tretinoin and Agranulocytosis

Amodiaquine (AQ) is associated with a relatively high incidence of idiosyncratic drug-induced liver injury (IDILI) and agranulocytosis. A previous study reported that a combination of high dose AQ and glutathione (GSH) depletion led to liver injury. However, the characteristics of this toxicity were very different from AQ-induced liver injury in humans. We developed a model of AQ-induced liver injury with characteristics similar to the injury in humans by treating mice with lower doses of AQ for several weeks. In this study we found that not only did GSH depletion not increase AQ covalent binding to hepatic proteins at this lower dose, but also it paradoxically prevented the liver injury. We extended the model to rats and found AQ treatment led to a mild delayed onset liver injury that resolved despite continued treatment with AQ. Immunohistochemistry indicated the presence of Kupffer cell activation, apoptosis and hepatocyte proliferation in the liver. There was also an increase in serum IL-2, IL-5, IL-9, IL-12, MCP-1 and TGFβ, but a decrease in leptin. Coincident with the elevated serum ALT, the number of liver CD4(+) T-cells, IL-17 secreting cells and TH17/Treg cells increased at Week 3 and decreased during continued treatment. Increases in NK1.1+ cells and activated M2 macrophages were also observed during liver injury. These results suggest that the outcome of the liver injury was determined by the balance between effector and regulatory cells. Co-treatment with cyclosporin prevented AQ-induced liver injury, which supports an immune mechanism. Retinoic acid (RA), which has been reported to enhance natural killer (NK) cell activity, exacerbated AQ-induced liver injury. These results suggest that AQ-induced IDILI is immune mediated and the subsequent adaptation appears to represent immune tolerance.

Topics: Agranulocytosis; Amodiaquine; Animals; Cells, Cultured; Chemical and Drug Induced Liver Injury; Cyclosporine; Cytokines; Disease Models, Animal; Humans; Killer Cells, Natural; Male; Mice; Mice, Inbred C57BL; Rats; Rats, Inbred BN; Remission, Spontaneous; Spinocerebellar Degenerations; T-Lymphocytes, Regulatory; Th17 Cells; Tretinoin

A 54-year-old female was admitted to our hospital for gingival bleeding and was diagnosed as acute promyelocytic leukemia (APL). She received induction therapy according to the AML92 protocol of the Japan Adult Leukemia Study Group (JALSG) with all-trans retinoic acid (ATRA) plus chemotherapeutic agents. She achieved complete remission, but one year later had a relapse in her external auditory canal without leukemic cell in the bone marrow. Extramedullary disease is rare in APL. This case suggests the importance of careful observation for extramedullary relapse in patients who are treated with ATRA.

Topics: Agranulocytosis; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Combined Modality Therapy; Cytarabine; Daunorubicin; Ear Canal; Female; Granulocyte Colony-Stimulating Factor; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Mercaptopurine; Middle Aged; Mitoxantrone; Neoplasm Proteins; Oncogene Proteins, Fusion; Radiotherapy; Recurrence; Remission Induction; Salvage Therapy; Tretinoin; Vindesine

Congenital agranulocytosis is a rare fatal infantile disease characterised by recurrent bacterial infections, persistent absence of neutrophils and maturation arrest at the promyelocyte/myelocyte stage. The effectiveness of retinoic acid in inducing differentiation of congenital agranulocytosis marrow myeloid progenitor cells was studied. Non-adherent mononuclear marrow cells were treated in an in vitro culture with retinoic acid at various concentrations from 1nM to 1 microM for seven days. Morphological and functional differentiation into mature granulocytes was induced by retinoic acid in a dose-response stimulation with a maximum response at a concentration of 1 microM. These results suggest a potential therapeutic role for retinoic acid in the treatment of congenital agranulocytosis.

Topics: Agranulocytosis; Bone Marrow; Cell Differentiation; Cells, Cultured; Dose-Response Relationship, Drug; Female; Granulocytes; Hematopoietic Stem Cells; Humans; Infant; Tretinoin

Congenital agranulocytosis is a rare and frequently fatal infantile disease characterized by recurrent bacterial infections, persistent absence of neutrophils in the peripheral blood and an arrest of myeloid maturation at the promyelocyte/myelocyte stage. The effect of human recombinant Granulocyte-Macrophage colony stimulating factor (GM-CSF) alone and in combination with retinoic acid, dimethylsulphoxide or actinomycin-D on the proliferation and differentiation of bone marrow cells from a child with congenital agranulocytosis was studied. Cells were treated at a concentration of 1 x 10(5) per ml in in-vitro culture with GM-CSF alone and in combination with retinoic acid, dimethylsulphoxide or actinomycin-D for 7 days at 37 degrees C in humidified incubator containing 5% CO2 in air. GM-CSF showed a profound stimulatory effect on the proliferation of myeloid progenitors from the child bone marrow and restored colony numbers in the retinoic acid-, dimethylsulphoxide- and actinomycin-D-inhibited cultures.

Topics: Agranulocytosis; Cell Differentiation; Cell Division; Colony-Stimulating Factors; Dactinomycin; Dimethyl Sulfoxide; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Substances; Hematopoietic Stem Cells; Humans; Infant; Recombinant Proteins; Tretinoin

Topics: Acne Vulgaris; Adolescent; Agranulocytosis; Humans; Isomerism; Isotretinoin; Male; Tretinoin

Topics: Acne Vulgaris; Adolescent; Agranulocytosis; Humans; Isotretinoin; Male; Neutropenia; Recurrence; Tretinoin

Topics: Acne Vulgaris; Adult; Agranulocytosis; Humans; Isotretinoin; Leukopenia; Male; Neutropenia; Time Factors; Tretinoin