Gliquidone

Abstract: The data from three clinical trials are presented, comparing the efficacy of different sulfonylureas in the treatment of type II diabetes. In a multicenter study, gliclazide improved control in 49% of patients who had failed on other drugs. When five groups of type II diabetic patients were treated concurrently with five randomly allocated different sulfonylureas over 1 year, the percentage of patients achieving normal HbA1 levels was best with gliclazide (80%) and glibenclamide (74%), when compared with chlorpropamide (17%), glipizide (40%), and gliquidone (40%). Secondary failure rate over 5 years was assessed in 248 type II diabetic patients randomly allocated to three different sulfonylureas and found to be lowest with gliclazide (7%) compared with glibenclamide (17.9%): p < 0.1) and glipizide (25.6%: p < 0.005). The incidence of hypoglycemia was significantly higher with glibenclamide than with gliclazide (p < 0.05). The differences in efficacy and secondary failure rate between sulfonylureas may be related to the mechanism of insulin release from the beta-cell and the more physiological action of gliclazide could partly explain this. These trials suggest that gliclazide is a potent sulfonylurea with a low rate of secondary failure and a low incidence of side effects and may be a better choice in long-term sulfonylurea therapy.

Abstract: 1. The effects of several K+ channel blockers (sulphonylureas, 4-aminopyridine and tetraethylammonium) on the antinociception induced by clonidine, baclofen and U50,488H were evaluated by use of a tail flick test in mice. 2. Clonidine (0.125-2 mg kg-1, s.c.) induced a dose-dependent antinociceptive effect. The ATP-dependent K+ (KATP) channel blocker gliquidone (4-8 micrograms/mouse, i.c.v.) produced a dose-dependent displacement to the right of the clonidine dose-response line, but neither 4-aminopyridine (4-AP) (25-250 ng/mouse, i.c.v.) nor tetraethylammonium (TEA) (10-20 micrograms/mouse, i.c.v.) significantly modified clonidine-induced antinociception. 3. The order of potency of sulphonylureas in antagonizing clonidine-induced antinociception was gliquidone > glipizide > glibenclamide > tolbutamide, which is the same order of potency as these drugs block KATP channels in neurones of the CNS. 4. Baclofen (2-16 mg kg-1, s.c.) also induced a dose-dependent antinociceptive effect. Both 4-AP (2.5-25 ng/mouse, i.c.v.) and TEA (10-20 micrograms/mouse, i.c.v.) dose-dependently antagonized baclofen antinociception, producing a displacement to the right of the baclofen dose-response line. However, gliquidone (8-16 micrograms/mouse, i.c.v.) did not significantly modify the baclofen effect. 5. None of the K+ channel blockers tested (gliquidone, 8-16 micrograms/mouse; 4-AP, 25-250 ng/mouse and TEA, 10-20 micrograms/mouse, i.c.v.), significantly modified the antinociception induced by U50,488H (8 mg kg-1, s.c.). 6. These results suggest that the opening of K+ channels is involved in the antinociceptive effect of alpha 2 and GABAB, but not kappa-opioid, receptor agonists. The K+ channels opened by alpha2-adrenoceptor agonists seem to be ATP-dependent channels, whereas those opened by GABAB receptor agonists are not.

Abstract: Most drugs currently employed in the treatment of type 2 diabetes either target the sulfonylurea receptor stimulating insulin release (sulfonylureas, glinides), or target the peroxisome proliferator-activated receptor (PPARgamma) improving insulin resistance (thiazolidinediones). Our work shows that sulfonylureas and glinides additionally bind to PPARgamma and exhibit PPARgamma agonistic activity. This activity was predicted in silico by virtual screening and confirmed in vitro in a binding assay, a transactivation assay, and by measuring the expression of PPARgamma target genes. Among the measured compounds, gliquidone and glipizide (two sulfonylureas), as well as nateglinide (a glinide), exhibit PPARgamma agonistic activity at concentrations comparable with those reached under pharmacological treatment. The most active of these compounds, gliquidone, is shown to be as potent as pioglitazone at inducing PPARgamma target gene expression. This dual mode of action of sulfonylureas and glinides may open new perspectives for the molecular pharmacology of antidiabetic drugs, because it provides evidence that drugs can be designed that target both the sulfonylurea receptor and PPARgamma. Targeting both receptors could increase pancreatic insulin secretion and improve insulin resistance. Glinides, sulfonylureas, and other acidified sulfonamides may be promising leads in the development of new PPARgamma agonists. In addition, we provide a unified concept of the PPARgamma binding ability of seemingly disparate compound classes.