Search

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

Dry eye is a common, multifactorial disease currently diagnosed by a combination of symptoms and signs. However, the subjective symptoms of dry eye poorly correlate to the current gold standard for diagnostic tests, reflecting the need to develop better objective tests for the diagnosis of dry eye. This review considers the role of ocular surface matrix metalloproteinase 9 (MMP-9) in dry eye and the implications of a novel point-of-care test that measures MMP-9 levels, InflammaDry (RPS, Sarasota, FL) on choosing appropriate therapeutic treatments.

Purpose To compare dry eye (DE) symptoms and signs in subjects who tested positive versus those who tested negative for ocular surface matrix metalloproteinase 9 ( MMP-9 ) using the InflammaDry point-of-care test (RPS, Sarasota, FL). Methods In this cross-sectional study, individuals seen in the Miami Veterans Affairs eye clinic with DE symptoms, as evidenced by DE questionnaire 5 ( DEQ5 ) ≥6, were given standardized questionnaires to assess DE symptoms and ocular and non-ocular pain complaints. Also, a complete evaluation was conducted to measure ocular surface signs of DE. MMP-9 testing was performed using the InflammaDry once in each eye, per the manufacturer's instructions. The main outcome measure was a comparison of DE symptoms and signs in MMP-9 positive versus negative subjects. Results Of 128 subjects, 50 (39%) were positive for MMP-9 for InflammaDry testing in either eye. No statistically significant differences in mental health indices, DE symptoms, or ocular surface signs were seen in subjects based on MMP-9 status. Conclusion In our population, there was no difference in the DE profile by both symptoms and signs between those testing positive versus negative for MMP-9 on the ocular surface. This suggests that clinical exam alone cannot predict patients with clinically significant inflammation.

Dry eye (DE) is a common disease whose symptoms of pain (described as discomfort, burning, and dryness) and blurry vision negatively impact quality of life.1 We previously demonstrated that approximately 1 in 6 United States (US) veterans carried a diagnosis of DE and that environmental factors (air pollution coupled with weather conditions) affected the occurrence of DE.2 By integrating health care data from the National Veterans Administration (VA) database and environmental data from the National Climatic Data Center (NCDC) and National Aeronautics and Space Administration (NASA), we found that air pollution and atmospheric pressure were the two most influential risk factors for DE. Building on this information, we subsequently used the same dataset to assess occurrence of DE by season. This analysis was performed to formally quantify the clinical impression that DE has a seasonal pattern. Patient information All patients seen in a VA eye clinic July 5, 2006 through July 4, 2011 were included in this retrospective analysis. DE cases were defined as those who had an ICD-9 code for DE (375.15) and used medication or underwent a procedure for the condition. The Miami VA Institutional Review Board approved this study, which was conducted in accordance with the principles of the Declaration of Helsinki. Findings During the study period, there were a total of 3.41 million visits to a VA eye clinic within the continental US. In total, 17.4% of veterans (95% confidence interval (CI) ±1.24) were diagnosed with DE. Looking at the distribution of cases, a clear seasonal pattern is evident (Figure 1 available at http://aaojournal.org), with the highest period prevalence of DE in winter and spring (18.7%±0.98 and 18.5%±4.16 respectively) and lowest prevalence in summer (15.3%±0.82). Furthermore, there was a higher monthly variation in the occurrence of DE during the spring season as compared to winter months, with a standard error of mean 4.16% in spring versus 0.98% in winter. The highest prevalence of DE occurred in April (20.9% ± 0.14). Interestingly, the year round prevalence of DE in Miami was higher than the national average by approximately 3.2% (p

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.

As survival of transplant recipients improves, long-term complications become more important. We reviewed epidemiologic literature on real-world risks of de novo neoplasia post-transplant. We searched the Medline/PubMed, Cochrane, and Embase databases for population-based studies on risk of neoplasia from 1998 to 2005. Selection criteria included: solid organ transplants, neoplastic outcomes, n > 500 subjects, age > or = 18 yr, and study design. Of 187 abstracts, 64 met criteria for study size, age range, topic, and design. We classified the articles by quality of reporting on components of cohort studies. Twelve of 64 studies reported cohort eligibility and exclusion criteria, defined time at risk, and ascertained incident neoplasms. Twenty-one studies reported prevalence of neoplasms for unspecified time periods, and only eight incidence studies reported person yr at risk. Three studies of all types of neoplasms in kidney recipients reported incidence ranging from 11.0 to 17.3 cases per 1000 person yr. Two studies of post-transplant lymphoproliferative disorders reported incidence of 0.4 to 2.5 cases per 1000 person yr in kidney recipients. More precise estimation of risks and rates, better description of study population, and more attention to confounding in comparisons of rates would make studies more meaningful. Reports should adhere to established guidelines for presenting methods and results in epidemiologic studies.

Indoline derivatives possess therapeutic potential within a variety of drug candidates. In this study, we found that indoline is aromatized by cytochrome P450 (P450) enzymes to produce indole through a novel dehydrogenation pathway. The indole products can potentially be bioactivated to toxic intermediates through an additional dehydrogenation step. For example, 3-substituted indoles like 3-methylindole and zafirlukast [4-(5-cyclopentyloxy-carbonylamino-1-methyl-indol-3-ylmethyl)-3-methoxy-N-o-tolylsulfonylbenzamide] are dehydrogenated to form 3-methyleneindolenine electrophiles, which react with protein and/or DNA nucleophilic residues to cause toxicities. Another potentially significant therapeutic consequence of indoline aromatization is that the product indoles might have dramatically different therapeutic potency than the parent indolines. In this study, indoline was indeed efficiently aromatized by human liver microsomes and by several P450s, but not by flavin-containing monooxygenase (FMO) 3. CYP3A4 had the highest aromatase activity. Four additional indoline metabolites [2,3,4,7-tetrahydro-4,5-epoxy-1H-indole (M1); N-hydroxyindole (M2), N-hydroxyindoline (M3), and M4 ([1,4,2,5]dioxadiazino[2,3-a:5,6-a']diindole)] were characterized; none was a metabolite of indole. M1 was an arene oxide from P450 oxidation, and M2, M3, and M4 were produced by FMO3. Our data indicated that indoline was oxidized to M3 and then to an intermediate indoline nitrone, which tautomerized to form M2, and subsequently dimerized to a di-indoline. This dimer was immediately oxidized by FMO3 or atmospheric oxygen to the final product, M4. No evidence was found for the P450-mediated production of an aliphatic alcohol from indoline that might dehydrate to produce indole. Therefore, P450 enzymes catalyze the novel "aromatase" metabolism of indoline to produce indole. The aromatase mechanism does not seem to occur through N-oxidation or dehydration of an alcohol but rather through a formal dehydrogenation pathway.

Transient receptor potential vanilloid 1 (TRPV1) is a calcium-selective ion channel expressed in human lung cells. We show that activation of the intracellular subpopulation of TRPV1 causes endoplasmic reticulum (ER) stress and cell death in human bronchial epithelial and alveolar cells. TRPV1 agonist (nonivamide) treatment caused calcium release from the ER and altered the transcription of growth arrest- and DNA damage-inducible transcript 3 (GADD153), GADD45alpha, GRP78/BiP, ATF3, CCND1, and CCNG2) in a manner comparable with prototypical ER stress-inducing agents. The TRPV1 antagonist N-(4-tert-butylbenzyl)-N'-(1-[3-fluoro-4-(methylsulfonylamino)-phenyl]ethyl)thiourea (LJO-328) inhibited mRNA responses and cytotoxicity. EGTA and ruthenium red inhibited cell surface TRPV1 activity, but they did not prevent ER stress gene responses or cytotoxicity. Cytotoxicity paralleled eukaryotic translation initiation factor 2, subunit 1 (EIF2alpha) phosphorylation and the induction of GADD153 mRNA and protein. Transient overexpression of GADD153 caused cell death independent of agonist treatment, and cells selected for stable overexpression of a GADD153 dominant-negative mutant exhibited reduced sensitivity. Salubrinal, an inhibitor of ER stress-induced cytotoxicity via the EIF2alphaK3/EIF2alpha pathway, or stable overexpression of the EIF2alpha-S52A dominant-negative mutant also inhibited cell death. Treatment of the TRPV1-null human embryonic kidney 293 cell line with TRPV1 agonists did not initiate ER stress responses. Likewise, n-benzylnonanamide, an inactive analog of nonivamide, failed to cause ER calcium release, an increase in GADD153 expression, and cytotoxicity. We conclude that activation of ER-bound TRPV1 and stimulation of GADD153 expression via the EIF2alphaK3/EIF2alpha pathway represents a common mechanism for cytotoxicity by cell-permeable TRPV1 agonists. These findings are significant within the context of lung inflammatory diseases where elevated concentrations of endogenous TRPV1 agonists are probably produced in sufficient quantities to cause TRPV1 activation and lung cell death.

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.

Epoxyeicosatrienoic acids produced by mouse CYP2B19 have been implicated in mechanisms regulating epidermal cornification (Ladd, P.A., Du, L., Capdevila, J.H., Mernaugh, R., Keeney, D.S., 2003. Epoxyeicosatrienoic acids activate transglutaminases in situ and induce cornification of epidermal keratinocytes. J. Biol. Chem. 278, 35184-35192). In this study, we aimed to identify CYPs that are up-regulated during keratinocyte differentiation and potentially responsible for epoxyeicosatrienoic acid formation in human skin. The cellular differentiation state of human epidermal cell cultures was manipulated to resemble the basal, spinous, and granular cell phenotypes in vivo. Changes in CYP mRNA levels were measured as a function of differentiation state for a panel of 15 CYPs that included known and putative arachidonate monooxygenases. Quantitative real-time PCR analyses showed that all of the CYPs were expressed in differentiating epidermal cell cultures and in human epidermis, with the exception of CYP2B6, which was poorly expressed in vitro. Six CYPs were strongly up-regulated at Day 6 and Day 8 of in vitro differentiation (CYP4B1, 2W1, 2C18, 3A4, 2C19, 2C9); the increase in mRNA levels ranged from 27- to 356-fold. Only CYP2U1 mRNA levels decreased (6-fold change) during cellular differentiation. Six CYPs showed little variation (

Summary Background The effect of low-dose aspirin on endoscopic ulcer incidence in cyclo-oxygenase-2-selective inhibitor or non-selective non-steroidal anti-inflammatory drug users remains controversial. Aim To compare prospectively the incidence of endoscopic ulcers in healthy subjects receiving low-dose aspirin plus celecoxib or naproxen. Methods In this double-blind, placebo-controlled, 1-week study, subjects (50–75 years) were randomized to receive aspirin 325 mg o.d. plus either celecoxib 200 mg o.d., naproxen 500 mg b.d., or placebo. Baseline and end of study endoscopies were performed. The primary end point was incidence of one or more gastric and duodenal ulcers. Results A lower incidence of gastric and duodenal ulcers was seen in celecoxib/aspirin-treated subjects (19%) vs. naproxen/aspirin (27%; RR: 0.63, 95% CI: 0.44–0.92). Both naproxen/aspirin and celecoxib/aspirin groups demonstrated a higher incidence of gastric and duodenal ulcers vs. placebo/aspirin (8%; RR: 3.7, 95% CI: 1.8–7.6 and RR: 2.6, 95% CI: 1.2–5.8, respectively). Conclusions Fewer endoscopic ulcers were observed in patients treated with celecoxib/aspirin vs. naproxen/aspirin. However, celecoxib/aspirin was associated with a significantly higher incidence of gastric and duodenal ulcers than aspirin alone. Further studies are required to determine the generalizability of these findings in the aspirin users and to determine the appropriate strategy to minimize risk in susceptible patients.

Objective: This study evaluated the overall safety and tolerability of once-weekly (OW) alendronate 70 mg oral solution (OS) versus OW placebo OS. Methods: Postmenopausal, osteoporotic women were enrolled at 51 centers in the United States in a 6-month double-blind, randomized trial. Patients were randomized (1:1) to OW alendronate 70 mg OS or placebo OS. The primary end point was the proportion of patients reporting any upper gastrointestinal (UGI) adverse event (AE) at 6 months. Secondary end points included mean percentage change in urinary N-telopeptide of type I human collagen (NTx) and serum bone-specific alkaline phosphatase (BSAP) at 6 months. Results: Initially, 454 women were enrolled; 392 (86.3%) completed the study. The mean (SD) age was 65.2 (10) years, and the mean (SD) time since menopause was 19.1 (12) years. The proportion of patients experiencing any UGI AE was significantly higher with alendronate OS (23.7%) compared with placebo solution (15.3%), with a treatment difference of 8.3% (95% CI, 0.8%–15.8%; P = 0.024). The proportion of patients experiencing any esophageal AE was 4.0% with alendronate and 3.0% with placebo (treatment difference, 1.0% [95% CI, −2.7% to 4.8%]). In addition, 4.5% of alendronate and 8.7% of placebo patients discontinued the study due to any clinical AE, and 3.3% of alendronate and 1.8% of placebo patients discontinued due to a UGI AE (difference, 1.5% [95% CI, −1.5% to 4.4%]). Alendronate OS produced significantly greater reductions in both NTx and BSAP than placebo (differences, −47.5% and −38.7%, respectively [both, P Conclusions: In this 6-month study, patients receiving OW alendronate 70 mg OS had a higher rate of UGI AEs than placebo patients. However, rates of serious UGI AEs, discontinuations due to UGI AEs, and esophageal AEs were similar between groups. UGI AEs in the study were generally mild to moderate in severity and did not result in treatment discontinuation. In addition, OW alendronate 70 mg OS significantly reduced biochemical markers of bone turnover.

Objective Bleeding from esophagogastric varices is a major complication of portal hypertension. Despite recent practice guidelines for the management of bleeding esophageal or gastric varices, the widespread application of these measures by gastroenterologists has not been evaluated. The purpose of this study was to continue the concept of membership-based research within diverse practice settings by expanding the American College of Gastroenterology (ACG) GI Bleeding Registry to assess the management and outcome of acute variceal bleeding. Methods All ACG members (domestic and foreign) were invited to participate during the 1997 Annual Fall meeting and by mail. Data were collected over 12 months. Information obtained included physician training, practice demographics, patient demographics, disease etiology and severity, clinical presentation, medications, transfusion needs, therapy, complications, and rebleeding within 2 wk. Results A total of 93 physicians/centers (79.6% domestic, 26.9% university and affiliated, 3.2% Veterans Affairs) participated. Complete demographic data were available for 725 of the 741 patients enrolled with index bleeding. The median age of these 725 patients was 52 yr and 73.3% were male. The most common single etiology for portal hypertension was cirrhosis (94.3%). The most common causes of cirrhosis were alcohol (56.7%), hepatitis C virus (30.3%), and hepatitis B virus (10.0%). Hemodynamic instability was noted in 60.7% of the patients (22.3% tachycardic, 9.7% orthostatic, 28.7% hypotensive). Index interventions included banding (40.8%; median five bands), sclerotherapy (36.3%), combination banding/sclerotherapy (6.2%), octreotide (52.6%; median 3 days), balloon tamponade (5.5%), transjugular intrahepatic portosystemic shunt (TIPS) (6.6%), liver transplantation (1.1%), surgical shunt (0.7%), and embolization (0.1%). Transfusion of packed red blood cells, fresh frozen plasma, and platelets was given in 83.4%, 44.7%, and 24.6% of the patients with index bleeding, respectively. Median transfusion was four units of packed red blood cells, three units of fresh frozen plasma, and 1.5 units of platelets. Rebleeding occurred in 92 of the 741 patients (12.6%) at a median of 7 days (mean 11 days) and was treated by banding (18.5%; median six bands), sclerotherapy (30.4%), octreotide (63%; median 2 days), balloon tamponade (17.4%), TIPS (15.2%), and surgical shunt (3.3%). Complications from the index bleeding and rebleeding within 2 wk included ulceration (2.6%, 2.2%), aspiration (2.4%, 3.3%), medication side effects (0.8%, 0%), dysphagia (2.3%, 0%), odynophagia (2.2%,0%), encephalopathy (13%,17.4%), and hepatorenal syndrome (2.4%, 2.2%), respectively. After the index bleeding, 46.2% of patients were treated with β-blockers and 8.2% with nitrates. The majority of patients with index bleeding had Child's B cirrhosis (61.5%). Patients presenting with recurrent bleeding had mostly Child's B (46.7%) or Child's C cirrhosis (44.6%). The overall short-term mortality after index bleeding was 12.9%. Conclusions Acute variceal hemorrhage occurs more often in patients with Child's B and C cirrhosis. Endoscopic banding is the most common single endoscopic intervention. Adjunctive pharmacotherapy is prevalent acutely and after stabilization. Both morbidity and mortality may be lower than reported in previous studies.

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.

The use of NSAIDs constitutes a significant risk for gastrointestinal bleeding and other ulcer complications. However, if they prove clinically effective in relieving arthritic symptoms, the new COX-2 selectively inhibiting NSAIDs may ultimately solve the problem of gastrointestinal toxicity with NSAIDs.

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.

Nonsteroidal anti-inflammatory drug (NSAID)associated injury to the gastrointestinal tract is now a well-established fact. Indeed, studies have shown a prevalence of peptic ulcer in 20 –25% of patients taking these agents. The incidence of gastrointestinal bleeding, perforation, or obstruction in these patients is 1–3%, indicating that approximately one out of every 10 NSAID-associated peptic ulcers becomes complicated (ie, development of hemorrhage, perforation, or obstruction). These complications occur most often in well-defined, high-risk patients, primarily those who are elderly, those who have a history of gastrointestinal disease, and those who are receiving high-dose or multiple-drug regimens. The evaluation of any mucosal-protective agent is extremely difficult. For example, what end-point should be measured to determine efficacy: hemorrhages and erosions in healthy volunteers, peptic ulcers in volunteers or patients, or complication rates in patients taking NSAIDs? It is now generally agreed by most investigators that hemorrhages seen in short-term healthy volunteer studies are of little use. In a study from our laboratory evaluating the ability of the H2-receptor antagonist cimetidine to prevent naproxen-induced gastric injury, it was shown that the antagonist prevented hemorrhages but had no effect on the occurrence of erosions or peptic ulcers. This finding suggests that hemorrhages are acid dependent and are unrelated to more important lesions. Erosions, on the other hand, are probably more significant lesions in short-term healthy volunteer studies, and trials evaluating the prevention of these lesions by various agents are often predictive of findings in arthritic patients during long-term studies. Erosions may therefore be useful as a positive screening mechanism for new prophylactic agents. Healthy volunteer studies have shown that sucralfate is generally ineffective in preventing erosions and ulcers, that H2-receptor antagonists prevent erosions and ulcers in the duodenum but not in the stomach, and that misoprostol prevents both gastric and duodenal erosions and ulcers. –7 Longer-term studies in arthritic patients using ulcer as the end point have demonstrated essentially the same findings. –13 The use of ulcer as an end-point in these longer-term patient studies is justified by the fact that the major complications of NSAID use are those associated with peptic ulcer disease; erosions are found in a high percentage of patients taking NSAIDs chronically, but they are not associated with complications. Studies evaluating sucralfate have shown that it is essentially ineffective in preventing any type of NSAID-associated peptic ulcer disease. Two large, multicenter studies evaluating the H2-receptor antagonist ranitidine, 150 mg twice daily, in the prevention of NSAID-associated peptic ulcer have shown that this agent is significantly better than placebo in the prevention of duodenal ulcer, whereas it has no effect on the prevention of gastric ulcer. However, a recent study has shown that the H2-receptor antagonist famotidine, in addition to preventing duodenal ulcer, significantly reduces the incidence of gastric ulcer when given at high dose in patients receiving chronic NSAID therapy, when compared with placebo. Finally, numerous studies in arthritic patients have shown that misoprostol prevents both gastric and duodenal ulcers in patients taking NSAIDs, –12 although the side-effects caused by misoprostol sometimes prevent its use.

Members of the CYP2F gene subfamily are selectively expressed in lung tissues and have been implicated as important catalysts in the formation of reactive intermediates from several pneumotoxic chemicals. Human CYP2F1 bioactivates 3-methylindole (3MI), while mouse CYP2F2 bioactivates naphthalene. Although 3MI is a potent pneumotoxin in ruminants and rodents, the participation of cytochrome P450s from the 2F subfamily in 3MI bioactivation has not been fully defined. To test the hypothesis that a goat lung 2F homologue uniquely catalyzes the dehydrogenation of 3MI to the putative electrophile 3-methylene-indolenine, the CYP2F3 cDNA was cloned from a goat lung cDNA library and expressed in Escherichia coli. The predicted amino acid sequence of CYP2F3 possessed 82% identity to both human CYP2F1 and mouse CYP2F2. CYP2F3 was mutated at the 5' end, expressed in E. coli, and shown to have a molecular mass of 50 kDa. The reconstituted enzyme uniquely catalyzed only the dehydrogenation of 3MI to form 3-methylene-indolenine, an electrophilic intermediate, without detectable formation of other products, thus demonstrating highly unusual selectivity for dehydrogenation rather than hydroxylation of a substrate. Immunoinhibition studies demonstrated that about 20% of the production of the intermediate in goat lung microsomal samples was produced by CYP2F3. The CYP2F3 enzyme had a specific activity that was similar to that of human cDNA-expressed CYP2F1. CYP2F3 also stereoselectively catalyzed the formation of the 1R,2S-oxide from naphthalene; this stereoisomer is the putative pneumotoxin. The enzyme, however, lacked catalytic activity with other common P450 substrates including 7-ethoxycoumarin, a substrate for CYP2F1, indicating that the substrate selectivity of CYP2F3 appears to be high.

Objective. To describe the frequency and costs of medical services for patients with osteoarthritis (OA) or rheumatoid arthritis (RA) in a managed care setting. Methods. Individual utilization records of medical and pharmacy services for OA and RA patients were obtained from a group-model health maintenance organization (HMO). Estimates were made for costs of drugs and medical services for arthritis from July 1, 1993 to June 30, 1994 using Medicare reimbursement schedules and average wholesale drug prices. Calculated rates for each population were expressed as counts of events or as dollars per person-year. Results. The average individual cost rate of arthritis-related care for 365 RA patients was $2,162 per year, and the total cost of RA care to the HMO was $703,053. Prescription medications accounted for 62% ($436,440) of the total cost of RA care, while ambulatory care accounted for 21% ($150,938), and hospital visits accounted for 16% ($115,674). With regard to 10,101 OA patients, the average individual cost rate was $543 per year, and total cost to the HMO was $4,728,425. Hospital care accounted for 46% ($2,170,890) of the total cost of OA care, medications accounted for 32% ($1,509,637), and ambulatory care accounted for 22% ($1,047,898). Conclusion. RA care, in the setting of this study, was characterized by intensive treatment, especially frequent use of medications that were delivered to most patients. Although the cost of RA care per patient was high, cost to the managed care provider was relatively low, owing to the rarity of RA. OA care tended to be infrequent, and the largest component of cost was hospital care for a small proportion of patients (5%). Owing to the greater prevalence of OA, care of OA was nearly 7 times more costly to the managed care provider than was care of RA.

We thank Dr Curry for an accurate summary1 of our study entitled ‘Use of depot medroxyprogesterone acetate contraception and incidence of bone fracture’.2 Nevertheless, we do not recommend more selective use of depot medroxyprogesterone acetate (DMPA) on account of fracture risk, as we believe that this recommendation would reduce access to an effective, safe contraceptive without actually reducing fracture risk. As we reported, in those subjects with at least 6 months of pre-DMPA medical history (176 pre-treatment fractures …

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.

Objective To describe the monitoring of liver function for patients using nonsteroidal anti-inflammatory drugs (NSAIDs), we reviewed the patterns of liver function testing in a medium-sized health maintenance organization. Methods We examined the interval between start of therapy and first performance of a liver function test during courses of therapy of the NSAIDs diclofenac sodium, naproxen and naproxen sodium, and piroxicam. For comparison, we also studied courses of lovastatin as a "positive control," in which the anticipated frequency of liver function testing was high. Results The frequency of liver function tests in patients using NSAIDs was generally low, although testing was more common in patients who used diclofenac. The probability of liver function testing was higher for patients treated in recent calendar years, for patients treated by rheumatologists, for patients who previously used NSAIDs, and for patients who had undergone a liver function test sometime in the 6 months preceding the onset of therapy. Conclusion Physicians ordered liver function tests less frequently than recommended, but the observed testing patterns appear rational in light of the very low reported frequency of serious hepatic disease in large, monitored populations of patients using NSAIDs.

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.

Compared with nonselective NSAIDs, cyclooxygenase (COX)-2-selective inhibitors have been associated with a lower incidence of gastroduodenal ulcers (in short-term endoscopic studies) and ulcer complications (in long-term trials).The aim of this study was to compare the effects of valdecoxib 20 mg BID and naproxen 500 mg BID, administered for 6.5 days, on the upper gastrointestinal (UGI) mucosa of healthy older subjects (aged 65-75 years) as assessed by UGI endoscopy.In this multicenter, double-blind, active-comparator, placebo-controlled, parallel-group study, eligible subjects who were free of NSAID or COX-2-selective inhibitor use for 2 weeks and who had normal UGI mucosa (mucosal grading score of 0, based on endoscopic evaluation of both the stomach and duodenum) were randomized. Serologic testing for Helicobacter pylori antibodies was conducted at baseline. No antiulcer medications were permitted. The primary end point was the incidence of gastroduodenal ulcers (gastric or duodenal mucosal grading score of 7, as indicated by any lesion with unequivocal depthor =3 mm in diameter) after 6.5 days of blinded treatment with valdecoxib, naproxen, or placebo. Secondary end points were incidence of gastric ulcers, duodenal ulcers, and gastroduodenal erosions/ulcers, and the incidence ofor =11 gastroduodenal erosions/ulcers. All documented adverse events were self-reported by subjects or were observed by investigators.Sixty-one patients were randomized to receive valdecoxib, 60 to naproxen, and 60 to placebo. Mean (SD) subject age was 68.8 (3.25) years in the valdecoxib group, 68.6 (2.76) years in the naproxen group, and 68.6 (3.14) years in the placebo group (P = NS). In the valdecoxib and naproxen groups, 47.5% and 58.3% of subjects were female, respectively, compared with 56.7% of the placebo group (P = NS). Valdecoxib and placebo were associated with significantly lower incidences of gastroduodenal ulcers than naproxen (1.6% [1 gastroduodenal ulcer/61 patients] and 1.7% [1/59], respectively, vs 22.0% [13/59]; P0.001). Compared with naproxen, both valdecoxib and placebo were associated with significantly lower incidences of gastric (1.6% [1/61] and 1.7% [1/59] vs 15.3% [9/59]; both, P0.03) and duodenal ulcers (0% [0/61] and 0% [0/59] vs 8.5% [5/59]; both,P0.03). In all cases, the incidence of ulcers with valdecoxib was not significantly different from placebo. Results were similar for any erosions/ulcers, and when analyzed by H pylori status. The number of adverse events was low in each group.In these healthy older subjects (aged 65-75 years), valdecoxib 20 mg BID was associated with a significantly lower rate of gastroduodenal, gastric, and duodenal ulcers than naproxen 500 mg BID, even after 6.5 days of therapy.

The bisphosphonate class of drugs are now utilized extensively in the treatment of patients with osteoporosis and Paget’s disease. Gastrointestinal (GI) adverse effects, especially those associated with esophageal injury, have been of increasing concern to clinicians. Studies in humans and animals have shown that the mucosal erosion and ulceration seen with bisphosphonates is a result of direct contact with these agents. Numerous endoscopic studies in healthy volunteers and postmenopausal women have also demonstrated the potential of bisphosphonates to cause stomach and duodenal ulcers. However, serious GI adverse events have not been noted in several large efficacy trials. Esophageal injury has for the most part been avoided by appropriate administration instructions, and gastroduodenal injury appears to be an acute phenomenon not associated with significant complications, except in certain high-risk situations, for example in the presence of existing distal esophageal disease or motility disorders, or with concurrent use of nonsteroidal anti-inflammatory drugs or anticoagulants. From the standpoint of GI safety, the bisphosphonates are well tolerated and not associated with serious adverse events.

Activation of the capsaicin receptor (VR1 or TRPV1) in bronchial epithelial cells by capsaicinoids and other vanilloids promotes pro-inflammatory cytokine production and cell death. The purpose of this study was to investigate the role of TRPV1-mediated calcium flux from extracellular sources as an initiator of these responses and to define additional cellular pathways that control cell death. TRPV1 antagonists and reduction of calcium concentrations in treatment solutions attenuated calcium flux, induction of interleukin-6 and 8 gene expression, and IL-6 secretion by cells treated with capsaicin or resiniferatoxin. Most TRPV1 antagonists also attenuated cell death, but the relative potency and extent of protection did not directly correlate with inhibition of total calcium flux. Treatment solutions with reduced calcium content or chelators had no effect on cytotoxicity. Inhibitors of arachidonic acid metabolism and cyclo-oxygenases also prevented cell death indicating that TRPV1 agonists disrupted basal arachidonic acid metabolism and altered cyclo-oxygenase function via a TRPV1-dependent mechanism in order to produce toxicity. These data confirm previous results demonstrating calcium flux through TRPV1 acts as a trigger for cytokine production by vanilloids, and provides new mechanistic insights on mechanisms of cell death produced by TRPV1 agonists in respiratory epithelial cells.

Cultured human lung epithelial cells (BEAS-2B) were treated in vitro with PM(2.5)-enriched particles of soil-derived mineral dust from nine sites in the western United States. The particle samples simulate windblown dust and vehicle-generated emissions from unpaved roads. Five of the sites yielded relatively benign dust. Particles from three sites caused IL-6 release when cells were treated for 24 h at doses from 20 to 80 microg/cm(2), and particles from one site were highly cytotoxic. The particle components or characteristics that caused the IL-6 release were stable at temperatures below 150 degrees C, but were inactivated by treatment at 300-550 degrees C. The active factors were also associated predominantly with the insoluble fraction, and were partially attenuated by leaching with aqueous and organic solvents. The IL-6 release caused by the particles was much greater than the cytokine response to either lipopolysaccharide (LPS) or to surrogate particles of titanium dioxide mixed with LPS, suggesting that endotoxin was not a major factor in the inflammatory response. The release of IL-8 in response to particle treatment was qualitatively similar to the IL-6 response, but release of TNF-alpha was not detected at the 24-h time point. The combined results support the hypothesis that some ambient dusts from geological sources can cause cell death and cytokine release in a lung cell line that is widely used as an in vitro model to study mechanisms of environmental respiratory injury.

Bisphosphonates are effective treatment for osteoporosis but have been associated with gastrointestinal (GI) mucosal injury. This study compared the incidence of gastric ulcers after treatment with risedronate, a pyridinyl bisphosphonate, or alendronate, a primary amino bisphosphonate, in healthy postmenopausal women stratified by Helicobacter pylori status.Subjects were randomized to receive risedronate 5 mg (n = 318) or alendronate 10 mg (n = 317) daily for 14 days. Endoscopy and evaluator-blind assessments of the esophageal, gastric, and duodenal mucosa were performed at baseline and on Days 8 and 15.Overall, gastric ulcersor = 3 mm were observed in 18 (6.0%) of 300 evaluable subjects in the risedronate group and 36 (12.1%) of 297 in the alendronate group during treatment (p = 0.013). On Day 8, the incidences of gastric ulcers in the risedronate and alendronate groups were 3.6% and 6.6%, respectively (p = 0.133), and on Day 15, they were 3.3% and 8.7% (p = 0.008). The incidence of gastric ulcers was not affected by H. pylori status. Mean gastric endoscopy scores at Days 8 and 15 were significantly lower in the risedronate group than in the alendronate group (p0.001). Mean esophageal and duodenal endoscopy scores were similar in the 2 groups at Days 8 and 15. When the treatment groups were combined, gastric endoscopy scores were significantly higher among H. pylori negative than H. pylori positive subjects at Days 8 and 15 (p0.05). Upper GI adverse events were reported by 18 (5.7%) subjects in the risedronate group (19 events) and 28 (8.8%) subjects in the alendronate group (32 events). Symptoms did not predict the presence of mucosal damage.Risedronate was associated with a significantly lower incidence of gastric ulcers than alendronate. H. pylori infection did not increase the incidence of bisphosphonate related gastric ulcers. The findings from this 14 day study in healthy volunteers support the hypothesis that bisphosphonates may differ from one another in their potential to produce upper GI mucosal damage.

Speech restoration after circumferential pharyngolaryngectomy with free jejunal repair for advanced tumors of the hypopharyngo-esophageal tract remains a difficult problem to solve. We report here the results of secondary voice restoration in six patients who received a Provox 2 type prosthesis and intensive speech therapy after circumferential pharyngolaryngectomy with free jejunum repair. No patient had operative or post-operative complications due to insertion of the prosthesis. No patient had to have the prosthesis removed during the follow-up (8 to 14 months). Analysis of some acoustic parameters of voice (fundamental frequency, waveform perturbations) and qualitative characteristics of speech (intelligibility, pleasantness and acceptability) demonstrated that all the patients were able to produce satisfactory speech after tracheojejunum puncture and speech therapy and were satisfied with their own ability to communicate. Our results are reassuring and we therefore advise that in patients undergoing free jejunum flap reconstruction of the hypopharyngo-esophageal tract voice restoration should be attempted by placing a voice prosthesis through a secondary tracheo-esophageal puncture and providing intensive speech training.

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.

3-Methylindole (3MI) is a naturally occurring pulmonary toxin that requires metabolic activation. Previous studies have shown that 3MI-induced pneumotoxicity resulted from cytochrome P-450-catalyzed dehydrogenation of 3MI to an electrophilic methylene imine (3-methyleneindolenine), which covalently bound to cellular macromolecules. Multiple cytochrome P-450s are capable of metabolizing 3MI to several different metabolites, including oxygenated products. In the present study, the role of human CYP2F1 in the metabolism of 3MI was examined to determine whether it catalyzes dehydrogenation rather than hydroxylation or ring oxidation. Metabolism was examined using microsomal fractions from human lymphoblastoid cells that expressed the recombinant human CYP2F1 P-450 enzyme. Expression of CYP2F1 in the lymphoblastoid cells proved to be an appropriate expression system for this enzyme. Products were analyzed using HPLC and the mercapturate, 3-[(N-acetylcystein-S-yl)methyl]indole, of the reactive intermediate was identified and quantified. Product analysis showed that human CYP2F1 efficiently catalyzed the dehydrogenation of 3MI to the methylene imine without detectable formation of indole-3-carbinol or 3-methyloxindole. High substrate concentrations of 3MI strongly inhibited production of the dehydrogenated product, a result that may indicate the existence of mechanism-based inhibition of CYP2F1 by 3MI. Recombinant CYP2F1 demonstrated remarkable selectivity for the bioactivation of 3MI to the putative dehydrogenated reactive electrophile. Bioactivation of naphthalene to its pneumotoxic epoxide by CYP2F1 was also demonstrated.

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.