Search Results (41)

This study focuses on the preparation of poly(HCQM-co-VP) copolymeric nanoparticles (NPs) to enhance the aqueous solubility and bioavailability of the hydrophobic and antitumor molecules HCQ (hydroxychloroquine) and α-TOS (α-tocopheryl succinate). HCQ is covalently incorporated into the polymer backbone, while α-TOS is encapsulated within the nanoparticles by non-covalent interactions. Poly(HCQM-co-VP) was synthesized from a vinyl derivative of HCQ (HCQM) and N-vinylpyrrolidone (VP), with a molar composition of 17% HCQM and 83% VP, providing the optimal hydrophobic/hydrophilic balance for forming, via nanoprecipitation, empty nanoparticles (NPs) with a diameter of 123.6 nm and a zeta potential of −5.8 mV. These nanoparticles effectively encapsulated α-TOS within their hydrophobic core, achieving an encapsulation efficiency (%EE) of 78%. These α-TOS-loaded NPs resulted in smaller diameters and more negative zeta potentials (71 nm, −19.2 mV) compared to the non-loaded NPs. The cytotoxicity of these NPs was evaluated using the AlamarBlue assay on MCF-7 breast cancer cells. The empty NPs showed no toxic effects within the tested concentration range, after 72 h of treatment. In contrast, the α-TOS-loaded NPs, exhibited a pronounced cytotoxic effect on MCF-7 cells with an IC₅₀ value of 100.2 μg·mL⁻¹, thereby demonstrating their potential as controlled drug delivery systems for cancer treatment. These findings contribute to the development of a new HCQ-based polymeric nanocarrier for α-TOS or other hydrophobic drugs for the treatment of cancer and other diseases treatable with these drugs. Full article

Background/Objectives: Hydroxychloroquine (HCQ) retinopathy can be underrecognized early, as structural changes in OCT may precede symptoms and are often subtle. Early detection is crucial to prevent irreversible damage. This study evaluated longitudinal OCT changes preceding overt HCQ toxicity using ellipsoid zone (EZ) mapping. Methods: Patients on long-term HCQ underwent two macular cube scans at least one year apart using Cirrus HD-OCT. Scans were analyzed with an EZ-mapping platform and manually validated. Patients with baseline OCT signs of toxicity or co-existing macular disease were excluded based on masked expert review. Results: Three hundred and seventy-three eyes of 373 patients were included. The mean age was 57.0 ± 12.6 years, the mean HCQ dose was 379.4 ± 59.4 mg, the treatment duration was 5.6 ± 3.7 years, and the OCT interval was 3.1 ± 0.9 years. Outer retinal metrics remained stable across the cohort. The mean en face EZ attenuation increased from 3.3% to 3.9% (p = 0.24). Thirty-four eyes (9.1%) experienced an absolute increase of ≥4% (~1.5 mm²) in EZ attenuation. This increase was significantly associated with age at HCQ initiation (p < 0.001), age at the time of the first and second OCT (p < 0.001), and baseline visual acuity (p = 0.01), and demonstrated changes in other outer retinal metrics (p < 0.01). Only 3/34 eyes (8.9%) were diagnosed by the managing clinician with HCQ toxicity at the time of the second OCT. However, 26 of these eyes (76.5%) had signs of HCQ toxicity by expert review, suggesting the overall greater sensitivity of these quantitative outer retinal metrics for detecting toxicity compared with clinician review. Conclusions: Longitudinal OCT assessment revealed overall stability in outer retinal metrics in eyes on HCQ, but a subset showed increased EZ attenuation, which correlated with age at the time of HCQ initiation, baseline visual acuity, and expert OCT review. These changes may help identify at-risk eyes and eyes with early toxicity and warrant further validation as potential screening biomarkers. Full article

Background and Clinical Significance: Central serous chorioretinopathy (CSCR) and hydroxychloroquine (HCQ) retinopathy can both cause outer retinal changes in systemic lupus erythematosus (SLE) patients treated with HCQ and corticosteroids. Differentiating between transient steroid-induced CSCR and irreversible HCQ toxicity is critical to avoid unnecessary discontinuation of essential therapy. Case Presentation: Three female SLE patients (ages 47, 41, and 37) on long-term HCQ (25, 9, and 6 years, respectively) and recent or ongoing low-dose prednisolone presented with unilateral OCT findings, parafoveal or pericentral photoreceptor defects, with the fellow eye unaffected. Review of clinical history and serial imaging revealed transient subretinal fluid in all cases, associated with recent corticosteroid use or dose escalation. Subsequent tapering or cessation of steroids led to resolution of the fluid, and earlier OCT scans confirmed normal outer retinal morphology, indicating that these changes were residual effects of resolved CSCR rather than HCQ toxicity. In Cases 1 and 2, the best-corrected visual acuity (BCVA) in the affected eye declined from 20/22 to 20/40 during the CSCR episode and improved to 20/30 and 20/25, respectively, after subretinal fluid resolution. In Case 3, by contrast, BCVA remained stable at 20/20 throughout the pre-, during-, and post-CSCR periods. Conclusions: Resolved CSCR can mimic HCQ retinopathy. These cases emphasize the importance of detailed medication history, serial multimodal retinal imaging, and comparison with prior and fellow-eye scans to distinguish resolved CSCR from HCQ retinopathy. Such thorough evaluation and careful differential diagnosis help ensure appropriate management—avoiding unnecessary HCQ discontinuation while protecting both ocular and systemic health. Full article

Background/Objectives: Although hydroxychloroquine (HCQ) is used to treat systemic lupus erythematosus (SLE), it is associated with retinal toxicity. Early diagnosis can prevent the further progression of HCQ-associated retinopathy by discontinuing HCQ treatments. This study aimed to evaluate the early diagnostic parameters in patients with SLE treated with HCQ and identify the best approach using multifocal electroretinography (mfERG) and swept-source optical coherence tomography (SS-OCT) to reflect subclinical retinal toxicity. Methods: Thirty-eight patients with SLE (76 eyes) and 18 healthy controls (36 eyes) were enrolled. They were referred for HCQ retinopathy screening without visual field defects. The patients were tested using a standard 61-hexagon mfERG stimulus and SS-OCT. Ten groups of the mfERG responses from the sectors were averaged to compare the quadrants, hemiretinal areas, consecutive ring amplitudes, and ring ratios (R1/R2–R5) from the center to the periphery. Additionally, the ganglion cell complex (GCC) analyses were performed using SS-OCT. Results: No difference was observed in GCC thickness on the OCT images, in the P1 amplitudes, and in the implicit time of mfERG. However, the R1/Rx ring ratios, except the R1/R2 ratio, showed significant differences among the three groups (p = 0.759, 0.018, 0.029, and 0.029, respectively). The R1/R3, R1/R4, and R1/R5 ring ratios demonstrated a correlation with the duration of HCQ therapy (r = −0.303, −0.279, and −0.266; p = 0.003, 0.006, and 0.009). The areas under the receiver operating characteristic curve of the ring ratios R1/R3–R5 were 0.730, 0.702, and 0.724, respectively (p = 0.004, 0.012, and 0.006), indicating the likelihood of being categorized as a high-risk group for subclinical HCQ retinopathy. Conclusions: The ring ratio of mfERG reflects the subclinical electrophysiological alterations induced by HCQ and can become more clinically useful by simplifying screening examinations. Full article

The existing treatments against Trypanosoma evansi are faced with several drawbacks, such as limited drug options, resistance, the relapse of infection, toxicity, etc., which emphasizes the necessity for new alternatives. We synthesized novel metal-based antiparasitic compounds using chitosan, hydroxychloroquine (HC), and ZnO nanoparticles (NPs) and characterized them for size, morphology, chemical interactions, etc. Molecular docking and protein interaction studies were performed in silico to investigate the inhibitory effects of HC, zinc-ligated hydroxychloroquine (HCZnONPs), and chitosan-zinc-ligated hydroxychloroquine (CsHCZnONPs) for two key proteins, i.e., heat shock protein 90 (Hsp90) and trypanothione reductase associated with T. evansi. In vitro trypanocidal activity and the uptake of zinc ions by T. evansi parasites were observed. The formulation was successfully synthesized, as indicated by its size, stability, morphology, elemental analysis, and functional groups. CsHCZnO nanoparticles strongly inhibit both Hsp90 and trypanothione reductase proteins. The inhibition of Hsp90 by these nanoparticles is even stronger than that of trypanothione reductase when compared to HC and HCZnONPs. This suggests that the presence of polymer chitosan enhances the nanoparticles’ effectiveness against the parasite. For the first time, CsHCZnO nanoparticles exhibited trypanocidal activity against T. evansi, with complete growth inhibition being observed at various concentrations after 72 h of treatment. Fluorescent microscopy using FluoZin-3 on T. evansi culture confirmed the presence of zinc on the surface of parasites. This innovative approach has shown promising results in the quest to develop improved antiparasitic compounds against T. evansi with enhanced effectiveness and safety, highlighting their potential as therapeutic agents against trypanosomiasis. Full article

Background: Lichen planopilaris (LPP) is an inflammatory cicatricial alopecia characterized by an irreversible destruction of the hair follicle resulting in its permeant destruction. The clinical presentation of LPP is a progressive patchy scarring alopecia. A variety of systemic agents is used to treat LPP with varying success. The aim of this retrospective, real-life analysis was to evaluate the treatment of hydroxychloroquine for LPP. Method: In this retrospective, single-center study, we analyzed 110 patients with LPP and frontal fibrosing alopecia (FFA) who received treatment over a 12-month period from March 2014 to March 2021 at the Department of Dermatology, University of Mainz Medical Center. Patient records were analyzed for response to treatment, co-morbidities, disease progression-free survival (DPFS), and safety. Clinical parameters associated with treatment response were determined with Cox regression modelling and logistic regression. Results: Overall, 77 of 110 patients were treated with a systemic agent. There was a clear association between LPP and the occurrence of Hashimoto thyroiditis. Topical treatment with corticosteroids did not improve clinical symptoms in the majority of patients (15 out of 101). In 71% of patients treated with systemic cyclosporine A and 62% of patients treated with hydroxychloroquine, we observed a significant resolution of the inflammatory process, which correlated with a robust durable clinical response (p < 0.001). Toxicity was observed in 17% (n = 9) of patients receiving systemic treatment with hydroxychloroquine and correlated with the duration of systemic treatment (p < 0.001). Treatment discontinuation was associated with a flare-up of clinical symptoms (29%), which required the re-initiation of second-line therapy in 13 out of 51 patients. Overall, the initiation of second-line treatment, either hydroxychloroquine or Cyclosporine A (CsA), yielded positive results, especially in the patient cohort treated with hydroxychloroquine (overall response rate, ORR = 100%), who showed disease progression during CsA or retinoids. Conclusions: Our results from this contemporary cohort of patients with LPP and FFA indicate that hydroxychloroquine and cyclosporine are effective systemic agents in decreasing clinical symptoms. However, our data also show that the discontinuation of treatment is often associated with the exacerbation of clinical symptoms. Response rates to second-line treatment were especially favorable in the patient cohort with hydroxychloroquine. Full article

Background/Objective: Hydroxychloroquine retinopathy, traditionally characterized by parafoveal or pericentral outer retinal damage, is explored for atypical presentations in Asian patients. This challenges conventional beliefs regarding onset, retinopathy pattern, and associated visual field defects. Methods: Ninety-five patients diagnosed with hydroxychloroquine retinopathy at Hanyang University Hospital underwent screening from January 2010 to December 2023. Swept-source optical coherence tomography (SS-OCT), ultra-widefield fundus autofluorescence (UWF-FAF), and automated visual fields (VF) were employed for detailed structural and functional evaluations. Multifocal electroretinography was performed in selected cases requiring additional objective evidence of retinal toxicity. Results: Among 95 patients, 14 (14.7%) exhibited atypical presentations, including very early onset (n = 1), (far) peripheral-dominant damages (n = 4), perivascular involvement (n = 1), bitemporal hemianopsia due to nasal extensive lesions (n = 1), unilateral involvement (n = 2), and asymmetric involvement in retinopathy pattern or severity between the eyes (n = 7). These findings underscore the importance of utilizing expanded imaging techniques, such as ultra-widefield FAF imaging, to identify atypical presentations of retinal involvement. Conclusions: Screening physicians should consider these atypical presentations to ensure timely diagnosis and appropriate management in patients undergoing hydroxychloroquine treatment. Full article

Background and Objective: Hydroxychloroquine sulfate (HCQ) is a lysosomotropic agent administered in systemic lupus erythematosus and rheumatoid arthritis that has fewer toxic effects than chloroquine. However, HCQ may still be responsible for retinal toxicity. In this study, we observed structural changes in the retinas of experimental rats after prolonged exposure to HCQ. Matherials and Methods: We investigated several aspects regarding retinal changes, at both the histopathological and ultrastructural levels. We used 96 male albino Wistar rats distributed into four equal groups (n = 24 per group): the first three groups were treated with different doses of HCQ (50, 100, and 200 mg/kg HCQ, injected intraperitoneally in a single dose daily), and the last group (the control group, n = 24) was treated with saline solution administered in the same way (0.4 mL of saline solution). The treated groups received HCQ daily for 4 months, and every month, six animals from each group were sacrificed to assess retinal changes. The eyes were examined via optical (OM) and electronic microscopy (EM). Statistical analysis was deployed, and results regarding retinal morpho-photometry were acquired. Results: We observed structural retinal changes in both high and low doses of HCQ; while high doses determined a significant thinning of the retina, lower doses caused retinal thickening. Morphological retinal changes upon exposure to HCQ are believed to be caused by accumulated HCQ in lysosomes found in retinal ganglion cells and in the inner nuclear and photoreceptor cell layers. Such changes were most evident in the group receiving HCQ intraperitoneally in doses of 100 mg/kg for a longer period (4 months). Conclusions: The present study highlights histopathological and ultrastructural retinal changes induced by chronic HCQ administration, which were strongly connected to the dosage and period of exposure. Full article

Phospholipidosis is a rare disorder which consists of an excessive intracellular accumulation of phospholipids and the appearance of zebra bodies or lamellar bodies when looking at them using electron microscopy. This disease is associated with certain genetic diseases or is secondary to drugs or toxins. Drug-induced phospholipidosis encompasses many types of pharmaceuticals, most notably chloroquine, amiodarone or ciprofloxacin. Clinically and histologically, renal involvement can be highly variable, with the diagnosis not being made until the zebra bodies are seen under an electron microscope. These findings may require genetic testing to discount Fabry disease, as its histological findings are indistinguishable. Most of the chemicals responsible are cationic amphiphilic drugs, and several mechanisms have been hypothesized for the formation of zebra bodies and their pathogenic significance. However, the relationship between drug toxicity and phospholipid accumulation, zebra bodies and organ dysfunction remains enigmatic, as do the renal consequences of drug withdrawal. We present, to our knowledge, the first case report of acute renal injury with a monoclonal gammopathy of renal significance, lesions, and sclerodermiform syndrome, with zebra bodies that were associated with the initiation of a hydroxychloroquine and amiodarone treatment, as an example of drug-induced-phospholipidosis. Full article

Triple-negative breast cancer (TNBC) lacks targeted therapies, leaving cytotoxic chemotherapy as the current standard treatment. However, chemotherapy resistance remains a major clinical challenge. Increased insulin-like growth factor 1 signaling can potently blunt chemotherapy response, and lysosomal processes including the nutrient scavenging pathway autophagy can enable cancer cells to evade chemotherapy-mediated cell death. Thus, we tested whether inhibition of insulin receptor/insulin-like growth factor 1 receptor with the drug BMS-754807 and/or lysosomal disruption with hydroxychloroquine (HCQ) could sensitize TNBC cells to the chemotherapy drug carboplatin. Using in vitro studies in multiple TNBC cell lines, in concert with in vivo studies employing a murine syngeneic orthotopic transplant model of TNBC, we show that BMS-754807 and HCQ each sensitized TNBC cells and tumors to carboplatin and reveal that exogenous metabolic modulators may work synergistically with carboplatin as indicated by Bliss analysis. Additionally, we demonstrate the lack of overt in vivo toxicity with our combination regimens and, therefore, propose that metabolic targeting of TNBC may be a safe and effective strategy to increase sensitivity to chemotherapy. Thus, we conclude that the use of exogenous metabolic modulators, such as BMS-754807 or HCQ, in combination with chemotherapy warrants additional study as a strategy to improve therapeutic responses in women with TNBC. Full article

Background: Screening for hydroxychloroquine (HCQ) retinopathy is crucial to detecting early disease. A novel machine-learning-based optical coherence tomography (OCT) biomarker, Ellipsoid Zone (EZ) At-Risk, can quantitatively measure EZ alterations and at-risk areas for progressive EZ loss in a fully automated fashion. The purpose of this analysis was to compare the EZ At-Risk burden in eyes with HCQ toxicity to eyes without toxicity. Methods: IRB-approved image analysis study of 83 subjects on HCQ and 44 age-matched normal subjects. SD-OCT images were reviewed for evidence of HCQ retinopathy. A ML-based, fully automatic measurement of the percentage of the macular area with EZ At-Risk was performed. Results: The mean age for HCQ subjects was 67.1 ± 13.2 years and 64.2 ± 14.3 years for normal subjects. The mean EZ At-Risk macular burden in the “toxic” group (n = 38) was significantly higher (10.7%) compared to the “non-toxic” group (n = 45; 2.2%; p = 0.023) and the “normal” group (1.4%; p = 0.012). Additionally, the amount of EZ At-Risk burden was significantly correlated with the HCQ dose based on the actual (p = 0.016) and ideal body weight (p = 0.033). Conclusions: The novel biomarker EZ-At Risk was significantly higher in subjects with evidence of HCQ retinopathy as well as significantly associated with HCQ dose. This novel biomarker should be further evaluated as a potential screening tool for subjects on HCQ. Full article

Immune checkpoint inhibitors (ICIs) are the standard of care for a growing number of malignancies. Unfortunately, they are associated with a broad range of unique toxicities that mimic the presentations of primary autoimmune conditions. These adverse events are termed immune-related adverse events (irAEs), of which ICI-lupus erythematosus (ICI-LE) constitutes a small percentage. Our review aims to describe the available literature on ICI-LE and ICI treatment for patients with pre-existing lupus. Most diagnoses of ICI-LE had findings of only cutaneous lupus; four diagnoses of ICI-LE had systemic lupus manifestations. Over 90% (27 of 29) of cases received anti-PD-1/PDL-1 monotherapy, 1 received combination therapy, and 1 received only anti-CTLA-4 treatment. About three-fourths (22 of 29 or 76%) of patients with ICI-lupus were managed with topical steroids, 13 (45%) received hydroxychloroquine, and 10 (34%) required oral corticosteroids. In our case series, none of the patients with pre-existing lupus receiving ICI therapy for cancer had a flare of their lupus, but few had de novo irAE manifestations, all of which were characterized as low-grade. The review of the literature yielded seven ICI-LE flares from a total of 27 patients with pre-existing lupus who received ICI. Most flares were manageable without need for ICI cessation. Full article

Zinc ions can hinder the synthesis of proteins required for accomplishing several stages of the viral life cycle. The intracellular zinc concentration can be increased by using zinc ionophores which transport zinc ions into the cells and hinder viral replication. (Hydroxy)chloroquine is an example of a zinc ionophore, but both zinc and (hydroxy)chloroquine can be toxic to the host organism. The nanocarriers may serve as camouflage to evade the adverse effects of drugs, chemicals, and nanoparticles on the host. We formulated ZnO nanoparticles with flower-like morphology (ZnONFs). It was further decorated with chitosan along with hydroxychloroquine (as a zinc ionophore) (CHCZnO NPs). We have chosen the cationic polymer chitosan since it is biocompatible, biodegradable and binds easily with the cells, and enhances the transport of drugs across cell membranes. The formulation was investigated for size, shape, surface charge, and interaction of chemicals used. We evaluated the formulations for cytotoxicity, and biocompatibility in embryonated chicks and their efficacy against bovine coronavirus (BCoV) isolated from a buffalo calf, and pneumo-enteric coronaviruses isolated from a buffalo calf with promising results in comparison to ZnONFs/hydroxychloroquine alone. Furthermore, we elucidate the mechanism underlying the lysosomotropic effect of various formulations on Vero cells infected with the buffalo coronavirus. Full article

Background: Pediatric lupus nephritis (LN) is one of the most serious manifestations of systemic lupus erythematosus (SLE) in children, determining the outcomes of the disease. There are no standardized treatment protocols for pediatric LN, and the role of biologics has not yet been conclusively defined. Objectives: analyze the safety and efficacy of rituximab biosimilar BCD020 in pediatric patients with lupus nephritis. Methods: in a retrospective cohort study, the data from the case histories of 25 patients with LN (10 boys and 15 girls) with an onset age of 13 (9–16) years, who failed conventional non-biologic treatment or developed corticosteroid dependence/toxicity, were included. The diagnosis was made using Systemic Lupus International Collaborating Clinics (SLICC) classification criteria. Rituximab biosimilar BCD020 was prescribed in a dosage of 375 mg/m² every week (2–4 infusions) with repeated courses every 6–12 months (2–4 infusions) according to disease activity, B-cell depletion, and IgG levels. The dynamics of clinical and laboratory data, the activity of the disease by SLEDAI, and corticosteroid doses were assessed at the onset and during the rituximab trial. Results: The main patient’s characteristics were: Pre-rituximab non-biologic conventional treatment included: cyclophosphamide 15 (60%), MMF 8 (32%), azathioprine 3 (12%), hydroxychloroquine 12 (48%), and pulse therapy of methylprednisolone followed by oral methylprednisolone 25 (100%). The time before rituximab was 7.0 (3.0–24.0) months, and the whole observation period was 7.0 (0; 24) months. The initial pre-rituximab treatment slightly reduced SLEDAI levels and the proportion of patients with LN. A significant reduction of SLEDAI, the anti-dsDNA level, proteinuria, hematuria, C4 complement, ESR, and the median corticosteroid dose by 80% from the initial value, as well as the proportion of patients without corticosteroids, was observed after rituximab administration. Two deaths were observed due to catastrophic SLE with macrophage activation syndrome, accompanied by a severe infection (invasive aspergillosis, n = 2). Three patients developed serious adverse events: pneumonia (n = 2), transient agranulocytosis (n = 1) after the third rituximab infusion, and meningitis, caused by Listeria monocytosis, after the first rituximab infusion. Eight patients received antibacterial treatment for different respiratory infections without hospital admissions. Conclusions: Rituximab biosimilar BCD020 showed effectiveness in LN, whereas previous non-biologic treatment was insufficiently effective. Randomized controlled trials are required to evaluate the efficacy and safety of rituximab and evaluate the benefits when compared with conventional SLE treatment. Full article

This review provides an overview of conventional and novel retinal imaging modalities for hydroxychloroquine (HCQ) retinopathy. HCQ retinopathy is a form of toxic retinopathy resulting from HCQ use for a variety of autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus. Each imaging modality detects a different aspect of HCQ retinopathy and shows a unique complement of structural changes. Conventionally, spectral-domain optical coherence tomography (SD-OCT), which shows loss or attenuation of the outer retina and/or retinal pigment epithelium–Bruch’s membrane complex, and fundus autofluorescence (FAF), which shows parafoveal or pericentral abnormalities, are used to assess HCQ retinopathy. Additionally, several variations of OCT (retinal and choroidal thickness measurements, choroidal vascularity index, widefield OCT, en face imaging, minimum intensity analysis, and artificial intelligence techniques) and FAF techniques (quantitative FAF, near-infrared FAF, fluorescence lifetime imaging ophthalmoscopy, and widefield FAF) have been applied to assess HCQ retinopathy. Other novel retinal imaging techniques that are being studied for early detection of HCQ retinopathy include OCT angiography, multicolour imaging, adaptive optics, and retromode imaging, although further testing is required for validation. Full article