Comparative evaluation of nephroprotective potential of resveratrol and piperine on nephrotic BALB/c mice.

OBJECTIVE: The objective of this study was to evaluate the nephroprotective potential of resveratrol and piperine at same dose on cationic bovine serum albumin (cBSA) induced immune complex glomerulonephritis (ICGN) in BALB/c mice. MATERIALS AND METHODS: Female BALB/c mice were divided into five groups. Group I served as normal control (complete Freund's adjuvant + Saline). Two weeks later, Groups II, III, IV, and V were administered cBSA (13 mg/kg) via the caudal vein 3 times/week every alternative day for 6 weeks to induce ICGN. Simultaneously, from the 3rd week, Groups III, IV were treated with resveratrol and piperine up to 6 weeks. Group V was treated with methylprednisolone considered as a reference standard. RESULTS: There was a significant decrease in albuminuria, serum creatinine, and blood urea nitrogen in Group IV animals when compared with Group III. In addition, Group III and IV have comparable results with cBSA treated animals. Concurrently, same groups showed significantly comparable variance in antioxidant enzymes, phagocytic index, and neutrophil adhesion assay. Group IV found to be more significant in IgG1 reduction than Group III. CONCLUSION: The findings of this study well-demonstrated that piperine has potential immunomodulatory and anti-inflammatory activity than resveratrol; therefore, piperine needs special attention in autoimmunity and inflammation research.

Cognitive effects of vanillic acid against streptozotocin-induced neurodegeneration in mice.

CONTEXT: Vanillic acid (VA), a flavoring agent used in food and drug products, obtained naturally from the plant Angelica sinensis (Oliv.) Diels (Apiaceae), used in the traditional Chinese medicine. It is reported to possess strong antioxidant, anti-inflammatory, and neuroprotective effects. However, the pharmacological effects on oxidative stress-induced neurodegeneration are not well investigated. OBJECTIVE: This study investigates the neuroprotective effect of VA on streptozotocin (STZ)-induced neurodegeneration in mice through behavioral and biochemical parameters. MATERIALS AND METHODS: The behavioral effects were determined using the Y-maze and open-field habituation memory. In biochemical parameters, acetylcholinesterase (AChE), corticosterone, tumor necrosis factor (TNF)-α, and antioxidants (superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase) were measured. Five groups of animals used were of control, negative control, and three separate groups treated with 25, 50, and 100 mg/kg of VA, respectively, for 28 d. Intracerebroventricular (ICV) injections of STZ were performed for all groups except control on 14th and 16th of 28 d of VA treatment. RESULTS: VA improved spatial learning and memory retention by preventing oxidative stress compared with control animals. VA at 50 and 100 mg/kg dose significantly (p < 0.001) improved the habituation memory, decreased the AChE, corticosterone, TNF-α, and increased the antioxidants (p < 0.001). VA (100 mg/kg) exhibited dose-dependent effect in all parameters with p < 0.001 except antioxidants in which VA showed the significance of p < 0.01. DISCUSSION AND CONCLUSION: VA exhibited reduction in AChE, TNF-α, and corticosterone with improved antioxidants to contribute neuroprotection and could be an effective therapeutic agent for treating neurodegenerative disorders.

Ameliorative effect of Elaeocarpus ganitrus on gentamicin-induced nephrotoxicity in rats.

OBJECTIVES: The present study was designed to evaluate the ameliorative effect of Elaeocarpus ganitrus on gentamicin (GM)-induced nephrotoxicity in rats. MATERIALS AND METHODS: E. ganitrus (100, 200, and 400 mg/kg body weight) was administered orally to male Wistar rats. GM (100 mg/kg) was used to induce nephrotoxicity. Study parameters include serum albumin, creatinine, blood urea nitrogen (BUN), uric acid, creatinine, and albuminuria. Total protein in serum, antioxidant enzymes activities, phagocytic index, and neutrophil adhesion assays were performed to determine oxidative stress and immunomodulatory action of E. ganitrus. RESULTS: The results revealed that coadministration of E. ganitrus significantly reduced the elevated level of serum creatinine, BUN, uric acid, and albuminuria with considerable increase in the serum albumin and urine creatinine. Furthermore, E. ganitrus noticeably increased serum total protein and antioxidant enzyme levels with significant alteration in phagocytic index and neutrophil adhesion assay when compared with GM-treated group in a dose-dependent manner. CONCLUSION: The present study revealed that ethanolic extract of E. ganitrus seeds has immunomodulatory and nephroprotective activity.

Application of validated RP-HPLC method for simultaneous determination of docetaxel and ketoconazole in solid lipid nanoparticles.

Docetaxel has significant single agent activity in prostate cancer and ketoconazole also has activity as a second line hormonal agent. In vitro, ketoconazole is synergistic with some chemotherapy agents by enhancing the intracellular retention of the cytotoxic agent. A potential drug-drug interaction exists though between docetaxel and ketoconazole because both agents are metabolized hepatically by the cytochrome P-450 system. Hence, a nanoparticulate system was formulated by loading both drugs for tumor targeting. Assay and in vitro release of the formulation were conducted by developing simple, precise, accurate, and validated analytical method for simultaneous determination docetaxel and ketoconazole using reversed-phase high-performance liquid chromatography (RP-HPLC). The RP-HPLC method was developed using Waters Symmetry C(18) column (25 cm × 4.5 mm, 5 µm) with a mobile phase consisting of acetonitrile and 0.2% triethylamine pH adjusted to 6.4 (48:52, v/v) at flow rate of 1 mL/min. Intra-day and inter-day variations were less than 2% over the linearity range, 0.5-20 µg/mL. The proposed two methods were successfully applied for the determination of docetaxel and ketoconazole in solid lipid nanoparticles.

Development and evaluation of nitrendipine loaded solid lipid nanoparticles: influence of wax and glyceride lipids on plasma pharmacokinetics.

Nitrendipine is an antihypertensive drug with poor oral bioavailability ranging from 10 to 20% due to the first pass metabolism. For improving the oral bioavailability of nitrendipine, nitrendipine loaded solid lipid nanoparticles have been developed using triglyceride (tripalmitin), monoglyceride (glyceryl monostearate) and wax (cetyl palmitate). Poloxamer 188 was used as surfactant. Hot homogenization of melted lipids and aqueous phase followed by ultrasonication at temperature above the melting point of lipid was used to prepare SLN dispersions. SLN were characterized for particle size, zeta potential, entrapment efficiency and crystallinity of lipid and drug. In vitro release studies were performed in phosphate buffer of pH 6.8 using Franz diffusion cell. Pharmacokinetics of nitrendipine loaded solid lipid nanoparticles after intraduodenal administration to conscious male Wistar rats was studied. Bioavailability of nitrendipine was increased three- to four-fold after intraduodenal administration compared to that of nitrendipine suspension. The obtained results are indicative of solid lipid nanoparticles as carriers for improving the bioavailability of lipophilic drugs such as nitrendipine by minimizing first pass metabolism.

Poly(amidoamine) (PAMAM) dendritic nanostructures for controlled site-specific delivery of acidic anti-inflammatory active ingredient.

The purpose of the investigation was to evaluate the potential of polyamidoamine (PAMAM) dendrimer as nanoscale drug delivery units for controlled release of water insoluble and acidic anti-inflammatory drug. Flurbiprofen (FB) was selected as a model acidic anti-inflammatory drug. The aqueous solutions of 4.0 generation (G) PAMAM dendrimer in different concentrations were prepared and used further for solubilizing FB. Formation of dendrimer complex was characterized by Fourier transform infrared spectroscopy. The effect of pH on the solubility of FB in dendrimer was evaluated. Dendrimer formulations were further evaluated for in vitro release study and hemolytic toxicity. Pharmacokinetic and biodistribution were studied in male albino rats. Efficacy of dendrimer formulation was tested by carrageenan induced paw edema model. It was observed that the loaded drug displayed initial rapid release (more than 40% till 3rd hour) followed by rather slow release. Pharmacodynamic study revealed 75% inhibition at 4th hour that was maintained above 50% till 8th hour. The mean residence time (MRT) and terminal half-life (THF) of the dendritic formulation increased by 2-fold and 3-fold, respectively, compared with free drug. Hence, with dendritic system the drug is retained for longer duration in the biosystem with 5-fold greater distribution. It may be concluded that the drug-loaded dendrimers not only enhanced the solubility but also controlled the delivery of the bioactive with localized action at the site of inflammation.

Solubility enhancement of indomethacin with poly(amidoamine) dendrimers and targeting to inflammatory regions of arthritic rats.

This work includes investigation on solubility enhancement of indomethacin (IND) in the presence of poly(amidoamine) (PAMAM) dendrimers and passive targeting of the PAMAM/IND complex so formed to the inflamed regions in an animal model. The complex formation was confirmed by infrared and (1)H nuclear magnetic resonance spectroscopy methods. Solubility of IND in aqueous G4-PAMAM followed Higuchi's A(N) curve depending on pH of the solubilizing medium. The solubility was decreased upon addition of dendrimer to the IND saturated solution at various pH, indicating aggregation behavior of the PAMAM/IND complex and conforming to the Higuchi's A(N) solubility profile. The in vitro release of IND from the PAMAM/IND complex through a cellophane membrane, from a Franz diffusion cell, showed 79 +/- 3.2% drug release in 24 h. The drug release was further retarded in the presence of human serum albumin (HSA) suggesting the significance of complex HSA binding in altering in vivo behavior of the complex. Intravenous administration of the PAMAM/IND complex formulation in rats showed a two-compartment pharmacokinetic profile. Enhanced effective IND concentrations in the inflamed regions were obtained for the prolonged time period with the PAMAM/IND complex compared to the free drug in arthritic rats indicating preferred accumulation of IND to the inflamed region. The targeting efficiency of PAMAM/IND complex was 2.29 times higher compared to free drug. In contrast to the previous investigations, two interesting findings reported here are: (a) solubility behavior of IND in G4-PAMAM dendrimer deviates from linearity with increasing concentrations of dendrimer at acidic to neutral pH values and (b) inspite of lymphatic drainage, retention of PAMAM/IND complexes occurs at the inflammatory site.

Enhanced intravenous transgene expression in mouse lung using cyclic-head cationic lipids.

Herein, we report enhanced intravenous mouse lung transfection using novel cyclic-head-group analogs of usually open-head cationic transfection lipids. Design and synthesis of the new cyclic-head lipid N,N-di-n-tetradecyl-3,4-dihydroxy-pyrrolidinium chloride (lipid 1) and its higher alkyl-chain analogs (lipids 2-4) and relative in vitro and in vivo gene transfer efficacies of cyclic-head lipids 1-4 to their corresponding open-head analogs [lipid 5, namely N,N-di-n-tetradecyl-N,N-(2-hydroxyethyl)ammonium chloride and its higher alkyl-chain analogs, lipids 6-8] have been described. In stark contrast to comparable in vitro transfection efficacies of both the cyclic- and open-head lipids, lipids 1-4 with cyclic heads were found to be significantly more efficient (by 5- to 11-fold) in transfecting mouse lung than their corresponding open-head analogs (5-8) upon intravenous administration. The cyclic-head lipid 3 with di-stearyl hydrophobic tail was found to be the most promising for future applications.