Iranian Journal of Pharmaceutical Research
Volume:19 Issue: 2, Spring 2020

In February 2020, the first sample test was confirmed as positive for corona virus in Masih Daneshvari Hospital that is the reference center in Iran for all pulmonary and respiratory diseases. The decisions made in a hospital or organization to manage a crisis is very vital. Success in managing any crisis requires a scientific and scholarly attitude. This paper was distilled from experiences gained in Masih Daneshvari Hospital in Tehran, capital of Iran, in March 2020 at the stubborn time of coping and managing corona virus crisis. This endeavor was an action research. This Action research involves five stages: statement of the problem, planning, data interpretation and analysis, action, and evaluation of the research process during performing the study. The whole hospital was equipped for corona virus patients in 10 phases during one week and 250 active beds were equipped for these patients. Three models, namely, “corona virus crisis management model”, “Pharmaceutical care management in coronavirus crisis model” and “nursing in coronavirus crisis model” were planned and implemented. During one month of implementing these three models, the supervision team monitored the accurate implementation of instructions and resolving or revising the possible deficiencies and faults. The Masih Daneshvari crisis management model in coronavirus, Management model in coronavirus crisis, Nursing care model in coronavirus crisis and Pharmaceutical care management model in coronavirus crisis can be a useful and applicable model in other corona virus centers.

Drug development is a key point in the research of new therapeutic treatments for increasing maximum drug loading and prolonged drug effect. Encapsulation of drugs into multivesicular liposomes (DepoFoam) is a nanotechnology that allow deliver of the active constituent at a sufficient concentration during the entire treatment period. This guarantees the reduction of drug administration frequency, a very important factor in a prolonged treatment. Currently, diverse DepoFoam drugs are approved for clinical use against neurological diseases and for post-surgical pain management while other are under development for reducing surgical bleeding and for post-surgical analgesia. Also, on pre-clinical trials on cancer DepoFoam can improve bioavailability and stability of the drug molecules minimizing side effects by site-specific targeted delivery. In the current work, available literature on structure, preparation and pharmacokinetics of DepoFoam are reviewed. Moreover, we investigated approved DepoFoam formulations and preclinical studies with this nanotechnology.

Propranolol HCl is a beta blocker commonly used worldwide; however, it shows a low bioavailability due to its extensive first-pass metabolism. To solve this problem, a novel drug delivery system such as buccoadhesive system might be helpful. The aim of the present investigation is to prepare the buccoadhesive tablet of propranolol HCl using different mucoadhesive polymers. Buccoadhesive tablets containing drug, lactose, and polymers such as HPMC K4M, carbomer 934P, PEO 8000000 and PEG 6000, in various concentrations, were prepared. The tablets were evaluated in terms of weight variation, thickness, hardness, friability, and mucoadhesive strength. Among thirteen prepared formulations, seven of them which had better physicochemical properties and mucoadhesive strength were undergone the release and swelling tests. Finally, two formulations were selected and uniformity, drug content, duration of mucoadhesion and kinetic studies were performed for them. All polymers except PEG 6000 were appropriate for being used in buccal mucoadhesive systems. Formulation F1 was considered as the most desirable formulation as it exhibited appropriate mucoadhesive strength (43.93 ± 12.4 g), extended duration of mucoadhesion (19.15 ± 0.29 h) and suitable swelling ability while having a prolonged drug release over 12 hours. Although the efficiency and mucosal irritation of propranolol HCl buccoadhesive tablets should be monitored under the in vivo conditions, However, based on the results, it seems that such tablets can be considered as an alternative route to bypass the first pass metabolism of propranolol HCl.

The aim of this study is to investigate the novel application of a ‎handheld near infra-red spectrophotometer coupled with classification methodologies as a screening approach in detection of adulterated lime juices. For this purpose, a miniaturized near infra-red spectrophotometer (Tellspec®) in the spectral range of 900–1700 nm was used. Three diffuse reflectance spectra of 31 pure lime juices were collected from Jahrom, Iran and 25 adulterated juices were acquired. Principal component analysis was almost able to generate two clusters. Partial least square discriminant analysis and k-nearest neighbors algorithms with different spectral preprocessing techniques were applied as predictive models. In the partial least squares discriminant analysis, the most accurate prediction was obtained with SNV transforming. The generated model was able to classify juices with an accuracy of 88% and the Matthew’s correlation ‎coefficient ‎value of 0.75 in the external validation set. In the k-NN model, the highest accuracy and Matthew’s correlation ‎coefficient in the test set (88% and 0.76, respectively) was obtained with multiplicative signal correction followed by 2nd-order derivative and 5th nearest neighbor. The results of this preliminary study provided promising evidence of the potential of the handheld near infra-red spectrometer and machine learning methods for rapid detection of lime juice adulteration. Since a limited number of the samples were used in the current study, more lime juice samples from a wider range of variability need to be analyzed in order to increase the robustness of the generated models and to confirm the promising results achieved in this study.

Alzheimer’s disease (AD) is a neurodegenerative brain disorder which has no effective treatment yet due to the blood barrier in the brain that limits the drugs with the potential of disease improvement. Extracellular vesicles (EVs) are biocompatible nanoparticles with a lipid membrane. These vesicles are secreted from various cells such as mesenchymal stem cells (MSCs) and can pass through biological barriers for transfer of information such as signals or be used as carriers for various proteins like Neprilysin (NEP). NEP is an active enzyme in the clearance of abnormal aggregated beta-amyloid sheets in the brain. In the present study, we used EVs to carry NEP for memory improvement in Alzheimer’s disease. For this purpose, bone marrow MSCs were isolated from rat femur. Stemness evaluation of established cells was characterized by differentiation potency and specific markers with flowcytometry. EVs were isolated from MSCs supernatant by ultracentrifugation and analyzed by scanning electron microscopy(SEM), dynamic light scattering(DLS) and western blotting. EVs were loaded with NEP by freeze-thaw cycle and then administrated intranasally in a rat model of the AD for 14 days. Our findings showed EV-loaded NEP caused a decrease in IL-1beta and also BAX but an increase in BCL2 expression level in the rat brain. Altogether, these data showed that EV-loaded NEP can improve brain-related behavioural functional which may be mediated through the regulation of inflammation and apoptosis. These findings suggest that EV-loaded NEP can be considered as a potential drug delivery system for the improvement of AD.

Cancer is now a global concern, and control of the function of cancer cells is recognized as an important challenge. Although many aggressive chemical and radiation methods are in practice to eliminate cancer cells, most imply severe adverse toxic effects on patients. Taking advantage of natural physical differences between cancer and normal cells might benefit the patient with more specific cytotoxicity and fewer adverse effects. Physical factors are the main means that can influence cell-biomaterial interaction. To explore the importance of attachment phenomena on cancer cells in this research, polydimethylsiloxane (PDMS) substrates with varied stiffness and roughness were synthesized and lung cancer cell’s behavior on these surfaces was examined. To achieve diverse surface topography SDBD plasma was used at various exposure times, and different stiffness was obtained by changing in curing agent amount. Atomic force microscopy (AFM) and tensile modulus were employed to the characterization of roughness and stiffness respectively. Lung cancer cell survival and growth were studied by MTT and image processing analysis. The results indicated that softer and rougher surface made lung cancer cells to die. The number of detached cells, mean space of the detached cells, cellular coverage of surface, and the ratio of detached/ all cellular coverage were significantly affected by roughness and stiffness. Therefore, physical factors can control cell function, especially in lung cancer cells and these results might provide a strong base to help cancer cell removal.

In recent years, green synthesis of nanoparticles has attracted a great attention because of medicine and biological applications. In this work, bismuth oxide nanoparticles (Bi2O3 NP) was prepared via green synthesis using mentha pulegium aqueous extract after 24 h at 90°C. The product was characterized by ultraviolet-visible (UV-VIS) spectrophotometer, Fourier transform infrared (FTIR), X-ray diffraction (XRD), dynamic light scattering (DLS), scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS), and diffuse reflection spectroscopy (DRS). The antibacterial activities of the samples were determined against Salmonella and Escherichia coli (E.Coli) as Gram-negative bacterial and Staphylococcus aureus (S.aureus) as Gram-positive bacterial. The objectives of this study were the green synthesis of bismuth oxide nanoparticles using aqueous extract with a good potential for UV blocking and antibacterial activity. Based on the obtained results, Bi2O3 NPs can have a good candidate for different applications.

Tumour cells may be resistant to radiotherapy that results in unsuccessful cancer treatment in patients. The aim of this study was to evaluate the sensitizing effect of atorvastatin (ATV) on breast cancer (MDA-MB-231) and non-small cell lung cancer (A-549) cells following exposure to ionizing radiation (IR). These cells were treated with ATV and exposed to X-ray at dose 4 Gy. The radiosensitizing effects of ATV were evaluated by flow cytometry and anti-proliferation assays. The production of reactive oxygen species (ROS) was determined in irradiated and treated cells with ATV. The findings of this study showed that ATV increased the percentage of apoptotic cells in irradiated breast and lung cancer cells. ATV exhibited anti-proliferative effect on cancer cells and increased cell death induced by IR. ATV increased ROS production in irradiated cells. The present study demonstrates that ATV has radiosensitizing effect on breast and lung cancer cells through increasing apoptosis, ROS production and cell death induced by IR.

The aim of the present study was to evaluate the effect of troxerutin (TXN) on Nickel (Ni) toxicity by using rats and in vitro model. Ni toxicity induced in male albino wistar rats (20 mg/kg body weight (b.w) was administered orally for 20 days). TXN was administered orally (100 mg/kg (b.w) for 20 days with administration of Ni. The toxic effect of Ni and the action of TXN was measure by determining the lipid peroxidation markers and antioxidant levels in plasma and various in vitro antioxidant systems. TXN exhibited a significant (p< 0.05) antioxidant activity in Ni induced toxicity by reversing the changes observed in TBARS, HP, Vitamin C, E and GSH. The free radical scavenging properties of TXN at different concentrations (10-50ug/ml) were investigated with various in vitro methods such as 2, 2’-diphenyl-1- picrylhydrazyl radical (DPPH), 2, 2’-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) radical (ABTS•+), hydroxyl radical, superoxide anion scavenging activity and reducing power. Among the different concentrations, 50μg/mL of TXN was more effective compared to other concentrations in all in vitro assays. The above study conclude that TXN possesses potent in vivo and in vitro antioxidant activity with effective free radical scavenger for potential therapeutic value.

One of the newest methods to reduce cerebral ischemia damages is cell therapy. The aim of this study is to evaluate the effect of Sertoli cell transplantation on ischemia-induced injuries in animal models of stroke. Rats were divided into four groups: transplant+ischemia, ischemia, sham, and control. Sertoli cells were separated from the other testis of rats and cultured. Unilateral Sertoli cell transplantation was performed in the right striatum by using stereotaxic surgery. For induction of brain ischemia, middle cerebral artery occlusion surgery was used 14 days after transplantation. By using western blotting method, expression of nuclear factor kappa (NF-кB) and Bax were evaluated. In this study, a remarkable decrease in neurological deficits, infection, blood-brain barrier permeability, and brain edema was observed in the cell transplant recipient group in comparison with the ischemia group. Probably, a reduction in inflammation (NF-кB factor) and apoptosis (Bax) following injection of Sertoli cells result in amelioration of ischemic damages induced by MCAO surgery.

Biosurfactants, the microbial originated surface active agents, can modify the physicochemical properties of surfaces and reduce the bacterial adhesion via changing bacterial adhesion interactions on surfaces.  They were also able to block oxidative chain reactions and might show antioxidant properties. The goal of this study was to evaluate the antioxidant and antibiofilm activities of biosurfactants which were derived from two autochthonous biosurfactant-producing strains, Bacillus amyloliquefaciens NS6 (surfactin), andPseudomonas aeruginosaMN1 (rhamnolipids). Their antioxidant activities were determined by ferric reducing antioxidant power (FRAP) and 1,1-diphenyl-2-picrylhydrazyl (DPPH) methods. Ferric thiocyanate (FTC) assay was used for determination of their lipid peroxidation inhibition capacity. Their effect to reduce the adhesion of Streptococcus mutans on polystyrene surfaces and disruption of its pre-formed biofilms were also investigated. Our results indicated that surfactin showed higher antioxidant activity than rhamnolipids and showed relatively similar efficiency to BHA that suggests it as a good alternative for synthetic antioxidants. In other hand, rhamnolipid conditioned surfaces showed higher antiadhesive and antibiofilm activity in comparison with surfactin treated surfaces.

Transdermal patches loaded with pravastatin was previously characterized in another published study by Serrano-Castañeda et al; 2015. These transdermal patches (TP) were generated by the plate casting technique, the in vitro percutaneous absorption studies of TP were evaluated for three different formulations of TP with different quantities of Pluronic F-127 (PF-127): i) without PF-127 (TP W), ii) 1% of PF-127 (TP 1%), and iii) 3% of PF-127 (TP 3%) and using solid microneedles as a penetration enhancer with two different lengths: i) 0.25mm and ii) 2.25mm and iii) in vitro permeation studies without using microneedles on TP. The fluxes (F), time lag (tLag) and permeability constants (kp) for each formulation were: TP W (F:38.5µg/cm2*h, tLag:18.97h and kp:5.9x10-3cm/h), TP W with microneedles of 0.25 mm (F:103.3 µg/cm2*h, tLag: 20.76 h and kp: 0.0158 cm/h), TP W and microneedles of 2.25 mm (F:105.2µg/cm2*h, tLag: 21.16 h and kp: 0.0159cm/h), TP 1% (F:90 µg/cm2*h, tLag: 19.48 h and kp: 0.0137 cm/h), TP 1% with microneedles of 0.25 mm (F:111.4µg/cm2*h, tLag:19.11h and kp:0.017cm/h), and TP 1% with microneedles of 2.25 mm (F:115.2µg/cm2*h, tLag:16.73h and kp:0.017cm/h), TP 3% (F:40.9µg/cm2*h, tLag:20.45h and kp:0.0062 cm/h), TP 3% with microneedles of 0.25 mm (F:67.1 µg/cm2*h, tLag: 21.79h and kp:0.0102cm/h) and TP 3% with microneedles of 2.25 (F:70.5 µg/cm2*h, tLag:20.44h and kp:0.0107cm/h). Results show that the formulation of TP affects the pravastatina flux and kp parameters, however the length of microneedles only has important effect on time lag (tLag).

This study aimed to improve delivery of lomustine as a chemotherapeutic agent and to increase its uptake by U87-MG cancer cells via synthesizes LN-FA-PG-SPIONs (lomustine loaded polyglycerol coated superparamagnetic iron oxide nanoparticles conjugated with folic acid). Nanoparticles were synthesized by thermal decomposition method and characterized using TEM (transmission microscope), FTIR (Fourier transform infrared spectroscopy), and VSM (vibrating sample magnetometer). Lomustine release from nanoparticles was determined by dialysis-bag diffusion technique. Nanoparticles cytotoxicity was evaluated by MTT assay. Mean size of SPIONs and FA-PG-SPIONs (PG-SPIONs conjugated with folic acid) were 7.1 ± 1.13 nm and 25.1 ± 3.94 nm, respectively. Based on FTIR spectra SPIONs were successfully coated by polyglycerol and conjugated with folic acid. Lomustine encapsulation efficiency was 46 ± 6.8 %. SPIONs were cytotoxic on U87-MG cells at concentration above 100 ug/ml (p <0.05) but PG-SPIONs do not reduce viability significantly (p > 0.05). Conjugation of folic acid with PG-SPIONs increased nanoparticles uptake by U87-MG cells (p < 0.05). We concluded that however FA-PG-SPIONs are proposed as a useful tracer for diagnostic and treatment of GBM but their drug delivery properties for lomustine is not satisfactory and more researches are necessary with this regard.

Prognosis of metastatic breast cancer is very poor which urges the necessity to develop novel potential drug candidates. We assessed two compounds with tri-aryl structures (A and B) for their potency to reduce primary breast tumor growth and lung metastasis in 4T1 mice model. MTT assay, 4T1 mammary mouse model and immunohistochemistry experiments were used in this study. In vitro results exhibited an anti–proliferative effect for compounds A and B towards MDA-MB-231 cancer cells. Our in vivo results displayed that administered compounds A and B could suppress the size of the primary tumor and the number of lung metastatic foci in 4T1 BALB/c mice model. Histopathological analysis revealed that both compounds treatment resulted in necrosis. Our findings provide new evidence that compound B may be promising for slowing the growth of tumor along with metastatic foci.

Mathematical algorithms offer a useful method for quantitative analysis of compounds in multi-component mixtures to overcome the overlapping problems occurred in UV spectrophotometry. The aim of this study is to develop a method to determine the bioactive compounds in herbal dosage forms produced from fenugreek extract. A UV- spectrophotometric method based on mathematical algorithm was used to simultaneous determination of trigonelline (TRG), diosgenin (DI) and nicotinic acid (NA). The maximum absorbance (λmax) was determined to be 232.65 nm, 296.23 nm, and 262.60 nm for TRG, DI and NA respectively. The calibration curves showed good linearity for all analytes in the concentration range of 1–20 μg/mL (R2=0.9995, 0.9997, 0.9994 for TRG, DI and NA respectively). The Intra- and inter-day precisions were in the range of 1.1-10.7% and 1.2-8.2% respectively. The accuracy of the method was 96.0% for TRG, 92.9% for DI, and 104.2% for NA. The limits of detection (LOD) and quantification (LOQ) were found to be 0.91 and 3.06 µg/mL for TRG, 0.99 and 3.30 µg/mL for DI and 0.33 and 1.10 µg/mL for NA. The validated method was applied for determination of the analytes in tablet, capsule and biofilm dosage forms prepared by fenugreek seed extract. The mean recovery percentages of the analytes were in the range of 90.0-97.4%, 85.6-105.4%, and 90.0-99.0% for tablet, capsule, and film dosage forms respectively. Generally,the validated method could be a good candidate for routine spectrophotometry determination of the analytes without any necessity for pre-analysis extraction.

Wnts are the major ligands responsible for activating Wnt signaling pathway through binding to Frizzled proteins (Fzd) as the receptors. Among these ligands, Wnt2 plays the main role in the tumorigenesis of several human cancers especially colorectal cancer (CRC). Therefore, it can be considered as a potential drug target.The aim of this study was to identify potential drug candidates against two binding sites of Wnt2. Structure-based virtual screening approaches were applied to identify compounds against binding sites of Wnt2 for inhibiting the interaction Wnt2 and Fzd receptors. The best hit compounds from molecular docking of National Cancer Institute diversity set II database were used for structural similarity search on ZINC database, obtaining large hit compounds query to perform a virtual screening and retrieving potential lead compounds. Eight lead compounds were selected while their binding affinity, binding modes interactions, and molecular dynamics simulations studies were assessed. Molecular docking studies showed that eight selected lead compounds can bind to the desired binding sites of Wnt2 in a high affinity manner. Bioavailability analysis of the selected lead compounds indicated that they possessed significant drug like properties. Thus, these lead compounds were considered as potential drug candidates for inhibiting Wnt signaling pathway through combining with the binding sites of Wnt2 and hindering the interaction of Wnt2 and Fzd receptors. Our findings suggest that Wnt2 binding sites may be a useful target for treatment for CRC fueling the future efforts for developing new compounds against Wnt signaling pathway.

Recent studies suggest that reducing the induction temperature would improve the quality of some recombinant inclusion bodies (IB) by providing a native-like secondary structure and leading to an improvement in protein recovery. This study focused on optimizing the solubilization condition of Reteplase, a recombinant protein with 9 disulfide bonds. The influence of lowering induction temperature and urea concentration was investigated on the secondary structure of the recombinant protein through FTIR analysis. Induction temperature reduction decreased the percentage of helixes and loops from 49 to 8. In addition, FTIR spectroscopy corroborates the drastic impact of this parameter on Reteplase secondary structure. Even though lowering urea concentration tripled the solubility of IBs expressed at lower induction temperature, the final yield is still quite low to be considered as optimum. On the other hand, the percentage of beta strands and turns in secondary structure of dissolved proteins were proportional to urea concentration. Therefore, in case of Reteplase, protein expression at low temperature (25°C) was not efficient to improve the protein recovery yield. Future studies need to focus on using other methods of solubilizing IBs to improve protein recovery.

A new phthalide, namely 7-methoxy-3-propylidenephthalide (1), along with two known compounds (2, 3) were isolated from the roots of the edible herb Levisticum officinale W.D.J. Koch, commonly known as lovage and well known in traditional medicine for its spasmolytic and diuretic effects. The structure of the new compound was established by HRMS and 1D & 2D NMR (1H 1H COSY, HMQC, and HMBC) spectroscopic analysis. All compounds are reported for the first time from L. officinale. Compounds 1-3 were tested against two Gram negative (Escherichia coli, Pseudomonas aeruginosa) and two Gram positive (Staphylococcus aureus and vancomycin-resistant Enterococcus [VRE] faecium) bacteria strains. Compound 3 was active against S. aureus, E. coli and vancomycin-resistant E. faecium with MIC values of 16, 64 and 128 μg/mL, respectively.

Recently Nutrition and Food Chemistry researches have been focused on plants and their products or their secondary metabolites having anti-alzheimer, anti-cancer, anti-aging, and antioxidant properties. Among these plants Salvia L. (Lamiaceae) species come into prominence with their booster effects due to high antioxidant contents, which have over 900 species in the world and 98 in Turkey. Some Salvia species are already in use as herbal treatment of vessel stiffness, Dementia like problems and cancer. Recently some species of Salvia are of extensive research topic. In this study, inhibitory potentials of secondary metabolites, rosmarinic acid, salvigenin, salvianolic acid A and B, tanshinone I and IIA, cyrtotanshinone, dihydrotanshinone I, carnosic acid, carnosol, and danshensu sodium salt were investigated against acetylcholinesterase, butyrylcholinesterase, urease and tyrosinase enzymes both in vitro and in slico in detail. Elevated inhibitory effects on acetyl- and butyryl-cholinesterase of dihydrotanshinone I (IC50: 1.50±0.02 and 0.50±0.01 µg/mL, respectively), carnosol (IC50: 11.15±0.05 ve 3.92±0.03 µg/mL) and carnosic acid (IC50: 31.83±0.65 ve 4.12±0.04 µg/mL) were observed. Furthermore, all other secondary metabolites were active against butyrylcholinesterase. Anti-urease (42.41±0.85%) and anti-tyrosinase (39.82±1.16%) activities of tanshinone I were also observed. Potential inhibitory effects of these molecules on target proteins were investigated using DOCK and molecular dynamics calculations. Dock score analysis and Lipinski parameters were demonstrated that these ligands are potential inhibitors against relevant enzymes. Our findings suggest that Salvia species can be utilized as a potential source of anti-alzheimer active compounds for designing novel products

Functional foods have emerged as a new approach to improve human health in term of nutraceutical to prevent people from illness rather than cure patients though medical treatment. In Asian society, particularly in Thailand, the utilizations of functional ingredients have been integrated in every parts of ordinary life. In this study, the tyrosine kinase activity of epidermal growth factor receptor (EGFR) inhibiting properties of 23 Thai’s herbs-ethanol extracts have been examined. The crude extracts of only four species that inhibit the activity of EGFR-tyrosine kinase, Azadirachta indica (neem, Sa-dao), Brucea javanica (L.) Merr. (Rajadad), Hibiscus sabdariffa L. (Roselle, Krachiap daeng), and Saccharum chinensis Roxb. (Red sugar cane). Moreover, only ethanol extractions from A. indica and B. javanica were also showed antitumor effect to non-small cell lung cancer, A549 cells.

This study aimed to evaluate the in-vitro and in-vivo biological activities of newly synthesized nanochelating based silver nanoparticles (AgNPs) in mouse model. Nanochelating technology was used to design and synthesize the AgNPs. The animals studies were including the lethal dose (LD50) determination by the intraperitoneal administration in mice, and determination of liver enzymes levels and hematological parameters. Flow cytometry analysis was used to quantitatively determine apoptosis and necrotic cells in-vitro. The NPs A and NPs B have LD50 = 250 mg/kg and LD50 = 350 mg/kg, respectively and classified as non-toxic. In general, minor alterations were observed in levels of liver enzymes as indicative of liver damage. For blood parameters several factors associated with significant changes in AgNPs treated animals. Regarding animals weight, combination therapy showed more effective to maintain animals weight losses after infection. Flow cytometry results showed that AgNPs induced cell apoptosis-necrosis depends on AgNP size, concentration and exposure time. Cells damage due to AgNPs (A) with lower size (20-25 nm) were relatively more than cells exposed to AgNPs (B) (30-35 nm). The findings support the potent antibacterial activities of nanochelating based AgNPs. Also, the present study showed that nanochelating based AgNPs induce a moderate level of apoptosis/necrosis in mice, and affected several clinical parameters like blood parameters, liver enzymes, and body weight with no definite signs of toxicity.

A target of best dissolution improvement of poorly soluble drugs is a necessity for the success of formulation in industry. The present work describes the preparation, optimization, and evaluation of a new spherical agglomeration technique for glimepiride as a model of poorly soluble drugs. It involved the emulsification of a drug solution containing a dispersed carrier that tailors the crystal habit of the drug to a perfect spherical geometry, in a poor solvent containing a hydrophilic polymer which imparts sphericity and strength to the formed agglomerates. The FTIR peaks of optimized product did not show any sign of chemical interaction between the drug and adsorbed carrier. The DSC and X ray diffractogram showed a peak characteristic of spherical agglomerates with much less intensity than that of glimepiride. The dissolution t1/2 of the drug slightly decreasedfrom 381 min to 334 min in plain agglomerates. Introducing polymers in the aqueous phase of emulsion led to an improvement in the dissolution, reflected in t1/2 ranging from 118 to 231 min. Agglomerates prepared with Starlac/PVP demonstrated the most optimum physicochemical characteristics being spherical, with the best flowability and packability parameters. The t1/2 was as short as 19 min. The new carrier/polymer system offered a synergistic combination that highly contributed in dissolution enhancement of glimepiride. The spheronization and amorphisation offered by the new technique could account for such improvement.

Since melanocytes are the origin of melanoma and some skin disorders such as melasma, they are important cells from the perspective of medicinal chemistry. Therefore, a medication that can simultaneously overcome these diseases will be a successful potential therapeutic agent. Arbutin with phenolic structure is a powerful natural anti-tyrosinase agent. Hence, the phenolic structure of this drug, prompted us to design its novel calix [4]arene-based cluster. Therefore, the present study reports the synthesis and in-vitro bio-activities of cyclic tetramer of arbutin in comparison to its simple drug unit as the reference medication. The in-vitro biological results showed amplified anti-tyrosinase (6-fold) and anti-melanoma (27-fold) activities, in addition to more aqueous solubility (8-fold) for this cluster in relation to arbutin. Therefore, compared to arbutin, more bioactive cluster can be considered as a novel water-soluble melanogenesis inhibitor with high anti-melanoma activity.

The present study was done to uncover the possible beneficial and/or detrimental effect(s) of nano-micelle curcumin (NMC) on oocyte in-vitro maturation and pre-implantation embryo development. Forty-eight mature female Wistar rats were assigned to control, 7.5, 15, and 30 mg/kg-1 NMC-receiving (orally, for 48 days) groups. To assess the cumulus-oocyte complexes (COCs), the ovaries were stimulated by administrating (i.p.) a 25 IU of the pregnant mare's serum gonadotropin (PMSG) hormone. Following 48-h, 15 IU of hCG was injected (i.p.), and the COCs were taken after 16-18-h. To analyze the pre-implantation embryo development ratio, the sperms were collected from clinically healthy male Wistar rats, and 3.0-3.6 × 106 per mL was added into the fertilization drop. The animals in 7.5 mg/kg-1 NMC-receiving group exhibited a higher oocyte number versus control and other NMC-receiving groups. The NMC, in a dose-dependent manner, decreased the Zygote, 2-cell, blastocyst percentages, as well as hatched embryos, compared to the control group (P < 0.05). The 15 and 30 mg/kg-1 NMC-receiving groups represented a remarkable enhancement in type I arrest. Meanwhile, a significant (P < 0.05) reduction was revealed in type III embryo arrest in the same groups. The NMC, at 7.5 mg/kg-1 potentially enhances the oocyte number, while it fairly reduces the pre-implantation embryo development, even when it is administrated in dose levels of 7.5 mg/kg-1 and/or higher. Although more studies are needed, the NMC could be considered as a suppressor of fertility potential, when consumed chronically even in low doses.

A new sensitive, selective and nonexpensive electrochemical sensor was developed for electrocatalyticdetermination of glutathione (GSH)in pharmaceutical and biological samples. GSH is a tripeptide thiol present in all eukaryotic and probiotic cells. A voltammetric studyof GSH has been carried out at the surface of carbon paste electrode modified with multiwall carbon nanotubes(MWCNTPE) in the presence of rutin as a mediator. The electrochemical oxidation of GSH was investigatedby cyclic voltammetry, chronoamperometry and square wave voltammetry (SWV) techniques. Under the optimized conditions, the peak current was linear to GSH concentration over the concentration rangeof 0.3 to 180μmol L−1 using SWV. The detection limit was 0.09μmol L−1. The proposed method wassuccessfully applied to the determination of GSH in the urine,tablet and hemolysed erythrocyte samples.

In the present study, nine compounds (1-9) were isolated from Talaromyces wortmannii LGT-4 (anendophytic fungus from Tripterygium wilfordi) which was cultured in CYM Medium. Their structures were determined as 4-hydroxyphthalide (1), Fumitremorgin C (2), Ergosterol (3), 3-(2-hydroxypropyl)-8-hydroxy-3,4- dihydroisocoumarin (4), Cis-cyclo(L-Ala-L-Pro) (5), 6-Amino-3-(4-hydroxybenzyl)- 1,4-diazonane-2,5-dione (6), Aspergillumarin B (7), Deacetylisowortmin B (8), and Entonaemin A (9) based on NMR spectral data, as well as comparing with previous literature data. This is the first report of the isolation of compounds 1-2 and 4-7 from Talaromyces genus. All compounds were tested for their monoamine oxidase and phosphoinositide 3-kinase (PI3Kα) inhibitory activities. Compound 1, 5 showed moderate anti-monoamine oxidase activity with IC50 value of 35 μg/mL, 28 μg/mL, respectively. Compound 9 showed PI3Kα inhibitory activity with IC50 value of 10.3 μg/mL.

Disease-related malnutrition of neurocritical illness harms its treatment, which increases the mortality rate. The aim of this study was evaluating the effect of a high protein diet on the dietary factors, clinical outcome, and mortality rate of neurocritical patients. In a randomized controlled trial, 15 neurocritical patients were recruited in each group. Patients in the intervention and control groups received high protein and conventional protein regimens, respectively. The Clinical Extended Glasgow Outcome Scale (GOSE) measured at one, two, and three months later. Acute Physiology and Chronic Health Evaluation II (APACHE-II) score, Glasgow Coma Scale (GCS), the serum level of transthyretin (TTR) on the first, 3rd and fifth days of admission, and nitrogen balance (NB) at the baseline and fifth day of the study recorded. Thirty patients, 15 in each group, entered into the study. There was no statistically significant difference in the baseline characteristics of the patients between the two groups of the study. The 28-days-mortality rate in the intervention and control group were 33.3% (n = 5) and 73.3% (n=11), P-value = 0.034, respectively. The GOSE scores were higher in patients who received a high protein diet, and lower in patients with lower baseline TTR, higher APACHE-II score, older age, and a baseline negative nitrogen balance. The high protein diet may decrease the mortality rate, and improve the clinical outcome of neurocritical patients. The baseline TTR level, APACHE II score, and NB are prognostic factors for the prediction of the GOSE in neurocritical patients.

A simple, rapid, and ultra sensitive dispersive solid phase extraction based on nano graphene oxide was developed for simultaneous measurement of trace amounts of metformin (MET) and linagliptin (LIN) in plasma samples by HPLC-UV-Vis. Affecting factors on the extraction of these drugs, including adsorbent weight, extraction time, organic solvent type, desorption situations, and composition of solvent were examined and optimized. In optimum conditions, the LOD (limit of detection) and LOQ (limit of quantification) of the suggested technique were 2.0 ngmL-1 and 6.1 (ngmL-1) for LIN and 3.0 ngmL-1 and 9.2 ngmL-1 for MET, respectively. Suitable linear behavior in the considered ranges of concentration (10-2000 ngmL-1) and good correlation coefficient of 0.9901 and 0.9903 (r2) for LIN and MET were obtained, respectively. The RSD (relative standard deviations) according to three replicate measurements at 2, 20, 200 ngmL-1 levels of these drugs was less than 8.0%. In the last step, applicability of the suggested technique was examined by analyzing the drugs in plasma samples and reasonable results were achieved.

Salvia reuterana Bioss. is an aromatic perennial plant traditionally used for its anxiolytic and sedative properties. In the present study, various fractions and essential oil of S. reuterana aerial parts were investigated to find its free radical scavenging principles. Hydroalcoholic fraction with IC50 value of 112.6 ±3.2 μg ml-1 in DPPH assay demonstrated the highest free radical scavenging activity and was selected to further phytochemical investigation. RP-18 and Sephadex LH-20 column chromatography of the hydroalcoholic fraction resulted in the isolation and structural elucidation of four phenolic derivatives, including apigenin-7-O-β-D-glucopyranoside (1), luteolin-7-O-β-D-glucopyranoside (2), rosmarinic acid (3) and luteolin (4). Isolated compounds showed potent free radical scavenging activities (5.1-34.2 μg ml-1), compared with BHT (21.30 ±1.9 μg ml-1). Twenty four compounds were also identified in GC-MS analysis of the plant essential oil, of which benzyl benzoate (26.64%), n-hexyl benzoate (22.99%) and n-hexyl isovalerate (6.04%) were the main compounds. The results of present study introduced S. reuterana as a valuable source of natural phenolic antioxidants which can be utilized in prevention of oxidative stress related diseases. Moreover, interesting composition of S. reuterana essential oil, dominated by non-terpenes compounds (76.17%) especially aromatic derivatives, make it an appropriate candidate for more in detailed studies.

In the last five decades study on plant secondary metabolites have been increasing. Higher plants with a wide range of secondary metabolites have been very important in the search of new therapeutic agents. Flavonoids are most widely distributed secondary natural metabolites that found in plants which occuring in free forms or as glycosides with polyphenolic structure. In this study secondary metabolites of Lathyrus armenus (Boiss. & Huet) which endemic for Turkey was studied. Flavonol glycosides (Rhamnocitrin-3-O-rhamninoside, Rhamnetin-3-O-rhamninoside, Rhamnazin- 3-O-rhamninoside, kaempferol3-O-rhamninoside and, kaempferol-3-O-glucosyl (1→2) rhamnoside) was isolated by different chromatographic methods and identified by 1H, 13C NMR, as well as 2D NMR and Mass spectroscopy techniques from ethyl acetate and aqueous fractions of L. armenus’s methanolic extract. This is the first study about secondary metabolites of Turkish Lathyrus species.

Cleistocactus winteri is a succulent plant of the Cactaceae family, commonly known as the golden rat tail. Many members of the Cactaceae family are the focus of chemical and biological studies as they contain bioactive compounds, well known for their health-related properties. We aimed to investigate Cleistocactus winteri stems both phytochemically and biologicallyfor the first timeincluding three biological effects. For the evaluation of theanti-inflammatory activity, Nitric oxide (NO) inhibition on lipopolysaccharide (LPS) stimulated Raw murine microphages (RAW 264.7) cell model was used. The cytotoxic activity was evaluated against hepatocarcinoma (HepG2), breast adenocarcinoma (MCF-7), colorectal carcinoma (HCT-116), and colon adenocarcinoma (CACO 2) human cancer cell lines using MTT (3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide) assay. The antioxidant activity was evaluated using 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay. Seven alkaloids were tentatively identified based on Mass bank on line library in addition to the isolation and identification of four known flavonoids and a β-sitosterol 3- O-glucoside from the studied extract. The stem methanol extract showed a 6% inhibition of NO production (up to 48 μmol/L). Furthermore, the IC50 of the total alkaloid fraction against HepG2, MCF-7, and CACO-2 cell lines was equal to 26.53, 23.8, and 13.07 µg/mL, respectively, while that of the methanol extract against Hep-G2 and HCT-116 was 181 µg/mL and 357 µg/mL, respectively with no effect against MCF-7 cell line. The antioxidant effect of the extract was about one third (112 µg/mL) that of ascorbic acid.

Clopidogrel is an antiplatelet agent currently used for preventing stent thrombosis. Despite certain clinical benefits of clopidogrel in patients undergoing percutaneous coronary intervention (PCI), adequate antiplatelet effect has not been obtained in some patients. The present study was designed to investigate the potential association of ABCB1 (ATP-Binding Cassette, Subfamily B, member1) gene polymorphism, and clopidogrel responsiveness in Iranian patients after PCI. Sixty-seven patients were included in the study. Blood samples were taken from patients at baseline, 2 h after administration of 600-mg loading dose of clopidogrel, 24 h and 30 days after PCI. Platelet aggregation was measured by light transmittance aggregometry (LTA) with two levels of adenosine diphosphate (ADP) concentrations (5 and 20 µM). ABCB1 genotyping was performed by restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR). The allelic frequencies of wild type, heterozygote, and homozygote genotypes of ABCB1 were 20.9%, 74.6%, and 4.5%, respectively. There was no significant association between polymorphism of ABCB1 and clopidogrel non-responsiveness (P > 0.05) in various situations. No significant difference was observed for demographic characteristics. Genetic and demographic factors had no significant effect on the platelet activity of clopidogrel in an Iranian population.

Pain after total abdominal hysterectomy (TAH) is a major concern. Pain management is very important issue after TAH. This study aimed to assess the efficacy of intraperitoneal instillation of lidocaine for postoperative pain relief after TAH. A double-blinded randomized placebo-controlled trial was conducted on patients undergoing total abdominal hysterectomy in Al-zahra hospital from June 2007 to July 2008. Forty patients were randomly assigned with equal number in two lidicaine (N = 20) and normal saline (N = 20) groups. The lidocaine group received 50 mL of 0.8% lidocaine with epinephrine and placebo group received 50 ml of saline 0.9%. We used 10 cm visual analog scale (VAS) for assessing pain at 8, 12, and 24 h at rest and 48 h on movement. Opioid consumption, patient’ satisfaction with pain control, and incidence of postoperative nausea and vomiting were assessed. Means of pain score at different times in lidocaine group were significantly lower than placebo group (P ˂0.05) the difference between mean dose of opioid consumption over 24 h between two groups was not significant (P =0.785). Patient’s satisfaction score in lidocaine group was significantly higher than saline group (P =0.034). Differences in incidence of postoperative nausea and vomiting between two groups were not significant (P =1.0). Intraperitoneal instillation of 50 mL of 0.8% lidocaine with epinephrine is an effective and safe technique for postoperative pain management after TAH. But this technique cannot reduce opioid consumption over 24 h after TAH.

Calcium Hydroxide (CH) is commonly employed as intracanal medicament in endodontics. In order to maximize its therapeutic effects, it is essential to develop new approaches for preparing the controlled drug release systems which, in turn, facilities the dissociation of CH into calcium and hydroxyl ions. This work studies the sustained-controlled release of calcium ions and the effect of pH changes on the different formulation of CH with hydrophilic natural polymers over a period of 30 days. Various formulations were prepared by combining CH with gelatin, aloe vera and gum tragacanth. Root canals of 60 human teeth were instrumented and filled with a different formulation of CH and suspended in plastic tubes containing distilled water. Three formulas of polymer/CH were evaluated, and pure CH powder was used as a control. At specific time intervals, the calcium ions release and the pH changes of the medium in different formulations were analyzed. The main interactions between the studied polymers and CH were investigated using FTIR spectra. The antibacterial activity of formulations against Enterococcus faecalis was also studied. Faster release of CH was observed for aloe vera/CH. Gum tragacanth/CH showed a slow-release during the first 15 days. In contrast, only Gelatin/CH formulation showed a prolonged release with statistically significant differences (P < 0.05). The pure CH showed significantly higher pH values than the other formulations. The Gelatin/CH formulation was a better sustained-release system than the pure CH, and it can be used as a promising vehicle for CH in the root canal treatment.

MicroRNAs has been shown to regulate lipogenesis in liver. The aim of the present study was to investigate whether the effects of resveratrol (RSV) on lipogenesis is associated with the changes in the expression of two miRNAs (miR-107 and miR-10b) that regulate lipogenic pathways. 30 wild type C57BL/6j male mice were randomly fed three diets: a standard chow diet (ND), a high fat diet (HFD, 60% fat) and the high fat diet supplemented with 0.4% RSV (HFD-RSV) for 16 weeks. HepG2 cells were treated with high glucose (33mM) and RSV (20µM) for 24 h. The expression of the genes and miRNAs were measured by real-time PCR. Triglyceride level was increased in the liver of mice and HepG2 cells. In both animal and in vitro experiments, triglyceride level was significantly decreased in groups treated with RSV. The expression of the miR-107 and miR-10b was significantly upregulated in the liver of HFD mice, whereas HFD-RSV group demonstrated a significant lower expression of both miRNAs compared to HFD group. In addition, RSV treatment significantly upregulated the expression of CPT-1a and PPARα genes in the liver of HFD mice. Moreover, treatment with RSV could reduce the expression of miR-107 and miR-10b and increase the expression of CPT-1a and PPARα in HG-treated HepG2 cells. These evidence, as a whole, suggest that RSV could exert its anti-lipogenic effect partially through alterations in the expression of miR-107 and miR-10b in liver cells.

Conducting cell apoptosis pathways is a novel strategy in cancer treatment. This study aimed to explain that C. botrys essential oil could induce apoptosis and arrest the cell cycle in HeLa cells. Cytotoxic and apoptogenic effects of the essential oil of Jerusalem-oak (Chenopodium botrys L.), which was obtained from the aerial parts of the plant, were evaluated in HeLa cells. Cell viability was assessed by MTT and LDH assays, and the mechanism of cell apoptosis was investigated using flow cytometry. Expression of the apoptosis-related genes was assessed using real-time polymerase chain reaction (PCR). GC-MS analysis of the herbal essential oil revealed 37 components. The major components were α-Eudesmol (16.81%), Elemol acetate (13.2%), Elemol (9.0%), and α-Chenopodiol-6-acetate (7.9%). The essential oil inhibited the growth of HeLa cells and increased the expression of p21 and p53. In addition, essential oil treatment increased the sub-G1 DNA content and induced apoptosis due to the increased Bax/Bcl-2 ratio and up-regulation of caspase-3 gene expression. According to the results, C. botrys essential oil exhibited anticancer effects through intrinsic apoptosis pathways and arresting cell proliferation.

Non-steroidal anti-inflammatory drugs (NSAIDs) identified effective in many diseases. One of which is neurodegenerative diseases including Alzheimer disease (AD). In this study gross alteration of gene expression in AD mice by ibuprofen treatment is investigated via Protein-protein interaction network (PPI) analysis. Expression profiling of microarray dataset GSE67306 was retrieved from GEO database and analyzed via GEO2R tool. PPI analysis was performed via Cytoscape 3.7.0. and its plug-ins including Network Analyzer, Gene MANIA, and CluePedia. Numbers of 10 central genes including Htr1a, Sstr2, Drd2, Htr1b, Penk, Pomc, Oprm1, Npy, Sst, and Chrm2 were identified as potential biomarkers. However, the role of Penk gene was highlighted. The finding indicates that ibuprofen changes gene expression level of several genes that are involved in AD.

In this study, methoxylated flavonoids and volatile constitutions of Agrostis gigantea Roth (Poaceae) were investigated for the first time. The flavonoids were identified by spectroscopic methods (1H-NMR, 13C-NMR, COSY, NOSEY, TCOSY, and HMBC). The volatile constitutions of aerial parts and seeds were analyzed by gas chromatography–mass spectrometry (GC-MS). Two methoxylated flavonoids, luteolin 5-methyl ether (1), cirsilineol (2) were isolated from the aerial parts of this plant. According to the GC-MS data the main constitutions of these volatile oils belong to the simple phenolic category which include coniferyl alcohol (18.80%) and eugenol (12.19%) in aerial parts and seeds, respectively. By using the computer- aided molecular modeling approaches, the binding affinity of these compounds was predicted in the catalytic domains of aryl hydrocarbon receptor (AhR). These two isolated flavonoids were investigated in vitro for their inhibitory activity on 4T1 breast carcinoma cells. It was predicted that these compounds could be well-matched in aryl hydrocarbon receptor (3H82) active site. but based on the in vitro assay, he IC50 values on cytotoxicity were 428.24 ±3.21 and 412.7±3.02 μg/ml for luteolin 5-methyl ether and cirsilineol, respectively. Thus it can be concluded that, these flavonoids exhibit low cytotoxicity against 4T1 breast carcinoma cell line.

The successful therapy strategy of gastric cancer is defined as devastating of the cancerous cells without exposing systematic toxicity and undesirable side effects. One strategy to overcome cancer treatment related difficulties could be combination therapy with natural products with anticancer drugs to introduce effective antitumor effects in addition to reduction of undesirable side effects. On the subject of the pointed fact, different extracts of mulberry leaf, isoquercetin and rutin as reported extracted flavonoids from M. alba in single doses as well as in combination with cisplatin against gastric cancer cell line were prescribed. This innovative treatment led to inspiration of cytotoxicity on gastric cancer in synergistic manner. The findings anticipated that these herbal products have exceptional potential for future gastric cancer therapy investigations.

Orexin can increase neuronal excitability and induce epileptic activity. In this study, the effects of suvorexant (orexin receptor antagonist) on pentylenetetrazol (PTZ) and maximal electroshock (MES)-induced seizure were investigated. Mice were divided into 5 groups of six animals each including normal saline (10 ml/kg), diazepam (2 mg/kg) and suvorexant (50, 100 and 200 mg/kg) groups. In PTZ test, the latency to first minimal clonic seizure (MCS), latency to the first generalized tonic–clonic seizures (GTCS), total duration of seizure and also protection against mortality were evaluated. In MES, the hind limb tonic extension (HLTE) and the protection against mortality were recorded. In order to evaluate the role of GABAA in anticonvulsant effect of suvorexant, flumazenil was used and to investigate the role of glutamate, the protein levels of AMPAR and NMDAR were measured in hippocampus by western blotting. In PTZ model, suvorexant (200mg/kg) increased MCS and GTCS latencies. Suvorexant (100 and 200 mg/kg) decreased total duration of seizure compared to control group. In PTZ model, flumazenil inhibited the prolongation of seizure latency induced by suvorexant. In MES, the HLTE was decreased by suvorexant (100 and 200 mg/kg) and suvorexant protected against mortality by 83.3%. Moreover, the protein levels of NMDAR and AMPAR were decreased by suvorexant. Suvorexant exerted anticonvulsant activity and in addition to its inhibitory effect on orexin receptors, this effect may be mediated, at least partly, through interaction with GABAA and glutamate receptors.

Hyperglycemia and hyperlipidemia have been symptoms of many serious diseases such as diabetes and atherosclerosis overall the world. Thus, drug researchers have focused on new, natural and healthy drug alternatives. Marine macroalgae is a great source of hypoglycemic, hypolipidemic or hypocholesterolemic agents. In this study, we investigated that hypoglycemic, hypolipidemic and cytotoxic potentials of 22 marine macroalgae from the Gulf of Izmir. According to our results, the cold methanol extract of Polysiphonia denudata exhibited the highest antioxidant activity (93.6%) compared to BHA (95.3%). Three Cystoseira species, Cystoseria crinita (91.9%), Cystoseria barbata (90.7%), Cystoseria compressa (89.8%) showed higher α-glucosidase inhibition rates than oral antidiabetic acarbose (79.5%). It has also been observed that same species are potent inhibitors of pancreatic lipase. Cytotoxicity test revealed that these extracts did not cause viability inhibition on MCF-7. The results of maltose- glucose assay indirectly displayed that Cystoseira cold methanolic extracts inhibited maltose consumption better than acarbose on HT29. The results of this screening study show that these Cystoseira species may provide non- toxic bioactive agents to control non-communicable diseases (NCDs) such as cardiovascular disease and diabetes mellitus.