Neurorretinitis bilateral y nefritis lúpica membranosa: dos manifestaciones infrecuentes en el lupus juvenil / Bilateral neuroretinitis and membranous lupus nephritis: 2 infrequent manifestations in juvenile lupus

Joven de 15 años, previamente sana, se presentó con dolor abdominal, vómitos, diarrea, eritema malar, edema palpebral y en miembros inferiores, artralgias, rigidez matinal y visión borrosa bilateral. Estudios de laboratorio y por imágenes junto con la clínica permitieron realizar el diagnóstico de síndrome nefrótico secundario a lupus eritematoso sistémico. Al examen oftalmológico se constató 8/10 de visión en ambos ojos y edema de papila bilateral con estrella macular parcial, hallazgos compatibles con una neurorretinitis bilateral. La biopsia renal estableció el diagnóstico de nefritis lúpica membranosa. Se inició tratamiento inmunosupresor, con mejoría clínica gradual. Si bien el lupus eritematoso sistémico con nefritis lúpica membranosa y neurorretinitis es una asociación muy infrecuente, frente a un paciente con neurorretinitis bilateral debemos considerar el lupus eritematoso sistémico dentro de los diagnósticos diferenciales (AU)

Fifteen-year-old female patient, previously healthy, referred to our center for presenting abdominal pain, vomiting, diarrhea, malar erythema, palpebral and lower limb edema, arthralgia, morning stiffness and bilateral blurred vision. Laboratory and imaging studies together with the clinic allowed the diagnosis of nephrotic syndrome secondary to systemic lupus erythematosus. Ophthalmology examination revealed a visual acuity of 8/10 in both eyes and bilateral disc edema with partial macular star, findings compatible with bilateral neuroretinitis. Renal biopsy established the diagnosis of membranous lupus nephritis. Immunosuppressive treatment was started, obtaining gradual clinical improvement. Although systemic lupus erythematosus with membranous lupus nephritis and neuroretinitis is a very infrequent association, when faced with a patient with bilateral neuroretinitis, we must consider systemic lupus erythematosus within the differential diagnoses (AU)

The effects of hydroxychloroquine on pregnancy outcomes in infertile women: a systematic review and meta-analysis.

A promising strategy for controlling repeated implantation failure (RIF) may be the use of hydroxychloroquine (HCQ). To the best of our knowledge, no systematic review has been conducted on the effects of hydroxychloroquine on pregnancy outcomes. A systematic research of the following electronic databases was conducted: Cochrane, EMBASE-Ovid, PubMed, Web of Science, and Scopus from inception to December 2021, using the following keywords [hydroxychloroquine] AND [infertility]. Fertilization and rate of live birth were significantly higher in the HCQ+ prednisone (PDN) group than in the PDN alone group. However, the abortion rate was not different between the two groups. The meta-analysis of two studies revealed no statistical significance between the PDN group and HCQ+PDN group regarding clinical pregnancy rate (OR=.14 [95%CI: 0.4-4.370]; heterogeneity; P=0.13; I2=54%; random effect model) and implantation rate (OR=1.99 [95%CI: 0.94-4.2]; heterogeneity; P=0.37; I2=0%; fixed-effect model). While HCQ may help improve fertilization and live birth rates, adding it to prednisone did not improve overall pregnancy outcomes. This systematic review should be used with caution due to the small size, study design, and difference in the studies' population.

Concerted and multidisciplinary management of COVID-19 drug therapies during the first two epidemic waves in a tertiary hospital in Marseille, France: Results of the PHARMA-COVID study.

OBJECTIVES: To evaluate the impact of local therapeutic recommendation updates made by the COVID multidisciplinary consultation meeting (RCP) at the Hôpital Européen Marseille (HEM) through the description of the drug prescriptions for COVID-19 during the first two waves of the epidemic. METHODS: This retrospective observational study analysed data from the hospital's pharmaceutical file. We included all patients hospitalized for COVID-19 between February 1, 2020 and January 21, 2021 and extracted specific anti-COVID-19 therapies (ST) from computerized patient record, as well as patients' demographic characteristics, comorbidities and outcome. The evolution of ST prescriptions during the study period was described and put into perspective with the updates of local recommendations made during the first (V1, from 2/24/2020 to 7/27/2020), and second (V2, from 7/28/2020 to 1/21/2021) epidemic waves. RESULTS: A total of 607 COVID-19 hospitalized patients, 197 during V1 and 410 during V2. Their mean age was 65 years-old, and they presented frequent comorbidities. In total, 93% of hospitalized patients received ST: anticoagulants (90%), glucocorticoids (39%) mainly during V2 (49% vs 17%, P<0.001), and azithromycin (30%) mainly during V1 (71% vs 10%, P<0.001). Lopinavir/ritonavir and hydroxychloroquine were prescribed to 17 and 7 inpatients, respectively, and only during V1. Remdesivir was never administered. A total of 22 inpatients were enrolled into clinical trials. CONCLUSIONS: The effective dissemination of evidence-based and concerted recommendations seems to have allowed an optimized management of COVID-19 drug therapies in the context of this emerging infection with rapidly evolving therapeutic questions.

[Multiform exudative erythema caused by hydroxychloroquine, diagnosed by epicutaneous tests: A case report]. / Eritema exudativo multiforme provocado por hidroxicloroquina, diagnosticado mediante pruebas epicutáneas: reporte de un caso.

INTRODUCTION: Multiform exudative erythema is a rare delayed hypersensitivity reaction associated with medications. The manifestations caused by hydroxychloroquine are exceptional; however, due to the increase in its prescription due to the recent SARS-CoV-2 pandemic, adverse reactions have been exacerbated. CASE REPORT: A 60-year-old female patient, who attended the Emergency Department for a picture of erythematous rash of one week of evolution, with involvement of the trunk, face and palms of the hands. Laboratory studies reported: leukocytosis with neutrophilia and lymphopenia, without eosinophilia or abnormal liver enzymes. The lesions continued to descend towards her extremities, with subsequent desquamation. She was prescribed prednisone 15 mg/24 h for three days, tapering to 10 mg/24 h, until her new assessment, in addition to antihistamines. Two days later, new macular lesions appeared in the presternal area and on the oral mucosa. Control laboratory studies did not show alterations. Skin biopsy reported: vacuolar interface dermatitis with spongiosis and parakeratosis, compatible with erythema multiforme. Epicutaneous tests were carried out with meloxicam and 30% hydroxychloroquine in water and vaseline, occluded for two days and interpreted at 48 and 96 hours, with a positive result for the latter. The diagnosis of multiform exudative erythema due to hydroxychloroquine was established. CONCLUSIONS: This study confirms the efficacy of patch tests in patients with delayed hypersensitivity reactions to hydroxychloroquine.

INTRODUCCIÓN: El eritema exudativo multiforme es una reacción de hipersensibilidad retardada poco frecuente asociada con medicamentos. Las manifestaciones provocadas por hidroxicloroquina son excepcionales; sin embargo, debido al incremento de su prescripción, por la reciente pandemia de SARS-CoV-2, las reacciones adversas se han exacerbado. REPORTE DE CASO: Paciente femenina de 60 años, que acudió al servicio de Urgencias por un cuadro de exantema eritematoso de una semana de evolución, con afectación hacia el tronco, la cara y las palmas de las manos. Los estudios de laboratorio informaron: leucocitosis con neutrofilia y linfopenia, sin eosinofilia ni alteración de las enzimas hepáticas. Las lesiones continuaron descendiendo hacia las extremidades, con posterior descamación. Se le indicó prednisona 15 mg/24 h durante tres días, con disminución a 10 mg/24 h, hasta su nueva valoración, además de antihistamínicos. Dos días posteriores aparecieron nuevas lesiones maculares en la zona preesternal y en la mucosa oral. Los estudios de laboratorio de control no mostraron alteraciones. La biopsia cutánea informó: dermatitis de interfase vacuolar con espongiosis y paraqueratosis, compatible con eritema multiforme. Se llevaron a cabo pruebas epicutáneas con meloxicam e hidroxicloroquina al 30% en agua y vaselina, ocluidos dos días e interpretados a las 48 y 96 horas, con resultado positivo para esta última. Se estableció el diagnóstico de eritema exudativo multiforme por hidroxicloroquina. CONCLUSIONES: Este estudio confirma la eficacia de las pruebas epicutáneas en pacientes con reacciones de hipersensibilidad retardada a hidroxicloroquina.

Salivary gland LAMP3 mRNA expression is a possible predictive marker in the response to hydroxychloroquine in Sjögren's disease.

Hydroxychloroquine (HCQ) is a lysosomotropic agent that is commonly used for treating Sjögren's disease (SjD). However, its efficacy is controversial because of the divergent response to the drug among patients. In a subgroup of SjD patients, lysosome-associated membrane protein 3 (LAMP3) is elevated in expression in the salivary glands and promotes lysosomal dysregulation and lysosome-dependent apoptotic cell death. In this study, chloroquine (CQ) and its derivative HCQ were tested for their ability to prevent LAMP3-induced apoptosis, in vitro and on a mouse model of SjD. In addition, efficacy of HCQ treatment was retrospectively compared between high LAMP3 mRNA expression in minor salivary glands and those with LAMP3 mRNA levels comparable with healthy controls. Study results show that CQ treatment stabilized the lysosomal membrane in LAMP3-overexpressing cells via deactivation of cathepsin B, resulting in decreased apoptotic cell death. In mice with established SjD-like phenotype, HCQ treatment also significantly decreased apoptotic cell death and ameliorated salivary gland hypofunction. Retrospective analysis of SjD patients found that HCQ tended to be more effective in improving disease activity index, symptom severity and hypergammaglobulinemia in patients with high LAMP3 expression compared those with normal LAMP3 expression. Taken together, these findings suggested that by determining salivary gland LAMP3 mRNA level, a patient's response to HCQ treatment could be predicted. This finding may provide a novel strategy for guiding the development of more personalized medicine for SjD.

Hydroxychloroquine protects against autoimmune premature ovarian insufficiency by modulating the Treg/Th17 cell ratio in BALB/c mice.

AIMS: The role of hydroxychloroquine (HCQ) in premature ovarian insufficiency (POI) remains unclear. The purpose of this study was to evaluate the effect of HCQ on ovarian function in mice with POI and to clarify its potential mechanisms. METHODS: POI was induced in mice by injection with zona pellucida 3 peptide (pZP3), and HCQ was administered intragastrically. Stages of the estrous cycle were determined using vaginal cytology. The ovarian structure was observed under a microscope after hematoxylin-eosin staining. The levels of serum hormones and anti-ZP antibody (aZPAb) were measured using enzyme-linked immunosorbent assay (ELISA). The expression levels of CD4, CD45, and ZP2, ZP3 were determined using immunofluorescence and immunohistochemistry, respectively. The T regulatory (Treg)/ T helper 17 (Th17) cell ratio was analyzed using flow cytometry analysis. Western blotting was performed to assess the expression levels of proteins, transcription factors and cytokines. RESULTS: Administration of HCQ to mice with POI greatly restored their estrus cycle. In the treatment group compared to the POI group, estradiol (E2 ) levels were higher, and follicle stimulating hormone (FSH) levels were lower. In addition, following pZP3, HCQ treatment increased ZP2 and ZP3 expression. Additionally, by inhibiting the activation of the TLR7 signaling pathway, HCQ attenuated the infiltration of inflammatory cells and prevented the activated naive CD4+ T cells from developing into Th17 cells. CONCLUSION: Our findings showed that HCQ effectively restored ovarian function by altering the Treg/Th17 cell ratio in mice with POI, indicating that HCQ maybe a promising therapeutic method for patients with POI.

Selective Action of Antimalarial Hydroxychloroquine on the Packing of Phospholipids and Interfacial Water Associated with Lysosomal Model Membranes: A Vibrational Sum Frequency Generation Study.

Understanding the structural change of lysosomal membranes induced by hydroxychloroquine (HCQ) drug is essential as it has been considered as one of the probable mechanisms of its antimalarial action. In this context, vibrational sum frequency generation (VSFG) spectra of the O-H region of water and C-H of the hydrocarbon chain of negatively charged and zwitterionic phospholipids associated with the lysosomal membrane in the absence and presence of different concentrations of HCQ have been measured at the air/water interface. The interfacial water at the negatively charged and zwitterionic lipids gets restructured in the presence of HCQ; however, the mechanism of restructuring is different due to the charge of the head groups of lipids. Interestingly, the presence of HCQ leads to a disorder in the negatively charged lipids, irrespective of their chemical nature, mainly by creating the gauche defect in the hydrocarbon chain of the lipid. In contrast, the ordering of the zwitterionic lipid does not show any appreciable change with the addition of HCQ. The finding on the selectivity of HCQ in affecting the ordering of the lipid depending on its head group charge and restructuring of interfacial water may be useful in understanding the molecular level mechanism of the antimalarial action of HCQ.

A multi-center, open-label, randomized study to explore efficacy and safety of baricitinib in active primary Sjogren's syndrome patients.

BACKGROUND: Primary Sjogren's syndrome (pSS) is a systemic autoimmune disease involving multiple organ systems. The Janus kinase/signal transduction and activator of transcription (JAK/STAT) signaling pathway is a key pathway involving the pathogenesis of pSS. Baricitinib, a selective JAK1 and JAK2 inhibitor, has been approved for treatment of active rheumatoid arthritis and reported in treatment of some other autoimmune diseases including systemic lupus erythematosus. We have found that baricitinib might be effective and safe in pSS in a pilot study. However, there is no published clinical evidence of baricitinib in pSS. Hence, we conducted this randomized study to further explore the efficacy and safety of baricitinib in pSS. METHODS: This is a multi-center, prospective, open-label, randomized study to compare the efficacy of baricitinib + hydroxychloroquine (HCQ) with HCQ alone in pSS patients. We plan to involve 87 active pSS patients with European League Against Rheumatism pSS disease activity index (ESSDAI) ≥ 5 from eight different tertiary centers in China. Patients will be randomized (2:1) to receive baricitinib 4 mg per day + HCQ 400 mg per day or HCQ 400 mg per day alone. We will switch HCQ to baricitinib + HCQ if the patient in the latter group has no ESSDAI response at week 12. The final evaluation will be at week 24. The primary endpoint is the percentage of ESSDAI response, or minimal clinically important improvement (MCII), which was defined as an improvement of ESSDAI at least three points at week 12. The secondary endpoints include EULAR pSS patient-reported index (ESSPRI) response, change of Physician's Global Assessment (PGA) score, serological activity parameters, salivary gland function test, and focus score on labial salivary gland biopsy. DISCUSSION: This is the first randomized controlled study to evaluate the clinical efficacy and safety of baricitinib in pSS. We hope that the result of this study can provide more reliable evidence of the efficacy and safety of baricitinib in pSS. TRIAL REGISTRATION: ClinicalTrials.gov NCT05016297. Registered on 19 Aug 2021.

Recent Update and Drug Target in Molecular and Pharmacological Insights into Autophagy Modulation in Cancer Treatment and Future Progress.

Recent evidence suggests that autophagy is a governed catabolic framework enabling the recycling of nutrients from injured organelles and other cellular constituents via a lysosomal breakdown. This mechanism has been associated with the development of various pathologic conditions, including cancer and neurological disorders; however, recently updated studies have indicated that autophagy plays a dual role in cancer, acting as a cytoprotective or cytotoxic mechanism. Numerous preclinical and clinical investigations have shown that inhibiting autophagy enhances an anticancer medicine's effectiveness in various malignancies. Autophagy antagonists, including chloroquine and hydroxychloroquine, have previously been authorized in clinical trials, encouraging the development of medication-combination therapies targeting the autophagic processes for cancer. In this review, we provide an update on the recent research examining the anticancer efficacy of combining drugs that activate cytoprotective autophagy with autophagy inhibitors. Additionally, we highlight the difficulties and progress toward using cytoprotective autophagy targeting as a cancer treatment strategy. Importantly, we must enable the use of suitable autophagy inhibitors and coadministration delivery systems in conjunction with anticancer agents. Therefore, this review briefly summarizes the general molecular process behind autophagy and its bifunctional role that is important in cancer suppression and in encouraging tumor growth and resistance to chemotherapy and metastasis regulation. We then emphasize how autophagy and cancer cells interacting with one another is a promising therapeutic target in cancer treatment.

COVID-19: Understanding the impact of anti-hypertensive drugs and hydroxychloroquine on the ACE1 and ACE2 in lung and adipose tissue in SHR and WKY rats.

Hypertensive individuals taking anti-hypertensive drugs from renin-angiotensin system inhibitors may exhibit a more severe evolution of the disease when contracting the SARS-CoV-2 virus (COVID-19 disease) due to potential increases in ACE2 expression. The study investigated ACE1 and ACE2 axes and hydroxychloroquine in the lungs and adipose tissue of male and female normotensive Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHRs). SHRs were treated with losartan (10 mg/kg/day) or captopril (10 mg/kg/day) for 14 days or 7 days with hydroxychloroquine (200 mg/kg/day) in drinking water. WKY rats were also treated for 7 days with hydroxychloroquine. Blood pressure (BP), protein, and mRNA expression of ACE1 and ACE2 were analyzed in serum, adipose, and lung tissues. Losartan and captopril reduced BP in both sexes in SHR, whereas hydroxychloroquine increased BP in WKY rats. Losartan reduced ACE2 in serum and lungs in both sexes and in adipose tissue of male SHRs. Captopril decreased ACE2 protein in the lung of females and in adipose tissue in both sexes of SHRs. Hydroxychloroquine decreased ACE1 and ACE2 proteins in the lungs in both sexes and adipose tissue in male SHRs. In female WKY rats, ACE2 protein was lower only in the lungs and adipose tissue. Losartan effectively inhibited ACE2 in male and captopril in female SHRs. Hydroxychloroquine inhibited ACE2 in male SHRs and female WKY rats. These results further our understanding of the ACE2 mechanism in patients under renin-angiotensin anti-hypertensive therapy and in many trials using hydroxychloroquine for COVID-19 treatment and potential sex differences in response to drug treatment.

Novel Tetrahydroisoquinoline-Based Heterocyclic Compounds Efficiently Inhibit SARS-CoV-2 Infection In Vitro.

The ongoing COVID-19 pandemic has caused over six million deaths and huge economic burdens worldwide. Antivirals against its causative agent, SARS-CoV-2, are in urgent demand. Previously, we reported that heterocylic compounds, i.e., chloroquine (CQ) and hydroxychloroquine (HCQ), are potent in inhibiting SARS-CoV-2 replication in vitro. In this study, we discussed the syntheses of two novel heterocylic compounds: tert-butyl rel-4-(((3R,4S)-3-(1H-indol-3-yl)-1-oxo-2-propyl-1,2,3,4-tetrahydroisoquinolin-4-yl)methyl)piperazine-1-carboxylate (trans-1) and rel-(3R,4S)-3-(1H-indol-3-yl)-4-(piperazin-1-ylmethyl)-2-propyl-3,4-dihydroisoquinolin-1(2H)-one (trans-2), which effectively suppressed authentic SARS-CoV-2 replication in Vero E6 cells. Compound trans-1 showed higher anti-SARS-CoV-2 activity than trans-2, with a half maximal effective concentration (EC50) of 3.15 µM and a selective index (SI) exceeding 63.49, which demonstrated comparable potency to CQ or HCQ. Additional anti-SARS-CoV-2 tests on Calu-3 human lung cells showed that trans-1 efficiently inhibited viral replication (EC50 = 2.78 µM; SI: > 71.94) and performed better than CQ (EC50 = 44.90 µM; SI = 2.94). The time of an addition assay showed that the action mechanism of trans-1 differed from that of CQ, as it mainly inhibited the post-entry viral replication in both Vero E6 and Calu-3 cells. In addition, the differences between the antiviral mechanisms of these novel compounds and CQ were discussed.

Affinity binding of COVID-19 drug candidates (chloroquine/hydroxychloroquine) and serum albumin: Based on photochemistry and molecular docking.

Chloroquine (CQ) and hydroxychloroquine (HCQ) show good efficacy in the treatment of SARS-CoV-2 in the early stage, while they are no longer recommended due to their side effects. As an important drug delivery carrier, serum albumin (SA) is closely related to the efficacy of drugs. Here, the affinity behaviour of chloroquine and hydroxychloroquine with two SA were investigated through the multispectral method of biochemistry and computer simulation. The results showed that the intrinsic emission of both SA was quenched by CQ and HCQ in a spontaneous exothermic entropy reduction static process, which relied mainly on hydrogen bonding and van der Waals forces. The lower binding constants suggested weak binding between the two drugs and SA, which might lead to differences in efficacy and possibly even to varying side effects. Binding site recognition demonstrated that CQ preferred to bind to the two sites of both SA, while HCQ tended to bind to site I of SA. The results of conformational studies demonstrated that CQ and HCQ could affect the structure of both SA by slightly increasing the α-helix content of SA. Finally, we combine the results from experimental start with molecular simulations to suggest drug modifications to guide the design of drugs. This work has important implications for guiding drug design improvements to select CQ derivatives with fewer side effects for the treatment of COVID-19.

Hydroxychloroquine to prevent SARS-CoV-2 infection among healthcare workers: early termination of a phase 3, randomised, open-label, controlled clinical trial.

OBJECTIVE: To assess the effectiveness and safety of hydroxychloroquine (HCQ) prophylaxis for the prevention of SARS-CoV-2 infection in healthcare workers (HCW) on duty during the COVID-19 pandemic. RESULTS: A total of 68 HCWs met the eligibility criteria were randomly allocated to receive HCQ (n = 36) or not (n = 32). There were no significant differences between groups in respects to age, gender, or medical history. Eight participants met the primary efficacy endpoint of SAR-CoV-2 infection during the study period; there was no difference in incidence of SARS-CoV-2 infections between both study arms (HCQ: 5 vs Control: 3, p = 0.538). The relative risk of SARS-CoV-2 infection in the HCQ arm was 1.69 compared to the control group (95%CI 0.41-7.11, p = 0.463); due to poor participant accrual, the resulting statistical power of the primary efficacy outcome was 11.54%. No serious adverse events occurred; however, two (2/36, 5.6%) participants no longer wished to participate in the study and withdrew consent due to recurring grade 1 and 2 adverse events. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT04414241. (Registered on June 4, 2020).

Hydroxychloroquine retinopathy screening guidelines: a false positive.

Hydroxychloroquine sulphate (HCQ) is widely used for the treatment of a variety of rheumatological and dermatological conditions. Despite the advantages of HCQ as a treatment option, it is important to be aware of its potential retinal toxicity, which may be irreversible and progressive. In December 2020, The Royal College of Ophthalmologists published revised recommendations on monitoring HCQ retinopathy. Our case report highlights some of the shortcomings of blindly following their monitoring algorithm by presenting a case where apparent HCQ retinopathy resolved after Yttrium Aluminium Garnet (YAG) laser capsulotomy. The case reiterates the importance of thorough clinical examination. We suggest that while the acquisition of the spectral domain optical coherence tomography and fundus autofluorescence may be objective, their interpretation is subjective. Even with the use of artificial intelligence algorithms, false positives may be generated if the tests are confounded by copathology. There is no gold-standard test for detecting HCQ toxicity.

Hydroxychloroquine daily dose, hydroxychloroquine blood levels and the risk of flares in patients with systemic lupus erythematosus.

BACKGROUND: Recent guidelines for SLE recommend using a hydroxychloroquine (HCQ) dose less than 5.0 mg/kg/day to reduce the risk of retinopathy. To determine if this dose reduction would have an impact on the clinical course of SLE, we compared flare incidence in a cohort of patients with SLE treated with two different oral HCQ dosages (≤5 mg/kg/day or >5 mg/kg/day). As a secondary analysis, we compared HCQ blood levels between the two different oral dosages, and evaluated the frequency of non-adherence in patients with SLE treated with HCQ. METHODS: We identified a cohort of patients with SLE taking HCQ for at least 6 months and followed for 24 months. At study entry and 6 months later, a blood venous sample was taken to measure HCQ blood levels by liquid chromatography. Incidence of new SLE flares after recruitment was put in relation to daily HCQ dose and mean HCQ blood levels. Cox regression analysis served to identify factors associated with SLE flares. RESULTS: 83 patients were enrolled. We observed 11 (16%) flares that developed in mean 14.8 months of follow-up. The difference in terms of flare rate and mean HCQ blood levels between the two oral dosages was not statistically significant. There was a trend (p=0.08) for high HCQ dose being associated with a lower flare rate. At Cox analysis, higher HCQ blood levels and older age at baseline were protective against flare occurrence, while concomitant immunosuppressant therapy showed significant positive association. HCQ blood levels did not correlate with prescribed HCQ dose. CONCLUSION: Patients with low oral HCQ dosage tend to have more flares, although the difference was not statistically significant. Higher HCQ blood levels were protective against flare occurrence. The risks and benefits must be balanced in choosing HCQ dose.

The 'myth of Hydroxychloroquine (HCQ) as post-exposure prophylaxis (PEP) for the prevention of COVID-19' is far from reality.

The efficacy of Hydroxychloroquine (HCQ) as post-exposure prophylaxis (PEP) for the prevention of COVID-19 was contentious. In this randomized control double-blind clinical trial, asymptomatic individuals with direct contact with laboratory-confirmed COVID-19 cases were randomized into PEP/HCQ (N = 574) and control/placebo (N = 594) group. The PEP/HCQ group received tablet HCQ 400 mg q 12 hourly on day one followed by 400 mg once weekly for 3 weeks, and the control/Placebo group received matching Placebo. The incidence of COVID-19 was similar (p = 0.761) in PEP [N = 24 out of 574, (4.2%)] and control [N = 27 out of 594, (4.5%)] groups. Total absolute risk reduction for the incidence of new-onset COVID-19 was -0.3% points with an overall relative risk of 0.91 (95% confidence interval, 0.52 to 1.60) and the number needed to treat (NNT) was 333 to prevent the incident of one case of COVID-19. The study found that, PEP with HCQ was not advantageous for the prevention of COVID-19 in asymptomatic individuals with high risk for SARS-CoV-2 infection. Though HCQ is a safer drug, the practice of irrational and indiscriminate use of HCQ for COVID-19 should be restrained with better pharmacovigilance.

MYC-mediated resistance to trametinib and HCQ in PDAC is overcome by CDK4/6 and lysosomal inhibition.

Pharmacological inhibition of KRAS>RAF>MEK1/2>ERK1/2 signaling has provided no clinical benefit to patients with pancreatic ductal adenocarcinoma (PDAC). Interestingly, combined inhibition of MEK1/2 (with trametinib [T]) plus autophagy (with chloroquine [CQ] or hydroxychloroquine [HCQ]) demonstrated striking anti-tumor effects in preclinical models and in a patient (Patient 1). However, not all patients respond to the T/HCQ regimen, and Patient 1 eventually developed resistant disease. Here we report that primary or acquired resistance is associated with focal DNA copy number gains encompassing c-MYC. Furthermore, ectopic expression of c-MYC in PDAC cell lines rendered them T/HCQ resistant. Interestingly, a CDK4/6 inhibitor, palbociclib (P), also induced autophagy and overrode c-MYC-mediated T/HCQ resistance, such that P/HCQ promoted regression of T/HCQ-resistant PDAC tumors with elevated c-MYC expression. Finally, P/HCQ treatment of Patient 1 resulted in a biochemical disease response. These data suggest that elevated c-MYC expression is both a marker and a mediator of T/HCQ resistance, which may be overcome by the use of P/HCQ.