Takako Komiyama

Susceptibility to 6‐MP toxicity conferred by a NUDT15 variant in Japanese children with acute lymphoblastic leukaemia

Genotyping of TPMT prior to 6‐mercaptopurine (6‐MP) administration in acute lymphoblastic leukaemia (ALL) patients has been integrated into clinical practice in some populations of European ancestry. However, the comparable rates of 6‐MP myelotoxicity, but rarity of TPMT variants, in Asians suggest that major determinants have yet to be discovered in this population. We genotyped 92 Japanese paediatric ALL patients for NUDT15 rs116855232, a 6‐MP toxicity‐related locus discovered in Asians. Logistic regression and survival analysis were used to evaluate its association with leucopenia, hepatotoxicity, 6‐MP dose reduction, therapy interruption and event‐free survival. The allele frequency of rs116855232 was 0·16, and leucopenia was more common in carriers of the T allele (odds ratio, 7·20; 95% confidence interval, 2·49–20·80; P = 2·7 × 10−4). As leucopenia results in 6‐MP dose reduction, we observed average doses during maintenance therapy of 40·7, 29·3 and 8·8 mg/m2 for patients with CC, CT and TT genotypes, respectively (P < 0·001). Hepatotoxicity was observed only in CC genotype patients. Event‐free survival did not significantly differ by NUDT15 genotype. rs116855232 is an important determinant of 6‐MP myelotoxicity in Japanese children with ALL and may represent the most robust toxicity‐related locus in Asians to date. Considerations for clinical application may be warranted.

The activity of the inosine triphosphate pyrophosphatase affects toxicity of 6-mercaptopurine during maintenance therapy for acute lymphoblastic leukemia in Japanese children

The association between inosine triphosphate pyrophosphatase (ITPA) activity and toxicity of 6-mercaptopurine (6-MP) was retrospectively evaluated in 65 Japanese children with acute lymphoblastic leukemia (ALL). Patients with an ITPA activity of less than 126 μmol/h/gHb presented with hepatotoxicity more frequently than those with higher ITPA activity (p<0.01). The average 6-MP dose during maintenance therapy administered to two patients with the ITPA deficiency was lower than that given to the other patients. Measuring ITPA activity is important for ensuring the safety of maintenance therapy for Asians with ALL because thiopurine S-methyl transferase mutations are rare in the Asian population.

Lower doses of 6-mercaptopurine/azathioprine bring enough clinical efficacy and therapeutic concentration of erythrocyte 6-mercaptopurine metabolite in Japanese IBD patients.

Background: Although 6-mercaptopurine (6-MP) and azathioprine (AZA) are prescribed at lower doses, their efficacy in patients with inflammatory bowel disease (IBD) in Japan is comparable to that in Europe/America. However, there has been no report concerning the measurement of erythrocyte 6-thioguanine nucleotides (6-TGN), which is an active metabolite of 6-MP or AZA, in Japanese IBD patients. This study was designed to elucidate the pharmacokinetic–pharmacodynamic properties of 6-MP and AZA in Japanese patients by measurement of erythrocyte 6-TGN level. Methods: 134 adult patients (99 males; 35 females) with IBD (75 ulcerative colitis; 59 Crohns disease) who had been receiving a constant dose of 6-MP or AZA for three months or longer were enrolled. Erythrocyte 6-TGN levels were measured using the low-pressure gradient HPLC method, and correlated with treatment efficacy. The genetic polymorphism of thiopurine methyltransferase (TPMT) genotype was also assessed. Results: The mean erythrocyte 6-TGN level (mean ± SD) was 342.3 ± 220.9 pmol/8 × 108RBC, which was supposed to be therapeutic concentration, although the mean daily doses of 6-MP and AZA were no more than 29.8 ± 9.9 mg/day of 6-MP equivalent. However, all patients were identified with the wild type of TPMT genotype. There was no significant difference in the mean 6-TGN levels between patients in remission and no-remission group. The mean 6-TGN level was significantly higher in the once-daily administration group than three times-daily group. Conclusion: Thirty mg/day of 6-MP or 50 mg/day of AZA, once-daily oral administration in Japanese IBD patients was sufficient to achieve the therapeutic target level of 6-TGN in Europeans/Americans.

Methylenetetrahydrofolate reductase gene haplotypes affect toxicity during maintenance therapy for childhood acute lymphoblastic leukemia in Japanese patients

Abstract The aim of this study was to investigate the influence of daily 6-mercaptopurine (6-MP) and low-dose weekly methotrexate (MTX) combination treatment and methylenetetrahydrofolate reductase (MTHFR) haplotypes on toxicity during maintenance therapy in Japanese childhood acute lymphoblastic leukemia (ALL). We retrospectively analyzed the MTHFR C677T and A1298C polymorphisms and influence of haplotypes on toxicity in 73 patients. Patients with the MTHFR 677TT and 677CT + 1298AC were associated with severe liver toxicity (p = 0.014, odds ratio [OR] = 3.82, 95% confidence interval [CI] = 1.27–11.46) and more rapid onset of liver toxicity (p = 0.010). Patients with MTHFR 677TT and 677CT + 1298AC were associated with lower frequency of 6-MP and MTX dose reduction due to leukopenia (p < 0.05). No difference was observed in average drug doses in the MTHFR genotypes. In conclusion, the MTHFR C677T and A1298C haplotypes might be useful for monitoring adverse effects in childhood ALL maintenance therapy in Japanese patients.

Optimal Erythrocyte Ribavirin Level to Reduce the Risk of Anemia and Obtain an Early Virological Response in Patients with Chronic Hepatitis C Caused by Genotype 1b Infection

Aims. To determine whether the erythrocyte phosphorylated ribavirin (RBV) level might be a useful index of EVR and risk of anemia and to determine the optimal dose of RBV in 24 patients with hepatitis C with pegylated interferon and RBV. Methodology. The RBV level was measured by a high-performance liquid chromatography. Results and Conclusion. In patients aged 50 years or over, a negative correlation (r = −0.548, P < .05) was observed between the RBV level at week 2 and rate of Hb reduction (ΔHb) at week 4. The ΔHb at week 4 was significantly greater in patients with RBV levels of ≥800 μM (−25.5 ± 10.1%) than in patients with RBV levels <800 μM (−15.6 ± 7.7%). None of the patients with RBV levels <600 μM at week 2 achieved EVR and SVR. Thus the optimal levels of erythrocyte phosphorylated RBV at week 2 of therapy in order to achieve EVR without anemia seemed to be 600–800 μM.

Pharmacokinetics and postoperative analgesia of epidural tramadol: A prospective, pilot study

BACKGROUND Tramadol, a centrally acting analgesic drug, can be administered via multiple routes and is generally well tolerated. OBJECTIVE This study was designed to assess the pharmacokinetics of epidural tramadol administered preoperatively in Japanese patients undergoing upper abdominal surgery. METHOD Japanese patients who were scheduled to undergo upper abdominal surgery in The Kitasato Institute Hospital, Tokyo, Japan, were included. Patients received tramadol 2 mg/kg with 5 mL of 1% mepivacaine epidurally 10 minutes before incision. The serum concentration of tramadol was determined by high-performance liquid chromatography for 21 hours after administration. Serum concentration was determined before tramadol administration and 10, 20, 30, and 60 minutes after tramadol administration, first postoperative night, and first postoperative day. Pain score and adverse events (AEs) were assessed at 1, 3, 6, 12, 18, 24, 36, and 48 hours after surgery by patient interview. RESULTS Eleven patients were assessed for enrollment. Seven patients (6 men, 1 woman; mean [SD] age, 61.3 [12.6] years; mean [SD] weight, 59.9 [8.9] kg) provided consent and completed the study. The mean (SD) serum Cmax of tramadol was 1385.5 (390.8) ng/mL, Tmax was 0.33 (0.22) hour, and terminal elimination half-life (t1/2β) was 10.5 (2.3) hours. Four patients complained of nausea; however, only 1 patient was administered an antiemetic. No other AEs were reported. CONCLUSION This pilot study found that epidural tramadol administered before incision induced a Cmax within 30 minutes of administration. The drug was detected in serum at ∼21 hours after surgery.

Differential induction of serum interleukin-6 and -12 by interferon-α and -β administration in chronic hepatitis C patients

Abstract Interferon (IFN) is widely used to manage chronic hepatitis C virus (HCV) infections. It contributes to the production of various cytokines, and alters cytokine interactions in vivo. Among them, interleukin (IL)-12, is thought to shift the immune system to Th-1 dominance and to, therefore, have a beneficial effect on eradication of HCV. On the other hand, IL-6 seems to be related to the acute inflammatory phenomenon, such as fever accompanied with IFN therapy. We studied the time courses of the serum IL-12 and IL-6 levels of patients with HCV infections treated with either IFN-α or IFN-β. On the first day, both IFN-α and IFN-β significantly induced serum IL-6, but when the administration was repeated, the serum IL-6 levels gradually decreased in both the IFN-α and the IFN-β groups. The serum IL-6 levels correlated well with the daily peak body temperature of the patients, which also went down with repeated IFN administration. Serum IL-12 production was induced by IFN-α not by IFN-β. The induced IL-12 decreased to baseline by repeating IFN-α administration. These results suggested that IFN-α and IFN-β induce cytokine production in a different manner, and that their effect on cytokine interactions is short-term and reduced by repeated administration. Therefore, the induction of serum IL-12 production by IFN did not seem to have a critical effect during the early stage of IFN therapy.

Rapidity and Severity of Hemoglobin Decreasing Associated with Erythrocyte Inosine Triphosphatase Activity and ATP Concentration during Chronic Hepatitis C Treatment.

The purpose of this study was to evaluate the association between therapy-induced hemoglobin (Hb) decreasing rapidity and severity with erythrocyte inosine triphosphatase (ITPase) activity and ATP concentration in chronic hepatitis C patients receiving chronic hepatitis C (HCV) treatment. Forty-three Japanese patients were included in the study. Erythrocyte ITPase activity before therapy was determined by HPLC-UV. Erythrocyte ATP concentrations before and during therapy were determined by luciferase assay. Genotyping for ITPA 94C>A (rs1127354) and IVS2+21 A>C (rs7270101) was conducted using TaqMan probes. The median ITPase activity (µmol/h/g hemoglobin) of ITPA 94 CC, CA, and AA genotypes was 136.8 (range, 80.4-289.6), 41.1 (24.3-93.1), and 11.8, respectively. ITPase activity and Hb decreasing showed a significantly inverse relationship at therapeutic weeks 2, 4, and 6 (p<0.01). Erythrocyte ATP concentration was decreased by therapy, and Hb decreasing was significantly and inversely correlated with erythrocyte ATP concentration at week 4 and after week 8 (p<0.001 and 0.05, respectively). ATP concentration for patients with ITPA 94CA was significantly lower than ITPA 94CC at week 4 (p=0.045). We concluded that ITPase activity plays an important function and that ATP concentration changes due to therapy are related to the Hb decreasing mechanism in the early period of therapy with HCV treatment.

Clinical Pharmacy Education in Japan: Using Simulated Patients in Laboratory-Based Communication-Skills Training before Clinical Practice

The Japanese pharmaceutical curriculum was extended from four to six years in 2006. Students now receive practical communication-skills training in their fourth year, before progressing to train in hospital and community pharmacies in their fifth year. Kitasato University School of Pharmacy, Tokyo, had established a program to meet these aims before the 2006 guidance. In the present study, we discuss and evaluate the features of this communication-skills training program. This study enrolled 242 fourth-year pharmacy students at Kitasato University. Students filled out a questionnaire survey after completing the laboratory element of their undergraduate education. As part of training, students were asked to obtain patient data from a model medical chart, before performing simulated patient interviews covering hospital admission and patient counseling. These simulations were repeated in a small group, and feedback was provided to students by both the simulated patient and the faculty after each presentation. It was found that students were able to develop their communication skills through this approach. Thus, an effective system of gradual and continuous training has been developed, which allows students to acquire clinical and practical communication skills.

Cluster analysis of pharmacists’ work attitudes

Few studies in Japan use clustering to examine the work attitudes of pharmacists. This study conducts an exploratory analysis to classify those attitudes based on previous studies to help staff pharmacists and their management to understand their mutually beneficial requirements.