Search Results (348)

Early in 2020, the WHO recommended that existing drugs be evaluated as a repurposed resource to fight the SARS-CoV-2 pandemic. Here, we investigate the trends of using repurposed and off-label drugs among people living with HIV in Central and Eastern Europe (CEE). From November 2020 to May 2021, data on the clinical outcomes of HIV-positive patients diagnosed with COVID-19 were collected on eCRFs (SurveyMonkey^® platform, Inc. San Mateo, CA, USA). Factors associated with the off-label drugs available at this time (chloroquine, hydroxychloroquine, favipiravir, oseltamivir, and lopinavir/ritonavir) were identified using logistic regression models. Of the 557 HIV-positive patients assessed with COVID-19 disease, 67 (12.0%) received off-label drugs, as well as 11.6% (16/138) of hospitalized and 12.2% (51/419) of ambulatory patients (p = 0.8564). In the adjusted logistic regression model, higher odds of off-label drug use were found in patients who had their diagnoses confirmed by an RT PCR test (aOR 5.08 [95%CI 1.17–22.0], p = 0.0396), and who came from a non-EU region (aOR 6.79 [95%CI 3.51–13.1], p < 0.0001). The only factor decreasing the odds of off-label drug use was co-infection (aOR 0.31 [95%CI 0.10–0.94], p < 0.0395). In a cohort of HIV patients from the CEE, 12% were prescribed off-label drugs for COVID-19. Symptomatic patients with confirmed SARS-CoV-2 infection or who were from non-EU countries were more likely to receive a repurposed drug. Drug repurposing is an immediate solution to emerging pandemics. All data regarding the safety and effectiveness of such use should be monitored, reported, and publicly available. Access patterns within and outside the EU should be analyzed to prevent potential inequalities in access to care during epidemics in European settings. Full article

Post-infectious bronchiolitis obliterans (PIBO) is a rare but severe chronic lung disease of childhood, characterized by irreversible small-airway obstruction following severe lower respiratory tract infections early in life. The disease course is often progressive and associated with long-term respiratory morbidity, while effective disease-modifying therapies remain limited. We report the case of a young child who developed severe PIBO following adenovirus pneumonia complicated by prolonged respiratory failure and multisystem involvement. Diagnosis was based on persistent respiratory symptoms, characteristic radiologic findings, and poor response to conventional anti-inflammatory treatment. Given the severity of the clinical course and steroid-refractory disease, an individualized immunomodulatory strategy, including hydroxychloroquine, was initiated within a multidisciplinary framework. During follow-up, the patient showed progressive clinical improvement, with gradual weaning from continuous oxygen supplementation, fewer respiratory exacerbations, simplification of systemic therapies, and radiologic findings consistent with partial improvement. Although causal conclusions regarding treatment efficacy cannot be drawn from a single case, the overall disease trajectory appeared more favorable than typically reported in PIBO cohorts. This case supports the emerging view of PIBO as an immune-mediated airway fibrotic disorder and underscores the importance of integrating detailed clinical phenotyping with evolving molecular insights to inform future precision medicine in pediatric post-infectious airway disease. Full article

Background/Objectives: Hydroxychloroquine (HCQ) is used to manage various autoimmune diseases, including systemic lupus erythematosus. The prolonged use of HCQ is associated with retinopathy and irreversible visual loss due to retinal toxicity. Despite adherence to dosage regimens, patients may develop functional rather than structural changes, without detectable abnormalities on routine examination using visual acuity and optical coherence tomography (OCT). The study aimed to detect early signs of retinopathy in patients with autoimmune diseases treated with HCQ. Methods: This cross-sectional study included patients (n = 36) with autoimmune diseases who were treated with HCQ. The control group (n = 35) comprised healthy volunteers matched for age and sex. All participants were screened using colour vision tests (Ishihara, Konan ColourDX high definition [HD]), and retinal thickness was evaluated using OCT. Results: Our findings suggest a significant reduction in the contrast threshold of the L and M-cone photoreceptors compared with that of the control using Konan ColourDX HD. The OCT measurements revealed no statistically significant difference in retinal thickness between patients and controls; however, the contrast sensitivity test showed a significant reduction at all spatial frequencies (p < 0.0001). Conclusions: The current study suggests that the Konan ColourDX cone contrast test HD and contrast sensitivity testing may be valuable for periodic monitoring of patients receiving HCQ, potentially enabling earlier detection of toxicity. However, longitudinal studies with larger cohorts are needed to confirm these findings and to further establish the clinical value of these functional visual tests. Full article

Background/Objectives: Hydroxychloroquine (HCQ) is widely used in the treatment of autoimmune rheumatologic diseases due to its immunomodulatory and anti-inflammatory properties. However, long-term HCQ therapy carries a risk of irreversible retinal toxicity caused by drug accumulation in the retinal pigment epithelium. The early identification of preclinical retinal changes is essential to prevent permanent visual impairment. Optical coherence tomography (OCT) and OCT-angiography (OCT-A) have emerged as key imaging modalities for the detection of structural and microvascular biomarkers of HCQ retinopathy. A narrative review of the literature was conducted using the PubMed database, focusing on studies published between January 2017 and February 2025. Search terms included “hydroxychloroquine” and “optical coherence tomography.” Eligible studies evaluated HCQ-related retinal toxicity using OCT and/or OCT-A in human subjects. Data were extracted regarding study population characteristics, treatment duration, cumulative HCQ dose, daily dose normalized to real body weight, and reported imaging findings. Results: We identified 223 scientific papers of which 88 studies met the inclusion criteria. Structural OCT parameters—particularly alterations in the ellipsoid zone, outer nuclear layer, and retinal pigment epithelium—were consistently associated with early HCQ toxicity, often preceding functional impairment. OCT-A studies demonstrated microvascular alterations, including reduced vessel density and foveal avascular zone enlargement, though interpretation may be confounded by underlying autoimmune-disease-related vasculopathy. Conclusions: HCQ retinopathy is a potentially vision-threatening condition associated with the cumulative dose, treatment duration, and patient-specific risk factors. OCT and OCT-A provide complementary structural and vascular biomarkers that aid in the detection of subclinical retinal toxicity. The integration of quantitative and automated OCT-derived metrics may improve screening strategies, facilitate early diagnosis, and support personalized care in patients receiving long-term HCQ therapy. Full article

This study presents a comprehensive evaluation and environmental risk assessment (ERA) of pharmaceutical residues in the Cerrón Grande Reservoir, one of the most important surface water bodies in El Salvador. Sampling campaigns were conducted over a one-year period, covering both the dry (January 2024) and rainy (July 2024) seasons. A total of 76 pharmaceutical compounds were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS), of which only five were not detected. During the dry season, the highest environmental concentrations were observed for mecamylamine (1710–6913 µg L⁻¹), 1,7-dimethylxanthine (379–2829 µg L⁻¹), chloroquine (2.29–362.7 µg L⁻¹), and hydroxychloroquine (5.02–315.4 µg L⁻¹). Concentrations generally decreased in the rainy season, with mecamylamine (1526–2198 µg L⁻¹), 1,7-dimethylxanthine (0.018–0.55 µg L⁻¹), and caffeine (0.2–0.474 µg L⁻¹) remaining the most prevalent. Compounds exceeding 1 µg L⁻¹ were assessed using predicted no-effect concentrations (PNEC) to calculate risk quotients (RQ). Chloroquine (RQ = 3346.3), mecamylamine (RQ = 1437.8), hydroxychloroquine (RQ = 1027.2), and manidipine (RQ = 271.0) posed the highest risks during the dry season, while only mecamylamine (RQ = 502.0) exceeded this threshold in the rainy season. To our knowledge, this represents the first in-depth study of pharmaceutical residues in Salvadoran surface waters, providing a foundational reference for future research and environmental policy in the region. Full article

Background/Objectives: Insulin resistance (IR) is a relevant metabolic concern in patients with rheumatic diseases; however, data regarding its clinical influence on the systemic sclerosis (SSc) phenotype is lacking. This study aimed to evaluate the characteristics of patients exhibiting IR in a monocentric SSc cohort. Methods: We conducted a cross-sectional study on 178 SSc patients, stratified according to the presence of IR, defined as a HOMA-IR value >1.85 for men and >2.07 for women, based on thresholds previously validated in the Estudio Epidemiológico de la Insuficiencia Renal en España (EPIRCE) cross-sectional study. The rationale for applying the current cut-offs is based on its discriminative potential when using sex- and age-specific thresholds in a nondiabetic population. This approach is particularly applicable to SSc, where the prevalence of diabetes is very low and the median ages of the two cohorts are comparable. Data collected included demographic-, clinical-, laboratory-, pulmonary function-, capillaroscopic-, and treatment-related parameters. A multivariable logistic regression model was used to identify independent predictors of IR. Results: Patients with IR (n = 76) had a significantly higher prevalence of diffuse cutaneous subset (26.3% vs. 11.8%, p = 0.012) and interstitial lung disease (39.5% vs. 17.6%, p = 0.001), along with the positivity for anti-Scl70 antibodies and the current presence of musculoskeletal symptoms (p = 0.021) and digital ulcers (p = 0.037). As expected, body mass index (BMI) was significantly higher in the IR population (24.6 ± 5.2 vs. 22.9 ± 4.1, p = 0.012), along with fasting glucose, insulin, HOMA-IR, and HbA1c levels. IR patients exhibited higher percentages of dyslipidemia and liver steatosis. Medications such as hydroxychloroquine, statins, and Iloprost were more frequently used in the IR group; as for corticosteroids usage (21.1% vs. 5.9%, p = 0.002), however, cumulative glucocorticoid dosage did not differ between the groups. In multivariable analysis, BMI (OR 1.09; p = 0.038) and interstitial lung disease (ILD) (OR 3.03; p = 0.034) were independent predictors of IR. Conclusions: In SSc, IR is associated with ILD, digital ulcers, musculoskeletal involvement, and anti-Scl70 autoantibodies. Full article

Background/Objectives: Acute generalized exanthematous pustulosis (AGEP) is a severe drug-induced cutaneous reaction characterized by the abrupt onset of sterile pustules, fever, neutrophilia, and a T cell-mediated type IVd hypersensitivity response. This narrative review synthesizes current evidence on pharmacological triggers, immunopathogenic mechanisms, diagnostic criteria, and differential diagnosis to provide a clinically oriented framework. Methods: A comprehensive literature search was conducted in PubMed/MEDLINE, Scopus, ScienceDirect, and SpringerLink for studies published between 2000 and 2025, complemented by selected clinical reference sources. Studies addressing clinical features, immunological pathways, pharmacovigilance signals, and diagnostic tools for AGEP were included. Synthesis of Evidence: β-lactam antibiotics remain the most frequent triggers, while increasing associations have been reported with hydroxychloroquine, targeted therapies, immune checkpoint inhibitors, psychotropic agents, and vaccines. Immunopathogenesis is driven by IL-36 activation, CXCL8/IL-8–mediated neutrophil recruitment, and IL36RN mutations, explaining overlap with pustular psoriasis. Diagnostic accuracy improves through integration of drug latency, clinical morphology, histopathology, biomarkers, and standardized tools such as the EuroSCAR score. Conclusions: AGEP is a complex pustular reaction induced by diverse drugs and amplified by IL-36-mediated inflammation. Accurate diagnosis requires a multidimensional approach supported by structured algorithms and robust pharmacovigilance to identify evolving drug-associated patterns. Full article

Hydroxychloroquine (HCQ), originally developed as an antimalarial agent, has been associated with hepatotoxic effects in experimental and clinical settings. Our study was designed to evaluate the effects of this agent on liver toxicity and to understand the protective roles of adenosine triphosphate (ATP), Liver-52 (Liv-52), and their combination. Male Wistar rats (250–280 g) were randomly assigned to five groups (n = 6): healthy control (C), HCQ only (H), ATP plus HCQ (AH), Liv-52 plus HCQ (LH), and ATP–Liv-52 plus HCQ (ALH). ATP (4 mg/kg) was administered intraperitoneally once daily, whereas Liv-52 (20 mg/kg) was administered orally via gavage. One hour later, all groups except C received HCQ (120 mg/kg, orally, twice daily). All treatments were continued for seven consecutive days. At the end of the experiment, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were measured, and liver tissues were analyzed for malondialdehyde (MDA), total glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) activities, along with histopathological evaluation. HCQ administration significantly increased oxidative stress, as evidenced by elevated MDA levels (p < 0.01) and reduced antioxidant parameters, including GSH, SOD, and CAT (p < 0.05), accompanied by prominent histopathological damage. Treatment with ATP or Liv-52 markedly ameliorated these alterations by decreasing MDA and restoring antioxidant markers. The combination treatment was observed to exhibit the most pronounced protective effect; it significantly reduced MDA levels, improved GSH, SOD, and CAT levels more effectively, and produced significant decreases in AST and ALT values (p < 0.05). Full article

Background: Hydroxychloroquine (HCQ), widely used in autoimmune and inflammatory diseases, has been associated with cardiotoxicity driven by oxidative, mitochondrial, and metabolic disturbances. However, no comparative evidence exists regarding whether thiamine, thiamine pyrophosphate (TPP), or their combination (TTPC) can mitigate HCQ-induced myocardial injury. Objective: This study examined the biochemical and histopathological effects of thiamine, TPP, and their combination in a rat model of HCQ-induced cardiomyopathy. Methods: Thirty male Wistar rats were assigned to five groups: healthy control, HCQ, thiamine + HCQ, TPP + HCQ, and TTPC + HCQ. Thiamine (20 mg/kg, intraperitoneal), TPP (20 mg/kg, intraperitoneal), or TTPC (20 mg/kg each, intraperitoneal) was administered once daily, followed by HCQ (120 mg/kg, oral, twice daily). After seven days, cardiac tissue was analyzed for MDA, tGSH, SOD, and CAT, while serum TnI, lactate, and LDH were measured from tail-vein blood samples. Cardiac samples underwent histopathological examination. Results: HCQ exposure markedly increased MDA, TnI, LDH, and lactate levels while reducing tGSH, SOD, and CAT, indicating severe oxidative and metabolic insult. Thiamine co-treatment failed to ameliorate these disturbances. Conversely, TPP restored redox balance, attenuated biomarker elevations, and improved cardiac biochemical profiles. TTPC produced comparable improvements but did not exceed those of TPP alone. Histopathologically, HCQ caused pronounced myocyte degeneration and mononuclear infiltration, whereas TPP and TTPC groups showed only mild inflammatory changes with preserved myocardial architecture. Conclusions: HCQ induces a marked redox imbalance accompanied by well-defined histopathological myocardial degeneration. TPP afforded robust cardio-protection, whereas thiamine offered no meaningful benefit. Collectively, these findings position TPP as a biologically plausible, clinically relevant candidate for mitigating HCQ-induced cardiomyopathy. Full article

Neutrophils, key effector cells of the innate immune system, combat pathogens through mechanisms including the production of reactive oxygen species (ROS) and the release of neutrophil extracellular traps (NETs). While these responses are critical for host defense, prolonged elevation of ROS and dysregulated NETosis mediated by neutrophils have been implicated in autoimmune diseases, chronic inflammation, and cancer. In pancreatic ductal adenocarcinoma (PDAC), a highly aggressive and inflammatory malignancy, an increase in neutrophils infiltrating the tumor microenvironment promotes cancer progression and metastasis through increased ROS production and NET release. Using bioluminescence imaging with the reporter L-012 and NET assays, we assessed ROS and NET release, respectively, induced by phorbol myristate acetate and platelet-activating factor in bone-marrow-isolated neutrophils from wild-type and syngeneic myeloperoxidase (MPO)-deficient mice ex vivo. MPO deficiency impaired both ROS generation and NET release, establishing a positive correlation between these processes. In vivo analyses using subcutaneous and spontaneous murine PDAC models revealed elevated ROS in tumors, which were significantly reduced upon genetic deletion of host MPO or peptidyl arginine deiminase 4, an essential enzyme for NET formation, or after treatment with hydroxychloroquine, a NET inhibitor. Furthermore, luminol and 4-[¹⁸F]fluoro-1-naphthol ([¹⁸F]4FN), functional L-012 analogs, also enabled non-invasive detection of intratumoral ROS by bioluminescence and PET imaging in vivo, respectively; [¹⁸F]4FN PET showed a three-fold increased uptake in PDAC tumors versus muscle. PDAC tissues and blood-isolated neutrophils obtained from PDAC patients exhibited elevated ROS compared to controls ex vivo. Importantly, ROS levels correlated strongly with NET formation in patient samples. These findings reveal a bidirectional relationship between ROS and NETs and highlight the potential utility of L-012- and [¹⁸F]4FN-based PET imaging for monitoring NET-associated inflammation in PDAC in vivo. Full article

Background/Objectives: Monkeypox is endemic to the African continent and has recently garnered global attention due to reported outbreaks in non-endemic nations. No approved drug is available for non-severe cases, and some isolates gained resistance to approved antivirals. In this study, we employed a drug repositioning strategy to evaluate the efficacy of existing FDA-approved antiviral drugs if repurposed for use against emerging Monkeypox, representing a cost-effective method for identifying novel therapeutic interventions. Methods: Methodology including Egyptian virus strain isolation, propagation and titration followed by in vitro studies, molecular docking and molecular dynamics simulations combined with binding free energy were carried out. Twenty-three FDA-approved drugs, including Abacavir, Acyclovir, Amantadine, Chloroquine, Daclatasvir, Dolutegravir, Entecavir, Favipiravir, Hydroxychloroquine, Lamivudine, Molnupiravir, Nevirapine, Oseltamivir, Penciclovir, Remdesivir, Ribavirin, Sofosbuvir, Tenofovir, Valaciclovir, Valganciclovir, Velpatasvir, Zanamivir, and Zidovudine, were screened for potential anti-monkeypox activity in vitro. In silico studies were carried out against three monkeypox proteins, Thymidylate Kinase, A42R Profilin-Like Protein, and VACV D13, to identify their potential targets. Results: In vitro testing showed that two antiviral drugs are positive. The employed computational methods indicate that remdesivir demonstrated superior binding patterns with elevated scores and stable complexes throughout the simulation. Conclusions: Our findings showed that Remdesivir therapeutic compound is potent against the tested strain of MPXV, and exhibited a robust binding affinity for Thymidylate Kinase, A42R Profilin-Like Protein, and VACV D13 enzymes, and thus may potentially be utilized as antiviral for the treatment of monkeypox virus. Full article

Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disorder in which ocular involvement represents a clinically significant yet frequently underrecognized contributor to morbidity. Ocular manifestations in SLE may arise from disease activity itself, but also as adverse effects of long-term pharmacological therapy. With the advent of targeted immunomodulatory agents, the therapeutic landscape of SLE has expanded beyond conventional drugs such as hydroxychloroquine and corticosteroids toward biologics and small molecules designed to interfere with specific immunological pathways. These advances have improved systemic disease control and survival; however, their ophthalmological safety profiles remain only partially defined. This review synthesizes current evidence on ocular adverse events associated with both traditional and emerging SLE therapies. Established agents, particularly hydroxychloroquine and corticosteroids, are consistently linked to complications including retinopathy, posterior subcapsular cataracts, steroid-induced glaucoma, and central serous chorioretinopathy. In contrast, recently approved or investigational therapies—such as belimumab, anifrolumab, voclosporin, dual BAFF/APRIL inhibitors, rituximab, JAK inhibitors, CD40/CD40L blockade, CD38 inhibition, and mesenchymal stromal cell-based strategies—have limited but evolving safety data, with potential ocular adverse events spanning inflammatory, vascular, neuro-ophthalmic, and structural domains. Although ocular complications appear infrequent in clinical trials, underdetection in real-world practice and insufficient long-term monitoring may underestimate their true incidence. These findings highlight the need for systematic ophthalmological surveillance in patients receiving immunomodulatory therapies for SLE. Early recognition and timely management of ocular toxicity are crucial to safeguarding visual function and optimizing long-term therapeutic outcomes in this vulnerable patient population. Full article

The overactivation of endosomal Toll-like receptor (TLR) in macrophages plays an important role in the pathogenesis of acute lung injury (ALI). There is currently still a lack of nano-formulated and macrophage-targeted endosomal TLR inhibitors that have been approved for clinical uses. We previously discovered that the elevation of endosomal pH using nanodevices provides a promising strategy to specifically inhibit endosomal TLRs in macrophages. The weakly basic drug hydroxychloroquine (HCQ) has been reported for its capability to accumulate in endolysosomes and modulate the acidity in these compartments. To enhance its macrophage-targeting ability and the therapeutic efficacy in vivo, herein we formulated HCQ into a nanoform using liposomes, named HCQ-L. We found that HCQ-L was less cytotoxic and more effective in inhibiting endosomal TLRs (including TLR3, TLR4, TLR 7/8) than the molecular HCQ. Subsequently, a hexapeptide, Pep12, was inserted onto the surface of HCQ-L to form HCQ-L-P12. Interestingly, Pep12 modification significantly improved the stability of liposomes in aqueous solution for at least 2 years; while having enhanced inhibitory effects on TLR7/8 signaling, HCQ-L-P12 displayed similar effects on inhibiting the TLR4 pathway and down-stream pro-inflammatory cytokine production when compared with HCQ-L. Furthermore, both HCQ nanoformulations potently elevated the endosomal pH. In vivo evaluation showed that HCQ-L-P12 and HCQ-L (but not molecular HCQ) were able to alleviate lung inflammation and injuries by decreasing inflammatory cell infiltration upon intratracheal instillation in a lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model. This research provides a new strategy to fabricate lipid-based nanocarriers for targeted delivery of endosomal pH modulators to treat ALI and other acute and chronic inflammatory disorders. Full article

The COVID-19 pandemic initially focused clinical efforts on hospitalized patients. However, as the pandemic progressed, attention shifted to outpatients who often experience milder symptoms yet still contribute to viral transmission. This scoping review aimed to document and evaluate the clinical outcomes assessed in randomized controlled trials (RCTs) involving outpatients with COVID-19, identifying gaps and areas for improvement in trial design. This review followed the PRISMA-ScR guidelines. A comprehensive search of four electronic databases (PubMed, Scopus, Cochrane CENTRAL, and Web of Science) was conducted for RCTs published between December 2019 and December 2023. Studies were included if they involved outpatients with confirmed COVID-19 and reported clinical outcomes. Data were extracted from eligible studies, and outcomes were categorized using the COMET taxonomy. A total of 91 studies were included, representing a wide geographical distribution, with the USA, Iran, and Brazil contributing the most studies. The most frequently investigated treatments included hydroxychloroquine, fluvoxamine, convalescent plasma, and ivermectin. Key outcomes focused on hospitalization rates, symptom resolution, and disease progression. Mortality, although less common in outpatients, was reported in 65 studies, underscoring the importance of outpatient interventions. This review highlights the need for standardized outcome measures in outpatient COVID-19 trials. Full article

Background: Multiple myeloma (MM) is essentially an incurable cancer, but treatments with proteasome inhibitors are widely used clinically to extend patient survival. While the mechanisms of proteasome inhibition by Bortezomib are well known, the cellular responses to this proteotoxic stress that leads to sensitivity by MM are not fully elucidated. This study reports on the application of an emerging method to investigate proteostasis by proteomics. Methods: We utilized metabolic labeling with azidohomoalanine (AHA) in a MM cell line in combination with Bortezomib treatment. AHA labeling facilitates the selective isolation and identification of proteins for investigations of protein synthesis or protein degradation. Results: The data collected reveals significant changes in gene protein synthesis upon Bortezomib treatment, including protein neddylation. The data also reveals a global increase in protein degradation, which suggests the induction of an autophagy-related process. The resulting data collected reveals significant changes upon Bortezomib treatment in protein synthesis of genes, including protein neddylation, and protein degradation data reveals a global increase in protein degradation, suggesting an induction of an autophagy-related process. Subsequent cellular and proteomic analysis investigated the additional treatment of an autophagy inhibitor, hydroxychloroquine, in combination with Bortezomib treatment by label-free proteomics to further characterize the proteome-wide changes in these two proteotoxic stresses. Conclusions: AHA metabolic labeling proteomics to investigate protein synthesis and degradation enables novel complementary insights into complex cellular responses compared to that of traditional label-free proteomics. Full article