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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 various animal models (A) effect on % change in serum triglyceride versus control and (B) effect on atherogenic dyslipidemia (TG/HDL-C) ratio in high fat-high cholesterol (HF-HC) diet fed Syrian Golden hamsters. Hamsters were kept on HF-HC diet and compound treatment was done for 14 days at 0.03, 0.1, 0.3, 1, 3, and 10 mg/kg. (C) Effect on serum triglyceride clearance in Swiss albino mice. Mice were treated with the compound for 6 days at 0.01, 0.03, 0.1, 0.3, 1, 3, and 10 mg/kg, and on day 7 overnight fasted animals were injected with 3.3% Intralipid as described in Methods. The values are calculated as percent change versus control and expressed as mean ± SEM (n = 7). #Indicates significantly different from normal diet control and *Indicates significantly different from HF-HC diet control P < 0.05 (ANOVA). In Figure (C) at 30 min serum triglyceride levels were significant (P < 0.05) at all doses of Saroglitazar, at 60 min time point 0.1–10 mg/kg dose levels and at 120 min time point 1–10 mg/kg dose levels showed significantly (P < 0.05) lowered triglyceride levels as compared to control group animals.
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fig05: Effect of Saroglitazar on lipids in various animal models (A) effect on % change in serum triglyceride versus control and (B) effect on atherogenic dyslipidemia (TG/HDL-C) ratio in high fat-high cholesterol (HF-HC) diet fed Syrian Golden hamsters. Hamsters were kept on HF-HC diet and compound treatment was done for 14 days at 0.03, 0.1, 0.3, 1, 3, and 10 mg/kg. (C) Effect on serum triglyceride clearance in Swiss albino mice. Mice were treated with the compound for 6 days at 0.01, 0.03, 0.1, 0.3, 1, 3, and 10 mg/kg, and on day 7 overnight fasted animals were injected with 3.3% Intralipid as described in Methods. The values are calculated as percent change versus control and expressed as mean ± SEM (n = 7). #Indicates significantly different from normal diet control and *Indicates significantly different from HF-HC diet control P < 0.05 (ANOVA). In Figure (C) at 30 min serum triglyceride levels were significant (P < 0.05) at all doses of Saroglitazar, at 60 min time point 0.1–10 mg/kg dose levels and at 120 min time point 1–10 mg/kg dose levels showed significantly (P < 0.05) lowered triglyceride levels as compared to control group animals.

Mentions: Hamsters showed significant increase in TG, TC, and LDL-C after 21 days of HF-HC diet. When these hyperlipidemic hamsters were treated with Saroglitazar for 14 days, the animals showed dose-dependent reduction in serum TG and TC levels (Table5 and Fig.5A). The ED50 for TG-lowering effect was 0.37 mg/kg and a reduction of 89.8% was found at 10 mg/kg. Treatment with Saroglitazar at 10 mg/kg caused 52.7% reduction in TC. Saroglitazar also showed 61% reduction in LDL-C and 62.4% reduction in LDL-C/HDL-C ratio at 10 mg/kg dose. The TG/HDL-C ratio, which is often used as measure of atherogenic dyslipidemia (AD), was reduced by 91% after Saroglitazar treatment at 10 mg/kg as compared to control group (Fig.5B). Whereas, pioglitazone was less efficacious at 30 mg/kg with a 27% reduction in TG and 16% reduction in TC 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 lipids in various animal models (A) effect on % change in serum triglyceride versus control and (B) effect on atherogenic dyslipidemia (TG/HDL-C) ratio in high fat-high cholesterol (HF-HC) diet fed Syrian Golden hamsters. Hamsters were kept on HF-HC diet and compound treatment was done for 14 days at 0.03, 0.1, 0.3, 1, 3, and 10 mg/kg. (C) Effect on serum triglyceride clearance in Swiss albino mice. Mice were treated with the compound for 6 days at 0.01, 0.03, 0.1, 0.3, 1, 3, and 10 mg/kg, and on day 7 overnight fasted animals were injected with 3.3% Intralipid as described in Methods. The values are calculated as percent change versus control and expressed as mean ± SEM (n = 7). #Indicates significantly different from normal diet control and *Indicates significantly different from HF-HC diet control P < 0.05 (ANOVA). In Figure (C) at 30 min serum triglyceride levels were significant (P < 0.05) at all doses of Saroglitazar, at 60 min time point 0.1–10 mg/kg dose levels and at 120 min time point 1–10 mg/kg dose levels showed significantly (P < 0.05) lowered triglyceride levels as compared to control group animals.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4492752&req=5

fig05: Effect of Saroglitazar on lipids in various animal models (A) effect on % change in serum triglyceride versus control and (B) effect on atherogenic dyslipidemia (TG/HDL-C) ratio in high fat-high cholesterol (HF-HC) diet fed Syrian Golden hamsters. Hamsters were kept on HF-HC diet and compound treatment was done for 14 days at 0.03, 0.1, 0.3, 1, 3, and 10 mg/kg. (C) Effect on serum triglyceride clearance in Swiss albino mice. Mice were treated with the compound for 6 days at 0.01, 0.03, 0.1, 0.3, 1, 3, and 10 mg/kg, and on day 7 overnight fasted animals were injected with 3.3% Intralipid as described in Methods. The values are calculated as percent change versus control and expressed as mean ± SEM (n = 7). #Indicates significantly different from normal diet control and *Indicates significantly different from HF-HC diet control P < 0.05 (ANOVA). In Figure (C) at 30 min serum triglyceride levels were significant (P < 0.05) at all doses of Saroglitazar, at 60 min time point 0.1–10 mg/kg dose levels and at 120 min time point 1–10 mg/kg dose levels showed significantly (P < 0.05) lowered triglyceride levels as compared to control group animals.
Mentions: Hamsters showed significant increase in TG, TC, and LDL-C after 21 days of HF-HC diet. When these hyperlipidemic hamsters were treated with Saroglitazar for 14 days, the animals showed dose-dependent reduction in serum TG and TC levels (Table5 and Fig.5A). The ED50 for TG-lowering effect was 0.37 mg/kg and a reduction of 89.8% was found at 10 mg/kg. Treatment with Saroglitazar at 10 mg/kg caused 52.7% reduction in TC. Saroglitazar also showed 61% reduction in LDL-C and 62.4% reduction in LDL-C/HDL-C ratio at 10 mg/kg dose. The TG/HDL-C ratio, which is often used as measure of atherogenic dyslipidemia (AD), was reduced by 91% after Saroglitazar treatment at 10 mg/kg as compared to control group (Fig.5B). Whereas, pioglitazone was less efficacious at 30 mg/kg with a 27% reduction in TG and 16% reduction in TC 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