trans-sodium-crocetinate and Hypoxia

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.. 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.. Further development of TSC for hemorrhagic shock and other hypoxic/ischemic conditions is being done by Diffusion Pharmaceuticals LLC.

Topics: Animals; Carotenoids; Clinical Trials, Phase I as Topic; Diffusion; Drug Evaluation, Preclinical; Erythrocytes; Humans; Hydrogen Bonding; Hypoxia; Ischemia; Male; Models, Animal; Oxygen; Oxygen Consumption; Plasma; Rats; Shock, Hemorrhagic; Swine; Vitamin A; Water

Intratumoral hypoxia is believed to be exhibited in high-grade gliomas. Trans sodium crocetinate (TSC) has been shown to increase oxygen diffusion to hypoxic tissues. In this research, the authors use oxygen-sensitive PET studies to evaluate the extent of hypoxia in vivo in a glioblastoma model and the effect of TSC on the baseline oxygenation of the tumor.. The C6 glioma cells were stereotactically implanted in the right frontal region of rat brains. Formation of intracranial tumors was confirmed on MR imaging. Animals were injected with Copper(II) diacetyl-di(N4-methylthiosemicarbazone) (Cu-ATSM) and then either TSC or saline (6 rats each). Positron emission tomography imaging was performed, and relative uptake values were computed to determine oxygenation within the tumor and normal brain parenchyma. Additionally, TSC or saline was infused into the animals, and carbonic anhydrase 9 (CA9) and hypoxia-inducing factor-1α (HIF-1α) protein expression were measured 1 day afterward.. On PET imaging, all glioblastoma tumors demonstrated a statistically significant decrease in uptake of Cu-ATSM compared with the contralateral cerebral hemisphere (p = 0.000002). The mean relative uptake value of the tumor was 3900 (range 2203-6836), and that of the contralateral brain tissue was 1017 (range 488-2304). The mean relative hypoxic tumor volume for the saline group and TSC group (6 rats each) was 1.01 ± 0.063 and 0.69 ± 0.062, respectively (mean ± SEM, p = 0.002). Infusion of TSC resulted in a 31% decrease in hypoxic volume. Immunoblot analysis revealed expression of HIF-1α and CA9 in all tumor specimens.. Some glioblastomas exhibit hypoxia that is demonstrable on oxygen-specific PET imaging. It appears that TSC lessens intratumoral hypoxia on functional imaging. Further studies should explore relative hypoxia in glioblastoma and the potential therapeutic gains that can be achieved by lessening hypoxia during delivery of adjuvant treatment.

Topics: Animals; Brain Neoplasms; Carotenoids; Frontal Lobe; Glioblastoma; Hypoxia; Neoplasm Transplantation; Radionuclide Imaging; Rats; Vitamin A

To examine whether a carotenoid, trans-sodium crocetinate, has beneficial effects on hemodynamic status and short-term outcome in a rat model of lethal hypoxemia.. Randomized, placebo-controlled study.. Medical school laboratory.. Eighteen spontaneously breathing, anesthetized Sprague-Dawley rats (six per group).. Rats underwent instrumentation to measure blood pressure, aortic and renal blood flow, arterial blood gases, bladder epithelial oxygen tension (by an intraluminal Clark electrode), and hepatic microvascular oxygen tension (measured by porphyrin phosphorescence). After stabilization, the rats were subjected to breathing 10% inspired oxygen concentration. After 10 mins, they were administered 1.25 mL/kg intravenous boluses of either isotonic saline (control), normal strength crocetinate (40 microg/mL), or a concentrated crocetinate solution (60 microg/mL). These boluses were repeated at 30-min intervals until either death or 3 hrs had elapsed.. With the onset of hypoxemia, we observed a rapid reduction in blood pressure and renal blood flow, maintenance of aortic blood flow, an increase in arterial base deficit, and falls in oxygen tensions in arterial blood, bladder epithelium, and hepatic microvasculature. A progressive deterioration in the control rats was noted, with only two of the six animals surviving for 3 hrs. However, all 12 rats in the two crocetinate groups survived for 3 hrs, with hemodynamic stability until 150 mins and a slow decline thereafter.. Trans-sodium crocetinate improved hemodynamic status and prolonged survival in this model of severe acute hypoxic hypoxia. To our knowledge, this is the first demonstration of an intravenous agent having such an effect.

Topics: Animals; Carotenoids; Dose-Response Relationship, Drug; Hypoxia; Injections, Intravenous; Male; Rats; Rats, Sprague-Dawley; Survival Rate; Time Factors; Vitamin A

The carotenoid compound crocetin has been hypothesized to enhance the diffusion of O(2) through plasma, and observations in the rat and rabbit have revealed improvement in arterial PO(2) when crocetin is given. To determine whether crocetin enhances diffusion of O(2) between alveolar gas and the red blood cell in the pulmonary capillary in vivo, five foxhounds, two previously subjected to sham and three to actual lobectomy or pneumonectomy, were studied while breathing 14% O(2) at rest and during moderate and heavy exercise before and within 10 min after injection of a single dose of crocetin as the trans isomer of sodium crocetinate (TSC) at 100 microg/kg iv. This dose is equivalent to that used in previous studies and would yield an initial plasma concentration of 0.7-1.0 microg/ml. Ventilation-perfusion inequality and pulmonary diffusion limitation were assessed by the multiple inert gas elimination technique in concert with conventional measurements of arterial and mixed venous O(2) and CO(2). TSC had no effect on ventilation, cardiac output, O(2) consumption, arterial PO(2)/saturation, or pulmonary O(2) diffusing capacity. There were minor reductions in ventilation-perfusion mismatching (logarithm of the standard deviation of perfusion fell from 0.48 to 0.43, P = 0.001) and in CO(2) output and respiratory exchange ratio (P = 0.05), which may have been due to TSC or to persisting effects of the first exercise bout. Spectrophotometry revealed that TSC disappeared from plasma with a half time of approximately 10 min. We conclude that, in this model of extensive pulmonary O(2) diffusion limitation, TSC as given has no effect on O(2) exchange or transport. Whether the original hypothesis is invalid, the dose of TSC was too low, or plasma diffusion of O(2) is not rate limiting without TSC cannot be discerned from the present study.

Topics: Animals; Antioxidants; Cardiac Output; Carotenoids; Dogs; Hypoxia; Male; Oxygen; Oxygen Consumption; Physical Exertion; Pneumonectomy; Pulmonary Alveoli; Pulmonary Gas Exchange; Ventilation-Perfusion Ratio; Vitamin A

Rabbits anesthesized with urethan and subjected to mild hypoxia (60-70 Torr arterial PO2) through a reduction of the minute volume were injected with a carotenoid compound, crocetin, or saline. The increased PO2 in the arterial blood seen subsequently with crocetin is attributed to increased diffusion through plasma. Blood flow rates remained constant and were unaffected by crocetin.

Topics: Animals; Cardiac Output; Carotenoids; Hypoxia; Male; Oxygen; Pulmonary Gas Exchange; Rabbits; Time Factors; Vitamin A