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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

Clinical observations for evaluation of minimum dose of CMX001 required for protection from RPV when treatment is begun 1 day post infection. Animals were dosed at concentrations and schedules as outlined in Table 2. (A) Average weight change for each group. (B) Average body temperatures for each group. (C) Average clinical scores for each group. Error bars represent SEM. (D) Representative photos of primary lesions for treatment groups at 5 dpi.
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f6-viruses-03-00063: Clinical observations for evaluation of minimum dose of CMX001 required for protection from RPV when treatment is begun 1 day post infection. Animals were dosed at concentrations and schedules as outlined in Table 2. (A) Average weight change for each group. (B) Average body temperatures for each group. (C) Average clinical scores for each group. Error bars represent SEM. (D) Representative photos of primary lesions for treatment groups at 5 dpi.

Mentions: Although all rabbits dosed with CMX001 survived, a dose dependent response in disease severity was observed between the treatment groups. The degree of weight loss and recovery from RPV disease measured by the return of weight gain was CMX001 dose dependent. Animals that received 2 mg/kg exhibited mild weight loss from 4 to 10 dpi while the weight loss exhibited by 5 mg/kg treated animals was similar in rate to the 2 mg/kg treatment group but returned to a positive weight gain by 8 dpi. Rabbits that received 10 or 20 mg/kg CMX001 showed few symptoms including no substantial weight loss with a general positive trend in weight change (Figure 6A). The maximum weight loss for each group was also evaluated (Figure 7B) and again demonstrated an inverse relationship between the dose of CMX001 and weight loss in which the higher doses of CMX001 demonstrated virtually no weight loss from baseline weight.


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)

Clinical observations for evaluation of minimum dose of CMX001 required for protection from RPV when treatment is begun 1 day post infection. Animals were dosed at concentrations and schedules as outlined in Table 2. (A) Average weight change for each group. (B) Average body temperatures for each group. (C) Average clinical scores for each group. Error bars represent SEM. (D) Representative photos of primary lesions for treatment groups at 5 dpi.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f6-viruses-03-00063: Clinical observations for evaluation of minimum dose of CMX001 required for protection from RPV when treatment is begun 1 day post infection. Animals were dosed at concentrations and schedules as outlined in Table 2. (A) Average weight change for each group. (B) Average body temperatures for each group. (C) Average clinical scores for each group. Error bars represent SEM. (D) Representative photos of primary lesions for treatment groups at 5 dpi.
Mentions: Although all rabbits dosed with CMX001 survived, a dose dependent response in disease severity was observed between the treatment groups. The degree of weight loss and recovery from RPV disease measured by the return of weight gain was CMX001 dose dependent. Animals that received 2 mg/kg exhibited mild weight loss from 4 to 10 dpi while the weight loss exhibited by 5 mg/kg treated animals was similar in rate to the 2 mg/kg treatment group but returned to a positive weight gain by 8 dpi. Rabbits that received 10 or 20 mg/kg CMX001 showed few symptoms including no substantial weight loss with a general positive trend in weight change (Figure 6A). The maximum weight loss for each group was also evaluated (Figure 7B) and again demonstrated an inverse relationship between the dose of CMX001 and weight loss in which the higher doses of CMX001 demonstrated virtually no weight loss from baseline weight.

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