Folinic acid, often known as leucovorin, is a drugs used to lower the poisonous results of methotrexate and pyrimethamine.[2][3] Additionally it is utilized in mixture with 5-fluorouracil to deal with colorectal most cancers and pancreatic most cancers, could also be used to deal with folate deficiency that leads to anemia, and methanol poisoning.[3][4] It’s taken by mouth, injection right into a muscle, or injection right into a vein.[3]
Unwanted effects might embrace bother sleeping, allergic reactions, or fever.[2][3] Use in being pregnant or breastfeeding is mostly thought to be secure.[2] When used for anemia it’s endorsed that pernicious anemia as a trigger be dominated out first.[3] Folinic acid is a type of folic acid that doesn’t require activation by dihydrofolate reductase to be helpful to the physique.[3]
Folinic acid was first made in 1945.[5] It’s on the World Well being Group’s Record of Important Medicines, the most secure and simplest medicines wanted in a well being system.[6]
Contents
Medical use[edit]
Folinic acid is given following methotrexate as a part of a complete chemotherapeutic plan, the place it might shield in opposition to bone marrow suppression or gastrointestinal mucosa irritation. No obvious impact is seen on pre-existing methotrexate-induced nephrotoxicity.[7] Folinic acid could be taken as a capsule (orally) or injected right into a vein (intravenously) or muscle (intramuscularly).[8]
Whereas not particularly an antidote for methotrexate, folinic acid might also be helpful within the remedy of acute methotrexate overdose. Totally different dosing protocols are used, however folinic acid ought to be redosed till the methotrexate stage is lower than 5 x 10−8 M.[9]
Moreover, folinic acid is typically used to cut back the negative effects of methotrexate in rheumatoid arthritis sufferers. This consists of reductions in nausea, stomach ache, irregular liver blood assessments, and mouth sores.[10]
Folinic acid can also be utilized in mixture with the chemotherapy agent 5-fluorouracil in treating colon most cancers. On this case, folinic acid isn’t used for “rescue” functions; somewhat, it enhances the impact of 5-fluorouracil by inhibiting thymidylate synthase.
Folinic acid can also be typically used to forestall poisonous results of excessive doses of antimicrobial dihydrofolate reductase inhibitors corresponding to trimethoprim and pyrimethamine. It could be prescribed within the remedy of toxoplasmosis retinitis, together with the folic acid antagonists pyrimethamine and sulfadiazine.
Folinic acid can also be used within the remedy of cerebral folate deficiency, a syndrome through which using folic acid can not normalize cerebrospinal fluid ranges of 5-MTHF.[11]
Unwanted effects[edit]
Folinic acid shouldn’t be administered intrathecally. This will produce extreme hostile results and even dying.[12]
Drug interactions[edit]
Fluorouracil: Folinic acid might improve the toxicity related to fluorouracil if the 2 are administered collectively. Some hostile results which have occurred, significantly in aged sufferers, embrace extreme enterocolitis, diarrhea, and dehydration.[13]
Sulfamethoxazole-trimethoprim: A possible drug interplay exists with concomitant use of sulfamethoxazole-trimethoprim and folinic acid. Folinic acid has been proven to lower the efficacy of sulfamethoxazole-trimethoprim within the remedy of Pneumocystis jirovecii (previously often called Pneumocystis carinii), a typical reason behind pneumonia in AIDS sufferers.[14]
Mechanism of motion[edit] – “calcium folinate”
Folinic acid is a 5-formyl by-product of tetrahydrofolic acid. It’s readily transformed to different diminished folic acid derivatives (e.g., 5,10-methylenetetrahydrofolate, 5-methyltetrahydrofolate), thus has vitamin exercise equal to that of folic acid. Because it doesn’t require the motion of dihydrofolate reductase for its conversion, its perform as a vitamin is unaffected by inhibition of this enzyme by medication corresponding to methotrexate. That is the classical view of folinic acid rescue remedy. In Nineteen Eighties, nonetheless, folinic acid was discovered to reactivate the dihydrofolate reductase itself even when methotrexate exists.
Though the mechanism isn’t very clear, the polyglutamylation of methotrexate and dihydrofolate in malignant cells is taken into account to play an vital function within the selective reactivation of dihydrofolate reductase by folinic acid in regular cells.[15]
Folinic acid, due to this fact, permits for some purine/pyrimidine synthesis to happen within the presence of dihydrofolate reductase inhibition, so some regular DNA replication processes can proceed.
Folinic acid has dextro- and levorotary isomers. Each levoleucovorin (the levorotary isomer) and racemic folinic acid (a combination of each isomers) have comparable efficacy and tolerability.[16] Levoleucovorin was accepted by the FDA in 2008.[17]
Historical past[edit]
Folinic acid was found as a wanted progress issue for the bacterium Leuconostoc citrovorum in 1948, by Sauberlich and Baumann. This resulted in it being known as “citrovorum factor,” which means citrovorum progress issue. It had an unknown construction, however was discovered to be a by-product of folate that needed to be metabolized within the liver earlier than it may help progress of L. citrovorum. The synthesis of citrovorum issue by liver cells in tradition was ultimately completed from pteroylglutamic acid within the presence of appropriate concentrations of ascorbic acid. The simultaneous addition of sodium formate to such methods resulted in elevated citrovorum issue exercise within the cell-free supernatants (producing, as now identified, the 5-formyl by-product), and from this technique of preparation of huge quantities of the issue, its construction as levo-folinic acid (5-formyl tetrahydrofolic acid) was ultimately deduced.[citation needed]
Names[edit]
Folinic acid ought to be distinguished from folic acid (vitamin B9). Nevertheless, folinic acid is a vitamer for folic acid and has the total vitamin exercise of this vitamin. Levofolinic acid and its salts are the 2S- type of the molecule. They’re the one types of the molecule which might be identified to be biologically lively.
It’s typically administered because the calcium or sodium salt (calcium folinate (INN), sodium folinate, leucovorin calcium, leucovorin sodium).