When it became clear that vaccinations could not provide the necessary protection and that treatment of the flu with vaccinations is not possible, scientists started looking for new antiviral chemotherapeutics. Oseltamivir and zanamivir are modern variants of these.
One of the first substances was the chemotherapeutical xenalamine, which was used as an antiviral drug in other viral illnesses (Magni, 1961). During the first period, antiviral drugs quickly entered the market with very promising names, such as Virusstat (N1-N1-anhydrobis-(beta-hydroxy-ethyl) biguanide hydrochloride) and Viractin. Upon closer examination, these drugs were completely ineffective and therefore disappeared just as quickly. In 1964, the antiviral efficacy of 1-Adamantanamine hydrochloride (Amantadine) was described for the first time by scientists such as Schild et al . For years, amantadine remained the only somewhat effective antiviral anti-influenza drug but unfortunately, resistance against this drug develops rapidly. Other chemotherapeutics from that time are chlorite-oxidized oxyamylose (COAM, oxoline), gossypol, bonaphthone and midantan (Russian drugs), U.K. 2371, 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (virazole, ICN 1229) or Ribavirin, Isoprinosine, rimantadine, 2,3-dihydroxy-6-bromo-pyrazino-[2,3-beta]-pyrazine, 9-methylstreptimidone (an interferon inducer), interferons, 3-substituted 1-adamantylthioureas; none have provided lasting results. The aforementioned substances originate from that time until 1980.
Exactly around that time, the anti-influenza efficacy of palmitoylethanolamide was discovered. But because PEA is a natural substance and not a pharmaceutically synthesised virus inhibitor, the anti-influenza efficacy of PEA did not generate broad interest. However, in the period up to 1980, seven major studies were carried out about the effect of PEA with impressive results, which have been recently summarised (Keppel Hesselink et al, 2013).
For a long time, the only other significant antiviral substance that remained was amantadine, but the biggest problem with this substance was (and still is) the quick development of resistance by the influenza virus to this substance, in animals as well as in humans (Wan et al, 2013). This is precisely the problem of the most modern anti-influenza drugs oseltamivir and zanamivir (Govorkova et al, 2013; Zhang et al, 2013).