Folinic acid, also known as leucovorin, is a medication used to decrease the toxic effects of

methotrexate Methotrexate, formerly known as amethopterin, is a chemotherapy agent and immunosuppressive drug, immune-system suppressant. It is used to treat cancer, autoimmune diseases, and ectopic pregnancy, ectopic pregnancies. Types of cancers it is u ...

and

pyrimethamine Pyrimethamine, sold under the brand name Daraprim among others, is a medication used with leucovorin (leucovorin is used to decrease side effects of pyrimethamine; it does not have intrinsic anti-parasitic activity) to treat the parasitic disea ...

. It is also used in combination with 5-fluorouracil to treat

colorectal cancer Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the Colon (anatomy), colon or rectum (parts of the large intestine). Signs and symptoms may include Lower gastrointestinal ...

and pancreatic cancer, may be used to treat folate deficiency that results in

anemia Anemia (also spelt anaemia in British English) is a blood disorder in which the blood has a reduced ability to carry oxygen. This can be due to a lower than normal number of red blood cells, a reduction in the amount of hemoglobin availabl ...

, and

methanol poisoning Methanol toxicity (also methanol poisoning) is poisoning from methanol, characteristically via ingestion. Symptoms may include an altered/decreased level of consciousness, poor or no coordination, vomiting, abdominal pain, and a specific smell o ...

. It is taken by mouth, injection into a muscle, or injection into a vein. Side effects may include trouble sleeping,

allergic reactions Allergies, also known as allergic diseases, are various conditions caused by hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic dermatitis, alle ...

, or

fever Fever or pyrexia in humans is a symptom of an anti-infection defense mechanism that appears with Human body temperature, body temperature exceeding the normal range caused by an increase in the body's temperature Human body temperature#Fever, s ...

. Use in

pregnancy Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...

breastfeeding Breastfeeding, also known as nursing, is the process where breast milk is fed to a child. Infants may suck the milk directly from the breast, or milk may be extracted with a Breast pump, pump and then fed to the infant. The World Health Orga ...

is generally regarded as safe. When used for anemia it is recommended that

pernicious anemia Pernicious anemia is a disease where not enough red blood cells are produced due to a deficiency of Vitamin B12, vitamin B12. Those affected often have a gradual onset. The most common initial symptoms are Fatigue, feeling tired and weak. Other ...

as a cause be ruled out first. Folinic acid is a form of

folic acid Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing and ...

that does not require activation by dihydrofolate reductase to be useful to the body. Folinic acid was first made in 1945. It is on the World Health Organization's List of Essential Medicines.

Medical use

Folinic acid can be taken as a pill (orally) or injected into a vein (intravenously) or muscle (intramuscularly).

To reduce effects of methotrexate

Folinic acid is given following

as part of a total chemotherapeutic plan, where it may protect against bone marrow suppression or gastrointestinal mucosa inflammation. No apparent effect is seen on pre-existing methotrexate-induced

nephrotoxicity Nephrotoxicity is toxicity in the kidneys. It is a poisonous effect of some substances, both toxic chemicals and medications, on kidney function. There are various forms, and some drugs may affect kidney function in more than one way. Nephrotoxin ...

. 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 redosed until the methotrexate level is less than 5 x 10⁻⁸ M. Additionally, folinic acid is sometimes used to reduce the side effects of methotrexate in

rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects synovial joint, joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and h ...

patients. This includes reductions in nausea, abdominal pain, abnormal liver blood tests, and mouth sores.

Other uses or indications

Folinic acid is also used in combination with the chemotherapy agent 5-fluorouracil in treating

colon cancer Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel ...

. 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 An antimicrobial is an agent that kills microorganisms (microbicide) or stops their growth (bacteriostatic agent). Antimicrobial medicines can be grouped according to the microorganisms they are used to treat. For example, antibiotics are used aga ...

dihydrofolate reductase inhibitors such as trimethoprim and

, although its value for this indication has not been clearly established. It may be prescribed in the treatment of

toxoplasmosis Toxoplasmosis is a parasitic disease caused by ''Toxoplasma gondii'', an apicomplexan. Infections with toxoplasmosis are associated with a variety of neuropsychiatric and behavioral conditions. Occasionally, people may have a few weeks or month ...

retinitis, in combination with the folic acid antagonists

and

sulfadiazine Sulfadiazine is an antibiotic. Used together with pyrimethamine, a dihydrofolate reductase inhibitor, it is the treatment of choice for toxoplasmosis, which is caused by a protozoan parasite. It is a second-line treatment for otitis media, pr ...

. Folinic acid is also used in the treatment of cerebral folate deficiency, a syndrome in which the use of

cannot normalize cerebrospinal fluid levels of 5-MTHF. In pyridoxine-dependent epilepsy, folinic acid may be used as additional therapy if pyridoxine or pyridoxal phosphate fails to fully control the seizures.

Side effects

Folinic acid should not be administered intrathecally. This may produce severe adverse effects or even death. Severe neurotoxicity due to intrathecal folinic acid as treatment for intrathecally-administered methotrexate was first noted in an 11-year-old boy being treated for acute lymphocytic leukemia In cancer patients, rare

hypersensitivity Hypersensitivity (also called hypersensitivity reaction or intolerance) is an abnormal physiological condition in which there is an undesirable and adverse immune response to an antigen. It is an abnormality in the immune system that causes Imm ...

reactions to folinic acid have been described.

Drug interactions

* Fluorouracil: Folinic acid may increase the toxicity associated with fluorouracil if the two are administered together. Some adverse effects that have occurred, particularly in elderly patients, include severe

enterocolitis Enterocolitis is an inflammation of the digestive tract, involving enteritis of the small intestine and colitis of the colon. It may be caused by various infections, with bacteria, viruses, fungi, parasites, or other causes. Common clinical mani ...

, diarrhea, and dehydration. * Sulfamethoxazole-trimethoprim: A potential drug interaction exists with concomitant use of sulfamethoxazole-trimethoprim and folinic acid. Folinic acid has been shown to decrease the efficacy of sulfamethoxazole-trimethoprim in the treatment of '' Pneumocystis jirovecii'' (formerly known as ''Pneumocystis carinii''), a common cause of pneumonia in AIDS patients.

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., 5,10-methylenetetrahydrofolate, 5-methyltetrahydrofolate), thus has vitamin activity 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. Folinic acid, therefore, allows for some

purine Purine is a heterocyclic aromatic organic compound that consists of two rings (pyrimidine and imidazole) fused together. It is water-soluble. Purine also gives its name to the wider class of molecules, purines, which include substituted puri ...

pyrimidine Pyrimidine (; ) is an aromatic, heterocyclic, organic compound similar to pyridine (). One of the three diazines (six-membered heterocyclics with two nitrogen atoms in the ring), it has nitrogen atoms at positions 1 and 3 in the ring. The oth ...

synthesis to occur in the presence of dihydrofolate reductase inhibition, so some normal

DNA Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...

replication processes can proceed. Folinic acid has dextro- and levorotary isomers. Both levoleucovorin (the levorotary isomer) and racemic folinic acid (a mixture of both isomers) have similar efficacy and tolerability. Levoleucovorin was approved by the FDA in 2008.

History

Folinic acid was discovered as a needed growth factor for the bacterium '' Leuconostoc citrovorum'' in 1948, by Sauberlich and Baumann. This resulted in it being called "citrovorum factor," meaning citrovorum growth factor. It had an unknown structure, but was found to be 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 now known, 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.Rabinowitz, J. C., & Pricer Jr, W. E. (1956). Formimino-tetrahydrofolic acid and methenyltetrahydrofolic acid as intermediates in the formation of N10-formyltetrahydrofolic acid. ''Journal of the American Chemical Society'', ''78''(21), 5702-5704.

Names

Folinic acid should be distinguished from

(vitamin B₉). However, folinic acid is a vitamer for folic acid and has the full vitamin activity of this vitamin. Levofolinic acid and its salts are the 2S-form of the molecule. They are the only forms of the molecule that are known to be biologically active. It is generally administered as the

calcium Calcium is a chemical element; it has symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to it ...

sodium Sodium is a chemical element; it has Symbol (chemistry), symbol Na (from Neo-Latin ) and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 element, group 1 of the peri ...

salt (calcium folinate ( INN), sodium folinate, leucovorin calcium, leucovorin sodium).

References

External links

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