Current medicinal chemistry
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Acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) are characterized by rapid-onset respiratory failure following a variety of direct and indirect insults to the parenchyma or vasculature of the lungs. Mortality from ALI/ARDS is substantial, and current therapy primarily emphasizes mechanical ventilation and judicial fluid management plus standard treatment of the initiating insult and any known underlying disease. Current pharmacotherapy for ALI/ARDS is not optimal, and there is a significant need for more effective medicinal chemical agents for use in these severe and lethal lung injury syndromes. ⋯ The biological and physiological complexity of ALI/ARDS requires the consideration of combined-agent treatments in addition to single-agent therapies. A number of pharmacologic agents have been studied individually in ALI/ARDS, with limited or minimal success in improving survival. However, many of these agents have complementary biological/biochemical activities with the potential for synergy or additivity in combination therapy as discussed in this article.
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Chemotherapy-induced neurotoxicity is a significant complication in the successful treatment of many cancers. Neurotoxicity may develop as a consequence of treatment with platinum analogues (cisplatin, oxaliplatin, carboplatin), taxanes (paclitaxel, docetaxel), vinca alkaloids (vincristine) and more recently, thalidomide and bortezomib. Typically, the clinical presentation reflects an axonal peripheral neuropathy with glove-and-stocking distribution sensory loss, combined with features suggestive of nerve hyperexcitability including paresthesia, dysesthesia, and pain. ⋯ The mechanisms underlying chemotherapy-induced neurotoxicity are diverse and include damage to neuronal cell bodies in the dorsal root ganglion and axonal toxicity via transport deficits or energy failure. More recently, axonal membrane ion channel dysfunction has been identified, including studies in patients treated with oxaliplatin which have revealed alterations in axonal Na(+) channels, suggesting that prophylactic pharmacological therapies aimed at modulating ion channel activity may prove useful in reducing neurotoxicity. As such, improved understanding of the pathophysiology of chemotherapy-induced neurotoxicity will inevitably assist in the development of future neuroprotective strategies and in the design of novel chemotherapies with improved toxicity profiles.
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Review
Pulmonary coagulopathy as a new target in lung injury--a review of available pre-clinical models.
Despite recent advances in supportive care, acute lung injury (ALI) and its more severe form acute respiratory distress syndrome (ARDS) are clinical entities with high morbidity and high mortality. In systemic inflammation, like sepsis, uncontrolled host defense can lead to systemic activation of coagulation on the one hand, and attenuation of fibrinolysis on the other. In ALI/ARDS similar but local disturbances in fibrin turnover occur, leading to excessive alveolar fibrin deposition compromising pulmonary integrity and function. ⋯ A solid base has to be provided by preclinical studies to justify clinical studies on new pharmacologic therapies for ALI/ARDS. In this systematic literature review we give an overview of the models for ALI/ARDS that have been used so far on the topic of pulmonary coagulopathy and focus on the pharmacological interventions that have been evaluated with these models. Finally, the applicability of the different approaches for future research on this subject will be discussed.
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Chronic myeloid leukemia (CML) is characterized by the presence of the Philadelphia (Ph) chromosome, which results from a reciprocal translocation between the long arms of the chromosomes 9 and 22 t(9;22)(q34;q11). This translocation creates two new genes, BCR-ABL on the 22q- (Ph chromosome) and the reciprocal ABL-BCR on 9q-. The BCR-ABL gene encodes for a 210-kD protein with deregulated tyrosine kinase (TK) activity, which is crucial for malignant transformation in CML. ⋯ One of these molecules, MK0457, has entered clinical trials, and initial reports indicate that this compound could be active in disease associated with T315I mutation. Thus, wide spectrum of new agents, with different mode of action, is currently in clinical development for CML. It is likely that combination therapy will be the best therapeutic strategy in the future.
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P. aeruginosa is a serious cause of infection with reported rates of mortality being up to 61%. Several studies evidenced a correlation between hospital mortality due to P. aeruginosa bloodstream infections and an inappropriate antimicrobial treatment. ⋯ Current consensus favours the use of empirical combination, balancing the potential for greater toxicity against the lower emergence of antimicrobial resistance and the greater killing that might be achieved by combination therapies acting synergistically. Advantages and disadvantages of combination therapy towards monotherapy for P. aeruginosa severe infections, current antibiotics used for P. aeruginosa severe infections and main studies published on this issue are reviewed.