فهرست مطالب

Pharmaceutical Research - Volume:16 Issue: 2, 2017
  • Volume:16 Issue: 2, 2017
  • تاریخ انتشار: 1396/03/24
  • تعداد عناوین: 47
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  • Mohadeseh Hashemi, Azadeh Haeri, Hamid Keshvari, Simin Dadashzadeh* Pages 413-422
    Glaucoma is a common progressive eye disorder and the treatment strategies will benefit from nanoparticulate delivery systems with high drug loading and sustained delivery of intraocular pressure lowering agents. Niosomes have been reported as a novel approach to improve drug low corneal penetration and bioavailability characteristics. Along with this, poor entrapment efficiency of hydrophilic drug in niosomal formulation remains as a major formulation challenge. Taking this perspective into consideration, dorzolamide niosomes were prepared employing two different loading methodologies (passive and remote loading methods) and the effects of various formulation variables (lipid to drug ratio, cholesterol percentage, drug concentration, freeze/thaw cycles, TPGS content, and external and internal buffer molarity and pH) on encapsulation efficiency were assessed. Encapsulation of dorzolamide within niosomes increased remarkably by the incorporation of higher cholesterol percentage as well as increasing the total lipid concentration. Remote loading method showed higher efficacy for drug entrapment compared to passive loading technique. Incorporation of TPGS in bilayer led to decrease in EE, however, retarded drug release rate. Scanning electron microscopy (SEM) studies confirmed homogeneous particle distribution and spherical shape with smooth surface. In conclusion, the highest encapsulation can be obtained using phosphate gradient method and 50% cholesterol in Span 60 niosomal formulation.
    Keywords: Niosome, glaucoma, dorzolamide, thin film hydration method, phosphate gradient method
  • Hamid Reza Moghimi *, Mahsa Narenji, Mohammad Reza Talaee Pages 423-431
    Liposomes are used widely as drug delivery systems in different forms including nanosuspensions, osmotic pumps, infusion pumps and IV injections. Some of these systems (e.g. infusion or osmotic pumps) might stay stagnant for a long time during or before administration, and therefore, might face phase separation. In spite of these, there is no data available about the behavior of liposomal systems upon stagnation in such drug delivery systems. As a part of a series of investigations on convective flow and stagnation of liposomes, the current work represents the effects of charge on liposomes separation upon stagnation.
    Positive, negative and neutral liposomes, with zeta potentials of , -50 and 1.4 mV respectively, were prepared and encountered gravity (separating force) in a designed sedimentation model. Samples were collected over 25 hrs and their D0.5 (diameter which half of the particles are smaller than), particle size distribution and phospholipid contents were evaluated. The ratio of the D0.5 in the last to the first sample, (Separation Factor) for positive, negative and neutral liposomes were calculated to be 1.00 (no separation), 0.98 (no separation) and 0.33 (separation) respectively. The same trend was observed for lipid contents and particles population. These data show that liposomes’ charge affect their separation under gravity and is a very important factor in their uniformity upon storage, pre-administrational steps and even during administration in systems such as infusion pumps.
    Keywords: Liposomes, Charge, Zeta potential, Particle size, Sedimentation, Storage, Separation
  • Mitra Jelvehgari *, Parastoo Tofighi, Saieedeh Soltani, Seyed Hassan Montazam, Seyed Ataollah Montazam Pages 432-441
    Background
    Tolmetin (Tol) is a pyrrole acetic acid derivative that acts as a highly effective topical anti-inflammatory agent. Topical administration of Tol is effective for the management of ocular inflammations.The aim of this study was to formulate and improve a topical ophthalmic delivery system of Tol.
    Materials And Methods
    In the present study, ocular inserts of Tol were prepared using hydroxypropyl methylcellulose (HPMC) and carbomer 934p (CP). Ocular films were prepared with the objective of reducing the frequency of administration and obtaining controlled release to improve the anti-inflammatory drug delivery. Ocular films were subjected to investigations for their physical and mechanical properties, swelling behaviors, ex vivo bioadhesion, and in vitro drug permeability.
    Results
    The physicochemical, bioadhesive, and swelling properties of films were found to vary significantly depending on the type and amount of polymers used and their combinations. The mixture of HPMC and CP films exhibited greater bioadhesion and showed higher ocular retentive time than the HPMC films. CP addition to the films significantly affected the properties of ocular inserts. HPMC to CP ratio (6:2.5) of ocular inserts sustained drug release for the longest span of 4 h.
    Conclusion
    Tol can therefore be developed as an ocular insert delivery system for the treatment of ocular inflammation.
    Keywords: Hydroxypropyl methylcellulose, Tolmetin, Carbopol 934p, Film, Ocular
  • Hoda Bahmanof, Simin Dadashzadeh, Afshin Zarghi, Alireza Shafaati, Mohsen Foroutan* Pages 442-450
    Coxibs such as celecoxib, rofecoxib and valdecoxib are introduced as selective COX-2 inhibitors to the market. It has been reported that inhibition of COX-2 beside traditional effects of NSAIDs, reduces the risk of colorectal, breast and lung cancers and slow the progress of Alzheimer’s disease. Zarghi et al. reported 8-benzoyl-2-(4-(methylsulfonyl)phenyl)quinoline-4-carboxylic acid (AZGH 102) as a novel compound with similar IC50 to celecoxib besides improved selectivity index (COX-1/COX-2 inhibitory potency) in comparison with celecoxib.
    In this study the physicochemical properties of AZGH 102 such as solubility, log P and stability was evaluated and the pharmacokinetic characteristics of this compound following intravenous (10 mg/kg), and oral administration (20 mg/kg), to male and female Wistar rats were investigated.
    As the data demonstrated the AZGH 102 classified as lipophil compound and had suitable stability. This derivative absorbs and distributes faster in female than male. The AUC 0-∞, absolute bioavailability, Cl and Vd were different in both sexes.
    According to the obtained data the AZGH 102 has a sex dependent pharmacokinetic in Wistar rats.
    Keywords: pharmacokinetic, sex-dependent, ketoprofen, selective COX-2 inhibitors, AZGH 102
  • Wen H. Lim *, Hui M. Er, Choy S. Lee, Shew F. Wong, Yann Jean Tan Pages 451-461
    Palm-based lipid nanoparticle formulation loaded with griseofulvin was prepared by hot homogenisation and a solvent-free method. The optimum griseofulvin loaded lipid nanoparticles were prepared via stages of optimisation, such as high pressure homogenisation (HPH) parameters, lipid and surfactant screening and selection of suitable lipid to surfactant ratios; followed by photon correlation study. A HPLC method has also been validated for the drug loading capacity study. The optimum HPH parameter was determined to be 1500 bar with 5 cycles and among the lipid based materials; Lipid C (triglycerides) was selected for the preparation of lipid nanoparticles. Tween 80 was chosenfrom the Tween series surfactantsfor its highest saturated solubility of griseofulvinat 53.1 ± 2.16 µg/mL. The optimum formulation of the griseofulvin loaded lipid demonstrated nano range particle size (179.8 nm) withintermediate distribution index (PDI) of 0.306, zeta potential of -27.9 mV and drug loading of 0.77%. The formulation was stable upon storage for 1 month at room temperature (25ºC) and higher temperature (45ºC) with consistent drug loading capacity.
    Keywords: palm-based lipid, lipid nanoparticles, griseofulvin
  • Mehdi Maham *, Rouhollah Karami-Osboo Pages 462-470
    The application of Pd/Fe3O4 nanoparticles (NPs) for the adsorption of sulfathiazole from urine samples prior to high performance liquid chromatography-ultraviolet detection was studied. Pd/Fe3O4 NPs were synthesized using plant extract. Possible impact parameters in the extraction process such as the magnetic adsorbents amount, extraction time, sample pH and desorption conditions were investigated and optimized. Under the optimum conditions, the detection and quantification limits were 10 and 30 ng mL−1, respectively. The relative standard deviation for five measurements of 100 ng mL-1 of STZ was 5.8 %. The proposed method was used to the analysis of different urine samples, and acceptable recoveries in the range of 87.6 – 101.3% were obtained. These results indicated that biosynthesized Pd/Fe3O4 NPs can be used as an efficient adsorbent for extraction of sulfathiazole from urine samples.
    Keywords: Extraction, Biosynthesis, Magnetic nanoparticles, Urine, HPLC-UV
  • Farzaneh Sotoudegan, Mohsen Amini, Mehrdad Faizi, Reza Aboofazeli * Pages 471-477
    A rapid, simple and reproducible HPLC method was developed and validated for the analysis of nimodipine (NM) and/or its metabolite, oxidized nimodipine (OX–NM) in rat cerebrospinal fluid (CSF) and artificial CSF. The NM and OX–NM were eluted in less than 10 min with no interferences from the endogenous CSF peaks. Analysis was carried out on a Eurospher Performance (RP-C18, 250 × 4.6 mm) column and UV detection at 236 nm. The mobile phase consisted of acetonitrile and water (70:30 v/v, respectively) with a flow rate of 1 mL/min. Limit of detection was 0.1 μg/mL for OX-NM. The calibration curve was linear over the concentration range of 0.5-10 µg/mL and analytical recovery was more than 95%. The coefficients of variation for intra-day and inter-day assays were less than 5%.
    Keywords: Nimodipine, Nimodipine oxide, HPLC, Cerebrospinal fluid, Polymeric micelle
  • Hamid Reza Akbari-Hasanajni *, Mahmoud Reza Sohrabi Pages 478-489
    Simultaneous spectrophotometric estimation of Fluoxetine and Sertraline in tablets were performed using UV–Vis spectroscopic and Artificial Neural Networks (ANN). Absorption spectra of two components were recorded in 200–300 (nm) wavelengths region with an interval of 1 nm. The calibration models were thoroughly evaluated at several concentration levels using the spectra of synthetic binary mixture (prepared using orthogonal design). Three layers feed-forward neural networks using the back-propagation algorithm (B.P) has been employed for building and testing models. Several parameters such as the number of neurons in the hidden layer, learning rate and the number of epochs were optimized.The Relative Standard Deviation (RSD) for each component in real sample was calculated as 1.06 and 1.33 for Fluoxetine and Sertraline, respectively. The results showed a very good agreement between true values and predicted concentration values. The proposed procedure is a simple, precise and convenient method for the determination of Fluoxetine and Sertraline in commercial tablets.
    Keywords: Fluoxetine, Sertraline, Artificial Neural Networks(ANN), Spectrophotometric, Chemometrics
  • Maryam Bavand Savadkouhi, Hossein Vahidi, Abdul Majid Ayatollahi, Shirin Hooshfar, Farzad Kobarfard* Pages 490-497
    A new, rapid, economical and isocratic reverse phase high performance liquid chromatography (RP-HPLC) method was developed for the determination of eptifibatide acetate, a small synthetic antiplatelet peptide, in bulk drug substance and pharmaceutical dosage forms. The developed method was validated as per of ICH guidelines. The chromatographic separation was achieved isocratically on C18 column (150 x 4.60 mm i.d., 5µm particle size) at ambient temperature using acetonitrile (ACN), water and trifluoroacetic acid (TFA) as mobile phase at flow rate of 1 ml/min and UV detection at 275 nm. Eptifibatide acetate exhibited linearity over the concentration range of 0.15-2 mg/ml (r2=0.997) with limit of detection of 0.15 mg/ml. The accuracy of the method was 96.4-103.8%. The intra-day and inter-day precision were between 0.052% and 0.598%, respectively. The present successfully validated method with excellent selectivity, linearity, sensitivity, precision and accuracy was applicable for the assay of eptifibatide acetate in bulk drug substance and pharmaceutical dosage forms.
    Keywords: Eptifibatide acetate, HPLC-UV, Determination, Drug substance, Formulation
  • Tamer Awad Ali *, Gehad G. Mohamed Pages 498-512
    This article is focused on the determination of lidocaine hydrochloride as a local anaesthetic drug. A potentiometric method based on modified screen-printed and modified carbon paste ion-selective electrodes was described for the determination of lidocaine hydrochloride in different pharmaceutical preparations. It was based on potentiometric titration of lidocaine hydrochloride using modified screen-printed and carbon paste electrodes as end point indicator sensors. The influences of the paste composition, different conditioning parameters and foreign ions on the electrodes performance were investigated and response times of the electrodes were studied. The electrodes showed Nernstian response of 58.9 and 57.5 mV decade-1 in the concentration range of 1×10-7–1×10-2 and 6.2×10-7–1×10-2 mol L-1 for modified screen-printed and carbon paste electrodes, respectively. The electrodes were found to be usable within the pH range of 2.0–8.0 and 2.0-7.5, exhibited a fast response time (about 6 and 9s), low detection limit (1×10-7 and 6.2×10-7 mol L-1), long lifetime (6 and 4 months) and good stability for modified screen-printed (Electrode VII) and carbon paste electrodes (Electrode III), respectively. The electrodes were successfully applied for the determination of lidocaine hydrochloride in pure solutions, pharmaceutical preparation and biological fluids (urine and serum) samples. The results obtained applying these potentiometric electrodes were comparable with British pharmacopeia. The method validation parameters were optimized and the method can be applied for routine analysis of lidocaine hydrochloride drug.
    Keywords: Modified screen-printed electrode, Modified carbon paste electrode, Lidocaine hydrochloride, Pharmaceutical preparation, urine, serum
  • Amirhossein Sakhteman, Najmeh Edraki, Bahram Hemmateenejad, Ramin Miri, Alireza Foroumadi, Abbas Shafiee, Mehdi Khoshneviszadeh * Pages 513-524
    The IL-1β play a major role in inflammatory disorders and IL-1β production inhibitors can be used in the treatment of inflammatory and related diseases. In this study, quantitative relationships between the structures of 46 pyridazine derivatives (inhibitors of IL-1β production) and their activities were investigated by Multiple Linear Regression (MLR) technique Stepwise Regression Method (ES-SWR). The genetic algorithm (GA) has been proposed for improvement of the performance of the MLR modeling by choosing the most relevant descriptors. The results show that eight descriptors are able to describe about 83.70% of the variance in the experimental activity of the molecules in the training set. The physical meaning of the selected descriptors is discussed in detail. Power predictions of the QSAR models developed were evaluated using cross-validation, and validation through an external prediction set. The results showed satisfactory goodness-of-fit, robustness and perfect external predictive performance. The applicability domain was used to define the area of reliable predictions. Furthermore, the in silico screening technique was applied in order to predict the structure and potency of new compounds of this type using the proposed QSAR model.
    Keywords: QSAR, IL-1? Pyridazine, in silico screening, MLR
  • Somaye Akbari, Tannaz Zebardast, Afshin Zarghi *, Zahra Hajimahdi Pages 525-532
    COX-2 inhibitory activities of some 1,4-dihydropyridine and 5-oxo-1,4,5,6,7,8-hexahydroquinoline derivatives were modeled by quantitative structure–activity relationship (QSAR) using stepwise-multiple linear regression (SW-MLR) method. The built model was robust and predictive with correlation coefficient (R2) of 0.972 and 0.531 for training and test groups, respectively. The quality of the model was evaluated by leave-one out (LOO) cross validation (LOO correlation coefficient (Q2) of 0.943) and Y-randomization. We also employed a leverage approach for the defining of applicability domain of model. Based on QSAR models results, COX-2 inhibitory activity of selected data set had correlation with BEHm6 (highest eigenvalue n. 6 of Burden matrix/weighted by atomic masses), Mor03u (signal 03/unweighted) and IVDE (Mean information content on the vertex degree equality) descriptors which derived from their structures.
    Keywords: COX-2 inhibitors, 1, 4-dihydropyridine, hydroquinolines, MLR, QSAR
  • Habib Motieghader, Sajjad Gharaghani, Yosef Masoudi-Sobhanzadeh, Ali Masoudi-Nejad * Pages 533-553
    Feature selection is of great importance in Quantitative Structure-Activity Relationship (QSAR) analysis. This problem has been solved using some meta-heuristic algorithms such as: GA, PSO, ACO, SA and so on. In this work two novel hybrid meta-heuristic algorithms i.e. Sequential GA and LA (SGALA) and Mixed GA and LA (MGALA), which are based on Genetic algorithm and learning automata for QSAR feature selection are proposed. SGALA algorithm uses advantages of Genetic algorithm and Learning Automata sequentially and the MGALA algorithm uses advantages of Genetic Algorithm and Learning Automata simultaneously. We applied our proposed algorithms to select the minimum possible number of features from three different datasets and we observed the MGALA and SGALA algorithms have the best outcome independently and in average compared to other feature selection algorithms. Through comparison of our proposed algorithms we deduced that the rate of convergence to optimal result in MGALA and SGALA algorithms is better than the rate of GA, ACO, PSO and LA algorithms. In the end, the results of GA, ACO, PSO, LA, SGALA, and MGALA algorithms were applied as the input of LS-SVR model and the results from LS-SVR models showed that the LS-SVR model has more predictive ability with the input from SGALA and MGALA algorithms than the input from all other mentioned algorithms. Therefore the results have corroborated that not only is the predictive efficiency of proposed algorithms better, but their rate of convergence is also superior to the all other mentioned algorithms.
    Keywords: QSAR, Feature Selection, Genetic Algorithm, Learning Automata, Drug Design
  • Edris Valadbeigi *, Shahram Ghodsi Pages 554-564
    A series of N-[2-(8-metoxy-2H-chromen-2-one)ethyl] piperazinyl quinolones containing a carbonyl related functional groups (oxo or oxyimino) on the ethyl spacer of coumarin and piperazin rings was synthesized and studied for their antibacterial and antifungal activities . The synthesis of compounds (6a-6l) was achieved through the versatile and efficient synthetic route that involved reaction of quinolones with appropriately α-bromo ketone or α-bromo oxime derivatives (2, 2a-c). The structures of the new compounds were confirmed by IR, Mass, 1H-NMR and 13C-NMR spectra. More good activities against gram-positive and gram-negative are shown in all compounds. Antibacterial screening of compounds 6a–l against gram-positive and gram-negative bacteria reveals that compounds 6g, 6h and 6i exhibit the most potent in-vitro antibacterial activity. The antifungal data reveals that all compounds have shown weak antifungal activity as compared to Nistatin.
    Keywords: Antimicrobial, Chemical synthesis, Coumarin, Piperazin derivative, Quinolones
  • Ahmad Reza Massah *, Ahmad Pesaran Seiied Bonakdar, Farzaneh Vafaei, Mahbobeh Farokhpour, Mohammad Hossein Nasr Esfahani Pages 565-568
    Chalcones, or 1,3–diaryl–2–propen–1–ones, one of the major classes of natural products and posses many useful properties like anticancer, antibacterial, antifungal, anti–inflammatory, antimalarial and anti–diabetic activity. We report in this communication the synthesis and anticancer study of a number of novel chalcone sulfonamides. Our results indicate that the synthesis of chalcone sulfonamide derivatives from the corresponding sulfonyl chlorides proceeds in the absence of solvent at room temperature, with good yields and high purity in relatively short reaction times and according to the principles of green chemistry. All the newly synthesized compounds were assayed for their in vitro anticancer activity against MCF-7. Most of the tested compounds showed anticancer activity less than Tamoxifen except compound 4. This chalcone sulfonamides containing 4–nitrophenyl and aryl sulfonamide group substituted with 4-methoxy (4) showed better anticancer activity than others.
    Keywords: Anticancer activity, Chalcone, Sulfonamide
  • Keyu Zhang *, Chunmei Wang, Xiaoyang Wang, Haihong Zheng, Juan Zhao, Mi Wang, Sui Xiao, Chenzhong Fei, Wenli Zheng, Lifang Zhang, Feiqun Xue Pages 569-585
    To investigate the cytotoxicity mechanism of quinocetone from the perspective of chemical structure, quinocetone and other new quinoxaline-1,4-dioxide derivatives were synthesized, and evaluated for their activities, and analysed for the metabolic characteristics. Quinocetone and other new quinoxaline-1,4-dioxide derivatives were synthesized, and evaluated for their activities, and analysed for the metabolic characteristics. The synthetic route started from 2-nitroaniline which was reacted with 3-bromopropanoic acid followed by the reaction of acetylacetone to afford 2-acetyl-3-methylquinoxaline-1,4-dioxide. The aldol condensation of the later compound with aromatic aldehydes led to the formation of the quinocetone structure similar compounds. A number of prepared derivatives exerted antimicrobial activities and cytotoxicity potency. Analysis of metabolic pathways in vitro displayed 2-propenyl and N→O groups were the major sites. The results suggested 2-propenyl group exert important role in cytotoxicity of quinocetone and is another major toxiccophore for quinocetone, and different electronic substituents in arylidene aryl ring could affect the electronic arrangement of 2-propenyl and N→O groups to chang the cytostatic potency.
    Keywords: quinocetone, 2-propenyl moiety, cytotoxicity mechanism, toxiccophore, Synthesis
  • Maryam Iman, Atefeh Saadabadi, Asghar Davood *, Hamed Shafaroodi, Ali Nikbakht, Abdollah Ansari, Masood Abedini Pages 586-595
    A series of compounds related to ameltolide were studied for anticonvulsant potential in the subcutaneous pentylenetetrazol (sc Ptz) test in mice. These compounds were synthesized and characterized by TLC followed by IR and H1NMR. In vivo screening data acquired indicate that most of analogs have the ability to protect against PTZ-induced seizure. Phenytoin (PHT) was employed as the reference prototype antiepileptic drug. All compounds exerted their maximal effects 30 min after administration. Out of the 6 compounds, compound 2 at 40 mg/kg dose is more potent than phenytoin (reference drug) on clonic seizure. Using a model of the open pore of the Na channel, docking study was performed by AutoDock4.2 program. Docking studies has revealed that these compounds are stabilized through at least one hydrogen bond rises from ketone of phthalimide and residue Thr-87 of domain G of sodium channel.
    Keywords: Anticonvulsant, Design, Isoindoline, Seizure, Synthesis
  • Naser Foroughifar *, Somayeh Karimi Beromi, Hoda Pasdar, Masoumeh Shahi Pages 596-601
    Heterocyclic compounds containing a pyrimidine nucleus are of special interests due to their applications in medicinal chemistry as they are the basic skeleton of several bioactive compounds such as antifungal, antibacterial, antitumor and antitubercular. As a part of our research in the synthesis of pyrimidine derivatives containing biological activities, some new tetrahydropyrimidine derivatives (1-10) were synthesized via Biginelli reaction using HCl or DABCO as a catalyst with good yields. All structures of products were confirmed by IR, 1H NMR and 13C NMR spectroscopy. The antibacterial activity of some synthesized compounds was investigated against Staphylococcus aureus (ATCC 6538), Staphylococcus epidermidis (ATCC 12228), Bacillus cereus (ATCC14579), Esherichia coli (ATCC 25922), Klebsiella pneumonia (ATCC 13883) and Pseudomonas aeruginosa (PAO1) bacteria. Some of these compounds such as 8 and 10 exhibited a good to significant antibacterial activity.
    Keywords: tetrahydropyrimidine, antimicrobial activity, Biginelli reaction, Bacteria, heterocyclic compounds
  • Siyavash Rahmani *, Soraya Shahhoseini, Reza Mohammadi, Mostafa Vojdani Pages 602-610
    The introduction of 2-[18F] fluor-2-deoxy-D-glucose (18FDG) has provided a valuable tool for the study of glucose metabolism in both normal and diseased tissue in conjunction with positron emission tomography (PET). 18FDG is the most important radiopharmaceutical to be used in Nuclear Medicine for studying the brain, heart and tumor. The advancement in synthesis and quality control of 18FDG and its approval by US FDA are main reasons for increasing clinical application of 18FDG over the last 20 years. In this manuscript we explain the synthesis, quality control and stability studies of 18FDG (evaluate the physicochemical and microbiological stability of 18FDG, stored at room temperature (18 - 23 °C), and 35 - 40 °C, at different time intervals). We investigated how the influence of environmental factors in different lengths of time, alters the quality of this radiopharmaceutical. The pH, radionuclidic identity and purity, radiochemical identity and purity, chemical purity, bacterial endotoxins and sterility of 18FDG were evaluated according to the European Pharmacopoeia 7ed. analytical methods and acceptance criteria. The results suggest that under experimental conditions 18FDG has physicochemical and microbiological stability up to 10 hours after the end of synthesis.
    Keywords: Fludeoxyglucose(18F-FDG), PET-CT, Quality control, stability, Radiopharmaceutical
  • Seyed Javad Khoramrouz, Mostafa Erfani *, Mitra Athari Allaf Pages 611-618
    Nuclear medicine imaging has been used to localize infection sites and efforts have been continued to develop modified infection specific radiopharmaceuticals. In this study gemifloxacin as a broad-spectrum quinolone has been labeled with [99mTc (CO)3 (H2O)3] core in order to evaluate its feasibility as an infection imaging agent for in vivo use. The stability of radioconjugate was checked in human serum at 37 °C and biodistribution was studied in mice. Labeling yield of >95% was obtained corresponding to a specific activity of 0.14 GBq/μmol. The radioconjugate showed good stability in human serum. Our main achievement was high accumulation in the infected muscle in mice (T/NT = 2.93 ± 0.3 at 1 h post injection) which may diagnostically be beneficial for differentiate sites of infection from sites of inflammation.
    Keywords: Infection, 99mTc-carbonyl, Gemifloxacin, Quinolone, Imaging
  • Fariba Johari-Doha, Siyavash Rahmani, Samira Rasaneh, Zahra Sheikholislam, Soraya Shahhosseini * Pages 619-629
    NHL is the most common hematologic cancer in adults. Rituximab is the FDA approved treatment of relapsed or refractory low grade B-cell Non-Hodgkin Lymphoma (NHL). But patients eventually become resistant to rituximab. Since lymphocytes and lymphoma cells are highly radiosensitive, low grade NHL that has relapsed or refractory to standard therapy is treated by RIT in which a beta-emitting radionuclide coupled to anti-CD20 antibody. The association of beta emitter radionuclide to rituximab enhances its therapeutic efficacy. The cells which lack antigen or cells which cannot be reached due to poor vascularization and intratumoral pressure in a bulky tumor would be irradiated and killed by cross fire effect of beta emitter. 90Y, a pure high energy -emitter with a half-life of 64 h, a maximum energy of 2.28 MeV, and maximum board of 11.3 mm in tissue is radionuclide of choice for radioimmunotherapy of outpatient administration.
    In this study, rituximab was conjugated to DOTA and radiolabeled with 90YCl3. The stability, affinity, and immunoreactivity of radiolabeled antibody was determined in vitro and the conditions were optimized. Biodistribution studies were done in normal mice. The optimum conditions of conjugation and radiolabeling was 1-2 hr at 37C and 1 hr at 45C, respectively. Results showed approximately 4 DOTA molecules conjugated per antibody molecule. The purified antibody was stable and intact over 6 months stored at -20C. The result of immunoreactivity (70%), affinity (3 nM) and biodistribution in normal mice are acceptable.
    Keywords: B-cell Non-Hodgkin Lymphoma, radioimmunotherapy, 90-Y, Rituximab, Immunoreactivity
  • Yassar Mortada, Khojasteh Joharchi *, Malek Zarei, Ardalan Mansouri, Masoumeh Jorjani Pages 630-639
    Neuropathic pain is a complication of inflammation, infection or some diseases such as diabetes. Opioids are used as a salvage therapy for neuropathic pain but tolerance restricts their use. In our previous study we have observed an increase of Nitric Oxide in diabetes and in morphine tolerance. This study was performed to clarify the role of inducible nitric oxide synthase, iNOS, and cationic amino acid transporter, CAT-2, in these conditions.
    Thus male rats were divided into four groups: control, diabetic, morphine tolerated and diabetic morphine tolerated. For evaluating tolerance Hot-Plate test was achieved. Molecular study was performed by real time PCR and Western blotting techniques to compare gene and protein expression.
    Our findings showed that in diabetic animals, morphine tolerance occurred prior to non-diabetic rats. In molecular study, the expression of iNOS was increased in the spinal cord whereas the CAT-2 did not change in diabetic morphine tolerated rats.
    It seems that the nitric oxide elevation in diabetic morphine tolerated state is mostly due to the increase of iNOS in male rats.
    Keywords: Diabetes, Morphine tolerance, Nitric Oxide Synthase, Cationic Amino Acid Transporter-2, Male Rat
  • Sina Asaadi, Mohammad Jahanbakhshi, Mahmoud Lotfinia, Nima Naderi * Pages 640-647
    The anticonvulsant effect of cannabinoid compound has been shown in various models of seizure. On the other hand, there are controversial findings about the role of large conductance calcium-activated potassium (BK) channels in the pathogenesis of epilepsy. In this study, the effect of arachidonyl-2′-chloroethylamide (ACEA), a CB1 receptor agonist, and a BK channel antagonist, paxilline, either alone or in combination was investigated. Both pentylenetetrazole (PTZ) and maximal electroshock (MES) acute models of seizure were used to evaluate the protective effects of drugs. Mice were randomly selected in different groups: (i) control group; (ii) groups received different doses of either paxilline or ACEA; and (iii) groups received combinations of ACEA and paxillin at different doses. In MES model, prevention of hindlimb tonic extension (HLTE) was considered as protective effect. In PTZ model, the required dose of PTZ (mg/kg) to induce tonic-clonic seizure with loss of righting reflex was considered as seizure threshold. In PTZ model, while administration of ACEA per se (5 and 10 mg/kg) caused protective effect against seizure, however, co-administration of ACEA and ineffective doses of paxilline attenuated the antiseizure effects of paxilline. In MES model, while pretreatment by ACEA showed protective effects against seizure, however, co-administration of paxilline and ACEA caused an antagonistic interaction for their antiseizure properties. Our results showed a protective effect of ACEA in both PTZ and MES acute models of seizure. This effect was attenuated by co-administration with paxilline, suggesting the involvement of BK channels in antiseizure activity of ACEA.
    Keywords: BK channel, Cannabinoid, pentylenetetrazole, Maximal Electroshock, Seizure, Mice
  • Sainaz Ghasemi, Amir Ahmad Salarian, Abbas Zare Mirakabadi, Somayeh Jafarinejhad, Mahmoud Ghazi-Khansari * Pages 648-652
    Scorpion venom toxicity is one of the major medical concerns from old years, due to its influence on human activities and health. From many years ago a lot of researches established to examine different aspects of venom toxicity and its effects on different organs. During these years researchers are doing more specific studies on the cytotoxicity of scorpion venom. In Iran, Odonthobuthus doriae, the yellow scorpion is one of the major threats based on its neuro toxicity and severe pathophysiologic effects and researchers tried to find the mechanism of these neuro toxic effects. The previous studies have shown that in isolated organs the yellow scorpion venom is affecting the ion channels. Also some studies showed that this venom has severe cytotoxic effects on the cell lines with many ion channels like nerve cell lines.
    In this study the cytotoxic effect of the crude venom of O.doriae on the 1321N1 cell line (cancerous nerve cells). primary cell cultured investigated in the presence of different ion channel blockers: Ouabain (1mmol as Na channel blocker), Verapamil (10μmol/l as Ca channel blocker), TEA (40mmol as K channel blocker) by MTT method. The result showed that the O.doriae crude venom has cytotoxic effect via Na channels.
    Keywords: Scorpion, Odonthobuthus doriae, 1321N1, Channel blocker, cell culture
  • Ozcan Ozkan *, Ersen Aydi, N. Ya?, Mur Pages 653-660
    In this study, Mesobuthus gibbosus and Mesobuthus eupeus eupeus venom samples were compared for lethality, in vivo effects and proteins. Neutralization capacity of monovalent Androctonus crassicauda antivenom (RSHA anti-Ac) was tested against the lethal effects of the venoms.
    Venom was obtained from mature scorpions by electrical stimulation of the telson. The lethality of the venom and potency of horse RSHA anti-Ac were determined in Swiss mice. The protein profiles of the scorpion venoms were analysed by NuPAGE® 4–12% Bis-Tris gradient gel followed by Coomassie blue staining. Western blotting was performed to determine immunogenic compounds in the venom samples.
    The median lethal doses of M. e. eupeus, M.gibbosus scorpion and A.crassicauda venoms were found to be 1.92 mg/kg by i.v., 0.67 mg/kg and 0.24 mg/kg by s.c., respectively.
    A.crassicauda venom was used as control for confirm to neutralization capacity of RSHA anti-Ac. One millilitre of the RSHA anti-Ac neutralises 23 LD50 of M. e. eupeus, 32 LD50 of M.gibbosus and 42 LD50 of A. crassicauda venom in mice. Analysis of electrophoresis indicates that three scorpion venoms posses low molecular weight proteins. Immunoblotting indicated that RSHA anti-Ac strongly reacted with both the specific venom and Mesobuthus species venoms which have antigenic similarity.
    Result of our study showed that M.e. eupeus and M.gibbosus could be medically important scorpions for humans, particullary children. The RSHA anti-Ac can be used in the treatment of envenomation by M. e.eupeus and M.gibbosus scorpion stings.
    Keywords: Turkish Scorpiofauna, Mesobuthus, lethality, Venom, Androctonus crassicauda antivenom
  • Malahat Ahmadi *, Masood Adibhesami Pages 661-669
    The microorganisms have been usual noted as the major cause of delayed wound healing. Pseudomonas aeruginosa is the most common pathogen causing these infections. Silver nanoparticles (AgNPs) show ample antibacterial activities. In present study, the effect of AgNPs alone and in combination with tetracycline investigated on inoculated wounds with Pseudomonas aeruginosa in mice. Twenty mice anesthetized and full-thickness skin wounds created on back of them and the bacterial suspension added to each wound bed. Wound infection assessed using total count of bacterial load and also wound healing monitored, macroscopically. In all groups treatments applied topically in the wound bed: AgNPs, tetracycline, AgNPs along with tetracycline and normal saline in control group. The tetracycline along with AgNPs achieved 100% wound closure on day 12. In the AgNPs group, the percentage of wound contraction has close figures compared to tetracycline and normal saline as 98, 99 and 79 percent, respectively. By day 12, all of the treated groups with AgNPs, tetracycline and AgNPs along with tetracycline showed decreases in surface bacterial concentration compared with control group. Also, significant decrease (P
    Keywords: Wound, Infection, Pseudomonas aeroginosa, Silver Nanoparticles, Mice
  • Behzad Khademi *, Shahram Bamdad, Mina Bamdad, Mahsa Khanlari, Yahya Daneshbod Pages 670-676
    Title: Teratogenic Effects of Intravitreal Injection of Bevacizumab in Pregnant Rat Models
    Aim: To investigate teratogenic effect of intravitreal injection of bevacizumab in pregnant rat model
    Methods
    Twenty seven female Wistar rat were inseminated. Pregnant rats were divided into 6 groups (three groups as case and three as control groups). Each case and control groups divided according to the day of intravitreal injections (day 2, 10 and 18). Rats in the case groups received 4 µl intravitreal injection of bevacizumab and the control groups received same volume of distilled water.
    Results
    The tail and umbilical cord length in case groups 1, 2 and 3 did not display any significant differences compared with their control groups. The fetal weight was significantly lower in the case groups 1 (p
    Conclusion
    Intravitreal bevacizumab has developmental effect when administered in the early stages of pregnancy; but it is safe when administered in the last week of pregnancy in rats.
    Keywords: Animal Model, Anti VEGF, Avastin, Itravitreal Injection, Peregnancy, Rat, Teratogenicity
  • Azadeh Ashtarinezhad, Ataollah Panahyab, Baharak Mohamadzadehasl, Farshad H. Shirazi * Pages 677-684
    Azole agents especially Miconazole are widely used even during pregnancy as antifungal agents. The aim of this study was to assess the usefulness of FTIR Micro-Spectroscopy for discriminating of Miconazole treated liver tissue from control liver tissue. The mice were injected with Miconazole (60 mg/Kg) on gestation day 9 and they were dissected on pregnancy day 15. The fetus fixed, dehydrated and embedded in paraffin. Sections of liver (10 μm) were prepared from control and treated fetus groups by Microtome and deparaffinized with xylene. The spectra were collected using FTIR-MSP in the region of 4000-400 cm-1. All spectra were normalized to amide II band (1454cm-1) after baseline correction of entire spectrum. The results were shown by 2nd derivatization of spectra and also subtracting from control spectra. Miconazole induces some minor changes in the mouse fetus liver at cellular levels when mother is exposed. The most important calculated alterations are in the production of fetus liver proteins. α helical and β sheet structures have shown significant variations, indicating protein alterations configurationally
    Keywords: FTIR-Microspectroscopy, Teratogenic, Mice fetus liver tissue, Miconazole, Biospectroscopy
  • Mahnoosh Fatemi *, Jamal Moshtaghian, Kamran Ghaedi, Narges Jafari, Gholamali Naderi Pages 685-693
    The extensive application of silver nanoparticles (AgNPs) has been increased due to their antimicrobial properties, however numerous concerns has been arisen about their toxicity potential. Since nanoparticles can cross through the placenta and accumulate in the embryonic organs especially liver, in this study, developmental hepatotoxicity of AgNPs was investigated.
    Pregnant rats were divided into two groups, vehicle control group and treated group. Treated group received AgNPs (25 mg/kg) through intra-gastric gavage in a period of gestational days 1-19. Pups were sacrificed after the birth and their livers collected. Histopathology, ICP- mass spectrometry, Spectrophotometric assay and ELISA were employed to evaluate AgNPs toxicity in the liver of pups.
    Glutathione peroxidase (GPX) activity and glutathione (GSH) level were significantly decreased and malondialdehyde (MDA) and caspase 9 levels were significantly increased, although there was no significant change in caspase 8 content in the liver of offspring. Fatty degeneration and congested dilated sinusoids were also observed in histo-pathological examination.
    These results suggest that maternal oral exposure to AgNPs may induce oxidative stress and apoptosis in the liver of their offspring. Further investigations are required to clarify molecular events behind this happening.
    Keywords: AgNPs, Apoptosis, Developmental hepatotoxicity, Liver, Oxidative stress, Rat
  • Zahra Memariani, Mannan Hajimahmoodi, Bagher Minaee, Fariba Khodagholi, Asal Yans, Roja Rahimi, Gholamreza Amin, Ghazaleh Moghaddam, Tayebeh Toliyat, Mohammad Sharifzadeh * Pages 694-704
    “VARD” formula consisting of Rosa damascena Mill. (Rosaceae) petal, and rhizomes of Glycyrrhiza glabra L. (Papilionaceae) and Nardostachys jatamansi DC. (Valerianaceae), has been proposed for gastric ulcer in Iranian traditional medicine. We investigated the antiulcer activity of each plant separately and in combination. The biochemical and molecular function of extracts was also evaluated. Each plant hydroalcoholic extract was standardized via determination of total phenolic and flavonoid, also phenolic compounds determination and specially glycyrrhizic acid in G. glabra by using HPLC. Rats received orally extracts of the plants (20, 40, and 80 mg/kg) and “VARD” (45 mg/kg) 1 h before ethanol administration. Two hours after receiving ethanol, animals were sacrificed; the stomach was removed for macroscopic and microscopic assessment. Also heme-oxygenase-1, glutathione, and catalase were measured in the gastric tissue of the rats pretreated by “VARD” and dose of 20 mg/kg of extracts. Among three extracts, R. damascena and G. glabra contained more total phenolic and flavonoid content respectively. Gallic acid was prominent compound in R. damascena. The extracts of R. damascena, G. glabra, and N. jatamansi significantly decreased ulcer index. ED50 values were 8.2, 31.86 and 25.08 mg/kg respectively. “VARD” significantly decreased ulcer index compared to 20 mg/kg of G. glabra (p
    Keywords: Antioxidant, Glycyrrhiza glabra, Heme-oxygenase-1, Inflammation, Nardostachys jatamansi, Peptic ulcer, Rosa damascena
  • Azar Hossein, Elaham Bakhtiari, Seyed Hadi Mousavi * Pages 705-710
    Doxorubicin (DOX) isan effective anticancer drug. But its clinical application is limited, because DOX induces apoptosis in cardiomyocytes and leads to permanent degenerative cardiomyopathy and heart failure. Recent trainings showed that Hibiscus sabdariffa exhibit pharmacological actions such as potent antioxidant. So, in this study we explored the protective effect of extract of H. sabdariffa against doxorubicin-induced cytotoxicity in H9c2 cells.Cell viability was quantified by MTT assay. Apoptotic cells were determined using PI staining of DNA fragmentation by flowcytometry (sub-G1 peak). Cells were cultured with 5 μM DOX for 24 hr to create the cell damage. H9c2 cells were pretreated with different concentrations (7.81-500 μg/ml) of H. sabdariffa extract (HSE) for 2 hr before DOX treatment in all trials. Pretreatment with HSE increased cell viability at concentration of 31.25-500 μg/ml. Compared to control cells apoptosis was induced in DOX treated cells after 24 hr, (𝑃
    Keywords: Hibiscus sabdariffa, H9c2 cells, Doxorubicin, Apoptosis
  • Benjamin I. Okeleye, Noxolo T. Mkwetshana, Roland Ndip Ndip* Pages 711-721
    We evaluated the in vitro antiproliferative and apoptotic potential of the ethyl acetate extract (EAE) of Peltophorum africanum, a member of the family Fabaceae (Sond) in order to validate its pharmacological use. Antiproliferation of human breast (MCF-7), colon (HT-29) and cervical (HeLa) cancer cell lines by EAE was investigated using the Cell Titer-Blue viability assay and the mechanism of action delineated using the Nucleic Acid and Protein Purification Nucleospin® Tissue Kit, Scanning Electron Microscope (SEM), propidium iodide (PI) and acridine orange (AO) double-staining techniques. Significant reduction in cell viability of the cells was noted as the MCF-7 cells were reduced from 100 - 54.33±1.84 % after 72 hrs of treatment with 5 µg/mL of EAE (P. value
    Keywords: Peltophorum africanum, Medicinal plant, antiproliferation, Apoptosis, Chemotherapy
  • Mahmoud Mosaddegh *, Soheyla Honary, Alireza Mozaffari Dehshiri Pages 722-733
    Iranian and Pakistani traditional physicians have derived the advantages of silver compounds by processing silver to a specific preparation called Kushta to treat skin cancers. This study investigated silver Kushtas in comparison with silver nanoparticles in the terms of morphology, silver content, and chemical composition.
    Materials And Methods
    Iranian silver Kushta (IKAg) powder was produced via the method of Iranian traditional medicine. Pakistani silver Kushta (PKAg) powder was purchased from Hamdard pharmaceutical company. Silver nanoparticles (AgNPs) were produced through a chemical reduction method using AgNO3 and NaBH4 at 4°C. Physicochemical properties of all three compounds were examined by scanning electron microscopy (SEM), dynamic light scattering (DLS), Fourier transform infrared (FTIR) ,UV spectra Analysis , Energy Dispersive X-ray analysis (EDX), and X-ray diffraction (XRD).
    Results
    IKAg and PKAg particles show different sizes. However, AgNPs were spherical-shaped and uniform in size. According to EDX analysis, the silver contents of IKAg and PKAg were 50.43% and 66.24%, respectively. IKAg, PKAg and AgNPs showed zeta potential values equal to -2.27, -12 and -18.5 mV, successively. IKAg, PKAg and AgNPs sizes were 190.4, 51.72 and 64.08 nm, respectively. Moreover, XRD results indicated that the composition of IKAg and PKAg are completely different.
    Keywords: Pakistani silver Kushtas, Iranian Silver Kushtas, Silver Nanoparticles, Iranian Traditional Medicine (ITM), size, XRD
  • Ali Hossein Rezayan, Safoura Hariri, Parisa Azerang, Ghazaleh Ghavami, Isabel Portugal, Soroush Sardari * Pages 724-752
    A series of new fluorene bisamide derivatives were synthesized through multi-component Ugi reaction and tested for their in vitro anti-mycobacterial activity. The structures of the products 5a-w were deduced from their IR, 1H NMR, and 13C NMR spectra. Elemental analyses (CHN) for novel compounds (5a, 5d, 5f, 5h, 5k, 5l, 5p, 5s, 5t, 5v, 5w) was done to. These compounds were evaluated as anti-bacterial agents against Mycobacterium bovis and M. tuberculosis, while their activity expressed as the minimum inhibitory concentration (MIC) in μg/mL. Among the twenty-three synthesized compounds, 5a was found to be the most active compound in vitro with MIC of 1.95μg/mL against Mycobactrium bovis and compound 5k showed greatest potency against sensitive and resistant strains of M. tuberculosis (H37Rv, IHMT149/09, HPV115/08 and HPV65/08).
    Keywords: multi-component reaction, Ugi reaction, Mycobacterium bovis, fluorene bisamide derivatives, brine shrimp toxicity study
  • Hossein Vahidi, Nastaran Nafissi-Varcheh, Bahram Kazemi, Reza Aboofazeli, Soraya Shahhosseini, Maryam Tabarzad * Pages 734-741
    Protein specific aptamers are highly applicable affinity ligands in different fields of research and clinical applications. They have been developed against various targets, in particular, bio-macromolecules such as proteins. Among human proteins, the coagulation factors are the most attractive targets for aptamer selection and their specific aptamers had valuable characteristics in therapeutic and analytical applications. In this study, a plasma derived coagulation factor VIII was considered as the protein target for DNA aptamer selection using size exclusion chromatography-SELEX. Potential aptameric oligonucleotides with high affinity and specificity were achieved during eight rounds of selection. Binding affinity constant of selected aptamer and aptameric enriched pool were in nanomolar range that was comparable to monoclonal antibodies. Further improvement studies can result in aptamers that are more promising as an industrial affinity ligand for the purification of anti-hemophilia factor from plasma source.
    Keywords: Aptamer, protein, coagulation factor VIII, affinity ligands, size exclusion chromatography, SELEX
  • Renata Dobrucka * Pages 753-759
    Nowadays green synthesis of metal nanoparticles is a developing area of research. In this study, titanium dioxide nanoparticles were biosynthesized using an aqueous solution of Echinacea purpurea herba extract as a bioreductant. This is novel and interesting method for synthesis of TiO2 nanoparticles. The prepared titanium dioxide nanoparticles were characterized using ultraviolet–visible spectroscopy (UV-VIS), transmission electron microscopy (SEM), total reflection X-Ray fluorescence analysis (TXRF) and Fourier-transform infrared spectroscopy (FTIR). The size of TiO2 nanoparticles was found to be in the range of 120 nm. Moreover, the alkaline reaction of the solution (pH=8) resulted in the increase in absorbance (280 nm), which facilitates the growth of the number of TiO2 nanoparticles in the studied solution. Also, synthesis of TiO2 nanoparticles using green resources like Echinacea purpurea herba is a better alternative to chemical synthesis, since this green synthesis is pollutant-free and eco-friendly.
    Keywords: Echinacea purpurea, nanotechnology, green-synthesis, titanium dioxide nanoparticles
  • Qamar Abbas, Muhammad Saleem, Abdul Rehman Phull, Muhammad Rafiq, Mubashir Hassan, Ki-Hwan Lee, Sung-Yum Seo * Pages 760-767
    Herbal nanoparticles gain lot of attention because of their pharmaceutical importance. The present study reports the eco-friendly synthesis, characterization and their tyrosinase activity of silver nanoparticles (AgNPs) using aqueous extract of Bidens frondosa. The appearance of brown color indicated the formation of B. frondosa AgNPs. The Formation of AgNPs was confirmed by UV–Vis spectroscopy, FTIR, FESEM and EDS analysis. The formation of herbal AgNPs of size ranging 20-70 nm further were assured by energy dispersive X-ray spectroscopy (EDS) and field emission scanning electron microscopy (FESEM).The mushroom tyrosinase inhibitory activity of synthesized AgNPs was evaluated. Nanoparticles were found to have significant higher tyrosinase inhibitory activity compared to control. The IC50 values of crude extract, AgNP and Kojic acid were found to be 9, 15, and 2.37 μg/mL, respectively. AgNPs of B. frondosa may be considered as potential candidate for the production of medical and cosmetic products.
    Keywords: Bidens frondosa, Medicinal Plants, Silver Nanoparticles, Tyrosinase Activity
  • Mojgan Naghitorabi *, Hamid Mir Mohammad Sadeghi, Javad Mohammadi Asl, Mohammad Rabbani, Abbas Jafarian-Dehkordi Pages 768-777
    Promoter methylation is one of the main epigenetic mechanisms that lead to the inactivation of tumor suppressor genes during carcinogenesis. Due to the reversible nature of DNA methylation, many studies have been performed to correct theses epigenetic defects by inhibiting DNA methyltransferases (DNMTs). In this case novel therapeutics especially siRNA oligonucleotides have been used to specifically knockdown the DNMTs at mRNA level. Also many studies have focused on transcriptional gene silencing in mammalian cells via siRNA mediated promoter methylation. The present study was designed to assess the role of siRNA mediated promoter methylation in DNMT3B knockdown and alteration of promoter methylation of CDH1, GSTP1 and DNMT3B genes in MDA-MB-453 cell line.
    MDA-MB-453 cells were transfected with siDNMT targeting DNMT3B promoter and harvested at 24 and 48 hours post transfection to monitor gene silencing and promoter methylation respectively. DNMT3B expression was monitored by quantitative RT-PCR method. Promoter methylation was quantitatively evaluated using differential high resolution melting analysis.
    A non-significant 20% reduction in DNMT3B mRNA level was shown only after first transfection with siDNMT, which was not reproducible. Promoter methylation levels of DNMT3B, CDH1 and GSTP1 were detected at about 15%, 70% and 10% respectively, in the MDA-MB-453 cell line, with no significant change after transfection.
    Our results indicated that siDNMT sequence were not able to affect promoter methylation and silencing of DNMT3B in MDA-MB-453 cells. However quantitation of methylation confirmed a hypermethylated phenotype at CDH1 and GSTP1 promoters as well as a differential methylation pattern at DNMT3B promoter in breast cancer.
    Keywords: Epigenetic, Promoter methylation, Gene silencing, siRNA, DNMT3B
  • Atefeh Ordoei Javan, Shervin Shokouhi, Zahra Sahraei *, Jamshid Salamzadeh, Saeed Azad Armaki Pages 778-787
    Background
    Nephrotoxicity has been a major long-standing concern about colistin. This study was designed to compare nephrotoxicity of high dose and conventional dose of colistin.
    Methods
    A randomized open-labeled clinical trial on 40 patients with multi-drug resistant gram negative infections was designed. Patients were allocated into two equal-size groups receiving high and conventional dose of colistin. Blood samples were taken on day 1, 3, 5, 7 and 10 of treatment for measuring serum cystatin C (Cys C) levels. Incidence of acute kidney injury (AKI) was also evaluated based on RIFLE criteria.
    Results
    Mean±sd of the difference between baseline and day 10 Cys C levels in high dose and conventional dose groups were 1.61±0.90 and 1.32±0.48, respectively (P=0.30). Within group analysis showed increase in Cys C levels in both groups (P= 0.001), however, no significant difference in Cys C levels was seen in between groups analysis (P=0.13). Prevalence of AKI based on RIFLE criteria was 60% and 15% in high dose and conventional dose groups, respectively (P= 0.003). Comparison of Cys C between AKI (mean±sd) and non-AKI (mean±sd) patients, irrespective of colistin dosage regimens, confirmed a significant difference (P
    Conclusion
    Although, colistin-induced nephrotoxicity, determined by Cys C levels, was not confirmed by our findings, however, higher incidence of AKI in high-dose group, defined by RIFLE criteria, along with higher levels of Cys C in AKI patients are supportive of the higher risk of renal toxicity associated with high-dose regimen of colistin.
    Keywords: Colistin, Conventional dose, Cystatin C, High dose, Nephrotoxicity
  • Farhad Assarzadegan, Mohammad Sistanizad* Pages 788-794
    Prophylactic migraine treatment has always been a challenge. Efficacy and tolerability are two main issues in current approved migraine prevention regimens. Since some migraineurs patients fail approved preventative agents, experts are always seeking newer agents. Memantine, a glutaminergic antagonist, could potentially be one of these agents. Objective of current study is assessing the efficacy of memantine as a preventative migraine treatment and its potential side effects.
    In this study, 127 migraineurs patients meeting the criteria for starting preventative therapy (> 4 headache days/month) were included. All patients previously failed at least one trial of adequate preventive therapy. After a 30-day baseline observation, patients started memantine for 3 months, beginning at 5 mg/day, which increased by 5 mg/week up to a maximum of 20 mg a day if symptoms did not improve. Headache frequency, duration, and severity were assessed at the end of the treatment phase. 102 patients completed the study.
    In the study population, headache frequency reduced from 9.9 days/month at baseline to 5 days/month at 3 months (P
    Keywords: Headache, Migraine, Memantine, Refractory migraine, NMDA
  • Daud Ali, Nawazish Alam *, Farhat Yasmin, Sajid Ali, Sarfaraz Alam, Sarfaraz Ahmad Pages 795-801

    The research study was designed to compare the safety and efficacy of the regimen of 5-flurouracil with cisplatin of investigational arm with the reference regimen of gemcitabine with cisplatin for the treatment of gallbladder cancer. A total of 60 patients were enrolled in the study. Out of 30 patients enrolled in arm-A (Gemcitabine with Cisplatin) and 30 patients enrolled in arm-B (5-Flurouracil with Cisplatin) for safety assessment. For the efficacy evaluation total of 16 patients enrolled which is equally divided in both arm. Total 150 cycles of chemotherapy were given to each arm of patients. Both arms were well balanced with respect to age, stage of disease and measurability. The overall response rate (ORR) was 62.5% in arm-A compared to 50% in arm-B (p=0.34). Whereas 95% confidence interval (CI) for the efficacy was found 46.25-8.74% vs 32.67-67.32% between arm-A and arm-B. The most prevalent toxicities were found anemia (p

    Keywords: Gallbladder cancer, Gemcitabine, 5-Flurouracil, Cisplatin, Overall response rate (ORR)
  • Shadi Ziaie *, Hamid Reza Aslani, Jamshid Salamzade, Sara Zaheri Pages 802-807
    Human cytomegalovirus (CMV) remains the most common infection affecting organ transplant recipients. Despite advances in the prophylaxis and acute treatment of CMV, it remains an important pathogen affecting the short- and long-term clinical outcome of solid organ transplant recipient. The emergence of CMV resistance in a patient reduces the clinical efficacy of antiviral therapy, complicates therapeutic and clinical management decisions, and in some cases results in loss of the allograft and/or death of the patient. Common mechanisms of CMV resistance to ganciclovir have been described chiefly with the UL97 mutations. Here we evaluate Incidence of ganciclovir resistance in 144 CMV-positive renal transplant recipients and its association with UL97 gene mutations. Active CMV infection was monitored by viral DNA quantification in whole blood, and CMV resistance was assessed by UL97 gene sequencing. Six mutations in six patients were detected. Three patients (2.6%) of 112 patients with history of GCV treatment had clinical resistance with single UL97 mutations at loci known to be related to resistance (including mutations at codon 594, codon 460, and codon 520). three patients who were anti-CMV drug naïve had single UL97 mutations (D605E) without clinical resistance. Our results confirm and extend our earlier findings on the specific mutations in the UL97 phosphotransferase gene in loci that have established role in ganciclovir resistance and also indicate that clinical ganciclovir resistance due to UL97 gene mutations is an issue in subjects with history of with ganciclovir treatment. D605E mutations remains a controversial issue that needs further investigations.
    Keywords: Cytomegalovirus, ganciclovir, UL97, Transplant Recipients, Resistance, Mutations
  • Aziz Eghbali, Shabnam Hajiani, Bahman Sadeghi Sedeh, Abdolghader Pakniyyat, Vahid Mansouri, Bahador Bagheri * Pages 808-813
    Background
    Hemangioma is a benign vascular tumor that shouldbe treated in problematic situations.Propranolol efficacy, target dose, range of age, duration of treatment and complications arenot conclusive for treatment of pediatric hemangioma. Our goal was to study efficacy and safety of propranolol for hemangiomatreating in children.
    Methods
    A randomized, open label crossover trial with two twenty four-week treatment phases separated by a one-week washout period, was conducted in Amir-Kabir Hospital, Arak, Iran. Thirty two patients with age of 1 month to 15 years were randomized to receive either oral propranolol 2 mg/kg/day or receivedno treatment. The primary outcome measure was change in hemangioma size assessed at baseline, day 3, day 7 and every month.
    Results
    At baseline, the mean surface area was 36.9±36.3 cm2. After 1 week of treatment, a decrease was seen in size of hemangiomas. After one month, a significant reduction was seen in size of lesionsin treatment group compared to observation group (30 cm2vs 16 cm2, p
    Conclusion
    The trial suggested that 24 week treatment with oral propranolol was effective for treatment of pediatric hemangiomas with acceptable safety profile.
    Keywords: hemangioma, Propranolol, children, drug therapy, Hospital
  • Farzaneh Foroughinia *, Shahriar Mazraie Pages 814-819
    Albumin is an expensive drug which imposes relatively high cost on the health care system. Doing ABC analysis in Shahid Motahari Hospital, it was revealed that albumin is categorized in class A. Therefore, the present study aimed to evaluate the pattern of albumin use and the physician's adherence to evidenced-based albumin guidelines in this large general non-teaching hospital in Shiraz, Iran.
    This study is an observational retrospective research on drug utilization. All patients admitted to Shahid Motahari hospital that had received albumin during the study period of one year (December 2013 to December 2014), were included in the study. To evaluate the appropriate use of albumin, an internal guideline was prepared using several evidence-based guidelines. Prescriptions were considered correct and appropriate if they were compliant with the standard guideline.
    The result of this study indicated that about 87.3% of patients had received albumin improperly. Nephrotic syndrome without hypoalbuminemia (23.6%) was the most prevalent reason for albumin misuse and internal ward was the most consuming unit.
    The findings of this study, similar to those of previous investigations in Iran, revealed the high percentage of inappropriate albumin usage in Iranian teaching and non-teaching hospitals. Regarding the high cost and short supply of this drug, educating physicians through educational programs to best implement the standard guidelines is highly recommended.
    Keywords: drug utilization evaluation, albumin, non-teaching hospital, ASHP guideline, appropriate use
  • Najmeh Moradi, Arash Rashidian, Hamid Rasekh*, Teymoor Mohammadi, Mahnoosh Foroughi, Alireza Olyaeemanesh Pages 820-830
    The aim of this study was to estimate monetary value of a QALY among heart disease patients and to identify its determinants.A cross-sectional survey with face-to-face interview was conducted with 196 cardiovascular disease patients from two heart hospitals in Tehran, Iran, to estimate the value of QALY using disaggregated and aggregated approaches. The Euro Qol -5d (EQ-5D) questionnaire, visual analogue scale (VAS), time trade-off (TTO) and contingent valuation WTP techniques were employed to, first, elicit patients’ preferences and to estimate WTP for QALY. The association of patients’ characteristics with WTP for QALY was assessed using the Heckman selection model. Mean willingness to pay per QALY estimated by the disaggregated approach ranged from 2,799 to 3599 US dollars. It is higher than the values estimated from aggregated methods (2,256 to 3,137 USD). In both approaches, the values were less than one gross domestic product (GDP) per capita of Iran.
    Significant variables were current health state, education, age, marital status, number of comorbidities, and household’s cost group. Our results challenge two major issues: the first is a policy challenge which concerns the WHO recommendation on using less than 3 GDP per capita as a cost-effectiveness threshold value. The second is an analytical challenge related to patients with zero QALY gain. More scrutiny is suggested on the issue of how patients with full health state valuation should be dealt and with what arbitrary value could be included in the estimation value of QALY when disaggregated approach was used.
    Keywords: willingness to pay, quality adjusted life year, contingent valuation, cost effectiveness threshold value, cardiovascular diseases
  • Nazila Yousefi, Gholamhossein Mehralian *, Hamidreza Rasekh, Mina Yousefi Pages 831-843
    In today’s competitive world, there are several strategies to deal with the fast changing environment, among which New product development (NPD) is a common strategy. However, almost half of the resources that companies devote to NPD are spent on products that may fail. This issue is particularly highlighted in the pharmaceutical industry mainly because of a long development-time, low success rate, high capital requirement, and market uncertainty in.
    This study identifies critical success factors of NPD based on the relevant literatures and expert opinions in Iranian pharmaceutical industry, then prioritizes them using the methodology of multiple criteria decision making (MCDM) through analyzing 50 filled questionnaires which is structured based on the AHP (Analytical Hierarchy Process) approach.
    Although the NPD success factors seem same in both generic and bio-generic pharmaceutical industries, the underlying factors and related sub-factors show the different importance in these two industries. However, this study reveal that, the "company capabilities" is the most important factor affecting new product development success in both pharmaceutical generic and bio-generic industry.
    The results of this study contribute to create baseline information for pharmaceutical industry especially Iranian pharmaceutical companies to be more effective in budget allocation on improving NPD success factors so that they can boost the success rate of NPD more effectively.
    Keywords: New product development, success factors, pharmaceutical industry, Multiple Criteria Decision Making, Analytical Hierarchy Process