Cardiac inotropy and cardiac calcium sensitization of PanLN800(-Forte), a cationic heptamethine indocyanine fluorescent contrast agent for intraoperative pan lymph node imaging.
Robin A Faber, Victor M Baart, Mark W Bordo, Taryn L March, Adrianus R P M Valentijn, Stefan Harmsen, Martin Pool, Jacobus Burggraaf, John V Frangioni, Alexander L Vahrmeijer
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引用次数: 0
Abstract
Introduction: Accurate staging of malignancies often requires comprehensive evaluation of lymph nodes. However, finding these lymph nodes during oncological surgery is a daunting and time-consuming task, which increases the risk of missed lymph nodes and complications. Near-infrared (NIR) fluorescence imaging with the experimental fluorescent contrast agent PanLN800(-Forte) could provide real-time identification of lymph nodes and may solve this longstanding problem. In the current study we performed the preclinical toxicology evaluation of PanLN800(-Forte) towards its clinical translation for intraoperative pan lymph node imaging in thoracic surgery.
Methods: A single extended dose toxicology study was conducted to determine the safety and potential toxicity of PanLN800(-Forte) after administration of a single intravenous dose to Wistar Han rats. The study included a control group and two treatment groups (5.0 mg/kg and 15.0 mg/kg PanLN800(-Forte)), each consisting of 10 male and 10 female rats. Experimental endpoints included moribundity/mortality, clinical signs, body weights, body weight gains, clinical pathology, toxicity, and gross necropsy observations.
Results: Unexpected acute mortality was observed after administration of 5.0 mg/kg PanLN800(-Forte) to rats. No clear cause of sudden death was found after gross necropsy and pathology observations. To understand the mechanism of toxicity of PanLN800(-Forte), several additional tests were performed. By elimination, acute cardiac toxicity appears to be the cause of acute mortality in rats, in which PanLN800(-Forte) was found to be a potent inotrope acting as a cardiac calcium sensitizer.
Conclusion: PanLN800(-Forte) is not a viable fluorescent contrast agent for lymph node imaging in surgery because of cardiac calcium sensitization but may be a novel treatment for heart failure.
期刊介绍：
Toxicology and Applied Pharmacology publishes original scientific research of relevance to animals or humans pertaining to the action of chemicals, drugs, or chemically-defined natural products.
Regular articles address mechanistic approaches to physiological, pharmacologic, biochemical, cellular, or molecular understanding of toxicologic/pathologic lesions and to methods used to describe these responses. Safety Science articles address outstanding state-of-the-art preclinical and human translational characterization of drug and chemical safety employing cutting-edge science. Highly significant Regulatory Safety Science articles will also be considered in this category. Papers concerned with alternatives to the use of experimental animals are encouraged.
Short articles report on high impact studies of broad interest to readers of TAAP that would benefit from rapid publication. These articles should contain no more than a combined total of four figures and tables. Authors should include in their cover letter the justification for consideration of their manuscript as a short article.
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