Oxymetazoline plus dexpanthenol in nasal congestion

Aims  To compare the efficacy and tolerability of Oxymetazoline 0.05 % plus Dexpanthanol 5% versus Xylometazoline 0.1 % nasal drops in patients with nasal congestion due to allergic rhinitis and following nasal surgery. Methods  An investigator-blind, randomized, controlled, phase IV clinical trial conducted in 100 patients with acute allergic rhinitis or patients post-nasal surgery. Patients received either Oxymetazoline 0.05% with Dexpanthanol 5% (OD) or Xylometazoline 0.1% (XO) nasal drops. Results  Relief from nasal congestion was significantly better in the OD group then in the XO group (mean nasal scores 1.24 vs 1.86). Significantly more improvement in sneezing and decrease in nasal discharge was seen in the OD group than the XO group. Nasal irritation in the OD group was significantly less as compared to XO group (0.38 v/s 1.12 on second day and 0.10 vs 0.36 on the fourth day). The recovery time for OD group was 1.08 hours, which was significantly (46 min) lesser than that of the XO group. Rebound congestion was significantly less in OD as compared to XO group (6.25% vs 82.98%). 93.75% of the physicians in the OD group and 51.28% in XO group reported response to therapy as good to excellent. 95.83% patients in the OD group and only 52.91% patients in the XO group rated tolerability to therapy as good to excellent. Conclusion  Oxymetazoline and dexpanthenol combination has a better efficacy, shorter recovery time, causes lesser rebound congestion and has better tolerability than xylometazoline.     

Apoptosis induced by novel aldehyde calpain inhibitors in human tumor cell lines

Calpain is a class of Ca(2+)-dependent cysteine proteases and has been suggested to be involved in several important signaling cascades. A series of novel aldehyde calpain inhibitors identified in our laboratory were more potent and specific than commercially available calpain inhibitors, and were used to assess the involvement of calpain in cancer. Our inhibitors demonstrated potent anti-proliferative activity in four cancer cell lines (PC-3, HeLa, Jurkat and Daudi) with IC(50)'s ranging from 2 to >30 microM. A non-cancer cell line (CV-1) was 4-7-fold less sensitive than the cancer cell lines. Apoptotic activity was determined and appeared to be inversely correlated to calpain expression levels in the different cell types. Leukemia cell lines (i.e., Daudi and Jurkat) with undetectable m-calpain were more susceptible to the apoptotic effects in response to calpain inhibition, while apoptosis was not detected in PC-3 prostate cancer cells, which highly express m-calpain. The extent of apoptosis in HeLa cells was moderate under identical conditions. Apoptosis induced by calpain inhibition was accompanied by caspase-3 activation. Furthermore, cell cycle analysis showed that aldehyde calpain inhibitors arrested cells at the G2/M boundary in a concentration-dependent manner. These results indicate that aldehyde calpain inhibitors exhibit their cytotoxic effects via induction of G2/M arrest and apoptosis. Importantly, the compounds failed to exert any inhibitory effects toward 20S proteasome. Collectively, our results suggest that calpain is a novel target for the treatment of a variety of cancer diseases and provide leads for further discovery and development of calpain inhibitors.     

Synthesis and pharmacological investigation of novel 1-alkyl-4-(4-substituted aryl/heteroaryl)-1,2,4-triazolo [4,3- a] quinazolin-5 (4H)-ones as a new class of H1-antihistaminic agents

A series of novel 1-alkyl-4-(4-substituted aryl/heteroaryl)- 1,2,4-triazolo [4,3-a] quinazolin-5(4H)-ones were synthesized by the cyclization of 2-hydrazino-3-(4-subst. aryl/heteroaryl) quinazolin-4(3H)-one with various carbon donors. The starting material, 2-hydrazino-3-(4-subst. aryl/heteroaryl) quinazolin-4(3H)-one, was synthesized from 4-subst. arylamine/ heteroarylamine by a novel innovative route. When tested for their in vivo Hi-antihistaminic activity on conscious guinea pigs, all the test compounds protected the animals from histamine induced bronchospasm significantly, whereby the compound 1-methyl-4-(2-py-ridyl)-1,2,4-triazolo[4,3-a] quinazolin-5(4H)-one (II) was found to be more potent (percent protection 71.43 %) when compared to the reference standard, chlorpheniramine maleate (percent protection 71 %). Compound II showed negligible sedation (8 %) when compared to chlorpheniramine maleate (25 %). Hence it could serve as prototype molecule for further development as a new class of H1-antihistamines.     

Preparation, characterization and in vitro drug release studies of novel polymeric nanoparticles

Polymeric nanoparticles of AADG cross-linked with MBA encapsulating water soluble macromolecules such as FITC-Dextran have been prepared in the reverse micellar system. The particles obtained were of >85nm in diameter which were highly monodisperse. An optically clear solution was obtained on redispersing these nanoparticles in aqueous buffer. Size and morphology of the particles remains the same on re-dispersing the lyophilized powder of these nanoparticles in aqueous buffer. The size dependency of the particles on the monomer and surfactant concentration was observed. The average size of the nanoparticles as obtained from DLS studies ranges from 74 to 114nm in case 0.06M AOT and 62-104nm in case of 0.1M AOT concentration. FITC-Dextran was entrapped into nanoparticles with high efficiency (>70%). The pH dependent release of the entrapped molecules from these nanoparticles was also studied. At pH 5.0 solution, approximately 43% of FITC-Dx was released and at pH 7.4 it was about 70%.     

Methoxychlor induces atresia of antral follicles in ERalpha-overexpressing mice.

Methoxychlor (MXC) is a pesticide that is known to bind to estrogen receptor alpha (ERalpha) and to induce atresia of antral ovarian follicles. Although studies have shown that MXC is toxic to the ovary, we hypothesize that perturbation to the estrogen-signaling system (i.e., increase or decrease in estrogen sensitivity) might alter ovarian responsiveness to MXC. Thus, we examined whether ERalpha overexpression alters the ability of MXC to increase follicle atresia. To do so, we employed a transgenic mouse model in which ERalpha can be inducibly overexpressed in animal tissues (ERalpha overexpressors). We dosed female controls and ERalpha overexpressors with sesame oil (vehicle control) or MXC (32 and 64 mg/kg/day) for 20 days. After dosing, the ovaries were collected for histological evaluation of follicle numbers and follicle atresia, while blood was collected for measurements of hormones. Estrous cycles were determined in all animals to ensure that all were terminated during estrus. Although there were no significant effects of MXC on the numbers of primordial, primary, and preantral follicles in both controls and ERalpha overexpressors, there was an effect on antral follicles. Specifically, our data indicate that 32 and 64 mg/kg MXC increased the percentage of atretic follicles compared to vehicle in both control and ERalpha overexpressor groups. Moreover, there was a clear trend toward greater sensitivity to 64 mg/kg MXC in ERalpha-overexpressing mice compared to control animals. Specifically, at the 64-mg/kg MXC dose, ERalpha-overexpressing mice had a significantly higher percentage of atretic follicles compared to control animals (controls = 21.5 +/- 3%, n = 5; ERalpha overexpressors = 37 +/- 23%, n = 9, p < or = 0.05 vs. controls). After 20 days of dosing, there were no differences in estradiol levels between controls and ERalpha-overexpressing mice in all treatment groups. Follicle-stimulating hormone (FSH) levels were similar in sesame oil-treated control mice and control mice treated with 32 mg/kg MXC, while control mice treated with 64 mg/kg MXC had significantly lower levels of FSH compared to sesame oil-treated controls (sesame oil = 4.31 +/- 0.7, MXC [64 mg/kg/day] = 1.89 +/- 0.4, n = 3, p < or = 0.02 vs. sesame oil). ERalpha-overexpressing mice treated with sesame oil, 32 or 64 mg/kg MXC, had similar FSH levels. Thus, we observed an increased percentage of atretic antral follicles in ERalpha-overexpressing mice treated with MXC compared to control mice treated with the same compound, suggesting that the ERalpha-signaling pathway plays an important role in MXC-induced atresia. The trend toward greater sensitivity to MXC in ERalpha-overexpressing mice compared to control animals cannot be explained by alterations in estradiol and/or FSH levels.     

Synthesis, characterization and in vitro biological activity studies of Cu-M (M = Cu2+, Co2+, Ni2+, Mn2+, Zn2+) bimetallic complexes

Six new bimetallic complexes of the type CuCu, CuCo, CuNi, CuZn and CuMn were prepared. The structures of these complexes and the ligand have been proposed on the basis of FAB mass, elemental analysis, UV-vis, IR, EPR and CV studies. All the complexes completely cleave pBS (SK-) DNA at a concentration of 10 microM; however, even at lower concentrations of 2 microM and 0.1 microM, the complexes (I and Ia) showed partial cleavage. The results of the fluorescence binding studies of the metal complexes with CT-DNA showed that the presence of aliphatic ligands added additional binding effects including electrostatic, hydrogen binding and vander Waals interactions. Complexes (I, Ia) showed 50% inhibition of COX-1 and COX-2 activities at as low a concentration as 12.5 microM, 13.5 microM, 14 microM and 14.5 microM. Inhibition assay of top I and top II by different complexes in mutant yeast strains (JN394, JN394 t(-1) and JN394 t(2-5)) with all the complexes showed significant inhibition of topoisomerase at 5 microM concentration. Complexes I and Ia exhibited good anti-microbial activities against all human pathogens tested except Klebsiella pneumoniae. The following studies showed that among the synthesized bimetallic complexes, complexes I and Ia seem to be promising candidates possessing DNA cleavage activities besides anti-microbial and anti-inflammatory properties to serve as chemical nucleases and chemotherapeutic agents.