INTRAVITREAL DEXAMETHASONE FOR THE TREATMENT OF MACULAR EDEMA SECONDARY TO HYDROXYCHLOROQUINE TOXICITY.

PURPOSE: Cystoid macular edema is a vision-threatening complication infrequently associated with hydroxychloroquine retinal toxicity. There are limited data on the best treatment for this pathology. METHODS: A retrospective case series is presented. RESULTS: In this series, we present three cases of cystoid macular edema in patients with diagnosed hydroxychloroquine maculopathy successfully treated with intravitreal dexamethasone implantation. CONCLUSION: Minimal literature has been published regarding the best management of cystoid macular edema related to hydroxychloroquine toxicity. Our case series suggests a possible new agent in the treatment of this rare occurrence.

A real-world analysis of trametinib in combination with hydroxychloroquine or CDK4/6 inhibitor as third- or later-line therapy in metastatic pancreatic adenocarcinoma.

BACKGROUND: There are no standard third-line treatment options for metastatic pancreatic ductal adenocarcinoma (mPDAC). Trametinib in combination with hydroxychloroquine (HCQ) or CDK4/6 inhibitors for pancreatic adenocarcinoma showed promising efficacy in preclinical studies. However, the regimens have not been well examined in patients with mPDAC. METHODS: Patients with mPDAC who received the combination of trametinib and HCQ or CDK4/6 inhibitors as third- or later-line therapy were reviewed. The efficacy and prognosis were further analyzed. RESULTS: A total of 13 mPDAC patients were enrolled, of whom 8 and 5 patients were treated with trametinib plus HCQ or a CDK4/6 inhibitor (palbociclib or abemaciclib), respectively. All enrolled patients had either KRAS G12D or G12V mutations and had received a median of 3 prior lines of therapy (range, 2-6). The median trametinib treatment duration was 1.4 months. Of the 10 patients with measurable disease, only 1 patient achieved stable disease, and the remaining patients had progressive disease. Moreover, in patients treated with trametinib plus HCQ and a CDK4/6 inhibitor, the median progression-free survival was 2.0 and 2.8 months, respectively, and the median overall survival was 4.2 and 4.7 months, respectively. Moreover, 5 (50%) patients experienced grade 3-4 adverse events in 10 patients with available safety data. CONCLUSIONS: The combination of trametinib and HCQ or CDK4/6 inhibitors may not be an effective later-line treatment for mPDAC, and the current preliminary findings need to be confirmed by other studies with larger sample sizes.

Hydroxychloroquine Dose per Ophthalmology Guidelines and the Risk of Systemic Lupus Erythematosus Flares.

This study of an academic medical center patient cohort with systemic lupus erythematosus (SLE) investigates the association between hydroxychloroquine dose based on current guidelines and risk of lupus flares.

Pulmonary Delivery of Aerosolized Chloroquine and Hydroxychloroquine to Treat COVID-19: In Vitro Experimentation to Human Dosing Predictions.

In vitro screening for pharmacological activity of existing drugs showed chloroquine and hydroxychloroquine to be effective against severe acute respiratory syndrome coronavirus 2. Oral administration of these compounds to obtain desired pulmonary exposures resulted in dose-limiting systemic toxicity in humans. However, pulmonary drug delivery enables direct and rapid administration to obtain higher local tissue concentrations in target tissue. In this work, inhalable formulations for thermal aerosolization of chloroquine and hydroxychloroquine were developed, and their physicochemical properties were characterized. Thermal aerosolization of 40 mg/mL chloroquine and 100 mg/mL hydroxychloroquine formulations delivered respirable aerosol particle sizes with 0.15 and 0.33 mg per 55 mL puff, respectively. In vitro toxicity was evaluated by exposing primary human bronchial epithelial cells to aerosol generated from Vitrocell. An in vitro exposure to 7.24 µg of chloroquine or 7.99 µg hydroxychloroquine showed no significant changes in cilia beating, transepithelial electrical resistance, and cell viability. The pharmacokinetics of inhaled aerosols was predicted by developing a physiologically based pharmacokinetic model that included a detailed species-specific respiratory tract physiology and lysosomal trapping. Based on the model predictions, inhaling emitted doses comprising 1.5 mg of chloroquine or 3.3 mg hydroxychloroquine three times a day may yield therapeutically effective concentrations in the lung. Inhalation of higher doses further increased effective concentrations in the lung while maintaining lower systemic concentrations. Given the theoretically favorable risk/benefit ratio, the clinical significance for pulmonary delivery of aerosolized chloroquine and hydroxychloroquine to treat COVID-19 needs to be established in rigorous safety and efficacy studies. Graphical abstract.

Hydroxychloroquine pre-exposure prophylaxis provides no protection against COVID-19 among health care workers: a cross-sectional study in a tertiary care hospital in North India.

OBJECTIVES: The use of Hydroxychloroquine (HCQ) prophylaxis has been recommended by the National task force constituted by the Indian Council of Medical Research (ICMR) for the prevention of corona virus disease 2019 (COVID-19) among healthcare workers (HCWs). However, this recommendation was based essentially on the preclinical data and limited clinical experience. The aim of this study was to evaluate the efficacy and safety of HCQ as a pre-exposure prophylaxis for COVID-19 infection among Indian HCWs. METHODS: A cross-sectional study was conducted among HCWs of a tertiary care hospital in north India. The HCQ prophylaxis was initiated among 996 HCWs and they were followed up to 8 weeks for conversion to COVID-19 positive status and any adverse drug reaction (ADR). RESULTS: About 10.3% of the study participants were tested positive for COVID-19 which was comparable to the positivity rate among HCWs not taking HCQ prophylaxis (9.7%). CONCLUSIONS: HCQ was well tolerated at a weekly dose of 400 mg for 8 weeks but provided no additional benefit in prevention of COVID-19 among HCWs.

Translational Modeling of Chloroquine and Hydroxychloroquine Dosimetry in Human Airways for Treating Viral Respiratory Infections.

PURPOSE: Chloroquine and hydroxychloroquine are effective against respiratory viruses in vitro. However, they lack antiviral efficacy upon oral administration. Translation of in vitro to in vivo exposure is necessary for understanding the disconnect between the two to develop effective therapeutic strategies. METHODS: We employed an in vitro ion-trapping kinetic model to predict the changes in the cytosolic and lysosomal concentrations of chloroquine and hydroxychloroquine in cell lines and primary human airway cultures. A physiologically based pharmacokinetic model with detailed respiratory physiology was used to predict regional airway exposure and optimize dosing regimens. RESULTS: At their reported in vitro effective concentrations in cell lines, chloroquine and hydroxychloroquine cause a significant increase in their cytosolic and lysosomal concentrations by altering the lysosomal pH. Higher concentrations of the compounds are required to achieve similar levels of cytosolic and lysosomal changes in primary human airway cells in vitro. The predicted cellular and lysosomal concentrations in the respiratory tract for in vivo oral doses are lower than the in vitro effective levels. Pulmonary administration of aerosolized chloroquine or hydroxychloroquine is predicted to achieve high bound in vitro-effective concentrations in the respiratory tract, with low systemic exposure. Achieving effective cytosolic concentrations for activating immunomodulatory effects and adequate lysosomal levels for inhibiting viral replication could be key drivers for treating viral respiratory infections. CONCLUSION: Our analysis provides a framework for extrapolating in vitro effective concentrations of chloroquine and hydroxychloroquine to in vivo dosing regimens for treating viral respiratory infections.

Acute and subacute oral toxicity of artemisinin-hydroxychloroquine sulfate tablets in rats.

Artemisinin-hydroxychloroquine sulfate tablets (AH) are considered a relatively inexpensive and novel combination therapy for treating all forms of malaria, especially aminoquinoline drugs-resistant strains of P.falciparum. We aim to carry out acute and subacute oral toxicity studies in rats to acquire preclinical data on the safety of AH. Acute toxicity was evaluated in Sprague-Dawley (SD) rats at a single dose of 1980, 2970, 4450, 6670, and 10000 mg/kg. A 14-days subacute toxicity was assessed in SD rats at doses of 0, 146, 219, 328, and 429 mg/kg. The median lethal dose (LD50) of acute oral administration of AH in rats is found to be 3119 mg/kg, and toxic symptoms include decreased spontaneous activity, dyspnea, bristling, soft feces, spasticity, and convulsion. Repeated doses of AH have toxic effects on the nervous system, skin, blood system, liver, kidney, and spleen in rats. The main toxic reactions include epilation, emaciation, mental irritability, decreased body weight gain and food consumption, changes in the hematological and biochemical parameters, especially pathological lesions in the liver, kidney, and spleen. The no-observed-adverse-effect level (NOAEL) and lowest-observed-adverse-effect level (LOAEL) of AH are considered to be 219 mg/kg and 328 mg/kg, respectively.

Flares after hydroxychloroquine reduction or discontinuation: results from the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort.

OBJECTIVES: To evaluate systemic lupus erythematosus (SLE) flares following hydroxychloroquine (HCQ) reduction or discontinuation versus HCQ maintenance. METHODS: We analysed prospective data from the Systemic Lupus International Collaborating Clinics (SLICC) cohort, enrolled from 33 sites within 15 months of SLE diagnosis and followed annually (1999-2019). We evaluated person-time contributed while on the initial HCQ dose ('maintenance'), comparing this with person-time contributed after a first dose reduction, and after a first HCQ discontinuation. We estimated time to first flare, defined as either subsequent need for therapy augmentation, increase of ≥4 points in the SLE Disease Activity Index-2000, or hospitalisation for SLE. We estimated adjusted HRs (aHRs) with 95% CIs associated with reducing/discontinuing HCQ (vs maintenance). We also conducted separate multivariable hazard regressions in each HCQ subcohort to identify factors associated with flare. RESULTS: We studied 1460 (90% female) patients initiating HCQ. aHRs for first SLE flare were 1.20 (95% CI 1.04 to 1.38) and 1.56 (95% CI 1.31 to 1.86) for the HCQ reduction and discontinuation groups, respectively, versus HCQ maintenance. Patients with low educational level were at particular risk of flaring after HCQ discontinuation (aHR 1.43, 95% CI 1.09 to 1.87). Prednisone use at time-zero was associated with over 1.5-fold increase in flare risk in all HCQ subcohorts. CONCLUSIONS: SLE flare risk was higher after HCQ taper/discontinuation versus HCQ maintenance. Decisions to maintain, reduce or stop HCQ may affect specific subgroups differently, including those on prednisone and/or with low education. Further study of special groups (eg, seniors) may be helpful.

Hydroxychloroquine and azithromycin used alone or combined are not effective against SARS-CoV-2 ex vivo and in a hamster model.

Drug repositioning has been used extensively since the beginning of the COVID-19 pandemic in an attempt to identify antiviral molecules for use in human therapeutics. Hydroxychloroquine and azithromycin have shown inhibitory activity against SARS-CoV-2 replication in different cell lines. Based on such in vitro data and despite the weakness of preclinical assessment, many clinical trials were set up using these molecules. In the present study, we show that hydroxychloroquine and azithromycin alone or combined does not block SARS-CoV-2 replication in human bronchial airway epithelia. When tested in a Syrian hamster model, hydroxychloroquine and azithromycin administrated alone or combined displayed no significant effect on viral replication, clinical course of the disease and lung impairments, even at high doses. Hydroxychloroquine quantification in lung tissues confirmed strong exposure to the drug, above in vitro inhibitory concentrations. Overall, this study does not support the use of hydroxychloroquine and azithromycin as antiviral drugs for the treatment of SARS-CoV-2 infections.

Clinical Characteristics and Outcomes of COVID-19 in Turkish Patients with Hematological Malignancies

Objective: Patients with solid malignancies are more vulnerable to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection than the healthy population. The outcome of SARS-CoV-2 infection in highly immunosuppressed populations, such as in patients with hematological malignancies, is a point of interest. We aimed to analyze the symptoms, complications, intensive care unit admissions, and mortality rates of patients with hematological malignancies infected with SARS-CoV-2 in Turkey. Materials and Methods: In this multicenter study, we included 340 adult and pediatric patients diagnosed with SARS-CoV-2 from March to November 2020. Diagnosis and status of primary disease, treatment schedules for hematological malignancies, time from last treatment, life expectancy related to the hematological disease, and comorbidities were recorded, together with data regarding symptoms, treatment, and outcome of SARS-CoV-2 infection. Results: Forty four patients were asymptomatic at diagnosis of SARS-CoV- 2 infection. Among symptomatic patients, fever, cough, and dyspnea were observed in 62.6%, 48.8%, and 41.8%, respectively. Sixty-nine (20%) patients had mild SARS-CoV-2 disease, whereas moderate, severe, and critical disease was reported in 101 (29%), 71 (20%), and 55 (16%) patients, respectively. Of the entire cohort, 251 (73.8%) patients were hospitalized for SARS-CoV-2. Mortality related to SARS-CoV-2 infection was 26.5% in the entire cohort; this comprised 4.4% of those patients with mild disease, 12.4% of those with moderate disease, and 83% of those with severe or critical disease. Active hematological disease, lower life expectancy related to primary hematological disease, neutropenia at diagnosis of SARS-CoV-2, ICU admission, and first-line therapy used for coronavirus disease-2019 treatment were found to be related to higher mortality rates. Treatments with hydroxychloroquine alone or in combination with azithromycin were associated with a higher rate of mortality in comparison to favipiravir use. Conclusion: Patients with hematological malignancy infected with SARS-CoV-2 have an increased risk of severe disease and mortality.

Comparison of individual and combination treatments with naproxen, prednisolone and hydroxychloroquine to treat Complete Freund's Adjuvant induced arthritis.

Aim of this study was to evaluate and compare the efficacy of anti-arthritic drugs (naproxen, prednisolone, and hydroxychloroquine) alone and in combination. The in vitro anti-arthritic activity was evaluated by stabilization of human erythrocytes (HRBCs) membrane assays. In vivo activity was carried out using Complete Freund's Adjuvant (CFA) induced arthritic model in Wistar rat. Individual and combination drugs were administered for 21 days in rats 8 days post inoculation with CFA (0.15 ml injected in right hind paw). Body weight and paw edema were measured at different intervals. Combination treatments exhibited more HRBC stabilization than individual treatments. All individual and combination treatments reduced the level of C-reactive protein (CRP), liver function enzymes, malondialdehyde, white blood cells and platelets, with the most pronounced activity exhibited by the combination of three drugs. The level of oxidative stress biomarkers (reduced glutathione, catalase, and superoxide dismutase), red blood cells, and hemoglobin were notably increased in all treatment groups in contrasts to diseased control rats. Histopathological evaluation of the paw showed that all the treatments had reduced (p < 0.05-0.001) the arthritic indices in contrasts to diseased control rats. The serum concentrations of TNF-α and PGE2 were provoked in diseased control rats but had been notably (p < 0.0001) restored by treatments with individual and combination drugs. It was also found that combination treatments, more precisely triple drug was remarkably effective in treating arthritis. It can be concluded that naproxen, prednisolone, and hydroxychloroquine effectively ameliorated the CFA-induced arthritis and were more effective in combination as compared to individual drug therapy probably due to reduction in oxidative stress and inflammatory markers. Moreover, two lower doses (half NPH/2 and one-third NPH/3) of triple combination therapy naproxen, prednisolone, and hydroxychloroquine (NPH) showed no significant difference in anti-arthritic effect as compared to the highest dose level of NPH.

[Chronic inflammatory bowel diseases: what happens when SARS-CoV-2 occurs? Preliminary results from a study conducted at the Hassan II University Teaching Hospital in Fes, Morocco (a case report)]. / Les maladies inflammatoires chroniques de l'intestin: que se passe-t-il quand le SARS-CoV-2 arrive? Résultats préliminaires du Centre Hospitalier Universitaire Hassan II de Fès, Maroc (à propos d'un cas).

SARS-CoV-2 infection is a major concern and a new threat to immunocompromised patients. Patients with chronic inflammatory bowel diseases (IBDs) are at increased risk of infections, in particular when they have active disease and are on immunosuppressive treatment. The purpose of this study was to assess the clinical, biological and radiological features of three patients with COVID-19 associated with chronic IBD as well as their management and outcomes. The study was conducted at the Hassan II University Teaching Hospital in Fes, Morocco over a 3-month period. We assessed all patients with disease onset. All patients had mild symptoms or were asymptomatic. No changes or delays in treatment regimens occurred and none of patients developed severe COVID-19. Reverse transcription polymerase chain reaction (RT-PCR) test results were positive in all patients. Radiological examinations were conducted. Chest scanner showed ground-glass opacities in one case. Treatment was based on hydroxychloroquine with azithromycin. Outcome was good in all cases. This preliminary report suggests that patients with chronic IBD aren't at higher risk of developing COVID-19 compared to the general population.