Stimulation of Endogenous Fibrinolysis
Cornelis Kluft in Tissue-Type Plasminogen Activator (t-PA): Physiological and Clinical Aspects, 1988
This is a recently introduced drug which, like GAGs, is extracted from mammals; it is a polydeoxynucleotide extracted from lung which is rich in purine-pyrimidine bases.108 It increased fibrinolysis in animals both in vitro and ex vivo;108,109 increased t-PA in rabbits;108 and increased the ability of rat aortic rings to release PGI2-like material.108 I.m. or i.v. injection shortened ECLT and increased euglobulin fibrin plate lysis in volunteers108,110 and in patients with peripheral arterial disease.111,112 In the latter group, fibrinolytic response to venous occlusion increased111 and α2-antiplasmin decreased;112 decreased ECLT and α2-antiplasmin levels were also observed after oral treatment.112 Defibrotide appears to be effective in prevention of postoperative deep vein thrombosis, and is also being evaluated in treatment of venous thrombosis, peripheral arterial disease, thrombotic renal failure, and renal transplantation.113
Monoclonal Antibody Mediated Treatment in Acute Myeloid Leukemia
Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey in Innovative Leukemia and Lymphoma Therapy, 2019
Meanwhile more data became available on the hepatotoxicity of GO, again showing that some patients developed clinical signs of VOD, which is thought to be due to CD33 expression in hepatic sinusoids and perhaps better described as “sinusoidal obstruction syndrome” (SOS) (23). Other factors involved may be the liver leukemia load or circulating soluble CD33 levels. A high incidence of VOD (in this particular single-center study as high as 64% of 14 patients) was noted among patients who were transplanted following reinduction with GO, mainly in patients who were transplanted shortly after GO treatment (24). This resulted in the recommendation to delay transplantation for at least 3.5 months following treatment with GO. However, in another series VOD also occurred in approximately 4% of patients without prior SCT history, as was also noted in the phase II studies described above (25). Several case reports suggest that defibrotide may be useful in preventing or treating GO-induced VOD, but no larger prospective or comparative studies have been performed (26,27).
Case 50
Atul B. Mehta, Keith Gomez in Clinical Haematology, 2017
He has developed veno-occlusive disease. The peak incidence is in the first 2–3 weeks post-allogeneic bone marrow transplant (BMT) and overall incidence is 20%–25%. The cause is unknown, but important risk factors are pre-existing liver disease, a previous myeloablative transplant, large doses of previous cytoreductive chemotherapy or high-intensity pre-transplant conditioning. Treatment is largely supportive but defibrotide has been shown to be effective and steroids are valuable in selected patients. Recombinant tissue plasminogen activator has been successfully used to lyse the intrahepatic blood clot.
Lipoplex-based therapeutics for effective oligonucleotide delivery: a compendious review
Published in Journal of Liposome Research, 2020
Pirthi Pal Singh, Veena Vithalapuram, Sunita Metre, Ravinder Kodipyaka
On April 2016, the FDA approved Defibrotide (Defitelio®) treatment of severe hepatic veno-occlusive disease [VOD, known as sinusoidal obstruction syndrome] occurring after high-dose chemotherapy and autologous bone marrow transplantation (Stein et al.2016b). The natural process of controlled depolymerization of porcine intestinal mucosal DNA is used for defibrotide generation. Defibrotide has a very complicated non-specific mechanism of action, most certainly based on the charge–charge interactions of its phosphodiester constituents with proteins. Although the mechanism of action of defibrotide is reported as too complex, Pescador et al. (2013) described the anti-coagulating ability of defibrotide in the hepatic sinusoidal endothelium. It increases plasma tissue plasminogen activator activity and decreases the activity of its inhibitor. It is also reported to release tissue-factor pathway inhibitor from endothelial cells and inhibit platelet aggregation by plasma prostaglandin E2 elevation (Coccheri et al.1988, Cella et al.2001).
Defibrotide sodium for the treatment of hepatic veno-occlusive disease/sinusoidal obstruction syndrome
Published in Expert Review of Clinical Pharmacology, 2018
Paul G. Richardson, Brandon M. Triplett, Vincent T. Ho, Nelson Chao, Fiona L. Dignan, Michelle Maglio, Mohamad Mohty
Although developments in transplantation technique and evolution of supportive care have improved the survival for patients with VOD/SOS, defibrotide meets a significant current clinical need. Defibrotide, which is thought to restore the thrombolytic–fibrinolytic balance and provides EC protection, has consistently demonstrated favorable Day +100 survival rates while offering an AE rate that is similar to best supportive care. The rarity and dismal outcomes associated with VOD/SOS with MOD impose ethical limitations on study design; however, when all the data are taken together, these studies show a consistent effect across a large proportion of patients with this disease. In contrast, alternative and unapproved treatment options typically have limited support for efficacy and/or problematic safety profiles. Defibrotide is the only therapy approved in the United States for treatment of VOD/SOS with renal or pulmonary dysfunction post-HSCT and the European Union for the treatment of severe VOD/SOS post-HSCT.
Chimeric antigen receptor T-cell therapy for the treatment of aggressive B-cell non-Hodgkin lymphomas: efficacy, toxicity, and comparative chimeric antigen receptor products
Published in Expert Opinion on Biological Therapy, 2019
Bradley D. Hunter, Michael Rogalski, Caron A. Jacobson
Clinical trials of the three products in aggressive B-NHL report incidences of neurotoxicity between 21% and 64%, with grade 3+ neurotoxicity seen in 12–28% of patients; the rate was highest on the ZUMA-1 study of axi-cel compared with the JULIET and TRANSCEND studies of t-cel and liso-cel. Although there have been reported deaths due to neurologic toxicity [57], these events are exceedingly rare with currently available CAR T-cell products in lymphoma patients. For the vast majority of patients, NT is fully reversible but can cause a great deal of stress to both the patient and family members. While CRS can be reasonably managed with tocilizumab, a similarly effective therapy does not exist at this time for NT. There are ongoing and planned trials targeting each of the above-mentioned potential mechanisms in varying stages of development. Anti-GM-CSF antibodies in murine models have been shown to reduce the incidence of both CRS and NT, supporting their prophylactic use following CAR T-cell infusion in patients [58]. Anakinra, an IL1a-receptor antagonist which is able to cross the blood-brain barrier, has also demonstrated efficacy both in treating and preventing neurotoxicity in murine models [52,53]. Defibrotide has shown efficacy in stabilizing vascular integrity in veno-occlusive disease of the liver following allogeneic stem cell transplantation [59] and has been proposed as a potential agent for the treatment or prevention of neurotoxicity [38].
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