Beta-hydroxy thujaplicin (BHT) is a naturally occurring tropolone found in the heartwood of the Western Red Cedar (Thuja plicata D.Don.). It has been found to possess both stimulatory and depressant components, depending on the dose, when administered to mice. It has also been shown to increase the toxicity of lead and in limited microbiological studies, it was found to be both bacteriostatic and fungistatic in vitro. The stimulant effects of BHT were manifest in mice by a hyperexcitability and in larger doses by convulsions. In rabbits, the convulsive pattern was obtained in EEG studies. Mice which exhibited convulsions or an intense degree of hyperexcitability in the absence of convulsions, invariably died. In this respect BHT differs from gamma-thujaplicin, where doses just sufficient to produce convulsions are not lethal. The intraperitoneal LD₅₀ and CD₅₀ (convulsive dose) in mice were found to be 155 ± 4.5 mgm/Kg. and 163 ± 6.2 mgm/Kg. respectively, which indicates that a convulsive dose differs little from a lethal dose. A period of depression always followed the convulsions and was manifest by ptosis, decreased respiration and hypokinesia. Death occurred in this stage. Convulsions were prevented by thiopental and hexobarbital but barbiturate sleeping time was not decreased - in fact it was increased. Hexobarbital exerted a protective effect against lethal doses of BHT whereas thiopental delayed but did not prevent death. The ability of BHT to prolong sleeping time was not extended to ethanol. In smaller doses, BHT exhibited depressant effects manifested by hypothermia, hypokinesia and ease in handling. The hypothermic action was most pronounced at room temperatures and sedation was found to be proportional to the magnitude of the temperature fall. A synergistic action as to hypothermia and hypokinesia was observed with chlorpromazine and to a lesser extent with reserpine. At elevated ambient temperatures, animals treated with BHT exhibited hyperthermia and hyperkinesia. At normal temperatures BHT further increased the hyperthermia produced by amphetamine, but antagonized the hyperkinetic effect. Ultimately, however, the temperature of these animals was depressed to a greater degree than was the activity. The point of maximum antagonism to the hyperkinetic effect of amphetamine occurred approximately one hour following administration of BHT, while the maximum hypothermic effect of BHT was delayed an additional two hours. BHT-Na (sodium salt of BHT) when administered intravenously or intra-arterially in rabbits, caused a precipitous rise in blood pressure. This pressor response appeared to be unrelated to the low voltage-fast activity pattern observed on the EEG. BHT exhibited both bacteriostatic and fungistatic properties when tested in vitro against a wide variety of organisms. However, it was found to be inactive against D. pneumoniae when tested in vivo. A possibility exists that BHT is inactivated by whole blood. The toxicity of lead salts was found to be increased by BHT. This action is probably due to the formation of an insoluble chelate, promoting lead retention in the tissues and increasing its uptake from the body fluids. The toxicity of lead acetate was increased by two-thirds In the presence of BHT. Preformed lead chelate of BHT produced no observable toxic symptoms in the doses tested. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Graduate

5-Isopropyltropolone(gamma-thujaplicin) is one of the three isomeric isopropyltropolones found in the heartwood of western red cedar(Thuja plicata D. Don). The tropolones as a class have been shown to be inhibitors of the enzyme catechol-O-methyltransferase(COMT). The effect of this tropolone on the responses of the isolated guinea-pig atria to a number of sympathomimetic amines has been studied. Gamma-thujaplicin was used in the form of water soluble sodium salt(T-Na). T-Na itself was found to possess a slow but prolonged stimulating effect on the atria. In the presence of T-Na greater than 0.4 mcg./ml, both the positive inotropic and chronotropic effects of all of the sympathomimetic amines studied were increased. In the case of the short acting catechol amines, prolongation of these responses was also produced. The effect of T-Na on the responses to the adrenergic amines was compared with that of cocaine and ethylenedxa-minetetraacetic acid(EDTA). Potentiation of the responses to the adrenergic stimuli by T-Na and the last two agents appeared to follow a similar dose-response pattern although T-Na was twice as potent. Potentiation by T-Na of responses to the direct acting catechol amines was not affected by reserpinization. When used in place of EDTA for the repletion of norepinephrine stores in reserpinized atria, T-Na has been proved to be more effective than the former agent in retarding the oxidation of norepinephrine. The effect of histamine on the isolated atria was also studied. In a low concentration (0.2-0. 4mcg/ml) histamine stimulated the atria to a prolonged response that can only be terminated by changing the bathing fluid. The response of the atria to histamine was neither affected by the presence of a high concentration of antihistamine (3mcg./ml), nor was it blocked by the pre-addition of a beta-receptor blocking agent. Cocaine and pyrogallol had no effect on the histamine induced response. Therefore it is not likely that norepinephrine is involved in the response of the atria to histamine. In the presence of T-Na, however, the response to histamine was increased in the normal preparation, but T-Na had little or no effect on the histamine induced response in reserpinized atria. These results together with the fact that EDTA potentiated the action of sympathomimetic amines in a similar manner to T-Na do not support the assumption that T-Na potentiation of adrenergic responses is due to COMT inhibition. It would appear that T-Na produces like EDTA, a non-specific sensitization of the atria muscle. This mechanism is not clear and no evidence has been found to indicate that it is due to a general depletion of ions as a result of the chelating action of these compounds. / Pharmaceutical Sciences, Faculty of / Graduate