Cinnamon modulates the pharmacodynamic & pharmacokinetic of amlodipine in hypertensive rats.

The objective of this study was to investigate the effects of cinnamon on the pharmacodynamic (PD) & pharmacokinetic (PK) of amlodipine in hypertensive rats. The hypertensive control group of Wistar rats received L-NAME (40 mg/kg, daily, orally) only. The cinnamon group of rats was treated with cinnamon (200 mg/kg, daily, orally) along with L-NAME. Following 14 days treatment period, blood pressures of rats were monitored at designated intervals over 24 h utilizing a tail-cuff system for measuring blood pressure. To assess the oral PK; amlodipine was administered as a single oral dose of 1 mg/kg to rats and blood samples were collected at specified intervals over 24 h and analysed by UPLC-LC MS/MS. Synergistic decreased in rat's blood pressure was observed in presence of cinnamon + amlodipine. Simultaneous administration of cinnamon ameliorates the Cmax and AUC0-t of amlodipine, the Cmax and AUC0-t was 11.04 ± 1.01 ng/ml and 113.76 ± 5.62 ng h/ml for the cinnamon + amlodipine group as compared to 4.12 ± 0.49 ng/ml and 48.59 ± 4.28 ng h/ml for the amlodipine alone group. The study demonstrates that the use of cinnamon considerably decreases the blood pressure levels and enhances the PK parameters of amlodipine in hypertensive rats.

Sinapic acid ameliorates cardiac dysfunction and cardiomyopathy by modulating NF-κB and Nrf2/HO-1 signaling pathways in streptozocin induced diabetic rats.

Hyperglycemia and hyperlipidemia-arbitrated mitochondrial oxidative insult is key reason for cardiac dysfunction and cardiomyopathy. Sinapic acid (SA) is a hydroxycinnamic acid (a polyphenolic acid) present in multiple plants and possesses several pharmacological activities. In this study, we examined the cardio protective effects of SA on streptozotocin (STZ)-induced cardiac insults. STZ and both STZ induced diabetes and normal control rats were administered with 20 and 40 mg/kg SA for 12 weeks. STZ rats demonstrated hyperglycemia and hyperlipidemia. Additionally, STZ administered rats exhibited various histological changes in the cardiac muscles and significantly enhanced CK-MB and LDH. The significant enhancement of oxidative stress, inflammation, and apoptotic markers, and the capacity to curb oxidative stress was significantly abridged in the STZ induced diabetic heart. Chronic treatment with SA (20-40 mg/kg) ameliorated the increased level of glucose, lipid, and cardiac function markers and curtailed histological changes in the cardiac muscles. Chronic treatment also repressed inflammation, oxidative stress and apoptosis thereby and restoring antioxidant defenses in the myocardium of STZ induced diabetic rats. STZ induced cardiac dysfunction and cardiomyopathy by promoting inflammation and oxidative stress. Sinapic acid ameliorates cardiac dysfunction and cardiomyopathy via improvement of hyperglycemia, hyperlipidemia, inflammation, oxidative stress, and apoptosis. Thus, SA possesses possible therapeutic value for the prevention of diabetic cardiac dysfunction and cardiomyopathy via the NRF2/HO-1 and NF-κB pathways.

Changes in Pharmacokinetics and Pharmacodynamics of Losartan in Experimental Diseased Rats Treated with Curcuma longa and Lepidium sativum.

The current study investigated "pharmacodynamics and pharmacokinetics interactions" of losartan with Curcuma longa (CUR) and Lepidium sativum (LS) in hypertensive rats. Hypertension was induced by oral administration of L-NAME (40 mg/kg) for two weeks. Oral administration of CUR or LS shows some substantial antihypertensive activity. The systolic blood pressure (SBP) of hypertensive rats was decreased by 7.04% and 8.78% 12 h after treatment with CUR and LS, respectively, as compared to rats treated with L-NAME alone. LS and CUR display the ability to potentiate the blood pressure-lowering effects of losartan in hypertensive rats. A greater decrease in SBP, by 11.66% and 13.74%, was observed in hypertensive rats treated with CUR + losartan and LS + losartan, respectively. Further, both the investigated herbs, CUR and LS, caused an increase in plasma concentrations of losartan in hypertensive rats. The AUC0-t, AUC0-inf and AUMC0-inf of losartan were increased by 1.25-fold, 1.28-fold and 1.09-fold in hypertensive rats treated with CUR + losartan. A significant (p < 0.05) increase in AUC0-t (2.41-fold), AUC0-inf (3.86-fold) and AUMC0-inf (8.35-fold) of losartan was observed in hypertensive rats treated with LS + losartan. The present study affirms that interactions between CUR or LS with losartan alter both "pharmacokinetics and pharmacodynamics" of the drug. Concurrent administration of losartan with either CUR or LS would require dose adjustment and intermittent blood pressure monitoring for clinical use in hypertensive patients. Additional investigation is necessary to determine the importance of these interactions in humans and to elucidate the mechanisms of action behind these interactions.

Eudragit-Coated Sporopollenin Exine Microcapsules (SEMC) of Phoenix dactylifera L. of 5-Fluorouracil for Colon-Specific Drug Delivery.

In this study, 5-fluorouracil (5-FU)-loaded pollens of Phoenix dactylifera and their coating with ERS was done and evaluated for the colon-targeted delivery of 5-FU to treat colon cancer. Sporopollenin exine microcapsules (SEMC) from the pollens of Phoenix dactylifera were extracted by the reflux method and 5-FU into SEMC was encapsulated by the vacuum-assisted loading method. 5-FU loaded SEMC was coated with Eudragit® RS-100 (ERS) by the organic solvent-evaporation technique under vacuum to avoid the discharge of 5-FU in the stomach and small intestine. Morphological and physicochemical characterization of drug-loaded SEMC (coated/uncoated) was performed by scanning electron microscopy (SEM), FTIR, XRD, and DSC. The encapsulation and drug loading were determined by the direct method, and an in vitro release study was performed in simulated gastric and intestinal fluids (SGF/SIF). The colon-specific delivery of 5-FU from the SEMC was assessed in terms of pharmacokinetics and gastrointestinal tract distribution after oral administration in rats. The successful encapsulation and loading of 5-FU into SEMC by a vacuum-assisted loading technique and its coating with ERS by a solvent-evaporation technique were achieved. SEM images of uncoated SEMC have shown porous structures, and coating with ERS reserved their morphology with a smooth surface and discrete microstructures and the 5% w/v ERS acetone solution. ERS-coated SEMC sustained the release of 5-FU until 24 h in SIF, while it was up to 12 h only from uncoated SEMC. The maximum plasma concentration (Cmax) of 5-FU from uncoated SEMC was 102.82 µg/mL after 1 h, indicating a rapid release of 5-FU in the upper gastrointestinal tract. This concentration decreased quickly with a half-life of 4 h, AUC0-t was 264.1 µg/mL.h, and MRT0-inf was 5.2 h. The Cmax of 5-FU from ERS-coated SEMC was 19.47 µg/mL at 16 h. The Cmax of 5-FU in small intestines was 406.2 µg/g at 1 h from uncoated SEMC and 1271.5 µg/g at 12 h from coated SEMC. Conclusively, a 249.9-fold higher relative bioavailability of 5-FU was achieved with the ERS-coated SEMC in colon tissues than that from uncoated SEMC.

Gastroprotective Effect of Sinapic Acid on Ethanol-Induced Gastric Ulcers in Rats: Involvement of Nrf2/HO-1 and NF-κB Signaling and Antiapoptotic Role.

Background: In the current study, we evaluated the therapeutic potential of sinapic acid (SA) in terms of the mechanism underlying its gastroprotective action against ethanol-induced gastric ulcers in rats. Methods: These effects were examined through gross macroscopic evaluation of the stomach cavity [gastric ulcer index (GUI)], alteration in pH, gastric juice volume, free acidity, total acidity, total gastric wall mucus, and changes in PGE2. In addition, we evaluated lipid peroxidation (malondialdehyde), antioxidant systems (catalase and glutathione), inflammatory markers [tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), and myeloperoxidase (MPO)], apoptotic markers (caspase-3, Bax, and Bcl-2), nuclear factor-κB [NF-κB (p65)], NO levels, and histopathological staining (H and E and PAS). Results: In rats with ethanol-induced ulcers, pre-treatment with SA (40 mg/kg p. o.) decreased the sternness of ethanol-induced gastric mucosal injuries by decreasing the GUI, gastric juice volume, free acidity, and total acidity. In addition, the pH and total gastric mucosa were increased, together with histopathological alteration, neutrophil incursion, and increases in PGE2 and NO2. These effects were similar to those observed for omeprazole, a standard anti-ulcer drug. SA was shown to suppress gastric inflammation through decreasing TNF-α, IL-6, and MPO, as well as curbing gastric oxidative stress through the inhibition of lipid peroxidation (MDA) and restoration of depleted glutathione and catalase activity. SA inhibited Bcl-2-associated X (Bax) and caspase-3 activity, and restored the antiapoptotic protein Bcl-2; these findings indicate the antiapoptotic potential of SA, leading to enhanced cell survival. SA also repressed NF-κB signaling and increased IκBα. Moreover, SA upregulated the nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), thereby restoring depleted antioxidant defense enzymes and implicating the NRF2/HO-1 signaling pathways. Conclusion: These results suggest that the prophylactic administration of SA (40 mg/kg) can ameliorate ethanol-induced gastric ulcers in rats primarily via the modulation of Nrf2/HO-1 and NF-κB signaling and subsequent enhancement of cell viability.