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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) glucose infusion rate (GIR) at 0–120 min (B) GIR at 60–120 min of hyperinsulinemic-euglycemic clamp done in Zucker fa/fa rats after 15 days oral administration. The values are calculated as percent change versus control and expressed as mean ± SEM (n ≥ 6). *Indicates significantly different from vehicle control P < 0.05 (ANOVA).
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fig04: Effect of Saroglitazar on (A) glucose infusion rate (GIR) at 0–120 min (B) GIR at 60–120 min of hyperinsulinemic-euglycemic clamp done in Zucker fa/fa rats after 15 days oral administration. The values are calculated as percent change versus control and expressed as mean ± SEM (n ≥ 6). *Indicates significantly different from vehicle control P < 0.05 (ANOVA).

Mentions: In Zucker fa/fa rats, blood glucose concentrations in steady state (100–120 mg/dL) were similar in Saroglitazar-treated Zucker fa/fa rats and controls (Table3). GIR, required to maintain this concentration in hyperinsulinemic condition was significantly higher in the Saroglitazar-treated Zucker fa/fa rats than in the controls (59% and 109% higher as compared to controls at 1 and 10 mg/kg dose, respectively) indicating that whole body insulin sensitivity was enhanced by Saroglitazar treatment (Fig.4A and B). When we calculated the AUC (0–120) for GIR it showed that Saroglitazar at 1 and 10 mg/kg showed 54% and 127% increase in AUC (0–120) GIR, respectively, in hyperinsulinemic clamp following once-daily oral treatment for 15 days. Insulin levels were decreased up to 42% at basal and there was no significant change when measured at the end of clamp period. It demonstrates that Saroglitazar has potent insulin-sensitizing activity.


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) glucose infusion rate (GIR) at 0–120 min (B) GIR at 60–120 min of hyperinsulinemic-euglycemic clamp done in Zucker fa/fa rats after 15 days oral administration. The values are calculated as percent change versus control and expressed as mean ± SEM (n ≥ 6). *Indicates significantly different from vehicle control P < 0.05 (ANOVA).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig04: Effect of Saroglitazar on (A) glucose infusion rate (GIR) at 0–120 min (B) GIR at 60–120 min of hyperinsulinemic-euglycemic clamp done in Zucker fa/fa rats after 15 days oral administration. The values are calculated as percent change versus control and expressed as mean ± SEM (n ≥ 6). *Indicates significantly different from vehicle control P < 0.05 (ANOVA).
Mentions: In Zucker fa/fa rats, blood glucose concentrations in steady state (100–120 mg/dL) were similar in Saroglitazar-treated Zucker fa/fa rats and controls (Table3). GIR, required to maintain this concentration in hyperinsulinemic condition was significantly higher in the Saroglitazar-treated Zucker fa/fa rats than in the controls (59% and 109% higher as compared to controls at 1 and 10 mg/kg dose, respectively) indicating that whole body insulin sensitivity was enhanced by Saroglitazar treatment (Fig.4A and B). When we calculated the AUC (0–120) for GIR it showed that Saroglitazar at 1 and 10 mg/kg showed 54% and 127% increase in AUC (0–120) GIR, respectively, in hyperinsulinemic clamp following once-daily oral treatment for 15 days. Insulin levels were decreased up to 42% at basal and there was no significant change when measured at the end of clamp period. It demonstrates that Saroglitazar has potent insulin-sensitizing activity.

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