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Cisplatin (CDDP) can combat various types of cancers, employing a multifaceted approach against these malignant diseases. Despite its efficacy, resistance to CDDP remains a significant clinical challenge, often resulting in treatment failure and disease progression. Currently, efforts are underway to unravel the mechanisms of CDDP drug resistance in cancer treatment. The elevated presence of glutathione S‐transferase pi‐1 (GSTP1‐1) within tumor cells plays a pivotal role in the development of resistance toward the effects of CDDP. GSTP1‐1 contributes to detoxification by conjugating glutathione (GSH) to CDDP, reducing its accumulation and effectiveness in the tumor cells. In this study, the efficacy of gliquidone, an antidiabetic drug, demonstrated its capacity to impede tumor cell proliferation in both lung cancer A549 cell lines and A549/CDDP cell lines. This was achieved by suppressing the expression of GSTP1‐1 within tumor cells (IC50: 16.8 ± 0.8 μM). Furthermore, through the establishment of a nude mouse model featuring lung adenocarcinoma A549/CDDP cell transplantation tumors, gliquidone demonstrated a significant therapeutic effect on the mice tumors, while avoiding discernible side effects. These findings suggest that gliquidone could potentially be repurposed as an adjunct therapy in CDDP‐resistant lung cancer. [ABSTRACT FROM AUTHOR]

Abstract Background Diabetic retinopathy (DR) is a common and potentially devastating microvascular complication of diabetes mellitus (DM). The main features of DR are inflammation and oxidative damage. Gliquidone (GLI) is confirmed to be a hypoglycemic drug by oral administration. The current study is aimed to investigate the role and mechanism of GLI on the pathogenesis of DR. Methods High glucose (HG)-induced human retinal endothelial cells (HRECs) were used to explore the anti-inflammatory and anti-oxidant effects of GLI on DR in vitro. Streptozotocin (STZ)-induced DM rats were used to investigate the effects of GLI on retinal structures, inflammation, and oxidative stress. The levels of SIRT1/Notch1 pathway-related proteins were determined by western blotting. Results GLI treatment promoted the viability and inhibited the apoptosis of HG-induced HRECs. Meanwhile, the levels of interleukin (IL)-6, IL-1β, tumour necrosis factor alpha and reactive oxygen species were suppressed, while both catalase and superoxide dismutase were elevated after GLI treatment in HG-induced HRECs. Furthermore, we found that Silencing information regulator 2 related enzyme 1 (SIRT1) silencing reversed the inhibiting effects of GLI on the levels of protein Notch1 and effector genes Hes1 and Hey2. Similar anti-inflammatory and anti-oxidant effects of GLI in STZ-induced DM rats were observed. Additionally, GLI administration also repressed vascular hyperpermeability in vivo. Conclusion GLI may be an effective agent to improve DR through repression of inflammation and oxidative stress via SIRT1/Notch1 pathway.

Fenpropathrin is a commonly used pesticide, which was ingested by humans through diet and water. Gliquidone is a common hypoglycemic drug that diabetic patients need for long-term use. This study aimed to investigate the effects of long-term exposure to fenpropathrin on the intestinal barrier and intestinal absorption of the model drug gliquidone. The Ussing Chamber study had shown that fenpropathrin can increase the transport of gliquidone in an isolated intestinal model. In addition, the intestinal absorption of fluorescein was significantly increased in fenpropathrin-exposed rats administered by gavage. Further research suggested that fenpropathrin exposure caused a series of pathological effects: the structure of the intestine was damaged, the expression of tight junction proteins in the intestinal tissue was decreased, the intestinal MDA was increased, the SOD was decreased, and the expression of inflammatory factors was increased. In the Caco-2 cell model, it was found that fenpropathrin can increase the transport of gliquidone in the Caco-2 cell monolayer, reduce the expression of tight junction proteins and increase reactive oxygen species in Caco-2 cells. Fenpropathrin exposure also resulted in decreasing expression of PPAR-γ and UCP-2 in intestinal tissue and Caco-2 cell model, while causing increased expression of p-P38. The above results indicated that fenpropathrin exposure could induce oxidative stress and destroy the intestinal barrier by affecting the expression of p-P38/P38/PPAR-γ/UCP-2 protein, thereby increasing the intestinal absorption of gliquidone. This study provides new insights into the hazards of fenpropathrin residues in the environment.

Background: Diabetic retinopathy (DR) is a common and potentially devastating microvascular complication of diabetes mellitus (DM). The main features of DR are inflammation and oxidative damage. Gliquidone (GLI) is confirmed to be a hypoglycemic drug by oral administration. The current study is aimed to investigate the role and mechanism of GLI on the pathogenesis of DR.Methods: High glucose (HG)-induced human retinal endothelial cells (HRECs) were used to explore the anti-inflammatory and anti-oxidant effects of GLI on DR in vitro. Streptozotocin (STZ)-induced DM rats were used to investigate the effects of GLI on retinal structures, inflammation, and oxidative stress. The levels of SIRT1/Notch1 pathway-related proteins were determined by western blotting.Results: GLI treatment promoted the viability and inhibited the apoptosis of HG-induced HRECs. Meanwhile, the levels of interleukin (IL)-6, IL-1β, tumour necrosis factor alpha and reactive oxygen species were suppressed, while both catalase and superoxide dismutase were elevated after GLI treatment in HG-induced HRECs. Furthermore, we found that Silencing information regulator 2 related enzyme 1 (SIRT1) silencing reversed the inhibiting effects of GLI on the levels of protein Notch1 and effector genes Hes1 and Hey2. Similar anti-inflammatory and anti-oxidant effects of GLI in STZ-induced DM rats were observed. Additionally, GLI administration also repressed vascular hyperpermeability in vivo.Conclusion: GLI may be an effective agent to improve DR through repression of inflammation and oxidative stress via SIRT1/Notch1 pathway. [ABSTRACT FROM AUTHOR]

The sulfonylurea drug gliquidone is FDA approved for the treatment of type 2 diabetes. Binding of gliquidone to ATP-sensitive potassium channels (SUR1, Kir6 subunit) in pancreatic β-cells increases insulin release to regulate blood glucose levels. Diabetes has been associated with increased levels of neuroinflammation, and therefore the potential effects of gliquidone on micro- and astroglial neuroinflammatory responses in the brain are of interest. Here, we found that gliquidone suppressed LPS-mediated microgliosis, microglial hypertrophy, and proinflammatory cytokine COX-2 and IL-6 levels in wild-type mice, with smaller effects on astrogliosis. Importantly, gliquidone downregulated the LPS-induced microglial NLRP3 inflammasome and peripheral inflammation in wild-type mice. An investigation of the molecular mechanism of the effects of gliquidone on LPS-stimulated proinflammatory responses showed that in BV2 microglial cells, gliquidone significantly decreased LPS-induced proinflammatory cytokine levels and inhibited ERK/STAT3/NF-κB phosphorylation by altering NLRP3 inflammasome activation. In primary astrocytes, gliquidone selectively affected LPS-mediated proinflammatory cytokine expression and decreased STAT3/NF-κB signaling in an NLRP3-independent manner. These results indicate that gliquidone differentially modulates LPS-induced microglial and astroglial neuroinflammation in BV2 microglial cells, primary astrocytes, and a model of neuroinflammatory disease.

The sulfonylurea drug gliquidone is FDA approved for the treatment of type 2 diabetes. Binding of gliquidone to ATP-sensitive potassium channels (SUR1, Kir6 subunit) in pancreatic β-cells increases insulin release to regulate blood glucose levels. Diabetes has been associated with increased levels of neuroinflammation, and therefore the potential effects of gliquidone on micro- and astroglial neuroinflammatory responses in the brain are of interest. Here, we found that gliquidone suppressed LPS-mediated microgliosis, microglial hypertrophy, and proinflammatory cytokine COX-2 and IL-6 levels in wild-type mice, with smaller effects on astrogliosis. Importantly, gliquidone downregulated the LPS-induced microglial NLRP3 inflammasome and peripheral inflammation in wild-type mice. An investigation of the molecular mechanism of the effects of gliquidone on LPS-stimulated proinflammatory responses showed that in BV2 microglial cells, gliquidone significantly decreased LPS-induced proinflammatory cytokine levels and inhibited ERK/STAT3/NF-κB phosphorylation by altering NLRP3 inflammasome activation. In primary astrocytes, gliquidone selectively affected LPS-mediated proinflammatory cytokine expression and decreased STAT3/NF-κB signaling in an NLRP3-independent manner. These results indicate that gliquidone differentially modulates LPS-induced microglial and astroglial neuroinflammation in BV2 microglial cells, primary astrocytes, and a model of neuroinflammatory disease. [ABSTRACT FROM AUTHOR]

Objective: To explore the clinical effect of gliquidone combined with compound anisodine in the treatment of diabetic papillitis. Methods: A total of 100 patients with diabetic papillitis,who were treated in People's Hospital of Xinjiang Uygur Autonomous Region from June 2019 to January 2020, were divided into experimental group and control group (50 cases in each group). The patients in the control group were given compound anisodine only, and the patients in the experimental group were treated with gliquidone on the basis of the control group's therapy. The treatment effect, vision level, average visual field defect degree, adiponectin level, hs-CRP level, vascular endothelial growth factor (VEGF) level, adverse mood and quality of life of the two groups were compared before and after treatment, and the incidence of adverse reactions during treatment was compared. Results: (1) The total effective rate was 98.00 % in the experimental group and 86.00 % in the control group, with significant difference between the two groups (P<0.05). (2) Before treatment, there was no significant difference in visual acuity and visual field average defect degree between the two groups, but after treatment, the visual acuity of the two groups was significantly improved, while the visual field average defect degree of the experimental group was higher than that of the control group (P<0.05). (3) Before treatment, the levels of adiponectin, hs-CRP and VEGF in the two groups were not significantly different (P>0.05), but after treatment, the levels of adiponectin in the experimental group were higher than those in the control group,but hs-CRP and VEGF in the experimental group were lower than those in the control group (P<0.05). (4) Before treatment, the scores of HAMA, HAMD and SF-36 in the two groups were not significantly different (P>0.05), while the scores of HAMA and HAMD in the experimental group were lower than those in the control group (P<0.05), and SF-36 was higher than that in the control group (P<0.05). (5) The total incidence of adverse reactions was 12.00 % in the experimental group and 10.00% in the control group, with little difference between the two groups (P>0.05). Conclusion: Gliquidone combined with compound anisodine has a good therapeutic effect on diabetic papillitis. It can significantly reduce the degree of visual field defect, improve patients' visual acuity, reduce the levels of inflammatory mediators and vascular growth factors, relieve patients' anxiety and depression, and improve patients' quality of life. At the same time, the treatment is safe and worthy of clinical application. [ABSTRACT FROM AUTHOR]

Background/Aims: Diabetic nephropathy is a common complication of diabetes. This study explored the renal protective effect and possible mechanism of gliquidone in mice with diabetic nephropathy. Methods: Animal model of diabetic nephropathy was established in KKAy mice. The renal protective effect of gliquidone was studied by evaluating the kidney function through measures of urinary protein, blood urea nitrogen (BUN), serum creatinine (Scr) and serum triglyceride (TG) that were performed using an automatic biochemical analyzer. The levels of oxidative stress indicators, such as nitric oxide (NO), superoxide dismutase (SOD) and malondialdehyde (MDA), were evaluated in renal tissue homogenates using the automatic biochemical analyzer. The inhibitory effect of gliquidone on renal interstitial fibrosis and its association with Notch / Snail1 signaling pathway in diabetic nephropathy was investigated using molecular biological techniques. Results: It was found that low-, medium- and high-dose gliquidone improved the mice’s general health condition, such as mental status, fur condition, eating, and drinking. Gliquidone reduced the body weight and the kidney weight /body weight ratio of mice. Gliquidone improved the kidney function, indicated by reductions in urinary protein, blood urea nitrogen, and serum creatinine and triglyceride. Gliquidone treatment increased levels of nitric oxide and superoxide dismutase, but decreased level of malondialdehyde. The expression of Jagged1/Notch1/hes1/Snail1/α-SMA decreased, while the expression of E-cadherin increased in gliquidone-treated kidneys. High dose gliquidone showed the best effect, one that was similar to that of the positive control drug irbesartan. Conclusion: Taken together, our results suggested that gliquidone can ameliorate the diabetic symptoms of diabetic nephropathy through inhibiting Notch / Snail1 signaling pathway, improving anti -oxidative response and delaying renal interstitial fibrosis. The efficacy of gliquidone is dose-dependent.

The present work embarks upon increasing the dissolution rate and the bioavailability of model anti-diabetic drug, gliquidone, a sulfonylurea class drug used for treating diabetes mellitus type 2. The gliquidone nanoparticles were prepared by using anti-solvent precipitation technique in which, gliquidone solution in acetone was added at a controlled rate to an aqueous solution containing polyvinylpyrrolidone K25 (PVP K25) as stabilizer. The effect of drug concentration (X1), polymer concentration (X2) and solvent to anti-solvent ratio (X3) on particle size and dissolution was studied using Box-Behnken design. The results revealed that by decreasing the drug concentration and by increasing the stabilizer concentration and solvent/anti-solvent ratio, reduction in the size of the particles was observed. The mentioned parameters were optimised and particle of size about 175 nm was achieved. The relative dissolution rate of prepared gliquidone nanoparticles in phosphate buffer pH 7.4 was ~ 4.7 times faster than original drug at t = 45 min. Further, the gliquidone nanoparticles were characterized by scanning electron microscope (SEM), Fourier transform-infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and X-ray powder diffraction (XRD). The particles revealed to be oval in shape with stabilizer molecules on surface and exhibited decreased crystalline nature when compared to free gliquidone. Finally, the in vivo studies using gliquidone nanoparticles revealed ~ 2.5-fold increase in Cmax when taken orally in the form of hard gelatin capsules in comparison to free gliquidone. Thus, overall investigation suggests that the developed strategy of gliquidone nanoparticles possess a keen potential for exhibiting anti-diabetic effect. [ABSTRACT FROM AUTHOR]

The main objective of this study is to increase the dissolution rate of gliquidone using its solid dispersions with pluronic F-68 by solvent evaporation method. The solid dispersion of the drug with pluronic at ratio 1:3 showed the highest dissolution efficiency (50.7%) after 10 min, so it was incorporated in fast dissolving tablets. Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) were used to study the interaction between gliquidone and pluronic in the solid state. The FTIR spectroscopic studies revealed no chemical interaction between the drug and pluronic, while the DSC results indicated the amorphous state of gliquidone in the solid dispersion. A 32 full factorial design was used to study the effect of varying concentrations of croscarmellose and sodium starch glycolate as superdisintegrants on the disintegration time and the percentage released after 10 min. The optimized formula showed a disintegration time of 39.1 ± 1.2 s and 85.43% ± 5.16% released after 10 min and was selected for the in-vivo studies in rabbits. The selected formula showed significant enhancement of gliquidone bioavailability, about 1.8 times compared with the commercial Glurenor tablets. [ABSTRACT FROM AUTHOR]

Background/Aims: Diabetic nephropathy is a common complication of diabetes. This study explored the renal protective effect and possible mechanism of gliquidone in mice with diabetic nephropathy. Methods: Animal model of diabetic nephropathy was established in KKAy mice. The renal protective effect of gliquidone was studied by evaluating the kidney function through measures of urinary protein, blood urea nitrogen (BUN), serum creatinine (Scr) and serum triglyceride (TG) that were performed using an automatic biochemical analyzer. The levels of oxidative stress indicators, such as nitric oxide (NO), superoxide dismutase (SOD) and malondialdehyde (MDA), were evaluated in renal tissue homogenates using the automatic biochemical analyzer. The inhibitory effect of gliquidone on renal interstitial fibrosis and its association with Notch / Snail1 signaling pathway in diabetic nephropathy was investigated using molecular biological techniques. Results: It was found that low-, medium- and high-dose gliquidone improved the mice's general health condition, such as mental status, fur condition, eating, and drinking. Gliquidone reduced the body weight and the kidney weight /body weight ratio of mice. Gliquidone improved the kidney function, indicated by reductions in urinary protein, blood urea nitrogen, and serum creatinine and triglyceride. Gliquidone treatment increased levels of nitric oxide and superoxide dismutase, but decreased level of malondialdehyde. The expression of Jagged1/Notch1/hes1/Snail1/α-SMA decreased, while the expression of E-cadherin increased in gliquidone-treated kidneys. High dose gliquidone showed the best effect, one that was similar to that of the positive control drug irbesartan. Conclusion: Taken together, our results suggested that gliquidone can ameliorate the diabetic symptoms of diabetic nephropathy through inhibiting Notch / Snail1 signaling pathway, improving anti -oxidative response and delaying renal interstitial fibrosis. The efficacy of gliquidone is dose-dependent. [ABSTRACT FROM AUTHOR]

Stability testing on gliquidone was conducted under different conditions followed by adoption of two smart and selective spectrophotometric methods namely; mean centering of ratio spectra and derivative ratio for the determination of gliquidone in presence of alkaline degradation products. Degradation products have been elucidated by LC/MS and IR spectroscopy. The spectrum of alkaline degradation products (10 μg/ml) was chosen as a divisor to resolve the overlapped spectra of gliquidone and its degradation products. Mean centering of ratio spectra method depends on using Matlab software and measuring the mean centered values at 260 nm. Derivative ratio method is based on the measurements of analytical signal at 253 nm. Instrumental parameters and divisor concentration were carefully studied. The adopted methods have been validated as per International Conference on Harmonization guidelines. Linearity was obeyed in the range 1-18 μg/ml and detection limit was found to be 0.180, 0.324 μg/ml for mean centering of ratio spectra and derivative ratio methods, respectively. The recommended procedures were successfully applied for the analysis of Glurenor® tablets with good respective recoveries of 103.40± 0.50 and 102.99± 0.62. The results were statistically analyzed using student’s t-test and F-ratio to confirm accuracy and precision. [ABSTRACT FROM AUTHOR]

Simple, smart and sensitive normal fluorescence and stability-indicating derivative synchronous spectrofluorimetric methods have been developed and validated for the determination of gliquidone in the drug substance and drug product. Normal spectrofluorimetric method of gliquidone was established in methanol at λ excitation 225 nm and λ emission 400 nm in concentration range 0.2–3 μg/ml with LOD equal 0.028. The fluorescence quantum yield of gliquidone was calculated using quinine sulfate as a reference and found to be 0.542. Stability-indicating first and third derivative synchronous fluorescence spectroscopy were successfully utilized to overcome the overlapped spectra in normal fluorescence of gliquidone and its alkaline degradation product. Derivative synchronous methods are based on using the synchronous fluorescence of gliquidone and its degradation product in methanol at Δ λ50 nm. Peak amplitude in the first derivative of synchronous fluorescence spectra was measured at 309 nm where degradation product showed zero-crossing without interference. The peak amplitudes in the third derivative of synchronous fluorescence spectra, peak to trough were measured at 316,329 nm where degradation product showed zero-crossing. The different experimental parameters affecting the normal and synchronous fluorescence intensity of gliquidone were studied and optimized. Moreover, the cited methods have been validated as per ICH guidelines. The peak amplitude-concentration plots of the derivative synchronous fluorescence were linear over the concentration range 0.05–2 μg/ml for gliquidone. Limits of detection were 0.020 and 0.022 in first and third derivative synchronous spectra, respectively. The adopted methods were successfully applied to commercial tablets and the results demonstrated that the derivative synchronous fluorescence spectroscopy is a powerful stability-indicating method, suitable for routine use with a short analysis time. Statistical comparison between the results obtained by normal fluorescence and derivative synchronous methods and the official one using student's t -test and F-ratio showed no significant difference regarding accuracy and precision. [ABSTRACT FROM AUTHOR]

Gliquidone (GQ) is an oral hypoglycemic agent, belonging to second-generation sulfonylurea derivatives. New high-performance thin-layer chromatography (HPTLC) and ultra-performance liquid chromatography (UPLC) methods have been developed and validated and used for complete stability study of GQ following International Conference on Harmonization guidelines. GQ was subjected to stress and forced degradation under hydrolytic, oxidative and photolytic conditions. The drug was found to be unstable under acidic, alkaline and oxidative conditions with the formation of gliquidone sulfonamide (GQS), while a marked stability was confirmed under thermal and photolytic stress conditions. GQS is the British pharmacopeial impurity A of GQ and also considered as its synthesis intermediate. The developed chromatographic methods have been utilized for anticipating the degradation behavior of GQ under the studied conditions and then used for quantitation of GQ and GQS either in their pure forms or in laboratory prepared mixtures. The methods were successfully applied to GQ in pharmaceutical formulation. The methods have the advantages of being sensitive and less time consuming compared with the reported methods. The obtained results were statistically compared with a reported HPLC method showing no significant difference regarding both accuracy and precision. [ABSTRACT FROM AUTHOR]

OBEJECTIVE: To probe into the efficacy of gliquidone combined with atorvastatin in treatment of early diabetic kidney disease(DKD). METHODS: 64 patients with early DKD were selected and divided into control group and observation group via random number table, with 32 cases in each. The control group was given 45-120 mg/d of gliquidone orally, while the observation group was given 10 mg/d of atorvastatin orally based on the control group,levels of serum creatinine(SCr),urinary albumin excretion rate in 24 h(24 h UAER),glycosylated hemoglobin(HbA1c),total cholesterol(TC) and low density lipoprotein cholesterin(LDL-C) of two groups were compared. RESULTS: After 3-month treatment,the HbA1c and 24 h UAER levels of both groups had been significantly decreased, with statistically significant differences(P<0.05); the 24 h UAER,TC and LDL-C levels of observation group were significantly lower than those of the control group, with statistically significant differences(P<0.05). After 6-month treatment,the HbA1c and 24 h UAER levels of both groups had been significantly decreased, with statistically significant differences(P<0.05); the Scr level of observation group was significantly lower than that of before treatment, with statistically significant differences(P<0.05), while there was no statistical significance in difference of SCr level in control group between before and after treatment(P<0.05); at 6 months after treatment,the 24 h UAER,SCr,TC and LDL-C levels of observation group were significantly lower than those of 3 months after treatment, and also significantly lower than those of the control group, with statistically significant differences(P<0.05). CONCLUSIONS: The combination of gliquidone and atorvastatin is more beneficial to the improvement of early DKD, which makes more significant differences in long-term blood lipid control and kidney protection. [ABSTRACT FROM AUTHOR]

Aims: Sulfonylurea drugs exert an insulinotropic effect through ATP-sensitive potassium (KATP) channel inhibition in pancreatic islet cells. These channels are also expressed in cardiomyocytes and vascular smooth muscle cells (VSMCs), suggesting potential for adverse cardiovascular effects. We evaluated the effects of Gliquidone (Glq) on sulfonylurea receptors in HIT-T15 cells (SUR1), cardiomyocytes (SUR2A), and VSMCs (SUR2B).Methods: The concentration-dependent effects of Glq (0.001-500 μM) on KATP channels were assessed using whole-cell patch clamp in HIT-T15 cells, rat cardiomyocytes, and VSMCs. Parallel studies using Glibenclamide (Glb) (0.001-10 μM) and Gliclazide (Glc) (0.01-500 μM)were conducted as controls.Results: In HIT-T15 cells, Glb exhibited the lowest IC50 (0.03 μM), as compared to Glq (0.45μM) and Glc (1.21μM). However, Glq had higher IC50 in cardiomyoctes and VSMCs, as compared to Glb (119.1 vs. 0.01 and 149.7 vs. 0.09 μM, respectively), suggesting that Glq is more selective to β-cells than Glb. Thus, Glq may have fewer side effects in cardiomyoctes and VSMCs.Conclusions: Glq is a highly selective SUR secretagogue with moderate affinity to β-cells, but low affinity to cardiomyocytes and VSMCs. Our data also reveal the non-selective nature of Glb, as evidenced by high binding affinity to KATP channels in all the three cell types examined. [ABSTRACT FROM AUTHOR]

Fenpropathrin is a commonly used pesticide, which was ingested by humans through diet and water. Gliquidone is a common hypoglycemic drug that diabetic patients need for long-term use. This study aimed to investigate the effects of long-term exposure to fenpropathrin on the intestinal barrier and intestinal absorption of the model drug gliquidone. The Ussing Chamber study had shown that fenpropathrin can increase the transport of gliquidone in an isolated intestinal model. In addition, the intestinal absorption of fluorescein was significantly increased in fenpropathrin-exposed rats administered by gavage. Further research suggested that fenpropathrin exposure caused a series of pathological effects: the structure of the intestine was damaged, the expression of tight junction proteins in the intestinal tissue was decreased, the intestinal MDA was increased, the SOD was decreased, and the expression of inflammatory factors was increased. In the Caco-2 cell model, it was found that fenpropathrin can increase the transport of gliquidone in the Caco-2 cell monolayer, reduce the expression of tight junction proteins and increase reactive oxygen species in Caco-2 cells. Fenpropathrin exposure also resulted in decreasing expression of PPAR-γ and UCP-2 in intestinal tissue and Caco-2 cell model, while causing increased expression of p-P38. The above results indicated that fenpropathrin exposure could induce oxidative stress and destroy the intestinal barrier by affecting the expression of p-P38/P38/PPAR-γ/UCP-2 protein, thereby increasing the intestinal absorption of gliquidone. This study provides new insights into the hazards of fenpropathrin residues in the environment. [Display omitted] • Fenpropathrin increases the permeability of the intestinal barrier. • Fenpropathrin increases the transport of gliquidone in isolated intestine and Caco-2 cell models. • Fenpropathrin induces oxidative stress in rat intestine via p-P38/P38/PPAR-γ/UCP-2 pathway. [ABSTRACT FROM AUTHOR]

The root of Astragalus membranaceus also known as Huang Qi in China is a common traditional Chinese herb with extensive pharmacological activities. Huangqi injection (HI), a common preparation of Huang Qi, was wildly co-administered with gliquidone to treat diabetes mellitus and diabetic nephropathy in clinic of China. The aim of the study was to investigate the effect of HI on the pharmacokinetics and hepatic uptake of gliquidone and related mechanism to ensure the safety and efficacy of their usage. Normal rats ( n = 5) and streptozotocin (STZ)-induced diabetic rats ( n = 5) were administered orally with 120 mg/kg gliquidone alone or in combination with 8 ml/kg HI (i.v.), HI was given intravenously 5 min before that of gliquidone. The plasma concentration of gliquidone was determined by HPLC-fluorescence. In addition, hepatic uptake of gliquidone with or without HI was evaluated in fresh primary rat hepatocytes. Co-administration of HI with gliquidone could significantly increased the bioavailability of gliquidone in normal and STZ-induced diabetic rats ( n = 5); the concentration of gliquidone in fresh primary rat hepatocytes was greatly decreased by HI. This study suggested that when HI and gliquidone co-administering to normal and diabetic rats, the pharmacokinetics of gliquidone was greatly changed, and these changes connect with HI inhibiting hepatic uptake of gliquidone, and transportation of gliquidone across liver mucosal membrane inhibited by HI would be the main mechanisms. [ABSTRACT FROM AUTHOR]

1. Gliquidone, a second generation sulfonylurea, is a widely used oral antidiabetic drug. Due to the differences in its rate of metabolism, gliquidone shows inter-subject variability in pharmacokinetic and pharmacodynamic profiles. 2. Cytochrome P450 (CYP450) isoforms are involved in the metabolism of a majority of drugs in clinical use and plays a significant role in reducing possible drug interactions. This research aimed to systematically study the contribution of various human CYP450 isoforms to gliquidone metabolism in vitro in rats and human. 3. In rat liver microsomes, gliquidone was metabolized mainly by the most abundant CYP2C. The other isoforms involved in the metabolism included CYP3A, CYP2D, CYP1A and CYP2E. 4. Further investigation of rat recombinant enzymes showed that CYP3A1 and CYP2C11 played a major role in gliquidone metabolism in vitro, while CYP2D1, CYP1A2 and CYP2E1 were also involved. 5. But the metabolism of gliquidone in the human liver microsomes was mainly mediated by CYP3A4. The other isoforms involved in this process were CYP2C9, CYP2C19 and CYP2D6. 6. The further study of human recombinant enzymes demonstrated that CYP3A4 was the principal isoform enzyme for the metabolism of gliquidone. The intrinsic clearance ( Vmax/ Km) of CYP3A4 during gliquidone metabolism was 3-12 times greater than that of other CYP450 isoforms including CYP2C9, CYP2D6 and CYP2C19. 7. These findings may assist in valuable prediction of potential interactions of gliquidone with other drugs that are CYP3A4 inhibitors or inducers and help to design more efficacious and safer pharmacotherapy for patients of diabetes mellitus. [ABSTRACT FROM AUTHOR]

The efficacy of gliquidone for the treatment of diabetic nephropathy was investigated by implanting micro-osmotic pumps containing gliquidone into the abdominal cavities of Goto-Kakizaki (GK) rats with diabetic nephropathy. Glycemic, 24h urinary protein and 24h urinary albumin levels were measured weekly. After 4-weeks of gliquidone therapy, pathological changes in the glomerular basement membrane were examined using an electron microscope. Real-time PCR, Western blot and immunohistochemistry were employed to detect glomerular expression of receptors for advanced glycation end products (RAGE), protein kinase C β (PKCβ) and protein kinase A (PKA) as well as tubular expression of the albumin reabsorption-associated proteins, megalin and cubilin. Human proximal tubular epithelial cells (HK-2 cell) were used to analyze the effects of gliquidone and AGEs (advanced glycation end products) on the expression of megalin and cubilin and on the absorption of albumin. Gliquidone lowered glycemic, 24h urine protein and 24h urine albumin levels in GK rats with diabetic nephropathy. The level of plasma C-peptide increased markedly and glomerular basement membrane and podocyte lesions improved dramatically after gliquidone treatment. Glomerular expression of RAGE and PKCβ decreased after gliquidone treatment, while PKA expression increased. AGEs markedly suppressed the expression of megalin and cubulin and the absorption of albumin in HK-2 cells in vitro, whereas the expression of megalin and cubilin and the absorption of albumin were all increased in these cells after gliquidone treatment. In conclusion, gliquidone effectively reduced urinary protein in GK rats with diabetic nephropathy by improving glomerular lesions and promoting tubular reabsorption. [ABSTRACT FROM AUTHOR]

Abstract: Background: Rapid, efficient and accurate RP-HPLC-UV method for the simultaneous determination and quality control of active pharmaceutical ingredient (API), pharmaceutical formulations and human serum containing drugs as rosuvastatin together with metformin, glimepiride and gliquidone has been proposed. Methods: The chromatographic system comprised mobile phase of methanol:water 90:10 v/v; pH adjusted to 3.0 with o-phosphoric acid, at 1ml/min through Prepacked Purospher Star C18 (5μm, 25×0.46cm) column with UV detection at isosbestic point 231nm. Results: The method showed good linearity in the range 0.25–25μg/ml for metformin and 0.5–50μg/ml for rosuvastatin, glimepiride and gliquidone with correlation co-efficient≥0.998; (precision %RSD<2) for all drugs in API, formulations and human serum. The recovery of all drugs was 98.9–101.91% in API and formulations and 99.92–102.08% in human serum. The sensitivity of method increased when drugs were analyzed after programming the detector at their individual λmax where their LODs shifted down to 5, 3, 10 and 9ng/ml from 10, 17, 15 and 14ng/ml when calculated at their isosbestic point respectively at least concentration 0.125μg/ml for metformin and 0.25μg/ml for rosuvastatin, glimepiride and gliquidone with correlation co-efficient≥0.998 in each case. Conclusions: The proposed drugs can be analyzed by this method for routine analysis and clinical studies with sensitivity at nanoscale with small sample volume. [Copyright &y& Elsevier]

Objective: To investigate the effect of high-altitude hypoxia on the pharmacokinetics parameters of gliquidone., Methods: Twelve healthy male Wistar rats were randomly divided into plain group and high-altitude group with 6 rats in each group. Blood samples were collected after intragastric administration of gliquidone (6.3 mg/kg). Ultra-fast liquid chromatography-tandem mass spectrometry (UFLC-MS/MS) was used to determine the concentration of gliquidone in rat plasma samples. And the expression of CYP2C9 in rat liver tissues was determined by Western blotting., Results: Compared with the plain group, the peak concentration of gliquidone in the high-altitude rats was significantly increased, the absorption rate constant was decreased, the elimination rate constant and the absorption half-life were increased, the elimination half-life was shortened, the mean residence time and apparent volume of distribution were decreased (all P <0.05). Western blotting showed that the expression of CYP2C9 was significantly up-regulated in the liver tissues of high altitude group rats, compared with the plain group (4.18 ±0.06 vs . 2.13±0.06, t =11.57, P< 0.01)., Conclusion: Under the high-altitude hypoxia environment, the absorption of gliquidone in rats was reduced and the metabolism was accelerated in rats, which may be related to the up-regulation of CYP2C9 expression in liver tissues.

In present paper, we describe in vitro drug interactions of antidiabetic agents; gliquidone and pioglitazone hydrochloride with an antihypertensive, losartan potassium. Co-administration of antihypertensive and antidiabetic drugs is most common, as both of these ailments are synergistic to each other and often occur together. These studies were carried out in different pH environments simulating human body compartments and using UV spectrophotometer and HPLC. Antidiabetic agents and losartan were found to inhibit or enhance each other's availability, which may affect their therapeutic efficacy. These results were further verified by IR and NMR spectroscopic studies and computational molecular modeling. [ABSTRACT FROM AUTHOR]

Controlling blood sugar levels is crucial for diabetic patients and is managed through administration of drugs such as gliquidone. Coadministration of antidiabetic drugs with H-receptor antagonists is common but is also a source of concern due to potential coadministered drug interaction, especially in patients prone to allergic disorders. In this work, we describe in vitro drug interactions of gliquidone with commonly coadministered H-receptor antagonists (fexofenadine hydrochloride, cetirizine dihydrochloride, and levocetirizine dihydrochloride). These studies were performed at 37°C in different pH environments simulating human body compartments using UV spectrophotometry and high performance liquid chromatography (HPLC). It was observed that the percentage availability values of gliquidone and H-receptor antagonists were not affected in the presence of each other. No significant difference between gliquidone and H-receptor antagonists and no remarkable changes in availability values were observed when these interactions were studied using UV-visible and HPLC techniques. This study thus supports the safe coadministration of gliquidone and H-receptor blockers as an effective diabetic health management regimen. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To probe into the short-term economic effects of 3 kinds of sulfonylurea drugs in the initial treatment of type II diabetes. METHODS: 180 patients with type II diabetes admitted into Hongqi Hospital of Mudanjiang Medical University from Aug. 2012 to Aug. 2015 were selected to be divided into glimepiride group, gliquidone group and glipizide group via the random number table, with 60 cases in each. Patients in glimepiride group were treated with glimepiride 4 mg, once a day; the gliquidone group were given gliquidone 15 mg, 3 times a day; and the glipizide group received glenn pyrazine 15 mg, once a day; 12 weeks for a treatment course. And the blood glucose, HbA1c were determined during the treatment process. RESULTS: The total effective rate of glimepiride group was was significantly higher than that of glipizide group; the decent percentage of blood glucose after 2 h and HbA1c of glimepiride group were significantly higher than those of gliquidone group and glipizide group , with statistically significant difference (P <0.05) .To set the indicators as decent percentage of 2 h postprandial blood glucose , compared with glipizide group, glimepiride group, gliquidone group had increased by 8.44 yuan, 17.54 yuan. And to set the indicators as decent percentage of HbA1c, compared with glipizide group , glimepiride group , gliquidone group had increased by 36.49 yuan, 53.96 yuan. The decent percentage of 2 h postprandial blood glucose and HbA1c were insensitive to the price of drugs; the differences of incidence of adverse drug reactions among three groups were not significant (P>0.05). CONCLUSIONS: The short-term economics effects of glimepiride is better than gliquidone and glipizide in the initial treatment of type 2 diabetes. [ABSTRACT FROM AUTHOR]

Abstract: Complexes of gliquidone with Mg(II), Ca(II), Cr(II), Mn(II), Fe(III), Co(II), Ni(II), Cu(II), Zn(II) and Cd(II) were obtained in methanolic solution to study the interaction of the drug with essential and trace elements present in human body or co administered during multivitamin therapy. These complexes were then characterized by spectroscopic techniques involving IR, 1H NMR, CHN elemental analysis, atomic absorption analysis and conductometric titrations. In most of the complexes, it is observed that the N–H stretch of sulfonamide and amide has disappeared. [Copyright &y& Elsevier]

This study was carried out with the aim to optimize the pharmacological profile of gliquidone (GLI)—a poorly bioavailable hypoglycaemic agent sparingly soluble in water- through complexation with cyclodextrins. In order to increase the apparent solubility of GLI, two cyclodextrins, namely β-cyclodextrin (βCD) and hydroxypropyl-β-cyclodextrin (HPβCD), were tested. The effect of cyclodextrin addition on the aqueous solubility of GLI was evaluated by the phase solubility method at different pH values. The amount of GLI in solution increased upon CD addition according to A type plots. The aqueous solubility of GLI was enhanced more at higher pH values and using HPβCD. On the basis of its performance, HPβCD was selected as host to prepare GLI oral formulations. GLI/HPβCD solid systems were prepared at 1:2 molar ratio by co-grinding, spray-drying and freeze-drying and characterized by DSC, FTIR and X-ray powder diffractometry. Powders were amorphous and showed an improved dissolution rate in comparison with GLI. GLI/HPβCD co-ground and freeze-dried products were the most interesting systems, since they dissolved 62 and 94% of total drug after 15 min, respectively. The hypoglycaemic effect of the most rapidly dissolving binary systems was evaluated after oral administration in fasted rats by measuring plasma glucose level in the time interval 0.5–36 h and compared to free GLI. Our findings indicate that cyclodextrin-containing formulations not only provide an onset of hypoglycaemic effect faster than GLI, but also enhance significantly the pharmacological effect due to improved biopharmaceutics. The association GLI/HPβCD allows a reduction of the oral dose and is expected to provide a better control over drug side effects, contributing to improve safety and efficacy of GLI. [Copyright &y& Elsevier]

Gliquidone was suggested to exert hypoglycemic effect through enhancing hepatic insulin sensitivity. However, inadequate in vivo evidences make this statement controversial. The aim of the present study was to clarify the insulin-sensitizer role of gliquidone in liver and muscle, so as to confirm its extra-pancreatic effects in vivo. TALEN technique was used to create Sur1 knockout (Sur1 −/− ) rats. Diabetic Sur1 −/− rat models were established by high-fat diet combined with streptozotocin, and which were randomly divided into three groups: gliquidone, metformin and saline, treated for 8 weeks. Fasting blood glucose (FBG) and body mass were tested each week. IPGTT, IPITT and hyperinsulinemic-euglycemic clamp tests were used to evaluate glucose tolerance and insulin sensitivity, respectively. Key mediators of glucose metabolism in liver and skeletal muscle and the activity of AKT and AMPK in these tissues were further analyzed. We found that gliquidone decreased FBG and increased insulin sensitivity without increasing insulin secretion in diabetic Sur1 −/− rats. Further exploration implied that gliquidone mainly increased hepatic glycogen storage and decreased gluconeogenesis, which were accompanied with activation of AKT, but not enhanced muscle GLUT4 expression. However, both these effects were still weaker than that of metformin. These results suggested that gliquidone could exerts an extra-pancreatic hypoglycemic effect by improving insulin sensitivity, which might be largely attributes to its additional insulin sensitizer role in hepatic glucose metabolism. [Display omitted] • Gliquidone decreases the level of blood glucose through extra-pancreatic actions in diabetic Sur1 −/− rats. • Gliquidone alleviates hepatic insulin resistance by increasing glycogen synthesis and decreasing gluconeogenesis in vivo. • The mechanism of gliquidone might be related to the activation of AKT, rather than AMPK. [ABSTRACT FROM AUTHOR]

Gliquidone (Glurenorm) and glibenclamide were compared in a cross-over study of 20 non insulin dependent diabetics. Both drugs achieved similar levels of control, as measured by self home monitoring, glycosylated haemoglobin and N-acetyl-β-D-glucosamidase levels. However, with glibenclamide hyperglycaemic control was only achieved at the expense of more hypoglycaemic episodes. The study examined the tailoring of drug dosage to the patients needs and found that in the majority of patients it was necessary to give both glibenclamide and gliquidone thrice daily. It confirmed the acceptability of self glucose monitoring in a home population. [ABSTRACT FROM AUTHOR]

Hypoglycaemic sulphonylureas bind to multilamellar liposomes formed of egg yolk phosphatidylcholine. In this artificial model, both specific and non-specific components of the binding phenomenon can be characterized by the same criteria as those used in studies performed with natural membranes. The relative ability of distinct sulphonylureas to inhibit the binding of H-glibenclamide or H-gliquidone to the liposomes parallels their relative potency as insulin secretagogues. It is proposed that the insertion of hypoglycaemic sulphonylureas into the phospholipid domain of the B cell membrane could represent a primary event in the mechanism by which these agents stimulate insulin release. [ABSTRACT FROM AUTHOR]

A standardized procedure for the assay and identification of hypoglycemic sulfonylureas in plasma is presented. External standards and plasma extracts containing glibenclamide, gliquidone, glipizide, or gliclazide were examined by high-performance liquid chromatography. The four sulfonylureas could be identified and measured with a precision of 5%-7% and a limit of detection close to 1-2 ng in injected external standards and 10-40 ng/ml in plasma samples. This method is suitable to study the pharmacokinetics of hypoglycemic sulfonylureas, for blood drug monitoring in diabetic patients, for diagnostic purposes in factitious hypoglycemia, and in cases relevant to forensic medicine. [ABSTRACT FROM AUTHOR]