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Expert Review of Hematology May 2017A defining feature of human hemoglobin is its oxygen binding affinity, quantified by the partial pressure of oxygen at which hemoglobin is 50% saturated (p50), and the... (Review)
Review
A defining feature of human hemoglobin is its oxygen binding affinity, quantified by the partial pressure of oxygen at which hemoglobin is 50% saturated (p50), and the variability of this parameter over a range of physiological and environmental states. Modulation of this property of hemoglobin can directly affect the degree of peripheral oxygen offloading and tissue oxygenation. Areas covered: This review summarizes the role of hemoglobin oxygen affinity in normal and abnormal physiology and discusses the current state of the literature regarding artificial modulation of p50. Hypoxic tumors, sickle cell disease, heart failure, and transfusion medicine are discussed in the context of recent advances in hemoglobin oxygen affinity manipulation. Expert commentary: Of particular clinical interest is the possibility of maintaining adequate end-organ oxygen availability in patients with anemia or compromised cardiac function via an increase in systemic p50. This increase in systemic p50 can be achieved with small molecule drugs or a packed red blood cell unit processing variant called rejuvenation, and human trials are needed to better understand the potential clinical benefits to modulating p50.
Topics: Anemia, Sickle Cell; Critical Illness; Hemoglobins; Humans; Hypoxia; Neoplasms; Oxygen
PubMed: 28402148
DOI: 10.1080/17474086.2017.1313699 -
British Journal of Cancer Jun 2006Efaproxiral (Efaproxyn, RSR13), a synthetic allosteric modifier of haemoglobin (Hb), decreases Hb-oxygen (O(2)) binding affinity and enhances oxygenation of hypoxic... (Comparative Study)
Comparative Study
Efaproxiral (Efaproxyn, 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 x 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 (> or =483 microg/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.
Topics: Aniline Compounds; Antisickling Agents; Brain Neoplasms; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Combined Modality Therapy; Dose-Response Relationship, Drug; Erythrocytes; Female; Humans; Male; Middle Aged; Prognosis; Propionates; Survival Analysis
PubMed: 16773073
DOI: 10.1038/sj.bjc.6603169 -
Journal of Experimental & Clinical... Jan 2009To study the efficacy of whole brain radiotherapy (WBRT) with radiosensitizer in comparison with WBRT alone for patients with brain metastases in terms of overall... (Meta-Analysis)
Meta-Analysis
PURPOSE
To study the efficacy of whole brain radiotherapy (WBRT) with radiosensitizer in comparison with WBRT alone for patients with brain metastases in terms of overall survival, disease progression, response to treatment and adverse effects of treatment.
METHODS
A meta-analysis of randomized controlled trials (RCT) was performed in order to compare WBRT with radiosensitizer for brain metastases and WBRT alone. The MEDLINE, EMBASE, LILACS, and Cochrane Library databases, in addition to Trial registers, bibliographic databases, and recent issues of relevant journals were researched. Significant reports were reviewed by two reviewers independently.
RESULTS
A total of 8 RCTs, yielding 2317 patients were analyzed. Pooled results from this 8 RCTs of WBRT with radiosensitizer have not shown a meaningful improvement on overall survival compared to WBRT alone OR = 1.03 (95% CI0.84-1.25, p = 0.77). Also, there was no difference in local brain tumor response OR = 0.8(95% CI 0.5 - 1.03) and brain tumor progression (OR = 1.11, 95% CI 0.9 - 1.3) when the two arms were compared.
CONCLUSION
Our data show that WBRT with the following radiosentizers (ionidamine, metronidazole, misonodazole, motexafin gadolinium, BUdr, efaproxiral, thalidomide), have not improved significatively the overall survival, local control and tumor response compared to WBRT alone for brain metastases. However, 2 of them, motexafin- gadolinium and efaproxiral have been shown in recent publications (lung and breast) to have positive action in lung and breast carcinoma brain metastases in association with WBRT.
Topics: Adult; Brain Neoplasms; Combined Modality Therapy; Cranial Irradiation; Disease Progression; Dose Fractionation, Radiation; Humans; Radiation-Sensitizing Agents; Radiotherapy, Adjuvant; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 19126230
DOI: 10.1186/1756-9966-28-1 -
Journal of Enzyme Inhibition and... Dec 2021A classical drug repurposing approach was applied to find new putative GPR40 allosteric binders. A two-step computational protocol was set up, based on an initial...
A classical drug repurposing approach was applied to find new putative GPR40 allosteric binders. A two-step computational protocol was set up, based on an initial pharmacophoric-based virtual screening of the DrugBank database of known drugs, followed by docking simulations to confirm the interactions between the prioritised compounds and GPR40. The best-ranked entries showed binding poses comparable to that of TAK-875, a known allosteric agonist of GPR40. Three of them (tazarotenic acid, bezafibrate, and efaproxiral) affect insulin secretion in pancreatic INS-1 832/13 β-cells with EC in the nanomolar concentration (5.73, 14.2, and 13.5 nM, respectively). Given the involvement of GPR40 in type 2 diabetes, the new GPR40 modulators represent a promising tool for therapeutic intervention towards this disease. The ability to affect GPR40 was further assessed in human breast cancer MCF-7 cells in which this receptor positively regulates growth activities (EC values were 5.6, 21, and 14 nM, respectively).
Topics: Allosteric Regulation; Aniline Compounds; Animals; Bezafibrate; Cells, Cultured; Dose-Response Relationship, Drug; Drug Repositioning; Fibric Acids; Humans; Insulin; Ligands; Molecular Docking Simulation; Molecular Structure; Propionates; Rats; Receptors, G-Protein-Coupled; Retinoids; Structure-Activity Relationship
PubMed: 33525941
DOI: 10.1080/14756366.2020.1864629 -
Molecules (Basel, Switzerland) Apr 2022Radiotherapy is a vital approach for brain tumor treatment. The standard treatment for glioblastoma (GB) is maximal surgical resection combined with radiotherapy and...
Radiotherapy is a vital approach for brain tumor treatment. The standard treatment for glioblastoma (GB) is maximal surgical resection combined with radiotherapy and chemotherapy. However, the non-sensitivity of tumor cells in the hypoxic area of solid tumors to radiotherapy may cause radioresistance. Therefore, radiotherapy sensitizers that increase the oxygen concentration within the tumor are promising for increasing the effectiveness of radiation. Inspired by hemoglobin allosteric oxygen release regulators, a series of novel phenoxyacetic acid analogues were designed and synthesized. A numerical method was applied to determine the activity and safety of newly synthesized compounds. In vitro studies on the evaluation of red blood cells revealed that compounds (∆P = 45.50 mmHg) and (∆P = 44.38 mmHg) improve the oxygen-releasing property effectively compared to positive control efaproxiral (∆P = 36.40 mmHg). Preliminary safety evaluation revealed that exhibited no cytotoxicity towards HEK293 and U87MG cells, while was cytotoxic toward both cells with no selectivity. An in vivo activity assay confirmed that exhibited a radiosensitization effect on orthotopically transplanted GB in mouse brains. Moreover, a pharmacokinetic study in rats showed that was orally available.
Topics: Animals; Brain Neoplasms; Cell Line, Tumor; Glioblastoma; HEK293 Cells; Humans; Mice; Oxygen; Radiation-Sensitizing Agents; Rats
PubMed: 35458626
DOI: 10.3390/molecules27082428 -
The Journal of Experimental Biology Jan 2022Physiological systems often have emergent properties but the effects of genetic variation on physiology are often unknown, which presents a major challenge to...
Physiological systems often have emergent properties but the effects of genetic variation on physiology are often unknown, which presents a major challenge to understanding the mechanisms of phenotypic evolution. We investigated whether genetic variants in haemoglobin (Hb) that contribute to high-altitude adaptation in deer mice (Peromyscus maniculatus) are associated with evolved changes in the control of breathing. We created F2 inter-population hybrids of highland and lowland deer mice to test for phenotypic associations of α- and β-globin variants on a mixed genetic background. Hb genotype had expected effects on Hb-O2 affinity that were associated with differences in arterial O2 saturation in hypoxia. However, high-altitude genotypes were also associated with breathing phenotypes that should contribute to enhancing O2 uptake in hypoxia. Mice with highland α-globin exhibited a more effective breathing pattern, with highland homozygotes breathing deeper but less frequently across a range of inspired O2, and this difference was comparable to the evolved changes in breathing pattern in deer mouse populations native to high altitude. The ventilatory response to hypoxia was augmented in mice that were homozygous for highland β-globin. The association of globin variants with variation in breathing phenotypes could not be recapitulated by acute manipulation of Hb-O2 affinity, because treatment with efaproxiral (a synthetic drug that acutely reduces Hb-O2 affinity) had no effect on breathing in normoxia or hypoxia. Therefore, adaptive variation in Hb may have unexpected effects on physiology in addition to the canonical function of this protein in circulatory O2 transport.
Topics: Altitude; Animals; Genetic Variation; Hemoglobins; Hypoxia; Mice; Oxygen; Peromyscus; Respiration
PubMed: 34913467
DOI: 10.1242/jeb.243595 -
American Journal of Physiology. Heart... Jul 2002Reducing the hemolobin (Hb)-O(2) binding affinity facilitates O(2) unloading from Hb, potentially increasing tissue mitochondrial O(2) availability. We hypothesized that...
Reducing the hemolobin (Hb)-O(2) binding affinity facilitates O(2) unloading from Hb, potentially increasing tissue mitochondrial O(2) availability. We hypothesized that a reduction of Hb-O(2) affinity would increase O(2) extraction when tissues are O(2) supply dependent, reducing the threshold of critical O(2) delivery (DO(2 CRIT)). We investigated the effects of increased O(2) tension at which Hb is 50% saturated (P(50)) on systemic O(2) uptake (VO(2) (SYS)), DO(2 CRIT), lactate production, and acid-base balance during isovolemic hemodilution in conscious rats. After infusion of RSR13, an allosteric modifier of Hb, P(50) increased from 36.6 +/- 0.3 to 48.3 +/- 0.6 but remained unchanged at 35.4 +/- 0.8 mmHg after saline (control, CON). Arterial O(2) saturations were equivalent between RSR13 and saline groups, but venous PO(2) was higher and venous O(2) saturation was lower after RSR13. Convective O(2) delivery progressively declined during hemodilution reaching the DO(2 CRIT) at 3.4 +/- 0.8 ml x min(-1) x 100 g(-1) (CON) and 3.6 +/- 0.6 ml x min(-1) x 100 g(-1) (RSR13). At Hb of 8.1 g/l VO(2) (SYS) started to decrease (CON: 1.9 +/- 0.1; RSR13: 1.8 +/- 0.2 ml x min(-1) x 100 g(-1)) and fell to 0.8 +/- 0.2 (CON) and 0.7 +/- 0.2 ml x min(-1). 100 g(-1) (RSR13). Arterial lactate was lower in RSR13-treated than in control animals when animals were O(2) supply dependent. The decrease in base excess, arterial pH, and bicarbonate during O(2) supply dependence was significantly less after RSR13 than after saline. These findings demonstrate that during O(2) supply dependence caused by severe anemia, reducing Hb-O(2) binding affinity does not affect VO(2) (SYS) or DO(2 CRIT) but appears to have beneficial effects on oxidative metabolism and acid base balance.
Topics: Acid-Base Equilibrium; Anemia; Aniline Compounds; Animals; Antisickling Agents; Arteries; Blood Volume; Disease Models, Animal; Hemodynamics; Hemoglobins; Hydrogen-Ion Concentration; Lactic Acid; Male; Oxidation-Reduction; Oxygen; Oxygen Consumption; Propionates; Rats
PubMed: 12063279
DOI: 10.1152/ajpheart.01066.2001 -
Journal of Neuro-oncology Jan 2010What evidence is available regarding the emerging and investigational therapies for the treatment of metastatic brain tumors?
QUESTION
What evidence is available regarding the emerging and investigational therapies for the treatment of metastatic brain tumors?
TARGET POPULATION
These recommendations apply to adults with brain metastases.
RECOMMENDATIONS
New radiation sensitizers Level 2 A subgroup analysis of a large prospective randomized controlled trial (RCT) suggested a prolongation of time to neurological progression with the early use of motexafin-gadolinium (MGd). Nonetheless this was not borne out in the overall study population and therefore an unequivocal recommendation to use the currently available radiation sensitizers, motexafin-gadolinium and efaproxiral (RSR 13) cannot be provided. Interstitial modalities There is no evidence to support the routine use of new or existing interstitial radiation, interstitial chemotherapy and or other interstitial modalities outside of approved clinical trials. New chemotherapeutic agents Level 2 Treatment of melanoma brain metastases with whole brain radiation therapy and temozolomide is reasonable based on one class II study. Level 3 Depending on individual circumstances there may be patients who benefit from the use of temozolomide or fotemustine in the therapy of their brain metastases. Molecular targeted agents Level 3 The use of epidermal growth factor receptor inhibitors may be of use in the management of brain metastases from non-small cell lung carcinoma.
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Combined Modality Therapy; Cranial Irradiation; Disease Progression; Evidence-Based Medicine; Metalloporphyrins; Radiation-Sensitizing Agents; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 19957013
DOI: 10.1007/s11060-009-0058-3 -
The Journal of Clinical Investigation Mar 1999Conventional approaches for the treatment of myocardial ischemia increase coronary blood flow or reduce myocardial demand. To determine whether a rightward shift in the...
Conventional approaches for the treatment of myocardial ischemia increase coronary blood flow or reduce myocardial demand. To determine whether a rightward shift in the hemoglobin-oxygen saturation curve would reduce the metabolic and contractile effects of a myocardial oxygen-supply imbalance, we studied the impact of a potent synthetic allosteric modifier of hemoglobin-oxygen affinity, a 2-[4-[[(3,5-disubstituted anilino)carbonyl]methyl] phenoxy] -2-methylproprionic acid derivative (RSR13), during low-flow ischemia. Changes in myocardial high-energy phosphate levels and pH were studied by 31P nuclear magnetic resonance (NMR) spectroscopy in 12 open-chest dogs randomized to receive RSR13 or vehicle control during a reversible reduction of left anterior descending (LAD) coronary artery blood flow. Changes in cardiac metabolites and regional ventricular function studied by pressure segment-length relations were also investigated in additional animals before and after RSR13 administration during low-flow LAD ischemia. The intravenous administration of RSR13 before ischemia resulted in a substantial increase in the mean hemoglobin p50 and attenuated the decline in cardiac creatine phosphate/adenosine triphosphate (PCr/ATP), percent PCr, and pH during ischemia without a change in regional myocardial blood flow, heart rate, or systolic blood pressure. RSR13 given after the onset of low-flow ischemia also improved cardiac PCr/ATP ratios and regional function as measured by fractional shortening and regional work. Thus, synthetic allosteric reduction in hemoglobin-oxygen affinity may be a new and important therapeutic strategy to ameliorate the metabolic and functional consequences of cardiac ischemia.
Topics: Aniline Compounds; Animals; Antisickling Agents; Dogs; Hemoglobins; Myocardial Ischemia; Oxygen; Oxygen Consumption; Phosphocreatine; Propionates
PubMed: 10074492
DOI: 10.1172/JCI6030 -
Journal of Applied Physiology... Oct 2017Exercise intolerance and claudication are symptomatic of peripheral arterial disease. There is a close relationship between muscle O delivery, microvascular oxygen...
Exercise intolerance and claudication are symptomatic of peripheral arterial disease. There is a close relationship between muscle O delivery, microvascular oxygen partial pressure (PO), and contractile performance. We therefore hypothesized that a reduction of hemoglobin-oxygen affinity via RSR13 would maintain a higher PO and enhance blood-muscle O transport and contractile function. In male Wistar rats (12 wk of age), we created hindlimb ischemia via right-side iliac artery ligation (AL). The contralateral (left) muscle served as control (CONT). Seven days after AL, phosphorescence-quenching techniques were used to measure PO at rest and during contractions (electrical stimulation; 1 Hz, 300 s) in tibialis anterior muscle (TA) under saline ( = 10) or RSR13 ( = 10) conditions. RSR13 at rest increased TA PO in CONT (13.9 ± 1.6 to 19.3 ± 1.9 Torr, < 0.05) and AL (9.0 ± 0.5 to 9.9 ± 0.7 Torr, < 0.05). Furthermore, RSR13 extended maintenance of the initial TA force (i.e., improved contractile performance) such that force was not decreased significantly until contraction 240 vs. 150 in CONT and 80 vs. 20 in AL. This improved muscle endurance with RSR13 was accompanied by a greater ΔPO (PO decrease from baseline) (CONT, 7.4 ± 1.0 to 11.2 ± 1.3; AL, 6.9 ± 0.5 to 8.6 ± 0.6 Torr, both < 0.05). Whereas RSR13 did not alter the kinetics profile of PO (i.e., mean response time) substantially during contractions, muscle force was elevated, and the ratio of muscle force to PO increased. In conclusion, reduction of hemoglobin-oxygen affinity via RSR13 in AL increased PO and improved muscle contractile performance most likely via enhanced blood-muscle O diffusion. This is the first investigation to examine the effect of RSR13 (erythrocyte allosteric effector) on skeletal muscle microvascular oxygen partial pressure kinetics and contractile function using an arterial ligation model of peripheral arterial disease in experimental animals. The present results provide strong support for the concept that reducing hemoglobin-O affinity via RSR13 improved tibialis anterior muscle contractile performance most likely via enhanced blood-muscle O diffusion.
Topics: Aniline Compounds; Animals; Electric Stimulation; Male; Muscle Contraction; Muscle, Skeletal; Oxygen Consumption; Partial Pressure; Peripheral Arterial Disease; Physical Endurance; Propionates; Rats, Wistar
PubMed: 28620055
DOI: 10.1152/japplphysiol.00257.2017