فهرست مطالب

Pharmaceutical Research - Volume:18 Issue: 4, 2019
  • Volume:18 Issue: 4, 2019
  • تاریخ انتشار: 1398/08/13
  • تعداد عناوین: 52
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  • Chun Tao, Xu Wen, Qian Zhang *, Hongtao Song Pages 1648-1658
    The clinical application of sirolimus (SRL) as an immunosuppressive agent is largely hampered by its narrow therapeutic range. This study focused on developing SRL tablets with a sustained release profile for better safety. SRL was highly water insoluble and its solubility has been efficiently enhanced by preparing self-microemulsifying drug delivery system (SMEDDS). The SRL-SMEDDS was physically adsorbed by microcrystalline cellulose (MCC). The sustained release of SRL was achieved by addition of hydroxypropyl methylcellulose (HPMC) to prepare tablets. The formulation of the tablets was optimized by single factor test and orthogonal design. The optimal formulation was composed of 10% of HPMC 100lv and 5% of HPMC K4M. The in-vitro release profiles of the optimal tablets were further investigated for the influence of hardness, shape, preparing method, release method, stirring speed, and medium. The release kinetic of SRL from the tablets was demonstrated to be erosion of HPMC. Pharmacokinetic study on beagle dogs showed that the SRL-SMEDDS tablets were bio-equivalent to the commercial tablets but lower Cmax and larger Tmax were achieved. In conclusion, the SMEDDS tablets were presented as promising delivery system for sustained release of SRL.
    Keywords: Sirolimus, Self-microemulsifying drug delivery system, Tablet, sustained release, Bio-equivalent
  • Zarin Sharifnia, Mojgan Bandehpour, Hamed Hamishehkar, Nariman Mosaffa, Bahram Kazemi, Nosratollah Zarghami * Pages 1659-1675
    Induction of protein synthesis by the external delivery of in-vitro transcription-messenger RNA (IVT-mRNA) has been a useful approach in the realm of cell biology, disease treatment, ‎reprogramming of cells, and vaccine design. Therefore, the development of new formulations for ‎protection of mRNA against nucleases is required to maintain its activity in-vivo. It was the aim of the present study to ‎investigate the uptake, toxicity, transfection efficiency as well as phenotypic consequences of ‎a nanoparticle (NP) in cell culture. NP consists of poly D, L-lactide-co-glycolide (PLGA) and polyethyleneimine (PEI) ‎for delivery of in-vitro transcription-messenger RNA (IVT- mRNA) encoded green fluorescent protein (GFP) in human monocyte-derived ‎dendritic cells (moDCs). Nanoparticles that were synthesized and encapsulated with synthetic GFP mRNA, exhibited size distribution in this formulation, with mean particle sizes ranging between 415 and 615 nm. Zeta potential was positive (above 12-13 mV) and the encapsulation efficiency exceeded 73.5%. Our results demonstrated that PLGA/PEI NPs encapsulation of GFP mRNA had ‎no toxic effect on immature monocyte-derived ‎dendritic cells and was capable of delivering of IVT-mRNA into moDCs and was highly effective. The expression of GFP protein 48 h after transfection was confirmed by flow cytometry, microscopic examination and western blotting assay. This NP can make a way to target moDCs to express a variety of antigens by IVT- mRNA. The ‎present study introduced the PLGA/PEI NP, which provided effective delivery of ‎IVT-mRNA that encodes the GFP protein.
    Keywords: PLGA, PEI, IVT- mRNA, GFP, Dendritic cells, Nanoparticle
  • Mohammad Reza Molaahmadi, Jaleh Varshosaz, Somayeh Taymouri *, Vajihe Akbari Pages 1676-1693
    Lipid nanocapsules (LNCs) represent a stable, biocompatible and worthwhile drug delivery system, demonstrating significant potential as gene/drug delivery platforms for cancer therapy. Imatinib, a potent tyrosine kinase inhibitor, has revolutionized the therapy of malignancies resulting from abnormal tyrosine kinase activity. However, its Clinical effectiveness in cancer treatment is hampered by its off-target side effects. In this study, we have investigated the potential benefits of LNCs as a novel drug delivery vehicle for imatinib with a view to improve drug efficacy. LNC formulations were prepared by phase-inversion temperature method and the effects of various formulation variables were assessed using full factorial design. The cytotoxicity and cellular uptake of optimized formulation were investigated against B16F10 melanoma cell line. Analysis of result by Design-Expert® software indicated that Solutol HS15 percent was the most effective parameter on the encapsulation efficiency, particle size, zeta potential, and release efficiency of LNCs. The optimized formulation revealed a particle size of 38.96 ± 0.84 nm, encapsulation efficiency of 99.17 ± 0.086 %, zeta potential of -21.5 ± 0.61 mV, release efficiencyof 60.03 ± 4.29, and polydispersity index of 0.24 ± 0.02. The imatinib loaded LNCs showed no hemolysis activity. Fluorescent microscopy test showed that the cellular uptake of LNCs was time dependent and density of fluorescent signals increased with time in cells. The in-vitro cytotoxicity study indicated that imatinib kept its pharmacological activity when loaded into LNCs. These results introduced imatinib loaded LNCs as a promising candidate for further investigation in cancer therapy.
    Keywords: Cancer chemotherapy, Imatinib, Lipid nanocapsules, Phase-inversion temperature method, B16F10 melanoma cells
  • Nima Hamzian, Maryam Hashemi, Mahdi Ghorbani, Seyed Amir Aledavood, Mohammad Ramezani *, Mohammad Hossein Bahreyni Toosi Pages 1694-1703
    This study aimed to modify the biological response of cells to ionizing radiation by combination therapy using radio-sensitizer agent and anticancer drug. Super paramagnetic iron oxide nanoparticles (SPIONs) were prepared and used with gemcitabine (Gem). These two agents were encapsulated simultaneously intopoly (D, L-lactic-co-glycolic acid) (PLGA) to form multifunctional drug delivery system. The physicochemical characteristics of the nanoparticles (NPs) were studied. The dose enhancement ratio (DER) of various treatment groups was calculated and compared using human breast cancer cell line (MCF-7). The DER for PLGA-SPION-Gem was the highest at 1 Gy60Co (3.18). Cumulative effect from simultaneous use of two radiosensitizer (Gem and SPIONs) was observed. Thus, we have successfully developed PLGA NPs loaded with gemcitabine and SPIONas a radiosensitizersystem which potentially could be used in radiotherapy.
    Keywords: Multifunctional drug delivery system, SPION-PLGA, Gemcitabine, Radiotherapy, Radiosensitizer
  • İsmail Yener, Hamdi Temel, Ozge Tokul, Olmez, Mehmet Fırat, Elif Varhan Oral *, Mehmet Akdeniz, Kerem Senturk, Erhan Kaplaner, Mehmet Ozturk, Abdulselam Ertaş Pages 1704-1724
    In this study, the branch, leaves, flowers, roots and mixed all parts of different nine Euphorbia species were analyzed for their trace element contents by using ICP-MS. The samples were digested by concentrated nitric acid and hydrogen peroxide in a microwave by ICP-MS before the analysis. The accuracy and precision of the method was evaluated by CRM 1573a Tomato Leaves. Trace element contents accumulated in different parts of each sample were contrasted. Minitab Statistical Software Inc., programme was used for the multivariate analysis of 12 toxic metals of seeds, roots, branches, leaves, flowers and mixed parts of Euphorbia species collected from Diyarbakir, Kayseri, Malatya, Mardin, Trabzon and Van cities.When the studied Euphorbia species are compared in terms of their metal contents; V, Tl, Cr and Ni metals in E. eriophora, Ba in E. aleppica, As and Co metals in E. segıieriana, Ag and Se metals in E. craspedia, Cu and Cd metals in E. fistulosa, Cs and Pb metals in E. grisophylla, Zn in E. macroclada and also Rb and Sr metals in E. denticulata were determined higher. It was determined that the studied species accumulated some metals at highly amounts especially in the root and leaf parts. In general, it can be said that Euphorbia species have high potential to become a biomonitor.For this reason, it can be predicted that these species will be used as ornamental plants in landscape architecture due to both their toxic metals retention properties and their beautiful appearance.
    Keywords: Euphorbia, Trace element, ICP-MS, Ornamental Plants, Chemometric Approach
  • Mehrnoush Kamali, Zeinab Pourghobadi * Pages 1725-1734
    In the present research, 4, 4'-biphenol was used as a homogeneous mediator for determining cysteine (CySH) on a Glassy Carbon Electrode (GCE). To describe the electrochemical properties of 4,4'-biphenol and to examine its electrocatalytic impacts on cysteine oxidation, both Cyclic Voltammetry (CV) and Linear Sweep Voltammetry (LSV) were employed. Our findings revealed that 4,4'-biphenol could significantly accelerate the reactions related to electron transfer to CySH. Moreover, the diffusion coefficient of CySH and its reaction with the catalytic constant of 4,4'-diphenoquinone was estimated via chronoamperometry technique.The results showed that cysteine concentration range of 10-1000 μM led to linear increases in the oxidation peaks, thus to providing a detection of 0.99 μM with R² = 0.993. A Relative Standard Deviation (RSD) of 2.5% was achieved after performing 7 cysteine replicates (100 μM), and CySH was successfully determined in real serum samples through the proposed approach.
    Keywords: Cysteine, 4, 4'-biphenol, Homogeneous mediator, Voltammetric determination
  • Behnam Dasht Bozorg, Ali Goodarzi, Fanak Fahimi, Payam Tabarsi, Nahid Shahsavari, Farzad Kobarfard, Farzaneh Dastan * Pages 1735-1741

    Therapeutic Drug Monitoring (TDM) of first-line anti-tuberculosis (TB) drugs is a decisive tool, allowing the clinician to successfully treat TB patients. The objective of the study was to develop and optimize a simple, sensitive, and reliable high-performance liquid chromatography (HPLC) method for the simultaneous determination of isoniazid (INH), pyrazinamide (PZA), and rifampin (RIF) levels in human plasma. Nicotinamide was used as the internal standard and the samples were prepared after protein precipitation using acetonitrile and zinc sulfate. The separation was achieved using a C18 reversed-phase applying gradient elution. The mobile phase was a combination of water–methanol solution with a ratio of 95:05 (v/v) at the initial phase. All calibration curves had good linearity (r2 > 0.99) and the inter- and intra-day RSDs were lower than 15%. The limit of detection with a signal-to-noise ratio (S/N) of 3:1 was 0.16, 0.5, and 0.33 μg mL–1 for INH, PZA, and RIF, respectively. The method presented here was selective, sensitive, and reproducible, and could be used for therapeutic drug monitoring in the patients who were under treatment with these drugs.

    Keywords: Anti-TB drugs, Therapeutic Drug Monitoring, HPLC-UV, Isoniazid, Pyrazinamide, Rifampin
  • Dhagash Vora, Neha Upadhyay, Kalpana Tilekar, Viral Jain, Ramaa C S * Pages 1742-1758
    Tuberculosis (TB) ranks second, next to AIDS making it most formidable disease if the present age. One of the crucial enzymes involved in cell wall synthesis of Mycobacterium tuberculosis, InhA (enoyl acyl carrier protein reductase) has been authenticated as an effective target for anti-mycobacterial drug development. In the current work, we have developed novel derivatives of 1,2,4-triazole-5-thione as promising InhA inhibitors. We rationally designed these 1,2,4-triazole-5-thione compounds, synthesized and spectrally characterized them. Anti-mycobacterial potential was determined by resazurin microtiter assay using Mtb H37Rv strain. The mechanism of action of these compounds was confirmed by InhA enzyme inhibition studies. The most active compound of the series displayed MIC of 0.19 µM in resazurin microtiter assay and InhA inhibition with IC50 of 90 nM.
    Keywords: Mycobacterium tuberculosis, 4-triazole-5-thiones, InhA inhibition, ADME, REMA
  • Leila Hejazi, Elham Rezaee *, Sayyed Abbas Tabatabai Pages 1759-1769
    Soluble epoxide hydrolase enzyme is a promising therapeutic target for hypertension, vascular inflammation, pain and some other risk factors of cardiovascular diseases. The most potent sEH inhibitors reported in the literature are urea-based ones which often have poor bioavailability. In this study, in a quest for finding potent inhibitors of soluble epoxide hydrolase, some 4,6-disubstituted pyridin-2(1H)-one derivatives were designed and synthesized. The designed compounds fit properly in the active site pocket of this enzyme in docking studies and have appropriate distances for effective hydrogen binding to important amino acids Tyr383, Tyr466, and Asp335. The results of biological evaluation of these compounds against soluble epoxide hydrolase enzyme indicate most compounds have acceptable inhibitory activity and compound 9c is the most potent inhibitor with inhibitory activity of 86%.
    Keywords: Soluble epoxide hydrolase, Pyridinone, docking, Inhibitor, Synthesis
  • G Wilson Cardona, R Angie Herrera, Laura Juliana Prieto, Laura Conesa Milián, Miguel Carda, Tonny Naranjo, Maria Elena Maldonado Pages 1770-1789

    We have synthesized a series of S-allyl cysteine ester-caffeic acid amide hybrids and evaluated them in order to determine their possible anticancer activity and selectivity in colorectal cancer, which is still one of the leading causes of morbidity and mortality worldwide. All compounds were tested against SW480 human colon adenocarcinoma cells and the non-malignant CHO-K1 cell line. Among the tested compounds, hybrids 6e, 9a, 9b, 9c and 9e exhibited the highest effect on viability (IC50 SW480-48h= 0.18, 0.12, 0.12, 0.11 and 0.12 mM, respectively) and selectivity (SI= 10.3, 1.5, >83.33, >90.91 and >83.33, respectively) in a time- and concentration-dependent manner. Besides, our results were even better as regards lead compounds (S-allyl cysteine and caffeic acid) and the standard drug (5-FU). Additionally, these five compounds induced mitochondrial depolarization that could be related with an apoptotic process. Moreover, hybrids 6e, 9a and 9e induced cell cycle arrest in G2/M phase, and compound 9c in S- phase, which suggests that these hybrid compounds could have also a cytostatic effect in SW480 cell line. The SAR analysis showed that hydroxyl groups increased the activity, besides, there was not a clear relationship between the antitumor properties and the length of the alkyl chain. Since hybrid compounds were much more selective than the conventional drug (5-FU), this make them promising candidates for further studies against colorectal cancer.

    Keywords: S-allyl cysteine, caffeic acid, hybrid, Cell death, Colorectal cancer
  • Seyyed Mohammad Ismaeil Mahboobirabbani, Roholah Vahabpour Rodsari, Zahra Hajimahdi *, Afshin Zarghi Pages 1790-1802
    HCV-induced hepatitis is one of the most debilitating diseases. The limited number of anti-HCV drugs and drug-resistance necessitate developing of new scaffolds with different mode of actions. HCV non-structural protein 5B (NS5B) is an attractive target for development of novel inhibitors of HCV replication. In this paper, new N'-arylidene-6-(benzyloxy)-4-oxo-1,4-dihydroquinoline-3-carbohydrazide derivatives were designed based on the pharmacophores of HCV NS5B active site binding inhibitors. Designed compounds were synthesized and evaluated for their inhibitory activities in a cell-based HCV replicon system assay. Among tested compounds, compounds 18 and 20 were found to be the most active (EC50 = 35 and 70 M, respectively) with good selectivity index (SI > 2) in the corresponding series. Molecular modeling studies showed that the designed compounds are capable of forming key coordination with the two magnesium ions as well as interactions with other key residues at the active site of HCV NS5B.
    Keywords: Synthesis, Design, 4-Oxo-1, 4-dihydroquinoline-3-carbohydrazide, HCV, NS5B polymerase, Molecular modeling studies
  • Chaoqing Wang, Yan Wang, Qingsong Deng, Xiujie Liu * Pages 1803-1815
    In our present investigation, a series of novel 4-methoxy-1,3-benzenediolyl-hydrazones were designed and synthesized, and their ability to inhibit platelet aggregation was evaluated by adenosine diphosphate (ADP) and arachidonic acid (AA). The structures of the synthesized compounds were confirmed by spectral data. Results demonstrated that the activities of all compounds excelled the positive drug Picotamide (25.1 % inhibition rate) and seven compounds (PNN01, PNN03, PNN05, PNN07, PNN09, PNN12, PNN14) have efficiently inhibited platelet aggregation even higher than Clopidogrel (37.6 % inhibition rate) induced by AA. Among them, PNN07 (39.8 % inhibition rate) was considered as the most potent analogue. Evaluation of cytotoxic activity of the compounds against L929 cell line revealed that none of the compounds have significant cytotoxicity. Thus, diolylhydrazones derives are potential to be antiplatelet aggregation inhibitors and maybe working in AA-induced selectively.
    Keywords: 4-methoxy-1, 3-benzenediolylhydrazones, Anti-platelet aggregation, Cytotoxicity, Picotamide
  • Seyed.Esmaeil Sadat Eebrahimi, Maryam Mirmohammadi, Zahra Mojallal Tabatabaei, Marjan Azimzadeh Arani, Sogol Jafari Ashtiani, Mahsa Hashemian, Parham Foroumadi, Azadeh Yahya Meymandi, Setareh Moghimi, Mohammad Hasan Moshafi, Peiman Norouzi, Sussan Kabudanian Ardestani, Alireza Foroumadi * Pages 1816-1822

    In this study, a series of novel compounds based on 5-(5-nitrothiophene-2-yl)-1,3,4-thiadiazole possessing (het)aryl thio pendant at C-2 position of thiadiazole ring is developed and evaluated as antileishmanial agents using MTT colorimetric assay. 10 New compounds containing aryl and hetero aryl derivatives, started from thiophene-2-carbaldehyde in five steps, were synthesized in good to excellent yields and characterized by 1H-NMR, 13C-NMR and IR spectroscopy. Through the compounds 6a-j, methylimidazole containing derivative 6e was recognized as the most active compound against L. major promastigotes exhibiting IC50 values of 11.2µg/ml and 7.1µg/ml after 24 and 48 hours, respectively. This compound is >4 fold more effective than Glucantime as a standard drug (IC50 = 50 µg/ml after 24 h and 25 µg/ml after 48 h).

    Keywords: Leishmaniasis, Promastigote, 4-Thiadiazole, MTT assay, Synthesis
  • Kiana Esfandiari Mazandaran, Sayed Ahmmad Mirshokraee, Khdijeh Didehban, Mohammad Hassan Houshdar Tehrani * Pages 1823-1830
    Cancer has emerged as a leading cause of death throughout the world. Peptides are a novel class of anticancer agents that can specifically target cancer cells with low toxicity to normal tissues and thus, offer new opportunities for future cancer treatment. On the other hand, Ciprofloxacin, an antibiotic, also known to its anticancer property for enabling cell cycle arrest and creating double strand breaks in nucleic acid, can trigger apoptosis of cancer cells. Thus, joining anticancer peptides with Ciprofloxacin may be good idea to get benefit of the both compounds’ properties and therefore gives better anticancer agents. The aim of this study was to synthesize Ciprofloxacin- cytotoxic peptide conjugates and investigate the anticancer activity of the resultant compounds. The conjugates were prepared by solid phase peptide synthesis technique using Fmoc strategy. Anticancer activity of these compounds was examined on three cancer cell lines, HT-29, MCF-7, MDA-MB-231 as well as skin fibroblast cells as a control, employing MTT test. . Our results showed that the cytotoxic activity of the synthesized compounds against cancer cells was raised considerably without producing a high toxicity on normal cells. Moreover, Ciprofloxacin-peptide conjugates showed selectivity against different kinds of breast cancer cells, especially on those with triple negative receptors. Therefore, it can be suggested that the strategy of making Ciprofloxacin- peptide conjugates as cytotoxic agents with safety profiles on the normal cells, rise promise to find better chemotherapeutic candidates to combat cancer.
    Keywords: Ciprofloxacin- peptide conjugates, Anticancer agents, colon cancer, Breast Cancer, Solid phase peptide synthesis, MTT test
  • Gulin Renda *, Arzu Özel, Burak Barut, Büşra Korkmaz, Nurettin Yaylı Pages 1831-1842
    The volatile organic compounds (VOCs) of two Coronilla species (Coronilla orientalis Miller and Coronilla varia L.) obtained by hydrodistillation (HD) and solid phase microextraction (SPME) techniques were identified by GC-FID/MS. The major compounds identified in the SPME extracts were limonene (43.4%) in C. orientalis, (Z)-β-ocimene and (E)-β-ocimene (34.3% and 32.4%) in C. varia, whereas, the essential oils of C. orientalis and C. varia were rich with γ-terpinene (22.4%) and phytol (30.7%), respectively. In addition, acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), tyrosinase, α-glucosidase enzyme inhibitory, and radical scavenging activities (DPPH) of chloroform, ethyl acetate, methanol, and water extracts, and also essential oils obtained from C. orientalis and C. varia were investigated. The tyrosinase activity was studied at the doses of 25 µg/mL, 50 µg/mL and 100 µg/mL. Tyrosinase inhibition percentage was observed to increase by dose and methanol extracts of the both species were found to have the highest activity. Essential oils of the both species were found to have significant acetylcholinesterase and butyrylcholinesterase inhibition activities. α-Glucosidase enzyme inhibition of the ethyl acetate and water extracts of C. orientalis was determined as 80.11 ± 4.07% and 80.32 ± 3.47% at the 100 µg/mL concentration, respectively. Essential oils, chloroform, ethyl acetate, methanol, and water extracts were determined to have moderate DPPH radical scavenging activities.
    Keywords: essential oil, SPME-GC-MS, Acetylcholinesterase, Butyrylcholinesterase, Tyrosinase, α-Glucosidase, DPPH
  • Abdollmajid Ayatollahi, Jalil Rahmati, Ahmad Salimi *, Jalal Pourahmad Pages 1843-1853
    Natural products isolated from plant sources are well known for their pharmacological potential in diversity of disease treatments such as inflammatory or cancer conditions. Mango (Mangifera indica L.) and Juglans regia are thought to be rich of functional phytochemicals. To elucidate the anticancer activity of Juglans regia (JR) and Mangifera indica L (MI) aqueous extract were investigated on chronic lymphocytic leukemia (CLL) B lymphocytes and their mitochondria and the results were compared with those of normal B lymphocytes. Cellular parameters such as viability and caspase 3 activity, and mitochondrial parameters such as reactive oxygen species (ROS), mitochondria membrane potential (MMP), mitochondrial swelling and cytochrome c release were evaluated. Our results showed the extract of Mangifera indica L increased cytotoxicity and caspase 3 activation through mitochondria pathway only in CLL B lymphocytes and also the extract of Juglans regia not showed cytotoxicity and caspase 3 activation on CLL and healthy B lymphocytes. Our in vitro findings on isolated mitochondria showed that mitochondrial ROS formation, MMP collapse, and mitochondrial swelling and cytochrome c release were significantly (P < 0.05) increased after addition of Mangifera indica only in cancerous mitochondria. These results showed that Mangifera indica can act as a promising source for anti-cancer drug candidates by directly and selectively targeting mitochondria and inducing selective mitochondria mediated apoptosis on CLL B lymphocytes.
    Keywords: Mangifera indica, Juglans regia, Chronic Lymphocytic Leukemia, Mitochondria, Cytotoxicity, Anticancer activity
  • Mariana G Selener, Orlando Elso, Carla Grosso, Jimena Borgo, Maria Clavin, Emilio L Malchiodi, Silvia I Cazorla, Flavia Redko, Valeria P Sülsen * Pages 1854-1861
    The anti-Trypanosoma cruzi activity of extracts from 13 Argentinean Asteraceae species was determined. Dichloromethane and methanol extracts of Acmella bellidioides, Aspilia silphioides, Viguiera tuberosa, Calyptocarpus biaristatus, Hyalis argentea, Helenium radiatum, Gaillardia megapotamica, Verbesina subcordata, Gymnocoronis spilanthoides, Viguiera anchusaefolia, Thelesperma megapotamicum, Zexmenia buphtalmiflora and Vernonia plantaginoides were evaluated in vitro against Trypanosoma cruzi epimastigotes. A. silphioides, V. tuberosa, V. subcordata, G. spilanthoides, G. megapotamica, T. megapotamicum and Z. buphtalmiflora dichloromethane extracts showed trypanocidal activity with inhibitions higher than 60% at a concentration of 10 µg/mL. The methanol extracts of H. radiatum and G. megapotamica were the most active with inhibitions of 70.1 and 77.7%, respectively at 10 µg/mL. The chromatographic profiles of the most active extracts showed bands and major peaks that could be attributed to flavonoids and terpenoid compounds.
    Keywords: Asteraceae, Chagas' disease, Flavonoids, terpenoids, Trypanosoma cruzi
  • Nika Khoshnevis, Shahla Rezaei, Hamid Forootanfar, Mohammad Ali Faramarzi * Pages 1862-1870
    Sustainable development in the bio-treatment of large-scale biomass bulks requires high performance enzymes adapted to extreme conditions. An extracellular keratinolytic extract was obtained from the culture broth of a halotolerant strain of Salicola marasensis. Keratin hydrolyzing activity of the concentrated enzyme extract was observed on a 100 mg of pretreated feather waste. The concentrated enzyme was able to hydrolyze the poultry feathers by 25% after 12 h incubation. The bio-waste material was optimally hydrolyzed at pH 9 and temperature of 40 °C. Among reductants, 1,4-dithiothreitol, L-cysteine, 2-mercaptoethanol, glutathione, and sodium sulfate showed the most remarkable effect on the bio-waste keratinolysis, while the tested surfactants and urea had no significant effect on the keratinolytic activity. Hexane and hexadecane indicated strong effect on keratinase activity and bio-treatment in the presence of 1-butyl-3-methylimidazolium hexafluorophosphate ([BMIM][PF6]) as a hydrophobic ionic liquid resulted in a maximal of 80% extraction yield of soluble proteins from feathers. Considering the stability of the extracellular keratinolytic content in [BMIM][PF6], the observed keratinase activity was noteworthy suggesting that the secreted enzyme may contribute to the bioconversion of feather wastes.
    Keywords: Salicola marasensis, Halotolerant, Keratinolytic activity, Feather wastes, Ionic liquid
  • Samaneh Karimi, Farzaneh Lotfipour, Solmaz Asnaashari, Parina Asgharian *, Yaser Sarvari, Saeid Hazrati Pages 1871-1883
    Due to the increase of microbial resistance to antibiotics and the occurrence of side effects, use of medicinal plants with anti-microbial properties seems to be rational. Hence, in this study, some plants of the Apiaceae, Asteraceae, Brassicaceae, and Cucurbitaceae families were evaluated for antimicrobial effects. The aerial parts of the plants were extracted by different solvents using a Soxhlet apparatus. Subsequently, the inhibitory effect of the extracts on different microbial species was assessed. Extracts with high growth inhibitory effect were fractionated and their MIC was determined. Furthermore, primary phytochemical and GC-MS analysis were used to identify the chemical compounds of potent samples of n-hexane extracts of Eryngium caerulum (E. caeruleum) and Eryngium thyrsoideum (E. thyrsoideum.) Both plants showed considerable antimicrobial activities against Staphylococcus epidermidis   among the fractions, 40% and 60% VLC fractions of n-hex extract of E. caeruleum and 40% VLC fraction of n-hexane extract of E. thyrsoideum illustrated the most growth inhibitory effect. Moreover, the results of preliminary phytochemical and GC-MS analysis confirmed that steroids, fatty acids and terpenoids play an important role to show anti-microbial activity, respectively. Among all samples, the 40% VLC fraction of n-hexane extract of E. thyrsoideum for possessing high amounts of fatty acids and terpenoids indicated the most anti-microbial potency.
    Keywords: Antimicrobial effect, Eryngium caeruleum, Eryngium thyrsoideum, GC-MS analysis, phytochemical profile
  • Razieh Nabimeybodi, Rahele Zareshahi, Mojgan Tansaz *, Marzieh Vahid Dastjerdi, Homa Hajimehdipoor Pages 1884-1901
    Introduction
    Cervicitis is an inflammatory condition of the cervix associated with upper genital tract infection and reproductive complications. Treatment for cervicitis in conventional system is the use of antibiotics and antifungal therapies and surgical interventions, but none of these treatments provides the definite efficacy in spite of high cost and side effect. So there is a need for an alternate therapy which is safe, effective, easily available and free from side effects. This review focuses on medicinal plants mentioned in main Iranian Traditional Medicine reference books.
    Materials and Methods
    Medicinal plants mentioned in Iranian Traditional Medicine for treatment of Cervicitis were elicited and searched in electronic databases including Pub Med, Scopus, Science direct and Google Scholar to find studies that confirmed their efficacy.
    Results and Discussion
    The findings included 31 plants belonging to 21 families. Research findings showed that the plants mentioned in Iranian Traditional Medicine resources can contribute to the recovery and treatment of cervicitis through anti- inflammatory, anti- oxidant, anti- bacterial and anti- fungal, wound healing and analgesic effects.
    Conclusion
    Finding the medicinal plants effective on cervicitis based on ITM could suggest a better strategy for relieving and management of cervicitis symptoms especially in recurrent or persistent condition.
    Keywords: Cervicitis, Iranian traditional medicine, Medicinal plants, Anti-inflammatory, Antibacterial, Antifungal, wound healing
  • Javad Ghasemian Yadegari, Sanaz Hamedeyazdan, Hossein Nazemiyeh, Fatemeh Fathiazad * Pages 1902-1911
    Astragalus is a well-known genus in Leguminosae family that represented more than 800 species growing in Iran. Nevertheless, there are a few reports on Astragalus plants endemic to Iran. The roots of Astragalus plants are rich in saponins, flavonoids and polysaccharides that possess various pharmacological activities. In present study, Chemical components, antioxidant and antibacterial activity of Astragalus crysostachys Boiss. roots were evaluated. For determination of phytochemicals in Astragalus chrysostachys Boiss. roots, total hydroalcoholic extract was fractionated with ethyl acetate and n-butanol. Ethyl acetate extract as a flavonoid rich extract was analyzed using vacuum liquid chromatography and preparative TLC and consequently a major flavonoid was isolated. The structure of the obtained compound was elucidated with 1D and 2D NMR experiments. Additionally, the essential oil of the roots was analyzed by GC-MS. Antioxidant activity of all extracts was evaluated by different assays. Moreover, antibacterial activities of the extracts were also investigated against 2 Gram-positive and 2 Gram-negative bacteria using Micro-dilution Broth method. Apigenin-6, 8-di-C-glucoside was detected in ethyl acetate extract for the first time in genus Astragalus. In addition, m-tolualdehyde, acetophenone, croweacin were found to be characteristics of the volatile oil of roots. Ethyl acetate extract revealed notable antioxidant activity in DPPH scavenging assay with IC50 value of 14.6 µg/mL. Evaluation of antibacterial activity on the tested extracts showed mild activity against Gram-positive bacteria. Since there have been no reports on Astragalus crysostachys Boiss. to date, the present data might be promising for application of this plant derivatives in phytotherapeutic practice.
    Keywords: Apigenin-6, 8-di-C-glucoside, Croweacin, GC, MS, DPPH scavenging, essential oil
  • Seyed Ahmad Emami, Shima Kheshami, Elham Ramazani, Maryam Akaberi, Milad Iranshahy, Seyed Mahammad Kazemi, Zahra Tayarani Najaran * Pages 1912-1920

    Chaharmahal and Bakhtiari province is a most important endemism states of flora of Iran with a considerable plant species diversity in the country. In the present study the cytotoxic activity of 13 plant species grown in Chaharmahal and Bakhtiari have been evaluated on prostate (PC-3), breast (MCF-7), liver (HepG2), ovary (CHO) and melanoma (B16-F10) cancer cell lines. The cytotoxicity and apoptotic activity of methanol extracts was valuated using resazurin reagent and flow cytometry of PI stained cells, respectively. Methanol extracts of Dionysia sawyeri, Stachys obtusicrena and Cicer oxyodon on CHO cell line (p <0.05) and D. sawyer and Linnum album on B16/F10 cell line (p <0.05) showed significant cytotoxic effects and increased apoptosis. It is generally suggested that plant species with low IC50 values are likely to be used as anti-cancer compounds in reducing cancer progression in scientific studies.

    Keywords: Cicer, Linnum, Dionysia, Stachys, cytotoxic, Apoptosis
  • Reyhaneh Babaei Khorzoughi, Fatemeh Namvarjah, Maryam Teimouri, Hossein Hosseini, Reza Meshkani * Pages 1921-1930
    Metformin and berberine have been reported to have lipid lowering effects. This study aims to investigate lipid lowering effects of berberine and metformin, alone and in combination, in HepG2 cells to determine whether berberine and metformin work synergistically and elucidate their mechanisms. HepG2 cells were treated with 33 mM glucose in the presence of various concentrations of berberine and metformin, alone and in combination, for 24 h. The cytotoxic effects of these compounds were determined by MTT assay. Oil red O staining, triglyceride measurement, and gene expression analyses were performed to evaluate the effects of these compounds on hepatocytes lipogenesis. Berberine at doses 20 µM and 40 µM and metformin at doses 1 mM  and 2 mM reduced total lipid content and triglyceride level in HepG2 cells. Metformin (mM) and berberine (µM) at combination ratios of 2:40, 1:20, 0.5:10, and 0.25:5 exhibited a synergistic lipid-lowering effect on HepG2 cells. These ratios could significantly decrease total lipid content and triglyceride level in HepG2 cells. The lowest dose of the combination [metformin (0.25 mM) and berberine (5 μM)] also synergistically reduced the expression of the FAS and SREBP-1c genes in HepG2 cells treated with high glucose. The combination of metformin and berberine exerted synergistic lipid-lowering effects on HepG2 cells by reducing total lipid content, triglyceride level, and the expression of the genes involved in lipogenesis.
    Keywords: Diabetes, Lipogenesis, Metformin, Berberine, Combination, NAFLD
  • Yadid Chávez Morales, Enrique Jiménez Ferrer, Gabriela Belen Martínezhernánde, Jaime Tortoriello, Rubén Román Ramos, Alejandro Zamilpa, Maribel Herrera Ruiz * Pages 1931-1946

    Depression affects more than 300 million people worldwide, represents one of the leading causes of disability worldwide. Treatment is based on the use of tricyclic antidepressant, selective serotonin reuptake inhibitors, between others; that although are clinically effective has a delayed onset activity and produce important side effects. Medicinal plants are presented as a source of study in the search for therapies, this study was aimed to assess the antidepressant effect (on forced swimming test -FST- and tail suspension test -TST-) of different fractions and tiliroside from Tilia americana. The organic fractions (FAC1-1, FAC1-2) and aqueous fractions (FAqC2-1, FAqC2-3) were obtained by column chromatography and the HPLC analysis allowed the standardization based on the concentration (mg/g) of several compounds: FAqC2-1 with tiliroside 20, quercitrin 41.7 and quercetin glucoside 73.8; FAqC2-3 with tiliroside 2.4, quercitrin 16.6 and 7-O-luteolin glucoside 35.9; FAC1-1 caffeic acid was quantified with 7.87 ; FAC1-2 with tiliroside 24.7 and quercitrin 19.8. Each fraction was tested in ICR mice at different dose in the FST and TST, as well as in the open field test (OFT); tiliroside was isolated and tested in such assays (at 0.05, 0.1, 0.5, and 1.0 mg/kg). All fractions were active, the better was FAC1-2, and induced a dose-dependent effect on FST with an ED50= 2.59 mg/kg and Emax=175.4 sec; with a sedative effect in OFT. Tiliroside with like-antidepressant activity, showed a dose-response behavior (ED50= 0.04 mg/kg and Emax=121.42 sec for FST; ED50= 0.014 mg/kg and Emax=78.28 sec for TST).

    Keywords: Tilia americana, Flavonoids, Tiliroside, Antidepressant, FST, TST
  • Mohammad Hossein Boskabady *, Mahsa Kaveh, Farzaneh Shakeri, Noema Mohammadian Roshan, Ramin Rezaee Pages 1947-1958
    Objective
    The effects of Portulaca oleracea (P. oleracea; PO) on total and differential WBC count, and oxidant/antioxidant biomarkers in bronchoalveolar lavage fluid (BALF) as well as on lung pathology in asthmatic rats were examined. Methods and
    Methods
    Rats were randomly divided into; control group (C), asthma group, asthma groups treated with either P. oleracea (rats that received PO 1, 2 and 4 mg/ml) or dexamethasone 1.25 μg/ml (D), (n=8 in each group). Total and differential white blood cells (WBC) count, nitrite (NO2), nitrate (NO3), malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT) and thiol levels in rats BALF were evaluated and lung pathological features were studied.
    Results
    Total WBC count, eosinophil, neutrophil and monocyte percentages, levels of NO2, NO3, MDA in the BALF and most pathological scores in the lung were increased but lymphocyte percentage, SOD, CAT and thiol levels were decreased in the BALF of asthmatic animals (p
    Conclusion
    Our results demonstrated the ameliorative effects of P. oleracea on total and differential WBC count and oxidant-antioxidant biomarkers levels in BALF as well as lung pathological features in asthmatic rats, which propose the usage of this extract as a preventive anti-inflammatory treatment against asthma.
    Keywords: Portulaca oleracea, WBC, Oxidant, antioxidant levels, Lung inflammation, Asthmatic rats
  • Hamzeh Pasban Aliabadi *, Vahid Sobhani, Saeed Esmaeili Mahani, Hamid Najafipour, Alireza Askari, Hamid Reza Jalalian Pages 1959-1966

    Pistacia atlantica is one of the species of Anacardiaceae that grows in the wild in different regions of Iran. Traditionally, anacardiaceae family has antibacterial, fungicidal and cytotoxic properties. Therefore, the present study was designed to investigate the possible cytotoxic and anti-proliferative properties of Baneh gum. Cytotoxicity of the plant gum was determined using MTT assay on MCF-7 human breast cancer cells. The cellular makers of apoptosis (caspase3 and P53) and cell proliferation (Cyclin-D1) were evaluated by western blotting. Doxorubicin was used as anticancer control drug in combination treatment. The result showed that Baneh gum (100 µg/ml) significantly induced cell damage, activated caspase3 and increased P53 protein level. In addition, Cyclin-D1 was significantly decreased in gum-incubated cells. Furthermore, combination treatment of cells with Baneh gum (25 µg/ml) and doxorubicin (200 nM) produced a significant cytotoxic effect as compared to each drug alone. In conclusion, Baneh gum (100 µg/ml) has a potential pro-apoptotic/anti-proliferative property against human breast cancer cells and its combination with doxorubicin in low doses may induce cell death effectively and be a potent modality to treat this type of cancer.

    Keywords: Baneh gum, anti-apoptotic, anti-proliferative, MCF-7, and doxorubicin
  • Rania Shebl * Pages 1967-1977
    Mutational inactivation of p53 is a key player in the development of human cancer. Thus, retrieving the tumor suppressor activity of p53 gene is considered a novel strategy in cancer therapy. Current study aimed to investigate the anti-cancer potentials of botulinum toxin type-A (BTX-A) and captopril as a trial to shed light on effective anti-cancer therapy with lower side effects. Cytotoxic effect of captopril and BTX-A was determined using MTT assay against colon (HCT116) and prostate cancer (DU145) cells compared to their effect on normal vero cells. Anti-proliferation assay and anti-metastatic effect were carried out using trypan blue exclusion method and wound scratch migration test, respectively. The ability of test drugs to induce apoptosis in cancer cells was examined using real time PCR. Recorded data revealed that captopril exhibited a statistically significant cytotoxicity (P < 0.05) to cancer cells (IC50 values of 1.5 and 1.2 mg/mL) with much lower toxicity to normal cells. At the same time, IC50 values post BTX-A treatment were 7.2 and 6.4 U/mL for HCT116 and DU145 cells, respectively without any toxicity to vero cells. Both drugs showed inhibitory potentials on cellular proliferation and the ability of cancer cells to migrate in scratched monolayers was obviously inhibited along with increasing their concentrations. P53 expression levels in captopril and BTX-A treated DU145 cells were elevated by 4 and 2.5 folds, respectively, while lower level of apoptosis induction in HCT116 cells was observed. Accordingly, BTX-A and captopril could present potential anti-cancer candidates through triggering cancer cells towards self-destruction.
    Keywords: Captopril, Botulinum toxin, Anti-cancer, Apoptosis, Metastasis
  • Fatemeh Honarvar, Vida Hojati, Nuredin Bakhtiari, Gholamhassan Vaezi, Mohammad Javan * Pages 1978-1988
    Neuronal survival in multiple sclerosis (MS) and other demyelinating diseases depends on the preservation of myelin and remyelination of axons. Myelin protection is the main purpose to decrease myelin damage in the central nervous system (CNS). Ursolic acid (UA) as a natural product in apple is suggested to protect neural cells. This study is the first to demonstrate an effect for UA on CNS myelin loss induced by cuprizone toxin. In the current study, we hypothesized that daily treatment with UA in drinking water (1 mg/ml) prevents myelin damage by 6 weeks administration of CPZ in mice pellet which lead to corpus callosum axonal demyelination. We assessed the myelin content and the number of myelinating cells in corpus callosum by FluoroMyelin and luxol fast blue staining as well as by immunostaining against MBP and Olig2. Our finding indicated that UA could decrease the extent of demyelination area and enhanced myelin stain intensity within CC and protected oligodendrocyte lineage cells against cuprizone toxin. We could conclude that myelinated structures could be protected by UA in corpus callosum, which provide favorable evidence for the possibility of application of UA in demyelinating diseases and traumatic injuries.
    Keywords: Multiple sclerosis, Myelin protection, Myelination, Ursolic acid, Corpus callosum, Mouse
  • Goksun Demirel *, Esra Guzel, Chad Craighton, Yeter Erol Ozturk, Ceyhun Kucuk, Hizir Asliuksek, Türkan Yurdun Pages 1989-1999
    Aim 3,4-methylenedioxymethamphetamine (MDMA) is one of the most widespread illegal drugs, used particularly by young people in the 15-34 age group. MicroRNAs (miRNAs) are endogenously synthesized, non-coding and small RNAs that post-transcriptionally regulate their target genes’ expression by inhibiting protein translation or degradation. miRNAs are increasingly implicated in drug-related gene expressions and functions. Notably, there are no reports of miRNA variation in the human brain in MDMA abuse. We here present a miRNA profiling study – the first such study, to the best of our knowledge – into the post-mortem human brains of a sample of people with MDMA abuse, along with non-drug dependent controls. Methods The miRNA profiling of nucleus accumbens (NAc) and ventral tegmental areas (VTA) was performed by microarray analysis. Subsequently, two candidate miRNA putative biomarkers were selected according to significant regional differential expression (miR-1202 and miR-7975), using quantitative reverse-transcription PCR (qRT-PCR). Results We showed that the expression level of miR-7975 was significantly lower in the VTA regions of the 30 MDMA users, as compared with the 30 control samples. Another significantly deregulated miR-1202 was down-regulated in the NAc regions of 30 MDMA samples in comparison to the control samples. Conclusions Alteration of these miRNAs can potentially serve as novel biomarkers for MDMA abuse, and warrant further research in independent and larger samples of patients.
    Keywords: MicroRNA, 4-methylenedioxymethamphetamine, Ventral tegmental area, Nucleus accumbens, Microarray research
  • Nima Bagherpasand, Soghra Mehri, Mahdieh Jafari Shahroudi, Seyed Meghdad Tabatabai, Ali Khezri, Mohammad Fathi, Khalil Abnous, Mohsen Imenshahidi, Hossein Hosseinzadeh * Pages 2000-2010
    In this study, the effect of topiramate, as an antiepileptic drug, was evaluated on morphine craving in rats. The conditioned place preference (CPP) test was used for this purpose. Repeated administration of morphine (10 mg/kg, i.p. for 4 days) induced significant CPP. Administration of topiramate (50 and 100 mg/kg, i.p. for 4 days) with each morphine administration decreased the acquisition of morphine-induced CPP. At the next step, the levels of extracellular signal-regulated kinase (ERK), p-ERK, cAMP responsive element binding (CREB), and p-CREB proteins were evaluated in hippocampus and cerebral cortex using western blot analysis. Following the repeated administration of morphine, the level of p-ERK protein markedly enhanced in both tissues, while topiramate could significantly reduce the phosphorylation of ERK in these brain regions. Additionally, the level of CREB and p-CREB proteins did not change in different groups. Memantine as a positive control reduced the acquisition of morphine-induced CPP. Also, memantine significantly decreased the level of p-ERK protein in hippocampus and cerebral cortex.  These results demonstrated that topiramate can attenuate the acquisition of morphine-induced CPP in rats. This effect in part can be mediated through down regulation of p-ERK protein in hippocampus and cerebral cortex.
    Keywords: Topiramate, Conditioned place preference, morphine, CREB, ERK
  • Ali Aydin *, Sengul Aslan Korkmaz Pages 2011-2027
    The present study was conducted in order to investigate the pharmacological activities of three heterobimetallic coordination compounds: [Cd(N-bishydeten)2][Ni(CN)4] (C1), [Cu2(N-bishydeten)2Co(CN)6].3H2O (C2), and K[Cd(N-bishydeten)Co(CN)6].1.5H2O (C3) (N-bishydeten = N,N-bis(2-hydroxyethyl)-ethylenediamine). This paper describes the ability of complexes to inhibit cell growth, cell migration and human topoisomerase I and to interact with DNA/BSA; this paper also evaluates the potential mechanisms of action exhibited by these compounds via the use of TUNEL, IHC, DNA fragmentation and restriction endonuclease inhibitor activity techniques. Studies on HT29, HeLa, C6 and Vero cells revealed that each compound demonstrated significant antiproliferative activity in conjunction with regressed cell migration velocity and caused apoptotic changes in cell surface morphology such as cell rounding, membrane blebbing and blistering followed by DNA fragmentations. There is strong data to suggest that the mechanisms of action exhibited by these compounds are associated with their DNA/BSA binding features. The IC50 and binding constant range for the compounds are 20-180 µM and 1.2-3.2 x 104 M-1, respectively. Moreover, we observed that these compounds alter the P53-Bcl-2 ratio, indicating differentiation in cellular fate leading to cell death. Furthermore, they also inhibit the relaxation activity of human topoisomerase I which regulates the topological states of the DNA and inhibit KpnI or BamHI restriction endonucleases. Both effects of these compounds may be used in combination with adjuvant therapy for cancer. In conclusion, preliminary information demonstrates that these compounds have found to exhibit effective antiproliferative activity against cancer cell lines, indicating that they are a potent candidate for further pharmacological studies.
    Keywords: Heterobimetallic compound, Cadmium, Cobalt, copper, antiproliferative, N-bis(2-hydroxyethyl)-ethylenediamine
  • Ezatollah Ghasemi, Fatemeh Ghaffarifar *, Abdolhossein Dalimi, Javid Sadraei Pages 2028-2041
    This study aimed to evaluate the antileishmanial efficacy of oxaliplatin against Leishmania major both in-vitro and in-vivo. The IC50, CC50, and SI of oxaliplatin against promastigotes, murine macrophages, Raw 264.7 cells, and intramacrophage amastigotes of L. major were investigated in-vitro. The effects of this drug on intracellular amastigotes were also assayed, and the percentage of infectivity and IIR were calculated. Flow cytometry was performed to assay apoptosis, using 50 and 100 µg/mL of oxaliplatin in the promastigotes and macrophages. In-vivo, the  BALB/c mice were classified into three groups, receiving oxaliplatin, glucantime, and phosphate-buffered saline for one month, respectively. The lesion size, IFN-γ, and IL-4 levels, and parasite burden were also evaluated in the animals. After 72 h, the IC50 and CC50 of oxaliplatin against promastigotes and macrophages were respectively 0.5 and 66.78 µg/mL. The apoptosis of promastigotes and macrophages using 50 µg/mL of oxaliplatin was 7.25% and 2.14%, respectively, while apoptosis induced at 100 µg/mL was 15.48% and 2.80%, respectively. Similar to the glucantime group, the mice treated with oxaliplatin showed a lower parasite burden and smaller lesions, compared with the PBS group (p < 0.01). Furthermore, higher IFN-γ levels were reported in mice receiving oxaliplatin in comparison with those receiving PBS (p < 0.01). The current findings indicated the efficacy of oxaliplatin against promastigote and amastigote forms of Leishmania and L. major-inducedleishmaniasis.
    Keywords: Leishmania, Oxaliplatin, Promastigote, Macrophage, BALB, c mice
  • Majid Keshavarzi, Forouzan Khodaei, Asma Siavashpour, Arastoo Saeedi, Afshin Mohammadi Bardbori * Pages 2042-2054

    The concerns about the possible risk of manufactured nanoparticles (NPs) have been raised recently. Nano- and micro-sized copper oxide (CO and CONP) are widely used in many industries. In this regard, in-vitro studies have demonstrated that CONP is a toxic compound in different cell lines. Despite their unique properties, NPs possess unexpected toxicity profiling relative to the bulk materials. This study was designed to examine and compare the toxic effects of CO and CONPs in-vivo and in isolated rat mitochondria. Male Wistar albino rats received 50 to 1000 mg/kg CO or CONP by gavage and several toxicological endpoints including biochemical indices and oxidative stress markers. Then, the pathological parameters in the multiple organs such as liver, brain, spleen, kidney, and intestine were assessed. Mitochondria were isolated from the rat liver and several mitochondrial indices were measured. The results of this study demonstrated that CO and CONP exhibited biphasic dose-response effects. CONPs showed higher toxicity compared with the bulk material. There were no significant changes in the results of CONP and CO in isolated rat liver mitochondria. The present studies provided more information regarding the hormetic effects of CO and CONPs in-vivo and in isolated rat mitochondria.

    Keywords: Copper oxide, Copper oxide nanoparticles, Hormesis effects, Mitohormesis, Mitotoxicity
  • Maryam Damercheli, Mahdi Behzad *, Bita Mehravi, Mehdi Shafiee Ardestani Pages 2055-2066
    Although metal-based anticancer drugs have been recognized as the most effective agents over the organic compounds, non-selectivity and high toxic effects have limited their applications in a way that only three Pt-analogues have progressed into clinical use. These problems have spurred chemists to develop different strategies based on alternative targets. This work focuses on predicting potency and mode of interactions of a series of salen type Schiff base transition metal complexes derived from meso-1,2-diphenyl-1,2-ethylenediamine, over some proteins (HDAC7, HDAC2, CatB, B-RAF kinase, TopII, RNR, TS, and rHA) using computational docking method, to be later considered as possible anticancer agents. The obtained results showed that all complexes exhibited higher affinity for HDAC7 than the other targets. Moreover, the bromo-derivatives of the copper compounds were more active on HDAC7 than the other derivatives. Such bromo compounds showed considerable interactions with Kinase, RNR, TS, and CatB. Contrary to Histone deacetylase (HAD)C7; HDAC2 was predicted to be relatively poor target. As expected, formation of the hydrophobic interactions between the metal complexes and the protein targets were essential for activity of the metal compounds. This study provides some more information for further optimizations and development of new metallodrugs as enzyme inhibitors for potential therapeutic agents.
    Keywords: Histone deacetylase, Anticancer, Schiff base, docking
  • Gholam, Reza Mahmoudiasl, Hojjat Allah Abbaszadeh *, Mostafa Rezaei, Tavirani, Mohammad, Amin Abdollahifar, Yousef Sadeghi, Maryam Sadat Khoramgah, Somayeh Niknazar, Shahram Darabi Pages 2067-2082
    Methamphetamine (Meth) is recognized as one of the most important new distributedabused drug that causes severe damage to the different parts of the brain, especiallyhippocampus. Previous studies have demonstrated that Meth can induce apoptosis and celldeath in the brain. In this study, we evaluated the long-term effects of Meth abuse in theCA1 region of postmortem hippocampus. Postmortem molecular and histological analysiswas performed for five non-addicted subjects and five Meth addicted ones. Iba-1 (microglia)and glial fibrillary acidic protein, GFAP (astrocytes) expression were assayed by westernblotting and immunohistochemistry (IHC) methods. Histopathological assessment was donewith stereological counts of hippocampal cells stained with hematoxylin and eosin (H and E).Tunel staining was used to detect DNA damage in human brains. In addition, protein-proteininteraction analysis network was investigated. Western blotting and immunohistochemistryassay showed overexpression of GFAP and Iba-1 protein in the CA1 hippocampal regionof Meth users’ brain. Stereological analysis in the CA1 region revealed increased neurondegeneration. Furthermore, significant apoptosis and cell death were confirmed by Tunel assayin the hippocampus. The prominent role of TLR4, IL1B, CASP1, and NLRP3 in the molecularmechanism of Meth was highlighted via PPI network analysis. Chronic Meth use can induceGFAP and Iba-1 upregulation and neuronal apoptosis in the CA1 region of the postmortemhippocampus.
    Keywords: Methamphetamine, CA1, Hippocampous, GFAP, IBA1, Apoptosis
  • Hamidreza Moghimi, Reza Zohdiaghdam *, Nader Riahialam, Zhaleh Behrouzkia Pages 2083-2092
    Nanoparticles are unique that enable many promising medical and technological applications intheir physical, and chemical properties. It is widely accepted that nanoparticles should bethoroughly tested for health nanotoxicity, but a moderate risk analysis is currently prevented by arevealing absence of mechanistic knowledge of nanoparticle toxicity. The purpose of this studywas to assess in-vitro cytotoxicity of Gadolinium oxide with diethylene glycol polymer (Gd2O3-DEG) and magneto liposome nanoparticles (MLNs) in Hepa 1-6 cell lines as models to assessnanotoxicity in-vitro. The effects of magnetic nanoparticles on these cell lines were evaluated by2light microscopy and standard cytotoxicity assays. The underlying interactions of thesenanoparticles with physiological fluids are key characteristics of the perception of their biologicalefficacy, and these interactions can perhaps be performed to relieve unpleasant toxic effects.Ourresults demonstrated that the Gd2O3-DEG and MLNs had significantlydifferent non-cytotoxiceffects. Our results suggest that these cell lines provide valuable models to assess the cytotoxicityof nanoparticles in-vitro. The results of the present study demonstrated that MLNs and Gd2O3-DEG with lower longitudinal relaxation time (T1) than Gadolinium Pentetic acid (Gd-DTPA) inHepa 1-6 cell lines are sensitive positive Magnetic Resonance Imaging (MRI) contrast agents thatcould be as attractive as candidates for cellular and molecular lipid content targets such as liverdiagnostic applications. These data reveal that MLNs is a useful positive contrast agent fortargeting and cell tracking. This will help to image of cells and special organs like liver that uptakesliposomal formulation very well.
    Keywords: Nanoparticles, Cytotoxicity, Cell line, Gd2O3-DEG, Magnetoliposomes
  • Kiandokht Ghanati, Farid Zayeri, Hedayat Hosseini * Pages 2093-2100
    In the present work, health risk of heavy metals such as As, Cd, Co, Cr, Cu, Hg, Ni, Pb, Zn in Iranian urban and rural samples including wheat, wheat flour, bread, pasta and sweets were assessed. The real amount of heavy metals in target samples were determined by inductively coupled plasma-atomic emission spectrometry (ICP-AES) and atomic absorption spectroscopy (AAS). Wet ashing and hydride generation techniques were used in sample preparation step. Results showed that heavy metal contaminations in cereal samples were significant. The average concentrations of heavy metals in cereal samples were between 0.01 mg kg−1 to 46 mg kg−1. Finally, the health risk assessment results showed that heavy metal contents in rural samples were higher than those in urban samples. The risk of Cu and Zn was significant in two areas and risk of Cr and Cd was not significant.
    Keywords: Health risk assessment, Heavy metal, Cereal samples, Inductively coupled plasma-atomic emission spectrometry, Atomic absorption spectrometry
  • Ahmad Reza Golnaraghi Ghomi, Mohammad Mohammadi, Khanaposhti, Hossein Vahidi, Farzad Kobarfard *, Mahdieh Ameri Shah Reza, Hamed Barabadi Pages 2101-2110
    Biological synthesis of nanoparticles (NPs) has gained extensive attention during recent years by using various biological resources such as plant extracts and microorganisms as reducing and stabilizing agents. The objective of the present study was to biosynthesize zirconium NPs using Penicillium species as a reliable and eco-friendly protocol for the first time. The synthesized NPs were characterized using Scanning Electron Microscope (SEM), Atomic Force Microscope (AFM), Dynamic Light Scattering (DLS), Energy Dispersive X-ray (EDX), and Fourier Transform Infrared (FT-IR). The results showed that three Penicillium species were able to synthesize zirconium NPs extracellularly with spherical morphology below 100 nm. Moreover, the preliminary antibacterial activity of zirconium NPs represented considerable antibacterial potential against Gram-negative bacteria. Overall, the current study demonstrated a novel bio-based approach for preparation of zirconium NPs. Further studies are required to expend this laboratory-based investigation to an industrial scale owing to their superiorities over traditional physicochemical methods such as cost-effectiveness and eco-friendliness.
    Keywords: Nanobiotechnology, Green synthesis, Penicillium family, Zirconium nanoparticles, Antibacterial activity
  • Shivasadat Gheflat, Abdolrahim Sadeghi, Mojgan Bandehpour, Keyvan Ramezani, Bahram Kazemi * Pages 2111-2116
    Background and Aim
    Diabetes is a common disorder worldwide, and exhaustive efforts have been made to cure this disease. Gene therapy has considered as a potential curative method that has more stability in comparison with the other pharmaceutical methods. However, the application of gene therapy as a definitive treatment demands further investigation. This study aim is to prepare a suitable high- performance vector for gene therapy in diabetes mellitus. The designed vector has prominent characteristics, such as directed replacement, which makes it a suitable method for treating or preventing other genetic disorders.
    Materials and Methods
    Whole rDNA sequence of the human genome was scanned. The 800 bp two homology arms were digested by EcoRI and synthesized and cloned into the pGEM-B1 plasmid (prokaryotic moiety). The carbohydrate sensitive promoter, L-pyruvate kinase, and insulin gene were sub-cloned between homologous arms (eukaryotic moiety). The PGEM-B1 plasmid was digested by EcoRI, and the eukaryotic fragment was purified and transfected into Hela cell and cultured. The 300 µg/ ml of glucose was added to the culture medium. Insulin expression in transfected cells with 200 and 400 ng of the construct, in compare with negative control was detected using western blot and ELISA. Results demonstrated that insulin was expressed toward glucose concentrates.
    Keywords: Diabetes mellitus, homologous recombination, HeLa Cell, LPK promoter, Gene therapy
  • Fatemeh Naddafi, Fatemeh Davami, Maryam Tabarzad, Farzaneh Barkhordari, S. Farshad Shirazi * Pages 2117-2123
    Blinatumomab, the bispecific T cell engager, has been demonstrated as the most successful BsAb to date. Throughout the past decade, vector design has great importance for the expression of monoclonal antibody in Chinese hamster ovary (CHO) cells. It has been indicated that expression plasmids based on the elongation factor-1 alpha (EF-1 alpha) gene and DHFR selection marker can be highly effective to produce populations of stably transfected cells in the selection medium. Since, the phiC31 integrase system is considered as an attractive and safe protein expression system in mammalian cells and it could integrate a donor plasmid of any size, as a single copy, with no cofactors, we decided to use phiC31 integrase technology in combination with DHFR amplification system to have an expression vector for blinatumomab gene amplification. The gene of interest (GOI) could be joined to DHFR selection marker with the insertion of an internal ribosome entry site (IRES). By positioning the DHFR downstream of the GOI and IRES, the transcription of the selection marker can depend on the successful transcription of the GOI upstream of it in the expression plasmid. In this study, we utilized FC550A-1 vector as the backbone. We successfully combined DHFR selection marker with phiC31 integrase technology to generate a high-expressing plasmid for future expression in CHO-DG44 cells.
    Keywords: Plasmid, blinatumomab, therapeutic antibody, biotechnology, mammalian cells
  • Arezoo Dehghani Mahmodabadi, Mostafa Langarizadeh *, Mohammad Hossein Mossaddegh Mehrjardi, Sima Emadi Pages 2124-2130
    Pharmaceutical performance is a critical factor in the hospital operation. Hospital pharmacyactivities require retrieving, processing, comparing, and updating the information. Dashboards arenew tools that can track key performance indicators by displaying information to managers in orderto improve the performance of the hospital pharmacy. We conducted this study to determine theperformance indicators of hospital pharmacies in Iran. This qualitative research was conducted in2016. The participants were hospital pharmacists and hospital managers. A semi-structuredquestionnaire was constructed to determine key performance indicators of the hospital pharmacydepartment. The questionnaire was used in face-to-face interviews and focus groups. The datawere analyzed using Framework analysis. The indicators comprised three domains, includingmanagerial indicators (satisfaction, education, staffing, and department management), clinicalindicators (patient safety), and financial indicators (income, costs, and financial utilization).Traditionally, pharmacy services included provision and distribution of drugs in the hospital;however, today, with an increase in the complexity and diversity of the drugs, hospital pharmacyservices include diverse fields beyond clinical affairs. It could be concluded that pharmaceuticalperformance has a vital role in successful hospital management. Hospital pharmacy managementis not possible without monitoring performance indicators.
    Keywords: Key performance indicator, Hospital pharmacy, Dashboard, Pharmacy management
  • Mojtaba Mojtahedzadeh, Hamidreza Taghvaye Masoumi, Atabak Najafi, Mehrnoush Dianatkhah, Hamidreza Sharifnia, Maryam Shahrokhi * Pages 2131-2135

    Spinal cord injury is a devastating chronic condition resulting in temporary or permanent motor,sensory or autonomic dysfunction of the cord. The manifestation of spinal cord injury based onthe severity and involved areas could be different. Numerous studies have demonstrated thatbradycardia, hypotension, and orthostatic hypotension are present insignificant number ofpatients after spinal cord injury which peaks at 4th day of injury. Although vasopressors arecommon drugs that have been used to restore blood pressure and heart rate in patients withneurogenic shock, there is limited data regarding pharmacologic management of bradycardia andhypotension after spinal cord injury. Midodrine is a potent vasopressor approved for themanagement of symptomatic orthostatic hypotension. Theophylline and aminophylline aremethylxanthine derivatives. There are very few case reports concerning the use of midodrine andmethylxanthines for treatment of hypotension in patients with spinal cord injury. In this casereport and review of the articles we report a 45 year old woman with a diagnosis of spinal cordinjury who was successfully managed with midodrine and aminophylline and then we reviewcurrent case reports. Based on our case report and other available data, midodrine as well asmethylxanthines can be suggested as therapeutic options for managing symptoms in spinal cordinjury patients.

    Keywords: Case report, Spinal cord injury, Midodrine, Methylxanthines, Hypotension, Bradycardia
  • Ensieh Golali, Mohammad Sistanizad *, Jamshid Salamzadeh, Mehrdad Haghighi, Mehrdad Solooki Pages 2136-2143
    We implemented a post prescribing review and feedback program to investigate its effect on appropriateness of antimicrobial use and antimicrobial consumption rate.A pre-post interventional study conducted in internal ward of Imam Hossein teaching hospital. For nine months of intervention phase, medical file of all patients who received intravenous antibiotic were reviewed by a clinical pharmacy specialist. Discrepancies from international and local guidelines were discussed with physicians. Outcome measures included appropriateness of antimicrobial usage, length of stay, and broad-spectrum antimicrobial usage rate.A total of 198 antibiotic courses (154 in intervention phase and 44 in pre-intervention phase) were reviewed. One-hundred sixty-seven recommendations in treatment course of 75.3% of patients were made. The most common recommendations were discontinuing antibiotics and changing from intravenous to oral therapy (35% and 22%). The acceptance rate was 80.2%.Rate of discrepancies from guidelines was compared between pre-intervention and two last months of intervention period which showed a significant reduction in antibiotic choosing (47%, P-value < 0.001), de-escalation (48%, P-value < 0.001), on time changing intravenous to oral therapy (60%, P-value < 0.001) and dosing schedule (30%, P-value = 0.003).Hospital length of stay showed a significant reduction from 16.1 days to 11.6 days (P-value < 0.05) between pre-intervention and post-intervention group. Mortality rate was not different in the patients that intervention in their treatment was accepted vs. rejected (P-value = 1.00). There was a reduction trend in consumption rate of Carbapenems, Vancomycin, and Ciprofloxacin.Therefore, prospective audit and feedback program effectively decreased inappropriate treatment and hospital length of stay with no effect on mortality.
    Keywords: Audit, Feedback Program, Appropriate antibiotic use, Antibiotic stewardship, Consumption rate, Patient outcomes
  • Mahmoud Ahmed Ebada *, Notila Fayed, Laila Fayed, Souad Alkanj, Ahmed Abdelkarim, Haya Farwati, Aya Hanafy, Ahmed Negida, Mohamed Ebada, Yousef Noser Pages 2144-2156
    Alpha-lipoic acid (ALA) is a naturally-occurring compound that has shown promising antioxidant and anti-inflammatory effects in experimental and human studies. The aim of this study was to assess the efficacy of ALA in the management of patients with diabetes mellitus (DM).We searched Medline (via PubMed), EBSCO, Scopus, and Web of Science for relevant randomized controlled trials. Data on glycated hemoglobin (HbA1c), blood glucose levels, lipid profile components, HOMA, and glutathione peroxidase (GPx) were extracted and pooled as the standardized mean difference (SMD) in a random effect model meta-analysis using RevMan version 5.3.Ten studies (n = 553 patients) were included. In the term of HBA1C, the overall SMD did not favor either of the two groups (SMD = 0.01, 95% CI [-0.32,0.35]; p = 0.94) in uncomplicated T2DM patients. Moreover, there was no statistically significant difference between the two groups in terms of FBG (SMD = -0.06, 95% CI [-0.44,0.33]; p = 0.78), PPBG (SMD = 0.04, 95% CI [-0.27,0.34]; p = 0.82), HDL (SMD = -0.05, 95% CI [-0.35,0.25]; p = 0.75), LDL (SMD = -0.05, 95% CI [-0.33,0.23]; p = 0.75). In terms of GPx, ALA was superior to placebo (SMD = 0.43, 95% CI [0.07,0.8]; p = 0.02).Our analysis showed that ALA was not superior to placebo in terms of HBA1C, LDL, HDL, TC, TG reduction in uncomplicated T2DM. However, in terms of GPx, ALA was significantly superior to the placebo. Further studies with larger sample sizes should investigate different doses of ALA in DM patients.
    Keywords: Alpha-lipoic acid, Diabetes mellitus, Thioctic Acid, Metabolic Diseases, Meta-Analysis
  • Sara Salarian, Raha Khosravi, Ghamartaj Khanbabei, Bahador Bagheri * Pages 2157-2162
    Objective
    Long term use of opioids and benzodiazepines are associated with important untoward effects. The α2 adrenergic agonist clonidine has sedative effects. Our goal was to study clonidine addition to total doses of fentanyl and midazolam and duration of ventilation in pediatric ICU (PICU).
    Methods
    This randomized, double-blind, placebo-controlled trial was conducted in PICU of Mofid Children Hospital. Hundred children aged from 2 to 15 years were randomized 1:1 to 5 μg/kg oral clonidine every 6 hours plus 1-5 µg/kg/hr IV fentanyl and 0.05- 0.1 mg/kg/hr IV midazolam or placebo plus 1-5 µg/kg/hr fentanyl and 0.05- 0.1 mg/kg/hr midazolam. Daily use of fentanyl and midazolam were measured. Ramsay sedation score was used for evaluation of sedation.
    Results
    96 patients were studied. Patients in placebo group received more midazolam and fentanyl compared with patients in intervention group. Mean total dose of midazolam was 4.3 ± 2.2 mg in the placebo group and 2.7 ± 2.9 mg in the intervention group (P < 0.05). Mean total dose of fentanyl was 34.4 ± 23.1 µg in the placebo group and 18.9 ± 10 µg in the intervention group (P < 0.01). No significant differences were observed in duration of ventilation and length of ICU stay. No case of severe adverse events was seen.
    Conclusion
    This trial showed a reduction in total doses of midazolam and fentanyl given in ventilated children who were administered clonidine as add-on therapy. Clonidine addition appeared to reduce ICU stay but had no effect on duration of mechanical ventilation.
    Keywords: Clonidine, Sedation, ventilation, pediatric intensive care, intubation
  • Mahdiye Abyarghamsari, Farshad Hosseini Shirazi, Maria Tavakoli Ardakani, Hamid Rezvani, Hamid Reza Mirzaei, Jamshid Salamzadeh * Pages 2163-2171

    This study was designed to evaluate the effect of excision repair crosscomplementing group 1 (ERCC1) rs11615 codon 118C/T gene polymorphisms ontreatment outcomes in Iranian patients receiving oxaliplatin-based regimens forcolorectal (CRC) and gastric cancers (GC). Patients, who were candidates to receiveoxaliplatin-based chemotherapy, entered into the study. In 2-week intervals, thepatients received combination regimen of oxaliplatin, fluorouracil, and leucovorin(FOLFOX) for 3 months. ERCC1 rs11615 codon 118C/T polymorphism was testedby restriction fragment length polymorphism polymerase chain reaction (RFLPPCR)method using patients’ peripheral blood lymphocytes. The tumor response tochemotherapy was evaluated by examining the size of the tumor using CT scan.Association between response rates, according to the RECIST criteria, and patients’genotypes was evaluated. Any relationship between response rate and possibleexplanatory factors was also determined. Overall, 40 patients (13 females (32.5%),and 27 males (67.5%)) enrolled in the study. Four patients (10.0%) carried the homozygousmutation (T/T genotype), ten patients (25.0%) were heterozygous (C/Tgenotype), and twenty-six patients (65%) were homozygous (C/C genotype).Response rate were 30.77%, 20.00%, and 0.00% for the genotypes C/C, C/T, andT/T, respectively. No significant association between response rate and genotypeswas observed (p = 0.64). Patients with well- and moderately-differentiatedhistological grade of the tumor showed a better response rate (100.00% of 2 patientsand 66.66% of 12 patients, respectively) compared to those with poorlydifferentiated (0.00% of 26 patients) histological grade (p < 0.001). Furthermulticenter studies are recommended to confirm conclusively our findings.

    Keywords: Oxaliplatin, polymorphism, Colorectal cancer, Gastric Cancer, ERCC1
  • Manoochehr Abdolvand, Ashraf Aleyasin, Mohammad Reza Javadi *, Mohammad Solduzian, Seyed Hossein Hosseini, Zohreh Ziaei, Samira Chaibakhsh, Kheirollah Gholami Pages 2172-2179
    Venous thromboembolism (VTE) occurs in about 5 percent of patients undergoing major abdominal surgeries. Prophylaxis of VTE is recommended using unfractionated heparin (UF) or low molecular weight heparin (LMWH) in high-risk patients. In spite of advantages and confirmed cost-effectiveness of LMWH, high costs of enoxaparin branded preparations limit its use. We aimed to compare the efficacy and safety of two enoxaparin preparations. In this open-label randomized clinical trial, 200 patients were recruited to recieve PDxane® or Clexane®, 40 mg subcutaneously daily, from the day of surgery for 10 days. The patients were evaluated for VTE occurrence and side effects considering clinical and laboratory examinations at the beginning and day 10. No cases of proximal or distal VTE or life threatening bleeding  were observed among 102 and 98 patients who received PDxane® and Clexane®, respectively. The adverse effects observed in PDxane® and Clexane® groups included injection site reactions (rash: P = 0.97; pain: P = 0.55 and erythema:P = 0.33), anemia (P = 0.32), hematuria (P = 0.16), confusion (P = 0.3), and increased liver transaminases (AST ≥ 3 × ULN: P = 0.16 and ALT ≥ 3 * ULN: P = 0.66). In according to the study results PDxane® was of similar efficacy and safety compared to Clexane® in preventing VTE following major obstetric-gynecological surgeries. Considering lower cost of PDxane®, it could be a safe and effective alternate for VTE prophylaxis in the patients undergoing such types of surgeries.
    Keywords: Venous thromboembolism, Enoxaparin, Primary Prevention, Surgery, cesarean section
  • Saeed Taheri, Ali Saffaei, Bahman Amani, Akbarzadeh Arash, Farzad Peiravian, Nazila Yousefi * Pages 2180-2190
    Introduction

    Diabetes mellitus has always been one of the most prevalent chronic diseases in the last decades. There exist a wide range of pharmacological agents for controlling this disease. However, these agents fare differently in terms of efficacy and safety. Hence, the aim of this study was to compare dulaglutide and liraglutide, two glucagon-like peptide-1 receptor agonists, in terms of efficacy and safety, drawing on a systematic review and meta-analysis.

    Methods

    A systematic review and meta-analysis were carried out in January 2018. The articles were evaluated by two independent investigators and their quality was evaluated using Jadad scale and the Cochrane Collaboration’s tools. Finally the eligible articles entered the study. HbA1c and FBS were considered as efficacy outcomes. Safety profile was evaluated based on several outcomes such as serious side effects and vital signs.

    Results

    Three articles met the inclusion and exclusion criteria. The results showed that the mean difference of HbA1c reduction was -0.10% (95% CI, -0.20% to -0.01%, P=0.03) in patients who received dulaglutide in comparison with patients who received liraglutide. In addition, dulaglutide was safer than liraglutide in terms of gastrointestinal problems (RR=0.85, 95% CI, 0.73 to 0.99, P=0.04, I2=55%) and heart rate (RR=-1.14, 95% CI, -1.90 to -0.38, P=0.003, I2=0%).

    Conclusion

    Once-weekly dulaglutide showed a further reduction in HbA1c compared to once-daily liraglutide. However, comparisons between these regimens indicated no significant difference between groups in either FBS reduction or safety profile. Similarly, no statistically significant difference was observed in treatment discontinuation, hypoglycemia events, and vital signs.

    Keywords: Diabetes Miletus, Dulaglutide, Liraglutide, Meta-Analysis, systematic review
  • Hossein Minaei, Mohammad Peikanpour, Nazila Yousefi, Payam Peymani, Farzad Peiravian *, Nikta Shobeiri, Zahra Karimi Majd, Javad Shamsaee Pages 2191-2203
    Introduction
    Evaluation of pharmaceutical systems performance is an essential prerequisite for promoting evidence-based policy-making, improvement in health system performance. This study attempts to evaluate the performance of Iran pharmaceutical system based on the world health organization (WHO)'s indicators, including access, quality, and rational use of medicines.
    Methods
    In this cross-sectional descriptive study, inspired by the instructions proposed by WHO, public and private pharmaceutical service-providers were evaluated in three dimensions and 16 indicators. Accordingly, eleven separate checklists were developed and, in terms of translation, face and content validity were certified by pharmaceutical sector’s experts. Sampling was randomly carried out in five cities. Depending on the type of indicators, retrospective or prospective approaches was determined for data collection. The data were collected from April to November 2018 and analyzed by SPSS 24.
    Results
    The availability of targeted key medicines in various cities as well as in public and private pharmacies was 97.5% with no significant difference. Although the medicines cost was higher in private sectors than in public ones, they were affordable in both sectors. In quality indicators, public sectors enjoyed a higher level than the private sectors did. The average number of medicines per prescription in public pharmacies was 3.2 and it was 3.4 in private ones. On average, in public sectors 33% and 32% of outpatients received antibiotics and injectable medicines, respectively. Finally, 77% of medicines were prescribed by using their generic names and 25% of prescriptions were in accordance with key medicines list.
    Keywords: Access, affordability, Rational use of medicines, Quality, Pharmaceutical policy
  • Mahnaz Samadbeik, Maryam Ahmadi *, Farahnaz Sadoughi, Ali Garavand Pages 2204-2215

    Identifying the factors and components of an electronic prescription system is of utmost importance in effective designing and implementation of this system. In this regard, the current study was conducted to determine the main factors affecting the national model of electronic prescription from the physicians’ point of view. This is a cross-sectional, descriptive-analytical research carried out in 2015. Based on the census sampling method, 104 members of the board of directors of the Iranian general practitioners’ associations, general practitioners’ alumni association of Iran, and physicians owner of a website or weblog were selected as samples for this study. Data were collected using a valid and reliable questionnaire. After analyzing the data with SPSS software (v.16), a model was proposed using a regression algorithm. The findings indicated that accessing the current medication data and medication history of patients during prescription, and also creating the electronic patient medication record (ePMR) are the most important selective components for physicians with frequency percent of 92.1%. Moreover, from the physicians’ viewpoint, the method of “transmission of prescriptions to the central national database and retrieving prescriptions information from the selected pharmacy of the patient” had the highest priority (weight coefficient) in the model of the national electronic prescription system. Therefore, the Iranian prescription system is required to be developed based on the centralized architecture and national electronic prescription database.

    Keywords: Electronic Prescribing, Main elements, National model, Physician, Model
  • Farahnaz Zeinali, Ali Rajabzadeh Ghatari *, Mehdi Mohammadzadeh, Fatemeh Mojibian Pages 2216-2225
    The unsteady increase in using pharmaceutical opioids is a phenomenon that has existed in human societies for a long time. Furthermore, the ever-growing trend of addiction to opioids affects communities in various economic, social, and cultural aspects. Since abusing pharmaceutical opioids is a complex dynamic problem, it is extremely difficult to recognize the factors influencing this abuse. Thus, applying such dynamic models as system dynamics (SD) plays an important role in addressing these complex dynamic problems. System dynamics model falls in two categories of qualitative and quantitative system dynamics. In this paper, causal loop diagrams (CLDs), which are conceptual qualitative stages were applied, and variables were elicited from literatures; then, the initial CLDs were generated, and afterward, some experts were interviewed in order for the CLDs model to be evaluated. Ultimately, a meeting was held for discussing the variables and validating the diagrams. In this study, variables are connected by causal relationships called reinforcing and balancing. Then, the CLD model clearly depicted how the variables interact with one another in different stages of the process. The CLDs model is a fundamental issue in developing quantitative system dynamic, assisting policymakers in forecasting the process of non-medical use of pharmaceutical opioids and finding some measures to reduce their usage.
    Keywords: System Dynamics, Qualitative model, Casual loop diagrams, Pharmaceutical opioids, Addiction
  • Behzad Najafi, Alireza Mahboub Ahari, Soraya Nouraei Motlagh, Seyed Alireza Otobideh, Bahlol Rahimi, Hosein Shabaninejad, Hasan Yusefzadeh * Pages 2226-2232

    The importance of drug as a valuable export product in the global economy becomes more clear every day. Understanding the problems of exports and factors affecting it, can be an important step to keep Iran’s position in the world markets and further export development of this product.In this study, Iranian pharmaceutical exports’ supply and demand functions were calculated using co-integration and error correction techniques through time series quarterly data of 2000-2014 in order to identify the factors affecting pharmaceutical exports and price and income elasticities.The long run price elasticity of demand of -2.28 indicates that an increase in Iran’s export price relative to competitor's export price will have a negative impact on pharmaceutical export volume.Also, the long run income elasticity of foreign demand for pharmaceutical exports of Iran is 1.11.That is an increase in income of foreign countries will have a positive impact on Iran’s pharmaceutical export.On the other hand, the long run price elasticity of export supply is 1.09, indicating that the supply of pharmaceutical export is sensitive to the relative price changes. In other words, an increase in export price relative to domestic price as well as an expansion of the pharmaceutical production capacity will increase its export supply. Being aware of the factors affecting the pharmaceutical exports can prepare the ground to develop the pharmaceutical industry and balance the supply and demand in the long run.Therefore, the results of this study can help Iran's policymakers and managers to choose a clearer path for the pharmaceutical trade policies.

    Keywords: Pharmaceutical industry, export, Supply, demand, elasticity