Arch Pharm Res
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Over the past few decades, a tremendous amount of work has been done on the molecular characterization of transport proteins in animals and humans, leading to a better understanding of the physiological roles of a number of transport proteins. Furthermore, there is increasing preclinical and clinical evidence to support the importance of transport proteins in the pharmacokinetics and toxicokinetics of a wide variety of structurally diverse drugs. As a consequence, the degree of expression and functionality of transport proteins may directly affect the therapeutic effectiveness, safety and target specificity of drugs. ⋯ However, increasing evidence suggests that some drug interactions result from changes in the activity and/or expression of drug transporters. Accordingly, assessment of the clinical relevance of transporter-mediated drug interactions has become a regulatory issue during the drug approval process and also the evaluation of drug interaction potential has become an integral part of risk assessment during drug development processes. Therefore, this review will highlight the role of some selected drug transporters in drug interactions, as well as their clinical implication.
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Myocardial ischemia is a condition in which lack of blood flow to the cardiac muscle occurs resulting in deficient oxygen and nutrient supply to the heart. The restoration of blood flow to an organ or tissue is termed reperfusion. ⋯ However, numerous experimental studies reveal that the cardioprotective effects of postconditioning are suppressed in various pathological states. This review critically discusses the mechanisms involved in the cardioprotective effects of postconditioning and factors affecting the cardioprotective potential of myocardial postconditioning.
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Sevoflurane, one of the most commonly used inhalation anesthetics, induces apoptosis and oxidative stress in lymphocytes. Propofol, an intravenous anesthetic, exhibits antiapoptotic and antioxidative activities. Therefore, the present study aimed to investigate whether propofol attenuates sevoflurane-induced cellular injury in human peripheral lymphocytes. ⋯ Five and ten μg/mL propofol attenuated the impact of sevoflurane on cell viability, apoptosis and ΔΦm, and 5, 10 and 25 μg/mL propofol inhibited the production of intracellular reactive oxygen species stimulated by sevoflurane. However, a combination of 50 μg/mL propofol and 8% sevoflurane led to more severe cellular injury than sevoflurane alone. The results suggest that propofol can attenuate sevoflurane-induced cellular injury of human peripheral lymphocytes in a concentration-dependent manner, providing a rational for the clinical use of sevoflurane combined with appropriate doses of propofol.
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Ischemic preconditioning can provide protection to neurons from subsequent lethal ischemia. The molecular mechanisms of neuronal ischemic tolerance, however, are still not well-known. The present study, therefore, examined the role of MAPK and PI3K/Akt pathways in ischemic tolerance induced by preconditioning with sublethal oxygen-glucose deprivation (OGD) in cultured rat cortical neurons. ⋯ Finally, treatment with an inhibitor of PI3K, wortmannin, applied from 15 min before and during lethal OGD abolished not only the preconditioning-induced neuroprotection but also the Akt activation. Concomitant with blockade of the Akt activation, PI3K inhibition also resulted in activation of Bad and GSK-3β. The results suggest that ischemic tolerance induced by sublethal OGD preconditioning is primarily mediated through activation of the PI3K/Akt pathway, but not the MAPK pathway, in rat cortical neurons.
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Melanoma has the capacity to spread via the blood stream to the brain, and has been notoriously resistant to drug therapy. An activating mutation in the gene encoding BRAF is known to be responsible for half of melanomas. This article provides a review of GSK2118436 and PLX4032 as potential therapeutics for the treatment of melanomas by inhibiting oncogenic BRAF.