Pharmacology Research Today is a free monthly online journal that collates and summarizes the latest research about Pharmacology, including details on pharmacogenomics, drug development, new medications.

The new oral anticoagulants.

Garcia D, Libby E, Crowther MA

University of New Mexico, MSC08-4630, 900 Camino de Salud NE, Albuquerque, NM 87131-0001. davgarcia@salud.unm.edu

Although their first application in clinical practice occurred in the 1940s, vitamin K antagonists remain the only form of oral anticoagulant medication approved for long-term use. Although the available vitamin K antagonists are highly effective for the prevention and/or treatment of most thrombotic disease, the significant interpatient and intrapatient variability in dose-response, the narrow therapeutic index, and the numerous drug and dietary interactions associated with these agents have led clinicians, patients, and investigators to search for alternative agents. Three new orally administered anticoagulants (apixaban, dabigatran, and rivaroxaban) are in the late stages of development and several others are just entering (or moving through) earlier phases of investigation. These novel anticoagulant medications are being studied for the prevention and treatment of venous thromboembolism, the treatment of acute coronary syndromes and the prevention of stroke in patients with atrial fibrillation. This review summarizes published clinical trial data pertinent to apixaban, dabigatran, and rivaroxaban.

Published 8 January 2010 in Blood, 115(1): 15-20.
Full-text of this article is available online (may require subscription).

Articles on Pharmacology published 31 December 2009:

Key factors in the discovery and development of new antiepileptic drugs.   Nat Rev Drug Discov, 9(1): 68-82.

Since the early 1990s, many new antiepileptic drugs (AEDs) that offer appreciable advantages in terms of their favourable pharmacokinetics, improved tolerability and lower potential for drug-drug interactions have entered the market. However, despite the therapeutic arsenal of old and new AEDs, approximately 30% of patients with epilepsy still suffer from seizures. Thus, there remains a substantial need for the development of more efficacious AEDs for patients with refractory seizures. Here, we ... [Abstract] [Full-text]

Subcellular targeting strategies for drug design and delivery.   Nat Rev Drug Discov, 9(1): 29-42.

Many drug targets are localized to particular subcellular compartments, yet current drug design strategies are focused on bioavailability and tissue targeting and rarely address drug delivery to specific intracellular compartments. Insights into how the cell traffics its constituents to these different cellular locations could improve drug design. In this Review, we explore the fundamentals of membrane trafficking and subcellular organization, as well as strategies used by pathogens to ... [Abstract] [Full-text]

An audience with...Marc Cluzel.   Nat Rev Drug Discov, 9(1): 14.

Executive Vice President, R&D, Sanofi-Aventis, Paris, France. In November 2009, Marc Cluzel was appointed executive Vice President (VP) of R&D at Sanofi-Aventis. He has a medical and biochemical education from the university of Montpellier, France, and was a Visiting Assistant Professor at the Johns Hopkins University, Baltimore, USA, then a Research Associate at Guy's Hospital in London, UK, before joining Sanofi-Aventis in 1991. He was appointed VP of International Development in ... [Abstract] [Full-text]

Adding calorimetric data to decision making in lead discovery: a hot tip.   Nat Rev Drug Discov, 9(1): 23-7.

Recognition of the limitations of high-throughput screening approaches in the discovery of candidate drugs has reawakened interest in structure-based and other rational design methods. Here, we describe how isothermal titration calorimetry can be used to obtain thermodynamic data on the binding of compounds to protein targets. We propose that these data--particularly the change in enthalpy--could provide a valuable, complementary addition to established tools for selecting compounds in lead ... [Abstract] [Full-text]

Articles on Pharmacology published 18 December 2009:

The pharmacogenomics of membrane transporters project: research at the interface of genomics and transporter pharmacology.   Clin Pharmacol Ther, 87(1): 109-16.

Since the cloning of the first membrane transporter, our understanding of the role of transporters in clinical drug disposition and response has grown enormously. In parallel, large-scale genome-wide variation studies and the emerging field of pharmacogenomics have ushered in a new understanding of variations in drug response. At the crossroads of pharmacogenomics and transporter biology is the National Institutes of Health-funded Pharmacogenomics of Membrane Transporters (PMT) project, ... [Abstract] [Full-text]

Transporters as drug targets: discovery and development of NPC1L1 inhibitors.   Clin Pharmacol Ther, 87(1): 117-21.

The potent cholesterol absorption inhibitor ezetimibe was developed as a first-in-class drug for treating hypercholesterolemia even before its molecular target, Niemann-Pick C1-like 1 (NPC1L1), had been identified. The NPC1L1 protein mediates sterol transport across the enterocyte brush border membrane and is essential for intestinal cholesterol absorption, a major pathway controlling whole-body cholesterol homeostasis. An elucidation of the mechanism underlying NPC1L1-dependent cholesterol ... [Abstract] [Full-text]

Transporter pharmacogenetics and statin toxicity.   Clin Pharmacol Ther, 87(1): 130-3.

Polymorphisms in transporter genes can have profound effects on statin pharmacokinetics. In particular, a common genetic variant of organic anion-transporting polypeptide 1B1 reduces the hepatic uptake of many statins, increasing the risk of statin-induced myopathy. Similarly, genetically impaired adenosine triphosphate (ATP)-binding cassette G2 transporter efflux activity results in a marked increase in systemic exposure to various statins. Importantly, the effects of these genetic ... [Abstract] [Full-text]

Articles on Pharmacology published 17 December 2009:

Drug effects viewed from a signal transduction network perspective.   J Med Chem, 52(24): 8038-46.

Understanding how drugs affect cellular network structures and how resulting signals are translated into drug effects holds the key to the discovery of medicines. Herein we examine this cause-effect relationship by determining protein network structures associated with the generation of specific in vivo drug-effect patterns. Medicines having similar in vivo pharmacology have been identified by a comparison of drug-effect profiles of 1320 medicines. Protein network positions reached by these ... [Abstract] [Full-text]

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