Novel alternate hemostatic agents for patients with inhibitors: beyond bypass therapy.
Hematology Am Soc Hematol Educ Program. 2017 Dec 08;2017(1):605-609
Authors: Ragni MV
Inhibitor formation is among the most severe complications of hemophilia treatment. With a cumulative incidence of ∼30% in those with severe hemophilia A and ∼3% in those with severe hemophilia B, inhibitors are caused by a T-cell response directed against infused coagulation factor; these inhibitors neutralize factor VIII or IX activity and disrupt normal hemostasis. Inhibitor patients become unresponsive to standard factor treatment and, as an alternative, use bypass treatment (eg, recombinant factor VIIa or factor VIII inhibitor bypass activity). However, response to bypass agents is poorer and the burden of disease is higher, with greater morbidity, hospitalization, cost, and mortality, than in noninhibitor patients. Furthermore, inhibitor formation interferes with prophylaxis to prevent bleeding episodes and is a contraindication to gene therapy. Thus, more effective therapies for inhibitor patients are greatly needed. In the last several years, there has been an explosion of novel alternative hemostatic agents for hemophilia patients with and without inhibitors. These agents take advantage of technologic manipulation of coagulation factors and natural anticoagulants to promote hemostasis. The approaches include the following: (1) mutants or mimics of coagulation factors, rendering them resistant to natural anticoagulants; or (2) knock-down or disruption of natural anticoagulants, preventing degradation of coagulation factors. The purpose of this article was to review these novel alternative hemostatic agents and their mechanisms of action, as well as the preliminary pharmacokinetic, safety, and efficacy data available from early-phase clinical trials.
PMID: 29222310 [PubMed - in process]
Treatment of inherited bone marrow failure syndromes beyond transplantation.
Hematology Am Soc Hematol Educ Program. 2017 Dec 08;2017(1):96-101
Authors: Calado RT, Clé DV
Despite significant progress in transplantation by the addition of alternative hematopoietic stem cell sources, many patients with inherited bone marrow failure syndromes are still not eligible for a transplant. In addition, the availability of sequencing panels has significantly improved diagnosis by identifying cryptic inherited cases. Androgens are the main nontransplant therapy for bone marrow failure in dyskeratosis congenita and Fanconi anemia, reaching responses in up to 80% of cases. Danazol and oxymetholone are more commonly used, but virilization and liver toxicity are major adverse events. Diamond-Blackfan anemia is commonly treated with corticosteroids, but most patients eventually become refractory to this treatment and toxicity is limiting. Growth factors still have a role in inherited cases, especially granulocyte colony-stimulating factor in congenital neutropenias. Novel therapies are warranted and thrombopoietin receptor agonists, leucine, quercetin, and novel gene therapy approaches may benefit inherited cases in the future.
PMID: 29222242 [PubMed - in process]
Antiangiogenic compounds: well-established drugs versus emerging natural molecules.
Cancer Lett. 2017 Dec 05;:
Authors: Ribeiro A, Abreu RMV, Dias MM, Barreiro MF, Ferreira ICFR
Angiogenesis is the natural and physiologic process of growing blood vessels from pre-existing ones. Pathological angiogenesis occurs when the precise balance of all the molecular pathways that regulate angiogenesis is disrupted, and this process is a critical step in many diseases, including cancer. A limited number of antiangiogenic synthetic drugs have been developed. However, due to toxicity and side effects issues, the search for alternative to existing drugs is ongoing. In this sense, natural molecules obtained from plants or macrofungi, have demonstrated extraordinary potential in the treatment of angiogenesis-related pathologies, specially taking into consideration its absence or very low toxicity, when compared to synthetic drugs. Using natural compounds as potential angiogenesis modulators is thus a promising field of research, supporting the creation of novel therapies able to reduce the use of drugs and associated side effects. In this review, the current status of antiangiogenic drugs and the wide variety of natural extracts and molecules with antiangiogenic capacities, as well as the angiogenesis molecular pathways and therapeutic targets, are presented. Finally, the challenges that need to be overcome in order to increase the use of natural compounds for clinical purposes are discussed.
PMID: 29222042 [PubMed - as supplied by publisher]