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.

The drug, after being poorly metabolized and being widely distributed, is almost completely excreted via glomerular filtration and tubular secretion: this implies a dose adjustment when administered to patients with renal failure or to the elderly, such as reducing the daily dose of 100 mg, instead of 200 mg. Acting on muscarinic receptors, some patients may experience anti-muscarinic adverse effects such as orthostatic hypotension, gastrointestinal discomfort (nausea, vomiting, anorexia), congestive heart failure [216] . Moreover, because Amantadine has some Central Nervous System (CNS) stimulatory properties, adults may complain of confusion, disorientation, jitteriness, anxiety, mood disorders, slurred speech, insomnia, ataxia, tremors, and, rarely, nightmares, oculogyric episodes. These symptoms are usually more common (up to 15-30%) when the drug is used for different weeks for prophylactic purpose. When instead used for treatment (less than a week), it is better tolerated. In rare cases, seizures, hallucinosis/hallucinations, coma, acute psychosis and cardiac arrhythmia may occur, usually in patients with underlying psychiatric comorbidities [216, 217] . Adult Respiratory Distress Syndrome (ARDS) has been rarely and anecdotally reported [218] . Crossing the placenta and being present in breast milk, it is teratogenic at least in animals, even though safety has not been established in pregnant women: for precaution sake, it belongs to class C. Pregnancy is recognized as one of the risk factors for catching influenza and untoward outcomes (higher morbidity, hospitalization and mortality rates), but cannot benefit from adamantanes. Also in children and in the elders, the effectiveness in preventing, treating and shortening the duration of influenza A appears to be limited, according to a recent systematic review [219] . Rimantadine can be administered as 100 mg tablets. It reaches peak plasma concentration after 3-6 hours. The plasma half-life is long (24-36 hours) . Rimantadine is more metabolized than Amantadine: only 25% is secreted unchanged [216] . It has a plasma protein binding of about 40%. Rimantadine is characterized by lower rates of ADRs [220] : compared to Amantadine, it is better tolerated by children and the elderly. Unfortunately, the use of M2 inhibitors has been limited by the emergence of drug-resistant strains of influenza viruses [221] , such as the mutations of pore-facing residues (V27A, A30T, S31N, G43E) , mutations of close interhelical residues located at the N-terminal half of the channel (L26F), and mutations of far interhelical residues far located at the C-terminal half of the channel (L38F) [221] [222] .