Shoichi Mizuno

New equol supplement for relieving menopausal symptoms: randomized, placebo-controlled trial of Japanese women.

Objectives: Equol, a metabolite of the isoflavone daidzein, is hypothesized to play a major role in the health benefits of soy. We examined the effect of a new S-equol supplement on menopausal symptoms and mood states. Design: We conducted a randomized, double-blind, placebo-controlled trial with our new equol supplement for 12 weeks with 134 Japanese women (aged 40-59 years). They were randomly assigned to three groups: placebo (n = 44), 10 mg of equol per day (EQ-1; n = 44), and 10 mg of equol three times per day (EQ-3; n = 46). Habitual isoflavone intake was limited to 20 mg/d. Participants completed menopausal symptom and Profile of Mood States questionnaires at baseline and postintervention. Physical examination and blood and 24-hour urine collection were performed at baseline and postintervention. Results: At baseline, total menopausal symptom score varied by menopausal and equol producer status (34.3% producers). A total of 127 participants (94.8%) completed the trial. No adverse effects were reported, except for a systemic rash in one EQ-3 woman. The anxiety scores of equol producers were lower than those of nonproducers (P < 0.05). Significant differences between premenopausal and perimenopausal/postmenopausal symptom scores were observed for anxiety, somatic, and total scores. After the EQ-3 intervention, perimenopausal/postmenopausal equol nonproducers showed significant decreases from baseline in all menopausal symptom scores except depression (P < 0.01). Compared with placebo, the EQ-3 group showed significant decreases in depression scores (P < 0.05), as well as significant decreases in Tension-Anxiety (P < 0.05), Depression-Dejection (P < 0.05) and Fatigue (P < 0.01) and increases in Vigor (P < 0.05) of the Profile of Mood States. Conclusion: S-equol supplement improved mood-related symptoms in perimenopausal/postmenopausal equol nonproducers.

Effects of soy isoflavone supplements on bone turnover markers in menopausal women: Systematic review and meta-analysis of randomized controlled trials

INTRODUCTION Effects of soy isoflavone supplements on bone turnover markers remain unclear. This up-to-date systematic review and meta-analysis of randomized controlled trials (RCTs) was performed primarily to more completely and precisely clarify the effects on urinary deoxypyridinoline (DPD) and serum bone alkaline phosphatase (BAP) and secondarily to evaluate the effects on other bone turnover markers, compared with placebo in menopausal women. METHODS PubMed, CENTRAL, ICHUSHI, and CNKI were searched in June 2009 for relevant studies of RCTs. Data on study design, participants, interventions, and outcomes were extracted and methodological quality of each included trial was assessed. RESULTS From 3740 identified relevant articles, 10 (887 participants), 10 (1210 participants), and 8 (380 participants) RCTs were selected for meta-analysis of effects on DPD, BAP, and serum osteocalcin (OC), respectively, using Review Manager 5.0.22. Daily ingestion of an average 56 mg soy isoflavones (aglycone equivalents) for 10 weeks to 12 months significantly decreased DPD by 14.1% (95% CI: -26.8% to -1.5%; P=0.03) compared to baseline (heterogeneity: P<0.00001; I(2)=93%; random effects model). The overall effect of soy isoflavones on DPD compared with placebo was a significant decrease of -18.0% (95% CI: -28.4% to -7.7%, P=0.0007; heterogeneity: P=0.0001; I(2)=73%; random effects model). Subgroup analyses and meta-regressions revealed that isoflavone dose and intervention duration did not significantly relate to the variable effects on DPD. Daily supplementation of about 84 mg and 73 mg of soy isoflavones for up to 12 months insignificantly increased BAP by 8.0% (95% CI: -4.2% to 20.2%, P=0.20; heterogeneity: P<0.00001; I(2)=98%) and OC by 10.3% (95% CI: -3.1% to 23.7%, P=0.13; heterogeneity: P=0.002; I(2)=69%) compared with placebo (random effects model), respectively. CONCLUSIONS Soy isoflavone supplements moderately decreased the bone resorption marker DPD, but did not affect bone formation markers BAP and OC in menopausal women. The effects varied between studies, and further studies are needed to address factors relating to the observed effects of soy isoflavones on DPD and to verify effects on other bone turnover markers.

A pharmacokinetic and pharmacodynamic analysis of CPT-11 and its active metabolite SN-38.

In the present study, an attempt was made to determine the precise pharmacokinetics of 7‐ethyl‐10‐[4‐(1‐piperidino)‐1‐piperidino]carbonyloxycamptothecin (CPT‐11) and its active metabolite, 7‐ethyl‐10‐hydroxycamptothecin (SN‐38). The relationship between pharmacokinetic parameters and pharmacodynamic effects was also investigated to elucidate the cause of interpatient variation in side effects. Thirty‐six patients entered the study. CPT‐11, 100 mg/m2, was administered by IV infusion over 90 min weekly for four consecutive weeks. The major dose‐limiting toxicities were leukopenia and diarrhea. There was a positive correlation between the area under the concentration‐time curve (AUC) of CPT‐11 and percent decrease of WBC (r=0.559). On the other hand, episodes of diarrhea had a better correlation with the AUC of SN‐38 (r=0.606) than that of CPT‐11 (r=0.408). Multivariate analysis revealed that the AUC of SN‐38, AUC of CPT‐11 and indocyanine green retention test were significant variables for the incidence of diarrhea and that both performance status and AUC of CPT‐11 were significant variables for percent decrease of WBC. The large interpatient variability of the degree of leukopenia and diarrhea is due to a great plasma pharmacokinetic variation in CPT‐11 or SN‐38. The AUCs of CPT‐11 and SN‐38 obtained from the first administration of CPT‐11 correlate with toxicities, but it is impossible to predict severe side effects before the administration of CPT‐11 at the present time.

Effects of soy isoflavone extract supplements on blood pressure in adult humans: systematic review and meta-analysis of randomized placebo-controlled trials.

Objective Reported effects of different soy products on blood pressure vary. This systematic review and meta-analysis was performed to clarify the effects of soy isoflavone extract supplements on systolic and diastolic blood pressure (SBP and DBP) in adult humans. Methods PubMed, CENTRAL, ICHUSHI, and CNKI were searched in June 2009 for relevant randomized placebo-controlled trials. Study data and indicators of methodological validity were independently extracted by two authors using predefined data fields. Meta-analysis was carried out in Review Manager 5.0.22. Results Searches identified 3740 articles, of which 14 randomized controlled trials (789 participants) were included. Daily ingestion of 25–375 mg soy isoflavones (aglycone equivalents) for 2–24 weeks significantly decreased SBP by 1.92 mmHg (95% confidence interval −3.45 to −0.39; P = 0.01) compared with placebo (heterogeneity P = 0.39, fixed effect model) in adults with normal blood pressure and prehypertension. The effect was not lost on sensitivity analysis. Subgroup analyses suggest greater effects in studies longer than 3 months, in Western populations, at lower doses, and in studies at lower risk of bias. Soy isoflavones did not affect DBP [−0.13 (95% confidence interval −1.03 to 0.78) mmHg, P = 0.78; heterogeneity P = 0.20, fixed effect model]. Conclusion Soy isoflavone extracts significantly decreased SBP but not DBP in adult humans, and no dose–response relationship was observed. Further studies are needed to address factors related to the observed effects of soy isoflavones on SBP and to verify the effect in hypertensive patients.

Leukemia and other malignancies among GH users.

The number of reported cases of leukemia developing in growth hormone (GH) users worldwide has reached 31. Twelve Japanese cases are briefly reviewed; five each of AML and ALL, and one each of CML and malignant histiocytosis. The underlying diseases of these patients consisted of 8 idiopathic disease, 3 tumors and one Fanconis anemia. Leukemia occurred during GH treatment in 9 cases and after cessation of GH in 3. The longest interval from the cessation of GH therapy was 10 years. GH administration from a younger age tended to be linked to myeloid type. Risk factors and possible mechanisms of leukemogenesis by growth hormone are discussed, and proposals for the future have been made by the Foundation for Growth Science in Japan.

The observed relationship between the occurrence of acute radiation effects and leukemia mortality among A-bomb survivors.

In an analysis of a follow-up study of a fixed population of 73,330 atomic bomb survivors in Hiroshima and Nagasaki, the slope of an estimated dose response between ionizing radiation and leukemia mortality was found to be steeper (P less than 0.002), by a factor of 2.4, among those who reported epilation within 60 days of the bombings, compared to those who did not experience this sign of acute radiation exposure. The strength of this empirical finding as evidence of biological association in individual radiosensitivity for these two end points is studied here. The major factor complicating the interpretation of this finding as evidence of such an association is the degree of imprecision of the radiation dosimetry system used in assignment of radiation doses to the A-bomb survivors. Using models recently suggested for dealing with dosimetry errors in epidemiological analysis of the A-bomb survivor data, the sensitivity of the apparent association between leukemia mortality and severe epilation to the assumed level of dosimetry error is investigated.

Impact of cigarette smoking on impaired insulin secretion and insulin resistance in Japanese men: The Saku Study

To assess the impact of smoking on impaired insulin secretion and insulin resistance in Japanese men.

A 50-Year Projection of Lung Cancer Deaths among Japanese Males and Potential Impact Evaluation of Anti-smoking Measures and Screening Using a Computerized Simulation Model

The lung cancer death rate among Japanese males was projected for 50 years to the year 2041 by a computerized simulation model. Long‐term effects of anti‐smoking measures and mass screening on lung cancer deaths were also evaluated. The simulation showed that the age‐adjusted lung cancer death rate would increase and reach a peak of 166 per 100,000 in 1989 and then decrease to 148 per 100,000 in 2003. It then shows an increasing tendency again, up to 255 per 100,000 in 2028. The smoking initiation rates estimated from the observed lung cancer death rates showed that the changes in death rates may be attributed to a lower smoking initiation rate among those born in the 1930s. Promotion of mass screening programs is effective more quickly than anti‐smoking measures but the reduction in annual cancer deaths is expected to be only 11%, even if 100% participation is achieved by the year 2000. A reduction in smoking initiation rate, on the other hand, affects lung cancer deaths very slowly. It was predicted that a 1% annual reduction in smoking initiation rate would result in a 20% decrease in the number of lung cancer deaths in 2041. A smoking cessation program is intermediate with regard to promptness. The predicted reductions in lung cancer deaths in 2041 were 13%, 47%, and 66%, respectively, when the annual smoking cessation rate was increased from 0.46% (present status) to 1%, 3%, and 5%. In conclusion, the combined application of all three preventive measures seems essential to realize the most effective reduction in lung cancer deaths.

A Limited Sampling Model for Estimating Pharmacokinetics of CPT-11 and Its Metabolite SN-38

The objective of this study was to develop a limited sampling model (LSM) to estimate the area under the curve (AUC) of 7‐ethyl‐10‐[4‐(1‐piperidino)‐1‐piperidino]carbonyloxycamptothecin (CPT‐11) and that of 7‐ethyl‐10‐hydroxycamptothecin (SN‐38) as predictive pharmacokinetic variables for leukopenia and episodes of diarrhea induced by CPT‐11 administration. The model was developed with a training set consisting of pharmacokinetic studies in 36 patients who received a 90‐min i.v. infusion of CPT‐11 at a dose of 100 mg/m2. A multiple regression analysis of CPT‐11 or SN‐38 concentrations observed at each time point in the training set was used to predict the AUC of CPT‐11 or SN‐38. The final sampling models using only two time points were: AUCCPT‐11=3.7891★C2.5+14.0479*C13.5+1.5463 AUCSN‐38=0.5319★C2.5+19.1468*C13.5+72.7349 where C2.5 and C13.5 are the plasma concentration of CPT‐11 (μg/ml) or SN‐38 (ng/ml) at 2.5 and 13.5 h after the initiation of CPT‐11 infusion, respectively. The models were validated prospectively on a separate test data set of 12 patients receiving the same dose of CPT‐11 investigated in a previous study. Validation of the final LSM on the test data set gave values of root mean square error (RMSE) of 12.72% and 5.97% for the AUC of CPT‐11 and that of SN‐38, respectively. The model can be used to monitor the AUCs of both CPT‐11 and SN‐38 for the early prediction of toxicities and to establish a pharmacokinetically based dose modification strategy for safe administration of CPT‐11.

Increased levels of serum uric acid among ex-smokers.

Background It remains unclear whether serum uric acid level increases after the cessation of smoking. Methods In 2000, we conducted a cross-sectional study on the effects of smoking cessation on serum uric acid levels by analyzing the results of annual health check-ups in the Japanese male working population (n = 16,642). Results The serum uric acid level (6.18 mg/dL) was the highest in ex-smokers, followed by that in never-smokers (6.10 mg/dL) and that in current smokers (5.98 mg/dL). Ex-smokers weighed 0.6 kg more than the never-smokers and 1.5 kg more than the current smokers. The frequency of alcohol intake was closely correlated to the smoking habits. The serum uric acid levels declined in all groups, after adjustments for age, body mass index, and alcohol intake, though the levels in ex-smokers were 0.2 mg/dL higher than those in current smokers. Conclusion The results suggested that alcohol intake contributed considerably to the serum uric acid levels and that smoking itself may have suppressed these levels via metabolic effects or the action of superoxides.