No abstract

Absence of cardiac valve dysfunction in obese patients treated with sibutramine. Obes Res. 1999;7:363-369. Objective: Serotonin-releasing agents prescribed as weightloss medications have been implicated as a cause of acquired aortic and mitral valve abnormalities. Sibutramine hydrochloride (MERIDIAB) is a serotonin and norepinephrine reuptake inhibitor with proven efficacy of weight reduction. The purpose of this study was to determine the incidence of cardiac valve disease in sibutraminetreated patients. Research Methods and Procedures: Obese patients with type 2 diabetes mellitus enrolled in an ongoing doubleblind, placebo-controlled, parallel-arm, 12-month study of sibutramine (followed by a 12-month open label extension) underwent transthoracic echocardiographic imaging and color Doppler interrogation for assessment of cardiac valve anatomy and function. Results: A total of 210 patients were evaluated. Of these, 133 were receiving sibutramine (72 in the double-blind period), and 77 were receiving placebo. The mean 2 Standard Deviation age was 5429 years, and the mean duration of treatment was 229+117 days (approximately 7.6 months). The prevalence of left-sided cardiac valve dysfunction was low and similar for the two treatment groups (sibutra- mine 31133, or 2.3%; placebo 2/77, or 2.6%). All five cases were cases of aortic insufficiency; four were mild, one was severe (in a placebo patient). All three sibutramine cases were patients over age 50; two had a history of systemic hypertension. Conclusion:The prevalence of left-sided cardiac valve dysfunction was not higher than background in obese patients treated with sibutramine for an average of 7.6 months.

Background: This study evaluated the safety and hemostatic effectiveness of a tranexamic acid-and aprotinin-free fibrin sealant versus an absorbable hemostat in soft tissue during elective retroperitoneal or intra-abdominal surgery. Materials and Methods: This randomized, active-controlled, multicenter study enrolled patients who were undergoing elective retroperitoneal or intra-abdominal surgery and required adjunctive hemostatic measures at the target bleeding site (TBS). Patients were randomized (time ¼ 0 minutes) to receive fibrin sealant or absorbable hemostat. The primary endpoint was the absence of bleeding at the TBS at 10 minutes. Secondary endpoints included the absence of bleeding at 4 and 7 minutes and the incidence of treatment failure (bleeding at 10 minutes or brisk bleeding requiring additional hemostatic measures), and the incidence of complications potentially related to bleeding. Adverse events were assessed. Results: Patients (N ¼ 124) were randomized to receive fibrin sealant (n ¼ 62) or absorbable hemostat (n ¼ 62). A higher percentage of patients who received fibrin sealant versus absorbable hemostat achieved hemostasis within 10 minutes (95.2% vs 82.3%; 95% CI, 1.02-1.35) and also at 4 (74.2% vs 54.8%; 95% CI, 1.04-1.80) and 7 (90.3% vs 77.4%; 95% CI, 1.00-1.39) minutes. A lower incidence of treatment failure was observed for patients receiving fibrin sealant. Similar incidences of adverse events and complications potentially related to bleeding were observed. Conclusions: This tranexamic acid-and aprotinin-free fibrin sealant is safe and effective for achieving hemostasis in soft tissue during elective retroperitoneal or intra-abdominal surgery.

A multicenter, parallel, double-blind, 181-patient study compared the safety and antihypertensive efficacy of immediate-release (IR) and extended-release (ER) hydralazine. After 2 to 4 weeks on diuretic, patients were maintained on diuretic and randomized to a hydralazine treatment regimen: IR thrice daily, ER twice daily, or ER once daily. Daily doses of hydralazine were 75, 150, or 300 mg. Although designed as a titration study, important dose-response data were available for analysis with nonlinear mixed effect modeling (NONMEM). Sitting diastolic blood pressure (BP) was selected as the response variable. Several factors were tested for importance, including body weight, time (week) effects, concomitant beta-blocker (BB) therapy, acetylator class, and treatment regimen. All factors were important (p less than 0.05) except treatment regimen (p greater than 0.30). The maximum antihypertensive response (Emax) to hydralazine was 9.4 mm Hg. The daily dose that elicited 50% of the maximum response (D50) was 0.87 mg/kg for slow acetylators and 1.68 mg/kg for fast acetylators. BP fell 0.52 mm Hg per week independent of other effects, and concomitant BB therapy induced a drop of 6.6 mm Hg in addition to hydralazine, diuretic and week effects. NONMEM's use assisted in evaluations and provided information not obtainable through traditional means.

BackgroundBleeding severity, anatomic location, tissue characteristics, and visibility are common challenges encountered while managing intraoperative bleeding, and conventional hemostatic measures (suture, ligature, and cautery) may sometimes be ineffective or impractical. While topical absorbable hemostats (TAH) are useful hemostatic adjuvants, each TAH has associated disadvantages.MethodsWe evaluated the safety and hemostatic efficacy of a new advanced biologic combination product―fibrin pad―to potentially address some gaps associated with TAHs. Fibrin pad was assessed as adjunctive hemostat in open partial nephrectomy in single-center, open-label, Phase I study (N = 10), and as primary hemostat in multicenter, single-blind, randomized, standard-of-care (SOC)-controlled Phase I/II study (N = 7) in Israel. It was used to control mild-to-moderate bleeding in Phase I and also spurting arterial bleeding in Phase I/II study. Phase I study assessed safety and Phase I/II study, proportion of successes at 10 min following randomization, analyzed by Fisher exact tests at 5% significance level.ResultsPhase I (N = 10): All patients completed the study. Hemostasis was achieved within 3–4 min (average = 3.1 min) of a single application in all patients. Fibrin pad was found to be safe for human use, with no product-related adverse events reported. Phase I/II (N = 7): Hemostatic success at 10 min (primary endpoint) was achieved in 3/4 patients treated with fibrin pad versus 0/3 patients treated with SOC. No clinically significant change in laboratory or coagulation parameters was recorded, except a case of post-procedural hemorrhage with fibrin pad, which was considered serious and related to the fibrin pad treatment, and required re-operation. Although Data Safety Monitoring Board authorized trial continuation, the sponsor decided against proceeding toward an indication for primary treatment of severe arterial hemorrhage as a replacement for sutures. The study was suspended after 7/30 planned subjects were enrolled.ConclusionsThe first-in-man trial of fibrin pad demonstrated its safety and efficacy as an adjunctive hemostatic technique for mild-to-moderate bleeding in partial nephrectomy. The study also suggested that the product should not replace sutures or meticulous surgical techniques for the treatment of severe arterial hemorrhage.Trial registrationPhase I/II trial, NCT00598130