فهرست مطالب

Pharmaceutical Research - Volume:16 Issue: 3, Summer 2017

Iranian Journal of Pharmaceutical Research
Volume:16 Issue: 3, Summer 2017

  • تاریخ انتشار: 1396/06/06
  • تعداد عناوین: 43
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  • Mohammad Mehdi Mahboobian, Ali Seyfoddinb, Ilva Rupenthalc, Reza Aboofazeli, Mohsen Foroutan * Pages 847-857
    Brinzolamide (BZ) is an intraocular pressure reducing agent with low bioavailability. The purpose of the present study was to overcome this issue by development of BZ containing nanoemulsions (NEs) as an ocular drug delivery system with desirable therapeutic efficacy. Brinzolamide NEs were prepared by the spontaneous emulsification method. Based on initial release studies, twelve formulations with the slowest release characteristics were subjected to further physicochemical investigations such as particle size, polydispersity index, pH, refractive index, osmolality and viscosity. The therapeutic efficacy of these formulations was assessed by measuring the intraocular pressure after instillation of the prepared NEs in normotensive albino rabbit eyes. Nanoemulsions with suitable physicochemical properties exhibited high formulation stability under different conditions. More over biological evaluations indicated that using lower drug concentrations in NE formulations (0.4%) had a similar or even better pharmacodynamic effect compared to the commercial suspension with a higher drug concentration (1%). Our findings suggest that NEs could be effectively used as carriers for enhancing the bioavailability of topically applied ophthalmic drugs.
    Keywords: ocular drug delivery, brinzolamide, nanoemulsion, physicochemical characterisation, ocular bioavailability, therapeutic efficacy
  • Farya Mirzaei, Naser Mohammadpour Dounighi *, Mohammad Reza Avadi, Mehdi Rezayat Pages 858-867
    In recent years, use of biodegradable polymers based nanoparticles has received high interest in the development of vaccines delivery vehicles. The aim of study was to prepare chitosan nanoparticles (CS NPs) for loading Echis carinatus (EC) venom and evaluate their potential as an adjuvant and antigen delivery system on a pilot scale. CS NPs were prepared using ionic gelation method, and their characteristics were optimized. Venom-loaded CS NPs prepared under optimum conditions and traditional venom-loaded adjuvants were used to hyperimmunization of horse. Under optimum conditions, particle size, polydispersity index (PDI), and zeta potential of CS NPs were 127.9 ± 15 nm, 0.29, and .8 ± 1.92 mV, while those of venom-loaded CS NPs were 182.4 ± 20 nm, 0.35, .8 ± 1.98 mv, respectively. All CS NPs had integrated surface and good morphology. Optimum loading concentration of EC venom was 500 μg/mL. The loading capacity (LC) and loading efficiency (LE) were 87% and 94%, respectively, and release profile of venom-loaded CS NPs showed suitable correlation with Higuchi kinetics. Stability test showed good stability of the venom encapsulated in CS NPs. Furthermore, antivenom plasma obtained using the new antigen delivery system had significantly higher potency (P
    Keywords: Chitosan, Nanoparticles, Echiscarinatus venom, Adjuvant, Hyperimmune plasma
  • Seyed Saeed Azandeh, Mohammadreza Abbaspour, Ali Khodadadi, Layasadat Khorsandi *, Mahmoud Orazizadeh, Abbas Heidari-Moghadam Pages 868-879
    Curcumin (Cur) has been found to be very efficacious against many different types of cancer cells. However, the major disadvantage associated with the use of Cur is its low systemic bioavailability. Our present work investigated the toxic effect of encapsulation of Cur in PLGA (poly lactic-coglycolic acid) nanospheres (NCur) on PC3 human cancer prostate cell. In the present study, we have investigated the effects of NCur on growth, autophagia, and apoptosis in PC3 cells, respectively, by MTT assay, fluorescence microscopy, and Flow cytometry. MTT assays revealed that the NCur at the concentration of 25 μg/mL for 48 h were able to exert a more pronounced effect on the PC3 cells as compared to free Cur. Apoptotic index was significantly increased in NCur-treated cells compared to free Cur. The percentage of autophagic cells (LC3- II positive cells) was also significantly increased in NCur treatment in comparison to free Cur. These data indicate that the NCur has considerable cytotoxic activity more than Cur on P3 cell lines, which is mediated by induction of both apoptotic and autophagic processes. Thus, NCur has high potential as an adjuvant therapy for clinical application in prostate cancer.
    Keywords: Programmed cell death, prostate cancer, Curcumin, Nanoparticles, PLGA
  • Seyed Ayoub Hosseini, Abolghasem Moghimi, Maryam Iman *, Firoz Ebrahimi Pages 880-892
    Acetylcholinesterase has important role in synaptic cleft. It breaks down the acetylcholineat cholinergic synapsesand terminates the cholinergic effects. Some chemical agents like organophosphorus compounds (OPCs) including nerve agents and pesticides react with acetylcholinesteraseirreversibly. They inhibit normal biological enzyme action and result in accumulation of acetylcholineand show toxic effects andcholinergic symptoms. The process of Acetylcholinesterase (AChE) inhibition can be reversed by a nucleophilic agent to dephosphorylate and reactivate the enzyme. In this study, design and docking studies of 15 novel nitrone based onoximes as reactivators were performed by using AutoDock program. Then, more effective reactivatorsoximes in terms of binding energy and orientation within the active site were synthesized and evaluated in-vitro on human AChE (hAChE) inhibited byparaoxon and compared to standard hAChE reactivators (2-PAM and obidoxime). Ourresults used to design new derivatives of Oxim with better efficacy than 2-PAM and obidoxime. Syntheses of some selected bis-pyridiniumoximes based on the nitrones are underway.
    Keywords: Reactivators, Oximes, Molecular docking, Nitrones, Organophosphorus compounds
  • Yasaman Rasouli, Asghar Davood *, Armin Alaee, Golnoush Dehqani, Hamed Shafaroodi, Mahboobeh Lotfinia, Mohsen Amini, Abbas Shafiee Pages 893-903
    Epilepsy is a chronic disorder of the brain affecting around 50 million people in the world. Up to 30% of epileptic patients do not respond to available drugs and medical therapies. In this paper, anticonvulsant screening of 10 synthesized new derivatives of 1, 4-dihydropyridine 3, 5-dicarboxamides was performed. Anticonvulsant activity was evaluated by intravenous and intraperitoneal pentylenetetrazole and maximal electroshock induced seizures tests. Nifedipine was used as reference drug. Our pharmacological results revealing the compounds 2, 4, 5, and 6 can be effective in both absence and grandmal seizures in human. These pharmacological studies have displayed that these new dihydropyridine derivatives are capable to inhibiting seizures induced by pentylenetetrazole and maximal electroshock in mice efficiently.
    Keywords: Dihydropyridine, Imidazole, Anticonvulsant, pentylenetetrazole, Maximal Electroshock
  • Alireza Foroumadi, Hadi Adibi *, Sussan Kabudanian Ardestani, Samira Shirooie, Arezoo Bozorgomid, Ali Jafari Pages 904-909
    A series of (5-nitrofuran-2-yl)-1, 3, 4-thiadiazole-2-yl derivatives 6a–6e have been synthesized and screened for in vitro anti-leishmanial activity against the promastigote form of L. major. The structure of Schiff bases were confirmed by 1H NMR, IR. Screening results indicate that all of the designed and synthesized final compounds (6a-6e) significantly reduced the viability of promastigotes of L. major in comparison to glucantime (IC50 3× 103 μg/ml). Meta and Para substitutions in benzene ring containing compounds were more potent than other derivative and the most potent compounds were 6d, 6e with IC50 value 94 µM and 77.6 µM, respectively. The experimental data proposes that (5-nitrofuran-2-yl)-1, 3, 4-thiadiazole-2-yl derivatives may be further investigated as a candidate drug for treatment of cutaneous leishmaniasis.
    Keywords: 1, 3, 4-Thiadiazole, Nitrofuran, Antileishmanial activity, Leishmania Major, Promastigote
  • Anand Gaurav *, Vertika Gautam Pages 910-923
    Phosphodiesterase 4 (PDE4) has been established as a promising target in asthma and chronic obstructive pulmonary disease. PDE4B subtype selective inhibitors are known to reduce the dose limiting adverse effect associated with non-selective PDE4B inhibitors. This makes the development of PDE4B subtype selective inhibitors a desirable research goal. To achieve this goal, ligand based pharmacophore modeling approach is employed. Separate pharmacophore hypotheses for PDE4B and PDE4D inhibitors were generated using HypoGen algorithm and 106 PDE4 inhibitors from literature having thiopyrano [3,2-d] Pyrimidines, 2-arylpyrimidines, and triazines skeleton. Suitable training and test sets were created using the molecules as per the guidelines available for HypoGen program. Training set was used for hypothesis development while test set was used for validation purpose. Fisher validation was also used to test the significance of the developed hypothesis. The validated pharmacophore hypotheses for PDE4B and PDE4D inhibitors were used in sequential virtual screening of zinc database of drug like molecules to identify selective PDE4B inhibitors. The hits were screened for their estimated activity and fit value. The top hit was subjected to docking into the active sites of PDE4B and PDE4D to confirm its selectivity for PDE4B. The hits are proposed to be evaluated further using in-vitro assays.
    Keywords: Phosphodiesterase 4, Pharmacophore, Hypogen, Virtual screening, Zinc database, docking
  • Ali Ramazani *, Behnam Khosravani, Jafar Taran Pages 924-928
    Because of expanding resistance to efficient and affordable antimalarial drugs like chloroquine, the search is continuing for more effective drugs against this disease. In vitro antiplasmodial activity and cytotoxicity of α-(acyloxy)-α-(quinolin-4-yl) acetamides on Plasmodium falciparum and structure-activity relationships of this new class of Passerini adducts is described. The in-vitro antiplasmodial activity of compounds was tested against chloroquine sensitive 3D7 strain. Toxicity of active compounds was investigated on HepG cell line. Compounds 1, 20 and 22 showed significant antiplasmodial activity with IC50 value of 1.511, 1.373 and 1.325 μM, respectively. The active compounds did not show noticeable toxicity when tested against HepG2 cell line. The present results bring essential elements which will be used for the synthesis of more active derivatives of α-(acyloxy)-α-(quinolin-4 yl) acetamides.
    Keywords: Plasmodium falciparum, Quinolines, Cytotoxicity, HepG2, 3D7 strain
  • Bangalore Nandha *, Laxmivenkatesh Gurachar Nargund, Shachindra L. Nargund, Kishore Bhat Pages 929-942
    Keeping in view the drawbacks associated with research on anti-TB drugs based on plant extracts and the non-availability of fluorinated natural products with antitubercular activity has prompted us to make an effort towards the synthesis and characterization of a novel series of fifteen substituted fluorobenzimidazoles. The newly synthesized compounds were characterized by I.R, 1H-NMR, 13C-NMR, Mass and elemental analysis. The synthesized compounds 4(a-f) and 5(b-j) have been evaluated for their in-vitro antimycobacterial activity against H37Rv strain (ATCC 27294) by MABA method. Incorporation of methylenedioxyphenyl moiety at 2- and 6-position of the benzimidazole ring furnished compounds 4d and 5i with antitubercular activity comparable or more potent than the naturally occurring compounds with reported antitubercular activity. Among the fifteen tested compounds, 4d and 5i emerged as promising hits characterized by MIC lower than that determined for sesamin against the pathogenic H37Rv strain. Antitubercular activity results indicate that these compounds may be suitable for further lead optimization. The cytotoxic effect of these active compounds on THP-1 cell line was assessed by MTT assay and the results suggest that these two molecules are potential candidates for further development as antitubercular agents.
    Keywords: Fluorobenzimidazole, Antitubercular activity, Mycobacterium tuberculosis, H37Rv strain, Natural products
  • Pardis Nazari, Alieh Bazi, Seyed Abdulmajid Ayatollahi, Hadi Dolati, Seyedehmahbobeh Mahdavi, Laleh Rafighdoost, Marzieh Amirmostofian * Pages 943-952
    Infections are one of the most important causes of death, disability and inappropriate conditions for millions of people around the world. Therefore, the development in prognosis, prevention and treatment of infectious diseases made a considerable progress in designing and synthesis of new antimicrobial drugs. Nowadays, due to the increase in microbial resistance, discovery of new compounds with broad spectrum effects is granted. 4H-pyran derivatives and spiro compounds are the most important fragments in some effective drugs with antimicrobial activity. Therefore, in this study, 6 compounds with spiro-4H-pyran core were synthesized and evaluated for their antimicrobial activity against four different bacterial species using microbroth dilution and disk diffusion methods. Minimum inhibitory concentration (MIC) has been measured for each compound and also for the standard antibiotic, gentamicin, and they were all compared together. According to our result, one of the spiropyran derivative (5d) containing both the indole and the cytosine ring, has been shown good antibacterial effects against standard and clinical isolates of Staphylococcus aureus and Streptococcus pyogenes.
    Keywords: spiro-4H-pyran, one-pot reaction, three-component reaction, Staphylococcus aureus, Streptococcus pyogenes, microbroth dilution, disk diffusion
  • Gildardo Rivera *, Syed Shoaib Ahmad Shahb, Daniel Arrieta-Baez, Isidro Palos, Antonio Monge, Luvia Enid Sanchez-Torres Pages 953-965
    Quinoxalines display diverse and interesting pharmacological activities as antibacterial, antiviral, antiparasitic and anticancer agents. Particularly, their 1,4-di-N-oxides derivatives have proved to be cytotoxic agents that are active under hypoxic conditions as that of solid tumours. A new series of quinoxaline 1,4-di-N-oxides substitutes at 7-position with esters group were synthetized and characterized by infrared (IR), proton nuclear magnetic resonance (1H-NMR) spectroscopy, and elemental analysis. Seventeen derivatives (M1-M3, E1-E8, P1-P3 and DR1-DR3) were selected and evaluated for antitumor activities using the NCI-60 human tumor cell lines screen. Results showed that E7, P3 and E6 were the most active compounds against the cell lines tested. Substitutions at 7-position with esters group not necessarily affect the biological activity, but the nature of the esters group could exert an influence on the selectivity. Additionally, substitutions at 2-position influenced the cytotoxic activity of the compounds.
    Keywords: Antitumor, Cancer, Drugs, Esters, Quinoxaline 1, 4-di-N-oxide
  • Eslam Pourbasheer *, Saadat Vahdani, Davood Malekzadeh, Reza Aalizadeh, Amin Ebadi Pages 966-980
    The 17β-HSD3 enzyme plays a key role in treatment of prostate cancer and small inhibitors can be used to efficiently target it. In the present study, the multiple linear regression (MLR), and support vector machine (SVM) methods were used to interpret the chemical structural functionality against the inhibition activity of some 17β-HSD3inhibitors. Chemical structural information were described through various types of molecular descriptors and genetic algorithm (GA) was applied to decrease the complexity of inhibition pathway to a few relevant molecular descriptors. Non-linear method (GA-SVM) showed to be better than the linear (GA-MLR) method in terms of the internal and the external prediction accuracy. The SVM model, with high statistical significance (R2 train = 0.938; R2 test = 0.870), was found to be useful for estimating the inhibition activity of 17β-HSD3 inhibitors. The models were validated rigorously through leave-one-out cross-validation and several compounds as external test set. Furthermore, the external predictive power of the proposed model was examined by considering modified 2 and concordance correlation coefficient values, Golbraikh and Tropsha acceptable model criteriaʹs, and an extra evaluation set from an external data set. Applicability domain of the linear model was carefully defined using Williams plot. Moreover, Euclidean based applicability domain was applied to define the chemical structural diversity of the evaluation set and training set.
    Keywords: QSAR, Genetic algorithms, Support vector machine, Multiple linear regressions, 17?-HSD3
  • Masood Fereidoonnezhad, Zeinab Faghih, Ayyub Mojaddami, Zahra Rezaei, Amirhossein Sakhteman * Pages 981-998
    Dichloroacetate (DCA) is a simple and small anticancer drug that arouses the activity of the enzyme pyruvate dehydrogenase (PDH) through inhibition of the enzyme pyruvate dehydrogenase kinases (PDK1-4). DCA can selectively promote mitochondria-regulated apoptosis, depolarizing the hyperpolarized inner mitochondrial membrane potential to normal levels, inhibit tumor growth and reduce proliferation by shifting the glucose metabolism in cancer cells from anaerobic to aerobic glycolysis. In this study, a series of DCA analogues were applied to quantitative structure–activity relationship (QSAR) analysis. A collection of chemometrics methods such as multiple linear regression (MLR), factor analysis–based multiple linear regression (FA-MLR), principal component regression(PCR), and partial least squared combined with genetic algorithm for variable selection (GA-PLS) were applied to make relations between structural characteristics and cytotoxic activities of a variety of DCA analogues. The best multiple linear regression equation was obtained from genetic algorithms partial least squares which predict 90% of variances. Based on the resulted model, an insilico-screening study was also conducted and new potent lead compounds based on new structural patterns were designed. Molecular docking as well as protein ligand interaction fingerprints (PLIF) studies of these compounds were also investigated and encouraging results were acquired. There was a good correlation between QSAR and docking results.
    Keywords: DCA, QSAR, in silico screening, descriptor analysis, Docking, PLIF studies
  • Mostafa Erfani *, Seyed Pezhman Shirmardi, Mohammad Shafiei Pages 999-1006
    Colchicine as a vascular disrupting agent creates microtubule destabilization which induces vessel blockage and consequently cell death. Accordingly, colchicines and its analogues radiolabeled with 99mTc may have potential for visualization of tumor. In this work, deacetylcolchicine a colchicine analogue was labeled with 99mTc via tricine as a coligand and characterized for its tumor targeting properties. The in-vitro radiochemical stability and the biodistribution were studied in 4T1 breast tumor model bearing mice. Labeling yield of more than 90% was obtained corresponding to a specific activity of 46 MBq/μmol. In-vivo biodistribution studies demonstrated that radiocomplex had high tumor to muscle and tumor to blood ratios at early time points. Planer gamma imaging of tumor bearing mice showed that this radioconjugate was able to clearly visualize tumors. According to high tumor uptake, presented radiocomplex may have a potential for targeted imaging studies.
    Keywords: Deacetylcolchicine, Labeling, Pharmacokinetics, Tricine, 4T1 Tumor
  • Anna Wzgarda *, Katarzyna Dettlaff, Martyna Rostalska, Ewa Pabian, Katarzyna Regulska, Beata Jadwiga Stanisz Pages 1007-1018
    The main aim of this study was determination of thermo- radio- and photostability of perindopril tert-butyloamine (PER) therefore the efficiency and safety of the therapy could be maintained. A chromatographic method (RP-HPLC) had been validated before use to determine PER loss. The evaluation of stability properties of PER in solid state under the influence of isothermal condition, relative humidity - RH = 0% and 76.4%, exposure to 6 mln lux h and ionizing radiation generated by beam of electrons of 25–400 kGy was investigated. Studies pointed out that presence of moisture changes a kinetic model of PER degradation; lack of moisture in the air generates a first-order kinetic model of the reaction, increase humidity generates the autocatalytic model. PER proved to be resistant for ionizing radiation. It is possible to use radiation sterilization and decontamination (dose 25 kGy) with no significant loss of content. Investigation of PER photostability proved, that after exposure to 6 mln lux h physicochemical parameters are acceptable. Among all the ACE-I, PER has one of the shortest t0,5. PER should be stored in closed containers, protected from high temperature and moisture. PER is referred to be photostable and resistant for radiodegradation.
    Keywords: Perindopril tert-butyloamine, stability, Photostability, Radiodegradation, ACE-I
  • Fardin Safari, Mohsen Keyvanfard *, Hassan Karimi-Maleh, Khadijeh Alizad Pages 1019-1029
    A multiwall carbon nanotubes-modified carbon paste electrode (MWCNTs/MCPE) was fabricated and used to study the electrooxidation of penicillamine (PA) by electrochemical methods in the presence of methyldopa (MDOP) as a homogeneous mediator. The electrochemical oxidation of PA on the new sensor has been carefully studied. The kinetic parameters such as electron transfer coefficient, α, and catalytic reaction rate constant, K/ h, were also determined using electrochemical approaches. The electrocatalytic oxidation peak current of PA showed a linear dependent on the PA concentrations and linear calibration curves were obtained in the ranges of 0.2-250.0 μM of PA concentration with square wave voltammetry (SWV) method. The detection limit (3σ) was determined as 0.1 μM. This sensor was also examined as a fast, selective, simple and precise new sensor for voltammetric determination of PA in real samples such as drug and urine.
    Keywords: Penicillamine, Multiwall carbon nanotubes, Modified electrode, Sensor, Electrocatalysis
  • Emine Ki, Li, Ckaya Selvi, U, Ur , Ahin *, Serkan , Ahan Pages 1030-1036
    This method was developed for the determination of trace amounts of aluminum(III) in dialysis concentrates using atomic absorption spectrometry after coprecipitation with lanthanum phosfate. The analytical parameters that influenced the quantitave coprecipitation of analyte including amount of lanthanum, amount of phosfate, pH and duration time were optimized. The % recoveries of the analyte ion were in the range of 95-105 % with limit of detection (3s) of 0.5 µg l-1. Preconcentration factor was found as 1000 and RSD % value obtained from model solutions was 2.5% for 0.02 mg L-1. The accuracy of the method was evaluated with standard reference material (CWW-TMD Waste Water). The method was also applied to most concentrated acidic and basic dialysis concentrates with satisfactory results.
    Keywords: Aluminum, Lanthanium phosphate, Coprecipitation, Dialysis concentrate, Atomic absorption spectrometer
  • Taher Alizadeh * Pages 1037-1047
    A new chromatographic procedure was proposed for the separation of propranolol (PRN) enantiomers based upon enantioselective chiral ligand-exchange chromatography. The separation was carried out on a short C8 column leading to considerably short separation time. L-alanine and Cu2 were applied as chiral selector and central bivalent complexing ion, respectively. It was found that the kind of copper salt could influence the enantioseparation efficiency. The separation on the C8 stationary phase was more efficient than that on the C18 column. It was shown that the pH of mobile phase, organic modifier content of mobile phase, mole ratio of chiral ligand to bivalent ion and Cu(L-alanine)2 concentration in the mobile phase were important in enantioseparation efficiency. Water/methanol (70:30) mixture containing L-alanine-Cu2 (7:1) was found to be the best mobile phase condition for PRN enantioseparation. All effective parameters were optimized in order to improve the separation efficiency. The optimized HPLC method was utilized for analysis of propranolol enantiomers in spiked human blood plasma samples.
    Keywords: L-alanine, Chiral separation, Propranolol, C8 column, Ligand exchange
  • Mohammad Rezaei, Nabi Shariatifar *, Shahram Shoeibi, Maryam Amir Ahmadi, Gholamreza Jahed Khaniki Pages 1048-1058
    Background
    Food safety has a direct impact on human health and as such is a growing concern worldwide. Presence of harmful pesticide residue in food is a serious cause for concern among consumers so it is important to monitor levels of pesticides in foods. The aim of this study was simultaneous determination of amounts of 58 pesticides in 40 wheat flour samples collected from the Tehran market in January, 2014.
    The city under study (Tehran) was divided into five districts and samples were collected independently from each district and sourced from different bakeries (n=40). A gas chromatography-mass spectrometry single quadrupole selected ion monitoring GC/MS-SQ-SIM was used to quantify residue of 58 pesticides in the wheat flour samples.
    Results
    Four of the 40 samples showed contamination with Malathion (2 samples: 50.96 and 62.088 ppb) and 2, 4-DDE (2 samples: 19.88 and 13.7 ppb), had levels below MRLs of these pesticides in Iran. Averages of recovery of pesticide at 6 concentration levels were in the range of 81.61-118.41%. The method was proven as repeatable with RSDr in the range of 6.5-29.45% for all concentration levels. The limit of quantification for 37 of the tested pesticides was calculated as15 ppb and for the other 21 tested pesticides, the amount was 25 ppb.
    Conclusions
    In summary, results of these tests suggested that the wheat flour consumed in Tehran, was within safety limits in terms of levels of pesticide residues.
    Keywords: Pesticides, GC, MS, Wheat, flour, Food safety
  • Maryam Khosravi, Rahmatollah Rahimi *, Jalal Pourahmad, Mohammad Hadi Zarei, Mahboubeh Rabbani Pages 1059-1070
    In this research, dipeptide (his-β-alanine) and porphyrin derivatives were choosen for comparing chelating ability of toxic metals such as Al3, Cu2, Hg2 and Pb2 in vitro. The reason for choosing these two compounds is that both of them are naturally present in biological systems and comparison of chelating ability of these two compounds has not yet been done. Synthesis and comparison of kinetic study of dipeptide (his-β-alanine), meso-tetrakis(4-trimethylanilinium) porphyrin (TAPP) and Tetrakis(4-sulfonatophenyl)porphyrin (TPPS4) were carried out by our team. In addition, cytotoxicity assays of metals and chelators were also performed using methylthiazoletetrazolium (MTT) test. Furthermore we investigated the protective effect of chelators against cytotoxicity, induced by differenrt toxic metals such as Al3, Cu2, Hg2 and Pb2 on human lymphocytes. EC50 values on humanlymphocytes obtained after 12 h incubation for Al3, Cu2 and Hg2 were 30, 51, 3 µM respectively and for Pb2 no cytotoxicity was observed on human lymphocyte up to 1000 µM concentration. EC50 obtained for chelators dipeptide, TPPS4 and TAPP were 948, 472 and 175 µM respectively. Pretreatment of human lymphocyte with subtoxic concentations of chelators reduced toxicity of the metals against human blood lymphocytes.
    Keywords: Dipeptide, Porphyrin, Chelator, Toxic metals, Cytotoxicity, EC50, lymphocytes
  • Mohammad Moradi, Faraz Mojab, Sepideh Arbabi Bidgoli * Pages 1071-1079
    The species Asteraceae Centaurea repens (Asteraceae), known as Acroptilon repens, and Talkhe in persian is used in folk medicine as an emetic, anti-epileptic, and anti-malaria herb in many parts of the world but its toxic effects have not determined yet. This study aimed to evaluate the acute and subchronic toxicity of this extract to find its possible adverse health effects through clinical, hematological, biochemical, and histopathological endpoints in both gender of mice. Aerial parts of the plant were air-dried and the terpene extract of aerial parts of plant was provided by percolation using methanol, petroleum ether, and diethyl ether. All clinical, biochemical and histopathological changes were assessed in appropriate endpoints and compared with control group. Although no mortality was seen in acute study by administrating doses up to 2000 mg/kg, repeated dose study on 1000 mg/kg doses in 28 days in both genders showed liver necrosis and rise of liver enzymes (p-value
    Keywords: Asteraceae Centaurea repens L, Acroptilon repens, Rhaponticum repens, Russian knapweed, liver toxicity, Asteraceae
  • Abbas Mohammadi, Hossein Fallah *, Ahmad Gholamhosseinian Pages 1080-1088
    Insulin resistance is a condition in which insulin signaling and action are impaired in insulin sensitive tissues and results in hyperglycemia, hyperlipidemia and type 2 diabetes mellitus. Our previous studies have shown that rosa damascena has antihyperglycemic effects on diabetic and normal rats. Therefore, we conducted a study to evaluate the effect of this medicinal plant on insulin sensitivity in rats. This study was performed on high fructose diet insulin resistant rats and pioglitazone, an insulin sensitizing drug, was used as a positive control. Insulin resistance was developed in animals by high fructose diet within six weeks. Then, rosa damascena extract and pioglitazone were administered by gavage for two weeks and results were compared with two control groups. After treatment period, serum glucose, insulin, adiponectin, triglyceride and cholesterol were assayed in fasting state. Plasma free fatty acid profile was analyzed by GC. Liver PPAR.γ and muscle GLUT.4 gene expressions were assessed by real time PCR and western blotting. Animals were treated with rosa damascena extract showed levels of insulin (42±2.7 pmol/l), adiponectin (5.6±0.17 μg/ml), glucose (129±4.7 mg/dl), and triglyceride (75±9 mg/dl) which were significantly improved as compared with control group insulin (137±34 pmol/l), adiponectin (3.9±0.15 μg/ml), glucose (187±15 mg/dl), and triglycerides (217±18 mg/dl). PPARγ protein level was also significantly increased in Rosa damascene treated group. Our results demonstrated that rosa damascena extract has useful effects on insulin resistant animals and by increasing insulin sensitivity can be considered as a potential agent in control of diabetes.
    Keywords: Iinsulin resistance, PPAR.? GLUT.4, Rosa damascena, Adiponectin
  • Danish Iqbal, Amir Khan, Irfan Ansari, M. Salman Khan* Pages 1089-1103
    The present study is premeditated to extenuate the role of Ficus virens extract and its bioactive compound on cigarette smoke, an important risk factor for CVD, induced oxidative stress and hyperlipidemia. Cigarette smoke (CS) exposure to rats results in significant loss of body weight and increases blood carbon monoxide saturation (carboxyhemoglobin), nicotine, plasma TC, TG, and LDL-C levels but reduced level of antiatherogenic HDL-C. Moreover, owing to substantial oxidative stress generated in rats due to cigarette smoke a significant increase in plasma and erythrocytes lipid peroxidation products were observed which was well correlated with increase in ex-vivo BDC (48%) and MDA (53%) level (p
    Keywords: Cigarette smoke, Oxidative stress, Hyperlipidemia, Ficus virens, bioactive compound
  • Seyed Hadi Mousavi *, Azar Hosseini, Abolfazl Kajavirad, Elham Bakhtiary, Samira Shahraki, Shahrzad Havakhah, Mohammad Sadegh Amiri Pages 1104-1112
    Renal cell carcinoma (RCC) is one of most fatal cancers. In most patients It is resistant to chemotherapy. Ferula gummosa gum, Scutellaria lindbergii, Kelussia odoratissima and Artemisia kopetdaghensis are herbs that there are some cytotoxic activity reports about them. In this study cytotoxic and apoptotic activity of these four extracts on RCC cell line (ACHN) were evaluated and compared.ACHN cells were treated with different concentrations of herbal extracts (15-500 μg/ml). Cell proliferation was determined after 24, 48, and 72 h by MTT assay. Apoptotic cells were determined using PI staining of DNA fragmentation by flow cytometry. Cell viability decreased with all herbal extracts in ACHN cells by 24, 48 and 72 h as compared with control. Extracts induced a sub-G1 peak in flow cytometry histogram of treated cells indicating apoptotic cell death is involved in extracts induced-toxicity. Results imply that four herbal extracts inhibit the growth of ACHN cells as a concentration- and time-dependent manner. Also results show that apoptosis is proposed as the possible mechanism of action. So four herbal extracts could be considered as good anticancer agents in RCC after further studies.
    Keywords: Apoptosis, Cytotoxicity, Ferula gummosa gum, Scutellaria lindbergii, Kelussia odoratissima, Artemisia kopetdaghensis
  • Usman Sumo Tambunan*, Arli Parikesit, Mochammad Arfin Nasution, Amalia Hapsari, Djati Kerami Pages 1113-1127
    The menace of cervical cancer has reached an alarming rate. There are more than 450.000 cases of cervical cancer yearly, with mortality rate of about 50%. This deadly cancer is caused by human papillomavirus (HPV), mainly subtypes 16 and 18. The pharmaceutical industry has produced drug for combating the virus, known as SAHA (suberoylanilide hydroxamic acid). It inhibits class II HDAC Homo sapiens (HDACi). The utilization of SAHA has some side effects, one of which is bone loss. Thus, searching for viable alternatives aside SAHA is inevitable. The objective of this research is to investigate the molecular interaction of selected Indonesian natural products with class II HDAC Homo sapiens. LigX tool in MOE 2008.10 was used as an instrument to investigate the molecular interaction. Then, computer aided drug discovery and development (CADDD) approach involving molecular docking and dynamics methods was utilized to screen the natural products library. In the end, we found that herbaric acid could act as a potential drug candidate for cervical cancer.
    Keywords: Cervical cancer, Human papillomavirus (HPV), Indonesian natural products, HDAC, HDACi, CADDD approach, Herbaric acid
  • Soroush Sardari *, Samaneh Feizi, Ali Hossein Rezayan, Parisa Azerang, Seyyed Mohammad Shahcheragh, Ghazaleh Ghavami, Azizollah Habibi Pages 1128-1140
    Thiosemicarbazides are potent intermediates for the synthesis of pharmaceutical and bioactive materials and thus, they are used extensively in the field of medicinal chemistry. The imine bond (-N=CH-) in these compounds are useful in organic synthesis, in particular for the preparation of heterocycles and non-natural β-aminoacids.In this paper the synthesis of some new thiosemicarbazide derivatives by condensation reaction of various aldehydes or ketones with 4-phenylthiosemicarbazide or thiosemicarbazide is reported. This synthesis method has the advantages of high yields and good bioactivity. The structures of these compounds were confirmed by IR, Mass, 1H NMR, 13C NMR, and single-crystal X-ray diffraction studies. All of these compounds were tested for their in vitro anti-mycobacterial activity. The influence of the functional group and position of substituent on anti-bacterial activity of compounds is investigated too. The preliminary results indicated that all the tested compounds showed good activity against the test organism. The compounds 11 and 30 showed the highest anti-tubercular activity (0.39 μg/mL).
    Keywords: Thiosemicarbazide derivatives, Biological evaluation, Mycobacterium bovis, anti-tubercular activity, Medicinal chemistry
  • Ayesha Siddiqui, Mustafa Kamal, Seyed Abdulmajid Ayatollahi *, Mohsin Ali, Mansoor Ahmed Pages 1141-1146
    Bacillus licheniformis RM44 was isolated from hot spring near Karachi and screened for the production of extracellular amylase Amy RM44. Amy RM44 was purified to homogeneity on a single step by affinity chromatography using insoluble corn starch. The molecular weight of Amy RM44 was estimated to be 66 kDa by SDS–PAGE and zymographic analysis. Nine fold purification was achieved with the specific activity of 870 U/mg that provides the total yield of the enzyme up to 31%. Studies on purified AmyRM44 characterization revealed that the optimum temperature of enzyme was 100 ºC. Amy RM44 was proved to be highly thermostable as it retained 50% activity after 2 h at 100 ºC. Amy RM44 was stable over wide range of pH with optimum activity at pH 5. Enzyme activity was not significantly inhibited by SDS and EDTA. Amy RM44 also exhibited its activity towards various carbohydrates such as dextrin, pullulan, α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin.
    Keywords: Amylase, affinity chromatography, thermostable, chelator resistant, SDSresistant
  • Shahla Shahsavandi *, Mohammad Majid Ebrahimi, Ameneh Hasaninejad Frahani Pages 1147-1154
    Sambucus nigra (elder) are broadly used species to treat microbial infections. The potential antiviral activity and mechanism action of elder fruit (EF) in human epithelium cell (A549) cultures infected with H9N2 influenza virus were determined. The effect of various concentrations of EF on influenza virus replication was examined by using virus titration, quantitative real time RT-PCR, fusion and lipid raft assays following two treatment procedures: A) pre-treated H9N2 virus with each concentration of EF extract and transfection of A5 cell cultures, and B) each concentrations of EF was added to H9N2 virus infected-cell cultures following virus adsorption. In both treatments with lower doses of EF increased viral titer as well as synthesized viral nucleoprotein as indicating the herb had no inhibitory effects on virus replication. In (B) trial with higher doses, 40 and 80 μg/mL of EF, a significant decrease in virus titer and viral protein synthesis were shown in EF treated cells indicating the herb affect either entry of viruses or inhibition virus particle release. The results suggest that EF treatment of the influenza virus infected-human epithelial cells may involve in lipid raft association which function as platform for formation of viral membrane fusion and budding. Differencesin treatment time and dose of EF extract in infected cells with influenza virus have a marked effect on the efficacy of the herb.
    Keywords: influenza virus, Hemagglutinin, Sambucus nigra, lipid raft, antiviral activity
  • Mostafa Kamyab, Euikyung Kim, Seyed Mehdi Hoseiny, Ramin Seyedian* Pages 1155-1160
    Snakebite is a common problem especially in tropical areas all over the world including Iran. Echis carinatus as one of the most dangerous Iranian snakes is spreading in this country excluding central and northwest provinces. In this study gelatinase and fibrinogenolytic properties as two disintegrating matrix metalloproteinase enzymes were evaluated by a strong clear halo between 56-72 kDa in addition to another band located 76-102 kDa for gelatinase and one major band around 38 kDa for fibrinogenolytic enzyme respectively. The electrophorectc profile of our venom demonstrated at least one protein band between 24-31 kDa like previous reports and another two bands between 52-76 kDa and below 17 kDa stemmed probably due to the effect of natural selection in one species. According to our results Razi institute antivenin could neutralize in-vitro effects of gelatinase enzyme comprehensively. The electrophoretic profile of Iranian commercial antivenom as the main intravenous treatment of envenomed patients showed impurities in addition to F (abʹ)2 weighing 96 kDa in SDS-PAGE analysis. It proposes more efforts for refinement to avoid short and long unwanted effects in envenomed patients.
    Keywords: Echis carinatus, Zymography, Antivenom, Gelatinase
  • Shuhong Mao, Xuerong Wang, Zhijiang Ge, An Su, Lixia Zhang, Yanqing Li, Xiaoguang Liu, Fuping Lu * Pages 1161-1166
    Microbial transformation has been successfully applied in the production of steroid intermediates with therapeutic use and commercial value in pharmaceutical industry due to its high regio- and stereo-selectivity. As such, it is still important to screen microbial strains with novel activity or more efficient abilities in the development of the commercial steroid industry. Biotransformation of steroid: 16α, 17α-epoxyprogesterone (EP) using Penicillium decumbens as biocatalyst was investigated and selective hydroxylation of EP was observed. The products were separated by flash chromatography, and the structure determination were performed by MS, NMR, and X-ray crystallography. Biotransformation of EP afforded 7β-hydroxy-16α, 17α-epoxyprogesterone 1 and 7β, 11α-dihydroxy-16α, 17α-epoxyprogesterone 2. The two novel metabolic products 1 and 2 were reported for the first time. Moreover, the identified C7β- and C11-α hydroxylation is a novel reaction of microbial transformation of steroids by P. decumbens. This indicated that P. decumbens was a potential strains to produce the valuable pharmaceutical ingredients and precursors.
    Keywords: Penicillium decumbens, 16?, 17?-Epoxyprogesterone, Hydroxylation, Biotransformation, Steroid
  • Naser Karimi *, Azam Chardoli, Ali Fattahi Pages 1167-1175
    The biogenic synthesis of metal nanomaterial offers an environmentally benign alternative to the traditional chemical synthesis routes. In the present study, the green synthesis of silver nanoparticles (AgNPs) from aqueous solution of silver nitrate (AgNO3) by using Nigella arvensis L. seed powder extract (NSPE) has been reported. AgNPs were characterized by UV–vis absorption spectroscopy with an intense surface plasmon resonance band at 435 nm which reveals the formation of nanoparticles. Fourier transmission infrared spectroscopy (FTIR) showed nanoparticles were capped with plant compounds. Transmission electron microscopy (TEM) showed silver nanoparticles with a size of 2-15 nm were spherical. The X-ray diffraction spectrum (XRD) pattern clearly indicates that AgNPs formed in the present synthesis were crystalline in nature. Stabilized films of exudate synthesized AgNPswere effective anti-bacterial agents. In addition these biologically synthesized nanoparticles were also proved to exhibit excellent cytotoxic effect on a human breast cancer cell line (MCF-7) and a human colorectal adenocarcinoma cell line(HT-29).Theresults confirmed that the ASPE is a very good ecofriendly and nontoxic source for the synthesis of AgNPsas compared to the conventional chemical/physical methods. Therefore, N. arvensis seed providesfuture opportunities in nanomedicine by tagging nanoparticles with secondary metabolites.
    Keywords: Nigella arvensis, Green synthesis, Antibacterial, Cytotoxicity, Silver nanoparticle
  • Rajiv Dahiya *, Sunil Singh Pages 1176-1184
    The synthesis of a proline-rich cyclic heptapeptide, fanlizhicyclopeptide A (8), previously isolated from the fruits of Annona squamosa (sugar-apples), is described via coupling of tetrapeptide l-prolyl-l-tyrosyl-l-leucyl-l-proline methyl ester with tripeptide Boc-glycyl-lvalyl- l-proline followed by cyclization of the linear fragment having seven amino acid units. Structure of the synthesized cyclooligopeptide was confirmed by the means of chemical and spectroscopic methods including FTIR, 1H NMR, 13C NMR, FABMS and further, subjected to the anthelmintic, antibacterial and the antifungal activity studies. Bioactivity results indicated that the newly synthesized cyclic peptide displayed potent anthelmintic activity against the three earthworm species Megascoplex konkanensis, Pontoscotex corethruses and Eudrilus eugeniae at 2 mg/mL and remarkable anti-dermatophytic activities against Trichophyton mentagrophytes and Microsporum audouinii at concentration of 6 μg/mL.
    Keywords: Fanlizhicyclopeptide A, Cyclic Heptapeptide, Solution-Phase Synthesis, Macrocyclization, Pharmacological Activity
  • Razieh Pourahmad Jaktaji *, Farzaneh Zarghampoor Pages 1185-1189
    AcrAB-TolC is a major efflux pump in Escherichia coli. It was reported that tolC is overexpressed and involves in improving the organic solvent tolerance level in Escherichia coli marR mutants that are resistant to several antibiotics, such as ciprofloxacin. Low and intermediate levels resistance did not improve organic solvent tolerance. Thus, in this descriptive-experimental study it was decided to measure tolC expression and organic solvent tolerance in high level ciprofloxacin resistant mutants. tolC expression was measured by real time PCR and organic solvent tolerance assay was conducted by counting bacterial colonies on LBGMg agar. Results showed that tolC expression was increased significantly (P
    Keywords: AcrAB-TolC efflux pump, Ciprofloxacin, E. coli, Organic solvent tolerance, tolC, marR
  • Ines Sifaoui *, Atteneri L., Oacute, Pez Arencibia, Carmen M. Mart, Iacute, N. Navarro, Mar, Iacute, A. Reyes Batlle, Mondher Mejri, Basilio Valladares, Jacob Lorenzo-Morales, Manef Abderabba, JosE Enrique Pi, Ntilde, Ero Pages 1190-1193
    Leishmaniasis represents a serious threat to the health as one of the most important neglected tropical diseases as designated by the World Health Organization. The disease is endemic in 82 countries, among them Tunisia is an indigenous area for cutaneous Leishmaniasis. In a previous work, two tritepenic acids namely oleanolic and maslinic acids have been isolated from olive leaf extract. In the present paper, the in vitro activity against amastigotes stage of Leishmania (L.) infantum and Leishmania (L.) amazonensis was investigated. Maslinic acid showed the highest activity, against L. amazonensis, with an IC50 of 1.417 ±0.401 µg/ml and a selectivity index of 9.405. Although, the oleanolic acid exhibit a better activity against L. infantum with an IC50 of 0.999 ± 0.089 µg/ml and selectivity index of 8.111.
    Keywords: Triterpenic acids, Anti-amastigotes activity, Selectivity index, Leishmania, Chemotherapy
  • Narges Rahmanian, Parastoo Tarighi, Mehdi Gharghabi, Maryam Torshabi, Ghorban Ali Tarfiei, Taiebeh Mohammadi Farsani, Seyed Naser Ostad, Mohammad Hossein Ghahremani * Pages 1194-1203
    The Runt related transcription factors (RUNX) are recognized as key players in suppressing or promoting tumor growth. RUNX3, a member of this family, is known as a tumor suppressor in many types of cancers, although such a paradigm was challenged by some researchers. The TGF-β pathway governs major upstream signals to activate RUNX3. RUNX3 protein consists of several regions and domains. The Runt domain is a conserved DNA binding domain and is considered as the main part of RUNX proteins since. Herein, we compared the effects of Runt domains and full-Runx3 in cell viability by designing two constructs of Runx3, including N-terminal region and Runt domain. We investigated the effect of full-Runx3, N-t, and RD on growth inhibition in AGS, MCF-7, A549, and HEK293 cell lines which are different in TGF-β sensitivity, in the absence and presence of TGF-β. The full length RUNX3 did not notably inhibit growth of these cell lines while, the N-t and RD truncates showed different trends in these cell lines. Cell proliferation in the TGF-β impaired context cell lines (AGS and MCF-7) significantly decrease while in the A549 significantly increase. On the other hand, transfection of N-t and RD did not considerably affect the cell proliferation in the HEK293.Our results show that full-lenght RUNX3 did not affect the cell viability. Conversely, the N-t and RD constructs significantly changed cell proliferation. Therefore, therapeutic potentials for these truncated proteins are suggested in tumors with RUNX proteins dysfunction, even in the TGF-β impair context.
    Keywords: Runt, Cancer, TGF-? Domain Analysis, Apoptosis
  • Asieh Aramvash, Azra Rabbani-Chadegani *, Safa Lotfi Pages 1204-1213
    Anthracycline antibiotics are potent anticancer drugs widely used in the treatment of solid tumors and hematological malignancies. Because of their extensive clinical use and their toxic effect on normal cells, in the present study the effect of these drugs on multipotent hematopoietic bone marrow cells was investigated employing, viability tests, PARP cleavage, Hoechst 33258 staining, DNA fragmentation and superoxide anion production techniques. The results revealed that daunorubicin and doxorubicin exhibited time and dose dependent cytotoxicity against the cells and upon increasing the drugs concentrations, apoptosis was occurred after 4 h of incubation and at low concentration of the drugs. The cleavage of poly ADP-ribose polymerase (PARP) demonstrated by daunorubicin and doxorubicin treatment of the cells, suggest that theapoptotic process is PARP dependent. The drugs induced DNA fragmentation and also anion superoxide production was increased upon rising drugs concentrations. From the results it is concluded that anthracycline antibiotics represent cytotoxic effect on hematopoietic progenitor/ stem cells of bone marrow, inducing apoptosis and in this process toxicity of daunorubicin is more pronounced compared to doxorubicin.
    Keywords: Apoptosis, Daunorubicin, Doxorubicin, Multipotent hematopoietic cells, PARP
  • Hassan Emami *, Reza Radfar Pages 1214-1222
    Background and scope: The current situation in Iran suggests a good basis for advancement in biotechnology industries because the patents for many hi-tech medicines registered in developed countries are ending. Biosimilar and technology-oriented companies without patents will have the opportunity to enter the biosimilar market and move toward innovative initiatives. The present research proposed a model by which one can evaluate commercialization of achievements obtained from research with a focus on the pharmaceutical biotechnology industry.
    Methodology
    This is a descriptive-analytic study where mixed methodology is followed by a heuristic approach. The statistical population was experts active in pharmaceutical biotechnology and those at universities and research centers in Iran. Structural equations were employed in this research.
    Findings: The results indicate that there are three effective layers within commercialization in the proposed model. These are a general layer (factors associated with management, human capital, legal infrastructure, communication infrastructure, technical and executive infrastructures, and financial factors), industrial layer (internal industrial factors and pharmaceutical industry factors), and a third layer that included national and international aspects. These layers comprise 6 domains, 21 indices, 41 dimensions, and 126 components.
    Conclusion
    Compilation of these layers (general layer, industrial layer, and national and international aspects) can serve commercialization of research and development as an effective evaluation package.
    Keywords: evaluation, commercialization indices, research, development, indices, pharmaceutical biotechnology
  • Mohsen Masjedi, Nafiseh Esmaeil, Ali Saffaei, Bahareh Abtahi-Naeini *, Mohsen Pourazizi, Shaghayegh Haghjooy Javanmard, Ali Asilian Pages 1223-1229
    Pemphigus vulgaris (PV) is a chronic autoimmune blistering disease of the skin, in which loss of adhesion between keratinocytes is caused by autoantibodies. It has been hypothesized that cytokines play an essential role in the pathogenesis of PV. This study aimed to investigate the other immunopathological aspects of PV by determining the serum levels of cytokines in PV patients to find another treatment strategy except corticosteroid therapy. Twenty-three patients with PV and a control group consisting of 24 healthy subjects were studied. Interleukin (IL)-2, IL-4, IL-6, IL10, IL-12, IL-17 and interferon-gamma (IFN-γ) were measured in the sera of patients by the enzyme-linked immunosorbent assay (ELISA) method. The serum levels of IL-2, IL-4, IL-17 and IFN-γ in most patients and controls were undetectable. The serum concentrations of IL-10 in the patients and controls were undetectable, nevertheless, the mean serum levels of this cytokine was 64.375 pg/mL in four patients. The mean serum levels of pro-inflammatory cytokine IL-6 increased significantly in the patients, compared to the controls (169.50 vs. 75.62 pg/mL) (P
    Keywords: Pemphigus vulgaris, TH1 cytokines, TH2 cytokines, Interleukin, Interferon
  • Sajad Rafiee, Masoumeh Rajabibazl, Reza Meshkani, Azam Daraei, Mehryar Zargari, Fahimeh Sharafeddin, Zahra Fazeli, Attabak Toffani Milani, Maryam Taherkhani * Pages 1230-1237
    Warfarin is a vitamin K antagonist that genetic and non-genetic factors affected on its dose requirement in the patients with cardio vascular disease. The aim of this study was whether the APOE and VKORC1 polymorphisms influence on warfarin dose requirements in the part of Iranian patients. Blood samples were collected from 86 warfarin-treated patients. After extraction of genomic DNA, the VKORC1 (rs9923231) and the APOE (rs429358 and r 7412) polymorphisms were genotyped by PCR-RFLP technique. We found that the Iranian patients carrying genotypes GA or AA of VKORC1 polymorphism tended to receive lower dose of warfarin (p = 0.018). Furthermore, the E3/E3 genotype was observed with the frequency more than 60% in the patients with low dose of warfarin. The BMI and weight also showed a positive correlation with warfarin dose. However, it was not statistically significant (p > 0.05). The results of this study may be useful in defining of warfarin dose algorithms for Iranian patients.
    Keywords: Warfarin therapy, APOE polymorphisms, VKORC1, Iranian population, Cardio vascular disease
  • Shahdah Khosropanah, Seyed Nooreddin Faraji, Hamzeh Habibi *, Majid Yavarian, Roohollah Mansoori, Sezaneh Haghpanah Pages 1238-1246
    Background
    Many cardiovascular diseases may require lifelong anticoagulation therapy. Warfarin is the most prescribed medication in this regard, however, it has serious side effects. Recently the new issue regarding to warfarin dosing is considered in which some single nucleotide polymorphisms (SNPs) affecting cytochrome P450 system can impact on warfarin metabolism and dosing.
    Methods
    230 cardiovascular patients have participated in the study. The INR levels was 1.5 - 3.5 with a mean range of 2.8. The subjects were divided into two case and control groups. The rs2108622 SNP of the CYP4F2 gene and its effect on warfarin dosing in these patients was accessed.
    Results
    The results of our study showed a correlation between age and warfarin dosage. The overall frequency of the CC and TT allele of rs2108622 was 53.1% and 18.6%. Daily average dose of warfarin in CC, CT and TT variants was 3.5 ± 1.6, 4.5 ± 2.1 and 5.3 ± 2.1 respectively. The daily warfarin dose in patients with CC allele was significantly lower than that for CT or TT. The patients with TT allele required a 1.8 mg/day higher dose of warfarin than that of CC.
    Conclusion
    While there are many studies regarding to relation of age and warfarin dose, however, there are different results about pharmacogentic status and warfarin dose in different ethnics. Our study demonstrates that polymorphism in the CYP4F2 rs2108622 has a significant impact on the warfarin requirements in Iranian patients. However the cost benefit of such test should be considered, too.
    Keywords: rs2108622, CYP4F2, polymorphism, warfarin, cardiovascular disease
  • Monireh Ghazaeian, Majid Mokhtari, Mehran Kouchek, Mirmohammad Miri, Reza Goharani, Robabeh Ghodssi Ghassemabadi, Mohammad Sistanizad * Pages 1247-1253
    Objectives
    The aim of this study was to evaluate the procalcitonin (PCT) changes in two different high-dose colistin regimens in the treatment of multi-drug resistant MDR gram negative infections in ICU patients.
    Method
    This is a prospective study of adult ICU patients with bacteremia and ventilator associated pneumonia (VAP) caused by MDR gram negative pathogens. Patients were assigned to two colistin administration groups. Group A received 9 and group B received 3 million international units every 24 and 8 hours respectively. Baseline characteristics and measurements of PCT concentrations at the start, the 3rd and the 5th day of the antibiotic therapy and their trends between the two groups were recorded and compared.
    Results
    Of 40 patients enrolled, 34 completed the study protocol, of whom 30 (88.2%) had VAP and 4 (11.8%) had bacteremia. There were no statistically significant differences in the baseline characteristics between the two groups. The mean PCT levels in two study groups were; 2.34, 1.24 and 0.95 in group A and 5.89, 1.24 and 0.8 in group B at the baseline, 3rd and 5th day of colistin administration respectively (P=0.47). The ICU length of stay (LOS) in days and ICU mortality were; 31.31, 35.3% and 32.06, 22.2% in groups A and B (P=0.39, 0.87), respectively.
    Conclusion
    We did not find any statistically significant differences in the serum PCT levels, ICU LOS or ICU mortality, between the two groups, who received maximum recommended dose of CMS with 2 different intervals of every 8 or 24 hours.
    Keywords: Procalcitonin, Colistin, Critically ill patients, Dosing interval, MDR infections
  • Amir Ebrahim Miroliaee, Jamshid Salamzadeh, Shervin Shokouhi, Alireza Fatemi, Seyed Hossein Ardehali, Mohammadreza Hajiesmaeili, Zahra Sahraei * Pages 1254-1263
    Ventilator-associated pneumonia (VAP) is a common and serious problem that develops after more than 48 hours of mechanical ventilation. Improving the activity of immune system with vitamin D, and its consequent impact on prognostic biomarkers of VAP was studied in the current study.
    A randomized double blind placebo controlled clinical trial was designed. A total of 46 patients with VAP, who were suffering from vitamin D deficiency, were randomly allocated into the study groups of placebo (n=22) and treatment (n=24). The treatment group received 300,000 units of intramuscular vitamin D. Serum levels of procalcitonin and vitamin D along with SOFA and CPIS scores were determined at baseline and on day 7 after intervention. The mortality rate of patients was also monitored for the succeeding 28 days after the injection.
    The administration of vitamin D significantly enhanced its levels (P
    Keywords: Procalcitonin, VAP, CPIS score, SOFA score, Vitamin D
  • Mona Zamanian Azodi, Mostafa Rezaei Tavirani *, Afsaneh Arefi Oskouie, Mostafa Hamdieh, Mohammad Kamran Derakhshan, Alireza Ahmadzadeh, Farid Zayeri, Naser Nejadi, Majid Rezaei Tavirani, Vahid Mansouri, Mohammad Rostami Nejad, Reza Vafaee Pages 1264-1271
    Obsessive-Compulsive Disorder (OCD) is one of the most common mental conditions. Proteome profiling may help identifying important proteins and finally shed lights to complexity of OCD underlying mechanisms. Here, by the application gel-based proteomic approach the proteome profile of patients with washing subtype of OCD before and after treatment with Fluoxetine (positive responders) are compared to healthy matched controls. However, only one of the differentially expressed proteins is examined and introduced in this paper. Proteomic analysis was by the application of two-dimensional polyacrylamide gel electrophoresis (2-D PAGE), combined with (MALDI-TOF-TOF MS)-based. Furthermore, Cytoscape Plug-in, CluePedia, conducted network analysis and biological annotation. The proteome comparison between groups identified protein with the significant expression changes (p
    Keywords: Obsessive-Compulsive Disorder (OCD)_Washing Subtype_Fluoxetine_Ig Kappa Chain C Region (IGKC)_Two-dimensional gel electrophoresis (2DE)_Matrix-assisted laser desorption-ionization Mass Spectrometry (MALDI-TOF MS)_PPI Network Analysis