1. It is mainly used as the antidote of folic acid antagonists (such as methotrexate, pyrimethamine or trimethoprim, etc.).
2. It can be used for the prevention of severe toxicity after excessive or large doses administration of methotrexate.
3. The megaloblastic anemia caused by folic acid deficiency.
4. In combination with fluorouracil, it is used for the treatment of advanced colon cancer and rectal cancer.
It is used for the rescue of the toxicity reaction caused by excessive amount of aminopterin and methotrexate as well as being used for the treatment of giant red blood cell anemia.
The efficacy of folate can offset the effects of folic acid antagonists. The folic acid antagonists rely on binding to folic acid dehydrogenase (DHFR), thereby preventing folate from converting to folic acid. Medically, after the chemotherapy of methotrexate, the calcium folinate can be used to reduce methotrexate toxicity. Calcium folinate can be used to enhances the cytotoxic effect of 5-fluorouracil in anticancer fields.
Adverse effects, contraindications and drug effects
There is occasionally rash, urticaria or asthma. Patients of megaloblastic anemia caused by pernicious anemia or vitamin B12 deficiency should be disabled. It is not suitable to be simultaneously applied together with folic acid antagonists such as methotrexate. Apply this drug after the high-dose usage of methotrexate for 24~48h; be cautious when using it for the methotrexate detoxification therapy on patients of acidic urine, ascites, dehydration, gastrointestinal obstruction, pleural effusion or renal dysfunction; for patients in critical conditions, the drug dose should be increased; the creatinine clearance rate should be measured before the treatment. After the application of high-dose methotrexate, we need to measure the plasma or serum methotrexate concentration every 12~24 h. Before or after the treatment of methotrexate, we need to measure the amount of serum creatinine every 24 h. In cases when the value after treatment is over 50% greater than that before treatment, this indicates severe renal toxicity;
Before or after the administration of methotrexate, we should monitor urine acidity every 6 h with the urine pH being maintained at value higher than 7. If necessary, we need to apply sodium bicarbonate and hydration treatment. Larger doses administration of it together with barbiturates, primidone or phenytoin sodium can affect the antiepileptic effect.
Usage and precautions
For the treatment of megaloblastic anemia, administrate orally 15 mg daily; or daily intramuscularly inject 1~5 mg; after 10~15 d, we can reduce the amount to 5 mg/d for oral administration until hemogram becomes normal and the symptoms disappear; if we can’t rule out the possibility of adenosine deficiency, we should combine with adenosine cobalt amine. For the rescue of methotrexate, apply 3 to 4 times per day with oral administration of 5~15 mg per time for 2d; or apply intramuscular injection of 3~6 mg; applying this drug is invalid for the treatment of patients who have administrated methotrexate for over 4 h. For the detoxification of pyrimethamine or trimethoprim, administrate orally 5~15 mg per day. Calcium folinate can be used in combination with fluorouracil at 20~30mg/m2. Administrate orally at half an hour after administration of fluorouracil.
antianemic, antidote to folic acid antagonists
Medicinal properties and application
Calcium folinate (CF) itself has no anti-tumor effect and is mainly used for high-dose rescue and concurrent use with fluorouracil to enhance the latter's therapeutic effect. The so-called high-dose methotrexate-leucovorin (HD MTX-CF) rescue therapy is applying intravenous infusion of MTX of over 100 times higher than the conventional dose, usually at 2~5 mg/m2 for drip of 4~6 h to make the blood concentration increase to a very high level, so that intracellular MTX can reach over 10-5 mol/L or more effective concentration. In this case, it can be spread to solid tumors with poor blood supply, and reach across physiological barriers such as blood-cerebrospinal fluid and testicular. However, high-dose of MTX can have a fatal toxicity, so at a certain period of time after the MTX dripping, we must immediately take detoxification measures. CF rescue should generally start at 2 to 18 hours after the MTX dripping. Apply intramuscular injection or intravenous injection of a dose of 6~15μg/m2 at 6 hour per time with the general medication of 3d and a total of 12 times. CF dose and injection time should be associated with the application of MTX, namely being able to reduce the blood concentration of MTX to below the safety threshold: 10-7 mol/L before stopping. In addition, we should also give auxiliary hydration, alkalization treatment to support. CF formulations are generally 6 mg water injection.
Another kind of therapy is the combination of calcium folinate and fluorouracil used to improve the efficacy of the latter one, commonly known as the CF-FU combination therapy. The basic principle is that: during the process of DNA synthesis, deoxyuridine (dUMP) needs to be catalyzed by adenylate synthase (TMPS) to accept the formyl group transferred from tetrahydrofolate (THF) to generate deoxyadenylic acid (dTMP). At this time, dihydrofolate reductase can convert dihydrofolate into tetrahydrofolic acid. The main mechanism of action of 5-fluorouracil is being converted to fluorouracil deoxynucleotide after entering into the body, causing inhibition of TMPS. During the reaction, TMPS, THF, dUMP 3 can form a transitional complex. Generally at the end of the reaction, the complex can dissociate, releasing dihydrofolate, TMPS and dTMP. But after the administration of FU, the complex can’t dissociate and the function of the enzyme is inhibited, leaving the dTMP being able to be generated.
The binding affinity between fluorouracil deoxynucleotide with the enzyme is positively correlated with the THF concentration. Increasing the supply of THF can enhance the inhibitory effect of FU on TMPS. Clinical specific application is generally: first apply 200~500 mg/m2CF for intravenous infusion of 2 h. After infusion, apply intravenous injection of FU370mg/m2 with continuous administration of 5d being a course of treatment; at 21~28d, we can repeat this treatment. This CF-FU combination treatment of colorectal cancer has a more excellent effect in treating the colon cancer, being superior to single administration of FU while adverse reactions are only slightly increased.
The antidote of folic acid antagonist
Calcium folinate is an antidote of the folic acid antagonists. At room temperature, it appears as yellowish white to yellow crystalline or amorphous powder, being odorless. It is easily soluble in water, but almost insoluble in ethanol or ether, and easily soluble in sodium hydroxide solution. Calcium folinate is a formylated derivative of folic acid, acting similarly to folic acid, being the activated form of folic acid in the body. After entering into the human body, it is converted to tetrahydrofolic acid under the action of tetrahydrofolate reductase, being effective in fighting against methotrexate-induced toxicity. Calcium folinate has effect of "rescuing" the in vivo toxicity of the excess amount of folic acid antagonists, being conducive to thymidine, DNA, RNA and protein synthesis, being able to stimulate white blood cell growth and maturation. This product can limit the damage degree of methotrexate to normal cells by competing with each other. It is also able to reverse the reaction of methotrexate on bone marrow and gastrointestinal mucosa, but has no effect on the existing methotrexate neurotoxicity. It is mainly for used as the antidote of the folic acid antagonists (such as methotrexate, aminopterin, phenytoin, phenobarbital, pyrimethamine or trimethoprim, etc.). When oral administration of folic acid yields poor efficacy, it is used for the treatment of stomatitis, diarrhea, malnutrition, pregnancy or infancy-caused megaloblastic anemia and leukopenia. But it is not applicable to vitamin B12 deficiency anemia.
In recent years, people have applied calcium folinate for the adjuvant therapy of colon and rectal cancer with combination with fluorouracil being able to prolong the survival period.
(1) moderate poisoning upon anti-folic acid metabolites, 6~12 mg once, every 6 hours 1 times, a total of 4 times.
(2) Megaloblastic anemia: 1mg per day, 1 time per day.
(3) Leukopenia: 3~6 mg per time, once per day. Intravenous infusion: anti-folic acid metabolites severe poisoning: completion of infusion administration of 75 mg in 12 hours, followed by intramuscular injection. Adverse reactions are rare, and occasionally rash, urticaria or asthma and other allergic reactions. Patients of acidic urine (pH <7), ascites, dehydration, gastrointestinal obstruction, pleural effusion or renal dysfunction should be taken with caution.
Oral administration of calcium folinate can yield good absorption. At 1.72 h ± 0.8h, serum reduced folic acid can reach peak; intramuscular injection could yield peak value at 0.71h ± 0.09 h. The t1/2 of serum reduced folic acid after intramuscular injection is 3.5 h. Regardless of oral or intramuscular injection, it can both be maintained 3~6h. After the effect of the liver and intestinal mucosa, this product is metabolized into 5-methyl tetrahydrofolate. Oral injection is more adequate then intramuscular metabolism. 80% to 90% is subject to renal excretion with a small amount being excreted with the feces.
Light yellow to yellow solid
Calcium folinate (CF) is a calcium salt of the calcium formyl tetrahydrofolate derivative, being the activated form of folic acid in the body. It is mainly used as the antidotes of the folic acid antagonist. For example, aminopterin, methotrexate, pyrimethamine and trimethoprim and other drugs can competitively inhibit the dihydrofolate reductase, making folic acid be not able to become tetrahydrofolic acid, leading to DNA synthesis disorders. Supplementation of calcium folinate can have detoxification effect and can treat folic acid-deficiency caused megaloblastic anemia, promote the differentiation, maturation and release of bone marrow hematopoietic cells. In recent years, a large number of experimental and clinical studies at home and abroad have fully proved that leucovorin can be used as a kind of highly efficient biochemical regulator, being able to significantly enhance the anti-tumor activity of the fluorouracil (5-FU) class drug. Fluorouracil is a kind of pyrimidine antagonist, being the major drugs for the treatment of gastrointestinal cancer, breast cancer, head and neck cancer, trophoblastic tumor and many other kinds of malignant tumors. Calcium folinate was easy to be absorbed by oral administration with the serum reduced folic acid reaching peak value at (1.72 ± 0.80) hours;
The time for reaching peak value is (0.71 ± 0.09) hours after intramuscular injection. Intramuscular injection of serum folic acid gives a half-life of 3.5 hours with the drugs effect being maintained for 3 to 6 hours. The metabolite product is 5-methyl tetrahydrofolate with 80% to 90% being subject to renal excretion.