August 2003 Blog with Durk and Sandy

‘After the Battle of Bunker Hill in June 1775, General Washington and the Continental army lay in wait around beleaguered, British-occupied Boston for nine months, refusing to attack.’ Why the delay? The city was gripped by an epidemic of smallpox, and Washington knew that, unlike British General Howe’s troops, his own forces had not been exposed to the disease as children. ‘Washington suspected that the British were deliberately planting smallpox victims among the refugees they permitted to leave Boston during the siege, in an attempt to infect the Continental army.’
— Donald J. Wear, M.D., in a review of The Greatest Killer: Smallpox in History by Donald R. Hopkins (JAMA, March 5, 2003)

Tragedy of the Commons — NOT

One example [of a commons problem] is the Swiss Alpine cheese makers. They had a commons problem. They live very high, and they have a grazing commons for their cattle. They solved that problem in the year 1200 A.D. For about 800 years, these guys have had that problem solved. They have a simple rule: If you’ve got three cows, you can pasture these three cows in the commons if you carried them over from last winter. But you can’t bring new cows in just for the summer. It’s very costly to carry cows over to the winter—they need to be in barns and be heated, they have to be fed. [The cheese makers] tie the right to the commons to a private property right with the cows.
— Economics Nobel laureate Vernon Smith, in an interview in the Competitive Enterprise Institute’s Monthly Planet (see www.cei.org)

Comment on the above: The problem of the commons in grazing lands in the arid West has also resulted in use of a system since the mid-1800s very similar to the one described for the Swiss Alpine cheese makers. In the grazing allotments found in the West, private ownership of water rights is required to have your cows graze the “public” lands. Your cows cannot live on just the forage found on these lands; they must have water, and in the West, water is scarce in most places. Thus, private ownership of water determines whose cattle can use the grazing lands that would otherwise be a commons. This system has worked well in allowing use of water (regulated by the prior appropriation doctrine under state—not federal—law, mostly in the arid West) and the forage on what was previously a commons for beneficial purposes, while giving the ranchers who own water rights a proprietary interest in maintaining the quality of their grazing areas in the previous commons.

Recent years have seen the development of political wars between owners/users of privately owned water under state law and interests supporting federal government takeover of state-controlled water. The tragedy of the commons in grazing allotments is that previous arrangements for which people have already paid (for example, the IRS estate taxes that ranchers have to pay on the value of their grazing allotments and the higher price ranchers have had to pay for a ranch that has an attached grazing allotment) and that have established a peaceful means for 140 years to make beneficial use of resources are now the subject of expensive and destructive political wars.

Caloric Restriction Does Not Increase the Lifespan of All Breeds of Mice

The authors of a recent paper¹ carried out a study to determine whether caloric restriction (CR) can increase the lifespan in all genetic strains of mice and whether the beneficial effects of CR accrue gradually or whether they are rapidly induced and reversible when there is a shift from ad libitum (AL) feeding to CR.

They compared the effects of CR on two mouse strains, C57BL/6 and DBA/2, and their first-generation hybrids, B6D2F1. Under AL conditions, the median lifespans of the strains of mice differed only slightly, with B6D2F1 and C57BL/6 mice living 1 to 2 months longer than DBA/2. However, under CR conditions, the C57BL/6 and B6D2F1 had a 6-to-7-month-longer median lifespan and an 8-to-11-month-longer maximum lifespan, whereas in the DBA/2 mice, CR resulted in a slight decrease in lifespan. Hence, CR did not increase the lifespan of all the strains studied.

In the second part of the study, one-half of the original group of AL mice in each genotype and age were switched and maintained in CR. Half of the original CR mice were switched to AL and maintained at AL. The groups were kept on these switched regimens for at least 11 weeks, along with control groups that remained on their original AL or CR regimens. The results showed that switching CR mice to AL at advanced age had little or no effect on mortality over the 11-week period compared to CR mice maintained on CR. The authors suggest that the beneficial effects of CR are, therefore, not rapidly reversible. Switching old AL-fed mice to CR failed to increase lifespan; in fact, it tended to increase mortality compared to AL mice maintained on AL. The increased mortality was evident by 17 months in the DBA/2 and C57BL/6 mice, but not until 24 months in the B6D2F1. The authors conclude that “CR instituted at a relatively advanced age may be without benefit and, depending on genotype, could have significant deleterious effects.”

The genetic difference between strains of mice is far, far smaller than the genetic difference between humans and mice or even humans and monkeys. Hence, since CR does not increase the lifespan of all mouse strains, and even if CR ultimately proves to increase mean or maximum lifespan in monkeys, it is still not clear whether lifelong caloric restriction would increase mean or maximum lifespan in humans.

This is an ideal problem for study with gene-expression microarray chips. The expression of many genes is altered by CR. The expression of the critical genes for the life-extending effect of CR will be different in the DBA/2 mice as compared to the C57BL6 and B6D2F mice. Once the genes that are responsible for the differences in CR in the mouse strains are identified, the effect of CR can then be studied on the homologous genes in human cells. We will be helping to support this research.

Forster, Morris, Sohal. Genotype and age influence the effect of caloric intake on mortality in mice. FASEB J, Feb 5, 2003.

Price Competition Between Dietary Supplements and Prescription Drugs Cannot Occur without Treatment Claims for Supplements

As we discussed in our last newsletter (April–May 2003), we and coplaintiffs have sued the FDA for violating our First Amendment free speech rights in prohibiting truthful statements on labels and in ads about the effects of dietary supplements on the treatment of an existing disease. The example we are using as the basis for the suit is saw palmetto, for which we seek to make the claim, “Consumption of 320 mg of saw palmetto extract daily may improve urine flow, reduce nocturia, and reduce voiding urgency associated with mild benign prostatic hyperplasia.” The claim is truthful and nonmisleading, yet the FDA has refused to review the claim, saying that a “treatment” claim is not permitted under the health claims provision of DSHEA. That is not true, and even if it were, the First Amendment prohibits government censorship of communication of truthful and nonmisleading information. For details on the saw palmetto suit, see www.emord.com. In fact, we argue that the information that we propose to communicate is scientific information that should receive full First Amendment protection, whether there is a commercial motive for saying it or not.

One of the consequences of our winning this suit would be that there would be direct competition between dietary supplements and prescription drugs that treat the same disease or symptoms of disease. It would result in price competition that would, at least at first, be highly unfavorable for many expensive prescription drugs. We found a good example in the New England Journal of Medicine¹ recently. Acetylcysteine is sold as a prescription drug with disease treatment claims (for example, it is used to treat acetaminophen poisoning), while it is also sold as a dietary supplement for which no treatment claims are permitted (unconstitutionally) by the FDA. The article¹ listed 1 gram of acetylcysteine as costing (2000 prices) $5.05 (Medicare) and $3.38 (catalog). The price of the same amount of acetylcysteine as a dietary supplement today is roughly $0.30 (the cost of 1 gram of cysteine, which we use rather than acetylcysteine, is about $0.20). There is currently very little competition between acetylcysteine as a dietary supplement and as a prescription drug, because of FDA information censorship (protecting the interests of pharmaceutical companies that do not want to compete, but damaging the interests of consumers, while driving up the costs of Medicare to hapless taxpayers).

Iglehart. Medicare and drug pricing. N Engl J Med 348(16):1593 (Apr 17, 2003)

Phytoestrogens: Neuroprotective Properties Independent of Estrogenic Effects

A fairly recent paper1 found no correlation between the cytoprotective (cell-protective) effects and estrogenic potency of various natural and synthetic mono- and polyphenolic compounds in cultures of mouse hippocampal HT22 cells and human SK-N-MC neuroblastoma cells. The authors studied the neuroprotective effects of molecules that lack estrogenic hormonal effects but are equally effective neuroprotective antioxidants compared with 17-beta-estradiol, the natural human female sex hormone. Major phytoestrogens (that do have some estrogenic effects) include some of the flavonoids, such as quercetin (found in onions) and catechins (found in tea), and the stilbenes, such as resveratrol (found in grapes and wine). There are also xenobiotic estrogenlike substances, such as bisphenol A (a plastic-material monomer), certain polymer plasticizers, and detergent-related chemicals.

One way the scientists tested the correlation between neuroprotection and estrogenic activity was to measure the antioxidative neuroprotective effect of the phenolic compounds while adding an antiestrogen (ICI 182780) to the cell medium. Thus, while the phenolic compounds have varying degrees of estrogenic activity, this experiment found that blocking the estrogenic activity did not interfere with the neuroprotective effects. In fact, the neuroprotective activities of 17-beta-estradiol, the natural female sex hormone, was not diminished by the concomitant administration of high doses of antiestrogens! A neuroprotective effect against glutamate toxicity was found in the HT22 cells exposed to the phenols serotonin, N-acetylserotonin, resveratrol, quercetin, or 4-dodecylphenol. This is extremely interesting because there are many phytoestrogens that are thought to mimic estrogen in the latter’s neuroprotective effects, yet these protective effects may actually be independent of the phytoestrogens’ estrogenic effects and depend, instead, on their phenolic structure.

Moosmann and Behl. The antioxidant neuroprotective effects of estrogens and phenolic compounds are independent from their estrogenic properties. Proc Natl Acad Sci USA 96:8867-72 (1999).

Epigallocatechin Gallate, a Constituent of Green Tea, Mimics Some of the Actions of Insulin

The authors of a recent paper studying antidiabetic agents from plants¹ examined the effects of the green tea flavonoid epigallocatechin gallate (EGCG) because it is reported to have glucose-lowering effects in animals, and Zucker rats injected with EGCG have been reported to have decreased obesity and blood glucose levels and increased insulin sensitivity.

The authors state that “A suitable antidiabetic agent should have actions similar to insulin, or it should bypass the defects in insulin action characterized by insulin resistance.” In this study, the researchers found that EGCG has some insulinomimetic effects in hepatoma cells. The insulinlike metabolic effects of EGCG were somewhat delayed and seemed to depend on redox-dependent changes in the cell.

The most exciting finding in the study was that EGCG at a concentration of 25 µM repressed glucose production by the hepatoma cells to basal levels comparably to insulin at the physiological concentration of 10 nM. The researchers found no further glucose-lowering effects by EGCG above 25 µM. One of the big problems in type 2 diabetes and insulin resistance is that certain of the physiological effects of insulin, such as the repression of glucose production and release by hepatic (liver) cells, are impaired. The liver of a diabetic human can convert body protein into glucose at a rate of up to 800 g/day.

The signaling pathways for insulin and EGCG for the repression of glucose production by the hepatoma cells were very similar. As the authors report, insulin activates PI3K, PKB, and p70s6k in H4IIE rat hepatoma cells. Cells were incubated with 50-µM EGCG or with 10-nM insulin for different times, and the effects on these kinases were compared. Effects were similar, but activities were increased by different amounts or at different times. As the researchers note, “The smaller effect of EGCG on the activation of these kinases is equivalent to that observed after treatment of H4IIE cells with 0.0l-nM insulin . . . .”

The researchers report that reactive oxygen species seemed to be increased after treatment of H4IIE cells with EGCG. Apparently, the increase in oxygen radicals is a part of at least some of the effects of EGCG, since treatment of cells with N-acetylcysteine (NAC) or superoxide dismutase (SOD) completely prevented the effect of EGCG on protein-tyrosine phosphorylation, as well as EGCG-mediated PEPCK and G6Pase gene repression. The actions of insulin, however, are mostly unaffected by NAC and SOD.

The authors conclude, “Our results reveal that EGCG is insulinomimetic in that it lowers glucose production in H4IIE cells and decreases the expression of genes that control gluconeogenesis, such as the PEPCK and G6Pase genes. Also, EGCG activates the same kinases as insulin and promotes the phosphorylation of insulin signaling proteins, such as IRS-1 and IR-beta.”

Waltner-Law et al. Epigallocatechin gallate, a constituent of green tea, represses hepatic glucose production. J Biol Chem 277(38):34933-40 (2002)

Rutin May Be Essential for the Antidepressant Activity of St. John’s Wort

Scientists studying a series of ethanolic and methanolic extracts of Hypericum perforatum (St. John’s Wort) in an animal model for antidepressant activity (the forced swimming test) found that only one methanolic research extract had no effect in the in vivo pharmacological experiments. They found by analytical characterization that the inactive extract had a reduced level of the diglycoside flavonoid rutin. Addition of rutin to the inactive extract to produce a rutin concentration in the normal range resulted in a pharmacological effect similar to that of the other extracts. According to their results, the amount of rutin needed was not dose-dependent, indicating the need for a threshold amount.¹

The authors suggest that, since flavonoids can modulate the bioavailability of drugs via transport through biological membranes, via interactions with P-glycoprotein multiple drug transporters or by modulating the cytochrome P450 drug-metabolizing enzyme system, rutin may enhance the bioavailability of Hypericum constituents necessary for its antidepressant actions.

Noldner and Schotz. Rutin is essential for the antidepressant activity of Hypericum perforatum extracts in the forced swimming test. Planta Med 68:577-80 (2002)

Amyloid Polypeptide Forms in Pancreatic Islet Cells in Type 2 Diabetes: Analogous to Alzheimer’s?

A recent paper¹ reports that type 2 diabetes is associated with the formation of pancreatic islet amyloid deposits that are associated with and may cause pancreatic beta-cell failure. Islet amyloid polypeptide (IAPP) is a neuroendocrine peptide hormone that is produced and cosecreted with insulin from beta cells. IAPP aggregates and forms fibrils (like the amyloid beta peptide in Alzheimer’s disease) and is thought to be toxic to beta cells. The paper notes that the normal physiological functions of IAPP are not completely understood, but suggestions have included suppression of food intake, gastric emptying, and arginine-stimulated glucagon secretion from pancreatic beta cells. The authors report that a recent study showed that mice lacking IAPP have modestly enhanced glucose-induced insulin secretion and glucose clearance compared to wild-type mice.

Islet amyloid deposits are reported to be found in up to 90% of patients with type 2 diabetes at autopsy, and the degree of amyloid deposition correlates with the severity of the disease in humans. Islet amyloid formation is also said to be associated with reduced beta-cell mass in both diabetic humans and nonhuman primates. Also, amyloid formation is reported to precede the onset of hyperglycemia in monkeys.

Similarly to the aggregated (fibrillar) amyloid deposits in Alzheimer’s that kill neurons, the aggregated (fibrillar) form of IAPP kills beta cells. Also just as in Alzheimer’s, the soluble form of the polypeptide is not toxic. Moreover, the amyloid beta peptides in the brain are direct competitive inhibitors of insulin binding and action;² it would obviously be a serious problem if the IAPP were also to be doing this in pancreatic beta cells. Thus, there may be a parallel process taking place both in the brains of Alzheimer’s patients and in the pancreatic beta cells of type 2 diabetics. One has to wonder whether substances that may remove aggregated amyloid from the brain or slow its buildup—such as nonsteroidal anti-inflammatory substances,³ melatonin,⁴ restoring normal cholinergic function,⁵ the green tea polyphenol epigallocatechin-3-gallate,⁶ and therapeutic levels of lithium⁷—would also do the same to the aggregated amyloid in the pancreatic islets.

Marzban et al. Islet amyloid polypeptide and type 2 diabetes. Exp Gerontol38:347-51 (2003).
Xie Ling et al. Amyloid beta antagonizes insulin-promoted secretion of the amyloid beta protein precursor. J Alz Dis 4:369-74 (2002). “. . . recent findings have demonstrated upregulation of insulin receptors and defective insulin-receptor signal transduction in AD brains.” “. . . [insulin] also reduces intracellular amyloid beta accumulation in neuronal cells.” “In fact the insulin-degrading enzyme (IDE), which is known to degrade both insulin and amyloid beta, may be extremely important for maintaining normal insulin signaling.”
Weggen et al. A subset of NSAIDs lowers amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature 414:212-16 (2001). The paper reports that the NSAIDs ibuprofen, indomethacin, and sulindac sulphide preferentially decrease the highly amyloidogenic Abeta42 peptide produced from a variety of cultured cells by as much as 80%.
Soto et al. Beta-sheet breaker peptides inhibit fibrillogenesis in a rat-brain model of amyloidosis: implications for Alzheimer’s therapy. Nature Med 4(7):822-6 (1998).
Georgievska et al. Cognitive changes and modified processing of amyloid precursor protein in the cortical and hippocampal system after cholinergic synapse loss and muscarinic receptor activation. Proc Natl Acad Sci96(21):12108-13 (1999).
Levites et al. Neuroprotection and neurorescue against Abeta toxicity and PKC-dependent release of nonamyloidogenic soluble precursor protein by green tea polyphenol epigallocatechin-3-gallate. FASEB J, March 28, 2003.
Phiel et al. GSK-3alpha regulates production of Alzheimer’s disease amyloid-beta peptides. Nature 423:435-9 (2003). “Here we show that therapeutic concentrations of lithium, a GSK-3 [glycogen synthase kinase-3] inhibitor, block production of amyloid beta peptides by interfering with APP [amyloid precursor protein] cleavage at the gamma-secretase step . . .”

Xanthine Oxidase and Muscle Damage in Strenuous Exercise

In a Research Letter of a recent JAMA,¹ researchers noted that the xanthine oxidase free radical-generating enzyme is involved in ischemia-reperfusion syndrome and may cause damage associated with exhaustive exercise. They therefore tested the effect of allopurinol, an inhibitor of xanthine oxidase, on the level of muscle damage in athletes after participating in the Tour de France bicycle race versus athletes receiving placebo.

The nine members of the U.S. Postal (U.S. Snail!) cycling team were randomly divided into two groups. One group of four was given a daily oral dose of 300 mg of allopurinol one hour before each racing stage; the other group received placebo at the same time.

Those who had received placebo had an increase in the activities of creatine kinase and aspartate aminotransferase, indicating muscle damage, only after the team trial stage where participants were putting out peak effort. There was no such change seen in those who received allopurinol. The researchers also found increased levels of malondialdehyde (an indication of lipid peroxidation) in all participants, but significantly higher levels were found in those on placebo compared to those receiving allopurinol.

There was no difference in performance between the two groups.

Gomez-Cabrera et al. Allopurinol and markers of muscle damage among participants in the Tour de France. JAMA 289(19):2503-4 (2003)

Xanthine Oxidase and Muscle Damage in Strenuous Exercise

There was no difference in performance between the two groups.

Gomez-Cabrera et al. Allopurinol and markers of muscle damage among participants in the Tour de France. JAMA 289(19):2503-4 (2003)

Clitoris NO—Arginine Yes

“The localization of NO synthase in human clitoral corpus cavernosum [the homologous female tissue to male penile corpus cavernosum] may . . . implicate arginase as a regulator of arginine bioavailability in this tissue . . . .”¹ It also implicates nitric oxide as a mediator of clitoral erection. Arginine may be processed by the arginase or nitric oxide synthase pathways: it is converted to citrulline and nitric oxide by nitric oxide synthase, and it is converted to ornithine and urea by the arginase pathway. The latter is part of the ammonia detoxifying process. The paper cited here found data supporting the hypothesis that arginase bioavailability appears to limit NO biosynthesis by removing available arginine from use by the NO synthase. This can be overcome by adequate supplies of extracellular (but not intracellular) arginine.

The authors also note that an additional factor in the use of arginine is the presence and compartmentalization of endogenous competitive inhibitors such as N^G-methyl-L-arginine and N^G,N^G-dimethyl-L-arginine, which can be displaced from the NO synthase active site by highly effective concentrations of substrate (arginine).

Kim et al. Probing erectile function: S-(2-boronoethyl)-L-cysteine binds to arginase in a transition state analogue and enhances smooth muscle relaxation in human penile corpus cavernosum. Biochemistry 40:2678-88 (2001). Thanks for the paper, Will

**Book Review: Libertarian Science Fiction, The Excalibur Alternative, by David Weber (2002)**

The Galactic Federation is a group of races dedicated to the proposition that they are justified in using their highly advanced technological military might to kill, control, and enslave the “inferior” races that cannot defend themselves from the Federation’s military. There were certain moral and ethical considerations in the Federation’s original constitution, but (surprise, surprise) two of the original founder races have “disappeared,” and ethical considerations in the Federation’s actions have also “disappeared,” although the remaining founder race continues to give lip service to them in a game of political one-upmanship.

Then a guild that is part of the Federation discovers a neat loophole. Although there is a “Prime Directive” that prohibits using modern weapons on the alien worlds (for fear that the aliens would get a hold of them), there is no prohibition on using weapons that are way behind Federation-level technology but are still advanced of the primitives. This guild then “acquires” a group of Roman warriors (i.e., kidnaps and enslaves them) and forces them to “serve” them, fighting against and slaughtering the primitive populations of worlds that don’t wish to trade on the guild’s terms. Later, a second guild sees how the guild with Romans is taking over and acquires their own group of warriors—English longbowmen. As the book jacket says, “Roman legions make dangerous pets . . . but English longbowmen are even worse. It may take a century or so, but the Galactics are about to discover what happens when the sword finally comes out of the stone.”

A wonderfully fun and intellectually stimulating read!

Preventing Falls with Vitamin D and Calcium—A Possible Mechanism

A recent paper¹ reports a double-blind, randomized trial of 122 elderly women (mean age 85.3 years) in long-stay geriatric care who received either 1200 mg calcium plus 800 IU cholecalciferol (Cal+D) or 1200 mg calcium (Cal) per day over a 12-week treatment period. The numbers of falls per person were compared between these two groups. The researchers also measured musculoskeletal function (summed score of knee flexor and extensor strength, grip strength, and the timed “up & go” test). Before treatment, the mean observed number of falls per person per week in the Cal+D group was 0.059, and in the Cal group it was 0.056. In the 12-week treatment period, the mean number of falls per person per week was 0.034 in the Cal+D group, and 0.076 in the Cal group. After adjustment, Cal+D treatment accounted for a 49% reduction in falls (95% CI, 14-71%; P<0.01). Musculoskeletal function improved significantly in the Cal+D group (P = 0.0094). In fact, a single intervention with vitamin D plus calcium over a 3-month period reduced the risk of falling by 49% compared with calcium alone.

Vitamin D may have direct effect on muscle

There has been evidence for a possible direct effect of vitamin D on muscle for quite some time. For example, a 1979 paper² reported improved muscle function in 11 patients treated with the vitamin D analogue 1-alpha-hydroxycholecalciferol and calcium for 3–6 months. In addition, they found that the treatment induced an increase in the relative number of oxidative fast-twitch a (or type IIA) muscle fibers accompanied by a reduction of the oxidative fast-twitch b (type IIB) fibers, with an increase in the cross-sectional area of the fast-twitch b fibers. There were no changes in the slow-twitch fibers. (The authors note that the vitamin D analogue they used is rapidly converted in vivo into the natural form of vitamin D, 1,25-dihydroxycholecalciferol.)

The cytokine IL-4 required for muscle growth

The process of muscle growth requires the fusion of myoblasts with myotubes. This process requires multiple steps involving cell migration, alignment, recognition, adhesion, and membrane fusion.³ A recent paper³ reports that the second phase of myoblast fusion that occurs with myotubes is dependent on the cytokine IL-4 and the IL-4Ralpha subunit of the IL-4 receptor. IL-4 had, before the publication of this new paper, already been known to be involved in the regulation of cell fusion in macrophages and, after the paper, in the fusion of muscle cells. The authors propose that IL-4 may mediate the fusion of myoblasts by increasing the expression of cell-adhesion molecules [for example, IL-4 can induce the expression of intracellular adhesion molecule-1 (ICAM-1) on myoblasts].

Vitamin D stimulates IL-4 production⁴

As reported in reference 4, vitamin D (1,25-dihydroxyvitamin D3) can either prevent or markedly suppress autoimmune diseases such as autoimmune encephalomyelitis, rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes, and inflammatory bowel disease. The autoimmune effects of vitamin D almost always require that animals be maintained on a normal or elevated calcium diet. Possible mechanisms for these effects have been studied, including vitamin D-stimulated transforming growth factor (TGFbeta-1) and interleukin 4 (IL-4) production. The increased IL-4 might, on the basis of the findings on IL-4 and muscle growth, help explain the muscle-function improvements found in the two clinical studies above.

Vitamin A antagonizes the calcium response to vitamin D5

This paper⁵ notes that the highest incidence of osteoporosis is found in northern Europe, where sunlight exposure is limited and vitamin A intake is high. These researchers studied the acute effects of vitamins A and D on calcium homeostasis in nine healthy humans. The effects on the subjects of 15 mg of retinyl palmitate (27,255 IU of vitamin A), 2 µg of 1,25-dihydroxyvitamin D3, 15 mg of retinyl palmitate plus 2 µg of 1,25-dihydroxyvitamin D3, and placebo were examined in a double-blind crossover study. Intake of retinyl palmitate resulted in a significant decrease of serum calcium when taken alone and diminished the response to vitamin D3 when A and D were taken in combination. They conclude that the amount of vitamin A found in about one serving of liver antagonizes the rapid intestinal calcium response to physiological levels of vitamin D in man.

Our current daily recommended intake of our basic daily multinutrient supplement contains 1000 IU of vitamin D and 5000 IU of vitamin A. Most people can take up to 2000 IU of vitamin D per day safely. We have reduced the vitamin A intake from 8000 to 5000 in recognition of, among other things, its interference with vitamin D.

Bischoff et al. Effects of vitamin D and calcium supplementation on falls: a randomized controlled trial. J Bone Min Res 18(2):343-51 (2003).
Sorensen et al. Myopathy in bone loss of ageing: improvement by treatment with 1-alpha-hydroxycholecalciferol and calcium. Clin Sci 56:157-61 (1979).
Horsley et al. IL-4 acts as a myoblast recruitment factor during mammalian muscle growth. Cell 113:483-94 (2003).
Deluca and Cantorna. Vitamin D: its role and uses in immunology. FASEB J15:2579-85 (2001).
Johansson and Melhus. Vitamin A antagonizes calcium response to vitamin D in man. J Bone Min Res 16(10):1899-1905 (2001)