RESUMO
BACKGROUND: White petrolatum is broadly used as an ointment vehicle, although hydrophilic drugs cannot be easily dissolved in the vehicle. METHOD: The aim of this study was to evaluate the release and skin permeation profiles of a model hydrophilic agent, N1-[2-(4-guanidinophenyl)-1(S)-(N-methylcarbamoyl)ethyl]-N4-hydroxy-2(R)-iso-butyl-3(S)-(3-phenylpropyl)succinamide hydrochloride (FYK-1388b), from the ointment. RESULTS: The release rate of FYK-1388b was very low; however, high skin permeation and skin content of the drug were found. We supposed that this was due to endogenous lipids or sebum, because white petrolatum had a high affinity to these lipids. To evaluate the effect of lipids on the enhanced release and skin permeation of FYK-1388b, 'preapplied white petrolatum' was made by applying the drug-free white petrolatum on the hairless rat skin for 6 hours. Then the drug ointment was prepared using the 'preapplied white petrolatum'. The release rate of FYK-1388b was markedly increased from the 'preapplied ointment' compared with the 'original ointment'. In addition, much higher skin permeation was also obtained using the 'preapplied ointment'. Separately, cholesteryl oleate, cholesterol, and ceramides were found in the 'preapplied white petrolatum'. CONCLUSION: Thus, these endogenous lipids on the skin surface may enhance the release and skin permeation of FYK-1388b from white petrolatum ointment.
Assuntos
Bases para Pomadas/química , Vaselina/química , Absorção Cutânea , Pele/metabolismo , Administração Tópica , Animais , Cromatografia Líquida de Alta Pressão , Guanidinas/administração & dosagem , Guanidinas/química , Guanidinas/farmacocinética , Ácidos Hidroxâmicos/administração & dosagem , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacocinética , Técnicas In Vitro , Lipídeos/química , Masculino , Estrutura Molecular , Pomadas , Ratos , Ratos Pelados , Absorção Cutânea/efeitos dos fármacos , SolubilidadeRESUMO
Thrombopoietin (TPO) regulates megakaryocytopoiesis and platelet production in vivo and in vitro. Exogenous overexpression of TPO in vivo by viral-mediated gene transfer induced bone marrow (BM) fibrosis and osteosclerosis. On the other hand, transgenic mice (Tg) overexpressing TPO using a liver-specific apolipoprotein E (Apo-E) promoter did not exhibit myelofibrosis or osteosclerosis. These discrepancies in phenotype are not fully understood. Then we have investigated the consequences of long-term in vivo overexpression of TPO in a mouse model. Murine TPO Tg mice driven by the IgH promoter were generated. The number of platelets and neutrophils in peripheral blood, and the number of megakaryocytes and granulocytic immature cells in the BM was elevated, together with the number of progenitor cells for megakaryocyte and myeloid cells. TPO Tg mice demonstrated anemia but the number of progenitor cells for the erythrocyte was increased. TPO Tg mice developed myelofibrosis and osteosclerosis as they aged with extramedullary hematopoiesis in the spleen. As plasma transforming growth factors (TGF)-beta1 and osteoprotegerin (OPG) levels were higher in TPO Tg mice than in wild-type mice, the development of myelofibrosis and osteosclerosis depends on local TPO levels in BM and might be due to elevated TGF-beta1 and OPG.
Assuntos
Células da Medula Óssea/fisiologia , Osteosclerose/genética , Mielofibrose Primária/genética , Trombopoetina/genética , Animais , Apolipoproteínas E/genética , Células da Medula Óssea/citologia , Clonagem Molecular , Primers do DNA , Eritropoetina/sangue , Rearranjo Gênico , Globinas/genética , Cadeias Pesadas de Imunoglobulinas/genética , Camundongos , Camundongos Transgênicos , Reação em Cadeia da Polimerase , Regiões Promotoras Genéticas , Coelhos , Valores de Referência , Trombopoetina/fisiologiaRESUMO
A 2-year-old Japanese boy who presented with multiple cervical, axillary, and inguinal lymphadenopathy was diagnosed by immunocytochemical analysis as having myeloid/natural killer (NK) cell precursor acute leukemia. Leukemic blasts in the bone marrow were positive for CD56 (NK marker), CD7 (T-cell marker), CD33 (myeloid marker), CD34, and HLA-DR. Tumor cells in a lymph node were also positive for CD2, cytoplasmic CD3 (T-cell marker), CD7, CD33, CD34, and CD56, but negative for peroxidase staining and other T-cell, NK, and myeloid markers. Southern blot analysis showed no rearrangement bands for T-cell receptor delta and immunoglobulin heavy chain. Chromosomal analysis revealed 46,XY,inv(7)(p21q21). Neither chemotherapy for acute lymphoblastic leukemia nor that for acute myeloid leukemia induced remission in this patient. However, complete remission was achieved by the administration of L-asparaginase (6,000 U/m2 for 5 days). Because the disease was considered refractory to standard chemotherapy, cord blood transplantation was performed from an HLA 1-locus mis-matched unrelated donor. The conditioning regimen consisted of total body irradiation, cytarabine, and cyclophosphamide, and cyclosporine and short-term methotrexate were employed for graft-versus-host disease (GVHD) prophylaxis. Hematological reconstitution was rapid, and only grade I acute GVHD was observed. The patient has been in remission for more than 24 months after transplantation. Our findings indicate that combination therapy with L-asparaginase and allogeneic stem cell transplantation may be useful for the treatment of myeloid/NK cell precursor acute leukemia.