Current drug discovery technologies
-
For more than 50 years, heparin(s) and warfarin have been the most important anticoagulant agents, and clinicians are accustomed to their specific antidotes (protamine sulfate and vitamin K/plasma [or factor concentrates], respectively). Recently, there has been an explosion of novel anticoagulant development: ideally, these newer agents should have advantages over traditional anticoagulants, such as fewer side effects, a more predictable pharmacokinetic profile (and potentially no need for monitoring), minimal drug-drug interactions, and so forth. But, unlike the older agents, the newer anticoagulants do not have specific antidotes. ⋯ Based on extrapolation from animal models, clinical anecdote, and an understanding of their mechanism of action, we recommend treating major bleeding complications of DTIs, as follows (in descending order of preference): activated PCCs; rFVIIa; and (non-activated) PCCs. For management of fondaparinux-associated bleeding, rFVIIa has some rationale (for which we provide an illustrative case). The increasing use of novel anticoagulants will require physicians to have an understanding of rational approaches to "reverse" their anticoagulant effects when true antidotes do not exist.
-
Curr Drug Discov Technol · Jun 2012
ReviewNew oral anticoagulants for venous thromboembolism: focus on factor Xa and thrombin inhibitors.
Several oral direct anti-Xa agents and one antithrombin agent are currently under clinical development for the prevention and treatment of venous thromboembolism (VTE). The anti-Xa inhibitors rivaroxaban (10 mg once daily) and apixaban (2.5 mg twice daily) as well as the thrombin inhibitor dabigatran (150 or 220 mg once daily) have been recently licensed for the prevention of VTE in total hip or knee replacement. The publication of the results of studies with rivaroxaban and apixaban in the prevention of VTE in medical patients are awaited. ⋯ The incidence of major or clinically relevant non-major bleeding was similar in patients receiving standard treatment and rivaroxaban or dabigatran. Clinical trials on VTE treatment are currently ongoing with apixaban and edoxaban. A number of phase II clinical trials are currently ongoing with several other antiXa agents in the prophylaxis and treatment of VTE.
-
Curr Drug Discov Technol · Jun 2011
ReviewCurrent advances in delivery of biotherapeutics across the blood-brain barrier.
Significant efforts through genomic approaches have been dedicated toward the identification of novel protein-protein interactions as promising therapeutic targets for indications such as Alzheimer's disease, Parkinson's disease and neuropsychiatric disorders. Additionally, the number of biotherapeutic agents entering the Pharmaceutical sector continues to increase and according to EvaluatePharma's "World Preview 2014" report, "the compounded annual growth rate of biologics is expected to be 8.5 percent from 2008-2014, eight to 10 times greater than the growth rate of small molecules". However, there are limited examples of success in developing biotherapeutic modalities for central nervous system (CNS) diseases in the drug development pipeline. ⋯ With acknowledgement that each approach has advantages and disadvantages, this review discusses the opportunities and challenges that are encountered during application of these methods across a variety of therapeutic areas such as, pain, obesity, neuroscience, and oncology. Utilizing an industrial perspective, including consideration of cost of goods and commercial feasibility for these approaches, this review highlights technology features which would enable industry investments toward novel BBB delivery technologies for biologics. Through continued development and improvement of such technology, new therapeutic options to treat and potentially cure central nervous system diseases could eventually evolve.
-
Curr Drug Discov Technol · Jun 2008
Solubilization and stabilization of sodium dicloxacillin by cyclodextrin inclusion.
The aim of this work is to analyze the effect of cyclodextrin (CD) complexation on the solubilization and stabilization of sodium dicloxacillin in acid aqueous solutions. The effect of four cyclodextrins alpha-, beta-, gamma- and hydroxypropyl-beta-CD was studied. Phase solubility diagrams obtained are AL or BS type, depending on the cyclodextrin used and on the pH of the solution. ⋯ The effect of gamma-CD and HPbeta-CD in the stability of the drug in solution was studied. The degradation of sodium dicloxacillin in solution follows a pseudo-first-order kinetics and the cyclodextrin do not change this fact. Both cyclodextrins increase the stability of the drug but the efficacy is higher with gamma-CD.
-
Curr Drug Discov Technol · Mar 2006
ReviewAdvanced glycation end products (AGEs) and their receptor (RAGE) system in diabetic retinopathy.
Vascular complications are a leading cause of blindness, end-stage renal failure, a variety of neuropathies and accelerated atherosclerosis, which could account for disabilities and high mortality rates in patients with diabetes. There is a growing body of evidence that formation and accumulation of advanced glycation end products (AGEs) progress during normal aging, and at an extremely accelerated rate in diabetes, thus being involved in the pathogenesis of diabetic vascular complications. ⋯ This review discusses the molecular mechanisms of diabetic retinopathy, especially focusing on the AGE-RAGE system. Several types of inhibitors of the AGE-RAGE system and their therapeutic implications are also reviewed here.