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Objective: Obesity was induced in rats by feeding on a high fat diet (HFD), 60% w/w cholesterol, 20% w/w carbohydrates, and 20% w/w proteins for two months., Materials and Methods: Animals were fed on a HFD and treated concurrently with a single daily dose of vehicle or TPPU (2 mg/kg p.o) for two months. Body weights, blood pressure, and biochemical investigations of all animals were registered at 0, 1, and 2 months of the experimental period., Results: Vehicle-treated rats fed on a HFD had a considerable increase in body weight compared to age-matched control animals fed on a regular diet (regular diet; 311.40 ±9.60 vs. HFD; 446 ± 12.67). The body weight of rats fed on a HFD and concurrently treated with 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4yl) urea (TPPU; 2 mg/kg p.o) daily for two months was significantly decreased (p<0.01). A significant (p<0.01) increase in the systolic blood pressure of animals and vascular dysfunction with blunted relaxant response to acetylcholine and sodium nitroprusside was evident in vehicle-treated animals fed on a HFD compared to control rats fed on a regular diet. These HFD-induced disorders were markedly attenuated in animals fed on a HFD and treated concurrently with a single daily dose of TPPU (2 mg/kg p.o). HFD diet-induced deleterious metabolic changes were prevented with concurrent administration of TPPU (2 mg/kg p.o). TPPU treatment decreased the HDF-induced increase in plasma creatinine levels (p<0.001) in rats. The adiponectin levels were decreased (p<0.001) in vehicle-treated rats fed on HFD for two months compared to control rats fed on a normal diet (p<0.001). Adiponectin levels were significantly (p<0.001) increased in rats fed on HFD and treated concurrently with TPPU (2 mg/kg p.o). HFD diet caused a marked increase in plasma leptin levels of animals which were significantly decreased in animals fed on a HFD and treated concurrently with TPPU for two months. Obese animals exhibited increased levels of plasma insulin compared to control animals fed on a regular diet which were significantly suppressed (p<0.001) by TPPU treatment. In the current investigation, TPPU treatment had a favorable impact on the levels of other metabolic parameters such as plasma cholesterol, triglycerides (TGs), low density lipoproteins (LDLs), and high density lipoproteins (HDL). HFD caused a profound increase in the serum liver enzymes, the effect was reversed by treatment of animals with TPPU (2 mg/kg p.o)., Conclusions: The findings of our current study indicate the promising therapeutic potential of TPPU as a new drug candidate to manage obesity-induced cardiovascular and metabolic disorders. Soluble epoxide hydrolase inhibitors such as TPPU could prevent HFD-induced obesity and related cardiovascular and metabolic complications.

Stabilization of epoxyeicosatrienoic acids (EETs) levels via soluble epoxide hydrolase (sEH) deletion or its pharmacological inhibition have been shown to have beneficial effects on inflammation, ischemia, hypertension and diabetes. Owing to the diverse role of EETs, current study was designed to evaluate the therapeutic potential of 1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl) urea (TPPU), a novel sEHI against fructose-induced diabetes and related complications in rats. Sprague-Dawley rats (200 - 230 g) were divided into four different groups, each containing 10 animals. One group served as a normal control and received standard diet and drinking water. The second group served as a diseased control and received standard diet, 25% fructose in drinking water and was treated with vehicle only. The third and fourth groups received standard diet, 25% fructose in drinking water and TPPU (2 mg/kg) or metformin (150 mg/kg), respectively. All treatments were given orally for 12 weeks. At the end of the study, blood samples were collected to measure serum insulin levels and other biochemical parameters. Animals were dissected to collect tissue specimens for histological and immunohistochemistry analysis. Animals fed on fructose and treated with vehicle demonstrated elevated blood insulin and glucose levels as well as high levels (P < 0.001) of triglycerides (TGs), cholesterol, low-density lipoprotein (LDL) and homeostatic model assessment of insulin resistance (HOMA-IR) compared to naive rats. Similarly, the levels of alkaline phosphatase (ALP), alanine aminotransferase (ALT), urea and uric acid were significantly (P < 0.001) increased in vehicle treated fructose fed animals. TPPU (2 mg/kg p.o.) and simultaneously fed on fructose for 12 weeks substantially decreased HOMA-IR levels, lowered blood glucose, serum cholesterol, LDLs and TGs) while high-density lipoproteins (HDL) levels were increased compared to untreated animals. Metformin, a standard reference drug showed similar results. Microscopic studies of liver and pancreatic sections of TPPU treated animals showed marked improvement in cellular architecture compared to untreated animals. Current study demonstrated profound therapeutic potential of TPPU against fructose induced-diabetes and related metabolic complications which was evident by its attenuating effect fructose-induced hyperglycemia, hyperlipidemia and impaired renal and hepatic serum markers.

Objective: This study evaluated the efficacy of the soluble epoxide hydrolase (sEH) inhibitor, TPPU on chronic NG-Nitro L-arginine methyl ester (L-NAME)-induced hypertension in rats and its effects on plasma Angiotensin II (Ang II), cardiac Angiotensin-converting enzyme (ACE) and Angiotensin II receptor type 1 (AT1R) expressions., Materials and Methods: Forty Sprague Dawley rats were divided into 5 groups. Two groups served as control and received orally either vehicle or TPPU (3 mg/kg) for five weeks. The other three groups were given L-NAME (50 mg/kg/day) in drinking water for five weeks. Two weeks after the L-NAME treatment, animals received orally either saline or TPPU (3 mg/kg/day) or lisinopril (10 mg/kg/day) daily for 3 weeks. Blood pressure (BP) was measured weekly. At the end of the experiment, plasma Ang II, cardiac ACE and AT1R protein and gene expressions were determined., Results: L-NAME caused a significant increase in BP of the animals. TPPU and lisinopril resulted in normalization of L-NAME-induced hypertension. They also caused a significant reduction in Ang II and ACE protein and gene expressions compared to L-NAME and vehicle-treated animals., Conclusions: This study demonstrates that TPPU effectively lowers L-NAME-induced hypertension in rats. The mechanism of its antihypertensive effect is likely mediated by the suppression of ACE gene and protein expression, leading to a lower Ang II level.

The present study was aimed to investigate the effect of piperine, a major active ingredient of black pepper, on the pharmacokinetics of domperidone in rats. Animals were given oral (p.o.) or intraperitoneal (i.p.) domperidone (20 mg/kg) alone or together with piperine (20 mg/kg, p.o.). Plasma samples were collected at 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0 and 12 hours after drug administration. The concentration of domperidone in the plasma was measured using a HPLC method. The concomitant administration of piperine with oral or intraperitoneal domperidone resulted in a significant (P<0.05) increase in the maximum plasma concentration (Cmax), the mean area under the plasma concentration-time curve (AUC), and the elimination half-life (t1/2) of domperidone as compared to those obtained for domperidone alone. These results suggest that an important pharmacokinetic interaction may occur if piperine is administered concurrently with domperidone.

Piperine, is the major active principal of black pepper. In traditional medicine, black pepper has been used as an analgesic, anti-inflammatory agent and in the treatment of epilepsy. This study was conducted to evaluate the in vivo analgesic and anticonvulsant effects of piperine in mice. The analgesic and anticonvulsant effects of piperine were studied in mice using acetic acid-induced writhing, tail flick assay, pentylenetetrazole (PTZ)- and picrotoxin (PIC)-induced seizures models. The intraperitoneal (i.p.) administration of piperine (30, 50 and 70 mg/kg) significantly inhibited (P<0.01) the acetic acid-induced writhing in mice, similar to the effect of indomethacin (20 mg/kg i.p.). In the tail flick assay, piperine (30 and 50 mg/kg, i.p.) and morphine (5 mg/kg, i.p.) caused a significant increase (P<0.01) in the reaction time of mice. Pre-treatment of animals with naloxone (5 mg/kg i.p.), reversed the analgesic effects of both piperine and morphine in the tail flick assay. Piperine (30, 50 and 70 mg/kg, i.p.) and standard drugs, valproic acid (200 mg/kg, i.p.), carbamazepine (30 mg/kg, i.p.) and diazepam (1 mg/kg, i.p.) significantly (P<0.01) delayed the onset of PTZ-and PIC-induced seizures in mice. These findings indicate that piperine exhibits analgesic and anticonvulsant effects possibly mediated via opioid and GABA-ergic pathways respectively. Moreover, piperine being the main constituent of black pepper, may be contributing factor in the medicinal uses of black pepper in pain and epilepsy.