DARU, Journal of Pharmaceutical Sciences
Volume:12 Issue: 1, Spring 2004

Abstract: As important therapeutic drug targets, matrix metalloproteinases (MMPs) have recently attracted great interest in the search for potent and selective inhibitors using computer-aided molecular modelling and docking techniques. Availability of more than 60 X-ray crystal structures or NMR solution structures related to MMPs in Protein Data Bank (PDB) of which more than half of them are in complex with various MMP inhibitors (MMPIs), provides a great opportunity for docking studies. In this study AutoDock 3.0.5 along with its LGA algorithm were used for automated flexible ligand docking of 32 MMPI-MMP complexes and docking accuracy and reliability of the estimated inhibition constants were evaluated. Twenty-six out of 32 docks had RMSD less than 3.0 Å which is considered as well-docked, however, for the most of the cases (15 out of 27), predicted pKi values were considerably overestimated in comparison to experimental values. To improve pKi prediction regarding MMPI-MMP complexes, inclusion of at least one such a complex in calibration of empirical free energy function in the next release of AutoDock is highly recommended.

Abstract: In order to investigate the effect of hydroxyl group containing tablet excipients on the duration of adhesion of mucoadhesive polymers, discs containing Carbopol 934 (C934), polycarbophil (PC), sodium carboxymethyl cellulose, hydroxypropylmethyl cellulose (HPMC), tragacanth (trag.) and sodium alginate (Na alg.), either alone or in the presence of various amounts of excipients were prepared. The duration of adhesion of the prepared discs were determined in pH 7.0 phosphate buffer at 37°C. All the excipients examined reduced the duration of adhesion and the relative durability of the polymer containing discs. HPMC discs despite showing the longest duration of mucoadhesion, suffered the greatest reduction in adhesive properties in the presence of excipients which were examined. Following HPMC, Na alg. and then trag. discs showed the greatest sensitivity to the presence of excipients. The least reduction in the duration of adhesion was observed with PC and C934. Among the excipients tested, spray-dried lactose produced the greatest reduction in the duration of adhesion, followed by polyethylene glycol 6000 and pregelatinized starch. The smallest reduction in the adhesive properties of the test polymers was due to talc powder. Hence, it seems that addition of the tablet excipients adversely reduce the adhesive properties of mucoadhesive dosage forms, which should be carefully considered during their formulation.

Abstract: Maternal hyperglycemia causes delay in early stages of embryonic growth and development, higher incidence of congenital malformations and spontaneous miscarriage compared with those of non-diabetic conditions. High glucosis tratogenicity seems to be related to reduction of Nitric Oxide production (NO) in hyperglycemic condition. In order to test this hypothesis, 2-cell stage embryos of normal mice were cultured with high concentration of glucose (30mM) and different concentrations of L-arginine (5,10,20 mM) or L-NAME, an NO syntase (NOS) inhibitor. In the end of culture, blastocysts were stained by by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) technique and apoptotic cells were detected by using a Fluorescence microscope. Finally the amount of nitrite in the cultured media was assayed by Griess method. The results indicated that high glucose reduces Nitric Oxide production by preimplantation embryos and increases apoptosis of embryonic cells, but 5-20mM of L-arginine significantly increases Nitric Oxide production and decreases apoptosis. On the contrary L-NAME significantly inhibits the development of pre-implantation embryos. In conclusion, this study indicated that reduced nitric oxide production in high glucosis condition is a main factor for embryonic damage, and supplementation of high glucose media with L-arginine has an important role in prevention of high glucosis embryotoxicity

Abstract: The protective and anti-inflammatory effects of azo and azo-linked polymeric prodrugs of 5-aminosalicylic acid (5-ASA) on acetic acid induced colitis in rats were investigated. Three azo prodrugs; 4,4 -dihydroxy-azobenzene-3-carboxilic acid (azo compound I), 4-hydroxy-azobenzene-3,4-dicarboxilic acid (azo compound II), 4,4-dihydroxy-3-formyl-azobenzene-3-carboxylic acid (azo compound III) and their polyethylene glycol (PEG 6000) derivatives were synthesized. Rats were pretreated orally (1 hour prior to induction of colitis) with sulfasalazin (300 mg/kg), azo compounds I, II, III and polyethylene glycol conjugates of azo compounds II and III in doses which had the same amount of 5-ASA as sulfasalazin contains. The colonic damage was examined 24 hours later and characterized by gross microscopic injury and colonic edema. Among prodrugs only azo compound III (215 mg/kg) produced a significant (p<0.01) protective effect against colonic injury comparable with sulfasalazin. Doubling the dose (430 mg/kg) showed more anti-colitis effects. Polyethylene glycol conjugate of azo compounds II and III also showed reduction in the extent of the cell death and tissue disorganization similar to sulfasalazin. While neither sulfasalazin, nor azo compound II and its PEG polymer produced anti-edema effects, both azo compound III and its PEG polymer decreased colon edema significantly (p<0.05). Histological examinations also indicated a marked reduction in tissue injury and inhibition in neutrophil infiltration in rats treated with azo compound III and PEG conjugates of azo compounds II and III. Results of this investigation provide experimental evidence supporting new cytoprotective, anti-inflammatory and anti-edema properties of the azo derivatives of 5-ASA and their PEGylated prodrugs.

Abstract: Antagonists of various components of the renin-angiotensin system have been the subject of many studies for the control of blood pressure. Compounds with a phenoxyphenylacetic acid moiety that mimic the structure of losartan which is a powerful competitive antagonist of angiotensin receptor, have shown to be effective. In this study, the affinity of some 2-alkylthio-1-[4-(N-α-ethoxycarbonylbenzyl)aminobenzyl]-5-hydroxymethyl imidazoles for the human AT1 receptor was assessed in a radioligand binding assay. It was found that an alkyl chain of appropriate length would be most suitable if situated on the imidazole ring. Furthermore, variations of the lower phenyl rings demonstrated that introduction of a methyl group in this position will account for the most desired effect.

Abstract: Achillea santolina, a common variety of Achillea in Golestan province of Iran has been used in traditional medicine for its anti-inflammatory properties. The effect of hydroalcoholic extract (300 mg/kg/day Intraperitoneally, for 20 days) of Achillea santolina on the spermatogenesis of mice was studied by the evaluation of morphologic characteristics by light microscope. The alterations observed were disorganized germ epithelium, exfoliation of immature germ cells, germ cell necrosis and increased number of metaphasfis in germinal epithelium of seminiferous tubules. We concluded that hydroalcoholic extract of Achillea santolina 300mg/kg/day intraperitoneally for 20 days as a different variety of Achillea has antispermatogenic effect similar to Achillea millefolium on mice.

Abstract: Human plasma proteins are important for therapy or prophylaxis of human diseases. Due to the preparation of human plasma proteins from human plasma pools and risk of contamination with human viruses, different viral reduction treatments such as: pasteurization, solvent/detergent, dry heat treatment, steam treatment, beta-propiolactone/UV and nanofiltration have been implemented. As pasteurization can be performed for liquid protein, this method (a 10-hour heat treatment of the aqueous solutions at 60°C) was introduced into the manufacturing procedure of IgM-enriched immunoglobulin, to improve its safety further. The efficiency of this method for inactivation of viruses was evaluated by the use of Foot-and-Mouth Disease Virus (a non-enveloped virus) and Infectious Bovine Rhinotracheitis (IBR) Virus (a lipid-enveloped virus). Pasteurization inactivated Foot-and-Mouth Disease Virus by 7 log10 and for IBR Virus by 5log10. These findings show a significant added measure of virus safety associated with pasteurization of IgM-enriched immunoglobulin preparation.

Abstract: It is well known that the modification of oligosaccharide moieties of the cell surface glycoproteins modulates the adhesion and metastatic potential of several cancerous cell lines. Based on this knowledge, the anti-metastatic property of Daphne mucronata crude extract and one of its newly characterized active component, Gnidilatimonoein, were evaluated in wehi-164 cells by measuring their adhesion to fibronectin coated plates, relative to Castanospermine and Tunicamycin treated cells.Twenty four hours after treatment of the cells with the plant crude extract (equivalent to 0.54 mg of the plant leaves powder/ml), Gnidilatimonoein (0.94 nM), Castanospermine (2.6 µM) and/or Tunicamycin (2.4 µM), their attachment to fibronectin-coated wells were depressed, by 24%, 30%, 26% and 58%, respectively. This data may classify the new anticancer compound, Gnidilatimonoein, as a strong glycosylation inhibitor.