Chemotherapy of Adenovirus Infections

Adenoviruses occupy a substantial place as causative agents of seasonal respiratory infections, the most characteristic and severe being epidemic keratoconjunctivitis (EKC). Moreover, adenovirus infections are very characteristic with their severe course in persons with impaired immune system. The absence of specific anti-adenovirals is the major problem, and the development of compounds effective against adenoviruses is a principal task. This chapter embraces the results of studies on search for antivirals with anti-adenovirus activity, nucleoside/nucleotide analogues and nonnucleoside compounds. Ganciclovir and cidofovir demonstrated effects against adenovirus serotypes in vitro and in animal ocular infection models. Cidofovir applied alone or in combination with cyclosporine manifested therapeutic effects on patients with EKC in a controlled clinical study. We characterized abitylguanide as anti-adenovirus agent in broad-scale investigations, including cell culture experiments, and in two double-blind trials with very beneficial results

Vitamin E and Influenza Virus Infection

Influenza is an infectious disease causing huge medical and economic losses. Influenza pathogenesis is associated with two processes in the human body: (i) lung damage due to viral replication in the columnar ciliary epithelium of bronchi and bronchioles and (ii) inflammatory burst inducing an increase in reactive oxygen species generation that causes extensive damage in cellular membranes of the small vessels. The oxidative stress in influenza virus-infected organism provokes free-radical oxidation of unsaturated lipid chains in the cell membranes. As vitamin E is a lipid-soluble substance and possesses a hydrophobic tail, it tends to accumulate within lipid membranes. There, it acts as the most important chain breaker, reacting with lipid peroxyl radicals much faster than they can react with adjacent fatty acid side chains. Among the antioxidants tested in influenza virus infections in mice, vitamin E occupies the leading position because of its efficacy in preventing oxidative damage through its free-radical scavenging activity. Although vitamin E is not possessing specific antiviral action, its antioxidant effect probably plays important role in lung and liver protection. Attention should be paid to the synergistic character of antiviral effect of the combination vitamin E and oseltamivir. Vitamin E could be recommended as a component in multitarget influenza therapy

Tannins as Antiviral Agents

Tannins possess a variety of biological effects, not a small part of which is of medical significance. Tannins, isolated from plants as well as synthetically obtained, manifest activity against a large spectrum of viruses: enteroviruses (polio- and coxsackie-), caliciviruses (feline calicivirus, mouse norovirus), rotavirus, influenza virus A, rhabdo- (vesicular stomatitis virus), paramyxoviruses (Sendai and Newcastle disease viruses), human immunodeficiency virus, herpes simplex virus, and adenoviruses. A special importance merits several ellagitannins manifesting pronounced effects against herpes simplex virus type 1 and 2 and on some herpes viruses affecting domestic animals, causing diseases of economic importance. An advantage of ellagitannins as anti-herpesvirus agents is that they have a non-nucleoside structure. Their targets are virus-specific proteins, so they retain activity against acyclovir-resistant strains of HSV types 1 and 2. Besides, these tannins manifest a synergistic effect with acyclovir when combined. Some initial results on their mechanism of action were carried out. In addition, it was found that most of the tannins have antioxidant properties in experimental models in vitro as well as in experimental influenza viral infection in mice

Urinary neopterin concentrations in patients with Balkan endemic nephropathy (BEN)

Urinary neopterin concentrations in patients with Balkan endemic nephropathy (BEN).BackgroundBalkan endemic nephropathy (BEN) is of great clinical importance in restricted areas of Bulgaria, Serbia, Croatia, Bosnia, Herzegovina, and Romania, since the etiology of BEN is still unknown.MethodsIn urine samples from 48 patients (41 females and 7 males, aged 65.6 ± 6.87years) with BEN living in an endemic area of Vratza district, Bulgaria, neopterin concentrations were measured by high-pressure liquid chromatography (HPLC) and compared with other clinical and laboratory investigations, including creatinine, hemoglobin, and erythrocyte sedimentation rates (ESRs).ResultsUrinary neopterin concentrations were 263 ± 128 (mean ± SD; range, 78 to 786 μmol/mol creatinine), 24 (50%) of BEN patients presented with increased concentrations as compared to the established normal ranges. Average ESRs were increased (1hour, 29.0 ± 14.7mm/hour) and hemoglobin was decreased (109.3 ± 16.4g/L). Hemoglobin correlated inversely with ESRs (rs = -0.787 and –0.780) and creatinine concentrations (r = -0.690, all P < 0.001), but not with neopterin concentrations. Neopterin concentrations also did not correlate with serum creatinine levels. There existed an age relationship of ESR, creatinine, and hemoglobin, but not of neopterin. Neopterin concentrations were slightly lower in five females with low titers of antibodies against local B1 hantavirus strain (P < 0.05).ConclusionThe findings can support an immune-mediated inflammatory process in the pathogenesis of BEN only in a subgroup of patients

The Oncolytic Virotherapy Era in Cancer Management: Prospects of Applying H-1 Parvovirus to Treat Blood and Solid Cancers

Non-Hodgkin lymphoma (NHL) and leukemia are among the most common cancers worldwide. While the treatment of NHL/leukemia of B-cell origin has much progressed with the introduction of targeted therapies, few treatment standards have been established for T-NHL/leukemia. As presentation in both B- and T-NHL/leukemia patients is often aggressive and as prognosis for relapsed disease is especially dismal, this cancer entity poses major challenges and requires innovative therapeutic approaches. In clinical trials, oncolytic viruses (OVs) have been used against refractory multiple myeloma (MM). In preclinical settings, a number of OVs have demonstrated a remarkable ability to suppress various types of hematological cancers. Most studies dealing with this approach have used MM or B- or myeloid-cell-derived malignancies as models. Only a few describe susceptibility of T-cell lymphoma/leukemia to OV infection and killing. The rat H-1 parvovirus (H-1PV) is an OV with considerable promise as a novel therapeutic agent against both solid tumors (pancreatic cancer and glioblastoma) and hematological malignancies. The present perspective article builds on previous reports of H-1PV-driven regression of Burkitt’s lymphoma xenografts and on unpublished observations demonstrating effective killing by H-1PV of cells from CHOP-resistant diffuse large B-cell lymphoma, cutaneous T-cell lymphoma, and T-cell acute lymphoblastic leukemia. On the basis of these studies, H-1PV is proposed for use as an adjuvant to (chemo)therapeutic regimens. Furthermore, in the light of a recently completed first parvovirus clinical trial in glioblastoma patients, the advantages of H-1PV for systemic application are discussed

Gene silencing of VP1 gene of coxsackievirus B3 neurotropic strain Nancy by dsRNAs and siRNAs

AbstractCoxsackieviruses are distributed worldwide and can cause serious diseases threatening human health and even human life. Genetic silencing is considered a new opportunity to treat viral infections. In this study, we produced in vitro dsRNAs and siRNAs specific for two sequences of different length from the VP1 genetic regions of CVB3, and introduced them into HEp-2 cells with Oligofectamine as the transfection agent. We used the neurotropic strain Nancy. The 100% inhibitory concentrations of the applied dsRNAs and siRNAs were 0.3 μmol/L and fell in the range of non-cytotoxic concentration values. The produced VP1-specific dsRNAs and siRNAs were effective at low concentrations, suggesting that the produced RNAs are safe to use and possess excellent potential to treat CVB3 infection

Preliminary investigation on the combined effect of S-adenosyl-L-methionine (SAM) and oseltamivir on experimental influenza А virus infection in mice

nfluenza is one of the most contageous viral diseases, caused by influenza virus and affects thousands of people every year. The infection causes changes in the intracellular redox balance, increased production of reactive oxygen species, development of antioxidant deficiency and conditions of oxidative stress. Decreased level of gluthatione during flu is responsible for the severe pathology and complications. The purpose of our studies was to follow the effect of the combination S-adenosyl-L-methionine (SAM) as a precursor of glutathione and the specific neuraminidase inhibitor oseltamivir in influenza infected mice. SAM was given as a single daily dose of 50,100 and 150 mg/kg, starting from 5 days before infection until day 4th after viral inoculation. Oseltamivir was given in a daily dose of 2.5 mg/kg in two intakes for 5 days, starting from 4th hour before infection. End-point evaluation was 14 day survival rate, avarege survival time, index of protection, and virus titer in lungs. The results showed that application of SAM alone did not have any antiviral prevention. In mice supplemented with oseltamivir only survival rate was 70%, but combination of oseltamivir and SAM in lower doses led to rising of 90% of protection. The present findings suggest that combined therapy of SAM as a precursor of glutathione and the specific inhibitor of inflienza virus replication oseltamivir could be effective on modulation of host defense mechanism(s) in low therapeutic doses