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Saroglitazar, a novel PPARα/γ agonist with predominant PPARα activity, shows lipid-lowering and insulin-sensitizing effects in preclinical models.

Jain MR, Giri SR, Trivedi C, Bhoi B, Rath A, Vanage G, Vyas P, Ranvir R, Patel PR - Pharmacol Res Perspect (2015)

Bottom Line: The ED50 for these effects was found to be 0.05, 0.19, and 0.19 mg/kg, respectively with highly significant (91%) reduction in serum insulin and AUC-glucose following oral glucose administration (59%) at 1 mg/kg dose.Saroglitazar also showed a significant decrease in SBP (22 mmHg) and increase (62.1%) in serum adiponectin levels in Zucker fa/fa rats.A 90-day repeated dose comparative study in Wistar rats and marmosets confirmed efficacy (TG lowering) potential of Saroglitazar and has indicated low risk of PPAR-associated side effects in humans.

View Article: PubMed Central - PubMed

Affiliation: Zydus Research Centre, Cadila Healthcare Limited Sarkhej-Bavla N.H. No. 8A, Moriya, Ahmedabad, 382 213, Gujarat, India.

ABSTRACT
Saroglitazar is a novel nonthiazolidinediones (TZD) and nonfibric acid derivative designed to act as dual regulator of lipids and glucose metabolism by activating peroxisome proliferator-activated receptors (PPAR). These studies evaluate the efficacy and safety profile of Saroglitazar in preclinical in vitro and in vivo models. The EC50 values of Saroglitazar assessed in HepG2 cells using PPAR transactivation assay for hPPARα and hPPARγ were 0.65 pmol/L and 3 nmol/L, respectively. In db/db mice, 12-day treatment with Saroglitazar (0.01-3 mg/kg per day, orally) caused dose-dependent reductions in serum triglycerides (TG), free fatty acids (FFA), and glucose. The ED50 for these effects was found to be 0.05, 0.19, and 0.19 mg/kg, respectively with highly significant (91%) reduction in serum insulin and AUC-glucose following oral glucose administration (59%) at 1 mg/kg dose. Significant reduction in serum TG (upto 90%) was also observed in Zucker fa/fa rats, Swiss albino mice, and in high fat -high cholesterol (HF-HC)-fed Golden Syrian hamsters. LDL cholesterol was significantly lowered in hApoB100/hCETP double transgenic mice and HF-HC diet fed Golden Syrian Hamsters. Hyperinsulinemic-Euglycemic clamp study in Zucker fa/fa rats demonstrated potent insulin-sensitizing activity. Saroglitazar also showed a significant decrease in SBP (22 mmHg) and increase (62.1%) in serum adiponectin levels in Zucker fa/fa rats. A 90-day repeated dose comparative study in Wistar rats and marmosets confirmed efficacy (TG lowering) potential of Saroglitazar and has indicated low risk of PPAR-associated side effects in humans. Based on efficacy and safety profile, Saroglitazar appears to have good potential as novel therapeutic agent for treatment of dyslipidemia and diabetes.

No MeSH data available.


Related in: MedlinePlus

Effect of Saroglitazar on (A) serum glucose and (B) AUC-glucose in oral glucose tolerance test in db/db mice treated for 12 days. Serum glucose was measured on pretreatment and on day 12 1 h post dose and on day 13 overnight fasted animals were subjected to oral glucose tolerance test with glucose load (1.5 g/kg) for AUC-glucose measurement. The values are calculated as percent change versus Control and expressed as mean ± SEM (n = 6). (C and D) Effect of Saroglitazar on expression of mRNA, in liver (C), and in white adipose tissue (D) of db/db mice treated with Saroglitazar for 12 days at 3 mg/kg dose determined by quantitative real-time PCR. The bars represent the fold change in the treatment groups compared with the vehicle control group, mean ± SEM (n = 6). *Indicates significantly different from vehicle-treated control group, P < 0.05 (ANOVA).
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fig02: Effect of Saroglitazar on (A) serum glucose and (B) AUC-glucose in oral glucose tolerance test in db/db mice treated for 12 days. Serum glucose was measured on pretreatment and on day 12 1 h post dose and on day 13 overnight fasted animals were subjected to oral glucose tolerance test with glucose load (1.5 g/kg) for AUC-glucose measurement. The values are calculated as percent change versus Control and expressed as mean ± SEM (n = 6). (C and D) Effect of Saroglitazar on expression of mRNA, in liver (C), and in white adipose tissue (D) of db/db mice treated with Saroglitazar for 12 days at 3 mg/kg dose determined by quantitative real-time PCR. The bars represent the fold change in the treatment groups compared with the vehicle control group, mean ± SEM (n = 6). *Indicates significantly different from vehicle-treated control group, P < 0.05 (ANOVA).

Mentions: Saroglitazar treatment demonstrated a dose-dependent reduction in serum glucose, TG, and FFA in db/db mice after 12 days of treatment (Table1 and Fig.2A). Saroglitazar treatment also showed a significant improvement in oral glucose tolerance (59% reduction in AUCglucose, Fig.2B) and 91% reduction in serum insulin levels at 1 mg/kg dose as compared to control group. The ED50 for glucose reduction was found to be 0.19 mg/kg and reduction observed was 64.6% at 3 mg/kg. Saroglitazar caused TG reduction by upto 54.9% at 3 mg/kg and ED50 was found to be 0.05 mg/kg. The ED50 of for FFA lowering was 0.19 mg/kg and Saroglitazar caused upto 56.1% reduction at 3 mg/kg. Whereas pioglitazone caused 63% reduction in glucose and 59% reduction in TG at the dose of 60 mg/kg as compared to control group.


Saroglitazar, a novel PPARα/γ agonist with predominant PPARα activity, shows lipid-lowering and insulin-sensitizing effects in preclinical models.

Jain MR, Giri SR, Trivedi C, Bhoi B, Rath A, Vanage G, Vyas P, Ranvir R, Patel PR - Pharmacol Res Perspect (2015)

Effect of Saroglitazar on (A) serum glucose and (B) AUC-glucose in oral glucose tolerance test in db/db mice treated for 12 days. Serum glucose was measured on pretreatment and on day 12 1 h post dose and on day 13 overnight fasted animals were subjected to oral glucose tolerance test with glucose load (1.5 g/kg) for AUC-glucose measurement. The values are calculated as percent change versus Control and expressed as mean ± SEM (n = 6). (C and D) Effect of Saroglitazar on expression of mRNA, in liver (C), and in white adipose tissue (D) of db/db mice treated with Saroglitazar for 12 days at 3 mg/kg dose determined by quantitative real-time PCR. The bars represent the fold change in the treatment groups compared with the vehicle control group, mean ± SEM (n = 6). *Indicates significantly different from vehicle-treated control group, P < 0.05 (ANOVA).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492752&req=5

fig02: Effect of Saroglitazar on (A) serum glucose and (B) AUC-glucose in oral glucose tolerance test in db/db mice treated for 12 days. Serum glucose was measured on pretreatment and on day 12 1 h post dose and on day 13 overnight fasted animals were subjected to oral glucose tolerance test with glucose load (1.5 g/kg) for AUC-glucose measurement. The values are calculated as percent change versus Control and expressed as mean ± SEM (n = 6). (C and D) Effect of Saroglitazar on expression of mRNA, in liver (C), and in white adipose tissue (D) of db/db mice treated with Saroglitazar for 12 days at 3 mg/kg dose determined by quantitative real-time PCR. The bars represent the fold change in the treatment groups compared with the vehicle control group, mean ± SEM (n = 6). *Indicates significantly different from vehicle-treated control group, P < 0.05 (ANOVA).
Mentions: Saroglitazar treatment demonstrated a dose-dependent reduction in serum glucose, TG, and FFA in db/db mice after 12 days of treatment (Table1 and Fig.2A). Saroglitazar treatment also showed a significant improvement in oral glucose tolerance (59% reduction in AUCglucose, Fig.2B) and 91% reduction in serum insulin levels at 1 mg/kg dose as compared to control group. The ED50 for glucose reduction was found to be 0.19 mg/kg and reduction observed was 64.6% at 3 mg/kg. Saroglitazar caused TG reduction by upto 54.9% at 3 mg/kg and ED50 was found to be 0.05 mg/kg. The ED50 of for FFA lowering was 0.19 mg/kg and Saroglitazar caused upto 56.1% reduction at 3 mg/kg. Whereas pioglitazone caused 63% reduction in glucose and 59% reduction in TG at the dose of 60 mg/kg as compared to control group.

Bottom Line: The ED50 for these effects was found to be 0.05, 0.19, and 0.19 mg/kg, respectively with highly significant (91%) reduction in serum insulin and AUC-glucose following oral glucose administration (59%) at 1 mg/kg dose.Saroglitazar also showed a significant decrease in SBP (22 mmHg) and increase (62.1%) in serum adiponectin levels in Zucker fa/fa rats.A 90-day repeated dose comparative study in Wistar rats and marmosets confirmed efficacy (TG lowering) potential of Saroglitazar and has indicated low risk of PPAR-associated side effects in humans.

View Article: PubMed Central - PubMed

Affiliation: Zydus Research Centre, Cadila Healthcare Limited Sarkhej-Bavla N.H. No. 8A, Moriya, Ahmedabad, 382 213, Gujarat, India.

ABSTRACT
Saroglitazar is a novel nonthiazolidinediones (TZD) and nonfibric acid derivative designed to act as dual regulator of lipids and glucose metabolism by activating peroxisome proliferator-activated receptors (PPAR). These studies evaluate the efficacy and safety profile of Saroglitazar in preclinical in vitro and in vivo models. The EC50 values of Saroglitazar assessed in HepG2 cells using PPAR transactivation assay for hPPARα and hPPARγ were 0.65 pmol/L and 3 nmol/L, respectively. In db/db mice, 12-day treatment with Saroglitazar (0.01-3 mg/kg per day, orally) caused dose-dependent reductions in serum triglycerides (TG), free fatty acids (FFA), and glucose. The ED50 for these effects was found to be 0.05, 0.19, and 0.19 mg/kg, respectively with highly significant (91%) reduction in serum insulin and AUC-glucose following oral glucose administration (59%) at 1 mg/kg dose. Significant reduction in serum TG (upto 90%) was also observed in Zucker fa/fa rats, Swiss albino mice, and in high fat -high cholesterol (HF-HC)-fed Golden Syrian hamsters. LDL cholesterol was significantly lowered in hApoB100/hCETP double transgenic mice and HF-HC diet fed Golden Syrian Hamsters. Hyperinsulinemic-Euglycemic clamp study in Zucker fa/fa rats demonstrated potent insulin-sensitizing activity. Saroglitazar also showed a significant decrease in SBP (22 mmHg) and increase (62.1%) in serum adiponectin levels in Zucker fa/fa rats. A 90-day repeated dose comparative study in Wistar rats and marmosets confirmed efficacy (TG lowering) potential of Saroglitazar and has indicated low risk of PPAR-associated side effects in humans. Based on efficacy and safety profile, Saroglitazar appears to have good potential as novel therapeutic agent for treatment of dyslipidemia and diabetes.

No MeSH data available.


Related in: MedlinePlus