EMBARGOED by American Society for Microbiology for 4:30 pm EST Tuesday, March 11, 2003
Single Dose of Oral Smallpox Drug Shown Effective in Cowpox-Infected Mice
When Given 3-5 Days Before or 1-3 Days After Infection
Two versions of an oral drug that halts the deadly action of smallpox and related orthopox viruses have been shown by researchers in Alabama and California to be effective in cowpox-infected mice, whether given three to five days before or two to three days after infection.
Presented Tuesday, March 11, 2003 at a Baltimore, Maryland Biodefense Symposium of the American Society for Microbiology (ASM), the study evaluated the dosage regimen and effectiveness of four different ether lipid analogs of cidofovir (CDV), a compound that blocks the activity of variola, the virus that causes smallpox, cowpox, vaccinia and other orthopox viruses. Shown most effective in treating lethal cowpox infection in mice were hexadecyloxypropyl-CDV (HDP-CDV) and octadecyloxyethyl-CDV (ODE-CDV). In addition, the study pinpointed the time period for effectiveness when the drug is administered prior to or after infection.
The four ether lipid analogs of CDV (which are compounds similar to, but differing slightly from CDV) were developed by researchers at the Veterans Affairs San Diego Healthcare System (VASDHS) and the University of California, San Diego (UCSD) School of Medicine. The new compounds were tested in tissue culture cells and in mice by Earl R. Kern, Ph.D., University of Alabama at Birmingham, who presented the results at the ASM meeting.
Drs. Karl Hostetler, left, and James Beadle manipulate a rotary evaporator that is removing solvents from a reaction mixture.
"This is the first demonstration that a single oral dose of an ether lipid analog of cidofovir can protect against lethal poxvirus infection several days in advance of infection or when given one to three days after," said the drug's developer Karl Hostetler, M.D., of VASDHS and UCSD. "This suggests that individuals who cannot be safely vaccinated could be protected from smallpox by taking an oral analog of CDV several times a month. Details of an appropriate treatment regimen remain to be worked out in human clinical testing."
Developed as part of a national research effort to design antiviral drugs for people infected by smallpox, the analogs of cidofovir are not yet available for human use. Additional testing in animals and safety trials in healthy people must still be done. Preclinical development activities have been started by Chimerix Inc. of San Diego, the licensee of the new compounds.
The study presented to the ASM meeting described groups of mice given a single oral dose of the CDV analogs. Groups of 15 mice each received HDP-CDV or ODE-CDV beginning five, three or one day prior to inoculation with cowpox virus. Additional groups of mice received the CDV analogs one or three days after being infected with the virus. A final group of infected mice was not given CDV, and all 15 mice in that group died.
With treatment 24 hours after infection, both HDP- and ODE-CDV were effective at preventing death and maintained efficacy when started as late as 72 hours following infection. Pre-treatment with HDP-CDV and ODE-CDV was also effective when given five, three or one day prior to infection.
The effectiveness of oral HDP-CDV to treat orthopox infections was first announced a year ago in a presentation to the 15th International Conference on Antiviral Research in Prague, Czech Republic (see * link at bottom). At that time, the researchers noted that an analog of CDV was 100 times more potent than CDV, itself, which had been shown to stop experimental poxvirus infection, but was absorbed poorly when given orally. The new analogs are ether lipid derivatives of CDV that exploit the cell's own machinery to get into cells more effectively.
Testing of the synthetic versions of CDV in cultured cells and in mice infected with poxviruses was done by the research groups headed by Kern at the University of Alabama at Birmingham using the CDV analogs developed by Hostetler, James Beadle, Ph.D., and Brad Wan, Ph.D.
Equipment in the Hostetler lab
Over the years, smallpox has killed millions of people. Caused by the 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 30 to 40 percent of cases, according to the World Health Organization. Routine vaccination against smallpox ended in 1972 and smallpox infection was considered to be 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.
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