Clinical pharmacology and therapeutics
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Clin. Pharmacol. Ther. · Dec 2013
ReviewConnecting the dots: applications of network medicine in pharmacology and disease.
In 2011, >2.5 million people died from only 15 causes in the United States. Ten of these involved complex or infectious diseases for which there is insufficient knowledge or treatment, such as heart disease, influenza, and Alzheimer's disease.(1) Complex diseases have been difficult to understand due to their multifarious genetic and molecular fingerprints, while certain infectious agents have evolved to elude treatment and prophylaxis. ⋯ The resulting "big picture" allows for the development of computational and mathematical methods to identify novel disease pathways and predict patient drug response, among others. In this review, we discuss recent advances in network medicine.
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Clin. Pharmacol. Ther. · Dec 2013
ReviewNetwork-based approaches in drug discovery and early development.
Identification of novel targets is a critical first step in the drug discovery and development process. Most diseases such as cancer, metabolic disorders, and neurological disorders are complex, and their pathogenesis involves multiple genetic and environmental factors. Finding a viable drug target-drug combination with high potential for yielding clinical success within the efficacy-toxicity spectrum is extremely challenging. ⋯ The objective of this article is to highlight network approaches for identifying novel targets with greater chances of gaining approved drugs with maximal efficacy and minimal side effects. Further enhancement of these approaches may emerge from effectively integrating computational systems biology with pharmacodynamic systems analysis. Coupling genomics, proteomics, and metabolomics databases with systems pharmacology modeling may aid in the development of disease-specific networks that can be further used to build confidence in target identification.
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Two parallel trends are occurring in drug discovery. The first is that we are moving away from a symptom-based disease classification system to a system based on molecules and molecular states. The second is that we are shifting from targeting a single molecule toward targeting multiple molecules, pathways, or networks. Network medicine is an approach to understanding disease and discovering therapeutics looking at many molecules and how they interrelate, and it may play a critical role in the adoption of both trends.
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Clin. Pharmacol. Ther. · Nov 2013
ReviewDemonstrating evidence of acceptability: the "catch-22" of pediatric formulation development.
Both researchers and practitioners have reached an influential period in the new era of developing pediatric medicines. Evolving regulatory reforms and guidance continue to serve as platforms steering research and development while distinctive opportunities and challenges in the field emerge. An advancing research need involves gaining a better understanding of end-user requirements and acceptability of formulations. This review considers solid oral forms to demonstrate the importance of such research to stakeholders in policy and practice.
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Clin. Pharmacol. Ther. · Oct 2013
ReviewRenin-angiotensin-aldosterone system inhibitors in heart failure.
Heart failure (HF) is a very common condition that, despite advances in treatment, carries significant morbidity and mortality. Although there is good evidence for the treatment of HF with reduced ejection fraction (HFrEF), the treatment for HF with preserved ejection fraction (HFpEF) is not well defined. The renin-angiotensin-aldosterone system (RAAS) has been shown to be an effective target in the treatment of HFrEF using angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone blockade, although the evidence in HFpEF is less clear. This review aims to look first at the evidence for these drugs, and second at the newer drugs that act on the RAAS, namely, direct renin inhibitors, neutral endopeptidase inhibitors, vasopeptidase inhibitors, and angiotensin receptor blockers.