Cuminum cyminum Ameliorates Urotoxic Effects of Cyclophosphamide by Modulating Antioxidant, Inflammatory Cytokines, and Urinary Bladder Overactivity: In vivo and in Silico Investigations.

Interstitial Cystitis (IC) is a chronic inflammatory disease that lacks effective treatment. The present study aimed to investigate the potential of aqueous ethanol extract of Cuminum cyminum (AEECC) on oxidative stress, inflammation and overactivity of urinary bladder induced by cyclophosphamide (CYP). Female Sprague-Dawley rats received intraperitoneal administration of cyclophosphamide (150 mg/kg, i. p. 1st , 4th , and 7th days). To investigate the urothelial damage, the bladder weight, nociception behavior, and Evans blue dye extravasation method was used. The antioxidants CAT, GPX and NO were measured. ELISA determined the IL-6 and TNF-α levels. The spasmolytic effect of AEECC was investigated on isolated bladder strips and its mechanisms were determined. The enhanced nociception behavior, bladder weight, vascular permeability, edema, hemorrhage, nitric oxide, IL-6 and TNF-α levels by CYP administration were significantly reduced by AEECC (250 and 500 mg/kg). A significant increase in serum antioxidant system such as CAT and GPx was also observed in AEECC-treated rats. The AEECC (3 mg/ml) significantly reduced urinary bladder tone in the strips pre-contracted with carbachol in both control and CYP-treated rats. This relaxation was demolished by atropine, nifedipine, glibenclamide, and indomethacin but not with propranolol. The plant extract showed the presence of antioxidant and anti-inflammatory phytochemicals. These results suggest that Cuminum cyminum offers uroprotective activity and can ameliorate CYP-induced bladder toxicity by modulating antioxidant parameters, pro-inflammatory cytokine levels and bladder smooth muscle overactivity. The in silico binding interactions of antioxidant 2I3Y and anti-inflammatory protein 1TNF with various ligands from Cuminum cyminum seeds revealed potential bioactive compounds with promising antioxidant and anti-inflammatory properties, providing valuable insights for drug development and nutraceutical research.

Fast dissolving oral films: An approach to co-load and deliver the atorvastatin and ezetimibe for better therapeutic response.

Atherosclerotic patients suffering with acute coronary disease are lying at high risk. This life-threatening problem can be curtailed by using statins e.g., ezetimibe (EZT), atorvastatin calcium (ATC). In this study, co-loaded Fast Dissolving oral films (FDOFs), of ATC-EZT with HPMC E5 prepared by solvent evaporation method. Prepared FDOFs were evaluated for physicochemical, thermal and mechanical properties. In-vivo animal studies were performed on albino rats against diet induced hyperlipidemia. Prepared FDOFs have rapid DT; 27sec, TDT >2min and in-vitro drug release 97% in a min. In DSC, FTIR and XRD analysis, prepared films were chemically compatible and no chemical interaction of drugs and excipient was found. In kinetic modeling, it was observed their EZT exhibited lowest R2 value for zero order kinetic and best fit model was first order kinetic (n, 0.9823). The korsmeyer peppas model films (n, 0.016) indicate fickian type drug diffusion. The groups treated with marketed suspension of drug and FODPs were compared with normal group and high fats diet group. Study reviled that combination FDOPs of both ATC/EZT significantly reduce hyperlipemia as compared to high fat diet group. It can be concluded that ATC and EZT encapsulated in FODFs provide instant drug release and better therapeutic outcomes.

Endothelium independent calcium channel blocking pathways mediate antihypertensive effect of morus nigra.

Present study was conducted to validate the folkloric claims of morus nigra l. (moraceae) using invasive blood pressure measuring and ex vivo vasorelaxant experimental techniques. Intravenous administration of mn. Aq in 0.01-30 mg/kg doses caused significant decrease in mean arterial pressure and heart rate in fructose-induced hypertensive rats. It also showed relaxation in high k+ [80 mm] and pe (1µm) mediated aortic contraction with ec50 1.25 and 3.72mg/ml values, respectively. Vaso-relaxant effect of mn.aq was partially blocked in presence of l-name with ec50, 5.32mg/ml value, but showed concentration dependent significant inhibition of ligand gated and voltage gated ca+2 channels and intracellular ca+2 release, similar to verapamil. Findings of current study designate that aqueous fraction of m. Nigra possesses antihypertensive activity with concentration-dependent vaso-relaxant effect predominantly mediated through endothelial-independent calcium channel blocking pathways accompanied by partial involvement of endothelium-dependent nos mediated relaxation.

An assessment of bioavailability of acrylate based pH-sensitive complexes of lovastatin.

Lovastatin (LSN), a potent anti-hyperlipidemic drug, possesses poor bioavailability due to its very low aqueous solubility. The objective of this study was to establish a relationship between increased drug solubility before reaching site of absorption or increasing drug solubility at target absorption site for accentuated bioavailability of LSN. Composites of LSN with oppositely natured pH-sensitive acrylate polymers, cationic Eudragit EPO (EPO) and anionic Eudragit L100 (L100), were fabricated with physical trituration and kneading methods. Formulations were characterized for solubility, FTIR, PXRD, DSC, SEM, dissolution and bioavailability studies in rats. Interestingly, we observed that physical mixtures of EPO outmatched its kneaded formulations, whereas the physical mixtures and kneaded dispersions of L100 were virtually similar in characteristics. EPO was superior in boosting LSN solubility in the respective medium than the L100. Moreover, EPO produced immediate release profile in gastric environment whereas L100 offered sustained release of LSN in intestinal milieu. Bioavailability studies in rats further supported the EPO formulation in terms of shorter Tmax, higher Cmax and heightened AUC.

A mechanistic evaluation of the traditional uses of Nepeta ruderalis in gastrointestinal and airway disorders.

CONTEXT: Nepeta ruderalis Buch.-Ham. (Lamiaceae), locally known as Badranj Boya, is an aromatic herb used traditionally as an antispasmodic, antidiarrhoeal, and anti-asthamatic remedy. OBJECTIVE: Aqueous methanolic extract of N. ruderalis was studied to investigate its traditional uses. MATERIALS AND METHODS: Study was conducted from September 2015 to February 2016. In vitro spasmolytic and broncho-relaxant activity of crude extract of N. ruderalis (whole plant) was evaluated at 0.01-10 mg/mL final bath concentration in isolated rabbit jejunum and tracheal tissues, using PowerLab data acquisition system (Transonic Systems Inc., Ithaca, NY). In vivo antidiarrhoeal activity was evaluated in castor oil-induced diarrhoeal mice at the dose of 300 and 500 mg of crude extract orally. RESULTS: Crude extract of N. ruderalis completely relaxed spontaneously contracting, high K+ (80 mM) and carbachol (1 µM) induced contracted jejunum with an EC50 value of 5.85 (5.45-6.27), 4.0 (3.80-4.23) and 2.86 (2.48-3.29), similar to verapamil. Nr.Cr relaxed high K+ and carbachol induced contractions, at 5 and 10 mg/mL with an EC50 value of 2.37 (2.11-2.67) and 3.26 (2.9-3.67), respectively, and also displaced calcium concentration-response curves toward right at 0.1 and 0.3 mg/mL. Nr.Cr exhibited antidiarrhoeal protection at a dose of 300 and 500 mg/kg, similar to verapamil, whereas no acute toxicity signs were seen up to 5 g/kg in healthy mice. DISCUSSION AND CONCLUSION: Results suggest the presence of spasmolytic and broncho-relaxant effects in the crude extract of N. ruderalis, possibly mediated through calcium channel-blocking activity, providing the pharmacological basis for its traditional uses in gastrointestinal and airway disorders.

Formulation of Modified-Release Bilayer Tablets of Atorvastatin and Ezetimibe: An In-Vitro and In-Vivo Analysis.

The objective of this work was to formulate co-loaded bilayer tablets containing ezetimibe (EZB) and atorvastatin (ATC). ATC loaded in the immediate-release (IR) layer is an HMG CoA reductase inhibitor, while EZB, added in the sustained-release (SR) layer, is a lipid-lowering agent. This study was conducted to evaluate the effects of polymer on the formulation and characterization of bilayer tablets, as well as the therapeutic impact of the concurrent use of both drugs having a sequential release pattern. To obtain the optimized results, four different formulations with variable compositions were developed and evaluated for different parameters. The drug release studies were carried out using a type II dissolution apparatus, using phosphate buffer solution (PBS) of 1.2 pH for IR of EZB for an initial 2 h, followed by 24 h studies for ATC in PBS 6.8 pH. The IR layer showed rapid drug release (96%) in 2 h, while 80% of the ATC was released in 24 h from the SR layer. Locally obtained, 6-week-old female albino rats were selected for in vivo studies. Both preventive and curative models were applied to check the effects of the drug combination on the lipid profile, atherosclerosis and physiology of different organs. Studies have shown that the administration of both drugs with different release patterns has a better therapeutic effect (p < 0.05), both in preventing and in curing hyperlipidemia. Conclusively, through the sequential release of ATC and EZB, a better therapeutic response could be obtained.

Ipomoea hederacea Jacq.: A plant with promising antihypertensive and cardio-protective effects.

ETHNOPHARMACOLOGICAL RELEVANCE: Seeds of Ipomoea hederacea Jacq. (family: Convolvulaceae) are traditionally used to treat high blood pressure and cardiac diseases. AIM OF THE STUDY: Present study was conducted to validate the traditional claim and explore the possible mechanism(s) of antihypertensive effects of I. hederacea. MATERIALS AND METHODS: Aqueous-ethanolic extract and activity based fractions of I. hederacea were evaluated using invasive blood pressure measuring technique, isolated tissue experiments, fructose induced hypertension/metabolic syndrome and biochemical analysis.Phytochemical analysis of active fraction was performed with aim to identify chemical composition of I. hederacea seeds. LC-MS analysis was also performed to identify the compounds proposed to be present in active fraction of I. hederacea seeds. RESULTS: Crude extract/fractions of I. hederacea showed dose (0.01-100 mg/kg) dependent significant hypotensive effect in normotensive anesthetized rats, similar to verapamil (0.01-30 mg/kg). Pretreatment with hexamethonium and atropine mediated no significant changes in hypotensive effect of butanol fraction of I. hederacea (Ih.Bn) at 3 mg/kg dose. However, a significant decrease in the hypotensive effect of Ih.Bn 3 mg/kg (-34.82 ± 3.36%; p < 0.05) was observed in the presence of L-NAME (20 mg/kg). Similarly, Ih.Bn (3 mg/kg) showed no significant effect on angiotensin-II response. However, response of phenylephrine (45.60 ± 9.63%; p < 0.05) and dobutamine (18.25 ± 2.10%; p < 0.01) was significantly decreased in the presence of Ih.Bn 3 mg/kg. Ih.Bn also exhibited dose dependent (0.01-100 mg/kg) antihypertensive effect in fructose induced hypertensive rats, similar to verapamil (0.01-30 mg/kg). Concomitant treatment with Ih.Bn (3, 10 and 30 mg/kg) for six weeks showed a dose dependent profound protection with significant (p < 0.01) effect at 30 mg/kg against fructose induced basal mean arterial pressure (142.2 ± 4.62 mmHg). Ih.Bn did not significantly change response of PE, Ang-II and Epi was observed in invasive and ex vivo techniques. However, Ih.Bn significantly (p < 0.01; p < 0.001) prevented against decrease in vascular response of acetylcholine in anesthetized rats and in isolated aorta of rat. A significant dose dependent decrease in triglyceride and glucose level (p < 0.001), and increase in HDL level (p < 0.05) was observed in Ih.Bn treated groups. Results of LC-MS analysis of Ih.Bn showed the presence of 24 compounds that belong to different chemical classes, including carboxylic acid, flavonoids, oligopeptides and tripeptide that are known to have antihypertensive and vasorelaxant properties. CONCLUSIONS: Results of present study indicate the presence of hypotensive/antihypertensive effect in crude extract/fractions of I. hederacea with most potent effect shown by butanol fraction (Ih.Bn), possibly mediated through α1 blocking, ß blocking and iNOS/cGMP stimulating activity.

A pharmacological evidence for the presence of antihistaminic and anticholinergic activities in Equisetum debile Roxb.

OBJECTIVE: The study was designed to evaluate possible antihistaminic and anticholinergic activities of Equisetum debile. MATERIALS AND METHODS: Effects of crude ethanolic (Ed.Eth) and effects of crude aqueous (Ed.Aq) extracts of E. debile were studied using isolated guinea pig ileum, rabbit jejunum, and rabbit trachea. Tissue responses were recorded using isotonic and isometric transducers, connected with PowerLab data acquisition system. RESULTS: A dose-dependent (0.1-0.3 mg/ml) rightward shift was demonstrated in histamine concentration-response curves. Whereas a complete relaxation of carbachol (1 µM)-induced contractions in isolated rabbit jejunum (3 mg/ml) and tracheal (10 mg/ml) preparations was observed, similar to dicyclomine at 1 and 3 µM, respectively. However, no significant difference between the effects of Ed.Eth and Ed.Aq was observed. CONCLUSION: Study provides pharmacological evidence for the presence of antihistaminic and anticholinergic activities in crude extracts of E. debile and also highlight its medicinal significance in the management of airway and gastrointestinal disorders.