Differential expression of PPAR gamma1 and gamma2 isoforms in human adipose tissue.

One of the essential factors for adipogenesis, peroxisome proliferator activated receptor gamma (PPAR gamma), is classified into two isoforms, gamma1 and gamma2 encoded by a single PPAR gamma gene. To examine the mode of expressions of both the PPAR gamma1 and gamma2 isoforms in human adipose tissue, we cloned a partial cDNA of the human PPAR gamma2 (hPPAR gamma2) from a human adipose tissue cDNA library. The sequence encoded an additional 28 amino acids amino-terminal to the first ATG codon of hPPAR gamma1. The simultaneous quantitation of hPPAR gamma1 and gamma2 mRNA in subcutaneous or visceral (mesenteric) fat tissue from 10 different individuals was performed by an RNase protection assay and revealed a relatively higher expression of gamma1 than gamma2 in all specimens examined.

[Pharmacokinetic studies of all-trans retinoic acid (ATRA) and pilot study of intermittent schedule of ATRA and chemotherapy in childhood acute promyelocytic leukemia. Children's Cancer and Leukemia Study Group].

A pharmacokinetic study of all-trans retinoic acid (ATRA) was performed in 8 patients with various types of leukemia and MDS. After oral administration at a dose of 30 mg/m2, the mean peak plasma concentration was 430 ng/ml and was reached at 150 min. In one patient who failed to respond a very low plasma ATRA level was seen. Though the plasma ATRA exposure decreased significantly with daily drug administration, an intermittent schedule of ATRA administration would yield higher plasma drug concentrations. We treated 2 patients with refractory acute promyelocytic leukemia (APL) in a pilot study of ATRA followed by intensive chemotherapy (APL-ATRA protocol). Two patients successfully achieved complete remission with ATRA after failing under conventional chemotherapy. Based on the pharmacokinetic study of ATRA, an intermittent schedule of ATRA in addition to chemotherapy suggests an effective regimen for children with APL. Phase II trials to evaluate the role of intermittent schedules of ATRA are planned in Children's Cancer and Leukemia Study Group.

[Treatment results of intermittent and cyclic regimen with ATRA and chemotherapy in childhood acute promyelocytic leukemia. Children's Cancer and Leukemia Study Group].

An intermittent and cyclic regimen with All-Trans Retinoic Acid (ATRA) and intensive chemotherapy was conducted due to pharmacokinetic studies on ATRA for acute promyelocytic leukemia (APL) in children. We have treated 17 children with APL using ATRA for remission induction followed by an intermittent schedule of ATRA plus intensive chemotherapy (APL-ATRA protocol). There were 10 males and 7 females. The median age was 9.0 years old. The median baseline white blood cell count was 12.1 x 10(3)/microliter, hemoglobin 7.8 g/dl, platelet 4.5 x 10(4) microliters at diagnosis. Sixteen patients showed t(15; 17) translocation. RT-PCR analysis was available in 15 patients and showed PML/RAR alpha rearrangement in all patients. Overall, 13 or 17 newly diagnosed patients (88%) achieved complete remission and EFS was 67%. Compared to the control (same chemotherapy without ATRA regimen), remission induction and EFS were significantly increased. The toxicity of ATRA consisted of retinoic acid syndrome in 1 and pseudotumor cerebli in another. Other toxicities included headache, chelitis, gastrointestinal trouble and bone pain. These results suggest that intermittent and cyclic regimen with ATRA and intensive chemotherapy (APL-ATRA protocol) is highly effective for APL patients.

4-oxo retinoic acid for refractory acute promyelocytic leukemia in children with all-trans retinoic acid therapy.

Therapy with all-trans retinoic acid (ATRA) achieves complete remission in a high proportion of patients with acute promyelocytic leukemia (APL), but the efficacy is reported to relate to plasma ATRA level after oral administration. The pharmacokinetics of ATRA and 4-oxo all-trans retinoic acid (4-oxo ATRA), a metabolite of ATRA, were studied in four children with APL at the time of initial oral administration. After administration of ATRA at a dose of 30 mg/m2, the peak plasma ATRA level was 20-741 ng/ml and was reached at 60-120 min. The patient with the lowest peak plasma level did not achieve complete remission and had a very high 4-oxo ATRA level compared to the patients with complete remission. These findings suggest that accelerated metabolism of ATRA plays a role in the failure of this agent in the patients without remission.

Pharmacokinetics of all-trans retinoic acid in pediatric patients with leukemia.

Since all-trans retinoic acid (ATRA) induces complete remission in a high proportion of patients with acute promyelocytic leukemia (APL), and its effectiveness appears to be related to the plasma or serum level, a pharmacokinetic study of ATRA was undertaken in nine patients with various leukemias. After oral administration at a dose of 30 mg/m2, the time required to reach the peak plasma level of ATRA (20-1198 ng/ml) was between 120 and 240 min and the apparent plasma elimination half life was 21-51 min. In addition, 13-cis retinoic acid was detected in the plasma of seven patients, indicating the occurrence of ATRA isomerization in vivo. ATRA therapy did not induce complete remission in all patients, even when high plasma levels were achieved. Among the six APL patients given ATRA therapy, one who failed to respond had a very low plasma ATRA level. These findings suggest that it may be useful to monitor plasma levels during oral ATRA therapy in order to achieve an appropriate treatment regimen.

[Induction and maintenance therapy in all-trans retinoic acid with relapsed acute promyelocytic leukemia].

We reported a 17-year-old girl with relapsed acute promyelocytic leukemia (APL) who achieved complete remission and has been received maintenance therapy with all-trans retinoic acid (ATRA). The patient was diagnosed as APL in 1986. The ANLL 861 protocol of the Children's Cancer and Leukemia Study Group induced complete remission, and the chemotherapy was discontinued in 1989. However, she suffered a relapse with APL in 1991 and begun receiving ATRA (30 mg/m2/day) therapy because of disseminated intravascular coagulation. Bleeding tendency was discontinued by day 5. During the treatment, the white blood cell count increased markedly to 35,510 per microliters on 15th day, however she achieved complete remission morphologically on day 18. After informed consent was obtained from the family, she has been given ATRA orally for more than three years at the time of this report. The pharmacokinetics examination (ATRA 20 mg/m2 single per os) was performed 12 and 22 months after the induction therapy. The each peak plasma level of ATRA was 89 and 149 ng/ml. The concentration of ATRA has yet reached a level despite the continuous ATRA therapy. We considered that it may be useful to monitor plasma levels of ATRA during the treatment.

[Pharmacokinetic and clinical evaluations of fluconazole in pediatric patients].

Fluconazole (FLCZ) is a novel antifungal agent and available both in oral and intravenous forms. It is characterized by a long plasma half-life and a good absorbability into tissues. Because of these, it is expected to be used safety and to exhibit good clinical efficacy in the deep seated mycosis of children. We evaluated the efficacy of FLCZ given orally or intravenously to 6 patients. Pathogenic fungi isolated from all patients were Candida, and diagnosises made were candidemia in 3 cases, gastro-intestinal candidiasis in 2 and skin candidiasis. The clinical efficacies of FLCZ in 5 cases were excellent in 2 cases of gastro-intestinal candidiasis and poor in 3 cases of candidemia. None of the patients reported any side effect. In clinical laboratory tests, no abnormalities that were judged to be related to FLCZ were noted. In the study, clinical efficacy was shown to be poor in candidemia, because these cases had severe underlying diseases and the proper therapy was started too late. Thus earlier diagnosis and earlier treatment seem to be important for FLCZ to exhibit good clinical efficacy in the treatment of deep-seated mycosis.