No description available.

No description available.

No description available.

No description available.

Isoidide dinitrate (IIDN), a new nitrate ester, an isomer of isosorbide dinitrate (ISDN) and isomannide dinitrate (IMDN), has been studied on the isolated rabbit intestine and on the anesthetized rat blood pressure. Potency was observed as was tachyphylaxis and the effect of certain blocking agents. On the isolated rabbit intestine similar results were obtained when nitroglycerin was substituted for IIDN. In both preparations IIDN was more potent than ISDN or IMDN and ISDN more potent than IMDN. The potency dependence on configuration suggests a possible action on specific receptor sites. A type of tachyphylaxis to IIDN which was prominent in the isolated rabbit intestine was almost absent in the anesthetized rat blood pressure. This is probably due to metabolism of the drug in the intact animal and further suggests an action on receptors. In these preparations the nitrate action was not blocked by: the beta adrenergic blocking agents DCI or nethalide, the alpha adrenergic blocking agent dibenzyline, or a combination of an alpha and a beta blocking agent. Drugs that are selectively blocked by these agents were used as controls to indicate the presence of the desired blocking action. Neither the primary bretylium-like action nor the secondary reserpine-like action of guanethidine blocked the effect of IIDN on the isolated rabbit intestine. Depletion of catechol amines by pretreating the animals with reserpine did not alter the response of either preparation to the nitrate esters. The antihistamine diphenhydramine did not block the vasodepressor action of IIDN on the anesthetized rat blood pressure. It was concluded that although IIDN probably does not exert its effect through combination with adrenergic or histaminergic receptors, it possibly acts on receptors which are specific for the nitrite or nitrate group. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Graduate

The alpha-glyceryl ethers (AGE) are widely distributed in nature, occurring in many marine organisms, land animals, plants, and humans. A series of preliminary experiments was begun to determine whether these compounds possessed possible pharmacological actions against inflammation. Anti-inflammatory tests utilized both the granuloma pouch and cotton pellet granulation methods. Possible glucocorticoid activity was checked by measuring liver glycogen deposition. The effects of AGE on growth and weight of the animals was also noted. Neither selachyl dihemisuccinate sodium (selachyl DHSS) nor selachyl alcohol decreased the exudate formation in the granuloma pouch experiments, although excellent results were obtained with hydrocortisone. The high dose of the AGE was the equivalent of ten milligrams; low doses were three hundred and six hundred micrograms. Routes of administration used were oral, intraperitoneal, and subcutaneous. In the cotton pellet granuloma test, some indication of anti-inflammatory activity was obtained, in accordance with previous results in this and other laboratories. Selachyl DHSS decreased granulation tissue formation by only 11.7% in growing rats, which is not significant; however, in mature rats, there was a decrease of 29.5%. The dosage used in this series was 30 milligrams per kilogram daily by the subcutaneous route, A definite and comparatively large increase in liver glycogen deposition was observed in rats allowed to eat freely, when given selachyl DHSS subcutaneously. These glycogen values were decreased radically by a paired feeding study in which the treated rats were allowed to eat only the same amount of food as their paired control animal. Thus food intake appears to be one of the factors responsible for the increased glycogen storage. The AGE appear to affect growth only by the Intraperitoneal route of administration. In this case, the growth of rats was retarded by 29.6%. It was also noted that these animals ate somewhat less food than the controls, although this did not appear to be an important enough difference to account for the lack of weight gain. Throughout these experiments one of the most notable observations was a lack of uniformity of the results. Factors which appeared to cause a variability in the outcome of tests included the age of the animals, length of time of preoperative housing in new quarters, route of administration, and dosage. A non-linear relationship between dose and effect appears probable. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Graduate

No description available.

The finding that the performance of a response during periods of drug exposure facilitates the development of tolerance to the effects of the drug on that response is commonly referred to as contingent drug tolerance. Contingent tolerance is typically demonstrated in before-and-after design experiments. One group of subjects receives drug before the performance of the criterion response (drug-before-test condition) and a second group of subjects receives drug after the performance of the criterion response (the drug-after-test condition). The usual finding is that substantial tolerance develops in the drug-before-test condition, but no tolerance whatsoever develops in the drug-after-test condition. Such demonstrations of contingent tolerance have led to the drug-effect theory of tolerance: the theory that tolerance to a particular drug effect is an adaptive response to the experience of that particular drug effect. The purpose of this thesis was to clarify the relation between drug exposure, drug effects, and the development of tolerance. Several experiments have demonstrated that no tolerance whatsoever develops to anticonvulsant drug effects if convulsive stimulation is administered prior to each drug injection (drug-after-test condition), rather than afterwards (drug-before-test condition). Be that as it may, a different experimental design was used in Experiments 1 and 2 to show that small amounts of tolerance develop in the absence of concurrent convulsive stimulation. Rats that received either 3 intraperitoneal injections of diazepam (5.0 mg/kg) per day for 10 days (Experiment 1) or 1 gastric intubation of ethanol (5 g/kg) for 21 days (Experiment 2) were significantly more tolerant than vehicle controls; however, the tolerance could be detected only by a sensitive savings measure. The purpose of Experiment 3 was to test a novel interpretation for the inconsistency between Experiments 1 and 2 on the one hand and the repeated failure to observe tolerance to anticonvulsant drugs following drug exposure without concurrent convulsive stimulation in the drug-after-test condition of before-and-after experiments on the other. This hypothesis is that small amounts of tolerance do develop following each drug injection in the drug-after-test condition but that it is dissipated the next day by the convulsive activity experienced in the absence of the drug. To test this hypothesis, one group of amygdala-kindled rats received 15 diazepam injections (2.5 mg/kg) each before a convulsive stimulation, one group received 15 diazepam injections each after a convulsive stimulation, one group received 15 diazepam injections with no convulsive stimulation, and one group received 15 vehicle injections either with or without convulsive stimulations. The drug-before-stimulation rats developed substantial tolerance as has been frequently reported, and the hypothesis was confirmed by the finding that the drug-only rats developed tolerance significantly faster than the rats in the drug-afterstimulation group and the rats in the vehicle-control group. The results of these experiments make two important points. First, tolerance develops following drug exposure even when the criterion response is not performed during drug exposure —albeit substantially less than when it is performed. Presumably, this is because a few of the neural circuits that are active during a convulsion are spontaneously active following the drug administration. Second, the reason why the subjects in the drug-after condition display no evidence of tolerance is because the drug-free performance of the criterion response prior to each drug exposure causes any tolerance that has developed to dissipate.

No description available.

The finding that the performance of a response during periods of drug exposure facilitates the development of tolerance to the effects of the drug on that response is commonly referred to as contingent drug tolerance. Contingent tolerance is typically demonstrated in before-and-after design experiments. One group of subjects receives drug before the performance of the criterion response (drug-before-test condition) and a second group of subjects receives drug after the performance of the criterion response (the drug-after-test condition). The usual finding is that substantial tolerance develops in the drug-before-test condition, but no tolerance whatsoever develops in the drug-after-test condition. Such demonstrations of contingent tolerance have led to the drug-effect theory of tolerance: the theory that tolerance to a particular drug effect is an adaptive response to the experience of that particular drug effect. The purpose of this thesis was to clarify the relation between drug exposure, drug effects, and the development of tolerance. Several experiments have demonstrated that no tolerance whatsoever develops to anticonvulsant drug effects if convulsive stimulation is administered prior to each drug injection (drug-after-test condition), rather than afterwards (drug-before-test condition). Be that as it may, a different experimental design was used in Experiments 1 and 2 to show that small amounts of tolerance develop in the absence of concurrent convulsive stimulation. Rats that received either 3 intraperitoneal injections of diazepam (5.0 mg/kg) per day for 10 days (Experiment 1) or 1 gastric intubation of ethanol (5 g/kg) for 21 days (Experiment 2) were significantly more tolerant than vehicle controls; however, the tolerance could be detected only by a sensitive savings measure. The purpose of Experiment 3 was to test a novel interpretation for the inconsistency between Experiments 1 and 2 on the one hand and the repeated failure to observe tolerance to anticonvulsant drugs following drug exposure without concurrent convulsive stimulation in the drug-after-test condition of before-and-after experiments on the other. This hypothesis is that small amounts of tolerance do develop following each drug injection in the drug-after-test condition but that it is dissipated the next day by the convulsive activity experienced in the absence of the drug. To test this hypothesis, one group of amygdala-kindled rats received 15 diazepam injections (2.5 mg/kg) each before a convulsive stimulation, one group received 15 diazepam injections each after a convulsive stimulation, one group received 15 diazepam injections with no convulsive stimulation, and one group received 15 vehicle injections either with or without convulsive stimulations. The drug-before-stimulation rats developed substantial tolerance as has been frequently reported, and the hypothesis was confirmed by the finding that the drug-only rats developed tolerance significantly faster than the rats in the drug-afterstimulation group and the rats in the vehicle-control group. The results of these experiments make two important points. First, tolerance develops following drug exposure even when the criterion response is not performed during drug exposure —albeit substantially less than when it is performed. Presumably, this is because a few of the neural circuits that are active during a convulsion are spontaneously active following the drug administration. Second, the reason why the subjects in the drug-after condition display no evidence of tolerance is because the drug-free performance of the criterion response prior to each drug exposure causes any tolerance that has developed to dissipate. / Arts, Faculty of / Psychology, Department of / Graduate