Salam F. Zakko

A comparison of midazolam and diazepam for conscious sedation during colonoscopy in a prospective double-blind study ☆ ☆☆ ★

BACKGROUND Midazolam and diazepam are commonly used for conscious sedation, but their comparative respiratory depressive effects have not been accurately studied. We used a novel real-time, on-line, computerized data acquisition system to compare the two agents in a randomized double-blind study. METHODS One hundred patients undergoing colonoscopy were studied. The maximum end-tidal carbon dioxide tension (PetCO2) and the minimum oxygen saturation by pulse oximetry (SpO 2) were recorded by computer every minute. Patients received meperidine (25 to 50 mg) and incremental doses of either midazolam or diazepam to an identical end point of slurred speech and/or ptosis. Sedation was scored from 1 (unarousable) to 5 (wide awake). RESULTS Sedation scores were 3.6 +/- 0.1 (mean +/- standard error) after each agent. The doses of midazolam and diazepam were 0. 031 +/- 0.002 and 0.106 +/- 0.009 mg/kg, respectively. In the first 45 minutes (PetCO2) was significantly higher with midazolam than with diazepam (p < 0.05). SpO2 was significantly depressed for 80 minutes after each agent, and the number of minutes when the minimum Sp O2 was less than 90% did not differ between the two agents. CONCLUSIONS Midazolam was 3.4 times more potent than diazepam. The duration of oxygen desaturation emphasizes the importance of monitoring SpO2 until ventilation and oxygenation have recovered. Although the degree of hypoxemia was comparable, midazolam led to higher end-tidal carbon dioxide tensions.

Budesonide Foam Induces Remission in Patients With Mild to Moderate Ulcerative Proctitis and Ulcerative Proctosigmoiditis

BACKGROUND & AIMS Budesonide is a high-potency, second-generation corticosteroid designed to minimize systemic adverse consequences of conventional corticosteroids. We performed 2 randomized, phase 3 trials to evaluate the ability of budesonide rectal foam, formulated to optimize retention and provide uniform delivery of budesonide to the rectum and distal colon, to induce remission in patients with ulcerative proctitis or ulcerative proctosigmoiditis. METHODS Two identically designed, randomized, double-blind, placebo-controlled trials evaluated the efficacy of budesonide foam for induction of remission in 546 patients with mild to moderate ulcerative proctitis or ulcerative proctosigmoiditis who received budesonide foam 2 mg/25 mL twice daily for 2 weeks, then once daily for 4 weeks, or placebo. RESULTS Remission at week 6 occurred significantly more frequently among patients receiving budesonide foam than placebo (Study 1: 38.3% vs 25.8%; P = .0324; Study 2: 44.0% vs 22.4%; P < .0001). A significantly greater percentage of patients receiving budesonide foam vs placebo achieved rectal bleeding resolution (Study 1: 46.6% vs 28.0%; P = .0022; Study 2: 50.0% vs 28.6%; P = .0002) and endoscopic improvement (Study 1: 55.6% vs 43.2%; P = .0486; Study 2: 56.0% vs 36.7%; P = .0013) at week 6. Most adverse events occurred at similar frequencies between groups, although events related to changes in cortisol values were reported more frequently with budesonide foam. There were no cases of clinically symptomatic adrenal insufficiency. CONCLUSIONS Budesonide rectal foam was well tolerated and more efficacious than placebo in inducing remission in patients with mild to moderate ulcerative proctitis and ulcerative proctosigmoiditis. ClinicalTrials.gov ID: NCT01008410 and NCT01008423.

Microprocessor-assisted solvent-transfer system for gallstone dissolution. In vitro and in vivo validation.

To improve the efficacy, safety, and convenience of contact dissolution of gallbladder stones, a microprocessor-assisted solvent transfer system was developed. The systems two pumps simultaneously infuse and aspirate solvent into and from the gallbladder at a high flow rate through a multilumen catheter. The microprocessor controls the pumps using a closed feedback loop control algorithm to regulate intragallbladder pressure to prevent solvent escape into the duodenum. Turbulent solvent flow at the catheter end in the gallbladder is designed to induce rapid stone dissolution and to suspend insoluble residue, thus promoting its aspiration. The systems response and gallbladder emptying capacity was 160-fold faster than the natural gallbladder emptying rate. The rate at which gallstones were dissolved by methyl tert-butyl ether using the system was compared with that achieved with a syringe pump. For 6 of 11 pairs of stones that totally dissolved, the mean dissolution time with the system was 10 +/- 6 minutes compared with 112 +/- 81 minutes for the syringe pump. In the 5 of 11 stone pairs which dissolved incompletely, insoluble residue was completely eliminated by the system in 21 +/- 9 minutes but not by the syringe pump even at 360 minutes. When the system was used in gallstone patients, solvent recovery was 99% +/- 1%, and the concentration of a nonabsorbable marker did not change, confirming the lack of appreciable absorption of methyl tert-butyl ether. These studies suggest that the microprocessor-assisted solvent transfer system is a device capable of safe, complete, and fully automatic contact dissolution of cholesterol gallbladder stones using methyl tert-butyl ether or similar solvents.

1052 Daily Mesalamine Fails to Prevent Recurrent Diverticulitis in a Large Placebo Controlled Multicenter Trial

3 focus groups of 45 SUDD patients and an expert panel of five gastroenterologists and surgeons. We developed the DV-QOL items based on our literature search and input from focus groups and experts, and obtained feedback from patients about those items in cognitive debriefing interviews. We administered the items to a cohort of SUDD patients with persistent symptoms following a confirmed diverticulitis event. We created scales based on factor analysis and evaluated the scales for reliability and validity. Results: Concept elicitation revealed a range of illness experiences attributed to SUDD. Coding of 20,490 transcribed words yielded 52 codes arranged in a network with 4 first-order condition-related concepts: (1) physical symptoms (e.g., pain, bloating); (2) behaviors (e.g., dietary, physical, and social restrictions); (3) cognitions and concerns (e.g., lack of control, feeling something wrong); and (4) impact and consequences (e.g., frustration, anxiety). Initially, we developed 46 items that reflected these four concepts. Using data from a cross-sectional validation sample of 197 patients, we reduced the DV-QOL to a 24-item instrument. The final instrument demonstrated strong internal consistency (Cronbachs Alpha = 0.95) and a reliable fourfactor solution (Tucker and Lewis Reliability Coefficient = 0.90). In our validation sample, the DV-QOL significantly discriminated between patients with recent (i.e., within last month) versus distant diverticulitis events (effect size of DV-QOL score difference = 0.66), and correlated strongly with both the Short-Form 36 subscales (mean correlation = -0.49) and hospital anxiety and depression (HAD) scores (mean correlation = 0.50). Conclusions: Patients with diverticular disease attribute a wide range of negative psychological, social, and physical symptoms to their condition, even outside of acute attacks. The DV-QOL captures these symptoms in a valid and reliable manner.

Human gallbladder morphology after gallstone dissolution with methyl tert-butyl ether

The effects of methyl tert-butyl ether exposure on the human gallbladder in five patients who were treated for gallstones by contact dissolution is described. Two patients underwent cholecystectomy within 1 week of methyl tert-butyl ether treatment, one patient 2 weeks after, another 10 weeks after, and one 12 weeks after. Indications for cholecystectomy were bilirubinate stones (resistant to methyl tert-butyl ether), catheter dislodgement, bile leakage, and gallstone recurrence (2 patients). Gallstones were dissolved completely in three patients, there was approximately 50% stone reduction in one patient, and no dissolution occurred in the fifth patient. Each gallbladder was examined grossly and histologically. Electron microscopic evaluation was performed in one cases. Typical inflammatory findings of chronic cholecystitis were observed in each gallbladder and were most conspicuous in the submucosa; the mucosal and serosal surfaces were intact. Mild acute inflammatory changes were noted in the submucosa in the two patients with the shortest interval between methyl tert-butyl ether administration and cholecystectomy. There were no ulcerations in the mucosa and no unusual wall thickening or fibrosis in any patient. These observations support the safety of methyl tert-butyl ether perfusion in the human gallbladder; the mild acute changes may be a transient and reversible phenomenon.

Once-daily Mesalamine Formulation for Maintenance of Remission in Ulcerative Colitis: A Randomized, Placebo-controlled Clinical Trial.

Goals: To evaluate the efficacy and safety of mesalamine granules 1.5 g once daily for maintenance of ulcerative colitis (UC) remission. Background: Mesalamine is a first-line treatment for induction and maintenance of UC remission. Study: A phase 3, randomized, double-blind, placebo-controlled trial of patients with a history of mild to moderate UC, currently in remission, who received mesalamine granules once daily for 6 months. The primary efficacy endpoint was percentage of patients maintaining UC remission at 6 months. Results: A significantly greater percentage of patients receiving mesalamine granules versus placebo were in remission at 6 months (79.9% vs. 66.7%; P=0.03). A greater percentage of patients receiving mesalamine granules maintained a revised Sutherland Disease Activity Index (SDAI)⩽2 with no individual component of revised SDAI>1 and rectal bleeding=0 at 6 months (72.0% vs. 58.1%; P=0.04). No significant differences between groups were observed for change from baseline to 6 months for total SDAI score or its components (ie, stool frequency, rectal bleeding, mucosal appearance, physician’s rating of disease). Mesalamine granules treatment resulted in a significantly longer remission duration versus placebo (P=0.02) and decreased patients’ risk of relapse by 43% (hazard ratio=0.57; 95% confidence interval, 0.35-0.93; P=0.02). Mesalamine granules were well tolerated, and adverse events related to hepatic, renal, and pancreatic function—potential concerns with long-term treatment—occurred at a rate similar to placebo. Conclusions: Once-daily mesalamine granules are efficacious and safe for the maintenance of UC remission.

Microprocessor-assisted solvent-transfer system for gallstone dissolution

Abstract To improve the efficacy, safety, and convenience of contact dissolution of gallbladder stones, a microprocessor-assisted solvent transfer system was developed. The systems two pumps simultaneously infuse and aspirate solvent into and from the gallbladder at a high flow rate through a multilumen catheter. The microprocessor controls the pumps using a closed-feedback loop control algorithm to regulate intragallbladder pressure to prevent solvent escape into the duodenum. Turbulent solvent flow at the catheter end in the gallbladder is designed to induce rapid stone dissolution and to suspend insoluble residue, thus promoting its aspiration. The systems response and gallbladder emptying capacity was 160-fold faster than the natural gallbladder emptying rate. The rate at which gallstones were dissolved by methyl tert -butyl ether using the system was compared with that achieved with a syringe pump. For 6 of 11 pairs of stones that totally dissolved, the mean dissolution time with the system was 10 ± 6 minutes compared with 112 ± 81 minutes for the syringe pump. In the 5 of 11 stone pairs which dissolved incompletely, insoluble residue was completely eliminated by the system in 21 ± 9 minutes but not by the syringe pump even at 360 minutes. When the system was used in gallstone patients, solvent recovery was 99% ± 1%, and the concentration of a nonabsorbable marker did not change, confirming the lack of appreciable absorption of methyl tert -butyl ether. These studies suggest that the microprocessor-assisted solvent transfer system is a device capable of safe, complete, and fully automatic contact dissolution of cholesterol gallbladder stones using methyl tert -butyl ether or similar solvents.

Once-daily mesalamine granules for maintaining remission of ulcerative colitis: pooled analysis of efficacy, safety, and prognostic factors

ABSTRACT Objectives: A capsule formulation of mesalamine granules (MG) was developed for once-daily dosing and better compliance. The study aim was to evaluate MG efficacy and tolerability in maintaining ulcerative colitis (UC) remission. Methods: Pooled analysis of 2 identical phase 3, randomized, double-blind trials of once-daily MG 1.5 g or placebo for up to 6 months. The primary endpoint was percentage of patients remaining relapse-free at month 6 versus placebo. Relapse was defined as revised Sutherland Disease Activity Index (SDAI) rectal bleeding score ≥1 and mucosal appearance score ≥2, UC flare, or UC–related adverse event (AE). Results: Data were pooled for patients receiving MG (n = 373) and placebo (n = 189). Significantly more patients were relapse-free at 6 months with MG (79.4%) than placebo (62.4%; P < 0.001) and across subgroups based on select demographic and baseline characteristics (P < 0.05). Secondary outcome measures including rectal bleeding, physician rating of disease activity, stool frequency, total SDAI score, and relapse-free duration favored MG (P < 0.01). Common AEs with MG and placebo, respectively, were headache (10.9% and 7.6%), diarrhea (7.9% and 7.0%), and abdominal pain (6.3% and 6.5%). Conclusion: Once-daily MG was more efficacious than and as well tolerated as placebo in maintaining UC remission. ClinicalTrials.gov identifiers: NCT00744016 and NCT00767728.

Ethyl propionate is more effective and less cytotoxic than methyl tert-butyl ether for topical gallstone dissolution.

BACKGROUND & AIMS Ethyl propionate and isopropyl acetate were identified as gallstone solvents with more favorable physicochemical properties than the currently used solvent methyl tert-butyl ether (MTBE). In this study, their efficacy and toxicity were compared. METHODS To compare efficacy, matched stones from 33 patients were subjected to dissolution with each solvent. To evaluate cytotoxicity, jejunal segments of the anesthetized rat were exposed to each solvent or saline; the segments were then perfused with markers for active absorption and passive permeability. RESULTS For 23 gallstone sets that dissolved completely with all three solvents, the average dissolution time was shorter with ethyl propionate (38 +/- 8 minutes) than with MTBE (60 +/- 13 minutes) (P = 0.03) or isopropyl acetate (55 +/- 12 minutes) (P < 0.001). Four stones did not dissolve with ethyl propionate, seven with MTBE, and eight with isopropyl acetate. After 2 minutes of exposure to the solvents, the dry weight of the segments decreased by 36% after MTBE but was unchanged after the other two solvents (P < 0.001). MTBE caused more inhibition of active absorption than the other solvents (P < 0.001) and a greater increase in passive permeation (P < 0.03). CONCLUSIONS Ethyl propionate and isopropyl acetate are less toxic to the intestinal mucosa than MTBE, and ethyl propionate is more effective for gallstone dissolution.

Local and Systemic Effects of Intraduodenal Exposure to Topical Gallstone Solvents Ethyl Propionate and Methyl tert-Butyl Ether in the Rabbit

During topical dissolution of gallstones,solvent can escape to the duodenum causing toxic effectsthat have not yet been adequately quantified. Wecompared the local intestinal cytotoxic and systemichepatotoxic effects of two gallstone solvents, methyltert-butyl ether and ethyl propionate, on the rabbitsduodenum. Methyl tert-butyl ether, ethyl propionate, orsaline (control) was infused intraduodenally for 3 hr in 32 male New Zealand rabbits. Thesolvents were infused either at a high infusion rate of8.5 μl/min or at a low rate of 4.0 μl/min. Bloodsamples were collected for biochemical analysis fromeach animal before and after the 3-hr infusionperiod. A standardized histologic scoring system wasused by a pathologist blinded to the treatments toquantify liver and intestinal tissue injury. None of the animals studied showed any significant changesin serum alkaline phosphatase, amylase, bilirubin, ortheir hepatic histology or histologic scoring formucosal necrosis and ulceration. At the higher dose, methyl tert-butyl ether produced significantlymore submucosal inflammation (P = 0.0017) and showed atrend of causing more submucosal edema than ethylpropionate, but ethyl propionate led to significantly higher elevations of aminotransferases thanmethyl tert-butyl ether as compared to saline. Therewere no detectable blood levels of methanol or ethanolin any of the animals studied. Ethyl propionate may be less damaging to the intestinal mucosa ofthe rabbit than methyl tert-butyl ether, but at thehigher dose (equivalent to 60 ml/3 hr in a 70-kg human)it appears to produce more biochemical liver injury when administered intraduodenally.