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lower in smokers than in nonsmokers (Nakazawa et al., 1983; Ortega et al., 1994; Piyathilake et al., 1994; Senti and Pilch, 1985; Subar et al., 1990; Witter et al., 1982), data suggest that low intake (Subar et al., 1990) rather than an increased requirement may account for the poorer folate status of smokers.

Folate-Drug Interactions

The effects of drug use on folate status reviewed in this section are limited to effects seen in drugs used in chronic drug therapy of nonneoplastic diseases that affect a large percentage of the population and to oral contraceptive drugs. No information is available on the effects of these drugs on homocysteine values.

Nonsteroidal Anti-inflammatory Drugs

When taken in very large therapeutic doses (e.g., 3,900 mg/day), nonsteroidal anti-inflammatory drugs, including aspirin, ibuprofen, and acetaminophen, may exert antifolate activity (Baggott et al., 1992; Eichner et al., 1979; Lawrence et al., 1984; Willard et al., 1992). However, routine use of low doses of these drugs has not been reported to impair folate status.

Anticonvulsants

Numerous studies have cited evidence of impaired folate status associated with chronic use of the anticonvulsants diphenylhydantoin (phenytoin and Dilantin®) and phenobarbital (Collins et al., 1988; Klipstein, 1964; Malpas et al., 1966; Reynolds et al., 1966). Diphenylhydantoin is known to inhibit the intestinal absorption of folate (Elsborg, 1974; Young and Ghadirian, 1989). Few studies, however, have controlled for potential differences in dietary folate intake between groups of anticonvulsant users and nonusers (Collins et al., 1988). Thus, definitive conclusions cannot be drawn relative to adverse effects of these drugs on folate status.

Methotrexate

Methotrexate is a folate antagonist that has been used frequently and successfully in the treatment of nonneoplastic diseases such as rheumatoid arthritis, psoriasis, asthma, primary biliary cirrhosis, and inflammatory bowel disease (Morgan and Baggott, 1995). Methotrexate has been especially effective in the treatment of rheumatoid



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