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In vitro Cytotoxicity and Pharmacokinetic Evaluation of Pharmacological Ascorbate in Dogs
Background: High-dose, pharmacological ascorbate (P-AscH − ) is preferentially cytotoxic to human cancer cells in vitro . Investigations on the efficacy of P-AscH − as an adjuvant treatment for multiple human cancers are on-going, but has yet to be formally investigated in dogs. The primary objectiv...
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Published in: | Frontiers in veterinary science 2019-11, Vol.6, p.385-385 |
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Main Authors: | , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | Background:
High-dose, pharmacological ascorbate (P-AscH
−
) is preferentially cytotoxic to human cancer cells
in vitro
. Investigations on the efficacy of P-AscH
−
as an adjuvant treatment for multiple human cancers are on-going, but has yet to be formally investigated in dogs. The primary objectives of this study were to determine the pharmacokinetic (PK) profile of P-AscH
−
in healthy Beagle dogs and the effects of P-AscH
−
on canine osteosarcoma cells
in vitro
.
Methods:
Eight purpose-bred, healthy, spayed female Beagle dogs, between 20 and 21 months old, and 8–10 kg were administered two doses of P-AscH
−
(550 or 2,200 mg/kg)
via
intravenous infusion over 6 h, on separate days. Plasma ascorbate concentrations were measured at 12 time points during and after infusion for PK analysis using nonlinear mixed-effects (NLME) and non-compartmental analysis (NCA). Clonogenic assays were performed on 2 canine osteosarcoma cell lines (D-17 and OSCA-8) and canine primary dermal fibroblasts after exposure to high concentrations of ascorbate (75 pmoles/cell).
Results:
Plasma ascorbate levels in the dogs peaked at approximately 10 mM following 2,200 mg/kg and returned to baseline 6–8 h after dosing. Minor adverse effects were seen in two dogs. Ascorbate (75 pmoles/cell) significantly decreased survival in both the osteosarcoma cell lines (D-17 63% SD 0.010,
P
= 0.005; OSCA-8 50% SD 0.086,
P
= 0.026), compared to normal fibroblasts (27% SD 0.056).
Conclusions:
Pharmacological ascorbate is preferentially cytotoxic to canine-derived cancer cells. High levels of ascorbate can be safely administered to dogs. Further studies are needed to determine the effects of P-AscH
−
on canine patients. |
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ISSN: | 2297-1769 2297-1769 |
DOI: | 10.3389/fvets.2019.00385 |