There are the trees; the subject lesson of "NSAID gastropathy".
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Biomedical subjects
Publications and source records attributed to S H Roth.
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A review of methodologically sound studies of the psychological responses of U.S. women after they obtained legal, nonrestrictive abortions indicates that distress is generally greatest before the abortion and that the incidence of severe negative responses is low. Factors associated with increased risk of negative response are consistent with those reported in research on other stressful life events.
Although the lethal effect of hydrogen sulfide (H2S) has long been known, the results of exposure to low levels of H2S have not been well documented. Rat dams and pups were exposed to low levels of H2S (less than or equal to 75 ppm) from d 1 of gestation until d 21 postpartum and analyzed for changes in circulating enzymatic activity and metabolites. Blood glucose was significantly elevated in maternal blood on d 21 postpartum at all exposure levels. This increase in glucose was accompanied by a possible decrease in serum triglyceride in the pups and in the dams on d 21 postpartum. There was no evidence of alterations in serum alkaline phosphatase, lactate dehydrogenase, or serum glutamate oxaloacetate transaminase.
Emesis and nausea are often associated with anaesthesia and continue to be a common clinical problem. Past clinical studies have demonstrated that halothane produces a higher incidence of vomiting compared with other anaesthetics, but some investigators have described an antiemetic effect. The purpose of this study was to investigate the effects of various doses of halothane on the emetic response in the decerebrate ferret. Following a control emetic response, a maximum of six increasing cumulative concentrations of halothane were delivered. At the end of each delivery period, the supradiaphragmatic vagal communicating branch, which has been shown to reproducibly elicit vomiting, was electrically stimulated and the emetic response was monitored. An increase in halothane concentration produced a marked depression of tongue, abdominal muscle, and diaphragm EMG activity as well as a decrease in central venous pressure. Licking, a prodromal response comparable to nausea in the human, appeared to be most sensitive. An increase in latency of the emetic response occurred as the concentration of halothane was increased. All phases of the response were observed at concentrations below 0.6 vol% halothane. At 0.6 vol% halothane, 75% of the animals vomited. At higher concentrations, the emetic response was completely abolished. One hour post-halothane, all latencies had returned to near control values. The methods utilized in this study provided a model that was not complicated by a large number of variables usually present in clinical studies. These data demonstrate that halothane exerts an inhibitory, concentration-dependent, and reversible effect on the emetic response in the ferret and provide further support that halothane alone does not possess emetic properties at clinical properties at clinical concentrations.
NSAID gastropathy is a serious, iatrogenic problem of common NSAID usage of major public health dimensions. Since ulcer bleeding and perforations can be disastrous, the issue clearly requires prevention. Various gastroprotective therapies exist, but since symptoms do not predict the evolving pathophysiology in most cases, the problem continues to be underestimated in clinical care. Endoscopy is of definitive value, but not generally thought appropriate for screening purposes. Under these circumstances, not driven by putative symptomatology, a long term basis for compliance with gastroprotective therapies is potentially compromised and always expensive. NSAID treatment strategy based on reducing putative gastrotoxicity is a primary goal. Present encouraging postmarketing surveillance experience, clinical research, and most recently, endoscopy evaluation suggest nabumetone as a potential prototype for a new generation of gastro-sparing NSAID therapies based on desirable pharmacological features.
A multicenter, double-blind, placebo-controlled trial was undertaken to evaluate the efficacy of the synthetic prostaglandin E1 analog misoprostol in preventing and healing gastric ulcer induced by nonsteroidal antiinflammatory drugs (NSAID) in patients receiving chronic NSAID therapy for osteoarthritis (OA). A total of 420 patients with OA and NSAID-associated abdominal pain who were receiving ibuprofen, piroxicam or naproxen were enrolled in the study. Endoscopy was performed at study entry and after 1, 2 and 3 months of continuous therapy with misoprostol 100 micrograms, misoprostol 200 micrograms or placebo given q.i.d. while NSAID therapy was continued. Treatment failure was defined as development of gastric ulcer (greater than 0.3 cm in diameter). The occurrence of ulcer in each misoprostol group (5.6% and 1.4% for 100 micrograms and 200 micrograms, respectively) was significantly lower (p less than 0.001) than that in the placebo group (21.7%). The statistically significant difference persisted when comparisons were restricted to development of ulcer greater than 0.5 cm in diameter (12.3, 4.2 and 0.7% for placebo, misoprostol 100 micrograms q.i.d. and misoprostol 200 micrograms q.i.d., respectively). Mild-to-moderate, self-limiting diarrhea was the most frequently reported adverse event attributed to misoprostol use.
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Hydrogen sulfide is a widespread environmental pollutant that may produce severe effects on the developing nervous system. Putative amino acid neurotransmitter levels in the rat cerebrum and cerebellum were determined to evaluate the effects of exposure to hydrogen sulfide during perinatal development. The levels of aspartate, GABA, glutamate, glycine and taurine were quantitated using high-performance liquid chromatography. With the exception of glycine, all of the amino acids examined were affected by the treatment. On day 21 postnatal, which was the last day of the exposure, aspartate, glutamate and GABA in the cerebrum and aspartate and GABA in the cerebellum were significantly depressed. The observed alterations in the amino acid levels during this critical phase of development may have chronically affected the activity of the neurotransmitters, their receptor sensitivity or their individual target areas. The consequence of one or a combination of such alterations may lead to behavioral and structural abnormalities.
Two anticonvulsants were administered pre- and postnatally to determine their effects on putative amino acid neurotransmitter levels in the rat cerebellum. The amino acids were quantitated using precolumn fluorescence derivatization and reverse-phase high performance liquid chromatography at various postnatal intervals. Treatment with clonazepam produced an initial depression in levels of most of the amino acids analyised. By three weeks postnatal all the amino acids, with the exception of GABA, had returned to control levels. GABA levels were still depressed five weeks after the cessation of treatment. Phenobarbital treatment produced an initial elevation in the level of GABA. At three weeks postnatal, both GABA and glutamate levels were elevated and remained so at eight weeks postnatal. In conclusion, the data demonstrated that each anticonvulsant produced unique, acute and chronic alterations in the levels of the cerebellar amino acids.
Low concentrations (0.15-15 microM) of sodium sulfide reversibly attenuated the contractile response of the isolated rat uterus to oxytocin without affecting angiotensin II responsiveness. These findings suggest that functionally important disulfide bonds in the rat uterine oxytocin receptor, but not the angiotensin receptor, are sensitive to hydrosulfide ion. Reduction of oxytocin receptors by hydrosulfide ion may be a mechanism by which low levels of H2S delay parturition in rats.
The relation between life stress and immune parameters was investigated for 33 female rheumatoid arthritis (RA) patients interviewed during three routine monthly clinic checkups. Life stress from major and minor events, coping efficacy, and self-reported psychological distress were assessed, and immunofluorescence of T-cells and B-cells was performed on the blood drawn during each visit. Small stressful events were positively related to the proportion of circulating B-cells, psychological distress was inversely related to proportion of circulating T-cells, and major life events were associated with lower T-helper/T-suppressor cell ratios.
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Non-steroidal anti-inflammatory drug (NSAID)-induced gastropathy is a serious public health problem. The United States Food and Drug Administration has recently proposed strong class labelling for NSAIDS, warning of the risk of ulceration, bleeding and perforation associated with their use. The adaptation of the gastric mucosa in response to NSAID intake in volunteers does not seem to occur to the same extent in rheumatic patients. In an ongoing study of patients with osteo- or rheumatoid arthritis, currently in its fourth year, nabumetone has been shown to be relatively gastric sparing when compared with naproxen. Nabumetone is at least as effective as naproxen. Long-term studies are important as treatment of arthritis may involve prolonged use of NSAIDs.
The enantiomers of pentobarbital had four different actions on the nicotinic receptor-rich membranes from Torpedo electroplaques. (i) Both inhibited cholinergically stimulated cation flux through the receptor's channel, with IC50 values of approximately 25 microM and extremely weak stereoselectivity. (ii) (R)-(+)-[14C]Pentobarbital bound to a saturable site with an apparent dissociation constant of 100 microM, a Hill coefficient of 1.2, and a stoichiometry of 1:1 with the acetylcholine binding sites. (S)-(-)-Pentobarbital also displaced (+)-[14C]pentobarbital but its IC50 was 4-fold higher than that of the (+)-enantiomer under the same conditions. (iii) Both enantiomers caused a stereoselective allosteric inhibition of [3H]acetylcholine binding, which occurred over the same concentration range and with the same stereoselectivity as barbiturate binding. (iv) Above 1 mM, pentobarbital caused an unexpected and sudden increase in [3H]acetylcholine binding, which lacked significant stereoselectivity. These results are consistent with a model where low concentrations of pentobarbital act on the receptor by binding to allosteric sites that have higher affinity but lower stereoselectivity for the open channel conformation than for the resting conformation, whereas the highest concentrations of pentobarbital act by nonspecific mechanisms mediated by general membrane perturbations.