Sistla Ramakrishna

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.

β-cyclodextrin complexes of celecoxib: Molecular-modeling, characterization, and dissolution studies

Celecoxib, a specific inhibitor of cycloxygenase-2 (COX-2) is a poorly water-soluble nonsteroidal anti-inflammatory drug with relatively low bioavailability. The effect of β-cyclodextrin on the aqueous solubility and dissolution rate of celecoxib was investigated. The possibility of molecular arrangement of inclusion complexes of celecoxib and β-cyclodextrin were studied using molecular modeling and structural designing. The results offer a better correlation in terms of orientation of celecoxib inside the cyclodextrin cavity. Phase-solubility profile indicated that the solubility of celecoxib was significantly increased in the presence of β-cyclodextrin and was classified as AL-type, indicating the 1∶1 stoichiometric inclusion complexes. Solid complexes prepared by freeze drying, evaporation, and kneading methods were characterized using differential scanning calorimetry, powder x-ray diffractometry, and scanning electron microscopy. In vitro studies showed that the solubility and dissolution rate of celecoxib were significantly improved by complexation with β-cyclodextrin with respect to the drug alone. In contrast, freeze-dried complexes showed higher dissolution rate than the other complexes.

Immune system: a double-edged sword in cancer

ObjectiveThe objective of the review is to examine the role of innate and adaptive immune cells in cancer.IntroductionImmune system functions as a host defensive mechanism protecting against invading pathogens and transformed cells, including cancer. However, a body of research carried out over the last few decades has disclosed the unexpected role of immune system in fostering the tumor growth.MethodsA computer-based online search was performed in the PubMed, Scopus and Web of Science databases for articles published, concerning natural killer (NK) cells, Macrophages, CD4+ and CD8+ T cells with relevance to cancer. After finding relevant articles within these search limits, a manual search was conducted through the references from these articles.Results and ConclusionsThis review summarizes the role of immune system in Immunosurveillance and Immunoediting. It then focused mainly on role of macrophages, regulatory T cells (Treg), TH17 cells and on the immunosuppressive mechanisms, which facilitate immune evasion of tumor cells. Our results shows that, immune cells, such as CD8+ cytotoxic T lymphocytes (CTL), CD4+ T helper (TH)1 cells and NK cells along with their characteristic cytokine interferon (IFN)-γ, function as major antitumor effector cells. Whereas CD4+TH2 cells, myeloid-derived suppressor cells (MDSCs) and their derived cytokines function as dominant tumor-promoting forces. In contrast to these cells, macrophages, Treg, and TH17 cells show a dual effect in cancer. Thus, it appears that most components of the immune system are potentially endowed with dual functions i.e., promoting tumor development on the one hand and restraining tumor development on the other and hence immune system can be considered as a double-edged sword in cancer.

Synthesis and anticancer activity of oxindole derived imidazo[1,5-a]pyrazines.

A series of oxindole derivatives of imidazo[1,5-a]pyrazines were prepared and confirmed by 1H NMR, mass and HRMS data. These compounds were evaluated for their anticancer activity against a panel of 52 human tumor cell lines derived from nine different cancer types: leukemia, lung, colon, CNS, melanoma, ovarian, renal, prostate and breast. Among them compound 7l showed significant anticancer activity with GI50 values ranging from 1.54 to 13.0 μM. Cell cycle arrest was observed in G0/G1 phase upon treatment of A549 cells with 6.5 μM (IC50) concentration of compound 7l and induced apoptosis. This was confirmed by Annexin V-FITC as well as DNA fragmentation analysis and interestingly this compound (7l) did not affect the normal cells.

Comparative in vivo evaluation of propranolol hydrochloride after oral and transdermal administration in rabbits

The purpose of this study was the in vivo evaluation of orally and transdermally administered propranolol hydrochloride in rabbits. Transdermal patches of propranolol hydrochloride (PPN) were formulated employing ethyl cellulose and polyvinylpyrrolidone as film formers. The pharmacodynamic (PD) and pharmacokinetic (PK) performance of PPN following transdermal administration was compared with that of oral administration. This study was carried out in a randomized cross-over design in male New Zealand albino rabbits. The PK parameters such as maximum plasma concentration (C(max)), time for peak plasma concentration (t(max)), mean residence time (MRT) and area under the curve (AUC(0-alpha)) were significantly (P<0.01) different following transdermal administration compared to oral administration. The terminal elimination half-life (t(1/2)) of transdermally delivered PPN was found to be similar to that following oral administration. In contrast to oral delivery, a sustained therapeutic activity was observed over a period of 24 h after transdermal administration compared to oral administration. The relative bioavailability of PPN was increased about fivefold to sixfold after transdermal administration as compared to oral delivery. This may be due to the avoidance of first pass effect of PPN. The sustained therapeutic activity was due to the controlled release of drug into systemic circulation following transdermal administration.

Antimicrobial activity of Ixora coccinea leaves

Ether and methanol extracts of Ixora coccinea dry leaves were tested for their antimicrobial activity. Ether fraction was found to be more active than the methanol fraction.

DNA-binding affinity and anticancer activity of β-carboline–chalcone conjugates as potential DNA intercalators: Molecular modelling and synthesis

A new series of DNA-interactive β-carboline-chalcone conjugates have been synthesized and evaluated for their in vitro cytotoxicity and DNA-binding affinity. It has been observed that most of these new hybrids have shown potent cytotoxic activities on A-549 (lung adenocarcinoma) cell lines with IC50 values lower than 10 μM. The hybrid 7b is more effective against some of the selected cancer cell lines with IC50 values less than 50 μM. In addition, compounds 7e, 7k, 7p-u has displayed significant elevation in ΔTm of DNA in comparison to Adriamycin, suggesting significant interaction and remarkable DNA stabilization. The DNA intercalation of these new hybrids has been investigated by fluorescence titration, DNA viscosity measurements, molecular docking as well as molecular dynamics and the results are in agreement with the thermal denaturation studies.

Microbial degradation of pyridine using Pseudomonas sp. and isolation of plasmid responsible for degradation

Pseudomonas (PI2) capable of degrading pyridine was isolated from the mixed population of the activated sludge unit which was being used for treating complex effluents, the strain was characterized. Aerobic degradation of pyridine was studied with the isolated strain and the growth parameters were evaluated. Pyridine degradation was further conformed by chromatography (HPLC) analysis. The process parameters like biomass growth and dissolved oxygen consumption were monitored during pyridine degradation. In order to conform with the plasmid capability to degrade pyridine, the requisite plasmid was isolated and transferred to DH 5alpha Escherichia coli. The subsequent biodegradation studies revealed the ability of the transformed plasmid capability to degrade the pyridine.

Synthesis of chalcone-amidobenzothiazole conjugates as antimitotic and apoptotic inducing agents

A series of chalcone-amidobenzothiazole conjugates (9a-k and 10a,b) have been synthesized and evaluated for their anticancer activity. All these compounds exhibited potent activity and the IC(50) of two potential compounds (9a and 9f) against different cancer cell lines are in the range of 0.85-3.3 μM. Flow cytometric analysis revealed that these compounds induced cell cycle arrest at G2/M phase in A549 cell line leading to caspase-3 dependent apoptotic cell death. The tubulin polymerization assay (IC(50) of 9a is 3.5 μM and 9f is 5.2 μM) and immuofluorescence analysis showed that these compounds effectively inhibit microtubule assembly at both molecular and cellular levels in A549 cells. Further, Annexin staining also suggested that these compounds induced cell death by apoptosis. Moreover, docking experiments have shown that they interact and bind efficiently with tubulin protein. Overall, the current study demonstrates that the synthesis of chalcone-amidobenzothiazole conjugates as promising anticancer agents with potent G2/M arrest and apoptotic-inducing activities via targeting tubulin.

First stereoselective total synthesis and anticancer activity of new amide alkaloids of roots of pepper.

The first stereoselective total synthesis of new natural amide alkaloids 1-3 have been achieved from commercially available starting materials. Wittig olefination, Sharpless asymmetric dihydroxylation, epoxidation, a trans regioselective opening of 2,3-epoxy alcohol, Horner-Wadsworth-Emmons (HWE) olefination and amide coupling are the key steps. The amide alkaloids 1-3 are evaluated for their anticancer activity against colon (HT-29), breast (MCF-7) and lung (A-549) human cancer cell lines for the first time.