Khoom Taw qhia
| Fluorocytosine Cov ntaub ntawv yooj yim |
| Txheej txheem cej luam Mechanism of action and resistance Pharmacokinetic and dosage Toxicity and side effects References |
| Khoom npe: | Fluorocytosine |
| Synonyms: | 4-amino-5-fluoro-2(1h)-pyrimidinon;4-Amino-5-fluoro-2(1H)-pyrmidinone;{{10} }fluorocystosine;5-fluorocytosin;5-fluoro-cytosin;fluocytosine;4-Amino-5-Fluoro-2(1H)-pyrimidine, Flucytosine, 5- FC; 5-Fluorocytosine98% |
| CAS: | 2022-85-7 |
| MF: | C4H4FN3O |
| MW: | 129.09 |
| EINECS: | 217-968-7 |
| Khoom Categories: | Nucleotides thiab Nucleosides; Antifungals rau Kev Tshawb Fawb thiab Kev Siv Tshuaj; Biochemistry; Tshuaj Reagents rau Pharmacology Research; Nucleobases thiab lawv cov analogs; Nucleosides, Nucleotides & Related Reagents; Pyrimidine series; Phenylacetic acid; ketone; Nucleic acids Heterocycles; PYRIMIDINE; Pyridines, Pyrimidines, Purines thiab Pteredines; API; amine|ketone| alkyl Fluorine; GLUCOTROL; Tshuaj tiv thaiv kab mob; 2022-85-7 |
| Mol File: | 2022-85-7.mol |
 |
|
| Fluorocytosine Chemical Properties |
| Melting point | 298-300 degree (dec.) (lit.) |
| ceev | 1.3990 (kwv yees) |
| vapor siab | 0Pa ntawm 25 degree |
| cia temp. | 2-8 degree |
| solubility | Sparingly soluble hauv dej, me ntsis soluble hauv ethanol (96 feem pua) |
| daim ntawv | Crystalline hmoov |
| pka ua | 3.26 (ntawm 25 degree) |
| xim | Dawb mus yuav luag dawb |
| Dej Solubility | 1.5g / 100mL (25 ºC) yog ' |
| rhiab heev | Lub teeb Sensitive |
| Merck | 14,4125 |
| BRN | 127285 |
| BCS Chav Kawm | 1 |
| Kev ruaj ntseg: | Lub teeb Sensitive |
| InChIKey | XRECTZIEBJDKEO-UHFFFAOYSA-N |
| LogP | -1.36 ntawm 22.1 degree thiab pH6.4-6.9 |
| Dissociation tas li | 2.74-10.71 ntawm 21.4 degree |
| CAS DataBase Reference | 2022-85-7(CAS DataBase Reference) |
| Cov ntaub ntawv kev nyab xeeb |
| Hazard Codes | Xn, T, Xi |
| Risk Statements | 40-36/37/38-63 |
| Cov lus hais txog kev nyab xeeb | 22-24/25-45-36/37-36/37/39-27-26 |
| WGK Germany | 2 |
| RTECS | HA6040000 |
| F | 10-23 |
| Ceeb toom | Toxic/light Sensitive |
| HazardClass | IRRITANT, LIGHT SENSITIVE |
| HS Code | 29335990 |
| Cov Ntaub Ntawv Muaj Xwm Ceev | 2022-85-7(Cov ntaub ntawv muaj phom sij) |
| Toxicity | LD50 in mice (mg/kg): >2000 hais lus thiab sc; 1 190;ib. 500 iv (Grunberg, 1963) |
| MSDS Cov Ntaub Ntawv |
| Tus kws kho mob | Lus |
|---|---|
| 2-Hydroxy-4-amino-5-fluoropyrimidine | Lus Askiv |
| SigmaAldrich | Lus Askiv |
| ACROS | Lus Askiv |
| ALFA | Lus Askiv |
| Fluorocytosine Siv thiab Synthesis |
| Txheej txheem cej luam | Ib qho fluorinated pyrimidine, 5-flucytosine (fluorocytosine; 5-FC, Fig. 1), yog thawj zaug tsim los ua tus neeg sawv cev tiv thaiv kab mob tab sis nws tsis muaj txiaj ntsig zoo hauv kev kho mob qog noj ntshav.[1]. Tom qab ntawd, 5-FC tau ua pov thawj tias ua haujlwm hauv kev sim candidiasis thiab cryptococcosis hauv nas.[2]thiab tau siv los kho cov kab mob tib neeg[3]. Ntxiv nrog rau nws cov haujlwm tiv thaiv Candida thiab Cryptococcus, 5-FC kuj tseem muaj cov haujlwm inhibitory tiv thaiv kab mob ua rau chromoblastomycosis[4]; Txawm li cas los xij, nws tsis muaj txiaj ntsig tiv thaiv kab mob los ntawm filamentous fungi. 5-FC muaj ntau qhov kev tiv thaiv thawj zaug hauv ntau hom kab mob fungal. Vim yog qhov kev tiv thaiv thawj zaug no, 5-FC feem ntau yog siv ua ke nrog lwm cov tshuaj tua kab mob (feem ntau yog amphotericin B, AmB) thiab tsis ntev los no nws tau raug tshawb xyuas nrog lwm cov tshuaj xws li fluconazole (FLU), ketoconazole (KTZ), itraconazole (ITRA), voriconazole (VORI) thiab echinocandins (piv txwv li, micafungin, MICA thiab caspofungin, CAS). Nws tsuas yog siv tsis tshua muaj neeg sawv cev xwb. Flucytosine (5-FC) yog ib qho hluavtaws antimycotic compound, thawj zaug synthesized hauv xyoo 1957. Nws tsis muaj peev xwm los tiv thaiv kab mob, tab sis tom qab nws tau coj los ntawm cov kab mob fungal, nws hloov mus rau hauv 5-fluorouracil ( 5-FU), uas yog ntxiv rau cov metabolites uas inhibit fungal RNA thiab DNA synthesis. Monotherapy nrog 5-FC raug txwv vim kev txhim kho tsis tu ncua. Ua ke nrog amphotericin B, 5-FC tuaj yeem siv los kho cov kab mob mycoses hnyav, xws li cryptococcosis, candidosis, chromoblastomycosis thiab aspergillosis.  Daim duab 1 cov qauv tshuaj ntawm Fluorocytosine |
| Mechanism ntawm kev txiav txim thiab tsis kam | 5-FC muaj zog tshaj tawm tsam cov poov xab, suav nrog Candida, Torulopsis thiab Cryptococcus spp., thiab tawm tsam cov kab mob dematiaceous ua rau chromomycosis (Phialophora thiab Cladosporium spp.) thiab Aspergillus spp.[5]MICs ntawm {{0}}FC txawv ntawm 0.1 mus rau 0.25 mg/L rau cov kab mob fungal no. Hauv Emmonsia crescens, Emmonsia parva, Madurella mycetomatis, Madurella grisea, Pyrenochaeta romeroi, Cephalosporium spp., Sporothrix schenckii thiab Blastomyces dermatitidis, MICs sib txawv ntawm 100 txog 1000 mg / L muaj xws li FC. Acanthamoeba culbertsoni ob leeg hauv vitro thiab hauv vivo thiab Leishmania spp. hauv cov neeg mob.[5] Antimycotic kev ua haujlwm ntawm 5-FC tshwm sim los ntawm nws qhov hloov pauv sai rau hauv 5-fluorouracil (5-FU) los ntawm enzyme cytosine deaminase, nyob rau hauv cov kab mob fungal. Muaj ob lub tswv yim koom nrog uas 5-fluorouracil siv nws cov tshuaj tiv thaiv kab mob. Thawj txheej txheem suav nrog kev hloov pauv ntawm 5-fluorouracil los ntawm 5-fluorouridine monophosphate (FUMP) thiab 5-fluorouridine diphosphate (FUDP) rau hauv 5-fluorouridine triphosphate (FUTP)[6]. FUTP tau ntxiv rau hauv cov kab mob RNA nyob rau hauv qhov chaw ntawm uridylic acid; Qhov no hloov cov aminoacylation ntawm tRNA, cuam tshuam cov amino acid pas dej thiab inhibits protein synthesis.[6]. Qhov thib ob mechanism yog cov metabolism ntawm 5-FU rau hauv 5-fluorodeoxyuridine monophosphate (FdUMP) los ntawm uridine monophosphate pyrophosphorylase[6]. FdUMP yog ib qho muaj zog inhibitor ntawm thymidylate synthase, uas yog ib qho tseem ceeb enzyme koom tes hauv DNA synthesis thiab nuclear division.[7]. Yog li, 5-FC ua los ntawm kev cuam tshuam nrog pyrimidine metabolism thiab protein synthesis hauv cov kab mob fungal. Cov kev ua ub no ua rau cell lysis thiab tuag. Qhov tshwm sim ntawm kev tawm tsam nrog kev siv 5-FC tau piav qhia dav dav thiab txwv tsis pub siv 5-FC ua ib tus neeg sawv cev[8, 10]Ob lub tswv yim tseem ceeb ntawm kev tiv thaiv tuaj yeem paub qhov txawv: (i) qee qhov kev hloov pauv tuaj yeem ua rau muaj qhov tsis txaus ntawm cov enzymes tsim nyog rau kev thauj mus los ntawm tes thiab nce ntawm 5-FC lossis rau nws cov metabolism (xws li cytosine permease, uridine monophosphate pyrophosphorylase lossis cytosine deaminase );[9,11](ii) kev tawm tsam tuaj yeem tshwm sim los ntawm kev sib txuas ntxiv ntawm pyrimidines, uas sib tw nrog cov tshuaj fluorinated antimetabolites ntawm 5-FC thiab yog li txo qis nws cov tshuaj tiv thaiv mycotic.[9]Nws tau raug pom tias tsis zoo uridine monophosphate pyrophosphorylase yog qhov tshwm sim ntau tshaj plaws ntawm kev kis tau 5-FC tsis kam hauv cov kab mob fungal.[12]Normark & Schönebeck tau tshaj tawm tias ob hom phenotypes ntawm 5-FC-resistant hom tuaj yeem lees paub:[10]Cov hom kab mob ntawm cov phenotype cov chav kawm 1 tsis cuam tshuam los ntawm 5-FC ntawm qhov siab siab (cov no yog cov kab mob siab (intrinsically) resistant), thaum cov chav kawm 2 muaj kev cuam tshuam rau 5-FC ntawm cov concentrations tsawg tab sis, tom qab ntev raug rau 5-FC (txawm tias nyob rau hauv high concentrations) kuj tsim (cov no yog hais tias yuav tiv taus ib nrab los yog tau txais kev tiv thaiv). Kev loj hlob ntawm kev tiv thaiv nyob rau hauv cov kab mob tom kawg tej zaum yuav tshwm sim los ntawm kev xaiv ntawm cov tsis-susceptible mutants, ua rau ib tug thib ob resistant pejxeem.[9] Qhov tshwm sim ntawm kev tiv thaiv rau 5-FC txawv ntawm hom.20 Txog li 7-8% ntawm cov kab mob intrinsically resistant muaj nyob rau hauv pretreatment cais ntawm C. albicans, unspeciated candida thiab Torulopsis glabrata. Hauv C. neoformans qhov tshwm sim ntawm qhov tsis kam yog qis dua (1-2%), tab sis hauv Candida spp. Lwm yam tshaj li C. albicans nws yog 22%, vim hais tias feem ntau tsis tshua muaj rhiab hom xws li Candida tropicalis thiab Candida krusei.[13]. Qhov tseeb tshwm sim ntawm thawj 5-FC tsis kam yog tsis meej. Cov neeg tshawb xyuas sib txawv tshaj tawm cov nqi sib txawv ntawm 8% thiab 44% rau Candida spp[14]. Tej yam tshwm sim uas ua rau muaj ntau yam no suav nrog cov txheej txheem susceptibility siv, hauv zos yam cuam tshuam nrog kev siv cov tshuaj tiv thaiv kab mob thiab qhov sib txawv ntawm qhov muaj ntau yam Candida spp.[14]. |
| Pharmacokinetic thiab ntau npaum | 5-FC yog nqus tau sai heev thiab yuav luag tag: 76–89% yog bioavailable tom qab tswj qhov ncauj.[16]Hauv cov neeg mob uas lub raum ua haujlwm tsis zoo, qhov siab tshaj plaws yog nyob rau hauv cov ntshav thiab lwm yam kua hauv lub cev tsis pub dhau 1-2 teev.[15, 16]. 5-FC nkag mus tau zoo rau hauv feem ntau lub cev, suav nrog cerebrospinal, vitreous thiab peritoneal kua, thiab mus rau hauv cov pob qij txha, vim nws yog me me thiab dej-soluble heev thiab tsis khi los ntawm cov proteins hauv cov ntshav mus rau qhov zoo.[15-17]. 5-FC feem ntau raug tshem tawm los ntawm ob lub raum thiab cov plasma clearance ntawm cov tshuaj yog ze ze rau creatinine clearance[15, 17]. 5-FC tsuas yog metabolized tsawg kawg nkaus hauv daim siab. Lub raum tshem tawm yog los ntawm glomerular filtration; tsis muaj tubular resorption los yog secretion tshwm sim. Lub neej ib nrab ntawm 5-FC yog c.3-4 h hauv cov neeg mob uas lub raum ua haujlwm tsis zoo, tab sis tuaj yeem txuas ntxiv mus txog 85 teev hauv cov neeg mob uas lub raum tsis txaus.[12, 16, 18]Lub raum tsis txaus hloov pauv 5-FC pharmacokinetics txij li nws ua rau qeeb nqus, ua kom cov ntshav qabzib ib nrab-lub neej thiab txo qis kev tshem tawm.[15]. Qhov pom meej ntim ntawm kev faib tawm ntawm 5-FC mus txog tag nrho cov dej hauv lub cev thiab tsis hloov pauv los ntawm lub raum tsis ua haujlwm. Kev noj tshuaj yuav tsum tau kho rau cov neeg mob lub raum tsis zoo. Ntau cov lus pom zoo tau ua[15-18]. Daneshmend & Warnock tau qhia cov lus qhia hauv qab no rau kev tswj hwm ntawm 5-FC rau cov neeg mob lub raum tsis txaus.[15]. In patients with a creatinine clearance of >40 mL / min, tus qauv koob tshuaj 37.5 mg / kg txhua 6 h yuav tsum tau siv. Yog tias qhov kev tshem tawm creatinine nyob nruab nrab ntawm 20 thiab 40 mL / min, cov koob tshuaj pom zoo yog 37.5 mg / kg txhua 12 teev. Hauv cov neeg mob uas muaj creatinine tshem tawm<20 mL/ minute, the dose of 5-FC should be 37.5 mg/kg once daily. Finally, if the creatinine clearance is <10 mL/min, frequent determinations of 5-FC concentration should be used as guidance for the frequency of dosing. |
| Toxicity thiab phiv | 5-FC paub tias muaj qee qhov kev mob tshwm sim me me, xws li xeev siab, ntuav thiab raws plab, nws kuj muaj cov kev mob tshwm sim hnyav dua, suav nrog kev mob hepatotoxicity thiab kev nyuaj siab pob txha. Kev mob plab hnyuv, feem ntau thiab muaj kev phom sij tsawg tshaj plaws uas cuam tshuam nrog 5-FC kev kho mob, suav nrog xeev siab, raws plab thiab, qee zaus, ntuav thiab mob plab. Lawv tshwm sim hauv kwv yees li 6% ntawm cov neeg mob kho nrog 5-FC[18]. Txawm hais tias cov kev mob tshwm sim no feem ntau tsis hnyav; Ob qhov xwm txheej ntawm ulcerative colitis thiab plab hnyuv perforation tau raug tshaj tawm[19]. Hepatotoxicity tuaj yeem tshwm sim thaum 5-FC kho. Feem ntau nws cuam tshuam nrog kev nce hauv cov ntshav siab ntawm transaminases thiab alkaline phosphatase.[20]. Qhov tshwm sim ntawm hepatotoxicity yog nyob nruab nrab ntawm 0 thiab 25%[20]. Qhov mob hnyav tshaj plaws uas cuam tshuam nrog 5-FC kev kho mob yog kev nyuaj siab pob txha pob txha. Muaj ntau cov ntaub ntawv qhia txog qhov mob hnyav lossis ua rau muaj kev phom sij rau lub neej, thrombocytopenia thiab / lossis pancytopenia.[21-23]. Lub tshuab ntawm toxicity ntawm 5-FC tseem tsis tau nkag siab tag nrho. Nws zoo li qee qhov kev mob tshwm sim los ntawm 5-FC, piv txwv li hepatotoxicity thiab pob txha pob txha kev nyuaj siab, yog nyob ntawm koob tshuaj, txawm hais tias tsis yog txhua daim ntawv qhia txhawb qhov kev xav no. Tsis tas li ntawd, nws tau raug tshaj tawm tias kev hloov pauv ntawm 5-FC mus rau qee yam metabolites, tshwj xeeb tshaj yog 5-FU, tuaj yeem yog ib qho ntawm cov txheej txheem ntawm kev txhim kho ntawm 5-FC-txog toxicity. |
| Cov ntaub ntawv |
Heidelberg C, Chaudhuri NK, Danneberg P et al. Fluorinated pyrimidines, chav kawm tshiab ntawm cov qog-inhibitory compounds. Xwm 1957; 179 (4561): 663–666 Grunberg E, Titsworth E, Bennett M. Chemotherapeutic kev ua haujlwm ntawm 5-fluorocytosine. Antimicrob Agents Chemother 1963; 161:566–568 Tassel D, Madoff MA. Kev kho mob Candida sepsis thiab Cryptococcus meningitis nrog 5-fluorocytosine. Ib tug tshiab antifungal neeg sawv cev. JAMA 1968; 206(4): 830–832 : kuv Benson JM, Nahata MC. Clinical siv cov tshuaj tiv thaiv kab mob. Clin Pharm 1988; 7(6): 424–438 Scholer, HJ (1980). Flucytosine. In Antifungal Chemotherapy, (Speller, DCE, Ed.), pp. 35–106. Wiley, Chichester. Waldorf AR, Polak A. Mechanisms of action of 5-fluorocytosine. Antimicrob Agents Chemother 1983; 23(1):79–85 : kuv Diasio RB, Bennett JE, Myers CE. Hom kev ua ntawm 5-fluorocytosine. Biochem Pharmacol 1978; 27(5):703–707 : kuv Polak, A. & Scholer, HJ (1975). Hom kev ua ntawm 5-fluorocytosine thiab cov txheej txheem ntawm kev ua haujlwm. Tshuaj Kho Mob 21, 113–30. Polak, A. (1977). 5-Fluorocytosine-tam sim no raws li txoj cai nrog tshwj xeeb hais txog hom kev ua thiab tshuaj tiv thaiv. Kev Pabcuam rau Microbiology thiab Immunology 4, 158–67. Normark, S. & Schönebeck, J. (1973). Hauv vitro kev tshawb fawb ntawm 5-fluorocytosine tsis kam hauv Candida albicans thiab Torulopsis glabrata. Antimicrobial Agents thiab Chemotherapy 2, 114–21. Fasoli, M. & Kerridge, D. (1988). Kev rho tawm thiab tus cwj pwm ntawm fluoropyrimidine-resistant mutants hauv ob hom Candida. Annals ntawm New York Academy of Sciences 544, 260–3. Francis, P. & Walsh, TJ (1992). Kev hloov pauv lub luag haujlwm ntawm flucytosine hauv cov neeg mob immunocompromised: kev nkag siab tshiab rau kev nyab xeeb, pharmacokinetics, thiab kev kho tshuaj tiv thaiv kab mob. Clinical Infectious Diseases 15, 1003–18. Medoff, G. & Kobayashi, GS (1980). Cov tswv yim hauv kev kho mob ntawm cov kab mob fungal. New England Journal of Medicine 302, 145–55. Armstrong, D. & Schmitt, HJ (1990). Cov tshuaj laus. Hauv Chemotherapy for Fungal Diseases, (Ryley, JF, Ed.), pp. 439–54. Springer-Verlag, Berlin. Daneshmend, TK & Warnock, DW (1983). Clinical pharmacokinetics ntawm systemic antifungal tshuaj. Clinical Pharmacokinetics 8, 17–42. Cutler, RE, Blair, AD & Kelly, MR (1978). Flucytosine kinetics hauv cov neeg uas muaj lub raum tsis ua haujlwm thiab lub raum tsis zoo. Clinical Pharmacology thiab Therapeutics 24, 333–42. Block, ER, Bennett, JE, Livoti, LG, Klein, WJ, MacGregor, RR & Henderson, L. (1974). Flucytosine thiab amphotericin B: hemodialysis cuam tshuam rau plasma concentration thiab clearance. Kev kawm hauv txiv neej. Annals of Internal Medicine 80, 613–7. Schönebeck, J., Polak, A., Fernex, M. & Scholer, HJ (1973). Kev tshawb fawb Pharmacokinetic ntawm qhov ncauj antimycotic tus neeg sawv cev 5-fluorocytosine hauv cov tib neeg uas muaj lub raum ua haujlwm tsis zoo. Tshuaj Kho Mob 18, 321–36. Benson, JM & Nahata, MC (1988). Clinical siv cov tshuaj tiv thaiv kab mob. Chaw Kho Mob 7, 424–38. Bennet, JE (1977). Flucytosine. Annals of Internal Medicine 86, 319–21. Kauffman, CA & Frame, PT (1977). Cov pob txha toxicity txuam nrog 5- fluorocytosine therapy. Antimicrobial Agents thiab Chemotherapy 11, 244–7. Schlegel, RJ, Bernier, GM, Bellanti, JA, Tej zaum, DA, Osborne, GB, Stewart, JL et al. (1970). Mob candidiasis cuam tshuam nrog thymic dysplasia, IgA deficiency, thiab cov teebmeem plasma antilymphocyte. Pediatrics 45, 926–36. Meyer, R. & Axelrod, JL (1974). Kev tuag aplastic anemia tshwm sim los ntawm flucytosine. Phau ntawv Journal of the American Medical Association 228, 1573. |
| Kev piav qhia | 5-Fluorocytosine (5-FC), ib qho fluorinated pyrimidine analog, yog cov tshuaj tua kab mob hluavtaws uas hloov los ntawm cytosine deaminase rau 5-fluorouracil. 5-Fluorouracil, siv dav siv tshuaj cytotoxic, yog ntxiv metabolized rau fluorinated ribo- thiab deoxyribonucleotides, ua rau inhibition ntawm DNA thiab protein synthesis, uas muaj ntau yam cuam tshuam nrog rau inhibition ntawmCandidahom thiabC. neoformanskab mob thiab cytotoxicity rau cov qog nqaij hlav cancer. Ua ke nrog ib qho kev rov ua dua cov vector uas nqa cov cytosine deaminase prodrug-activate gene, 5-FC tau pom tias xaiv tshem tawm CT26 thiab Tu-2449 cov qog hlwb.hauv vitro(IC50s=4.2 thiab 1.5 μM, feem) thiab txhawm rau txhim kho kev ciaj sia thiab txo cov qog loj (ntawm ib koob ntawm 500 mg / kg) hauv ob qhov sib txawv syngeneic nas glioma qauv. |
| Chemical Properties | Dawb Crystalline Khoom |
| Keeb kwm | Ancobon, Roche, USA, 1972 |
| Siv | 5-FC yog tshuaj tua kab mob / tshuaj tua kab mob |
| Siv | 5-Fluorocytosine ua raws li cov tshuaj tua kab mob, tshuaj tua kab mob thiab tshuaj tua kab mob. Nws muaj txiaj ntsig zoo rau kev kho mob ntawm cov kab mob loj tshwm sim vim muaj kab mob Candida lossis Cryptococcus neoformans thiab chromomycosis. Tsis tas li ntawd, nws tau ua haujlwm hauv kev tshawb fawb ntawm TMP biosynthesis. |
| Txhais | ChEBI: Flucytosine yog ib qho organofluorine compound uas yog cytosine uas tau hloov ntawm txoj hauj lwm 5 los ntawm fluorine. Ib tug prodrug rau antifungal 5-fluorouracil, nws yog siv rau kev kho mob ntawm cov kab mob fungal. Nws muaj lub luag hauj lwm raws li ib tug prodrug. Nws yog ib qho organofluorine compound, pyrimidone, aminopyrimidine, nucleoside analogue thiab pyrimidine antifungal tshuaj. Nws muaj feem cuam tshuam nrog cytosine. |
| Cov lus qhia | Flucytosine (Ancobon) yog ib qho hluavtaws, fluorinated pyrimidine uas muaj feem cuam tshuam nrog fluorouracil (FU) thiab floxuridine. Nws tuaj yeem yog fungistatic thiab fungicidal. Txawm hais tias nws tau siv ntau zaus hauv kev kho mob ntawm cov kab mob uas tshwm sim los ntawm Candida thiab Cryptococcus, dermatologic indications yuav suav nrog kev kis kab mob vim chromomycosis, sporotrichosis, Cladosporium, thiab Sporothrix hom. Nws feem ntau tsis muaj txiaj ntsig rau hom Aspergillus. |
| Kev tsim khoom | Kev npaj ntawm 5-fluorouracil yog muab nyob rau hauv "Fluorouracil." Raws li tau piav qhia hauv Teb Chaws Asmeskas Patent 3,040,026, 5-fluorouracil tom qab ntawd raug ua raws li cov kauj ruam hauv qab no los muab flucytosine. Kauj Ruam 1: 2, 4-Dichloro-5-Fluoropyrimidine - Kev sib xyaw ntawm 104 grams (0.8 mol) ntawm 5- fluorouracil, 1,472 grams (9.6 mols) ntawm phosphorus oxychloride thiab 166 grams (1.37 mols) ntawm dimethylaniline tau nplawm hauv qab reflux rau 2 teev. Tom qab txias rau chav sov, phosphorus oxychloride raug tshem tawm los ntawm distillation ntawm 18 mus rau 22 mm thiab 22 degree txog 37 degree. Tom qab ntawd cov residue yog poured rau hauv ib lub zog stirred sib tov ntawm 500 ml ntawm ether thiab 500 grams dej khov. Tom qab sib cais cov ether txheej, txheej aqueous tau muab rho tawm nrog 500 ml, ces 200 ml ntawm ether. Cov ether feem ua ke tau qhuav dhau sodium sulfate, lim, thiab ether tshem tawm los ntawm lub tshuab nqus tsev distillation ntawm 10 degree txog 22 degree. Cov residue, cov khoom daj melting ntawm 37 degree mus rau 38 degree, hnyav 120 grams sib npaug rau 90% tawm los. Nqus distillation ntawm 115 grams ntawm cov khoom no ntawm 74 degree mus rau 80 degree (16 hli) muab 108 grams ntawm dawb khoom melting ntawm 38 degree mus rau 39 degree sib thooj rau 84.5% tawm los. Kauj Ruam 2: 2-Chloro-4-Amino-5-Fluoropyrimidine - Rau kev daws ntawm 100 grams (0.{{27} }6 mol) ntawm 2,4-dichloro-5-fluoropyrimidine hauv 100 ml ntawm ethanol, 25 ml ntawm concentrated aqueous ammonia tau maj mam ntxiv. Qhov kev daws teeb meem me ntsis opalescent tshwm sim. Qhov ntsuas kub maj mam nce mus rau 35 degree. Tom qab ntawd cov tshuaj tau txias rau hauv dej khov rau 18 degree thiab tom qab ntawd tseem nyob hauv qab 30 degree. Tom qab peb teev, Volhard titration pom tias 0.0545 mol ntawm chlorine muaj nyob rau hauv daim ntawv ionic. Cia hauv lub tub yees thaum hmo ntuj ua rau qee qhov crystallization ntawm ammonium chloride. Cov sludge dawb, uas tshwm sim los ntawm evaporation ntawm cov tshuaj tiv thaiv sib tov ntawm 40 degree, yog slurried nrog 75 ml ntawm dej, lim thiab ntxuav tsis muaj chloride. Tom qab ziab hauv lub tshuab nqus tsev, cov khoom melted ntawm 196.5 degree rau 197.5 degree, tawm los 6.44 grams. Evaporation ntawm niam cawv tau txais txiaj ntsig thib ob ntawm 0.38 gram, nce tag nrho cov txiaj ntsig mus rau 6.82 grams (79.3%). Kauj Ruam 3: 5-Fluorocytosine - Ib qho slurry ntawm 34.0 grams (0.231 mol) ntawm 2-chloro-4- amino-5-fluoropyrimidine Nyob rau hauv 231 ml ntawm concentrated hydrochloric acid yog rhuab nyob rau hauv ib da dej ntawm 93 degree mus rau 95 degree rau 125 feeb. Cov tshuaj tiv thaiv tau ua raws li kev siv ultraviolet spectrophotometric siv qhov nqus ntawm 245, 285, thiab 300 mμ raws li kev qhia. Qhov nqus ntawm 300 mμ tau nce mus rau qhov siab tshaj plaws tom qab 120 feeb thiab tom qab ntawd poob me ntsis. Cov tshuaj ntshiab yog txias rau 25 degree hauv ib da dej dej khov, ces evaporated rau dryness hauv lub tshuab nqus tsev ntawm 40 degree. Tom qab slurrying nrog dej peb zaug thiab reevaporating, cov residue yog yaj nyob rau hauv 100 milliliters dej. Rau qhov kev daws teeb meem no, txias hauv dej khov, 29 ml ntawm cov ntsiab lus ammonia tau ntxiv dropwise. Lub resulting precipitate tau lim, ntxuav tsis muaj chloride nrog dej, ces nrog cawv thiab ether. Tom qab ziab hauv vacuo ntawm 65 degree, cov khoom hnyav 22.3 grams. Ib qho ntxiv 6.35 grams tau txais los ntawm evaporation ntawm niam cawv, yog li yielding tag nrho ntawm 28.65 grams (96.0%). |
| Hom lub npe | Ancobon (Valeant). |
| Kev kho mob muaj nuj nqi | Tshuaj tua kab mob |
| Antimicrobial kev ua haujlwm | Cov spectrum ntawm kev ua si yog txwv rau Candida spp., Cryptococcus spp. thiab qee cov kab mob ua rau chromoblastomycosis. |
| Tau txais kev tiv thaiv | Txog 2-3 ntawm Candida spp. cais tawm (ntau dua hauv qee lub chaw) tiv taus ua ntej kev kho mob pib, thiab kev tiv thaiv tuaj yeem tshwm sim thaum kho. Qhov feem ntau ua rau kev tiv thaiv zoo li poob ntawm enzyme uridine monophosphate pyrophosphorylase. |
| Kev siv tshuaj | Ib qho hluavtaws fluorinated pyrimidine muaj rau kev txhaj tshuaj hauv qhov ncauj lossis kev tswj qhov ncauj. |
| Biochem/physiol Actions | Nucleoside analogues uas muaj cov tshuaj tua kab mob. 5-FC yog deaminated los ntawm cytosine deaminase rau cov khoom 5-fluorouracil, ua rau RNA miscoding. 5-Fluorocytosine inhibits DNA thiab RNA synthesis thiab cuam tshuam nrog ribosomal protein synthesis. |
| Mechanism ntawm kev ua | Flucytosine (5-flucytosine, 5-FC; Ancoban) yog ib qho fluorinated pyrimidine analogue ntawm cytosine uas yog tsim los rau kev siv tau los ua tus neeg sawv cev antineoplastic. Nws yog qhia tsuas yog rau kev kho mob ntawm cov kab mob loj uas tshwm sim los ntawm cov kab mob Candida thiab Cryptococcus spp.Cov txheej txheem ntawm kev ua ntawm 5-fluorocytosine (5-FC) tau kawm kom ntxaws.Cov tshuaj nkag mus rau hauv fungal cell los ntawm active thauj onATPases uas nquag thauj pyrimidines. Thaum nyob rau hauv lub cell, 5-fluorocytosine deaminated nyob rau hauv cov tshuaj tiv thaiv catalyzedby cytosine deaminase kom tawm los 5-fluorouracil(5-FU). 5-Fluorouracil yog cov nquag metabolite ntawm cov tshuaj. Cov fluororibonucleotidetriphosphates tau muab tso rau hauv RNA, ua rau RNA synthesis tsis raug. Txoj kev no ua rau cell tuag. Hauv cov deoxyribonucleotide series, 5-fluorodeoxyuridinemonophosphate (F-dUMP) khi rau 5,10-methylenetetrahydrofolicacid, cuam tshuam cov pas dej ib-carbon substratethat pub thymidylate synthesis. Yog li ntawd, DNA synthesis blocked. |
| Pharmacology | 5-FC tau nqus tau qhov ncauj zoo, nrog ntau dua 90% bioavailability. Cov ntshav ib nrab ntawm lub neej yog 3 mus rau 5 teev, nrog cov ntshav qab zib nce siab tom qab 4 mus rau 6 teev tom qab noj ib zaug.Cov tshuaj tau dav dav hauv cov kua dej hauv lub cev, nrog rau cov kua dej cerebrospinal qib 60 txog 80% ntawm cov ntshav ntshav.Cov tshuaj kuj nkag mus zoo. mus rau hauv cov zis, aqueous lom zem, thiab bronchial secretions.Minimal serum protein binding tso cai ntau tshaj 90% ntawm txhua koob tshuaj mus rau hauv cov zis; Kev txo cov koob tshuaj tseem ceeb yuav tsum tau ua thaum muaj lub raum tsis zoo. 5-FC tuaj yeem raug tshem tawm los ntawm ob qho tib si hemodialysis thiab peritoneal dialysis. 5-FC hloov mus rau cov tshuaj lom metabolites tuaj yeem tshwm sim hauv cov hlwb ntawm cov tsiaj me rau qhov tsawg, uas suav rau 5-FC toxicity. |
| Pharmacokinetics | Qhov ncauj nqus: ua kom tiav Cmax25 mg/kg 6-ib teev ntawm qhov ncauj: 70–80 mg/L tom qab 1–2 teev Plasma ib nrab lub neej: 3-6 h Kev faib tawm ntim: 0.7–1 L/kg Plasma protein khi c. 12% Kev nqus tau qeeb qeeb hauv cov neeg uas lub raum tsis ua haujlwm, tab sis qhov siab tshaj plaws yog siab dua. Cov qib hauv CSF yog nyob ib ncig ntawm 75% ntawm cov ntshav ntshav ib txhij. Ntau tshaj 90% ntawm ib koob tshuaj flucytosine raug tso tawm hauv cov zis hauv daim ntawv tsis hloov pauv. Cov piam thaj ib nrab ntawm lub neej yog ntev dua nyob rau hauv lub raum tsis ua haujlwm, yuav tsum tau hloov kho cov tshuaj noj: rau cov neeg mob uas muaj creatinine tshem tawm qis dua 40 mL / min, lub sijhawm noj tshuaj yuav tsum tau muab ob npaug rau 12 teev; nyob rau hauv lub raum tsis ua hauj lwm hnyav, lub sij hawm noj tshuaj yuav tsum tau nce ntxiv mus rau ib zaug ib hnub lossis tsawg dua, raws li kev ntsuas cov tshuaj hauv cov ntshav ntau. |
| Kev siv tshuaj kho mob | Flucytosine muaj cov tshuaj tiv thaiv kab mob tseem ceeb tiv thaiv C. albicans, lwm yam Candida spp., C. neoformans, thiab cov kab mob fungal uas muaj lub luag haujlwm rau chromomycosis. Tsis suav tias yog cov tshuaj xaiv rau cov kab mob fungal no, 5-FC tseem muaj txiaj ntsig ua ib feem ntawm kev kho mob ua ke rau cov kab mob candidiasis thiab cryptococcal meningitis thiab ua lwm yam tshuaj rau chromomycosis. Thaum nws siv los ua monotherapy, kev tiv thaiv thiab kev kho mob tsis ua haujlwm yog qhov tshwm sim. Cov txheej txheem muaj peev xwm rau cov tshuaj tiv thaiv muaj xws li txo cov kab mob ntawm cov cell membrane permeability thiab txo cov qib ntawm fungal cytosine deaminase. Kev sib xyaw ua ke nrog amphotericin B thiab flucytosine hauv kev kho mob cryptococcal meningitis thiab kab mob Candida sib sib zog nqus, xws li mob caj dab thiab kab mob meningitis, tso cai txo kev noj tshuaj amphotericin B thiab tiv thaiv qhov tshwm sim ntawm 5-FC tsis kam. Thaum siv cov koob tshuaj ntau dua ntawm amphotericin B, kev kho ua ke nrog 5-FC tsis muaj txiaj ntsig kho mob ntxiv tshwj tsis yog kev kho mob Candida endophthalmitis, qhov chaw nkag mus rau cov ntaub so ntswg tseem muaj teeb meem. |
| Kev siv tshuaj kho mob | Candidosis (ua ke nrog amphotericin B lossis fluconazole) Cryptococcosis (ua ke nrog amphotericin B lossis fluconazole) Kev saib xyuas ntawm flucytosine concentration yog qhov xav tau rau txhua tus neeg mob, thiab yuav tsum tau ua rau cov neeg mob raum tsis zoo. |
| Kev mob tshwm sim | Kev xeev siab, ntuav, mob plab thiab raws plab yog tshwm sim. Cov kev mob tshwm sim hnyav muaj xws li myelosuppression thiab mob siab toxicity; Lawv tshwm sim ntau zaus thaum cov ntshav ntshav ntau tshaj 100 mg / L. Cov teebmeem nephrotoxic ntawm amphotericin B tuaj yeem ua rau cov ntshav nce siab ntawm flucytosine, thiab qib ntawm cov tshuaj tom kawg yuav tsum tau saib xyuas thaum cov tshuaj sib xyaw ua ke. Thaum 5-FC tau muab tshuaj ib leeg rau cov neeg mob uas lub raum ua haujlwm tsis zoo, ua pob khaus ntawm daim tawv nqaij, mob epigastric, raws plab, thiab siab enzyme tuaj yeem tshwm sim. |
| Synthesis | Flucytosine, 5-fluorocytosine (35.4.4), yog tsim los ntawm fluorouracil (30.1.3.3). Fluorouracil yog reacted nrog phosphorous oxychloride nyob rau hauv dimethylaniline ua 2, 4-dichloro-5-fluoropyrimidine (35.4.2), uas yog reacted nrog ammonia los ua ib yam khoom hloov nrog chlorine ntawm plaub txoj hauj lwm ntawm lub nplhaib pyrimidine —4-amino- 2-chloro-5-fluoropyrimidine (35.4.3). Hydrolysis ntawm chlorovinyl fragment ntawm no compound nyob rau hauv ib tug daws ntawm hydrochloric acid muab cov yam xav tau flucytosine. Lwm txoj hauv kev ntawm kev sib txuas muaj xws li ua flucytosine los ntawm ib qho precursor ntawm fluorouracil-5-fluoro-2-methylthiouracil (30.1.3.2) siv cov tswv yim zoo sib xws. Kev kho mob 5-fluoro-2-methylthiouracil (30.1.3.2) nrog phosphorous pentachloride muab 4-chloro-5-fluoro-2-methylthiopyrimidine (35.4.5), uas thaum raug reacted nrog ammonium hloov mus rau hauv 4-amino-5-fluoro-2-methylthiopyrimidine (35.4.6). Hydrolysis ntawm methylthiovinyl fragment siv cov concentrated hydrobromic acid muab qhov xav tau flucytosine.  |
| Cov tshuaj sib cuam tshuam | Tej zaum yuav muaj kev phom sij nrog lwm cov tshuaj Cytarabine: concentration ntawm flucytosine tejzaum nws txo. |
| Metabolism | Flucytosine nws tus kheej tsis yog cytotoxic tab sis, theej, yog ib qho tshuaj tiv thaiv uas tau coj los ntawm cov kab mob thiab metabolized rau 5-fluorouracil (5-FU) los ntawm fungal cytidine deaminase. Tom qab ntawd, 5-FU hloov mus rau 5-fluorodeoxyuridine, uas yog thymidylate synthase inhibitor cuam tshuam nrog cov protein thiab RNA biosynthesis. 5-Fluorouracil yog cytotoxic thiab ua haujlwm hauv kev kho mob qog noj ntshav. Tib neeg lub hlwb tsis muaj cytosine deaminase thiab, yog li ntawd, tsis txhob hloov flucytosine rau 5-FU. Qee lub plab hnyuv, txawm li cas los xij, hloov cov tshuaj mus rau 5-FU, yog li tib neeg toxicity tshwm sim los ntawm cov metabolism hauv no. |
| Fluorocytosine Preparation Products Thiab Raw Materials |
| Cov khoom nyoos | Phosphorus oxychloride-->N-Methylaniline-->5-Fluorouracil-->4-Amino-2-chloro-5-fluoropyrimidine-->2,4-Dichloro-5-fluoropyrimidine-->5-FLUORO-4-HYDROXY-2-METHOXYPYRIMIDINE-->Phosphorus oxychloride |
| Cov khoom npaj | 2',3'-Di-O-acetyl-5'-deoxy-5-fuluro-D-cytidine |
Cim npe nrov: Tuam Tshoj fluorocytosine manufacturers, lwm tus neeg, Hoobkas
Tug: Diphenyl Sulfone
Tom ntej: Methanesulfonic Anhydride
Koj Tseem Yuav Zoo Li
Xa kev nug
