Beneficial or Supportive Interaction, with Professional Management
	Potential or Theoretical Adverse Interaction of Uncertain Severity

Emerging

Effect and Mechanism of Action

Given a perception of aspirin and vitamin E as both acting as blood thinners (e.g., reducing platelet aggregations), an additive effect from coadministration of these substances has been proposed.

Research

The emerging body of human research into the potential interaction between vitamin E and aspirin has yet to reach the plateau of evolution and clarity necessary to understanding the apparent inconsistencies between clinical practice and the scientific literature. Steiner et al. ¹⁴ conducted a double-blind, randomized clinical trial investigating the antiaggregating agent containing vitamin E in 100 patients at risk for transient ischemic attacks (TIAs). Over 2 years, subjects were administered either aspirin (325 mg) or aspirin plus vitamin E (400 IU/day). Comparing two randomized subgroups from both sets of subjects, those receiving the combination medication demonstrated a significant reduction in ischemic events and platelet adhesiveness. There was no significant difference in the incidence of hemorrhagic stroke, although both individuals who developed it were taking vitamin E. The authors noted that the coadministration of vitamin E and aspirin appears to be safe and concluded that “combination of vitamin E and a platelet antiaggregating agent (e.g., aspirin) significantly enhances the efficacy of the preventive treatment regimen in patients with transient ischemic attacks and other ischemic cerebrovascular problems.” ¹⁴

In a double-blind clinical trial into the related issue of vitamin E's impact in patients undergoing chronic warfarin therapy, Kim and White ¹⁵ found that none of the subjects who received vitamin E had a significant change in the international normalized ratio (INR). Looking at the controversial topic of antioxidant use by smokers, Liede et al. ¹⁶ performed an endpoint examination of a random sample of 409 male smokers, age 55 to 74 years, who had participated in a larger, controlled, double-blind clinical trial. They reported a statistically significant increase in gingival bleeding among subjects taking the combination of acetylsalicylic acid (ASA) and alpha-tocopherol (50 mg/day) compared with those taking aspirin alone (33.4% vs. 25.8%); ASA alone increased bleeding only slightly. These authors concluded that alpha-tocopherol supplementation, particularly when combined with aspirin, might increase the risk of bleeding gums and other clinically important hemorrhage.

Subsequently, in an in vitro study, Celestini et al. ¹⁷ investigated the capacity of vitamin E to enhance the antiplatelet effect of aspirin by assessing the dose-response curves of platelet aggregation, dense body secretion, phospholipase C activation, and calcium mobilization in aspirin-treated platelets incubated with and without added vitamin E (50 and 100 mg daily). They also looked at the important issue of vitamin E's role in reducing platelet adhesion to collagen. These researchers demonstrated significant induction of maximal platelet aggregation and calcium mobilization compared with controls and concluded that vitamin E can potentiate the antiplatelet activity of aspirin by inhibiting the early events of platelet activation pathways induced by collagen.

The clear direction of this research, collectively, supports further research into the combined use of vitamin E, preferably naturally occurring tocopherols, together with aspirin, in the prevention of undesirable platelet aggregation, particularly thrombotic complications in atherosclerotic patients. ¹⁷

Nutritional Therapeutics, Clinical Concerns, and Adaptations

For decades, clinicians and patients have been exposed to research and subjected to debate on the potential benefits of both aspirin and vitamin E in the prevention of cardiovascular disease. ^18-24 Unfortunately, the certainty of the evidence and its penetration into common knowledge have been delayed and obscured by the often contradictory and hyperbolic nature of the claims and counterclaims. At the time of this review, the evolving body of evidence suggests that the probable additive effect from coadministration of aspirin and vitamin E could enhance valuable antiplatelet activity or produce undesirable effects on hemorrhagic tendencies, depending on characteristics of the patient population, respective dosage and forms employed, and coordination of attending health care providers. Given the high likelihood that conscientious patients could be using both vitamin E and aspirin as daily preventive measures, it would seem critical that the nature and implications of this potentially beneficial interaction be clarified and guidelines for integrative practice management be developed and implemented. Innovative approaches, similar to the “polypill” proposed by Wald and Law, ²⁵ incorporating tocopherols deserve further investigation as the clinical implications of vitamin E and antioxidants in relation to aspirin, statin therapy, and other conventional approaches reveal their nuances to well-designed clinical trials, especially if clinicians experienced in the dosage and forms of the nutrients involved are integrated into the research process. In particular, therapeutic use of both vitamin E and aspirin might benefit from a fresh view that expands beyond the long-held conception of their beneficial action deriving solely, or even primarily, from their effects on coagulability and opens into supportive and even nutritive effects. Through development of such integrative approaches to polypharmacy, especially toward preventive effects, clinicians of all therapeutic schools would do well to disown their historical prejudices for or against pharmaceuticals and natural products per se and focus instead on our shared avowed dedication to the health and well-being of those who entrust us with their care.

Pending further research, combined use of aspirin and vitamin E, particularly as d-alpha-tocopherol or other naturally-occurring forms, presents a potentially valuable asset in the emerging repertoire of pharmacological and behavioral tools for the prevention of excess coagulation and reduction of the incidence of hemorrhagic stroke, especially among individuals at increased at risk for TIAs. Nevertheless, there is a critical need to remain cognizant of the potentially dangerous increased tendency to bleed, which may represent a manifestation of vitamin E toxicity in some cases. Although individual needs must be assessed within the clinical context of each patient's genetic susceptibility, lifestyle risks, medical history, and other factors, 100 IU tocopherol, mixed or d-alpha, and 80 mg aspirin per day may provide a conservative starting point for such integrative care.

Prevention or Reduction of Drug Adverse Effect

Emerging

Effect and Mechanism of Action

Anthralin causes skin inflammation as a result of free-radical formation, through lipid peroxidation and production of inflammatory endoperoxides or by a more direct mechanism.

Research

In a clinical trial, Finnen et al. ²⁶ determined that topical application of the tocopherol form of vitamin E inhibited inflammation of forearm skin by scavenging free radicals of the oxygen species.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing anthralin as a topical antipsoriatic might reduce the risk of adverse effects by requesting that the pharmacist compound alpha-tocopherol into the preparation.

	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, Not Requiring Professional Management
	Adverse Drug Effect on Nutritional Therapeutics, Strategic Concern

Mixed

Effect and Mechanism of Action

Through their intended effect of limiting absorption and assimilation of dietary lipids, bile acid sequestrants may prevent absorption of vitamin E, as well as of folic acid and other fat-soluble vitamins (A, D, K, carotenoids, and coenzyme Q10). ^27-31

Research

Researchers have investigated both supportive and depleting interactions between vitamin E and bile acid sequestrants, especially colestipol. Hodis et al. ³² found that the combination of colestipol, vitamin E (100 IU/day) and niacin was associated with added benefits on progression of coronary atherosclerotic lesions, as demonstrated in serial coronary angiographic studies. Schwarz et al. ³³ observed that during 24 months of colestipol therapy plus diet, serum vitamin A and E concentrations did decrease in the five patients with good drug adherence, but deemed the resultant concentrations as within normal limits and hence insignificant. In monitoring plasma levels of fat-soluble vitamins, including vitamin E, and several other nutrients in young patients with familial hypercholesterolemia after 5 years of colestipol therapy, Schlierf et al. ³⁴ observed no adverse drug effects with respect to the previous parameters and noted that plasma levels of carotenoids and vitamin E were elevated in the patients according to elevated concentrations of lipoproteins. Tonstad et al. ³⁵ conducted a study of 37 boys and 29 girls age 10 to 16 years with familial hypercholesterolemia, first in an 8-week, double blind, placebo-controlled protocol, then in open treatment for 44 to 52 weeks. They found that levels of serum folate, vitamin E, and carotenoids were reduced in the colestipol group.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Although bile acid sequestrants inherently reduce absorption of fat-soluble nutrients such as vitamin E and alter their availability and functionality within the body, evidence is lacking as to whether and when this impingement on normal physiological processes results in clinically significant effects and deleterious outcomes. Depletion due to unintended effects on absorption of fat-soluble nutrients, including vitamin E, may not be adequate to adversely affect many segments of the population to a clinically significant degree, or at least one discernible using standard research methodology. Importantly, plasma levels of fat-soluble vitamins, especially vitamin E, are typically elevated along with the elevated concentrations of lipoproteins that are carriers of nutrients. Further, any such impact may be potentially problematic in susceptible individuals most at risk for deficiency patterns and increased risk of cardiovascular dysfunction and disease, especially through extended courses of treatment. If vitamin E is being taken as part of an explicit strategy to reduce oxidative stress, thereby possibly reducing risk of cardiovascular disease, and support healthy lipid metabolism, the potential interference from these agents needs to be considered in establishing dosage, timing, and form of any concomitant therapy using vitamin E. Water-soluble forms of d-alpha-tocopherol provides one readily available means of circumventing this potential adverse interference with normal assimilation of nutrients in individuals for whom vitamin E plays an essential role in clinical care strategy, whether for cardiovascular effects or other preventive or therapeutic effects. Otherwise, regular use of a high-potency multivitamin/mineral formulation will replace the nutrients depleted by the drug. Individuals taking vitamin E, or other nutritional supplements and some drugs, may reduce interference of absorption by cholestyramine, colestipol, or other bile acid sequestrants by allowing an interval of 1 hour before or 4 to 6 hours after the medication.

Including cisplatin ( cis-diaminedichloroplatinum, CDDP; Platinol, Platinol-AQ), cyclophosphamide (Cytoxan, Endoxana, Neosar, Procytox), docetaxel (Taxotere), doxorubicin (Adriamycin, Rubex), etoposide (Eposin, Etophos, VePesid, VP-16), fluorouracil (5-FU; Adrucil, Efudex, Efudix, Fluoroplex), gemcitabine (Gemzar), irinotecan (camptothecin-11, CPT-11; Campto, Camptosar), methotrexate (Folex, Maxtrex, Rheumatrex), mitomycin (Mutamycin), paclitaxel (Paxene, Taxol), vinblastine (AlkabanAQ, Velban, Velsar), vincristine (Leurocristine, Oncovin, VincasarPFS), vinorelbine (Navelbine).

	Potentially Harmful or Serious Adverse Interaction—Avoid
	Bimodal or Variable Interaction, with Professional Management
	Drug-Induced Adverse Effect on Nutrient Function, Coadministration Therapeutic, with Professional Management
	Drug-Induced Effect on Nutrient Function, Supplementation Contraindicated, Professional Management Appropriate
	Beneficial or Supportive Interaction, with Professional Management
	Drug-Induced Nutrient Depletion, Supplementation Contraindicated, Professional Management Appropriate

Mixed

Effect and Mechanism of Action

Oxygen radicals have increasingly come under investigation as highly toxic stressors contributing to the causes of many diseases, including many forms of cancer. Vitamins E, C, and A 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 that antioxidants might be contraindicated during chemotherapy because one way in which chemotherapeutic agents attack cancer cells is by causing oxidative damage. ^36,37

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 types of cancer. ^36,38-44 In a double-blind study, Wagdi et al. ⁴⁵ found that an antioxidant combination consisting of vitamin C, vitamin E, and NAC provided protection against heart damage induced by chemotherapy without reducing its effectiveness. NAC therapy may be useful therapy in advanced cervical cancers, especially squamous cell carcinomas. 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. After performing a comprehensive review of the relationship between chemotherapy and antioxidants, Weijl et al. ⁴⁶ rebuffed warnings that antioxidants need to be avoided during chemotherapy, but also determined that definitive evidence was lacking to support the use of antioxidants to provide relief from the adverse side effects of chemotherapy. Subsequently, however, conference reports (unpublished proceedings) by Salignik and Zeisel at a 1999 American Society of Cell Biology meeting suggest that vitamin A–deficient and vitamin E–deficient mice were less susceptible to brain tumor progression than non–vitamin-deficient control animals. Salignik et al. ⁴⁷ suggested suppression of free radicals by the antioxidant vitamins may suppress apoptosis (programmed cell death).

In a randomized, double-blind, placebo-controlled trial among 540 head and neck cancer patients treated with radiation therapy, Bairati et al. ⁴⁸ found that coadministration of alpha-tocopherol (400 IU/day) and beta-carotene (30 mg/day) administered during radiation therapy and for 3 years thereafter resulted in “less severe acute adverse effects during radiation therapy” (vs. placebo), with that reduction being “statistically significant…for adverse effects to the larynx…and overall at any site.” However, “quality of life was not improved” by the nutrient coadministration. Moreover, the “rate of local recurrence of the head and neck tumor tended to be higher in the supplement arm of the trial.” Notably, “beta-carotene was discontinued because of ethical concerns” during trial. The authors concluded that concomitant treatment “with high doses of alpha-tocopherol and beta-carotene during radiation therapy could reduce the severity of treatment adverse effects,” but they cautioned that their data suggest that “use of high doses of antioxidants as adjuvant therapy might compromise radiation treatment efficacy.” ⁴⁸

Kennedy et al. ⁴⁹ conducted a 6-month observational study of 103 children with acute lymphoblastic leukemia (ALL) being treated with chemotherapy. They reported that a large percentage of children undergoing ALL treatment have inadequate intakes of antioxidants and vitamin A, and that lower intakes of antioxidants are associated with increases in the adverse side effects of chemotherapy. In particular, greater vitamin E intake at 3 months was associated with a lower incidence of infections.

Birdsall et al. ⁵⁰ and Cancer Treatment Centers of America conducted an exploratory trial to investigate effect of concomitant naturopathic therapies on clinical tumor response to radiation for early-stage prostate cancer (tumor stages 1b through 2, N0,M0). External-beam radiation therapy of up to 72 Gy was given to 22 patients on a conventional 8-week treatment regimen, whereas the 13 patients in the naturopathic group received at least one antioxidant supplement, with the most frequent antioxidant naturopathic treatments including green tea extract, melatonin, and a high-potency multivitamin, vitamin C, or vitamin E. “All patients were monitored for at least 12 months (range 12-42) and no patient received concomitant hormonal therapy.” The investigators reported that in the patients “who did not receive naturopathic [antioxidant] treatments, the median pretreatment PSA level was 5.4 ng/mL, the median PSA nadir was 0.66 ng/mL, and the median time to PSA nadir was 16.0 months,” and in the “patients who did receive naturopathic treatments, the corresponding values were 5.8 ng/mL; 0.59 ng/mL; and 16.0 months.” One tumor treatment failure occurred in the nonnaturopathic group “based on PSA elevation >2 ng from nadir which occurred at 14 months,” but there were no treatment failures in the patients who received concomitant naturopathic regimens. The authors noted as “also significant that 9/9 patients in the non-CAM group were considered to be low risk (based on pretreatment PSA levels of 4-10 ng) whereas 3 patients in the CAM group were classified as intermediate risk (PSA >10-20 ng) and 1 patient as high risk (PSA >20 ng)” (PSA, prostate-specific antigen; CAM, complementary and alternative medicine). Thus, the authors concluded that “concomitant naturopathic treatment does not appear to inhibit the capacity of external beam radiation therapy to control localized prostate cancer, and does not interfere with either the magnitude of the response, the velocity of the response, or its durability for at least 1 year.” They added that these “results provide definitive evidence that antioxidant-based CAM modalities, designed to improve patient tolerance, quality of life, and possibly improve survival, do not inhibit tumor responses that depend on oxidative [tumor] killing mechanisms elicited by external beam radiation therapy.” ⁵⁰ Although encouraging, this small, retrospective study did not have sufficient power to draw any statistically significant conclusions. Similar studies involving much larger groups of patients receiving radiotherapy are warranted.

Clinical Implications and Adaptations

Some oncologists have raised reasonable concerns that supplementation with antioxidants might interfere with or limit the effectiveness of chemotherapeutic agents and radiation therapy. However, no substantial prospective, randomized, controlled clinical research has emerged to support this speculation or to warrant considering antioxidants as contraindicated during chemotherapy or radiotherapy, and emerging evidence indicates that effects of coadministration (particularly during radiotherapy) are more likely to be beneficial or negligible than harmful. ^50a Many nutritionally oriented health care professionals consider the oxidative damage caused by chemotherapy to be a particularly troublesome adverse 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 a nutritionally trained health care professional about the potential value of adding antioxidants to their regimen before starting such concomitant use. Well-designed clinical trials addressing this issue are sorelyneeded, but are moving into the necessary state of refinement. Such trials are particularly difficult to perform because the potential antioxidant contribution from diet, and its extreme variability among cancer patients during treatment, can seriously confound the effects of adjunctive antioxidant intake. For studies to be meaningful, diet needs to be standardized, which is logistically difficult. Studies that use a small number of antioxidants (i.e, fewer than four agents) concurrently with high oxidative stress inducers, such as chemotherapy and radiation, in patients consuming an antioxidant-poor diet, also are likely seeing the oxidant effects of the “antioxidant” compounds, because the antioxidant network necessary to recycle oxidized antioxidants is severely compromised.

Prevention or Reduction of Drug Adverse Effect

Emerging

Effect and Mechanism of Action

Acute reductions in plasma concentrations of essential nutrients, including alpha-tocopherol, have been associated with impaired immune responses in some clinical settings. In particular, oral mucositis, inflammation of mucous membranes, represents one of the most frequent complications during conventional cancer therapy using chemotherapy or radiotherapy. Topical vitamin E has been proposed as a preventive agent based on effects on inflammation and lipid peroxidation.

Research

In a randomized, double-blind, placebo-controlled study involving 18 patients, Wadleigh et al. ⁵¹ 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, whereas lesions did not resolve completely in eight of nine patients who received placebo. Lopez et al. ⁵² conducted further studies examining the efficacy of topical vitamin E for the treatment of this condition and found that although topical vitamin E applied once daily was beneficial to some subjects, others did not experience relief from their symptoms.

In 1998, Mills ⁵³ demonstrated the beneficial modifying effect of beta-carotene on oral mucositis caused by radiation and chemotherapy. Subsequently, in a preliminary study, topical application of honey also proved to be of benefit against radiation-induced mucositis. ⁵⁴ More recently, Ferreira et al. ⁵⁵ conducted a randomized, placebo-controlled clinical trial involving 54 patients receiving radiotherapy as the only treatment for cancers of the mouth and oropharynx. Subjects were administered an oil solution containing 400 IU vitamin E twice daily or a placebo (presumed to be nonactive) containing 500 mg evening primrose oil twice daily, before every conventional fraction of 2 Gy (200 rad) and again 8 to 12 hours later during the 5 to 7 weeks of radiotherapy. Participants were instructed to dissolve each capsule and hold the oil in their mouth for 5 minute before swallowing. At the conclusion of the study, the occurrence of painful mucositis events was significantly less (21.6% vs. 33.5%) among subjects who had received vitamin E than those receiving placebo. Likewise, pain and eating restrictions were significantly less in participants receiving vitamin E compared with the placebo group. These findings demonstrate that vitamin E can be useful in preventing and reducing the severity of mucositis in patients receiving radiotherapy for head and neck cancer. The equivalent survival statistics between the two groups would argue against any interference by vitamin E's antioxidant activity with efficacy of the radiotherapy.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

The research reviewed might be considered weak or unreliable because of its limited scale, but the collective conclusions indicate that topical vitamin E represents a potentially effective approach to the prevention of mouth sores typically associated with chemotherapy and radiation. The trend revealed in the extant research recommends that well-designed, placebo-controlled trials are warranted. In the meantime, conservative principles of care, with a preventive orientation and integrative repertoire, suggest that vitamin E may provide a safe and inexpensive remedy to a highly probable adverse effect. 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. Formulations combining vitamin E and selenomethionine might also be considered, especially as a radioprotective agent.

	Prevention or Reduction of Drug Adverse Effect
	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management
	Beneficial or Supportive Interaction, with Professional Management

Emerging

Effect and Mechanism of Action

Cisplatin is one of the most active antineoplastic agents for the treatment of various malignant tumors. However, platinum-based chemotherapy regimens are often associated with a wide range of adverse effects and often irreversible damage, including nephrotoxicity, peripheral neuropathy, ototoxicity, gastrointestinal dysfunction, and myelosuppression. In particular, cisplatin therapy reduces antioxidant levels in the blood at the same time that it increases levels of free radicals and lipid peroxidation. Peripheral neuropathy is a particularly common adverse effect, especially affecting the hands and feet. Dorsal root ganglia are key sites in cisplatin-induced neurotoxicity because these are the neural tissue with the highest degree of platinum accumulation ⁵⁶ ; these ganglia also are the most vulnerable neural structures in vitamin E deficiency neuropathies. ⁵⁷ Cisplatin neurotoxicity has been attributed to demyelinization of the sensitive axons of the peripheral nerve sheaths, gangliar cell loss of the dorsal root ganglion and neural body, and axonal degeneration of the posterior horns of the spinal cord, paralleling the neurotoxic damage induced by chronic alpha-tocopherol deficiency. ⁵⁸ Oxaliplatin is a novel, third-generation, platinum-based anticancer agent, recently approved and now widely used to treat colorectal cancer, and it appears to be even more neurotoxic than cisplatin. Vitamin E supplementation apparently enhances antioxidant activity and prevents or limits free-radical damage.

Research

The neuropathy induced by cisplatin is characterized by symptoms of peripheral sensory neuropathy, with ataxia and areflexia, similar to that observed in alpha-tocopherol deficiency syndromes. McCarron et al. ⁵⁹ observed that alpha-tocopherol deficiency determines a peripheral neuropathy and spinocerebellar ataxia caused by retrograde degeneration of the large-caliber axons in the peripheral nerves and degeneration of the posterior columns in the spinal cord.

Pathak et al. ⁶⁰ reported potentiation of the effect of paclitaxel and carboplatin on a human lung squamous carcinoma cell line after pretreatment with an antioxidant mixture containing vitamin C, vitamin E, and beta-carotene.

A team of Italian researchers investigating the issue of cisplatin-induced neurotoxicity and potential benefits of vitamin E administration published two important papers in 2003. An animal study, with accompanying in vitro research, demonstrated that alpha-tocopherol supplementation provided for decreased severity of adverse effects, particularly protection from drug-induced lipid peroxidation and toxic sequelae, without compromising therapeutic effect, thus contributing to enhanced survival. ⁵⁸ In their human trial, the team randomly assigned 27 individuals, age 28 to 74, with a wide range of cancers to receive cisplatin chemotherapy alone or cisplatin chemotherapy combined with alpha-tocopherol, 300 IU daily. Supplementation began 3 days before onset of cisplatin therapy and concluded after 3 months, with both objective and subjective assessments at the beginning, midpoint, and conclusion of the therapeutic trial. Subjects receiving both vitamin E and cisplatin reported significantly lower neurotoxicity scores at the conclusion of their treatment (2.1), compared with participants who been given cisplatin alone (4.7). Only 31% of the group receiving alpha-tocopherol developed nerve damage, whereas such adverse reactions occurred in more than 85% of those receiving cisplatin alone. The severity of nerve damage was significantly different, with only mild to moderate effects among the nutrient-supplemented group, whereas two members of the drug-only group experienced severe neuropathies. ⁶¹

In a randomized, open-label, controlled trial, Argyriou et al. ⁶² investigated the effects of oral vitamin E (600 mg/day) on chemotherapy-induced peripheral neuropathy in 40 patients who underwent six courses of cumulative cisplatin, paclitaxel, or a combination regimen. Treatment was administered during chemotherapy and for 3 months after treatment cessation. Thirty-one patients completed the study; 4 of 16 patients in the vitamin E group demonstrated neurotoxicity versus 11 of 15 patients in the control group. One vitamin E patient and three controls experienced mild neurotoxicity. Moderate toxicity occurred in three vitamin E patients and five controls. Three controls developed severe neurotoxicity. The researchers concluded that the “relative risk (RR) of developing neurotoxicity was significantly higher in the control group than in the treatment group, RR=0.34,” and recommended a large, randomized placebo-controlled trial. ⁶²

Nutritional Therapeutics, Clinical Concerns, and Adaptations

The evolution of research into the interaction of vitamin E and cisplatin is clearly heading in a promising direction. Although the studies thus far are limited in scale and inherently preliminary in nature, they indicate that vitamin E coadministration, preferably with naturally occurring tocopherol(s), not only can compensate for nutrient depletion pattern and mitigate adverse drug effects, but also can offer the potential for employing higher concentrations of cisplatin, thus improving the antitumor agent's therapeutic index. Research with oxaliplatin may also reveal similar potential for coadministration. Strategic integrative protocols, adapted to the particular characteristics and needs of the individual patient, offer expanded possibilities for enhanced care and improved outcomes within the context of collaborative care involving health care professionals trained and experienced in both conventional oncology and nutritional therapeutics.

	Beneficial or Supportive Interaction, with Professional Management
	Prevention or Reduction of Drug Adverse Effect
	Potential or Theoretical Adverse Interaction of Uncertain Severity

Emerging

Effect and Mechanism of Action

The use of cyclosporine as an immunosuppressive agent in the treatment of allograft patients presents with a significant incidence of adverse effects, particularly nephrotoxicity. The risk of such events is heightened because the drug is poorly bioavailable (∼30%). Some individuals are unable to achieve or maintain therapeutic cyclosporine blood levels. Further, the antioxidant activity of vitamin E may provide protective support against the reactive oxygen species (ROS) induced by the drug's action and the lipid peroxidation products suspected in its toxic effects within the kidneys. Concomitant administration of vitamin E during cyclosporine therapy may enhance bioavailability and decrease clearance and steady-state volume of distribution of the drug, as well as reduce adverse effects and cost. Such a supportive interaction could potentially allow for decreased dosage levels of the medication. Vitamins E and C have also been used as adjunctive therapy in transplant patients on the basis that they might slow progression of transplant-associated arteriosclerosis.

Research

In a small study published in 1996, Chang et al. ⁶³ investigated the effect of water-soluble vitamin E (d-alpha-tocopheryl polyethylene glycol 1000 succinate) on the oral pharmacokinetics of cyclosporine in 10 healthy volunteers. In those individuals who randomly received the vitamin E after two doses of cyclosporine (10 mg/kg orally), cyclosporine clearance and steady-state volume of distribution for the drug were significantly decreased, and an increased area under the curve (AUC) for cyclosporine was observed. In a human trial, using the same water-soluble vitamin E at 6.25 IU/kg twice daily, Pan et al. ⁶⁴ determined that cyclosporine blood levels during the early posttransplant period were significantly improved in 26 liver transplant patients (both adults and children) previously unable to achieve or maintain therapeutic levels. In contrast, in a different application of cyclosporine, a subsequent in vitro study using a P-glycoprotein–expressing human lung cancer cell line suggested that alpha-tocopherol could antagonize the multidrug-resistance–reversal activity of cyclosporine A and other chemosensitizing agents. ⁶⁵ Elsewhere, Parra Cid et al. ⁶⁶ reported that antioxidant nutrients, including vitamin E, protect against cyclosporine A nephrotoxicity.

In a recent retrospective study of data on 22 consecutive heart transplant patients, reduced trough levels of cyclosporine were observed in those who took twice-daily doses of 400 IU vitamin E and 500 mg vitamin C, as compared to other patients. These researchers found no other interactions between the antioxidants and cyclosporine, but cyclosporine trough levels decreased from 136 to 103 ng/mL in the first 2 weeks after antioxidants were administered. The average decrease in trough concentrations was 25% but in some patients was as high as 60%. The authors concluded: “We also don’t know what the mechanism of this interaction is, so that should be studied in a more detailed analysis.” ⁶⁷

On a practical level, many substances interact with cyclosporine, and because of its erratic pharmacokinetics, drug levels are routinely used to determine doses. With such monitoring, any undesirable interaction effects can be readily corrected. Cyclosporine is a classic CYP3A4 intestinal enzyme substrate; some physicians routinely administer cyclosporine with grapefruit juice (which contains a CYP3A4 enzyme inhibitor) to reduce drug costs, since a smaller dose of the drug will produce a higher blood level due to a reduction in the first-pass drug metabolism by intestinal CYP3A4 enzyme. Vitamin E, or the combination of vitamins E and C, may have various effects on cyclosporine pharmacokinetics, but more research is needed to establish this.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Individuals undergoing immunosuppressive therapy with cyclosporine may benefit from concomitant administration of vitamin E, and possibly other antioxidants such as vitamin C. Such adjunctive therapy may reduce adverse effects and enable lower drug dosage levels while maintaining therapeutic efficacy. Effective care of these patients will require active collaboration among physicians trained and experienced in both conventional pharmacology and nutritional therapeutics within an integrative therapeutic strategy. Given that vitamin E and allied nutrients might alter cyclosporine absorption and pharmacokinetics and that a wide range in individual responses has been reported, drug levels need to be checked regularly, perhaps more frequently than usual, starting at 2 weeks.

Prevention or Reduction of Drug Adverse Effect

Preliminary

Effect and Mechanism of Action

Dapsone is strongly oxidative in a way that damages the membranes of RBCs and can result in hemolysis.

Research

In several trials, individuals with leprosy or dermatitis herpetiformis taking dapsone were given 800 IU of vitamin E for periods ranging from 4 weeks to 3 months. Kelly et al. ⁶⁸ found that dl-alpha-tocopherol acetate, 800 mg/day for up to 3 months, did not substantially ameliorate the hemolytic effect of dapsone at 100 mg/day. In another study of patients with dermatitis herpetiformis, vitamin E therapy was followed by vitamin C therapy, and then combined therapy with vitamins E and C. This study concluded that the vitamin C had exerted no beneficial effect, but that oral administration of 800 units of vitamin E daily for 4 weeks confers partial protective effect against dapsone-induced hemolysis in patients with dermatitis herpetiformis. ⁶⁹ Subsequently, Lardo et al. ⁷⁰ studied patients with leprosy and concluded that oral vitamin E, 800 IU/day, conferred partial protective effect but did not correct the hemolysis parameters produced by dapsone treatment, 100 mg/day, except for methemoglobin levels, which were a more sensitive indicator of the oxidant damage.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Preliminary clinical evidence suggests that vitamin E may counter the adverse effects of dapsone but remains somewhat inconclusive. However, supplementation of 800 IU daily could provide many other potential benefits for such individuals beyond the antioxidant effect against dapsone-induced hemolysis indicated in these studies. Furthermore, clinicians are advised to consider recommending a strict gluten-free diet for certain patients. Dermatitis herpetiformis is often secondary to an unrecognized gluten sensitivity (celiac sprue); such an approach over time may make dapsone treatment unnecessary in these cases.

Prevention or Reduction of Drug Adverse Effect

Preliminary

Effect and Mechanism of Action

Doxorubicin is a highly effective antineoplastic agent, but cardiotoxicity, acute and chronic, is an adverse effect occurring in up to one third of the patients treated after a cumulative dose of 300 mg/m ² , and increasing sharply beyond a cumulative dose of 360 mg/m ² . Consequently, it is often used in less-than-optimal doses in an attempt to mitigate resultant irreversible and dose-dependent cardiomyopathy. As an antioxidant with a particular affinity for cardiac tissue, vitamin E has been investigated as a potential tool in mitigating such adverse effect and enabling treatment with higher dosage levels of doxorubicin. ⁷¹

The cardiotoxicity of anthracycline chemotherapy agents can be of rapid onset and persist for decades, often absent cardiac complaints. The cardiotoxicity is multifactorial and involves oxidative stress, in part mediated by an iron-catalyzed Fenton reaction; iron-chelating agents have been shown to decrease doxorubicin cardiac toxicity. Two conditions of cardiotoxicity have been recognized. The first is a dose-independent idiosyncratic phenomenon appearing immediately after anthracycline administration and is based on a pericarditis-myocarditis syndrome in patients without previous cardiac disease. The second condition is dose related and characterized by progressive decline of left ventricular systolic function, as assessed by the ejection fraction on nuclear medicine and echocardiographic studies, which may lead to congestive heart failure (CHF). Diastolic dysfunction may also lead to CHF, with or without concomitant compromise of left ventricular ejection fraction. On pathological examination, progressive anthracycline-related cardiac damage may include restrictive endomyocardial disease, characterized by fibrous thickening of the endomyocardium, and dilated cardiomyopathy, as a result of myocardial fibrosis and hypertrophy of surviving myocytes. Symptoms can appear many years after completion of chemotherapy, although sequential assessment of left ventricular systolic and diastolic function will show compromise long before symptomatic CHF ensues. Risk of anthracycline-induced CHF is increased by radiotherapy fields that involve all or part of the heart. ^72-74 In a longitudinal assessment of cardiac function in the 22 patients treated with anthracycline for osteogenic sarcoma or malignant fibrous histiocytoma, Brouwer et al. ⁷⁵ found systolic dysfunction in more than a quarter of the patients and diastolic dysfunction in almost half after two decades (median, 22 years). Moreover, cardiac dysfunction was progressive, as measured at 9, 14, and 22 years.

Hair loss is another adverse effect typically associated with doxorubicin.

Cardiac Toxicity for Anthracycline Class of Antineoplastic Agents

Cardiac toxicity is similar between equipotent doses of doxorubicin and daunorubicin, slightly lower for epirubicin, and only one-sixth that of doxorubicin for equipotent doses of mitoxantrone. Doxil and DaunoXome (liposomal doxorubicin and daunorubicin, respectively) have negligible cardiotoxicity, presumably because of negligible cardiac exposure to the active drug with the pharmacokinetics of the liposome-encapsulated preparation.

Research

Initial studies using rodents found that vitamin E exerted a protective effect against doxorubicin-induced cardiotoxicity. ^76,77 In 1979, Krivit ⁷⁸ proposed that alpha-tocopherol might ameliorate or prevent cardiac dysfunction without impairing the drug's antitumor effectiveness. Subsequently, a study by Legha et al. ⁷⁹ showed that use of the vitamin did not compromise the drug's antitumor activity but also failed to demonstrate substantial protection against doxorubicin-induced cardiac toxicity.

Wood ⁸⁰ reported the severity of hair loss typically associated with doxorubicin therapy might be ameliorated by administration of tocopherol at 1600 IU/day, a relatively high dosage. These findings were supported by a subsequent study using doxorubicin-treated rabbits that showed evidence of protection against doxorubicin-dependent inhibition of new hair growth after being fed a alpha-tocopherol–supplemented diet; ⁸¹ human trials have not been published confirming such potential efficacy.

Other investigations have focused on possible synergistic relationships between vitamin E and doxorubicin. In vitro research with human prostatic carcinoma cells by Ripoll et al. ⁸² found that vitamin E enhanced the medication's chemotherapeutic effects.

Review teams led by Weijl ⁴⁶ and Quiles ⁷¹ noted that antioxidant activity can protect against chemotherapy-induced cellular oxidative damage and suggested that the body of evidence indicates that vitamin E coadministration might enable tolerance of higher doxorubicin dose levels, but concluded that evidence from human trials of the nutrient's ability to attenuate the drug's cardiotoxicity remained inadequate.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Pending further positive research findings, no substantive evidence exists to support the use of alpha-tocopherol as a method of reducing cardiac toxicity caused by doxorubicin. In the meantime, clinicians seeking to integrate such nutritional support into their treatment protocols might consider ubiquinone (coenzyme Q10, L-taurine, L-caritine, fish oils, and/or ginkgo), for which there is more substantial evidence of cardiac protection from doxorubicin.

	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, Not Requiring Professional Management
	Drug-Induced Adverse Effect on Nutrient Function, Coadministration Therapeutic, with Professional Management

Mixed

Effect and Mechanism of Action

Gemfibrozil may reduce serum antioxidant levels (coenzyme Q10, alpha-tocopherol, gamma-tocopherol) in a manner paralleling changes in lipid levels, but through mechanisms as yet unclear. ⁸³

Research

The evidence provides an incomplete understanding of the interaction between gemfibrozil and vitamin E. In a randomized, placebo-controlled, crossover trial of 21 men with combined hyperlipidemia, 10 to 12 weeks of gemfibrozil therapy reduced alpha- and gamma-tocopherol serum levels to the levels comparable to those of normolipemic control subjects. ⁸³ Other researchers, also in 1998, reported an antioxidant activity attributable to gemfibrozil that resulted in significantly decreased LDL lipid peroxides and an increased LDL vitamin E/lipid peroxide ratio, with no observable effect on vitamin E status. ⁸⁴

Nutritional Therapeutics, Clinical Concerns, and Adaptations

The contradictory and incomplete evidence concerning the interaction(s) between gemfibrozil and vitamin E could be interpreted to suggest a depletion pattern. Clarification of this potential adverse interaction may require a larger study sample and a longer time. However, these seemingly contradictory findings may simply reflect individual pharmacogenomic variability and a normal physiological response to a reduction in serum cholesterol levels. Further, the context of the entire discussion is to some degree held in abeyance, pending further developments in the ongoing controversy regarding the respective roles of antihyperlipidemic drugs and antioxidants in promoting cardiovascular health and treating lipid disorders.

Beneficial or Supportive Interaction, with Professional Management

Effect and Mechanism of Action

Glyburide is a sulfonylurea drug used in the treatment of type 2 (non-insulin-dependent) diabetes mellitus (NIDDM) and as such is designed to lower blood glucose levels. The nutritive status and physiological status of vitamin E have often been considered factors of potentially major significance in dysglycemia and development of type 2 diabetes mellitus. This long-standing hypothesis has grown more complex and subtle with the increased knowledge of the interplay between glycemic control and oxidative stress in health and disease. Thus, in addition to normalization of lipid peroxidation, vitamin E might stimulate pancreatic insulin-producing function. Both actions could improve blood glucose control in many individuals with type 2 diabetes and alter the appropriate dose levels of hypoglycemic medications. Notably, oxidative damage plays a central role in many of the pathological changes associated with diabetes, particularly peripheral neuropathies and diabetic retinopathy.

Research

Paolisso et al. ^85,86 published two relevant papers in 1993. In a double-blind human trial with 10 healthy control subjects and 15 NIDDM subjects, they observed reduced oxidative stress and improved insulin action in response to 900 mg vitamin E per day for 4 months, compared to placebo. ⁸⁵ After a randomized clinical trial with 25 type 2 diabetic subjects, they concluded that d-alpha-tocopherol (900 mg/day) for 3 months “seems to produce a minimal but significant improvement in metabolic control but not insulin secretion in elderly type 2 diabetic patients.” ⁸⁶ Subsequently, Balabolkin et al. ^86a prescribed vitamin E in daily doses 600 and 1200 mg to 41 type 2 diabetic patients, who were then divided into four treatment groups: “(1) diets, (2) predian, (3) glyburide, and (4) sugar-reducing drugs and insulin”. The authors concluded that while receiving vitamin E, all groups demonstrated enhanced pancreatic insulin production and normalization of lipid peroxidation. ⁸⁵ Sharma et al. ⁸⁷ subsequently investigated the role of vitamin E in reducing levels of oxidative stress in diabetic patients, in the uncontrolled diabetic state or under good glycemic control. They found that maintenance of glycemic control only partially reduced oxidative stress and that oxidant injury continued despite optimal control of the diabetes. After administering supplemental vitamin E for 4 weeks, they reevaluated these patients and observed a further reduction in the oxidative stress, suggesting that vitamin E supplementation might be helpful in reducing free-radical–induced oxidant injury in diabetic patients. These collective findings could be interpreted as supporting the hypothesis that vitamin E may promote blood glucose stabilization and prevent the oxidative damage typically resulting from dysglycemia and likely contributing to the cascading sequelae common among diabetic individuals.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Enhanced vitamin E intake, through dietary or supplemental sources, may modulate blood glucose levels and reduce oxidative stress resulting from dysglycemic states. Individual genetic susceptibility, diet, lifestyle and contextual stress (or supportive) factors, and pharmacogenomic variability in response to nutrients and medications all significantly influence vitamin E status and the impact of vitamin E supplementation in diabetic individuals taking glyburide or other oral sulfonylurea hypoglycemic agents. Individuals taking any medication for blood glucose and insulin control need to be especially attentive with self-monitoring whenever any of these variables is altered. In particular, changes that enhance glycemic control increase the risk of an unforeseen hypoglycemic reaction.

	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management
	Prevention or Reduction of Drug Adverse Effect
	Drug-Induced Adverse Effect on Nutrient Function, Coadministration Therapeutic, with Professional Management

Mixed

Effect and Mechanism of Action

Haloperidol may deplete vitamin E levels and produce adverse effects similar to those of vitamin E deficiency and characteristic of conditions responsive to vitamin E therapy, particularly tardive dyskinesia. Treatment with conventional antipsychotic medications increases free-radical production and oxidative damage, which exerts neurotoxic effects and appears to contribute to the development of dyskinetic phenomena.

Research

Tardive dyskinesia is a common adverse effect of long-term therapy using haloperidol and related neuroleptic drugs and also occurs outside the context of drug reactions, for which some clinicians have found vitamin E to be an effective therapy. An animal study compared the effects of haloperidol on rats fed a normal or a vitamin E–deficient diet and found depleted vitamin E levels in the deprived group. ⁸⁸ In 1993, Gattaz et al. ⁸⁹ examined the issue of tardive dyskinesia as part of an investigation of vitamin E's ability to attenuate the development of haloperidol-induced dopaminergic hypersensitivity in rats. In a series of short-term, controlled trials, Adler et al. ^90,91 investigated the therapeutic efficacy of alpha-tocopherol in the treatment of tardive dyskinesia, with generally positive findings, culminating in the 1998 publication of a 36-week study involving 40 subjects who received d-alpha vitamin E (1600 IU/day) or placebo, which confirmed and extended the earlier results. ⁹² However, shortly thereafter the same research group published a larger, prospective, randomized, nine-site trial of up to 2 years that showed no significant advantage from a similar treatment protocol. ⁹³ A 1998 meta-analysis of studies focusing on vitamin E and tardive dyskinesia published since 1987 noted that the collective findings indicated that a significant subgroup (28.3%) of patients with neuroleptic-induced tardive dyskinesia who were treated with vitamin E showed a modest improvement, and that the supplementation was well tolerated, with only rare and clinically insignificant adverse effects. ⁹⁴

Nutritional Therapeutics, Clinical Concerns, and Adaptations

The role of increased oxidative damage in cases of tardive dyskinesia resulting from antipsychotic medications has become increasingly clear. However, as clinical studies have evolved, the weight of the evidence continues to shift away from exclusive use of tocopherol toward a greater appreciation of broader antioxidant approaches for prevention of neurotoxic effects and treatment of long-standing tardive dyskinesia. ⁹⁵ The increasing use of atypical antipsychotics as effective treatments may also reduce the prevalence and incidence of drug-induced tardive dyskinesia. The emerging tools of pharmacogenomic assessment offer the potential for prescribing medications more precisely suited to a given patient, and thus less likely to produce adverse effects, and for sorting potential antioxidant nutrients or combinations to prevent oxidative damage and ameliorate drug-induced neurotoxicity. Pending further clinical trials with modified supportive protocols and drug-nutrient combinations, physicians prescribing haloperidol can present coadministration of vitamin E, preferably as naturally occurring tocopherols and possibly within a broader antioxidant formulation, as a potentially beneficial means of moderating adverse drug effects, with no known risk of interfering with the haloperidol's therapeutic action.

	Potential or Theoretical Adverse Interaction of Uncertain Severity
	Drug-Induced Adverse Effect on Nutrient Function, Coadministration Therapeutic, with Professional Management
	Beneficial or Supportive Interaction, with Professional Management

Preliminary and Mixed

Effect and Mechanism of Action

Vitamin E has long been presented as preventing the oxidative damage to LDL cholesterol that is generally considered a major component of heart disease. Vitamin E appears to support the therapeutic action of 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase inhibitors (statins) and reduce their adverse effects, in the prevention and treatment of cardiovascular disease, particularly hyperlipidemia and atherosclerosis. In the critical area of endogenous antioxidant activity and inhibition of lipid peroxidation, statin drugs appear to exert an adverse impact on oxidative status, and statin therapy may enhance oxidizability of alpha-tocopherol and ubiquinol (coenzyme Q10). More recently, concerns have been raised that antioxidants, including vitamin E, may interfere with the HDL-elevating activity of statin-niacin combinations, even though statins alone generally lower HDL as well as LDL (with possible exception of atorvastatin). Vitamin E's specific role in such potential interference, including possible mechanisms of action, has not been presented in a precise and substantiated form. Nevertheless, simvastatin is metabolized by CYP3A4, ⁹⁶ an important observation given the hypothesis that alpha-tocopherol may stimulate drug metabolism, particularly through its effect on PXR. ⁹⁷

Concomitant intake of vitamin E and other antioxidants with conventional lipid-lowering agents may improve some lipid parameters, particularly LDL cholesterol and triglycerides. ⁹⁸

Research

Over the past decade, emerging trends in both pathophysiologic and therapeutic research have expanded beyond the earlier emphasis on cholesterol to a deepening appreciation of the fundamental role of inflammation in cardiovascular risk and outcomes, as well as other disease processes. ⁹⁹ Within this context, previous conceptions of both statin therapies and vitamin E, as an antioxidant and beyond, have yet to form a comprehensive model encompassing healthy function and prevention, therapeutics, and mechanisms of action.

The issue of cholesterol's contribution to heart disease, especially coronary artery disease (CAD), has often focused on the particular risks associated with oxidative damage to LDL cholesterol. Coronary endothelial function has been shown to improve under lipid-lowering and antioxidant therapy. Chen et al. ¹⁰⁰ conducted initial research into the antiatherosclerotic effects of vitamin E, through preservation of endogenous antioxidant activity and inhibition of lipid peroxidation, when used with lovastatin and amlodipine (a calcium channel blocker). Palomaki et al. ^101,102 showed that lovastatin treatment enhanced oxidizability of alpha-tocopherol and ubiquinol (coenzyme Q10). A subsequent randomized, double-masked, crossover clinical trial involving 28 men with coronary heart disease and hypercholesterolemia determined that alpha-tocopherol supplementation (450 IU daily) significantly increased the antioxidative capacity of LDL when measured ex vivo, which was partially abolished by concomitant lovastatin therapy. ¹⁰³ In a small study of seven patients with hypercholesterolemia, Neunteufl et al. ¹⁰⁴ found that coadministration of simvastatin (20 mg) and vitamin E (300 IU) improved markers of blood vessel elasticity, reduced total cholesterol and LDL cholesterol, and augmented alpha-tocopherol levels (normalized to LDL) more than simvastatin monotherapy.

Recent studies suggest that antioxidant nutrients, including vitamin E, may interfere with the therapeutic action of combination statin-niacin medications, which have become an innovative and increasingly respected form of statin therapy because of the synergistic interaction of the drug and vitamin. This combination has been shown to be effective in lowering LDL cholesterol and raising HDL cholesterol levels in high-risk individuals with hyperlipidemia, particularly in the context of personal history of cardiac events, malignant family history of heart disease, elevated inflammatory index markers (IIMs), or other high-risk factors. ^105,106 As part of the HDL Atherosclerosis Treatment Study (HATS), researchers investigated the respective and collective roles of statins, niacin, and antioxidants (vitamins E and C, beta-carotene, selenium) in cardiovascular protection in patients with CAD and low HDL cholesterol. Cheung et al. ¹⁰⁷ found that simvastatin-niacin substantially improved HDL parameters, but that these favorable responses were blunted by the antioxidants, especially with regard to Lp(A-I). In an accompanying paper, focusing on coronary atherosclerotic plaques and the occurrence of a first cardiovascular event, Brown et al. ¹⁰⁸ found that the niacin-simvastatin combination was significantly superior to placebo with regard to average stenosis progression, but in participants also receiving antioxidants, this benefit was reduced to 0.7%, a finding interpreted as possible interference by antioxidants. When surrogate markers of cholesterol absorption and synthesis were later measured in a subset of HATS participants, at 24 months (on treatment) and at 38 months (off treatment), treatment with simvastatin-niacin continued to be associated with favorable changes in cholesterol metabolism and stenosis. ¹⁰⁹ These findings were subsequently interpreted in many quarters as suggesting that adjuvant antioxidant administration was contraindicated in the treatment of hyperlipidemia and prevention of cardiovascular disease. ^110,111

A more critical analysis of the data suggests that the primary observed adverse interaction is between niacin and antioxidants, not statins and antioxidants. The HDL increases that occurred were probably attributable to the niacin therapy because low-dose simvastatin monotherapy has only limited effects in raising the levels of HDL cholesterol and apolipoprotein (apo) A-I. Thus, one or more of the antioxidants might be interfering with niacin's ability to alter the expression of proteins responsible for the formation of HDL. Further, the findings derived from the population studied may have limited general relevance to individuals who have only elevated LDL cholesterol levels (and normal HDL levels) and to women (who made up only 13% of the cohort). Also, with regard to HDL status, there was no detriment to the antioxidants alone (i.e., given to a group without simvastatin/niacin), and actually a slight benefit, which if involving thousands of patients as in the previous statin and thrombolytic trials, might have become a trend, or even statistically significant. Lastly, the composition of the antioxidant nutrient formulation used has been questioned. Given that niacin depletes the liver of methyl donors, thereby raising homocysteine levels and contributing significantly to the vitamin's hepatotoxicity, researchers might have obtained different results if they had included methyl donor–relevant nutrients with the antioxidants (e.g., folic acid, choline/betaine, and possibly coenzyme Q10, the synthesis of which is inhibited by statins). The principles of nutritional therapeutics also suggest that nutrient therapies might gain potency by looking beyond single-nutrient supplementation to multi-constituent formulations analogous to the antioxidant composition of fruits and vegetables, which involve complex mixtures of many antioxidant compounds rather than single entities.

Nevertheless, evidence from other quarters suggests that some forms of vitamin E may enhance clearance of statin drugs, as well as other hepatotoxic compounds. In particular, alpha-tocopherol can stimulate the activity of pregnane X receptor (PXR), which regulates a constellation of genes involved in detoxification of xenobiotics and upregulates phase I, II, and III enzymes, especially CYP3A. ⁹⁷ Given that simvastatin appears to be metabolized by CYP3A, ⁹⁶ a valid case might be made that alpha-tocopherol, although not gamma-tocopherol, ¹ may be facilitating liver clearance of the statin drug in a manner consistent with its protective function in xenobiotic detoxification. Significantly, especially when looking at integrative therapeutic options, fluvastatin and pravastatin are the two statins that are not metabolized by the cytochrome P450 3A4 system; they are also the two statins that have exhibited very low propensities to elicit myopathy when combined with other agents. ¹¹² Apart from the necessary continuing research to confirm and elaborate these emerging findings, there remain unanswered fundamental strategic concerns arising from the adverse effects of any therapeutic agent(s) that obstruct and potentially damage normal liver function.

A broadening of the approach to prevention and therapeutics of CAD is coinciding with a growing understanding that the action of statins on cholesterol is not their exclusive or even primary therapeutic mechanism. The emerging emphasis on the role of inflammation in the pathogenesis of cardiovascular disease may provide a clearer understanding of the respective roles of both vitamin E and statins, as well as opening the discussion into further considerations of the potential therapeutic roles of natural thrombolytic agents, such as nattokinase and urokinase, proteolytic enzymes, and natural anti-inflammatory agents such as green tea, omega-3 fatty acids, garlic, and curcumin. The broad incidence and life-threatening implications of CAD and other forms of cardiovascular disease make further research into these complex questions imperative and indicate that building refinement and personalization into study design might open pathways to more definite conclusions and effective interventions better than would premature declarations and prohibitions.

In a related piece of innovative research, Hecht and Harman ¹¹³ used electron-beam tomography to assess the relationship of aggressiveness of lipid-lowering treatment to changes in calcified plaque burden in patients with subclinical atherosclerosis. They found that calcified coronary plaque progression appears to be unaffected by the degree of lipid lowering achieved by statin therapy. This study suggests that simply focusing on lowering LDL cholesterol levels may not produce the clinical outcomes presumed by manipulation of isolated pathophysiological phenomenon, as least with regard to slowing progression of subclinical disease in asymptomatic patients. Subsequently, Arad et al. ⁹⁸ conducted a double-blind, placebo-controlled, randomized clinical trial investigating whether coadministration of conventional lipid-lowering therapy and antioxidants could retard the progression of coronary calcification and prevent atherosclerotic cardiovascular disease (ASCVD) events. They administered atorvastatin (20 mg daily), vitamin C (1 g daily), and vitamin E (alpha-tocopherol, 1000 U daily), versus matching placebos, to 1005 asymptomatic, apparently healthy men and women age 50 to 70 with coronary calcium scores at or above the 80th percentile for age and gender. Notably, all subjects received concomitant aspirin (81 mg daily). The authors halted the trial prematurely, after more than 4 years, because no statistically significant effect was observed on progression of coronary calcium score. They concluded that the combined treatment “induced substantial and sustained reductions in LDL cholesterol and triglycerides but failed to achieve conventional levels of statistical significance in the reduction of either all ASCVD events or CAD events, though statistically significant reduction of CAD events was found in analysis of the subgroup with a baseline calcium score of >400.” ⁹⁸ The lack of a group taking atorvastatin and aspirin with placebo antioxidant vitamins also makes the study uninterpretable in regard to the contribution, if any, of vitamins C and E.

Although these preliminary studies are important, the most definitive studies will be large, well-designed, randomized, double-blind trials of these therapies with clinical endpoints, such as cardiac events and survival, rather than the myriad of shorter-term surrogate endpoints, which have not been firmly established and universally accepted as “clinically relevant.” Such studies are expensive, however, and tend not to involve natural products, which carry no patent protection and therefore (presumably) cannot subsequently be marketed profitably enough to recoup the considerable clinical research costs. Such studies will of necessity be funded by public institutions, which have the public health as their foremost concern.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Given the unresolved state of current knowledge, the collective evidence warns against overstated conclusions and generic clinical guidelines. Coadministration of vitamin E may reduce adverse effects and enhance efficacy of simple statin therapy (i.e., without niacin). However, the introduction of niacin into antihyperlipidemic therapy complicates the issue. In addition, individual variations in liver function and lipid metabolism, as well as pharmacogenomic variability in clinical response to conventional interventions, further confound any generic statin drug protocol that fails to account for each patient's characteristics and needs and a willingness to modify periodically the course of treatment in a flexible manner based on regular monitoring and patient preferences.

Integrative Medicine Approaches to Lipid Management

In clinical practice, it may be reasonable to add nutraceuticals to the standard diet and exercise phase of lipid management, then add a statin if the lipid profile is not brought into what is currently considered an acceptable risk profile. Likewise, future clinical trials investigating hypercholesterolemia and cardiovascular health might incorporate and extend the principle of reflecting healthy dietary intake by including not only the previously mentioned nutrients but also magnesium, vitamin B ⁶ , copper, zinc, and chromium and liver-supporting agents such as silymarin, apha-lipoic acid, L-carnitine, and flavonoids. For example, the emergence of policosanol also offers a potential natural alternative to statin therapy in some patients; it has been shown, in some but not all studies, to reduce serum cholesterol levels with a more favorable adverse effect profile than the statins. Furthermore, genetic factors influence individual variations in cardiovascular risk factors, lipid metabolism, and pharmacogenomic response to conventional antihyperlipidemic drugs. Thus, Zambon et al. ¹¹⁴ showed that in middle-aged men with established CAD and dyslipidemia, the hepatic lipase (HL) gene −514 C→T polymorphism significantly predicts changes in coronary stenosis with lipid-lowering treatment that appear to involve an HL-associated effect on LDL metabolism. Subjects with the C:C genotype had the greatest decrease in HL activity and the most improvement in LDL density and HDL(2)-C with therapy, as well as the greatest angiographic improvement, compared with the other genotypes studied.

Beneficial or Supportive Interaction, Not Requiring Professional Management

Preliminary

Effect and Mechanism of Action

Mucosal damage in erosive esophagitis is mediated primarily by free radicals. The antioxidant properties of vitamin E can increase the mucosal resistance in gastroesophageal reflux.

Research

Mirmomen et al. ¹¹⁵ conducted a preliminary double-blind, placebo-controlled clinical trial involving 58 individuals with moderate to severe erosive esophagitis; 29 received omeprazole 20 mg every other day plus vitamin E 800 mg daily, and 29 received omeprazole 20 mg every other day along with a daily placebo. At entry, all patients had been cured of endoscopically confirmed esophagitis by antisecretory therapy. All patients underwent endoscopic control to assess relapse rates at 24 and 48 weeks, or when they presented with symptoms. At 24 weeks, 82.8% of patients in the vitamin E group were still in remission compared with only 58.6% in the placebo group. Later, at 48 weeks, 79.3% and 55.2%, respectively, were in remission. Further, 68.9% of patients in the vitamin E group were symptom free versus 48.2% in the placebo group. The authors concluded that the combination of low-dose omeprazole and vitamin E is more effective than omeprazole alone for maintenance of moderate to severe esophagitis. ¹¹⁵

Nutritional Therapeutics, Clinical Concerns, and Adaptations

The concomitant administration of omeprazole and vitamin E may provide an effective tool to physicians treating patients with recurrent esophagitis. In addition to expanding and extending proton pump inhibitor therapy by addressing underlying oxidative stress and inflammation and supporting restoration of healthy tissue and function, this integrative treatment option might also allow a lower dose of omeprazole. Further clinical trials involving a larger subject population are warranted.

	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, Not Requiring Professional Management
	Prevention or Reduction of Drug Adverse Effect
	Adverse Drug Effect on Nutritional Therapeutics, Strategic Concern

Emerging

Effect and Mechanism of Action

Orlistat inhibits gastric and pancreatic lipases in the lumen of the gastrointestinal (GI) tract to decrease systemic absorption of dietary fat, along with fat-soluble nutrients.

Research

Clinical trials and observational data indicate that orlistat may reduce absorption of vitamin E, and that in some individuals, this effect may be dramatic enough to result in deficiency symptoms. ^116-118 In one trial involving 12 healthy volunteers who were administered a single oral dose of 400 IU vitamin E, pharmacokinetic assessment revealed that orlistat significantly reduced the absorption of vitamin E (∼43% according to maximum concentration, and ∼60% according to area under concentration-time curve), but not that of vitamin A. In a clinical trial involving 17 obese African-American and Caucasian adolescents receiving orlistat, 120 mg three times daily, McDuffie et al. ¹¹⁹ observed several significant nutrient depletion patterns despite coadministration of a daily multivitamin supplement containing vitamin A (5000 IU), vitamin D (400 IU), vitamin E (300 IU), and vitamin K (25 μg). In particular, during 3 to 6 months of orlistat treatment, acute absorption of alpha-tocopherol was significantly reduced compared with baseline levels ( p<0.001), but serum levels of alpha-tocopherol did not change significantly.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

A vitamin E supplementation strategy is advised in the event vitamin deficiency occurs in patients undergoing orlistat therapy. ¹²⁰ More proactively, individuals taking orlistat for extended periods would benefit from prophylactic vitamin E supplementation, ^118,121 400 IU daily of naturally occurring tocopherols. Alternatively, employing a water-soluble form of the nutrient could bypass this interference, if nutritional treatment using vitamin E supplementation is part of a broader therapeutic strategy including orlistat.

	Minimal to Mild Adverse Interaction—Vigilance Necessary
	Biomodal or Variable Interaction, with Professional Management
	Beneficial or Supportive Interaction, with Professional Management

Mixed or Preliminary

Effect and Mechanism of Action

Vitamin E may indirectly enhance the anticoagulant effect of warfarin by altering production of vitamin K–dependent coagulation factors, specifically at the vitamin K–dependent step of carboxylation at the gamma position of precursor prothrombin (factor II), as well as the other three vitamin K–dependent coagulation cascade enzymes, thus potentiating the warfarin-induced functional vitamin K insufficiency. Although no mechanism for vitamin E's action in these situations had been known until 2004, reductions in fully gamma-carboxylated vitamin K–dependent coagulation factors (II, VII, IX, and X) have previously been observed in subjects taking supplemental vitamin E.

Research

Corrigan and Ulfers ¹²² administered vitamin E (100 or 400 IU/day) orally for 4 weeks to 12 individuals receiving warfarin. The subjects showed no significant change in the prothrombin time (PT), factor II coagulant activity, or factor II antigen (which measures the amount of prothrombin present, but not its activity). However, a significant reduction was observed compared with pretreatment ratios on using a ratio of factor II activity to factor II antigen, as measured by the immunoreactive protein technique, suggesting that vitamin E influences the final activation step (gamma carboxylation) of prothrombin production, which is mediated by vitamin K. Further research by Corrigan ¹²³ has supported the hypothesis that coagulation characteristics in normal individuals (i.e., those without vitamin K deficiency) are unaffected by vitamin E and that doses significantly higher than 400 IU/day are generally necessary to induce adverse effects in susceptible individuals.

In two independent, randomized clinical trials, Booth et al. ¹²⁴ investigated the effect of 12 weeks of supplementation with RRR-alpha-tocopherol (1000 IU/day) on vitamin K status, as represented by several biochemical indicators, in 38 men and women with rheumatoid arthritis (study A) and in 32 healthy men (study B), none of whom were taking oral anticoagulants. Plasma phylloquinone (vitamin K ¹ ) concentrations and the percentage of undercarboxylated osteocalcin (a marker of vitamin K insufficiency unrelated to coagulation proteins) did not change significantly in response to the vitamin E. However, the degree of mean PIVKA-II increased from 1.7 to 11.9 ng/mL in study A and from 1.8 to 5.3 ng/mL in study B after the 12 weeks of vitamin E supplementation, which represent highly significant increases. PIVKA-II is an abbreviation for the underactive form of prothrombin produced in the presence of either vitamin K deficiency due to dietary or endogenous production defects, or to the presence of a vitamin K antagonist such as Coumadin (warfarin). This significant increase in PIVKA-II, indicative of poor vitamin K status in adults not receiving oral anticoagulant therapy, strongly suggests that high doses of vitamin E may functionally antagonize vitamin K's activity in catalyzing gamma-carboxylation (activation) of at least factor II, and possibly also of factors VII, IX, and X. Insufficient levels of any one of these four vitamin K–dependent coagulation factors will prolong the PT/INR, although lowering of all four factors to a therapeutic level is necessary for full protection from inappropriate clot formation in the thrombophilic patient.

Reports

Cases of enhanced anticoagulant effect in response to high-dose vitamin E supplementation have been reported among patients taking oral anticoagulants. A single case report from 1974 led to a long-standing perception of risk from simultaneous use of warfarin and vitamin E and repeated warnings of contraindication. In this event, a vitamin K–deficient patient on warfarin therapy began to exhibit a range of adverse effects, including bleeding, ecchymoses, and prolonged PT, suggesting excessive anticoagulation within 2 months of beginning consumption of up to 1200 IU/day of vitamin E. Nevertheless, although decreased serum concentrations of blood-clotting factors were reported, warfarin serum concentrations were not altered, suggesting an enhancement of the warfarin effect on vitamin K–dependent coagulation factor synthesis. The patient's coagulation status normalized within 1 week of discontinuing the vitamin E supplementation. ¹²⁵ Subsequently, Kim and White ¹⁵ investigated the pharmacological effect of concomitant warfarin and vitamin E in a randomized, double-blind clinical trial with 21 subjects receiving chronic warfarin therapy and found no significant changes in warfarin activity or INR in those who received vitamin E at doses up to 1200 IU/day. Within the context of integrative clinical management, the patient in the case report likely could have continued the vitamin E and reduced the dose of warfarin until the PT was again in the therapeutic range.

Clinical Implications and Adaptations

For many years, warnings have been voiced regarding potential adverse effects from use of vitamin E supplementation by individuals undergoing warfarin therapy, but only recently is the evidence beginning to suggest a possible basis for such contraindications. Continued research is warranted to determine whether the effects of this nutrient interaction are beneficial or adverse in and of themselves, whether they might be reversed by concomitant supplementation with vitamin K, and how they might affect oral anticoagulant therapy. Nevertheless, prudence supports operating under the assumption that the intended effect of warfarin therapy to cause functional vitamin K insufficiency, as reflected by a therapeutically prolonged PT and INR, may be enhanced by vitamin E coadministration, at least in some individuals undergoing long-term anticoagulant therapy. Furthermore, certain individuals with pharmacogenomic variations in vitamin K and warfarin metabolism, particularly in the context of vitamin K deficiency, may experience differing degrees of alteration in coagulation status in response to vitamin E supplementation. High doses of vitamin E for sustained periods may also mildly inhibit platelet activation. In the event of clinically significant changes in anticoagulant effects from concomitant use of warfarin and vitamin E, such effects would most likely be delayed in onset and of moderate severity. Physicians prescribing anticoagulant therapy are advised to monitor INR levels more frequently in patients who are beginning or increasing the dosage levels of vitamin E therapy, especially if those doses exceed 1000 IU/day, as well as in patients who significantly reduce their intake of vitamin E after sustained periods of supplementation.

Amiodarone (Cordarone, Pacerone).

Research using human pulmonary artery endothelial cells, in vitro, suggests that alpha-tocopherol may reduce lung toxicity associated with amiodarone. ¹²⁶ Establishing efficacy of and clinical protocols for this potentially protective interaction warrants further research.

Benzamycin, benzoyl peroxide.

Benzoyl peroxide (BPO), one of the two components in Benzamycin (and also widely used in OTC acne preparations), is well known for promoting carcinogenesis in animals. An in vitro study, using a human keratinocyte cell line, found that human skin cells exposed to vitamin E were more resistant to cytotoxicity caused by BPO. ¹²⁷ A subsequent human trial determined that alpha-tocotrienol supplementation significantly counteracted BPO-induced lipid peroxidation, although it did not significantly mitigate drug-induced barrier perturbation in the stratum corneum and increased transepidermal water loss. ¹²⁸ Whether these medications cause similar adverse effects in humans, and whether any countervailing effect is exerted by vitamin E, have yet to be researched in controlled human trials. Physicians prescribing such agents might suggest to their patients that supplemental vitamin E could potentially provide a means of reducing adverse effects associated with BPO and minimizing risk of further complications.

Chloroquine, Chlorpromazine, Desipramine, and Propranolol.

Cationic amphiphilic drugs (CADs) represent a wide range of therapeutic classes of medications used in the treatment of arrhythmias, depression, and seizure disorders and are well known for adverse effects on lysosomal phospholipid (PL) storage. Scuntaro et al. ¹²⁹ conducted an in vitro study investigating the mechanisms of alpha-tocopherol action on drug kinetics and PL storage using a model of human cultured fibroblasts exposed to single and repetitive doses of desipramine and other CADs. They found that although alpha-tocopherol did not influence the initial, pH-dependent, rapid phase of drug uptake, it did inhibit, in a dose-dependent manner, the slow and cumulative phases of drug uptake and the accumulation of cellular phospholipids. The researchers hypothesized that this activity was caused by competition between alpha-tocopherol and CADs for PL complex formation and noted that the influence of alpha-tocopherol on drug uptake varies among different CADs. Although these findings suggest that alpha-tocopherol may counteract many adverse effects of CAD exposure on lysosomal PL storage and appear to restore normal membrane recycling, further research is necessary to determine if such benefits would be obtained in human subjects, and whether such activity would interfere with the effectiveness of the medications. Knowledge of the clinical implications of this apparent supportive interaction is too preliminary to suggest implementation in a clinical setting.

Clofibrate (Aromid-S).

The issue of an interaction between vitamin E and clofibrate has been raised in two primary forms. A small, randomized, double-blind clinical trial investigated the effect of tocopherol on serum cholesterol and triglycerides in hyperlipidemic patients treated with diet and clofibrate and found no significant effect. ¹³⁰ Others have voiced concern that clofibrate may impair absorption of vitamin E. ¹³¹ The severity of any resulting depletion, the frequency with which it occurs, and its clinical implications have yet to be determined in any conclusive form. However, because this is no longer a widely used lipid-lowering agent, further work in this area seems unlikely.

Cyclophosphamide (Cytoxan, Endoxana, Neosar, Procytox).

Oxidation in the liver is required for activation of cyclophosphamide. Vitamin E and other antioxidant nutrients could theoretically interfere with this process and reduce the agent's antitumor activity. However, separate animal studies have found that both vitamin A and vitamin C supplementation potentiated the antineoplastic activity of cyclophosphamide, particularly in the context of nutrient deficiency, without introducing any adverse effects. ^38,132 In another animal study, combined cyclophosphamide treatment and vitamin E administration increased level of key enzymes (LDH, SGPT, SGOT, acid phosphatase, alkaline phosphatase) and produced greater efficacy in the treatment of fibrosarcoma in rats. ¹³³ Furthermore, in a preliminary human trial, researchers reported increased survival among patients with small cell lung cancer (SCLC) whose treatment with cyclophosphamide and radiation was supplemented with a combination of beta-carotene, vitamin A, and vitamin E, compared with most published chemoradiation treatment regimens alone. ¹³⁴ Because the current standard of care for SCLC involves platinum and etoposide with concurrent radiation treatment, however, it is difficult to extrapolate from the cyclophosphamide/radiation/vitamin E study. No research, human or otherwise, has been published investigating the occurrence or clinical implications of such a potential interaction specifically involving vitamin E. Well-designed clinical trials are warranted to determine the beneficial or detrimental nature of this potential interaction and to develop clinical protocols to optimize outcomes based on such emergent understanding. As noted previously, well-designed randomized clinical trials of cancer treatment, with and without antioxidant supplements, that carefully standardize the antioxidant contribution of diet are sorely needed.

Recent findings indicate that d-alpha-tocopherol interacts with the pregnane X receptor (PXR) and increases its activity. ¹³⁵ PXR is a promiscuous nuclear receptor that is expressed in the liver and intestine and is activated by a broad array of endogenous and exogenous toxic compounds, especially lipophilic xenobiotics, including prescription drugs, herbs, pesticides, endocrine disruptors, and other environmental contaminants. On activation, PXR coordinately regulates a number of genes involved in drug clearance via the liver (cytochrome P450s) and intestine (P-glycoprotein) and thus upregulates phase I, II, and III enzymes. ¹³⁶ This activity can provide a protective effect, especially in relation to xenobiotic clearance, but it also strongly suggests a potential for drug interactions, particularly involving medications metabolized by the CYP3A phase I enzymes. No work documenting actual drug interactions of clinical significance has been published at this time. However, more than 50% of the most frequently used prescription medications are metabolized by members of the CYP3A group. ⁹⁷ Vitamin E acting as a PXR ligand could alter these PXR-mediated reactions. Unfortunately, the extent to which pharmacological doses of vitamin E modulate these pathways in vivo has not been determined. Although PXR regulation of hepatic alpha-tocopherol metabolism appears to be of central importance, other hepatic systems, such as P-glycoprotein (MDR2), participate in vitamin E trafficking and excretion. ¹ If patients are taking vitamin E when they start a drug, and this drug is titrated to either effect (e.g., blood pressure) or blood level (e.g., cyclosporine), it most likely would be of no consequence, as long as they continued to take vitamin E. Starting or stopping vitamin E supplementation, however, while stable on a medication metabolized by those enzymes, could potentially be problematic, especially outside the context of professional supervision. Further research into this metabolic activity and related pharmacovigilance are warranted.

Fenofibrate (Lofibra, Tricor, Triglide).

In one controlled human trial, researchers found that the combination of 1000 IU d-alpha-tocopherol and 2 g ascorbic acid and prior to ultraviolet (UV) exposure dramatically blocked UV phototoxic lysis of erythrocytes associated with fenofibrate. ¹³⁷ An animal study found that alpha-tocopherol content was decreased by 51% in the livers of fenofibrate-treated mice. ¹³⁸ In another animal study, Chaput et al. ¹³⁹ observed that coadministration of alpha-tocopherol and fenofibrate produced a synergistic effect in which fenofibrate's lag phase was prolonged and its lipoprotein oxidation parameters were improved. Pending further controlled human trials, these preliminary findings suggest that coadministration of vitamin E, preferably as naturally occurring mixed tocopherols, might provide potential support to individuals undergoing fenofibrate therapy with minimal risk.

Gentamicin (G-Mycin, Garamycin, Jenamicin).

Animal research indicates that alpha-tocopherol interferes with gentamicin-induced free-radical formation and suggests that this drug may be useful in preventing aminoglycoside oto-vestibulo-toxicity. ¹⁴⁰ Vitamin B ¹² may provide a complementary protective effect. ¹⁴¹ Familial susceptibility to aminoglycoside ototoxicity has been discussed in several studies ^142-144 and appears to be caused by the A1555G mutation in the mitochondrial DNA. ¹⁴⁵

Griseofulvin (Fulvicin, Grifulvin, Gris-PEG, Grisactin, Gristatin).

Research involving children and guinea pigs indicates that vitamin E coadministration can elevate blood levels of this antifungal medication and thus allow for reduced dosage levels of griseofulvin, well known for its adverse effects. ^146,147 It appears that elevated alpha-tocopherol levels can reduce activity of the cytochrome P450 system enzymes that metabolize griseofulvin, thereby slowing the rate of griseofulvin biotransformation, which in turn allows for significantly sustained elevation of blood and skin concentrations of the medication. Even though these findings are still at a preliminary stage, physicians prescribing griseofulvin may want to discuss the option of concomitant vitamin E, 100 IU daily, with their patients as a safe and potentially effective means of reducing griseofulvin dosage levels and attendant adverse effects, without compromising efficacy. Conversely, the unsupervised concomitant use of griseofulvin and vitamin E, at significant dosages, could potentially increase severity of the drug's adverse effects due to CYP450 inhibition and subsequent elevation of blood and skin levels.

HRT, estrogens: Chlorotrianisene (Tace); conjugated equine estrogens (Premarin); conjugated synthetic estrogens (Cenestin); dienestrol (Ortho Dienestrol); esterified estrogens (Estratab, Menest, Neo-Estrone); estradiol, topical/transdermal/ring (Alora Transdermal, Climara Transdermal, Estrace, Estradot, Estring FemPatch, Vivelle-Dot, Vivelle Transdermal); estradiol cypionate (Dep-Gynogen, Depo-Estradiol, Depogen, Dura-Estrin, Estra-D, Estro-Cyp, Estroject-LA, Estronol-LA); estradiol hemihydrate (Estreva, Vagifem); estradiol valerate (Delestrogen, Estra-L 40, Gynogen L.A. 20, Progynova, Valergen 20); estrone (Aquest, Estragyn 5, Estro-A, Estrone ‘5’, Kestrone-5); estropipate (Ogen, Ortho-Est); ethinyl estradiol (Estinyl, Gynodiol, Lynoral).

HRT, estrogen/progestin combinations: Conjugated equine estrogens and medroxyprogesterone (Premelle cycle 5, Prempro); conjugated equine estrogens and norgestrel (Prempak-C); estradiol and dydrogesterone (Femoston); estradiol and norethindrone, patch (CombiPatch); estradiol and norethindrone/norethisterone, oral (Activella, Climagest, Climesse, FemHRT, Trisequens); estradiol valerate and cyproterone acetate (Climens); estradiol valerate and norgestrel (Progyluton); estradiol and norgestimate (Ortho-Prefest).

Extrapolated, based on similar properties: HRT, estrogen/testosterone combinations: Esterified estrogens and methyltestosterone (Estratest, Estratest HS).

Over 6 months, Clemente et al. ¹⁴⁸ treated 15 postmenopausal women with climacteric symptoms using 50 μg/24 hours estradiol transdermally applied twice a week for 21 days and a daily dose of 10 mg oral medroxyprogesterone acetate, which was added for 12 days in each treatment cycle. Their preliminary findings suggest that HRT can preserve the content of alpha-tocopherol and beta-carotene in LDL particles and keep the LDL in a reduced antioxidant state. In a randomized study involving 66 postmenopausal women, Inal et al. ¹⁴⁹ found that concomitant administration of transdermal estradiol and vitamin E (600 mg/day, orally) improved LDL, HDL, and total cholesterol status, compared to pretreatment levels. However, within the Women's Angiographic Vitamin and Estrogen (WAVE) Trial, all-cause mortality increased in postmenopausal women, with at least one coronary stenosis at baseline coronary angiography, who were administered 400 IU vitamin E plus 500 mg vitamin C, both twice daily, eversus placebo. ¹⁵⁰ These apparently contradictory findings strongly suggest further research into hormone metabolism and variable responses to exogenous administration of estrogen compounds, particularly in the presence of nutritional supplementation.

Women appear to clear CYP3A substrates more efficiently than men ¹⁵¹ and may possess additional alternative vitamin E–metabolizing systems, perhaps under the regulation of estrogen. Estrogen is metabolized by CYP3A4 ¹⁵² (phase II), and some CYP3As may be regulated by estrogen. Alpha-tocopherol appears to induce the metabolic activity of PXR, a known regulator of steroid hormone and sterol homeostasis, ¹⁵³ and thereby upregulate CYP3A4, resulting in stimulation of drug metabolism. Consequently, estrogen and alpha-tocopherol may interact through nuclear receptors, particularly nuclear estrogen receptor (ER) and PXR. The clinical implications of these potential interactions remain unclear, particularly given the evolving evidence concerning HRT's effect on cardiovascular risk and the emerging state of knowledge regarding estrogen conjugation and related detoxification systems.

Animal-source insulin (Iletin); human analog insulin (Humanlog); human insulin (Humulin, Novolin, NovoRapid, Oralin).

Clinical experience and some human trials have suggested possible efficacy of vitamin E in improving glucose tolerance in individuals with diabetes. If such findings are confirmed by well-designed clinical trials, the central issue of an interaction between insulin and vitamin E must be the avoidance of hypoglycemic states. In such cases, clinical management within an integrative strategy characterized by collaboration among health care professionals experienced in conventional pharmacology and nutritional therapeutics becomes imperative. However, to further complicate the always-complex and individual issue of dysglycemia and physiological compensations, a trial by Skrha et al. ^153a reported that 3 months of vitamin E (600 mg daily) was associated with a deterioration in insulin action and fibrinolysis in obese type 2 diabetic patients. Such seemingly contradictory findings remind us that further research is necessary to establish a clear understanding of the complex interrelationships among insulin resistance, glucose regulation, oxidative stress, and obesity. Pending such discoveries, caution is warranted regarding self-prescribing of high doses of supplemental vitamin E by diabetic individuals; conservative practice would especially caution against rapid escalation of dosage levels among obese diabetic patients. As with any introduction of changes intended to alter metabolism significantly and affect a disease process, a moderate pace of change, close observation, and collaboration among health care professionals trained in both conventional pharmacology and nutritional therapeutics are central to safe and effective application of integrative therapeutics.

Isoniazid (isonicotinic acid hydrazide, INH; Laniazid, Nydrazid); combination drugs: isoniazid and rifampicin (Rifamate, Rimactane); isoniazid, pyrazinamide, and rifampicin (Rifater).

Isoniazid may interfere with the activity of vitamin E and many other nutrients. Pending further evidence from well-designed clinical trials looking at drug-induced nutrient depletion patterns and compensatory interventions, physicians prescribing isoniazid may want to present patients with the option of using a daily multivitamin/multimineral supplement.

Acitretin (Soriatane), bexarotene (Targretin), etretinate (Tegison), isotretinoin (13- cisretinoic acid; Accutane), tretinoin (all- transretinoic acid, ATRA; Atragen, Avita, Renova, Retin-A, Vesanoid, Vitinoin).

Several potent retinoids deplete vitamin E levels in the skin, which increases the skin toxicity (e.g., cheilosis, drying, The chapping) of these agents. The results of a phase I trial indicate that alpha-tocopherol substantially reduces the initial toxicity of high-dose 13- cisretinoic acid (isotretinoin) without compromising drug efficacy. ¹⁵⁴ A daily dose of 800 IU alpha-tocopherol has been suggested to reduce retinoid toxicity. ¹⁵⁵ In another direction of emerging integrative therapeutics, some clinicians and researchers have been investigating coadministration of 13- cisretinoic acid and alpha-tocopherol, often in conjunction with other agents, in the treatment of various cancers recalcitrant to conventional chemotherapy. Several other potent retinoids have also become standard treatments for certain malignancies, such as all- transretinoic acid (etretinate) in acute promyelocytic leukemia, acitretin, and bexarotene for cutaneous T-cell lymphoma (mycosis fungoides), although bexarotene does not have prominent skin toxicity, other than as a photosensitizer. Many clinicians have found that co-prescribing vitamin E (800-1000 IU daily) with these agents reduces their skin toxicity significantly. Large, randomized trials are needed to ensure that there is also no interference with therapeutic efficacy.

Lindane (Kwell Shampoo).

Lindane use is associated with a wide range of often significant adverse effects, including promotion of tumor formation. ¹⁵⁶ In particular, in vitro studies have found that vitamin E protects human leukocytes against toxic effects of lindane. ¹⁵⁷ At this time, evidence is lacking to confirm such protective effects from concomitant use of vitamin E during lindane therapy. However, given that the nutrient is generally considered nontoxic, supplementation at moderate levels during treatment might be judicious.

Mineral Oil (Agoral, Kondremul Plain, Liquid Parafin, Milkinol, Neo-Cultol, Petrogalar Plain).

Mineral oil, as a lipid solvent, may also absorb many substances and interfere with normal absorption of alpha-tocopherol and other nutrients. ¹⁵⁸ Some disagree, but most researchers have found that mineral oil interferes with the absorption of many nutrients, including beta-carotene, calcium, phosphorus, potassium, and vitamins A, D, K, and E. ^159,160 Chronic use of mineral oil may cause a deficiency of these nutrients, the clinical significance of which is as yet undetermined. Individuals taking mineral oil for any extended period may benefit from regular use of a multivitamin supplement that includes all the fat-soluble vitamins. Malabsorption of fat-soluble vitamins from ingestion of mineral oil can also be minimized by administering mineral oil on an empty stomach or consuming vitamin or mineral supplements at least 2 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 1 week.

Ethinyl estradiol and desogestrel (Desogen, Ortho-TriCyclen).

Ethinyl estradiol and ethynodiol (Demulen 1/35, Demulen 1/50, Nelulen 1/25, Nelulen 1/50, Zovia).

Ethinyl estradiol and levonorgestrel (Alesse, Levlen, Levlite, Levora 0.15/30, Nordette, Tri-Levlen, Triphasil, Trivora).

Ethinyl estradiol and norethindrone/norethisterone (Brevicon, Estrostep, Genora 1/35, GenCept 1/35, Jenest-28, Loestrin 1.5/30, Loestrin1/20, Modicon, Necon 1/25, Necon 10/11, Necon 0.5/30, Necon 1/50, Nelova 1/35, Nelova 10/11, Norinyl 1/35, Norlestin 1/50, Ortho Novum 1/35, Ortho Novum 10/11, Ortho Novum 7/7/7, Ovcon-35, Ovcon-50, Tri-Norinyl, Trinovum).

Ethinyl estradiol and norgestrel (Lo/Ovral, Ovral).

Mestranol and norethindrone (Genora 1/50, Nelova 1/50, Norethin 1/50, Ortho-Novum 1/50).

Related, internal application: Etonogestrel/ethinyl estradiol vaginal ring (Nuvaring).

Use of oral contraceptives (OCs) is associated with increased risk of thrombosis in women, at least in part because of their adverse effects on vitamins and enzymes involved in the oxidative defense system; this risk is known to be significantly elevated by smoking. ¹⁶¹ Susceptibility to lipid peroxidation is greater when antioxidant status is impaired, which may further increase the risk of thrombosis. ¹⁶² Supplementation with vitamin E may mitigate some of these adverse effects and elevated risks, although large clinical trials would be necessary to confirm this.

See also Hormone Replacement Therapy.

Paclitaxel (Paxene, Taxol).

Paclitaxel monotherapy is not generally associated with significant cardiotoxicity, but it can dramatically increase the cardiac toxicity of anthracyclines such as doxorubicin. In a double-blind pilot study involving 13 cancer patients receiving chemotherapy and 12 patients receiving radiotherapy, Japanese researchers found that an antioxidant regimen (vitamin E, vitamin C, and N-acetylcysteine) protected against chemotherapy-induced heart damage without interfering with the action of the primary therapies. ⁴⁵ Although these preliminary results suggest efficient cardioprotection by this nontoxic and inexpensive adjunctive supplementation, the study's small size precludes a definitive conclusion. Larger, well-designed clinical trials are warranted for confirmation.

Pentoxifylline (Pentoxil, Trental).

In a clinical trial of 43 patients, presenting with 50 symptomatic radiation-induced fibrosis (RIF) areas involving the skin and underlying tissues, were treated with a combination of pentoxifylline (800 mg/day) and tocopherol (1000 IU/day). Dramatic regression of chronic radiotherapy damage was demonstrated, with all assessable injuries exhibiting continuous clinical regression and functional improvement. ¹⁶³ Based on these preliminary findings of reversal of human chronic radiotherapy damage, and because no other treatment is presently available for RIF, the researchers concluded that coordinated use of these two agents in a supportive interaction should be considered a therapeutic measure. Further research with larger, well-designed trials is warranted to confirm these findings and develop therapeutic protocols.

Carbamazepine (Carbatrol, Tegretol), clonazepam (Klonopin), clorazepate (Tranxene), divalproex semisodium, divalproex sodium (Depakote), ethosuximide (Zarontin), ethotoin (Peganone), felbamate (Felbatol), fosphenytoin (Cerebyx, Mesantoin), levetiracetam (Keppra), mephenytoin, methsuximide (Celontin), oxcarbazepine (GP 47680, oxycarbamazepine; Trileptal), phenobarbital (Luminal, Phenobarbitone, Solfoton), phenytoin (Dilantin, Phenytek), piracetam (Nootropyl), primidone (Mysoline), sodium valproate (Depacon), topiramate (Topamax), trimethadione (Tridione), valproate semisodium, valproic acid (Depakene, Depakene Syrup), vigabatrin (Sabril), zonisamide (Zonegran).

Two studies conducted by a Japanese research team found lower serum vitamin E levels in individuals taking phenobarbital and phenytoin compared with those who received no anticonvulsant medications for seizures. In the first study, 10 patients undergoing anticonvulsant therapy who had demonstrated low vitamin E levels were then administered dl-alpha-tocopherol acetate, 100 mg/day; after 1 month, both their serum vitamin E levels and hemolysis tests returned to normal, having been abnormal before supplementation. ¹⁶⁴ These researchers recommended coadministration with vitamin E for some patients undergoing anticonvulsant therapy. These findings indicate that long-term use of anticonvulsants, particularly phenytoin and phenobarbital, can result in a deficiency of vitamin E, as well as of zinc, which may produce several problems, especially in children. ¹⁶⁵ The full clinical implications of this nutrient depletion pattern have yet to be investigated in a large trial, but physicians prescribing anticonvulsant therapy, especially for children, are advised to present the option of supplementing with 100 to 200 IU of vitamin E daily, preferably in a naturally occurring tocopherol form, as prophylaxis against deficiency and its sequelae.

Benazepril (Lotensin), captopril (Capoten), cilazapril (Inhibace), enalapril (Vasotec), fosinopril (Monopril), lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril (Aceon), quinapril (Accupril), ramipril (Altace), trandolapril (Mavik); combination drugs: benazepril and amlodipine (Lotrel); enalapril and felodipine (Lexxel); enalapril and hydrochlorothiazide (Vaseretic); lisinopril and hydrochlorothiazide (Prinzide, Zestoretic).

Long-term data from the Heart Outcomes Prevention Evaluation (HOPE) study might be interpreted to suggest a potential interaction between vitamin E and ramipril (and possibly other ACE inhibitors). ¹³ In high-risk individuals with diabetes or heart disease undergoing ramipril therapy, concomitant use of vitamin E appears to be associated with increased risk of heart failure. The observed pattern more likely is simply an effect of using large doses of a single antioxidant supplement in patients likely to have high oxidative stress, rather than a true interaction. Until more is known, concomitant use of ACE inhibitors and any single antioxidant nutrient preparation in high doses should be avoided.

Rifampicin (Rifadin, Rifadin IV); combination drugs: isoniazid and rifampicin (Rifamate, Rimactane); isoniazid, pyrazinamide, and rifampicin (Rifater).

In an in vitro experiment, both vitamin E and rifampicin activated PXR, an orphan nuclear receptor central to xenobiotic metabolism. Production of vitamin E metabolites increased when hepatocytes were incubated with rifampicin and vitamin E (all-racemic alpha-tocopherol). This observation suggests that a CYP3A-type cytochrome initiates tocopherol metabolism by omega oxidation. ¹⁶⁶ The clinical implications of this potential interaction are unknown at this time.

Risperidone (Risperdal).

In a case report of a 74-year-old woman being treated for schizoaffective disorder with risperidone, coadministration of vitamins E and B ⁶ was efficacious in reversing neuroleptic malignant syndrome (NMS), an adverse effect associated with the medication. ¹⁶⁷ Although encouraging, further research with well-designed clinical trials into the general effectiveness of adjunctive vitamins E and B ⁶ to treat (or prevent) NMS in individuals taking risperidone is necessary to confirm these observations and develop therapeutic recommendations.

Verapamil (Calan, Calan SR, Covera-HS, Isoptin, Isoptin SR, Verelan, Verelan PM); combination drug: trandolapril and verapamil (Tarka).

P-glycoprotein (P-gp) mediates resistance of cancer cells to chemotherapy agents that are, or are derived from, natural products. In an in vitro experiment, using a P-gp–expressing human small cell lung cancer line, the inclusion of alpha-tocopherol antagonized the multidrug-resistance (MDR)–modifying ability of verapamil, as well as other chemosensitizing agents, and prevented restoration of sensitivity to both doxorubicin and vinblastine. ⁶⁵ The clinical implications of such observations in humans are untested and unknown.

Zidovudine (azidothymidine, AZT, ZDV, zidothymidine; Retrovir); combination drugs: zidovudine and lamivudine (Combivir); abacavir, lamivudine, and zidovudine (Trizivir).

In vitro and animal studies indicate that coadministration of AZT and vitamin E (as d-alpha-tocopherol acid succinate) enhanced antiviral activity and therapeutic efficacy, compared with AZT alone. ¹⁶⁸ Further research found that this form of vitamin E increased erythroid colony-forming unit (CFU-E)–derived colonies and provided protection against AZT-induced toxicity to bone marrow at a level equivalent to recombinant human erythropoietin (rhEpo). ¹⁶⁹ The clinical significance of such findings has yet to be explored in human trials.

Vitamin E works synergistically with other antioxidant nutrients to “quench” free radicals, peroxides, and other potentially harmful substances. Antioxidants function best as a network to quench high levels of free radicals safely and effectively. Vitamin E can spare other antioxidants, and vice versa. When given singly, especially at higher dosage levels, antioxidant agents can induce variable antioxidant or pro-oxidant effects in different physiological settings.

Large doses of vitamin E in patients likely to be under oxidative stress (based on their pathology and lifestyle, e.g., smoking, alcohol, recreational drugs) who do not consume a diet rich in antioxidants may contribute to further oxidative stress. In general, individuals with established cardiovascular disease and diabetes represent populations particularly characterized by high oxidative stress. Consequently, long-term daily use of even 400 mg of d-alpha-tocopherol, outside the context of other antioxidant support, by such patients can carry a significant risk that they will produce tocopherol radicals in excess of their ability to quench them. A parallel phenomenon has also been reported with beta-carotene in smokers. This susceptibility applies to all antioxidants, with the possible exception of oligomeric proanthocyanadins (OPCs), and other complex mixtures of flavonoids, such as anthocyanins and anthocyanidin, which contain a variety of compounds with differing redox potentials, and thus have some intrinsic network characteristics. Vitamin E is particularly cardiotrophic and may therefore exert special stress on cardiac tissue. Ultimately, somewhere in the network, a compound is needed that can decompose harmlessly after accepting the electron that has been passed around. A single chemical entity, such as tocopherol or a carotenoid (especially synthetic), usually cannot perform this critical function adequately. Thus, antioxidants are best utilized in a form that maximizes their network effect and minimizes the risk of a paradoxical pro-oxidative effect. At least five antioxidant supplements should be combined, preferably more (e.g., tocopherol, coenzyme Q10, ascorbate, mixed carotenes, vitamin A, selenium, flavonoids). Foods with high ORAC (oxygen radical–absorbing capacity) should always be encouraged in the diet as well.

Chitosan, a supplement proposed to promote weight loss, decreases dietary absorption of fats and therefore also of vitamin E and other fat-soluble nutrients, as shown in an animal model. ¹⁷⁰ The clinical significance of this probable pharmacokinetic interaction has yet to be investigated in clinical trials. However, separating intake of therapeutic nutrients such as vitamin E by at least 2 hours before or 4 hours after taking chitosan can avert nutrient depletion in susceptible individuals undergoing long-term use of this nutraceutical.

Vitamin E can counteract the pro-oxidant activity of iron by, for example, attenuating oxidative stress induced by intravenous iron in patients on hemodialysis. ¹⁷¹ Nevertheless, the mineral can bind and inactivate vitamin E. Vitamin E can also decrease the hematological response to iron salts to a degree that may be clinically significant, particularly in anemic children. ¹⁷² Monitoring is warranted.

High dietary intake of polyunsaturated fatty acids (PUFAs) can induce decreased vitamin E levels. ¹⁷³ Such long-term dietary patterns require increased vitamin E intake, possibly through supplementation.

Selenium potentiates the antioxidant activity of vitamin E. Selenium and vitamin E act synergistically and are more effective when taken together. Among other activities, glutathione peroxidase, the enzyme that recycles oxidized glutathione to its reduced (active) form, is selenium dependent.

High levels of vitamin E intake may interfere with the absorption of vitamin A.

Vitamin C facilitates regeneration of vitamin E and restoration of its antioxidant activity, an example of how an antioxidant network functions. Zandi et al. ¹⁷⁴ examined data from the Cache County Study, a large, population-based investigation of the prevalence and incidence of Alzheimer's disease and other dementias. They determined that regular use of vitamin E in nutritional supplement doses, especially in combination with vitamin C, may protect the aging brain against pathological changes associated with Alzheimer's disease and reduce the risk of developing the condition. Further study with randomized prevention trials is needed before drawing firm conclusions about the protective effects of such coordinated antioxidant supplementation. If effective, the use of these (and possibly other) antioxidant nutrients may play an important role in a safe and inexpensive strategy for the prevention of Alzheimer's disease.

Bruno et al. ¹⁷⁵ have conducted extensive research into the relationship between vitamin C and alpha-tocopherol, with a focus on the conditions of high oxidative stress found in smokers. First, they found that vitamin E “disappearance is accelerated in cigarette smokers due to their increased oxidative stress and is inversely correlated with plasma vitamin C concentrations.” Then, in a double-blind, placebo-controlled, randomized crossover trial, Bruno et al. ¹⁷⁶ demonstrated that ascorbic acid (500 mg twice daily for weeks) doubled “plasma ascorbic acid concentrations in both groups and attenuated smokers’, but not nonsmokers’, plasma alpha- and gamma-tocopherol…fractional disappearance rates by 25% and 45%, respectively. Likewise, smokers’ plasma deuterium-labeled alpha- and gamma-tocopherol concentrations were significantly higher…at 72 h during ascorbic acid supplementation compared with placebo.” Based on these findings, they concluded that “cigarette smoking increased plasma alpha- and gamma-tocopherol fractional disappearance rates, suggesting that the oxidative stress from smoking oxidizes tocopherols and that plasma ascorbic acid reduces alpha- and gamma-tocopheroxyl radicals to nonoxidized forms, thereby decreasing vitamin E disappearance in humans.” ¹⁷⁶ Therefore, these investigators confirmed faster plasma vitamin E disappearance in smokers and its normalization with vitamin C administration.

Vitamin E in high doses may interfere with the absorption and utilization of vitamin K and induce vitamin K deficiency. ¹²⁴ This potential pattern might be playing a role in cases in which enhanced anticoagulant effect has been reported among patients taking oral anticoagulants following high-dose vitamin E administration. Vitamin E, at levels greater than 1000 IU per day, may alter the activity of vitamin K–dependent clotting factor production and thus coagulation status, possibly increasing the risk of an excessive hypoprothrombinemic response in some individuals on warfarin therapy. (See Warfarin for further discussion.)