Stepwise dose increase of febuxostat is comparable with colchicine prophylaxis for the prevention of gout flares during the initial phase of urate-lowering therapy: results from FORTUNE-1, a prospective, multicentre randomised study.

OBJECTIVES: To determine whether febuxostat with stepwise dose increase is as useful as colchicine prophylaxis in reducing gout flares during the initial introduction of urate-lowering therapy in patients with gout in comparison with febuxostat with no dose titration. METHODS: In this prospective, multicentre, randomised open-label comparative study, patients were randomised to group A (stepwise dose increase of febuxostat from 10 to 40 mg/day), group B (fixed-dose febuxostat 40 mg/day plus colchicine 0.5 mg/day) or group C (fixed-dose febuxostat 40 mg/day) and observed for 12 weeks. Gout flare was defined as non-steroidal anti-inflammatory drug use for gout symptoms. RESULTS: A total of 255 patients were randomised, and 241 patients were treated. Among the treated patients, gout flares were experienced by 20/96 (20.8%) in group A, 18/95 (18.9%) in group B and 18/50 (36.0%) in group C. The incidence of flare was significantly lower in groups A and B than that in group C (P=0.047 and P=0.024, respectively), although the differences were not significant after correction for multiple comparisons. No significant difference was noted between the incidence of gout flare in groups A and B. CONCLUSIONS: Our data suggested that stepwise dose increase of febuxostat and low-dose colchicine prophylaxis effectively reduced gout flares in comparison with fixed-dose febuxostat alone. Stepwise dose increase of febuxostat may be an effective alternative to low-dose colchicine prophylaxis during the introduction of urate-lowering therapy. TRIAL REGISTRATION NUMBER: UMIN 000008414.

Pharmacokinetics of abiraterone in healthy Japanese men: dose-proportionality and effect of food timing.

PURPOSE: Abiraterone acetate (AA) was recently approved for castration-resistant prostate cancer in Japan. Two phase 1 studies were conducted to assess the pharmacokinetics of abiraterone after single-dose administration in Japanese healthy men and to evaluate the effects of food timing on abiraterone pharmacokinetics after single-dose administration of AA in Japanese and Caucasian healthy men. METHODS: In the dose-proportionality study, subjects (n = 30 Japanese) were randomly assigned to receive single doses of 250, 500, and 1,000 mg AA, and in the food-timing study, subjects (n = 22 Japanese and n = 23 Caucasian) randomly received single doses of 1,000 mg AA under fasted (overnight) and three different modified fasting conditions. RESULTS: Mean C(max) and AUC(∞) for abiraterone increased dose-dependently in Japanese healthy men; however, 90 % confidential interval (CI) was outside the predefined dose-proportionality criteria. Based on geometric mean ratios and 90 % CIs (versus overnight fasting condition), abiraterone exposure (AUC) increased significantly with dosing 1 h premeal, 2 h postmeal, or in between two meals 4 h apart by 57 %, 595 %, and 649 %, respectively. CONCLUSION: No clinically meaningful difference was observed in the pharmacokinetics of abiraterone between Caucasian and Japanese subjects.

Factors affecting efficacy and safety of add-on combination chemotherapy for non-small-cell lung cancer: a literature-based pooled analysis of randomized controlled trials.

BACKGROUND: Several clinical trials of chemotherapy for non-small-cell lung cancer (NSCLC) have been conducted to date. However, these studies have not been effective at identifying category 1 recommended strategies for systemic chemotherapy according to the National Comprehensive Cancer Network clinical practice guidelines. PURPOSE AND METHOD: To investigate the factors that influence the efficacy and safety of add-on combination chemotherapy for NSCLC based on published reports, we searched the PubMed and EMBASE for reports of randomized, controlled trials that compared efficacy and safety between groups with and without the use of add-on drugs to base chemotherapy in patients with NSCLC. For all the selected articles, we systematically retrieved and assessed the full published report. RESULTS: Of the 753 citations yielded by the electronic search, 82 comparison pairs from 76 articles were selected. The logistic regression analysis showed the second- or third-line treatment for target patients (Line2_3), dose modification of the base drug(s) in the investigational arm, characteristics of the add-on drug, and the number of total combination drugs that had negative coefficients, and the percent of patients with performance status 2 who had positive coefficients for efficacy. For safety, Line2_3, and the percent of female patients had positive coefficient. CONCLUSIONS: The present results indicate that the following points are important when investigating new regimen for add-on combination chemotherapy: (1) the number of total combination drugs should be reduced if at all possible; (2) an add-on drug should be noncytotoxic and should not necessitate dose modification (reduction) of the base drug(s).

Cell-cycle-dependent pharmacology of methotrexate in HL-60.

The role of the susceptibility of cells and the pharmacokinetics of MTX on the time-dependent change of methotrexate (MTX) pharmacologic action in HL-60 (human leukemia cell) was investigated from the viewpoints of the rhythm of DNA synthesis. The highest activity of MTX was observed at the time when DNA synthesis, dihydrofolate reductase (DHFR) activity, DHFR content, and DHFR mRNA content increased and the lowest activity was observed at the time when they decreased. There were significant time-dependent changes in MTX efflux. The result corresponded to the rhythm in MTX activity. The present study suggests that the time-dependent change of MTX activity is caused by a change in the sensitivity of cells and the pharmacokinetics of the drug. Therefore, the choice of dosing time associated with cell rhythmicity may help to achieve rational chronotherapeutics, increasing therapeutic effects.

Simultaneous determination of hydrogen cyanide and volatile aliphatic nitriles by headspace gas chromatography, and its application to an in vivo study of the metabolism of acrylonitrile in the rat.

A method for the simultaneous determination of hydrogen cyanide (HCN) and aliphatic nitriles using manual headspace (HS) gas chromatography (GC) with a capillary porous polymer column GS-Q and a nitrogen-phosphorus detector is described. With a HS incubation at 50 degrees C for 30 min and a GC temperature at 180 degrees C, HCN and volatile nitriles [acetonitrile, acrylonitrile (VCN), propionitrile, isobutyronitrile] were well separated and could be detected within 7 min with a detection limit of 0.7-2.4 ng/ml in blood samples. The HS-GC method was used in an in vivo study of VCN metabolism. VCN was administered orally (at nearly one-half its LD(50)) to rats, and heart blood and urine were sampled. Blood concentrations of HCN and VCN were measured by HS-GC, and plasma and urinary thiocyanate concentrations were measured by the König colorimetric method. Blood levels of HCN and VCN peaked 1.5 h after VCN administration, at which time the cyanide level (about 0.7 microg/ml) is close to the fatal level. HCN levels were observed to be at almost background levels at 10 h, although 50 ng/ml VCN was still detectable. The plasma thiocyanate level increased, reaching a peak (about 30 microg/ml) at 5 h. The cumulative urinary thiocyanate amount gradually increased, and at 10 h more than 1 mg thiocyanate was excreted into the urine. It is therefore possible to clarify the cause of cyanide poisoning using HS-GC analysis, when someone has taken volatile nitriles.

Role of ultrasonography in treatment selection.

In spite of difficulties impacting objectivity and reproducibility due to its dependence on the technical and diagnostic ability of each examiner, ultrasonography (US) in general can evaluate very well soft tissue lesions, especially small lesions of 1 cm or less in size. US can reliably delineate the nature of several lesions, and can detect dilated mammary ducts and lymph nodes. On the other hand, US may miss ductal spread or lymph node metastasis of breast cancer, especially if the lesions are too minute to be detected by the instrument. US should be used together with X-ray or MR mammography to prevent false negative cases. US is useful for evaluating the local nature and characteristics of cancerous lesions such as size, invasiveness, histological type, intraductal spread etc, and can evaluate regional lymph node and liver metastasis for pre-treatment staging. In addition, US-guided techniques are essential for preoperative pathological diagnosis by FNAC or CNB and for marking the marginal line for partial mastectomy. US should be more actively used to monitor intra-mammary recurrence after breast conserving surgery.

Cell kinetics-dependent antitumor effect of irinotecan hydrochloride induced by the synchronizing effect of hydroxyurea: cell kinetics and dosing time.

Influence of hydroxyurea (HU) on the antitumor effect of irinotecan hydrochloride (CPT-11) was investigated in ICR male mice transplanted with sarcoma 180 cells (S-180). A single dose of CPT-11 (100 mg/kg) was injected at various times after a single dose of HU (300 mg/kg). The relative tumor weight varied significantly depending on the timing of CPT-11 injection after HU injection (P < 0.01). The higher antitumor effect of CPT-11 was observed when DNA synthesis of S-180 cells increased (20 hr), and the lower effect was observed when the DNA synthesis decreased (0 hr). The loss of body weight also varied significantly depending on the timing of CPT-11 injection after HU injection (P < 0.01). The toxicity of CPT-11 was higher when the inhibitory effect of HU on DNA synthesis of bone marrow cells was stronger (15 hr), and the lower toxicity was observed when the inhibitory effect was not observed (0 hr). The plasma SN-38 concentration at 2 hr after CPT-11 injection was higher at 20 hr after HU injection than at 0 hr after HU injection. The difference in plasma esterase activity between 0 hr and 20 hr after HU injection was regarded as the mechanism underlying the dosing time-dependent difference of the SN-38 concentration. These experiments suggest that HU can produce a different phase of cell cycle between tumor cells and normal cells. This leads to increase the antitumor effect of CPT-11 without increasing the adverse effect of the drug. It is essential to consider the dosing time in the two-drug combination therapy.