Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 8 de 8
Filter
1.
Inflammopharmacology ; 29(6): 1795-1805, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1505910

ABSTRACT

Hydroxychloroquine has attracted attention in the treatment of COVID-19. Many conflicting findings have been reported regarding the efficacy and safety of this drug, which has been used safely in the rheumatological diseases for years. However, these studies lacked measurement methods that allow accurate assessment of hydroxychloroquine and its metabolite levels. The aim of this study was to measure hydroxychloroquine and its metabolite levels in whole blood samples of patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjogren's syndrome (SS) and scleroderma (Scl) by a robust, simple and accurate validated tandem mass spectrometric method, and to investigate the relationship between these levels with drug-related adverse effects and disease activity scores. The validated LC-MS/MS method was applied to measure blood hydroxychloroquine and its metabolite levels of patients with RA, SLE, SS, Scl. Various haematological and biochemical parameters were measured with Beckman-Coulter AU 5800 and Beckman Coulter LH 780 analyzers, respectively. QTc intervals were calculated with Bazett's formula, and the patients were followed up by clinicians in terms of clinical findings and adverse effects. Hydroxychloroquine levels of patients were similar to previous studies. There was a negative correlation between disease activity scores and hydroxychloroquine levels, while the highest correlation was between QTc interval, creatinine and GFR levels with desethylchloroquine. Bidetylchloroquine had the highest correlation with RBC count and liver function tests. Our findings showed that hydroxychloroquine and its metabolite levels were associated with disease activity scores, renal, hepatic function, QTc prolongation, and hematological parameters.


Subject(s)
Antimalarials/adverse effects , Antimalarials/blood , COVID-19/complications , Connective Tissue Diseases/complications , Hydroxychloroquine/adverse effects , Hydroxychloroquine/blood , Adult , Aged , Chromatography, High Pressure Liquid , Creatinine/blood , Electrocardiography , Erythrocyte Count , Female , Glomerular Filtration Rate/drug effects , Humans , Kidney Function Tests , Liver Function Tests , Long QT Syndrome/chemically induced , Male , Middle Aged , Tandem Mass Spectrometry , Young Adult
2.
PLoS One ; 16(3): e0247356, 2021.
Article in English | MEDLINE | ID: covidwho-1119472

ABSTRACT

BACKGROUND: Hydroxychloroquine (HCQ) and azithromycin (AZM) are antimalarial drugs recently reported to be active against severe acute respiratory syndrome coronavirus- 2 (SARS-CoV-2), which is causing the global COVID-19 pandemic. In an emergency response to the pandemic, we aimed to develop a quantitation method for HCQ, its metabolites desethylhydroxychloroquine (DHCQ) and bisdesethylchloroquine (BDCQ), and AZM in human plasma. METHODS: Liquid chromatography tandem mass spectrometry was used to develop the method. Samples (20 µL) are extracted by solid-phase extraction and injected onto the LC-MS/MS system equipped with a PFP column (2.0 × 50 mm, 3 µm). ESI+ and MRM are used for detection. Ion pairs m/z 336.1→247.1 for HCQ, 308.1→179.1 for DHCQ, 264.1→179.1 for BDCQ, and 749.6→591.6 for AZM are selected for quantification. The ion pairs m/z 342.1→253.1, 314.1→181.1, 270.1→181.1, and 754.6→596.6 are selected for the corresponding deuterated internal standards (IS) HCQ-d4, DHCQ-d4, BDCQ-d4, and AZM-d5. The less abundant IS ions from 37Cl were used to overcome the interference from the analytes. RESULTS: Under optimized conditions, retention times are 0.78 min for BDCQ, 0.79 min for DHCQ, 0.92 min for HCQ and 1.87 min for AZM. Total run time is 3.5 min per sample. The calibration ranges are 2-1000 ng/mL for HCQ and AZM, 1-500 ng/mL for DHCQ and 0.5-250 ng/mL for BDCQ; samples above the range are validated for up to 10-fold dilution. Recoveries of the method ranged from 88.9-94.4% for HCQ, 88.6-92.9% for DHCQ, 88.7-90.9% for BDCQ, and 98.6%-102% for AZM. The IS normalized matrix effect were within (100±10) % for all 4 analytes. Blood samples are stable for at least 6 hr at room temperature. Plasma samples are stable for at least 66 hr at room temperature, 38 days at -70°C, and 4 freeze-thaw cycles. CONCLUSIONS: An LC-MS/MS method for simultaneous quantitation of HCQ, DHCQ, BDCQ, and AZM in human plasma was developed and validated for clinical studies requiring fast turnaround time and small samples volume.


Subject(s)
Anti-Bacterial Agents/blood , Antimalarials/blood , Azithromycin/blood , Chloroquine/analogs & derivatives , Hydroxychloroquine/analogs & derivatives , Hydroxychloroquine/blood , Blood Specimen Collection/methods , Chloroquine/blood , Chromatography, High Pressure Liquid/methods , Drug Monitoring/methods , Edetic Acid/blood , Humans , Limit of Detection , Tandem Mass Spectrometry/methods
3.
Clin Biochem ; 89: 70-76, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-1032517

ABSTRACT

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.


Subject(s)
COVID-19/blood , Chromatography, High Pressure Liquid/methods , Hydroxychloroquine/blood , Antimalarials/administration & dosage , Antimalarials/blood , COVID-19/drug therapy , COVID-19/pathology , COVID-19/virology , Calibration , Chromatography, High Pressure Liquid/standards , Hemolysis , Humans , Hydroxychloroquine/administration & dosage , Quality Control , Reference Standards , SARS-CoV-2/isolation & purification , Uncertainty
4.
Antimicrob Agents Chemother ; 64(9)2020 08 20.
Article in English | MEDLINE | ID: covidwho-654170

ABSTRACT

Previously, ivermectin (1 to 10 mg/kg of body weight) was shown to inhibit the liver-stage development of Plasmodium berghei in orally dosed mice. Here, ivermectin showed inhibition of the in vitro development of Plasmodium cynomolgi schizonts (50% inhibitory concentration [IC50], 10.42 µM) and hypnozoites (IC50, 29.24 µM) in primary macaque hepatocytes when administered as a high dose prophylactically but not when administered in radical cure mode. The safety, pharmacokinetics, and efficacy of oral ivermectin (0.3, 0.6, and 1.2 mg/kg) with and without chloroquine (10 mg/kg) administered for 7 consecutive days were evaluated for prophylaxis or radical cure of P. cynomolgi liver stages in rhesus macaques. No inhibition or delay to blood-stage P. cynomolgi parasitemia was observed at any ivermectin dose (0.3, 0.6, and 1.2 mg/kg). Ivermectin (0.6 and 1.2 mg/kg) and chloroquine (10 mg/kg) in combination were well-tolerated with no adverse events and no significant pharmacokinetic drug-drug interactions observed. Repeated daily ivermectin administration for 7 days did not inhibit ivermectin bioavailability. It was recently demonstrated that both ivermectin and chloroquine inhibit replication of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro Further ivermectin and chloroquine trials in humans are warranted to evaluate their role in Plasmodium vivax control and as adjunctive therapies against COVID-19 infections.


Subject(s)
Antimalarials/pharmacology , Chloroquine/pharmacology , Ivermectin/pharmacology , Liver/drug effects , Malaria/drug therapy , Plasmodium cynomolgi/drug effects , Animals , Antimalarials/blood , Antimalarials/pharmacokinetics , Biological Availability , Chloroquine/blood , Chloroquine/pharmacokinetics , Drug Administration Schedule , Drug Combinations , Drug Synergism , Female , Hepatocytes/drug effects , Hepatocytes/parasitology , Ivermectin/blood , Ivermectin/pharmacokinetics , Liver/parasitology , Macaca mulatta , Malaria/parasitology , Male , Parasitemia/drug therapy , Plasmodium cynomolgi/growth & development , Plasmodium cynomolgi/pathogenicity , Primary Cell Culture , Schizonts/drug effects , Schizonts/growth & development
5.
Emerg Infect Dis ; 26(10): 2513-2515, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-623269

ABSTRACT

Because of in vitro studies, hydroxychloroquine has been evaluated as a preexposure or postexposure prophylaxis for coronavirus disease (COVID-19) and as a possible COVID-19 curative treatment. We report a case of COVID-19 in a patient with sarcoidosis who was receiving long-term hydroxychloroquine treatment and contracted COVID-19 despite adequate plasma concentrations.


Subject(s)
Antimalarials/therapeutic use , Coronavirus Infections/complications , Hydroxychloroquine/therapeutic use , Pneumonia, Viral/complications , Sarcoidosis, Pulmonary/complications , Sarcoidosis, Pulmonary/drug therapy , Adult , Antimalarials/blood , COVID-19 , Coronavirus Infections/diagnosis , France , Humans , Hydroxychloroquine/blood , Male , Pandemics , Pneumonia, Viral/diagnosis , Time Factors , Tomography, X-Ray Computed
6.
Clin Pharmacol Ther ; 108(5): 1055-1066, 2020 11.
Article in English | MEDLINE | ID: covidwho-277084

ABSTRACT

Chloroquine has been used for the treatment of malaria for > 70 years; however, chloroquine pharmacokinetic (PK) and pharmacodynamic (PD) profile in Plasmodium vivax malaria is poorly understood. The objective of this study was to describe the PK/PD relationship of chloroquine and its major metabolite, desethylchloroquine, in a P. vivax volunteer infection study. We analyzed data from 24 healthy subjects who were inoculated with blood-stage P. vivax malaria and administered a standard treatment course of chloroquine. The PK of chloroquine and desethylchloroquine was described by a two-compartment model with first-order absorption and elimination. The relationship between plasma and whole blood concentrations of chloroquine and P. vivax parasitemia was characterized by a PK/PD delayed response model, where the equilibration half-lives were 32.7 hours (95% confidence interval (CI) 27.4-40.5) for plasma data and 24.1 hours (95% CI 19.0-32.7) for whole blood data. The estimated parasite multiplication rate was 17 folds per 48 hours (95% CI 14-20) and maximum parasite killing rate by chloroquine was 0.213 hour-1 (95% CI 0.196-0.230), translating to a parasite clearance half-life of 4.5 hours (95% CI 4.1-5.0) and a parasite reduction ratio of 400 every 48 hours (95% CI 320-500). This is the first study that characterized the PK/PD relationship between chloroquine plasma and whole blood concentrations and P. vivax clearance using a semimechanistic population PK/PD modeling. This PK/PD model can be used to optimize dosing scenarios and to identify optimal dosing regimens for chloroquine where resistance to chloroquine is increasing.


Subject(s)
Antimalarials/pharmacokinetics , Chloroquine/pharmacokinetics , Malaria, Vivax/drug therapy , Plasmodium vivax/drug effects , Administration, Oral , Adult , Antimalarials/administration & dosage , Antimalarials/blood , Biotransformation , Chloroquine/administration & dosage , Chloroquine/analogs & derivatives , Chloroquine/blood , Drug Dosage Calculations , Drug Resistance , Female , Humans , Malaria, Vivax/blood , Malaria, Vivax/diagnosis , Malaria, Vivax/parasitology , Male , Models, Biological , Parasite Load , Plasmodium vivax/growth & development , Treatment Outcome , Young Adult
7.
Travel Med Infect Dis ; 35: 101735, 2020.
Article in English | MEDLINE | ID: covidwho-186305

ABSTRACT

The rapidly spreading Coronavirus Disease (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2), represents an unprecedented serious challenge to the global public health community. The extremely rapid international spread of the disease with significant morbidity and mortality made finding possible therapeutic interventions a global priority. While approved specific antiviral drugs against SARS-CoV-2 are still lacking, a large number of existing drugs are being explored as a possible treatment for COVID-19 infected patients. Recent publications have re-examined the use of Chloroquine (CQ) and/or Hydroxychloroquine (HCQ) as a potential therapeutic option for these patients. In an attempt to explore the evidence that supports their use in COVID-19 patients, we comprehensively reviewed the previous studies which used CQ or HCQ as an antiviral treatment. Both CQ and HCQ demonstrated promising in vitro results, however, such data have not yet been translated into meaningful in vivo studies. While few clinical trials have suggested some beneficial effects of CQ and HCQ in COVID-19 patients, most of the reported data are still preliminary. Given the current uncertainty, it is worth being mindful of the potential risks and strictly rationalise the use of these drugs in COVID-19 patients until further high quality randomized clinical trials are available to clarify their role in the treatment or prevention of COVID-19.


Subject(s)
Antimalarials/therapeutic use , Antiviral Agents/therapeutic use , Betacoronavirus/physiology , Coronavirus Infections/drug therapy , Hydroxychloroquine/therapeutic use , Pneumonia, Viral/drug therapy , Animals , Antimalarials/adverse effects , Antimalarials/blood , Antimalarials/pharmacokinetics , Antiviral Agents/blood , Antiviral Agents/pharmacokinetics , Betacoronavirus/drug effects , Biological Availability , COVID-19 , Coronavirus Infections/virology , Half-Life , Humans , Hydroxychloroquine/adverse effects , Hydroxychloroquine/blood , Hydroxychloroquine/pharmacokinetics , Pandemics , Pneumonia, Viral/virology , SARS-CoV-2 , Treatment Outcome , Virus Internalization/drug effects , Virus Replication/drug effects
8.
Clin Pharmacol Ther ; 108(4): 766-769, 2020 10.
Article in English | MEDLINE | ID: covidwho-133605

ABSTRACT

Hydroxychloroquine is an antimalarial drug being tested as a potential treatment for the novel coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2. Although the efficacy of hydroxychloroquine for COVID-19 remains uncertain, it may serve as a potential prophylactic agent especially in those at high risk, such as healthcare workers, household contacts of infected patients, and the immunocompromised. Our aim was to identify possible hydroxychloroquine dosing regimens through simulation in those at high risk of infections by optimizing exposures above the in vitro generated half maximal effective concentration (EC50 ) and to help guide researchers in dose-selection for COVID-19 prophylactic studies. To maintain weekly troughs above EC50 in > 50% of subjects at steady-state in a pre-exposure prophylaxis setting, an 800 mg loading dose followed by 400 mg twice or 3 times weekly is required. In an exposure driven, post-exposure prophylaxis setting, 800 mg loading dose followed in 6 hours by 600 mg, then 600 mg daily for 4 more days achieved daily troughs above EC50 in > 50% subjects. These doses are higher than recommended for malaria chemoprophylaxis, and clinical trials are needed to establish safety and efficacy.


Subject(s)
Antimalarials/administration & dosage , Betacoronavirus/drug effects , Coronavirus Infections/prevention & control , Hydroxychloroquine/administration & dosage , Malaria/drug therapy , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Pre-Exposure Prophylaxis/methods , Antimalarials/blood , COVID-19 , Coronavirus Infections/blood , Humans , Hydroxychloroquine/blood , Malaria/blood , Models, Biological , Pneumonia, Viral/blood , SARS-CoV-2 , Treatment Outcome
SELECTION OF CITATIONS
SEARCH DETAIL