Literature Review and Commentary
by Alan R. Gaby, MD

L-arginine for dementia

Sixteen elderly patients (mean age, 79 years) with cerebrovascular disease who had been living in a nursing home for 2-4 years received 1.6 g/day of L-arginine for 3 months. Cognitive function was determined by a revised version of Hasegawa's Dementia Scale (which is comparable to the Mini-Mental State Examination). Thirty is a perfect score and less than 20 is considered to reflect dementia. The mean score improved from 16 at baseline to 23 (p < 0.0001) at the end of the treatment period. However, 3 months after L-arginine was discontinued, the score had fallen to 17. In general, patients showed more expressive faces and quicker responses while receiving L-arginine. No side effects were seen.

Comment: Arginine is a precursor to nitric oxide, which has been reported to function as a neurotransmitter that plays a role in learning and memory. In addition, nitric oxide functions as a vasodilator and might, therefore, promote increased blood flow to the brain. Tissue concentrations of nitric oxide and arginine decline with age, suggesting that arginine deficiency may be a contributing factor to age-related mental decline. This open trial suggests that supplementation with a relatively small amount of L-arginine (a typical diet contains approximately 3 times that amount) improved cognitive function in patients with cerebrovascular disease. Controlled trials are needed to confirm this promising study.

Ohtsuka Y, et al. Effect of oral administration of L-arginine on senile dementia. Am J Med 2000;108:439.

Unexplained dialysis dementia/encephalopathy caused by thiamine deficiency

Ten patients on dialysis (9 hemodialysis) with altered mental status, the cause of which was unidentified after an initial work-up, were studied. Manifestations included confusion, chorea, acute visual loss, rapidly progressive dementia, myoclonus, convulsions, and coma. Of 7 patients in whom serum thiamine concentrations were measured, all had subnormal levels. All 10 patients received an intravenous injection of 200 mg of thiamine, followed by 100 mg/day intravenously until they could consume a normal diet. The neurological deficits resolved dramatically in 9 of the 10 patients; the other patient failed to respond because of a delay in treatment. Five of the 10 patients had been receiving oral B vitamin supplements before developing thiamine deficiency.

Comment: Patients with end-stage renal disease undergoing regular dialysis are at risk of developing encephalopathy, the cause of which is often unclear. Dialysis patients are also at risk of developing thiamine deficiency, which can mimic many of the complications of uremia, including encephalopathy. Although peritoneal dialysis patients are routinely given supplemental thiamine, thiamine supplementation of hemodialysis patients is controversial. The results of the present study suggest that, in regular dialysis patients, unexplained encephalopathy is due primarily to thiamine deficiency (e.g., Wernicke's encephalopathy).

Hung SC, et al. Thiamine deficiency and unexplained encephalopathy in hemodialysis and peritoneal dialysis patients. Am J Kidney Dis 2001;38:941-947.

Dementia and Alzheimer's disease: environmental illnesses?

A total of 2,459 community-dwelling Yoruba residents of Ibadan, Nigeria, without dementia, and 2,147 community-dwelling African-American residents of Indianapolis, Indiana without dementia (all aged 65 years or older) were followed prospectively for a mean of 5.1 years and 4.7 years, respectively. The age-standardized annual incidence rates were significantly lower among Yoruba than among African-Americans for dementia (1.35% vs. 3.24%) and for Alzheimer's disease (1.15% vs. 2.52%).

Comment: The results of this study indicate that the incidence rates for dementia and Alzheimer's disease are significantly lower among individuals from a non-industrialized country than among those from an industrialized country. That finding suggests that environmental factors play a role in the development of dementia and Alzheimer's disease. There is evidence that exposure to aluminum can increase the risk of Alzheimer's disease; however, not all studies agree. It is likely that other environmental toxins, or chronic consumption of modern processed foods, make it difficult for old brains to remain healthy.

Hendrie HC, et al. Incidence of dementia and Alzheimer disease in 2 communities: Yoruba residing in Ibadan, Nigeria, and African Americans residing in Indianapolis, Indiana. JAMA 2001;285:739-747.

Choline, parenteral nutrition, and cognitive decline

Eleven patients who had received total parenteral nutrition (TPN) for more than 80% of their nutritional needs for at least 12 weeks were randomly assigned to receive their usual TPN regimen (n = 6; mean age, 34.0 years) or their usual TPN regimen plus 2 g/day of choline chloride (n = 5; mean age, 37.3 years). The following neuropsychological tests were administered at baseline and after 24 weeks: Weschler Adult Intelligence Scale-Revised (WAIS-R, intellectual functioning), Weschler Memory Scale-Revised (WMS-R, 2 subtests, verbal and visual memory), Rey-Osterrieth Complex Figure Test (visuospatial functioning and perceptual organization), Controlled Oral Word Association Test (verbal fluency), Grooved Pegboard (manual dexterity and motor speed), California Verbal Learning Test (CVLT, rote verbal learning ability), and Trail Making Parts A & B (visual scanning, psychomotor speed and set shifting). Compared with the placebo group, significant improvements were seen in the choline group in the delayed visual recall of the WMS-R (p = 0.028), and borderline improvements were seen in the List B subset of the CVLT (p = .06) and the Trails A test (p = .067).

Comment: This study demonstrates that both verbal and visual memory may be impaired in patients receiving long-term parenteral nutrition, and that both of these deficits may be improved with choline supplementation. As a component of acetylcholine, choline plays an important role in normal brain function. Choline deficiency is uncommon, because it can be manufactured in the body and is present in many foods. However, patients receiving choline-free parenteral nutrition as their main source of nutrition are apparently not capable of manufacturing sufficient amounts of this compound. Because of the wide range of nutritional deficiencies that have been reported in patients fed intravenously, it would be more appropriate to change the term "total parenteral nutrition" to "sub-total parenteral nutrition."

Buchman AL, et al. Verbal and visual memory improve after choline supplementation in long-term total parenteral nutrition: a pilot study. J Parenter Enteral Nutr 2001;25:30-35.

Nutritional supplement enhances cognitive function in the elderly

Ninety-six apparently healthy Canadians older than 65 years of age (mean age, 75 years) were randomly assigned to receive, in double-blind fashion, a nutritional supplement containing modest doses of vitamins and trace minerals or a placebo for 12 months. The supplement provided daily: vitamin A (400 retinol equivalents), beta-carotene (16 mg), thiamine (2.2 mg), riboflavin (1.5 mg), niacin (16 mg), vitamin B6 (3 mg), folic acid (400 mcg), vitamin B12 (4 mcg), vitamin C (80 mg), vitamin D (4 mcg), vitamin E (44 mg), iron (16 mg), zinc (14 mg), copper (1.4 mg), selenium (20 mcg), iodine (0.2 mg), calcium (200 mg), and magnesium (100 mg). The placebo contained calcium (200 mg) and magnesium (100 mg). Compared with placebo, the supplement produced significant improvements in 6 of 7 tests of memory, abstract thinking, problem-solving ability, and attention (p < 0.001 to p < 0.05).

Comment: This study showed that supplementation with modest amounts of vitamins and trace minerals can improve cognitive function in healthy elderly individuals. Nutritional status tends to decline with advancing age, because of factors such as poor dentition, economic hardship, greater difficulty shopping for fresh produce, age-related malabsorption, and use of medications that interfere with absorption or utilization of nutrients. In addition to improving mental function, supplementing with a broad-spectrum nutritional formula has been shown to improve immune function and to reduce the incidence of infections in the elderly.

Chandra RK. Effect of vitamin and trace-element supplementation on cognitive function in elderly subjects. Nutrition 2001;17:709-712.

St. John’s wort flunks another test: or does it?

Some 340 adults with major depression and a score on the Hamilton Depression Scale (HAM-D) of at least 20 were randomly assigned to receive, in double-blind fashion, either 1) Hypericum perforatum (St. John’s wort; SJW) extract LI-160, 2) placebo, or 3) sertraline for 8 weeks. Based on clinical response, the daily dose of SJW could range from 900 to 1,500 mg and that of sertraline from 50 to 100 mg. The primary outcome measures were 1) change in the HAM-D total score from baseline to 8 weeks, and 2) rates of full response, determined by the HAM-D and Clinical Global Impressions (CGI) scores. On the 2 primary outcome measures, neither sertraline nor SJW was significantly different from placebo. The mean decrease (improvement) in the HAM-D score from baseline to week 8 was 9.20 for placebo, 8.68 for SJW, and 10.53 for sertraline (differences not significant). A full response occurred in 31.9% of the placebo-treated patients, 23.9% of the SJW-treated patients and 24.8% of sertraline-treated patients (differences not significant). Sertraline was better than placebo on the CGI improvement scale (p = 0.02), which was a secondary measure in this study. The authors concluded that St. John’s wort was not effective in this group of patients with moderately severe major depression.

Comment: Numerous controlled trials have shown that St. John’s wort is more effective than a placebo in the treatment of mild-to-moderate depression, and that its efficacy is similar to that of drugs such as fluoxetine (Prozac®), sertraline (Zoloft®), and imipramine. The new study is one of two recently published reports that failed to confirm the beneficial effect of St. John’s wort. However, each of these studies had flaws. In the first study (JAMA 2001;285:1978 – 86), although the remission rate was significantly greater with St. John’s wort than with placebo, only 14.3% of the patients who received the herb went into remission, causing the researchers to question St. John’s wort’s efficacy. However, the 4.9% remission rate in the placebo group was far below the placebo response rate seen in other studies of depression. That finding suggests that many of the patients recruited for this study were poor responders and would not have benefited from any treatment. In the new study cited above, St. John’s wort was no more effective than placebo, but by many measures neither was sertraline. The relatively poor outcome with sertraline makes one wonder whether the design of the study, or the criteria used to select participants, may have somehow skewed the results to make St. John’s wort appear less effective than it really is. The bulk of the scientific evidence still indicates that St. John’s wort is a safe and effective treatment for mild-to-moderate depression.

Hypericum Depression Trial Study Group. Effect of Hypericum perforatum (St John’s Wort) in major depressive disorder: a randomized controlled trial. JAMA 2002;287:1807-1814.

Calcium-fortified orange juice blocks absorption of ciprofloxacin

Fifteen healthy volunteers participated in a randomized, crossover study in which they consumed single doses of oral ciprofloxacin with water, with orange juice, and with calcium-fortified orange juice. Compared with water, the peak serum concentration (Cmax) of ciprofloxacin was significantly lower when the drug was given with orange juice (-23%; p = 0.001) and with calcium-fortified orange juice (-41%; p < 0.001). The 24-hour ciprofloxacin area under the concentration-time curve (AUC) was also decreased with both forms of the orange juice (-22% and -38%, respectively). The Cmax and AUC was 22% (p = 0.005) and 21% (p = 0.015) lower with fortified than with nonfortified orange juice.

Comment: Current FDA labeling states that ciprofloxacin and most other fluoroquinolones are safe to take with food and dietary calcium but not with calcium supplements. The results of the present study indicate that calcium-fortified orange juice behaves more like a calcium supplement than a food, with respect to ciprofloxacin bioavailability. Concurrent administration of calcium-fortified orange juice significantly reduces the bioavailability of ciprofloxacin, possibly leading to decreased efficacy and the promotion of antibiotic resistance.

Neuhofel AL, et al. Lack of bioequivalence of ciprofloxacin when administered with calcium-fortified orange juice: a new twist on an old interaction. J Clin Pharmacol 2002;42:461-466.

More on the vitamin A/osteoporosis connection: margarine and vitamin K

During the hydrogenation of phylloquinone (vitamin K1)-rich oils (such as soybean and canola oil), phylloquinone is converted to its hydrogenated form, dihydrophylloquinone. The mean intake of dihydrophylloquinone by US adults is approximately 20 mcg/day, or about 20% of the total vitamin K in the diet. To determine whether the hydrogenation of vitamin K affects its biological activity, 15 healthy men and women consumed a phylloquinone-restricted diet (10 mcg/day) for 15 days and were then randomly assigned to a 10-day repletion period with 200 mcg/day of either purified phylloquinone or dihydrophylloquinone. After a washout period of at least 4 weeks, they underwent the same vitamin K depletion protocol and were then repleted with the alternate supplement. There was an increase and subsequent decrease in measures of bone formation (p = 0.002) and resorption (p = 0.08) after phylloquinone restriction and repletion, respectively, but dihydrophylloquinone had no effect on measures of bone formation and resorption. In addition, the absorption of dihydrophylloquinone was less than that of phylloquinone. These results indicate that dihydrophylloquinone is not as well absorbed as phylloquinone, and also lacks vitamin K activity, at least where bone formation and resorption are concerned.

Comment: In a previous issue of the Townsend Letter, I discussed the controversy concerning whether modest increases in vitamin A intake can promote the development of osteoporosis. I pointed out that vitamin A intake, in today's vitamin A-fortified, processed-food environment, is a marker for the consumption of processed foods such as margarine and sugary breakfast cereals. I suggested that the trans-fatty acids in margarine, rather than the added vitamin A, might have an adverse effect on bone. The results of the present study suggest that the consumption of margarine and other sources of hydrogenated vegetable oils may promote bone loss through an additional mechanism; namely, the destruction of vitamin K. This study strengthens the notion that consuming partially hydrogenated vegetable oils is not a good idea, whereas modest increases in dietary vitamin A intake probably do not cause osteoporosis.

Booth SL, et al. Effects of a hydrogenated form of vitamin K on bone formation and resorption. Am J Clin Nutr 2001;74:783-790.

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