Glyburide use is associated with a greater likelihood of mortality or rehospitalization after acute coronary syndrome compared to gliclazide use in adults with type 2 diabetes: A cohort study.

AIM: To examine the likelihood of mortality or rehospitalization following acute coronary syndrome with glyburide versus gliclazide use in adults with type 2 diabetes undergoing cardiac catheterization. RESEARCH DESIGN AND METHODS: This retrospective cohort study used clinical data linked with administrative health data from Alberta, Canada between April 2008 and March 2021. Three methods were used to define exposure to glyburide and gliclazide in the year before catheterization. Multivariable logistic regression was used to compare the likelihood of a composite outcome of 1-year mortality or rehospitalization with use of glyburide versus use of gliclazide. RESULTS: A total of 11 140 individuals with type 2 diabetes had a cardiac catheterization for acute coronary syndrome. Their mean age was 66 years and 31% were female. In the year before catheterization, 5% used glyburide and 19% used gliclazide. Any glyburide or gliclazide exposure in the year before catheterization was associated with a similar likelihood of all-cause mortality or rehospitalization (adjusted odds ratio [aOR] 1.14, 95% confidence interval [CI] 0.93-1.41; p = 0.20). However, current glyburide exposure (aOR 1.37, 95% CI 1.06-1.79; p = 0.018) and long exposure to glyburide (aOR 1.37, 95% CI 1.03-1.83; p = 0.030) were associated with a higher likelihood of the composite outcome compared to current and long exposure to gliclazide, respectively. CONCLUSIONS: Current and long exposure to glyburide was associated with a greater likelihood of mortality or rehospitalization following cardiac catheterization for acute coronary syndrome, when compared to similar gliclazide exposure definitions. This study adds further evidence of the need to avoid using glyburide if a sulphonylurea is required for type 2 diabetes management.

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.

In Silico Prediction of N-Nitrosamine Formation Pathways of Pharmaceutical Products.

The recent discovery of N-nitrosodimethylamine (NDMA), a mutagenic N-nitrosamine, in pharmaceuticals has adversely impacted the global supply of relevant pharmaceutical products. Contamination by N-nitrosamines diverts resources and time from research and development or pharmaceutical production, representing a bottleneck in drug development. Therefore, predicting the risk of N-nitrosamine contamination is an important step in preventing pharmaceutical contamination by DNA-reactive impurities for the production of high-quality pharmaceuticals. In this study, we first predicted the degradation pathways and impurities of model pharmaceuticals, namely gliclazide and indapamide, in silico using an expert-knowledge software. Second, we verified the prediction results with a demonstration test, which confirmed that N-nitrosamines formed from the degradation of gliclazide and indapamide in the presence of hydrogen peroxide, especially under alkaline conditions. Furthermore, the pathways by which degradation products formed were determined using ranitidine, a compound previously demonstrated to generate NDMA. The prediction indicated that a ranitidine-related compound served as a potential source of nitroso groups for NDMA formation. In silico software is expected to be useful for developing methods to assess the risk of N-nitrosamine formation from pharmaceuticals.

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.

Long-Lived States Provide Insights from NMR into the ß-Cyclodextrin Drug Assemblies.

In the last two decades, extending spin memory in NMR has been used for several purposes. Long-lived states (LLS) or singlet states are one of the first spin memory enhancement techniques used. LLS have the potential to extract structural information and intra- and intermolecular interactions of complex systems other than studying slow phenomenon. The motional regime of ß-cyclodextrin (ß-CD) drug inclusion complexes generally lies in the intermediate region, where ωτc ≈ 1, and the standard methods of studying these interactions, i.e., NOE and chemical shift monitoring, suffer from insufficient output information. The sensitivity of LLS toward the environmental changes is utilized here to gain insights into the drug assemblies formed by ß-CD. One can use change in relaxation of LLS to study the structural changes during complexation. The examples of ß-CD with the drugs indomethacin, paracetamol, gliclazide, and CI-933 (a precursor 4-methoxybenzamide) were studied. Indomethacin, paracetamol, and 4-methoxybenzamide show strong interaction through the para-substituted benzene ring, unlike gliclazide. Relaxation of LLS in ß-CD-drug complexes is modeled using standard Redfield Relaxation Theory. Computational studies performed support the experimental observations. Docking and molecular dynamics simulation provided the explanation of the relaxation properties of these drug molecules.

ADVANCE to ADVANCE-ON: Unfolding the "Legacy Story" in Diabetes.

Type 2 diabetes mellitus (T2DM) is a progressive disease. The importance of early intensive glucose lowering in preventing vascular complications in diabetes is well established. Sulfonylureas (SU) is recommended by most guidelines and widely used for the management of T2DM. However, there has been ambiguity around the long-term benefits with regard to microvascular and macrovascular outcomes with SUs. The United Kingdom Prospective Diabetes Study (UKPDS) provided evidence of sustained cardiovascular (CV) and microvascular benefits of previous intensive glycemic control with SUs or insulin in T2DM patients. The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release (MR) Controlled Evaluation (ADVANCE) trial, another landmark study in T2DM patients and its posttrial observational follow-up (FU) study [ADVANCE-Observational Study (ADVANCE-ON)] together provide definite evidence for sustained renal benefits of gliclazide MR based intensive glucose control initiated early during the course of diabetes. These effects, however, may be specific to gliclazide. Evidence from other studies and reviews also suggests that gliclazide MR may hold a distinct place among currently available SUs and reinforce its utility in diabetes management.

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.

Differential metabolic network construction for personalized medicine: Study of type 2 diabetes mellitus patients' response to gliclazide-modified-release-treated.

Individual variation in genetic and environmental factors can cause the differences in metabolic phenotypes, which may have an effect on drug responses of patients. Deep exploration of patients' responses to therapeutic agents is a crucial and urgent event in the personalized treatment study. Using machine learning methods for the discovery of suitability evaluation biomarkers can provide deep insight into the mechanism of disease therapy and facilitate the development of personalized medicine. To find important metabolic network signals for the prediction of patients' drug responses, a novel method referred to as differential metabolic network construction (DMNC) was proposed. In DMNC, concentration changes in metabolite ratios between different pathological states are measured to construct differential metabolic networks, which can be used to advance clinical decision-making. In this study, DMNC was applied to characterize type 2 diabetes mellitus (T2DM) patients' responses against gliclazide modified-release (MR) therapy. Two T2DM metabolomics datasets from different batches of subjects treated by gliclazide MR were analyzed in depth. A network biomarker was defined to assess the patients' suitability for gliclazide MR. It can be effective in the prediction of significant responders from nonsignificant responders, achieving area under the curve values of 0.893 and 1.000 for the discovery and validation sets, respectively. Compared with the metabolites selected by the other methods, the network biomarker selected by DMNC was more stable and precise to reflect the metabolic responses in patients to gliclazide MR therapy, thereby contributing for the personalized medicine of T2DM patients. The better performance of DMNC validated its potential for the identification of network biomarkers to characterize the responses against therapeutic treatments and provide valuable information for personalized medicine.

Prevalence of hepatic steatosis in patients with type 2 diabetes and response to glucose-lowering treatments. A multicenter retrospective study in Italian specialist care.

AIM: Type 2 diabetes (T2D) is a risk factor for metabolic dysfunction-associated fatty liver disease (MAFLD), which is becoming the commonest cause of chronic liver disease worldwide. We estimated MAFLD prevalence among patients with T2D using the hepatic steatosis index (HSI) and validated it against liver ultrasound. We also examined whether glucose-lowering medications (GLM) beneficially affected HSI. METHODS: We collected data from 46 diabetes clinics (n = 281,381 T2D patients), extracted data to calculate HSI and validated it against ultrasound-detected hepatic steatosis. We then examined changes in HSI among patients with a follow-up visit within 1 year after initiating newer GLMs. RESULTS: MAFLD (defined by HSI > 36, i.e., a high probability of steatosis) was present in 76.3% of the 78,895 included patients, while only 2.7% had HSI < 30 (low probability of steatosis). After age- and sex-adjusting, higher HSI was associated with higher prevalence of chronic kidney disease (odds ratio 1.35; 95%CI 1.22-1.51) and macroangiopathy (odds ratio 1.18; 95%CI 1.07-1.30). Among 2,179 subjects in the validation cohort, the prevalence of MAFLD was 67.8% and was greater in those with high HSI. Performance of HSI for ultrasound-detected MAFLD was moderate (AUROC 0.70), yet steatosis prevalence was > threefold higher among subjects with HSI > 36 than among those with HSI < 30. Notably, HSI declined significantly ~ 6 months after initiation of dapagliflozin or incretin-based therapies, but not gliclazide. CONCLUSION: About three quarters of patients with T2D have HSI values suggestive of MAFLD, a condition associated with macroangiopathy and nephropathy. Treatment with dapagliflozin or incretin therapies might improve MAFLD in T2D.

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.

Sensitive detection of antidiabetic compounds and one degradation product in wastewater samples by a new SPE-LC-MS/MS method.

As environment emerging contaminants of anthropogenic origin, antidiabetic drugs are present in the range of high ng/L to ng/mL in the influent and the effluent of the waste water treatment plant (WWTP). The metformin compound is the most used hypoglycemic agent in the world. The aim of this study was to develop a new analytic method, based on solid phase extraction followed by liquid chromatography coupled with mass spectrometric detector (SPE-LC-MS/MS), for identification and quantification of 5 antidiabetic compounds (glibenclamide/glyburide, glimepiride, metformin, glipizide, guanyl urea, gliclazide) and one degradation product (guanyl urea). The investigated environmental samples were the influent and the effluent of four urbans WWTP's. By validating of the analytical method, it was obtained low LOQ's (0.2-4.5 ng/L), satisfactory recovery rates (53.6-116.8%), and corresponding performance parameters: inter-day precision (4.9-8.4%) and reproducibility (11.3-14.6%). The concentrations of antidiabetics were as follow in influent and effluent: metformin 76-2041ng/L and 2-206ng/L, gliclazide (14.1-42.4 ng/L, and 3.3-19.1), glipizide (7.5-11.2 ng/L and 6.5-10ng/L), guanyl urea (6.2-7.3 and 8.3-21.3 ng/L). The efficiency of elimination of the antidiabetics in WWTP's was maximum for metformin (67.6-98.5%), followed, by gliclazide (72.9-78.2%). The lowest elimination efficiency was calculated for glipizide (10.7-13.3%). The guanyl urea undergoes a formation process (74.5-84.2%) in effluent, from the metformin contained in influent.

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.

The renal hemodynamic effects of the SGLT2 inhibitor dapagliflozin are caused by post-glomerular vasodilatation rather than pre-glomerular vasoconstriction in metformin-treated patients with type 2 diabetes in the randomized, double-blind RED trial.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve hard renal outcomes in type 2 diabetes. This is possibly explained by the fact that SGLT2i normalize the measured glomerular filtration rate (mGFR) by increasing renal vascular resistance, as was shown in young people with type 1 diabetes and glomerular hyperfiltration. Therefore, we compared the renal hemodynamic effects of dapagliflozin with gliclazide in type 2 diabetes. The mGFR and effective renal plasma flow were assessed using inulin and para-aminohippurate clearances in the fasted state, during clamped euglycemia (5 mmol/L) and during clamped hyperglycemia (15 mmol/L). Filtration fraction and renal vascular resistance were calculated. Additionally, factors known to modulate renal hemodynamics were measured. In 44 people with type 2 diabetes on metformin monotherapy (Hemoglobin A1c 7.4%, mGFR 113 mL/min), dapagliflozin versus gliclazide reduced mGFR by 5, 10, and 12 mL/min in the consecutive phases while both agents similarly improved Hemoglobin A1c (-0.48% vs -0.65%). Dapagliflozin also reduced filtration fraction without increasing renal vascular resistance, and increased urinary adenosine and prostaglandin concentrations. Gliclazide did not consistently alter renal hemodynamic parameters. Thus, beyond glucose control, SGLT2i reduce mGFR and filtration fraction in type 2 diabetes. The fact that renal vascular resistance was not increased by dapagliflozin suggests that this is due to post-glomerular vasodilation rather than pre-glomerular vasoconstriction.

SARS-CoV-2 E protein is a potential ion channel that can be inhibited by Gliclazide and Memantine.

COVID-19 is one of the most impactful pandemics in recorded history. As such, the identification of inhibitory drugs against its etiological agent, SARS-CoV-2, is of utmost importance, and in particular, repurposing may provide the fastest route to curb the disease. As the first step in this route, we sought to identify an attractive and viable target in the virus for pharmaceutical inhibition. Using three bacteria-based assays that were tested on known viroporins, we demonstrate that one of its essential components, the E protein, is a potential ion channel and, therefore, is an excellent drug target. Channel activity was demonstrated for E proteins in other coronaviruses, providing further emphasis on the importance of this functionally to the virus' pathogenicity. The results of a screening effort involving a repurposing drug library of ion channel blockers yielded two compounds that inhibit the E protein: Gliclazide and Memantine. In conclusion, as a route to curb viral virulence and abate COVID-19, we point to the E protein of SARS-CoV-2 as an attractive drug target and identify off-label compounds that inhibit it.

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.