[Adverse effects of certain antibiotics].
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The effects of three nonsteroidal antiinflammatory drugs (NSAIDs), namely, indomethacin, aspirin, and mefenamate (ponstan), on the lymphokine-activated killer (LAK) cell activities generated from coculturing recombinant interleukin-2 (rIL-2) and normal human peripheral blood mononuclear cells (PBMCs) for 3 to 4 days were investigated. The LAK cell activities were measured by a 4 hour 51Cr release microcytotoxicity assay using HL-60 and K-562 as target cells. Indomethacin was found to have significant augmenting effect on LAK cell activity at the concentration of 5 x 10(-5) M, whereas aspirin and ponstan did not show the same effect at the same concentration. Additional experiments, however, demonstrated that all of these 3 agents could effectively suppress the production of prostaglandin E2 (PGE2) in the culture medium. These results indicated that PGE2 suppression may not be the only mechanism of indomethacin for upregulation of LAK cell activity, and even immune functions.
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A Menstrual Symptom Questionnaire was administered to 1,066 women students from Mexico City. The questionnaire included general data and 12 symptoms related to dysmenorrhea. The mean age of the participants was 18 +/- 3.2 years. The mean age of menarche was 12.3 +/- 1.3 years. The prevalence of dysmenorrhea was 52.1% for the group < 15 years of age, 63.8% for women between 15-19 years, and 52.3% for the group of 20-24 years. The frequency of absenteeism as a result of dysmenorrhea in the group < 15 years was 4.3%, 9.3% for the group 15-19 years and 19.8% for the group 20-24 years. Systemic symptoms accompanying dysmenorrhea were clustered for analysis. The most frequent symptoms associated with dysmenorrhea were nervousness, depression, irritability and sleeplessness. Self-medication was prevalent, the most utilized drugs being antispasmodics.
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A theoretical conformational analysis of fenamates, which are N-arylated derivatives of anthranilic acid or 2-aminonicotinic acid with different substituents on the aryl (phenyl) group, is reported. The analysis of these analgesics, which are believed to act through the inhibition of prostaglandin biosynthesis, was carried out using semi-empirical potential functions. The results and available crystallographic observations have been critically examined in terms of their relevance to drug action. Crystallographic studies of these drugs and their complexes have revealed that the fenamate molecules share a striking invariant feature, namely, the six-membered ring bearing the carboxyl group is coplanar with the carboxyl group and the bridging imino group, the coplanarity being stabilized by resonance interactions and an internal hydrogen bond between the imino and carboxyl groups. The results of the theoretical analysis provide a conformational rationale for the observed invariant coplanarity. The second six-membered ring, which provides hydrophobicity in a substantial part of the molecule, has limited conformational flexibility in meclofenamic, mefenamic and flufenamic acids. Comparison of the conformational energy maps of these acids shows that they could all assume the same conformation when bound to the relevant enzyme. The present study provides a structural explanation for the difference in the activity of niflumic acid, which can assume a conformation in which the whole molecule is nearly planar. The main role of the carboxyl group appears to be to provide a site for intermolecular interactions in addition to helping in stabilizing the invariant coplanar feature and providing hydrophilicity at one end of the molecule. The fenamates thus provide a good example of conformation-dependent molecular asymmetry.
Non-steroidal anti-inflammatory drugs (NSAIDs) induce apoptosis in gastrointestinal cancer cell lines. Similar actions on normal gastric epithelial cells could contribute to NSAID gastropathy. The present work therefore compared the actions of diclofenac, ibuprofen, indomethacin, and the cyclo-oxygenase-2 selective inhibitor, NS-398, on a primary culture of guinea-pig gastric mucous epithelial cells. Cell number was assessed by staining with crystal violet. Apoptotic activity was determined by condensation and fragmentation of nuclei and by assay of caspase-3-like activity. Necrosis was evaluated from release of cellular enzymes. Ibuprofen (250 microM for 24 h) promoted cell loss, and apoptosis, under both basal conditions and when apoptosis was increased by 25 microM N-Hexanoyl-D-sphingosine (C(6)-ceramide). Diclofenac (250 microM for 24 h) reduced the proportion of apoptotic nuclei from 5.2 to 2.1%, and caused inhibition of caspase-3-like activity, without causing necrosis under basal conditions. No such reduction in apoptotic activity was evident in the presence of 25 microM C(6)-ceramide. The inhibitory effect of diclofenac on basal caspase-3-like activity was also exhibited by the structurally similar mefenamic and flufenamic acids (1 - 250 microM), but not by niflumic acid. Inhibition of superoxide production by the cells increased caspase-3-like activity, but the inhibitory action of diclofenac on caspase activity remained. Diclofenac did not affect superoxide production. Diclofenac inhibited caspase-3-like activity in cell homogenates and also inhibited human recombinant caspase-3. In conclusion, NSAIDs vary in their effect on apoptotic activity in a primary culture of guinea-pig gastric mucous epithelial cells, and the inhibitory effect of diclofenac on basal apoptosis could involve an action on caspase activity.