Human pharmacokinetics and comparative bioavailability of loperamide hydrochloride.

A pharmacokinetic study of the antidiarrheal agent loperamide hydrochloride (Imodium) was conducted in six male subjects. The study utilized a random crossover design and employed a 2-mg capsule and a 0.2-mg/ml syrup formulation. Each treatment consisted of a single oral dose of 8 mg loperamide HCl followed by a two-week interval before the next treatment. Serum and urine samples obtained at various times after drug administration were assayed for loperamide using a radioimmunoassay specific for the drug. The mean biologic half-life, calculated from the elimination phase of the log serum concentration-versus-time data, was 10.8 +/- 0.6 hours for the overall study, 10.2 +/- 0.6 hours for the syrup formulation, and 11.2 +/- 0.8 hours for the capsules. The loperamide from the syrup was absorbed more rapidly than from the capsule formulation, with the peak serum levels observed at a mean time of 2.4 +/- 0.7 hours for the syrup and 5.2 +/- 0.3 hours for the capsule formulation. The relative areas under the serum loperamide concentration-versus-time curves suggested that the two formulations have comparable physiologic availability. The maximum observed serum concentrations were also similar, indicating the safety of the syrup formulation. Excretion of approximately 1 per cent of the dose in the urine as unchanged loperamide after seven days was observed independent of the particular dosage form that was administered.

Inhibition of rabbit platelet phosphodiesterase activity and aggregation by calcium channel blockers.

Rabbit platelet cyclic AMP phosphodiesterase is inhibited by the three calcium channel blockers nifedipine, diltiazem, and verapamil with IC50's of 100 microM, 100 microM and 420 microM, respectively. Also, platelet aggregation induced by 4 microM ADP is inhibited by those compounds. Verapamil is the most potent aggregation inhibitor with an IC50 of 260 microM while diltiazem and nifedipine have IC50's of 630 microM and 840 microM, respectively. All three compounds display a maximum inhibition of 80-85%. Diltiazem and PGD2 potentiate the antiaggregatory activity of each other in that the inhibitions occurring in the presence of the combination of the two (at varying concentrations) exceed the calculated sums of the inhibitions produced by each alone. On the other hand, the antiaggregatory activities of verapamil or nifedipine, are additive with that of PGD2 in that no significant differences exist between the observed inhibitions produced by the combinations and the calculated summed values of the individual inhibitions. Our data suggest, therefore, that in addition to lowering intracellular calcium ions, which are required for platelet aggregation, the three calcium channel blockers inhibit the breakdown of cyclic AMP thereby promoting antiaggregation.

Potent and selective effects of suprofen on uterine prostaglandin synthesis.

Suprofen is a non-narcotic, peripheral analgesic that exhibits potent prostaglandin (PG) synthesis inhibitory activities in a variety of subcellular tissue preparations and in vivo. The results of the present study show suprofen to be significantly more potent than either ibuprofen (6-fold) or aspirin (1000-fold) as an inhibitor of PG production by cell-free preparations of guinea pig uteri. It is selectively more potent against the production of PGF2 alpha and PGE2 than against the formation of 6-keto PGF1 alpha, the stable metabolite of prostacyclin. Suprofen is markedly more potent inhibiting the conversion of arachidonic acid to PGF2 alpha than is ibuprofen (30 times) or aspirin (1250 times). Taken together with the important role PGF2 alpha plays in the etiology of dysmenorrhea and the observation (Hahn et al., 1982) that suprofen is more potent and effective than a number of other PG synthesis inhibitors, including ibuprofen and aspirin, at reducing in vivo guinea pig uterine contractions induced by arachidonic acid, the results of the present study suggest a mechanism to support the clinical findings that suprofen is a very effective treatment for the signs and symptoms of dysmenorrhea.

Altered susceptibility of arthritic rats to the gastric lesion-inducing effects of aspirin or ethanol and the antilesion effect of rioprostil.

It is well known that nonsteroidal antiinflammatory agents produce gastric mucosal lesions in both laboratory animals and man. However, the effect of an arthritic condition on their susceptibility to ulcerogenic agents and on the efficacy of antiulcer agents is less definitive. As a model to explore these questions, the effect of oral administration of aspirin or ethanol on gastric lesion formation was examined in rats with or without established adjuvant-induced polyarthritis. In addition, the antilesion efficacy of rioprostil, a primary alcohol prostaglandin E1 analog, was evaluated in both groups of rats. The results demonstrated that arthritic rats were more sensitive to the lesion-inducing effect of aspirin, but were more resistant to the lesion-inducing effect of ethanol when compared to normal rats. An increase in endogenous gastric prostaglandin production in arthritic rats may account for their relative resistance to ethanol. Aspirin inhibited the prostaglandin synthetic capacity of the stomach in both normal and arthritic rats, which may be responsible for eliminating the relative resistance of arthritic rats to gastric irritation. Rioprostil effectively prevented aspirin or ethanol-induced lesion formation in both arthritic and nonarthritic rats, but its potency against either irritant was decreased in arthritic rats.

Tissue selectivity and variability of effects of acetaminophen on arachidonic acid metabolism.

Acetaminophen has variable effects on prostaglandin synthesis depending on the tissue preparation used. The present study was designed to determine the effects of acetaminophen on arachidonic acid metabolism in different tissues simultaneously removed from the same animals treated with the compound. The ex vivo conversion of 14C-arachidonic acid into 14C-prostaglandins was monitored in homogenates or slices of tissues to which no exogenous cofactors were supplied. Administered orally at doses of 100-300 mg/kg to guinea pigs, acetaminophen stimulated prostaglandin production by cell-free preparations of stomach, but had no effect in lung or kidney medulla. At doses ranging from 25-300 mg/kg, p.o., to rats, acetaminophen stimulated stomach, but inhibited cerebral cortex prostaglandin production. These same effects were mimicked qualitatively when acetaminophen was added in vitro at 10(-4)M to 10(-2)M to similar preparations. In addition, at these same high concentrations, acetaminophen inhibited 5-lipoxygenase activity in cultured RBL-1 cells. It is speculated that the multiple and tissue variable effects that acetaminophen had on arachidonic acid metabolism depend on the inherent cofactors associated with each tissue type.