Synthesis, biological evaluation and kinetic studies of glyceride prodrugs of diclofenac

The prodrugs (glyceride derivatives) 3a and 3b of diclofenac were prepared by reacting 1, 2, 3-trihydroxy propane-1,3-dipalmitate/stearate with the acid chloride of diclofenac as potential prodrugs to reduce the gastrointestinal toxicity associated with them. These prodrugs were evaluated for their ulcerogenicity, anti-inflammatory and analgesic activity. It was found that the prodrugs were significantly less irritating to the gastric mucosa as indicated by severity index of 0.86, 0.78 compared to 1.6 of diclofenac. The prodrugs 3a and 3b showed better anti-inflammatory and analgesic activity than the parent drugs. The hydrolysis of prodrugs 3a and 3b were studied at pH 3, 4, 5 and 7.4. The HPLC analysis showed that the prodrugs were resistant to hydrolysis at pH 3, 4 and 5 indicating that they did not hydrolyze in acidic environment, whereas at pH 7.4 the prodrugs readily released the parent drug in significant quantities. The plasma levels of diclofenac were also analyzed by HPLC in rats after single oral dose of the prodrugs. The results indicated that the parent drugs were readily released. The concentration of diclofenac during the study was found higher in animals treated with prodrugs 3a and 3b compared with animals treated with diclofenac. The concentration of diclofenac was found to be 38.59, 33.6 and 30.36 microg/ml in animals treated with prodrugs 3a, 3b and diclofenac respectively. In conclusion, all these studies indicated that the glyceride prodrugs of diclofenac might be considered as potential biolabile prodrugs of diclofenac.     

Synthesis and characterization of novel carboxymethyl Assam Bora rice starch for the controlled release of cationic anticancer drug based on electrostatic interactions

Carboxymethyl Assam Bora rice starch (CM-ABRS) was chemically synthesized in non-aqueous medium with the optimum degree of substitution (DS) of 1.23, and physicochemically characterized by FT-IR, DSC, XRD, and SEM analysis. Comparative evaluation of CM-ABRS with native starch (ABRS) for powder flow characteristics, swelling index, apparent solubility, rheological properties, textural properties, and mucoadhesive studies were carried out. The aim of the current work was to investigate the potential of CM-ABRS as a novel carrier for the water-soluble chemotherapeutic, doxorubicin hydrochloride (DOX). Formation of drug/polymer complex (DOX-CM-ABRS) via electrostatic interaction has been evaluated for the controlled release of DOX in three different pH media (phosphate-buffered saline (PBS), pH 7.4, 6.8, and 5.5). In vitro drug release studies illustrated faster release of drug in PBS at pH 5.5 as compared to pH 6.8 and pH 7.4, respectively, indicating the importance of pH-sensitive drug release from the DOX-CM-ABRS complex in malignant tissues.     

Sensitivity to house dust mite allergens and prevalence of allergy-causing house dust mite species in Pothwar,Pakistan

This study is the first report on the epidemiological status of house dust mite (HDM) allergy in Pothwar, Pakistan. Allergy data of 2087 symptomatic patients were obtained, of whom 1706 (81.7%) patients were skin-prick-test positive for HDM allergens. This percentage was significantly higher than for pollen and food allergens. In the results of this study Dermatophagoides farinae (61%) and D. pteronyssinus (29%) were the predominant species in the study area. Besides these pyroglyphids, predatory Cheyletus sp. (10%) and an oribatid mite sp. (1%) were also observed. Random and patients’ houses showed 87.4 and 87.1% positive mite infestation, respectively. Mean (±?SEM) D. farinae counts per g of dust in random samples was 235.4 ± 7.93 compared to 274.7 ± 10.78 from patients’ homes. Mean D. pteronyssinus counts from random houses compared to patients’ houses were 115.0 ± 4.57 and 124.6 ± 5.76, respectively. Mite counts depicted seasonal variation, with peaks during monsoon season. ELISA results of dust samples demonstrated that of the dust samples with?>?10 µg/g of dust, the threshold value described as a risk factor for developing asthma, 57.6% had Der f1 and 20% Der p1 allergen load. Mean Der f1 burden was significantly higher than Der p1, with maximum levels during monsoon and autumn seasons. This research established a better awareness about the epidemiological status of HDM allergy and prevalence of allergy causing HDM species in Pakistan.     

Multielement proton-induced X-ray emission analysis of betel leaves,betel nuts,and lime

Proton-induced X-ray emission (PIXE) method was employed to study the concentration of heavy elements in betel leaves, betel nuts, and mineral lime consumed in Bangladesh. The samples were collected from different parts of Bangladesh and analyzed by the thicktarget external beam technique of the PIXE method. The samples were exposed to the proton beam as 1-mm thick pellets and irradiated with 2.0-MeV protons having 20-nA beam intensity. The concentration of some 15 elements (K, Ca, Ti, V, Cr, Mn, Fe, Ni, Cu, Zn, Se, Br, Rb, Sr, and Pb) was measured by comparison with a calibration curve constructed from the NBS orchard leaf standard SRM 1571. The validity of the procedure has been established by comparative measurements of Cu and Zn with atomic absorption spectrophotometry. The significance of the results is discussed in view of their implications in health and disease.     

Melittin peptides exhibit different activity on different cells and model membranes

Melittin (MLT) is a lytic peptide with a broad spectrum of activity against both eukaryotic and prokaryotic cells. To understand the role of proline and the thiol group of cysteine in the cytolytic activity of MLT, native MLT and cysteine-containing analogs were prepared using solid phase peptide synthesis. The antimicrobial and cytolytic activities of the monomeric and dimeric MLT peptides against different cells and model membranes were investigated. The results indicated that the proline residue was necessary for antimicrobial activity and cytotoxicity and its absence significantly reduced lysis of model membranes and hemolysis. Although lytic activity against model membranes decreased for the MLT dimer, hemolytic activity was increased. The native peptide and the MLT-P14C monomer were mainly unstructured in buffer while the dimer adopted a helical conformation. In the presence of neutral and negatively charged vesicles, the helical content of the three peptides was significantly increased. The lytic activity, therefore, is not correlated to the secondary structure of the peptides and, more particularly, on the propensity to adopt helical conformation.     

Proline-rich antimicrobial peptides: potential therapeutics against antibiotic-resistant bacteria

The increasing resistance of pathogens to antibiotics causes a huge clinical burden that places great demands on academic researchers and the pharmaceutical industry for resolution. Antimicrobial peptides, part of native host defense, have emerged as novel potential antibiotic alternatives. Among the different classes of antimicrobial peptides, proline-rich antimicrobial peptides, predominantly sourced from insects, have been extensively investigated to study their specific modes of action. In this review, we focus on recent developments in these peptides. They show a variety of modes of actions, including mechanism shift at high concentration, non-lytic mechanisms, as well as possessing different intracellular targets and lipopolysaccharide binding activity. Furthermore, proline-rich antimicrobial peptides display the ability to not only modulate the immune system via cytokine activity or angiogenesis but also possess properties of penetrating cell membranes and crossing the blood brain barrier suggesting a role as potential novel carriers. Ongoing studies of these peptides will likely lead to the development of more potent antimicrobial peptides that may serve as important additions to the armoury of agents against bacterial infection and drug delivery.