Iranian Journal of Pharmaceutical Research
Volume:14 Issue: 4, Autumn 2015

In-vitro labeling of RBC with 99mTc is an intricate procedure and there is always a need for an alternate blood pool imaging agent. The aim of this study was to prepare an effective nano sized liposome (NLs) similar to human RBC for blood pool scintigraphy. This study formulates PEG-NLs and non-PEG-NLs using film method plus high pressure homogenization technique. Biodistribution studies were performed on BALB/C mice 1, 4 and 24 h after tail vein injection of labeled NLs with 99mTc hexamethylpropylene-amine-oxime (99mTc-HMPAO). Planar images were acquired using a 256 × 256 matrix following99m Tc-HMPAO-NLs injection into ear vein of rabbits 1, 2 and 24 h later. SPECT images were obtained 15 minutes after the injection (64 slices, 30 second/projection). The mean diameter, zeta potential and polydispersity index (PDI) of the PEG-NLs and the NLs were (80.88 ± 0.594 nm, -12.5 ± 0.56 mv, 0.158 ± 0.025) and (94.14 ± 0.114 nm, -35.5 ± 0.67 mv and 0.198 ± 0.007), respectively. 99mTc-HMPAO PEG-NLs showed a significant circulation tracer activity (7.74 ± 1.63%ID/g at 1 h and 4.9 ± 0.77 %ID/g at 4 h), with low liver accumulation (12.07 ± 3.66 %ID/g at 1 h and 14.85 ± 1.3 %ID/g at 4 h). Heart to liver, spleen and background ROIs (region of interests) for 99m c-HMPAO-PEG NLs were 1.25, 4 and 4.28 respectively at 2 h which changed to 1.06, 1.75 and 2.51 respectively at 24 h. The 99mTc-HMPAO-PEG-NLs with a prolonged blood circulation time could be an excellent RBC alternative for scintigraphy and gastrointestinal bleeding.

Solid lipid nanoparticles of atovaquone (ATQ-SLN) were prepared by high shear homogenization method using tripalmitin, trilaurin, and Compritol 888 ATO as the lipid matrices and Phospholipon 90H, Tween 80, and poloxamer 188 as the surfactants. Optimization of the formulations was conducted using 6 sets of 24 full-factorial design based on four independent variables that were the number of homogenizing cycles, concentration of the lipid, concentration of the co-surfactant, and concentration of the main surfactant. The dependent variables were particle size and polydispersity index (PdI). The homogenizing cycles showed a negative influence on the dependent variables which reduced both the particle size and the PdI value. Moreover, a combination of certain percentages of the main surfactant and co surfactant also showed a negative influence that reduced both the particle size and PdI value. Selected formulations from each design were further characterized for the entrapment efficiency and yield. The optimised formulation of ATQ-SLN consisted of trilaurin, Phospholipon 90H and Tween 80 with a particle size of 89.4 ± 0.2 nm and entrapment efficiency of 83.0 ± 1.7%. The in-vitro release evaluation of the formulation showed a complete and immediate release of ATQ from the SLN that could be a solution to improve the poor aqueous solubility and hence poor bioavailability of the drug.

Some drugs have low bioavailability due to their poor aqueous solubility and/or slow dissolution rate in biological fluids. Stiripentol (STP) is a novel anticonvulsant drug that is structurally unrelated to the currently available antiepileptics. It has poor aqueous solubility and its solubility has to be enhanced accordingly. Polyethyleneglycol 6000 (PEG-6000) is commonly utilized as a hydrophilic carrier for poorly water soluble drugs in order to improve their bioavailability. STP and PEG-6000 binary system was obtained by physical mixture, solvent evaporation, co-evaporation and melting methods using different weight ratios. The properties of the prepared binary systems were evaluated using dissolution rate, phase solubility, Fourier-transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC) and scanning electron microscope (SEM) studies. The FTIR spectroscopic studies showed the stability of STP and absence of STP-PEG-6000 interaction. The DSC and SEM studies indicated the amorphous state of STP in its binary systems with PEG-6000. Dissolution profile of STP was significantly improved via complexation with PEG-6000 as compared with the pure drug. The binary system which was prepared using melting method showed the highest dissolution rate. The promising results of the prepared binary systems open the avenue for further oral formulation of STP.

One of the most significant issues in pharmaceutical industries, prior to commercialization of a pharmaceutical preparation is the “preformulation” stage. However, far too attention has been paid to verification of the software assisted statistical designs in preformulation studies. The main aim of this study was to report a step by step preformulation approach for a semisolid preparation based on a statistical mixture design and to verify the predictions made by the software with an in-vitro efficacy bioassay test. Extreme vertices mixture design (4 factors, 4 levels) was applied for preformulation of a semisolid Povidone Iodine preparation as Water removable ointment using different PolyEthylenGlycoles. Software Assisted (Minitab) analysis was then performed using four practically assessed response values including; Available iodine, viscosity (N index and yield value) and water absorption capacity. Subsequently mixture analysis was performed and finally, an optimized formulation was proposed.The efficacy of this formulation was bioassayed using microbial tests in-vitro and MIC values were calculated for Escherichia coli, pseudomonaaeruginosa, staphylococcus aureus and Candida albicans. Results indicated the acceptable conformity of the measured responses. Thus, it can be concluded that the proposed design had an adequate power to predict the responses in practice. Stability studies, proved no significant change during the one year study for the optimized formulation. Efficacy was eligible on all tested species and in the case of staphylococcus aureus;the prepared semisolid formulation was even more effective.

Thymol, an important and advantageous component of many essential oils, has been applied as an antimicrobial agent in animals. To increase the duration of action of this compound in ruminants, it was decided here to prepare a controlled release carrier for thymol. Hydroxy propyl methyl cellulose (HPMC) and ethyl cellulose (EC) were used as the matrix polymer here. Mixtures of thymol with eight different ratios of these polymers were then prepared using emulsion solvent evaporation method (F1 to F8). The prepared microparticles were evaluated for production yield, entrapment efficiency, drug content, particle size, drug release behavior, release kinetics (zero order, first order and Fickian matrix diffusion for spheres) and characterized by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). Mean particle size of microparticles was 1.03 ± 0.02 mm. SEM study revealed that the microparticles were slightly irregular, rough and porous. The formulation with HPMC: EC ratio of 5:1 (F6) showed the highest drug loading (38.8%) and entrapment efficiency 61.2%). This formulation also showed optimum in-vitro drug release. The best fit of release kinetics was achieved with Fickian matrix diffusion for spheres (linear amount released vs t0.43). The FTIR spectroscopic and DSC studies show possible interaction between drug and polymers. In this study, thymol was successfully loaded in microparticles prepared from HPMC and EC. These microparticles can be used in further trials to evaluate the effect of slow release thymol on rumen fermentation parameters in ruminants.

The solubility of naproxen in binary mixtures of polyethylene glycol 200 (PEG 200) + water at the temperature range from 298.0 K to 318.0 K were reported. The combinations of Jouyban-Acree model + van’t Hoff and Jouyban-Acree model + partial solubility parameters were used to predict the solubility of naproxen in PEG 200 + water mixtures at different temperatures. Combination of Jouyban-Acree model with van’t Hoff equation can be used to predict solubility in PEG 200 + water with only four solubility data in mono-solvents. Theobtained solubility calculation errors vary from ~ 17 % up to % depend on the number of required input data.Non-linear enthalpy-entropy compensation was found for naproxen in the investigated solvent system and the Jouyban−Acree model provides reasonably accurate mathematical descriptions of the thermodynamic data of naproxen in the investigated binary solvent systems.

A rapid, sensitive and reproducible HPLC method was developed and validatedfor the analysis of amifostine (AMF) and/or its metabolite, WR-1065 inhuman plasma. The method involves the alkylation of free sulfydryl group with iodoacetic acid followed by derivatization of the drug and its metabolite witho-phthaldialdehyde (OPA) andUVdetection at 340 nm. The derivatized AMF and WR-1065 were eluted inless than 11 min, and in the case of the metabolite with no interferences from the endogenous plasma peaks. Cystein was used as the internal standard. Analysis was carried out on a Eurosphere Performance (RP-18e, 100 × 4.6 mm) analytical column. The mobile phase was a mixture of methanol and phosphate buffer 0.03 M pH = 2.7 at a ratio of 40: 60v/v, respectively, with a flow rate of 1.5 mLmin-1.Limit of detection was 0.5µgmL-1.The method involved a simple extraction procedure for AMF and/or its metabolite and analytical recovery was 90 ± 0.9%.The calibration curve was linear over the concentration range of 1-200 µgmL-1. The coefficients of variationfor intra-day and inter-day assayswere less than 10%.

Fluvoxamine maleate is a selective serotonin reuptake inhibitor, which is used for the treatment of different types of depressive disorders. In the present study, a stability indicating HPLC method was developed and validated for the determination of fluvoxamine maleate. The chromatographic separation was carried out using a Nova-Pak CN column and a mixture of K2HPO4 50 mM (pH 7.0) and acetonitrile (60: 40, v/v) as the mobile phase. Target compounds were detected using a UV detector set at 235 nm. The developed method was linear over the concentration range of 1-80 μg/ml with acceptable precision (CV values < 2.0%) and accuracy (error values < 1.6%). The degradation studies showed that fluvoxamine maleate is relatively unstable under acidic, basic and oxidative conditions and also when exposed to UV radiation. On the other hand, the bulk powder of fluvoxamine maleate was relatively stable when exposed to visible light or heat. The proposed method was successfully applied for the determination of active ingredient of fluvoxamine dosage form without any interference from tablet excipients.

Recent studies have indicated that 1, 4-dihydropyridine-3, 5-dicarboxamidederivativesshow significant anti-tubercular activity. In this research, new derivatives of 1, 4-dihydropyridine were designed and synthesized using Hantzsch condensation in which dicyclohexyl and different dicyclohexylcarbamoylwere substituted at C-3 and C-5 positions of the DHP ring.In addition, 4 (5)-chloro-2-methyl-5 (4)-imidazolylmoiety was substituted at C-4 position of DHP.The structure of synthetized compounds were characterized by TLC, IR, elemental analysis and proton NMR.Based on the in-vitro screening data, all of the designed and synthetized compounds (3a-3g)showed agood ability to inhibit the mycobacterium tuberculosis growth in terms of MIC. Aromatic carboxamide containing compounds were more potent than cyclohexylderivative and the most potent compound was 3a (4-nitrophenyl derivative). The experimental data are in agreement with our computational predictions in terms of partial atomic charge of carbonyl moieties at the C-3 and C-5 positions of DHP ring and partition coefficient of the molecules.

A series of indole-based aryl(aroyl)hydrazone analogs of antiplatelet indole-3 carboxaldehyde phenylhydrazone were synthesized by the Schiff base formation reaction and their antiplatelet activity was assessed using human platelet rich plasma. The platelet concentrate was obtained using a two-step centrifugation protocol and ADP, arachidonic acid and collagen were used as inducers of platelet aggregation. Based on the results, substituted phenylhydrazones showed promising activity. Among them, compound 1i was the most potent derivative with an IC50 comparable to that of indomethacin as a standard drug. The hydrazone derivatives were also tested for their cytotoxicity using on platelet concentrates and fibroblast L929 cells. The majority of the derivatives showed an acceptable selectivity towards antiplatelet aggregation activity. Based on the activity data, phenylhydrazone derivatives (1a-i) exhibited considerable antiplatelet activity and minimal toxic effect on platelet cells. The results of the present study could provide a better understanding of the structure activity relationship of antiplatelet indolehydrazones.

As a continuous research for discovery of new COX-2 inhibitors, chemical synthesis, in vitro biological activity and molecular docking study of anew group of 1,4-dihydropyridine (DHP) derivatives were presented. Novel synthesized compounds possessing a COX-2 SO Me pharmacophore at the para position of C-4 phenyl ring, different hydrophobic groups (R1) at C-2 position and alkoxycarbonyl groups (COOR2) at C-3 position of 1,4 dihydropyridine, displayed selective inhibitory activity against COX-2 isozyme. Among them, compound 5e was identified as the most potent and selective COX-2 inhibitor with IC50 value of 0.30 mcgM and COX-2 selectivity index of 92. Molecular docking study was performed to determine probable binding models of compound 5e. The study showed that the p-SO2Me-phenyl fragment of 5e inserted inside secondary COX-2 binding site (Arg513, Phe518, Gly519, and His90). The structure-activity relationships acquired reveal that compound 5e with methyl and ethoxycarbonyl as R1 and COOR2 substitutions has the necessary geometry to provide selective inhibition of the COX-2 isozyme and it can be a good basis for the development of new hits.

Quinolone antibacterials are one of the most important classes of pharmacological agents known as potent inhibitors of bacterial DNA gyrase and topoisomerase IV that efficiently inhibit DNA replication and transcription by generating several double-stranded DNA break. Some quinolone derivatives demonstrated inhibitory potential against eukaryote topoismarase II and substantial dose-dependent cytotoxic potential against some cancerous cells. In present study, synthesis and cytotoxic activity evaluation of new series of N-pipearzinyl quinolones containing N-2-(furyl-2 or 3-yl)-2-(chlorobenzyloxyimino) ethyl moiety 7a-i have been studied. Reaction of quinolone, with 2-bromo-1-(furan-2 or 3-yl)ethanone-O-substituted chlorobenzyloxime in DMF in presence of NaHCO3 at room temperature, gave the title compounds N-2-(furan-2 or 3-yl)-2-(chlorobenzyloxyiminoethyl) quinolone 7a-i. Synthesized compounds were further evaluated in-vitro against three human breast tumor cell lines. Preliminary screening indicated that compound 7 g demonstrated significant growth inhibitory potential against all evaluated cell lines. The results of structure-activity relationship study exhibited that quinolone derivatives are superior in cytotoxic potential compared to 1, 8-naphthyridone series. Furthermore, ethyl quinolone derivatives were more potent cytotoxic agents comparing with cyclopropyl quinolones.

Sulfonic acid functionalized SBA-15 (SBA-Pr-SO3H) with pore size 6 nm as an efficient heterogeneous nanoporous solid acid catalyst exhibited good catalytic activity in the Biginelli-like reaction in the synthesis of spiroheterobicyclic rings with good yield and good recyclability. Spiro-pyrimidinethiones/spiro-pyrimidinones-barbituric acid derivatives were synthesized in a simple and efficient method using the one-pot three-component reaction of a cyclic 1,3- dicarbonyl compounds (barbituric acid), an aromatic aldehyde and urea or thiourea in the presence of nanoporous silica SBA-Pr-SO3H under solvent free conditions. Urease inhibitory activity of spiro compounds were tested against Jack bean urease using Berthelot alkaline phenol–hypochlorite method. Five of 13 compounds were inhibitor and two of them were enzyme activators. Analysis of the docking results showed that, in most of the spiro molecules, one of the carbonyl groups is coordinated with both nickel atoms, while the other one is involved in the formation of hydrogen bonds with important active-site residues. The effect of inserting two methyl groups on N atoms of barbiturate ring, S substituted, ortho, meta and para substituted compounds were investigated too.

With the aim of obtaining information about drug-drug interaction (DDI) between acetaminophen and some of antidepressant drugs (fluoxetine, sertraline and nortriptyline), in the present work we studied the electrochemical oxidation of acetaminophen (paracetamol) in the presence of these drugs by means of cyclic voltammetry and Controlled-potential coulometry. The reaction between N-acetyl-p benzoquinone-imine (NAPQI) produced from electrooxidation of acetaminophen and antidepressant drugs (see scheme 1) cause to reduce the concentration of NAPQI and decreases the effective concentration of antidepressants.The cyclic voltammetric data were analyzed by digital simulation to measure the homogeneous parameters for the suggesting electrode mechanism. The calculated observed homogeneous rate constants (kobs) for the reaction of electrochemically generated N-acetyl-para benzoquinn-imine with antidepressant drugs was found to vary in the order kobsnortriptyline> kobssertraline > kobsfluoxetineat biological pH.

Lithium (Li), a glycogen synthase kinase-3β (GSK-3β) inhibitor, has used to attenuate the cannabinoid-induced dependence/withdrawal signs, but molecular mechanisms related to this are unclear. Recent studies indicate the involvement of upstream extracellular signal kinase1/ (ERK1/2) and downstream GSK-3β pathways in the development of cannabinoid-induced dependence. This is mediated through cannabinoid receptor 1 (CB1) enriched in cerebellar granular neurons (CGNs). Accordingly, the present study aimed to investigate the mechanism of modulatory/neuroprotective effects of Li on a cannabinoid agonist (WIN 55,212-2 (WIN))-induced dependence, through quantitative analysis of some involved proteins such as ERK1/2, GSK-3β and related signaling pathways including their phosphorylated forms; and cAMP level as the other molecular mechanisms leading to dependence, in CGNs model. The CGNs were prepared from 7-day-old Wistar rat pup in a 12-well plate, pretreated with Li (1mM) and an ERK1/2 inhibitor SL327 (SL, 10 μM). The WIN (1 μM) was added 30 minutes prior to treatment and AM251 (AM, 1 μM), as a cannabinoid antagonist was co-treated with WIN. The cAMP level, as an indicator of cannabinoid-induced dependence, was measured by ELISA following forskolin (FSK) stimulation. Western blot analyses determined the phosphorylated forms of ERK1/2 (p-ERK1/2), GSK-3β (p-GSK-3β) as well as their total expressions in various treatment times and doses in CGNs. WIN alone could down regulate the cAMP/p-ERK1/2 cascade compared to AM treatment. However, P-GSK-3β was up-regulated with Li and WIN or with SL and Li pretreatment to AM-induced cellular response, which was the highest 60 minutes after CGNs exposure. Results further suggested the potential role of Li pretreatment to diminish the development of cannabinoid-induced dependence/neuronal injury through possible mechanisms of modulating the cAMP/p-ERK1/2 cascade independent of p-GSK-3β signaling pathway in vitro.

In this study, we aimed to investigate the peripheral antinociception effects of specific phosphodiesterase 5 (PDE-5) inhibitor vardenafil on carrageenan-induced nociception in rats, and the role of calcium besides the L-arginine- nitric oxide (NO)- cyclic guanosine monophophate (cGMP) pathway in these effects. Hyperalgesia was induced by the intraplantar injection of 0.1 mL fresh carrageenan solution to right hind-paw whereas, saline as a vehicle of carrageenan was injected to the left paw. This procedure was used for measuring mechanic nociception pressure via an analgesimeter. Pressure which produced nociception was measured before (0 minute) and after(15, 30, 60 and 120 minutes) carrageenan injection. Local administration of vardenafil produced a dose-dependent antinociceptive effect. Pretreatment with NW-nitro-L arginine methyl ester (L-NAME, nitric oxide synthase inhibitor), oxadiazolo (4, 3, a) quinoxalin -1 one (ODQ, inhibitor of guanylyl cyclase) or A23187 (calcium ionophore) decreased the effect of vardenafil. In contrast, L-arginine (nitric oxide donor) seemed to potentiate the vardenafilinduced antinociception. Our results suggest that phosphodiesterase type-5 inhibitor vardenafil may offer a new therapeutic tool to treat pain. It’s effect was probably result from L arginine/ NO-cGMP pathway activation and Ca + 2 channels are also involved.

Parkinson’s disease (PD) is a rather common movement disorder as a result of the degeneration of dopaminergic neurons within the substantianigra. Current treatments for PD afford symptomatic relief with no prevention of disease progression. Due to the neuroprotective and anti-apoptotic potential of the isoquinoline alkaloid berberine (BBR), this study was conducted to assess whether BBR pretreatment could attenuate behavioral and neuronal derangement in 6-hydroxydopamine (6-OHDA)-induced model of PD in the rat. Unilateral intrastriatal 6-OHDA-lesioned rats received BBR at doses of 25 and/or 50 mg/kg (i.p.) three times at an interval of 24 h, started 2 days before the surgery. After 1 week, apomorphine caused significant contralateral rotations and a significant reduction in the number of Nissl-stained and tyrosine-hydroxylase (TH)-positive neurons on the left side of the substantianigra. BBR pretreatment at a dose of 50 mg/kg significantly reduced rotations and prevented loss of TH-positive neurons. These results indicate pre-lesion administration of BBR could protect against 6-OHDA toxicity and this may be of benefit besides other available therapies in PD.

We aimed to develop a cost-effective and robust method to predict drug resistance in individual patients. Representative tissue fragments were obtained from tumors removed from female patients, aged 24-74 years old. The tumor tissue was taken by a histopathology’s or a surgeon under sterile conditions. Cells obtained by enzymatic dissociation from tumor after surgery, were cultured as a monolayer for 6 days. Paclitaxel, doxorubicin, carboplatin and endoxan alone or in combination were added at the beginning of culture and after 6 days, Alamar blue test was used for showing action on cell proliferation why caspase- 3 activity assays for verifying action on apoptosis. Inhibitory action on cell proliferation was noted in 2 of 12 patients tumor treated with both single and combined drugs. Using caspase-3 assay we showed that 50% of tumor cells was resistant to single chemotherapeutic drugs and 40% for combined. In 2 of 12 tumors, which did not reacted on single drugs, positive synergistic action on cell proliferation was observed in combination of D + E and C + E. This pilot study suggests: 1) monolayer culture of tumor cells, derived from individual patients, before chemotherapy could provide a suitable model for studying resistance for drugs; 2) caspase-3 activity is cheap and useful methods; 3) Alamar blue test should be taken into consideration for measuring cell proliferation.

Glycyrrhiza glabra L. is used in folk medicine for treatment of stomach disorders including peptic ulcers. The hydroalcoholic extract of Glycyrrhiza glabra L. (HEGG) was evaluated for antiulcerogenic activity and acute toxicity profile in mice. Various doses of HEGG (50-200 mg/kg) were administered orally to animals of different groups. Omeprazole and cimetidine at doses of 30 and 100 mg/kg were used as positive controls, respectively. Stomach was opened along the greater curvature then ulceration index was determined examining the inner lining of stomach. Oral administration of the extract at 1600 mg/kg did not produce toxic symptoms and mortality in mice. 2950 mg/kg was determined as the oral LD50. The HEGG (50–200 mg/kg) showed a significant reduction in ulcer index in HCl/Ethanol-induced ulcer. G. glabra extract (50-150 mg/kg) showed antiulcer activity against indomethacin-induced gastric lesions dose dependently. The extract effectively inhibited formation of gastric lesions induced by ethanol. The extract (200 mg/kg) was more potent than omeprazole (30 mg/kg). HEGG reduced the ulcer index in hypothermic stress induced gastric ulcers in mice and the antiulcer effect was comparable to that of cimetidine. The results indicated that G. glabra hydroalcoholic extract exerted an antiulcergenic effect that could be associated with increase in gastric mucosal defensive factors.

Serious concerns have been expressed about potential health risks of Nano silver containing consumer products (AgNPs) therefore regulatory health risk assessment on such nanoparticles has become mandatory for the safe use of AgNPsinbiomedicalproducts with special concerns to the mutagenic potentials. In this study, we examined the inhibitory and mutagenicity effects of AgNPs in three different sizes of three colloidal AgNPs by Minimal Inhibitory concentration (MIC), Minimal Bactericidal Concentration (MBC) and Bacterial Reverse Mutation Assay (Ames test).All samples were characterized by transmission electron microscopy (TEM), X-Ray Diffraction (XRD) and Dynamic Light Scattering (DLS). DLS analysis showed lack of large agglomeration of the AgNPs and TEM results showed the spherical AgNPswith the average sizes of 15, 19.6, 21.8 nms. Furthermore the XRD analysis showed the crystalline samples with a face centered cubic structure of pure silver.AmestestresultsonColloidal silver nanoparticles showed lack of any mutation in TA100, TA98, YG1029S. typhymuriumstrains.In addition colloidal silver nanoparticles reduced the mutation ratesin all three strains in a concentration dependent manner. This finding creates a new issue in the possible antimutagenic effects of colloidal AgNPsas a new pharmaceutical productwhich should be consideredinfuture studiesby focusing onthephysicochemical properties of AgNPs.

The oxidative stress causes many diseases in human, therefore antioxidants have a special position in the medicinal chemistry. Tyrosol is an important antioxidant with a plenty of biological properties. There are many strategies such as clustering single drug units in order to develop new drugs. The cluster effect can increase drug effects relative to single drug unit. Calixtyrosol is the novel cluster of tyrosol that shows a more effective antioxidant activity than single tyrosol. In fact, tyrosol can be considered as 1/4 of the cluster. Four hydroxyethyl moieties have been grafted at the upper rim of the calix[4]arene in allsyn orientation, giving novel agent in the field of antioxidant agents. Free radical scavenging tests were determined by the 2, 2-diphenyl-1-picrylhydrazyl radical in methanol for four antioxidants: calixtyrosol, tyrosol, hydroxytyrosol and 3, 5-di-tert-buty l-4-hydroxytoluene to compare their antioxidant activity. Free radical scavenging test showed that calixtyrosol has enhanced antioxidant activity in comparison to the corresponding single tyrosol unit (> 5 fold), it has even more active than the other test antioxidants (2 fold). Presumably, it is attributed to tethering and arraying of four impacted tyrosol units, which make a synergistic effect in interactions with radicals for creating effective radical scavenging activity. This method is in debt of synergistic effect, tethering and arraying of single units in the cluster structure.

Toxicity bioassays are important tools to determine biological effects of chemical agents on species. The questions remained on, what effects have been imposed on each of the different molecular site of cells by chemical exposure and how to find a pattern for chemical toxicity. To address the questions, HepG2 cell lines were exposed to the different concentrations of cisplatin for 24 hours to result cell mortality in the range of one to one hundred percent. Fourier Transform Infrared spectroscopy (FTIR) has been used in this study to analyze the chemical alterations on HepG2 cell line by cisplatin. Partial least square regression (PLS) analysis was then applied to the FTIR spectrum results to search for a biomarker peak and present the desire cellular effects of cisplatin. The comparison of cellular FTIR spectra after exposure to different concentrations of cisplatin confirmed the binding of cisplatin to DNA through direct interaction of platinum to guanine and thymine bases of DNA. Biochemical Index Spectra (BIS) were defined based on the differences between of normal and cisplatin exposed cells. Information from the BIS was subjected to PLS analysis to trigger any particular relationship between the toxicity spectral response and cisplatin concentration. This approach was capable of predicting the concentration of cisplatin for any particular effects observed in the cellular FTIR spectrum (R2=0.968±0.037).Our work supports the promises that, FTIR can demonstrate the trace of toxicity before the cells dies. Finally, PLS of FTIR data directly predicts the effective concentration of chemicals in particular cellular components.

Some animal models have been used to study Alzheimer's disease (AD). AD is an irreversible progressive neurodegenerative disease and the most common cause of dementia. Animal studies have shown that there is a relation between decrease in cholinergic functions in the nucleus basalis of Meynert (NBM) and loss of learning capability and memory. The aim of this study was to investigate the effect of Rheum ribes extract (RR) on memory deficit in one of the rat models of AD. Plant (1500gr) was collected from Saman (kahkesh) region of Chaharmahal Va Bakhtiari province in Iran. RR hydro-alcoholic extracts were prepared using maceration method. Rat model of Alzheimer was induced by Nucleus Basalis of Meynert lesions (NBML). Animals (n = 32) received extracts for 20 days and then passive avoidance and Morris water maze tasks were performed for memory evaluation. FRAP and HPLC methods were used for measurement of the antioxidant and Malondialdehyde (MDA) levels in blood. In water maze experiment, probe trial results showed that NBML group spent significantly less time in target quadrant, in which the platform was located on the preceding day. In addition, the time spent in target quadrant was significantly increased in NBML + RR groups (250 and 500 mg/kg) compared to the NBML group. In passive avoidance task, mean initial latency time and step-though latency were significantly decreased in NBML group. RR extracts significantly prolonged step-through latency in NBML + RR groups. Results of this study suggest that Rheum ribes extracts can improve memory deficits induced by bilateral NBM lesions in rats.

Diabetes mellitus is associated with complications in several different systems of the body, and the incidence of diabetes is rapidly increasing worldwide. The objective of the present study was to evaluate the effect of aqueous extract of Cydonia oblonga Mill. Fruit on lipid profile and some biochemical parameters in streptozotocin-induced diabetic rats. The extract showed anti hyper lipidemic activity as evidenced by significant decreases in serum triglyceride, total cholesterol, and low density lipoprotein cholesterol (LDL-C) levels along with the elevation of high density lipoprotein cholesterol (HDL-C) in the diabetic rats. The biochemical liver functional tests were also analyzed and it was shown that serum biomarkers of liver dysfunction, including alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP) were significantly reduced in aqueous extract of Cydonia oblonga Mill. treated diabetic rats. In addition, our results showed that the oral administration of the extract prevented diabetes-induced increase in serum urea and creatinine levels as the markers of renal dysfunction. In conclusion, the present study indicates that aqueous extract of Cydonia oblonga Mill. Is able to improve some of the symptoms associated with diabetes and possesses hypolipidemic, hepatoprotective, and renoprotective effects in streptozotocin-induced diabetic rats.

Polycystic ovary syndrome (PCOS) is a reproductive and metabolic disorder in which the level of oxidative elements in blood rises. Green tea is a potent antioxidant since it contains catechins. In this study, the effect of hydro-alcoholic green tea extract on PCOS rats was examined. For PCOS induction, 96 mature Wistar rats were given estradiol valerate. After 60 days, the rats were divided into four groups including PCOS group and three experimental groups, which were given 50, 100 and 200 mg/Kg BW green tea extract 10 days, intraperitoneally. The serum concentration level of FSH, LH, testosterone and insulin were measured using ELISA method, while the serum concentration level of glucose was measured using glucose oxidase methods. Insulin resistance was calculated using HOMA-IR formulation. The data were analyzed using the one-Way ANOVA method considering P<005/ level of significance. There were a significant reduction in LH serum level, body and ovarian weight between the green tea extract treated-groups compare to PCOS. Moreover, a significant reduction in insulin resistance index was seen in the treatment groups related to PCOS. Histomorphometric studies also showed the significant changes in the number of follicles and theca layer thickness. These changes demonstrated a marked improvement in the symptoms of PCOS which may be due to green tea effects on oxidative stress pathways. Green tea can be considered as a potentially effective drug for treatment of PCOS, Insulin resistance and Type II diabetes.

Epidemiologic studies show that the cardiovascular diseases are associated with multiple factors such as raised serum total cholesterol, increased LDL, increased platelet aggregation, hypertension and smoking. In-vitro studies have confirmed the ability of some plants of Allium species to reduce these parameters. Therefore, we evaluated anti-platelet aggregation effect of some Allium species (Allium ampeloprasum, A. hirtifolium, A. haemanthoides, A. vavillovi, A. atroviolaceum, A. jesdianum, A. shelkovnikovii) using arachidonic acid (AA) and adenosine diphosphate (ADP) as platelet aggregation inducers. The screening results for methanolic extract of Allium species showed that the maximum effect of anti-platelet aggregation was related to A. atroviolaceum. This extract inhibited the in-vitro platelet aggregation induced by AA and ADP with IC50 values of 0.4881 (0.4826-0.4937) mg/ml and 0.4945 (0.4137-0.5911) mg/ml respectively. These results support the hypothesis that the dietary intake of Allium could be beneficial for prevention of cardiovascular diseases.

The chemical composition of the essential oil of fruits of Pimpinella haussknechtiiBoiss.was studied by GC-MS. After GC-MS analysis, one unknown component (56.7%) was observed, which was not characterized in the GC-MS library. The essential oil of P.hauskenekhtii was injected to HPLC using YMC-Pak-Sil column (250 × 20 mm) with gradient system of hexane (A), and hexane: ethyl acetate, 9:1 (B) to yield the interested compound as a new phenylpropanoid derivative. Its structure was elucidated as 4-(prop-2-enyl)-phenyl-3'-methylbutanoate (1) based on 13C- and 1H-NMR as well as 2D-NMR, IR and different MS spectra. In the essential oil analysis, thirty-six components, comprising 94.9% of the total oil, were identified. 4-(2-propenyl)-phenyl 3'-methylbutyrate (56.7%), bicyclogermacrene (8.9%), germacrene D (7.6%), perilla aldehyde (3.5%), and β-caryophyllene (2.9%) were found to be the major constituents of the oil. The oil of the fruits of P. haussknechtii consisted of eight monoterpene hydrocarbons (1.7%), two oxygenated monoterpenes (3.9%), sixteen sesquiterpene hydrocarbons (26.8%), two oxygenated sesquiterpenes (2.1%) and five phenylpropanoids (58.7%). Three other nonterpenic compounds also comprised 1.7% of the oil.

This study aimed to determine phenolic compounds of Artemisia spicigera (family Asteraceae) growing in East-Azarbaijan province of Iran. 20%, 40 % and 60% SPE fractions of methanolic extract of A. spicigera, were subjected to reversed phase preparative HPLC, with the mobile phase consisted of methanol and water. Structural identification of phytochemicals by spectroscopic methods including UV and NMR spectroscopy, yielded 4, 6-di methoxy acetophenone-2-O-β-D-glucopyranoside from 20%, 5-methoxyluteolin 7-O-β-D-glucopyranoside, luteolin and chrysoeriol 7-O-β-D-glucopyranoside from 40% and 5-methoxy luteolin from 60% SPE fractions. Although within identified pure compounds, luteolin was the only phenolic reported from some other species of Artemisia, but occurrence of remained identified phenolics in this study, was firstly reported from Artemisia genus. Further phytochemical investigations were proposed in order to isolate some other active fractions and pure compounds.

Berberine was loaded in yeast cells of Saccharomyces cerevisiaeas a novel pharmaceutical carrier to improve the treatment ofmany diseases. The yeast-encapsulated active materialsshowedhigh stability and bioavailability due to the enhanced solubility and sustained releasing. In this study, different characteristics of prepared berberine loaded yeast cells (loading capacity, release kinetic order, MIC and stability) were evaluatedby different analytical methods (fluorescence spectroscopy, HPLC and SEM).The loading capacity was about 78% ± 0.6%.Berberine release patterns of microcapsules happened in two different stages and followed by zero and first-order kinetic,respectively. About 99% of all active material released during 34 h. MIC was improved by berberine loaded microcapsules in comparison withberberine powder. The microcapsules were completely stable. Berberine loaded Sac. Cerevisiae could be considered as a favorite sustained release drug delivery system. The yeast would be applied as an efficient carrier to improve various properties of different active materials.

Resistance to oxyimino cephalosporins antibiotics in Enterobacteriaceae is primarily done by the extended spectrum β-lactamases (ESBLs). Clear identification of risk factors for ESBL-producing infections is necessary. Therefore, efficient strategies can be developed to decrease outbreak of these infections. The aim of this study was to determine the antibacterial susceptibility and ESBLs pattern of diarrhogenic Escherichia coli (E. coli) strains isolated from adult patients. In the present study, Diarrheogenic E. coli strains were isolated from 54 patients from the University of Medical Sciences hospitals in Shiraz. Antimicrobial susceptibility testing was done by disk diffusion method by CLSI criteria. The presence of blaTEM, blaSHV and blaCTX-M genes was investigated by PCR using designated primers. The prevalence of ESBLs-producer E. coli strains was 12.96%. Antimicrobial resistance testing showed a high resistance to cefexime, trimethoprim-sulfamethoxazole, ampicillin and penicillin. Overall, β-lactamase genes were identified in 52 (96.30%) isolates which were identified as 45 (83.33%) blaTEM, 17 (31.48%) blaSHV and 11 (20.37%) blaCTX-M. ESBL-producer E. coli is very prevalent in Diarrheogenic strains isolated from adult patients. Also, this study clearly showed that the blaTEM gene for ESBL-producer E. coli was widespread in Iran.

Because of less systemic side effects of topical medications in pain relief of the painful form of diabetic peripheral neuropathy, this study aimed to compare the effect of amitriptyline and capsaicin cream in relieving pain in this condition. In this randomized, double-blind and non -inferiority trial, 102 patients received amitriptyline 2% and capsaicin 0.75% creams 3 times a day for 12 weeks on the feet. Pain relief was measured by the visual analog scale (0–10). Treatment responding was considered as cure rate greater than 50% from baseline. Evaluations of the pain severity, compliance and drugs adverse effects were performed at each of the 4-week follow -up visits. Both drugs significantly relieved pain in 12 weeks compared with baseline values (P < 0.001 for both). Treatment responders were similar in both groups (P = 0.545). Intention-To-Treat analysis showed no significant difference in the efficacy between the two treatments (P = 0.703). Adverse events were more common in capsaicin group (P = 0.001). Dermatologic complications were the most common: itching, blister formation and erythema in the capsaicin group and skin dryness and itching in the amitriptyline group. This study demonstrates the similar efficacy of amitriptyline cream with capsaicin cream in managing diabetic neuropathic pain with fewer side effects.

The aim of this study was to evaluate the effects of Atorvastatin on negative symptoms in patients with chronic schizophrenia. The study was a prospective, double-blind, 6-week trial. Forty patients participated in the study; 19 patients were assigned to the Atorvastatin group as well as 21 patients to the placebo group. For assessing negative signs, we used Scale for the Assessment of Negative Symptoms (SANS) in weeks 1st, 3nd, 4th, and 6th. Moreover, patients were randomly assigned to treatment groups with Risperidone (6 mg/day) plus 20 mg Atorvastatin or with Risperidone (6 mg/day) plus placebo. Mean scores of Scale for the Assessment of Negative Symptoms (SANS) decreased during the treatment but there was no significant difference between the mean scores of two groups. The result of this trial suggested that Atorvastatin can be effective in reducing negative sign in schizophrenia although further studies seem to be needed.

Carpal tunnel syndrome (CTS) is a neuropathy due to the compression of the median nerve. It is shown that gabapentin in high doses is effective in treatment of CTS patients. In this study we evaluated the efficacy of low doses of gabapentin in treatment of CTS patients. Ninety patients with CTS were randomly assigned to groups A, B and C. Gabapentin was administered to group A with dose of 100 mg/day and to group B with dose of 300 mg/day for 2 months. Group C received no treatment. Before and after treatment, patients were evaluated using Visual analogue scale (VAS) for pain and parasthesia, Boston carpal tunnel questionnaire (BCTQ) including Symptom Severity Scale (SSS) and Functional Status Scale (FSS) to evaluate the efficacy of the treatment. The pinch and grip strength was also measured. There was significant improvement in VAS, grip strength, pinch strength, SSS, FSS and BCTQ score in all three groups (p < 0.05), but the changes in CMAP and SNAP was not significant. Groups A and B in comparison to group C had significantly better improvement in VAS, pinch strength, SSS, FSS and BCTQ total score (p < 0.05). There was significantly more improvement in pinch strength and SSS score in group B compared to group A (p < 0.05). Gabapentin in low doses is a useful drug in treatment of CTS symptoms with no side effects and intolerance. Gabapentin with dose of 300 mg/day is more effective than the dose of 100 mg/day.

In order to investigate the effect of pharmacist intervention on vancomycin use, this study was performed on all patients receiving vancomycin in the intensive care unit (ICU) and hematology-oncology ward of Taleghani Educational Hospital in Tehran, Iran. Vancomycin use was assessed during a pre- and post-intervention period in accordance with the Center of Disease Control and prevention (CDC) and Infectious Diseases Society of America (IDSA) guidelines. Following the intervention, there was a significant change in appropriate initiation of vancomycin (P = 0.009) and no significant improvement was observed in adequate dosage and the duration of therapy (P = 0.15 and P = 0.54 respectively); however, informing the physician resulted in discontinuation of the drug in 50% of inappropriate cases and vancomycin dosage was adjustedin 31% of cases. Temperature charts, culture results and pre-treatment CBC tests changed significantly (P = 0.02, P = 0.009 and P = 0.04 respectively). The rate of infusion related adverse drug reactions did not decrease significantly (P = 0.06); yet in 100% of patients, these reactions were resolved after notifying the nursing team. After pharmacist intervention,vancomycin use improved in some aspects. A significant improvement in appropriate initiation of therapy was observed; however, treatments continued despite negative cultures. It is necessary to optimize the use of vancomycin by performing more educational interventions.

Lamotrigine is an antiepileptic drug used as a treatment for partial and generalised seizures as well as for bipolar disorder type I. Till date, very few cases of lamotrigine overdose have been reported. The spectra of clinical effects of lamotrigine in acute overdose are not well established. In severe cases of poisoning, serious effects such as coma, respiratory depression, recurrent seizures and intraventricular conduction disturbances have been noted. Here, we report a case of lamotrigine overdose in a 26-year-old divorcee with paradoxical seizure activity and coma. On admission, the patient had a reduced level of consciousness. Serum evaluation revealed high lamotrigine levels without any other aetiology for mental dysfunction. To the best of our knowledge, this is the first report to describe a patient overdosed with 40 g of lamotrigine alone, which is the highest amount of lamotrigine overdose reported so far. During hospitalisation, the patient’s haemoglobin level reduced from 12.9 to 7.7 g/dl and potassium level decreased repeatedly. More importantly, severe menorrhagia was noted. Following prompt supportive treatment with early intubation, along with the use of potassium chloride for hypokalaemia and administration of sodium bicarbonate, the patient’s conditions improved and she was discharged from the hospital after 13 days.

Sunitinib is an oral tyrosine kinase inhibitor which prevents tumor growth and metastatic progression. It was approved for treatment of advanced renal cell cancer, gastrointestinal stromal tumor and advanced pancreatic neuroendocrine tumors. It has several adverse reactions on multi organ systems including hematologic system. Although the neutropenia and thrombocytopenia commonly happens as Grade 3 or 4 abnormalities following bone marrow suppression, in the rare cases, the immune mediated abnormality may drive the sunitinib-induced hematologic disorder. In this report, we present a case of immune-mediated thrombocytopenia induced by sunitinib. One month after first treatment cycle with sunitinib, leucopenia and thrombocytopenia were occurred. The patient had a normal bone marrow aspiration and biopsy, the thrombocytopenia was resistant to platelet transfusion which successfully was treated with prednisolone.

Managing the supply chain plays an important role in creating competitive advantages for companies. Adequate information flow in supply chain is one of the most important issues in SCM. Therefore, using certain Information Systems can have a significant role in managing and integrating data and information within the supply chain. Pharmaceutical supply chain is more complex than many other supply chains, in the sense that it can affect social and political perspectives. On the other hand, managing the pharmaceutical supply chain is difficult because of its complexity and also government regulations in this field. Although, Iran has progressed a lot in pharmaceutical manufacturing, still there are many unsolved issues in managing the information flow in the pharmaceutical supply chain. In this study, we reviewed the benefits of using different levels of an integrated information system in the supply chain and the possible challenges ahead.

Decision-making for medicines to be accepted in Iran’s public health insurance reimbursement list is a complex process and involves factors, which should be considered in applying a coverage for medicine costs. These processes and factors are not wholly assessed, while assessment of these factors is an essential need for getting a transparent and evidence-based approach toward medicine reimbursement in Iran. This paper aims to show an evidence-based approach toward medicine selection criteria to inform the medical reimbursement decision makers in Iranian health insurance organizations. To explore an adaptable decision-making framework while incorporating a method called “Borda” in medicine reimbursement assessment, we used the help of an expert group including decision makers and clinical researchers who are also policy makers to appraise the five chief criteria that have three sub criteria (Precision, Interpretability, and Cost). Also software “Math-lab”7, “SPSS” 17 and Excel 2007 were used in this study. “Borda” estimates the amount of perceived values from different criteria and creates a range from one to five while providing a comprehensive measurement of a large spectrum of criteria. Participants reported that the framework provided an efficient approach to systematic consideration in a pragmatic format consisting of many parts to guide decision-makings, including criteria and value (a model with the core of Borda) and evidences (medicine reimbursement based on criteria). The most important criterion for medicine acceptance in health insurance companies, in Iran, is the "life-threatening" factor and "evidence quality" is accounted as the fifth important factor. This pilot study showed the usefulness of incorporating Borda in medicine reimbursement decisions to support a transparent and systematic appraisal of health insurance companie's deeds. Further research is needed to advance Borda-based approaches that are effective on health insurance decision making.

This paper has two objectives. First, it establishes a model for scoring the access to pharmaceutical services. Second, it develops a model for measuring socioeconomic indicators independent of the time and place of study. These two measures are used for measuring equity in access to pharmaceutical services using concentration curve. We prepared an open-ended questionnaire and distributed it to academic experts to get their ideas to form access indicators and assign score to each indicator based on the pharmaceutical system. An extensive literature review was undertaken for the selection of indicators in order to determine the socioeconomic status (SES) of individuals. Experts’ opinions were also considered for scoring these indicators. These indicators were weighted by the Stepwise Adoption of Weights and were used to develop a model for measuring SES independent of the time and place of study. Nine factors were introduced for assessing the access to pharmaceutical services, based on pharmaceutical systems in middle-income countries. Five indicators were selected for determining the SES of individuals. A model for income classification based on poverty line was established. Likewise, a model for scoring home status based on national minimum wage was introduced. In summary, five important findings emerged from this study. These findings may assist researchers in measuring equity in access to pharmaceutical services and also could help them to apply a model for determining SES independent of the time and place of study. These also could provide a good opportunity for researchers to compare the results of various studies in a reasonable way; particularly in middle-income countries.