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Levomefolic acid
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<h2 id="metabolism">Metabolism</h2> <h2 id="medical-uses">Medical uses</h2> <h3>Major depressive disorder</h3> <p>Research suggests that levomefolic acid (L-methylfolate) taken with a <a href="/facts/First_line_agent/2ytkGbgT">first-line</a> <a href="/facts/Antidepressant/N62ND3Fa">antidepressant</a> provides a modest <a href="/facts/Adjunctive_therapy/rtvKq6Pq">adjunctive</a> antidepressant effect for individuals who do not respond or have only a partial therapeutic response to <a href="/facts/Selective_serotonin_reuptake_inhibitor/L6jjcmEH">SSRI</a> or <a href="/facts/Serotonin%25E2%2580%2593norepinephrine_reuptake_inhibitor/PSr56Vxh">SNRI</a> medication,<a class="footnote-ref" id="fnref:6" href="#fn:6"><sup>6</sup></a><a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a> and might be a more cost-effective adjunctive agent than <a href="/facts/Atypical_antipsychotic/PQYUYXMu">second-generation antipsychotics</a>.<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a> </p> <h3>Cardiovascular disease and cancer</h3> <p>Levomefolic acid (and folic acid in turn) has been proposed for treatment of cardiovascular disease<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> and advanced cancers such as breast and <a href="/facts/Colorectal_cancer/nV592sW7">colorectal cancers</a>.<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a> It bypasses several metabolic steps in the body and better binds <a href="/facts/Thymidylate_synthase/zKtHApFJ">thymidylate synthase</a> with <a href="/facts/FdUMP/UBhuEr6e">FdUMP</a>, a metabolite of the drug <a href="/facts/Fluorouracil/6xH4uUaf">fluorouracil</a>. </p> <h2 id="patent-issues">Patent issues</h2> <p>In March 2012, <a href="/facts/Merck_KGaA/5wXLtNQF">Merck & Cie</a> of <a href="/facts/Switzerland/LcGuxeTe">Switzerland</a>, <a href="/facts/Pamlab/Tje9hhmj">Pamlab</a> LLC (maker of <a href="/facts/Metanx/UuKH213B">Metanx</a> and <a href="/facts/Cerefolin/fLnx3Yqq">Cerefolin</a>, Neevo DHA, and Deplin), and South Alabama Medical Science Foundation (SAMSF) (the plaintiffs) filed a complaint in the <a href="/facts/United_States_District_Court_for_the_Eastern_District_of_Texas/Eqsd5sfT">United States District Court for the Eastern District of Texas</a> 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.<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> The Macoven products named in the suit are: "Vitaciric-B", "ALZ-NAC", "PNV DHA", and l-methylfolate calcium (levomefolate calcium).<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> </p><p>In September 2012, the same three plaintiffs filed a complaint requesting that the <a href="/facts/United_States_International_Trade_Commission/asV33MQG">International Trade Commission</a> begin a <a href="/facts/Title_19_of_the_United_States_Code/7MIJr9kB">19 U.S.C.</a> <a href="https://www.law.cornell.edu/uscode/text/19/1337">§ 1337</a> 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: <a href="https://worldwide.espacenet.com/textdoc?DB=EPODOC&IDX=US5997915">US 5997915</a> , <a href="https://worldwide.espacenet.com/textdoc?DB=EPODOC&IDX=US6673381">US 6673381</a> , and <a href="https://worldwide.espacenet.com/textdoc?DB=EPODOC&IDX=US7172778">US 7172778</a> .<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> </p> <h2 id="formulations">Formulations</h2> <ul><li>Levomefolate calcium, a calcium <a href="/facts/Salt_(chemistry)/lsSKwGpn">salt</a> of levomefolic acid is sold under the brand name Metafolin<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> and incorporated in Deplin.<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a></li></ul> <ul><li>Levomefolate magnesium is a magnesium salt of levomefolic acid, manufactured as DeltaFolate, a primary ingredient in EnLyte.<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a></li></ul> <ul><li>Levomefolate calcium (a calcium <a href="/facts/Salt_(chemistry)/lsSKwGpn">salt</a> of levomefolic acid) is manufactured as <i>Cerebrofolate</i>.<a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a></li></ul> <h2 id="see-also">See also</h2> <ul><li><a href="/facts/5%2c10-Methylenetetrahydrofolate/qwUqo7zp">5,10-Methylenetetrahydrofolate</a></li> <li><a href="/facts/S-Adenosylmethionine/oAsJ0SSR">S-Adenosylmethionine</a> (SAMe)</li></ul> <h2 id="external-links">External links</h2> <ul><li><a href="http://www.fao.org/docrep/008/a0044e/a0044e05.htm#bm5.3">Calcium L5-methyltetrahydrofolate (L-5-MTHF-Ca)</a></li> <li>Brockton NT (October 2006). "Localized depletion: the key to colorectal cancer risk mediated by MTHFR genotype and folate?". <i>Cancer Causes & Control</i>. 17 (8): 1005–16. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1007%2Fs10552-006-0051-5">10.1007/s10552-006-0051-5</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/16933051">16933051</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:20394873">20394873</a>.</li> <li>Stahl SM (October 2007). "Novel therapeutics for depression: L-methylfolate as a trimonoamine modulator and antidepressant-augmenting agent". <i>CNS Spectrums</i>. 12 (10): 739–44. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1017%2FS1092852900015418">10.1017/S1092852900015418</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/17934378">17934378</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:27000937">27000937</a>.</li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Pietrzik K, Bailey L, Shane B (August 2010). "Folic acid and L-5-methyltetrahydrofolate: comparison of clinical pharmacokinetics and pharmacodynamics". Clinical Pharmacokinetics. 49 (8): 535–48. doi:10.2165/11532990-000000000-00000. PMID 20608755. S2CID 12876272. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>"5-methyltetrahydrofolate – Compound Summary", PubChem, NCBI, retrieved 25 September 2012 <a href="https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?q=all&cid=444412#ec" target="_blank">https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?q=all&cid=444412#ec</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>"CerefolinNAC Caplets Package Insert" (PDF). <a href="http://intetlab.com/site/products/Cerefolin-NAC_package-insert_%204-26-10.pdf" target="_blank">http://intetlab.com/site/products/Cerefolin-NAC_package-insert_%204-26-10.pdf</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>"Vitamin B12-folate interrelationships". <a href="https://pubmed.ncbi.nlm.nih.gov/3927946/" target="_blank">https://pubmed.ncbi.nlm.nih.gov/3927946/</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>"Cellular folate vitamer distribution during and after correction of vitamin B12 deficiency: a case for the methylfolate trap". <a href="https://pubmed.ncbi.nlm.nih.gov/16445837/" target="_blank">https://pubmed.ncbi.nlm.nih.gov/16445837/</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>Maruf, Abdullah Al; Poweleit, Ethan A.; Brown, Lisa C.; Strawn, Jeffrey R.; Bousman, Chad A. (2022). "Systematic Review and Meta-Analysis of L-Methylfolate Augmentation in Depressive Disorders". Pharmacopsychiatry. 55 (3): 139–147. doi:10.1055/a-1681-2047. ISSN 1439-0795. PMID 34794190. <a href="https://pubmed.ncbi.nlm.nih.gov/34794190/" target="_blank">https://pubmed.ncbi.nlm.nih.gov/34794190/</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>Lam, Nelson Siu Kei; Long, Xin Xin; Li, Xuegang; Saad, Mirette; Lim, Florence; Doery, James CG; Griffin, Robert C.; Galletly, Cherrie (2022). "The potential use of folate and its derivatives in treating psychiatric disorders: A systematic review". Biomedicine & Pharmacotherapy. 146: 112541. doi:10.1016/j.biopha.2021.112541. PMID 34953391. S2CID 245436052. <a href="https://linkinghub.elsevier.com/retrieve/pii/S0753332221013287" target="_blank">https://linkinghub.elsevier.com/retrieve/pii/S0753332221013287</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></p></li> <li id="fn:8"><p>Wade RL, Kindermann SL, Hou Q, Thase ME (January 2014). "Comparative assessment of adherence measures and resource use in SSRI/SNRI-treated patients with depression using second-generation antipsychotics or L-methylfolate as adjunctive therapy". Journal of Managed Care Pharmacy. 20 (1): 76–85. doi:10.18553/jmcp.2014.20.1.76. PMC 10438233. PMID 24372461. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10438233" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10438233</a> <a href="#fnref:8" class="footnote-back-ref">↩</a></p></li> <li id="fn:9"><p>Willems FF, Boers GH, Blom HJ, Aengevaeren WR, Verheugt FW (March 2004). "Pharmacokinetic study on the utilisation of 5-methyltetrahydrofolate and folic acid in patients with coronary artery disease". British Journal of Pharmacology. 141 (5). Nature Publishing Group: 825–30. doi:10.1038/sj.bjp.0705446. PMC 1574248. PMID 14769778. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1574248" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1574248</a> <a href="#fnref:9" class="footnote-back-ref">↩</a></p></li> <li id="fn:10"><p>Ströhle A, Wolters M, Hahn A (June 2005). "Folic acid and colorectal cancer prevention: molecular mechanisms and epidemiological evidence (Review)". International Journal of Oncology. 26 (6): 1449–64. doi:10.3892/ijo.26.6.1449. PMID 15870856. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:10" class="footnote-back-ref">↩</a></p></li> <li id="fn:11"><p>The six patents named were US 5997915 , US 6011040 , US 6254904 , US 6673381 , US 7674490 and US 7172778 . <a href="https://worldwide.espacenet.com/textdoc?DB=EPODOC&IDX=US5997915" target="_blank">https://worldwide.espacenet.com/textdoc?DB=EPODOC&IDX=US5997915</a> <a href="#fnref:11" class="footnote-back-ref">↩</a></p></li> <li id="fn:12"><p>"Pernix Therapeutics' Subsidiary Macoven Pharmaceuticals, LLC Named in Suit by Merck, Pamlab, L.L.C. and Others for Alleged". Bloomberg. 6 March 2012. Retrieved 1 October 2012. <a href="https://www.bloomberg.com/apps/news?pid=conewsstory&tkr=MKGAF:US&sid=aVfdD6EGy6Nc" target="_blank">https://www.bloomberg.com/apps/news?pid=conewsstory&tkr=MKGAF:US&sid=aVfdD6EGy6Nc</a> <a href="#fnref:12" class="footnote-back-ref">↩</a></p></li> <li id="fn:13"><p>Schweibenz EW (10 September 2012). "SAMSF, Merck, and Pamlab File New 337 Complaint Regarding Certain Reduced Folate Nutraceutical Products and L-methylfolate Raw Ingredients Used Therein". Oblon, Spivak, McClelland, Maier & Neustadt, L.L.P. Archived from the original on 30 January 2013. <a href="https://archive.today/20130130195443/http://www.oblon.com/samsf-merck-and-pamlab-file-new-337-complaint-regarding-certain-reduced-folate-nutraceutical-product" target="_blank">https://archive.today/20130130195443/http://www.oblon.com/samsf-merck-and-pamlab-file-new-337-complaint-regarding-certain-reduced-folate-nutraceutical-product</a> <a href="#fnref:13" class="footnote-back-ref">↩</a></p></li> <li id="fn:14"><p>"Metafolin". MilliporeSigma. Retrieved 28 November 2022. Metafolin® is our manufactured calcium salt of L-5-methyltetrahydrofolic or L-methylfolate. ... The life science business of Merck KGaA, Darmstadt, Germany operates as MilliporeSigma in the US and Canada. <a href="https://www.emdmillipore.com/US/en/products/small-molecule-pharmaceuticals/bulk-api/folates/l-metafolin/Metafolin/okeb.qB.qsoAAAFp2m8bIm4h,nav" target="_blank">https://www.emdmillipore.com/US/en/products/small-molecule-pharmaceuticals/bulk-api/folates/l-metafolin/Metafolin/okeb.qB.qsoAAAFp2m8bIm4h,nav</a> <a href="#fnref:14" class="footnote-back-ref">↩</a></p></li> <li id="fn:15"><p>"DEPLIN®". For Healthcare Professionals. Retrieved 28 November 2022. <a href="https://www.deplin.com/hcp" target="_blank">https://www.deplin.com/hcp</a> <a href="#fnref:15" class="footnote-back-ref">↩</a></p></li> <li id="fn:16"><p>"EnLyte with DeltaFolate". dailymed.nlm.nih.gov. Retrieved 28 November 2022. <a href="https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e83b2dd3-a9a0-40bc-ade4-6cd4db433b06" target="_blank">https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e83b2dd3-a9a0-40bc-ade4-6cd4db433b06</a> <a href="#fnref:16" class="footnote-back-ref">↩</a></p></li> <li id="fn:17"><p>Malik M, HUSSAIN A AND HASHMI A,"COMPARATIVE IN VITRO EVALUATION OF (6S)-5- METHYLTETRAHYDROFOLATE BRANDS: THE POST MARKET SURVEILLANCE FOR QUALITY ASSESSMENT". ijbpas.com. Retrieved 28 November 2022. <a href="https://ijbpas.com/archive/archive-single-pdf/6008" target="_blank">https://ijbpas.com/archive/archive-single-pdf/6008</a> <a href="#fnref:17" class="footnote-back-ref">↩</a></p></li> </ol>