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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 treatment at 1.5 mg/kg dose on % change in serum triglyceride versus control on various treatment days in female common marmosets. Serum triglyceride was measured on pretreatment and on day 15, 30, and 90th of treatment at 1 h post dose. The values are calculated as percent change versus control and expressed as mean ± SEM (n = 4).
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fig07: Effect of Saroglitazar treatment at 1.5 mg/kg dose on % change in serum triglyceride versus control on various treatment days in female common marmosets. Serum triglyceride was measured on pretreatment and on day 15, 30, and 90th of treatment at 1 h post dose. The values are calculated as percent change versus control and expressed as mean ± SEM (n = 4).

Mentions: Female Wistar rats and female marmosets were administered with Saroglitazar (1.5 and 15 mg/kg) or vehicle for 90 days. Treatment with Saroglitazar did not cause any unexpected changes in behavioral or clinical parameters in either species. There was no effect on body weights and feed consumption. As expected from PPARα agonists, Saroglitazar-treated Wistar rats showed higher liver weights and elevated serum ALT levels as compared to control group. Since Saroglitazar has relatively weaker PPARγ activity as compared to PPARα, the PPARγ mediated effects (reduction in hematocrit, body weight gain) were evident only at higher doses, which shows exposure about 66-fold higher than the exposure in human subjects observed at clinically effective dose of 4 mg. There were no other gross pathology findings associated with Saroglitazar treatments. Histopathological examination did not reveal any adverse lesions in vital organs except liver, which showed expected PPARα-mediated mild hepatocellular hypertrophy and minimal to mild single cell necrosis. Marmosets concurrently treated with similar doses of Saroglitazar also showed no behavioral changes and/or clinical signs, but showed significant (upto 53.4%) reduction in TG at 1.5 mg/kg (Fig.7) on day 90 as compared to control group which was expected efficacy end point. In contrast to rodents, organ weight data in marmosets did not reveal any changes in liver weight or gross morphology. Biochemical analysis showed no significant changes in serum alanine amino transferase (ALT) or serum electrolytes. Similarly, there were no gross pathological findings associated with the drug treatment. Histopathological examination revealed no adverse changes in any vital organs in the marmoset. Unlike rodents, livers of marmosets showed no changes in histomorphology. These clinical, pathological, and histopathological investigations revealed that Saroglitazar did not show any adverse toxic effects at doses upto at 15 mg/kg in marmosets.


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 treatment at 1.5 mg/kg dose on % change in serum triglyceride versus control on various treatment days in female common marmosets. Serum triglyceride was measured on pretreatment and on day 15, 30, and 90th of treatment at 1 h post dose. The values are calculated as percent change versus control and expressed as mean ± SEM (n = 4).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig07: Effect of Saroglitazar treatment at 1.5 mg/kg dose on % change in serum triglyceride versus control on various treatment days in female common marmosets. Serum triglyceride was measured on pretreatment and on day 15, 30, and 90th of treatment at 1 h post dose. The values are calculated as percent change versus control and expressed as mean ± SEM (n = 4).
Mentions: Female Wistar rats and female marmosets were administered with Saroglitazar (1.5 and 15 mg/kg) or vehicle for 90 days. Treatment with Saroglitazar did not cause any unexpected changes in behavioral or clinical parameters in either species. There was no effect on body weights and feed consumption. As expected from PPARα agonists, Saroglitazar-treated Wistar rats showed higher liver weights and elevated serum ALT levels as compared to control group. Since Saroglitazar has relatively weaker PPARγ activity as compared to PPARα, the PPARγ mediated effects (reduction in hematocrit, body weight gain) were evident only at higher doses, which shows exposure about 66-fold higher than the exposure in human subjects observed at clinically effective dose of 4 mg. There were no other gross pathology findings associated with Saroglitazar treatments. Histopathological examination did not reveal any adverse lesions in vital organs except liver, which showed expected PPARα-mediated mild hepatocellular hypertrophy and minimal to mild single cell necrosis. Marmosets concurrently treated with similar doses of Saroglitazar also showed no behavioral changes and/or clinical signs, but showed significant (upto 53.4%) reduction in TG at 1.5 mg/kg (Fig.7) on day 90 as compared to control group which was expected efficacy end point. In contrast to rodents, organ weight data in marmosets did not reveal any changes in liver weight or gross morphology. Biochemical analysis showed no significant changes in serum alanine amino transferase (ALT) or serum electrolytes. Similarly, there were no gross pathological findings associated with the drug treatment. Histopathological examination revealed no adverse changes in any vital organs in the marmoset. Unlike rodents, livers of marmosets showed no changes in histomorphology. These clinical, pathological, and histopathological investigations revealed that Saroglitazar did not show any adverse toxic effects at doses upto at 15 mg/kg in marmosets.

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