The efficacy and safety of bazedoxifene in postmenopausal women by baseline kidney function status.

INTRODUCTION: Two global, double-blind, placebo- and active-controlled, phase-3 studies (2-year prevention (n = 1583) and 3-year treatment (n = 7492)) have shown that bazedoxifene (BZA) is safe and effective for prevention and treatment of postmenopausal osteoporosis. OBJECTIVE: To evaluate the efficacy/safety of BZA according to baseline kidney function. METHODS: Data for the BZA 20- and 40-mg and placebo groups from both studies were integrated for assessment of bone turnover markers (BTMs), bone mineral density (BMD), and fracture incidence (treatment study only). Safety was assessed using integrated data for the BZA, placebo, and raloxifene 60-mg groups from both studies. Baseline glomerular filtration rate (GFR) was estimated by the Modification of Diet in Renal Disease Study equation; among subjects with baseline GFR, renal function categories were defined by GFR (ml/min per 1.73 m(2)): normal (GFR ≥ 90; n = 1982), mild impairment (60 ≤ GFR < 90; n = 6032), or moderate/severe impairment (GFR < 60; n = 723). RESULTS: Demographics were similar across treatment groups and within GFR subgroups. Across GFR subgroups, BZA 20 and 40 mg reduced BTM levels and improved lumbar spine and total hip BMD versus placebo. At month 24, there were significant treatment-by-GFR (p = 0.003) and treatment-by-serum creatinine (p = 0.034) interactions for the increase in lumbar spine BMD versus placebo. Fracture incidence was lower with BZA than placebo across all GFR categories, with no treatment-by-GFR interaction. There were no significant differences among treatment groups in incidences of overall, serious, or renal-related adverse events across GFR subgroups. CONCLUSIONS: Mild to moderate kidney impairment did not affect the efficacy and safety of BZA in postmenopausal women.

Safety and tolerability of bazedoxifene in postmenopausal women with osteoporosis: results of a 5-year, randomized, placebo-controlled phase 3 trial.

UNLABELLED: Findings from this 5-year phase 3 study of postmenopausal women with osteoporosis showed that bazedoxifene was associated with an overall favorable safety and tolerability profile, with no evidence of endometrial or breast stimulation. Overall, the results at 5 years were consistent with those seen at 3 years. INTRODUCTION: We report safety and tolerability findings from a 5-year randomized, double-blind, phase 3 study of bazedoxifene in postmenopausal women with osteoporosis. METHODS: In the core study, healthy postmenopausal women with osteoporosis (N=7,492; mean age, 66.4 years) were randomized to daily doses of bazedoxifene 20 or 40 mg, raloxifene 60 mg, or placebo for 3 years. During the 2-year study extension, the raloxifene 60-mg treatment arm was discontinued after the 3-year database was finalized, and subjects receiving bazedoxifene 40 mg were transitioned in a blinded manner to bazedoxifene 20 mg (bazedoxifene 40-/20-mg group) after 4 years. Safety and tolerability data are reported for subjects in the bazedoxifene 20- and 40-/20-mg and placebo groups; efficacy findings are reported elsewhere. RESULTS: A total of 3,146 subjects in the bazedoxifene 20- and 40-mg and placebo groups were enrolled in the extension study (years 4 and 5). Overall, the 5-year incidence of adverse events (AEs), serious AEs, and discontinuations due to AEs were similar among groups. The incidence of hot flushes and leg cramps was higher with bazedoxifene compared with placebo. Venous thromboembolic events, primarily deep vein thrombosis, were more frequently reported in the bazedoxifene groups compared with the placebo group. Reports of cardiac disorders and cerebrovascular events were few and evenly distributed among groups. Bazedoxifene showed a neutral effect on the breast and endometrium. CONCLUSION: Bazedoxifene was associated with an overall favorable safety and tolerability profile in postmenopausal women with osteoporosis over 5 years of therapy, consistent with findings at 3 years.

Neurotoxicity produced by dibromoacetic acid in drinking water of rats.

An evaluation of potential adverse human health effects of disinfection byproducts requires study of both cancer and noncancer endpoints; however, no studies have evaluated the neurotoxic potential of a common haloacetic acid, dibromoacetic acid (DBA). This study characterized the neurotoxicity of DBA during 6-month exposure in the drinking water of rats. Adolescent male and female Fischer 344 rats were administered DBA at 0, 0.2, 0.6, and 1.5 g/l. On a mg/kg/day basis, the consumed dosages decreased greatly over the exposure period, with average intakes of 0, 20, 72, and 161 mg/kg/day. Weight gain was depressed in the high-concentration group, and concentration-related diarrhea and hair loss were observed early in exposure. Testing with a functional observational battery and motor activity took place before dosing and at 1, 2, 4, and 6 months. DBA produced concentration-related neuromuscular toxicity (mid and high concentrations) characterized by limb weakness, mild gait abnormalities, and hypotonia, as well as sensorimotor depression (all concentrations), with decreased responses to a tail-pinch and click. Other signs of toxicity at the highest concentration included decreased activity and chest clasping. Neurotoxicity was evident as early as one month, but did not progress with continued exposure. The major neuropathological finding was degeneration of spinal cord nerve fibers (mid and high concentrations). Cellular vacuolization in spinal cord gray matter (mostly) and in white matter (occasionally) tracts was also observed. No treatment-related changes were seen in brain, eyes, peripheral nerves, or peripheral ganglia. The lowest-observable effect level for neurobehavioral changes was 20 mg/kg/day (produced by 0.2 g/l, lowest concentration tested), whereas this dosage was a no-effect level for neuropathological changes. These studies suggest that neurotoxicity should be considered in the overall hazard evaluation of haloacetic acids.

Effects of cardiac sympathetic innervation on coronary blood flow.

BACKGROUND: The role of cardiac sympathetic nerves in regulating coronary blood flow is controversial. We sought to determine the degree to which cardiac efferent sympathetic signals modulate coronary blood flow. The heterogeneous sympathetic reinnervation in transplanted hearts provides a model for studying the vasomotor responses to adrenergic stimulation in reinnervated and denervated coronary territories of the same heart. METHODS: We studied 14 cardiac-transplant recipients who had normal coronary arteries and no evidence of rejection and 8 normal subjects. We used positron-emission tomography with [(11)C]hydroxyephedrine, an analogue of norepinephrine, to delineate sympathetic innervation. Using [(13)N]ammonia, we measured myocardial blood flow at rest, during adenosine-induced hyperemia, and in response to sympathetic stimulation induced by cold pressor testing. RESULTS: In the transplant recipients, the uptake of [(11)C]hydroxyephedrine was greater in the territory served by the left anterior descending artery (0.15+/-0.01) than in those served by the right coronary artery (0.07+/-0.01, P<0.001) or the circumflex artery (0.09+/-0.01, P<0.001). The basal flow was similar in all three regions, as was the percent increase in flow during hyperemia. However, the increase in flow in response to cold pressor testing was higher in the territory of the left anterior descending artery (46+/-10 percent) than in those of the right coronary artery (16+/-5 percent, P=0.01) or the circumflex artery (23+/-6 percent, P=0.06), although the changes in hemodynamics and levels of circulating catecholamines were similar. No such regional differences were observed in the normal subjects. CONCLUSIONS: Increases in coronary blood flow in response to sympathetic stimulation correlated with the regional norepinephrine content in the cardiac sympathetic-nerve terminals. These findings suggest that cardiac adrenergic signals play an important part in regulating myocardial blood flow.

Intraabdominal bleeding following laparoscopic adnexal surgery. A report of three cases.

BACKGROUND: The incidence of major complications from laparoscopy is reported to be 0.6-2.5%. The literature reviewing laparoscopic adnexal surgery reports few cases of intraoperative or postoperative complications. CASES: We describe three cases of intraabdominal bleeding following laparoscopic oophorectomy and salpingo-oophorectomy and salpingo-oophorectomy. In two of the three cases, postoperative exploratory laparotomy failed to identify the source of bleeding. CONCLUSION: Possible causes of postoperative bleeding are loosening of clips from an automated stapling device and delayed bleeding from vessels tamponaded by the pneumoperitoneum. Many complications of operative laparoscopy probably are underreported and, when present, may occur outside a health care facility since many of these cases are performed on an ambulatory basis. Some patients will acquire medical and/or surgical intervention.

Contemporary management of a potentially lethal fetal anomaly: a successful perinatal approach to epignathus.

Prenatal diagnosis of epignathus (a teratoma originating in the oropharynx) has been reported previously. However, in many of these cases the neonates succumbed to acute respiratory distress secondary to airway obstruction at the time of birth. We describe a case of antepartum diagnosis of epignathus using ultrasonography and magnetic resonance imaging as complementary techniques. The ability to accurately define the fetal anomaly permitted us to plan a unique strategy for peripartum management. After cesarean delivery of the infant from the uterus, the umbilical cord was not clamped and the fetoplacental circulation was left undisturbed. A tracheostomy was then performed, after which the umbilical cord was clamped and the infant was stabilized. Several hours later, a debulking procedure was performed in the operating room to remove the tumor from its attachment to the bony palate. Both mother and infant did well postoperatively. The ability to plan and perform a controlled tracheostomy while the infant remained oxygenated and ventilated proved to be lifesaving in this case.

Early hospital discharge after percutaneous transluminal coronary angioplasty.

To determine the safety and efficacy of early hospital discharge after percutaneous transluminal coronary angioplasty (PTCA), 100 patients were studied prospectively. A telemetry observation unit was established to monitor patients having uncomplicated procedures. A total of 170 lesions were dilated, with a procedural success rate of 96% and a clinical success rate of 91%. There were no deaths or patients who required emergency bypass surgery. Four patients developed abrupt vessel closure in the catheterization laboratory. No major complications developed in the telemetry observation unit or after discharge. Patients with high-risk lesion morphology, based on the American College of Cardiology/American Heart Association Task Force guidelines, tended to have a lower success rate and more procedural complications. Coronary dissections were angiographically detected in 33 patients and stratified into 6 types. To reduce possible adverse sequelae, all patients with complex dissections were triaged in the catheterization laboratory to an in-patient monitored unit for additional management. Accordingly, 20 patients were admitted to an in-patient unit for extended observation. Excluding 4 patients with myocardial infarction, 75% (12 of 16) were discharged the next day. Initial experience with early discharge suggests that under proper conditions the procedure is safe and effective. Patients with complex coronary dissections who are at high risk for abrupt vessel closure can be promptly identified after dilatation and triaged to an appropriate monitoring area. Early discharge after PTCA offers more efficient use of hospital facilities and the opportunity to reduce hospital costs.