ピリメタミン
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出典(authority):フリー百科事典『ウィキペディア(Wikipedia)』「2014/01/21 19:46:47」(JST)
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Pyrimethamine
|
Systematic (IUPAC) name |
5-(4-chlorophenyl)-6-ethyl- 2,4-pyrimidinediamine |
Clinical data |
Trade names |
Daraprim |
AHFS/Drugs.com |
monograph |
MedlinePlus |
a601050 |
Pregnancy cat. |
B3 (AU) C (US) |
Legal status |
℞ Prescription only |
Routes |
Oral |
Pharmacokinetic data |
Bioavailability |
well-absorbed |
Protein binding |
87% |
Metabolism |
Hepatic |
Half-life |
96 hours |
Excretion |
Renal |
Identifiers |
CAS number |
58-14-0 Y |
ATC code |
P01BD01
QP51AX51 (combinations) |
PubChem |
CID 4993 |
DrugBank |
DB00205 |
ChemSpider |
4819 Y |
UNII |
Z3614QOX8W Y |
KEGG |
D00488 Y |
ChEBI |
CHEBI:8673 Y |
ChEMBL |
CHEMBL36 Y |
Chemical data |
Formula |
C12H13ClN4 |
Mol. mass |
248.71 g/mol |
SMILES
- Clc2ccc(c1c(nc(nc1CC)N)N)cc2
|
InChI
-
InChI=1S/C12H13ClN4/c1-2-9-10(11(14)17-12(15)16-9)7-3-5-8(13)6-4-7/h3-6H,2H2,1H3,(H4,14,15,16,17) Y
Key:WKSAUQYGYAYLPV-UHFFFAOYSA-N Y
|
Y (what is this?) (verify) |
Pyrimethamine (trade name Daraprim) is a medication used for protozoal infections. It is commonly used as an antimalarial drug (for both treatment and prevention of malaria), and is also used (combined with sulfadiazine) in the treatment of Toxoplasma gondii infections in immunocompromised patients, such as HIV-positive individuals. It is also currently being evaluated[1] in clinical trials as a treatment for ALS. In 2011, researchers have discovered that Pyrimethamine can increase ß-hexosaminidase activity, thus slowing down the progression of Late-Onset Tay–Sachs disease.
Contents
- 1 Mechanism of action
- 2 Mechanism of resistance
- 3 Clinical use
- 4 Use in mass drug administrations
- 5 Contraindications
- 6 Notes
- 7 References
Mechanism of action[edit]
Pyrimethamine interferes with tetrahydrofolic acid synthesis from folic acid by inhibiting the enzyme dihydrofolate reductase (DHFR). Tetrahydrofolic acid is needed for DNA and RNA synthesis in many species, including protozoa. It has also found to inhibit SOD1, a key protein involved in ALS.
Mechanism of resistance[edit]
Resistance to pyrimethamine is widespread. Mutations in the malarial gene for dihydrofolate reductase may reduce the effectiveness of pyrimethamine.[2] These mutations decrease the binding affinity between pyrimethamine and dihydrofolate reductase via loss of hydrogen bonds and steric interactions.[3]
Clinical use[edit]
Pyrimethamine is typically given with a sulfonamide and folinic acid:
- sulfonamides inhibit dihydropteroate synthetase, an enzyme that participates in folic acid synthesis from para-aminobenzoic acid. Hence, sulfonamides work synergistically[citation needed] with pyrimethamine by blocking a different enzyme needed for folic acid synthesis.
- folinic acid (leucovorin) is a folic acid derivative that is converted to tetrahydrofolate (the primary active form of folic acid) in vivo without relying on dihydrofolate reductase. By doing so, folinic acid reduces side effects related to folate deficiency.
Use in mass drug administrations[edit]
Pyrimethamine has been extensively used as monotherapy in mass drug administrations in Asia and South America, which is likely to have contributed to the emergence and spread of pyrimethamine-resistant Plasmodium falciparum strains.
Side effects[edit]
Pyrimethamine may deplete folic acid in humans, resulting in hematologic side effects associated with folate deficiency.
Side effects include:
- hypersensitivity reactions
- megaloblastic anemia
- leukopenia
- thrombocytopenia
- pancytopenia
- atrophic glossitis
- hematuria
- cardiac arrhythmias
- pulmonary eosinophilia (rare)
- hyperphenylalaninemia (particularly when used with a sulfonamide)
- Stevens–Johnson syndrome (particularly when used with a sulfonamide)
- toxic epidermal necrolysis (particularly when used with a sulfonamide)
Contraindications[edit]
Pyrimethamine is contraindicated in patients with:
- hypersensitivity to pyrimethamine
- megaloblastic anemia – depletion of folic acid may aggravate this condition
Notes[edit]
- ^ "Pyrimethamine ALS trial".
- ^ Gatton M.L. et al. (2004). "Evolution of resistance to sulfadoxine-pyrimethamine in Plasmodium falciparum". Antimicrob Agents Chemother 48 (6): 2116–23. doi:10.1128/AAC.48.6.2116-2123.2004. PMC 415611. PMID 15155209.
- ^ Sirichaiwat C. et al. (2004). "Target guided synthesis of 5-benzyl-2,4-diamonopyrimidines: their antimalarial activities and binding affinities to wild type and mutant dihydrofolate reductases from Plasmodium falciparum". J Med Chem 47 (2): 345–54. doi:10.1021/jm0303352. PMID 14711307.
References[edit]
- Daraprim – Package insert (PDF file)
- Fansidar – sulfadoxine and pyrimethamine
Antiparasitics – antiprotozoal agents – Chromalveolate antiparasitics (P01)
|
|
Alveo-
late |
Apicom-
plexa |
Conoidasida/
(Coccidiostats) |
Cryptosporidiosis |
|
|
Isosporiasis |
- trimethoprim/sulfamethoxazole#
|
|
Toxoplasmosis |
- pyrimethamine
- sulfadiazine
|
|
|
Aconoidasida |
Malaria |
Individual
agents |
Hemozoin
inhibitors |
aminoquinolines |
- (4-): amodiaquine#
- chloroquine#
- (8-): primaquine#
- pamaquine
|
|
4-methanolquinolines |
- mefloquine#
- quinine#
- quinidine
|
|
Other |
|
|
|
Antifolates |
DHFR inhibitors
(antifols) |
- proguanil#
- chlorproguanil
|
|
Sulfonamides |
- sulfadoxine
- sulfamethoxypyrazine
|
|
Coformulation |
- sulfadoxine/pyrimethamine (SP)#
|
|
|
Sesquiterpene
lactones |
- artemether#
- artesunate#
- dihydroartemisinin
- artemotil
- artemisinin
|
|
Other |
- atovaquone (with proguanil as Malarone)
- tetracycline
- doxycycline#
- clindamycin
- pyronaridine
- piperaquine
|
|
|
Combi-
nations |
Fixed-dose (coformulated) ACTs |
- artemether/lumefantrine#
- artesunate/amodiaquine (ASAQ)
- artesunate/mefloquine (ASMQ)
- dihydroartemisinin/piperaquine
- artesunate/pyronaridine
|
|
Other combinations
(not co-formulated) |
- artesunate/SP
- artesunate/mefloquine
- quinine/tetracycline
- quinine/doxycycline
- quinine/clindamycin
|
|
|
|
Babesiosis |
|
|
|
|
Cilio-
phora |
- Balantidiasis: Tetracycline
|
|
|
Hetero-
kont |
- Blastocystosis: Metronidazole
|
|
- #WHO-EM
- ‡Withdrawn from market
- Clinical trials:
- †Phase III
- §Never to phase III
|
|
UpToDate Contents
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English Journal
- Capillary zone electrophoresis as a potential technique for the simultaneous determination of sulfadoxine and pyrimethamine in tablet formulations.
- Amin NC, Blanchin MD, Aké M, Fabre H.SourceLaboratoire de Chimie Analytique, Contrôle physico-chimique des médicaments, Institut des Biomolécules Max Mousseron, UMR 5247, Faculté de Pharmacie, BP 14491, 34093 Montpelier, France; Université de Cocody, UFR Sciences Pharmaceutiques, Laboratoire de Chimie analytique, chimie minérale et chimie générale, BPV 34 Abidjan, Côte d'Ivoire.
- Journal of pharmaceutical and biomedical analysis.J Pharm Biomed Anal.2012 Jan 25;58:168-71. Epub 2011 Oct 1.
- A novel, simple and rapid capillary zone electrophoresis method with UV detection has been developed for the simultaneous determination of pyrimethamine and sulfadoxine in tablet formulations. The compounds are separated in 6min in a fused silica capillary, 30cm long (20cm to detector)×50μm using
- PMID 22014652
- Molecular monitoring of Plasmodium falciparum resistance to antimalarial drugs after adoption of sulfadoxine-pyrimethamine plus artesunate as the first line treatment in Iran.
- Afsharpad M, Zakeri S, Pirahmadi S, Djadid ND.SourceMalaria and Vector Research Group (MVRG), Biotechnology Research Center (BRC), Pasteur Institute of Iran, Pasteur Avenue, PO Box 1316943551, Tehran, Iran.
- Acta tropica.Acta Trop.2012 Jan;121(1):13-8. Epub 2011 Oct 2.
- The main objective of this investigation was whether the combination therapy of sulfadoxine pyrimethamine (SP) plus artesunate (AS) protects against the spread of resistance to SP in malaria-endemic south-eastern Iran. Infected blood samples of Plasmodium falciparum (n=170) were collected during 200
- PMID 22001304
Japanese Journal
- Plasmodium falciparum: differential selection of drug resistance alleles in contiguous urban and peri-urban areas of Brazzaville, Republic of Congo.
- Tsumori Yoko,Ndounga Mathieu,Sunahara Toshihiko,Hayashida Nozomi,Inoue Megumi,Nakazawa Shusuke,Casimiro Prisca,Isozumi Rie,Uemura Haruki,Tanabe Kazuyuki,Kaneko Osamu,Culleton Richard
- PLoS One 6(8), e23430, 2011-08-15
- … Mutations known to be associated with resistance to the antimalarial drugs chloroquine and pyrimethamine were determined by sequencing the relevant portions of the crt and dhfr genes, respectively. … Crucially, we found that the frequencies of genetic markers of drug resistance against pyrimethamine and chloroquine differed significantly between the sites, indicative of differing selection pressures in the two areas. …
- NAID 120003457273
- Disruption of multidrug and toxin extrusion MATE1 potentiates cisplatin-induced nephrotoxicity.
- Nakamura Takanori,Yonezawa Atsushi,Hashimoto Shinya,Katsura Toshiya,Inui Ken-Ichi
- Biochemical pharmacology 80(11), 1762-1767, 2010-12-01
- … Furthermore, the combination of a selective MATE inhibitor, pyrimethamine, with cisplatin also elevated creatinine and BUN levels compared to cisplatin alone. …
- NAID 120002619612
Related Links
- Sulfadoxine / Pyrimethamine [SP] スルファドキシン/ピリメタミン, 抗マラリア薬 1. 商品名 先発品 ファンシダール錠 【中外製薬】 2. 日本における発売年 1987(昭和62)年 3. 特長 マラリア原虫の葉酸代謝経路を2重ブロックして,相乗的 に ...
- Easy to read patient leaflet for pyrimethamine. Includes indications, proper use, special instructions, precautions, and possible side effects. ... If OVERDOSE is suspected: Contact 1-800-222-1222 (the American Association of ...
Related Pictures
★リンクテーブル★
[★]
- ☆case33 頭痛と混乱
- ■glossary
- accompany
- vt.
- (人)と同行する、(人)に随行する。(もの)に付随する。~と同時に起こる。~に加える(添える、同封する)(with)
- slurred n. 不明瞭
- 強直間代痙攣 tonic-clonic convulsion
- 意識消失とともに全身の随意筋に強直痙攣が生じ(強直痙攣期tonic convulsion)、次いで全身の筋の強直と弛緩とが律動的に繰り返される時期(間代痙攣期clonic convulsion)を経て、発作後もうろう状態を呈する一連の発作。
- ■症例
- 28歳、女性 黒人 南アフリカ 手術室看護師 ロンドン住在
- 主訴:頭痛と混乱
- 現病歴:過去3週間で頭痛が続いており、ひどくなってきた。現在も頭痛が持続しており、頭全体が痛い。友人曰く「過去六ヶ月で体重が10kg減っていて、最近、混乱してきたようだ」。発話は不明瞭。救急室にいる間に強直間代痙攣を起こした。
- ・診察 examination
- やせている。55kg。38.5℃。口腔カンジダ症(oral candidiasis)。リンパ節腫脹無し。心血管、呼吸器系、消化器系正常。痙攣前における神経検査では時間、場所、人の見当識無し。神経局所症状無し(no focal neurological sign)。眼底両側に乳頭浮腫有り。
- ・検査 investigation
- 血算:白血球増多
- 血液生化学:ナトリウム低下
- CT:供覧
- ■キーワード&着目するポイント
- ・口腔カンジダ症(oral candidiasis)
- ・頭痛、精神症状、強直間代痙攣
- ・眼底両側に乳頭浮腫
- ・CT所見
- ・低ナトリウム血症は二次的なもの
- ■アプローチ
- ・口腔カンジダ症(oral candidiasis) → 細胞免疫低下状態(DM、免疫抑制、AIDSなど) or 常在細菌叢の攪乱(長期の抗菌薬の使用)
- ・The occurrence of thrush in a young, otherwise healthy-appearing person should prompt an investigation for underlying HIV infection.(HIM.1254)
- ・More commonly, thrush is seen as a nonspecific manifestation of severe debilitating illness.(HIM.1254)
- ・精神症状、強直間代痙攣 → 一次的、あるいは二次的な脳の疾患がありそう
- ・頭痛 → 漠然としていて絞れないが、他の症状からして機能性頭痛ではなく症候性頭痛っぽい。
- ・眼底両側に乳頭浮腫 → 脳圧亢進の徴候 → 原因は・・・脳腫瘍、ことにテント下腫瘍と側頭葉の腫瘍、クモ膜下出血、脳水腫など、そのほか、眼窩内病変、低眼圧などの局所的要因、悪性高血圧、血液疾患、大量出血、肺気腫などの全身的要因 (vindicate本のp342も参考になる)
- ・頭痛と脳圧亢進 → 頭蓋内圧占拠性病変、脳炎(IMD.274)
- ・CT所見 → ringformの病変、脳浮腫、脳圧亢進
- ・低ナトリウム血症 → 脳ヘルニアに続発して起こることがあるらしい。実際には下垂体にトキソプラズマによる病変が形成されることにより起こりうる。
- ・そのほか出身地、体重減少もHIVを疑わせる点
- パターン認識でHIV + 精神症状 + てんかん発作(強直間代痙攣) + 脳圧亢進 + CT所見 = 一番ありそうなのはToxoplasma gondiiによるトキソプラズマ脳症 cerebral toxoplasosis (トキソプラズマ脳炎 toxoplasmic encephalitis)
- ■Toxoplasma gondii
- 原虫 胞子原虫類
- (感染予防学 080521のプリント、CASES p,92、HIM p.1305-)
- ・疫学:西洋では30-80%の成人がトキソプラズマの感染の既往がある・・・うぇ(CASES)。日本では10%前後(Wikipedia)。
- ・生活環
- ・終宿主:ネコ:ネコの小腸上皮細胞で有性・無性生殖 糞便にオーシストの排泄
- ・中間宿主:ヒト.ブタを含むほ乳類と鳥類:無性生殖で増殖、シストの形成
- 急性期の増殖盛んな急増虫体tachyzoiteとシスト内の緩増虫体bradyzoite
- ・病原、病因 phathogenesis
- ・緩増虫体(bradyzoite)、接合子嚢(oocyst)
- ・感染経路
- 1. オーシストの経口摂取
- 2. 中間宿主の生肉中のシストの経口摂取
- 3. 初感染妊婦からの経胎盤感染。既感染なら胎盤感染しないらしい(HIM.1306)
- (4)移植臓器、輸血。確率は低い(at low rate)(HIM.1306)
- ・病態
- 1. 先天性トキソプラズマ症 congenital toxoplasmosis
- ①網脈絡膜炎、 ②水頭症、 ③脳内石灰化、 ④精神・運動障害
- 2. 後天性トキソプラズマ症 acquired toxoplasmosis
- (1) 健常者
- ・多くは不顕性感染。発熱、リンパ節腫脹、皮疹(rash)
- ・(少数例)筋肉痛、暈疼痛、腹痛、斑状丘疹状皮疹(maculopapular rash)、脳脊髄炎、混乱(HIM.1308)
- ・(まれ)肺炎、心筋炎、脳症、心膜炎、多発筋炎
- ・網膜、脈絡叢に瘢痕や、脳に小さい炎症性の病変を残すことあり(CASES)。
- ・急性感染の症状は数週間で消失 筋肉や中枢神経系に緩増虫体が残存
- (2)HIV感染者、臓器移植例、がん化学療法例
- シスト内緩増虫体→急増虫体→播種性の多臓器感染
- AIDSでは、トキソプラズマ性脳炎が指標疾患 AIDS-defineing illness(CASES)
- ・治療
- (日本)アセチルスピラマイシン、ファンシダール(感染予防学 080521)
- ■トキソプラズマ脳炎 toxoplasmic encephalitis、トキソプラズマ脳症 cerebral toxoplasosis
- ・症状
- 発熱、頭痛、混乱m、痙攣、認知の障害、局所神経徴候(不全片麻痺、歯垢、脳神経損傷、視野欠損、感覚喪失)(CASES)
- ・画像検査
- (CT,MRI)多発性、両側性、ring-enhancing lesion、特に灰白質-白質境界、大脳基底核、脳幹、小脳が冒されやすい(CASES)
- ・鑑別診断(臨床症状・画像診断の所見で)
- リンパ腫、結核、転移性脳腫瘍(CASES)
- ・病歴と画像所見からの鑑別診断
- リンパ腫、結核、転移性腫瘍
- ?
- このCTがcerebral toxoplasmosisに特徴的かは不明
- □最後に残る疑問
- AIDSでWBC(leukocyte)の数はどうなるんだろう???AIDSの初診患者ではWBCが低い人が多いらしいし()、HIVはCD4+ T cellとmacrophageに感染して殺すから、これによってB cellは減るだろうし、CD8+ T cellも若干減少するだろうからWBCは減るんじゃないか?!好中球はAIDSとは関係ない?好中球は他の感染症に反応性に増加している?ちなみに、好酸球は寄生虫(原虫)の感染のために増える傾向にあるらしい(HIMのどこか)。
- スルファジアジン
- sulfadiazine
- ピリメタミン
- pyrimethamine
- 葉酸拮抗剤である。
- サルファ剤と併用され、抗トキソプラズマ薬、抗ニューモシチス・カリニ薬として相乗的に働く。
- ST合剤
- SMX-TMP
- スルファメトキサゾール・トリメトプリム合剤 sulfamethoxazole and trimethoprim mixture
- □AIDSの定義(http://en.wikipedia.org/wiki/CDC_Classification_System_for_HIV_Infection_in_Adults_and_Adolescents)
- A CD4+ T-cell count below 200 cells/μl (or a CD4+ T-cell percentage of total lymphocytes of less than 14%).
- or he/she has one of the following defining illnesses:
-
- 01. Candidiasis of bronchi, trachea, or lungs
- 02. Candidiasis esophageal
- 03. Cervical cancer (invasive)
- 04. Coccidioidomycosis, disseminated or extrapulmonary
- 05. Cryptococcosis, extrapulmonary
- 06. Cryptosporidiosis, chronic intestinal for longer than 1 month
- 07. Cytomegalovirus disease (other than liver, spleen or lymph nodes)
- 08. Encephalopathy (HIV-related)
- 09. Herpes simplex: chronic ulcer(s) (for more than 1 month); or bronchitis, pneumonitis, or esophagitis
- 10. Histoplasmosis, disseminated or extrapulmonary
- 11. Isosporiasis, chronic intestinal (for more than 1 month)
- 12. Kaposi's sarcoma
- 13. Lymphoma Burkitt's, immunoblastic or primary brain
- 14. Mycobacterium avium complex
- 15. Mycobacterium, other species, disseminated or extrapulmonary
- 16. Pneumocystis carinii pneumonia
- 17. Pneumonia (recurrent)
- 18. Progressive multifocal leukoencephalopathy
- 19. Salmonella septicemia (recurrent)
- 20. Toxoplasmosis of the brain
- 21. Tuberculosis
- 22. Wasting syndrome due to HIV
- People who are not infected with HIV may also develop these conditions; this does not mean they have AIDS. However, when an individual presents laboratory evidence against HIV infection, a diagnosis of AIDS is ruled out unless the patient has not:
-
- AND
- □AIDSのステージング
- ■参考文献
- HIM = Harrison's Principles of Internal Medicine 17th Edition
- CASES = 100 Cases in Clinical Medicine Second edition
- IMD = 内科診断学第2版
[★]
- 英
- pteridine
- 関
- ジヒドロプテロイン酸
- |←dihydropteroate synthetase |-sulfonamides
- |+[グルタミン酸]]
- |←hidyrofolate reductase |-trimetoprim, methotrexate, pyrimethamine
[★]
- 英
- pyrimethamine
- 関
- スルファドキシン・ピリメタミン合剤 pyrimethamine-sulfadoxine
[★]
- 関
- pyrimethamine