Compounds with anti-influenza activity: present and future of strategies for the optimal treatment and management of influenza. Part I: influenza life-cycle and currently available drugs

GASPARINI, R.; AMICIZIA, D.; LAI, PL.; BRAGAZZI, NL.; PANATTO, D.

Influenza is a contagious acute respiratory viral disease characterized by a short incubation period, high fever, respiratory (e.g. runny and stuffy nose) and systemic symptoms (e.g. muscle or body aches) [1] . Most of the people affected by influenza recover in a few days or, at most, in 2 weeks. However, some patients may develop complications that may be very serious. The most common complications are bronchitis, pneumonia, ear infections, etc. People with underlying diseases, such as asthma, subjects with Chronic Obstructive Pulmonary Disease (COPD) or individuals with heart disease are at high risk of complications [2] . Related complications, such as myositis, acute encephalopathy or Reye's syndrome, are rare [3] . Reye's syndrome is classically characterized by rashes, vomiting and liver damage. It can typically occur during viral illness in children who have been taking aspirin for a long period [4] . Pneumonia can be caused by bacterial superinfection also called secondary pneumonia or viral pneumonitis [5, 6] . This is characterized by the complex interactions of host-co-infecting pathogens [7] , and, in particularly frail and debilitated subjects, can result in the impairment of physical capabilities, dysregulation of immune responses and a delayed return to homeostasis [5, 6] . The burden of influenza is very heavy. Indeed, the World Health Organization (WHO) estimates that annual epidemics affect 5-15% of the world's population, causing up to 4-5 million severe cases and from 250,000 to 500,000 deaths [7] . The European Centre for Disease Prevention and Control (ECDC) estimates that approximately 10% of Europeans are infected each year [8] . Furthermore, the US government estimates that 5-20% of US residents catch influenza each year [9] . Influenza viruses belong to the Ortomyxoviridae family [10] , with the other two genera being Isavirus and Thogotovirus, and have the ability to change their surface antigens relatively frequently [11] . When a major variation occurs, if the virus adapts to humans during zoonotic spill-over, widespread diffusion of the virus is possible, resulting in a pandemic [12] . The most severe influenza pandemic was that of 1918, which caused 500 million cases and from 50 to 100 million deaths [13, 14] . During that devastating pandemic, the treatment of patients suffering from influenza was empirical and symptomatic, and was intended primarily to relieve fever and pain (e.g. aspirin administration), while epinephrine was used to treat forms of secondary pneumonia [15] . Only in the 1960s did the first antiviral drug against influenza, namely Amantadine, become available in the US [16, 17] , while in 1993 another drug, Rimantadine, was authorized [18] . Later, in 1999, the anti-neuraminidase (NA) medications Zanamivir and Oseltamivir were both licensed in the US [19] . Since 1999, much knowledge concerning viral replication has been acquired, and new experimental hypotheses have been advanced for the development of new flu drugs and new protocols for both prevention and treatment. Anti-influenza drugs are an important complement to vaccination, which is the most efficacious weapon against the disease. In this review, it therefore seemed useful to deal with the issue of new/potential antiviral medications against influenza infections, especially in the light of the most recent scientific advances.