Amprenavir 150mg capsules

Gastroesophageal reflux disease (GERD) significantly impacts patient quality of life and is a major risk factor for the development of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). Proton pump inhibitors (PPIs) are the standard-of-care for GERD and are among the most prescribed drugs in the world, but do not protect against nonacid components of reflux such as pepsin, or prevent reflux-associated carcinogenesis. We recently identified an HIV protease inhibitor amprenavir that inhibits pepsin and demonstrated the antireflux therapeutic potential of its prodrug fosamprenavir in a mouse model of laryngopharyngeal reflux. In this study, we assessed the capacity of amprenavir to protect against esophageal epithelial barrier disruption in vitro and related molecular events, E-cadherin cleavage, and matrix metalloproteinase induction, which are associated with GERD severity and esophageal cancer. Herein, weakly acidified pepsin (though not acid alone) caused cell dissociation accompanied by regulated intramembrane proteolysis of E-cadherin. Soluble E-cadherin responsive matrix metalloproteinases (MMPs) were transcriptionally upregulated 24 h post-treatment. Amprenavir, at serum concentrations achievable given the manufacturer-recommended dose of fosamprenavir, protected against pepsin-induced cell dissociation, E-cadherin cleavage, and MMP induction. These results support a potential therapeutic role for amprenavir in GERD recalcitrant to PPI therapy and for preventing GERD-associated neoplastic changes.

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Abstract Background Laryngopharyngeal reflux (LPR) causes chronic cough, throat clearing, hoarseness, and dysphagia and can promote laryngeal carcinogenesis. More than 20% of the US population suffers from LPR and there is no effective medical therapy. Pepsin is a predominant source of damage during LPR which disrupts laryngeal barrier function potentially via E‐cadherin cleavage proteolysis and downstream matrix metalloproteinase (MMP) dysregulation. Fosamprenavir (FDA‐approved HIV therapeutic and prodrug of amprenavir) is a pepsin‐inhibiting LPR therapeutic candidate shown to rescue damage in an LPR mouse model. This study aimed to examine amprenavir protection against laryngeal monolayer disruption and related E‐cadherin proteolysis and MMP dysregulation in vitro. Methods Laryngeal (TVC HPV) cells were exposed to buffered saline, pH 7.4 or pH 4 ± 1 mg/mL pepsin ± amprenavir (10–60 min). Analysis was performed by microscopy, Western blot, and real time polymerase chain reaction (qPCR). Results Amprenavir (1 μM) rescued pepsin acid‐mediated cell dissociation ( p < .05). Pepsin acid caused E‐cadherin cleavage indicative of regulated intramembrane proteolysis (RIP) and increased MMP‐1,3,7,9,14 24‐h postexposure ( p < .05). Acid alone did not cause cell dissociation or E‐cadherin cleavage. Amprenavir (10 μM) protected against E‐cadherin cleavage and MMP‐1,9,14 induction ( p < .05). Conclusions Amprenavir, at serum concentrations achievable provided the manufacturer's recommended dose of fosamprenavir for HIV, protects against pepsin‐mediated cell dissociation, E‐cadherin cleavage, and MMP dysregulation thought to contribute to barrier dysfunction and related symptoms during LPR. Fosamprenavir to amprenavir conversion by laryngeal epithelia, serum and saliva, and relative drug efficacies in an LPR mouse model are under investigation to inform development of inhaled formulations for LPR.

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Gastroesophageal reflux disease (GERD) is associated with inflammatory and neoplastic changes in the esophageal epithelium. Despite widespread PPI use, esophageal adenocarcinoma (EAC) incidence continues to rise, implicating non-acidic reflux components such as pepsin in disease progression. We performed transcriptomic profiling to assess pepsin-induced changes and the protective effect of amprenavir in vitro. Het-1A (normal) and BAR-T (Barrett’s) cells (n = 3) were treated at pH 7.0 with pepsin and/or 10 μM amprenavir for 1 h. RNA-seq identified DEGs (FDR ≤ 0.05, |log₂FC| ≥ 0.375), and Ingenuity Pathway Analysis revealed enriched pathways. Pepsin exposure altered mitochondrial function, oxidative phosphorylation, epithelial integrity, signaling, and inflammatory pathways in both cell lines. Amprenavir attenuated these transcriptomic perturbations, preserving mitochondrial and stress-response pathways. Notably, BAR-T cells exhibited heightened activation of wound-healing and epithelial repair pathways, whereas Het-1A cells showed greater mitochondrial and systemic stress pathway alterations. Pepsin drives transcriptomic dysregulation in esophageal epithelial cells under non-acidic conditions, and amprenavir shows potential to counteract peptic injury. Further studies are needed to validate these findings and explore amprenavir’s therapeutic utility in GERD management and EAC prevention.

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Background While antiretroviral therapy (ART) has transformed HIV-1 into a manageable chronic illness, its long-term affordability and accessibility remain major challenges in resource-limited settings. Additionally, adverse side effects can compromise treatment adherence and effectiveness. These limitations highlight the need for novel, affordable therapeutic alternatives. In this study, we evaluated the anti-HIV-1 activity of Product Nkabinde (PN), a traditional herbal formulation comprising four plant extracts, and Gnidia sericocephala ( G. sericocephala ), to assess their potential as alternative or complementary therapies. Methods HIV-1 subtype B and subtype C viral stocks were produced by transfecting HEK293T cells with envelope plasmids and an env -deficient HIV-1 backbone vector using polyethylenimine. TZM-bl cells were treated with PN and G. sericocephala extracts, alone or combined with antiretrovirals (AZT, raltegravir, maraviroc, amprenavir), then infected with the viruses. Viral infectivity was measured using the luciferase assay, and results were validated in peripheral blood mononuclear cells (PBMCs) using HIV-1 p24 ELISA. Results The PN extract exhibited a dose-dependent antiviral effect, with the optimal concentration achieving 93% and 96% inhibition of HIV-1 subtype B and C, respectively, in TZM-bl cells, comparable to AZT. In HIV-1 infected PBMCs, treatment with AZT, PN, or G. sericocephala resulted in a sustained reduction of p24 antigen levels over 11 days compared to untreated controls. While NL4.3 showed partial inhibition (p24 levels >20,000 pg/mL), strains CM070P.1, YU2, and CM019P.1.2 exhibited consistently low p24 production levels (<20,000 pg/mL), indicating strain-dependent antiviral activity. PN, combined with maraviroc inhibited YU2 replication by 81.3% (p = 0.0361), while combinations with raltegravir and AZT suppressed subtype C strains CM070P.1 and CM019P.1.2 by 98.7% (p = 0.0083) and 99% (p = 0.0428), respectively, compared to either PN or the antiretroviral alone. Gnidia sericocephala combined with AZT inhibited NL4.3 by 80.3% (p = 0.0105), and its combinations with maraviroc, raltegravir, and amprenavir suppressed CM070P.1 replication by 87% (p = 0.0093), 86% (p = 0.0168), and 90% (p = 0.0006), respectively, relative to either test agent alone. Fractional inhibitory concentration index (FICI) analysis indicated no synergistic or antagonistic interactions. Conclusion Thus, this current data suggests that PN and G. sericocephala possess anti-HIV-1 activity.

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Numerous prior studies have identified therapeutic targets that could effectively combat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, including the angiotensin-converting enzyme 2 (ACE2) receptor, RNA-dependent RNA polymerase (RdRp), and Main protease (Mpro). In parallel, antiviral compounds like abacavir, acyclovir, adefovir, amantadine, amprenavir, darunavir, didanosine, oseltamivir, penciclovir, and tenofovir are under investigation for their potential in drug repurposing to address this infection. The aim of the study was to determine the effect of modifying the functional groups of the aforementioned antivirals in silico. Using the genetic optimization for ligand docking algorithm on software Maestro (version 11.1), the modified antivirals were docked onto ACE2 receptor, RdRp, and Mpro. Using QuickProp (Maestro v11.1), PASS (prediction of activity spectra for the substances), and altogether with SwissADME, the ADMET (absorption, distribution, metabolism, excretion, and toxicity) of the modified antivirals, as well as their bioavailability and the predicted activity spectra, were determined. Discovery studio software was used to undertake post-docking analysis. Among the 10 antivirals, N(CH3)2 derivative of darunavir, N(CH3)2 derivative of amprenavir and NCH3 derivative of darunavir exhibited best binding affinities with ACE2 receptor (docking scores: -10.333, -9.527 and -9.695 kJ/mol, respectively). Moreover, NCH3 derivative of abacavir (-6.506 kJ/mol), NO2 derivative of didanosine (-6.877 kJ/mol), NCH3 derivative of darunavir (-7.618 kJ/mol) exerted promising affinity to Mpro. In conclusion, the results of the in silico screenings can serve as a useful information for future experimental works.

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The landscape of clinical management for metastatic melanoma (MM) and other solid tumors has been modernized by the advent of immune checkpoint inhibitors (ICI), including programmed cell death-1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors. While these agents demonstrate efficacy in suppressing tumor growth, they also lead to immune-related adverse events (irAEs), resulting in the exacerbation of autoimmune diseases such as rheumatoid arthritis (RA), ulcerative colitis (UC), and Crohn's disease (CD). The immune checkpoint inhibitors offer promising advancements in the treatment of melanoma and other cancers, but they also present significant challenges related to irAEs and autoimmune diseases. Ongoing research is crucial to better understand these challenges and develop strategies for mitigating adverse effects while maximizing therapeutic benefits. In this manuscript, we addressed this challenge using network-based approaches by constructing and analyzing the molecular and signaling networks associated with tumor-immune crosstalk. Our analysis revealed that IL6 is the key regulator responsible for irAEs during ICI therapies. Furthermore, we conducted an integrative network and molecular-level analysis, including virtual screening, of drug libraries, such as the Collection of Open Natural Products (COCONUT) and the Zinc15 FDA-approved library, to identify potential IL6 inhibitors. Subsequently, the compound amprenavir was identified as the best molecule that may disrupt essential interactions between IL6 and IL6R, which are responsible for initiating the signaling cascades underlying irAEs in ICI therapies.

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