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street name for lysergic acid diethylamide (同)back breaker, battery-acid, dose, dot, Elvis, loony toons, Lucy in the sky with diamonds, pane, superman, window pane, Zen
any of various water-soluble compounds having a sour taste and capable of turning litmus red and reacting with a base to form a salt
having the characteristics of an acid; "an acid reaction"
a drug that neutralizes or counteracts the effects of another drug
a muscle that relaxes while another contracts; "when bending the elbow the triceps are the antagonist"

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酸性の / 酸味のある,すっぱい(sour) / (言葉・態度などが)厳しい,しんらつな / 酸 / すっぱいもの / 《俗》=LSD
対立する人,敵対者,競争相手(opponent)

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/11/28 01:23:10」(JST)

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Dihydrofolate reductase (DHFR)

Folic acid

Antifolates are a class of antimetabolite medications that antagonise (that is, block) the actions of folic acid (vitamin B₉).^[1] Folic acid's primary function in the body is as a cofactor to various methyltransferases involved in serine, methionine, thymidine and purine biosynthesis. Consequently, antifolates inhibit cell division, DNA/RNA synthesis and repair and protein synthesis. Some such as proguanil, pyrimethamine and trimethoprim selectively inhibit folate's actions in microbial organisms such as bacteria, protozoa and fungi. The majority of antifolates work by inhibiting dihydrofolate reductase (DHFR).

Comparison of available agents

Drug	Class	Pharmacologic target	Myelosuppressive effect	US pregnancy category	Indications	Notable adverse effects
Methotrexate^[2]	Antineoplastic & immunosuppressant	Mammalian DHFR	+++	X	Malignancies (esp. haematologic malignancies and osteosarcoma), ectopic pregnancy and autoimmune conditions (esp. rheumatoid arthritis, psoriasis, Granulomatosis with polyangiitis, Goodpasture's syndrome, etc.)	Kidney or liver failure, Stevens-Johnson syndrome, toxic epidermal necrolysis, infection, aplastic anaemia, opportunistic infections and GI effects.
Pemetrexed^[3]	Antineoplastic	Mammalian DHFR, TS, GARFT	+++	D	Non-small cell lung carcinoma & mesothelioma	Nausea, vomiting, dyspnoea, constipation, chest pain, diarrhoea, weight loss, stomatitis, rash, fever, peripheral neuropathy, dehydration, kidney, Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme.
Proguanil^[4]	Antimalarial	Protozoal DHFR	+/-	C	Malaria, prevention and treatment	Abdominal pain, headaches, increased LFTs, myalgia, nausea, opportunistic infections, diarrhoea, vomiting, etc. Less commonly Stevens-Johnson syndrome, toxic epidermal necrolysis, agranulocytosis, liver failure, anaphylaxis, etc.
Pyrimethamine^[5]	Antiprotozoal	Protozoal DHFR	+/-	C	Malaria, toxoplasmosis and pneumocystis jiroveci pneumonia.	Stevens-Johnson syndrome, toxic epidermal necrolysis, agranulocytosis and aplastic anaemia.
Trimethoprim^[6]	Broad-spectrum antimicrobial	Microbial DHFR	+/-	C	Numerous (especially when in combination with the sulfonamide, sulfamethoxazole); treatment & prophylaxis for pneumocystis jiroveci pneumonia, malaria and toxoplasmosis. Treatment of melioidosis, shigellosis, listeria, urinary tract infections, acute infectious exacerbations of chronic bronchitis, infection prophylaxis in HIV-positive individuals, etc.	Stevens-Johnson syndrome, toxic epidermal necrolysis, agranulocytosis and aplastic anaemia.

Mechanism

Many are primarily DHFR inhibitors, but raltitrexed is an inhibitor of thymidylate synthase, and pemetrexed inhibits both and a third enzyme.

Antifolates act specifically during DNA and RNA synthesis, and thus are cytotoxic during the S-phase of the cell cycle. Thus, they have a greater toxic effect on rapidly dividing cells (such as malignant and myeloid cells, and GI & oral mucosa), which replicate their DNA more frequently, and thus inhibits the growth and proliferation of these non-cancerous cells as well as causing the side-effects listed.

Limitations

Side-effects

The antifolate action specifically targets the fast-dividing cells, and tend to have adverse effects on the bone marrow, skin, and hair. As folate is vital in the first trimester of pregnancy for healthy fetal development, the use of antifolates is strongly contraindicated in pregnancy and carries significant teratogenic risk.

Low doses of methotrexate can deplete folate stores and cause side-effects that are similar to folate deficiency. Both high-folate diets and supplemental folic acid may help reduce the toxic side-effects of low-dose methotrexate without decreasing its effectiveness.^[7]^[8] Anyone taking low-dose methotrexate for the health problems listed above should consult with a physician about the need for a folic acid supplement.

Resistance

While the role in folate as a cancer treatment is well established, its long-term effectiveness is diminished by cellular response. In response to decreased tetrahydrofolate (THF), the cell begins to transcribe more DHF reductase, the enzyme that reduces DHF to THF. Because methotrexate is a competitive inhibitor of DHF reductase, increased concentrations of DHF reductase can overcome the drugs inhibition.

Many new drugs are under development to reduce antifolate drug resistance.^[9]^[10]

Images

Folic acid
Methotrexate
Pemetrexed
Raltitrexed
Pralatrexate

References

^ "NCI: antifolate".
^ "Trexall, Rheumatrex (methotrexate) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 10 January 2014.
^ "Alimta (pemetrexed) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. 10 January 2014.
^ "Paludrine (proguanil) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 10 January 2014.
^ "Daraprim (pyrimethamine) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 12 January 2014.
^ "Primsol, Proloprim (trimethoprim) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 10 January 2014.
^ Morgan SL, Baggott JE, Alarcon GS (1997). "Methotrexate in rheumatoid arthritis: folate supplementation should always be given". BioDrugs. 8 (1): 164–75. doi:10.2165/00063030-199708030-00002. PMID 18020507.
^ Morgan SL, Baggott JE, Lee JY, Alarcon GS (1998). "Folic acid supplementation prevents deficient blood folate levels and hyperhomocysteinemia during long-term, low-dose methotrexate therapy for rheumatoid arthritis: Implications for cardiovascular disease prevention". Journal of Rheumatology. 25 (3): 441–6. PMID 9517760.
^ Takimoto CH (1996). "New Antifolates: Pharmacology and Clinical Applications". Oncologist. 1 (1 & 2): 68–81. PMID 10387971.
^ Gangjee A, Jain HD, Kurup S (September 2007). "Recent advances in classical and non-classical antifolates as antitumor and antiopportunistic infection agents: part I". Anticancer Agents Med Chem. 7 (5): 524–42. doi:10.2174/187152007781668724. PMID 17896913.

External links

Antifolates at the US National Library of Medicine Medical Subject Headings (MeSH)

UpToDate Contents

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1. ビタミンB12および葉酸欠乏症の病因および臨床症状 etiology and clinical manifestations of vitamin b12 and folate deficiency
2. 疾患予防におけるビタミン補給 vitamin supplementation in disease prevention
3. 妊娠中の葉酸補充 folic acid supplementation in pregnancy
4. ビタミンB12および葉酸欠乏症の診断および治療 diagnosis and treatment of vitamin b12 and folate deficiency
5. 炎症性腸疾患における栄養障害 nutrient deficiencies in inflammatory bowel disease

English Journal

Methotrexate-induced bone marrow adiposity is mitigated by folinic acid supplementation through the regulation of Wnt/β-catenin signalling.

Georgiou KR1, Nadhanan RR, Fan CM, Xian CJ.
Journal of cellular physiology.J Cell Physiol.2015 Mar;230(3):648-56. doi: 10.1002/jcp.24788.
Antimetabolite Methotrexate (MTX) is commonly used in childhood oncology. As a dihydrofolate reductase inhibitor it exerts its action through the reduction of cellular folate, thus its intensive use is associated with damage to soft tissues, bone marrow, and bone. In the clinic, MTX is administered
PMID 25187349

Methemoglobinemia as a complication of topical dapsone.

Swartzentruber GS, Yanta JH, Pizon AF.
The New England journal of medicine.N Engl J Med.2015 Jan 29;372(5):491-2. doi: 10.1056/NEJMc1408272#SA1.
PMID 25629756