Effect of Recent Exacerbation History on the Efficacy of Once-Daily Single-Inhaler Fluticasone Furoate/Umeclidinium/Vilanterol Triple Therapy in Patients with Chronic Obstructive Pulmonary Disease in the FULFIL Trial.

Background: In the FULFIL trial, once-daily single-inhaler triple therapy with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) resulted in reduced moderate/severe exacerbation rates and conferred significant improvements in lung function and health status in patients with chronic obstructive pulmonary disease (COPD) versus twice-daily budesonide/formoterol (BUD/FOR) dual therapy. Methods: FULFIL was a Phase III, randomized, double-blind, double-dummy, parallel-group study. Patients ≥40 years of age with symptomatic COPD were randomized 1:1 to FF/UMEC/VI 100/62.5/25 mcg or BUD/FOR 400/12 mcg. In this post hoc analysis, patients were categorized by exacerbation history in the year prior to study entry (≥1 moderate/severe exacerbation [recent exacerbation] versus no recent exacerbation). Endpoints included annual rate of on-treatment moderate/severe exacerbations up to Week 24, annual rate of on-treatment severe exacerbations up to Week 24, change from baseline in trough forced expiratory volume in 1 second at Week 24, and change from baseline in health status as measured by St George's respiratory questionnaire total score at Week 24. Results: Of the 1810 patients in the intent-to-treat population, 1180 (65%) had one or more moderate/severe exacerbation in the year prior to entry, while 630 (35%) patients did not. FF/UMEC/VI versus BUD/FOR significantly reduced moderate/severe exacerbation rates in the recent exacerbation subgroup (mean annualized rate: 0.19 vs 0.29; rate ratio [95% confidence interval [CI]]: 0.64: [0.45, 0.91]; p=0.014) and numerically reduced moderate/severe exacerbation rates in the no recent exacerbation subgroup (mean annualized rate: 0.29 vs 0.43; rate ratio [95% CI]: 0.67 [0.43, 1.04]; p=0.073). Severe exacerbation rates were numerically reduced with FF/UMEC/VI versus BUD/FOR treatment across both subgroups. FF/UMEC/VI conferred significant improvements in lung function and health status versus BUD/FOR, regardless of recent exacerbation history. Conclusion: FF/UMEC/VI reduced moderate/severe and severe exacerbation rates and improved lung function and health status versus BUD/FOR in patients with symptomatic COPD, regardless of recent exacerbation history.

The role of ondansetron in the treatment of schizophrenia.

OBJECTIVE: To evaluate the efficacy of ondansetron for the treatment of schizophrenia. DATA SOURCES: Searches of MEDLINE (1950-March 2010) and Google Scholar were performed. Key search terms included ondansetron, Zofran, serotonin antagonists, 5-HT(3) serotonin receptor, and schizophrenia. STUDY SELECTION AND DATA EXTRACTION: All articles published in English identified from the data sources were evaluated. All studies and case reports evaluating ondansetron for the treatment of schizophrenia were reviewed. DATA SYNTHESIS: Six clinical trials, including 3 double-blind, randomized trials, and 2 case reports pertinent to ondansetron use in schizophrenia, were identified. Ondansetron daily doses ranged from 4 to 16 mg, with doses administered once or twice daily. Ondansetron was used as monotherapy in 3 trials and as an adjunct to therapy with clozapine, haloperidol, or risperidone, respectively, in 3 trials. Studies were of varying durations, ranging from a single-dose study with a 3-hour follow-up to three 12-week studies. Most studies evaluated ondansetron's efficacy in treating schizophrenia as measured with changes in Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale, and Clinical Global Impression scale scores. In the 2 largest trials, with a combined patient population of 151, treatment with adjunctive ondansetron resulted in statistically significant improvement in negative symptoms as assessed with PANSS. In all studies, ondansetron was well tolerated, with no severe adverse reactions reported. CONCLUSIONS: Ondansetron may be effective as an adjunct to antipsychotics for the treatment of schizophrenia, specifically negative symptoms, as assessed with PANSS. Due to the variation in concurrent therapies and dosing regimens, it is difficult to establish an optimal dose from the reviewed trials. Further large, randomized, double-blind, active-controlled studies would be helpful in determining the role of ondansetron in the treatment of schizophrenia.

Role of gabapentin in the treatment of uremic pruritus.

OBJECTIVE: To evaluate the efficacy of gabapentin for the treatment of uremic pruritus (UP). DATA SOURCES: Literature retrieval was accessed through MEDLINE (1950-March week 3, 2008; In-Process & Other Non-Indexed Citations, April 1, 2008) and International Pharmaceutical Abstracts (1970-March 2008) using the terms gabapentin, pruritus, itch, urem$ (truncated), dialysis, and kidney disease. The Google Scholar search engine was used to identify articles that MEDLINE did not capture with the described search terms. Additionally, reference citations from publications identified were reviewed. STUDY SELECTION AND DATA EXTRACTION: All articles in English and studies conducted in humans were identified and evaluated. DATA SYNTHESIS: UP is an unpleasant itching sensation that affects approximately 30% of patients on hemodialysis (HD). The current mainstays of therapy include antihistamines and topical therapies, although many patients remain symptomatic despite these treatments. Alternative therapeutic approaches, including topical, oral, and intravenous drugs; dialysis modifications; homeopathic therapies; and physical treatments have been used, but few evidence-based studies exist to support their utility. Gabapentin has been evaluated for the treatment of UP in 2 small, randomized, placebo-controlled studies, 1 pilot evaluation, and 1 index case. Gabapentin has demonstrated efficacy in the treatment of multiple types of itch and shows promise in treating patients with UP who are unresponsive to standard therapies. All of the controlled studies consisted of 4 weeks of active treatment, and no patients discontinued gabapentin due to adverse events. The most common adverse events noted in these trials were consistent with gabapentin's safety profile (dizziness, somnolence, fatigue, nausea). CONCLUSIONS: Available data support the use of gabapentin as a well-tolerated and effective treatment option for patients with UP who are unresponsive to traditional therapies. Further well-designed trials are warranted to establish the most appropriate dosing regimen in patients on HD.

Pilot study of once-daily simplification therapy with abacavir/lamivudine/zidovudine and efavirenz for treatment of HIV-1 infection.

OBJECTIVE: The purpose of this pilot study was to explore the efficacy and safety of the abacavir/lamivudine/zidovudine fixed-dose combination tablet administered as two tablets once daily (qd) versus one tablet twice daily (bid) in combination with efavirenz (EFV). METHOD: This was a prospective, randomized, open-label, multicenter study with a 24-week treatment period in 7 outpatient HIV clinics in the United States. Patients currently receiving an initial regimen of abacavir/lamivudine/zidovudine bid plus EFV qd for at least 6 months with HIV-1 RNA <50 copies/mL for at least 3 months and a screening CD4+ cell count > or = 200 cells/mm3 were eligible. Thirty-six patients enrolled, and 35 (97%) completed the study. Participants were randomized to switch to 2 tablets of abacavir/lamivudine/zidovudine qd plus EFV qd (QD arm) or continue current treatment (BID arm) for 24 weeks. RESULTS: Efficacy, safety, and adherence were evaluated. Median baseline CD4+ cell count was 521 cells/mm3. At week 24, HIV-1 RNA <50 copies/mL was achieved for 94% of participants in the QD arm and 89% in the BID arm by intent-to-treat, missing = failure analysis (95% confidence interval for difference: > or = 0.29 to +0.18, p = 1.000). At week 24, median CD4+ cell count change from baseline was +26 cells/mm3 for the QD arm and -39 cells/mm3 for BID arm. One patient randomized to the QD arm met virologic failure criteria (confirmed HIV-1 RNA >120 copies/mL) at week 20 and viral genotype showed M184V. After failure, this patient revealed he never took EFV throughout the entire study after randomization, effectively receiving only abacavir/lamivudine/zidovudine qd alone. Median adherence was slightly higher in the QD arm, although both arms had broad variability and overlapping interquartile ranges. Adverse events were infrequent and occurred with similar frequency between arms; treatment-related adverse events were abdominal pain, flatulence, nausea, headache, and abnormal dreams (1 patient [3%] for each adverse event). No patients withdrew due to adverse events, and no abacavir hypersensitivity reactions were reported. CONCLUSION: In this pilot study of patients suppressed on abacavir/lamivudine/zidovudine bid plus EFV, 94% of participants switching to abacavir/lamivudine/zidovudine qd plus EFV maintained virologic suppression, compared to 89% of participants continuing abacavir/lamivudine/zidovudine bid plus EFV.

Defining stem cell types: understanding the therapeutic potential of ESCs, ASCs, and iPS cells.

Embryonic, adult, artificially reprogrammed, and cancer…- there are various types of cells associated with stemness. Do they have something fundamental in common? Are we applying a common name to very different entities? In this review, we will revisit the characteristics that define 'pluripotency', the main property of stem cells (SCs). For each main type of physiological (embryonic and adult) or synthetic (induced pluripotent) SCs, markers and functional behavior in vitro and in vivo will be described. We will review the pioneering work that has led to obtaining human SC lines, together with the problems that have arisen, both in a biological context (DNA alterations, heterogeneity, tumors, and immunogenicity) and with regard to ethical concerns. Such problems have led to proposals for new operative procedures for growing human SCs of sufficiently high quality for use as models of disease and in human therapy. Finally, we will review the data from the first clinical trials to use various types of SCs.