Mini reviews in medicinal chemistry
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Paroxysmal nocturnal hemoglobinuria (PNH) is a hematological disorder characterized by complementmediated hemolytic anemia, thrombophilia and bone marrow failure. The clinical hallmark of PNH is evident chronic hemolysis due to the absence of the complement regulators CD55 and CD59 on PNH erythrocytes. Intravascular hemolysis drives the major clinical features of PNH, including anemia, hemoglobinuria, fatigue and other hemolysisrelated disabling symptoms, such as painful abdominal crises, dysphagia and erectile dysfunction. ⋯ Here we critically review the available clinical results of eculizumab treatment for PNH patients, pointing out the recent insights into the pathophysiology of the disease. We discuss the role of the different components of the complement cascade leading to hemolysis, in both the absence and presence of the terminal effector pathway inhibition by eculizumab. Finally, we provide a theoretical rationale for the development of novel strategies of complement inhibition which could in the future further improve on the already substantial efficacy of eculizumab.
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POCD describes a decline in cognitive function after surgery with a predominance in the elderly patient. Although there is general agreement that POCD is likely to be multifactorial, whether its occurrence is a result of the effects of surgery or general anesthesia remains unclear. This review provides a synopsis of the available clinical and preclinical data and summarizes recent research relevant to the occurrence of POCD and possible pharmacologic algorithms for its prevention and treatment.
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Review
Treating age-related macular degeneration - interaction of VEGF-antagonists with their target.
The neutralization of VEGF is the current treatment of choice for age-related macular degeneration. Current approaches include anti-VEGF-antibodies and -Fab Fragments, aptamers, soluble receptors (Traps) and siRNA. The molecular properties of VEGF and its antagonists are reviewed and the pathways of action of these substances are discussed.
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Review
Structural and physicochemical profiling of morphine and related compounds of therapeutic interest.
A concise account of the physicochemical properties of morphine and its derivatives of therapeutic interest is provided. Such properties include macroscopic and microscopic acid/base parameters, lipophilicity, solubility, permeability that all influence the fate of drugs in the body. The dependence of these parameters on pH is discussed and subsequent implications in drug administration and formulation are presented.
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Clofarabine is a second generation of purine nucleoside analogues designed to combine the most favorable pharmacokinetic properties of fludarabine and cladribine. Clofarabine acts by inhibiting DNA polymerases and ribonucleotide reductase as well as by inducing apoptosis in cycling and non-cycling cells. Phase I/II clinical studies revealed its efficacy in hematological malignancies, and in 2004 clofarabine was approved by the United States Food and Drug Administration for the treatment of pediatric relapsed or refractory acute lymphoblastic leukemia after at least two prior chemotherapy regimens. The mechanism of action, pharmacology and clinical activity of clofarabine is the subject of this review.