Abstract |
SY 161-P5, a polyethylene glycol derivatized (PEGylated) mutant of the recombinant Staphylokinase (rSak) variant SakSTAR, exhibiting reduced antigenicity is in clinical development for treatment of acute myocardial infarction as a single bolus injection. A series of safety studies were performed in vivo as a routine toxicology program with SY 161-P5 (PEG-rSakSTAR) and with the recombinant Staphylokinase variant Sak42D (rSak42D). For both compounds, intravenous single bolus injections of up to 100-fold therapeutic equivalent, as well as repeated injections during 7 to 28 days revealed no significant pathological findings in mice, rats or hamsters. However, New Zealand white rabbits developed clinically silent, multifocal myocarditis following single or repeat doses of SY 161-P5 or of Sak42D. These findings were dose-independent and reversible. A similar species-specific cardiotoxic effect has previously been described for other proteolytic proteins, including the approved drugs Streptokinase and Acetylated Plasminogen Streptokinase Complex ( APSAC). The large experience with these drugs, as well as the clinical data accumulated both with PEGylated and non-PEGylated rSak variants to date, do not indicate cardiotoxic hazards associated with the use of these drugs in humans.
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Authors | L Moons, I Vanlinthout, I Roelants, R Moreadith, D Collen, H J Rapold |
Journal | Toxicologic pathology
(Toxicol Pathol)
2001 May-Jun
Vol. 29
Issue 3
Pg. 285-91
ISSN: 0192-6233 [Print] United States |
PMID | 11442014
(Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Fibrinolytic Agents
- Recombinant Proteins
- Polyethylene Glycols
- Metalloendopeptidases
- SY 161-P5
- auR protein, Staphylococcus aureus
- Cysteine
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Topics |
- Animals
- Cysteine
(chemistry)
- Dose-Response Relationship, Drug
- Female
- Fibrinolytic Agents
(toxicity)
- Heart
(drug effects)
- Injections, Intravenous
- Male
- Metalloendopeptidases
(toxicity)
- Mice
- Myocardial Infarction
(chemically induced, pathology)
- Myocarditis
(chemically induced, pathology)
- Polyethylene Glycols
(chemistry)
- Rabbits
- Rats
- Recombinant Proteins
(toxicity)
- Species Specificity
- Toxicity Tests
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