The Experts below are selected from a list of 945 Experts worldwide ranked by ideXlab platform
Bruce D. Hammock - One of the best experts on this subject based on the ideXlab platform.
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exploring the size of the lipophilic unit of the soluble epoxide hydrolase inhibitors
Bioorganic & Medicinal Chemistry, 2019Co-Authors: Sandra Codony, Bruce D. Hammock, Christophe Morisseau, Elena Valverde, Rosana Leiva, Jose Brea, Isabel M Loza, Santiago VazquezAbstract:Abstract Soluble epoxide hydrolase (sEH) inhibitors are potential drugs for several diseases. Adamantyl ureas are excellent sEH inhibitors but have limited metabolic stability. Herein, we report the effect of replacing the adamantane group by alternative polycyclic hydrocarbons on sEH inhibition, solubility, permeability and metabolic stability. Compounds bearing smaller or larger polycyclic hydrocarbons than adamantane yielded all good inhibition potency of the human sEH (0.4 ≤ IC50 ≤ 21.7 nM), indicating that sEH is able to accommodate inhibitors of very different size. Human liver microsomal stability of diamantane containing inhibitors is lower than that of their corresponding adamantane counterparts.
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1 3 disubstituted and 1 3 3 trisubstituted adamantyl ureas with isoxazole as soluble epoxide hydrolase inhibitors
Bioorganic & Medicinal Chemistry Letters, 2015Co-Authors: V V Burmistrov, Christophe Morisseau, Dmitry V Danilov, Todd R Harris, I L Dalinger, Irina A Vatsadze, Tatiana Shkineva, G M Butov, Bruce D. HammockAbstract:Adamantyl ureas are good soluble epoxide hydrolase (sEH) inhibitors; however they have limited solubility and rapid metabolism, thus limiting their usefulness in some therapeutic indications. Herein, we test the hypothesis that nodal substitution on the adamantane will help solubilize and stabilize the compounds. A series of compounds containing adamantane derivatives and isoxazole functional groups were developed. Overall, the presence of methyl on the nodal positions of adamantane yields higher water solubility than previously reported urea-based sEH inhibitors while maintaining high inhibition potency. However, it did not improve microsomal stability.
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1 3 disubstituted and 1 3 3 trisubstituted adamantyl ureas with isoxazole as soluble epoxide hydrolase inhibitors
Bioorganic & Medicinal Chemistry Letters, 2015Co-Authors: V V Burmistrov, Christophe Morisseau, Dmitry V Danilov, Todd R Harris, I L Dalinger, Irina A Vatsadze, Tatiana Shkineva, G M Butov, Bruce D. HammockAbstract:Adamantyl ureas are good soluble epoxide hydrolase (sEH) inhibitors; however they have limited solubility and rapid metabolism, thus limiting their usefulness in some therapeutic indications. Herein, we test the hypothesis that nodal substitution on the adamantane will help solubilize and stabilize the compounds. A series of compounds containing adamantane derivatives and isoxazole functional groups were developed. Overall, the presence of methyl on the nodal positions of adamantane yields higher water solubility than previously reported urea-based sEH inhibitors while maintaining high inhibition potency. However, it did not improve microsomal stability.
Ian G Barr - One of the best experts on this subject based on the ideXlab platform.
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adamantane resistance in influenza a h1 viruses increased in 2007 in south east asia but decreased in australia and some other countries
Antiviral Research, 2008Co-Authors: Ian G Barr, Yimo Deng, Pina Iannello, Aeron C Hurt, Naomi KomadinaAbstract:The Adamantanes (amantadine and rimantadine) were the initial antivirals licensed for use against influenza A viruses and have been used in some countries to control seasonal influenza and have also been stockpiled for potential pandemic use. While high rates of resistance have been observed in recent years with A(H3) viruses, the rates of resistance with A(H1) viruses has varied widely. In this study we analysed 281 human influenza A viruses isolated in 2007 that were referred to the WHO Collaborating Centre for Reference and Research in Melbourne, mainly from Australia and the surrounding regions, for evidence of resistance to Adamantanes and a subset of these was examined for resistance to the neuraminidase inhibitors (NIs). We found that the rates of adamantane resistance in A(H3) viruses continued to increase in most countries in 2007 but a distinct variation was seen with A(H1) resistance levels. A(H1) viruses from Australia, New Zealand and Europe had low rates of resistance (2-9%) whereas viruses from a number of South East (SE) Asian countries had high rates of resistance (33-100%). This difference can be attributed to the spread of A/Brisbane/59/2007-like viruses to many parts of the world with the exception of SE Asia where A/Hong Kong/2652/2006-like viruses continue to predominate. When these two A(H1) subgroups were compared for their in vitro sensitivity to the other class of influenza antiviral drugs, the neuraminidase inhibitors, no difference was seen between the groups with both showing normal levels of sensitivity to these drugs, The finding of reducing A(H1) resistance rates in Australia and rising levels in SE Asia in 2007, reverses the trend seen in 2006 when A(H1) resistance levels were rising in Australia and elsewhere but remained low in most of SE Asia.
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increased adamantane resistance in influenza a h3 viruses in australia and neighbouring countries in 2005
Antiviral Research, 2007Co-Authors: Ian G Barr, Pina Iannello, Aeron C Hurt, C Tomasov, Nicola Deed, Naomi KomadinaAbstract:The prevention and control of disease caused by seasonal and potential pandemic influenza viruses is currently managed by the use influenza vaccines and antivirals. The Adamantanes (amantadine and rimantadine) were the first antivirals licensed for use against influenza A viruses and have been used extensively in some countries. Since the early 2000s increased resistance to these drugs has been reported especially in the A(H3) viruses. In this study we analysed recent human influenza A strains isolated in Australia and regionally for evidence of resistance to Adamantanes and found evidence of significant resistant emerging during 2005.
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Susceptibility of highly pathogenic A(H5N1) avian influenza viruses to the neuraminidase inhibitors and Adamantanes.
Antiviral research, 2006Co-Authors: Aeron C Hurt, Naomi Komadina, Paul Selleck, Robert Shaw, Lorena E. Brown, Ian G BarrAbstract:Since 2003, highly pathogenic A(H5N1) influenza viruses have been the cause of large-scale death in poultry and the subsequent infection and death of over 140 humans. A group of 55 influenza A(H5N1) viruses isolated from various regions of South East Asia between 2004 and 2006 were tested for their susceptibility to the anti-influenza drugs the neuraminidase inhibitors and Adamantanes. The majority of strains were found to be fully sensitive to the neuraminidase inhibitors oseltamivir carboxylate, zanamivir and peramivir; however two strains demonstrated increased IC50 values. Sequence analysis of these strains revealed mutations in the normally highly conserved residues 116 and 117 of the N1 neuraminidase. Sequence analysis of the M2 gene showed that all of the A(H5N1) viruses from Vietnam, Malaysia and Cambodia contained mutations (L26I and S31N) associated with resistance to the adamantane drugs (rimantadine and amantadine), while strains from Indonesia were found to be a mix of both adamantane resistant (S31N) and sensitive viruses. None of the A(H5N1) viruses from Myanmar contained mutations known to confer adamantane resistance. These results support the use of neuraminidase inhibitors as the most appropriate class of antiviral drug to prevent or treat human A(H5N1) virus infections.
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Resistance to anti-influenza drugs: Adamantanes and neuraminidase inhibitors.
Expert review of anti-infective therapy, 2006Co-Authors: Aeron C Hurt, Ian G BarrAbstract:Development of effective drugs for the treatment or prevention of epidemic and pandemic influenza is important in order to reduce its impact. Adamantanes and neuraminidase inhibitors are two classes of anti-influenza drugs available for influenza therapy currently. However, emergence of resistance to these drugs has been detected, which raises concerns regarding their widespread use. In this review, resistance to the Adamantanes and neuraminidase inhibitors will be discussed in relation to both epidemic and pandemic influenza viruses.
V V Burmistrov - One of the best experts on this subject based on the ideXlab platform.
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1 3 disubstituted and 1 3 3 trisubstituted adamantyl ureas with isoxazole as soluble epoxide hydrolase inhibitors
Bioorganic & Medicinal Chemistry Letters, 2015Co-Authors: V V Burmistrov, Christophe Morisseau, Dmitry V Danilov, Todd R Harris, I L Dalinger, Irina A Vatsadze, Tatiana Shkineva, G M Butov, Bruce D. HammockAbstract:Adamantyl ureas are good soluble epoxide hydrolase (sEH) inhibitors; however they have limited solubility and rapid metabolism, thus limiting their usefulness in some therapeutic indications. Herein, we test the hypothesis that nodal substitution on the adamantane will help solubilize and stabilize the compounds. A series of compounds containing adamantane derivatives and isoxazole functional groups were developed. Overall, the presence of methyl on the nodal positions of adamantane yields higher water solubility than previously reported urea-based sEH inhibitors while maintaining high inhibition potency. However, it did not improve microsomal stability.
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1 3 disubstituted and 1 3 3 trisubstituted adamantyl ureas with isoxazole as soluble epoxide hydrolase inhibitors
Bioorganic & Medicinal Chemistry Letters, 2015Co-Authors: V V Burmistrov, Christophe Morisseau, Dmitry V Danilov, Todd R Harris, I L Dalinger, Irina A Vatsadze, Tatiana Shkineva, G M Butov, Bruce D. HammockAbstract:Adamantyl ureas are good soluble epoxide hydrolase (sEH) inhibitors; however they have limited solubility and rapid metabolism, thus limiting their usefulness in some therapeutic indications. Herein, we test the hypothesis that nodal substitution on the adamantane will help solubilize and stabilize the compounds. A series of compounds containing adamantane derivatives and isoxazole functional groups were developed. Overall, the presence of methyl on the nodal positions of adamantane yields higher water solubility than previously reported urea-based sEH inhibitors while maintaining high inhibition potency. However, it did not improve microsomal stability.
Larisa V Gubareva - One of the best experts on this subject based on the ideXlab platform.
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neuraminidase inhibitor resistance in influenza viruses and laboratory testing methods
Antiviral Therapy, 2012Co-Authors: Ha Nguye, Alicia M. Fry, Larisa V GubarevaAbstract:: Infection with influenza viruses, including seasonal, avian and pandemic viruses, remains a worldwide public health problem. Although influenza virus infection is both vaccine preventable and drug treatable, high rates of mutation and reassortment of viruses can result in reduced effectiveness of vaccines or drugs. Currently, two classes of drugs, Adamantanes (M2 blockers) and neuraminidase (NA) inhibitors (NAIs), are available for treatment and chemoprophylaxis of influenza infections. Given these limited antiviral therapy options, resistance to anti-influenza drugs is a constant concern. The emergence and global spread of adamantane-resistant H3N2 viruses in 2003-2004 and oseltamivir-resistant seasonal H1N1 viruses in 2007-2009 demonstrated the ability of drug-resistant variants to rapidly become predominant worldwide. Since the 2009 H1N1 pandemic, all influenza viruses circulating in humans are M2-blocker-resistant and, in general, NAI-susceptible. However, pandemic H1N1 viruses with resistance to the NAI oseltamivir have been reported. 'Permissive' drift mutations and reassortment of viral gene segments have been proposed as mechanisms underlying the retained replicative fitness of resistant viruses. Nevertheless, the precise role of these genetic changes in the efficient transmission and maintenance of resistant viruses in the absence of drug pressure remains poorly understood. In this review, we summarize NAI resistance in influenza viruses and discuss recent challenges in laboratory testing methods. Close monitoring of antiviral resistance among all influenza viruses, both locally and globally, are essential to inform public health strategies for the control of influenza infections.
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dual resistance to Adamantanes and oseltamivir among seasonal influenza a h1n1 viruses 2008 2010
The Journal of Infectious Diseases, 2011Co-Authors: Tiffany G Sheu, Alicia M. Fry, Alexander Klimov, Varough M Deyde, Rebecca Garten, Thein Shwe, Lesley Bullion, Patrick J Peebles, Larisa V GubarevaAbstract:Two distinct genetic clades of seasonal influenza A(H1N1) viruses have cocirculated in the recent seasons: clade 2B oseltamivir-resistant and adamantane-susceptible viruses, and clade 2C viruses that are resistant to Adamantanes and susceptible to oseltamivir. We tested seasonal influenza A(H1N1) viruses collected in 2008-2010 from the United States and globally for resistance to antivirals approved by the Food and Drug Administration. We report 28 viruses with both adamantane and oseltamivir (dual) resistance from 5 countries belonging to 4 distinct genotypes. Because of limited options for antiviral treatment, emergence of dual-resistant influenza viruses poses a public health concern, and their circulation needs to be closely monitored.
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detection of adamantane resistant influenza on a microarray
Journal of Clinical Virology, 2008Co-Authors: Michael B Townsend, Larisa V Gubareva, Alexander Klimov, James A Smagala, Erica D Dawson, Varough M Deyde, Robert D Kuchta, Kathy L RowlenAbstract:Abstract Background Influenza A has the ability to rapidly mutate and become resistant to the commonly prescribed influenza therapeutics, thereby complicating treatment decisions. Objective To design a cost-effective low-density microarray for use in detection of influenza resistance to the Adamantanes. Study design We have taken advantage of functional genomics and microarray technology to design a DNA microarray that can detect the two most common mutations in the M2 protein associated with adamantane resistance, V27A and S31N. Results In a blind study of 22 influenza isolates, the antiviral resistance-chip (AVR-Chip) had a success rate of 95% for detecting these mutations. Microarray data from a larger set of samples were further analyzed using an artificial neural network and resulted in a correct identification rate of 94% for influenza virus samples that had V27A and S31N mutations. Conclusions The AVR-Chip provided a method for rapidly screening influenza viruses for adamantane sensitivity, and the general approach could be easily extended to detect resistance to other chemotherapeutics.
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surveillance of resistance to Adamantanes among influenza a h3n2 and a h1n1 viruses isolated worldwide
The Journal of Infectious Diseases, 2007Co-Authors: Varough M Deyde, Larisa V Gubareva, Rick A Bright, Xiyan Xu, Michael Shaw, Catherine B Smith, Ye Zhang, Alexander KlimovAbstract:: Our previous reports demonstrated an alarming increase in resistance to Adamantanes among influenza A(H3N2) viruses isolated in 2001-2005. To continue monitoring drug resistance, we conducted a comprehensive analysis of influenza A(H3N2) and A(H1N1) viruses isolated globally in 2005-2006. The results obtained by pyrosequencing indicate that 96.4% (n=761) of A(H3N2) viruses circulating in the United States were adamantane resistant. Drug resistance has reached 100% among isolates from some Asian countries. Analysis of correlation between the appearance of drug resistance and the evolutionary pathway of the hemagglutinin (HA) gene suggests at least 2 separate introductions of resistance into circulating populations that gave rise to identifiable subclades. It also indicates that resistant A(H3N2) viruses may have emerged in Asia in late 2001. Among A(H1N1) viruses isolated worldwide, resistance reached 15.5% in 2005-2006; in the United States alone, it was 4.0%. Phylogenetic analysis of the HA and M genes indicates that the acquisition of resistance in A(H1N1) viruses can be linked to a specific genetic group and was not a result of reassortment between A(H3N2) and A(H1N1) viruses. The results of the study highlight the necessity of close monitoring of resistance to existing antivirals as wells as the need for new therapeutics.
Alexander Klimov - One of the best experts on this subject based on the ideXlab platform.
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dual resistance to Adamantanes and oseltamivir among seasonal influenza a h1n1 viruses 2008 2010
The Journal of Infectious Diseases, 2011Co-Authors: Tiffany G Sheu, Alicia M. Fry, Alexander Klimov, Varough M Deyde, Rebecca Garten, Thein Shwe, Lesley Bullion, Patrick J Peebles, Larisa V GubarevaAbstract:Two distinct genetic clades of seasonal influenza A(H1N1) viruses have cocirculated in the recent seasons: clade 2B oseltamivir-resistant and adamantane-susceptible viruses, and clade 2C viruses that are resistant to Adamantanes and susceptible to oseltamivir. We tested seasonal influenza A(H1N1) viruses collected in 2008-2010 from the United States and globally for resistance to antivirals approved by the Food and Drug Administration. We report 28 viruses with both adamantane and oseltamivir (dual) resistance from 5 countries belonging to 4 distinct genotypes. Because of limited options for antiviral treatment, emergence of dual-resistant influenza viruses poses a public health concern, and their circulation needs to be closely monitored.
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detection of adamantane resistant influenza on a microarray
Journal of Clinical Virology, 2008Co-Authors: Michael B Townsend, Larisa V Gubareva, Alexander Klimov, James A Smagala, Erica D Dawson, Varough M Deyde, Robert D Kuchta, Kathy L RowlenAbstract:Abstract Background Influenza A has the ability to rapidly mutate and become resistant to the commonly prescribed influenza therapeutics, thereby complicating treatment decisions. Objective To design a cost-effective low-density microarray for use in detection of influenza resistance to the Adamantanes. Study design We have taken advantage of functional genomics and microarray technology to design a DNA microarray that can detect the two most common mutations in the M2 protein associated with adamantane resistance, V27A and S31N. Results In a blind study of 22 influenza isolates, the antiviral resistance-chip (AVR-Chip) had a success rate of 95% for detecting these mutations. Microarray data from a larger set of samples were further analyzed using an artificial neural network and resulted in a correct identification rate of 94% for influenza virus samples that had V27A and S31N mutations. Conclusions The AVR-Chip provided a method for rapidly screening influenza viruses for adamantane sensitivity, and the general approach could be easily extended to detect resistance to other chemotherapeutics.
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surveillance of resistance to Adamantanes among influenza a h3n2 and a h1n1 viruses isolated worldwide
The Journal of Infectious Diseases, 2007Co-Authors: Varough M Deyde, Larisa V Gubareva, Rick A Bright, Xiyan Xu, Michael Shaw, Catherine B Smith, Ye Zhang, Alexander KlimovAbstract:: Our previous reports demonstrated an alarming increase in resistance to Adamantanes among influenza A(H3N2) viruses isolated in 2001-2005. To continue monitoring drug resistance, we conducted a comprehensive analysis of influenza A(H3N2) and A(H1N1) viruses isolated globally in 2005-2006. The results obtained by pyrosequencing indicate that 96.4% (n=761) of A(H3N2) viruses circulating in the United States were adamantane resistant. Drug resistance has reached 100% among isolates from some Asian countries. Analysis of correlation between the appearance of drug resistance and the evolutionary pathway of the hemagglutinin (HA) gene suggests at least 2 separate introductions of resistance into circulating populations that gave rise to identifiable subclades. It also indicates that resistant A(H3N2) viruses may have emerged in Asia in late 2001. Among A(H1N1) viruses isolated worldwide, resistance reached 15.5% in 2005-2006; in the United States alone, it was 4.0%. Phylogenetic analysis of the HA and M genes indicates that the acquisition of resistance in A(H1N1) viruses can be linked to a specific genetic group and was not a result of reassortment between A(H3N2) and A(H1N1) viruses. The results of the study highlight the necessity of close monitoring of resistance to existing antivirals as wells as the need for new therapeutics.
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adamantane resistance among influenza a viruses isolated early during the 2005 2006 influenza season in the united states
JAMA, 2006Co-Authors: Rick A Bright, David K Shay, Bo Shu, Nancy J Cox, Alexander KlimovAbstract:ContextThe Adamantanes, amantadine and rimantadine, have been used as first-choice antiviral drugs against community outbreaks of influenza A viruses for many years. Rates of viruses resistant to these drugs have been increasing globally. Rapid surveillance for the emergence and spread of resistant viruses has become critical for appropriate treatment of patients.ObjectiveTo investigate the frequency of adamantane-resistant influenza A viruses circulating in the United States during the initial months of the 2005-2006 influenza season.Design and SettingInfluenza isolates collected from 26 states from October 1 through December 31, 2005, and submitted to the US Centers for Disease Control and Prevention were tested for drug resistance as part of ongoing surveillance. Isolates were submitted from World Health Organization collaborating laboratories and National Respiratory and Enteric Virus Surveillance System laboratories.Main Outcome MeasuresUsing pyrosequencing and confirmatory assays, we identified viruses containing mutations within the M2 gene that are known to confer resistance to both amantadine and rimantadine.ResultsA total of 209 influenza A(H3N2) viruses isolated from patients in 26 states were screened, of which 193 (92.3%) contained a change at amino acid 31 (serine to asparagine [S31N]) in the M2 gene known to be correlated with adamantane resistance. Two of 8 influenza A(H1N1) viruses contained the same mutation. Drug-resistant viruses were distributed across the United States.ConclusionsThe high proportion of influenza A viruses currently circulating in the United States demonstrating adamantane resistance highlights the clinical importance of rapid surveillance for antiviral resistance. Our results indicate that these drugs should not be used for the treatment or prophylaxis of influenza in the United States until susceptibility to Adamantanes has been reestablished among circulating influenza A isolates.Published online February 2, 2006 (doi:10.1001/jama.295.8.joc60020).
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incidence of adamantane resistance among influenza a h3n2 viruses isolated worldwide from 1994 to 2005 a cause for concern
The Lancet, 2005Co-Authors: Rick A Bright, Nancy J Cox, Mariejo Medina, Gilda Perezoronoz, Teresa R Wallis, Xiaohong M Davis, Laura Povinelli, Alexander KlimovAbstract:Summary Background Adamantanes have been used to treat influenza A virus infections for many years. Studies have shown a low incidence of resistance to these drugs among circulating influenza viruses; however, their use is rising worldwide and drug resistance has been reported among influenza A (H5N1) viruses isolated from poultry and human beings in Asia. We sought to assess adamantane resistance among influenza A viruses isolated during the past decade from countries participating in WHO's global influenza surveillance network. Methods We analysed data for influenza field isolates that were obtained worldwide and submitted to the WHO Collaborating Center for Influenza at the US Centers for Disease Control and Prevention between Oct 1, 1994, and Mar 31, 2005. We used pyrosequencing, confirmatory sequence analysis, and phenotypic testing to detect drug resistance among circulating influenza A H3N2 (n=6524), H1N1 (n=589), and H1N2 (n=83) viruses. Findings More than 7000 influenza A field isolates were screened for specific aminoacid substitutions in the M2 gene known to confer drug resistance. During the decade of surveillance a significant increase in drug resistance was noted, from 0·4% in 1994–1995 to 12·3% in 2003–2004. This increase in the proportion of resistant viruses was weighted heavily by those obtained from Asia with 61% of resistant viruses isolated since 2003 being from people in Asia. Interpretation Our data raise concerns about the appropriate use of Adamantanes and draw attention to the importance of tracking the emergence and spread of drug-resistant influenza A viruses.