A review on pharmacophoric designs of antiproliferative agents

Past few decades have witnessed the dawn of new diseases in which cancer is a major problem and the race ensued to eradicate cancer by charting out various effective therapeutic regimens. Circumventing resistance issues and combating the toxicity and selectivity problems are matter-of-concern in cancer treatment. Persistent failure to ensure complete remission and eradication of cancer instigated the researchers to exploit the strategies of combining pharmacophores as targeted therapeutic agents. Momentous improvement in the pharmacokinetic as well as pharmacodynamic profile resulting in the enhancement of bioavailability was seen with the introduction of these pharmacophores. The scope of molecular hybridization can be clearly exemplified through the US-FDA approved estramustine and others such as CUDC-101, CBLC-137, PLX3397, E-3810, and CUDC-907 that are currently in different phases of clinical trials. This review seeks to highlight and discuss anti-proliferative activity of some important hybrid, dual, and multi-targeted pharmacophores reported to date along with their designs, structure activity relationships, scope, and limitations. Further, an emphasis has been made to summarize US-FDA approved as well as drugs currently undergoing clinical trials of anticancer drug development.     

Patent foramen ovale in a large population of ischemic stroke patients: diagnosis, age distribution, gender, and race

BACKGROUND: Patent foramen ovale (PFO) is a well-recognized risk factor for ischemic strokes. The true prevalence of PFO among stroke patients is still under debate. Transesophageal echocardiography (TEE) is the "gold standard" in diagnosing PFO but the physiology requires right-to-left atrial shunting. In this report, we evaluate the prevalence of PFO in a diverse group of ischemic stroke patients studied by TEE. METHODS: TEE of 1,663 ischemic stroke patients were reviewed for cardiac source of embolism, including PFO and atrial septal aneurysm (ASA). Agitated saline bubble injection was performed to look for right to left atrial shunting. Success of maneuvers to elevate right atrial pressure (RAP) was noted by looking at the atrial septal bulge. RESULTS: Among 1,435 ischemic stroke patients analyzed, the presence or absence of PFO could not be determined in 32.1% because bulging of the septum could not be demonstrated in patients with negative contrast study despite aggressive maneuvers to elevate RAP. Of the remaining 974 patients, 294 patients (30.2%) had a PFO. The mean age was 61.5 years in both groups, with a bimodal distribution of PFO and the highest prevalence occurring in < or =30-year-old group. Prevalence of PFO was similar in men (32.4%) and women (28.15%, P = 0.15); and in Caucasian (32.1%) and African American (27.7%; P = 0.15). ASA was present in 2.02% and hypermobile septum in 2.49% of the 1,435 patients. PFO was seen in 79.3% of the patients with ASA. CONCLUSION: Successful elevation of RAP cannot be achieved in a significant number of patients undergoing TEE and determination of PFO may be difficult. In our series, the true prevalence of PFO among ischemic stroke patients was 30.2% taking into account only those patients who showed no shunting despite bulging of the atrium septum into the left atrium (PFO absent group) during the contrast study. There was no gender or racial difference in the prevalence of PFO, but there was a bimodal distribution in prevalence with age.     

Postoperative Atrial Fibrillation or Flutter Following Transcatheter or Surgical Aortic Valve Replacement: PARTNER 3 Trial

ObjectivesThe aim of this study was to assess the incidence and prognostic impact of early and late postoperative atrial fibrillation or flutter (POAF) in patients with severe aortic stenosis (AS) treated with transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (SAVR).BackgroundThere is an ongoing controversy regarding the incidence, recurrence rate, and prognostic impact of early (in-hospital) POAF and late (postdischarge) POAF in patients with AS undergoing TAVR or SAVR.MethodsIn the PARTNER (Placement of Aortic Transcatheter Valve) 3 trial, patients with severe AS at low surgical risk were randomized to TAVR or SAVR. Analyses were performed in the as-treated population excluding patients with preexistent atrial fibrillation or flutter.ResultsAmong 781 patients included in the analysis, early POAF occurred in 152 (19.5%) (18 of 415 [4.3%] and 134 of 366 [36.6%] following TAVR and SAVR, respectively). Following discharge, 58 new or recurrent late POAF events occurred within 1 year following the index procedure in 55 of 781 patients (7.0%). Early POAF was not an independent predictor of late POAF following discharge (odds ratio: 1.04; 95% CI: 0.52-2.08; P = 0.90). Following adjustment, early POAF was not an independent predictor of the composite outcome of death, stroke, or rehospitalization (hazard ratio: 1.10; 95% CI: 0.64-1.92; P = 0.72), whereas late POAF was associated with an increased adjusted risk for the composite outcome (hazard ratio: 8.90; 95% CI: 5.02-15.74; P < 0.0001), irrespective of treatment modality.ConclusionsIn the PARTNER 3 trial, early POAF was more frequent following SAVR compared with TAVR. Late POAF, but not early POAF, was significantly associated with worse outcomes at 2 years, irrespective of treatment modality.     

Exercise and yoga during pregnancy: a survey

The primary objective of this survey was to ascertain the opinions, practices and knowledge about exercise, including yoga, during pregnancy; the secondary objective to compare the responses among women with body mass index (BMI) <30?kg/m² versus ≥30?kg/m². Survey consisted of 20 multiple choice questions assessing demographics and exercise practices, and five questions testing their knowledge about it during pregnancy (ACOG Committee Opinion # 267). Of the 500 surveys distributed, 84% (422) responses were analyzed. While 86% of women responded that exercise during pregnancy is beneficial, 83% felt it was beneficial to start prior to pregnancy, and walking was considered the most beneficial (62%). The majority (64%) of respondents were currently exercising during pregnancy and 51% exercised 2–3 times/week. Among the five questions testing knowledge about prenatal exercise, majority (range 60 to 92%) were aware of ACOG recommendations. About half had a BMI ≥30. Knowledge about benefits of exercise during pregnancy did not differ significantly between obese and non-obese. Yoga was tried significantly more among non-obese, 65% believed it is beneficial, and 40% had attempted yoga before pregnancy. In our population, the majority believes that exercise, including yoga, is beneficial and they are active.     

2-Methoxyestradiol overcomes drug resistance in multiple myeloma cells

2-Methoxyestradiol (2ME2) an estrogen derivative, induces growth arrest and apoptosis in leukemic cells and is also antiangiogenic. In this study, we demonstrate that 2ME2 inhibits growth and induces apoptosis in multiple myeloma (MM) cell lines and patient cells. Significantly, 2ME2 also inhibits growth and induces apoptosis in MM cells resistant to conventional therapies including melphalan (LR-5), doxorubicin (Dox-40 and Dox-6), and dexamethasone (MM.1R). In contrast to its effects on MM cells, 2ME2 does not reduce the survival of normal peripheral blood lymphocytes. Moreover, 2ME2 enhances Dex-induced apoptosis, and its effect is not blocked by interleukin-6 (IL-6). We next examined the effect of 2ME2 on MM cells in the bone marrow (BM) milieu. 2ME2 decreases survival of BM stromal cells (BMSCs), as well as secretion of vascular endothelial growth factor (VEGF), and IL-6 triggered by the adhesion of MM cells to BMSCs. We show that apoptosis induced by 2ME2 is mediated by the release of mitochondrial cytochrome-c (cyto-c) and Smac, followed by the activation of caspases-8, -9, and -3. Finally, 2ME2 inhibits MM cell growth, prolongs survival, and decreases angiogenesis in a murine model. These studies, therefore, demonstrate that 2ME2 mediates anti-MM activity directly on MM cells and in the BM microenvironment. They provide a framework for the use of 2ME2, either alone or in combination with Dex, to overcome drug resistance and to improve outcome in MM.     

Syringe Administration of Epinephrine by Emergency Medical Technicians for Anaphylaxis

Objective: In recent years, the costs of epinephrine autoinjectors (EAIs) in the United States have risen substantially. King County Emergency Medical Services implemented the “Check and Inject” program to replace EAIs by teaching emergency medical technicians (EMTs) to manually aspirate epinephrine from a single-use 1 mg/mL epinephrine vial using a needle and syringe followed by prehospital intramuscular administration of the correct adult or pediatric dose of epinephrine for anaphylaxis or serious allergic reaction. Treatment was guided by an EMT protocol that required a trigger and symptoms. We sought to determine if the “Check and Inject” program was safely implemented by EMTs treating presumed prehospital anaphylaxis or serious allergic reaction. Methods: We conducted a prospective investigation of all cases treated as part of the “Check and Inject” program from July 2014 through December 2016 in suburban King County, Washington, and January 2016 through December 2016 within the city of Seattle. All cases were prospectively collected using a custom quality improvement data form completed by the first responding EMTs. Two physicians completed a structured review of each EMS medical record to determine if the EMTs followed the Check and Inject protocol and determine if epinephrine was clinically-indicated based on physician review. Results: Of the 411 cases eligible for analysis, EMTs followed the protocol appropriately in 367 (89.3%) cases. In the remaining 44 (10.7%) cases, the EMS incident report form failed to document either a clear inciting allergic trigger or an appropriate symptom from the protocol list. Physician review determined that epinephrine was clinically indicated in 36 of the 44 cases. Among the remaining 8 cases (1.9%) that did not meet protocol criteria and were not clinically-indicated based on physician review, none had a documented adverse reaction to the epinephrine. Conclusion: We observed that EMTs successfully implemented the manual “Check and Inject” program for severe allergic reactions and anaphylaxis in a manner that typically agreed with physician review and without any overt identified safety issues.     

Imaging the myocardial ischemic cascade

Non-invasive imaging plays a growing role in the diagnosis and management of ischemic heart disease from its earliest manifestations of endothelial dysfunction to myocardial infarction along the myocardial ischemic cascade. Experts representing the North American Society for Cardiovascular Imaging and the European Society of Cardiac Radiology have worked together to organize the role of non-invasive imaging along the framework of the ischemic cascade. The current status of non-invasive imaging for ischemic heart disease is reviewed along with the role of imaging for guiding surgical planning. The issue of cost effectiveness is also considered. Preclinical disease is primarily assessed through the coronary artery calcium score and used for risk assessment. Once the patient becomes symptomatic, other imaging tests including echocardiography, CCTA, SPECT, PET and CMR may be useful. CCTA appears to be a cost-effective gatekeeper. Post infarction CMR and PET are the preferred modalities. Imaging is increasingly used for surgical planning of patients who may require coronary artery bypass.