Mar. 20, 2002 March 20, 2002 – An oral drug that halts the deadly action of smallpox and related orthopox viruses in lab tissue culture cells and in cowpox-infected mice has been developed by researchers at the Veterans Affairs San Diego Healthcare System (VASDHS) and the University of California, San Diego (UCSD) School of Medicine, and is being evaluated by the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID).
Called hexadecyloxypropyl-cidofovir (HDP-CDV), the antiviral drug blocks the activity of variola, the virus that causes smallpox and orthopox viruses, halting their ability to replicate and spread.
Developed as part of a national research effort to design antiviral drugs for people infected by smallpox, HDP-CDV is not yet available for human use. The drug must still undergo additional testing in animals and safety trials in healthy people.
Announced today at the 15th International Conference on Antiviral Research in Prague, Czech Republic, HDP-CDV is a potent derivative of an existing compound, cidofovir, which inhibits smallpox virus replication. However, cidofovir must be administered intravenously, thus limiting its fast application in the event of a bioterrorism attack or widespread epidemic.
Found to be 100 times more potent then cidofovir, which is not readily taken up by cells, HDP-CDV is a modified cidofovir that exploits the cell’s own machinery to get in more effectively. HDP-CDV was developed by Karl Y. Hostetler, M.D., director, Endocrine and Metabolism Clinic, Veterans Affairs San Diego Healthcare System and UCSD professor of medicine, and James Beadle, Ph.D., VASDHS and UCSD research professor, who presented their results at the international conference.
The VASDHS/UCSD work was done in collaboration with research groups headed by John Huggins, Ph.D., USAMRIID, Fort Detrick, Maryland and Earl Kern, Ph.D., University of Alabama, Birmingham.
The effort was initiated in 1999 when the National Institute of Allergy and Infectious Diseases (NIAID) asked the VASDHS/UCSD team to develop an oral version of cidofovir.
NIAID, USAMRIID and the Centers for Disease Control and Prevention (CDC) in Atlanta, oversee most of the country’s effort to develop antiviral therapies for smallpox. After screening hundreds of existing compounds for activity against smallpox while working in the CDC’s Biosafety Level 4 (maximum containment) Laboratory in Atlanta, USAMRIID identified cidofovir as active against smallpox. The drug is currently used to treat retinal infections caused by cytomegalovirus.
"Cidofovir’s drawback is poor oral bioavailability. It can only be given intravenously," Hostetler said. "If you’ve got thousands of people exposed to smallpox, a drug that needs to be injected would be difficult to use widely."
If continuing studies support HDP-CDV’s effectiveness and safety, the drug could be given in pill or capsule form over 5 to 14 days for the prevention and treatment of smallpox in persons exposed to the disease, Hostetler said.
The Huggins group from USAMRIID announced at the 15th International Conference on Antiviral Research that HDP-CDV was effective in blocking the replication of several strains of smallpox in tissue culture. Surprisingly, the HDP-CDV compound was 100 times more active than cidofovir in slowing smallpox reproduction.
Also presented at the conference were Huggins’ results of HDP-CDV therapy in mice infected with cowpox, a poxvirus closely related to smallpox. Working in collaboration with Hostetler’s group, Huggins and coworkers at USAMRIID found that 5 daily oral doses of HDP-CDV given after infection prevented death from cowpox infection.
The Huggins group also found that virus levels in the lungs of infected animals was reduced to nearly undetectable levels by oral administration of HDP-CDV, but not by intravenous administration of comparable amounts of cidofovir.
In additional research presented at the conference, HDP-CDV was found by Kern to be active in lab tissue cultures against infections caused by cytomegalovirus, herpes virus, varicella zoster virus, and Epstein Barr virus, raising the possibility that the compound might be useful for a variety of more common viral infections. Smallpox continues to be a top concern, however.
"Until now, the eradication and control of smallpox relied upon vaccination," Hostetler said. "The results from the VASDHS/UCSD, USAMRIID, CDC and the University of Alabama suggest that antiviral drugs given orally in a regimen consisting of as few as 5 doses might be used as an alternative to treat and contain a future outbreak of smallpox, especially in those individuals who cannot safely be vaccinated."
Over the years, smallpox has killed millions of people. Caused by variola virus, the disease is spread from one person to another by direct contact or by infected saliva droplets carried through the air when someone coughs. Although the majority of smallpox patients recover, death occurs in up to 30 percent of cases, according to the World Health Organization.
Routine vaccination against smallpox ended in 1972 and many considered smallpox infection eliminated from the world in 1977. However, the level of immunity, if any, among persons who were vaccinated before 1972 is uncertain, the CDC says. Therefore, these persons are assumed to be susceptible.
Although the United States has an emergency supply of smallpox vaccine, the CDC says vaccination against smallpox is associated with some risk for adverse reactions, such as brain inflammation, and vaccination is not currently recommended until after a smallpox outbreak has been identified, when a mass vaccination campaign utilizing the national stockpile would occur.
Hostetler’s research was supported by grants from the Department of Defense, the NIAID, the National Eye Institute, and the Veterans Affairs San Diego Healthcare System.
UCSD is handling the licensing for a joint VASDHS/UCSD invention covering a family of compounds that includes HDP-CDV.
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