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

SYMBOL Mixed

Effect and Mechanism of Action

Cutaneous photosensitivity, with subsequent increased tendency to sunburn, is one of the more common adverse effects associated with amiodarone, occurring in as many as 70% of patients. In rare cases, extended use of the drug (≥12 months) can cause gradual onset of a slate-gray or violaceous discoloration of sun-exposed sites. Onset of photosensitivity primarily occurs during the second year of therapy, presumably from drug accumulation, and discontinuation of the medication usually leads to resolution of these effects within 2 years. ^9-14 Early research by Ferguson et al. ¹⁵ indicated that amiodarone has a phototoxic potential against erythrocytes, suggesting a membrane-directed effect. Studying red blood cell hemolysis, Kahn and Fleischaker ¹⁶ reported that photo-oxidation of membrane proteins and photoperoxidation of unsaturated fatty acids of membrane lipids could be responsible for this amiodarone-induced damage. Using electron spin resonance (ESR) Guerciolini et al. ¹⁷ determined that the triggering mechanism is the creation of a long-lived excited state (triplet state) in the photosensitizer after the absorption of a photon.

Data on the effects of pyridoxine on the phototoxicity of amiodarone are mixed and inconclusive. Cozzani and Jori ¹⁸ observed inactivation of L-glutamate decarboxylase from Escherichia coli,sensitized by the coenzyme pyridoxal phosphate. Kaufmann ¹⁹ reported that coadministration of pyridoxine can “suppress the photosensitivity” of patients with amiodarone-induced photosensitivity. He suggested that amiodarone inhibits melanin formation in the skin via a “hypothetical anti-vitamin-B ⁶ effect, and that after a latent period of several months, it causes hypersensitivity to solar irradiation.” ¹⁹ In response, Guerciolini et al. ¹⁷ cited the work of Cozzani and Jori, as well as other findings, and proposed that pyridoxine can enhance the phototoxicity of amiodarone, although they specifically declared that this “does not rule out a protective effect of pyridoxine in vivo.”

Research

In a randomized controlled trial, Mulrow et al. ²⁰ indicated that pyridoxine may exacerbate amiodarone-induced photosensitivity. However, no subsequent research or reports have corroborated this preliminary findings, and the predominant trend in the available data suggests that a protective effect is probable.

Reports

In a letter, Kaufmann ¹⁹ described successful amelioration of photosensitivity with coadministration of oral pyridoxine in three patients who had experienced “a marked tendency to sunburn, caused by amiodarone.” These patients were able to continue amiodarone treatment, with initial pyridoxine doses ranging from 40 to 300 mg, and maintain good tolerance of solar irradiation with 20 to 40 mg daily doses. He noted that the vitamin B ⁶ “in no way impaired the desired pharmacological effects of amiodarone” and concluded that the “minimum effective daily dose of pyridoxine remains to be established.” ¹⁹

In related research, Ross and Moss ²¹ reported two cases of erythropoietic protoporphyria in which use of pyridoxine was associated with a marked reduction in photosensitivity without evidence of adverse effects. These patients had been only moderately responsive to beta-carotene and sunscreens.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing amiodarone for extended use as an antiarrhythmic and coronary vasodilator are advised to be watchful for cutaneous toxicity symptoms and consider coadministration of pyridoxine as a preventive or in response to such effects. Despite the suggestion of potential adverse effects from concomitant intake of amiodarone and vitamin B ⁶ based on preliminary research, no clinical research or qualified case reports have confirmed such concerns. An initial trial dose of 100 to 200 mg pyridoxine daily for 3 months followed by 20 to 40 mg daily would usually be appropriate. However, both the scientific literature and clinical experience show that the effective dosage levels to prevent or reverse adverse effects of amiodarone vary considerably among individual patients, and that initial dosage levels are typically larger than maintenance doses. Close supervision is warranted during initial higher dose levels because of the possible, but improbable, risk of B ⁶ -induced neuropathy.

Short-term use of amiodarone prophylaxis with major cardiac surgery is unlikely to result in drug accumulation, although administration of vitamin B ⁶ (as well as folic acid, B ² , and B ¹² ) may be indicated in the strategic approach to cardiovascular care in such individuals, at least in relationship to hyperhomocysteinemia.

	Minimal to Mild Adverse Interaction—Vigilance Necessary
	Potentially Harmful or Serious Adverse Interaction—Avoid
	Bimodal or Variable Interaction, with Professional Management
	Beneficial or Supportive Interaction, with Professional Management
	Prevention or Reduction of Drug Adverse Effect
	Drug-Induced Adverse Effect on Nutrient Function, Coadministration Therapeutic, with Professional Management
	Adverse Drug Effect on Nutritional Therapeutics, Strategic Concern

SYMBOL Preliminary and SYMBOL Mixed

Effect and Mechanism of Action

High doses of pyridoxine can increase metabolism and decrease serum levels of certain anticonvulsants and barbiturates, specifically phenytoin and phenobarbitone, in some individuals, although not in others. Pyridoxine may accelerate hepatic metabolism of antiepileptic drugs (AEDs) by increasing enzyme activity. ²² However, no mechanism for this reported activity has been confirmed.

Chronic anticonvulsant therapy can exert differing effects on vitamin B ⁶ metabolism and levels, which may vary for different individuals or different agents or act through diverse mechanisms. Plasma pyridoxal 5′-phosphate (PLP) levels can be significantly decreased with chronic use of carbamazepine and valproic acid, especially in children. Both valproic acid and PLP are strongly protein bound, and valproic acid tends to displace PLP from protective protein-binding sites and induce a deficit in PLP. ²³ Conversely, prolonged phenobarbitone and phenytoin (diphenylhydantoin) therapy is associated with fine structural changes in hepatocytes and significantly elevated serum levels of vitamins B ⁶ and B ¹² . ²⁴

Pyridoxine-dependent seizures result from an increased genetically derived requirement for the nutrient within the CNS. Researchers have reported that, in some but not all patients, the “binding affinity of glutamate decarboxylase (GAD) to the active form of pyridoxine is low in cases of pyridoxine-dependent seizures (PDS) and that a quantitative imbalance between excitatory (i.e. glutamate) and inhibitory (i.e. gamma-aminobutyric acid, GABA) neurotransmitters could cause refractory seizures.” ²⁵ Continued administration of vitamin B ⁶ in pharmacological doses has contributed to a marked reduction in infantile seizures in some cases. The combination of B ⁶ and valproic acid or phenobarbital may work synergistically in these patients, even in patients lacking typical indicators of B ⁶ deficiency. ²⁶

The reported effect of AEDs on vitamin B ⁶ levels may be causal to or exacerbating of the elevated levels of homocysteine (Hcy) found in some individuals with seizure disorders using anticonvulsant medications or barbiturates. ^27-33 Although Hcy has been used as an experimental convulsant, this hyperhomocysteinemia may be attributable to the underlying disease process, the medication, or both. Enzyme-inducing AEDs, including phenytoin, phenobarbital, and primidone, are associated with numerous adverse effects on B vitamins and Hcy regulation, including low PLP concentrations, decreased folate absorption, decreased plasma folate concentrations, low riboflavin concentrations, and elevated total Hcy concentrations in adults and in children. These effects vary among individuals, with genetic variables, with monotherapy or polytherapy, and with drug mechanisms of action. Coadministration of B ⁶ , folate, and related nutrients, at low to moderate doses, may normalize Hcy levels, particularly in patients receiving AED monotherapy.

Research and Reports

Over more than three decades, researchers have reported numerous possible and proven interactions between vitamin B ⁶ and related nutrients in individuals undergoing therapy with anticonvulsants and barbiturates. Evidence indicates the probability of interactions that might adversely affect drug activity and nutrient levels and function, but other research suggests that coadministration under medical supervision may be beneficial in certain patients by mitigating drug-induced hyperhomocysteinemia or enhancing therapeutic response.

Effect on Drug Activity

A study conducted by Hansson and Sillanpaa ²² constitutes the primary, if not singular, published paper mentioned in most accounts of the interactions between vitamin B ⁶ and the broad range of medications commonly clustered together as antiepileptic drugs. In many instances the details of the report have been misrepresented, exaggerated, or overextended. In this short letter the authors reported marked drops in serum concentrations of phenytoin or phenobarbitone in a small number of patients receiving “long-term multiple antiepileptic medications,” most of whom were significantly compromised with “non-progressive brain-damage syndromes in addition to mental retardation and epilepsy.” Doses of pyridoxine of 200 or 400 mg daily for 4 weeks elicited the most frequent changes in drug levels, up to 50% in some cases. However, in “several other cases, pyridoxine added to the anticonvulsant treatment did not alter the phenytoin or phenobarbitone concentrations.” The most extreme case of decreased serum phenytoin concentrations following administration of 200 mg and then 400 mg per day of pyridoxine involved a 6-year-old girl “during subacute intoxication.” The authors noted that the “doses used were arbitrarily chosen,” and no attempt was made to determine the “real amount needed per day.” Levels of PLP were not assessed. While offering no supportive evidence, the authors suggested that the addition of the pyridoxine may have “increased activity of pyridoxal-phosphate-dependent enzymes involved in the biotransformation (hydroxylation?) of the drugs.” ²² Such alterations in drug concentrations could theoretically trigger seizures, but these authors did not relate any such occurrences in their small study. Subsequent research from controlled trials is lacking to confirm these preliminary findings and establish their clinical implications.

Effects on Nutrients and Homocysteine

A broad range of sources present as “incontrovertible” that anticonvulsants decrease the levels and impair the function of numerous key nutrients, including vitamin B ⁶ . Notably, seizures are a known effect of vitamin B ⁶ deficiency, and certain seizure disorders are specifically pyridoxine dependent. Furthermore, decreased levels of B ⁶ and related nutrients (folate, B ² , B ¹² ) are also strongly associated with elevations in plasma Hcy. Nevertheless, the body of evidence available at this time, although highly suggestive, is mixed and inadequate to confirm or disprove the hypothesis that AEDs promote clinically significant B ⁶ deficiency or that AED-induced hyperhomocysteinemia inherently results in increased adverse outcomes, or to determine which drugs are more likely to induce such changes and what patient characteristics are associated with increased vulnerability to Hcy elevations and subsequent adverse events. Moreover, some studies have found that serum levels of vitamin B ⁶ (and/or B ¹² ) are elevated in some patients treated with AEDs.

Anticonvulsant medications appear capable of either lowering or elevating levels of vitamin B ⁶ . In a study involving patients with epilepsy on long-term antiepileptic treatment Hagberg et al. ³⁴ found that plasma PLP concentrations were normal in single determinations using tryptophan load tests. However, in patients followed before and during therapy using antiepileptic medication with hydantoin and succinimide (ethosuximide), Reinken ³⁵ observed significant repeated decreases in serum concentrations of PLP. Subsequent research by Reinken ³⁶ suggested an association between anticonvulsant therapy and possible depletion of vitamin B ⁶ in children.

Haust et al. ²³ reported “increased levels of erythrocyte protoporphyrin (EP)” and a “progressive fall in plasma pyridoxal 5′-phosphate (B6-P)” as well as decreased levels of 5-aminolevulinic acid dehydratase (ALA-D) and uroporphyrinogen I synthetase (URO-S) in an epileptic boy undergoing long-term treatment with valproic acid (VPA, 1.3 g/day), CBMZP (0.9 g/day), and folic acid (7.5 mg/day). They administered “pyridoxine HCl (B6-HCl), 87.5 mg/d followed by administration of both B6-HCl and preformed B6-P (50 mg/d each)” and were subsequently able to achieve “the eventual withdrawal of VPA and a net reduction of CBMZP to 450 mg/d.” They obtained increases in ALA-D and URO-S before any reduction of CBMZP with pyridoxine hydrochloride alone and then normalization of enzyme levels after “administration of both B6-HCl and B6-P and withdrawal of VPA. During stepwise reduction of VPA, EP remained elevated to values as high as 2.48 μmol/L (upper reference limit, 1.33 μmol/L). Only after permanent withdrawal of VPA did concentrations of EP fall to normal levels.” The authors interpreted these findings to suggest “that VPA displaced B6-P from protective protein binding sites” because “both VPA and B6-P are strongly protein-bound,” and “that the resulting deficit in B6-P (rather than CBMZP) reduced ALA-D and URO-S activities via primary reduction of ALA-synthetase activity.” ²³

In contrast, other researchers have observed apparent elevations of vitamin B ⁶ levels in individuals being treated with AEDs. Dastur and Dave ²⁴ observed that contrasting pattern when they studied the effects of prolonged anticonvulsant medication in 27 epileptic patients, primarily from low socioeconomic groups, age 15 to 54 years. These subjects had received phenobarbitone (90 mg/day phenobarbital) and diphenylhydantion (300 mg/day phenytoin) regularly for 3 to 32 years and had no history of B-vitamin supplementation. “Besides reduced serum and cerebrospinal fluid (CSF) folate levels, significantly increased levels of total vitamin B ⁶ in CSF and serum and of vitamin B ¹² in serum were found in patients as compared with normal healthy subjects.” Furthermore, despite a lack of “clinical hepatic involvement, liver biopsy performed in nine of twenty-seven patients revealed fine structural changes in hepatocytes suggestive of varying degrees of drug-induced changes. A ramifying network of short, smooth, endoplasmic cisternae with depleted rough endoplasmic reticulum (RER), distended sinusoids with Kupffer cells, dark shrunken hepatocytes with reduced mitochondria, and increased lipofuscin were observed.” The authors suggested that these elevations in serum vitamin levels, along with “significant elevation of serum triglycerides and/or cholesterol,” might be the result of hepatic damage, specifically “an adaptive response of the liver, a reversible change.” ²⁴

The recycling of folate cofactors depends on vitamin B ⁶ and riboflavin, and riboflavin is necessary for activating vitamin B ⁶ to PLP. Plasma Hcy levels tend to be elevated in individuals undergoing long-term AED therapy and may play a role in the increased incidence of atherosclerosis, vascular disease, and stroke observed in this patient population. Although controversial, numerous epidemiological data indicate that chronic AED administration is associated with various occlusive vascular disease. ^37-40

Numerous researchers have demonstrated that treatment with phenytoin, phenobarbital, and primidone and other enzyme-inducing AEDs is associated with elevated total homocysteine (tHcy) concentrations or decreased plasma folate concentrations in adults and in children. ^27,28,41-45 For example, Schwaninger et al. ²⁹ conducted a controlled trial involving 51 consecutive outpatients in an epilepsy clinic receiving stable, individually adjusted AED treatment and 51 gender- and age-matched controls. Assessing plasma concentrations of tHcy and vitamin B ⁶ and serum levels of vitamin B ¹² and folate in fasted subjects, they observed that “patients and controls differed significantly in concentrations of folate (13.5±1.0 vs. 17.4±0.8 nM) and vitamin B ⁶ (39.7±3.4 vs. 66.2±7.5 nM), whereas serum concentrations of vitamin B ¹² were similar.” Furthermore, they found that plasma Hcy concentration was “significantly increased to 14.7±3.0 microM in patients compared with controls” and that “number of patients with concentrations of >15 microM was significantly higher in the patient group than among controls.” The authors noted that these patterns were present with both AED polytherapy and with carbamazepine monotherapy. However, they also cautioned that the observed elevations in homocysteine might be “associated with the disease and not the treatment.” ²⁹

Verrotti et al. ³⁰ evaluated hyperhomocysteinemia in 60 epileptic children (29 females, 31 males), age 14.2 to 17.9 years, receiving sodium valproate (VPA) and carbamazepine (CBZ), monotherapy. They observed “no significant differences in fasting and post-methionine Hcy, plasma PLP, serum folate, erythrocyte folate and serum vitamin B ¹² values between the control group and the two groups of epileptic children” before the initiation of therapy. However, “patients treated with VPA and CBZ showed a significant increase of the plasma concentrations of Hcy when compared to baseline data and controls values” and demonstrated “a significant decrease of serum folate and plasma PLP” after 1 year of therapy. Notably, “serum vitamin B ¹² and erythrocyte folate levels remained in the normal range.” The authors suggested two possible interpretations for the increased plasma concentrations of Hcy with prolonged VPA or CBZ treatment. They proposed that remethylation of Hcy to methionine uses 5-methyltetrahydrofolate as a methyl donor and vitamin B ¹² as a cofactor, or “Hcy may conjugate with serine to form cystathionine in a reaction which requires pyridoxal 5′-phosphate … as a cofactor.” ³⁰ Thus, significantly decreased levels of PLP (P5P) or folate in presence of increased Hcy levels might be predicted with carbamazepine, a potent enzyme inducer, whereas only a small reduction of folate values might be associated with valproate, an AED with less enzyme-inducing activity. ^46,47

Yoo and Hong ⁴¹ (1999) and Ono et al. ³² (2002) suggested that a drug-gene interaction involving the C677T variant of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene might be related to AED-mediated decrease in plasma folate concentrations and an independent predictor of hyperhomocysteinemia in patients receiving AED therapy. Nevertheless, Apeland et al. ⁴⁸ (2003) reported that patients receiving enzyme-inducing AEDs (carbamazepine monotherapy; phenytoin, phenobarbital, and/or primidone) had low PLP concentrations that were negatively correlated with plasma Hcy concentrations as well as high plasma flavin nucleotide/riboflavin concentration ratios with low riboflavin concentrations. Notably, these patients had higher plasma tHcy concentrations (fasting and after methionine loading) than controls, but such changes in tHcy were not observed in patients who received valproate.

However, more recent research indicates that elevated Hcy levels may not be clinically significant in AED-treated epileptic patients with adequate folate intake. Tamura et al. ³¹ measured blood concentrations of Hcy, folate, vitamin B ¹² , and PLP and determined MTHFR genotypes in sixty-two patients receiving AED monotherapy (phenytoin, lamotrigine, carbamazepine, or valproate). They reported hyperhomocysteinemia in only 7 (11.4%) of 62 patients overall and 3 (15.0%) of the 20 patients receiving phenytoin. Notably, more than 55% of the patients overall exhibited PLP concentrations below the normal range. In contrast, serum vitamin B ¹² concentrations were elevated in patients treated with valproate. The authors concluded that “hyperhomocysteinemia is not a serious clinical concern in AED-treated epileptic patients” with adequate folate nutriture. However, only “three patients had the homozygous thermolabile genotype of MTHFR; therefore, meaningful statistical analysis [of that particular factor] was not possible in this study.” ³¹ Five years later, Gidal, Tamura, et al. ³³ found that 32 weeks of treatment with lamotrigine (mean daily dose, 250 mg) had “no significant effect on concentrations of plasma total homocysteine (tHcy), plasma and red-cell folate and plasma vitamin B ¹² ” but that “2070 mg of valproate resulted in a 57% increase in plasma vitamin B ¹² concentrations over the baseline value and a 27% decline in plasma tHcy concentrations.” The authors concluded that the data indicated “hyperhomocysteinemia may not be a serious clinical problem” among patients with epilepsy treated with either lamotrigine or valproate. ³³ Thus, despite minimal data, it appears that newer AEDs, such as lamotrigine, which lack hepatic enzyme-inducing activity, are less likely to be associated with altered folate concentrations or Hcy metabolism.

Coadministration Benefits

Pyridoxine, alone and in concert with conventional AEDs, has been efficacious in the treatment of certain forms of seizure disorders. Some seizures are pyridoxine dependent, including inborn errors of metabolism, and require an increased intake of the nutrient. Furthermore, low vitamin B ⁶ is associated with a lowered seizure threshold. ^49,50

In a trial involving 20 patients with infantile spasms, Ito et al. ²⁶ studied the effects of “high doses of vitamin B ⁶ ,” valproic acid, or both and concluded that the combination of vitamin B ⁶ and valproic acid was effective and safe in the treatment of infantile spasms (i.e., seizures). Their research found that although vitamin B ⁶ alone provided some benefit, patients who were given a combination of vitamin B ⁶ and valproic acid had significantly fewer seizures and better electroencephalogram findings than did the group treated initially with vitamin B ⁶ alone. However, “vitamin B ⁶ therapy alone was continued in a single patient who remained seizure-free during the 15-month follow-up period.” ²⁶ Pietz et al. ^50a found that 300 mg/kg/day of vitamin B ⁶ (pyridoxine HCl orally) reduced infantile spasms in 5 of 17 children within the first 2 weeks of treatment, and within 4 weeks, all five 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 B ⁶ .” Notably, “no serious adverse reactions were noted,” with gastrointestinal symptoms, reversible after dosage reduction, being the primary adverse effects reported. Noting “the life-threatening side effects of treatment with ACTH/corticosteroids or valproate,” the authors concluded by recommending a controlled clinical trial with “high-dose vitamin B ⁶ ” to either prove or disprove efficacy. ^50a In a controlled study, Walter-Sack and Klotz ⁵¹ found that coadministration of vitamin B ⁶ , 200 mg daily for 4 weeks, resulted in a 45% reduction in phenobarbital blood levels.

Subsequently, Goto et al. ²⁵ investigated binding affinity of glutamate decarboxylase (GAD) in relation to cerebrospinal fluid (CSF) glutamate/GABA concentrations to determine the etiology of pyridoxine-dependent seizures (PDS) and the mechanisms of pyridoxine action in seizure control. They described a patient with PDS whose generalized seizures terminated after intravenous pyridoxine phosphate. This patient's condition had been refractory to conventional antiepileptic medicines and was not accompanied by an elevated CSF glutamate concentration. “No seizure occurred once oral pyridoxine (13.5 mg/Kg per day) was started in combination with phenobarbital sodium (PB, 3.7 mg/Kg per day). The electroencephalogram (EEG) normalized approximately 8 months after pyridoxine was started.” Based on these observations, they suggested that pyridoxine-dependent seizure “is not a discrete disease of single etiology in that insufficient activation of GAD may not account for seizure susceptibility in all cases and (2) mechanism(s) of anti-convulsive effect of pyridoxine, at least in some cases, may be independent of GAD activation.” ²⁵

In a rat model, Reyes-Garcia et al. ⁵² found that B vitamins can enhance the antiallodynic effect of gabapentin (Neurontin). These researchers induced neuropathic pain and measured paw withdrawal in Wistar rats. Tactile allodynia was determined after oral administration of gabapentin (30-300 mg/kg), B vitamins (75-600 mg/kg), or a combination of gabapentin and B vitamins. Their findings “indicate that systemic administration of gabapentin and B vitamins can interact synergistically to reduce neuropathic pain in the rat and suggest the use of this combination to relieve neuropathy in humans.” ⁵²

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing AEDs and related barbiturates are advised to be aware that these medications can decrease circulating levels of vitamin B ⁶ or its activated form, pyridoxal 5′phosphate (PLP), and may cause elevations in plasma homocysteine, with attendant risks. The probability of such adverse effects appears to be significantly greater with enzyme-inducing AEDs (carbamazepine monotherapy; phenytoin, phenobarbital, and/or primidone) than in those receiving valproate or lamotrigine monotherapy; in general, AED polytherapy carries greater risks for this and other adverse effects than does AED monotherapy with any agent. Furthermore, pharmacogenomic variability in metabolism of AEDs and genetic variants affecting folate metabolism, particularly MTHFR polymorphism C677T, can significantly influence drug efficacy and toxicity.

Coadministration of vitamin B ⁶ , usually in combination with folate, vitamin B ¹² , and riboflavin, may be warranted to mitigate adverse effects of these medications on nutrient metabolism as well as increased risks of teratogenicity, hyperhomocysteinemia, and other well-known toxic effects. Moreover, within the context of appropriate clinical management by experienced health care professionals, vitamin B ⁶ may be indicated as a component of an integrative approach to treatment of seizure disorders, and coadministration with AEDs may enhance the therapeutic response.

Close supervision and regular monitoring is warranted with concomitant use, particularly B ⁶ doses greater than 200 mg/day. It is particularly important to regularly evaluate serum concentrations of phenytoin and phenobarbital and clinical response in patients receiving concomitant pyridoxine at doses of 200 mg/day or greater. Evidence is lacking to suggest that the small dose levels of vitamin B ⁶ in typical multivitamins and B-complex formulations might interfere with effective drug dose and therapeutic response.

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

SYMBOL Preliminary to SYMBOL AMPERSANDthinsp; SYMBOL Emerging

Effect and Mechanism of Action

Vitamin B ⁶ may reduce the severity of certain adverse effects associated with several chemotherapeutic agents but may also diminish the therapeutic efficacy of some medications. Palmar-plantar erythrodysesthesia (PPE) syndrome is an adverse effect often associated with antineoplastic treatment using 5-fluorouracil, docetaxel, and doxorubicin HCl liposome injection. This painful condition often constitutes the limiting toxicity of such therapies. ⁵³ Pyridoxine has been shown to mitigate this painful cutaneous toxicity, but the mechanisms of these activities have yet to be elucidated. ^54-57 Pyridoxine can reduce altretamine-associated neurotoxicity but may diminish the therapeutic activity of altretamine (hexamethylmelamine) when used in combination with cisplatin. ⁵⁸ Again, the mechanisms for these effects are as yet unknown.

Research and Reports

Molina, Fabian, et al. ^54,56 published two papers on the coadministration of pyridoxine therapy for palmar-plantar erythrodysesthesia associated with low dose continuous infusion 5-fluorouracil (200-300 mg/m ² /day). Their preliminary report (1987) described reversal of PPE, without impairment of therapeutic efficacy, in colon cancer patients receiving 200 mg/m ² /day continuous 5-FU following coadministration of 100 mg/day of pyridoxine. ⁵⁴ Three years later they published their complete findings showing that concomitant pyridoxine therapy can reverse 5-FU–induced PPE without any adverse effects or interruption of chemotherapy. “Five previously untreated patients who developed PPE received 50 or 150 mg of pyridoxine/day when moderate PPE changes were noted. Reversal of PPE without interruption of the 5-FU was seen in 4/5 patients. Four of these patients who received pyridoxine had responded to 5-FU treatment. No adverse affect of pyridoxine on clinical response was noted.” ⁵⁶

Vukelja et al. ⁵⁹ reported two cases in which symptoms of PPE began to resolve within 12 to 24 hours after initiation of pyridoxine, 50 mg three times daily, and continued to improve for several weeks.

In a randomized, double-blind clinical trial involving 41 dogs with non-Hodgkin's lymphoma, Vail et al. ⁵⁷ compared concomitant pyridoxine therapy to placebo in preventing the development of PPE (PPES) during chemotherapy using Doxil, a doxorubicin-containing pegylated (Stealth) liposome. They observed that the “likelihood of developing serious PPES and having to decrease or discontinue Doxil therapy was 4.2 times (relative risk) greater in placebo group dogs than in pyridoxine group dogs.” Although pyridoxine “did not completely abrogate PPES, it occurred later and less dramatically than in placebo-treated dogs and resulted in fewer treatment delays or discontinuations, allowing a higher cumulative dose of Doxil to be received.” Furthermore, “no difference was observed in remission rates (71.4 versus 75%) achieved between groups” and a “trend (P = 0.084) toward prolongation of remission length was observed in dogs receiving pyridoxine, which was likely attributable to their ability to receive more Doxil without delay or discontinuation.” The authors concluded “that pyridoxine is effective in delaying the onset and severity of PPES in this canine model.” ⁵⁷

Altretamine, also known as hexamethylmelamine (HMM), is a synthetic cytotoxic antineoplastic s-triazine derivative associated with a small but significant occurrence of neurological toxicity. Fabian et al. ⁶⁰ administered prophylactic pyridoxine or the drug alone in a Phase II trial of hexamethylmelamine (HEX) involving 98 patients with metastatic breast cancer, heavily pretreated with other agents. They reported “a 2% response rate in 89 partially or fully evaluable patients. Seven percent of these patients developed neurologic toxicity which occurred in the HEX-alone group only.” ⁶⁰ Subsequently, Wiernik et al. ⁵⁸ conducted a trial involving a total of 248 analyzable patients with stages III-IV ovarian epithelial cancer (114 with and 134 without prior chemotherapy) who were randomized to one of four cisplatin (DDP)–hexamethylmelamine (HMM) regimens. Pyridoxine was coadministered at a dose of 300 mg/m ² orally to evaluate its ability to reduce the neurotoxicity of HMM. Applying multivariate analysis, they identified prior chemotherapy, pyridoxine administration, recent diagnosis, and large tumor size as factors adversely affecting response duration. They concluded: “Although pyridoxine administration significantly reduced neurotoxicity, its adverse effect on response duration suggests that the agent should not be administered with DDP or HMM.” The authors recommended further investigation of the “mechanism by which pyridoxine may unfavorably affect response duration.” ⁵⁸

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Pyridoxine coadministration represents a valuable option for adjunctive use with certain forms of chemotherapy (e.g., 5-fluorouracil, docetaxel, doxorubicin HCl liposome injection) as a means of preventing or reducing specific adverse effects, particularly PPE syndrome and neurotoxicity. In contrast, administration of pyridoxine during chemotherapy using altretamine (HMM), especially in conjunction with cisplatin, while potentially beneficial, warrants caution and should be considered as contraindicated in most cases. Safe and effective implementation of any therapeutic strategy combining chemotherapy and pyridoxine requires clinical management within the context of integrative care involving health care professionals trained and experienced in both conventional pharmacology and nutritional therapeutics.

The usual dosage of vitamin B ⁶ ranges from 50 to 100 mg, three times daily orally, and inherently requires close supervision and regular monitoring given the increased risk for pyridoxine toxicity in compromised patients and potential interference with therapeutic efficacy of the concomitant antineoplastic therapy. Physicians and other health care professionals may consider reviewing the potential for such synergistic strategies with appropriate patients and provide referral information to centers specializing in such integrative approaches. The available evidence is limited but suggestive of a broader pattern deserving further research with large, well-designed clinical trials.

Beneficial or Supportive Interaction, with Professional Management

SYMBOL AMPERSANDthinsp; SYMBOL AMPERSANDthinsp; SYMBOL Consensus

Effect and Mechanism of Action

Bendectin was introduced in the United States in 1956 by Merrell Dow as medication specifically for nausea and vomiting of pregnancy (NVP). Originally it was formulated as a combination of “doxylamine succinate, an antihistamine with antiemetic properties, dicyclomine hydrochloride, an antispasmodic agent, and pyridoxine hydrochloride (vitamin B ⁶ ) to prevent possible deficits during pregnancy and to synergize the antinauseant activity.” ⁶¹ Based on results of randomized control trials comparing each component alone and in combination versus placebo, dicyclomine hydrochloride was dropped from the formulation in 1976. The standard formulation of Diclectin as of 2003 was 10 mg vitamin B ⁶ and 10 mg doxylamine per tablet.

Research

Beginning in 1969, allegations and lawsuits appeared, based on single case incidents, claiming possible teratogenic effects of Bendectin resulting in congenital limb deformities. These legal claims were based on limited evidence and failed in court. Several clinical trials and a meta-analysis of 20 studies, including review of Bendectin use by 200,000 patients, failed to demonstrate any causal relationship between Bendectin and congenital malformations. ^62-66 Nevertheless, Merrell Dow withdrew Bendectin from the U.S. market and ceased worldwide production in 1983 because of business rather than medical factors, specifically adverse publicity, rising legal costs, and insurance premiums, despite winning their legal battles and continued evidence of safety and efficacy. Diclectin is the only prescription medication recommended for the treatment of NVP available in Canada and is considered the drug of choice.

Physicians have continued to prescribe doxylamine-pyridoxine, and further research has investigated its therapeutic application in subsequent years even as the legal and market history of the medication are cited as a striking example of poorly founded litigation interfering with rational, safe, and effective therapeutics. ^67-69 According to a review by Bishai et al., ⁷⁰ the “efficacy of the delayed-release combination of doxylamine and pyridoxine (Bendectin, Diclectin) has been shown in several randomized, controlled trials.” Nevertheless, a significant discrepancy appears to exist between the reported rate of taking Diclectin and physicians’ self-reported prescribing practices for Diclectin. ⁷¹ Thus, in 1999, 90% of physicians reported prescribing Diclectin to their pregnant women with NVP, but only 66% of respondents in a study were actually taking the medication. ⁷²

In a population-based case-control study, Boneva et al. ⁷³ investigated nausea during pregnancy and congenital heart defects. They found that, overall, early nausea and use of antinausea medication, particularly Bendectin “was associated with a lower risk for congenital heart defects compared with: 1) absence of nausea…, and 2) nausea without medication use.” These researchers concluded that these “results suggest that pregnancy hormones and factors or, alternatively, a component of Bendectin (most probably pyridoxine) may be important for normal heart development” and proposed that their “findings outline potential areas for future research on and prevention of congenital heart defects.” ⁷³

Fear of litigation, cautious prescribing, and inadequate communication have all contributed to a pattern of suboptimal dosing in patients treated with doxylamine-pyridoxine. In an observational, prospective study, Atanackovic et al. ⁷⁴ determined the incidence of adverse maternal and fetal effects and pregnancy outcome in 225 women taking doxylamine-pyridoxine for NVP at the recommended or higher-than-recommended doses. They reported “two pregnancies with major malformation, a finding that is consistent with the rates of birth defects in the general population.” They concluded that “the higher than standard dose of Diclectin, when calculated per kg of body weight, does not affect either the incidence of maternal adverse effects or pregnancy outcome.” The authors recommended that “if needed, Diclectin can be given at doses higher than four tablets per day to normalize for body weight or optimize efficacy.” ⁷⁴ Likewise, in a clinical trial involving 68 women with moderate to severe NVP, Boskovic et al. ^74a found that “most women (50/68) were receiving 2 tablets a day of Diclectin instead of the recommended dose of 4 tablets a day.”

An innovative study suggests that compliance in use of medications such as doxylamine-pyridoxine is influenced by many factors and that cultivation of a strong physician-patient relationship might deserve greater attention. Using survey data from interviews with 59 women recruited from the Motherisk Nausea and Vomiting Helpline, Baggley et al. ⁷² investigated factors that influence women's decision making on whether to treat NVP pharmacologically. Although all participants were informed that Diclectin was considered safe for use during pregnancy, investigators found that at “a follow-up telephone call, 34% were not using any pharmacologic treatment, and of those who were taking the drug, 26% were using less than the recommended dose.” These researchers learned that the rationale offered “for not using the medication were insufficient safety data, preference for non-pharmacologic methods, and being made to feel uncomfortable by the physician.” Notably, “of the women who did use Diclectin, the most convincing reassuring information that it was safe to use came from friends and family.” ⁷² Moreover, in a survey conducted by Hollyer et al., ⁷⁵ women suffering from NVP expressed significant fear of using “drugs” during pregnancy and stated that they were more comfortable using “natural” and “alternative” therapies to treat NVP and engaged in such self-care with little or no supervision by their medical or naturopathic physicians.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

The combination of doxylamine and pyridoxine represents a poignant example of the promises and hazards of drug-nutrient interactions as both therapeutic synergy and medicolegal challenge. The body of evidence indicates that this medication can safely and effectively reduce NVP when used at recommended doses, which at four tablets per day provides 40 mg each of pyridoxine and doxylamine. As mentioned, one study found that the inclusion of vitamin B ⁶ might actually enhance fetal development and reduce the risk of congenital heart malformations. Most importantly, the tortured history of this innovative medication suggests that the cultivation of a frank, honest, and trusting therapeutic relationship may play a greater role in patient decision making and compliance than any claims of safety or efficacy and attendant scientific “evidence.” Further research is warranted, as might be investigation of concomitant use of ginger (Zingiber officinale),which has also been shown to be safe and effective in NVP, with doxylamine and pyridoxine. ^76-78

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

SYMBOL AMPERSANDthinsp; SYMBOL Emerging, SYMBOL Mixed

Effect and Mechanism of Action

Erythropoietin (EPO) therapy increases hemoglobin synthesis, which can decrease erythrocyte pyridoxine status and increase nutritional requirements.

The water-soluble nature and small-to-medium molecular size of vitamin B ⁶ , as well as folic acid and vitamin B ¹² , renders B ⁶ particularly susceptible to being lost in the dialsylate in patients undergoing either peritoneal dialysis or hemodialysis, especially with high-flux dialysis.

Research

It is well known that vitamin B ⁶ deficiency, from many causes, develops in the majority of patients with chronic renal failure and in patients during various forms of renal replacement therapy. Mydlik, Derzsiova, and Zemberova ^79-81 have conducted a series of studies investigating erythrocyte levels of various B vitamins in kidney disease as well as the influence of water, furosemide, and sodium diuresis on the metabolism and urinary excretion of vitamin B ⁶ , oxalic acid, and vitamin C in patients with chronic renal failure. Their most important finding was that erythrocyte vitamin B ⁶ is consumed by the stimulated hemoglobin synthesis at an increased rate during EPO treatment in hemodialysis patients. In a 1993 study involving 26 patients undergoing regular dialysis treatment (RDT), they investigated the influence of recombinant human erythropoietin (r-HuEPO) on erythrocyte vitamins B ¹ , B ² , and B ⁶ by comparing vitamin erythrocyte levels with and without EPO. The non-EPO group received oral pyridoxine 5 mg daily for 9 months while the EPO-treated group received oral pyridoxine 5 mg daily for the first 6 months and 20 mg daily during the following 3 months. They observed a significant elevation in erythrocyte vitamin B ² levels and a significant decrease in erythrocyte vitamin B ⁶ . However, after administration of the higher doses of pyridoxine (20 mg daily), subjects exhibited “a significant increase in vitamin B ⁶ and at the end of the 9 months, the values of vitamin B ⁶ were within the normal range.” ⁷⁹ Further, after establishing that intravenous administration of furosemide (20 mg) leads to an increase of urinary excretion and fraction excretion of vitamin B ⁶ in patients with chronic renal failure, this research team found that a “daily oral dose of pyridoxine 6 mg was optimal for the patients without erythropoietin (EPO) treatment during the period of 12 months of CAPD.” Using pyridoxal 5-phosphate (PLP) as an indirect method of determining erythrocyte vitamin B ⁶ , they concluded that for “prevention of vitamin B ⁶ deficiency in hemodialysis and CAPD patients we recommend the following doses of pyridoxine: for patients without EPO treatment 5 mg/day, and with EPO treatment 20 mg/day.” They also noted that a “favorable effect of pyridoxine 50 mg/day has also been found on several parameters of cellular immunity in hemodialysis patients.” ⁸⁰ Subsequently, they published the results of a 15-month study investigating the influence of erythropoietin on the biochemical parameters of several nutrients. Among these they demonstrated that “erythrocyte vitamin B ⁶ and folic acid significantly decreased due to erythropoietin treatment.” In response, they found that oral administration of vitamin B ⁶ (20 mg/day) and folic acid (5 mg/week) during the last 3 months positively “influenced the deficiency of erythrocyte vitamin B ⁶ and folic acid.” ⁸¹

In related research, Kasama et al. ⁸² found the “average in vivoPLP clearance for six patients on standard hemodialysis increased by more than 50%... at average blood flows of 375 mL/min” and that levels of “PLP decreased from a baseline of 50±13.8 ng/mL to 24±9.7 ng/mL … after 3 months of HF/HE [high-flux/high-efficiency] treatments; the levels returned to 45±6.4 ng/mL on resumption of standard dialysis treatments.” They concluded that HF/HE dialysis “treatments can have a dramatic impact on vitamin B ⁶ homeostasis.” The authors also noted that the use of different types of dialysis membranes and reprocessing in dialysis significantly affected PLP clearance to varying degrees. ⁸²

In a 1999 review of comprehensive approaches to patients being treated with EPO, Horl ⁸³ summarized the available research regarding pyridoxine and concluded: “Vitamin B ⁶ requirements are increased during epoetin therapy, and supplementation at a dose of 100-150 mg/week is recommended.”

Peripheral polyneuropathy (PPN) is a known adverse effect of nutrient depletion from high-flux hemodialysis. Okada et al. ⁸⁴ found that vitamin B ⁶ coadministration can improve PPN in patients with chronic renal failure on high-flux hemodialysis (HD) and r-HuEPO. Their study included 36 patients undergoing chronic high-flux HD and receiving r-HuEPO, 26 of whom suffered from PPN. After determining initial predialysis serum pyridoxal 5′-phosphate (P5P) levels and ranking PPN symptoms in these patients, they administered vitamin B ⁶ (60 mg/day) prescribed to 14, randomly assigned, and vitamin B ¹² (500 µg/day) to the others. Notably, “predialysis serum P5P levels of HD patients with PPN were not significantly lower than those of matched HD patients without PPN.” However, they demonstrated that “supplementation with vitamin B ⁶ for 4 weeks significantly increased the predialysis level of P5P and dramatically attenuated PPN symptoms compared with initial symptoms.” In contrast, no improvement was observed in response to administration of vitamin B ¹² . Thus, coadministration of B ⁶ was beneficial to HD patients on EPO therapy even though indications of B ⁶ deficiency, as ascertained by serum levels, were absent. ⁸⁴

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians administering EPO therapy, particularly in the context of hemodialysis, are advised to consider coadministration of vitamin B ⁶ , 20 to 50 mg/day orally, as well as folic acid, 1 mg/day orally, to prevent or reverse adverse effects on these nutrients and their physiological functions. The body of available evidence strongly suggests that such nutritional support is often appropriate in the absence of overt signs or standard laboratory indications of deficiency. Vitamin B ⁶ intake at these levels is generally considered safe, although regular monitoring would be judicious in compromised patients, such as those with chronic renal failure. Folic acid is safe at all relevant levels of intake, although care should be taken to rule out concurrent B ¹² deficiency states.

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

SYMBOL Preliminary

Effect and Mechanism of Action

Furosemide acutely increases urinary excretion of oxalic acid and vitamin B ⁶ (as well as vitamin C) in individuals with chronic renal failure. This effect could reverse the tendency in uremic patients toward accumulation of oxalic acid, which can result in elevated plasma levels.

Research

Several preliminary human trials have reported increased excretion of vitamin B ⁶ in individuals administered furosemide and investigated the influence of the nutrient on hyperoxalemia and increased oxalic acid excretion with furosemide.

In a small trial involving eight chronic hemodialysis patients with secondary hyperoxalemia, Balcke et al. ⁸⁵ observed that pyridoxine administration decreased mean plasma oxalic acid concentration from 149.5 to 99.0 μmol/L within 2 weeks and to 93.8 μmol/L after 4 weeks, with a 46% mean reduction. Notably, the “decrease in plasma oxalic acid levels was most pronounced in patients with the highest pretreatment values.” Furthermore, the “two patients who received pyridoxine therapy prior to the beginning of the study had low initial values of plasma oxalic acid concentrations and showed no further decline.” ⁸⁵

Subsequently, Mydlik et al. ^86,87 conducted a series of investigations of the effect of furosemide on urinary excretion of oxalic acid, vitamin C, and vitamin B ⁶ in patients with chronic renal failure (CRF). In one controlled clinical trial (1998), they observed an increased urinary excretion of oxalic acid, vitamin C, and vitamin B ⁶ during the first 3 hours after a single intravenous (IV) dose of 20 mg furosemide in a control group and in CRF patients without dialyzation treatment. They noted that this effect persisted for 6 hours in CRF patients without dialysis. “The authors described a new hitherto unknown positive side-effect of furosemide, i.e. enhanced urinary oxalic acid excretion in the control group and in patients with chronic renal failure without dialyzation treatment and a negative side-effect of furosemide, i.e. increased urinary vitamin B6 excretion in both examined groups.” In conclusion, based on these findings, they recommended monitoring of vitamin C and of “vitamin B ⁶ in plasma during long-term administration of large doses of furosemide to patients with chronic renal failure as deficiency of these vitamins could develop.” ⁸⁶ A year later these researchers published results of another trial in which they compared urinary excretion of vitamin B ⁶ , oxalic acid, and vitamin C in three groups: 15 healthy subjects during maximal water diuresis, 12 patients in polyuric stage of CRF without dialysis treatment receiving a diet high in sodium chloride (15 g/day), and 15 patients in polyuric stage of CRF without dialysis treatment after IV administration of 20 mg furosemide. “Urinary excretion of vitamin B ⁶ , oxalic acid and vitamin C significantly increased during maximal water diuresis while during high intake of sodium chloride the urinary excretions of these substances were not affected.” The authors interpreted these results to suggest that “urinary excretion of vitamin B ⁶ , oxalic acid and vitamin C depends on the urinary excretion of water” and to confirm their earlier findings that IV furosemide (20 mg) increases urinary excretion of vitamin B ⁶ , as well as oxalic acid and vitamin C, in patients with CRF. ⁸⁷

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing furosemide or related loop diuretics are advised to monitor levels of vitamin B ⁶ and other nutrients and to supplement as indicated, particularly in patients with CRF and on dialysis. Because furosemide also depletes thiamine (vitamin B ¹ ), it is probably best to supplement a B-complex preparation with adequate amounts of B ¹ and B ⁶ . Close supervision is warranted with these patients, especially after introducing a new medication or nutrient or changing the dose or combination of any agents.

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

SYMBOL Preliminary

Effect and Mechanism of Action

Pyridoxal 5′-phosphate (PLP), the active form of vitamin B ⁶ , readily forms complexes with gentamicin, as well as a wide variety of other potentially toxic substances. This pharmacodynamic interaction interferes with vitamin B ⁶ metabolism, specifically resulting in a reduction of renal PLP, and has been associated with B ⁶ depletion. Concomitant vitamin B ⁶ appears to prevent adverse effects associated with gentamicin, particularly nephrotoxicity, without reducing the drug's efficacy.

Research

A number of animal studies, many conducted by Enriquez, Keniston, Weir, and associates, have documented the adverse effects of gentamicin on vitamin B ⁶ metabolism and plasma concentrations and the potential benefit of B ⁶ coadministration. Using a rat model, Keniston et al. ⁸⁸ found that “PLP protected against GM-induced neuromuscular paralysis and death.” Kacew ⁸⁹ observed that coadministration of PLP for 4 days lowered gentamicin levels in the kidneys and restored renal concentration of PLP to normal levels, but 14 days of PLP administration was required to inhibit gentamicin-induced nephrotoxicity in the rat. Similarly, Weir et al. ⁹⁰ reported gentamicin administration in rabbits led to a 47% drop in plasma PLP levels. Their findings also suggested that “gentamicin interferes with vitamin B ⁶ metabolism, but that vitamin B ⁶ status does not affect levels of gentamicin.” Subsequently, these researchers demonstrated that vitamin B ⁶ can protect against the nephrotoxicity of gentamicin in rabbits, particularly acute tubular necrosis. They did note, however, the possibility of interstitial nephritis with intramuscular injection of high doses of vitamin B ⁶ based on the reaction of one rabbit. ⁹¹ In other research using a rat model, Smetana et al. ⁹² determined that a “specific concentration of pyridoxal-5-phosphate may be necessary to provide protection against all manifestations of aminoglycoside-induced renal damage.” Ali and Bashir ⁹³ found that although PLP, at the doses used, “reduced significantly the severity of some of the manifestations of nephrotoxicity,... [it] was ineffective in completely preventing the development of nephrotoxicity.”

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing gentamicin or other aminoglycoside antibiotics are advised to consider the potential benefit of coadministering vitamin B ⁶ to mitigate adverse effects, particularly aminoglycoside-induced nephrotoxicity. The available evidence is consistent in its findings but limited by the exclusive presence of animal studies. The research reviewed suggests that such concomitant intake is unlikely to impair the therapeutic efficacy of the medication. Clinical trials are warranted to investigate patterns of adverse effects and interactions and to determine guidelines for a safe and effective clinical response.

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

SYMBOL AMPERSANDthinsp; SYMBOL AMPERSANDthinsp; SYMBOL Consensus

Effect and Mechanism of Action

Tardive dyskinesia and parkinsonian symptoms, especially dystonia, are adverse effects typically associated with haloperidol and other psychotropic medications. Neuroleptic agents are known to induce oxidative stress, and lipid peroxidation appears to play a central role in the development of tardive dyskinesia. ⁹⁴

Vitamin B ⁶ plays a key role in the synthesis of serotonin, dopamine, norepinephrine, and gamma-aminobutyric acid (GABA) and other neurotransmitters, all of which have been proposed to be involved in the development of tardive dyskinesia. Concomitant administration of vitamin B ⁶ can prevent or reduce drug-induced tardive dyskinesia and related extrapyramidal symptoms but may not enhance therapeutic outcomes in the management of psychotic symptoms in schizophrenic and schizoaffective patients. ⁹⁵

Research

Miodownik, Lerner, Kotler, and colleagues have conducted a series of small trials investigating the use of vitamin B ⁶ in the treatment of neuroleptic-induced tardive dyskinesia (TD). They have consistently found that coadministration or addition of vitamin B ⁶ (100-500 mg/day) produced “clinically significant (greater than 30%) improvement on measures of involuntary movement” using the Abnormal Involuntary Movement Scale (AIMS), Barnes Akathisia Rating Scale (BARS), the Simpson-Angus Scale (SAS), and the Extrapyramidal Symptom Rating Scale (ESRS). In some cases, they also measured “clinically significant improvement” on the Brief Psychiatric Rating Scale (BPRS). ^95,96 Subsequently, they reported “significant improvement in tardive dyskinesia and parkinsonian symptoms” in a double-blind crossover trial lasting 9 weeks involving 15 patients, suffering from schizophrenia and schizoaffective disorder with positive psychotic symptoms and TD, who received up to 400 mg vitamin B ⁶ daily. However, their findings in this study “did not show any therapeutic effect on psychotic symptoms from vitamin B ⁶ added to antipsychotic agents,” which patients received on a constant basis. ⁹⁷ None of the patients in these trials experienced adverse effects attributable to vitamin B ⁶ . The emerging pattern in these studies strongly suggested that continued research is warranted to clarify the relationship between vitamin B ⁶ and TD.

These investigators examined whether basal levels of vitamin B ⁶ might serve as a predictive marker to distinguish which patients might be more vulnerable to such adverse reactions. In one paper they reported that, “although patients in the TD group were exposed to neuroleptic drugs for significantly longer periods of time, there were no differences” in serum PLP levels between the treated group and controls. Based on these findings, they concluded that “reports of the effectiveness of vitamin B ⁶ supplementation in the treatment of TD could therefore be explained by the assumption that central nervous system or intracellular vitamin B ⁶ levels, which are involved in the pathogenesis of TD, are not the same as vitamin B ⁶ peripheral serum levels.” ⁹⁸ Likewise, in a subsequent paper, these researchers noted that there was “no direct correlation between pathological symptoms and the serum baseline level of vitamin B ⁶ nor its level during the treatment.” ⁹⁷ Thus, the available evidence has yet to reach a level of clarity to confirm that these medications consistently deplete functional levels of vitamin B ⁶ or to clarify the mechanisms involved in the adverse effects or their mitigation.

In a review of research on the treatment of TD and tardive dystonia, Simpson ⁹⁹ wrote: “Tardive dyskinesia not only may be painful and disfiguring, but it also predicts poor outcome in patients with schizophrenia …. The best treatment for tardive dyskinesia and dystonia is prevention, which is a function of medication choice.”

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing neuroleptic drugs known to cause TD and related adverse extrapyramidal effects are advised to coadminister vitamin B ⁶ to prevent or reduce the occurrence and severity of such reactions. The pyridoxine levels, 200 to 400 mg daily, indicated in such situations are potentially capable of causing adverse neurological effects (primarily peripheral neuropathy) and require close supervision and regular monitoring.

	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management
	Drug-Induced Adverse Effect on Nutrient Function, Coadministration Therapeutic, with Professional Management
	Bimodal or Variable Interaction, with Professional Management
	Impaired Drug Absorption and Bioavailability, Precautions Appropriate

SYMBOL Preliminary

Effect and Mechanism of Action

Hydralazine and vitamin B ⁶ can bind to form a complex that is excreted in the urine, potentially decreasing available levels of hydralazine, depleting pyridoxine, and impairing B ⁶ -related functions. ¹⁰⁰ Thus, hydralazine acts as pyridoxine antagonist, inhibits a number of enzymes requiring pyridoxal as a cofactor, and may increase vitamin B ⁶ requirements and/or cause anemia, peripheral neuritis, or other B ⁶ -deficiency neuropathies. ¹⁰¹ Conversely, such pharmacokinetic interaction with vitamin B ⁶ may decrease the therapeutic effectiveness of hydralazine. ¹⁰²

Reports and Research

Pyridoxine-deficiency neuropathy and other B ⁶ -related adverse effects due to hydralazine have been well known for decades, beginning with a case report published in 1965 by Raskin and Fishman. ¹⁰¹ Rumsby and Shepherd ¹⁰⁰ elaborated on the effect of hydralazine (as well as penicillamine and phenelzine) on the function of PLP. Subsequently, Vidrio ¹⁰² investigated the potential role of hydralazine's interaction with pyridoxal as the basis for its hypotensive effect. He noted that the “drug interacts with pyridoxal and can produce B ⁶ deficiency; it also inhibits a number of enzymes requiring pyridoxal as a cofactor, but there is no apparent relation between its enzymatic and blood pressure effects.” Using a rat model, he found that “responses to hydralazine were diminished by pyridoxine and [that the] inhibitory effect of pyridoxine was absent when rats were pretreated with the calcium antagonists verapamil or cinnarizine. Hydralazine hypotension in anesthetized rats was also reduced by pyridoxal pretreatment.” The author concluded that these findings “suggest that at least part of hydralazine-induced hypotension may be related to interaction with pyridoxal, possibly through interference with an effect of the vitamer on calcium and/or sodium transport into vascular smooth muscle,” a “vitamer” being one or more related chemical substances that fulfill the same specific vitamin function. ¹⁰²

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing hydralazine, alone or as a combination drug, are advised to consider potential benefits of vitamin B ⁶ coadministration. Such concomitant pyridoxine therapy may prevent or reverse adverse effects due to the known actions of the medication. Furthermore, an integrative approach combining these agents may be potentially valuable strategically (preventing hyperhomocysteinemia and potentially reducing the risk of vascular disease, stroke, and dementia). Nevertheless, evidence from well-designed and adequately powered human trials is lacking to confirm need for and benefit of vitamin B ⁶ coadministration or increased pyridoxine intake. Further research is warranted, although it may be a low priority because of the substantially decreased clinical usage of this agent over the past few decades.

In cases where pyridoxine is indicated, certain precautions are recommended. A daily dose of 50 to 100 mg vitamin B ⁶ would be typical in such usage. At such levels the probability of adverse effects from the nutrient are low, but extended use could theoretically cause toxicity symptoms in some individuals. Attention to the potential for adverse effects is judicious within the usual schedule of supervision and monitoring for individuals being treated for hypertension. Caution patients to separate intake of hydralazine and vitamin B ⁶ by at least 2 hours to minimize the risk of any diminished bioavailability of either agent due to complex formation.

	Drug-Induced Adverse Effect on Nutrient Function, Coadministration Therapeutic, with Professional Management
	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management
	Prevention or Reduction of Drug Adverse Effect
	Bimodal or Variable Interaction, with Professional Management
	Potential or Theoretical Adverse Interaction of Uncertain Severity

SYMBOL AMPERSANDthinsp; SYMBOL Emerging

Effect and Mechanism of Action

A number of antitubercular drugs exert significant adverse effects on normal metabolism and function of vitamin B ⁶ , as well as folate and niacin/niacinamide. These medications are occasionally used as single agents but are more often administered in multidrug regimens for the treatment of tuberculosis (TB), especially in patients co-infected with HIV.

Isoniazid is a hydrazine derivative and pyridoxine antagonist that reacts with PLP to form a metabolically inactive hydrazone, inactivating PLP, and thereby producing a functional vitamin B ⁶ deficiency. Thus, isoniazid can interfere with the normal activity of pyridoxine through competitive inhibition, usually in a dose-dependent manner. ¹⁰³ These effects may lead to anemia or peripheral neuropathies. ^104-108 Further, the ingestion of toxic amounts of isoniazid, as little as 1.5 g in adults, can cause increasingly severe adverse effects, with refractory seizures, profound metabolic acidosis, coma, and occasionally death at doses larger than 30 mg/kg. ¹⁰⁹ Intravenous pyridoxine is considered the specific antidote for acute isoniazid neurotoxicity and is often used before or along with hemodialysis. ^110,111

Cycloserine acts as a pyridoxine antagonist by forming a metabolically inactive oxime. The resulting impairment of vitamin B ⁶ availability reduces blood levels of pyridoxine and may lead to anemia or peripheral neuropathies. ^112,113 However, seizures, which may accompany cycloserine administration, may result from pyridoxine depletion associated with the underlying tubercular infection rather from a direct pyridoxine antagonism by the drug. ¹¹⁴

Both isoniazid and cycloserine inhibit human erythrocyte pyridoxal kinase using pyridoxal, but not pyridoxamine, as substrate and can react with pyridoxal or PLP to form covalent complexes. Kinetic studies suggest that the observed pyridoxal kinase inhibition resulted from these formed complexes. ¹¹⁵

Ethionamide, an antileprosy drug sometimes used in combination with other agents for treating multidrug-resistant tuberculosis, may also increase vitamin B ⁶ requirements. ¹⁰⁶

Research

The action of isoniazid and related antitubercular drugs as pyridoxine antagonists is generally agreed on, and the efficacy of pyridoxine in countering the toxic effects of isoniazid is well established. ^107,113 Nevertheless, the issue of whether all patients are vulnerable to clinically significant adverse effects with typical clinical practice involving antitubercular drugs has been contentious, and the benefits of routine vitamin B ⁶ coadministration have been the subject of long-standing controversy.

The relationship between the toxic effects of isoniazid and other anti-TB drugs and their interference with vitamin B ⁶ has been developed over many years and is regarded as consensus. ^{107,112,113,116} Several early studies by Polish researchers focused on the effects of isoniazid and ethionamide on pyridoxine metabolism in children and the use of the tryptophan test as an assay for determining pyridoxine levels. ^106,117,118 However, an investigation of the effect of cycloserine on pyridoxine-dependent metabolism in TB by Nair et al. ¹¹⁴ indicated that the pathological processes of TB itself contributed significantly to B ⁶ depletion. Measuring urinary tryptophan metabolites, they observed an “abnormally high level of xanthurenic acid excretion in untreated patients,” which they interpreted to suggest “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.” The authors noted that “throughout the study, no significant changes in 5-hydroxyindoleacetic acid excretion were observed” and suggested that “the convulsions which may sometimes accompany cycloserine administration are not due to a direct pyridoxine antagonism by the drug.” ¹¹⁴

In a 1980 review of the scientific literature on pyridoxine administration during isoniazid therapy, Snider ¹⁰³ reported on the frequency of INH-induced neuropathy in various studies and identified population groups at relatively high risk of developing this often-serious complication. He reported that pyridoxine administration “during isoniazid (INH) therapy is necessary in some patients to prevent the development of peripheral neuropathy” and concluded that the “routine use of pyridoxine supplementation to prevent peripheral neuropathy in high risk populations is recommended.” ¹⁰³ Subsequently, Mbala et al. ¹¹⁹ conducted a prospective, single-blind, placebo-controlled, randomized trial involving 85 children with TB in Zaire. These researchers observed no occurrences of “neurological or neuropsychiatric disorder … in the two groups during the 6 months of the treatment and 3 months after the treatment” and interpreted their findings to “suggest that the vitamin B ⁶ supplementation of isoniazid therapy is unnecessary in childhood TB.” ¹¹⁹ However, in a review article on recognition and management of isoniazid overdose, also published in 1998, Romero and Kuczler ¹⁰⁹ cautioned that “physicians must be aware of its potentially fatal effects.” They concluded: “Given in gram-per-gram amounts of the isoniazid ingested, pyridoxine (vitamin B ⁶ ) 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.” Overall, the consensus within the scientific literature indicates that patient characteristics are more significant than drug toxicity alone in determining the need for nutrient coadministration, but that pyridoxine is effective in the prevention and treatment of isoniazid toxicity. ¹²⁰

The coadministration of isoniazid (INH) and pyridoxine has frequently been used in the treatment of HIV-infected individuals at risk for or diagnosed with TB. Chaisson ¹²¹ and Gordin et al. ¹²² reported the findings of two independent clinical trials that compared combinations of isoniazid with pyridoxine or rifampin and pyrazinamide (PZA) in the treatment of patients with HIV and latent TB infections and prevention of active TB development. INH/pyridoxine given for 6 to 12 months was effective in preventing TB in dually infected adults. However, treatment with rifampin and pyrazinamide, dosed either daily or twice weekly, required only 2 months of treatment to prevent TB effectively in such patients.

In 1957, McCune et al. ¹²³ conducted in vivo animal studies suggesting that administration of high doses of vitamin B ⁶ can interfere with the effect of isoniazid and indicating that the appearance of this isoniazid antagonism might be delayed. Evidence from human trials is lacking to confirm this proposed interaction or to determine its clinical significance and frequency.

Reports

Haden ¹⁰⁵ described a case of pyridoxine-responsive sideroblastic anemia due to antitubercular drugs.

Brent et al. ¹¹¹ reported “three cases of obtundation secondary to isoniazid overdose that was immediately reversed by intravenous pyridoxine.” Status epilepticus seizures were stopped by IV pyridoxine administration in two of these cases; although the patients remained comatose for prolonged periods, the comas were immediately reversed by the administration of additional pyridoxine. In the third case, isoniazid-induced lethargy was treated by IV pyridoxine on presentation, and the patient responded with immediate reversal of lethargy. The authors concluded that pyridoxine is “effective in treating not only isoniazid-induced seizures, but also the mental status changes associated with this overdose” and noted that the “dose required to induce awakening may be higher than that required to control seizures.” ¹¹¹

Chan ¹²⁴ described a case in which administration of 10 mg/day of pyridoxine was ineffective in reversing isoniazid-induced psychosis. This dose is relatively low, and the author suggested that a larger dose, such as 50 mg/day, might have been necessary.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians treating individuals with latent or active TB are advised to consider coadministration of vitamin B ⁶ (as well as folic acid and niacinamde) to prevent or counter potential adverse drug effects, particularly development of nutrient deficiency and peripheral neuropathy, associated with isoniazid and related antitubercular drugs. Assessment of risk for nutrient deficiency at the initiation of treatment and testing of nutrient levels during therapy may be warranted in certain cases.

Although almost certain to occur to some degree, clinically significant adverse effects on vitamin B ⁶ levels and related functions are generally considered improbable in most healthy, well-nourished patients with typical dosage levels, such as isoniazid (INH) 5 mg/kg. However, these medications can pose significant risks in major segments of the populations at greatest risk of exposure to TB, latent TB infection, or active TB: impoverished, malnourished, or homeless persons; IV drug users; HIV-positive individuals; institutionalized elderly persons; and those with severe illness or compromised health. Risks of adverse drug effects are also heightened in patients who are pregnant, have underlying seizure disorders, or are at significant risk for the development of peripheral neuropathy due to comorbid conditions such as malnutrition, diabetes, HIV infection, alcoholism, or uremia.

In cases where pyridoxine is indicated certain precautions are recommended. Although no recommended dosage level has been established, a daily dose of 50 mg vitamin B ⁶ is typical in such cases. At such low levels, the probability of adverse effects from the nutrient are low. Monitoring for potential adverse effects from pyridoxine is nevertheless recommended as judicious because extended use, especially with ‘higher doses,’ could theoretically cause toxicity in some individuals. However, the intercurrent development of peripheral neuropathy while receiving antitubercular treatment could also reflect inadequate pyridoxine status, so there may be a role for laboratory evaluation in such cases.

The general toxicity, and hepatotoxicity in particular, associated with antitubercular medications remains a significant clinical concern in all patients. In particular, isoniazid, pyrazinamide, and rifampin are not recommended for patients with a history of liver toxicity related to any antitubercular medication or underlying liver disease and should be used with caution in patients being treated with other potentially hepatotoxic drugs. Close supervision and regular monitoring are recommended, beginning with complete blood count, platelet levels, and hepatic functioning at the initiation of treatment, then monthly in patients being treated with single-drug therapy (INH or rifampin) and at 2, 4, 6, and 8 weeks for those receiving both rifampin and pyrazinamide for 2 months. Clinical monitoring consists of a detailed review for possible signs and symptoms of drug-induced hepatitis or other adverse effects, including rash, fever, fatigue, nausea, vomiting, jaundice, right upper quadrant abdominal pain, and paresthesias. Refractory seizures and metabolic acidosis are hallmarks of toxicity and demand urgent intervention with parenteral pyridoxine. “Isoniazid should be discontinued in symptomatic patients whose serum aminotransferases are more than three times normal and in asymptomatic patients whose aminotransferases are more than five times normal.” ¹²⁵

	Minimal to Mild Adverse Interaction—Vigilance Necessary
	Drug-Induced Nutrient Depletion, Supplementation Contraindicated, Professional Management Appropriate

SYMBOL Consensus

Effect and Mechanism of Action

Pyridoxal 5′-phosphate (PLP) acts as a cofactor in the conversion of levodopa to dopamine. Levodopa acts as a vitamin B ⁶ antagonist, and increased levels can increase the metabolic requirements for pyridoxine. Concomitant low-dose vitamin B ⁶ can prevent or reverse nutrient depletion and adverse sequelae. Conversely, excessive levels of pyridoxine can accelerate peripheral metabolism of levodopa to dopamine (in the gastrointestinal tract). Because levodopa can cross the blood-brain barrier, but dopamine cannot, this reduces the levodopa normally available to the central nervous system (CNS). ^126-128 Pyridoxine may also alter levodopa metabolism by Schiff-base formation. ¹²⁹ Consequently, high levels of pyridoxine intake can reduce the availability of dopa for conversion to dopamine and impair the therapeutic activity of levodopa administered in the treatment of Parkinson's disease. However, combining a DDI such as carbidopa or benserazide with levodopa reduces excessive metabolism of levodopa and increases amounts available to the CNS. Under such conditions, pyridoxine, even at high concentrations, is usually unlikely to affect peripheral metabolism, diminish serum levels of levodopa, or impair drug activity. ¹³⁰

Reports and Research

Stockley ¹²⁹ characterizes the interaction between pyridoxine and levodopa as “clinically important, well documented and well established.” Beginning in 1969, a series of reports described and studies consistently demonstrated a pattern of predictable interaction between these two agents. Barham Carter ¹³¹ noted that in “the treatment of parkinsonism with levodopa it is often necessary to prescribe drugs to combat the nausea which occasionally occurs,” and thus vitamin B ⁶ had been recommended or self-prescribed based on its potential benefit in alleviating nausea and vomiting. In a much-cited paper, Duvoisin et al. ¹³² delineated the basic pattern of the antagonism of the effects of levodopa by pyridoxine. They reported that high-dose pyridoxine, 750 to 1000 mg daily, produced a noticeable reduction in the effects of levodopa within 24 hours, and that the effects of the medication were completely abolished within 3 to 4 days. Further, the effects of levodopa were reduced or abolished with daily doses of 50 to 100 mg per day. Notably, daily intake of 5 to 10 mg pyridoxine was associated with an increase in the signs and symptoms of parkinsonism in eight of ten patients. Leon et al. ¹³³ observed a 66% reduction in plasma levodopa levels and exacerbation of Parkinson's disease symptoms in three of four patients administered 50 mg pyridoxine daily concomitantly. A number of other reports and trials confirmed these findings, and a consensus was established by the early 1970s. ^126,134-139

Yahr and Duvoisin ¹⁴⁰ determined that a pyridoxine-deficient diet is probably unnecessary to achieve avoidance of B ⁶ -induced impairment of levodopa therapy and might result in pyridoxine deficiency and subsequent adverse effects.

A DDI such as carbidopa or benserazide can neutralize the interactions between pyridoxine and levodopa but may also deplete vitamin B ⁶ . In 1972, Papavasiliou et al. ¹³⁰ demonstrated the lack of adverse effect from pyridoxine when carbidopa was coadministered with levodopa in a paper describing the “potentiation of central effects with a peripheral inhibitor.” In a small study involving six patients on chronic levodopa treatment for Parkinson's disease, Mars ¹⁴¹ reported that mean levodopa plasma levels dropped by from 356 to 109 ng/mL (70%), when 50 mg pyridoxine was coadministered with 250 mg levodopa. In contrast, with levodopa-carbidopa, their mean plasma levels of levodopa increased to 845 ng/mL, almost threefold. Moreover, with 50 mg pyridoxine, mean plasma levels of levodopa rose slightly higher, to 891 ng/mL, although the plasma-integrated area was 22% less than that observed with levodopa-carbidopa. However, in a series of in vitro, animal, and preliminary human studies, Bender et al. ^142-145 suggested that benserazide and carbidopa may cause vitamin B ⁶ depletion by forming hydrazones, inhibiting enzymes in the oxidative pathway of tryptophan metabolism and of nicotinamide nucleotide synthesis, and depleting niacin. Overall, most researchers and reviewers concur that use of a DDI with levodopa functionally eliminates the probability of a clinically significant impairment of levodopa's activity and therapeutic efficacy from vitamin B ⁶ at typical dosage levels. Thus, Stockley's review concludes that “even in the presence of large amounts of pyridoxine, the peripheral metabolism remains unaffected and the serum levels of levodopa are virtually unaffected.” ¹²⁹ Research is lacking to substantiate the suggestion that either carbidopa or benserazide may deplete vitamin B ⁶ levels to a greater degree than levodopa alone.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing levodopa as monotherapy need to caution patients to avoid unplanned consumption of vitamin B ⁶ above typical dietary levels, such as greater than 5 mg per day, particularly in the form of B ⁶ supplements or multivitamins containing pyridoxine. Such contraindications are generally considered moot for individuals administered levodopa combined with a DDI such as carbidopa or benserazide, as is currently the standard of care in Parkinson's disease management.

Concomitant administration of low-dose vitamin B ⁶ , 5 to 10 mg per day, may be appropriate to prevent drug-induced pyridoxine deficiency and attendant adverse effects from levodopa or benserazide and carbidopa. Vitamin B ⁶ may also be indicated in certain patients for prevention of dietary deficiencies, reduction of known health risks, and treatment of comorbid conditions. Close supervision and regular monitoring for decreased effects of levodopa are necessary in individuals for whom vitamin B ⁶ is indicated during levodopa therapy (without a DDI), particularly since the dose required to counter nutrient depletion overlaps with the lowest dose observed to reduce the therapeutic effect of non-DDI protected levodopa. Limited pyridoxine intake may also be prudent in patients being treated with levodopa-carbidopa (Sinemet) or levodopa-benserazide (Madopar) because these agents may deplete B ⁶ , but high doses of pyridoxine might potentially overwhelm the protective effect of the DDI. In general, any vitamin B ⁶ intake should be accompanied by food, a meal, or a light snack at bedtime, and separated from levodopa by at least 2 hours. Patients should be advised that increased parkinsonian symptoms would be the typical warning sign of diminished drug activity.

Drug-Induced Adverse Effect on Nutrient Function, Coadministration Therapeutic, with Professional Management

SYMBOL AMPERSANDthinsp; SYMBOL AMPERSANDthinsp; SYMBOL Consensus

Effect and Mechanism of Action

Because inflammation causes tissue-specific depletion of vitamin B ⁶ , individuals with rheumatoid arthritis (RA) more likely tend be to be vitamin B ⁶ depleted, and abnormal vitamin B ⁶ status is associated with severity of symptoms in patients with RA. ^146-149

Homocysteine (Hcy) can be metabolized by various pathways, requiring various enzymes, such as methylenetetrahydrofolate reductase and cystathionine beta-synthase, involving reactions that require vitamin B ⁶ and folate as cofactors. Specifically, vitamin B ⁶ is involved in the formation of cystathionine from Hcy and is critical to the formation of 5,10-methylenetetrahydrofolate from tetrahydrofolate. Folate and vitamin B ¹² are involved in the remethylation of Hcy to methionine via a B ¹² -dependent reaction. Elevated plasma total homocysteine (tHcy) has been established as an independent risk factor for cerebrovascular disease, coronary atherosclerosis, peripheral vascular disease, and thrombosis, although the preventive and therapeutic benefit of nutritional therapies to lower Hcy remains to be conclusively demonstrated.

Methotrexate interferes with folate and Hcy metabolism. Both methotrexate and decreased vitamin B ⁶ (and folate) status can contribute to increased Hcy levels and attendant risks. Coadministration of vitamin B ⁶ , usually with folic acid or activated folic acid, may lower Hcy levels and reduce related pathogenic processes and risks.

Research

A series of studies by Chiang, Selhub, Roubenoff, and colleagues have focused on the relationship between inflammatory processes, RA, and vitamin B ⁶ status. They reported that plasma pyridoxal 5′-phosphate (PLP) concentration is correlated with functional vitamin B ⁶ indices in patients with RA and marginal vitamin B ⁶ status. ¹⁵⁰ Furthermore, they have documented strong and consistent associations between vitamin B ⁶ status and several indicators of inflammation in patients with RA and observed an inverse correlation between circulating vitamin B ⁶ levels and clinical indicators, including the disability score, length of morning stiffness, degree of pain, and biochemical markers, including erythrocyte sedimentation rate and C-reactive protein levels. ^146,148 Based on these findings, they have suggested that “such strong associations imply that impaired vitamin B ⁶ status in these patients results from inflammation.” ¹⁴⁹ Subsequently, they conducted a cross-sectional, case-controlled, human clinical trial in parallel with experiments in an animal model of inflammation to investigate whether inflammation directly alters vitamin B ⁶ tissue contents and its excretion in vivo. Human subjects with RA had low plasma PLP levels compared with healthy control subjects, but normal erythrocyte PLP and urinary 4-pyridoxic acid excretion. Adjuvant arthritis induced in rats did not affect 4-pyridoxic acid excretion or muscle storage of PLP, but did result in significantly lower PLP levels in circulation and in liver during inflammation. Based on these findings, they concluded that the “low plasma pyridoxal 5′-phosphate levels seen in inflammation are unlikely to be due to insufficient intake or excessive vitamin B ⁶ excretion,” but that instead, “inflammation induced a tissue-specific depletion of vitamin B ⁶ ” as vitamin B ⁶ coenzymes are removed from the circulation to meet the higher demands of certain tissues during inflammation. ¹⁴⁹

Although the issue of methotrexate's adverse effect on the role of vitamin B ⁶ in regulating Hcy is largely agreed on, the clinical significance of Hcy, and its possible elevation by methotrexate, remains contentious. In a 12-month, randomized double-blind trial involving 62 patients with RA and elevated Hcy (≥12 μmol/L), Yxfeldt et al. ¹⁵¹ investigated the effects of administering a combination of vitamins B ⁶ , B ¹² , and folic acid on Hcy levels and analyzed the relationship between Hcy levels and inflammatory variables, and/or methotrexate (MTX) treatment. The Hcy level decreased significantly in the subjects treated with B vitamins compared with those given placebo. Furthermore, in a “multiple regression model there was an association between the alteration in Hcy level over 0-12 months and MTX treatment, as well as the alteration in CRP, adjusted for B-vitamin treatment.” The authors concluded that Hcy levels in patients with RA can be reduced by treatment with B vitamins, and that Hcy levels were related to markers of inflammation and MTX treatment. ¹⁵¹ However, in a pilot study involving 17 juvenile idiopathic arthritis patients and 17 age-matched and gender-matched healthy children, Huemer et al. ¹⁵² found that hyperhomocysteinemia in children with juvenile idiopathic arthritis is not influenced by MTX treatment and folic acid supplementation.

Further research is warranted to determine the degree to which methotrexate adversely influences levels and functions of vitamin B ⁶ , as well as factors influencing interpatient variability, alterations in Hcy status, the influence of B-vitamin supplementation on clinical outcomes, and appropriate nutrient support levels when administration is indicated.

No sources reviewed cited any evidence to suggest that concurrent administration of vitamin B ⁶ , alone or in a multivitamin formulation, might impair the therapeutic efficacy of methotrexate in the treatment of RA or other nononcological applications.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians administering methotrexate for the treatment of rheumatoid arthritis are advised to consider coadministration of vitamin B ⁶ (50-100 mg/day) with folic acid, possibly in an activated form, such as folinic acid or 5- L-methyl folate. Such concurrent nutrient support may be effective in countering adverse effects of methotrexate on the physiological activities of vitamin B ⁶ , particularly in the regulation of Hcy, and thereby may reduce related risks of vascular disease. More broadly, individuals with RA are more likely to be nutritionally compromised and benefit from enhanced intake of all key nutrients. Similarly, evaluation of patients for genetic polymorphisms, such as MTHFR 677 C→T, are potentially at greater risk for adverse effects from medications that impair folate metabolism or deplete folate levels.

	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, Not Requiring Professional Management
	Prevention or Reduction of Drug Adverse Effect

SYMBOL Preliminary (though generally regarded as SYMBOL AMPERSANDthinsp; SYMBOL AMPERSANDthinsp; SYMBOL Consensus )

Effect and Mechanism of Action

Neomycin may impair the activity of vitamin B ⁶ . ¹⁵³ Furthermore, oral neomycin can decrease absorption or increase elimination of folic acid and other nutrients, including beta-carotene, calcium, carbohydrates, fats, iron, magnesium, potassium, sodium, vitamin A, vitamin B ¹² , vitamin D, and vitamin K. ^116,154 The effects on folic acid and vitamin B ¹² , in particular, can adversely effect vitamin B ⁶ activity. These effects increase with time in long-term neomycin therapy and can be most significant in the elderly population. ¹⁵⁵

Research

Faloon et al. ¹⁵⁶ (1966) documented the adverse effects of neomycin on intestinal absorption of nutrients. Hardison and Rosenberg ¹⁵⁷ further elucidated the effect of neomycin on bile salt metabolism and fat digestion in humans. Subsequently, the adverse effects of neomycin on nutrient status were explored extensively in the pioneering work of Daphne A. Roe, MD (1923–1993), of Cornell University, Division of Nutritional Sciences, through publications such as “Drug-Induced Nutritional Deficiencies” (1976). As such, this interaction has largely passed into the “consensus” of the literature documenting adverse drug effects and drug-induced nutrient depletions, without passing through the stages of published case reports, human trials, reviews, etc., which constitute the emerging standard within the scientific literature of drug-nutrient interactions. Further research may be warranted.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing a course of oral neomycin lasting more than a few days are advised to coadminister a multivitamin-mineral supplement containing vitamin B ⁶ . Depletion is improbable with short-term use of oral neomycin associated with surgery or perioperative care. A course of probiotic flora is also appropriate following broad-spectrum antibiotics to restore normal gut ecology.

	Prevention or Reduction of Drug Adverse Effect
	Beneficial or Supportive Interaction, Not Requiring Professional Management

SYMBOL Mixed

Effect and Mechanism of Action

Oral contraceptives (OCs) are associated with many symptoms suggestive of a drug-induced vitamin B ⁶ deficiency and in many ways parallel to postpartum depression or gestational diabetes mellitus. However, these iatrogenic elevations of exogenous estrogen and progestins may contribute to adverse effects such as depression, premenstrual syndrome, and dysglycemia by altering the metabolism and functions of vitamin B ⁶ more than by directly affecting vitamin B ⁶ status or causing B ⁶ deficiency.

Oral contraceptives can interfere in the role that vitamin B ⁶ plays in facilitating the tryptophan conversion to niacinamide pathway. PLP-dependent enzymes are required in the conversion of L-tryptophan to 5-hydroxytryptamine and L-tyrosine to norepinephrine, as well as synthesis of dopamine, norepinephrine, and gamma-aminobutyric acid (GABA). OCs appear to impair 5-hydroxtryptamine (5-HT, serotonin) formation through interference with 5-hydroxytryptophan decarboxylase and thus contribute to depression due to resulting decreased brain levels of serotonin. Tryptophan dioxygenase is a glucocorticoid-induced enzyme. Elevating concentrations of pyridoxal phosphate by administering pyridoxine reduces synthesis and activity of this enzyme and attenuates the response to glucocorticoid hormones. The resulting reduction in the oxidative metabolism of tryptophan increases the amount of tryptophan available for CNS synthesis of serotonin. OCs with higher estrogen dose increase levels of estrogen metabolites that inhibit kynureninase. The resulting increased tissue and blood concentrations of xanthurenic acid tend to complex with insulin to form a relatively inactive complex and thus impair glucose tolerance. ^158,159 Furthermore, abnormal metabolism of tryptophan results not only from induced hepatic tryptophan oxygenase, but also from specific changes in the activity of enzymes beyond kynurenine in the pathway of tryptophan metabolism. ^160-162 Additionally, abnormally elevated excretion of tryptophan metabolites could potentially cause some degree of true vitamin B ⁶ deficiency. ^163-165

Coadministration of vitamin B ⁶ may ameliorate symptoms associated with OCs, especially when exacerbated in women with compromised nutritional status or other susceptibility factors. ^158,166-169 Concomitant pyridoxine support during OC use appears to enable a direct effect of pyridoxal phosphate in inducing tryptophan oxidase and thereby corrects the effects of OCs on tryptophan metabolism, even in the absence of preexisting deficiency. ^{6,164,170-178} Vitamin B ⁶ can also enhance glucose tolerance by activating apokynureninase or kynureninase that has been inactivated by undergoing transamination. ¹⁷⁹ The dosage of estrogen in the OC formulation appears to influence the probability of adverse effects, at least in some women.

In regard to adverse cardiovascular effects of OCs and other exogenous estrogens, it is noteworthy that pyridoxal 5-phosphate is essential for the metabolism of the atherogenic amino acid homocysteine.

Nutritional requirements for riboflavin may also be higher in OC users because this nutrient is needed to oxidize pyridoxine phosphate to pyridoxal phosphate. Conversely, niacin requirements may be reduced due to alterations in tryptophan metabolism.

Research

A large body of scientific literature indicates that OCs can cause a number of adverse effects in some women, but the issue of whether vitamin B ⁶ is necessary and should be routinely coadministered to prevent such outcomes remains contentious and unresolved.

Several studies have documented that vitamin B ⁶ deficiency is relatively common in the U.S. and U.K. population, and numerous papers have reported that reduced levels of vitamin B ⁶ in women using OCs compared with the general population. ^2-4,180-184

The impact of OCs on vitamin B ⁶ itself and its functions and the clinical benefit of concurrent pyridoxine administration have been the subject of debate for decades. Variations in the choice of subjects, characteristics of controls, composition and dosage levels of the OCs tested, measures of B ⁶ status used, adverse effects assessed, and duration of the trials have all contributed to inconsistencies in findings and mixed conclusions.

Over more than a decade the research team of Adams, Rose, Wynn, and colleagues conducted a series of investigations into the relationship between OCs and vitamin B ⁶ . In 1972 they reported that 80% of women taking OCs had abnormal tryptophan metabolism and about 20% demonstrated evidence for absolute deficiency of the nutrient. ¹⁸⁵ Reviewing the scientific literature on the subject in early 1973, they wrote that “the altered excretion of tryptophan metabolites observed in women on o.c. is similar to that found in nutritional vitamin-B ⁶ deficiency, and is corrected by the administration of vitamin B ⁶ . Vitamin B ⁶ requirements may be further increased by the effect of oestrogen conjugates competitively inhibiting pyridoxal phosphate.” ^{158,160,186-188} Then, in a double-blind, crossover trial involving 22 women “whose depression was thought on clinical grounds to be due to o.c. administration,” these researchers observed positive clinical responses on depression with coadministration of B ⁶ (20 mg twice daily), but notably only in that half of subjects with “absolute vitamin-B ⁶ deficiency.” They suggested that other factors needed to be considered for depression in the other half of depressed women and mentioned insufficient substrate due to tryptophan deficiency as a possible factor. ¹⁶¹ Their continued investigation into the effects of excretion of metabolites after oral loading doses of L-kynurenine led them to conclude that OC use “does not generally change the requirement for vitamin B ⁶ but rather produces a specific change in activity of enzymes beyond kynurenine in the pathway of tryptophan metabolism.” ¹⁶² Bennink and Schreurs ¹⁸¹ reported that “vitamin B ⁶ blood concentration was not affected” in 50 women using combined OCs but also observed that “OCs increased XA [xanthurenic acid] excretion after tryptophan administration in 80% of the users.” Amatayakul et al. ¹⁵⁹ reported no significant adverse effects on B ⁶ status but also noted that “urinary xanthurenic acid excretion … [was] significantly increased by OC treatment, although this excessive XA excretion was adequately corrected with 18 mg of daily vitamin B-6 supplementation.” In a 6-month trial, van der Vange et al. ¹⁸⁹ investigated the effect of seven low-dose OC preparations, containing equivalent amounts of ethinyl estradiol but different amounts and types of progestagen, on vitamin B ⁶ status in 55 women. They observed increases in erythrocyte glutamic-oxaloacetic transaminase (EGOT) activity, a pyridoxal phosphate–dependent enzyme, and the calculated total EGOT activity after 6 months’ treatment, but no changes were observed in the degree of in vitro stimulation, considered a more reliable parameter. Plasma PLP levels initially decreased during the first 3 months of treatment, but levels returned to normal after 6 months. Based on these findings, the authors concluded that “the low-dose preparations investigated in this study have no any adverse effects on vitamin B ⁶ status.” ¹⁸⁹ Notably, several studies used women with intrauterine devices (IUDs) as controls; a questionable proposition given the emerging understanding of the impact of inflammation on B ⁶ status.

Massé et al. ¹⁹⁰ investigated the effects of a low-dose triphasic OC preparation (30 µg estrogen) in 14 young female subjects (and nine matched controls). They found that short-term OC use did not demonstrably alter PLP levels in plasma and erythrocytes in the majority of women with adequate dietary intake. Although by employing two methods of assessment, “only one case (7%) of deficiency due to OC was evidenced, ... a disturbance in vitamin B ⁶ metabolism was detected. PL levels in both blood components have increased steadily and did not subside to pretreatment values at the end of the experiment.” They concluded by suggesting that “the single use of the PLP vitamer can be misleading as demonstrated by other investigators” and suggested the need to explore B ⁶ status further by evaluating “the other aldehydic form of vitamin B ⁶ , to fully establish and comprehend hormone-induced adverse effects on this metabolism, particularly those of progesterone/progestin that have not yet been explored.” ¹⁹⁰ In a double blind, placebo-controlled trial, involving women taking low-dose OCs, Villegas-Salas et al. ¹⁹¹ reported no significant benefit in the prevention of adverse effects, such as nausea, vomiting, dizziness, depression, and irritability, from coadministration of up to 150 mg of pyridoxine daily.

In overview, the trend in the scientific literature indicates that OCs, especially in lower dose forms, usually do not directly deplete vitamin B ⁶ in most women, but may increase such risk or may be more likely to contribute to related adverse effects in those with higher B ⁶ requirements or compromised nutritional intake. However, most but not all researchers have found that OCs present a significant risk of altering several normal physiological pathways that involve B ⁶ -dependent enzymes, and that in many cases, coadministration of pyridoxine, even in low doses, can prevent or reverse adverse effects related to hyperestrogenism, such as depression, dysglycemia, and premenstrual syndrome. Evidence is lacking at this time to support routine supplementation because of the inconsistencies in methodology and limited nature of the available research. Further investigation through well-designed and adequately powered long-term clinical trials is warranted to evaluate which patients are at greatest risk for adverse effects and most likely to benefit from nutrient support, as well as clinical parameters for determining dosage levels and concomitant nutrients indicated for optimal intervention.

The issue of whether or not concomitant vitamin B ⁶ supplementation might be beneficial or necessary in women taking OCs remains unresolved, but the discussion of adverse effects from such coadministration has usually not extended beyond the usual medical caution regarding dose-related pyridoxine toxicity. However, in 1973, Adams et al. ¹⁶¹ suggested that women with low daily protein consumption might be at increased risk for adverse effects with pyridoxine supplementation due to an increase in amino acid catabolism as a result of excess pyridoxine relative to protein intake. Throughout the lengthy but limited history of human research on this issue, the absence of incidents of actual adverse effects attributable to excess pyridoxine intake is notable, especially given the loud warnings so often voiced regarding the potential risk of nutrient-induced toxicity.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing OCs are advised to assess the patient's individual physiological characteristics, medical history, and nutritional status to determine the probability of an adverse reaction to the treatment. Based on such evaluation, or in response to a patient's expressed concern, it would then be appropriate to consider whether vitamin B ⁶ coadministration might reduce the risk and severity of potential adverse effects of the exogenous hormones, including effects on pyridoxine levels and function and increased incidence and severity of depression, dysglycemia, premenstrual syndrome, and disorders associated with elevated estrogen levels. Although the typical supplemental dose for pyridoxine in such situations is 10 to 75 mg per day, higher levels in the range of 100 to 400 mg per day may be indicated for short periods in cases where individual preventive and therapeutic requirements may be greater. Adverse effects from pyridoxine are improbable at lower doses, but such higher doses of vitamin B ⁶ may have significant risk of causing adverse effects and require caution, professional supervision, and regular monitoring, even for short periods. In cases where broader nutritional deficits are apparent, the administration of a multivitamin-mineral formulation may be more appropriate than a narrower pyridoxine prescription.

The tryptophan load test may provide a functional assessment of vitamin B ⁶ status and its influence upon tryptophan metabolism. With depression, as with any complex condition, the presence of OCs is unlikely to constitute the sole cause, or even be the decisive factor. Nevertheless, in certain cases, OCs may be inappropriate because of adverse effects.

Experienced practitioners of natural therapies frequently coadminister a range of agents to women who seek care for presumed adverse effects from OCs. Botanical preparations such chasteberry (Vitex agnus castus),dandelion root (Taraxacum officinale),fringetree root and bark (Chionanthus virginicus),dong quai (Angelica sinensis),burdock root (Arctium lappa),and wild yam root (Dioscorea villosa)have an extensive history of traditional usage and are administered clinically to enhance hepatic conjugation of estrogen, facilitate hormonal self-regulatory systems, and mitigate hyperestrogenism. Calcium, magnesium, evening primrose oil, riboflavin, folic acid, ascorbic acid, vitamin B ¹² , and vitamin E may also be beneficial for some women, particularly with preexisting insufficiency or drug-induced deficiency. Individualized assessment and an evolving therapeutic response involving collaboration of health care professionals trained and experienced in the various therapeutic modalities applied are usually essential to successful clinical outcomes.

	Impaired Drug Absorption and Bioavailability, Precautions Appropriate
	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management
	Prevention or Reduction of Drug Adverse Effect

SYMBOL Emerging

Effect and Mechanism of Action

Penicillamine can act as a pyridoxine antagonist by reacting with pyridoxal 5′-phosphate (PLP) to form a metabolically inactive thiazolidine. This pharmacokinetic interaction can increase vitamin B ⁶ excretion, reduce its physiological activity, and over time, increase the risk for a functional pyridoxine deficiency. ^100,192,193 Vitamin B ⁶ may be coadministered to counteract potential adverse effects, such as anemia and peripheral neuritis. ¹⁹⁴

The formation of a metabolically inactive chelate could also potentially interfere with penicillamine to impair its therapeutic action to a clinically significant degree.

Separating the intake of two substances that tend to bind by several hours usually minimizes such interaction in the gastrointestinal tract.

Research

The long-term use of penicillamine may increase pyridoxine requirements. Pyridoxine administration can prevent or reverse pyridoxine deficiency as a result of this interaction.

Vitamin B ⁶ can act as an anticonvulsant. Conversely, seizures have been induced by DL-penicillamine and other vitamin B ⁶ antagonists, such as hydrazine and thiosemicarbazide. Using a mouse model, Abe and Matsuda observed that “the onset of convulsions induced by these convulsants coincides with the fall in GABA [gamma-aminobutyric acid] content and GAD [glutamic acid decarboxylase] activity in the mesencephalon area, and in contrast, the cessation of the convulsions by PN [pyridoxine] supplement coincides with the recovery in both the parameters.” ^195,196

Researchers have noted an interrelationship between zinc and magnesium depletion and pyridoxine inactivation in autoimmune complications and other adverse effects associated with D-penicillamine. ^197,198 In a trial involving 144 rheumatoid arthritis patients treated with penicillamine (125-1000 mg/day), Rumsby and Shepherd ¹⁹⁹ found that 17% developed vitamin B ⁶ deficiency. However, clinical signs of deficiency were absent, using in vitro measurement of percentage stimulation of erythrocyte alanine aminotransferase (ALT) on addition of an excess of PLP to the blood sample. The investigators observed significantly higher unstimulated activity of PLP, a PLP-dependent apoenzyme, in penicillamine-treated subjects than in controls, as expected if ALT were deficient in its PLP coenzyme. Furthermore, they reported less marked in vitro ALT stimulation by PLP at intermediate penicillamine dosage levels, compared to controls. Such a pattern suggests that a pyridoxine deficiency is more likely in the early stages of penicillamine therapy, after which some degree of recovery might occur, and that lasting or recurrent deficiency is more likely in individuals later administered higher doses of the drug. These findings suggest that, barring clinical signs of pyridoxine deficiency, most patients are unlikely to require pyridoxine coadministration, unless they have a history of poor nutritional intake or other compromising factors. ¹⁹⁹ Nevertheless, Rothschild ¹⁹⁴ and other investigators have suggested that coadministration of vitamin B ⁶ , in daily doses as high as 50 mg, may be indicated. Other methods of assessing B ⁶ deficiency might also be sensitive, such as measuring urinary xanthurenic acid excretion following an oral tryptophan load test.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing penicillamine are advised that coadministration of vitamin B ⁶ may be prudent. Substantive evidence is lacking to confirm the need for and benefit of routine B ⁶ coadministration, and further research with well-designed and adequately powered clinical trials may be warranted. Nevertheless, the available evidence is adequately consistent from both pharmacological and clinical perspectives to warrant preventive measures, especially since they carry minimal risk. Monitoring of pyridoxine status may be warranted with chronic penicillamine therapy.

Certain patients are at higher risk for adverse reactions to penicillamine and risk of complications from pyridoxine deficiency. In particular, because of their dietary restrictions, individuals with Wilson's disease and cystinuria being treated with penicillamine would benefit from 25 mg of pyridoxine daily during therapy. Likewise, a daily supplement of pyridoxine is also indicated for patients with rheumatoid arthritis whose nutrition is impaired. In general, individuals taking penicillamine for any reason should supplement with the relatively small dose of 5 to 20 mg of vitamin B ⁶ daily. However, given the potential for binding, oral intake should be separated by at least 2 hours.

	Impaired Drug Absorption and Bioavailability, Precautions Appropriate
	Bimodal or Variable Interaction, with Professional Management
	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management
	Prevention or Reduction of Drug Adverse Effect

SYMBOL Preliminary

Effect and Mechanism of Action

The conversion of tryptophan to serotonin (5-hydroxytryptamine) is catalyzed by a PLP-dependent enzyme. Dopamine, norepinephrine, and gamma-aminobutyric acid (GABA) are other neurotransmitters synthesized using PLP-dependent enzymes. CNS serotonin is metabolized by monoamine oxidase (MAO) to 5-hydroxyindoleacetic acid (5-HIAA). MAO inhibitors elevate serotonin concentrations (along with other monoamine neurotransmitters, e.g., dopamine) by inhibiting such metabolic breakdown of the monoamine neurotransmitters.

Phenelzine can act as a pyridoxine antagonist by reacting with PLP to form a metabolically inactive hydrazone compound and reduce blood levels of vitamin B ⁶ . Isoniazid and hydralazine, agents with chemical structures similar to phenelzine, are known to cause vitamin B ⁶ deficiency. ^107,108,178 Thus, these drugs can decrease pyridoxine status and induce peripheral neuropathy, carpal tunnel syndrome, and other conditions associated with pyridoxine deficiency.

Reports and Research

There have been numerous reports of vitamin B ⁶ deficiency and subsequent adverse effects associated with long-term MAO inhibitor therapy. Despite the well-documented adverse effects of similar substances, there has been no definitive confirmation of the consistent but anecdotal and preliminary evidence involving phenelzine and related agents. Likewise, substantive evidence is lacking to prove benefit from nutrient coadministration. Research through well-designed and adequately powered clinical trials is warranted.

Harrison et al. ²⁰⁰ published a case report of carpal tunnel syndrome associated with tranylcypromine in 1983. That same year, Heller and Friedman ²⁰¹ reported a case of pyridoxine deficiency and peripheral neuropathy associated with long-term phenelzine therapy. In 1984, Demers et al. ²⁰² reported pyridoxine deficiency in two young men treated with phenelzine. “Alleviation of symptoms possibly associated with this deficiency and correction of subnormal serum B ⁶ levels occurred with the administration of pyridoxine.” Several years later, Goodheart et al. ²⁰³ described the cases of two patients in whom clinical and electrophysiological findings confirmed sensorimotor peripheral neuropathy associated with phenelzine therapy. “Symptoms were predominantly sensory, and improvement occurred after withdrawal of phenelzine. Electrophysiologic findings were consistent with an axonal process.”

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing phenelzine or related MAO inhibitors need to be alert to the possibility of this potential adverse interaction and instruct patients to eat a diet providing adequate amounts of vitamin B ⁶ . Preventive coadministration of vitamin B ⁶ supplements may be warranted, especially in patients with compromised nutritional intake or comorbid conditions or medications that might also impair B ⁶ status. Many providers trained and experienced in nutritional therapeutics routinely advise patients treated with these medications to supplement with vitamin B ⁶ , usually at moderate levels, such as 25 to 50 mg per day. Alternately, nutrient support can be initiated if untoward reactions occur during phenelzine treatment suggestive of B ⁶ deficiency. Monitoring of pyridoxine status may be warranted with chronic MAO inhibitor therapy. Although the MAO inhibitors are much less frequently used in the modern era of psychopharmacology, because of their well-known and dangerous interactions with medications such as meperidine, propoxyphene, and dextromethorphan, as well as food components such as tyramine, they remain important agents for certain patients with bipolar or unipolar depression who respond to none of the other classes of agents.

	Beneficial or Supportive Interaction, with Professional Management
	Bimodal or Variable Interaction, with Professional Management
	Impaired Drug Absorption and Bioavailability, Precautions Appropriate
	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management

SYMBOL Emerging

Effect and Mechanism of Action

Oral B vitamin intake, including pyridoxine, may interfere with tetracycline pharmacokinetics, impairing absorption and bioavailability. Such an interaction would also impair bioavailability of the nutrient(s). Tetracyclines can also increase vitamin B ⁶ urinary excretion.

Research

Omray and Varma ²⁰⁴ demonstrated that oral administration of a formulation containing vitamin B complex and vitamin C could impair absorption and reduce bioavailability of tetracycline through pharmacokinetic interference.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing tetracycline or related antibiotic medications can prudently advise patients regularly supplementing with vitamin B ⁶ , alone or within a B-complex vitamin formulation, to take such supplements and the medication at least 4 hours apart. Although depletion of vitamin B ⁶ (from simultaneous intake and binding) may not have clinical significance with short-term use of tetracycline, individuals using the drug longer than 2 weeks may benefit from supplementation. A moderate supplemental dose of pyridoxine is usually in the range of 20 to 25 mg per day, easily obtained through most multivitamin formulas. Sustained use of higher doses of B ⁶ can potentially result in adverse effects and warrants supervision. Significant dietary sources of vitamin B ⁶ include bananas, lentils, potatoes, raisin bran, turkey, and tuna.

Prudence suggests that individuals treated with tetracyclines or other broad-spectrum antibiotics for an extended time be administered a course of probiotic flora for an equivalent duration to restore intestinal microbiota. Short-term use of tetracyclines may not lead to clinically significant alterations in the gastrointestinal ecology.

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

SYMBOL AMPERSANDthinsp; SYMBOL AMPERSANDthinsp; SYMBOL Consensus

Effect and Mechanism of Action

Theophylline is a potent noncompetitive inhibitor of pyridoxal kinase, the enzyme needed to convert vitamin B ⁶ to its active form, pyridoxal 5′-phosphate (PLP) and therefore is a pyridoxine antagonist. ^115,205 Theophylline also, paradoxically, induces pyridoxal kinase synthesis, thus speeding up pyridoxine metabolism, depending on the balance of these two opposing actions, and sometimes may result in depressed circulating PLP concentrations and body stores of pyridoxine, even though circulating pyridoxal levels may remain unchanged. ^90,206-210 The resultant deficit of PLP results in multiple decreased B ⁶ -dependent enzyme activities, including GABA synthesis, and can increase the risk of seizures, hand tremor, and other adverse CNS effects of theophylline. ²⁰⁹ Thus, theophylline may increase intake requirements for vitamin B ⁶ , whereas concomitant pyridoxine or pyridoxal administration may normalize B ⁶ levels and reduce many theophylline-induced adverse effects without impairing the therapeutic activity of theophylline. ^211,212 This beneficial effect may result, at least in part, from the modulating effect of pyridoxine and that of theophylline on catecholamine release. ^213,214 Moreover, pyridoxine levels tend to be low in many asthmatic individuals, and its administration may play an important role in the treatment of asthma.

Research

A large number of animal experiments and human trials consistently demonstrate an adverse effect of theophylline on vitamin B ⁶ levels and functions that can be clinically significant, a high probability of benefit from administration of B ⁶ in some form, and a lack of adverse effects from concurrent intake.

Delport, Ubbink, Bartel, and colleagues at the University of Pretoria researched the interaction between theophylline and vitamin B ⁶ in many studies over several years. ²¹⁵ In a 1988 study they reported that plasma PLP concentrations were significantly lower in a group of 28 asthmatic women, compared to 33 controls, although plasma pyridoxal levels were not different between the two groups. When they administered theophylline to 17 volunteers, they observed “large reductions in plasma pyridoxal-5′-phosphate levels, while plasma pyridoxal levels and urinary 4-pyridoxic acid excretion were unaffected by theophylline therapy.” ²⁰⁵ The following year, in a 4-week placebo-controlled, double-blind trial involving apparently healthy young men, they demonstrated that theophylline greatly reduced serum vitamin B ⁶ levels and erythrocyte PLP levels through noncompetitive inhibition of erythrocyte pyridoxal kinase, and that both plasma PLP levels and the tryptophan load test normalized after 1 week of pyridoxine vitamin B ⁶ (10 mg/day). ²⁰⁶ Subsequently, they “demonstrated a significant correlation…between drug plasma levels and erythrocyte pyridoxal kinase activities” and showed that vitamin B ⁶ coadministration produced “a four-fold increase in circulating pyridoxal 5′-phosphate levels.” ²¹¹

Other researchers have also reported depression of vitamin B ⁶ levels due to theophylline. Using a rabbit model, Weir et al. ⁹⁰ observed that 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.” They described the mechanism of the theophylline-B ⁶ interaction as “obscure” but noted that the “ethylenediamine in some theophylline preparations binds directly to PLP, potentially increasing the less direct theophylline effect.” Furthermore, they cautioned that “pyridoxine supplementation resulted in higher average PLP levels but did not prevent death in animals with profoundly low PLP levels.” ⁹⁰ In a study of 26 asthmatic children, Shimizu et al. ²¹⁶ found a depression of serum PLP levels existed in asthmatic children treated with theophylline compared with those not receiving theophylline; thus a “significant negative correlation between the serum levels of PLP and theophylline was demonstrated in the subjects.” Oral administration of 200 mg of theophylline (Theo-Dur) to five children with asthma significantly depressed serum PLP levels 4 hours after the drug intake, whereas theophylline did not affect serum pyridoxal levels. Subsequently, this team of researchers studied 23 asthmatic children, 7 to 15 years old, including 16 patients who were treated with slow-release theophylline and seven patients not receiving any theophylline preparation. They evaluated steady-state serum theophylline and vitamin A, B ¹ , B ² , B ⁶ , B ¹² , and C levels and demonstrated a “significant negative correlation between theophylline and circulating levels of vitamin B ⁶ ,” with serum vitamin B ⁶ levels lowered by 40% in the children treated with slow-release theophylline for more than a year. ²¹⁷ Likewise, Tanaka et al. ²⁰⁹ investigated the effect of sustained-release theophylline preparations on circulating vitamin B ⁶ concentrations in 26 children with asthma and determined that “serum PL and PLP concentrations in children within theophylline therapeutic ranges (5 to 15 micrograms/mL) were significantly lower than those with theophylline concentrations of less than 5 micrograms/mL.” Martinez de Haas et al. ²¹⁸ studied 141 adults and found that both geriatric and nongeriatric patients with chronic obstructive pulmonary disease being treated with theophylline exhibited markedly higher prevalence of subnormal vitamin B ⁶ status, as measured by PLP in whole blood, than did those not being treated with theophylline. Notably, 70% of the 40 chronic obstructive pulmonary disease (COPD) patients not treated with theophylline and 56% of the 84 geriatric non-COPD patients also had a subnormal vitamin B ⁶ status, suggesting a rather high baseline B ⁶ deficiency rate in the geriatric population.

The adverse effects of theophylline on the nervous system are well documented, with theophylline-induced seizures, in particular, being widely recognized for their significant morbidity and mortality given their recalcitrance to treatment. Glenn et al. ²⁰⁸ investigated the relationship between depressed plasma PLP levels and decreased GABA synthesis with theophylline treatment and the occurrence of seizures in experiments involving mice and rabbits. They observed that pyridoxine administration significantly decreased rates of seizure and death, and that “serum theophylline levels and plasma PLP levels showed significant negative correlation prior to pyridoxine infusion.” They noted that “all six rabbits developed abnormal EEGs during theophylline infusion and all six rabbit EEG patterns returned to baseline during treatment with pyridoxine.” ²⁰⁸ In a randomized, double-blind, placebo-controlled, crossover study, the South African researchers previously discussed administered theophylline to 15 young, healthy adults daily for 4 weeks, at a dosage level adjusted to produce plasma levels of 10 mg/L (10 µg/mL), combined with either placebo or 15 mg pyridoxal hydrochloride. Theophylline-induced tremor was greatly reduced with vitamin B ⁶ administration “after a single dose of theophylline and a similar but nonsignificant trend was observed with repeated doses.” Subjects treated with pyridoxine also reported lessening of faint feeling, trembling, irritability, and other adverse effects on nervous system function associated with theophylline. Nevertheless, a variety of psychomotor and electrophysiological tests and self-report questionnaires failed to confirm any significant response differences within these parameters. ²¹⁹ More recently, Seto et al. ²¹⁰ measured serum pyridoxal (PAL) levels in children with bronchial asthma treated with theophylline to study whether a theophylline-related seizure is caused by a decrease in serum vitamin B ⁶ . They determined that the serum PAL levels of 31 asthmatic children treated with theophylline were significantly lower than those of 21 control subjects. Moreover, three of the four subjects who experienced a seizure, with or without fever, exhibited low PAL levels within 24 hours.

None of the studies reviewed reported an adverse interaction with concurrent intake of pyridoxal and theophylline.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing theophylline or related medications for extended periods are advised to coadminister vitamin B ⁶ , 10 to 25 mg per day, to prevent or reverse adverse effects of the medication. The probability of drug-induced adverse effects is relatively high, especially at higher doses, given for extended periods, and in patients at higher risk for compromised nutritional status (e.g., children, elderly, chronically ill), and the safety profile of vitamin B6 at these conservative dosage levels is quite strong. Supervision and monitoring are appropriate, particularly in unstable patients or those undergoing a change in medication or dosage.

Beneficial or Supportive Interaction, with Professional Management

SYMBOL Preliminary

Effect and Mechanism of Action

The conversion of tryptophan to serotonin (5-hydroxytryptamine) is catalyzed by a PLP-dependent enzyme. Dopamine, norepinephrine, and GABA are other neurotransmitters synthesized using PLP-dependent enzymes.

Research

Vitamin B ⁶ deficiency may be more common in individuals diagnosed with depression than in the general population. In a small study, Russ et al. ²²⁰ found that four of seven patients suffering from depression had subnormal plasma concentrations of PLP, the active form of vitamin B ⁶ . Likewise, Stewart et al. ²²¹ observed that among a group of 101 depressed outpatients, 21% of those assessed had low plasma levels of pyridoxine.

In a small clinical trial involving 14 institutionalized geriatric patients diagnosed as depressed, Bell et al. ²²² reported improved cognitive functioning and depression ratings with coadministration of vitamins B ¹ , B ² , and B ⁶ (10 mg each) at the start of tricyclic antidepressant (TCA) therapy using nortriptyline.

Well-designed and adequately powered clinical trials are warranted to further investigate this possible synergy and determine the parameters of its clinical application.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing nortriptyline or related TCA medications are advised to evaluate the patient's nutritional status, especially B vitamins and vitamin D. Nutrient coadministration may be prudent, pending more conclusive evidence from qualified case reports and substantive clinical trials, given the potential for benefit. A low dose of vitamin B ⁶ (e.g., 10-25 mg/day) may be adequate, especially when used in combination with thiamine and cyanocobalamin (B ¹ and B ¹² ); other nutrients such as vitamin D warrant significantly higher dose levels (e.g., 800-2000 IU/day). No available research suggests significant risk of adverse effects or interference with the therapeutic efficacy of TCA therapy with recommended doses.

Health care providers are advised to educate patients about the therapeutic benefits of a balanced healthy diet, supportive social engagement, regular exercise, and exposure to sunlight and fresh air and strongly encourage such building of these synergistic lifestyle practices.

Amphetamine aspartate monohydrate, amphetamine sulfate, dextroamphetamine saccharate, dextroamphetamine sulfate; D-amphetamine, Dexedrine.

Methylphenidate (Metadate, Methylin, Ritalin, Ritalin-SR; Concerta).

Combination drug: Mixed amphetamines: Amphetamine and dextroamphetamine (Adderall; dexamphetamine).

Compulsive behavior and anxiety develop in some patients treated with amphetamines, even after the medication is discontinued. Frye and Arnold ²²³ described the case of an 8-year-old boy in whom anxiety and persistent dextroamphetamine-induced compulsive rituals declined significantly within 3 weeks after initiation of pyridoxine (200 mg) daily for 1 week, followed by by a reduced dose of 100 mg daily. The positive response manifested after a few months of concomitant treatment, with elimination of the drug-induced adverse effects.

Bhagavan and Brin ¹⁹³ studied serotonin and pyridoxal phosphate (PLP) levels in the blood of 11 hyperactive children and 11 controls and noted significantly lower levels of serotonin in the hyperactive patients than in controls. They found no differences in PLP content of blood between the two groups. However, when four children who had displayed low serotonin levels were administered oral doses of pyridoxine, these investigators observed an appreciable increase in the serotonin content and a very large increase in the PLP content of blood in the hyperactive patients. These preliminary and indirect research findings suggest that pyridoxine intake, especially relative to tryptophan intake, can alter serotonin levels. However, the clinical significance of these data to vitamin B ⁶ supplementation in human patients being treated with mixed amphetamines has yet to be thoroughly and systematically researched.

Clinical trials investigating coadministration of pyridoxine/B vitamins along with stimulant medications prescribed for attention-deficit disorder (ADD) may be warranted.

Beta-1-adrenoreceptor antagonists (beta-1 blocking agents)

Oral forms (systemic)

Evidence: Bisoprolol (Zebeta), metoprolol (Lopressor, Toprol XL).

Extrapolated, based on similar properties: Acebutolol (Sectral), atenolol (Tenormin); combination drugs: atenolol and chlortalidone (Co-Tendione, Tenoretic); atenolol and nifedipine (Beta-Adalat, Tenif), betaxolol (Kerlone); carteolol (Cartrol), esmolol (Brevibloc), labetalol (Normodyne, Trandate); metoprolol combination drug: metoprolol and hydrochlorothiazide (Lopressor HCT); nadolol (Corgard), nebivolol (Nebilet), oxprenolol (Trasicor), penbutolol (Levatol), pindolol (Visken), propranolol (Betachron, Inderal LA, Innopran XL, Inderal); combination drug: propranolol and bendrofluazide (Inderex); sotalol (Betapace, Betapace AF, Sorine), timolol (Blocadren).

Calcium channel blockers

Amlodipine (Norvasc); combination drug: amlodipine and benazepril (Lotrel); bepridil (Bapadin, Vascor), diltiazem (Cardizem, Cardizem CD, Cardizem SR, Cartia XT, Dilacor XR, Diltia XT, Tiamate, Tiazac), felodipine (Plendil); combination drugs: felodipine and enalapril (Lexxel); felodipine and ramipril (Triapin); gallopamil (D600), isradipine (DynaCirc, DynaCirc CR), lercanidipine (Zanidip), nicardipine (Cardene, Cardene I.V., Cardene SR), nifedipine (Adalat, Adalat CC, Nifedical XL, Procardia, Procardia XL); combination drug: nifedipine and atenolol (Beta-Adalat, Tenif); nimodipine (Nimotop), nisoldipine (Sular), nitrendipine (Cardif, Nitrepin), verapamil (Calan, Calan SR, Covera-HS, Isoptin, Isoptin SR, Verelan, Verelan PM); combination drug: verapamil and trandolapril (Tarka).

Evidence of direct pharmacological interactions between vitamin B ⁶ and either calcium channel blockers or beta blockers is lacking, but there is a broader strategic interaction in terms of cardiovascular risk factors and comprehensive therapeutic strategies related to pyridoxine's role in homocysteine (Hcy) metabolism.

The biochemical conversion of homocysteine to cysteine depends on two consecutive, vitamin B ⁶ –dependent reactions. Homocysteine is strongly associated with atherosclerosis, coronary artery disease, thromboembolism, and vascular endothelial cell injury. There is strong evidence that the prothrombotic and endothelial vascular dysfunction produced by Hcy may result from oxidative stress and subsequent endothelial cell damage. Furthermore, inflammation causes tissue-specific depletion of vitamin B ⁶ . The pathogenic effects of Hcy, inflammation, and cholesterol are 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.

Ubbink et al. ²²⁴ performed oral methionine load tests on 22 vitamin B ⁶ –deficient asthma patients treated with theophylline (a B ⁶ antagonist) and 24 age-matched and gender-matched controls with 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 homocysteine (tHcy) and cystathionine concentrations in B ⁶ -deficient subjects compared with controls. However, 6 weeks of vitamin B ⁶ administration (20 mg/day) significantly reduced post–methionine load increases in circulating tHcy concentrations in deficient subjects, but had no significant effect on the increase in tHcy concentrations in controls. These investigators concluded that a vitamin B ⁶ deficiency may contribute to metabolic changes associated with premature vascular disease.

Physicians prescribing beta blockers or calcium channel blockers are advised to consider a comprehensive cardiovascular care strategy incorporating vitamin B ⁶ along with vitamins B ² , B ¹² , omega-3 fatty acids (fish oils), magnesium, and coenzyme Q10. Typical therapeutic dosages of B ⁶ are in the range of 50 to 200 mg per day, with higher dosages warranting monitoring due to potential adverse effects associated with higher dosages for an extended period.

Betamethasone (Celestone), cortisone (Cortone), dexamethasone (Decadron), fludrocortisone (Florinef), hydrocortisone (Cortef), methylprednisolone (Medrol) prednisolone (Delta-Cortef, Orapred, Pediapred, Prelone), prednisone (Deltasone, Liquid Pred, Meticorten, Orasone), triamcinolone (Aristocort).

Similar properties but evidence indicating no or reduced interaction effects: Inhaled or topical corticosteroids.

Many review articles suggest that prednisone and related oral corticosteroid drugs can contribute to depletion of vitamin B ⁶ . However, in a double-blind, placebo-controlled trial, Sur et al. ²⁰⁷ found that concomitant therapy with inhaled steroids and pyridoxine (300 mg/day) produced no significant differences (vs. placebo in place of pyridoxine) in the treatment of 31 patients with steroid-dependent asthma for 9 weeks.

Physicians prescribing oral corticosteroids for longer than 2 weeks are advised to evaluate the potential need to coadminister vitamin B ⁶ to counter the depleting effects of the medication. The limited available evidence suggests that coadministration of vitamin B ⁶ at low dose levels (e.g., 25-50 mg/day) may be sufficient to prevent drug-induced deficiency, and that larger doses may not provide any additional benefit. However, patients also being treated with theophylline may have greater vitamin B ⁶ requirement because that agent acts as a B ⁶ antagonist.

Diclofenac potassium (Cataflam), diclofenac sodium (Voltaren).

Using a rat model, Rocha-Gonzalez et al. ²²⁵ investigated a possible synergistic interaction between oral diclofenac and B vitamins (100:100:1 of vitamin B ¹ , B ⁶ , and B ¹² , respectively) in increasing the analgesic effect of diclofenac and reducing inflammatory pain. “Diclofenac (0.31-316 mg/Kg), B-vitamins (32-178 mg/Kg), or a combination of B-vitamins and diclofenac was administered orally and the antinociceptive effect was determined” in the rat formalin test. During second phase of the test, they found that diclofenac, B vitamins, and “fixed-ratio B-vitamins–diclofenac combinations dose-dependently reduced flinching behavior.” These researchers concluded that their findings “indicate that oral diclofenac and B-vitamins can interact synergistically to reduce inflammatory pain in the formalin test and suggest the use of those combinations to relief this kind of pain in humans.” ²²⁵

Medina-Santillan et al. ²²⁶ reported that B vitamins can increase the analgesic effect of ketorolac in the formalin test in the rat. “Ketorolac (0.32-10 mg/Kg, po), B-vitamins (56-316 mg/Kg), or a combination of B-vitamins (either 100:100:1 or 100:100:5 proportion of vitamin B ¹ , B ⁶ and B ¹² , respectively) and ketorolac was administered orally and the antinociceptive effect was determined.” During second phase of the test, they found that ketorolac, B vitamins, and “fixed-ratio B-vitamins–ketorolac combinations dose-dependently reduced flinching behavior.” These researchers concluded that their findings “indicate that oral ketorolac and B-vitamins can interact synergistically to reduce inflammatory pain in the formalin test and suggest the use of those combinations to relief this kind of pain in humans.” ²²⁶

These preliminary findings suggest that further research appears warranted, particularly given other emerging data elucidating the relationship between inflammation and depletion of vitamin B ⁶ . ^148,149

Erythromycin oral (EES, EryPed, Ery-Tab, PCE Dispertab, Pediazole), troleandomycin (Tao).

Extrapolated, based on similar properties: Azithromycin (Zithromax), clarithromycin (Biaxin), dirithromycin (Dynabac).

Related but evidence against extrapolation: Erythromycin topical (A/T/S, Akne-Mycin, Erygel, Erycette, Eryderm, Erygel).

Oral erythromycin therapy, especially with long-term administration, may interfere with the absorption and activity of vitamin B ⁶ , and other B vitamins, as well as minerals such as calcium and magnesium. Simple preventive action through coadministration of a multivitamin-mineral formulation is prudent when antibiotics are used for more than 2 weeks or repeatedly. Evidence is lacking, and claims of drug impairment are absent, regarding potential pharmacokinetic interference that might occur if these agents were ingested simultaneously; separation of oral intake by at least 2 hours would be judicious, pending substantive research findings.

Broad-spectrum antimicrobial agents tend to damage the ecology of the gastrointestinal tract by eliminating probiotic flora. Synthesis of B vitamins is among the many important functions performed by intestinal microbiota, and their restoration through oral intake of probiotic flora is recommended after use of any significant course of antibiotic medications. Nevertheless, the evidence pertaining to the effects of macrolide antibiotics specifically on vitamin B ⁶ is suggestive but remains preliminary or inconclusive. The burgeoning body of research underway into the critical role of gut microflora in the normal functioning of the digestive tract, immune system, neurotransmitter synthesis, and other central physiological processes portends a significantly greater knowledge and deeper understanding of this fundamental symbiotic relationship.

Bezafibrate (Bezalip), ciprofibrate (Modalim), clofibrate (Atromid-S), gemfibrozil (Apo-Gemfibrozil, Lopid, Novo-Gemfibrozil), fenofibrate (Lofibra, Tricor, Triglide).

See also Folic Acid monograph.

Fenofibrate and other fibrates can greatly increase plasma homocysteine levels. Vitamin B ⁶ , along with folic acid, B ¹² , and riboflavin, plays a key role in Hcy metabolism and increasing nutrient intake can lower plasma Hcy concentration. However, circulating levels of these vitamins are not typically lower with fibrates. Although the benefits of folic acid coadministration have been investigated and confirmed, evidence from human research focusing on the interaction between fibrates and vitamin B ⁶ is lacking. Clinical trials investigating the potential benefits of pyridoxine coadministration during fibrate therapy is warranted. Pending conclusive findings, physicians prescribing fibrates are advised to consider coadministration of vitamins B ⁶ , B ¹² , riboflavin, and folic acid as prudent. In addition to regular exercise and prudent dietary habits, enhanced intake of magnesium, omega-3 fatty acids, L-carnitine, pantethine, and fiber, as well as coenzyme Q10 therapy, may also be beneficial in these cases.

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

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

HRT, estrogen/testosterone combinations:Esterified estrogens and methyltestosterone (Estratest, Estratest HS).

See also Oral Contraceptives.

The potential adverse effects of exogenous estrogen (with or without progestins) on the levels and functions of vitamin B ⁶ remain an area of controversy and discovery. Research into the interactions between OCs and vitamin B ⁶ has demonstrated an adverse effect on B ⁶ -dependent enzymes along the tryptophan-niacin pathway and revealed the breadth, complexity, and nuances of these issues, particularly with regard to hormone formulations and interindividual variability in drug response.

Conjugated estrogens may be associated with compromised vitamin B ⁶ status or deficiency. In a small, preliminary trial, Haspels et al. ²²⁷ observed a “relative pyridoxine deficiency … in all of 12 women using conjugated estrogens unopposed by progestagens.” They attributed this effect to “disturbed tryptophan metabolism, expressed in increased xanthurenic acid (XA) excretion (greater than or equal to 60 μmol/8 h) during 8 h following oral administration of 2 g L-tryptophan.” This finding parallels the results from a number of studies focusing on OCs and potentially extrapolates to such patterns of interaction involving HRT in postmenopausal women. The authors found that this “disturbance is clear after 1 yr of oestrogen treatment,” and that “xanthurenic acid excretion was only slightly increased in 3 women who used progestagens in high dosages at the same time.” Based on these findings, the authors suggested that “biochemical changes induced could easily be corrected by administration of vitamin B ⁶ ” and concluded by noting that their “cyclic treatment regimen now consists of 25 days of oestrogens per month,” after which “a 250 mg tablet per day of vitamin B ⁶ is prescribed.” ²²⁷ Further research through well-designed and adequately powered clinical trials is warranted to confirm this adverse interaction, delineate patterns of susceptibility, and develop clinical guidelines for individualized hormone prescription and nutrient coadministration.

Hydroxychloroquine (Plaquenil).

In 1991, McCarty ²²⁸ reported a case of complete reversal of rheumatoid nodulosis in a woman with a history of seropositive rheumatoid arthritis (RA) of 12 years’ duration (with attacks of palindromic rheumatism for 3 years) after treatment with D-penicillamine, pyridoxine, and hydroxychloroquine. The author noted that “this is the first instance of complete resolution of all nodules in a patient with RA with the nodulosis variant.” The specific role of vitamin B ⁶ in this clinical response remains uncertain, as does its generalizability to other patients with RA or similar autoimmune conditions. Further research through well-designed clinical trials may be appropriate.

Ketorolac (Toradol).

See Diclofenac, Ketorolac, and Related Nonsteroidal Anti-Inflammatory Drugs (NSAIDs).

Nitrofurantoin (Furadantin, Macrobid, Macrodantin).

Lacerna and Chien ²²⁹ described the case of an elderly female patient who developed paresthesias after concomitant intake of nitrofurantoin and vitamin B ⁶ for an extended period. Corroborative evidence of such an interaction is lacking, as is research specifically investigating the mechanisms of action involved and parameters of clinical significance. The concerns previously discussed regarding the potential adverse effect on vitamin B ⁶ status due to the antimicrobial activity against probiotic flora in the gastrointestinal tract can be reasonably extrapolated to nitrofurantoin. However, specific human research is lacking to confirm this interaction or any potential benefit of supplementing probiotic flora, vitamin B ⁶ , or other relevant nutrients during or after nitrofurantoin therapy.

Risperidone (Risperdal).

Dursun et al. ²³⁰ described the case of a 74-year-old woman who developed neuroleptic malignant syndrome while being treated for schizoaffective disorder with risperidone. Administration of “high-dose vitamin E plus vitamin B ⁶ ” effectively alleviated this known adverse drug reaction.

Evidence from further qualified case reports and/or research findings from clinical trials is lacking to confirm whether coadministration of vitamin E and vitamin B ⁶ might help prevent this condition in patients treated with risperidone and, if so, what dose would be appropriate.

Selegiline (deprenyl, L-deprenil, L-deprenyl; Atapryl, Carbex, Eldepryl, Jumex, Movergan, Selpak).

Selegiline is a highly potent and selective, irreversible inhibitor of B-type monoamine oxidase (MAO), a predominantly glial enzyme in the brain.

Several case reports have described individuals exhibiting the characteristic clinical picture of an extrapyramidal movement disorder due to aromatic L-amino acid decarboxylase (AADC) deficiency, which results in in an impaired synthesis of catecholamines and serotonin and manifests as oculogyric crises and vegetative symptoms. Many of these patients have demonstrated significant clinical improvement when treated with a combination of pyridoxine (an AADC cofactor), selegiline, and bromocriptine, especially when treatment is initiated during the first year of life. ²³¹

Citalopram (Celexa), duloxetine (Cymbalta), escitalopram (S-citalopram; Lexapro), fluoxetine (Prozac, Sarafem), fluvoxamine (Faurin, Luvox), paroxetine (Aropax, Deroxat, Paxil, Seroxat), sertraline (Zoloft), venlafaxine (Effexor).

The conversion of tryptophan to serotonin (5-hydroxytryptamine) is catalyzed by a PLP-dependent enzyme. Dopamine, norepinephrine, and GABA are other neurotransmitters synthesized using PLP-dependent enzymes.

Vitamin B ⁶ deficiency may be more common in individuals diagnosed with depression than in the general population. In a small study, Russ et al. ²²⁰ found that four of seven patients suffering from depression had subnormal plasma concentrations of PLP, the active form of vitamin B ⁶ . Likewise, Stewart et al. ²²¹ observed that among a group of 101 depressed outpatients, 21% of those assessed had low plasma levels of pyridoxine.

Several animal and human studies have reported an interaction between pyridoxine intake and tryptophan or histidine affecting brain serotonin and histamine metabolism. Using a rat model and applying different levels of pyridoxine, Lee et al. ²³² observed that “when dietary tryptophan was fed at the requirement level, excess pyridoxine caused essentially no changes in hypothalamic serotonin and 5HIAA … [but that with] elevated tryptophan intake, excess pyridoxine significantly increased serotonin and 5HIAA (+32%, +20%) in the hypothalamus.” They interpreted these findings to “indicate a clear interaction between substrate and coenzyme precursor which influences brain metabolism of histamine and serotonin.” Ten years later (1998), Schaeffer et al. ²³³ fed seven female rats (vs. one 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.” They found that “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.” Bhagavan and Brin ¹⁹³ studied serotonin and pyridoxal phosphate (PLP) levels in the blood of 11 hyperactive children and 11 controls and noted significantly lower levels of serotonin in the hyperactive patients compared with controls. They found no differences in PLP content of blood between the two groups. However, when four children who had displayed low serotonin levels were administered oral doses of pyridoxine, these investigators observed an appreciable increase in the serotonin content and a very large increase in the PLP content of blood in the hyperactive patients. These preliminary and indirect research findings suggest that pyridoxine intake, especially relative to tryptophan intake, can alter serotonin levels. However, the clinical significance of these data to vitamin B ⁶ supplementation in human patients being treated with serotonin reuptake inhibitors has yet to be thoroughly and systematically researched.

Physicians treating individuals diagnosed with depression or other conditions using serotonin reuptake inhibitors are advised to assess vitamin B ⁶ status and consider coadministration of vitamin B ⁶ , or possibly a B-complex formulation. However, close supervision, regular monitoring, and dose titration are warranted given the theoretical potential for excessive serotonin buildup with suppression of reuptake. Patients stabilized on antidepressants should be advised to avoid sudden changes in dose levels of pyridoxine or other B vitamins, including abrupt termination of supplementation. Further research through well-designed and adequately powered clinical trials is recommended to determine the safety and efficacy of such concomitant therapy and, on confirmation, clinical guidelines for synergistic support. Research into the concomitant application of vitamin B ⁶ and an SSRI for the management of premenstrual syndrome also deserves consideration.

Health care providers are advised to educate patients as to the therapeutic benefits of a balanced healthy diet, supportive social engagement, regular exercise, and exposure to sunlight and fresh air and strongly encourage building these synergistic lifestyle practices.

Sodium sulfacetamide (AK-Sulf, Bleph-10, Sodium Sulamyd), sulfamethoxazole (Gantanol), sulfanilamide (AVC), sulfasalazine (Salazosulfapyridine, salicylazosulfapyridine, suphasalazine; Apo-Sulfasalazine, Azulfidine, Azulfidine EN-Tabs, PMS-Sulfasalazine, Salazopyrin, Salazopyrin EN-Tabs, SAS), sulfisoxazole (Gantrisin); combination drug: sulfamethoxazole and trimethoprim (cotrimoxazole, co-trimoxazole, SXT, TMP-SMX, TMP-sulfa; Bactrim, Bactrim DS, Cotrim, Septra, Septra DS, Sulfatrim, Uroplus); triple sulfa (Sultrin Triple Sulfa).

Sulfamethoxazole and other sulfonamides may interfere with the activity of vitamin B ⁶ , as well as that of folic acid and vitamin K. However, the limited data available suggest that the risk of a clinically significance adverse effect on the physiological functions of vitamin B ⁶ evidence is low in most individuals treated with sulfamethoxazole for 2 weeks or less. Furthermore, evidence is lacking to indicate that this interaction might occur with trimethoprim alone, apart from combination with sulfamethoxazole.

Physicians prescribing sulfamethoxazole or trimethoprim-sulfamethoxazole for longer than 2 weeks are advised to consider coadministration of vitamin B ⁶ and other nutrients that may be depleted. Monitoring of nutrient levels may be warranted, especially in individuals with compromised nutritional intake or immune status. Patients may generally benefit from systematic intake of probiotic bacterial flora for several weeks to months after any substantial antibiotic therapy, because 6 months of supplementation with at least 10 billion organisms daily is considered necessary to ensure full restoration of the symbiotic gut flora.

Coenzyme Q10: CoQ10

Coenzyme Q10 and vitamin B ⁶ exhibit a synergistic relationship both physiologically and clinically. “The endogenous biosynthesis of the quinone nucleus of coenzyme Q10 (CoQ10) from tyrosine is dependent on adequate vitamin B ⁶ nutriture.” ²³⁴ Blood levels of both nutrients tend to decline with age and are associated with many pathological conditions more prevalent among the elderly population.

Coenzyme Q10 and vitamin B ⁶ have been widely applied in nutritional therapeutics to support healthy cardiovascular function and for the treatment of cardiovascular disease. However, other researchers have focused on the functions and therapeutics of these nutrients in relation to neurological conditions and immune function, some of which are also associated with elevated homocysteine levels.

Folkers et al. ²³⁵ observed that blood levels of both CoQ10 and immunoglobulin G (IgG) increased when CoQ10 and pyridoxine were administered together, and when CoQ10 was administered alone, to three groups of human subjects. Likewise, the blood levels of T4 lymphocytes and the ratio of T4/T8 lymphocytes increased when CoQ10 and pyridoxine were administered together and separately. The authors concluded that “these increases in IgG and T4-lymphocytes with CoQ10 and vitamin B ⁶ are clinically important for trials on AIDS, other infectious diseases, and on cancer.” Willis et al. ²³⁴ collected blood samples from 29 patients who were not currently taking either CoQ10 or vitamin B ⁶ as nutritional supplements. They found that “means for all parameters were within normal ranges,” but that a “strong positive correlation was found between CoQ10 and the specific activity of EGOT … and between CoQ10 and the percent saturation of EGOT with PLP.” These authors suggested that it would be “prudent to recommend that patients receiving supplemental CoQ10 be concurrently supplemented with vitamin B ⁶ to provide for better endogenous synthesis of CoQ10 along with the exogenous CoQ10.”

In a preliminary study involving 27 patients with Alzheimer's disease, Imagawa ²³⁶ demonstrated considerable effectiveness of mitochondrial activation therapy with CoQ10, iron, and vitamin B ⁶ . Subsequently, in a published letter, Imagawa et al. ²³⁷ reported that progression of genetically confirmed familial Alzheimer's disease had been halted for 18 to 24 months in a subset of these patients, two sisters, treated with a daily combination of CoQ10 (60 mg), vitamin B ⁶ (180 mg), and iron (sodium ferrous citrate, 150 mg). Both patients exhibited improved mental status. The younger sister, 49 years old, who had “had a 1-year history of progressive memory impairment,” showed marked improvement, such that her “mental state improved to almost normal after 6 months of therapy.” The authors concluded that, in contrast to the rapid progression typical in such familial Alzheimer's disease patients, they “consider that treatment prevented the progression of dementia for 1.5-2 years.” ²³⁷

Folic Acid (Folate)

Vitamin B ⁶ and folate work together in a wide range of physiological processes, including the regulation of homocysteine. Their coadministration, often in conjunction with folic acid and riboflavin, can favorably alter methionine and cysteine metabolism and reduce plasma Hcy levels. In a controlled trial involving healthy individuals, Mansoor et al. ²³⁸ found that concomitant administration of folic acid (0.3 mg) and of pyridoxine hydrochloride (120 mg) for 5 weeks produced a greater plasma tHcy response than did either nutrient alone. Furthermore, these authors noted that long-term oral administration of vitamin B ⁶ alone might reduce concentrations of serum folate. Consequently, it would be prudent to “combine low to medium divided doses” of folic acid with vitamin B ⁶ routinely, particularly in individuals with known or significant risk for hyperhomocysteinemia.

Iron

See final paragraph of previous Coenzyme Q10 section for Imagawa's Alzheimer's disease study. ^236,237

Magnesium

Magnesium Magnesium and vitamin B ⁶ exhibit an interdependent relationship both physiologically and clinically. Concomitant vitamin B ⁶ can increase bioavailability of oral magnesium by facilitating active transport across cell membranes and significantly elevate mean plasma and red blood cell (RBC) magnesium levels. ¹⁹⁷ Conversely, magnesium deficiency can impair conversion of pyridoxine hydrochloride to PLP; consequently, PLP may be more effective with patients experiencing magnesium (or zinc) deficiency or liver disease. Pyridoxine, magnesium, and zinc are all required for the action of delta-6 desaturase, the initial step in the conversion of essential fatty acids to prostaglandins and related regulatory compounds. ²³⁹ Concurrent administration of magnesium may prevent insomnia reportedly associated with high-dose intake of vitamin B ⁶ . These two nutrients have been used in combination with zinc and manganese in the treatment of Osgood-Schlatter disease. Likewise, some clinicians have suggested the combination of vitamin B ⁶ and magnesium for treating social, communication, and behavioral responses of children and adults with autism; research findings have been mixed and inconclusive. ²⁴⁰

Vitamin B ² (Riboflavin)

Vitamin B ⁶ and riboflavin work together in a wide range of physiological processes, including the regulation of homocysteine. Their coadministration, often in conjunction with folic acid and vitamin B ¹² , can favorably alter methionine and cysteine metabolism and reduce plasma Hcy levels.

Vitamin B ¹²

Vitamin B ⁶ and B ¹² work together in a wide range of physiological processes, including the regulation of homocysteine. Their coadministration, often in conjunction with folic acid and riboflavin, can favorably alter methionine and cysteine metabolism and reduce plasma Hcy levels.

Zinc

Zinc is involved in the activation of pyridoxine. Pyridoxal kinase, in particular, requires a zinc-ATP complex as a substrate and a zinc-metallothioneine is necessary for the formation of that zinc-ATP complex. ²⁴¹ Pyridoxine, zinc, and magnesium are all required for the action of delta-6 desaturase, the initial step in the conversion of essential fatty acids to prostaglandins and related regulatory compounds. ²³⁹

In a rat model, Evans ²⁴² found that vitamin B ⁶ enhances the absorption of zinc. In contrast, in a study involving 40 lactating women, Moser-Veillon and Reynolds ²⁴³ observed that B ⁶ intake significantly increased plasma total vitamin B ⁶ , plasma pyridoxal phosphate (PLP), and milk total vitamin B ⁶ but exhibited no effect on plasma, erythrocyte, or milk zinc concentrations. However, zinc deficiency can impair conversion of pyridoxine hydrochloride to PLP; consequently, PLP may be more effective with patients experiencing zinc (or magnesium) deficiency or liver disease.

These two nutrients have been used in combination with magnesium and manganese in the treatment of Osgood-Schlatter disease. Likewise, some clinicians have suggested the combination of vitamin B ⁶ and zinc for treating mental illness, but such approaches remain controversial and unsupported by substantive evidence from well-designed and adequately powered clinical trials. ^244,245

Ginger (Zingiber officinale)

According to most, but not all, researchers and clinicians, vitamin B ⁶ and ginger (Zingiber officinale)can safely and effectively relieve the severity of nausea and vomiting in early pregnancy in many cases. ^{76-78,246-249} Their concomitant use is common in clinical practice but has not been the subject of high-quality clinical trials; such research is warranted.