Shunji Okubo

Lack of Long-Term Effect of Vitamin C Supplementation on Blood Pressure

Abstract—In a double-blinded randomized controlled trial, we investigated the long-term effect of vitamin C supplementation on blood pressure. A total of 439 Japanese subjects with atrophic gastritis initially participated in the trial using vitamin C and &bgr;-carotene to prevent gastric cancer. Before and on early termination of &bgr;-carotene supplementation, 134 subjects dropped out of this trial, whereas 120 and 124 subjects took the vitamin C supplement daily at either 50 mg or 500 mg, respectively, for 5 years. Before supplementation, neither systolic nor diastolic blood pressure was significantly related with the serum vitamin C concentration. This relationship was unchanged after adjustment for age, body mass index, and alcohol intake or after stratification by gender. After 5 years, systolic blood pressure significantly increased in groups, regardless of vitamin C dose, compared with baseline. Systolic blood pressure in the high-dose group (500 mg daily) increased from 125.4 to 131.7 mm Hg (5.88 mm Hg increase; 95% confidence interval [CI], 3.11 to 8.65). This value was similar with that of the low-dose group (5.73 mm Hg increase; 95% CI, 2.62 to 8.83) and of the dropout group (4.52 mm Hg increase; 95% CI, 1.26 to 7.77). There was no difference in change of diastolic blood pressure among the 3 groups. In conclusion, we observed no reduction in blood pressure with long-term moderate doses (500 mg/day) of vitamin C supplementation in a high-risk population for stomach cancer and stroke.

Blood pressure change in a free-living population-based dietary modification study in Japan.

Objective To assess whether dietary intervention in free-living healthy subjects is effective in improving blood pressure levels. Design Open randomised, controlled trial. Setting Free-living healthy subjects in two rural villages in north-eastern Japan. Participants Five hundred and fifty healthy volunteers aged 40–69 years. Interventions Tailored dietary education to encourage a decrease in sodium intake and an increase in the intake of vitamin C and carotene, and of fruit and vegetables. Main outcome measures Blood pressure, dietary intake and urinary excretion of sodium, dietary carotene and vitamin C, and fruit and vegetable intake data were collected at 1 year after the start of the intervention. Results During the first year, changes differed significantly between the intervention and control groups for dietary (P = 0.002) and urinary excretion (P < 0.001) of sodium and dietary vitamin C and carotene (P = 0.003). Systolic blood pressure decreased from 127.9 to 125.2 mmHg (2.7 mmHg decrease; 95% confidence interval, −4.6 to −0.8) in the intervention group, whereas it increased from 128.0 to 128.5 mmHg (0.5 increase; −1.3 to 2.3) in the control group. This change was statistically significant (P = 0.007). In contrast, the change in diastolic blood pressure did not significantly differ between the groups. In hypertensive subjects, a significant difference in systolic blood pressure reduction was seen between the groups (P = 0.032). Conclusion Moderate-intensity dietary counseling in free-living healthy subjects achieved significant dietary changes, which resulted in a significant decrease in systolic blood pressure.

The effect of 5-year vitamin C supplementation on serum pepsinogen level and Helicobacter pylori infection

We conducted a population‐based, double‐blind, randomized controlled trial to examine the effect of vitamin C supplementation on serum pepsinogen (PG) level, Helicobacter pylori (H. pylori) infection, and cytotoxin‐associated gene A (Cag A) status. Subjects aged 40 to 69 years living in one village in Akita prefecture, a high‐risk area for gastric cancer in Japan, were recruited through annual health check‐up programs. Among 635 subjects diagnosed as having chronic gastritis on the basis of serum PG levels, after excluding ineligible cases, 439 subjects were assigned to one of four groups using a 2×2 factorial design (0 or 15 mg/day β‐carotene and 50 or 500 mg/day vitamin C). However, based on the results from two β‐carotene trials in the United States, we discontinued β‐carotene (vitamin C supplementation was continued). Finally, 120 subjects in the low‐dose group (vitamin C 50 mg), and 124 subjects in the high‐dose group (vitamin C 500 mg) completed the 5‐year supplementation. The difference in the change of PGI/II ratio between baseline and after 5‐year follow up was statistically significant between the intervention groups among those who completed the supplementation: ‐0.25 for the low‐dose group and ‐0.13 for the high‐dose group (P=0.046). To conclude, vitamin C supplementation may protect against progression of gastric mucosal atrophy. (Cancer Sci 2003; 94: 378–382)

Effect of vitamin C on common cold: randomized controlled trial

Objective:To investigate the relationship between the common cold and vitamin C supplementation.Design:A double-blind, 5-year randomized controlled trial.Setting:A village in Akita prefecture, one of the regions in Japan with the highest mortality from gastric cancer.Subjects:Participants in annual screening programs for circulatory diseases conducted under the National Health and Welfare Services Law for the Aged, and diagnosed as having atrophic gastritis. Of the 439 eligible subjects, 144 and 161 were assigned to receive 50 or 500 mg of vitamin C, respectively, after protocol amendment. During the supplementation phase, 61 dropped out, and 244 completed the trial.Intervention:Daily vitamin C supplementation of 50 mg (low-dose group) or 500 mg (high-dose group).Results:Total number of common colds (per 1000 person-months) was 21.3 and 17.1 for the low- and high-dose groups, respectively. After adjustment for several factors, the relative risks (95% confidence interval (CI)) of suffering from a common cold three or more times during the survey period was 0.34 (0.12–0.97) for the high-dose group. No apparent reduction was seen for the severity and duration of the common cold.Conclusion:A randomized, controlled 5-year trial suggests that vitamin C supplementation significantly reduces the frequency of the common cold but had no apparent effect on the duration or severity of the common cold. However, considering several limitations due to protocol amendment, the findings should be interpreted with caution.Sponsorship:This study was supported in part by Grants-in-Aid for Cancer Research and for the Second Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labor and Welfare of Japan.

A Randomized Controlled Trial for Chemoprevention of Gastric Cancer in High-risk Japanese Population; Study Design, Feasibility and Protocol Modification

We have initiated a population‐based, double‐blind, randomized controlled trial to examine the effects of supplementation of beta‐carotene and vitamin C on the incidence of gastric cancer. The subjects were participants in an annual health screening program conducted by four municipalities in Akita prefecture, one of the regions with the highest mortality from gastric cancer in Japan. We measured their serum levels of pepsinogens (PGs) I and II, and asked persons diagnosed with chronic atrophic gastritis (defined as PGI < 70 ng/ml and PGI/PGII ratio <3.0) to take diet supplements containing 0 or 15 mg/day beta‐carotene and 50 or 500 mg/day vitamin C for 5 years. During the first year of recruitment conducted in one village from June through September, 1995, 52% (635/1214) of screening participants had chronic atrophic gastritis and 73% (439/602) of eligible persons responded. However, in response to a National Cancer Institute press report released on January 18, 1996, indicating that two beta‐carotene trials had shown no benefit and potential harm from the supplement, we discontinued the beta‐carotene and continued with the trial using only vitamin C. Of 397 participants remaining at this point, 77% (305) consented to stay in the study. The results indicate that a randomized controlled trial for cancer prevention is feasible in the Japanese asymptomatic population.

Protective Effect of Vitamin C on Oxidative Stress: a Randomized Controlled Trial

BACKGROUND Although a number of reports regarding the role of reactive oxygen species (ROS) as the first step in cancer induction exist, few studies have investigated how vitamin C influences ROS in human plasma. AIM OF THE STUDY Using the ROS assay system, a method recently established by one of the authors, we aimed to evaluate the effect of vitamin C supplementation on serum ROS among subjects diagnosed with chronic gastritis. METHODS A total of 244 Japanese subjects with atrophic gastritis were randomized to take 5-year supplementation of either 50 mg or 500 mg of vitamin C. RESULTS The adjusted difference in the changes of total ROS between baseline and after 5-year supplementation was statistically significant between the intervention groups: 2.70 decrease (corresponds to 1.26% decrease) in the high-dose group and 4.16 increase (corresponds to 3.79% increase) in the low-dose group, p for difference = 0.01. CONCLUSION Vitamin C was suggested to reduce oxidative stress among subjects with atrophic gastritis.

Long-term vitamin C supplementation has no markedly favourable effect on serum lipids in middle-aged Japanese subjects

Antioxidant vitamins have been reported to be associated with an improvement in blood lipid profiles, but results are not consistent. The present study was designed to determine whether long-term vitamin C supplementation could alter serum lipid concentrations in subjects who completed a 5-year population-based double-blind intervention trial. A total of 439 Japanese subjects with atrophic gastritis initially participated in the trial using vitamin C and beta-carotene to prevent gastric cancer. Before and upon early termination of beta-carotene supplementation, 134 subjects dropped out of the trial; finally, 161 subjects assigned to the high-dose group (500 mg vitamin C/d) and 144 subjects assigned to the low-dose group (50 mg vitamin C/d) were studied. No favourable effect of vitamin C supplementation on serum concentrations of total cholesterol, HDL- and LDL-cholesterol, and triacylglycerol was observed, although high-dose vitamin C supplementation increased serum vitamin C concentrations substantially. Among women, the mean change in serum triacylglycerol decreased (-0.12 mmol/l, 95 % CI -0.32, 0.09) in the high-dose group, but increased (+0.12 mmol/l, 95 % CI 0.03, 0.22) in the low-dose group. In addition, the mean change in serum triacylglycerol among women with hypertriacylglycerolaemia was statistically significant (-1.21, 95 % CI -2.38, -0.05) after high-dose vitamin C supplementation. The 5-year vitamin C supplementation had no markedly favourable effects on the serum lipid and lipoprotein profile. However, our present results do not preclude the possibility that vitamin C supplementation may decrease triacylglycerol concentrations among women with hypertriacylglycerolaemia.

Effects of Three-month Oral Supplementation of β-Carotene and Vitamin C on Serum Concentrations of Carotenoids and Vitamins in Middle-aged Subjects: A Pilot Study for a Randomized Controlled Trial to Prevent Gastric Cancer in High-risk Japanese Population

Prior to a randomized controlled trial to prevent gastric cancer by oral supplementation of β‐carotene and vitamin C in a high‐risk Japanese population, we examined the serum response to threemonth oral supplementation of β‐carotene (0, 3, 30 mg/day) and vitamin C (0, 50, 1000 mg/day) by a three‐by‐three factorial design using 54 subjects (age range=40–69 years). Serum concentrations of carotenoids, α‐tocopherol, and ascorbic acid were examined at baseline, and one, two, and threemonth points. Both serum β‐carotene and ascorbic acid were significantly higher in high‐dose groups than in each placebo group during the supplementation. The serum β‐carotene increased gradually (597–830% increase) during the study, whereas the serum ascorbic acid reached nearly a steady‐state at the one‐month point and remained stable thereafter (88–95% increase). No statistically significant interaction between β‐carotene and vitamin C supplementations was observed either for serum β‐carotene or for serum ascorbic acid. Among carotenoids and α‐tocopherol examined, serum lycopene in the high‐dose β‐carotene group was significantly higher than in the placebo group at all points. No unfavorable change in carotenoids and α‐tocopherol was observed in any group.

Gastric small cell carcinoma with marked response to neoadjuvant chemotherapy.

We report a patient with gastric small cell carcinoma (SCC) who showed a marked response to neoadjuvant chemotherapy. The patient was a 72-year-old Japanese man who was admitted because of epigastralgia. Subsequent examination revealed the presence of advanced gastric carcinoma in the lesser curvature of the lower body of the stomach, with multiple abdominal lymph node metastases. Endoscopic biopsy specimens from the tumor revealed SCC with moderately differentiated adenocarcinoma. The patient received neoadjuvant chemotherapy consisting of carboplatin (400 mg/m2, for 1 day), epirubicin (27 mg/m2, for 1 day), etoposide (70 mg/m2, for 3 days), and 5-fluorouracil (330 mg/m2, for 11 days). Clinically, the primary tumor and lymph node metastases were markedly reduced. Subsequently the patient underwent curative surgery and was alive without recurrence for more than 3 years after the surgery.

A Pilot Study for a Randomized Controlled Trial to Prevent Gastric Cancer in High‐risk Japanese Population: Study Design and Feasibility Evaluation

Observational epidemiological studies suggest that some nutrients reduce the risk of gastric cancer and that individuals with atrophic gastritis are at high risk of developing gastric cancer. One possible measure for gastric cancer prevention is therefore nutritional supplementation for the high risk group. Before recommending this strategy for the general public, however, a randomized controlled trial (RCT) is necessary. To evaluate the feasibility of an RCT, the authors conducted a pilot study using recipients of a health check‐up program in a general hospital in Japan. The subjects who were asked to participate in the trial had been diagnosed as having atrophic gastritis on the basis of serum pepsinogen I <70 ng/ml and the ratio of pepsinogen I to II <3.0. They were requested to ingest double‐blinded capsules containing different levels of vitamin C and β‐carotene every day. Out of the 219 subjects (118 males, 101 females) who were eligible for the study and had the required pepsinogen measurement, 90 (41%) met the criteria for atrophic gastritis. Among them, 55 (61%) (35 males, 20 females) gave their informed consent to participate in the RCT. Fifty‐four participants completed a 3‐month course of supplementation, and all of them agreed to a 5‐year supplementation period. The authors concluded that an RCT using double‐blinded nutritional supplements and targeting apparently healthy individuals is feasible in an intervention study for cancer prevention in Japan.