Iranian Journal of Pharmaceutical Research
Volume:9 Issue: 1, winter2010

The bioavailability and intrinsic toxicity of many potential drugs affect their pharmacological profile and, in turn, their therapeutic efficacy and therefore, preventing them from late-stage pharmaceutical development. Hence, pharmaceutical industries are recently being forced to renew creatively their drug discovery programs and design more and better drug candidates for clinical development. Incorporation of nanotechnology at the early stage of drug development process could be considered as a potential source of new drug design strategies. During the past few decades, remarkable advances in particle engineering and design of nanoscale drug delivery systems have been occurred, such that recently, nanotechnology has been used successfully in the design of particulate systems with uniform particle size, desired surface characteristics and geometrical forms. The great advantage of nanotechnology is its potential capability of manipulating and modification of the arrangement of single atoms and molecules and creating unique structures with unique characteristics, leading to an improvement of membrane penetration, increase in solubility of poorly soluble drugs, increase in stability of biomolecules and their bioavailabilities and consequently an improvement in drug delivery efficiency. One of the most recent strategies proposed to incorporate nanotechnology principles is through the application of carbon nanotubes (CNTs), which leads to the modulation of undesired effects and creating new conjugates with promising and improved pharmacological profiles. CNTs have been proposed and actively explored as multipurpose innovative carriers for drug delivery and diagnostic applications. Their intrinsic physicochemical features enable covalent and non-covalent binding of several pharmaceutical entities and allow for rational design of novel candidate nanoscale structures for drug development. CNTs can be functionalized with different functional groups to carry simultaneously several moieties for targeting, imaging and therapy.

A topical preparation containing aceclofenac was developed using an o/w microemulsion system. Isopropyl myristate was chosen as the oil phase as it showed a good solubilising capacity. Pseudo-ternary phase diagrams were used to obtain the concentration ranges of the oil, surfactant (Labrasol) and co-surfactant (plurol oleique) for microemulsion formation. Five different formulations were formulated with various amount of the oil (5-25%), water (10-50%), and the mixture of surfactant and co-surfactant at the ratio of 4 (45-65%). In vitro permeability of aceclofenac from the microemulsions was evaluated using Keshary Chien diffusion cells with 0.45-µm cellulose acetate membrane. The amount of the aceclofenac permeated was analyzed by HPLC and the droplet size and zeta potential of the microemulsions was determined using a Zetasizer Nano-ZS. The mean diameters of the microemulsion droplets approximately ranged between 154 - 434 nm, and the permeability of aceclofenac incorporated into the microemulsion systems was 3 folds higher than that of the marketed formulation. These results indicate that the microemulsion system studied is a promising tool for percutaneous delivery of aceclofenac.

In the present investigation an attempt has been made to increase therapeutic efficacy, to reduce frequency of administration and to improve patient compliance by developing a sustained release matrix tablets of isosorbide-5-mononitrate. Sustained release matrix tablets of isosorbide-5-mononitrate were developed by using different drug: polymer ratios, such in F1 (1:0.75), F2 (1:1), F3 (1:1.5), F4 (1:1.75) and F6 (1:2). Xanthan gum was used as matrix former and microcrystalline cellulose as diluent. All the lubricated formulations were compressed, using 8mm flat faced punches. Compressed tablets were evaluated for uniformity of weight, content of active ingredient, friability, hardness, thickness, in vitro dissolution study using basket method and swelling index. Each formulation showed compliance with pharmacopoeial standards. Among all formulations, F5 showed a greater sustained release pattern of drug over a 12 h period with 92.12% of drug being released. The kinetic studies showed that drug release follows the Higuchi model (r2 =0.9851). Korsemeyer and Peppas equation gave an n-value of 0.4566, which was close to 0.5, indicating that drug release follows the Fickian diffusion. Thus, xanthan gum can be used as an effective matrix former to extend the release of isosorbide-5-mononitrate. No significant difference was observed in the dissolution profile of optimized formulation, using basket and paddle apparatus.

The aim of the present study was to prepare and evaluate an osmotically controlled mucoadhesive cup-core (OCMC) containing aceclofenac. A special technique was used while preparing an OCMC. Stability of OCMC was determined in natural human saliva, and it was found that both pH and device are stable in human saliva. OCMC was evaluated by weight uniformity, thickness, hardness, friability, swelling, mucoadhesive strength and in vitro drug release. Swelling index was higher with formulations containing hydroxypropyl methylcellulose (HPMC) K4M alone, and it decreases with its decreasing concentration in the OCMC. The in vitro drug release studies showed a release with the composition of formulation up to 12 h. The mechanism of drug release was found to be zero order kinetics with diffusion controlled drug release. It has shown significant anti-inflammatory activity (P<0.001) and no hypersensitive reaction. It can be concluded that by changing the content of OCMC system, a desire effect is generated and it overcomes the drawback associated with the conventional buccal adhesive tablet.

An agar well diffusion bioassay method for determination of clarithromycin in human plasma, using Micrococcus Luteus ATCC 9341 as the assay organism, was compared with a selective high-performance liquid chromatographic (HPLC) method with UV detection. Spiked plasma was used to prepare standard and control samples for both methods. The results of the bioassay analyses with spiked plasma samples were concordant by HPLC methods (R2 =0.871, P < 0.001).The Bland-Altman method also showed good agreement between the results of two methods. HPLC demonstrated an improved precision (0.88-19.86% versus 4.51-26.78%) and accuracy (99.27-103.42 % versus 78.52-131.19 %), compared to those of the bioassay method. The range of linearity obtained by both methods (from 62.5 to 3000 ng/ml for HPLC and from 250 to 3000 ng/ml for the bioassay) includes the range of concentrations of clarithromycin which are considered clinically relevant. However, comparison between HPLC and microbiological assays after oral administration of clarithromycin in healthy volunteers indicated significant differences between the two methods in mean plasma concentration–time profiles. The Bland-Altman method revealed no agreement between the two methods, which can be explained by the presence of active metabolites of clarithromycin in plasma.

Fluoride is recognized as an effective agent for dental caries prevention. Generally, the main source of fluoride intake is drinking water. In this study, fluoride content in 18 commercial brands of bottled waters was investigated. Six samples from each batch of 18 Iranian commercial brands of bottled waters were supplied. The fluoride content of samples was analyzed by Fluoride Ion Selective Electrode. The mean ± SD fluoride content of the bottled waters was 0.202 ± 0.00152 mg/L with a range from 0.039 to 0.628 mg/L which was lower than the accepted limits for fluoride content of drinking water (1 mg/L). This finding suggested that in the region which water has high fluoride content, drinking bottled water is preferred to drinking tap water, as it could lower the risk of fluorosis. However, the risk of dental caries increases in people who mainly drink bottled waters; thus, they should use fluoride supplements.

Quinolones are a large and widely consumed class of synthetic drugs. Expanded-spectrum quinolones, like ciprofloxacin are highly effective against Gram-negative bacteria, especially Escherichia coli. In E. coli the major target for quinolones is DNA gyrase. This enzyme is composed of two subunits, GyrA and GyrB encoding by gyrA and gyrB, respectively. Mutations in either of these genes cause quinolone resistance. Mutations in QRDR section of gyrA are more common in quinolone resistant clinical isolates. However, a mutation outside of this region was also reported. Thus, this study was aimed to provide more information on mutations sites in gyrA. For this purpose, spontaneous ciprofloxacin resistant mutants arisen in cultures of E. coli ATCC 25922 and MG1655 were isolated on LB agar containing ciprofloxacin. Next, the MICs of these clones were measured and the presence of mutation in gyrA was investigated. Results showed that the frequency of ciprofloxacin resistant mutants in cultures of E. coli strains was low. However, these mutants had different MICs, depending on the day of isolation. Most of ciprofloxacin-resistant mutants possess mutations in QRDR region and precisely at Ser-83. However, mutations outside of this region were also found at Tyr-50 and Ala-119. In conclusion, the presence of mutations at amino acids 50 and 119 suggests that in addition to QRDR section and Tyr-122, these sites are also essential for DNA gyrase activity.

Mebudipine is a new dihydropyridine calcium channel blocker, synthesized in our laboratory, for treatment of hypertension. It has shown a better efficacy than other drugs in this group. For assessing the risks of this drug, certain safety tests in the preclinical stage have been performed. In this study mutagenic effect of mebudipine was evaluated using Ames assay that could assess the mutagenicity of drugs and their metabolites using liver enzymes (S-9 mix). This procedure is approved as a predictive test, with a high predictive value. Salmonella TA102 (Ames assay) was used with and without S-9 in this study. For preparing S-9 mix, rat liver enzymes induced by phenobarbital were separated in KCl 0.154 M (0.154 M), as the solvent. Mebudipine was dissolved in polyethylenglycol 400. Mutagenicity test was performed in 6 doses from 39 µg to 1250 µg per every plate, in the presence and absence of the S-9 mix. The positive control sodium azide was dissolved in a dose of 5 µg/plate dissolved in polyethylenglycol 400 and negative control was polyethylenglycol 400 with no added agent. The colony counts of all doses in plates with S-9 were between 200-400 and in plates without S9 was between100-300. The colony counts in both states (with and without S-9) of all doses were in the range suggested by Ames assay for the safe drugs and were different from the positive control groups and equal to the negative controls. Mebudipine and its metabolites were not found to be mutagen on Salmonella TA102, based on Ames assay.

Statins have been reported to show preventive effect on nitrate tolerance in normal rats, but there are no reports on their effect in diabetic animals. In this study, diabetes was induced in male wistar rats by a single intraperitoneal injection of streptozotocin (45 mg/kg). Five groups of diabetic and five groups of normal rats were treated; groups 1 (of normal and diabetic rats) received atorvastatin (10 mg/kg/d p.o. for 8 weeks) and groups 2 received atorvastatin (10 mg/kg/d p.o. for last 3 days). Groups 3 and groups 4 were similar to groups 1 and 2 respectively, except that they received nitroglycerin (50 mg/kg/d, b.i.d. for last 3 days of the study). Groups 5 received neither atorvastatin nor nitroglycerin. After 8 weeks, relaxations to nitroglycerin (0.01 to 10 nM) and nitroprusside (0.01 to 10 nM) were determined on phenylephrine-preconstricted aortic rings. The relaxation response to nitroglycerin in diabetic and normal aorta were not significantly different. The results showed that 8 weeks treatment with atorvastatin prevents nitrate tolerance in diabetic and normal rats, but in nitrate tolerant animals, 3 days treatment with atorvastatin was not effective on protection against nitrate tolerance.

Tigecycline is a new glycylcycline antibiotic structurally similar to minocycline antibiotic. It has broad spectrum activity, including Staphylococcus aureus infections. This is the first study that evaluated the activity of Tigecycline against Staphylococcus aureus isolated from biological samples in Iran. In vitro activity of tigecycline against 160 Staphylococcus aureus including 99 methicillin-resistant S. aureus and 61 methicillin-susceptible S. aureus from inpatients at Imam Khomeini Hospital, Tehran, Iran was assessed. Bacterial susceptibility tests were performed by the disk diffusion method and also E-test for methicillin-resistant S. aureus isolates. All isolated had inhibition zone of ≥ 19 mm, with the minimum inhibitory concentration 50 (MIC50) and MIC90 of 0.19 and 0.5 μg/mL, respectively. The study results indicated that all methicillin-resistant S. aureus and methicillin-susceptible S. aureus isolates were susceptible to tigecycline.

The non-enzymatic carbamylation of low density lipoprotein (LDL) is a naturally occurring chemical modification of apolipoprotein B as a result of condensation between lysine residues and cyanate derived from urea. Carbamylated LDL is poorly recognized by LDL receptors and initiates different processes that can be considered proatherogenic. Thus, LDL carbamylation may contribute to the increased risk of atherosclerosis in patients with kidney failure. The objective of this study was to investigate in vitro effects of flavonoids on LDL carbamylation. LDL was isolated from plasma using ultracentrifuge technique with a single step discontinuous gradient. Then, cyanate was added to LDL and LDL carbamylation level was estimated in absence and presence of flavonoids by a colorimetric method at 530 nm. The results of this study showed that a number of flavonoids including rutin, catechin, morin, myricetin, kaempferol, taxifolin, luteolin, naringin and quercetin decreased LDL carbamylation in a dose dependent manner. Also, it was demonstrated that these nutrients decreased electrophoretic mobility of carbamylated LDL. Based on the results obtained in this study, it is suggested that flavonoids are able to inhibit LDL carbamylation (probably by scavenging cyanate ions) and thus, may have a role in ameliorating atherosclerotic risk of patients with kidney failure.

The antioxidant potential of crude methanol extract (CE) as well as chloroform (CF), ethyl acetate (EF) and n-butanol (NF) soluble fractions of Enhydra fluctuans Lour, which is widely used in indigenous system of medicine for different purposes, were studied. The antioxidant potential of extract/different fractions were evaluated using different in vitro antioxidant models. In addition, total amount of polyphenolics compounds, DPPH (1,1-diphenyl-2-picryl hydrazyl) radical, nitric oxide, superoxide anion, hydroxyl radical scavenging activities and reductive power of crude extracted its different fractions were determined. It was found that ethyl acetate fraction have maximum amount of polyphenolics compounds (179.7 ± 18.23 μg / mg pyrocatechol equivalent). This fraction was found more effective than crude extract and other fractions in all the above mentioned assays.

Many species of tea (Camellia sinensis) and cowslip (Echium amoenum) are used in Iranian traditional medicine. The aim of this study was to conduct the survey on the ability of Iranian black tea and cowslip extracts on secretion of tumor necrosis factor-alpha (TNF-alpha) by non-infected and infected mouse macrophages. A macrophage infection model with Legionella pneumophila and enzyme linked immunosorbent assay (ELISA) technique was used in this study. Research showed that the concentrations of TNF-alpha in non-infected and infected macrophage culture supernatant treated with various concentrations of Iranian black tea and cowslip extracts was significantly higher than the control. Various concentrations of cowslip (0.5, 5 and 50 µg/mL) had significantly a great effect on the induction of TNF-alpha secretion in comparison with the Iranian black tea extract (P < 0.0001). In conclusion, we demonstrated the ability of Iranian black tea and cowslip on the induction of TNF-alpha, which can exert an anti-L. pneumophila activity on macrophages at a low dose. However, further studies to elucidate the mechanism(s) of the induction of macrophages by Iranian black tea and cowslip as well as their potential inhibitory effects on the growth of infected cells and their possible antitumor effects should be carried out in future works.

Abortion is an important problem in obstetrics throughout the world. The common and standard method for pregnancy termination at first trimester is surgery (curettage). Nowadays، an effective method of pregnancy termination at first trimester is medical treatments. The aim of this study is to compare misoprostol alone or in combination with methotrexate for pregnancy termination at first trimester. This study is a randomized clinical trial. A total of 200 pregnant women at first trimester were randomizedly divided into two groups for termination of pregnancy. The first group received 800 µg vaginal misoprostol. If conceptus residual remained، the same dose of misoprostol was repeated. The second group received 50 mg/m² intramuscular methotrexate، and then 800 µg vaginal misoprostol was administered after 72 h. If conceptus residual remained، the same dose of misoprostol was repeated after 24 h. Abdominal ultrasonography was performed at seventh day for both groups. Should conceptus residual remained or if pregnancy continued، curettage was performed. The results were analyzed statistically in terms of chi-square، and student’s t-test، using the SPSS software. A P-value equal or smaller than 0. 05، was considered statistically significant. In this study، 83% of the first group and 81% of the second group had successful abortion. There was a significant correlation between the dose of misoprostol and abortion (P = 0. 001) and between type of pregnancy and need for curettage (P < 0. 000) in both groups، but there was no significant correlation between gestational age and the numberof doses administered (P = 0. 932). In conclusion it seems that pregnancy termination by misoprostol alone or in combination with methotrexate is a safe and cost-effective method.