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1、SARS 病人之藥物治療,中國醫藥學院附設醫院內科部 感染科 陳志銘,The clinical progression of SARS Phase I,Week 1 was characterised by fever, myalgia, and other systemic symptoms that generally improve after a few days. The increasing viral load during this phase suggests that the symptoms are largely related to the effect of vir
2、al replication and cytolysis.,Lancet 09 May, 2003,The clinical progression of SARSPhase II,As the disease progressed into week 2Recurrence of fever, onset of diarrhoea, and oxygen desaturation. Strikingly, nearly half the patients had shifting radiographic shadows.,Lancet 09 May, 2003,Lancet 09 May,
3、 2003,Seroconversion of IgG,The timing of the IgG seroconversion, which starts on day 10, seems to correlate with falls in viral load, which occurs from between day 10 and 15.,Lancet 09 May, 2003,Viral loads of nasopharyngeal aspirate,Progressive decrease in rates of viral shedding from nasopharynx,
4、 stool, and urine from day 10 to 21 after onset of symptoms.,Lung pathology of fatal SARS,SARS is associated with Epithelial-cell proliferation and an increase in macrophages in the lung. The presence of haemophagocytosis supports the contention that cytokine dysregulation may account, at least part
5、ly, for the severity of the clinical disease.Lung damage at this phase is related to immunopathological damage as a result of an overexuberant host response, rather than uncontrolled viral replication.,Lancet 16 May, 2003,The clinical progression of SARS Phase III,20% of patients in this cohort prog
6、ressed to the third phase, characterised by ARDS necessitating ventilatory support.,Lancet 09 May, 2003,Lancet 09 May, 2003,SARS發病的可能病理過程,Acute lung injury and SARS virus,SARS的致病機制及治療,1.第一期（17天）：病毒複製期，抗病毒藥物2.第二期（714天）：細胞激素風暴期（cytokine storm），肺部發炎、破壞，用類固醇3.第三期（14天-）：肺纖維化（呼吸治療）、繼發細菌真菌感染應注意藥物副作用、免疫抑制,感
7、染 -7,發病 0,7,14,第一期,第二期,第三期,Goals,Prevent transmission: reduce viral shedding Reduce mortality Prevent intubation: improve oxygenation, stop clinical progression to ARDS Shorten hospitalization: rapid recovery Reduce long-term sequelae,Standard treatment protocol for SARS in adult patients,Antibacter
8、ial treatment Cover typical and atypical pneumonia.Ribavirin MethylprednisoloneVentilation,Standard treatment protocol for SARS in adult patients,Antibacterial treatment Cover typical and atypical pneumonia.Start levofloxacin 500 mg once daily intravenously or orallyOr clarithromycin 500 mg twice da
9、ily orally plus coamoxiclav (amoxicillin and clavulanic acid) 375 mg three times daily orally if patient 18 years, pregnant, or suspected to have tuberculosis,Lancet 10 May, 2003,Standard treatment protocol for SARS in adult patients,Ribavirin and methylprednisoloneAdd combination treatment when:Ext
10、ensive or bilateral chest radiographic involvementOr persistent chest radiographic involvement and persistent high fever for 2 daysOr clinical, chest radiographic, or laboratory findings suggestive of worseningOr oxygen saturation 95% in room air,Lancet 10 May, 2003,Ribavirin regimen,Ribavirin regim
11、en for 1014 daysRibavirin 400 mg every 8 h (1200 mg daily) intravenously for at least 3 days (or until condition becomes stable)Then ribavirin 1200 mg twice daily (2400 mg daily) orally,Lancet 10 May, 2003,Corticosteroid regimen,Standard for 21 days Methylprednisolone 1 mg/kg every 8 h (3 mg/kg dail
12、y) intravenously for 5 daysThen methylprednisolone 1 mg/kg every 12 h (2 mg/kg daily) intravenously for 5 daysThen prednisolone 05 mg/kg twice daily (1 mg/kg daily) orally for 5 daysThen prednisolone 05 mg/kg daily orally for 3 daysThen prednisolone 025 mg/kg daily orally for 3 daysThen off,Lancet 1
13、0 May, 2003,Pulsed methylprednisolone,Give pulsed methylprednisolone if clinical condition, chest radiograph, or oxygen saturation worsens (at least two of these), and lymphopenia persistsGive as methylprednisolone 500 mg twice daily intravenously for 2 days, then back to standard corticosteroid reg
14、imen,Lancet 10 May, 2003,Ventilation,Consider non-invasive ventilation or mechanical ventilationif oxygen saturation 6 L per min oxygen orif patient complains of increasing shortness of breath,Lancet 10 May, 2003,Treatment regimen,RibavirinGuanosine analogueinhibits replication of many RNA and DNA v
15、iruses,Ribavirin,Treatment regimen,Ribavirin activitiesRSVInfluenza A and B,HSV-1 and HSV-2ParainfluenzaAerosol therapy:- not employedmay help spreading of virus,Clinical studies,RSV bronchiolitis and pneumonia in hospitalized children: aerosol +/- IVIGChronic hepatitis C: oral ribavirin + IFNLassa
16、fever + elevated AST or high-titer viremia: IV or oral ribavirin (within 6 days of illness)Viral hemoorhagic fever with renal syndrome Hantavirus pulmonary syndrome Post-exposure prophylaxis in contacts of Lassa fever and other viral hemorragic fever,Mechanism of action:,3 hypotheses:decrease intrac
17、ellular pools of guanosine triphosphate, suppress synthesis of viral nucleic acidsynthesis of RNA with abnormal 5 cap structures leads to inefficicent translation of viral transcriptsdirect suppressive effect on viral polymerase activities,Ribavirin - mechanisms of action,Ribavirin,Contraindications
18、:chronic anemia and Hb 10g/dlCrCl 30ml/minhypersensitivity to the drugPrecautions:predisposition goutrenal and hepatic impairment (dosage reduction),Ribavirin,Contraindications:chronic anemia and Hb 10g/dlCrCl 30ml/minhypersensitivity to the drugPrecautions:predisposition goutrenal and hepatic impai
19、rment (dosage reduction),Side effects:,haemolytic anaemia (mild to moderate, reversible)CNSdizziness, headache, fatigue, fever, insomnia, irritability, depression, emotional lability, impaired concentrationNausea, vomitingTeratogenic and carcinogenicContraindicated in pregnancy?,Adverse Effects of R
20、ibavirin,Canada, 144為SARS病人中的126位Loading dose 2gm, 然後 1gm IV Q6H 用4天，接著500mg Q8H 口服3天。副作用：Hb 2gm/dl：49%Hemolysis：76%Bradycardia：14%Sore throat：4%Aminotransferase：40%18%病人因副作用而停止用藥。,Precautions,Teratogenicity: contraceptive cover 6 months after cessation females & males,類固醇治療,約在發病7天後（進入細胞激素風暴期），才開始使用
21、。一種劑量使用五天後，才開始減少劑量。Methylprednisolone 效果比Decadron好。,恢復期血清療法,香港中文大學醫學院，40位SARS病患甲組：使用康復者血清 20位 無人死亡乙組：沒有使用康復者血清 20位 3人死亡,恢復期血清療法,香港中文大學沈祖堯醫師發病兩週內使用恢復期血清療法：住院及發燒時間縮短死亡率降低,恢復期血清療法,限制：需由康復者捐出需選擇合適血型有病毒血症之問題適應症：病情發展快，有生命危險之人有潛在疾病之老年人孕婦,Neuramidase In SARS?,The significance of neuramidase in SARS is this:
22、 There is NO KNOWN neuramidase in any known coronavirus.Neuramidase is found in influenza viruses.SARS appears possibly to be an influenza orthomyxovirus - coronavirus hybrid.Neuramidase cleaves sialic acid inside cells and mediates viral attachment to the respiratory epithelium of the host and cons
23、equent infection of susceptible cells.,Neuramidase In SARS?,If this is, in fact, neuramidase, this would be the first known appearance of neuramidase in any coronavirus and would further suggest that SARS is an orthomyxovirus - coronavirus hybrid. Interestingly, the hemagglutinin-esterase in SARS sh
24、ows some relationship to a Type C Influenza as well - but SARS IS a coronavirus. a very weird coronavirus. but still a coronavirus.If SARS coronavirus is a naturally occurring coronavirus, efforts should be directed toward discovery of other orthymyxovirus-coronavirus hybrid-like viruses. There may
25、be sufficient evidence developed in time to reveal that SARS is not a true coronavirus nor a true orthomyxovirus and so become an entirely new species of virus all together.,Neuramidase In SARS?,Oseltamivir phosphate (Tamiflu)Action: inhibition of influenza virus neuraminidase with possible alterati
26、on of virus particle aggregation and release.,Neuramidase In SARS?,廣東鍾南山醫師Tamiflu 75mg 每天一顆口服，給工作人員使用，可降低染病率，若染病，症狀亦較輕微。,威爾斯醫院治療經驗,138 位病人 SARS 病人Positive response:退燒超過四天X光片infiltration 減少25%不再需要氧氣,威爾斯醫院治療經驗,Ribavirin and low dose steroid: 31(18%)有陽性反應High dose steroid therapy/pulse therapy: 95為有陽性反
27、應Total response rate: 126(95%),威爾斯醫院治療經驗,死亡率： 75: 28.6%,威爾斯醫院治療經驗,68% 死亡病人有一個或一個長期疾病。,威爾斯醫院治療經驗,死亡病例：發病到入院 7 日存活病例：發病到入院 5 日,香港治療經驗,Pamela Youde Nethersole Eastern Hospital, Hong Kong31位SARS病患，其中1位只用抗生素便痊癒，17位接受標準治療處方即有明顯改善，另外13位在增加類固醇劑量後也得到改善。有4位病人需要non-invasive ventilation，無人接受氣管插管。Lancet 2003: 361: 161517,SARS virus life cycle,第二線及第三線治療藥物,15 May, 2003,18 May, 2003,20 May, 2003,非典比愛滋容易攻剋 何大一,非典科學研究的進展步伐是驚人的，短短幾個月，科學家不僅發現了非典病毒，測定了病毒的基因組序列，開發出防治非典用的猴子動物模型，而且開始尋早抑制劑等藥物，雖然具體時間誰也不敢打包票，但長遠來說，人們會找到非典藥物和疫苗。,
