J Am Board Fam Pract: first published as 10.3122/jabfm.8.3.206 on 1 May 1995. Downloaded from Vi~amins As Therapy In The 1990s

Randall Swain, MD, and Barbara Kaplan, PharmD

Background: At one time were considered as essential nutrients needed only in very small amounts to prevent deficiency syndromes. Many vitamins and their derivatives, however, are currently being used in the mainstream of medicine as therapeutic modalities. Methods: A MEDLINE literature search for clinical reviews and original studies on the use of vitamins in medicine was conducted along with a search of the obtained papers' bibliographies. The primary years of search were 1990-1994. Research reports written before 1990 were used after cross-referencing from more recent articles. Results and Conclusions: Based on the literature review, several recommendations for the use of vitamins for treatment and prevention are presented. They include topical A derivatives () for the treatment of acne and age-related skin damage, oral vitamin Aderivatives for severe cystiC acne () and (), vitamin D3 for the treatment and prevention of osteoporosis in postmenopausal females, topical in pSOriasis patients, and for serum cholesterol reduction. appears to decrease the incidence of neural tube defects if given in the preconception phase of pregnancy. Finally, recent preliminary evidence suggests the possible benefit of antioxidants (vitamins C, E, and beta-) in the prevention of atherosclerosis and cancer. (J Am Board Fam Pract 1995; 8:206-16.)

Recently the lay press has emphasized vitamins as covered were 1990 to 1994. The key words em­ the panacea for the 1990s. In fact, physicians ployed were "vitamins," "antioxidants," "cancer often see results of the latest vitamin study first prevention," "skin diseases," and "hypercholes­ on the evening news before it appears in any jour­ terolemia." Research articles published before nal, and after critical review the reader might find 1990 were cited after cross-referencing from that particular study shows only a possible epi­ more recent articles. demiologic association. Vitamins are widely used by the American public. Annual sales of over-the­ Skin Conditions and Vitamin Therapy counter vitamin products are in excess of $3 bil­ Acne lion.1 "Wbat are the true medical indications for Although not a disabling condition, acne vulgaris http://www.jabfm.org/ using vitamins as therapy? Our purpose is to re­ is almost universal in the teenage population and view the current indications and uses of vitamins results in much social and psychological concern. as therapy for some select medical conditions, in­ Topical , or tretinoin (Retin-A), is a cluding acne, psoriasis, osteoporosis, and hyper­ derivative of that has been used for this cholesterolemia. We will also critically review re­ condition since its introduction in liquid form

cent studies on the antioxidants and assess their in 1971. Acne is thought to be caused by excess on 1 October 2021 by guest. Protected copyright. usefulness for clinical practice for the primary sebum production, keratinization disorders, and care physician. increases in the bacteria Propionibacterium acnes.2 Most other nonvitamin therapies only address Methods sebum production by utilizing drying agents A literature search was conducted using MED­ (alcohol, benzoyl peroxide) or focus on bacteria LINE to select clinical reviews and original stud­ control with antibiotics either topically (benzoyl ies on the use of vitamins in medicine. The years peroxide, erythromycin, clindamycin) or orally (erythromycin, tetracycline). Often patients im­

Submitted, revised, 21 December 1994. prove, but relapse is common. From the Department of Family Medicine and Sports Medi­ When a patient with acne is examined, the cine (RS), and the Department of Clinical Phannacy (BK), West physician looks at the face to see whether inflam­ Virginia University - Charleston Division. Address reprint re­ mation predominates. The back and chest are quests to Randall Swain, MD, Department of Family Medicine, West Virginia University - Charleston, 1201 Washington Street also examined for inflammation. Topical agents East, Suite 108, Charleston, WV 25301. . that are applied to the face are not effective once

206 JABFP May-June 1995 Vol. 8 No.3 systemic involvement occurs. If local inflamma­ cent of patients receiving isotretinoin: J Am Board Fam Pract: first published as 10.3122/jabfm.8.3.206 on 1 May 1995. Downloaded from tion exists, local antibiotics can be useful; if general (dry, blistering lips), dry eyes or nose, eye irrita­ inflammation exists, a systemic antibiotic is often tion, pruritus, epistaxis, mild alopecia, and some necessary. photosensitivity.4 Sometimes patients are unable Most cases of acne will benefit from topical to wear prescription contact lenses as a result of application of tretinoin. This agent works by nor­ these types of side effects. malizing the keratinization process of the pilose­ Other more rare side effects can include baceous unit and helps prevent obstruction of the pseudotumor cerebri, premature epiphyseal clo­ follicular unit. Therapy is begun with the 0.025 sure, and birth defects.s The teratogenicity of this percent formulation, and a small amount is ap­ drug has been well documented, and most physi­ plied to the face at bedtime. The beneficial effects cians will require documentation that absolute often take several weeks and initially can make the birth control is being practiced throughout the condition mildly worse as the old follicles are re­ treatment course. 6 Often in female patients the placed. Side effects are mild but include some physician will obtain serial pregnancy tests with stinging and reddening of the treated areas and the other required blood work. The risk of birth possible photosensitivity. Treatment can some­ defects is extreme; about 30 percent of women times require stronger formulations (0.05 per­ who become pregnant during treatment will have cent, 0.1 percent) or can occasionally be de­ abnormal fetal development. Defects are wide­ creased to three times a week. The regimen will spread and include craniofacial, cardiac, and cen­ vary with each patient. tral nervous system abnormalities. The manufac­ Although topical tretinoin cream is helpful for turer recommends that women of childbearing severe cystic acne, it might not be sufficient, even age practice contraception during treatment and for those treated concurrently with antibiotics. If for 1 month before and 1 month after treatment these more conservative approaches fail, use of with isotretinoin. In addition, many physicians systemic vitamin A derivatives has been effective. advise a pregnancy test 2 weeks before initiating The preparation being used widely now is isotret­ therapy. inoin (Accutane). The dosage is initially begun at 0.5 mg/kg to 1.0 mglkg divided into two doses. Sun-damaged and Aging Skin The maximum recommended dose is 2 mg/kg/d. 'Within the last several years much publicity re­ The tablets come in 10-mg, 20-mg, and 40-mg garding the positive effects of topical tretinoin on capsules. Usually, a 50 percent reduction in the sun- and age-related damage to the skin has been http://www.jabfm.org/ number of facial lesions is evident after 2 months, generated. Multiple, well-controlled studies have and the same reduction is seen in other parts of been performed on elderly patients and have the body at :3 months. Treatment course usually shown that topical tretinoin can reverse skin lasts 4 to 6 months and improves the condition by wrinkling, thickening, and sagging, reduce the an average of 85 percent. Beneficial effects often number of senile lentigines (brown spots),

last many months after discontinuation. If, and reduce numbers and sizes of actinic keratoses on 1 October 2021 by guest. Protected copyright. 2 months after discontinuing isotretinoin, further that are considered to be precancerous.7-9 Not treatment is needed, then a repeat course can be only is there subjective improvement, but patho­ considered. A recent 9-year follow-up study logic improvement has also been observed on skin showed that only 23 percent required retreatment biopsies, i.e., a decrease in the amount of type I with isotretinoin and that 61 percent of those collagen formation. 10 treated initially were still clear.3 Therapy is prescribed in a manner similar to Unfortunately, side effects are not uncommon, that for patients who use isotretinoin for acne; and close monitoring must be maintained for however, most physicians suggest that 3 times a those receiving isotretinoin therapy. Transient week dosing is optimal. Often elderly patients will abnormalities of liver function tests, lipids, and require only the 0.025 percent preparation. Side glucose can occur during therapy, and routine effects, as mentioned previously, include skin red­ testing is often performed monthly by physicians. ness and photosensitivity. A sunscreen is advised Much more common are the following mucocu­ during outside activities. Apparently a new reti­ taneous side effects, which occur in up to 90 per- noid, arotinoid methyl sulfone, is as effective as

Vitamins as Therapy 207 topical tretinoin but causes much less scaling and suIt from transferred ointment. Studies have been J Am Board Fam Pract: first published as 10.3122/jabfm.8.3.206 on 1 May 1995. Downloaded from local irritation. This product, however, is not cur­ conducted for up to 1 year with no other adverse rently available in the United Statesy,ll effects noted and no loss in potency.19 Unfortu­ nately, two case reports have noted serum hyper­ Psoriasis calcemia after large amounts of the ointment Psoriasis is a dermatologic disorder classified in were used in a short amount of time (4, 100-mg the group of papulosquamous diseases. It is a tubes in 10 days; and 2, 100-g tubes in 7 days).2o chronic condition causing large red plaques with As a result, a maximum of a 100-g tube per week considerable amounts of scale. The lesions usu­ has been recommended. Patients should be in­ ally appear on the scalp, elbows, knees, and the structed to apply a thin layer to the affected skin gluteal folds. Often the lesions are present in a twice daily and to rub it in gently and completely. linear fashion, called Koebner phenomenon, and In a double-blind, placebo-controlled study of nail pitting is present in most patients. The disor­ psoriasis patients using topical calcipotriene, pa­ der is a lifelong process with constant changes in tients had no change in calcium levels,21,22 so ab­ the numbers and sizes of skin lesions. The cause normal serum calcium metabolism should be a of psoriasis is poorly understood; however, 30 rare finding. In summary, topical calcipotriene percent of patients have a family history of the appears to be a rational first-line for mild to mod­ disease. Treatment in the past has included topical erate psoriasis. Primary care physicians should be tars, which are quite messy, topical anthralin, pso­ comfortable prescribing this agent, because it is ralens with ultraviolet light (so-called PUVA so nontoxic; however, base-line and periodic cal­ therapy), and methotrexate. Considerable utiliza­ cium determinations should probably be made, tion of potent topical corticosteroids has also especially with patients who have extensive areas been necessary in the past. 12 of involvement. Recently a topical derivative of vitamin D has For severe psoriasis researchers have sought al­ been approved by the Food and Drug Adminis­ ternatives to oral methotrexate and oral bursts of tration (FDA) for use in psoriasis patients (calci­ prednisone, because of the toxic side effects of potriene [DovonexJ, 0.005 percent ointment). Al­ these . Another derivative of vitamin though its mechanism of action is not well A, systemic etretinate, has been used with success understood, it probably involves the normaliza­ in pustular, erythrodermic, and plaque-type pso­ tion of cell proliferation.13 In double-blind, pla­ riasis as well as psoriatic arthropathies.23 The

cebo-controlled studies on patients with mild to problem with all of the systemic vitamin A com­ http://www.jabfm.org/ moderate psoriasis, topical calcipotriene, when pounds, however, is a narrow therapeutic index applied twice daily, was effective at clearing the and high potential for teratogenesis. Another plaques of psoriasis. 14-16 These improvements problem with etretinate is that the half-life in were detectable within 1 to 2 weeks, while maxi­ some can be as long as 120 days.24 The manufac­ mum effects were observed at 6 to 8 weeks. Up to turer recommends contraception for 2 years after 63 percent of the patients treated experienced use of this product. marked improvement. Isotretinoin (Accutane) has little effect on pso­ on 1 October 2021 by guest. Protected copyright. \Vhen compared with betamethasone valerate riasis unless used with combined with ointment (0.1 percent), a high-potency topical ultraviolet light (PUVA).2s Etretinate (Tegison) is corticosteroid, calcipotriene was shown to be often effective as monotherapy for pustular and slightly more effective, although both agents were erythrodermic psoriasis at a recommended start­ highlyefficacious.17,18 ing dose of 0.75 to 1 mg/kg/d in divided doses Side effects of topical calcipotriene are few. with a maximum of 1.5 mglkg/d. Erythrodermic The most common problem is skin irritation, psoriasis might respond to lower initial doses, which was observed in 5 to 10 percent of patients. e.g., 0.25 mg/kg/d. Attempts should be made to In most patients the local irritation resolved de­ lower the maintenance dose to 0.5 to 0.75 mglkg/d spite continued treatment.19 Facial regions are after 8 to 16 weeks of therapy. 23 Therapy is usually particularly prone to this irritation; therefore, discontinued when the patient's lesions have suffi­ treatment is not recommended for the face. Good ciently resolved. Etretinate can cause a transient hand-washing is also advised, as irritation can re- exacerbation of psoriasis during the initial period

208 JABFP May-June 1995 Vol. 8 No.3

..... of therapy. In addition, patients should be coun­ with treatment and the need for adjuvant thera­ J Am Board Fam Pract: first published as 10.3122/jabfm.8.3.206 on 1 May 1995. Downloaded from seled to administer this drug with food, which in­ pies. In rural areas, however, where health care creases the absorption. Often for plaque-type access is difficult, it would be appropriate to work psoriasis, monotherapy with etretinate is not suf­ with a specialist to administer care to a patient ficient. In his review,23 Fritsch states that only under this regime. slightly more than one-half of patients show a 75 percent response after 8 weeks of treatment. Osteoporosis and Vitamin D Often, combinations with topical corticosteroids, Since its role in the pathogenesis of rickets was tar, anthralin, ultraviolet light B (UVB), and elucidated, vitamin D has long been known to be PUVA are necessary. Methotrexate is not recom­ associated with aspects of bone health. The main mended in combination with etretinate because function of this vitamin in humans is the mainte­ of the combined risk of liver toxicity. After 3 to 4 nance of intra- and extra-cellular calcium levels. weeks, any psoriatic-associated joint symptoms Most humans are able to meet the daily require­ are often decreased. ments of vitamin D by being exposed to sunlight In contrast to used for the short-term for 5 to 10 minutes, 4 to 5 times per week. \\'hat treatment of acne (maximum of 6 months), one role vitamin D plays in those with osteoporosis is problem with the use of etretinate for psoriasis is unclear. It is known that active vitamin D metabo­ the chance of long-term toxicities. In a review on lites are found to be 30 percent lower in women the subject, Vahlquist26 stated that the three main with postmenopausal osteoporosis than in their at-risk organ systems are the liver, the musculo­ age-matched counterparts without osteo­ skeletal system, and the cardiovascular system. porosis.28 One hypothesis for how vitamin D The liver can be directly adversely affected by might help prevent bone calcium loss is that vita­ etretinate, and chronic hepatitis might result. min D derivatives increase absorption of calcium Risk factors for liver toxicity include previous tox­ in the small intestine. icity with vitamin A derivatives, liver disease, and Earlier trials using (1, 25-dihydroxy severe obesity. Monitoring liver function tests is vitamin D 3), an active metabolite of vitamin D, recommended as well as avoiding alcohol. have been inconsistent. Two out of nine studies29•3o Prompt discontinuation of the drug should occur showed a decrease in bone mass, and three other if the results of liver function tests are markedly studies revealed increased bone mass. 31 -33 The re­ abnormal (greater than three times the upper maining three studies done with calcitriol showed limits of normal). Musculoskeletal side effects no difference in bone mass or fracture rate.34-36 http://www.jabfm.org/ include myalgias, diffuse idiopathic skeletal Only the studies by Gallagher, et al.32 and Tilyard, hyperostosis, premature epiphyseal closure, and et alY showed any decrease in fracture rates; extraskeletal ossification. The exact incidences of however, Tilyard, et al,37 have appropriately recog­ these findings have not been established. Vahl­ nized that there were many differences between quist recommended minimizing dose and dura­ all these studies. They cite differences in enroll­

tion of therapy with etretinate, avoiding prescrib­ ment criteria, dosage of calcitriol, and efficacy cri­ on 1 October 2021 by guest. Protected copyright. ing the drug for children who have open teria. The main discrepancy appeared to have epiphyses, and monitoring the patient's skeletal been the small numbers in most studies, leading system with radiographic studies every 2 to to possible inaccuracies attributable to low statis­ 3 years. The major cardiac problems are pro­ tical power. Also, many of these researchers duced by the ability of the drug to decrease high­ looked at bone mass rather than fracture rate as density lipoprotein (HDL) cholesterol and to in­ an endpoint. It can be expected that most patients crease low-density lipoprotein (LDL) cholesterol, with postmenopausal osteoporosis will continue which might increase the patient's chance for pre- to lose bone mass under treatment, although per­ - mature cardiovascular diseaseP Monitoring peri­ haps at a slower rate. The more pertinent ques­ odic lipid levels is suggested. tion to study seems to be, is the fracture rate Because of the potential adverse effects, it ap­ affected? Conversely, in the Tilyard, et al. study37 pears that long-term treatment with etretinate is a large number of patients were enrolled, and a probably best left to dermatologists; they are pre­ protective effect of calcitriol on the rate of frac­ pared to handle the many complications associated ture was found.

Vitamins as Therapy 209 Data can be extrapolated from the two largest menopausal osteoporosis in those who are unable J Am Board Fam Pract: first published as 10.3122/jabfm.8.3.206 on 1 May 1995. Downloaded from studies because of their large size and superior re­ or unwilling to take estrogen replacement therapy. search methodology. In women who had mild to Comparison studies with hormonal therapy, eti­ moderate postmenopausal osteoporosis, Tilyard, dronate, and calcitonin are needed before wide­ et aI.37 showed a highly significant decrease in spread use is advocated. vertebral fracture rates after 2 years of therapy with 0.25 mg of calcitriol twice a day compared· Niacin and Hypercholesterolemia with a control group on 1 gld of calcium.37 Frac-' Niacin is an essential vitamin comprising two iso­ ture rate was reduced from 25 fractures per 100 mers - nicotinic acid and . It was patient-years in the control group compared with first reported to be an effective cholesterol-lower­ 9.3 in the treatment group in the second year. In ing agent in 1955 both in normal subjects39 and in the third year an even greater benefit was seen: those with high cholesterollevels.40 Several stud­ 31.5 fractures per 100 patient-years in the control ies have documented the reduction of mortality in group compared with 9.9 in the treatment group. atherosclerosis among users of niacin.41 -43 Niacin This study also showed that there were 11 non­ was recognized as a first-line therapy for hyper­ vertebral fractures in the vitamin D group and 22 lipidemia in 198844 and again in the most recent in the calcium group. A subsequent study with an recommendations in 1993.45 A considerable even larger population (1763) confirmed that an­ amount of attention has recently been given to other vitamin D3 derivative () plus HDL cholesterol and its beneficial effect on ath­ 1.2 gld of calcium seemed to decrease the risk of erosclerosis and heart disease. Of the currently hip fractures by 43 percent and other nonverte­ available cholesterol-lowering agents, niacin is bral fractures by 32 percent.38 It seems that vita­ the most effective drug at elevating the HDL lev­ min D3 treatment plus calcium in the postmeno­ els. It elevates HDL levels up to 37 percent pausal woman could be effective at decreasing higher than base-line levels46 compared with the fractures, but this combination needs to be com­ 10 percent elevation that gemfibrozil achieves.47 pared in studies with estrogen replacement plus Niacin is also effective in lowering triglyceride calcium. Vitamin D3 might be an effective alter­ levels from 35 to 55 percent and LD L levels by 20 native to those who are not candidates for estro­ to 35 percent. gen or those who will not use hormone replace­ Despite its efficacy and extremely low cost, ni­ ment because of the possibility of menstruation. acin has not been used as extensively as other,

One concern with the treatment with vitamin more expensive agents (e.g., hydroxymethylglu­ http://www.jabfm.org/ D3 metabolites is the risk of hypercalcemia. taryl-eoA reductase inhibitors, gemfibrozil), Tilyard, et al. 37, however, found no safety differ­ partly because the pharmaceutical industry has ences in their study between calcium-treated promoted other more profitable agents. Because groups and calcitriol-treated groups. Only 2 of nicotinic acid is available over the counter at very the 314 patients in the calcitriol group had to reasonable prices, minimal promotional activities drop out of the study because of persistent hyper­ are attempted. Another problem is the perceived on 1 October 2021 by guest. Protected copyright. calcemia. In the larger study by Chapuy, et a1. 38 difficulty with side effects. Side effects can include the treatment groups took vitamin D3 and cal­ cutaneous flushing, gastric irritation, nausea, pru­ cium. Only 1 patient of 1634 had mild elevations ritus, skin rash, and elevation of liver enzymes. of calcium levels. None had renal calculi. Never­ Additionally, niacin is not recommended for dia­ theless, serial calcium determinations seem to be betic patients or those who have gout, as it has a necessary when using this regimen. Also, some tendency to exacerbate these conditions by caus­ authors advocate monitoring urine calcium levels ing glucose intolerance or hyperuricemia. Never­ to keep the level less than 8.75 mmolld to help theless, several studies have shown niacin to be prevent nephrolithiasis, even though this adverse well tolerated by 73 to 83 percent of patients who event has not been clinically important in the were usually noncompliant.48,49 Nearly 100 per­ large studies. The most common side effects ap­ cent of patients experience cutaneous flushing 20 pear to be gastrointestinal. to 30 minutes after ingesting this . In summary, vitamin D3 derivatives seem to be This reaction can be circumvented by taking 5 a viable alternative in the prevention of post- grains of aspirin or 400 mg of ibuprofen 30 min-

210 JABFP May-June 1995 Vol. 8 No.3 of the problems with epidemiologic research and utes before taking the niacin, a prophylactic strat­ J Am Board Fam Pract: first published as 10.3122/jabfm.8.3.206 on 1 May 1995. Downloaded from egy that complicates the regimen. In his recent revealed the need for randomized, blinded, pla­ editorial recommending the increased usage of cebo-controlled trials to evaluate the potential of niacin for cholesterol reduction, Felicetta50 notes these agents. that most patients experience tachyphylaxis to the Interest in the cardioprotective effect of vita­ flushing after a few weeks. The more serious side min therapy began when studies showed that oxi­ effects are the elevation of liver enzymes and, oc­ dation of LDL might be the true proatherogenic casionally, frank hepatitis. These reactions are al­ step.55-57 Both a- () and most always associated with the sustained release ascorbate () have been reported to de­ form as opposed to the immediate release form. 51 crease the susceptibility ofLDL to oxidation.58-61 A recent study by McKenney, et al,52 confirmed Subsequent studies of LDL oxidation, however, this finding by showing that 52 percent of those failed to show any short-term benefit from com­ who received the sustained release niacin de­ bined antioxidant therapy compared with vitamin veloped hepatotoxicity compared with none of E alone.62-64 Two large, prospective, case-control those taking the immediate release product. studies were primarily responsible for bringing For these reasons a rational way to prescribe this issue to the public forum. Rimm, et al.65 ob­ niacin is to have the patient get over-the-counter served more than 39,000 male health profession­ immediate release niacin and start with small doses als for 4 years using dietary and health question­ three times daily with each meal (50 to 100 mg naires. Controlling for other cardiac risk factors, three times per day). Gradually increase each dose they found a relative risk for cardiac disease to be slowly and obtain serial cholesterol and liver func­ 0.63 in patients consuming more than 100 IV of tion tests 3 weeks after each major dosage change. vitamin E per day (recommended daily allowance Eventually, 1 to 3 g orally three times a day are nec­ [RDA] 30 IV/d) for at least 2 years compared with essary to obtain the desirable reductions in serum those not taking vitamin E supplementation. cholesterol. Patient education and premedication Beta-carotene was not associated with a decreased with 5 grains of aspirin or 400 mg of ibuprofen, if incidence of atherosclerosis in those who had necessary, will help avoid noncompliance result­ never smoked. In smokers, however, there was a ing from the facial flushing side effects. reduced relative risk of 0.30, and in previous smokers, 0.60. In this study vitamin C did not Vitamins and Prevention seem to reduce coronary disease in any groups.

Perhaps the most exciting possible uses of vitamins The authors concluded that vitamin E might be http://www.jabfm.org/ are in the area of disease prevention in normally effective in the reduction of heart disease risk. healthy individuals who get adequate nutrition. Previously, research showed that 10 to 100 times Two examples are folic acid to avoid neural tube the RDA of vitamin E is needed to increase resist­ defects in the pregnant population and antioxi­ ance of LD L to oxidation.59-64 Fortunately, this dant vitamins to prevent heart disease and cancer. level of intake seemed nontoxic during a moder­ Epidemiologic studies have shown that 0.4 mg/d ate follow-up period.64 The authors also con­ on 1 October 2021 by guest. Protected copyright. of folic acid in the periconceptional period leads cluded that vitamin C might not be effective, be­ to a 72 percent reduction in the risk of recurrent cause it acts as a free radical scavenger only in neural tube defects in live births.53 Recently another hydrophilic environments, as it is water soluble, case-control study by Werler, et al. 54 also revealed and the atherosclerotic areas are lipophilic. a 60 percent reduction in the risk of first-time Another study by Stampfer, et al.,67 observing neural tube defects. In fact, the VS Public Health 87,000 female nurses and using a prospective Service now recommends that all women of case-control design, showed a reduced relative child-bearing age receive 0.4 mg of folate per day. risk of heart disease (0.66) in patients with median The possibility of reducing two of the nation's daily vitamin E intakes of approximately 200 IU/d. largest killers, cancer and heart disease, is certainly Vitamin C and beta-carotene consumption were an exciting prospect. Recent media attention not actively studied. highlighting antioxidant vitamins (i.e., beta-caro­ The popularity of antioxidants recently de­ tene, vitamin C, and vitamin E) in reducing the creased when a randomized, double-blind, risk of heart disease and cancer has exposed some placebo-controlled primary-prevention trial on

Vitamins as Therapy 211 J Am Board Fam Pract: first published as 10.3122/jabfm.8.3.206 on 1 May 1995. Downloaded from more than 29,000 elderly Table 1. Cost Comparison Chart of Selected Vitamin Products. male smokers, during a 5- to 8-year period, failed to show Cost Per Cost Per Dosage Strength and ~ondI ~ondI any benefit in cancer preven­ Brand Name Generic Name Form (Brand) ($)t (Generic) ($):1= tion.68 Other previous epi­ Accutane* demiologic work had shown a Isotretinoin 20 mg, 40 mg, 326.14 N/A capsules 378.91 possible benefit in antioxi­ AquasolA* Vitamin A 10,000 IV, capsules dants in the prevention of 34.94§ 2.17 Aquasol E Vitamin E cancer, especially of the 100 IV, capsules 64.38 2.51 Delta-D Cholecalciferol lungs.69-73 The mechanism 400 IV, capsules 5.0011 3.00'11 (D,) for cancer reduction was hy­ Dovonex* pothesized to be due to anti­ Calcipotriene 0.005%, ointment 39.1 N/A oxidant effects and the pos­ 74.37# N/A Beta-carotene 25,000 IV, capsules sible control of cell growth N/A 4.02 Niacor* Niacin and differentiation. These au­ 500 mg, tablets 12.80 3.72 thors' observations can be Os-Cal Calcium carbonate 250 mg, 500 mg, 69.41 4.83 with D tablets 82.37** criticized because of several 5.13 Protegra Vitamin E, vitamin 200 IV vitamin E, 7.93 N/A factors. First, the focus of the C, beta-carotene, 250 mg vitamin C, study was lung cancer, and the zinc, copper, sele- 3.0 mg beta-carotene, microscopic changes that nium, manganese 7.5 mg zinc, 1.5 mg selenium, 1.5 mg begin this process could have manganese; tabletstt taken place before the rela­ Retin-A* Tretinoin 0.025% cream, 23.82 N/A tively short 5- to 8-year study 0.01% gel, 0.05% 45.24 period. Also, the dosage of liquid 19.20 vitamin E was relatively small 45.4 (50 IV/d) compared with pre­ 37.92** vious epidemiologic findings Rocaltrol* Calcitriol 0.25 j.lg, capsules 96.33 N/A that showed 100 IV or higher Tegison" Etretinate 10 mg, 25 mg, 53.91 N/A capsules to be effective. Thus, the po- 84.36§§ --tential benefits of antioxidant NIA - information not available vitamins might not be suffi­ "Prescription products, otherwise, listed products are over-the-counter or nonprescrip­ http://www.jabfm.org/ tion status. cient to offset the negative ef­ tCost for dIe brand name product was obtained by using dIe average wholesale price fects of cigarette smoking, the (AWP) for the corresponding strength from dIe 1993 Drug Topics Redbook74 for package dosage of vitamin E might sizes of 100 units. - teost for the generic product was obtained by averaging the AWP for three available not have been sufficient, or generic products for package sizes of 100 units, unless otherwise noted. the study period might not §Brand name price is the AWP for 30 mL of the SOOO-IV drops. liB rand name price is the AWP for 250 of the 400-IV capsules. have been sufficiently long. on 1 October 2021 by guest. Protected copyright. 'Generic price is the AWP for 90 of the 400-IV capsules. Second, vitamin C was not liB rand name price is the cash price for 30 mg and 60 mg of cream, respectively. studied in this trial. Finally, *-Brand name prices are the AWP for 60 of the 250 mg and 500 mg tablets, respectively. the authors stated that there ttprotegra tablet package size =50 tablets. HBrand name prices are th~ AWP for 20 mg and 45 mg of the cream and gel; liquid price was a very slight increase is the AWP for 28 mL (cc). in the rate of hemorrhagic §§Brand name prices are the AWP for 30 of the IO-mg and 25-mg capsules. stroke in those taking vitamin E (7.8 percent versus 5.2 per- cent). They did not state whether this finding spective clinical trials can be conducted. Patients was statistically significant. who are already taking antioxidant vitamins (such as Protegra, Lederle) are unlikely to experience Summary any major toxicity with this regimen. Large doses Antioxidant therapy is probably one of the most of beta-carotene can sometimes cause a yellowish exciting areas in medicine. Information given to discoloration of the skin. Patients can experience patients should remain conservative until pro- toxicities from some over-the-coun~er vitamin

212 JABFP May-June 1995 Vol. 8 No.3 J Am Board Fam Pract: first published as 10.3122/jabfm.8.3.206 on 1 May 1995. Downloaded from Table 2. Recommended Daily Allowances (RDAs) of Selected Vitamins; Deficiency Signs and Toxicities. *

Vitamin RDAt Deficiency Signs and Symptoms Signs of Toxicity

Hypervitaminosis A syndrome: fatigue, malaise, Fat soluble A 5000IU Night blindness. Bitot spots, photophobia, xero­ sis of cornea, corneal distortion, increased sus­ lethargy, abdominal upset, bone and joint pain, ceptibility to infection, follicular hyperkeratosis throbbing headaches, insomnia, restlessness, and drying, loss of appetite, impaired taste and night sweats, loss of body hair, brittle nails, smell, impaired equilibrium, increased cerebro­ rough and scaly skin, peripheral edema, chronic spinal fluid (CSF) pressure liver disease. Actual toxicity reported with doses of25,000 IU: single doses of greater than 660,000 IU have caused central nervous system symptoms (nausea, vomiting, vertigo, increased CSF pressure): larger doses could be fatal

D 400IU Reflected as calcium abnormalities, specifically Hypervitaminosis D: anorexia, nausea, weakness, those involved with bone formation; rickets weight loss, polyuria, constipation, vague acnes, manifested by soft bones and deformed joints; stiffness, soft tissue calcification, nephrocalcino­ osteomalacia sis, hypertension, anemia, hypercalcemia, acido­ sis, irreversible renal failure (1600-2000 IU)*

E 30IU Infants: edema, hemolytic anemia, reticulocyto­ Relatively nontoxic at doses of 100 to 1000IU sis, thrombocytosis. Adults: erythrocyte daily; hazards or long-term high-dose therapy hemolysis, deposition of ceroid (age) pigments, unknown; ?platelet dysfunction creatinuria, altered erythropoiesis, myopathy

Water soluble B12 Macrocytic anemia, glossitis, epithelial changes Excessive doses have not resulted in toxicity, nor along digestive tract, paresthesia, poor muscle has any benefit been reported from non deficient () coordination, mental confusion, agitation, optic patients taking large quantities ofB12 atrophy, hallucinations, and overt psychosis

B6 () 2mg Infants: convulsive disorders, irritability; adults: Severe sensory neuropathy and ataxia (1 g/d) pellagra-like , scaliness around nose, mouth and eyes, oral lesions, peripheral neurop­ athy, dulling mentation

Beta-carotene See vitamin A section Carotene does not produce toxicity rapidly due to its slow rate of conversion to vitamin A: eat­ ing large amounts of carrots may result in caro­ tenemia, which can produce a yellow skin hue

Folic acid Macrocytic anemia (see ) Usually none; occasional seizure observed with

intravenous doses greater than 15 mg http://www.jabfm.org/

Niacin 20mg 3 Ds (dermatitis, diarrhea, Gastrointestinal (Gl) symptoms (nausea, vomit­ dementia) ="pellagra," characteristic rash, neu­ ing, diarrhea), hepatotoxicity, skin lesions, ropathy, glossitis, stomatitis, proctitis tachycardia, hypertension, atopecia, flushing, hyperkeratotic pigmented skin lesions, pruritis, peptic ulcer, (doses greater than 1 gld can cause GI symptoms and flushing) C (ascorbic acid) 60mg Malaise, weakness, capillary hemorrhag~s and Increased oxalate excretion, which can produce petechiae, hyperkeratotic follicles, swollen hem­ nephrolithiasis, possible hemolysis in patients on 1 October 2021 by guest. Protected copyright. orrhagic gums, bone changes, impaired hearing; with glucose 6-phosphate dehydrogenase defi­ (scurvy) ciency, GI disturbances

*From Covington TR, et aI.75 tRDA represents the recommended daily allowance for the various vitamins for adults and children 4 years of age and older. *Dose at which toxicities have been observed. preparations, especially the fat-soluble vitamins A References and D; therefore, moderation of vitamin intake 1. Ehrlich FJ. Drugstores and nutrition: played right, a should be encouraged until further data on the winning combination. Drug Topics 1985 (Feb 4); beneficial effects of antioxidants are obtained. 129:28-31. A comparison of the costs ofvarious vitamins and 2. Lever L, Marks R. Current views on the aetiology, pathogenesis and treatment of acne vulgaris. Drugs their derivatives (Table 1) and the recommended 1990; 39:681-92. daily allowances and signs of toxicity of available vi­ 3. Layton AM, Knaggs H, Taylor JP, Cunliffe '\\J. Iso­ tamins (fable 2) are included for reference. tretinoin for acne vulgaris - 10 years later: a safe

Vitamins as Therapy 213 J Am Board Fam Pract: first published as 10.3122/jabfm.8.3.206 on 1 May 1995. Downloaded from and successful treatment. Br J Dermatol 1993; 17 -valerate ointment in patients with psoriasis vul- 129:292-6. garis.J Am Acad Dermatol26 (5 pt 1) 736-43. 4. McElwee NE, Schumacher MC, Johnson SC, Weir 19. Kragballe K, Gjertsen BT, De Hoop D, Karlsmark TW, Greene SL, Scotvold MJ. An observational T, van de KerkhofPC, Larko 0, et a1. Double-blind, study of isotretinoin recipients treated for acne in a right-left comparison of and betametha- health maintenance organization. Arch Dermatol sone valerate in the treatment of psoriasis vulgaris. 1991; 127:341-6. Lancet 1991; 337:193-6. 5. Winston MH, Shalita AR. Acne vulgaris. Patho- 20. Kragballe K. Treatment of psoriasis with calcipotriol genesis and treatment. Pediatr Clin North Am 1991; and other . J Am Acad Dermatol 38:889-903. 1992; 27:1001-8. 6. Mitchell AA. Teratogens and the dermatologist. 21. Dwyer C, Chapman RS. Calcipotriol and hypercal- New knowledge, responsibilities, and opportunities. cemia. Lancet 1991; 338:764-5. Arch Dermatol1991; 127:399-401. 22. Mortensen L, Kragballe K, Charles P, Amtssygehuf 7. Ellis CN, Weiss JS, Hamilton TA, Headington JT, A. Effect of calcipotriol on psoriasis: a double blind, Zelickson AS, Voorhees JJ. Sustained improvement placebo-controlled study of calcipotriol (MC 903) with prolonged topical tretinoin (retinoic acid) and calcium metabolism. In: Norman AW, Bouillon for photoaged skin. J Am Acad Dermatol 1990; R, Thomasset M, editors. Vitamin D: gene regula- 23(4 pt 1):629-37. tion, structure-function analysis and clinical applica- 8. Kligman AM. Guidelines for the use of topical tret- tion. Proceedings of the Eighth Workshop on Vita- inoin (Retin-A) for photoaged skin. J Am Acad Der- min D. Paris, France,July 5 to 10, 1991. New York: mato11989; 21(3 pt 2):650-4. Walter de Gruyter, 1991:443-4. 9. Misiewicz J, Sendagorta E, Golebiowska A, Lorenc 23. 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Postgrad Med 1992; 92:191-6,199- etretinate: possible mechanisms and consequences. 200. Br J Dermatol 1986; 114:401-7. 12. Roenigk HH. Review of the 5th International Pso- 28. Gallagher JC, Riggs BL, Eisman J, Hamstra A, Ar- http://www.jabfm.org/ riasis Symposium. Semin Dermatol1992; 11:313-6. naud SB, DeLuca HF. Intestinal calcium absorption 13. Weinstein GD, White GM. An approach to the and serum vitamin D metabolites in normal subjects treatment of moderate to severe psoriasis with rota- and osteoporotic patients. J Clin Invest 1979; tional therapy.J Am Acad Dermatol1993; 28:454-9. 64:729-36. 14. Kragballe K, Wildfang 11. Calcipotriol (MC 903), a 29. Christiansen C, Christensen MS, Rodbro P, Hagen novel vitamin D3 analogue stimulates terminal dif- C, Transbol I. Effect of 1,25-dihydroxyvitamin D3 in ferentiation and inhibits proliferation of cultured hu- itself or combined with hormone treatment in pre- on 1 October 2021 by guest. Protected copyright. man deratinocytes. Arch Dermatol Res 1990; venting postmenopausal osteoporosis. Eur J Clin In- 282:164-7. vest 1981; 11:305-9. 15. Kragballe K, Beck HI, Sogaard H. Improvement of 30. Jensen GF, Meinecke B, Boesen], Transbol I. Does psoriasis by a topical vitamin D3 analogue (MC 903) 1,25(OH)2D3 accelerate spinal bone loss? A con- in a double-blind study. Br J Dermatol 1988; trolled therapeutic trial in 70-year-old women. Clin 119:223-30. Orthop 1985; 192:215-21. 16. Kragballe K. Treatment of psoriasis by the topical 31. Caniggia A, Nuti R, Lore F, Vattimo A. The hormo- application of the novel cholecalciferol analogue nal form of vitamin D in the pathophysiology and calcipotriol (MC 903). Arch Dermatol 1989; therapy of postmenopausal osteoporosis. J Endo- 125:1647-52. crinol Invest 1984; 7:373-8. 17. Staberg B, Roed-PedersenJ, Menne T. Efficacy of 32. 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214 JABFP May-June 1995 Vol. 8 No.3 .. gg % J Am Board Fam Pract: first published as 10.3122/jabfm.8.3.206 on 1 May 1995. Downloaded from citriol. A randomized controlled study. Ann Intern tant but underutilized drug. Am] Med 1991; 91: Med 1990; 113:649-55. 239-46. 34. Aloia ]F, Vaswani A, Yeh K, Ellis K, Yasumura S, 49. Schectman G, Hiatt J, Hartz A. Evaluation of the Cohn SH. Calcitriol in the treatment of postmeno- effectiveness of lipid-lowering therapy (bile acid pausal osteoporosis. Am] Med 1988; 84(3 pt 1): sequestrants, niacin, psyllium, and lovastatin) for 401-8. treating hypercholesterolemia in veterans. Am] Car- 35. Falch]A, Oftebro H, Haug E. Early postmenopausal dio11993; 71:759-65. bone loss is not associated with a decrease in circulat- 50. FelicettaJY. Why aren't we using more niacin? Arch ing levels of 25-hydroxyvitamin D, 1,25-dihydroxy Fam Med 1994; 3:324-6. vitamin D, or vitamin D-binding protein.] Clin 51. Etchason]A, Miller TD, Squires RW, Allison TG, Endocrinol Metab 1987; 64:836-41. Gau GT, Marttila ]K, et al. Niacin-induced hepa- 36. Ott SM, Chesnut CH 3d. Calcitriol treatment is not titis: a potential side effect with low-dose time- effective in postmenopausal osteoporosis. Ann In- release nicotinic acid. Mayo Clinic Proc 1991; ternMed 1989; 110:267-74. 66:23-8. 37. Tilyard MW, Spears GF, Thompson], Dovey S. 52. McKenney]M, Proctor ]0, Harris S, Chinchili VM. Treatment of postmenopausal osteoporosis with cal- A comparison of the efficacy and toxic effects of sus- citriol or calcium. N EnglJ Med 1992; 326:357-62. tained vs immediate release niacin in hypercholes- 38. Chapuy MC, Arlot ME, Ouboef F, Brun J, Crouzet terolemic patients. JAMA 1994; 271 :672-7. B, Arnaud S, et al. Vitamin D3 and calcium to pre- 53. Prevention of neural tube defects: results of the vent fractures in elderly women. N EnglJ Med 1992; Medical Research Council Vitamin Study. MRC 327:1637-42. Vitamin Study Research Group. Lancet 1991; 39. Altschul R, Hoffer A, Stephen]D. Influence of nico- 338:131-7. tinic acid on serum cholesterol in man. Arch Bio- 54. Werler MM., Shapiro S, Mitchell M. Periconceptual chern Biophys 1955; 54(2):558-9. folic acid exposure and risk of occurrent neural tube 40. Parsons WB, Achor RW, Berge KG, McKenzie BF, defects.JAMA 1993; 269:1257-61. Barker NW. Changes in concentration of blood 55. Henriksen T, Mahoney EM, Steinberg D. Enhanced lipids following prolonged administration of large macrophage degradation of biologically modified low- doses of nicotinic acid to persons with hypercholes- density lipoprotein. Arteriosclerosis 1983; 3: 149-59. terolemia; preliminary observations. Mayo Clin Proc 56. Morel Ow, Hessler ]R, Chisolm GM. Low-density 1956; 31:377-90. lipoprotein cytotoxicity induced by free radical 41. Canner PL, Berge KG, Wenger NK, Stamler], peroxidation ofIipid.] Lipid Res 1983; 24:1070-6. Friedman L, Prineas R], et al. Fifteen year mortality 57. Quinn MT, Parthasarathy S, Fong LG, Steinberg D. in Coronary Drug Project patients, long-term ben- Oxidatively modified low density lipoproteins: a po- efitwith niacin.] Am Coil Cardiol1986; 8:1245-55. tential role in recruitment and retention of mono- LA, cyte macrophages during atherogenesis. Proc Nat! 42. Carlson Rosenhamer G. Reduction of mortality http://www.jabfm.org/ in the Stockholm Ischaemic Heart Disease Second- Acad Sci USA 1987; 84:2995-8. ary Prevention Study by combined treatment with 58. Witztum]L, Steinberg D. Role of oxidized low den- clofibrate and nicotinic acid. Acta Med Scand 1988; sity lipoprotein in atherogenesis.] Clin Invest 1991; 233:405-18. 88:1785-92. 43. Clofibrate and niacin in coronary heart disease. 59. Dieber-Rotheneder M, Puhl H, Waeg G, Striegl G, ]AMA 1975; 231:360-81. Esterbauer H. Effect of oral supplementation with 44. Report of the National Cholesterol Education Pro- D-alpha-tocopherol in the vitamin E content of

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216 JABFP May-June 1995 Vol. 8 No.3