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Mechanism of Action

PEDMARK is an investigational drug and has not yet been approved by the U.S. Food and Drug Administration (FDA) or any regulatory authority.

Animal and two Phase 3 human studies suggest that PEDMARKTM can provide protection against cisplatin-induced hearing loss.

PEDMARKTM may act in several ways to protect cells from platinum toxicity. These mechanisms of chemoprotection are not mutually exclusive. PEDMARKTM can inactivate platinum complexes and render them non-cytotoxic by covalently binding electrophilic platinum with thiol (Howell 1980). Although free platinum largely disappears from circulation four hours after administration in rats (Dickey, Wu et al. 2005) and pigs (Neuwelt, Brummett et al. 1996), protection against platinum-associated hearing loss by PEDMARKTM was effective with delayed administration up to eight hours after platinum administration (see below). This suggests that PEDMARKTM avidly binds platinum/protein complexes thereby minimizing their toxicity and that a potential mechanism of the hearing loss caused by platinum results from the deposition of protein bound platinum in the cochlea. Other mechanisms by which PEDMARKTM may protect against ototoxicity are by scavenging reactive oxygen species and by enhancing levels of endogenous reducing agents such as GSH (Dorr 1991; Elferink 1986, Tabuchi et al., 2011). In the inner ear, the cochlea may concentrate PEDMARKTM in the perilymph or endolymph and may locally enhance PEDMARKTM chemoprotection against ototoxicity (Neuwelt 1996). Thus, it is suggested that cisplatin-mediated (via ROS) hair cell apoptosis is impeded by the reducing properties of STS (Bijarnia et al., 2015).

Publications

Brock PR, et al. J Clin Oncol 2012;20:2408-2417
Brock PR, Knight K, Freyer DR, et al. Platinum-Induced Ototoxicity in Children: A Consensus
Review on Mechanisms, Predisposition, and Protection, Including a New International Society of Pediatric Oncology Boston Ototoxicity Scale. J Clin Oncol 2012;20:2408-2417

Doolittle ND, et al. Clin Cancer Res 2001;7(3):493-500.
Doolittle ND, Muldoon LL, Brummett RE, et al. Delayed sodium thiosulfate as an otoprotectant against carboplatin-induced hearing loss in patients with malignant brain tumors. Clin Cancer Res 2001;7(3):493-500.

Gilmer Knight KR, et.al. J Clin Oncol 2005;23(34):8588-8596
Gilmer Knight, KR, Kraemer, DF, Neuwelt, EA. Ototoxicity in Children Receiving Platinum Chemotherapy: Underestimating a Commonly Occurring Toxicity That May Influence Academic and Social Development. J Clin Oncol 2005;23(34):8588-8596

Neuwelt EA, et al.,J Pharmacol Exp Ther 1998;286(1):77-84
Neuwelt EA, Brummet RE, Doolittle ND, et al. First evidence of otoprotection against carboplatin-induced hearing loss with a two-compartment system in patients with central nervous system malignancy using sodium thiosulfate. J Pharmacol Exp Ther 1998;286(1):77-84.

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