Iranian Journal of Pharmaceutical Research
Year:2017 | Volume:16 | Issue:3|Papers Count:43

Brinzolamide (BZ) is an intraocular pressure reducing agent with low bioavailability. Thepurpose of the present study was to overcome this issue by development of BZ containingnanoemulsions (NEs) as an ocular drug delivery system with desirable therapeutic efficacy. Brinzolamide NEs were prepared by the spontaneous emulsification method. Based on initialrelease studies, twelve formulations with the slowest release characteristics were subjected tofurther physicochemical investigations such as particle size, polydispersity index, pH, refractiveindex, osmolality and viscosity. The therapeutic efficacy of these formulations was assessed bymeasuring the intraocular pressure after instillation of the prepared NEs in normotensive albinorabbit eyes. Nanoemulsions with suitable physicochemical properties exhibited high formulationstability under different conditions. more over biological evaluations indicated that using lowerdrug concentrations in NE formulations (0. 4%) had a similar or even better pharmacodynamiceffect compared to the commercial suspension with a higher drug concentration (1%). Ourfindings suggest that NEs could be effectively used as carriers for enhancing the bioavailabilityof topically applied ophthalmic drugs.

In recent years, use of biodegradable polymers based nanoparticles has received highinterest in the development of vaccines delivery vehicles. The aim of study was to preparechitosan nanoparticles (CS NPs) for loading Echis carinatus (EC) venom and evaluate theirpotential as an adjuvant and antigen delivery system on a pilot scale. CS NPs were preparedusing ionic gelation method, and their characteristics were optimized. Venom-loaded CS NPsprepared under optimum conditions and traditional venom-loaded adjuvants were used tohyperimmunization of horse. Under optimum conditions, particle size, polydispersity index(PDI), and zeta potential of CS NPs were 127. 9 ± 15 nm, 0. 29, and +19. 8 ± 1. 92 mV, whilethose of venom-loaded CS NPs were 182. 4 ± 20 nm, 0. 35, +26. 8 ± 1. 98 mv, respectively. AllCS NPs had integrated surface and good morphology. Optimum loading concentration of ECvenom was 500 μ g/mL. The loading capacity (LC) and loading efficiency (LE) were 87% and94%, respectively, and release profile of venom-loaded CS NPs showed suitable correlationwith Higuchi kinetics. Stability test showed good stability of the venom encapsulated in CSNPs. Furthermore, antivenom plasma obtained using the new antigen delivery system hadsignificantly higher potency (P < 0. 05) for neutralizing the venom than that obtained usingconventional system. These results suggested that venom-loaded CS NPs could be a suitablealternative to conventional adjuvant for development antivenom.

Curcumin (Cur) has been found to be very efficacious against many different types of cancercells. However, the major disadvantage associated with the use of Cur is its low systemicbioavailability. 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 thepresent study, we have investigated the effects of NCur on growth, autophagia, and apoptosisin PC3 cells, respectively, by MTT assay, fluorescence microscopy, and Flow cytometry. MTTassays revealed that the NCur at the concentration of 25 μ g/mL for 48 h were able to exert a morepronounced effect on the PC3 cells as compared to free Cur. Apoptotic index was significantlyincreased 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 PC3cell 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

Acetylcholinesterase has important role in synaptic cleft. It breaks down the acetylcholineatcholinergic synapsesand terminates the cholinergic effects. Some chemical agents likeorganophosphorus compounds (OPCs) including nerve agents and pesticides react withacetylcholinesteraseirreversibly. They inhibit normal biological enzyme action and resultin accumulation of acetylcholineand show toxic effects andcholinergic symptoms. Theprocess of Acetylcholinesterase (AChE) inhibition can be reversed by a nucleophilic agentto dephosphorylate and reactivate the enzyme. In this study, design and docking studies of 15novel nitrone based onoximes as reactivators were performed by using AutoDock program. Then, more effective reactivatorsoximes in terms of binding energy and orientation withinthe active site were synthesized and evaluated in-vitro on human AChE (hAChE) inhibited byparaoxon and compared to standard hAChE reactivators (2-PAM and obidoxime). Our resultsused 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.

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 thispaper, anticonvulsant screening of 10 synthesized new derivatives of 1, 4-dihydropyridine-3, 5-dicarboxamides was performed. Anticonvulsant activity was evaluated by intravenous and intraperitoneal pentylenetetrazoleand maximal electroshock induced seizures tests. Nifedipine was used as reference drug. Ourpharmacological results revealing the compounds 2, 4, 5, and 6 can be effective in both absenceand grandmal seizures in human. These pharmacological studies have displayed that these new dihydropyridine derivativesare capable to inhibiting seizures induced by pentylenetetrazole and maximal electroshock inmice efficiently.

A series of (5-nitrofuran-2-yl)-1, 3, 4-thiadiazole-2-yl derivatives 6a– 6e have beensynthesized and screened for in-vitro anti-leishmanial activity against the promastigote formof L. major. The structure of Schiff bases were confirmed by 1H NMR, IR. Screening resultsindicate that all of the designed and synthesized final compounds (6a-6e) significantly reducedthe viability of promastigotes of L. major in comparison toglucantime (IC50 3× 103 μ g/mL). Meta and Para substitutions in benzene ring containing compounds were more potent thanother derivative and the most potent compounds were 6d, 6e with IC50 value 94 μ m and 77. 6μ m, 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 cutaneousleishmaniasis.

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.

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 a- (acyloxy) -a- (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 HepG2 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 a- (acyloxy) -a - (quinolin-4-yl) acetamides.

Keeping in view the drawbacks associated with research on anti-TB drugs based on plantextracts and the non-availability of fluorinated natural products with antitubercular activity hasprompted us to make an effort towards the synthesis and characterization of a novel series offifteen substituted fluorobenzimidazoles. The newly synthesized compounds were characterizedby I. R, 1H-NMR, 13C-NMR, Mass, and elemental analysis. The synthesized compounds 4(af)and 5(b-j) have been evaluated for their in-vitro antimycobacterial activity against H37Rvstrain (ATCC 27294) by MABA method. Incorporation of methylenedioxyphenyl moiety at2-and 6-position of the benzimidazole ring furnished compounds 4d and 5i with antitubercularactivity comparable or more potent than the naturally occurring compounds with reportedantitubercular activity. Among the fifteen tested compounds, 4d and 5i emerged as promisinghits characterized by MIC lower than that determined for sesamin against the pathogenicH37Rv strain. Antitubercular activity results indicate that these compounds may be suitablefor further lead optimization. The cytotoxic effect of these active compounds on THP-1 cellline was assessed by MTT assay and the results suggest that these two molecules are potentialcandidates for further development as antitubercular agents.

Infections are one of the most important causes of death, disability and inappropriateconditions for millions of people around the world. Therefore, the development in prognosis, prevention and treatment of infectious diseases made a considerable progress in designing andsynthesis 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 andspiro compounds are the most important fragments in some effective drugs with antimicrobialactivity. Therefore, in this study, 6 compounds with spiro-4H-pyran core were synthesizedand evaluated for their antimicrobial activity against four different bacterial species usingmicrobroth dilution and disk diffusion methods. Minimum inhibitory concentration (MIC) hasbeen measured for each compound and also for the standard antibiotic, gentamicin, and theywere 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 effectsagainst standard and clinical isolates of Staphylococcus aureus and Streptococcus pyogenes.

Quinoxalines display diverse and interesting pharmacological activities as antibacterial, antiviral, antiparasitic and anticancer agents. Particularly, their 1ˏ 4-di-N-oxide derivatives haveproved to be cytotoxic agents that are active under hypoxic conditions as that of solid tumours. A new series of quinoxaline 1ˏ 4-di-N-oxide substitutes at 7-position with esters group weresynthetized 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 celllines screen. Results showed that E7, P3 and E6 were the most active compounds againstthe cell lines tested. Substitutions at 7-position with esters group not necessarily affect thebiological 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.

The 17β-HSD3 enzyme plays a key role in treatment of prostate cancer and small inhibitorscan 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 structuralfunctionality against the inhibition activity of some 17β-HSD3inhibitors. Chemical structuralinformation 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 moleculardescriptors. 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, withhigh statistical significance (R2train = 0. 938; R2test = 0. 870), was found to be useful for estimatingthe inhibition activity of 17β-HSD3 inhibitors. The models were validated rigorously throughleave-one-out cross-validation and several compounds as external test set. Furthermore, theexternal predictive power of the proposed model was examined by considering modified R2 andconcordance correlation coefficient values, Golbraikh and Tropsha acceptable model criteriaʹ s, and an extra evaluation set from an external data set. Applicability domain of the linear modelwas carefully defined using Williams plot. Moreover, Euclidean based applicability domainwas applied to define the chemical structural diversity of the evaluation set and training set.

Dichloroacetate (DCA) is a simple and small anticancer drug that arouses the activityof the enzyme pyruvate dehydrogenase (PDH) through inhibition of the enzyme pyruvatedehydrogenase kinases (PDK1-4). DCA can selectively promote mitochondria-regulatedapoptosis, depolarizing the hyperpolarized inner mitochondrial membrane potential to normallevels, inhibit tumor growth and reduce proliferation by shifting the glucose metabolism incancer cells from anaerobic to aerobic glycolysis. In this study, a series of DCA analogueswere applied to quantitative structure– activity relationship (QSAR) analysis. A collectionof chemometrics methods such as multiple linear regression (MLR), factor analysis– basedmultiple linear regression (FA-MLR), principal component regression (PCR), and partial leastsquared combined with genetic algorithm for variable selection (GA-PLS) were applied tomake relations between structural characteristics and cytotoxic activities of a variety of DCAanalogues. The best multiple linear regression equation was obtained from genetic algorithmspartial least squares, which predict 90% of variances. Based on the resulted model, an in silicoscreeningstudy was also conducted and new potent lead compounds based on new structuralpatterns were designed. Molecular docking as well as protein ligand interaction fingerprints(PLIF) studies of these compounds were also investigated and encouraging results wereacquired. There was a good correlation between QSAR and docking results.

Colchicine as a vascular disrupting agent creates microtubule destabilization whichinduces vessel blockage and consequently cell death. Accordingly, colchicines and itsanalogues 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 coligandand characterized for its tumor targeting properties. The in-vitro radiochemical stability andthe biodistribution were studied in 4T1 breast tumor model bearing mice. Labeling yield ofmore than 90% was obtained corresponding to a specific activity of 46 MBq/μ mol. In-vivobiodistribution studies demonstrated that radiocomplex had high tumor to muscle and tumor toblood ratios at early time points. Planer gamma imaging of tumor bearing mice showed that thisradioconjugate was able to clearly visualize tumors. According to high tumor uptake, presentedradiocomplex may have a potential for targeted imaging studies.

The main aim of this study was determination of thermo-radio-and photostability ofperindopril tert-butyloamine (PER) therefore the efficiency and safety of the therapy could bemaintained. A chromatographic method (RP-HPLC) had been validated before use to determinePER loss. The evaluation of stability properties of PER in solid state under the influence ofisothermal condition, relative humidity-RH = 0% and 76. 4%, exposure to 6 mln lux h andionizing 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, increasehumidity generates the autocatalytic model. PER proved to be resistant for ionizing radiation. Itis possible to use radiation sterilization and decontamination (dose 25 kGy) with no significantloss of content. Investigation of PER photostability proved, that after exposure to 6 mln lux hphysicochemical parameters are acceptable. Among all the ACE-I, PER has one of the shortestt0, 5. PER should be stored in closed containers, protected from high temperature and moisture. PER is referred to be photostable and resistant for radiodegradation.

A multiwall carbon nanotubes-modified carbon paste electrode (MWCNTs/MCPE) wasfabricated and used to study the electrooxidation of penicillamine (PA) by electrochemicalmethods in the presence of methyldopa (MDOP) as a homogeneous mediator. Theelectrochemical oxidation of PA on the new sensor has been carefully studied. The kineticparameters such as electron transfer coefficient, α , and catalytic reaction rate constant, K/h, werealso determined using electrochemical approaches. The electrocatalytic oxidation peak currentof PA showed a linear dependent on the PA concentrations and linear calibration curves wereobtained in the ranges of 0. 2-250. 0 μ M of PA concentration with square wave voltammetry(SWV) method. The detection limit (3σ ) was determined as 0. 1 μ M. This sensor was alsoexamined as a fast, selective, simple and precise new sensor for voltammetric determination ofPA in real samples such as drug and urine.

This method was developed for the determination of trace amounts of aluminum(III) indialysis concentrates using atomic absorption spectrometry after coprecipitation with lanthanumphosphate. The analytical parameters that influenced the quantitative coprecipitation of analyteincluding 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. 5μ g l-1. Preconcentration factor was found as 1000 and Relative Standard Deviation (RSD) %value obtained from model solutions was 2. 5% for 0. 02 mg L-1. The accuracy of the method wasevaluated with standard reference material (CWW-TMD Waste Water). The method was alsoapplied to most concentrated acidic and basic dialysis concentrates with satisfactory results.

A new chromatographic procedure was proposed for the separation of propranolol (PRN)enantiomers based upon enantioselective chiral ligand-exchange chromatography. Theseparation was carried out on a short C8 column leading to considerably short separationtime. 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 enantioseparationefficiency. The separation on the C8 stationary phase was more efficient than that on theC18 column. It was shown that the pH of mobile phase, organic modifier content of mobilephase, mole ratio of chiral ligand to bivalent ion and Cu (L-alanine) 2 concentration in themobile phase were important in enantioseparation efficiency. Water/methanol (70: 30) mixturecontaining L-alanine-Cu2+ (7: 1) was found to be the best mobile phase condition for PRNenantioseparation. All effective parameters were optimized in order to improve the separationefficiency. The optimized HPLC method was utilized for analysis of propranolol enantiomersin spiked human blood plasma samples.

Food safety has a direct impact on human health and as such is a growing concernworldwide. Presence of harmful pesticide residue in food is a serious cause for concern amongconsumers so it is important to monitor levels of pesticides in foods. The aim of this studywas simultaneous determination of concentrations of 58 pesticides in 40 wheat flour samplescollected from Tehran market in January, 2014. The city under study (Tehran) was divided intofive districts and samples were collected independently from each district and sourced fromdifferent bakeries (n=40). A gas chromatography-mass spectrometry single quadrupole selectedion monitoring «GC/MS-SQ-SIM» method was used to quantify residue of 58 pesticides inthe wheat flour samples. Four of the 40 samples showed contamination with Malathion (2samples: 50. 96 ± 11. 38 and 62. 088 ± 11. 38 ppb) and 2, 4-DDE (2 samples: 19. 88± 15. 24 and13. 7 ± 15. 24 ppb). that had levels below MRLs of these pesticides in Iran. Averages of recoveryof pesticides at 6 concentration levels were in the range of 81. 61-118. 41%. The method wasproven as repeatable with RSDr in the range of 6. 5-29. 45% for all concentration levels. Thelimit of quantification for 37 of the tested pesticides was calculated as 15 ppb and for the other21 tested pesticides, the concentration was 25 ppb. In summary, results of these tests suggestedthat the wheat flour consumed in Tehran, was within safety limits in terms of levels of pesticideresidues.

In this research, dipeptide (his-β-alanine) and porphyrin derivatives were choosen forcomparing chelating ability of toxic metals such as Al3+, Cu2+, Hg2+ and Pb2+ in-vitro. The reasonfor choosing these two compounds is that both of them are naturally present in biologicalsystems 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 werealso performed using methylthiazoletetrazolium (MTT) test. Furthermore we investigated theprotective effect of chelators against cytotoxicity, induced by differenrt toxic metals such asAl3+, Cu2+, Hg2+ and Pb2+ on human lymphocytes. EC50 values on human lymphocytes obtainedafter 12 h. incubation for Al3+, Cu2+ and Hg2+ were 30, 51, 3 μ M respectively and for Pb2+ nocytotoxicity was observed on human lymphocyte up to 1000 μ M concentration. EC50 obtainedfor chelators dipeptide, TPPS4 and TAPP were 948, 472 and 175 μ M respectively. Pretreatmentof human lymphocyte with subtoxic concentations of chelators reduced toxicity of the metalsagainst human blood lymphocytes.

The species Asteraceae Centaurea repens (Asteraceae), known as Acroptilon repens, andTalkhe in persian is used in folk medicine as an emetic, anti-epileptic, and anti-malaria herbin many parts of the world but its toxic effects have not determined yet. This study aimed toevaluate the acute and subchronic toxicity of this extract to find its possible adverse healtheffects through clinical, hematological, biochemical, and histopathological endpoints in bothgender of mice. Aerial parts of the plant were air-dried and the terpene extract of aerial partsof plant was provided by percolation using methanol, petroleum ether, and diethyl ether. Allclinical, biochemical and histopathological changes were assessed in appropriate endpoints andcompared with control group. Although no mortality was seen in acute study by administratingdoses up to 2000 mg/kg, repeated dose study on 1000 mg/kg doses in 28 days in both gendersshowed liver necrosis and rise of liver enzymes (p-value < 0. 05). Histopathological studiesdidn’ t show any other organ toxicity in dosed up to 1000 mg/kg. At the same time this studyshowed for the first the antihyperlipidemic properties of the aerial extract of Acroptilin in micemodel. The pharmacological and histopathological results of the present study proved that thetotal parts of Acroptilon repens could be studied for supporting the traditional assertion in folkmedicine to heal hyperlipidemia, diabetes, and cancer in lower doses although we performedthe present study and concluded liver toxicity by subchronic use of Acropitolon repens extract.

Insulin resistance is a condition in which insulin signaling and action are impaired in insulinsensitive tissues and result in hyperglycemia, hyperlipidemia, and type 2 diabetes mellitus. Ourprevious studies have shown that Rosa damascena has antihyperglycemic effects on diabeticand normal rats. Therefore, we conducted a study to evaluate the effect of this medicinal planton insulin sensitivity in rats. This study was performed on high fructose diet insulin resistant ratsand pioglitazone, an insulin sensitizing drug, was used as a positive control. Insulin resistancewas developed in animals by high fructose diet within six weeks. Then, Rosa damascena extractand pioglitazone were administered by gavage for two weeks and results were compared withtwo control groups. After treatment period, serum glucose, insulin, adiponectin, triglyceride, and cholesterol were assayed in fasting state. Plasma free fatty acid profile was analyzed byGC. Liver PPAR. γ and muscle GLUT. 4 gene expressions were assessed by real time PCR andwestern blotting. Animals were treated with rosa damascena extract showed levels of insulin(42 ± 2. 7 pmol/L). adiponectin (5. 6± 0. 17 μ g/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 μ g/mL). glucose (187± 15 mg/dL). and triglycerides(217± 18 mg/dL). PPARγ protein level was also significantly increased in Rosa damascenetreated group. Our results demonstrated that rosa damascena extract has useful effects oninsulin resistant animals and by increasing insulin sensitivity can be considered as a potentialagent in control of diabetes.

The present study is premeditated to extenuate the role of Ficus virens extract and itsbioactive compound on cigarette smoke, an important risk factor for CVD, induced oxidativestress and hyperlipidemia. Cigarette smoke (CS) exposure to rats results in significant loss ofbody 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 significantincrease in plasma and erythrocytes lipid peroxidation products were observed which was wellcorrelated with increase in ex-vivo BDC (48%) and MDA (53%) level (p < 0. 001). Simultaneousadministration of FVBM extract at higher dose (100 mg/rat) and F18 (n-Octadecanyl-O-α-Dglucopyranosyl(6’ → 1’ ’ )-O-α-D-glucopyranoside) compound to CS-exposed rats effectivelyblocked the increase in plasma lipid and lipoprotein levels (p < 0. 001) which was due to themarked suppression in the hepatic HMG-CoA reductase activity (p < 0. 001) and significantlyinhibit the lipid peroxidation process thus preventing the membrane damage, LDL oxidation, and in turn subsequent atherosclerosis. Thus, the results clearly demonstrated the protectiverole of FVBM extract and F18 compound in risk factor induced cardiovascular disease.

Renal cell carcinoma (RCC) is one of most fatal cancers. In most patients it is resistantto chemotherapy. Ferula gummosa gum, Scutellaria lindbergii, Kelussia odoratissima, andArtemisia kopetdaghensis are herbs about which there are some cytotoxic activity reports. Inthis 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 ofherbal extracts (15-500 μ g/mL). Cell proliferation was determined after 24, 48, and 72 h. byMTT assay. Apoptotic cells were determined using PI staining of DNA fragmentation by flowcytometry. Cell viability decreased with all herbal extracts in ACHN cells by 24, 48, and 72h. as compared with control. Extracts induced a sub-G1 peak in flow cytometry histogram oftreated cells indicating apoptotic cell death is involved in extracts induced-toxicity. Resultsimply that four herbal extracts inhibit the growth of ACHN cells as a concentration-and timedependentmanner. Also, results show that apoptosis is proposed as the possible mechanismof action. So, four herbal extracts could be considered as good anticancer agents in RCC afterfurther studies.

The menace of cervical cancer has reached an alarming rate. There are more than 450. 000cases of cervical cancer yearly, with mortality rate of about 50%. This deadly cancer is causedby human papillomavirus (HPV), mainly subtypes 16 and 18. The pharmaceutical industryhas produced drug for combating the virus, known as SAHA (suberoylanilide hydroxamicacid). It inhibits class II HDAC Homo sapiens (HDACi). The utilization of SAHA has someside effects, one of which is bone loss. Thus, searching for viable alternatives aside SAHA isinevitable. The objective of this research is to investigate the molecular interaction of selectedIndonesian natural products with class II HDAC Homo sapiens. LigX tool in MOE 2008. 10was used as an instrument to investigate the molecular interaction. Then, computer-aided drugdiscovery and development (CADDD) approach involving molecular docking and dynamicsmethods was utilized to screen the natural products library. In the end, we found that herbaricacid could act as a potential drug candidate for cervical cancer.

Thiosemicarbazides are potent intermediates for the synthesis of pharmaceutical andbioactive materials and thus, they are used extensively in the field of medicinal chemistry. Theimine bond (-N=CH-) in this compounds are useful in organic synthesis, in particular for thepreparation of heterocycles and non-natural β-aminoacids. In this paper the synthesis of somenew thiosemicarbazide derivatives by condensation reaction of various aldehydes or ketoneswith 4-phenylthiosemicarbazide or thiosemicarbazide is reported. This synthesis method hasthe advantages of high yields and good bioactivity. The structures of these compounds wereconfi rmed by IR, mass, 1H NMR, 13C NMR, and single-crystal X-ray diffraction studies. Allof these compounds were tested for their in-vitro anti-mycobacterial activity. The influenceof the functional group and position of substituent on anti-bacterial activity of compounds isinvestigated too. The preliminary results indicated that all of the tested compounds showedgood activity against the test organism. The compounds 11 and 30 showed the highest antitubercularactivity (0. 39 μ g/mL). This synthesis method has the advantages of high yields andgood bioactivity.

Bacillus licheniformis RM44 was isolated from hot spring near Karachi and screened forthe production of extracellular amylase Amy RM44. Amy RM44 was purified to homogeneityon a single step by affinity chromatography using insoluble corn starch. The molecular weightof Amy RM44 was estimated to be 66 kDa by SDS– PAGE and zymographic analysis. Nine foldpurification was achieved with the specific activity of 870 U/mg that provides the total yieldof the enzyme up to 31%. Studies on purified AmyRM44 characterization revealed that theoptimum temperature of enzyme was 100 º C. Amy RM44 was proved to be highly thermostableas it retained 50% activity after 2 h at 100 º C. Amy RM44 was stable over wide range of pHwith optimum activity at pH 5. Enzyme activity was not significantly inhibited by SDS andEDTA. Amy RM44 also exhibited its activity towards various carbohydrates such as dextrin, pullulan, α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin.

Sambucus nigra (elder) are broadly used species to treat microbial infections. Thepotential 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 variousconcentrations 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 A549 cellcultures, and B) each concentrations of EF was added to H9N2 virus infected-cell culturesfollowing virus adsorption. In both treatments with lower doses of EF increased viral titer aswell as synthesized viral nucleoprotein as indicating the herb had no inhibitory effects on virusreplication. In (B) trial with higher doses, 40 and 80 μ g/mL of EF, a significant decrease invirus titer and viral protein synthesis were shown in EF treated cells indicating the herb affecteither entry of viruses or inhibition virus particle release. The results suggest that EF treatmentof the influenza virus infected-human epithelial cells may involve in lipid raft associationwhich function as platform for formation of viral membrane fusion and budding. Differencesintreatment time and dose of EF extract in infected cells with influenza virus have a marked effecton the efficacy of the herb.

Snakebite is a common problem especially in tropical areas all over the world includingIran. Echis carinatus as one of the most dangerous Iranian snakes is spreading in this countryexcluding central and northwest provinces. In this study gelatinase and fibrinogenolyticproperties as two disintegrating matrix metalloproteinase enzymes were evaluated by a strongclear halo between 56-72 kDa in addition to another band located 76-102 kDa for gelatinase andone major band around 38 kDa for fibrinogenolytic enzyme respectively. The electrophorectcprofile of our venom demonstrated at least one protein band between 24-31 kDa like previousreports and another two bands between 52-76 kDa and below 17 kDa stemmed probably due tothe effect of natural selection in one species. According to our results Razi institute antivenincould neutralize in-vitro effects of gelatinase enzyme comprehensively. The electrophoreticprofile of Iranian commercial antivenom as the main intravenous treatment of envenomedpatients showed impurities in addition to F (abʹ )2 weighing 96 kDa in SDS-PAGE analysis. Itproposes more efforts for refinement to avoid short and long unwanted effects in envenomedpatients.

Microbial transformation has been successfully applied in the production of steroidintermediates with therapeutic use and commercial value in pharmaceutical industry due to itshigh regio-and stereo-selectivity. As such, it is still important to screen microbial strains withnovel activity or more efficient abilities in the development of the commercial steroid industry. Biotransformation of steroid: 16α , 17α-epoxyprogesterone (1). using Penicilliumdecumbens asbiocatalyst was investigated and selective hydroxylation of 1 was observed. The products wereseparated by silica gel column chromatography, and the structure determination was performedby MS, NMR, and X-ray crystallography. Biotransformation of 1 afforded 7β-hydroxy-16α , 17α-epoxyprogesterone (2). and 7β , 11α-dihydroxy-16α , 17α-epoxyprogesterone (3). The twonovel metabolic products 2 and 3 were reported for the first time. Moreover, the identifiedC7β-and C11-α hydroxylation is a novel reaction of microbial transformation of steroids byP. decumbens.

The biogenic synthesis of metal nanomaterial offers an environmentally benign alternativeto the traditional chemical synthesis routes. In the present study, the green synthesis of silvernanoparticles (AgNPs) from aqueous solution of silver nitrate (AgNO3) by using Nigellaarvensis L. seed powder extract (NSPE) has been reported. AgNPs were characterized byUV– vis absorption spectroscopy with an intense surface plasmon resonance band at 435 nmwhich reveals the formation of nanoparticles. Fourier transmission infrared spectroscopy(FTIR) showed that nanoparticles were capped with plant compounds. Transmission electronmicroscopy (TEM) showed silver nanoparticles, with a size of 2-15 nm, were spherical. TheX-ray diffraction spectrum (XRD) pattern clearly indicates that AgNPs formed in the presentsynthesis were crystalline in nature. Stabilized films of exudate synthesized AgNPs wereeffective anti-bacterial agents. In addition, these biologically synthesized nanoparticles werealso proved to exhibit excellent cytotoxic effect on a human breast cancer cell line (MCF-7) and a human colorectal adenocarcinoma cell line (HT-29). The results confirmed that theNSPE is a very good ecofriendly and nontoxic source for the synthesis of AgNPs as comparedto the conventional chemical/physical methods. Therefore, N. arvensis seed provides futureopportunities in nanomedicine by tagging nanoparticles with secondary metabolites.

The synthesis of a proline-rich cyclic heptapeptide, fanlizhicyclopeptide A (8), previouslyisolated from the fruits of Annona squamosa (sugar-apples), is described via coupling oftetrapeptide 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 andspectroscopic methods including FTIR, 1H NMR, 13C NMR, FABMS and further, subjected tothe anthelmintic, antibacterial and the antifungal activity studies. Bioactivity results indicatedthat the newly synthesized cyclic peptide displayed potent anthelmintic activity against the threeearthworm species Megascoplex konkanensis, Pontoscotex corethruses and Eudrilus eugeniaeat 2 mg/mL and remarkable anti-dermatophytic activities against Trichophyton mentagrophytesand Microsporum audouinii at concentration of 6 μ g/mL.

AcrAB-TolC is a major efflux pump in Escherichia coli. It was reported that tolC is overexpressed andinvolves in improving the organic solvent tolerance level in Escherichia coli marR mutants that are resistantto several antibiotics, such as ciprofloxacin. Low and intermediate levels resistance did not improve organicsolvent tolerance. Thus, it was decided to measure tolC expression and organic solvent tolerance in high levelciprofloxacin resistant mutants. tolC expression was measured by real time PCR and organic solvent toleranceassay was conducted by counting bacterial colonies on LBGMg agar. Results showed that tolC expression wasincreased significantly (P<0. 05) and organic solvent tolerance was slightly improved in high resistant mutants. It was concluded that high organic solvent tolerance may need higher expression of tolC.

Leishmaniasis represents a serious threat to the health as one of the most important neglectedtropical diseases as designated by the World Health Organization. The disease is endemic in82 countries, among them Tunisia is an indigenous area for cutaneous Leishmaniasis. In aprevious work, two tritepenic acids namely oleanolic and maslinic acids have been isolatedfrom olive leaf extract. In the present paper, the in vitro activity against amastigotes stage ofLeishmania (L. ) infantum and Leishmania (L. ) amazonensis was investigated. Maslinic acidshowed the highest activity, against L. amazonensis, with an IC50 of 1. 417 ± 0. 401 μ g/mL anda selectivity index of 9. 405. Although, the oleanolic acid exhibit a better activity against L. infantum with an IC50 of 0. 999 ± 0. 089 μ g/mL and selectivity index of 8. 111.

The Runt related transcription factors (RUNX) are recognized as key players in suppressingor promoting tumor growth. RUNX3, a member of this family, is known as a tumor suppressorin many types of cancers, although such a paradigm was challenged by some researchers. TheTGF-β pathway governs major upstream signals to activate RUNX3. RUNX3 protein consistsof several regions and domains. The Runt domain is a conserved DNA binding domain andis considered as the main part of RUNX proteins. Herein, we compared the effects of Runtdomains and full-Runx3 in cell viability by designing two constructs of Runx3, includingN-terminal region and Runt domain. We investigated the effect of full-Runx3, N-t, and RD ongrowth 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 notablyinhibit growth of these cell lines while, the N-t and RD truncates showed different trends inthese 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, transfectionof N-t and RD did not considerably affect the cell proliferation in the HEK293. Our results showthat full-lenght RUNX3 did not affect the cell viability. Conversely, the N-t and RD constructssignificantly changed cell proliferation. Therefore, therapeutic potentials for these truncatedproteins are suggested in tumors with RUNX proteins dysfunction, even in the TGF-β impaircontext.

Anthracycline antibiotics are potent anticancer drugs widely used in the treatment of solidtumors and hematological malignancies. Because of their extensive clinical use and their toxiceffect on normal cells, in the present study the effect of these drugs on multipotent hematopoieticbone marrow cells was investigated employing, viability tests, PARP cleavage, Hoechst 33258staining, DNA fragmentation and superoxide anion production techniques. The results revealedthat daunorubicin and doxorubicin exhibited time and dose dependent cytotoxicity againstthe cells and upon increasing the drugs concentrations, apoptosis was occurred after 4 h ofincubation 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 anionsuperoxide production was increased upon rising drugs concentrations. From the results it isconcluded that anthracycline antibiotics represent cytotoxic effect on hematopoietic progenitor/stem cells of bone marrow, inducing apoptosis and in this process toxicity of daunorubicin ismore pronounced compared to doxorubicin.

The current situation in Iran suggests an appropriate basis for developing biotechnologyindustries, because the patents for the majority of hi-tech medicines registered in developedcountries are ending. Biosimilar and technology-oriented companies which do not have patentswill 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 ofachievements obtained from research with a focus on the pharmaceutical biotechnologyindustry. This is a descriptive-analytic study where mixed methodology is followed by aheuristic approach. The statistical population was pharmaceutical biotechnology experts atuniversities and research centers in Iran. Structural equations were employed in this research. The results indicate that there are three effective layers within commercialization in theproposed model. These are a general layer (factors associated with management, human capital, legal infrastructure, communication infrastructure, a technical and executive infrastructures, and financial factors), industrial layer (internal industrial factors and pharmaceutical industryfactors), and a third layer that included national and international aspects. These layers comprise6 domains, 21 indices, 41 dimensions, and 126 components. Compilation of these layers (general layer, industrial layer, and national and internationalaspects) can serve commercialization of research and development as an effective evaluationpackage.

Pemphigus vulgaris (PV) is a chronic autoimmune blistering disease of the skin, in whichloss of adhesion between keratinocytes is caused by autoantibodies. It has been hypothesizedthat cytokines play an essential role in the pathogenesis of PV. This study aimed to investigatethe other immunopathological aspects of PV by determining the serum levels of cytokines inPV patients to find another treatment strategy except corticosteroid therapy. Twenty-three patients with PV and a control group consisting of 24 healthy subjects werestudied. Interleukin (IL)-2, IL-4, IL-6, IL10, IL-12, IL-17 and interferon-gamma (IFN-γ ) weremeasured 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 wereundetectable. 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. Themean 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 < 0. 05). The same was observed foranother pro-inflammatory cytokine, IL-12 (135. 33 vs. 86. 28 pg/mL) (P < 0. 05). Based on the results of this study it can be concluded that the Type 2 T helper cytokine(IL-6) and macrophage-derived cytokine (IL-12) have essential roles in PV pathophysiology. In addition, the potential clinical application of Th1/Th2 type cytokine-based therapy in PVshould be considered in next studies.

Warfarin is a vitamin K antagonist that genetic and non-genetic factors affected on its doserequirement in the patients with cardio vascular disease. The aim of this study was whetherthe APOE and VKORC1 polymorphisms influence on warfarin dose requirements in the partof Iranian patients. Blood samples were collected from 86 warfarin-treated patients. Afterextraction of genomic DNA, the VKORC1 (rs9923231) and the APOE (rs429358 and rs7412)polymorphisms were genotyped by PCR-RFLP technique. We found that the Iranian patientscarrying genotypes GA or AA of VKORC1 polymorphism tended to receive lower dose ofwarfarin (p = 0. 018). Furthermore, the E3/E3 genotype was observed with the frequency morethan 60% in the patients with low dose of warfarin. The BMI and weight also showed a positivecorrelation with warfarin dose. However, it was not statistically significant (p > 0. 05). Theresults of this study may be useful in defining of warfarin dose algorithms for Iranian patients.

Introduction: Since 1950s that warfarin was used as anoral anticoagulant medication, yet it is the onlyoral anticoagulant approved by the US Food andDrug Administration (1). Use of warfarin is stillincreasing so that during 1998 to 2004 years, itsprescription has increased to 45% (2). Warfarinhas many applications such as prevention ofthromboembolic events, pulmonary embolismand stroke, coronary malfunction, atrialfibrillation, and in prosthetic valve placements(3-5).

The aim of this study was to evaluate the procalcitonin (PCT) changes in two different highdosecolistin regimens in the treatment of multi-drug resistant MDR gram negative infectionsin ICU patients. This is a prospective study of adult ICU patients with bacteremia and ventilator associatedpneumonia (VAP) caused by MDR gram negative pathogens. Patients were assigned to twocolistin administration groups. Group A received 9 and group B received 3 million internationalunits every 24 and 8 h respectively. Baseline characteristics and measurements of PCTconcentrations at the start, the 3rd and the 5th day of the antibiotic therapy and their trendsbetween the two groups were recorded and compared. 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 baselinecharacteristics 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 ofcolistin administration respectively (P=0. 47). The ICU length of stay (LOS) in days and ICUmortality 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 recommendeddose of CMS with 2 different intervals of every 8 or 24 h.

Ventilator-associated pneumonia (VAP) is a common and serious problem that developsafter more than 48 h of mechanical ventilation. Improving the activity of immune system withvitamin D, and its consequent impact on prognostic biomarkers of VAP was studied in thecurrent study. A randomized double blind placebo controlled clinical trial was designed. A total of 46patients with VAP, who were suffering from vitamin D deficiency, were randomly allocatedinto the study groups of placebo (n=22) and treatment (n=24) The treatment group received300, 000 units of intramuscular vitamin D. Serum levels of procalcitonin and vitamin D alongwith SOFA and CPIS scores were determined at baseline and on day 7 after intervention. Themortality rate of patients was also monitored for the succeeding 28 days after the injection. The administration of vitamin D significantly enhanced its levels (P<0. 0001) in the treatedpatients (12. 28 ± 8. 26) in comparison to placebo group (1. 15 ± 1. 50). The levels of PCT weresignificantly decreased (p=0. 001) in the treatment group (– 0. 02 ± 0. 59 ng/mL) compared to thatof placebo group (0. 68 ± 1. 03 ng/mL). However, changes in (SOFA) and CPIS scores were notsignificantly different between study groups (p=0. 63 and p=0. 32, respectively). Interestingly, the mortality rate of patients in the treatment group (5/24) was significantly lower (p=0. 04) thanthat of the placebo group (11/22). In conclusion, our results indicate that vitamin D supplementation can significantly reducethe procalcitonin in (VAP) patients, and must be considered as a preventive and/or therapeuticstrategy.

Obsessive-Compulsive Disorder (OCD) is one of the most common mental conditions. Proteome profiling may help identifying important proteins and finally shed lights to complexityof OCD underlying mechanisms. Here, by the application gel-based proteomic approach theproteome profile of patients with washing subtype of OCD before and after treatment withFluoxetine (positive responders) are compared to healthy matched controls. However, only oneof the differentially expressed proteins is examined and introduced in this paper. Proteomicanalysis was done by the application of two-dimensional polyacrylamide gel electrophoresis(2-D PAGE), combined with (MALDI-TOF-TOF MS)-based. Furthermore, network analysisand biological annotation were handled by Cytoscape Plug-in and CluePedia. The proteomecomparison between groups identified protein with the significant expression changes (p<0. 05and fold change ≥ 1. 5). While the expression level of Ig Kappa Chain C Region is significantlydecreased in OCD patients before any treatments, the trend is almost normalized after treatmentwith Fluoxetine in positive responders. In addition, interaction profile of IGKC shows thatthe interacting proteins may be affected as the expression pattern of IGKC changes in OCDpatients. In conclusion, IGKC may be introduced as potential biomarker in our study; yet, investigation in bigger sample size and application of validation methods is a requirement.