Epalrestat is a carboxylic acid derivative that acts as aldose reductase inhibitor. Epalrestat is proven to have beneficial effects in diabetic neuropathy in many controlled clinical trials. In hyperglycemia, Epalrestat significantly reduces intracellular sorbitol accumulation by an uncompetitive aldose reductase inhibition. Epalrestat improves motor and sensory nerve conduction velocity and subjective neuropathy symptoms in patients with diabetic neuropathy 49-51 . So this combination of Epalrestat and Methylcobalamin treated patients were more efficacious and well tolerated with safety for the management of diabetic neuropathy than monotherapy of Epalrestat and Methylcobalamin. The combination therapy showed faster onset and quick relief of symptoms. Apart from this as per our observation, in general people with diabetes who smoke and drink alcohol are more likely to develop neuropathy. Hyperglycemia promotes the synthesis of an endogenous protein kinase C activator, diacylglycerol. This excess protein kinase C activation induces ischemia and promotes vascular permeability and thickening of the basement memberane and causes neuropathy 75-77 . So, inactivation of protein
Recent Background: Diabetic neuropathy is one of the major complications in long standing hy- perglycemic patients. Though exact mechanism of neuronal damage is unclear, accumulation of excess sorbitol through polyol pathway is be- lieved to contribute significantly. Epalrestat and methylcobalamin are extensively used in this area to counter neuronal damage. This study was aimed to evaluate the combined effect of these drugs. Materials and Methods: A total of 220 patients with diabetic neuropathy were in- cluded in this study. The patients were divided into two groups; group A was administered com- bination of epalrestat 50 mg and methylcobala- min 500 mcg while group B was administered epalrestat 50 mg alone (both thrice daily). The treatment period was 12 weeks with monitoring on week 4, 8 and 12 of the study. At baseline and at follow up visits following parameters were evaluated: loss of sensation, burning sensation, numbness, muscle cramps, spontaneous pain, weakness, dizziness, loss of the thermal sensi- tivity, tendon reflexes, muscle strength and pain intensity using visual analog scale (VAS). Results: All the parameters were improved in both the groups compared to baseline. In group A sig- nificant improvement was seen on week 4 itself and continued for the rest of the study in all the measured parameters. Group B showed signifi- cant improvement from 8th week onwards. The inter-group difference is statistically significant in favour of the combination therapy. Conclu-
Epalrestat is Aldose reductase inhibitor. Epalrestat inhibited high glucose-mediated Neutrophilendo- thelial adhesion molecules not only through inhibition of a PKC-dependent pathway,but also through increased endothelial NO production.It is Used in treatment of Diabetes. Chemically it is described 2-[(5Z)-5-[(E)-3-phenil-2-methylprop-2- enylidene]-4-oxo-2-thioxo-3-thiazolidinyl]acetic acid. [1-2] Methylcobalamin is use as Vitamin supplement. The synthesis of methionine from homocysteine requires a folate coenzyme as vitamin B12-dependent enzyme. Chemically it is described Coα-[α-(5,6-Dimethylbenz-1H-imidazolyl)]-
All taking Epineuron SR had marked regression in blister healing while 06 cases of control group had exacerbation of blister (Table 6). All the patients on Epineuron SR (Epalrestat and Methylcobalamin composit) had marked relief in agonizing pain in 60(62) where as majority 52(62) of control group remained without any relief of pain though 4(62) had increase in pain agony (Table 7). The mean duration required in achieving healing of blister and relief of pain is 9±2 and 14±4days respectively. All cases of group B show excellent clinical response whether only 2 of control group show fair clinical response. No patients of group B presented with any associated presentation while patients of control group presented with various presentation during therapy or post therapy period (Table 8).
8) Goti PP, Patel PB, Development and validation of ratio derivative spectrophotometric method for simultaneous estimation of Gabapentin, Methylcobalamin and alpha lipoic acid in tablet formulation, Journal of Pharmacy research, june 2013; 6(6):
The objective of present work is to achieve improvement in solubility and dissolution using Epalrestat with β-cyclodextrin ternary complex with addition of L-arginine. Kneading method with and without incorporation of L-arginine was used to obtain the solid systems (binary and ternary complex) of Epalrestat with β-cyclodextrin and characterized for DSC, PXRD, SEM. Phase solubility, saturation solubility, dissolution and stability studies were carried out. The effect of L-arginine was investigated on complexation efficiency of β-cyclodextrin towards Epalrestat in an aqueous media through phase solubility according to Higuchi and Connors. Phase solubility studies showed A L (linear) type of solubility curve in presence of L-arginine, the complexation efficiency and
INTRODUCTION: Epalrestat was chemically 2- [(5Z)-5- [(E)-2-methyl-3-phenylprop-2-enylidene]- 4-oxo-2-sulfanylidene-1, 3-thiazolidin-3-yl] acetic acid, epalrestat is a carboxylic acid derivative and a noncompetitive and reversible used for the treatment of which is one of the most common long-term complications in patients. It reduces the accumulation of intracellular sorbitol, which is believed to be the cause of diabetic neuropathy. Pregabalin was chemically (3S)-3-(aminomethyl)- 5-methylhexanoic acid.
Preparation of the drug solution MCA :- Solution was prepared by dissolving methylcobalamin (Himedia) in distilled water. The drug solution was stored in air tight amber coloured bottles at room temperature in a cool and dry place away from moisture and sunlight. The solutions were freshly prepared at the time of dosing for daily administration. The volume of drug solutions were calculated based upon the body weight of the animal.
Our results indicate that in untreated group of animals (DU), there was no glycemic control, which led to hyperalgesia and allodynia in the models of tail immersion (hot and cold) and hot plate mothod. Whereas by a proper check on blood glucose levels by pioglitasone 10 mg/kg, O.D alongwith the supplementation of methylcobalamin 500 mcg/kg, I.P protected the diabetic animals from algesia produced by noxious and non- noxious stimuli.
Precision of an analytical method is usually expressed as the standard deviation. The repeatability studies were carried out by estimating response of Epalrestat 150μg/ml and Pregabalin 75μg/ml six times. The intra-day and inter-day precision studies (intermediate precision) were carried out by estimating the corresponding responses three times on the same day and on three different days for three same concentrations and the results are reported in terms of relative standard deviation. See Table no.3
The system suitability of the method was checked by repeated preparations for 160 µg/mL for methylcobalamin, 120 µg/mL for alpha-lipoic acid, 80 µg/mL for pyridoxine hydrochloride, and 40 µg/mL for folic acid. The typical values for evaluating system suitability of a chromatographic procedure are RSD <2%, tailing factor <2%, and theoretical plates >2000. The retention time, peak area, theoretical plates, and tailing factor were evaluated for the system suitability data of methylcobalamin, alpha-lipoic acid, pyridoxine hydrochloride, and folic acid are shown in Table 1. Table 1: System suitability parameters for methylcobalamin, alpha-lipoic acid, pyridoxine hydrochloride, and folic acid Parameters Methylcobalamin Alpha-lipoic acid Pyridoxine hydrochloride Folic acid Acceptance criteria
Introduction: Vitamin B complex has been used for peripheral neuropathy for a long time and continues to be part of current practice despite lack of strong evidence for its use and its non-inclusion in treatment guidelines. Objective: To determine the clinical and neurophysiological effects of 1500 μgm/day of oral methylcobalamin among subjects with diabetic polyneuropathy. Methodology: We conducted a prospective, open-label study on adult diabetic subjects with polyneuropathy who were given 1500 μgm/day of oral methylcobalamin over 24-weeks. The pri- mary outcome measure was the Toronto Clinical Scoring System (CSS) and secondary measures were Subjective Impression of Change, Clini- cians Impression of Change and neurophysi- ological parameters. Results: Out of forty eight subjects, thirty seven completed treatment and twenty one agreed to have repeat neurophysi- ologic study post-treatment. At the end of treatment, there was a significant decline in the Toronto CSS score (p < 0.0001) indicating im- provement. This was observed across all stages of severity and in any duration of diabetes whether more or less than 10 years. The symp- toms that improved compared to baseline and that did not emerge over the course of 24 weeks were tingling (p < 0.03), upper limb symptoms (p < 0.003), ataxia (p < 0.004), and signs of im- paired position (p < 0.009) sense, vibration sense (p < 0.0001), pinprick sensation (p < 0.004) and knee reflex (p < 0.004). No significant im- provement was seen in the secondary outcomes (both p = 0.06) except for ulnar nerve amplitude and distal latency. Conclusion: This 24-week open label study demonstrated that symptoms of diabetic polyneuropathy significantly im-
is reversible, and the reasonability of the choice of treatment will directly decide treatment outcome [2,3] . Epalrestat belongs to aldose reductase inhibitor, it reversibly inhibits the aldose reductase in the polyol metabolism process to reduce the production of sorbitol that affects nerve cell function, and it has been successfully applied in diabetic peripheral neuropathy  . At present, some scholars put forward that epalrestat can also optimize renal function and can be used as the adjuvant drug for EDN, but the relevant research reports are fewer. In the following study, the influence of adjuvant epalrestat treatment of early diabetic nephropathy on renal function and oxidative stress was analyzed.
Objective: The present study was designed to evaluate the protective effects of epalrestat (EPS) on memory and learning in type-2 diabetes. Methods: Sixty percent high-fat diet for 2 weeks and a single dose of streptozotocin (35 mg/kg, ip) was used to induce memory impairment in rats. Once the diabetes is confirmed, test drug (EPS - 13.5, 27, and 54 mg/kg, oral) and donepezil (1 mg/kg, oral) were administered to different groups of rats for 4 weeks followed by an assessment of memory and learning deficit using behavioral paradigms: Elevated plus maze (EPM), Morris water maze (MWM), and passive avoidance test.
AR contributes to collagen-induced platelet aggregation under NG and HG conditions. We next tested the effect of 5.5 or 25 mmol/l glu- cose (basal or hyperglycemia) on human platelets in the presence or absence of epalrestat (selective AR inhibitor [ARI]). As shown in Figure 3, glucose again potentiated collagen-stimulated aggre- gation in human platelets. In response to 1 μg/ml collagen, the aggregation in 25 mmol/l glucose was 25% higher than that in 5.5 mmol/l glucose and was attenuated by treatment with 1–10 μmol/l epalrestat (Figure 3, A–C), suggesting that such aggregation was abolished by inhibition of AR. The concentration of epalrestat used in the present study was based on the dose-response curve (Supplemental Figure 1; supplemental material available online with this article; doi:10.1172/JCI59291DS1), which is consistent with previous studies (14). To corroborate the spectrophotometric aggregation assays, P selectin, the marker for platelet activation, was analyzed using flow cytometry. As in Figure 2F, collagen- induced P selectin surface expression was enhanced in HG com- pared with NG (Figure 3, D–F), and epalrestat effectively attenu- ated the increase in P selectin. In addition, genetic knockdown of AR reduced the P selectin translocation to membrane in collagen- stimulated megakaryocyte (MEG-01) platelet-like particles in NG (Supplemental Figure 2). We further reconfirmed the specificity in response to collagen activation using 2 concentrations of col- lagen, arachidonic acid (AA), ADP, and thrombin receptor agonist peptide (TRAP) in addition to epalrestat (Supplemental Figure 3). These results combined suggest that AR plays a central role in col- lagen-induced platelet aggregation under NG, but particularly under HG, conditions. Supporting these data, we found that HG alone or collagen treatment in NG increased AR activity and that the combination of collagen and HG potentiated this effect (Fig- ure 4A). This increase in activity could not be accounted for by increased AR expression, as collagen treatment (in NG or HG, but not HG alone) induced only a modest increase in AR expression (Figure 4B), which did not correlate with the degree of activation (Figure 4A). Mannitol was used as osmotic control to demonstrate that AR expression is not affected by the increased osmolarity. Thus, collagen and HG synergize in activating AR.
respectively and results were given in table 5. Robustness of the method is the ability of the method to remain unaffected by small deliberate changes in parameters like flow rate, mobile phase composition and column temperature. To study the effect of flow rate of the mobile phase it was changed to 0.1 units from 1.0 mL to 0.8 mL and 1.2 mL. The effect of column temperature also checked by changing temperature to ± 5 o C. This deliberate change in the above parameters has no significant effect on chromatographic behaviour of the samples and results were given in table 6. LOD and LOQ of Epalrestat and Pregabalin were evaluated based on relative standard deviation of the response and slope of the calibration curve. The detection limits were found to be 0.19µg/mL and 0.50µg/mL for Epalrestat and Pregabalin respectively. The quantification limits were found to be 0.57µg/mL and 1.51µg/mL for Epalrestat and Pregabalin respectively. The results were given in the table 7.
The subjects were randomly assigned to each arm, according to an Fx-115ms computer generated simple randomisation list. The oral methylcobalamin arm was an 1mg lozenge supplied and certified by Jarrow Formulas Inc, Los Angeles, USA. The rationale for choosing the dose size and frequency of consumption of the methylcobalamin was to ensure that there was an effect in the duration of the study, which also took into account any inadvertent dosage changes due to possible methylcobalamin instability.