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1.  LC-MS Method for Studying the Pharmacokinetics and Bioequivalence of Clonidine Hydrochloride in Healthy Male Volunteers 
A simple and sensitive high performance liquid chromatography-electrospray ionization mass spectrometry method has been evaluated for the assignment of clonidine hydrochloride in human plasma.
The mobile phase composed of acetonitrile-water 60:40 (v/v) and 0.2% formic acid 20 μl of sample was chromatographically analyzed using a repacked ZORBAX-XDB-ODS C18 column (2.1 mm×30 mm, 3.5 μ). Detection of analytes was achieved by tandem mass spectrometry with Electrospray Ionization (ESI) interface in positive ion mode operated under the multiple-reaction monitoring mode (m/z 230.0 →213). Sample pretreatment consisted of a one-step Protein Precipitation (PPT) with methanol and perchloric acid (HClO4) of 0.10 ml plasma.
Standard curve was linear (r=0.998) over the concentration range of 0.01–10.0 ng/ml and showed suitable accuracy and precision. The Limit of Quantification (LOQ) was 0.01 ng/ml. The mean (SD) Cmax, Tmax, AUC0–t and AUC0–∞ values after administration of the test and reference formulations, respectively, were in this manner: 6.16 (0.32) versus 6.21 (0.07) ng/ml, 30.12 (0.86) versus 30.13 (0.73) hr, 290.37 (1.13) versus 293.39 (1.22) ng/ml/hr, and 350.17 (1.98) versus 352.96 (1.67) ng/ml/hr. The mean (SD) t1/2 was 120.12 (1.90) hr for the test formulation and 120.96 (1.54) hr for the reference formulation. No statistical differences were showed for Cmax and the area under the plasma concentration-time curve for test and reference tablets.
The method is rapid, simple, very steady and precise for the separation, assignment, pharmacokinetic and bioavailability evaluation of clonidine in healthy Iranian adult male volunteers.
PMCID: PMC4842247  PMID: 27141268
Clonidine hydrochloride; High performance liquid chromatography; Pharmacokinetics
2.  Simple and Sensitive High-Performance Liquid Chromatography (HPLC) Method with UV Detection for Mycophenolic Acid Assay in Human Plasma. Application to a Bioequivalence Study 
Advanced Pharmaceutical Bulletin  2015;5(4):563-568.
Purpose: A simple and available reversed-phase high performance liquid chromatography (HPLC) method with UV detection has been developed and validated for mycophenolic acid (MPA) assay in human plasma.
Methods: MPA was extracted from plasma with protein precipitation method by acetonitrile: percholeric acid: methanol (75:5:20 v/v/v). The drug separation was achieved using a C8 analytical column and a mobile phase of 0.1M triethylammonium phosphate (pH=5.4)-acetonitril (65:35, v/v), with a flow rate of 1.5 ml/min. The detection wavelength was 304 nm. Limit of detection (LOD) of the method was determined as the lowest MPA concentration producing a signal-to-noise (S/N) ratio of about 3. Limit of quantitation (LOQ) was determined as the lowest MPA concentration capable of being quantitated with enough accuracy and precision.
Results: The method showed significant linear response-concentration relationship throughout the MPA concentration range of 0.2-10 µg/ml. A typical linear regression equation of the method was: y = 8.5523 x + 0.094, with x and y representing MPA concentration (in µg/ml) and peak height respectively, and the regression coefficient (r) of 0.9816. The average within-run and between-run variations of 7.81 and 4.78 percent. The average drug recovery from plasma was 95.24 percent throughout the linear concentration range. The limits of detection (LOD) and quantitation (LOQ) of the method were 0.05 and 0.2 µg/ml, respectively. The practical applicability of the method was proven throughout a bioequivalence study.
Conclusion: The results showed the acceptable degree of linearity, sensitivity, precision, accuracy and recovery for the method. The method was used successfully for quantitation of MPA in plasma samples of healthy volunteers throughout a bioequivalence study.
PMCID: PMC4729343  PMID: 26819930
Mycophenolic acid (MPA); Mycophenolic acid (MPA) assay; Reversed-phase HPLC
3.  Repaglinide-loaded solid lipid nanoparticles: effect of using different surfactants/stabilizers on physicochemical properties of nanoparticles 
Repaglinide is an efficient anti-diabetic drug which is prescribed widely as multi-dosage oral daily regimens. Due to the low compliance inherent to each multi-dosage regimen, development of prolonged-release formulations could enhance the overall drug efficacy in patient populations.
Repaglinide-loaded solid lipid nanoparticles (SLNs) were developed and characterized in vitro. Various surfactants were used in this study during the nanocarrier preparation procedure and their corresponding effects on some physicochemical properties of SLNs such as size, zeta potential; drug loading parameters and drug release profiles was investigated. Stearic acid and glyceryl mono stearate (GMS) were used as lipid phase and phosphatidylcholin, Tween80, Pluronic F127, poly vinyl alcohol (PVA) and polyvinyl pyrrolidone (PVP) were used as surfactant/stabilizer.
The results showed some variations between formulations; where the Tween80-based SLNs showed smallest size, the phosphatidylcholin-based SLNs indicated most prolonged drug release time and the highest loading capacity. SEM images of these formulations showed morphological variations and also confirmed the nanoscale size of these particles. The FTIR and DSC results demonstrated no interaction between drug and excipients. The invitro release profiles of different formulations were studied and observed slow release of drug from all formulations. However significant differences were found among them in terms of their initial burst release as well as the whole drug release profile. From fitting these data to various statistical models, the Peppas model was proposed as the best model to describe the statistical indices and, therefore, mechanism of drug release.
The results of this study confirmed the effect of surfactant type on SLNs physicochemical properties such as morphological features, loading parameters, particle sizes and drug release kinetic. With respect to the outcome data, the mixture of phosphatidylcholin/Pluronic F127 was selected as the best surfactant/stabilizer to coat the lipid core comprising stearic acid and GMS.
PMCID: PMC4578325  PMID: 26392174
4.  The impact of polymer coatings on magnetite nanoparticles performance as MRI contrast agents: a comparative study 
Superparamagnetic iron oxide nanoparticles (SPIONs) are the most commonly used negative MRI contrast agent which affect the transverse (T2) relaxation time. The aim of the present study was to investigate the impact of various polymeric coatings on the performance of magnetite nanoparticles as MRI contrast agents.
Ferrofluids based on magnetite (Fe3O4) nanoparticles (SPIONs) were synthesized via chemical co-precipitation method and coated with different biocompatible polymer coatings including mPEG-PCL, chitosan and dextran.
The bonding status of different polymers on the surface of the magnetite nanoparticles was confirmed by the Fourier transform infrared spectroscopy (FT-IR) and thermogravimetric analysis (TGA). The vibrating sample magnetometer (VSM) analysis confirmed the superparamagnetic behavior of all synthesized nanoparticles. The field–emission scanning electron microscopy (FE-SEM) indicated the formation of quasi-spherical nanostructures with the final average particle size of 12–55 nm depending on the type of polymer coating, and X-ray diffraction (XRD) determined inverse spinel structure of magnetite nanoparticles. The ferrofluids demonstrated sufficient colloidal stability in deionized water with the zeta potentials of −24.2, −16.9, +31.6 and −21 mV for the naked SPIONs, and for dextran, chitosan and mPEG-PCL coated SPIONs, respectively. Finally, the magnetic relaxivities of water based ferrofluids were measured on a 1.5T clinical MRI instrument. The r2/r1 value was calculated to be 17.21, 19.42 and 20.71 for the dextran, chitosan and mPEG-PCL coated SPIONs, respectively.
The findings demonstrated that the value of r2/r1 ratio of mPEG-PCL modified SPIONs is higher than that of some commercial contrast agents. Therefore, it can be considered as a promising candidate for T2 MRI contrast agent.
PMCID: PMC4574187  PMID: 26381740
5.  pH-Triggered Magnetic-Chitosan Nanogels (MCNs) For Doxorubicin Delivery: Physically vs. Chemically Cross Linking Approach 
Advanced Pharmaceutical Bulletin  2015;5(1):115-120.
Purpose: This paper evaluates the impact of cross linking strategy on the characteristics of magnetic chitosan nanogels (MCNs) as targeted drug delivery system for doxorubicin.
Methods: Sodium tripolyphosphate (TPP) and glutaraldehyde were used as physical (electrostatic) and chemical (covalent binding) cross-linker agents, respectively. MCNs were characterized by means of X-ray diffraction (XRD), Scanning electron microscopy (SEM), fourier transform infrared (FT-IR) spectroscopy and vibrating sample magnetometer (VSM). Scanning electron microscopy (SEM) indicated the formation of spherical nanostructures with the final average particle size of around 35-40 nm.
Results: The finding proved the superparamagnetic properties of the MCNs with relatively high-magnetization values which indicate that the MCNs were enough sensitive to external magnetic fields as a magnetic drug carrier. To understand the differences between the drug delivery properties of chemically and physically cross linked MCNs, the drug release studies were also conducted. Altogether, the results of this study clearly indicate that, however, both MCNs exhibited sustained drug release behaviour, the chemically cross linked MCNs provided enhanced controlled drug release characteristics in comparison to physically cross linked MCNs. Besides, according to the drug release behaviour of MCNs in buffer solutions in two different medium with the pH values of 5.3 and 7.4, it was clear that both nanoparticles exhibited pH sensitivity where the extent of drug release in the acidic media was significantly higher than neutral media.
Conclusion: It can be concluded that chemically cross linked MCNs may serve as an ideal carrier for stimuli-triggered and controlled anticancer drug delivery.
PMCID: PMC4352213  PMID: 25789228
Magnetite; Chitosan; Doxorubicin; Nanocomposites
6.  Artemia salina as a model organism in toxicity assessment of nanoparticles 
Because of expanding presence of nanomaterials, there has been an increase in the exposure of humans to nanoparticles that is why nanotoxicology studies are important. A number of studies on the effects of nanomatrials in in vitro and in vivo systems have been published. Currently cytotoxicity of different nanoparticles is assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay on different cell lines to determine cell viability, a tedious and expensive method. The aim of this study was to evaluate the Artemia salina test in comparison with the MTT assay in the assessment of cytotoxicity of nanostructures because the former method is more rapid and convenient and less expensive.
At the first stage, toxicity of different nanoparticles with different concentrations (1.56–400 μg/mL) was measured by means of the brine shrimp lethality test. At the second stage, the effect of nanoparticles on the viability of the L929 cell line was assessed using the MTT assay. Experiments were conducted with each concentration in triplicate.
The results obtained from both tests (A. salina test and MTT assay) did not have statistically significant differences (P > 0.05).
These findings suggest that the A. salina test may expedite toxicity experiments and decrease costs, and therefore, may be considered an alternative to the in vitro cell culture assay.
PMCID: PMC4344789  PMID: 25888940
Artemia salina; Toxicity; Nanoparticle; Cell culture
7.  Synthesis and characterization of dextran coated magnetite nanoparticles for diagnostics and therapy 
BioImpacts : BI  2015;5(3):141-150.
Introduction: Expansion of efficacious theranostic systems is of pivotal significance for medicine and human healthcare. Magnetic nanoparticles (MNPs) are known as drug delivery system and magnetic resonance imaging (MRI) contrast agent. MNPs as drug carriers have attracted significant attention because of the delivery of drugs loaded onto MNPs to solid tumors, maintaining them in the target site by an external electromagnetic field, and subsequently releasing drugs in a controlled manner. On the other hand, it is believed that MNPs possess high potential as MRI contrast agents. The aim of this work was to payload curcumin into dextran coated MNPs and investigate their potential as theranostic systems for controlled drug delivery and MRI imaging.
Methods: MNPs were synthesized as a core and coated with dextran as polymeric shell to provide steric stabilization. Curcumin as anticancer drug was selected to be loaded into NPs. To characterize the synthesized NPs, various techniques (e.g., DLS, FESEM, FT-IR, XRD, and VSM) were utilized. In vitro drug release of curcumin was evaluated at 37˚C at the pH value of 5.4 and 7.4.The feasibility of employment of dextran coated MNPs as MRI contrast agents were also studied.
Results: Formulations prepared from dextran coated MNPs showed high loading (13%) and encapsulation efficiency (95%). In vitro release study performed in the phosphate-buffered saline (PBS, pH= 7.4, 5.4) revealed that the dextran coated MNPs possess sustained release behavior at least for 4 days with the high extent of drug release in acidic media. Vibrating sample magnetometer (VSM) analysis proved the superparamagnetic properties of the dextran coated MNPs with relatively high-magnetization value indicating that they were sufficiently sensitive to external magnetic fields as magnetic drug carriers. Furthermore, dextran coated MNPs exhibited high potential as T2 contrast agents for MRI.
Conclusion: Based on our findings, we propose the dextran coated MNPs as promising nanosystem for the delivery of various drugs such as curcumin and MRI contrast agent.
PMCID: PMC4597162  PMID: 26457252
Magnetic nanoparticles; Curcumin; Dextran; MRI contrast agent
8.  Biodegradable m-PEG/PCL Core-Shell Micelles: Preparation and Characterization as a Sustained Release Formulation for Curcumin 
Advanced Pharmaceutical Bulletin  2014;4(Suppl 2):501-510.
Purpose: Among the potent anticancer agents, curcumin is known as a very efficacious against many different types of cancer cells, but its clinical applications has been limited because of hydrophobicity, low gastrointestinal absorption, poor bioavailability and rapid metabolism. In this way, a novel micellar delivery system with mPEG–PCL was synthesized and the release profile of the curcumin from the drug-loaded micelles was evaluated.
Methods: In this study, curcumin was encapsulated within monomethoxypoly(ethylene glycol)-poly(ε-caprolactone) (mPEG-PCL) micelles through a single-step nano-precipitation method, leading to creation of curcumin-loaded mPEG-PCL (Cur/mPEG-PCL) micelles. Di-block mPEG-PCL copolymers were synthesized and used to prepare micelles. mPEG-PCL copolymer was characterized in vitro by HNMR, FTIR, DSC and GPC techniques. Then, mPEG–PCL copolymers with curcumin were self-assembled into micelles in aqueous solution. The resulting micelles were characterized further by various techniques such as dynamic light scattering (DLS) and atomic force microscopy (AFM).
Results: The findings showed the successful formation of smooth and spherical curcumin-loaded micelles. The encapsulation efficiency of curcumin was 88 ± 3.32%. The results of AFM revealed that the micelles have spherical shapes with size of 73.8 nm. The release behavior of curcumin from micelles was compared in different media. In vitro release of curcumin from curcumin-entrapped micelles was followed remarkably sustained profile. The sustained release of drug was hypothetically due to the entrapment of curcumin in core of micelles.
Conclusion: The results indicate the successful formulation of curcumin loaded m-PEG/PCL micelles. From the results, iIt can be concluded that curcumin m-PEG-PCL micelles may be considered as an effective treatment strategy for cancer in the future.
PMCID: PMC4312397  PMID: 25671181
mPEG-PCL; Micelles; Curcumin; Drug delivery
9.  The Anticancer Agent Prodigiosin Is Not a Multidrug Resistance Protein Substrate 
DNA and Cell Biology  2013;32(3):90-97.
The brilliant red pigments prodiginines are natural secondary metabolites that are produced by select species of Gram-negative and Gram-positive bacteria. These molecules have received significant attention due to their reported antibacterial, antifungal, immunosuppressive, and anticancer activities. In this study, a Serratia marcescens SER1 strain was isolated and verified using 16s rDNA. The prodigiosin was purified using silica chromatography and was analyzed by 1H-NMR spectroscopy. The cell cytotoxic effects of the purified prodigiosin on multiple drug resistant cell lines that overexpress MDR1, BCRP, or MRP2 pumps were analyzed. Prodigiosin had nearly identical cytotoxic effects on the resistant cells in comparison to their parental lines. In agreement with the same prodigiosin cytotoxicity, FACS analysis of prodigiosin accumulation and efflux in MDR overexpressing cell lines also indicated that this pro-apoptotic agent operates independently of the presence of the MDR1, BCRP, or MRP transporter and may be a potential treatment for malignant cancer cells that overexpress multidrug resistance transporters.
The anticancer agent prodigiosin is not a multidrug resistance protein substrate. Prodigiosin, produced by Serratia marcescens, has cytotoxic effects on cells irrespective of whether the cells express MDR1, MRP2, or BCRP pumps of the multidrug resistance families. Therefore this drug may be potentially useful as a treatment for malignancies that overexpress the MDR pumps.
PMCID: PMC3589871  PMID: 23373476
10.  Modeling of thermodynamic and physico-chemical properties of coumarins bioactivity against Candida albicans using a Levenberg–Marquardt neural network 
In recent years, due to vital need for novel fungicidal agents, investigation on natural antifungal resources has been increased. The special features exhibited by neural network classifiers make them suitable for handling complex problems like analyzing different properties of candidate compounds in computer-aided drug design. In this study, by using a Levenberg–Marquardt (LM) neural network (the fastest of the training algorithms), the relation between some important thermodynamic and physico-chemical properties of coumarin compounds and their biological activities (tested against Candida albicans) has been evaluated. A set of already reported antifungal bioactive coumarin and some well-known physical descriptors have been selected and using LM training algorithm the best architecture of neural model has been designed for forecasting the new bioactive compounds.
PMCID: PMC3170013  PMID: 21918627
Levenberg/Marquardt algorithm; coumarin; neural network

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