in the US. A meta-analysis from 2011 found that zanamivir resistance had been rarely reported. Antiviral resistance can emerge during or after treatment with antivirals in certain people (e.g., immunosuppressed). In 2013 genes expressing resistance to zanamivir (and oseltamivir) were found in Chinese patients infected with avian influenza A H7N9. Adverse effects Dosing is limited to the inhalation route. This restricts its usage, as treating asthmatics could induce bronchospasms. In 2006 the Food and Drug Administration (FDA) found that breathing problems (bronchospasm), including deaths, were reported in some patients after the initial approval of Relenza. Most of these patients had asthma or chronic obstructive pulmonary disease. Relenza therefore was not recommended for treatment or prophylaxis of seasonal influenza in individuals with asthma or chronic obstructive pulmonary disease. In 2009 the zanamivir package insert contains precautionary information regarding risk of bronchospasm in patients with respiratory disease. GlaxoSmithKline (GSK) and FDA notified healthcare professionals of a report of the death of a patient with influenza having received zanamivir inhalation powder, which was solubilized and administered by mechanical ventilation. In adults there was no increased risk of reported adverse events in trials. There was little evidence of the possible harms associated with the treatment of children with zanamivir. Zanamivir has not been known to cause toxic effects and has low systemic exposure to the human body. Mechanism of action Zanamivir works by binding to the active site of the neuraminidase protein, rendering the influenza virus unable to escape its host cell and infect others. It is also an inhibitor of influenza virus replication in vitro and in vivo. In clinical trials, zanamivir was found to reduce the time-to-symptom resolution by 1.5 days if therapy was started within 48 hours of the onset of symptoms. The bioavailability of zanamivir is 2%. After inhalation, zanamivir is concentrated in the lungs and oropharynx, where up to 15% of the dose is absorbed and excreted in urine. History Zanamivir was first made in 1989 by scientists led by Peter Colman and Joseph Varghese at the Australian CSIRO, in collaboration with the Victorian College of Pharmacy, and the Monash University. Zanamivir was the first of the neuraminidase inhibitors. The discovery was initially funded by the Australian biotechnology company Biota and was part of Biota's ongoing program to develop antiviral agents through rational drug design. Its strategy relied on the availability of the structure of influenza neuraminidase by X-ray