Acute Toxicology and Pharmacokinetic Assessment of a Ribozyme (ANGIOZYME™) Targeting Vascular Endothelial Growth Factor Receptor mRNA in the Cynomolgus Monkey
| Autor: | Tom J. Parry, Karin S. Blanchard, Vann P. Parker, Florence A. Caputo, David Sweedler, Christopher D. Sproul, Douglas J. Kornbrust, James A. Powell, Laurent Bellon, Jennifer A. Sandberg, Lawrence M. Blatt |
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| Rok vydání: | 2000 |
| Předmět: |
Male
Angiozyme medicine.medical_specialty Injections Subcutaneous Angiogenesis Inhibitors Spleen Pharmacology Biology Drug Administration Schedule Toxicology chemistry.chemical_compound Bolus (medicine) Pharmacokinetics Internal medicine Genetics medicine Animals RNA Catalytic Receptors Growth Factor RNA Messenger Infusions Intravenous Receptor Chromatography High Pressure Liquid Hematology Receptor Protein-Tyrosine Kinases Complement System Proteins Blood Coagulation Factors Acute toxicity Vascular endothelial growth factor Macaca fascicularis Receptors Vascular Endothelial Growth Factor medicine.anatomical_structure Endocrinology chemistry Gene Targeting Injections Intravenous Female Blood Chemical Analysis |
| Zdroj: | Antisense and Nucleic Acid Drug Development. 10:153-162 |
| ISSN: | 1087-2906 |
| DOI: | 10.1089/oli.1.2000.10.153 |
| Popis: | The potential acute toxicity of a ribozyme (ANGIOZYME) targeting the flt-1 vascular endothelial growth factor (VEGF) receptor mRNA was evaluated in cynomolgus monkeys following i.v. infusion or s.c. injection. ANGIOZYME was administered as a 4-hour i.v. infusion at doses of 10, 30, or 100 mg/kg or a s.c. bolus at 100 mg/kg. End points included blood pressure, electrocardiogram (ECG), clinical chemistry, hematology, complement factors, coagulation parameters, and ribozyme plasma concentrations. ANGIOZYME was well tolerated, with no drug-associated morbidity or mortality. There was no clear evidence of ANGIOZYME-related adverse effects in this study. Slight increases in spleen weight and lymphoid hyperplasia were observed in several animals. However, these changes were not dose dependent. Steady-state concentrations of ANGIOZYME were achieved during the 4-hour infusion of 10, 30, or 100 mg/kg. Dose-dependent elimination of ANGIOZYME was observed, with faster clearance at the two highest doses. ANGIOZYME was slowly absorbed after s.c. administration, resulting in steady-state concentrations for the 9-hour sampling period. Monkeys in this toxicology study received significant plasma ANGIOZYME exposure by both the s.c. and i.v. routes. |
| Databáze: | OpenAIRE |
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