Drugs antifolate

In malaria chemotherapy, resistant parasites have significantly reduced the efficiency of classic antifolate drugs. In the search for novel inhibitors of... 

Antifolate Drugs or Glutamine Analogs Block Purine Nucleotide Biosynthesis... 

Several reactions of IMP biosynthesis require folate derivatives and glutamine. Consequently, antifolate drugs and glutamine analogs inhibit purine biosynthesis. 

Trimethoprim produces the predictable adverse effects of an antifolate drug, especially megaloblastic anemia, leukopenia, and granulocytopenia. The combination trimethoprim-sulfamethoxazole may cause all of the untoward reactions associated with sulfonamides. Nausea and vomiting, drug fever, vasculitis, renal damage, and central nervous system disturbances occasionally occur also. Patients with AIDS and pneumocystis pneumonia have a particularly high frequency of untoward reactions to trimethoprim-sulfamethoxazole, especially fever, rashes, leukopenia, diarrhea, elevations of hepatic aminotransferases, hyperkalemia, and hyponatremia. 

Trimethoprim produces the predictable adverse effects of an antifolate drug, especially megaloblastic anemia, leukopenia, and granulocytopenia. This can be prevented by the simultaneous administration of folinic acid, 6-8 mg/d. Use of folinic acid to prevent hematologic... 

The isolation of the gene coding for H. volcanii DHFR (Rosenshine et al, 1987) deserves special mention. As mentioned above, H. volcanii is very sensitive to the antifolate drug trimethoprim. Spontaneous resistant colonies arise at frequencies of 10 10-10 9. The molecular basis for the resistance in all the resistant mutants studied so far is... 

One of the most common infections in man is caused by the protozoan, Toxoplasma gondii, which is transmitted to humans when they consume raw or inadequately cooked, infected meat. Infected pregnant women can transmit the organism to the fetus. Cats are the only animals that shed oocysts that can infect other animals as well as man. The treatment of choice for this condition is the antifolate drug, pyrimethamine [peer i METH a meen] (see p. 353). A combination of sulfadiazine (see p. 289) and pyrimethamine is also efficacious. Leucovorin is often administered to protect against folate deficiency. Other inhibitors of folate biosynthesis, such as trimethoprim (see p. 293) and sulfamethoxazole (see p. 289) are without therapeutic efficacy in toxoplasmosis. [Note At the first appearance of a rash, pyrimethamine should be discontinued since hypersensitivity to this drug can be severe.]... 

Folate (pteroylglutamic acid) is essential for the synthesis and methylation of DNA during fetal and early postnatal development (Nunn et al., 1986). Folate deficiency may result from poor diet, malabsorption, from treatment with anticonvulsant drugs such as phenytoin or primidone, as well as from antifolate drugs such as methotrexate. Folate deficiency during pregnancy leads to an increased prevalence of fetal malformations such as spina bifida and related neural tube defects. Findings... 

The benefits are reduced joint pain, swelling and stiffness, and less joint damage in the long term. The principal mechanism which is important in achieving these results is not rmderstood with certainty for any of the DMARDs, although some actions are known, e.g. methotrexate and sulpha-salazine are primarily antifolate drugs, whilst ciclo-sporin affects T-cell function. 

Computational Chemistry Studies of Antifolate Drugs for Treatment of Pneumocystis carinii Pneumonia (PCP) in AIDS Patients Trimetrexate and Analogues. ... 

Folinic acid is a reduced form of folic acid. The adverse effects of antifolate drugs that are tetrahydrofolate reductase inhibitors, such as methotrexate, cannot be prevented by giving folic acid, since antifolate drugs inhibit the conversion of foUc acid to folinic acid. Folinic acid is therefore given instead, as calcium folinate (leucovorin). Flowever, in patients who take antifolate drugs intermittently (for example methotrexate once a week in psoriasis or rheumatoid arthritis) folic acid taken on another day is adequate. 

Purines, pyrimidines and their nucleosides and nucleoside triphosphates are synthesized in the cytoplasm. At this stage the antifolate drugs (sulphonamides and dihydrofolate reductase inhibitors) act by interfering with the synthesis and recycling of the co-factor dihydrofolic acid (DHF). Thymidylic acid (2-deoxy-thymidine monophosphate, dTMP) is an essential nucleotide precursor of DNA synthesis. It is produced by the enzyme thymidylate synthetase by transfer of a methyl group from tetrahydrofolic acid (THF) to the uracil base on uridylic acid (2-deoxyuridine monophosphate, dUMP) (Fig. 12.5). THF is converted to DHF in this process and must be reverted to THF by the enzyme dihydrofolate reductase (DHFR) before... 

Dietary folates must be chemically reduced to their tetrahy-dro forms, with four hydrogens on the pteridine ring, to be active. The enzyme responsible for this reduction is dihydrofolate reductase (DHFR), a key enzyme whose actions are inhibited by methotrexate and other antifolates. The result of this inhibition is depletion of intracellular pools of reduced folates (tetrahydrofolates) essential for thymidylate and purine synthesis. Lack of either thymidine or purines prevents synthesis of DNA. The DHFR-mediated effects of antifolate drugs on normal and probably also on cancerous cells may be neutralized by supplying reduced folates exogenously. The reduced folate used clinically for rescue is leucovorin (folinic acid), which bypasses the metabolic block induced by DHFR inhibitors. ... 

Methotrexate One of a number of antifolate drugs. Methotrexate is an analog of folate which competitively inhibits dihydrofolate reductase. Since a plentiful supply of THF is required for ongoing synthesis of the pyrimidine nucleotide thymidylate, synthesis of this nucleotide is inhibited resulting in decreased DNA synthesis. 

Yang PM et al (2010) Inhibition of histone deacetylase activity is a novel function of the antifolate drug methotrexate. Biochem Biophys Res Commun 391(3) 1396-1399... 

Wang, P., Wang, Q., Aspinall, T. V., Sims, P. F., and Hyde, J. E. (2004b). Transfection studies to explore essential folate metabolism and antifolate drug synergy in the human malaria parasite Plasmodium falciparum. Mol. Microbiol. 51,1425-1438. 

What are called antifolate drugs pertain in general to blocking the biosynthesis of purines and pyrimidines, the heterocyclic bases used in the further synthesis of DNA and RNA, where folic acid is required as a coenzyme (or vitamin) for the enzyme dihydrofolate reductase. The previously mentioned compound called methotrexate or amethopterin (4-amino-A °-methyl folic acid), being a structural analog of folate or folic acid, locks up the enzyme dihydrofolate reductase, which in turn blocks the synthesis of a thymidine nucleotide necessary for cell division. 

Surprisingly, a method of antifolate resistance commonly cited in tumor cells is gene amplification resulting in increased target protein and decreased anti-folate efficacy, which has yet to be identified in any clinically relevant isolate. A further difference in antifolate resistance between mammalian cells and the parasitic cell is altered polyglutamation of die antifolate drugs. In mammalian cells, folates are taken up by a folate transport system and once inside the cell are poly-glutamated to trap the folates intracellularly. A reported mechanism of resistance in the cancer cell is the loss of... 

Antifolates are important in the treatment of cancer and infectious diseases. Discuss mechanisms of antifolate drug resistance in cancer and malaria. 

Studies of the binding of antifolate drugs to the enzyme dihydrofolate reductase (DHFR) carried out by Feeney and Roberts and their colleagues at the National Institute for Medical Research (Mill Hill) provide examples of a diverse range of NMR applications. 

Sulfonamides or sulfones usually account for most toxicity associated with coadministration of these antifolate drugs (see Chapter 43). The combination of pyrimethamine (25 mg) and sulfa-doxine (500 mg) (fansidar) causes severe and even fatal cutaneous reactions in up to 1 in 5000 people. This combination also has been associated with serum sickness-type reactions, urticaria, exfoliative dermatitis, and hepatitis. Pyrimethamine-sulfadoxine is contraindicated in individuals with previous reactions to sulfonamides, lactating mothers, and infants <2 months of age. Administration of pyrimethamine with dapsone (MALOPRIM, unavailable in the U.S.), occasionally has been associated with agranulocytosis. Higher doses pyrimethamine (75 mg daily) used along... 

Fisher C L, V A Roberts and A T Hagler 1991. Influence of Environment on the Antifolate Drug Trimethoprim Energy Minimization Studies Biochemistry 30 3518-3526... 

C. Pharmacodynamics Folic acid is converted to tetrahydrofolate by the action of dihydrofolate reductase (Figure 33-2, reaction 3). One important set of reactions involving tetrahydrofolate and dihydrofolate constitutes the dTMP cycle (Figure 33-2, reaction 2), which supplies the dTMP required for DNA synthesis. Rapidly dividing cells, in which DNA must be rapidly synthesized, are highly sensitive to folic acid deficiency. For this reason, antifolate drugs are useful in the treatment of various infections and cancers. 

Describe the mechanisms of antibacterial action of sulfonamides and trimethoprim on bacterial folic acid synthesis and the mechanisms involved in bacterial resistance to the antifolate drugs. 

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