Epidemiological survey on the benefit of neuraminidase inhibitors on severe acute respiratory syndrome due to COVID-19 / Levantamento epidemiológico do benefício de inibidores de neuraminidase na síndrome respiratória aguda grave por COVID-19 / Encuesta epidemiológica del beneficio de inhibidores de neuraminidase en síndrome respiratorio agudo severo por COVID-19

Background and objectives: The COVID-19 pandemic and its consequent severe acute respiratory syndrome (SARS) have taken the lives of millions since 2020. The use of neuraminidase inhibitors is a promising alternative in treating this disease, with several studies on off-label use being conducted since the beginning of the pandemic, but none of them have a large sample size and analyze multiple risk factors. The purpose of this article is to identify possible associations between various factors and risk of hospitalization, need for ventilation and death, as well as the influence of the prescription of Zanamivir and Oseltamivir on these same indicators. Methods: In this transversal study, approximately 900,000 medical records from all regions of Brazil were collected from the Ministry of Health database, and after that, proper statistical analysis of the variables was performed. Results: Hospitalization was associated with gender, ethnicity, education, local urbanization, State, and its percentage of elderly, as well as the climate. The prescription of Zanamivir and Oseltamivir was associated with higher incidence of symptoms, lower hospitalization and death rate, and lower need for invasive and non-invasive ventilation. Medical records from146,160 patients were excluded due to SARS not caused by COVID-19. Conclusion: From this data, it is possible to draw a risk profile for hospitalization by SARS and consider the use of Zanamivir and Oseltamivir as a treatment for these patients.(AU)

Justificativa e objetivos: A pandemia de COVID-19 e sua consequente síndrome respiratória aguda grave (SRAG) levaram milhões de pessoas a óbito desde 2020. O uso de inibidores da neuraminidase é uma alternativa promissora no tratamento dessa doença, com vários estudos sobre o uso off-label sendo conduzidos desde o início da pandemia, mas nenhum que tenha um grande tamanho amostral e que analise vários fatores de risco. O objetivo deste artigo é identificar possíveis associações entre diversos fatores e risco de hospitalização, necessidade de ventilação e óbito, assim como a influência da prescrição de Zanamivir e Oseltamivir nos mesmos indicadores. Métodos: Neste estudo transversal, foi feito o levantamento de aproximadamente 900 mil prontuários de todas as regiões do Brasil, provenientes de dados do Ministério da Saúde, e em seguida foi realizado o tratamento estatístico adequado das variáveis. Resultados: A hospitalização foi associada a sexo, etnia, escolaridade, urbanização do local, Estado e porcentagem de idosos do mesmo, assim como o clima. Já a prescrição de Zanamivir e Oseltamivir foi associada a maior incidência de sintomas, menor taxa de hospitalização e óbito e menor necessidade de ventilação invasiva e não-invasiva. Foram excluídos 146.160 prontuários devido a SRAG não ocasionada pela COVID-19. Conclusão: Com esses dados, é possível traçar um perfil de risco para hospitalização por SRAG e considerar o uso de Zanamivir e Oseltamivir como tratamento para esses pacientes.(AU)

Justificación y objetivos: la pandemia Covid-19 y su consiguiente síndrome respiratorio agudo severo (SRAS) han muerto millones de personas desde 2020. El uso de inhibidores de la neuraminidasa es una alternativa prometedora en el tratamiento de esta enfermedad, con varios estudios sobre el uso off-label que se realiza desde el principio de la pandemia, pero ninguno que tenga un tamaño de muestra grande y analice múltiples factores de riesgo. El propósito de este artículo es identificar posibles asociaciones entre varios factores y el riesgo de hospitalización, necesidad de ventilación y muerte, así como la influencia de la prescripción de Zanamivir y Oseltamivir en los mismos indicadores. Métodos: En este estudio transversal, se encuestaron a los datos del Ministerio de Salud de aproximadamente 900,000 registros de todas las regiones de Brasil, después de que se realizó un tratamiento estadístico adecuado de las variables. Resultados: La hospitalización se asoció con género, etnia, educación, urbanización del sitio, Estado y porcentaje de ancianos, así como el clima. La prescripción de zanamivir y oseltamivir se asoció con la mayor incidencia de síntomas, menor hospitalización y tasa de mortalidad y menor necesidad de ventilación invasiva y no invasiva. Se excluyeron 146,160 registros médicos debido a SRAS no causado por Covid-19. Conclusión: con estos datos, es posible dibujar un perfil de riesgo para la hospitalización por SRAS y considerar el uso de zanamivir y oseltamivir como tratamiento para estos pacientes.(AU)

Efficacy of oseltamivir compared with zanamivir in COPD patients with seasonal influenza virus infection: a randomized controlled trial

Influenza viruses exacerbate chronic obstructive pulmonary disease (COPD) with considerable morbidity and mortality. Zanamivir and oseltamivir are effective in treating influenza. However, their efficacy in relieving influenza symptoms in COPD patients remains unknown, with the lack of controlled trials in this subject. Therefore, we conducted this randomized controlled trial to investigate the clinical efficacy of both interventions in this population. Patients were allocated to two groups (80 patients each): oseltamivir (OSELTA) and zanamivir (ZANA) groups. Oseltamivir (75 mg) was orally administered twice daily for 5 days, while zanamivir (10 mg) was inhaled twice daily for 5 days. Clinical parameters including body temperature, influenza symptoms (i.e., sore throat, cough, etc.), and serial blood tests were recorded on days 1, 3, and 7. We analyzed primary (changes in body temperature) and secondary outcomes (changes in non-specific symptoms) using the pre-protocol and intention-to-treat analyses. Differences between groups were assessed using t-test. Oseltamivir and zanamivir significantly reduced body temperature on the 3rd day after treatment; however, the number of patients who reported clinical improvement in influenza-like symptoms was significantly higher in the OSELTA group compared to the ZANA group on days 3 (85 vs 68.8%, P=0.015) and 7 (97.5 vs 83.8%, P=0.003). However, no significant changes in hematological (white blood cells and its subtypes) and inflammatory (C-reactive protein) parameters were noted (P>0.05). Our results suggested that oseltamivir and zanamivir are effective in reducing body temperature, while oseltamivir led to better clinical improvement regarding influenza-like symptoms in patients with COPD.

Treatment and prophylaxis of influenza

Influenza is an acute respiratory disease caused by the influenza virus. Each year, it causes a significant disease burden, especially in older adults. Furthermore, influenza pandemics occasionally occur because of antigenic change. Common signs and symptoms of influenza include fever, cough, sore throat, headache, myalgia, and runny nose. Severe cases may progress to pneumonia, which causes shortness of breath, tachycardia, hypotension, and the need for supportive respiratory interventions. Mild cases are self-limited and supportive care is sufficient. Antiviral treatment shortens the clinical course if it is administered within 48 hours from the onset of disease. Neuraminidase inhibitors, such as oseltamivir, zanamivir, and peramivir, are widely used. Although annual vaccination is the best means of prevention, its effectiveness can vary from year to year and among different age and risk groups.

Abordaje diagnostico terapéutico de la neumonía viral grave / Diagnostic therapeutic approach to severe viral pneumonia

La guía de referencia rápida tiene como objetivo proporcionar al usuario las recomendaciones clave de la guía. Abordaje diagnóstico y terapéutico de la neumonía viral grave, seleccionadas con base a su impacto en salud por el grupo desarrollador, las cuales pueden variar en función de la intervención de que se trate, así como del contexto regional o local en el ámbito de su aplicación.

Influenza / 대한내과학회지

Influenza causes variable epidemics annually and imposes public health problems and socioeconomic burden. They cause epidemic acute respiratory disease, characterized by fever, cough and systemic symptoms. The annual epidemics of seasonal influenza can affect any age group and result in serious illness or death, particularly in high risk populations such as adults > 65 years old, children < 2 years old and those with chronic medical condition at any age. Three types (A, B, and C) are recognized as well as many subtypes within the type A. New influenza A virus subtypes sporadically emerge in humans to cause widespread disease or pandemics. Antiviral therapy with oseltamivir or zanamivir is available and shorten the duration of illness and reduce the rate of complications. Influenza vaccines are effective in the prevention of influenza illness, although improved vaccines are needed.

Detection of influenza B viruses with reduced sensitivity to neuraminidase inhibitor in Morocco during 2014/15 season

We monitored phenotypic and genotypic susceptibility of influenza viruses circulating in Morocco during 2014-2015 to oseltamivir and zanamivir. Throat and nasal swab specimens were collected from outpatients [with influenza-like illness] and inpatients [with severe acute respiratory illness] and tested for influenza viruses using real-time reverse transcription polymerase chain reaction. Positive samples were inoculated in MDCK cells and virus phenotypic susceptibility to neuraminidase inhibitors [NAIs] was assessed using fluorescent NA inhibition. Of 440 specimens, 135 were positive for influenza B Yamagata-like virus, 38 were A[H1N1] pdm09 and 25 were A[H3N2]. Sixty influenza B viruses isolated from MDCK cells showed no significant resistance to NAIs. However, two of these strains, B/Morocco/176H/2015 and B/Morocco/CP10/2015, showed reduced susceptibility to oseltamivir. The two influenza B viruses with reduced susceptibility to oseltamivir show that ongoing NAI susceptibility surveillance is essential

Susceptibility of human influenza A (H3N2) viruses to neuraminidase inhibitors isolated during 2011-2012 in China / 中华预防医学杂志

<p><b>OBJECTIVE</b>To analyze the susceptibility of influenza A (H3N2) viruses to neuraminidase inhibitors during 2011-2012 in Mainland China.</p><p><b>METHODS</b>All the tested viruses were obtained from the Chinese National Influenza Surveillance Network, which covers 31 provinces in mainland China, including 408 network laboratories and 554 sentinel hospitals. In total 1 903 viruses were selected with isolation date from January 1, 2011 to December 31, 2012 in Mainland China, among these viruses, 721 were confirmed to be influenza A (H3N2) virus by Chinese National Influenza Center and tested for the susceptibility to oseltamivir and zanamivir using chemiluminescence-based assay. The neuraminidase inhibitor sensitive reference virus A/Washington/01/2007 (119E) and oseltamivir resistant virus A/Texas/12/2007 (E119V) were used as control in this study. The t -test was used to compare the difference of NAI susceptibility of viruses isolated from different years.</p><p><b>RESULTS</b>The half maximal inhibitory concentration (IC₅₀) of A/Washington/01/2007 for oseltamivir and zanamivir was (0.10 ± 0.02) and (0.30 ± 0.05) nmol/L, respectively. The IC₅₀ of A/Texas/12/2007 for oseltamivir and zanamivir was (4.27 ± 1.60) and (0.20 ± 0.03) nmol/L, respectively. Among the 721 influenza A (H3N2) viruses, 132 influenza A (H3N2) viruses were isolated in 2011 and 589 influenza A (H3N2) viruses were isolated in 2012. The IC50 for oseltamivir ranged from 0.04 to 0.62 nmol/L for viruses isolated in 2011 and ranged from 0.02 to 0.95 nmol/L for viruses in 2012, and the IC₅₀ of all the viruses tested was within 10-fold IC₅₀ (1.0 nmol/L) of the neuraminidase inhibitor sensitive reference virus A/Washington/01/2007. The IC50 of zanamivir ranged from 0.12 to 0.80 nmol/L for viruses in 2011 and ranged from 0.04 to 0.72 nmol/L for viruses in 2012, and was within 10-fold IC₅₀ (3.0 nmol/L) of the neuraminidase inhibitor sensitive reference virus A/Washington/01/2007.</p><p><b>CONCLUSION</b>The influenza A(H3N2) viruses isolated during 2011-2012 in Mainland China were tested to be sensitive to oseltamivir and zanamivir.</p>

Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children

BACKGROUND: Neuraminidase inhibitors (NIs) are stockpiled and recommended by public health agencies for treating and preventing seasonal and pandemic influenza. They are used clinically worldwide. OBJECTIVE: To describe the potential benefits and harms of NIs for influenza in all age groups by reviewing all clinical study reports of published and unpublished randomised, placebo-controlled trials and regulatory comments. METHODS Search methods: We searched trial registries, electronic databases (to 22 July 2013) and regulatory archives, and corresponded with manufacturers to identify all trials. We also requested clinical study reports. We focused on the primary data sources of manufacturers but we checked that there were no published randomised controlled trials (RCTs) from non-manufacturer sources by running electronic searches in the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE (Ovid), EMBASE, Embase.com, PubMed (not MEDLINE), the Database of Reviews of Effects, the NHS Economic Evaluation Database and the Health Economic Evaluations Database. Selection criteria: Randomised, placebo-controlled trials on adults and children with confirmed or suspected exposure to naturally occurring influenza. Data collection and analysis: We extracted clinical study reports and assessed risk of bias using purpose-built instruments. We analysed the effects of zanamivir and oseltamivir on time to first alleviation of symptoms, influenza outcomes, complications, hospitalisations and adverse events in the intention-to-treat (ITT) population. All trials were sponsored by the manufacturers. MAIN RESULTS: We obtained 107 clinical study reports from the European Medicines Agency (EMA), GlaxoSmithKline and Roche. We accessed comments by the US Food and Drug Administration (FDA), EMA and Japanese regulator. We included 53 trials in Stage 1 (a judgement of appropriate study design) and 46 in Stage ...

Gripe ou resfriado? Sinusite ou rinite? / Influenza or cold? Sinusitis or rhinitis?

Resfriado comum e gripe são habitualmente confundidos, principalmente se o resfriado for mais intenso. Coriza é rotulada tanto como alergia como sinusite. Os processos inflamatórios das vias aéreas superiores envolvidos nessas entidades clínicas conjugam fatores comuns, embora tenham etiologias diferentes. Graças a isso, diagnósticos equivocados geram tratamento inadequado, geralmente com emprego desnecessário de antibióticos. O resfriado comum e a gripe (influenza) são infecções virais do trato respiratório, assim como a maioria das rinossinusites. Já a rinite é, em sua maior parte, manifestação da atopia respiratória.

Common cold and flu are usually confused, especially if the cold is more intense. Many times, coryza is labeled as being allergy or sinusitis. The inflammation of the upper airways involved in these clinical entities combine common factors, although they have different etiologies. As a result, misdiagnosis generates inadequate treatment, usually with unnecessary use of antibiotics. The common cold and the flu (influenza) are viral infections of the respiratory tract, as well as most cases of rhinosinusitis. On the other hand, rhinitis is, most of the time, a manifestation of respiratory atopy.

Drug susceptibility of wild-type and mutant H7N9 neuraminidase to zanamivir and oseltamivir / 病毒学报

This study aimed to investigate the drug susceptibility of wild-type and mutant avian influenza A (H7N9) virus neuraminidase (NA) to oseltamivir and zanamivir. Codon optimized DNA of H7N9 (A/ Hangzhou/1/2013) NA was synthesized and constructed into the pcDNA3.1/His vector (NA(H7N9-WT)). Mutant NA(H7N9-H274Y) and NA(H7N9-R292K) plasmids were constructed by directed mutagenesis PCR using NA(H7N9-WT) plasmid as the template followed by sequencing. NA plasmids were transfected into 293T cells and cell lysates containing NAs were collected 48 h post-transfection. Wild-type and mutant NAs were analyzed by Western blotting and their activities were tested by the 4-MUNANA-based assay. All three NAs were expressed and enzymatic activities were confirmed. The effects of oseltamivir and zanamivir on all three NAs were then tested. It showed that the half maximal inhibitory concentrations (IC50s) of oseltamivir carboxylate on NA(H7N9-WT), NA(H7N9-H274Y) and NA(H7N9-R292K) were 1.6 nM, 15.1 nM, and > 1 000 nM with fold changes of 9 and > 625, respectively. The IC50 values of zanamivir on NA(H7N9-WT), NA(H7N9-H274Y), and NA(H7N9-R292K) were 1.1 nM, 1.4 nM, and 38.0 nM with fold changes of 1.3 and 34, respectively. These results indicated that oseltamivir and zanamivir could significantly inhibit NA(H7N9-WT). NA(H7N9-R292K) showed high-level resistance to both drugs (34-fold and 625-fold) and NA(H7N9-H274Y) was sensitive to both (1.3-fold and 9-fold). These results indicated that both oseltamivir and zanamivir could be used for patients infected with the H7N9 virus. However, when patients carried the H7N9 virus with a NA R292K mutation, other medications would be preferred over oseltamivir or zanamivir.

Zanamivir Oral Delivery: Enhanced Plasma and Lung Bioavailability in Rats

The objective of this study was to enhance the oral bioavailability (BA) of zanamivir (ZMR) by increasing its intestinal permeability using permeation enhancers (PE). Four different classes of PEs (Labrasol(R), sodium cholate, sodium caprate, hydroxypropyl beta-cyclodextrin) were investigated for their ability to enhance the permeation of ZMR across Caco-2 cell monolayers. The flux and Papp of ZMR in the presence of sodium caprate (SC) was significantly higher than other PEs in comparison to control, and was selected for further investigation. All concentrations of SC (10-200 mM) demonstrated enhanced flux of ZMR in comparison to control. The highest flux (13 folds higher than control) was achieved for the formulation with highest SC concentration (200 mM). The relative BA of ZMR formulation containing SC (PO-SC) in plasma at a dose of 10 mg/kg following oral administration in rats was 317.65% in comparison to control formulation (PO-C). Besides, the AUC0-24 h of ZMR in the lungs following oral administration of PO-SC was 125.22 +/- 27.25 ng hr ml(-1) with a Cmax of 156.00 +/- 24.00 ng/ml reached at 0.50+/-0.00 h. But, there was no ZMR detected in the lungs following administration of control formulation (PO-C). The findings of this study indicated that the oral formulation PO-SC containing ZMR and SC was able to enhance the BA of ZMR in plasma to an appropriate amount that would make ZMR available in lungs at a concentration higher (>10 ng/ml) than the IC50 concentration of influenza virus (0.64-7.9 ng/ml) to exert its therapeutic effect.

Occurrence and characterization of oseltamivir-resistant influenza virus in children between 2007-2008 and 2008-2009 seasons / 소아과

PURPOSE: There was a global increase in the prevalence of oseltamivir-resistant influenza viruses during the 2007-2008 influenza season. This study was conducted to investigate the occurrence and characteristics of oseltamivir-resistant influenza viruses during the 2007-2008 and 2008-2009 influenza seasons among patients who were treated with oseltamivir (group A) and those that did not receive oseltamivir (group B). METHODS: A prospective study was conducted on 321 pediatric patients who were hospitalized because of influenza during the 2007-2008 and 2008-2009 influenza seasons. Drug resistance tests were conducted on influenza viruses isolated from 91 patients. RESULTS: There was no significant difference between the clinical characteristics of groups A and B during both seasons. Influenza A/H1N1, isolated from both groups A and B during the 2007-2008 and 2008-2009 periods, was not resistant to zanamivir. However, phenotypic analysis of the virus revealed a high oseltamivir IC50 range and that H275Y substitution of the neuraminidase (NA) gene and partial variation of the hemagglutinin (HA) gene did not affect its antigenicity to the HA vaccine even though group A had a shorter hospitalization duration and fewer lower respiratory tract complications than group B. In addition, there was no significant difference in the clinical manifestations between oseltamivir-susceptible and oseltamivir-resistant strains of influenza A/H1N1. CONCLUSION: Establishment of guidelines to efficiently treat influenza with oseltamivir, a commonly used drug for treating influenza in Korean pediatric patients, and a treatment strategy with a new therapeutic agent is required.

Establishment of drug screening assay and pharmacodynamic evaluation method targeting influenza RNA polymerase / 药学学报

Influenza virus RNA-dependent RNA polymerase (RdRP) is essential for replication and expression of influenza virus genome. Viral genomic sequences encoding RdRP are highly conservative, thus making it a potential anti-influenza drug target. A cell-based influenza RdRP inhibitor screening assay was established by a luciferase reporter system to analyze the activity of RdRP. Specificity study and statistic analysis showed that the screening assay is sensitive and reproducible.

An uncontrolled open-label, multicenter study to monitor the antiviral activity and safety of inhaled zanamivir (as Rotadisk via Diskhaler device) among Chinese adolescents and adults with influenza-like illness / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>It is the first multicenter clinical study in China to investigate zanamivir use among Chinese adolescents and adults with influenza-like illness (ILI) since 2009, when inhaled zanamivir (RELENZA(®)) was marketed in China.</p><p><b>METHODS</b>An uncontrolled open-label, multicentre study to evaluate the antiviral activity, and safety of inhaled zanamivir (as Rotadisk via Diskhaler device); 10 mg administered twice daily for 5 days in subjects ≥ 12 years old with ILI. Patients were enrolled within 48 hours of onset and followed for eight days. Patients were defined as being influenza-positive if the real-time reverse transcriptase-polymerase chain reaction (rRT-PCR) test had positive results.</p><p><b>RESULTS</b>A total of 400 patients ≥ 12 years old were screened from 11 centers in seven provinces from March 2010 to January 2011. Three hundred and ninety-two patients who took at least one dose of zanamivir were entered into the safety analysis. The mean age was 33.8 years and 50% were male. Cardiovascular diseases and diabetes were the most common comorbidities. All the reported adverse events, such as rash, nasal ache, muscle ache, nausea, diarrhea, headache, occurred in less than 1% of subjects. Mild sinus bradycadia or arrhythmia occurred in four subjects (1%). Most of the adverse events were mild and did not require any change of treatment. No severe adverse events (SAE) or fatal cases were reported. Bronchospasm was found in a 38 years old woman whose symptoms disappeared after stopping zanamivir and without additional treatment. All the 61 influenza virus isolates (43 before enrollment, 18 during treatment) proved to be sensitive to zanamivir.</p><p><b>CONCLUSIONS</b>Zanamivir is well tolerated by Chinese adolescents and adults with ILIs. There is no evidence for the emergence of drug-resistant isolates during treatment with zanamivir.</p>

Virological surveillance and antiviral resistance of human influenza virus in Argentina, 2005–2008 / Vigilancia virológica y resistencia a los antivíricos del virus de la gripe humana en la Argentina, 2005–2008

Objective. To describe the virological characteristics of the influenza strains circulating in Argentina in 2005–2008 and to assess the prevalence of antiviral resistance. Methods. On the basis of their geographical spread and prevalence, influenza A and B isolates grown in Madin–Darby canine kidney cells were selected after antigenic and genomic characterization to be analyzed for antiviral resistance by enzymatic assay and pyrosequencing. Amantadine susceptibility was evaluated by pyrosequencing for known resistance markers on 45 strains of influenza A. Susceptibility to oseltamivir and zanamivir was evaluated by enzymatic assay of 67 influenza A and 46 influenza B strains, some of which were further analyzed by sequencing the neuraminidase gene. Results. Resistance to amantadine was observed only on A(H3N2) strains (29/33); all of them carried the mutation S31N in their M2 sequence. Oseltamivir resistance was observed in 12 (34.3%) of the 35 A(H1N1) strains from 2008; all of them carried the mutation H275Y in their neuraminidase sequence. All these viruses remained sensitive to zanamivir. Conclusions. This study describes a high incidence of amantadine-resistant influenza A(H3N2) viruses since 2006 and an unprecedented increase in oseltamivir resistance detected only in influenza A(H1N1) viruses isolated in 2008. Influenza A and B viruses were more sensitive to oseltamivir than to zanamivir, and influenza A viruses were more sensitive to both neuraminidase inhibitors than the influenza B viruses. The national data generated and analyzed in this study may help increase knowledge about influenza antiviral drug resistance, which is a problem of global concern.

Objetivo. Describir las características virológicas de las cepas de virus de la gripe que circulaban en la Argentina entre el 2005 y el 2008, y evaluar la prevalencia de la resistencia a los antivíricos. Métodos. Según su diseminación geográfica y su prevalencia, se seleccionaron aislados de gripe A y B cultivados en células renales caninas de Madin-Darby después de su caracterización antigénica y genómica, y se analizó su resistencia a los antivíricos mediante análisis enzimático y pirosecuenciación. La sensibilidad a la amantadina se evaluó por pirosecuenciación para los marcadores conocidos de resistencia en 45 cepas de gripe A. La sensibilidad al oseltamivir y al zanamivir se evaluó mediante análisis enzimático de 67 cepas de gripe A y 46 cepas de gripe B, algunas de las cuales se analizaron en mayor profundidad mediante la secuenciación del gen de la neuraminidasa. Resultados. Se observó resistencia a la amantadina solo en las cepas de gripe A (H3N2) (29/33); todas ellas tenían la mutación S31N en su secuencia de M2. Se observó resistencia al oseltamivir en 12 (34,3%) de las 35 cepas de gripe A (H1N1) aisladas en el 2008; todas ellas tenían la mutación H275Y en su secuencia de neuraminidasa. Todos estos virus conservaron su sensibilidad al zanamivir. Conclusiones. En este estudio se describe una incidencia elevada del virus de la gripe A (H3N2) resistente a la amantadina desde el 2006 y un aumento sin precedentes de la resistencia al oseltamivir detectada solo en los virus de la gripe A (H1N1) aislados en el 2008. Los virus de la gripe A y B fueron más sensibles al oseltamivir que al zanamivir y los virus de la gripe A fueron más sensibles a ambos inhibidores de la neuraminidasa que los virus de la gripe B. Los datos nacionales generados y analizados en este estudio pueden ayudar a aumentar los conocimientos acerca de la resistencia a los fármacos antivíricos dirigidos contra el virus de la gripe, lo que es un motivo de preocupación mundial.

Frequently used antiviral agents in the clinical environment

More than 60 antiviral agents for various infectious diseases such as herpes, hepatitis, influenza, and AIDS are currently prescribed worldwide. Among the viral infections, hepatitis B and influenza are those frequently seen in primary care situations in Korea. This review discusses the anti-hepatitis B (HBV) drugs entecavir and adefovir, and the anti-influenza drugs oseltamivir and zanamivir. In addition, the pharmacology and therapeutic guidance suggested by the Korean Association for the Study of the Liver were reviewed for entecavir and adepovir, the most frequently prescribed anti-HBV drugs. For influenza, oseltamivir is commonly used despite debates on neuropsychiatric safety issues and zanamivir may be used when an inhalation form is necessary. Although currently used drugs show considerable clinical efficacy, efforts to optimize their use and further research to find new molecules that may overcome their limitations are necessary.

First Fatal Oseltamivir-Resistant 2009 Pandemic Influenza A (H1N1) Case in an Adult in Korea / 전남의대학술지

It has been suggested that oseltamivir-resistant influenza viruses harboring the H274/275Y mutation are less virulent than are those that are oseltamivir-sensitive, and fatality attributed to infection with an oseltamivir-resistant virus is very rare. Here we report the first fatal adult case of oseltamivir-resistant 2009 pandemic influenza A (H1N1) in Korea. A 60-year-old Korean male who had hypertension, diabetes mellitus, chronic kidney disease, and dilated cardiomyopathy visited Chonnam National University Hospital because of a 7-day history of chest pain and dyspnea. The patient was at another clinic and had been medicated with oseltamivir (75 mg twice daily) beginning 7 days before admission. Empirical antibiotics were started on the first day of hospitalization. Reverse-transcriptase polymerase chain reaction for 2009 pandemic influenza A (H1N1) was reported to be positive, and a double dose of oseltamivir (150 mg twice per day) was started on day four of hospitalization. However, the pneumonia worsened and the patient died, despite 3 days of high-dose antiviral therapy and 6 days of antibacterial therapy. An H275Y mutation was detected in the neuraminidase gene sequence. This case shows that oseltamivir resistance after short-term drug exposure is possible and can be fatal, emphasizing that early use of zanamivir should be considered in suspicious cases.

First Fatal Oseltamivir-Resistant 2009 Pandemic Influenza A (H1N1) Case in an Adult in Korea / 전남의대학술지

It has been suggested that oseltamivir-resistant influenza viruses harboring the H274/275Y mutation are less virulent than are those that are oseltamivir-sensitive, and fatality attributed to infection with an oseltamivir-resistant virus is very rare. Here we report the first fatal adult case of oseltamivir-resistant 2009 pandemic influenza A (H1N1) in Korea. A 60-year-old Korean male who had hypertension, diabetes mellitus, chronic kidney disease, and dilated cardiomyopathy visited Chonnam National University Hospital because of a 7-day history of chest pain and dyspnea. The patient was at another clinic and had been medicated with oseltamivir (75 mg twice daily) beginning 7 days before admission. Empirical antibiotics were started on the first day of hospitalization. Reverse-transcriptase polymerase chain reaction for 2009 pandemic influenza A (H1N1) was reported to be positive, and a double dose of oseltamivir (150 mg twice per day) was started on day four of hospitalization. However, the pneumonia worsened and the patient died, despite 3 days of high-dose antiviral therapy and 6 days of antibacterial therapy. An H275Y mutation was detected in the neuraminidase gene sequence. This case shows that oseltamivir resistance after short-term drug exposure is possible and can be fatal, emphasizing that early use of zanamivir should be considered in suspicious cases.

Uso de oseltamivir durante la pandemia de gripe a (H1N1): análisis de las reacciones adversas reportadas al sistema nacional de farmacovigilancia de ANMAT / Use of oseltamivir during influenza A (H1N1) pandemic: analysis of adverse reactions reported to the ANMAT national pharmacovigilance system

INTRODUCCIÓN: Oseltamivir es un medicamento antiviral usado para profilaxis y tratamiento de la gripe. Sus efectos adversos son conocidos a través de los ensayos clínicos y por la experiencia adquirida en la última epidemia de gripe aviar. Dentro de las reacciones más graves se han reportado casos de anafilaxia, eventos cutáneos y manifestaciones psiquiátricas como alucinaciones, delirium e ideación suicida. OBJETIVO: en julio de 2009, el departamento de Farmacovigilancia de ANMAT lanzó el Plan Nacional de Farmacovigilancia para Drogas Antivirales con el objetivo de recolectar mayor información de seguridad de estos medicamentos durante su uso masivo, con especial atención a las manifestaciones cutáneas, hepáticas y neuropsiquiátricas. MÉTODOS: se analizaron todas las notificaciones recibidas durante junio - noviembre de 2009. Los datos considerados fueron: sexo, edad, notificador, modalidad terapéutica, severidad, clasificación delefecto adverso principal e imputabilidad asignada. RESULTADOS: serecibieron 179 notificaciones, la mayoría asociadas a la modalidad tratamiento. Las reacciones adversas más reportadas involucraron al sistema gastrointestinal, siendo en su mayoría leves y autolimitadas. Con respecto a los casos psiquiátricos reportados, su severidad y variabilidad obliga a prestar especial atención a estas notificaciones. Se reportaron además casos de prolongación del Intervalo QTc, evento no descripto previamente en la literatura. CONCLUSIÓN: Dada la escasa experiencia en la Argentina y el estrecho perfil de seguridad de este fármaco, es indispensable continuar con una vigilancia activa del mismo.

INTRODUCTION: Oseltamivir is an antiviral drug used for profhylaxis and treatment of influenza. Adverse effects are known through clinical trials and in large part by the experience gained after its use in the last outbreak of avian influenza in Asia. Among the most serious reactions are reported cases of anaphylaxis, cutaneous events and psychiatric symptoms such as hallucinations, delirium and suicidal behaviour. OB JECTIVE: in line with various international regulatory authori ties, during July 2009, the ANMAT through Pharmacovigilance Department launched the National Pharmacovigilance Plan for antiviral drugs used for prophylaxis and treatment of the pandemic H1N1 influenza virus. The plan called for reporting any signs or symptoms, paying particular attention to the cutaneous, hepatic and neuropsychiatric symptoms. METHOD:we analyzed all reports received during June to November 2009. The data considered were: sex, age, notifier, therapeutic modality, severity, classification of main side effect and imputation assigned. RESULTS: 179 notifications were received, most associated with treatment modality. As can be seen world wide, in Argentina, the great majority of reported adverse reactions involve the gastrointestinal system, being mostly mild and self-limiting. Given the variability and severity of psychiatric cases reported it is very important to pay close attention to these reports. Reported cases include the QTc interval prolongation, an event not previously described in the literature. CONCLUSIONS: it is essential to continu e with proactive monitoring of this drug because of the limited current experience and the benefits/ risks ratio of the safety profile of this drug.

Estrategias para la reducción de la brecha del conocimiento a la acción en Argentina: la prevención y tratamiento de la influenza A (H1N1) en embarazadas como caso de análisis / Knowledge to action gap reduction strategies in Argentina: influenza A (H1N1) prevention and treatment in pregnant women as a case of analysis

Los reportes rápidos basados en la evidencia constituyen una de las estrategias para la reducción de la brecha del conocimiento a la acción. Objetivo: comunicar los resultados y lecciones aprendidas a partir de la elaboración de un reporte rápido sobre la efectividad y seguridad del uso de vacunas y antivirales para la influenza pandémica en embarazadas. Métodos: revisión sistemática sobre efectividad y seguridad del uso de antivirales y vacunas para influenza tipo A (H1N1) en embarazadas. Resultados: se recuperaron 166 citas: aunque sólo 88 cumplieron los criterios de inclusión. Los reportes epidemiológicos de la afectación de la pandemia señalan un riesgo de hospitalización tres a cinco veces más alto en embarazadas en comparación con la población general. Dos revisiones recientes indican que el oseltaminivir no estaría asociado con un mayor riesgo teratogénico. La evidencia sobre el zanamivir es escasa, absorción sistémica. A noviembre de 2009, la evidencia sobre la efectividad y seguridad de la vacuna para influenza A (H1N1) en embarazadas era escasa (dos ensayos en curso). Conclusión: los reportes rápidos constituyen una estrategia eficiente para el intercambio de conocimiento entre investigadores y decisores, aún en el contexto de una pandemia; sin embargo, es necesario encontrar métodos que permitan optimizar su implementación de manera sistemática y transparente.

Evidence-based rapid reviews constitute one of the knowledge to action GAP reduction strategies. Objective: to communicate the results and learned lessons during the elaboration of an evidence-based rapid review about the effectiveness and safety of vaccines and antivirals for influenza pandemic in pregnant women. Methods: all document containing evidence on adverse events and / or vaccines for influenza type A (H1N1) in pregnant women or that describes the evolution of the pandemic in this population was considered for analysis. Results: 166 articles were retrieved, although only 88 accomplished the inclusion criteria. Epidemiological reports of the pandemic situation indicate three to five times higher risk of hospitalization in pregnant women compared with the general population. Two recent reviews indicate that oseltamivir would not be associated with increased teratogenic risk. The evidence on the zanamivir is scarce, but the risk associated with its use is considered low because of its reduced systemic absortion. Through november 2009, evidence on effectiveness and safety of the H1N1 vaccine in pregnant women was scarce (two on-going clinical trials). Conclusion: evidence-based rapid reviews constitute an efficient strategy for researchers and decision-makers knowledge exchange, even in the context of a pandemic. However, methods that optimize its implementation through a systematic and transparent way are needed.