Inhibition of adenovirus serotype 14 infection by octadecyloxyethyl esters of (S)-[(3-hydroxy-2-phosphonomethoxy)propyl]- nucleosides in vitro.

On September 22, 2008, a physician on Prince of Wales Island, Alaska, notified the Alaska Department of Health and Social Services (ADHSS) of an unusually high number of adult patients with recently diagnosed pneumonia (n = 10), including three persons who required hospitalization and one who died. ADHSS and CDC conducted an investigation to determine the cause and distribution of the outbreak, identify risk factors for hospitalization, and implement control measures. This report summarizes the results of that investigation, which found that the outbreak was caused by adenovirus 14 (Ad14), an emerging adenovirus serotype in the United States that is associated with a higher rate of severe illness compared with other adenoviruses. Among the 46 cases identified in the outbreak from September 1 through October 27, 2008, the most frequently observed characteristics included the following: male (70%), Alaska Native (61%), underlying pulmonary disease (44%), aged > or = 65 years (26%), and current smoker (48%). Patients aged > or = 65 years had a fivefold increased risk for hospitalization. The most commonly reported symptoms were cough (100%), shortness of breath (87%), and fever (74%). Of the 11 hospitalized patients, three required intensive care, and one required mechanical ventilation. One death was reported. Ad14 isolates obtained during the outbreak were identical genetically to those in recent community-acquired outbreaks in the United States which suggests the emergence of a new, and possibly more virulent Ad14 variant. Clinicians should consider Ad14 infection in the differential diagnosis for patients with community-acquired pneumonia, particularly when unexplained clusters of severe respiratory infections are detected

Therapy and Long-Term Prophylaxis of Vaccinia Virus Respiratory Infections in Mice with an Adenovirus-Vectored Interferon Alpha (mDEF201)

An adenovirus 5 vector encoding for mouse interferon alpha, subtype 5 (mDEF201) was evaluated for efficacy against lethal vaccinia virus (WR strain) respiratory infections in mice. mDEF201 was administered as a single intranasal treatment either prophylactically or therapeutically at doses of 106 to 108 plaque forming units/mouse. When the prophylactic treatment was given at 56 days prior to infection, it protected 90% of animals from death (100% protection for treatments given between 1–49 days pre-infection), with minimal weight loss occurring during infection. Surviving animals re-challenged with virus 22 days after the primary infection were protected from death, indicating that mDEF201 did not compromise the immune response against the initial infection. Post-exposure therapy was given between 6–24 h after vaccinia virus exposure and protection was afforded by a 108 dose of mDEF201 given at 24 h, whereas a 107 dose was effective up to 12 h. Comparisons were made of the ability of mDEF201, given either 28 or 1 day prior to infection, to inhibit tissue virus titers and lung infection parameters. Lung, liver, and spleen virus titers were inhibited to nearly the same extent by either treatment, as were lung weights and lung hemorrhage scores (indicators of pneumonitis). Lung virus titers were significantly (>100-fold) lower than in the placebo group, and the other infection parameters in mDEF201 treated mice were nearly at baseline. In contrast, viral titers and lung infection parameters were high in the placebo group on day 5 of the infection. These results demonstrate the long-acting prophylactic and treatment capacity of mDEF201 to combat vaccinia virus infections

Triple Combination of Amantadine, Ribavirin, and Oseltamivir Is Highly Active and Synergistic against Drug Resistant Influenza Virus Strains In Vitro

The rapid emergence and subsequent spread of the novel 2009 Influenza A/H1N1 virus (2009 H1N1) has prompted the World Health Organization to declare the first pandemic of the 21st century, highlighting the threat of influenza to public health and healthcare systems. Widespread resistance to both classes of influenza antivirals (adamantanes and neuraminidase inhibitors) occurs in both pandemic and seasonal viruses, rendering these drugs to be of marginal utility in the treatment modality. Worldwide, virtually all 2009 H1N1 and seasonal H3N2 strains are resistant to the adamantanes (rimantadine and amantadine), and the majority of seasonal H1N1 strains are resistant to oseltamivir, the most widely prescribed neuraminidase inhibitor (NAI). To address the need for more effective therapy, we evaluated the in vitro activity of a triple combination antiviral drug (TCAD) regimen composed of drugs with different mechanisms of action against drug-resistant seasonal and 2009 H1N1 influenza viruses. Amantadine, ribavirin, and oseltamivir, alone and in combination, were tested against amantadine- and oseltamivir-resistant influenza A viruses using an in vitro infection model in MDCK cells. Our data show that the triple combination was highly synergistic against drug-resistant viruses, and the synergy of the triple combination was significantly greater than the synergy of any double combination tested (P<0.05), including the combination of two NAIs. Surprisingly, amantadine and oseltamivir contributed to the antiviral activity of the TCAD regimen against amantadine- and oseltamivir-resistant viruses, respectively, at concentrations where they had no activity as single agents, and at concentrations that were clinically achievable. Our data demonstrate that the TCAD regimen composed of amantadine, ribavirin, and oseltamivir is highly synergistic against resistant viruses, including 2009 H1N1. The TCAD regimen overcomes baseline drug resistance to both classes of approved influenza antivirals, and thus may represent a highly active antiviral therapy for seasonal and pandemic influenza

Coumarins and pyranocoumarins, potential novel pharmacophores for inhibition ofmeasles virus replication

A series of coumarin and pyranocoumarin analogues were evaluated in vitro for antiviral efficacy against measles virus (MV), strain Chicago. Of the 22 compounds tested for inhibition, six were found to have selectivity indices greater than 10. These were compounds 5-hydroxy-7-propionyloxy- 4-propylcoumarin (2a), 5,7-bis(tosyloxy)-4- propylcoumarin (7); 5-hydroxy-4-propyl-7-tosyloxy- coumarin (8); 6,6-dimethyl-9-propionyloxy-4- propyl-2H,6H-benzo[1,2-b:3,4-b′]dipyran-2-one (9); 6,6-dimethyl-9-pivaloyloxy-4-propyl-2H,6Hbenzo[ 1,2-b:3,4-b′]dipyran-2-one (10); and 7,8-cis- 10,11,12-trans-4-propyl-6,6,10,11-tetramethyl- 7,8,9-trihydroxy-2H,6H,12H-benzo[1,2-b:3,4-b′:5,6- b′′]tripyran-2-one (18). Three of the active drugs were propyl coumarin analogues (2a, 7 and 8), two were dipyranone or chromeno-coumarins (9 and 10), and one was a benzotripyranone with a coumarin nucleus (18). Some appeared to be rather specific and potent inhibitors of MV with EC50 values ranging from 0.2 to 50 μg/ml and the majority of the EC50 values being less than 5 μg/ml. The compounds inhibited an additional nine strains of MV, and in virucidal tests the drugs did not physically disrupt the virion to inhibit virus replication. The inhibitory activity for one of the compounds tested (7) was somewhat dependent on virus concentration and it was still active when added to cells up to 24 h after virus exposure. When used in combination with ribavirin, compound 7 appeared not to profoundly affect the antiviral efficacy of ribavirin or its cell-associated toxicity. However, a slightly antagonistic MVinhibitory effect was observed at the highest concentration of ribavirin used in combination with most concentrations of compound 7 tested. This and related compounds may be valuable leads in the development of a potent and selective class of MV inhibitors that could be used in future in the clinic

A Molecularly Engineered Antiviral Banana Lectin Inhibits Fusion and is Efficacious Against Influenza Virus Infection in Vivo

There is a strong need for a new broad-spectrum antiinfluenza therapeutic, as vaccination and existing treatments are only moderately effective. We previously engineered a lectin, H84T banana lectin (H84T), to retain broad-spectrum activity against multiple influenza strains, including pandemic and avian, while largely eliminating the potentially harmful mitogenicity of the parent compound. The amino acid mutation at position 84 from histidine to threonine minimizes the mitogenicity of the wild-type lectin while maintaining antiinfluenza activity in vitro. We now report that in a lethal mouse model H84T is indeed nonmitogenic, and both early and delayed therapeutic administration of H84T intraperitoneally are highly protective, as is H84T administered subcutaneously. Mechanistically, attachment, which we anticipated to be inhibited by H84T, was only somewhat decreased by the lectin. Instead, H84T is internalized into the late endosomal/lysosomal compartment and inhibits virus–endosome fusion. These studies reveal that H84T is efficacious against influenza virus in vivo, and that the loss of mitogenicity seen previously in tissue culture is also seen in vivo, underscoring the potential utility of H84T as a broad-spectrum antiinfluenza agent

Inhibition of measles virus replication by 5\u27-Norcarbocyclic nucleoside analogs

Despite intense efforts to increase vaccine coverage, measles virus (MV) still causes significant morbidity and mortality in the world, sometimes as the result of severe, chronic, lethal disease. In an effort to develop therapies to supplement immunization strategies, a number of 5′-nor carbocyclic adenosine analogues were evaluated for anti-MV activity in CV-1 monkey kidney cells. Of those compounds tested, those either unsubstituted at C4 or possessing a hydroxyl, azido or amino substituent at that position were the most active, with particularly significant inhibition of MV, strain Chicago-1. The EC50 values against this strain ranged from100 mg/ml in actively growing and stationary-phase cells. Results suggest that these compounds may be clinically useful anti-MV virus agents

Efficacy of Combined Therapy with Amantadine, Oseltamivir, and Ribavirin In Vivo against Susceptible and Amantadine-Resistant Influenza A Viruses

The limited efficacy of existing antiviral therapies for influenza – coupled with widespread baseline antiviral resistance – highlights the urgent need for more effective therapy. We describe a triple combination antiviral drug (TCAD) regimen composed of amantadine, oseltamivir, and ribavirin that is highly efficacious at reducing mortality and weight loss in mouse models of influenza infection. TCAD therapy was superior to dual and single drug regimens in mice infected with drug-susceptible, low pathogenic A/H5N1 (A/Duck/MN/1525/81) and amantadine-resistant 2009 A/H1N1 influenza (A/California/04/09). Treatment with TCAD afforded >90% survival in mice infected with both viruses, whereas treatment with dual and single drug regimens resulted in 0% to 60% survival. Importantly, amantadine had no activity as monotherapy against the amantadine-resistant virus, but demonstrated dose-dependent protection in combination with oseltamivir and ribavirin, indicative that amantadine's activity had been restored in the context of TCAD therapy. Furthermore, TCAD therapy provided survival benefit when treatment was delayed until 72 hours post-infection, whereas oseltamivir monotherapy was not protective after 24 hours post-infection. These findings demonstrate in vivo efficacy of TCAD therapy and confirm previous reports of the synergy and broad spectrum activity of TCAD therapy against susceptible and resistant influenza strains in vitro

Galaxy Clustering in Early SDSS Redshift Data

We present the first measurements of clustering in the Sloan Digital Sky Survey (SDSS) galaxy redshift survey. Our sample consists of 29,300 galaxies with redshifts 5,700 km/s < cz < 39,000 km/s, distributed in several long but narrow (2.5-5 degree) segments, covering 690 square degrees. For the full, flux-limited sample, the redshift-space correlation length is approximately 8 Mpc/h. The two-dimensional correlation function \xi(r_p,\pi) shows clear signatures of both the small-scale, ``fingers-of-God'' distortion caused by velocity dispersions in collapsed objects and the large-scale compression caused by coherent flows, though the latter cannot be measured with high precision in the present sample. The inferred real-space correlation function is well described by a power law, \xi(r)=(r/6.1+/-0.2 Mpc/h)^{-1.75+/-0.03}, for 0.1 Mpc/h < r < 16 Mpc/h. The galaxy pairwise velocity dispersion is \sigma_{12} ~ 600+/-100 km/s for projected separations 0.15 Mpc/h < r_p < 5 Mpc/h. When we divide the sample by color, the red galaxies exhibit a stronger and steeper real-space correlation function and a higher pairwise velocity dispersion than do the blue galaxies. The relative behavior of subsamples defined by high/low profile concentration or high/low surface brightness is qualitatively similar to that of the red/blue subsamples. Our most striking result is a clear measurement of scale-independent luminosity bias at r < 10 Mpc/h: subsamples with absolute magnitude ranges centered on M_*-1.5, M_*, and M_*+1.5 have real-space correlation functions that are parallel power laws of slope ~ -1.8 with correlation lengths of approximately 7.4 Mpc/h, 6.3 Mpc/h, and 4.7 Mpc/h, respectively.Comment: 51 pages, 18 figures. Replaced to match accepted ApJ versio

The Sloan Digital Sky Survey Quasar Catalog I. Early Data Release

We present the first edition of the Sloan Digital Sky Survey (SDSS) Quasar Catalog. The catalog consists of the 3814 objects (3000 discovered by the SDSS) in the initial SDSS public data release that have at least one emission line with a full width at half maximum larger than 1000 km/s, luminosities brighter than M_i^* = -23, and highly reliable redshifts. The area covered by the catalog is 494 square degrees; the majority of the objects were found in SDSS commissioning data using a multicolor selection technique. The quasar redshifts range from 0.15 to 5.03. For each object the catalog presents positions accurate to better than 0.2" rms per coordinate, five band (ugriz) CCD-based photometry with typical accuracy of 0.05 mag, radio and X-ray emission properties, and information on the morphology and selection method. Calibrated spectra of all objects in the catalog, covering the wavelength region 3800 to 9200 Angstroms at a spectral resolution of 1800-2100, are also available. Since the quasars were selected during the commissioning period, a time when the quasar selection algorithm was undergoing frequent revisions, the sample is not homogeneous and is not intended for statistical analysis.Comment: 27 pages, 4 figures, 4 tables, accepted by A

Treatment of Late Stage Disease in a Model of Arenaviral Hemorrhagic Fever: T-705 Efficacy and Reduced Toxicity Suggests an Alternative to Ribavirin

A growing number of arenaviruses are known to cause viral hemorrhagic fever (HF), a severe and life-threatening syndrome characterized by fever, malaise, and increased vascular permeability. Ribavirin, the only licensed antiviral indicated for the treatment of certain arenaviral HFs, has had mixed success and significant toxicity. Since severe arenaviral infections initially do not present with distinguishing symptoms and are difficult to clinically diagnose at early stages, it is of utmost importance to identify antiviral therapies effective at later stages of infection. We have previously reported that T-705, a substituted pyrazine derivative currently under development as an anti-influenza drug, is highly active in hamsters infected with Pichinde virus when the drug is administered orally early during the course of infection. Here we demonstrate that T-705 offers significant protection against this lethal arenaviral infection in hamsters when treatment is begun after the animals are ill and the day before the animals begin to succumb to disease. Importantly, this coincides with the time when peak viral loads are present in most organs and considerable tissue damage is evident. We also show that T-705 is as effective as, and less toxic than, ribavirin, as infected T-705-treated hamsters on average maintain their weight better and recover more rapidly than animals treated with ribavirin. Further, there was no added benefit to combination therapy with T-705 and ribavirin. Finally, pharmacokinetic data indicate that plasma T-705 levels following oral administration are markedly reduced during the latter stages of disease, and may contribute to the reduced efficacy seen when treatment is withheld until day 7 of infection. Our findings support further pre-clinical development of T-705 for the treatment of severe arenaviral infections