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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 lipids in hApoB100/hCETP double transgenic mice (A) effect on % change in serum LDL-C versus control (B) effect on % change in serum total cholesterol versus control. Animals were treated with Saroglitazar for 14 days at 0.1, 0.3, 1, 3, and 10 mg/kg. The values are calculated as percent change versus control and expressed as mean ± SEM (n = 6).
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fig06: Effect of Saroglitazar on lipids in hApoB100/hCETP double transgenic mice (A) effect on % change in serum LDL-C versus control (B) effect on % change in serum total cholesterol versus control. Animals were treated with Saroglitazar for 14 days at 0.1, 0.3, 1, 3, and 10 mg/kg. The values are calculated as percent change versus control and expressed as mean ± SEM (n = 6).

Mentions: Oral once-daily treatment of hApoB100/hCETP double transgenic mice with Saroglitazar for 14 days resulted in dose-dependent reductions in serum LDL-C with ED50 of 0.11 mg/kg (Table7). The reduction in LDL-C found was 72% on day 14 at 10 mg/kg dose. Saroglitazar also showed dose-dependent reduction in TC and TG levels on day 14 of the treatment. Saroglitazar at 1 mg/kg showed 67% reduction in LDL-C (Fig.6A), 50% reduction in TC (Fig.6B), 39% reduction in TG, and 61% reduction in LDL-C/HDL-C atherogenic ratio following once-daily oral treatment for 14 days.


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 lipids in hApoB100/hCETP double transgenic mice (A) effect on % change in serum LDL-C versus control (B) effect on % change in serum total cholesterol versus control. Animals were treated with Saroglitazar for 14 days at 0.1, 0.3, 1, 3, and 10 mg/kg. The values are calculated as percent change versus control and expressed as mean ± SEM (n = 6).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig06: Effect of Saroglitazar on lipids in hApoB100/hCETP double transgenic mice (A) effect on % change in serum LDL-C versus control (B) effect on % change in serum total cholesterol versus control. Animals were treated with Saroglitazar for 14 days at 0.1, 0.3, 1, 3, and 10 mg/kg. The values are calculated as percent change versus control and expressed as mean ± SEM (n = 6).
Mentions: Oral once-daily treatment of hApoB100/hCETP double transgenic mice with Saroglitazar for 14 days resulted in dose-dependent reductions in serum LDL-C with ED50 of 0.11 mg/kg (Table7). The reduction in LDL-C found was 72% on day 14 at 10 mg/kg dose. Saroglitazar also showed dose-dependent reduction in TC and TG levels on day 14 of the treatment. Saroglitazar at 1 mg/kg showed 67% reduction in LDL-C (Fig.6A), 50% reduction in TC (Fig.6B), 39% reduction in TG, and 61% reduction in LDL-C/HDL-C atherogenic ratio following once-daily oral treatment for 14 days.

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