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The traditional de novo drug discovery is time consuming, costly and in some instances the drugs will fail to treat the disease which result in a huge loss to the organization. Drug repurposing is an alternative drug discovery process to overcome the limitations of the De novo drug discovery process. Ithelps for the identification of drugs to the rare diseases as well as in the pandemic situationwithin short span of time in a cost-effective way. The underlying principle of drug repurposing is that most of the drugs identified on a primary purpose have shown to treat other diseases also. One such example is Tocilizumab is primarily used for rheumatoid arthritis and it is repurposed to treat cancer and COVID-19. At present, nearly30% of the FDA approved drugs to treat various diseases are repurposed drugs. The drug repurposing is either drug-centric or disease centric and can be studied by using both experimental and in silico studies. The in silico repurpose drug discovery process is more efficient as it screens thousands of compounds from the diverse libraries within few days by various computational methods like Virtual screening, Docking, MD simulations,Machine Learning, Artificial Intelligence, Genome Wide Association Studies (GWAS), etc. with certain limitations.These limitationscan be addressed by effective integration of advanced technologies to identify a novel multi-purpose drug.Copyright © 2023, Association of Biotechnology and Pharmacy. All rights reserved.
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The safety of COVID-19 pharmacotherapy is a relevant issue, first of all, because of the current lack of experience with using particular medicinal products and with off-label prescribing. The aim of the study was to analyse information on potential adverse drug reactions (ADRs) and their predictors in etiology- and pathogenesis-oriented COVID-19 therapy. According to literature data, the main clinically significant risk factors for COVID-19 patients to develop an ADR are the duration of their hospital stay, combined use of antivirals, polypharmacy, and their history of drug allergies. The most common adverse reactions to antivirals, to virus-neutralising antibodies, and to human anti-COVID-19 immunoglobulin and convalescent plasma are, respectively, gastrointestinal and hepatobiliary disorders;gastrointestinal disorders, neurological disorders, and allergic reactions;and transfusion reactions (fever, chills, etc.). For pathogenesis-oriented therapy with systemic glucocorticosteroids, the most characteristic ADR is hyperglycaemia. Janus kinase inhibitors and interleukin inhibitors are most often associated with gastrointestinal disorders and hypertransaminasemia;neutropenia is also characteristic of a number of interleukin inhibitors. Haemostatic adverse reactions to anticoagulants depend on the patient's dosing regimen and condition. Drug-drug interactions are a common problem in COVID-19 treatment, with the combination of nirmatrelvir and ritonavir showing the largest number of significant interactions attributed to their pharmacokinetics. Currently, there is data on the role of pharmacogenetic biomarkers in the safety and clinical outcomes of COVID-19 therapy. Thus, to improve the safety of COVID-19 therapy, an integrated approach is needed that will take into account both the clinical, demographic, and pharmacogenetic predictors of ADRs and the risk of drug-drug interactions.Copyright © 2023 Safety and Risk of Pharmacotherapy. All rights reserved.
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Background: To assess the safety, tolerability, and pharmacokinetic (PK) profile in humans of the novel inhaled epithelial sodium channel blocker ETD001. Method(s): Inhaled ETD001 or placebo, delivered via nebulizer, have been administered in a 3:1 ratio to 96 healthy subjects in a blinded, first-inhuman clinical trial (ClinicalTrials.gov Identifier: NCT04926701). The study consisted of two parts. Part A evaluated single ascending doses (SADs) up to 10.8 mg, and Part B evaluated multiple ascending doses (MADs) up to 3.1 mg once daily (QD) for 7 days and 4.65 mg twice daily (BID) for 14 days. Safety was assessed by monitoring for adverse events (AEs), laboratory safety tests (including blood potassium monitoring), vital signs, 12-lead electrocardiogram (ECG), and spirometry. Systemic exposurewas assessed using serial pharmacokinetic blood draws. Result(s): Therewere no serious AEs. Twenty-four subjects reported 38 AEs, all of mild to moderate intensity and all resolved. There were no clinically relevant changes in laboratory safety tests, vital signs, ECGs, or spirometry measurements. All blood potassium assessments were within normal range at all doses. Three subjects withdrew in Part B;all withdrawals were considered unrelated to study drug: one on day 6 from the 3.1-mg QD cohort for personal reasons, one after the first dose of the 3.1-mg BID cohort because of vasovagal syncope at time of venipuncture triggering atrial fibrillation that spontaneously resolved, and one on Day 4 of the 3.1- mg BID cohort because of a positive COVID-19 test. Pharmacokinetic parameters were approximately dose proportional in Part A, with peak concentrations 1 to 2 hours after dose and exposure out to 12 to 24 hours at all doses, indicating good lung retention. Part B plasma concentrations displayed dose-independent kinetics and showed minimal accumulation, with a mean of 1.11-fold observed over 14 days. Conclusion(s): ETD001 was well tolerated at single doses up to 10.8 mg and multiple doses of 3.1 mg QD for 7 days and 4.65 mg BID for 14 days. The wide safety margin is predicted to enable doses capable of durable target engagement in the lung, which are expected to enhance mucociliary clearance in people with cystic fibrosis.Copyright © 2022, European Cystic Fibrosis Society. All rights reserved
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The pharmacokinetic (PK) drug-drug interactions (DDIs) of nelfinavir and cepharanthine combination is limited information in human. In addition, the dosage regimen of this combination is not available for COVID-19 treatment. The objective of this study was to perform in silico simulations using GastroPlusTM software to predict physicochemical properties, PK parameters using the physiologically based pharmacokinetic (PBPK) model of healthy adults in different dosage regimens. The DDIs analysis of nelfinavir and cepharanthine combination was carried out to optimize the dosage regimens as a potential against COVID-19. The Spatial Data File (SDF) format of nelfinavir and cepharanthine structures obtained from PubChem database were used to carry out in silico predictions for physicochemical properties and PK parameters using several aspects of modules such as ADMET Predictor, Metabolism and Transporter, PBPK model. Subsequently, all data were utilized in the DDIs simulations. The dynamic simulation feature was selected to calculate and investigate the Cmax, AUC0-120, AUC0-inf, Cmax ratio, AUC0-120 ratio, and AUC0-inf ratio. The victim or nelfinavir dosage regimens were used four oral administration regimens of 500 mg and 750 mg in every 8 and 12 hours for simulations. The perpetrator or cepharanthine oral dosage regimens were used in several regimens from 10 mg to 120 mg in every 8, 12, and 24 hours. From all predicted results, the dosage regimen as a potential combination against COVID-19 was nelfinavir 500 mg every 8 hours and cepharanthine 10 mg every 12 hours.Copyright © 2023 by Faculty of Pharmacy, Mahidol University, Thailand is licensed under CC BY-NC-ND 4.0. To view a copy of this license, visit https://www.creativecommons.org/licenses/by-nc-nd/4.0/.
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SARS-CoV-2 is a kind of coronavirus that produces Covid-19 illness, which is still a public health concern in Indonesia. Meanwhile, an effective drug has not yet been found and although vaccination has been carried out, in several regions and neighboring countries there is still an increase in Covid-19 cases. This study aimed to obtain bioactive compounds from sea urchins (Echinometra mathaei) that have greater antiviral potential and lower toxicity than remdesivir. This research was started by predicting druglikeness with SwissADME, followed ADMET predicition with pkCSM online, and docking of molecule using the Molegro Virtual Docker (MVD) 5.5 software against the main protease (Mpro) target (PDB ID: 6W63). The results showed that six compounds from sea urchins (Echinometra mathaei) had antiviral activity, where the bioactive compound from sea urchins (Echinometra mathaei) with the highest affinity was shown by Spinochrome C a smaller rerank score compared with Remdesivir and native ligand (X77). So that Spinochrome C compounds are candidates as SARS-CoV-2 inhibitors potential developed drug.Copyright Published by Oriental Scientific Publishing Company © 2023.
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The Coronavirus Disease 2019 (COVID-19), also known as a novel coronavirus (2019-n-CoV), reportedly originated from Wuhan City, Hubei Province, China. Coronavirus Disease 2019 rapidly spread all over the world within a short period. On January 30, 2020, the World Health Organization (WHO) declared it a global epidemic. COVID-19 is a Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) evolves to respiratory, hepatic, gastrointestinal, and neurological complications, and eventually death. SARS-CoV and the Middle East Respiratory Syndrome coron-avirus (MERS-CoV) genome sequences similar identity with 2019-nCoV or Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2). However, few amino acid sequences of 2019-nCoV differ from SARS-CoV and MERS-CoV. COVID-19 shares about 90% amino acid sequence simi-larity with SARS-CoV. Effective prevention methods should be taken in order to control this pandemic situation. To date, there are no effective treatments available to treat COVID-19. This review provides information regarding COVID-19 history, epidemiology, pathogenesis and molecular diagnosis. Also, we focus on the development of vaccines in the management of this COVID-19 pandemic and limiting the spread of the virus.Copyright © 2022 Bentham Science Publishers.
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OBJECTIVE To summarize the basic information, mechanism of action, pharmacokinetics, efficacy, safety, interactions, and precautions of azvudine, to provide references for its clinical use. METHODS Literatures related to azvudine from the official website of Chinese clinical trial regi stry, clinicaltrials.gov, Pubmed, CNKI and Wanfang were systematically searched and summarized. RESULTS Azvudine is an oral small-molecule corona virus disease(COVID-19) treatment drug independently developed by China. As a nucleoside analogue targeting to viral RNA-dependent RNA polymerases (RdRp), it can inhibit RNA virus reverse transcription process and replication process. The results of phase III clinical trials showed that azvudine could significantly shorten the time of nucleic acid conversion in patients with mild to moderate corona virus disease (COVID-19). Compared with the control group, the azvudine group can significantly shorten the improvement time of pneumonia. For moderate and severe patients, azvudine treatment also showed significant therapeutic effects in the time of nucleic acid conversion, discharge, and rehabilitation. CONCLUSION The drug possesses good safety and tolerability in patients, which provide a choice for the clinical treatment of COVID-19.Copyright © 2022 Chinese Pharmaceutical Association. All rights reserved.
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Molnupiravir is one of the drugs for the etiotropic therapy of a new coronavirus infection COVID-19. It has confirmed its clinical efficacy in the treatment of patients with mild and moderate COVID-19, including those who are at high risk of progressing to severe disease. The aim of the study was to evaluate bioequivalence of the generic drug molnupiravir ALARIO-TL and the original drug Lagevrio with a single oral administration in healthy volunteers. Materials and methods. This bioequivalence study was an open, randomized, two-period crossover study. In each of the two periods, volunteers received a single dose of the test drug, or reference drug molnupiravir, in the form of capsules at the dose of 200 mg. The washout period between the doses was 3 days. To determine pharmacokinetic (PK) parameters and bioequivalence, the concentration the concentration of N-hydrozycytidine (NHC), the main molnupiravir metabolit in the blood plasma of volunteers was evaluated. The blood plasma sampling was carried out in the range from 0 to 16 hours in each of the study periods. Bioequivalence was assessed by comparing 90% confidence intervals (CIs) for the ratio of geometric means of AUC(0-16) and Cmax of the test drug and reference drugs with the established equivalence limits of 80.00 - 125.00%. Results. A total of 28 healthy male volunteers were included in the study. According to the results of the statistical analysis, after the administration of the test and reference drugs, the 90% CIs for the ratio of the geometric means of AUC (0-16) and Cmax were 96.31% - 113.64% and 91.37% - 114.8%, respectively. These intervals fit within the established limits of 80.00-125.00%, which confirms the bioequivalence of the drugs. When comparing the frequency of the individual adverse events registration, no significant differences were found out after the administration of the test and reference drugs. Conclusion. Based on the results of this study, it can be concluded that the test and reference drugs of molnupiravir are bioequivalent. In addition, the data obtained indicate that the drugs have similar safety profiles.Copyright © 2022 Volgograd State Medical University, Pyatigorsk Medical and Pharmaceutical Institute. All rights reserved.
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Introduction: Biologics (biopharmaceuticals) present new promising therapies for many diseases such as cancers, chronical inflammatory diseases and today's biggest challenge - COVID-19. Research: Today, most biologics have been synthetized using modern methods of biotechnology, in particular DNA recombinant technology. Current pharmaceutical forms of protein/peptide biopharmaceuticals are intended for parenteral route of administration due to their instability and large size of molecules. In order to improve patient compliance, many companies are working on developing adequate forms of biopharmaceuticals for alternative, non-invasive routes of administration. The aim of this work is to review current aspirations and problems in formulation of biopharmaceuticals for alternative (non-parenteral) routes of administration and to review the attempts to overcome them. These alternative routes of administration could be promising in prevention and treatment of COVID-19, among other serious diseases. Conclusion(s): The emphasis is on stabilizing monoclonal antibodies into special formulations and delivery systems;their application should be safer, more comfortable and reliable. When it comes to hormones, vaccines and smaller peptides, some companies have already registered drugs intended for nasal and oral delivery.Copyright © 2022 Sciendo. All rights reserved.
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BACKGROUND: Remdesivir (RDV) is an RNA polymerase inhibitor approved for treatment of COVID-19 (200 mg loading dose, 100 mg qd thereafter) in adult and pediatric patients, primarily metabolized by the high-capacity carboxylesterase 1 pathway (80% of metabolism), and by cathepsin A and CYP3A (10% each). The extensive hepatic contribution to RDV elimination and the prevalence of liver comorbidities in COVID-19 patients warranted a study in participants with hepatic impairment (HI). METHOD(S): This is a phase 1, open-label study of RDV consisting of moderate and severe HI participants and healthy matched controls (HMC) based on age (+/- 10 years), sex, and BMI (+/- 20%). Participants received a single 100 mg IV dose of RDV and remained in the clinic for 8 days. The primary endpoint was pharmacokinetic (PK) parameters of RDV and metabolites. RESULT(S): Preliminary PK and safety data from 10 moderate and 6 severe HI participants and their HMC are available. The average PK fold-change for all analytes and matrices assessed in the study are presented (Table). No serious treatment-related adverse events and no clinically significant changes in participant lab values were reported. CONCLUSION(S): The 1.52 RDV AUCinf fold increase is within expected ranges and justifies no dose adjustment in COVID-19 patients with impaired hepatic function. (Table Presented).
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OBJECTIVE To summarize the basic information, mechanism of action, pharmacokinetics, efficacy, safety, interactions, and precautions of azvudine, to provide references for its clinical use. METHODS Literatures related to azvudine from the official website of Chinese clinical trial regi stry, clinicaltrials.gov, Pubmed, CNKI and Wanfang were systematically searched and summarized. RESULTS Azvudine is an oral small-molecule corona virus disease(COVID-19) treatment drug independently developed by China. As a nucleoside analogue targeting to viral RNA-dependent RNA polymerases (RdRp), it can inhibit RNA virus reverse transcription process and replication process. The results of phase III clinical trials showed that azvudine could significantly shorten the time of nucleic acid conversion in patients with mild to moderate corona virus disease (COVID-19). Compared with the control group, the azvudine group can significantly shorten the improvement time of pneumonia. For moderate and severe patients, azvudine treatment also showed significant therapeutic effects in the time of nucleic acid conversion, discharge, and rehabilitation. CONCLUSION The drug possesses good safety and tolerability in patients, which provide a choice for the clinical treatment of COVID-19.
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Ethnopharmacological relevance: Scutellaria baicalensis Georgi. contains varieties of function compounds, and it has been used as traditional drug for centuries. Baicalein is the highest amount of flavonoid found in Scutellaria baicalensis Georgi., which exerts various pharmacological activities and might be a promising drug to treat COVID-19. Aim of the study: The present work aims to investigate the metabolism of baicalein in humans after oral administration, and study the pharmacokinetics of BA and its seven metabolites in plasma and urine. Materials and methods: The metabolism profiling and the identification of baicalein metabolites were performed on HPLC-Q-TOF. Then a column-switching method named MPX™-2 system was applied for the high-throughput quantificationof BA and seven metabolites. Results: Seven metabolites were identified using HPLC-Q-TOF, including sulfate, glucuronide, glucoside, and methyl-conjugated metabolites. Pharmacokinetic study found that BA was extensively metabolized in vivo, and only 5.65% of the drug remained intact in the circulatory system after single dosing. Baicalein-7-O-sulfate and baicalein-6-O-glucuronide-7-O-glucuronide were the most abundant metabolites. About 7.2% of the drug was excreted through urine and mostly was metabolites. Conclusion: Seven conjugated metabolites were identified in our assay. A high-throughput HPLC-MS/MS method using column switch was established for quantifying BA and its metabolites. The method has good sensitivity and reproducibility, and successfully applied for the clinical pharmacokinetic study of baicalein and identified metabolites. We expect that our results will provide a metabolic and pharmacokinetic foundation for the potential application of baicalein in medicine. © 2022
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Objective: To explore the mechanism of Xuanbai chengqi decoction and Sangbei power in the treatment of epidemic-closed lung type COVID-19 by network pharmacology. Method(s): The potential blood active components and gene targets of Xuanbai chengqi decoction and Sangbei power were screened and predicted by TCMSP;The angiotensin converting enzyme 2(ACE2)related gene targets were downloaded;The PPI network of components-targets was plotted by STRING database.The intersection of ACE2-related genes and target genes of Xuanbai chengqi decoction and Sangbei power was extracted;The DAVID database was used to analyze and screen the key targets and mechanisms of Xuanbai chengqi decoction and Sangbei power. Result(s): A total of 496 active ingredients related to Xuanbai chengqi decoction and Sangbei power were retrieved from TCMSP database.According to the pharmacokinetic parameters, 78 active components in blood were screened and 761 targets were retrieved.5 556 ACE2-related genes were downloaded.49 key genes were obtained after the intersection of Chinese medicine component targets and ACE2 related gene targets;The genes affected by Xuanbai chengqi decoction and Sangbei power were mainly involved in cytoketone metabolism, intracellular protein transport, internal peptidase inhibitor activity and others, which were mainly related to the signaling pathway of the Jak-STAT, the intestinal immune network pathway of producing IgA, complement and coagulation cascade pathway, etc. Conclusion(s): Xuanbai chengqi decoction and Sangbei power can act on ACE2 through 49 gene loci, and its mechanism is related to cellular ketone metabolism and inhibition of protein entry into cells. Copyright © 2021, Central Station of Chinese Medicinal Materials Information, National Medical Products Administration. All right reserved.
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Background: Enpatoran is a selective and potent dual toll-like receptor (TLR) 7/8 inhibitor in development for the treatment of cutaneous and systemic lupus erythematosus (CLE/SLE). Enpatoran inhibits TLR7/8 activation in vitro and suppresses disease activity in lupus mouse models.1 Enpatoran was well tolerated and had linear pharmacokinetic (PK) parameters in healthy volunteers.2 As TLR7/8 mediate immune responses to single-stranded RNA viruses, including SARS-CoV-2, it was postulated that enpatoran may prevent hyperinfammation and cytokine storm in COVID-19. Objectives: In response to the COVID-19 pandemic, we conducted an exploratory Phase II trial to assess safety and determine whether enpatoran prevents clinical deterioration in patients (pts) hospitalized with COVID-19 pneumonia. PK and pharmacodynamics (PD) of enpatoran were also evaluated. Methods: ANEMONE was a randomized, double-blind, placebo (PBO)-con-trolled study conducted in Brazil, the Philippines, and the USA (NCT04448756). Pts aged 18-75 years, hospitalized with COVID-19 pneumonia (WHO 9-point scale score =4) but not mechanically ventilated, with SpO2 <94% and PaO2/FiO2 ≥150 (FiO2 maximum 0.4) were eligible. Those with a history of uncontrolled illness, active/unstable cardiovascular disease and SARS-CoV-2 vaccination were excluded. Pts received PBO or enpatoran (50 or 100 mg twice daily [BID]) for 14 days, with monitoring to Day 28 and safety follow-up to Day 60. Primary outcomes were safety and time to recovery (WHO 9-point scale ≤3). Clinical deterioration (time to clinical status >4, WHO 9-point scale) was a secondary outcome. Exploratory endpoints were enpatoran and biomarker concentrations (cytokines, C-reactive protein [CRP], D-dimer and interferon gene signature [IFN-GS] scores) assessed over time. Results: 149 pts received either PBO (n=49), or enpatoran 50 mg (n=54) or 100 mg (n=46) BID;88% completed treatment and 86% received concomitant steroids. Median age was 50 years (77% <60 years old), 66% were male, and 50% had ≥1 comorbidity (40% hypertension, 24% diabetes). Overall, 59% pts reported a treatment-emergent adverse event (TEAE) with three non-treatment-related deaths;11% reported a treatment-related TEAE. The proportion of pts in the enpatoran group reporting serious TEAEs was low (50 mg BID 9%;100 mg BID 2%) vs PBO (18%). Gastrointestinal disorders were most common (PBO 8%;50 mg BID 28%;100 mg BID 9%). The primary outcome of time to recovery with enpatoran vs PBO was not met;medians were 3.4-3.9 days. A positive signal in time to clinical deterioration from Day 1 through Day 28 was observed;hazard ratios [95% CI] for enpatoran vs PBO were 0.39 [0.13, 1.15] (50 mg BID) and 0.30 [0.08, 1.08] (100 mg BID). Mean enpatoran exposure was dose-proportional, and PK properties were within expectations. The median (quartile [Q]1-Q3) interleukin 6 (IL-6), CRP and D-dimer baseline concentration across the groups were 5.7 (4.0-13.5) pg/mL, 30.04 (11.40-98.02) and 0.62 (0.39-1.01) mg/L, respectively. Baseline IFN-GS scores were similar across groups. Conclusion: The ANEMONE trial was the frst to evaluate the safety and efficacy of a TLR7/8 inhibitor in an infectious disease for preventing cytokine storm. Enpa-toran up to 100 mg BID for 14 days was well tolerated by patients acutely ill with COVID-19 pneumonia. Time to recovery was not improved with enpatoran, perhaps due to the younger age of patients who had fewer comorbidities compared to those in similar COVID-19 trials. However, there was less likelihood for clinical deterioration with enpatoran than placebo. This trial provides important safety, tolerability, PK and PD data supporting continued development of enpatoran in SLE and CLE (NCT04647708, NCT05162586).
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Background: The key link in the therapeutic drug monitoring of methotrexate (MTX) is the measurement of the concentrations of its most stable metabolites, as well as products of the early and late stages of MTX conversion (short-chain polyglutamates). Metabolic rate of MTX can depend on the clinical characteristics of patients and concomitant drug therapy. Objectives: To reveal the regularity of the distribution of various metabolites in patients who responded and did not respond to MTX therapy. To compare groups of patients with different responses to MTX according to clinical characteristics. Methods: The study included 79 RA diagnosis according to ACR/EULAR 2010 criteria, 65 (82%) women and 14 (18%) men, aged 53 ± 11 years, naiive to MTX. All patients had normal renal excretory function (GFR more than 60 ml/min). All patients were prescribed MTX of 10-15 mg/m2 of body surface. Achievement of therapy targets was established according to the EULAR therapy response criteria. The determination of MTX monoglutamate in erythrocytes (ER) and mono-nuclear cells (MO), as well as the main metabolites of MTX-polyglutamates with 2,3 and 4 glutamate residues (MTXPG 2-4), as well as 7-hydroxymethotrexate (7-OH-MTX) was measured by the tandem chromatomass spectrometry after 4, 12 and 24 weeks of therapy, the result was expressed in nmol/L. The calculation was performed using the statistical data analysis package Statistica 10 for Windows (StatSoft Inc., USA) using the methods of parametric and nonparametric statistics. Results: By the 24th week of therapy, 34 (43%) (group 1) patients achieved the targets of therapy, 36 (46%) did not achieve (group 2). MTX withdrawn in 5 (6%) patients-due to adverse reactions. 4 (5%) were unable to continue to participate due to SARS-CoV2 pandemic. After 4 weeks of treatment, the concentration of various MTX metabolites did not differ in the groups. After 12 weeks of therapy, signifcant differences were found in the content of 7-OH MTX in the ER: 28.19 [7.28;58.07] and 5.89 [0.79;20.03], respectively (p=0.002);the concentration of the remaining fractions did not differ. Group 1 showed a higher concentration of 7-OH-MTX in MO after 24 weeks of therapy-5.23 [1.39;12.52] and 1.05 [0.07;3.55], respectively (p = 0.006). No differences between the concentrations of other MTX metabolites were found. The groups were matched for age, body mass index, duration of RA, and disease activity at the baseline. In group 2, patients used statins more often (2 (6%) versus 6 (37%), p = 0.01), however, there were no statistically signifcant differences in the concentration of MTX metabolites in the groups of patients taking and not taking statins. Conclusion: The concentration of 7-OH-MTX after 12 and 24 weeks of therapy is statistically higher in the group of patients who responded to therapy. 7-OH-MTX appears to be a more persistent metabolite of MTX, therefore, it is more applicable for therapeutic drug monitoring of MTX. Patients taking statins may be potential nonresponders to MTX therapy.
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Cancer gene therapy based on various gene delivery vectors has some potential but also has obvious disadvantages. In this study, a new M13 phage-based oncolytic virus is constructed that carried the RGD peptides to target tumor cells and the 3C gene of Seneca Valley virus (SVV) preceded by a eukaryotic initial transcriptional region (ITR) to transcribe an oncolytic protein to kill tumor cells. Recombinant virus particles of 1200 nm in length are obtained in large quantities by transfecting the recombinant M13 phage plasmid into the host BL2738 and are investigated in vitro in tumor cells and in vivo in tumor-bearing mice to evaluate their antitumor effect. The experiments using Hela cells confirm that the engineered M13 phage can target and enter Hela cells, and express the SVV 3C protein, resulting in apoptosis of target cells by upregulating the expression of caspase 3. Furthermore, the results of experiments in vivo also show that the recombinant phage significantly inhibits the enhanced tumor volume in nude mice compared to the control groups. The M13 phage may be engineered to fuse with a variety of oncolytic proteins to inhibit the growth of tumor cells in the future, providing a promising phage-based targeted oncolytic reagent.
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Background: Nivolumab (NIVO), a programmed death-1 immune checkpoint inhibitor, has demonstrated clinical efficacy across patients with different tumor types, including clear cell renal cell carcinoma (ccRCC), when administered via IV infusion. As an alternative to IV infusion, subcutaneous (SC) administration alleviates the need for IV ports, thereby lowering the risk of associated complications such as infections and phlebitis. SC formulation also reduces the time for dose preparation and administration, which may decrease overall treatment burden and reduce patient time in the clinic, benefiting patients and healthcare providers and improving overall healthcare resource utilization. SC-administered NIVO consists of NIVO co-formulated with the recombinant human hyaluronidase PH20 enzyme (NIVO + rHuPH20), which aims to increase the dispersion and absorption of NIVO within the SC space. SC NIVO + rHuPH20 was shown to be safe and well tolerated in a phase 1/2 study, warranting further investigation (Lonardi S et al. J Clin Oncol 2021;39(suppl 15):2575). Methods: CheckMate 67T is a multicenter, randomized, open-label, phase 3 study that will evaluate the noninferiority of SC NIVO + rHuPH20 versus IV NIVO in patients with advanced or metastatic ccRCC who have progressed after receiving ≤ 2 prior systemic treatment regimens. Key inclusion criteria are age ≥ 18 years, histologically confirmed advanced or metastatic ccRCC, measurable disease by RECIST v1.1 within 28 days prior to randomization, and a Karnofsky performance status ≥ 70. Key exclusion criteria are untreated symptomatic metastases to the central nervous system, other malignancy, autoimmune diseases, HIV-positive status with AIDS-defining infection within past year or current CD4 count < 350 cells/μL, other serious or uncontrolled disorders including severe, acute SARS-CoV-2 infection, and prior treatment with immune checkpoint inhibitors, other T-cell-targeting antibody drugs, or live attenuated vaccines within 30 days of first study treatment. At least 454 eligible patients will be randomized to receive SC NIVO + rHuPH20 or IV NIVO. The primary objectives are to demonstrate pharmacokinetic (PK) noninferiority of SC NIVO versus IV NIVO, as measured by time-averaged serum concentration over the first 28 days (Cavgd28) and trough serum concentration at steady state (Cminss) (co-primary endpoints). Secondary endpoints include objective response rate by blinded independent central review, additional PK parameters, safety, efficacy, and immunogenicity of SC NIVO and IV NIVO. This study is currently enrolling patients globally.