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.

A Monoclonal Antibody for Malaria Prevention.

BACKGROUND: Additional interventions are needed to reduce the morbidity and mortality caused by malaria. METHODS: We conducted a two-part, phase 1 clinical trial to assess the safety and pharmacokinetics of CIS43LS, an antimalarial monoclonal antibody with an extended half-life, and its efficacy against infection with Plasmodium falciparum. Part A of the trial assessed the safety, initial side-effect profile, and pharmacokinetics of CIS43LS in healthy adults who had never had malaria. Participants received CIS43LS subcutaneously or intravenously at one of three escalating dose levels. A subgroup of participants from Part A continued to Part B, and some received a second CIS43LS infusion. Additional participants were enrolled in Part B and received CIS43LS intravenously. To assess the protective efficacy of CIS43LS, some participants underwent controlled human malaria infection in which they were exposed to mosquitoes carrying P. falciparum sporozoites 4 to 36 weeks after administration of CIS43LS. RESULTS: A total of 25 participants received CIS43LS at a dose of 5 mg per kilogram of body weight, 20 mg per kilogram, or 40 mg per kilogram, and 4 of the 25 participants received a second dose (20 mg per kilogram regardless of initial dose). No safety concerns were identified. We observed dose-dependent increases in CIS43LS serum concentrations, with a half-life of 56 days. None of the 9 participants who received CIS43LS, as compared with 5 of 6 control participants who did not receive CIS43LS, had parasitemia according to polymerase-chain-reaction testing through 21 days after controlled human malaria infection. Two participants who received 40 mg per kilogram of CIS43LS and underwent controlled human malaria infection approximately 36 weeks later had no parasitemia, with serum concentrations of CIS43LS of 46 and 57 µg per milliliter at the time of controlled human malaria infection. CONCLUSIONS: Among adults who had never had malaria infection or vaccination, administration of the long-acting monoclonal antibody CIS43LS prevented malaria after controlled infection. (Funded by the National Institute of Allergy and Infectious Diseases; VRC 612 ClinicalTrials.gov number, NCT04206332.).

Malaria epidemiology and anti-malarial drug efficacy in Guinea: a review of clinical and molecular studies.

Malaria is one of the leading causes of mortality and morbidity in Guinea. The entire country is considered at risk of the disease. Transmission occurs all year round with peaks occurring from July through October with Plasmodium falciparum as the primary parasite species. Chloroquine (CQ) was the first-line drug against uncomplicated P. falciparum in Guinea until 2005, prior to the adoption of artemisinin-based combination therapy (ACT). In this review, data on therapeutic efficacy of CQ and artemisinin-based combinations reported in published literature is summarized. Against CQ, a failure rate of 27% (12/44) was reported in a study in 1992; a median failure rate of 15.6% [range: 7.7-28.3; 8 studies] was observed during 1996-2001, and 81% (17/21) of the patients failed to clear parasitaemia in a study conducted in 2007. For artemisinin-based combinations, three published studies were identified (1495 patients; 2004-2016); all three studies demonstrated day 28 polymerase chain reaction corrected efficacy > 95%. One study characterized kelch-13 mutations (389 tested; samples collected in 2016) with no evidence of mutations currently known to be associated with artemisinin resistance. The impact of the ongoing COVID-19 pandemic and widespread usage of counterfeit medicines are immediate challenges to malaria control activities in Guinea.

Challenges for malaria surveillance during the COVID-19 emergency response in Nampula, Mozambique, January - May 2020.

Since the announcement of the coronavirus disease (COVID-19) pandemic in January 30th 2020, 68 countries reported to the World Health Organization that they were experiencing disruptions in malaria diagnosis and treatment. This situation had the potential to lead to delays in diagnosis and treatment, which could result in an increase in severe cases and deaths. This analysis was based on findings from a field visit, carried out between June 30th and July 1st, 2020, to a warehouse, to two health facilities, and a meeting with a community health worker, and an descriptive epidemiologic data analysis of health information system (HIS) to evaluate trends of the number of people tested for malaria and number of malaria cases reported, by comparing data from 2018, 2019 and 2020 for the period between January and May. The two health facilities and the warehouse had about two months of stock of antimalarial drugs, and patients with malaria symptoms were being tested for malaria at the COVID-19 screening site. The HIS data showed that the number of reported malaria cases decreased by 3.0% (177.646/172.246) in April, and 7.0% (173.188/161.812) in May, when comparing 2019 and 2020 data. People tested for malaria in community increased by 39.0% (190.370/264.730), between 2019 and 2020. The COVID-19 may have had a negative impact on the diagnosis and treatment of malaria in health facility (HF). The decrease in people tested for malaria in the health facilities may have overwhelmed the activities of the community.

System for administering and monitoring hydroxychloroquine prophylaxis for COVID-19 in accordance with a national advisory: preliminary experience of a tertiary care institute in India.

BACKGROUND: Hydroxychloroquine (HCQ) was one of the earliest drugs to be recommended for tackling the COVID-19 threat leading to its widespread usage. We provide preliminary findings of the system, established in a tertiary care academic center for the administration of HCQ prophylaxis to healthcare workers (HCW) based on Indian Council of Medical Research (ICMR) advisory. METHODS: A dedicated clinical pharmacology and internal medicine team screened for contraindications, administered informed consent, maintained compliance and monitored for adverse events. RESULTS: Among the 194 HCWs screened for ruling out contraindications for prophylaxis, 9 were excluded and 185 were initiated on HCQ. A total of 55 adverse events were seen in 38 (20.5%) HCWs out of which 70.9%, 29.1% were mild and moderate & none were severe. Before the completion of therapy, a total of 23 participants discontinued. Change in QTc interval on day 2 was 5 (IQR: -3.75, 11) ms and the end of week 1 was 15 ms (IQR: 2, 18). Out of the 5 HCW who turned positive for COVID-19, 2 were on HCQ. CONCLUSION: HCQ prophylaxis was found to be safe and well tolerated in HCW when administered after appropriate screening and with monitoring for adverse events.

COVID-19 pandemic: challenges ahead.

Since December 2019, health systems worldwide have faced the pandemic caused by the new severe acute respiratory syndrome coronavirus 2. The pandemic began in China and has spread throughout the world. This new coronavirus has a high transmission capacity and elevated lethality in people over 60 years old and in those with risk factors (obesity, diabetes, and systemic arterial hypertension); those characteristics have a different proportion in each country. At present, there is no specific, effective, and safe treatment to treat this virus. In this review, an analysis is made on the differences in epidemiological aspects of the disease and its presentation in pediatric patients; the poorly-based recommendation for using an empirical combination of antimalarials plus antimicrobials as antiviral treatment; the indication of intravenous steroids; and the possible influence of antihypertensive drugs on the course of the disease.

A partir de diciembre de 2019, los sistemas de salud de todos los países se han enfrentado a la pandemia causada por un nuevo coronavirus (SARS-CoV-2), el cual fue notificado por primera vez en China y se ha esparcido por todo el mundo. Este nuevo coronavirus posee una alta capacidad para transmitirse. A escala mundial la letalidad ha sido más alta en la población mayor de 60 años y en aquellos que tienen factores de riesgo (obesidad, diabetes e hipertensión arterial sistémica). Sin embargo, estas características varían en proporción en cada país. Hasta el momento no hay un tratamiento específico, eficaz y seguro para combatir este virus. En este artículo se realiza un análisis sobre las diferencias globales en los aspectos ­epidemiológicos y con relación a su presentación en pacientes pediátricos, así como de la recomendación, con pobre fundamento, del uso de la combinación de antimaláricos y antimicrobianos empíricos como antivirales. También se analizan la indicación de esteroides intravenosos y la posible influencia de los fármacos antihipertensivos en el curso de la enfermedad.

Clinical features and outcomes of hospitalized COVID-19 patients in a low burden region.

Data on the clinical features and outcomes of COVID-19 patients from countries with low disease burden are rare. Greece, however, presented a low burden of COVID-19 disease during the first pandemic outbreak. This is a retrospective study of COVID-19 hospitalized patients in Greece. Clinical data were extracted from medical records using univariable and multivariable logistic regression analyses to assess the factors associated with Intensive Care Unit (ICU) admission and in-hospital death. Eighty-five patients were included in this study, 49 (57.7%) male with median (25th-75th) age 60 (49-72) years old. Sixty-one (72%) of them had at least one comorbidity with hypertension being the most common (45,6%). More than half (56%) had severe or critical disease, 20% required ICU care (14% received invasive ventilation) and 10.7% died. Solid tumor (p = 0.021) and NEWS score (p = 0.048), thrombocytopenia (p = 0.036) or involvement of all lung fields in chest x-ray (p = 0.002) on admission were independent risk factors for ICU admission. Immunosuppression (p = 0.032) and thrombocytopenia (p = 0.049) were independent predictors of death. Hospitalized COVID-19 patients in a European country with a low burden of the disease, in which hospital capacities had not been overwhelmed, had lower mortality rate compared to those reported for patients hospitalized in regions with a high burden of the disease.

Assessing QT interval in COVID-19 patients:safety of hydroxychloroquine-azithromycin combination regimen.

BACKGROUND: Hydroxychloroquine (HCQ) and azithromycin (AZT) have been proposed for COVID-19 treatment. Data available in the literature reported a potential increased risk of fatal arrhythmias under these therapies. The aim of this study was to assess the effects of these drugs on QT interval and outcome in a COVID-19 population. METHOD: A total of 112 consecutive COVID-19 patients were included in this analysis and were divided in 3 groups according to the receiving therapeutic regimens: 19 (17%) patients in Group 1 (no treatment), 40 (36%) in Group 2 (HCQ only), 53 (47%) in Group 3 (HCQ/AZT). RESULTS: A prolonged QTc interval was found in 61% of patients treated with HCQ alone or in combination with AZT, but only 4 (4%) patients showed a QTc > 500 ms. HCQ/AZT combination determined a greater increase of QTc duration compared to the other two strategies (Group 3 452 ± 26.4 vs Group 2 436.3 ± 28.4 vs Group 1 424.4 ± 24.3 ms, respectively; p < 0.001). Multivariate analysis demonstrated that HCQ/AZT combination (OR 9.02, p = 0.001) and older age (OR 1.04, p = 0.031) were independent predictors of QTc prolongation. The risk increased with age (incremental utility analysis p = 0.02). Twenty patients (18%) died, and no cardiac arrest neither arrhythmic fatalities were documented. CONCLUSIONS: The HCQ/AZT combination therapy causes a significantly increase of QT interval compared to HCQ alone. Older patients under such regimen are at higher risk of experiencing QT prolongation. The use of such drugs may be considered as safe relating to arrhythmic risk in the treatment of COVID-19 patients as no arrhythmic fatalities occurred.

COVID-19 mimics endemic tropical diseases at an early stage: a report of two symptomatic COVID-19 patients treated in a polymerase chain reaction void zone in Cameroon.

At the end of December 2019, they emerged a new coronavirus (SARS-CoV-2), triggering a pandemic of an acute respiratory syndrome (COVID-19) in humans. We report the relevant features of the first two confirmed cases of COVID-19 recorded from the 29th April 2020 in the Far North Region of Cameroon. We did a review of the files of these two patients who were admitted to the internal medicine ward of a medical Centre in Maroua Town, Far North Region. We present 2 cases of symptomatic COVID-19 patients, both males and health personnel, with an average age of 53 years, with no recent history of travel to a COVID-19 zone at risk and working in a then COVID-19 free region. They presented with extreme fatigue as their main symptom. Both were treated initially for severe malaria with quinine sulfate infusion with initial relief of symptoms. In the first confirmed case, at his re-hospitalization with an acute respiratory syndrome, a polymerase chain reaction (PCR) test in search of SARS-CoV-2 was requested with his results available 7 days into admission. For the second case, he had his results 48 hours on admission while he was prepared to be discharged. Both control PCR tests for COVID-19 came back negative 14 days after hospitalization. Health personnel remains a group at risk for the COVID-19 infection. The clinical manifestation at an early stage may be atypical mimicking endemic tropical infections. Also, the therapeutic potential of quinine salts in the relief of symptoms of COVID-19 is questionable and remains a subject to explore in our context.

Estimation of the uncertainty of values assigned to calibration materials prepared in-house: An example for hydroxychloroquine calibrators in blood-hemolysate-based matrix.

BACKGROUND: Hydroxychloroquine is an antimalarial drug that has been prescribed for the treatment of patients with COVID-19 infection. To assist in clinician decision-making, several clinical laboratories have developed and validated measurement procedures in-house based on HPLC or HPLC-MS/MS to measure the mass concentration of hydroxychloroquine in different biological fluids. In these cases, laboratories produce their calibration materials but rarely estimate the measurement uncertainty of their assigned values. Thus, we aimed to show how this uncertainty can be calculated, using the preparation of hydroxychloroquine calibrators in blood-hemolysate-based matrix as an example. METHODS: A bottom-up approach was used to estimate the uncertainty related to the values assigned to end-user calibration materials prepared in-house. First, a specification of the measurand and a measurement equation were proposed. Then, different sources of uncertainty related to the preparation of hydroxychloroquine calibration materials were identified and quantified. Afterwards, the combined uncertainty was calculated using the law for the propagation of uncertainty resulting in the final expanded uncertainty. RESULTS: In this study, the most significant source of uncertainty was that associated with the hydroxychloroquine's reference material mass obtained via balance, while the smallest contribution was from the uncertainty associated with the hydroxychloroquine reference material purity. CONCLUSIONS: A simple procedure to estimate the measurement uncertainty of values assigned to calibration materials is presented here, which would be easy to implement in clinical laboratories. Also, it could be put into practice for other pharmacological quantities measured by in-house HPLC or HPLC-MS/MS procedures commonly used in clinical laboratories.

Unusual association of COVID-19, pulmonary tuberculosis and human immunodeficiency virus, having progressed favorably under treatment with chloroquine and rifampin.

Infection with the new coronavirus has been declared an international health emergency. Its curative treatment is unknown and is the subject of several clinical trials. In addition, the concomitant association of COVID-19 with tuberculosis and the human immunodeficiency virus, hitherto never described, is potentially fatal. We report the illustrative case of a 32-year-old patient who presented this trifecta of infections and who did well under treatment with chloroquine and anti-mycobacterial drugs. This patient arrived at the ER with respiratory discomfort that had been evolving over a month with symptoms of flu and deterioration of her general condition. A chest CT scan revealed an aspect of lung miliary tuberculosis with isolation of Koch's bacilli in the sputum. A polymerization chain reaction (PCR) was positive for COVID-19 on a nasopharyngeal swab. HIV serology was positive. The course was marked by a spectacular clinical improvement and two negative COVID-19 PCR controls at the end of treatment (at days 9 and 10). Anti-tubercular drugs (especially, rifampin) are powerful enzyme inducers that can reduce the effectiveness of chloroquine in our patient. This therapeutic success may be linked to the effect of anti-tubercular drugs against SARS ncov-2, especially rifampin, inhibiting the formation of messenger RNAs of SARS ncov-2 or to the synergistic effect of chloroquine and rifampin. Researchers should explore the effect of these drugs on SARS ncov-2.

Sofosbuvir and daclatasvir for the treatment of COVID-19 outpatients: a double-blind, randomized controlled trial.

INTRODUCTION: Effective treatments are urgently needed to tackle the novel coronavirus disease 2019 (COVID-19). This trial aims to evaluate sofosbuvir and daclatasvir versus standard care for outpatients with mild COVID-19 infection. METHODS: This was a randomized controlled clinical trial in outpatients with mild COVID-19. Patients were randomized into a treatment arm receiving sofosbuvir/daclatasvir plus hydroxychloroquine or a control arm receiving hydroxychloroquine alone. The primary endpoint of the trial was symptom alleviation after 7 days of follow-up. The secondary endpoint of the trial was hospital admission. Fatigue, dyspnoea and loss of appetite were investigated after 1 month of follow-up. This study is registered with the IRCT.ir under registration number IRCT20200403046926N1. RESULTS: Between 8 April 2020 and 19 May 2020, 55 patients were recruited and allocated to either the sofosbuvir/daclatasvir treatment arm (n = 27) or the control arm (n = 28). Baseline characteristics were similar across treatment arms. There was no significant difference in symptoms at Day 7. One patient was admitted to hospital in the sofosbuvir/daclatasvir arm and four in the control arm, but the difference was not significant. After 1 month of follow-up, two patients reported fatigue in the sofosbuvir/daclatasvir arm and 16 in the control arm; P < 0.001. CONCLUSIONS: In this study, sofosbuvir/daclatasvir did not significantly alleviate symptoms after 7 days of treatment compared with control. Although fewer hospitalizations were observed in the sofosbuvir/daclatasvir arm, this was not statistically significant. Sofosbuvir/daclatasvir significantly reduced the number of patients with fatigue and dyspnoea after 1 month. Larger, well-designed trials are warranted.

Efficacy of early hydroxychloroquine treatment in preventing COVID-19 pneumonia aggravation, the experience from Shanghai, China.

The aim of this study is to assess the efficacy of multiple treatments, especially hydroxychloroquine, used in different disease stages of coronavirus disease 2019 (COVID-19). All consecutive patients with COVID-19 admitted to Shanghai Public Health Clinical Center (Shanghai, China) between January 20, 2020, and April 30, 2020, were enrolled, and their clinical data were retrospectively collected. Binary logistic regression was used to screen the factors associated with disease aggravation, and multivariable analyses with the Cox proportional hazards model were used to estimate the effects of prognostic factors on the improvement time and PCR conversion days in throat swabs and stool swabs. A total of 616 patients, including 50 (8.11%) severe and 18 (2.92%) critical patients, were enrolled in our retrospective cohort study. The early use of hydroxychloroquine was a protective factor associated with disease aggravation (95% CI: 0.040-0.575, p = 0.006). Clinical improvement by 20 days was significantly different between patients with hydroxychloroquine used early and those with hydroxychloroquine not used (p = 0.016, 95% CI: 1.052-1.647). The median time to clinical improvement was 6 days in the hydroxychloroquine used early group, compared with 9 days in the without hydroxychloroquine used group and 8 days in the with hydroxychloroquine not used early group (p < 0.001). Hydroxychloroquine used early was associated with earlier PCR conversion in both throat swabs (HR = 1.558, p = 0.001) and stool swabs (HR = 1.400, p = 0.028). The use of hydroxychloroquine at an early stage is a potential therapeutic strategy for treating patients before irreversible severe respiratory complications occur. The early use of hydroxychloroquine decreased the improvement time and the duration of COVID-19 detection in throat and stool swabs.

Safety and Efficacy of Ixekizumab and Antiviral Treatment for Patients with COVID-19: A structured summary of a study protocol for a Pilot Randomized Controlled Trial.

OBJECTIVES: A severe epidemic of COVID-19 has broken out in China and has become a major global public health event. We focus on the Acute Respiratory Distress Syndrome (ARDS)-like changes and overactivation of Th17 cells (these produce cytokines) in patients with COVID-19. We aim to explore the safety and efficacy of ixekizumab (an injectable drug for the treatment of autoimmune diseases) to prevent organ injury caused by the immune response to COVID-19. Ixekizumab is a human monoclonal antibody that binds to interleukin-17A and inhibits the release of pro-inflammatory cytokines and chemokines. TRIAL DESIGN: The experiment is divided into two stages. In the first stage, the open trial, 3 patients with COVID-19 are treated with ixekizumab, and the safety and efficacy are observed for 7 days. In the second stage, 40 patients with COVID-19 are randomly divided into two groups at 1:1 for 14 days. This is a two-center, open-label, randomized controlled pilot trial with 2-arm parallel group design (1:1 ratio). PARTICIPANTS: Patients with COVID-19 aged 18-75 with increased Interleukin (IL)-6 levels will be enrolled, but patients with severe infections requiring intensive care will be excluded. The trial will be undertaken in two centers. The first stage is carried out in Xiangya Hospital of Central South University, and the second stage is carried out simultaneously in the Third Xiangya Hospital of Central South University. INTERVENTION AND COMPARATOR: In the first stage, three subjects are given ixekizumab ("Taltz") (80 mg/ml, 160 mg as a single hypodermic injection) and antiviral therapy (α-interferon (administer 5 million U by aerosol inhalation twice daily), lopinavir/ritonavir (administer 100mg by mouth twice daily, for the course of therapy no more than 10 days), chloroquine (administer 500mg by mouth twice daily, for the course of therapy no more than 10 days), ribavirin (administer 500mg by intravenous injection two to three times a day, for the course of therapy no more than 10 days), or arbidol (administer 200mg by mouth three times a day, for the course of therapy no more than 10 days), but not more than 3 types). The treatment course of the first stage is 7 days. In the second stage, 40 randomized patients will receive the following treatments--Group 1: ixekizumab (80 mg/ml, 160 mg as a single hypodermic injection) with antiviral therapy (the same scheme as in the first stage); Group 2: antiviral therapy alone (the same scheme as in the first stage). The length of the second treatment course is 14 days. MAIN OUTCOMES: The primary outcome is a change in pulmonary CT severity score (an imaging tool for assessing COVID-19, which scores on the basis of all abnormal areas involved). Pulmonary CT severity score is assessed on the 7th day, 14th day, or at discharge. RANDOMISATION: In the second stage, 40 patients with COVID-19 are randomly divided into two groups at 1:1 for 14 days. The eLite random system of Nanjing Medical University is used for randomization. BLINDING (MASKING): The main efficacy indicator, the CT results, will be evaluated by the third-party blinded and independent research team. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): In the second stage, 40 patients with COVID-19 are randomly divided into two groups at 1:1 for 14 days. TRIAL STATUS: Trial registration number is ChiCTR2000030703 (version 1.7 as of March 19, 2020). The recruitment is ongoing, and the date recruitment was initiated in June 2020. The anticipated date of the end of data collection is June 2021. TRIAL REGISTRATION: The name of the trial register is the Chinese Clinical Trial Registry. The trial registration number is ChiCTR2000030703 ( http://www.chictr.org.cn/ ). The date of trial registration is 10 March 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting the dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

Psychiatric side effects of chloroquine in COVID-19 patients: two case reports.

Chloroquine and hydroxy chloroquine are widely use in Africa and all over the world as anti-malarial drugs but also in the treatment of chronic inflammatory diseases. Since the outbreak of COVID-19 pandemic, Morocco have included this medication in the COVID-19 treatment guidelines in association with azithromycine. Besides dermatologic problems, ocular impairments and gastro-intestinal effects, quinolines may also cause rarely described psychiatric adverse effects. To our knowledge, there has been no reports of psychiatric side effects of chloroquine or hydroxy chloroquine in the actual context of COVID-19 pandemic. Here, we present the description of two COVID-19 patients who showed psychiatric side effects after chloroquine treatment. One patient expressed psychotic symptoms and the other one experienced acute and intense anxiety. In both cases, and according to Naranjo score, the association between chloroquine and psychiatric side effects was probable.