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UDP-glucuronosyltransferase (UGT) is an enzyme that catalyses a major phase II reaction in drug metabolism. Glucuronidation occurs mainly in the liver, but UGTs are also expressed in extrahepatic tissues, where they play an important role in local metabolism. UGT1A isoforms catalyse the glucuronidation of several drugs, neurotransmitters and neurosteroids that exert pharmacological and physiological effects on the brain. The aim of the current study was to determine UGT1A mRNA expression levels and glucuronidation activities in different regions of the rat brain (namely the cerebellum, frontal cortex, parietal cortex, piriform cortex, hippocampus, medulla oblongata, olfactory bulb, striatum and thalamus). It was found that all UGT1A isoforms were expressed in all the nine regions, but their expression levels differed between the regions. The difference between the regions of the brain where the mRNA levels were highest and those where they were lowest ranged between 2.1- to 7.8-fold. Glucuronidation activities were measured using the UGT substrates such as mycophenolic acid, p-nitrophenol and umbelliferone. Glucuronidation activity was detected in all nine regions of the brain. Activity levels differed between the regions, and were highest in the cerebellum, medulla oblongata and olfactory bulb. Differences in glucuronidation activity between regions with the highest rates and those with the lowest rates ranged from 5.3- to 10.1-fold. These results will contribute to our current understanding of the physiological and pharmacokinetic roles of drug-metabolizing enzymes in the brain. Copyright © 2016 John Wiley & Sons, Ltd.

UDP-glucuronosyltransferase (UGT) is an enzyme that catalyses a major phase II reaction in drug metabolism. Glucuronidation occurs mainly in the liver, but UGTs are also expressed in extrahepatic tissues, where they play an important role in local metabolism. UGT1A isoforms catalyse the glucuronidation of several drugs, neurotransmitters and neurosteroids that exert pharmacological and physiological effects on the brain. The aim of the current study was to determine UGT1A mRNA expression levels and glucuronidation activities in different regions of the rat brain (namely the cerebellum, frontal cortex, parietal cortex, piriform cortex, hippocampus, medulla oblongata, olfactory bulb, striatum and thalamus). It was found that all UGT1A isoforms were expressed in all the nine regions, but their expression levels differed between the regions. The difference between the regions of the brain where the mRNA levels were highest and those where they were lowest ranged between 2.1- to 7.8-fold. Glucuronidation activities were measured using the UGT substrates such as mycophenolic acid, p-nitrophenol and umbelliferone. Glucuronidation activity was detected in all nine regions of the brain. Activity levels differed between the regions, and were highest in the cerebellum, medulla oblongata and olfactory bulb. Differences in glucuronidation activity between regions with the highest rates and those with the lowest rates ranged from 5.3- to 10.1-fold. These results will contribute to our current understanding of the physiological and pharmacokinetic roles of drug-metabolizing enzymes in the brain. Copyright © 2016 John WileySons, Ltd.

The findings of morphologically dysplastic features in haemopoietic cells in de novo acute myeloid leukaemia (AML) has been named AML with trilineage myelodysplasia (AML/TMDS). We analysed the clinical data, karyotypes, and treatment outcomes of 230 de novo AML patients treated with the Japan Adult Leukaemia Study Group AML-87 protocol. 40 (17%) patients had AML/TMDS. Platelet count was significantly higher (P = 0.006) and bone marrow blasts were fewer (P = 0.01) in the AML/TMDS group than in the AML without TMDS. Abnormal karyotype was shown in 12/30 patients (40%) analysed. The complete remission (CR) rate for AML/TMDS was significantly lower than AML without TMDS (63% v 81%) (P = 0.01). The overall survival curves showed that the 40 patients with TMDS had a significantly worse survival than the 190 without TMDS (P = 0.0005). AML/TMDS also showed significantly worse disease-free survival (DFS) (P = 0.0001). Multivariate analysis revealed that the absence of TMDS in AML was the most significant factor in obtaining CR (P = 0.01) and a significant factor in predicting longer DFS (P = 0.04). Our data suggest that AML/TMDS responds poorly to intensive chemotherapy. Further study is required to determine the best treatment strategy for AML/TMDS and the biological differences between AML/TMDS and other types of AML.

Background. It was assessed whether addition of vincristine (VCR) to remission induction therapy would increase the complete remission (CR) rate, and, secondarily, whether 12 courses of maintenance—intensification therapy would produce longer survival than 4 courses in adult acute myeloid leukemia (AML). Methods. A randomized comparison of individualized induction therapy was conducted between daunorubicin, behenoyl cytarabine, 6-mercaptopurine, and prednisolone with or without VCR. After 3 courses of intensive consolidation therapy, maintenance—intensification therapy was randomized to 4 or 12 courses given every 6 weeks. Results. Of 265 patients registered, 252 were evaluable. CR was obtained in 78%; 80% in 205 patients of age younger than 60 years, and 65% in 47 of age 60 years or older. Addition of VCR reduced the CR rate significantly (84% to 70%, P = 0.007). Predicted 4-year survival, continuing CR, and disease-free survival (DFS) rates of 196 CR patients are 45%, 41%, and 35%, respectively. Patients receiving 12 courses of maintenance—intensification showed better DFS. By multivariate analyses, significant factors for achievement of CR were performance status 0 to 2, age younger than 60 years, and no VCR; and those for longer DFS were achievement of CR by one course, age younger than 50 years, and French—American—British (FAB) classification M3 or M5. Among 131 patients randomized to the maintenance, the administration of 12 courses was the most important factor (P = 0.0040) for longer DFS, followed by FAB M3 or M5, and by achievement of CR by one course. Conclusions. Addition of VCR in remission induction therapy was harmful, and longer intensive maintenance therapy prolonged DFS in adult AML.

In this study, the involvement of sulfate conjugation and drug efflux transporter multidrug resistance-associated protein 2 (Mrp2) in sex-related differences in the pharmacokinetics of a new quinolone antimicrobial agent, garenoxacin, was investigated in Sprague-Dawley (SD) rats and Eisai hyperbilirubinemic rats (EHBRs) lacking Mrp2. The disappearance of garenoxacin from plasma in female SD rats was significantly faster than that in male SD rats after a single intravenous injection of garenoxacin (5 mg/kg). The systemic clearance of garenoxacin in female rats was approximately threefold larger than that of male rats (2.43 ± 0.31 and 0.87 ± 0.06 l/h/kg, respectively), suggesting the existence of sex-related differences in the pharmacokinetics of garenoxacin. When rats received a constant-rate infusion of garenoxacin, the contribution of biliary and renal excretion of garenoxacin was small, and no significant difference in the biliary (CL(BILE)) clearance of garenoxacin was observed between male and female SD rats. The metabolic clearance [CL(M (SULF))] of garenoxacin to garenoxacin sulfate conjugate (which is mainly excreted into the bile) in female SD rats was 8.5-fold larger than that in male SD rats (27.9 ± 2.94 and 3.28 ± 0.07 ml/h/kg, respectively). The CL(BILE) of garenoxacin was decreased in male and female EHBRs by approximately 50% compared with that in male and female SD rats. These results suggest that sulfate conjugation, but not Mrp2, is mainly involved in the sex-related differences in the pharmacokinetics of garenoxacin.

l-P-Z)-Arabinofuranosylcytosine-5’-stearylphosphate (fosteabine) was administered orally to patients with myelodysplastic syndromes (MDS); refractory anemia with excess of blasts (RAEB), RAEB in trans

Thirty-seven adults with acute myelogenous leukemia (AML) were treated with a combination of daunorubicin, cytosine arabinoside, 6-mercaptopurine riboside, and prednisolone (DCMP) for remission induction. Twenty-three of 37 patients (62.2%) achieved complete remission, three, partial remission and 11, failure. Patients with prior therapy responded as well as patients without it. The median survival time of the patients who received DCMP for their initial remission induction therapy was 10.3 months and that of the patients who obtained complete remission was 17 months. Complete remission occurred in 21 out of 28 patients (75%) less than 40 years old but in only two out of nine patients (22.2%) more than 40 years old. The most common toxic effects were severe myelosuppression and liver function abnormalities. DCMP therapy is an effective remission induction chemotherapy for adults with AML.

The effect of immunotherapy with a protein-bound polysaccharide preparation termed PSK on remission duration and survival of adults with acute nonlymphocytic leukemia (ANLL) was studied in a prospective randomized cooperative trial. After having achieved complete remission and receiving a consolidation therapy, 73 patients were randomized either to maintenance chemotherapy or to maintenance chemotherapy plus immunotherapy with PSK. Ultimately 36 patients in the chemotherapy group and 31 in the chemoimmunotherapy group were evaluable. Six months after the last entry, immunotherapy with PSK showed a borderline beneficial effect on remission duration (P = 0.089) and on duration of survival (P = 0.062). When the data were analyzed 12, 18, and 24 months after the last entry there were no significant differences in duration of remission and survival between the two groups. However, analysis of the data of patients who had maintained complete remission for more than 270 days revealed that immunotherapy had a suggestive beneficial effect (P = 0.105), prolonging the 50% remission period by 418 days (885 vs 467 days). Thus, immunotherapy with PSK seems to be active in the treatment of adult ANLL when used for maintenance therapy in combination with chemotherapy, especially in patients with a good prognosis.

Sixteen Long-Evans rats with leukemias induced by 7,12-dimethylbenz(a)anthracene were studied for evidence of naturally occurring immunologic responses to their own leukemic cells with an immune adherence hemagglutination technique which was designed to detect fresh serum auto-antibodies to the membrane of the leukemic cells. Auto-antibodies to the cell membranes were found in 14 out of 16 rats, but were not demonstrable in the other two rats. Autochthonous thymus cells used as controls did not show positive immune adherence hemagglutination reactions with their own sera, nor did the leukemic cells show positive reactions with the pooled normal rat serum. These findings suggest a possibility that the leukemic rats are able to produce humoral antibodies against membrane-specific antigens of autochthonous leukemic cells.