Introduction

Introduction

Why there is a need for a more effective influenza treatment

Advantages of Relenza over previous treatments

Comparison of the symptoms of the 'flu with that of a common cold

The effect of Relenza on patients with respiratory diseases

Relenza (Zanamivir for oral inhalation) is the first in a new generation of influenza virus-specific drugs known as neuraminidase inhibitors, which work by interferring with the life cycles of influenza viruses A and B. It prevents the virus spreading infection to other cells by blocking the neuraminidase enzyme present on the surface of the virus. Relenza is available as a powder that is administered by inhalation of 2 blisters from the rotadisk inside the diskhaler (Fig. 1) twice daily for five days. This means that 20mg of Relenza is delivered to the principal site of viral replication each day.

The main method for preventing influenza since the 1960s is by vaccination and although this and anti-viral drugs such as amantadine and its analogue rimantadine have long been available (since 1976 and 1993 respectively), they are only of limited use because of the constant mutation of the virus. This chameleon-like nature also means that the virus can become unrecognizable to the human immune system and thus repeatedly infect millions of people year after year.

Fig 1: The diskhaler used to administer Relenza. Each blister in the Rotadisk contains 5mg of the drug

Why there is a need for a more effective influenza treatment:

At present influenza is basically an uncontrolled disease and an effective method is needed for both the prevention and treatment of it. In the 20^th century there were some major pandemics such as the 1918-1919 Spanish 'flu which killed 20 million people world wide, the 1957 Asian 'flu, the 1968 Hong Kong 'flu and the 1977 Russian 'flu¹² These viruses also affect different animals, especially domesticated chickens and turkeys and in Hong Kong in 1997 a virulent bird flu virus, started infecting and killing people for the first time ever. Of the 18 people affected 6 died, although there was no evidence that the virus was able to spread between people. Given the antigenic properties of the influenza virus, in the future the virus may be passed from person to person, and because human immune systems are not prepared for avian viruses the effects on the population could be grave. It would not be possible to prepare vaccines in time and anti-viral drugs are not always adequate.

Top of page

Advantages of Relenza over previous treatments:

Relenza has a number of advantages over the existing treatments for influenza. It does not cause significant side effects and the development of zanamivir-resistant viruses is not expected to occur readily in patients. This is because selection of drug-resistant mutants characterized by changes in neuraminidase requires prolonged passage in tissue culture and may be a biological cripple. If started within two days of the onset of influenza symptoms and if a fever is present, the duration of illness is decreased by an average of 1.5 days. It appears to decrease the severity of flu symptoms for the remainder of the illness, as well as decreasing the number of complications from the flu. It is also possible that Relenza could be used as a method of 'flu prevention although it has not yet been approved for this use.

Comparison of the symptoms of the 'flu with that of a common cold:

People infected by an influenza virus suffer a lot more than those with a cold. As you can see from the table below, some of the symptoms are similar, but with a cold they are less severe. Influenza also becomes more serious when it leads to secondary bacterial pneumonia or primary influenza viral pneumonia or when it exacerbates underlying medical conditions such as pulmonary or cardiac disease. In children, the symptoms are similar to those observed in adults, however children often have higher fevers and younger ones may develop gastrointestinal manifestations. It should be noted that Relenza is not effective on people with colds or other viral illnesses.

Influenza	Cold
Sore throat	Mild sore throat
High fever and chills	Low-grade fever
Non-productive cough	Cough
Severe muscle aches	Congestion
Headache
Intense fatigue.

The effect of Relenza on patients with respiratory diseases:

Relenza is not generally recommended for the treatment of patients with respiratory dieseases such as asthma or chronic obstructive pulmonary disease (COPD) and has carried an approval since its approval in July 1999. Some patients with underlying airway diseases have experienced serious adverse events following treatment, with some fatal outcomes although causality has been difficult to establish. It has been recommended that patients with asthma have a fast-acting bronchodilator inhaler available and use it about 15 minutes before taking Relenza.

Successfulness of Relenza:

The sialidase inhibitory activities (determined by methods described in reference 7) of Relenza compared to the more recent neuraminidase inhibitor Oseltamivir are shown in the table below⁹. IC50 is the concentration that reduces enzyme activity by 50%.

Compound	Influenza A IC50 (µM)	Influenza B IC50 (µM)
Relenza	0.005	0.004
Oseltamivir	0.002	0.032

The results demonstrate that both compounds are good inhibitors of influenza A and B, with Oseltamivir being more selective towards Influenza A and Relenza showing a better overall performance. In phase I and II tests reported by the Lancet⁵, no important adverse effects were found in healthy patients or those reported to have mild to moderate asthma following an inhaled administration of 40mg/day of Relenza. There was a significant improvement of the symptoms of people taking Relenza compared to those taking the placebo..