DARU, Journal of Pharmaceutical Sciences
Volume:16 Issue: 4, Winter 2008

The inherent shortcomings of conventional drug delivery systems containing estrogens and the potential of nanoparticles (NPs) have offered tremendous scope for investigation. Although polymeric NPs have been used as drug carriers for many active agents, the use of appropriate polymer and method of NP preparation to overcome different challenges is very important. Poly lactide-co-glycolide (PLGA) NPs containing estradiol valerate were prepared by the modified spontaneous emulsification solvent diffusion method. Several parameters including the drug/polymer ratios in range of 2.5-10%, poly vinyl alcohol (PVA) in concentration of 0-4% as stabilizer and internal phase volume and composition were examined to optimize formulation. The size distribution and morphology of the NPs, encapsulation efficacy and in vitro release profile in phosphate buffer medium (pH 7.4) during 12 hrs were then investigated. The NPs prepared in this study were spherical with a relatively mono-dispersed size distribution. By adjustment of the process parameters, the size and the drug encapsulation efficacy as well as the drug release kinetics can be optimally controlled. The mean particle size of the best formula with encapsulation efficiency of 100% was 175 ± 19, in which release profile was best fitted to Higuchi''s model of release which showed that release mechanism was mainly controlled by diffusion of the drug to the release medium. According to the size and surface properties of the prepared particles, it may be concluded that they are a good formulation for non-parenteral routes of administration.

Background and the purpose of the study: In determination of the permeability of the intestinal wall by external perfusion techniques, several models have been proposed. In the present study three models were used for experimental results that differ in their convection and diffusion assumptions. Permeability coefficients for 13 compounds (metoprolol, propranolol, naproxen, ketoprofen, furosemide, hydrochlorothiazide, cimetidine, ranitidine, atenolol, piroxicam, antipyrine, ibuprofen and carbamazepine) with known human intestinal permeability values were determined in anaesthetized rats by different mass transfer models and plotted versus the observed human intestinal permeabilities. The calculated dimensionless wall permeability values were in the range of 0.37 - 4.85, 0.38-6.54 and 0.41-16.59 for complete radial mixing, mixing tank and laminar flow models respectively. The results indicated that all of the models work relatively well for our data despite fundamentally different assumptions. The wall permeabilities were in the order laminar flow > mixing tank > complete radial mixing. Although laminar flow model provides the most direct measure of the intrinsic wall permeability, it has limitations for highly permeable drugs such as ibuprofen. The normal physiological hydrodynamics is more complex and more investigation is required to find out the real hydrodynamics.

Background and the purpose of the study: A suitable high-performance liquid chromatography (HPLC) method for determination of celecoxib levels in plasma is of prime need for the pharmacokinetics and bioequivalence studies of celecoxib preparations. The present study describes a simple, rapid, sensitive, reliable, and economic HPLC method for determination of celecoxib in human plasma which is more feasible than reported celecoxib HPLC assays. The drug and internal standard were extracted using n-hexane /isoamyl alcohol (97:3) and analyzed on a C18 µ-Bondapak HPLC column with KH2PO4 (0.01M, pH= 4) - acetonitrile (60:40) as the mobile phase, at 260 nm. The method involved simple one-step liquid-liquid extraction procedure with extraction recovery of greater than 90%. The standard curve covering 0.01-2.0 μg/ml concentration range was linear. The coefficients of variation and relative errors for inter- and intra-day assay ranged from 5.67 to 9.83 and 0.35 to 7.89 %, respectively. HPLC assay was performed isocratically on a reversed-phase column with UV detection. By this method a limit of quantification of 10 ng/ml of a sample size of 0.5 ml is achieved which is comparable or even better than the reported methods. The developed method was applied to the analysis of celecoxib levels in plasma collected from healthy volunteers who participated in a pharmacokinetic study.

A new herbal drug setarud (IMODTM) containing selenium, carotene, and flavonoids, was expected to have positive effects on lipid metabolism and liver functions, due to the nature of its primary components. This study was designed to determine effectiveness of the drug in reducing the risk of development of diet-induced hypercholesterolemia in laboratory animals. Two groups of male rabbits (n=10 per group) as: intact and control groups on regular chow, were fed a high-cholesterol diet, and two experimental groups were maintained on the same diet and treated with different daily doses (0.02 g/kg and 0.04 g/kg) of setarud (brand name IMOD®, Pars Roos, Iran). The treatment groups were then compared with the intact and control groups and with one another for the effects of the drug which was determined by changes in blood sugar, serum lipid levels, and liver function tests. Results showed that drug had important benefits in alleviating the impact of high-cholesterol diet on serum lipids and liver function markers in drug-treated groups relative to hyperlipidemic controls (p < 0.001). A more favorable modification of total cholesterol and triglyceride levels and the atherogenic index was found in animals, which received 0.04 g/kg drug, as compared to the 0.02 g/kg dose group (p < 0.05). Assessment of serum total protein, albumin, transaminases, and bilirubin levels showed that no changes in liver function of control and drug-treated animals during the period of the study. From the results of this study it may concluded that setarud has dose-dependent positive effects on liver and lipid metabolism and may acts as an effective anti-hyperglycemic agent.

Setarud (IMODTM) is a new herbal drug that has demonstrated immune modulating activity in preliminary investigations. The aim of this study was to evaluate the potential of mutagenicity and genotoxic properties of Setarud following the guidelines of the Organization for Economic Co-operation and Development (OECD) for the Testing of Chemicals. Ames Salmonella/mammalian microsome mutagenesis assay was used to evaluate the ability of the drug and its metabolites to induce mutation in Salmonella tester strains. Setarud was applied in concentrations of 0.1-1000 µg/dish. The effect of the drug metabolites which were formed in the presence of rat liver microsomal fraction S9 was investigated using complete and incomplete microsomal activation mixtures, separately. Induction of dominant lethal mutations in spermatogenic stem cells of male mice was also assessed. In the Ames test, the drug preparation did not cause a significant increase in the number of revertant bacterial colonies as compared with negative control meaning that Setarud within the tested range did not exhibit mutagenic activity. The level of post-implantation losses and as a result the number of lethal mutations in germ cells at different stages of spermatogenesis in mice treated with Setarud was not statistically higher than that of control. Under experimental conditions which were employed, the drug was not mutagenic or genotoxic.

Background and the purpose of the study: Erica arborea L. (Ericaceae) has been used in Turkey folk medicine as a diuretic, urinary antiseptic and laxative. However, its other pharmacological effects have not been yet elucidated clearly. The aim of this study was to investigate analgesic effects of its methanolic (MeOH) extract in mice using formalin test, as a model of tonic inflammatory pain. The MeOH extract of aerial parts and its fractions (20, 40, 60, 80 and 100% MeOH in water) were prepared by maceration and solid phase extraction method respectively. Effects of the MeOH extract (10, 20 and 30 mg/kg, i.p.) and different fractions (5 mg/kg, i.p.) were compared with analgesic effects of the morphine (10 mg/kg, i.p.) and indomethacine (5 mg/kg, i.p.) as standard analgesic drugs. Results and major Results showed that the MeOH extract of E. arborea (10 mg/kg, i.p.) similar to the morphine (10 mg/kg, i.p.) and indomethacen (5 mg/kg, i.p.) decreased formalin-induced paw licking time,. Among the prepared-fractions of the MeOH extract, only fraction of 20% (5 mg/kg, i.p.) caused significant decrease in paw licking behavior. Moreover, the MeOH extract (10 mg/kg, i.p.) did not produce any motor deficit effects in rotarod test. From the results it may be concluded that the MeOH extract and faction of 20% of E. arborea have a good analgesic effects in formalin test.

Background and purpose of the study: Probable antiarrhythmic effects of Cynodon dactylon (L.) pers. (family Poaceae) against ischemia/reperfusion (I/R)-induced arrhythmias were investigated in isolated rat heart. The hearts were subjected to 30min regional ischemia followed by 30min reperfusion and perfused with hydroalcoholic extract of rhizome of C. dactylon (25, 50, 100 and 200µg/ml). During ischemia, the extract produced marked reduction in the number, duration and incidences of ventricular tachycardia (VT) at 25 and 50µg/ml (p<0.001 and p<0.01, respectively). Total number of ischemic ventricular ectopic beats (VEBs) were lowered by 25-100µg/ml (p<0.001, p<0.001 and p<0.05, respectively). At the reperfusion phase, C. dactylon (25 and 50µg/ml) decreased incidence of VT from 100% (control) to 13 and 33% (p<0.001 and p<0.05) respectively. Duration and number of VT and total VF incidence were also reduced at the same concentration (p<0.05 for all). Perfusion of the extract (25-100µg/ml) was markedly lowered reversible VF duration from 218±99sec to 0 sec, 0 sec and 10±5sec (p<0.01, p<0.01 and p<0.05) respectively. Moreover, C. dactylon (25 and 50µg/ml) decreased number of total VEBs from 349±73 to 35±17 (p<0.001) and 66±26 (p<0.01). In this study, it was also shown that perfusion of the extract produced a marked and concentration-dependent positive inotropic effect. The findings of this study indicate that C. dactylon produce protective effects against I/R-induced arrhythmias in isolated rat hearts probably by increase in the myocardial contractility and as a result by improvement of hemodynamic factors.

Background and purpose of the study: Amorphophallus campanulatus is widely distributed in Bangladesh, India, and Africa and the tuberous roots of the plant has many traditional uses and is an important source of biologically active compounds. In the present study in vitro antibacterial, antifungal and cytotoxic activities of 3,5-diacetyltambulin which is a flavonoid isolated from Amorphophallus campanulatus was studied. In vitro antibacterial and antifungal activities was evaluated by disc diffusion and MICs technique was determined by serial dilution technique. Cytotoxicity was determined against brine shrimp nauplii.Results and Major The compound showed significant antibacterial activities against four Gram-positive bacteria (Bacillus subtilis, Bacillus megaterium, Staphylococcus aureus, Streptococcus β-haemolyticus) and six Gram-negative bacteria (Escheichia coli, Shigella dysenteriae, Shigella sonnei, Shigella flexneri, Pseudomonus aeruginosa, Salmonella typhi). The MIC values against these bacteria ranged from 8 to 64 µg/ml but had weak antifungal activity against a number of fungi. In cytotoxicity determination, LC50 of the compound against brine shrimp nauplii was 10.02 μg/ml.

Swertia spp. (Gentianaceae) grow widely in eastern and southern Asian countries such as Japan, China and India and are used as traditional remedy for gastrointestinal complains because of their bitter principles. Several studies have been carried out on hypoglycemic, hepatoprotective, mono amino oxidase inhibitory and antidepressant effects of these plants and it has been shown that xanthones and iridoids are responsible for their activities.Purpose of the study: In order to gain better knowledge of endemic plants of Flora Iranica, Swertia longifolia Boiss. growing in the northern parts of Iran, was subjected to phytochemical studies. Dried and milled aerial parts of the plant were extracted with petroleum ether and ethanol of which results of petroleum ether extract has been reported previously. For purification of ethanol extract, it was acidified with acetic acid and subsequently extracted with chloroform and then with n-butanol. The n-butanol extract was analyzed using different chromatographic methods and the structures of the isolated components were established by means of spectroscopic techniques. Four components including an iridoid glycoside (loganic acid), a secoiridoid glycoside (gentiopicroside), a secoiridoid dilactone (gentiolactone) and a nucleoside (uridine) were isolated from n-butanol extract of the plant.Major Similar to other species of Swertia, iridoid and secoiridoid glycosides could be considered as major constituents of Swertia longifolia Boiss.

Background and the purpose of the study: The low affinity penicillin-binding protein (PBP) 5 of Enterococcus faecium is responsible for intrinsic resistance to beta-lactam antibiotics. This study was conducted to determine the MICs of ampicillin against E. faecium strains cultured from Iranian patients (n=54) in Tehran hospitals and to sequence the C-terminal ends of pbp5s from selected strains (n=15) in order to determine possible mechanism of resistance to ampicllin Initially, the minimum inhibitory concentrations (MICs) of ampicllin against 54 isolates of E. faecium were determined using broth macro-dilution assay. A PCR was designed to target pbp5 gene. The PCR products corresponding to the C-terminal ends of PBP5s for each strains (n=15) were sequenced. Up to 44% of isolates were highly resistant to ampicillin (MIC ³ 64 µg/ml). Amino acid substitutions were found at position number of 485 (Met 485 to A(T) and also an additional serine residue inserted just after Ser 466 among the high level resistant isolates (MIC ³ 64 µg/ml). Other substitutions were also found at Q461K and V586L in these strains. It appears that amino acid alternations near the SDN motif, mainly the amino acid at position 485, were responsible for high-level resistance to ampicillin. Other substitutions outside of this motif (n=7) had no observable effect on resistance.

Omeprazole (OMZ) is a substituted benzimidazole, which is used in the treatment of gastric acid related disorders. The aim of this study was the development and validation of a rapid, simple and reliable fluorimetric method for determination of OMZ in pharmaceutical formulations based on fluorescence quenching of Tb3+-1, 10-phenanthroline complex. For the determination of OMZ, aliquots of Tb3+, bis (2-ethylhexyl) sulfosuccinate sodium (AOT), 1,10-phenanthroline (phen) solutions (in optimal concentrations), aliquots of working OMZ solution and Tris-HCl buffer (pH 7.0) solution were added to 5 mL volumetric flasks. The mixture was then diluted with distilled water and allowed to stand for 30 min and the fluorescence intensity was then measured at 545 nm using an excitation wavelength of 300 nm. Matrix systems of OMZ (OMZ capsules with a nominal of 20 mg) were prepared by powdering and mixing the contents of ten capsules of OMZ. A portion of 10.0 mg of this powder was then accurately weighed and dissolved in about 10 mL of 0.1 M NaOH solution and filtered into a 100 mL volumetric flask. The residue was washed several times with water and solution was diluted to the mark. A suitable aliquot of this solution was applied for fluorimetric determination of OMZ. The recovery assay was carried out using the same procedure by addition of known amounts of OMZ. It was found that the fluorescence intensity of Tb3+-1, 10-phenanthroline complex can be greatly quenched by omeprazole in the presence of AOT. Under optimal conditions, the quenched fluorescence intensity was found to be proportional to the concentration of omeprazole in the range of 0.05-10 µg/mL. The detection limit was 0.016 µg/mL. The relative standard deviation values for 6 replicated determinations of 0.3 and 1.5 µg/mL of OMZ were 3.5 and 1.5 %, respectively, The RSD of intraday was 2.6 and that of interday was 3.4 % for 4 and 2 µg/mL of OMZ, respectively. Based on the obtained results, a simple, rapid and selective spectrofluorimetric method was developed for determination of omeprazole in its capsule formulations with excellent reproducibility and allowed the interference-free determination of OMZ in real samples.

Background and purpose of the study: The vasorelaxant action of the dihydropyridines (DHPs) provides many useful clinical indications. However, their negative effects on cardiac contractility is still of a great concern especially in patients with heart failure. Design and synthesis of dual action compounds, i. e. smooth muscle calcium channel antagonist/cardiac muscle calcium channel agonist provides better and safer compounds particularly in patients with compromised cardiac contractility. In the present study, dual cardioselective Ca2+ channel agonists / vascular selective smooth muscle Ca2+ channel antagonists as third generation of DHP drugs were synthesized by a reported method. Synthetic procedure involved condensation of isopropyl-3-aminocrotonate with nitroacetone and 1-methyl-5-nitroimidazole2-carboxaldehyde and condensation of alkylacetoacetates with 3-aminocrotonitryl and 1-methyl-5-nitro-1H-imidazole-2-carbaldehyde for the preparation of 1,4-Dihydo-2,6-dimethyl-3-nitro and cyano-4-(1-methyl-5-nitro-1H-imidazol-2-yl)-5-pyridinecarboxylates, respectively. The in vitro effects of the synthesized compounds were evaluated on longitudal Smooth Muscle (GPILSM) and Guinea Pig Left Atrium (GPLA) preparations and finally, their conformations and structure-activity relationships were assessed.Results and major All compounds showed calcium channel antagonist activity on isolated guinea pig ileum and some of them showed calcium channel agonist effects (or positive inotropic effect instead of calcium channel agonist effect) on isolated guinea-pig left atrium. QSAR and conformational analyses showed that conformation and charge of aryl substituents at C4 position have a main role in antagonistic activity while carbonyl group at C5 position plays an important role in agonistic effects.