Aldose Reductase as a Drug Target for Treatment of Diabetic Nephropathy: Promises and Challenges.
ElGamal Heba,Munusamy Shankar
Protein and peptide letters
Diabetic nephropathy (DN) is one of the most serious microvascular complications of diabetes mellitus and the leading cause of end stage renal disease. One of the key pathways activated in DN is the polyol pathway, in which glucose is converted to sorbitol (a relatively nonmetabolizable sugar) by the enzyme aldose reductase (AR). Shunting of glucose into this pathway causes disruption to glucose metabolism and subsequently damages the tissues via increased oxidative stress, protein kinase c activation and production of advanced glycation end products (AGE) in the kidney. This review aims to provide a comprehensive overview of the AR enzyme structure, substrate specificity and topology in normal physiology; to elaborate on the deleterious effects of AR activation in DN; and to summarize the potential therapeutic benefits and major challenges associated with AR inhibition in patients with DN.
Renoprotective Effects of Aldose Reductase Inhibitor Epalrestat against High Glucose-Induced Cellular Injury.
El Gamal Heba,Eid Ali Hussein,Munusamy Shankar
BioMed research international
Diabetic nephropathy (DN) is the leading cause of end stage renal disease worldwide. Increased glucose flux into the aldose reductase (AR) pathway during diabetes was reported to exert deleterious effects on the kidney. The objective of this study was to investigate the renoprotective effects of AR inhibition in high glucose milieu in vitro. Rat renal tubular (NRK-52E) cells were exposed to high glucose (30 mM) or normal glucose (5 mM) media for 24 to 48 hours with or without the AR inhibitor epalrestat (1 M) and assessed for changes in Akt and ERK1/2 signaling, AR expression (using western blotting), and alterations in mitochondrial membrane potential (using JC-1 staining), cell viability (using MTT assay), and cell cycle. Exposure of NRK-52E cells to high glucose media caused acute activation of Akt and ERK pathways and depolarization of mitochondrial membrane at 24 hours. Prolonged high glucose exposure (for 48 hours) induced AR expression and 1 cell cycle arrest and decreased cell viability (84% compared to control) in NRK-52E cells. Coincubation of cells with epalrestat prevented the signaling changes and renal cell injury induced by high glucose. Thus, AR inhibition represents a potential therapeutic strategy to prevent DN.
LC-MS/MS method for the quantification of aldose reductase inhibitor-epalrestat and application to pharmacokinetic study.
Nirogi Ramakrishna,Kandikere Vishwottam,Ajjala Devender Reddy,Bhyrapuneni Gopinadh,Muddana Nageswara Rao
Journal of pharmaceutical and biomedical analysis
A simple and rapid LC-MS/MS method was developed and validated for the quantification of epalrestat, an aldose reductase inhibitor for the treatment of diabetic neuropathy. Following protein precipitation epalrestat and IS were eluted with 10mM ammonium acetate and acetonitrile using a rapid gradient program on reverse phase column. Multiple reaction monitoring mode was used to monitor the transitions of m/z 318→58 for epalrestat and m/z 410→348 for the IS. The assay exhibited a linear dynamic range of 2-5,000 ng/mL for epalrestat in rat plasma. Acceptable precision and accuracy were obtained for concentrations over the standard curve range. The within batch accuracy was in the range of 101.3-108.0% with precision in the range of 3.0-12.3%. All the other validation parameters were within the acceptable limits. Validated method was applied to analyze rat plasma samples obtained from a pharmacokinetic study. After oral administration of epalrestat at 10mg/kg to wistar rats (n=3) mean C(max), AUC(0-24) (ngh/mL) and t(1/2) were found to be 4077 ± 1327 ng/mL, 8989 ± 1590 ngh/mL and 2.9 ± 1.4h, respectively. Bioavailability was found to be 90 ± 14% for epalrestat in male wistar rats.
Sensitive analysis and pharmacokinetic study of epalrestat in C57BL/6J mice.
Huang Jingqiu,Sun Runbin,Feng Siqi,He Jun,Fei Fei,Gao Haoxue,Zhao Yuqing,Zhang Yue,Gu Huilin,Aa Jiye,Wang Guangji
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences
Epalrestat is clinically applied for the management of diabetic peripheral neuropathy, yet its pharmacokinetic properties are not well understood. In this study, a rapid and sensitive LC-MS/MS method was established for assaying epalrestat in bio-samples of mice. The method was validated and it showed a good linearity over the range of 2-5000ng/mL, a precision of less than 12.3%, and recovery and matrix effects of 112.5-123.6% and 87.9-89.5%, respectively. After administration of a single dose of epalrestat administered, the exposure level of AUC was positively dose-dependent and the mean C, AUC, T, and MRT were 36.23±7.39μg/mL, 29,086.5μg/Lh, 1.2h and 1.8h, respectively. Epalrestat was highly exposed in stomach, intestine, liver and kidney, and only a small amount was detected in brain, urine and feces. Multi-dose of epalrestat significantly increased MRT and apparent volume of distribution (V) relative to those of a single-dose.
A Specific Probe Substrate for Evaluation of CYP4A11 Activity in Human Tissue Microsomes and a Highly Selective CYP4A11 Inhibitor: Luciferin-4A and Epalrestat.
Yamaori Satoshi,Araki Noriyuki,Shionoiri Mio,Ikehata Kurumi,Kamijo Shinobu,Ohmori Shigeru,Watanabe Kazuhito
The Journal of pharmacology and experimental therapeutics
The specificity of cytochrome P450 4A11 (CYP4A11) against luciferin-4A -demethylation in human liver microsomes (HLMs) and human renal microsomes (HRMs) and selectivity of CYP4A11 inhibition by epalrestat were investigated. Kinetic analysis of luciferin-4A -demethylation yielded and values of 39.7 pmol/min per milligram protein and 43.2 M for HLMs (Hill coefficient 1.24) and 39.4 pmol/min per milligram protein and 33.8 M for HRMs (Hill coefficient 1.34), respectively. Among the selective CYP inhibitors tested, HET0016 (CYP4 inhibitor) exclusively inhibited luciferin-4A -demethylation by HLMs and HRMs. Furthermore, anti-CYP4A11 antibody nearly abolished the activity of both tissue microsomes. Luciferin-4A -demethylase activity of HLMs was significantly correlated with lauric acid -hydroxylase activity, a marker of CYP4A11 activity ( = 0.904, < 0.0001). Next, effects of epalrestat on CYP-mediated drug oxidations were examined. Epalrestat showed the most potent inhibition against CYP4A11 (IC = 1.82 M) among the 17 recombinant enzymes tested. The inhibitory effect of epalrestat on CYP4A11 was at least 10-fold stronger than those on CYP4F2, CYP4F3B, and CYP4F12. For known CYP4 inhibitors, in contrast, HET0016 inhibited the activities of CYP4A11 and CYP4F2 (IC = 0.0137-0.0182 M); 17-octadecynoic acid reduced activities of CYP4A11, CYP4F2, CYP4F3B, and CYP4F12 to a similar extent (IC = 5.70-17.7 M). Epalrestat selectively and effectively inhibited the CYP4A11 activity of HLMs (IC = 0.913 M) and HRMs (IC = 0.659 M). These results indicated that luciferin-4A -demethylase activity is a good CYP4A11 marker of HLMs and HRMs, and that epalrestat is a more selective CYP4A11 inhibitor compared with known CYP4 inhibitors.
Treatment of diabetic neuropathy and neuropathic pain: how far have we come?
At least one of four diabetic patients is affected by distal symmetric polyneuropathy, which represents a major health problem, since it may present with partly excruciating neuropathic pain and is responsible for substantial morbidity, increased mortality, and impaired quality of life. Treatment is based on four cornerstones: 1) causal treatment aimed at (near)-normoglycemia, 2) treatment based on pathogenetic mechanisms, 3) symptomatic treatment, and 4) avoidance of risk factors and complications. Recent experimental studies suggest a multifactorial pathogenesis of diabetic neuropathy. From the clinical point of view, it is important to note that, based on these pathogenetic mechanisms, therapeutic approaches could be derived, some of which are currently being evaluated in clinical trials. Among these agents, only alpha-lipoic acid is available for treatment in several countries and epalrestat in Japan. Although several novel analgesic drugs such as duloxetine and pregabalin have recently been introduced into clinical practice, the pharmacologic treatment of chronic painful diabetic neuropathy remains a challenge for the physician. Individual tolerability remains a major aspect in any treatment decision. Epidemiological data indicate that not only increased alcohol consumption but also the traditional cardiovascular risk factors such as hypertension, smoking, and cholesterol play a role in development and progression of diabetic neuropathy and hence need to be prevented or treated.
Efficacy and safety of mirogabalin (DS-5565) for the treatment of diabetic peripheral neuropathic pain: a randomized, double-blind, placebo- and active comparator-controlled, adaptive proof-of-concept phase 2 study.
Vinik Aaron,Rosenstock Julio,Sharma Uma,Feins Karen,Hsu Ching,Merante Domenico,
OBJECTIVE:We aimed to identify doses of mirogabalin (DS-5565) providing clinically meaningful efficacy with manageable side effects for treatment of diabetic peripheral neuropathic pain (DPNP). RESEARCH DESIGN AND METHODS:Adults (≥18 years) with type 1 or 2 diabetes, HbA₁c ≤10% at screening, and DPNP for ≥6 months were eligible for study participation. Subjects (n = 452) were randomized (2:1:1:1:1:1:1 ratio) to placebo, dose-ranging mirogabalin (5, 10, 15, 20, and 30 mg/day), or pregabalin (300 mg/day) for 5 weeks. The primary end point was weekly change in average daily pain score (ADPS; 0 to 10 numeric rating scale) from baseline to week 5 (minimally meaningful effect, ≥1.0-point decrease versus placebo). ANCOVA was conducted using last observation carried forward, and treatment effect least squares (LS) means were provided for each contrast. Safety assessments included adverse events (AEs), clinical laboratory tests, and electrocardiograms. RESULTS:LS mean differences in change in ADPS from baseline to week 5 versus placebo were -0.22, -0.53, -0.94, -0.88, and -1.01 for the mirogabalin 5-, 10-, 15-, 20-, and 30-mg/day treatment groups, respectively, and -0.05 in the pregabalin group (P < 0.05 versus placebo for mirogabalin 15, 20, and 30 mg/day). Most frequent AEs (n = 277) were primarily mild to moderate dizziness (9.4%), somnolence (6.1%), and headache (6.1%); otherwise, mirogabalin was well tolerated. CONCLUSIONS:Mirogabalin 15, 20, and 30 mg/day had statistically significant reductions in ADPS versus placebo, and mirogabalin 30 mg/day also met the criteria of minimally meaningful effect. Mirogabalin may be a promising new treatment option for patients with DPNP.
Effects of treatments for symptoms of painful diabetic neuropathy: systematic review.
Wong Man-chun,Chung Joanne W Y,Wong Thomas K S
BMJ (Clinical research ed.)
OBJECTIVE:To evaluate the effects of treatments for the symptoms of painful diabetic neuropathy. DESIGN:Systematic review. DATA SOURCES:Articles (English and full text) on double blind randomised trials found by searching with the key words anticonvulsant, antidepressant, non-steroidal anti-inflammatory drugs, tramadol, opioid, ion channel blocker, diabetic neuropathy, diabetic peripheral neuropathy, peripheral neuropathy, and neuropathy. The search included Medline, Embase, EMB reviews-AP Journal club, and the Cochrane central register of controlled trials. STUDY SELECTION:Randomised controlled trials comparing topically applied and orally administered drugs with a placebo in adults with painful diabetic neuropathy. DATA EXTRACTION:Data were extracted to examine quality of methods, characteristics of studies and patients, efficacy, and side effects. The primary outcome was dichotomous information for 50% or moderate reduction of pain. Secondary outcomes were 30% reduction of pain and withdrawals related to adverse events. RESULTS:Odds ratios were calculated for achievement of 30%, 50%, or moderate pain relief and for withdrawals related to adverse effects. Twenty five reports were included and seven were excluded. The 25 included reports compared anticonvulsants (n=1270), antidepressants (94), opioids (329), ion channel blockers (173), N-methyl-D-aspartate antagonist (14), duloxetine (805), capsaicin (277), and isosorbide dinitrate spray (22) with placebo. The odds ratios in terms of 50% pain relief were 5.33 (95% confidence interval 1.77 to 16.02) for traditional anticonvulsants, 3.25 (2.27 to 4.66) for newer generation anticonvulsants, and 22.24 (5.83 to 84.75) for tricylic antidepressants. The odds ratios in terms of withdrawals related to adverse events were 1.51 (0.33 to 6.96) for traditional anticonvulsants, 2.98 (1.75 to 5.07) for newer generation anticonvulsants, and 2.32 (0.59 to 9.69) for tricylic antidepressants. Insufficient dichotomous data were available to calculate the odds ratios for ion channel blockers. CONCLUSION:Anticonvulsants and antidepressants are still the most commonly used options to manage diabetic neuropathy. Oral tricyclic antidepressants and traditional anticonvulsants are better for short term pain relief than newer generation anticonvulsants. Evidence of the long term effects of oral antidepressants and anticonvulsants is still lacking. Further studies are needed on opioids, N-methyl-D-aspartate antagonists, and ion channel blockers.
Use of natural compounds in the management of diabetic peripheral neuropathy.
Galuppo Maria,Giacoppo Sabrina,Bramanti Placido,Mazzon Emanuela
Molecules (Basel, Switzerland)
Nephropathy, retinopathy cardiomyopathy and peripheral neuropathy are all recognized as important complications in about 50% of diabetes mellitus (DM) patients, mostly related to a poor glycemic control or to an improper management of this pathology. In any case, amongst others, diabetic peripheral neuropathy (DPN) seems the leading and most painful complication usually affecting many DM patients. For this reason, this work was conceived to review the large variety of strategies adopted for management of DPN, starting from the most conventional therapies to arrive at alternative approaches. From this perspective, both the most popular pharmacological treatments used to respond to the poorly effect of common analgesics--non-steroidal anti-inflammatory drugs (NSAIDS) and opioids--understood as gabapentin vs. pregabalin clinical use, and the guidelines provided by Oriental Medicine as well as by a long list of natural compounds that many authors identify as possible therapeutic or alternative agents to replace or to combine with the existing therapies will be included. Moreover, in the effort to provide the widest panel of remedies, the most antique techniques of acupuncture and electrostimulation will be considered as alternative, which are useful approaches to take into account in any non-pharmacological strategy for DPN management.
Tapentadol-ER for the treatment of diabetic peripheral neuropathy.
Games Gina,Hutchison Amber
The Consultant pharmacist : the journal of the American Society of Consultant Pharmacists
With the prevalence of diabetes mellitus (DM) increasing, pathologic complications such as diabetic peripheral neuropathy (DPN) are also becoming more common. Of those diagnosed with DM, 10% to 20% of patients suffer from painful DPN. Until recently, only pregabalin and duloxetine possessed Food and Drug Administration (FDA) approval for this condition. However, FDA recently approved tapentadol-ER [extended release] (Nucynta ER) for painful DPN. Tapentadol-ER is an opioid analgesic commonly used for the treatment of moderate-to-severe chronic pain that contains a unique dual mechanism acting as both a weak mu-opiod receptor agonist and norepinephine-reuptake inhibitor. It is by way of this unique dual mechanism that allows for effective analgesic effects with increased tolerability. This new FDA approval provides an additional therapeutic option to treat DPN in symptomatic patients.
Pharmacotherapy for diabetic peripheral neuropathy pain and quality of life: A systematic review.
Waldfogel Julie M,Nesbit Suzanne Amato,Dy Sydney M,Sharma Ritu,Zhang Allen,Wilson Lisa M,Bennett Wendy L,Yeh Hsin-Chieh,Chelladurai Yohalakshmi,Feldman Dorianne,Robinson Karen A
OBJECTIVE:To systematically assess the effect of pharmacologic treatments of diabetic peripheral neuropathy (DPN) on pain and quality of life. METHODS:We searched PubMed and Cochrane Database of Systematic Reviews for systematic reviews from 2011 to October 12, 2015, and PubMed, Embase, and the Cochrane Central Register of Controlled Trials for primary studies from January 1, 2013, to May 24, 2016. We searched Clinicaltrials.gov on March 9, 2016. Two reviewers independently evaluated studies for eligibility, serially abstracted data, and independently evaluated risk of bias and graded strength of evidence (SOE). RESULTS:We updated a recently completed systematic review of 57 eligible studies with 24 additional published studies and 25 unpublished studies. For reducing neuropathy-related pain, the serotonin-norepinephrine reuptake inhibitors duloxetine and venlafaxine (moderate SOE), the anticonvulsants pregabalin and oxcarbazepine (low SOE), the drug classes tricyclic antidepressants (low SOE) and atypical opioids (low SOE), and botulinum toxin (low SOE) were more effective than placebo. We could not draw conclusions about quality of life due to incomplete reporting. All studies were short-term (less than 6 months), and all effective drugs had more than 9% dropouts from adverse effects. CONCLUSIONS:For reducing pain, duloxetine and venlafaxine, pregabalin and oxcarbazepine, tricyclic antidepressants, atypical opioids, and botulinum toxin were more effective than placebo. However, quality of life was poorly reported, studies were short-term, drugs had substantial dropout rates, and opioids have significant risks. Future studies should evaluate longer-term outcomes, use methods and measures recommended by pain organizations, and assess patients' quality of life.