Reviews on Recent Clinical Trials - Volume 8, Issue 2, 2013

Objective: In this retrospective study, we aimed to evaluate platelet changes in patients taking clozapine for a variety of psychiatric disorders and hypothesized that there would be any changes in the course of the treatment. Methods: Diagnoses were based on Diagnostic and Statistical Manual of Mental Disorders 4th edition. Forty-three patients, with the mean age of 3 6.23±6.35 years were included into final analysis. Morning venous blood samples were used for platelet counts. Correlation analyses were performed between platelet counts and clozapine doses. Results: Paired t test did not reveal a significant change in platelet counts at the end visit compared to those of first assessment (p>0.05). Seven (17.9%) of 39 patients had platelet count below 180000 per cubic millimeter at least one time during their clozapine use. In five of these patients, the platelet count returned to a level above 180000 per cubic millimeter, without any dose change or other interventions. On the other hand, as for the issue of increased platelet count, results demonstrated that seven (17.9%) had platelet count above 400000 per cubic millimeter at least one time during clozapine use. Conclusion: The present investigation revealed that platelet changes beyond WBC changes should be taken into consideration when using clozapine. Clinicians should be aware of the deviations from absolute threshold values.

Given the increasing prevalence of atrial fibrillation, the need for safe and effective stroke prophylaxis will continue to rise. Warfarin has been around for many years and has proven efficacy in preventing stroke, but it has major limitations due to its variable dosing, food and drug interactions, and requirement for regular monitoring. Newer agents which include dabigatran, rivaroxaban, and apixaban have recently or will soon be available and may provide an improved efficacy in stroke prevention, an improved safety profile, and improved user-friendliness. Dabigatran was the first of the agents to be widely available, and in the RE-LY study, dabigatran (150 mg dose) showed superiority to warfarin in preventing ischemic stroke and a significant reduction in intracranial bleeding. Rivaroxaban was studied in the ROCKETAF trial, and with once daily dosing, it showed noninferiority to warfarin in preventing stroke with a significant reduction in intracranial bleeding. The ARISTOTLE trial showed apixaban was superior to warfarin for stroke prevention, significantly reduced all major bleeding, and resulted in a significant reduction in all-cause mortality. While all three trials have important limitations, they were very large randomized trials with more than 14,000 patients each and show a clear overall net clinical benefit when compared with warfarin. Key features of the drugs as well as an individual’s preferences and stability on warfarin will help guide the ultimate drug choice for any given patient, but these newer anticoagulant agents are likely to usher in a new era in stroke prevention in atrial fibrillation.

Bleeding complications in patients with acute coronary syndromes are a significant predictor of mortality. Trans-radial approach (TRA) is a promising strategy to reduce bleedings in patients undergoing invasive coronary procedures. Recently, two multicentre prospective randomized trials aimed to test whether TRA, compared to trans-femoral approach (TFA), may improve clinical outcome in patients with ST-elevation myocardial infarction: the RIFLE STEAC and STEMI-RADIAL. In the RIFLE STEACS, the primary endpoint of 30-day NACEs occurred in 68 patients (13.6%) in the TRA arm and 105 patients (21.0%) in the TFA arm (p = 0.003). In particular, compared with TFA, TRA was associated with significantly lower rates of cardiac mortality (5.2% vs. 9.2% , p = 0.020), bleeding (7.8% vs. 12.2%, p = 0.026), and shorter hospital stay (5 days, [range, 4 to 7 days]; vs. 6 [range, 5 to 8 days]; p = 0.03). In the STEMI-RADIAL, the primary endpoint of major bleeding or access site complications occurred in 7.2 percent of the TFA patients and 1.4 percent of the TRA patients (p=0.0001). The rate of MACE at 30 days was 4.2 percent in the TFA group, a nd 3.5 percent in the TRA group (p=0.7). The results of two recent trials support the systematic adoption of TRA instead of TFA approach to improve the clinical outcome of STEMI patients. In the present paper, we overview the results of these two trials and put them in the context of previous scientific evidences collected in this field.

During the past few years, oncologists have witnessed the reclassification of non small cell lung cancer (NSCLC) as not one disease, but several molecularly defined subsets of disease with relevant therapeutic implications in the field of molecularly targeted therapies. Two not very common genetically defined subsets of NSCLC, including those with EGFR or ALK activating mutations, and show high sensitivity to tyrosine-kinase inhibitors such that patients frequently have sustained clinical responses to therapy. However, the largest subset harbours an activating KRAS mutation and up to now, no successful targeted therapy has been developed for RAS-mutant lung cancer, with few compounds being assessed by clinical trials. In fact, KRAS has remained an elusive target for cancer therapy for biologic reasons. The chief value of KRAS lies in providing information about the other biomarkers that are directly druggable, that is, EGFR and ALK. The presence of mutated KRAS rules out ALK and EGFR, and KRAS may therefore form part of an efficient pathway in a testing algorithm. Currently, KRAS itself remains undruggable despite decades of effort, but attention has recently focused on inhibition of the Ras-contingent downstream signalling. Selumetinib (AZD6244; ARRY-142886) is an oral, tight-binding, uncompetitive inhibitor of mitogen-activated protein kinase kinases (MEK) 1 and 2, downstream of KRAS, with preclinical evidence of synergistic activity with docetaxel in KRAS-mutant cancers and currently in clinical development. The Ras/RAF/MEK/ERK pathway is frequently deregulated in cancer and a number of inhibitors that target this pathway are currently in clinical development. Recently, in a randomised, phase II trial selumetinib plus docetaxel has proven to improve progression free survival compared to docetaxel alone in previously treated patients with advanced KRAS-mutant NSCLC.

Introduction: Cetuximab and irinotecan are effective agents in advanced colorectal cancer (CRC) after either irinotecanor oxaliplatin-based first-line chemotherapy. Here, the efficacy of this combination in patients with the KRAS wild-type gene as second- or further-line therapy is reviewed and data are collected in a pooled analysis. Methods: Studies that enrolled pretreated CRC patients for second-line therapy or beyond were identified using electronic databases (PubMed and EMBASE). A systematic analysis was conducted using Comprehensive Meta Analysis (version 2.2.064) to calculate the event rate of response and the 95% confidence interval. The weighted median overall survival (OS) and progression-free survival (PFS) were also calculated with NCSS 2007 software. We tested for significant heterogeneity using Cochran’s chi-square test and the I² index. Results: Twenty-five studies published between 2007 and 2012 were eligible for this analysis, with a total of 1,712 KRAS wild-type patients enrolled. The overall response rate was 31.9% with similar response rates of 28.7% for second-line treatment and 31.1% for third or further lines. The overall weighted median OS and PFS were 12.5 and 6 months with a weighted OS of 11.56 and 12.2 months for second- and further-line CRC settings, respectively. Conclusion: In metastatic KRAS wild-type CRC patients pretreated with one or more lines of therapy, cetuximab plus irinotecan-based chemotherapy is an active treatment. Response rates and survival outcomes appear similar in second-line therapy or beyond.

Alzheimer’s disease (AD) is the leading cause of dementia worldwide. Clinically, it is characterized by progressive cognitive impairment and the emergence of neuropsychiatric disturbances. In recent years, many drug candidates aimed at disease modification have advanced into large, randomized controlled trials, but none have demonstrated efficacy in slowing down the relentless progression of AD. While the exact cause of AD is still being fervently investigated, the field is moving toward earlier identification and treatment of the disease, as it is believed this may be the main reason for so many clinical trial failures. There are currently four main mechanisms of action that are being actively developed in AD therapeutics: Drugs aimed at reducing Aβ production, notably secretase inhibitors; Drugs aimed at reducing Aβ plaque burden via inhibition of aggregatio or disruption of aggregates; Drugs aimed at promoting Aβ clearance via active or passive immunotherapy; and Drugs aimed at preventing tau protein phosphorylation. In this review, recent findings from clinical and preclinical studies in each of these categories will be discussed, as well as a category entitled ‘ other therapies,’ that includes treatments that do not fit under a single mechanism of action, but represent rational interventions for the underlying pathology of Alzheimer’s disease.

Somatic treatments other than psychotropic drugs are increasingly used in the patients with obsessive compulsive disorder (OCD), however there has been little systematic review of them. Therefore, the present review deals with a variety of somatic treatment methods excluding psychotropic drugs. A literature search was performed on the PubMed database from the beginning of 1980, to September 2012, for published English, Turkish and French-language articles of somatic treatment approaches (excluding psychopharmacological agents) in the treatment of OCD. The search was carried out by using some terms in detail. Afterwards, the obtained investigations on electroconvusive therapy (ECT), deep brain stimulation (DBS), neurosurgical methods and transcranial magnetic stimulation (TMS) were presented. Although psychopharmacological treatment and psychotherapeutic approaches are primary treatment modalities in the management of OCD, other somatic treatment options seem to be used as alternatives, especially for patients with treatmentresistant OCD.

In the present article, structural, neurochemical and functional neuroimaging investigations performed on patients with social anxiety disorder were reviewed. A PubMed search was performed to identify all structural and functional neuroimaging studies published between 1980 and February 2013. The studies and case reports on neuroimaging in social anxiety disorder were grouped under the subheadings of structural, functional and magnetic resonance spectroscopic imaging. It seems that structural studies involve examination of abnormalities in the basal ganglia structures like caudate nucleus, thalamus, and putamen, hippocampus and amygdala abnormalities in summary. Neurochemical investigations reveal the deficiencies in the GABAergic system and over-activation in the glutamatergic system in social anxiety disorder. Functional neuroimaging investigations implicate the role of limbic-medial prefrontal circuit.

The high incidence of cardiovascular disease and colorectal cancer in the world's population means that these two conditions may coexist in the same patient. In addition fluoropyrimidines, backbone for the treatment of colorectal cancer in both early stage and advanced disease, have a well-characterized cardio-toxicity, which limits their use in patients with heart disease and limits their reintroduction in those patients who have shown this toxicity. For the treatment of this, increasing proportion of patients is now possible to consider fluoropyrimidines-free chemotherapy regimens that are examined in this work, with the attempt to provide a possible treatment algorithm for various situations encountered in clinical practice.