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From the Townsend Letter for Doctors & Patients
June 2003

Literature Review and Comment

by Alan R. Gaby, MD
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Zinc and selenium improve health of cancer patients
Sixty patients (median age 55 years) with cancer of the digestive tract (colon, stomach, or esophagus) who were undergoing chemotherapy were randomly assigned to receive supplemental zinc (21 mg/day) and selenium (200 mcg/day) for 50 days or no supplemental zinc and selenium (controls). At baseline and after 60 days, all patients were malnourished, as determined by various anthropometric and biochemical parameters. However, 70% of patients treated with zinc and selenium showed no further worsening of nutritional status and experienced a significant decrease of asthenia and an increase of appetite. In contrast, only 20% of control patients showed no further worsening of nutritional status.

Comment: These results suggest that supplementation with selenium and zinc may improve the general condition of patients with cancer of the digestive tract who are undergoing chemotherapy. Some oncologists have expressed concern that concomitant use of antioxidants such as zinc and selenium might interfere with the anticancer effect of chemotherapy. The basis of their concern is that many chemotherapy drugs promote the formation of oxygen-derived free radicals, and that these free radicals might be scavenged or quenched by antioxidants. It is true that many chemotherapeutic agents cause free radicals to form; however, the anticancer effects of these drugs do not, in general, seem to depend on the formation of free radicals. Consequently, antioxidants might reduce the adverse effects of the drugs, without inhibiting their beneficial effects. While the bulk of the evidence available to date supports that possibility, more research is needed to determine which antioxidants can be used safely and effectively with which chemotherapeutic agents.

Federico A, et al. Effects of selenium and zinc supplementation on nutritional status in patients with cancer of digestive tract. Eur J Clin Nutr 2001;55:293-297.

High-dose vitamin K2 decreases mortality in patients with liver cancer
One hundred twenty-one patients with hepatocellular carcinoma were randomly assigned to receive conventional therapy, with or without the addition of oral vitamin K2 (45 mg/day). At 12 months, the incidence of portal vein invasion was 2% in the vitamin K2 group and 23% in the control group. At 2 years, these percentages were 23% and 47%, respectively. One-year survival was 76% in the vitamin K2 group and 66% in controls. Two-year survival was 66% in the vitamin K2 group and 28% in controls.

Comment: Previous studies have shown that vitamin K2 inhibits the growth of hepatocellular carcinoma cells in vitro. The results of this new study suggest that vitamin K2 can slow the progression of hepatocellular carcinoma and increase survival times. Vitamin K2, which is synthesized by intestinal bacteria, differs to a small extent from the vitamin K1 (phytonadione), which is present in food. It is not known whether vitamin K1 would have the same anticancer effect as vitamin K2. The latter has been used in Japan for the past several years as a treatment for osteoporosis, and appears to be safe when administered at a dose of 45 mg/day.

Jancin B. Vitamin K cuts hepatocellular Ca mortality. Fam Pract News 2002(July 15):16.

Proteolytic enzymes beneficial for multiple myeloma
Two hundred sixty-five patients with multiple myeloma stages I-III were treated with standard chemotherapy. One hundred sixty-six of these patients also received oral enzymes for more than six months, while 99 patients either did not receive enzymes or received them for less than six months (control group). Treatment allocation was not randomized, but was assigned on the basis of the availability of the enzymes on the first day of chemotherapy. The enteric-coated enzyme preparation (Wobe-Mugos) contained 100 mg of papain, 40 mg of trypsin, and 40 mg of chymotrypsin per tablet. The dose was 2 tablets 3 times per day for 1 year, starting on the first day of chemotherapy; in most cases the dose was reduced to 1 tablet 3 times per day after the first year, and was continued indefinitely. The proportion of patients achieving complete remission, partial remission, or stable disease was significantly higher in the enzyme group than in the control group (97.6% vs. 69.7%; p = 0.001). In stage III patients, the proportion of nonresponders was 3.7% in the enzyme group and 38.9% in the control group (p < 0.001). The median survival time in stage III patients was 47 months in the control group and 83 months in the enzyme group (77% increase; p < 0.002), corresponding to a 3-year increase in survival time. The observation period was not long enough to estimate the survival times for patients in stages I and II.

Comment: Proteolytic enzymes have been used for many years in the treatment of various types of cancer, but there is only a small amount of published research supporting its use. The present study has a potential flaw, in that patients who discontinued enzyme treatment (perhaps because they were too sick to continue) were counted as not having received the treatment. In addition, the non-random selection of patients may have biased the results. Nevertheless, the outcome was markedly better in the enzyme group than in the control group, suggesting that enzyme treatment increases the response rate and prolongs survival in patients with multiple myeloma. Although the mechanism of action is not known, it has been suggested that proteolytic enzymes help break through a protective coating produced by cancer cells, thereby giving the immune system a better chance to attack the tumor cells.

Sakalova A, et al. Retrolective cohort study of an additive therapy with an oral enzyme preparation in patients with multiple myeloma. Cancer Chemother Pharmacol 2001;47(Suppl):S38-S44.

Soy milk for essential hypertension
Forty men and women (mean age, 48 years) with mild-to-moderate hypertension were randomly assigned to receive, in double-blind fashion, 500 ml twice daily of soy milk or cow's milk for three months. After three months, compared with baseline, the mean systolic blood pressure decreased by 18.4 mm Hg in the soy group and by 1.4 mm Hg in the cow's milk group (p < 0.0001 for group difference), while mean diastolic blood pressure decreased by 15.9 vs. 3.7 mm Hg (p < 0.0001). Urinary genistein was significantly (p = 0.002) correlated with the decrease in blood pressure, particularly diastolic pressure.

Comment: These results indicate that consumption of 1 liter per day of soy milk for three months can produce a clinically important reduction in blood pressure in people with essential hypertension. Although the mechanism of action of soy is not clear, the effect is probably not due to isoflavones, as supplementation with soy isoflavones alone did not reduce blood pressure in a previous study. Soy protein has also been shown to reduce serum cholesterol, another major risk factor for cardiovascular disease. The present study adds to a growing body of evidence that the inclusion of soy products as part of a balanced, whole-foods diet, may help prevent heart disease.

Rivas M, et al. Soy milk lowers blood pressure in men and women with mild to moderate essential hypertension. J Nutr 2002;132:1900-1902.

Natural alternative to Viagra
Forty-five men (mean age, 56.7 years) with erectile dysfunction (ED) were randomly assigned to receive, in a 3-way double-blind crossover trial, 1) 3.25 of L-arginine (provided by 6 g of L-arginine glutamate) plus 6 mg of yohimbine hydrochloride (AY), 2) 6 mg of yohimbine hydrochloride alone (Y), or 3) placebo. During each of the 2-week crossover periods, the treatment was taken orally, on an empty stomach, 1-2 hours before intended sexual intercourse. The primary endpoint was the change in the Erectile Function Domain score of the International Index of Erectile Function. Higher scores indicate better erectile function; the maximum score is 30. At the end of the treatment periods, the mean Erectile Function Domain scores for AY, Y and placebo were 17.2, 15.4 and 14.1, respectively. The difference between AY and placebo was significant (p = 0.006), but the difference between Y and placebo was not. The treatment was considered successful by 40% of patients receiving AY, 28.9% of those receiving Y, and 17.8% of those receiving placebo (p = 0.02 for difference between AY and placebo). Patients with initially mild-to-moderate ED had a better response to treatment than did patients with more severe ED. No serious side effects were reported.

Comment: L-Arginine (a conditionally essential amino acid) and yohimbine (a compound present in the herb yohimbe) have each been shown to be effective in the treatment of ED. However, neither of these compounds has been found to be effective for on-demand use (i.e., immediately prior to intended sexual activity); rather, consistent use is necessary to achieve an effect. The present study demonstrates that on-demand administration of these substances is effective, if they are taken in combination. Both of these compounds are considered relatively safe, although yohimbine can cause hypertension, irritability, or other side effects in some cases. Single-dose treatment with yohimbine plus L-arginine is probably safer than sildenafil (Viagra®) and is also much less expensive.

Lebret T, et al. Efficacy and safety of a novel combination of L-arginine glutamate and yohimbine hydrochloride: a new oral therapy for erectile dysfunction. Eur Urol 2002;41:608-613.

Low-dose vitamin A does not cause osteoporosis
Eighty healthy men (aged 18-58 years) were randomly assigned to receive, in single-blind fashion, 25,000 IU/day of vitamin A (retinol palmitate) or placebo for 6 weeks. Compared with the placebo group, there was no significant change in the vitamin A group in various markers of bone formation and resorption; e.g., bone specific alkaline phosphatase, N-telopeptide of type 1 collagen (NTx), and osteocalcin.

Comment: This short-term study suggests that a moderate dose of vitamin A does not promote the development of osteoporosis. This finding is in contrast to several epidemiological studies, in which consumption of as little as 3,300 IU/day of vitamin A from food was associated with an increased risk of hip fracture. High-dose vitamin A intake in animals is also known to cause bone disease. However, animal studies have used an enormous dose, the human equivalent of 7 million IU per day, to induce bone disease, whereas amounts on the order of 100,000 IU per day (human equivalent) do not seem to affect animals' bones. Concerning the epidemiological studies, the major contributors to vitamin A intake in the American diet (aside from liver) are fortified milk* (1,500 mcg/L), fortified sugary breakfast cereals (up to 375 mcg per serving), fortified margarine (approximately 150 mcg per tablespoon), and eggs (95 mcg per egg). A high-vitamin A diet would therefore presumably contain relatively large amounts of one or more of the following: animal protein and phosphorus (from eggs, milk, and liver), trans-fatty acids (from margarine), refined sugar (from breakfast cereals), and xenobiotic chemicals (from liver). One or more of these components of the diet, rather than the vitamin A, may account for the increased risk of osteoporosis associated with higher vitamin A intake.

*While many assume that drinking milk helps prevent bone loss, a number of studies indicate that milk is not protective, and may even increase the risk of osteoporotic fractures.

Kawahara TN, et al. Short-term vitamin A supplementation does not affect bone turnover in men. J Nutr 2002;132:1169-1172.

Osteoporosis therapy: don't forget the phosphorus
The effect of calcium intake on the absorption of phosphorus was assessed in 543 studies of healthy women aged 35-65 years and in 93 men and women aged 19-78 years. Mean net absorption of phosphorus was 60.3% for the first group and 53% for the second group. For each 500-mg increase in calcium intake, phosphorus absorption decreased by 166 mg.

Comment: This study indicates that increasing dietary intake of calcium decreases the absorption of phosphorus. A deficiency of phosphorus can lead to impaired bone mineralization, which might account for the equivocal results seen in some calcium supplementation trials. The authors of the present study point out that one of the most effective trials in elderly patients used tricalcium phosphate as the calcium source (N Engl J Med 1992;327:1637-42). The interaction between calcium and phosphorus should not be of concern for many individuals, since most Western diets contain ample or excessive amounts of phosphorus. However, individuals with marginal nutritional status (such as the elderly) who supplement with large amounts of calcium may be at risk of developing phosphorus deficiency. The presence of a low serum or urinary phosphorus level may indicate low or suboptimal phosphorus status. When the potential for calcium-induced phosphorus deficiency is a concern, it may be advisable to administer a proportion of the supplemental calcium in the form of a calcium phosphate preparation (e.g., Posture®).

Heaney RP, Nordin BEC. Calcium effects on phosphorus absorption: implications for the prevention and co-therapy of osteoporosis. J Am Coll Nutr 2002;21:239-244.

Nutritional supplement improves antisocial behavior among criminals
Two-hundred-thirty-one young-adult prisoners (aged 18 years or older) were randomly assigned to receive, in double-blind fashion, a multivitamin/mineral formula plus essential fatty acids (Efamol Marine) or a placebo for an average of 20 weeks. The nutritional supplement contained the following: beta-carotene (4.5 mg), vitamin D (400 IU), thiamine (1.2 mg), riboflavin (1.6 mg), niacinamide (18 mg), pantothenic acid (4 mg), folic acid (400 mcg), vitamin B6 (2 mg), vitamin B12 (3 mcg), vitamin C (60 mg), vitamin E (10 IU), biotin (100 mcg), calcium (100 mg), magnesium (30 mg), iron (12 mg), zinc (15 mg), copper (2 mg), chromium (200 mcg), selenium (50 mcg), manganese (3 mg), iodine (140 mcg), molybdenum (250 mcg), phosphorus (77 mg), linoleic acid (1,260 mg), gamma-linolenic acid (160 mg), eicosapentaenoic acid (80 mg), and docosahexaenoic acid (44 mg). Compared with the placebo group, the supplemented group committed an average of 26.3% fewer offenses that required disciplinary action (p < 0.03).

Comment: There is evidence that individuals who engage in antisocial behavior consume diets lacking in essential nutrients and that this could adversely affect their behavior. The results of the present study suggest that antisocial behavior, including violence, among prisoners can be reduced by supplementation with vitamins, minerals and essential fatty acids. These findings may also have implications for those eating poor diets in the community. It is likely that more than one component of the supplement regimen was responsible for the observed improvement, and that different participants responded to different nutrients. Biochemical testing and individualized supplement regimens would likely improve the outcome in some cases, although a "shotgun approach," as used in the present study, appears to be a cost-effective method of helping a large number of people.

Gesch CB, et al. Influence of supplementary vitamins, minerals and essential fatty acids on the antisocial behaviour of young adult prisoners. Randomised, placebo-controlled trial. Br J Psychiatry 2002;181:22-28.

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