فهرست مطالب

Pharmaceutical Research - Volume:21 Issue: 1, Winter 2022
  • Volume:21 Issue: 1, Winter 2022
  • تاریخ انتشار: 1401/02/18
  • تعداد عناوین: 25
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  • Mahnaz Samadbeik, Maryam Ahmadi*, Farahnaz Sadoughi, Ali Garavand Page 1

    Evaluation of electronic prescribing systems (EPS) can contribute to their quality assurance, and motivate users and policy-makers to implement these systems, directly influencing the health of society. An appropriate evaluation tool plays a determining role in the identification of proper EPS. The present study aimed to develop a multifaceted evaluation tool for assessing the EPS. This study was conducted in two main steps in 2018. In the first step, we conducted a literature review to find the main features and capabilities of the prosperous EPS. In the second step, a Delphi method was used for determining the final criteria for evaluating EPS. After preparing a primary questionnaire based on the first step results, 27 expert stakeholders from related fields participated in this 3-phase Delphi study. The narrative content analysis and descriptive statistics were used for data analysis. The final evaluation tool consists of 61 questions in 10 main dimensions, including practical capabilities of the process/user and patient safety, data storage and transfer, prescription control and renewal, technical functions, user interfaces, security and privacy, reporting, portability, hardware and infrastructure, and system failure/recovery. The evaluation tool developed in this study can be used for the critical appraisal of features of EPS. It is recommended that this multifaceted evaluation tool be employed to help buyers compare different systems and assist EPS software vendors in prioritizing their activities regarding the system development. By using this tool, healthcare organizations can also choose a system that improves many aspects of health care.

    Keywords: Electronic Prescribing, Evaluation Tool, Assessment, Prescription, E-prescribing
  • Elaheh Mahmoudzadeh, Hossein Nazemiyeh, Sanaz Hamedeyazdan* Page 2

    The Symphytum genus has been mainly used in traditional medicine, containing its anti-inflammatory activity. Symphytum spp.’s active components, such as allantoin, polyphenols, flavonoids, and alkaloids, can act on several intentions in the signaling pathway, constrain pro-inflammatory enzymes, reducing the construction of inflammatory chemokine’s and cytokines, and decreasing oxidative stress, which afterward suppresses inflammation procedures. Preclinical and clinical trials have reported the prevailing anti-inflammatory effect of several Symphytum species. This review presents an overview of the anti-inflammatory activities of different products and bioactive constituents in this genus. The papers with the English language were gathered from 2000 to 2021. This review may provide a scientific base for establishing innovative and alternative techniques for isolating a single individual from this genus to attenuate inflammatory disorders. The Symphytum genus is waiting for researchers to develop safe and effective anti-inflammatory agents for additional investigation of other different mechanisms of action.

    Keywords: Inflammation, Boraginacea, Comfrey, Wound Healing, Arthritis, Rheumatoid
  • Amir Farnudian-Habibi, Mobina Mirjani, Vahideh Montazer, Shima Aliebrahimi, Iman Katouzian, Saeed Abdolhosseini, Ali Rahmani, Hossein Keyvani, Seyed Nasser Ostad, Mazda Rad-Malekshahi* Page 3

    The last generation of Coronavirus named COVID-19 is responsible for the recent worldwide outbreak. Concerning the widespread and quick predominance, there is a critical requirement for designing appropriate vaccines to surmount this grave problem. Correspondingly, in this revision, COVID-19 vaccines (which are being developed until March 29th, 2021) are classified into specific and non-specific categories. Specific vaccines comprise genetic-based vaccines (mRNA, DNA), vector-based, protein/recombinant protein vaccines, inactivated viruses, live-attenuated vaccines, and novel strategies including microneedle arrays (MNAs), and nanoparticles vaccines. Moreover, specific vaccines such as BCG, MRR, and a few other vaccines are considered Non-specific. What is more, according to the significance of Bioinformatic sciences in the cutting-edge vaccine design and rapid outbreak of COVID-19, herein, Bioinformatic principles including reverse vaccinology, epitopes prediction/selection and, their further applications in the design of vaccines are discussed. Last but not least, safety, challenges, advantages, and future prospects of COVID-19 vaccines are highlighted.

    Keywords: COVID-19, Reverse Vaccinology, Bioinformatic, Epitope Prediction, mRNA Vaccine
  • Zohreh Jafari, Mojgan Bandehpour, Shivasadat Gheflat, Nasrin Mohammadi, BahramKazemi* Page 4

    Ecarin is a metalloproteinase found in snake venom (SVMP) with an important role in coagulation and control of hemostasis. It can specifically produce active-thrombin from prethrombin-2 and does not differentiate between normal and abnormal prothrombin. It is used in diagnostic tests and to evaluate the treatment process of many diseases. There are many drawbacks associated with separating these compounds from snake venom. Therefore, in this study, full-length recombinant Ecarin (r-Ecarin) was cloned, expressed, and purified in eukaryotic host cells. To determine the most effective form of the enzyme, r-Ecarin was compared with the recombinant truncated form, which has only the metalloprotease domain of the protein (r-Ecamet) in terms of function and expression. Briefly, A DNA construct composed of sequence-encoding Ecarin was designed and cloned into pCAGGS expression vector and, subsequently, expressed in Chinese Hamster Ovary (CHO) cells. To identify the enzymatic activity of expressed protein, a bioactivity assay was performed. Blood coagulation time and expression levels of r-Ecarin and r-Ecamet proteins were compared. Also, a histopathological assessment was carried out on the liver of mice treated with these proteins. Comparison of r-Ecarin and r-Ecamet expression pattern demonstrated that full-length Ecarin expression has at least 2-fold higher expression in eukaryotic cells. Determination of r-Ecarin function proved that this protein is capable of prothrombin cleavage and producing thrombin. Comparison of PT test results between the r-Ecarin and r-Ecamet showed that there is a significant difference in the activity of the two enzymes and the full-length protein coagulates the blood in less time.

    Keywords: Recombinant Protein, Prothrombin Activator, Echis carinatus, Metalloproteinase, Protein Expression
  • Mahshid Daryab, Mehrdad Faizi, Arash Mahboubi *, Reza Aboofazeli Page 5

    Microemulsion-based gels (MBGs) were prepared for transdermal delivery of lidocaine and evaluated for their potential for local anesthesia. Lidocaine solubility wasmeasured in various oils, and phase diagrams were constructed tomap the concentration range of oil, surfactant, cosurfactant, and water for oil-in-water (o/w)microemulsion (ME) domains, employing the water titrationmethod at different surfactant/cosurfactant weight ratios. Refractive index, electrical conductivity, droplet size, zeta potential, pH, viscosity, and stability of fluid o/w MEs were evaluated. Carbomer® 940 was incorporated into the fluid drug-loaded MEs as a gelling agent. Microemulsion-based gels were characterized for spreadability, pH, viscosity, and in-vitro drug release measurements, and based on the results obtained, the best MBGs were selected and subsequently subjected to ex-vivo rat skin permeation anesthetic effect and irritation studies. Data indicated the formation of nano-sized droplets of MEs ranging from 20 - 52 nm with a polydispersity of less than 0.5. In-vitro release and ex-vivo permeation studies on MBGs showed significantly higher drug release and permeation in comparison to the marketed topical gel. Developed MBG formulations demonstrated greater potential for transdermal delivery of lidocaine and advantage over the commercially available gel product, and therefore, they may be considered as potential vehicles for the topical delivery of lidocaine.

    Keywords: Lidocaine, Microemulsion, Microemulsion-Based Gel, Phase Diagrams, Skin Permeation, Local Anesthesia
  • Endah Endah, Febri Wulandari, Yurananda Putri, Riris Istighfari Jenie, Edy Meiyanto* Page 6

    Pentagamavunon-1 performs more potent anti-cancer effects than curcumin against various cancer cells, but it remains to be optimized. Piperine shows the activity as an enhancer of a therapeutic agent. This study expects to achieve higher effectiveness of PGV-1 on 4T1 breast cancer cells through co-treatment with piperine with exploring the effect of cytotoxicity, mitotic catastrophe, cellular senescence, and target proteins of PGV-1 and piperine on the regulation of mitosis in TNBC cells (4T1). The assays emphasize MTT assay, May Grünwald-Giemsa staining, SA-β-galactosidase assay, and bioinformatics analysis, respectively, to elicit the respected activities. The results revealed that PGV-1 performed a cytotoxic effect with an IC50 value of 9 µM while piperine showed a lower cytotoxic effect with an IC50 value of 800 µM on 4T1 cells 24 h treatment. However, the combination treatment of both showed a synergistic cytotoxic enhancement effect with an average CI value < 1. Furthermore, the combination of PGV-1 and piperine induced mitotic catastrophe and senescence better than the single treatment. Treatment of 1 µM of PGV-1 and 400 µM of piperine increased the percentage of senescent cells by 33%. Bioinformatics analysis revealed that PGV-1 and piperine target proteins play a role in mitotic regulation, namely CDK1, KIF11, AURKA, AURKB, and PLK1, to contribute to mitotic catastrophe. Therefore, piperine increases the effectiveness of PGV-1 to suppress 4T1 cells growth synergistically that may occur through mitotic catastrophe and senescence targeting on mitotic regulatory proteins.

    Keywords: Pentagamavunon-1 (PGV-1), Piperine, 4T1 Cells, TNBC, Mitotic Catastrophe, Senescence, Protein Target
  • Narges Aryanpour, Golrokh Farnam, Reyhaneh Behtaj, Farshad H Shirazi * Page 7

    Breast cancer is a heterogeneous disease in which many factors and receptors are effective in the disease process and response to treatment. Currently, estrogen, progesterone, and HER2 receptors are among the most important factors in choosing a treatment regimen. Other metabolic factors that may affect the treatment outcome include diabetes and hyperinsulinemia. In order to evaluate the role and complexity of cross-talk between different pathways initiating from various receptors, value the most common drugs in the treatment of breast cancer are investigated on different cell lines in this manuscript at the cell culture level. The result of different doses of Tamoxifen and estradiol on the cells with various levels of the estrogenic, progesterone, and HER2 receptors is examined alone, or in combinations, and the presence or absence of insulin. The effects of these variables on the cells’ growth pattern and survival in various breast cancer cells are investigated using cell counting, colony counting, and MTT assays. Our results have further confirmed the complexity of deciding on the outcome of treatment for breast cancer with such a wide variability in the kind of receptors and biochemical agents present in the body of a cancer patient.

    Keywords: Breast Cancer Cell Lines, Tamoxifen, Estradiol, Insulin
  • Mehmet Koca, Rukiye Sevinç Özakar *, Emrah Ozakar, Recep Sade, Berhan Pirimoglu, Nihal ¸Simsek Özek, Ferhunde Aysin Page 8

    Iodine-based contrast agents have limitations such as rapid clearance, potential renal toxicity, non-specific blood pool distribution, headache, and adverse events. Nowadays, it is quite common to work with nanosized systems in order to eliminate the side effects of contrast agents. This study aims to synthesize a new iodinated contrast agent, prepare its nanosuspension by using the nanoprecipitation method, investigate its cytotoxicity, and compare its contrast properties with iohexol and iopromide through in-vitro experiments. The values of nanosuspension particle size and zeta potential have been found to be ~ 400 nm and ~ (-) 15 mV, respectively. In-vitro cellular viability findings indicated that the nanosuspension has lower cytotoxicity than the iohexol and iopromide. In the computed tomography (CT) imaging study of contrast features of nanosuspensions and two commercial agents, which involved 86 CT examinations using 31 parameters and two different devices, it was found that iodine had a stronger presence in its nanosuspension form than in iohexol and iopromide, which were the other two commercial contrast agents, when used in equal amounts. Thus in the case of nanosuspensions contrast brightness was achieved by using less iodine, while the same brightness could be obtained with higher doses of iohexol and iopromide. CT imaging therefore be done without much chemical use, which indicates that it may witness fewer side effects in the future.

    Keywords: Radiocontrast Agent, CT Imaging, Cytotoxicity, Nanosuspension, Synthesis, Viscosity, Stability
  • Manijeh Nematpour, Elham Rezaee *, Maryam Nazari, Omid Hosseini, Sayyed AbbasTabatabai Page 9

    Impaired cell cycle regulation and disturbance in signal transduction pathway are twomajor causes of a condition defined as cancer, one of the significant reasons formortality worldwide. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been commonly used as anticancer agents, and the majority of this medications possess quinazoline moiety as a heteroaromatic core. In this study, two novel series of EGFR-TKIs containing quinazolinone core were designed and synthesized. Most compounds showed reasonable inhibitory activity against EGFR-TK compared to that of erlotinib, a reversible inhibitor of this enzyme. Compound 8b, 2-((2-chlorobenzyl)amino)-6-phenoxyquinazolin-4(1H)-one, with an IC50 value of 1.37 nM exhibited the highest potency. Molecular docking study of compound 8b showed that it had the same direction of erlotinib and formed proper hydrogen bonds and hydrophobic interactions with the important amino acid residues of the active site. Based on in-silico calculations of ADME properties, our novel compounds have the potential to be orally active agents.

    Keywords: Anticancer, Biological Activity, EGFR, Quinazolinone, Tyrosine Kinase
  • Mehrnaz Lotfaliei, Elham Rezaee *, Zahra Hajimahdi, Mohammad Mahboubi Rabbani, Rezvan Zabihollahi, Mohammad Reza Aghasadeghi, Sayyed Abbas Tabatabai Page 10

    HIV, the virus that causes AIDS (acquired immunodeficiency syndrome), is one of the world’s most severe health and development challenges. In this study, a novel series of 2-(diphenyl methylidene) malonic acid derivatives were designed as triple inhibitors of HIV reverse transcriptase, integrase, and protease. Docking models revealed that the target compounds have appropriate affinities to the active sites of the three HIV key enzymes. The synthesized malonic acid analogs were evaluated for their activities against the HIV virus (NL4-3) in HeLa cells cultures. Among them, compound 3 was the most potent anti-HIV agent with 55.20% inhibition at 10 µM and an EC50 of 8.4 µM. Interestingly, all the synthesized compounds do not show significant cytotoxicity at a concentration of 10 µM. As a result, these compounds may serve as worthy hits for the development of novel anti-HIV-agents.

    Keywords: Molecular Docking, Synthesis, Malonic Acid S, Anti-HIV, Drug Multiple Ligands
  • Nadia Salehi, Seyedeh Maryam Mortazavi, Hamidreza Moghimi* Page 11

    Topical products are not stable following application to the skin due to the evaporation of volatile components. Such changes have been demonstrated in liquid emulsions, but there is almost no study available for creams in this respect. The aim of the present investigation is to evaluate the changes in cream properties following topical application and their influence on product efficiency. A method has also been designed and validated to mimic cream application to the skin. To perform this investigation, five different creams were prepared and alterations of type of creams, size of droplets of the dispersed phase, occlusivity, water content and rate of water loss were studied after application. These changes were then attributed to the type of cream, water content, presence of humectant, and time post application. The results demonstrated that creams changed intensely after application, including the phase inversion of O/W formulations, changes in the occlusivity of creams, reduction of water content, rate of water evaporation and droplet size. Such changes could be controlled partly by humectants. The present results suggest that formulators should be aware of such possible changes and required precautions should be taken in advance.

    Keywords: Topical Creams, Skin Application, Stability, Water Content, Phase Inversion, Occlusivity, Formulation Changes
  • Atefeh Fakharian* Page 12

    More than a year after the onset of the coronavirus disease pandemic in 2019, the disease remains amajor global health issue. During this time, health organizations worldwide have tried to provide integrated treatment guidelines to control coronavirus disease 2019 (COVID-19) at different levels. However, due to the novel nature of the disease and the emergence of new variants, medical teams’ updating medical information and drug prescribing guidelines should be given special attention. This version is an updated instruction of the National Research Institute of Tuberculosis and Lung Disease (NRITLD) in collaboration with a group of specialists from Masih Daneshvari Hospital in Tehran, Iran, which is provided to update the information of caring clinicians for the treatment and care of COVID-19 hospitalized patients.

    Keywords: Acute Respiratory Distress Syndrome (ARDS), Coronavirus Disease, Clinical Management, SARS-COV-2, TreatmentGuidelines
  • Burhan Basaran *, Ozlem Faiz Page 13

    In this study, exposure risk assessment was made by determining the acrylamide levels of some traditional foods frequently consumed by the Turkish society and registered geographical indication. For this purpose, acrylamide levels of 20 traditional foods [7 meat products, 3 loaves of bread, 3 bagels (simit), and 7 desserts] obtained from different bakeries, patisseries, and restaurants were determined by LC-MS/MS. Acrylamide levels were determined between 12.7 - 299µg/kg in meat products, 11.8 - 69.3µg/kg in bread, 11.8 - 179 µg/kg in bagels, 11.7 - 85.0 µg/kg in baked desserts, and 32.3 - 527 µg/kg in deep-fried desserts. According to the portion size, the food with the highest acrylamide level in meat products is Adana kebab (17.70 µg/180 g). Formulation and cooking techniques are thought to be the main determinants of acrylamide level detected in traditional foods. Dietary acrylamide exposure was calculated according to the deterministic model. Exposure was calculated as 0.20, 0.53, and 0.98 µg/kg bw per day for good, average and bad scenarios, respectively. The calculated acrylamide exposure value is below the reference values stated by FAO/WHO. The acrylamide dietary exposure was not of concern concerning neurotoxicity and carcinogenicity. The results can be used to reduce acrylamide levels in foods and risk assessment studies.

    Keywords: Acrylamide, Bakery Products, Meat Products, Desserts, Adana Kebap, Baklava, Dietary Exposure
  • Ali Dini *, Ali Esmaeili Nadimi, Khosro Behmaram Page 14

    Pistachio has high nutritional value and popularity. The susceptibility of pistachio to aflatoxin contamination caused establishing a monitoring system introduced and implemented by the Ministry of Health in Iran to ensure consumers’ access to safe and hygienic pistachios. In this research, aflatoxin contamination level in all consignments (7298) exporting to E.U. was examined using HPLC with fluorescence detection after immunoaffinity column clean up from Nov 2012 to Oct 2018. The average recoveries ranged 78.6% - 97.6%, with a relative standard deviation for reproducibility below 8.5% and expanded uncertainty of aflatoxin B1 (AFB1) at spiked levels 1, 4, and 8 ng/g were 0.17, 0.57, 0.89 ng/g, respectively. The results showed that aflatoxin B1 and total (AFT) were detected in 1921 (23.4%) and 1927 cases (23.5%), with the mean values ranging from 2.18 - 4.6 ng/g and 2.8 - 5.1 ng/g during six consecutive years, respectively. Implementing an effective monitoring system for pistachio nuts could determine consignments contaminated with aflatoxins. Concerning AFB1, risk assessments recorded for dietary exposure dose, margin of exposure (MOE), Hazard Index (HI), estimated liver cancer risk, and cancer incidence attributable to dietary ranged 0.0132 - 0.1180 ng/kg.bw/day, 1441 - 12843, 0.21 - 1.84, 0.00071 - 0.00633 cases/105 population/year, 0.02 - 0.2%, respectively. Identification and rejection of contaminated cargos lead to an increase in MOE (> 10000), and it also guarantees that pistachio consumption is safe from a toxicology point of view. Due to the monitoring system, the estimation of liver cancer incidence attributable to dietary AFB1 was reduced (≤0.02%). It indicates that the consumption of pistachio poses no health risk for Europeans and Iranians.

    Keywords: Pistachio, Aflatoxins, Risk Assessment, Dietary Exposure, HPLC
  • Ali Hojat, Shabnam Jeibouei, Amir Reza Aref, Alireza Kalbasi, Maryam Moghaddam, Farzaneh Mohammadi, Seyed Mohammadreza Javadi, Mohammad Ajoudanian, Kazem Sharifi, Hakimeh Zali *, Mohammad Esmaeil Akbari Page 15

    Surgery is the standard treatment for breast malignancies, although local and distant relapses might occur. Previous studies have shown that surgery-induced wound fluid (WF) contains tumor-initiating and progressing factors; however, these experiments have only been performed on breast cancer cell lines. Since a cancerous tumor includes various components like malignant cells, recruited non-malignant cells and extracellular matrix, those investigations that only focused on cancer cell lines themselves are not adequate to establish WF’s effects. We conducted a 3D model study where we mimicked the tumor microenvironment to re-assess previous in-vitro findings. We generated human-derived breast tumor spheroids from 23 patient specimens, dissociated and cultured them in microfluidic devices. The spheroids from each sample were treated with the patients’ WF or RPMI medium. The proportion of live and dead cells was assessed using live/dead assays and fluorescent imaging on day 6. In 22 samples, the percentage of live cells was significantly higher in the WF-treated group than in the RPMI-treated group. In one sample, we observed an opposite trend. The results were contrary in one of the samples, and we reported that case with more details. We compared the two groups using the 3D culture environment of human-derived tumor spheroids prepared from different microfluidic devices to mimic the tumor environment heterogeneity. Our findings showed that most patients with breast cancer benefit from surgical wound healing. However, removal of the surgical-induced serum may not be a method of inhibiting the tumor in all patients.

    Keywords: Breast Cancer, Wound Fluid (WF), Microfluidics, 3D Cell Culture, Tumor
  • Ilad Alavi-Darazam, Kimia Forouhar, Omid Moradi, Ali Saffaei, Sara Asadi, Zahra Sahraei* Page 16
    Background

    Recently, a few studies based on anti-factor Xa activity levels have propounded doubtful and sub-prophylactic levels by the usual dose of enoxaparin in surgical and critically ill patients. In this study, we assessed two doses of enoxaparin in adult non-critically ill patients.

    Methods

    Patients were randomly assigned into two groups of intervention and control. While the intervention group received enoxaparin with a daily dose of 60 mg, the control group received enoxaparin 40 mg. Anti-factor Xa activity was measured based on the peak steady-state levels. The level of 0.2 to 0.4 IU/mL was considered as a prophylactic goal. All individuals were followed for bleeding or thromboembolic events during admission.

    Results

    The mean levels of anti-factor Xa were 0.29 ± 0.13 IU/mL in the control group (n = 31) and 0.44 ± 0.19 IU/mL in the intervention group (n = 29). More patients in the control group had an optimal level of anti-factor Xa compared to the patients in the intervention group (62.1% vs. 29%). No adverse outcomes were detected in any of the groups.

    Conclusions

    Enoxaparin dose of 60 mg daily provided anti-factor Xa level higher than desired in most patients. In non-critically ill patients, the dose of 40 mg is the proper dose for thromboprophylaxis.

    Keywords: Venous Thromboembolism, Thromboprophylaxis, Anticoagulants, Enoxaparin
  • Sajjad Nasseri, Mohammad-Reza Delnavazi, Farshad H. Shirazi, Faraz Mojab* Page 17

    Cytotoxic activity of crude extract and fractions (petroleum ether, dichloromethane, and n-butanol) of Artemisia haussknechtii aerial parts was investigated by MTT assay. Dichloromethane fraction showed the highest cytotoxic effect on MCF-7 cell line (IC50 = 297.17 ± 7.99 µg/mL). Phytochemical analysis of the most effective fraction was carried out using normal phase column chromatography (CC) to get eight sub-fractions (A-H). Thin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC) were used for further purification. Four known compounds with cytotoxic effects on cancer cell lines were isolated from the most active fraction, including 5-Hydroxy-3’,4’,6,7-tetramethoxyflavone (eupatilin 7-methyl ether), 5-hydroxy 3,3’,4’,6,7-pentamethoxy-flavone (artemetin), 6-methoxy-7-hydroxycoumarin (scopoletin), and methyl caffeate. Structure elucidation of isolated compounds was done using spectroscopic techniques, including ESIMS and 1D-NMR (1H and 13C). Cytotoxic activity of A. haussknechtii is probably due to coumarin and flavonoid compounds.

    Keywords: Artemisia haussknechtii, MTT Assay, Phytochemical Analysis, 5-Hydroxy-3’, 4’, 6, 7-tetramethoxyflavone, Artemetin, Scopoletin, Methyl Caffeate
  • Fatemeh Tajabadi, Farahnaz Khalighi-Sigaroodi *, Majid Ghorbani Nahooji, Mona Ghiaci-Yekta, Vahid Ghasemi Page 18

    In this study, a fast and precise method for determining three opium alkaloids (morphine, codeine, and thebaine) in different parts of some Papaver species was developed and validated with a low limit of detection (LOD) of 0.05 - 0.20 mg/L. The proposed method was based on three extraction steps by alkaline aqueous solution/chloroform/acidic aqueous solution and analysis by ion mobility spectrometry (IMS) and high-performance liquid chromatography (HPLC). After optimizing IMS parameters based on an experimental design, IMS was applied to analyze the extracts of seeds, stems, leaves, and capsules of seven Papaver species collected from different regions of Iran. All prepared samples were analyzed by HPLC and IMS at the same time. Then, the obtained results of the two instrumental methods were compared. The HPLC did not detect morphine in the prepared samples, while IMS results showed trace amounts of morphine in the capsules and leaves of four Papaver species. Other results were comparable and showed that IMS is more sensitive, affordable, and faster than HPLC for alkaloid analysis.

    Keywords: Thebaine, Papaver Species, High-Performance Liquid Chromatography
  • Mohammad Sharifzadeh, Negar Mottaghi-Dastjerdi *, Mohammad Soltany Rezae Raad Page 19

    The Coronavirus disease 2019 (COVID-19) pandemic has affected more than 269 million worldwide, with more than five million deaths as of early December 2021. The main concerns in this pandemic include the asymptomatic nature of COVID-19, leading to the infection of many healthy people, the infectious nature of the pathogen, and its high spreading rate. The disease features have highlighted the importance of controlling this pandemic via vaccines. There has been a worldwide race to produce better, more protective, and efficacious vaccines. Simultaneously, different new variants of the virus are emerging. Therefore, there is a concern about the efficacy of the vaccines against new variants. The platform used for COVID-19 vaccine development needs to be flexible enough to enable the manufacturer to react suitably to new virus variants. We performed a comprehensive search in the online databases of PubMed, Scopus, Google Scholar, clinicaltrials.gov, WHO, ICTRP, and Cochrane until December 10th, 2021. There are 331 candidate vaccines in clinical development, with 194 in the preclinical stage and 137 in different clinical phases. Eleven platforms have been used for the development of COVID-19 vaccines, including inactivated/live attenuated virus, protein subunit, virus-like particle (VLP), non-replicating/replicating viral vectors (VVnr or VVr), VVr or VVnr plus antigen-presenting cell, bacterial antigenspore expression vector, DNA, and RNA. The VLP-based vaccine platform is a safe, highly immunogenic, and flexible platform for developing vaccines. This review focuses on VLP-based vaccine platforms and explicitly discusses the six VLP-based COVID-19 vaccines in clinical trial phases.

    Keywords: 2019-nCoV, COVID-19, Novel Coronavirus, SARS-CoV-2, Vaccines, Virus-Like Particle
  • Atefeh Mousavi, Hossein Zare, Aydin Asadian, Mehdi Mohammadzadeh* Page 20
    Background

    Product life cycle (PLC) refers to the time ranging from when a product is introduced into the market to when it is taken off the shelves. The PLC management can guarantee product survival and prevent its decline.

    Objectives

    This study investigated generic antibiotic PLCs and detected factors affecting them in the competitive pharmaceutical market of Iran to improve the PLC management of such drugs.

    Methods

    To study the PLC of antibiotics, data were collected from 2002 to 2017, and then the PLC curves were analyzed. Accordingly, factors affecting the PLC of antibiotics were illustrated in two sections: all PLC curves and the PLC curves with one sales peak. Using a generalized linear model combined with a machine learning approach, we identified the sales patterns and the effect of the productrelated and the competition-related factors on the PLC curves, peak height, and the time to reach peak sales.

    Results

    According to the findings, 16, 11.87, 13.03, and 59% of the antibiotics had linear, binomial, one-peak, and oscillating sales patterns, respectively. The most crucial factors affecting the PLC shape were the quality, microbial spectrum, dosage forms, number of competitors, and entry arrangement.

    Conclusions

    This is the first study examining factors affecting the PLC patterns of generic pharmaceutical products. The findings would provide more insights into the generic pharmaceutical market as one of the less-studied markets in many countries.

    Keywords: Product Life Cycle, Generalized Linear Model (GLM), Machine Learning, Pharmaceutical, Antibiotics
  • Noushin Bolourchian *, Mina Shafiee Panah Page 21

    The present study mainly aimed to prepare solid dispersions (SDs) of a poorly water-soluble compound, carvedilol (CA), in the presence of pluronic F68 (F68) and myrj 52 by adopting wet milling technique in order to enhance drug dissolution. The process enabled the preparation of SDs without using any toxic organic solvents. SDs with different CA, surfactant ratios were prepared by adopting wet milling followed by freeze-drying method and evaluated for their particle size and dissolution. They were also characterized based on/using X-ray diffraction (XRD), differential scanning calorimetry (DSC), fourier transform infrared (FTIR) spectroscopy, scanning electron microscope (SEM), and saturated solubility. The effect of cryoprotectant type on the dissolution and particle size of SDs was also investigated. Wet milling process resulted in the reduced particle size depending on the type of surfactant. The significant drug dissolution and saturated solubility enhancement were recorded for milled SD formulations. In this regard, Myrj had a greater impact compared to F68. Dissolution efficiencies (DE30) obtained for the myrj-included SDs were up to 8.2-fold higher than that of untreated CA. The type of cryoprotectant was also found to affect the drug dissolution. According to the results, partial amorphization occurred in wet-milled samples, as confirmed by XRD and DSC analysis. It was concluded that using an appropriate surfactant along with wet-milling method may have been an effective approach for improving the dissolution rate of CA, a poorly soluble compound.

    Keywords: Carvedilol, Surfactant, Wet Milling, Solid Dispersion, Cryoprotectant, Dissolution, PoorWater-Soluble
  • Mojtaba Ansari*, Mostafa Rezaei Tavirani Page 22

    The determination of radioiodine remnant ablation (RRA) dosage in post-operation thyroid residual tissues resection has been largely subject of discussion, yet no concise conclusion is released through systematic review studies. In this study, we conducted a systematic review of comparative experiments to evaluate and compare the efficacy of different prescribed dosages of radioiodine in post-op thyroid residual tissues resection among low, intermediate, and high-risk patients to approve the common method. Using automated searches, studies were collected from PubMed, Google Scholar, Elsevier, Scopus, and UpToDate, all until April 2021. Alongside the aforementioned sources, comparative experiments were added in for further investigation. Overall, 4000 patients with papillary thyroid cancer, differentiated thyroid carcinoma (DTC), metastasized and non-metastasized thyroid cancer took part in twenty-one trials are assessed. We discovered no significant difference in successful thyroid residual tissues excision between lowactivity and high-activity radioiodine treatment in people with low and intermediate risk. In these individuals, there was no significant difference between the high therapeutic dose of 3700 MBq and the lesser dose of 1850 MBq for RRA. However, high-dose treatment usually yielded superior results. Low activity RRA causes fewer adverse effects in metastasis-free patients than high-activity 3.7 GBq. There was no significant therapeutic difference regarding treatment efficacy in patients with low and moderate risks. However, in patients with high-risk status, applying a high-dose regimen of RRA produced a significantly better response.

    Keywords: Radioiodine, Thyroid, Treatment, Dosage, Side Effect
  • Nikta Shobeiri, Farzad Peiravian, Nazila Yousefi * Page 23
    Background

    Uncertainty in real-world product profiles is themain barrier to pharmaceuticalmarket access. Managed entry agreements (MEAs) are the formal arrangements to overcome these uncertainties. Despite the extensive experience of developed countries in implementing such agreements, the experience of developing countries is minimal. As health decision-makers in Iran have moved towards implementing MEAs since 2020, seeking stakeholders’ insights is crucial for filling this experience gap and facilitating the optimal implementation of these new policies.

    Methods

    Our research was done in three phases: (1) Focus group interviews to disclose the main objectives of implementing MEAs in Iran, (2) the AHP approach to prioritize uncertainties, and (3) individual semi-structured interviews to carry out strengths, weaknesses, opportunities, and threats (SWOT) analysis.

    Results

    Based on our stakeholders’ views, increasing flexibility in improving patients’ access to innovative and expensive drugs and responding to budget impact uncertainty seems highly prioritized for conducting MEAs in Iran. The SWOT analysis showed that although MEAs have the chance for success due to their strengths and opportunities, such as providing early and assured access, allocating resources efficiently, and enhancing the efficiency of post-marketing studies, policymakers should consider the weaknesses and threats such as difficulty in defining outcomes, high transaction cost, and lack of suitable infrastructure to increase the success rate.

    Conclusions

    Efficient implementation of MEAs depends on the weaknesses and threats and considering the views of relevant stakeholders. Constructive interaction among all stakeholders is essential for adequately executing MEAs.

    Keywords: Managed Entry Agreements, Pharmaceuticals, Uncertainties, SWOT, Iran
  • Ramin Beheshtizadeh, Shila Safaeian*, Elham Moslemi, Rezvan Mosavi Nadushen, Kasra Esfahani Page 24
    Background

    Soybean and maize are the most cultivated genetically modified (GM) plants. Because of the increase in the imports of GM products to Iran, infant formula and baby food, which is consumed by babies during their first month of life, can also contain soybean and maize. It has become fundamental to screen these types of products.

    Objectives

    The present study aimed to investigate the GM corn and soybean in baby food and infant formula using real-time polymerase chain reaction (PCR).

    Methods

    A total of 60 baby food and infant formulas were collected randomly from the local drugstores in Tehran. Genomic DNA was extracted from all samples, then by real-time PCR detection, tested Pat/NOS. Internal control genes zein and lectin were used for maize and soybean, respectively.

    Results

    Results showed that 5% of infant formulas and 5% of baby food, two Iranian and one imported baby food, and two imported and one Iranian infant formula were positive for pat. However, NOS was detected in none of the samples. The results showed positive results for the presence of the pat gene in the products without an appropriate label.

    Conclusions

    This article provides evidence of GM maize and soybean presence in baby food and infant formula in Iran.

    Keywords: Corn, Detection, GMO, Quantitative PCR, Soybean
  • Mohsen Soltanshahi, Saeid Taghiloo, Hossein Asgarian-Omran* Page 25

    Tumor-targeted therapy with small-molecule inhibitors (SMIs) has been demonstrated to be a highly effective therapeutic strategy for various cancers. However, their possible associations with immune evasion mechanisms remain unknown. This study examined the association of inhibitors of the protein kinase B (AKT), mammalian target of rapamycin (mTOR), and Bruton’s tyrosine kinase (BTK) signaling pathways with the expression of immune checkpoint ligands programmed death-ligand 1 (PD-L1), CD155, and galectin-9 (Gal-9) in a breast cancer cell line. MCF-7 cells were treated with everolimus, MK-2206, and ibrutinib. AnMTT assay was used to determine the optimal dose for all drugs. A real-time polymerase chain reaction was utilized to measure the mRNA expression of PD-L1, CD155, and Gal-9. The western blot technique was also employed to evaluate the protein expression of the phosphorylated signal transducer and activator of transcription 3 (STAT3). The optimal doses of everolimus, MK-2206, and ibrutinib were observed to be 200, 320, and 2000 nM, respectively. The PD-L1 and CD155 mRNA expression was significantly decreased following the treatment with everolimus and ibrutinib, but not with MK-2206. There were no differences in Gal-9 expression between the single-treated and control groups; however, combined treatment with everolimus and ibrutinib increased its mRNA expression. Everolimus and ibrutinib both inhibited constitutive STAT3 phosphorylation in MCF-7, which was more pronounced in combination treatment. The findings regarding the modulation of PD-L1, CD155, and Gal-9 molecules by SMIs emphasize the crosstalk between the expression of these immune checkpoint molecules and AKT/mTOR/BTK signaling pathways through STAT3 as a critical transcription factor.

    Keywords: Breast Cancer, Small-Molecule Inhibitors, PD-L1, CD155, Galectin-9, STAT3