ABSTRACT
Chloroquine (CQ) phosphate has been suggested to be clinically effective in the treatment of coronavirus disease 2019 (COVID-19). To develop a physiologically-based pharmacokinetic (PBPK) model for predicting tissue distribution of CQ and apply it to optimize dosage regimens, a PBPK model, with parameterization of drug distribution extrapolated from animal data, was developed to predict human tissue distribution of CQ. The physiological characteristics of time-dependent accumulation was mimicked through an active transport mechanism. Several dosing regimens were proposed based on PBPK simulation combined with known clinical exposure-response relationships. The model was also validated by clinical data from Chinese patients with COVID-19. The novel PBPK model allows in-depth description of the pharmacokinetics of CQ in several key organs (lung, heart, liver, and kidney), and was applied to design dosing strategies in patients with acute COVID-19 (Day 1: 750 mg BID, Days 2-5: 500 mg BID, CQ phosphate), patients with moderate COVID-19 (Day 1: 750 mg and 500 mg, Days 2-3: 500 mg BID, Days 4-5: 250 mg BID, CQ phosphate), and other vulnerable populations (.., renal and hepatic impairment and elderly patients, Days 1-5: 250 mg BID, CQ phosphate). A PBPK model of CQ was successfully developed to optimize dosage regimens for patients with COVID-19.
ABSTRACT
Since the outbreak of coronavirus disease 2019 (COVID-19) in the late 2019, a variety of antiviral drugs have been used in the first-line clinical trial. The Diagnostic and Treatment Protocol for COVID-19 (Trial Version 6) in China recommends chloroquine phosphate for the first time as an anti-coronavirus trial drug. As a classic drug for treatment of malaria and rheumatism, chloroquine phosphate has been used clinically for more than 80 years, and has also shown good results in the treatment of various viral infections. As the plasma drug concentration varies greatly among different races and individuals and due to its narrow treatment window, chloroquine in likely to accumulate in the body to cause toxicity. Among the treatment regimens recommended for COVID-19, reports concerning the safety of a short-term high-dose chloroquine regimen remain scarce. In this review, the authors summarize the current research findings of chloroquine phosphate in the treatment of COVID-19, and examine the pharmacokinetic characteristics, antiviral therapy, the therapeutic mechanism and safety of chloroquine.
Subject(s)
Humans , Antiviral Agents , Betacoronavirus , China , Chloroquine , Therapeutic Uses , Coronavirus Infections , Drug Therapy , Pandemics , Pneumonia, Viral , Drug TherapyABSTRACT
A novel coronavirus disease (COVID-19) was identified in Wuhan City, Hubei Province of China by the end of 2019, and then, the disease spread across China and became a global pandemic. Nevertheless, there are no effective treatments or vaccines for COVID-19 until now. In addition to the treatment of patients with COVID-19, the China Medical Treatment Expert Group for COVID-19 is active to study and screen effective antiviral drugs, and has found that chloroquine, an old antimalarial,shows activity against SARS-CoV-2. Then, chloroquine was included in the Guidelines for the Diagnosis and Treatment of COVID-19 in China (version 6) issued by National Health Commission of the People’s Republic of China. Currently, chloroquine phosphate and hydroxychloroquine sulfate, two chloroquine derivatives, are under clinical use. Although these two agents exhibit similar mechanisms of drug actions, there is a difference between these two chemicals in terms of target populations, therapeutic efficacy and adverse reactions. This paper summarizes the currently available data and experiences from clinical treatment for malaria with chloroquine drugs, so as to provide insights into the more rational use of chloroquine agents for the treatment of COVID-19.
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Objective:To establish a rapid HPLC testing method for chloroquine phosphate,hydroxychloroquine sulfate and amodiaquine hydrochloride.Methods:The chromatographic separation was performed on a GRACE prevail C18(53 mm×7 mm,3 μm)column,and the column temperature was maintained at 30℃.Acetonitrile-0.3% triethylamine acetonitrile solution (adjusting pH to 3.0 with phosphoric acid) (12∶88) was used as the mobile phase,the flow rate was 1.0 ml· min-1 and the UV detection wavelength was 254 nm.The qualitative research was performed using relative retention time and spectral similarity as the double indicators.The relative correction factor in the quantification analysis was used for the content determination.Results:Three anti-malarial drugs showed good behavior in one chromatographic system.The rapid HPLC testing analysis could be achieved.The qualitative research was more accurate by using the double indicators (UV spectral similarity and relative capacity factor).The HPLC qualitative accuracy was increased.The relative correction factor method for the quantification could effectively reduce the use of reference substances and speed up the analysis of HPLC.Conclusion:The method is rapid and simple,and suitable for the rapid determination of drugs.
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Objective To investigate the role of autophagy in radiation-induced death response of human nasopharyngeal carcinoma cells.Methods MTT method was used to detect cell viability of CNE-2 cells in different time after irradiation.Clonogenic survival assay was used to evaluate the effect of autophagy inhibitor (chloroquine phosphate) and autophagy inductor (rapamycin) on radiosensitivity of nasopharyngeal carcinoma cells.Cell apoptosis was assessed by flow cytometry.The expressions of LC3 and P62 were measured with Western blot.Cell ultrastructural analysis was performed under an electron microscope.Results Irradiation with 10 Gy induced a massive accumulation of autophagosomes accompanied with up-regulation of LC3-Ⅱ expression in CNE-2 cells.Compared with radiation alone,chloroquine phosphate (CDP) enhanced radiosensitivity significantly by decreasing cell viability (F =25.88,P ＜ 0.05),autophagic ratio (F =105.15,P ＜ 0.05),and LC3-Ⅱ protein level(F =231.68,P ＜0.05),while up-regulating the expression of P62 (F =117.52,P ＜ 0.05).Inhibition of autophagy increased radiation-induced apoptosis (F =143.72,P ＜ 0.05).Rapamycin (RAPA) also significantly decreased cell viability,but increased autophagic ratio and LC3-Ⅱ protein level while down-regulated the expression of P62.Induction of autophagy increased radiation-induced apoptosis(F =167.32,P ＜ 0.05).Conclusions Blockage of autophagy with CDP could enhance radiosensitivity in human nasopharyngeal carcinoma cells,suggesting that inhibition of autophagy could be used as an adjuvant treatment to nasopharyngeal carcinoma.
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Medicinal plants and drugs are usually abused through wrong dose usage. These practises may pose a great health risk to the users. The objective of this work is to compare the effect of chronic administration of extract of Landolphia owariensis and Chloroquine phosphate on the activities of enzymes in the kidney, liver, and serum. The methanol extract of Landolphia owariensis and Chloroquine phosphate were administered orally to albino rats on daily doses of 250mg/kg and the activities of enzymes were monitored for 12 days. A total of 36 albino rats were divided into three. Chloroquine phosphate was administered to 12 rats, Landolphia owariensis was administered to another 12 rats and saline solution was administered to the remaining 12 as control. The results revealed that the rats administered with Landolphia owariensis showed an insignificant increase in alkaline and acid phosphatase activities in both liver and kidney. The activity of enzymes in the liver and kidney decreases significantly with chloroquine administration P< 0.05. The comparative studies of the chloroquine and Landolphia owariensis extract showed that chronic administration of chloroquine has detrimental effect on tissues, while the chronic administration of Landolphia owariensis extract causes little or no damage to the tissues.
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A study was conducted on the packing and cohesive properties of chloroquine phosphate in binary mixtures with lactose and dicalcium phosphate powders. The maximum volume reduction due to packing as expressed by the Kawakita constant, a, and the angle of internal flow, θ, were the assessment parameters. The individual powders were characterized for their particle size and shape using an optical microscope. Binary mixtures of various proportions of chloroquine phosphate with lactose and dicalcium phosphate powders were prepared. The bulk and tapped densities, angles of repose and internal flow, as well as compressibility index of the materials were determined using appropriate parameters. The calculated and determined values of maximum volume reduction for the binary mixtures were found to differ significantly (P< 0.05), with the Kawakita plot being more reliable in determining the packing properties. Diluent type was found to influence the flow properties of the mixtures, with dicalcium phosphate giving predictable results while mixtures containing lactose were anomalous with respect to flow. The characterization of the packing and cohesive properties of the binary mixtures of chloroquine with lactose and dicalcium phosphate would be useful in the production of powders, tablets, capsules and other drug delivery systems containing these powders with desirable and predictable flow properties.
Realizou-se estudo das propriedades de empacotamento e de coesão do fosfato de cloroquina em misturas binárias com lactose e fosfato dicálcico em pó. O volume máximo de redução devido ao empacotamento, segundo expresso pela constante de Kawakita, a, e o ângulo de fluxo interno, θ, foram os parâmetros de avaliação. Os pós individuais foram caracterizados por seu tamanho e forma de partículas, utilizando microscópio óptico. Prepararam-se misturas binárias de várias proporções de fosfato de cloroquine e lactose e fosfato dicálcico em pó. As densidades de bulk and tapped, os ângulos de repouso e de fluxo interno e o índice de compressibilidade dos materiais foram determinados utilizando-se parâmetros apropriados. Os valores calculados e determinados do volume máximo de redução para as misturas binárias mostraram-se significativamente diferentes (P< 0,05), sendo o traçado de Kawakita mais confiável na determinação das propriedades de empacotamento. O tipo de diluente influenciou as propriedades de fluxo das misturas com fosfato dicálcico, dando resultados previsíveis, enquanto as misturas contendo lactose mostraram-se anômalas com relação ao fluxo. A caracterização das propriedades de empacotamento e de coesão das misturas binárias de cloroquina com lactose e fosfato dicálcico seria útil na produção de pós, comprimidos, cápsulas e outros sistemas de liberação de fármacos contendo esses pós com propriedade de fluxo desejada e previsível.
Subject(s)
Chemical Compounds , Chloroquine , Calcium/chemistry , Lactose , Phosphates , Product Packaging/methodsABSTRACT
Objective To observe the effects of chloroquine phosphate on apoptosis of leukemic cell line U937, and investigate whether chloroquine phosphate induces leukemic cell apoptosis by normalizing protein PNAS-2's abnormal subcellular location. Methods Chloroquine phosphate of different concentrations were added into culture fluid of leukemic cell line U937 at logarithmic phase. MTr was used to measure cell proliferation, flow cytometry and laser confocal microscopy were applied to detect cell apoptosis, and immunofluorescence technology was employed to observe the effects of chloroquine phosphate on the changes of subcellular location of protein PNAS-2. Results Apoptosis of leukemic cell line U937 was significantly induced by 50 μg/mL chloroquine phosphate, and subcellular location of protein PNAS-2 was changed. Conclusion Chlorequine phosphate can induce apoptosis of leukemic cell line U937, and the mechanism may be related to the normalization of PNAS-2's abnormal subcellular location in U937 cell line. Chloroquine phosphate has the potential to be used in leukemic therapy.