Drugs of today
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Advanced melanoma traditionally has had poor prognosis with limited, modestly effective and relatively toxic systemic treatment options like cytotoxic chemotherapy (dacarbazine) and immunomodulating agents (high-dose interleukin-2 and ipilimumab) which have response rates of 6-20%. With the identification of BRAF mutations found to be present in 50% of melanomas and the clinical success of serine/threonine-protein kinase B-raf inhibitors the prognostic landscape of melanoma has changed considerably. Vemurafenib and dabrafenib have been at the forefront of antimelanoma-targeted agents with a tolerable side effect profile and efficacy that compared well with the standard chemotherapy. ⋯ However, these agents are not curative and have a short life span primarily due to rapidly occurring drug resistance. More recently, mitogen-activated protein kinase kinase (MEK) inhibitors have been found to have strong anticancer activity independently as well as when combined with other agents like B-raf inhibitors due to their activity downstream of RAF. Preclinical data and limited clinical data suggest that MEK inhibitors may be a component of effective therapy for a broad spectrum of cancers with other oncogenic drivers.
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Chronic obstructive pulmonary disease (COPD) is a worldwide problem causing prolonged and progressive morbidity as well as premature mortality. Pharmacologic treatment consists primarily in the relief of symptoms and preventing or minimizing the consequences of exacerbations. Central to the pharmacologic management of COPD is the use of bronchodilator therapy. ⋯ The availability of "ultra-long"-acting β-adrenoceptor agonists and long-acting antimuscarinic agents opens the way for combinations of these agents to be used in maintenance therapy. Such a combination offers the potential of enhanced efficacy due to additive effects and better compliance as the result of once-daily treatment. This article reviews the rationale for current bronchodilator therapy of COPD as well as the current status of a fixed-dose combined inhaler using two novel long-acting agents: glycopyrronium bromide and indacaterol maleate.
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After AIDS, tuberculosis (TB) is the leading killer worldwide due to a single infectious agent. Recently, drug-resistant strains of Mycobacterium tuberculosis elicited even more severe versions of TB. Bedaquiline inhibits mycobacterial ATP synthase. ⋯ At the end of 2012, the U. S. Food and Drug Administration approved bedaquiline (Sirturo®) as part of a combination therapy to treat adults with multidrug-resistant TB.
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Dapagliflozin is a selective, competitive inhibitor of sodium/glucose cotransporter 2 (SGLT2) acting to block reabsorption of filtered glucose in the kidney. Independent of pancreatic β cell function or the modulation of insulin sensitivity, this novel treatment strategy promotes glucosuria and direct lowering of plasma glucose concentrations. Dapagliflozin has been approved for the treatment of type 2 diabetes in the European Union; however, the United States Food and Drug Administration rejected the approval of dapagliflozin based on lack of clinical data to effectively assess the benefit-to-risk profile. This manuscript will highlight the physiology of renal glucose regulation and reabsorption, briefly outline the pharmacology of dapagliflozin and discuss the results of completed clinical trials as well as the current status of the drug.
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Ponatinib is a novel, next-generation, small-molecule tyrosine kinase inhibitor with potent activity against the BCR-ABL fusion oncogene as well as all other ABL kinase domain mutations that confer resistance to earlier generation tyrosine kinase inhibitors. Due to its unique structure, it is the only tyrosine kinase inhibitor with the capability to counter the highly resistant T315I or gate-keeper mutation in leukemic cells that express the Philadelphia chromosome. This review will focus on the preclinical pharmacology, pharmacokinetics and clinical utility of ponatinib in the treatment of chronic myeloid leukemia and Philadelphia chromosome-positive adult acute lymphoblastic leukemia.