环胞苷(CC)与无环鸟苷(ACV)对小鼠三叉神经节内潜伏单纯疱疹病毒的作用

本文用试管内复活的HSV-1模型研究了CC和ACV对小鼠三叉神经节内潜伏HSV的作用。实验显示CC 10μg/ml和ACV 2.5μg/ml对潜伏病毒复活有明显抑制作用,CC 25μg/ml能达到与ACV 10μg/ml相当的作用强度,但在除去药物后其作用的维持时间不如ACV长。持续提供药物可以阻止潜伏病毒在试管内复活,即使采用间断给药方法亦不能完全排除潜伏病毒,但可以显著降低神经节内病毒滴度。二药联合应用对抑制潜伏病毒复活有协同作用。     

喜炎平注射液对人鼻病毒感染小鼠的抗病毒作用研究

目的：观察喜炎平注射液对人鼻病毒致小鼠感染的抗病毒作用。方法采用人鼻病毒感染小鼠作为模型,测定不同浓度喜炎平注射液对感染小鼠病死率及平均生活日的影响;测定其对感染小鼠气管—肺脏匀浆中的病毒滴度的影响,观察其抗病毒的能力。结果在观察的时间内,喜炎平注射液中剂量组与模型组比较,可显著减少病死率;与模型组相比,喜炎平可显著延长动物平均生存时间;喜炎平不同剂量组对病毒感染小鼠的肺脏病变均有不同程度的改善作用;喜炎平注射液可明显降低气管—肺脏组织匀浆中病毒滴度。结论喜炎平注射液具有抗人鼻病毒的治疗作用,在体内可有效抑制人鼻病毒增殖,能减轻受试动物呼吸道病变,提高存活率,不良反应很低,为进一步临床推广应用提供了实验依据。     

夏桑菊抗呼吸道合胞病毒的实验研究

目的 评价夏桑菊抗呼吸道合胞病毒(RSV)的疗效.方法 以病毒唑为对照,通过体外观察病毒致细胞病变效应(CPE)、病毒滴度、抗病毒指数;在体内观察其对染毒小鼠的死亡保护作用以及对小鼠心、脑、肺内病毒增殖的影响,从而判定夏桑菊抗RSV作用.结果 夏桑菊能抑制RSV的增殖,其有效浓度为544.59 μg/ml,并显示出病毒的感染性滴度随药物浓度的增加而下降;治疗RSV感染鼠结果 发现夏桑菊对RSV感染鼠有保护作用,10 g/(kg*d)时,RSV感染鼠的存活率为50%,平均存活天数为(10.9±2.3)d,随着药物剂量增加,疗效增强,该药物还能降低组织内病毒滴度,阻止体内病毒复制,抗RSV作用类似于同剂量的病毒唑.结论 夏桑菊是一种抗呼吸道合胞病毒的有效药物.     

双黄连口服液抗呼吸道合胞病毒的实验研究

目的:评价双黄连口服液抗呼吸道合胞病毒(RSV)的活性。方法:以病毒唑为对照,通过体外观察病毒致细胞病变效应(CPE)、病毒滴度、抗病毒指数,在体内观察其对染毒小鼠的死亡保护作用,以及对小鼠心、脑、肺内病毒增殖的影响,从而判定双黄连口服液抗RSV作用。结果:双黄连口服液能抑制RSV的增殖,其有效浓度为12ug/mL,并显示出病毒的感染性滴度随药物浓度的增加而下降;治疗RSV感染鼠结果发现,双黄连口服液对RSV感染鼠有保护作用,6.7g.k-g 1.d-1时,RSV感染鼠的存活率为75%,平均存活天数为(12.9±2.8)d,随着药物剂量增加,疗效增强;该口服液还能降低组织内病毒滴度,阻止体内病毒复制,抗RSV作用类似于同剂量的病毒唑。结论:双黄连口服液是一种有效的抗RSV中药复方制剂。     

铁皮枫斗颗粒对放射损伤小鼠造血功能的影响

目的研究铁皮枫斗颗粒(DCWD)对放射损伤小鼠造血功能的影响。方法BALB/c小鼠125只,随机分为正常对照组、单纯照射组及DCWD大、中、小剂量组。采用直线加速器6 mV X射线8.0 Gy或5.0Gy全身单次均匀照射,照前连续灌胃10 d,每天1次,照后继续给药至小鼠死亡或活杀。观察受8.0 Gy照射小鼠的存活情况,检测受5.0 Gy照射小鼠外周血白细胞计数(PWBC)、骨髓有核细胞数(BMC)及脾指数。结果8.0 Gy照射后,受照各组小鼠平均存活时间均在10 d之内,较正常对照组明显缩短(P<0.01),给药组较单纯照射组延长3~4 d(P<0.01);5.0 Gy照射后小鼠PWBC、BMC和脾指数均显著下降,给药组高于单纯照射组(P<0.05),且恢复快,但给药各组之间差异无统计学意义。结论DCWD能明显延长受照小鼠平均存活时间,提高其存活率,显著提高其PWBC、BMC和脾指数;DCWD对放射损伤具有一定的保护作用,其机制可能与促进骨髓造血功能恢复有关。     

黄金方防治甲型H_1N_1流感病毒感染小鼠肺炎的实验研究

目的:观察黄金方对甲型H1N1流感病毒FM1株和PR8株感染小鼠肺炎的防治作用。方法:采用滴鼻感染正常小鼠和免疫低下小鼠建立流感病毒感染肺炎模型,分别采用治疗和预防性给药,观察对小鼠肺指数、死亡率、生存时间的影响。结果:治疗给药试验中黄金方大剂量组(6 g.kg-1)、中剂量组(3g.kg-1)可明显降低正常小鼠感染流感病毒FM1株或PR8株后肺指数(与模型组比较,P<0.05),3个剂量组均可明显减少正常小鼠感染流感病毒FM1株或PR8株后死亡率并延长生存时间(与模型组比较,P<0.01);预防给药试验中黄金方大剂量组(6 g.kg-1)、中剂量组(3 g.kg-1)可明显降低免疫低下小鼠感染流感病毒FM1株或PR8株后肺指数(与模型组比较,P<0.05),3个剂量组均可减少正常小鼠感染流感病毒FM1株后死亡率并明显延长生存时间(与模型组比较,P<0.01)。结论:黄金方在体内对H1N1流感病毒感染有较好的治疗和预防作用。     

青蒿鞣质抗单纯疱疹病毒机理初探

目的探讨青蒿鞣质(CTA)抗单纯疱疹病毒2型(HSV-2)的作用机理。方法采用细胞病变效应(CPE)抑制法和MTT法，以阿昔洛韦(ACV)为阳性对照药物，研究青蒿鞣质在体外对HSV-2的直接杀灭、病毒感染阻断、不同时间感染后的CPE抑制效果。结果CTA对病毒具有明显的直接杀灭作用，可以阻断病毒的吸附过程和抑制病毒在细胞内的复制，而且CTA对病毒的抑制作用受病毒吸附时间的影响很小，具有明显的治疗作用，其效果与阳性对照药物无环乌苷(ACV)相当。结论CTA体外抗HSV-2作用可以通过多种途径发挥作用。     

五麦党黄口服液对辐射损伤小鼠防护作用的初步研究

目的研究抗辐射复方中药五麦党黄口服液(WMDH)的辐射防护作用。方法将小鼠分为5组,即正常对照组、模型组、3个给药剂量组,连续给药14 d,末次给药后3 h采用60Coγ射线一次性全身照射(7.5 Gy),于照射后记录各给药组存活时间及30 d存活率;另分组及给药剂量同前,连续给药14 d,采用60Coγ射线一次性全身照射(3.0 Gy),测定各给药组动物外周血白细胞数、胸腺、脾脏指数。结果WMDH口服液可显著延长受照射小鼠的存活时间,升高外周血白细胞数、胸腺指数、脾脏指数。结论WMDH口服液对试验小鼠核辐射损伤具有明显的保护作用,值得进一步研究和开发。     

青蒿鞣质抗单纯疱疹病毒机理初探

目的　探讨青蒿鞣质 (CTA)抗单纯疱疹病毒 2型 (HSV- 2 )的作用机理。方法　采用细胞病变效应 (CPE)抑制法和MTT法 ,以阿昔洛韦 (ACV)为阳性对照药物 ,研究青蒿鞣质在体外对HSV -2的直接杀灭、病毒感染阻断、不同时间感染后的CPE抑制效果。结果　CTA对病毒具有明显的直接杀灭作用 ,可以阻断病毒的吸附过程和抑制病毒在细胞内的复制 ,而且CTA对病毒的抑制作用受病毒吸附时间的影响很小 ,具有明显的治疗作用 ,其效果与阳性对照药物无环乌苷 (ACV)相当。结论　CTA体外抗HSV 2作用可以通过多种途径发挥作用。     

甘西鼠尾草注射液与丹参注射液对化学性缺氧小鼠能量代谢影响的比较

目的 :比较甘西鼠尾草注射液与丹参注射液对急性化学性缺氧小鼠能量代谢的影响。方法 :通过注射NaNO2 造成小鼠急性化学性缺氧 ,记录小鼠存活时间 ,用ATPase、LD检测试剂盒分别检测脑组织中Na K ATPase、Ca2 ATPase和乳酸 (LD)含量 ,比较两药对能量代谢的影响。结果 :两药均可延长化学性缺氧小鼠存活时间 ,增强Na K ATPase。Ca2 ATPase活力 ,降低LD含量 ,其中大剂量甘西鼠尾草注射液较大剂量丹参注射液更能增强Na K ATPase活力 ,而小剂量的甘西鼠尾草注射液在增强Ca2 ATPase活力上较小剂量的丹参注射液作用更强 ;在降低缺氧小鼠脑组织LD含量方面 ,两药作用基本相似。结论 :丹参注射液和甘西鼠尾草注射液对缺氧小鼠的能量代谢均有改善作用。两药均可延长缺氧小鼠存活时间 ,降低脑组织LD含量 ,提高ATPase活力 ,但甘西鼠尾草注射液在提高ATP酶活力方面优于丹参注射液     

Efficacy of (E)-5-(2-bromovinyl)-2′-deoxyuridine in the treatment of experimental herpes simplex virus encephalitis in mice

Systemic treatment of mice with (E)-5-(2-bromovinyl)-2′-deoxyuridine (BVDU) showed a significant therapeutic efficacy against herpes simplex type 1 virus (HSV-1) encephalitis. With treatment initiated 12 h after viral inoculation and continued for 10 consecutive days, BVDU administered intraperitoneally in daily doses of 100–500 mg/kg increased the 21-day survival rates from 30 to 100% and reduced brain virus titers by 3–4 log₁₀ on day 6 post-infection. Furthermore, at doses of 300–500 mg/kg per day BVDU prevented the establishment of latent virus infection in the trigeminal ganglia following intracerebral HSV-1 inoculation.     

格尔德霉素体内外抑制单纯疱疹病毒l型的复制

格尔德霉素(GA)是一种抗生素,它的作用靶点是热休克蛋白Hsp90 N末端的ATP/ADP结合位点.在我们对抗病毒的抗生素筛选中,发现格尔德霉素显著抗单纯疱疹病毒1型(HSV一1).体外在Vero细胞内GA显著抑制HSv-1的复制,IC50为0,093μmol/L,GA对Vero细胞的毒性CC50为350μmol/L,治疗指数可达3763.HSV-1腹腔(ip)感染1h后腹腔(ip)注射GA(0.093～0.37mg/kg)可以将存活率增加到67%～100%,皮下(sc)给药(0.37mg/kg)的存活率为43.8%,都明显高于生理盐水对照组(ipP＜0.001.scP＜0.05).GA对小白鼠的急性LD50为15.5mg/kg(ip).格尔德霉素不影响病毒的吸附、穿人.由于GA在体内外都能抑制单纯疱疹病毒1型,GA可以成为新的抗单纯疱疹病毒感染的药物.     

Efficacy of oral treatment with BV-araU against cutaneous infection with herpes simplex type 1 in shaved mice.

The effect of oral BV-araU was tested in cutaneous model infections of shaved Balb/c mice with herpes simplex virus type 1 (HSV-1). Progression of cutaneous symptoms associated with cutaneous infection with HSV-1 F strain was inhibited by BV-araU at doses of 20 and 50 mg/kg twice daily, beginning one day post-infection, resulting in significant increase in the survival rate. Onset of disease was suppressed in most animals receiving 100 mg of BV-araU per kg. BV-araU (20 mg/kg or more) also significantly increased the survival rate of mice infected with HSV-1 WT-51 strain. The efficacy of BV-araU was not affected by gender or age (6-9 weeks) of the mice. BV-araU was effective even when the treatment was started 2.5 days post-infection. The efficacy of BV-araU against F strain infection was comparable to that of acyclovir, but acyclovir showed therapeutic effects at lower doses compared with BV-araU against WT-51 strain infection. Against infection of cyclophosphamide-treated immunosuppressed mice with HSV-1 KOS(S) strain, BV-araU decreased the morbidity rate and severity of symptoms at doses of 200 and 100 mg/kg, respectively, and all mice given 50 mg of BV-araU or more per kg survived, suggesting oral efficacy can be achieved against HSV-1 infections in immunosuppressed individuals.     

C3H/HeN mouse model for the evaluation of antiviral agents for the treatment of Venezuelan equine encephalitis virus infection

The TC-83 vaccine strain of Venezuelan equine encephalitis virus (VEEV) causes encephalitis and death in C3H/HeN mice infected by intranasal (i.n.) instillation. Since TC-83 is exempt as a select agent, this mouse model was used in the evaluation of antiviral therapies. Virus titers in the brains of infected mice peaked on 4 dpi and persisted at high levels until death at 9.4+/-0.5 dpi. Mouse brains appeared histologically normal on 2 dpi, but developed meningoencephalitis, neuropil vacuolation, and gliosis by 8 dpi. Results from a protein cytokine array showed significant elevations over time in interleukin (IL)-1alpha, IL-1beta, IL-6, IL-12, MCP-1, IFNgamma, TNFalpha, MIP-1alpha, and RANTES in homogenized brain samples of infected mice. Immunohistochemical staining showed a colocalization of viral antigen with neuron markers. Treatment with interferon-alpha B/D or ampligen significantly improved survival, brain virus titer and cytokine levels, mean day-to-death, and weight change in infected mice. The time-course of infection and disease parameters of mice infected with TC-83 VEEV were similar in many ways to disease parameters in mice infected with other VEEV strains. Thus, infection of C3H/HeN mice with TC-83 VEEV may serve as a suitable model for the evaluation of antiviral compounds for the treatment of this viral disease.     

Broad-spectrum antiviral activity of the acyclic guanosine phosphonate (R,S)-HPMPG

(R,S)-9-(3-hydroxy-2-phosphonomethoxypropyl)guanine [(R,S)-HPMPG] exhibits broad spectrum antiviral activity with an ED50 of less than 1 microM against herpes simplex virus (HSV) types 1 and 2, varicella zoster virus, human cytomegalovirus (HCMV) and vaccinia in plaque reduction assays. Wild type HSV-2 and its thymidine kinase deficient variant are equally sensitive to (R,S)-HPMPG. (R,S)-HPMPG is 100-fold more potent than acyclovir (ED50 = 0.45 microM vs. 44 microM, respectively) against HCMV in cell culture, and 10-fold more active than acyclovir in extending survival time in mice intraperitoneally infected with 70 LD50 HSV-1. However, (R,S)-HPMPG is toxic when administered repeatedly at 44 mg/kg/day in uninfected adult mice. The diphosphoryl derivative of HPMPG was enzymatically synthesized and is a competitive inhibitor of HSV-1 DNA polymerase relative to dGTP (K1 = 0.03 microM). HPMPG-PP is 70-fold less active at inhibiting HeLa DNA polymerase alpha than HSV-1 DNA polymerase. At concentrations between 0.3 and 1.5 microM (R,S)-HPMPG inhibited HSV-1 DNA replication greater than or equal to 50% in infected cells as measured by nucleic acid hybridization. Consistent with inhibition of viral DNA synthesis, 6 to 30 microM (R,S)-HPMPG reduces late viral polypeptide synthesis in HSV-1 infected cells. These data indicate that (R,S)-HPMPG is a thymidine kinase independent broad spectrum antiviral drug which is capable of inhibiting viral DNA polymerase.     

Mortality in mice infected with an amyocarditic coxsackievirus and given a subacute dose of mercuric chloride

An amyocarditic strain of coxsackievirus B3 (CVB3/0) induces heart damage when inoculated into selenium (Se)-deficient mice. Mercury (Hg), an Se antagonist, is known to aggravate viral infections. The experiments reported here assessed the effect of prior Hg treatment in mice subsequently inoculated with an amyocarditic strain of coxsackievirus. A pilot study showed that under our conditions the maximum tolerated dose of HgCl2 in uninfected mice was 6 mg HgCl2/kg body weight. In the main study, doses of 0, 3 or 6 mg HgCl2/kg body weight were administered intraperitoneally (ip) to 7-wk-old male mice fed a standard chow diet. Two hours later, half the mice were inoculated ip with CVB3/0. Ten days postinoculation, no mortality was observed in mice given only virus. In mice not given virus, 10% injected with 6 mg HgCl2/kg body weight died. On the other hand, 64% of the mice given both virus and 6 mg HgCl2/kg body weight died. Fifteen percent of the hearts from virus-infected mice given 3 mg HgCl2/kg body weight and 33% of the hearts from virus-infected mice given 6 mg HgCl2/kg body weight exhibited a higher incidence of lesions than hearts from mice-given virus alone. Moreover, viral heart titers were elevated in infected mice injected with 6 mg HgCl2/kg body weight compared to infected mice receiving no Hg. Thus, an amyocarditic coxsackievirus given to mice after a nonlethal subacute dose of Hg results in mortality, increased incidence of heart lesions, and elevated viral heart titers. These results demonstrate the important role of toxic elements in determining the severity of viral infections.     

Evaluation of anti-herpesvirus activity of (1'S,2'R)-9-[[1',2'-bis(hydroxymethyl)cycloprop-1'-yl]methyl]- guanine (A-5021) in mice.

The anti-herpesvirus activity of (1'S,2'R)-9-[[1',2'-bis(hydroxymethyl)cycloprop-1'-yl]methyl]guani ne (A-5021) was evaluated in murine cells and in several murine models of herpes simplex virus (HSV) infection. Against HSV type 1 (HSV-1), A-5021 was 15-30- and 30-60-fold more active, and against HSV type 2 (HSV-2), it was 2- and 8-fold more active than acyclovir and penciclovir in Balb/3T3 cells, respectively. When antiviral compounds were administered orally (once daily) to mice infected intraperitoneally with HSV-1 (Tomioka), A-5021 was more active than acyclovir or famciclovir in spite of its relatively low oral bioavailability. A-5021 was as active as penciclovir when the antiviral compounds were given intravenously (three times daily) to mice infected intraperitoneally with HSV-2 (186). In mice with a cutaneous HSV-1 (KOS) infection, three times daily oral therapy with A-5021 at 25 mg/kg per day produced more significant reduction in severity of skin lesions than equivalent treatment with acyclovir or famciclovir. In mice infected intracerebrally with HSV-1 (Tomioka), complete survival was observed in the group treated intravenously with A-5021 at 25 mg/kg per day (three times daily), while more than 50% of mice died in the groups treated intravenously with acyclovir of up to 100 mg/kg per day (three times daily). Moreover, A-5021 was more effective than acyclovir in clearing infectious virus from the brain. These findings demonstrate that A-5021 has potent anti-HSV activity in several murine models.     

Antiviral activity of the marine alga Symphyocladia latiuscula against herpes simplex virus (HSV-1) in vitro and its therapeutic efficacy against HSV-1 infection in mice

The antiviral activities of extracts from 5 species of marine algae collected at Haeundae (Pusan, Korea), were examined using plaque reduction assays. Although the activity of a methanol (MeOH) extract of Sargassum ringoldianum (Sargassaceae) was the most potent against several types of viruses, it was also cytotoxic. A MeOH extract of Symphyocladia latiuscula (Rhodomelaceae) and its fractions exhibited antiviral activities against acyclovir (ACV) and phosphonoacetic acid (PAA)-resistant (AP(r)) herpes simplex type 1 (HSV-1), thymidine kinase (TK(-)) deficient HSV-1 and wild type HSV-1 in vitro without cytotoxicity. The major component, 2,3,6-tribromo-4,5-dihydroxybenzyl methyl ether (TDB) of a CH(2)Cl(2)-soluble fraction was active against wild type HSV-1, as well as AP(r) HSV-1 and TK(-) HSV-1 (IC(50) values of 5.48, 4.81 and 23.3 microg/ml, respectively). The therapeutic effectiveness of the MeOH extract and TDB from S. latiuscula was further examined in BALB/c mice that were cutaneously infected with HSV-1 strain 7401H. Three daily oral administrations of the MeOH extract and TDB significantly delayed the appearance of score 2 skin lesions (local vesicles) and limited the development of further score 6 (mild zosteriform) lesions in infected mice without toxicity compared with controls. In addition, TDB suppressed virus yields in the brain and skin. Therefore TDB should be a promising anti HSV agent.     

Efficacy of Thai medicinal plant extracts against herpes simplex virus type 1 infection in vitro and in vivo

Twenty Thai medicinal plant extracts were evaluated for anti-herpes simplex virus type 1 (HSV-1) activity. Eleven of them inhibited plaque formation of HSV-1 more than 50% at 100 μg/ml in a plaque reduction assay. Aglaia odorata, Moringa oleifera, and Ventilago denticulata among the 11 were also effective against thymidine kinase-deficient HSV-1 and phosphonoacetate-resistant HSV-1 strains. These therapeutic efficacies were characterized using a cutaneous HSV-1 infection in mice. The extract of M. oleifera at a dose of 750 mg/kg per day significantly delayed the development of skin lesions, prolonged the mean survival times and reduced the mortality of HSV-1 infected mice as compared with 2% DMSO in distilled water (P<0.05). The extracts of A. odorata and V. denticulata were also significantly effective in limiting the development of skin lesions (P<0.05). There were no significant difference between acyclovir and these three plant extracts in the delay of the development of skin lesions and no significant difference between acyclovir and M. oleifera in mean survival times. Toxicity of these plant extracts were not observed in treated mice. Thus, these three plant extracts may be possible candidates of anti-HSV-1 agents.