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Dyspeptic symptoms are common with aspirin and clinicians frequently recommend that it be taken with food to reduce these side effects. However, food can interfere with absorption, especially with enteric-coated aspirin formulations. We evaluated whether food interferes with the bioavailability of a new, pharmaceutical lipid-aspirin complex (PL-ASA) liquid-filled capsule formulation. In this randomized, open label, crossover study, 20 healthy volunteers fasted for ≥ 10 h and then randomized as either “fasted”, receiving 650 mg of PL-ASA, or as “fed”, with a standard high-fat meal and 650 mg of PL-ASA 30 min later. After a washout of 7 days, participants crossed over to the other arm. The primary outcome was comparison of PK parameters of the stable aspirin metabolite salicylic acid (SA) between fasted and fed states. Mean age of participants was 36.8 years and 55% were male. The ratios for the fed to fasted states of the primary SA PK parameters of AUC0−t and AUC0−∞ were 88.7% and 88.8% respectively, with 90% confidence intervals between 80 and 125%, which is consistent with FDA bioequivalence guidance. Mean peak SA concentration was about 22% lower and occurred about 1.5 h later in the fed state. Food had a modest effect on peak SA levels and the time required to reach them after PL-ASA administration, but did not impact the extent of exposure (AUC) compared with intake in a fasted state. These data demonstrate that PL-ASA may be co-administered with food without significant impact on aspirin bioavailability.Clinical Trial Registration:http://www.clinicaltrials.gov Unique Identifier: NCT01244100

Aspirin (acetylsalicylic acid, ASA) can lead to gastrointestinal mucosal injury through disruption of its protective phospholipid bilayer. A liquid formulation of a novel pharmaceutical lipid–aspirin complex (PL-ASA) was designed to prevent this disruption. We sought to determine the pharmacokinetic (PK)/pharmacodynamic (PD) characteristics of PL-ASA compared with immediate release aspirin (IR-ASA). In this active-control crossover study, 32 healthy volunteers were randomized to receive 1 of 2 dose levels (a single dose of 325 mg or 650 mg) of either PL-ASA or IR-ASA. After a 2-week washout period between treatment assignments, subjects received a single dose of the alternative treatment, at the same dose level. The primary objectives of the study were to assess, for PL-ASA and IR-ASA at 325 mg and 650 mg dose levels, PK and PD bioequivalence, and safety, over a 24–h period after administration of both drugs. PK parameters were similar for PL-ASA and IR-ASA, and met FDA-criteria for bioequivalence. Regarding PD, both drugs also showed Cmin TxB2 values below 3.1 ng/mL (cut-off associated with decreased cardiovascular events) and > 99% inhibition of serum TxB2 ( ≥ 95% inhibition represents the cut-off for aspirin responders) along with similar results in several secondary PK/PD parameters. There were no serious adverse events or changes from baseline in vital signs or laboratory values in either of the 2 treatment groups. PL-ASA’s novel liquid formulation has similar PK and PD performance compared with IR-ASA, supporting functional and clinical equivalence. These data coupled with the improved gastric safety of PL-ASA suggest that this novel formulation may exhibit an improved benefit-risk profile, warranting evaluation in future trials.Clinical trial registration:http://www.clinicaltrials.gov. Unique Identifier: NCT04008979

OBJECTIVE:: Depot medroxyprogesterone acetate (DMPA) reversibly reduces bone mineral density. To estimate the extent to which DMPA might increase fracture risk we undertook a retrospective cohort study of fractures in DMPA users and users of non-DMPA contraceptives using the General Practice Research Database. METHODS:: Eligible women were aged younger than 50 years at the qualifying first contraceptive prescription. The DMPA users were classified by DMPA exposure (cumulative and time of last dose) based on prescription records. All incident fractures were included; fracture incidence and risk factors before starting contraceptive use (DMPA or other) also were estimated. RESULTS:: We identified 11822 fractures in 312395 women during 1722356 person-years of follow-up. Before contraceptive use started DMPA users had higher fracture risk than nonusers (incidence rate ratio 1.28 95% confidence interval [CI] 1.07-1.53). After DMPA started crude fracture incidence was 9.1 per 1000 person-years for DMPA users and 7.3 for nonusers (crude incidence rate ratio 1.23 95% CI 1.16-1.30). Fracture risk in DMPA users did not increase after starting DMPA (incidence rate ratio after or before 1.08 95% CI 0.92-1.26). There was little confounding by age or other factors that could be measured. Fracture incidence was 9.4 per 1000 person-years in low-exposure DMPA users and 7.8 per 1000 in high-exposure DMPA users. The DMPA users had higher fracture risk than nonusers at the start of contraceptive use with no discernible induction period. CONCLUSION:: Although DMPA users experienced more fractures than nonusers this association may be the result of confounding by a pre-existing higher risk for fractures in women who chose DMPA for contraception. LEVEL OF EVIDENCE:: II.

Background/Aims: The effect of inflammatory skin diseases on pregnancy has been incompletely characterized. We sought to estimate the incidence of pregnancy and pregnancy outcomes among women with inflammatory skin diseases. Methods: Cohort study of women with atopic dermatitis (AD), psoriasis, other inflammatory skin diseases, and comparison group, followed for pregnancies and pregnancy outcomes. Results: There were 3,131 pregnancies among 64,773 woman-years (4.8/100) in women with skin diseases, and 2,592 pregnancies among 59,826 woman-years (4.3/100) in the comparison group. The age-standardized incidence of pregnancy was similar to the comparison group [rate ratio (RR) = 1.2, 95% confidence interval (CI) 1.0–1.4 for AD, RR = 1.1, 95% CI 1.0–1.2 for psoriasis, and RR = 1.1, 95% CI 1.0–1.1 for other]. Spontaneous abortion was also similar to the comparison group (RR = 1.2 for AD, 95% CI 1.0–1.4, RR = 1.1, 95% CI 1.0–1.2 for psoriasis, and RR = 1.1, 95% CI 1.0–1.1 for other). Conclusions: Our results suggest little effect of skin disease on incidence or outcome of pregnancy.

Alendronate (10 mg daily) has been shown in long term clinical trials to be an effective treatment for postmenopausal osteoporosis. A weekly dosing regimen of alendronate is preferred by both patients and physicians, as it has the potential to provide greater convenience and enhance compliance. In a 1-yr clinical trial, alendronate (70 mg once weekly) was equally efficacious and at least as well tolerated as the 10-mg daily dose in the treatment of postmenopausal osteoporosis, despite the higher unit dosage required. We conducted a randomized, double blind, placebo- and active-controlled endoscopy study to confirm the results of this clinical trial. We hypothesized that mean endoscopic gastric erosion scores would be similar in subjects receiving alendronate (70 mg once weekly) and those receiving a placebo.Two hundred seventy-seven subjects (90 men and 187 women) were randomized to one of three treatment groups: 1) alendronate (70 mg once weekly) for 10 wk (N = 126), 2) placebo (once weekly) for 10 wk (N = 126), or 3) placebo (once weekly) for 10 wk followed by aspirin (650 mg q.i.d.) for the last week as the positive control (N = 25). Esophagogastroduodenoscopy was performed 5 to 7 days after the last dose of alendronate or matching placebo.The mean gastric erosion scores (Lanza scale) were similar in subjects given alendronate (70 mg once weekly) and those given a placebo (0.32 vs 0.35, respectively; 95% CI for difference = -0.22-0.16, p = 0.75), whereas scores in both groups were significantly lower than in those given aspirin (3.09; p0.001). Endoscopic gastroduodenal ulcers occurred in no alendronate (0%), two placebo (1.7%), and five aspirin (23.8%) subjects. The mean erosion scores in the esophagus and duodenum of alendronate and placebo subjects were also similar. The incidences of upper GI symptoms were similar in the alendronate and placebo subjects and did not suggest a relationship with endoscopic lesions.Alendronate (70 mg once weekly) was not associated with any increase in endoscopic lesions in the upper GI tract relative to a placebo.

Bisphosphonates are effective treatment for osteoporosis, but upper gastrointestinal injury associated with some compounds has caused concern. This study compared the incidence of gastric ulcers after treatment with risedronate, a pyridinyl bisphosphonate, and alendronate, a primary amino bisphosphonate. Esophageal and gastroduodenal injury assessed by endoscopy scores was a secondary endpoint.Healthy, postmenopausal women (n = 515) received 5 mg risedronate (n = 255) or 10 mg alendronate (n = 260) for 2 weeks. At baseline and on days 8 and 15, subjects underwent endoscopy and evaluator-blinded assessment of the esophageal, gastric, and duodenal mucosa.Gastric ulcers were observed during the treatment period in 9 of 221 (4.1%) evaluable subjects in the risedronate group compared with 30 of 227 (13.2%) in the alendronate group (P0.001). Mean gastric endoscopy scores for the risedronate group were lower than those for the alendronate group at days 8 and 15 (P/= 0.001). Mean esophageal and duodenal endoscopy scores were similar in the 2 groups at days 8 and 15. Esophageal ulcers were noted in 3 evaluable subjects in the alendronate group, compared with none in the risedronate group, and duodenal ulcers were noted in 1 evaluable subject in the alendronate group and 2 in the risedronate group.At doses used for the treatment of osteoporosis, risedronate was associated with a significantly lower incidence of gastric ulcers than alendronate. These findings confirm that bisphosphonates differ in their potential to damage the gastroesophageal mucosa.

Background and Objectives: Oropharyngeal carcinoma tends to be aggressive and deeply infiltrative of nearby sites, with an high incidence of lymphnode metastases. The last treatment decision generally depends on the stage of the lesion and the patient's general status. Oropharyngeal tumor is generally treated by integrated treatments. Methods: We retrospectively studied 115 patients with locally advanced oropharyngeal tumors treated in our institution with combined therapies compare the results in two differents groups of patients (surgery plus radiotherapy and chemotherapy plus radiotherapy). Results: The 3-year overall survival rate in patients who underwent surgery plus radiotherapy was 82% and in those who underwent chemotherapy plus radiotherapy was 49%. Conclusion: The results suggest that surgery followed by radiotherapy seems to be the best treatment in the case of locally advanced oropharyngeal tumor.

Background. The combination of ranitidine bismuth citrate (RBC) and clarithromycin (CLR) was compared with each treatment alone for the eradication of H. pylori and healing of duodenal ulcers in patients infected with H. pylori. Methods. This two-phase, randomized, double-blind, placebo-controlled, multicenter study evaluated 203 patients with an active duodenal ulcer treated with either (1) RBC 400 mg BID for 4 weeks plus CLR 500 mg TID for the first 2 weeks; (2) RBC 400 mg BID for 4 weeks plus placebo TID for the first 2 weeks; (3) placebo BID for 4 weeks plus CLR 500 mg TID for the first 2 weeks; or (4) placebo BID for 4 weeks plus placebo TID for the first 2 weeks. Patients with healed ulcers after treatment entered a 24-week observation phase for the assessment of H. pylori and ulcer relapse. Results. Four-week ulcer healing rates were higher with RBC + CLR (71%) and RBC alone (66%) compared with placebo (15%;p < 0.05) and CLR alone (49%). H. pylori eradication rates were significantly higher with RBC + CLR (86%) compared with RBC alone (0%, p < .001) or CLR alone (24%, p < .001). Ulcer recurrence rates after 6 months were lower in patients eradicated of H. pylori infection (17%) compared with patients who remained infected (43%). All treatments were well tolerated. Conclusions. Ranitidine bismuth citrate plus clarithromycin is a simple, convenient, and well-tolerated dual therapy regimen that is effective in eradicating H. pylori and healing duodenal ulcers in patients infected with H. pylori. The eradication of H. pylori in patients with healed ulcers significantly reduces the rate of ulcer relapse.

The objective of this study was to endoscopically assess in healthy subjects the gastrointestinal effects of over-the-counter (OTC) doses of ketoprofen. Ketoprofen is a potent nonsteroidal antiinflammatory agent (NSAID) recently approved for OTC use as an analgesic/antipyretic at doses of 75 mg versus the usual dose ofor = 300 mg daily. In epidemiological studies, ketoprofen at prescription doses has consistently been in the higher relative risk group of NSAIDs in the occurrence of gastrointestinal complications of therapy. The gastrointestinal effects of the OTC (US) dose of ketoprofen have not been reported.In a randomized, double blind, three way crossover study, 24 healthy subjects received 7 days of therapy with ketoprofen 75 mg/day, acetaminophen 4000 mg/day, and placebo. Gastroduodenal endoscopy was performed before and at the end of each treatment period. The condition of the mucosa was graded compositely for the gastric antrum, fundus, body, and duodenum.Significantly more frequent and severe gastric mucosal injury was observed after dosing with ketoprofen compared with acetaminophen (p = 0.0001). The acetaminophen group showed no difference from placebo (p = 0.8783). Two subjects developed frank gastric ulcers with ketoprofen therapy. Marginally more frequent (p = 0.0703) and significantly more severe (p = 0.0117) duodenal mucosal injury was seen. No significant differences were observed between treatment groups with respect to subjective symptoms of gastric discomfort or adverse events.These results indicate that even at lower (OTC) doses (75 mg/day) ketoprofen is associated with significant gastrointestinal irritation.

Objectives: This single-center, double-blind, randomized study assessed the effect of alendronate 5 and 10 mg on the gastroduodenal mucosa. Methods: Overall, 95 postmenopausal women without a recent history of major upper gastrointestinal (GI) disease and not taking gastric-irritant drugs, were screened with an upper GI endoscopy. Fourteen women (15% of the total) were found to have baseline endoscopic gastric and/or duodenal abnormalities, including mucosal hemorrhages (n = 4), erosions (n = 11), and ulcers (n = 3). Two additional women had baseline esophageal abnormalities. Thus, 79 postmenopausal women (mean age 51 yr, range 41–64 yr), free of esophageal, gastric and/or duodenal erosions or ulcer, were enrolled. Subjects received placebo, alendronate 5 mg/day or 10 mg/day, or aspirin 650 mg q.i.d. for 14 days. Endoscopy was repeated on Day 8 and on Day 15. Gastric and duodenal mucosae were graded separately using a 5-point scale for erosive mucosal injury. Results: The proportions of subjects with a gastric or duodenal erosion score ≥ 2 (presence of at least one mucosal erosion) on either Day 8 or 15 were four of 22 (18.2%) in the placebo group; four of 22 (18.2%) in the alendronate 5 mg group; five of 21 (23.8%) in the alendronate 10 mg group; and 14 of 14 (100.0%) in the aspirin group. Thirty-five of 76 (46%) subjects were H. pylori -positive (Pyloritek test), and were equally distributed across treatment groups. Conclusions: Alendronate 5 and 10 mg/day for 2 wk was associated with a lower incidence of gastric erosions than aspirin. The incidence of gastric erosions in the alendronate groups did not differ significantly from the placebo group. In this study, unlike aspirin, alendronate did not induce gastric erosions.

OBJECTIVE AND IMPORTANCE: The association of subarachnoid hemorrhage (SAH) with spinal lesions is well known, but hemorrhage from a cervical schwannoma is exceedingly rare. The histopathology and the mechanism of bleeding are discussed. CLINICAL PRESENTATION: We report a healthy 37-year-old man presenting with SAH after intense physical stress caused by bleeding of a cervical neuroma. INTERVENTION: A C6-T1 laminectomy disclosed an ovoid lesion, 4 cm in diameter; extremely dilated veins originated from the tumor. Removal of the spinal lesion resulted in immediate decongestion of the related venous network. The histopathological examination confirmed that the lesion was a telangiectatic schwannoma. The mechanism of bleeding of the intraforaminal cervical schwannoma is discussed. CONCLUSION: Telangiectatic neuromas may be a cause of occult SAH. The importance of magnetic resonance imaging of the cervical spine is emphasized to explain SAH with negative findings on four-vessel angiography in patients whose SAH may have a surgically correctable cause distant from the intracranial compartment.

This study compared spontaneous bone healing and regeneration obtained with deproteinised bovine graft in residual cavities after mandibular cyst enucleation using computed tomography (CT) Dentascan.Eighty patients with a radiological diagnosis of mandibular cyst underwent surgical enucleation. Patients were divided into a control group (spontaneous healing, 40 patients) and a test group (deproteinised bovine graft, 40 patients). All patients underwent follow-up CT Dentascan 12 months after the procedure. For each residual cavity, apical-coronal and mesial-distal distance, average pixel intensity and volume were calculated and results compared between two groups using the t test.The control group showed mean volume, apical-coronal and mesial-distal distance of 703.2 ± 185.3 mm(3), 28.6 ± 9.4 mm and 25 ± 2.84 mm, respectively. In the test group, values were 738.2 ± 189.2 mm(3), 27.5 ± 3.6 mm and 25.3 ± 2.97 mm, respectively. There was no statistically significant difference between groups. Average pixel intensity was 1,102.8 ± 124.3 in the test group and 624.9 ± 133.3 in the control group, with a significant difference between groups (p0.0001).The significantly higher average pixel intensity observed in the test group demonstrates the cavalue of treatment with biomaterials to obtain earlier bone regeneration.

Thirty-five healthy adults were randomized to receive either: (1) ibuprofen 800 mg tablets; (2) ibuprofen 800 mg aqueous suspension; (3) ibuprofen 800 mg orange juice suspension; or (3) 325 mg aspirin tablets. All treatments were tid for 7 days. Pharmacokinetic sampling was conducted on days 1, 4 and 8. Gastroduodenoscopy was performed on days 1 and 8. Side effects and safety laboratory tests were monitored throughout the study. On day 8 the aspirin group showed significantly more gastric irritation than all of the ibuprofen groups (P less than .005). Both ibuprofen suspension groups showed more gastric irritation than the ibuprofen tablet group (P less than .1). The duodenal scores did not differ among the treatment groups. The aspirin group experienced a higher rate of tinnitus and abdominal pain. The rate and extent of absorption of the ibuprofen suspensions were significantly less than that of the tablets. These data suggest that the taking of ibuprofen as an extemporaneous suspension is therapeutically inferior to ibuprofen tablets and therefore should be discouraged.

Bisphosphonates are effective treatments for osteoporosis. Since some primary amino bisphosphonates are associated with oesophageal injury, we conducted a study of the upper gastrointestinal effects of risedronate, a pyridinyl bisphosphonate.Healthy, postmenopausal women received risedronate 5 mg (n=26), aspirin 2600 mg (n=27), or placebo (n=27) daily for 14 days and underwent endoscopy at baseline, Day 8 and Day 15.Oesophageal erosions were noted in one subject in the aspirin group, two in the placebo group, and none in the risedronate group, and an ulcer in one aspirin-treated subject. Gastric erosions and ulcers were observed most frequently in the aspirin group. Gastric ulcers were noted in eight subjects in the aspirin group, one in the placebo group, and none in the risedronate group (P=0.010, placebo vs. aspirin; P=0.002, risedronate vs. aspirin). Duodenal erosions and ulcers were observed in the aspirin group only. Gastroduodenal erosion scores of three or more occurred more frequently in the aspirin than in the risedronate and placebo groups (P0.001).Risedronate 5 mg was not associated with oesophageal or gastroduodenal ulcers in healthy, postmenopausal women, a population representative of patients who will receive risedronate in the clinical setting.

Benign thyroid nodules is a significant clinical problem since it involves more than 90% of all thyroid surgery. This has led the authors to perform a retrospective study of 190 patients suffering from this pathology out of 299 patients who underwent surgery from 1979 to 1995. 89 total thyroidectomies and 101 radical hemithyroidectomies were performed in patients suffering from benign thyroid nodules. Two cases of recurrent monolateral paralysis were found as well as 3 cases of permanent hypoparathyroidism in those patients who underwent total thyroidectomies. The results of numerous authors as well as the present case review indicate that more radical surgery does not significantly affect the degree of permanent complications. For this reason the authors are convinced that such radical surgery should be the treatment of choice, particularly in young patients whose life expectancy is long and where the likelihood of recurrence is greater.

Serious, although rare, ventricular arrhythmias and deaths have been reported in patients taking cisapride monohydrate. Without quantification of the risk involved, it is impossible to develop rational therapeutic guidelines.Arrhythmic events (sudden deaths and other events compatible with serious ventricular arrhythmias) were sought among 36,743 patients prescribed cisapride in the United Kingdom and Saskatchewan, Canada. Prescriptions and cases were identified from computerized medical claims data and physicians' office records. We compared rates of events between periods of recent cisapride use and nonrecent use, using cohort analysis. Potential confounding factors, including concomitant treatment with agents that inhibit CYP3A4 metabolism or that prolong the QT interval, were assessed in a nested case-control study.In the cohort analysis, the incidence of the arrhythmic events was 1.6 times greater (95% confidence interval [CI]: 0.9 to 2.9) in periods of recent use. With adjustment for clinical history, use of CYP3A4 inhibitors, and use of drugs that prolong the QT interval, the odds ratio for cisapride and cardiac outcomes was 1.0 (95% CI: 0.3 to 3.7). There was no identifiable increase in risk when cisapride was dispensed at about the same time as QT-prolonging drugs or CYP3A4 inhibitors. QT-prolonging agents were associated with a 2.5-fold increase in the risk of arrhythmic events (95% CI: 1.1 to 5.8).Serious rhythm disorders were not associated with cisapride use, although the upper confidence bounds do not rule out an increase in risk.

Compared with currently available NSAIDs (which inhibit COX-1 and COX-2 isoforms of cyclooxygenase), MK-0966 (a specific COX-2 inhibitor) is expected to cause less gastrointestinal toxicity.To compare the effect on the upper gastrointestinal mucosae of a high dose of MK-0966 with that of conventional doses of ibuprofen and aspirin.Healthy subjects (n = 170; age range 18-54 years) with endoscopically normal gastric and duodenal mucosa were randomized to either MK-0966 250 mg q.d. (n = 51), ibuprofen 800 mg t.d.s. (n = 51), aspirin 650 mg q.d.s. (n = 17), or placebo (n = 51) in this 7-day, double-blind, parallel-group study. The mucosae were evaluated by endoscopy using a predefined scale; scores could range from 0 to 4. The primary end-point was the percentage of subjects who developed a mucosal score/= 2 (i.e. the development of one or more erosions). To evaluate COX-1 activity, serum thromboxane B2 levels were determined in a subset of the population.The percentage of subjects who developed a mucosal score/= 2 in the MK-0966 group (12%) was significantly lower (P0.001) than that in the ibuprofen (71%) and aspirin (94%) groups, and was similar to that in the placebo group (8%). Only ibuprofen and aspirin significantly (P0.0001) reduced baseline thromboxane B2 levels. All treatments were generally well tolerated.In this acute short-term endoscopic study, MK-0966 250 mg q.d. (a dose at least 10 times higher than that demonstrated to reduce the signs and symptoms of osteoarthritis) produced significantly less gastrointestinal mucosal damage than either ibuprofen 800 mg t.d.s. or aspirin 650 mg q.d.s. and was comparable to placebo in this regard.

GM-IVA is a short and effective induction therapy of non M3 de novo AML including GM-CSF (300 mcg 12 hrs before starting therapy), Ara-C (250 mg/sqm c.i. x 3 days), VP16 (100 mg/sqm x 3 days) and idarubicin (12 mg/sqm x 3 days); it was followed by a fludarabine containing salvage protocol (FLANG). Patients60 years of age achieving CR received 2 courses of FLANG and autologous or allogeneic BMT when possible. Patients60 years of age in CR received a second course of GM-IVA. Twenty-one consecutive patients (mean age 64, range 29-85) entered the study. Three patients (14%) died during induction therapy. After one course of GM-IVA, CR was achieved in 12 patients (57%). Two further patients were salvaged with FLANG therapy so that the final CR rate was 14/21 (67%). In elderly patients the final CR rate (62%) is noteworthy, considering that 6 patients were70 years of age and 3 were80. All three patients80 achieved CR (lasting 5 to 7 months). The median time of granulocyte and platelet recovery was 15 days. Our scheme was well tolerated. In the group of elderly patients 3 out of 14 died during induction (21%) and 4 life-threatening infections were observed (28%). The short duration of cytotoxic therapy and perhaps the use of G-CSF contributed to a reduction of the hospitalization period (median of 22 days), thus providing major savings on induction costs and allowing for better utilization of beds as well as significantly improving patients' quality of life.

We have applied a double-determinant immune assay (DDIA) to measure soluble beta2-microglobulin (beta2-micro)-free HLA class I heavy chains in serum. The mean concentration of beta2-micro-free HLA class I heavy chains in serum from 120 healthy subjects was 0.21+/-0.24 microg/ml. The individual serum levels of beta2-micro-free HLA class I heavy chains had a wide distribution, did not seem to be related with HLA phenotype, were stable over time and did not change with age. The serum levels of soluble beta2-micro-free HLA class I heavy chains did not correlate with those of soluble beta2-micro-associated HLA class I heavy chains, suggesting that their release is independently regulated. Three forms of soluble beta2-micro-free HLA class I heavy chains, with apparent molecular masses of 44, 39 and 37-35 kD, respectively, circulate in human serum. These results provide a useful background to assess the serum level of soluble beta2-micro-free HLA class I heavy chains in pathological conditions and to evaluate their putative immunoregulatory function.

To investigate the efficacy and safety of SC-58635 (celecoxib), an antiinflammatory and analgesic agent that acts by selective cyclooxygenase 2 (COX-2) inhibition and is not expected to cause the typical gastrointestinal (GI), renal, and platelet-related side effects associated with inhibition of the COX-1 enzyme.Four phase II trials were performed: a 2-week osteoarthritis efficacy trial, a 4-week rheumatoid arthritis efficacy trial, a 1-week endoscopic study of GI mucosal effects, and a 1-week study of effects on platelet function.The 2 arthritis trials identified SC-58635 dosage levels that were consistently effective in treating the signs and symptoms of arthritis and were distinguished from placebo on standard arthritis scales. In the upper GI endoscopy study, 19% of subjects receiving naproxen (6 of 32) developed gastric ulcers, whereas no ulcers occurred in subjects receiving SC-58635 or placebo. The study of platelet effects revealed no meaningful effect of SC-58635 on platelet aggregation or thromboxane B2 levels, whereas aspirin caused significant decreases in 2 of 3 platelet aggregation measures and thromboxane B2 levels. In all 4 trials, SC-58635 was well tolerated, with a safety profile similar to that of placebo.SC-58635 achieves analgesic and antiinflammatory efficacy in arthritis through selective COX-2 inhibition, without showing any evidence of 2 of the toxic effects of COX-1 inhibition associated with nonsteroidal antiinflammatory drugs.

We used automated health insurance claims records of a New England insurer to assess the relation between salmeterol and severe nonfatal asthma. We identified 61,712 members who received a beta-agonist from January 1, 1993 to August 31, 1995, including 2, 708 recipients of salmeterol. Compared with recipients of other beta-agonists, future salmeterol recipients had higher rates of asthma hospitalization and dispensings of asthma medications during the year before they received salmeterol. We selected as a comparison group 3,825 recipients of sustained-release theophylline. We defined a baseline period as the year before the start of the follow-up period, and we characterized patients according to age, sex, calendar period, presence of baseline hospitalizations for asthma, presence of chronic obstructive pulmonary disease (COPD), and baseline dispensings of asthma medications. After adjusting for baseline factors, incidence rates of severe asthma in the salmeterol group were not elevated for emergency care (rate ratio estimate [RR] = 0.69, 95% confidence intervals [CI] = 0.42, 1.11), hospitalization (RR = 1.09, 95% CI = 0.60, 1.98), or intensive care unit (ICU) stays (RR = 0.81, 95% CI = 0.25, 2.62). We conclude that salmeterol was prescribed preferentially to high-risk patients and, after adjusting for baseline risk, salmeterol recipients did not have a greater risk than theophylline recipients of severe nonfatal asthma.

BackgroundTreatment with amoxicillin plus omeprazole results in disappointing cure rates of Helicobacter pylori infection. The minimal inhibitory concentration of lansoprazole for H. pylori in vitro is lower than that for omeprazole, prompting interest in treatment with amoxicillin plus lansoprazole. Materials and Methods.H. pylori-infected patients with endoscopically documented duodenal ulcer either currently or within the past year were randomized to 14 days of (1) lansoprazole, 30 mg bid, plus amoxicillin, 1 gm tid; (2) lansoprazole, 30 mg tid, plus amoxicillin, 1 gm tid; (3) lansoprazole, 30 mg tid alone; or (4) amoxicillin, 1 gm tid alone. Endoscopy was done at enrollment and at 4 to 6 weeks after completion of treatment or for recurrent symptoms. H. pylori status was assessed by culture and histology. Ulcer prevalence was evaluated at follow-up endoscopy. Results.Two hundred sixty-two patients met enrollment criteria and were treated. By per-protocol analysis, H. pylori infection was cured in 57% of those treated with lansoprazole twice daily plus amoxicillin and in 67% of those treated with lansoprazole three times daily plus amoxicillin, compared with 0% treated with lansoprazole alone or amoxicillin alone (p < .001 for dual therapy versus either monotherapy). Amoxicillin resistance was not observed. At follow-up endoscopy, ulcer prevalence was 17% in patients treated with lansoprazole twice daily plus amoxicillin, 23% in those treated with lansoprazole three times daily plus amoxicillin, 33% in those treated with lansoprazole alone, and 35% in those treated with amoxicillin alone (p= .024; lansoprazole twice daily plus amoxicillin versus amoxicillin alone). Conclusions.Treatment with amoxicillin plus lansoprazole, 30 mg tid, led to cure of H. pylori infection in 67% of patients with active or recently healed duodenal ulcer.

To demonstrate the involvement of T lymphocytes reactive to autoantigens in the pathogenesis of autoimmune diseases and to analyse their clinical relevance.The frequency of T cell clones reactive to double strand DNA (dsDNA), Nucleohistone (NH) complex and Dnase I was calculated for the peripheral blood mononuclear cells (PBMC) of 15 SLE patients and 9 healthy subjects by proliferation assay.DsDNA- and NH-specific T cell clones were found in the majority of the patients analysed (frequency ranging from 2 to 50 clones/10(7) PBMC), while their absence or very low frequency (2 clones/10(7) PBMC) was observed in the control PBMC. Their frequency significantly correlated with decreased serum concentrations of C3 and C4 and with the systemic lupus erythematosus disease activity index (P = 0.03). A very low frequency of Dnase I-reactive T cell clones was observed in both SLE and healthy subjects.Our results suggest that dsDNA- and NH-reactive T lymphocytes may be involved in the pathogenesis of SLE and that their quantification in the peripheral blood of patients could be a useful tool to follow the clinical course of the disease.

Advances in vascular radiology techniques for superselective transfemoral arterial infusion prompted us to evaluate the effects of high-dose rapid regional carboplatin infusion for patients with advanced head and neck squamous cell carcinomas. Twenty untreated patients received three infusions of carboplatin (300-350 mg/m2) every 2 weeks with this method. All the infusions were performed without any complication. Treatment was well tolerated, with moderate (Grade 1-3 WHO) local toxicity (stomatitis, dermatitis and alopecia) and minimal (Grade 1-2 WHO) myelosuppression. The total response index (complete response plus partial response) was 94% for primary tumors and 50% for neck metastases. Neoadjuvant chemotherapy employing superselective rapid infusion of high-dose carboplatin is a feasible, relatively nontoxic, effective technique and may have important applications in multimodality therapy of untreated patients with advanced head and neck cancer.

Numerous studies have shown that higher doses of nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with increased levels of mucosal injury and ulceration in both normal volunteers and patients. The present dose-ranging study was designed to determine whether escalating doses of a commonly prescribed NSAID, flurbiprofen, when expressed as mg/kg dosages, were associated with increased mucosal injury and ulceration. Subjects received either the recommended dose of 300 mg/day of flurbiprofen (N = 10), or the higher than recommended doses of 400 mg/day (N = 20) and 500 mg/day (N = 10), for a period of 7 days. Endoscopic examination was performed on day 0 and day 7, and the stomach was evaluated on day 7 for mucosal injury on a 0-4 scale, and for the presence or absence of ulcer. One gastric ulcer was seen in each of the 300- and 400-mg groups. However, in the 500 mg/day group, four gastric ulcers were seen (40%) (p = 0.04). Three of the six subjects developing gastric ulcer were of a fairly low body weight (two women, one man), and when the data were analyzed on a mg/kg basis, all six ulcers occurred in 19 of the 40 subjects receiving5.95 mg/kg, whereas no gastric ulcers were seen in the 21 subjects receiving dosages below that level (p0.01). These data suggest that, at least for this agent, a threshold level may exist above which gastric ulcers are much more likely to occur. This may in part explain why elderly debilitated, low-body-weight female patients are more prone to NSAID-related gastric ulcer.

This multicenter randomized, double-blind, 4-wk study compared the new H2-receptor antagonistic roxatidine (R) to placebo (P) for treatment of endoscopically diagnosed active duodenal ulcer disease. Subjects were evaluated after 2 and 4 wk of treatment. Those whose ulcer was unhealed at 2 wk received 2 more weeks of treatment before final evaluation. Ulcer healing (endoscopically determined) with roxatidine was more effective than placebo at both wk 0-2 (R = 33.9%, P = 21.9%, p = 0.018) and wk 2-4 (R = 68.2%, P = 29.7%, p less than 0.001), with an overall 4-wk effectiveness of 78.9% compared to 44.8% (p less than 0.001). At the end of treatment, average maximum ulcer diameter diminished 83% in R and 50% in P (p less than 0.001). Roxatidine was also more effective than placebo in decreasing abdominal pain (p less than 0.001), decreasing the number of antacid tablets taken for pain relief (p less than 0.001), improving dyspeptic symptoms (p less than 0.001), and permitting return to a normal routine for subjects with previous illness-imposed restrictions on work and/or other daily activities. The profile of laboratory values and adverse experiences demonstrated roxatidine to be safe and well-tolerated. The efficacy of roxatidine as evaluated by the healing rate of duodenal ulcer and reduction in abdominal pain emphasize its value as an addition to the family of H2-receptor antagonists.

Ninety-one normal, healthy volunteers participated in a single-center, double-blind, placebo-controlled, randomized, parallel group study: 1) to compare the prostaglandin E1 analog, misoprostol, given at a dose of 200 micrograms bid, with the recommended dose of 200 micrograms qid in protecting the gastroduodenal mucosa against injury due to anti-inflammatory doses of aspirin (3900 mg/day); and 2) to determine whether the reduced dose was associated with a lesser incidence of gastrointestinal (GI) side effects, particularly diarrhea. All subjects received 975 mg of aspirin qid with meals and at bedtime. They were concurrently administered either misoprostol 200 micrograms qid, misoprostol 200 micrograms bid and placebo bid, or placebo qid. All subjects were endoscopically normal at the onset of the study and were re-endoscoped on the morning of the 7th day of therapy, 2 h after the morning dose of medications. Gastric and duodenal mucosa were assessed separately on a 0-7 scale which gave a greater weight to erosions than to hemorrhages. GI symptoms, especially bowel habits, were assessed by means of diary cards. Subjects in both misoprostol groups had significantly less gastric and duodenal mucosal injury than subjects who received placebo (p less than 0.007 for each pairwise comparison). There was no statistically significant difference between the two misoprostol groups (p less than 0.093). Subjects in the misoprostol 200 micrograms qid group had significantly more loose and watery bowel movements than the subjects in the misoprostol 200 micrograms bid group (p less than 0.013), whereas there were no significant differences in bowel habits between the misoprostol 200 micrograms bid and placebo groups (p less than 0.122). More subjects in the misoprostol 200 micrograms qid group reported abdominal pain, loose stools, watery stools, flatulence, dyspepsia, and nausea than in the misoprostol 200 micrograms bid and placebo groups. In conclusion, the adverse events in the misoprostol 200 micrograms bid group were not significantly different from those in the placebo group, and were significantly better than in the misoprostol 200 micrograms qid group. The lower dose retained mucosal protective activity that was statistically indistinguishable from that of misoprostol 200 micrograms qid.

When 60 staff nurses at a Veterans Administration hospital were asked to respond to vignettes in which a nurse is subjected to varying degrees of assault, blaming the nurse was at its highest level in response to the mild assault vignette, rather than to the extreme conditions (no physical contact or severe physical assault). When asked directly who was to blame for the assault in the vignette, not one nurse cited the patient.

This study asked whether Helicobactor pylori infection accentuated the severity of NSAID-induced mucosal injury of the stomach or duodenum. We evaluated the severity of acute mucosal injury and H. pylori status in 61 normal volunteers (ages 22-43 yr) receiving naproxen (1000 mg, n = 30) or aspirin (3900 mg, n = 31) daily for 7 days. NSAID-induced gastric and duodenal mucosa each were endoscopically graded separately for hemorrhages and erosions-ulcers on a scale of 0 to 4. H. pylori infection was identified by a sensitive and specific ELISA. Nine of the 30 subjects in the naproxen group and 12 of the 31 subjects in the aspirin group were H. pylori positive (p = NS). There was no statistically significant difference between the frequency of mucosal hemorrhage in those with and those without H. pylori infection (44% compared with 33% for those receiving naproxen and 90% of those receiving ASA, p = NS for each). There were also no differences in the frequency or severity of erosive mucosal injury seen, e.g., acute ulcers were found in 16.5% and 17.5% of infected and uninfected subjects, respectively. We conclude that the presence of H. pylori infection does not influence the degree or type of mucosal damage associated with the acute administration of naproxen or aspirin.

Objective : To compare the efficacy of two doses of lansoprazole with that of placebo in preventing recurrence of erosive esophagitis in a 12-month period. Design : Randomized, double-blind, parallel, placebo-controlled trial. Setting : 25 U.S. medical centers. Patients : 173 patients with documented healing of erosive esophagitis after 8 weeks of acid-suppressing therapy. Intervention : Lansoprazole, 15 mg or 30 mg, or placebo once daily for as long as 12 months. Measurements : Endoscopy and symptom evaluation after 1, 2, 3, 6, 9, and 12 months of treatment. Endoscopy was also done whenever symptoms suggested erosive changes. Results : Lansoprazole was significantly superior to placebo in maintaining healing and preventing recurrence of symptoms. By month 1, 45% of placebo recipients remained healed compared with more than 90% of patients in either lansoprazole group. By month 12, only 24% of placebo recipients remained healed compared with 79% of patients receiving 15 mg of lansoprazole and 90% of patients receiving 30 mg of lansoprazole. During the same period, 35% of placebo recipients remained asymptomatic compared with 72% of recipients of 15 mg of lansoprazole and 67% of recipients of 30 mg of lansoprazole. The 15-mg and 30-mg lansoprazole doses did not differ significantly in maintaining healing and controlling symptoms. Follow-up after recurrence of erosion indicated that during the 12 months, 35% of placebo recipients and 2% of lansoprazole recipients had three or more recurrences. Conclusion : Lansoprazole effectively maintains healing of erosive esophagitis. The 15-mg and 30-mg lansoprazole doses did not differ significantly for use as maintenance treatment.

The effects of various nonsteroidal antiinflammatory drugs on the gastric mucosa were endoscopically evaluated in 40 normal volunteers. Eight groups, each containing five subjects were designed: aspirin (3600 mg/d); placebo; ibuprofen (1600 mg/d); ibuprofen (2400 mg/d); indomethacin (100 mg/d); indomethacin (150 mg/d); naproxen (500 mg/d); and naproxen (750 mg/d). All volunteers took medication for seven days and gastroscopy was carried out on day one and day eight. All findings were documented by photography. Severe gastric mucosal injury occurred with aspirin (P less than 0.05), both doses of indomethacin, and the higher dose of naproxen. Lesser changes were seen with the lower dose of naproxen, both doses of ibuprofen and placebo. The higher doses of ibuprofen, indomethacin, and naproxen caused a greater degree of gastric mucosal injury, but statistical significance was achieved only with naproxen (P less than 0.01). Subjective gastrointestinal complaints generally correlated with endoscopic pathology; however, nine volunteers had evidence of severe injury to the gastric mucosa with no symptomatology. This was confined to the patients on indomethacin, naproxen, and ibuprofen. Aspirin patients all had some degree of symptomatology but to a lesser degree than expected in view of the endoscopic findings.

A single-blind, randomized endoscopic tolerance study was conducted to compare daily doses of flurbiprofen (Ansaid, Upjohn) at 100, 150, and 200 mg per day with 2,600 mg of aspirin per day. Ten normal volunteers were enrolled in each of the flurbiprofen groups, and five were enrolled in the aspirin group. Analysis of the mean gastric mucosal injury scores obtained on day eight revealed statistically significant lower mean scores (p = 0,05) in the 100-mg and 150-mg flurbiprofen treatment groups when compared with the 200mg flurbiprofen group and the aspirin group. No significant differences were found between any of the treatment groups in duodenal mucosal injury scores. Mean scores for gastric mucosal Injury in the three groups receiving flurbiprofen showed a definite dose relationship. The aspirin-treated subjects had significantly decreased uric acid levels (p = 0.006) and a significantly higher incidence of tinnitus (p = 0.04) compared with the flurbiprofen treatment groups. There was a poor correlation between subjective symptomatology and endoscopic pathologic findings.

This 7-day, single blind, randomized endoscopic tolerance study compared daily doses of 100, 150 and 200 mg flurbiprofen with 2600 mg aspirin. After seven days the flurbiprofen 100 and 150 mg groups had significantly less gastric irritation than the flurbiprofen 200 mg and aspirin groups. Flurbiprofen showed a linear dose-response relationship with respect to gastric injury and serum drug levels. Four subjects each on aspirin and flurbiprofen with the most severe injuries continued on their medications plus cimetidine and antacids for four more weeks. Both drug groups showed clinical improvement in the gastroduodenal area. In conclusion, flurbiprofen and aspirin therapy can be tolerated in the presence of gastroduodenal irritation by concomitantly administering cimetidine and antacids.

Ninety normal volunteers were entered into a double-blind, placebo-controlled study to compare the efficacy of misoprostol (200 micrograms q.i.d.) vs. cimetidine (300 mg q.i.d.) in protecting the gastric and duodenal mucosa from tolmetin-induced (400 mg q.i.d.) injury. After 6 days of treatment, the degree of mucosal injury between treatments was compared by endoscopy, using a predetermined rating scale of 0 (normal mucosa) to 4+ (greater than 25 hemorrhages or erosions or an invasive ulcer). Utilizing a score of less than or equal to 2+ (2-10 hemorrhages or erosions) as a therapeutic success, the overall success rates were 8/30 (26.7%) for placebo, 19/30 (63.3%) for cimetidine, and 27/29 (93.1%) for misoprostol (p less than 0.001). Pairwise comparisons were also significant: misoprostol vs. placebo (p less than 0.001), misoprostol vs. cimetidine (p = 0.006), and cimetidine vs. placebo (p = 0.004). A separate analysis of the gastric scores alone revealed success rates identical to those in the overall evaluation; however, success rates in the duodenum for both misoprostol (29/29) and cimetidine (29/30) were extremely high and did not differ. It is concluded that misoprostol is highly effective and significantly better than cimetidine in protecting the gastric mucosa from tolmetin-induced injury; however, both agents were highly protective in the duodenum.

Sixty volunteers were endoscopically evaluated to compare gastric mucosal injury following oral administration of sulindac, naproxen, aspirin, or placebo for two consecutive seven-day periods. A single-blind technique was utilized wherein the endoscopist was unaware which drug each volunteer had received. The following dosages were employed for the two study periods: sulindac, 150 and 200 mg, b.i.d., naproxen, 250 and 375 mg, b.i.d., and aspirin, 650 and 975 mg, q.i.d. The only subject who developed a frank ulcer with mucosal bleeding was in the sulindac group, however volunteers taking sulindac demonstrated statistically less significant mucosal injury on endoscopic examination than those receiving naproxen or aspirin.

Acetaminophen has been proposed as an agent which protects the gastric mucosa against damage induced by aspirin and other non-steroidal anti-inflammatory agents. In order to evaluate this proposal further, 45 normal human volunteers were divided into three groups (n = 15); group one received ibuprofen 2400 mg daily (600 mg qid); group two received acetaminophen 3900 mg daily (975 mg qid) and group three received both drugs at the same dosages. There was no significant difference in the mucosal injury scores noted at endoscopy between the ibuprofen and the ibuprofen-acetaminophen group. The acetaminophen group had virtually no observed mucosal injury and this was statistically significant in comparison with the other groups (p less than 0.01). We conclude that contrary to previously reported studies using single doses of aspirin, acetaminophen failed to decrease the mucosal injury seen with ibuprofen when given for a period of seven days in combination with acetaminophen.

THE damaging effect of aspirin on the gastric mucosa has been well documented by endoscopy1 2 3 4 5 6 and by studies of fecal blood loss.7 , 8 Because of the unquestioned value of aspirin in the th...

The effect on the gastroduodenal mucosa of alcohol combined either with aspirin or ibuprofen was studied in 60 normal volunteers. The volunteers were divided into six groups comprised of 10 subjects receiving ibuprofen, placebo, or aspirin with or without alcohol. Medications consisted of 1) three 325-mg aspirin tablets, or three identical placebo tablets, 2) one 600-mg ibuprofen tablet, and 3), three ounces of 100 proof vodka diluted in 6 ounces of orange juice, or alcohol placebo made by diluting 3 ounces of water in orange juice. All subjects received 4 doses over a 24-hr period and underwent endoscopic examination the following morning. The gastroduodenal mucosa was graded according to a 0 to 4 + scale. Aspirin caused considerably greater duodenal and gastric damage than did either ibuprofen or placebo. The addition of alcohol to all drugs increased the damage seen in the stomach but not to a significant degree; this effect was slightly more pronounced with ibuprofen than with placebo or aspirin and approached significance (0.1 greater than p greater than 0.05). These results are compatible with alcohol being a mild damaging agent or a potentiating agent for damage from other drugs.

Forty-five normal volunteers were divided into 3 equal groups, each receiving indomethacin or placebo once daily in he evening as a capsule or suppository for 10 days. The dose of indomethacin was 50 mg for the first 5 days and 100 mg for the second 5 days. Endoscopic evaluation of the gastric mucosa was carried out on days 1, 6 and 11. It was found that indomethacin capsules caused significantly more gastric irritation than indomethacin suppositories (p less than .01) or placebo (p less than .0001). No significant difference was found in the incidence of gastric injury observed in the indomethacin suppository and placebo groups.

Seventy-three upper gastrointestinal endoscopic polypectomies were performed in 63 patients over a period of five years. Thiry-eight patients (52%) had adenomatous polyps, two of which contained carcinoma in situ and 26 (36%) were inflammatory in nature. Four lesions were removed from the duodenum. Hemodynamically significant hemorrhage occurred in five cases and persistent symptomatic ulcer in three cases. All complications occurred early in the series and responded to conservative measures. There was no mortality or need for surgical intervention in any case. It was concluded that: 1. upper gastrointestinal tract endoscopic polypectomy is a safe and relatively simple procedure; 2. postprocedural complications can be markedly reduced by prophylactic conservative antiulcer therapy and 3. especially in the area of adenomatous polyps, excision of the entire lesion is superior to biopsy in the detection of early malignancy.

Patients who have demonstrated a gastric mucosal sensitivity to aspirin often react to other nonsteroidal, anti-inflammatory drugs to a similar or lesser degree. In a single-blind crossover study, five healthy volunteers who had previously developed erosive gastritis secondary to one week of aspirin therapy were randomly assigned to seven-day courses of treatment with ibuprofen, tolmetin and placebo. Treatment schedules were separated by washout periods to eliminate residual drug effects. Ibuprofen produced less gastric mucosal injury than tolmetin and, over all, appeared to be better tolerated. It was also noted that clinical symptoms often do not reflect the severity of gastroscopic findings, which may explain silent hemorrhaging in patients treated with agents of this type.

Studies in normal volunteers from our laboratory and by other investigators have demonstrated that non-steroidal anti-inflammatory agents (NSAIDs) can significantly damage the gastroduodenal mucosa. This damage is maximal with plain and buffered aspirin products. The injury produced by non-aspirin NSAIDs in anti-inflammatory doses is less than with aspirin but depends primarily on the dosages used. Pro-drugs and enteric-coated aspirin tend to produce less injury. The incidence of gastric ulcer in 1064 normal volunteers studied in our laboratory over a period of 7 years is reviewed. Seventy-two (6.7%) normal subjects developed a gastric ulcer after 7 days of therapy with anti-inflammatory doses of these drugs. The largest number of ulcers were seen with plain and buffered aspirin, and the lowest number with the lower anti-inflammatory doses of the non-aspirin NSAIDs.

Sucralfate is a nonsystemic drug used in the therapy of peptic ulcer disease. It is an aluminum salt of a sulfated disaccharide which adheres to ulcerated sites and forms a cytoprotective barrier to acid peptic digestion. The purposes of this study were to determine whether sucralfate had antacid activity in humans and to test the validity of the in vitro antacid qualifying test by comparing its results for tableted products with those of in vivo studies. In the in vitro antacid qualifying test Maalox #1 (4 tablets) passes and sucralfate (1 gm.) failed. These findings were consistent with the results of in vivo tests utilizing a telemetric device, the Heidelberg capsule and tube aspirations. We conclude that sucralfate does not possess antacid properties and that the results of the standard in vitro antacid qualifying test correlated well with those of in vitro studies.

Although bougienage is widely used to treat benign esophageal stricture, the rate of stricture recurrence and the long-term effectiveness of bougienage are unknown. We studied the natural history of esophageal stricture in 154 patients in whom bougienage was used as primary therapy. Dilatations were considered successful in terms of relief or major improvement of dysphagia in 84.5% of 103 patients followed 6 mo or longer (median, 26 mo). The risk of requiring esophageal dilatation after the initial episode was greatest in the first year of follow-up; thereafter, a smaller fraction of patients required dilatation each year. Forty-three percent of patients required no further dilatations, and a life-table analysis showed that 36% of patients would require no further dilatation during a projected 4-yr follow-up. The median frequency of subsequent dilatation was less than once a year. We were unable to identify any significant factors, such as initial severity of stricture, cause of stricture, presence of active esophagitis, or initial caliber of dilatation, that could predict the need for subsequent dilatation. Our results suggest that patients with benign strictures fall into two groups. In one group, the natural history was to improve or become asymptomatic after an initial series of dilatations, and only a small proportion eventually developed recurrent symptoms. The second group (46% of patients) required further dilatations to treat dysphagia during the first year of follow-up. Two-thirds of these patients needed regular dilatations in subsequent years. We conclude that bougienage is effective treatment for benign esophageal strictures, and should be utilized as primary therapy for most strictures.

The effects of fenbufen (1,000 mg a day), indomethacin (150 mg a day), naproxen (750 mg a day), and placebo on gastric mucosa were determined by endoscopy and recorded photographically. One hundred normal subjects, randomly divided into equal, parallel-treatment groups, were given the drugs in divided daily doses for seven consecutive days. The results revealed that the effects of fenbufen on gastric mucosa were significantly (p less than or equal to 0.05) less than those of either naproxen or indomethacin and not statistically different from those observed with placebo.

The effect of ranitidine in preventing mucosal damage caused by nonsteroidal antiinflammatory drugs (NSAIDs) was evaluated for eight weeks in a prospective study of 144 patients requiring NSAIDs. Patients with normal endoscopic findings were randomly assigned to receive either ranitidine 150 mg twice daily or placebo for eight weeks, along with either ibuprofen, indomethacin, naproxen, sulindac, or piroxicam. Duodenal damage was significantly less in the ranitidine group compared with the placebo group by weeks 4 and 8 (P less than or equal to 0.01). Duodenal ulcers did not develop in any patients on ranitidine (0/57) compared with 4/49 patients (8%) on placebo (P = 0.02). No significant difference was found between treatment groups with respect to gastric damage; 6/60 (10%) in the ranitidine group compared with 6/50 (12%) in the placebo group developed gastric ulcers. These findings suggest that acid suppression is of greater importance for mucosal protection in the duodenum than in the stomach, where other defense mechanisms may be operative. While ranitidine is an effective prophylaxis for NSAID-induced damage in the duodenum, further studies are needed to define specific risk groups and to assess the potential usefulness of more complete acid suppression in preventing gastric mucosal damage.

Ibuprofen, a commonly proscribed nonsteroidal anti-inflammatory drug that is also available in many countries, including the United States, without a prescription, is known to cause hemorrhage and erosion of the gastroduodenal mucosa. This study was conducted to compare the efficacy of 200, 100, and 50 micrograms of misoprostol and placebo administered qid for 6 days, with a final dose on the morning of the 7th day, in the prevention of gastric and duodenal lesions induced by the concurrent administration of 800 mg of ibuprofen qid. A total of 120 healthy subjects with endoscopically normal gastric and duodenal mucosae were enrolled in the study. The endoscopic examination was repeated 2 h after the final dose on day 7, and the mucosae were graded on a 0 to 4+ scale. In the stomach, all three misoprostol groups were significantly more protective than placebo and did not differ significantly from each other. In the duodenum, the endoscopic scores of the 200- and 100-micrograms misoprostol groups, but not the 50-micrograms group differed significantly from placebo. The 200- and 100-microgram groups did not differ significantly from each other, but both differed from the 50-micrograms group for duodenal mucosal injury. Subjective symptoms thought to be primarily attributable to the NSAID (e.g., pain, indigestion/heartburn and nausea) were recorded by each subject in a diary. Subjects in the 200-micrograms misoprostol group attained the greatest degree of mucosal protection and had a significantly higher incidence of indigestion/heartburn and abdominal pain than the placebo group. One can conclude that misoprostol in both antisecretory (200- and 100-micrograms) and non-antisecretory (50-micrograms) doses protects the gastric mucosa from injury from high anti-inflammatory doses of ibuprofen (3200 mg/day). Only the antisecretory doses (100 and 200 micrograms qid) were effective in the duodenum, suggesting that acid suppression is necessary for mucosal protection to occur in the duodenum.

A double-blind, placebo-controlled, randomized crossover study was made of 60 patients with chronic heartburn to test the efficacy of foaming antacid in promoting symptom relief. Heartburn was induced by a meal consisting of chili, black coffee, and a spicy tomato drink mix. Of the 60 patients, 40 (67%) had relief within 15 minutes after taking foaming antacid tablets as compared to only 17 (28%) after taking a placebo. The difference in response was significant (P less than .05). Foaming antacid appears to be an effective therapy for acute postprandial heartburn.

Twenty-five normal volunteers were randomized into five equal parallel groups. Groups I received ibuprofen (2,400 mg./day); group II received tolmetin (2,000 mg./day); group III received indomethacin (150 mg./day); group IV received naproxen (750 mg./day) and group V received placebo (four tablets daily). All drugs were given on a q.i.d. basis except naproxen which was given b.i.d. The doses selected represented the manufacturer's highest recommended dosage for the treatment of arthritic disorders. A single-blind technic was used in which the investigators were unaware of which drug each volunteer was taking. Upper gastrointestinal endoscopy and photography were carried out before and after seven days of administration of each medication. Gastric and duodenal mucosal injury was graded on a 0-4 + scale. Three of the four drugs studied produced essentially equal gastric and duodenal mucosal injury with tolmetin producing the most damage followed by naproxen and indomethacin. Ibuprofen produced gastric mucosal injury equivalent to that seen with naproxen and indomethacin but no duodenal mucosal injury was seen with this drug. Extremely poor correlation was found between subjective symptomatology and endoscopic findings.