ABSTRACT
Essentials Antiangiogenic drugs are indicated as therapies for hereditary hemorrhagic telangiectasia. We interrogated the response to four antiangiogenic drugs for anemia and intestinal bleeding. Sorafenib and a pazopanib analog significantly improved while erlotinib worsened anemia. Some oral antiangiogenic drugs were effective in reducing intestinal bleeding. SUMMARY: Background Epistaxis and gastrointestinal (GI) tract hemorrhages are common symptoms of aged hereditary hemorrhagic telangiectasia (HHT) patients that result in anemia. Clinical as well as animal studies have suggested that vascular endothelial growth factor (VEGF) neutralizing antibodies lessen hemorrhage associated with adult-onset arteriovenous malformations (AVMs). Objectives The goal of this study is to evaluate potential therapeutic effects of oral delivery of four antiangiogenic tyrosine-kinase inhibitors (TKIs) in the development of adult-onset AVMs in a murine model of HHT. Methods An adult activin receptor-like kinase 1 (Alk1)-inducible knockout (iKO) model was utilized to evaluate the effect of oral administration of sorafenib, sunitinib, erlotinib and a pazopanib analog (GW771806) on hemoglobin level, GI hemorrhages and formation of wound-induced skin AVMs. Results and Conclusions Sorafenib and GW771806 significantly improved, yet erlotinib worsened, anemia and GI-bleeding in the Alk1-iKO model. However, none of these TKIs appeared to be effective for inhibiting the development of wound-induced skin AVMs. Taken together, these results suggest that oral delivery of antiangiogenic TKIs is selectively more effective for GI bleeding than mucocutaneous AVMs, and it may provide an experimental basis for selective therapeutic options depending on the symptoms of HHT.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Telangiectasia, Hereditary Hemorrhagic/drug therapy , Telangiectasia, Hereditary Hemorrhagic/genetics , Activin Receptors, Type I/metabolism , Activin Receptors, Type II , Administration, Oral , Administration, Topical , Anemia/drug therapy , Anemia/genetics , Animals , Arteriovenous Malformations , Disease Models, Animal , Erlotinib Hydrochloride/administration & dosage , Gastrointestinal Hemorrhage , Hemoglobins/analysis , Image Processing, Computer-Assisted , Indazoles/administration & dosage , Mice , Mice, Knockout , Niacinamide/administration & dosage , Niacinamide/analogs & derivatives , Phenylurea Compounds/administration & dosage , Pyrimidines/administration & dosage , Skin/blood supply , Sorafenib , Sulfonamides/administration & dosage , Sulfones/administration & dosage , Tyrosine/chemistry , Vascular Endothelial Growth Factor A/metabolism , Wound HealingABSTRACT
The mechanical circulatory support system using moving-actuator mechanisms were developed by Seoul National University and Korea University. AnyHeart is a fully implanted pulsatile bi-ventricular assist device, and T-PLS is a pulsatile flow versatile extracorporeal life support system. Through lots of in-vitro and in-vivo experiments, the developed mechanical systems are faced to produce on commercial scale. This paper describes the recent progress of two mechanical circulatory support systems, AnyHeart and T-PLS.
ABSTRACT
A new and efficient method for the facile synthesis of C-2 branched carbohydrates has been developed using an intramolecular radical cyclization fragmentation reaction. The desired C-2 branched glucopyranosides were isolated in 40-84% yield. Additionally, an unexpected furanoside was obtained from a tributyltin iodide-promoted rearrangement of the radical intermediate. The C-2 formyl glycal was also isolated in good yield using tris(trimethylsilyl)silane (TTMSS) as the reducing agent. This method was extended to synthesize a beta C-2 branched glucopyranoside, a C-2 branched galactoside and a C-2 cyano glucopyranoside.