Long-Term Treatment With Ranirestat (AS-3201), a Potent Aldose Reductase Inhibitor, Suppresses Diabetic Neuropathy and Cataract Formation in Rats

Matsumoto, Takafumi; Ono, Yoshiyasu; Kuromiya, Akemi; Toyosawa, Kaoru; Ueda, Yoshinaka; Bril, Vera

doi:10.1254/jphs.08071fp

Cited by 43 publications

(49 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Examples of natural products with known AR inhibitory activity are extracts from indigenous plants like Ocimum sanctum, Withania somnifera, Curcuma longa, and Azadirachtaindica [14,15]. Several experimental studies support the role of ARI such as Ranirestat [16], Fidarestat [17] and Kinostat [18] in preventing and not only delaying diabetic cataract formation in diabetic rat and dog models. A number of different antioxidants have been reported to delay cataract formation and progression in diabetic animals.…”

Section: Retarding Cataract Progression: Major Interventionsmentioning

confidence: 99%

The Pathophysiology of Cataract and Major Interventions to Retarding Its Progression: A Mini Review

Nartey

2017

AOVS

View full text Add to dashboard Cite

Cataracts are the principal cause of blindness, globally, affecting the older cohort (specifically those in their fifth decades and beyond). In fact, there are more cases of cataracts worldwide than there are of glaucoma, macular degeneration and diabetic retinopathy (DR) combined, according to Prevent Blindness America (PBA). Whilst ageing remains the predominant risk factor for cataract formation, other predisposing factors such as diabetes mellitus (DM), nutritional and trace element deficiency, ultraviolet radiations, smoking, etc., have been implicated in this sight threatening condition. The pathophysiology of cataract is not fully understood albeit aldose-reductase inhibitors and antioxidants have proven beneficial in the prevention and management of this vision threatening condition in vitro and in vivo experimental studies. This paper seeks to provide an overview of the understanding of the pathophysiology of cataract and the major interventions that have been deployed to help retard its progression, as highlighted in extant literature.

show abstract

Section: Retarding Cataract Progression: Major Interventionsmentioning

confidence: 99%

The Pathophysiology of Cataract and Major Interventions to Retarding Its Progression: A Mini Review

Nartey

2017

AOVS

View full text Add to dashboard Cite

show abstract

“…Rat lenses were collected under anesthesia with sodium pentobarbital (Abbott, Abbott Park, IL, USA), and lens AR was prepared and purified according to the method of Matsumoto et al (10,11). To compare the inhibitory effects of ranirestat on AR from different species, recombinant human aldose reductase (rhAR) was purchased from Wako Pure Chemical Industries, Ltd. (Osaka).…”

Section: Preparation Of Armentioning

confidence: 99%

“…AR activity was determined according to the method of Matsumoto et al (10,11). In brief, the decrease in absorbance of coenzyme NADPH due to its oxidation into NADP was measured at 340 nm and taken as a measure of AR activity.…”

Section: Determination Of Ar Activitymentioning

confidence: 99%

“…Sorbitol accumulation in rat erythrocytes was determined according to the method of Matsumoto et al (10,11) with a slight modification. An aliquot of washed erythrocytes was added to Krebs-Henseleit buffer containing glucose at a concentration of 90 or 500 mg / dl.…”

Section: Sorbitol Accumulation In Rat Erythrocytes and Sciatic Nervesmentioning

confidence: 99%

“…Sorbitol and fructose levels in rat sciatic nerves were measured according to the method of Matsumoto (10,11) and expressed in μmol / g wet weight of tissue. To determine the percent inhibition of diabetes-induced increase in sorbitol or fructose content at each dose of ranirestat, the difference in mean sorbitol content between the non-diabetic control and diabetic control groups was taken as the diabetes-induced increase in sorbitol content and % inhibition of this increase was calculated based on sorbitol content in each of the ranirestat-treated diabetic groups using the following equation: % Inhibition = [1 − (AS − NC) / (DC − NC)] × 100, where NC, DC, and AS indicate sorbitol contents (μmol / g wet weight) in the non-diabetic control group, diabetic control group, and the ranirestat-treated diabetic group, respectively.…”

Section: Measurement Of Sorbitol and Fructose In The Sciatic Nervesmentioning

confidence: 99%

See 2 more Smart Citations

Improvement of Motor Nerve Conduction Velocity in Diabetic Rats Requires Normalization of the Polyol Pathway Metabolites Flux

et al. 2009

Self Cite

View full text Add to dashboard Cite

Abstract. Using ranirestat, an aldose reductase (AR) inhibitor, we investigated the relationship between sorbitol and fructose levels in the sciatic nerve and motor nerve conduction velocity (MNCV) in streptozotocin (STZ)-treated diabetic rats. Ranirestat inhibited rat and recombinant human AR with similar IC 50 values and equipotently prevented sorbitol accumulation in rat erythrocytes and sciatic nerves in vitro. One week after STZ administration, sorbitol levels in rat erythrocytes and sciatic nerves significantly increased while MNCV decreased. Oral administration of ranirestat (0.03 -1.0 mg / kg per day) for 3 weeks dose-dependently decreased the elevated sorbitol and fructose levels in the rat sciatic nerves without affecting blood glucose level. Particularly, at doses of 0.1 mg / kg per day or higher, ranirestat normalized both sorbitol and fructose levels in the sciatic nerves of STZ-treated rats. Ranirestat (0.1 -1.0 mg / kg per day) also improved the STZ-induced decrease in MNCV in a dose-dependent manner. This improvement correlated with the decrease of sorbitol and fructose levels in the rat sciatic nerves. These findings indicate that ranirestat improves MNCV via normalization of sorbitol and fructose accumulation in the sciatic nerve.

show abstract

Pharmacokinetics and Safety of Ranirestat in Patients With Hepatic Impairment

Itou¹,

Fujita

Inoue

et al. 2020

The Journal of Clinical Pharma

View full text Add to dashboard Cite

Ranirestat is an aldose reductase inhibitor hypothesized to improve diabetic neuropathy. An open‐label, single‐dose, parallel‐group study was conducted to compare pharmacokinetic (PK) characteristics of an oral dose of ranirestat across subjects with normal hepatic function and patients with mild and moderate hepatic impairment because ranirestat is expected to be used by patients with diabetes mellitus, possibly including those with hepatic impairment. To evaluate the necessity for dose adjustment, PK profiles and tolerability were studied at the dose of 40 mg, the expected optimal clinical dose in patients with diabetic neuropathy and normal hepatic function. In total, 20 subjects, including 5, 10, and 5 subjects with normal hepatic function, mild hepatic impairment, and moderate hepatic impairment, respectively, completed the study. Serial PK sampling was conducted up to 504 hours, and PK parameters were calculated and compared between healthy subjects and patients with mild or moderate hepatic impairment. The geometric mean ratios of peak concentration and area under the concentration‐time curve in patients with mild hepatic impairment (90%CI) were 86.7% (55.3% to 135.9%) and 84.7% (68.5% to 104.8%), respectively. The values in patients with moderate hepatic impairment were 81.3% (48.8% to 135.5%) and 91.7% (72.1% to 116.7%), respectively. These results demonstrated that plasma ranirestat exposure and the plasma protein binding of the drug were not substantially altered by normal, mild, or moderate hepatic impairment (protein binding 99.22%, 99.29%, and 99.00%, respectively). All adverse events were mild in severity. Based on these findings, no dose adjustment will be required for ranirestat in patients with mild or moderate hepatic impairment.

show abstract

Long-Term Treatment With Ranirestat (AS-3201), a Potent Aldose Reductase Inhibitor, Suppresses Diabetic Neuropathy and Cataract Formation in Rats

Cited by 43 publications

References 30 publications

The Pathophysiology of Cataract and Major Interventions to Retarding Its Progression: A Mini Review

The Pathophysiology of Cataract and Major Interventions to Retarding Its Progression: A Mini Review

Improvement of Motor Nerve Conduction Velocity in Diabetic Rats Requires Normalization of the Polyol Pathway Metabolites Flux

Pharmacokinetics and Safety of Ranirestat in Patients With Hepatic Impairment

Contact Info

Product

Resources

About