関: Leucovorin

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street name for lysergic acid diethylamide (同)back breaker, battery-acid, dose, dot, Elvis, loony toons, Lucy in the sky with diamonds, pane, superman, window pane, Zen
any of various water-soluble compounds having a sour taste and capable of turning litmus red and reacting with a base to form a salt
having the characteristics of an acid; "an acid reaction"

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酸性の / 酸味のある,すっぱい(sour) / (言葉・態度などが)厳しい,しんらつな / 酸 / すっぱいもの / 《俗》=LSD

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/05/21 17:39:22」(JST)

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Levofolinic acid

Folinic acid (INN) or leucovorin /luːkoʊˈvɔːrɪn/ (USAN), generally administered as calcium or sodium folinate (or leucovorin calcium/sodium), is an adjuvant used in cancer chemotherapy involving the drug methotrexate.^[1] It is also used in synergistic combination with the chemotherapy agent 5-fluorouracil.

Levofolinic acid and its salts are the enantiopure drugs (in this case, the levo form), and are the only molecules that are biologically active. They are configurated S at the remaining asymmetric carbon atom (see below).

Folinic acid was first discovered in 1948 as citrovorum factor and occasionally is still called by that name.^[2] Folinic acid should be distinguished from folic acid (Vitamin B9). However, folinic acid is a vitamer for folic acid, and has the full vitamin activity of this vitamin. It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.^[3]

Medical use

Folinic acid is administered at the appropriate time following methotrexate as part of a total chemotherapeutic plan, where it may "rescue" bone marrow and gastrointestinal mucosa cells from methotrexate. There is no apparent effect on preexisting methotrexate-induced nephrotoxicity.^[4]

While not specifically an antidote for methotrexate, folinic acid may also be useful in the treatment of acute methotrexate overdose. Different dosing protocols are used, but folinic acid should be re-dosed until the methotrexate level is less than 5 x 10⁻⁸ M^[5]

Folinic acid is also used in combination with the chemotherapy agent 5-fluorouracil in treating colon cancer. In this case, folinic acid is not used for "rescue" purposes; rather, it enhances the effect of 5-fluorouracil by inhibiting thymidylate synthase.

Folinic acid is also sometimes used to prevent toxic effects of high doses of antimicrobial dihydrofolate reductase inhibitors such as trimethoprim and pyrimethamine. Folinic acid may be prescribed in the treatment of toxoplasmosis retinitis, in combination with the folic acid antagonists pyrimethamine and sulfadiazine.

Folinic acid has dextro- and levo-isomers, only the latter one being pharmacologically useful. As such, Levoleucovorin was approved by the FDA in 2008.^[6]

It has been investigated for use in Down's syndrome, but a benefit has not been demonstrated.^[7]

Side effects

Folinic acid should not be administered intrathecally. This may produce severe adverse effects or even death.^[8] And Folinic Acid should not be administered to pregnant woman because it can weaken the unborn baby's immune system

Mechanism of action

Folinic acid is a 5-formyl derivative of tetrahydrofolic acid. It is readily converted to other reduced folic acid derivatives (e.g., tetrahydrofolate), and, thus, has vitamin activity that is equivalent to that of folic acid. Since it does not require the action of dihydrofolate reductase for its conversion, its function as a vitamin is unaffected by inhibition of this enzyme by drugs such as methotrexate. This is the classical view of Folinic acid rescue therapy.

In 1980s, however, folinic acid was found to reactivate the dihydrofolate reductase itself even when methotrexate exists. Although the mechanism is not very clear, the polyglutamylation of methotrexate and dihydrofolate in malignant cells is considered to play an important role in the selective reactivation of dihydrofolate reductase by folinic acid in normal cells.^[9]

Folinic acid, therefore, allows for some purine/pyrimidine synthesis to occur in the presence of dihydrofolate reductase inhibition, so that some normal DNA replication processes can proceed.

History

Folinic acid was discovered as a needed growth factor for the bacterium Leuconostoc citrovorum in 1948, by Sauberlich and Baumann. This so-called "citrovorum factor," which then had an unknown structure, was a derivative of folate that had to be metabolized in the liver before it could support growth of L. citrovorum. The synthesis of citrovorum factor by liver cells in culture was eventually accomplished from pteroylglutamic acid in the presence of suitable concentrations of ascorbic acid. The simultaneous addition of sodium formate to such systems resulted in increased citrovorum factor activity in the cell-free supernatants (producing, as we know now, the 5-formyl derivative), and from this method of preparation of large amounts of the factor, its structure as levo-folinic acid (5-formyl tetrahydrofolic acid) was eventually deduced.

References

^ Keshava C, Keshava N, Whong WZ, Nath J, Ong TM (February 1998). "Inhibition of methotrexate-induced chromosomal damage by folinic acid in V79 cells". Mutat. Res. 397 (2): 221–8. doi:10.1016/S0027-5107(97)00216-9. PMID 9541646.
^ http://www.jbc.org/content/200/1/223.full.pdf Citrovorum factor discovery
^ "WHO Model List of EssentialMedicines". World Health Organization. October 2013. Retrieved 22 April 2014.
^ Therapeutic Information Resources Australia (2004). Calcium Folinate (Systemic) in AUSDI: Australian Drug Information for the Health Care Professional. Castle Hill: Therapeutic Information Resources Australia.
^ http://www.cancercare.on.ca/pdfdrugs/leucovo.pdf
^ Drugs.com (2008-05-07). "FDA Approves Levoleucovorin". Retrieved 2009-06-07.
^ Ellis JM, Tan HK, Gilbert RE, et al (March 2008). "Supplementation with antioxidants and folinic acid for children with Down's syndrome: randomised controlled trial". BMJ 336 (7644): 594–7. doi:10.1136/bmj.39465.544028.AE. PMC 2267988. PMID 18296460.
^ Jardine, LF et al (1996). "Intrathecal Leucovorin After Intrathecal Methotrexate Overdose". J Pediatr Hematol Oncol 18 (3): 302–304. doi:10.1097/00043426-199608000-00014. PMID 8689347.
^ Goldman ID, Matherly LH (1987). "Biochemical Factors in the Selectivity of Leucovorin Rescue: Selective Inhibition of Leucovorin Reactivation of Dihydrofolate Reductase and Leucovorin Utilization in Purine and Pyrimidine Biosynthesis by Methotrexate and Dihydrofolate Polyglutamates". NCI monographs 5: 17–26. PMID 2448654.

External links

U.S. National Library of Medicine: Drug Information Portal - Folinic acid

UpToDate Contents

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1. 高用量メトトレキサートの治療使用および毒性 therapeutic use and toxicity of high dose methotrexate
2. 転移性大腸癌に対する全身化学療法：終了した臨床試験 systemic chemotherapy for metastatic colorectal cancer completed clinical trials
3. 成人における抗癌剤の投与 dosing of anticancer agents in adults
4. 切除III期（リンパ節陽性）結腸癌に対する補助化学療法 adjuvant therapy for resected stage iii node positive colon cancer
5. 低用量メトトレキサートの主な副作用 major side effects of low dose methotrexate

English Journal

Efficacy and Toxicity of Different Chemotherapy Regimens in the Treatment of Advanced or Metastatic Pancreatic Cancer: A Network Meta-Analysis.

Liu GF1, Li GJ2, Zhao H3.
Journal of cellular biochemistry.J Cell Biochem.2018 Jan;119(1):511-523. doi: 10.1002/jcb.26210. Epub 2017 Jul 17.
PMID 28608558

Capecitabine versus S-1 as adjuvant chemotherapy for patients with stage III colorectal cancer (JCOG0910): an open-label, non-inferiority, randomised, phase 3, multicentre trial.

Hamaguchi T1, Shimada Y2, Mizusawa J3, Kinugasa Y4, Kanemitsu Y5, Ohue M6, Fujii S7, Takiguchi N8, Yatsuoka T9, Takii Y10, Ojima H11, Masuko H12, Kubo Y13, Mishima H14, Yamaguchi T15, Bando H16, Sato T17, Kato T18, Nakamura K3, Fukuda H3, Moriya Y19.
The lancet. Gastroenterology & hepatology.Lancet Gastroenterol Hepatol.2018 Jan;3(1):47-56. doi: 10.1016/S2468-1253(17)30297-2. Epub 2017 Oct 24.
PMID 29079411

Phase III trial comparing UFT + PSK to UFT + LV in stage IIB, III colorectal cancer (MCSGO-CCTG).

Miyake Y1, Nishimura J2, Kato T3, Ikeda M4, Tsujie M5, Hata T2, Takemasa I2, Mizushima T2, Yamamoto H2, Sekimoto M4, Nezu R1, Doki Y2, Mori M2; Multi-center Clinical Study Group of Osaka, Colorectal Cancer Treatment Group (MCSGO).
Surgery today.Surg Today.2018 Jan;48(1):66-72. doi: 10.1007/s00595-017-1555-1. Epub 2017 Jun 20.
PMID 28634730

Japanese Journal

造血幹細胞移植後の口内炎予防におけるロイコボリンの有用性の検討

杉田純一,松下貴恵,柏崎晴彦,高橋正二郎,白鳥聡一,井端淳,重松明男,藤本勝也,遠藤知之,近藤健,橋野聡,田中淳司,豊嶋崇徳
北海道醫學雜誌 = Acta medica Hokkaidonensia 87(6), 272, 2012-11-01
NAID 10031131113

メトトレキサートの投与量,投与方法による使い分けと副作用対策 (特集血液内科領域における抗腫瘍薬の作用機序・副作用に基づく使い分け)

磯部泰司
血液内科 65(4), 488-497, 2012-10
NAID 40019489500

Efficacy of folinic acid in preventing oral mucositis in allogeneic hematopoietic stem cell transplant patients receiving MTX as prophylaxis for GVHD

Sugita Junichi,Matsushita Takae,Kashiwazaki Haruhiko,Kosugi Mizuha,Takahashi Shojiro,Wakasa Kentaro,Shiratori Souichi,Ibata Makoto,Shono Yusuke,Shigematsu Akio,Obara Masato,Fujimoto Katsuya,Endo Tomoyuki,Nishio Mitsufumi,Kondo Takeshi,Hashino Satoshi,Tanaka Junji,Asaka Masahiro,Imamura Masahiro
Bone Marrow Transplantation 47(2), 258-264, 2012-02
… Since the safety of folinic acid administration and its efficacy for reducing the toxicity of methotrexate (MTX) remain controversial, we assessed the effect of folinic acid administration after MTX treatment for GVHD prophylaxis on the incidence of oral mucositis and acute GVHD. …
NAID 120004405533

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★リンクテーブル★

リンク元	「フォリン酸」「calcium folinate」

「フォリン酸」

Folinic acid
Systematic (IUPAC) name
	(2S)-2-{[4-[(2-amino-5-formyl-4-oxo-5,6,7,8-; tetrahydro-1H-pteridin-6-yl)methylamino]; benzoyl]amino}pentanedioic acid
Clinical data
Trade names	Many
AHFS/Drugs.com	monograph
Pregnancy cat.	A (AU) C (US)
Legal status	℞ Prescription only
Routes	Intravenous, oral
Pharmacokinetic data
Bioavailability	Dose dependent
Protein binding	~15%
Half-life	6.2 hours
Excretion	Urinary
Identifiers
CAS number	1492-18-8
ATC code	V03AF03
PubChem	CID 6006
DrugBank	DB00650
ChemSpider	5784
UNII	RPR1R4C0P4
ChEMBL	CHEMBL1679
Chemical data
Formula	C20H23N7O7
Mol. mass	473.44 g/mol
	SMILES O=C(O)[C@@H](NC(=O)c1ccc(cc1)NCC3N(/C2=C(/N/C(=N\C2=O)N)NC3)C=O)CCC(=O)O;
	InChI InChI=1S/C20H23N7O7/c21-20-25-16-15(18(32)26-20)27(9-28)12(8-23-16)7-22-11-3-1-10(2-4-11)17(31)24-13(19(33)34)5-6-14(29)30/h1-4,9,12-13,22H,5-8H2,(H,24,31)(H,29,30)(H,33,34)(H4,21,23,25,26,32)/t12?,13-/m0/s1 ; Key:VVIAGPKUTFNRDU-ABLWVSNPSA-N ;
Physical data
Melt. point	245 °C (473 °F) decomp
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　　[★]

英: folinic acid
関: ロイコボリン、ホリナートカルシウム

「calcium folinate」

　　[★]

ホリナートカルシウム

関: folinic acid、Leucovorin

[pmid9541646-1] Keshava C, Keshava N, Whong WZ, Nath J, Ong TM (February 1998). "Inhibition of methotrexate-induced chromosomal damage by folinic acid in V79 cells". Mutat. Res. 397 (2): 221–8. doi:10.1016/S0027-5107(97)00216-9. PMID 9541646.

[2] ttp://www.jbc.org/content/200/1/223.full.pdf Citrovorum factor discovery

[3] "WHO Model List of EssentialMedicines". World Health Organization. October 2013. Retrieved 22 April 2014.

[4] Therapeutic Information Resources Australia (2004). Calcium Folinate (Systemic) in AUSDI: Australian Drug Information for the Health Care Professional. Castle Hill: Therapeutic Information Resources Australia.

[5] ttp://www.cancercare.on.ca/pdfdrugs/leucovo.pdf

[6] Drugs.com (2008-05-07). "FDA Approves Levoleucovorin". Retrieved 2009-06-07.

[pmid18296460-7] Ellis JM, Tan HK, Gilbert RE, et al (March 2008). "Supplementation with antioxidants and folinic acid for children with Down's syndrome: randomised controlled trial". BMJ 336 (7644): 594–7. doi:10.1136/bmj.39465.544028.AE. PMC 2267988. PMID 18296460.

[8] Jardine, LF et al (1996). "Intrathecal Leucovorin After Intrathecal Methotrexate Overdose". J Pediatr Hematol Oncol 18 (3): 302–304. doi:10.1097/00043426-199608000-00014. PMID 8689347.

[pmid2448654-9] Goldman ID, Matherly LH (1987). "Biochemical Factors in the Selectivity of Leucovorin Rescue: Selective Inhibition of Leucovorin Reactivation of Dihydrofolate Reductase and Leucovorin Utilization in Purine and Pyrimidine Biosynthesis by Methotrexate and Dihydrofolate Polyglutamates". NCI monographs 5: 17–26. PMID 2448654.

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folinic acid