Thirty-five children (aged 1-15 years) with atopic dermatitis due to food allergy were treated with oral cromolyn sodium (also called sodium cromoglycate). The initial dose was 100 mg/day; this was increased progresively to 200-600 mg/day, depending on the response. The treatment improved the skin lesions and prevented reactions to allergenic foods. In most cases, the effects were noticeable after two weeks. The effective dose varied from patient to patient. Cromolyn was ineffective in patients with raised IgG4 levels.

Comment: Cromolyn sodium is a synthetic compound that consists of two molecules of quercetin bound together. It has been shown to inhibit mast cell degranulation, which is one of the mediators of allergic reactions. Both open and controlled trials have found that cromolyn sodium can block food-allergic reactions and ameliorate a wide array of symptoms that result from food allergies. In addition to inhibiting the immune response in the gut wall, cromolyn sodium prevents antigen entry into the circulation. The medication is fairly well tolerated, although in it's most readily available form (Gastrocrom®) it is rather expensive. Less expensive generic versions can be obtained through compounding pharmacists.

While this treatment does not address the cause of food allergies, and while avoidance of allergenic foods is preferable, cromolyn sodium can be considered for people who are unable or unwilling to stop eating their allergens. Moreover, continued use of cromolyn sodium might reduce a person's allergic reactivity, in the same way that avoiding the allergens would. Some practitioners have used quercetin to block food allergies, but there are no published reports on its efficacy.

Molkhou P, Waguet JC. Food allergy and atopic dermatitis in children: treatment with oral sodium cromoglycate. Ann Allergy 1981;47:173-175.

Forty-nine patients with migraines were randomly assigned to receive, in double-blind fashion, daily treatment with 1) a combination of riboflavin 400 mg, magnesium 300 mg, and feverfew 100 mg, or 2) "placebo" (riboflavin 25 mg) for 3 months. The proportion of patients achieving a 50% or greater reduction in migraine frequency (the primary outcome measure) was 42% in the combination group and 44% in the low-dose-riboflavin group (p = 0.87). Both treatments reduced the frequency of migraines by approximately one-third, and decreased the number of migraine days by about one-fourth. In addition, mean headache severity (p = 0.04) and the number of days with tension headache decreased (p = 0.01) in the low-dose-riboflavin group, but not in the group receiving combination therapy. The effect of low-dose riboflavin was greater than that reported for placebo in previous migraine trials.

Comment: Previous studies have demonstrated impaired mitochondrial energy production in brain tissue of patients with recurrent migraines. Riboflavin, as a component of flavin adenine dinucleotide (FAD), has the capacity to enhance energy production, through its participation in the electron transport chain. In open and placebo-controlled studies, a dose of 400 mg/day of riboflavin was effective for preventing migraine recurrences. That dose, which is at least 200 times the amount present in a typical diet, was presumably chosen to give the treatment the best chance of working. While riboflavin does not appear to cause significant adverse effects even at high doses, taking large amounts of any single nutrient might cause subtle imbalances in body chemistry. For that reason, if lower doses were found to be equally effective, they would be preferable to the higher amounts used in earlier studies.

Although there was no true placebo group in the current study, the results suggest that a relatively low dose of riboflavin can prevent migraines. The combination treatment used in this study consisted of three compounds that have each been shown, when given alone, to reduce the incidence of migraines. While it is somewhat surprising that low-dose riboflavin was at least as effective as this combination treatment, it is possible that one or more of the substances in the combination product interfered with the effect of the others, or that massive doses of riboflavin are less effective than more moderate doses.

Maizels M, et al. A combination of riboflavin, magnesium, and feverfew for migraine prophylaxis: a randomized trial. Headache 2004;44:885-890.

Eighty-nine postmenopausal women with osteoporosis or at least 3 risk factors for osteoporosis were randomly assigned to receive, in double-blind fashion, 1 of 4 treatments for 2 years: 1) 500 ml/day of soymilk containing 76 mg/day of isoflavones; 2) transdermal progesterone; 3) the combination of soy and progesterone; or 4) placebo (isoflavone-poor soymilk, containing 1 mg/day of isoflavones). In the progesterone group, 30 g of progesterone cream, containing a total of 540 mg of progesterone, was applied topically over a 3-week period, with a 1-week break before repeating the cycle. All patients received supplemental calcium, magnesium, vitamin D, and other nutrients known to play a role in bone health. The mean change in lumbar-spine bone mineral density (BMD) was +1.1% in the soy group (p < 0.01 vs. placebo), -1.1% in the progesterone group (not significant vs. placebo), -2.8% in the combined treatment group (not significant vs. placebo), and -4.2% in the placebo group. The respective changes in bone mineral content were +2.0% for soy (p = 0.006 vs. placebo), +0.4% for progesterone (p = 0.03 vs. placebo), and -2.4% for combined treatment (not significant vs. placebo), and -4.3% for placebo. No significant changes occurred in femoral-neck BMD.

Comment: The results of this study indicate that daily ingestion of soymilk prevented lumbar-spine bone loss in postmenopausal women. Transdermal progesterone had a modest bone-sparing effect but, when combined with soymilk, a negative interaction occurred, resulting in greater bone loss than with either treatment alone. The apparent negative interaction between soymilk and progesterone may have been due in part to the higher proportion of smokers in the combined-treatment group than in the other groups.

The results seen with progesterone are somewhat disappointing, as they fail to confirm Dr. John Lee's report that transdermal progesterone increased BMD by an average of about 15% over a 3-year period in postmenopausal women (Med Hypotheses 1991;35:316-318). A study by Leonetti et al (Obstet Gynecol 1999;94:225-228) also failed to confirm Lee's work, and found no bone-sparing effect at all from topical progesterone cream. After Leonetti's study was published, Lee argued that progesterone works only in older postmenopausal women who are past the period of rapid postmenopausal bone loss. The mean age of Lee's patients was 65.2 years, compared with 52.5 years for Dr. Leonetti's patients. The patients in the current study had an average age of 58.2 years, and the results were better than those seen by Leonetti, but far worse than those reported by Lee.

A controlled study enrolling older women is needed to determine whether Lee's original uncontrolled trial can be replicated. Dr. Leonetti is planning such a trial, and is attempting to enroll women in the Philadelphia, PA, area. Those interested in participating should contact her at (610) 882-3100, ext. 224.

Lydeking-Olsen E, et al. Soymilk or progesterone for prevention of bone loss: a 2 year randomized, placebo-controlled trial. Eur J Nutr 2004;43:246-257.

Mice were fed diets containing 0, 10, or 35 mmol of choline per kg of diet for 3 weeks. At the end of the diet period, a methionine load was administered. Two hours after the methionine load, choline-deficient mice had plasma homocysteine concentrations twice those of choline-fed mice. In a second study, eight men were fed a choline-adequate diet (550 mg per 70 kg of body weight per day) for 10 days, and then a choline-deficient diet (approximately 50 mg/day) until they developed fatty liver, or for a maximum of 42 days. Among the four men judged to be choline-depleted on the basis of having developed fatty liver, the mean plasma homocysteine concentration 4 hours after a methionine load (100 mg/kg of body weight) was 35% higher than among the men judged not to be choline-depleted (p < 0.05). These results suggest that choline deficiency accentuated the rise in plasma homocysteine concentrations following a methionine load, in both humans and mice.

Comment: Hyperhomocysteinemia is a risk factor for cardiovascular disease, stroke, habitual abortion, thrombophlebitis, and osteoporosis. Elevated homocysteine concentrations can be caused by decreased methylation of homocysteine to methionine, as occurs in folic acid deficiency. A parallel pathway exists for methylation of homocysteine, in which betaine, a metabolite of choline, is the methyl donor. Choline and betaine appear to be more effective than folic acid for suppressing increases in homocysteine levels induced by a meal or a methionine load, whereas betaine (and presumably choline) is somewhat less effective than folic acid in decreasing fasting plasma homocysteine levels. Choline/betaine and folic acid modulate homocysteine metabolism by different mechanisms, each of which appears to play an important role in regulating homocysteine levels. Good food sources of choline include eggs, beef, wheat germ, and soybeans. Foods high in betaine include wheat germ, wheat bran, whole wheat, spinach, and beets.

da Costa KA, et al. Choline deficiency in mice and humans is associated with increased plasma homocysteine concentration after a methionine load. Am J Clin Nutr 2005;81:440-444.

A large multicenter trial reported in 1999 that vitamin A given intramuscularly at a dose of 5,000 IU 3 times per week for 4 weeks decreased the risk of the combined outcome of bronchopulmonary dysplasia or death in extremely-low-birth-weight (ELBW) infants from 62% to 55%. This 7% absolute reduction gives a "number needed to treat" of 14 to 15, meaning that for every 14 or 15 infants treated, one additional infant would survive without BPD. This "number needed to treat" is smaller (more favorable) than for many other therapies used in neonates, infants, and adults. Moreover, many neonatal treatment methods have been used despite methodologically weak evidence of safety and efficacy.

To determine whether the evidence regarding vitamin A therapy is being incorporated into clinical practice, a questionnaire was sent to 102 neonatal-perinatal training program directors (TPDs) and 105 randomly selected directors of neonatal intensive care units (non-training program directors, NTPDs) in the United States. Ninety-nine percent of TPDs and 94% of NTPDs responded. In a minority of programs (20% of TPDs, 13% of NTPDs), more than 90% of eligible ELBW neonates were supplemented with vitamin A, whereas in most programs (69% of TPDs, 82% of NTPDs), routine supplementation was not being practiced. The most common reason that TPDs gave for not supplementing with vitamin A was the perceived small benefit, whereas the most common reason given by NTPDs was that they considered the intervention unproven.

Comment: This study demonstrates an inconsistency in practicing evidence-based medicine in neonatal practice, where therapies are often administered on the basis of weaker evidence of safety and benefit than that which supports vitamin A supplementation. Although we have come a long way, many doctors still appear to have a bias against the use of micronutrients. As Paul Simon said, "a man hears what he wants to hear and disregards the rest."

Ambalavanan N, et al. Survey of vitamin A supplementation for extremely-low-birth-weight infants: is clinical practice consistent with the evidence? J Pediatr 2004;145:304-307.

Nineteen patients (mean age, 63 years) who presented with left ventricular dysfunction after sudden emotional stress were studied. Clinical presentations included chest pain, pulmonary edema, and cardiogenic shock. Only one patient had angiographic evidence of clinically significant coronary disease. Severe left ventricular dysfunction was present on admission (median ejection fraction, 20%) and rapidly resolved in all patients (median ejection fraction at 2-4 weeks, 60%). Endomyocardial biopsy showed mononuclear infiltrates and contraction-band necrosis. Plasma catecholamine levels at presentation were markedly higher among patients with stress-induced cardiomyopathy than among those with myocardial infarction (median epinephrine level, 3.36 times higher; norepinephrine level, 2.08 times higher). The authors concluded that emotional stress can precipitate severe, reversible left ventricular dysfunction in patients without coronary artery disease. Exaggerated sympathetic stimulation probably plays a role in the etiology of this syndrome.

Comment: An outpouring of catecholamines causes magnesium to be released from cells into the bloodstream, and then excreted in the urine. This depletion of intracellular magnesium not only increases the vulnerability of myocardial cells to necrosis, but also exacerbates the deleterious effects of catecholamines. Administration of magnesium has been shown to prevent catecholamine-induced myocardial necrosis in animals.

People subjected to severe stress might do well to supplement with magnesium and to relax a few times a week in a warm Epsom salt (magnesium sulfate) bath. Furthermore, parenteral magnesium might be beneficial in the treatment of acute, stress-induced myocardial dysfunction. People who may have intracellular potassium depletion should receive a potassium supplement in conjunction with parenteral magnesium therapy, because magnesium promotes the cellular uptake of potassium, potentially leading to hypokalemia.

Wittstein IS, et al. Neurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med 2005;352:539-548.

Ten women (mean age, 25.5 years; mean body mass index, 23.2 kg/m2) were randomly assigned to eat or to omit breakfast daily for two weeks. After a two-week washout period, each person switched to the alternate breakfast assignment for an additional two weeks. Total energy intake was significantly lower during the breakfast period than during the no-breakfast period (p = 0.001). Resting energy expenditure did not differ significantly between the two periods. Omitting breakfast was associated with significantly higher fasting total and LDL cholesterol than was eating breakfast (3.14 and 3.43 mmol/L, and 1.55 and 1.82 mmol/L, respectively; p = 0.001). The area under the curve of insulin response to a test meal was significantly lower after eating breakfast than after omitting breakfast (p < 0.01).

Comment: These results suggest that eating breakfast causes people to consume fewer total calories during the day, without a concomitant decrease in resting energy expenditure. Eating breakfast also results in beneficial changes in cholesterol levels and insulin sensitivity. If these effects are sustained, then eating breakfast might help overweight people lose weight. Previous studies have shown that energy intake in the morning is particularly satiating, and that higher energy intake in the morning can reduce the total amount of energy ingested for the day. In contrast, energy intake late at night lacks satiating value and can result in greater overall daily energy intake.

Farshchi HR, et al. Deleterious effects of omitting breakfast on insulin sensitivity and fasting lipid profiles in healthy lean women. Am J Clin Nutr 2005;81:388-396.

Forty-three hypercholesterolemic patients were randomly assigned to receive 500 mg of berberine twice a day (n = 32) or placebo (n = 11) for 3 months. In the berberine group, compared with baseline, the mean serum cholesterol level fell by 29% (p < 0.0001), LDL-cholesterol fell by 25% (p < 0.0001), and triglycerides fell by 35% (p < 0.0001), whereas the mean HDL-cholesterol level did not change. Changes in the placebo group were small and not statistically significant. No side effects were reported, except for mild constipation in one patient.

Comment: Berberine is an alkaloid present in several medicinal plants, including goldenseal and Oregon grape. Although best known for its antimicrobial activity, Berberine is also used in Asia to treat congestive heart failure. In a recent study it was found to decrease ventricular premature complexes and mortality in patients with heart failure (Am J Cardiol 2003;92:173-176). The current study extends the apparent cardioprotective effects of this compound. In human hepatoma cells, berberine was shown to up-regulate LDL-receptor expression; therefore, the mechanism of its cholesterol-lowering action differs from that of statin drugs.

Kong W, et al. Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat Med 2004;10:1344-1351.