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精品Trifluorothymidine(三氟胸腺嘧啶核苷)课件_6

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精品 Trifluorothymidine 胸腺 嘧啶 核苷 课件 _6
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单击此处编辑母版标题样式 单击此处编辑母版副标题样式 1 Antiviral Agents GAO Fen Fei Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial Overview Viruses are obligate intracellular parasites their replication depends primarily on synthetic processes of the host cell Antiviral agents must either block viral entry into or exit from the cell or be active inside the host cell Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial Research in Antiviral Chemotherapy In the early 1950s IdUR and Trifluorothymidine 三氟胸腺嘧啶核苷 In the mid 1970s Adenine arabinoside Vidarabine ara A 阿糖腺苷 In the late 1970s Acyclovir 阿昔洛韦 With the appearance of AIDS epidemic in the 1990s Inhibitor reverse transcriptase or the protease Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial Antiretroviral Anti HIV Agents The first available agents Nucleoside analog class competitive inhibition of the viral reverse transcriptase Nonnucleoside reverse transcriptase inhibitors The protease inhibitors The combination of at least two antiretroviral agents cocktail therapy enhancing potency and delaying resistance Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 病毒 RNA 互补双螺 旋DNA 掺入宿主 基因组 反转录酶HIV整合酶 转录 翻译 多聚 蛋白 小分子功 能蛋白 HIV蛋白酶 Drugs NRTIs NNRTIs PIs Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial Viral RNA double helix DNA Incorporated into host genome reverse transcriptase HIV integrase transcription translation Polyproteins Final structural proteins HIV protease Drugs NRTIs NNRTIs PIs Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial Nucleoside Reverse Transcriptase Inhibitors Derivatives of Pyramine AZT ddC d4T 3TC Derivatives of Purine ddI ABC Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial Mechanism of Action Competitive inhibition of HIV 1 reverse transcriptase Incorporated into the growing viral DNA chain cause termination Drugs requires intracytoplasmic activation phosphorylation triphosphate form Most have activity against HIV 2 as well as HIV 1 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial Zidovudine Azidothymidine 叠氮胸腺嘧啶 AZT Deoxythymidine analog anti HIV 1 and HIV 2 Well absorbed from the gut and distributed to most body tissues and fluids including the cerebrospinal fluid Eliminated primarily by renal excretion following glucuronidation in the liver Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial Decrease the rate of clinical disease progression and prolong survival Treatment HIV associated dementia 痴呆 and thrombocytopenia 血小板减少 Reduce the rate of vertical mother to newborn transmission of HIV Adverse effect myelosuppression 骨髓抑制 anemia or neutropenia gastrointestinal intolerance headachs insomnia 失眠 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial Zalcitabine ddC Cytosine analog Anti HIV 1 Zalcitabine Zidovudine one protease inhibitor Long intracellular half life of 10hs Dose dependent peripheral neuropathy Contraindication to use with other drugs that may cause neuropathy Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial Stavudine Thymidne analog d4T not used with AZT because AZT may reduce the phosphorylation of d4T Anti HIV 1 and HIV 2 High oral bioavailability 86 that is not food dependent Plasma protein binding is negligible mean cerebrospinal fluid concentrations are 55 of those of plasma Excretion is by active tubular secretion and glomerular filtration Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial Adverse effects Dose limiting toxicity is a dose related peripheral sensory neuropathy Pancreatitis arthralgias 关节痛 elevation in serum aminotransferases 转氨酶 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial Didanosine ddI Synthetic analog of deoxyadenosine Plasma protein binding is low 5 cerebrospinal fluid concentrations are 20 of serum concentrations Eliminated by glomerular filtration and tubular secretion Should be taken on an empty stomach Anti HIV activity of ddI is potentiated by hydroxyurea 羟基脲 due to a depletion of intracellular pools of dATP so two agents is administered in combination Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial Adverse effects Dose dependent pancreatitis Painful peripheral distal neuropathy Diarrhea Hepatitis Esophageal ulceration 食管溃疡 Cardiomyopathy Central nervous system toxicity headach irritability insomnia Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial Nonnucleoside reverse transcriptase inhibitors Including delavirdine nevirapine efavirenz Bind directly to a site on the viral reverse transcriptase that is near to but distinct from the binding site of the NRTIs Neither compete with nucleoside triphosphates nor require phosphorylation to be active The binding to the enzyme s active site results in blockade of RNA and DNA dependent DNA polymerase activities Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial Specific activity against HIV 1 Cross resistance among this class of agents The rapid emergence of resistance prohibits monotherapy with any of the NNRTIs No cross resistance between the NNRTIs and the NRTIs or the protease inhibitors Oral bioavailability is high Metabolized by the CYP3A P450 isoform excreted in the urine Adverse effects skin rash Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial Protease inhibitors Including ritonavir nelfinavir saquinavir indinavir and amprenavir Gag and Gag Pol gene Polyproteins Immature budding particles translate Final structural proteins Mature virioncore protease Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial Combination therapy with other agents is recommended to avoid emergence of resistance because of specific genotypic alterations Adverse effect Syndrome of altered body fat distribution buffalo hump and truncal obesity with facial and peripheral atrophy Insulin resistance Hyperlipidemia 高脂血症 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial Others Antiviral Agents Including Nucleoside antiviral agents Nonnucleoside antiviral agents Immune enhancement agent Mechanism of action Compete the receptors eg Heparin Polysaccharide Block viral adsorption to and penetration into host cells and uncoating of viral nucleic acid eg amantadine Block viral biosynthesis eg idoxuridine Enhance the host immune activity eg interferon Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial Nucleoside Antiviral Agents Including Purine nucleoside and Pyrimidine nucleoside Drugs requires intracytoplasmic activation phosphorylation triphosphate form competitive inhibition of viral DNA polymerase Incorporated into the growing viral DNA chain cause termination Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial Acyclovir ACV An acyclic guanosine derivative Pharmacological effects Against HSV 1 and HSV 2 and against varicella zoster virus Epstein Barr virus and cytomegalovirus Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial Mechanism Three phosphorylation steps for activation First converted to the monophosphate derivative by the virus specified thymidine kinase selective activation Then to the di and triphosphate compounds by host s cellular enzymes Acyclovir triphosphate inhibits viral DNA synthesis by two mechanisms Competitive inhibition of deoxyGTP for the viral DNA polymerase with binding to the DNA template as an irreversible complex Incorporation into the viral DNA chain termination Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial Resistance HSV or VZV alteration in either the viral thymidine kinase or the DNA polymerase resistance Cross resistance to valacyclovir 伐昔洛韦 famciclovir 泛昔洛韦 and ganciclovir 更昔洛韦 Agents such as foscarnet 膦甲酸 cidofovir 西 多福韦 and trifluridine 三氟尿苷 do not require activation by viral thymidine kinase and thus have preserved activity against the most prevalent acyclovir resistant strains Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial Pharmacokinetics Available in oral intravenous and topical formulations Oral bioavailability is 15 20 Plasma protein binding is low diffuses into most tissues and body fluids Cleared primarily by glomerular filtration and tubular secretion Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial Clinical uses Treatment of HSV infection first selection Topical acyclovir is much less effective than oral therapy for primary HSV infection It is of no benefit in treating recurrences VZV is less susceptible to acyclovir than HSV high doses are required Adverse reactions Nausea diarrhea headach Intravenous infusion renal insufficiency or neurologic toxicity Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial Valacyclovir The L valyl ester of acyclovir It is rapidly converted to acyclovir after oral administration achieving serum levels three to five times greater than those achieved with oral acyclovir Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial Ganciclovir An acyclic guanosine 鸟苷 analog Against CMV is up to 100 times greater than that of acyclovir Adverse reactions Myelosuppression 骨髓抑制 particularly neutropenia 嗜中性白血球减少症 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial Trifluridine 曲氟尿苷 Trifluorothymidine 三氟胸腺嘧啶核苷 Fluorinated pyrimidine nucleoside Against HSV 1 HSV 2 vaccinia 牛痘 and some adenoviruses 腺病毒 Incorporation of trifluridine triphosphate into both viral and cellular DNA prevents its systemic use Therapy for keratoconjunctivitis 角膜结膜炎 and for recurrent epithelial keratitis due to HSV 1 and HSV 2 Topical application alone or in combination with interfon alfa has been used successfully in treatment of acyclovir resistant HSV infections Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial Vidarabine ara A Adenosine analog Against HSV VZV CMV HBV and some RNA viruses Phosporylated intracellular by host enzymes to form ara ATP incorporated into both viral and cellular DNA excessive toxicity Rapidly metobolized to hypoxanthine arabinoside Instability and toxicity limited its clinical utility Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial Topical application for acute keratoconjunctivitis 角膜结膜炎 superficial keratitis 表皮角膜炎 and recurrent epithelial keratitis due to HSV 1 and HSV 2 Intravenous for treatment of HSV encephalitis neonatal herpes and VZV infection in immunocompromised patients Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial Idoxuridine Competitive inhibition of thymidylic acid synthase block DNA synthesis No effect on RNA virus Only topical application because of its greater side effects in systemic application Treatment of ocular or dermal infections due to herpesvirus or cowpox virus especially acute epithelial keratitis due to herpesvirus Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial Ribavirin Virazole Guanosine analog Phosphorylated intracellularly by host cell enzymes Mechanism to interfere with the synthesis of guanosine triphosphate to inhibit capping of viral messenger RNA and to inhibit the viral RNA dependent RNA polymerase of certain viruses Ribavirin triphosphate inhibits the replication of a wide range of DNA and RNA viruses including influenza A and B parainfluenza 副流感病毒 respiratory syncytial virus 呼吸道合胞病毒 paramyxoviruses 副粘病毒 HCV 丙 肝病毒 and HIV 1 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial Lamivudine 3TC Cytosine analog Against HIV 1 synergistic with a variety of antiretroviral nucleoside analogs including zidovudine and stavudine Treatment of chronic hepatitis B infection Oral bioavailability exceeds 80 and is not food dependent The majority of lamivudine is eliminated unchanged in the urine Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial Nonnucleoside Antiviral Agents Including Rimantadine and Amantadine Foscarnet Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial Rimantadine and Amantadine Rimantadine is Amantadine s methyl derivative Cyclic amines Inhibit uncoating of the viral RNA of influenza A within infected host cells Prevention of influenza A virus infection Reduce the duration of symptoms of influenza when administered within 48h of onset Adverse effects gastrointestinal intolerance central nervous system complaints nervous difficulty in concentrating lightheadedness Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial Foscarnet An inorganic 无机的 pyrophosphate 焦磷酸 盐 compound Inhibit viral DNA polymerase RNA polymerase and HIV reverse transcriptase directly without activation by phosphorylatio
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