbital (20 mg/kg/injection) through an implanted intravenous cannula. 3. The rats were allowed to receive an injection after the completion of a fixed amount of behavioral activity counted from the preceding injection, and therefore, the sedative and hypnotic effects of pentobarbital were used as an index in the determination of the injection intervals. 4. During pentobarbital treatment, the number of pentobarbital injections per day rapidly increased and stabilized (approximately 40: male, approximately 30: female) on the third to fifth day. 5. Upon withdrawal, the female and male rats who were maintained on pentobarbital administration of more than 30 and 40 injections/day for approximately 10 days manifested withdrawal signs which included spontaneous convulsion. 6. These results suggest that a new infusion method exists to produce a high degree of physical dependence in rats on a short-acting barbiturates, pentobarbital.

Modification of the effects of naloxone in morphine-dependent mice.

Mice were rendered dependent on morphine by mixing morphine with their food (2 mg/g) for three days. Increasing doses of naloxone precipitated dose-dependent withdrawal reactions such as weight loss and jumping. These withdrawal reactions were antagonized by morphine pretreatment. Effects of morphine, such as increased locomotor activity, inhibition of intestinal transport, and analgesia were antagonized by naloxone in both non-dependent and dependent subjects. The antagonist actions of naloxone were increased in dependent subjects; lower doses of naloxone were sufficient to antagonize effects of morphine. The present results confirm earlier studies indicating that precipitation of withdrawal can be antagonized by morphine pretreatment suggesting that withdrawal reactions are due to actions of naloxone at the same receptor at which opioid agonists act. The increased antagonist potency of naloxone in dependent subjects extends earlier results obtained with analgesic effects to several other agonist effects of morphine and is consistent with the interpretation that exposure to an opioid agonist induces a change in the conformation of opioid receptors.

[The effects of noscapine and chlorpheniramine on physical dependence and antitussive activity of dihydrocodeine].

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.

[Effects of flutropium bromide, a new antiasthma drug, on mediator release from mast cells and actions of mediators].

The effects of flutropium bromide (Ba598Br), a new antiasthma drug possessing the quarternary ammonium structure of atropine derivatives, on mediator release from mast cells and on actions of leukotriene (LT) D4 and serotonin were investigated. Flutropium bromide (3 and 10 mg/kg, i.v.) showed an inhibitory action on the 48 hr homologous PCA in guinea pigs. Atropine showed no inhibitory effect. Flutropium bromide also inhibited the release of histamine from isolated rat mast cells stimulated by antigen, although the inhibitory action was weaker than that of disodium cromoglycate. Atropine also had no inhibitory action in this case. Flutropium bromide and atropine showed no antagonistic action against LTD4-induced contraction of isolated tracheal smooth muscle of guinea pigs. Inhalation of flutropium bromide (0.3%) also showed no antagonistic action against serotonin-induced bronchoconstriction in dogs. From the above results, it is indicated that flutropium bromide has a weak mast cell stabilizing action, but no antagonistic action against LTD4 and serotonin.

Effects of antiallergic drugs on bronchial and cutaneous anaphylaxis in Lewis rats.

Effects of antiallergic agents on 2,4-dinitrophenylated Ascaris extract (DNP-As)-induced bronchial asthma were studied in Lewis rats, and compared with those on passive cutaneous anaphylaxis (PCA). Effects of methysergide and chlorpheniramine on the bronchial asthma model were also investigated. Rats were actively sensitized with DNP-As antigen and with killed Bordetella pertussis. After 8 d, asthmatic response was provoked by inhalation of DNP-As. The bronchomotor response was measured with a modified Konzett-Rössler method in diaphragm-sectioned rats. The inhalation of DNP-As caused a marked asthmatic bronchoconstriction without significant effect on systemic blood pressure and heart rate. Disodium cromoglycate (DSCG), 10 mg/kg, i.v., trans-4-guanidinomethylcyclohexanecarboxylic acid p-tert-butylphenyl ester hydrochloride (NCO-650) and tranilast at doses of 30 and 100 mg/kg, intraduodenally, significantly inhibited the asthmatic response. Chlorpheniramine and methysergide at a dose of 1 mg/kg, i.v. also significantly inhibited it. The above doses of NCO-650 and tranilast significantly inhibited 48 h PCA, while DSCG almost abolished the PCA. These results indicate that 1) NCO-650 and tranilast inhibited both the asthmatic response and PCA in almost the same degree, 2) DSCG inhibited PCA much more strongly than asthmatic response, and 3) histamine and 5-hydroxytryptamine may be involved in this asthmatic response.

Effect of opioid agonist-antagonist interaction on morphine dependence in rats.

Morphine dependence was induced by treatment with morphine-admixed food (0.25mg/g of food) for 7 days. Withdrawal was precipitated by injecting naloxone (0.5mg/kg, s.c.). Rats treated with morphine exhibited body weight loss upon the naloxone injection. When morphine-dependent rats were injected subcutaneously with morphine, codeine, meperidine and pentazocine 30 min before the naloxone injection, these drugs significantly suppressed the naloxone-precipitated loss of body weight in a dose-dependent manner. However, body weight loss induced through coadministration of naloxone and Mr-2266 BS were not suppressed by morphine pretreatment. These results suggest that opioids protect against naloxone-precipitated loss of body weight, and that mu and kappa opiate receptors play an important role in the protection against naloxone-precipitated withdrawal.

Genetic differences in the development of physical dependence on pentobarbital in four inbred strains of rats.

Fischer 344 (F344), Lewis (LEW), spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) rats were chronically fed food containing pentobarbital on an escalating drug dosage schedule over a period of 47 days. During treatment, the growth curve in LEW, SHR and WKY rats was suppressed as compared with the respective controls. Motor incoordination was evaluated by a rotarod performance test. The ranking of the motor incoordination was as follows: WKY much greater than LEW greater than SHR greater than F344. After substitution of normal food for the pentobarbital-admixed food, various signs of pentobarbital withdrawal occurred. The withdrawal signs from pentobarbital in F344, LEW and SHR rats were mild as compared with those in WKY rats. The order of the severity of withdrawal signs in four inbred strains was parallel to that for motor incoordination. These results suggest that the differences between strains in withdrawal can be attributed to differences in the degree of chronic CNS depression produced by pentobarbital.

Strain difference in an allergic asthma model in rats.

A new rat asthma model was devised, and with the model, allergic bronchoconstrictor responses and effects of disodium cromoglycate (DSCG) were compared among Wistar, Lewis and Fischer 344 rats. Rats were actively sensitized with DNP-Ascaris antigen (DNP-As) and killed Bordetella pertussis vaccine. After eight days, asthmatic response was provoked by inhalation of DNP-As. The bronchomotor response was measured with a modified Konzett-Rössler method in diaphragm-sectioned rats. The inhalation of DNP-As using a newly devised apparatus caused a marked asthmatic response with negligible effects on systemic blood pressure and heart rate. The extent of the bronchoconstriction provoked was of the following order: Wistar greater than Lewis = Fischer 344. There was no relationship between the individual 48 hr PCA titer and the bronchoconstriction that occurred in any strain of rats. The bronchoconstrictions were inhibited by DSCG (10 mg/kg, i.v.) and the inhibition ratios were 28%, 36% and 33% in Wistar, Lewis and Fischer 344 rats, respectively. The inhibitions were statistically significant in the latter two strains. Fischer 344 rats were more susceptible to the damage resulting from the operative procedures. The above findings suggest that Lewis rats are the most suitable among the above strains as a model for studying the effects of antiallergic agents.

Effects of mast cell stabilizers on a new bronchial asthma model using compound 48/80 in dogs.

Development of a nonimmunologically induced experimental asthma model using compound 48/80 was attempted. Male mongrel dogs anesthetized with pentobarbital-Na were immobilized with decamethonium bromide under artificial respiration. Airway resistance was measured with a modified Konzett-Rössler method and expressed as a change in ventilation overflow (VO). Inhalation of compound 48/80 caused no change in VO even in high concentrations up to a 1% solution. Infusion of compound 48/80 into the bronchial artery at a dose of 0.2 mg/min for 10 min by using the right bronchial perfusion method caused a marked increase in VO accompanied by decreases in perfusion pressure and systemic blood pressure. The compound 48/80-induced bronchoconstriction was inhibited 58% by surgical vagotomy and was almost abolished by chlorpheniramine (10 mg/kg, intraduodenally (i.d.)). Disodium cromoglycate (inhalation of 1% solution along with 5 mg/kg, i.v.), tranilast (300 mg/kg, i.d.) and NCO-650, a new antiallergic drug (100 mg/kg, i.d.) significantly inhibited the compound 48/80-induced bronchoconstriction. These results indicate that compound 48/80 infusion into the bronchial artery produces an asthma-like bronchoconstriction, the main chemical mediator involved in this response would be histamine acting through H1-receptors, and effects of mast cell stabilizers can be evaluated with this model.

[Physical dependence liability test of 4-(o-benzylphenoxy)-N-methylbutylamine hydrochloride (MCI-2016) in rats].

An acute administration of MCI-2016 at the doses of 30, 100 and 300 mg/kg (p.o.), and 10, 20 and 30 mg/kg (i.p.) produced a slight CNS depression in rats, such as, sedation, ptosis, decrease in motor activity and systemic muscle relaxation. In a direct physical dependence test, rats were fed the MCI-2016-admixed food together with drinking water ad libitum for 24 hours daily for 51-71 days (mean MCI-2016 intake 29.9-210.7 mg/kg/day), on the gradedly increased dosage schedule with a dosage level of 0.25 and 0.5 mg/g food to 4 mg/g food. In a natural withdrawal following administration of MCI-2016, no significant withdrawal signs were observed in any group. In a naloxone-precipitation test the rats that were treated with MCI-2016-admixed food did not show any withdrawal signs. In a substitution test in either morphine or barbital dependent rats, no suppression of withdrawal signs or maintenance of dependence were observed by cross-administration of MCI-2016. In conclusion, MCI-2016 was considered to have no physical dependence potential.

The effects of chlorpheniramine and antiallergic drugs on Ascaris suum antigen-induced active cutaneous anaphylaxis in dogs.

Effects of chlorpheniramine and two antiallergic drugs on the active cutaneous anaphylaxis (ACA) reaction induced by intradermal injection of Ascaris suum antigen in naturally sensitized dogs were investigated. Chlorpheniramine (10 mg/kg, intraduodenally (i.d.)) almost abolished the ACA reaction. NCO-650 (100 mg/kg, i.d.) had no inhibitory effect, while tranilast (300 mg/kg, i.d.) showed a weak inhibitory effect. These findings show that the ACA reaction is almost totally mediated by histamine and ACA reaction is considerably resistant to antiallergic drugs such as tranilast and NCO-650.