Edaravone

174.19900

174.20

201-891-0

758622|26139|2629|12

DTXSID9021130

MONOCLINIC PRISMS FROM WATER|WHITE POWDER OR CRYSTALS

N - Nervous system

2933199090

32.67000

1.3

1-phenyl-3-methyl-5-pyrazolone appears as white to off-white powder or crystals. (NTP, 1992)

1.12

127 °C

287 °C @ Press: 105 Torr

155.2ºC

1.606

H2O: 3 g/L (20 ºC)

Store in a tightly closed container. Store in a cool, dry, well-ventilated area away from incompatible substances. Store protect

less than 0.01 mm Hg at 68 °F (NTP, 1992)

LD50 orl-rat: 3500 mg/kg LONZA# 08FEB79

7None

7.0

Insoluble in water.

Amides and Imides

Amines are chemical bases. They neutralize acids to form salts plus water. These acid-base reactions are exothermic. The amount of heat that is evolved per mole of amine in a neutralization is largely independent of the strength of the amine as a base. Amines may be incompatible with isocyanates, halogenated organics, peroxides, phenols (acidic), epoxides, anhydrides, and acid halides. Flammable gaseous hydrogen is generated by amines in combination with strong reducing agents, such as hydrides.

NONH for all modes of transport

1

R36/37/38

S26-S36

UQ9625000

Xi

Stable under normal temperatures and pressures.

P261-P305 + P351 + P338

H302-H315-H319-H335

DHEW/NCI; Bioassay of 1-Phenyl-3-methyl-5-pyrazolone for Possible Carcinogenicity (1978) Technical Rpt Series No. 141 DHEW Pub No. (NIH) 78-1396

Flash point data for this chemical are not available. It is probably combustible. (NTP, 1992)

|Warning|H302 (26.34%): Harmful if swallowed [Warning Acute toxicity, oral]|P261, P264, P270, P271, P272, P273, P280, P301+P312, P302+P352, P304+P340, P305+P351+P338, P312, P321, P330, P332+P313, P333+P313, P337+P313, P362, P363, P403+P233, P405, and P501|Aggregated GHS information provided by 220 companies from 22 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.|H317: May cause an allergic skin reaction [Warning Sensitization, Skin]|P261, P272, P280, P302+P352, P321, P333+P313, P363, and P501

Fires involving this material can be controlled with a dry chemical, carbon dioxide or Halon extinguisher. (NTP, 1992)

SMALL SPILLS AND LEAKAGE: Should a spill occur while you are handling this chemical, FIRST REMOVE ALL SOURCES OF IGNITION, then you should dampen the solid spill material with ethanol and transfer the dampened material to a suitable container. Use absorbent paper dampened with ethanol to pick up any remaining material. Seal the absorbent paper, and any of your clothes, which may be contaminated, in a vapor-tight plastic bag for eventual disposal. Solvent wash all contaminated surfaces with ethanol followed by washing with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned. STORAGE PRECAUTIONS: You should store this material in a refrigerator. (NTP, 1992)

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with an organic vapor/acid gas cartridge (specific for organic vapors, HCl, acid gas and SO2) with a dust/mist filter. (NTP, 1992)

No reported evidence of carcinogenic, mutagenic or teratogenic potential. Oral LD50 value is 1,915 mg/kg (Rat). Adverse effects include rashes, hypertension, altered hepatic function, and acute renal impairment. Hematological abnormalities, lung injury and rhabomyolysis may occur with no known incidences.

Serum aminotransferase elevations occur in a small proportion of patients on edaravone therapy, but the frequency, timing of onset, duration and severity of these elevations has not been defined. The rates of abnormal liver tests during edaravone therapy were said to be similar to those during placebo treatment. Most elevations resolved spontaneously, and there were no reports of drug discontinuation for serum enzyme elevations. Clinically apparent liver injury due to edaravone was not reported in the prelicensure trials and has not been reported with subsequent clinical use of edaravone, but the numbers of patients treated have been few. Thus, clinically apparent liver injury from edaravone must be rare if it occurs at all.

A bioassay of 1-phenyl-3-methyl-5-pyrazolone for possible carcinogenicity was conducted using Fischer 344 rats and B6C3Fl mice. l-Phenyl-3-methyl-5-pyrazolone was admin in the feed, at either of two concn, to groups of 49 or 50 male and 50 female animals of each species. The high and low concn of 1-phenyl-3-methyl-5-pyrazolone utilized were, respectively, 5,000 and 2,500 ppm for rats and 15,000 and 7,500 ppm for mice. Twenty animals of each species and sex were placed on test as controls. After a 103 wk period of chemical admin, there was an additional observation period of 2 wk for rats. A 102 wk period of chemical admin was followed by an additional 2 wk observation period for mice. In both species adequate numbers of animals survived sufficiently long to be at risk from late developing tumors. ... Under the conditions of this bioassay, there was no evidence for the carcinogenicity of 1-phenyl-3-methyl-5-pyrazolone to Fischer 344 rats or B6C3Fl mice. ... Levels of Evidence of Carcinogenicity: Male Rats: Negative; Female Rats: Negative; Male Mice: Negative; Female Mice: Negative.

The in vitro binding rates of edaravone to human serum protein and albumin are 92% and 89-91%, respectively, with no concentration-dependence.

Indicated for improving neurological symptoms and damage from acute ischemic stroke and delaying disease progression of ALS.|FDA Label

Edaravone is a free radical scavenger and neuroprotective agent used for therapy of amyotrophic lateral sclerosis. Edaravone is associated with a low rate of serum aminotransferase elevations during therapy but has not been linked to instances of clinically apparent, acute liver injury.

Amyotrophic Lateral Sclerosis Agents

Edaravone scavenges free hydroxyl radicals and peroxynitrite radicals which are highly associated with neuronal damage/death from many cerebral vascular disorders such as ischemic strokes and degenerative neurological disorders such as ALS. It exerts a neuroprotective and antioxidant effect and delays disease progression by limiting the extent of lipid peroxidation via free radical generation and cell membrane damage from oxidative stress. It reversed the reduction in regional blood flow and cerebral edema in a case of ischemic stroke.

Substances that eliminate free radicals. Among other effects, they protect PANCREATIC ISLETS against damage by CYTOKINES and prevent myocardial and pulmonary REPERFUSION INJURY. (See all compounds classified as Free Radical Scavengers.)|Drugs intended to prevent damage to the brain or spinal cord from ischemia, stroke, convulsions, or trauma. Some must be administered before the event, but others may be effective for some time after. They act by a variety of mechanisms, but often directly or indirectly minimize the damage produced by endogenous excitatory amino acids. (See all compounds classified as Neuroprotective Agents.)

The peak plasma concentration of the parent drug is reached at the end of infusion, without accumulation of the drug with multiple dosing regimen. The mean Cmax value in healthy male adults is 888ng/mL for intravenous infusion. The values of AUC and Cmax are increased in a dose-proportional relationship. The oral bioavailability in mouse studies is 38% of the I.V. delivery.|About 0.7-0.9% of the dose is excreted as unchanged drug and 71.0-79.9% of the dose is excreted as metabolites (mostly as glucuronide conjugates) through mainly renal elimination.|The mean Vd value following an intravenous infusion of a single 30mg dose is 18.5L/kg.|The mean total plasma drug clearance following an intravenous infusion of a single 30mg dose is 0.1L/min.

Multiple renal and hepatic uridine diphosphate glucuronosyltransferase (UGT) isoforms catalyze glucuronidation reaction of edaravone to form glucuronide conjugates. Edaravone is also metabolized into sulfate conjugates via sulfotransferase activity, which is the main metabolite form predominantly found circulating in plasma. It is predicted that the sulfate conjugate is hydrolyzed back to edaravone, which is then converted to the glucuronide conjugate in the human kidney before excretion into the urine. These metabolites have no pharmacological activity.

The mean terminal elimination half-life of edaravone is 4.5 to 6 hours and the half-lives of its metabolites are 2 to 2.8 hours.

Nootropic and neuroprotective effects are mediated through inhibiting lipid peroxidation and scavenging free radicals. Edaravone acts to increase prostacyclin production, decrease lipoxygenase metabolism of arachidonic acid by trapping hydroxyl radicals, and inhibit alloxan-induced lipid peroxidation and quench active oxygen species. It targets various kinds of cells, including neurons, endothelial cells and myocardial cells. There is also evidence of reduction of neuronal nitric oxide synthase (nNOS) levels and potentiation of SOD1 levels after transient ischemia in rabbits thus preventing spinal cord injury.

SYMPTOMS: Symptoms of exposure to this compound may include irritation of the skin, eyes and mucous membranes. ACUTE/CHRONIC HAZARDS: This compound may cause skin and eye irritation. It is moderately toxic by ingestion. When heated to decomposition it emits toxic fumes. (NTP, 1992)

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop. SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. If symptoms such as redness or irritation develop, IMMEDIATELY call a physician and be prepared to transport the victim to a hospital for treatment. INHALATION: IMMEDIATELY leave the contaminated area; take deep breaths of fresh air. If symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop, call a physician and be prepared to transport the victim to a hospital. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be used; if not available, use a level of protection greater than or equal to that advised under Protective Clothing. INGESTION: DO NOT INDUCE VOMITING. If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Be prepared to transport the victim to a hospital if advised by a physician. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital. (NTP, 1992)

1 Phenyl 3 methyl 5 pyrazolone

Synthetic dye and pigment manufacturing|3H-Pyrazol-3-one, 2,4-dihydro-5-methyl-2-phenyl-: ACTIVE

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