epalrestat and Neuralgia

Diabetic neuropathy (DN) is the most frequent among peripheral neuropathies. Since its pathophysiology is so complicated, neither classification nor therapeutic management of DN has been established. Sensory/autonomic polyneuropathy (DP) is the main type of DN. Since diabetic patients occasionally have one or more subtypes of DN and/or other polyneuropathy including treatable neuropathy like CIDP, the treatment for DP has to be conducted after excluding the possibility of other conditions. Glycemic control is most essential to prevent the development of DP. However, it is practically difficult to keep HbA1c under 6.5% so that drinking and smoking better be restricted and blood pressure be properly maintained to retard the progression of DP. Aldose reductase inhibitor is only one commercially available drug for DP and its efficacy must be evaluated by nerve function tests along with subjective symptoms. More vigorous therapeutic procedure is expected by obtaining not only more potential drugs based on pathogenic mechanisms but also the technique targeting of DNA/siRNA of given peptides at dorsal root ganglion neurons.

Topics: Aldehyde Reductase; Diabetic Nephropathies; Enzyme Inhibitors; Genetic Therapy; Humans; Hypoglycemic Agents; Imidazolidines; Neuralgia; Neurologic Examination; Regenerative Medicine; Rhodanine; Thiazolidines

Transdermal penetration of therapeutic moieties from topical dosage forms always remains a challenge due to the presence of permeation impeding keratin which should be addressed. The purpose of the study was to formulate quercetin and 4-formyl phenyl boronic acid (QB complex) used for the preparation of nanoethosomal keratolytic gel (EF3-G). The QB complex was confirmed by Fourier transform infrared spectroscopy while skin permeation, viscosity, and epalrestat entrapment efficiency were used for the optimization of nanoethosomal gel. The keratolytic effect of the proposed nanoethosomal gel with urea (QB + EPL + U) was calculated in rat and snake skin. The spherical shape of nanoethosomes was confirmed by scanning electron microscopy. According to the findings of stability studies, viscosity decreases as temperature increases, proving their thermal stability. The negative charge of optimized EF3 with 0.7 PDI proved narrow particle size distribution with homogeneity. Optimized EF3 showed two folds increase of epalrestat permeation in highly keratinized snake skin as compared to rats' skin after 24 h. Antioxidant behaviors of EF3 (QB) > QB complex > quercetin > ascorbic acid proved reduction of oxidative stress in DPPH reduction analysis. Interestingly, the hot plate and cold allodynia test in the diabetic neuropathic rat model reduced 3-fold pain as compared to the diabetic control group which was further confirmed by in vivo biochemical studies even after the eight week. Conclusively, ureal keratolysis, primary dermal irritation index reduction, and improved loading of epalrestat render the nanoethosomal gel (EF3-G) ideal for the treatment of diabetic neuropathic pain.

Topics: Administration, Cutaneous; Animals; Antioxidants; Diabetes Mellitus; Neuralgia; Particle Size; Quercetin; Rats

Among the oral route, mouth dissolving tablets (MDTs) offer a benefit for drugs with slow dissolution and having low oral bioavailability. Epalrestat is one of the best effective diabetic neuropathy medication used for treating nerve pain. The problem associated with this drug is high first pass metabolism and low solubility in acidic media as well in basic media leads to short half-life, delayed dissolution and side effects. Therefore, the goal of the current work is to developed an epalrestat MDTs tablet that will provide quick drug dissolution and a quick onset of action for the treatment of nerve pain. MDTs of epalrestat were formulated by direct compression using natural superdis integrants obtained from the various sources such as fenugreek, gum karaya and banana powder. All of the pre- and post-compression parameter results were shown to be in accordance with established specifications. In comparison to other formulations of MDTs, formulation F3 with 15 mg (7.5%) of banana powder displayed a higher rate of dissolution. It was determined that epalrestat MDTs containing natural superdisintegrant were successfully formulated with acceptable physical and chemical properties, quick oral cavity disintegration, a quick onset of action and improved patient compliance.

Topics: Humans; Mouth; Neuralgia; Powders; Solubility; Tablets

Diabetic peripheral neuropathy is the most common complication of diabetes mellitus. Epalrestat, an aldose reductase inhibitor, has been approved for clinical therapy for diabetic peripheral neuropathic pain. In the present study, solid lipid-based nanoparticles are used for oral administration of epalrestat (E-SLN) and evaluated against diabetic neuropathic pain in a rat model.. Experimental diabetes in rats was induced by a single dose of streptozotocin (STZ) administration. The therapeutic efficiency of Epalrestat nanoparticles (0.25, 0.50, 1, and 5 mg/kg) in diabetic rats was studied. STZinduced diabetic rats were treated with different doses of E-SLN for 8 weeks. The nanoparticles were orally administered at a single dose in rats, and the various parameters related to peripheral neuropathy were evaluated and compared with the bare drug. The blood glucose level was estimated by standard glucometer, HbA1c, triglycerides, total cholesterol, and liver function test (ALT and AST) were analyzed by blood samples collected from retro-orbital plexus. Oxidative stress markers and Na+K+ATPase, TNF-α, and IL-1β levels were measured in the homogenate of sciatic nerves. Behavioral tests were also performed by the hot plate method and tail-flick method.. E-SLN synthesized by the micro-emulsification method was 281 ± 60 nm in size, and encapsulation efficacy was found to be 88 ± 2%. Optimized E-SLN were characterized and found to be optimum in size, spherical shape, decent encapsulation efficiency, stable at acidic gastric pH, and suitable for oral delivery. E-SLNs did not significantly reverse the STZ-induced elevated blood glucose level (FBS and PPBS), HbA1c, triglycerides, and total cholesterol but significantly improved TNF-α, IL-1β, and increased Na+K+ATPase levels, oxidative stress marker and ALT, AST in the treated rat group as compared with the diabetic group. Doses of E-SLN, i.e. 0.5, 1.0, 2.5, and 5 mg/kg, significantly increased the tail-flick latency time and hot plate response time in a dose-dependent manner compared with the diabetic group.. Thus, it is suggested that E-SLN were equally effective and less hepatotoxic compared with the standard treatment of epalrestat. To the best of our knowledge, we, for the first time, propose the orally deliverable E-SLN that ameliorates STZ-induced diabetes neuropathic pain effectively as compared with conventional epalrestat.

Topics: Adenosine Triphosphatases; Aldehyde Reductase; Animals; Blood Glucose; Cholesterol; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Glycated Hemoglobin; Lipids; Neuralgia; Rats; Streptozocin; Triglycerides; Tumor Necrosis Factor-alpha