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.

Randomized Trial of Ciprofloxacin Doxycycline and Hydroxychloroquine Versus Budesonide in Active Crohn's Disease.

BACKGROUND: Increased mucosa-associated E. coli are present in Crohn's disease, but their role in pathogenesis is uncertain. AIMS: To assess efficacy and safety of an antibiotic/hydroxychloroquine combination effective against E. coli inside macrophages. METHODS: Adults with moderately active disease (CDAI > 220-450 plus C reactive protein ≥ 5 mg/l and/or fecal calprotectin > 250 µg/g) were randomized to receive (open-label) oral budesonide (Entocort CR 9 mg/day 8 weeks, 6 mg/day 2 weeks, 3 mg/day 2 weeks) or oral ciprofloxacin 500 mg bd, doxycycline 100 mg bd, hydroxychloroquine 200 mg tds for 4 weeks, followed by doxycycline 100 mg bd and hydroxychloroquine 200 mg tds for 20 weeks. Primary endpoints were remission (CDAI ≤ 150) at 10 weeks, remission maintained to 24 weeks, and remission maintained to 52 weeks. Patients not responding (CDAI fall by > 70) by 10 weeks were invited to crossover onto the alternative therapy. RESULTS: Fifty-nine patients were recruited across 8 sites. Including crossover, 39 patients received antibiotics/hydroxychloroquine and 39 received budesonide. At 10 weeks, 24 weeks, and 52 weeks on initial therapy, only 2/27, 2/27, and 1/27 were in remission on antibiotics/hydroxychloroquine compared with 8/32, 1/32, and 1/32 on budesonide (P = 0.092 at 10 weeks). Withdrawals by 10 weeks due to adverse events were seen in 15 receiving antibiotics/hydroxychloroquine and 6 budesonide. Results including crossover were more promising with 9/24 patients receiving antibiotics/hydroxychloroquine per protocol in remission by 24 weeks. No correlation was seen between response to antibiotics/hydroxychloroquine and ASCA/OmpC antibody status or disease location. CONCLUSION: Overall results with this antibiotic/hydroxychloroquine combination were unimpressive, but long-term remission is seen in some patients and justifies further study.

Combination treatments with hydroxychloroquine and azithromycin are compatible with the therapeutic induction of anticancer immune responses.

Amid controversial reports that COVID-19 can be treated with a combination of the antimalarial drug hydroxychloroquine (HCQ) and the antibiotic azithromycin (AZI), a clinical trial (ONCOCOVID, NCT04341207) was launched at Gustave Roussy Cancer Campus to investigate the utility of this combination therapy in cancer patients. In this preclinical study, we investigated whether the combination of HCQ+AZI would be compatible with the therapeutic induction of anticancer immune responses. For this, we used doses of HCQ and AZI that affect whole-body physiology (as indicated by a partial blockade in cardiac and hepatic autophagic flux for HCQ and a reduction in body weight for AZI), showing that their combined administration did not interfere with tumor growth control induced by the immunogenic cell death inducer oxaliplatin. Moreover, the HCQ+AZI combination did not affect the capacity of a curative regimen (cisplatin + crizotinib + PD-1 blockade) to eradicate established orthotopic lung cancers in mice. In conclusion, it appears that HCQ+AZI does not interfere with the therapeutic induction of therapeutic anticancer immune responses.

Does zinc supplementation enhance the clinical efficacy of chloroquine/hydroxychloroquine to win today's battle against COVID-19?

Currently, drug repurposing is an alternative to novel drug development for the treatment of COVID-19 patients. The antimalarial drug chloroquine (CQ) and its metabolite hydroxychloroquine (HCQ) are currently being tested in several clinical studies as potential candidates to limit SARS-CoV-2-mediated morbidity and mortality. CQ and HCQ (CQ/HCQ) inhibit pH-dependent steps of SARS-CoV-2 replication by increasing pH in intracellular vesicles and interfere with virus particle delivery into host cells. Besides direct antiviral effects, CQ/HCQ specifically target extracellular zinc to intracellular lysosomes where it interferes with RNA-dependent RNA polymerase activity and coronavirus replication. As zinc deficiency frequently occurs in elderly patients and in those with cardiovascular disease, chronic pulmonary disease, or diabetes, we hypothesize that CQ/HCQ plus zinc supplementation may be more effective in reducing COVID-19 morbidity and mortality than CQ or HCQ in monotherapy. Therefore, CQ/HCQ in combination with zinc should be considered as additional study arm for COVID-19 clinical trials.

Renoprotective effects of artemisinin and hydroxychloroquine combination therapy on IgA nephropathy via suppressing NF-κB signaling and NLRP3 inflammasome activation by exosomes in rats.

Immunoglobulin A nephropathy (IgAN) is an autoimmune kidney disease with complex pathogenesis leading to end-stage renal damage. The prime pathological characteristics of IgAN are IgA immune complexes deposition accompany with mesangial cell proliferation and urine protein elevation. Artemisinin (ART) is extracted from traditional Chinese medicine Artemisia annua L. Hydroxychloroquine (HCQ) is a classical antimalarial drug applied in the treatment of autoimmune diseases. Both of them possess anti-inflammatory and immunomodulatory properties. The purpose of this research was to investigate the pharmacological effects of ART combined with HCQ (AH) and discuss thoroughly the potential molecular mechanisms in IgAN. In vivo, our results demonstrated that AH could efficiently ameliorate kidney damage by improving kidney dysfunction and reducing the levels of 24 h urine protein, IgA and IgG immune complexes deposition in glomerulus of IgAN rats. Interestingly, AH obviously promoted the secretion of exosomes in renal tissues, inhibited the expressions of nuclear factor-κB (NF-κB) signaling and NLRP3 inflammasome-related proteins, including IκB-α, p-p65, NLRP3, ASC, IL-1ß and caspase-1 in IgAN rats. In vitro, further mechanistic study illustrated that exosomes derived from human renal tubular epithelial cells (HK-2) were significantly enhanced by AH, which could be utterly taken up in human mesangial cells (HMCs) and inhibited the activation of NF-κB pathway and NLRP3 inflammasome after AH intervention. However, GW4869 interdicted the promotive effect of AH on exosomes from HK-2 cells and the suppression of exosomes on NF-κB/NLRP3 activation in HMCs. Taken together, this study demonstrated that there was an inhibitory effect of AH therapy on NF-κB/NLRP3 signaling via mediating exosomes release in IgAN rats, which provided an alternative approach for IgAN treatment.

Adherence to Hydroxychloroquine Dosing Guidelines by Rheumatologists: An Electronic Medical Record-Based Study in an Integrated Health Care System.

PURPOSE: To study the adherence of rheumatologists to the hydroxychloroquine (HCQ) dosing guidelines established by the American Academy of Ophthalmology in 2011 and 2016. DESIGN: Retrospective review of electronic medical records (EMRs) in an integrated health care system. PARTICIPANTS: All rheumatology patients started on HCQ who were seen by a NorthShore ophthalmologist between the years 2009 and 2016. METHODS: Data on patient weights, height, gender, and HCQ dosage were extracted from the EMR. The recommended maximum starting dose was determined using 2 formulas based on ideal or actual body weight. MAIN OUTCOME MEASURES: The percentage of patients whose dose exceeded the recommended maximum. RESULTS: A total of 554 patients on HCQ were identified. Some 50% of the patients had been placed on excess initial doses according to the 2011 guidelines, and 47% of the patients had been placed on excess initial doses according to the 2016 guidelines. The introduction of the guidelines had no appreciable effect on HCQ dosing. A separate analysis of all patients currently receiving maintenance HCQ therapy demonstrated excess dosing in 297 of 527 (56%), according to the 2016 guidelines. CONCLUSIONS: Approximately one half of all patients started on HCQ by NorthShore rheumatologists received doses in excess of the recommended maximum, and slightly more than one-half of all patients currently on treatment continue to receive excess doses. Our data suggest that the publication of the consensus guidelines in 2011 had no appreciable effect on HCQ dosing and that transitioning to the 2016 dosing modification is unlikely to change this outcome unless additional steps are taken to improve adherence.

Effect of Chinese herbal medicines for nourishing yin, supplementing qi, and activating blood on reproductive endocrine activity and immune functions in patients with primary Sjogren's syndrome.

OBJECTIVE: To investigate the effect of Chinese herbal medicines for nourishing yin, supplementing qi, and activating blood on the reproductive endocrine-immune network and its mechanisms in patients with primary Sjogren's syndrome (pSS). METHODS: Seventy pSS patients were randomly assigned to two groups using a randomized digital table: the integrative therapy group (36 cases) and the control group (34 cases). Thirty healthy subjects were taken as a normal group. The control group was treated with hydroxychloroquine sulfate tablets alone, and the integrative therapy group was treated by Chinese herbal medicines for nourishing yin, supplementing qi, and activating blood combined with hydroxychloroquine sulfate tablets. The treatment course was 6 months for both groups. Before and after treatment, serum estradiol (E2), testosterone (T), luteinizing hormone (LH), prolactin (PRL) by radioimmunoassay and immunoglobulin (IgG) by immunodiffusion, erythrocyte sedimentation rate (ESR) by Westergren, interferon-γ (IFN-γ) and interleukin-4 (IL-4) by enzyme linked immunosorbent assay were determined. RESULTS: E2 and T levels in all patients were lower than those of normal subjects before treatment (P<0.05) and were increased significantly after 6-month treatment (P<0.05). ESR, FSH, LH, IgG, IFN - γ, IL - 4 and ratios of E2/T, and IFN -γ/IL in the patients were higher than those of normal subjects before the treatments (P<0.05), and were reduced significantly after the treatments (P<0.05). The T and IFN - γ levels and E2/T ratio in the patients treated with integrative therapy were reduced significantly compared with the control group (P<0.05). However, the PRL levels before and after treatment were not significantly changed in the two groups (P>0.05). The ratios of E2/T and IFN -γ/IL-4, and levels of IgG and ESR were positively correlated before and after treatment (P<0.05). CONCLUSIONS: The ratios of E2/T and IFN -γ/IL-4 might be used as indicators of pSS activity. Chinese herbal medicines for nourishing yin, supplementing qi, and activating blood combined with Western medicine could improve the therapeutic effect by regulating the reproductive endocrine-immune network in pSS patients.

Subacute cutaneous lupus erythematosus: a case report of Polypodium leucotomos as an adjuvant therapy.

Subacute cutaneous lupus erythematosus (SCLE) is an uncommon autoimmune disease that results in substantial photosensitivity of affected patients. Eruptions often are triggered or exacerbated by UV light (UVL) exposure. We present a case of a patient with SCLE who was moderately controlled with hydroxychloroquine sulfate but achieved near total remission of disease after the addition of oral Polypodium leucotomos supplement which has photoprotective effects on human keratinocytes. We report sustained clinical response with the use of P leucotomos in lupus and suggest that it may have future application in photosensitizing dermatoses.

Conventional combination treatment versus biological treatment in methotrexate-refractory early rheumatoid arthritis: 2 year follow-up of the randomised, non-blinded, parallel-group Swefot trial.

BACKGROUND: Analysis of the Swedish Farmacotherapy (Swefot) trial at 12 months showed that the addition of an anti-tumour-necrosis-factor agent gave an improved clinical outcome compared with the addition of conventional disease-modifying antirheumatic drugs in patients with methotrexate-refractory early rheumatoid arthritis. Here we report the 2 year follow-up assessment. METHODS: In this randomised, non-blinded, parallel-group trial, we enrolled adult patients older than 18 years with rheumatoid arthritis and a symptom duration of less than 1 year from 15 rheumatology units in Sweden between December, 2002 and December, 2006. All patients were started on methotrexate. After 3-4 months, those who failed treatment were randomly assigned (1:1) to group A (conventional treatment; additional sulfasalazine and hydroxychloroquine) or group B (biological treatment; additional infliximab). Randomisation was done with a computer-generated sequence. We analysed clinical outcomes at months 18 and 24 by the response criteria of the American College of Rheumatology and the European League Against Rheumatism, and radiographs of patients' hands and feet at months 12 and 24 using the Van der Heijde modification of the Sharp score. Analysis was by intention to treat. This trial is registered with www.ClinicalTrials.gov, number NCT00764725. FINDINGS: Of 493 screened individuals, we enrolled 487, of whom 258 were randomly allocated to treatment. The proportion of patients in group B who received a EULAR-defined good response was non-significantly greater than it was in group A at 18 months (49 of 128 [38%] vs 38 of 130 [29%]) and at 24 months (49 of 128 [38%] vs 40 of 130 [31%]; p=0·204). After 24 months, radiological disease progression was greater in patients in group A than it was in those in group B (mean 7·23 [SD 12·72] vs 4·00 [10·0]; p=0·009). We recorded three serious adverse events: an extended generalised illness in group A, an extended febrile episode in group B, and a generalised illness in group B. INTERPRETATION: Additional biological treatment is a valid option for patients who fail initial methotrexate treatment. However, improved clinical outcomes after 12 months and better radiographical results after 24 months should be weighed against the absence of a convincing clinical difference at 24 months and substantially higher costs. Therefore, for many patients who fail initial methotrexate treatment, add-on treatment with disease-modifying antirheumatic drugs is an appropriate treatment option. FUNDING: Swedish Rheumatism Association, Stockholm County, and Schering-Plough/Merck Sharp and Dohme.

Systemic lupus erythematosus complicated with femoral head ischemic necrosis treated by Chinese medicine therapy for activating blood and dredging collaterals method.

OBJECTIVE: To observe the effect and mechanism of Chinese medicine therapy for activating blood and dredging collaterals (ABDC) on treating systemic lupus erythematosus complicated with avascular necrosis of the femoral head (SLE-ANFH). METHODS: Thirty-four patients (51 joints) with SLE-ANFH were assigned by a random number table to two groups: 22 patients (32 joints) in the treatment group and 12 patients (19 joints) in the control group. All received Western medical conventional treatment for anti-inflammation and immunosuppression, but an additional Chinese medicine decoction prescribed based on ABDC principle was administered to patients in the treatment group. The observation on the patients' condition and therapeutic effect lasted for 3 years. RESULTS: The patients' conditions in the two groups, as assessed by Association for Research Circulation Osseous (ARCO) staging, were similar before treatment. After treatment, comparison between groups showed significant difference (P<0.05), and the raised Harris functional scores in the treatment group were higher than that in the control group (P<0.01). The post-treatment symptom improving rate in the treated group was 72.73%, which was higher than that in the control group (50.00%, P<0.05). Moreover, the former was superior in improving hematologic and hemorrheologic parameters in terms of prolonging activated partial thromboplastin time, lowering whole blood middle/low shear viscosity, and plasma viscosity (P<0.05 or P<0.01). Two patients in the control group but none in the treatment group received hip joint replacement operation during the observation period. CONCLUSIONS: Chinese medicine ABDC therapy could effectively alleviate clinical symptoms and improve joint function of patients with SLE-ANFH. The mechanism may be related to its effects on improving high coagulation manner and trend for getting embolism.

The good initial response to therapy with a combination of traditional disease-modifying antirheumatic drugs is sustained over time: the eleven-year results of the Finnish rheumatoid arthritis combination therapy trial.

OBJECTIVE: To evaluate the evolution of functional and clinical outcomes over 11 years in patients with early rheumatoid arthritis (RA) initially treated with a combination of 3 disease-modifying antirheumatic drugs (DMARDs) or with a single DMARD. METHODS: A cohort of 199 patients with early active RA were initially randomized to receive treatment with a combination of methotrexate, sulfasalazine, and hydroxychloroquine with prednisolone or treatment with a single DMARD (initially, sulfasalazine) with or without prednisolone. After 2 years, the drug treatment strategy became unrestricted, but still targeted remission. At 11 years, function was assessed with the Health Assessment Questionnaire (HAQ), and clinical outcomes were assessed with the modified Minimal Disease Activity (MDA) measure and the American College of Rheumatology (ACR) criteria for remission. RESULTS: At 11 years, 138 patients were assessed (68 in the combination-DMARD group and 70 in the single-DMARD group). The mean+/-SD HAQ scores were 0.34+/-0.54 in the combination-DMARD group and 0.38+/-0.58 in the single-DMARD group (P=0.88). Modified MDA was achieved by 63% (95% confidence interval [95% CI] 51, 77) and by 43% (95% CI 32, 55) (P=0.016) of the combination-DMARD group and the single-DMARD group, respectively, and ACR remission by 37% (95% CI 26, 49) and by 19% (95% CI 11, 29) (P=0.017), respectively. CONCLUSION: Initial therapy with a combination of DMARDs in early RA results in higher rates of patients achieving modified MDA and strict ACR remission even over the long term than initial single-DMARD therapy. Targeting remission with tight clinical controls results in good functional and clinical outcomes in most RA patients.

[Psoriasis and systemic lupus erythematosus: a rare association with specific therapeutic problems]. / Psoriasis et lupus érythémateux disséminé: une association rare, des problèmes thérapeutiques spécifiques.

The association psoriasis and systemic lupus erythematosus (SLE) is a very uncommon association. We report three cases, diagnosed in an Internal Medicine department between 1993 and 2000. Few cases of psoriasis/SLE have been published in the literature. Psoriasis generally precedes the diagnosis of SLE. Psoriasis can also be associated with discoid lupus erythematosus. In some cases, SLE appears as a complication of ultraviolet phototherapy indicated for the psoriasis. The association psoriasis/SLE does not seem to have distinctive immunologic features. Specific therapeutic difficulties may occur. Indeed, hydroxychloroquine may exacerbate the psoriasis. Systemic use of corticosteroids raises the risk of severe psoriasis relapse during withdrawal. In addition, the diagnosis of psoriasic arthropathy is more difficult in this setting. The psoriasis/SLE association might be a good indication for using methotrexate.

Coexistence of osteopoikilosis and discoid lupus erythematosus: a case report.

Osteopoikilosis is an uncommon, benign sclerosing bone dysplasia characterised by typical roentgenographic findings and usually seen in patients with dermatological problems. We report a case of osteopoikilosis and discoid lupus erythematosus presenting with skin and mucosal involvement, an association that has never previously been reported. We also discuss the differential diagnosis and the clinical pathologies accompanying osteopoikilosis in the literature.

High-dose hydroxychloroquine treatment of porphyria cutanea tarda.

BACKGROUND: High-dose hydroxychloroquine is rarely used in the treatment of porphyria cutanea tarda (PCT). OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety of a novel high-dose hydroxychloroquine regimen in patients with PCT. METHODS: Sixty-five first episodes and 28 recurrent episodes of PCT were treated with hydroxychloroquine, 250 mg three times daily, for 3 days. In patients with a high urine porphyrin concentration a single phlebotomy of 500 ml was performed before therapy of the first episode. Modified high-dose hydroxychloroquine regimens were used in patients with markedly elevated liver transaminases with or without associated chronic liver disease. RESULTS: Long-term follow-up data showed an overall relapse rate of 33%, significantly higher among male patients (45%) than among female patients (17%) (p less than 0.05). A transient hepatotoxic reaction occurred in the majority of patients. The reaction seemed to be especially severe among phlebotomized female patients. CONCLUSION: Hydroxychloroquine, 250 mg three times daily, is a rapid, efficacious, and safe treatment in patients with PCT.