Effects of the Allosteric Modification of Hemoglobin on Brain Oxygen and Infarct Size in a Feline Model of Stroke

Watson, Joe C.; Bullock, M. Ross; Zauner, Alois; Rice, Melody R.; Abraham, Donald J.; Young, Harold F.

doi:10.1161/01.str.28.8.1624

Cited by 38 publications

(32 citation statements)

References 14 publications

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“…Whole-brain radiation therapy (WBRT) is a standard treatment for brain metastases (Zimm et al, 1981;Egawa et al, 1986); however, patients may not achieve maximum benefit from WBRT owing to tumour hypoxia, which decreases radiation sensitivity of solid tumours (Rampling et al, 1994;De Santis et al, 1998). Efaproxiral (Efaproxynt, RSR13) is a synthetic allosteric modifier of haemoglobin (Hb), which binds noncovalently in the central water cavity of the Hb tetramer (Wireko et al, 1991;Safo et al, 2001), thereby reducing the Hb-oxygen (O 2 ) binding affinity to facilitate the release of O 2 from Hb to the tissues (Randad et al, 1991;Khandelwal et al, 1993;Kunert et al, 1996;Watson et al, 1997;Steffen, 1998;Eichelbronner et al, 1999). This pharmacodynamic (PD) effect is measured either as a decrease in standard cutaneous pulse oximetry (SpO 2 ) or as an increase in the partial pressure of O 2 (pO 2 ) to produce 50% saturation of Hb (p50).…”

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confidence: 99%

Efaproxiral red blood cell concentration predicts efficacy in patients with brain metastases

et al. 2006

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Efaproxiral (Efaproxynt, RSR13), a synthetic allosteric modifier of haemoglobin (Hb), decreases Hb-oxygen (O 2 ) binding affinity and enhances oxygenation of hypoxic tumours during radiation therapy. This analysis evaluated the Phase 3, Radiation Enhancing Allosteric Compound for Hypoxic Brain Metastases; RT-009 (REACH) study efficacy results in relation to efaproxiral exposure (efaproxiral red blood cell concentration (E-RBC) and number of doses). Recursive partitioning analysis Class I or II patients with brain metastases from solid tumours received standard whole-brain radiation therapy (3 Gy/fraction Â 10 days), plus supplemental O 2 (4 l/min), either with efaproxiral (75 or 100 mg/kg daily) or without (control). Efaproxiral red blood cell concentrations were linearly extrapolated to all efaproxiral doses received. Three patient populations were analysed: (1) all eligible, (2) non-small-cell lung cancer (NSCLC) as primary cancer, and (3) breast cancer primary. Efficacy endpoints were survival and response rate. Brain metastases patients achieving sufficient E-RBC (X483 mg/ml) and receiving at least seven of 10 efaproxiral doses were most likely to experience survival and response benefits. Patients with breast cancer primary tumours generally achieved the target efaproxiral exposure and therefore gained greater benefit from efaproxiral treatment than NSCLC patients. This analysis defined the efaproxiral concentration-dependence in survival and response rate improvement, and provided a clearer understanding of efaproxiral dosing requirements.

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confidence: 99%

Efaproxiral red blood cell concentration predicts efficacy in patients with brain metastases

et al. 2006

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“…Furthermore, during the extreme hypoxic conditions of cerebral ischemia, others have shown that increasing the P 50 of red cell Hb with an allosteric inhibitor or using liposome-encapsulated Hb with a P 50 of 40 Torr reduces infarct volume from experimental stroke [32][33][34]. On the other hand, the experiments that used recombinant HBOCs with P 50 ranging from 3 to 18 Torr also demonstrated substantial reductions in infarct volume [8,9].…”

Section: Interpretation Of Results With Hboc Possessing Different Oxymentioning

confidence: 99%

Insensitivity of cerebral oxygen transport to oxygen affinity of hemoglobin-based oxygen carriers

Koehler

Fronticelli

Bucci

2008

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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The cerebrovascular effects of exchange transfusion of various cell-free hemoglobins that possess different oxygen affinities are reviewed. Reducing hematocrit by transfusion of a non-oxygencarrying solution dilates pial arterioles on the brain surface and increases cerebral blood flow to maintain a constant bulk oxygen transport to the brain. In contrast, transfusion of hemoglobins with P 50 of 4-34 Torr causes constriction of pial arterioles that offsets the decrease in blood viscosity to maintain cerebral blood flow and oxygen transport. The autoregulatory constriction is dependent on synthesis of 20-HETE from arachidonic acid. This oxygen-dependent reaction is apparently enhanced by facilitated oxygen diffusion from the red cell to the endothelium arising from increased plasma oxygen solubility in the presence of low or high-affinity hemoglobin. Exchange transfusion of recombinant hemoglobin polymers with P 50 of 3 and 18 Torr reduces infarct volume from experimental stroke. Cell-free hemoglobins do not require a P 50 as high as red blood cell hemoglobin to facilitate oxygen delivery.

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“…After tracheal intubation, the lungs were mechanically ventilated (tidal volume ϳ2.5 ml, respiratory rate ϳ60 breaths/min) to maintain normocapnia (37)(38)(39)(40)(41)(42). Surgery was performed with aseptic technique, and all surgical fields were infiltrated with 1% lidocaine.…”

Section: Experiments 2: Effects Of Hypothermia and Rsr13-induced Incrementioning

confidence: 99%

“…Wei et al (38) found decreased cerebral venous blood Hb saturation after treatment with RSR13. Finally, Watson et al (37) found increased brain tissue PO 2 in cats subjected to an ischemic insult when given RSR13. Accordingly, RSR13 can serve as a tool to define the effect of hypothermia-induced P 50 changes on brain damage resulting from a cerebral ischemic insult.…”

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confidence: 94%

Pharmacological correction of hypothermic P₅₀shift does not alter outcome from focal cerebral ischemia in rats

Wainwright

Sheng²,

Sato³

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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. Pharmacological correction of hypothermic P 50 shift does not alter outcome from focal cerebral ischemia in rats. Am J Physiol Heart Circ Physiol 282: H1863-H1870, 2002; 10.1152/ajpheart.00863.2001.-Hypothermia decreases the arterial PO 2 at which hemoglobin is 50% saturated (P50), increasing hemoglobin O2-binding affinity. We used RSR13, a synthetic allosteric modifier of hemoglobin that increases P 50, to study the role of altered hemoglobin O2-binding affinity in mild hypothermic neuroprotection. RSR13 (150 mg/kg iv) restored P50 to normothermic values. Rats underwent 70 min of middle cerebral artery occlusion (MCAO) at 30.0, 34.0, or 37.5°C with hemoglobin saturation held at 98-100%. The 34.0°C group received RSR13 or vehicle before ischemia. After 7 days of recovery, infarct volumes were reduced in all hypothermic groups, without evidence of a detrimental effect on infarct size or neurological score as a result of P 50 correction. To examine for a beneficial effect of P50 correction, ischemia duration was increased to 120 min in rats maintained at 34.0°C. Correction of P50 by RSR13 did not alter cerebral infarct sizes or neurological scores. The decrease in P 50, caused by mild hypothermia, could not be associated with infarct size or neurological deficit resulting from ischemic brain hypoxia in rats.brain; allosteric modification; hypothermia; RSR13 IN LABORATORY MODELS of focal and global cerebral ischemia, mild (34.0°C) and moderate (30.0°C) hypothermia have been shown to reduce brain injury (8,14,17,30,31). Although the efficacy of induced hypothermia remains unproven in humans sustaining ischemic brain injury, intense investigation continues with the hope of defining conditions where benefits may be obtained (12,20,34,36,43).Mild hypothermia produces multiple effects on the ischemic brain. Cerebral metabolic rate is modestly reduced (29), as is the accumulation of glutamate in the extracellular space (9, 41). However, the importance of these effects has been questioned (32, 42). In vitro, mild hypothermia reduces calcium uptake by neurons (2, 6). Mild hypothermia has no effect on protein synthesis during early recirculation (4) but hastens recovery of protein synthesis several hours after reperfusion (39) and diminishes membranebound protein kinase C activity in selectively vulnerable regions (10). Hypothermia also reduces the cerebral formation of reactive oxygen species and nitric oxide (18,22,23,26). The frequency of peri-infarct spontaneous depolarizations is also decreased in hypothermic rats (11).Hypothermia exerts another biological effect, the significance of which has not been examined. The PO 2 at which 50% of hemoglobin (Hb) binding sites are occupied by oxygen (P 50 ) is reduced in a temperature-dependent fashion. It can be speculated that this effect on Hb O 2 -binding affinity may be either beneficial or detrimental to the ischemic brain. Because hypothermia increases the affinity of Hb for O 2 , release of O 2 into tissue could be reduced. In contrast, when Hb affinity for O 2 is incre...

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Effects of the Allosteric Modification of Hemoglobin on Brain Oxygen and Infarct Size in a Feline Model of Stroke

Abstract: These results are evidence that allosteric hemoglobin modification is protective to the brain after acute focal ischemia, providing a new opportunity for neuroprotection and raising the possibility of enhancing the protective effect of thrombolysis and ion channel blockade.

Cited by 38 publications

References 14 publications

Efaproxiral red blood cell concentration predicts efficacy in patients with brain metastases

Efaproxiral red blood cell concentration predicts efficacy in patients with brain metastases

Insensitivity of cerebral oxygen transport to oxygen affinity of hemoglobin-based oxygen carriers

Pharmacological correction of hypothermic P₅₀shift does not alter outcome from focal cerebral ischemia in rats

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Effects of the Allosteric Modification of Hemoglobin on Brain Oxygen and Infarct Size in a Feline Model of Stroke

Abstract: These results are evidence that allosteric hemoglobin modification is protective to the brain after acute focal ischemia, providing a new opportunity for neuroprotection and raising the possibility of enhancing the protective effect of thrombolysis and ion channel blockade.

Cited by 38 publications

References 14 publications

Efaproxiral red blood cell concentration predicts efficacy in patients with brain metastases

Efaproxiral red blood cell concentration predicts efficacy in patients with brain metastases

Insensitivity of cerebral oxygen transport to oxygen affinity of hemoglobin-based oxygen carriers

Pharmacological correction of hypothermic P50shift does not alter outcome from focal cerebral ischemia in rats

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Pharmacological correction of hypothermic P₅₀shift does not alter outcome from focal cerebral ischemia in rats