Symptoms of an influenza viral infection were described by Hippocrates 2400 years ago. In recent recorded history there have been pandemics such as the 1918-1920 Spanish Flu and the more recent 2009 Swine Flu. In modern medical times, there were only two medications indicated to treat an influenza infection: amantadine, and rimantadine. This changed in 1999 with the introduction of Tamiflu (oseltamivir): an antiviral drug used to treat influenza A and B. It is usually used within the first 48 hours of influenza symptoms in the general population. For people who are at high risk it is sometimes used as a preventative treatment if a high-risk person has been exposed to influenza A or B and has not been vaccinated. Recommendations like these are initiated to lessen the development of resistance to the medication.
The story of the prodrug Tamiflu began when virologists (scientists who study viruses) identified a viral enzyme called neuraminidase, which is produced by many strains of viruses. An enzyme is a chemical that organisms make to speed up chemical reactions. In this case, the enzyme helped the virus to be released from human cells that it had infected, therefore, if this enzyme could be blocked it would lessen the impact of viral infections by inhibiting replication. The virus uses neuraminidase to break open cell walls thus releasing viral particles that have replicated inside the host cell.
The first neuraminidase inhibitor to reach the market was Relenza (zanamivir). Ironically, this drug was not recommended for approval by the FDA advisory committee. However, the FDA leadership overruled the committee’s disapproval and approved it anyway, based on the results of a single clinical trial that showed positive results. Other clinical trials had shown no significant effectiveness over a placebo. However, Relenza did validate that neuraminidase was a viable target for antiviral medications. The problem with Relenza was its method of administration. It was inhaled as a powder, which proved to be inconvenient and cumbersome and had very poor oral absorption properties.
The scientists at the Gilead Sciences Inc., a pharmaceutical company, became interested in neuraminidase inhibitors and soon developed GS-4701, a neuraminidase inhibitor that has a 3700-fold increase in neuraminidase inhibition. This molecule had a different enough structure to be eligible for a separate patent. However, GS-4701 did not show much greater oral absorption than Relenza. What finally occurred at Gilead was the creation of Tamiflu (oseltamivir), which is a prodrug. A prodrug is a drug that is metabolized in the body to release the active compound. A prodrug is better absorbed in the body. When Tamiflu is ingested orally it is metabolized to the GS-4701 molecule that has the neuraminidase inhibition activity.
This is a particularly good example of using prodrugs to bring to market important pharmaceuticals that can be administered more conveniently, thus creating more compliance and effectiveness. Other examples of familiar prodrugs are aspirin and codeine. The first synthetic antimicrobial drug, arsphenamine, used to treat syphilis, was a prodrug, as was the first “sulfa” antibiotic Prontosil. It is estimated that 10% of the drugs currently marketed worldwide are prodrugs.
In the near future Tamiflu may be one of the drugs that can be dispensed by a pharmacist who has obtained Test and Treat Certification in the State of Florida. In the past year, the Florida Legislature passed legislation that will allow patients to be treated for influenza and streptococcus infections at a community pharmacy without having to go to a physician’s office, in order to make treatment for influenza and streptococcus infections more available to the public where timeliness is important.
Currently Tamiflu is not indicated for the treatment of the Sars-Cov-2 (Covid-19) virus.
Stay informed and stay healthy.
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