Edaravone Injection (Radicava)

Number: 0918

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses edaravone injection (Radicava) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification:

Precertification of edaravone (Radicava) is required of all Aetna participating providers and members in applicable plan designs. For precertification of edaravone (Radicava), call (866) 752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.

Note: Site of Care Utilization Management Policy applies.  For information on site of service for edaravone, see Utilization Management Policy on Site of Care for Specialty Drug Infusions.

1. Prescriber Specialties

   This medication must be prescribed by or in consultation with a neurologist, neuromuscular specialist or physician specializing in the treatment of amyotrophic lateral sclerosis (ALS).

2. Criteria for Initial Approval

   Aetna considers edaravone (Radicava) medically necessary for the treatment of amyotrophic lateral sclerosis (ALS) when all the following criteria are met:

   1. Diagnosis of definite or probable ALS (e.g., medical history and diagnostic testing including, nerve conduction studies, imaging and laboratory values to support the diagnosis); and
   2. Member has scores of at least 2 points on all 12 areas of the revised ALS Functional Rating Scale (ALSFRS-R); and
   3. Continuous use of ventilatory support during the day and night is not required (noninvasive or invasive).

   Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).  

3. Continuation of Therapy

   Aetna considers continuation of edaravone (Radicava) therapy medically necessary when the following criteria are met:

   1. Diagnosis of definite or probable ALS; and
   2. There is a clinical benefit from Radicava therapy; and
   3. Invasive ventilation is not required.

Note: This policy addresses edaravone injection. Refer to pharmacy CPB for oral edaravone (Radicava ORS) and the pharmacy benefit plan for sodium phenylbutyrate/taurursodiol (Relyvrio).

Dosage and Administration

Edaravone is available as Radicava and supplied for injection as 30 mg/100 mL in a single-dose polypropylene bag. 

The recommended dosage of edaravone (Radicava) is 60 mg administered as an intravenous (IV) infusion over 60 minutes as follows:

• Initial treatment cycle: daily dosing for 14 days followed by a 14-day drug-free period;
• Subsequent treatment cycles: daily dosing for 10 days out of 14-day periods, followed by 14-day drug-free periods.

Source: MT Pharma America, 2022

Experimental and Investigational

Aetna considers edaravone experimental and investigational for the following (not an all-inclusive list):

• Acute encephalopathy
• Acute ischemic stroke
• Acute kidney injury
• Acute lung injury
• Acute pancreatitis-induced pancreatic and intestinal injury
• Alzheimer's disease
• Asthma
• Autoimmune thyroiditis
• Brain radionecrosis
• Choroidal neovascularization
• Cisplatin-induced chronic renal injury
• Doxorubicin-induced cardiotoxicity / nephrotoxicity
• Intra-cerebral hemorrhage
• Multiple sclerosis
• Myocardial damage after ischemia and re-perfusion
• Nephropathy
• Osteoarthritis
• Parkinson disease
• Post-stroke depression
• Rheumatoid arthritis
• Seizure
• Stroke
• Subarachnoid hemorrhage
• Traumatic brain injury
• Wound healing.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :
Other CPT codes related to the CPB:
96365	Intravenous infusion, for therapy, prophylaxis, or diagnosis(specify substance or drug); initial, up to 1 hour
HCPCS codes covered if selection criteria are met:
J1301	Injection, edaravone, 1 mg
ICD-10 codes covered if selection criteria are met:
G12.21	Amyotrophic lateral sclerosis
ICD-10 codes not covered for indications listed in the CPB:
E06.3	Autoimmune thyroiditis
F06.31	Mood disorder due to known physiological condition with depressive features
G20	Parkinson's disease
G30.0 - G30.9	Alzheimer's disease
G35	Multiple sclerosis
G40.001 - G40.919	Epilepsy and recurrent seizures
G93.40	Encephalopathy, unspecified
H31.8	Other specified disorders of choroid [choroidal neovascularization]
I25.5	Ischemic cardiomyopathy [myocardial damage after ischemia and re-perfusion]
I60.00 - I60.9	Nontraumatic subarachnoid hemorrhage
I61.0 - I61.9	Nontraumatic intracerebral hemorrhage
I63.00 - I63.9	Cerebral infarction
I69.398	Other sequelae of cerebral infarction
J45.20 - J45.998	Asthma
K85.00 - K85.92	Acute pancreatitis
M05.00 - M06.9	Rheumatoid arthritis
M15.0 - M19.93	Osteoarthritis
N00.0 - N08	Glomerular diseases [nephropathy]
N10 - N16	Renal tubulo-interstitial diseases [nephropathy]
N14.1	Nephropathy induced by other drugs, medicaments and biological substances [cisplatin-induced chronic renal injury] [doxorubicin-induced nephrotoxicity]
N17.0 - N19	Acute kidney failure and chronic kidney disease [nephropathy]
N25.0 - N29	Other disorders of kidney and ureter [nephropathy]
R56.00 - R56.9	Convulsions, not elsewhere classified
Numerous Options	Wound healing
S06.340A - S06.369S	Traumatic hemorrhage of cerebrum
S06.9x0A - S06.9x9S	TBI (traumatic brain injury)
S27.301A - S27.399S	Other and unspecified injuries of lung
S36.200A - S36.299S	Injury of pancreas
S36.500A - S36.599S	Injury of colon
T46.991A - T46.996S	Poisoning by, adverse effect of and underdosing of other agents primarily affecting the cardiovascular system [doxorubicin-induced cardiotoxicity]
T66.xxxA - T66.xxxS	Radiation sickness [brain radionecrosis]

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Radicava is indicated for the treatment of amyotrophic lateral sclerosis (ALS).

Edaravone is available as Radicava (Mitsubishi Tanabe Pharma Corporation). The mechanism by which edaravone exerts its therapeutic effect in patients with ALS is unknown.

Radicava carries labeled warnings and precautions for hypersensitivity reactions and sulfite allergic reactions. The most common adverse reaction (at least 10% and greater than placebo) include contusion, gait disturbance, and headache (MT Pharma America, 2022).

Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig’s disease, is a progressive, neurodegenerative disease that destroys motor neurons.  Patients with ALS gradually lose their ability to control voluntary muscles that are involved in breathing, chewing, talking, and walking; resulting in paralysis and finally death.  The Centers for Disease Control and Prevention estimates that approximately 12,000 to 15,000 Americans have ALS; and the majority of patients with ALS die from respiratory failure, usually within 3 to 5 years from when the symptoms first commence.  Riluzole is the only currently approved mildly effective treatment; it received marketing authorization in the U.S. in 1995 in the U.S. and in Europe in 1996.  In the years that followed, over 60 molecules have been investigated as a possible treatment for ALS.  Despite significant research efforts, the majority of clinical studies have failed to demonstrate clinical effectiveness.  In the past year, oral masitinib and intravenous (IV) edaravone (a synthetic-free radical scavenger) have emerged as promising new therapeutic agent for the treatment of ALS (Petrov et al, 2017). 

In a double-blind, parallel-group, placebo-controlled study, Abe and colleagues (2014) examined the safety and effectiveness of edaravone in patients with ALS.  These researchers conducted a 36-week clinical trial, consisting of 12-week pre-observation period followed by 24-week treatment period.  Patients received placebo (n = 104) or edaravone (n= 102) IV infusion over 60 minutes for the first 14 days in cycle 1, and for 10 of the first 14 days during cycles 2 to 6.  The efficacy primary end-point was changes in the revised ALS functional rating scale (ALSFRS-R) scores during the 24-week treatment period.  Changes in ALSFRS-R during the 24-week treatment period were -6.35 ± 0.84 in the placebo group and -5.70 ± 0.85 in the edaravone group, with a difference of 0.65 ± 0.78 (p = 0.411).  Adverse events (AEs) amounted to 88.5 % (92/104) in the placebo group and 89.2 % (91/102) in the edaravone group.  The authors concluded that the reduction of ALSFRS-R was smaller in the edaravone group than in the placebo group.  Levels and frequencies of reported AEs were similar in the 2 groups.  These investigators stated that although the elimination of free radicals by means of edaravone to inhibit the degeneration of motor neurons appeared to be a promising new strategy for the treatment of ALS, this study did not demonstrate effectiveness of edaravone in delaying the progression of ALS.  They noted that while the primary end-point was not attained, they considered that these findings were helpful to identify the patient population in which edaravone could be expected to show effectiveness.  On the basis of this information, these researchers designed a phase-III clinical trial.

Noto and associates (2016) stated that therapies that inhibit neuronal hyper-excitability may be effective in arresting the progression of ALS.  These investigators searched Medline and ClinicalTrials.gov and selected randomized controlled trials (RCTs) that covered neuro-protective therapy.  Riluzole has been established to reduce neuronal hyper-excitability.  More recently, initial studies of Na(+) channel blockers (mexiletine and flecainide) have been investigated.  Separately, a trial of a K(+) channel activator (retigabine) is underway, while edaravone is currently being considered for licensing by drug approval agencies based on a hypothesis that the elimination of free radicals may lead to protection of motor neurons.  The authors concluded that initial clinical trials with Na(+) channel blockers have not yet established effectiveness in ALS.  Currently, retigabine is under evaluation as a potential therapy; and edaravone has recently been approved as a new therapeutic option for ALS in Japan.

Sawada (2017) noted that although the pathogenesis remains unresolved, oxidative stress is known to play a pivotal role.  Edaravone works in the central nervous system as a potent scavenger of oxygen radicals.  In ALS mouse models, edaravone suppresses motor functional decline and nitration of tyrosine residues in the cerebro-spinal fluid (CSF).  These investigators reviewed 3 clinical trials: 1 phase-II open-label trial and 2 phase-III RCTs.  In all trials, the primary outcome measure was the changes in scores on the ALSFRS-R to evaluate motor function of patients.  The phase-II, open-label trial suggested that edaravone is safe and effective in ALS, markedly reducing 3-nitrotyrosine levels in the CSF.  One of the 2 RCTs showed beneficial effects in ALSFRS-R, although the differences were not significant.  The last trial demonstrated that edaravone provided significant effectiveness in ALSFRS-R scores over 24 weeks where concomitant use of riluzole was permitted.  Eligibility was restricted to patients with a relatively short disease duration and preserved vital capacity.  Therefore, combination therapy with edaravone and riluzole should be considered earlier.

Martinez and colleagues (2017) reviewed all the ALS ongoing clinical trials (up to November 2016).  They described them in a comprehensive way and grouped them in the following sections: biomarkers, biological therapies, cell therapy, drug repurposing and new drugs.  Despite multiple obstacles that explain the absence of effective drugs for the treatment of ALS, joint efforts among patient's associations, public and private sectors have fueled innovative research in this field, resulting in several compounds that are in the late stages of clinical trials.  The authors noted that edaravone was recently approved in Japan and is pending in the U.S.

On May 5, 2017, the Food and Drug Administration (FDA) approved edaravone (Radicava) for the treatment of patients with ALS.  The effectiveness of edaravone for the treatment of ALS was demonstrated in a 6-month, randomized, placebo-controlled, double-blind study conducted in Japanese patients with ALS who were living independently and met the following criteria at screening:

• Functionality retained most activities of daily living (defined as scores of 2 points or better on each individual item of the ALS Functional Rating Scale – Revised [ALSFRS-R; described below])
• Normal respiratory function (defined as percent-predicted forced vital capacity values of [%FVC] greater than or equal to  80 %)
• Definite or Probable ALS based on El Escorial revised criteria
• Disease duration of 2 years or less.

The study enrolled 69 patients in the Radicava arm and 68 in the placebo arm.  Baseline characteristics were similar between these groups, with over 90 % of patients in each group being treated with riluzole.  Radicava was administered as an IV infusion of 60 mg given over a 60-minute period according to the following schedule:

• An initial treatment cycle with daily dosing for 14 days, followed by a 14-day drug-free period (Cycle 1)
• Subsequent treatment cycles with daily dosing for 10 days out of 14-day periods, followed by 14-day drug-free periods (Cycles 2 to 6).

The primary efficacy end-point was a comparison of the change between treatment arms in the ALSFRS-R total scores from baseline to Week 24.  The ALSFRS-R scale consists of 12 questions that evaluate the fine motor, gross motor, bulbar, and respiratory function of patients with ALS (speech, salivation, swallowing, handwriting, cutting food, dressing/hygiene, turning in bed, walking, climbing stairs, dyspnea, orthopnea, and respiratory insufficiency).  Each item is scored from 0 to 4, with higher scores representing greater functional ability.  The decline in ALSFRS-R scores from baseline was significantly less in the Radicava-treated patients as compared to placebo.  The most common AEs reported by subjects receiving edaravone were 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 Radicava orphan drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

Mitsubishi Tanabe Pharma Corporation’s Package Insert on “Radicut Injection” (2015) lists 3 clinical studies regarding the use of edaravone injection for the treatment of ALS.

First Confirmatory Study

When edaravone or placebo was intravenously administered at 60 mg in patients with ALS (warranting “Definite”, “Probable” or “Probable-laboratory-supported” according to the El Escorial and the revised Airlie House diagnostic criteria for ALS, rated as grade 1 or 2 in Japan ALS severity classification, having %FVC not less than 70 %, and illness duration within 3 years) in 6 cycles of treatmentFootnote1*, mean changes from baseline in the ALSFRS-R as primary end-point were not significantly different between the edaravone-treated and placebo-treated groups (-5.70 ± 0.85 versus -6.35 ± 0.84; p = 0.411).

Second Confirmatory Study

When edaravone or placebo was intravenously administered at 60 mg in patients with ALS (warranting “Definite” or “Probable” according to the El Escorial and the revised Airlie House diagnostic criteria for ALS, rated as grade 1 or 2 in Japan ALS severity classification, having %FVC not less than 80 % and illness duration within 2 years) in 6 cycles of treatmentFootnote1*, there were significant differences in mean changes from baseline in the ALSFRS-R as primary end-point between the edaravone-treated and placebo-treated groups (-5.01 ± 0.64 versus -7.50 ± 0.66; p = 0.0013).

A Placebo-Controlled Double-Blind Comparative Study in Patients with Japan ALS Severity Classification of Grade 3

When edaravone or placebo was intravenously administered at 60 mg in patients with Japan ALS severity classification of grade 3 ALS in 6 cycles of treatmentFootnote1*, mean changes from baseline in the ALSFRS-R as primary end-point were significantly different between the edaravone-treated and placebo-treated groups (-6.52 ± 1.78 versus -6.00 ± 1.83; p = 0.8347).

Footnote1* Once-daily consecutive administration for 14 days and subsequent cessation for 14 days of this product were combined in the 1st cycle of treatment.  After completion of the 1st cycle, this product was administered for 10 of 14 days followed by cessation for 14 days from the 2nd to 6th cycle (the treatment cycle was repeated 5 times).

Edaravone is also being investigated in the treatment of various conditions/diseases (e.g., acute ischemic stroke, choroidal neovascularization, intra-cerebral hemorrhage, myocardial damage after ischemia and re-perfusion, nephropathy, and osteoarthritis); however, its effectiveness for these indications has not been established.

Other Indications

Acute Encephalopathy

Hayakawa and colleagues (2020) noted that treatments for pediatric acute encephalopathy are largely empiric with limited evidence to support.  These investigators examined recent trends in clinical practice patterns for pediatric acute encephalopathy at a national level.  Discharge records were extracted for children with acute encephalopathy from 2010 to 2015 using a national inpatient database in Japan.  They ascertained the secular trends in medications, diagnostic and therapeutic procedures, healthcare costs, in-hospital mortality, and length of hospital stays (LOS), using mixed effect linear or logistic regression models.  These researchers also ascertained variations and clustering of the practice patterns across different hospitals using hierarchical cluster analyses.  A total of 4692 eligible inpatients were identified, these investigators observed increasing trends in hospitalization costs, corticosteroid and edaravone use and a decreasing trend in LOS.  Despite changes in treatments, the rates of home respiratory support and in-hospital mortality were constant during the study period.  Hierarchical cluster analyses showed that 6 hospital groups showed largely different therapeutic strategies to the same disease regardless of mortality rates.  Hospitals with more intensive treatment practices were likely to have higher mortality, while hospitals with less intensive treatment practices were likely to have the lower mortality.  However, hospitals in one group (group 1) had less intensive treatment practice even though they had the highest mortality.  The authors provided novel insights into the recent trends in treatments for pediatric acute encephalopathy; therapeutic strategies varied among hospitals, suggesting the importance of pursuing evidence-based therapeutic strategy and promoting standardized practices to pediatric acute encephalopathy.

Furthermore, UpToDate reviews on “Acute toxic-metabolic encephalopathy in children” (Chiriboga, 2019) and “Clinical features, diagnosis, and treatment of neonatal encephalopathy” (Wu, 2019) do not mention edaravone as a therapeutic option.

Acute Kidney Injury

In a rat resuscitation model, Fu and colleagues (2020) examined if edaravone (5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol3-one, EDR) can ameliorate renal warm ischemia-reperfusion injury (IRI) by modulating endoplasmic reticulum stress (ERS) and its down-stream effector after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR).  Rats (n = 10) experienced anesthesia and intubation followed by no CA inducement were defined as the sham group.  Trans-esophageal alternating current stimulation was employed to establish 8-min of CA followed by conventional CPR for a resuscitation model.  The rats with successful restoration of spontaneous circulation (ROSC) randomly received EDR (3 mg/kg, EDR group, n = 10) or equal volume normal saline solution (the NS group, n = 10).  At 24 hours after ROSC, serum creatinine (SCR), blood urea nitrogen (BUN) levels, and cystatin-C (Cys-C) levels were determined and the protein level of glucose-regulated protein (GRP78), C/EBP homologous protein (CHOP), extracellular signal-regulated kinase (ERK), phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2), Bax/Bcl-2, and caspase-3 were detected by Western blot method.  At 24 hours after ROSC, SCR, BUN and Cys-C were obviously increased and the proteins expression, including GRP78, CHOP and p-ERK1/2, cleaved-caspase 3 Bax/Bcl-2 ratio, were significantly up-regulated in the NS group compared with the sham group (p < 0.05).  The remarkable improvement of these adverse outcomes was observed in the EDR group (p < 0.05).  The authors concluded that EDR ameliorated renal warm IRI by down-regulating ERS and its down-stream effectors in a rat AKI model evoked by CA/CPR.  These data may provide evidence for future therapeutic benefits of EDR against acute kidney injury (AKI) induced by CA/CPR.

Acute Lung Injury

Kassab and colleagues (2020) stated that EDR is a potent free radical scavenger that has a promising role in combating many acute lung injuries.  Ischemia/reperfusion (i/R) process is a serious condition that may lead to multiple-organ dysfunctions.  These investigators examined the novel mechanisms underlying I/R-induced lung injury and assessed the protective role of EDR.  A total of 30 adult male rats were divided into 3 experimental groups: operated with no ischemia (sham-group), I/R group, and EDR-I/R group.  Hind-limb ischemia was carried out by clamping the femoral artery.  After 2 hours of ischemia for the hind-limb, the rat underwent 24-hour of reperfusion.  Rats in the EDR-I/R group received EDR (3 mg/kg), 30 mins before induction of ischemia.  At the end of the I/R trial, specimens from the lungs were processed for histological, immunohistochemical, enzyme assay, and RT-qPCR studies.  Specimens from I/R group showed focal disruption of the alveolar architecture.  Extensive mononuclear cellular infiltration particularly with neutrophils and dilated congested blood capillaries were observed.  A significant increase in inducible nitric oxide synthase (iNOS), nuclear factor-κB (NFκB), and cyclooxygenase-2 (COX-2) immunoreaction was detected and confirmed by RT-qPCR.  Ultra-structural examination showed red blood cells (RBCs) and fluid inside alveoli, cellular infiltration, and vacuolations of the inter-alveolar septum.  In contrast, minimal changes were observed in rats that received EDR before the onset of the ischemia.  The authors concluded that EDR exerted a potent protective effect against lung injury induced by a hind-limb I/R in rats through its antioxidant and anti-inflammatory activities.

Acute Pancreatitis-Induced Pancreatic and Intestinal Injury

Wang and Lin (2020) noted that acute pancreatitis (AP) is a type of acute surgical abdominal disease in the world.  It causes intestinal damage with subsequent bacterial migration, endotoxemia and secondary pancreatic infections.  These investigators examined if EDR could reduce pancreatic and intestinal injury after AP in mice.  This was demonstrated by a reduction in histological score, apoptosis, interleukin (IL)-6, IL-1β and tumor necrosis factor-alpha (TNF-α), along with obstructing activation of Toll-like receptor 4 (TLR4) and NFκB.  The authors concluded that the findings of this study suggested that EDR exerted its protective effects against pancreatic and intestinal injury after AP via regulation of the TLR4/NFκB pathway.  These researchers stated that the findings provided the basis for EDR to treat AP-induced pancreatic and intestinal injury, even might develop as a potential therapy for other inflammatory diseases.

Acute Stroke (e.g., Acute Ischemic Stroke and Intra-Cerebral Hemorrhage)

Yang and colleagues (2015) evaluated the effectiveness of edaravone for acute stroke including acute ischemic stroke (AIS) and intra-cerebral hemorrhage (ICH).  These investigators identified RCTs with comprehensive searches and performed systematic reviews according to the Cochrane methods of systematical reviews.  Edaravone can reduce the rate of death or long-term disability significantly for AIS (relative risk [RR] = 0.65; 95 % confidence intervals [CI]: 0.48 to 0.89, p = 0.007).  However, sensitivity analysis yielded a different result.  Edaravone can also improve the short-term neurological impairment of AIS (mean difference (MD) = 7.09; 95 % CI: 5.12 to 9.05, p < 0.00001), and ICH (MD = -4.32; 95 % CI: -5.35 to -3.29, p < 0.00001).  The authors concluded that edaravone is beneficial in improving neurological impairment resulting from AIS and ICH.  However, there is currently insufficient evidence that edaravone reduces death or long-term disability for AIS and ICH.

Bao and associates (2018) stated that cerebral vasculature and neuronal networks will be largely destroyed due to the oxidative damage by over-produced reactive oxygen species (ROS) during a stroke, accompanied by the symptoms of ischemic injury and blood-brain barrier (BBB) disruption.  Ceria nanoparticles, acting as an effective and recyclable ROS scavenger, have been shown to be highly effective in neuro-protection.  However, the brain access of nanoparticles can only be achieved by targeting the damaged area of BBB, leading to the disrupted BBB being unprotected and to turbulence of the micro-environment in the brain.  Nevertheless, the integrity of the BBB will cause very limited accumulation of therapeutic nanoparticles in brain lesions.  This dilemma is a great challenge in the development of efficient stroke nano-therapeutics.  These researchers developed an effective stroke treatment agent based on monodisperse ceria nanoparticles, which were loaded with edaravone and modified with Angiopep-2 and poly(ethylene glycol) on their surface (E-A/P-CeO2).  The as-designed E-A/P-CeO2 features highly effective BBB crossing via receptor-mediated transcytosis to access brain tissues and synergistic elimination of ROS by both the loaded edaravone and ceria nanoparticles.  As a result, the E-A/P-CeO2 with low toxicity and excellent hemo-/histo-compatibility can be used to effectively treat strokes due to great intra-cephalic uptake enhancement and, in the meantime, effectively protect the BBB, holding great potentials in stroke therapy with much mitigated harmful side effects and sequelae.

Oguru and co-workers (2018) noted that argatroban is a thrombin inhibitor agent for acute non-cardioembolic ischemic stroke in Japan.  These researchers studied the prognosis in patients with acute stroke treated by argatroban in comparison with the control group with ozagrel.  A total of 513 patients with acute non-cardioembolic ischemic stroke were enrolled retrospectively from the authors’ hospital database.  Of all patients with stroke, 353 were administered with argatroban.  The other 160 control patients were administered with ozagrel.  Patients were examined as to their stroke types, the neurological severity according to the National Institutes of Health Stroke Scale (NIHSS), and clinical outcomes on discharge were determined according to the modified Rankin Scale (mRS).  A total of 353 patients with acute non-cardioembolic stroke, including 138 with lacunar infarction (LIs) and 215 with athero-thrombotic infarction (ATI) showed functional recovery by argatroban, but the effectiveness of argatroban was not superior to ozagrel therapy defined by the control group.  A total of 255 patients with ATI who were treated with both argatroban and ozagrel showed improvement by 1 point.  These investigators could not find any significant difference between argatroban and ozagrel in the 2 stroke subtypes, LI and ATI.  They also found that combination therapy of argatroban and edaravone was not superior to argatroban monotherapy in clinical outcome.  The authors concluded that argatroban therapy was not superior to control with ozagrel therapy in acute non-cardioembolic ischemic stroke, including LI and ATI, regardless of the use of edaravone.

Naganuma and associates (2018) stated that uric acid (UA), an anti-oxidant with neuroprotective effects, favorably affects stroke outcome.  However, the effect has not been examined in patients treated with edaravone, a frequently used free radical scavenger.  These investigators examined if the use of edaravone affected the relationship between UA levels and outcome in acute ischemic stroke (AIS).  They retrospectively evaluated 1,114 consecutive ischemic stroke patients with pre-morbid mRS scores of less than 2 admitted within 24 hours of onset (mean age of 74 years; median UA levels, 333 μmol/L).  These researchers divided the patients into 2 groups using the median UA value as a cut-off, a low UA group (less than or equal to 333 μmol/L; n = 566) and a high UA group (greater than 333 μmol/L; n = 548), and compared their clinical characteristics and favorable outcomes (mRS less than 2) at 90 days.  These researchers examined the associations between UA levels and 90-day stroke outcome in patients with and without edaravone treatment.  The high UA group had a higher proportion of men, hypertension, atrial fibrillation, and cardio-embolic stroke than the low UA group.  The high UA group also had a higher proportion of patients with mRS of less than 2 at 90 days (61.5 versus 54.1 %, p = 0.013), but the significance was diminished in multi-variate analysis (OR 1.30, 95 % CI: 0.94 to 1.71).  In subgroup analysis, the high UA group without edaravone exhibited a higher proportion of patients with mRS of less than 2 at 90 days than the low UA group (OR 2.87, 95 % CI: 1.20 to 7.16).  The high UA group with edaravone did not exhibit this difference.  The authors concluded that in AIS, the favorable association between high UA levels and outcome at 90 days was not evident in patients treated with edaravone.

Kobayashi and colleagues (2019) examined the effect of edaravone on neurological symptoms in patients with ischemic stroke stratified by stroke subtype.  Subjects were 61,048 patients aged 18 years or older who were hospitalized for less than or equal to 14 days after onset of an AIS and were registered in the Japan Stroke Data Bank, a hospital-based multi-center stroke registration database, between June 2001 and July 2013.  Patients were stratified according to ischemic stroke subtype (large-artery atherosclerosis, cardio-embolism, small-vessel occlusion, and cryptogenic/undetermined) and then divided into 2 groups (edaravone-treated and no edaravone).  Neurological symptoms were evaluated using the NIHSS.  The primary outcome was changed in neurological symptoms during the hospital stay (ΔNIHSS=NIHSS score at discharge-NIHSS score at admission).  Data were analyzed using multi-variate linear regression with inverse probability of treatment weighting after adjusting for the following confounding factors: age, gender, and systolic and diastolic blood pressure at the start of treatment, NIHSS score at admission, time from stroke onset to hospital admission, infarct size, co-morbidities, concomitant medication, clinical department, history of smoking, alcohol consumption, and history of stroke.  After adjusting for potential confounders, the improvement in NIHSS score from admission to discharge was greater in the edaravone-treated group than in the no edaravone group for all ischemic stroke subtypes (mean [95 % CI] difference in ΔNIHSS: -0.46 [-0.75 to -0.16] for large-artery atherosclerosis, -0.64 [-1.09 to -0.2] for cardio-embolism, and -0.25 [-0.4 to -0.09] for small-vessel occlusion).  The authors concluded that for any ischemic stroke subtype, edaravone use (compared with no use) was associated with a greater improvement in neurological symptoms, although the difference was small (less than 1 point NIHSS) and of limited clinical significance.

Alzheimer's Disease

Parikh and associates (2018) stated that Alzheimer's disease (AD) is a devastating neurodegenerative disorder that lacks any disease-modifying drug for the prevention and treatment.  Edaravone (EDR), an approved free radical scavenger, has proven to have potential against AD by targeting multiple key pathologies including amyloid-beta (Aβ), tau phosphorylation, oxidative stress, and neuro-inflammation.  To enable its oral use, novel edaravone formulation (NEF) was previously developed.  These researchers evaluated the safety and efficacy of NEF by using in-vitro/in-vivo disease model.  In-vitro therapeutic potential of NEF over EDR was studied against the cytotoxicity induced by copper metal ion, H2O2 and Aβ42 oligomer, and cellular uptake on SH-SY5Y695 amyloid-β precursor protein (APP) human neuroblastoma cell line.  For i- vivo safety and efficacy assessment, a total of 7 groups of APP/PS1 (5 treatment groups, 1 each as a basal and sham control) and 1 group of C57BL/6 mice as a positive control for behavior tests were used; 3 groups were orally treated for 3 months with NEF at an equivalent dose of EDR 46, 138, and 414 µmol/kg, whereas 1 group was supplied with each Donepezil (5.27 µM/kg) and Soluplus (amount present in NEF of 414 µmol/kg dose of EDR).  Behavior tests were conducted to assess motor function (open-field), anxiety-related behavior (open-field), and cognitive function (novel objective recognition test, Y-maze, and Morris water maze).  For the safety assessment, general behavior, adverse effects, and mortality were recorded during the treatment period.  Moreover, biochemical, hematological, and morphological parameters were determined.  Compared to EDR, NEF showed superior cellular uptake and neuroprotective effect in SH-SY5Y695 APP cell line.  Furthermore, it showed nontoxicity of NEF up to 414 µM/kg dose of EDR and its potential to reverse AD-like behavior deficits of APP/PS1 mice in a dose-dependent manner.  The authors concluded that these findings indicated that oral delivery of NEF holds promise as a safe and effective therapeutic agent for AD.

Asthma

Pan and colleagues (2020) noted that asthma is a chronic disease that threatens public health worldwide.  Multiple studies have shown that oxidative stress plays an important role in the pathogenesis of asthma.  Edaravone has been shown to have a protective effect against lung injury due to its ability to eliminate reactive oxygen species.  These investigators examined the effect of EDR on asthma and the mechanism underlying its actions.  An experimental asthma model was induced in mice, before they were treated with different doses of EDR.  Measurements of airway responsiveness to methacholine (Mch), cell counts and cytokine levels in broncho-alveolar lavage fluid (BALF) and of the oxidative products and antioxidant enzymes in lung tissue were taken in these asthma model mice and compared with control mice.  Protein levels of kelch-like ECH-associated protein-1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) and hemeoxygenase-1 (HO-1) were determined in the lung tissue of normal mice and Nrf2 and HO-1-deficient mice subject to the asthma model to examine the mechanisms underlying EDR action.  The results indicated that EDR effectively reduced airway responsiveness to Mch.  The total number of cells and the numbers of eosinophils, lymphocytes and neutrophils in BALF of asthma model mice were also significantly reduced by EDR treatment when compared with normal saline treatment.  EDR treatment significantly alleviated peri-vascular edema, peri-bronchial inflammation and macrophage infiltration in the alveolar space and decreased the levels of inflammatory cytokines released in BALF compared with control.  EDR also significantly reduced the levels of oxidative stress markers in BALF and restored the levels of antioxidative enzyme, superoxide dismutase, when compared with control.  The Keap1/Nrf2 ratio was significantly decreased with EDR compared with control due to an increase in Nrf2 and a decrease in Keap1 expression.  HO-1 expression was increased by EDR.  The airway responsiveness of Nrf2-/- mice or HO-1-/- mice to Mch was significantly higher compared with normal mice treated with EDR.  The authors concluded that the findings of the this study showed that EDR exerted anti-inflammatory and antioxidative effects, which suggested a potential use for EDR in reduction of asthma severity.  The activated Keap1/Nrf2 pathway and HO-1 may be involved in the anti-asthmatic effect of EDR.

Autoimmune Thyroiditis

Li and co-workers (2018) noted that autoimmune thyroiditis is among the most prevalent of all the auto-immunities in population.  It is characterized as both cellular immune responses with T, B cells infiltrating to the thyroid gland followed by hypothyroidism as a result of destruction of the thyroid follicles and fibrous replacement of the parenchymal tissue, as well as immune response for TPO and Tg-antibody production.  Experimental autoimmune thyroiditis (EAT) has been proven to be an ideal model to study autoimmune thyroiditis.  In the present study, these researchers induced an EAT model in rats and examined the effect of edaravone on EAT severity and explored the mechanism.  The results showed that edaravone reduced the severity score of thyroiditis dose-dependently and the levels of serum TPOAb, TgAb, T3 and T4.  Edaravone significantly decreased the mRNA level of IL-17, but increased the mRNA level of IL-10, IL-4, TNF-α and IFN-γ.  EAT model significantly induced oxidative stress, which was inhibited by the treatment of 10 mg/kg, 20 mg/kg or 40 mg/kg of edaravone.  The EAT model significantly increased the Akt and STAT3 phosphorylation, but when rats were treated with 20 mg/kg or 40 mg/kg edaravone, they were significantly inhibited.  The HO-1 expression was greatly increased by 20 mg/kg or 40 mg/kg edaravone.  The PI3K inhibitor LY294002, Akt inhibitor triciribine or STAT3 inhibitor WP1066 all significantly decreased the severity score of thyroiditis in the EAT model group, while the HO-1 inhibitor ZnPP-IX increased the severity score of thyroiditis.  The authors concluded that these findings confirmed the involvement of ROS and HO-1-dependent STAT3/PI3K/Akt pathway in the process of Hashimoto's thyroiditis and suggested the potential usage of edaravone in the therapy of it.

Brain Radionecrosis

Chung and colleagues (2018) stated that brain radionecrosis can occur following high-dose radiotherapy to brain tissue and can have a significant impact on a person's quality of life (QOL) and function.  The underlying pathophysiological mechanism remains unclear for this condition, which makes establishing effective treatments challenging.  In a Cochrane review, these investigators evaluated the effectiveness of interventions used for the treatment of brain radionecrosis in adults over 18 years old.  In October 2017, these researchers searched the Cochrane Register of Controlled Trials (CENTRAL), Medline, Embase and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) for eligible studies.  They also searched unpublished data through Physicians Data Query, www.controlled-trials.com/rct, www.clinicaltrials.gov, and www.cancer.gov/clinicaltrials for ongoing trials and hand-searched relevant conference material.  These investigators included RCTs of any intervention directed to treat brain radionecrosis in adults over 18 years old previously treated with radiation therapy to the brain.  These investigators anticipated a limited number of RCTs, so they also planned to include all comparative prospective intervention trials and quasi-randomized trials of interventions for brain radionecrosis in adults as long as these studies had a comparison group that reflects the standard of care (i.e., placebo or corticosteroids).  Selection bias was likely to be an issue in all the included non-randomized studies therefore results were interpreted with caution.  Two review authors independently extracted data from selected studies and completed a “risk of bias” assessment.  For dichotomous outcomes, the odds ratio (OR) for the outcome of interest was reported.  For continuous outcomes, treatment effect was reported as MD between treatment arms with 95 % CIs.  Two RCTs and 1 prospective non-randomized study evaluating pharmacological interventions met the inclusion criteria for this review.  As each study evaluated a different drug or intervention using different end-points, a meta-analysis was not possible.  There were no trials of non-pharmacological interventions that met the inclusion criteria.  A very small randomized, double-blind, placebo-controlled trial of bevacizumab versus placebo reported that 100 % (7/7) of participants on bevacizumab had reduction in brain edema by at least 25 % and reduction in post-gadolinium enhancement, whereas all those receiving placebo had clinical or radiological worsening or both.  This was an encouraging finding but due to the small sample size these researchers did not report a relative effect.  The authors also failed to provide adequate details regarding the randomization and blinding procedures.  Therefore, the certainty of this evidence was low and a larger RCT adhering to reporting standards is needed.  An open-label RCT demonstrated a greater reduction in brain edema (T2 hyper-intensity) in the edaravone plus corticosteroid group than in the corticosteroid alone group (MD was 3.03 (95 % CI: 0.14 to 5.92; low-certainty evidence due to high risk of bias and imprecision); although the result approached borderline significance, there was no evidence of any important difference in the reduction in post-gadolinium enhancement between arms (MD = 0.47, 95 % CI: - 0.80 to 1.74; low-certainty evidence due to high risk of bias and imprecision).  In the RCT of bevacizumab versus placebo, all 7 participants receiving bevacizumab were reported to have neurological improvement, whereas 5 of 7 participants on placebo had neurological worsening (very low-certainty evidence due to small sample size and concerns over validity of analyses).  While no AEs were noted with placebo, 3 severe AEs were noted with bevacizumab, which included aspiration pneumonia, pulmonary embolus and superior sagittal sinus thrombosis.  In the RCT of corticosteroids with or without edaravone, the participants who received the combination treatment were noted to have significantly greater clinical improvement than corticosteroids alone based on LENT/SOMA scale (OR = 2.51, 95 % CI: 1.26 to 5.01; low-certainty evidence due to open-label design).  No differences in treatment toxicities were observed between arms.  One included prospective non-randomized study of alpha-tocopherol (vitamin E) versus no active treatment was found but it did not include any radiological assessment.  As only 1 included study was a double-blinded RCT, the other studies were prone to selection and detection biases.  None of the included studies reported QOL outcomes or adequately reported details about corticosteroid requirements.  A limited number of prospective studies were identified but subsequently excluded as these studies had a limited number of participants evaluating different pharmacological interventions using variable end-points.  The authors concluded that there is a lack of good certainty evidence to help quantify the risks and benefits of interventions for the treatment of brain radionecrosis after radiotherapy or radiosurgery.  In an RCT of 14 patients, bevacizumab showed radiological response that was associated with minimal improvement in cognition or symptom severity.  Although it was a randomized trial by design, the small sample size limited the quality of data.  A trial of edaravone plus corticosteroids versus corticosteroids alone reported greater reduction in the surrounding edema with combination treatment but no effect on the enhancing radionecrosis lesion.  Due to the open-label design and wide CIs in the results, the quality of this data was also low.  There was no evidence to support any non-pharmacological interventions for the treatment of radionecrosis.  They stated that further prospective randomized studies of pharmacological and non-pharmacological interventions are needed to generate stronger evidence; 2 ongoing RCTs, 1 evaluating bevacizumab and 1 evaluating hyperbaric oxygen therapy were identified.

Choroidal Neovascularization

Masuda and colleagues (2016) stated that choroidal neo-vascularization (CNV) is a main characteristic in exudative type of age-related macular degeneration.  These researchers examined the effects of edaravone on laser-induced CNV, which was induced by laser photocoagulation to the subretinal choroidal area of mice and common marmosets.  Edaravone was administered either intra-peritoneally (IP) twice-daily for 2 weeks or intravenously just once after laser photocoagulation.  The effects of edaravone on laser-induced CNV were evaluated by fundus fluorescein angiography, CNV area measurements, and the expression of 4-hydroxy-2-nonenal (4-HNE) modified proteins, a marker of oxidative stress.  Furthermore, the effects of edaravone on the production of hydrogen peroxide (H2O2)-induced reactive oxygen species (ROS) and vascular endothelial growth factor (VEGF)-induced cell proliferation were evaluated using human retinal pigment epithelium cells (ARPE-19) and human retinal microvascular endothelial cells, respectively.  Choroidal neo-vascularization areas in the edaravone-treated group were significantly smaller in mice and common marmosets.  The expression of 4-HNE modified proteins was up-regulated 3 hours after laser photocoagulation, and intravenously administered edaravone decreased it.  In in-vitro studies, edaravone inhibited H2O2-induced ROS production and VEGF-induced cell proliferation.  The authors concluded that these findings suggested that edaravone may protect against laser-induced CNV by inhibiting oxidative stress and endothelial cell proliferation.

Cisplatin-Induced Chronic Renal Injury

Koike and colleagues (2021) noted that cisplatin has been widely used as an anti-cancer agent for a wide range of tumors, however, it had nephrotoxicity that was mainly caused by oxidative stress.  Edaravone has reportedly been validated to have a protective effect against renal injury induced by reactive oxygen species.  However, most of these reports were against AKI, and few studies have examined the effect of chronic renal injury.  These investigators examined the effect of edaravone on cisplatin nephropathy in the chronic phase.  A total of 25 male Wistar rats were divided into 5 groups: control, cisplatin, cisplatin + edaravone 1 mg kg-1, cisplatin + edaravone 10 mg kg-1, and cisplatin + edaravone 100 mg kg-1.  Edaravone was administrated intra-peritoneally every other day for 5 weeks, starting 1 week before cisplatin administration (6 mg kg-1, i.p.).  As a result, proximal tubule injury, interstitial fibrosis, and mononuclear cell infiltration were ameliorated histologically in the group of rats treated with high edaravone dose.  In the cisplatin group, the number of α-SMA-, CD68-, and CD3-positive cells increased markedly compared with the control group, but these numbers were significantly decreased by higher doses of co-administered edaravone.  The authors concluded that while there was no clear mRNA expression variation in antioxidant enzymes, the apoptosis-promoting factors, caspase8, were markedly reduced in the high-dose edaravone co-administration group compared with the cisplatin group.  These researchers stated that these findings suggested that cisplatin-induced renal injury in the chronic phase was ameliorated by edaravone.

Doxorubicin-Induced Cardiotoxicity / Nephrotoxicity

Hassan and associates (2020) stated that doxorubicin (DOX) is a potential chemotherapeutic agent but its use is restricted due to cardiotoxicity.  Edaravone is a potent-free radical scavenging agent used in cerebral ischemia.  Benidipine is a triple calcium channel blocker (CCB).  These investigators examined the potential cardio-protective effects of EDR and benidipine alone and their combination against DOX-induced cardiotoxicity.  Cardiotoxicity was induced by administering 6 equal injections of DOX (2.5 mg/kg) on alternative days for 2 weeks.  DOX-treated group showed significant increase level of lipid peroxide and decrease in antioxidant status along with mitochondrial enzymatic activity.  Cardiotoxic effect of DOX illustrated by significantly increased the cardiac biomarkers such as cardiac troponin-I, brain natriuretic peptide (BNP), creatine kinase-MB in serum.  Significant increased activation of TNF-α, caspase-3 activity and myocardial infarct (MI) size in DOX-treated group.  Histopathological evaluation also confirmed the DOX-induced cardiotoxicity.  Pre-treated with EDR and benidipine significantly attenuated level of thiobarbituric acid reactive substance, endogenous enzymes, mitochondrial enzyme activities and cardiac biomarkers.  Furthermore, pre-treated group showed decreased activation of TNF-α, caspase-3 activity along with reduction in the MI size.  Histopathological evaluation also strengthened the above results.  The authors concluded that these findings suggested that the pre-treatment with EDR and benidipine have potential protective effect against DOX-induced cardiotoxicity.

Demir and colleagues (2020) examined the nephroprotective effect of EDR on DOX-induced nephrotoxicity.  A total of 28 Wistar male rats were used; they were separated into 4 groups (n = 7 for each group).  Group І (control) rats were treated with saline (4 ml/kg); in group ІІ (DOX), nephrotoxicity was induced by 3 doses of 18 mg/kg/i.p. DOX, at a 24-hour interval on the 12th, 13th, and 14th days; in group ІІІ (EDR), rats were treated with EDR (30 mg/kg/for 14 days), and in group ІV (EDR + DOX), rats were treated with EDR (30 mg/kg/for 14 days) and DOX were injected (18 mg/kg/for 3 days; at a 24-hour interval on the 12th, 13th, and 14th days).  On the 15th day of the experiment, technetium-99m-labeled dimercaptosuccinic acid ([99mTc]DMSA) uptake was obtained in both kidneys and biochemical parameters from serum and kidney tissue were measured.  DOX led to nephrotoxicity through elevation of serum BUN, creatinine and TNF-α, NO, and IL-6 in kidney tissue and decreased [99mTc]DMSA uptake level in the kidney when compared with control group (p < 0.01).  The authors concluded that pre-treatment EDR significantly decreased BUN and creatinine, also kidney tissue TNF-α, IL-6, NO, and increased [99mTc]DMSA uptake level compared with the DOX; EDR had a significant nephron-protective effect through the attenuation of oxidative stress and inflammatory markers during DOX-induced nephrotoxicity in rats.

Multiple Sclerosis

Agresti and colleagues (2020) stated that multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) leading to demyelination and neurodegeneration, with a complex and still to be clarified etiology.  Data coming from patients' samples and from animal models showed that oxidative status (OS) plays an important role in MS pathogenesis.  Over-production of reactive oxidative species by macrophages/microglia could bring about cellular injury and ensuing cell death by oxidizing cardinal cellular components.  Oxidized molecules are present in active MS lesions and are associated with neurodegeneration.  These researchers undertook a structured search of bibliographic databases for peer-reviewed research literature focusing on OS in MS.  The contents of the selected papers were described in the context of a conceptual framework.  A special emphasis was given to the results of the authors’ study in the field.  The results of their 3 recent studies were put in the context and discussed taking into account the literature on the topic.  Oxidative damage underpinned an imbalance shared by MS and neurodegenerative diseases such as AD and PD.  In people with clinically isolated syndrome (an early phase of MS) oxidative stress proved to contribute to disease pathophysiology and to provide biomarkers that may help predict disease evolution.  A drug screening platform based on multiple assays to test the re-myelinating potential of library of approved compounds showed 2 anti-oxidants, edaravone and 5-methyl-7-methoxyisoflavone, as active drugs.  Moreover, an analysis of “structure activity relationship” showed off-targets sites of these compounds that accounted for their re-myelinating activity, irrespective of their antioxidant action.  The authors concluded that edaravone emerged as a candidate to treat complex disease such as MS, where inflammation, oxidative stress and neurodegeneration contribute to disease progression, together or individually, in different phases and disease types.  Furthermore, approaches based on drug re-positioning appeared to maintain the promise of helping discover novel treatment for complex diseases, where molecular targets are largely unknown.

Myocardial Damage After Ischemia and Re-Perfusion

Zheng and associates (2015) evaluated the safety and effectiveness of edaravone for myocardial damage during myocardial ischemia and reperfusion (I/R).  These researchers included RCTs that compared edaravone with placebo or no intervention in patients with acute myocardial infarction (MI) or undergoing coronary artery bypass.  Two authors selected eligible trials, assessed trial quality and independently extracted the data.  A total of 7 clinical trials were eventually included and analyzed in this study, involving 148 participants; 4 trials were defined as waiting assessment.  All of the 3 remaining trials compared edaravone and another treatment combined with other treatment alone, used the same dose of edaravone injections (60 mg/day) and course of treatment (14 days), evaluated the effect of edaravone at different times, applied different methods, reported AEs, and showed no differences between the treatment group and the control group.  When pooling all of the trials in 1 dataset, edaravone appeared to decrease the proportion of participant with marked myocardial damage during I/R as compared with the control group.  The meta-analysis also revealed decreased cardiac markers such as creatine kinase myocardial b fraction (CK-MB), cardiac troponin I (cTnI) and erythrocyte membrane malonyldialdehyde (MDA), and increased content of superoxide dismutase (SOD).  The authors concluded that as a consequence of the moderate risk of bias and small sample, the observation of an effective treatment trend of edaravone for I/R requires future larger, high-quality trials to confirm.

Nephropathy

Varatharajan and colleagues (2016) stated that edaravone has been reported to reduce ischemia-reperfusion-induced renal injury by improving tubular cell function, and lowering serum creatinine (Cr) and renal vascular resistance.  These researchers examined the effect of edaravone in diabetes mellitus-induced nephropathy in rats.  A single administration of streptozotocin (STZ, 55 mg/kg, IP) was employed to induce diabetes mellitus in rats.  The STZ-administered diabetic rats were allowed for 10 weeks to develop nephropathy.  Mean body weight, lipid alteration, renal functional and histopathology were analyzed.  Diabetic rats developed nephropathy as evidenced by a significant increase in serum Cr and urea, and marked renal histopathological abnormalities like glomerulo-sclerosis and tubular cell degeneration.  The kidney weight to body weight ratio was increased.  Moreover, diabetic rats showed lipid alteration as evidenced by a significant increase in serum triglycerides and decrease in serum high-density lipoproteins (HDLs).  Edaravone (10 mg/kg, IP, last 4-weeks) treatment markedly prevented the development of nephropathy in diabetic rats by reducing serum Cr and urea and preventing renal structural abnormalities.  In addition, this treatment, without significantly altering the elevated glucose level in diabetic rats, prevented diabetes mellitus-induced lipid alteration by reducing serum triglycerides and increasing serum HDLs.  Interestingly, the reno-protective effect of edaravone was comparable to that of lisinopril (5 mg/kg, P.O. 4 weeks, standard drug).  The authors concluded that edaravone prevented renal structural and functional abnormalities and lipid alteration associated with experimental diabetes mellitus; it has the potential to prevent nephropathy without showing an anti-diabetic action, implicating its direct reno-protection in diabetic rats.

Osteoarthritis

Huang and colleagues (2016) stated that osteoarthritis (OA) is a degenerative joint disease affecting millions of people.  The degradation and loss of type II collagen induced by pro-inflammatory cytokines secreted by chondrocytes, such as tumor necrosis factor-alpha (TNF-α) is an important pathological mechanism to the progression of OA.  Whether edaravone has a protective effect in articular cartilage has not been reported.  These researchers examined the chondrocyte protective effects of edaravone on TNF-α induced degradation of type II collagen, and found that TNF-α treatment resulted in degradation of type II collagen, which can be ameliorated by treatment with edaravone in a dose-dependent manner.  It  was found that the inhibitory effects of edaravone on TNF-α-induced reduction of type II collagen were mediated by matrix metalloproteinase 3 (MMP-3) and MMP-13.  The authors concluded that edaravone alleviated TNF-α induced activation of signal transducer and activator of transcription 1 (STAT1) and expression of interferon regulatory factor 1 (IRF-1); these findings suggested a potential protective effect of edaravone in OA.

Parkinson Disease

Karba and colleagues (2018) noted that Parkinson's disease (PD) is one of the most common neurodegenerative disorder with intricate progressive pathology.  Currently, available conventional options for PD have certain limitations of their own, and as a result, patient compliance and satisfaction are low.  Current therapeutic options provide only symptomatic relief with limited control to prevent disease progression, resulting in poor patient compliance and satisfaction.  Several emerging pharmacotherapies for PD are in different stages of clinical development.  These therapies include adenosine A2A receptor antagonists, glutamate receptor antagonists, monoamine oxidase inhibitors, anti-apoptotic agents, and antioxidants such as coenzyme Q10, N-acetyl cysteine, and edaravone.  Other emerging non-pharmacotherapies include viral vector gene therapy, microRNAs, transglutaminases, RTP801, stem cells and glial-derived neurotrophic factor (GDNF).  In addition, surgical procedures including deep brain stimulation, pallidotomy, thalamotomy and Gamma Knife surgery have emerged as alternative interventions for advanced PD patients who have completely utilized standard treatments and still suffer from persistent motor fluctuations.  Complementary and alternative medicine (CAM) modalities such as Yoga, acupuncture, Tai Chi, music therapies etc. are highly practiced in several countries, offer some of the safer and effective treatment modalities for PD.  While several of these therapies hold much promise in delaying the onset of the disease and slowing its progression, more pharmacotherapies and surgical interventions need to be investigated in different stages of PD.  It is hoped that these emerging therapies and surgical procedures will strengthen our clinical armamentarium for improved treatment of PD.

Post-Stroke Depression

Kong and colleagues (2020) examined the effect of EDR on depression relief in symptomatic patients with intra-cranial stenosis and its relationship with the expression of sex hormones.  These investigators recruited 112 patients with symptomatic intra-cranial arterial stenosis from Renmin Hospital, Wuhan University, between October 2014 and October 2017.  All patients were divided into the traditional or experimental (traditional treatment + intravenous infusion of EDR 30 mg twice-daily for 14 days) treatment groups.  The general clinical data were collected, and neurological functional recovery using the mRS and NIHSS scores were recorded.  Symptom Checklist 90 (SCL-90) was used to assess the general psychological changes of the patient, followed by the 24 Hamilton Depression Scale (HAMD) to examine the incidence of post-stroke depression (PSD).  This divided the patients into the mild, moderate, and severe depression groups.  These researchers also measured the serum protein expression of the sex hormones estradiol (E2), testosterone (T), follicle stimulating hormone (FSH), prolactin (PRL), and luteinizing hormone (LH).  The mRS and NIHSS scores were significantly lower in the experimental group than in the control group (p < 0.05).  There was no significant difference in SCL90 score before intervention (p > 0.05); the scores were significantly lower in the experimental group after intervention (p < 0.05)>  There was a significant difference in SCL-90 and HAMD scores between groups before treatment (p < 0.05), with significantly lower scores in the experimental group post-treatment (p < 0.05).  The incidence of depression was significantly reduced in the experimental group post-treatment.  Furthermore, the expression of E2 and FSH was significantly higher (p < 0.01) and lower (p < 0.001), respectively, in women than in men in the experimental group post-treatment.  Interestingly, the expression of T was significantly lower in men in the experimental group post-treatment (p < 0.001).  The authors concluded that EDR significantly improved the clinical efficacy of stent implantation in intra-cranial artery stenosis treatment by alleviating depression and reducing the incidence of PSD.

The authors stated that there were some drawbacks in this study, such as the lack of long-term continuity, further clinical follow-up, and prospective clinical data.  In this trial, these investigators collected clinical data from patients at 7 days and 4 weeks post-treatment.  Further prospective studies will be carried out to collect clinical data at baseline, and 3, 6, 12, and 24 months after intervention to further evaluate the clinical efficacy of EDR and its relationship with the sex hormones.  In addition, the study lacked further clinical follow-up data, such as sub-group analyses of the specific infarct location, degree of arterial stenosis, and location of the symptomatic intra-cranial arterial stenosis.  Finally, there was a lack of prospective clinical data.

Rheumatoid Arthritis

Zhang and colleagues (2020) stated that current research suggests that synovial phagocytic cells remove excessive amounts of free oxygen radicals (reactive oxygen species [ROS]), thereby preventing damage to synovial tissues.  Moreover, ROS may affect the expression of growth arrest and DNA damage inducible α (GADD45A), thus further promoting the activation of synovial fibroblasts.  In this study, male adult rats were examined for progression of collagen-induced arthritis (CIA) using a macroscopic arthritis scoring system of the hind-paws and by measuring the changes in the rat's body weight, and activity level before and after diagnosis of CIA.  Rats were intraperitoneally injected twice-daily with EDR at doses of 3, 6, and 9 ml/kg.  Samples were taken at 2, 4, and 6 weeks, respectively.  EDR was found to significantly reduce macroscopic arthritis and microscopic pathology scores in CIA rats.  The concentration of endothelial NOS-6, glutathione, and heme oxygenase-1 in the serum of rats decreased, as was the production of ROS around the synovium and inflammatory factors.  Moreover, ROS-1 increased the expression of the NF-κB p65 protein by altering the expression level of GADD45A, causing aggravation of tissue damage.  EDR also significantly improved the physiological condition of CIA rats, including appetite, weight changes, and loss of fur, as well as limb mobility.  The authors believed that EDR acted to reduce the expression of NF-ĸB p65 by clearing ROS, which causes reduced expression of GADD45A, and subsequently reduced the level of apoptosis and inflammatory response proteins, thus, reducing the symptoms of CIA.  These researchers proposed that EDR is an effective option for clinical treatment of rheumatoid arthritis.

Seizure

Hao and colleagues (2020) stated that previous studies have demonstrated that excessive free radicals play an essential role in the initiation and progression of epilepsy and that a novel exogenous free radical scavenger EDR exerts some neuroprotective effects on seizure-induced neuronal damage.  These researchers examined the possible molecular mechanisms of EDR associated with procaspase-3 denitrosylation and activation through the FasL-Trx2 pathway in seizures rats.  They examined the effects of EDR on the regulation of the combination of Fas ligand/Fas receptor and the major components of the death-inducing signaling complex (DISC) in the hippocampus of kainic acid (KA)-treated Sprague-Dawley (SD) rats.  Treatment with EDR could attenuate the increased expression of FasL induced by KA and prevent procaspase-3 denitrosylation and activation via suppression of the FasL-Trx2 signaling pathway, which alleviated the neuronal damage in seizures.  The authors concluded that these findings provided experimental evidence that EDR functions by preventing the denitrosylation and activation of procaspase-3 and that EDR acts as a therapeutic option for epilepsy.

Subarachnoid Hemorrhage

Cai and colleagues (2020) examined the effects of EDR combined with cinepazide maleate on neurocyte autophagy and neurological function in rats with subarachnoid hemorrhage (SAH).  A total of 80 Sprague Dawley rats were selected to establish SAH rat models, which were divided into sham operation group, SAH group, MCI group and combined group.  Hippocampal tissue of each group was taken to observe the number of neurocytes.  The expression levels of Beclin-1 and (light chain LC3)-II of rats in each group were detected by ELISA.  Pearson's correlation factors were used to analyze the correlation between Beclin-1 and LC3-11, and neurological function tests were performed on rats of each group 14 and 28 days after administration.  The morphological and structural damage of nerve cells in the combined group was further alleviated, and the survival rate of neurons significantly increased at all time-points (p < 0.05).  The expression levels of Beclin-1 and LC3-11 in combined group was significantly higher than those in SAH group and CMI group (p < 0.05), and Beclin-1 was positively correlated with LC3-11 (r = 0.9454).  Longa score of the combined group was significantly lower than that of the other 2 groups, and muscle strength score was significantly higher than that of the other 2 groups (p < 0.05).  The authors concluded that EDR combined with cinepazide maleate could enhance the survival rate of brain cells and promote the volatilization of neurological function in the treatment of hemorrhage in the subretinal space of the omentum, which is worthy of popularization and application.

Traumatic Brain Injury

Zhang and colleagues (2019) stated that traumatic brain injury (TBI) is among the leading causes of irreversible neurological damage and death worldwide.  These investigators examined if edaravone (EDA) had a neuroprotective effect on TBI and identified the potential mechanism.  Results demonstrated that EDA suppressed inflammatory and oxidative responses in mice following TBI.  This was evidenced by a reduction in glutathione peroxidase, interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α) and hydrogen peroxide levels, in addition to an increase in hemeoxygenase-1, quinone oxidoreductase 1 and superoxide dismutase levels, thus mitigating neurofunctional deficits, cell apoptosis and structural damage.  These researchers found that EDA prevented the transfer of NF-κB protein from the cytoplasm to the nucleus, while promoting the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) protein in mice following TBI.  The authors concluded that these findings indicated that EDA exerted neuroprotective effects, including impeding neurofunctional deficits, cell apoptosis and structural damage, in mice with TBI, potentially via suppression of NF-κB-mediated inflammatory activation and promotion of the Nrf2 antioxidant pathway.  These researchers stated that these findings provided evidence for the potential clinical application of EDA in the treatment of TBI.

Wound Healing

Tamer and colleagues (2018) noted that a novel wound healing material composed of chitosan (Ch) and hyaluronan (HA) boosted with edaravone (Ed) as an anti-inflammatory drug was developed.  The fabricated membranes were verified using FT-IR, and the thermal properties were estimated employing TGA instrument.  Moreover, physical characterizations of the prepared membranes demonstrated a decrease in the membrane wettability, whereas an increase in membrane roughness was monitored due to the effect of edaravone supplementation.  A comparative study of free-radical scavenging activity of edaravone itself was carried out by 2 in-vitro approaches: uninhibited/inhibited hyaluronan degradation and de-colorization of ABTS methods in normal and simulated inflammation condition (acidic condition).  Accordingly, the scavenging activity of edaravone was significantly diminished to OH and peroxy-/alkoxy-type radicals in acidic conditions in compared to the neutral reactions.  The biochemical studies evidenced the hemo-compatibility of the examined membranes.  The consequence of membranes composed of Ch/HA/Ed on the wound healing of the rat's skin was studied, and the macroscopic and microscopic investigations revealed remarkable healing at 21st day post-surgery compared with injuries treated with cotton gauze as a negative control in addition to Ch/HA membrane without edaravone.  For these reasons, the Ch/HA/Ed membrane could be implemented as wound dressing material.

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Appendix

ALS Functional Rating Scale-Revised [ALSFRS-R]

The ALSFRS-R scale consists of 12 questions that evaluate the fine motor, gross motor, bulbar, and respiratory function of patients with ALS (speech, salivation, swallowing, handwriting, cutting food, dressing/hygiene, turning in bed, walking, climbing stairs, dyspnea, orthopnea, and respiratory insufficiency).  Each item is scored from 0 to 4, with higher scores representing greater functional ability.

ALSFRS-R Scale and Calculator

Revised El Escorial and Awaji Diagnostic Criteria for ALS

Progressive Symptoms

Lower Motor Neuron (LMN) Signs by Region

• clinical: weakness, atrophy, fasiculations
• EMG (limbs: 2 or more muscles innervated by different roots/nerves. Bulbar and throacic: 1 or more muscles):
  
  
  • lower motor neuron loss: fibrillation potentials, positive sharp waves, fasiculation potentials (Awaji only)
  • reinnervation: large motor untis and reduced recruitment

Upper Motor Neuron (UMN) Signs by Region

• clinical: hyperreflexia, spasticity, pathologic reflexes

Clinically Possible ALS

• Clincal/EMG evidence of UMN and LMN signs in 1 region; or
• Isolated UMN signs in 2 or more regions; or
• LMN signs rostral to UMN signs.

Clinically Probable Laboratory-supported ALS (El Escorial only)

• Clinical UMN and LMN signs in 1 region and LMN signs in 2 regions.

Clinically Probable ALS

• Clinical/EMG evidence of LMN and UMN signs in 2 or more regions
• Some UMN signs necessarily rostral to LMN signs

Clinically Definite ALS

• Clinical/EMG evidence of LMN and UMN signs in 3 or more regions.

Source: Elman and McCluskey, 2020

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References