Unpublished Clinical Trials Research Articles

Dosing and Antipyretic Efficacy of Oral Acetaminophen in Children

BackgroundA standardized approach to dosing acetaminophen in pediatric populations was published in 1983. That review proposed specific weight-related dosing for infants and children weighing 6 through 95 lb and an age-based schedule for children aged <4 months through 11 years. Subsequent clinical studies evaluating these and alternative doses of acetaminophen supported the recommended 10–15-mg/kg dose. ObjectiveThis article reviewed published and unpublished pediatric antipyretic data to provide a critical assessment of the 10–15-mg/kg oral dose and the current pediatric oral dosing schedules for acetaminophen. MethodsPublished literature and unpublished clinical trials that evaluated the antipyretic efficacy of acetaminophen in children were reviewed. The PubMed database was searched using the term acetaminophen or paracetamol, with study criteria limited to randomized, controlled trials; oral dosing; patient age <12 years; and publication between 1982 and August 2012. All of the sponsor’s unpublished antipyretic clinical studies completed between 1980 and August 2012 and involving at least 1 oral-formulation acetaminophen-only treatment arm were identified. Data from published literature containing sufficient detail to verify doses; dosing frequency; and, when necessary, estimates from figures, and from acetaminophen arms of the unpublished studies were analyzed. ResultsThirteen unpublished trials enrolled 705 children to receive an oral dose of 10–15 mg/kg of acetaminophen. This dose resulted in a rapid onset of temperature reduction, with a maximum temperature decrement of ~3 hours following administration. Results from 40 published clinical trials in which 2332 children received oral acetaminophen for fever support these findings. The most common adverse events reported in any of the reported studies were gastrointestinal in nature and generally mild in intensity. ConclusionsData support the recommended 10–15-mg/kg oral dose and demonstrate that the age and weight schedules for over-the-counter acetaminophen proposed in 1983 remain appropriate.

Aclidinium Bromide: An Alternative Long-Acting Inhaled Anticholinergic in the Management of Chronic Obstructive Pulmonary Disease

To evaluate the efficacy and safety of aclidinium bromide, a novel, long-acting inhaled muscarinic receptor antagonist approved by the Food and Drug Administration (FDA) in July 2012, as a treatment in the management of moderate to severe chronic obstructive pulmonary disease (COPD). Literature was identified through PubMed/MEDLINE (2000-March 2013) and International Pharmaceutical Abstracts using the search terms aclidinium, COPD, chronic bronchitis, emphysema, anticholinergic, and muscarinic antagonist. In addition, US government websites, including fda.gov and clinicaltrials.gov, were reviewed for pertinent information. Forest Laboratories, Inc provided previously unpublished clinical trial data. All reference citations from identified publications were reviewed for possible inclusion. All identified Phase 1, 2a, 2b, and 3 studies evaluating the safety and efficacy of aclidinium bromide were reviewed. Once- and twice-daily aclidinium bromide was assessed for efficacy and safety in patients with moderate to severe COPD. In comparison to placebo, aclidinium significantly improves trough and peak forced expiratory volume in 1 second (FEV1). Significant increases in trough and peak FEV1 were sustainable for up to 64 weeks. In addition to improvement in trough and peak FEV1, twice-daily aclidinium 400 μg induced clinically meaningful improvements in the health status of patients with moderate to severe COPD. Aclidinium was generally well tolerated, with headache, cough, diarrhea, and nasopharyngitis the most common treatment-related adverse effects noted in clinical trials. Aclidinium did not demonstrate a difference in the incidence of systemic anticholinergic-associated adverse effects in comparison to placebo or active comparator. Aclidinium bromide is a novel, inhaled, long-acting anticholinergic that, when administered at the FDA-approved dose, safely produces clinically and statistically significant bronchodilation and improves health status in patients with moderate to severe COPD. Long-term clinical trials assessing the efficacy and safety of aclidinium are warranted.

Rituximab for thyroid-associated ophthalmopathy

Thyroid associated ophthalmopathy (TAO) is the most frequent extrathyroidal manifestation of Graves' disease, affecting up to 50% of patients, and has a great impact on quality of life. Rituximab is a human/murine chimeric monoclonal antibody that targets CD20, a transmembrane protein expressed on the surface of pre-B and mature B lymphocytes, but not on stem cells, pro-B lymphocytes or plasma cells. Preliminary work has shown that blocking the CD20 receptor on B-lymphocytes with rituximab affects the clinical course of TAO, by reducing inflammation and the degree of proptosis. The aim of this review was to investigate the effectiveness and safety of rituximab for the treatment of TAO. We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2013, Issue 3), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE, (January 1950 to April 2013), EMBASE (January 1980 to April 2013), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to April 2013), OpenGrey (System for Information on Grey Literature in Europe) (www.opengrey.eu/), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov), the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en) and the EU Clinical Trials Register (www.clinicaltrialsregister.eu). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 15 April 2013. We manually searched references of review articles and used the Science Citation Index to identify additional studies citing trials. We contacted the lead investigators of relevant trials on ClinicalTrials.gov and the WHO ICTRP for information and data from as yet unpublished clinical trials. We contacted experts in the field for information about any ongoing trials. We contacted the manufacturers of rituximab for details of any sponsored trials. We sought to include randomised controlled trials (RCTs) of rituximab treatment by intravenous infusion for the treatment of patients with TAO, compared with placebo or intravenous glucocorticoid treatment. Two review authors independently scanned titles and abstracts, as well as independently screened the full reports of the potentially relevant studies. At each stage, the results were compared and disagreements were solved by discussion. No studies were identified that met the inclusion criteria. There are three ongoing studies which are likely to meet inclusion criteria once published, and thus be included in future updates of this review. There is currently insufficient evidence to support the use of rituximab in patients with TAO. There is a need for large RCTs, investigating rituximab versus placebo or corticosteroids in patients with active TAO to make adequate judgement on the efficacy and safety of this novel therapy for this condition.

Cervical pessary for preventing preterm birth.

Preterm birth is a major health problem and contributes to more than 50% of the overall perinatal mortality. Preterm birth has multiple risk factors including cervical incompetence and multiple pregnancy. Different management strategies have been tried to prevent preterm birth, including cervical cerclage. Cervical cerclage is an invasive technique that needs anaesthesia and may be associated with complications. Moreover, there is still controversy regarding the efficacy and the group of patients that could benefit from this operation. Cervical pessary has been tried as a simple, non-invasive alternative that might replace the above invasive cervical stitch operation to prevent preterm birth. To evaluate the efficacy of cervical pessary for the prevention of preterm birth in women with risk factors for cervical incompetence. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (1 September 2012), Current Controlled Trials and the Australian New Zealand Clinical Trials Registry (1 September 2012). We selected all published and unpublished randomised clinical trials comparing the use of cervical pessary with cervical cerclage or expectant management for prevention of preterm birth. We did not include quasi-randomised trials. Cluster-randomised or cross-over trials were not eligible for inclusion. Two review authors independently assessed trials for inclusion. The review included one randomised controlled trial. The study included 385 pregnant women with a short cervix of 25 mm or less who were between 18 to 22 weeks of pregnancy. The use of cervical pessary (192 women) was associated with a statistically significantly decrease in the incidence of spontaneous preterm birth less than 37 weeks' gestation compared with expectant management (22% versus 59 %; respectively, risk ratio (RR) 0.36, 95% confidence interval (CI) 0.27 to 0.49). Spontaneous preterm birth before 34 weeks was statistically significantly reduced in the pessary group (6% and 27% respectively, RR 0.24; 95% CI 0.13 to 0.43). Mean gestational age at delivery was 37.7 + 2 weeks in the pessary group and 34.9 + 4 weeks in the expectant group. Women in the pessary group used less tocolytics (RR 0.63; 95% CI 0.50 to 0.81) and corticosteroids (RR 0.66; 95% CI 0.54 to 0.81) than the expectant group. Vaginal discharge was more common in the pessary group (RR 2.18; 95% CI 1.87 to 2.54). Among the pessary group, 27 women needed pessary repositioning without removal and there was one case of pessary removal. Ninety-five per cent of women in the pessary group would recommend this intervention to other people. Neonatal paediatric care admission was reduced in the pessary group in comparison to the expectant group (RR 0.17; 95% CI 0.07 to 0.42). The review included only one well-designed randomised clinical trial that showed beneficial effect of cervical pessary in reducing preterm birth in women with a short cervix. There is a need for more trials in different settings (developed and developing countries), and with different risk factors including multiple pregnancy.

Disparities between high-impact clinical trials in oncology and disease burden.

e17591 Background: Recent research has identified a discrepancy between NIH funding in oncology and various measures of disease burden by tumor type. We sought to identify whether this disparity exists in recent high impact publications. Methods: 833 clinical trials published in five high impact general medicine and clinical oncology journals between January, 2009 and October, 2012 were reviewed. 692 trials were included in this analysis after excluding those that studied &gt;1 tumor type. Disease burden was measured as person-years of life lost (YLLs), reported in the Surveillance, Epidemiology, and End Results database, and disability adjusted life years (DALYs), reported by the World Health Organization. We used a chi square goodness of fit test to compare the overall distribution of trials by tumor type to the distribution of annual YLLs and DALYs. Results: Breast cancer was the most published tumor, accounting for 14% of all trials, followed by lung (13%) and colorectal (7%) cancers. More than half of the trials (56%) were for patients with metastatic disease, and most (81%) were phase 2 and 3 clinical trials. Nearly half of all publications studied targeted therapies (45%), and the majority received industry support (61%). 67% of trials with a comparator arm met their primary endpoint. The distribution of trials by cancer site differed significantly from the distribution of both measures of disease burden (YLLs and DALYs) (both p&lt;0.001). The findings were unchanged in analyses that accounted for the total number of subjects enrolled in the trials (both p&lt;0.001). The most underrepresented malignancies based on burden of disease were lung and pancreatic cancers, while the most overrepresented were breast cancer, leukemia, and melanoma. Conclusions: The number of trials published by tumor type does not directly reflect the burden of these diseases in the population as assessed by YLL or DALY. Future studies examining potential confounders such as funding availability by cancer type or number of unpublished clinical trials may further clarify the observed disparities.

Results from the First Decade of Research Conducted by the Research on Adverse Drug Events and Reports (RADAR) Project

In 1998, a multidisciplinary team of investigators initiated the Research on Adverse Drug events And Reports (RADAR) project, a post-marketing surveillance effort that systematically investigates and disseminates information describing serious and previously unrecognized serious adverse drug and device reactions (sADRs). Herein, we describe the findings, dissemination efforts, and lessons learned from the first decade of the RADAR project. After identifying serious and unexpected clinical events suitable for further investigation, RADAR collaborators derived case information from physician queries, published and unpublished clinical trials, case reports, US FDA databases and manufacturer sales figures. All major RADAR publications from 1998 to the present are included in this analysis. For each RADAR publication, data were abstracted on data source, correlative basic science findings, dissemination and resultant safety information. RADAR investigators reported 43 serious ADRs. Data sources included case reports (17 sADRs), registries (5 sADRs), referral centers (8 sADRs) and clinical trial reports (13 sADRs). Correlative basic science findings were reported for ten sADRs. Thirty-seven sADRS were described as published case reports (5 sADRs) or published case-series (32 sADRs). Related safety information was disseminated as warnings or boxed warnings in the package insert (17 sADRs) and/or 'Dear Healthcare Professional' letters (14 sADRs). An independent National Institutes of Health-funded post-marketing surveillance programme can supplement existing regulatory and pharmaceutical manufacturer-supported drug safety initiatives.

Effectiveness of oseltamivir in adults: a meta-analysis of published and unpublished clinical trials

Oseltamivir is widely used for the treatment of influenza. Previous systematic reviews suggest that they reduce complications, but had significant methodologic limitations. To assess the effect of oseltamivir on duration of symptoms, complications and hospitalizations in adults. We searched Medline without time or language restrictions, and trial registries maintained by the manufacturer. We included published and unpublished randomized double-blinded, placebo-controlled trials of oseltamivir in adults with suspected influenza that reported duration of symptoms, complications or hospitalizations. We abstracted data regarding study quality, the duration of symptoms and rates of complications and hospitalization. Three published and eight unpublished studies met our inclusion criteria. For the intention-to-treat (ITT) population, the mean reduction in the duration of symptoms was 20.7 hours [95% confidence interval (CI) 13.3 to 28.0 hours]. Two large unpublished studies in the elderly and in adults with chronic disease did not find a significant reduction in the symptom duration. There was no difference in the likelihood of hospitalization in the ITT population (33/2633 patients for oseltamivir versus 20/1694 for placebo). The rate of complications in the intention-to-treat infected (ITTI) population was reduced when acute bronchitis was included (-2.8%, 95% CI -0.6 to -4.9), but not when it was excluded. The risk of pneumonia was reduced in the ITTI population (-0.9%, 95% CI -0.1 to -1.7) but not in the ITT population. There is no evidence that oseltamivir reduces the likelihood of hospitalization, pneumonia or the combined outcome of pneumonia, otitis media and sinusitis in the ITT population.

The 2012 AHS/AAN Guidelines for Prevention of Episodic Migraine: A Summary and Comparison With Other Recent Clinical Practice Guidelines

Updated guidelines for the preventive treatment of episodic migraine have been issued by the American Headache Society (AHS) and the American Academy of Neurology (AAN). We summarize key 2012 guideline recommendations and changes from previous guidelines. We review the characteristics, methods, consistency, and quality of the AHS/AAN guidelines in comparison with recently issued guidelines from other specialty societies. To accomplish this, we reviewed the AHS/AAN guidelines and identified comparable recent guidelines through a systematic MEDLINE search. We extracted key data, and summarized and compared the key recommendations and assessed quality using the Appraisal of Guidelines Research and Evaluation-II (AGREE-II) tool. We identified 2 additional recent guidelines for migraine prevention from the Canadian Headache Society and the European Federation of Neurological Societies. All of the guidelines used structured methods to locate evidence and linked recommendations with assessment of the evidence, but they varied in the methods used to derive recommendations from that evidence. Overall, the 3 guidelines were consistent in their recommendations of treatments for first-line use. All rated topiramate, divalproex/sodium valproate, propranolol, and metoprolol as having the highest level of evidence. In contrast, recommendations diverged substantially for gabapentin and feverfew. The overall quality of the guidelines ranged from 2 to 6 out of 7 on the AGREE-II tool. The AHS/AAN and Canadian guidelines are recommended for use on the basis of the AGREE-II quality assessment. Recommendations for the future development of clinical practice guidelines in migraine are provided. In particular, efforts should be made to ensure that guidelines are regularly updated and that guideline developers strive to locate and incorporate unpublished clinical trial evidence.

Antidepressant Clinical Trials and Subject Recruitment: Just Who Are Symptomatic Volunteers?

Antidepressant Clinical Trials and Subject Recruitment: Just Who Are Symptomatic Volunteers?

Meta-analysis of efficacy and safety of intravenous ferric carboxymaltose (Ferinject) from clinical trial reports and published trial data.

BackgroundRecommendations given for intravenous iron treatment are typically not supported by a high level of evidence. This meta-analysis addressed this by summarising the available date from clinical trials of ferric carboxymaltose using clinical trial reports and published reports.MethodsClinical trial reports were supplemented by electronic literature searches comparing ferric carboxymaltose with active comparators or placebo. Various outcomes were sought for efficacy (attainment of normal haemoglobin (Hb), increase of Hb by a defined amount, for example), together with measures of harm, including serious adverse events and deaths.ResultsFourteen studies were identified with 2,348 randomised patients exposed to ferric carboxymaltose, 832 to oral iron, 762 to placebo, and 384 to intravenous iron sucrose. Additional data were available from cohort studies. Intravenous ferric carboxymaltose was given up to the calculated iron deficit (up to 1,000 mg in one week) for iron deficiency anaemia secondary to chronic kidney disease, blood loss in obstetric and gynaecological conditions, gastrointestinal disease, and other conditions like heart failure. The most common comparator was oral iron, and trials lasted 1 to 24 weeks. Intravenous ferric carboxymaltose improved mean Hb, serum ferritin, and transferrin saturation levels; the mean end-of-trial increase over oral iron was, for Hb 4.8 (95% confidence interval 3.3 to 6.3) g/L, for ferritin 163 (153 to 173) μg/L, and for transferrin saturation 5.3% (3.7 to 6.8%). Ferric carboxymaltose was significantly better than comparator in achievement of target Hb increase (number needed to treat (NNT) 6.8; 5.3 to 9.7) and target Hb NNT (5.9; 4.7 to 8.1). Serious adverse events and deaths were similar in incidence in ferric carboxymaltose and comparators; rates of constipation, diarrhoea, and nausea or vomiting were lower than with oral iron.ConclusionsThis review examined the available trials of intravenous ferric carboxymaltose using details from published papers and unpublished clinical trial reports. It increases the evidence available to support recommendations given for intravenous iron treatment, but there are limited trial data comparing different intravenous iron preparations.

Antiemetics for reducing vomiting related to acute gastroenteritis in children and adolescents.

Vomiting is a common manifestation of acute gastroenteritis in children and adolescents. When untreated it can be a hindrance to oral rehydration therapy, which is the cornerstone in the management of acute gastroenteritis. Evidence is needed concerning the safety and efficacy of antiemetic use for vomiting in acute gastroenteritis in children. To assess the safety and effectiveness of antiemetics on gastroenteritis induced vomiting in children and adolescents. We searched the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group Trials Register comprising references identified from comprehensive electronic database searches and hand searches of relevant journals and abstract books of conferences.The search was re-run and is up to date as on 20 July 2010. Randomized controlled trials comparing antiemetics with placebo or no treatment, in children and adolescents under the age of 18, for vomiting due to gastroenteritis. Two review authors independently assessed trial quality and extracted data. We included seven trials involving 1,020 participants. Mean time to cessation of vomiting in one study was 0.34 days less with dimenhydrinate suppository compared to placebo (P value = 0.036). Pooled data from three studies comparing oral ondansetron with placebo showed: a reduction in the immediate hospital admission rate (RR 0.40, NNT 17, 95% CI 10 to 100) but no difference between the hospitalization rates at 72 hours after discharge from the Emergency Department (ED); a reduction in IV rehydration rates both during the ED stay (RR 0.41, NNT 5, 95% CI 4 to 8), and in follow-up to 72 hours after discharge from the ED stay (worst-best scenario for ondansetron RR 0.57, NNT 6, 95% CI 4 to 13) and an increase in the proportion of patients with cessation of vomiting (RR 1.34, NNT 5, 95% CI 3 to 7)). No significant difference was noted in the revisit rates or adverse events, although diarrhea was reported as a side effect in four of the five ondansetron studies. In one study the proportion of patients with cessation of vomiting in 24 hours was (58%) with IV ondansetron, (17%) placebo and (33%) in the metoclopramide group (P value = 0.039). Oral ondansetron increased the proportion of patients who had ceased vomiting and reduced the number needing intravenous rehydration and immediate hospital admission. Intravenous ondansetron and metoclopramide reduced the number of episodes of vomiting and hospital admission, and dimenhydrinate as a suppository reduced the duration of vomiting.

Performance Measures for Cardiology Focus on Improving Patient Outcomes

M. Schwartz, MD, MS, of Dartmouth Medical School in Hanover, NH, have noted that while the FDA has been criticized for being too close to industry, its reviews are a unique source of published and unpublished data about drug performance (a search page for FDA reviews of drugs is available at http://www .accessdata.fda.gov/scripts/cder /drugsatfda/index.cfm), and readers can learn of the reviewers’ opinions of the drugs they evaluated (Woloshin S and Schwartz LM. Arch Intern Med. 2009; 169[21]:1985-1987). However, they also noted that the FDA should make its reviewers’ knowledge more accessible through standardized executive summaries of drug reviews. Other critics point out that the FDA does not make available unpublished clinical trial data that are not discussed at advisory committee meetings. “The FDA is now somewhat more transparent, but it’s not transparent enough,” said Steven Nissen, MD, chair of the department of cardiovascular medicine at the Cleveland Clinic. “For reasons I can’t understand, it still keeps information secret,” he added. The FDA recently formed an internal Transparency Task Force to develop recommendations for making information about FDA activities and decision making more readily available while protecting confidential information (http: //tinyurl.com/3mazd5q). According to Avorn, this initiative focuses primarily on access to reports of adverse events that are spontaneously provided by physicians and patients after a drug has been approved. “Of greater concern are adverse events identified by drug companies during the clinical trials that they conduct,” he said. “This is more relevant information, but it is also where company ownership of data often comes into conflict with the public’s right to know, and the public often loses that battle.”

Targeted therapies in systemic lupus erythematosus: successes, failures and future

PurposeThe author's goal is to review recent phase III clinical trials in patients with systemic lupus erythematosus (SLE), with emphasis on outcomes and on mechanisms by which the experimental drugs/biological...

Acupuncture for Posttraumatic Stress Disorder: Conceptual, Clinical, and Biological Data Support Further Research

Posttraumatic stress disorder (PTSD) is common, debilitating, and has highly heterogeneous clinical and biological features. With the exception of one published preliminary clinical trial, rationale in support of the efficacy of acupuncture, a modality of Chinese medicine (CM), for PTSD has not been well described. This is a focused review of conceptual and clinical features of PTSD shared by modern western medicine (MWM) and CM, and of biological mechanisms of acupuncture that parallel known PTSD pathology. MWM and CM both recognize individual developmental variables and interactions between external conditions and internal responses in the genesis of PTSD. There is one published and one unpublished clinical trial that preliminarily support the efficacy of acupuncture for PTSD. Although there have been no mechanistic studies of acupuncture in human PTSD, extant research shows that acupuncture has biological effects that are relevant to PTSD pathology. Conceptual, clinical, and biological data support possible efficacy of acupuncture for PTSD. However, further definitive research about simultaneous clinical and biological effects is needed to support the use of acupuncture for PTSD in health care systems.

Efficacy of Second Generation Antidepressants in Late-Life Depression: A Meta-Analysis of the Evidence

Objective:Second-generation antidepressants are commonly used to treat major depression in late-life. This systematic review and meta-analysis was undertaken to assess the evidence for efficacy of second-generation antidepressants in late-life major depression. Methods:The Cochrane Library (2006 (3)), MEDLINE (1966 to August 2006), and meeting presentations were searched for trials of second-generation antidepressants (nontricyclics) marketed in the United States. Published and unpublished placebo-controlled randomized clinical trials in outpatients 60 years and older, with nonpsychotic, unipolar major depression were selected. Clinical characteristics and outcomes were extracted. Outcomes were expressed as odds ratios (OR), risk differences, and weighted mean differences. Results:Ten unique trials (four unpublished) with 13 contrasts met selection criteria. Trials were 6–12 weeks duration, and included 2,377 patients who received active drug and 1,788 received placebo. The ORs by meta-analysis for respon...

Meta‐Analysis of a Possible Signal of Increased Mortality Associated with Cefepime Use

On the basis of meta-analyses, concern has been raised regarding a possible signal of increased mortality associated with the use of cefepime versus other beta-lactam antibiotics. To further investigate this possible signal, we accessed findings and data from published and unpublished cefepime clinical trials. We performed meta-analyses using trial- and patient-level data from comparative trials. Trial-level analyses were performed using summary data from all patients in the trials, and patient-level analyses were performed on trials for which patient-level data were available. Thirty-day, all-cause mortality was analyzed using the Mantel-Haenszel adjusted risk difference (ARD) method. The trial-level meta-analysis was based on 88 trials (9467 cefepime patients and 8288 comparator patients). The 30-day, all-cause mortality rates were 6.21% (588/9467) for the cefepime patients and 6.00% (497/8288) for comparator patients (ARD per 1000 population, 5.38; 95% confidence interval [CI], -1.53 to 12.28). In the patient-level analysis (35 trials, 5058 cefepime patients, and 3976 comparator patients), 30-day, all-cause mortality rates were 5.63% (285/5058) for cefepime patients and 5.68% (226/3976) for comparator patients (ARD per 1000 population, 4.83; 95% CI, -4.72 to 14.38). A sensitivity analysis based solely on the 24 febrile neutropenia trials did not show a statistically significant increase in mortality with cefepime use (ARD per 1000 population, 9.67; 95% CI, -2.87 to 22.21). In both trial-level and patient-level meta-analyses, we did not identify a statistically significant increase in mortality among cefepime-treated patients, compared with those treated with other antibacterials.

Platelet-Rich Plasma in Sinus Augmentation Procedures: A Systematic Literature Review: Part II

Although platelet-rich plasma (PRP) has been extensively studied for over a decade, there are no definitive reports, which prove the benefit of using PRP in sinus augmentation procedures. In addition, no systematic literature review has been done to report the benefit of treatment outcome in patients who received PRP in conjunction with bone/bone substitutes in maxillary sinus augmentation procedures. Therefore, it can be rightly stated that evidence for an adjunctive benefit of using PRP with bone grafts in sinus augmentation procedures is equivocal and inconclusive. : The objective of this systematic literature review was to examine this literature in determining whether PRP with bone and bone substitutes leads to more rapid and effective bone regeneration clinically, radiographically, and histologically with sinus augmentation procedures and was there any clinical data parallel to animal experiments providing clinical evidence in sinus augmentation procedures? A systematic review of randomized clinical trials of at least 6 months duration was conducted comparing PRP and bone/bone substitutes (test group) to bone/bone substitutes (control group) alone. Electronic databases such as MEDLINE and CENTRAL (Cochrane central register of controlled clinical trials) were searched for relevant articles. The reference list of all included articles was searched along with unpublished clinical trials whose abstracts were available. Although, there is a lack of human studies, which show benefit of using PRP in conjunction with bone grafting materials, it can be stated that use of PRP does lead to early regeneration and reduction in healing time of soft and hard tissues. However, no significant statistical or clinical benefit was reported from studies that would satisfy the inclusion criteria. This study answers the question very clearly that at this point of time, there is no human study that strongly supports the benefit of using PRP in sinus augmentation procedures. There is a paucity of clinically controlled trials regarding benefits of PRP in sinus augmentation procedures. Theoretically, it seems to have significant beneficial effects on the soft and hard tissue healing; however, the disparity in study design, surgical techniques, and different outcome assessment variables used, makes it difficult to assess the practical benefit of its clinical use. Although no obvious positive effects of PRP on healing of bone graft material in maxillary sinus augmentation procedures were noted, the handling of the particulate bone grafts was improved.

Dronedarone: Current Evidence and Future Questions

Atrial fibrillation (AF) is the most common sustained arrhythmia, affecting more than 2.2 million Americans. ACC/AHA/ESC guidelines for the management of patients with AF recommend amiodarone for maintaining sinus rhythm. Dronedarone is a derivative of amiodarone indicated for the treatment of AF. To provide an overview of dronedarone with a focus on the phase III trials and discuss unresolved questions of dronedarone. A literature search was conducted via the PubMed database using the keyword "dronedarone." Search was limited to human trials in english. The FDA website was searched for briefing documents and subcommittee meetings on dronedarone. Clinicaltrials.gov was searched with the keyword dronedarone for upcoming or unpublished clinical trials. Five phase III trials are available for dronedarone: ANDROMEDA, EURIDIS/ADONIS, ATHENA, ERATO, and DIONYSIS. EURIDIS/ADONIS and ATHENA demonstrated a reduction AF recurrence with dronedarone compared to placebo. The ANDROMEDA trial recruited patients with recent hospitalization for heart failure and was terminated due to an excess of deaths in the dronedarone group. The DIONYSIS trial was a comparative effectiveness trial that demonstrated less efficacy for dronedarone but improved tolerability compared to amiodarone. Dronedarone represents an option in the management of AF in select patients. Dronedarone is not appropriate in patients with recently decompensated heart failure or those treated with strong CYP3A4 inhibitors or medications prolonging the QT interval. Dronedarone appears to have improved tolerability at the expense of decreased efficacy when compared to amiodarone. Questions remain on the long-term safety, use in patients with heart failure, retreatment after dronedarone or amiodarone failure, and comparative efficacy with a rate control strategy.

Egg-allergic patients gain greater access to H1N1 vaccine after completion of clinical trial

Egg-allergic Quebecers have obtained greater access to the pandemic (H1N1) 2009 vaccine as a result of the first rapid clinical trial completed by Canada’s new influenza research network, which hopes its work will extend access to similar patients across Canada. The unpublished clinical trial,

Use of granisetron transdermal system in the prevention of chemotherapy-induced nausea and vomiting: a review

Use of granisetron transdermal system in the prevention of chemotherapy-induced nausea and vomiting: a review Albert TucaPalliative Care Hospital Team, Palliative Care Department, Institut Catal&agrave; d&rsquo;Oncologia, L&rsquo;Hospitalet de Llobregat, Barcelona, SpainAbstract: Until now only intravenous and oral formulations of 5HT3 receptor antagonists have been available. Recently a new formulation of a 5HT3 receptor antagonist, transdermal granisetron, has been developed, and approved by the FDA. Three phase I studies to evaluate its pharmacokinetic profile have shown that granisetron administered by a transdermal delivery system is absorbed by passive diffusion and maximal concentration is reached 48 hours after patch application. The patch of 52 cm2, which contains 34.3 mg of granisetron, releases 3.3 mg of the drug every day and maintains a stable average plasma concentration of 2.2 ng/mL over 6 days, similar to levels obtained with 2 mg of oral granisetron, administered every day during the same period of time. Two randomized as yet unpublished clinical trials (phase II/III) have been conducted to evaluate the antiemetic efficacy of transdermal granisetron in chemotherapy-induced nausea and vomiting, in patients receiving moderately and highly emetogenic chemotherapy, compared with 2 mg of oral granisetron. More than 800 cancer patients were included in the trials. The rate of complete control of acute emesis was 49% for the phase II trial and 60% for the phase III trial. Neither trial showed a statistically significant difference between transdermal and oral granisetron. The control of delayed emesis was observed in 46% of patients, and there were no statistically significant differences between transdermal and oral granisetron. The most common adverse effects in both trials were constipation (&lt;7%) and headache (&lt;1%); there were no statistically significant differences between transdermal and oral granisetron. These data show that transdermal granisetron is effective and safe in controlling acute emesis induced by chemotherapy with both moderate and high emetogenic potential. Efficacy and safety of transdermal granisetron are fully comparable with that of oral granisetron. More clinical trials using regimens of 2 or 3 drugs, including dexamethasone and/or aprepitant, are needed to confirm the place of transdermal granisetron in the control of chemotherapy-induced nausea and vomiting.Keywords: cancer chemotherapy induced nausea and vomiting, selective antagonists of 5HT3 receptors, granisetron, transdemal delivery system