Iranian Journal of Pharmaceutical Research
Volume:16 Issue: 4, Autumn 2017

Specific delivery of therapeutic agents to solid tumors and their bioavailability at the target site are the most clinically important and challenging goals in cancer therapy. Liposomes are promising nanocarriers and have been well investigated for cancer therapy. In spite of preferred accumulation in tumors via the enhanced permeability and retention (EPR) effect, inefficient drug release at the target site and endosomal entrapment of long circulating liposomes are very important obstacles for achieving maximum anticancer efficacy. Thus, additional strategies such as stimulus-sensitive drug release are necessary to improve efficacy. Stimuli-sensitive liposomes are stable in blood circulation, however, activated by responding to external or internal stimuli and control the cargo release at the target site. This review focuses on state of the art of stimuli-responsive liposomes. Both external stimuli-responsive liposomes, including hyperthermia (HT), magnetic, light, and ultrasound-sensitive liposomes and internal stimuli (pH, reduction, and enzyme) responsive liposomes are covered.

Wilms tumor (WT) is the most common pediatric malignant primary renal tumor. Carboplatin (CRB), a platinum compound is widely used in the treatment of multiple cancers including ovarian, lung, head and neck, and wilm’s tumor. However lower uptake of CRB in cancer cells and toxicity concerns in healthy cells often limited its clinical outcome. The aim of this study was to investigate the antitumor effect of CRB in SK-NEP-1 wilm’s cancer cells. Earlier, CRB was formulated in nanoparticulate formulations and characterized its biophysical parameters. SK-NEP-1 cell growth in vitro was assessed by MTT. Then, apoptosis potential was investigated by TUNEL, Hoechst, and colony formation assay. CRB treatment resulted in inhibition of cell proliferation of SK-NEP-1cells in a dose-dependent manner. TUNEL, Hoechst, and colony formation assay demonstrated that CRB was more effective in killing wilm’s cancer cell when encapsulated in nanoparticle formulations. Overall, present study demonstrates that CRB treatment resulted in marked inhibition of cell proliferation and cell apoptosis. These results may pave way for the effective treatment of wilm’s tumor in clinical models.

An electroanalytical method has been introduced for highly sensitive determination of hydralazine hydrochloride (Hy-HCl) based on its oxidation at a glassy carbon electrode modified with multiwalled carbon nanotubes (MWCNT/GCE). Studies showed that the electrochemical oxidation of Hy-HCl was accompanied by adsorption and highly sensitive responses could be achieved by adsorptive stripping voltammetry. The electrooxidation of Hy-HCl at MWCNT/GCE occurred at ∼32 mV which was lower than that observed at bare GCE (∼52 mV). The optimum working conditions for determination of the drug using differential-pulse adsorptive stripping voltammetry (DPAdSV) were established. The method exhibited linear responses to Hy-HCl in the concentration range 10-220 nM with a detection limit of 2.7 nM. The proposed method was successfully applied to the determination of this compound in pharmaceutical dosage forms.

Cationic polymeric nanoparticles have great potential for developing drug delivery systems with limited side effects for tumor medication. The goal of this research is investigation of cationic dextran-spermine polymer (DS) efficacy for improvement of hydrophilic drug delivery to negatively charged cancerous cells. Capecitabine (as a hydrophilic antineoplastic drug) was loaded into the magnetic dextran-spermine nanoparticles (DS-NPs) via ionic gelation. Design of experiments was applied to specify how the significant factors affect size, surface charge and capecitabine entrapment efficiency of the DS-NPs. Physicochemical properties, in-vitro release profile and cellular studies of the optimized DS-NPs were evaluated. The experimental results indicated that DS-NPs with favorable properties can be achieved at an optimized condition of 2 mg/mL DS and 0.75 mg/mL tri-polyphosphate (TPP) concentrations, TPP addition rateof 35 mL/min, pH 3 of DS solution and super paramagnetic iron oxide nanoparticles (SPION)/DS mass ratio of 0.5. The entrapment efficiency of capecitabine was 26.1% at optimum condition and drug release at neutral pH after 24 h and acidic pH within 3 h was 56 and 98%, respectively. The cytotoxicity assessment exhibited that capecitabine loaded DS-NPs was more toxic than corresponding free drug as control. Significant cellular uptake of capecitabine loaded DS NPs by U87MG glioblastoma cells were proved by Prussian blue staining and TEM, qualitatively. DS-NPs are suitable candidates for delivery of the hydrophilic drugs in cancer treatment and due to positive charge of the dextran-spermine, the uptake of the hydrophilic drugs by the cancerous cells was improved.

Nanocrystals of tadalafil, a poorly water-soluble drug, were successfully prepared by sonoprecipitation technique for improving the solubility and dissolution rate. Tween80 was selected as an efficient surfactant to inhibit aggregation in stabilization of drug nanocrystals. Response surface methodology based on central composite design (CCD) was utilized to evaluate the formulation factors affecting the size of nanosuspensions. Under optimum conditions, relatively spherical nanocrystals with a mean particle size of 358.47±11.95 nm were obtained. FTIR analysis indicated that the precipitated nanoparticles had the same chemical structure as the raw tadalafil. By DSC analysis, no substantial crystalline change was found in the nanocrystals compared with the unprocessed drug. In addition, the dissolution rate of the processed tadalafil nanocrystals in 120 min was significantly increased (3.61-fold) as compared to that of the raw material. Therefore, it was concluded that the sonoprecipitation technique could be a simple and useful technique to prepare poorly water-soluble drug particles with reduction in particle size, a narrow particle size distribution and enhanced dissolution properties.

Guaifenesin, a highly water-soluble active (50 mg/mL), classified as a BCS class I drug. Owing to its poor flowability and compressibility, formulating tablets especially high-dose one, may be a challenge. Direct compression may not be feasible. Bilayer tablet technology applied to Mucinex®, endures challenges to deliver a robust formulation. To overcome challenges involved in bilayer-tablet manufacturing and powder compressibility, an optimized single layer tablet prepared by a binary mixture (Two-in-one), mimicking the dual drug release character of Mucinex® was purposed. A 3-factor, 3-level Box-Behnken design was applied to optimize seven considered dependent variables (Release “%” in 1, 2, 4, 6, 8, 10 and 12 h) regarding different levels of independent one (X1: Cetyl alcohol, X2: Starch 1500®, X3: HPMC K100M amounts). Two granule portions were prepared using melt and wet granulations, blended together prior to compression. An optimum formulation was obtained (X1: 37.10, X2: 2, X3: 42.49 mg). Desirability function was 0.616. F2 and f1 between release profiles of Mucinex® and the optimum formulation were 74 and 3, respectively. An n-value of about 0.5 for both optimum and Mucinex® formulations showed diffusion (Fickian) control mechanism. However, HPMC K100M rise in 70 mg accompanied cetyl alcohol rise in 60 mg led to first order kinetic (n = 0.6962). The K values of 1.56 represented an identical burst drug releases. Cetyl alcohol and starch 1500® modulated guaifenesin release from HPMC K100M matrices, while due to their binding properties, improved its poor flowability and compressibility, too.

Avulsed teeth that are replanted dried are more prone to loss. Recent tissue engineering studies focus on fabrication of various cell delivery systems to improve the overall prognosis of such teeth. To evaluate this new cell transplant method, we initially aimed at designing of PRF scaffold and determiningBMMSCs viability and function on the fabricated scaffold. To test this concept in-vitro, human BMMSCs were isolated and characterized by cell surface marker, and their potential on osteogenic/adipogenic differentiation. The biological effects of PRF scaffold on human BMMSCs were then investigated by cell proliferation assay. The data were quantified for statistical analysis. It was found that PRF significantly induced BMMSCs proliferation throughout the incubation period due to its growth factor secretion. Results of MTT assay showed an increasing trend during the testing period from day 1 to day 7. The result of scanning electron microscopy showed that BMMSCs could tightly adhere to fibrin scaffold just shortly after seeding. These data suggest that the BMMSCs/PRF construct has the potential to improve the clinical prognosis of replanted avulsed teeth in future. Additional studies are needed to be performed before its clinical use.

A series of ethyl 2-[2-arylamino-4-(thiophen-2-yl)thiazol-5-yl] acetates (5a-5k) and ethyl 2-[2-(arylhydrazino)-4-(thiophen-2-yl)thiazol-5-yl] acetates (9a-9g) were synthesized and screened for their anti-inflammatory, analgesic, and antioxidant activities. In vivo test results showed that the compounds with halogen substitution (5c, 5g, 5h, 5i and 5j) at the para position on the 2-aryl amino group exhibited good anti-inflammatory and analgesic activities, similar to that of indomethacin and aspirin, respectively. The ethyl 2-[2-(arylhydrazino)-4-(thiophen-2-yl)thiazol-5-yl] acetates (9a-9g) showed better anti-oxidant activity than compounds 5a-5k, comparable to ascorbic acid. However, these compounds showed moderate to weak anti-inflammatory and analgesic activities. Further, a molecular docking study was performed to predict the possible binding modes on cyclooxygenase-1 (COX-1) and COX-2 for the tested compounds. Good correlation was observed between the anti-inflammatory activity of the compounds and the results of the binding modes in COX-2.

There is no other naturally occurring defense agent against cancer that has a stronger effect than paclitaxel, commonly known under the brand name of Taxol®. The major drawback for the more widespread use of paclitaxel and its precious precursor, 10-deacetylbaccatin III (10 DAB III), is that they require large-scale extraction from different parts of yew trees (Taxus species), cell cultures, taxane-producing endophytic fungi, and Corylus species. In our previous work, a novel online two-dimensional heart-cut liquid chromatography process using hydrophilic interaction/ reversed-phase chromatography was used to introduce a semi-preparative treatment for the separation of polar (10-deacetylbaccatin III) and non-polar (paclitaxel) taxanes from Taxus baccata L. In this work, a combination of the absorbent (Diaion® HP- 20) and a silica based solid phase extraction is utilized as a new, efficient, and cost effective method for large-scale production of taxanes. This process avoids the technical problem of two-dimensional preparative liquid chromatography. The first stage of the process involves discarding co-extractive polar compounds including chlorophylls and pigments using a nonpolar synthetic hydrophobic absorbent, Diaion® HP-20. Extract was then loaded on to a silica based hydrophilic interaction solid phase extraction (silica 40-60 micron). Taxanes was eluted using a mixture of water and methanol at the optimized ratio of 70:30. Finally, the fraction containing taxanes was applied to semi-preparative reversed phase HPLC. The results revealed that using this procedure, paclitaxel and 10-DAB III could be obtained at 8 and 3 times more, respectively than by the traditional method of extraction.

Transcription factor NF-κB and relevant cytokines IL-6 and IL-8 play a pivotal role in the pathogenesis of inflammation. Sinapic acid is a natural product and was demonstrated to possess anti-inflammatory activity. In this paper, we synthesized a series of sinapic acid derivatives and evaluated their anti-inflammatory effects. The result suggested that all of the targets compounds 7a-j inhibit NF-κB activation and decrease IL-6 and IL-8 expression in BEAS- 2B cells. By our biological assays, we found that all of the prepared compounds displayed stronger anti-inflammatory activities than their precursor sinapic acid. Especially, compounds 7g and 7i, with electron-drawing groups (nitro and fluoro moieties) in the benzimidazole ring, exhibited remarkable anti-inflammation activity, which was even stronger than the reference drug dexamethasone.

99mTc-Macroaggregated Albumin (99mTc-MAA) has been used as a perfusion agent. This study described development of the 68Ga-MAA via commercially available kits from Pars-Isotopes Company as a 99mTc-MAA kit. 68Ge/68Ga generator was eluted with suprapure HCl (0.6 M, 6 mL) in 0.5 mL fractions. The two fractions with the highest 68GaCl3 activity were generally used for labeling purposes. After labeling, the final product was centrifuged 2 times to purify the solution. Five rats were sacrificed at each exact time interval (from 15 minutes to 2 hours post injection) and the percentage of injected dose per gram (%ID/g) of each organ was measured by direct counting from 11 harvested organs of rats. The RTLC showed that labeling yields before centrifuges were 90% and 95% for Pars-Isotopes and GE kits, respectively and after centrifuges, they became 100%. The microscopic size examination showed a shift in the particle sizes post centrifuges and the biodistribution data revealed the efficiency and benefits of centrifuges in terms of preventing the of liver and bone marrow uptakes especially for Pars-Isotopes kits. Our results showed that after centrifuges of the final product, the lung uptakes increased from 89% to more than 97% of %ID/g after 5 min post injections. The whole procedure took less than 25 min from elution to the final product. Since 99mTc-MAA remained longer than 68Ga-MAA in the lung and 68Ga-MAA showed better image qualities, using 68Ga-MAA is recommended.

This study investigated the protective effect of fish oil (FO) on cisplatin (CP) toxicity in the rat liver. Twenty-eight rats were divided equally into four groups, with the first being a control group. The second group (CP group) was given 7 mg/kg of CP and the third group (FO group) was given 1 FO softgel/rat/day for 14 days. The rats in the fourth group (CP FO group) were treated with both CP and FO at the above doses. CP treatment caused significant oxidative damage via an increase in thiobarbituric acid reactive substances (TBARS) and reduced antioxidant defenses through a decrease in the activities of catalase (CAT), superoxide dismutase (SOD), reduced glutathione (GSH), and glutathione peroxidase (GPx) in rat liver tissue. Also, CP caused histopathological abnormalities, including necrosis, in the liver tissue. However, concurrent FO treatment prevented the negative oxidative and histopathological effects of CP. In conclusion, CP treatment can cause hepatotoxicity in rats, but dietary supplementation with FO can attenuate the oxidative and histological changes caused by CP. Thus, FO may be useful in preventing CP-induced hepatotoxicity in cancer patients.

Paclitaxel is the one of the most common chemotherapeutic drugs used for the treatment of prostate cancer. However, its current clinical utility has been limited due to numerous serious side effects and drug resistance. Noscapine is an antitussive opium alkaloid that showed antitumor activity against a variety of cancer while has not exhibited severe side effects.
This study investigates the anticancer activity of noscapine in combination with paclitaxel against two LNCaP and PC-3 human prostate cancer cell lines. LNCaP and PC-3 cells were treated with noscapine or paclitaxel or combination. Cell viability was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test. Apoptosis was assessed by acridine orange/ ethidium bromide (AO/EB) staining. The mRNA expression of Bax, Bcl-2, AR and PSA in the cellular response to treatments was investigated. MTT assay indicated the combination treatment of paclitaxel and noscapine significantly decreased viability compared to single-agent treatment and control groups. The results obtained with AO/EB double staining showed increased percentages of apoptotic cells in the presence of the combination of paclitaxel and noscapine. Furthermore, combinational treatment of paclitaxel and noscapine showed significant decrease in the mRNA expression of B-cell CLL/Lymphoma (Bcl-2) and increase in the mRNA expression of Bcl-2-associated X protein (Bax(, and Bax/Bcl-2 ratio in LNCaP and PC-3 cells (p

Aspirin eugenol ester (AEE) is a promising drug candidate, which is used for the treatment of inflammation, pain and fever and the prevention of cardiovascular diseases. This study focuses on the effect of AEE on five proteins which are related to inflammation and thrombosis, including cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), C-reactive protein (CRP), prothrombin (FII) and arachidonate 5-lipoxygenase (ALOX5). Meanwhile, the study was administrated to compare the drug effect between AEE and its precursor from the view of chemical-protein interactions. Healthy rats were given AEE, aspirin, eugenol and integration of aspirin and eugenol. Carboxyl methyl cellulose sodium (CMC-Na) was used as control. After drugs were administered intragastrically for seven days, the blood samples were collected to measure the proteins concentration by enzyme linked immuno-sorbent assay (ELISA). The results showed that the concentrations of key endogenic bioactive enzymes are significantly reduced in AEE groups when compared with CMC-Na and aspirin groups (P

Antidepressant activity of crocin, saffron main component, has been established before. Based on previous study, it is suggested that elevation in the levels of BDNF (brain-derived neurotrophic factor), CREB (cAMP response element binding) and VGF neuropeptide could be considered as one probable molecular mechanisms involved in antidepressant activity of long term crocin administration in the rat hippocampus. In this study we further investigated whether the antidepressant activity of crocin in long term administration was associated with alteration in these factors in the rat cerebellum.
Crocin (12.5, 25 and 50 mg/kg/day) and imipramine (10 mg/kg/day) were administered interaperitoneally for 21 days to rats. At the end of experiment, animals were sacrificed and cerebellums were dissected. BDNF, VGF, CREB and phospho-CREB (P-CREB) protein and mRNA levels in the rat cerebellum were evaluated using Western blot and quantitative reverse transcription-polymerase chain reaction (qRT-PCR).
In the current study significant increases in mRNA and protein levels of VGF, CREB and BDNF in long term crocin treatment were not observed in the rat cerebellum. Although a slight increase was observed in protein level of P-CREB compared to normal saline, but it was not significant.
It is concluded that antidepressant activity of crocin might be partially mediated to CREB. Moreover other factors rather than BDNF and VGF neuropeptides may alter following long term crocin treatment in the cerebellum. To understand the precise mechanism of crocin antidepressant effects in the cerebellum, longer duration of crocin treatment in further studies is recommended.

The major challenge to treat Parkinson’s disease (PD) is penetration of target molecule into the brain to improve the efficacy of drugs. To achieve better brain penetration and targeted delivery, 1,9-Pyrazoloanthrone (1,9-P) loaded liposomes were developed by solvent injection technique using ultrasonication and evaluated for particle size, morphology, entrapment efficiency, FT-IR, and in-vitro drug release studies. The potential of 1,9-Pyrazoloanthrone (1,9-P), a c-Jun-N-terminal Kinase (JNK-3) inhibitor which could stop or retard the rate of apoptosis of neuronal cells was also evaluated. In-vivo pharmacokinetic and brain uptake studies of liposomes were performed to investigate the bioavailability and brain distribution of 1,9-P. Cytotoxicity and neuroprotection were done on SH-SY5Y cell line using MTT and AO/EB apoptosis assay. The optimized batch of liposomes showed an average size of 112.33 ± 0.84 nm with a zeta potential value of -19.40 mV and 78.96 ± 0.28% drug entrapment efficiency. The in-vitro release studies demonstrated the sustained release profile of liposome up to 24 h. The pharmacokinetic data in Wistar rats over the period of 12 h demonstrated 4.82-folds greater AUC (0-12 h) for liposome in brain compared with 1,9-P suspension. Cytotoxicity assay showed no sign of toxicity, whereas apoptosis assay revealed a neuroprotective action of liposomes. The results demonstrated successful targeting of the 1,9-P, to brain as a novel strategy having significant therapeutic potential to treat PD.

Studies show that cancer cell invasion or metastasis is the primary cause of death in malignancies including breast cancer. The existence of cancer stem cells (CSCs) in breast cancer may account for tumor initiation, progression, and metastasis. Recent studies have reported different effects of cannabinoids on cancer cells via CB1 and CB2 cannabinoid receptors. In the present study, the effects of ACEA (a selective CB1 receptor agonist) and AM251 (a selective CB1 antagonist) on CSCs and their parental cells were investigated. Breast CSCs derived from MDA-MB-231 cell line were sorted and characterized with CD44ﰠ/low/ESA phenotype. It was observed that ACEA decreased CD44ﰠ/low/ESA cancer stem cell invasiveness. Conversely, AM251 increased the invasion by more than 20% (at the highest concentrations) in both MDA-MB-231 and CSCs. Our results did not show any correlation between reduced invasion and cytotoxic effects of the drug. Since one of the main cancer recurrence factors is anti-cancer drugs fail to inhibit CSC population, this observation would be useful for cancer treatment.

Sulfur mustard (SM) is a strong alkylating and mutagenic compound that targets human airway system. We considered the expression of Forkhead box M1 (FOXM1) and apolipoprotein E (APOE) genes, which are responsible for cell proliferation, differentiation, tumorigenesis, and increased risk of lung cancer, in the lung bronchial tissue of patients exposed to SM. After performing pulmonary functional tests (PFTs), 11 human subjects (five controls and six SM-exposed patients) were entered in this study. Total RNA were extracted from all biopsy samples and then cDNA was synthesised for each specimen using RT-PCR. Changes in gene expression were measured using a RT2 Profiler ™PCR Array. PFTs have demonstrated more obstructive and restrictive spirometric patterns among patients compared to the controls. A higher expression was recorded for both examined genes in bronchial of SM-exposed patients. Expression of FOXM1 and APOE genes in bronchial of the patients was significantly (p

The present study was conducted to investigate the possible anxiolytic and sedative of an acute administration and 4-day repeated dosing of an aqueous extract of flowers of Alcea aucheri (Boiss.) Alef. (EFA) in rats subjected to the elevated plus-maze (EPM), open-field, and horizontal wire tests. All drugs were administered intraperitoneally. Phytochemical screening confirmed the presence of phenolic compounds, flavonoids, and polysaccharides in the extract. Repeated dosing of EFA (at dose of 35 mg/kg) significantly increased percentage of time spent on open arms and of open arms entries, and also decreased percentage of time spent on closed arms and of closed arms entries; compared with saline control, 24 h after treatment. In addition, repeated dosing of EFA (at dose of 175 mg/kg) significantly increased open armactivity 48 h after treatment, versus saline group. This effect was also observed following acute administration of EFA at 175 mg/kg. In open field, acute administration of EFA at doses of 17.5, 35, 70, 175, 350, and 700 mg/kg induced a statistically significant and dose-dependent decrease in locomotor activity, compared with saline control. ED50 value for EFA-induced decrease in locomotor activity was 194 mg/kg. Furthermore, unlike diazepam; EFA didn´t decrease the percent of the rats grasping the wire. These data suggest that Alcea aucheri extract may have anxiolytic and sedative properties and some of the components in the extract such as phenolic compounds may have contributed to the observed effects.

This study was designed in order to correlate the flavonoid and lipoidal matters content of Spinach roots and flowers to their hypolipidemic potential.
The total flavonoid content was measured via complexation with aluminum chloride while determination of fatty acids methyl esters and unsaponifiable matters contents in both organs was performed using GC/MS. In an in vitro study, the crude ethanol extracts of both organs and their different fractions were separately examined for inhibition of β-hydroxy-β-methyl glutaryl coenzyme A reductase (HMGCoA reductase); the rate limiting enzyme of cholesterol biosynthesis.
The percentage inhibition of alcohol extracts of roots and flowers were 78.19% and 72.68% respectively when compared to the control. The crude alcohol extracts of both organs were further examined in vivo. Results showed that both extracts improved the investigated parameters by variable degrees compared to fenofibrate reference drug. The root extract showed significant improvement of TC, HDL-C, LDL-C, TG and total lipids (52.75, 209.85, 21.84, 49.26 and 29.62% respectively) when compared to hypercholesterolemic rats. The histopathological picture of liver showed a noticeable amelioration after treatment with root extract. The flavonoid content was higher in flower than root (983.4 and 300.2 mg/kg respectively) while the percentage of sterols and triterpenes in roots was greater than flowers (27.87% and 20.45 % respectively).
In conclusion, the root ethanolic extract recorded more potent activity than flower as hypolipidemic agent either in vitro or in vivo examination which was more correlated to the sterol content than to the flavonoid content.

Plants gums are complex mixtures of different polysaccharides with a variety of biological activities and pharmaceutical applications. Few studies have focused on physicochemical and biological properties of gums obtained from different plants.
This study was designed to determine potential pharmaceutical and pharmacological values of the gum exudates and its isolated biopolymers obtained from Astragalus myriacanthus Boiss [syn. Astracantha myriacantha (Boiss.) Podlech] (Fabaceae).
The physicochemical, rheological and mucoadhesion properties of the gum and its fractions was measured at 7, 27, and 37°C with and without the presence of NaCl (1%). Also, the structural and immunomodulatory properties of several water soluble biopolymers isolated using ion exchange and size exclusion chromatographic methods were investigated on Jurkat cells at concentrations of 31.25, 62.5, 125, 250, 500 and 1000 μg/mL.
The consistency and shear-thinning property of the gum and its fractions decreased as temperature increased. In the presence of NaCl, the consistency increased but no regular pattern was observed regarding to shear-thinning behavior. The mucoadhesion strength was 40.66 ± 2.08 g/cm2 which is suitable for use as a formulary mucoadhesive polymer. The isolated biopolymers had proteo-arabinoglycan structure. Their molecular weight was calculated to be 1.67-667 kDa. One biopolymer had a proliferative effect and others had dose dependent cytotoxic/proliferative properties.
The crude gum and its insoluble fraction showed suitable mucoadhesion, swellability and rheological properties which makes them suitable for designing drug delivery systems. The gum proteo-arabinoglycans with different molecular weight and structures had different immunomodulatory properties.

Hexane, ethyl acetate and methanol extracts of Onopordum espinae leaves were investigated for their antibacterial activities against Bacillus cereus, Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa and Salmonella enteritidis. The in vitro antibacterial activity of Onopordum espinae extracts was qualitatively assessed by the diameter of inhibition zones (IZD) and quantitatively by the determination of the MIC and MBC values. Ethyl acetate extract was the most toxic with inhibition zone diameters to Gram-positive bacteria ranging between 15 and 30 mm and MIC values of 0.2 to 0.4 mg/mL. Two products, hispidulin 1 and dehydromelitensin-8-(4'-hydroxy-methacrylate) 2 were isolated from the ethyl acetate extract of leaves and identified by 2D-NMR for the first time from this species. Ethyl acetate extract's total flavonoid content was the highest, as 78.73 mg quercetin equivalents (QE)/g. The methanol extract showed the highest total phenolic content as 243.43 mg gallic acid equivalents (GAE)/g and gave the most important 2,2-diphenyl-1-picrylhydrazyl (DPPH)-scavenging activity (EC50 = 86 µg/mL).

Nowadays, there is increasing interest in the production of functional foods, particularly probiotic foods. Lactic acid bacteria (LAB) particularly strains of Lactobacillus are important bacteria in food microbiology and human nutrition due to their ability to fermented food production and have received considerable attention as probiotics. The traditional fermented dairy foods as a rich source of wild LAB can be introduced new Lactobacillus strain with probiotic properties into food products. So, the present study was aimed to isolate and identify Lactobacilli spp. in traditional dairy products and assessing their some probiotic properties. For this study, fifty samples including homemade yogurt and cheese were purchased from several rural areas and the intragenic transcribed spacer-PCR (16-23s rDNA) was used for identification of Lactobacilli. Some probiotic properties were assayed including resistant to acid and bile, antimicrobial activity and antibiotic susceptibility.
The isolates were characterized as L.plantarum, L.casei, L.paracasei and L.rhamnosus. Out of the fifty six isolates identified phenotypically as lactobacillus, twenty four strains were tolerant to pH 2.5 and 0.3% bile salt after 3 h of incubation and only 6 strains showed antimicrobial activity and antibiotic susceptibility. In conclusion six strains showed potentially probiotic properties including resistant to acid and bile, antimicrobial activity and antibiotic susceptibility, so we can consider these strains as a native probiotic but extra examinations was required for introduction into food products.

Designing enriched probiotic supplements may have some advantages including protection of probiotic microorganism from oxidative destruction, improving enzyme activity of the gastrointestinal tract and probably increasing half-life of micronutrient. In this study Saccharomyces cerevisiae enriched with α-tocopherol produced as an accumulator and transporter of a lipid soluble vitamin for the first time. By using one variable at the time screening studies, three independent variables were selected. Optimization of the level of dl-α-tocopherol entrapment in S. cerevisiae cells was performed by using Box-Benkhen design via design expert software. A modified quadratic polynomial model appropriately fit the data. The convex shape of three-dimensional plots reveal that we could calculate the optimal point of the response in the range of parameters.The optimum points of independent parameters to maximize the response were dl-α-tocopherol initial concentration of 7625.82µg/ml, sucrose concentration of 6.86 % w/v, and shaking speed of 137.70 rpm. Under these conditions, the maximum level of dl-α-tocopherol in dry cell weight of S. cerevisiae was 5.74µg/g. The resemblance between the R-squared and adjusted R-squared and acceptable value of C.V% revealed acceptability and accuracy of the model.

Recombinant protein production in Pichia pastoris is based on alcohol oxidase promoters which are regulated by methanol. However, the use of methanol has several disadvantages, which is why current trends in bioprocess development with Pichia pastoris (P. pastoris) are focusing on methanol mixed feeding strategies. This work aimed to develop a new experimental method and compare the effect of various fractions of sorbitol in mixed feeding strategy with stepwise addition of methanol to maximize the productivity of human growth hormone. Accordingly, fed-batch culture performed with a mixed feed of sorbitol/methanol. Sorbitol at concentrations of 30, 40, 50 and 60 gram per liter was added in batch-wise mode to the mediumat the beginning of induction phase and the rate of methanol addition was increased stepwise during the first 12 h of production and then kept constant. In order to understand the effects of various co-substrate feeding strategies on P. pastoris and its production of hGH, cellmass, dry cell weight, total protein, hGH expression level and hGH concentration were analyzed and the results compared with the basic feeding protocol using one-way analysis of variance (ANOVA). According to the obtained results, sorbitol at a concentration of 50 g/L could significantly increase the production yield. Under such optimal conditions cell biomass was 108 g/L(DCW), total protein was 0.807 g/L, expression level was 83.1% and rhGH concentration was 0.667 g/L following 30 h induction.

Among the two types of bacterial L-asparaginases, only type II enzymes have been used in the treatment of acute lymphoblastic leukemia owing to their higher affinity for L asparagine. However, current screening media used for the isolation of L-asparaginase-producing microorganisms do not discriminate between the two types of L-asparaginase. During an optimization study conducted to increase L-asparaginase production by environmental Halomonas isolates, it was noticed that the pattern of L-asparaginase production in response to variations in glucose concentration varied between different isolates suggesting that they differ in their ability to produce type II L-asparaginases, an observation that was confirmed by further experiments. Bioinformatics analysis of available Halomonas whole genome sequences revealed that indeed some species of this genus possess both L-asparaginase types while others possess only type I enzymes. By comparing the growth pattern of these isolates on different media, we propose that by omitting glucose, reducing the concentration of L-asparagine and providing an alternative nitrogen source in L-asparaginase screening media it may be possible to differentiate between type I and type II activities.

Concomitant oral administration of NFX with TNZ may affect NFX absorption and consequently its blood concentration and pharmacological effect. The present study was undertaken to investigate the effect of TNZ on the pharmacokinetics of NFX in healthy volunteers.
This study was conducted as an open-label, randomized, two-way crossover experimental design. After an overnight fast, subjects were randomized to receive a single oral dose of NFX 400 mg alone and the fixed-dose combination (FDC) of NFX /TNZ 400 mg/600mg on two different occasions separated by 1-week washout period between treatments. The pharmacokinetic properties of NFX after FDC administration were compared with NFX administered alone.
The 90% CIs between NFX alone and when co-administered with TNZ indicated the presence of an interaction between NFX and TNZ, which would significantly increase the systemic rate and exposure of NFX absorption. The co-administration of TNZ with NFX increased the AUC and Cmax of NFX significantly compared with administration of NFX alone. Both Tmax and Ka of NFX showed a significant decrease after administration of the combination compared to administration of NFX alone.
Both NFX and TNZ were well tolerated. The interaction of TNZ with fluroquinolones should be investigated to determine whether this interaction is limited to NFX or if other fluroquinolones have the same pharmacokinetic interactions. Further studies are necessary to determine the role of P-gp and other transporters on NFX disposition and pharmacokinetics. Additionally, the influence of TNZ on the physiological activity of GIT should be investigated.

Ischemia reperfusion injury (IRI) is one of the main causes of delay graft function (DGF) in deceased-donor kidney transplantation (DDKT). Evidences suggest that hypertonic saline (HS) has beneficial effects on IRI. The objective of the present study is to determine the effect of intraoperative HS, on graft function and urinary biomarkers of interleukin 18 (IL-18) and neutrophil gelatinase-associated lipocalin (NGAL), in patients with DDKT. The design of the study is a randomized, open-label, pilot trial in patients with DDKT. The intervention of the study is administration of 4 mL/kg HS, 5% before graft reperfusion. The primary endpoint was DGF. Fifty-eight (58) adult patients were randomized (HS, n = 32; control, n = 26). There were no significant differences between the two groups in terms of recipient, donor, and transplant characteristics. The rate of DGF was 20% in the HS group compared with 31.8% in the control group (Relative risk 0.63; 95% CI 0.23–1.67; P = 0.36). Serial serum creatinine in the first two days after surgery in addition to urine volumes during the first day after transplantation was significantly different in the HS group (P ≤ 0.05). The urinary NGAL and IL-18 were significantly lower in HS vs. control, at 24 h after transplantation (P ≤ 0.05). The frequency of adverse reactions was similar between groups. This study did not show any significant benefits from HS administration immediately before allograft reperfusion in terms of reducing DGF, serum creatinine at hospital discharge or length of hospital stay in deceased-donor kidney transplant patients.

Previous studies have reported inconsistent findings regarding the efficacy of omega-3 fatty acids on pregnant women with major depressive disorder (MDD). This meta-analysis was conducted to systematically evaluate the clinical applicability of omega-3 fatty acids in treating depression in pregnant women.
Randomized controlled trials (RCTs) that compared omega-3 fatty acids to placebo for short-course treatment of depression in pregnant women were systematically reviewed between March 1999 and April 2015. The search terms used were ‘depression’, ‘omega-3 fatty acids’, ‘fish oil’, ‘eicosapentaenoic acid’ and ‘docosahexaenoic acid’. Standardized difference in means of depression scale was used as the main outcome. Random effect model was used. The effects of baseline depression scores were studying by meta-regression analysis.
Four high-quality RCTs were included, composed of 182 patients received placebo and 185 patients received omega-3 fatty acids. The pooled standardized difference in means was 0.75 with 95% CI= (0.47, 1.04). The baseline depression scores had no effect on the efficacy. None of the recruited patients was withdrawn.
The abovementioned results showed that omega-3 fatty acids could produce a beneficial effect on depression in pregnant women compared with placebo. The clinical applicability of omega-3 fatty acids showed greater promise and should be further explored.

Aberrant DNA methylation has been reported as an important phenotype in acute myeloid leukemia. However the clinical significance of methylation changes has not been clear yet. In this study methylation Specific Melting Curve Analysis (MS-MCA) and real time PCR was used to assess the CDKN2B promoter hyper-methylation and gene expression in 59 Iranian acute myeloid leukemia (AML) patients. The incidence of aberrant hyper methylation of CDKN2B gene and cytogenetic abnormalities were 37.3% (22 of 59 patients) and 35.6% (21 of 59) respectively in our patients. We observed that CDKN2B expression level was lower than normal mesenchymal stem cells. Our data revealed significant correlation between methylated CDKN2B promoter region and mRNA gene expression (P= 0.007). Also, our data indicated that AML patients with aberrant methylation of CDKN2B gene had a lower survival rates (P=0.043). In addition they had a higher proportion of leukemic blast cells (P=0.022) and higher white blood cell count in peripheral blood (P=0.0123). Aberrant methylation of CDKN2B was observed to higher in M2 subtype and lower in M3 and M4 subtypes. Although we observed a significant correlation between Methylation and survival, there was no significant correlation between CDKN2B methylation and treatment outcome of AML patients (P= 0.187). Furthermore, our data didn’t illustrated a significant correlation between CDKN2B expression and survival (P=0.93). In conclusion our study showed that the aberrant methylation is one of molecular mechanisms involved in CDKN2B gene expression, moreover we can consider the CDKN2B methylation, as a prognostic marker in predict AML patients’ survival.

Antibiotic resistance is a major public health concern. This study was conducted to evaluate the knowledge, attitudes of community pharmacists regarding antibiotic use and potential drug resistance besides assessing their behaviors about dispensing antibiotic without prescription and correlation of the outcomes with demographic variables. A cross-sectional survey was conducted on a random sample of 250 pharmacies in Aleppo, using validated self-administered questionnaire. The total scores of the pharmacist's knowledge and attitudes were correlated with participant demographics using Chi-squared test. One-hundered-seventy-three pharmacies out of 250 agreed to participate in the study. The overall prevalence of dispensing antibiotic without prescription was 85.5%. Only 30.8% of participants exhibited good attitude and 37% had adequate knowledge about antibiotic resistance. Good attitude was strongly correlated with age (P = 0.023), years of experience (P = 0.007), socioeconomic location of the pharmacy (P = 0.009) and number of clinics near pharmacy (P = 0.008). The results of this study confirmed that dispensing antibiotic without prescription is a common practice in Aleppo pharmacies despite being unlawful. The half of community pharmacists has a poor attitude and inadequate knowledge with regard to antibiotic resistance, reflecting the need for awareness-raising campaigns directed to community pharmacists to equip them for their main role in the community.

Drug abuse is a serious problem causing health, economical and psycho-social negative outcomes. Methadone is commonly used drug for management of drug addiction. Exhaled breath condensate (EBC) is a promising non-invasive biological sample which attracted more attention in recent years. This work aimed to extend the applicability of a developed preconcentration – liquid chromatographic method for analysis of methadone in serum and urine samples. Drug concentrations in EBC, serum and urine are also investigated for dose-concentration and their inter-correlations. Biological samples were collected from 53 patients receiving methadone and the concentrations were determined using a validated analytical method after a pre-concentration step. Methadone measured in all samples and there are correlations between administered dose of methadone and its serum and urine concentrations. A weak correlation is observed between dose and EBC concentration. Wider variations in EBC concentrations of methadone could be justified concerning a number of affecting parameters such as relative humidity of the collection area and further investigations are required for standardization of EBC as a non-invasive biological sample to be used in clinical practice.

N-acetylcysteine (NAC) is a potent antioxidant that acts through regenerating glutathione stores and scavenging oxygen-free radicals. This study assesses the short-term effects of NAC in cadaveric kidney transplant (KT) recipients. A double blind, randomized, placebo controlled trial was designed and patients were randomly assigned to receive either NAC or placebo. Glutathione peroxidase (GPX) activity in erythrocytes and serum malondialdehyde (MDA) levels were measured and serum creatinine levels and estimated glomerular filtration rate (eGFR) determined in the early phase after transplantation, were also compared between two study groups.37 males and 20 females, with mean ± SD age of 44.6 ± 12.4 years completed the study. Significant difference (P = 0.02) was seen between GPX activity reduction in the placebo group, and that of the NAC group and on the levels of MDA there was no significant difference between two study groups (P = 0.53). Significant improvement in immediate graft function (IGF), (68% versus 40%, P = 0.05) and the first week eGFR were observed in the NAC group compared to the placebo group (52.46 ± 2.77 versus 38.75 ± 19.67 mL/min/1.73 m2, P = 0.02).
It seems that the protective mechanisms of NAC, other than its antioxidant properties, can be favorable in KT patients.

This study aimed to investigate the efficacy and the underlining mechanism of aspirin desensitization among patients with Aspirin Exacerbated Respiratory Disease (AERD). Thirtyeight patients, who had undergone an aspirin challenge test and were diagnosed as having AERD, were engaged in a double-blind randomized clinical trial. They were divided into two groups—an active group of patients who went through aspirin desensitization, and the control group, receiving placebo. Clinical symptoms and the quality of life of the patients—in addition to the levels of interleukin 4 and 5 (IL4), (IL5)—were documented at the beginning of the study and again after six months of aspirin desensitization. The quality of life of the patients was significantly higher in the active group after six months (P = 0.001). Medication requirements and symptom score were manifested to be significantly lower in the active group after six months than at the beginning of the study (P = 0.005, 0.017 respectively). Forcedexpiratory volume in the second one (FEV1) was, also, significantly higher in the active group after six months of the study (P = 0.032). IL5 was found to be significantly lower in the active group after six months (P = 0.019). However, no significant difference was observed in the levels of IL4 between the two groups (P = 0.152). The study revealed that aspirin desensitization can improve the quality of life of patients with AERD, lessen their symptoms and medication requirements, lower their levels of IL5, and improve some pulmonary function tests such as FEV1.

This study aims to measure the production capacity and capacity utilization in pharmaceutical industry. The capacity utilization is the ratio of actual production level to the potential production level which shows the gap between real production and production capacity.
Through econometric methods, the short-run translog cost function is estimated with the cost share function of production factors using iterative seemingly unrelated regression equations (SURE) as a multi-variable regression presented by zeller.
Findings: The capacity used during the study years has had a downward trend. The capacity utilization measured by industry weighted average had also a downward trend and its amount has always been much less than the industry simple average during the study years. Industry’s capacity utilization average in five years study is 57% while the average capacity utilization measured by industry weighted average method is 37%.
To enhance the economic capacity, the proper use of resources, creating a desirable economic structure and having a system of efficiency in industry are required. In spite of the large amount of unused capacity in pharmaceutical industry, there is no need for further investment except in new fields and it is obvious that increase in investment leads to the changes in capacity utilization.

The influence of company reputation, or what is often referred to as corporate reputation on branding strategy and producing intangible asset for different industries has been researched in western countries, but there is a gap for the generalizability of findings to countries out of the United State and Europe . To establish the western researcher’s external validity of theories in other countries and to obtain a better understanding of the influences of branding and company reputation on pharmaceutical business markets, the researchers applied this study for Iran, a country in the Middle East. The obtained results using SEM (by P.L.S. 2.0 software ) showed good relationship between value creation and brand differentiation (β = 0.360 and t-value = 3.167), between corporate communication and brand differentiation (β = 0.022 and t-value = 3.668) and between strategic resources and brand differentiation (β = 0.289 and t-value = 2.247 ). This study is a pioneering attempt in Iran to measure the impact of corporate reputation on brand differentiation strategy.