Influence of the cytochrome P450 2D6 *10/*10 genotype on the pharmacokinetics of paroxetine in Japanese patients with major depressive disorder: a population pharmacokinetic analysis.

Objective: Although the reduced function of the cytochrome P450 2D6*10 (CYP2D6*10) allele is common among Asian populations, existing evidence does not support paroxetine therapy adjustments for patients who have the CYP2D6*10 allele. In this study, we attempted to evaluate the degree of the impact of different CYP2D6 genotypes on the pharmacokinetic (PK) variability of paroxetine in a Japanese population using a population PK approach.

Methods: This retrospective study included 179 Japanese patients with major depressive disorder who were being treated with paroxetine.

Determination of the Optimal Concentration of Valproic Acid in Patients with Epilepsy: A Population Pharmacokinetic-Pharmacodynamic Analysis.

Valproic acid (VPA) is one of the most widely prescribed antiepileptic drugs for the treatment of epileptic seizures. Although it is well known that the doses of VPA and its plasma concentrations are highly correlated, the plasma concentrations do not correlate well with the therapeutic effects of the VPA. In this study, we developed a population-based pharmacokinetic (PK)-pharmacodynamic (PD) model to determine the optimal concentration of VPA according to the clinical characteristics of each patient.

Impact of the superoxide dismutase 2 Val16Ala polymorphism on the relationship between valproic acid exposure and elevation of γ-glutamyltransferase in patients with epilepsy: a population pharmacokinetic-pharmacodynamic analysis.

Background: There has been accumulating evidence that there are associations among γ-glutamyltransferase (γ-GT) elevation and all-cause mortality, cardiovascular diseases and metabolic diseases, including nonalcoholic fatty liver disease. The primary objective of this study was to evaluate the impact of the most common and potentially functional polymorphisms of antioxidant enzyme genes, i.e.

Possible impact of the CYP2D6*10 polymorphism on the nonlinear pharmacokinetic parameter estimates of paroxetine in Japanese patients with major depressive disorders.

It has been suggested that the reduced function allele with reduced cytochrome P450 (CYP) 2D6 activity, CYP2D6*10, is associated with the interindividual differences in the plasma paroxetine concentrations, but there is no data presently available regarding the influence of the CYP2D6*10 polymorphism on the pharmacokinetic parameters, eg, Michaelis-Menten constant (Km) and maximum velocity (Vmax), in Asian populations. The present study investigated the effects of the CYP2D6 polymorphisms, including CYP2D6*10, on the pharmacokinetic parameters of paroxetine in Japanese patients with major depressive disorders. This retrospective study included 15 Japanese patients with major depressive disorders (four males and eleven females) who were treated with paroxetine.

Effects of CYP2C19 and P450 oxidoreductase polymorphisms on the population pharmacokinetics of clobazam and N-desmethylclobazam in japanese patients with epilepsy.

Background: Clobazam (CLB) is a 1,5-benzodiazepine with antiepileptic properties. More than 70% of administered CLB is dealkylated to yield N-desmethylclobazam (N-CLB), a pharmacologically active metabolite, by cytochrome P450 (CYP) 3A4 and CYP2C19. The subsequent inactivation of N-CLB is primarily catalyzed by CYP2C19.

Super-acute onset of tumor lysis syndrome accompanied by hypercytokinemia during treatment of Hodgkin's lymphoma with ABVD chemotherapy.

Background: Tumor lysis syndrome (TLS) is a group of life-threatening metabolic complications that can occur after initiation of cancer chemotherapy. Onset of TLS in the middle of chemotherapy, however, has not been reported previously in patients with hematologic malignancies.

Objective: We report a case of a patient who experienced TLS of super-acute onset accompanied by hypercytokinemia during chemotherapy treatment with a combination of doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD).

TAK1-mediated serine/threonine phosphorylation of epidermal growth factor receptor via p38/extracellular signal-regulated kinase: NF-{kappa}B-independent survival pathways in tumor necrosis factor alpha signaling.

The kinase TAK1, a mitogen-activated protein kinase kinase kinase (MAP3K), has been widely accepted as a key kinase activating NF-kappaB and MAPKs in tumor necrosis factor alpha (TNF-alpha) signaling. We have recently reported that TAK1 regulates the transient phosphorylation and endocytosis of epidermal growth factor receptor (EGFR) in a tyrosine kinase activity-independent manner. In the present study, we found that Thr-669 in the juxtamembrane domain and Ser-1046/1047 in the carboxyl-terminal regulatory domain were transiently phosphorylated in response to TNF-alpha.

Cross interference with TNF-alpha-induced TAK1 activation via EGFR-mediated p38 phosphorylation of TAK1-binding protein 1.

Transforming growth factor-alpha-activated kinase 1 (TAK1) has been widely recognized as a kinase that regulates multiple intracellular signaling pathways evoked by cytokines and immune receptor activation. We have recently reported that tumor necrosis factor-alpha (TNF-alpha) triggers internalization of epidermal growth factor receptor (EGFR) through a TAK1-p38alpha signaling pathway, which results in a transient suppression of the EGFR. In the present study, we investigated the pathway of intracellular signaling in the opposite direction.

Ligation of CD44 leads to killing activity in human peripheral mononuclear cells via MAP kinase and tyrosine kinases.

CD44 is a widely distributed transmembrane glycoprotein associated with various lymphocyte functions, including lympho-hemopoiesis, adhesion to the extracellular matrix, and T cell activation. In this study, we examined the mechanisms of CD44 involvement in regulating the killing activity of human peripheral mononuclear cells (PMC). An anti-CD44 monoclonal antibody (mAb) J173 enhanced the killing activity of PMC against Daudi and K562 cells in a dose-dependent manner.

Probable interaction between warfarin and antitumor agents used in R-ESHAP chemotherapy.

Background: The pharmacologic effects of warfarin might be altered by various factors, including drug-drug interaction.

Case Summary: A 49-year-old Japanese man (height, 174 cm; weight, 68 kg) presented with a 20-month history of malignant lymphoma (diffuse large B cell lymphoma, clinical stage IV). He was treated with a combination of rituximab chemotherapy and etoposide, cisplatin, high-dose cytarabine, and methyl-prednisolone (R-ESHAP).

Allogeneic hematopoietic stem cell transplantation for Epstein-Barr virus-associated T/natural killer-cell lymphoproliferative disease in Japan.

Epstein-Barr virus (EBV)-associated T/NK-cell lymphoproliferative disease (LPD) has been linked to several different disorders. Its prognosis is generally poor and a treatment strategy has yet to be established. There are reports, however, that hematopoietic stem cell transplantation (HSCT) can cure this disease.

Restrictive usage of monoclonal immunoglobulin lambda light chain germline in POEMS syndrome.

POEMS syndrome is a rare plasma cell disorder characterized by peripheral neuropathy, monoclonal gammopathy, and high levels of serum vascular endothelial growth factor, the pathogenesis of which remains unclear. A unique feature of this syndrome is that the proliferating monoclonal plasma cells are essentially lambda-restricted. Here we determined complete nucleotide sequences of monoclonal immunoglobulin lambda light chain (IGL) variable regions in 11 patients with POEMS syndrome.

CD44 and hyaluronan engagement promotes dexamethasone resistance in human myeloma cells.

Dexamethasone (Dex) is an effective therapeutic agent against multiple myeloma (MM); however, resistance to it often becomes a clinical issue. CD44 is an adhesion molecule that serves as a cell surface receptor for extracellular matrix components, including hyaluronan (HA). HA is an extracellular matrix component that is involved in survival and progression in MM.

Zoledronate has an antitumor effect and induces actin rearrangement in dexamethasone-resistant myeloma cells.

New strategies are needed to overcome the resistance of multiple myeloma (MM) to dexamethasone (Dex). Several recent in vitro studies demonstrated the antitumor effect of nitrogen-containing amino-bisphosphonates (N-BPs) in various tumor cell lines. Inhibition of the prenylation of small G proteins is assumed to be one of the principal mechanisms by which N-BPs exert their effects.

[Hepatitis B virus reactivation in patients with HBs antibodies after allogeneic hematopoietic stem cell transplantation].

We retrospectively investigated the clinical characteristics of reactivation of hepatitis B (HB) virus after allogeneic hematopoietic stem cell transplantation (HSCT). Of 2002 patients who received transplantation between January 1994 and December 2004, seven patients who were anti-HB surface antibody (anti-HBs) positive and HB surface antigen (HBs-Ag) negative developed reactivation of the HB virus after allogeneic HSCT. The patients' median age was 49 years, and they consisted of 5 males and 2 females.

Chronic graft-versus-host disease after allogeneic bone marrow transplantation from an unrelated donor: incidence, risk factors and association with relapse. A report from the Japan Marrow Donor Program.

Chronic graft-versus-host disease (GVHD) remains the major cause of late morbidity and mortality after allogeneic stem cell transplantation. We retrospectively analysed 2937 patients who underwent bone marrow transplantation from an unrelated donor (UR-BMT) facilitated by the Japan Marrow Donor Program (JMDP) and survived beyond day 100 after transplantation. The cumulative incidence of chronic GVHD (limited + extensive) or extensive chronic GVHD at 5 years post-transplant was 45.

Clinicopathological features in patients with hepatic graft-versus-host disease.

Background/aims: Hepatic graft-versus-host disease (GVHD) is a frequent complication after bone marrow transplantation and often results in a fatal outcome. However, hepatic manifestation of chronic GVHD accompanied by unresolved acute GVHD has not been clarified so far. The present study was intended to examine clinicopathological features in patients in which acute GVHD appeared to progress gradually into chronic GVHD.

Expression of the fetal-oncogenic fibroblast growth factor-8/17/18 subfamily in human hematopoietic tumors.

The fibroblast growth factors (FGFs) are involved in hematopoiesis and tumorigenesis. However, little is known about the contribution of the FGFs identified within the past 10 years to leukemogenesis. To elucidate whether these FGFs (FGF-8, -9, -10, -11, -12, -13, -14, -16, -17, -18, -19, -20, and -21) are expressed in leukemic cells, we performed RT-PCR analyses using 28 cell lines.

Lamivudine treatment in a patient with hepatitis B virus reactivation after allogenic peripheral bone marrow transplantation.

We report the case of a 52-year-old woman with hepatitis B virus (HBV) reactivation during treatment for chronic graft vs. host disease (GVHD) after peripheral bone marrow transplantation (PBSCT) to treat chronic myelocytic leukemia. She was given cyclosporine and prednisolone orally to treat chronic GVHD after PBSCT.

Clinical characteristics and prognostic implications of NPM1 mutations in acute myeloid leukemia.

Recently, somatic mutations of the nucleophosmin gene (NPM1), which alter the subcellular localization of the product, have been reported in acute myeloid leukemia (AML). We analyzed the clinical significance of NPM1 mutations in comparison with cytogenetics, FLT3, NRAS, and TP53 mutations, and a partial tandem duplication of the MLL gene (MLL-TD) in 257 patients with AML. We found NPM1 mutations, including 4 novel sequence variants, in 64 of 257 (24.

Methylation silencing of the Apaf-1 gene in acute leukemia.

Apaf-1 is important for tumor suppression and drug resistance because it plays a central role in DNA damage-induced apoptosis. Inactivation of the Apaf-1 gene is implicated in disease progression and chemoresistance of some malignancies. In this study, we attempted to clarify the role of Apaf-1 in leukemogenesis.

Reduced-intensity conditioning allogeneic stem cell transplantation for multiple myeloma: results from the Japan Myeloma Study Group.

We conducted a retrospective survey of multiple myeloma (MM) patients who underwent reduced-intensity conditioning allogeneic stem cell transplantation (RIST) at 11 hospitals participating in the Japan Myeloma Study Group. Forty-five patients (median age, 53 years) were included in this study. The conditioning regimen consisted of a fludarabine-based regimen in 24 patients and a regimen based on total body irradiation (1-2 Gy) in 18 patients.