Big Chemical Encyclopedia

Chemical substances, components, reactions, process design ...

Articles Figures Tables About

Folate folinic acid

Formyl H4-folate (folinic acid, leucovorin, citrovorum factor)... [Pg.71]

Methotrexate (MTX, chemical structure shown in Fig. 1.) competitively inhibits the dehyrofolate reductase, an enzyme that plays an essential role in purine synthesis. The dehydrofolate reductase regenerates reduced folates when thymidine monophosphate is formed from deoxyuridine monophosphate. Without reduced folates cells are unable to synthesize thymine. Administration of N-5 tetrahydrofolate or N-5 formyl-tetrahydrofolate (folinic acid) can bypass this block and rescue cells from methotrexate activity by serving as antidote. [Pg.147]

The folate antagonists, pyrimethamine and sulfadiazine, inhibit the parasite s DHFR/TS synthase enzyme complex and the DHPS, respectively (Fig. 4) (see antimalarial drugs). To avoid deficiency of folic acid in patients treated with antifolate antagonists, folinic acid supplementation is recommended to reduce bone-marrow suppression. [Pg.178]

TK), 5-FU is activated to 5-fluorodeoxyuridine monophosphate (5-FdUMP). Potent inhibition of thymidylate synthase (TS) by 5-FdUMP is considered critical for 5-FU cytotoxicity. TS catalyzes the rate-limiting step of DNA synthesis, such as the conversion of dUMP into dTMP. Optimal TS function requires the formation of a covalent ternary complex consisting of TS, the folate cofactor 5,10-methylenetetra-hydrofolate (CH2THF), and 5-FdUMP. Inadequate cellular levels of 5,10-methyle-netetrahydrofolate reduce the stability of the ternary complex and consequently the inhibition of TS by 5-FdUMP. For this reason, 5-FU is administered in association with folinic acid, a precursor of 5,10-methylenetetrahydrofolate [40]. [Pg.290]

Patients sustain convulsions and neurological deterioration. The urine contains low levels of the metabolites of serotonin, norepinephrine and dopamine. The reductase also plays a role in the maintenance of tetrahydrofolate levels in brain, and some patients have had low folate levels in the serum and CNS. Treatment has been attempted with tryptophan and carbidopa to improve serotonin homeostasis and with folinic acid to replete diminished stores of reduced folic acid. This therapy is sometimes effective. Diagnosis involves assay of DHPR in skin fibroblasts or amniotic cells. Phenylalanine hydroxylase activity is normal. [Pg.673]

Recently, Choy et al. also reported that LDHs are an efficient drug reservoir for folate derivatives [187]. Folic acid derivatives, folinic acid and methotrexate (MTX), have been successfully hybridized with Mg/Al LDHs by ion-exchange reactions. Cellular uptake tests with the MTX-LDH hybrids were carried out in the fibroblast (human tendon) and osteosarcoma (SaOS-2) cell lines by in vitro assay. They found that the LDH not only plays a role as a biocompatible delivery matrix for drugs but also facilitates a significant increase in the delivery efficiency. [Pg.210]

These are pyrimidine derivatives and are effective because of differences in susceptibility between the enzymes in humans and in the infective organism. Anticancer agents based on folic acid, e.g. methotrexate, inhibit dihydrofolate reductase, but they are less selective than the antimicrobial agents and rely on a stronger binding to the enzyme than the natural substrate has. They also block pyrimidine biosynthesis. Methotrexate treatment is potentially lethal to the patient, and is usually followed by rescue with folinic acid (A -formyl-tetrahydrofolic acid) to counteract the folate-antagonist action. The rationale is that folinic acid rescues normal cells more effectively than it does tumour cells. [Pg.455]

Folate deficiency can be dietary, especially in the eiderly, due to increased demand like in pregnancy, or due to maiabsorption syndromes. Agents which can cause folic acid deficiency with long-term use include phenytoin, oral contraceptives, isoniazid and glucocorticosteroids. In rare instances the use of dihydrofolate reductase inhibitors like trimethoprim, methotrexate or pyrimethamine can contribute to the occurrence of folate deficiency. Folinic acid can circumvent the need for the inhibited dihydrofolate reductase. [Pg.369]

Folic acid is used for the treatment of folate deficiency. Oral folic acid is usually the therapy of choice. For megaloblastic anemia doses of 5 mg daily for 4 months should be effective. Folinic acid is available in a parenteral formulation which may be indicated when oral therapy is not feasible and for rescue treatments following certain anti-cancer regimens. [Pg.369]

The adverse effects of methotrexate include gastrointestinal complaints, bone marrow suppression, alopecia and nephrotoxicity. The toxic effects of methotrexate may be terminated by administering the fully reduced folate coenzyme leucovorin (folinic acid). Leucovorin rescue permits the administration of high doses of methotrexate, for example in situations where partially resistance has occurred or to obtain cytotoxic concentrations of methotrexate in the CNS. [Pg.452]

Mechanism of Action A folate antagonist that blocks bacterial biosynthesis of nucleic acids and proteins by interfering with the metabolism of folinic acid. Therapeutic Effect Bacteriostatic. [Pg.1273]

Sulfadiazine in combination with pyrimethamine is first-line therapy for treatment of acute toxoplasmosis. The combination of sulfadiazine with pyrimethamine, a potent inhibitor of dihydrofolate reductase, is synergistic because these drugs block sequential steps in the folate synthetic pathway blockade (Figure 46-2). The dosage of sulfadiazine is 1 g four times daily, with pyrimethamine given as a 75-mg loading dose followed by a 25-mg once-daily dose. Folinic acid, 10 mg orally each day, should also be administered to minimize bone marrow suppression. [Pg.1033]

Ramaekers VT, Hausler M, Opladen T, Heimann G, Blau N (2002) Psychomotor retardation, spastic paraplegia, cerebellar ataxia and dyskinesia associated with low 5-methyltetrahydro-folate in cerebrospinal fluid a novel neurometabolic condition responding to folinic acid substitution. Neuropediatrics 33 301-308... [Pg.724]

Trimethoprim can produce the effects of folate deficiency, that is, megaloblastic anemia, leukopenia, and granulocytopenia. These reactions can be reversed by the simultaneous administration of folinic acid, which does not enter bacteria (see p. 379). [Pg.304]

Inhibition of nudeobase synthesis (2). Tet-rahydrofolic acid (THF) is required for the synthesis of both purine bases and thymidine. Formation of THF from folic acid involves dihydrofolate reductase (p. 274). The folate analogues aminopterin and methotrexate (amethopterin) inhibit enzyme activity. Cellular stores of THF are depleted. The effect of these antimetabolites can be reversed by administration of folinic acid (5-formyl-THF, leucovorin, citrovorum factor). Hydroxyurea (hydroxycarbamide) inhibits ribonucleotide reductase that normally converts ribonucleotides into deoxyribonucleotides subsequently used as DNA building blocks. [Pg.300]

At least nine fragile sites are present in human chromosomes. The fragility refers to chromosomal sites that break easily in the presence of certain compounds such as aphidocolin, methotrexate, and high doses of caffeine (Sutherland, 1979a, b). These sites are generally (GCC) stretches and in most cases are protected if folate, thymidine, or folinic acid is in the medium (Sutherland, 1979a, b,... [Pg.323]

Oral use of sulfonamides, pyrimethamine, and trimethoprim can canse blood dyscrasias such as hemolytic anemia, aplastic anemia, lenkopenia, and agran-nlocytosis. Becanse these blood changes are due to a drug-induced folic acid deficiency, administering folinic (not folic) acid can coimteract the toxicity. Use of folinic acid bypasses the need fc>r dihydrofolate reductase by supplying the fully reduced folate. [Pg.194]

Proguardl (t) 17 h) inhibits dihydrofolate reductase which converts folic to folinic acid, deficiency of which inhibits plasmodial cell division. Plasmodia, like most bacteria and unlike humans, cannot make use of preformed foUc acid. Pyrimethamine and trimethoprim, which share this mode of action, are collectively known as the antifols. Their plasmod-icidal action is markedly enhanced by combination with sulphonamides or sulphones because there is inhibition of sequential steps in folate synthesis (see Sulphonamide combinations, p. 231). [Pg.273]

Inhibition of the Reductase affects folate metabolism leading to decreased glycine formation from serine and decreased purine synthesis which requires CH3-THF. To facilitate normal cells folinic acid (Leucovorin) is given along with methotrexate. This acid aids normal cells by its conversion to the coenzyme of Thymidyiate S)mthetase, thus bypassing the block. Since the thymidine nucleotide requirements of rapidly proliferating cells are much greater than for quiescent cells folinic acid cannot meet the demands of the cancer cells. [Pg.385]

In a meta-analysis of 307 patients with rheumatoid arthritis from seven randomized clinical trials, of whom 147 took folate supplementation, hematological adverse effects were not significantly reduced in the folate group (8). However, there was a 79% reduction in mucosal and gastrointestinal adverse effects in patients taking folic acid and a non-significant trend toward a reduction (42%) in patients taking folinic acid. Disease activity was not modified by low doses of folate. Finally, the authors noted that folinic acid is more expensive. [Pg.2278]

Pancytopenia is a rare but potentially fatal complication, and numerous reports have been published. The characteristics and incidence of pancytopenia have been carefully re-evaluated from case reports and clinical trials published from 1980 to 1995 (38). Of 70 reported cases, 12 patients died (17%). Impaired renal function was the most important contributing factor (54%), particularly in fatal cases (10/12). Other important susceptibility factors included advanced age (over 65 years), hypoalbuminemia, concurrent infection, and/or concomitant multiple medications (particularly co-trimoxazole). The mean cumulative dosage was 675 (10-4800) mg, and the minimal cumulative methotrexate dose leading to fatal pancytopenia was 10 mg. This confirms that pancytopenia can occur at any time during treatment, even in the absence of known susceptibility factors. Bone marrow biopsy showed megaloblastosis and hypocellularity. Eosinophilia and increased mean corpuscular volume were rarely observed. In an overall review of five long-term prospective studies (511 patients), the calculated incidence of methotrexate-induced pancytopenia was 1.4%. Although severe myelo-suppression sometimes required folinic acid, there are as yet no data to determine whether prophylactic folate supplementation can reduce the incidence of pancytopenia. [Pg.2280]

It is estimated that the minimum daily requirement of folate is 5 micrograms/kg. Liver stores are about 160 micrograms in premature children, and 220 micrograms in full-term infants. Infants who require parenteral nutrition will rapidly become folate deficient unless fohc acid is included in the regimen. Since many multivitamin supplements do not contain folic acid, its inclusion should be ensured by the addition of folic or folinic acid. [Pg.2708]

Most interactions of trimethoprim and co-trimoxazole with other drugs are due to fohc acid antagonism. This may be more pronounced with co-trimoxazole than with either drug alone. Such interactions have previously been suspected with anticonvulsants, such as barbiturates, phe-nytoin, and primidone, which themselves produce folic acid deficiency and megaloblastic anemia (88). In order to circumvent the risk of folate deficiency, folic acid or folinic acid can be given. There is some concern that folate replacement may antagonize the desired antimicrobial effect, particularly in some protozoal parasites, but this concern has been debated (89). [Pg.3517]

Methotexate is an antineoplastic folic add analogue that blocks the conversion of dihydrofolate (FHj) to tetrahydro-folate (FH4) by binding to dihydrofolate reductase (DHFR) enzyme. Folate is essential for the normal synthesis of purines and pyrimidines, and therefore DNA and RNA. In order for folate to function as a cofactor, it must be reduced to FH by DHFR. Methotrexate binds to DHFR, prevents the conversion of FH2 to FH4, and, consequently, inhibits purine and pyrimidine synthesis. The antimetabolites are considered cell cycle specific, with most activity for cells in the S (synthesis) phase. With high-dose methotrexate, leucovorin rescue is often used to prevent severe toxicity to normal body tissues. Leucovorin (folinic acid) is a reduced form of folate (similar to FH ) that does not require the use of DHFR. Leucovorin is transported into healthy cells and is utilized for DNA and RNA synthesis. Tumor cells tend to have impaired transport mechanisms and usually cannot use leucovorin. Leucovorin is usually started within 24 to 36 hours of high-dose methotrexate administration and continues until methotrexate serum levels are below nontoxic levels (0.1 to 0.05 mol/L). [Pg.145]


See other pages where Folate folinic acid is mentioned: [Pg.154]    [Pg.178]    [Pg.1286]    [Pg.322]    [Pg.324]    [Pg.333]    [Pg.334]    [Pg.335]    [Pg.643]    [Pg.344]    [Pg.163]    [Pg.127]    [Pg.390]    [Pg.276]    [Pg.154]    [Pg.291]    [Pg.146]    [Pg.217]    [Pg.62]   
See also in sourсe #XX -- [ Pg.385 ]




SEARCH



Folate acid

Folin

Folinate

Folinates

Folinic acid

© 2024 chempedia.info