Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0268596 (EMA)
 2,520 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The treatment of pulmonary embolism is going to be deeply modified by the development of Direct Oral Anticoagulants (DOACs). There are currently three anti-Xa factors (rivaroxaban, apixaban, edoxaban) and one anti-IIa factor (dabigatran) labeled by the FDA and the EMA. All these drugs are direct anticoagulant, orally effective, without the need for adaptation to hemostasis test. As kidney excretion is involved for all of them, they are contra-indicated in patients with severe renal failure (creatinine clearance < 30 mL/min according to Cockcroft & Gault formula). All the anti-Xa factor drugs are metabolized by liver cytochromes and then contra-indicated in case of liver insufficiency. Of note, the four DOACS have been evaluated in non-inferiority trials, including one open-label trial (the EINSTEIN program with the rivaroxaban). Moreover, two of them (rivaroxaban and apixaban) were evaluated in a single drug approach (provided initial increased doses: 15 mg bid during 21 days for rivaroxaban and 10 mg bid during 7 days for apixaban) whereas the two others (edoxaban and dabigatran) were evaluated after at least 5 days of parenteral heparin. They were found to be non-inferior to the conventional treatment, but also seem to be associated with a decreased risk of major bleeding, in a quite young and without significant comorbidities population. The risk/benefit ratio of DOACs in specific subgroups deserves prospective validations.
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PMID:Treatment of pulmonary embolism. 2654 78

Before the modern era of HIV/AIDS therapeutics, which enabled a cascade of early recognition of infection, prompt initiation of effective antiretroviral therapies, and close follow-up, severe forms of microvascular clotting disorders known as thrombotic microangiopathies (TMAs) were frequent in the setting of advanced HIV disease. Their incidence was as high as 7% in the period 1984-1999, but fell dramatically, to <0.5%, by 2002. This profound change was predicated on one critical development: availability of new classes of anti-HIV drugs, enabling reduction and maintenance of HIV viral loads to undetectable levels. Another development in the period 1999-2002 related to TMA therapy: with recognition of autoantibodies against the von Willebrand factor cleaving protease ADAMTS13 as the etiology of most cases of one major form of TMA, thrombotic thrombocytopenic purpura, it permitted appropriate use of life-saving interventions based on plasma exchange and immune suppression. A more recent factor in TMA therapeutics was the 2011 approval by the US FDA and European EMA of eculizumab, a humanized monoclonal antibody against complement component C5, for the treatment of atypical hemolytic uremic syndrome, another major form of TMA. Despite these milestones, life- and organ-threatening TMAs still occur in untreated HIV disease and, to a much lesser extent, in those patients with suppressed viral loads. Confusion in terms of the differential diagnosis of these TMAs also impedes use of directed treatments. This report utilizes a case study of a young woman with advanced AIDS who presented with a severe TMA, characterized by coma and renal failure, to highlight the diagnostic and therapeutic challenges raised by complex hematologic conditions occurring in the setting of HIV.
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PMID:Thrombotic Microangiopathy in the Setting of HIV Infection: A Case Report and Review of the Differential Diagnosis and Therapy. 2750 35

A recent survey on the use of direct oral anticoagulants (DOACs) revealed that 43% of patients with atrial fibrillation and renal impairment were potentially overdosed and had a hazard ratio for major bleeding of 2.19. In this review, we analyse and discuss the effect of renal failure on the pharmacokinetics and pharmacodynamics of DOACs and of strategies proposed to adjust doses according to the level of renal dysfunction. The pharmacokinetic characteristics of available DOACs (dabigatran, rivaroxaban, apixaban, edoxaban, betrixaban) differ substantially as regards oral bioavailability, plasma protein binding and the relative involvement of renal and non-renal elimination. In this respect, 80% of dabigatran is excreted as an unchanged drug in urine, whereas edoxaban, rivaroxaban, apixaban and betrixiban are excreted unchanged by, respectively, 50, 33, 27 and 11% of the dose. Therefore, drug exposure (the area under the concentration-time curve, AUC) is expected to increase to differing extents, depending on the residual renal function and the contribution of the kidneys to the excretion of each drug. Our analysis found that the increased AUC in patients with severe renal dysfunction was greater than expected in the case of dabigatran, betrixaban and rivaroxaban, indicating that other pharmacokinetic parameters may be altered besides renal clearance. Although DAOC pharmacodynamics do not seem to be altered by renal diseases (the correlation between plasma levels and anticoagulant effects overlaps that of healthy subjects), renal failure per se is associated with an increased risk of bleeding and thromboembolism. Guidelines on dose adjustments in patients with renal dysfunction have been published by three National Drug Agencies (FDA, EMA, HC), but many of their items do not match one another, reflecting our substantial paucity of knowledge in advanced renal failure. Routine monitoring of DOAC anticoagulant effects or plasma concentrations is not recommended, since no validated therapeutic ranges have been established. However, this approach may be useful in emergency situations such as bleeding or thrombotic events, urgent surgery, pharmacokinetic interactions, etc. We conclude that more experimental work is needed to improve our knowledge of DOAC pharmacology in renal failure and to provide clinicians with valid tools to adjust therapy.
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PMID:Clinical Pharmacokinetics and Pharmacodynamics of Direct Oral Anticoagulants in Patients with Renal Failure. 3016 98