E3024 (3-but-2-ynyl-5-methyl-2-piperazin-1-yl-3,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one tosylate) is a dipeptidyl peptidase-IV (DPP-IV) inhibitor that was expected to be an antidiabetic agent. Its safety, tolerabil...E3024 (3-but-2-ynyl-5-methyl-2-piperazin-1-yl-3,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one tosylate) is a dipeptidyl peptidase-IV (DPP-IV) inhibitor that was expected to be an antidiabetic agent. Its safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) were investigated in a randomized, double-blind, placebo-controlled, ascending single-dose study in 48 healthy Japanese male subjects. Fasted subjects were orally administered E3024 (5, 10, 20, 40, or 80 mg) or placebo. E3024 was rapidly absorbed, with tmax values ranging between 0.33 and 3 h after dosing. The mean t1/2 ranged from 5.34 to 11.68 h. AUC0-inf and Cmax increased dose-proportionately. PK-PD relationship of E3024 was evaluated by using an Imax model, indicating that plasma E3024 concentrations and inhibitory effects of plasma DPP-IV activity were well correlated. The IC50 value was calculated as 33.7 ng/mL, which was consistent with in vitro data. Thus, E3024 showed a good PK profile and inhibited DPP-IV dose-dependently. Of 30 subjects administered E3024, 12 (40%) experienced adverse events (AEs). Dose escalation to 160 mg was abandoned owing to undesired subjective/objective findings in 4 of 6 subjects receiving 40 mg and 5 of 6 subjects receiving 80 mg. The most prominent AE was rash, but there were no serious AEs or deaths. The maximum tolerated dose was considered to be 20 mg. We hypothesized that histamine was a cause of the rash induction, and examined blood histamine levels of normal Fischer rats treated with E3024. Blood histamine levels were increased significantly by E3024 at 500 mg/kg (p < 0.001), but not by vildagliptin or valine-pyrrolidide (DPP-IV inhibitors) at the same dose. No blood histamine increases were observed in genetically mast cell-deficient Ws/Ws rats treated with E3024 at 500 mg/kg. In in vitro assays, E3024 induced histamine release from normal rat peritoneal mast cells in a concentration-dependent manner, but not from basophils. The structure-activity relationship study suggested that a piperazine group N-linked to the 2-position of the 5,6-membered fused heterocyclic rings was a key structural element for triggering histamine release.展开更多
Emotional and motivational disorders in adults are often considered to be the result of altered neurodevelopment. Clinical and experimental data provide evidence that serine protease dipeptidyl peptidase-IV (DPP-IV, E...Emotional and motivational disorders in adults are often considered to be the result of altered neurodevelopment. Clinical and experimental data provide evidence that serine protease dipeptidyl peptidase-IV (DPP-IV, EC 3.4.14.5) is involved in the pathophysiology of psycho-emotional disorders. Recently, we have shown that adolescent and adult rats exhibit an increase in anxiety and depression-related behaviors after neonatal administration of a synthetic non-competitive inhibitor of DPP-IV, methionyl-2(S)-cyano-pyrrolidine. In the present study, we tested the effects of two competitive, selective DPP-IV inhibitors, sitagliptin (4 mg/kg) and diprotin A (2 mg/kg), administered at postnatal days 5 - 18 on the emotional and motivational behavior of adolescent and adult rats. We observed increased anxiety in one-month-old diprotin A- or sitagliptin-treated rats in the elevated plus maze;diprotin A also enhanced the animals’ anxiety score using a ranked scale for evaluating anxiety and phobias. In the sucrose consumption and preference test, depressive-like behavior was pronounced in both the diprotin A- and sitagliptin-treated one-month-old animals, while only the diprotin A-treated rats exhibited a decrease in sucrose consumption at the age of 2 months. The diprotin A-treated rats also demonstrated behavioral despair and decreased activity in the forced swimming test within 1 - 3 months of age. Increased aggression was observed in 1 - 3-month-old diprotin A-treated rats and in two-month-old sitagliptin-treated rats. These findings support the hypothesis that DPP-IV is involved in the genesis of emotional and motivational disorders. Additionally, the results show that diprotin А impairs the adolescent and adult rats’ behavior more significantly than sitagliptin when the animals were treated with the DPP-IV inhibitors in the early postnatal period.展开更多
The enzyme, dipeptidyl peptidase IV（DPP IV）, is a novel target for the treatment of type 2 diabetes. Dipeptidyl peptidase IV inhibition improves the impaired insulin secretion and decrease postprandial concentration...The enzyme, dipeptidyl peptidase IV（DPP IV）, is a novel target for the treatment of type 2 diabetes. Dipeptidyl peptidase IV inhibition improves the impaired insulin secretion and decrease postprandial concentrations of glucagon by enhancing the incretin hormone levels lucagon-like peptide-1（GLP-1） and glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide（GIP）. Recently, DPP IV inhibitors have attracted more and more attention, several of which have entered pre-clinical and clinical trials, and one has received approval for use as an anti-diabetic agent. Among the DPP IV inhibitors, two leading agents（sitagliptin and vildagliptin） have been shown to be effective in reducing glycosylated hemoglobin（HbAlc） and fasting plasma glucose（FPG） in patients with type 2 diabetes. This review summarizes the evidence supporting DPP IV inhibitors as potential antidiabetic agents.展开更多
Objective To evaluate the effects of incretin-based therapies on body weight as the primary outcome,as well as on body mass index(BMI)and waist circumference(WC)as secondary outcomes.Methods Databases including Medlin...Objective To evaluate the effects of incretin-based therapies on body weight as the primary outcome,as well as on body mass index(BMI)and waist circumference(WC)as secondary outcomes.Methods Databases including Medline,Embase,the Cochrane Library,and clinicaltrials.gov(www.clinicaltrials.gov)were searched for randomized controlled trials(RCTs).Standard pairwise meta-analysis and network meta-analysis(NMA)were both carried out.The risk of bias(ROB)tool recommended by the Cochrane handbook was used to assess the quality of studies.Subgroup analysis,sensitivity analysis,meta-regression,and quality evaluation based on the Grading of Recommendations Assessment,Development,and Evaluation(GRADE)were also performed.Results A total of 292 trials were included in this study.Compared with placebo,dipeptidyl-peptidase IV inhibitors(DPP-4 Is)increased weight slightly by 0.31 kg[95%confidence interval(CI):0.05,0.58]and had negligible effects on BMI and WC.Compared with placebo,glucagon-like peptide-1 receptor agonists(GLP-1 RAs)lowered weight,BMI,and WC by-1.34 kg(95%CI:-1.60,-1.09),-1.10 kg/m2(95%CI:-1.42,-0.78),and-1.28 cm(95%CI:-1.69,-0.86),respectively.Conclusion GLP-1 RAs were more effective than DPP-4 Is in lowering the three indicators.Overall,the effects of GLP-1 RAs on weight,BMI,and WC were favorable.展开更多
Describing a reported case of acute pancreatitis in a patient receiving sitagliptin. We present the biochemical and findings of a 60 year-old male who presented with severe abdominal pain and was found to have acute p...Describing a reported case of acute pancreatitis in a patient receiving sitagliptin. We present the biochemical and findings of a 60 year-old male who presented with severe abdominal pain and was found to have acute pancreatitis. This occurred one month after the commencement of sitagliptin, a dipeptidyl peptidase IV inhibitor, for the treatment of uncontrolled type 2 diabetes. Results: Pancreatic enzymes were elevated (i.e. amylase 204, lipase: 525.3) with a normal liver function test and a normal lipid profile. Ultrasound abdomen was unremarkable. In the absence of an identifiable cause for the patient’s pancreatitis, sitagliptin was considered a potential trigger and on ceasing this agent, the patient recovered from his condition. Conclusion: Incretin-based therapy is an effective line in the treatment of type 2 diabetes mellitus. FDA issued a warning letters to the drug company because of emerging reports of acute pancreatitis in patients receiving sitagliptin. This is unfortunately not the first reported case of acute pancreatitis in a patient receiving sitagliptin and it supports the possibility that acute pancreatitis may be the effect of incretin-based therapy.展开更多
文摘E3024 (3-but-2-ynyl-5-methyl-2-piperazin-1-yl-3,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one tosylate) is a dipeptidyl peptidase-IV (DPP-IV) inhibitor that was expected to be an antidiabetic agent. Its safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) were investigated in a randomized, double-blind, placebo-controlled, ascending single-dose study in 48 healthy Japanese male subjects. Fasted subjects were orally administered E3024 (5, 10, 20, 40, or 80 mg) or placebo. E3024 was rapidly absorbed, with tmax values ranging between 0.33 and 3 h after dosing. The mean t1/2 ranged from 5.34 to 11.68 h. AUC0-inf and Cmax increased dose-proportionately. PK-PD relationship of E3024 was evaluated by using an Imax model, indicating that plasma E3024 concentrations and inhibitory effects of plasma DPP-IV activity were well correlated. The IC50 value was calculated as 33.7 ng/mL, which was consistent with in vitro data. Thus, E3024 showed a good PK profile and inhibited DPP-IV dose-dependently. Of 30 subjects administered E3024, 12 (40%) experienced adverse events (AEs). Dose escalation to 160 mg was abandoned owing to undesired subjective/objective findings in 4 of 6 subjects receiving 40 mg and 5 of 6 subjects receiving 80 mg. The most prominent AE was rash, but there were no serious AEs or deaths. The maximum tolerated dose was considered to be 20 mg. We hypothesized that histamine was a cause of the rash induction, and examined blood histamine levels of normal Fischer rats treated with E3024. Blood histamine levels were increased significantly by E3024 at 500 mg/kg (p < 0.001), but not by vildagliptin or valine-pyrrolidide (DPP-IV inhibitors) at the same dose. No blood histamine increases were observed in genetically mast cell-deficient Ws/Ws rats treated with E3024 at 500 mg/kg. In in vitro assays, E3024 induced histamine release from normal rat peritoneal mast cells in a concentration-dependent manner, but not from basophils. The structure-activity relationship study suggested that a piperazine group N-linked to the 2-position of the 5,6-membered fused heterocyclic rings was a key structural element for triggering histamine release.
文摘Emotional and motivational disorders in adults are often considered to be the result of altered neurodevelopment. Clinical and experimental data provide evidence that serine protease dipeptidyl peptidase-IV (DPP-IV, EC 3.4.14.5) is involved in the pathophysiology of psycho-emotional disorders. Recently, we have shown that adolescent and adult rats exhibit an increase in anxiety and depression-related behaviors after neonatal administration of a synthetic non-competitive inhibitor of DPP-IV, methionyl-2(S)-cyano-pyrrolidine. In the present study, we tested the effects of two competitive, selective DPP-IV inhibitors, sitagliptin (4 mg/kg) and diprotin A (2 mg/kg), administered at postnatal days 5 - 18 on the emotional and motivational behavior of adolescent and adult rats. We observed increased anxiety in one-month-old diprotin A- or sitagliptin-treated rats in the elevated plus maze;diprotin A also enhanced the animals’ anxiety score using a ranked scale for evaluating anxiety and phobias. In the sucrose consumption and preference test, depressive-like behavior was pronounced in both the diprotin A- and sitagliptin-treated one-month-old animals, while only the diprotin A-treated rats exhibited a decrease in sucrose consumption at the age of 2 months. The diprotin A-treated rats also demonstrated behavioral despair and decreased activity in the forced swimming test within 1 - 3 months of age. Increased aggression was observed in 1 - 3-month-old diprotin A-treated rats and in two-month-old sitagliptin-treated rats. These findings support the hypothesis that DPP-IV is involved in the genesis of emotional and motivational disorders. Additionally, the results show that diprotin А impairs the adolescent and adult rats’ behavior more significantly than sitagliptin when the animals were treated with the DPP-IV inhibitors in the early postnatal period.
文摘The enzyme, dipeptidyl peptidase IV（DPP IV）, is a novel target for the treatment of type 2 diabetes. Dipeptidyl peptidase IV inhibition improves the impaired insulin secretion and decrease postprandial concentrations of glucagon by enhancing the incretin hormone levels lucagon-like peptide-1（GLP-1） and glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide（GIP）. Recently, DPP IV inhibitors have attracted more and more attention, several of which have entered pre-clinical and clinical trials, and one has received approval for use as an anti-diabetic agent. Among the DPP IV inhibitors, two leading agents（sitagliptin and vildagliptin） have been shown to be effective in reducing glycosylated hemoglobin（HbAlc） and fasting plasma glucose（FPG） in patients with type 2 diabetes. This review summarizes the evidence supporting DPP IV inhibitors as potential antidiabetic agents.
基金supported by the National Natural Science Foundation of China[No.81302508,71673003,81473067,and 91646107].
文摘Objective To evaluate the effects of incretin-based therapies on body weight as the primary outcome,as well as on body mass index(BMI)and waist circumference(WC)as secondary outcomes.Methods Databases including Medline,Embase,the Cochrane Library,and clinicaltrials.gov(www.clinicaltrials.gov)were searched for randomized controlled trials(RCTs).Standard pairwise meta-analysis and network meta-analysis(NMA)were both carried out.The risk of bias(ROB)tool recommended by the Cochrane handbook was used to assess the quality of studies.Subgroup analysis,sensitivity analysis,meta-regression,and quality evaluation based on the Grading of Recommendations Assessment,Development,and Evaluation(GRADE)were also performed.Results A total of 292 trials were included in this study.Compared with placebo,dipeptidyl-peptidase IV inhibitors(DPP-4 Is)increased weight slightly by 0.31 kg[95%confidence interval(CI):0.05,0.58]and had negligible effects on BMI and WC.Compared with placebo,glucagon-like peptide-1 receptor agonists(GLP-1 RAs)lowered weight,BMI,and WC by-1.34 kg(95%CI:-1.60,-1.09),-1.10 kg/m2(95%CI:-1.42,-0.78),and-1.28 cm(95%CI:-1.69,-0.86),respectively.Conclusion GLP-1 RAs were more effective than DPP-4 Is in lowering the three indicators.Overall,the effects of GLP-1 RAs on weight,BMI,and WC were favorable.
文摘Describing a reported case of acute pancreatitis in a patient receiving sitagliptin. We present the biochemical and findings of a 60 year-old male who presented with severe abdominal pain and was found to have acute pancreatitis. This occurred one month after the commencement of sitagliptin, a dipeptidyl peptidase IV inhibitor, for the treatment of uncontrolled type 2 diabetes. Results: Pancreatic enzymes were elevated (i.e. amylase 204, lipase: 525.3) with a normal liver function test and a normal lipid profile. Ultrasound abdomen was unremarkable. In the absence of an identifiable cause for the patient’s pancreatitis, sitagliptin was considered a potential trigger and on ceasing this agent, the patient recovered from his condition. Conclusion: Incretin-based therapy is an effective line in the treatment of type 2 diabetes mellitus. FDA issued a warning letters to the drug company because of emerging reports of acute pancreatitis in patients receiving sitagliptin. This is unfortunately not the first reported case of acute pancreatitis in a patient receiving sitagliptin and it supports the possibility that acute pancreatitis may be the effect of incretin-based therapy.
