Iranian Journal of Pharmaceutical Research
Volume:13 Issue: 2, Spring 2014

Competitiveness is considered as a key criterion for assessing the success of countries, industries and companies. World Economic Forum defines competitiveness as the set of institutions, policies and factors that determine the level of productivity. Moreover, competitiveness can be defined as acquisition more market share, greater profitability and long-term stability and growth of these indicators thereby improving the welfare and living standards of people. Putting it in perspective, companies and industries must be well competitive in domestic and international markets in order to survive. With respect to recent competitive and dynamic environment if companies want to be successful in competition arena, they must have competitive advantage which means creating and sustaining superior performance. The strength of competition depends on both the conduct of firms and the external business environment in which they compete, the state of infrastructure, legal framework and the effectiveness of the financial system. Mostly, barriers to competition in developing countries stemming from inappropriate government policies, and anti-competitive behavior of firms are common.

GC-FID and HPLC-DAD were developed for determination of menadione (MN) and menadione sodium bisulphite (MSB). By means of each method, quantitative analysis of MSB in commercial pharmaceutical was performed in both direct analysis of MSB and analysis of MN by converting MSB to MN with sodium carbonate. GC-FID method was carried out on the HP-5 capillary column using nitrogen gas. HPLC-DAD method was achieved on the reversed phase C8 column by using a mobile phase consisting methanol and water. The calibration curves of GC-FID and HPLC-DAD for both analytes were linear in the same concentration range (0.5–20 μg/mL). Both methods were validated in terms of precision, accuracy, recovery and limits of detection (LOD) and quantitation (LOQ). Although LOD values of HPLC-DAD method (0.010 μg/mL for MN and 0.005 μg/mL for MSB) is lower than obtained values with GC-FID method (0.04 μg/mL for MN and 0.06 μg/mL for MSB), both methods gave similar and favorable results in terms of precision and accuracy. The Student''s t-test was applied to investigate the significant of the different between the results of MSB determination with direct analysis of MSB and analysis of MN by converting MSB to MN by means of GC-FID and HPLC-DAD method in dosage form.

Glimepiride/metformin(2/500mg) is an oral antihyperglycemic agent for the treatment of type 2 diabetes. A generic glimepiride/metformin(2/500mg) fixed-dose combination(FDC) tablet was developed recently. This study was designed to collect data for submission to Korean regulatory authorities to allow the marketing of the test formulation. We evaluated the comparative bioavailability and tolerability of the test and reference formulations in healthy male adult volunteers. This single-dose, randomized, double-blind, two-way crossover trial was conducted at Bestian Medical Center in Bucheon, Korea. In total, 40male Korean volunteers were enrolled. The subjects were randomized to receive an FDC tablet containing the glimepiride/metformin(2/500mg) test or reference formulation, and pharmacokinetic (PK) parameters were measured. After a 1-week washout period, the other formulation was administered and the PK parameters were measured again. The Cmax and AUC∞ were determined from blood samples obtained at 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, and 24h after drug administration. Bioequivalence was considered established if the 90%CIs of the geometric mean ratios(GMRs) of the test-to-reference formulations for Cmax and AUC∞ were within the predetermined regulatory range of 80-125%. In total, 40 healthy male subjects were enrolled and completed the study(mean[SD]age, 23.2[2.26]years[range, 19-30years]; weight, 68.95[8.30]kg[range, 52.0-87.0kg]; and height, 175.4[5.34]cm[range, 164-189cm]). The GMRs(90% CI) of the glimepiride Cmax and AUC∞ were 1.006 (0.947-1.069) and 1.010 (0.953-1.071), respectively. For metformin, the values were 1.019 (0.959-1.083) and 1.035 (0.989-1.084), respectively. The two formulations had similar PK parameters. The test formulation of glimepiride/metformin(2/500mg) FDC tablets met the Korean regulatory criteria for bioequivalence.

In this study, a new reaction system for quantitative determination of ascorbic acid was introduced. The developed method is based on inhibitory effect of ascorbic acid on the Orange G-bromate system. The change in absorbance was followed spectrophotometrically at 478 nm. The dependence of sensitivity on the reaction variables including reagents concentration, temperature and time was investigated. Under optimum experimental conditions, calibration curve was linear over the range 0.7 – 33.5 μg mL-1 of ascorbic acid including two linear segments and the relative standard deviations (n = 6) for 5.0 and 20.0 μg mL–1 of ascorbic acid were 1.08 and 1.02%, respectively. The limit of detection was 0.21 μg mL−1 of ascorbic acid. The effect of diverse species was also investigated. The developed method was successfully applied for the determination of ascorbic acid in pharmaceutical samples. The results were in a good agreement with those of reference method.

A bioequivalence study of two verapamil formulations (generic verapamil tablets and Isoptin® tablets) was performed by comparing pharmacokinetic parameters of the parent drug and its major metabolite, norverapamil following a single dose administration of 80 mg verapamil hydrochloride in 22 healthy volunteers according to a randomized, two-period, crossover-design study. Moreover, the feasibility of proving bioequivalence of verapamil oral dosing form by means of norverapamil pharmacokinetic parameters was evaluated. Concentrations of verapamil and norverapamil were quantified in plasma using a validated high-performance liquid chromatography (HPLC) with fluorescence detection. The 90% CIs for the log-transformed ratios of verapamil Cmax and AUC0–∞ were 73 to 101 and 80 to 103, respectively. Similarly, the corresponding ranges for norverapamil were 80-100 and 84-103, respectively. According to the parent drug data, the 90% confidence intervals around the geometric mean ratio of AUC happened to fit within preset bioequivalence limits of 80–125%, whereas those for Cmax did not. The 90% confidence intervals for both Cmax and AUC of norverapamil met preset bioequivalence limits. The AUC and Cmax of metabolite, when compared to parent drug, showed a much lower degree of variability and the 90% confidence intervals of the metabolite were therefore narrower than those of the parent drug. These observations indicate that bioequivalence studies using metabolite, norverapamil, could be a more suitable and preferable approach to assess bioequivalence of verapamil formulations due to its much lower variability and therefore lower number of volunteers that are required to conduct the study.

Omega-3 fatty acids (FAs) have been shown to prevent cardiovascular disease. The most commonly used omega-3 fatty acids like eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are highly vulnerable to oxidation and therefore, have short shelf life. Recent advances in nanoliposomes provided a biocompatible system for stabilizing omega-3 FAs. Several methods could be implemented to prepare nanoliposomes. To the best of our knowledge, the performances of these methods in preparation omega-3 FAs have not been examined. Nanoliposomes were prepared by thin film hydration followed by one of the following 1- extrusion, ultrasonic irradiation; 2- bath sonication; 3- probe sonication; or 4- combined probe and bath sonication. The size of liposomes obtained from methods 1 to 4 were 99.7 ± 3.5, 381.2 ± 7.8, 90.1 ± 2.3, and 87.1± 4.10 nm with ξ potential being -42.4 ± 1.7, -36.3 ± 1.6, -43.8 ± 2.4, and 31.6 ± 1.9 mV, respectively. The encapsulation efficiency (EE) for DHA was 13.2 ± 1.1%, 26.7 ± 1.9%, 56.9 ± 5.2%, and 51.8 ± 3.8% for methods 1 to 4, respectively. The corresponding levels for EPA were 6.5 ± 1.3%, 18.1 ± 2.3%, 38.6 ± 1.8%, and 38 ± 3.7%, respectively. The EE for DHA and EPA of liposomes for both methods 3 and 4 increased significantly (p < 0.05). Propanal, as the major volatile product formed during liposomal preparations, amounts from 81.2 ± 4.1 to 118.8 ± 2.3 µgg-1.

Vascular endothelial growth factor receptor-2 (VEGFR-2); a cell surface receptor for vascular endothelial growth factors, is a key pharmacological target involved in the cell proliferation/angiogenesis. It has been revealed that VEGFR-2 induces proliferation through activation of the extracellular signal-regulated kinases pathway. In this regard, targeting the VEGFR-2 has been considered as an efficient route to develop anti-tumor agents. Motesanib is a small-molecule antagonist of VEGFR-1, 2, and 3 (IC50s; 2 nM, 3 nM, 6 nM, respectively). It is an experimental drug candidate undergoing clinical trials against some types of cancer. In the present study, Motesanib (AMG 706) was evaluated in terms of its binding energies with individual amino acids of VEGFR-2 active site (amino acid decomposition analysis). For this purpose, functional B3LYP associated with split valence basis set using polarization functions (Def2-SVP) was used. Comparative conformational analysis of the ligand in optimized and crystallographic states revealed that Motesanib does not necessarily bind to the VEGFR-2 active site in its minimum energy conformer.

A molecular imprinted polymer (MIP) was computationally designed and synthesized for the selective extraction of metaproterenol (MTP), from human plasma. In this regards semi empirical MP3 and mechanical quantum (DFT) calculations were used to find a suitable functional monomers. On the basis of computational and experimental results, acrylic acid (AA) and DMSO:MeOH (90:10 %V/V) were found to be the best choices of functional monomer and polymerization solvents, respectively. This polymer was then used as a selective sorbent to develop a molecularly imprinted solid-phase extraction (MISPE) procedure followed by differential pulse voltammetry by using modified carbon nanotube electrode. The analysis was performed in phosphate buffer, pH 7.0. Peak currents were measured at +0.67 V versus Ag/AgCl. The linear calibration range was 0.026–8.0 μg mL-1 with a limit of detection 0.01 μg mL-1. The relative standard deviation at 0.5 μg mL-1 was 4.76% (n=5). The mean recoveries of 5 μg mL-1 MTP from plasma was 92.2% (n=5). The data of MISPE-DPV were compared with the MISPE-HPLC-UV. Although, the MISPE-DPV was more sensitive but both techniques have similar accuracy and precision.

In this study, a high-performance liquid chromatographic method (HPLC) and UV spectrophotometric method were developed, validated and applied for the determination of theophylline in biological fluids. Liquid- liquid extraction is performed for isolation of the drug and elimination of plasma and saliva interferences. Urine samples were applied without any extraction. The chromatographic separation was achieved on a C18 column by using 60:40 methanol:water as mobile phase under isocratic conditions at a flow rate of 0.75 mL/min with UV detection at 280 nm in HPLC method. UV spectrophotometric analysis was performed at 275 nm.The results of HPLC analysis were as follows: the limit of quantification: 1.1 µg/mL for urine, 1.9 µg/mL for saliva, 3.1 µg/mL for plasma; recovery: 94.85% for plasma, 100.45% for saliva, 101.39% for urine; intra-day precision: 0.22–2.33%, inter-day precision: 3.17-13.12%. Spectrophotometric analysis results were as follows: the limit of quantitation: 5.23 µg/mL for plasma, 8.7 µg/mL for urine; recovery: 98.27% for plasma, 95.25% for urine; intra-day precision: 2.37 – 3.00%, inter-day precision: 5.43-7.91%.It can be concluded that this validated HPLC method is easy, precise, accurate, sensitive and selective for determination of theophylline in biological samples. Also spectrophotometric analysis can be used where it can be applicable.

A quantitative analysis method for fudosteine in human serum by high-performance liquid chromatography-electrospray ionization tandem mass spectrometry (HPLC-ESI/MS/MS) was established, which shows high sensitivity and selectivity. The mobile phase composition was 75% 20 mM acetic acid and 25% acetonitril, which was pumped at a flow rate of 0.40 mL/min. The overall chromatographic run time was approximately 7 min. The autosampler was set with an injection volume of 10 μl. The calibration curve was linear in the concentration range of 0.1~15.0 µg/mL. The coefficient of determination (r) was greater than 0.9998. This method has been fully validated and shown to be specific, accurate and precise. The method was simple, rapid and the sample preparation was minimal. It was successfully applied to the analysis of healthy volunteer serum samples during a phaseⅠclinical pharmacokinetic study of fudosteine.

The high performance liquid chromatography (HPLC) enantioseparation of four β-blocking agents metoprolol, bisoprolol, propranolol and atenolol was performed on amylose tris-(3,5-dimethylphenylcarbamate) chiral stationary phase using n-hexane-ethanol-diethylamine (DEA) as the mobile phase and related chiral recognition mechanisms were discussed. Enantiomeric separation of the fourβ-blockers was a result of more than one type of interaction between solutes and CSP. Besides hydrogen bonding, there was another type interaction that was independent of solvent polarity and responsible for enantiomeric selectivity, such as π-π interactions. Both the groups close to the chiral centers and the substituent groups on the phenyl rings, which were far away from the chiral centers, could contribute to the good separation. The separations of the four β-blocker enantiomers were all enthalpy driven process. In the range of 293–308K(20–35℃), as the temperature increased, the retention as well as the resolution decreased. The molecular size rather than concentration of the alcohol modifiers affected the resolution and retention.

Epilepsy is the most frequnt nearological affiction and afflicts 1% about of the worlds population. Currently there is an urgent need for the development of novel anticonvulsants with higher levels of potency and lower levels of toxicity. In this paper, a series of new 6-(substituted-phenyl)thiazolo[3,2-b][1,2,4]triazole derivatives were synthesized and tested for their anticonvulsant activity using the maximal electroshock (MES) and subcutaneous pentylenetetrazole (PTZ) screens, which are the most widely employed seizure models for early identification of candidate anticonvulsants. Their neurotoxicity was determined applying the rotarod test. In these compounds, 6-(4-fluorophenyl)thiazolo[3,2-b][1,2,4]triazole (3c) showed selective protection against the MES seizures with an ED50 value of 49.1 mg/kg and a TD50 value of 94.1 mg/kg, which provided compound 3c a protective index (PI = TD50/ED50) of 1.9 in the MES test. 6-(4-Propoxyphenyl)thiazolo[3,2-b][1,2,4]triazole (5b) was found to be active in both models, i.e. MES test and PTZ test. In the PTZ screen, compound 5b gave an ED50 of 63.4 mg/kg and a TD50 of 105.6 mg/kg, resulting in a PI value of 1.7 which is higher than carbamazepine.

A capillary electrophoresis method was used for assay of some degradation products of carvedilol. The optimized parameters were as; running buffer 80 mM acetate dissolved in methanol/ethanol mixture (65:35 v/v), applied voltage of 19 kV, temperature is 20 ºC and the wavelength range of 200-350 nm. The results indicate that the proposed CE method could effectively separate carvedilol from its degradation products and can be employed as a stability indicating assay method. In addition, the presence of a new unknown degradation product was discovered by this method. In addition, CE behaviour of carvedilol in photo/force degradation conditions gave valuable information concerning the dissimilarities of their ionization. Results indicated that the CE proposed method can be used for the determination of carvedilol in human serum. Finally, accuracy of the proposed method was established by recovery experiments from spiked human serum samples.

A new series of N-(5-Mercapto-1,3,4-thiadiazol-2-yl)-2-phenylacetamide derivatives (3a-3j) were synthesized via an amidation reaction using EDC and HOBt in acetonitrile solvent at room temperature condition. Chemical structures were characterized by 1H NMR, IR and MS spectroscopic methods and related melting points were also determined. The anticancer activity was evaluated using MTT procedure in vitro. All compounds were tested against SKNMC (Neuroblastoma), HT-29 (Colon cancer) and PC3 (Prostate cancer) cell lines. According to the toxicological data, none of the synthesized derivatives exerted superior activity than doxorubicin as reference drug. Derivatives with Ortho chlorine (compound 3d), meta methoxy (compound 3h) and meta fluorine (compound 3b) substituents on the phenyl ring exhibited the best cytotoxic activity against SKNMC (IC50 = 4.5 ± 0.035 µM), HT-29 (IC50 = 3.1 ± 0.030 µM) and PC3 (IC50 = 12.6 ± 0.302 µM) cell lines respectively.

High performance liquid chromatography (HPLC) with diode array detection (DAD) and electrospray ionization tandem mass spectrometry (ESI/MS/MS) was used to analyze the main components in the methanol extract of Fructus Aurantii (FA) and the metabolites in rat biological samples after oral administration of the methanol extract of FA. There were 31 constituents identified in the extract of FA including 2 alkaloids, 1 coumarin, 10 flavonoid glycosides and 18 ploymethoxylated flavones. According to the UV spectrum and MS fragment character of main components in the methanol extract of FA, 18 parent constituents and 11 metabolites were tentatively identified in rat biological samples. Three groups of components in biological samples detected included flavonoid glycosides, their glucuronides and ploymethoxylated flavones. It was interested that flavonoid glycosides, their glucuronides and ploymethoxylated flavones can be investigated in rat plasma and urine, while in rat feces samples only flavonoid glycosides were detected. Triglycosyl, naringenin, neoeriocitrin, neoeriocitrin narirutin and hesperidin were the main components in rat feces which were found either in the plasma or in urine samples. However, naringin and neohesperidin were the main flavonoid glycosides which absorbed after oral administration. Except flavonoid glycosides and their glucuronides, ploymethoxylated flavones also the constituents absorbed because it was investigated mainly in rat plasma and urine but not in feces samples. The identification and elucidation of parent and metabolism components analyzed in biological samples provided the data for further pharmacological and clinical research on FA

Methanol extracts of Callistemon viminalis (Sol. Ex Gaertner) G.Don Ex Loudon fruits, bark and leaves were tested for molluscicidal activity. Snails were collected and kept in dechlorinated water under standard condition. Ten adults B. Alexandrina, of the same size, were introduced in plastic acquaria for each experiment. The powdered organs extracted with methanol and the dried extracts were kept for testing as molluscicides. Different extracts proved to have molluscicidal activity against the vector of schistosomiasis, Biomphalaria alexandrina snails. LC50 values for C. viminalis fruits, bark and leaves were 6.2, 32 and 40 ppm respectively. The C. viminalis fruits extract showed the highest effect against the tested snails. Histopathological studies proved that the site of action of all tested extracts was localized in the digestive system and hermaphrodite gland.

General toxicity, antiproliferative, antibacterial and antioxidant activities of Caulerpa peltata J.V.Lamouroux (Caulerpaceae) collected from Oman Sea were investigated. Dried, ground alga was Soxhlet-extracted with hexane, dichloromethane and methanol successively. The methanol extract was subjected to vacuum liquid chromatography (VLC) fractionation on silica gel using a step gradient of different mixture of solvents. A known alkaloid, caulerpin, was subsequently isolated from the fraction eluted by ethyl acatete100%. The antioxidant activity of all extracts was assessed by using the (DPPH) assay. Antiproliferative activity of the all extracts and caulerpin against the cancerous cell line was evaluated using MTT assay. General toxicity of extracts was determined using Brine Shrimp Lethality Assay (BSLA). Based on our results, a weak activity observed for all extracts in MTT assay, while they were toxic toward brine shrimp nauplii comparing to the podophylotoxin. This is the first report on phytochemistry and bioactivity of C.peltata which collected from Oman Sea.

Several complications attributed with Herpes virus related infections and the emergence of drug resistant viruses prompt scientists to search for new drugs. Several terpenoids and coumarins have shown anti HSV effects while no sesquiterpene coumarin have been previously tested for HSV treatment. Three sesquiterpene coumarins [badrakemin acetate (1), kellerin (2) and samarcandin diasteromer (3) were isolated from the gum resin of Ferula assa-foetida, a herbal medicine with antimicrobial, antiprotozoal and antiviral effects. Compounds were identified by 1D and 2D- NMR spectroscopy and comparison with literature data. A comparative evaluation of cytotoxicity and anti-viral activity showed that kellerin (2) could significantly inhibit the cytopathic effects and reduce the viral titre of the herpes virus type 1 (HSV-1) DNA viral strains KOS at concentrations of 10, 5 and 2.5 µg/mL.

The HPTLC analysis, antioxidant, and antigout activity of Asparagus racemosus, Withania somnifera, Vitex negundo, Plumbago zeylanica, Butea monosperma and Tephrosia purpurea extracts were investigated. The chemical fingerprinting were carried out by high performance thin layer chromatography (HPTLC), antioxidant activity by ABTS, DPPH, FRAP radical scavenging assays, and antiogout activity by cow milk xanthine oxidase. The HPTLC fingerprint qualitatively revealed predominant amount of flavonoids. The TEAC values ranged from 45.80 to 140 µM trolox/100 g dry weight for ABTS, from 85 to 430 µM trolox/ 100 g dw DPPH, and 185 to 560 µM trolox/100 g dw for FRAP respectively. Plants used in this study was found to inhibit the toxicity, as seen from the decreased LPO and increased GSH, SOD and CAT levels. The total phenolic and flavonoid content ranged from 10.21 to 28.17 and 5.80 to 10.1 mg of gallic acid equivalents (GAE)/100 gdw respectively. The plant extracts demonstrated significant xanthine oxidase inhibitory activity at 100 g/ml and revealed an inhibition greater than 50 % and IC50 values below the standard. This effect was almost similar to the activity of allopurinol (Standard drug) against xanthine oxidase (90.2 ± 0.4 %). These plant root extract will be subjected for further extensive studies to isolate and identify their active constituents which are useful for against inflammation and gout.

The oldest method for the managing of the illness is the use of medicinal plants. The use of herbal products as the first choice in self-treatment of minor conditions continues to expand rapidly across Iran. This makes the safety of herbal products an important public health issue.Pesticides are used widely in agriculture to increase the production by controlling the harmful insects and disease vectors, however it has some hazards on biological system of human especially children. The present study evaluated the residual amount of organophosphorus pesticides (Diazinon and Chlorpyrifos) in children herbal medicines available in the Iranian market. Five children herbal medicine liquid dosage forms were purchased from pharmacy store. They were extracted with SPME (Solid Phase Microextraction) using the PDMS-DVB fibre. Then the extracts were injected into a GC. The gas chromatograph was Younglin model YL 6100 equipped with a flame ionization detector. The column was Technokroma 60 m length, 0.53 mm internal diameter and 1.25µm film coated. Standard curves showed the presence and quantity of diazinon and chlorpyrifos. Some herbal medicines had trace amounts of chlorpyrifos and diazinon. Based on European pharmacopeia, threshold limits of chlorpyrifos and diazinon residues for medicinal plant materials are 0.2 and 0.5 mg/kg respectively. Our analysis results showed that residue limits of these two pesticides in five children herbal medicines are ignorable. Key Word: Diazinon, Chlorpyrifos, SPME (Solid-Phase Microextraction), GC-FID, Children herbal medicine

Total phenolic contents (TPC) of five different extracts (petroleum ether, dichloromethane, ethyl acetate, ethanol and ethanol-water) of Artemisia biennis Willd were measured in this work. The antioxidant activity was investigated by three different β-carotene bleaching (BCB) test, 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging method and ferrous ion chelating (FIC) assay. Among all the extracts analyzed, the hydroethanolic extract exhibited a significantly higher phenolic content and antioxidant activity than other samples. Vacuum liquid chromatography of this extract yielded seven fractions (A to G) which were subjected to all aforementioned experiments. The highest total phenolic content and free radical scavenging activites were present in the same sample (Fraction D) but the only statistically significant correlation between TPC and EC50 values was observed for BCB.

The aim of this study was to evaluate the antibacterial effects of Thymus vulgaris, Thymus caramanicus, Zataria multiflora, Ziziphora clinopodioides and Ziziphora tenuior against four foodborne and four other bacteria including Staphylococcus aureus, Shigella dysenteriae, Salmonella typhimurium, Escherichia coli, Staphylococcus epidermidis, Bacillus subtilis, MRSA and Pseudomona aeruginosa and measuring the amount of total phenolics of the plants.The extracts were prepared by maceration method. Pre-evaluation of the antimicrobial effect was utilized by cup-plate technique and then Minimum Inhibitory Concentration was determined by agar dilution method according to NCCLS. The total phenolics as a possible cause of antibacterial effect, was measured by Folin-Ciocalteu colorimetry.The results showed that T. caramanicus and Z. multiflora were the most effective ones with MIC values between 0.78-3.125 mg/ml against all of the Bactria and Z. tenuior and Z. clinopodioides had the minimum antimicrobial activity. Total phenolic contents of these five plants were different and followed the general pattern of the antimicrobial effect.The antibacterial effects and the total phenolic content of T. caramanicus and Z. multiflora were remarkable and should be investigated more in future studies.

The aim of this investigation was to assess the in vitro interaction of two antifungal agents, econazole-nitrate and chelerythrine, against ten fluconazole-resistant clinical isolates and one ATCC type strain 10231 of Candida albicans. The checkerboard microdilution method was performed according to the recommendations of the National Committee for Clinical Laboratory Standards, and the results were determined by visual examination. The interaction intensity was tested in all isolates using the fractional inhibitory concentration index (FICI). These experiments showed synergism between econazole-nitrate and chelerythrine in antifungal activity against C. albicans, and no antagonistic activity was observed in any of the strains tested. Moreover, time-kill curves were performed with selected strains to confirm the positive interactions. The similarity between the results of the FICI values and the time-kill curves revealed that chelerythrine greatly enhances the antifungal effects of econazole-nitrate against isolates of C. albicans. This synergistic effect may markedly reduce the dose of econazole-nitrate required to treat candidiasis, thereby decreasing the econazole-nitrate toxic side effects. This novel synergism might provide a potential combination treatment against fungal infections.

The backbone of treatment in advanced non-small cell lung cancer is platinum-based doublet chemotherapy. We intended to compare the effectiveness of two commonly used regimens in real world practice. This single institute, parallel comparative post marketing study included 100 patients with chemo-naïve advanced (stage IIIB, IV) non-small cell lung cancer and Eastern Cooperative Oncology Group performance status of 0 to 2. They were randomly assigned by stratified blocks to receive Docetaxel/Cisplatin (DC, n=50) on day 1 or Paclitaxel/Carboplatin AUC 5 (PC, n=50) on day 1, every 3 weeks for up to six cycles. Primary end point was progression free survival (PFS); secondary end points were objective response rate, overall survival (OS) and toxicity. The administered dosage could be modified according to clinician’s discretion for each individual patient. PFS was similar between DC and PC arms (4.5±0.3 v 4.6±1.8 months, respectively; HR= 1.337; 95% CI: 0.874 to 2.046, P= 0.181). Although median overall survival for DC arm was longer (17.2±4.4 m) than PC arm (10.6±0.7 m) but was not statistically significant (P=0.300). The 1-year survival rates were in favor of DC arm (53.1% v 37.9%). Objective response rates were similar in both groups. In our study, hematologic toxicity and neuropathy were more frequent in DC and PC arms, respectively. In our study two commonly used regimens of DC and PC showed statistically similar outcomes in terms of PFS and OS, albeit numerically results of OS and 1-year survival were in favor of DC arm.

Heparin and enoxaparin possess anti-inflammatory properties. We compared the effects of these drugs on inflammatory biomarkers in patients with ST-segment Elevated Myocardial Infarction (STEMI). Thirty four patients with STEMI randomly separated in two groups and received standard doses of heparin and enoxaparin. The serum concentration of Serum Amyloid A (SAA), C-Reactive Protein (CRP), Interleukin (IL)-6, ferritin and Myeloperoxidase(MPO) were measured at baseline, 12, 24 and 48 hours after drug administration. Serum concentrations of SAA (P: 0.02), CRP (P: 0.02) and ferritin (P: 0.01) significantly reduced in heparin group during measurements compared to baseline, circulating levels of IL-6 (P: 0.002), SAA (P: 0.009), CRP (P: 0.01) were significantly decreased in enoxaparin group. The overall difference in inflammatory biomarkers between heparin and enoxaparin group was not significant. Both heparin and enoxaparine reduced serum levels of inflammatory biomarkers in patients with STEMI. This effect may provide additional clinical benefit of these drugs in the treatment of STEMI patients.

Ischemic stroke is amongst the top four causes of mortality and the leading cause of disability in the world. The aim of this study was to evaluate the efficacy of a high dose memantine on neurological function of patients with ischemic stroke. In a randomized, 2 armed, open-label study, patients with mild to moderate cerebral thromboembolic event (CTEE) who admitted to Imam Hossein Hospital, Tehran, Iran, during preceding 24 hours, entered the study. Patients allocated in two study groups of memantine (as add-on therapy) and control. All patients were managed based on the American Heart Association and American Stroke Association (AHA/ASA) guidelines. Patients in memantine group received conventional treatment plus memantine 20mg TID. The National Institute of Health Stroke Scale (NIHSS) was determined and recorded daily. The primary objective was comparison of the changes in NIHSS in the study groups at day 1 and day 5 of intervention. Significance level of p Patients were randomly allocated in control (15 women and 14 men, age 70.78±10.92 years) and memantine (16 women and 8 men, age 73.33±9.35 years) groups. There were no significant differences in age and sex distribution of two study groups as well as in comorbidities and concurrent drugs. NIHSS changes were significantly different between control (1.24±0.96) and memantine group (2.96±0.1), (p<0.0001). Our results reveal that memantine added to standard treatment of CTEE could result in a remarkable decrease in the NIHSS confirming improvement of the neurological function of the patients.

Timolol is a non-selective beta-adrenergic receptor antagonist administered for treating glaucoma, heart attacks and hypertension. In the present study, we set out to determine whether or not timolol can provoke cataract formation, thus the influence of timolol on the amyloid-type aggregation of crystallin was investigated. We then provided experimental evidence of crystallin aggregation and its induction by timolol using different spectroscopic measurements. Turbidimetric measurements as well as ThT fluorescence data indicated that timolol induce extent of crystallin amyloid formation. The kinetic of protein aggregation was also changed in presence of increasing concentrations of the drug suggesting that long-term drug administration may contribute to the development of cataract. Since the consequence of timolol-crystallin interaction has yet to be identified, additional data on it may help us to postpone amyloid cataract formation.

This study aimed to observe the effects of doxycycline (DOX) on gap junction remodeling after MI and the susceptibility of rats to cardiac arrhythmia. The proximal left anterior descending coronary artery of rats was ligated to establish a myocardial infarction animal model. DOX, methylprednisolone (MP), or vehicle was intraperitoneally injected into the animals for two weeks. Then, the heart size and heart function of all animals were determined through echocardiography. The experimental animals were sacrificed after the electrophysiologic study. Myocardial tissues were sampled to analyze the distribution of Cx43 using immunofluorescence; the Cx43 content was analyzed using western blot analysis; and the MMP-2 and MMP-9 activity in the myocardium was analyzed using gelatin zymography. The distribution of Cx43 in the border of the infarcted myocardia in the MI and MP groups was clearly disrupted and the Cx43 content was significantly reduced. In addition, the distribution of Cx43 in the border of the infarct in the DOX group was relatively regular, whereas two weeks of DOX treatment significantly inhibited MMP activity. Meanwhile, the induction rate of arrhythmia in the rats after DOX treatment was lower than those in the MI and MP groups. The results show that DOX treatment after myocardial infarction improves gap junction remodeling in the myocardial tissue near the infarcted area by inhibiting MMP activity and reducing susceptibility to cardiac arrhythmia.

This study aimed to explore and validate a new juvenile osteopenic (JO) rat model then examine the efficacy of moghat (Glossostemon bruguieri) as an alternative reversal therapy for JO. Phytochemical screening analysis showed that moghat contains 5.8% alkaloids, 1.5% flavonoids and 13.2% total phenols. Juvenile osteopenia was induced in 15 days old Sprague- Dawley female rats by feeding them free Ca and vitamin D synthetic diet for 21 days. Osteopenic rats were either treated with moghat (0.8g dried plant tissue/kg body weight, orally), or with a reference nutritional supplements of calcium chloride (14mg Ca /kg) and vitamin D3 (7 IU/kg), for extra 21 days. Both untreated and treated groups were compared to a control group that fed a regular pelleted food. our results showed that osteopenic rats lost normal bone tissue architecture, 30 % of body mass, 54 % of bone mass and finally 93% of bone calcium mass. Furthermore, these rats showed a markedly increase in serum phosphate, PTH, alkaline phosphatase, aspartate transaminase activities and creatinine level as compared to the control group. Moghat administration was successfully reversed osteopenia by normalizing body and bone masses to the reference ranges, increased the bone calcium mass by 17 fold without any detectable side effects on liver and kidney physiological performance. Therefore, moghat could be considered as potent safe –JO- reversal extract.

A “cocktail”of several probe drugs is often used to evaluate metabolic activity of multiple cytochrome P450 enzymes in one session. Some interactions among probe drugs can appear and may impact the rate of biotransformation of other ones. Our presented work was to aim on the influence of bupropion on rat cytochrome P450-mediated metabolism of tolbutamide. The biotransformation rates of tolbutamide administered either separately or in combined with bupropion were compared in this our study. The results revealed that bupropion had no significant effect on tolbutamide hydroxylation. Thus, due to stability in cytochrome P450 enzyme metabolic activity in the case of combining of two model probe drugs the procedure can show to no extent differential results comparing to the single-marker use.

Alismatis Rhizoma Decoction (ARD) is a classical Traditional Chinese Medicine (TCM) formula for treatment of vertigo with its long history of successful clinical effect. Since vertigo is a symptom of hyperlipidemia, this study aimed at evaluating the hypolipidemic effect of ARD in hyperlipidemia mice induced by high fat diet (HFD) and investigated the rationality of formula combination of Alismatis Rhizoma (AR) and Atractylodis Macrocephalae Rhizoma (AMR). Compared with control group, hyperlipidemia mice in AR and ARD groups displayed a reduction of following parameters: body weight, liver and serum total cholesterol, triglyceride concentration, liver and spleen coefficients, activities of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT); whereas the serum HDL-cholesterol levels were significantly elevated in both AR and ARD groups. AR and ARD treatments significantly down regulated the expressions of 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMG-CoA reductase) and sterol regulatory element binding factor-2 (SREBF-2). These findings clearly provided evidences that the suppression on biosynthesis of cholesterol in liver may in part contribute to the hypolipidemic effects of ARD and AR. Since no significantly hypolipidemic effect of AMR was observed, the more prominent effect of ARD than that of AR indicated synergistic effects of AR and AMR, and confirmed the rationality of ARD formula.

Persea americana is a plant used by traditional medicine practitioners to treat ailments including diarrhoea and diabetes mellitus in Nigeria. Hence, the chloroform and the methanol fractions of the chloroform-methanol extract of the leaves of P. americana were evaluated for their acute toxicity as well as anti-diarrhoeal effects in Wistar rats to substantiate this claim. The chloroform and methanol fractions [at graded doses of 100 and 200 mg/kg body weight (b.w) of each] were studied for their anti-diarrhoeal effects in terms of the reductions in the wetness of faeces and the frequency of defaecation of castor oil-induced diarrhoea. To understand the mechanism of their anti-diarrhoeal effects, their actions were further evaluated on castor oil-induced enteropooling (intestinal fluid accumulation). The median lethal dose (LD50) of the methanol fraction was found to be less than 5000 mg/kg b.w. At the two doses, the chloroform and the methanol fractions showed dose-dependent significant (p<0.05) reductions in the wetness of faeces and the frequency of defaecation with the 200 mg/kg b.w of the chloroform fraction being the most effective. Results of the fractions were comparable with those of the standard anti-diarrhoeal drug, hyoscine butylbromide (3 mg/kg b.w). Both fractions produced remarkable (p<0.05) dose-related inhibition of castor oil-induced enteropooling as shown by the significant (p<0.05) decreases in the weight and volume of the intestinal contents. Experimental findings show that the chloroform-methanol extract of the leaves of P. americana possesses significant anti-diarrhoeal effect and may be a potent source of anti-diarrhoeal drug(s) in future.

Human endometrium contains mesenchymal stem cells (eMSC) which have the ability to differentiate into three cell lineages and the potential in therapeutic applications. We hypothesize that using environmental induction in culture media such as dexamethasone, human recombinant insulin and human epidermal growth factor (hEGF) can differentiate endometrial stem cells into myoblast. These agents have a broad range of effects in myoblast differentiation in vitro. We used immunohystochemistry analysis and RT –PCR to evaluate the presence of skeletal muscle - specific proteins some of which are expressed in the early stage of differentiation including myoD and Desmin which expressed at later stages of differentiation. In conclusion eMSC can differentiate in culture media which contains above mentioned factors and use for therapeutic purpose in muscular degenerative disease.

Sophora pachycarpa Schrenk ex C.A.Mey. belongs to the family Fabaceae. Some species of the genus Sophora have shown to possess anti-proliferative and apoptosis-inducing activites in cancer cells. However, there is no available information addressing this effect in S. pachycarpa. Here, we investigated the cytotoxic effects of methanol extract and different fractions obtained from S. pachycarpa root on different cancer cell lines including A549, HeLa, HL-60, MCF-7, and PC3 cell lines and also leukocytes as non-malignant cells. Apoptotic cells were determined using PI staining of DNA fragmentation by flow cytometry (sub-G1 peak). The degree of DNA fragmentation was analyzed using agarose gel electrophoresis based on the formation of internucleosomal units. S. pachycarpa inhibited the growth of malignant cells in a dose-dependent manner and the CH2Cl2 fraction showed the lowest IC50 values ranging from 30 to 50 μg/mL in various cancer cell lines. HeLa cells as the most sensitive cells were chosen for further mechanistic studies. The sub-G1 peak in flow cytometry histogram of S. pachycarpa treated HeLa cells indicates apoptotic cell death in S. pachycarpa-induced toxicity. In conclusion, S. pachycarpa exerts cytotoxic effects in different cancer cell lines in which apoptosis plays an important role. Thus, S. pachycarpa could be considered as a potential chemotherapeutic agent in cancer treatment.

Edaravone, an antioxidant and radical scavenger, showed protective effects against oxidative stress-like condition. Paraquat (PQ) is a toxic herbicide considerable evidence suggests that oxidative stress and mitochondrial dysfunction contribute to PQ toxicity. In this study, protective effect of edaravone against PQ induced toxicity and reactive oxygen species (ROS) generation in A549 cells and lung isolated mitochondria were evaluated. A549 cells and lung isolated mitochondria were divided into control group, PQ group, edaravone group and PQ plus edaravone-pretreated group. Cellular and mitochondrial viability assayed using MTT test and ROS generations in both cellular and mitochondrial fraction were determined by fluorometry using DCFH-DA as indicator.Our results showed that edaravone (5–100 µM) prevented PQ (500 µM) induced cytotoxicity in A549 cells that the best protective effect was observed at concentration of 50 µM of edaravone. In addition, PQ-induced ROS generation in A549 cells significantly inhibited by edaravone. Moreover, PQ decreased mitochondria viability and also increased ROS generation in lung isolated mitochondria that edaravone (25–400 µM) markedly inhibited these toxic effects. In overall, the results of this study suggest that lung mitochondria maintenance is essential for maintaining PQt cytotoxicity and Edaravone is a protective drug against PQ toxicity in vitro.

It has been reported that CXCL12 binding to CXCR4 induces several intracellular signaling pathways, and enhances survival, proliferation, and migration of malignant cells. Herein we examined the effects of anti-estrogen tamoxifen and anti-allergic tranilast drugs as a single or in combination on invasion by two in vitro invasion assays, wound-healing and matrigel invasion on MCF-7 and MDA-MB-231 human breast cancer cell lines. The mRNA expression levels of CXCR4 and CXCL12 were measured by quantitative real time-RT PCR and CXCL12 protein levels were evaluated by ELISA assay. The data showed that treatment with tamoxifen and tranilast as a single or in combination resulted in decreased CXCR4 and CXCL12 mRNA and CXCL12 protein expression levels. Both in vitro invasion assays markedly showed synergistic effect of tamoxifen when combined with tranilast drug. Either ER-positive or ER-negative breast cancer cells were sensitive to this combination therapy. In conclusion, tranilast increases antimetastatic effect of tamoxifen. The synergistic effect of tranilast is not estrogen dependent; however tamoxifen may sensitize the cells for the action of tranilast. The data also support the importance of the CXCR4/CXCL12 interaction in breast cancer metastasis, and further suggest that CXCR4 and CXCL12 are critical targets for tamoxifen and tranilast in combination or alone.

Neurodegeneration is the pathophysiological basis for permanent neurological disabilities in multiple sclerosis (MS); thus neuroprotection is emerging as a therapeutic approach in MS research. Modulation of excitotoxicity by inhibition of NMDARs has been suggested for neuroprotection, but selective antagonisation of the NR2B subtype of these receptors, a subtype believed to play a more pivotal role in neurodegeneration, has not been tested in MS. In this study inhibition of NR2B-containing NMDAR was evaluated on the animal model of MS, experimental autoimmune encephalomyelitis (EAE). EAE induction was done using MOG in C57BL/6 mice. Therapeutic administration of different doses of highly selective NR2B-containing NMDAR inhibitor (RO25-6981) was compared with memantine (non-selective NMDAR antagonist) and vehicle. Neurological deficits in EAE animals were more efficiently decreased by selective inhibition of NR2B-containing NMDARs. Histological studies of the spinal cords also showed decreased inflammation, myelin degradation and neuro-axonal degeneration when RO25-6981was administered with higher doses. The effects were dose dependent. Regarding the role of NR2B-containing NMDARs in excitotoxicity, selective inhibition of these receptor subtypes seems to modulate the neurological disabilities and pathological changes in EAE. Further elucidation of the exact mechanism of action as well as more experimental studies can suggest NR2B-containing NMDAR inhibition as a potentially effective treatment strategy for slowing down the clinical deterioration of disability in MS.

Low calorie diets are always difficult for obese subjects to follow and lead to metabolic and behavioral adaptation. Therefore, we evaluated the effect of caffeine treatment with calorie shifting diet (CSD) on weight loss. Female subjects (n=98; BMI≥25) completed 4-weeks control diet, 6-weeks CSD (3 repeated phases; each 2-weeks) and 4-weeks follow-up diet, with or without caffeine treatment (5mg/kg/day). The first 11 days of each phase included calorie restriction with four meals every day and 4 hours intervals. Significant weight and fat loss were observed after 4-weeks of CSD (5.7 ±1.24 kg and 4.84±1.53 kg) or CSD+Caffeine (7.57±2.33 kg and 5.24±2.07 kg) which was consistent for one month of the follow-up (CSD: 5.24±1.83 kg and 4.3±1.62 kg, CSD+Caffeine: 12.11±2.31 kg and 9.85±1.6 kg, pThese findings indicated that combination of caffeine treatment with CSD could be an effective alternative approach to weight and fat loss with small changes in RMR and improved tolerance of subjects to the new diet.

Boswellia has been widely used in traditional medicine for the treatment of different diseases such as cancer in Iran. The aim of this study was to evaluate the effect of the gum methanol extract of Boswellia thurifera on the viability and P53 gene expression of cultured breast cancer cells. The gum methanol extract was obtained in various concentrations using the maceration method. Normal (HEK-293) and cancer (MDA-MB-231) human cells were cultured and treated with various concentrations of the extract. Then MTT assay was used for the study of cytotoxic effect of the extract and real time PCR method was also applied for the investigation of P53 gene expression in cancer cells. The IC50 of the extract against cancer cells was 80 µg/ml and had less cytotoxic effect in normal cells. The effect of the extract was dose dependent. Induction of P53 expression by extract was also significantly more in treated cancer cells than untreated cells. This inductive effect in cells was higher after 12 h treatment than it was after 6 h. The results of the current study show that gum methanol extract of Boswellia thurifera has probably anti-cancer effects and could induce P53 gene transcription and toxicity in the cultured breast cancer cell line. The increase of P53 gene specific mRNA may be a mechanism of gum methanol extract induced cytotoxicity. However, for a definitive conclusion, further studies on other cell lines as well as animal models and subsequent clinical studies are warranted.

Implementation of electronic prescribing system can overcome many problems of the paper prescribing system, and provide numerous opportunities of more effective and advantageous prescribing. Successful implementation of such a system requires complete and deep understanding of work content, human force, and workflow of paper prescribing. The current study was designed in order to model the current business process of outpatient prescribing in Iran and clarify different actions during this process. In order to describe the prescribing process and the system features in Iran, the methodology of business process modeling and analysis was used in the present study. The results of the process documentation were analyzed using a conceptual model of workflow elements and the technique of modeling “As-Is” business processes. Analysis of the current (as-is) prescribing process demonstrated that Iran stood at the first levels of sophistication in graduated levels of electronic prescribing, namely electronic prescription reference, and that there were problematic areas including bottlenecks, redundant and duplicated work, concentration of decision nodes, and communicative weaknesses among stakeholders of the process. Using information technology in some activities of medication prescription in Iran has not eliminated the dependence of the stakeholders on paper-based documents and prescriptions. Therefore, it is necessary to implement proper system programming in order to support change management and solve the problems in the existing prescribing process. To this end, a suitable basis should be provided for reorganization and improvement of the prescribing process for the future electronic systems.