WO2008144916A1 - Method of reducing side effects of isoniazid - Google Patents

Method of reducing side effects of isoniazid Download PDF

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Publication number
WO2008144916A1
WO2008144916A1 PCT/CA2008/001026 CA2008001026W WO2008144916A1 WO 2008144916 A1 WO2008144916 A1 WO 2008144916A1 CA 2008001026 W CA2008001026 W CA 2008001026W WO 2008144916 A1 WO2008144916 A1 WO 2008144916A1
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isoniazid
pyridoxal
phosphate
administration
day
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PCT/CA2008/001026
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French (fr)
Inventor
Albert D. Friesen
Dawson James Reimer
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Medicure International Inc.
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Publication of WO2008144916A1 publication Critical patent/WO2008144916A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4409Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/66Phosphorus compounds
    • A61K31/675Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/02Drugs for disorders of the nervous system for peripheral neuropathies
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00General protective or antinoxious agents

Definitions

  • This invention relates to a method of reducing the side effects of isoniazid. Specifically, the invention relates to administration of pyridoxal 5'-phosphate to reduce or mitigate the side effects of isoniazid.
  • Isoniazid is the most common, first line defense commonly prescribed for the treatment of tuberculosis (TB).
  • Isoniazid is an effective treatment. However, upon the introduction of isoniazid, physicians began to notice peripheral neuropathy among the patients.
  • pyridoxine results in high plasma levels of pyridoxine which can lead to toxic effects such as peripheral neuropathy (Schaumburg et a/, 1983).
  • peripheral neuropathy Scholaburg et a/, 1983.
  • the sensory neuropathy that occurs following administration of large dose levels of oral pyridoxine has been attributed to high circulating concentrations of pyridoxine per se.
  • High concentrations of pyridoxine lead to the inhibition of P5P binding to apoenzymes resulting in decreased levels of plasma P5P (the active form) (Bassler, 1988) and thus greater levels of P5P are achieved by its direct administration.
  • Pyridoxal 5'-phosphate (3-hydroxy-2-methyl-5-[(phosphonooxy)methyl]-4- pyridine-carboxaldehyde, or "P5P"
  • P5P is a naturally occurring metabolite of pyridoxine and is formed in mammalian cells by phosphorylation and oxidation reactions.
  • ATP adenosine triphosphate
  • P5P can be chemically synthesized in a number of ways, for example, by the action of ATP on pyridoxal, by the action of phosphorus oxychloride on pyridoxal in aqueous solution, and by phosphorylation of pyridoxamine with concentrated phosphoric acid followed by oxidation.
  • a method for mitigating the side effects of isoniazid in a patient being treated with isoniazid when employed as a monotherapy or as part of a combination regimen, for example, peripheral neuropathy, comprising administration of pyridoxal 5'-phosphate.
  • the administration is concurrent with the isoniazid treatment.
  • the administration is previous to the isoniazid treatment.
  • the administration is after the isoniazid treatment.
  • the mammal is a human and the administration is an oral administration of between 100 - 4000 mg/day, for example, between 100 - 750 mg/day or about 250 mg/day.
  • kits comprising: (a) a pharmaceutical preparation for oral administration comprising pyridoxal 5'-phosphate; (b) instructions for the administration of said preparation; wherein said instructions specify that the preparation is to be administered, concurrently with, before, or after isoniazid therapy, for the mitigation of the side effects of that therapy.
  • the side effect may be peripheral neuropathy.
  • the instructions further specify that the administration should be in a dosage form of between 100 - 4000 mg/day, for example, between 100 - 750 mg/day or about 250 mg/day.
  • a pharmaceutical composition comprising isoniazid and pyridoxal 5'-phosphate.
  • the side effect is peripheral neuropathy.
  • the medicament comprises between 100-4000 mg of pyridoxal 5'-phosphate, for example, between 100-750 mg of pyridoxal 5'-phosphate, or about 250 mg of pyridoxal 5'-phosphate.
  • the side effect is peripheral neuropathy.
  • the use of pyridoxal 5'-phosphate comprises administration of between 100-4000 mg/day, for example, between 100-750 mg/day or about 250 mg/day, to a patient in need of reduction of the side effect of isoniazid.
  • pyridoxal 5'-phosphate is safe and low in side effects at high concentrations, previously not considered for the mitigation of side effects of isoniazid, including concentrations previously known to be undesirable for pyridoxine.
  • P5P is thus more tolerable than previously thought, and more tolerable than pyridoxine, and has a much higher dosage requirement to result in toxicity.
  • P5P more specifically, high doses of P5P are recognized as an improvement in treatment over pyridoxine.
  • Subjects enrolled in this study were members of the community at large.
  • Subject screening procedures included informed consent, inclusion/exclusion check, demography, medical history, medication history, physical examination, height, weight, body mass index, a concomitant medication check, vital signs measurements (blood pressure, pulse rate, respiratory rate, and oral temperature), a 12-lead electrocardiogram (ECG), a urine drug screen, a urine pregnancy test (female subjects), hematology, biochemistry, urinalysis, and HIV and hepatitis testing. All participating subjects were judged eligible for the study when assessed against the inclusion and exclusion criteria.
  • Subjects were administered a single oral dose of study medication, as a 1 x 250 mg (Cohort 1 ), 3 x 250 mg (Cohort 2; total dose of 750 mg), 4 x 250 mg (Cohort 3; total dose of 1000 mg), or 16 x 250 mg (Cohort 4; total dose of 4000 mg) enteric- coated tablets.
  • the pharmacokinetic parameters to determine bioavailability for this study were: area under the concentration-time curve from time zero to time of last non-zero concentration (AUCo- t ), maximum observed concentration (C max ), time of observed C max (T max ) and elimination half-life (equivalent to t ⁇ / 2 ).
  • P5P produced optimal effects when administered at 250 mg due to a directly proportional relationship between the dose administered and the variability of plasma P5P concentrations achieved in a subject (Table 1 ), most likely due to unknown enzymatic activities.
  • 125 patients suffering from tuberculosis are randomly separated into five random groups of 25 patients: control, pyridoxine (300 mg/day), low dose of P5P (100 mg/day), medium dose of P5P (250 mg/day), and high dose of P5P (750 mg/day). All patients are given isoniazid therapy, at recommended dosages. All P5P and pyridoxine dosages are administered orally for 3 months, and incidences and extent of peripheral neuropathy are recorded. [0039] All patients receiving P5P benefit from decreased peripheral neuropathy as compared to both control patients and patients receiving pyridoxine. Extent of side effects is significantly improved with 100 mg/day of P5P, and again significantly improved with 250 mg/day of P5P. Dosages above 250 mg/day are found to be a significant improvement over 100 mg/day or control patients, but no significant improvement is found through increasing dosage past 250 mg/day.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Neurosurgery (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Toxicology (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

This invention relates to a method of reducing the side effects of isoniazid. Specifically, the invention relates to administration of pyridoxal 5'-phosphate to reduce or mitigate the side effects of isoniazid. Also provided is the use of pyridoxal 5'-phosphate in the preparation of a medicament for the reduction of the side effects of isoniazid, a pharmaceutical composition comprising isoniazid and pyridoxal 5'-phosphate, and kits comprising pyridoxal 5'-phosphate and instructions for use of same to combat the side effects of isoniazid.

Description

METHOD OF REDUCING SIDE EFFECTS OF ISONIAZID CROSS-REFERENCE TO RELATED APPLICATION This application claims priority to and the benefit of Canadian Patent Application No. 2,590,104 filed May 28 2007, which is incorporated herein by reference.
Field of the Invention [0001] This invention relates to a method of reducing the side effects of isoniazid. Specifically, the invention relates to administration of pyridoxal 5'-phosphate to reduce or mitigate the side effects of isoniazid.
Background of Invention [0002] Isoniazid is the most common, first line defense commonly prescribed for the treatment of tuberculosis (TB).
[0003] Isoniazid is an effective treatment. However, upon the introduction of isoniazid, physicians began to notice peripheral neuropathy among the patients.
[0004] Studies have shown that patients who have isoniazid administered have low plasma pyridoxal 5'-phosphate (P5P) levels, as compared to the patient's own base line level (Visser et al., 2004) This is thought to be because isoniazid appears to prevent the phosphorylation of pyridoxine. It has thus been recommended that treatment with isoniazid be accompanied by pyridoxine supplementation, to mitigate the peripheral neuropathy.
[0005] It is also known that in the early stages of TB patients possess plasma P5P levels lower than normal or healthy individuals, reiterating the necessity of pyridoxine supplementation (Visser et al., 2004). [0006] Unfortunately, pyridoxine has been known to produce toxicity at high doses, and limits plasma P5P levels and the U.S. National Academy of Sciences has therefore recommended 100 mg as the Tolerable Upper Intake Level (unlikely to pose risks of adverse health effects in healthy people) for pyridoxine (National Academy of Science, 1998). With respect to safety, the main toxicity associated with vitamin B6 is neurotoxicity. The administration of pyridoxine results in high plasma levels of pyridoxine which can lead to toxic effects such as peripheral neuropathy (Schaumburg et a/, 1983). The sensory neuropathy that occurs following administration of large dose levels of oral pyridoxine has been attributed to high circulating concentrations of pyridoxine per se. High concentrations of pyridoxine lead to the inhibition of P5P binding to apoenzymes resulting in decreased levels of plasma P5P (the active form) (Bassler, 1988) and thus greater levels of P5P are achieved by its direct administration.
[0007] Treatment with P5P is similarly thought to be best done at low dosages, to avoid toxicity. There is currently significant hesitancy in administering high dosages of pyridoxine, due to its toxic nature and adverse side effects. Because of this, there is also hesitancy in administering high dosages of P5P.
[0008] Typically, with most drugs, increasing the dosage of the drug is desirable, rendering the drug more efficacious. This increase in dosage is mitigated by side effects and toxicity, which typically increase with dosage.
[0009] Pyridoxal 5'-phosphate (3-hydroxy-2-methyl-5-[(phosphonooxy)methyl]-4- pyridine-carboxaldehyde, or "P5P") is a naturally occurring metabolite of pyridoxine and is formed in mammalian cells by phosphorylation and oxidation reactions. A recent evaluation demonstrated that P5P inhibits adenosine triphosphate (ATP) induced calcium ion influx into cells. Results suggest that this action is due to an inhibition of purinergic receptors known as P2 purinoceptors. [0010] P5P can be chemically synthesized in a number of ways, for example, by the action of ATP on pyridoxal, by the action of phosphorus oxychloride on pyridoxal in aqueous solution, and by phosphorylation of pyridoxamine with concentrated phosphoric acid followed by oxidation.
[0011] It would be desirable to have a method for reducing the side effects of isoniazid, for example, prevention of peripheral neuropathy, that can be provided to a patient at relatively high concentrations, with a minimum of side effects or toxicity, either concurrently with, or before or after isoniazid therapy.
Summary of the Invention
[0012] In one embodiment of the present invention is provided a method for mitigating the side effects of isoniazid in a patient being treated with isoniazid, when employed as a monotherapy or as part of a combination regimen, for example, peripheral neuropathy, comprising administration of pyridoxal 5'-phosphate.
[0013] In one aspect, the administration is concurrent with the isoniazid treatment.
[0014] In a further aspect, the administration is previous to the isoniazid treatment.
[0015] In a further aspect, the administration is after the isoniazid treatment.
[0016] In one aspect, the mammal is a human and the administration is an oral administration of between 100 - 4000 mg/day, for example, between 100 - 750 mg/day or about 250 mg/day.
[0017] In another embodiment of the present invention is provided a kit comprising: (a) a pharmaceutical preparation for oral administration comprising pyridoxal 5'-phosphate; (b) instructions for the administration of said preparation; wherein said instructions specify that the preparation is to be administered, concurrently with, before, or after isoniazid therapy, for the mitigation of the side effects of that therapy. For example, the side effect may be peripheral neuropathy.
[0018] In one aspect, the instructions further specify that the administration should be in a dosage form of between 100 - 4000 mg/day, for example, between 100 - 750 mg/day or about 250 mg/day.
[0019] In another embodiment of the present invention is provided a pharmaceutical composition comprising isoniazid and pyridoxal 5'-phosphate.
[0020] In another embodiment is provided the use of pyridoxal 5'-phosphate in the preparation of a medicament for the reduction of the side effects of isoniazid.
[0021] In one aspect, the side effect is peripheral neuropathy.
[0022] In a further aspect, the medicament comprises between 100-4000 mg of pyridoxal 5'-phosphate, for example, between 100-750 mg of pyridoxal 5'-phosphate, or about 250 mg of pyridoxal 5'-phosphate.
[0023] In another embodiment of the present invention is provided the use of pyridoxal 5'-phosphate to reduce a side effect of isoniazid.
[0024] In one aspect, the side effect is peripheral neuropathy.
[0025] In another aspect, the use of pyridoxal 5'-phosphate comprises administration of between 100-4000 mg/day, for example, between 100-750 mg/day or about 250 mg/day, to a patient in need of reduction of the side effect of isoniazid.
Detailed Description [0026] The present inventors have surprisingly found that pyridoxal 5'-phosphate is safe and low in side effects at high concentrations, previously not considered for the mitigation of side effects of isoniazid, including concentrations previously known to be undesirable for pyridoxine.
[0027] The present inventors have found that P5P is thus more tolerable than previously thought, and more tolerable than pyridoxine, and has a much higher dosage requirement to result in toxicity. P5P, more specifically, high doses of P5P are recognized as an improvement in treatment over pyridoxine.
Example 1
Safety and Tolerance of Pyridoxal 5'-Phosphate Enteric-Coated Tablet
[0028] A Phase I, single center, single-dose, open-label, sequential ascending dose study to evaluate the safety and tolerance of pyridoxal 5'-phosphate, in an enteric- coated tablet, following a single dose of 250 mg, 750 mg, 1000 mg, and 4000 mg in healthy subjects under fasting conditions was conducted.
[0029] A total of 32 healthy, adult subjects signed the study-specific Informed Consent Form and were confined in the clinical study unit; of these subjects, 24 (6 subjects in each dose level; 3 males and 3 females) were dosed and were enrolled in the study; all of these enrolled subjects completed the study. Subjects were confined to the SFBC Anapharm Clinical Research Facility from at least 12 hours prior to drug administration until after the 24.0-hour post-dose blood draw.
[0030] Subjects enrolled in this study were members of the community at large. Subject screening procedures included informed consent, inclusion/exclusion check, demography, medical history, medication history, physical examination, height, weight, body mass index, a concomitant medication check, vital signs measurements (blood pressure, pulse rate, respiratory rate, and oral temperature), a 12-lead electrocardiogram (ECG), a urine drug screen, a urine pregnancy test (female subjects), hematology, biochemistry, urinalysis, and HIV and hepatitis testing. All participating subjects were judged eligible for the study when assessed against the inclusion and exclusion criteria.
[0031] All cohorts were sequentially dosed in an ascending fashion. Subsequent cohorts were dosed only after the completion of clinical part of the previous cohort and after revision, by the Sponsor and the Qualified Investigator, of the safety data.
[0032] Subjects were administered a single oral dose of study medication, as a 1 x 250 mg (Cohort 1 ), 3 x 250 mg (Cohort 2; total dose of 750 mg), 4 x 250 mg (Cohort 3; total dose of 1000 mg), or 16 x 250 mg (Cohort 4; total dose of 4000 mg) enteric- coated tablets.
[0033] After a supervised overnight fast of at least 10 hours, subjects were administered the medication as a single oral dose of 1 , 3, 4, or 16 enteric-coated tablets containing 250 mg of P5P (total dose of 250mg, 750 mg, 1000 mg, or 4000 mg), with 300 ml_ of water. Subjects were dosed as specified in the protocol, and subsequently fasted for at least 4 hours. Subjects in Cohorts 2 to 4 did not receive their dose until the clinical part of the preceding dose level was completed, the safety data reviewed by the Principal Investigator and the Sponsor, and a decision taken to proceed or not with the next dose level.
[0034] Clinical laboratory tests (hematology, biochemistry, and urinalysis) were performed for each subject at the time of the screening and post-study procedures and prior to dosing.
[0035] The pharmacokinetic parameters to determine bioavailability for this study were: area under the concentration-time curve from time zero to time of last non-zero concentration (AUCo-t), maximum observed concentration (Cmax), time of observed Cmax (Tmax) and elimination half-life (equivalent to tι/2).
[0036] P5P produced optimal effects when administered at 250 mg due to a directly proportional relationship between the dose administered and the variability of plasma P5P concentrations achieved in a subject (Table 1 ), most likely due to unknown enzymatic activities.
Table 1- Summary of baseline-corrected pharmacokinetic parameters for the enteric- coated tablet
Figure imgf000008_0001
[0037] All of the patients proceeded to the highest dosage form, and none of the patients presented any significant side effects or evidence of toxicity. Thus P5P was found to be well tolerated in patients in dosages up to 4000 mg.
Example 2
Prevention of Side Effects of Isoniazid through the administration of P5P
[0038] 125 patients suffering from tuberculosis are randomly separated into five random groups of 25 patients: control, pyridoxine (300 mg/day), low dose of P5P (100 mg/day), medium dose of P5P (250 mg/day), and high dose of P5P (750 mg/day). All patients are given isoniazid therapy, at recommended dosages. All P5P and pyridoxine dosages are administered orally for 3 months, and incidences and extent of peripheral neuropathy are recorded. [0039] All patients receiving P5P benefit from decreased peripheral neuropathy as compared to both control patients and patients receiving pyridoxine. Extent of side effects is significantly improved with 100 mg/day of P5P, and again significantly improved with 250 mg/day of P5P. Dosages above 250 mg/day are found to be a significant improvement over 100 mg/day or control patients, but no significant improvement is found through increasing dosage past 250 mg/day.

Claims

Claims:
1. A method for the mitigation of the side effects of isoniazid in a patient being treated with isoniazid, said method comprising administration of pyridoxal 5'-phosphate.
2. The method of claim 1 wherein the side effect mitigated is peripheral neuropathy.
3. The method of claim 1 wherein the administration of pyridoxal 5'-phosphate is concurrent to the isoniazid treatment.
4. The method of claim 1 wherein the administration of pyridoxal 5'-phosphate is previous to the treatment with isoniazid.
5. The method of claim 1 wherein the administration of pyridoxal 5'-phosphate is after the isoniazid treatment.
6. The method of claim 1 wherein the patient is a human and the administration is an oral administration of between 100 - 4000 mg/day.
7. The method of claim 6 wherein the adminstration is of between 100 - 750 mg/day.
8. The method of claim 6 wherein the administration is of about 250 mg/day.
9. A kit comprising:
(a) a pharmaceutical preparation for oral administration comprising pyridoxal 5'- phosphate;
(b) instructions for the administration of said preparation; wherein said instructions specify that the preparation is to be administered to a patient receiving isoniazid therapy, for the mitigation of the side effects of said therapy.
10. The kit of claim 9 wherein the instructions further specify that the preparation should be administered in a dosage range of between 100 - 4000 mg/day.
11. The kit of claim 10 wherein the instructions further specify that the preparation should be administered in a dosage range of between 100 - 750 mg/day.
12. The kit of claim 10 wherein the instructions further specify that the preparation should be administered in a dosage range of about 250 mg/day.
13. The kit of claim 10 wherein the instructions further specify that the preparation should be administered concurrently with the isoniazid.
14. The kit of claim 10 wherein the instructions further specify that the preparation should be administered before the isoniazid.
15. The kit of claim 10 wherein the instructions further specify that the preparation should be administered after the isoniazid.
16. A pharmaceutical preparation comprising isoniazid and pyridoxal 5'-phosphate.
17. Use of pyridoxal 5'-phosphate in the preparation of a medicament for the reduction of side effects of isoniazid.
18. The use of claim 17 wherein the side effect is peripheral neuropathy.
19. The use of claim 17 wherein the medicament comprises between 100-4000 mg of pyridoxal 5'-phosphate.
20. The use of claim 19 wherein the medicament comprises between 100 - 750 mg of pyridoxal 5'-phosphate.
21. The use of claim 19 wherein the medicament comprises about 250 mg of pyridoxal 5'-phosphate.
22. Use of pyridoxal 5'-phosphate to reduce a side effect of isoniazid.
23. The use of claim 22 wherein the side effect is peripheral neuropathy.
24. The use of claim 22 comprising administration of between 100 - 4000 mg of pyridoxal 5'-phosphate per day.
25. The use of claim 23 comprising administration of between 100 - 750 mg of pyridoxal 5'-phosphate per day.
26. The use of claim 23 comprising administration of about 250 mg of pyridoxal 5'- phosphate per day.
PCT/CA2008/001026 2007-05-28 2008-05-28 Method of reducing side effects of isoniazid WO2008144916A1 (en)

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Non-Patent Citations (11)

* Cited by examiner, † Cited by third party
Title
AM. REV. RESPIR. DIS., vol. 126, no. 4, October 1982 (1982-10-01), pages 714 - 716 *
DATABASE MEDLINE [online] ATKINS: "Maternal plasma concentration of pyridoxal phosphate during pregnancy: adequacy of vitamin B6 supplementation during isoniazid therapy", Database accession no. (7125367) *
DATABASE MEDLINE [online] BONNER ET AL.: "Seizures induced by theophylline and isoniazid in mice", Database accession no. (10349711) *
DATABASE MEDLINE [online] EBADI ET AL.: "Drug-pyridoxal phosphate interactions", Database accession no. (6087425) *
DATABASE MEDLINE [online] SISKIND ET AL.: "Isoniazid-induced neurotoxicity in chronic dialysis patents: report of three cases and a review of the literature", Database accession no. (8321366) *
DATABASE MEDLINE [online] ZBINDEN ET AL.: "Comparative studies on the effect of pyridoxine, pyridoxal-5'-phosphate and pyridoxalisonicotinyl-hydrazone on experimental isoniazid-neuritis in rats", Database accession no. (13262930) *
INT. Z. VITAMINFORSCH. BEIH., vol. 26, no. 1-2, 1955, pages 130 - 137 *
LHEUREUX ET AL.: "Pyridoxine in clinical toxicology: a review", EUR. J. EMERG. MED., vol. 12, no. 2, April 2005 (2005-04-01), pages 78 - 85 *
NEPHRON, vol. 64, no. 2, 1993, pages 303 - 306 *
Q. REV. DRUG METAB. DRUG INTERACT, vol. 4, no. 4, 1982, pages 289 - 331 *
VET. HUM. TOXICOL., vol. 41, no. 3, 1999, pages 175 - 177 *

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