Efaproxiral (RSR13)
(Synonyms: 乙丙昔罗,RSR13) 目录号 : GC32887
An allosteric hemoglobin modifier
Cas No.:131179-95-8
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Efaproxiral is an allosteric hemoglobin (Hb) modifier that reduces the affinity of Hb for oxygen, increasing the diffusion of oxygen from blood to tissue.1 In isolated human whole blood, efaproxiral (1.75 mM) increases the partial pressure of oxygen at which Hb is 50% saturated (p50) from 26.75 to 38.63 mm Hg and decreases the percent oxyhemoglobin (Hb-O2) saturation from 48 to 33.8% at a partial oxygen pressure (pO2) of 26 mm Hg. Efaproxiral (150 mg/kg) increases tumor pO2 from 5.2 to 13.1 mm Hg 30 minutes after administration in a RIF-1 mouse fibrosarcoma flank tumor model.2 Efaproxiral (100 μM) enhances radiation-induced cytotoxicity in EMT6 mouse breast cancer cells grown under hypoxic conditions and increases radiosensitization and inhibits tumor growth in a hypoxic Lewis lung tumor mouse model when administered at a dose of 100 mg/kg.3 It also increases the running capacity of normal mice and mice with left coronary artery (LCA) ligation-induced myocardial infarction (MI) when administered at a dose of 150 mg/kg.4
1.Steffen, R.P.Effect of RSR13 on temperature-dependent changes in hemoglobin oxygen affinity of human whole bloodAdv. Exp. Med. Biol.454653-661(1998) 2.Hou, H., Khan, N., O'Hara, J.A., et al.Effect of RSR13, an allosteric hemoglobin modifier, on oxygenation in murine tumors: An in vivo electron paramagnetic resonance oximetry and bold MRI studyInt. J. Radiat. Oncol. Biol. Phys.59(3)834-843(2004) 3.Teicher, B.A., Wong, J.S., Takeuchi, H., et al.Allosteric effectors of hemoglobin as modulators of chemotherapy and radiation therapy in vitro and in vivoCancer Chemother. Pharmacol.42(1)24-30(1998) 4.Watanabe, T., Takeda, T., Omiya, S., et al.Reduction in hemoglobin-oxygen affinity results in the improvement of exercise capacity in mice with chronic heart failureJ. Am. Coll. Cardiol.52(9)779-786(2008)
| Cas No. | 131179-95-8 | SDF | |
| 别名 | 乙丙昔罗,RSR13 | ||
| Canonical SMILES | CC(C)(OC1=CC=C(CC(NC2=CC(C)=CC(C)=C2)=O)C=C1)C(O)=O | ||
| 分子式 | C20H23NO4 | 分子量 | 341.4 |
| 溶解度 | DMSO : ≥ 150 mg/mL (439.37 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.9291 mL | 14.6456 mL | 29.2912 mL |
| 5 mM | 0.5858 mL | 2.9291 mL | 5.8582 mL |
| 10 mM | 0.2929 mL | 1.4646 mL | 2.9291 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
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1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
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Efaproxiral (RSR13) plus oxygen breathing increases the therapeutic ratio of carboplatin in EMT6 mouse mammary tumors
Exp Biol Med (Maywood) 2006 Mar;231(3):317-21.PMID:16514179DOI:10.1177/153537020623100312.
Carboplatin, a member of the platinum family of alkylating agents, is often used in combination with radiotherapy. Some studies, including a recent publication from our laboratory, have suggested that the cytotoxic effects of platinum compounds may be altered by changes in the post-treatment oxygenation. The study reported here assessed whether post-treatment changes in tumor oxygenation caused by oxygen breathing alone or in combination with Efaproxiral (RSR13) altered the effects of carboplatin. Efaproxiral, which allosterically modifies hemoglobin-oxygen binding to increase tumor pO(2), has been shown to increase the effects of radiation in animal tumor models and is in a second, confirmatory phase III clinical trial as an adjuvant to radiotherapy. These studies with EMT6 tumors in BALB/c Rw mice used clonogenic assays to assess tumor cell survival and tumor growth studies to assess antineoplastic activity and treatment-related toxicity. Efaproxiral plus oxygen breathing for 5 hrs after carboplatin treatment significantly increased the antineoplastic effects of carboplatin. The increased antineoplastic effects of carboplatin produced by efaproxiral plus oxygen breathing occurred without a concomitant increase in host toxicity. These findings suggest that the increases in tumor oxygenation produced by Efaproxiral plus oxygen breathing increased the therapeutic ratio of carboplatin.
Efaproxiral: a radiation enhancer used in brain metastases from breast cancer
Ann Pharmacother 2005 Dec;39(12):2038-45.PMID:16249270DOI:10.1345/aph.1G077.
Objective: To review the mechanism of action and clinical data of Efaproxiral use in brain metastases of breast cancer. Data sources: Articles were identified through MEDLINE (1966-June 2005) and EMBASE (1980-May 2005) searches using the key words Efaproxiral and RSR13. Published abstracts over the previous 10 years from various scientific meetings, including American Society of Clinical Oncology and San Antonio Breast Cancer Symposium, were also searched for investigations of Efaproxiral. Data on Efaproxiral were also provided by Allos Therapeutics. Study selection and data extraction: All published clinical data in humans regarding Efaproxiral use in brain metastases from breast cancer were selected for this review. In addition, published studies in humans that discussed the pharmacokinetics, pharmacodynamics, and safety of Efaproxiral were evaluated. Data synthesis: Efaproxiral is a synthetic allosteric modifier of hemoglobin that results in a shift of the hemoglobin oxygen dissociation curve to the right. Therefore, oxygen is more readily released from hemoglobin into tissues. Efaproxiral demonstrated a significant survival benefit when used as a radiation enhancer in patients with brain metastases originating from breast cancer. The safety profile of Efaproxiral and improved survival rates make this agent advantageous over radiation alone. Further investigation and results from the ongoing clinical trials will help to define the role of Efaproxiral in clinical practice. Conclusions: Efaproxiral is the first synthetic allosteric modifier to demonstrate significant improvement in survival in patients undergoing radiation therapy for brain metastases of breast cancer. Validation of this effect in ongoing clinical trials will be important in determining the role of Efaproxiral in brain metastases from breast cancer.
Detection of Efaproxiral (RSR13) and its metabolites in equine by liquid chromatography tandem mass spectrometry
J Mass Spectrom 2014 Jan;49(1):57-67.PMID:24446264DOI:10.1002/jms.3304.
Efaproxiral (RSR 13) is an experimental synthetic allosteric modifier of haemoglobin (Hb) that acts by increasing the release of oxygen from Hb to the surrounding tissues. It has been shown to increase maximum oxygen uptake (VO(2max)) in a canine skeletal muscle model. The ability to increase maximal muscle oxygen uptake makes efaproxiral a potential performance-enhancing agent and is therefore prohibited by the World Anti-Doping Agency. In this study, a method for the detection and elimination of efaproxiral in equine plasma and urine after a 2.5 g intravenous administration of efaproxiral is described. Post administration plasma and urine samples were collected up to 120 h. Efaproxiral was detected up to 120 h in urine and up to 78 h in plasma. In plasma, the peak concentration was 42 µg/ml and detected at 5 min post administration. In urine, the peak concentration was 2.8 mg/ml and detected at 0-1 h post administration. A validated liquid chromatography tandem mass spectrometry method was used for the quantitation of efaproxiral in equine plasma and urine. The limit of detection of the method is 0.05 ng/ml in plasma and 0.1 ng/ml in urine. The method is highly sensitive and specific with good precision, accuracy and recovery. The manuscript also describes the systematic identification of efaproxiral metabolites detected in post administration equine urine samples. The metabolites were identified by use of enhanced mass spectra and enhanced product ion scans. Both positive and negative mode ionizations were utilized for metabolite identification and plausible fragmentation pathways were proposed for the phase 1 metabolite identified. In addition to free efaproxiral, one phase 1 metabolite and two phase 2 metabolites were identified in post administration urine.
Efaproxiral: GSJ 61, JP 4, KDD 86, RS 4, RSR 13
Drugs R D 2005;6(3):178-85.PMID:15869322DOI:10.2165/00126839-200506030-00007.
Efaproxiral [RSR 13, GSJ 61, JP 4, KDD 86, RS 4] is a synthetic, small-molecule, radiation-sensitising agent being developed by Allos Therapeutics primarily for the treatment of cancer. It works by binding and allosterically stabilising deoxyhaemoglobin in hypoxic regions of tumour tissue. This increases oxygen uptake of the tumour tissue and restores its sensitivity to radiation therapy, making therapy potentially more successful. This first-of-its-class compound is particularly applicable for the treatment of certain tumour types that lack oxygen, such as brain metastases. In contrast to conventional chemotherapeutic agents or radiation sensitisers, there is no requirement for Efaproxiral to be administered directly into tumours or to cross the blood-brain barrier for it to display efficacy. Efaproxiral is under review for approval in the US and EU as an adjunct to whole-brain radiation therapy (WBRT) for the treatment of brain metastases originating from breast cancer. It is also under clinical evaluation for a variety of other cancers, including glioblastoma, non-small cell lung cancer (NSCLC) and cervical cancer. Allos is seeking partnership opportunities for Efaproxiral's development and marketing. The company has indicated that the development of Efaproxiral would be in cooperation with a corporate partner, according to its 2003 Annual Report. In 1994, Allos Therapeutics acquired exclusive worldwide rights to intellectual property relating to Efaproxiral from the Center for Innovative Technology (CIT). Allos has entered into arrangements with two contract manufacturers for the supply of Efaproxiral, and a third manufacturer for the supply of the formulated drug product. Hovione FarmaCiencia is the primary supplier of Efaproxiral, and is contracted to manufacture sufficient quantities on a commercial scale. In addition, a second manufacturer, Raylo Chemicals, is also producing quantities of Efaproxiral. In December 2003, Allos entered into a long-term development and supply agreement with Baxter Healthcare who will formulate the Efaproxiral into an injection. Allos is also seeking to establish an alternate supplier of Efaproxiral injection. Allos submitted a rolling NDA to the US FDA consisting of three data components. Submission began in the third quarter of 2003 and was completed by the fourth quarter of 2003. The first part of the application containing non-clinical information was submitted on 5 August 2003. The second part of the NDA containing information about Efaproxiral's chemistry, manufacture and controls (CMC) was submitted in October 2003. Allos submitted its final component of the rolling NDA in December 2003. In February 2004, Allos announced that the FDA had accepted the company's NDA under priority review status. The FDA granted Efaproxiral orphan drug status in August 2004 as an adjunct to WBRT for the treatment of brain metastases among breast cancer patients. Efaproxiral also received fast-track status in November 2000 for the same indication in the US. In February 2004, Allos initiated a phase III trial, called ENRICH (Enhancing Whole Brain Radiation Therapy In Patients with Breast Cancer and Hypoxic Brain Metastases) to investigate Efaproxiral as an adjunct to WBRT for the treatment of brain metastases. Median survival time is the primary endpoint of the study. The National Breast Cancer Coalition (NBCC) is collaborating with the company to support trial enrolment and to gain additional insight about ways to improve radiation treatment in this patient population. The ENRICH trial protocol was approved by the FDA under a Special Protocol Assessment process; as part of the protocol, two interim analyses for safety and efficacy will be performed.This multicentre, randomised, open-label study has a target enrolment of approximately 360 patients at >100 medical centres across the US, Canada, Europe and South America. Allos announced in September 2004 that recruitment of clinical sites for the trial is ongoing across the US and Canada. Completion of trial enrolment in North America is anticipated in December 2005. Subsequently, Allos announced in January 2005 that recruitment into the ENRICH trial has commenced and is ongoing in Europe; enrolment at European sites is expected to conclude by the third quarter of 2006. Allos Therapeutics announced in June 2004 that it had filed an MAA with the EMEA for marketing of exaproxiral as an adjunct to WBRT for treatment of patients with brain metastases originating from breast cancer. The application is based on positive data from a pivotal phase III (REACH, RT-009) trial in this indication. The completed REACH trial investigated Efaproxiral among patients with brain metastases undergoing WBRT. The trial was conducted at multiple sites in 11 countries, including the US, Canada, Europe and Australia. In August 2002 Allos completed the enrolment of 538 patients in the study. Initially only 408 patients were to be enrolled, but the company increased the size of the trial to conduct an appropriately powered subgroup analysis in patients with brain metastases from breast and NSCLC. The study was designed to demonstrate a 35% increase in median survival in the subgroup of patients compared with standard WBRT alone. The primary endpoint was survival. Allos began screening US patients for a phase III trial in NSCLC in early 2003. However, in May 2003, the company announced that as part of its revised operating plan it had suspended the screening of patients for this trial. The trial, which was known as ELITE (Enhanced Lung cancer treatment with Induction chemotherapy and Thoracic radiation and Efaproxiral), was comparing induction chemotherapy followed by thoracic radiation therapy with supplemental oxygen, with or without Efaproxiral. The trial was enrolling patients with locally advanced, unresectable NSCLC. ELITE was planned to enrol up to 600 patients across North America and Western and Eastern Europe. Phase II trials in patients with inoperable NSCLC have been conducted in the US and Canada. Patient enrolment in one of these studies was completed in August 2000, with a total of 52 patients enrolled. This was an open-label, multicentre study of induction therapy with paclitaxel plus carboplatin followed by chest irradiation and Efaproxiral in patients with locally advanced NSCLC. Positive results from this study were reported at the annual meeting of the European Society for Therapeutics Radiology and Oncology in September 2002. Efaproxiral has completed phase I trials as a treatment of surgical hypoxia in elective surgery patients receiving general anaesthesia. However, no recent development has been reported for these indications. In 1994, Allos signed an agreement with CIT for the exclusive worldwide rights to 17 US patents, a European patent covering the UK, France, Italy and Germany plus two pending patents in these territories, two issued patents in Japan, and a pending patent in Canada. These patents cover methods of allosterically modifying haemoglobin with Efaproxiral and other compounds, the binding site of Efaproxiral and therapy in certain indications including cancer, ischaemia and hypoxia. In addition to the licensed patents from CIT, Allos exclusively owns two patent families with pending applications directed to a formulation of Efaproxiral and to methods of its use in BLOD MRI (blood oxygenation level-dependent magnetic resonance imaging) applications. These patents are pending in the US, Canada and Europe, and include an international patent application. In a May 2002 interview with the Wall Street Transcript, the CEO of Allos estimated the overall market for radiation therapy to be approximately 750 000 patients/year. Of this, brain metastases, NSCLC and glioblastoma therapy accounts for about 170 000, 140 000 and 6000 patients, respectively. Allos intend to use a speciality sales force to market Efaproxiral directly to radiation therapists in North America. To penetrate the non-oncology market in the US, the company will seek partnership with one or more pharmaceutical companies with direct sales forces and with established distribution systems. Allos is also hoping to secure an oncology marketing partner for non-North American territories. At the time, the company had been issued 21 patents in the US, Canada, Europe and Japan.
Efaproxiral: a novel radiation sensitiser
Expert Opin Investig Drugs 2004 May;13(5):543-50.PMID:15155129DOI:10.1517/13543784.13.5.543.
Efaproxiral (RSR13) is a synthetic allosteric modifier of haemoglobin that reduces its oxygen binding affinity. By facilitating the release of oxygen from haemoglobin, efaproxiral causes an increase in whole blood P 50 (partial pressure of oxygen which results in 50% haemoglobin saturation) and an increase in the PO2 (partial pressure of oxygen) in the tissue. The therapeutic strategy of enhancing oxygen unloading from haemoglobin to tissue emulates and amplifies physiological tissue oxygenation and can enhance the oxygenation of hypoxic tumours. Since hypoxia is known to decrease the effectiveness of radiation therapy, the use of efaproxiral as a radiation sensitiser may be advantageous. Unlike previous radiation sensitisers, efaproxiral does not need to enter the cancer cells to increase radiosensitivity. Phase I-III trial data have defined the safety profile and dosing of the drug, with the potential benefit for extended survival.