Androgenic repression of hexobarbitone metabolism and action in Crl:CD-1 (ICR)BR mice.

Mice of the Crl:CD-1 (ICR)BR strain exhibit a sexual dimorphism in hexobarbitone metabolism and action. Compared to females, males have a lower Vmax and a higher Km for hepatic microsomal hexobarbitone hydroxylase. In agreement with the enzyme studies, hexobarbitone-induced sleeping times were greater for males than for females. Results from experiments measuring hexobarbitone metabolism and action in castrate, testosterone and gonadotropin-treated mice indicate that the sexual differences in drug metabolism and action found in Crl:CD-1 (ICR)BR mice are due to the normally repressive effects of testicular androgens on the activities of the hepatic mono-oxygenases. These findings are in dramatic contrast to studies with rats where it has been shown that androgens induce mono-oxygenases. Furthermore, in the case of the mouse, changes in the activity of hexobarbitone hydroxylase in response to alterations in androgen levels require weeks, while in the rat, androgenic-induced changes are apparent within a matter of days.

Taloximine, a new respiratory stimulant with brochodilator properties.

1. A novel phthalazine analogue taloximine (1-hydroxyimino-4(2-dimethyl-aminoethoxy)-1,2-dihydrophthalazine monohydrochloride monohydrate) stimulated respiration in conscious rabbits at doses of 7 mg/kg and above.2. Taloximine antagonized the depressant action of morphine on respiration in rabbits at doses of 10 mg/kg. At high doses it resuscitated rabbits after they had been given lethal doses of sodium pentobarbitone.3. In in vitro preparations of the trachea or bronchus taloximine was about equiactive with aminophylline. In the Konzett-Rössler preparation the intravenous ED50 for taloximine was about 18% of that of aminophylline, whereas after oral administration the two drugs were equiactive.4. Taloximine, unlike aminophylline, did not protect guinea-pigs against anaphylactic microshock to egg albumen.5. Taloximine shortened the duration of the loss of righting reflex in mice due to hexobarbitone more effectively than bemegride, nikethamide or vanillic acid diethylamide.6. In the dose required to stimulate respiration taloximine had only slight cardiovascular effects. Up to four times this dose produced no evidence of general excitation of the central nervous system.

The effect of thyroid hormones on the action of some centrally acting drugs.

1. The effect of administration of thyroxine or thyroidectomy on the pharmacological action of (+)-amphetamine, caffeine, hexobarbitone and morphine was determined in rats or mice.2. Locomotor activity induced by (+)-amphetamine or caffeine was increased by hyperthyroidism and decreased by hypothyroidism.3. The LD50s of (+)-amphetamine and caffeine in hyperthyroid rats were 1/30 and 2/5 that of control rats. With each drug, the LD50 regression lines in hyperthyroid and control rats were not parallel, suggesting that hyperthyroidism modifies the mechanism of the toxic effects. Hypothyroidism reduced toxicity to (+)-amphetamine.4. Hexobarbitone sleeping time was prolonged in hyperthyroid male rats, but was shortened in hyperthyroid female rats. In control rats, sleeping time was approximately four times as long in females as it was in males. Ethinyloestradiol treatment and castration also prolonged sleeping time in male rats. No further prolongation was produced by combined administration of thyroxine and ethinyloestradiol, but thyroxine further prolonged the sleeping time of castrated rats indicating that its mode of action in producing these changes is not mediated via sex hormones.5. In contrast to rats, a sex difference in the duration of action of hexobarbitone was not found in mice. Thyroxine prolonged sleeping time equally in each sex.6. Analgesia induced by morphine in mice was unaffected by hyperthyroidism. No increase in sedative or ;Straub tail' activity could be detected, but toxicity was increased when higher doses of morphine were used.7. The mechanism by which thyroid hormones produce these changes in sensitivity to centrally acting drugs is discussed. It is suggested that the effects of thyroxine vary according to whether the mode of action of the drug or its metabolism is modified.

Sex-related differences in cadmium-induced alteration of drug action in the rat.

3 days after pretreatment of rats of both sexes with cadmium (2 mg/kg, 1.p.) the duration of hypnosis induced by hexobarbital (75 mg/kg, 1.p.) was potentiated in males but not females. Likewise similar treatment with cadmium leads to significant inhibition of the metabolism of hexobarbital by hepatic microsomal enzymes obtained from male but not female animals. These data suggest that there is a sex-related difference in the ability of cadmium to alter drug action in rats.

Cardiovascular effects of two potential beta-hydroxylase inhibitors.

The purpose of this study was to evaluate the cardiovascular effects of two potential beta-hydroxylase inhibitors, a dithiocarbamate and a thiourea derivative of d-amphetamine, 1 and 2, respectively. These compounds when given intravenously elicited a significant dose-dependent depressor effect in normotensive rats and dogs anesthetized with chloralose-urethane. The hypotensive effect of these compounds appears to be the result of a combination of two action components: (a) the major component, which can be blocked by atropine, exerted through the parasympathetic division and (b) a decreased availability of sympathetic neurotransmitter at the synaptic cleft. A CNS-stimulant effect of these compounds is suggested by their ability to reduce hexobarbital sleeping time in mice and their analeptic effect in all anesthetized animals employed.

Interaction of the competitive AMPA receptor antagonist NBQX with hexobarbital.

IP administration of hexobarbital to rats caused a mean sleeping time of 93.6 min (SD 21.5). IV infusion of 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX) at a dose rate of 0.11 mg/kg/min starting 30 min after administration of hexobarbital prolonged the mean sleeping time to 132.2 min (SD 14.9). Dose rates of 0.33 and 1.10 mg/kg/min prolonged the mean sleeping times to 176.4 min (SD 33.3) and 444.1 min (SD 72.0), respectively. Measured 180 and 450 min after the start of the study, there were no differences in the plasma concentrations of hexobarbital in groups receiving hexobarbital alone compared to groups receiving the high-dose rate of NBQX starting 30 min after administration of hexobarbital. The present results demonstrate that by IV infusion NBQX dose dependently prolonged the sleeping time of hexobarbital. There were no indications of interactions on hexobarbital elimination of either isomer. It is therefore likely that NBQX acts synergistically with hexobarbital to depress the central nervous activity.

Hepatoprotective effects of Wedelia calendulacea.

The alcoholic extract of whole plant Wedelia calendulacea exhibited protective activity against carbon tetrachloride-induced liver injury in vivo. The extract also increased the bile flow in rats suggesting a stimulation of liver secretory capacity. The minimum lethal dose was greater than 200 mg/kg p.o. in mice.

Synthesis and CNS activities of pyridopyrazinone and pyridodiazepinone derivatives.

New tricyclic derivatives with cyclocondensed pyrido-pyrazine 7,10 and pyrido-diazepine 20a,20b skeletons were synthetized and biologically investigated. The compounds, preliminarily tested on explorative, muscle relaxing, antinociceptive, spontaneous motor activities and influence on the narcotic effect of Evipan, revealed interesting CNS depressant and analgesic activities. The pyrido[2,3-e]pyrrolo[1,2-a]pyrazine structure of 7 appeared the most promising for analgesic and neuroleptic activities. The above compounds were assayed also for their capacity to inhibit DNA synthesis in Ehrlich ascites tumor cells; 20a appeared to be able of inducing a significant inhibition.

[Anticonvulsant effects of indoline derivatives]. / Antikonvulsive Wirkungen von Indolinderivaten.

The anticonvulsant activities of several indoline derivatives were tested in mice using the pentetrazole (PTZ) and electroshock seizure model. Furthermore, the toxicity and the influence on hexobarbitone anaesthesia were determined. 2-oxoindoline--the most potent anticonvulsant compound--shows a characteristic modification of PTZ-induced seizures, especially a suppression of the tonic phase and a marked prolongation of survival time at lethal PTZ-doses as well as in doses of 100 mg/kg a complete protection effect to maximum electroshock. The majority of indolines possess also a marked sedative effect. The LD50 values of the derivatives under investigation are differing considerably, however, majority of compounds being within the range of 300 to 800 mg/kg (i.p.).

A comparative study of the effect of some steroid hormones on the response of rats to other drugs.

The effect of a series of steroid hormones on the pentetrazol convulsing action, hexobarbital narcotic action and hepatic drug metabolizing enzyme activities was determined in rats. All steroid compounds used antagonized the pentetrazol effect: the most potent was cortisone and the least potent testosterone. Glucocorticoids and androgens shortened the hexobarbital sleeping time and increased the hepatic drug metabolizing enzyme activity. Estradiol exhibited the opposite effect, whereas progesterone and desoxycorticosterone did not affect these two parameters.

Thyroliberin (thyrotropin releasing hormone): antagonism of halothane and hexobarbital narcosis in mice. Comparison with pentetrazol, caffeine, d-amphetamine and adrenaline.

The effect of L-pyroglutamyl-L-histidyl-L-prolinamide (thyroliberin, thyrotropin releasing hormone, TRH) on halothane and hexobarbital narcosis was investigated in mice and compared with pentetrazol, caffeine, d-amphetamine and adrenaline. TRH shortened dose-dependently the halothane and hexobarbital sleeping-time with ED50 values of 3.1 and 6.6 mg/kg s.c., respectively. The analeptic effect of TRH was superior to all reference compounds in terms of potency, efficacy and drug safety. Due to its ergotropic activity TRH may be a useful aid in anaesthesiology and intensive care.

[Hexobarbital sleep in rats treated with polyvinylpyrrolidone]. / Kheksobarbitalov sun pri plukhove, tretirani s polivinilpirolidon

Young male rats, breed Wistar, underwent daily intravenous injections with 10 ml per kilogram body weight polyvinyl pyrrolidone, over a period of five days. As a control group, non injected rats of the same age were used. The duration of sleep after interaperitoneal injection of hexobarbital natrium at dose 100 mg/kg weight was checked in both groups. It was established that in the animals treated with polyvinyl pyrrolidone the duration of sleep was shorter. In a second group of animals, treated with polyvinyl pyrrolidone, the concentration of aminopyrine N-demethylase in the liver was traced.

[Effect of the diethylamide of nicotinic acid (cordiamine) on the hydroxylating function of the liver]. / K voprosu o vliianii diétilamida nikotinovoi kisloty (kordiamina) na gidroksiliruiushchuiu funktsiiu pecheni.

Diethylamide of nicotinic acid (subcutaneously, 40 and 120 mg/kg, once a day for 4 days) was shown to exert no influence on p-hydroxylation of aniline and to increase the rate of N-demethylation of amidopyrine and ethylmorphine in the rat liver microsomal fraction by 21 and 47% as compared with the control. At the same dose of 40 mg/kg and the same schedule of administration the drug was found to increase urine excretion of antipyrine metabolites: nor-antipyrine, 4-hydroxy-antipyrine and the sum of metabolites by 229, 89 and 80%, respectively, during the first 90 min of the experiment. Excretion of antipyrine, 3-hydroxymethyl-antipyrine and 3-carboxymethyl-antipyrine underwent no significant changes. The duration of hexobarbital-induced sleep of the rats was shown to be decreased by 26%.

3,4,5-Trihydroxy benzoic acid (gallic acid), the hepatoprotective principle in the fruits of Terminalia belerica-bioassay guided activity.

Compound I isolated from fraction TB5 of Terminalia belerica and finally identified as 3,4,5-trihydroxy benzoic acid (gallic acid) was evaluated for its hepatoprotective activity against carbon tetrachloride (CCl4)-induced physiological and biochemical alterations in the liver. The main parameters studied were hexobarbitone-induced sleep, zoxazolamine induced paralysis, serum levels of transaminases and bilirubin. The hepatic markers assessed were lipid peroxidation, drug metabolising enzymes, glucose-6-phosphatase and triglycerides. Administration of Compound I led to significant reversal of majority of the altered parameters. Our results confirm the presence of hepatoprotective activity in altered parameters. Our results confirm the presence of hepatoprotective activity in Compound I.

[Effect of cocaine molecule fragments on the central nervous system]. / Deistvie fragmentov molekuly kokaina na tsentral'nuiu nervnuiu sistemu.

The influence of ecgonine, tropine, tropinon, and some of their derivatives, propan, N-methylpyrrholidine, N-methylpiperidine on impulse summation in the central nervous system, conditioned reflex of avoidance, antagonism to hexenal, synergisim to cocaine and also their toxicity (LD50) have been studied under experimental conditions. As shown, benzoyl-ecgonine, ecgonine methyl ester, ecgonine, tropine, pseudotropine, carbomethoxytropinon, tropinon, tropine, tropan N-methylpyrrolidine, and N-methylpiperidine produced a pronounced stimulating effect on the central nervous system activity; in this respect they were similar to cocaine. The following conclusions were made: the substances whose molecules contained tropan structure or one of its fragments possess the central stimulating effect. The stimulating effect of cocaine on the central nervous system could be due to the tropan fragment of its molecule.