Iranian Journal of Pharmaceutical Research
Volume:15 Issue: 1, Winter 2016

Gene therapy is a therapeutic approach to deliver genetic material into cells to alter their function in entire organism. One promising form of gene delivery system (DDS) is liposomes. The success of liposome-mediated gene delivery is a multifactorial issue and well-designed liposomal systems might lead to optimized gene transfection particularly in vivo. Liposomal gene delivery systems face different barriers from their site of application to their target, which is inside the cells. These barriers include presystemic obstacles (epithelial barriers), systemic barriers in blood circulation and cellular barriers. Epithelial barriers differ depending on the route of administration. Systemic barriers include enzymatic degradation, binding and opsonisation. Both of these barriers can act as limiting hurdles that genetic material and their vector should overcome before reaching the cells. Finally liposomes should overcome cellular barriers that include cell entrance, endosomal escape and nuclear uptake. These barriers and their impact on liposomal gene delivery will be discussed in this review.

Phytochemical investigation of the aerial parts of Euphorbia erythradenia Bioss. (Euphorbiaceae), one of Iranian endemic Euphorbias, with particular attention to triterpene constituents, using methanol solvent extraction was carried out. Five known triterpenes, including four cycloartanes and oleanolic acid, were isolated for the first time and identified using NMR and Mass techniques. Anti HIV activity of the isolated triterpenes and ingenoid diterpenes was evaluated using single cycle replicable HIV-1 (SCR HIV-1) virions. Molecular features of the most active compound (IC50 = 0.008 μM, CC50 = 3.264 μM, TI = 380.64), which showed higher therapeutic index than nevirapine, was assessed using molecular docking. Docking studies demonstrated three hydrogen bonds between HIV-1 virion protease active site and this compound with a distance less than 3 A° which can be responsible for the observed anti HIV-1 activity.

A series of hydroxysemicarbazone derivatives of substituted diaryl ketones and acetophenones were synthesized and their structures were confirmed by analytical and spectroscopic methods including elemental analysis, infrared and nuclear magnetic resonance spectroscopy. The derivatives were prepared by a condensation reaction between N-hydroxysemicarbazide and substituted diaryl ketones or acetophenones leading to the desired hydroxysemicarbazones with excellent purity. The synthesized hydrazones were then evaluated for their inhibitory activity against bacterial strains including S. aureus, E. Coli, P. aeruginosa, K. pneumonia and M. luteus. Among the tested derivatives, compounds 2, 6 and 7 exhibited the highest bioactivity. Analysis of the activity data suggests that hydrophilicity is an important factor for the bioactivity of compounds 2 and 6 and also their selectivity over the gram-negative bacteria.

The side effects associated with the usage of synthetic antidiabetic drugs make it imperative to search for alternative drugs from medicinal plants. Therefore, this study was aimed at evaluating the α-amylase and α-glucosidase inhibitory potential of Calotropis procera leaf, as well as its possible mode of inhibiting these enzymes. Acetone, aqueous and ethanolic extracts of C. procera leaf was subjected to standard enzymes’ inhibitory assay in-vitro using porcine pancreatic α-amylase and rat intestinal α-glucosidase. Results obtained showed that out of all the extracts tested, ethanolic and aqueous extracts possessed the best inhibition of α-amylase (IC50 7.80 mg/mL) and α-glucosidase (3.25 mg/mL) respectively. The kinetic analysis of the mode of inhibition of these enzymes by the leaf extracts of C. procera, revealed that these extracts inhibited both enzymes in a non-competitive manner. It is speculated that the α-amylase and α-glucosidase inhibitory properties of leaf extracts of C. procera may be due to the presence of some phytochemicals such as flavonoids, tannins and saponins in the plant. It can be concluded from this study that the Calotropis procera extracts could serve as source of antidiabetic agents which may act through the inhibition of carbohydrate hydrolyzing enzymes, α-amylase and α-glucosidase.

The present study was conducted to test the effect of Origanum Majoranum Extract (OME) of leaves on alterations induced in a model of type 2 diabetic rats. Adult male Wistar rats were fed high fat diet for 3 weeks and injected a single dose of streptozotocin (35 mg/kg) intraperitoneally to induce type 2 diabetic rats. Diabetic rats were given aqueous extract of OME in a dose of 20 mg/kg orally for 3 weeks. Changes in lipid profiles, glucose, insulin, expression of some genes related to glucose metabolism and histopathological changes in liver and kidney were examined. Administration of OME improved and normalized dyslipidemia recorded in type 2 diabetic rats together with reduction in glucose and insulin levels. OME induced up-regulation in gene expression of glucose [adiponectin and glucose transporter-2 (GLUT-2)] and lipid metabolism [lipoprotein lipase (LPL)]. Moreover, OME normalized histopathological changes occurred in liver and kidney of diabetic rats. OME decreased lipids accumulation in liver and kidney and increased regeneration of hepatic parenchyma and normal renal architecture with disappearance of fat droplets. In conclusion, OME improved dyslipidemia associated with type 2 diabetes by regulating the expression of genes related to glucose and lipid metabolism.

New series of spiroindeno[1,2-b]pyrido[2,3-d]pyrimidine-5,3′-indolines as new urease inhibitors were synthesized by the catalytic procedure in high yield and short reaction time. In this method, biacidic carbon was prepared as a novel heterogeneous acid and was subsequently used as an efficient catalyst in this synthesis. The inhibitory activities of synthesized compounds were tested against Jack bean urease using Berthelot colorimetric assay and docking simulation using AutoDock 4.2. The compound 4a with IC50 =1.94 µM has the most inhibitor activity in this study. Other derivatives such as 4b, 4d, 4e and 7a were found to be more potent urease inhibitors than the standard inhibitor hydroxyurea, yielding IC50 values of 4.35, 5.557, 7.44, 2.81 and 14.46 μM, respectively (IC50 of hydroxyurea = 100 μM).

Isoniazid (INH) was studied with regard to its electrochemical treatment on a strongly alkaline solution of a poly (3,4-ethylenedioxythiophene)-modified gold electrode, using both cyclic voltammetry and controlled potential techniques. This composite electrode exhibited 4-fold higher oxidation of INH, in accordance with peak densities, than the bare gold electrode. It was used the central composite design method to obtain optimum experimental conditions, and used critical parameters (pH (A), scan rate (mV/s, B) and temperature (C, C) to assess the effects on amperometric response. Optimum experimental conditions were achieved by using a pH of 9.2 with a scan rate of 260 mV/s and a temperature of 30C. Under these conditions, a good linear relationship was observed between peak current densities and INH concentration in the range of 0.05-2 μM, with correlation coefficient of 0.9998. Furthermore, the method was very sensitive (limit of quantitation, 0.0043 μM), accurate (relative error, -5.65 to 4.03) and precise (relative standard deviation %, ≤7.97). The method was also applied to determine INH in pharmaceutical formulations, and statistically compared the results with the official method using the two one-sided equivalence test; the results were in good agreement with those obtained by the official and reported methods.

Amiodarone is used in treatment of cardiac arrhythmias. Therapeutic use of amiodarone is limited by its side effects, including pulmonary toxicity. Human Placenta Extract (HPE) contains a variety of bio-active substances. Thus, the present study aimed to quantitatively evaluate the protective effects of HPE on the structural lung changes induced by amiodarone using stereological methods. Sprague-Dawley male rats were divided into four groups. The first, second, and third groups received no treatment, amiodarone (100 mg/kg, i.p.), and HPE (500µl/kg, i.p.), respectively. The fourth group was treated with amiodaroneᳱ. The animal's lungs were removed after 10 days. The lung volume was estimated using the Cavalieri principle on the embedded and cut tissue and corrected for shrinkage. The volume density of the parenchyma, alveolar space, and septa were estimated using point-counting method. The surface area of the alveoli, the volume-weighted means alveoli volume, and mean septum thickness were also estimated in all groups. The total volume and thickness of the alveolar septum were increased by 40% and 28%, respectively. However, the total volume of the alveolar space was decreased by 31% in the amiodarone treated-rats. The mean alveolar volume was decreased by 64% on the average in the amiodarone treated group. Yet, these changes were not detected in the amiodaroneᳱ group. Moreover, RBC accumulation in the alveolar space and septa was ameliorated after HPE treatment. HPE can protect the lung tissue from the structural changes induced by amiodarone.

Oxidative stress is one of the important mechanisms involved in Dexamethasone (Dex)-induced hypertension. Protocatechuic acid (PCA) is a natural compound with high antioxidant capacity. In this investigation, the effect of pretreatment with PCA was studied in Dex-induced hypertensive male Wistar rats. For induction of hypertension, Dex was injected subcutaneously for 14 days. PCA (50, 100 and 200 mg/kg) was started from 4 days before Dex administration and continued during the test period. Systolic blood pressure (SBP) was recorded using tail-cuff method. Measurement of thymus weight was done as a marker of glucocorticoid activity. The hydrogen peroxide (H2O2) concentration and ferric reducing antioxidant power (FRAP) were determined in plasma samples. Significant increase in SBP and plasma H2O2 concentration and decrease in FRAP value and in the body and thymus weights were observed in Dex-induced hypertensive rats. PCA dose-dependently prevented hypertension and body weight loss, and reduced plasma H2O2 concentration and increased FRAP values. These results suggest the antihypertensive and antioxidant effects of PCA against Dex-induced hypertension.

The present study aimed to evaluate the protective effect of crocin on gastric mucosal lesions caused by ischemia-reperfusion (I/R) injury in rats.Forty male rats were randomly divided into sham, control (I/R injury) and three crocin-pretreated groups. To induce I/R lesions, the celiac artery was clamped for 30 min and then the clamp was removed to allow reperfusion for 3 h. Pretreated-rats received crocin (7.5, 15 or 30 mg/kg, i.p.) 30 min prior to the induction of I/R injury. Samples of gastric mucosa were collected to measure the following variables: 1. mRNA expression of superoxide dismutase (SOD) and glutathione peroxidase (Gpx) by RT-PCR; 2.activity of superoxide dismutase and glutathione peroxidase and 3.tissue levels of malonyldehaldehyde (MDA).
Pretreatment with crocin decreased the total area of gastric lesions. Messenger RNA expressions of SOD and Gpx in control I/R injury rats were significantly decreased as compared with sham-operated group (P

Cancer is the leading cause of death worldwide. Current anticancer drugs involve various toxic side effects; efforts are ongoing to develop new anticancer agents especially from the screening of natural compounds. Present study investigated cytotoxic effects and mode of cell death induced by the Caspian cobra venom in some human cancer cell lines.
Cytotoxic effects of snake venom toxins (SVT) were investigated via monitoring of morphological changes, MTT, trypan blue exclusion and LDH release assays. Mechanism of cell death was determined by AO/EtBr double staining, caspase-3 activity assay, flow cytometric analysis of apoptosis and mitochondrial membrane potential measurement.
In morphological analysis, apoptotic alterations related to apoptosis such as cytoplasmic blebbing, chromatin condensation and irregularity in shape were seen. IC50 of SVT in HepG2, MCF7and DU145 cell lines were 26.59, 28.85 and 21.17µg/ml, respectively and significantly different from the MDCK normal cell line (IC50=47.1 µg/ml). AO/EtBr double staining showed the best apoptotic/necrotic ratio at 15 µg/ml after 48 h. LDH release showed no significant differences between 10 µg/ml SVT and cisplatin. Flowcytometric analysis confirms mitochondrial membrane potential loss and more than 95% apoptotic cell death at 15 µg/ml. Caspase-3 was significantly activated at doses higher than 2.5 μg/ml with a maximal activity at 10 μg/ml.
Results from this study demonstrate that SVT induces mitochondrial and caspase-3 dependent apoptosis in cancer cell lines with minimum effects on studied normal cell. This potential might candidate this venom as a suitable choice for cancer treatment

Data about the prevalence of communicable and non-communicable diseases, as one of the most important categories of epidemiological data, is used for interpreting health status of communities. This study aims to calculate the prevalence of outpatient diseases through the characterization of outpatient prescriptions. The data used in this study is collected from 1412 prescriptions for various types of diseases from which we have focused on the identification of ten diseases. In this study, data mining tools are used to identify diseases for which prescriptions are written. In order to evaluate the performances of these methods, we compare the results with Naïve method. Then, combining methods are used to improve the results. Results showed that Support Vector Machine, with an accuracy of 95.32%, shows better performance than the other methods. The result of Naive method, with an accuracy of 67.71%, is 20% worse than Nearest Neighbor method which has the lowest level of accuracy among the other classification algorithms. The results indicates that the implementation of data mining algorithms resulted in a good performance in characterization of outpatient diseases. These results can help to choose appropriate methods for the classification of prescriptions in larger scales.

Depressive disorders are more common among persons with chronic diseases such as inflammatory bowel disease and anti-inflammatory effect of some antidepressants such as amitriptyline has been reported. Acetic acid colitis was induced in both reserpinised (depressed) and non-reserpinised (normal) rats. Reserpinised groups received reserpine (6 mg/kg, i.p.) one hour prior to colitis induction. Then Amitriptyline (5, 10, 20 mg/kg, i.p.) was administered to separate groups of male Wistar rats. All treatments were carried out two hours after colitis induction and continued daily for four days. Dexamethasone (1 mg/kg) and normal saline (1 ml/kg) were used in reference and control groups, respectively. At day five, animals were euthanized and colonic tissue injuries were assessed macroscopically and pathologically. Myeloperoxidase activity as a marker of neutrophil infiltration was also measured in colonic tissues. Results showed that reserpine (6 mg/kg, i.p.) intensified colitic condition. Compared to control, amitriptyline (10, 20 mg/kg) and dexamethasone significantly decreased weight of colon and ulcer index in normal and reserpine-induced depressed rats. Myeloperoxidase activity and pathological assessments also proved anti-inflammatory effect of amitriptyline. Our results suggest that amitriptyline, a tricyclic antidepressant, could reduce inflammatory and ulcerative injuries of colon both in normal and depressed rats. So among the wide spread anti-depressant drugs, amitriptyline is a good choice to treat depression comorbidities in patients with IBD.

A series of structurally related 2,4-dioxopyrimidine-1-carboxamide derivatives as highly potent inhibitors against acid ceramidase were subjected to hologram quantitative structure-activity relationship (HQSAR) analysis. A training set containing 24 compounds served to establish the HQSAR model. The best HQSAR model was generated using atoms, bond, connectivity, donor and acceptor as fragment distinction and 3–6 as fragment size with six components showing cross-validated q2 value of 0.834 and conventional r2 value of 0.965. The model was then employed to predict the potency of test set compounds that were excluded in the training set, and a good agreement between the experimental and predicted values was observed exhibiting the powerful predictable capability of this model ( r2pred = 0.788 ). Atom contribution maps indicate that the electron-withdrawing effects at position 5 of the uracil ring, the preferential acyl substitution at N3 position and the substitution of eight-carbon alkyl chain length at N1 position predominantly contribute to the inhibitory activity. Based upon these key structural features derived from atom contribution maps, we have designed novel inhibitors of acid ceramidase possessing better inhibitory activity.

The present study reports formulation of a traditionally used poly herbal product for wound healing and its chromatographic analysis by HPTLC. Herbal therapy was the common treatment prescribed by Iranian physicians for wound healing. “Zemad”, the most ancient pharmaceutical dosage form used in the Iranian Traditional Medicine (ITM) for skin diseases. In this study, a poly herbal paste (PHP) with hydrophilic base, according to the ITM has been made for wound healing. Powder of Aloe vera gel, oleo gum resins of Boswellia carteri and Commiphora myrrha were used in PHP. PHP were made base on Hydrogel. The physical stability of the formulation was evaluated by testing the physical changes like phase separation, color, odor, and consistency. The HPTLC fingerprint has been used efficiently for the identification and quality assessment of the formulation, also proving the presence of the mentioned herbs in the formula. In order to extract PHP components for HPTLC, PHP was extracted with methanol. Methanol fraction of A. vera, C. myrrha and B. carterri were used as standard materials. Stability and rheological behavior evaluation as well as microbiological tests showed that the prepared formulation was stable with no growth of pathogenic microorganisms and suitable for topical application. HPTLC fingerprinting of PHP confirmed the presence of compounds corresponding to each of the three plants used in the formula. Regarding to, the antioxidant, anti-inflammatory and antimicrobial effects of the constituents of PHP, the product could be an appropriate candidate for wound healing with respect to its traditional use in ITM.

Antibiotic prophylaxis is usually used in allogenic stem cell transplantation, but its use in Autologous Stem Cell Transplantation (ASCT) is controversial. We evaluated the efficacy of ciprofloxacin prophylaxis in ASCT.
To identify the efficacy of ciprofloxacin on the incidence of neutropenic fever and its complications, 72 patients had been admitted to Taleghani Hospital for ASCT between 2010 and 2012 were evaluated in our study. Oral ciprofloxacin 500 mg BID was administered to 30 patients on the same day of high dose chemotherapy until the first febrile episode or until the recovery of neutropenia and the results were analyzed and compared with the historical control group 42 other transplanted patients who had not previously received ciprofloxacin.
The incidence of neutropenic fever was 80% with no difference between the two groups. But in ciprofloxacin group, duration of fever (1.7 days VS 3.5 days P=0.017), hospitalization deu to stem cell transfusion (18.2 days VS 12.2 days p=0.03), incidence of bacteremia 3.3 % VS 33.3%, p=0.002) and platelet recovery (13.9 VS 17.7 days= 0.035) and platelet transfusions (P=0.04) were significantly lower than the control group no side effects and no delay in.
Based on this study oral ciprofloxacin prophylaxis is rational, efficacious and economic in ASCT.

A fast and simple modified QuEChERS extraction method was developed for determination of Benzo[a]pyrene (BaP) in 137 traditional (Sangak), semi-industrial (Sangak) and industrial bread samples using spiked calibration curves by GC/MS. Sample preparation includes extraction of BaP into acetone followed by cleanup with dispersive solid phase extraction. The limit of detection and limit of quantification were 0.3 ng/g and 0.5 ng/g, respectively. The values for recoveries and RSD were calculated as 110.5-119.85% and 1 ng/g. BaP content in all industrial samples was lower than LOQ.
Assuming the consumption of bread in Tehran and Shiraz is limited to these kinds of breads, the daily intake of BaP in Tehran and Shiraz population through bread consumption was estimated to be 170.6 and 168.7 ng/day, respectively. This is the first report concerning contamination of bread samples with BaP in Iran.

Ethanol has a vast consumption around the world. Many researches confirmed some adverse effect of this component on human health. In addition, recent studies showed significant alteration in both cellular population, and protein profile of human foreskin fibroblast cell line (HFFF2) in the specific dosage of ethanol. Here, the role and interaction of some proteins (characterized by significant alteration in expression due to ethanol effect) analyzed by proteomics and evaluated by considering cancerous case. 2D-electrophoresis findings of comparison of normal fibroblast cells and treated fibroblast with 270 mM dosage of ethanol analyzed by using SameSpots software, R software, and Cytoscape for protein-protein interaction (PPI) investigation. Six proteins with significantly altered expression associated with fundamental properties in a cell identified in ethanol-treated sample. These include AnnexinA5, Heterogeneous nuclear ribonucleoprotein A1, Rho-GDP dissociation inhibitor, Cathepsin L, Cu/Zn-SOD, Rho-GDP dissociation inhibitor, and Serpin peptidase inhibitor. Surprisingly, all these proteins were down-regulated and this pattern is similar to nasopharyngeal carcinoma-associated stromal fibroblast sample. Additionally, protein-protein interaction (PPI) indicates that HNRNPA1, SERPINE1 are hub proteins. Once their expression alters, it can impose vast changes on other molecular function. Based on this approach, ethanol may target same pathways that are related to cancer onset. In addition, some epidemiologic studies proved that ethanol consumption is related to increment of cancer risk. Therefore, more investigation is required in this regard to elicit the feasible relationship.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that affects regions of the brain that control cognition, memory, language, speech and awareness to one’s physical surroundings. The pathological initiation and progression of AD is highly complex and its prevalence is on the rise. In his study, Alzheimer's disease was induced with single injection of amyloid-β (Aβ) peptides (30ng, by stereotaxy) in each hemisphere of the brain. Then memory dysfunction, oxidative stress and apoptosis induced by Aβ peptide were investigated on isolated brain mitochondria obtained from infected rat. Our results showed memory impairment in rats after receiving an Aβ peptide. We also found significant rise (P

Chamaemelum nobile (Asteraceae) commonly known as 'Roman chamomile' is a medicinal plant used for numerous diseases in traditional medicine, although its anticancer activity is unknown. The present study was carried out to investigate the anticancer as well as apoptotic activity of ethyl acetate fraction of C. nobile on different cancerous cell lines. The cells were treated with varying concentrations (0.001- 0.25 mg/ml) of this fraction for 24, 48 and 72 h. Apoptosis induced in MCF-7 cells following treatment with ethyl acetate fraction was measured using Annexin V/PI, flowcytometry and western blotting analysis. The results showed that C. nobile ethyl acetate fraction revealed relatively high antiproliferative activity on MCF-7 cells; however, it caused minimal growth inhibitory response in normal cells. The involvement of apoptosis as a major cause of the fraction-induced cell death was confirmed by annexin- V/PI assay. In addition, ethyl acetate fraction triggered the mitochondrial apoptotic pathway by decreasing the Bcl-2 as well as increasing of Bax protein expressions and subsequently increasing Bax/Bcl-2 ratio. Furthermore, decreased proliferation of MCF-7 cells in the presence of the fraction was associated with G2/M phase cell cycle arrest.These findings confirm that ethyl acetate fraction of C.nobile may contain a diversity of phytochemicals which suppress the proliferation of MCF-7 cells by inducing apoptosis.

Microspheres formulated from poly (D,L-lactic-co-glycolide) (PLGA), a biodegradable polymer, have been extensively evaluated as a drug delivery system. In this study, the preparation, characterization and drug release properties of the PLGA microspheres were evaluated. Simvastatin (SIM)-loaded PLGA microspheres were prepared by oil-in-water emulsion/solvent evaporation method. The microspheres were then frozen to −80 °C, they were freeze dried for 24 h. Characterization of SIM-loaded PLGA microspheres was evaluated by X-ray diffraction analysis, Fourier transform infrared spectroscopy analysis, and scanning electron microscopy (SEM). Drug release potential was evaluated by UV-spectrophotometry. The experimental results revealed that SIM-loaded PLGA microspheres can be successfully obtained through solvent evaporation method with appropriate morphologic characteristics and high encapsulation efficiency. The drug release characteristic of the microspheres ascertained that the burst release was about 27% for SIM-loaded microspheres, which occurred within the first 6 days after maintaining the microspheres in phosphate buffer saline (PBS). Also, the microspheres successfully presented a slow release and the duration of the release lasted for more than 20 days. The drug release profile confirmed a burst release was about 27% for SIM-loaded microspheres, which occurred within the first 6 days after maintaining the microspheres in PBS. It can be concluded that SIM-loaded PLGA microspheres hold great promise for using as a drug-delivery system in biomedical applications, especially in drug delivery systems and tissue engineering.