Samir F. Saad

Influence of certain anticonvulsants on the concentration of γ-aminobutyric acid in the cerebral hemispheres of mice

Abstract A study was made, in mice, of the effects of certain drugs of the barbiturate and hydantoin groups, used in the treatment of grand-mal epilepsy, on the GABA content of normal cerebral hemispheres and of cerebral hemispheres depleted of GABA. It was shown that: (1) i.p. administration of the sodium salts of phenobarbital, prominal, diphenylhydantoin and mesantoin increased cerebral hemisphere GABA content of mice. (2) the GABA content increased to a peak 1 hr after the administration of the sodium salts of prominal and mesantoin, 2 hr after phenobarbital and 3 hr after diphenylhydantoin and then returned to normal. (3) the sodium salts of phenobarbital, prominal, primidone, diphenylhydantoin and mesantoin significantly increased the cerebral hemisphere concentration of GABA, previously reduced by isoniazid, to normal concentrations and antagonized the convulsions produced by isoniazid. The present results suggest a probable mechanism, in terms of their effect on the cerebral hemisphere GABA content, by which these anticonvulsants produce their action.

The effect of ovariectomy on the γ-aminobutyric acid content in the cerebral hemispheres of young rats

BROOKES, P., TERRY, R. J. & WAXKER., J (1957). J . chem. Soc., 3165-3172. HAWKING, F. & SEWELL, P. (1948). Br. J . Pharmac. Chemother., 3 , 285-296. NAGPAL, K. L. & DHAR, M. M. (1965). Ind. J . Chem., 3, 126-128. REINERTSON, J. W.f& THOMAS, P. E. (1955). SEWELL, P. & HAWKING, F. (1950). Br. J . Phnrmac. Chemother., 5 , 239-260. WADIA, P. S., ANAND, N. & DHAR, M. L. (1958a). WADIA, P. S. & ANAND, N. (1958b). WADIA, P. S., ASTHANA, T. C., ANAND, N. & DHAR, M. L. (1958). Ibid., 17B, 11-24. Antibiotics Chemother., 5 , 561-70.

Effect of a progestogen and an oestrogen on the γ-aminobutyric acid content in the cerebral hemispheres of ovariectomized rats

Ovariectomy increased the y-aminobutyric acid (GABA) content in the cerebral hemispheres of young rats (Saad, 1970). I now report how a progestogen and an oestrogen affect the GABA content in the cerebral hemispheres of adult rats of 150 to 200 g. Of four groups each of 6 rats, one group received no treatment. Another group was ovariectomized and left for 30 days, two other groups were ovariectomized, left for 27 days, then given daily for 3 successive days either progesterone (5 mg/kg) or diethyldioxystilben dipropionate (Cyren B ; Bayer, 0.5 mg/kg). The animals were then killed and the cerebral hemispheres of 2 rats were pooled and analysed for GABA (Saad, 1970). The increase in GABA content in the cerebral hemispheres 30 days after ovariectomy of adult female rats amounts to 20% above the normal value. This appears to be the reverse of the effect of castration on GABA content (Tzu Yu Li & Chang Hua Wu, 1964). The intramuscular injection of progesterone, 5 mglkg, for 3 successive days to the 27 days ovariectomized rats produced a significant decrease of 17.7% in their raised GABA content. The increased concentration of GABA of the 27 days ovariectomized rats returned to normal after the progesterone treatment. The intramuscular injection of diethyldioxystilben dipropionate for 3 successive days to the 27 days ovariectomized rats did not produce any significant difference in their cerebral hemisphere GABA content.

Behavioral effects of acute and chronic triazolam treatments in albino rats

Previous behavioral studies on triazolam (TZ), which are small in number, could only speculate about tolerance to the anxiolytic effect of TZ, as the experiments did not cover sufficient time (of 4 to 7 days) for tolerance to develop. Therefore longer time for chronic TZ administration is used. We investigated the effects of TZ on motor activity and exploratory behavior using plus maze and open field. Three experiments were conducted. In the first, five groups of rats were acutely treated with different doses of TZ (0.25 mg/kg-4.0 mg/kg). In the second set of experiments, rats were treated chronically with a single daily dose of TZ (started with 0.25 mg/kg and increased by time to 1.0 mg/kg) for 5 weeks (representing clinical use). In the third, rats were treated chronically with three daily doses of TZ (started with 0.25 mg/kg and increased by time to 0.5 mg/kg) for 20 days (mimicking drug abuse). Acute TZ administration produced dose dependent anxiolytic effects and a decrease in motor activity with higher doses. Chronically treated rats, either once daily or three times daily doses, showed tolerance to both anxiolytic and sedative effects of TZ. It may be concluded that tolerance to the anxiolytic and sedative effects of TZ would develop after chronic administration either with clinical use or its abuse.

Influence of Certain Calcium‐channel Blockers on Some Aspects of Lorazepam‐dependence in Mice

The effect of acute and chronic treatments of the calcium‐channel blockers, isradipine, diltiazem and flunarizine in protecting against lorazepam dependence has been demonstrated in mice.

Synthesis, anti-hypertensive and β-adrenoreceptor antagonist activities of 3-[4-[3-(4-aryl-1-piperazinyl)-isopropanoloxy]-phenyl]-4(3H quinazolones

Abstract The synthesis of seven 2-substituted 3-[4-[3-(4-aryl-1-piperazinyl)-isopropanoloxy]-phenyl]-4(3 H )quinazolones is described. Pharmacological tests showed that some of the synthesized compounds ( 3a–c and 3e ) possessed pronounced and sustained hypotensive effects, as tested in anesthetized normotensive rabbits, adrenoreceptor antagonist properties with respect to the α- and β-receptors and central nervous system depressant effect.

Pharmacokinetic Profile of Methotrexate and 5-Fluorouracil in Normal and Bilharzial-infested Mice

The pharmacokinetics of two commonly used anticancer drugs, methotrexate (MTX) and 5-fluorouracil (5-FU), were investigated in normal and bilharzial-infested mice. Liver glucose-6-phosphatase activity and antipyrine clearance were used as parameters of liver function. Liver glucose-6-phosphatase activity was significantly reduced in bilharzial-infested mice compared with the normal controls. Bilharzial infestation caused a significant reduction in the elimination (beta) and clearance rate (Cl) of antipyrine, whereas its elimination half-life (t1/2 beta) was increased in comparison with the normal controls. A similar pattern was also obtained after MTX and 5-FU administration in bilharzial mice, compared to controls. These results indicate that hepatic bilharziasis causes a significant reduction in the hepatic clearance and elimination of MTX and 5-FU, whereas their areas under the concentration-time curve were significantly increased. These findings may have to be considered in the treatment of bilharzial cancer patients.

The effect of isoniazid and some anticonvulsant drugs on the γ‐aminobutyric acid content of mouse brain in insulin hypoglycaemia

Phenobarbitone, prominal and primidone protect mice from insulin convulsions and raise their lowered cerebral hemisphere GABA content. Phenobarbitone and primidone are superior to prominal and produce a significant increase in the insulin depleted GABA content. Isoniazid potentiates insulin convulsions and significantly lowers the insulin depleted GABA content. It is probable that insulin depletion of cerebral hemisphere GABA content is a rationale of hypolgycaemic convulsions.

Brain glycine levels in triazolam-treated albino rats.

Summary. The present study investigates the effects of acute and chronic administration of triazolam in albino rats on glycine levels in different brain areas. Three experiments were conducted. In the first, five groups of rats were acutely treated with different doses of triazolam (0.25 mg/kg−4.0 mg/kg i.p.). In the second experiment, rats were treated chronically by a single daily dose of triazolam (started by 0.25 mg/kg and increased by time to 1.0 mg/kg) for 5 weeks, simulating clinical use. In the third, rats were treated chronically three daily doses of triazolam (started by 0.25 mg/kg and increased by time to 0.5 mg/kg) for 20 days, simulating a form of drug abuse. Brain levels of glycine and plasma levels of triazolam were measured using HPLC technique. The acute triazolam administration produced an increase in glycine levels in almost all brain areas studied. The chronic administration of single daily dose of triazolam produced normal glycine levels in most of the brain areas; this indicates the development of tolerance to glycine content increasing action of triazolam. The chronic administration of three daily doses of triazolam produced a decrease in glycine levels in almost all brain regions studied, which might be a prerequisite for oncoming withdrawal syndrome.

Possible oestrogenic and anti-androgenic effects in rats treated with the oral hypoglycaemic agents tolbutamide and acetohexamide

Tolbutamide has an oestrogenic activity; when administered in four oral daily doses of 125, 250 and 500 mg/kg to ovariectomized young rats, it significantly increased their uterine weight. Tolbutamide, when administered in five oral daily doses to castrated young male rats, decreased the weight of the prostatic tissue; the effect was significant with a dose of 250 mg/kg. Acetohexamide in oral doses of 125, 250 and 500 mg/kg, had no significant effect either on the prostatic or the uterine weight.