Neuroprotective effects of combined trimetazidine and progesterone on cerebral reperfusion injury.

Cerebral ischemia-reperfusion injury induces multi-dimensional damage to neuronal cells through exacerbation of critical protective mechanisms. Targeting more than one mechanism simultaneously namely, inflammatory responses and metabolic energy homeostasis could provide additional benefits to restrict or manage cerebral injury. Being proven neuroprotective agents both, progesterone (PG) and trimetazidine (TMZ) has the potential to add on the individual therapeutic outcomes. We hypothesized the simultaneous administration of PG and TMZ could complement each other to synergize, or at least enhance neuroprotection in reperfusion injury. We investigated the combination of PG and TMZ on middle cerebral artery occlusion (MCAO) induced cerebral reperfusion injury in rats. Molecular docking on targets of energy homeostasis and apoptosis assessed the initial viability of PG and TMZ for neuroprotection. Animal experimentation with MCA induced ischemia-reperfusion (I/R) injury in rats was performed on five randomized groups. Sham operated control group received vehicle (saline) while the other four I-R groups were pre-treated with vehicle (saline), PG (8 â€‹mg/kg), TMZ treated (25 â€‹mg/kg), and PG â€‹+ â€‹TMZ (8 and 25 â€‹mg/kg) for 7 days by intraperitoneal route. Neurological deficit, infarct volume, and oxidative stress were evaluated to assess the extent of injury in rats. Inflammatory reactivity and apoptotic activity were determined with alterations in myeloperoxidase (MPO) activity, blood-brain barrier (BBB) permeability, and DNA fragments. Reperfusion injury inflicted cerebral infarct, neurological deficit, and shattered BBB integrity. The combination treatment of PG and TMZ restricted cellular damage indicated by significant (p â€‹< â€‹0.05) decrease in infarct volume and improvement in free radical scavenging ability (SOD activity and GSH level). MPO activity and LPO decreased which contributed in improved BBB integrity in treated rats. We speculate that inhibition of inflammatory and optimum energy utilization would critically contribute to observed neuroprotection with combined PG and TMZ treatment. Further exploration of this neuroprotective approach for post-recovery cognitive improvement is worth investigating.

Safety of Routine Invasive Versus Selective Invasive Therapy in Women with Non-ST-Elevation Acute Coronary Syndrome.

INTRODUCTION: Prior studies suggested that a routine invasive approach in the management of non-ST-elevation acute coronary syndrome (NSTE-ACS) is beneficial in men, but the data are less conclusive in women. One study conducted exclusively in women found that routine invasive therapy was associated with a markedly increased risk of major bleeding. This pilot randomized controlled trial compared the safety of a routine invasive versus a selective invasive strategy among women. METHODS: Women with NSTE-ACS and an additional high-risk characteristic were randomized to a routine invasive versus a selective invasive strategy. The primary outcome was the risk of major bleeding. The secondary outcome was the first occurrence of all-cause death, myocardial infarction, stroke, re-hospitalization for ACS, or major bleeding within 6 months. RESULTS: Twenty-three women were assigned to routine invasive therapy and 17 to selective invasive therapy. Twenty-seven women (68%) had elevated troponin T (mean 0.33 ng/mL) and/or creatinine kinase-MB (mean 23 ng/mL). The risk of major bleeding was similar with both approaches (P = 0.99). At 6 months, the secondary outcome occurred in 9% of the routine invasive group versus 18% of the selective invasive group (risk ratio = 0.49, 95% confidence interval 0.09-2.63, P = 0.63). CONCLUSION: This pilot study demonstrated that a routine invasive approach is safe in women. There was suggestion of benefit from routine invasive therapy compared with selective invasive therapy. These data could be used to design an appropriately powered trial to determine the optimal management strategy among women with NSTE-ACS.

Risk Based Monitoring (RBM): A global study focusing on perception and merits among clinical investigational sites.

BACKGROUND: Several approaches to clinical trial monitoring, including the Risk Based Monitoring (RBM) are aimed at the protection of the human subjects (safety), improved data quality, and ultimately, reducing the cost of drug development and operations. There exists minimal evidence globally about the perceptions and the level of confidence among the clinical staff on the merits of RBM. The present study assessed the perception among clinical research staff globally (developed and emerging countries) on the applicability and adaptability of RBM. METHODS: An electronic questionnaire survey consisting of twelve items was developed, validated, and then circulated globally via email to three thousand clinical research staff members at various investigational sites. This survey collected information on the use of RBM and factors that relate to clinical trial cost, data quality, subject safety, and the readiness to adopt RBM practices. The survey responses were summarized and analyzed by using the information e.g. responder's age, sex, clinical research role, global location, and experience in clinical research trials. RESULTS: Responses were received from ten countries, six emerging and four developed. Of the 3000 surveys sent to emerging (1,000) and developed (2,000) countries, a total response of 595 (261 vs 334) participants was received, respectively. The emerging versus developed group had 100 vs 137 participants with complete responses (CR); 34 vs 35 participants with partial responses (PR); and 127 vs 162 participants were disqualified with no exposure (NE) responses. About 67% of the overall responders were investigators, followed by 23%, 10% coordinator and other staff respectively. There was not significant difference in feedback between the researchers in developing versus emerging countries (p = 0.20) with regards to their perception of RBM reducing the overall cost of conducting a clinical research. Responders from emerging countries had a more favorable response than in the developed countries. Similarly, when asked if RBM will be more effective in addressing data quality (p = 0.006), patient safety (p = 0.05) and findings fraud/fabrication (p = 0.01), researchers from emerging countries indicated more confidence than researchers from developed countries. There was also a significant difference in the readiness to adopt RBM between responders of emerging versus developed markets (p < 0.0001). CONCLUSION: This unique study performed across ten emerging and developed countries strongly supported the need for systematic global training, education, and implementation of RBM regulatory guidance, with an aim for better safety of subjects and improved quality of clinical trial data. Furthermore, studies with larger sample sizes are recommended to provide an evidence-based approach.

A Cohort Study of Myocardial Perfusion Imaging in Veteran Patients Without Symptoms: Contributing Factors and Results of Testing.

Myocardial perfusion imaging (MPI) is commonly used to detect ischemia. Concerns about silent ischemia may encourage orders for MPI in asymptomatic patients. Factors contributing to this practice are poorly described and the clinical utility is questionable.We conducted a single center retrospective cohort investigation on Veterans who underwent MPI between December 2010 and July 2011. We gathered data on symptoms, baseline characteristics, results of MPI, and cardiovascular events within 1 year. MPI were categorized using 2009 appropriate use criteria (AUC).Of 592 patients, 127 (21.5%) had no symptoms at the time of MPI. Comparing symptomatic and asymptomatic patients, no differences were observed in baseline characteristics except abnormal ECG, more common in asymptomatic patients (n = 86, 67.7% vs. n = 232, 49.9% for symptomatic patients, P < 0.0001). Asymptomatic MPI were more commonly inappropriate (n = 26, 21.5% vs. n = 31, 6.7% for appropriate/uncertain, P < 0.0001). Detection of ischemia between patients with and without symptoms was not different (P = 0.86); however, among asymptomatic MPI that also demonstrated ischemia, none were inappropriate (n = 10 appropriate, n = 7 uncertain). In multivariate regression, 2 factors were associated with asymptomatic status, abnormal ECG (odds ratio [OR] 2.29, 95% confidence interval [CI] 1.5-3.49) and age over the median (OR 0.63, 95% CI: 0.41-0.95).A substantial portion of MPI tests are ordered for patients without symptoms. When compared to symptomatic patients, MPI for asymptomatic patient were more commonly inappropriate; however, the prevalence of ischemia was similar. MPI may be clinically relevant in some asymptomatic patients and decisions to test should be based on the AUC.

Critical Appraisal of Bivalirudin versus Heparin for Percutaneous Coronary Intervention: A Meta-Analysis of Randomized Trials.

Percutaneous coronary intervention with bivalirudin plus bail-out glycoprotein IIb/IIIa inhibitors has been shown to be as effective as unfractionated heparin plus routine glycoprotein IIb/IIIa inhibitors in preventing cardiac ischemic events, but with a lower bleeding risk. It is unknown whether bivalirudin would have the same beneficial effects if compared with heparin when the use of glycoprotein IIb/IIIa inhibitors was similar between treatment arms. We searched the MEDLINE, Web of Science, and Cochrane databases from inception until March 2015 for randomized trials that compared bivalirudin to heparin in patients undergoing percutaneous coronary intervention. We required that the intended use of glycoprotein IIb/IIIa inhibitors was similar between the study groups. Summary estimates were principally constructed by the Peto method. Fifteen trials met our inclusion criteria, which yielded 25,824 patients. Bivalirudin versus heparin was associated with an increased hazard of stent thrombosis (odds ratio [OR] 1.49, 95% confidence interval [CI] 1.15-1.92, P = .002, I2 = 16.9%), with a similar hazard of myocardial infarction (OR 1.09, 95% CI 0.98-1.22, P = .11, I2 = 35.8%), all-cause mortality (OR 0.88, 95% CI 0.72-1.08, P = .21, I2 = 31.5%) and major adverse cardiac events (OR 1.04, 95% CI 0.94-1.14, P = .46, I2 = 53.9%). Bivalirudin was associated with a reduced hazard of major bleeding (OR 0.80, 95% CI 0.70-0.92, P = .001, I2 = 63.5%). The dose of heparin in the control arm modified this association; when the dose of unfractionated heparin in the control arm was ≥ 100 units/kg, bivalirudin was associated with a reduction in major bleeding (OR 0.55, 95% CI 0.45-0.68, P < .0001), but when the dose of unfractionated heparin was ≤ 75 units/kg, bivalirudin was not associated with reduction in bleeding (OR 1.09, 95% CI 0.91-1.31, P = .36). Among patients undergoing PCI, bivalirudin was associated with an increased hazard of stent thrombosis. Bivalirudin may be associated with a reduced hazard of major bleeding; however, this benefit was no longer apparent when compared with a dose of unfractionated heparin ≤ 75 units/kg.

A prospective observational study to assess quality of life and prescription pattern in osteoarthritis patients at tertiary health centre in Mumbai.

BACKGROUND: Osteoarthritis (OA) is a major cause of disability and is focused in "Bone and Joint Decade" declared by WHO which substantially affect different dimensions of quality of life. The aim of present study was to find the disease pattern in OA patients, monitoring prescription pattern to assess prognosis of osteoarthritis by WOMAC index. MATERIALS AND METHODS: An observational study on prospective data collected for the evaluation of Quality of Life (QOL) in OA was conducted at tertiary health care centre in Mumbai. Patients with a diagnosis of OA were enrolled. The patient's history and clinical examination was based on classification criteria of the American College of Rheumatology; drugs prescribed were noted on case record form. Same procedure was carried out for the first and second follow-ups at 6 th and 12 th weeks respectively. RESULTS: The patients belong to primary OA (84%) as compared to secondary OA (16%). Females (70.56% and 10%) were affected more commonly than males (13.44% and 6%). Knee Joint was worst affected in 76%, followed by hip joint in 16% and shoulder, ankle, wrist, elbow joint each having 2% (n=1) involvement. NSAIDs continued to dominate prescriptions given to 84% of patients followed by antiarthritic drugs and calcium supplements in 54% cases. The WOMAC score was higher in most of patients. After medication hydroxy chloroquine sulfate has shown maximum reduction in average WOMAC sore followed by paracetamol, indomethacin and diclofenac sodium. CONCLUSION: Osteoarthritis has a significant impact on quality of life, only partly ameliorated by anti-arthritic drugs, as assessed by the WOMAC scale in this study population. Further, a study with larger sample size is needed to further support our findings.