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The carotenoid compound trans-sodium crocetinate (TSC) has been shown to increase oxygenation in various tissues, including the brain. Notably, TSC can enhance oxygenation under conditions of reduced blood flow, thus attenuating the depth of an ischemic challenge. This study examined the impact of TSC on neuronal loss in an animal model of intracerebral hemorrhage (ICH). Utilizing a rat model of collagenase injection, TSC was shown to reduce perihematomal cellular loss after ICH, as assessed by Fluoro-Jade B staining in tissue sections. This is the first evidence demonstrating that TSC is capable of limiting hemorrhagic injury to neurons in the brain. The finding supports the concept that TSC may represent a candidate therapeutic for early intervention regardless of whether a stroke is hemorrhagic or ischemic in nature.

Trans-sodium crocetinate (TSC) is a novel carotenoid compound capable of enhancing the diffusion of small molecules in aqueous solutions. TSC improves the diffusion of oxygen and glucose, and increases oxygenation in ischemic brain tissue. TSC also dampens the intensity of an ischemic challenge during an ongoing ischemic event. The current study examined the impact of TSC in rat models of ischemic and hemorrhagic stroke. Rat three vessel occlusion (3VO), and combined 3VO and one vessel occlusion (3VO/1VO) models of ischemic stroke were evaluated for structural and behavioral outcomes. The effects of TSC were also tested in a rat model of intracerebral hemorrhage (ICH). Delayed treatment with TSC reduced infarct volume in a rodent model of transient focal ischemia involving either 2 or 6 h of ischemia. Neurological outcomes, based on a multi-scale assessment and automated gait analysis, also were improved by TSC treatment. Additionally, TSC reduced edema and hemorrhagic volume in a rat model of ICH. An optimal therapeutic candidate for early intervention in ischemic stroke should be effective when administered on a delayed basis and should not aggravate outcomes associated with hemorrhagic stroke. The current findings demonstrate that delayed TSC treatment improves outcomes in experimental models of both ischemic and hemorrhagic stroke. Together, these findings suggest that TSC may be a safe and beneficial therapeutic modality for early stroke intervention, irrespective of the type of stroke involved.

Background: Trans-sodium crocetinate (TSC) is a novel compound that offers promise as a treatment for conditions caused by hypoxia or ischemia. TSC was originally developed at the University of Virginia for hemorrhagic shock, as part of the battlefield casualty program sponsored by the US Office of Naval Research. Animal toxicology studies have demonstrated that high levels of TSC are well-tolerated, and a Phase I clinical study has shown that TSC is also safe in humans. Objective: The drug acts via a mechanism that has not been previously exploited in a pharmaceutical. TSC increases the rate of oxygen diffusion between the erythrocytes and the tissues by altering the ‘structure’ of water in blood plasma. It does this by causing additional hydrogen bonds to form among the water molecules. Conclusion: Further development of TSC for hemorrhagic shock and other hypoxic/ischemic conditions is being done by Diffusion Pharmaceuticals LLC.

Trans sodium crocetinate is a novel drug, which has been shown previously to increase whole-body oxygen consumption during hemorrhagic shock. TSC has been suggested to work by increasing the diffusion rate of oxygen through plasma rather than on a specific symptom of hemorrhagic shock and has been suggested as a general treatment for hypoxemia. Thus, it might also be beneficial for treating respiratory insufficiencies. This study employed an oleic acid model of acute lung injury to determine if TSC could increase arterial PO2 in that model.

Object Adjuvant treatment with radiation (radiation therapy or radiosurgery) is a mainstay of treatment for patients harboring glioblastomas multiforme (GBM). Hypoxic regions within the tumor make cells less sensitive to radiation therapy. Trans sodium crocetinate (TSC) has been shown to increase oxygen diffusion in the brain and elevate the partial brain oxygen level. The goal of this study was to evaluate the radiosensitizing effects of TSC on GBM tumors. Methods A rat C6 glioma model was used, in which C6 glioma cells were stereotactically injected into the rat brain to create a tumor. Following creation of a right frontal tumor, animals were randomized into 1 of 4 groups: 1) TSC alone (animal treated with moderate-dose TSC only); 2) radiation (animals receiving 8 Gy of cranial radiation); 3) radiation and low-dose TSC (animals receiving 8 Gy of radiation and 50 μg/kg of TSC); or 4) radiation and moderate-dose TSC (animals receiving 8 Gy of radiation and 100 μg/kg of TSC). Animals were observed clinically for 60 days or until death. Magnetic resonance (MR) imaging was performed at 2-week intervals on each animal and quantitatively evaluated for tumor response. Immunohistochemical analysis was performed on all brain tumors. Survival differences were also evaluated using the Kaplan–Meier method. Results On MR imaging, a statistically significant reduction in tumor size was seen in the group receiving moderate-dose TSC and radiation treatment compared with the group receiving radiation treatment alone. The rate of tumor growth was significantly less for the combination of TSC and radiation treatment compared with either modality alone. Median survival times for the TSC-only and the radiation therapy–only groups were 15 and 30 days, respectively. The 60-day median survival times for the groups receiving a combination of either low- or moderate-dose TSC with radiation therapy were statistically improved compared with those for the other treatment groups. Conclusions Use of TSC improves the extent of GBM tumor regression following radiation therapy and enhances survival. Radiosensitization of hypoxic tumors through increased oxygen diffusion may have clinical utility in patients with GBM tumors but must be explored in a clinical trial.

2031 Background: Trans sodium crocetinate (TSC) was developed to increase tissue oxygenation. Since hypoxia may enhance radiation resistance, we tested TSC along with radiation therapy (RT) in GBM ...

The purpose of the research under this contract is to support the transition of the novel drug trans sodium crocetinate (TSC) from pre-clinical to clinical use, especially as to advanced drug formulation, stability testing and chemical characterization and data documentation and analysis tasks required by the U.S. FDA. TSC was invented at the University of Virginia by Professor John Gainer, who has received funding from the Office of Naval Research (ONR) since 1995 to advance the development of TSC for the treatment of hemorrhagic shock. ONR is currently supporting Diffusion Pharmaceuticals LLC, Charlottesville, VA in development of TSC for clinical testing. An important step is the development of a drug product formulation that has the required solubility, stability, pH and osmolality characteristics for use both in humans and in high-dosage animal toxicology tests. As previously reported, manufacture of the basic API (active pharmaceutical ingredient), including five related ("analog") molecules, has been completed by CarboGen to Good Manufacturing Practice (GMP) standards. During this quarter, stability tests were conducted by CarboGen (of Switzerland) on the API up through the 9-month time point, and stability tests were conducted on the final, formulated drug product through the 6-month time point by Aptuit of Kansas City. Both the API and the final drug product show good stability in these tests, which suggests that TSC can be safely stored under various conditions, both as a raw drug and as a final, formulated drug product. The improved formulation to support animal toxicology testing shipped in March, 2006.

BACKGROUND: Trans sodium crocetinate (TSC) was developed at UVA to increase tissue oxygenation. Since hypoxic tumors are more resistant to radiation therapy (RT), TSC was demonstrated to increase survival in a rat GBM model.TSC has been used in an open GBM clinical trial in conjunction with TMZ and RT. All patients have undergone at least one year of treatment/check-ups. METHODS: 59 patients with newly diagnosed GBM were enrolled between January 2012 and March 2013. Patients received standard of care RT and TMZ. TSC was also administered 3/week, prior to the RT sessions. The trial began with a Phase I portion to establish the safety of dosing TSC in 3 half-dose patients. Then 6 more patients received TSC for the full 6 weeks of RT. Since there were no dose-limiting toxicities, 50 more Phase II patients were enrolled at the higher dosage of TSC. Four weeks after completion of RT, patients resumed TMZ for 5 days every 4 weeks, but no further TSC was administered. The patients continued to receive bi-monthly check-ups for MRI, KPS scores and Quality of Life questions. The principal efficacy measurement is survival at 24 months as compared to a historical control (Stupp 2005). RESULTS: At a time of 12 months since the diagnosis of GBM: survival = 70% of the 56 full-dose patients are alive as compared to 61% in the Stupp 2005 trial; radiologic response shows 6 full-dose patients who began RT with partially-resected tumors now show no tumor, while another 13 show declining tumors. 7 patients who began RT following complete resections still show no detectable tumor. Thus, 46% of the patients exhibit decreased or zero tumor volumes; SAFETY: The patients tolerated the concurrent dosing of TMZ and TSC during RT extremely well. Only one patient experienced TMZ-induced thrombocytopenia.