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In a program to identify new anti-ulcer compounds, a series of N-acyl derivatives of alpha-amino acids were screened for their in vitro H(+)/K(+) ATPase inhibitory activity, and in vivo efficacy in Pylorus ligation model. 3D-QSAR studies were carried out and a representative compound 13 was studied for the nature of its proton pump inhibition.

1. The effects of dopaminergic agonists and antagonists were investigated on withdrawal signs in lorazepam-dependent rats. Physical dependence was developed by giving lorazepam admixed with food in the following dose schedules: 10 x 4, 20 x 4, 40 x 4, 80 x 4 and 120 x 7 mg/kg, daily for x days. 2. The parameters observed during the periods of administration of lorazepam and after its withdrawal were spontaneous locomotor activity (SLA), reaction time to pain, foot shock aggression (FSA) and audiogenic seizures. 3. During the withdrawal period, rats were divided into groups of 10 rats each. One group did not receive any drug and served as the control withdrawal groups. Three other groups received, separately, one of the following dopamimetic drugs: (i) 200 mg/kg per day, i.m., L-dihydroxyphenylalanine (DOPA; +50 mg/kg per day, i.m., carbidopa); (ii) 2 mg/kg per day, i.m., amphetamine; or (iii) 1 mg/kg per day, i.m., apomorphine. The remaining groups received one of the following dopamine antagonists: (i) 0.1 mg/kg per day, i.m., SCH 23390; (ii) 0.5 mg/kg per day, i.m., haloperidol; (iii) 0.5 mg/kg per day, i.m., centbutindol; and (iv) either 1 or 20 mg/kg per day, i.m., clozapine. 4. The withdrawal signs observed in the control group were hyperkinesia, hyperaggression and audiogenic seizures. 5. L-Dihydroxyphenylalanine (+ carbidopa), amphetamine and apomorphine potentiated hyperaggression and audiogenic seizures. The dopamine D2 receptor antagonists haloperidol, centbutindol and clozapine (at 20 mg/kg, i.m.) blocked all withdrawal signs. The D1 receptor antagonist SCH 23390 inhibited hyperkinesia and hyperaggression. The D4 receptor antagonist clozapine (at 1 mg/kg, i.m.) had no effect on any of the withdrawal signs. 6. It may be concluded that dopamine D2 receptors exert a dominant facilitatory influence, with partial contribution of D1 receptors, on the benzodiazepine withdrawal syndrome.

1. Polyriboinosinic-polyribocytidylic acid (Poly I:Poly C), an interferon inducer was studied for its effect on gastric ulceration in rats. Polyriboinosinic-polyribocytidylic acid (1, 2 and 4 mg/kg, i.m.) showed a dose-dependent inhibition of gastric ulcers induced by aspirin, cold restraint stress and pylorus ligation (Shay's model). Protective dose (PD50) +/- SEM values of Poly I:Poly C on these models of ulcers were 1.9 +/- 0.2, 2.3 +/- 0.4 and 2.8 +/- 0.4 (mg/kg, i.m.) respectively. 2. Polyriboinosinic-polyribocytidylic acid (10-60 micrograms) produced dose-dependent inhibition of gastric proton pump (H+/K(+)-ATPase) activity in the gastric parietal microsomal fraction. The concentration of Poly I:Poly C causing a 50% inhibition (IC50) +/- SEM was found to be 17.6 +/- 1.2 micrograms. 3. Polyriboinosinic-polyribocytidylic acid caused a significant decrease in free and total acid and pepsin and an increase in mucin content in Shay (pylorus-ligated) rat. 4. Polyriboinosinic-polyribocytidylic acid did not exert a significant influence on isolated tissue preparations for anti-cholinergic (acetylcholine-induced contraction of guinea-pig ileum) and H2-anti-histaminic (histamine-induced contraction of rat uterus and guinea-pig auricle) activities. 5. Thus, the present study indicates that Poly I:Poly C may possess anti-gastric ulcer activity as a result of inhibition of the gastric proton pump.

1. The effects of dopaminergic agonists and antagonists were investigated on withdrawal signs in lorazepam-dependent rats. Physical dependence was developed by giving lorazepam admixed with food in the following dose schedules: 10 x 4, 20 x 4, 40 x 4, 80 x 4 and 120 x 7 mg/kg, daily for x days. 2. The parameters observed during the periods of administration of lorazepam and after its withdrawal were spontaneous locomotor activity (SLA), reaction time to pain, foot shock aggression (FSA) and audiogenic seizures. 3. During the withdrawal period, rats were divided into groups of 10 rats each. One group did not receive any drug and served as the control withdrawal groups. Three other groups received, separately, one of the following dopamimetic drugs: (i) 200 mg/kg per day, i.m., L-dihydroxyphenylalanine (DOPA; +50 mg/kg per day, i.m., carbidopa); (ii) 2 mg/kg per day, i.m., amphetamine; or (iii) 1 mg/kg per day, i.m., apomorphine. The remaining groups received one of the following dopamine antagonists: (i) 0.1 mg/kg per day, i.m., SCH 23390; (ii) 0.5 mg/kg per day, i.m., haloperidol; (iii) 0.5 mg/kg per day, i.m., centbutindol; and (iv) either 1 or 20 mg/kg per day, i.m., clozapine. 4. The withdrawal signs observed in the control group were hyperkinesia, hyperaggression and audiogenic seizures. 5. L-Dihydroxyphenylalanine (+ carbidopa), amphetamine and apomorphine potentiated hyperaggression and audiogenic seizures. The dopamine D2 receptor antagonists haloperidol, centbutindol and clozapine (at 20 mg/kg, i.m.) blocked all withdrawal signs. The D1 receptor antagonist SCH 23390 inhibited hyperkinesia and hyperaggression. The D4 receptor antagonist clozapine (at 1 mg/kg, i.m.) had no effect on any of the withdrawal signs. 6. It may be concluded that dopamine D2 receptors exert a dominant facilitatory influence, with partial contribution of D1 receptors, on the benzodiazepine withdrawal syndrome.

It is necessary to use experimental animals with behavioural, physiological and disease susceptibility pattern similar to man so that the results have a clinical predictive value. For such studies the non-human primate is the animal of choice. Rhesus monkey is a good choice for this purpose but information about its behaviour is fragmentary. In order to obtain a quantitative baseline data for psychopharmacological studies, a protocol has been developed to score various social and solitary behaviours in adult male and female rhesus monkeys. The study was conducted on rhesus monkeys in a social colony of one male and seven female living in a semi-restricted environment. The behavioural patterns were quantitated so as to compare effect on various components of behaviour. Aggressiveness and vigilance were prominent in the male while social affiliative behaviour was dominant in the female. Other behavioural responses were of similar magnitude in both sexes. It is however necessary to have data with some standard CNS active agents on these behavioural protocol. Therefore, initially the behavioural effects of amphetamine and haloperidol were studied. Significant effects observed following d-amphetamine (1-4 mg/kg, im); it induced dose dependent suppression of social behaviour (approach, contact, grooming), feeding, hypervigilance, stereotypy and oral hyperkinesia. On the other hand haloperidol (0.01-0.04 mg/kg, im) produced decrease in social and solitary behaviour and marked cataleptic posture. It is possible to quantitate drug effects on various aspects of behaviour of the rhesus monkey and to develop neuropsychitric models with the help of this protocol for use in study of drug effects on behaviour.

Effect of diphenhydramine was investigated on withdrawal signs in lorazepam dependent rats. Physical dependence was produced by giving lorazepam admixed with the food in the following dose schedule: 10 x 4, 20 x 4, 40 x 4, 80 x 4 and 120 x 7 (mg/kg, daily x days). The parameters observed during the periods of administration of lorazepam and after its withdrawal were spontaneous locomotor activity (SLA), body temperature, reaction time to pain, foot shock aggression (FSA) and audiogenic seizures. Diphenhydramine was administered orally in the dose schedules of once daily (10, 20 and 40 mg/kg) and twice daily (5, 10 and 20 mg/kg) in separate groups during the withdrawal period. The withdrawal signs observed in control group (without diphenhydramine) were hyperkinesia, hyperthermia, hyperaggression and audiogenic seizures. Hyperkinesia and hyperthermia were blocked in all the groups of diphenhydramine-treated rats. FSA was inhibited only by diphenhydramine (10 and 20 mg/kg) given twice daily. Audiogenic seizures were completely blocked by once daily (20 and 40 mg/kg) as well as twice daily (20 mg/kg) doses of diphenhydramine. It may be concluded that diphenhydramine exerts a protective effects on benzodiazepine withdrawal syndrome.

Effects of calcium channel blockers were investigated on withdrawal signs in lorazepam dependent rats. Physical dependence was produced by giving lorazepam admixed with the food in the following dose schedule: 10 x 4, 20 x 4, 40 x 4, 80 x 4 and 120 x 7 (mg/kg daily x days). Parameters such as body weight, food intake, spontaneous locomotor activity (SLA), body temperature, reaction time to pain, foot shock-aggression (FSA) and audiogenic seizures were observed during the period of administration of lorazepam and after its withdrawal. Calcium channel blockers viz. verapamil, nifedipine and nimodipine in different doses were administered orally twice daily in separate groups during the withdrawal period. The withdrawal signs observed in control group (without calcium channel blockers) were hyperkinesia, hyperthermia, hyper-aggression and audiogenic seizures. The administration of verapamil (5-20 mg/kg), nifedipine (1.75-7 mg/kg) and nimodipine (5-20 mg/kg) during the withdrawal period of lorazepam showed dose dependent significant blockade of all the withdrawal signs. Audiogenic seizures were completely blocked by 20 mg/kg dose of verapamil and nimodipine while nifedipine was partially effective. It may be concluded that calcium channel blockers exert protective effects on benzodiazepine withdrawal syndrome.

Intracerebroventricular administration of adrenaline, noradrenaline phenylephrine, clonidine and histamine produced a significant rise in plasma cortisol concentration whereas isoprenaline had no effect. alpha-Adrenoceptor blockers (yohimbine or piperoxon) per se did not alter the plasma cortisol level. Central pretreatment with yohimbine or piperoxin, blocked the rise in plasma cortisol level induced by icv noradrenaline, phenylephrine and clonidine. In another set of experiments, both H1 and H2 receptor antagonists (mepyramine, and metiamide) per se had not significant effect on plasma cortisol concentration. Central histamine induced rise in plasma cortisol concentration was significantly blocked by icv pretreatment with both H1 and H2 receptor blockers. Furthermore, yohimbine also significantly prevented the rise of plasma cortisol level induced by icv histamine.

A large-scale epidemiological study of oral cancer and precancer was initiated in 1966 in several regions of India. Phase 1 of the study consisted of a cross-section survey to determine the prevalence of cancer and precancerous lesions, while phase 2 was a 10-year follow-up survey to determine the incidence and natural history of oral precancer. Following these preliminary investigations, an intervention study was started to try to persuade subjects to give up tobacco, and to measure the subsequent changes in the incidence and regression rate of oral precancer. In each of the three study areas, 12 000 adult tobacco users were selected, examined, and interviewed in a house-to-house survey. Information on the ill effects of tobacco use was given through individual discussions with a social scientist, film shows, and posters. The population was reviewed after one year and the proportions of subjects who had discontinued tobacco use were found to be 2% in Ernakulam, 1% in Bhavnagar, and 5% in Srikakulam. Additionally, between 1% and 16% had reduced their tobacco use. In Bhavnagar and Ernakulam the regression rate of leukoplakia was significantly higher among those who had stopped or reduced their tobacco consumption. In Srikakulam there was a highly significant correlation between reduction in tobacco consumption and regression of palatal lesions.

The effect of injecting the alpha-adrenoceptor stimulating drugs adrenaline, noradrenaline and phenylephrine and the beta-adrenoceptor stimulating drug, isoprenaline into the lateral ventricles (i.c.v.) of the brains of dogs on the plasma cortisol concentration was investigated. Adrenaline, noradrenaline and phenylephrine produced a significant rise in the plasma cortisol concentration. Isoprenaline had no effect on the plasma cortisol concentration. The effect of noradrenaline and phenylephrine on the plasma cortisol concentration was completely blocked by yohimbine (i.c.v.). This indicates that the stimulation of central alpha-adrenoceptors can cause the release of adrenocorticotrophic hormone.