Psychological responses after abortion.

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.

NSAID gastropathy. A new understanding.

Nonsteroidal anti-inflammatory drug (NSAID) gastropathy is associated with substantial morbidity and mortality, which result in high costs to both the patient and society. The subset of patients who are at greatest risk for developing NSAID gastropathy continues to be better defined, but various risk factors, such as age and previous gastrointestinal tract disease, have been identified. In patients receiving older NSAIDs, the choice of NSAID should be based on differences in formulations at the lowest effective dose. Gastroprotective cotherapy should be instituted if treatment with older NSAIDs is continued in at-risk patients; misoprostol is currently the only agent approved for this indication. The impact of misoprostol on clinical gastrointestinal tract end points has recently been documented. Newer NSAIDs may have an improved safety profile over older NSAIDs; some have a clinically documented reduction in the incidence of adverse gastrointestinal tract effects. An understanding of these issues should enable the informed clinician to choose an NSAID on the basis of risk-benefit and cost-benefit considerations.

Nonsteroidal anti-inflammatory drug gastropathy. Recognition and response.

Gastropathy, recognized as gastric lesional disease ranging from erosions to actual ulcer craters, represents the most ubiquitous significant complication of common nonsteroidal anti-inflammatory drug (salicylate and nonsalicylate) use. Recently, this association has been established as distinct from classic peptic ulcer disease, which is primarily acid-mediated, duodenal, and more prevalent in a younger, often male, population. Nonsteroidal anti-inflammatory drug gastropathy is usually antral/prepyloric disease, and research indicates it is mediated through blockade of cyclooxygenase with reduction in cytoprotective gastric prostaglandins. The previous literature has been confounded with short-term studies on healthy volunteers and animals that emphasize the resiliency of normal gastric adaptation to heal such gastropathy. Newer long-term studies in patients with arthritis undergoing anti-inflammatory therapy on a sustained basis indicate fatigue of normal adaptation, with persisting gastropathy leading to bleeding and even death. In addition, silent lesions are more common as symptomatology is not synchronous with lesional disease. Since endoscopy is an expensive, not always utilized procedure, it is important to identify the population most at risk for appropriate cytoprotective management as well as modification of the anti-inflammatory therapy program.

Cimetidine therapy in nonsteroidal anti-inflammatory drug gastropathy. Double-blind long-term evaluation.

To assess the efficacy of cimetidine in treating and preventing gastric mucosal lesions associated with nonsteroidal anti-inflammatory drug (NSAID) therapy (NSAID gastropathy), we endoscopically studied 104 patients taking NSAIDs for a variety of rheumatic diseases. Fifty-six percent (22/43) of patients randomized to cimetidine 300 mg four times a day and 52% (22/42) of those randomized to placebo showed progression of endoscopic lesions during the eight-week short-term phase. Thirty-nine patients whose endoscopic lesions improved were then randomized to a ten-month maintenance regimen of either cimetidine 400 mg at bedtime or placebo. Fifty percent (7/14) of placebo-treated and 42% (5/12) of cimetidine-treated patients showed progression of lesions during the maintenance phase. The failure of cimetidine to offer any significant benefit under these protocol conditions reflects the fundamental difference in pathophysiologic features between classic acid-mediated ulcer disease and NSAID gastropathy.

Around-the-clock, controlled-release oxycodone therapy for osteoarthritis-related pain: placebo-controlled trial and long-term evaluation.

BACKGROUND: Although opioid analgesics have well-defined efficacy and safety in treatment of chronic cancer pain, further research is needed to define their role in treatment of chronic noncancer pain. OBJECTIVE: To evaluate the effects of controlled-release oxycodone (OxyContin tablets) treatment on pain and function and its safety vs placebo and in long-term use in patients with moderate to severe osteoarthritis pain. METHODS: One hundred thirty-three patients experiencing persistent osteoarthritis-related pain for at least 1 month were randomized to double-blind treatment with placebo (n = 45) or 10 mg (n = 44) or 20 mg (n = 44) of controlled-release oxycodone every 12 hours for 14 days. One hundred six patients enrolled in an open-label, 6-month extension trial; treatment for an additional 12 months was optional. RESULTS: Use of controlled-release oxycodone, 20 mg, was superior (P<.05) to placebo in reducing pain intensity and the interference of pain with mood, sleep, and enjoyment of life. During long-term treatment, the mean dose remained stable at approximately 40 mg/d after titration, and pain intensity was stable. Fifty-eight patients completed 6 months of treatment, 41 completed 12 months, and 15 completed 18 months. Common opioid side effects were reported, several of which decreased in duration as therapy continued. CONCLUSIONS: Around-the-clock controlled-release oxycodone therapy seemed to be effective and safe for patients with chronic, moderate to severe, osteo-arthritis-related pain. Effective analgesia was accompanied by a reduction in the interference of pain with mood, sleep, and enjoyment of life. Analgesia was maintained during long-term treatment, and the daily dose remained stable after titration. Typical opioid side effects were reported during short- and long-term therapy.

A controlled study comparing the effects of nabumetone, ibuprofen, and ibuprofen plus misoprostol on the upper gastrointestinal tract mucosa.

BACKGROUND: This study was developed to compare the incidence of endoscopically diagnosed ulcers in elderly patients taking nabumetone, ibuprofen, or concomitant ibuprofen/misoprostol. Further research is indicated to better establish the clinical relevance of these endoscopy findings. METHODS: We conducted a prospective, multicenter, randomized, endoscopist-blinded, 12-week study involving 171 patients with osteoarthritis aged 60 years and older. Patients were randomized to receive nabumetone, 1000 mg (n = 58); ibuprofen, 600 mg four times daily (n = 53); or ibuprofen, 600 mg four times daily, administered concomitantly with misoprostol, 200 micrograms four times daily (n = 60). Endoscopy was performed at baseline and at weeks 2, 6, and 12. Endoscopy results were scored on a scale of 1 to 9. Significant ulcers were defined as breaks in the mucosa greater than 5 mm with appreciable depth. RESULTS: Of the 171 randomized patients, 148 completed the study. There was no significant difference in the incidence of significant ulcers between the nabumetone group and the ibuprofen/misoprostol group (one vs zero). There were significantly fewer significant ulcers in the nabumetone and ibuprofen/misoprostol groups than in the ibuprofen monotherapy group (one and zero vs eight; P < .01). There also was a significant difference in the time to ulcer development, with a greater risk of developing an ulcer sooner with ibuprofen treatment (P < .01) than either nabumetone or ibuprofen/misoprostol treatment. The severity of osteoarthritis, based on physicians' assessments, improved in 64% of patients in the nabumetone group, 55% of those in the ibuprofen group, and 63% of those in the ibuprofen/misoprostol group. CONCLUSIONS: Nabumetone is equivalent in ulcerogenicity to concomitant ibuprofen/misoprostol and is significantly less ulcerogenic than ibuprofen alone.

Endoscopy-controlled study of the safety of nabumetone compared with naproxen in arthritis therapy.

Nonsteroidal anti-inflammatory drug (NSAID) gastropathy is now a commonly recognized and reported complication of such arthritis therapy. Significant gastric lesions develop in up to 40 percent of arthritic patients treated with long-term anti-inflammatory doses of NSAIDs, 20 percent of which represents actual ulcer crater disease. This 12-week endoscopy-controlled, double-blind study was constructed to evaluate the safety and efficacy of nabumetone 1,000 mg at bedtime compared with naproxen 250 mg twice daily. A total of 37 patients completed the study, including 29 patients with a diagnosis of osteoarthritis and eight with a diagnosis of rheumatoid arthritis. By posttreatment endoscopy, nabumetone was significantly less toxic to the gastrointestinal tract than was naproxen. The nabumetone-treated group also showed greater improvement in all efficacy variables, with significant improvement noted in three of these five variables in both rheumatoid and osteoarthritic patients.

From experiment to experience: side effects of nonsteroidal anti-inflammatory drugs.

As part of the approval process, new drugs are first studied in controlled clinical trials with carefully selected patients. After gaining approval, however, these drugs are often used in the general community under widely different circumstances. This report explores the effects of such differences on the frequency and severity of side effects using the nonsteroidal anti-inflammatory drugs as a prototype. A review of clinical trials is compared with the accumulated experience at the Stanford and Phoenix Arthritis Centers. Statistical analysis of patient records was accomplished using the American Rheumatism Association Medical Information System Computer Data-Base System. To overcome potential biases in different methods of detecting side effects, a questionnaire was mailed directly to 390 patients, including subjects who were and were not participants in formal drug studies. Agreement between experiment and experience was generally quite good. However, a tendency for severe side effects to occur more frequently in community use than would be predicted from clinical trials was noted.

Sucralfate treatment of nonsteroidal anti-inflammatory drug-induced gastrointestinal symptoms and mucosal damage.

In a randomized, double-blind trial, sucralfate therapy, 1 g four times daily, was compared with placebo in 143 symptomatic patients to assess the treatment of gastrointestinal symptoms and gastric mucosal damage associated with nonsteroidal anti-inflammatory drugs (NSAIDs). All patients followed a fixed regimen of NSAIDs, were assigned to one of two groups based on the presence or absence of gastric erosions at baseline endoscopy, and were then assigned randomly to receive sucralfate or placebo for four weeks. Patients were then followed for up to six months while receiving open-label sucralfate 1 g twice daily to up to 1 g four times daily. After four weeks of double-blind therapy, patients taking either nonsalicylate NSAIDs or long half-life NSAIDs and who were treated with sucralfate experienced a significant reduction in both peptic symptom frequency and intensity (p less than 0.03) as compared with patients receiving placebo. Sucralfate-treated patients with baseline endoscopic lesions showed a significant reduction in lesion scores (p less than 0.005) at four weeks as compared with baseline, whereas no improvement was observed in gastric mucosal lesions of patients given placebo. Long-term sucralfate therapy resulted in continued improvement in gastrointestinal symptoms and gastric lesion scores in patients receiving all types of NSAIDs. The results indicate that sucralfate used in conjunction with NSAIDs may allow patients to continue therapy by relieving gastrointestinal symptoms and mucosal damage associated with NSAID therapy.

An in vitro study of copper and copper chelators on the crayfish stretch receptor.

This study demonstrates the effects of micromolar concentrations of copper on the discharge firing activity of the isolated crayfish stretch receptor. Different pharmacological profiles of action were obtained with the divalent (cupric) and monovalent (cuprous) salt solutions. Cupric solutions produced a concentration-dependent triphasic effect (depression-excitation-depression); in contrast, a monophasic effect (depression) was produced by cuprous solutions. The effectiveness of copper chelators, in reversing these effects, were compared with normal physiological solution. Only the first phase of the effects of cupric were partially reversed with physiological solution or ethylenediamine tetraammonium (EDTA). In the presence of D-penicillamine and triethylene tetramine (trien), all phases of the effects of both cuprous and cupric salts were completely restored to control values. In addition, copper was shown to be the most neurotoxic divalent cation examined. The results demonstrate that effects of copper on neuronal activity are dependent on time, concentration and valency state.

Benzodiazepines produce contrasting effects on the active membrane properties of an invertebrate neuron.

A perturbation of excitable membranes mediated by non-receptor (non-specific) mechanisms might be predicted from the hydrophobic nature of 1,4-benzodiazepines. Since correlations between membrane properties and neuronal effects have not been described for benzodiazepines, the effects of flurazepam, oxazepam and the benzodiazepine antagonist flumazepil (Ro 15-1788) were examined on both passive and active electrical properties of the membrane and neuronal discharge frequency. In this study, the isolated sensory neuron of the crayfish has been utilized as a neuronal model system. Flurazepam and flumazepil both enhanced the discharge frequency, in contrast to the depression produced by oxazepam. Discharge frequency was directly correlated with the maximum rate of rise of membrane potential during the threshold phase and was inversely correlated with spike threshold. In addition, the discharge frequency appeared to exhibit little dependence on peak amplitude, duration and the maximum rate of depolarization of the action potential. These findings are discussed in relation to non-specific mechanism(s) of action for benzodiazepines. It is suggested that, in the absence of a specific drug-receptor interaction, benzodiazepines in larger concentrations (greater than or equal to 50 mumol/l) exhibit selective membrane perturbations.

[Rationale for using nabumetone and clinical experience]. / Modalités d'utilisation de la nabumétone et expérience clinique.

Nabumetone's position as one of the most commonly used nonsteroidal anti-inflammatory drugs (NSAIDs) in the world today is based upon over a decade of clinical experience. The popularity of this drug lies in both its unique pharmacokinetic profile and special safety features in pharmacodynamic terms. This nonacidic prodrug with an active 6-methoxy-2-naphthylacetic acid (6-MNA) metabolite has COX-2 preferential features and is also devoid of enterohepatic recirculation. It is felt that these characteristics have provided the basis for its unique long term tolerability, documented in various at-risk osteoarthritis and rheumatoid arthritis populations. The excellent tolerability of nabumetone and its 24-hour half-life, which provides the advantages of a once-daily dosage regimen, make it uniquely suitable for long term anti-inflammatory therapy in arthritis. The tolerability profile of nabumetone has also demonstrated clear cost-effectiveness advantages, as confirmed by comparative and epidemiological studies. Selective COX-2 NSAIDs are likely to prove more expensive because of the increasing costs and demands of clinical research prior to FDA approval. These higher costs may limit and influence patient access, depending on the healthcare delivery system, and many years of experience will be required to document the putative tolerability advantages of these newer COX-2 inhibitor agents. In the meantime, it is comforting that nabumetone has established such an advantageous tolerability profile together with acknowledged efficacy.

NSAID gastropathy. The central issue.

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.

Naproxen: antirheumatic efficacy and safety in patients with pre-existing gastrointestinal disease.

Nonsteroidal antiinflammatory drugs (NSAIDs) effectively reduce pain and inflammation of rheumatoid arthritis (RA). To further refine the appropriate uses of NSAID therapy, NSAIDs have been evaluated for possible gastrotoxicity, particularly in patients who have pre-existing gastrointestinal (GI) disease. In the present study, 58 such RA patients (36 women, 22 men) treated long-term with naproxen were monitored for periods up to 2.5 years to determine if any gastrotoxicity were induced by naproxen. We found an extremely low incidence of fecal occult blood, patient complaints of GI discomfort, complications documented by GI studies, and patient discontinuance of naproxen therapy because of complaints. Studies reported in the medical literature support our observations that naproxen can be well tolerated and is effective as long-term RA treatment when patients who have clinically significant pre-existing GI disease are managed with conventional treatments and appropriate monitoring.

Merits and liabilities of NSAID therapy.

The clinical usefulness of nonsteroidal anti-inflammatory drugs (NSAIDs) in antirheumatic therapy is discussed, along with the adverse reaction profile. The authors focus on the recent required gastrointestinal class labeling for NSAIDs as they impact on host population responses. Finally, the risk/benefit and cost/benefit considerations are reviewed.

An open trial of naproxen in rheumatoid arthritis patients with significant esophageal, gastric, and duodenal lesions.

To confirm the reported lack of major gastrointestinal side effects of naproxen, we gave 58 patients with active rheumatoid arthritis and significant gastrointestinal disease therapeutic doses of naproxen while closely monitoring them for signs and symptoms of gastrointestinal dysfunction. All patients underwent upper gastrointestinal x-ray examinations at the start of the trail, and, when indicated, during the course of the study. Endoscopies were also performed when indicated. Forty patients had hiatus hernia and 35 had peptic ulcer (23 duodenal ulcer and 12 gastric ulcer). Twenty-six patients had a combination of hiatus hernia with either type of peptic ulcer. After 262 patient visits over a period of 52 weeks, 35 patients remained in the study, all having had more than six months of naproxen therapy in dosages ranging from 500 to 750 mg daily. In 33 of the 35, the response to naproxen had generally been good to excellent. Only seven patients dropped out of the trial because of complaints referable to side effects. There were no major related upper gastrointestinal side effects as monitored by continuing clinical evaluation, stool occult blood, comprehensive laboratory examination, and, where indicated, upper gastrointestinal x-ray studies. Approximately 70 per cent of the patients demonstrated efficacy on long-term naproxen therapy by subjective and objective parameters. Naproxen appears to be an efficacious and remarkably safe drug in the long-term therapy of rheumatoid arthritis, even in the presence of significant upper gastrointestinal symptomatology.

Evidence that activation of in vitro hippocampal theta rhythm only involves muscarinic receptors.

The present study was conducted for two purposes: the first was to evaluate whether activation of nicotinic receptors in the hippocampal formation in vitro (slice) preparation was capable of producing type 2 (atropine-sensitive) theta rhythm. The cholinergic nature and involvement of muscarinic receptors in this type of theta has been previously well documented. The second purpose was to determine whether perfusion of a number of (other) putative neurotransmitters shown to be present in the hippocampal formation could elicit type 1 (atropine-resistant) theta in the slice preparation. Further experiments were conducted to determine if these agents interacted in any manner with cholinergically-induced type 2 theta. Electroencephalic (EEG) theta activity was not induced by nicotine, providing evidence for an exclusive muscarinic receptor involvement in this cholinergically-induced type 2 theta. In addition, theta activity was not elicited by the application of gamma-aminobutyric acid (GABA), glutamate, norepinephrine, dopamine or serotonin. The application of any of these agents did not significantly alter the production of cholinergically-induced theta. These results suggest that type 1 theta originates in regions extrinsic to the hippocampus, or is the result of the interaction of several neurotransmitters on different receptors.

The development of carbachol-induced EEG 'theta' examined in hippocampal formation slices.

The development of carbachol-induced EEG theta (theta) activity was studied in the CA1 and dentate regions of hippocampal formation slices obtained from neonatal rats (4, 6, 8, 10, 12 and 14 days of age). When perfused with carbachol (50 microM), 4- and 6-day-old hippocampal slices exhibited only short-lasting irregular activity. The initial appearance of carbachol-induced rhythmic waves were observed in slices obtained from 8-day-old rats. From the time that theta appeared at 8 days of age, a steady increase in amplitude and frequency was noted. This observed in vitro developmental pattern of hippocampal theta-rhythm closely resembles the development of theta activity in in vivo preparations.

Carbachol-induced EEG 'theta' in hippocampal formation slices: evidence for a third generator of theta in CA3c area.

The topography of carbachol-induced EEG theta activity was studied using the hippocampal formation slice preparation. Systematic tracking with electrodes exhibited two amplitude maxima of cholinergic-induced theta, one located in the stratum oriens of the CA1 pyramidal cells and the other in a region of CA3c pyramidal neurons. In addition, mapping experiments demonstrated EEG theta in the CA3a and CA3b cell body layers, but not in the subicular and parasubicular regions, or the ventral blade of the dentate gyrus. Furthermore, transected slice (trans-slice) preparations used in the present study revealed that the CA3c region could generate carbachol-induced theta independently of CA1 and dentate gyrus generator zones and conversely, CA1 and dentate gyrus areas were capable of generating cholinergic-induced theta rhythm independently of the CA3c region. These results provide strong evidence for 3 independent, anatomically separated generators of theta: one located in the stratum oriens of CA1 neurons, a second in the stratum moleculare of the dentate gyrus and a third one in the region of Ca3c cells. In addition, the results support previous in vivo suggestions that theta rhythm can be either elicited or blocked by cholinergic agents acting on sites within the hippocampal formation.

Phase shifting of CA1 and dentate EEG theta rhythms in hippocampal formation slices.

Carbachol-induced hippocampal EEG theta-rhythms were recorded simultaneously from the CA1 and dentate areas in rat hippocampal brain slices. Phase shifts ranging from 0 to 180 degrees between the CA1 and dentate theta generators were observed. The differences in slow wave theta phase relations between in vitro and in vivo preparations were interpreted as resulting from deafferentation of the hippocampal slices.