Prejunctional regulatory actions of androgens on a hormone sensitive muscle.

The influence of androgens and time course of effects induced by hormone deprivation were examined on the spontaneous transmitter release in the levator ani (LA) muscle of 30-180-day-old male rats. The resting membrane potential (RMP) and miniature endplate potentials (mepps) were recorded intracellularly from LA muscle fibers of intact animals or gonadectomized at different ages. In intact animals, the frequency of mepps increased proportionately to the muscle fiber growth up to 60 days, stabilizing thereafter. Gonadectomy at any age did not affect the RMP, but increased the frequency of mepps by 65% to 140%. The effect was detected after 15 days and was unrelated to the degree of muscle atrophy. Independently of the age of gonadectomy control values of mepp frequency were restored after 90 days, while the accompanying postjunctional changes persisted. These results indicate that androgens exert a prejunctional inhibitory influence on the spontaneous transmitter release in the rat LA muscle. The transient nature of the prejunctional effect induced by hormone deprivation indicates an adjustment of nerve terminals to persistent postjunctional alterations.

Substrate stereoselectivity and enantiomer/enantiomer interaction in propranolol metabolism in rat liver microsomes.

The substrate stereoselectivity and enantiomer/enantiomer interaction of (S)- and (R)- propranolol for the formation of their metabolites were investigated in rat liver microsomal fractions. The enantiomers of primary metabolites of propranolol, 4-, 5-, 7-hydroxy- and N-desisopropyl-propranolol were separated and assayed by an HPLC method employing a chiral ovomucoid column. Regioselective substrate stereoselectivity (R < S for 4- and 5-hydroxylations; R > S for 7-hydroxylation; R = S for N-desisopropylation) was observed in the formation of propranolol metabolites when the individual enantiomers or a racemic mixture of propranolol were used as substrates. Concentration-dependent metabolic inhibition of propranolol enantiomers by their optical isomers was also observed. In addition, the inhibition of propranolol 4-, 5- and 7-hydroxylations between the enantiomers showed a typical competitive nature. These findings suggested that the propranolol enantiomers competed for the same enzyme, probably a cytochrome P450 isozyme in the CYP2D subfamily.

Androgen regulation of the nicotinic acetylcholine receptor-ionic channel in a hormone-dependent skeletal muscle.

The trophic influence of testosterone on the nicotinic acetylcholine receptor-ionic channel (AChR) was studied in the levator ani (LA) muscle of adult male rats (120 days) intact (C) or gonadectomized when 90 days old (G). In the indirectly elicited muscle twitch, the LA from G rats was less sensitive to d-tubocurarine (0.1-1 microM) than control muscles (IC25: C = 0.30 microM, G = 0.46 microM). In G rats, the amplitude of neurally evoked endplate currents (EPC) was reduced by 70%, but the EPC time constant was not changed. Maximal junctional binding of [125I]alpha-bungarotoxin in the LA (C: 72.5 +/- 13.2 amol/endplate) was reduced by 1.8-fold in LA from G rats, with no change of the association rate constant (C: 5.64 +/- 1.29 10(6) M-1 min-1). The results indicate that testosterone deprivation reduces the junctional AChR density in the rat LA without modifying the binding properties of the receptor.

Pharmacological screening of Ageratum conyzoides L. (Mentrasto).

The pharmacological activities of a water extract (WE) of Ageratum conyzoides L, a plant popularly known for its analgesic and anti-inflammatory properties, were studied in vivo and in vitro preparations. Oral administration (p.o.) of the water extract (WE, 0.1 to 5 g/kg) to rats and mice induced quietness and reduced the spontaneous motility. The sleeping time induced by sodium pentobarbital (50 mg/kg, i.p.) in mice was not altered by previous treatment with WE (2 g/kg, p.o.). The same treatment did not influence the paw edema induced by carrageenan or dextran, nor did it reduce the chronic paw edema induced by complete Freund's adjuvant or formaldehyde in rats. The tail flick response in immersion test and writhings induced by 0.8% acetic acid in mice were not altered by WE either. In isolated guinea-pig ilea WE (0.4 to 4 mg/ml) did not alter the EC50 values of histamine or acetylcholine, but reduced the maximal response to the agonists by 20 to 50%. WE (0.01 to 10 mg/ml) produced tonic contractions of the ileal smooth muscle proportional to the doses, reaching a maximum of 75% relatively to the maximum obtained with histamine. Those contractions were blocked by diphenhydramine (10 nM) and reduced by 32% in presence of atropine (10 nM). The results indicated that oral treatment of rodents with A. conyzoides L neither reduced the inflammatory edema nor did it decrease the reaction to pain stimuli. In vitro the extract presented an unexpected histamine-like activity characteristic of a partial agonist. The results did not confirm the popular medicinal indications of the plant.

Androgen regulation of the nicotinic acetylcholine receptor-ionic channel in a hormone-dependent skeletal muscle

The trophic influence of testosterone on the nicotinic acetylcholine receptor-ionic channel (AChR) was studied in the levator ani (LA) muscle of adult malr rats (120 days) intact (C) or gonadectomized when 90 days old (G). In the indirectly elicited muscle twitch, the LA from G rats was less sensitive to d-tubocurarine (0.1-1µM) than control muscles (IC25:C = 0.30µM,G=0.46µM). In G rats, the amplitude of neurally evoked endplate currents (EPC) was reduced by 70%, but the EPC time constant was not changed. Maximal junctional binding of [125I] alfa-bungarotoxin in the LA(C: 72.5 ñ 13.2 amol/endplate) was reduced by 18.8-fold in LA from G rats, with no change of the association rate constant (C: 5.64 ñ 1.29 10**6 M-1 min**-1). The results indicate that testosterone deprivation reduces the junctional AChR density in the rat LA without modifying the binding properties of the receptor

Analysis of in vitro dissolution of whole vs. half controlled-release theophylline tablets.

Controlled-release (CR) drug products dissolve more slowly than conventional-release products, reflecting their quality of sustaining a prolonged therapeutic effect. A frequent practice with scored tablets when only half the dosage is desired is to divide the tablet at the score mark and administer only half of the product. The dissolution characteristics of the divided tablets are unknown. It is only an assumption that the halved tablet behaves similarly to the whole tablet both in vitro and in vivo. A series of in vitro dissolution analyses was performed on whole and half CR theophylline tablets from different manufacturers. Statistical tests were carried out between the dissolution results of whole and those of halved tablets to determine whether the mean overall percentages dissolution (averaged over sampling times) were similar and whether the patterns of percentage dissolution over time were similar. The dissolution of halved tablets was slightly faster compared to that of intact (whole) tablets. However, these small differences were not large enough to cause concern or to require bioavailability studies.