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BackgroundThere is no effective drug treatment for the organ failure (OF) caused by severe acute pancreatitis (SAP).ObjectiveWe aimed to evaluate the efficacy of cyclooxygenase-2 inhibitors (COX-2-Is) on the treatment of SAP and its safety.DesignIn this multicentre, double-blind, randomised, placebo-controlled, investigator-initiated trial, 348 patients with acute pancreatitis aged 18–75 years, <1 week from onset of illness to admission, and Acute Physiology and Chronic Health Evaluation II Score ≥7 or modified Marshall Score ≥2, were randomly assigned (1:1) to the COX-2-Is group (parecoxib sequential with imrecoxib) or the placebo group. SAP occurrence, duration of OF, local complications, clinical outcomes and serum inflammatory mediators were measured.ResultsCompared with the placebo group, SAP occurrence was reduced by 20.7% (77.6% vs 61.5%, p=0.001) and the persistent OF duration in SAP was shortened by 2 days (p<0.001) after COX-2-Is treatment. For patients enrolled within or after 48 hours from symptom onset, SAP occurrence was reduced by 23.8% (p=0.001) and 8.5% (p=0.202), and the persistent OF duration in SAP was shortened by 3 days (p=0.001) and 2 days (p=0.010) after COX-2-Is treatment, respectively. The occurrence of local complications in the COX-2-Is group was significantly lower than those in the placebo group, 33.7% vs 49.1%, p=0.004. The serum levels of inflammatory mediators and 30-day mortality (from 8.6% to 3.4%) were significantly reduced after COX-2-Is treatment, p<0.05. The incidence of adverse events was similar between the two treatment groups.ConclusionParecoxib sequential with imrecoxib was effective and well tolerated in reducing the occurrence and duration of SAP and local complications through suppression of systemic inflammatory response, leading to decreased morbidity.

When administered to patients for pain control after coronary-artery bypass surgery, valdecoxib and its intravenous prodrug, parecoxib, were found to be associated with an increased risk of cardiovascular thromboembolic events. These findings add to the growing concern that the use of COX-2 inhibitors increases the risk of cardiovascular events, particularly in persons who are at risk for such events. When administered to patients for pain control after coronary-artery bypass surgery, valdecoxib and its intravenous prodrug, parecoxib, were found to be associated with an increased risk of cardiovascular thromboembolic events. Nonsteroidal antiinflammatory drugs (NSAIDs) are established pharmacologic tools for treating postoperative pain. However, concern about the possibility of gastric ulceration, renal injury, and bleeding has limited the use of NSAIDs in some surgical and critical care settings. 1 The selective cyclooxygenase-2 (COX-2) inhibitor valdecoxib (Bextra, Pfizer) and its intravenous prodrug parecoxib (Dynastat, Pfizer) were found to exert significant opioid-sparing effects after dental, gynecologic, orthopedic, and other noncardiac surgical procedures, apparently without causing serious adverse effects. 2 – 5 Similar efficacy was demonstrated in a study of parecoxib and valdecoxib in patients recovering from coronary-artery bypass grafting (CABG). 6 In that study, however, these drugs . . .

We evaluated the efficacy and safety of the investigational long-acting injectable antipsychotic agent paliperidone palmitate (PP) in the treatment of schizophrenia. Patients were randomized to receive gluteal injections of placebo or PP (50 or 100 mg eq., fixed doses), without oral supplementation, on days 1, 8, and 36 (9-wk, double-blind phase) in this phase 2b study. Patients (n=197, intent-to-treat analysis set) were 62% men, mean (s.d.) age 39 (10) yr, with a baseline mean (s.d.) Positive and Negative Syndrome Scale (PANSS) total score of 87.0 (12.5). Mean (s.d.) PANSS total scores showed significant improvement at endpoint (primary measure) for both the PP 50 mg eq. [−5.2 (21.5)] and PP 100 mg eq. [−7.8 (19.4)] groups, vs. placebo [6.2 (18.3)] (p⩽0.001, each dose vs. placebo). This improvement was detected by day 8 and maintained to endpoint (p⩽0.011) for both doses. In the safety analysis set (n=247), fewer PP-treated patients (2%) discontinued for treatment-emergent adverse events vs. placebo-treated (10%). Rates of treatment-emergent extrapyramidal syndrome-related adverse events were comparable between active treatment and placebo, with the exception of parkinsonism-related disorders (50 mg eq. 5%, 100 mg eq. 8%, placebo 1%). Results of other safety measures suggest PP to be generally well-tolerated. Throughout the study, investigators rated injection-site pain as absent (56–71%), mild (24–39%), moderate (2–12%), or severe (0–2%). PP (50 and 100 mg eq. doses) administered as a gluteal intramuscular injection was efficacious and generally tolerated in these patients with acute symptomatic schizophrenia.

Sitaxsentan may benefit patients with pulmonary arterial hypertension by blocking the vasoconstrictor effects of endothelin-A while maintaining the vasodilator/clearance functions of endothelin-B receptors. Patients with pulmonary arterial hypertension that was idiopathic, related to connective tissue disease or congenital heart disease, were randomized to receive placebo (n = 60), sitaxsentan 100 mg (n = 55), or sitaxsentan 300 mg (n = 63) orally once daily for 12 weeks. The primary endpoint was change in peak VO(2) at Week 12. Secondary endpoints included 6-minute walk, New York Heart Association class, VO(2) at anaerobic threshold, VE per carbon dioxide production at anaerobic threshold, hemodynamics, quality of life, and time to clinical worsening. Although the 300-mg group increased peak VO(2) compared with placebo (+3.1%, p < 0.01), none of the other endpoints derived from cardiopulmonary exercise testing were met. However, both the 100-mg dose and the 300-mg dose, compared with placebo, increased 6-minute walk distance (100 mg: +35 m, p < 0.01; 300 mg: +33 m, p < 0.01); functional class, cardiac index, and pulmonary vascular resistance also improved (p < 0.02 for each parameter at both doses). The incidence of elevated aminotransferase values (> three times normal) was 3% for the placebo group, 0% for the 100-mg group, and 10% for the 300-mg group.

In this randomized trial of children with polyarticular juvenile rheumatoid arthritis, methotrexate achieved slightly better outcomes than leflunomide; at 16 weeks the respective rates of 30 percent improvement were 89 percent and 68 percent. In each group, the clinical improvement observed at 16 weeks was maintained at 48 weeks. Methotrexate appears to be slightly more effective than leflunomide for juvenile rheumatoid arthritis, but both drugs produced high rates of response. Juvenile rheumatoid arthritis, with an estimated prevalence of 0.07 to 4.01 per 1000 children, 1 has three major subtypes differentiated on the basis of onset: systemic, pauciarticular, and polyarticular (defined by the involvement of at least five joints). Treatments for juvenile rheumatoid arthritis include nonsteroidal antiinflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDs). 2 – 7 DMARDs have been shown radiographically to inhibit progression in adults with rheumatoid arthritis. 8 Methotrexate is the most commonly used DMARD for juvenile rheumatoid arthritis. In six-month trials, both methotrexate and sulfasalazine were more effective than placebo in children with juvenile rheumatoid arthritis and had acceptable short-term safety . . .

Paliperidone palmitate (PP) is a recently (USA) approved injectable new-generation antipsychotic. This 53-wk, Phase-III double-blind study was designed to assess the non-inferiority of PP to risperidone long-acting injectable (RIS-LAI) in schizophrenia treatment. Acutely symptomatic patients (n=749), with a Positive and Negative Syndrome Scale (PANSS) total score between 60 and 120 were randomly allocated to gluteal injections of either (a) PP: 50 mg eq. on days 1 and 8, and flexible dosing [25–100 mg eq. (i.e. 39–156 mg USA dosing)] once-monthly; or (b) RIS-LAI: bi-weekly injections of 25 mg on days 8 and 22, and flexible dosing (25–50 mg) starting from day 36, with allowed oral supplementation. Patients (n=747) were 59% men, 92% white, mean (s.d.) age of 41 (11.95) yr and 45% (n=339) completed the study. Mean (s.d.) change from baseline to endpoint in PANSS total score was: −11.6 (21.22) PP; and −14.4 (19.76) RIS-LAI (per-protocol analysis set, primary measure); least-squares means difference was −2.6 (95% CI −5.84 to 0.61), with a prespecified 5-point non-inferiority margin. PP's suboptimal dosing regimen (<150 mg eq. initial dose) resulted in lower median plasma levels of the active moiety in PP-treated vs. RIS-LAI-treated patients. Insomnia was the most common treatment-emergent adverse event, with a similar incidence in both groups (15%). PP did not demonstrate comparable efficacy to RIS-LAI, which may be attributable to the initiation dosing strategy employed. Tolerability of both treatments was comparable to previous studies, with no new safety signals detected.

Background Poor postoperative pain control is frequently associated with complications and delayed discharge from a hospital. Preemptive analgesia is one of the methods suggested for reducing postoperative pain. Opioids are effective for pain control, but there known addictive properties make physicians cautious about using them. Parecoxib and ketorolac are potent non-opioid NSAIDs that are attractive alternative drugs to opioids to avoid opioid-related side effects. However, there are no good head-to-head comparisons between these two drugs in the aspect of preemptive analgesic effects in lumbar spinal fusion surgery. This study aimed to compare the efficacy in terms of postoperative pain control and safety of parecoxib with ketorolac as preemptive analgesia in posterior lumbar spinal fusion patients. Methods A prospective, double-blinded randomized controlled trial was carried out in patients undergoing posterior lumbar spinal fusion, who were randomized into 3 groups (n = 32). Parecoxib, ketorolac or a placebo was given to each patient via injection around 30 minutes prior to incision. The efficacy of postoperative pain control was assessed by a verbal numerical rating score (0–10). And various postoperative things were monitored for analysis, such as total opioid consumption, complications, and estimated blood loss. Results Both the ketorolac and parecoxib groups showed significantly better early postoperative pain reduction at the postanesthesia care unit (PACU) than the control group ( p  < 0.05). There were no differences between the pain scores of ketorolac and parecoxib at any time points. Complications and bleeding were not significantly different between all three groups. Conclusions Preemptive analgesia using both ketorolac and parecoxib showed a significantly better early postoperative pain control in the PACU than the control group in patients undergoing lumbar spinal fusion. Trial registration ClinicalTrials.gov NCT01859585 . Registered 15 May 2013.

Objectives AUY922 is a novel heat shock protein inhibitor with preclinical activity in pancreatic cancer. This phase II study evaluated the efficacy of AUY922 in patients with advanced pancreatic cancer previously treated with chemotherapy. Methods In this single-arm, Simon two-stage phase II trial, patients with metastatic or locally advanced pancreatic ductal adenocarcinoma who had progressed on at least one line of chemotherapy and were of good performances status (ECOG 0 or 1) were treated with AUY922 at a dose of 70 mg/m 2 IV weekly. The primary endpoint was disease control rate (objective response and stable disease ≥16 weeks). Results Twelve patients were accrued, all of whom received treatment. At least possibly related ≥grade 3 adverse events included fatigue (8 %) and AST elevation (8 %). Ten patients were evaluable for response with 1 (10 %) having stable disease and 9 (90 %) progressive disease. The median progression-free survival was 1.6 months, and the median overall survival was 2.9 months. Conclusions AUY922 was not associated with significant efficacy in previously treated patients with advanced pancreatic cancer.

Objective To compare matched paliperidone-ER- and olanzapine-treated schizophrenic patients on measures of glucose and lipid metabolism. Methods Eighty hospitalized patients with schizophrenia (DSM-IV) were randomly assigned to treatment with paliperidone ER or olanzapine for a period of 12 weeks. At baseline and every 4 weeks, we assessed weight, subcutaneous fat, waist and hip circumferences, fasting glucose, insulin, glycohemoglobin A1, cholesterol, triglycerides, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, and prolactin. We also assessed at every time point body mass index (BMI), homeostasis insulin resistance (HOMA-IR), and homeostasis β-cell function (HOMA-B). Results Thirty-three patients randomly assigned to paliperidone ER and 23 patients randomly assigned to olanzapine groups completed the entire 12-week treatment. Within-group analyses showed that fasting measures in both groups increased for weight, BMI, waist circumferences, hip circumference, subcutaneous fat, cholesterol, triglycerides, and prolactin. In contrast, fasting glucose, LDL, and HOMA-B increased during treatment only in the olanzapine group. We also detected significantly different serum prolactin levels at all time point between the paliperidone ER- and olanzapine-treated groups, as well as a statistical trend for HOMA-B to increase more in the olanzapine compared to paliperidone-ER group over the 12 weeks of the trial. We did not detect, however, differential drug effects over the 12 weeks of the trial on fasting measures of BMI, glucose, glycohemoglobin A1, insulin, HDL, LDL, cholesterol, triglyceride, or HOMA-IR. Conclusion This study reinforces the necessity of regularly monitoring metabolic parameters in patients with schizophrenia taking atypical antipsychotics, including paliperidone ER.

Background The purpose of this study was to evaluate the safety and effectiveness of iloperidone for the prevention of relapse in schizophrenia. Methods Study subjects were adults with schizophrenia who started on oral open-label iloperidone titrated to an initial target dose of 12 mg/day (6 mg twice daily) and then stabilized on a flexible-dose iloperidone regimen (range 8–24 mg/day) for up to 24 weeks. Subjects meeting stabilization criteria then entered the relapse-prevention phase and were randomized 1:1 in a double-blind fashion to continue with iloperidone or placebo withdrawal for up to 26 weeks or until meeting relapse or other withdrawal criteria. Results A total of 303 subjects were randomized to the relapse-prevention phase; 153 continued to receive iloperidone, and 150 were withdrawn to placebo. The modal total daily dose for iloperidone in all phases of the study was 12 mg/day. The pre-defined unblinded interim analysis upon reaching 68 relapse events confirmed the hypothesis that iloperidone ( n  = 97) was more effective than placebo ( n  = 96) in preventing relapse events, and the trial was stopped early. The estimated relapse rates were 63.4 % (Kaplan–Meier [KM] estimate) for placebo compared with 20.4 % (KM estimate) for those continuing to receive iloperidone (log rank test: p  < 0.0001). The mean time to relapse was 71 days for placebo and 139 days for iloperidone (hazard ratio 4.7; 95 % confidence interval 2.7–8.3; p  < 0.0001). The safety profile observed in previous short-term studies was also reaffirmed in this maintenance treatment setting. The most common treatment-emergent adverse events (TEAEs) in the stabilization phase were dizziness (11.6 %), somnolence (8.3 %), and dry mouth (6.8 %). Rates of reported extrapyramidal disorder or akathisia during stabilization were 2.5 and 3.7 %, respectively. Conclusions Flexible dosing of iloperidone for maintenance-phase therapy, with a modal dose of 12 mg/day was effective in preventing relapse in subjects previously stabilized on iloperidone. The adverse event profile for iloperidone was consistent with other studies, and the low extrapyramidal symptom and akathisia burden during stabilization was sustained during the course of the study. ClinicalTrials.gov identifier: NCT01291511.