Gliquidone

Gliquidone is an antagonist of ATP-sensitive K+ channel with IC50 value of 27.2 nM [1].

ATP-sensitive K+ channel is a type of K+ channel that is gated by intracellular ATP and ADP. ATP-sensitive K+ channel mainly exists in plasma membrane.

Gliquidone is an ATP-sensitive K+ channel antagonist. In mice, gliquidone (10 or 40 μg) antagonized morphine (20 mg/kg) induced hypermotility in a dose-dependent way. These results suggested that ATP-sensitive K+ channels played an important role in morphine-induced hypermotility [1]. In mice, gliquidone (2-8 μg) antagonized the antinociceptive effect induced by R-PIA (the adenosine A1 receptor agonist) in a dose-dependent way, which suggested that ATP-sensitive K+ channels mediated antinociception induced by R-PIA [2].

In patients with type 2 diabetes mellitus, gliquidone reduced the mean plasma glucose levels by 15% and increased insulin levels by 40% [3]. In Caucasian patients with new-onset diabetes mellitus (NODM) after kidney transplantation, gliquidone reduced fasting blood glucose (FBG) from 154 mg/dl to 120 mg/dl [4].

References:
[1].  Ocaña M, Del Pozo E, Baeyens JM. Gliquidone, an ATP-dependent K+ channel antagonist, antagonizes morphine-induced hypermotility. Eur J Pharmacol, 1993, 239(1-3): 253-255.
[2].  Ocaña M, Baeyens JM. Role of ATP-sensitive K+ channels in antinociception induced by R-PIA, an adenosine A1 receptor agonist. Naunyn Schmiedebergs Arch Pharmacol, 1994, 350(1): 57-62.
[3].  von Nicolai H, Brickl R, Eschey H, et al. Duration of action and pharmacokinetics of the oral antidiabetic drug gliquidone in patients with non-insulin-dependent (type 2) diabetes mellitus. Arzneimittelforschung, 1997, 47(3): 247-252.
[4].  Tuerk TR, Bandur S, Nuernberger J, et al. Gliquidone therapy of new-onset diabetes mellitus after kidney transplantation. Clin Nephrol, 2008, 70(1): 26-32.

The effect of gliquidone on KATP channels in pancreatic beta-cells, cardiomyocytes, and vascular smooth muscle cells.[Pubmed:26044612]

Diabetes Res Clin Pract. 2015 Aug;109(2):334-9.

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 muM) 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 muM) and Gliclazide (Glc) (0.01-500 muM)were conducted as controls. RESULTS: In HIT-T15 cells, Glb exhibited the lowest IC50 (0.03 muM), as compared to Glq (0.45muM) and Glc (1.21muM). However, Glq had higher IC50 in cardiomyoctes and VSMCs, as compared to Glb (119.1 vs. 0.01 and 149.7 vs. 0.09 muM, respectively), suggesting that Glq is more selective to beta-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 beta-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.

Gliquidone versus metformin: differential effects on aorta in streptozotocin induced diabetic rats.[Pubmed:24709184]

Chin Med J (Engl). 2014;127(7):1298-303.

BACKGROUND: Diabetic cardiovascular complication is a major cause of mortality in type 2 diabetic patients. Hyperglycemia markedly increases the risk of cardiovascular disease. Endothelial dysfunction is common in type 2 diabetes mellitus (DM) and is an early indicator of diabetic vascular disease. Therefore, it is necessary to identify the effect of different hypoglycemic agents on vascular endothelium. The aim of the study was to examine and compare the effects of metformin and Gliquidone on atherosclerotic lesions in streptozotocin-induced diabetic rats. METHODS: Forty male Sprague-Dawley rats (age, 8 weeks; weight, 180-200 g) were included in this study and fed with a normal chow diet for 1 week. Rats (n = 10) served as the normal control group (NC group) were fed with a normal chow for another 2 weeks and received an injection of saline. The rest 30 rats fed with a high-fat diet for 2 weeks and injected streptozotocin were randomly assigned to three groups (n = 10 rats per group) as follow: type 2 DM group (DM group), DM + Gliquidone group (GLI group) and DM + metformin group (MET group). Five weeks later, all rats were fasted overnight and taken tail blood samples for biochemical determinations. Then rats in the NC and DM groups were administrated with normal saline, while rats in the MET and GLI groups were administrated with metformin (100 mg/kg) or Gliquidone (10 mg/kg), respectively. All medicines were given via intragastric administration for 8 weeks. After 16 weeks, plasma triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) were measured. The aortic arch was isolated from diabetic rats and was assessed by pathological sectioning using H&E staining. RESULTS: Metformin treatment prevented weight gain ((315.80 +/- 52.16) g vs. (318.70 +/- 68.48) g, P = 0.773), improved plasma TG, HDL-C and LDL-C levels (P = 0.006, 0.003, 0.001, respectively, all P < 0.05). However, Gliquidone showed no significant effects on plasma TG and TC levels (P = 0.819, 0.053, respectively). LDL-C and HDL-C in the GLI group changed ((0.46 +/- 0.10) mmol/L vs. (0.36 +/- 0.14) mmol/L, P = 0.007; (0.99 +/- 0.27) mmol/L vs. (1.11 +/- 0.18) mmol/L, P = 0.049). Both metformin and Gliquidone treatment lowered blood glucose levels (P = 0.001, 0.004, respectively, P < 0.05). Under light microscopy, no changes were observed in the aortic wall structure of each layer; the intima was smooth and the membrane elastic fibers were normal in the NC group. In the DM group, the aortic wall structure was unclear, the intima was thickened with irregular intima, and membrane elastic fibers collapsed. The aortic intima in the MET and GLI groups was smoother compared with the DM group, but the endothelial structure of the MET group was closer to that of the NC group. CONCLUSIONS: Both metformin and Gliquidone have anti-atherosclerotic effects. But the endothelial structure of the MET group was closer to that of the NC group. Metformin and Gliquidone therapy can reduce serum level of LDL-C and increase level of HDL-C, whereas Gliquidone therapy did not lose weight and decrease serum level of TG. These data may have important implications for the treatment of patients with type 2 DM.

Pharmacokinetics and hepatic uptake of gliquidone affected by Huangqi injection.[Pubmed:24085486]

Eur J Drug Metab Pharmacokinet. 2014 Dec;39(4):255-61.

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.

Gliquidone decreases urinary protein by promoting tubular reabsorption in diabetic Goto-Kakizaki rats.[Pubmed:24254365]

J Endocrinol. 2014 Jan 8;220(2):129-41.

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. Blood glucose, 24 h urinary protein, and 24 h urinary albumin levels were measured weekly. After 4 weeks of Gliquidone therapy, pathological changes in the glomerular basement membrane (GBM) were examined using an electron microscope. Real-time PCR, western blotting, and immunohistochemistry were employed to detect glomerular expression of receptors for advanced glycation end products (RAGE) (AGER), protein kinase C beta (PKCbeta), 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 cells) were used to analyze the effects of Gliquidone and advanced glycation end products (AGEs) on the expression of megalin and cubilin and on the absorption of albumin. Gliquidone lowered blood glucose, 24 h urinary protein, and 24 h urinary albumin levels in GK rats with diabetic nephropathy. The level of plasma C-peptide increased markedly and GBM and podocyte lesions improved dramatically after Gliquidone treatment. Glomerular expression of RAGE and PKCbeta 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 treatment effectively reduced urinary protein in GK rats with diabetic nephropathy by improving glomerular lesions and promoting tubular reabsorption.