Vitamin A

Common Name: Vitamin A

Clinical Names: Beta-carotene, Retinol

Summary

Vitamin A

forms: Beta-carotene, Retinol

overview of interactions:
• nutrient affecting drug toxicity: Chemotherapy

• nutrient affected by drug: Cholestyramine

• Beta-Carotene affected by drug: Colchicine

• nutrients affected by drug: Colestipol

• Vitamin A affected by drug: Corticosteroids, including Prednisone

• Antioxidant nutrients (Vitamin A, Beta-Carotene and Vitamin E) affecting drug performance: Cyclophosphamide

• Vitamin A affecting drug performance: Fluorouracil

• Beta-carotene affecting drug performance: Fluorouracil

• nutrient affected by drug: Lovastatin

• nutrient affecting drug performance: Methotrexate

• nutrient affected by drug: Mineral Oil

• Vitamin A and Beta-Carotene affected by drug: Neomycin

• nutrient affected by drug: Oral Contraceptives

• nutrient affecting drug toxicity: Retinoic Acid (Accutane®)

• nutrient affected by drug: Tetracyclines

chemistry:
• Water miscible preparations of retinol usually lead to greater concentrations in the plasma.
• Oil-soluble preparations lead to a greater storage of retinol in the liver.

• Carotenoids alpha, gamma, and beta are converted to vitamin A primarily in the intestinal mucosa. Theoretically, ß carotene should be twice as active as the alpha and gamma carotenoids because it is composed of 2 molecules of retinol while the others contain only one molecule of retinol. Approximately 1/3 of ß carotene from foods gets converted to retinol and only one-third of ß carotene gets absorbed. As the intake of carotene goes above 5,000 IU per day the % absorption rate goes down significantly. Thus, ß carotene is considered to be significantly less biologically active (approximately 1/6) than pure retinol.

• Blood carotene levels reflect dietary carotene and not the storage of vitamin A. Therefore, with decreased intake, a rather rapid drop in serum carotene occurs.
• Vitamin A is stable to heat and light and is thus resistant to most processing and cooking.

metabolism:
• More than 90% of all dietary retinol is in the form of esters, usually retinyl palmitate. These esters must be hydrolyzed in the intestinal lumen by pancreatic enzymes and within the brush border of the intestinal epithelial cells before absorption. Retinol is transported across intestinal epithelial cells by a carrier mediated mechanism which involves a protein called cellular retinol-binding protein.
• In average doses, retinol is almost entirely absorbed. Peak concentrations are reached in 4 hours.
• When large amounts are taken, some is excreted in the feces.
Absorption is reduced in patients with pancreatic, hepatic or intestinal pathologies.
• Retinol is absorbed 2-4 times as efficiently as ß carotene. Only one-third of ingested ß carotene is absorbed. Of that which is absorbed, about two-thirds is converted into retinyl esters. The remainder stays as ß carotene. Carotenes rely on bile salts for absorption to a much greater extent than retinol does.
• ß carotene is stored in fat deposits and the adrenals rather than in the liver. Serum levels of ß carotene directly reflect daily consumption, not storage.
• Both thyroxine and vitamin E enhance the conversion of carotene to retinol.
• Most ingested retinol is stored in the liver. Retinol storage has a half life of 50-100 days.
• Minor amounts of B-carotene get converted to retinol in the liver and the lungs.
• Considerable debate among researchers has focused on the relative benefits of natural and synthetic forms of beta-carotene. Recent research has demonstrated that synthetic beta-carotene could not provide the same protective effects against lung cancer that had been found to be associated with food sources of beta-carotene.
(Shekelle RB, et al. Lancet 1981;ii:1185-1190; Hennekens CH, et al. N Engl J Med 1996;334:11145-11149.)

functions:
• Anti-cancer function: Numerous studies have shown that retinoid deficiency enhances susceptibility to carcinogenesis both in experimental animals and in humans. Analogues of vitamin A, or retinoids, are being used in humans to treat cancers (particularly skin, lung, bladder, cervical or breast) which involve epithelial tissues.
• Epithelial tissue development and maintenance: Retinoic acid is needed for the differentiation of basal cells into mucus epithelial cells. A deficiency results in keratinization of mucus membranes that line the respiratory tract, intestines, urinary tract, and epithelium of the eye. This decreases the protective barrier role played by these membranes, resulting in an increased number of infections and other pathologies.
• Growth and bone development: Vitamin A (the retinoic acid form) is necessary for growth and development of skeletal and soft tissues through its effect upon protein synthesis. It has an essential role in the differentiation of bone cells. Normal enamel-forming epithelial cells also require vitamin A to develop. A deficiency of vitamin A in the first 5 years of life results in a deficient enamel layer on teeth.
• Immunity: As previously mentioned, vitamin A maintains the integrity of the mucus membranes and, thus, is vital for protecting the body against bacterial, viral or parasitic infections. This has led vitamin A to be called the anti-infective vitamin. It is also involved in humoral and cell-mediated immunity. The number of T lymphocytes, as well as their response to mitogens, is reduced in vitamin A deficiency.
• Reproduction: Vitamin A is involved in steroid hormone synthesis and cell differentiation. It is critical for healthy growth, normal reproduction and lactation.
• Vision: Both retinyl esters and ß carotene from the diet are converted to retinal (11 cis isomer). Retinal is combined with the protein opsin to form rhodopsin in the rods of the retina and iodopsin in the cones. Light hitting the retina causes visual excitation and changes the cis configuration into the all trans form of retinaldehyde. The rods are particularly sensitive to vitamin A deficiency. When it is in low supply, the all trans form that is generated during the light reaction cannot be converted back to the active rhodopsin.

dietary sources:
• Beta Carotene comes from vegetable sources. Vitamin A comes from animal sources.
• Liver, egg yolk, whole milk, whole milk cheese, butter, cream, yellow, green and orange colored fruits and vegetables, particularly carrots, green leafy vegetables- kale, spinach, and turnip greens; melon, squash, yams
• The richest source of vitamin A is fish liver oil, especially cod liver oil.

supplemental sources:
Synthetic beta-carotene is used in most supplements. This form contains a single molecule of all trans beta-carotene in contrast to naturally-occurring beta-carotene which also contains 9-cis beta-carotene. Absorption of 9-cis molecule from food sources may be poor but it is converted to all trans beta-carotene quickly after assimilation.

deficiency:
• Symptoms may result from low intake, problems with absorption and/or storage, or from interference with the conversion of ß carotene to retinol.
• In addition, a deficiency of protein or zinc can reduce the amount of vitamin A released from the liver.
• Symptoms include night blindness, dry eyes, keratinization, opacity and sloughing of the epithelial cells of the cornea.
• Other symptoms include respiratory infections, follicular hyperkeratosis (commonly seen on the anterior thighs and posterior arms due to keratinization of the hair follicles), reduced immunity, diarrhea, loss of tooth enamel, loss of bone mass, and the loss of both taste and smell.

known or potential therapeutic uses: Acne, cancer, cervical dysplasia (abnormal Pap), chalazion, dry eyes (Sicca syndrome), follicular hyperkeratosis (keratosis pilaris), ichthyosis, immune enhancement, lupus (SLE), macular degeneration, menorrhagia, night blindness, photosensitivity disorders including erythropoietic protoporphyria (EPP), prevention of sunburn, psoriasis, seborrheic keratosis or senile keratosis, wound healing,

maintenance dose: 25,000 IU per day.
• RDA:
1,000 RE men (5,000 IU)
800 RE women (4,000 IU)
Pregnancy: 1,000 RE
Lactation: 1,200 RE
Note: The 5,000 IU assumes a mixed diet of two-thirds vegetable and one-third animal sources of vitamin A.
• Optimal daily intake:
15,000 IU Retinol (with caution near or during the time of conception)
25,000 IU ß carotene

therapeutic dose: 100,000-300,000 IU per day, short term only, under supervision of a healthcare professional experienced in nutritional therapies.

side effects:
• High dietary intake of retinol seems to be associated with osteoporosis and increased risk for hip fracture.
(Melhus H, et al. Ann Intern Med 1998 Nov 15;129(10):770-778.)
• Some recent double-blind research indicates that supplementation with synthetic beta-carotene by smokers may be associated with an increased risk of lung cancer. This may be due to a resulting relative deficiency of other antioxidants.
(Albanes D, et al. J Natl Cancer Inst 1996;88:1560-1570; Omenn GS, et al. N Engl J Med 1996;334:1150-1155.)

toxicity:
• 50,000 IU long term may cause headaches, fatigue, constipation, insomnia, restlessness, abdominal discomfort, dry scaly skin, liver damage. If toxicity is detected, the symptoms will disappear in several days once supplementation is discontinued. Vitamin C can help prevent effects of vitamin A toxicity.

Vitamin A (retinol) toxicity:
• Toxicity to vitamin A varies greatly with the individual. Sketchy reports of toxicity have been reported in subjects supplementing as low as 20,000 IU per day.
• Alleged toxicity at this lower dose has occurred in persons with liver dysfunction caused by drugs, viral hepatitis, aging, or protein calorie malnutrition.
• Most cases of toxicity in nonpregnant females result from more than 200,000 IU per day supplementation for at least 6-8 months.
• The synthetic water form of retinol has the most toxicity. Reports of side effects have been caused by 20,000 IU per day supplementation for 4-6 months. However, doses as high as 500,000 - 1,000,000 IU per day extending over several years have not caused any adverse effects in many people.

• Typical symptoms, especially in children, include drowsiness, fatigue, irritability, vomiting and bulging of the fontanelle. In adults, bone pain, headaches, dry scaly skin, brittle nails, alopecia, gingivitis, cheilosis, hepatosplenomegaly, and visual disturbances have been reported.
• Generally, discontinuation of supplemental vitamin A causes symptoms to disappear within a few days with no permanent repercussions.

The greatest concern about toxicity occurs during early pregnancy.
• A report in the N Engl J Med reported doses of vitamin A greater than 10,000 IU per day during the first 7 weeks of conception increased birth defects. Another recent study actually showed a decreased incidence of birth defects with doses over 10,000 IU per day. It seems highly unlikely that such low doses could increase the risk of birth defects. If this were true, we would see a much higher incidence of birth defects in cultures like the Eskimos where people normally consume larger amounts of vitamin A from foods. Furthermore, there are many women in the U.S. who consume more than 10,000 IU of vitamin A from both dietary sources and supplements and no associated increase in birth defects has been observed.

NY State Dept of Health studied 16 out of 492 women who took between 15,000 IU to 50,000 IU per day with no side effects and no birth defects. Intakes in excess of 50,000 IU may lead to increased risk of birth defects according to animal studies. To date there is at least one anecdotal study that involves a woman ingesting 150,000 IU per day for two months before and three months after conception. Her pregnancy had to be terminated because of fetal malformations at 23 weeks.
(National Research Council. 1989, 516; Von Lennep E, et al. Prenatal Diag. 1985;5:35-40; Hathcock J, et al. Am J Clin Nutr, 1990;52:183-202; Bernhardt I, Dorsey D. Obstet. Gynecol 1974;43, 750-755.)

Beta Carotene toxicity:
• Supplemental intake of Beta-carotene is not normally associated with side effects. However, excessive intake (more than 100,000 IU, or 60 mg per day) sometimes giving the skin a yellow-orange hue.
• The ingestion of ß carotene and the rest of the carotenoids in very high amounts may result in hypercarotenemia and reversible yellow discoloration of the skin. This can be distinguished from jaundice by the absence of scleral pigmentation. Beta carotene may have antagonistic effects on vitamin E status. Thus, it is a good idea to supplement vitamin E if large doses of beta carotene are given for prolonged periods. For that matter, it is wise to give all the fat soluble nutrients to someone who is taking large doses of beta carotene for prolonged periods of time. There have been some reports of women who consume large amounts of carotenoids from foods becoming amenorrheic.
• The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group studied 29,000 men in Finland who smoked and drank alcohol. These men were divided into several groups. It was found that the group that consumed only beta carotene had an 18% increase in lung cancer. The group that also took vitamin E had no such increase and even saw a significant decrease in prostate cancer.
(N Engl J Med. 1994 Apr 14;330(15):1029-1035.)
• In another large trial in the U.S., the CARET study, over 18,000 men and women who were smokers and/or asbestos workers showed, after 4 years of 50,000 IU per day, a 28% increase in lung cancer and a 17% increase in cancer mortality. That study was discontinued prematurely because of this finding. Dr. Alan Gaby has theorized that beta carotene may decrease levels of other carotenes such as lycopene and lutein in the body. In smokers and people exposed to asbestos these carotene levels may already be low. Some clinicians have suggested clinical trials with multiple carotenes as well as vitamin E and with vitamin E alone to differentiate the effects of these nutrients which should prove beneficial.
(Carotene and Retinol Efficacy Trial Cancer Research 1994;54, 2038S-2043S; Omenn GS, et al. Cancer Res. 1994 Apr 1;54(7 Suppl):2038S-2043S.)

contraindications:
• High doses (over 10,000 IU per day) of supplemental retinol contraindicated in women who are or might be come pregnant.
• Retinol contraindicated with compromised liver, hepatitis or any liver disease.

measurements:
• Until 1974 the U.S. used international units (IU) to describe the potency of the different forms of vitamin A. IU's represent equivalent potencies of preformed vitamin A (or its precursor, carotene) which cause a specific growth response in rats whose reserves of vitamin A have been depleted.
• The unit of measure was changed to retinol equivalents (RE). The advantage of the form, retinol equivalents, is that it takes into consideration the variation in absorption and conversion of different precursors into vitamin A.

1 RE = 1 mcg of retinol = 3.33 IU retinol
1 RE = 6 mcg of ß-carotene = 10 IU retinol
1 RE = 12 mcg of other carotenoids

1000 RE = 1 mg of retinol = 3,333 IU retinol

1 mg of beta-carotene = 1670 IU beta-carotene



Interactions

nutrients affecting drug toxicity: Vitamin A and Vitamin E for Mouth Sores due to Chemotherapy

• mechanism: Chemotherapeutic agents are responsible for a wide variety of adverse effects in patients receiving them due to damage of healthy cells and derangement of normal metabolic processes. Vitamin A and vitamin E are well known for their abilities to enhance restoration of healthy cells and tissues.

• adverse drug effects: Mouth sores are a common side effect of chemotherapy treatment.

• research: Mills examined the beneficial effect provided by beta-carotene on mouth sores, specifically oral mucositis, induced by radiation and chemotherapy induced oral mucositis. When compared to controls receiving equivalent radiation and chemotherapy, subjects receiving alpha-tocopherol, 400,000 IU daily for three weeks followed by 125,000 IU for four weeks, experienced slower onset and decreased severity of mouth inflammation. In a later randomized, double-blind, placebo-controlled study involving 18 patients Wadleigh et al used topical vitamin E in the treatment of oral mucositis in patients receiving chemotherapy. They found that six of nine patients receiving vitamin E had complete resolution of their oral lesions while lesions did not resolve completely in eight of nine patients who received placebo. Lopez et al conducted further studies looking at the efficacy of topical vitamin E for the treatment of this condition and found that while topical vitamin E, applied once daily, was beneficial to some subjects, others did not experience relief from their symptoms.
(Mills EED. Brit J Cancer 1988 Apr;57(4):416-417; Wadleigh RG, et al. Am J Med 1992 May;92(5):481-484; Lopez I, et al. Ann Med Interne (Paris) 1994;145(6):405-408.)

• nutritional support: While the research thus far has not been conclusive many individuals suffering from mouth sores due to chemotherapy would probably experience decreased symptoms and faster healing through the application of vitamin E. Such treatment carries no significant risks and has been shown to help some patients. In such cases topical application of alpha tocopherol twice daily would be the form most likely to be effective; with alpha tocopheryl being the less preferred form.

nutrient affecting drug performance: Vitamin A and late-stage breast cancer

• research: In controlled clinical trials French researchers found that postmenopausal women with late-stage breast cancer experienced enhanced remission rates, compared to controls, when they took 350,000-500,000 IU of vitamin A daily along with their chemotherapy. Premenopausal women did not benefit from the combined therapy to a significant degree.
(Israel L, et al. Ann Med Interne (Paris) 1985;136(7):551-554.)

• nutritional synergy: While the use of high doses of vitamin A to complement conventional chemotherapy may be promising its implementation involves potential risks and requires supervision. In particular the levels of vitamin A administered as part of the study cited above are well into the toxic range. Individuals receiving chemotherapy for breast cancer should consult their treating physician and/or a nutritionally trained healthcare professional about potential value of adding vitamin A to their regime before starting such supplementation. Physician oversight is required for proper dosing of vitamin A at high levels and for monitoring of both its effects and the disease process itself.

nutrient affecting drug performance: 13-cis retinoic acid and arachadonic acid cascade inhibitors

• research: 13-cis retinoic acid is a form of vitamin A. Based on the findings of previous in vivo research Spingarn et al conducted test tube studies on the potential synergistic effects of combining 13-cis retinoic acid and arachadonic acid cascade inhibitors on growth of head and neck squamous cell carcinoma (HNSCC). When they investigated the effects of several arachadonic acid cascade inhibitors (AACIs) (indomethacin, curcumin, phenidone, nordihydroguaiaretic acid, 5,8,11,14-eicosatetraynoic acid, and 13-cisretinoic acid) on the growth of two HNSCC cell lines they found that AACIs caused dose-dependent growth inhibition of both cell lines. When they combined these substances with 13-cis retinoic acid they found that, except for indomethacin, they were able to inhibit HNSCC cell growth at lower concentrations of these drugs.
(Spingarn A, et al. Otolaryngol Head Neck Surg 1998 Feb;118(2):159-164.)

• nutritional support: While provocative and encouraging this initial research has not yet matured to the level of practical implementation in a clinical setting. Individuals receiving chemotherapy for cancer should consult their treating physician and/or a nutritionally trained healthcare professional about potential value of adding any of these substances to their regime before starting such supplementation.

nutrient affecting drug toxicity: Antioxidants and Chemotherapy

• mechanism: Oxygen radicals have increasingly come under investigation as highly toxic stressors contributing to the causes of many disease, including many forms of cancer. Vitamin A and Vitamin C are well known antioxidant agents. N-acetylcysteine (NAC) is a free radical scavenger and might access the endothelial cell thus increasing intracellular glutathione (GSH) stores. Even so, some concerns have been raised antioxidants might be contraindicated during chemotherapy because one way in which chemotherapeutic agents attack cancer cells is by causing oxidative damage.
(Weijl NI, et al. Ann Oncol 1998 Dec;9(12):1331-1337; Kong Q, Lillehei KO. Med Hypotheses 1998 Nov;51(5):405-409.)

• research: A variety of test tube-based and animal studies have found vitamin A, C and E to increase the effectiveness of chemotherapy in several kinds of cancer. NAC therapy may be useful therapy in advanced cervical cancers, especially squamous cell carcinomas. In a double-blind study Wagdi et al found that an antioxidant combination consisting of vitamin C, vitamin E, and N-acetylcysteine (NAC) provided protected against heart damage induced by chemotherapy without reducing with the drug's effectiveness. Several researchers have offered the seemingly paradoxical conclusion that the appropriate administration of antioxidant inhibitors and/or free-radical-generating compounds may be a useful strategy in the treatment of solid tumors. More recently, however, conference reports by Salignik R, and co-worker Zeisel SH, at the 1999 American Society of Cell Biology's annual meeting suggest that vitamin A and vitamin E-deficient mice were less susceptible to brain tumor progression than non-vitamin-deficient control animals. Salignik suggested suppression of free radicals by the anti-oxidant vitamins may suppress apoptosis (programmed cell death). After performing a comprehensive review of the relationship between chemotherapy and antioxidants Weijl et al rebuffed warnings that antioxidants needed to be avoided during chemotherapy but also determined that there substantive evidence was lacking to support the use of antioxidants to provide relief from the adverse side effects of chemotherapy.
(Sacks PG, et al. Int J Cancer 1995;61:409-415; Taper HS, et al. Int J Cancer 1987;40:575-579; Kurbacher CM, et al. Cancer Letters 1996:103-119; Gillissen A, Nowak D. Respir Med 1998 Apr;92(4):609-623; Fujiwaki R, et al. Anticancer Res 1997 Sep-Oct;17(5B):3751-3755.Wagdi P, et al. Jpn Heart J 1996;37:353-359; Weijl NI, et al. Cancer Treatment Rev 1997;23:209-240; Kong Q, Lillehei KO. Med Hypotheses 1998 Nov;51(5):405-409; Domenighetti G, et al. Rev Mal Respir 1999 Feb;16(1):29-37; Kodama J, et al. Gan To Kagaku Ryoho 1999 Jan;26(1):89-92; Albini A, et al. Int J Cancer 1995 Mar 29;61(1):121-129; Weijl NI, et al. Cancer Treatment Rev 1997 Jul;23(4):209-240; Salignik R, et al. 39th Annual Meeting of the American Society for Cell Biology, Dec 11-15th, 1999.)

• nutritional concerns: Concerns have been raised by some oncologists that supplementation with antioxidants might in some way interfere with or limit the effectiveness of chemotherapeutic agents. However, no substantial research has emerged to support this speculation or to warrant considering antioxidants as contraindicated during the course of chemotherapy. Many nutritionally oriented healthcare professionals consider the oxidative damage caused by chemotherapy to be a particularly troublesome side effect given that evidence increasingly points to oxidative damage as being a contributing factor in the causation of many cancers. Individuals receiving chemotherapy should consult their treating physician and/or a nutritionally trained healthcare professional about potential value of adding antioxidants to their regime before starting such supplementation.

• Note: See also Antioxidants interaction below for further comment on vitamins A and E as antioxidants in relation to chemotherapy.

nutrient affected by drug: Cholestyramine

• mechanism: Bile acid sequestrants, such as cholestyramine, decrease lipid digestion and absorption, as well as absorption of the fat-soluble vitamins and other nutrients.
(Longnecker JB, Basu SG. Fed Proc.1965;24:375; Roe DA. 1985: 158-159; Watkins DW, et al. Dig Dis Sci 1985 May;30(5):477-482; Hathcock JN. Fed Proc. 1985 Jan;44(1 Pt 1):124-129; West RJ, Lloyd JK. Gut. 1975 Feb;16(2):93-98.)

• nutritional support: Regular use of a high-potency multiple vitamin/mineral will replace the nutrients impeded by the drug.

Beta-Carotene affected by drug: Colchicine

• mechanism: Colchicine has been linked to impaired absorption of these nutrients.
(Robinson C, Weigly E. 1984, 46-54.)

• nutritional support: Individuals taking colchicine would most likely benefit from taking a high-potency multivitamin/mineral supplement to compensate for these interactions.

nutrient affected by drug: Colestipol; along with Vitamin D, Vitamin E, Vitamin K and Folate

• mechanism: Colestipol, by design, reduces fat absorption and hence interferes with absorption of fat-souble nutrients.
(Tonstad S, et al. Arch Dis Child 1996 Feb;74(2):157-160.)

• clinical concerns: This interaction raises serious questions given the accumulating experimental, epidemiological, and clinical evidence of an association between anti-oxidant vitamin intake and reduced risk of coronary heart disease.

• research: Hodis et al have reported an association between supplementary vitamin E intake and angiographically demonstrated reduction in coronary artery lesion progression. Tonstad et al conducted a study of 37 boys and 29 girls aged 10-16 years with familial hypercholesterolemia first in an eight week double blind, placebo controlled protocol, then in open treatment for 44-52 weeks. They found that levels of serum folate, vitamin E, and carotenoids were reduced in the colestipol group. After one year of colestipol, those who took > or = 80% of the prescribed dose had a greater decrease in serum 25-hydroxyvitamin D levels than those who took < 80%.
(Hodis HN, et al. JAMA 1995 Jun 21;273(23):1849-1854; Tonstad S, et al. Arch Dis Child 1996 Feb;74(2):157-160.)

• nutritional support: Supplementation with carotenoids, as well as other related nutrients, in the form of a multi-vitamin-mineral formulation would probably be of benefit for individuals taking colestipol.

Vitamin A affected by drug: Corticosteroids, including Prednisone

• research: Steroidal anti-inflammatory drugs can contribute to depletion of vitamin A. In one study using adult male rats Atukorala et al found that the administration of large doses of corticosterone resulted in a rapid loss of vitamin A from the plasma, liver, adrenals and thymus. Of the organs studied, the thymus appeared to be the most sensitive to treatment. Further research showed that supplementation with vitamin A, in conjunction with the corticosterone, resulted in a reversal of the steroid-mediated depression of vitamin A levels in plasma and tissue.
(Atukorala TM, et al. Ann Nutr Metab 1981;25(4):234-238; Pronsky, Z. 1991, 60.)

• nutritional support: Individuals considering the use of supplemental vitamin A while using corticosteroids should consult with their prescribing physician and/or a nutritionally trained healthcare professional. Daily doses of up to 25,000 IU (7,500 mcg) of vitamin A are considered safe for men and postmenopausal women. However, women at risk of becoming pregnant should restrict their daily intake of vitamin A to less than 10,000 IU (3,000 mcg). On the other hand, daily doses of 25,000 IU (15 mg), or even as high as 100,000 IU (60 mg), are considered safe when beta-carotene is used as the supplemental source.
(Yamaguchi T. Shikwa Gakuho 1967 Nov;67(11):1329-1339; Corball M, et al. Ir J Med Sci 1985 Aug;154(8):306-310.)

Antioxidant nutrients (Vitamin A, Beta-Carotene and Vitamin E) affecting drug performance: Cyclophosphamide

• research: Preliminary studies on humans undergoing chemotherapy with cyclophosphamide have indicated promise of increased survival rates when supplemented with antioxidant nutrients. While antioxidants might have many benefits as supplements, evidence as to their effectiveness in patients taking cyclophosphamide are inconclusive.
(Jaakkola K, et al. Anticancer Res 1992 May;12(3):599-606; Venugopal M, et al. Life Sci 1996;59(17):1389-1400; Vinitha R, et al. Jpn J Med Sci Biol 1995 Jun;48(3):145-156.)

• nutritional concerns: Since activation of cyclophosphamide requires oxidation in the liver there has been concern that antioxidant supplementation might interfere with its effectiveness. However, at this time such concern remains speculative as no conclusive evidence as emerged to confirm an adverse interaction of this type.
(Labriola D, Livingston R. Oncology (Huntingt). 1999 Jul;13(7):1003-1008.)

nutrient affecting drug performance: Fluorouracil

• mechanism: Animal studies indicate that vitamin A may enhance antitumor effect of 5-Fluorouracil.
(Nakagawa, M, et al. Jpn J Cancer Res 1985 Sep;76(9):887-894.)

• nutritional support: Supplementation with vitamin A might enhance the therapeutic efficacy of 5-FU. However, individuals being treated with 5-Fluorouracil should consult their prescribing physician and/or a nutritionally trained healthcare professional before starting such a program of supplementation. High doses of vitamin A can be toxic. Women who could become pregnant should avoid dosages over 10,000 IU (3,000 mcg) per day of vitamin A because it can cause birth defects; though the 5-FU itself presents significant risks for causing birth defects. Generally, dosages up to 25,000 IU (7,500 mcg) of vitamin A per day are considered safe for postmenopausal women and males.

Beta-carotene affecting drug performance: Fluorouracil

research: Beta-carotene has been associated with reduction of 5-fluorouracil (5-FU) activity.
(Teicher BA, et al. Cancer Chemother Pharmacol. 1994;34(3):235-241.)

• nutritional caution: Individuals receiving treatment with 5-Fluorouracil (5-FU) should refrain from supplementing with beta-carotene unless they are have consulted with and are being directly supervised by their prescribing physician, preferably in concert with a healthcare professional trained in nutritional therapies.

nutrient affected by drug: Lovastatin

• research: Muggeo et al found that thirty-seven subjects were treated with diet and hepatic HMG CoA reductase inhibitors (statins). Postabsorptive serum retinol was determined at baseline and every 3 months. After 2 years of treatment, serum retinol increased in diet- and statin-treated groups.
(Muggeo M, et al. Metabolism 1995;Mar;44(3):398-403.)

• nutritional concerns: While this modest increase in vitamin A levels does not pose a significant risk for most people it might be appropriate for individuals taking lovastatin to limit their use of vitamin A supplements, separately or as part of multivitamin formulations. Individuals taking lovastatin should inform their prescribing physician and/or pharmacist of any current vitamin A supplementation. Likewise it would be advisable to consult with the prescribing physician and/or a nutritionally trained healthcare professional before starting any vitamin A supplementation.

nutrient affecting drug performance: Methotrexate

• mechanism: Researchers have found that vitamin A enhances antitumor activity in animals taking methotrexate.
(Nakagawa, M, et al. Jpn J Cancer Res 1985;76:887-894.)

• nutritional support: Individuals using methotrexate for the treatment of tumors should consult their prescribing physician and/or a nutritionally-oriented healthcare professional before initiating or increasing supplementation of vitamin A.

nutrient affected by drug: Mineral Oil

• mechanism: Mineral oil, as a lipid solvent, may absorb many substances and/or interfere with normal absorption of retinol, beta-carotene and other nutrients.

• research: While there is some disagreement, most research has found that mineral oil interferes with the absorption of many nutrients, including beta-carotene, calcium, phosphorus, potassium, and vitamins A, D, K, and E. Chronic use of mineral oil can cause a deficiency of vitamins A, D, E, and K, being fat soluble, as a result of their being absorbed.
(Clark JH, et al. Am J Dis Child 1987 Nov;141(11):1210-1212 ; Holt GA.1998, 176.)

• nutritional concerns: If using mineral oil for any extended period of time, regular use of a multivitamin supplement would be beneficial. Malabsorption of fat-soluble vitamins due to ingestion of mineral oil can be minimized by administering mineral oil on an empty stomach or consuming vitamin or mineral supplements at least two hours before or after the mineral oil. In general it is advisable to limit the internal use of mineral oil to periods of less than one week.

Vitamin A and Beta-Carotene affected by drug: Neomycin

• research: Orally administered neomycin impairs absorption of both beta-carotene and vitamin A.
(Robinson C, Weigly E. 1984, 46-54; Barrowman JA, et al. Clin Sci. 1972 Apr;42(4):17P; Favaro RM, et al. Int J Vitam Nutr Res. 1994;64(2):98-103.)

• nutritional support: Individuals taking neomycin internally for more than 2-3 days may benefit from taking supplemental beta-carotene at doses of 25,000 IU (15 mg) per day. Individuals using neomycin topically will not experience problems related to malabsorption.

nutrient affected by drug: Oral Contraceptives

• research: Several studies have reported an association between the use of oral contraceptives and increased serum levels of Vitamin A. Horwitt et al found that women using oral contraceptives had the lowest average levels of carotenoids corresponding to the highest average levels of vitamin A in the serum, and that estrogens seemed to increase the rate of conversion of carotene to vitamin A. The clinical implications of this potential interaction are uncertain at this time.
(Mooij PN, et al. Contraception 1991 Sep;44(3):277-288; Cumming FJ, Briggs MH. Br J Obstet Gynaecol 1983 Jan;90(1):73-77; Wynn V. Lancet 1975 Mar 8;1(7906):561-564; Horwitt MK, et al. Am J Clin Nutr 1975 Apr;28(4):403-412.)

nutrient (Retinol) affected by drug: Pravastatin

• research: Muggeo et al found that thirty-seven subjects were treated with diet and hepatic HMG CoA reductase inhibitors (statins). Postabsorptive serum retinol was determined at baseline and every 3 months. After two years of treatment, serum retinol increased in groups treated using statin drugs and dietary changes alone.
(Muggeo M, et al. Metabolism 1995;Mar;44(3):398-403.)

• nutritional concerns: While this modest increase in vitamin A levels does not pose a significant risk for most people it might be appropriate for individuals taking pravastatin to limit their use of vitamin A supplements, separately or as part of multivitamin formulations. Individuals taking pravastatin should inform their prescribing physician and/or pharmacist of any current vitamin A supplementation. Likewise it would be advisable to consult with the prescribing physician and/or a nutritionally trained healthcare professional before starting any vitamin A supplementation.

nutrient affecting drug toxicity: Retinoic Acid (Accutane®)

• mechanism: Vitamin A supplementation increases levels of retinoic acid compounds in human plasma.
(Wiegand UW, et al. Int J Vitam Nutr Res 1998;68(6):411-416; Chen C, et al. J Clin Pharmacol 1996 Sep;36(9):799-808; Eckhoff C, Nau H. Arch Toxicol. 1990;64(6):502-503.)

• nutritional concerns: Conservative practice would suggest that supplemental use of vitamin A be avoided while taking Accutane. Even though no studies have confirmed interactions, the structural similarities between and significant toxicities of both Accutane and natural vitamin A warrant caution. Consequently, supplementation of vitamin A by anyone using Accutane should only be undertaken under the supervision of an appropriately trained healthcare professional. These concerns are amplified for women of child-bearing age as the risk of birth defects inherent to either substance is increased by their simultaneous use.

nutrient affected by drug: Tetracyclines

• interaction: The concurrent use of tetracycline and high doses of vitamin A has been associated with severe headaches. Such adverse interactions may be attributable to increased blood pressure in the brain (benign intracranial hypertension); this condition and pseudotumor cerebri have been associated with both hypervitaminosis A and tetracycline use independently. Vitamin A and tetracycline are both used in the treatment of acne vulgaris so their simultaneous use is not uncommon.
(Walters BN, Gubbay SS. Br Med J (Clin Res Ed) 1981 Jan 3;282(6257):19-20; Holt GA. 1998, 258; Lee AG. Cutis 1995 Mar;55(3):165-168.)

• nutritional concerns: Individuals using tetracycline and high doses of vitamin A at the same time should be aware of such possible side effects. Likewise, individuals taking tetracycline should consult with their prescribing physician and/or a nutritionally trained healthcare professional before starting to supplement vitamin A.

Please read the disclaimer concerning the intent and limitations of the information provided here.
Do not rely solely on the information in this article.

References

[No authors listed]  MRC/BHF Heart Protection Study of cholesterol-lowering therapy and of antioxidant vitamin supplementation in a wide range of patients at increased risk of coronary heart disease death: early safety and efficacy experience. Eur Heart J. 1999 May;20(10):725-741.
Abstract: AIMS: In observational studies, prolonged lower blood total cholesterol levels - down at least to 3 mmol. l-1 - are associated with lower risks of coronary heart disease. Cholesterol-lowering therapy may, therefore, be worthwhile for individuals at high risk of coronary heart disease events irrespective of their presenting cholesterol levels. Observational studies also suggest that increased dietary intake of antioxidant vitamins may be associated with lower risks of coronary heart disease. The present randomized trial aims to assess reliably the effects on mortality and major morbidity of cholesterol-lowering therapy and of antioxidant vitamin supplementation in a wide range of different categories of high-risk patients. METHODS AND RESULTS: Men and women aged 40 to 80 years were eligible provided they were considered to be at elevated risk of coronary heart disease death because of past history of myocardial infarction or other coronary heart disease, occlusive disease of non-coronary arteries, diabetes mellitus or treated hypertension; had baseline blood total cholesterol of 3.5 mmol. l-1 or greater; and no clear indications for, or contraindications to, either of the study treatments. Eligible patients who completed a pre-randomization run-in phase on active treatment were randomly allocated to receive simvastatin (40 mg daily) or matching placebo tablets and, in a '2x2 factorial' design, antioxidant vitamins (600 mg vitamin E, 250 mg vitamin C and 20 mg beta-carotene daily) or matching placebo capsules. Follow-up visits after randomization are scheduled at 4, 8 and 12 months, and then 6-monthly, for at least 5 years.Between July 1994 and May 1997, 15 454 men and 5082 women were randomized, with 9515 aged over 65 years at entry. Diagnostic criteria overlapped, with 8510 (41%) having had myocardial infarction (most of whom were either female, or elderly or with low blood cholesterol), 4869 (24%) some other history of coronary heart disease, 3288 (16%) cerebrovascular disease, 6748 (33%) peripheral vascular disease, 5963 (29%) diabetes mellitus (of whom 3985 had no history of coronary heart disease) and 8455 (41%) treated hypertension. Baseline non-fasting total cholesterol levels were less than 5.5 mmol. l-1 in 7882 (38%) participants, and LDL (low density lipoprotein) cholesterol less than 3.0 mmol. l-1 in 6888 (34%).During a mean follow-up of 25 months (range: 13 to 47 months), no significant differences had been observed between the treatment groups in the numbers of patients with muscle symptoms, other possible side-effects leading to termination of study treatment, or elevated liver and muscle enzymes. After 30 months of follow-up, 81% of randomized patients remained compliant with taking their study simvastatin or placebo tablets, and allocation to simvastatin produced average reductions in non-fasting blood total and LDL cholesterol of about 1.5-1.6 mmol. l-1 and 1.1-1.2 mmol. l-1 respectively. Eighty-seven per cent of patients remained compliant with taking their vitamin or placebo capsules, and allocation to the vitamin supplement produced an average increase in plasma vitamin E levels of about 24 micromol. l-1. Based on this initial follow-up period, the estimated annual rate of non-fatal myocardial infarction or fatal coronary heart disease is 2.4%, annual stroke rate is 1.3%, and annual all-cause mortality rate is 2. 2%. CONCLUSION: The Heart Protection Study is large, it has included a wide range of patients at high risk of vascular events, and the treatment regimens being studied are well-tolerated and produce substantial effects on blood lipid and vitamin levels. The study should, therefore, provide reliable evidence about the effects of cholesterol-lowering therapy and of antioxidant vitamin supplements on all-cause or cause-specific mortality and major morbidity in a range of different categories of individuals for whom uncertainty remains about the balance of benefits and risks of these treatments.

[No authors listed] Leads from the MMWR. Use of supplements containing high-dose vitamin A--New York State, 1983-1984. JAMA 1987 Mar 13;257(10):1292, 1297.

[No authors listed]  The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med. 1994 Apr 14;330(15):1029-1035.
Abstract: The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group studied 29,000 men in Finland who smoked and drank alcohol. These men were divided into several groups. It was found that the group that consumed only beta carotene had an 18% increase in lung cancer. The group that also took vitamin E had no such increase and even saw a significant decrease in prostate cancer.

[No authors listed] ?Use of supplements containing high-dose vitamin A--New York State, 1983-1984. MMWR Morb Mortal Wkly Rep. 1987 Feb 20;36(6):80-82.

Ahmed F, Bamji MS. Vitamin supplements to women using oral contraceptives (studies of vitamins B1, B2, B6 and A). Contraception 1976 Sep;14(3):309-318.

Albanes D, Heinonen OP, Taylor PR, Virtamo J, Edwards BK, Rautalahti M, Hartman AM, Palmgren J, Freedman LS, Haapakoski J, Barrett MJ, Pietinen P, Malila N, Tala E, Liippo K, Salomaa ER, Tangrea JA, Teppo L, Askin FB, Taskinen E, Erozan Y, Greenwald P, Huttunen JK. Alpha-tocopherol and beta-carotene supplements and lung cancer incidence in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study: effects of base-line characteristics and study compliance. J Natl Cancer Inst 1996;88:1560-1570.
Abstract: BACKGROUND: Experimental and epidemiologic investigations suggest that alpha-tocopherol (the most prevalent chemical form of vitamin E found in vegetable oils, seeds, grains, nuts, and other foods) and beta-carotene (a plant pigment and major precursor of vitamin A found in many yellow, orange, and dark-green, leafy vegetables and some fruit) might reduce the risk of cancer, particularly lung cancer. The initial findings of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC Study) indicated, however, that lung cancer incidence was increased among participants who received beta-carotene as a supplement. Similar results were recently reported by the Beta-Carotene and Retinol Efficacy Trial (CARET), which tested a combination of beta-carotene and vitamin A. PURPOSE: We examined the effects of alpha-tocopherol and beta-carotene supplementation on the incidence of lung cancer across subgroups of participants in the ATBC Study defined by base-line characteristics (e.g., age, number of cigarettes smoked, dietary or serum vitamin status, and alcohol consumption), by study compliance, and in relation to clinical factors, such as disease stage and histologic type. Our primary purpose was to determine whether the pattern of intervention effects across subgroups could facilitate further interpretation of the main ATBC Study results and shed light on potential mechanisms of action and relevance to other populations. METHODS: A total of 29,133 men aged 50-69 years who smoked five or more cigarettes daily were randomly assigned to receive alpha-tocopherol (50 mg), beta-carotene (20 mg), alpha-tocopherol and beta-carotene, or a placebo daily for 5-8 years (median, 6.1 years). Data regarding smoking and other risk factors for lung cancer and dietary factors were obtained at study entry, along with measurements of serum levels of alpha-tocopherol and beta-carotene. Incident cases of lung cancer (n = 894) were identified through the Finnish Cancer Registry and death certificates. Each lung cancer diagnosis was independently confirmed, and histology or cytology was available for 94% of the cases. Intervention effects were evaluated by use of survival analysis and proportional hazards models. All P values were derived from two-sided statistical tests. RESULTS: No overall effect was observed for lung cancer from alpha-tocopherol supplementation (relative risk [RR] = 0.99; 95% confidence interval [CI] = 0.87-1.13; P = .86, logrank test). beta-Carotene supplementation was associated with increased lung cancer risk (RR = 1.16; 95% CI = 1.02-1.33; P = .02, logrank test). The beta-carotene effect appeared stronger, but not substantially different, in participants who smoked at least 20 cigarettes daily (RR = 1.25; 95% CI = 1.07-1.46) compared with those who smoked five to 19 cigarettes daily (RR = 0.97; 95% CI = 0.76-1.23) and in those with a higher alcohol intake (> or = 11 g of ethanol/day [just under one drink per day]; RR = 1.35; 95% CI = 1.01-1.81) compared with those with a lower intake (RR = 1.03; 95% CI = 0.85-1.24). CONCLUSIONS: Supplementation with alpha-tocopherol or beta-carotene does not prevent lung cancer in older men who smoke. beta-Carotene supplementation at pharmacologic levels may modestly increase lung cancer incidence in cigarette smokers, and this effect may be associated with heavier smoking and higher alcohol intake. IMPLICATIONS: While the most direct way to reduce lung cancer risk is not to smoke tobacco, smokers should avoid high-dose beta-carotene supplementation.

Alexander, M., et al. Oral Beta carotene can increase the number of OK4+ cells in human blood. Immunol. 1994;9, 221-225. (Letter)
Abstract: Daily supplementation of 300,000 I.U. beta carotene/day for 7 days increased the frequency of OK4+(helper inducer T cells) by about 30% and after 14 days increased all T cells.

Anstead GM. Steroids, retinoids, and wound healing. Adv Wound Care 1998 Oct;11(6):277-285. (Review)
Abstract: Glucocorticoids (corticosteroids) cause dehiscence of surgical incisions, increased risk of wound infection, and delayed healing of open wounds. They produce these effects by interfering with inflammation, fibroblast proliferation, collagen synthesis and degradation, deposition of connective tissue ground substances, angiogenesis, wound contraction, and re-epithelialization. These actions are mediated by the antagonism of various growth factors and cytokines. Vitamin A restores the inflammatory response and promotes epithelialization and the synthesis of collagen and ground substances. However, vitamin A does not reverse the detrimental effects of glucocorticoids on wound contraction and infection. In this paper, the known mechanisms of the interaction of glucocorticoids and retinoids are reviewed. The mutually inhibitory interplay between glucocorticoids and retinoids may serve to regulate the processes of inflammation, immunity, and connective tissue repair.

Atukorala TM, Basu TK, Dickerson JW. Effect of corticosterone on the plasma and tissue concentrations of vitamin A in rats. Ann Nutr Metab 1981;25(4):234-238.
Abstract: The administration of large doses of corticosterone to normal adult male rats resulted in a rapid loss of vitamin A from the plasma, liver, adrenals and thymus. Of the organs studied, the thymus appeared to be the most sensitive to treatment. The steroid-mediated depression of plasma and tissue contents of vitamin A was reversed when animals were treated with corticosterone in combination with vitamin A.

Ayres, S. Jr., Mihan R. Acne vulgaris and lipid peroxidation: New concepts in pathogenesis and treatment. Int H Dermatol 1978;17:305.
Abstract: Over 100 patients with acne were successfully treated with average. daily doses of 100,000 I.U. vitamin A and 800 I.U. of vitamin E. Most responded within weeks and maintenance of control was obtained with lower doses.

Barrowman JA, Broomhall J, Cannon AM, Christmas S, D'Mello A, Herxheimer A, Pring DW, Robson TW, Woolf AD. Impairment of vitamin A absorption by neomycin. Clin Sci. 1972 Apr;42(4):17P.

Basu TK. Vitamins - cytotoxic drug interaction. Int J Vitam Nutr Res Suppl. 1983;24:225-233.

Baum MK, Shor-Posner G, Lu Y, Rosner B, Sauberlich HE, Fletcher MA, Szapocznik J, Eisdorfer C, Buring JE, Hennekens CH. Micronutrients and HIV-1 disease progression. AIDS. 1995 Sep;9(9):1051-1056.
Abstract: OBJECTIVE: To determine whether nutritional status affects immunological markers of HIV-1 disease progression. DESIGN: A longitudinal study, to evaluate the relationship between plasma levels of nutrients and CD4 cell counts, along and in combination with beta 2-microglobulin (beta 2M; AIDS index) over an 18-month follow-up. METHODS: Biochemical measurements of nutritional status including plasma proteins, zinc, iron and vitamins B1, B2, B6, B12 (cobalamin), A, E, C and folate and immunological markers [lymphocyte subpopulations (CD4) and beta 2M] were obtained in 108 HIV-1-seropositive homosexual men at baseline and over three 6-month time periods. Changes in nutrient status (e.g., normal to deficient, deficient to normal), were compared with immunological parameters in the same time periods using an autoregressive model. RESULTS: Development of deficiency of vitamin A or vitamin B12 was associated with a decline in CD4 cell count (P = 0.0255 and 0.0377, respectively), while normalization of vitamin A, vitamin B12 and zinc was associated with higher CD4 cell counts (P = 0.0492, 0.0061 and 0.0112, respectively). These findings were largely unaffected by zidovudine use. For vitamin B12, low baseline status significantly predicted accelerated HIV-1 disease progression determined by CD4 cell count (P = 0.041) and the AIDS index (P = 0.005). CONCLUSIONS: These data suggest that micronutrient deficiencies are associated with HIV-1 disease progression and raise the possibility that normalization might increase symptom-free survival.

Bays HE, Dujovne CA.  Drug interactions of lipid-altering drugs. Drug Saf. 1998 Nov;19(5):355-371. (Review)

Ben-Amotz A, Levy Y. Bioavailability of a natural isomer mixture compared with synthetic all-trans beta-carotene in human serum. Am J Clin Nutr 1996;63:729-734.

Bendich A, Langseth L. Safety of vitamin A. Am J Clin Nutr 1989;49:358-371.

Bernhardt I, Dorsey D. Hypervitaminosis A and congenital renal anomalies in a human infant. Obstetr. Gynecol 1974;43, 750-755.

Bitterman N, Melamed Y, Ben-Amotz A. Beta-carotene and CNS oxygen toxicity in rats. J Appl Physiol 1994;76:1073-1076.

Brevard PB. beta-Carotene increases monocyte numbers in peripheral rat blood.
Int J Vitam Nutr Res. 1994;64(1):21-25.

Chen C, Mistry G, Jensen B, Heizmann P, Timm U, van Brummelen P, Rakhit AK.Pharmacokinetics of retinoids in women after meal consumption or vitamin A supplementation. J Clin Pharmacol 1996 Sep;36(9):799-808.
Abstract: These studies were conducted to evaluate the pharmacokinetics of several retinoids after meal consumption or vitamin A supplementation to establish a reference for future assessment of teratogenic risks of retinoid therapeutic agents. In the first study, 36 healthy young female volunteers consumed single meals containing vitamin A amounts ranging from 1,305 to 169,474 IU. In the second study, 24 other female volunteers took vitamin A supplements at a dose level of 5,000, 10,000, or 25,000 IU/day for 60 days. Plasma concentrations of tretinoin, isotretinoin, 4-oxo-tretinoin, and 4-oxo-isotretinoin in samples collected during the studies were analyzed using a high-performance liquid chromatography method with ultraviolet detection. Pharmacokinetic parameters for the retinoids were calculated using model-independent methods. Plasma concentrations of tretinoin were not altered by meal consumption or vitamin A supplementation. Plasma levels of 4-oxo-tretinoin were below the assay detection limit (0.3 ng/mL) in the majority of samples collected throughout the studies. Linear relationships between dose and maximum concentration (Cmax) and dose and area under the concentration-time curve (AUC) for isotretinoin and 4-oxo-isotretinoin were derived from data from the meal study. For the most bioavailable formulation used in the supplement study, daily ingestion of 5,000 IU of vitamin A caused increases of 141 +/- 53% and 171 +/- 77% from baseline in the 24-hour AUCs of isotretinoin and 4-oxo-isotretinoin, respectively. Dose-related increases in systemic exposure to retinoids were observed after ingestion of vitamin A by means of a meal or a supplement. Findings from these studies can be used as a basis for future safety evaluations of retinoid compounds.

Clark JH, Russell GJ, Fitzgerald JF, Nagamori KE. Serum beta-carotene, retinol, and alpha-tocopherol levels during mineral oil therapy for constipation. Am J Dis Child 1987 Nov;141(11):1210-1212 .
Abstract: Twenty-five children with chronic constipation underwent serial monitoring of serum beta-carotene, retinol (vitamin A1), and alpha-tocopherol (vitamin E) levels during mineral oil therapy. Mineral oil was administered between meals. Patients were monitored for up to four months of therapy. Mean serum beta-carotene levels fell from 1.0 +/- 0.5 mumol/L (55.7 +/- 26.0 micrograms/dL) to 0.7 +/- 0.4 mumol/L (35.9 +/- 22.1 micrograms/dL) after the first month of mineral oil therapy and remained depressed throughout the remainder of the study. Serum alpha-tocopherol levels remained unchanged throughout the observation period. There was a modest increase in serum retinol levels during the study, especially after three months (from 1.48 +/- 0.84 mumol/L [42.3 +/- 24.1 micrograms/dL] to 2.22 +/- 0.77 mumol/L [63.5 +/- 22.1 micrograms/dL]). We conclude that while a short course of mineral oil can induce a reduction in the serum level of beta-carotene, the treatment has no adverse effect on serum levels of retinol and alpha-tocopherol.

Corball M, O'Dwyer P, Brady MP. The interaction of vitamin A and corticosteroids on wound healing. Ir J Med Sci 1985 Aug;154(8):306-310.

Coutsoudis, Hons, Kiepiela, Coovadia, Broughton. Vitamin A supplementation enhances specific IgG antibody levels and total lymphocyte numbers while improving morbidity in measles. The Pediatric Infectious Disease Journal 1992;11(3):203-209.
Abstract: In a randomized double blind trial, 31 African children, aged 4-24 months, infected with measles, were given either 100,000 I.U. of retinyl palmitate (if under 12 months of age), 200,000 I.U. retinyl palmitate (if over 12 mo.), or placebo. The supplemented group had a significant reduction in morbidity during the acute (Day 8, P=0.006) and chronic (Day 42, P=0.02; 6 months, P=0.002) phases. In the treated group there was an increase in total number lymphocytes P=0.05 and measles IgG antibody concentrations (Day 8 P=.02), both of which have been shown to correlate more closely with outcome in measles than other immunologic factors.

Cumming FJ, Briggs MH. Changes in plasma vitamin A in lactating and non-lactating oral contraceptive users. Br J Obstet Gynaecol 1983 Jan;90(1):73-77.
Abstract: Plasma vitamin A and retinol-binding protein (RBP) concentrations have been studied in women using oral contraceptives (OC) for up to 4 years. In eight women taking an oestrogenic OC(1 mg of norethisterone acetate + 50 micrograms of ethinyloestradiol) values almost doubled within 6 months, but diminished somewhat after 4 years. Saturation of RBP with retinol remained fairly constant. Five lactating women who took progestogen-only OC (30 micrograms of levonorgestrel or 350 micrograms of norethisterone) showed no significant alteration in plasma vitamin A or RBP concentrations as compared with nine lactating non-OC users. All lactating women showed significant differences between the highest and lowest plasma vitamin A (P less than 0.005) and RBP (P less than 0.05) concentrations during the first 6 months of lactation. Highest values occurred 11-12 weeks postpartum and the lowest at 15-17 weeks. Percentage saturation of RBP with retinol was significantly higher (P less than 0.005) when vitamin A concentration was highest.

Eckhoff C, Nau H. Vitamin A supplementation increases levels of retinoic acid compounds in human plasma: possible implications for teratogenesis. Arch Toxicol. 1990;64(6):502-503.
Abstract: The concentrations of retinoic acid compounds were monitored by a newly developed highly sensitive HPLC procedure in plasma of six volunteers who received 833 IU vitamin A per kg body weight per day during a 20-day period. There was a significant increase of all-trans-retinoic acid (two-fold), 13-cis-retinoic acid (7-fold) and 13-cis-4-oxoretinoic acid (5-fold) over endogenous plasma levels of these retinoids. The same compounds had previously been found after treatment with the teratogenic drug isotretinoin (Roaccutan, Accutane). Our results raise the possibility that high vitamin A intake may carry a teratogenic risk attributable to increased levels of retinoic acid compounds generated from retinol by metabolic processes.

Elinder LS, Hadell K, Johansson J, Molgaard J, Holme I, Olsson AG, Walldius G.
Probucol treatment decreases serum concentrations of diet-derived antioxidants. Arterioscler Thromb Vasc Biol 1995 Aug;15(8):1057-1063.
Abstract: The effect of probucol, which is both a cholesterol-lowering drug and an antioxidant, on the serum concentrations of diet-derived antioxidants vitamin E, beta-carotene, lycopene, and vitamin A was studied in 303 hypercholesterolemic subjects. In a 3-year, double-blind, randomized trial we investigated to determine whether combined treatment with diet, cholestyramine, and probucol could reduce the progression of femoral atherosclerosis. Serum and lipoprotein antioxidant levels were measured by reverse-phase high-performance liquid chromatography. Cholestyramine significantly lowered serum concentrations of vitamin E by 7%, beta-carotene by 40%, and lycopene by 30% (all P < .001) due to impairment of gastrointestinal absorption and to serum cholesterol lowering. Probucol reduced serum vitamin E by 14% (P < .001) secondary to cholesterol and triglyceride lowering. The carotenoids were reduced by probucol by 30% to 40% (P < .001) most probably due to reductions in lipoprotein particle size and to competition with these substances for incorporation into VLDL during its assembly in the liver. This study shows that the use of a lipid-soluble antioxidant and cholesterol-lowering drug may have unfavorable effects on blood levels of diet-derived antioxidants.

Ehrlich HP, Hunt TK. Effects of cortisone and vitamin A on wound healing. Ann Surg 1968 Mar;167(3):324-328.

Farmer JA, Gotto AM Jr. Antihyperlipidaemic agents. Drug interactions of clinical significance. Drug Saf 1994 Nov;11(5):301-309.
Abstract: The available antihyperlipidaemic drugs are generally safe and effective, and major systemic adverse effects are uncommon. However, because of their complex mechanisms of action, careful monitoring is required to identify and correct potential drug interactions. Bile acid sequestrants are the most difficult of these agents to administer concomitantly, because their nonspecific binding results in decreased bioavailability of a number of other drugs, including thiazide diuretics, digitalis preparations, beta-blockers, coumarin anticoagulants, thyroid hormones, fibric acid derivatives and certain oral antihyperglycaemia agents. Although the incidence is low, nicotinic acid may cause hepatic necrosis and so should not be used with drugs that adversely affect hepatic structure or function. With the HMG-CoA reductase inhibitors, relatively new agents for which clinical data are still being accumulated, the major problems appears to be rhabdomyolysis, associated with the concomitant use of cyclosporin, fibric acid derivatives or erythromycin, and mild, intermittent hepatic abnormalities that may be potentiated by other hepatotoxic drugs. Fibrates also have the potential to cause rhabdomyolysis, although generally only in combination with HMG-CoA reductase inhibitors, and are subject to binding by concomitantly administered bile acid sequestrants. The major interaction involving probucol is a possible additive effect with drugs or clinical conditions that alter the prolongation of the QTc interval, increasing the potential for polymorphic ventricular tachycardia.

Faloon WW, Paes IC, Woolfolk D, Nankin H, Wallace K, Haro EN. Effect of neomycin and kanamycin upon intestinal absortion. Ann N Y Acad Sci. 1966 Jun 14;132(2):879-887.

Faloon WW. Metabolic effects of nonabsorbable antibacterial agents. Am J Clin Nutr. 1970 May;23(5):645-651.

Farmer JA, Gotto AM Jr. Choosing the right lipid-regulating agent. A guide to selection. Drugs 1996 Nov;52(5):649-661.

Favaro RM, Silva HC, Vannucchi H. Bioavailability of vitamin A in the rat following ingestion of neomycin sulfate or aluminium hydroxide. Int J Vitam Nutr Res. 1994;64(2):98-103.
Abstract: The objective of the present paper was to study the interaction of Neomycin and aluminium hydroxide with vitamin A in terms of the effect of these drugs on the bioavailability of vitamin A in the rat. Bioavailability was determined on the basis of the effects of the drugs on growth and on the plasma and hepatic levels of the vitamin. Vitamin A deficient animals were used in assay 1 and normal animals in assay 2. In each assay the animals were divided into 3 groups: one received Neomycin sulfate (0.1% in the diet), the second received aluminium hydroxide (0.05% in the diet) and the third (control) received no drug. Each of these three groups was subdivided into two groups receiving two different concentrations of vitamin A palmitate. The bioavailability of vitamin A was estimated by the parallel line method from the concentration of vitamin A in the diet and in the liver of the animals. No significant differences in growth or plasma retinol levels were observed between the groups of animals studied in assays 1 and 2. Total vitamin A concentration in the liver of the animals which received Neomycin was lower (p < 0.05) than that observed in the controls. Neomycin reduced the bioavailability of vitamin A by 13.9% (maximum, 18.1% and minimum, 9.6%) in assay 1 and by 13.5% (maximum, 17.7% and minimum, 9.3%) in assay 2. Aluminium hydroxide at the level tested did not affect the bioavailability of vitamin A.

Hathcock JN, Hattan DG, Jenkins MY, McDonald JT, Sundaresan PR, Wilkening VL. Evaluation of Vitamin A Toxicity. Am J Clin Nutr, 1990 Aug;52(2):183-202.
Abstract: Toxicity has been associated with abuse of vitamin A supplements and with diets extremely high in preformed vitamin A. Consumption of 25,000-50,000 IU/d for periods of several months or more can produce multiple adverse effects. The lowest reported intakes causing toxicity have occurred in persons with liver function compromised by drugs, viral hepatitis, or protein-energy malnutrition. Certain drugs or other chemicals may markedly potentiate vitamin A toxicity in animals. Especially vulnerable groups include children, with adverse effects occurring with intakes as low as 1,500 IU.kg-1.d-1, and pregnant women, with birth defects being associated with maternal intakes as low as approximately 25,000 IU/d. The maternal dose threshold for birth defects cannot be identified from present data. An identifiable fraction of the population surveyed consumes vitamin A supplements at 25,000 IU/d and a few individuals consume much more. beta-Carotene is much less toxic than vitamin A.

Hathcock JN. Metabolic mechanisms of drug-nutrient interactions. Fed Proc. 1985 Jan;44(1 Pt 1):124-129. (Review)

Hardison WG, Rosenberg IH.  The effect of neomycin on bile salt metabolism and fat digestion in man. J Lab Clin Med. 1969 Oct;74(4):564-573.

Hennekens CH, Buring JE, Manson JE, Stampfer M, Rosner B, Cook NR, Belanger C, LaMotte F, Gaziano JM, Ridker PM, Willett W, Peto R. Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med. 1996 May 2;334(18):1145-1149.
Abstract: BACKGROUND. Observational studies suggest that people who consume more fruits and vegetables containing beta carotene have somewhat lower risks of cancer and cardiovascular disease, and earlier basic research suggested plausible mechanisms. Because large randomized trials of long duration were necessary to test this hypothesis directly, we conducted a trial of beta carotene supplementation. METHODS. In a randomized, double-blind, placebo-controlled trial of beta carotene (50 mg on alternate days), we enrolled 22,071 male physicians, 40 to 84 years of age, in the United States; 11 percent were current smokers and 39 percent were former smokers at the beginning of the study in 1982. By December 31, 1995, the scheduled end of the study, fewer than 1 percent had been lost to follow-up, and compliance was 78 percent in the group that received beta carotene. RESULTS. Among 11,036 physicians randomly assigned to receive beta carotene and 11,035 assigned to receive placebo, there were virtually no early or late differences in the overall incidence of malignant neoplasms or cardiovascular disease, or in overall mortality. In the beta carotene group, 1273 men had any malignant neoplasm (except nonmelanoma skin cancer), as compared with 1293 in the placebo group (relative risk, 0.98; 95 percent confidence interval, 0.91 to 1.06). There were also no significant differences in the number of cases of lung cancer (82 in the beta carotene group vs. 88 in the placebo group); the number of deaths from cancer (386 vs. 380), deaths from any cause (979 vs. 968), or deaths from cardiovascular disease (338 vs. 313); the number of men with myocardial infarction (468 vs. 489); the number with stroke (367 vs. 382); or the number with any one of the previous three end points (967 vs. 972). Among current and former smokers, there were also no significant early or late differences in any of these end points. CONCLUSIONS. In this trial among healthy men, 12 years of supplementation with beta carotene produced neither benefit nor harm in terms of the incidence of malignant neoplasms, cardiovascular disease, or death from all causes.

Henquin N, Havivi E, Reshef A, Barak F, Horn Y. Nutritional monitoring and counselling for cancer patients during chemotherapy. Oncology 1989;46(3):173-177.
Abstract: The objective of the study was to try to monitor the nutritional status of cancer patients during chemotherapeutic treatment. Concomitantly with chemotherapeutic treatment administered to patients with cancer of the gastrointestinal tract and metastatic carcinoma of unknown origin, levels of carotene, retinol, thiamine, riboflavin, pyridoxine, iron, total protein and hemoglobin were measured in the blood periodically. In addition, anthropometric studies were performed and the nutritional status was established. A total of 19 patients were subject for final evaluation. These patients formed 3 groups according to their nutritional status (good, medium, poor). The effect of chemotherapy was correlated to the nutritional status at 3 different periods of chemotherapy. Most patients with good clinical status maintained the initial nutritional status. Half of the patients with medium nutritional status improved clinically during therapy, and patients initially with poor nutritional status further deteriorated. The levels of most vitamins decreased to a certain degree during therapy and returned to initial values thereafter. Our impression is that cancer patients might benefit from intensive ongoing personal nutritional monitoring and counselling. The results presented have a preliminary meaning because of the small number of patients included in this study.

Hill FW. An investigation of the effects of oral neomycin on intestinal absorption and serum cholesterol levels in the dog. Br Vet J. 1973 Jul-Aug;129(4):337-44.

Hodis HN, Mack WJ, LaBree L, Cashin-Hemphill L, Sevanian A, Johnson R, Azen SP. Serial coronary angiographic evidence that antioxidant vitamin intake reduces progression of coronary artery atherosclerosis. JAMA 1995 Jun 21;273(23):1849-1854.
Abstract: OBJECTIVE--To explore the association of supplementary and dietary vitamin E and C intake with the progression of coronary artery disease. DESIGN--A subgroup analysis of the on-trial antioxidant vitamin intake database acquired in the Cholesterol Lowering Atherosclerosis Study, a randomized, placebo-controlled, serial angiographic clinical trial evaluating the risk and benefit of colestipol-niacin on coronary artery disease progression. SETTING--Community- and university-based cardiac catheterization laboratories. SUBJECTS--A total of 156 men aged 40 to 59 years with previous coronary artery bypass graft surgery. INTERVENTION--Supplementary and dietary vitamin E and C intake (nonrandomized) in association with cholesterol-lowering diet and either colestipol-niacin or placebo (randomized). OUTCOME--Change per subject in the percentage of vessel diameter obstructed because of stenosis (%S) determined by quantitative coronary angiography after 2 years of randomized therapy on all lesions, mild/moderate lesions (< 50%S), and severe lesions (> or = 50%S). RESULTS--Overall, subjects with supplementary vitamin E intake of 100 IU per day or greater demonstrated less coronary artery lesion progression than did subjects with supplementary vitamin E intake less than 100 IU per day for all lesions (P = .04) and for mild/moderate lesions (P = .01). Within the drug group, benefit of supplementary vitamin E intake was found for all lesions (P = .02) and mild/moderate lesions (P = .01). Within the placebo group, benefit of supplementary vitamin E intake was not found. No benefit was found for use of supplementary vitamin C exclusively or in conjunction with supplementary vitamin E, use of multivitamins, or increased dietary intake of vitamin E or vitamin C. CONCLUSIONS--These results indicate an association between supplementary vitamin E intake and angiographically demonstrated reduction in coronary artery lesion progression. Verification from carefully designed, randomized, serial arterial imaging end point trials is needed.

Holt GA. Food and Drug Interactions. Chicago: Precept Press, 1998.

Horwitt MK, Harvey CC, Dahm CH Jr. Relationship between levels of blood lipids, vitamins C, A, and E, serum copper compounds, and urinary excretions of tryptophan metabolites in women taking oral contraceptive therapy. Am J Clin Nutr 1975 Apr;28(4):403-412.
Abstract: To evaluate which women using oral contraceptive agents might be at risk, biochemical indices known to be affected by the estrogens and progestogens were studied in women who take oral contraceptive agents, in women who do not use oral contraceptive agents, in women in third trimester of pregnancy and 6 weeks after parturition, and in men with normal and high blood lipid levels. The most consistent changes due to oral contraceptive agents were in serum levels of copper, triglycerides, and vitamin A and in the urinary excretion of xanthurenic acid and niacin derivatives before and after a tryptophan load test. There was only a slight suggestion, with no statistical significance, that serum vitamin C levels decreased when the serum levels of ceruloplasmin were high. The highest blood pressures and serum triglycerides and vitamin A levels were obtained in those women who ingested the highest level of estrogens. Pregnant women had the lowest levels of serum vitamin A. The oral contraceptive agents users had the lowest average levels of carotenoids corresponding to the highest average levels of vitamin A in the serum. Thus, estrogens not only increase the rate of change of tryptophan to niacin but may also increase the rate of conversion of carotene to vitamin A. Relative reactivity to oral contraceptive agents and possible risk to a patient might be evaluated by a profile of blood pressure and serum triglycerides, copper, and vitamin A.

Hozumi M, Murata T, Morinobu T, Manago M, Kuno T, Tokuda M, Konishi K, Mingci Z, Tamai H. Plasma beta-carotene, retinol, and alpha-tocopherol levels in relation to glycemic control of children with insulin-dependent diabetes mellitus. J Nutr Sci Vitaminol (Tokyo). 1998 Feb;44(1):1-9.
Abstract: Plasma beta-carotene, alpha-tocopherol and retinol were measured in 15 female and 5 male children with insulin-dependent diabetes mellitus (IDDM), and the correlations with plasma hemoglobin A1c (HbA1c) and fructosamine were analyzed. Twelve female and 8 male children served as age-matched controls. The plasma beta-carotene and alpha-tocopherol levels of the IDDM children were significantly higher than those of the control children, but there were no differences in plasma retinol or total lipid levels. The plasma beta-carotene level, beta-carotene/retinol ratio and beta-carotene/total lipids ratio each showed significant correlations with serum HbA1c and fructosamine in all subjects studied. Similarly, the plasma alpha-tocopherol level and alpha-tocopherol/total lipids ratio were correlated with these indexes of glycemic control. These findings suggest certain mechanisms may exist to prevent lipid peroxidation and vascular complications in IDDM patients.

Israel L, Hajji O, Grefft-Alami A, Desmoulins D, Succari M, Cals MJ, Miocque M, Breau JL, Morere JF. [Vitamin A augmentation of the effects of chemotherapy in metastatic breast cancers after menopause. Randomized trial in 100 patients]. Ann Med Interne (Paris) 1985;136(7):551-554. [Article in French]
Abstract: Vitamin A was administered to randomly allocated patients in a group of 100 patients with metastatic breast carcinoma treated by chemotherapy. The daily doses (given indefinitely) ranged from 350,000 to 500,000 IU according to body weight. A significant increase in the complete response rate was observed. When subgroups determined by menopausal status were considered, it was observed that serum retinol levels were only significantly increased in the post-menopausal group on high dose Vitamin A. Response rates, duration of response and projected survival were only significantly increased in this subgroup. The therapeutic and biological implications of these findings are discussed.

Jaakkola K, Lahteenmaki P, Laakso J, Harju E, Tykka H, Mahlberg K. Treatment with antioxidant and other nutrients in combination with chemotherapy and irradiation in patients with small-cell lung cancer. Anticancer Res 1992 May;12(3):599-606.
Abstract: Eighteen non-randomized patients with small cell lung cancer (4 women and 14 men, mean age 60.4, SD 7.8 years) received in addition to conservation small cell lung cancer treatment antioxidant treatment with vitamins, trace elements and fatty acids. All patients were out-patients who, except for one were also treated with chemotherapy and/or irradiation at regular intervals at a university of central hospital. Five patients (28%) were in an advanced stage of the disease. At the end of the follow-up period (31.7.90) the median survival time for the whole group was 505 days. Fourteen (77%) of the patients survived for more than 12 months and six patients (33%) for more than two years. One patient (5%) survived more than five years. Eight patients (44%) were still alive with a mean survival time of 32 months at the end of the study. Ten patients succumbed earlier from progression of the disease. Antioxidant treatment, in combination with chemotherapy and irradiation, prolonged the survival time of patients with small cell lung cancer compared to most published combination treatment regimens alone. We also noticed that the patients receiving antioxidants were able to tolerate chemotherapy and radiation treatment well. Surviving patients started antioxidant treatment in general earlier than those who succumbed.

Kligman AM, Mills OH Jr, Leyden JJ, Gross PR, Allen HB, Rudolph RI. Oral vitamin A in acne vulgaris. Preliminary report. Int J Dermatol. 1981 May;20(4):278-285.
Abstract: Oral vitamin A (retinol) is generally not considered useful in the treatment of acne vulgaris. We conducted a study which showed that retinol was indeed ineffective at the usual doses of 50,000 to 100,000 IU daily. Retinol was highly efficacious in doses of 300,000 units for women and 400,000 to 500,000 units for men, toxicity was slight and limited mainly to skin (xerosis) and mucous membranes (cheilitis). The danger of hypervitaminosis A in this dosage range has been exaggerated. Retinol is a valuable drug for treating stubborn, severely inflammatory acne vulgaris. It is administered until the disease is brought under control, usually within three to four months. Then the dosage is progressively reduced relying on conventional drugs to keep the disease in abeyance.

Oral vitamin A (retinol) is generally not considered useful in the treatment of acne vulgaris. We conducted a study which showed that retinol was indeed ineffective at the usual doses of 50,000 to 100,000 IU daily. Retinol was highly efficacious in doses of 300,000 units for women and 400,000 to 500,000 units for men, toxicity was slight and limited mainly to skin (xerosis) and mucous membranes (cheilitis). The danger of hypervitaminosis A in this dosage range has been exaggerated. Retinol is a valuable drug for treating stubborn, severely inflammatory acne vulgaris. It is administered until the disease is brought under control, usually within three to four months. Then the dosage is progressively reduced relying on conventional drugs to keep the disease in abeyance.

Knodel LC, Talbert RL. Adverse effects of hypolipidaemic drugs. Med Toxicol 1987 Jan;2(1):10-32.
Abstract: Cholestyramine, colestipol, clofibrate, gemfibrozil, nicotinic acid (niacin), probucol, neomycin, and dextrothyroxine are the most commonly used drugs in the treatment of hyperlipoproteinaemic disorders. While adverse reaction data are available for all of them, definitive data regarding the frequency and severity of potential adverse effects from well-controlled trials using large numbers of patients (greater than 1000) are available only for cholestyramine, clofibrate, nicotinic acid and dextrothyroxine. In adult patients treated with cholestyramine, gastrointestinal complaints, especially constipation, abdominal pain and unpalatability are most frequently observed. Continued administration along with dietary manipulation (e.g. addition of dietary fibre) and/or stool softeners results in diminished complaints during long term therapy. Large doses of cholestyramine (greater than 32 g/day) may be associated with malabsorption of fat-soluble vitamins. Most significantly, osteomalacia and, on rare occasions, haemorrhagic diathesis are reported with cholestyramine impairment of vitamin D and vitamin K absorption, respectively. Paediatric patients have been reported to experience hyperchloraemic metabolic acidosis or gastrointestinal obstruction. Concurrent administration of acidic drugs may result in their reduced bioavailability. Serious adverse reactions to clofibrate will probably limit its role in the future. Of particular concern are ventricular arrhythmias, induction of cholelithiasis and cholecystitis, and the potential for promoting gastrointestinal malignancy which far outweigh the reported benefits in preventing new or recurrent myocardial infarction, cardiovascular death and overall death. Patients with renal disease are particularly prone to myositis, secondary to alterations in protein binding and impaired renal excretion of clofibrate. Drug interactions with coumarin anticoagulants and sulphonylurea compounds may produce bleeding episodes and hypoglycaemia, respectively. Nicotinic acid produces frequent adverse effects, but they are usually not serious, tend to decrease with time, and can be managed easily. Dermal and gastrointestinal reactions are most common. Truncal and facial flushing are reported in 90 to 100% of treated patients in large clinical trials. Significant elevations of liver enzymes, serum glucose, and serum uric acid are occasionally seen with nicotinic acid therapy. Liver enzyme elevations are more common in patients given large dosage increases over short periods of time, and in patients treated with sustained release formulations.

Kong Q, Lillehei KO. Antioxidant inhibitors for cancer therapy. Med Hypotheses 1998 Nov;51(5):405-409.
Abstract: Built-in cellular defense mechanisms play a major role in a tumor's protection against non-surgical antineoplastic therapies. Of these, the overexpression of antioxidants such as superoxide dismutase (SOD) may be the most important. Oxygen radicals are highly toxic, and have been implicated in various diseases, including carcinogenesis and aging. They produce a variety of pathological changes through lipid peroxidation and DNA damage. Therefore, treating free-radical-induced diseases with antioxidants has been an accepted therapeutic approach. Ironically, however, the underlying mechanism that most chemotherapeutic agents and ionizing radiation exert on tumor cell kill is not increased antioxidation but rather the production of more free radicals leading to irreversible tissue injury. A small increase in reactive oxygen species (ROS) following non-surgical antineoplastic therapies induces the expression of antioxidants such as SOD, but overproduction of ROS, conversely, exhausts the production of SOD and other adaptive antioxidant defenses. Based on these considerations, we hypothesize that the appropriate administration of antioxidant inhibitors and/or free-radical-generating compounds may be a useful strategy in the treatment of solid tumors.

Kuznetsova LM, Kovaleva VM. [Effect of cortisone on the content and conversion of vitamin A forms in rats]. Ukr Biokhim Zh 1965;37(3):397-404. [Article in Ukrainian]

Krausz MM, Feinsod M, Beller AJ. Bilateral transverse sinus obstruction in benign intracranial hypertension due to hypervitaminosis A. Isr J Med Sci 1978 Aug;14(8):858-861.
Abstract: Hypervitaminosis A may be associated with benign intracranial hypertension. So far, the explanation for this phenomenon has remained obscure. A 17-year-old patient with benign intracranial hypertension, following chronic vitamin A intake of 150,000 units daily for acne vulgaris, is presented. Bilateral papilledema was present and bilateral obstruction of the transverse sinuses was demonstrated in the late venous phase of cerebral angiography. Discontinuation of vitamin A and acetazolamide treatment was followed by complete regression of the signs and symptoms of intracranial hypertension. Bilateral sinus obstruction with interference of cerebral sinus outflow is suggested as a critical factor in the pathogenesis of benign intracranial hypertension in vitamin A intoxication. Menstrual dysfunction and tetracycline therapy cannot be completely excluded as possible causative factors.

Labriola D, Livingston R. Possible interactions between dietary antioxidants and chemotherapy. Oncology (Huntingt). 1999 Jul;13(7):1003-1008; discussion 1008, 1011-1012.
Abstract: Many patients treat themselves with oral antioxidants and other alternative therapies during chemotherapy, frequently without advising their conventional health care provider. No definitive studies have demonstrated the long-term effects of combining chemotherapeutic agents and oral antioxidants in humans. However, there is sufficient understanding of the mechanisms of action of both chemotherapeutic agents and antioxidants to predict the obvious interactions and to suggest where caution should be exercised with respect to both clinical decisions and study interpretation. This article will describe these potential interactions and areas of concern, based on the available data. It will also suggest several potential courses of action that clinicians may take when patients indicate that they are taking or plan to use alternative therapies.

Lee AG. Pseudotumor cerebri after treatment with tetracycline and isotretinoin for acne. Cutis 1995 Mar;55(3):165-168. (Review)
Abstract: Tetracyclines and isotretinoin are widely used treatments for patients with acne. Although generally safe, the use of these agents has been associated with pseudotumor cerebri and combination therapy with these agents may increase the risk for pseudotumor cerebri. A 14-year-old boy presented with headaches and bilateral visual loss secondary to papilledema. He had been treated with tetracycline and isotretinoin for acne for three weeks prior to presentation and was subsequently diagnosed as having pseudotumor cerebri. He required long-term medical therapy and eventually underwent bilateral optic nerve sheath decompression. The literature regarding pseudotumor cerebri in association with tetracyclines and isotretinoin treatment for acne is reviewed. Dermatologists should be aware of the risk of pseudotumor cerebri in patients receiving tetracycline or isotretinoin treatment for acne and should be particularly cautious about using both agents simultaneously.

Lithgow DM, Politzer W. Vitamin A in the treatment of menorrhagia. S Afr Med J. 1977;51:191-193.
Abstract: 71 women with menorrhagia were found to have significantly lower serum vitamin A levels than healthy controls. 40 of these women were treated with vitamin A 25,000 I.U. b.i.d. daily for 15 days. Menstruation returned to normal in 57.5% and diminished in an additional 35%.

Liu S, Ajani U, Chae C, Hennekens C, Buring JE, Manson JE. Long-term beta-carotene supplementation and risk of type 2 diabetes mellitus: a randomized controlled trial. JAMA. 1999 Sep 15;282(11):1073-1075.
Abstract: CONTEXT: Recent data suggest a protective role of carotenoids in the development of type 2 diabetes mellitus (DM), possibly via an antioxidant effect, but no randomized trial has directly assessed the efficacy of beta-carotene to prevent DM. OBJECTIVE: To determine whether long-term beta-carotene supplementation reduces the risk of developing type 2 DM. DESIGN, SETTING, AND PARTICIPANTS: A total of 22, 071 healthy US male physicians aged 40 to 84 years in a randomized, double- blind, placebo-controlled trial, from 1982 to 1995. More than 99% of the participants had complete follow-up (median duration, 12 years). INTERVENTION: Subjects were randomly assigned to receive beta-carotene (50 mg on alternate days) or placebo. MAIN OUTCOME MEASURE: Incidence of type 2 DM. RESULTS: A total of 10, 756 subjects were assigned to beta-carotene and 10, 712 to placebo. Incidence of type 2 DM did not differ between groups: 396 men in the beta-carotene group and 402 men in the placebo group developed type 2 DM (relative risk, 0.98; 95% confidence interval, 0.85-1.12). The lack of association between beta-carotene supplementation and incidence of type 2 DM persisted despite multivariate adjustment. There was no evidence of benefit when the period of risk was subdivided into years of follow-up or increasing duration of treatment. CONCLUSION: In this trial of apparently healthy men, supplementation with beta-carotene for an average of 12 years had no effect on the risk of subsequent type 2 DM.

Liu T, Soong SJ, Wilson NP, Craig CB, Cole P, Macaluso M, Butterworth CE Jr. A case control study of nutritional factors and cervical dysplasia. Cancer Epidemiol Biomarkers Prev 1993 Nov-Dec;2(6):525-30.
Abstract: The association of nutritional factors with cervical dysplasia was examined through a case-control study. Analysis was conducted in 257 cases and 133 controls confirmed both by cytological examination and colposcopic findings. A 24-h dietary recall questionnaire was used to assess nutritional intake. Various risk factors (including age at first intercourse, number of sexual partners, parity, cigarette smoking, oral contraceptive use, human papillomavirus type 16 infection, and age and race) were adjusted for their potential confounding effects. While analyses were also performed to adjust for total calories, results were not changed significantly. Among the nutrients examined, vitamin A intake showed a significantly increased risk at the lowest quartile compared to the highest quartile, with an odds ratio of 2.2 (95% confidence interval, 1.2-4.2). A significant trend of increasing risk was also observed with lower intake of vitamin A (P = 0.05). Riboflavin showed increased risk at the two lower quartiles of intake with a trend test P value of 0.04. Increased risk was also found for lower intakes of vitamin C compared to the highest intake level. For folate, increased risk was found in the second highest quartile compared with the highest quartile with an odds ratio of 2.0 (95% confidence interval, 1.0-3.8). The calcium:phosphorus ratio showed an increased risk at the lowest level (odds ratio, 2.0; 95% confidence interval, 1.0-4.3). Insufficient intake of vitamin A, riboflavin, ascorbate, and folate is associated with an increased risk of cervical dysplasia.

Longnecker JB, Basu SG. Effects of cholestyramine on absorption of amino acids and vitamin A in man. Fed Proc. 1965;24:375.

Malila N, Virtamo J, Virtanen M, Albanes D, Tangrea JA, Huttunen JK. The effect of alpha-tocopherol and beta-carotene supplementation on colorectal adenomas in middle-aged male smokers. Cancer Epidemiol Biomarkers Prev. 1999 Jun;8(6):489-493.

Marz R. Medical Nutrition From Marz. Second Edition. Portland, OR. 1997

Meigel WN. How safe is oral isotretinoin? Dermatology 1997;195 Suppl 1:22-28; discussion 38-40. (Review)
Abstract: Since oral isotretinoin (Roaccutane/Accutane) is the only therapy to address all major acne causes, it remains the most effective antiacne therapy available. Due to this unique efficacy and its potential side effects that are predictable and can be managed easily and effectively, it is widely used also in acne patients suffering from serious systemic diseases. As the primary mechanism of action of oral isotretinoin is suppression of sebaceous gland activity, mucocutaneous side effects such as dry lips, nasal passages and eyes are predictable. Pretreatment counseling and concomitant use of moisturizing agents usually manage these side effects effectively; in unusual cases of particularly poor tolerability, dose adjustments suffice. Severe side effects are rare, the most common being aches and pains requiring no therapy, aspirin or paracetamol. As with other retinoids, reliable contraception is mandatory for women of childbearing potential. Acne patients with serious concomitant systemic disease, such as insulin-dependent diabetes, epilepsy or spina bifida, transplant patients, patients with renal failure, multiple sclerosis motor neuron disease and other can also safe be treated with a standard cumulative dose of 120 mg/kg per treatment course.

Mejia LA, Chew F. Hematological effect of supplementing anemic children with vitamin A alone and in combination with iron. Am J Clin Nutr 1988;48:595-600.

Melhus H, Michaelsson K, Kindmark A, Bergstrom R, Holmberg L, Mallmin H, Wolk A, Ljunghall S. Excessive dietary intake of vitamin A is associated with reduced bone mineral density and increased risk for hip fracture. Ann Intern Med 1998 Nov 15;129(10):770-778.
Abstract: BACKGROUND: The highest incidence of osteoporotic fractures is found in northern Europe, where dietary intake of vitamin A (retinol) is unusually high. In animals, the most common adverse effect of toxic doses of retinol is spontaneous fracture. OBJECTIVE: To investigate whether excessive dietary intake of vitamin A is associated with decreased bone mineral density and increased risk for hip fracture. DESIGN: A cross-sectional study and a nested case-control study. SETTING: Two counties in central Sweden. PARTICIPANTS: For the cross-sectional study, 175 women 28 to 74 years of age were randomly selected. For the nested case-control study, 247 women who had a first hip fracture within 2 to 64 months after enrollment and 873 age-matched controls were selected from a mammography study cohort of 66,651 women 40 to 76 years of age. MEASUREMENTS: Retinol intake was estimated from dietary records and a food-frequency questionnaire. Bone mineral density was measured with dual-energy x-ray absorptiometry. Hip fracture was identified by using hospital discharge records and was confirmed by record review. RESULTS: In multivariate analysis, retinol intake was negatively associated with bone mineral density. For every 1-mg increase in daily intake of retinol, risk for hip fracture increased by 68% (95% CI, 18% to 140%; P for trend, 0.006). For intake greater than 1.5 mg/d compared with intake less than 0.5 mg/d, bone mineral density was reduced by 10% at the femoral neck (P = 0.05), 14% at the lumbar spine (P = 0.001), and 6% for the total body (P = 0.009) and risk for hip fracture was doubled (odds ratio, 2.1 [CI, 1.1 to 4.0]). CONCLUSION: High dietary intake of retinol seems to be associated with osteoporosis. and increased risk for hip fracture. Melhus H, Michaelsson K, Kindmark A, Bergstrom R, Holmberg L, Mallmin H, Wolk A, Ljunghall S. Excessive dietary intake of vitamin A is associated with reduced bone mineral density and increased risk for hip fracture.

Mills EED. The modifying effect of beta-carotene on radiation and chemotherapy induced oral mucositis. Brit J Cancer 1988 Apr;57(4):416-417.

Mitchell AA. Oral retinoids. What should the prescriber known about their teratogenic hazards among women of child-bearing potential? Drug Saf. 1992 Mar-Apr;7(2):79-85. (Review)

Mooij PN, Thomas CM, Doesburg WH, Eskes TK. The effects of oral contraceptives and multivitamin supplementation on serum ferritin and hematological parameters. Int J Clin Pharmacol Ther Toxicol 1992 Feb;30(2):57-62.
Abstract: We have studied the effects of oral contraceptive (OC) use and of subsequent multivitamin supplementation on several hematological parameters. Hemoglobin (Hb), hematocrit (Ht), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular hemoglobin (MCH), and serum iron status (serum iron, total iron binding capacity and ferritin) were tested in groups of women with and without OC in view of preconceptional status. The group taking sub-50 OC comprised 28 women while 31 women were included in the group of non-OC users. Blood samples were taken on days 3 and 23 of the first cycle to obtain baseline values of each analyte. Multivitamin supplementation started on day 1 of the second cycle and this was continued daily throughout three consecutive cycles until the end of the study. Comparison of the baseline values of each parameter as determined on days 3 and 23 of the first cycle of the two groups revealed no significant different hematological parameters due to OC-use unlike the parameters of serum iron status which were all significantly increased for the group of OC-users as compared to the group of non-OC users. The effects of multivitamin supplementation on the hematological and iron status parameters were studied within each group. The consistency of each effect of multivitamin supplementation between the two groups was also tested. A multivitamin supplementation significantly decreased MCHC within either group, and caused increases of MCV, whereas Ht and MCH remained unaltered. With respect to the iron balance, serum iron and total iron binding capacity significantly increased, whereas serum ferritin decreased during multivitamin supplementation.

Muggeo M, Zenti MG, Travia D, Sartori A, Trimeloni S, Grigolini L, Graziani MS, Cigolini M. Serum retinol levels throughout two years of cholesterol-lowering therapy. Metabolism 1995;Mar;44(3):398-403.
Abstract: Some studies have reported an inverse correlation between serum cholesterol level and risk of cancer. This correlation might be due to a decrease in serum retinol, a lipid-soluble vitamin that controls cell proliferation and differentiation. We evaluated the influence of cholesterol-lowering therapy on serum retinol in 102 subjects (mean +/- SE: aged 47.1 +/- 4.1 years; body mass index, 23.8 +/- 0.6 kg/m2) with primary hypercholesterolemia treated for 2 years with different therapeutic protocols. Twenty-two subjects had been treated with diet alone, 35 with diet and fibrates, 37 with diet and hepatic hydroxymethyl glutaryl coenzyme A (HMG CoA) reductase inhibitors (statins), and eight with diet and cholestyramine. Postabsorptive serum retinol, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride levels were determined at baseline and every 3 months. Baseline TC and LDL-C were significantly lower in the diet-treated group than in other groups. No intergroup differences were found in pretreatment levels of triglycerides and serum retinol. After 2 years of treatment, TC and LDL-C serum levels were not significantly decreased in the diet-alone group, whereas they were decreased by 20% and 24%, respectively, in the gemfibrozil group, 28% and 34% in the statins group; and 21% and 27% in the cholestyramine group. In the entire population (N = 102), serum retinol was 3.46 +/- 0.08 mumol/L before therapy and 3.76 +/- 0.07 after 2 years of therapy (P < .001). Serum retinol increased in diet- and statin-treated groups, but not in fibrate- and resin-treated groups.

Nakagawa M, Yamaguchi T, Ueda H, Shiraishi N, Komiyama S, Akiyama S, Ogata J, Kuwano M. Potentiation by vitamin A of the action of anticancer agents against murine tumors. Jpn J Cancer Res 1985 Sep;76(9):887-894.
Abstract: Combinations of retinol palmitate (RP) and six different anticancer agents were examined to determine their effects on the life-span of mice bearing ascites sarcoma 180 or P388 leukemia. With ascites sarcoma 180, administration of a fixed dose of RP (3.3 mg/kg) considerably enhanced the antitumor effects of 5-fluorouracil (5-FU) (5 mg/kg, or 20 mg/kg), methotrexate (MTX) (0.5 mg/kg, or 1 mg/kg) and 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU) (12.5 mg/kg), when given by intraperitoneal injection. However RP failed to potentiate the antitumor effects of adriamycin (ADM) and 6-mercaptopurine (6-MP) against sarcoma 180. With P388 leukemia, RP (167 mg/kg, or 333 mg/kg) enhanced the antitumor effects of 6-MP (25 mg/kg, or 50 mg/kg), MTX (1 mg/kg, or 2 mg/kg), ADM (0.2 mg/kg), ACNU (5 mg/kg) and cis-dichlorodiammine-platinum (CDDP) (1 mg/kg) to a considerable extent, but it did not potentiate the antitumor effect of 5-FU. The combination of RP with ACNU or CDDP was particularly effective against P388 leukemia.

NRC (National Research Council). Diet and Health: Implications for Reducing Chronic Disease Risk. Washington, D.C.: The National Academy Press 1989, 516.
Abstract: NY State Dept of Health studied 16 out of 492 women who took between 15,000 I.U. to 50,000 I.U. per day with no side effects and no birth defects. Intakes in excess of 50,000 I.U. may lead to increased risk of birth defects according to animal studies. To date there is at least one anecdotal study that involves a woman ingesting 150,000 I.U. q.d. for 2 months before and 3 months after conception. Her pregnancy had to be terminated because of fetal malformations at 23 weeks.

Omenn GS, Goodman G, Thornquist M, Grizzle J, Rosenstock L, Barnhart S, Balmes J, Cherniack MG, Cullen MR, Glass A, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 1996;334:1150-1155.

Omenn GS, Goodman G, Thornquist M, Grizzle J, Rosenstock L, Barnhart S, Balmes J, Cherniack MG, Cullen MR, Glass A, et al. The beta-carotene and retinol efficacy trial (CARET) for chemoprevention of lung cancer in high risk populations: smokers and asbestos-exposed workers. Cancer Res. 1994 Apr 1;54(7 Suppl):2038S-2043S.
Abstract: The CARET study (Carotene and Retinol Efficacy Trial Cancer Research 54, 2038S-43S, 1994), over 18,000 men and women who were smokers and/or asbestos workers showed, after 4 years of 50,000 I.U. q.d., a 28% increase in lung cancer and a 17% increase in cancer mortality. That study was discontinued prematurely because of this finding. Dr. Gaby has theorized that beta carotene may decrease levels of other carotenes such as lycopene and lutein in the body. In smokers and people exposed to asbestos these carotene levels may already be low. Surely it would make sense to do a trial with multiple carotenes as well as vitamin E and with vitamin E alone to differentiate the effects of these nutrients which should prove beneficial.

Prasad AS, Oberleas D, Moghissi KS, Stryker JC, Lei KY. Effect of oral contraceptive agents on nutrients: II. Vitamins. Am J Clin Nutr 1975 Apr;28(4):385-391.
Abstract: Clinical, biochemical and nutritional data were collected from a large population of women using oral contraceptive agents. Higher incidence of abnormal clinical signs related to malnutrition were observed in the lower (B) as compared to the higher (A) socioeconomic groups, and also in the nonsupplemented groups as compared to the supplemented groups in the B subjects. As a rule the intake of oral contraceptive agent subjects of vitamin A, C, B6 and folic acid did not differ from that of the controls As expected, subjects from the supplemented groups had higher intake of vitamin A, C, B6, thiamin, riboflavin and folic acid, and A groups had higher intake of vitamin C, B6, riboflavin and folic acid. Increased plasma vitamin A and decreased carotene levels were observed in oral contraceptive agent users. In general oral contraceptive agents had little or no effect on plasma ascorbic acid. Urinary excretion of both thiamin and riboflavin in subjects using oral contraceptive agents were lower in A groups. Erythrocyte folate and plasma pyridoxal phosphate was decreased in A groups due to oral contraceptive agents. Subjects who took supplements had higher levels of plasma vitamin A, ascorbic acid and folate. But urinary thiamin and riboflavin were higher only in group A subjects who took supplements.

Pronsky Z. Powers and Moore's Food-Medications Interactions. Ninth Edition. Food-Medication Interactions. Pottstown, PA, 1991.

Rautalahti MT, Virtamo JR, Taylor PR, Heinonen OP, Albanes D, Haukka JK, Edwards BK, Karkkainen PA, Stolzenberg-Solomon RZ, Huttunen J. The effects of supplementation with alpha-tocopherol and beta-carotene on the incidence and mortality of carcinoma of the pancreas in a randomized, controlled trial. Cancer. 1999 Jul 1;86(1):37-42.

Robinson C, Weigly E. Basic Nutrition and Diet Therapy. New York: MacMillan, 1984.

Roe DA. Diet and Drug Interactions. New York: Van Nostrand Reinhold, 1989.

Roe DA. Drug-induced Nutritional Deficiencies. 2nd ed. Westport, CT: Avi Publishing, 1985.

Roe DA. Risk factors in drug-induced nutritional deficiencies. In: Roe DA, Campbell T, eds. Drugs and Nutrients: The Interactive Effects. New York: Marcel Decker, 1984: 505-523.

Sacks PG, Harris D, Chou T-C. Modulation of growth and proliferation in squamous cell carcinoma by retinoic acid: A rationale for combination therapy with chemotherapeutic agents. Int J Cancer 1995 May 4;61(3):409-415.
Abstract: We have previously shown that beta-all trans retinoic acid (RA) inhibits macrocellular growth of a multicellular tumor spheroid model for squamous carcinoma, as measured by spheroid size, but allows for continuing DNA synthesis and cell cycle progression, the two being reconciled by a cell death effect. DNA synthesis in the presence of growth inhibition suggested a rationale for examining combination chemotherapy with RA-inhibited cells. To this aim, we have extended this observation to a series of 8 squamous carcinoma cell lines. Cells were treated with 1 microM RA for 7 days and cell growth parameters monitored. Although growth inhibition ranged from 0% (A431) to approx. 80% (MDA 886Ln), [3H]-thymidine incorporation (cpm/microgram protein) and percent S-phase (by flow cytometry) in 7-day RA-treated cells was equal or higher than in their control vehicle-treated cells in 7/8 SCC cell lines. Thus RA-induced growth inhibition is not just cytostasis. Combination therapy was examined with MDA 886Ln, MDA 686Ln, 1483 and A431 cells pre-treated for 7 days with 1 microM RA followed by cisplatin or 5-fluorouracil treatment. An increased effectiveness for the combination was shown using 5-day tetrazolium dye (MTT) growth assays when cells were growth-inhibited by RA. Computerized analysis of data using median-effect and isobologram techniques indicated that the interaction of RA with these chemotherapeutic agents was synergistic. With squamous carcinoma, RA treatment inhibits growth while allowing for continuing DNA synthesis, and these RA-treated, growth-inhibited cells exhibit increased sensitivity to chemotherapeutic agents.

Salignik R, et al. Avoiding vitamins A and E may improve cancer therapy. 39th Annual meeting of the American Society for Cell Biology, Dec 11-15th, 1999.
Abstract: Apoptosis, or programmed cell death, eliminates selectively precancerous and cancerous cells. Since reactive oxygen species (ROS) act as essential mediators of apoptosis, antioxidants inhibit this protective form of cell death. Most anticancer drugs kill cancer cells by apoptosis and antioxidants interfere with their anticancer effect. Since depletion of ROS decreases apoptosis, we reasoned that increasing the level of ROS might enhance apoptotic death of cancer cells and inhibit thereby tumor growth. Here, using a defined transgenic brain tumor model, we test the impact of feeding an antioxidant depleted diet, capable of increasing ROS accumulation, on apoptosis and tumor growth. Dramatically increased apoptosis occurs within tumors in antioxidant-depleted mice, but not in normal tissues. Detectably increased oxidant stress indicates that the likely mechanism of enhanced tumor apoptosis is via a rise in ROS. Tumor growth is significantly inhibited in mice fed an antioxidant-depleted diet. In clear contrast, an oxidant-enriched diet had no impact on tumor growth.

Santos MS, Gaziano JM, Leka LS, Beharka AA, Hennekens CH, Meydani SN. Beta-carotene-induced enhancement of natural killer cell activity in elderly men: an investigation of the role of cytokines. Am J Clin Nutr. 1998 Jul;68(1):164-170.
Abstract: We showed previously that natural killer (NK) cell activity is significantly greater in elderly men supplemented with beta-carotene than in those taking placebo. In an attempt to determine the mechanism of beta-carotene's effect, we analyzed the production of NK cell-enhancing cytokines (interferon alpha, interferon gamma, and interleukin 12). Boston-area participants in the Physicians' Health Study (men aged 65-88 y; mean age, 73 y) who had been supplemented with beta-carotene (50 mg on alternate days) for an average of 12 y were enrolled in a randomized, placebo-controlled, double-blind study. Elderly subjects taking beta-carotene supplements had significantly greater plasma beta-carotene concentrations than those taking placebo. Beta-carotene-supplemented elderly men had significantly greater NK cell activity than did elderly men receiving placebo. Percentages of NK cells (CD16+CD56+) were not significantly different between the beta-carotene and placebo groups. Production of interleukin 12, interferon alpha, or concanavalin A-stimulated interferon gamma by cultured peripheral blood mononuclear cells was not significantly different between beta-carotene-supplemented elderly and those taking placebo. Our results indicate that beta-carotene-induced enhancement of NK cell activity is not mediated by changes in percentages of CD16+CD56+ NK cells nor through up-regulation of interleukin 12 or interferon alpha.

Shekelle RB, Lepper M, Liu S, Maliza C, Raynor WJ Jr, Rossof AH, Paul O, Shryock AM, Stamler J. Dietary vitamin A and risk of cancer in the Western Electric Study. Lancet 1981 Nov 28;2(8257):1185-1190.
Abstract: Intake of dietary provitamin A (carotene) was inversely related to the 19-year incidence of lung cancer in a prospective epidemiological study of 1954 middle-aged men. The relative risks of lung cancer in the first (lowest) to fourth quartiles of the distribution of carotene intake were respectively, 7.0, 5.5, 3.0, and 1.0 for all men in the study, and 8.1, 5.6, 3.9, and 1.0 for men who had smoked cigarettes for 30 or more years. Intake of preformed vitamin A (retinol) and intake of other nutrients were not significantly related to the risk of lung cancer. Neither carotene nor retinol intake was significantly related to the risk of other carcinomas grouped together, although for men in whom epidermoid carcinomas of the head and neck subsequently developed, carotene intake tended to be below average. These results support the hypothesis that dietary beta-carotene decreased the risk of lung cancer. However, cigarette smoking also increases the risk of serious diseases other than lung cancer, and there is no evidence that dietary carotenoids affect these other risks in any way.

Tamai H, Morinobu T, Murata T, Manago M, Mino M. 9-cis beta-carotene in human plasma and blood cells after ingestion of beta-carotene. Lipids. 1995 Jun;30(6):493-498.
Abstract: For 44 wk, thirty male volunteers were given daily either 60 mg of synthesized all-trans beta-carotene, a naturally-occurring beta-carotene derived from Dunaliella bardawil, or a placebo. Basal levels of 9-cis beta-carotene in plasma, platelets, and mononuclear cells were 10, 20, and 25% of those of the all-trans form, respectively. The plasma levels reached a maximum after two weeks of administration and plateaued thereafter in the subjects who took the beta-carotene preparations. The all-trans beta-carotene level in the subjects given the synthesized all-trans form was almost twice that for the Dunaliella preparation. The plasma 9-cis level was found to be higher in the all-trans beta-carotene group than in the Dunaliella group, despite no intake of the 9-cis form in the all-trans group and the higher intake of the 9-cis form in the Dunaliella group. This finding suggests that isomerization of the all-trans form to the 9-cis form may occur in the body either during or after absorption.

Teicher BA, Schwartz JL, Holden SA, Ara G, Northey D. In vivo modulation of several anticancer agents by beta-carotene. Cancer Chemother Pharmacol. 1994;34(3):235-241.
Abstract: The ability of the collagenase inhibitor minocycline and of beta-carotene to act as positive modulators of cytotoxic anticancer agents was assessed in vitro and in vivo. Cell-culture studies were conducted using the human SCC-25 squamous carcinoma cell line. Simultaneous exposure of the cells to minocycline and beta-carotene or 13-cis-retinoic acid along with cisplatin (CDDP) resulted in a small decrease in the cytotoxicity of the CDDP. The addition of each of the modulator combinations for 1 h or 24 h to treatment with melphalan (L-PAM) or carmustine (BCNU) resulted in greater-than-additive cytotoxicity with each of four regimens. The modulator combinations of minocycline and beta-carotene applied for 1 h or 24 h and the modulator combination of minocycline and 13-cis-retinoic acid produced greater-than-additive cytotoxicity at 50 microM 4-hydroperoxycyclophosphamide (4-HC), whereas minocycline and 13-cis-retinoic acid applied for 1 h was antagonistic with 4-HC and the other modulator treatments at low concentrations of 4-HC resulted in subadditive cytotoxicity. The effect of treatment with beta-carotene alone and in combination with several different anticancer agents was examined in two murine solid tumors, the FSaII fibrosarcoma and the SCC VII carcinoma. Administration of the modulators alone or in combination did not alter the growth of either tumor. Whereas increases in tumor growth delay occurred with the antitumor alkylating agents and beta-carotene and with minocycline and beta-carotene, a diminution in tumor growth delay was produced by 5-fluorouracil in the presence of these modulators. The modulator combination also resulted in increased tumor growth delay with adriamycin and etoposide. Tumor-cell survival assay showed increased killing of FSaII tumor cells with the modulator combination and melphalan or cyclophosphamide as compared with the drugs alone. These results indicate that further investigation of this modulator strategy is warranted.

Tomita Y. Immunological role of vitamin A and its related substances in prevention of cancer. Nutr Cancer. 1983;5(3-4):187-194.
Abstract: The antitumor effects of vitamin A and its related substances, vitamin E, vitamin K, beta-carotene, ubiquinone, phytol, and squalene, were examined using a syngeneic murine tumor system. Intraperitoneal administration of these substances (0.19 mumol/mouse/day) slightly suppressed the growth of Meth A fibrosarcoma cells inoculated s.c. into Balb/c mice. Administration of all test substances except beta-carotene significantly suppressed the growth of Meth A fibrosarcoma cells rechallenged in Meth A-primed mice on day 10, but did not influence the growth of Meth 1 fibrosarcoma cells (another syngeneic tumor of Balb/c origin) rechallenged in Meth A-primed mice on day 10. The growth of Meth A tumor cells was suppressed when Meth A was inoculated together with lymph node cells obtained from the Meth A-primed Balb/c mice treated with vitamin A, vitamin E, phytol, or squalene. Our findings suggest that certain constituents in green-yellow vegetables may contribute to the prevention of cancer by augmenting an immunological response against tumor cells in the early stages of carcinogenesis.

Tonstad S, Sivertsen M, Aksnes L, Ose L. Low dose colestipol in adolescents with familial hypercholesterolaemia. Arch Dis Child 1996 Feb;74(2):157-160.
Abstract: The effects of orange flavoured colestipol granules, 10 g/day, in 37 boys and 29 girls aged 10-16 years with familial hypercholesterolaemia were examined first in an eight week double blind, placebo controlled protocol, then in open treatment for 44-52 weeks. All patients were on a low fat diet. Low density lipoprotein cholesterol levels were reduced by 19.5% by colestipol v 1.0% by placebo. Levels of serum folate, vitamin E, and carotenoids were reduced in the colestipol group, but not the vitamin E/cholesterol and carotenoid/cholesterol ratios or serum concentrations of vitamins A and D. After one year of colestipol, two thirds of the participants remained in the study, of whom half took > or = 80% of the prescribed dose. Those who took > or = 80% of the dose had a greater decrease in serum 25-hydroxyvitamin D levels than those who took < 80%. No adverse effects on weight gain or linear growth velocity were observed. Although low dose colestipol effectively reduces low density lipoprotein cholesterol levels, only a minority of adolescents adhered to the new formulation for one year. Folate and possibly vitamin D supplementation is recommended.

Tornwall ME, Virtamo J, Haukka JK, Aro A, Albanes D, Huttunen JK. The effect of alpha-tocopherol and beta-carotene supplementation on symptoms and progression of intermittent claudication in a controlled trial. Atherosclerosis. 1999 Nov 1;147(1):193-197.
Abstract: We evaluated the effect of long-term supplementation with vitamin E (alpha-tocopherol) and beta-carotene on occurrence of claudication symptoms and risk for peripheral vascular surgery among men with intermittent claudication. Subjects, 50-69-year old male smokers, were participants in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, who reported intermittent claudication through a structured questionnaire (Rose) at study entry (n=1484). They were randomly assigned to receive either 50 mg/day of alpha-tocopherol, or 20 mg/day of beta-carotene, or both, or placebo, in a 2x2 design. During follow-up, claudication was evaluated by repeating use of the questionnaire once a year. Information on peripheral vascular surgery came from the National Hospital Discharge Register. We observed no effect of alpha-tocopherol and beta-carotene supplementation on claudication during a mean follow-up of 3.7 years. A slightly increased risk (odds ratio (OR) 1.60, 95% confidence interval (CI) 1.05-2.44) for vascular surgery was observed among beta-carotene supplemented men compared to those who did not receive beta-carotene. Alpha-tocopherol supplementation had no effect. In conclusion, long-term supplementation with alpha-tocopherol and beta-carotene showed no beneficial effect on symptoms and progression of intermittent claudication.

Trovato A, Nuhlicek DN, Midtling JE. Drug-nutrient interactions. Am Fam Physician 1991 Nov;44(5):1651-1658.(Review)

USDA: Composition of Foods. USDA Handbook #8 Washington DC, ARS, USDA, 1976-1986.

Vinitha R, Thangaraju M, Sachdanandam P. Effect of administering cyclophosphamide and vitamin E on the levels of tumor-marker enzymes in rats with experimentally induced fibrosarcoma. Jpn J Med Sci Biol 1995 Jun;48(3):145-156.

Von Lennep E, El Khazen N, De Pierreux G, Amy JJ, Rodesch F, Van Regemorter N. A case of partial sirenomelia and possible vitamin A teratogenesis. Prenat Diagn. 1985 Jan-Feb;5(1):35-40.

Walters BN, Gubbay SS. Tetracycline and benign intracranial hypertension: report of five cases. Br Med J (Clin Res Ed) 1981 Jan 3;282(6257):19-20.
Abstract: Benign intracranial hypertension occurred in four young women taking tetracycline for acne; two were also taking vitamin A. In a fifth case a 14-year-old boy developed papilloedema after taking a short course of tetracycline for bronchitis. All symptoms disappeared soon after stopping the drugs, though in two cases the papilloedema persisted for many months. Benign intracranial hypertension should be sought in any young woman complaining of headache during treatment with tetracycline. Moreover, young women given vitamin A and tetracycline in combination for acne may be at special risk and should be kept under surveillance.

Watkins DW, Khalafi R, Cassidy MM, Vahouny GV. Alterations in calcium, magnesium, iron, and zinc metabolism by dietary cholestyramine. Dig Dis Sci 1985 May;30(5):477-482.
Abstract: Cholestyramine is an effective drug for the reduction of plasma cholesterol because of its ability to sequester intestinal bile acids. Since metabolic alterations, including diminished intestinal absorption of vitamin D and osteomalacia have been reported with long-term use of this resin, the influence of cholestyramine on dietary balance of four mineral elements has been investigated. Wistar-strain rats were fed either a 2% cholestyramine or control diet for one month. Dietary intakes and fecal and urinary excretions of calcium, magnesium, iron, and zinc were determined using atomic absorption spectrophotometry during three, 3-day balance periods. Cholestyramine-fed rats had a net negative balance for calcium and a lower net positive balance for magnesium, iron, and zinc than the controls. Other effects of cholestyramine were an increased urinary excretion of calcium and magnesium, a decreased urinary zinc, and an alkalinization of urine. Blood and tissue cation content was unchanged except for a reduction in serum magnesium with resin feeding. Alterations in calcium, magnesium, and zinc metabolism might be explained by inadequate vitamin D absorption from the intestine followed by an increased secretion of parathyroid hormone. A diminished iron absorption due to resin binding could account for the reported disturbance in iron balance.

Weijl NI, Hopman GD, Wipkink-Bakker A, Lentjes EG, Berger HM, Cleton FJ, Osanto S. Cisplatin combination chemotherapy induces a fall in plasma antioxidants of cancer patients. Ann Oncol 1998 Dec;9(12):1331-1337.
Abstract: BACKGROUND: Antioxidants protect the body against cellular oxidative damage and thus some of the adverse effects induced by cisplatin and other cytostatic drugs. PATIENTS AND METHODS: The effect of cisplatin-combination chemotherapy on concentrations of plasma antioxidants was studied in 36 cancer patients, including osteosarcoma and testicular carcinoma patients. RESULTS: Eight to 15 days after the start of each cytostatic drug infusion concentrations of various plasma antioxidants were measured and compared to pretreatment values: vitamin C and E, uric acid and ceruloplasmin levels fell significantly (P < 0.01-0.005) and returned to baseline levels before the start of the next chemotherapy cycle. Levels of the antioxidants bilirubin albumin and the ratio vitamin E/cholesterol + triglycerides measured three weeks after the start of chemotherapy significantly decreased compared to pretreatment levels and remained low thereafter (P < 0.001-0.002). Dietary intake of antioxidants and anthropometric measurements, evaluated in 14 patients did not change during the whole treatment period. CONCLUSIONS: Cisplatin-combination chemotherapy induces a fall in plasma antioxidant levels, that may reflect a failure of the antioxidant defense mechanism against oxidative damage induced by commonly used anticancer drugs. This probably results from consumption of antioxidants caused by chemotherapy induced-oxidative stress as well as renal loss of water-soluble, small molecular weight antioxidants such as uric acid.

Weijl NI, Cleton FJ, Osanto S. Free radicals and antioxidants in chemotherapy-induced toxicity. Cancer Treatment Rev 1997 Jul;23(4):209-240 (Review)

Werbach MR. Foundations of Nutritional Medicine. Tarzana, CA: Third Line Press, 1997, 221-222. (Review).

West RJ, Lloyd JK. The effect of cholestyramine on intestinal absorption. Gut. 1975 Feb;16(2):93-98.
Abstract: Cholestyramine in a mean dosage of 0-6 g/kg/day has been given to 18 children with familial hypercholesterolaemia for between one and two and a half years. With prolonged treatment folate deficiency occurred, as evidenced by a fall in the mean serum folate concentration from 7-7 ng/ml before treatment to 4-4 ng/ml for patients on treatment for over one year; a corresponding lowering of red cell folate was also seen. Oral folic acid 5 mg daily overcame this depletion, and should be given to all patients on long-term anion exchange resins. Prothrombin time has remained normal in all patients; there has been a significant decrease in the mean serum concentrations of vitamins A and E and of inorganic phosphorus over the first two years of treatment, although values remain within the normal range. The routine administration of fat-soluble vitamins appears unnecessary but it is prudent to measure prothrombin time and serum vitamins A and E at intervals. In children who were having a normal intake of dietary fat five out of seven tested had faecal fat of over 5 g/day while on cholestyramine. No child has developed diarrhoea, and growth has been normal. The concentrations of serum iron, vitamin B12, plasma calcium, and protein did not change significantly in any patient.

Wiegand UW, Hartmann S, Hummler H. Safety of vitamin A: recent results. Int J Vitam Nutr Res 1998;68(6):411-416. (Review)
Abstract: A still unresolved public health concern is that excessive vitamin A intake, like vitamin A deficiency, possibly causes birth defects not only in animals but also in man. Due to the low incidence of possibly vitamin A-related malformations in man, available data cannot convincingly define the upper safe limit of periconceptional vitamin A intake. Direct human intervention studies are not feasible for ethical reasons. Therefore, a novel approach in addressing this issue was chosen by combining teratogenicity data from a validated animal model with data on systemic exposure to vitamin A and its major metabolites in female volunteers. In a study in pregnant women endogenous plasma concentrations of vitamin A metabolites during early pregnancy ranged from 0.26 to 7.72 ng/ml. Since they did not cause any foetal malformations, retinoid plasma levels in this range can be considered non-teratogenic. Results of a trial in non-pregnant women document that daily oral vitamin A supplements of 4000, 10,000 and 30,000 IU given for 3 weeks were in the range or slightly above the range of endogenous plasma levels seen in early pregnancy. Even after a 3-week treatment with 30,000 IU/day, peak plasma levels of retinoic acid and isotretinoin were within or just slightly above the range of their physiological levels. In cynomolgus monkeys (average weight: 3-4 kg), a NOAEL (no observed adverse effect level) of 7500 IU per kg body weight and a LOAEL (lowest observed adverse effect level) for developmental toxicity of 20,000 IU/kg was found. Considering these results in the cynomolgus monkey, a dose of 30,000 IU/day should also be considered as non-teratogenic in man.

Woodson K, Albanes D, Tangrea JA, Rautalahti M, Virtamo J, Taylor PR. ?Association between alcohol and lung cancer in the alpha-tocopherol, beta-carotene cancer prevention study in Finland. Cancer Causes Control. 1999 Jun;10(3):219-226.
Abstract: OBJECTIVES: We evaluated the association between alcohol intake and lung cancer in a trial-based cohort in Finland, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC Study). METHODS: During an average of 7.7 years of follow-up, 1059 lung cancer cases were diagnosed among the 27,111 male smokers with complete alcohol and dietary information. The relationship between alcohol and lung cancer was assessed in multivariate Cox regression models that adjusted for age, smoking, body mass index and intervention group. RESULTS: Nondrinkers, 11% of the study population, were at increased lung cancer risk compared to drinkers (RR = 1.2, 95% CI: 1.0-1.4), possibly due to the inclusion of ex-drinkers who had stopped drinking for health reasons. Among drinkers only, we observed no association between lung cancer and total ethanol or specific beverage (beer, wine, spirits) intake. We found no significant effect modification by level of smoking, dietary micronutrients or trial intervention group; however, for men in the highest quartile of alcohol intake, we observed a slight increase in risk for lighter smokers (<1 pack/day) and reduced risk among the heaviest smokers (>30 cigarettes/day). CONCLUSIONS: We concluded that alcohol consumption was not a risk factor for lung cancer among male cigarette smokers, and its effect was not significantly modified by other factors, notably smoking history.

Wynn V. Vitamins and oral contraceptive use. Lancet 1975 Mar 8;1(7906):561-564.
Abstract: Reports concerning the interaction between steroidal contraceptives (the combined pill) and vitamins indicate that in users the mean serum-vitamin-A level is raised and the mean serum-vitamin-B2 (riboflavine), vitamin-B6 (pyridoxine), vitamine-C, folic-acid, and vitamin-B12 levels are reduced. Other vitamins have been insufficiently studied for comment. Biochemical evidence of co-enzyme deficiency has been reported for vitamin B2, vitamin B6, and folic acid. Clinical effects due to vitamin deficiency have been described for vitamin B6--namely, depression and impaired glucose tolerance. Folic-acid deficiency with megaloblastic anaemia has been reported in only 21 cases.

Yamaguchi T. [Effect of various drugs on the abnormality induced by excessive intake of vitamin A. 1. Effect of cortisone]. Shikwa Gakuho 1967 Nov;67(11):1329-1339. [Article in Japanese]

Yeum K-J, Azhu S, Xiao S, et al. Beta-carotene intervention trial in premalignant gastric lesions. J Am Coll Nutr 1995;14:536. (Abstract)

You C-S, Parker RS, Goodman KJ, et al. Evidence of cis-trans isomerization of 9-cis-beta-carotene during absorption in humans. Am J Clin Nutr 1996;64:177-183.

Xu MJ, Plezia PM, Alberts DS, et al. Reduction in plasma or skin alpha-tocopherol concentration with long-term oral administration of beta-carotene in humans and mice. J Natl Cancer Inst 1992;84:1559-1565.