Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences最新文献

Purpose: COVID-19 strangely kills some youth with no history of physical weakness, and in addition to the lungs, it may even directly harm other organs. Its complex mechanism has led to the loss of any significantly effective drug, and some patients with severe forms still die daily. Common methods for identifying disease mechanisms and drug design are often time-consuming or reductionist. Here, we use a novel holistic systems biology approach to predict its molecular mechanisms (in vitro), significant molecular relations with SARS, and repurpose drugs.

Methods: We have utilized its relative phylogenic similarity to SARS. Using the available omics data for SARS and the fewer data for COVID-19 to decode the mechanisms and their significant relations, We applied the Cytoscape analyzer, MCODE, STRING, and DAVID tools to predict the topographically crucial molecules, clusters, protein interaction mappings, and functional analysis. We also applied a novel approach to identify the significant relations between the two infections using the Fischer exact test for MCODE clusters. We then constructed and analyzed a drug-gene network using PharmGKB and DrugBank (retrieved using the dgidb).

Results: Some of the shared identified crucial molecules, BPs and pathways included Kaposi sarcoma-associated herpesvirus infection, Influenza A, and NOD-like receptor signaling pathways. Besides, our identified crucial molecules specific to host response against SARS-CoV-2 included FGA, BMP4, PRPF40A, and IFI16.

Conclusion: We also introduced seven new repurposed candidate drugs based on the drug-gene network analysis for the identified crucial molecules. Therefore, we suggest that our newly recommended repurposed drugs be further investigated in Vitro and in Vivo against COVID-19.

Background: Clove volatile oil (CVO) and its major compound, eugenol (EUG), have anxiolytic effects, but their clinical use has been impaired due to their low bioavailability. Thus, their encapsulation in nanosystems can be an alternative to overcome these limitations.

Objectives: This work aims to prepare, characterize and study the anxiolytic potential of CVO loaded-nanoemulsions (CVO-NE) against anxious-like behavior in adult zebrafish (Danio rerio).

Methods: The CVO-NE was prepared using Agaricus blazei Murill polysaccharides as stabilizing agent. The drug-excipient interactions were performed, as well as colloidal characterization of CVO-NE and empty nanoemulsion (B-NE). The acute toxicity and potential anxiolytic activity of CVO, EUG, CVO-NE and B-NE against adult zebrafish models were determined.

Results: CVO, EUG, CVO-NE and B-NE presented low acute toxicity, reduced the locomotor activity and anxious-like behavior of the zebrafish at 4 - 20 mg kg^-1. CVO-NE reduced the anxious-like behavior of adult zebrafish without affecting their locomotor activity. In addition, it was demonstrated that anxiolytic activity of CVO, EUG and CVO-NE is linked to the involvement of GABAergic pathway.

Conclusion: Therefore, this study demonstrates the anxiolytic effect of CVO, in addition to providing a new nanoformulation for its administration.

Purpose: Knowledge advancement exposes the pharmacists to new ethical and professional challenges in providing pharmaceutical care. The pharmacist's attitude towards the ethical challenges of pharmacy practice could be of great help in assessing pharmacist's ethical sensitivity. This study aimed to design a valid and reliable questionnaire for measuring pharmacists' attitudes.

Methods: The present study is the second phase of a sequential exploratory mixed‑method study for designing and psychometric evaluation of the questionnaire. In the first phase the questionnaire was developed using semi-structured interviews followed by content analysis. The psychometric evaluation of the questionnaire was performed examining the validity (face, content, and construct), and reliability (internal consistency and Intraclass Correlation Coefficient and Standard Error of Measurement) in a sample of pharmacists practicing in community pharmacies in Tehran and Tabriz, Iran (n = 504). The construct validity of the questionnaire was determined using exploratory and confirmatory factor analysis.

Results: The Scale‑Content Validity Index/Average (S‑CVI/AVE) was calculated at 0.84. The results of exploratory factor analysis supported 22 items in four factors including regulations and rules, professional communications, providing and supplying medicine, and consultation and providing pharmaceutical care that are explained by a total of 49.50% of the variance. Also, confirmatory factor analysis confirmed goodness of fit indices and model fit. Cronbach's alpha Coefficient was 0.919 and ICC was 0.914.

Conclusions: The psychometric evaluation of the present questionnaire shows a native, valid and reliable instrument to assess pharmacists' attitudes toward ethical challenges which could be a mirror of pharmacists ethical sensitivity.

Background: Producing therapeutic proteins can be done quickly and on a large scale through Transient Gene Expression (TGE). Chinese hamster ovary (CHO) cell lines are commonly used to achieve this. Although there are few comparative studies, TGE has been observed in suspension-adapted CHO cells.

Objectives: We tested TGE's effectiveness in DG-44, CHO-S, and ExpiCHO-S cell lines with four transfection reagents.

Methods: A design of experiments (DoE) was followed to optimize transfection using a recombinant monoclonal antibody (mAb) construct. To evaluate the efficacy, flow cytometry and ELISA were used. Feeding strategies and temperature shifts were implemented to enhance transfection effectiveness. The quality of the mAb was assessed through ELISA, SDS-PAGE, and proliferation inhibition assays.

Results: We adapted all cell lines to grow in suspension using a serum-free medium. Our findings from flow cytometry and ELISA tests indicate that PEI and Pmax reagents had a higher rate of transfection and mAb production than the ExpiCHO commercial transfection reagent. While DG-44 cells had better transfection efficiency than CHO-S and ExpiCHO-S, there was no significant difference between CHO-S and ExpiCHO-S. Our TGE system was more productive at 32 °C than at 37 °C. In the optimized TGE of Pmax-based transfection in DG-44 at 37 and 32 °C, the production level of mAb was more than half of the amount of the commercial ExpiCHO-S expression system. Still, the number of transfected cells was three times higher, making it more efficient. The purified mAb from all transfected cell lines had similar structural and functional properties under different conditions.

Conclusion: Our research shows that using Pmax and DG-44 cells in the TGE system is a cost-effective and efficient way to produce humanized monoclonal antibodies. We discovered that this method outperforms the ExpiCHO-S kit.

Background: Currently, two-drug antiretroviral regimens are emerging fields in life-long treatment in people living with HIV.

Objectives: This randomized non-inferiority open-label controlled trial was designed to compare the 48-week efficacy and safety of tenofovir alafenamide plus dolutegravir versus the standard triple therapy in virologically suppressed people living with HIV. To the best of our knowledge this combination has not been studied before.

Methods: This open-label randomized controlled trial was conducted in treatment-experienced people with HIV who had HIV-RNA < 47 copies/mL for at least two years. Patients received either tenofovir alafenamide plus dolutegravir combination (26 patients) or a standard three-drug regimen (29 patients). The primary outcome was the proportion of patients maintaining HIV-RNA < 47 copies/mL during 48 weeks, and the secondary outcomes were CD4 cell count changes, the adherence rate, and adverse drug reactions, all over 48 weeks of study.

Results: HIV viral load remained undetectable (HIV-RNA < 47 copies/mL) during the 48 weeks of the study in both arms. The absolute CD4 cell count change was not significant between the two groups. The overall proportion of adverse effects in each group was comparable. The rate of adherence to treatment was acceptable in both groups, and no significant difference was observed.

Conclusions: Treatment simplification with tenofovir alafenamide plus dolutegravir regimen as maintenance therapy was non-inferior in terms of efficacy and safety compared to the standard triple therapy. Comparing efficacy of antiretroviral therapy.

Objectives: Cancer stem cells (CSCs), a small subpopulation of cells with high tumorigenesis and strong intrinsic drug resistance, exhibit self-renewal and differentiation abilities. CSCs play a crucial role in tumor progression, drug resistance, recurrence and metastasis,and conventional therapy is not enough to eradicate them. Therefore, developing novel therapies targeting CSCs to increase drug sensitivity and preventing relapse is essential. The objective of this review is to present nanotherapies that target and eradicate the tumor "seeds".

Evidence acquisition: Evidence was collected and sorted from the literature ranging from 2000 to 2022, using appropriate keywords and key phrases as search terms within scientific databases such as Web of Science, PubMed and Google Scholar.

Results: Nanoparticle drug delivery systems have been successfully applied to gain longer circulation time, more precise targeting capability and better stability during cancer treatment. Nanotechnology-based strategies that have been used to target CSCs, include (1) encapsulating small molecular drugs and genes by nanotechnology, (2) targeting CSC signaling pathways, (3) utilizing nanocarriers targeting for specific markers of CSCs, (4) improving photothermal/ photodynamic therapy (PTT/PDT), 5)targeting the metabolism of CSCs and 6) enhancing nanomedicine-aided immunotherapy.

Conclusion: This review summarizes the biological hallmarks and markers of CSCs, and the nanotechnology-based therapies to kill them. Nanoparticle drug delivery systems are appropriate means for delivering drugs to tumors through enhanced permeability and retention (EPR) effect. Furthermore, surface modification with special ligands or antibodies improves the recognition and uptake of tumor cells or CSCs. It is expected that this review can offer insights into features of CSCs and the exploration of targeting nanodrug delivery systems.

Background: Adiposity and non-alcoholic fatty liver disease (NAFLD) are common characteristics of metabolic syndrome (MS). Understanding the underlying pathogenesis is crucial for the development of new remedies. Resveratrol controls obesity and glycemic disorders in patients with MS.

Objectives: This study aimed to evaluate the effect of resveratrol and dulaglutide on adipose tissues and liver in rats with MS, declaring their possible mechanisms.

Methods: Rats allocated as Control, MS (induced by a high fat/ high sucrose diet for eight weeks), MS + Resveratrol (30 mg/kg/day orally), and MS + Dulaglutide (0.6 mg/kg twice weekly SC); drugs administration was in the last four weeks. Serum biochemical measurements were done. Liver and visceral fat were processed for biochemistry, histopathology, and immunohistochemistry.

Results: MS results demonstrated significantly increased systolic and diastolic blood pressure, anthropometric measurements, serum levels of alanine aminotransferase (ALT), glycemic indices, and lipids with decreased HDL-C. Tissue levels of leptin, malondialdehyde (MDA), and TNF-α reactivity significantly increased. Expression of adiponectin, PPARγ, and insulin growth factor-1 (IGF-1) decreased. Also, Western blotting mRNA gene expression of liver SIRT-1 was down-regulated. Resveratrol and dulaglutide significantly and effectively reversed MS complexity, ameliorating all findings, particularly NAFLD and adiposity-induced inflammation. Resveratrol significantly appears superior to dulaglutide regarding the effects on hemodynamics, lipids, adipokines, IGF-1 levels, and adipocyte size. Parallel, dulaglutide has more influence on glycemic control.

Conclusion: Protective effects of the drugs may be through correlations between SIRT-1/adipokines/IGF-1 and PPARγ, improving the cross-talk between insulin resistance, obesity markers, liver dysfunction, and TNF-α. Promising multi-beneficial therapies of resveratrol or dulaglutide in MS are recommended clinically for this purpose. Showing the Experimental Design.

Objectives: This scoping review aims to present flavonoid compounds' promising effects and possible mechanisms of action on potential therapeutic targets in the SARS-CoV-2 infection process.

Methods: A search of electronic databases such as PubMed and Scopus was carried out to evaluate the performance of substances from the flavonoid class at different stages of SARS-CoV-2 infection.

Results: The search strategy yielded 382 articles after the exclusion of duplicates. During the screening process, 265 records were deemed as irrelevant. At the end of the full-text appraisal, 37 studies were considered eligible for data extraction and qualitative synthesis. All the studies used virtual molecular docking models to verify the affinity of compounds from the flavonoid class with crucial proteins in the replication cycle of the SARS-CoV-2 virus (Spike protein, PLpro, 3CLpro/ MPro, RdRP, and inhibition of the host's ACE II receptor). The flavonoids with more targets and lowest binding energies were: orientin, quercetin, epigallocatechin, narcissoside, silymarin, neohesperidin, delphinidin-3,5-diglucoside, and delphinidin-3-sambubioside-5-glucoside.

Conclusion: These studies allow us to provide a basis for in vitro and in vivo assays to assist in developing drugs for the treatment and prevention of COVID-19.

Objectives: Lipid nanoparticles, as a nucleic acid delivery system, have been used as an alternative to treat ocular diseases, since they can cross the ocular barrier and efficiently transfecting nucleic acids to various cells of the eye. The size influences the transfection of genes, biological distribution, diffusion, and cellular uptake. It is therefore important to establish a relationship between size, formulation, and encapsulation percentage.

Evidence acquisition: In this review, we used a search strategy to compare studies of nanomedicine systems aimed at eye diseases where the size of the nanoparticles and the efficiency of encapsulation of genetic material are reported based on the criteria of Preferred Reporting Items for Systematic Reviews (PRISMA ScR 2020 guidelines).

Results: Out of the initial 5932, 169 studies met the inclusion criteria and were included to form the basis of the analysis. Nanoparticles reported are composed mainly of PEG-modified lipids, cholesterol, and cationic lipids, that in combination with messenger or interference RNA, allow the formulation of a nanoparticle with an encapsulation efficiency greater than 95%. The diseases treated mainly focus on conditions related to the retina and cornea. Certain characteristics of nanoparticles increase encapsulation efficiency, such as the size of the nanoparticle and the charge of the outer layer of the nanoparticle.

Conclusion: It is still unknown what characteristics lipid nanoparticles should have to successfully treat human eye illnesses. The in vitro and in vivo investigations covered in this review, however, present encouraging results. To improve encapsulation effectiveness and disease gene silencing, nanoparticle formulation is essential. The most stable nanoparticles are those made mostly of cationic lipids, PEG lipids, and cholesterol, which also effectively encapsulate RNA. The encapsulation efficiency is not only influenced by size, but also by other factors such as methods of preparation.

Background: To have a better and longer effect, botulinum neurotoxin (BoNT) is injected several times in a treatment course, which could increase side effects and cost. Some of the most cutting-edge strategies being investigated for proteins to their physiologic targets involve the reformulation of BoNT based on peptide-based delivery systems. For this purpose, cell-penetrating peptides (CPPs) are of particular interest because of their capacity to cross the biological membranes.

Objectives: A short and simple CPP sequence was used as a carrier to create nanocomplex particles from BoNT/A, with the purpose of increasing toxin entrapment by target cells, reducing diffusion, and increasing the duration of the effect.

Method: CPP-BoNT/A nanocomplexes were formed by polyelectrolyte complex (PEC) method, considering the anionic structure of botulinum toxin and the cationic CPP sequence. The cellular toxicity, and absorption profile of the complex nanoparticles were evaluated, and the digit abduction score (DAS) was used to assess the local muscle weakening efficacy of BoNT/A and CPP-BoNT/A.

Results: The provided optimized polyelectrolyte complex nanoparticles had a 244 ± 20 nm particle size and 0.28 ± 0.04 PdI. In cellular toxicity, CPP-BoNT/A nanocomplexes as extended-release formulations of BoNT/A showed that nanocomplexes had a more toxic effect than BoNT/A. Furthermore, the comparison of weakening effectiveness on muscle was done among nanoparticles and free toxin on mice based on the digit abduction score (DAS) method, and nanocomplexes had a slower onset effect and a longer duration of action than toxin.

Conclusion: Using PEC method allowed us to form nanocomplex from proteins, and peptides without a covalent bond and harsh conditions. The muscle-weakening effect of toxin in CPP-BoNT/A nanocomplexes showed acceptable efficacy and extended-release pattern.