Zanamivir , influenza virus treatment

Influenza viruses A and B can cause pneumonia in pediatric and adult patients. Amantidine and rimantidine are available oral agents with activity against influenza virus type A. If started within 48 hours of the onset of the first symptoms, they reduce the duration of the illness by about 1.3 days. Oseltamivir and zanamivir also are oral agents and are active against both type A and B viruses. These agents also reduce the duration of the illness by about 1.3 days if initiated within 40 to 48 hours of the first symptoms.29 For active infection beyond the first 48 hours, none of these agents is effective in treating the infection, and supportive care is the best treatment for these patients. 

Currently, two classes of drugs are available with antiviral activity against influenza viruses inhibitors of the ion channel activity of the M2 membrane protein, amantadine and rimantadine, and the neuraminidase inhibitors oseltamivir, and zanamivir. H5N1 viruses isolated from poultry and humans in Thailand and Viet Nam in 2004 invariably showed an amantadine-resistance indicating that amantadine treatment is not an option during the ongoing outb-treak in South-East Asia. 

Neuraminidase inhibitors prevent the release of influenza A and B viruses. Normally, the viral neuraminidase splits off N-acetyl-neuraminic (sialic) acid residues on the cellular surface coat, thereby enabling newly formed viral particles to be detached from the host cell. Zanamivir is given by inhalation oseltamivir is suitable for oral administration because it is an ester prodrug. Possible uses include treatment and prophylaxis of influenza virus infections. 

Compound 28, named zanamivir, was selected for clinical studies for the prophylaxis and treatment of influenza virus. Zanamivir was found to be suitable as a drug because it is highly selective for influenza type A and B viruses, which it inhibits with high potency... 

Influenza A viruses cause severe infections in the respiratory system and are responsible for seasonal epidemics and sporadic pandemics. The primary method for prevention is through vaccination but vaccine production by current methods cannot be carried out in time to stop the progress of a new strain of the influenza virus. Therefore, effective antiviral agents are used for prophylactic and therapeutic treatments. Among several viral molecular targets for anti-influenza drugs, the surface glycoprotein neuraminidase appears particularly attractive. Selective inhibitors of this enzyme have been developed and two of which, oseltamivir phosphate 18 (Tamiflu ) " and zanamivir 19 (Relenza ), have been approved for human use (Scheme 6). 

In the clinical setting, zanamivir 12 and oseltamivir 19 are effective in both the prevention and treatment of influenza A and B infection. Benefit in treatment is restricted to patients treated within 48 h of symptom onset (Fleming 2003). Importantly, the effects of drug treatment are a rednction in the severity of illness, and in the incidence of secondary complications. The term of illness is generally rednced between 1 and 2.5 days. The evalnation of zanamivir (Calfee and Hayden 1998 Oxford 2000 Fleming 2003), oseltamivir (Doncette and Aoki 2001 Oxford 2005) and peramivir (Sidwell and Smee 2002) for the treatment, and prophylaxis, of inflnenza virus infection has been reviewed. The reader is directed to these reviews for further details of drug pharmacodynamics and clinical trial data. 

Two neuraminidase inhibitors (oseltamivir carboxylate and zanamivir) are approved for prevention and treatment of infections with both influenza A and B viruses as discussed in chapter by Itzstein and Thomson, this volume. Oseltamivir carboxylate (OC) has gained most use because it can be taken orally, whereas the current formulation of zanamivir has to be inhaled. In addition, the WHO reconunends oseltamivir for treatment of clinically confirmed cases of H5N1 and for post-exposme prophylaxis to control recent H5N1 avian influenza outbreaks. 

The two classes of antiviral drugs available for treatment of influenza are the same as those available for prophylaxis and include the adamantanes, amantadine and rimantadine, and the neuraminidase inhibitors, oseltamivir and zanamivir. Because of widespread resistance to the adamantanes among influenza A viruses in the United States, amantadine and rimantadine are not recommended for treatment of influenza until susceptibility can be reestablished. 

Zanamivir is indicated for treatment of uncomplicated acute influenza A and B virus in patients aged 7 and older. Treatment should be initiated no later than 2 days after the onset of symptoms. Zanamivir shortens the duration of illness by 1 to 1.5 days. It is also an effective prophylaxis against influenza however, the FDA has not approved this indication at the time of publication. 

Neuraminidase is an essential viral glycoprotein for virus replication and release. The neuraminidase inhibitors zanamivir and oseltamivir have recently been approved for the treatment of acute uncomplicated influenza infection. When a 5-day course of therapy is initiated within 36-48 hours after the onset of symptoms, use of either agent shortens the severity and duration of illness and may decrease the incidence of respiratory complications in children and adults. Unlike amantadine and rimantidine, zanamivir and oseltamivir have activity against both influenza A and influenza B. Zanamivir is administered via oral inhaler. The compound displays poor oral bioavailability, limited plasma protein binding, rapid renal clearance, and absence of significant metabolism. Nasal and throat discomfort may occur—as well as bronchospasm in patients with reactive airway disease. 

Oseltamivir and zanamivir are neuraminidase inhibitors that have activity against both influenza A and influenza B viruses. When administered within 48 hours of the onset of illness, oseltamivir and zanamivir may reduce the duration of illness by approximately 1 day versus placebo. Oseltamivir is approved for treatment in those older than the age of 1 year, while zanamivir is approved for treatment in those older than the age of 7 years. The recommended dosages vary by agent and age (see Table 41-3), and the recommended duration of treatment for both agents is 5 days. The FDA has received 103 reports, occurring between August 29,2005, and July 6,2006, of delirium, hallucinations, and self-injury in pediatric patients (mostly from Japan) following treatment with oseltamivir. 

Zanamivir has been evaluated in the prevention and treatment of influenza A and B, and was effective against both viruses. In placebo-controlled trials, the adverse events profile, including local nasal irritation, did not differ significantly between zanamivir and placebo (3,6-8). Phase II and III chnical studies have shown that zanamivir by inhalation, either orally or combined orally and intranasally, slightly shortened the duration and severity of influenza symptoms and in high-risk patients reduced... 

The MIST (Management of Influenza in the Southern Hemisphere Triahsts) Study Group. Randomised trial of efficacy and safety of inhaled zanamivir in treatment of influenza A and B virus infections. Lancet 1998 352(9144) 1877-81. 

Inhaled zanamivir is effective for the prevention and treatment of influenza A and B virus infections. Early zanamivir treatment (10 mg twice daily for 5 days) of febrile influenza in ambulatory adults and children >5 years old shortens the duration of illness by 1—3 days and in adults reduces by 40% the risk of lower respiratory tract complications requiring antibiotic use. Once-daily zanamivir is highly protective against community-acquired influenza illness, and when given for 10 days, protects against household transmission. 

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