Efficacy of the New Neuraminidase Inhibitor CS-8958 against H5N1 Influenza Viruses

Currently, two neuraminidase (NA) inhibitors, oseltamivir and zanamivir, which must be administrated twice daily for 5 days for maximum therapeutic effect, are licensed for the treatment of influenza. However, oseltamivir-resistant mutants of seasonal H1N1 and highly pathogenic H5N1 avian influenza A viruses have emerged. Therefore, alternative antiviral agents are needed. Recently, a new neuraminidase inhibitor, R-125489, and its prodrug, CS-8958, have been developed. CS-8958 functions as a long-acting NA inhibitor in vivo (mice) and is efficacious against seasonal influenza strains following a single intranasal dose. Here, we tested the efficacy of this compound against H5N1 influenza viruses, which have spread across several continents and caused epidemics with high morbidity and mortality. We demonstrated that R-125489 interferes with the NA activity of H5N1 viruses, including oseltamivir-resistant and different clade strains. A single dose of CS-8958 (1,500 µg/kg) given to mice 2 h post-infection with H5N1 influenza viruses produced a higher survival rate than did continuous five-day administration of oseltamivir (50 mg/kg twice daily). Virus titers in lungs and brain were substantially lower in infected mice treated with a single dose of CS-8958 than in those treated with the five-day course of oseltamivir. CS-8958 was also highly efficacious against highly pathogenic H5N1 influenza virus and oseltamivir-resistant variants. A single dose of CS-8958 given seven days prior to virus infection also protected mice against H5N1 virus lethal infection. To evaluate the improved efficacy of CS-8958 over oseltamivir, the binding stability of R-125489 to various subtypes of influenza virus was assessed and compared with that of other NA inhibitors. We found that R-125489 bound to NA more tightly than did any other NA inhibitor tested. Our results indicate that CS-8958 is highly effective for the treatment and prophylaxis of infection with H5N1 influenza viruses, including oseltamivir-resistant mutants

Physiological and ecological studies of Calanus euxinus (Hulsemann) from the Black Sea with comments on its life cycle

Ecological and physiological study of Calanus euxinus population from the Black Sea was carried out during the cruise of RN Bilim in Autumn 1996. The population was divided into two: active individuals, represented by all developmental stages, and diapausing CVs. The active CIV-CVIs underwent daily vertical migrations, while the diapausing CVs stayed at depth all day long. The population seemed to reproduce actively indicated by the large number of eggs and nauplii in the samples as well as the large proportion of spawning females (up to 80% of the total number of adult females). Egg production rate ranged from 5 to 25 eggs/female/day. The percentage of copepods with food changed with location and time; at night it varied from 10 to 97 in the upper layer, being less than 1 at the depth. Food remains was never observed in the guts of diapausing CVs. Up to 60% of gut in the upper layer, being less than 1 at the depth. Food remains was never observed in the guts of diapausing CVs. Up to 60% of gut contents consisted debris. The recognizable remains were parts of crustacean exoskeleton and dynoflagellates 10-60 mkm in size.Shipboard feeding experiments showed extremely low consumptions of chlorophyll (2.39-7.41 ng/ind/d in CVs and 5.67-14.33 ng/ind/d in females). The analysis of size classes distribution allowed the distinction of two groups among both diapausing and active CVs pointing on the heterogenity of the population. No difference between the length of males and females CVs was found. The state of gonad development differed between active and diapausing CVs. In the former gonad size ranged from 0.075 to 0.65 mm, in the latter small (0.1-0.15 mm) gonads before sex differentiation prevailed. An increase in gonad size was accompanied by a decrease in oil content. The active and diapausing CVs differed in their motor activity, respiration and excretion rates. Relationships between these indices and oxygen concentration were obtained. Under all oxygen concentrations studied, the indices for active CVs were higher than for diapausing CVs by a factor of 2 or 3

A Non-VH1-69 Heterosubtypic Neutralizing Human Monoclonal Antibody Protects Mice against H1N1 and H5N1 Viruses

<div><p>Influenza viruses are among the most important human pathogens and are responsible for annual epidemics and sporadic, potentially devastating pandemics. The humoral immune response plays an important role in the defense against these viruses, providing protection mainly by producing antibodies directed against the hemagglutinin (HA) glycoprotein. However, their high genetic variability allows the virus to evade the host immune response and the potential protection offered by seasonal vaccines. The emergence of resistance to antiviral drugs in recent years further limits the options available for the control of influenza. The development of alternative strategies for influenza prophylaxis and therapy is therefore urgently needed. In this study, we describe a human monoclonal antibody (PN-SIA49) that recognizes a highly conserved epitope located on the stem region of the HA and able to neutralize a broad spectrum of influenza viruses belonging to different subtypes (H1, H2 and H5). Furthermore, we describe its protective activity in mice after lethal challenge with H1N1 and H5N1 viruses suggesting a potential application in the treatment of influenza virus infections.</p> </div

Fatores de risco e medidas profiláticas nas pneumonias adquiridas na comunidade Risk factors and prophylaxis of community-acquired pneumonias

Este artigo revisa os efeitos do envelhecimento, tabagismo, DPOC, insuficiência cardíaca, colonização da orofaringe, aspiração (micro e macro), alcoolismo, cirrose hepática, deficiência nutricional, imunossupressão e fatores ambientais sobre o risco de adquirir pneumonia na comunidade e sua gravidade. Na segunda parte, é feita revisão sobre a ação profilática das vacinas antiinfluenza e antipneumococo, assim como a ação das drogas antivirais, na profilaxia e tratamento das pneumonias adquiridas na comunidade.<br>This article reviews the effects of aging, tobacco-smoking, chronic bronchitis and emphysema, heart failure, oropharyngeal colonization, aspiration (micro and macro), alcoholism, hepatic cirrhosis, nutritional deficiency, immunosuppression, and environmental factors on the risk of community-acquired pneumonia and its severity. In the second part, the authors review the prophylactic action of anti-influenza and anti-pneumococcus vaccines as well as the role of prevention and treatment of antiviral agents in community-acquired pneumonia