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May 5, 2017
The U.S. Food and Drug Administration today approved Radicava (edaravone) to treat patients with amyotrophic lateral sclerosis (ALS), commonly referred to as Lou Gehrig’s disease.
“After learning about the use of edaravone to treat ALS in Japan, we rapidly engaged with the drug developer about filing a marketing application in the United States,” said Eric Bastings, M.D., deputy director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “This is the first new treatment approved by the FDA for ALS in many years, and we are pleased that people with ALS will now have an additional option.”
ALS is a rare disease that attacks and kills the nerve cells that control voluntary muscles. Voluntary muscles produce movements such as chewing, walking, breathing and talking. The nerves lose the ability to activate specific muscles, which causes the muscles to become weak and leads to paralysis. ALS is progressive, meaning it gets worse over time. The Centers for Disease Control and Prevention estimates that approximately 12,000-15,000 Americans have ALS. Most people with ALS die from respiratory failure, usually within three to five years from when the symptoms first appear.
Radicava is an intravenous infusion given by a health care professional. It is administered with an initial treatment cycle of daily dosing for 14 days, followed by a 14-day drug-free period. Subsequent treatment cycles consist of dosing on 10 of 14 days, followed by 14 days drug-free.
The efficacy of edaravone for the treatment of ALS was demonstrated in a six-month clinical trial conducted in Japan. In the trial, 137 participants were randomized to receive edaravone or placebo. At Week 24, individuals receiving edaravone declined less on a clinical assessment of daily functioning compared to those receiving a placebo.
The most common adverse reactions reported by clinical trial participants receiving edaravone were bruising (contusion) and gait disturbance.
Radicava is also associated with serious risks that require immediate medical care, such as hives, swelling, or shortness of breath, and allergic reactions to sodium bisulfite, an ingredient in the drug. Sodium bisulfite may cause anaphylactic symptoms that can be life-threatening in people with sulfite sensitivity.
The FDA granted this drug orphan drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.
The FDA granted approval of Radicava to Mitsubishi Tanabe Pharma America, Inc,
Edaravone (brand name ラジカット, Radicut) is a nootropic and neuroprotective agent used for the purpose of aiding neurological recovery following acute brain ischemia and subsequent cerebral infarction. It acts as a potent antioxidant and strongly scavenges free radicals, protecting against oxidative stress and neuronal apoptosis. It has been marketed solely in Japan by Mitsubishi Pharma since 2001. It is also marketed in India by Edinburgh Pharmaceuticals by the brand name Arone.
On June 26, 2015, Mitsubishi Tanabe Pharma Corporation announced it has received approval to market Radicut for treatment of ALS in Japan. The phase III clinical trial began in 2011 in Japan. The company was awarded Orphan Drug Designation for Radicut by the FDA and EU in 2015. Radicut is an intravenous drug and administrated 14 days followed by 14 days drug holiday.
The biotech company Treeway is developing an oral formulation of edaravone (TW001) and is currently in clinical development. Treeway was awarded orphan drug designation for edaravone by the EMA in November 2014 and FDA in January 2015.
Edaravone has been shown to attenuate methamphetamine– and 6-OHDA-induced dopaminergic neurotoxicity in the striatum and substantia nigra, and does not affect methamphetamine-induced dopamine release or hyperthermia. It has also been demonstrated to protect against MPTP-mediated dopaminergic neurotoxicity to the substantia nigra, though notably not to the striatum.
Edaravone (CAS NO.: 89-25-8), with other name of 3-Methyl-1-phenyl-2-pyrazolin-5-one, could be produced through many synthetic methods.
Following is one of the synthesis routes: By direct cyclization of phenylhydrazine (I) with ethyl acetoacetate (II) in refluxing ethanol.
Edaravone, chemical name: 3-methyl-1-phenyl-2-pyrazoline-5-one, of the formula: Formula: CiciHltlN2O, molecular weight: 174.20, the formula:
 Edaravone is a brain-protecting agent (free radical scavenger). Clinical studies suggest that N- acetyl aspartate (NAA) is a specific sign of the survival of nerve cells, dramatically reducing the initial content of cerebral infarction. In patients with acute cerebral infarction Edaravone suppressed reduce peri-infarct regional cerebral blood flow, so that the first concept of days after the onset of brain NAA glycerol content than the control group significantly increased. Preclinical studies suggest that rats after ischemia / reperfusion of ischemic intravenous edaravone, can prevent the progress of cerebral edema and cerebral infarction, and relieve the accompanying neurological symptoms, suppress delayed neuronal death. Mechanism studies suggest that edaravone can scavenge free radicals, inhibiting lipid peroxidation, thereby inhibiting brain cells, endothelial cells, oxidative damage nerve cells.
For the synthesis of edaravone reported some use of benzene and methyl ethyl ketone amide corpus obtained, but methyl ethyl ketone amide difficult to obtain and slow reaction, which now has basically been abandoned; some use benzene corpus and ethyl acetoacetate in ethanol (see US4857542A, Synthesis Example 1) or water (Dykhanov NN Ethyl and butyl acetoacetates, Med Prom SSSR, 1961,15 (1):. 42-45) refluxing the reaction of the reaction The resulting purity edaravone poor, and the yield is not high, only about 70%.
Edaravone, chemical name: 2,4_-dihydro-5-methyl-2-phenyl pyrazole -3H- – one, of the formula: CiciHltlN2O, molecular weight: 174.20, the formula:
edaravone is a clear cerebral infarction harmful factors (free radicals), protection of new therapeutic agents for cerebral infarction nerve cells. Clinical studies have shown that N- acetyl aspartate (NAA) is a specific sign of the survival of nerve cells, dramatically reducing the initial content of cerebral infarction. When patients with acute cerebral infarction Edaravone, peri-infarct rCBF decrease has improved, and the first 28 days after the onset of brain NAA content was significantly higher than that in the control group glycerol. Mechanism studies suggest that edaravone can clear the brain is highly cytotoxic hydroxyl radicals, inhibiting the synthesis of lipids free radicals, which can suppress brain infarction after reperfusion edema, protecting brain from damage and improve nerve impairment symptoms, and the delayed neuronal death inhibition, to protect the brain.
The first is by phenylhydrazine and methyl ethyl ketone amide (National API process compilation, 1980.737-739) condensation reaction in water at 50 ° C, a yield of up to 97%, but the raw material ketone amide ( CH3C0CH2C0NH2) are not readily available. Formula I
Edaravone synthetic route for the reaction:
 The second is to phenylhydrazine and ethyl acetoacetate in ethanol or water at reflux the reaction, sodium bisulfite as the preparation of the catalyst. From the perspective of the chemical reaction, acetyl ethyl ketone amide more than hydrazine reacted with benzene and ethyl acetoacetate more readily available, the price is cheaper, but lower reaction yield of about 70%. Formula 2 for the synthesis route Edaravone reaction formula:
1 Edaravone Synthesis Example  Example
 (1) Weigh benzene hydrochloride corpus 13. 5g (94mmol), was added to IOOml water, stirred for 0.5 hours, sodium hydroxide was added an equimolar 3. 76g, stirred for 0.5 hours;  ( 2) To the reaction solution was added dropwise ethyl acetoacetate 11. 7g (90mmol), the reaction exotherm, the reaction was heated to reflux for 2.5 hours, heating was stopped, cooled to room temperature with stirring, filtered and dried to give a pale yellow granular crude 15. 5g;
 (3) The crude product was added 30ml volume ratio of 2: 1 isopropanol – water, 2g of activated carbon was added and refluxed for 1 hour, filtered hot, cooled to room temperature a white solid was precipitated to give 14 a white crystalline powder. 8g, yield 90%, mpU9 ° C, with a purity of 99.9% 0
2 Edaravone Synthesis Example  Example
 (1) Weigh 15g of benzene hydrochloride corpus (I (Mmmol), was added to 120ml of water and stirred for 0.5 hours, sodium hydroxide was added an equimolar 4. 16g, stirred for 0.5 hours;
 (2) To the reaction solution was added dropwise 13g of ethyl acetoacetate (lOOmmol), the reaction exotherm, the reaction was heated to reflux for 2.5 hours, heating was stopped, cooled to room temperature with stirring, filtered and dried to give a pale yellow granular crude 16. 7g;
(3) The crude product was added 40ml volume ratio of 2: 1 isopropanol – water, 2. 5g of activated carbon was added and refluxed for 1 hour, filtered hot, cooled to room temperature to precipitate a white solid, as a white crystalline powder 16. lg, a yield of 88.9%, mpU8 ° C, with a purity of 99.9% 0
3 Edaravone Synthesis Example  Example
 (1) Weigh 22g of benzene hydrochloride corpus (152mm0l), was added to 200ml of water and stirred for 0.5 hours, sodium hydroxide was added an equimolar 6. 08g, stirred for 0.5 hours;
 (2) To the reaction solution was added dropwise 19g of ethyl acetoacetate (146mm0l), the reaction exotherm, the reaction was heated to reflux for 3 hours, heating was stopped, cooled to room temperature with stirring, filtered and dried to give a pale yellow granular crude 24. Sg;
 (3) The crude product was added 50ml volume ratio of 2: 1 isopropanol – water, 3g of activated carbon was added and refluxed for 1 hour, filtered hot, cooled to room temperature a white solid was precipitated to give 23 a white crystalline powder. 2g, a yield of 87. 8%, mpU8 ° C, with a purity of 99.9% 0
 Comparative Example
 The ethyl acetoacetate 65g (0. 5mol) and 180ml of anhydrous ethanol mixed, with stirring at 50 ° C was added dropwise benzyl corpus 54g (0. 5mol) and a solution consisting of 30ml absolute ethanol, dropwise at reflux for 2 Bi hours, ethanol was distilled off 60ml, cooled, suction filtered, washed crystals with cold absolute ethanol twice, and dried in vacuo to give pale yellow crystals 70g. Recrystallized twice from absolute ethanol to give pale yellowish white crystals 56g (yield 65%).
Example 1: Preparation of phenylhydrazine edaravone.
 a. Weigh 5.1g phenylhydrazine (47mmol), was added under stirring to water containing 45mL round-bottom flask, take appropriate concentrated hydrochloric acid solution was adjusted to pH 6.0 with PH meter.
 b. To the above solution was slowly added dropwise ethyl acetoacetate 5.85g (45mmol), the reaction exotherm, was added 1.5g sodium dithionite (Na2S2O6), heated to 105 ° C to room temperature until reflux After 3h, heating was stopped, and then stirred, cooling, filtration, and dried to give a pale yellow granular edaravone crude.
 c. With anhydrous ethanol recrystallization, filtration, and dried to obtain a white crystalline powder that is refined edaravone, 85% yield, 99.2% purity 0
 Example 2: Preparation of phenylhydrazine hydrochloride edaravone.
 a. Weigh 6.8g phenylhydrazine hydrochloride (47mmol), was added under stirring to water containing 45mL round-bottomed flask, the pH of the solution adjusted to 6.0 with aqueous ammonia.
 b. To the above solution was slowly added dropwise ethyl acetoacetate 5.85g (45mmol), the reaction exotherm, 1.25g was added sodium dithionite (Na2S2O6), heated to 105 ° C to room temperature until reflux After 3h, heating was stopped, and then stirred, cooling, filtration, and dried to give a pale yellow granular edaravone crude.
 c. With anhydrous ethanol recrystallization, filtration, and dried to obtain a white crystalline powder that is refined edaravone, 84% yield, with a purity of 99.2%.  Comparative Example:
Under the  state of agitation will phenylhydrazine 10.2g (94mmol) added to a round bottom flask equipped with IOOmL water in an appropriate amount of concentrated hydrochloric acid was dubbed the volume ratio of 1: 1 aqueous hydrochloric acid, with a PH adjusting pH of the solution was measured 6.0. After weighing Ethylacetoacetate 11.7g (90mmol) added to the reaction mixture, the reaction was exothermic and cooling to room temperature, sodium bisulfite (NaHSO3), heated to 105 ° C under reflux for 3h, the hot solution Water was added into the beaker and mechanical stirring, cooling, filtration, and dried to give the yellow edaravone crude, 73% yield, with a purity of 99.1%.
IR (KBr) max/cm-1 : 3431, 3129, 1602, 1599, 1580;
1 H NMR (300 MHz, CDCl3): δ 7.86 (d, J = 7.5 Hz, 2H, ArH), 7.40 (m, 2H, ArH), 7.18 (m, 1H, ArH), 3.41 (d, J =0.6 Hz, 2H, CH2), 2.19 (s, 3H, CH3);
13C NMR (75 MHz, CDCl3): 170.6, 156.4, 130.1, 128.8, 125.0, 118.9, 43.1, 17.0;
1 H NMR (300 MHz, DMSO-d6): δ 11.5 (bs, 1H, NH), 7.71 (m, 2H, ArH), 7.40 (m, 2H, ArH), 7.22 (m, 1H, ArH), 5.36 (s, 1H, CH), 2.12 (s, 3H, CH3);
13C NMR (75 MHz, DMSO-d6):171.7, 158.9, 148.7, 139.2, 138.6, 129.3,125.4, 124.8, 118.4, 43.5, 17.1, 14.2.
These values are in accordance with the previous published in literature1 .
In the carbon spectrum in DMSO presented in Figure SM 188.8.131.52.8 is evident the presence of the two major tautomeric structures of edaravone, signals are identified by different colours in both structures in the figure. Also in the IR analysis of the solid material (Figure SM 184.108.40.206.9) is possible to see either the NH form (max/cm-1, 3129), the OH form (max/cm- 1 , 3431) and the C=O (max/cm-1, 1599) of the enol and keto tautomeric forms of edaravone.
1. S. Pal, J. Mareddy and N. S. Devi, J. Braz. Chem. Soc., 2008, 19, 1207.
We have shown that the short reaction time, in combination with good yields can make microwave assisted reaction of hydrazines with β-ketoesters ideal for a rapid entry to pyrazolones. All the compounds synthesized are characterized by spectroscopic (1H NMR, IR and MS) data. While determination of tautomeric composition of compound 3 is quite challenging as eight possible tautomeric forms need to be considered, interestingly, two major tautomeric forms of compound 3a was observed in two different solvents. For example, it exists as 1,2-dihydro pyrazolone (T-1, Figure 2) in DMSO and 2,4-dihydro form (T-2, Figure 2) in chloroform as indicated by 1H NMR spectra (Figure 3). The olefinic proton of T-1 appeared at 5.36 δ whereas the methylene hydrogens appeared at 3.43 δ in case of T-2. Additionally, the NH proton of T-1 at 11.40 δ was not observed incase of T-2 confirmed the absence of NH in the 2,4-dihydro form. Existence of two major tautomeric forms was also observed in case compound 3b (see 1H NMR data in the experimental section). However, X-ray study on single crystal of 2-(4-chlorophenyl)-5-methyl-1,2-dihydro pyrazol-3-one (3i) indicates that 2-aryl pyrazol-3-ones e.g. 3a-b, 3e-f and 3i exist as 1,2-dihydro form in crystal state. 27 It is mention worthy that the aryl ring of all these 2-aryl pyrazol-3-ones remain twisted with respect to the pyrazole plane as indicated by the crystallographic data of 3i [the dihedral angle between the pyrazole and benzene ring planes was found to be 15.81 (11)º].27
5-Methyl-2-phenyl-1,2-dihydro pyrazol-3-one (3a)
mp 125-127 ºC (lit21 126-130 ºC);
IR (KBr) νmax/cm-1: 3127, 1597, 1525, 1498, 1454;
1H NMR (400 MHz, DMSO-d6) δ 11.40 (bs, 1H), 7.71-7.69 (m, 2H), 7.42-7.38 (m, 2H), 7.21-7.18 (m, 1H), 5.36 (s, 1H), 2.10 (s, 3H);
13C NMR (50 MHz, DMSO-d6) δ 170.6, 156.2, 138.1, 128.8 (2C), 124.9, 118.9 (2C), 43.1, 16.9;
Mass (CI, m/z) 175 (M+1, 100).
1H NMR (400 MHz, CDCl3)δ 7.85 (d, J 8.3 Hz, 2H), 7.40-7.37 (m, 2H), 7.24-7.18 (m, 1H), 3.43 (s, 2H), 2.20 (s, 3H).
21. Makhija, M. T.; Kasliwal, R. T.; Kulkarni, V. M.; Neamati, N.; Bioorg. Med. Chem. 2004, 12, 2317. [ Links ]
|CN101830852A||Mar 22, 2010||Sep 15, 2010||海南美兰史克制药有限公司||Edaravone compound synthesized by new method|
|CN102060771A||Nov 18, 2009||May 18, 2011||南京长澳制药有限公司||Edaravone crystal form and preparation method thereof|
|CN102180834A||Mar 24, 2011||Sep 14, 2011||江苏正大丰海制药有限公司||Preparation method for edaravone|
- Doherty, Annette M. (2002). Annual Reports in Medicinal Chemistry, Volume 37 (Annual Reports in Medicinal Chemistry). Boston: Academic Press. ISBN 0-12-040537-7.
- Watanabe T, Tanaka M, Watanabe K, Takamatsu Y, Tobe A (March 2004). “[Research and development of the free radical scavenger edaravone as a neuroprotectant]”. Yakugaku Zasshi (in Japanese). 124 (3): 99–111. doi:10.1248/yakushi.124.99. PMID 15049127.
- Higashi Y, Jitsuiki D, Chayama K, Yoshizumi M (January 2006). “Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a novel free radical scavenger, for treatment of cardiovascular diseases”. Recent Patents on Cardiovascular Drug Discovery. 1 (1): 85–93. doi:10.2174/157489006775244191. PMID 18221078.
- Yoshida H, Yanai H, Namiki Y, Fukatsu-Sasaki K, Furutani N, Tada N (2006). “Neuroprotective effects of edaravone: a novel free radical scavenger in cerebrovascular injury”. CNS Drug Reviews. 12 (1): 9–20. doi:10.1111/j.1527-3458.2006.00009.x. PMID 16834755.
- Yuan WJ, Yasuhara T, Shingo T, et al. (2008). “Neuroprotective effects of edaravone-administration on 6-OHDA-treated dopaminergic neurons”. BMC Neuroscience. 9: 75. doi:10.1186/1471-2202-9-75. PMC . PMID 18671880.
- Kawasaki T, Ishihara K, Ago Y, et al. (August 2006). “Protective effect of the radical scavenger edaravone against methamphetamine-induced dopaminergic neurotoxicity in mouse striatum”. European Journal of Pharmacology. 542 (1-3): 92–9. doi:10.1016/j.ejphar.2006.05.012. PMID 16784740.
- Kawasaki T, Ishihara K, Ago Y, Baba A, Matsuda T (July 2007). “Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a radical scavenger, prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity in the substantia nigra but not the striatum”. The Journal of Pharmacology and Experimental Therapeutics. 322 (1): 274–81. doi:10.1124/jpet.106.119206. PMID 17429058.
- Yokoyama H, Takagi S, Watanabe Y, Kato H, Araki T (June 2008). “Role of reactive nitrogen and reactive oxygen species against MPTP neurotoxicity in mice”. Journal of Neural Transmission (Vienna, Austria : 1996). 115 (6): 831–42. doi:10.1007/s00702-008-0019-6. PMID 18235988.
- Yokoyama H, Yano R, Aoki E, Kato H, Araki T (September 2008). “Comparative pharmacological study of free radical scavenger, nitric oxide synthase inhibitor, nitric oxide synthase activator and cyclooxygenase inhibitor against MPTP neurotoxicity in mice”. Metabolic Brain Disease. 23 (3): 335–49. doi:10.1007/s11011-008-9096-3. PMID 18648914.
|Chemical and physical data|
|Molar mass||174.20 g/mol|
|3D model (Jmol)|
Bayer seeks EMA approval for marketing of regorafenib to treat GIST
Bayer HealthCare has submitted an application to the European Medicines Agency (EMA) for marketing authorisation regarding the oral multi-kinase inhibitor, regorafenib.
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Lee Pharma buys China Rights for Kalbitor (ecallantide – for treatment of Hereditary Angioedema) from Dyax
Ecallantide It is an inhibitor of the protein kallikrein and a 60-amino acid polypeptide.
- CAS No.:460738-38-9
- Molecular Weight:7053.82798
- [Glu20,Ala21,Arg36,Ala38,His39,Pro40,Trp42]tissue factor pathway inhibitor (human)-(20-79)-peptide (modified on reactive bond region Kunitz inhibitor 1 domain containing fragment)
KALBITOR (ecallantide) is a human plasma kallikrein inhibitor for injection for subcutaneous use.
11 FEB 2013
Dyax Corp. a developer of novel biotherapeutics for unmet medical needs, and CVie Therapeutics (CVie), a subsidiary of Lee’s Pharmaceutical Holdings Ltd., announced today a strategic partnership for the development and commercialization of KALBITOR® (ecallantide) in the treatment of hereditary angioedema (HAE) and other angioedema indications in China, Hong Kong and Macau.
KALBITOR is currently marketed in United States for the treatment of acute attacks of HAE in
patients 16 years of age and older. Under the terms of the exclusive license agreement, Dyax will receive an upfront payment and is eligible to receive future development, regulatory and sales milestones. Dyax is also eligible to receive royalty on net product sales. CVie is solely responsible for all costs associated with development, regulatory activities, and the commercialization of KALBITOR in China, Hong Kong
and Macau. Additionally, CVie will purchase drug product from Dyax on a cost-plus basis for
If approved in China, KALBITOR would become the first novel therapy available for HAE in China, where presently only steroids are used.
KALBITOR (ecallantide injection) is a clear and colorless, sterile, and nonpyrogenic solution. Each vial contains 10 mg ecallantide as the active ingredient, and the following inactive ingredients: 0.76 mg disodium hydrogen orthophosphate (dihydrate), 0.2 mg monopotassium phosphate, 0.2 mg potassium chloride, and 8 mg sodium chloride in water for injection, USP. KALBITOR (ecallantide injection) is preservative free, with a pH of approximately 7.0. A 30 mg dose is supplied as 3 vials each containing 1 mL of 10 mg/mL KALBITOR (ecallantide injection) . Each vial contains a slight overfill. Vials are intended for single use. Ecallantide is a 60-amino-acid protein produced in Pichia pastoris yeast cells by recombinant DNA technology.
The Ecallantide, with the IUPAC name of [Glu20,Ala21,Arg36,Ala38,His39,Pro40,Trp42]tissue factor pathway inhibitor (human)-(20-79)-peptide (modified on reactive bond region Kunitz inhibitor 1 domain containing fragment), is one kind of inhibitor. This chemical’s classification codes are Plasma Kallikrein Inhibitor; Reduction of Blood Loss During Cardiothoracic Surgery (Plasma Kallikrein Inhibitor); Treatment of Hereditary Angioedema. Ecallantide (trade name Kalbitor, investigational name DX-88) is an inhibitor of the protein kallikrein used for hereditary angioedema (HAE) and in the prevention of blood loss in cardiothoracic surgery. If approved for cardiothoracic surgery, it could become a replacement for aprotinin, which was withdrawn in 2007 after being shown to cause complications.
Ecallantide (trade name Kalbitor, investigational name DX-88) is a drug used for the treatment of hereditary angioedema (HAE) and in the prevention of blood loss incardiothoracic surgery. It is an inhibitor of the protein kallikrein and a 60-amino acidpolypeptide which was developed from a Kunitz domain through phage display to mimic antibodies inhibiting kallikrein. On November 27, 2009, ecallantide was approved by theU.S. Food and Drug Administration for the treatment of acute attacks of hereditary angioedema for persons over 16 years of age.
If approved for cardiothoracic surgery, it could become a replacement foraprotinin, which was withdrawn in 2007 after being shown to cause complications.
- Lehmann A (August 2008). “Ecallantide (DX-88), a plasma kallikrein inhibitor for the treatment of hereditary angioedema and the prevention of blood loss in on-pump cardiothoracic surgery”. Expert Opin Biol Ther 8 (8): 1187–99. doi:10.1517/147125220.127.116.117.PMID 18613770.
- Waknine, Yael (December 4, 2009). “FDA Approves Ecallantide for Hereditary Angioedema”. Medscape. Retrieved 2009-12-07.
- Dyax Corp. (2009). “Full prescibing information Kalbitor”. Retrieved 2010-05-02.
- Bhoola, K. D.; Figueroa, C. D.; Worthy, K. (1992). “Bioregulation of kinins: Kallikreins, kininogens, and kininases”. Pharmacological reviews 44 (1): 1–80. PMID 1313585. edit
- Stefan Offermanns; Walter Rosenthal (2008). Encyclopedia of Molecular Pharmacology. Springer. pp. 673–. ISBN 978-3-540-38916-3. Retrieved 11 December 2010.