Viral community-acquired pneumonia: What’s new since COVID-19 emerged?

Expert Review of Respiratory Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: March 12, 2025

Introduction All over the world, viral pneumonia has a significant impact on morbidity and mortality, especially among vulnerable populations. The most common respiratory viruses causing include influenza virus, syncytial adenoviruses rhinovirus. COVID-19 pandemic changed landscape of reshaped our understanding role in this disease. We are now more aware importance early diagnosis, co-infections, effects variants, long-term consequences post-viral pneumonia.

Language: Английский

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Drug-Drug Interactions Leading to Tacrolimus Toxicity in a Renal Transplant Patient With COVID-19: The Role of Paxlovid and the Mitigating Use of Phenytoin

Cureus, Journal Year: 2025, Volume and Issue: unknown

Published: March 20, 2025

Tacrolimus, a calcineurin inhibitor widely used in transplant immunosuppression, requires careful monitoring due to its narrow therapeutic index and metabolism by cytochrome P450 CYP3A4. We present case of 72-year-old kidney recipient who developed acute tacrolimus toxicity following treatment with nirmatrelvir/ritonavir (Paxlovid) for COVID-19. The patient presented altered mental status, injury, supratherapeutic levels (>90 ng/mL). Given persistent toxicity, was held, intravenous phenytoin initiated enhance clearance through CYP3A4 induction. demonstrated improvement renal function levels, allowing cautious reinitiation immunosuppression. This highlights the critical need vigilant drug-drug interactions recipients potential role as an effective strategy managing induced inhibitors well urgent developing COVID-19 outpatient treatments minimal interaction tacrolimus.

Language: Английский

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Treatment of feline infectious peritonitis in cats with molnupiravir: clinical observations and outcomes for 54 cases

Australian Veterinary Journal, Journal Year: 2025, Volume and Issue: unknown

Published: April 15, 2025

Objective To evaluate the clinical applications and treatment outcomes using molnupiravir for of naturally occurring feline infectious peritonitis virus (FIPv). Methods Ninety‐two client‐owned cats with confirmed or presumptive FIP were retrospectively recruited from 35 veterinary practices, primarily in Australia, between February 2023 March 2024. Cats categorised based on received: Cohort A: Molnupiravir treatment: monotherapy, maintenance rescue therapy; B: Remdesivir and/or GS‐441524 treatment. Seventy‐eight enrolled. was administered orally a median 84 days, at dose 13.3 mg/kg BID. Remission defined as resolution FIP‐related signs (i) normalisation serum globulin concentrations A:G ratio (≥0.6), (ii) sustained remission least 100 days after stopping anti‐viral therapy. Cure rate percentage achieving remission, without requiring therapy experiencing relapsed disease. Results monotherapy resulted cure 72% (13/18) while achieved 86% (25/29), utilised 100% (7/7). Treatment remdesivir/GS‐441524 71% (17/24 cats). Survival analysis revealed no difference treated those remdesivir/GS‐441524. Adverse events associated included neutropenia, transient elevations hepatic enzymes. Conclusion demonstrated comparable survival to treating serves an accessible, effective option across various presentations, including ocular neurologic forms.

Language: Английский

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Overview of Drug-Drug Interactions Between Ritonavir-Boosted Nirmatrelvir (Paxlovid) and Targeted Therapy and Supportive Care for Lung Cancer

JTO Clinical and Research Reports, Journal Year: 2022, Volume and Issue: 4(2), P. 100452 - 100452

Published: Dec. 17, 2022

Language: Английский

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Drug-Repurposing Screening Identifies a Gallic Acid Binding Site on SARS-CoV-2 Non-structural Protein 7

ACS Pharmacology & Translational Science, Journal Year: 2023, Volume and Issue: 6(4), P. 578 - 586

Published: March 7, 2023

SARS-CoV-2 is the agent responsible for acute respiratory disease COVID-19 and global pandemic initiated in early 2020. While record-breaking development of vaccines has assisted control COVID-19, there still a pressing demand antiviral drugs to halt destructive impact this disease. Repurposing clinically approved provides an opportunity expediate treatments into clinic. In effort facilitate drug repurposing, FDA-approved library containing 2400 compounds was screened against non-structural protein 7 (nsp7) using native mass spectrometry-based assay. Nsp7 one components replication/transcription complex essential optimal viral replication, perhaps serving off-load RNA from nsp8. From library, gallic acid identified as compound that bound tightly nsp7, with estimated Kd 15 μM. NMR chemical shift perturbation experiments were used map ligand-binding surface on indicating pocket centered protein's four α-helices (α2). The identification acid-binding site nsp7 may allow therapeutic via artificial-intelligence-based virtual docking other strategies.

Language: Английский

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Effects of itraconazole and carbamazepine on the pharmacokinetics of nirmatrelvir/ritonavir in healthy adults

British Journal of Clinical Pharmacology, Journal Year: 2023, Volume and Issue: 89(9), P. 2867 - 2876

Published: May 15, 2023

Aims The objective of this study was to evaluate the effects a strong cytochrome P450 family (CYP) 3A4 inhibitor (itraconazole) and inducer (carbamazepine) on pharmacokinetics safety nirmatrelvir/ritonavir. Methods Pharmacokinetics were measured in two phase 1, open‐label, fixed‐sequence studies healthy adults. During Period oral nirmatrelvir/ritonavir 300 mg/100 mg twice daily administered alone; during 2, it with itraconazole or carbamazepine. Nirmatrelvir/ritonavir as repeated doses one dose carbamazepine studies, respectively. Nirmatrelvir ritonavir plasma concentrations adverse event (AE) rates both periods analysed. Results Each included 12 participants. Following administration (Test) alone (Reference), test/reference ratios adjusted geometric means (90% CIs) for nirmatrelvir AUC tau C max 138.82% (129.25%, 149.11%) 118.57% (112.50%, 124.97%), After inf 44.50% (33.77%, 58.65%) 56.82% (47.04%, 68.62%), generally safe when without No serious severe AEs reported. Conclusions Coadministration CYP3A4 CYP3A used pharmacokinetic enhancement (i.e., ritonavir) resulted small increases exposure, whereas coadministration substantially decreased systemic exposures suggesting contraindication label inducers. Administration safe.

Language: Английский

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A path from synthesis to emergency use authorization of molnupiravir as a COVID-19 therapy

Bioorganic Chemistry, Journal Year: 2024, Volume and Issue: 147, P. 107379 - 107379

Published: April 17, 2024

Language: Английский

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Nirmatrelvir/Ritonavir Regimen for Mild/Moderately Severe COVID-19: A Rapid Review With Meta-Analysis and Trial Sequential Analysis

The Annals of Family Medicine, Journal Year: 2024, Volume and Issue: 22(4), P. 336 - 346

Published: July 1, 2024

BACKGROUND

The efficacy, effectiveness, and safety of the approved nirmatrelvir/ritonavir regimen for treatment laboratory-confirmed mild/moderately severe COVID-19 remains unclear.

METHODS

We systematically identified randomized controlled trials (RCTs) real-world studies (RWS; observational studies) efficacy/effectiveness and/or COVID-19. pooled appropriate data (adjusted estimates RWS) using an inverse variance, random-effects model. calculated statistical heterogeneity I² statistic. Results are presented as relative risk (RR) with associated 95% CI. further assessed bias/study quality conducted trial sequential analysis evidence from RCTs.

RESULTS

included 4 RCTs (4,070 persons) 16 RWS (1,925,047 adults (aged ≥18 years). One 3 were low unclear bias, respectively. good quality. Nirmatrelvir/ritonavir significantly decreased hospitalization compared placebo/no (RR = 0.17; CI, 0.10-0.31; 77.2%; 2 RCTs, 3,542 persons), but there was no significant difference decrease worsening severity 0.82; 0.66-1.01; 47.5%; 1,824 viral clearance 1.19; 0.93-1.51; 82%; 528 adverse events 1.41; 0.92-2.14; 70.6%; 4,070 serious 0.41-1.62; 0%; 3,806 all-cause mortality 0.27; 0.04-1.70; 49.9%; although suggested that current total sample sizes these outcomes not large enough conclusions to be drawn. Real-world also showed 0.48; 0.37-0.60; 95.0%; 11 RWS, 1,421,398 0.24; 0.14-0.34; 65%; 7 286,131 treatment.

CONCLUSIONS

appears promising preventing potentially decreasing persons COVID-19, is weak. More needed.

Language: Английский

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9-aminominocycline potentiates the efficacy of EIDD-1931 and PF-332 by targeting the papain like protease enzyme of SARS-CoV-2

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: Feb. 15, 2025

The 3-chymotrypsin-like protease (3CLpro), papain-like (PLpro), and RNA-dependent RNA polymerase (RdRp) are key enzymes in SARS-CoV-2 replication serve as critical targets for an antiviral drug. Currently, Paxlovid® Lagevrio™ specifically target 3CLpro RdRp, respectively, COVID-19 treatment. However, no antivirals the PLpro enzyme, essential viral suppression of host immune response. This study identified 9-aminominocycline (9-AMN) a potent inhibitor PLpro. Unlike parent compound minocycline, 9-AMN inhibits PLpro's proteolytic deubiquitinase activities by approximately 90%, with IC50 values 4.15 µM 4.55 µM, while showing effect on enzymatic activity or RdRp. Enzyme kinetics reveal that functions mixed binds to its active site, disrupting function predicted computer modeling. Furthermore, demonstrates, efficacy against Delta Omicron variants, EC50 1.04 2.35 respectively. When combined EIDD-1931 (an form molnupiravir) nirmatrelvir (PF-332), exhibits synergistic effects, significantly reducing doses required inhibit variant. In conclusion, replication, activity, highlighting potential promising candidate treatment strategies.

Language: Английский

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In Silico and In Vitro Studies of the Approved Antibiotic Ceftaroline Fosamil and Its Metabolites as Inhibitors of SARS-CoV-2 Replication

Viruses, Journal Year: 2025, Volume and Issue: 17(4), P. 491 - 491

Published: March 28, 2025

The SARS-CoV-2 proteases Mpro and PLpro are critical targets for antiviral drug development the treatment of COVID-19. 1,2,4-thiadiazole functional group is an inhibitor cysteine proteases, such as papain cathepsins. This chemical moiety also present in ceftaroline fosamil (CF), FDA-approved fifth-generation cephalosporin antibiotic. study investigates interactions between CF, its primary metabolites (M1 dephosphorylated CF M2 opened β-lactam ring) derivatives (protonated M1H M2H), open rings (open-M1H open-M2H) with evaluates CF’s effects on vitro viral replication. In silico analyses (molecular docking molecular dynamics (MD) simulations) demonstrated that potential inhibitors Mpro. Docking analysis indicated majority ligands were more stable than PLpro; however, biochemical preferred target CF. inhibited replication human Calu-3 cell model at submicromolar concentrations when added to culture medium 12 h. Our results suggest should be evaluated a repurposing agent COVID-19, considering not only but other relevant cellular pathways. Additionally, reactivity sulfur warrants further exploration protease inhibitors.

Language: Английский

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