Antagonists folate

Folate antagonists (eg, methotrexate and certain antiepileptics) are used ia treatment for various diseases, but their adininistration can lead to a functional folate deficiency. Folate utilization can be impaired by a depletion of ziac (see Zinc compounds). In humans, the intestinal bmsh border folate conjugase is a ziac metaHoenzyme (72). One study iadicates that the substantial consumption of alcohol, when combiaed with an iaadequate iatake of folate and methionine, may iacrease the risk of colon cancer (73). Based on this study, it is recommended to avoid excess alcohol consumption and iacrease folate iatake to lower the risk of colon cancer. 

Folate antagonists Methotrexate Ralitrexed Pemetrexed (alimta)... 

Antimetabolites interfere with normal metabolic pathways. They can be grouped into folate antagonists and analogues of purine or pyrimidine bases. Their action is limited to the S-phase of the cell cycle and therefore they target a smaller fraction of cells as compared with alkylating agents. 

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. 

The synthesis of pyrido[2,3-d]pyrimidines has attracted considerable interest in heterocyclic chemistry. This ring system constitutes a deaza-analogue of the pyrazino[2,3-d]pyrimidine heterocychc core of fohc acid, analogues which can exhibit a wide range of biological properties as folate antagonists. Thus, the synthesis of this motif by MCR imder microwave-assisted conditions has the potential to rapidly introduce diversity into a biologically relevant scaffold. 

Drug efficacy is directly related to its intracellular concentration level, so it is necessary to evaluate the MTX concentration in cells. In particular, MTX is a folate antagonist, thus it binds to dihydrofolate reductase in competition with folate [71-77]. A low intracellular level of MTX caused by high efflux and low uptake in resistant cells is also the main disadvantage of MTX medication [78,79]. This leads to a high dosage of MTX for cancer treatment, which is also directly associated with adverse effects. 

Cephalexin is considered safe and effective. Nitrofurantoin should not be used after week 37 due to concern for hemolytic anemia in the newborn. Sulfa-containing drugs may increase risk for kernicterus in the newborn and should be avoided during the last weeks of gestation. Folate antagonists, such as trimethoprim, are relatively contraindicated during the first trimester because of their association with cardiovascular malformations. Fluoroquinolones and tetracyclines are contraindicated. 

E. A. Pastore, Proton magnetic resonance studies of folate and folate antagonists. In Folate Antagonists as Chemotherapeutic Agents, Ann. N.Y. Acad. Sci. 186, 43 (1971). 

Q7 has an increased risk of neonatal haemolysis during the third trimester Q8 may cause vestibular or auditory nerve damage Q9 should be stopped at least 2 days before delivery Q10 consists of a folate antagonist that poses a teratogenic risk... 

Co-trimoxazole is a folate antagonist and should be avoided in the first and the third trimesters of pregnancy. In the third trimester there is an increased risk of neonatal haemolysis and methaemoglobinaemia, whereas in the first trimester there is a teratogenic risk caused by the trimethoprim (folate antagonist) component. 

Vincristine has been shown to enhance the accumulation of the folate antagonist methotrexate in murine leukemia cells, and the enhancement has been shown to involve inhibition of a specific efflux route for methotrexate (25) the suggestion has been made that the effect of vincristine on methotrexate efflux may be related to alterations of cell membrane electrical activity that appear to occur when cells are treated with vincristine. In this connection, it is worth mentioning that association of tubulin with membrane structures from bovine brain has been described 25a). Both vinblastine and vincristine have been reported to enhance the accumulation of the folate antagonist methotrexate in human leukemic cells (S) there is no evidence, however, to indicate that this interaction has significance in a clinical setting. 

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. 

Pharmacology Trimetrexate, a 2.4-diaminoquinazoline, nonclassical folate antagonist, is a synthetic inhibitor of the enzyme dihydrofolate reductase. The end result is disruption of DNA, RNA, and protein synthesis, with consequent cell death. Pharmacokinetics Clearance was 38 15 ml /min/m and volume of distribution at steady state (Vdgs) was 20 8 L/m. The plasma concentration time profile declined... 

Trimethoprim (TMP)-Sulfamethmazole (SMX) [Co-Trimoxazole] (Bactrim, Septra) [Antibiotic/Folate Antagonist] Uses un Rx prophylaxis, otitis media, sinusitis, bronchitis Action SMX T synth of dihydro-folic acid TMP T dihydrofolate reductase to impair protein synth Dose Adul. 1 DS tab PO bid or 5-20 mg/kg/24 h (based on TMP) IV in 3-4 doses P. jiroveci ... 

Many drugs interact with folate to affect its absorption, antagonize its biochemical activity, or increase its loss from the body. These drugs include ethanol, phenytoin, and oral contraceptives. Salicylates can compete with foUc acid for plasma protein binding. Methotrexate, a cytotoxic agent, is a folate antagonist that inhibits the biosynthesis of this coenzyme. 

Mecfianism of Action A sulfonamide and folate antagonist that blocks bacterial synthesis of essential nucleic acids. Therapeutic Effect Bactericidal in susceptible microorganisms. 

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. 

Mechanism of Action A folate antagonist that inhibits the enzyme dihydrofolate reductase (DHFR). Therapeutic Effect Disrupts purine, DNA, RNA, protein synthesis,... 

Folate antagonists Purine antimetabolites Pyrimidine antimetabolites... 

The pivotal role of folates in purine synthesis and consequently cell growth has been addressed earlier, as has the use of folate antagonists as cytotoxic agents. 

Methotrexate (53-6), one of the first modified pteridines investigated as a folate antagonist, is still used quite extensively in the chemotherapy of cancer and to a minor extent in other indications calling for cytotoxic agents. 

The main folate antagonist is methotrexate, an analogue of folic acid. Methotrexate competitively inhibits dihydrofolate reductase, the enzyme responsible for the synthesis of purine and pyramidine from folic acid. Trimetrexate, a methotrexate analogue, is useful in treating methotrexate-resistant tumours. It is also used to treat Pneumocystis carinii infections. Methotrexate is usually given orally, but may also be given intravenously or intrathecally. In addition to its use in cancer therapy, it is used in the treatment of psoriasis. Methotrexate can cause an obstructive nephropathy due to its precipitation in the renal calyx. 

Trimethoprim- sulfamethoxazole Synergistic combination of folate antagonists blocks purine production and nucleic acid synthesis Bactericidal activity against susceptible bacteria Urinary tract infections Pneumocystis jiroveci pneumonia toxoplasmosis nocardiosis Oral, IV renal clearance (half-life 8 h) dosed every 8-12 h t formulated in a 5 1 ratio of sulfamethoxazole to trimethoprim Toxicity Rash, fever, bone marrow suppression, hyperkalemia... 

Sulfadoxine-pyrimethamine (Fansidar) Folate antagonist combination Treatment of infections with some chloroquine-resistant P falciparum, including combination with artesunate intermittent preventive therapy in endemic areas... 

Atovaquone-proguanil (Malarone) Quinone-folate antagonist combination Treatment and chemoprophylaxis of P falciparum infection... 

In many areas, resistance to folate antagonists and sulfonamides is common for P falciparum and less common for P vlvax. Resistance is due primarily to mutations in dihydrofolate reductase and dihydropteroate synthase, with increasing numbers of mutations leading to increasing levels of resistance. At present, resistance seriously limits the efficacy of sulfadoxine-pyrimethamine (Fansidar) for the treatment of malaria in most areas, but in Africa most parasites exhibit only moderate resistance, such that antifolates appear to continue to offer preventive efficacy against malaria. Because different mutations may mediate resistance to different agents, cross-resistance is not uniformly seen. 

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