Antidiabetic drug administration prevents bone mineral density loss: Evidence from a two-sample Mendelian randomization study.

The aim of this study was to investigate the effect of common antidiabetic drugs on BMD by two-sample Mendelian randomization (MR). The single nucleotide polymorphisms that were strongly associated with insulin, metformin, rosiglitazone and gliclazide were extracted as instrumental variables (IVs) for MR analysis. The inverse variance weighted (IVW) method was used as the primary MR method to assess the causal effect of antidiabetic drugs on BMD, and other MR methods, including Weighted median, MR Egger and Weighted mode, were used for complementary analysis. Reliability and stability were assessed by the leave-one-out test. In the present work, IVW estimation of the causal effect of insulin on heel BMD demonstrated that there was a null effect of insulin on heel BMD (ß = 0.765; se = 0.971; P = 0.430), while metformin treatment had a positive effect on heel BMD (ß = 1.414; se = 0.460; P = 2.118*10-3). The causal relationship between rosiglitazone and heel BMD analysed by IVW suggested that there was a null effect of rosiglitazone on heel BMD (ß = -0.526; se = 1.744; P = 0.763), but the causal effect of gliclazide on heel BMD evaluated by IVW demonstrated that there was a positive effect of gliclazide on heel BMD (ß = 2.671; se = 1.340; P = 0.046). In summary, the present work showed that metformin and gliclazide have a role in reducing BMD loss in patients with diabetes and are recommended for BMD loss prevention in diabetes.

Crude extract from Euphorbia prostrata extended curative period of glibenclemide in alloxan-induced diabetic rats.

OBJECTIVES: Euphorbia prostrata is traditionally used alongside antidiabetic agents to manage diabetes. Bioactive ingredients of medicinal herbs may alter the overall pharmacokinetics of antidiabetic agents. METHODS: We assessed hypoglycemic activities of ethanolic plant extract (EPE) singly and its effects on antidiabetic properties of gliclazide, glibenclemide and metformin in allaxonized rats. Varying concentrations of EPE (250 and 500 mg/kg) with or without metformin (10 mg/kg), glibenclemide (2 mg/kg) and gliclazide (5 mg/kg) were orally administered to evaluate herb-drug interaction. RESULTS: The levels of blood glucose declined significantly after treatment with metformin, glibenclemide and gliclazide singly (p<0.01) or concomitantly with EPE (p<0.001). Concentration dependent mild to moderate reduction (5.2 and 10.0%) was registered in blood glucose for 250 and 500 mg/kg of EPE respectively. The overall reduction in blood glucose due to combined treatment with EPE and standard agents was additive. On the other hand, synergistic herb-drug interaction was registered for insulin levels in rats that received glibenclamide and gliclazide alongside EPE. Extract with metformin had antagonistic insulin outcome. Regarding the duration of hypoglycemic activities, periodical changes were similar in case of glibenclamide and gliclazide separately or in combination with EPE. However, in case of metformin with extract, the blood glucose continued to decline for 14 h and retained at 15.0% below the baseline values even after 24 h of treatment. CONCLUSIONS: In conclusion, the extract itself had weak hypoglycemic effects but prolonged the therapeutic duration of metformin to more than 24 h when administered combinedly.

Effect of Nigella sativa oil on pharmacokinetics and pharmacodynamics of gliclazide in rats.

Nigella sativa oil (NSO) has been used widely for its putative anti-hyperglycemic activity. However, little is known about its potential effect on the pharmacokinetics and pharmacodynamics of antidiabetic drugs, including gliclazide. This study aimed to investigate herb-drug interactions between gliclazide and NSO in rats. Plasma concentrations of gliclazide (single oral and intravenous dose of 33 and 26.4 mg/kg, respectively) in the presence and absence of co-administration with NSO (52 mg/kg per oral) were quantified in healthy and insulin resistant rats (n = 5 for each group). Physiological and treatment-related factors were evaluated as potential influential covariates using a population pharmacokinetic modeling approach (NONMEM version 7.4). Clearance, volume of distribution and bioavailability of gliclazide were unaffected by disease state (healthy or insulin resistant). The concomitant administration of NSO resulted in higher systemic exposures of gliclazide by modulating bioavailability (29% increase) and clearance (20% decrease) of the drug. A model-independent analysis highlighted that pre-treatment with NSO in healthy rats was associated with a higher glucose lowering effect by up to 50% compared with that of gliclazide monotherapy, but not of insulin resistant rats. Although a similar trend in glucose reductions was not observed in insulin resistant rats, co-administration of NSO improved the sensitivity to insulin of this rat population. Natural product-drug interaction between gliclazide and NSO merits further evaluation of its clinical importance.

Effect of berberine on in vitro metabolism of sulfonylureas: A herb-drug interactions study.

Patients with type 2 diabetes may co-ingest herbal and prescription medicines to control their blood sugar levels. Competitive binding of drug and herb may mutually affect their metabolism. This can alter the level of drug and its kinetics in the body, potentially causing toxicities or loss of efficacy. Understanding how the metabolism of sulfonylureas like glyburide and gliclazide can be affected by the presence of berberine and vice versa can provide valuable information on the possible risk of toxicities caused by co-ingestion of drugs. METHODS: Berberine and sulfonylureas (glyburide and gliclazide) were co-incubated with rat liver microsomes in the presence of a NADPH-regenerating system. The metabolites of berberine and sulfonylureas were analysed using liquid chromatography with high-resolution mass spectrometry in the positive ion mode. The role of individual isozymes in the metabolism of berberine, glyburide and gliclazide was investigated by using specific inhibitors. RESULTS: In vitro metabolism of berberine led to the formation of demethyleneberberine (B1a) and its isomer B1b through demethylenation. Berberrubine (B2a) and its isomer B2b were formed through demethylation. The isozymes CYP3A and CYP2D were found to be involved in the metabolism of berberine. In vitro metabolism of glyburide and gliclazide led to the formation of hydroxylated metabolites. The isozymes CYP3A and CYP2C were found to be involved in the metabolism of glyburide. Gliclazide was metabolised by CYP2C. In vitro co-incubation of glyburide or gliclazide with berberine showed that each drug's metabolism was compromised as they share a common isozyme. A strong negative linear correlation of glyburide or gliclazide metabolite levels and the concentration of berberine confirmed the effect of berberine on the metabolism of sulfonylureas. CONCLUSIONS: The metabolism of sulfonylureas and berberine was affected when these compounds were co-incubated with each other. This may be attributable to competitive binding of the herb and drug to the catalytic sites of the same isozymes.

Preclinical and clinical results regarding the effects of a plant-based antidiabetic formulation versus well established antidiabetic molecules.

Diabetes mellitus (DM) is a complex syndrome with debilitating long-term complications, comprising alterations of carbohydrate, protein and lipid metabolisms, along increased oxidative stress and chronic low-grade inflammation. Diet management and plant-based formulations can improve the metabolic status of patients, being used as adjuvants of classic antidiabetic therapy. The purpose of our study was to evaluate the impact of a plant-based antidiabetic formulation (PBAF), containing Vaccinium myrtillus, Ribes nigrum, Rosa canina and Capsicum annuum, on the increased oxidative burden found in diabetes mellitus, comparing it with the effects of metformin and gliclazide. Firstly, we characterized the individual plant-derived components of this formulation and also assessed their in vitro radical scavenging capacity. We devised a preclinical study protocol to examine the impact of the PBAF, along metformin and gliclazide, on tissue histology as well as on the redox status of tissue, mitochondria, serum and serum lipoproteins of alloxan-induced diabetic Wistar rats. Subsequently, we assessed their long-term impact on the redox status of serum and isolated serum lipoproteins of type 2 DM (T2DM) patients, taking into consideration their cardiometabolic profile. In the preclinical stage, we found that PBAF was able to enhance total serum antioxidant defense, while metformin yielded the best results regarding the advanced glycation and protein/lipid oxidation of serum and of serum lipoproteins. The latter also improved overall serum redox status and HDL redox function. Also, antidiabetic treatment seemed to increase mitochondrial redox activity, without overturning overall tissue redox balance. Histologically, liver and brain tissues of treated diabetic rats were fairly similar to those of non-diabetic rats. In T2DM patients, the most striking results involved the effects on serum lipoproteins. The tested PBAF exerted protective antioxidant effects on low-density and, especially, on high density lipoproteins. We conclude that this formulation might constitute a good addition to the well-established pharmacological approach of DM, contributing to the reduction of overall oxidative burden.

Nanofibers mat as sampling module of direct analysis in real time mass spectrometry for sensitive and high-throughput screening of illegally adulterated sulfonylureas in antidiabetic health-care teas.

In this work, novel ionic liquid (IL) functionalized polyacrylonitrile nanofibers mat (IL/PAN-NFsM) was firstly prepared through thiol-ene "click" reaction and evaluated for the establishment of a sensitive and high-throughput screening method. Because of its excellent pre-separation efficiency, IL/PAN-NFsM can adsorb trace-level targets from complex sample matrix within tens of seconds by performing a solid-phase extraction (SPE) process, and then served as sampling modules of direct analysis real time mass spectrometry (DART-MS) without any additional processing. This means the target analytes concentrated on IL/PAN-NFsM were directly desorbed, ionized, and detected by DART-MS. To verify the feasibility of the proposed method, three illegal added synthetic drugs (gliclazide, glimepiride, and gliquidone) were screened in six types of antidiabetic health-care tea samples. The results indicated that the sensitivity is in the level of ng g-1, while total analysis time does not exceed 1.0 min per sample. Moreover, the stability expressed as relative standard deviation (RSD) varies from 1.7% to 17.3%. We proposed a new screening mode based on the direct combination of functionalized NFsM and DART-MS, which is expected to become a universal method in food safety analysis.

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.

Updates on Managing Type 2 Diabetes Mellitus with Natural Products: Towards Antidiabetic Drug Development.

Over the years, natural products have shown success as antidiabetics in in vitro, in vivo studies and clinical trials. Because natural product-derived drugs are more affordable and effective with fewer side-effects compared to conventional therapies, pharmaceutical research is increasingly leaning towards the discovery of new antidiabetic drugs from natural products targeting pathways or components associated with type 2 diabetes mellitus (T2DM) pathophysiology. However, the drug discovery process is very lengthy and costly with significant challenges. Therefore, various techniques are currently being developed for the preclinical research phase of drug discovery with the aim of drug development with less time and efforts from natural products. In this review, we have provided an update on natural products including fruits, vegetables, spices, nuts, beverages and mushrooms with potential antidiabetic activities from in vivo, in vitro and clinical studies. Synergistic interactions between natural products and antidiabetic drugs, and potential antidiabetic active compounds from natural products are also documented to pave the way for combination treatment and new drug discovery, respectively. Additionally, a brief idea of the drug discovery process along with the challenges that arise during drug development from natural products and the methods to conquer those challenges are discussed to create a more convenient future drug discovery process.

Efficacy and safety of metformin and sitagliptin based triple antihyperglycemic therapy (STRATEGY): a multicenter, randomized, controlled, non-inferiority clinical trial.

Despite the current guideline's recommendation of a timely stepwise intensification therapy, the "clinical inertia", termed as the delayed treatment intensification, commonly exists in the real world, which may be partly due to the relatively little substantial evidence and no clear consensus regarding the efficacy and safety of triple oral agents in patients inadequately controlled with dual therapy. In this clinical trial performed in 237 centers in China, 5,535 type 2 diabetic patients inadequately controlled by previous therapies were treated with a stable metformin/sitagliptin dual therapy for 20 weeks. The patients who did not reach the glycated hemoglobin A1c (HbA1c) goal were then further randomized into glimepiride, gliclazide, repaglinide, or acarbose group for an additional 24-week triple therapy. A mean HbA1c reduction of 0.85% was observed when sitagliptin was added to the patients inadequately controlled with metformin in 16 weeks. Further HbA1c reductions in the 24-week triple therapy stage were 0.65% in glimepiride group, 0.70% in gliclazide group, 0.61% in repaglinide group, and 0.45% in acarbose group. The non-inferiority criterion for primary hypotheses was met for gliclazide and repaglinide, but not for acarbose, compared with glimepiride, when added to metformin/sitagliptin dual therapy. The incidences of adverse events (AEs) were 29.2% in the dual therapy stage and 30.3% in the triple therapy stage. Metformin/sitagliptin as baseline therapy, with the addition of a third oral antihyperglycemic agent, including glimepiride, gliclazide, repaglinide, or acarbose, was effective, safe and well-tolerated for achieving an HbA1c <7.0% goal in type 2 diabetic patients inadequately controlled with previous therapies. The timely augmentation of up to three oral antihyperglycemic agents is valid and of important clinical benefit to prevent patients from exposure to unnecessarily prolonged hyperglycemia.

Renoprotective effect of Hypericum perforatum against diabetic nephropathy in rats: Insights in the underlying mechanisms.

Oxidative stress and inflammation play a key role in the initiation and progression of diabetic nephropathy (DN). The present study aimed to investigate the possible protective effect of hypericum perforatum (HP) against DN. Rats were allocated into six groups: control, received normal saline; diabetic untreated (DM), received single dose of streptozotocin (STZ) after injection of nicotinamide (NA); gliclazide, received STZ,NA + gliclazide (10 mg/kg); DM + HP50, DM + HP100, DM + HP200, received STZ,NA and HP 50, 100, 200 mg/kg, respectively. Gliclazide and HP were administered daily via gavage for 8 weeks. Serum glucose, insulin, kidney function and histopathological picture were assessed. Furthermore, oxidative/nitrosative stress, inflammatory cytokines, apoptotic and fibrotic markers were measured. Diabetic untreated group showed increase in serum glucose, urea, creatinine with albuminurea. Renal expression of protein for nuclear factor kappa-B (NF-кB), renal expression of inducible nitric oxide synthase (iNOS), cyclooxygenase II (COXII), collagen IV, fibronectin were elevated. Malondialdehyde (MDA), nitric oxide (NO), tumour necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), intracellular adhesion molecule (ICAM-1), monocellular chemoattractant protein-1 (MCP-1), tumour growth factor- ß (TGF-ß), caspase-3 and cytochrome c contents were also increased consequently with decline of serum insulin, expression of peroxisome proliferator-activated receptor (PPARγ), renal reduced glutathione (GSH) content and superoxide dismutase (SOD) activity. Treatment with either gliclazide or HP mitigated the deleterious effects of STZ on the tested parameters. These findings indicate for the first time that HP may have a renoprotective effect against DN through reduction of oxidative/nitrosative stress, enhancement of antioxidant defense mechanisms, decline of inflammatory cytokines, antifibrotic, antiapoptotic and blood glucose lowering properties.

Effect of a New Antioxidant Enoxifol on Platelet Aggregation and Blood Rheological Properties in Rats with Experimental Diabetes Mellitus.

Effect of a new antioxidant enoxifol exhibiting antiplatelet activity in vitro and in vivo on hemostasis parameters was assessed in laboratory rats with experimental diabetes mellitus. Gliclazide, a hypoglycemic agent with antiplatelet properties, and pentoxifylline, a preparation improving blood rheology, were used as the reference drugs. Enoxifol produced a pronounced inhibitory effect on platelet aggregation in rats with experimental diabetes comparable to the effect of gliclazide and decreased blood viscosity thus demonstrating a significant effect comparable to that of pentoxifylline. In view of the fact that oxidative stress is a pathogenetic components of vascular complications in diabetes, it can be assumed that improvement of hemostasis parameters under the effect of enoxifol is determined by its antiplatelet and antioxidant activities.

[Alisma versus Gliclazide in the Treatment of Primary Diabetes in Goto-Kakizaki Rats].

OBJECTIVE: To compare the roles of alisma and gliclazide in the treatment of diabetes in Goto-Kakizaki (GK) rats. METHODS: GK rats were randomly divided into alisma group, gliclazide group, and blank group, and Wistar rats were used as the normal group. After two weeks of treatment, body weight, food intake,fasting glucose, impaired glucose tolerance, and other indicators were measured. RESULTS: The body weight increased after the treatment in the normal group,blank group,and gliclazide group [(241.3 ± 7.0)g vs.(263.5 ± 11.1)g, (242.8 ± 7.1)g vs.(267.9 ± 16.8)g, (243.9 ± 12.2)g vs.(277.9 ± 9.8)g, P<0.05] but decreased in alisma group [(244.6 ± 9.2)g vs.(227.9 ± 13.7)g, P<0.05]. The food intake showed no significant change before and after administration among different groups(P>0.05). Fasting glucose was significantly lower in normal group than in control group,alisma group,and gliclazide group [(4.8 ± 0.2) mmol/L vs.(8.2 ± 1.4) mmol/L,(8.1 ± 0.6) mmol/L, (8.1 ± 0.9)mmol/L, P<0.05] one week after drug administration; it was not significantly different among blank group,alisma group,and gliclazide group before drug administration (P>0.05); however, it significantly decreased in alisma group and gliclazide group two weeks after administration [(6.9 ± 0.7) mmol/L vs.(8.1 ± 0.6) mmol/L; (5.8 ± 0.5) mmol/L vs.(8.1 ± 0.9) mmol/L, P<0.05]; compared with the blank group, the fasting glucose was significantly lower in the alisma group and gliclazide group,and it was also significantly different between these two groups [(6.9 ± 0.7) mmol/L vs.(8.8 ± 0.6) mmol/L,(5.8 ± 0.5)mmol/L vs.(8.8 ± 0.6)mmol/L, (6.9 ± 0.7) mmol/L vs.(5.8 ± 0.5)mmol/L, P<0.05]. Compared with the normal group,glucose tolerance was abnormal in blank group,alisma group,and gliclazide group;after two weeks of treatment,glucose tolerance was significantly improved in alisma group (P<0.05); compared with the pretreatment level and that in the blank group,the glucose tolerance in gliclazide group showed no significant difference (P> 0.05). CONCLUSIONS: Both alisma and gliclazide monotherapy is effective in lowering fasting blood glucose. As a single-target drug,gliclazide has stronger effecacy in lowering fasting glucose. However, alisma, as a mixture, can also control weight and improve glucose intolerance.

Alisma versus Gliclazide in the Treatment of Primary Diabetes in Goto-Kakizaki Rats / 中国医学科学院学报

<p><b>OBJECTIVE</b>To compare the roles of alisma and gliclazide in the treatment of diabetes in Goto-Kakizaki (GK) rats.</p><p><b>METHODS</b>GK rats were randomly divided into alisma group, gliclazide group, and blank group, and Wistar rats were used as the normal group. After two weeks of treatment, body weight, food intake,fasting glucose, impaired glucose tolerance, and other indicators were measured.</p><p><b>RESULTS</b>The body weight increased after the treatment in the normal group,blank group,and gliclazide group [(241.3 ± 7.0)g vs.(263.5 ± 11.1)g, (242.8 ± 7.1)g vs.(267.9 ± 16.8)g, (243.9 ± 12.2)g vs.(277.9 ± 9.8)g, P<0.05] but decreased in alisma group [(244.6 ± 9.2)g vs.(227.9 ± 13.7)g, P<0.05]. The food intake showed no significant change before and after administration among different groups(P>0.05). Fasting glucose was significantly lower in normal group than in control group,alisma group,and gliclazide group [(4.8 ± 0.2) mmol/L vs.(8.2 ± 1.4) mmol/L,(8.1 ± 0.6) mmol/L, (8.1 ± 0.9)mmol/L, P<0.05] one week after drug administration; it was not significantly different among blank group,alisma group,and gliclazide group before drug administration (P>0.05); however, it significantly decreased in alisma group and gliclazide group two weeks after administration [(6.9 ± 0.7) mmol/L vs.(8.1 ± 0.6) mmol/L; (5.8 ± 0.5) mmol/L vs.(8.1 ± 0.9) mmol/L, P<0.05]; compared with the blank group, the fasting glucose was significantly lower in the alisma group and gliclazide group,and it was also significantly different between these two groups [(6.9 ± 0.7) mmol/L vs.(8.8 ± 0.6) mmol/L,(5.8 ± 0.5)mmol/L vs.(8.8 ± 0.6)mmol/L, (6.9 ± 0.7) mmol/L vs.(5.8 ± 0.5)mmol/L, P<0.05]. Compared with the normal group,glucose tolerance was abnormal in blank group,alisma group,and gliclazide group;after two weeks of treatment,glucose tolerance was significantly improved in alisma group (P<0.05); compared with the pretreatment level and that in the blank group,the glucose tolerance in gliclazide group showed no significant difference (P> 0.05).</p><p><b>CONCLUSIONS</b>Both alisma and gliclazide monotherapy is effective in lowering fasting blood glucose. As a single-target drug,gliclazide has stronger effecacy in lowering fasting glucose. However, alisma, as a mixture, can also control weight and improve glucose intolerance.</p>

Characterization of gliclazide release from Isabgol husk hydrogel beads by validated HPLC method.

Isabgol husk, a medicinally important natural polysaccharide was applied for fabrication of hydrogel beads by ionic gelation method to incorporate gliclazide. Different strengths of Isabgol husk and sodium alginate were utilized for assessing the process variables on formulation performance. Aqueous solution of calcium chloride in 2, 5 and 8% w/v strength was used as cross-linker for polymeric blends of Isabgol husk and sodium alginate. The formulations were characterized for various parameters such as particle size, swelling index, entrapment efficiency, in vitro release, and release kinetics. The quantification of gliclazide throughout the study was performed by HPLC method which was validated according to ICH guidelines for system suitability, linearity, accuracy, sensitivity, precession, robustness, and ruggedness. The surface morphology of beads was observed by scanning electron microscopy. The formed beads were brown, free flowing, spherical, and irregular in structure. The size in different formulations varied from 752.83 +/- 0.630 to 838.62 +/- 0.741 microm. The beads remained for 2-3 h in alkaline phosphate buffer (pH 7.4), after that they showed disintegration. The formulations released up to 95% of loaded gliclazide in phosphate buffer (pH 7.4) within 8 h. No significant difference was observed in parameters studied such as particle size, entrapment efficiency and swelling index for hydrogel beads during accelerated stability study (p > 0.05). The regression equation developed by HPLC method was linear (r5 > 0.9990) over the range 2.5 to 10 microg/mL. The limit of detection (LOD) and limit of quantification (LOQ) were 0.037619 microg/mL and 0.113997 microg/mL, respectively. The observed values for number of theoretical plates (N > or = 2000), tailing factor (T < or = 2), asymmetry factor (AF < or = 1), and relative standard deviation (RSD < or = 1%) of applied method showed the reliability for gliclazide estimation in Isabgol husk hydrogel beads.

Gastrointestinal transition and anti-diabetic effect of Isabgol husk microparticles containing gliclazide.

Isabgol husk with sodium alginate was formulated into gliclazide loaded microparticles which were characterized for particle size, swelling index, entrapment efficiency, in vitro release, release kinetics, stability, hypoglycemic effect, surface morphology, and gastrointestinal transition. The particle size in different formulations varied from 752.83 ± 0.630 to 872.03 ± 0.293 µm. It was analyzed by dissolution study that up to 98% of loaded gliclazide was released in simulated intestinal fluid (SIF, pH 7.4) within 8h. The formulations containing sodium alginate and Isabgol husk-sodium alginate showed bioequivalency with marketed sustained release tablets (Glizid MR 60(®)) in terms of release pattern. The drug maintained its integrity in terms of functional groups after fabrication in formulations as observed by FTIR analysis. The hypoglycemic effect of gliclazide loaded Isabgol husk-sodium alginate microparticles was found to be 37 ± 6.356% in terms of changes of blood glucose level from base glucose level (100%) in diabetic condition after 24h of oral administration and it was more than marketed conventional tablets (95.5 ± 3.286%). The retention of microparticles was observed in small intestine up to 10h during whole body X-ray imaging. The study revealed that microparticles composing of Isabgol husk may have the potential for regulating blood glucose level in diabetic animals with controlled release of gliclazide.

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.

In vitro inhibition of metabolism but not transport of gliclazide and repaglinide by Cree medicinal plant extracts.

ETHNOPHARMACOLOGICAL RELEVANCE: Interactions between conventional drug and traditional medicine therapies may potentially affect drug efficacy and increase the potential for adverse reactions. Cree traditional healing is holistic and patients may use medicinal plants simultaneously with the conventional drugs. However, there is limited information that these medicinal plants may interact with drugs and additional mechanistic information is required. In this study, extracts from traditionally used Cree botanicals were assessed for their potential interaction that could alter the disposition of two blood glucose lowering drugs, gliclazide (Diamicron) and repaglinide (Gluconorm) though inhibition of either metabolism or transport across cell membranes. MATERIALS AND METHODS: The effect of 17 extracts on metabolism was examined in a human liver microsome assay by HPLC and individual cytochrome P450s 2C9, 2C19, 2C8 and 3A4 in a microplate fluorometric assay. Gliclazide, rhaponticin and its aglycone derivative, rhapontigenin were also examined in the fluorometric assay. The effect on transport was examined with 11 extracts using the intestinal epithelial Caco-2 differentiated cell monolayer model at times up to 180 min. RESULTS: Both blood glucose lowering medications, gliclazide and repaglinide traversed the Caco-2 monolayer in a time-dependent manner that was not affected by the Cree plant extracts. Incubation of the Cree plant extracts inhibited CYP2C9, 2C19, 2C8 and 3A4-mediated metabolism, and the formation of four repaglinide metabolites: M4, m/z 451-A, m/z 451-B and the glucuronide of repaglinide in the human liver microsome assay. Gliclazide caused no significant inhibition. Likewise, rhaponticin had little effect on the enzymes causing changes of less than 10% with an exception of 17% inhibition of CYP2C19. By contrast, the aglycone rhapontigenin showed the greatest effects on all CYP-mediated metabolism. Its inhibition ranged from a mean of 58% CYP3A4 inhibition to 89% inhibition of CYP2C9. While rhaponticin and the aglycone did not show significant effects on repaglinide metabolism, they demonstrated inhibition of gliclazide metabolism. The aglycone significantly affected levels of gliclazide and its metabolites. CONCLUSION: These studies demonstrate that the Cree plant extracts examined have the potential in vitro to cause drug interactions through effects on key metabolic enzymes.

Liuwei dihuang pills enhance the effect of Western medicine in treating type 2 diabetes: A meta-analysis of randomized controlled trials.

OBJECTIVE: To perform meta-analyses evaluating the efficacy of adding Liuwei Dihuang Pills (, LDP) to Western medicine in improving treatment outcomes for type 2 diabetes. METHODS: Medline, PubMed, Cochrane Library, and Chinese databases, including the Chinese National Knowledge Infrastructure were searched to identify eligible studies; i.e., if the study involved a randomized clinical trial in which the experimental group combined LDP with Western drugs and the control group used the corresponding Western drugs alone to treat type 2 diabetes. Outcomes were measured in terms of fasting blood glucose (FBG), postprandial blood glucose (2hPG) and HbA1c level. Efficacy was also measured by using control and response rates. The combined odds ratio (OR), mean difference (MD), and 95% confidence intervals (95% CI) were calculated. RESULTS: Studies included in the analysis were less adequate than expected in terms of methodological quality. A total of 1,609 patients from 18 studies were included. We found that adding LDP can lower patients' FBG (MD=0.54 mmol/L, 95% CI [0.15, 0.93], P=0.007), 2hPG (MD=1.05 mmol/L, 95% CI [0.29, 1.81], P<0.01) and HbA1c (MD=0.23, 95% CI [0.02, 0.45], P=0.008). There were also improvements in treatment response rates (OR=3.41, 95% CI [2.38, 4.90], P<0.01) and control rates (OR=2.47, 95% CI [1.91, 3.20], P<0.01). CONCLUSION: Adding LDP to Western medicine might improve treatment outcomes of diabetes, including FBG, 2hPG, response rates and control rates.

Comparative evaluation of the anti-diabetic activity of Pterocarpus marsupium Roxb. heartwood in alloxan induced diabetic rats using extracts obtained by optimized conventional and non conventional extraction methods.

The aim of the present study was to assess the anti-diabetic activity of Pterocarpus marsupium Roxb. heartwood in alloxan induced diabetic rats using extracts obtained by optimized conventional and non conventional extraction methods. Aqueous and ethanol extracts of Pterocarpus marsupium heartwood were prepared by conventional methods (infusion, decoction, maceration and percolation) and non conventional methods, such as ultrasound-assisted extraction (UAE) and microwave-assisted extraction (MAE). The crude aqueous extracts were administered orally to both normal and alloxan induced male albino rats (Sprague-Dawley strain). The experimental set up consisted of 48 male albino rats divided into 6 groups: Normal control, diabetic control (sterile normal saline, 1 ml/100 g body weight), standard (gliclazide, 25 mg/1000g of body weight), groups 4-6 (crude aqueous percolation, optimized UAE and MAE extract, 250 mg/1000g of body weight). In acute treatment, the reduction of blood glucose level was statistically significant with the oral administration of UAE and percolation aqueous extracts to the hyperglycemic rats. In sub-acute treatment, the UAE aqueous extract led to consistent and statistically significant (p<0.001) reduction in the blood glucose levels. There was no abnormal change in body weight of the hyperglycemic animals after 10 days of administration of plant extracts and gliclazide. This study justifies the traditional claim and provides a rationale for the use of Pterocarpus marsupium to treat diabetes mellitus. The antidiabetic activity of Pterocarpus marsupium can be enhanced by extracting the heartwood by non conventional method of UAE.

Fisetin averts oxidative stress in pancreatic tissues of streptozotocin-induced diabetic rats.

Persistent hyperglycemia is associated with chronic oxidative stress which contributes to the development and progression of diabetes-associated complications. The sensitivity of pancreatic ß-cells to oxidative stress has been attributed to their low content of antioxidants compared with other tissues. Bioactive compounds with potent antidiabetic properties have been shown to ameliorate hyperglycemia mediated oxidative stress. Recently, we have reported that oral administration of fisetin (10 mg/Kg b.w.), a bioflavonoid found to be present in strawberries, persimmon, to STZ-induced experimental diabetic rats significantly improved normoglycemia. The present study was aimed to evaluate the antioxidant potential of fisetin in both in vitro and in vivo. Diabetes was induced by single intraperitoneal injection of streptozotocin (50 mg/kg body weight). Fisetin was administered orally for 30 days. At the end of the study, all animals were killed. Blood samples were collected for the biochemical estimations. The antioxidant status was evaluated. Histological examinations were performed on pancreatic tissues. Fisetin treatment showed a significant decline in the levels of blood glucose, glycosylated hemoglobin (HbA1c), NF-kB p65 unit (in pancreas) and IL-1ß (plasma), serum nitric oxide (NO) with an elevation in plasma insulin. The treatment also improved the antioxidant status in pancreas as well as plasma of diabetic rats indicating the antioxidant potential of fisetin. In addition, the results of DPPH and ABTS assays substantiate the free radical scavenging activity of fisetin. Histological studies of the pancreas also evidenced the tissue protective nature of fisetin. It is concluded that, fisetin possesses antioxidant and anti-inflammatory property and may be considered as an adjunct for the treatment of diabetes.