Mechanistic aspects of the synergistic antiviral effect of xanthates and monocarbonic acids

The xanthate tricyclodecan-9-yl-xanthogenate (D609) displays antiviral and antitumoral properties that are inversely proportional in vitro to the serum concentration. Accordingly, it has been found that D609 binds to serum albumin. Recently, we have reported that D609, in combination with undecanoic acid, has a synergistic antiviral effect, which appears, as shown here, to be due to competition for the same binding domain on serum albumin. Furthermore, undecanoic acid fosters the binding of D609 to the cell. Both the competition of D609 with monocarbonic acid for binding on serum albumin and the enhanced binding of xanthate to the cell are dependent, in accordance with previously reported results, on the chain length of the fatty acids. Eleven to 14 C-atoms (undecanoic, lauric and myristic acid) were found to be appropriate while shorter (C6) and larger (C18) monocarbonic acids were shown to lack synergistic properties.     

Synergistic inhibition of herpesvirus replication by docosanol and antiviral nucleoside analogs

Interactions between docosanol (n-docosanol, behenyl alcohol) and nucleoside or pyrophosphate analogs were investigated in vitro. The anti-HSV activity of acyclovir (ACV) was synergistically enhanced by treatment of cells with docosanol as judged by inhibition of progeny virus production and plaque formation. This drug interaction between ACV and docosanol was observed with laboratory strains of herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), oral and genital clinical isolates of HSV, cytomegalovirus (CMV), and varicella zoster virus (VZV). Near optimal concentrations of docosanol plus ACV inhibited HSV replication >99% more than either drug alone, including emergence of ACV-resistant variants. The response was observed with African Green Monkey kidney cells, normal human foreskin cells, and normal human lung cells. Treatment of cells with docosanol also synergistically intensified the inhibition of HSV production by all tested nucleoside analogs, including trifluorothymidine (TFT), adenine arabinoside (Ara-A), and ribavirin. An additive anti-HSV effect was observed with docosanol and phosphonoformate (PFA). No evidence was found for either synergistic inhibition of cellular DNA synthesis or induction of overt cellular toxicity when docosanol was combined with ACV, TFT, Ara-A, ribavirin, PFA, 8-azaguanine, or 5-fluorouracil. The ability of docosanol treatment to increase the antiviral activities of nucleoside analog antiviral drugs, coupled with a lack of toxic interactions, translates to substantial improvements in drug selectivity ratios.     

In vitro antiviral activity of aphidicolin and its derivates. Synergistic effects of aphidicolin with other antiviral drugs

Twenty derivatives of aphidicolin were tested against HSV (herpes simplex virus), HCMV (human cytomegalovirus) and adenovirus in vitro. In addition, the antiviral activity of aphidicolin (CAS 38966-21-1) in combination with aciclovir (CAS 59277-89-3) or cidofovir (CAS 113852-37-2) against HSV was determined. The antiviral effects were evaluated using plaque reduction assay in Vero cells or human Foreskin Fibroblasts (HFF) for HSV and HCMV, respectively. Combination indexes were calculated using the method of Chou and Talalay. Two derivatives (K14254 and K14266) that are considered to be prodrugs of aphidicolin were shown to inhibit HCMV and HSV replication comparably to aphidicolin. None of the tested substances inhibited adenovirus replication. Aphidicolin acted synergistically with aciclovir in a 1:1 molar ratio and with cidofovir in different ratios. Aphidicolin and its two antiviral active derivatives might represent useful additional tools for antiviral therapy of HSV and HCMV infections, especially in combination with clinically used drugs.     

抗病毒新药17997抗病毒效应的细胞微量量热的研究

目的研究抗病毒新药17997对细胞代谢的影响和抑制病毒复制时细胞热效应的变化。方法利用微量量热的方法。结果热代谢曲线表明 ,在有效抑制病毒复制浓度下 ,17997不影响宿主细胞的正常代谢 ,且能明显地降低病毒复制时的细胞热代谢。结论17997能够抑制病毒复制 ,对宿主细胞的热代谢没有影响。     

Synergistic effect of cephalexin with mecillinam

In vitro and in vivo synergistic effects of cephalexin and mecillinam against Escherichia coli, Klebsiella pneumoniae, Enterobacter sp., Serratia marcescens and Proteus sp. were demonstrated and their action mechanism were also discussed. The growth curve after the exposure of cephalexin and mecillinam at the concentrations at which these antibiotics had no effects when given alone showed a decreased of the turbidity and the presence of a bactericidal effect. In experimental infection in mice, the combination of both drugs showed a synergistic effect and excellent therapeutic effect. The blood concentration ratio of cephalexin to mecillinam was coincident with the concentration ratio of these antibiotics at which the synergistic effect was observed in vitro. Phase-contrast and scanning electron somewhat elongated bacteria and formation of spindle cells with swelling in the central part. A leakage of the cellular contents from part of the swelled cell wall was observed by transmission electron microscope. Cephalexin showed an affinity for penicillin binding proteins (PBPs)-1a and 3 in Escherichia coli and mecillinam showed an affinity for PBP-2. When these antibiotics were used concurrently, they exerted an additive effect to increase the affinity for PBPs. The lytic activity was increased much more after the combination of two antibiotics than after a single exposure.     

千金藤素抗病毒作用的免疫学机制研究

目的 探索千金藤素体内外的抗病毒作用,并基于抗病毒天然免疫通路探究其抗病毒作用的分子机制。方法 CCK-8 法检测千金藤素（0.062 5～64.000 0 μmol·L^-1）对 A549 细胞活力的影响;利用表达绿色荧光蛋白的水疱性口炎病毒（VSV-GFP）感染 A549 细胞模型,结合流式细胞术检测千金藤素对病毒复制的影响并探究预处理、吸附过程及吸附后加药对 VSV-GFP 病毒复制的影响;实时荧光定量 PCR（qRT-PCR）检测千金藤素对甲型流感病毒（H1N1）、脑心肌炎病毒（EMCV）和单纯疱疹病毒 I 型（HSV-1）复制的影响;构建 VSV 感染小鼠模型探究千金藤素的体内抗病毒作用;A549细胞中利用生物信息学方法探究其抗病毒机制;qRT-PCR 检测药物处理 A549 和原代胚胎成纤维细胞（MEF）后 IFNB1 及干扰素刺激基因 （ISGs） 表达变化;免疫印迹法 （Immunoblotting） 检测人源单核细胞白血病细胞（THP-1）中 TBK1 和STAT1 的磷酸化水平。结果 与模型组相比,千金藤素在 A549 细胞中显著抑制 VSV、H1N1、EMCV 和 HSV-1 复制;千金藤素不影响 VSV 的吸附过程,而预处理或吸附后给药可以显著抑制病毒复制;千金藤素提高 VSV 感染小鼠的存活率;千金藤素激活基于IFN-I通路的抗病毒天然免疫应答。结论 千金藤素通过激活基于IFN-I通路的抗病毒天然免疫发挥体内外抗病毒作用。     

Synergistic antiviral activity of acyclovir and vidarabine against herpes simplex virus types 1 and 2 and varicella-zoster virus

Acyclovir and vidarabine both exhibit anti-herpetic activity. Because different mechanisms of action of vidarabine and acyclovir have been reported, we analyzed their combined anti-herpetic activity on plaque formation of herpes simplex virus (HSV)-1, HSV-2, and varicella-zoster virus (VZV) by isobolograms. The results indicate that acyclovir and vidarabine have a synergistic effect on wild type HSV-1, HSV-2, and VZV. The susceptibility of thymidine kinase-deficient HSV-1 to vidarabine was not affected by the presence of acyclovir, suggesting that phosphorylation of acyclovir is essential for synergism. The combined anti-HSV activity of acyclovir and vidarabine against phosphonoacetic acid-resistant HSV-1 with DNA polymerase mutation did not show synergism in contrast to that against wild-type herpesviruses. Alteration of the substrate specificity of viral DNA polymerase to acyclovir and vidarabine annihilated the synergism. Thus, the nature of their binding sites on DNA polymerase is important to the synergistic anti-herpesvirus activity of acyclovir and vidarabine.     

海洋抗生素吲哚-2,3-二酮的抗病毒作用

目的研究天然海洋抗生素吲哚-2,3-二酮(ISA)的抗病毒作用和免疫调节作用。方法建立仙台病毒(SV)感染BHK-21细胞模型,用细胞病变效应(CPE)法观察ISA的抗病毒活性;建立SV感染小鼠模型,通过血凝抑制实验观察ISA对小鼠的免疫功能调节作用。结果ISA浓度在0.313 mg.mL-1以上时,对细胞显示毒性作用;在0.156~0.039mg.mL-1范围内,药物的细胞毒性作用消失,显示抗病毒作用,并具有一定的量效关系;血凝抑制试验显示ISA高剂量(2%)可以促进血抑抗体产生。结论吲哚-2,3-二酮具有抗病毒作用,同时具有免疫增强作用。     

柴黄双解颗粒抗菌、抗病毒作用的研究

目的：观察柴黄双解颗粒抗菌、抗病毒的作用。方法体外观察柴黄双解颗粒对常见致病菌抑制作用、对流感病毒甲1型、甲3型和腺病毒致细胞病变作用的影响。结果柴黄双解颗粒体外对所试病毒所致的细胞病变及所试常见致病菌均显示抑制作用。结论柴黄双解颗粒体外有抗甲型流感病毒、腺病毒及抗菌的作用。     

The safety and antiviral effect of protease inhibitors in children

STUDY OBJECTIVE: To determine the safety and antiviral effect of protease inhibitors (PIs) over 36 months in pediatric patients infected with the human immunodeficiency virus (HIV). DESIGN: Observational study SETTING: Pediatric immunodeficiency clinic. PATIENTS: Twenty-one children. INTERVENTION: Demographics, dosage regimens, genotype data, viral RNA and CD4+ lymphocyte counts, adverse drug events (ADEs), laboratory tests, and compliance were evaluated over 3 years. Data were analyzed by chi2, repeated measures analysis of variance, and paired t tests. MEASUREMENTS AND MAIN RESULTS: Twenty-one pediatric patients (aged 3 mo-15 yrs) received PIs over the study period. Average daily doses were ritonavir 26 mg/kg in 12 patients, nelfinavir 94 mg/kg in 16, indinavir 49 mg/kg in 5, and saquinavir 43 mg/kg in 4. Five patients developed resistance to an existing PI. Overall compliance was 70%. Baseline HIV-1 RNA plasma concentrations were significantly higher than average follow-up concentrations during 3-36 months in patients taking ritonavir (p<0.001) and nelfinavir (p<0.001). Sample size was insufficient for indinavir or saquinavir. Sixty ADEs occurred, diarrhea being most common. Of patients with ADEs, 55% required increased monitoring and 43% treatment. Ritonavir was associated with the most ADEs (28), followed by nelfinavir (16), indinavir (11), and saquinavir (5). Significant increases between baseline and follow-up cholesterol levels were found with ritonavir (p=0.02) and nelfinavir (p=0.001), and for serum creatinine (p=0.02) and triglycerides (p=0.02) with ritonavir. Follow-up triglycerides were significantly higher than baseline for indinavir (p=0.003). CONCLUSION: Nelfinavir and ritonavir were effective in decreasing HIV-1 viral loads and improving CD4+ lymphocyte counts. Ritonavir was associated with more ADEs than other PIs. Changes in cholesterol, serum creatinine, and triglycerides were noted with some PIs.     

Protein kinase C and the antiviral effect of human interferon

Protein kinase C (PKC) inhibitors: Hidaka's compounds H-7 (10 microM) and H-8 (20 microM), palmitoyl-carnitine (10 microM) and phloretin (50 microM), did not modify the antiviral effect of human natural or recombinant interferon alpha and of natural interferon beta. The tumor promoter 12-o-tetradecanoyl-phorbol-13-acetate (TPA) (200 nM), known as activator of PKC induced an antiviral state when tested on human embryo fibroblasts challenged with the vesicular stomatitis virus. The battery of PKC inhibitors used inhibited the antiviral effect induced by TPA. Palmitoyl-carnitine (10 microM) exerted a toxic effect that was reversed by interferon treatment (2,000 IU/ml interferon alpha). These results suggest that PKC, possibly activated by interferon-receptor interaction, is not essential for inducing the antiviral effect of interferon, but, probably, mediates the antiviral effect of TPA.     

Formation and antiviral effect of N-(adamantyl-91))-thiocarbamides

Formation and Virus Inhibitory Activity of N-[1-Adamantyl]-thioureas Interaction of 1 -amino-adamantane ( 1 ) with isothiocyanates ( 2 ) results in the formation of N-[ 1 -adamantyl]-thioureas ( 3 ). Chemical structure proof of 3 has been adduced by an independent synthesis involving the reaction of 1 -adamantyl-isothiocyanate ( 4 ) with the corresponding amines ( 5 ).