Eighteen patients with inoperable primary liver cancer and 21 with metastatic liver cancer were treated with oral urea over an 11-year period. The usual dose was 12-15 g/day in 6 divided doses per day, administered in syrup. In two patients with large liver tumors, doses up to 30 g/day were given for up to 29 months. Most patients reported improvements after about two weeks, including weight gain, better performance, and increased well being. Regression of liver enlargement was noted after about three months. The median survival time for the entire group was 20 months. The longest survival time was 93 months in a patient with hepatoma and 113 months in a patient with metastatic adenocarcinoma; the latter patient was still alive and in excellent condition. Seven patients were still alive at the time of this report. These survival times are much longer than those reported for similar patients treated with chemotherapy. Urea was well tolerated and did not cause side effects, even after years of treatment.

Comment: Urea is toxic to many different types of cancer cells. However, since the kidneys rapidly excrete urea, it is impossible to attain adequate concentrations in most body tissues after oral or intravenous administration. The only exception is the liver, because orally administered urea reaches the liver in high concentrations via the portal vein.

Because of its short half-life, urea must be administered frequently throughout the day. It has a bitter taste, which can be masked by dissolving it in fruit juice or tomato juice, or by dissolving the full daily dose in 1-2 quarts of water. People who are taking urea will often have extremely high blood urea nitrogen (BUN) levels, which might be erroneously thought to indicate renal failure, if the doctor is unaware the patient is taking urea. Despite these high BUN levels, urea does not appear to have any deleterious effects on the kidneys.

Although urea is inexpensive, safe, and apparently effective against liver cancer, this treatment has received little attention among oncologists.

Danopoulos ED, Danopoulou IE. Eleven years experience of oral urea treatment in liver malignancies. Clin Oncology 1981;7:281-289.

Fifteen patients who had had surgery or radiation therapy for prostate cancer a mean of 65 months previously, who were symptom-free but had experienced at least 3 consecutive increases in prostate-specific antigen (PSA) values over a minimum of 9 months, were treated with 2,000 IU (50 mcg)/day of vitamin D3 (cholecalciferol). The median follow-up period was 8 months (range, 4-21 months). Eight of the 15 patients had a decrease in serum PSA after starting vitamin D; this decrease was sustained for 5-17 months. In another patient, PSA levels fluctuated around the baseline value for 21 months and did not show any clear trend of increase at the time of last follow-up. In the group as a whole, the rate of PSA rise decreased after administration of vitamin D (p = 0.005), compared with before treatment. The median PSA doubling time increased from 14.3 months prior to vitamin D treatment to 25 months after starting vitamin D; 14 of 15 patients had a prolongation of PSA doubling time. No side effects were reported. Serum calcium levels remained normal in all but one patient, who was later found to have a functioning parathyroid adenoma.

Comment: Previous studies have demonstrated anti-cancer and immune-enhancing properties of vitamin D, although most of the research has been observational or in laboratory animals. One previous study in humans found a high prevalence of vitamin D deficiency in patients with metastatic prostate cancer; in those patients vitamin D supplementation reduced bone pain and increased muscle strength. The results of the present study suggest that vitamin D may also delay the progression of prostate cancer. This trial took place in Toronto, where people tend to be low in vitamin D, because of the low amount of sunlight exposure at that geographical latitude. Whether men in sunny Florida would derive the same benefit from vitamin D supplementation remains to be determined. Recent research has suggested that vitamin D doses up to 4,000 IU/day are safe, and some investigators believe that the upper limit of safety is around 10,000 IU/day. Future research might consider whether higher doses are more effective than 2,000 IU/day in the treatment of prostate cancer.

Woo TCS, et al. Pilot study: potential role of vitamin D (cholecalciferol) in patients with PSA relapse after definitive therapy. Nutr Cancer 2005;51:32-36

Six hundred twenty-eight Japanese patients (mean age, 71 years) with residual hemiplegia at least one year after their first ischemic stroke were randomly assigned to receive, in double-blind fashion, 5 mg/day of folic acid and 1,500 mcg/day of vitamin B12 (methylcobalamin) for two years. At baseline, the mean plasma homocysteine concentration was above the reference range, and the mean serum vitamin B12 concentration was below the reference range for the healthy Japanese elderly population. After two years, the mean plasma homocysteine concentration decreased by 38% in the treatment group and increased by 31% in the placebo group (p < 0.001). In intent-to-treat analysis, after 2 years, hip fractures had occurred in 6 patients in the treatment group and in 27 in the placebo group (1.9% vs. 8.6%; 78% reduction; p < 0.001). The mean number of falls per patient did not differ between groups, and the mean reduction in metacarpal BMD on both the hemiplegic and intact sides did not differ significantly between groups. Based on these results, it was calculated that 1 hip fracture would be prevented for every 15 patients treated. No significant adverse effects were reported.

Comment: Stroke increases the risk of subsequent hip fracture by 2- to 4-fold. Hip fractures usually occur relatively late after stroke onset and almost always on the paretic side of the body, apparently because bone mineral density (BMD) declines on that side as a result of inactivity. Hyperhomocysteinemia, which is a risk factor for both ischemic stroke and osteoporotic fractures in elderly men and women, may result in part from a deficiency of folic acid or vitamin B12.

The results of the present study indicate that treatment with folic acid and vitamin B12 reduced the incidence of hip fractures in hyperhomocysteinemic patients following a stroke. Since treatment did not influence BMD, the beneficial effect may have been due to an improvement in bone quality. Homocysteine has been shown to interfere with the formation of collagen cross-links, an effect that may lead to abnormalities of bone matrix, potentially resulting in increased bone fragility.

Other people with high homocysteine levels might also benefit from taking these vitamins. In addition to folic acid and vitamin B12, several other nutrients play a role in lowering homocysteine levels; these include vitamin B6, choline, and betaine.

Sato Y, et al. Effect of folate and mecobalamin on hip fractures in patients with stroke: a randomized controlled trial. JAMA 2005;293:1082-1088.

Ninety patients with atrophic (dry) age-related macular degeneration were randomly assigned to receive, in double-blind fashion, one of three treatments for one year: 1) lutein 10 mg/day (an amount present in approximately 60 g of spinach); 2) lutein plus a supplement containing antioxidants, vitamins, and minerals; or 3) placebo. The supplement provided daily 2,500 IU vitamin A, 15,000 IU natural beta-carotene, 1,500 mg vitamin C, 400 IU vitamin D, 500 IU vitamin E, 50 mg thiamine, 10 mg riboflavin, 70 mg vitamin B3, 50 mg pantothenic acid, 50 mg vitamin B6, 500 mcg vitamin B12, 800 mcg folic acid, 300 mcg biotin, 500 mg calcium, 300 mg magnesium, 75 mcg iodine, 25 mg zinc, 1 mg copper, 2 mg manganese, 200 mcg selenium, 200 mcg chromium, 160 mg bilberry extract (standardized to 25% anthocyanosides), 150 mg alpha-lipoic acid, 200 mg N-acetylcysteine, 100 mg quercetin, 100 mg rutin, 900 mg taurine, and several other nutrients.

The mean macular pigment optical density increased by 0.09 log unit in group 1 (p = 0.1 vs. placebo) and by 0.08 log unit in group 2 (p = 0.02), and decreased by 0.03 log unit in the placebo group. Snellen equivalent visual acuity improved by a mean of 5.4 letters (equivalent to approximately 1 line on the eye chart) in group 1 (p = 0.01 vs. baseline and vs. placebo). In group 2 the mean improvement was 3.5 letters (p = 0.04 vs. baseline; p = 0.08 vs. placebo). Contrast sensitivity improvement significantly in both active-treatment groups; the degree of improvement was greater in the group receiving combination therapy then in those receiving antioxidants alone; no significant improvement was seen in the placebo group. Active treatment was effective at all stages of age-related macular degeneration (stages II, III, and IV).

Comment: These results indicate that supplementation with lutein or lutein together with other nutrients can increase macular pigment optical density and improve visual function in patients with age-related macular degeneration, By some, but not all, measures, combination therapy was more effective than lutein alone.

Lutein is a carotenoid found primarily in spinach, corn, other vegetables, and eggs. It is a normal component of the macular pigment, where it filters the retina-damaging blue-light portion of the sun's rays. A thicker macular pigment (increased macular pigment optical density) provides greater protection than a thinner macular pigment, and lutein supplementation has been shown to increase the thickness of the macular pigment. Antioxidants such as selenium, vitamin E, vitamin C, and quercetin may protect retinal tissue against oxidative damage, and nutrients such as zinc, taurine and anthocyanosides appear to have direct effects on ocular tissues (e.g., stabilizing cell membranes or enhancing visual function).

Richer S, et al. Double-masked, placebo-controlled, randomized trial of lutein and antioxidant supplementation in the intervention of atrophic age-related macular degeneration: the Veterans LAST study (Lutein Antioxidant Supplementation Trial). Optometry 2004;75(4):1-15.

One hundred eight postmenopausal women (mean age, 55 years) were randomly assigned to receive, in double-blind fashion, one of the following for three years: 1) placebo, 2) a daily supplement containing 500 mg of calcium, 10 mg of zinc, 150 mg of magnesium, and 320 IU of vitamin D (MD group), or 3) the same nutrients as in the MD group, plus 1 mg/day of vitamin K1 (MDK group). After three years, the elastic properties of the carotid artery (as determined by parameters such as compliance coefficient, distensibility coefficient, and pulse pressure) remained unchanged in the MDK group, but decreased in the MD and placebo groups (p < 0.05 for each comparison between MDK and placebo). There were no significant differences between MD and placebo.

Comment: These results indicate that, in postmenopausal women taking calcium, zinc, magnesium, and vitamin D, supplementation with 1 mg/day of vitamin K1 for three years prevented a deterioration of the elastic properties of the carotid artery wall. Vitamin K plays a role in the synthesis of matrix-Gla Protein (MGP), which is a strong inhibitor of vascular calcification. A deficiency of vitamin K in vascular tissues results in the formation of inactive MGP, which is a potential risk factor for calcification. In observational studies, poor vitamin K status was associated with increased risk of both coronary artery calcification and coronary heart disease-related mortality. In addition, treatment of rats with the vitamin K antagonist warfarin resulted in calcification of arteries, an effect that has also been reported in observational studies in humans.

Adequate vitamin K status appears to be important not only for normal blood clotting function and bone metabolism, but also to maintain vascular health. Good food sources of vitamin K include green leafy vegetables, soybean oil, and olive oil.

Braam LAJLM, et al. Beneficial effects of vitamins D and K on the elastic properties of the vessel wall in postmenopausal women: a follow-up study. Thromb Haemost 2004;91:373-380.

One hundred women (mean age, 35 years) with non-specific vaginitis (NSV; bacterial vaginosis) were randomly assigned to receive, in double-blind fashion, vitamin C vaginal tablets (250 mg) or placebo once a day at bedtime for 16 days. The vitamin C product was specially formulated to release the vitamin over a period of hours, in order to enhance its action and to prevent irritation of the vaginal epithelium. It was not specified whether ascorbic acid or buffered vitamin C was used. In intent-to-treat analysis, one week after the end of treatment, NSV was still present in more women in the placebo group than in the vitamin C group (35.7% vs. 14.0%; p = 0.02). Two weeks after the end of treatment, NSV was present in 34.1% and 21.7% of patients, respectively (p = 0.06). Clue cells disappeared in 79% of patients treated with vitamin C and in 53% of patients on placebo; bacteria disappeared in 77% and 54%, respectively; and lactobacilli reappeared in 79.1 and 53.3%, respectively; all of these differences were statistically significant. Adverse events occurred in 4 patients, 2 on placebo (pruritus, cystitis) and 2 on vitamin C (candidiasis).

Comment: NSV is a common and often difficult-to-treat gynecological condition. The results of the present study suggest that intravaginal administration of vitamin C is a safe and moderately effective treatment for this problem. A slow-release preparation, as used in this study, may be preferable to a regular vitamin C tablet or capsule, both for increasing tolerability and enhancing efficacy.

Petersen EE, Magnani P. Efficacy and safety of vitamin C vaginal tablets in the treatment of non-specific vaginitis. A randomised, double blind, placebo-controlled study. Eur J Obstet Gynecol Reprod Biol 2004;117:70-75.

The mean serum ferritin concentration was significantly lower in 53 French children (mean age, 9.2 years; range, 4-14) with attention deficit-hyperactivity disorder (ADHD) than in 27 age-matched controls without ADHD (23 vs. 44 ng/ml; p < 0.001). Serum ferritin levels were below normal (< 30 ng/ml) in 84% of children with ADHD and 18% of controls (p < 0.001). Low serum ferritin levels were correlated with more severe general ADHD symptoms, as measured with the Conners' Parent Rating Scale (r = -0.34; p < 0.02), and with greater cognitive deficits (r = -0.38; p < 0.01).

Comment: Iron deficiency can cause a wide range of abnormalities in mood and behavior. In addition, iron deficiency in early childhood can adversely affect brain development. Previous studies have shown that iron supplementation can improve various parameters of mental function in children with iron deficiency. Moreover, one study showed that iron supplementation improved behavioral and cognitive symptoms in children with ADHD who did not have laboratory evidence of iron deficiency. In that study, the mean ferritin concentration at baseline was towards the lower end of the normal range (25.9 ng/ml), and increased by about 70% after iron supplementation. Thus, the children may have had sub-optimal iron status, even though they did not fulfil standard criteria for iron deficiency.

Iron status should be measured in all children with ADHD. Those who are deficient, and possibly those whose ferritin levels are near the bottom of the normal range, should receive iron supplementation.

Konofal E, et al. Iron deficiency in children with attention-deficit/hyperactivity disorder. Arch Pediatr Adolesc Med 2004;158:1113-1115.

Some 23,296 postmenopausal women aged 50 to 79 years participating in the Women's Health Initiative study were randomly assigned, based on hysterectomy status, to active treatment or placebo in either the estrogen plus progestin (E + P) or estrogen alone trials. The E + P hormones were 0.625 mg/day of conjugated equine estrogens plus 2.5 mg/day of medroxyprogesterone acetate (CEE + MPA); estrogen alone consisted of 0.625 mg/day of CEE. After one year of treatment, compared with placebo, CEE alone and CEE + MPA increased the incidence of urinary incontinence among continent women and worsened the incontinence among women who were symptomatic at baseline. The increased incidence of incontinence was seen for all types of incontinence (stress, urge, and mixed), although the increased incidence for urge incontinence was significant only in the CEE trial.

Comment: Although hormone therapy is often prescribed to treat urinary incontinence, the results of the present study demonstrate that CEE (Premarin®) actually makes the problem worse. This study adds to the list of documented adverse effects of CEE, which now include increased risks of breast cancer, cognitive decline, dementia, thrombophlebitis, gallbladder disease, and possibly heart disease. This growing list of adverse effects is an ongoing embarrassment for the medical community which, until a few years ago, was vigorously recommending that most postmenopausal women receive CEE.

For more than 20 years, Dr. Jonathan Wright and others have pointed out that CEE, which is derived from horse urine, contains a wide range of hormonally active compounds that are foreign to the human body, and may therefore not be an appropriate treatment for humans. Moreover, the fact that CEE is derived from pregnant mares' urine indicates that even the horses did not want it.

Hopefully, the impending demise of CEE will remind practitioners that hormone-replacement therapy should more logically consist of low doses of those hormones that are manufactured by the human ovary (estrogens, progesterone, DHEA, and testosterone), individualized according to each person's needs.

Hendrix SL, et al. Effects of estrogen with and without progestin on urinary incontinence. JAMA 2005;293:935-948.