Vitamin B6

Common Names: Vitamin B6; PLP

Clinical Names: Pyridoxine, Pyridoxal-5'-phosphate

Summary

Vitamin B6

forms: Pyridoxine, Pyridoxal-5'-phosphate

overview of interactions:
• nutritional synergy: Beta-adrenergic Blockers

• nutritional synergy: Calcium Channel Blockers

• nutrient affected by drug: Corticosteroids

• nutrient affected by drug: Cycloserine

• nutrient affecting drug toxicity: Docetaxel

• nutrient affected by drug: Gentamicin

• nutrient affected by drug: Hydralazine

• nutrient affected by drug: Isoniazid

• nutrient affecting drug performance: L-Dopa

• nutrient affected by drug: Monoamine Oxidase Inhibitors (MAOI)

• nutrient affected by drug: Neomycin

• nutrient affected by drug: Oral Contraceptives

• nutrient affected by drug: Penicillamine

• nutrient affected by drug: Phenelzine

• homocysteine-related effects of drug: Phenobarbital

• multiple interactions: Phenytoin (Dilantin®)

• nutrient affecting drug performance: SSRI's (Selective Serotonin Reuptake Inhibitors)

• nutrient affected by drug: Tetracyclines

• nutrient affected by drug: Theophylline

• nutrient affecting drug performance: Valproic Acid

chemistry:
• Pyridoxine is water soluble and stable to heat in acid mediums.
• It is unstable in alkaline solutions and very unstable to light.
• Freezing of vegetables decreases B-6 by 20%, canning by 54%, and processing of grains by 40-90%

metabolism:
• Pyridoxine is absorbed in the upper small intestine by simple diffusion.
• The more acidic the milieu, the greater the absorption.

function:
Vitamin B6 plays a central role in the metabolism of amino acids, the formation of key several neurotransmitters, and the production of serotonin, melatonin, and dopamine. Its active form is pyridoxine 5 phosphate (P5P or PLP).
More specifically, it is involved in:
• Transamination: the transfer of NH2 to other amino acids.
• Deamination: removal of amino groups from certain amino acids to be used for an energy source.
• Desulfuration: transfer of the sulfhydryl group (HS) from one amino acid, methionine, to another, serine, to form cysteine.
• Decarboxylation: the removal of COOH groups from certain amino acids to form another compound. Required in the synthesis of the neurotransmitters serotonin, norepinephrine, and histamine from tryptophan, tyrosine, and histamine, P5P can be highly concentrated in the brain even when low levels exist in the blood.
• It is thought that dementia is associated with reduced transport.
• Required for the formation of alpha aminolevulinic acid, a precursor of heme in hemoglobin.
Tryptophan -----> PLP -----> Niacin
• Promotes release of glycogen from liver and muscle as glucose-1-phosphate.
Linoleic acid -----> GLA -----> PGE1 and small amounts of arachadonic acid.
• Vital for the formation of sphyngolipids involved in the development of the myelin sheath surrounding nerve cells.
• Involved with the synthesis of the intrinsic factor.

dietary sources: Pork, organ meats, meat, poultry, fish, corn, legumes, seeds, grains, wheat, potatoes, bananas, green leafy vegetables, green beans, brewer's yeast, avocados, wheat germ, wheat bran, soybeans, walnuts, blackstrap molasses, cantaloupe, cabbage, milk, egg yolks, green peppers, carrots, peanuts and pecans.
note: Cooking and food processing destroys vitamin B6.

deficiency:
• Vitamin B6 deficiency can manifest as impaired immunity, skin lesions, and mental confusion. However, frank deficiencies are considered rare.
• Marginal B6 deficiency patterns have been noted among women using birth control pills, alcoholics, and patients with kidney failure.
• Adults given deoxypyridoxine (antagonist) developed depression, nausea, vomiting, mucous membrane lesions, seborrheic dermatitis and peripheral neuritis. Also ataxia, hyperacusis, hyperirritability, altered mobility and alertness, abnormal head movements and convulsions.
• Analysis of our food supply indicates that many of us are consuming less than the RDA amount. This is due to practices of milling that remove up to 90% of vitamin B6. As of yet, there are no laws requiring the enrichment of milled grains with pyridoxine.
• Probably the biggest cause of deficiency (or an increased requirement) is the addition of antagonists in the environment over the last 50 years.
• Other causes of deficiency include pregnancy, malabsorption, and age-related.

Antagonists include:
• Hydrazine compounds: INH (isonicotinic acid hydrazine), hydralazine, phenelzine, succinic acid 2,2-Dimethylhydrazide, maleic hydrazide, tartrazine (yellow dye #5), peroxides and free radicals, birth control pills, PCBs, environmental toxins, and L-canavanine.
• Alcohol has been shown to deplete vitamin B6 stores.
• Caramel coloring acts as an antagonist to vitamin B6.

known or potential therapeutic uses: Acne, alcohol withdrawal support, asthma, attention deficit disorder, autism, carpal tunnel syndrome, celiac disease, coronary heart disease, dementia, depression (associated with birth control pills), diabetes mellitus, diabetic neuropathy, elevated homocysteine, HIV support, hypoglycemia, infant seizures, iron-resistant anemia, kidney stones, monosodium glutamate (MSG) sensitivity, nausea of pregnancy, photosensitivity, premenstrual syndrome, retinopathy, rheumatism, seborrheic dermatitis, sickle cell anemia, sideroblastic anemia, tardive dyskinesia, toxemia of pregnancy.

maintenance dose: 10-40 mg per day.
• RDA:
Infants and children 0.1-1 mg
Men and Women: 1.3-1.7 mg, increasing with age
Pregnant and nursing women: 2 mg

• Optimal daily intake:
Women: 50 mg
Men: 35 mg

therapeutic dose: 50 mg - 500 mg daily; typically safe at levels of 200-300 mg per day; even so, individuals using more than 100-200 mg per day for more than two months should consult with a nutritionally-trained healthcare professional.

maximum dose: According to the U.S Institute of Medicine conservative practice recommends that adults not take more than 100 milligrams per day of vitamin B6 because intakes above this amount could cause sensory neuropathy, a nerve disorder that can lead to pain, numbness and weakness in the limbs. Even so 200-300 mg per day of vitamin B6 is usually safe, with infrequent problems reported in this dosage range. Even under physician supervision a daily dose of 500 mg should never be exceeded.

side effects: Side effects from vitamin B6 are dose-dependent. While therapeutic doses of 3000 mg per day have been used, toxic side effects from vitamin B6 become more common when intake reaches 2,000 mg per day.
Note: Pregnant and lactating women should avoid daily doses of vitamin B6 greater than 100 mg.

toxicity:
• Watch for peripheral neuropathy at doses of greater than 500 mg per day. Large doses may result in increased urinary excretion of other B vitamins, leading to imbalances. In one case it was determined that 200 mg per day resulted in peripheral neuropathy. This was an anecdotal study done by Katrina Dalton. Normally 2-5 gms over a few months is the dose required to get toxic symptoms consisting of numbness and tingling in the extremities. In a study by Parry and Bredesen sensory neuropathy was observed with "low-dose pyridoxine", defined as 0.2 to 5 g per day. These symptoms usually disappear once the vitamin B-6 is discontinued, but may linger for a few months if severe.
(Dalton K, Dalton MJ. Acta Neurol Scand 1987 Jul;76(1):8-11; Parry G, Bredesen DE. Neurology 1985 Oct;35(10):1466-1468)

contraindications:
• Pregnant and lactating women should avoid daily doses of vitamin B6 greater than 100 mg.
• Individual on L-Dopa for Parkinson's disease.



Interactions

nutritional synergy: Beta-adrenergic Blockers and Calcium Channel Blockers

• mechanism: The biochemical conversion of homocysteine to cysteine is dependent upon two consecutive, vitamin B6-dependent reactions. Homocysteine produces atherosclerosis, thromboembolism, and vascular endothelial cell injury. There is strong evidence that vascular dysfunction produced by homocysteine may be due to oxidative stress and subsequent endothelial cell damage. The combined effect of homocysteine and cholesterol is additive. Hyperhomocysteinemia is associated with numerous conditions, including coronary disease, stroke, peripheral vascular disease (carotid artery and cerebrovascular atherosclerosis), venous thrombosis, renal disease, diabetes mellitus, and organ transplant.
(Bollani G, et al. Cardiologia. 1999 Jan;44(1):75-81; Prasad K. Intl J Angiology 1999 Jan;8(1):76-86.)

• research: Ubbink et al performed oral methionine load tests on 22 vitamin B6-deficient asthma patients treated with theophylline (a vitamin B6 antagonist) and 24 age- and sex-matched controls with a normal vitamin B6 status. Both groups had normal circulating vitamin B12 and folate concentrations. Methionine loading resulted in significantly higher increases in circulating total homocysteine and cystathionine concentrations in vitamin B6-deficient patients compared with controls. However, six weeks of vitamin B6 supplementation (20 mg per day) significantly reduced post-methionine load increases in circulating total homocysteine concentrations in deficient subjects, but had no significant effect on the increase in total homocysteine concentrations in controls. They concluded that a vitamin B6 deficiency may contribute to metabolic changes associated with premature vascular disease.
(Ubbink JB, et al. J Clin Invest 1996 Jul 1;98(1):177-184.)

• nutritional support: Individuals taking beta-blockers or calcium channel blockers should consult with their prescribing physician and/or a healthcare provider trained in nutritional therapies about the potential benefits of supplementing with vitamin B6. Typical therapeutic dosages of B6 are in the range of 100-200 mg of per day, with higher dosages warranting monitoring by a healthcare professional due to adverse effects potentially associated with supplementing at higher dosages for an extended period.

nutrient affected by drug: Corticosteroids

• mechanism: Corticosteroid drugs, including prednisone, can contribute to depletion of vitamin B6.
(Pronsky, Z. 1991, 60; Holt GA. 1998, 83.)

• nutritional support: Individuals using corticosteroids for periods longer than two weeks should consult with their prescribing physician and/or a nutritionally trained healthcare professional about the potential need to supplement with vitamin B6 to counter the depleting effects of the drug(s). A typical dose in such situations would be in the range of 25-50 mg of vitamin B6 per day.

nutrient affected by drug: Cycloserine

• research: Many studies have found that cycloserine impairs availability of vitamin B6 in the body. The clinical significance of this interaction remains uncertain.

• nutritional support: An individual taking cycloserine might protect themselves against Vitamin B6 depletion by supplementing their diet with 25 mg of vitamin B6 per day. Some research indicates that such nutrient support might also aid against adverse side effects of the drug.
(Goldshtein VD, et al. Probl Tuberk 1971;49(11):15-19; Haden HT. Arch Intern Med 1967 Nov;120(5):602-606; Laine-Cessac P, et al. Biochem Pharmacol 1997 Oct 15;54(8):863-870; Nair S, et al. J Clin Pharmacol 1976 Aug;16(8-9):439-443; Roe D. 1984, 288-89, 505-23.)

nutrient affecting drug toxicity: Docetaxel

• adverse drug effect: Some individuals receiving treatment with docetaxel have suffered from painful swelling and inflammation in their hands and feet.

• research: Vukelja et al reported two cases in which individuals experiencing these drug-induced side effects responded positively to supplementation with vitamin B6, 50 mg three times daily. The patients in this study reported initial relief from their symptoms within twelve to twenty-four hours with continued improvement over subsequent weeks.
(Vukelja SJ, et al. J Natl Cancer Inst 1993 Sep 1;85(17):1432-1433.)

• nutritional support: Vitamin B6 supplementation might counteract some of the adverse effects of treatment with docetaxel. While daily dosages of 200-500 mg can be used under supervision, vitamin B6 in dosages of over 100-200 mg per day for extended periods could potentially damage sensory nerves. As indicated by preliminary research, moderate dosages, well within the range considered generally safe, could be adequate for countering these adverse affects of docetaxel. Individuals being treated with docetaxel should consult their prescribing physician and/or a nutritionally trained healthcare professional before starting supplementation with vitamin B6.

nutrient affected by drug: Gentamicin

• mechanism: Pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, readily forms complexes with gentamicin, as well as a wide variety of other potentially toxic substances. This interaction results in a reduction of renal PLP.

• research: Numerous animal studies have reported that gentamicin interferes with vitamin B6 metabolism, and that vitamin B6 supplementation can prevent adverse side effects from gentamicin without reducing the drug's efficacy.
(Keniston RC, et al. Toxicol Appl Pharmacol. 1987 May;88(3):433-441; Kacew S. J Pharmacol Exp Ther. 1989 Jan;248(1):360-366; Weir MR, et al. Vet Hum Toxicol. 1990 Jun;32(3):235-238; Enriquez JI Sr, et al. Vet Hum Toxicol. 1992 Feb;34(1):32-35.)

• nutritional support: Vitamin B6 supplementation might counteract some of the adverse effects of treatment with gentamicin. While daily dosages of 200-500 mg can be used under supervision, vitamin B6 in dosages of over 100-200 mg per day for extended periods could potentially damage sensory nerves. Individuals taking gentamicin should consult their prescribing physician, pharmacist, and/or a nutritionally trained healthcare professional about the value and appropriate dosage of vitamin B6 as a means of preventing nutrient depletion and resultant adverse effects from the drug.

nutrient affected by drug: Hydralazine

• mechanism: Hydralazine alters enzymatic pathways and increases B6 excretion to lessen levels of Vitamin B6 in the body.

• adverse drug effects: B6 deficiency neuropathies possible.

• nutritional support: Individuals taking hydralazine should consult with their prescribing physician and/or a nutritionally trained healthcare professional regarding the use of vitamin B6 to counter adverse effects of hydralazine. Those taking hydralazine might benefit from supplementing with 50-100 mg vitamin B6 per day. However, extended use of B6 at this level can produce side effects in some individuals.

nutrient affected by drug: Isoniazid

• mechanism: This hydrazine derivative is a B6 antagonist, inactivating PLP and sometimes leading to peripheral neuropathies. Intravenous pyridoxine is considered the specific antidote for seizures due to acute isoniazid neurotoxicity.

• nutritional support: Supplement B6 to patients taking Isoniazid. Optimal dose unknown. One study of children with TB found no significant benefit from supplementation with Vitamin B6. However, a review concluded that: "Given in gram-per-gram amounts of the isoniazid ingested, pyridoxine (vitamin B6) usually eliminates seizure activity and helps to correct the patient's metabolic acidosis."
(Mbala L, et al. Trop Doct 1998 Apr;28(2):103-104; Romero JA, et al. Am Fam Physician 1998 Feb 15;57(4):749-752; Glenn GM, et al. Vet Hum Toxicol 1995 Aug;37(4):342-245; Snider DE Jr. Tubercle 1980 Dec;61(4):191-196.)

nutrient affecting drug performance: L-Dopa

• mechanism: Levodopa is a vitamin B6 antagonist.

• nutritional concerns: Supplementation of Vitamin B6 at different levels can produce significantly different effects. Vitamin B6 deficiency can be avoided by supplementing at low levels of 5-10 mg per day or less. While larger doses of B6 should be avoided as they allow L-dopa to be metabolized to dopamine and can inactivate the drug. Note, however, that this contraindication does not hold for patients using Sinemet as the carbidopa component inhibits the effect of vitamin B6 on the dopa pathway. Thus, patients using Sinement will not experience any adverse interaction from supplementing with vitamin B6.
(Trovato, A, et al. Am Family Phys 1991;44:1651-1658; Long, JW. 1992.)

nutrient affected by drug: Monoamine Oxidase Inhibitors (MAOI)

• research: Anecdotal evidence indicates that MAO Inhibitors, especially Nardil, can cause vitamin B6 deficiencies. As of yet, there has been no definitive confirmation of this interaction.

• nutritional support: Given that several related drugs, such as Nardil, hydralazine and isoniazid, can induce vitamin B6 deficiencies, some nutritionally-trained physicians advise patients taking these or similar drugs to supplement with vitamin B6, usually at moderate levels such as 50 mg per day.

nutrient affected by drug: Neomycin

• mechanism: Neomycin may inactivate vitamin B6 when taken orally.

• nutritional support: Individuals taking neomycin internally for more than 2-3 days may benefit from taking supplemental vitamin B6 at doses of 25-50 mg per day. Individuals using neomycin topically will not experience problems related to inactivation of vitamin B6.

nutrient affected by drug: Oral Contraceptives

• research: Oral contraceptives have been associated with vitamin B6 depletion and depression, most likely associated with interference in the role that vitamin B6 plays in facilitating the tryptophan to niacinamide pathway. In a 1973 double-blind study of women using oral contraceptives who were diagnosed with depression, Adams et al found that 20 mg per day vitamin B6 was associated with decreased depression, especially among the 50% of the women in the study who demonstrated a measurable vitamin B6 deficiency. Subsequent research by Brown, Rose and Adams indicated that oral contraceptives may not directly change the requirement for vitamin B6; instead, supplementation with B6 may prevent a contraceptive-induced change in the activity of enzymes in the pathway of tryptophan metabolism and thereby promote an improvement in glucose tolerance. In regard to adverse cardiovascular effects of oral contraceptives, it is also important to note that pyridoxal 5-phosphate is essential for the metabolism of the atherogenic amino acid homocysteine.
(Rose DP, et al. Am J Clin Nutr 1975 Aug;28(8):872-878; Adams PW, et al. Lancet 1973 Apr 28;1(7809):899-904; Adams PW, et al. Lancet 1976 Apr 10;1(7963):759-764; Brown RR, et al. Acta Vitaminol Enzymol 1975;29(1-6):151-157; Wynn V, et al. J Steroid Biochem 1975 Jun;6(6):965-970; Leklem JE, et al. Am J Clin Nutr 1975 Feb;28(2):146-156; Rose DP, et al. J Clin Pathol 1972 Mar;25(3):252-258.)

• nutritional support: Women taking oral contraceptives could reduce their adverse effects upon pyridoxine levels, and subsequent outcomes such as increased incidence and severity of premenstrual syndrome, through supplementation with vitamin B6. While the typical supplemental dose for pyridoxine is 10-25 mg per day, higher levels in the range of 200-500 mg per day may be indicated in instances such as the use of oral contraceptives where preventive and therapeutic requirements are greater. Women using oral contraceptives and interested in gaining the benefits of Vitamin B6 supplementation should consult with their prescribing physician and/or a nutritionally trained healthcare provider.

nutrient affected by drug: Penicillamine

• nutritional support: Due to increased excretion and reduced activity of vitamin B6, penicillamine increases the risk of Pyridoxine deficiency and the requirement for Pyridoxine supplementation. Because of their dietary restrictions, individuals with Wilson's disease and cystinuria using penicillamine would benefit from 25 mg per day of pyridoxine during therapy. Rheumatoid arthritis patients whose nutrition is impaired should also be given a daily supplement of pyridoxine. In general, individuals taking penicillamine for any reason should supplement with the relatively small dose of 5-20 mg of vitamin B6 daily.
(Jaffe IA. Ann N Y Acad Sci 1969 Sep 30;166(1):57-60; Bhagavan HN, Brin M. Curr Concepts Nutr 1983;12:1-12.)

nutrient affected by drug: Phenelzine

• research: There have been several reports of vitamin B6 (Pyridoxine) deficiency and peripheral neuropathy associated with long-term phenelzine therapy. Likewise, isoniazid and hydralazine, drugs with chemical structures similar to phenelzine, are known to cause vitamin B6 deficiency.
(Demers RG, et al. South Med J 1984 May;77(5):641-642; Heller CA, Friedman PA. Am J Med 1983 Nov;75(5):887-888; Goodheart RS, et al. Aust N Z J Med 1991 Jun;21(3):339-340.)

• nutritional support: Individuals using phenelzine should discuss the issue of potential depletion of vitamin B6 with their prescribing physician or a nutritionally-trained healthcare professional, especially if they have experienced any symptoms of peripheral neuropathy. vitamin B6 levels can be monitored and any course of supplementation should be supervised.
(Demers RG, et al. South Med J 1984 May;77(5):641-642; Heller CA, Friedman PA. Am J Med 1983 Nov;75(5):887-888; Goodheart RS, et al. Aust N Z J Med 1991 Jun;21(3):339-340.)

homocysteine-related effects of drug: Phenobarbital

• research: The use of phenobarbital has often been found to be associated with decreased levels of vitamin B6 and vitamin B12, as well as a related elevation in plasma concentrations of homocysteine. Apart from its emerging reputation as a risk factor in cardiovascular disease homocysteine has been used as an experimental convulsant. Several researchers have found elevated levels of homocysteine in epileptics using anticonvulsant medications but at this point evidence is mixed as to whether this is attributable to the underlying disease process, the medication, or both. However, the clinical implications of this potential interaction are uncertain at this time.
(Schwaninger M, et al. Epilepsia 1999 Mar;40(3):345-350.)

• nutritional support: Some nutritionally oriented healthcare professionals might consider supplementation with vitamin B6, vitamin B12, or folate as offering therapeutic potential since nutritional deficiencies of these nutrients are associated with increased homocysteine plasma concentrations. While vitamin B12 is generally considered nontoxic, supplemental use of vitamin B6 at high dosages (200 mg or more per day) carries known risks, including eventual damage to sensory nerves. Individuals taking any anti-convulsant drug should consult their prescribing physician about possible benefits and risks from the simultaneous use of vitamin B6 and/or vitamin B12, and only undertake such use under supervision.

multiple interactions: Phenytoin (Dilantin®)

• nutrient affecting drug performance: There have been some reports that vitamin B6, supplemented in doses as low as 80 mg daily, may reduce the effectiveness of phenytoin by up to 50%.
(Hansson O, Sillanpaa M. Lancet 1976 Jan 31;1(7953):256.)

• nutrient affected by drug: Phenytoin can lower plasma levels of vitamin B6. Apart from its emerging reputation as a risk factor in cardiovascular disease homocysteine has been used as an experimental convulsant. Several researchers have found elevated levels of homocysteine in epileptics using anticonvulsant medications, but at this point evidence is mixed as to whether this is attributable to the underlying disease process, the medication, or both. Supplementation with vitamin B6, vitamin B12, or folate has been considered as offering therapeutic potential since nutritional deficiencies of these nutrients are associated with increased homocysteine plasma concentrations.
(Schwaninger M, et al. Epilepsia 1999 Mar;40(3):345-350.)

• nutritional support and concerns: Supplemental use of vitamin B6 at high dosages (200 mg or more per day) carries known risks, including eventual damage to sensory nerves. Individuals using phenytoin should consultant with their prescribing physician and/or a nutritionally trained healthcare professional before introducing supplemental vitamin B6 into their therapeutic regime.

nutrients affecting drug performance: SSRI's (Selective Serotonin Reuptake Inhibitors)

• mechanism: Vitamin B6 plays a central role in the metabolism of amino acids, the formation of key several neurotransmitters, and the production of serotonin, melatonin, and dopamine. Its active form is pyridoxine 5 phosphate (P5P or PLP). Animal studies indicate that high dietary intakes of B vitamins, especially pyridoxine, contribute to a substrate-cofactor interaction between dietary histidine or tryptophan and pyridoxine in the brain. Researchers noted that the degree of this interaction changed according to the level of tryptophan intake, with excess pyridoxine causing essentially no changes in hypothalamic serotonin in the presence of dietary tryptophan at the requirement level, but with elevated tryptophan intake and excess pyridoxine together being associated with significantly increased serotonin.
(Dakshinamurti K, et al. Klin Wochenschr 1990 Jan 19;68(2):142-145; Schaeffer MC, et al. J Nutr. 1998 Oct;128(10):1829-1835; Lee NS, et al. Pharmacol Biochem Behav. 1988 Mar;29(3):559-564.)

• research: Bhagavan et al studied serotonin (hydroxytryptamine) and pyridoxal phosphate (PLP) levels in the blood of eleven hyperactive children and eleven controls and noted significant lower levels of serotonin in the hyperactive patients as compared with controls. They found no differences in PLP content of blood between the two groups. When four children who had displayed low serotonin levels were administered oral doses of pyridoxine researchers observed an appreciable increase in the serotonin content and a very large increase in the PLP content of blood in these hyperactive patients.

• nutritional support: Supplementation with a vitamin B6, or possibly a B complex formulation, may benefit those taking SSRI drugs. A physician can perform a tryptophan load test to determine if there is a deficiency of pyridoxine. However, individuals taking SSRI agents should inform their prescribing physician about ongoing intake of supplements containing B vitamins, especially B6, as the presence of the vitamin(s) may alter the performance of the drug. Likewise, it would be advisable to consult with the prescribing physician and/or a nutritionally trained healthcare professional before starting to take or significantly altering the dosages of any such vitamin supplements while undergoing SSRI therapy. The dosage of the prescription may need to be adjusted to take into account the effects of the vitamin supplementation and obtain the best results from this potential interaction.

nutrient affected by drug: Tetracyclines

• mechanism: Research indicates that tetracycline impairs vitamin B6 absorption.
(Holt GA. 1998, 258; Robinson C, Weigly E. 1984:46-54.)

• nutritional support: While depletion of vitamin B6 may not have clinical significance with short-term use of tetracycline, individuals using the drug for periods longer than two weeks may benefit from supplementation with pyridoxine. Anyone using tetracycline for an extended period should consult with their prescribing physician and/or a nutritionally trained healthcare professional before starting vitamin B6 supplementation. A moderate supplemental dose of pyridoxine is usually in the range of 20-25 mg per day, easily obtained through most multivitamin formulas. Sustained use of higher doses of B6 can result in side effects. Significant dietary sources of vitamin B6 include bananas, lentils, potatoes, raisin bran, turkey, and tuna.

nutrient affected by drug: Theophylline

• mechanism: Theophylline is a potent inhibitor of pyridoxal kinase which is needed to convert vitamin B6 to pyridoxal-5'-phosphate (PLP). Thus theophylline induces a depression of circulating PLP levels while plasma pyridoxal levels remain unchanged. The resultant lack of PLP results in multiple decreased B6 dependent enzyme activities.
(Delport R, et al. Int J Vitam Nutr Res 1988;58(1):67-72; Ubbink JB, et al. J Lab Clin Med 1989 Jan;113(1):15-22; Ubbink JB, et al. Ann N Y Acad Sci 1990;585:285-294; Weir MR, et al. Ann Allergy 1990 Jul;65(1):59-62; Dan-Shya D. et al. Clinical Pharmacol Ther 1983;31:358; Weinberger M, Ginchansky E. J Pediatr 1977 Nov;91(5):820-824.)

• research: In a short-term study Ubbink et al found that theophylline reduced serum vitamin B6 levels in healthy adults and that subsequent supplementation with 10 mg per day normalized those vitamin B6 levels. Later Bartel et al found that vitamin B6 supplementation could reduce tremor and other nervous system side effects associated with a pyridoxal-5-phosphate deficiency due to theophylline. Shimizu et al in a study of twenty-six asthmatic children found a depression of serum PLP levels existed in asthmatic children treated with theophylline compared to those not receiving theophylline. Oral administration of 200 mg of theophylline (TheoDur) to 5 children with asthma significantly depressed serum PLP levels four hours after the drug intake, whereas theophylline did not affect serum pyridoxal levels. Finally, Martinez de Haas et al studied adults with chronic obstructive pulmonary disease and concluded that patients who used theophylline demonstrated a higher prevalence of subnormal vitamin B-6 status than did patients who did not.
(Shimizu T, et al. Pharmacology 1994 Dec;49(6):392-389; Martinez de Haas MG, et al. Ned Tijdschr Geneeskd 1997 Nov 8;141(45):2176-2179; Ubbink JB, et al. J Nutr 1990 Nov;120(11):1352-1359; Bartel PR, et al. Am J Clin Nutr 1994 Jul;60(1):93-99.)

• nutritional support: Theophylline clearly exerts an adverse impact on vitamin B6 status. Fortunately, these side effects are preventable, and may even be reversible, with vitamin B6 supplementation. The conservative daily dose of 10 mg vitamin B6 supported by the literature could provide the desired benefits at minimal risk. Even so, individuals concerned about the interaction between vitamin B6 and theophylline and its repercussions for their health should consult their prescribing physician and/or a nutritionally oriented health care professional.
(Bartel PR, et al. Am J Clin Nutr 1994 Jul;60(1):93-99; Ubbink JB, et al. J Lab Clin Med 1989 Jan;113(1):15-22; Ubbink JB, et al. J Nutr 1990 Nov;120(11):1352-1359.)

nutrient affecting drug performance: Valproic Acid

• research: Ito et al studied the effects of high doses of vitamin B6, valproic acid, or both on twenty patients with infantile spasms and concluded that the combination of vitamin B6 and valproic acid was effective and safe in the treatment of infantile spasms.. Their research found that while vitamin B6 alone provided some benefit, patients who were given a combination of vitamin B6 and valproic acid had significantly fewer seizures and better electroencephalograms than did the group treated initially with vitamin B6 alone. Pietz et al found that 300 mg/kg/day of vitamin B6 (pyridoxine-HCl, orally) reduced infantile spasms in 5 of 17 children within the first two weeks of treatment and within 4 weeks all five patients were free of seizures.
(Ito M, et al. Pediatr Neurol 1991 Mar-Apr;7(2):91-96; Pietz J, et al. Epilepsia 1993 Jul-Aug;34(4):757-763.)

Apart from its emerging reputation as a risk factor in cardiovascular disease homocysteine has been used as an experimental convulsant. Several researchers have found elevated levels of homocysteine in epileptics using anticonvulsant medications but at this point evidence is mixed as to whether this is attributable to the underlying disease process, the medication, or both. The clinical implications of this potential interaction are uncertain at this time. However, supplementation with vitamin B6, vitamin B12, or folate has been considered as offering therapeutic potential since nutritional deficiencies of these nutrients are associated with increased homocysteine plasma concentrations.
(Schwaninger M, et al. Epilepsia 1999 Mar;40(3):345-350.)

• nutritional synergy: Supplemental use of vitamin B6 at high dosages (200 mg or more per day) carries known risks, including eventual damage to sensory nerves. Individuals taking valproic acid should consult their prescribing physician about possible benefit and risks from the simultaneous use of vitamin B6 and only undertake such use under supervision.

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Do not rely solely on the information in this article.

References

Abraham GE, Hargrove JT. Effect of Vitamin B6 on premenstrual symptoms in women with PMS. A double blind crossover study. Infertility. 1980;3(2):155-165.
Abstract: 25 women with moderate to severe PMS were studied for 6 menstrual cycles. During 3 of these cycles they received a single sustained-release tablet containing 500mg of B6 each day. During the other 3 cycles they were given an inert placebo that appeared identical to the B6 tablets. Throughout the entire 6 month period women kept a symptom diary. A total of 19 symptoms were rated using a 4 point scale. The daily symptom score was totalled for each day and for each 3 month cycle. At the end of the study, 21 of 25 subjects had lower PMS scores while taking the vitamin B6 compared to the placebo. In each case the difference was statistically significant.

Adams PW, Rose DP, Folkard J, Wynn V, Seed M, Strong R. Effect of pyridoxine hydrochloride (vitamin B6) upon depression associated with oral contraception. Lancet 1973 Apr 28;1(7809):899-904.

Adams PW, Wynn V, Folkard J, Seed M. Influence of oral contraceptives, pyridoxine (vitamin B6), and tryptophan on carbohydrate metabolism. Lancet 1976 Apr 10;1(7963):759-764.
Abstract: Carbohydrate metabolism and vitamin-B6 status were assessed before and after pyridoxine administration in 46 women taking combined oestrogen-progestagen oral contraceptives (O.C.). 18 women had evidence of tissue depletion of vitamin B6, although all the women had abnormal tryptophan metabolism, including increased urinary xanthurenic acid (X.A.) excretion. In the women with vitamin B6 deficiency, administration of this vitamin caused elevation of fasting blood-pyruvate levels, and reduction in plasma glucose, insulin, and blood-pyruvate responses after an oral glucose load. These changes in carbohydrate metabolism were not found in the 28 non-vitamin-B6-deficient women. These results indicate that carbohydrate intolerance in women on O.C. is unlikely to be mediated by the formation of a complex of X.A. with insulin, as has formerly been proposed. Since the synthesis of the tryptophan metabolite quinolinic acid, an inhibitor of the heptaic enzyme phosphoenolpyruvate carboxykinase, may be enhanced by the administration of pyridoxine, it is suggested that this metabolite might be the important factor in the improvement of glucose tolerance in the vitamin-B6-deficient women. This conclusion is supported by the improvement in glucose tolerance observed in 6 women on O.C. and in 4 patients with glucocorticoid excess who were not vitamin-B6 deficient, when they were given tryptophan to augment the synthesis of quinolinic acid.

Adler M, Girsh-Solomonovich Z, Raikhlin-Eisenkraft B. [Pyridoxine for severe metabolic acidosis and seizures due to isoniazid overdose]. Harefuah 1993 May 16;124(10):616-618. [Article in Hebrew]
Abstract: A 15-year-old girl took 3 g of isoniazid (15 tablets) in a suicide attempt and was brought unconscious to the emergency room. She was in respiratory failure, with seizures that could not be stopped with diazepam. Severe metabolic acidosis with normal serum lactate developed (pH 6.85), but did not improve after infusion of bicarbonate. Intravenous administration of pyridoxine led to prompt cessation of the seizures and to gradual improvement of acid-base status. She recovered consciousness after several hours and was discharged a week later.

Bamji MS, Safaya S, Prema K. Low dose injectable contraceptive norethisterone enanthate 20mg monthly - II. Metabolic side effects. Contraception 1981 Jan;23(1):23-36.
Abstract: Metabolic effects of a long-acting low dose injectable contraceptive, norethisterone enanthate 20-mg, monthly injections (Neten-20), was tested in 13 women belonging to the low income groups over a period of 1 year. No change was observed in hemoglobin, hematocrit, glucose tolerance, plasma lipids, iron, calcium, or serum glutamate-oxaloacetate transaminase after treatment. Marginal rise in albumin and fall in some globulin fractions was observed. The slight fall seen in serum alkaline phosphatase could be attributed to a change in lactation status. Vitamin A, pyridoxine and riboflavin status were not altered. A peculiar aberration in the tryptophan-niacin pathway as indicated by rise in kynurenic acid excretion after tryptophan load was observed. This could be corrected by multivitamin therapy. These data suggest that the use of Neten-20 for one year does not lead to adverse metabolic effects analogous to those seen with combination type oral contraceptives.

Bartel PR, Ubbink JB, Delport R, Lotz BP, Becker PJ. Vitamin B-6 supplementation and theophylline-related effects in humans. Am J Clin Nutr 1994 Jul;60(1):93-99.
Abstract: This study investigates whether vitamin B-6 supplementation reduces the stimulatory effects of theophylline (a pyridoxal kinase antagonist) on the nervous system. Twenty young, healthy adults entered this double-blind, randomized, crossover study but only 15 completed the experiment. The dependent measures were a battery of psychomotor tests, electrophysiological tests, and self-report questionnaires. Most tests, including spectral electroencephalography, aspects of the electromyograph, the Sternberg Test of information processing, and questionnaires of sleep quality and daytime sleepiness failed to distinguish between vitamin B-6 and placebo supplementation. However, theophylline-related tremor was markedly reduced (p < 0.01) with vitamin B-6 supplementation after a single dose of theophylline and a similar but nonsignificant trend was observed with repeated doses. There was a tendency for vitamin B-6 supplementation to reduce many side effects related to nervous system function. These findings suggest that vitamin B-6 supplementation with theophylline therapy may have some beneficial effects.

Baum M, Cassetti L, Bonvehi P, Shor-Posner G, Lu Y, Sauberlich H. Inadequate dietary intake and altered nutrition status in early HIV-1 infection. Nutrition 1994 Jan-Feb;10(1):16-20.
Abstract: Recent studies indicate that multiple nutritional abnormalities occur relatively early in the course of human immunodeficiency virus (HIV-1) infection. Decreased plasma levels of vitamins B6, B12, A, and E and zinc have been correlated with dietary intake and associated with significant alterations in immune response and cognitive function. To determine the level of intake consistent with normal plasma nutrient levels, we examined nutrition status in relation to food consumption and nutrient supplementation in HIV-1-seropositive (HIV+) and -seronegative (HIV-) homosexual men. The mean level of total intake (diet plus supplements) for all nutrients was significantly higher in HIV+ men. To achieve normal plasma nutrient values, the HIV+ men appeared to require intake in multiples of the recommended dietary allowance (RDA) for vitamins A, E, B6, and B12 and zinc. For the HIV+ men, a relatively high proportion of biochemical deficiency was associated with consumption of vitamin B6 and zinc at the RDA level. Because little evidence of deficiency was observed with elevated intake in both groups, an effective program of nutritional supplementation may be beneficial in maintaining adequate plasma nutrient levels.

Baumblatt MJ, Winston F. Pyridoxine and the pill. Lancet 1970 Apr 18;1(7651):832-833.
Abstract: 58 women depressed and taking BCP were treated with vitamin B6 in doses of 25mg b.i.d. at the first sign of any premenstrual depression. After 3 months of therapy, more than 75% of the women reported either complete relief or considerable improvement in their symptoms. The 44 women who appeared to respond to the B6 were then asked to discontinue it for a while to see if symptoms would return. All of the women refused.

Berger AR, Schaumburg HH, Schroeder C, Apfel S, Reynolds R. Dose response, coasting, and differential fiber vulnerability in human toxic neuropathy: a prospective study of pyridoxine neurotoxicity. Neurology 1992 Jul;42(7):1367-1370.
Abstract: We administered either 1 or 3 g/d of pyridoxine (vitamin B6) to five healthy volunteers and repeatedly followed serum pyridoxal phosphate levels, clinical symptoms and signs, quantitative sensory thresholds (QSTs), and sural nerve electrophysiology. Pyridoxine was discontinued at the first sign of either clinical or laboratory abnormality. In all subjects, sensory symptoms and QST abnormalities occurred concurrently. Subjects receiving higher doses became symptomatic earlier than low-dose subjects. Elevation of thermal QSTs preceded or exceeded that for vibration in the three low-dose subjects; vibration and thermal QST became abnormal simultaneously in the higher-dose subjects. A reduction in the amplitude of the sural sensory potential lagged behind QST changes in two of three subjects. Symptoms continued to progress ("coasting") for 2 to 3 weeks despite stopping pyridoxine administration and the return of serum pyridoxal phosphate levels to normal. This study suggests that (1) there is a clear dose-percent relationship for pyridoxine-induced neuropathy, (2) QST is a sensitive measurement for detecting early peripheral neuropathy; QST abnormalities may precede changes in nerve conduction studies, (3) coasting appears unrelated to persistently elevated blood levels of the toxin, and (4) a dose-dependent vulnerability may exist among nerve fibers of different caliber when exposed to an axonal toxin, such as pyridoxine.

Bermond P. Therapy of side effects of oral contraceptive agents with vitamin B6. Acta Vitaminol Enzymol 1982;4(1-2):45-54.
Abstract: Studies carried out in different countries during the last 15 years have provided evidence that supplementation with (or excess of) estro-progestational hormones may be accompanied by an increased urinary excretion of tryptophan metabolites, as happens in pyridoxine deficiency. Further methods of assessment of vitamin B6 in humans have confirmed an impaired status in women using hormonal contraception. Disturbances in the metabolism of tryptophan have been shown to be responsible for such symptoms as depression, anxiety, decrease of libido and impairment of glucose tolerance occurring in some of the OCA users. Administration of 40 mg of vitamin B6 daily not only restores normal biochemical values but also relieves the clinical symptoms in those vitamin B6 deficient women taking OCA's. Further studies are justified to clarify whether vitamin B6 supplementation may contribute to improving depression also in other situations with hyperoestrogenism (pregnancy, puerperium, estro-progestational treatments, etc.), as well as correcting metabolic impairments, such as a minor alteration of glucose tolerance.

Bernstein AL. Vitamin B6 in clinical neurology. Ann N Y Acad Sci 1990;585:250-260. (Review)
Abstract: Many conditions in clinical neurology may be responsive to pyridoxine as a therapeutic agent. The current difficulty is in trying to isolate the conditions that are most likely to respond. Treating seizures is a major part of a neurologic practice. Our current therapeutic agents are only partially successful and limited by multiple side effects. One problem is that patients often have to take these agents for an entire lifetime, further raising the risk of toxicity. If pyridoxine supplementation can improve the efficacy of currently used medications, it will be gladly accepted into our therapeutic arsenal. Headache, chronic pain, and depression all appear to run together in many of our patients. The observations that serotonin deficiency is a common thread between them and that pyridoxine can raise serotonin levels open a wide range of therapeutic options. Small studies have been carried out with mixed success. Comparison with amitriptyline in the treatment of headache appears to show about equal efficacy, although side effects would be expected to be more of a problem with the amitriptyline. Behavioral disorders are relatively common and continue to be a major problem, disrupting the lives of the patients and their families. Current treatments are not acceptable to most people because of the risk of side effects with long-term usage. If, as Dr. Feingold suggests, many of these problems are caused by "toxic" exposures to chemicals that are pyridoxine antagonists, supplementation at early ages may reduce the incidence of hyperactivity and aggressive behavior. This raises the question of safety. Is pyridoxine safe for long-term use in large segments of the population, including children? The studies on children with Down's syndrome and autism, utilizing much higher doses than are used for other therapeutic purposes, seem to indicate relative safety if carefully monitored. Studies involving large population groups with carpal tunnel syndrome, all adults, using 100-150 mg/day have shown minimal or no toxicity in five- to 10-year studies. Women self-medicating for PMS taking 500 to 5000 mg/day have shown peripheral neuropathy within one to three years. It would appear from this retrospective analysis that pyridoxine is safe at doses of 100 mg/day or less in adults. In children there is not enough data to make any sort of suggestion. Because the major neurologic complication is a peripheral neuropathy and the causes of this condition are myriad, pyridoxine may cause neuropathy only in patients with a pre-existing susceptibility to this condition.

Bhagavan HN, Brin M. Drug--vitamin B6 interaction. Curr Concepts Nutr 1983;12:1-12. (Review)
Abstract: In conclusion, there are several drug types that can interfere with vitamin B6 metabolism. In most cases, the interaction involves a complex formation between the drug (or a derivative) and the reactive coenzyme PLP, resulting in a Schiff base. Such an interaction leads to an inactivation of PLP (and also of the drug). Other types of interaction involve (a) stimulation of vitamin B6-dependent pathways and (b) competition with PLP for the binding site on the enzyme. Examples of the above are the steroid hormones (oral contraceptives). In most instances, overt symptoms of vitamin B6 deficiency due to chronic ingestion of these drugs are observed, and neurological problems seem to be rather frequent. Because of the reactive nature of the coenzyme PLP and the ease with which it can interact with drugs, sub-clinical (marginal) vitamin B6 deficiency should be suspected in the absence of overt clinical signs. Once the vitamin B6 problem has been identified, the condition can usually be treated by judicious use of large doses of vitamin B6 without compromising the clinical efficacy of the drug.

Bhagavan HN, Coleman M, Coursin DB.  The effect of pyridoxine hydrochloride on blood serotonin and pyridoxal phosphate contents in hyperactive children. Pediatrics. 1975 Mar;55(3):437-441.
Abstract: The contents of serotonin (hydroxytryptamine) and pyridoxal phosphate (PLP) in the blood of 11 hyperactive children and 11 controls were determined on an outpatient basis. A significant decrease in serotonin content was found in blood samples from hyperactive patients as compared with controls. There were no differences in PLP content of blood between the two groups. Four children were selected for a study of the effects of pyridoxine hydrochloride (vitamin B6) on low serotonin levels. Oral doses of pyridoxine resulted in an appreciable increase in the serotonin content and a very large increase in the PLP content of blood in these hyperactive patients.

Biskind, Morton, Gerson, Gerson, Leonard. B6 deficiency in the etiology of menorrhagia, metrorrhagia, cystic mastitis, and premenstrual tension. Surgery, Gynecology and Obstetr. Jan 1944. 49-57.
Abstract: Biskind discovered that when he fed rats a diet deficient in B vitamins they lost the ability to metabolize estrogen at normal rates. Suspecting that women who had a deficiency in B vitamins might have symptoms associated with excess estrogen: such as heavy menstrual flow, irregular bleeding, cystic breasts, and premenstrual tension: he surveyed B vitamin deficient women. Of 39 women questioned, 37 had gynecological problems. In treating their B vitamin deficiency, he found that they also experienced dramatic relief of their gynecological symptoms. In another 52 patients without obvious B vitamin deficiency he gave B vitamins for one or more gynecologic complaints and these women also experienced great relief.

Bollani G, Ferrari R, Bersatti F, Ferrari M, Cattaneo M, Zighetti ML, Visioli O, Assanelli D. [A hyperhomocysteinemia study in a population with a familial factor for acute myocardial infarct and sudden cardiac death at a young age]. Cardiologia. 1999 Jan;44(1):75-81. [Article in Italian]
Abstract: The alterations of the metabolism of methionine determining an accumulation of homocysteine in blood (hyperhomocysteinemia) recognize a multifactorial etiology, hereditary as well as acquired. To date several case-control studies have documented that the condition of hyperhomocysteinemia can be considered an independent risk factor of coronary disease and its noxious effects are dose-dependent. It exerts its effect by different mechanisms both prothrombotic and endothelial. In our study we started from an initial cohort of 2227 subjects (1210 males, 1017 females) aged between 45 and 64 years among which we selected 22 persons with at least 2 first-degree relatives below age 50 who had had either a major cardiovascular event (acute myocardial infarction or sudden death) or angiographically documented cardiac disease. We reconstructed the proper pedigrees obtaining 22 families in whom we identified four main subgroups to carry out analyses and comparisons: case-control, composed respectively of all the subjects who survived a major cardiovascular event or a coronary disease documented angiographically and clinically healthy subjects; affected line and non affected line, composed respectively of members belonging to the family line of the proband and members of collateral family line. Each of the subjects involved in the study underwent a complete history regarding job and sports activities, a standardized physical examination, 12-lead digital ECG according to the European Standard Communication Protocol. A blood sample was taken in fasting conditions to determine total cholesterol, HDL and LDL cholesterol, triglycerides, glycemia, fibrinogen, plasma homocysteine. The results indicate how among the cases there were more subjects with homocysteine higher than the 95 degrees percentile in males alone (p = 0.03), the estimated odds ratio calculated from Fisher's test was 8.34 (95% confidence interval 1.32-52.7). Despite the fact that mean age was significantly lower (p = 0.01) in males of the affected line compared to those of the non affected line, the results show much higher homocysteine values in the affected family line in both males and females: a difference quite evident in the distribution especially as regards the 95 degrees percentile. These results obtained in the subjects belonging to the same families emphasize that familial aggregation, which influences the sharing of the genetic patrimony, socio-cultural environment and food habits can induce a differential risk for homocysteinemia. The study of mutations of genes coding for the key enzymes of the metabolism of homocysteine, methylenetetrahydrofolate reductase and cystathionine beta-synthase, which we prepared, will enable use to evaluate the relative influence feeding habits and genetic factors have in the development of hyperhomocysteinemia.

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.

Bremenep SM, Alferova VA, Zgurskaia GN, Zubkova EI, Pipko AS, Rogova KP. [Changes in metabolism of vitamins B6, Bl2, PP, pantothenic acid and vitamin C in patients with chronic colitis of various etiology treated with tetracycline]. Antibiotiki 1967 Apr;12(4):343-347. [Article in Russian]

Brophy MH, Siiteri PK. Pyridoxal phosphate and hypertensive disorders of pregnancy. Am J Obstet Gynecol 1975 Apr 15;121(8):1075-1079.
Abstract: Pyridoxal phosphate (vitamin B6) concentrations in peripheral and cord blood obtained at the time of delivery were measured in 30 women. The average plasma concentration in nine women with normal pregnancy was 4.3 ng. per milliliter; in 10 women with pre-eclampsia, 3.3 ng. per milliliter; and in nonpregnant women, 17 ng. per milliliter. The average cord blood plasma concentration of normal infants was 28.4 ng. per milliliter, whereas that of infants of pre-eclamptic mothers was 12.2 ng. per milliliter. This twofold difference in the cord plasma concentrations was statistically significant (p smaller than 0.001). Pyridoxal phosphate concentrations in the infants' cord plasma were increased in all pregnancies studied by administration of pyridoxine either orally or intravenously. These findings together with other data, demonstrating (1) that B6 deficiency during pregnancy may lead to abnormal neurologic development in experimental animals and (2) that brain development in infants of toxemic mothers may be retarded, suggest that dietary supplementation with vitamin B6 should be instituted in women at high risk for development of toxemia of pregnancy.

Brown RR, Rose DP, Leklem JE, Linkswiler HM. Effects of oral contraceptives on tryptophan metabolism and vitamin B6 requirements in women. Acta Vitaminol Enzymol 1975;29(1-6):151-157.
Abstract: To evaluate the effect of oral contraceptive usage on the nutritional requirement for vitamin B6, control women and oral contraceptive users were depleted of vitamin B6 for 1 month followed by a month of repletion with 0.8, 2.0, or 20.0 mg of pyridoxine hydrochloride per day. At weekly intervals a number of indices of vitamin B6 nutrition were measured. Marked elevation in excretion of tryptophan metabolites occurred in oral contraceptive users after tryptophan loads. However, other indices of vitamin B6 nutritional state, including urinary 4-pyridoxic acid excretion, urinary cystathionine excretion, plasma pyridoxal phosphate concentrations, and erythrocyte aspartate and alanine aminotransferases were not different between controls and oral contraceptive users. The excretion of metabolites after oral loading doses of L-kynurenine (which bypasses tryptophan oxygenase) was elevated in oral contraceptive users indicating that abnormal metabolism of tryptophan was not due only to induced tryptophan oxygenase. The data indicate that use of oral contraceptives does not generally change the requirement for vitamin B6 but rather produces a specific change in activity of enzymes beyond kynurenine in the pathway of tryptophan metabolism.

Collipp PJ, Goldzier S 3d, Weiss N, Soleymani Y, Snyder R. Pyridoxine treatment of childhood bronchial asthma. Ann Allergy 1975 Aug;35(2):93-97.
Abstract: Urinary xanthurenic and kynurenic acid levels were measured in five patients while they were receiving 50 mg and 100 mg of pyridoxine. The levels of tryptophane metabolite decreased progressively as the dose was increased but remained above basal levels. There was marked clinical improvement in these patients while receiving the higher dose only. The double-blind study with 76 asthmatic children followed for five months indicated significant improvement in asthma following pyridoxine therapy (200 mg daily) and reduction in dosage of bronchodilators and cortisone. The data suggest that these children with severe bronchial asthma had a metabolic block in tryptophane metabolism, which was benefitted by long-term treatment with large doses of pyridoxine.

Collipp PJ, Chen SY, Sharma RK, Balachandar V, Maddaiah VT. Tryptophane metabolism in bronchial asthma. Ann Allergy 1975 Sep;35(3):153-158.
Abstract: Seventeen out of 21 children with severe asthma had an abnormal increase in urinary Kynurenic (KA) and Xanthurenic (XA) acid following oral tryptophane administration. In a second study 11 asthmatic children had significantly greater increases in XA and KA than nine normal healthy children. A micro-assay of KA and XA by column chromatography was performed. The data suggest the presence of a partial block in the metabolism of tryptophane in some children with bronchial asthma.

Curhan GC, Willett WC, Rimm EB, Stampfer MJ. A prospective study of the intake of vitamins C and B6, and the risk of kidney stones in men. J Urol 1996 Jun;155(6):1847-1851.
Abstract: PURPOSE: The association between the intake of vitamins C and B6, and kidney stone formation was examined. MATERIALS AND METHODS: We conducted a prospective study of the relationship between the intake of vitamins C and B6 and the risk of symptomatic kidney stones in a cohort of 45,251 men 40 to 75 years old with no history of kidney calculi. Vitamin intake from foods and supplements was assessed using a semiquantitative food frequency questionnaire completed in 1986. RESULTS: During 6 years of followup 751 incident cases of kidney stones were documented. Neither vitamin C nor vitamin B6 intake was significantly associated with the risk of stone formation. For vitamin C the age-adjusted relative risk for men consuming 1,500 mg. daily or more compared to less than 250 mg. daily was 0.78 (95% confidence interval 0.54 to 1.11). For vitamin B6 the age-adjusted relative risk for men consuming 40 mg. daily or more compared to less than 3 mg. daily was 0.91 (95% confidence interval 0.64 to 1.31). After adjusting for other potential stone risk factors the relative risks did not change significantly. CONCLUSIONS: These data do not support an association between a high daily intake of vitamin C or vitamin B6 and the risk of stone formation, even when consumed in large doses.

Curhan GC, Willett WC, Speizer FE, Stampfer MJ. Intake of vitamins B6 and C and the risk of kidney stones in women. J Am Soc Nephrol 1999 Apr;10(4):840-845.
Abstract: Urinary oxalate is an important determinant of calcium oxalate kidney stone formation. High doses of vitamin B6 may decrease oxalate production, whereas vitamin C can be metabolized to oxalate. This study was conducted to examine the association between the intakes of vitamins B6 and C and risk of kidney stone formation in women. The relation between the intake of vitamins B6 and C and the risk of symptomatic kidney stones were prospectively studied in a cohort of 85,557 women with no history of kidney stones. Semiquantitative food-frequency questionnaires were used to assess vitamin consumption from both foods and supplements. A total of 1078 incident cases of kidney stones was documented during the 14-yr follow-up period. A high intake of vitamin B6 was inversely associated with risk of stone formation. After adjusting for other dietary factors, the relative risk of incident stone formation for women in the highest category of B6 intake (> or =40 mg/d) compared with the lowest category (<3 mg/d) was 0.66 (95% confidence interval, 0.44 to 0.98). In contrast, vitamin C intake was not associated with risk. The multivariate relative risk for women in the highest category of vitamin C intake (> or =1500 mg/d) compared with the lowest category (<250 mg/d) was 1.06 (95% confidence interval, 0.69 to 1.64). Large doses of vitamin B6 may reduce the risk of kidney stone formation in women. Routine restriction of vitamin C to prevent stone formation appears unwarranted.

Dakshinamurti K, Sharma SK, Bonke D. Influence of B vitamins on binding properties of serotonin receptors in the CNS of rats. Klin Wochenschr 1990 Jan 19;68(2):142-145.
Abstract: Treatment of normal adult rats with pyridoxine or a B-vitamin mixture resembling Neurobion led to an increase in serotonin content of various brain areas and to a decrease in the number of serotonin S2 receptors. The results indicate that the pyridoxal phosphate level in regions of the brain regulates the extent of decarboxylation of 5-hydroxytryptophan, the precursor of serotonin. The results also suggest a continuum from deficiency in pyridoxine to treatment of animals with a moderate excess of pyridoxine which is reflected in the synthesis and secretion into the synaptic cleft of the neurotransmitter serotonin.

Dakshinamurti K, Paulose CS, Viswanathan M, Siow YL. Neuroendocrinology of pyridoxine deficiency. Neurosci Biobehav Rev 1988 Fall-Winter;12(3-4):189-193.
Abstract: Dihydroxyphenylalanine decarboxylase and 5-hydroxytryptophan decarboxylase respectively have high and low affinities for pyridoxal phosphate. In the pyridoxine-deficient animal, hypothalamic serotonin content is significantly reduced without any change in catecholamine levels. Hypothalamic neurotransmitters affect the hypothalamo-pituitary-end organ axes. Specifically, the decrease in hypothalamic serotonin in the pyridoxine-deficient rat results in tertiary hypothyroidism. In addition, pineal function is affected in deficient animals due to decreased synthesis of melatonin.

Dalton K, Dalton MJ. Characteristics of pyridoxine overdose neuropathy. Acta Neurol Scand 1987 Jul;76(1):8-11.
Abstract: A newly recognised neurotoxic syndrome due to pyridoxine (B6) overdose is described. It is the largest series of B6 intoxication hitherto reported. A raised serum B6 level was present in 172 women of whom 60% had neurological symptoms, which disappeared when B6 was withdrawn and reappeared in 4 cases when B6 was restarted. The mean dose of B6 in the 103 women with neurological symptoms was 117 +/- 92 mgs, compared with 116.2 +/- 66 mgs in the control group. There was a significant difference (P less than 0.01) in the average duration of ingestion of B6 in the neurotoxic group of 2.9 +/- 1.9 years compared with 1.6 +/- 2.1 years in controls. The symptoms were paraesthesia, hyperaesthesia, bone pains, muscle weakness, numbness and fasciculation, most marked on the extremities and predominantly bilateral unless there was a history of previous trauma to the limb. These women were taking a lower dose of B6 than previously described (1,2), which may account for the complete recovery within 6 months of stopping B6.

Delport R, Ubbink JB, Vermaak WJ, Becker PJ. Theophylline increases pyridoxal kinase activity independently from vitamin B6 nutritional status. Res Commun Chem Pathol Pharmacol 1993 Mar;79(3):325-333.
Abstract: Asthmatics treated with theophylline, a potent inhibitor of pyridoxal kinase and therefore a vitamin B6 antagonist, demonstrated a significant correlation (r = 0.71; p < 0.001) between drug plasma levels and erythrocyte pyridoxal kinase activities. A cross-over, placebo controlled study was completed on 15 healthy volunteers to investigate the mechanism by which theophylline induces pyridoxal kinase activity. The subjects were supplemented with vitamin B6 or placebo for two weeks before theophylline therapy was started. Vitamin B6 supplementation resulted in a four-fold increase in circulating pyridoxal 5'-phosphate levels, while placebo had no effect. When theophylline therapy was commenced, erythrocyte pyridoxal kinase activities increased significantly (p < 0.001) irrespective of whether vitamin B6 or placebo was supplemented. It is concluded that a depressed vitamin B6 status is not responsible for higher erythrocyte pyridoxal kinase activities encountered during theophylline therapy, but that the drug is directly responsible for elevated enzyme levels.

Delport R, Ubbink JB, Serfontein WJ, Becker PJ, Walters L. Vitamin B6 nutritional status in asthma: the effect of theophylline therapy on plasma pyridoxal-5'-phosphate and pyridoxal levels. Int J Vitam Nutr Res 1988;58(1):67-72.
Abstract: Plasma pyridoxal-5'-phosphate concentrations were significantly lower (p less than 0.001) in a group of 28 asthmatic women when compared to 33 controls. Plasma pyridoxal levels in the two groups were not different. Theophylline was administered to a group of 17 volunteers and resulted in large reductions in plasma pyridoxal-5'-phosphate levels, while plasma pyridoxal levels and urinary 4-pyridoxic acid excretion were unaffected by theophylline therapy. An in vitro study showed that theophylline did not interfere with the high performance liquid chromatography assay for pyridoxal-5'-phosphate, indicating that theophylline could affect liver metabolism of vitamin B6.

Demers RG, McDonagh PH, Moore RJ. Pyridoxine deficiency with phenelzine. South Med J 1984 May;77(5):641-642.
Abstract: Pyridoxine (vitamin B6) deficiency developed in two young men treated with phenelzine. Alleviation of symptoms possibly associated with this deficiency and correction of subnormal serum B6 levels occurred with the administration of pyridoxine. With the increased use of phenelzine, all physicians should be alert to this potential problem and instruct patients to eat an adequate amount of foods containing B6. If untoward reactions occur during phenelzine treatment, B6 deficiency should be considered.

Demiroglu H, Dundar S. Vitamin B6 responsive sideroblastic anaemia in a patient with tuberculosis. Br J Clin Pract 1997 Jan-Feb;51(1):51-52.
Abstract: A 39-year-old woman was admitted with fatigue, weight loss, and fever. Nothing, except skin pallor could be found on physical examination. Her haemoglobin (Hb) was 6.3 g/dl. The blood picture showed dimorphic red cell changes and there were dyserythropoiesis and ring sideroblasts in the bone marrow. After detailed investigations, she was diagnosed with tuberculosis, and anaemia was assigned to chronic disease. With anti-tuberculosis therapy (including isoniazid), her Hb and bone marrow findings returned to normal. After cessation of therapy, Hb fell to 8.9 g/dl. Bone marrow examination again showed dyserythropoietic morphologic abnormalities and ring sideroblasts. No reason could be identified to explain the recurrence of anaemia. When we realised that preparations of isoniazid included vitamin B6 to prevent the development of sideroblastic anaemia, we challenged with pyridoxin 200 mg daily. Her Hb rose to 14.6 g/dl. We suggest that in any cases with sideroblastic anaemia, if no cause can be identified, or anaemia persists or recurs despite therapy, pyridoxine therapy should be instituted.

Ellis JM, McCully KS. Prevention of myocardial infarction by vitamin B6. Res Commun Mol Pathol Pharmacol 1995 Aug;89(2):208-220.
Abstract: Vitamin B6 is effective in the treatment of carpal tunnel syndrome and related disorders in patients with vitamin B6 deficiency. Hyperhomocysteinemia, a risk factor for atherosclerosis, is associated with deficiencies of vitamin B6, folate, and cobalamin. Patients who were given vitamin B6 for carpal tunnel syndrome and other degenerative diseases were found to have 27% of the risk of developing acute cardiac chest pain or myocardial infarction, compared with patients who had not taken vitamin B6. Among elderly patients of the author (JE) expiring at home, the average age at death from myocardial infarction was 8 years later in those who had taken vitamin B6, compared with those who had not taken vitamin B6. The preventive effect of vitamin B6 on progression of coronary heart disease may be related to increased formation of pyridoxal phosphate, the coenzyme that is required for catabolism of the atherogenic amino acid, homocysteine.

Ellis JM, Folkers K, Levy M, Shizukuishi S, Lewandowski J, Nishii S, Schubert HA, Ulrich R. Response of Vitamin B-6 deficiency and the carpal tunnel syndrome to pyridoxine. Proc Natl Acad Sci U S A 1982 Dec;79(23):7494-7498.
Abstract: The specific activities and percentage deficiencies of the glutamic oxaloacetic transaminase of erythrocytes (EGOT) were determined for patients with carpal tunnel syndrome (CTS) diagnosed by clinical examination and electrical conduction data; the EGOT data revealed a severe deficiency of vitamin B-6. After double-blind treatment with pyridoxine and placebo, two physicians identified those receiving pyridoxine (clinically improved) and those receiving placebo (did not improve) without error, P less than 0.0078. Correcting a deficiency of the coenzyme at receptors of existing molecules of the apoenzyme appears to take place within days; correction of the deficiency in the number of molecules of the transaminase takes place over 10-12 weeks. The clinical response, appraised by the diminution of the symptoms of CTS, was correlated only with the restored levels of the transaminase which presumably results from a translational long-term increase in the number of molecules of EGOT by a mechanism activated by correcting a deficiency of pyridoxal 5'-phosphate. Apparent Km values of EGOT were identical for groups of patients with CTS and others without CTS but with identical specific activities, indicating that CTS is a primary deficiency of vitamin B-6 rather than one of a dependency state. Clinical improvement of the syndrome with pyridoxine therapy may frequently obviate hand surgery.

Ellis JM, Folkers K. Clinical aspects of treatment of carpal tunnel syndrome with vitamin B6. Ann N Y Acad Sci 1990;585:302-320.

Ellis JM, Presley J. Vitamin B6: The Doctor's Report. NY: Harper and Row, 1973.
Abstract: 225 pregnant women were treated for edema with between 50-450 mg B6 q.d. In a few cases IM injections were used. Only 6 out of the 225 failed to respond. Some of the women lost between 10-15 lbs in 2 weeks. It was recommended that the B6 be given with magnesium. Ellis believes pregnant women should get 50 mg B6 q.d. throughout pregnancy.

Ellis JM. Treatment of carpal tunnel syndrome with vitamin B6. South Med J 1987 Jul;80(7):882-884.

Enriquez JI Sr, Schydlower M, O'Hair KC, Keniston RC, Nadjem MA, Delgado I. Effect of vitamin B6 supplementation on gentamicin nephrotoxicity in rabbits. Vet Hum Toxicol. 1992 Feb;34(1):32-35.

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

Findling RL, Maxwell K, Scotese-Wojtila L, Huang J, Yamashita T, Wiznitzer M. High-dose pyridoxine and magnesium administration in children with autistic disorder: an absence of salutary effects in a double-blind, placebo-controlled study. J Autism Dev Disord 1997 Aug;27(4):467-478.
Abstract: Several reports have described salutary effects such as decreased physical aggression and improved social responsiveness being associated with the administration of high doses of pyridoxine and magnesium (HDPM) in open-labeled and controlled studies of patients with autism. Despite this fact, this intervention remains controversial. A 10-week double-blind, placebo-controlled trial was undertaken to examine both the efficacy and safety of HDPM in autism. Twelve patients were enrolled, and 10 patients (mean age 6 years 3 months) were able to complete the study. HDPM at an average dose of 638.9 mg of pyridoxine and 216.3 mg of magnesium oxide was ineffective in ameliorating autistic behaviors as assessed by the Children's Psychiatric Rating Scale (CPRS), the Clinical Global Impression Scale, and the NIMH Global Obsessive Compulsive Scale. Furthermore, no clinically significant side effects were noted during HDPM administration. A trend for a transient change on the CPRS was found that was possibly due to a placebo response. This study raises doubts about the clinical effectiveness of HDPM in autistic disorder.

Flores L, Pais R, Buchanan I, Arnelle D, Camp VM, Kutner M, Faraj BA, Eckman J, Ragab A. Pyridoxal 5'-phosphate levels in children with sickle cell disease. Am J Pediatr Hematol Oncol 1988 Fall;10(3):236-240.
Abstract: Pyridoxal 5'-phosphate (PLP), the major coenzyme form of vitamin B6, is known to have antisickling properties in vitro. Recently, low plasma PLP levels were reported in a group of adults with sickle cell anemia. We measured the plasma PLP levels in a group of 55 asymptomatic nontransfused children with sickle cell diseases (SCD) to determine the prevalence of low plasma PLP levels in this population. Comparative studies were made with the measurement of PLP in three other groups serving as controls: Group A (black children, n = 36); Group B (white children, n = 37); and Group C (black adults, n = 13). PLP was measured directly in plasma by a radioenzymatic technique. The results of these comparisons showed that there was no statistically significant difference in plasma PLP of black children with SCD (10.7 +/- 10.0 ng/ml) as compared with black control children (group A, 9.0 +/- 12.3 ng/ml). The low plasma levels PLP in these two groups were significantly lower than that of the plasma PLP of white control children (group B, 15.85 +/- 15.92 ng/ml). This data suggest that a high prevalence of low PLP levels exists in black children seen at Grady Memorial Hospital, both with and without SCD.

Franzblau A, Rock CL, Werner RA, Albers JW, Kelly MP, Johnston EC. The relationship of vitamin B6 status to median nerve function and carpal tunnel syndrome among active industrial workers. J Occup Environ Med 1996 May;38(5):485-491.

Franzblau A, Rock CL, Werner RA, Albers JW. Vitamin B6, vitamin C, and carpal tunnel syndrome. J Occup Environ Med. 1998 Apr;40(4):305-309. (Letter; Comment)

Gaby AR. Literature review and commentary. Townsend Letter for Doctors. June 1990;338-339.

Gant H, Reinken L, Dapunt O, Scholz K. [Vitamin b6 depletion in women with hyperemesis gravidarum]. Wien Klin Wochenschr 1975 Sep 5;87(16):510-513. {Article in German]
Abstract: The serum pyridoxal 5-phosphate (vitamin B6) level was measured in 20 women with hyperemesis gravidarum before and after therapy with vitamin B6. Control specimens were obtained from 22 healthy pregnant, women during the first trimester, 18 healthy prgnant women during the last trimester and from 29 healthy non-pregnant women of comparable age. The determinations were performed by means of decarboxylation of L-tyrosine-1-14 C.

Glenn GM, Krober MS, Kelly P, McCarty J, Weir M. Pyridoxine as therapy in theophylline-induced seizures. Vet Hum Toxicol 1995 Aug;37(4):342-245.
Abstract: Theophylline-induced seizures have significant morbidity and mortality and are difficult to treat. Theophylline therapy for asthma has been observed to depress plasma pyridoxal 5'-phosphate (PLP) levels which may decrease gamma-aminobutyric acid (GABA) synthesis and thereby contribute to seizures. We hypothesized that treatment with pyridoxine might prove beneficial in theophylline-induced seizures. One hundred thirty-nine mice were injected with 250 mg theophylline/kg ip and 89 mice were injected with 250-750 mg pyridoxine/kg ip as treatment. Decreased rates of seizure (42 vs 70%, p < 0.002) and death (29 vs 56%, p < 0.002) were observed. Six New Zealand White rabbits were given 115 mg theophylline/kg iv over 50 min followed by treatment with an iv bolus of 115 mg pyridoxine/kg, with subsequent continuous drip infusion of 230 mg/kg over 50 min. Serum theophylline levels and plasma PLP levels showed significant negative correlation prior to pyridoxine infusion with a mean peak theophylline level of 182 micrograms/ml and a mean low PLP level of 64 nM/L. Electroencephalogram (EEG) tracings were obtained before infusions, during theophylline infusion and during pyridoxine infusion. All 6 rabbits developed abnormal EEGs during theophylline infusion and all 6 rabbit EEG patterns returned to baseline during treatment with pyridoxine. These findings suggest that pyridoxine may partially reverse theophylline-induced central nervous system toxicity.

Gnam W, Flint A, Goldbloom D. Isoniazid-induced hallucinosis: response to pyridoxine. Psychosomatics 1993 Nov;34(6):537-539. (Letter)

Goodheart RS, Dunne JW, Edis RH. Phenelzine associated peripheral neuropathy -- clinical and electrophysiologic findings. Aust N Z J Med 1991 Jun;21(3):339-340.
Abstract: Phenelzine associated sensorimotor peripheral neuropathy is reported in two patients. Symptoms were predominantly sensory, and improvement occurred after withdrawal of phenelzine. Electrophysiologic findings were consistent with an axonal process.

Goldshtein VD, Fondaminskaia LD, Semenova AS. [The influence of cycloserine on the metabolism of several B complex vitamins in pulmonary tuberculosis]. Probl Tuberk 1971;49(11):15-19. [Article in Russian]

Haden HT. Pyridoxine-responsive sideroblastic anemia due to antituberculous drugs. Arch Intern Med 1967 Nov;120(5):602-606.

Hansson O, Sillanpaa M. Letter: Pyridoxine and serum concentration of phenytoin and phenobarbitone. Lancet 1976 Jan 31;1(7953):256.

Heller CA, Friedman PA. Pyridoxine deficiency and peripheral neuropathy associated with long-term phenelzine therapy. Am J Med 1983 Nov;75(5):887-888.
Abstract: A 51-year-old, nonalcoholic, nondiabetic woman with sensorimotor peripheral neuropathy and pyridoxine deficiency associated with long-term phenelzine therapy is described. Since phenelzine, like hydralazine and isoniazid, is a hydrazine capable of reducing pyridoxine levels in the rat, it is suggested that phenelzine, like hydralazine and isoniazid, may cause a pyridoxine-responsive peripheral neuropathy in humans.

Hines JD. Metabolic abnormalities of vitamin B6 and magnesium in alcohol-induced sideroblastic anemia. Erythrocyte structure and function 1976 Jun 2. 621-642.
Abstract: Chronic and excessive alcohol abuse has been shown to create cellular depletion of folate, pyridoxal phosphate (PLP), potassium and magnesium in a significant number of patients. Studies reported herein document a striking association of hypokalemia, hypomagnesemia and abnormalities of vitamin B6 metabolism frequently resulting in erythroid mitochondrial iron-overloading. Selected well nourished, chronic alcoholic subjects were studied, utilizing metabolic balance studies. Graded amounts of ethanol in the form of 86 proof bar whiskey were isocalorically substituted for carbohydrate and the patients were observed from 40 to 60 days. The results of these investigations revealed the following: 1) a progressive fall in serum and erythrocyte PLP and magnesium concentration; 2) a state of negative magnesium balance, but not of potassium or calcium; 3) a progressive decrease in erythrocyte pyridoxal phosphokinase concentrations not corrected by administration of magnesium or pulse doses of pyridoxine; 4) the demonstration of a plasma inhibitor of erythrocyte and hepatic pyridoxal phosphokinase in certain of these subjects.

Hines, Love. Vitamin B-6 metabolism in sideroblastic anemia: Effect of pyridoxal phosphate therapy. Clin Res. 1975;23:403A.
Abstract: 18/34 patients with sideroblastic anemia unresponsive to vitamin B-6 and folate had subnormal concentrations of serum and red blood cell PLP and in vitro evidence of defective phosphorylation of pyridoxine and pyridoxal to P5P. Treatment of these patients with parenteral PLP 25-50mg 4x daily for 8-10 days produced significant elevation of hemoglobin in 11 cases.

Hoffer A. Isoniazid and pyridoxine. CMAJ 1993 Nov 1;149(9):1232. (Letter)

Holt GA. Food and Drug Interactions. Chicago: Precept Press, 1998, 82-83.

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

Ito M, Okuno T, Hattori H, Fujii T, Mikawa H. Vitamin B6 and valproic acid in treatment of infantile spasms. Pediatr Neurol 1991 Mar-Apr;7(2):91-96.
Abstract: Twenty patients with infantile spasms were treated with high doses of vitamin b6, valproic acid, or both. Three of 13 patients (23%) treated initially with high doses of vitamin B6 demonstrated a definite reduction in seizures; 2 patients had no improvement on electroencephalography. Vitamin B6 therapy alone was continued in a single patient (8%) who remained seizure-free during the 15-month follow-up period. Initial treatment with vitamin B6 and valproic acid improved the electroencephalogram significantly more (P less than 0.05) than initial vitamin B6 treatment alone. The group which had valproic acid added to vitamin B6 therapy had significantly fewer seizures (P less than 0.05) and better electroencephalograms (P less than 0.01) than did the group treated initially with vitamin B6 alone. There were no significant differences among the group treated initially with vitamin B6, the group treated initially with valproic acid, and the group in which valproic acid was substituted for vitamin B6. ACTH was more effective in abolishing seizures than was valproic acid or vitamin B6 and valproic acid. ACTH had an excellent effect on seizures in 86% of patients who did not respond well to vitamin B6, valproic acid, or both; however, many of these patients had later recurrence of infantile spasms. The combination of vitamin B6 and valproic acid is effective and safe in the treatment of infantile spasms.

Jaffe IA. Antivitamin B6 effect of D-penicillamine. Ann N Y Acad Sci 1969 Sep 30;166(1):57-60.

Jaffe IA. The antivitamin B 6 effect of penicillamine: clinical and immunological implications. Adv Biochem Psychopharmacol 1972;4:217-26. (Review)

Jiao FY, Gao DY, Takuma Y, Wu S, Liu ZY, Zhang XK, Lieu NS, Ge ZL, Chui W, Li HR, Cao YM, Bai AN, Liu SB. Randomized, controlled trial of high-dose intravenous pyridoxine in the treatment of recurrent seizures in children. Pediatr Neurol 1997 Jul;17(1):54-57.
Abstract: To determine the efficacy of pyridoxine in treating seizures, 90 infants and children with recurrent convulsions primarily due to acute infectious diseases were enrolled in the present study. Forty patients were treated with high-dose pyridoxine (30 or 50 mg/kg/day) by intravenous infusion, and 50 subjects served as controls. Antiepileptic drugs and other therapies were similar in the two groups except for pyridoxine. Clinical efficacy criteria were based on the frequency of convulsions per day and on the duration of individual seizures after therapy was initiated. The results indicated that total response rates in the pyridoxine group and control group were 92.5% and 64%, respectively (chi-square = 14.68, P < .001). After initiation of therapy, seizures resolved after 2.4 +/- 1.4 days in the pyridoxine group and after 3.7 +/- 2.0 days in the control group (t = 3.67, P < .001). No adverse effects of pyridoxine were apparent during the observation period. We conclude that pyridoxine is an effective, safe, well-tolerated, and relatively inexpensive adjunct to routine antiepileptic drugs for treatment of recurrent seizures in children.

Jonas C, Etienne T, Barthelemy C, Jouve J, Mariotte N. [Clinical and biochemical value of Magnesium + vitamin B6 combination in the treatment of residual autism in adults]. Therapie 1984 Nov-Dec;39(6):661-669. [Article in French]

Kacew S. Inhibition of gentamicin-induced nephrotoxicity by pyridoxal-5'-phosphate in the rat. J Pharmacol Exp Ther. 1989 Jan;248(1):360-366.

Kendall KE, Schnurr PP. The effects of vitamin B6 supplementation on premenstrual symptoms. Obstet Gynecol 1987 Aug;70(2):145-149.
Abstract: A double-blind controlled study of the effects of vitamin B6 supplementation on premenstrual symptoms was conducted. Fifty-five women who reported moderate to severe premenstrual mood changes participated in the study. Symptoms were monitored prospectively through daily home record-keeping over a one-month baseline period followed by two months of treatment. Subjects were randomly assigned to receive daily supplements of 150 mg of vitamin B6 or placebo over the entire two-month treatment period. Analysis of covariance suggested that even though vitamin B6 may improve premenstrual symptoms related to autonomic reactions (eg, dizziness and vomiting) and behavioral changes (eg, poor performance and decreased social activities), a significant amount of physical and affective symptomatology remained during the premenstrual phase. In light of recently reported, potentially toxic effects of low doses of vitamin B6, our results call for caution in using this therapy for premenstrual symptoms.

Kendall MJ, Chan K. Drug-induced malabsorption. Xenobiotica 1973 Nov;3(11):727-744. (Review)

Keniston RC, Cabellon S Jr, Yarbrough KS. Pyridoxal 5'-phosphate as an antidote for cyanide, spermine, gentamicin, and dopamine toxicity: an in vivo rat study. Toxicol Appl Pharmacol. 1987 May;88(3):433-441.

Keniston RC, Nathan PA, Leklem JE, Lockwood RS. Vitamin B6, vitamin C, and carpal tunnel syndrome. J Occup Environ Med 1997;39:949-959.

Kleijnen J, Ter Riet G, Knipschild P. Vitamin B6 in the treatment of the premenstrual syndrome--a review. Br J Obstet Gynaecol 1990 Sep;97(9):847-852.

Laine-Cessac P, Cailleux A, Allain P. Mechanisms of the inhibition of human erythrocyte pyridoxal kinase by drugs. Biochem Pharmacol 1997 Oct 15;54(8):863-870.
Abstract: The aim of this study was to investigate the interaction between drugs chosen for their clinical neurotoxicity or chemical structure and vitamin B6 metabolism. After a preliminary screening of drugs to determine their potential inhibitory effect on erythrocyte nonpurified pyridoxal kinase (PLK) (EC 2.7.1.35), additional investigations, including kinetic studies and detection of chemical reactivity between the inhibiting drugs and pyridoxal (PL) or pyridoxal-5'-phosphate (PLP), using UV-visible spectrophotometry and mass analysis, were carried out to specify the mechanism of PLK inhibition. Depending on the results, the inhibiting drugs were divided into three groups. The first group included theophylline and progabide and inhibited PLK using either PL or pyridoxamine (PM) as substrate and thereby were true inhibitors. Moreover, they did not form covalent complexes with PL or PLP. The second group, which included cycloserine, dopamine, isoniazid, and thiamphenicol glycinate, inhibited PLK using PL, but not PM, as substrate. They were able to react with PL or PLP to form covalent complexes, and kinetic studies suggested that the observed PLK inhibition was due to these formed complexes. A third group, which consisted of levodopa, D-penicillamine, and muzolimine, inhibited PLK using PL, but not PM, as substrate. They formed, with PL or PLP, chemical derivatives that probably had no inhibitory effect on PLK. These results and the clinical consequences of such interactions are discussed and compared with results of previous studies.

Langdana A, Agarwal M, Kelgeri C, Kamat P. Pyridoxine in acute isoniazid overdose. Indian Pediatr 1996 Feb;33(2):132-134.

Lee NS, Muhs G, Wagner GC, Reynolds RD, Fisher H. Dietary pyridoxine interaction with tryptophan or histidine on brain serotonin and histamine metabolism. Pharmacol Biochem Behav. 1988 Mar;29(3):559-564.
Abstract: We studied the metabolic effects of high dietary intakes of pyridoxine and of the substrate-cofactor interaction between dietary histidine or tryptophan and pyridoxine in rat brain. In the substrate-cofactor interaction study, histamine and serotonin levels were determined in rats fed elevated or requirement levels of substrate (histidine: 0.3% and 0.8%, tryptophan: 0.15% and 0.6%) and excess or requirement levels of pyridoxine HCl (7 mg vs. 3,000 mg/kg). Excess pyridoxine intake caused a differential effect on brain histamine concentration--inhibitory with the requirement level of histidine (-29%), and stimulatory (+21%) with the elevated level of histidine. When dietary tryptophan was fed at the requirement level, excess pyridoxine caused essentially no changes in hypothalamic serotonin and 5HIAA (-2%, -2%). With elevated tryptophan intake, excess pyridoxine significantly increased serotonin and 5HIAA (+32%, +20%) in the hypothalamus. These results indicate a clear interaction between substrate and coenzyme precursor which influences brain metabolism of histamine and serotonin.

Leeda M, Riyazi N, de Vries JI, Jakobs C, van Geijn HP, Dekker GA. Effects of folic acid and vitamin B6 supplementation on women with hyperhomocysteinemia and a history of preeclampsia or fetal growth restriction. Am J Obstet Gynecol 1998 Jul;179(1):135-139.
Abstract: OBJECTIVE: Our purpose was to assess the incidence of hyperhomocysteinemia in patients with a history of preeclampsia or fetal growth restriction, to evaluate the effects of vitamin supplementation on the methionine loading test, and to study the course of subsequent pregnancies in women with hyperhomocysteinemia and a history of preeclampsia or fetal growth restriction. STUDY DESIGN: A total of 207 consecutive patients with a history of preeclampsia or fetal growth restriction was tested for hyperhomocysteinemia. Thirty-seven were found to be positive and were treated with folic acid and vitamin B6, and 27 had a second methionine loading test after vitamin supplementation. Fourteen patients became pregnant again while receiving vitamins and aspirin. RESULTS: All patients who underwent a methionine loading test after vitamin supplementation had a completely normalized methionine loading test. Of the 14 pregnancies in women receiving vitamins and aspirin, 7 were complicated by preeclampsia. Birth weights were 2867 +/- 648 g compared with 1088 +/- 570 g in the previous pregnancies. CONCLUSIONS: Vitamin B6 and folic acid correct the methionine loading test in patients with hyperhomocysteinemia. Perinatal outcome in patients with a history of preeclampsia or fetal growth restriction and hyperhomocysteinemia appears to be favorable.

Leklem JE, Brown RR, Rose DP, Linkswiler H, Arend RA. Metabolism of tryptophan and niacin in oral contraceptives users receiving controlled intakes of vitamin B6. Am J Clin Nutr 1975 Feb;28(2):146-156.

Lelord G, Callaway E, Muh JP. Clinical and biological effects of high doses of vitamin B6 and magnesium on autistic children. Acta Vitaminol Enzymol 1982;4(1-2):27-44.
Abstract: In 1973 Rimland reported that some autistic children responded favorably to high doses of vitamin B6. Since this finding, different studies were performed to identify apparently B6 responsive subjects and to critically evaluate clinical and biological B6 responsiveness. Magnesium was included because large doses of B6 might increase irritability. 44 patients (mean age 9.3 years) were examined. All selected children had marked autistic symptoms. The children received a complete diagnostic work-up, including psychiatric, psychological, neurological and medical evaluation. Clinical data were scored using an estimate of global clinical state and numerical rating on a 18 item scale (Behavior Summarized Evaluation). In a first open trial 15 out of 44 children exhibited moderate clinical improvement with worsening on termination of the trial. Thirteen responders and 8 non responders were re-tested in a 2-week crossover, double-blind trial and the responses to the open trial were confirmed. Biochemical data analysis revealed that a significant decrease in urinary homovanillic acid (HVA) levels was observed during B6-Mg administration. During B6-Mg treatment, middle latency evoked potentials exhibited a significant increase of amplitude.

Lelord G, Muh JP, Barthelemy C, Martineau J, Garreau B, Callaway E. Effects of pyridoxine and magnesium on autistic symptoms--initial observations. J Autism Dev Disord 1981 Jun;11(2):219-230.
Abstract: In an open trial, a heterogeneous group of 44 children with autistic symptoms were treated with large doses of vitamin B6 and magnesium. Clinical improvement with worsening on termination of the trial was observed in 15 children. Thirteen responders and 8 nonresponders were retested in a 2-week, crossover, double-blind trial, and the responses to the open trial were confirmed.

Long, JW. The Essential Guide to Prescription Drugs 1992. New York: Harper Perennial, 1991.

Mahashur AA. Isoniazid induced peripheral neuropathy. J Assoc Physicians India 1992 Oct;40(10):651-652.

Martineau J, Barthelemy C, Cheliakine C, Lelord G. Brief report: an open middle-term study of combined vitamin B6-magnesium in a subgroup of autistic children selected on their sensitivity to this treatment. J Autism Dev Disord 1988 Sep;18(3):435-447.

Martineau J, Garreau B, Barthelemy C, Callaway E, Lelord G. Effects of vitamin B6 on averaged evoked potentials in infantile autism. Biol Psychiatry 1981 Jul;16(7):627-641.
Abstract: In autistic children, averaged evoked potentials have been reported to have lower amplitudes and shorter latencies than those of normal children. Also, moderate clinical improvement has been observed in some autistic children after treatment with vitamin B6 and magnesium. We have studied biochemical and electrophysiological effects of vitamin B6 and magnesium in 12 autistic children and in 11 normal children. During treatment of the autistic children with B6, an increase of amplitude of middle-latency evoked potentials and a decrease of urinary homovanillic acid were found. The reverse was noted in the normal subjects.

Martineau J, Barthelemy C, Lelord G. Long-term effects of combined vitamin B6-magnesium administration in an autistic child. Biol Psychiatry 1986 May;21(5-6):511-518.

Martineau J, Barthelemy C, Garreau B, Lelord G. Vitamin B6, magnesium, and combined B6-Mg: therapeutic effects in childhood autism. Biol Psychiatry 1985 May;20(5):467-478.
Abstract: This article reports the behavioral, biochemical, and electrophysiological effects of four therapeutic crossed-sequential double-blind trials with 60 autistic children: Trial A--vitamin B6 plus magnesium/magnesium; Trial B--vitamin B6 plus magnesium; Trial C--magnesium; and Trial D--vitamin B6. Therapeutic effects were controlled using behavior rating scales, urinary excretion of homovanillic acid (HVA), and evoked potential (EP) recordings. The behavioral improvement observed with the combination vitamin B6-magnesium was associated with significant modifications of both biochemical and electrophysiological parameters: the urinary HVA excretion decreased, and EP amplitude and morphology seemed to be normalized. These changes were not observed when either vitamin B6 or magnesium was administered alone.

Martinez de Haas MG, Poels PJ, de Weert CJ, Thomas CM, Rooyackers JM, Hoefnagels WH. Subnormal vitamin B6 levels in theophylline users. Ned Tijdschr Geneeskd 1997 Nov 8;141(45):2176-2179 [in Dutch].
Abstract: OBJECTIVE: To study the effect of theophylline use on the vitamin B-6 status. DESIGN: Descriptive. SETTING: Department of Geriatric Medicine of Nijmegen Academic Hospital and Department of Pulmonary Diseases, University of Nijmegen, the Netherlands. PATIENTS AND METHODS: Vitamin B-6 status was determined by measuring pyridoxal-5'-phosphate (PLP) in whole blood (using a high performance liquid chromatography method, reference values: 35-107 mumol/l) in 141 patients from the Geriatric department (84 non-chronic obstructive pulmonary disease (COPD), 40 COPD patients without theophylline and 17 COPD patients with theophylline) and in 25 non-geriatric COPD patients on theophylline. RESULTS: Of the 84 geriatric non-COPD patients (mean age: 82 years; SD: 6) 56% had a subnormal vitamin B-6 status, of the 40 geriatric COPD patients without theophylline (82 years; SD: 6) 70%, of the 17 geriatric COPD patients on theophylline (80 years; SD: 5) 94% and of the 25 non-geriatric COPD patients on theophylline (62 years; SD: 11) 96%. CONCLUSION: In patients who used theophylline a higher prevalence of subnormal vitamin B-6 status was found than in patients who did not.

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

Mayer GG, Chase T, Farvar B, Waidh MA, Longo F, Karp F, Zinsser HH. Metabolic studies on the formation of calcium oxalate stones, with special emphasis on vitamin B6 and uric acid metabolism. Bull N Y Acad Med 1968 Jan;44(1):28-44.

Mayer J. Iatrogenic malnutrition. Postgrad Med. 1971 Mar;49(3):247-249.

Mbala L, Matendo R, Nkailu R. Is vitamin B6 supplementation of isoniazid therapy useful in childhood tuberculosis.  Trop Doct 1998 Apr;28(2):103-104.
Abstract: We present the results of a prospective single blind placebo controlled study performed to establish whether vitamin B6 supplementation of isoniazid therapy is useful in childhood tuberculosis. Eighty-five children suffering from tuberculosis (TB) and admitted between 1 October 1993 and 31 March 1995 to the Hospital of IME-Kimpese (Lower Zaire) were included. All were treated with isoniazid and other antitubercular drugs and were randomized to receive either vitamin B6 supplementation or placebo. No case of neurological or neuropsychiatric disorder was observed in the two groups during the 6 months of the treatment and 3 months after the treatment. These results suggest that the vitamin B6 supplementation of isoniazid therapy is unnecessary in childhood TB.

Nair S, Maguire W, Baron H, Imbruce R. The effect of cycloserine on pyridoxine-dependent metabolism in tuberculosis. J Clin Pharmacol 1976 Aug;16(8-9):439-443.
Abstract: Measurements were made of urinary tryptophan metabolites of 13 tuberculosis patients in order to reveal characteristics of pyridoxine-dependent metabolism before and during cycloserine treatment. The abnormally high level of xanthurenic acid excretion in untreated patients suggests a decreased availability of pyridoxal phosphate related to the disease process. Although plasma cycloserine levels were kept high once therapy began, xanthurenic acid excretion before and after tryptophan load became progressively more normal as symptoms diminished. This observation suggests that the convulsions which may sometimes accompany cycloserine administration are not due to a direct pyridoxine antagonism by the drug. Throughout the study, no significant changes in 5-hydroxyindoleacetic acid excretion were observed. Presumably, the metabolic pathway of serotonin is unaffected by tryptophan loading, cycloserine administration, or the apparent pyridoxine depletion associated with tuberculosis.

Nankivell BJ. Vitamin B6 deficiency on hemodialysis causing sideroblastic anemia. Nephron 1991;59(4):674-675. (Letter)

Natta CL, Reynolds RD. Apparent vitamin B6 deficiency in sickle cell anemia. Am J Clin Nutr 1984 Aug;40(2):235-239.
Abstract: In 16 patients with sickle cell anemia, plasma pyridoxal phosphate (PLP) concentrations were significantly lower than in 16 controls (p less than 0.0001) whereas sickle cell anemia erythrocyte PLP concentrations were significantly elevated (p less than 0.0005), possibly reflecting a greater affinity of PLP to the sickle Hb beta chain compared to the normal beta chain. Oral supplementation of five patients with 50 mg pyridoxine twice daily for 2 months resulted in increased plasma and erythrocyte PLP levels and a slight, but not significant, increase in erythrocyte cell number, Hb, concentration, and hematocrit. In one subject there was also a reduction in the frequency and duration of painful crises and a virtual elimination of hospitalizations for the treatment of the painful crises. Since pyridoxal and PLP have been shown to have antisickling properties in vitro, these studies suggest that pyridoxine supplementation may also be of therapeutic benefit in vivo in sickle cell anemia.

Omray A, Varma KC. Evaluation of pharmacokinetic parameters of tetracycline hydrochloride upon oral administration with vitamin C and vitamin B complex. Hindustan Antibiot Bull 1981;23:33-7

Parry G, Bredesen DE. Sensory neuropathy with low-dose pyridoxine. Neurology 1985 Oct;35(10):1466-1468.
Abstract: We describe 16 patients with neuropathy associated with pyridoxine abuse. The clinical picture of a pure sensory central-peripheral distal axonopathy was consistent. Pyridoxine dose was 0.2 to 5 g/d, and duration of consumption before symptoms was inversely proportional to the daily intake. In all patients with adequate follow-up, improvement followed discontinuation of pyridoxine. The ready availability of up to 1-gram tablets makes it likely that this neuropathy will continue to be seen.

Pellock JM, Howell J, Kendig EL Jr, Baker H. Pyridoxine deficiency in children treated with isoniazid. Chest 1985 May;87(5):658-661.
Abstract: Isoniazid-induced deficiency of pyridoxine (vitamin B6) is reportedly not uncommon in adults but rare in children. In the present study, 38 children had serum levels of pyridoxine tested while receiving therapy with isoniazid. A biologic assay using the protozoan Tetrahymena thermophila determined pyridoxine status after 2 to 18 months of therapy with isoniazid. Five children (13 percent) were deficient. None had definitive clinical symptoms or signs consistent with pyridoxine deficiency. Three had normal nerve conduction velocity. Children receiving isoniazid in dosages greater than 10 mg/kg/day had a higher incidence of deficiency. Present recommendations for withholding pyridoxine prophylaxis from children receiving isoniazid therapy must be reconsidered in light of these findings, particularly in those children who are debilitated or have a poor nutritional history with a known pyridoxine deficit prior to therapy with isoniazid.

Pfeiffer SI, Norton J, Nelson L, Shott S. Efficacy of vitamin B6 and magnesium in the treatment of autism: a methodology review and summary of outcomes. J Autism Dev Disord 1995 Oct;25(5):481-493. (Review)
Abstract: Pauling's orthomolecular hypothesis appeared in 1968, stating that some forms of mental illness and disease are related to biochemical errors in the body. Vitamin therapy is believed to be a means of compensating for such errors. There have been few empirical studies on vitamin therapy in individuals with autism. This article presents a critical analysis of the 12 published studies located through an extensive computerized search. Studies were systematically evaluated to provide an objective assessment of empirical evidence supporting the efficacy of vitamin treatment. The majority of studies report a favorable response to vitamin treatment. However, interpretation of these positive findings needs to be tempered because of methodological shortcomings inherent in many of the studies. For example, a number of studies employed imprecise outcome measures, were based on small samples and possible repeat use of the same subjects in more than one study, did not adjust for regression effects in measuring improvement, and omitted collecting long-term follow-up data. Recommendations are offered to assist researchers in designing future investigations.

Phalen, George. 99th Annual Meeting of the Am. Med. Assoc.
Abstract: In 1950 George Phalen, M.D., who was a pioneer in the surgical treatment of CTS, presented his first 11 cases of CTS at the 99th annual meeting of the Am. Med. Assoc. Until then few physicians were familiar with the condition.

Pietz J, Benninger C, Schafer H, Sontheimer D, Mittermaier G, Rating D. Treatment of infantile spasms with high-dosage vitamin B6. Epilepsia 1993 Jul-Aug;34(4):757-763.
Abstract: High-dose vitamin B6 (pyridoxine-HCl, 300 mg/kg/day orally) was introduced as the initial treatment of recently manifested infantile spasms in 17 children (13 symptomatic cases with identified brain lesion and 4 cryptogenic cases). 5 of 17 children (2 cryptogenic, 2 with severe pre/perinatal brain damage and one with Sturge-Weber syndrome) were classified as responders to high-dose vitamin B6. In all 5 cases the response to vitamin B6 occurred within the first 2 weeks of treatment and within 4 weeks all patients were free of seizures. Two patients developed other seizures (partial seizures, etiologically unclear blinking attacks), but no relapse of infantile spasms was observed among the five responders to vitamin B6. No serious adverse reactions were noted. Side effects were mainly gastrointestinal symptoms, which were reversible after reduction of the dosage. Considering the life-threatening side effects of treatment with ACTH/corticosteroids or valproate, a controlled clinical trial with high-dose vitamin B6 would appear justified to either prove or disprove efficacy.

Prasad AS, Lei KY, Moghissi KS, Stryker JC, Oberleas D. Effect of oral contraceptives on nutrients. III. Vitamins B6, B12, and folic acid. Am J Obstet Gynecol 1976 Aug 15;125(8):1063-1069.
Abstract: The interactions of oral contraceptive agents (OCA's) with vitamins were studied in a large population of women. In the upper socioeconomic groups, higher incidences of abnormal clinical signs related to vitamin deficiencies were seen in OCA users than in the control subjects. Plasma pyridoxal phosphate and red cell and serum folate were lower in subjects using OCA's in the upper socioeconomic group as compared to levels in the control subjects. Reduction in erythrocyte glutamic oxalacetic transaminase (EGOT) activity and elevation in the EGOT-stimulation test were observed in subjects using OCA's in both upper and lower socioeconomic groups. These observations suggest a relatively deficient state with respect to vitamins B6 and folic acid in OCA users. No significant effect on serum vitamin B12 was observed as a result of OCA administration.

Prasad K. Homocysteine, a Risk Factor for Cardiovascular Disease. Intl J Angiology 1999 Jan;8(1):76-86.
Abstract: Fasting hyperhomocysteinemia is an independent risk factor for coronary artery disease, stroke, peripheral vascular atherosclerosis, and for arterial and venous thromboembolism. The risk for cardiovascular disease with homocysteine is similar to conventional risk factors. The interaction of hyperhomocysteinemia with hypertension and smoking is strong and the combined effect is more than multiplicative. The combined effect of homocysteine and cholesterol is additive. Homocysteine produces atherosclerosis, thromboembolism, and vascular endothelial cell injury. Vascular dysfunction produced by homocysteine may be due to endothelial cell damage. Homocysteinemia-induced atherosclerosis is probably due to various factors including endothelial cell injury, inability to sustain S-nitroso-homocysteine formation because of imbalance between production of nitric oxide by dysfunctional endothelium and homocysteine, smooth muscle cell proliferation, and thromboembolism. There is strong evidence that endothelial cell injury is associated with oxidative stress produced by homocysteine. Hyperhomocysteinemia is associated with numerous conditions, including coronary disease, stroke, peripheral vascular disease (carotid artery and cerebrovascular atherosclerosis), venous thrombosis, renal disease, diabetes mellitus, and organ transplant. Folic acid, vitamin B12 and B6 have been shown to be beneficial in reducing plasma homocysteine levels. Folic acid is specifically very effective, safe and inexpensive.

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

Raskin NH, Fishman RA. Pyridoxine-deficiency neuropathy due to hydralazine. N Engl J Med 1965 Nov 25;273(22):1182-1185.

Reinken L, Gant H. Vitamin B6 nutrition in women with hyperemesis gravidarum during the first trimester of pregnancy. Clin Chim Acta 1974 Aug 30;55(1):101-102.

Reynolds TM, Marshall PD, Brain AM. Hip fracture patients may be vitamin B6 deficient. Controlled study of serum pyridoxal-5'-phosphate. Acta Orthop Scand 1992 Dec;63(6):635-638.
Abstract: Deficiency of vitamin B6 in rats may result in defective bone formation, possibly due to decreased activity of the enzyme ornithine decarboxylase which requires pyridoxal-5'-phosphate (PLP) as a co-factor and is responsible for production of intracellular putrescine, a metabolic regulator. We studied 3 groups of patients (62 fit ambulant out-patients, 21 elective arthroplasty patients, and 20 hip fracture patients) and assayed their PLP status by high performance liquid chromatography. The reference range derived from the out-patients was 13-106 nmol/L. 3 of the arthroplasty group and 10 of the fracture group had serum PLP concentrations less than 13 nmol/L (P < 0.01). We conclude that PLP may be an etiologic factor in hip fracture by virtue of its role in the activity of a key regulatory protein.

Reynolds RD. Bioavailability of vitamin B-6 from plant foods. Am J Clin Nutr 1988 Sep;48(3 Suppl):863-867. (Review)
Abstract: The major factors that affect bioavailability of vitamin B-6 are formation of reaction products during food processing, fiber type and content, and presence of the conjugated pyridoxine glucoside. The bioavailability of vitamin B-6 from animal products is quite high, reaching 100% for many foods. In general the bioavailability from plant foods is lower. The presence of fiber reduces the bioavailability by 5-10% whereas the presence of pyridoxine glucoside reduces the bioavailability by 75-80%. This glucoside is found in a variety of plant foods, with the highest content occurring in the crucifers. The percent of total vitamin B-6 that exists as the glucoside has been suggested to be the best indicator of bioavailability. Data from Nepalese vegetarian lactating women suggest that the low vitamin B-6 status of these mothers and their infants, as determined by their concentrations of plasma pyridoxal phosphate, may be adversely affected by the dietary intake of the naturally occurring pyridoxine glucoside.

Reynolds RD, Natta CL. Depressed plasma pyridoxal phosphate concentrations in adult asthmatics. Am J Clin Nutr 1985 Apr;41(4):684-688.
Abstract: 15 patients had significantly lower levels of plasma and red blood cell P5P than non-asthmatics. 7 patients and 6 controls received 50mg B-6 2x/day. Both plasma and red blood cell pyridoxal phosphate levels only increased significantly in the controls. However, all asthmatics reported a dramatic decrease in the frequency, duration and severity of asthmatic attacks and wheezing ceased in about one week.

Reynolds TM. Vitamin B6 deficiency may also be important. Clin Chem 1998 Dec;44(12):2555-2556. (Letter)

Rimland B. Controversies in the treatment of autistic children: vitamin and drug therapy. J Child Neurol 1988;3 Suppl:S68-72. (Review)
Abstract: A survey of approximately 4,000 questionnaires completed by parents of autistic children provided ratings on a variety of treatments and interventions. Among the biomedical treatments, the use of high-dosage vitamin B6 and magnesium (n = 318) received the highest ratings, with 8.5 parents reporting behavioral improvement to every one reporting behavioral worsening. Deanol (n = 121) was next most highly rated, with 1.8 parents reporting improvement to each one reporting worsening. Fenfluramine (n = 104) was third, with a ratio of 1.5:1. Thioridazine hydrochloride (Mellaril), by far the most often used drug on the list (n = 724), was fourth with a helped-worsened ratio of 1.4:1. The research literature on the use of vitamin B6-magnesium is briefly reviewed, and mention is made of recent findings regarding high-dosage folic acid in autism and biotin in Rett syndrome.

Rimland B. High dose vitamin B6 and magnesium in treating autism: response to study by Findling et al. J Autism Dev Disord 1998 Dec;28(6):581-582.

Rimland B, Callaway E, Dreyfus P. The effect of high doses of vitamin B6 on autistic children: a double-blind crossover study. Am J Psychiatry 1978 Apr;135(4):472-475.
Abstract: The authors used data from an earlier nonblind study to identify 16 autistic-type child outpatients who had apparently improved when given vitamin B6 (pyridoxine). In a double-blind study each child's B6 supplement was replaced during two separate experimental trial periods with either a B6 supplement or a matched placebo. Behavior was rated as deteriorating significantly during the B6 withdrawal.

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

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

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

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

Romero JA, Kuczler FJ Jr. Isoniazid overdose: recognition and management. Am Fam Physician 1998 Feb 15;57(4):749-752. (Review)
Abstract: Since isoniazid is increasingly being used to control the spread of tuberculosis, physicians must be aware of its potentially fatal effects. The ingestion of toxic amounts of isoniazid causes recurrent seizures, profound metabolic acidosis, coma and even death. In adults, toxicity can occur with the acute ingestion of as little as 1.5 g of isoniazid. Doses larger than 30 mg per kg often produce seizures. When ingested in amounts of 80 to 150 mg per kg or more, isoniazid can be rapidly fatal. The first signs and symptoms of isoniazid toxicity usually appear 30 minutes to two hours after ingestion and include nausea, vomiting, slurred speech, dizziness, tachycardia and urinary retention, followed by stupor, coma and recurrent grand mal seizures. The seizures produced by isoniazid toxicity are often refractory to anticonvulsant therapy. Given in gram-per-gram amounts of the isoniazid ingested, pyridoxine (vitamin B6) usually eliminates seizure activity and helps to correct the patient's metabolic acidosis. Isoniazid toxicity should be suspected in any patient who presents with refractory seizures and metabolic acidosis.

Rose DP, Adams PW. Oral contraceptives and tryptophan metabolism: effects of oestrogen in low dose combined with a progestagen and of a low-dose progestagen (megestrol acetate) given alone. J Clin Pathol 1972 Mar;25(3):252-258.

Rose DP, Leklem JE, Brown RR, Linkswiler HM. Effect of oral contraceptives and vitamin B6 deficiency on carbohydrate metabolism. Am J Clin Nutr 1975 Aug;28(8):872-878.
Abstract: Oral glucose tolerance, urinary xanthurenic acid excretion, and plasma pyridoxal phosphate concentrations were determined in nine women taking oral contraceptives and in four controls. The tests were repeated after 4 weeks ingestion of a vitamin B6-deficient diet, and again after pyridoxine supplementation. Vitamin B6 deficiency, as judged by an increased xanthurenic acid excretion and reduced plasma pyridoxal phosphate, was associated with a deterioration in the glucose tolerance of the contraceptive steroid-treated group despite normal or elevated plasma insulin levels. This abnormality was reversed by pyridoxine. There was no change in the glucose tolerance of the vitamin B6-deficient controls. The observed pyridoxine-responsive alteration in carbohydrate metabolism may involve the complexing of insulin with xanthurenic acid with a consequent loss of biological activity. In addition, oral contraceptives may enhance gluconeogensis.

Sahakian V, Rouse D, Sipes S, Rose N, Niebyl J. Vitamin B6 is effective therapy for nausea and vomiting of pregnancy: a randomized, double-blind placebo-controlled study. Obstet Gynecol. 1991 Jul;78(1):33-36.
Abstract: Fifty-nine women completed a randomized, double-blind placebo-controlled study of pyridoxine hydrochloride (vitamin B6) for the treatment of nausea and vomiting of pregnancy. Thirty-one patients received vitamin B6, 25-mg tablets orally every 8 hours for 72 hours, and 28 patients received placebo in the same regimen. Patients were categorized according to the presence of vomiting: severe nausea (score greater than 7) or mild to moderate nausea (score of 7 or less). The severity of nausea (as graded on a visual analogue scale of 1-10 cm) and the number of patients with vomiting over a 72-hour period were used to evaluate response to therapy. Twelve of 31 patients in the vitamin B6 group had a pre-treatment nausea score greater than 7 (severe) (mean 8.2 +/- 0.8), as did ten of 28 patients in the placebo group (mean 8.7 +/- 0.9) (not significant). Following therapy, there was a significant difference in the mean "difference in nausea" score (ie, baseline - post-therapy nausea) between patients with severe nausea receiving vitamin B6 (mean 4.3 +/- 2.1) and placebo (mean 1.8 +/- 2.2) (P less than .01). In patients with mild to moderate nausea and in the group as a whole, no significant difference between treatment and placebo was observed. Fifteen of 31 vitamin B6-treated patients had vomiting before therapy, compared with ten of 28 in the placebo group (not significant). At the completion of 3 days of therapy, only eight of 31 patients in the vitamin B6 group had any vomiting, compared with 15 of 28 patients in the placebo group (P less than .05).

Schaeffer MC, Gretz D, Gietzen DW, Rogers QR. Dietary excess of vitamin B-6 affects the concentrations of amino acids in the caudate nucleus and serum and the binding properties of serotonin receptors in the brain cortex of rats. J Nutr. 1998 Oct;128(10):1829-1835.
Abstract: Vitamin B-6 is a cofactor in many reactions of nitrogen metabolism. Deficiency alters tissue amino acid concentrations but effects of excess vitamin B-6 have not been well described. We fed female rats (218 g, 7 per group) 1 (control), 10, 100, 175 or 250x) the National Research Council recommended level of pyridoxine HCl (7 mg/kg) for 10 wk and measured serum amino acids, amino acids and neurotransmitters in brain regions and the binding properties of serotonin receptors in the cerebral cortex using a ketanserin binding assay. Rats were decapitated, and unheparinized blood was obtained. In the caudate nucleus, concentrations of glutamate, threonine, taurine, methionine, gamma-amino-butyric acid and the sum of the essential amino acids in groups 10X and 100X were approximately 130 to 180% of control levels (P < 0.05); groups 1X, 175X and 250X were not different. A similar pattern was seen in the serum for serine, glycine, aspartate and ornithine; the latter two amino acids increased to over 200% of control in group 100X. In the ketanserin binding assay, both the antagonist binding affinity and the maximal number of binding sites were higher for group 100X than for 1X, 175X and 250X, and were higher for 10X than for 1X. Norepinephrine in the raphe nucleus followed a similar biphasic pattern. Excess dietary pyridoxine affected brain and serum concentrations of some amino acids and binding properties of cortical serotonin receptors in a biphasic pattern over the range of concentrations fed in this study.

Schaumburg H, Kaplan J, Windebank A, Vick N, Rasmus S, Pleasure D, Brown MJ. Sensory neuropathy from pyridoxine abuse. A new megavitamin syndrome. N Engl J Med 1983 Aug 25;309(8):445-448.
Abstract: We describe seven adults who had ataxia and severe sensory-nervous-system dysfunction after daily high-level pyridoxine (vitamin B6) consumption. Four were severely disabled; all improved after withdrawal. Weakness was not a feature of this condition, and the central nervous system was clinically spared. Although consumption of large doses of pyridoxine has gained wide public acceptance, this report indicates that it can cause sensory neuropathy or neuronopathy syndromes and that safe guidelines should be established for the use of this widely abused vitamin.

Schwaninger M, Ringleb P, Winter R, Kohl B, Fiehn W, Rieser PA, Walter-Sack I. Elevated plasma concentrations of homocysteine in antiepileptic drug treatment. Epilepsia 1999 Mar;40(3):345-350.
Abstract: PURPOSE: Homocysteine is an experimental convulsant and an established risk factor in atherosclerosis. A nutritional deficiency of vitamin B6, vitamin B12, or folate leads to increased homocysteine plasma concentrations. During treatment with carbamazepine (CBZ), phenytoin, or phenobarbital, a deficiency in these vitamins is common. The objective of the study was to test the hypothesis that antiepileptic drug (AED) treatment is associated with increased homocysteine plasma concentrations. METHODS: A total of 51 consecutive outpatients of our epilepsy clinic receiving stable, individually adjusted AED treatment and 51 sex- and age-matched controls were enrolled in the study. Concentrations of total homocysteine and vitamin B6 were measured in plasma; vitamin B12 and folate were measured in the serum of fasted subjects. RESULTS: Patients and controls differed significantly in concentrations of folate ( 13.5+/-1.0 vs. 17.4+/-0.8 nM and vitamin B6 (39.7+/-3.4 vs. 66.2+/-7.5 nM), whereas serum concentrations of vitamin B12 were similar. The homocysteine plasma concentration was significantly increased to 14.7+/-3.0 microM in patients compared with controls (9.5+/-0.5 microM; p < 0.05, Wilcoxon rank-sum test). The number of patients with concentrations of >15 microM was significantly higher in the patient group than among controls. The same result was obtained if only patients with CBZ monotherapy were included. Patients with increased homocysteine plasma concentrations had lower folate concentrations. CONCLUSIONS: These data support the hypothesis that prolonged AED treatment may increase plasma concentrations of homocysteine, although the alternative explanation that increased homocysteine plasma concentrations are associated with the disease and not the treatment cannot be completely excluded at the moment.

Shah BR, Santucci K, Sinert R, Steiner P. Acute isoniazid neurotoxicity in an urban hospital. Pediatrics 1995 May;95(5):700-704.
Abstract: OBJECTIVES. To describe the presentation and treatment of acute isoniazid (INH) neurotoxicity appearing at an inner-city municipal hospital. DESIGN. Case series. PARTICIPANTS. Seven patients (eight patient visits) with an age range of 5 days to 14.9 years. RESULTS. At our institution, no children appeared with acute INH neurotoxicity in the period 1985 through 1990, whereas seven patients were treated from 1991 through 1993. This paralleled the rise in the number of children with tuberculous infection and disease seen at our institution, from an average 96 per year to 213 per year during these two time periods. All seven patients were receiving INH daily for tuberculosis (TB) prophylaxis. Accidental ingestion (five episodes) and suicidal attempts (three episodes) accounted for these visits. The total amount ingested range from 14.3 to 99.3 mg/kg (mean, 54 mg/kg). All but one patient presented with afebrile seizures. One patient presented twice with seizures. Acute INH neurotoxicity was not suspected on the first admission; however, when readmitted 4 weeks later with another seizure, the diagnosis of acute INH neurotoxicity was made. INTERVENTION. Intravenous pyridoxine was used in five episodes. Because it was not a stocked item in our pediatric emergency cart (as well as at another hospital, necessitating a transfer of a patient with refractory seizures to our hospital), the average delay was 5.8 hours (range, 1.3 to 13 hours) before it was given. Two patients with refractory seizures failed to respond to anticonvulsants, and their seizures were controlled only after parenteral pyridoxine. CONCLUSIONS. We have seen an increased incidence of acute INH neurotoxicity because of the resurgence of TB in New York City. Others as well may see a similar rise based on local trends in TB infection and disease. Acute INH toxicity should be suspected in children presenting with seizures with or without fever. In patients with a known access to INH, seizures should be considered to be caused by INH toxicity unless proved otherwise. Parenteral pyridoxine, the specific antidote for INH-induced refractory seizures, should be readily available in every emergency department in the areas similarly experiencing increasing trends of TB.

Sherertz EF. Acneiform eruption due to "megadose" vitamins B6 and B12. Cutis 1991 Aug;48(2):119-120.
Abstract: Medications and other exogenous factors are known to be capable of exacerbating acne or precipitating acneiform eruptions. This case illustrates an eruption resembling acne rosacea that was temporally associated with daily ingestion of high-dose B vitamin supplement. The eruption failed to respond to the usual treatment regimens for rosacea, but promptly improved when use of the vitamin supplement was discontinued.

Shimizu T, Maeda S, Mochizuki H, Tokuyama K, Morikawa A. Theophylline attenuates circulating vitamin B6 levels in children with asthma. Pharmacology 1994 Dec;49(6):392-397.
Abstract: This study was undertaken to investigate the effect of theophylline on circulating vitamin B6 levels in children with asthma. Twenty-six asthmatic children, including 20 patients who were treated with slow-release theophylline and 6 patients not receiving any type of theophylline preparation, were enrolled in this study. Steady state serum theophylline and vitamin B6 [pyridoxal 5'-phosphate (PLP) and pyridoxal (PL)] levels were evaluated in these patients. A depression of serum PLP levels existed in asthmatic children treated with theophylline compared to those not receiving theophylline (5.3 +/- 0.5 vs. 9.0 +/- 1.4 ng/ml, mean +/- SEM; p < 0.05). A significant negative correlation between the serum levels of PLP and theophylline was demonstrated in the subjects of this study (rs = -0.609, p < 0.001). Oral administration of 200 mg of theophylline (TheoDur) to 5 children with asthma significantly depressed serum PLP levels 4 h after the drug intake (p < 0.05), whereas theophylline did not affect serum PL levels. From these results, we conclude that theophylline induces a depression of circulating PLP levels in asthmatic children.

Smith GP, Rudge PJ, Peters TJ. Biochemical studies of pyridoxal and pyridoxal phosphate status and therapeutic trial of pyridoxine in patients with carpal tunnel syndrome. Ann Neurol 1984;15:104-107.

Snider DE Jr. Pyridoxine supplementation during isoniazid therapy. Tubercle 1980 Dec;61(4):191-196. (Review)
Abstract: Vitamin B6 (pyridoxine) supplementation during isoniazid (INH) therapy is necessary in some patients to prevent the development of peripheral neuropathy. In vivo pyridoxine is converted into coenzymes which play an essential role in the metabolism of protein, carbohydrates, fatty acids, and several other substances, including brain amines, INH apparently competitively inhibits the action of pyridoxine in these metabolic functions. The reported frequency of INH-induced neuropathy in various studies is reviewed and population groups at relatively high risk of developing this complication are identified. The routine use of pyridoxine supplementation to prevent peripheral neuropathy in high risk populations is recommended.

Snider D. Pyridoxine therapy for premenstrual acne flare. Arch Dermatol. Arch Dermatol 1974 Jul;110(1):130-131. (Letter)
Abstract: 106 young women patients received vitamin B-6 50mg/day for 1 week prior to and during menses. 72% improved.

Stewart A.Vitamin B6 in the treatment of the premenstrual syndrome--review. Br J Obstet Gynaecol 1991 Mar;98(3):329-330. (Letter)

Threlkeld DS, ed. Central nervous system drugs, antidepressants, monoamine oxidase inhibitors. In: Facts and Comparisons Drug Information. St. Louis, MO: Facts and Comparisons, Apr 1997.

Threlkeld DS, ed. Gastrointestinal Drugs, Histamine H2 Antagonists. In: Facts and Comparisons Drug Information. St. Louis, MO: Facts and Comparisons, Sep 1995.

Threlkeld DS, ed. Hormones, Oral Contraceptives. In: Facts and Comparisons Drug Information. St. Louis, MO: Facts and Comparisons, Jul 1994.

Threlkeld DS, ed. Respiratory Drugs, Bronchodilators, Xanthine Derivatives. In: Facts and Comparisons Drug Information. St. Louis, MO: Facts and Comparisons, Feb 1991.

Tolomelli B, Caudarella R, Rizzoli E, Marchetti M. Relationships between some lithogenetic factors and vitamin B6-status in idiopathic calcium lithiasis. Int J Vitam Nutr Res 1991;61(4):304-309.
Abstract: Several researchers have shown that a reduced intake of vitamin B6 can induce increased oxalate urinary excretion leading to a higher incidence of calcium oxalate stones. Furthermore, the treatment with pyridoxine in patients with urinary stones and high oxalate excretion has led to contradictory results as the excretion of oxalate was either decreased, unchanged or increased. To verify if these divergent results were linked to a different B6 status of the patients undergoing the treatment, we studied the vitamin B6 and the main lithogenetic factor levels in patients with idiopathic calcium lithiasis as compared to normal subjects. The results showed that a high oxalate excretion is not necessarily coupled with a low vitamin B6 status and viceversa. However, some stone formers present a non homogeneous vitamin pattern that could be the consequence of an abnormal vitamin B6 metabolism.

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

Ubbink JB, Delport R, Becker PJ, Bissbort S. Evidence of a theophylline-induced vitamin B6 deficiency caused by noncompetitive inhibition of pyridoxal kinase. J Lab Clin Med 1989 Jan;113(1):15-22.
Abstract: A placebo-controlled, double-blind study indicated that theophylline administration to apparently healthy, young men induced significantly depressed plasma pyridoxal-5'-phosphate levels. Plasma pyridoxal levels were not affected by theophylline therapy. The effect of theophylline on circulating pyridoxal-5'-phosphate levels is explained by the observation that theophylline acts as a noncompetitive inhibitor for erythrocyte pyridoxal kinase (EC 2.7.1.35) with an apparent inhibition constant (Ki) of 1.28 x 10(-5) mol/L. Theophylline did not affect erythrocyte pyridoxamine (pyridoxine)-5'-phosphate oxidase (EC 1.4.3.5) activity. During theophylline therapy, erythrocyte pyridoxal kinase levels increased nearly twofold from an initial mean level of 24.2 +/- 4.0 (+/- SD) nmol to 46.9 +/- 7.3 nmol pyridoxal-5'-phosphate per gram of hemoglobin per hour. This partially counteracted the effect of theophylline on vitamin B6 metabolism. Nevertheless, erythrocyte pyridoxal-5'-phosphate levels in subjects given theophylline decreased significantly (p = 0.03) from pretreatment levels. The oral tryptophan load test resulted in significantly (p = 0.007) increased urinary xanthurenic acid excretion after 4 weeks of theophylline therapy. Both plasma pyridoxal-5'-phosphate levels and the tryptophan load test results normalized after 1 week of pyridoxine supplementation, indicating that 10 mg pyridoxine per day was effective to counteract the antagonistic effect of short-term theophylline therapy on vitamin B6 metabolism.

Ubbink JB, Delport R, Bissbort S, Vermaak WJ, Becker PJ. Relationship between vitamin B-6 status and elevated pyridoxal kinase levels induced by theophylline therapy in humans. J Nutr 1990 Nov;120(11):1352-1359.
Abstract: Theophylline administration to seven healthy male volunteers resulted in a rapid and significant decline in both plasma and erythrocyte pyridoxal-5'-phosphate levels. Total erythrocyte pyridoxal kinase levels increased during 15 wk of theophylline treatment from a mean initial activity of 19.23 +/- 5.03 (mean +/- SD) to 62.64 +/- 11.59 nmol pyridoxal-5'-phosphate formed/(g hemoglobin.h). Although plasma pyridoxal levels remained normal, the threefold increase in total erythrocyte pyridoxal kinase activity levels did not normalize plasma and erythrocyte pyridoxal-5'-phosphate levels. Pyridoxal-5'-phosphate hydrolysis was not affected by theophylline therapy. Increased pyridoxal oxidation was confirmed by elevated urinary 4-pyridoxic acid excretion after 15 wk of theophylline treatment. Mean erythrocyte alanine aminotransferase activity declined by 70%, and aspartate aminotransferase activity declined by 50%, indicating that decreased availability of pyridoxal-5'-phosphate can have widespread metabolic consequences. We conclude that the effect of theophylline on vitamin B-6 metabolism is not transitory and cannot be overcome by elevated intracellular levels of pyridoxal kinase. However, pyridoxine supplementation (10 mg/d for 1 wk) normalized indices of vitamin B-6 status and reversed the downward trend in both alanine aminotransferase and aspartate aminotransferase activity levels.

Ubbink JB, van der Merwe A, Delport R, Allen RH, Stabler SP, Riezler R, Vermaak WJ. The effect of a subnormal vitamin B-6 status on homocysteine metabolism. J Clin Invest 1996 Jul 1;98(1):177-184.
Abstract: Homocysteine, an atherogenic amino acid, is either remethylated to methionine or metabolized to cysteine by the transsulfuration pathway. The biochemical conversion of homocysteine to cysteine is dependent upon two consecutive, vitamin B-6-dependent reactions. To study the effect of a selective vitamin B-6 deficiency on transsulfuration, we performed oral methionine load tests on 22 vitamin B-6-deficient asthma patients treated with theophylline (a vitamin B-6 antagonist) and 24 age- and sex-matched controls with a normal vitamin B-6 status. Both groups had normal circulating vitamin B-12 and folate concentrations. Methionine loading resulted in significantly higher increases in circulating total homocyst(e)ine (P < 0.01) and cystathionine (P < 0.05) concentrations in vitamin B-6-deficient patients compared with controls. 6 wk of vitamin B-6 supplementation (20 mg/d) significantly (P < 0.05) reduced post-methionine load increases in circulating total homocyst(e)ine concentrations in deficient subjects, but had no significant effect on the increase in total homocyst(e)ine concentrations in controls. The increases in post-methionine load circulating cystathionine concentrations were significantly (P < 0.01) reduced in both groups after vitamin supplementation. It is concluded that a vitamin B-6 deficiency may contribute to impaired transsulfuration and an abnormal methionine load test, which is associated with premature vascular disease.

Ubbink JB, Vermaak WJ, Delport R, Serfontein WJ, Bartel P. The relationship between vitamin B6 metabolism, asthma, and theophylline therapy. Ann N Y Acad Sci 1990;585:285-294. (Review)

USDA Handbook #8 Series. Washington, DD, ARS, USDA, 1976-1986

Vukelja SJ, Baker WJ, Burris HA 3d, Keeling JH, Von Hoff D. Pyridoxine therapy for palmar-plantar erythrodysesthesia associated with Taxotere. J Natl Cancer Inst 1993 Sep 1;85(17):1432-1433. (Letter)

Wachstein, G. Influence of B6 on the incidence of pre-eclampsia. Gyn. 1956; 8: 177.
Abstract: 820 middle income women were divided in half. 410 received a multivitamin without B6 and 410 received the multivitamin with 20 mg B6. The B6 half developed toxemia at a rate of 1.7% while the group without B6 had an incidence of 4.4%.

Weinstein. Oral Administration of B6 in the treatment of nausea and vomiting of pregnancy. Am J Obs Gyn. 1944;47:389-394.
Abstract: 78 women were treated first with 100mg IM then by mouth. Nearly all women responded in 1-3 days. Of the 10 patients with the most severe nausea and vomiting, 8 lost their symptoms entirely after this treatment.

Weir MR, Keniston RC, Enriquez JI Sr, McNamee GA. Depression of vitamin B6 levels due to gentamicin.Vet Hum Toxicol. 1990 Jun;32(3):235-238.
Abstract: The renal toxicity of gentamicin is altered by dietary protein modifications, bicarbonate and acetazolamide administration, magnesium supplementation, polyaspartic acid, piperacillin, hypercalcemia and calcium channel blockers. Renal tissue gentamicin levels have an undetermined role. Reduction of renal pyridoxal 5'-phosphate (PLP) by gentamicin has been shown, as has protection from nephrotoxicity by administration of vitamin B6. To explore an interaction between gentamicin and vitamin B6, gentamicin (5 mg/kg) was given to rabbits by ip injection, with either pyridoxine (10 mg) or isovolemic saline for 3 weeks. There was not a difference between gentamicin levels for animals given gentamicin and pyridoxine versus those given gentamicin and saline. Gentamicin administration led to a 47% fall (p = .0001) in plasma PLP levels. Three days after the last gentamicin administration, the animals maintained a 32% decrease from the pre-gentamicin baseline values (p = 0.02). When pyridoxine was administered concurrently with gentamicin, the PLP rise of 49% was significant (p = 0.001). The mean level after the study (6%) was not significantly lower than baseline (p = .6). We believe that gentamicin interferes with vitamin B6 metabolism, but that vitamin B6 status does not affect levels of gentamicin. A number of drugs affect B6 levels, creating the potential for hypovitaminosis B6 to be an important mechanism of drug-drug interaction in seriously ill patients, particularly in sick newborns or the elderly with lower average PLP levels.

Weir MR, Keniston RC, Enriquez JI, McNamee GA. Depression of vitamin B6 levels due to theophylline. Ann Allergy 1990 Jul;65(1):59-62.
Abstract: Theophylline overdosage can cause life-threatening symptoms, that include seizures and cardiac arrhythmias, and can be fatal. Neither the onset of toxicity nor the severity of symptoms is well predicted by serum theophylline concentrations. Since depressed vitamin B6 plasma levels can occur in patients receiving theophylline, we explored a B6-theophylline interaction in a rabbit model. Administration of theophylline preparations intraperitoneally (aminophylline) or orally (sustained release anhydrous theophylline) resulted in a 47% depression of plasma pyridoxal 5'-phosphate (PLP) levels. The 87% increase in PLP with pyridoxine administration was only 18% when aminophylline was also given. The mechanism of the theophylline-B6 interaction is obscure. Ethylenediamine in some theophylline preparations binds directly to PLP, potentially increasing the less direct theophylline effect. Pyridoxine supplementation resulted in higher average PLP levels but did not prevent death in animals with profoundly low PLP levels. If these data apply to humans, B6 deficiency may contribute to chronic theophylline toxicity; however, pyridoxine administration in the dosage used may not prevent toxicity. Larger doses may prove beneficial after further investigation.

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

Winston F. Oral contraceptives, pyridoxine, and depression. Am J Psychiatry 1973 Nov;130(11):1217-1221.

Williams MJ, Harris RI, Dean BC. Controlled trial of pyridoxine in the premenstrual syndrome. J Int Med Res 1985;13(3):174-179.
Abstract: A total of 617 patients diagnosed by their general practitioner, according to set criteria, as having premenstrual symptoms were treated in general practice for three menstrual cycles with either pyridoxine or placebo. Treatment was randomized and administered blind. In the 434 patients analyzed, an improvement was found in 7 of the 9 symptoms assessed for both treatments, but the differences between treatments did not reach conventional significance levels. However, improvement as measured by global assessment after three cycles was significantly greater in the patients treated with pyridoxine (p less than 0.02).

Willis. Dept of OB, Baylor College of Medicine.
Abstract: Administration of 25-50 mg B-6 IV or IM to 37 women resulted in complete or partial relief of symptoms. The following year other physicians confirmed these results. Complete relief was experienced by 38/40 women treated with IV B-6. Oral doses of 30-80mg were of no use. Improvement generally occurred within 6 to 24 hours after the first injection. 22 patients experienced complete and permanent relief after the first injection. Also, 6 patients with seborrheic dermatitis noted great improvement in their skin.

Winston F. Oral contraceptives, pyridoxine, and depression. Am J Psychiatry 1973 Nov;130(11):1217-1221.

Wynn V, Adams PW, Folkard J, Seed M. Tryptophan, depression and steroidal contraception. J Steroid Biochem 1975 Jun;6(6):965-70.