Levomefolic acid - Revision history

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2024-04-05T10:16:14Z

Marked this version for translation

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	\| MeSHName=5-methyltetrahydrofolate		\| MeSHName=5-methyltetrahydrofolate

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	'''Levomefolic acid''' ([[International Nonproprietary Name\|INN]], also known as '''L-5-MTHF''', '''<small>L</small>-methylfolate''' and '''<small>L</small>-5-methyltetrahydrofolate''' and '''(6''S'')-5-methyltetrahydrofolate''', and '''(6''S'')-5-MTHF''') is the primary biologically active form of [[folate]] used at the cellular level for [[DNA]] reproduction, the [[cysteine]] cycle and the regulation of [[homocysteine]]. It is also the form found in circulation and transported across membranes into tissues and across the [[blood–brain barrier]]. In the cell, <small>L</small>-methylfolate is used in the [[methylation]] of homocysteine to form [[methionine]] and [[tetrahydrofolate]] (THF). THF is the immediate acceptor of one carbon unit for the synthesis of [[thymidine]]-DNA, [[purine]]s (RNA and DNA) and methionine. The un-methylated form, [[folic acid]] (vitamin B<sub>9</sub>), is a synthetic form of folate, and must undergo enzymatic reduction by [[dihydrofolate reductase]] (DHFR) to become biologically active.		'''Levomefolic acid''' ([[International Nonproprietary Name\|INN]], also known as '''L-5-MTHF''', '''<small>L</small>-methylfolate''' and '''<small>L</small>-5-methyltetrahydrofolate''' and '''(6''S'')-5-methyltetrahydrofolate''', and '''(6''S'')-5-MTHF''') is the primary biologically active form of [[folate]] used at the cellular level for [[DNA]] reproduction, the [[cysteine]] cycle and the regulation of [[homocysteine]]. It is also the form found in circulation and transported across membranes into tissues and across the [[blood–brain barrier]]. In the cell, <small>L</small>-methylfolate is used in the [[methylation]] of homocysteine to form [[methionine]] and [[tetrahydrofolate]] (THF). THF is the immediate acceptor of one carbon unit for the synthesis of [[thymidine]]-DNA, [[purine]]s (RNA and DNA) and methionine. The un-methylated form, [[folic acid]] (vitamin B<sub>9</sub>), is a synthetic form of folate, and must undergo enzymatic reduction by [[dihydrofolate reductase]] (DHFR) to become biologically active.

			<!--T:4-->
	It is synthesized in the absorptive cells of the small intestine from polyglutamylated dietary folate. It is a methylated derivative of tetrahydrofolate.		It is synthesized in the absorptive cells of the small intestine from polyglutamylated dietary folate. It is a methylated derivative of tetrahydrofolate.

			<!--T:5-->
	Levomefolic acid is generated by [[methylenetetrahydrofolate reductase]] (MTHFR) from [[5,10-methylenetetrahydrofolate]] (MTHF) and used to recycle homocysteine back to methionine by [[methionine synthase]] (MS).		Levomefolic acid is generated by [[methylenetetrahydrofolate reductase]] (MTHFR) from [[5,10-methylenetetrahydrofolate]] (MTHF) and used to recycle homocysteine back to methionine by [[methionine synthase]] (MS).

			<!--T:6-->
	<small>L</small>-Methylfolate is water-soluble and primarily excreted via the kidneys. In a study of 21 subjects with coronary artery disease, peak plasma levels were reached in one to three hours following oral or [[parenteral]] administration. Peak concentrations were found to be more than seven times higher than folic acid (129 [[Nanogram\|ng]]/ml vs. 14.1 ng/ml).		<small>L</small>-Methylfolate is water-soluble and primarily excreted via the kidneys. In a study of 21 subjects with coronary artery disease, peak plasma levels were reached in one to three hours following oral or [[parenteral]] administration. Peak concentrations were found to be more than seven times higher than folic acid (129 [[Nanogram\|ng]]/ml vs. 14.1 ng/ml).

	==Metabolism==		==Metabolism== <!--T:7-->

			<!--T:8-->
	[[File:MTHFR metabolism.svg\|center\|thumb\|650px\|MTHFR metabolism: folate cycle, methionine cycle, trans-sulfuration and [[hyperhomocysteinemia]]. [[5-MTHF]]: 5-methyltetrahydrofolate; 5,10-methyltetrahydrofolate; [[Bcl-2-associated X protein\|BAX]]: Bcl-2-associated X protein; [[BHMT]]: betaine-homocysteine S-methyltransferase; [[cystathionine beta synthase\|CBS]]: cystathionine beta synthase; [[cystathionine gamma-lyase\|CGL]]: cystathionine gamma-lyase; [[dihydrofolate\|DHF]]: dihydrofolate (vitamin B9); [[dimethylglycine\|DMG]]: dimethylglycine; [[dTMP]]: thymidine monophosphate; [[dUMP]]: deoxyuridine monophosphate; [[flavin adenine dinucleotide\|FAD]]<sup>+</sup> flavine adenine dicucleotide; [[10-formyltetrahydrofolate\|FTHF]]: 10-formyltetrahydrofolate; [[methionine synthase\|MS]]: methionine synthase; [[MTHFR]]: methylenetetrahydrofolate reductase; [[S-adenosyl-L-homocysteine\|SAH]]: S-adenosyl-L-homocysteine; [[S-adenosyl-L-methionine\|SAME]]: S-adenosyl-L-methionine; [[tetrahydrofolate\|THF]]: tetrahydrofolate.]]		[[File:MTHFR metabolism.svg\|center\|thumb\|650px\|MTHFR metabolism: folate cycle, methionine cycle, trans-sulfuration and [[hyperhomocysteinemia]]. [[5-MTHF]]: 5-methyltetrahydrofolate; 5,10-methyltetrahydrofolate; [[Bcl-2-associated X protein\|BAX]]: Bcl-2-associated X protein; [[BHMT]]: betaine-homocysteine S-methyltransferase; [[cystathionine beta synthase\|CBS]]: cystathionine beta synthase; [[cystathionine gamma-lyase\|CGL]]: cystathionine gamma-lyase; [[dihydrofolate\|DHF]]: dihydrofolate (vitamin B9); [[dimethylglycine\|DMG]]: dimethylglycine; [[dTMP]]: thymidine monophosphate; [[dUMP]]: deoxyuridine monophosphate; [[flavin adenine dinucleotide\|FAD]]<sup>+</sup> flavine adenine dicucleotide; [[10-formyltetrahydrofolate\|FTHF]]: 10-formyltetrahydrofolate; [[methionine synthase\|MS]]: methionine synthase; [[MTHFR]]: methylenetetrahydrofolate reductase; [[S-adenosyl-L-homocysteine\|SAH]]: S-adenosyl-L-homocysteine; [[S-adenosyl-L-methionine\|SAME]]: S-adenosyl-L-methionine; [[tetrahydrofolate\|THF]]: tetrahydrofolate.]]

	==Medical uses==		==Medical uses== <!--T:9-->

	=== Major depressive disorder ===		=== Major depressive disorder === <!--T:10-->

			<!--T:11-->
	Research suggests that levomefolic acid (<small>L</small>-methylfolate) taken with a [[First line agent\|first-line]] [[antidepressant]] provides a modest [[Adjunctive therapy\|adjunctive]] antidepressant effect for individuals who do not respond or have only a partial therapeutic response to [[Selective serotonin reuptake inhibitor\|SSRI]] or [[Serotonin–norepinephrine reuptake inhibitor\|SNRI]] medication, and might be a more cost-effective adjunctive agent than [[Atypical antipsychotic\|second-generation antipsychotics]].		Research suggests that levomefolic acid (<small>L</small>-methylfolate) taken with a [[First line agent\|first-line]] [[antidepressant]] provides a modest [[Adjunctive therapy\|adjunctive]] antidepressant effect for individuals who do not respond or have only a partial therapeutic response to [[Selective serotonin reuptake inhibitor\|SSRI]] or [[Serotonin–norepinephrine reuptake inhibitor\|SNRI]] medication, and might be a more cost-effective adjunctive agent than [[Atypical antipsychotic\|second-generation antipsychotics]].

	=== Cardiovascular disease and cancer ===		=== Cardiovascular disease and cancer === <!--T:12-->

			<!--T:13-->
	Levomefolic acid (and folic acid in turn) has been proposed for treatment of cardiovascular disease and advanced cancers such as breast and [[colorectal cancer]]s. It bypasses several metabolic steps in the body and better binds [[thymidylate synthase]] with [[FdUMP]], a metabolite of the drug [[fluorouracil]].		Levomefolic acid (and folic acid in turn) has been proposed for treatment of cardiovascular disease and advanced cancers such as breast and [[colorectal cancer]]s. It bypasses several metabolic steps in the body and better binds [[thymidylate synthase]] with [[FdUMP]], a metabolite of the drug [[fluorouracil]].

	==Patent issues==		==Patent issues== <!--T:14-->
	In March 2012, [[Merck KGaA\|Merck & Cie]] of [[Switzerland]], [[Pamlab]] LLC (maker of [[Metanx]] and [[Cerefolin]], Neevo DHA, and Deplin), and South Alabama Medical Science Foundation (SAMSF) (the plaintiffs) filed a complaint in the [[United States District Court for the Eastern District of Texas]] against four defendants: Macoven Pharmaceuticals (owned by Pernix Therapeutics), Gnosis SpA of Italy, Gnosis U.S.A and Gnosis Bioresearch Switzerland. The plaintiffs alleged that the defendants infringed on several of the plaintiffs' patents. The Macoven products named in the suit are: "Vitaciric-B", "ALZ-NAC", "PNV DHA", and l-methylfolate calcium (levomefolate calcium).		In March 2012, [[Merck KGaA\|Merck & Cie]] of [[Switzerland]], [[Pamlab]] LLC (maker of [[Metanx]] and [[Cerefolin]], Neevo DHA, and Deplin), and South Alabama Medical Science Foundation (SAMSF) (the plaintiffs) filed a complaint in the [[United States District Court for the Eastern District of Texas]] against four defendants: Macoven Pharmaceuticals (owned by Pernix Therapeutics), Gnosis SpA of Italy, Gnosis U.S.A and Gnosis Bioresearch Switzerland. The plaintiffs alleged that the defendants infringed on several of the plaintiffs' patents. The Macoven products named in the suit are: "Vitaciric-B", "ALZ-NAC", "PNV DHA", and l-methylfolate calcium (levomefolate calcium).

			<!--T:15-->
	In September 2012, the same three plaintiffs filed a complaint requesting that the [[United States International Trade Commission\|International Trade Commission]] begin a {{uscsub\|19\|1337\|}} investigation of the same four defendants. The complaint states that Gnosis' "Extrafolic-S" and products which are made from it, infringe upon three of their patents: {{patent\|US\|5997915}}, {{patent\|US\|6673381}}, and {{patent\|US\|7172778}}.		In September 2012, the same three plaintiffs filed a complaint requesting that the [[United States International Trade Commission\|International Trade Commission]] begin a {{uscsub\|19\|1337\|}} investigation of the same four defendants. The complaint states that Gnosis' "Extrafolic-S" and products which are made from it, infringe upon three of their patents: {{patent\|US\|5997915}}, {{patent\|US\|6673381}}, and {{patent\|US\|7172778}}.

	==Formulations==		==Formulations== <!--T:16-->
	Levomefolate calcium, a calcium [[salt (chemistry)\|salt]] of levomefolic acid is sold under the brand name Metafolin and incorporated in Deplin. Levomefolate magnesium is a magnesium salt of levomefolic acid, manufactured as DeltaFolate, a primary ingredient in EnLyte.		Levomefolate calcium, a calcium [[salt (chemistry)\|salt]] of levomefolic acid is sold under the brand name Metafolin and incorporated in Deplin. Levomefolate magnesium is a magnesium salt of levomefolic acid, manufactured as DeltaFolate, a primary ingredient in EnLyte.

	== See also ==		== See also == <!--T:17-->
	* [[5,10-Methylenetetrahydrofolate]]		* [[5,10-Methylenetetrahydrofolate]]
	* [[S-Adenosylmethionine]] (SAMe)		* [[S-Adenosylmethionine]] (SAMe)

	== External links ==		== External links == <!--T:18-->
	*[http://www.fao.org/docrep/008/a0044e/a0044e05.htm#bm5.3 Calcium L5-methyltetrahydrofolate (L-5-MTHF-Ca)]		*[http://www.fao.org/docrep/008/a0044e/a0044e05.htm#bm5.3 Calcium L5-methyltetrahydrofolate (L-5-MTHF-Ca)]
	* {{cite journal \| vauthors = Brockton NT \| title = Localized depletion: the key to colorectal cancer risk mediated by MTHFR genotype and folate? \| journal = Cancer Causes & Control \| volume = 17 \| issue = 8 \| pages = 1005–16 \| date = October 2006 \| pmid = 16933051 \| doi = 10.1007/s10552-006-0051-5 \| s2cid = 20394873 }}		* {{cite journal \| vauthors = Brockton NT \| title = Localized depletion: the key to colorectal cancer risk mediated by MTHFR genotype and folate? \| journal = Cancer Causes & Control \| volume = 17 \| issue = 8 \| pages = 1005–16 \| date = October 2006 \| pmid = 16933051 \| doi = 10.1007/s10552-006-0051-5 \| s2cid = 20394873 }}
	* {{cite journal \| vauthors = Stahl SM \| title = Novel therapeutics for depression: L-methylfolate as a trimonoamine modulator and antidepressant-augmenting agent \| journal = CNS Spectrums \| volume = 12 \| issue = 10 \| pages = 739–44 \| date = October 2007 \| pmid = 17934378 \| doi = 10.1017/S1092852900015418 \| s2cid = 27000937 }}		* {{cite journal \| vauthors = Stahl SM \| title = Novel therapeutics for depression: L-methylfolate as a trimonoamine modulator and antidepressant-augmenting agent \| journal = CNS Spectrums \| volume = 12 \| issue = 10 \| pages = 739–44 \| date = October 2007 \| pmid = 17934378 \| doi = 10.1017/S1092852900015418 \| s2cid = 27000937 }}

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	{{Vitamin}}		{{Vitamin}}

			<!--T:20-->
	{{二次利用\|date=27 February 2024}}		{{二次利用\|date=27 February 2024}}
	[[Category:Folates]]		[[Category:Folates]]

Fire: Created page with " {{chembox | ImageFile=5-Methyltetrahydrofolate.png | ImageSize=220px | IUPACName=(2''S'')-2-[ [4-[(2-Amino-5-methyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl) methylamino]benzoyl]amino]pentanedioic acid | OtherNames=(L-5-Me-THFA, L-5-Me-H₄FA),
anion: L-5-methyltetrahydrofolate (L-5-Me-THF, L-5-Me-H₄F), L-methylfolate
Metafolin |Se..."

2024-04-05T10:05:58Z

Created page with "<languages /> <translate> {{chembox | ImageFile=5-Methyltetrahydrofolate.png | ImageSize=220px | IUPACName=(2''S'')-2-[ [4-[(2-Amino-5-methyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl) methylamino]benzoyl]amino]pentanedioic acid | OtherNames=(L-5-Me-THFA, L-5-Me-H4FA), anion: L-5-methyltetrahydrofolate (L-5-Me-THF, L-5-Me-H4F), L-methylfolate Metafolin |Se..."

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<languages />
<translate>
{{chembox
| ImageFile=5-Methyltetrahydrofolate.png
| ImageSize=220px
| IUPACName=(2''S'')-2-[ [4-[(2-Amino-5-methyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl) methylamino]benzoyl]amino]pentanedioic acid
| OtherNames=(L-5-Me-THFA, L-5-Me-H4FA), anion: L-5-methyltetrahydrofolate (L-5-Me-THF, L-5-Me-H4F), L-methylfolate Metafolin
|Section1={{Chembox Identifiers
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 8S95DH25XC
| UNII1_Ref = {{fdacite|correct|FDA}}
| UNII1 = A9R10K3F2F
| UNII1_Comment = (calcium salt)
| ChemSpiderID = 392351
| ChEBI = 136009
| SMILES = CN1c2c([nH]c(nc2=O)N)NC[C@@H]1CNc3ccc(cc3)C(=O)N[C@@H](CCC(=O)O)C(=O)O
| InChI = 1/C20H25N7O6/c1-27-12(9-23-16-15(27)18(31)26-20(21)25-16)8-22-11-4-2-10(3-5-11)17(30)24-13(19(32)33)6-7-14(28)29/h2-5,12-13,22H,6-9H2,1H3,(H,24,30)(H,28,29)(H,32,33)(H4,21,23,25,26,31)/t12-,13-/m0/s1
| InChIKey = ZNOVTXRBGFNYRX-STQMWFEEBP
| StdInChI = 1S/C20H25N7O6/c1-27-12(9-23-16-15(27)18(31)26-20(21)25-16)8-22-11-4-2-10(3-5-11)17(30)24-13(19(32)33)6-7-14(28)29/h2-5,12-13,22H,6-9H2,1H3,(H,24,30)(H,28,29)(H,32,33)(H4,21,23,25,26,31)/t12-,13-/m0/s1
| StdInChIKey = ZNOVTXRBGFNYRX-STQMWFEESA-N
| CASNo= 31690-09-2
| CASNo1 = 151533-22-1
| CASNo1_Comment = (calcium salt)
| PubChem=444412
| PubChem1 = 15341110
| PubChem1_Comment = (calcium salt)
| KEGG = D09353
| MeSHName=5-methyltetrahydrofolate

}}
|Section2={{Chembox Properties
| C=20 | H=25 | N=7 | O=6
| Appearance=
| Density=
| MeltingPt=
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| Solubility=
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| Bioavail =
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'''Levomefolic acid''' ([[International Nonproprietary Name|INN]], also known as '''L-5-MTHF''', '''L-methylfolate''' and '''L-5-methyltetrahydrofolate''' and '''(6''S'')-5-methyltetrahydrofolate''', and '''(6''S'')-5-MTHF''') is the primary biologically active form of [[folate]] used at the cellular level for [[DNA]] reproduction, the [[cysteine]] cycle and the regulation of [[homocysteine]]. It is also the form found in circulation and transported across membranes into tissues and across the [[blood–brain barrier]]. In the cell, L-methylfolate is used in the [[methylation]] of homocysteine to form [[methionine]] and [[tetrahydrofolate]] (THF). THF is the immediate acceptor of one carbon unit for the synthesis of [[thymidine]]-DNA, [[purine]]s (RNA and DNA) and methionine. The un-methylated form, [[folic acid]] (vitamin B9), is a synthetic form of folate, and must undergo enzymatic reduction by [[dihydrofolate reductase]] (DHFR) to become biologically active.

It is synthesized in the absorptive cells of the small intestine from polyglutamylated dietary folate. It is a methylated derivative of tetrahydrofolate.

Levomefolic acid is generated by [[methylenetetrahydrofolate reductase]] (MTHFR) from [[5,10-methylenetetrahydrofolate]] (MTHF) and used to recycle homocysteine back to methionine by [[methionine synthase]] (MS).

L-Methylfolate is water-soluble and primarily excreted via the kidneys. In a study of 21 subjects with coronary artery disease, peak plasma levels were reached in one to three hours following oral or [[parenteral]] administration. Peak concentrations were found to be more than seven times higher than folic acid (129 [[Nanogram|ng]]/ml vs. 14.1 ng/ml).

==Metabolism==

[[File:MTHFR metabolism.svg|center|thumb|650px|MTHFR metabolism: folate cycle, methionine cycle, trans-sulfuration and [[hyperhomocysteinemia]]. [[5-MTHF]]: 5-methyltetrahydrofolate; 5,10-methyltetrahydrofolate; [[Bcl-2-associated X protein|BAX]]: Bcl-2-associated X protein; [[BHMT]]: betaine-homocysteine S-methyltransferase; [[cystathionine beta synthase|CBS]]: cystathionine beta synthase; [[cystathionine gamma-lyase|CGL]]: cystathionine gamma-lyase; [[dihydrofolate|DHF]]: dihydrofolate (vitamin B9); [[dimethylglycine|DMG]]: dimethylglycine; [[dTMP]]: thymidine monophosphate; [[dUMP]]: deoxyuridine monophosphate; [[flavin adenine dinucleotide|FAD]]+ flavine adenine dicucleotide; [[10-formyltetrahydrofolate|FTHF]]: 10-formyltetrahydrofolate; [[methionine synthase|MS]]: methionine synthase; [[MTHFR]]: methylenetetrahydrofolate reductase; [[S-adenosyl-L-homocysteine|SAH]]: S-adenosyl-L-homocysteine; [[S-adenosyl-L-methionine|SAME]]: S-adenosyl-L-methionine; [[tetrahydrofolate|THF]]: tetrahydrofolate.]]

==Medical uses==

=== Major depressive disorder ===

Research suggests that levomefolic acid (L-methylfolate) taken with a [[First line agent|first-line]] [[antidepressant]] provides a modest [[Adjunctive therapy|adjunctive]] antidepressant effect for individuals who do not respond or have only a partial therapeutic response to [[Selective serotonin reuptake inhibitor|SSRI]] or [[Serotonin–norepinephrine reuptake inhibitor|SNRI]] medication, and might be a more cost-effective adjunctive agent than [[Atypical antipsychotic|second-generation antipsychotics]].

=== Cardiovascular disease and cancer ===

Levomefolic acid (and folic acid in turn) has been proposed for treatment of cardiovascular disease and advanced cancers such as breast and [[colorectal cancer]]s. It bypasses several metabolic steps in the body and better binds [[thymidylate synthase]] with [[FdUMP]], a metabolite of the drug [[fluorouracil]].

==Patent issues==
In March 2012, [[Merck KGaA|Merck & Cie]] of [[Switzerland]], [[Pamlab]] LLC (maker of [[Metanx]] and [[Cerefolin]], Neevo DHA, and Deplin), and South Alabama Medical Science Foundation (SAMSF) (the plaintiffs) filed a complaint in the [[United States District Court for the Eastern District of Texas]] against four defendants: Macoven Pharmaceuticals (owned by Pernix Therapeutics), Gnosis SpA of Italy, Gnosis U.S.A and Gnosis Bioresearch Switzerland. The plaintiffs alleged that the defendants infringed on several of the plaintiffs' patents. The Macoven products named in the suit are: "Vitaciric-B", "ALZ-NAC", "PNV DHA", and l-methylfolate calcium (levomefolate calcium).

In September 2012, the same three plaintiffs filed a complaint requesting that the [[United States International Trade Commission|International Trade Commission]] begin a {{uscsub|19|1337|}} investigation of the same four defendants. The complaint states that Gnosis' "Extrafolic-S" and products which are made from it, infringe upon three of their patents: {{patent|US|5997915}}, {{patent|US|6673381}}, and {{patent|US|7172778}}.

==Formulations==
Levomefolate calcium, a calcium [[salt (chemistry)|salt]] of levomefolic acid is sold under the brand name Metafolin and incorporated in Deplin. Levomefolate magnesium is a magnesium salt of levomefolic acid, manufactured as DeltaFolate, a primary ingredient in EnLyte.

== See also ==
* [[5,10-Methylenetetrahydrofolate]]
* [[S-Adenosylmethionine]] (SAMe)

== External links ==
*[http://www.fao.org/docrep/008/a0044e/a0044e05.htm#bm5.3 Calcium L5-methyltetrahydrofolate (L-5-MTHF-Ca)]
* {{cite journal | vauthors = Brockton NT | title = Localized depletion: the key to colorectal cancer risk mediated by MTHFR genotype and folate? | journal = Cancer Causes & Control | volume = 17 | issue = 8 | pages = 1005–16 | date = October 2006 | pmid = 16933051 | doi = 10.1007/s10552-006-0051-5 | s2cid = 20394873 }}
* {{cite journal | vauthors = Stahl SM | title = Novel therapeutics for depression: L-methylfolate as a trimonoamine modulator and antidepressant-augmenting agent | journal = CNS Spectrums | volume = 12 | issue = 10 | pages = 739–44 | date = October 2007 | pmid = 17934378 | doi = 10.1017/S1092852900015418 | s2cid = 27000937 }}

{{Vitamin}}

{{二次利用|date=27 February 2024}}
[[Category:Folates]]
[[Category:Coenzymes]]
[[Category:Medical food]]
[[Category:Patent case law]]
</translate>