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Efficacy of CMX001 as a prophylactic and presymptomatic antiviral agent in New Zealand white rabbits infected with rabbitpox virus, a model for orthopoxvirus infections of humans.

Rice AD, Adams MM, Lampert B, Foster S, Robertson A, Painter G, Moyer RW - Viruses (2011)

Bottom Line: CMX001 has dramatically increased potency versus CDV against all dsDNA viruses and, in contrast to CDV, is orally available and has shown no evidence of nephrotoxicity in healthy volunteers or severely ill transplant patients to date.In the absence of human cases of smallpox, new treatments must be tested for efficacy in animal models.Our results should also be applicable to monkeypox virus infections and for treatment of adverse reactions to smallpox vaccination.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610, USA. amandar@ufl.edu

ABSTRACT
CMX001, a lipophilic nucleotide analog formed by covalently linking 3-(hexdecyloxy)propan-1-ol to cidofovir (CDV), is being developed as a treatment for smallpox. CMX001 has dramatically increased potency versus CDV against all dsDNA viruses and, in contrast to CDV, is orally available and has shown no evidence of nephrotoxicity in healthy volunteers or severely ill transplant patients to date. Although smallpox has been eliminated from the environment, treatments are urgently being sought due to the risk of smallpox being used as a bioterrorism agent and for monkeypox virus, a zoonotic disease of Africa, and adverse reactions to smallpox virus vaccinations. In the absence of human cases of smallpox, new treatments must be tested for efficacy in animal models. Here we first review and discuss the rabbitpox virus (RPV) infection of New Zealand White rabbits as a model for smallpox to test the efficacy of CMX001 as a prophylactic and early disease antiviral. Our results should also be applicable to monkeypox virus infections and for treatment of adverse reactions to smallpox vaccination.

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Related in: MedlinePlus

Disease severity measurements for evaluation of survival when dosage with CMX001 is delayed up to six days post infection. Animals were dosed at concentrations and schedules as outlined in Table 3. (A) Average of maximum clinical scores for each animal per group over the course of the experiment. (B) Average of maximum percent weight loss from weight at day 0 for each animal per group over the course of the experiment.
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f9-viruses-03-00063: Disease severity measurements for evaluation of survival when dosage with CMX001 is delayed up to six days post infection. Animals were dosed at concentrations and schedules as outlined in Table 3. (A) Average of maximum clinical scores for each animal per group over the course of the experiment. (B) Average of maximum percent weight loss from weight at day 0 for each animal per group over the course of the experiment.

Mentions: Maximum clinical score and weight loss were again used as indications of maximal illness over for all groups tested. It was observed that in groups in which all animals survived (0 to 3 dpi) with few clinical symptoms the maximum average clinical scores were significantly lower than that of the vehicle treated animals (Figure 9A). Animals that began treatment 1 day prior to infection had a lower maximum clinical score than that of vehicle treated animals, it was, however, not significant. There was an advantage noted to having treatment for five days in the presence of virus infection when comparing the group in which treatment was initiated on −1 dpi as compared to those that began treatment 0 to 2 dpi. As treatment was initiated later in infection, as expected the disease severity increased, showing a time of treatment dependence in the maximum disease severity observed. In groups in which not all the animals survived (5 and 6 dpi treatment groups), there was little difference in the maximum clinical score as compared to vehicle treated animals.


Efficacy of CMX001 as a prophylactic and presymptomatic antiviral agent in New Zealand white rabbits infected with rabbitpox virus, a model for orthopoxvirus infections of humans.

Rice AD, Adams MM, Lampert B, Foster S, Robertson A, Painter G, Moyer RW - Viruses (2011)

Disease severity measurements for evaluation of survival when dosage with CMX001 is delayed up to six days post infection. Animals were dosed at concentrations and schedules as outlined in Table 3. (A) Average of maximum clinical scores for each animal per group over the course of the experiment. (B) Average of maximum percent weight loss from weight at day 0 for each animal per group over the course of the experiment.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3045966&req=5

f9-viruses-03-00063: Disease severity measurements for evaluation of survival when dosage with CMX001 is delayed up to six days post infection. Animals were dosed at concentrations and schedules as outlined in Table 3. (A) Average of maximum clinical scores for each animal per group over the course of the experiment. (B) Average of maximum percent weight loss from weight at day 0 for each animal per group over the course of the experiment.
Mentions: Maximum clinical score and weight loss were again used as indications of maximal illness over for all groups tested. It was observed that in groups in which all animals survived (0 to 3 dpi) with few clinical symptoms the maximum average clinical scores were significantly lower than that of the vehicle treated animals (Figure 9A). Animals that began treatment 1 day prior to infection had a lower maximum clinical score than that of vehicle treated animals, it was, however, not significant. There was an advantage noted to having treatment for five days in the presence of virus infection when comparing the group in which treatment was initiated on −1 dpi as compared to those that began treatment 0 to 2 dpi. As treatment was initiated later in infection, as expected the disease severity increased, showing a time of treatment dependence in the maximum disease severity observed. In groups in which not all the animals survived (5 and 6 dpi treatment groups), there was little difference in the maximum clinical score as compared to vehicle treated animals.

Bottom Line: CMX001 has dramatically increased potency versus CDV against all dsDNA viruses and, in contrast to CDV, is orally available and has shown no evidence of nephrotoxicity in healthy volunteers or severely ill transplant patients to date.In the absence of human cases of smallpox, new treatments must be tested for efficacy in animal models.Our results should also be applicable to monkeypox virus infections and for treatment of adverse reactions to smallpox vaccination.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610, USA. amandar@ufl.edu

ABSTRACT
CMX001, a lipophilic nucleotide analog formed by covalently linking 3-(hexdecyloxy)propan-1-ol to cidofovir (CDV), is being developed as a treatment for smallpox. CMX001 has dramatically increased potency versus CDV against all dsDNA viruses and, in contrast to CDV, is orally available and has shown no evidence of nephrotoxicity in healthy volunteers or severely ill transplant patients to date. Although smallpox has been eliminated from the environment, treatments are urgently being sought due to the risk of smallpox being used as a bioterrorism agent and for monkeypox virus, a zoonotic disease of Africa, and adverse reactions to smallpox virus vaccinations. In the absence of human cases of smallpox, new treatments must be tested for efficacy in animal models. Here we first review and discuss the rabbitpox virus (RPV) infection of New Zealand White rabbits as a model for smallpox to test the efficacy of CMX001 as a prophylactic and early disease antiviral. Our results should also be applicable to monkeypox virus infections and for treatment of adverse reactions to smallpox vaccination.

Show MeSH
Related in: MedlinePlus