Folic Acid

References

[No authors listed] Sulfasalazine inhibits folate absorption. Nutr Rev. 1988 Sep;46(9):320-323.

Alarcon GS, Morgan SL. Guidelines for folate supplementation in rheumatoid arthritis patients treated with methotrexate: comment on the guidelines for monitoring drug therapy. Arthritis Rheum 1997 Feb;40(2):391; discussion 391-392. (Letter)

Alter HJ, Zvaifler MJ, Ruth CE. Interrelationship of rheumatoid arthritis, folic acid and aspirin. Blood 1971 Oct;38(4):405-416.

Back DJ, Orme ML. Pharmacokinetic drug interactions with oral contraceptives. Clin Pharmacokinet 1990 Jun;18(6):472-484.
Oral contraceptive steroids are used by an estimated 60 to 70 million women world-wide. Over the past 20 years there have been both case reports and clinical studies on the topic of drug interactions with these agents. Some of the interactions are of definite therapeutic relevance, whereas others can be discounted as being of no clinical significance. Pharmacological interactions between oral contraceptive steroids and other compounds may be of 2 kinds: (a) drugs may impair the efficacy of oral contraceptive steroids, leading to breakthrough bleeding and pregnancy (in a few cases, the activity of the contraceptive is enhanced); (b) oral contraceptive steroids may interfere with the metabolism of other drugs. A number of anticonvulsants (phenobarbital, phenytoin, carbamazepine) are enzyme-inducing agents and thereby increase the clearance of the oral contraceptive steroids. Valproic acid has no enzyme-inducing properties, and thus women on this anticonvulsant can rely on their low dose oral contraceptive steroids for contraceptive protection. Researchers are now beginning to unravel the molecular basis of this interaction, with evidence of specific forms of cytochrome P450 (P450IIC and IIIA gene families) being induced by phenobarbital. Rifampicin, the antituberculous drug, also induces a cytochrome P450 which is a product of the P450IIIA gene subfamily. This isozyme is one of the major forms involved in 2-hydroxylation of ethinylestradiol. Broad spectrum antibiotics have been implicated in causing pill failure; case reports document the interaction, and general practitioners are convinced that it is real. The problem remains that there is still no firm clinical pharmacokinetic evidence which indicates that blood concentrations of oral contraceptive steroids are altered by antibiotics. However, perhaps this should not be a surprise, given that the incidence of the interaction may be very low. It is suggested that an individual at risk will have a low bioavailability of ethinylestradiol, a large enterohepatic recirculation and gut flora particularly susceptible to the antibiotic being used. Two drugs, ascorbic acid (vitamin C) and paracetamol (acetaminophen), give rise to increased blood concentrations of ethinylestradiol due to competition for sulphation. The interactions could have some significance to women on oral contraceptive steroids who regularly take high doses of either drug. Although on theoretical grounds adsorbents (e.g. magnesium trisilicate, aLuminium hydroxide, activated charcoal and kaolin) could be expected to interfere with oral contraceptive efficacy, there is no firm evidence that this is the case. Similarly, there is no evidence that smoking alters the pharmacokinetics of oral contraceptive steroids. These agents are now well documented as being able to alter the pharmacokinetics of other concomitantly administered drugs.

Baggott JE, Morgan SL, Ha TS, Alarcon GS, Koopman WJ, Krumdieck CL. Antifolates in rheumatoid arthritis: a hypothetical mechanism of action. Clin Exp Rheumatol 1993 Mar-Apr;11 Suppl 8:S101-105. (Review)

Baum CL, Selhub J, Rosenberg IH. Antifolate actions of sulfasalazine on intact lymphocytes. J Lab Clin Med 1981 Jun;97(6):779-784.
Abstract: SASP, the drug most widely used for the treatment of Crohn's disease and ulcerative colitis, is a competitive inhibitor of intestinal folate metabolism and transport. Some of the therapeutic effects of the drug could be related to antifolate actions on lymphocytes, which predominate in the inflammatory reaction in inflammatory bowel diseases. Experiments were designed to examine the effect of SASP on folate-dependent systems in cultured lymphocytes. In rat spleen lymphocytes, THF-dependent conversion of glycine to serine was inhibited by SASP, with 50% inhibition occurring at 0.1 mM. Further evidence of folate antagonism was obtained with the dU suppression test, which depends on the function of a folate-dependent pathway in the de novo synthesis of DNA. Folate antagonists like methotrexate or folate depletion reduces the incorporation of dU into DNA and thus favors incorporation of [3H]thymidine into DNA by an alternate pathway. SASP inhibited the folate-dependent pathway in proliferating virally transformed human lymphocytes (Raji cells). To confirm that SASP acts as a folate antagonist in this system, THF was demonstrated to partly reverse the action of SASP. The significance of this antifolate action by SASP in intact lymphocytes deserves further study in relation to the actions of SASP in patients with inflammatory bowel disease.

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

Berg MJ, Fincham RW, Ebert BE, Schottelius DD. Decrease of serum folates in healthy male volunteers taking phenytoin. Epilepsia 1988 Jan-Feb;29(1):67-73.
Abstract: The effect of phenytoin (PHT) on serum folate and the effect of additional oral folic acid (FA) on serum folate during continued treatment with PHT were studied in 13 healthy male subjects 20-35 years of age. The study was divided into two phases: Phase I determined Vmax (mg/kg/day) and Km (microgram/ml) of PHT in order to calculate the PHT doses needed for the second phase. Phase II was a four-way cross-over study to examine the effect of 1 and 5 mg FA on total serum PHT concentrations 1 microgram/ml less and 5 micrograms/ml greater than the subject's Km, Km-1 and Km+5, respectively. Both phases examined the effect of PHT on serum folate. In Phase I, serum folate decreased by a mean and standard deviation of 42.15 +/- 21.44% after an average of 24.15 +/- 5.63 days of PHT administration, with a mean steady-state total serum PHT concentration of 8.45 +/- 2.70 micrograms/ml. Mean percentage decreases in serum folate before the addition of 1 and 5 mg FA in Phase II were 12.80 +/- 31.45% and 23.24 +/- 21.24% for Km-1 and Km+5, respectively. The average numbers of days of PHT administration and total serum PHT concentrations before FA administration were 9.52 +/- 3.34 and 15.84 +/- 7.02 days, and 2.60 +/- 2.18 and 8.64 +/- 3.44 micrograms/ml, for Km-1 and Km+5, respectively.

Berg MJ, Stumbo PH, Chenard CA, et al. Folic acid improves phenytoin pharmacokinetics. J Am Diet Assoc 1995 Mar;95(3):352-356.
Abstract: Phenytoin (PHT) therapy to control seizures decreases serum folate levels in half of epileptic patients, thus increasing the risk of folate depletion. Supplementation with folic acid prevents deficiency but also changes PHT pharmacokinetics. Kinetic monitoring of PHT when folic acid is provided as a supplement has not been reported in women of child-bearing age. This study of six fertile women examined the interdependence of PHT and folic acid in a randomized crossover study of two treatments: treatment 1 consisted of 300 mg sodium PHT per day and treatment 2 consisted of 300 mg sodium PHT plus 1 mg folic acid per day. Dietary folic acid intake was calculated daily. During treatment 1, serum folate level decreased 38.0 +/- 18.6% (mean +/- standard deviation) and serum PHT concentration was in the low therapeutic range (43.92 +/- 14.52 mumol/L). During treatment 2, serum folate level increased 26.0 +/- 33.4%, and serum PHT level (39.04 +/- 14.16 mumol/L) was similar to that in treatment 1. Only one subject attained PHT steady state during treatment 1, but four subjects achieved steady state during treatment 2. Dietary folate intakes during treatments 1 and 2 were not significantly different. This study suggests an interdependence between PHT and folic acid and supports the observation that fertile women treated with PHT require folic acid supplementation to maintain a normal serum folate level.

Biale Y, Lewenthan H. Effect of folic acid supplementation on congenital malformations due to anticonvulsive drugs. Eur J Obstet Gynecol 1984 Nov;18(4):211-216.
Abstract: A study was conducted to determine the frequency of malformations among newborn infants of mothers receiving anticonvulsive therapy, with and without supplementation of folic acid. In the retrospective part of the study, the frequency of congenital malformations among the 66 newborn of 24 women who received anticonvulsive drugs without the supplementation of folic acid was 15% (10 children). The defects noted were congenital heart disease, cleft lip and palate, neural tube defects and skeletal abnormalities. Three out of the 10 children were stillborn or died immediately after delivery. In the prospective study of the 22 epileptic women with folic acid supplementation to their anticonvulsive regimen, 33 infants were born alive, without congenital malformations and of normal body weight. The teratogenic activity of anticonvulsant drugs seems to be mediated by interference with folic acid metabolism, and such activity might be influenced by hereditary and environmental factors. When an epileptic woman wishes to become pregnant, it is recommended that folic acid be added to her regimen.

Bjornson BH, McIntyre AP, Harvey JM, Tauber AI. Studies of the effects of trimethoprim and sulfamethoxazole on human granulopoiesis.Am J Hematol 1986 Sep;23(1):1-7.
Abstract: Trimethoprim and sulfamethoxazole (Bactrim r) is a widely used antibiotic combination effective against a broad spectrum of microbial organisms. There are reports of neutropenia developing during even brief periods of oral therapy, particularly in individuals with either folate deficiency or increased folate requirements. We have investigated the effects of these drugs on circulating granulocyte precursors (CFU-C) from normal donors and the mechanism of inhibition on granulopoiesis using an in vitro CFU-C assay. In 12 healthy adults, the number of circulating granulocytes and granulocyte progenitors was not significantly altered by a 5-day course of therapy. However, in experiments that simulated the in vivo condition of folate deficiency (folate-free cultures were prepared with cells harvested from normal donors), trimethoprim (8 micrograms/ml) resulted in a 47% decrease in the total number of colonies; this inhibitory effect was prevented when 100 ng of folinic acid was also added to the culture. Sulfamethoxazole (40 micrograms/ml) had no discernible effect on granulopoiesis. The combination of 8 micrograms/ml of trimethoprim and 40 micrograms/ml of sulfamethoxazole resulted in a 52% decrease in the number of colonies generated and this inhibition was again prevented by folinic acid. Our results suggest that the neutropenia occasionally observed in patients treated with trimethoprim-sulfamethoxazole is due to the inhibitory effects on granulopoiesis by trimethoprim, namely its antifolate action, which is reversed by folinic acid. Based on these studies, in patients with either folate deficiency or increased folate requirements, trimethoprim-sulfamethoxazole should be used with caution.

Botez, Cadotte, Beaulieu, Pichette. Neurologic disorders responsive to folate therapy. Can Med Assoc J. 1976;115:217-223.
Abstract: 3 women with acquired folate deficiency had mild signs and symptoms of restless legs, depression, muscular and mental fatigue, depressed ankle jerks, dimunation of vibratory sensation in the legs, a stocking type hypoesthesia, and chronic constipation. All 3 recovered with folate treatment.

Botez MI, Botez T, Ross-Chouinard A, Lalonde R. Thiamine and folate treatment of chronic epileptic patients: a controlled study with the Wechsler IQ scale. Epilepsy Res 1993 Oct;16(2):157-163.
Abstract: Seventy-two epileptic patients receiving phenytoin (PHT) alone or in combination with phenobarbital for more than 4 years were divided into four groups, the first taking two placebo tablets per day; the second folate (5 mg/day) and placebo; the third placebo and thiamine (50 mg/day); and the fourth both vitamins. The clinical trial lasted 6 months. At baseline assessment, 31% of the patients had subnormal blood thiamine levels and 30% had low folate. The vitamin deficiencies were independent phenomena. It was found that thiamine improved neuropsychological functions in both verbal and non-verbal IQ testing. In particular, higher scores were recorded on the block design, digit symbol, similarities and digit span subtests. Folate treatment was ineffective. These results indicate that, in epileptics chronically treated with PHT, thiamine improves neuropsychological functions, such as visuo-spatial analysis, visuo-motor speed and verbal abstracting ability.

Branda RF, Nelson NL. Inhibition of 5-methyltetrahydrofolic acid transport by amphipathic drugs. Drug Nutr Interact 1981;1(1):45-53.

Brattstrom L, Israelsson B, Olsson A, Andersson A, Hultberg B. Plasma homocysteine in women on oral oestrogen-containing contraceptives and in men with oestrogen-treated prostatic carcinoma. Scand J Clin Lab Invest 1992 Jun;52(4):283-287.
Abstract: The mechanism by which oral oestrogen-containing contraceptives in women and oestrogen treatment of prostatic carcinoma in men increases the risk of vascular disease is unclear. These agents decrease serum concentrations of vitamin B12, pyridoxal 5-phosphate, and folate, all of which are essential for the metabolism of the atherogenic amino acid homocysteine. We found serum vitamin B12 concentrations to be lower in 17 women using oral contraceptives (219 +/- 84 pmol l-1) than in 13 age-matched female controls (385 +/- 129, p less than 0.001), but similar values were obtained in the two groups both for fasting plasma homocysteine concentrations (9.1 +/- 2.4 vs 9.2 +/- 3.6 mumol l-1) and for the increase in these concentrations after methionine loading (19.2 +/- 7.5 vs 17.8 +/- 5.2 mumol l-1). In five men with prostatic carcinoma, high-dose oestrogen treatment decreased serum vitamin B12 concentrations by a mean of 30% (p less than 0.05) within 4 weeks, during which fasting plasma homocysteine concentrations decreased (13.8 +/- 4.5 vs 10.5 +/- 2.8 mumol l-1) and response to methionine loading increased (12.4 +/- 3.4 vs 17.3 +/- 5.1 mumol l-1), though the latter changes were non-significant. Our findings do not support the hypothesis that hyperhomocysteinemia explains cardiovascular risk in women using oral oestrogen-containing contraceptives, or in oestrogen-treated men with prostatic carcinoma.

Bugge JF. Severe hyperkalaemia induced by trimethoprim in combination with an angiotensin-converting enzyme inhibitor in a patient with transplanted lungs. J Intern Med. 1996 Oct;240(4):249-251.

Buist RA. Drug-nutrient interactions - an overview. Intl Clin Nutr Rev 1984;4(3):114. (Review)

Butterworth CE Jr, Hatch KD, Macaluso M, Cole P, Sauberlich HE, Soong SJ, Borst M, Baker VV. Folate deficiency and cervical dysplasia. JAMA 1992 Jan 22-29;267(4):528-533.
Abstract: OBJECTIVE--To test the hypothesis that nutritional deficiency affects the incidence of cervical dysplasia in young women. DESIGN AND SETTING--Case-control study. Participants were derived from community family-planning clinics and referrals to a colposcopy center. PARTICIPANTS--A total of 726 subjects were screened, yielding 294 cases of dysplasia and 170 controls defined by coexistent cytologic and colposcopic evidence. MAIN OUTCOME MEASURES--Planned prior to data collection. Odds ratios were computed using logistic regression models to evaluate association between cervical dysplasia and sociodemographic, sexual, and reproductive factors; smoking; oral contraceptive use; human papillomavirus (HPV) infection; and 12 nutritional indices determined by blind analysis of nonfasting blood specimens. RESULTS--The number of sexual partners, parity, oral contraceptive use, and HPV-16 infection were significantly associated with cervical dysplasia. Plasma nutrient levels were generally not associated with risk. However, red blood cell folate levels at or below 660 nmol/L interacted with HPV-16 infection. The adjusted odds ratio for HPV-16 was 1.1 among women with folate levels above 660 nmol/L but 5.1 (95% confidence interval, 2.3 to 11) among women with lower levels. Interactions of red blood cell folate levels with cigarette smoking and parity were also present but were not statistically significant. CONCLUSION--Low red blood cell folate levels enhance the effect of other risk factors for cervical dysplasia and, in particular, that of HPV-16 infection.

Butterworth CE, Hatch KD, Mueller H, Gore H. Folate-induced regression of cervical intraepithelial neoplasia (CIN) in users of oral contraceptive agents (OCA). Am J Clin Nutr 1980;33:926.

Butterworth CE Jr, Tamura T. Folic acid safety and toxicity: a brief review. Am J Clin Nutr 1989;50:353-358.

Butterworth CE Jr, Hatch KD, Gore H, Mueller H, Krumdieck CL. Improvement in cervical dysplasia associated with folic acid therapy in users of oral contraceptives. Am J Clin Nutr 1982 Jan;35(1):73-82.
Abstract: Forty-seven young women with mild or moderate dysplasia of the uterine cervix (cervical intraepithelial neoplasia) diagnosed by cervical smears, received oral supplements of folic acid, 10 mg, or a placebo (ascorbic acid, 10 mg) daily for 3 months under double-blind conditions. All had used a combination-type oral contraceptive agent for at least 6 months and continued it while returning monthly for follow-up examinations. All smears and a biopsy obtained at the end of the trial period were classified by a single observer without knowledge of treatment status using an arbitrary scoring system (1 normal, 2 mild, 3 moderate, 4 severe, 5 carcinoma in situe). Mean biopsy scores from folate supplemented subjects were significantly better than in folate-unsupplemented subjects (2.28 versus 2.92, respectively; p less than 0.05). Final versus initial cytology scores were also significantly better in supplemented subjects (1.95 versus 2.32, respectively; p less than 0.05), unchanged in patients receiving the placebo (2.27 versus 2.30, respectively). Before treatment the mean red cell folate concentration was lower among oral contraceptive agent users than nonusers (189 versus 269 ng/ml, respectively; p less than 0.01) and even lower among users with dysplasia (161 versus 269 ng/ml, respectively; p less than 0.001). Morphological features of megaloblastosis were associated with dysplasia and also improved in folate supplemented subjects. These studies indicate that either a reversible, localized derangement in folate metabolism may sometimes be misdiagnosed as cervical dysplasia, or else such a derangement is an integral component of the dysplastic process that may be arrested or in some cases reversed by oral folic acid supplementation.

Bygbjerg IC, Lund JT, Hording M. Effect of folic and folinic acid on cytopenia occurring during co-trimoxazole treatment of Pneumocystis carinii pneumonia. Scand J Infect Dis 1988;20(6):685-686.
Abstract: 12 AIDS/ARC patients with or suspected of Pneumocystis carinii pneumonia were treated with co-trimoxazole and received supplementary folic or folinic acid to avoid peripheral blood cytopenia. Most patients developed decreased numbers of neutrophils and hemoglobin while receiving co-trimoxazole. Supplementary folate/folinate could not abolish the drug-induced cytopenia. Routine prescription of folinic acid is not recommended. Folic acid is cheap and may be beneficial and should be prescribed.

Carl GF, Hudson FZ, McGuire BS Jr. Phenytoin-induced depletion of folate in rats originates in liver and involves a mechanism that does not discriminate folate form. J Nutr 1997 Nov;127(11):2231-2238.

Collins CS, Bailey LB, Hillier S, Cerda JJ, Wilder BJ. Red blood cell uptake of supplemental folate in patients on anticonvulsant drug therapy. Am J Clin Nutr 1988 Dec;48(6):1445-1450 .
Abstract: A group of epileptics (n = 18) and a control group (n = 10) of subjects aged 21-42 y were given 1-mg supplements of folate daily for 1 mo. Anticonvulsant therapy involved phenytoin alone or in combination with phenobarbital. Serum and red blood cell (RBC) folate levels were determined on days 1, 14, and 28. Mean serum and RBC folate levels were greater (p less than 0.05) for the control subjects compared with the epileptic subjects throughout the study. The percent increase in either serum or RBC folate was not different (p greater than 0.05) between the groups. The percent increase in serum folate when expressed as a percent of RBC folate was greater (p less than 0.05) for those epileptics who initially had deficient blood folate levels (serum folate less than 7 nmol/L; RBC folate less than 317 nmol/L) than those who did not. Deficient epileptics may have had an impaired RBC incorporation of circulating (serum) folate compared with nondeficient epileptics.

Coppen. Folic Acid Enhances Lithium Prophylaxis. J Affective Disorders 1986;10:9-13.
Abstract: 42 patients undergoing lithium therapy for affective disorders received either folate 200 mcg q.d. or placebo. After one year, there was a small but insignificant change in the affective morbidity index (AMI) in both groups. However, depression scores were significantly lower in the folate supplemented group. When the supplemented group was broken down according to mean folate levels at the end of the study, it was found that the half with the highest mean folate levels had the best scores for both AMI and depression.

Coronato A, Glass GB. Depression of the intestinal uptake of radio-vitamin B 12 by cholestyramine. Proc Soc Exp Biol Med 1973 Apr;142(4):1341-1344.

Cravo ML, et al.    Microsatellite instability in non-neoplastic mucosa of patients with ulcerative colitis: effect of folate supplementation. Am J Gastroenterol. 1998 Nov;93(11):2060-2064.

Crawford P, Chadwick DJ, Martin C, Tjia J, Back DJ, Orme M. The interaction of phenytoin and carbamazepine with combined oral contraceptive steroids. Br J Clin Pharmacol 1990 Dec;30(6):892-896.
Abstract: Patients taking oral contraceptive steroids (OCS) are known to suffer contraceptive failure while taking anticonvulsants such as phenobarbitone, phenytoin and carbamazepine. We have studied the single dose kinetics of ethinyloestradiol (EE2); 50 micrograms, and levonorgestrel (Ng); 250 micrograms in groups of women before and 8-12 weeks after starting therapy with phenytoin (n = 6) and carbamazepine (n = 4). The area under the plasma concentration-time curve (AUC) was measured over a 24 h period for each steroid and significant reductions were seen with both anticonvulsants. Phenytoin reduced the AUC for EE2 from 806 +/- 50 (mean +/- s.d.) to 411 +/- 132 pg ml-1 h (P less than 0.05) and for Ng from 33.6 +/- 7.8 to 19.5 +/- 3.8 ng ml-1 h (P less than 0.05). Carbamazepine reduced the AUC for EE2 from 1163 +/- 466 to 672 +/- 211 pg ml-1 h (P less than 0.05) and for Ng from 22.9 +/- 9.4 to 13.8 +/- 5.8 ng ml-1 h (P less than 0.05). These changes are compatible with the known enzyme inducing effects of phenytoin and carbamazepine. Patients taking these anticonvulsants will need to be given increased doses of OCS (equivalent to 50-100 micrograms EE2 daily) to achieve adequate contraceptive effects.

Cronkite E, Bullis J, Honikel L. Partial amelioration of AZT-induced macrocytic anemia in the mouse by folic acid. Stem Cells. 1993 Sep;11(5):393-397.
Abstract: CBA/Ca mice being maintained on azidothymidine (AZT) in drinking water were given vitamin B12 and folate in an effort to ameliorate the macrocytic anemia associated with AZT administration. The B12/folate regimen was ineffectual, but higher doses of folate given daily resulted in an increase in RBC and a decrease in mean corpuscular hemoglobin (MCH) and polychromatophilic erythrocytes (PCE) while mean corpuscular volume (MCV) remained relatively constant. The implications of these findings on RBC production and hemoglobin synthesis are discussed.

Daly LE, Kirke PN, Molloy A, et al. Folate levels and neural tube defects. JAMA 1995;274:1698-1702.

Dansky LV, Andermann E, Rosenblatt D, Sherwin AL, Andermann F. Anticonvulsants, folate levels, and pregnancy outcome: a prospective study. Ann Neurol 1987 Feb;21(2):176-182.
Abstract: Folate levels in serum and red cells, as determined by a microbiological assay using Lactobacillus casei, and plasma anticonvulsant concentrations were monitored concurrently in nonpregnant (50 subjects) and pregnant (49 pregnancies in 46 subjects) epileptic women. Twenty-three (46%) nonpregnant women had subnormal serum folate levels and 4 nonpregnant women (8%) showed subnormal red cell folate levels. In pregnant women not taking folate supplements, the incidence of folate deficiency increased as the pregnancy advanced. Pregnant women taking folate supplements achieved normal or supranormal blood folate concentrations. In both nonpregnant and pregnant women, serum and red cell folate levels were inversely correlated with plasma concentrations of phenytoin and of phenobarbital, and with the number of anticonvulsants. In 49 pregnancies, there were 10 abnormal outcomes (20.4%): 4 spontaneous abortions (8.2%) and 6 children with major congenital malformations (12.2%). Blood folate levels were significantly lower in pregnancies with an abnormal outcome than in those with a normal outcome. The results suggest a dose-response relationship among anticonvulsants, folate, and adverse pregnancy outcome.

Drew HJ, Vogel RI, Molofsky W, Baker H, Frank O. Effect of folate on phenytoin hyperplasia. J Clin Periodontol 1987 Jul;14(6):350-356.
Abstract: There have been some reports that folic acid inhibits phenytoin-induced gingival hyperplasia. The purpose of this double-blind study was to quantify clinically the effects of both systemic and topical administration of folic acid on phenytoin-induced gingival overgrowth in man. For a period of 6 months, one group of phenytoin patients received 2 daily topical applications of a folate solution. An additional group received 2 daily doses of systemic folate while a control group received placebo medication. Results indicate that throughout the 180-day period of the study, the topical folate significantly inhibited gingival hyperplasia to a greater extent than either systemic folate or placebo groups.

Duell PB, Malinow MR. Homocyst(e)ine: an important risk factor for atherosclerotic vascular disease. Curr Opin Lipidol 1997 Feb;8(1):28-34. (Review)
Abstract: Homocysteine is an intermediate compound formed duringmetabolism of methionine. The results of many recent studies have indicated that elevated plasma levels of homocyst(e)ine are associated with increased risk of coronary atherosclerosis, cerebrovascular disease, peripheral vascular disease, and thrombosis. The plasma level of homocyst(e)ine is dependent on genetically regulated levels of essential enzymes and the intake of folic acid, vitamin B6 (pyridoxine), and vitamin B12 (cobalamin). Impaired renal function, increased age, and pharmacologic agents (e.g. nitrous oxide, methotrexate) can contribute to increased levels of homocyst(e)ine. Plausible mechanisms by which homocyst(e)ine might contribute to atherogenesis include promotion of platelet activation and enhanced coagulability, increased smooth muscle cell proliferation, cytotoxicity, induction of endothelial dysfunction, and stimulation of LDL oxidation. Levels of homocysteine can be reduced with pharmacologic doses of folic acid, pyridoxine, vitamin B12, or betaine, but further research is required to determine the efficacy of this intervention in reducing morbidity and mortality associated with atherosclerotic vascular disease.

Durand P, Prost M, Blache D. Folic acid deficiency enhances oral contraceptive-induced platelet hyperactivity. Arterioscler Thromb Vasc Biol 1997 Oct;17(10):1939-1046.
Abstract: In previous studies conducted in female rats and in women, oral contraceptives (OC) were found to induce a platelet hyperactivity that was related to an oxidative stress. Because cases of megaloblastic anemia have been reported to occur in women taking OC, these treatments are suspected of depleting folate stores. In the study presented herein, which was conducted in rats, we sought to determine the influence of dietary folic acid deficiency (FD) on the thrombogenicity of OC. Animals were fed for 6 weeks with either a folic acid-deficient diet (250 micrograms/kg folic acid) or a control diet (750 micrograms/kg). One-half of the animals in each group were treated with OC (ethinyl estradiol plus lynestrenol). FD and OC individually potentiated platelet aggregation in response to thrombin and ADP and the release and metabolism of arachidonic acid, in particular, the biosynthesis of thromboxane. These platelet activities were further enhanced in animals given both the folic acid-deficient diet and the OC treatment. In addition, FD enhanced the pro-oxidant state in OC-treated rats characterized by (1) a fall in platelet and plasma n-3 fatty acids, (2) an increase in plasma lipid peroxidation products such as conjugated dienes, lipid peroxides, and thiobarbituric reactive substances, (3) a rise in ex vivo erythrocyte susceptibility to free radicals. Moreover, we found that OC treatment led to a reduction of plasma and erythrocyte folate concentrations associated with a moderate hyperhomocysteinemia. Under our experimental conditions, we did not find significant synergistic effects between OC and FD. We propose that, although the untoward effects associated with the OC treatment may not primarily be dependent on FD, the folic acid deficiency magnified OC-induced oxidative stress, which resulted in platelet hyperactivity by elevating the pro-oxidant homocysteine plasma concentration. Despite the limitations of this animal model, the data of the present study suggest that in addition to cigarette smoking, inadequate folic acid intake might predispose those taking OC to vascular thrombosis.

Elmazar MM, Nau H. Ethanol potentiates valproic acid-induced neural tube defects (NTDs) in mice due to toxicokinetic interactions. Reprod Toxicol 1995 Sep-Oct;9(5):427-433.
Abstract: Both the antiepileptic drug valproic acid (VPA) and ethanol interfere with fetal folate metabolism, which may contribute to their mechanism of teratogenesis. Therefore, the possible interaction between VPA and ethanol was investigated in mice. Ethanol (2 x 2.5 g/kg) was given orally 4 and 1 h prior to VPA (300 and 400 mg/kg, SC) in day 8.25 pregnant NMRI mice. Fetuses were examined for exencephaly, embryolethality, and fetal weight retardation on day 18 of gestation. Higher doses of ethanol (2 x 5 g/kg, orally) at day 7.5 and 8 of gestation resulted in 22% embryolethality and 1.7% exencephaly with no effect on fetal weight. Ethanol, however, increased VPA (400 mg/kg, SC)-induced exencephaly, embryolethality, and fetal weight retardation. It also increased VPA (300 mg/kg, SC)-induced exencephaly without affecting embryotoxicity. A minimum of two oral doses of 2.5 g/kg ethanol, 1 and 4 h, or 1 and 6 h prior to VPA administration were needed to produce maximum potentiation of the effects observed. These ethanol doses increased plasma VPA levels of day 8.25 pregnant mice given 400 mg/kg VPA to values comparable to the levels of mice given only VPA at a higher dose level (500 mg/kg). The incidence of exencephaly was increased from 35% for VPA (400 mg/kg) to 59% when VPA was given with ethanol. This incidence was similar to that of 60% for the high dose of VPA (500 mg/kg) administered without ethanol. Maternal plasma ethanol concentration peaked at 193, 196, and 183 mg/dL 15, 30, and 60 min, respectively, after oral ethanol administration (2.5 g/kg), and fell to 110 mg/dL by 2 h.

Elsborg L. Vitamin B12 and Folic Acid in Crohn's Disease. Dan Med Bull 1982; 29:362-365.

Evers S, Di Padova K, Meyer M, Fountoulakis M, Keck W, Gray CP. Strategies towards a better understanding of antibiotic action: folate pathway inhibition in Haemophilus influenzae as an example.Electrophoresis 1998 Aug;19(11):1980-1988.
Abstract: Two-dimensional electrophoresis was applied to the global analysis of the cellular response of Haemophilus influenzae to sulfamethoxazole and trimethoprim, both inhibitors of tetrahydrofolate synthesis. Deregulation of the synthesis rate of 118 proteins, involved in different metabolic pathways, was observed. The regulation of the genes involved in the metabolism of the amino acids methionine, threonine, serine, glycine, and aspartate was investigated in detail by analysis of protein synthesis and Northern hybridization. The results suggested that the synthesis of methionine biosynthetic enzymes in H. influenzae is regulated in a similar fashion as in Escherichia coli. A good correlation between the results obtained by Northern hybridization and quantification of protein synthesis was observed. In contrast to trimethoprim, sulfamethoxazole triggered the increased synthesis of the heat shock proteins DnaK, GroEL, and GroES.

Falguera M, Perez-Mur J, Puig T, Cao G. Study of the role of vitamin B12 and folinic acid supplementation in preventing hematologic toxicity of zidovudine. Eur J Haematol. 1995 Aug;55(2):97-102.
Abstract: A prospective, randomized study was conducted to evaluate the role of vitamin B12 and folinic acid supplementation in preventing zidovudine (ZDV)-induced bone marrow suppression. Seventy-five human immunodeficiency virus (HIV)-infected patients with CD4+ cell counts < 500/mm3 were randomized to receive either ZDV (500 mg daily) alone (group I, n = 38) or in combination with folinic acid (15 mg daily) and intramascular vitamin B12 (1000 micrograms monthly) (group II, n = 37). Finally, 15 patients were excluded from the study (noncompliance 14, death 1); thus, 60 patients (31 in group I and 29 in group II) were eligible for analysis. No significant differences between groups were found at enrollment. During the study, vitamin B12 and folate levels were significantly higher in group II patients; however, no differences in hemoglobin, hematocrit, mean corpuscular volume, and white-cell, neutrophil and platelet counts were observed between groups at 3, 6, 9 and 12 months. Severe hematologic toxicity (neutrophil count < 1000/mm3 and/or hemoglobin < 8 g/dl) occurred in 4 patients assigned to group I and 7 assigned to group II. There was no correlation between vitamin B12 or folate levels and development of myelosuppression. Vitamin B12 and folinic acid supplementation of ZDV therapy does not seem useful in preventing or reducing ZDV-induced myelotoxicity in the overall treated population, although a beneficial effect in certain subgroups of patients cannot be excluded.

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

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

Fava M, Borus JS, Alpert JE, Nierenberg AA, Rosenbaum JF, Bottiglieri T. Folate, vitamin B12, and homocysteine in major depressive disorder. Am J Psychiatry 1997 Mar;154(3):426-428.
Abstract: OBJECTIVE: The authors examined the relationships between levels of three metabolites (folate, vitamin B12, and homocysteine) and both depressive subtype and response to fluoxetine treatment in depressed patients. METHOD: Fluoxetine, 20 mg/day for 8 weeks, was given to 213 outpatients with major depressive disorder. At baseline, depressive subtypes were assessed, and a blood sample was collected from each patient. Serum metabolite levels were assayed. Response to treatment was determined by percentage change in score on the 17-item Hamilton Depression Rating Scale. RESULTS: Subjects with low folate levels were more likely to have melancholic depression and were significantly less likely to respond to fluoxetine. Homocysteine and B12 levels were not associated with depressive subtype or treatment response. CONCLUSIONS: Overall, the results are consistent with findings linking low folate levels to poorer response to antidepressant treatment. Folate levels might be considered in the evaluation of depressed patients who do not respond to antidepressant treatment.

Fiskerstrand T, Ueland PM, Refsum H. Folate depletion induced by methotrexate affects methionine synthase activity and its susceptibility to inactivation by nitrous oxide. J Pharmacol Exp Ther 1997 Sep;282(3):1305-1311.
Abstract: We compared the effects of methotrexate (MTX) and nitrous oxide on the methionine (Met) synthase system in two variants of a human glioma cell line. The cells were protected from cytotoxic effect of MTX by adding thymidine and hypoxanthine to the cell culture medium. MTX (0-1 microM) was associated with a dose- and time-dependent reduction in 5-methyltetrahydrofolate (5-methyl-THF) in both cell lines. Already after 3 hr of exposure, 5-methyl-THF was reduced by 50% and after additional 48 hr, the level was undetectable. In addition to reduction in folate level, homocysteine (Hcy) remethylation in intact cells was markedly inhibited as judged by an increased export of Hcy from the cells, and Met synthase activity in cell extracts and level of cellular methylcobalamin (CH3Cbl) declined. MTX reduced Hcy remethylation and CH3Cbl level more efficiently than nitrous oxide. In both cell variants, the inactivation of Met synthase by nitrous oxide was almost completely prevented in cells pre-exposed to MTX. This indicates that there is no catalytic turnover in cells exposed to MTX, and emphasizes the importance of the sequence of administration for synergistic effect of this drug combination. In conclusion, our data show that MTX through depletion of 5-methyl-THF reduces both the Met synthase activity and the cellular CH3Cbl level. Moreover, the effect of MTX on the Hcy remethylation is more pronounced than the inhibition caused by nitrous oxide. These observations should be taken into account in studies on MTX pharmacodynamics.

Fitchie JG, Comer RW, Hanes PJ, Reeves GW. The reduction of phenytoin-induced gingival overgrowth in a severely disabled patient: a case report. Compendium 1989 Jun;10(6):314, 317-20.
Abstract: Gingival overgrowth frequently occurs in patients medicated with phenytoin (5,5-diphenylhydantoin) to control epileptic seizures. In a recent study, gingival overgrowth was observed in a patient in an experimental group evaluating an automatic toothbrushing system for severely disabled patients. During the evaluation period, which included an oral hygiene regimen provided by an attendant or housemate and a regimen with the Mississippi Dental Care System (MDCS), the patient's gingival overgrowth was noticeably reduced. The results of this study indicate that control of local factors with the MDCS is significantly better than the routine home care regimen, and that the phenytoin-associated gingival overgrowth in this patient was reduced by MDCS.

Francetti L, Maggiore E, Marchesi A, Ronchi G, Romeo E. Oral hygiene in subjects treated with diphenylhydantoin: effects of a professional program. Prev Assist Dent 1991 May-Jun;17(3):40-43. [Article in Italian]
Abstract: The purpose of the present study was to investigate, on a longitudinal basis, the effectiveness of a specific preventive dental program for patients who are taking phenytoin for seizure control. The results confirm that a preventive dental program, consisting on frequent prophylaxis and plaque control, is effective in minimizing clinically gingival enlargement associated with phenytoin therapy, even in patients who present histological aspects of gingival hyperplasia.

Ghadirian. Folate deficiency and depression. Psychosomatics 1980;21(11):926-929.
Abstract: A study of 48 psychiatric in-patients showed that serum folate levels in depressed patients were significantly lower than in non-depressed patients who were either medically or psychiatrically ill. These levels negatively correlated with the degree of depression.

Giovannucci E, Stampfer MJ, Colditz GA, Hunter DJ, Fuchs C, Rosner BA, Speizer FE, Willett WC. Multivitamin use, folate, and colon cancer in women in the Nurses' Health Study. Ann Intern Med 1998 Oct 1;129(7):517-524.
Abstract: BACKGROUND: High intake of folate may reduce risk for colon cancer, but the dosage and duration relations and the impact of dietary compared with supplementary sources are not well understood. OBJECTIVE: To evaluate the relation between folate intake and incidence of colon cancer. DESIGN: Prospective cohort study. SETTING: 88,756 women from the Nurses' Health Study who were free of cancer in 1980 and provided updated assessments of diet, including multivitamin supplement use, from 1980 to 1994. PATIENTS: 442 women with new cases of colon cancer. MEASUREMENTS: Multivariate relative risk (RR) and 95% CIs for colon cancer in relation to energy-adjusted folate intake. RESULTS: Higher energy-adjusted folate intake in 1980 was related to a lower risk for colon cancer (RR, 0.69 [95% CI, 0.52 to 0.93] for intake > 400 microg/d compared with intake < or = 200 microg/d) after controlling for age; family history of colorectal cancer; aspirin use; smoking; body mass; physical activity; and intakes of red meat, alcohol, methionine, and fiber. When intake of vitamins A, C, D, and E and intake of calcium were also controlled for, results were similar. Women who used multivitamins containing folic acid had no benefit with respect to colon cancer after 4 years of use (RR, 1.02) and had only nonsignificant risk reductions after 5 to 9 (RR, 0.83) or 10 to 14 years of use (RR, 0.80). After 15 years of use, however, risk was markedly lower (RR, 0.25 [CI, 0.13 to 0.51]), representing 15 instead of 68 new cases of colon cancer per 10,000 women 55 to 69 years of age. Folate from dietary sources alone was related to a modest reduction in risk for colon cancer, and the benefit of long-term multivitamin use was present across all levels of dietary intakes. CONCLUSIONS: Long-term use of multivitamins may substantially reduce risk for colon cancer. This effect may be related to the folic acid contained in multivitamins.

Goggin T, Gough H, Bissessar A, Crowley M, Baker M, Callaghan N. A comparative study of the relative effects of anticonvulsant drugs and dietary folate on the red cell folate status of patients with epilepsy. Q J Med 1987 Nov;65(247):911-919.

Gomez G. Effect of folate supplementation on the incidence of dysplasia and cancer in chronic ulcerative colitis. Gastroenterology. 1991 Jun;100(6):1789-1790.

Grindulis KA, McConkey B. Does sulphasalazine cause folate deficiency in rheumatoid arthritis? Scand J Rheumatol 1985;14(3):265-270.
Abstract: Sulphasalazine impairs folic acid absorption and metabolism but rarely leads to folate deficiency in inflammatory bowel disease (IBD). In rheumatoid arthritis (RA), however, serum and red cell folate concentrations are often low and sulphasalazine might stress folate metabolism. In a prospective study, 2 g sulphasalazine was compared with 500 mg penicillamine daily in 30 patients over 24 weeks. Pre-treatment serum and red cell folate concentrations were low-normal. Improvements in disease activity and haemoglobin occurred in both treatment groups, but MCV increased only in patients taking sulphasalazine. Serum and red cell folate concentrations did not change in either group. Increased MCV with sulphasalazine might therefore reflect reticulocytosis secondary to drug-induced haemolysis. The mechanisms by which sulphasalazine antagonizes folate metabolism are dose-dependent and, consequently, higher doses might precipitate folate deficiency.

Haagsma CJ, Blom HJ, van Riel PL, van't Hof MA, Giesendorf BA, van Oppenraaij-Emmerzaal D, van de Putte LB. Influence of sulphasalazine, methotrexate, and the combination of both on plasma homocysteine concentrations in patients with rheumatoid arthritis. Ann Rheum Dis 1999 Feb;58(2):79-84.
Abstract: OBJECTIVE: To study the influence of sulphasalazine (SSZ), methotrexate (MTX), and the combination (COMBI) of both on plasma homocysteine and to study the relation between plasma homocysteine and their clinical effects. METHODS: 105 patients with early rheumatoid arthritis (RA) were randomised between SSZ (2-3 g/day), MTX (7.5-15 mg/week), and the COMBI (same dose range) and evaluated double blindly during 52 weeks. Plasma homocysteine, serum folate concentrations, and vitamin B12 were measured. The influence of the C677T mutation of the enzyme methyl-enetetrahydrofolatereductase (MTHFR) gene was analysed. RESULTS: A slight trend towards increased efficacy and an increased occurrence of minor gastrointestinal toxicity was present in the COMBI group, no differences existed clinically between SSZ and MTX. Only a slight and temporary increase in plasma homocysteine was found in the SSZ group, in contrast with the persistent rise in the MTX group and the even greater increase in the COMBI patients. Patients homozygous for the mutation in the MTHFR gene had significantly higher baseline homocysteine, heterozygous MTHFR genotype induced a significantly higher plasma homoeysteine at week 52 compared with no mutation. No correlation was found between clinical efficacy variables and homocysteine. Patients with gastrointestinal toxicity had a significantly greater increase in homocysteine. CONCLUSION: A persistent increase in plasma homocysteine concentrations was observed in patients treated with MTX alone and more pronounced in combination with SSZ, in contrast with SSZ alone. An increase in plasma homocysteine is related to the C677T mutation in MTHFR. A relation in the change in homocysteine concentrations with (gastrointestinal) toxicity was found, no relation with clinical efficacy existed.

Halsted CH, Gandhi G, Tamura T. Sulfasalazine inhibits the absorption of folates in ulcerative colitis. N Engl J Med 1981 Dec 17;305(25):1513-1517.

Hansen DK, Grafton TF, Dial SL, Gehring TA, Siitonen PH. Effect of supplemental folic acid on valproic acid-induced embryotoxicity and tissue zinc levels in vivo. Teratology 1995 Nov;52(5):277-285.
Abstract: Valproic acid (VPA) is an anti-convulsant drug known to cause spina bifida in humans. Administration of the vitamin, folic acid, has been shown to decrease the recurrence and possibly also the occurrence of neural tube defects, primarily spina bifida, in humans. Additionally, treatment with a derivative (folinic acid) of folic acid has been reported to decrease the frequency of VPA-induced exencephaly in mice treated with the drug in vivo. A protective effect by folinic acid has not been observed in vitro. The purpose of this investigation was to reexamine the ability of folinic acid to decrease the incidence of VPA-induced neural tube defects in vivo. We also examined the effect of increased intake of folic acid on zinc levels in various maternal and embryonic tissues. Folinic acid, whether administered by intraperitoneal injection or in osmotic mini-pumps, did not decrease the number of mouse fetuses with VPA-induced exencephaly. Dietary supplementation with 10-20 times the daily required intake of folic acid in rodents also failed to decrease the embryotoxicity of VPA. Such dietary supplementation had no effect on zinc levels in maternal liver, brain, or kidney, nor in embryonic tissues. These results indicate that folic acid is not able to reverse the embryotoxicity induced by the anticonvulsant, that there is no apparent effect of high dietary folate intake on maternal or embryonic zinc levels and suggest that folate is probably not involved in the mechanism of VPA-induced embryotoxicity.

Harper JM, Levine AJ, Rosenthal DL, Wiesmeier E, Hunt IF, Swendseid ME, Haile RW. Erythrocyte folate levels, oral contraceptive use and abnormal cervical cytology. Acta Cytol 1994 May-Jun;38(3):324-330.
Abstract: The initial hypothesis of this study was that folate depletion is a risk factor for human papillomavirus infection and cervical epithelial cell abnormalities, including dysplasia. The prevalences of low erythrocyte folate levels (defined as < 140 ng/mL erythrocytes and determined by the growth of Lactobacillus) were measured in 250 University of California at Los Angeles students. Among oral contraceptive users, low erythrocyte folate was a risk factor for an abnormal cytologic smear in both benign atypia and squamous intraepithelial lesions. Odds ratios were statistically significant for biopsied women who did not have condyloma and for those who did not have squamous intraepithelial lesions but not for those with histologically confirmed intraepithelial lesions. Low erythrocyte folate was a risk factor for a positive Virapap result in oral contraceptive users. If the folate effects are causal, the findings suggest that erythrocyte folate levels should be higher in oral contraceptive users than in nonusers to protect against an abnormal cytologic smear.

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

Hayes C, Werler MM, Willett WC, Mitchell AA. Case-control study of periconceptional folic acid supplementation and oral clefts. Am J Epidemiol 1996;143:1229-1234.

Heimburger DC, Alexander CB, Birch R, Butterworth CE Jr, Bailey WC, Krumdieck CL. Improvement in bronchial squamous metaplasia in smokers treated with folate and vitamin B12. Report of a preliminary randomized, double-blind intervention trial. JAMA 1988 Mar 11;259(10):1525-1530.
Abstract: To test whether changes in folate and vitamin B12 nutrition modify the severity of potentially premalignant lesions identified by cytology in sputum samples of smokers, we conducted a randomized, controlled prospective intervention trial in smokers with bronchial squamous metaplasia. Seventy-three men with a history of 20 or more pack-years of cigarette smoking who had metaplasia on one or more sputum samples were stratified according to smoking level and randomly assigned to four months' treatment with either placebo or 10 mg of folate plus 500 micrograms of hydroxocobalamin. Direct cytological comparison of the two groups after four months showed significantly greater reduction of atypia in the supplemented group. This provides preliminary evidence that atypical bronchial squamous metaplasia may be reduced by supplementation with folate and vitamin B12. However, the significance of these findings is tempered by substantial spontaneous variation in sputum cytologies, the small study population, the short duration of the trial, and the supraphysiological doses of folate and B12 used. The results should not be construed as pointing to a potential way of preventing lung cancer in individuals who continue to smoke or as supporting self-medication with large doses of folate or B12 by smokers.

Hendel J, Dam M, Gram L, Winkel P, Jorgensen I. The effects of carbamazepine and valproate on folate metabolism in man. Acta Neurol Scand 1984 Apr;69(4):226-231.
Abstract: The effect of carbamazepine and valproate treatment on folate metabolism was studied in 11 epileptic patients. The absorption of folic acid and of Pteroyl-gamma-L-glutamyl-gamma-L-glutamyl-L-glutamic acid, a synthetic substrate for intestinal folate deconjugase, was measured prior to and after 2 months of antiepileptic therapy with either carbamazepine (5 cases) or valproate (6 cases). After 2 months' treatment, the area under plasma concentration versus time curve was significantly decreased and t-max (time when maximal plasma concentration is obtained) was significantly prolonged. No inhibition of intestinal folate deconjugation was observed and the liver metabolism of folic acid was found to be unaffected by the treatment. These findings are interpreted as an inhibition of intestinal folic acid absorption caused by the antiepileptic therapy.

Herbert V, Colman N, Spivack M, Ocasio E, Ghanta V, Kimmel K, Brenner L, Freundlich J, Scott J. Am J Obstet Gynecol 1975 Sep 15;123(2):175-179.
Abstract: Folic acid deficiency in the United States: folate assays in a prenatal clinic. Veterans Hospital Bronx, N.Y. Abstract: A study of 110 pregnant women from low income families in NYC found that 16% had definite folate deficiency and another 14% had marginal folate levels.

Hiilesmaa VK, Teramo K, Granstrom ML, Bardy AH. Serum folate concentrations during pregnancy in women with epilepsy: relation to antiepileptic drug concentrations, number of seizures, and fetal outcome. Br Med J (Clin Res Ed) 1983 Aug 27;287(6392):577-579.
Abstract: Serum folate concentrations, blood counts, and antiepileptic drug concentrations were measured during 133 pregnancies of 125 women with epilepsy. There was an inverse correlation between serum folate concentrations and concentrations of phenytoin and phenobarbitone. The number of epileptic seizures during pregnancy showed no association with serum folate concentrations. No cases of maternal tissue folate deficiency or fetal damage attributable to low maternal serum folate were observed. Maternal serum folate concentrations for infants with structural birth defects, "fetal hydantoin syndrome," or perinatal death were similar to those for healthy babies. A low dose (100 to 1000 micrograms daily) of folate supplement appeared sufficient for pregnant women with epilepsy despite the antifolic action of antiepileptic medication. Monitoring folate concentrations in pregnant women with high serum concentrations of phenytoin or phenobarbitone is recommended.

Hodges R. Drug-nutrient interaction. In: Nutrition in Medical Practice. Philadelphia: W.B. Saunders, 1980:323-331.

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

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

Houston DK, Johnson MA, Nozza RJ, et al. Age-related hearing loss, vitamin B-12, and folate in elderly women. Am J Clin Nutr 1999;69:564-571.

Hunt PG, Rose CD, McIlvain-Simpson G, Tejani S. The effects of daily intake of folic acid on the efficacy of methotrexate therapy in children with juvenile rheumatoid arthritis. A controlled study. J Rheumatol 1997 Nov;24(11):2230-2232.
Abstract: OBJECTIVE: To determine the effect of 1 mg/day of folic acid on the efficacy of methotrexate (MTX) to control disease activity in children with juvenile rheumatoid arthritis (JRA). METHODS: Randomized, double blind, placebo controlled, crossover trial of 13 weeks' duration. Nineteen children with the diagnosis of JRA, fulfilling the American College of Rheumatology diagnostic criteria, who had been receiving MTX for at least 6 months and whose disease status had remained stable for at least one month before entry were enrolled in the study. Subjects were randomly assigned to receive 1 mg/day of liquid folic acid or a liquid placebo for 6 weeks, followed by a one week washout period, and subsequent crossover to the alternate form for another 6 weeks. Disease activity indicators, including swollen joint count, duration of morning stiffness, physician and patient global assessment, and C-reactive protein, were assessed at study entry and at 6 and 13 weeks. RESULTS: One patient flared during the first 2 weeks while taking placebo, requiring study withdrawal and exclusion from outcome analysis. For the remaining 18 patients, there was no statistical difference in disease activity indicators with folic acid treatment compared to placebo. CONCLUSION: Supplementation with 1 mg/day of folic acid may not affect the clinical efficacy of oral weekly MTX in children with JRA.

Iivanainen M, Savolainen H. Side effects of phenobarbital and phenytoin during long-term treatment of epilepsy. Acta Neurol Scand Suppl 1983;97:49-67.
Abstract: Phenobarbital and phenytoin have good antiepileptic effect, but clinically significant untoward effects occur during their long-term use. Phenobarbital may cause hyperactivity, behavioral problems, sedation, and even dementia; these effects are dose related to some extent. Side effects of phenytoin include sedation, a cerebellar syndrome, phenytoin encephalopathy, psychosis, locomotor dysfunction, hyperkinesia, megaloblastic anemia, decreased serum folate level, decreased bone mineral content, liver disease, IgA deficiency, gingival hyperplasia, and a lupus-like hypersensitivity syndrome. Especially susceptible to the neurotoxic effects of phenytoin are epileptic children with severe brain damage who are on multiple drugs. In those children, balance disturbance may develop and be followed by gradual loss of locomotion. Among 131 mentally retarded epileptic patients, phenytoin intoxication occurred in 73 (56%), of whom 18 experienced persistent loss of locomotion. There is experimental evidence that the toxic action of phenytoin lies at the cellular level, predominantly in the cerebellum. Many experts avoid the long-term use of phenytoin because of its insidious and potentially dangerous side effects.

Jackson EK. Diuretics. In: Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York: McGraw Hill, 1996: 706.

Joosten E, Pelemans W. Megaloblastic anaemia in an elderly patient treated with triamterene. Neth J Med 1991 Jun;38(5-6):209-211.
Abstract: The case is presented of an elderly woman in whom megaloblastic anaemia due to folate deficiency was diagnosed. It is speculated that this disorder was induced by treatment with triamterene.

Kahn, SB, Fein, SA, Brodsky, I. Effects of trimethoprim on folate metabolism in man. Clin Pharmacol Ther 1968;9:550-560.

Kamen B. Folate and antifolate pharmacology. Semin Oncol 1997 Oct;24(5 Suppl 18):S18-30-S18-39. (Review)
Abstract: Folic acid is a water-soluble vitamin associated with the other B vitamins. In its fully reduced form (tetrahydrofolate), folate serves as a 1-carbon donor for synthesis of purines and thymidine as well as in the remethylation cycle of homocysteine to methionine. Folate is essential for normal cell growth and replication. It therefore is not surprising that folate analogues have served and continue to serve well as antibiotics and cytotoxic drugs in the treatment of cancer, autoimmune diseases, psoriasis, and bacterial and protozoal infections. During the past 50 years, many of the enzymes requiring folate as a co-factor (ie, thymidylate synthase), and molecules critical in folate homeostasis (ie, the reduced folate carrier, folylpolyglutamate synthase), have been purified and even crystallized. The genes have been cloned, sequenced, and mapped, providing detailed knowledge of their regulation and three-dimensional structure. This has, in part, led to the rational synthesis of a large number of folate analogues that differ from methotrexate, the "classical antifolate," in transport, metabolism, and intracellular targets. Currently, several new folate analogues with unique biochemical properties and clinical applications are being tested. The goals of this brief review are to review folate homeostasis, to highlight the similarities and differences between natural folate and antifolates with respect to biochemistry and metabolism, and to present the pharmacology of methotrexate and several next-generation folate analogues, such as trimetrexate and raltritrexed, with an emphasis on mechanisms of drug resistance.

Kishi T, Fujita N, Eguchi T, Ueda K. Mechanism for reduction of serum folate by antiepileptic drugs during prolonged therapy. J Neurol Sci 1997 Jan;145(1):109-112.
Abstract: To determine whether the induction of liver enzymes by antiepileptic drugs play a major role in folate depletion, serum concentrations of folate were measured in age-matched control subjects without anemia and in epileptic outpatients who were being treated with a single antiepileptic drug. Two of the four drugs being administered were enzyme inducers. A protein binding radioassay was used to measure folate levels. Compared with serum folate levels in controls (5.14 +/- 1.88 ng/ml: n = 74), mean serum folate levels were reduced significantly in patients treated with phenobarbitone (3.91 +/- 1.73 ng/ml, p < 0.01: n = 33) and carbamazepine (3.85 +/- 1.02 ng/ml, p < 0.01: n = 36): both of which are enzyme-inducing agents. In contrast, patients treated with the non-enzyme-inducer valproate (5.39 +/- 1.71 ng/ml: n = 41) or zonisamide (5.59 +/- 2.60 ng/ml: n = 25) exhibited serum folate levels that did not differ significantly from values in controls. Findings showed that a reduction in serum folate is associated with the induction of enzymes by antiepileptic drugs. Thus, the induction of microsomal liver enzymes may be critical to the depletion of folate by antiepileptic drugs.

Klipstein FA, Schenk EA, Samloff IM. Folate repletion associated with oral tetracycline therapy in tropical sprue. Gastroenterology 1966 Sep;51(3):317-332.

Klipstein FA, Samloff IM. Folate synthesis by intestinal bacteria. Am J Clin Nutr 1966 Oct;19(4):237-246.

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

Kornberg A, Segal R, Theitler J, Yona R, Kaufman S. Folic acid deficiency, megaloblastic anemia and peripheral polyneuropathy due to oral contraceptives. Isr J Med Sci 1989 Mar;25(3):142-145.
Abstract: A 34-year-old woman developed megaloblastic anemia and peripheral polyneuropathy following the use of oral contraceptives for 4 years. Low levels of folic acid and vitamin B12 were found. Both the complete recovery after therapy with the v