Alpha emitter radium-223 and survival in metastatic prostate cancer.

BACKGROUND: Radium-223 dichloride (radium-223), an alpha emitter, selectively targets bone metastases with alpha particles. We assessed the efficacy and safety of radium-223 as compared with placebo, in addition to the best standard of care, in men with castration-resistant prostate cancer and bone metastases. METHODS: In our phase 3, randomized, double-blind, placebo-controlled study, we randomly assigned 921 patients who had received, were not eligible to receive, or declined docetaxel, in a 2:1 ratio, to receive six injections of radium-223 (at a dose of 50 kBq per kilogram of body weight intravenously) or matching placebo; one injection was administered every 4 weeks. In addition, all patients received the best standard of care. The primary end point was overall survival. The main secondary efficacy end points included time to the first symptomatic skeletal event and various biochemical end points. A prespecified interim analysis, conducted when 314 deaths had occurred, assessed the effect of radium-223 versus placebo on survival. An updated analysis, when 528 deaths had occurred, was performed before crossover from placebo to radium-223. RESULTS: At the interim analysis, which involved 809 patients, radium-223, as compared with placebo, significantly improved overall survival (median, 14.0 months vs. 11.2 months; hazard ratio, 0.70; 95% confidence interval [CI], 0.55 to 0.88; two-sided P=0.002). The updated analysis involving 921 patients confirmed the radium-223 survival benefit (median, 14.9 months vs. 11.3 months; hazard ratio, 0.70; 95% CI, 0.58 to 0.83; P<0.001). Assessments of all main secondary efficacy end points also showed a benefit of radium-233 as compared with placebo. Radium-223 was associated with low myelosuppression rates and fewer adverse events. CONCLUSIONS: In this study, which was terminated for efficacy at the prespecified interim analysis, radium-223 improved overall survival. (Funded by Algeta and Bayer HealthCare Pharmaceuticals; ALSYMPCA ClinicalTrials.gov number, NCT00699751.).

Meta-analysis of antisecretory and gastrokinetic compounds in functional dyspepsia.

In view of therapeutic advances, we carried out meta-analysis of results from 18 randomized, controlled clinical studies to update a previous meta-analysis and to provide an overview of clinical trials involving treatment of functional dyspepsia. The studies were included only if they satisfied inclusion and exclusion criteria and assessed treatment of functional dyspepsia with the antisecretory compounds cimetidine and ranitidine and the gastrokinetic compounds cisapride and domperidone. Outcomes of each of these trials were classified in terms of differences in therapeutic success between active treatment and placebo. For antisecretory treatments, the 95% confidence intervals for the difference in therapeutic success between active treatment and placebo were inconsistent for cimetidine, but analysis of both ranitidine trials gave favorable results. For the gastrokinetic compounds cisapride and domperidone, the differences in success rates were generally higher and more in favor of active treatment than placebo. By combining the results from both antisecretory treatments and comparing them with the combined results for gastrokinetic compounds, we observed that gastrokinetic compounds had a greater difference in success rates than did antisecretory agents. Overall, our meta-analysis shows that antisecretory treatment with cimetidine or ranitidine offers little advantage over placebo, whereas gastrokinetic treatment with cisapride or domperidone is significantly better than placebo for treatment of functional dyspepsia.

Weight gain with valproate or carbamazepine--a reappraisal.

The use of valproate has traditionally been held to be associated with a greater incidence of weight gain than that of other anticonvulsants. This paper presents an analysis of body weight data gathered during a randomized trial comparing valproate with carbamazepine in 260 children aged 4-15 years with newly-diagnosed epilepsy. There were more reports of weight gain as an adverse event in the valproate group than in the carbamazepine group (22 reports in 14 patients vs. nine reports in five patients). However, amongst the 211 patients (103 on valproate and 108 on carbamazepine) in whom objective weight measurements were taken during treatment, there were no differences between the treatments in percentage weight gain from baseline or incidence of excessive weight velocity. Eight patients reporting weight gain on valproate were switched to carbamazepine because of poor seizure control and/or adverse events including weight gain, but three of the four patients for whom body weight measurements were available continued to gain weight on carbamazepine. It is concluded that weight gain may be erroneously attributed to valproate treatment.

Comparative efficacy and safety of ciprofibrate and sustained-release bezafibrate in patients with type II hyperlipidaemia.

The hypolipidaemic efficacy and safety of ciprofibrate were compared with a sustained-release formulation of bezafibrate (Bezalip Mono) in 174 patients with type II hyperlipidaemia. This multicenter, open, parallel-group study was conducted in general practice. A total of 83 patients received 100 mg ciprofibrate once daily and 91 received 400 mg bezafibrate once daily for eight weeks. Concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides were measured at baseline (after stabilisation on a lipid-lowering diet) and after eight weeks. Safety was assessed from reports of adverse events and by measuring haematological and biochemical parameters. After eight weeks, ciprofibrate produced a significantly greater decrease in total cholesterol (-17.8% vs -12.5%), low-density lipoprotein cholesterol (-22.4% vs -17.2%), and triglycerides (-33.9% vs -26.1%). High-density lipoprotein cholesterol concentrations were increased significantly by both drugs (19.6% with ciprofibrate, 24.9% with bezafibrate) but the differences between drugs were non-significant. Both drugs were well tolerated, with headache the most widely reported adverse event.

The immunosuppressive properties of enisoprost and a 5-lipoxygenase inhibitor (SC-45662).

Metabolic derivatives of arachidonic acid such as prostaglandins and leukotrienes may alter immune responses. Enisoprost (ENO), a synthetic prostaglandin E analog, inhibited the response of human peripheral blood mononuclear cells to phytohemagglutinin in a concentration-dependent fashion: .1, 1.0, and 10 micrograms/ml yielding 4.0, 21.7, and 74.3% inhibition, respectively. ENO also potently inhibited both IL-2 production (measured by ELISA) and IL-2 responsiveness (measured by CTLL-2 response to IL-2) in a concentration-dependent manner, yet did not inhibit acquisition of IL-2 receptors. ENO similarly diminished efferent immune function in a concentration-dependent fashion, as measured by inhibition of cytotoxic T cell and natural killer effector function. A 5-lipoxygenase inhibitor (5-LO), SC-45662, also inhibited mononuclear cell response to PHA in a concentration-dependent manner: 0.1, 1.0, and 10 micrograms/ml yielding 5.0, 9.7, and 79.7% inhibition, respectively. Although 5-LO potently inhibited IL-2 production, it had no effect on IL-2 responsiveness or IL-2 receptor acquisition. Like ENO, 5-LO impaired CTL and NK effector function yet was not as potent in inhibiting CTL effector function. In summary, ENO and 5-LO inhibit afferent and efferent immune function. The inhibitory effects of these drugs are not related to cytotoxicity as cell viability is maintained for 72 hr in the presence of these drugs, and the inhibitory effect is reversible when the drugs are removed. The 5-LO does not inhibit mononuclear cell responses simply by shunting the formation of arachidonic acid precursors to form inhibitory prostaglandins, since it does not impair IL-2 responsiveness in a manner similar to ENO. These two compounds may prove to have clinical utility in organ transplantation if safely achieved serum concentrations of these drugs yield in vivo immunosuppression parallel to our in vitro results.