Gliclazide Reduces Colitis-Associated Colorectal Cancer Formation by Deceasing Colonic Inflammation and Regulating AMPK-NF-κB Signaling Pathway.

BACKGROUND: Gliclazide is a potential anti-cancer drug candidate for preventing carcinogenesis. However, the effect of gliclazide on colitis-associated colorectal cancer remains unknown. AIMS: We aimed to evaluate whether gliclazide plays a protective role in colitis-associated colorectal cancer and the underlying molecular mechanism. METHODS: The administration of azoxymethane (AOM) followed by dextran sulfate sodium (DSS) aimed to induce colitis-associated colorectal cancer in mice. C57BL mice were gavaged with gliclazide (6 mg/kg by gavage 5 days a week) for 12 weeks immediately following AOM administration. After sacrificing the mice, colon tissues were measured for tumor number and tumor burden. The proliferation- and inflammation-related molecular mechanisms were explored. RESULTS: The administration of gliclazide significantly reduced the tumor number and tumor burden in mice. Cell proliferation decreased in the gliclazide group compared with the control group, as indicated by reduced Ki-67 expression. Furthermore, gliclazide alleviated colonic inflammation, significantly decreased pro-inflammatory factor TNF-α levels and increased anti-inflammatory factor IL-10 levels in vivo. In vivo and vitro, it was shown that gliclazide increased the level of phospho-AMPK (p-AMPK) and inhibited NF-κB activity. Further studies demonstrated that the inhibition of NF-κB activity induced by gliclazide was mediated by p-AMPK in vitro. CONCLUSIONS: Gliclazide effectively alleviated colonic inflammation and prevented colonic carcinogenesis in an AOM-DSS mouse model by modulating the AMPK-NF-κB signaling pathway. Thus, gliclazide holds potential as a chemopreventive agent for colitis-associated colorectal cancer.

Polydimethylsiloxane Organic-Inorganic Composite Drug Reservoir with Gliclazide.

A novel organic-inorganic gliclazide-loaded composite bead was developed by an ionic gelation process using acidified CaCl2, chitosan and tetraethylorthosilicate (TEOS) as a crosslinker. The beads were manufactured by crosslinking an inorganic silicone elastomer (-OH terminated polydimethylsiloxane, PDMS) with TEOS at different ratios before grafting onto an organic backbone (Na-alginate) using a 32 factorial experimental design. Gliclazide's encapsulation efficiency (EE%) and drug release over 8 h (% DR 8 h) were set as dependent responses for the optimisation of a pharmaceutical formula (herein referred to as 'G op') by response surface methodology. EE % and %DR 8 h of G op were 93.48% ± 0.19 and 70.29% ± 0.18, respectively. G op exhibited a controlled release of gliclazide that follows the Korsmeyer-Peppas kinetic model (R2 = 0.95) with super case II transport and pH-dependent swelling behaviour. In vitro testing of G op showed 92.17% ± 1.18 cell viability upon testing on C2C12 myoblasts, indicating the compatibility of this novel biomaterial platform with skeletal muscle drug delivery.

Sitagliptin Is More Effective Than Gliclazide in Preventing Pro-Fibrotic and Pro-Inflammatory Changes in a Rodent Model of Diet-Induced Non-Alcoholic Fatty Liver Disease.

A diet-induced non-alcoholic fatty liver disease (NAFLD) model causing obesity in rodents was used to examine whether sitagliptin and gliclazide therapies have similar protective effects on pathological liver change. METHODS: Male mice were fed a high-fat diet (HFD) or standard chow (Chow) ad libitum for 25 weeks and randomly allocated to oral sitagliptin or gliclazide treatment for the final 10 weeks. Fasting blood glucose and circulating insulin were measured. Inflammatory and fibrotic liver markers were assessed by qPCR. The second messenger ERK and autophagy markers were examined by Western immunoblot. F4/80, collagens and CCN2 were assessed by immunohistochemistry (IHC). RESULTS: At termination, HFD mice were obese, hyperinsulinemic and insulin-resistant but non-diabetic. The DPP4 inhibitor sitagliptin prevented intrahepatic induction of pro-fibrotic markers collagen-IV, collagen-VI, CCN2 and TGF-ß1 and pro-inflammatory markers TNF-α and IL-1ß more effectively than sulfonylurea gliclazide. By IHC, liver collagen-VI and CCN2 induction by HFD were inhibited only by sitagliptin. Sitagliptin had a greater ability than gliclazide to normalise ERK-protein liver dysregulation. CONCLUSION: These data indicate that sitagliptin, compared with gliclazide, exhibits greater inhibition of pro-fibrotic and pro-inflammatory changes in an HFD-induced NAFLD model. Sitagliptin therapy, even in the absence of diabetes, may have specific benefits in diet-induced NAFLD.

Indonesia DIA-RAMADAN Study: A Real-life, Prospective and Observational of Gliclazide MR in Type-2 Diabetes Patients During Ramadan Fasting.

BACKGROUND: Sulfonylureas (SUs) have been widely used in many countries for T2DM treatment. Gliclazide is one of the SUs with the lowest risk of hypoglycemia; however, the safety and effectiveness of gliclazide MR during Ramadan has not yet been reported in Indonesia. This study aimed to assess safety, efficacy, and tolerability of gliclazide modified release (MR) during Ramadan fasting. METHODS: The study was a part of DIA-RAMADAN study, a prospective observational study with subjects of T2DM patients aged >18 years, who had either controlled or sub-optimally controlled blood glucose level, performed Ramadan fasting. Subjects had been treated with gliclazide MR for at least 90 days prior the study, and were examined for their body mass index (BMI), fasting plasma glucose (FPG) and HbA1c levels 6 to 8 weeks before Ramadan (V0) and 4 to 6 weeks after the end of Ramadan (V1). RESULTS: Out of 198 subjects participating in the study, there were only two subjects (1.0%) who reported symptomatic HEs (either confirmed or not confirmed) and no severe HEs had been reported. There were no significant changes in HbA1c and FPG levels (p>0.05). Interestingly, there was a reduction of bodyweight (-0.4kg) from pre- to post-Ramadan (p < 0.001). Almost no subjects reported discontinuation of gliclazide MR throughout the entire study; however, there was one subject who reported a change of diabetic treatment into diet only. CONCLUSION: gliclazide MR is safe, well tolerated and can maintain glycemic control effectively for Indonesian patients with T2DM who perform Ramadan fasting.

Synthesis and hyperglycemic, biochemical and histopathological evaluation of novel sulfonylbiguanide and sulfonylurea derivatives as potent anti-diabetic agents.

New sulfonylbiguanide hydrochloride salts and sulfonylurea derivatives containing two sulfonyl groups were synthesized through the reaction of arylsulfonohydrazides with cyanoguanidine and p-tolylsulfonylisocyanate, respectively. Oral treatment of hyperglycemic rats with the synthesized sulfonylbiguanide derivatives 2 and sulfonylurea derivatives 3 revealed that sulfonylurea derivatives 3a and 3c possessed significant decrease of the elevated glucose in compression with the anti-diabetic standard drugs. Effects of the synthesized sulfonylurea derivatives 3a and 3c on the diabetic properties towards α-amylase, liver function enzyme levels (AST, ALT, ALP, TB and γ-GT), kidney functions (urea and creatinine), lipids profiles (TG, TL, TC and HDL-C) were studied. Also, the effect of sulfonylurea derivatives 3a and 3c as antioxidants (reduced glutathione and lipid peroxide) was evaluated. Histopathological examination of hepatic and pancreatic tissues was investigated. The obtained results suggested that the most potent sulfonylurea derivatives 3a and 3c might be possible used as novel diabetic inhibitor agents.

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.

Dual-drug amorphous formulation of gliclazide.

Amorphization is a well-established strategy to enhance the dissolution properties of poorly water-soluble drugs. However, the amorphous state is inherently unstable toward recrystallization. Coamorphous systems of a drug and a small-molecule excipient or of two complementary drugs often show an enhanced stability. Diabetes and hypertension are frequently coexistent. In this paper a study on the coamorphization of the poorly water-soluble antidiabetic drug gliclazide (glz) and the antihypertensive drug valsartan (val) is reported. Amorphous glz recrystallized after 1 d under ambient conditions, whereas coamorphous glz-val containing glz and val in a 1:1 or 1:2 molar ratio was stable for at least four months at 20 °C and 56% relative humidity. The dissolution rate of glz increased in the order crystalline glz < glz-val_1:1 < glz-val_1:2. Furthermore, ternary coamorphous systems of glz, val and an excipient were prepared; glz-val_1:1_PVP, glz-val_1:1_HPC, glz-val_1:1_ALM, glz-val_1:1_MCC (PVP = polyvinylpyrrolidone, HPC = hydroxypropyl cellulose, ALM = α-lactose monohydrate, MCC = microcrystalline cellulose). MCC and HPC did not affect the stability of the coamorphous system, while ALM promoted the recrystallization of glz in glz-val_1:1_ALM during storage and freshly prepared glz-val_1:1_PVP contained small amounts of crystalline glz. Glz-val_1:1_MCC showed enhanced dissolution properties compared to crystalline glz and glz-val_1:1 and is a viable fixed-dose formulation.

In Vitro Investigation of Binding Interactions between Albumin-Gliclazide Model and Typical Hypotensive Drugs.

Type 2 diabetes management usually requires polytherapy, which increases the risk of drug-to-drug interactions. Among the multiple diabetes comorbidities, hypertension is the most prevalent. This study aimed to investigate the binding interactions between the model protein, bovine albumin, and the hypoglycemic agent gliclazide (GLICL) in the presence of typical hypotensive drugs: quinapril hydrochloride (QUI), valsartan (VAL), furosemide (FUR), amlodipine besylate (AML), and atenolol (ATN). Spectroscopic techniques (fluorescence quenching, circular dichroism) and thermodynamic experiments were employed. The binding of the gliclazide to the albumin molecule was affected by the presence of an additional drug ligand, which was reflected by the reduced binding constant of the BSA-DRUG-GLICL system. This may indicate a possible GLICL displacement and its enhanced pharmacological effect, as manifested in clinical practice. The analysis of the thermodynamic parameters indicated the spontaneity of the reaction and emphasized the role of hydrogen bonding and van der Waals forces in these interactions. The secondary structure of the BSA remained almost unaffected.

How Does Glycation Affect Binding Parameters of the Albumin-Gliclazide System in the Presence of Drugs Commonly Used in Diabetes? In Vitro Spectroscopic Study.

In this research, the selected drugs commonly used in diabetes and its comorbidities (gliclazide, cilazapril, atorvastatin, and acetylsalicylic acid) were studied for their interactions with bovine serum albumin-native and glycated. Two different spectroscopic methods, fluorescence quenching and circular dichroism, were utilized to elucidate the binding interactions of the investigational drugs. The glycation process was induced in BSA by glucose and was confirmed by the presence of advanced glycosylation end products (AGEs). The interaction between albumin and gliclazide, with the presence of another drug, was confirmed by calculation of association constants (0.11-1.07 × 104 M-1). The nature of changes in the secondary structure of a protein depends on the drug used and the degree of glycation. Therefore, these interactions may have an influence on pharmacokinetic parameters.

Formulation, Pharmacokinetics evaluation, and IVIVC Assessment of Gliclazide Multiparticulates in Rat Model.

In vitro and in vivo studies of gliclazide (GLZ)-loaded freeze-dried alginate-gelatin (AL-GL) beads were carried out, aiming to modify its oral bioavailability. Crosslinked freeze-dried GLZ AL-GL beads (particle size: 1.5- and 3.0-mm) were prepared. In vitro evaluation of GLZ AL-GL beads included SEM, DSC, FT-IR, and release rate study in gradient media. In vivo study was single-dose (4 mg/kg), randomized, parallel-group design, two-treatment (T: test GLZ AL-GL beads and R: reference product Diamicron® 30-mg MR tablet) conducted in 96 healthy rats. Each group was subdivided into 2 sub-groups (G1 and G2) having different blood sampling schemes for up to 72 h. Assessment of level A in-vitro-in-vivo correlation (IVIVC) model was carried out. AL-GL beads successfully increased GLZ release rate compared to R. GLZ percent released (Q4h) was 109.34, 86.85, and 43.43% for 1.5-mm and 3.0-mm beads and R, respectively. DSC analysis confirmed the interaction of AL-GL via crosslinking. No chemical interaction of GLZ has occurred as proved by FT-IR. Relative bioavailability (T/R) for AUC0-∞ was 132.45% for G1 and 146.16% for G2. No significant differences between T and R in the primary pharmacokinetic parameters were determined. Tmax values were found to be earlier in the case of G1 than those of G2. A secondary absorption peak of GLZ was clearly detected in the case of R while its sharpness was minimized in T. High IVIVC was established, and hence, the proposed in vitro release model perfectly correlated with the in vivo study. The current study design might be a platform to enable panoramic view for GLZ variability in vivo.

LINAGLIPTIN AND GLICLAZIDE DI-LOADED EXTENDED-RELEASE NANOPARTICLES: FORMULATION AND EVALUATION.

OBJECTIVE: The aim: This work aimed to formulate gliclazide and linagliptin extended-release nanoparticles. PATIENTS AND METHODS: Materials and methods: A HPLC method was developed and validated to determine gliclazide and linagliptin at the same time without interference. The nanoparticles were prepared by emulsion solvent evaporation using two polymers, namely hydroxypropyl methylcellulose (HPMC) 4000 cps and xanthan gum. RESULTS: Results: Nanoparticles prepared were characterized for drug contents, production yield and entrapment efficiency, zeta potential, particle size, morphology by transmission electronic microscopy (TEM) and in-vitro release rate. The formulae GLH1, GLX1 and GHX1 showed release of linagliptin more than 75% after 8 hrs. While the only formula among the three (GHX1) showed release of gliclazide more than 80% after 8 h. So, the formula GHX1 showed acceptable release of more than 80% of both gliclazide and linagliptin after 8 h. CONCLUSION: Conclusions: The formula GHX1 which containing (0.5:1 xanthan gum: drugs) was the best nanoparticles formula which released more than 80% of both drugs after 8 h and could achieve good extended release over 24 h.

Gliclazide attenuates cisplatin-induced nephrotoxicity through inhibiting NF-κB and caspase-3 activity.

Cisplatin (CP), as a chemotherapeutic drug, causes nephrotoxicity that has limited the clinical utility of CP. Gliclazide (GLZ), as an antihyperglycemic drug, at low dose has antioxidant property. In this study, we aimed to investigate the protective effect of GLZ against CP-induced acute renal injury. Sixty-four BALB/c mice were randomly divided into eight groups. The groups were included as control, GLZ (5, 10, and 25 mg/kg), CP, and GLZ (5, 10, and 25 mg/kg) + CP. Renal function markers (serum creatinine and blood urea nitrogen), oxidative stress markers (malondialdehyde and glutathione), apoptotic marker (caspase-3), and NF-κB were histopathologically evaluated. The results of our study showed that increased urea and creatinine were evidence of CP-induced nephrotoxicity. Histopathological examination revealed tubular epithelial and Bowman degeneration, edema, and cytoplasmic vacuolation in renal tissue structure. Administration of GLZ reduced oxidative stress, caspase-3, and NF-κB activity, and improved kidney function markers in CP-treated mice compared with CP alone group. Also, we observed that the histological tissue structure of the kidney was maintained. GLZ at dose of 25 mg/kg had higher protective effect as compared with other doses. Overall, our study suggests that GLZ with antioxidant, antiapoptotic, and anti-inflammatory properties may be a promising new therapeutic agent to prevent CP-induced nephrotoxicity.

Gliclazide attenuates acetic acid-induced colitis via the modulation of PPARγ, NF-κB and MAPK signaling pathways.

Ulcerative Colitis is a universal autoimmune disease with high incidence rates worldwide. It is characterized by the existence of many other concurrent immune-associated ailments, including diabetes. The used strategies for the management of this highly costing and complicated disease face great challenges. Therefore, the urge for new medication with fewer side effects and high efficacy is growing. The peroxisome proliferator-activated receptor-gamma (PPARγ) and nuclear factor Kappa-B (NF-κB) can be considered as crucial targets for the treatment of ulcerative colitis. Several studies reported the antioxidants, anti-inflammatory, and antiapoptotic actions of gliclazide and evaluated its cardioprotective and renoprotective effects. However, its impact on ulcerative colitis has never been investigated. This study delineated the effect of gliclazide administration on ulcerative colitis induced by acetic acid in rats and the underlying molecular mechanisms. Gliclazide (10 mg/kg; p.o) prominently decreased colon tissue injury as assessed by the histopathological analysis as well as myeloperoxidase, and intercellular adhesion molecule-1 levels. Gliclazide significantly alleviated the proinflammatory mediator, IL-6, promoted the anti-inflammatory cytokine, IL-10 and, withheld oxidative stress in the injured colon tissues. The protective effect of gliclazide was mediated through the upregulation of PPARγ and downregulation of NF-κB expression. The diminution of ulcerative colitis was also accompanied by an inhibition of the elevated activity and expression of mitogen-activated protein kinases and caspase-3 as assessed by Western blot and immunohistochemistry, respectively. Our findings spotlight, for the first time, the potential of the antidiabetic agent, gliclazide, to attenuate the experimentally induced ulcerative colitis. Therefore, gliclazide might be a propitious agent for the management of ulcerative colitis in diabetic patients.

The potential hepatoprotective effects of lovastatin combined with oral hypoglycemic agents in streptozotocin-induced diabetes in rats.

Aims: Epidemiologic studies have shown that individuals with diabetes have a higher risk of hepatic diseases which represent a true clinical problem. The purpose of the present study was to assess the possible modulatory effect of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor lovastatin on therapeutic efficiency of traditional antidiabetics, as metformin and gliclazide, regarding hepatic complications in streptozotocin (STZ)-induced diabetes in rats.Methods: Animals were divided into seven groups; normal control group, STZ control group (50 mg/kg, i.p., single dose), lovastatin group, metformin group, gliclazide group, lovastatin plus metformin group and lovastatin plus gliclazide group. Serum HMG-CoA reductase, in addition to serum alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) as hepatocyte integrity loss markers, hepatic tissue thiobarbituric acid reactive substances (TBARS), glutathione reduced (GSH), glutathione-S-transferase (GST), superoxide dismutase (SOD) and catalase as oxidative stress markers, as well as serum tumor necrosis factor-alpha (TNF-α) and C-reactive protein (CRP) and hepatic nitric oxide end products (NOx) as inflammatory markers were assessed, coupled with a confirmatory histopathological study.Results: The combined effect of lovastatin with metformin or gliclazide was significantly better than either drug alone regarding serum AST, ALP and TNF-α, and hepatic TBARS, GSH, GST, SOD and NOx levels.Conclusions: Hepatic complications associated with diabetes could be improved by combination of metformin or gliclazide with lovastatin.

Visualized analysis and evaluation of simultaneous controlled release of metformin hydrochloride and gliclazide from sandwiched osmotic pump capsule.

The aim of this study was to develop the Metformin Hydrochloride and Gliclazide (MH-GZ) sandwiched osmotic pump capsule which could overcome the problems associated with short half-life and burst release. The system could deliver drugs with different solubility simultaneously at zero-order rate, in which MH-GZ were filled in both sides of the push layer respectively. The single factor and orthogonal test were employed to obtain the optimized formulation with the evaluation index of similarity factor (ƒ2). R language was used to visualized analyze the main influence factors of drug release and their correlations. Pharmacokinetic study was performed in beagle dogs compared to the marketed conventional product, which showed decreased Cmax, prolonged Tmax, and improved bioavailability, independent of pH and agitational speed but related to osmotic pressure differences across the semi permeable membrane. The designed sandwiched osmotic pump capsule proposed a promising substitute for the marketed product for the treatment of type 2 diabetes.

Advanced and multifaceted stability profiling of the first-line antidiabetic drugs metformin, gliclazide and glipizide under various controlled stress conditions.

The antidiabetic drugs metformin, gliclazide and glipizide have been widely used and studied in terms of pharmacological and antidiabetic effects, and their individual stability has been studied in the literature. However, the drugs' combined stability profiling remains poorly understood, and hence the aim of this study was to investigate the collective stability profiling of different combinations at various controlled conditions. Degradation assessments were carried out on metformin, glipizide and gliclazide by applying a stability-indicating HPLC method that was developed and validated in accordance with ICH guidelines. Glipizide, gliclazide, metformin and the binary mixtures (metformin/glipizide and metformin/gliclazide) were subjected to different forced degradation conditions and were detected at 227 nm by an isocratic separation on an Alltima CN column (250 mm × 4.6 mm × 5µ) utilizing a mobile phase that consists of 20 mM ammonium formate buffer (pH 3.5) and acetonitrile at a ratio of (45:55, v/v). The method is linear (R2 = 0.9999) at the concentration range 2.5-150 µg/ml for metformin and 1.25-150 µg/ml for sulfonylureas respectively and offers a specific and sensitive tool for their determination in <10 min chromatographic run. All drug peaks were sharp and well separated. Stress degradation revealed that metformin has a remarkable sensitivity to alkaline stress, glipizide was more sensitive to thermal degradation while gliclazide exhibited almost full degradation in acidic, alkaline and oxidative stress conditions.

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.

Synthesis, structural characterization and in vivo anti-diabetic evaluation of some new sulfonylurea derivatives in normal and silicate coated nanoparticle forms as anti-hyperglycemic agents.

Series of new sulfonylurea derivatives (gliclazide analogues) was synthesized and characterized. Thus, p-tolylsulfonylisocyanate was left to react with different amino derivatives under mild conditions to afford the desired sulfonylurea derivatives 1-5. The molecular structure of the compound N-(2,6-Dichlorophenylcarbamoyl)-4-methylbenzenesulfonamide, 1c has been elucidated by single crystal X-ray diffraction. Anti-diabetic properties of the synthesized compounds relative to anti-diabetic drug (gliclazidem MR60) were carried out, where most of the tested compounds showed significant activity for reducing the blood glucose level. The results revealed that compounds 1c and 5 showed better anti-diabetic activities compared with gliclazide. Activity of the most potent derivatives of sulfonylurea compounds namely 1c and 5 were increased using coated nanostructure tetraethyl orthosilicate (TEOS) as a modified release (MR) agent. The effect of the prepared sulfonylurea compounds against the diabetic condition was investigated using specific selected biomarkers as of liver enzyme activities as transaminases (AST, ALT) and alkaline phosphatase (ALP), lipids profiles; total cholesterol (TC), triacylglycerols (TG) and total lipid (TL). The antioxidants, oxidative stress biomarkers and histological examination were also examined and discussed.

Smile: saluto-metabolic interventions for life enhancement.

The article highlights the need to follow a multifactorial, comprehensive approach while managing diabetes. Apart from glycaemic control, blood pressure, lipid, weight and platelet management are equally important if one is to ensure optimal therapeutic outcomes. The mnemonic SMILE (salute-metabolic interventions for life enhancement) includes all evidence-based therapies which help in improving metabolic health, and in preventing morbidity and mortality. It allows evenhanded addressal of all vasculo metabolic parameters, so as to bring SMILEs on faces of all persons involved in diabetes.

Gliclazide alone or in combination with atorvastatin ameliorated reproductive damage in streptozotocin-induced type 2 diabetic male rats.

OBJECTIVES: Type 2 diabetes (T2DM) is one of the most serious challenges of the 21th century with life-threatening complications and excessive health care costs. In diabetic patients, the main goal in T2DM treatment is the regulation of both blood glucose and lipid levels. For that, Gliclazide (GLZ), an oral antidiabetic, and Atorvastatin (ATV), a lipid lowering agent, are widely used drugs as combination. Diabetes has been reported severe impacts on male reproductive system; however, data obtained about ATV and GLZ treatment alone or in combination are conflicted or insufficient. Herein the effects of ATV and GLZ on male reproductive system in type 2 diabetic male rats have been investigated in the present study. METHODS: T2DM was induced by high-fat diet and single injection of streptozotocin (STZ) (35 mg/kg) in young adult male Sprague-Dawley rats. The diabetic rats were given ATV (10 mg/kg), GLZ (10 mg/kg) and ATV/GLZ (1:1, 10 mg/kg) combination by oral gavage for 28 days. The hormone levels were determined in the cardiac blood samples; and the histopathological and ultrastructural analyses were conducted in the testicular tissues and epididymal sperms. RESULTS: It was observed that diabetes had severe effects on testicular tissue and spermatogenesis. ATV treatment did not affect sperm count and testes structure (p > 0.05), however ameliorated sperm morphology (p < 0.05). GLZ treatment increased sperm count, and improved sperm morphology, testes structure and spermatogenesis (p < 0.05). ATV/GLZ combination treatment enhanced sperm morphology and improved testicular structure (p < 0.05) while did not affect sperm count (p > 0.05). CONCLUSION: GLZ treatment regenerated testicular damage and sperm parameters whether alone or in combination with ATV in diabetic rats without affecting hypothalamic-pituitary-gonadal axis.