Possible involvement of 5-hydroxytryptamine and cyclic-AMP in tolerance to tremorine analgesia in mice.

The phenomenon of tolerance to the analgesic action of tremorine in mice was studied by the hot-plate and tail-clip methods. Reduction in 5-HT levels in brain by parachlorophenylalamine pretreatment decreased the ED50 of tremorine analgesia in tremorine tolerant mice. 5-Hydroxyptophan, L-Dopa or alpha-methyl-para-tyrosine did not influence the analgesic response to tremorine in tremorine tolerant animals. However, theophylline was found to enhance the tolerance to tremorine analgesia. Brain 5-HT and cAMP are probably involved in tremorine tolerance, whereas neither noradrenaline nor dopamine is involved in the phenomenon.

Involvement of gamma-amino butyric acid (GABA) in the anticonvulsant action of methaqualone.

The effects of methaqualone on isonicotinic acid hydrazide, 6-mercapto propionic acid, picrotoxin, and strychnine-induced convulsion were studied in mice and the results compared with diazepam. Methaqualone, like diazepam, was found to be a selective antagonist of isoniazid-induced convulsion and a much less effective inhibitor of strychnine convulsion. Methaqualone elicits muscle-relaxant, sedative, and anticonvulsant effects at different dose levels. At low, nonsedative doses the drug produces anticonvulsant effects, and at higher doses, muscle-relaxant and sedative effects. It appears that the mechanism(s) of action of methaqualone in on GABA deficiency or receptor blockade, rather than on glycine receptors.

Attenuation of stereotyped behaviour by sex steroids.

Effects of sex steroids, testosterone, progesterone, and estradiol on PEA-induced stereotyped behaviour (SB) has been studied in normal, castrated, and ovariectomised mice. Effects of sex steroids on amphetamine-induced sterotypy and hyperactivity are also described. In castrated and ovariectomised mice B-phenylethylamine (PEA) increased SB. Pretreatment with sex steroids attenuated PEA-induced stereotypy in normal, castrated, and ovarietomised mice. Sex steroid pretreatment significantly inhibited PEA- and amphetamine-induced SB, but failed to alter increased motor activity due to amphetamine or PEA. The possible effect of sec steroids on SB through changes in central neurotransmitters are discussed.

Effect of muscimol, a central GABA receptor agonist, on the catalepsy, striatal homovanillic acid increase, and analgesia induced by pilocarpine in rats.

Muscimol, a structural analog of GABA, significantly potentiated pilocarpine-induced analgesia in rats, but failed to alter pilocarpine-induced catalepsy. It also failed to affect pilocarpine-elicited increase in homovanillic acid levels in the striatum. These findings suggest that the potentiation of pilocarpine-induced analgesia by muscimol is unrelated to an interaction of the GABAergic system with the striatal cholinergic or dopaminergic systems.

Measurement of antipyretic activity of ibuprofen and paracetamol in children.

The antipyretic activity of ibuprofen (Brufen) and paracetamol (Crocin) was compared in 22 children with pyrexia who received either ibuprofen or paracetamol in syrup form. Both axillary and rectal temperatures were recorded prior to drug administration and 1/2, 1, 2, 3, 4, 5, 6, 8, and 12 hours after dosing. Analysis of the results in terms of rate of temperature decrease and degree and duration of decrease in temperature indicated that both drugs produced significant reduction in temperature and in the rate of temperature decrease. The maximum effect of the two drugs was similar. However, ibuprofen was more effective than paracetamol at 6 and 8 hours after administration, and its duration of action was longer. The associated antipyretic and antiinflammatory features of ibuprofen could provide an advantage in the control of exudative forms of upper respiratory tract infections.

A study of interaction of low-dose combination oral contraceptive with Ampicillin and Metronidazole.

Plasma levels of norethisterone (NET), ethinyl estradiol (EE), Ampicillin or Metronidazole were estimated in 16 women, who were taking low-dose oral combination contraceptive pills (containing norethisterone acetate 1 mg and ethinyl estradiol 30 microgram) and in whom concurrently, either Ampicillin (6 women) or Metronidazole therapy (10 women) was given. Neither Ampicillin nor Metronidazole therapy altered the 'peak' or 24-hour plasma levels and area under the curve, for NET and EE. Furthermore, oral contraceptive treatment did not alter the 'peak' levels of Ampicillin or Metronidazole. Progesterone (P) levels were in the anovulatory range in all Ampicillin treated cycles. However, in Metronidazole treated group, two out of 10 women showed a P rise of more than 4 ng/ml. The study was expanded to include another group of 15 women treated with Metronidazole, where only one women showed a P rise of more than 4 ng/ml. The occurrence of 'escape ovulation' as suggested by P rise of more than 4 ng/ml in three out of 25 Metronidazole treated women is either a chance incidence due to a different pharmacological response in them, or most probably due to the default in the regular intake of pills in these women. This is supported by the observation that one out of three women showing a P rise (greater than 4 ng/ml( during concurrent Metronidazole therapy, also showed ovulatory P values in oral contraceptive-only treated cycles. Furthermore, in the control group also, one out of 10 women had ovulatory P levels (greater than 4 ng/ml) in oral contraceptive-only treated cycles.

PIP: Plasma levels of (NET) norethisterone, (EE) ethinyl estradiol, Ampicillin, or Metronidazole were estimated in 16 women who were taking low-dose (OC) oral contraceptives (containing norethisterone acetate, 1 mg, and ethinyl estradiol, 30 mcg) and in whom concurrently, either Ampicillin (6 women) or Metronidazole therapy (10 women) was given. Neither drug altered the peak or 24-hour plasma levels and area under the curve for NET and EE. Furthermore, OC treatment did not alter the peak levels of either Ampicillin or Metronidazole. (P) Progresterone levels were in the anovulatory range in all Ampicillin-treated cycles. However, in Metronidazole-treated group, 2 of 10 women showed a P rise of more than 4 ng/ml. The study was expanded to include another group of 15 women treated with Metronidazole and only 1 woman showed a P rise of more than 4 ng/ml. The occurrence of 'escape ovulation' as suggested by a P rise of more than 4 ng/ml in 3 of 25 Metronidazole-treated women is either a chance incidence due to a different pharmacological response in them, or most probably due to the default in the regular intake of pills in these women. This is supported by the observation that 1 out of 3 women showing a P rise ( 4 ng/ml) during concurrent Metronidazole therapy also showed ovulatory P values in OC-only treated cycles. Furthermore, in the control group, 1 out of 10 women had ovulatory P levels ( 4 ng/ml) in OC-only treated cycles.

A study of interaction of a low-dose combination oral contraceptive with anti-tubercular drugs.

Low-dose combination contraceptive (containing norethisterone acetate 1 mg and ethinyl estradiol 30 micrograms) was administered to women receiving concurrent therapy with either Rifampicin or "triple" antitubercular treatment consisting of paraaminosalicylic acid (PAS), isonicotinic acid hydrazide (INH) and streptomycin. Plasma levels of norethisterone (NET) and ethinyl estradiol (EE), PAS and INH were measured and the area under curve (AUC) was calculated for NET and EE. Rifampicin treatment (9 women) caused a statistically significant reduction of the plasma NET levels as well as the AUC of NET. In this group of women, though a trend for reduction in EE levels was observed in individual subjects, it was not statistically significant. Out of 7 regularly menstruating women on Rifampicin therapy, 2 showed a premenstrual rise of plasma progesterone (P) levels (> 4 ng/ml) suggesting an ovulatory cycle and 3 experienced menstrual irregularities. In contrast, plasma levels of NET and EE as well as their AUCs were not altered in 8 women receiving "triple" antitubercular therapy. Only one woman out of 8, had menstrual irregularity and all women had P levels in the anovulatory range. Furthermore, oral contraceptive treatment did not alter the plasma levels of PAS and INH.

Rate of metabolism of norethisterone in women from different populations.

The rate of metabolism of orally administered norethisterone was compared in fourteen centres by measuring plasma levels of the steroid by radioimmunoassay at varying times after oral administration of a 1 mg dose. The inter-centre differences were of the same order as the intra-centre differences. Variations in metabolism appeared not to be due to variations in body size.

Pharmacokinetics of ethynyloestradiol in women for different populations.

The pharmacokinetics of a dose of 50 microgram ethynyloestradiol administered orally was studied in fourteen centres. Absorption was rapid and the highest serum concentrations of total ethynyloestradiol were found in most subjects at 1 h and by 24 h concentrations were less than 250 pg/ml. Calculation of the half-lives for absorption, distribution and elimination showed wide variations between subjects, the half-life of elimination varying from 2.5 h to more than 30 h. Bioavailability as measured by the area under the serum ethynyloestradiol concentration-time curve also showed more than a ten-fold variation. Intra-centre differences in the various parameters measured were as large as the inter-centre differences.

Pharmacokinetics of mefloquine in children aged 6 to 24 months.

The study was carried out in 12 children aged 6 months to 2 years, with uncomplicated falciparum malaria admitted to the Hospital for Tropical Diseases, Bangkok. They were treated with mefloquine in the form of MSP (mefloquine 250 mg+sulfadoxine 500 mg+pyrimethamine 25 mg) at a single dose of 25 mg mefloquine base/kg body weight. All of them were cured (28 days follow-up) with minimal side effects. Pharmacokinetic parameter determination was carried out in 9 cases. The results revealed that MRT, t1/2 and tmax in this study (children 6-24 months old) are comparable to the values in children aged 5-12 years, but shorter than in adult patients. Cmax and AUC in children 6-24 months old are comparable to those in children of 5-12 years, but much higher than in adult patients. Vz/f values in this study are comparable to those in children 5-12 years old, but lower than in adult patients.