Advanced Pharmaceutical Bulletin
Volume:9 Issue: 1, Feb 2019

Ketamine-propofol combination (ketofol) is being used to provide a safe and effective procedural sedation (PS) in emergency department (ED) and may theoretically have beneficial effects since using lower doses of each drug may result in a reduction of the adverse events of both agents while maintaining optimal conditions for performing procedures. This systematic review was conducted to evaluate the efficacy, advantages and disadvantages of these two drugs for PS. The PRISMA statement was used for this systematic review. We searched the databases of PubMed, Scopus, ProQuest, Medline (Ovid) from 1990 to August 2017 for randomized clinical trials (RCTs) in which the study population aged ≥18 and was referred to ED. Full-texts of the studies performed in adults that were published in English were reviewed for inclusion. Both authors independently evaluated all studies. Five articles were eligible for the meta-analysis based on their common outcomes. The total number of subjects was 1250, of which 635 were treated with propofol and 615 were treated with ketofol. Although two of the five studies showed a better quality of sedation with ketofol, the other three did not find any significant difference between propofol and ketofol. This systematic review found a lower incidence of respiratory adverse effects in ketofol group than propofol group. Ketamine/propofol mixture (ketofol) has less respiratory adverse effects than propofol alone in ED procedural sedation.

As one of the four major families of pattern recognition receptors (PRRs), toll like receptors (TLRs) are crucial and important components of the innate immune system. Peroxisome proliferatoractivated receptors (PPARs) with three isoforms are transcription factors classified as a subfamily of nuclear receptor proteins, and are of significant regulatory activity in cellular differentiation, development, metabolism, and tumorigenesis. It is well established that PPARs agonists display anti-inflammatory effects through inhibition of the nuclear factor-kappa B (NF-κB) pathway, a key regulator of immune and inflammatory responses, in a sense that TLRs signaling pathways are mainly toward activation of NF-κB. Through a systematic review of previous studies, we aimed to address and clarify the reciprocal interaction between TLRs and PPARs in hope to find alternative therapeutic approaches for inflammatory diseases. Among the available scientific database, 31 articles were selected for this review. A comprehensive review of this database confirms the presence of a cross-talk between PPARs and TLRs, indicating that not only PPARs stimulation may affect the expression level of TLRs via several mechanisms leading to modulating TLRs activities, but also TLRs have the potential to moderate the expression of PPARs. We, therefore, conclude that, as a key regulator of the innate immune system, the interaction between PPARs and TLRs is a potential therapeutic target in disease treatment.

Exposure to food toxins generate multiple adverse health effects. Heavy metals, antibiotics residue, mycotoxins, pesticides and some food additives are examples of the most important food toxins. The common mechanism of toxicity and carcinogenicity effects of food toxins is the generation of oxidative stress that leads to DNA damages. Moreover, based on epidemiologic evidence unhealthy eating habits and food toxicities are associated with cancers occurrence. Therefore, application of bioactive food additives as harmless or safe components in food industry is expensive. Nigella sativa L. is a broadly used herb-drug for various diseases all over the world and has been used as preservative and food additive. Based on various studies N. sativa has shown various pharmacological activities including therapeutic efficacy against different human diseases and antioxidant anti-inflammatory effects against environmental toxins. N. sativa decreases the adverse health effects induced by mentioned food toxins via modulating the action of antioxidant enzymes such as glutathione peroxidase (GPx), glutathione-S-transferase catalase and act as reactive oxygen species (ROS) scavengers in different organs. Besides, N. sativa and thymoquinone (TQ) have protective effects on food products through removal and inhibition of various toxic compounds. Therefore, in the present review we will describe all protective effects of N. sativa and its main constituents, TQ, against food induced toxicities.

All cells encounter various signals coming from the surrounding environment and they need to receive and respond to these signals in order to perform their functions. Cell surface receptors are responsible for signal transduction .Platelets are blood cells which perform several functions using diverse receptors. Platelet concentrate is one of the most consumed blood products. However, due to the short lifespan of the platelets and platelets damage during storage, we face shortage of platelet products. One of the damages that platelets undergo during storage is the loss of surface receptors. Since cell surface receptors are responsible for all cell functions, the loss of platelet receptors reduces the quality of platelet products. In this study, we reviewed the important receptors involved in platelet activation and their associated signaling pathways. We also looked at the platelet receptors that shed during storage and the causes of this incident. We found that GPIbα, P-selectin, CD40 and GPVI are platelet receptors that fall during platelet storage at room temperature. Considering that GPVI and GPIbα are the most important receptors which involved in platelet activation, their shedding can cause decrease in platelet activation after transfusion and decrease thrombus consistence. Shear stress and platelet contact with the container wall are among the mechanisms discussed in this process, but studies in this area have to be continued.

Male sex is more prone to cerebrovascular disorders, yet the exact role of androgens in cerebral ischemia remains unclear. Here we reviewed current understanding of testosterone (TES) neuroprotective activity against ischemic stroke and mechanisms underlying these effects in aging. TES may exert a neuroprotective effect in aging through pathways including inhibition of oxidant molecules production, enhancing the enzymatic antioxidant capacity of the brain and modulation of apoptotic cell death. Given this, a better understanding of the neuroprotective roles of TES may propose an effective therapeutic strategy to improve the quality of life and decrease androgen-related cerebrovascular problems in the aging men.

Mesenchymal stem cells (MSCs) have been shown to reduce the activity of immune cells, including dendritic cells (DCs). But the exact mechanism of mesenchymal inhibition of DCs is still unknown. In this study, the effect of mesenchymal cells on the expression of indoleamine dioxygenase (IDO) and Qa2 molecules in DCs was evaluated. MSCs and DCs were respectively isolated from the bone marrow and spleen of BALB/c mice. Then DCs were co-cultured with MSCs in the present and absence of lipopolysaccharides (LPS). Then the expression of mRNA and protein of IDO and Qa2 molecules were investigated in DCs that were treated with MSCs. The expression of IDO and Qa2 mRNA in DCs that were treated with MSCs did not significantly differ from the control group. The expression of IDO protein in DCs that were cocultured with MSCs (in 1:10 and 1:50 ratios) in absence of LPS was increased, although they were not statistically significant (P values: 0.24 and 0.18, respectively). The expression of Qa2 protein in DCs that were co-cultured with MSCs (in 1:10 and 1:50 ratios) in presence of LPS was increased, although they were not statistically significant (P-values: 0.09 and 0.33, respectively). Our results denied the possibility that MSCs led to the induction of tolerogenic DCs by increasing the expression of the IDO and Qa2 immunomodulatory molecules.

The single-chain variable fragment (scFv) domain of antibodies is now considered as one of the therapeutic tools that can be produced by phage display technology (PDT). Antibody purification is one of the most important steps in antibodies production. The aim of study was purification and characterization of anti-VEGFR2 scFv antibody fragments. After the coating of vascular endothelial growth factor receptor 2 (VEGFR2) peptide in ELISA microplates, the phage display library of Tomlinson was used for antibody isolation. The targeted scFv was purified by chromatography using a zeolite-based column. The purity and functional assessment of purified scFv were evaluated by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and western blotting techniques, respectively. Affinity binding was evaluated by surface plasmon resonance (SPR). The desired scFv was selected after four stages of biopanning. SDS-PAGE analysis showed a 28 kDa scFv with high purity (>90%). The western bloting analysis confirmed the binding of produced scFv antibody to the desired peptide. The affinity binding of scFv antibody analyzed by SPR was about 60 μM. In this study, the novel scFv antibody against VEGFR2 peptide was purified by chromatography column containing zeolite. Based on our findings the produced antibody may be applied for diagnosis or targeting of VEGFR2 in antibody-based therapy strategies.

Although it has been frequently confirmed that HLA-G plays an important role in the reproduction and pregnancy, the pattern of HLA-G gene and its protein expression are rarely addressed in studies. Therefore we conducted this study in regard to evaluate the HLA-G gene and its protein expression in the women’s placenta with recurrent miscarriage. Placental samples were obtained from the women who were admitted for delivery or abortion in Al Zahra and Taleghani hospitals, Tabriz, Iran. HLA-G gene expression was determined by real-time polymerase chain reaction (PCR) and HLA-G protein expression was assessed by western blotting and immunofluorescence staining in the tissue samples. The results showed a significant decrease in the expression of gene and proteins of HLA-G in the women with recurrent miscarriage compared to the control placental tissues. According to the obtained results, it was concluded that the decrement of HLA-G gene and protein expressions are associated with recurrent miscarriage. Since there are conflicting results from other studies, it is suggested to conduct a more comprehensive similar study with greater sample size.

To investigate the protective effect of preconditioning with non-toxic dose of hydrogen peroxide (H2O2) as a possible cell signaling molecule, against cell death induced by toxic concentration of H2O2 or by serum deprivation in human Wharton’s jelly-derived mesenchymal stem cells (HWJ-MSCs) and underlying mechanisms. HWJ-MSCs were isolated and identified using flow cytometry. After finding non-toxic concentration of H2O2, cells preconditioning was performed by H2O2 (20 μM) for 12 h and cell tolerance against serum deprivation or toxic levels of H2O2 was assayed by MTT test. Effect of preconditioning on mRNA and protein expression of Akt-1, Bcl-2 and Bax were examined using reverse transcription polymerase chain reaction (RT-PCR) and western blotting respectively. Role of hypoxia-inducible factor (HIF)-1α was explored in presence HIF-1α inhibitor. Preconditioning with 20 μM H2O2 for 12 h was non-toxic and decreased cell death induced by oxidative stress and serum deprivation in MSC cultures. However, the increased tolerance reversed in the presence of inhibitor of HIF-1α. By regards to RT-PCR and western blotting data, although expression of Akt-1, Bcl-2 and Bax was not change considerably but phosphorylated Akt-1 (pAkt-1) was up regulated after treatment with 20 μM H2O2 compared to control group. Moreover after exposure to 100 μM H2O2, western blotting analysis showed that cell pretreatment with 20 μM H2O2, decremented Bax/Bcl2 ratio and up-regulated HIF-1α and pAkt-1 compared to the control group. Increased tolerance of H2O2-pretreated cells led to the suggestion that transplantation of H2O2 preconditioned MSCs may improve therapeutic potential of stem cells in cell therapy procedures.

In this review, a set of aryl halides analogs were identified as potent checkpoint kinase 1 (Chk1) inhibitors through a series of computer-aided drug design processes, to develop models with good predictive ability, highlight the important interactions between the ligand and the Chk1 receptor protein and determine properties of the new proposed drugs as Chk1 inhibitors agents. Three-dimensional quantitative structure–activity relationship (3D-QSAR) modeling, molecular docking and absorption, distribution, metabolism, excretion and toxicity (ADMET) approaches are used to determine structure activity relationship and confirm the stable conformation on the receptor pocket. The statistical analysis results of comparative -molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models that employed for a training set of 24 compounds gives reliable values of Q2 (0.70 and 0.94, respectively) and R2 (0.68 and 0.96, respectively). Computer–aided drug design tools used to develop models that possess good predictive ability, and to determine the stability of the observed and predicted molecules in the receptor pocket, also in silico of pharmacokinetic (ADMET) results shows good properties and bioavailability for these new proposed Chk1 inhibitors agents.

The aim of this study was to prepare formulations of theophylline microbeads using pregelatinized breadfruit starch (Artocarpus altilis, family Moraceae) in combination with sodium alginate and chitosan at various polymer: drug ratios. Microbead formulations for controlled delivery of theophylline would be better alternatives to conventional dosage forms for optimized drug therapy. The native and pregelatinized starches were characterized for morphology (scanning electron microscope), crystallinity (Fourier transform intra-red spectroscopy, FTIR and X-ray diffractometer, XRD), thermal flow (differential scanning colorimeter), density and flow properties. Theophylline microbeads were prepared by ionic gelation and characterized using size, swelling index, entrapment efficiency and time required for 15% and 50% drug release (t15 and t50 respectively). FTIR and XRD spectra revealed the orderly arrangement of granules of the semi-crystalline breadfruit starch was disrupted on gelatinization. The viscosity and flow of pregelatinized starch were enhanced. Theophylline microbeads were near spherical in shape with size range 1.09 ± 0.672 to 1.58 ± 0.54 mm. FTIR and XRD spectra confirmed there was no drug-polymer interaction. Microsphere size, swelling increased while entrapment and dissolution time (t50) reduced with polymer: drug ratio. The entrapment efficiency ranged from 30.99 ± 1.32 to 78.50 ± 2.37%. Optimized formulation, starch: alginate ratio 3:1 at polymer: drug ratio of 2:1, gave a prolonged dissolution time (t50 = 8.40 ± 1.20 h). Breadfruit starch was suitable as a copolymer for the controlled delivery of theophylline in microbeads which could serve as a substitute to synthetic polymers in drug delivery.

Different compositions of copper oxide (CuO)-doped calcium silicate clusters were used to treat the cancer cells. The influence of CuO content on the morphology, drug delivering ability, physicochemical properties and cytotoxicity was investigated. The microcrystalline structure revealed the decrement of the size from (20-36 nm) to (5-7 nm) depending on the copper content percentages. Drug delivering ability of doxycycline hyclate (Dox) was down regulated from 58% to 28%in the presence of the CuO. The inclusion of CuO and Dox didn’t show any remarkable changes on the physicochemical properties of the CuO-doped calcium silicate nanoparticles. The CuO-doped calcium silicate sample (5 weight %) exhibited great cytotoxicity against the tested cell lines compared to the CuO-free sample. CuO-doped materials displayed significant anticancer effect; this sheds light on its implication in the treatment of cancer.

Drug-abuse, namely morphine (MO) affects the metabolism of neurotransmitters such as dopamine (DA). Therefore, it is crucial to devise a sensitive sensing technique to simultaneously determine both compounds in real samples. The fabrication of the sensor is based on in situ modification of a carbon paste (CP) electrode with cobalt oxide nanoparticles, graphene, and ionic liquid crystal in presence of sodium dodecyl sulfate; CoGILCCP-SDS. The modified sensor is characterized using scanning electron microscopy, electrochemical impedance spectroscopy and voltammetry measurements. Electron transfer kinetics and analytical performance of the proposed sensor were enhanced due to the synergistic role of all the modifiers. The simultaneous determination of MO and DA achieved low detection limits of 0.54 nmol L−1 and 0.25 nmol L−1, respectively. Besides, a carbon-based electrochemical sensor is fabricated for the nano-molar determination of MO in real samples and formulations. The sensor showed fouling resistance and anti-interference ability in presence of other species in human fluids. The real sample analysis of MO was successfully achieved with good recovery results in urine samples and pharmaceutical tablets. Linear dynamic range, sensitivity, detection limit and quantification limit of MO in urine were 5 nmol L−1 to 0.6 μmol L−1, 6.19 μA/μmol L-1, 0.484 nmol L−1 and 1.61 nmol L−1, respectively. This sensor has great ability to be extended for electrochemical applications in assaying of many drugs.

The objective of the current study was to compare the anticancer efficacy of doxorubicin-loaded cellulose based magnetic (Fe3O4), zinc oxide (ZnO) nanoparticles on and free doxorubicin (DOX) on MCF-7 breast cancer cells. Novel pH-sensitive cellulose-graft poly acrylic acid based Fe3O4 (Cellulose-g-PAAg- PAcMNPs) and ZnO (Cellulose-g-PAA-g-PAcZnO) nanocomposites were synthesized via polymerization of acrylic acid and modified 3-(trimethoxysilyl) propyl methacrylate onto the cellulosic backbone via reversible addition-fragmentation chain transfer (RAFT) method. Cellulose-g-PAA-g-PAcMNPs and Cellulose-g-PAA-g-PAcZnO nanocarriers with mean diameter of 15 and 38 nm were prepared successfully. DOX was loaded effectively to the ZnO and Fe3O4 nanocarriers via complexing and electrostatic force with great encapsulation efficiency of 99.07% and 98.92%, respectively. DOX-loaded nanocarriers showed obvious pHdependent tumor specific drug release pattern. MTT assay results indicated that IC50 of the DOX loaded Cellulose-g-PAA-g-PAcZnO, DOX loaded Cellulose-g-PAA-g-PAcMNPs and free DOX after 48 hours treatment with MCF7 cell lines were about 24.03, 49.27 and 99.76 μg mL−1, respectively. Therefore both DOX nanoformulations significantly increase antitumor ability compared to free DOX (P < 0.05). The results of MTT assay and DAPI staining revealed that DOX-loaded Cellulose-g-PAA-g-PAcZnO NPs show higher chemotherapy efficiency in MCF7 breast cancer cell line compare to the DOX-loaded Cellulose-g-PAA-g-PAcMNPs due to high interaction of ZnO with DOX. The formation of the complexes between the DOX and ZnO nanoparticles at the chelating sites of the quinone and the phenolic oxygen molecules of DOX, lead to more sustained drug release and enhanced chemotherapy effectiveness by increasing the intracellular concentration of DOX.

The novel sodium dodecyl sulfate modified carbon nanotube paste electrode (SDS/ CNTPE) was used as a sensitive sensor for the electrochemical investigation of L-tyrosine (TY). The electrochemical analysis of TY was displayed through cyclic voltammetry (CV) and differential pulse voltammetry (DPV). The surface morphology of SDS/CNTPE and bare carbon nanotube past electrode (BCNTPE) was reviewed trough field emission scanning electron microscopy (FESEM). The functioning SDS/CNTPE shows a voltammetric response with superior sensitivity towards TY. This study was conducted using a phosphate buffer solution having neutral pH (pH=7.0). The correlation between the oxidation peak current of TY and concentration of TY was achieved linearly in CV method, in the range 2.0×10-6 to 5 ×10-5 M with the detection limit 729 nM and limit of quantification 2.43 μM. The investigated voltammetric study at SDS/CNTPE was also adopted in the examination of TY concentration in a pharmaceutical medicine as a real sample with the recovery of 97% to 98%. The modified electrode demonstrates optimum sensitivity, constancy, reproducibility, and repeatability during the electrocatalytic activity of TY.

In this investigation, a new version of magnetic solid phase extraction (MSPE) performed in a narrow–bore tube has been proposed. In this study, hydrophobic octyl (C8) functionalized Fe3O4 magnetic nanoparticles (MNPs) stabilized by SiOH groups (Fe3O4@SiO2@C8) are used as magnetic nano–sorbents for the extraction of cardiovascular drugs from human plasma prior to their determination by high performance liquid chromatography–photodiode array detection. After precipitation of the plasma proteins, the supernatant is diluted with deionized water and filled into the narrow–bore tube. Then mg–level of the sorbent is added into the tube. The sorbent is dispersed and moved down through the solution instead of passing the solution from the cartridge. Using an external magnet, the collected nano–sorbents at the bottom of the tube are transferred on top of the solution and released to move down through the solution for three times to increase the extraction efficiency. The linearity of the assay was ranging from 0.4–500 mg mL-1. The limits of detection and quantification of the method were obtained in the ranges of 0.05–0.07 and 0.16–0.24 mg L-1, respectively. The extraction recoveries were obtained in the range of 31–49%. Intra– and inter–day precisions were calculated and obtained in the ranges of 5–8 and 7%–9% for 0.5 mg L-1 of each analyte, and 5–6 and 6%–8% for 2 mg L-1 of each analyte, respectively. The proposed method was successfully used in determination of the studied drugs in patient’s plasmas.

A stereoselective high performance liquid chromatographic analytical method with photodiode array detector was developed and validated as per the International Conference on Harmonization (ICH) guidelines for the determination of alogliptin (ALO) enantiomers in formulations and rat plasma. Enantiomeric separation was performed on a Phenomenex Lux Cellulose-2 chiral column. Box-Behnken design was used to identify the optimum conditions of the three independent variables for the desired output responses. The HPLC peaks of ALO enantiomers and the internal standard pioglitazone were achieved before 8 min with a resolution of 0.77 min between R and S enantiomer and resolution of more than 2.0 between each enantiomer and pioglitazone (internal) with more than 95% recovery. The linearity range and the limit of quantification of both the enantiomers in rat plasma were 10-70 ng mL-1 and 1.2 ng mL-1 respectively. The developed method after validation was successfully applied for estimation of ALO enantiomers in formulations. Single oral dose of 25 mg of the ALO racemate tablets were administered to a group of 6 healthy rats for a comparative pharmacokinetic study of both the enantiomers.

In this study, we aimed to prepare an extended drug delivery formulation of clarithromycin (CAM) based on a semi-interpenetrating polymer network (semi-IPN) hydrogel. Synthesis of semi-IPN hydrogel nanocomposite made of chitosan (CS), acrylic acid (AA), acrylamide (AAm), polyvinylpyrrolidone (PVP), and montmorillonite (MMT) was performed by free radical graft copolymerization method. Swelling kinetic studies were done in acidic buffer solutions of hydrochloric acid (pH = 1.2), acetate (pH = 4), and also distilled water. Also, the effects of MMT on the swelling kinetic, thermal stability, and mechanical strength of the hydrogels were evaluated. Moreover, in vitro release behavior of CAM and its release kinetics from hydrogels were studied in a hydrochloric acid buffer solution. Fourier transform infrared spectroscopy (FTIR) results revealed that synthesis of semi- IPN superabsorbent nanocomposite and CAM incorporation into hydrogel was performed, successfully. Introducing MMT into hydrogel network not only improved its thermal stability but also increased mechanical strength of the final hydrogel product. Also, in comparison with neat hydrogel (1270 g/g), hydrogel nanocomposite containing 13 wt% MMT exhibited greater equilibrium swelling capacity (1568 g/g) with lower swelling rate. In vitro drug release experiments showed that CS-g-poly(AA-co-AAm)/PVP/MMT/CAM formulation possesses a sustained release character over extended period of time compared with CS-g-poly(AA-co- AAm)/PVP/CAM formulation. In the presence of MMT, the effective life time of drug is prolonged, demonstrating a sustained release property. The reason is that interlinked porous channels within superabsorbent nanocomposite network hinder penetration of aqueous solutions into hydrogel and subsequently cause a slower drug release.

Medication errors (MEs) are a leading cause of morbidity and mortality, yet they have remained as confusing and underappreciated concept. The complex pharmacotherapy in hospitalized patients necessitates continued report and surveillance of MEs as well as persistent pharmaceutical care. This study evaluated the frequency, types, clinical significance, and costs of MEs in internal medicine wards. In this 8-month prospective and cross-sectional study, an attending clinical pharmacist visited the patients during each physician’s ward round at the morning. All MEs including prescription, transcription, and administration errors were detected, recorded, and subsequently appropriate corrective interventions were proposed during these rounds. The changes in the medications’ cost after implementing clinical pharmacist’s interventions were compared to the calculated medications’ cost, assuming that the MEs would not have been detected by clinical pharmacist and continued up to discharge time of the patients. 89% of the patients experienced at least one ME during their hospitalization. A mean of 2.6 errors per patient or 0.2 errors per ordered medication occurred in this study. More than 70% of MEs happened at the prescription stage by treating physicians. The most prevalent prescription errors were inappropriate drug selection, unauthorized drugs and untreated indication. The highest MEs occurred on cardiovascular agents followed by antibiotics, and vitamins, minerals, and electrolytes. The net effect of clinical pharmacist’s contributions in medication therapy management was to decline medications’ costs by 33.9%. The role of clinical pharmacy services in detection, prevention and reducing the cost of MEs is of paramount importance to internal medicine wards.