Computational Drug Repurposing: Current Trends

Biomedical discovery has been reshaped upon the exploding digitization of data which can be retrieved from a number of sources, ranging from clinical pharmacology to cheminformatics-driven databases. Now, supercomputing platforms and publicly available resources such as biological, physicochemical, and clinical data, can all be integrated to construct a detailed map of signaling pathways and drug mechanisms of action in relation to drug candidates. Recent advancements in computer-aided data mining have facilitated analyses of 'big data' approaches and the discovery of new indications for pre-existing drugs has been accelerated. Linking gene-phenotype associations to predict novel drug-disease signatures or incorporating molecular structure information of drugs and protein targets with other kinds of data derived from systems biology provide great potential to accelerate drug discovery and improve the success of drug repurposing attempts. In this review, we highlight commonly used computational drug repurposing strategies, including bioinformatics and cheminformatics tools, to integrate large-scale data emerging from the systems biology, and consider both the challenges and opportunities of using this approach. Moreover, we provide successful examples and case studies that combined various in silico drug-repurposing strategies to predict potential novel uses for known therapeutics

Potential of Natural Biomaterials in Nano-scale Drug Delivery

Background: The usage of natural biomaterials or naturally derived materials intended for interface with biological systems has steadily increased in response to the high demand of amenable materials, which are suitable for purpose, biocompatible and biodegradable. There are many naturally derived polymers which overlap in terms of purpose as biomaterials but are equally diverse in their applications. Methods: This review examines the applications of the following naturally derived polymers; hyaluronic acid, silk fibroin, chitosan, collagen and tamarind polysaccharide (TSP); further focusing on the biomedical applications of each as well as emphasising on individual novel applications. Results: Each of the polymer was found to demonstrate a wide variety of successful biomedical applications fabricated as wound dressings, scaffolds, matrices, films, sponges, implants or hydrogels to suit the therapeutic need. Interestingly, blending and amelioration of polymer structures were but two of a selection of strategies to modify the functionality of the polymers to suit the purpose. Further these polymers have shown promise to deliver small molecule drugs, proteins and genes as nano-scale delivery systems. Conclusion: The review highlights the breadth and depth of applications of the aforementioned polymers as biomaterials. Hyaluronic acid, silk fibroin, chitosan, collagen and TSP have been successfully utilised as biomaterials in the subfields of implant enhancement, wound management, drug delivery, tissue engineering and nanotechnology. Whilst there are a number of associated advantages (i.e. biodegradability, biocompatibility, non-toxic, non-antigenic as well as amenability) the select disadvantages of each individual polymer provide significant scope for their further exploration and overcoming challenges like feasibility of mass production at a relatively low cost

Effect of Alirocumab on Lipoprotein(a) and Cardiovascular Risk After Acute Coronary Syndrome

BACKGROUND Lipoprotein(a) concentration is associated with cardiovascular events. Alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, lowers lipoprotein(a) and low-density lipoprotein cholesterol (LDL-C).OBJECTIVES A pre-specified analysis of the placebo-controlled ODYSSEY Outcomes trial in patients with recent acute coronary syndrome (ACS) determined whether alirocumab-induced changes in lipoprotein(a) and LDL-C independently predicted major adverse cardiovascular events (MACE).METHODS One to 12 months after ACS, 18,924 patients on high-intensity statin therapy were randomized to alirocumab or placebo and followed for 2.8 years (median). Lipoprotein(a) was measured at randomization and 4 and 12 months thereafter. The primary MACE outcome was coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or hospitalization for unstable angina.RESULTS Baseline lipoprotein(a) levels (median: 21.2 mg/dl; interquartile range [IQR]: 6.7 to 59.6 mg/dl) and LDL-C [corrected for cholesterol content in lipoprotein(a)] predicted MACE. Alirocumab reduced lipoprotein(a) by 5.0 mg/dl (IQR: 0 to 13.5 mg/dl), corrected LDL-C by 51.1 mg/dl (IQR: 33.7 to 67.2 mg/dl), and reduced the risk of MACE (hazard ratio [HR]: 0.85; 95% confidence interval [CI]: 0.78 to 0.93). Alirocumab-induced reductions of lipoprotein(a) and corrected LDL-C independently predicted lower risk of MACE, after adjustment for baseline concentrations of both lipoproteins and demographic and clinical characteristics. A 1-mg/dl reduction in lipoprotein(a) with alirocumab was associated with a HR of 0.994 (95% CI: 0.990 to 0.999; p = 0.0081).CONCLUSIONS Baseline lipoprotein(a) and corrected LDL-C levels and their reductions by alirocumab predicted the risk of MACE after recent ACS. Lipoprotein(a) lowering by alirocumab is an independent contributor to MACE reduction, which suggests that lipoprotein(a) should be an independent treatment target after ACS. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402) (C) 2020 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.Cardiolog

Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome

Cardiolog

Effects of Alirocumab on Cardiovascular Events After Coronary Bypass Surgery

BACKGROUND Patients with acute coronary syndrome (ACS) and history of coronary artery bypass grafting (CABG) are at high risk for recurrent cardiovascular events and death.OBJECTIVES This study sought to determine the clinical benefit of adding alirocumab to statins in ACS patients with prior CABG in a pre-specified analysis of ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab).METHODS Patients (n = 18,924) 1 to 12 months post-ACS with elevated atherogenic lipoprotein levels despite high-intensity statin therapy were randomized to alirocumab or placebo subcutaneously every 2 weeks. Median follow-up was 2.8 years. The primary composite endpoint of major adverse cardiovascular events (MACE) comprised coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or unstable angina requiring hospitalization. All-cause death was a secondary endpoint. Patients were categorized by CABG status: no CABG (n = 16,896); index CABG after qualifying ACS, but before randomization (n = 1,025); or CABG before the qualifying ACS (n = 1,003).RESULTS In each CABG category, hazard ratios (95% confidence intervals) for MACE (no CABG 0.86 [0.78 to 0.95], index CABG 0.85 [0.54 to 1.35], prior CABG 0.77 [0.61 to 0.98]) and death (0.88 [ 0.75 to 1.03], 0.85 [0.46 to 1.59], 0.67 [0.44 to 1.01], respectively) were consistent with the overall trial results (0.85 [ 0.78 to 0.93] and 0.85 [0.73 to 0.98], respectively). Absolute risk reductions (95% confidence intervals) differed across CABG categories for MACE (no CABG 1.3% [0.5% to 2.2%], index CABG 0.9% [-2.3% to 4.0%], prior CABG 6.4% [0.9% to 12.0%]) and for death (0.4% [-0.1% to 1.0%], 0.5% [-1.9% to 2.9%], and 3.6% [0.0% to 7.2%]).CONCLUSIONS Among patients with recent ACS and elevated atherogenic lipoproteins despite intensive statin therapy, alirocumab was associated with large absolute reductions in MACE and death in those with CABG preceding the ACS event. (ODYSSEY OUTCOMES: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402) (C) 2019 by the American College of Cardiology Foundation.Cardiolog