Cost-effectiveness and budget impact analysis of Daratumumab, Lenalidomide and dexamethasone for relapsed-refractory multiple myeloma.

BACKGROUND: The prominent efficacy in terms of increasing progression-free survival (PFS) of Daratumumab, Lenalidomide and dexamethasone (DRd) triplet therapy versus Carfilzomib, Lenalidomide and dexamethasone (KRd) was proven previously in relapsed-refractory multiple myeloma (RRMM). However, the cost effectiveness of DRd versus KRd is unknown. METHODS: We developed a Markov model by using an Iranian payer perspective and a 10-year time horizon to estimate the healthcare cost, Quality-adjusted life years (QALYs) and life years gain (LYG) for DRd and KRd triplet therapies. Clinical data were obtained from meta-analyses and randomized clinical trials (RCTs). One-way and probabilistic sensitivity analysis were performed to assess model uncertainty. Budget impact analysis of 5 years of treatment under the DRd triplet therapy was also analysed. RESULTS: DRd was estimated to be more effective compared to KRd, providing 0.28 QALY gain over the modelled horizon. DRd-treated patients incurred $264 in total additional costs. The incremental cost utility ratio (ICUR) and cost effectiveness ratio (ICER) were $956/QALY and $472/LYG respectively. The budget impact analysis indicates that adding Daratumumab to Lenalidomide and dexamethasone regimen, in the first 5 years, will increase the healthcare system's expenses by $6.170.582. CONCLUSION: DRd triplet therapy compared to KRd is a cost-effective regimen for RRMM under Iran willingness-to-pay threshold.

Design, synthesis, α-glucosidase inhibition, pharmacokinetic, and cytotoxic studies of new indole-carbohydrazide-phenoxy-N-phenylacetamide derivatives.

A new series of indole-carbohydrazide-phenoxy-N-phenylacetamide derivatives 7a-l were designed, synthesized, and screened for their α-glucosidase inhibitory abilities and cytotoxic effects. The results obtained in the α-glucosidase inhibition assay indicated that most of the synthesized derivatives displayed good to moderate inhibitory abilities (Ki values ranging from 14.65 ± 2.54 to 37.466 ± 6.46 µM) when compared with the standard drug acarbose (Ki = 42.38 ± 5.73 µM). Among them, 2-mehoxy-phenoxy derivatives 7l and 7h with 4-nitro and 4-chloro substituents on the phenyl ring of the N-phenylacetamide moiety, respectively, displayed the most inhibition effects. The inhibitory mechanism of these compounds was investigated by molecular docking studies. The in vitro cytotoxicity assay showed that only one compound, 2-methoxy-phenoxy derivative 7k with a 4-bromo substituent on the phenyl ring of the N-phenylacetamide moiety, exhibited moderate cytotoxicity against the human non-small-cell lung cancer cell line A549 and the rest of the compounds show almost no cytotoxicity. Further cytotoxic evaluations were also performed on compound 7k. The in silico pharmacokinetic study predicted that the selected compounds 7l and 7h are likely to be orally active.

Design and synthesis of phenoxymethybenzoimidazole incorporating different aryl thiazole-triazole acetamide derivatives as α-glycosidase inhibitors.

A novel series of phenoxymethybenzoimidazole derivatives (9a-n) were rationally designed, synthesized, and evaluated for their α-glycosidase inhibitory activity. All tested compounds displayed promising α-glycosidase inhibitory potential with IC50 values in the range of 6.31 to 49.89 µM compared to standard drug acarbose (IC50 = 750.0 ± 10.0 µM). Enzyme kinetic studies on 9c, 9g, and 9m as the most potent compounds revealed that these compounds were uncompetitive inhibitors into α-glycosidase. Docking studies confirmed the important role of benzoimidazole and triazole rings of the synthesized compounds to fit properly into the α-glycosidase active site. This study showed that this scaffold can be considered as a highly potent α-glycosidase inhibitor.

Rational Design, Synthesis, in Vitro, and in Silico Studies of Chlorophenylquinazolin-4(3H)-One Containing Different Aryl Acetohydrazides as Tyrosinase Inhibitors.

Tyrosinase plays a pivotal role in the hyperpigmentation and enzymatic browning of fruit and vegetable. Therefore, tyrosinase inhibitors can be of interest in industries as depigmentation compounds as well as anti-browning agents. In the present study, a series of chlorophenylquinazolin-4(3H)-one derivative were rationally designed and synthesized. The formation of target compounds was confirmed by spectral characterization techniques such as IR, 1 H-NMR, 13 C-NMR, and elemental analysis. Among the synthesized derivatives, compound 8l was proved to be the most potent inhibitor with an IC50 value of 25.48±1.19 µM. Furthermore, the results of the molecular docking study showed that this compound fitted well in the active site of tyrosinase with the binding score of -10.72.

New 4-phenylpiperazine-carbodithioate-N-phenylacetamide hybrids: Synthesis, in vitro and in silico evaluations against cholinesterase and α-glucosidase enzymes.

A series of novel 4-phenylpiperazine-carbodithioate-N-phenylacetamide hybrids (6a-n) was designed, synthesized, and evaluated for their in vitro inhibitory activity against the metabolic enzymes, acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and α-glucosidase. The obtained results showed that most of the synthesized compounds exhibited high to good anti-AChE and anti-BChE activity in the range of nanomolar concentrations in comparison to tacrine as a positive control. Molecular modeling of the most potent compounds 6e and 6i demonstrated that these compounds interacted with important residues of the AChE and BChE active sites. Moreover, all the newly synthesized compounds 6a-n had significant Ki values against α-glucosidase when compared with the positive control acarbose. Representatively, N-2-fluorophenylacetamide derivative 6l, with a Ki value of 0.98 nM as the most potent compound, was 126 times more potent than acarbose with a Ki value of 123.70 nM. This compound also fitted in the α-glucosidase active site and interacted with key residues. An in silico study of the druglikeness/absorption, distribution, metabolism, and excretion (ADME)/toxicity profile of the selected compounds 6e, 6i, and 6l predicts that these compounds are drug-like and have the appropriate properties in terms of ADME and toxicity.

Coronavirus disease 2019 (COVID-19): An overview of the immunopathology, serological diagnosis and management.

SARS-CoV-2 is a novel human coronavirus responsible for the Coronavirus disease 2019 (COVID-19) pandemic. Pneumonia and acute respiratory distress syndrome are the major complications of COVID-19. SARS-CoV-2 infection can activate innate and adaptive immune responses and result in massive inflammatory responses later in the disease. These uncontrolled inflammatory responses may lead to local and systemic tissue damage. In patients with severe COVID-19, eosinopenia and lymphopenia with a severe reduction in the frequency of CD4+ and CD8+ T cells, B cells and natural killer (NK) cells are a common feature. COVID-19 severity hinges on the development of cytokine storm characterized by elevated serum levels of pro-inflammatory cytokines. Moreover, IgG-, IgM- and IgA-specific antibodies against SARS-CoV-2 can be detected in most patients, along with the viral RNA, forming the basis for assays that aid in patient diagnosis. Elucidating the immunopathological outcomes due to COVID-19 could provide potential targets for immunotherapy and are important for choosing the best clinical management by consultants. Currently, along with standard supportive care, therapeutic approaches to COVID-19 treatment involve the use of antiviral agents that interfere with the SARS-CoV-2 lifecycle to prevent further viral replication and utilizing immunomodulators to dampen the immune system in order to prevent cytokine storm and tissue damage. While current therapeutic options vary in efficacy, there are several molecules that were either shown to be effective against other viruses such as HIV or show promise in vitro that could be added to the growing arsenal of agents used to control COVID-19 severity and spread.

Clinical, immunological, and genetic features in 780 patients with autoimmune lymphoproliferative syndrome (ALPS) and ALPS-like diseases: A systematic review.

BACKGROUND: Autoimmune lymphoproliferative syndrome (ALPS) is a group of genetic disorders characterized by early-onset lymphoproliferation, autoimmune cytopenias, and susceptibility to lymphoma. The majority of ALPS patients carry heterozygous germline mutations in the TNFRSF6 gene. In this study, we conducted a systematic review of patients with ALPS and ALPS-like syndrome. METHODS: The literature search was performed in Web of Science, Scopus, and PubMed databases to find eligible studies. Additionally, the reference list of all included papers was hand-searched for additional studies. Demographic, clinical, immunological, and molecular data were extracted and compared between the ALPS and ALPS-like syndrome. RESULTS: Totally, 720 patients with ALPS (532 genetically determined and 189 genetically undetermined ALPS) and 59 cases with ALPS-like phenotype due to mutations in genes other than ALPS genes were assessed. In both ALPS and ALPS-like patients, splenomegaly was the most common clinical presentation followed by autoimmune cytopenias and lymphadenopathy. Among other clinical manifestations, respiratory tract infections were significantly higher in ALPS-like patients than ALPS. The immunological analysis showed a lower serum level of IgA, IgG, and lymphocyte count in ALPS-like patients compared to ALPS. Most (85%) of the ALPS and ALPS-like cases with determined genetic defects carry mutations in the FAS gene. About one-third of patients received immunosuppressive therapy with conventional or targeted immunotherapy agents. A small fraction of patients (3.3%) received hematopoietic stem cell transplantation with successful engraftment, and all except two patients survived after transplantation. CONCLUSION: Our results showed that the FAS gene with 85% frequency is the main etiological cause of genetically diagnosed patients with ALPS phenotype; therefore, the genetic defect of the majority of suspected ALPS patients could be confirmed by mutation analysis of FAS gene.

Synthesis and biological evaluation of a new series of benzofuran-1,3,4-oxadiazole containing 1,2,3-triazole-acetamides as potential α-glucosidase inhibitors.

A series of new benzofuran-1,3,4-oxadiazole containing 1,2,3-triazole-acetamides 12a-n as potential anti-α-glucosidase agents were designed and synthesized. α-Glucosidase inhibition assay demonstrated that all the synthesized compounds 12a-n (half-maximal inhibitory concentration [IC50 ] values in the range of 40.7 ± 0.3-173.6 ± 1.9 µM) were more potent than standard inhibitor acarbose (IC50 = 750.0 ± 12.5 µM). Among them, the most potent compound was compound 12c, with inhibitory activity around 19-fold higher than acarbose. Since the most potent compound inhibited α-glucosidase in a competitive mode, a docking study of this compound was also performed into the active site of α-glucosidase. In vitro and in silico toxicity assays of the title compounds were also performed.

Quinazolinone-dihydropyrano[3,2-b]pyran hybrids as new α-glucosidase inhibitors: Design, synthesis, enzymatic inhibition, docking study and prediction of pharmacokinetic.

A series of new quinazolinone-dihydropyrano[3,2-b]pyran derivatives 10A-L were synthesized by simple chemical reactions and were investigated for inhibitory activities against α-glucosidase and α-amylase. New synthesized compounds showed high α-glucosidase inhibition effects in comparison to the standard drug acarbose and were inactive against α-amylase. Among them, the most potent compound was compound 10L (IC50 value = 40.1 ± 0.6 µM) with inhibitory activity around 18.75-fold more than acarboase (IC50 value = 750.0 ± 12.5 µM). This compound was a competitive inhibitor into α-glucosidase. Our obtained experimental results were confirmed by docking studies. Furthermore, the cytotoxicity of the most potent compounds 10L, 10G, and 10N against normal fibroblast cells and in silico druglikeness, ADME, and toxicity prediction of these compounds were also evaluated.

Design, synthesis, and α-glucosidase-inhibitory activity of phenoxy-biscoumarin-N-phenylacetamide hybrids.

Thirteen new phenoxy-biscoumarin-N-phenylacetamide derivatives (7a-m) were designed based on a molecular hybridization approach as new α-glucosidase inhibitors. These compounds were synthesized with high yields and evaluated in vitro for their inhibitory activity against yeast α-glucosidase. The obtained results revealed that a significant proportion of the synthesized compounds showed considerable α-glucosidase-inhibitory activity in comparison to acarbose as a positive control. Representatively, 2-(4-(bis(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl)phenoxy)-N-(4-bromophenyl)acetamide (7f), with IC50 = 41.73 ± 0.38 µM against α-glucosidase, was around 18 times more potent than acarbose (IC50 = 750.0 ± 10.0 µM). This compound was a competitive α-glucosidase inhibitor. Molecular modeling and dynamic simulation of these compounds confirmed the obtained results through in vitro experiments. Prediction of the druglikeness/ADME/toxicity of the compound 7f and comparison with the standard drug acarbose showed that the new compound 7f was probably better than the standard drug in terms of toxicity.

Synthesis and biological evaluation of new benzimidazole-1,2,3-triazole hybrids as potential α-glucosidase inhibitors.

In this study, a series of benzimidazole-1,2,3-triazole hybrids 8a-n as new α-glucosidase inhibitors were designed and synthesized. In vitro α-glucosidase inhibition activity results indicated that all the synthesized compounds (IC50 values ranging from 25.2 ± 0.9 to 176.5 ± 6.7 µM) exhibited more inhibitory activity in comparison to standard drug acarbose (IC50 = 750.0 ± 12.5 µM). Enzyme kinetic study on the most potent compound 8c revealed that this compound was a competitive inhibitor into α-glucosidase. Moreover, the docking study was performed in order to evaluation of interaction modes of the synthesized compounds in the active site of α-glucosidase and to explain structure-activity relationships of the most potent compounds and their corresponding analogs.

Synthesis and pharmacological properties of polysubstituted 2-amino-4H-pyran-3-carbonitrile derivatives.

2-Amino-3-cyano-4H-chromenes are structural core motifs that received increasing attention in the last years due to their interesting potential pharmacological properties. In this review, the synthetic methods for these compounds are classified based on the type of catalyst in the pertinent reactions. In addition, the wide range of pharmacological properties of these compounds is covered in a separate section.

Synthesis, characterization, molecular docking, and biological activities of coumarin-1,2,3-triazole-acetamide hybrid derivatives.

Coumarins and their derivatives are receiving increasing attention due to numerous biochemical and pharmacological applications. In this study, a series of novel coumarin-1,2,3-triazole-acetamide hybrids was tested against some metabolic enzymes including α-glycosidase (α-Gly), α-amylase (α-Amy), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), human carbonic anhydrase I (hCA I), and hCA II. The new coumarin-1,2,3-triazole-acetamide hybrids showed Ki values in the range of 483.50-1,243.04 nM against hCA I, 508.55-1,284.36 nM against hCA II, 24.85-132.85 nM against AChE, 27.17-1,104.36 nM against BChE, 590.42-1,104.36 nM against α-Gly, and 55.38-128.63 nM against α-Amy. The novel coumarin-1,2,3-triazole-acetamide hybrids had effective inhibition profiles against all tested metabolic enzymes. Also, due to the enzyme inhibitory effects of the new hybrids, they are potential drug candidates to treat diseases such as epilepsy, glaucoma, type-2 diabetes mellitus (T2DM), Alzheimer's disease (AD), and leukemia. Additionally, these inhibition effects were compared with standard enzyme inhibitors like acetazolamide (for hCA I and II), tacrine (for AChE and BChE), and acarbose (for α-Gly and α-Amy). Also, those coumarin-1,2,3-triazole-acetamide hybrids with the best inhibition score were docked into the active site of the indicated metabolic enzymes.

Anticancer properties of N-alkyl-2, 4-diphenylimidazo [1, 2-a] quinoxalin-1-amine derivatives; kinase inhibitors.

Structure activity correlation revealed that the quinoxaline ring is a satisfactory backbone for anticancer activity and a specific functional group at position 1 and 2 can improve the activity. In this basis, besides quinoxaline, imidazoles as potential anticancer agents were used as a supplementary agents for cancer treatment. In this paper, a new series of N-alkyl-2, 4-diphenylimidazo [1, 2-a] quinoxalin-1-amine derivatives were synthesized in a simple and efficient step. The products are fully characterized by 1H NMR, 13C NMR, FT-IR, HRMS, and CHN elemental analysis. Several starting materials with different functionalities have been used for the synthesis of the final products with high isolated yields. The biological activities of the synthesized compounds were evaluated in kinase inhibition and cytotoxic activity in several cancerous cell lines. All compounds (6) were evaluated for inhibition of the cell proliferation using 4 cancerous cell lines. Five of the more active compounds were studied for determination of IC50%. Compounds 6(32-34) showed good activity on some of cancerous cell lines. The results showed that compound 6-32 has the highest biological activity (IC50% 9.77 for K562 cell line). An IC50% value of 15.84 µM was observed for 6-34. Furthermore 6-34 exhibited inhibition of ABL1 and c-Src kinases with an IC50% value of 5.25 µM and 3.94 µM respectively. Docking simulation was performed to position active synthesized compounds 6-32, 6-33, and 6-34 over the ABL1 active site in two different wild-type (DFG-in and DFG-out motif conformer) and T315I mutant to determine the probable binding orientation, conformation and mode of interaction. According to docking study, the docked location in wild type forms is similar and can be found near the P-loop region while in the case of T315I mutant form, the compounds have a distinct docked location which is close to the αC helix and activation loop. Also, it concluded the role of R1 substituent on phenyl ring produced higher interaction energy. Additionally, the detailed inter-molecular energy and types of non-bonding interaction of these compounds over the wild-type and mutant form of ABL1.

Biscoumarin-1,2,3-triazole hybrids as novel anti-diabetic agents: Design, synthesis, in vitro α-glucosidase inhibition, kinetic, and docking studies.

A novel series of biscoumarin-1,2,3-triazole hybrids 6a-n was prepared and evaluated for α-glucosidase inhibitory potential. All fourteen derivatives exhibited excellent α-glucosidase inhibitory activity with IC50 values ranging between 13.0 ±â€¯1.5 and 75.5 ±â€¯7.0 µM when compared with the acarbose as standard inhibitor (IC50 = 750.0 ±â€¯12.0 µM). Among the synthesized compounds, compounds 6c (IC50 = 13.0 ±â€¯1.5 µM) and 6g (IC50 = 16.4 ±â€¯1.7 µM) exhibited the highest inhibitory activity against α-glucosidase and were non-cytotoxic towards normal fibroblast cells. Kinetic study revealed that compound 6c inhibits the α-glucosidase in a competitive mode. Furthermore, molecular docking investigation was performed to find interaction modes of the biscoumarin-1,2,3-triazole derivatives.

A new series of Schiff base derivatives bearing 1,2,3-triazole: Design, synthesis, molecular docking, and α-glucosidase inhibition.

A series of new Schiff bases bearing 1,2,3-triazole 12a-o was designed, synthesized, and evaluated as α-glucosidase inhibitors. All the synthesized compounds showed promising inhibition against α-glucosidase and were more potent than the standard drug acarbose. The kinetic study on the most potent compound 12n showed that this compound acted as a competitive α-glucosidase inhibitor. The docking study revealed that the synthesized compounds interacted with the important residues in the active site of α-glucosidase.

Anticholinesterase activities of novel isoindolin-1,3-dione-based acetohydrazide derivatives: design, synthesis, biological evaluation, molecular dynamic study.

In pursuit of developing novel cholinesterase (ChE) inhibitors through molecular hybridization theory, a novel series of isoindolin-1,3-dione-based acetohydrazides (compounds 8a-h) was designed, synthesized, and evaluated as possible acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. In vitro results revealed IC50 values ranging from 0.11 ± 0.05 to 0.86 ± 0.02 µM against AChE and 5.7 ± 0.2 to 30.2 ± 2.8 µM against BChE. A kinetic study was conducted on the most potent compound, 8a, to ascertain its mode of inhibition, revealing its competitive mode against AChE. Furthermore, the binding interaction modes of the most active compound within the AChE active site was elucidated. Molecular dynamics simulations of compound 8a were performed to assess the stability of the 8a-AChE complex. In silico pharmacokinetic predictions for the most potent compounds indicated their potential as promising lead structure for the development of new anti-Alzheimer's disease (anti-AD) agents.

Aryl-quinoline-4-carbonyl hydrazone bearing different 2-methoxyphenoxyacetamides as potent α-glucosidase inhibitors; molecular dynamics, kinetic and structure-activity relationship studies.

Regarding the important role of α-glucosidase enzyme in the management of type 2 diabetes mellitus, the current study was established to design and synthesize aryl-quinoline-4-carbonyl hydrazone bearing different 2-methoxyphenoxyacetamide (11a-o) and the structure of all derivatives was confirmed through various techniques including IR, 1H-NMR, 13C-NMR and elemental analysis. Next, the α-glucosidase inhibitory potentials of all derivatives were evaluated, and all compounds displayed potent inhibition with IC50 values in the range of 26.0 ± 0.8-459.8 ± 1.5 µM as compared to acarbose used as control, except 11f and 11l. Additionally, in silico-induced fit docking and molecular dynamics studies were performed to further investigate the interaction, orientation, and conformation of the newly synthesized compounds over the active site of α-glucosidase.

Immune checkpoints and cancer immunotherapies: insights into newly potential receptors and ligands.

Checkpoint markers and immune checkpoint inhibitors have been increasingly identified and developed as potential immunotherapeutic targets in various human cancers. Despite valuable efforts to discover novel immune checkpoints and their ligands, the precise roles of their therapeutic functions, as well as the broad identification of their counterpart receptors, remain to be addressed. In this context, it has been suggested that various putative checkpoint receptors can be induced upon activation. In the tumor microenvironment, T cells, as crucial immune response against malignant diseases as well as other immune central effector cells, such as natural killer cells, are regulated via co-stimulatory or co-inhibitory signals from immune or tumor cells. Studies have shown that exposure of T cells to tumor antigens upregulates the expression of inhibitory checkpoint receptors, leading to T-cell dysfunction or exhaustion. Although targeting immune checkpoint regulators has shown relative clinical efficacy in some tumor types, most trials in the field of cancer immunotherapies have revealed unsatisfactory results due to de novo or adaptive resistance in cancer patients. To overcome these obstacles, combinational therapies with newly discovered inhibitory molecules or combined blockage of several checkpoints provide a rationale for further research. Moreover, precise identification of their receptors counterparts at crucial checkpoints is likely to promise effective therapies. In this review, we examine the prospects for the application of newly emerging checkpoints, such as T-cell immunoglobulin and mucin domain 3, lymphocyte activation gene-3, T-cell immunoreceptor with Ig and ITIM domains (TIGIT), V-domain Ig suppressor of T-cell activation (VISTA), new B7 family proteins, and B- and T-cell lymphocyte attenuator, in association with immunotherapy of malignancies. In addition, their clinical and biological significance is discussed, including their expression in various human cancers, along with their roles in T-cell-mediated immune responses.

Phenyl-quinoline derivatives as lead structure of cholinesterase inhibitors with potency to reduce the GSK-3ß level targeting Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder that leads to cognitive decline and memory loss. Unfortunately, there is no effective treatment for this condition, so there is a growing interest in developing new anti-AD agents. In this research project, a series of phenyl-quinoline derivatives were designed as potential anti-AD agents. These derivatives were substituted at two different positions on benzyl and phenyl rings. The structures of the derivatives were characterized using techniques such as IR spectroscopy, 1H NMR, 13C NMR, and elemental analysis. During the in vitro screening, the derivatives were tested against both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). It was observed that most of the derivatives showed higher selectivity against BChE compared to AChE. Among the derivatives, analog 7n (with a methoxy group at R1 and a 4-bromine substituent at R2 exhibited the highest potency, with a 75-fold improvement in the activity compared to the positive control. Importantly, this potent analog demonstrated no toxicity at the tested concentration on SH-SY5Y cells, indicating its potential as a safe anti-AD agent. The level of GSK-3ß was also reduced after treatments with 7n at 50 µM. Overall, this study highlights the design and evaluation of phenyl-quinoline derivatives as promising candidates for developing novel anti-AD agents.