COVID-19–RELATED ADVERSE EVENTS IN THE PHASE 3 POETYK TRIALS OF THE ALLOSTERIC TYROSINE KINASE 2 INHIBITOR, DEUCRAVACITINIB, IN PATIENTS WITH MODERATE TO SEVERE PLAQUE PSORIASIS

BackgroundDeucravacitinib is a first-in-class, oral, selective, allosteric tyrosine kinase 2 (TYK2) inhibitor approved in multiple countries for the treatment of adults with plaque psoriasis. Deucravacitinib suppresses signaling of cytokines involved in the pathogenesis of immune-mediated diseases including psoriasis, psoriatic arthritis, and systemic lupus erythematosus. Deucravacitinib was efficacious compared with placebo in phase 2 trials in psoriatic arthritis and systemic lupus erythematosus.[1,2] In two phase 3 trials in patients with moderate to severe plaque psoriasis (POETYK PSO-1 [NCT03624127], PSO-2 [NCT03611751]), deucravacitinib showed superior efficacy versus placebo and apremilast.[3,4] Upon completion of either psoriasis trial, patients could enroll in the POETYK long-term extension (LTE) trial (NCT04036435).ObjectivesTo evaluate the incidence rate and severity of adverse events (AEs) due to COVID-19 with deucravacitinib treatment in the POETYK PSO-1 and POETYK PSO-2 trials and open-label POETYK LTE trial.MethodsIn PSO-1 (N=666) and PSO-2 (N=1020), adult patients with moderate to severe plaque psoriasis were randomized 2:1:1 to deucravacitinib 6 mg once daily, placebo, or apremilast 30 mg twice daily. At Week 16, placebo patients in both trials switched to deucravacitinib. Based on their Week 24 PASI response, apremilast patients continued with apremilast or switched to placebo or deucravacitinib. In PSO-1, patients randomized to deucravacitinib continued treatment for 52 weeks;in PSO-2, some patients randomized to deucravacitinib had a randomized treatment withdrawal period. At Week 52, patients could enroll in the open-label LTE and receive deucravacitinib. Incidence rates and severity of COVID-19–related AEs in the POETYK trials (n=1364;2076.7 person-years [PY] of follow-up) were compared with the Janssen/Johnson & Johnson COVID-19 vaccine trial placebo group (n=19,544;3096.1 PY of follow-up). This reference population was selected due to the study design and timing of the trial, which occurred when variants were in circulation.ResultsAs of October 1, 2021, 1519 patients received ≥1 dose of deucravacitinib over a 2-year follow-up period;1364 patients met criteria for this analysis, with deucravacitinib exposure since the pandemic onset (estimated to be January 1, 2020). In total, 153 deucravacitinib patients reported a COVID-19–related AE, for an overall exposure-adjusted incidence rate (EAIR) of 7.4/100 PY (95% CI, 6.2–8.6). Serious COVID-19–related AEs occurred in 43 patients (EAIR, 2.1/100 PY;95% CI, 1.5–2.8), including 30 with COVID-19 and 13 with COVID-19 pneumonia;this rate was within the margins of those for moderate to severe COVID-19 reported in the reference population (EAIR, 16.5/100 PY;95% CI, 15.0–17.9). Deaths due to COVID-19 occurred in 6 patients (EAIR, 0.3/100 PY;95% CI, 0.1–0.6), with the COVID-19–related mortality rate being consistent with the reference population (EAIR, 0.23/100 PY;95% CI, 0.1–0.5). Treatment was discontinued due to COVID-19 or COVID-19 pneumonia in 7 patients, including the 6 patients who died due to COVID-19.ConclusionCOVID-19 was among the most frequently reported AEs during the 2-year period of the pooled PSO-1, PSO-2, and LTE trials due to the temporal overlap of the pandemic with the trials. However, COVID-19 infection and death rates did not differ from the reference population;most infections were not serious and did not lead to treatment discontinuation. Based on this analysis, deucravacitinib did not appear to increase the risk of COVID-19 nor its progression to severe outcomes.References[1]Mease PJ, et al. Ann Rheum Dis. 2022;81:815-822.[2]Morand E, et al. Arthritis Rheumatol. 2022;Nov 11 (Epub ahead of print).[3]Armstrong A, et al. J Am Acad Dermatol. 2022;S0190-9622(22)02256-3.[4]Strober B, et al. J Am Acad Dermatol. 2022;S0190-9622(22)02643-3.AcknowledgementsThese clinical trials were sponsored by Bristol Myers Squibb.Disclosure of InterestsDiamant Thaçi Speakers bureau: AbbVie, Almirall, Amgen, Biogen Idec, Boeh inger Ingelheim, Bristol Myers Squibb, Eli Lilly, Galapagos, Galderma, Janssen-Cilag, Leo Pharma, Novartis, Pfizer, Regeneron, Roche, Sandoz-Hexal, Sanofi, Target Solution, and UCB, Consultant of: AbbVie, Almirall, Amgen, Biogen Idec, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Galapagos, Galderma, Janssen-Cilag, Leo Pharma, Novartis, Pfizer, Regeneron, Roche, Sandoz-Hexal, Sanofi, Target Solution, and UCB, Grant/research support from: AbbVie, Almirall, Amgen, Biogen Idec, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Galapagos, Galderma, Janssen-Cilag, Leo Pharma, Novartis, Pfizer, Regeneron, Roche, Sandoz-Hexal, Sanofi, Target Solution, and UCB, Kenneth B Gordon Consultant of: Amgen, Almirall, Dermira, Leo Pharma, Pfizer, and Sun Pharma, Grant/research support from: Amgen, Almirall, Dermira, Leo Pharma, Pfizer, and Sun Pharma, AbbVie, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, and UCB, Melinda Gooderham Speakers bureau: Glenmark, Actelion, AbbVie, Galderma, Leo Pharma, Pfizer, and Regeneron, Amgen, Boehringer Ingelheim, Celgene, Eli Lilly, Janssen, Novartis, Sanofi Genzyme, and Valeant, Consultant of: Amgen, Boehringer Ingelheim, Celgene, Eli Lilly, Janssen, Novartis, Sanofi Genzyme, and Valeant, Andrew Alexis Speakers bureau: Pfizer, Regeneron, and Sanofi Genzyme, Consultant of: AbbVie, Allergan, Almirall, Amgen, Arcutis, AstraZeneca, Bausch Health, Beiersdorf, Bristol Myers Squibb, Dermavant, Galderma, Janssen, Leo Pharma, L'Oreal, Pfizer, Sanofi-Regeneron, Sol-Gel, UCB, Valeant, VisualDx, and Vyne, Grant/research support from: Almirall, Amgen, Arcutis, Bristol Myers Squibb, Cara, Galderma, Leo Pharma, Menlo, Novartis, and Valeant (Bausch Health), Varsha Lalchandani Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Julie Scotto Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Lauren Hippeli Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Matthew J Colombo Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Subhashis Banerjee Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Tamara Lezhava Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Mark Lebwohl Consultant of: Aditum Bio, Almirall, AltruBio, AnaptysBio, Arcutis, Arena, Aristea, Arrive Technologies, Avotres, BiomX, Boehringer Ingelheim, Brickell Biotech, Bristol Myers Squibb, Cara, Castle Biosciences, CorEvitas' (Corrona) Psoriasis Registry, Dermavant, Dr. Reddy's Laboratories, Evelo Biosciences, Evommune, Forte Biosciences, Helsinn Therapeutics, Hexima, Leo Pharma, Meiji Seika Pharma, Mindera, Pfizer, Seanergy, and Verrica, Grant/research support from: AbbVie, Amgen, Arcutis, Avotres, Boehringer Ingelheim, Dermavant, Eli Lilly, Incyte, Janssen, Ortho Dermatologics, Regeneron, and UCB.

INTAKE OF ACETAMINOPHEN SUPPRESSES ANTIVIRAL HUMORAL IMMUNE RESPONSES IN PATIENTS WITH RA FOLLOWING VACCINATION WITH ANTI SARS-CoV-2 mRNA BASED VACCINES

BackgroundAcetaminophen (APAP = paracetamol) may potentially impact vaccine-associated immune responses as the intake of APAP has been associated with a worse outcome in tumor patients receiving checkpoint inhibitors.[1]Different DMARD regimen have been shown to impair the humoral immune response to mRNA SARS-CoV-2 vaccines in patients with rheumatoid arthritis but the effect of paracetamol has not been explored thus far.ObjectivesTo analyse whether the intake of APAP may interfere with antiviral humoral immune responses following two doses of an anti-SARS-CoV-2 mRNA based vaccine in patients with rheumatoid arthritis (RA) on DMARD therapy.MethodsThe RECOVER trial (Rheumatoid Covid-19 Vaccine Immune Response) was a non-randomised, prospective observational control group trial and enrolled 77 RA patients on DMARD therapy and 21 healthy controls (HC). We performed a posthoc analysis of blood samples taken before the first vaccine dose (T0), two (T1) and three (T2) weeks after the first and second vaccine dose, and at 12 (T3) weeks. APAP intake was measured using ELISA. The antibody response (anti-S) to the receptor binding domain (RBD) within the SARS-CoV-2 S1 protein was measured with the Elecsys Anti-SARS-CoV-2-S (Roche Diagnostics GmbH) test. The neutralizing activity NT50 at week 12 was assessed using an HIV-based pseudovirus neutralization assay against Wuhan-Hu-1.ResultsBaseline characteristics of participants are detailed in Table 1. The immunogenicity analyses were based on 73 RA patients after exclusion of 4 patients with previously unnoticed SARS-CoV-2 infection (positive for anti-nucleoprotein at baseline). APAP was detected in serum samples from 34/73 (25%) RA patients and in 7/21 (33%) HC (least at one timepoint T0, T1 and/or T2). APAP intake in HC did not affect levels of anti-S at any timepoint and all HC developed potent neutralizing activity (NT50 ≥ 250) at week 12. RA patients, who tested positive for APAP at T1, showed comparable anti-S levels at T1, T2 and T3 compared to RA patients not exposed to APAP. The detection of APAP at T2 corresponded to lower anti-S levels at T2 (Figure 1 A, B). The detection of APAP at T2 was associated with a significantly lower SARS-CoV-2 neutralizing activity at week 12 compared to patients without perivaccination APAP exposure (p =0.04) (Figure 1 C).ConclusionA decrease of antiviral humoral immune responses was observed in RA patients (but not in HC) who were exposed to APAP at the time of the second mRNA vaccine dose compared to patients in whom APAP was not detected. Our data suggest that the use of paracetamol within the time period around vaccination may impair vaccine-induced immune responses in patients with an already higher risk for blunted immune responses.Reference[1]Bessede A et al. Ann Oncol 2022;33: 909-915Table 1.Baseline characteristics: RA patients and HC with/without APAP exposureRA APAP – n = 37RA APAP + n = 36p-valueHC APAP – n = 8HC APAP + n = 13p-valueAge (yrs), mean (± SD)62 (13)67 (10)0.07 (NS)45 (12)44 (14)0.90 (NS)Female sex, n (%)24 (65)19 (53)0.29 (NS)2 (25)5 (38)0.53 (NS)Vaccination type/schedulemRNA-1273, n (%)4 (11)8 (22.2)0.19 (NS)0 (0)0 (0)BNT162b2, n (%)33 (89)28 (77.8)0.19 (NS)8 (100)13 (100)RA disease characteristicsACPA ± RF, n (%)17/37 (46)19/36 (53)0.56 (NS)NANANARA disease duration (yrs ± SD)9.2 (9.8)10.2 (8.1)0.67 (NS)NANANADMARD therapycsDMARD-mono, n (%)13/37 (35)9/36 (25)0.35 (NS)NANANAbDMARD-mono/combo, n (%)16/37 (43)16/36 (44)0.92 (NS)NANANAtsDMARDs-mono/combo, n (%)8/37 (22)11/36 (31)0.38 (NS)NANANAPrednisone, n (%)15/37 (41)12/36 (33.3)0.52 (NS)NANANAMean daily dose prednisone (mg ± SD)4.6 ± 1.13.9 ± 2.30.39 (NS)NANANA* APAP = acetaminophenFigure 1.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

Safety of Pharmacotherapy in COVID-19 Patients: A Literature Review.

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.

THE USE OF JANUS KINASE INHIBITORS ANTI-INTERLEUKIN THERAPY IN THE RUSSIAN FEDERATION WITH COVID-19: PHARMACOEPIDEMIOLOGICAL SRUDY

The objective of this study was to assess the volume of consumption of anti-interleukins and janus kinase inhibitors in the period 2018–2021, used as well as preventive pathogenetic therapy of COVID-19.Materials and methods. Based on actual sales data in the segments of public procurement (including regional and federal preferential drug provision) and retail sales segment in the period 2018–2021, obtained from the IQVIA database. All data was recalculated into the number of established daily doses (DDDs), with the calculation of pharmacoepidemiological indicators «Incidence of prescribing drugs», «Cumulative risk of prescribing drugs», as well as «Prescribing prevalence per year» for tocilizumab, olokizumab, levilimab, sarilumab, kanakinumab, anakinra, baricitinib, tofacitinib and upadacitinib. Results and discussion. The growth of total sales volumes was demonstrated in all market segments, but mostly in the segment of regional purchases, primarily related to the purchase of these groups of medicines for COVID-19 therapy in the period 2020–2021. It was demonstrated that the increase in the number of cases, accompanied by the expansion of prescribing preventive pathogenetic therapy, led to a twofold increase in the number of new cases of prescribing of janus kinase inhibitors and an increase in this indicator for anti-interleukins by 1.5 times, taking into account the estimated number of patients with moderate and severe COVID-19. The cumulative risk of prescribing these classes of drugs increased proportionally: for JAK inhibitors from 14 to 32%, and for anti-IL drugs from 38 to 69%. Calculations showed that the proportion of people over 18 years of age in the Russian Federation who received at least one dose of janus kinase inhibitors and anti-interleukins increased many times, in 1000 times and 500 times. Conclusions. Taking into account the expansion of the use of these groups of medicines, careful monitoring of information about their safety is required. © 2023, HIV Infection and Immunosuppressive Disorders.All Rights Reserved.

ASYNCHRONOUS TELECONSULTATION BY WHATSAPP CHATBOT IN CONTROLLED AXIAL SPONDYLOARTHRITIS (SPA) PATIENTS UNDER BIOLOGICAL THERAPY: CLINICAL RESULTS OF A SINGLE CENTER

BackgroundThe use of telehealth in the control of rheumatic diseases had been scarce, but COVID pandemic forced to try alternatives to classic face-to-face consultation, and an overflow of telehealth consultations appeared, mainly synchronous (phone, video calls), and finally asynchronous. We try to demonstrate that asynchronous WhatsApp teleconsultation is a good alternative, at least for followup of patients that find it difficult to attend face-to-face visits. We chose axial spondyloarthritis (AxSPA) patients under biological therapy with controlled disease and we proposed teleconsultation with a WhatsApp platform chatbot created for this purpose. The chatbot sends PROMS (BASDAI, VAS for patient global disease assessment, ASDAs, and 3 questions for extraarticular disease), and receive feedback and schedule for the following visits.ObjectivesTo prove that teleconsultation through WhatsApp platform is not inferior to face-to-face consultation in terms of maintaining axial SPA patients disease controlled.MethodsProspective study with retrospective control of patients diagnosed of Axial SPA, fulfilling ASAS criteria and with stable disease under biological therapy for the previous year, recruited from 01 jan to 30 nov 2021. We recruited 62 patients, but two of them gave up (personal reasons, one moved to other region), so we finally include 60 patients. We offer them two teleconsultation visits with their personal mobile device, every four months, and a face-to-face final visit one year after inclusion. In the case of lab test or PROMs deviation or when the patient asks for contact (possible via WhatsApp) he/she is called up by the person in charge (nurse/doctor) that solves the question and arranges an additional presential visit if needed. We consider disease controlled if BASDAI <4, ASDAS < 2,1 or if in rheumatologist´s opinion there is no need to change treatment. We collect patient and disease information (age, gender, employment, characteristics of the disease, previous and actual treatment), activity (BASDAI, PCR, ASDAS), physical function (BASFI), and Quality of life (AsQol).Results60 patients (50 men, 83,3%) were included, mean aged 48,22 years (SD 12,128), 36% were under 45 years at the time of inclusion. They were mostly Ankylosing Spondylitis (AS) (90%;only 6 non radiographic SPA), positive HLA B27 (85%) and with longstanding disease (mean 23 years, SD 12,8), and only 6 patients less than five years. 25% had peripheral impairment (arthritis/dactylitis/enthesitis), and more than 40% presented extraarticular manifestations, mainly psoriasis (26,7%) and uveitis (21%)71,7% were under their first biological (TNF inhibitor, mostly adalimumab), 23,3% were refractory to the first, and 3 patients to at least two biologicals. 51,7% of patients were treated with tapered dose of TNF inhibitors. At inclusion 93,3 % presented remission/LDA by ASDAS/BASDAI-RCP. Only 4 patients included presented higher activity scores but were considered clinically controlled.Table 1.We did not find meaningful clinical differences between basal to final visits in BASDAI, BASFI, ASDAS-RCP or AsQOL.3 patients with reduced dose of biological drug needed to increase to standard dose with no other need to treatment adjustment.ConclusionWe consider asynchronous teleconsultation is promising, and not inferior to face to face consultation in terms of keeping disease control and quality of life, especially for follow-up in patients with stable rheumatic disease, The clinical results presented here are consistent with this considerations.AcknowledgementsGrupo INNOBIDE.Disclosure of InterestsNone Declared.

Clinical evolution of patients with AF and diabetes mellitus in the COVID-19 pandemic. REFADI Registry

Introduction and objectives: To analyze the evolution of patients with atrial fibrillation (AF) and diabetes in the mid-term follow-up during the COVID-19 pandemic and to describe its impact on this population. Method(s): Multicenter and prospective registry that included patients with AF and diabetes attended in cardiology clinics. A multivariate analysis was performed to determine the variables associated with the occurrence of clinical events and mortality. Recruitment was performed in February-December 2019. Result(s): The evolution of 633 patients, 96,2% of those included in the REFADI registry with a median follow-up of 835 days was analyzed (mean age 73.8 +/- 8.5 years, 54.3% male, CHA2DS2-VASc 4,34 +/- 1,4, HAS-BLED 2,47 +/- 0,96) were analyzed. The proportion of anticoagulated patients remained constant (95.6% vs 94.5%;P = .24). There was a decrease in the prescription of vitamin K antagonists (from 31.4% to 19.7%;P < .01), and an increase in the use of direct anticoagulants (from 62.0% to 70.3%;P < .01). During the follow-up there was an increase in the prescription of SGLT2 inhibitors (from 20.0% to 25.5%;P < .01) and GLP1 agonists (from 4.2% to 9.1%;P < .01). During this period, 17.2% of patients died, the majority from cardiovascular causes, 6.4% from COVID-19, 2.8% from stroke, and 1.8% from hemorrhage. Older age, lower ejection fraction, lower hemoglobin levels, and especially lower direct anticoagulants prescription were associated with mortality. Conclusion(s): Patients with AF and diabetes have a high thromboembolic risk and a high risk of developing complications, especially of cardiovascular origin.Copyright © 2023 Sociedad Espanola de Cardiologia

Drug utilization study in patients affected with COVID-19 in a dedicated COVID hospital

Background: There exists a treatment dilemma regarding the optimal and effective use of therapeutic drugs (hydroxychloroquine/chloroquine/azithromycin) for COVID-19. Furthermore, with changing guidelines, the data on drug utilization patterns across India are limited. Hence, this study was conducted to assess the prescription pattern and drug utilization trends in COVID-19 patients with the aim to study the drug utilization pattern in patients affected with COVID-19 in a dedicated COVID-19 hospital. Aims and Objectives: The objectives of the study are as follows: (1) To study drug utilization patterns according to the severity of the disease. (2) To study the prevalence of adverse drug reactions (ADRs). Materials and Methods: Data were collected retrospectively from 100 medical records of patients 18 years irrespective of sex admitted in the COVID ward and ICU of a dedicated COVID hospital from May to August 2020. Pregnant and lactating women were excluded from the study. ADRs reported were also analyzed. Results: About 71% were mild in this study, 18% were moderate, and 11% were severe COVID-19 patients. Overall, the most common drugs prescribed were multivitamins, followed by pantoprazole, paracetamol, and azithromycin. Hydroxychloroquine was prescribed in 22%, favipiravir in 7%, and remdesivir in 3% of cases. The majority of moderate COVID patients received injectables piperacillin-tazobactam, methylprednisolone, and enoxaparin. The mean number of medications, duration of admission, and number of days on oxygen were higher and significant in moderate compared to mild and severe COVID patients. Overall, ADRs were encountered in 9% of cases. Conclusion: The prescribed pattern of drugs was by the national standard guidelines. Multivitamins, followed by pantoprazole, paracetamol, and azithromycin dominated the prescription pattern. Polypharmacy was encountered, which needs to be addressed for the rational use of drugs.

In silico assessment of diterpenes as potential inhibitors of SARS-COV-2 main protease

Aim: We aimed to investigate the potential inhibitory effects of diterpenes on SARS-CoV-2 main protease (Mpro). Materials & methods: We performed a virtual screening of diterpenoids against Mpro using molecular docking, molecular dynamics simulation and absorption, distribution, metabolism and excretion) analysis. Results: Some tested compounds followed Lipinski's rule and showed drug-like properties. Some diterpenoids possessed remarkable binding affinities with SARS-CoV-2 Mpro and drug-like pharmacokinetic properties. Three derivatives exhibited structural deviations lower than 1 angstrom. Conclusion: The findings of the study suggest that some of the diterpenes could be candidates as potential inhibitors for Mpro of SARS-CoV-2.

Type 1 diabetes and environment . . . and other stories

A linked ecological analysis of environmental and demographic variables identified several factors, including poor air quality, outdoor light at night, and higher population density that were negatively associated with the incidence of diabetes (Diabetologia doi:10.1007/s00125-020-05087-7). A case-control study using a database of people known to have autoimmune disease raises anxiety about central nervous system inflammatory events (JAMA Neurol doi:10.1001/jamaneurol.2020.1162). A history of exposure to TNF inhibitors carried a threefold increase in risk both of demyelinating diseases, such as multiple sclerosis and optic neuritis, and of non-demyelinating conditions, such as encephalitis, neurosarcoidosis, and vasculitis.

Therapeutic prospects of naturally occurring p38 MAPK inhibitors tanshinone IIA and pinocembrin for the treatment of SARS-CoV-2-induced CNS complications.

P38 mitogen-activated protein kinase (p38 MAPK) signaling pathway is closely related to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) replication and hyperinflammatory responses in coronavirus disease 2019 (COVID-19). Therefore, blood-brain barrier-penetrating p38 MAPK inhibitors have good potential for the treatment of central nervous system (CNS) complications of COVID-19. The aim of the present study is the characterization of the therapeutic potential of tanshinone IIA and pinocembrin for the treatment of CNS complications of COVID-19. Studies published in high-quality journals indexed in databases Scopus, Web of Science, PubMed, and so forth were used to review the therapeutic capabilities of selected compounds. In continuation of our previous efforts to identify agents with favorable activity/toxicity profiles for the treatment of COVID-19, tanshinone IIA and pinocembrin were identified with a high ability to penetrate the CNS. Considering the nature of the study, no specific time frame was determined for the selection of studies, but the focus was strongly on studies published after the emergence of COVID-19. By describing the association of COVID-19-induced CNS disorders with p38 MAPK pathway disruption, this study concludes that tanshinone IIA and pinocembrin have great potential for better treatment of these complications. The inclusion of these compounds in the drug regimen of COVID-19 patients requires confirmation of their effectiveness through the conduction of high-quality clinical trials.

Plasma Levels of MMPs and TIMP-1 in Patients with Osteoarthritis After Recovery from COVID-19.

BACKGROUND: Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPS) play a key role in the pathogenesis of osteoarthritis (OA). Recent research showed the involvement of some MMPs in COVID-19, but the results are limited and contradictory. OBJECTIVE: In this study, we investigated the levels of MMPs (MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, MMP-10) and TIMP-1 in the plasma of patients with OA after recovery from COVID- 19. METHODS: The experiment involved patients aged 39 to 80 diagnosed with knee OA. All study participants were divided into three research groups: the control group included healthy individuals, the group OA included patients with enrolled cases of OA, and the third group of OA and COVID-19 included patients with OA who recovered from COVID-19 6-9 months ago. The levels of MMPs and TIMP-1 were measured in plasma by enzyme-linked immunosorbent assay. RESULTS: The study showed a change in the levels of MMPs in patients with OA who had COVID- 19 and those who did not have a history of SARS-CoV-2 infection. Particularly, patients with OA who were infected with coronavirus established an increase in MMP-2, MMP-3, MMP-8, and MMP-9, compared to healthy controls. Compared to normal subjects, a significant decrease in MMP-10 and TIMP-1 was established in both groups of patients with OA and convalescent COVID-19. CONCLUSION: Thus, the results suggest that COVID-19 can affect the proteolysis-antiproteolysis system even after a long postinfectious state and may cause complications of existing musculoskeletal pathologies.

Virus infection participates in the occurrence and development of human diseases through monoamine oxidase.

Monoamine oxidase (MAO) is a membrane-bound mitochondrial enzyme that maintains the steady state of neurotransmitters and other biogenic amines in biological systems through catalytic oxidation and deamination. MAO dysfunction is closely related to human neurological and psychiatric diseases and cancers. However, little is known about the relationship between MAO and viral infections in humans. This review summarises current research on how viral infections participate in the occurrence and development of human diseases through MAO. The viruses discussed in this review include hepatitis C virus, dengue virus, severe acute respiratory syndrome coronavirus 2, human immunodeficiency virus, Japanese encephalitis virus, Epstein-Barr virus, and human papillomavirus. This review also describes the effects of MAO inhibitors such as phenelzine, clorgyline, selegiline, M-30, and isatin on viral infectious diseases. This information will not only help us to better understand the role of MAO in the pathogenesis of viruses but will also provide new insights into the treatment and diagnosis of these viral diseases.

Apremilast Add-On Benefits Over Conventional Drugs (ABCD) in Unstable Non-segmental Vitiligo: A 12-Week Single-Center Randomized Controlled Trial.

Background Apremilast is an oral phosphodiesterase-4 enzyme inhibitor that modulates the immune system by increasing intracellular cyclic adenosine monophosphate levels and inhibiting inflammatory cytokines synthesis. We aimed to compare the efficacy and safety of add-on apremilast in combination therapy with standard treatment in patients with unstable, non-segmental vitiligo. Methods The study was a 12-week randomized, controlled, parallel-group, open-labeled trial. The control group received standard treatment (n=15), and the intervention group received 30 mg apremilast twice daily in addition to standard treatment (n= 16). Time to the first sign of re-pigmentation, halt in progression, and change in vitiligo area scoring index (VASI) score is the primary outcomes. Normality was assessed, and appropriate parametric and nonparametric tests were undertaken. Results Thirty-seven participants were randomized into two groups, and analysis was done on thirty-one participants. Over the treatment duration of 12 weeks, the median time to observe the first sign of re-pigmentation was four weeks in the add-on apremilast group compared to seven weeks in the control group (p=0.018). The halt in progression was observed more in the add-on Apremilast group (93.75%) compared to the control group (66.66%) (p=0.08). The VASI score decreased by 1.24 in the add-on apremilast group and 0.05 in the control group (p= 0.754). Parameters including body surface area, dermatology life quality index, and body mass index reduced significantly, while the visual analog scale increased significantly in the add-on apremilast group. However, results were comparable between groups. Conclusions Treatment with add-on apremilast accelerated clinical improvement. It also reduced disease progression and improved the disease index among participants. However, add-on apremilast had a lower tolerability profile than the control group.

Recent Advances in Covalent Drug Discovery.

In spite of the increasing number of biologics license applications, the development of covalent inhibitors is still a growing field within drug discovery. The successful approval of some covalent protein kinase inhibitors, such as ibrutinib (BTK covalent inhibitor) and dacomitinib (EGFR covalent inhibitor), and the very recent discovery of covalent inhibitors for viral proteases, such as boceprevir, narlaprevir, and nirmatrelvir, represent a new milestone in covalent drug development. Generally, the formation of covalent bonds that target proteins can offer drugs diverse advantages in terms of target selectivity, drug resistance, and administration concentration. The most important factor for covalent inhibitors is the electrophile (warhead), which dictates selectivity, reactivity, and the type of protein binding (i.e., reversible or irreversible) and can be modified/optimized through rational designs. Furthermore, covalent inhibitors are becoming more and more common in proteolysis, targeting chimeras (PROTACs) for degrading proteins, including those that are currently considered to be 'undruggable'. The aim of this review is to highlight the current state of covalent inhibitor development, including a short historical overview and some examples of applications of PROTAC technologies and treatment of the SARS-CoV-2 virus.

Efficacy and Durability of Dolutegravir- or Darunavir-Based Regimens in ART-Naïve AIDS- or Late-Presenting HIV-Infected Patients.

BACKGROUND: Since limited data are available, we aimed to compare the efficacy and durability of dolutegravir and darunavir in advanced naïve patients. METHODS: Retrospective multicenter study including AIDS- or late-presenting (def. CD4 ≤ 200/µL) HIV-infected patients starting dolutegravir or ritonavir/cobicistat-boosted darunavir+2NRTIs. Patients were followed from the date of first-line therapy initiation (baseline, BL) to the discontinuation of darunavir or dolutegravir, or for a maximum of 36 months of follow-up. RESULTS: Overall 308 patients (79.2% males, median age 43 years, 40.3% AIDS-presenters, median CD4 66 cells/µL) were enrolled; 181 (58.8%) and 127 (41.2%) were treated with dolutegravir and darunavir, respectively. Incidence of treatment discontinuation (TD), virological failure (VF, defined as a single HIV-RNA > 1000 cp/mL or two consecutive HIV-RNA > 50 cp/mL after 6 months of therapy or after virological suppression had been achieved), treatment failure (the first of TD or VF), and optimal immunological recovery (defined as CD4 ≥ 500/µL + CD4 ≥ 30% + CD4/CD8 ≥ 1) were 21.9, 5.2, 25.6 and 1.4 per 100 person-years of follow-up, respectively, without significant differences between dolutegravir and darunavir (p > 0.05 for all outcomes). However, a higher estimated probability of TD for central nervous system (CNS) toxicity (at 36 months: 11.7% vs. 0%, p = 0.002) was observed for dolutegravir, whereas darunavir showed a higher probability of TD for simplification (at 36 months: 21.3% vs. 5.7%, p = 0.046). CONCLUSIONS: Dolutegravir and darunavir showed similar efficacy in AIDS- and late-presenting patients. A higher risk of TD due to CNS toxicity was observed with dolutegravir, and a higher probability of treatment simplification with darunavir.

The effect of ACE inhibitors and ARBs on outcomes in hospitalized patients with COVID-19.

BACKGROUND: Contradictory opinions exist regarding the use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in patients with hypertension, which is the most common comorbidity associated with COVID-19. Herein, the effects of ACEIs and ARBs on outcomes of COVID-19 patients were evaluated. METHODS: In this cross-sectional study, the outcomes of COVID-19 patients were compared between patients who received pretreatment ACEIs or ARBs and those who did not. RESULTS: The incidence of moderate and severe forms of COVID-19 was significantly higher in patients taking ACEI/ARB drugs (P-value = 0.012). Also, patients taking ACEI/ARB drugs (P-value = 0.034), patients with hypertension (P-value = 0.011), and patients with dyslipidemia (P-value = 0.011) experienced more severe forms of COVID-19. There was an association between increased length of hospital stay and dyslipidemia (P-value = 0.033) and the use of ACEI/ARB drugs (P-value = 0.041), while no correlation was found between other parameters in univariate linear regression analysis as well as multivariate linear regression. There was an association between increased mortality of patients with increasing age (P-value < 0.001), BMI greater than 30 kg/m2 (P-value = 0.02), asthma (P-value = 0.003), and dyslipidemia (P-value = 0.045). CONCLUSIONS: ACEI/ARB drugs put COVID-19 patients at high risk for moderate to severe forms of COVID-19 and higher length of hospital stay. Although, it is notable that these drugs did not significantly affect specific adverse outcomes of COVID-19, such as the need for admission to the intensive care unit (ICU), length of ICU stay, ventilation, and mortality.

Molecular Epidemiology of SARS-CoV-2 Omicron Sub-Lineages Isolated from Turkish Patients Infected with COVID-19.

Early detection and characterization of new variants and their impacts enable improved genomic surveillance. This study aims to evaluate the subvariant distribution of Omicron strains isolated from Turkish cases to determine the rate of antiviral resistance of RdRp and 3CLpro inhibitors. The Stanford University Coronavirus Antiviral & Resistance Database online tool was used for variant analyses of the strains uploaded to GISAID as Omicron (n = 20.959) between January 2021 and February,2023. Out of 288 different Omicron subvariants, B.1, BA.1, BA.2, BA.4, BE.1, BF.1, BM.1, BN.1, BQ.1, CK.1, CL.1, and XBB.1 were the main determined subvariants, and BA.1 (34.7%), BA.2 (30.8%), and BA.5 (23.6%) were reported most frequently. RdRp and 3CLPro-related resistance mutations were determined in n = 150, 0.72% sequences, while the rates of resistance against RdRp and 3CLpro inhibitors were reported at 0.1% and 0.6%, respectively. Mutations that were previously associated with a reduced susceptibility to remdesivir, nirmatrelvir/r, and ensitrelvir were most frequently detected in BA.2 (51.3%). The mutations detected at the highest rate were A449A/D/G/V (10.5%), T21I (10%), and L50L/F/I/V (6%). Our findings suggest that continuous monitoring of variants, due to the diversity of Omicron lineages, is necessary for global risk assessment. Although drug-resistant mutations do not pose a threat, the tracking of drug mutations will be necessary due to variant heterogenicity.

Understanding preclinical and clinical immunogenicity risks in novel biotherapeutics development.

Immunogenicity continues to pose a challenge in the development of biotherapeutics like conventional therapeutic-proteins and monoclonal antibodies as well as emerging modalities such as gene-therapy components, gene editing, and CAR T cells. The approval of any therapeutic is based on a benefit-risk evaluation. Most biotherapeutics address serious medical conditions where the standard of care has a poor outcome. Consequently, even if immunogenicity limits the utility of the therapeutic in a sub-set of patients, the benefit-risk assessment skews in favor of approval. Some cases resulted in the discontinuation of biotherapeutics due to immunogenicity during drug development processes, This special issue presents a platform for review articles offering a critical assessment of accumulated knowledge as well as novel findings related to nonclinical risks that extend our understanding of the immunogenicity of biotherapeutics. Some of the studies in this collection leveraged assays and methodologies refined over decades to support more clinically relevant biological samples. Others have applied rapidly advancing methodologies in pathway-specific analyses to immunogenicity. Similarly, the reviews address urgent issues such as the rapidly emerging cell and gene therapies which hold immense promise but could have limited reach as a significant number of the patient population could potentially not benefit due to immunogenicity. In addition to summarizing the work presented in this special issue we have endeavored to identify areas where additional studies are required to understand the risks of immunogenicity and develop appropriate mitigation strategies.

DPP-4 inhibitors for treating T2DM - hype or hope? an analysis based on the current literature.

DPP-4 inhibition is an interesting line of therapy for treating Type 2 Diabetes Mellitus (T2DM) and is based on promoting the incretin effect. Here, the authors have presented a brief appraisal of DPP-4 inhibitors, their modes of action, and the clinical efficiency of currently available drugs based on DPP-4 inhibitors. The safety profiles as well as future directions including their potential application in improving COVID-19 patient outcomes have also been discussed in detail. This review also highlights the existing queries and evidence gaps in DPP-4 inhibitor research. Authors have concluded that the excitement surrounding DPP-4 inhibitors is justified because in addition to controlling blood glucose level, they are good at managing risk factors associated with diabetes.