Burger R A, Billingsley J L, Huffman J H, Bailey K W, Kim C U, Sidwell R W
Center for Persons with Disabilities, Utah State University, Logan, UT 84322-6895, USA.
Immunopharmacology. 2000 Apr;47(1):45-52. doi: 10.1016/s0162-3109(99)00184-8.
Oseltamivir (GS4104), the ethyl ester prodrug of the carbocyclic transition state sialic acid analog GS4071, has been reported to be a striking inhibitor of influenza A and B virus infections in mice and ferrets. Multiple studies indicate this material to also be active against the disease in humans, and it has recently been approved for human use. The effect of oral gavage (p.o.) therapy of oseltamivir on various immune factors considered to be of importance in primary influenza virus infection was studied in mice. Both uninfected animals and those infected with influenza A/NWS/33 (H1N1) virus were used. Doses of 100 mg kg(-1) day(-1) were administered twice daily for 5 days beginning 16 h pre-virus exposure. Two hours after end of treatment, the mice were killed and their spleens assayed for cytotoxic T lymphocyte (CTL) and natural killer (NK) cell activity. Subpopulations of splenic T, T-helper, T-cytotoxic and B lymphocytes as well as macrophages were determined using flow cytometry. Similar significant (P<0.01) increases in CTL activity were seen at effector:target cell ratios of 60:1 and 30:1 in the infected mice treated with oseltamivir or with placebo. NK cell activity was greater in the infected mice than in uninfected mice; the levels in all animals were not significantly affected by treatment with oseltamivir. Macrophage, T, T-helper, T-cytotoxic and B lymphocyte populations were similar in both treated and untreated animals. These data indicate treatment with oseltamivir does not adversely affect the primary in vivo cellular immune responses to influenza virus infection assayed in this study. The experiment was repeated to show that treatment with this compound significantly prevented the development of the infection and inhibited virus titers in the lung. Surviving treated mice on day 21 had mean neutralizing antibody titers of 1:208, and withstood rechallenge with the virus at this time, indicating the initial virus-inhibitory effect also did not prevent the animals from developing an adequate humoral immunity to the virus.
奥司他韦（GS4104）是环碳过渡态唾液酸类似物GS4071的乙酯前药，据报道它是小鼠和雪貂体内甲型和乙型流感病毒感染的显著抑制剂。多项研究表明该物质对人类疾病也有活性，并且它最近已被批准用于人类。在小鼠中研究了口服灌胃（p.o.）奥司他韦治疗对原发性流感病毒感染中被认为重要的各种免疫因子的影响。使用了未感染动物和感染甲型/新泽西/33（H1N1）病毒的动物。从病毒暴露前16小时开始，每天两次给予100mg kg⁻¹天⁻¹的剂量，持续5天。治疗结束后两小时，处死小鼠并检测其脾脏的细胞毒性T淋巴细胞（CTL）和自然杀伤（NK）细胞活性。使用流式细胞术测定脾脏T细胞、辅助性T细胞、细胞毒性T细胞和B淋巴细胞亚群以及巨噬细胞。在用奥司他韦或安慰剂治疗的感染小鼠中，在效应细胞：靶细胞比例为60:1和30:1时，CTL活性出现了类似的显著（P<0.01）增加。感染小鼠中的NK细胞活性高于未感染小鼠；所有动物的水平均未受到奥司他韦治疗的显著影响。在治疗和未治疗的动物中，巨噬细胞、T细胞、辅助性T细胞、细胞毒性T细胞和B淋巴细胞群体相似。这些数据表明，奥司他韦治疗不会对本研究中检测的流感病毒感染的原发性体内细胞免疫反应产生不利影响。重复该实验以表明用该化合物治疗可显著预防感染的发展并抑制肺中的病毒滴度。存活的治疗小鼠在第21天的平均中和抗体滴度为1:208，并且此时能够抵抗病毒的再次攻击，这表明最初的病毒抑制作用也并未阻止动物对病毒产生足够的体液免疫。
