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A successful unified pharmacophore/receptor model which has guided the synthesis of subtype selective compounds is reviewed in light of recent developments both in ligand synthesis and structural studies of the binding site itself. The evaluation of experimental data in combination with a comparative model of the alpha1beta2gamma2 GABA(A) receptor leads to an orientation of the pharmacophore model within the Bz BS. Results not only are important for the rational design of selective ligands, but also for the identification and evaluation of possible roles which specific residues may have within the benzodiazepine binding pocket.

We recently developed a stochastic-based program that allows individual molecules in a cell signalling pathway to be simulated. This program has now been used to model the Tar complex, a multimeric signalling complex employed by coliform bacteria. This complex acts as a solid-state computational cassette, integrating and disseminating information on the presence of attractants and repellents in the environment of the bacterium. In our model, the Tar complex exists in one of two conformations which differ in the rate at which they generate labile phosphate groups and hence signal to the flagellar motor. Individual inputs to the complex (aspartate binding, methylation at different sites, binding of CheB, CheR and CheY) are represented as binary flags, and each combination of flags confers a different free energy to the two conformations. Binding and catalysis by the complex are performed stochastically according to the complete set of known reactions allowing the swimming performance of the bacterium to be predicted. The assumption of two conformational states together with the use of free energy values allows us to bring together seemingly unrelated experimental parameters. Because of thermodynamic constraints, we find that the binding affinity for aspartate is linked to changes in phosphorylation activity. We estimate the pattern of Tar methylation and effective affinity constant of receptors over a range of aspartate levels. We also obtain evidence that both the methylating and demethylating enzymes must operate exclusively on one or other of the two conformations, and that sites of methylation of the complex are occupied in sequential order rather than independently. Detailed analysis of the response to aspartate reveals several quantitative discrepancies between simulated and experimental data which indicate areas for future research.

The effectiveness of naproxen sodium and its parent compound, naproxen, has been assessed in the treatment of a variety of obstetric and gynecologic problems, particularly pain states. This article summarizes the literature on the efficacy of the naproxen compounds in treatment of the following conditions: primary and secondary dysmenorrhea, insertion of a contraceptive intrauterine device, suction curettage, postpartum pain, pelvic inflammatory disease, gynecologic surgery, menorrhagia, premature labor and menopause. The data from the studies compiled demonstrate the usefulness of naproxen sodium or naproxen as an effective analgesic in treating pain and inflammation associated with these conditions.Naproxen sodium, a nonsteroidal anti-inflammatory drug that blocks prostaglandin synthesis, has been shown to be effective for relief of mild to moderate pain. This article summarizes the literature on the efficacy of the naproxen compounds in the treatment of the following conditions: primary and secondary dysmenorrhea, IUD insertion, suction curettage, postpartum pain, pelvic inflammatory disease, gynecologic surgery, menorrhagia, premature labor, and menopause. Since naproxen does not affect the reproductive cycle, it appears to be ideal for obstetrics-gynecology use. Pediatricians, family practitioners, internists, surgeons, and geriatric specialists will also encounter patients requiring relief from pain caused by gynecologic pathology. The combined therapeutic use of nonsteroidal anti-inflammatory drugs and antibiotics for infections of the female reproductive tract appears indicated. The literature has established therapeutic success with naproxen and naproxen sodium as compared to a placebo in the treatment of dysmenorrhea and pain associated with IUD insertion, suction curettage, and postpartum conditions; joint pain in menopausal women; pain and inflammation associated with pelvic infections; and gynecologic surgery.

Splenic lymphocytes from both the Storrs and Davis strains of muscular dystrophic chickens and the C57BL/6J-2J strain of muscular dystrophic mice cap FITC-Con A and FITC-Ig in a manner similar to normal controls. In analyses of testcross progeny of Storrs muscular dystrophic chickens, no difference in the ability of lymphocytes to cap were observed among the segregating progeny. Neither were any significant differences observed in lymphocyte capping among F2 segregating progeny of C57BL/6J-2J mice. These studies do not support the systemic membrane defect hypothesis for muscular dystrophy.