Assessment of preclinical pharmacokinetics and acute toxicity of pioglitazone and telmisartan combination

The prevalence of hypertension is very common amongst the diabetic patients and is reported as the major cause of mortality in diabetes. Pioglitazone reported to have an ability to alter the blood cholesterol level and cardioprotective efficiency along with its antidiabetic activity. Telmisartan, through activation of PPAR-γ receptor exerts insulin sensitizing property in addition to its primary cardioprotective efficiency. Theoretically, a combination of pioglitazone and telmisartan may be beneficial to effectively control the high blood glucose level and management of coexisting cardiovascular complication in diabetes. The aim of this research was to experimentally evaluate the pharmacokinetic interaction of pioglitazone and telmisartan when are coadministered in rat. Pioglitazone and telmisartan were administered orally as a single dose individually and in combination to the rats. The plasma samples of the pharmacokinetic study were analyzed using a validated LCMS method. The acute toxicity of the combination with a high dose in rats was also evaluated as a part of the determination its safety profile. There was no significant change in pharmacokinetic parameters were resulted due to coadministration of pioglitazone and telmisartan in rat. Absence of major toxicological effect supports the safety of the combination in vivo

Effects of Telmisartan and Pioglitazone on High Fructose Induced Metabolic Syndrome in Rats

Metabolic syndrome (MS) is a cluster of hypertension, insulin resistance, dyslipidaemia and hyperuricemia. This study was designed to assess the effect of telmisartan and pioglitazone on high fructose induced metabolic syndrome.35 Male albino rats were classified into 5 groups: A: Normal diet-fed; B: High Fructose-fed (HFD) subdivided into B1 (HFD only), B2 (telmisartan 5mg/kg), B3 (pioglitazone10mg/kg) and B4 (telmisartan + pioglitazone). Drugs started 4 weeks after staring HFD lasts for 4 weeks. Body weight (BW), blood pressure (BP) measurement, estimation of the level of fasting glucose, fasting insulin, uric acid (UA), total cholesterol, triglycerides (TG), high density lipoprotein (HDL-c), low density lipoprotein (LDL-c), blood urea nitrogen (BUN), creatinine and (nitric oxide) NO were done. Compared to group-B1:Telmisartan sig decrease BP, BW, serum glucose, insulin, UA, urea, cholesterol, TGA, LDL and sig increase HDL; pioglitazone sig decrease BP, serum glucose, insulin, UA, urea, creat., cholesterol, TGA, LDL and sig increase HDL. Co-administration of Pioglitazone + telmisartan sig decrease insulin, urea and creat compared to telmisartan alone. Combined telmisartan plus pioglitazone allow better control of BP, hyperglycaemia, insulin resistance and the amelioration of BW increase that may be associated with pioglitazone treatment.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Formulation and Therapeutic Evaluation of Isoxsuprine-Loaded Nanoparticles against Diabetes-Associated Stroke

Ischemic stroke is the second-leading cause of death. Hyperglycemia, which is characteristic of diabetes mellitus, contributes to the development of endothelial dysfunction and increases the risk of stroke. Isoxsuprine is an efficient beta-adrenergic agonist that improves blood flow to the ischemic aria and stops the infarct core from growing. However, low bioavailability, a short biological half-life, and first-pass hepatic metabolism reduce the therapeutic efficacy of oral isoxsuprine. Therefore, the authors focused on developing isoxsuprine-loaded liposomes containing ethanol and propylene glycol (ILEP) formulation as nasal drops for the treatment of ischemic stroke in diabetic patients. Different ILEP formulations were optimized using Design Expert software, and the selected formulation was examined in vivo for its anti-stroke effect using a rat model of diabetes and stroke. The optimized ILEP, composed of 15% propylene glycol, 0.16% cholesterol, 10% ethanol, and 3.29% phospholipid, improved the sustainability, permeation, and targeting of isoxsuprine. Furthermore, the in vivo studies verified the improved neurological behavior and decreased dead shrunken neurons and vascular congestion of the rats treated with the optimized ILEP formulation, demonstrating its anti-stroke activity. In conclusion, our study found that treatment with an optimized ILEP formulation prevented the initiation and severity of stroke, especially in diabetic patients

Regulatory landscape of AGE-RAGE-oxidative stress axis and its modulation by PPAR. activation in high fructose diet-induced metabolic syndrome

Background: The AGE-RAGE-oxidative stress (AROS) axis is involved in the onset and progression of metabolic syndrome induced by a high-fructose diet (HFD). PPAR\u3b3 activation is known to modulate metabolic syndrome; however a systems-level investigation looking at the protective effects of PPAR\u3b3 activation as related to the AROS axis has not been performed. The aim of this work is to simultaneously characterize multiple molecular parameters within the AROS axis, using samples taken from different body fluids and tissues of a rat model of HFD-induced metabolic syndrome, in the presence or absence of a PPAR\u3b3 agonist, Rosiglitazone (RGZ). Methods: Rats were fed with 60% HFD for the first half of the treatment duration (21 days) then continued with either HFD alone or HFD plus RGZ for the second half. Results: Rats receiving HFD alone showed metabolic syndrome manifestations including hypertension, dyslipidemia, increased glucose levels and insulin resistance, as well as abnormal kidney and inflammatory parameters. Systolic blood pressure, plasma triglyceride and glucose levels, plasma creatinine, and albuminuria were significantly improved in the presence of RGZ. The following molecular parameters of the AROS axis were significantly upregulated in our rat model: carboxymethyl lysine (CML) in urine and liver; carboxyethyl lysine (CEL) in urine; advanced glycation end products (AGEs) in plasma; receptor for advanced glycation end products (RAGE) in liver and kidney; advanced oxidation protein products (AOPP) in plasma; and 4-hydroxynonenal (HNE) in plasma, liver, and kidney. Conversely, with RGZ administration, the upregulation of AOPP and AGEs in plasma, CML and CEL in urine, RAGE in liver as well as HNE in plasma and liver was significantly counteracted/prevented. Conclusions: Our data demonstrate (i) the systems-level regulatory landscape of HFD-induced metabolic syndrome involving multiple molecular parameters, including HNE, AGEs and their receptor RAGE, and (ii) attenuation of metabolic syndrome by PPAR\u3b3 modulation