Antidiabetic effect of mangiferin in combination with oral hypoglycemic agents metformin and gliclazide.

BACKGROUND: Diabetes mellitus poses serious threat to the global population due to the alarming diabetic complications it leads to. The current therapeutic options available can be improved for better efficiency and maximum benefits. Combination therapy has been commonly used to improve the efficacy and to minimize the side effects of drugs in current clinical use. PURPOSE: The present study aims to assess the interaction between a natural molecule mangiferin with the commercially available oral hypoglycemic drugs metformin and gliclazide in diabetic rats. METHODS: In this study, the in vitro cytotoxicity and glucose uptake studies were performed in HepG2 cells. Based on experimental data, the combination index of the hypoglycemic drugs like metformin and gliclazide in combination with different doses of mangiferin was determined using COMPUSYN software. Further, in vivo studies were performed in HFD + STZ induced diabetic male Sprague Dawley rats. Serum parameters, enzyme markers, hepatic oxidative stress markers, gene and protein expression studies and histopathological analyses were performed in rat liver to identify the mode of action of the combination drug administration. RESULTS: The in vitro studies on HepG2 cells suggest a positive interaction of mangiferin with both metformin and gliclazide at specific concentrations as evidenced by glucose uptake. The hepatic enzymes, oxidative stress markers, carbohydrate metabolizing enzymes, gene (AMPK, Akt, ACC ß and Glut-2) and protein (PPARα, PPARγ) expression confirmed the results of the in vitro studies. Both the combinations of mangiferin with metformin and mangiferin with gliclazide exhibited potent antidiabetic effect. The combination of mangiferin with metformin was insulin dependent (Akt pathway) whereas the combination of mangiferin and gliclazide was insulin independent (AMPK pathway). CONCLUSION: The overall results suggest that combination of mangiferin with both metformin and gliclazide alleviates diabetic conditions potentially at specific doses and modulates the adverse effect of high dose of commonly used OHD's. This combination therapy can be translated for its clinical use as a diabetes management strategy.

Development of novel gastroretentive drug delivery system of gliclazide: hollow beads.

AIM: The current communication deals with the development of hollow floating beads of gliclazide. The primary effect of this drug is to potentiate glucose-stimulated insulin release from pancreatic islet-ß-cells by induction of a decrease in potassium efflux from these cells. Because of the poor aqueous solubility, its absorption is limited. Thus, an attempt was made to improve its release profile. METHODS: The hollow drug-loaded alginate beads in combination with low methoxyl pectin and hydroxypropylmethylcellulose (HPMC) were prepared by a simple ionotropic gelation method. The beads were evaluated for particle size and morphology using optical microscopy and scanning electron microscopy (SEM), respectively. Mucoadhesion test was done using goat stomach mucosal membrane. Release characteristics of the gliclazide-loaded hollow beads were studied in 0.1 N HCl (pH 1.2) and phosphate buffer (pH 5.8). RESULTS: The developed beads were spherical in shape with hollow internal structure and had a particle size in the range of 0.730 ± 0.05 to 0.890 ± 0.03 mm. The incorporation efficiency of alginate -pectin beads was higher than alginate -HPMC beads. The Fourier transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC) and X-ray diffraction analysis showed stable character of drug in the drug-loaded hollow beads and revealed the absence of any drug -polymer interactions. The beads remained buoyant for more than 12 h. The drug release from beads followed Fickian diffusion with swelling. CONCLUSION: The preliminary results of this study suggest that the developed beads containing gliclazide could enhance drug entrapment efficiency, reduce the initial burst release and modulate the drug release.

Development of novel gastroretentive floating particulate drug delivery system of gliclazide.

The objective of present project was to improve the dissolution profile of gliclazide by developing floating alginate beads using various biodegradable polymers like gelatin, pectin and hydroxypropylmethylcellulose (HPMC). The floating beads were prepared by a simple ionotropic gelatin method using calcium carbonate as gas generating agent. The developed beads were characterized by Fourier transform infrared spectroscopy analysis, differential scanning calorimetry, X-ray diffraction analysis and scanning electron microscopy (SEM). The prepared beads showed good in vitro floatation, which was dependent on the concentration of gas-forming agent. SEM photomicrographs confirmed that the developed beads were spherical in shape and had particle size in the range of 730 to 890 µm. The incorporation efficiency was found to be in the range of 59.96 to 85.1%. The cumulative percent drug release from the beads after 10 h dissolution study at pH 1.2 and pH 5.8 was in the range of 33 to 46% and 82 to 95% respectively. The concentration of the gas generating agent was found to influence the release rate. The mechanism of drug release was Fickian diffusion with swelling. The in vivo sub-acute hypoglycemic study in high fat diet induced diabetic C57BL/6J mice demonstrated significant (p < 0.05) hypoglycemic effect over a period of 12 h and 24 h, respectively, with HPMC and pectin beads. A significant (p & 0.05) reduction in fasting and non-fasting blood glucose levels, reduction in fasting plasma insulin level and a significant improvement in glucose tolerance were observed in animals treated with formulations. The developed beads were suitable carriers for improving the systemic absorption of gliclazide and maintaining reduced blood glucose levels.

Adverse cardiovascular events during treatment with glyburide (glibenclamide) or gliclazide in a high-risk population.

AIMS: Sulphonylureas promote insulin release by inhibiting pancreatic potassium channels. Older sulphonylureas such as glyburide (glibenclamide), but not newer ones such as gliclazide, antagonize similar channels in myocardium, interfering with the protective effects of ischaemic preconditioning. Whether this imparts a higher risk of adverse cardiac events is unknown. METHODS: We conducted a population-based cohort study of patients aged 66 years and older who were hospitalized for acute myocardial infarction or who underwent percutaneous coronary intervention between 1 April 2007 and 31 March 2010 while receiving either glyburide or gliclazide. We used a high-dimensional propensity score matching process to ensure similarity of glyburide- and gliclazide-treated patients. The primary outcome was a composite of death or hospitalization for myocardial infarction or heart failure. RESULTS: During the 2-year study period, we matched 1690 patients treated with glyburide to 984 patients treated with gliclazide at the time of hospitalization for acute myocardial infarction or percutaneous coronary intervention. We found no difference in the risk of the composite outcome among patients receiving glyburide (adjusted hazard ratio 1.01; 95% CI 0.86-1.18). We found similar results in secondary analyses of each outcome individually, and in two supplementary analyses (haemorrhage and pneumonia) in which we anticipated no difference between the two patient groups. CONCLUSIONS: Among older patients hospitalized for acute myocardial infarction or percutaneous coronary intervention, treatment with glyburide is not associated with an increased risk of future adverse cardiovascular events relative to gliclazide, suggesting that the effect of glyburide on ischaemic preconditioning is of little clinical relevance.

Protective effects of combined therapy of gliclazide with curcumin in experimental diabetic neuropathy in rats.

Diabetic neuropathy is the most common chronic complication of diabetes. The aim of the present study was to evaluate the protective effects of curcumin against neuropathy in gliclazide-treated diabetic rats. Diabetes was induced by an intraperitoneal injection of streptozotocin (45 mg/kg). Diabetic animals were given gliclazide (10 mg/kg, orally) alone or combined with curcumin (100 mg/kg, orally) or gabapentin (30 mg/kg, intraperitoneally as a positive control). Behavioral responses to thermal (hot plate and tail flick) and mechanical (tail pinch) pain, and some biochemical tests (serum glucose, C-peptide, peroxynitrite, lipid peroxides, and tumor necrosis factor-α) were assessed after 5 consecutive weeks of daily treatment. Combined treatment of curcumin with gliclazide significantly increased hot-plate and tail-flick latencies in comparison with that of the diabetic control group. The threshold of mechanical hyperalgesia was also significantly elevated. Serum glucose and C-peptide levels were significantly increased in the combined treatment compared with the diabetic control group, whereas serum levels of peroxynitrite, lipid peroxide, and tumor necrosis factor-α production were significantly decreased. The data suggest that the combination of curcumin with gliclazide may protect against the development of diabetic neuropathy, with favorable effects with respect to the gliclazide/gabapentin combination.

Novel tamarind seed polysaccharide-alginate mucoadhesive microspheres for oral gliclazide delivery: in vitro-in vivo evaluation.

Novel tamarind seed polysaccharide (TSP)-alginate mucoadhesive microspheres were prepared using TSP and alginate as blend in different ratios with different calcium chloride (CaCl(2)) concentration as a cross linker by ionotropic gelation. The prepared microspheres were of spherical shape having rough surfaces, and average particle sizes within the range of 752.12 ± 6.42 to 948.49 ± 20.92 µm. The drug entrapment efficiency of these microspheres were within the range between 58.12 ± 2.42 to 82.78 ± 3.43% w/w. Fourier transform infrared (FTIR) studies indicated that there were no reactions between gliclazide, and polymers (TSP, and sodium alginate) used. Different formulations of gliclazide loaded TSP-alginate microspheres showed prolonged in vitro release profiles of gliclazide over 12 hours in both stomach pH (pH 1.2), and intestinal pH (pH 7.4). It was found that the gliclazide release in gastric pH was comparatively slow and sustained than intestinal pH. These TSP-alginate microspheres also exhibited good mucoadhesivity. The in vivo studies on alloxan-induced diabetic rats (Animal Ethical Committee registration number: IFTM/837ac/0160) demonstrated the significant hypoglycemic effect of selected formulation of TSP-alginate mucoadhesive microspheres containing gliclazide on oral administration. This developed gliclazide loaded new TSP-alginate mucoadhesive microspheres may be very much useful for prolonged systemic absorption of gliclazide for proper maintaining blood glucose level and advanced patient compliance.

Formulation and evaluation of Ficus glomerata mucilage sustained release matrix tablets of gliclazide.

The main aim of present investigation was to develop sustained release matrix tablets of Gliclazide using fruit mucilage from the plant Ficus glomerata. Varying ratios of drug and polymer viz. 1:0.25, 1:0.5, 1:0.75, 1:1.0 and 1:1.25 were selected for the study. The flow properties of powdered mucilage and physical properties of matrix tablets were performed. The swelling behavior and release rate characteristics were studied. The in vitro drug release data was analyzed by zero order, first order, Higuchi plot, Peppas plot and Hixon-Crowell Models. It was observed that as the proportion of mucilage increased the release of drug from the matrix tablets was retarded. Stability studies were conducted at 40±2ºC and RH 75±5% for 3 months indicates that Gliclazide was stable in the matrix tablets. The Differential Scanning Calorimetric (DSC) and Fourier Transform Infrared (FTIR) study revealed that there was no negative chemical interaction between drug and the mucilage used. From the dissolution study, it was concluded that dried Ficus glomerata mucilage can be used as an excipient for making sustained release matrix tablets.

Design and development of gliclazide-loaded chitosan microparticles for oral sustained drug delivery: in-vitro/in-vivo evaluation.

OBJECTIVES: The objective of this study was to prepare gliclazide-chitosan microparticles with tripolyphosphate by ionic crosslinking. METHODS: Chitosan microparticles were produced by emulsification and ionotropic gelation. The effects of process variables including chitosan concentration, pH of tripolyphosphate solution, glutaraldehyde volume and release modifier agent such as pectin added to the tripolyphosphate crosslinking solution were evaluated. The microparticles were examined with scanning electron microscopy, infrared spectroscopy and differential scanning colorimetry. The serum glucose lowering effect of gliclazide microparticles was studied in streptozotocin-diabetic rabbits compared with the effect of pure gliclazide powder and gliclazide commercial tablets. KEY FINDINGS: The particle sizes of tripolyphosphate-chitosan microparticles were over the range 675-887 µm and the loading efficiency of drug was greater than 94.0%. In-vivo testing of the gliclazide-chitosan microparticles in diabetic rabbits demonstrated a significant antidiabetic effect of gliclazide-chitosan microparticles after 8 h that lasted for 18 h compared with gliclazide powder, which produced a maximum hypoglycaemic effect after 4 h. CONCLUSIONS: The results suggests that gliclazide-chitosan microparticles are a valuable system for the sustained delivery of gliclazide.

Design and development of gliclazide mucoadhesive microcapsules: in vitro and in vivo evaluation.

In this study an attempt was made to prepare mucoadhesive microcapsules of gliclazide using various mucoadhesive polymers designed for oral controlled release. Gliclazide microcapsules were prepared using sodium alginate and mucoadhesive polymer such as sodium carboxymethyl cellulose (sodium CMC), carbopol 934P or hydroxy propylmethyl cellulose (HPMC) by orifice-ionic gelation method. The microcapsules were evaluated for surface morphology and particle shape by scanning electron microscope. Microcapsules were also evaluated for their microencapsulation efficiency, in vitro wash-off mucoadhesion test, in vitro drug release and in vivo study. The microcapsules were discrete, spherical and free flowing. The microencapsulation efficiency was in the range of 65-80% and microcapsules exhibited good mucoadhesive property in the in vitro wash off test. The percentage of microcapsules adhering to tissue at pH 7.4 after 6 h varied from 12-32%, whereas the percentage of microcapsules adhering to tissue at pH 1.2 after 6 h varied from 35-68%. The drug release was also found to be slow and extended for more than 16 h. In vivo testing of the mucoadhesive microcapsules in diabetic albino rats demonstrated significant antidiabetic effect of gliclazide. The hypoglycemic effect obtained by mucoadhesive microcapsules was for more than 16 h whereas gliclazide produced an antidiabetic effect for only 10 h suggesting that mucoadhesive microcapsules are a valuable system for the long term delivery of gliclazide.

Hypoglycemic effects of a sesquiterpene glycoside isolated from leaves of loquat (Eriobotrya japonica (Thunb.) Lindl.).

Sesquiterpene glycoside, nerolidol-3-O-alpha-l-rhamnopyranosyl(1-->4)-alpha-l-rhamnopyranosyl(1-->2)-[alpha-l-rhamnopyranosyl(1-->6)]-beta-d-glucopyranoside was isolated from dried leaves of loquat [Eriobotrya japonica (Thunb.) Lindl., Rosaceae]. Hypoglycemic effects of this natural product were assessed in normal and alloxan-diabetic mice model. Animals received orally administration of the sesquiterpene glycoside in dose of 25 and 75 mg/kg. The anti-hyperglycemic effect was compared with gliclazide's. The dose of 25 and 75 mg/kg both exerted a significant (p<0.05) hypoglycemic effect in alloxan-diabetic mice throughout the test and a slight effect in normal mice.

Preparation and in vitro/in vivo evaluation of gliclazide loaded Eudragit nanoparticles as a sustained release carriers.

The aim of this study was to formulate and optimize gliclazide-loaded Eudragit nanoparticles (Eudragit L100 and Eudragit RS) as a sustained release carrier with enhanced efficacy. Eudragit L 100 nanoparticles (ELNP) were prepared by controlled precipitation method whereas Eudragit RSPO nanoparticles (ERSNP) were prepared by solvent evaporation method. The influence of various formulation factors (stirring speed, drug:polymer ratio, homogenization, and addition of surfactants) on particle size, drug loading, and encapsulation efficiency were investigated. The developed Eudragit nanoparticles (L100 and RS) showed high drug loading and encapsulation efficiencies with nanosize. Mean particle size altered by changing the drug:polymer ratio and stirring speed. Addition of surfactants showed a promise to increase drug loading, encapsulation efficiency, and decreased particle size of ELNP as well as ERSNP. Dissolution study revealed sustained release of gliclazide from Eudragit L100 as well as Eudragit RSPO NP. SEM study revealed spherical morphology of the developed Eudragit (L100 and RS) NP. FT-IR and DSC studies showed no interaction of gliclazide with polymers. Stability studies revealed that the gliclazide-loaded nanoparticles were stable at the end of 6 months. Developed Eudragit NPs revealed a decreased t(min) (ELNP), and enhanced bioavailability and sustained activity (ELNP and ERSNP) and hence superior activity as compared to plain gliclazide in streptozotocin induced diabetic rat model and glucose-loaded diabetic rat model. The developed Eudragit (L100 and RSPO) NP could reduce dose frequency, decrease side effects, and improve patient compliance.

The mushroom Agaricus Blazei Murill in combination with metformin and gliclazide improves insulin resistance in type 2 diabetes: a randomized, double-blinded, and placebo-controlled clinical trial.

BACKGROUND: Complementary and alternative medicine use in adults with type 2 diabetes is popular. Although most of the herbs and supplements appear to be safe, there is still insufficient evidence that demonstrates their definitive beneficial effects. This study was done to determine whether the supplement of Agaricus blazei Murill extract improves insulin resistance in type 2 diabetes. MATERIALS AND METHODS: This study was a clinical randomized, double-blind, placebo-controlled trial. Of a population of 536 registered diabetes patients with 72 subjects (1) aged between 20 and 75 years, (2) being Chinese, (3) having type 2 diabetes for more than 1 year, and (4) having been taking gliclazide and metformin for more than 6 months were enrolled in this study. The enrolled patients were randomly assigned to either receiving supplement of Agaricus blazei Murill (ABM) extract or placebo (cellulose) 1500 mg daily for 12 weeks. Homeostasis model assessment for insulin resistance (HOMA-IR) was used as the major outcome measurement. RESULTS: At the end of the study, subjects who received supplement of ABM extract (n = 29) showed significantly lower HOMA-IR index (3.6[standard deviation, 2.5] versus 6.6[standard deviation, 7.4], p = 0.04) than the control group (n = 31). The plasma adiponectin concentration increased 20.0(standard deviation, 40.7)% in the ABM group after 12 weeks of treatment, but decreased 12.0(20.0)% among those taking the placebo (p < 0.001). CONCLUSIONS: Supplement of ABM extract improves insulin resistance among subjects with type 2 diabetes. The increase in adiponectin concentration after taking AMB extract for 12 weeks might be the mechanism that brings the beneficial effect. Studies with longer periods of follow-up should be conducted in the future.

Clinical observation on effect of Kaixin capsule in treating 40 patients with diabetic myocardial ischemia.

OBJECTIVE: To observe the effect of Kaixin Capsule (KXC) on myocardial ischemia and plasma endothelin (ET) level in patients with diabetic heart disease (DHD). METHODS: The 72 subjects for observation were randomly selected from inpatients whose diagnosis fit to the standard of DHD. The 32 patients allocated in the control group were treated with conventional Western medicine, and the 40 patients in the treated group were treated with conventional Western medicine in combination with KXC, with the therapeutic course for both groups as 60 days. RESULTS: On ECG, the total effective rate and markedly effective rate in the treated group was 85.0% and 37.5% respectively, higher than those in the control group's 68.7% and 28.1% respectively, and showing significant difference between the two groups (P < 0.05). The level of ET in patients in both groups was significantly higher than normal range, after treatment, but reduced to different extent, and the comparison between them also showed that the difference was significant (P < 0.05). CONCLUSION: KXC might, by way of inhibiting and blocking the release of ET, lower its level in plasma so as to improve the myocardial ischemic condition of patients with DHD.

[Effect of oral antidiabetic agents on fructose biosynthesis]. / Viianie protivodiabeticheskikh sredtstv dlia priema vnutr' na obrazovanie fruktozamina.

The oral antidiabetic drugs (glyformin, glyclaside, glycvidon, glybenclamide) at a concentration of 10-196 mM affect the synthesis of fructosamine in an incubation medium containing 40 mM of glucose and 5% of human serum albumin. All these drugs decrease the fructosamine yield measured in the medium on the 4th day of incubation at 37-198 degrees C, while the effect of glycvidon is pronounced even on the 7th day. The introduction of glyformin, glycvidon, and glybenclamide at an amount close to the maximum daily dose over a period of one month reduces the level of fructosamine in the blood of rats with experimental diabetes mellitus, while not affecting the level of glucose in the blood of test animals. Thus, the oral antidiabetic drugs reduce the level of fructosamine--an agent known to modify the protein structure, thus favoring the development of complications in the course of diabetes under permanent hyperglycemia conditions.

The effects of gliclazide and other sulfonylureas on low-density lipoprotein oxidation in vitro.

Diabetes is associated with increased oxidant stress. This may contribute to the development of diabetic macrovascular complications through increased oxidation of low-density lipoprotein (LDL), which is thought to be a crucial step in the development of atherosclerosis. The sulfonylurea gliclazide has been shown to have free radical-scavenging activity in vitro, but its effects on LDL oxidation, and these effects of other sulfonylureas, are unknown. To investigate this we studied the effects of in vitro supplementation with gliclazide 1 mumol/L on copper-induced oxidation of LDL isolated from 20 control subjects and 22 type II diabetic patients. The effects of 1 mumol/L vitamin C, a known water-soluble antioxidant, were studied simultaneously. The resistance to oxidation, expressed as the lag time between the addition of copper and commencement of oxidation, was significantly increased by both gliclazide and vitamin C, and the effect was similar for LDL from diabetic and control subjects. The baseline oxidation lag time was 63.4 +/- 2.1 minutes, and increased to 108 +/- 4.4 minutes with gliclazide and 88.7 +/- 5.6 minutes with vitamin C (P = .0001, baseline v either treatment). The increase in lag time with gliclazide of 70% +/- 3% was greater than the 30% +/- 5% increase with vitamin C (P < .0005). In a separate experiment, LDL isolated from eight control and 10 diabetic subjects was supplemented with 1 mumol/L gliclazide, glibenclamide, glipizide, and tolbutamide. For each LDL sample, all drugs were studied simultaneously and the oxidation lag time was compared against that of untreated LDL. Gliclazide increased the lag time from 53.7 +/- 2.4 minutes to 108.4 +/- 4.5 minutes (P = .0001). None of the other sulfonylureas had any effect on lag time. These findings demonstrate that gliclazide is an effective inhibitor of in vitro LDL oxidation, and in this respect, it is more potent on a molar basis than vitamin C. This antioxidant property of gliclazide was not shared by the other sulfonylureas studied.

[Clinical observation on diabetic nephropathy treated with alcohol of Abelmoschus manihot].

Sixty-eight cases of non-insulin dependent diabetes mellitus (NIDDM) complicated with nephropathy were randomly divided into two groups: treated group, 35 cases treated with alcohol extraction of Abelmoschus manihot, Gliclazide and Captopril tablets; control group, 33 cases treated with Gliclazide and Captopril tablets, over a period of 8 weeks. The total effective rate in treated and control group were 83.87% and 31.03%(P < 0.01), urinary micro-albumin were 31.7 mg/L and 76.3 mg/L (P < 0.05), proteinuria were 0.41 g/24h and 0.77 g/24h (P < 0.01), blood beta 2-microglobulin were 3317.8 ng/ml and 3473.1 ng/ml (P < 0.05), urinary beta 2-microglobulin were 367.2 ng/ml and 641.5 ng/ml (P < 0.01), urinary N-acetyl-beta-glucosaminidase (NAG) were 26.3 u/L and 66.7 u/L (P < 0.01), plasma lipid peroxide (LPO) were 6.13 nmol/L and 8.78 nmol/L (P < 0.05), and plasma superoxide anion were 8.36 kcpm and 10.42 kcpm respectively (P < 0.05). It was suggested that Abemoschus manihot alcohol extraction could eliminate oxygen free radicals, alleviate renal tubular-interstitial diseases, improve renal function and reduce proteinuria.