Iranian Journal of Pharmaceutical Research
Year:2015 | Volume:14 | Issue:2|Papers Count:35

Pharmaceuticals are often considered as the most significant cost driver of health care expenditures and at the same time have a major impact on patients’ curative processes and outcomes. Other pieces of evidence emphasize that drugs are the input for the production of good health. They are considered as the most important and expensive element in the healthy supply chain and are more associated with the management and economics rather than other factors. So, the availability of the relevant, effective, and payable drugs at the time of need and their rapid diffusion at affordable prices are important indicators of the utilization of health services. They can be considered as the most visible determinant of quality and the major driver source of the phenomenal increase in longevity of the human race over the past decades.....

Various nanoparticles have been investigated as novel drug delivery systems, including solid lipid nanoparticles (SLNs). Due to their rapid clearance from systemic circulation, nanoparticles do not provide sustained action in most cases. Different strategies have been employed to overcome this problem. In this direction, the present study introduces erodible insitu forming gel systems as potential vehicles for prolonged release of SLNs. SLNs were prepared by solidification of an oil-in-water microemulsion containing stearic acid, surfactants and co-surfactants. Nanoparticles were then dispersed in a thermosensitive Poloxamer 407 aqueous solution (sol) at 4 ° C and their effects on gel forming ability, sol-gel transition and rheological behavior of the system were investigated over 5-50 ° C. Thermal behavior of the system was investigated by differential scanning calorimetry too. Erosion rate of the gel in the presence and absence of SLN was measured by gravimetric method. Integrity of SLNs in the system was investigated by scanning electron microscopy (SEM) and particle size analysis. SLN showed particle size and zeta potential of 130 ± 1. 39 nm and-44 ± 2. 1 mV respectively. Particle size analysis and SEM studies after gel erosion revealed presence of intact SLN in the hydrogel. SLN reduced erosion rate of Poloxamer gel and increased its sol-gel transition temperature from 26 to 29 ° C. However, gelling kinetic did not change significantly after addition of SLN. Damping factor <1 indicated stability of the SLN-containing system. Present results indicate potential of sol-gel systems for controlled nanoparticle delivery and show that SLN affects properties of the system.

The goal of this research is preparation, optimization and in-vitro evaluation of rifampinloaded silica nanoparticles in order to use in the pulmonary drug delivery. Nanoparticles are exhaled because of their small size. Preparation of nanoaggregates in a micron-size scale and re-dispersion of them after deposition in the lung is an approach to overcome this problem. We used this approach in our research. Rifampin was selected as a model lipophilic molecule since it was a well-documented and much used anti tuberculosis drug. A half factorial design was used to identify significant parameters of the spray drying process. The results showed that feed concentration, feed pH and the interaction between feed flow rate and gas atomizer flow rate had statistically significant effects on the particle size of nanoaggregates. The Box-Behnken design was employed to optimize the spray drying process. Finally, a quadratic equation which explains the relation between independent variables and aerodynamic diameter of nanoaggregates was obtained. Rifampin-loaded silica nanoaggregates underwent different in-vitro tests including: SEM, Aerosol performance and drug release. The in-vitro drug release was investigated with buffer phosphate (pH=7. 4). Regarding the drug release study, a triphasic pattern of release was observed. The rifampin-loaded silica nanoaggregates were capable of releasing 90% drug content after 24 h in combination patterns of release. The prepared rifampin-loaded nanoaggregates seem to have a potential to be used in a pulmonary drug delivery.

The aim of the present study was to formulate poly (lactide-co-glycolide) (PLGA) nanoparticles loaded with 18-β-glycyrrhetinic acid (GLA) with appropriate physicochemical properties and antimicrobial activity. GLA loaded PLGA nanoparticles were prepared with different drug to polymer ratios, acetone contents and sonication times and the antibacterial activity of the developed nanoparticles was examined against different gram-negative and gram-positive bacteria. The antibacterial effect was studied using serial dilution technique to determine the minimum inhibitory concentration of nanoparticles. Results demonstrated that physicochemical properties of nanoparticles were affected by the above mentioned parameters where nanoscale size particles ranging from 175 to 212 nm were achieved. The highest encapsulation efficiency (53. 2 ± 2. 4%) was obtained when the ratio of drug to polymer was 1: 4. Zeta potential of the developed nanoparticles was fairly negative (-11± 1. 5). In-vitro release profile of nanoparticles showed two phases: an initial phase of burst release for 10 h followed by a slow release pattern up to the end. The antimicrobial results revealed that the nanoparticles were more effective than pure GLA against P. aeuroginosa, S. aureus and S. epidermidis. This improvement in antibacterial activity of GLA loaded nanoparticles when compared to pure GLA may be related to higher nanoparticles penetration into infected cells and a higher amount of GLA delivery in its site of action. Herein, it was shown that GLA loaded PLGA nanoparticles displayed appropriate physicochemical properties as well as an improved antimicrobial effect.

In the last step of desolvation method for preparation of albumin nanoparticles, glutaraldehyde (GA) is added to stabilize the newly formed nanoparticles. Due to undesirable effects of GA, the objective of this study was to evaluate alternative methods of crosslinking including ultraviolet (UV) irradiation, adding of glucose and combination of both methods. The nanoparticles were prepared by desolvation procedure. Final particle size, zeta potential, FTIR, scanning electron micrograph, cellular uptake and cell toxicity of nanoparticles crosslinked with UV and/or glucose were compared with commonly crosslinked nanoparticles with GA. Moreover, drug release and stability parameters of docetaxel-loaded albumin nanoparticles were investigated. Size of all nanoparticles prepared by different methods was in the same range (100-200 nm). Zeta potential showed the same results except for those treated with UV. The results of FTIR assay were the same for all groups. Although crosslinking by UV or glucose alone resulted in cytotoxic effects, combination of UV and glucose had less cytotoxic effects compared to GA. Cellular uptake of nanoparticles crosslinked with UV + glucose and GA showed similar results. The release of docetaxel from UV + glucose and GA crosslinked nanoparticles showed the same biphasic release. These data support the idea that crosslinking with a combination of UV and glucose can be a promising alternative method for production of docetaxel-loaded albumin nanoparticles with the advantage of omitting toxic GA.

Herein, 1F2, an anti-HER2 monoclonal antibody (mAb), was covalently coupled to the surface of 5-Fluorouracil (5-FU) loaded bovine serum albumin (BSA) nanoparticles. Concerning two different crosslinkers for conjugation of 1F2, Maleimide-poly (ethylene glycol)-Succinimidyl carbonate (Mal-PEG5000-NHS) was selected due to its higher conjugation efficiency (23 ± 4%) obtained in comparison to N-succinimidyl 3-(2-Pyridyl Dithio) Propionate (SPDP) (8 ± 2%). A slight increase in the average particle size with a negligible prolongation of the 5-FU release was observed after 1F2 coupling. The 1F2-coupled 5-FU-loaded BSA nanoparticles interacted with nearly all HER2 receptors available on the surface of HER2-positive SKBR3 cells. No cellular uptake was observed for HER2-negative MCF7 cells. Physicochemical and biological properties of the mAb-modified nanoparticles did not significantly alter after three months of storage at room temperature. The in-vitro cytotoxicity evaluation by MTT assay, demonstrated lower SKBR3 viability (50. 7 ± 9 %) after 5 hours contact with 1F2-coupled 5-FU-loaded BSA nanoparticles in comparison with the other control systems due to their cell attachment and internalization after washing. In addition, no significant toxicity was observed on MCF7 cells. This novel system can efficiently be employed for targeted delivery of 5-FU to HER2-positive cancerous cells.

The present study was an attempt to develop galactosylated albumin nanoparticles of Simvastatin for treatment of hypercholesterolemia. By developing the galactosylated nanoparticulated delivery, the required action of the drug at the target site at the liver can be provided. The advantage of targeting helps to reduce the systemic side effects that may occur due to the distribution of the drug to the other organs and thus helps in maintaining the required concentration of drug at the desired site. The galacotsylated albumin nanoparticles were prepared for the selective delivery of a Simvastatin to the 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) the rate-limiting enzyme in the pathway of cholesterol biosynthesis that is particularly presents on hepatocytes. The asialoglycoprotein receptor (ASGP-R) which is particularly presents on mammalian hepatocytes can be utilize for active targeting by using its natural and synthetic ligands. By utilizing this receptors can provides a unique means for the development of liver-specific carriers, such as liposomes, recombinant lipoproteins, and polymers for drug or gene delivery to the liver, especially to hepatocytes. These receptors recognize the ligands with terminal galactose or N-acetylgalactosamine residues, and endocytose the ligands for an intracellular degradation process. The albumin nanoparticles (NPs) were prepared by using desolvation method and efficiently conjugated with galactose. Various parameters such as particle size, zeta potential, percentage entrapment efficiency and drug loading efficiency, percentage yield, in-vitro drug release were determined. The size of nanoparticles (both plain and coated NPs) was 200 and 250 nm. The zeta potential of plain nanoparticles was-3. 61 and that of galactose-coated nanoparticles was 64. 1. The maximum drug content was in between 79. 98% to 79. 8 % respectively in plain, and galactose coated nanoparticles while the maximum entrapment efficiency was 70. 10% and 71. 03% in plain and coated nanoparticles. It was found that coating of nanoparticles increases the size of nanoparticles.

A series of novel 2-aminopyrimidine and 2-Substituted-4, 6-diaminopyrimidine derivatives have been synthesized and their antiplatelet aggregation activities were assessed against ADP and arachidonic acid-induced platelet aggregation in human plasma using light transmission aggregometry. Among the tested derivatives, compounds Ia, Ib, IB and II16 exhibited the highest antiplatelet aggregation activity (36. 75, 72. 4, 62. 5 and 80 μ M). None of the compounds showed satisfactory activity against the aggregation induced by ADP but acceptable activities were observed against the aggregation induced by arachidonic acid. 2-aminopyrimidines were more active than 4, 6-diaminopyrimidines in this respect.

Carvedilol is administered as a racemic mixture of the R(+)-and S(-)-enantiomers, although it was demonstrated that the two enantiomers exhibit different pharmacological effects and stereoselective pharmacokinetics. The aim of this study was the evaluation of several native and derivatized cyclodextrines as chiral selectors for the separation of carvedilol enantiomers. Stereoselective interactions were observed with four cyclodextrines (β-CD, hydroxypropyl-β-CD, randomly methylated β-CD and sulfobuthyl ether-β-CD). The effects of CD concentration, pH value and composition of the background electrolyte, capillary temperature, running voltage and injection parameters have been investigated. The method was validated for precision of peak-area response, linearity range and limits of detection and quantification. An efficient stereoselective capillary zone electrophoretic method was developed for the determination of carvedilol enantiomers using a simple 25 mM phosphate buffer at a pH = 2. 5 and 10 mM β-CD as chiral selector, resulting in baseline separation of the two enantiomers with sharp peaks and relatively short analysis time. Highly satisfactory results were obtained from the analysis of carvedilol from tablets, indicating that the method is suitable for routine analysis of carvedilol in pharmaceutical products.

A mixture of acetaminophen, diphenhydramine hydrochloride and pseudoephedrine hydrochloride is used for the symptomatic treatment of common cold. In this study, a derivative spectrophotometric method based on zero-crossing technique was proposed for simultaneous determination of acetaminophen, diphenhydramine hydrochloride and pseudoephedrine hydrochloride. Determination of these drugs was performed using the 1D value of acetaminophen at 281. 5 nm, 2D value of diphenhydramine hydrochloride at 226. 0 nm and 4D value of pseudoephedrine hydrochloride at 218. 0 nm. The analysis method was linear over the range of 5-50, 0. 25-4, and 0. 5-5 μ g/mL for acetaminophen, diphenhydramine hydrochloride and pseudoephedrine hydrochloride, respectively. The within-day and between-day CV and error values for all three compounds were within an acceptable range (CV<2. 2% and error<3%). The developed method was used for simultaneous determination of these drugs in pharmaceutical dosage forms and no interference from excipients was observed.

Determination of Bosentan in Pharmaceutical Preparations by Linear Sweep, Square Wave and Differential Pulse Voltammetry Methods

Investigation of the redox properties of drugs and their determination are performed by electrochemical techniques. Data obtained from electrochemical techniques are often correlated with molecular structure and pharmacological activity of drugs. In this regard, different modified electrodes were applied as sensors for quantification of different drugs. A nanocomposite of reduced graphene oxide-cobalt hexacyanoferrate was synthesized by a simple precipitation route. Scanning electron microscopy revealed that the nanocomposite comprised nanoparticles of cobalt hexacyanoferrate attached to the reduced graphene oxide nanosheets. A nanocomposite-modified carbon paste electrode was then fabricated. It represented prominent activity toward the electrocatalytic oxidation of ascorbic acid, and the kinetics of the electrooxidation process was evaluated. Finally, an amperometric method was developed for the quantification of ascorbic acid in different pharmaceutical formulations.

The voltammetric performance of edge-plane pyrolytic graphite (EPG) electrode via adsorptive stripping voltammetry was investigated for study of the electrochemical behavior of omeprazole (OMZ) in aqueous solution. The results revealed that the oxidation of OMZ is an irreversible pH-dependent process that proceeds with the transfer of one electron and one proton in an adsorption-controlled mechanism. The determination conditions, such as the pH values of the supporting electrolyte, accumulation time and scan rate were optimized. Simplicity, high reproducibility and low detection limit (3 nM) of the electrode response as well as wide linear range (0. 01 to 4. 0 μ M) can be stated as significant features of this electrode. The EPG electrode was successfully applied for the determination of OMZ in pharmaceutical formulations and satisfactory results were obtained.

The method has been developed and validated for the determination of hydroquinone in liposomal formulation. The samples were dissolved in methanol and evaluated in 293 nm. The validation parameters such as linearity, accuracy, precision, specificity, limit of detection (LOD) and limit of quantitation (LOQ) were determined. The calibration curve was linear in 1-50 μ g/mL range of hydroquinone analyte with a regression coefficient of 0. 9998. This study showed that the liposomal hydroquinone composed of phospholipid (7. 8 %), cholesterol (1. 5 %), alpha ketopherol (0. 17 %) and hydroquinone (0. 5 %) did not absorb wavelength of 293 nm if it diluted 500 times by methanol. The concentration of hydroquinone reached 10 μ g/mL after 500 times of dilution. Furthermore, various validation parameters as per ICH Q2B guideline were tested and found accordingly. The recovery percentages of liposomal hydroquinone were found 102 ± 0. 8, 99 ± 0. 2 and 98 ± 0. 4 for 80%, 100% and 120% respectively. The relative standard deviation values of inter and intra-day precisions were <%2. LOD and LOQ were 0. 24 and 0. 72 μ g/mL respectively.

Numerous interventional studies in clinical and preclinical setting stated that intake of curcumin may provide protection against cardiovascular disease. The aim of this trial was investigation of curcumin efficiency on some cardiovascular risk factors in patients with coronary artery disease (CAD). A total of 33 patients with CAD who fulfilled inclusion and exclusion criteria were entered the study. Patients were randomly assigned to receive curcumin or placebo, 500 mg capsules, four times daily for 8 weeks. Lipid profile, blood glucose and high sensitive C-reactive protein (hs-CRP) levels were analyzed at baseline and two months after treatment. Serum levels of triglycerides (P=0. 01), LDL-cholesterol (P=0. 03) and VLDLcholesterol (P=0. 04) significantly decreased in the curcumin group compared to baseline, without significant changes in total cholesterol, HDL-cholesterol, blood glucose and hs-CRP levels. In all mentioned laboratory parameters, significant difference was not detected between curcumin and placebo. Although curcumin improved some of lipid profile components, it did not show appreciable effect on inflammatory markers in patients with CAD. Therefore, more detailed assessment of metabolic effects or anti-inflammatory activities of curcumin need to perform by extensive human study.

Anemia of chronic diseases (ACD) is a common problem in patients with infectious diseases and can influence the quality of life and patients› survival. Despite the clinical importance of ACD, data are still lacking regarding this problem in the infectious diseases. This study aimed to evaluate the prevalence, related factors, outcome and approaches to anemia in the infectious diseases ward. This retrospective study was performed to review the medical records of patients admitted to the infectious diseases department of Imam Khomeini hospital during a two-year period between 2009 and 2011. A standard protocol was developed to evaluate anemia. Patients’ demographic data approaches to manage anemia and routine laboratory tests were recorded and compared with the protocol. Totally, 1, 120 medical records were reviewed. ACD was recognized in 705 patients (63%). Only 5. 1% of diagnostic and 8. 7% of treatment approaches was based on the protocol. The majority of patients (89. 4%) were received inappropriate treatment regarding. Mortality rate of patients with ACD was 3. 4%. Moreover, a significant correlation between anemia and mortality was detected (r = 0. 131; p = 0. 026). A statistically significant correlation was also identified between patients’ Hgb and ESR, CRP, reasons of admission, number of medications, and underlying diseases. In conclusion, results of this study suggested that ACD is a common problem in infectious diseases patients and significantly associated with patients’ mortality. Moreover, the majority of studied patients were not received an appropriate diagnostic and treatment approach which arises more concerns regarding the management of ACD in infectious diseases setting.

Evaluation and improvement of drug management process are essential for patient safety. The present study was performed whit the aim of assessing risk of drug management process in Women Surgery Department of QEH using HFMEA method in 2013. A mixed method was used to analyze failure modes and their effects with HFMEA. To classify failure modes; nursing errors in clinical management model, for classifying factors affecting error; approved model by the UK National Health System, and for determining solutions for improvement; Theory of Inventive Problem Solving, were used. 48 failure modes were identified for 14 sub-process of five steps drug management process. The frequency of failure modes were as follow: 35. 3% in supplying step, 20. 75% in prescription step, 10. 4% in preparing step, 22. 9% in distribution step and 10. 35% in follow up and monitoring step. Seventeen failure modes (35. 14%) were considered as non-acceptable risk (hazard score≥ 8) and were transferred to decision tree. Among 51 Influencing factors, the most common reasons for error were related to environmental factors (21. 5%), and the less common reasons for error were related to patient factors (4. 3%). HFMEA is a useful tool to evaluating, prioritization and analyzing failure modes in drug management process. Revision drug management process based focus-PDCA, assessing adverse drug reactions (ADR), USE patient identification bracelet, holding periodical pharmaceutical conferences to improve personnel knowledge, patient contribution in drug therapy; are performance solutions which were placed in work order.

The occurrence of emerging Fusarium mycotoxins beauvericin (BEA), enniatins (ENNs) (A, A1, B, B1), Fusaproliferin and moniliformin was evaluated by a liquid chromatography/ electrospray ionization-tandem mass spectrometric (LC/ESI-MS/MS) technique in 65 domestic rice samples produced in Gilan and Mazandaran Provinces in Iran. The results showed that 46% of the samples were contaminated with at least one of the emerging mycotoxins. BEA was the most prevalent mycotoxin, which was found in 26 out of 65 rice samples at the concentrations up to 0. 47 μ g/Kg. Enniatin A1 which was the only member of ENNs was detected in the samples, occurred in 7. 7% of samples with an average level of 0. 06 μ g/Kg. No detectable level of Fusaproliferin and moniliformin was found. This is the first report concerning the contamination of Iranian domestic rice samples with the emerging Fusarium mycotoxins.

One of the major complications in cancer chemotherapy with cisplatin as one of the important medicines in treatment regimens of different cancers is the development of resistance. One of the most described cellular defense mechanisms involved in resistance is glutathione (GSH), thus in this study, the effects of cisplatin on the total intracellular GSH level (GSHi) in some sensitive and resistant variants of human cell lines (hepatocarcinoma HepG2, sking A375, cisplatin sensitive glioblastoma U373MG and cisplatin resistant glioblastoma U373MGCP, cisplatin sensitive ovary A2780S and cisplatin resistant A2780CP cells) were studied. MTT assay was performed to measure cytotoxicity of cisplatin (33. 3 μ M for 1 hour). Following cisplatin exposure, GSHi (per million cells) was evaluated using a photometrical assay up to 90 minutes. Our results indicate that there are significant differences between GSHi content of A2780CP and U373MGCP cells compared to other cell lines. Moreover, IC50 of cisplatin in different cells seems to have a relation with mean of GSH level in 90 minutes (GSH (mean)90). As a conclusion, it seems that resistance to cisplatin in different cell lines is more related with the diverse patterns of GSHi variations following cisplatin exposure than its original level, and/or its cellular increase or decrease. It is also suggested that GSH (mean)90 may be used as a factor for the prediction of cellular resistance to cisplatin.

The polyphenol silybin has anti-oxidant and anti-cancer properties. The poor bioavailability of some polyphenols (flavonoids, and terpenoids) can be improved by binding them to phosphatidylcholine (phytosome technology). Many studies have focused on the most common phytosome, silybin-phosphatidylcholine, particularly for its hepatoprotective effects. However, in recent years, studies have also been conducted to determine its anti-cancer effect. Considering that the serum starvation should not be used for studies that are not focused on cell cycle arrest, we studied the effect of silybin-phosphatidylcholine from Silybin Advanced™ in 1: 2 ratio (one part silybin bound to two parts phosphatidylcholine) on HER2 gene expression on the SKBR3 breast cancer cell line which were cultured in complete medium (not serum deprivation). The results were compared with our previous study of silybin on HER2 expression on SKBR3 cells. An MTT test was used to determine concentrations for cell treatment, and the gene expression was defined by real-time RT-PCR. Outcomes showed significant concentration-and time-dependent cell growth inhibitory effects of silybin, and silybin-phosphatidylcholine and HER2 down regulation on SKBR3 cells. Silybin-phosphatidylcholine concentrations had a much larger inhibitory and HER2 down regulate effect on cell growth than the same silybin concentrations on SKBR3 cells.

Luteolin is a flavone in medicinal plants as well as some vegetables and spices. It is a natural anti-oxidant with less pro-oxidant potential but apparently with a better safety profile. The purpose of this study was to investigate the molecular mechanism of luteolin-mediated apoptosis of MG-63 human osteosarcoma cells. MTT assay kit was employed to evaluate the effects of luteolin on MG-63 cells proliferation. Then, we performed Annexin V-FITC/PI to analyze the apoptotic rate of the cells. Furthermore, the inhibitory effects of luteolin on the expressions of BCL-2, BAX, Caspase-3 and Survivin were detected by Western blotting. As expected, luteolin (0. 5, 2. 5, 12. 5 μ g/mL) inhibited the growth of MG-63 cells by inhibiting cell proliferation and inducing cell apoptosis. Western blotting demonstrated that luteolin (0. 5, 2. 5, 12. 5 μ g/mL) inhibited the expressions of BCL-2, Caspase-3 and Survivin, and promoted the expression of BAX in MG-63 cells with a concentration dependent way. Luteolin can inhibit osteosarcoma cell proliferation and induce apoptosis effectively in a dose dependent manner through down-regulating the expression of BCL-2, Caspase-3 and Survivin proteins levels and up-regulating the expression of BAX protein level. These findings indicated that luteolin may be used as a novel herbal medicine for the treatment of osteosarcoma.

Cancer is one of the main causes of mortality in the world which is created by the effect of enviromental physico-chemical mutagen and carcinogen agents. The identification of new cytotoxic drugs with low side effects on immune system has developed as important area in new studies of pharmacology. Thymoquinone (TQ), derived from the medicinal spice Nigella sativa (also calledt black cumin) exhibit anti-inflammatory and anti-cancer activities. In this study we employed nanogel-based nanoparticle approach to improve upon its effectiveness. Myristic acid-chitosan (MA-chitosan) nanogels were prepared by the technique of selfassembly. Thymoquinone was loaded into the nanogels. The surface morphology of the prepared nanoparticles was determined using SEM and TEM. The other objective of this study was to examine the in-vitro cytotoxic activity of cell death of Thymoquinone and nanothymoquinone on human breast adenocarcinoma cell line (MCF7). Cytotoxicity and viability of Thymoquinone and nanothymoquinone were assessed by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and dye exclusion assay. Transmission electron microscopy confirmed the particle diameter was between 150 to 200 nm. Proliferation of MCF7 cells was significantly inhibited by Thymoquinone and nanothymoquinone in a concentration-dependent manner in defined times. There were significant differences in IC50 Thymoquinone and nanothymoquinone. TQ-loaded nanoparticles proved more effective compared to TQ solution. The high drug-targeting potential and efficiency demonstrates the significant role of the anticancer properties of TQ-loaded nanoparticles.

Regarding the therapeutic properties of Nigella sativa (NS), the effects of the plant hydro – alcoholic extract on learning, memory and brain tissues oxidative damage were investigated in penthylenetetrazole (PTZ)-induced repeated seizures. There were 4 experimental groups including: 1-control group; received saline, 2-PTZ group; received saline and PTZ (50 mg/Kg, i. p), 3-PTZ-NS 200 and 4-PTZ-NS 400; received 200 and 400 mg/Kg of NS extract respectively, before PTZ injection in 5 consecutive days. Seizure scores were lower in PTZ – NS 200 and 400, furthermore the seizure onset latencies were higher in these groups than PTZ group (P<0. 05 and P<0. 01 ). In Morris water maze, the time spent in target quadrant by PTZ group was lower than control group (P<0. 05); while, 400 mg/Kg of the extract increased it (P<0. 01). In the passive avoidance test, delay time to enter the dark by PTZ group was lower than control at 1 and 24 hours after training (P<0. 01-P<0. 001); while, 400 mg/Kg of the extract increased it (P<0. 05). The total thiol concentration in hippocampal and cortical tissues of PTZ group was reduced while, MDA concentration was higher than control (p<0. 05-p<0. 001). Administration of the extract increased the total thiol and decreased the MDA concentrations (p<0. 01-p<0. 001). It is concluded that the hydro-alcoholic extract of NS possess beneficial effects on learning and memory impairments in repeated seizures model which is accompanied by antioxidant effects in the brain.

This study aimed to observe the protective effects of sufentanil pretreatment on rat cerebral injury during cardiopulmonary bypass (CPB) and to explore the underlying mechanism. Twenty-four male adult Sprague Dawley (SD) rats were divided into 4 groups. Then, the rat CPB model was established. A 14G trocar was inserted into the atrium dextrum. For rats in S1 and S5 groups, sufentanil (1 μ gKg-1 and 5 μ gKg-1) were applied before CPB process. After the operation, rat brain samples were harvested for measurement of the water content of the brains, total calcium in brain tissue and the level of serum S100β . Compared with the Sham group, the water content and the total calcium of the brain tissue, and the expression of S100β in serum were significantly increased in the CPB group (P<0. 05). Compared with the CPB group, sufentanil treatment significantly reduced the water content of the brains, the total calcium and S100β expression (P<0. 05). The blood pressure and heart rate were significantly decreased in groups CPB, S1, and S5 compared with Sham group during CPB. Compared with the Sham group, the levels of pH and blood lactate in other groups were decreased and increased, respectively, in the post-CPB period. During the CPB and post-CPB periods, the hematocrit levels were significantly down-regulated in groups CPB, S1, and S5 compared with Sham group. In conclusion, sufentanil pretreatment was effective in reducing the cerebral injury during CPB. Reduction in calcium overload may be a potential mechanism in such process.

Inhalational insulin was withdrawn from the market due to its potential to produce airway hyper-reactivity and bronchoconstriction. So the present study was designed to explore the acute effects of insulin on airway reactivity of guinea pigs and protective effects of salbutamol and beclomethasone against insulin induced airway hyper-responsiveness on isolated tracheal smooth muscle of guinea pig. Effects of varying concentrations of insulin (10-7 to 10-3 M), insulin pretreated with fixed concentration of salbutamol (10-7 M) and beclomethasone (10-6 M) were studied on isolated tracheal tissue of guinea pig by constructing cumulative concentration response curves. Changes in tracheal smooth muscle contractions were recorded on four channel oscillograph. The mean ± SEM of maximum amplitudes of contraction with increasing concentrations of insulin, insulin pretreated with fixed concentration of salbutamol and beclomethasone were 35 ± 1. 13 mm, 14. 55 ± 0. 62 mm and 22 ± 1. 154 mm respectively. Although salbutamol and beclomethasone both had a profound inhibitory effect on insulin induced airway hyper-reactivity, yet salbutamol is more efficacious than beclomethasone. So we suggest that pretreatment of inhaled insulin with salbutamol may be preferred over beclomethasone in amelioration of its potential respiratory adverse effects such as bronchoconstriction.

Experimental evidence suggested that sodium ferulate (SF) and oxymatrine (OMT) combination had synergistic anti-inflammatory and antioxidant effects. We hypothesized that SF and OMT combination treatment might have protective effects on paraquat-induced acute lung injury. In our study, the Swiss mice were randomly divided into seven groups, including control, paraquat (PQ), SF (6. 2 mg/Kg/day); OMT (13. 8 mg/Kg/day) and three SF+OMT groups (3. 1 + 6. 9; 6. 2 + 13. 8 and 12. 3 + 27. 7 mg/Kg/day). The mortality and death time were monitored. Sprague-Dawley rats were randomly divided into seven groups including control, PQ, SF (3. 1 mg/Kg/day); OMT (6. 9 mg/Kg/day) and three SF+OMT groups (1. 6 + 3. 4; 3. 1 + 6. 9 and 6. 2 + 13. 8 mg/Kg/day). The lung wet/dry weight (W/D) ratio, lung histopathologic changes, C-reactive protein (CRP), interleukin-6 (IL-6), nuclear factor κ B (NF-κ B), malondialdehyde (MDA) and superoxidase dismutase (SOD) were analysed. Compared with PQ group, the mortality significantly decreased and the death time prolonged in SF and OMT combination treatment groups of mice. Also in SF and OMT combination treatment groups of rats, the increased lung W/D ratio and histopathological score induced by PQ injection were significantly decreased; the levels of CRP, IL-6, NF-κ B and MDA in serum and lung homogenate were significantly decreased; the SOD activities in serum and lung homogenate were improved. These results suggested that SF and OMT combination had an obvious protective effect on PQ-induced lung injury. The anti-infl ammatory and antioxidant effect might be involved in the mechanism.

Safranal, the main component of Crocus sativus essential oil, exhibits different pharmacological activities. In this study, the effects of safranal, on blood pressure of normotensive and desoxycorticosterone acetate (DOCA)-salt induced hypertensive rats in chronic administration were investigated. Three doses of safranal (1, 2 and 4 mg/Kg/day) and spironolactone (50 mg/Kg/day) were administrated to the different groups of normotensive and hypertensive rats (at the end of 4 weeks treatment by DOCA-salt) for Five weeks. Then the effects of safranal on mean systolic blood pressure (MSBP) and heart rate (HR) were evaluated using tail cuff method. The duration of effect of safranal on SBP, was also evaluated. Our results indicated that chronic administration of safranal could reduce the MSBP in DOCA salt treated rats in a dose dependent manner. Safranal did not decrease the MSBP in normotensive rats. The data also showed that antihypertensive effects of safranal did not persist. In summary, our results showed that safranal exhibits antihypertensive and normalizing effect on BP in chronic administration.

Morphine’ s effects on learning and memory processes are well known to depend on synaptic plasticity in the hippocampus. Whereas the role of the hippocampus in morphine-induced amnesia and state-dependent learning is established, the biochemical and molecular mechanisms underlying these processes are poorly understood. The present study intended to investigate whether administration of morphine can change the expression level of rat hippocampal proteins during learning of a passive avoidance task. A step-through type passive avoidance task was used for the assessment of memory retention. To identify the complex pattern of protein expression induced by morphine, we compared rat hippocampal proteome either in morphine-induced amnesia or in state-dependent learning by two-dimensional gel electerophoresis and combined mass spectrometry (MS and MS/MS). Post-training administration of morphine decreased step-through latency. Pre-test administration of morphine induced state-dependent retrieval of the memory acquired under post-training morphine influence. In the hippocampus, a total of 18 proteins were identified whose MASCOT (Modular Approach to Software Construction Operation and Test) scores were inside 95% confidence level. Of these, five hippocampal proteins altered in morphine-induced amnesia and ten proteins were found to change in the hippocampus of animals that had received post-training and pre-test morphine. These proteins show known functions in cytoskeletal architecture, cell metabolism, neurotransmitter secretion and neuroprotection. The findings indicate that the effect of morphine on memory formation in passive avoidance learning has a morphological correlate on the hippocampal proteome level. In addition, our proteomic screen suggests that morphine induces memory impairment and state-dependent learning through modulating neuronal plasticity.

The formation of hemozoin (malaria pigment) has been proposed as an ideal drug target for antimalarial screening programs. In this study, we used an improved, cost-effective and highthroughput spectrophotometric assay to screen plant extracts for finding novel antimalarial plant sources. Fifteen extracts with different polarity from three Iranian Artemisia species, A. ciniformis, A. biennis and A. turanica, were assessed for their antimalarial activity by invitro β-hematin formation assay. The most potent effect was observed in dichloromethane (DCM) extract of A. ciniformis with IC50 and IC90 values of 0. 92 ± 0. 01 and 1. 29 ± 0. 02 mg/ mL, respectively. Ethyl acetate (EtOAC) extracts of A. biennis and A. turanica also showed significant antimalarial activities with IC50 values of 1. 11 ± 0. 02 and 1. 35 ± 0. 08 mg/mL and IC90 values of 1. 22 ± 0. 04 and 2. 81 ± 0. 21 mg/mL, respectively. Based on these results, it is possible to conclude that the components with strong antimalarial activity have been concentrated in the medium-polar extracts.

It is believed that the inhibition of carbohydrate hydrolyzing enzymes including α-amylase and α-glucosidase is one of the therapeutic approaches to decrease the postprandial glucose level after a meal, especially in the people with type 2 diabetes. Medicinal plants and their extracts are one of the main sources to find new inhibitors to the enzymes. In our study four flavonoids, namely luteolin 7-O-glucoside (1), luteolin 7-O-glucuronide (2), diosmetin 7-O-glucuronide (3) and salvigenin (4) were isolated from aerial parts of Salvia chloroleuca. The inhibitory activity of these compounds against α-amylase and α-glucosidase were evaluated. Compounds 1, 2 and 3 showed potent α-glucosidase inhibitory effect with IC50 values of 18. 3, 14. 7, and 17. 1 μ M, respectively. Also these compounds exhibited moderate α-amylase activity with IC50 values 81. 7, 61. 5, and 76. 3 μ M, respectively.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of TNF family, is an interesting ligand which selectively induces apoptosis in tumor cells and, therefore, it has been developed for cancer therapy. This ligand has been produced by various hosts such as E. coli. However, protein expression in E. coli cytoplasm leads to problems such as incorrect folding, reduction in biological activity, inclusion body formation, and sophisticated downstream. The aim of this study is to develop an expression system for the production of recombinant TRAIL secreted to the E. coli periplasm instead of cytoplasm. By using Overlapping Extension PCR, an OmpA signal sequence was fused to TRAIL cDNA and OmpA-TRAIL fragment was then cloned in pET-22b plasmid. This construct was confirmed by PCR and DNA sequencing. Promoter was induced in E. coli BL21 (DE3) and periplasmic expressed proteins were released using osmotic shock procedure. SDS-PAGE analysis showed that about 37% of recombinant TRAIL was transferred into the periplasm and its identity was confirmed by western blot analysis. Finally, the cytotoxic activity of TRAIL against HeLa cell line was confirmed by using MTT assay. The results demonstrate that our expression system may be useful for the production of TRAIL in the periplasmic space.

Staphylococcus aureus is an opportunistic pathogen and remains a common cause of burn wound infections. Different studies have shown that entrapment of plant-derived compounds into liposomes could increase their anti-Staphylococcus aureus activity. Silymarin is the bioactive extract from the known plant Silybum marianum L. The objective of this study was to evaluate efficacy of silymarin in free and nanoliposomal forms against isolated methicillinresistant Staphylococcus aureus (MRSA) strain. Silymarin-loaded nanoliposomes were prepared by extrusion method. The minimum inhibitory concentrations (MICs) of silymarin in free and nanoliposomal forms against MRSA were determined by broth dilution method. The killing rate of free and nanoliposomal forms of silymarin were analyzed. Ultimately, invivo therapeutic efficacy of nanoliposomes in burned mice infected by isolated MRSA was examined. The MICs of free and nanoliposomal forms of silymarin against isolated strain were 500 and 125 mg/L, respectively. The killing rate of silymarin-loaded nanoliposomes was higher than those of free silymarin. Topically treatment by silymarin in free and nanoliposomal forms resulted in almost 20 and 100% survival rates, respectively. The results suggest that silymarinloaded nanoliposomes may provide a basis for future treatment of MRSA infections.

HPV vaccine has been recently added to the Iran Drug List, so decision makers need information beyond that available from RCTs to recommend funding for this vaccination. Modeling and economic studies have addressed some of those information needs. We reviewed cost effectiveness studies to find a suitable model for Iranian population to determine the potential cost effectiveness of HPV vaccine program based on domestic available epidemiologic data. Articles were obtained from an extensive literature search to determine the cost effectiveness of implementing an HPV vaccination program with routine cervical cancer screening. A total of 64 studies were included in this review. Although the studies used different model structures, baseline parameters and assumptions (either a Markov, Hybrid, or Dynamic model). Most of the proposed cost effectiveness models need to model the probability of HPV acquisition, the possible progression from HPV infection to CIN I, CIN II, CIN III and cervical cancer, the probability of HPV transmission which are not available in Iranian epidemiologic data. Based on the available epidemiologic data in Iran, the simplified and it requires substantially fewer assumptions than the other more complex Markov and hybrid models, therefore we decided to use this model for the evaluation of cost effectiveness of HPV vaccine in Iran.

Prescribing behavior of physicians affected by many factors. The present study is aimed at discovering the simultaneous effects of the evaluated factors (including: price, promotion and demographic characteristics of physicians) and quantification of these effects. In order to estimate these effects, Fluvoxamine (an antidepressant drug) was selected and the model was figured out by panel data method in econometrics. We found that insurance and advertisement respectively are the most effective on increasing the frequency of prescribing, whilst negative correlation was observed between price and the frequency of prescribing a drug. Also brand type is more sensitive to negative effect of price than to generic. Furthermore, demand for a prescription drug is related with physician demographics (age and sex). According to the results of this study, pharmaceutical companies should pay more attention to the demographic characteristics of physicians (age and sex) and their advertisement and pricing strategies.

Some physicochemical parameters of honey have been introduced by the International Honey Commission to evaluate its quality and origin but processes such as heating and filtering can affect these parameters. In traditional Iranian medicine, deslagging process involves boiling honey in an equal volume of water and removing the slag formed during process. The aim of this study was to determine the effects of deslagging process on parameters of color intensity, diastase evaluation, electrical conductivity, pH, free acidity, refractive index, hydroxy methyl furfural (HMF), proline and water contents according to the International Honey Committee (IHC) standards. The results showed that deslagged honey was significantly different from control honey in terms of color intensity, pH, diastase number, HMF and proline content. It can be concluded that the new standards are needed to regulate deslagged honey.