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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

Timeline of disease in 8–10 week old New Zealand White rabbits infected intradermally with 1000 pfu rabbitpox virus (RPV). Symptoms in boxes above the timeline represent clinical measurements that contribute to euthanasia guidelines. Clinical symptoms are located below the timeline. Reproduced with permission from American Society for Microbiology [19].
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f1-viruses-03-00063: Timeline of disease in 8–10 week old New Zealand White rabbits infected intradermally with 1000 pfu rabbitpox virus (RPV). Symptoms in boxes above the timeline represent clinical measurements that contribute to euthanasia guidelines. Clinical symptoms are located below the timeline. Reproduced with permission from American Society for Microbiology [19].

Mentions: The standardization of the rabbit/RPV model has been previously published [19] by our laboratory and the timing of both clinical symptoms and euthanasia criteria appearance are shown in Figure 1. The model is reviewed and summarized here to highlight the features important to evaluating antiviral compounds. Only the features of smallpox and rabbitpox virus infections are compared but monkeypox virus infections share similar properties. This model, which uses New Zealand White (NZW) rabbits infected with 100–1000 pfu of RPV (administered bilaterally) by intradermal injection, if untreated, is almost uniformly lethal (Figure 2A). There are few differences between 100 and 1000 pfu observed in RPV infected nine week old NZW rabbits most likely due to the fact the doses are 10× and 100×, respectively, the LD50 dose. The appearance of swelling at the primary site of infection occurs 12–24 hours earlier in animals infected with 1000 pfu as compared to 100 pfu, but the overall symptomology follows the same time line. The disease begins with a local reaction at the site of virus introduction visualized as a raised red swelling within 1–2 days post infection (dpi). The lesion continues to grow in both diameter and thickness over the next 6–8 days. Necrosis at the primary site of infection develops by 3 to 4 dpi. The lesion reaches maximal diameter of 8–10 cm, with a thickness of 1–2 cm and encompasses the entire flank of the rabbit at the time of euthanasia. The progression of the primary lesion over time is shown in Figure 3.


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)

Timeline of disease in 8–10 week old New Zealand White rabbits infected intradermally with 1000 pfu rabbitpox virus (RPV). Symptoms in boxes above the timeline represent clinical measurements that contribute to euthanasia guidelines. Clinical symptoms are located below the timeline. Reproduced with permission from American Society for Microbiology [19].
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1-viruses-03-00063: Timeline of disease in 8–10 week old New Zealand White rabbits infected intradermally with 1000 pfu rabbitpox virus (RPV). Symptoms in boxes above the timeline represent clinical measurements that contribute to euthanasia guidelines. Clinical symptoms are located below the timeline. Reproduced with permission from American Society for Microbiology [19].
Mentions: The standardization of the rabbit/RPV model has been previously published [19] by our laboratory and the timing of both clinical symptoms and euthanasia criteria appearance are shown in Figure 1. The model is reviewed and summarized here to highlight the features important to evaluating antiviral compounds. Only the features of smallpox and rabbitpox virus infections are compared but monkeypox virus infections share similar properties. This model, which uses New Zealand White (NZW) rabbits infected with 100–1000 pfu of RPV (administered bilaterally) by intradermal injection, if untreated, is almost uniformly lethal (Figure 2A). There are few differences between 100 and 1000 pfu observed in RPV infected nine week old NZW rabbits most likely due to the fact the doses are 10× and 100×, respectively, the LD50 dose. The appearance of swelling at the primary site of infection occurs 12–24 hours earlier in animals infected with 1000 pfu as compared to 100 pfu, but the overall symptomology follows the same time line. The disease begins with a local reaction at the site of virus introduction visualized as a raised red swelling within 1–2 days post infection (dpi). The lesion continues to grow in both diameter and thickness over the next 6–8 days. Necrosis at the primary site of infection develops by 3 to 4 dpi. The lesion reaches maximal diameter of 8–10 cm, with a thickness of 1–2 cm and encompasses the entire flank of the rabbit at the time of euthanasia. The progression of the primary lesion over time is shown in Figure 3.

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