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30-day intravenous administration of VRCTC-310-ONCO in rabbits
Nestor O Stanchi1, Daniel Arias, Pablo E Martino
1Cáttedra de Microbiologia, Facultad de Ciencias Veterinarias, UNLP, La Plata, Argentina.
Abstract:
VRCTC-310-ONCO, an agent based on the snake phospholipase A2 (crotoxin), is currently under clinical development. After phase I study in patients by intramuscular administration, the interest of intravenous (IV) dosing arose. To evaluate IV administration of VRCTC-310-ONCO in rabbits, ten animals were subjected to surgical implant of fixed jugular catheter, by which they received daily IV doses of 0.03 mg/kg body weight of VRCTC-310-ONCO for 30 days (n = 8) or saline (n = 2). The procedure was well tolerated in all rabbits. One of the animals died after the sixth dose of VRCTC-310-ONCO with CNS involvement; two additional rabbits required dose-reduction. All other rabbits achieved 30 days of treatment and were sacrificed. All rabbits (even controls) developed lymphocytosis and mild anaemia, without changes in blood neutrophils. No changes were found in serum transaminases (GOT and GPT), cholesterol, triglycerides, and y-glutamyl transpeptidase. At necropsy, chronic granulation tissue was found surrounding the implant in all rabbits. VRCTC-3 10-ONCO-treated rabbits presented generalised and marked swelling of hepatocytes, with areas of cytoplasmic vacuolisation. No abnormalities were found in kidney, heart, lung, spleen, adrenal gland, uterus, testes and ovary. Additional studies with IV route for VRCTC-310-ONCO, including humans, are required to define its toxicity in the clinical setting.
Insights
Intravenous administration of VRCTC-310-ONCO, a crotoxin-based agent, showed potential toxicity in rabbits, including CNS involvement and liver swelling. Further studies are needed to assess its safety in humans.
Area of Science:
- Pharmacology
- Toxicology
- Preclinical Research
Background:
- VRCTC-310-ONCO, a snake phospholipase A2 agent derived from crotoxin, is in clinical development.
- Previous intramuscular administration prompted investigation into intravenous (IV) dosing.
Purpose of the Study:
- To evaluate the safety and toxicity of intravenous VRCTC-310-ONCO in a rabbit model.
- To assess the effects of daily IV administration over 30 days.
Main Methods:
- Ten rabbits received surgically implanted jugular catheters.
- Eight rabbits received daily IV doses of 0.03 mg/kg VRCTC-310-ONCO for 30 days; two received saline as controls.
- Hematological and serum chemistry analyses were performed, followed by necropsy.
Main Results:
- One rabbit died with central nervous system (CNS) involvement; two required dose reduction.
- All rabbits exhibited lymphocytosis and mild anemia; VRCTC-310-ONCO treated rabbits showed hepatocyte swelling and vacuolization.
- No significant changes were observed in serum enzymes, lipids, or major organs besides the liver.
Conclusions:
- Intravenous VRCTC-310-ONCO demonstrated potential toxicity, including CNS and liver effects, in rabbits.
- Further clinical studies in humans are necessary to fully define the toxicity profile of IV VRCTC-310-ONCO.