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Trefond L, Lhote R, Mathian A, de Chambrun MP, Pha M, Hie M, Miyara M, Papo M, Moyon Q, Taieb D, Saade S, Salem TB, Haroche J, Chasset F, Aubart FC, Zahr N, Amoura Z. Identification of new risk factors for hydroxychloroquine and chloroquine retinopathy in systemic lupus erythematosus patients. Semin Arthritis Rheum 2024; 66:152417. [PMID: 38394986 DOI: 10.1016/j.semarthrit.2024.152417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 12/20/2023] [Accepted: 02/05/2024] [Indexed: 02/25/2024]
Abstract
BACKGROUND Long-term hydroxychloroquine (HCQ) or chloroquine (CQ) intake causes retinal toxicity in 0.3-8 % of patients with rheumatic diseases. Numerous risk factors have been described, eg, daily dose by weight, treatment duration, chronic kidney disease, concurrent tamoxifen therapy and pre-existing retinal or macular disease. However, those factors cannot explain the entire risk of developing antimalarial retinopathy. OBJECTIVE This study was undertaken to identify new risk factors associated with HCQ or CQ retinopathy (QRNP) in systemic lupus erythematosus (SLE) patients. METHODS This case-control (1:2) study compared SLE patients with QRNP (cases) to those without (controls). Controls were matched for sex and known QRNP risk factors: HCQ and/or CQ treatment duration (±1 year) and age (±5 year) at SLE diagnosis. RESULTS Forty-eight cases were compared to 96 SLE controls. Multivariable logistic-regression analysis retained the following as independent determinants significantly associated with QRNP: concomitant selective serotonin-reuptake inhibitor (SSRI) or serotonin- and norepinephrine-reuptake inhibitor (SNRI) intake (OR [95 % confidence interval] 6.6 [1.2 to 40.9]; p < 0.01); antiphospholipid syndrome (OR=8.9 [2.2 to 41.4] p < 0.01); blood hydroxychloroquine/desethylchloroquine concentration ([HCQ]/[DCQ]) ratio <7.2 (OR 8.4 [2.7 to 30.8]; p < 0.01) or skin phototype ≥4 (OR 5.5 [1.4 to 26.5]; p = 0.02), but not daily HCQ dose, blood [HCQ] or body mass index. CONCLUSION The results of this case-control study identified blood [HCQ]/[DCQ] ratio, concurrent SSRI/SNRI therapy, skin phototype ≥4 and antiphospholipid syndrome as new risk factors for QRNP.
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Affiliation(s)
- Ludovic Trefond
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris (APHP), Groupe Hospitalier Pitié-Salpêtrière, French National Referral Center for Systemic Lupus Erythematosus, Antiphospholipid Antibody Syndrome and Other Autoimmune Disorders, Service de Médecine Interne 2, Institut E3M, Inserm UMRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France; Médecine Interne, Centre Hospitalier Universitaire Gabriel-Montpied, M2iSH, Inserm UMR, Université Clermont-Auvergne, 63000 Clermont-Ferrand, France
| | - Raphael Lhote
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris (APHP), Groupe Hospitalier Pitié-Salpêtrière, French National Referral Center for Systemic Lupus Erythematosus, Antiphospholipid Antibody Syndrome and Other Autoimmune Disorders, Service de Médecine Interne 2, Institut E3M, Inserm UMRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France
| | - Alexis Mathian
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris (APHP), Groupe Hospitalier Pitié-Salpêtrière, French National Referral Center for Systemic Lupus Erythematosus, Antiphospholipid Antibody Syndrome and Other Autoimmune Disorders, Service de Médecine Interne 2, Institut E3M, Inserm UMRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France
| | - Marc Pineton de Chambrun
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris (APHP), Groupe Hospitalier Pitié-Salpêtrière, French National Referral Center for Systemic Lupus Erythematosus, Antiphospholipid Antibody Syndrome and Other Autoimmune Disorders, Service de Médecine Interne 2, Institut E3M, Inserm UMRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France
| | - Micheline Pha
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris (APHP), Groupe Hospitalier Pitié-Salpêtrière, French National Referral Center for Systemic Lupus Erythematosus, Antiphospholipid Antibody Syndrome and Other Autoimmune Disorders, Service de Médecine Interne 2, Institut E3M, Inserm UMRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France
| | - Miguel Hie
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris (APHP), Groupe Hospitalier Pitié-Salpêtrière, French National Referral Center for Systemic Lupus Erythematosus, Antiphospholipid Antibody Syndrome and Other Autoimmune Disorders, Service de Médecine Interne 2, Institut E3M, Inserm UMRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France
| | - Makoto Miyara
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris (APHP), Groupe Hospitalier Pitié-Salpêtrière, French National Referral Center for Systemic Lupus Erythematosus, Antiphospholipid Antibody Syndrome and Other Autoimmune Disorders, Service de Médecine Interne 2, Institut E3M, Inserm UMRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France
| | - Matthias Papo
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris (APHP), Groupe Hospitalier Pitié-Salpêtrière, French National Referral Center for Systemic Lupus Erythematosus, Antiphospholipid Antibody Syndrome and Other Autoimmune Disorders, Service de Médecine Interne 2, Institut E3M, Inserm UMRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France
| | - Quentin Moyon
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris (APHP), Groupe Hospitalier Pitié-Salpêtrière, French National Referral Center for Systemic Lupus Erythematosus, Antiphospholipid Antibody Syndrome and Other Autoimmune Disorders, Service de Médecine Interne 2, Institut E3M, Inserm UMRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France
| | - Dov Taieb
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris (APHP), Groupe Hospitalier Pitié-Salpêtrière, French National Referral Center for Systemic Lupus Erythematosus, Antiphospholipid Antibody Syndrome and Other Autoimmune Disorders, Service de Médecine Interne 2, Institut E3M, Inserm UMRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France
| | - Sonia Saade
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris (APHP), Groupe Hospitalier Pitié-Salpêtrière, French National Referral Center for Systemic Lupus Erythematosus, Antiphospholipid Antibody Syndrome and Other Autoimmune Disorders, Service de Médecine Interne 2, Institut E3M, Inserm UMRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France
| | - Thouraya Ben Salem
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris (APHP), Groupe Hospitalier Pitié-Salpêtrière, French National Referral Center for Systemic Lupus Erythematosus, Antiphospholipid Antibody Syndrome and Other Autoimmune Disorders, Service de Médecine Interne 2, Institut E3M, Inserm UMRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France
| | - Julien Haroche
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris (APHP), Groupe Hospitalier Pitié-Salpêtrière, French National Referral Center for Systemic Lupus Erythematosus, Antiphospholipid Antibody Syndrome and Other Autoimmune Disorders, Service de Médecine Interne 2, Institut E3M, Inserm UMRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France
| | - François Chasset
- Sorbonne Université, Faculté de Médecine, APHP, Service de Dermatologie et Allergologie, Hôpital Tenon, Paris, France
| | - Fleur Cohen Aubart
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris (APHP), Groupe Hospitalier Pitié-Salpêtrière, French National Referral Center for Systemic Lupus Erythematosus, Antiphospholipid Antibody Syndrome and Other Autoimmune Disorders, Service de Médecine Interne 2, Institut E3M, Inserm UMRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France
| | - Noël Zahr
- Service de Pharmacologie, APHP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
| | - Zahir Amoura
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris (APHP), Groupe Hospitalier Pitié-Salpêtrière, French National Referral Center for Systemic Lupus Erythematosus, Antiphospholipid Antibody Syndrome and Other Autoimmune Disorders, Service de Médecine Interne 2, Institut E3M, Inserm UMRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France.
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Islam MM, Rahman MF, Islam A, Afroz MS, Mamun MA, Rahman MM, Maniruzzaman M, Xu L, Sakamoto T, Takahashi Y, Sato T, Kahyo T, Setou M. Elucidating Gender-Specific Distribution of Imipramine, Chloroquine, and Their Metabolites in Mice Kidney Tissues through AP-MALDI-MSI. Int J Mol Sci 2024; 25:4840. [PMID: 38732055 PMCID: PMC11084644 DOI: 10.3390/ijms25094840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 04/24/2024] [Accepted: 04/26/2024] [Indexed: 05/13/2024] Open
Abstract
Knowledge of gender-specific drug distributions in different organs are of great importance for personalized medicine and reducing toxicity. However, such drug distributions have not been well studied. In this study, we investigated potential differences in the distribution of imipramine and chloroquine, as well as their metabolites, between male and female kidneys. Kidneys were collected from mice treated with imipramine or chloroquine and then subjected to atmospheric pressure matrix-assisted laser desorption ionization-mass spectrometry imaging (AP-MALDI-MSI). We observed differential distributions of the drugs and their metabolites between male and female kidneys. Imipramine showed prominent distributions in the cortex and medulla in male and female kidneys, respectively. Desipramine, one of the metabolites of imipramine, showed significantly higher (*** p < 0.001) distributions in the medulla of the male kidney compared to that of the female kidney. Chloroquine and its metabolites were accumulated in the pelvis of both male and female kidneys. Interestingly, they showed a characteristic distribution in the medulla of the female kidney, while almost no distributions were observed in the same areas of the male kidney. For the first time, our study revealed that the distributions of imipramine, chloroquine, and their metabolites were different in male and female kidneys.
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Affiliation(s)
- Md. Monirul Islam
- Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-Ku, Hamamatsu City 431-3192, Shizuoka, Japan; (M.M.I.); (M.F.R.); (A.I.); (M.S.A.); (M.A.M.); (T.S.); (Y.T.); (T.S.); (T.K.)
- Institute of Food and Radiation Biology, Atomic Energy Research Establishment, Bangladesh Atomic Energy Commission, Dhaka 1349, Bangladesh
| | - Md Foyzur Rahman
- Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-Ku, Hamamatsu City 431-3192, Shizuoka, Japan; (M.M.I.); (M.F.R.); (A.I.); (M.S.A.); (M.A.M.); (T.S.); (Y.T.); (T.S.); (T.K.)
| | - Ariful Islam
- Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-Ku, Hamamatsu City 431-3192, Shizuoka, Japan; (M.M.I.); (M.F.R.); (A.I.); (M.S.A.); (M.A.M.); (T.S.); (Y.T.); (T.S.); (T.K.)
- Department of Biochemistry and Microbiology, School of Health and Life Sciences, North South University, Bashundhara, Dhaka 1229, Bangladesh
- Preppers Co., Ltd., Hamamatsu City 431-3192, Shizuoka, Japan
| | - Mst. Sayela Afroz
- Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-Ku, Hamamatsu City 431-3192, Shizuoka, Japan; (M.M.I.); (M.F.R.); (A.I.); (M.S.A.); (M.A.M.); (T.S.); (Y.T.); (T.S.); (T.K.)
| | - Md. Al Mamun
- Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-Ku, Hamamatsu City 431-3192, Shizuoka, Japan; (M.M.I.); (M.F.R.); (A.I.); (M.S.A.); (M.A.M.); (T.S.); (Y.T.); (T.S.); (T.K.)
- Preppers Co., Ltd., Hamamatsu City 431-3192, Shizuoka, Japan
| | - Md. Muedur Rahman
- Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-Ku, Hamamatsu City 431-3192, Shizuoka, Japan; (M.M.I.); (M.F.R.); (A.I.); (M.S.A.); (M.A.M.); (T.S.); (Y.T.); (T.S.); (T.K.)
- Preppers Co., Ltd., Hamamatsu City 431-3192, Shizuoka, Japan
| | - Md Maniruzzaman
- Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-Ku, Hamamatsu City 431-3192, Shizuoka, Japan; (M.M.I.); (M.F.R.); (A.I.); (M.S.A.); (M.A.M.); (T.S.); (Y.T.); (T.S.); (T.K.)
| | - Lili Xu
- Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-Ku, Hamamatsu City 431-3192, Shizuoka, Japan; (M.M.I.); (M.F.R.); (A.I.); (M.S.A.); (M.A.M.); (T.S.); (Y.T.); (T.S.); (T.K.)
| | - Takumi Sakamoto
- Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-Ku, Hamamatsu City 431-3192, Shizuoka, Japan; (M.M.I.); (M.F.R.); (A.I.); (M.S.A.); (M.A.M.); (T.S.); (Y.T.); (T.S.); (T.K.)
- Preppers Co., Ltd., Hamamatsu City 431-3192, Shizuoka, Japan
| | - Yutaka Takahashi
- Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-Ku, Hamamatsu City 431-3192, Shizuoka, Japan; (M.M.I.); (M.F.R.); (A.I.); (M.S.A.); (M.A.M.); (T.S.); (Y.T.); (T.S.); (T.K.)
- Preppers Co., Ltd., Hamamatsu City 431-3192, Shizuoka, Japan
- International Mass Imaging Center, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-Ku, Hamamatsu City 431-3192, Shizuoka, Japan
| | - Tomohito Sato
- Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-Ku, Hamamatsu City 431-3192, Shizuoka, Japan; (M.M.I.); (M.F.R.); (A.I.); (M.S.A.); (M.A.M.); (T.S.); (Y.T.); (T.S.); (T.K.)
- International Mass Imaging Center, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-Ku, Hamamatsu City 431-3192, Shizuoka, Japan
| | - Tomoaki Kahyo
- Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-Ku, Hamamatsu City 431-3192, Shizuoka, Japan; (M.M.I.); (M.F.R.); (A.I.); (M.S.A.); (M.A.M.); (T.S.); (Y.T.); (T.S.); (T.K.)
- International Mass Imaging Center, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-Ku, Hamamatsu City 431-3192, Shizuoka, Japan
| | - Mitsutoshi Setou
- Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-Ku, Hamamatsu City 431-3192, Shizuoka, Japan; (M.M.I.); (M.F.R.); (A.I.); (M.S.A.); (M.A.M.); (T.S.); (Y.T.); (T.S.); (T.K.)
- Preppers Co., Ltd., Hamamatsu City 431-3192, Shizuoka, Japan
- International Mass Imaging Center, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-Ku, Hamamatsu City 431-3192, Shizuoka, Japan
- Department of Systems Molecular Anatomy, Institute for Medical Photonics Research, Preeminent Medical Photonics Education and Research Center, 1-20-1 Handayama, Chuo-Ku, Hamamatsu City 431-3192, Shizuoka, Japan
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Yamazoe Y, Yamamura Y, Yoshinari K. Construction of a fused grid-based CYP2C8-Template system and the application. Drug Metab Pharmacokinet 2024; 55:100492. [PMID: 38609777 DOI: 10.1016/j.dmpk.2023.100492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 01/03/2023] [Accepted: 01/16/2023] [Indexed: 01/22/2023]
Abstract
A ligand-accessible space in the CYP2C8 active site was reconstituted as a fused grid-based Template∗ with the use of structural data of the ligands. An evaluation system of CYP2C8-mediated metabolism has been developed on Template with the introduction of the idea of Trigger-residue initiated ligand-movement and fastening. Reciprocal comparison of the data of simulation on Template with experimental results suggested a unified way of the interaction of CYP2C8 and its ligands through the simultaneous plural-contact with Rear-wall of Template. CYP2C8 was expected to have a room for ligands between vertically standing parallel walls termed Facial-wall and Rear-wall. Both the walls were separated by a distance corresponding to 1.5-Ring (grid) diameter size, which was termed Width-gauge. The ligand sittings were stabilized through contacts with Facial-wall and the left-side borders of Template including specific Position 29, left-side border of Rings I/J, or Left-end, after Trigger-residue initiated ligand-movement. Trigger-residue movement is suggested to force ligands to stay firmly in the active site and then to initiate CYP2C8 reactions. Simulation experiments for over 350 reactions of CYP2C8 ligands supported the system established.
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Affiliation(s)
- Yasushi Yamazoe
- Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai, 980-8578, Japan; Division of Risk Assessment, National Institute of Health Sciences, Tonomachi 3-25-26, Kawasaki-ku, Kawasaki, 210-9501, Japan.
| | - Yoshiya Yamamura
- Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan; Non-Clinical Regulatory Science, Applied Research & Operations, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba, Ibaraki, 305-8585, Japan
| | - Kouichi Yoshinari
- Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan
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Li X, Le Y, Li Y, Chen S, Guo L, Fu X, Manjanatha MG, Mei N. Evaluation of weak genotoxicity of hydroxychloroquine in human TK6 cells. Toxicol Lett 2024; 393:84-95. [PMID: 38311193 PMCID: PMC11369915 DOI: 10.1016/j.toxlet.2024.01.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 01/25/2024] [Accepted: 01/29/2024] [Indexed: 02/10/2024]
Abstract
Hydroxychloroquine (HCQ), a derivative of chloroquine (CQ), is an antimalarial and antirheumatic drug. Since there is limited data available on the genotoxicity of HCQ, in the current study, we used a battery of in vitro assays to systematically examine the genotoxicity of HCQ in human lymphoblastoid TK6 cells. We first showed that HCQ is not mutagenic in TK6 cells up to 80 μM with or without exogenous metabolic activation. Subsequently, we found that short-term (3-4 h) HCQ treatment did not cause DNA strand breakage as measured by the comet assay and the phosphorylation of histone H2A.X (γH2A.X), and did not induce chromosomal damage as determined by the micronucleus (MN) assay. However, after 24-h treatment, both CQ and HCQ induced comparable and weak DNA damage and MN formation in TK6 cells; upregulated p53 and p53-mediated DNA damage responsive genes; and triggered apoptosis and mitochondrial damage that may partially contribute to the observed MN formation. Using a benchmark dose (BMD) modeling analysis, the lower 95% confidence limit of BMD50 values (BMDL50) for MN induction in TK6 cells were about 19.7 μM for CQ and 16.3 μM for HCQ. These results provide additional information for quantitative genotoxic risk assessment of these drugs.
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Affiliation(s)
- Xilin Li
- Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, Jefferson, AR 72079, USA.
| | - Yuan Le
- Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, Jefferson, AR 72079, USA
| | - Yuxi Li
- Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, Jefferson, AR 72079, USA
| | - Si Chen
- Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079, USA
| | - Lei Guo
- Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079, USA
| | - Xin Fu
- Division of Pharmacology Toxicology Review, Office of Safety and Clinical Evaluation, Center for Drug Evaluation and Research, Silver Spring, MD 20993, USA
| | - Mugimane G Manjanatha
- Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, Jefferson, AR 72079, USA
| | - Nan Mei
- Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, Jefferson, AR 72079, USA.
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Jatta N, Stanslas J, Yong ACH, Ho WC, Wan Ahmad Kammal WSL, Chua EW, How KN. Whole blood hydroxychloroquine: Does genetic polymorphism of cytochrome P450 enzymes have a role? Clin Exp Med 2023; 23:4141-4152. [PMID: 37480404 DOI: 10.1007/s10238-023-01142-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 07/12/2023] [Indexed: 07/24/2023]
Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a wide range of clinical manifestations and multifactorial etiologies ranging from environmental to genetic. SLE is associated with dysregulated immunological reactions, with increased immune complex formation leading to end-organ damages such as lupus nephritis, cutaneous lupus, and musculoskeletal disorders. Lupus treatment aims to reduce disease activity, prevent organ damage, and improve long-term patient survival and quality of life. Antimalarial, hydroxychloroquine (HCQ) is used as a first-line systemic treatment for lupus. It has shown profound efficacy in lupus and its associated conditions. However, wide variation in terms of clinical response to this drug has been observed among this group of patients. This variability has limited the potential of HCQ to achieve absolute clinical benefits. Several factors, including genetic polymorphisms of cytochrome P450 enzymes, have been stipulated as key entities leading to this inter-individual variation. Thus, there is a need for more studies to understand the role of genetic polymorphisms in CYP450 enzymes in the clinical response to HCQ. Focusing on the role of genetic polymorphism on whole blood HCQ in lupus disorder, this review aims to highlight up-to-date pathophysiology of SLE, the mechanism of action of HCQ, and finally the role of genetic polymorphism of CYP450 enzymes on whole blood HCQ level as well as clinical response in lupus.
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Affiliation(s)
- Njundu Jatta
- Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
| | - Johnson Stanslas
- Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
| | - Audrey Chee Hui Yong
- School of Pharmacy, MAHSA University, Bandar Saujana Putra, Jenjarom, Selangor, Malaysia
| | - Wen Chung Ho
- Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
- Dermatology Unit, Hospital Sultan Abdul Aziz Shah, Universiti Putra Malaysia, Serdang, Malaysia
| | - Wan Syazween Lyana Wan Ahmad Kammal
- Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
- Dermatology Unit, Hospital Sultan Abdul Aziz Shah, Universiti Putra Malaysia, Serdang, Malaysia
| | - Eng Wee Chua
- Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, Kuala Lumpur, Malaysia
| | - Kang Nien How
- Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia.
- Dermatology Unit, Hospital Sultan Abdul Aziz Shah, Universiti Putra Malaysia, Serdang, Malaysia.
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Khojasteh SC, Argikar UA, Cheruzel L, Cho S, Crouch RD, Dhaware D, Heck CJS, Johnson KM, Kalgutkar AS, King L, Liu J, Ma B, Maw H, Miller GP, Seneviratne HK, Takahashi RH, Wang S, Wei C, Jackson KD. Biotransformation research advances - 2022 year in review. Drug Metab Rev 2023; 55:301-342. [PMID: 37737116 DOI: 10.1080/03602532.2023.2262161] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 06/05/2023] [Indexed: 09/23/2023]
Abstract
This annual review is the eighth of its kind since 2016 (Baillie et al. 2016, Khojasteh et al. 2017, Khojasteh et al. 2018, Khojasteh et al. 2019, Khojasteh et al. 2020, Khojasteh et al. 2021, Khojasteh et al. 2022). Our objective is to explore and share articles which we deem influential and significant in the field of biotransformation.
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Affiliation(s)
- S Cyrus Khojasteh
- Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc, South San Francisco, CA, USA
| | - Upendra A Argikar
- Non-clinical Development, Bill and Melinda Gates Medical Research Institute, Cambridge, MA, USA
| | - Lionel Cheruzel
- Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc, South San Francisco, CA, USA
| | - Sungjoon Cho
- Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc, South San Francisco, CA, USA
| | - Rachel D Crouch
- Department of Pharmacy and Pharmaceutical Sciences, Lipscomb University College of Pharmacy, Nashville, TN, USA
| | | | - Carley J S Heck
- Medicine Design, Pfizer Worldwide Research, Development and Medical, Groton, CT, USA
| | - Kevin M Johnson
- Drug Metabolism and Pharmacokinetics, Inotiv, MD Heights, MO, USA
| | - Amit S Kalgutkar
- Medicine Design, Pfizer Worldwide Research, Development and Medical, Cambridge, MA, USA
| | - Lloyd King
- Quantitative Drug Discovery, UCB Biopharma UK, Slough UK
| | - Joyce Liu
- Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc, South San Francisco, CA, USA
| | - Bin Ma
- Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc, South San Francisco, CA, USA
| | - Hlaing Maw
- Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT, USA
| | - Grover P Miller
- Department of Biochemistry and Molecular Biology, University of AR for Medical Sciences, Little Rock, AR, USA
| | | | - Ryan H Takahashi
- Drug Metabolism and Pharmacokinetics, Denali Therapeutics, South San Francisco, CA, USA
| | - Shuai Wang
- Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc, South San Francisco, CA, USA
| | - Cong Wei
- Drug Metabolism and Pharmacokinetics, Biogen Inc, Cambridge, MA, USA
| | - Klarissa D Jackson
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, NC, USA
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7
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Paludetto MN, Kurkela M, Kahma H, Backman JT, Niemi M, Filppula AM. Hydroxychloroquine is Metabolized by Cytochrome P450 2D6, 3A4, and 2C8, and Inhibits Cytochrome P450 2D6, while its Metabolites also Inhibit Cytochrome P450 3A in vitro. Drug Metab Dispos 2023; 51:293-305. [PMID: 36446607 DOI: 10.1124/dmd.122.001018] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 10/26/2022] [Accepted: 10/31/2022] [Indexed: 12/05/2022] Open
Abstract
This study aimed to explore the cytochrome P450 (CYP) metabolic and inhibitory profile of hydroxychloroquine (HCQ). Hydroxychloroquine metabolism was studied using human liver microsomes (HLMs) and recombinant CYP enzymes. The inhibitory effects of HCQ and its metabolites on nine CYPs were also determined in HLMs, using an automated substrate cocktail method. Our metabolism data indicated that CYP3A4, CYP2D6, and CYP2C8 are the key enzymes involved in HCQ metabolism. All three CYPs formed the primary metabolites desethylchloroquine (DCQ) and desethylhydroxychloroquine (DHCQ) to various degrees. Although the intrinsic clearance (CLint) value of HCQ depletion by recombinant CYP2D6 was > 10-fold higher than that by CYP3A4 (0.87 versus 0.075 µl/min/pmol), scaling of recombinant CYP CLint to HLM level resulted in almost equal HLM CLint values for CYP2D6 and CYP3A4 (11 and 14 µl/min/mg, respectively). The scaled HLM CLint of CYP2C8 was 5.7 µl/min/mg. Data from HLM experiments with CYP-selective inhibitors also suggested relatively equal roles for CYP2D6 and CYP3A4 in HCQ metabolism, with a smaller contribution by CYP2C8. In CYP inhibition experiments, HCQ, DCQ, DHCQ, and the secondary metabolite didesethylchloroquine were direct CYP2D6 inhibitors, with 50% inhibitory concentration (IC50) values between 18 and 135 µM. HCQ did not inhibit other CYPs. Furthermore, all metabolites were time-dependent CYP3A inhibitors (IC50 shift 2.2-3.4). To conclude, HCQ is metabolized by CYP3A4, CYP2D6, and CYP2C8 in vitro. HCQ and its metabolites are reversible CYP2D6 inhibitors, and HCQ metabolites are time-dependent CYP3A inhibitors. These data can be used to improve physiologically-based pharmacokinetic models and update drug-drug interaction risk estimations for HCQ. SIGNIFICANCE STATEMENT: While CYP2D6, CYP3A4, and CYP2C8 have been shown to mediate chloroquine biotransformation, it appears that the role of CYP enzymes in hydroxychloroquine (HCQ) metabolism has not been studied. In addition, little is known about the CYP inhibitory effects of HCQ. Here, we demonstrate that CYP2D6, CYP3A4, and CYP2C8 are the key enzymes involved in HCQ metabolism. Furthermore, our findings show that HCQ and its metabolites are inhibitors of CYP2D6, which likely explains the previously observed interaction between HCQ and metoprolol.
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Affiliation(s)
- Marie-Noëlle Paludetto
- Department of Clinical Pharmacology and Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Finland (M.-N.P., M.K., H.K., J.T.B., M.N., A.M.F.); HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland (J.T.B., M.N.); and Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland (A.M.F.)
| | - Mika Kurkela
- Department of Clinical Pharmacology and Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Finland (M.-N.P., M.K., H.K., J.T.B., M.N., A.M.F.); HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland (J.T.B., M.N.); and Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland (A.M.F.)
| | - Helinä Kahma
- Department of Clinical Pharmacology and Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Finland (M.-N.P., M.K., H.K., J.T.B., M.N., A.M.F.); HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland (J.T.B., M.N.); and Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland (A.M.F.)
| | - Janne T Backman
- Department of Clinical Pharmacology and Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Finland (M.-N.P., M.K., H.K., J.T.B., M.N., A.M.F.); HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland (J.T.B., M.N.); and Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland (A.M.F.)
| | - Mikko Niemi
- Department of Clinical Pharmacology and Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Finland (M.-N.P., M.K., H.K., J.T.B., M.N., A.M.F.); HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland (J.T.B., M.N.); and Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland (A.M.F.)
| | - Anne M Filppula
- Department of Clinical Pharmacology and Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Finland (M.-N.P., M.K., H.K., J.T.B., M.N., A.M.F.); HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland (J.T.B., M.N.); and Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland (A.M.F.)
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8
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Effect of Binding Linkers on the Efficiency and Metabolite Profile of Biomimetic Reactions Catalyzed by Immobilized Metalloporphyrin. Metabolites 2022; 12:metabo12121269. [PMID: 36557309 PMCID: PMC9783926 DOI: 10.3390/metabo12121269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 12/03/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022] Open
Abstract
The investigation of liver-related metabolic stability of a drug candidate is a widely used key strategy in early-stage drug discovery. Metalloporphyrin-based biomimetic catalysts are good and well-described models of the function of CyP450 in hepatocytes. In this research, the immobilization of an iron porphyrin was performed on nanoporous silica particles via ionic interactions. The effect of the metalloporphyrin binding linkers was investigated on the catalytic efficiency and the metabolic profile of chloroquine as a model drug. The length of the amino-substituted linkers affects the chloroquine conversion as well as the ratio of human major and minor metabolites. While testing the immobilized catalysts in the continuous-flow reactor, results showed that the presented biomimetic system could be a promising alternative for the early-stage investigation of drug metabolites regarding analytical or synthetic goals as well.
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9
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Li X, Wang W, Yan S, Zhao W, Xiong H, Bao C, Chen J, Yue Y, Su Y, Zhang C. Drug-induced liver injury in COVID-19 treatment: Incidence, mechanisms and clinical management. Front Pharmacol 2022; 13:1019487. [PMID: 36518661 PMCID: PMC9742434 DOI: 10.3389/fphar.2022.1019487] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Accepted: 11/14/2022] [Indexed: 07/21/2023] Open
Abstract
The COVID-19 outbreak triggered a serious and potentially lethal pandemic, resulting in massive health and economic losses worldwide. The most common clinical manifestations of COVID-19 patients are pneumonia and acute respiratory distress syndrome, with a variety of complications. Multiple organ failure and damage, ultimately leading to patient death, are possible as a result of medication combinations, and this is exemplified by DILI. We hope to summarize DILI caused by the antiviral drugs favipiravir, remdesivir, lopinavir/ritonavir, and hydroxychloroquine in COVID-19 patients in this review. The incidence of liver injury in the treatment of COVID-19 patients was searched on PubMed to investigate DILI cases. The cumulative prevalence of acute liver injury was 23.7% (16.1%-33.1%). We discuss the frequency of these events, potential mechanisms, and new insights into surveillance strategies. Furthermore, we also describe medication recommendations aimed at preserving DILI caused by treatment in COVID-19 patients.
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Affiliation(s)
- Xichuan Li
- Tianjin Key Laboratory of Animal and Plant Resistance, College of Life Sciences, Tianjin Normal University, Tianjin, China
| | - Wanting Wang
- Department of Colorectal Surgery, Tianjin Institute of Coloproctology, The Institute of Translational Medicine, Tianjin Union Medical Center of Nankai University, Tianjin, China
- Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Suying Yan
- Department of Colorectal Surgery, Tianjin Institute of Coloproctology, The Institute of Translational Medicine, Tianjin Union Medical Center of Nankai University, Tianjin, China
- Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Weipeng Zhao
- Department of Breast Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China
| | - Hui Xiong
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
| | - Cuiping Bao
- Departments of Radiology, Tianjin Union Medical Center, Tianjin, China
| | - Jinqian Chen
- Departments of Pharmacy, NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital, Tianjin, China
| | - Yuan Yue
- Tianjin Key Laboratory of Animal and Plant Resistance, College of Life Sciences, Tianjin Normal University, Tianjin, China
| | - Yanjun Su
- Department of Lung Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Lung Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China
| | - Chunze Zhang
- Department of Colorectal Surgery, Tianjin Institute of Coloproctology, The Institute of Translational Medicine, Tianjin Union Medical Center of Nankai University, Tianjin, China
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10
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Santos HFP, Guaraldo L, Pedro RS, Damasceno LS, Daniel-Ribeiro CT, Brasil P. Methods to Assess Adult and Adolescent Patients' Adherence to Antimalarial Treatment: A Systematic Review. Front Pharmacol 2022; 13:796027. [PMID: 35571076 PMCID: PMC9092497 DOI: 10.3389/fphar.2022.796027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 03/17/2022] [Indexed: 11/25/2022] Open
Abstract
Malaria is a curable disease for which early diagnosis and treatment, together with the elimination of vectors, are the principal control tools. Non-adherence to antimalarial treatment may contribute to therapeutic failure, development of antimalarial resistance, introduction or resurgence of malaria in non-endemic areas, and increased healthcare costs. The literature describes several methods to directly or indirectly assess adherence to treatment, but no gold standard exists. The main purpose of this review is to systematize the methods used to assess patient adherence to antimalarial treatment. A systematic review was performed, in accordance with the PRISMA statement, of the following databases: LILACS, EMBASE, PUBMED, COCHRANE, GOOGLE SCHOLAR, WEB OF SCIENCE, SCOPUS, and OPENGREY, through 14 December 2021. A snowball search was also performed by screening the references of the included studies as well as those cited in relevant reviews. Inclusion criteria were reporting assessment of the patient's adherence to antimalarials in individuals with laboratory diagnosis of malaria, the description of antimalarials prescribed, and adherence estimates. Exclusion criteria were studies exclusively about directly observed therapy, studies of populations ≤12 yo and guidelines, commentaries, reviews, letters, or editorials. Study quality was assessed using MINORS and the Cochrane Risk of Bias Tool. Proportions were calculated to measure frequencies considering the number of articles as the denominator. Twenty-one studies were included in this review. Most of them (76.5%) assessed adherence to falciparum malaria treatment. Seventeen studies (80.9%) used a combination of methods. The methods described were pill counts, self-reports, biological assays, use of electronic pillboxes, and clinical cure. It was possible to identify different adherence classifications for all the methods used. Our review found that indirect methods like pill counts and self-reports are the most commonly used. Combining an method that gives solid proof of the ingestion of medication and a method that completes the research with information regarding factors, beliefs or barrier of adherence seems to be the best approach. Future studies of antimalarial treatment should standardize adherence classifications, and collect data on the types and causes of nonadherence, which can contribute to the development of tools to promote medication adherence. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020148054, identifier CRD42020148054.
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Affiliation(s)
- Heloísa Ferreira Pinto Santos
- Clinical Research Laboratory on Acute Febrile Illnesses, Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, Brazil
| | - Lusiele Guaraldo
- Clinical Research Laboratory on Acute Febrile Illnesses, Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, Brazil
| | - Renata Saraiva Pedro
- Clinical Advice, Instituto de Tecnologia em Imunobiológicos, Fiocruz, Rio de Janeiro, Brazil
| | - Luana Santana Damasceno
- Clinical Research Laboratory on Acute Febrile Illnesses, Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, Brazil
| | - Cláudio Tadeu Daniel-Ribeiro
- Malaria Research Laboratory, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, Brazil
- Centro de Pesquisa, Diagnóstico e Treinamento em Malária, Fiocruz and Secretaria de Vigilância em Saúde, Ministério da Saúde, Rio de Janeiro, Brazil
| | - Patrícia Brasil
- Clinical Research Laboratory on Acute Febrile Illnesses, Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, Brazil
- Centro de Pesquisa, Diagnóstico e Treinamento em Malária, Fiocruz and Secretaria de Vigilância em Saúde, Ministério da Saúde, Rio de Janeiro, Brazil
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11
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Guo J, Li F, Cheng F, Ma L, Liu X, Durairaj P, Zhang G, Tang D, Long X, Zhang W, Du L, Zhang X, Li S. Bacterial Biosynthetic P450 Enzyme PikC D50N: A Potential Biocatalyst for the Preparation of Human Drug Metabolites. J Org Chem 2021; 86:14563-14571. [PMID: 34662127 DOI: 10.1021/acs.joc.1c01407] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Human drug metabolites (HDMs) are important chemicals widely used in drug-related studies. However, acquiring these enzyme-derived and regio-/stereo-selectively modified compounds through chemical approaches is complicated. PikC is a biosynthetic P450 enzyme involved in pikromycin biosynthesis from the bacterium Streptomyces venezuelae. Here, we identify the mutant PikCD50N as a potential biocatalyst, with a broad substrate scope, diversified product profile, and high catalytic efficiency, for preparation of HDMs. Remarkably, PikCD50N can mediate the drug-metabolizing reactions using the low-cost H2O2 as a direct electron and oxygen donor.
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Affiliation(s)
- Jiawei Guo
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong 266237, China.,Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, Shandong 266237, China
| | - Fengwei Li
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong 266237, China
| | - Fangyuan Cheng
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong 266237, China
| | - Li Ma
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong 266237, China
| | - Xiaohui Liu
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong 266237, China
| | - Pradeepraj Durairaj
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong 266237, China
| | - Gang Zhang
- Fujian Universities and Colleges Engineering Research Center of Marine Biopharmaceutical Resources, Xiamen Medical College, Xiamen, Fujian 361023, China
| | - Dandan Tang
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong 266237, China
| | - Xiangtian Long
- Tianjin Hankang Pharmaceutical Biotechnology Co. Ltd., Tianjin 300409, China
| | - Wei Zhang
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong 266237, China
| | - Lei Du
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong 266237, China
| | - Xingwang Zhang
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong 266237, China
| | - Shengying Li
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong 266237, China.,Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, Shandong 266237, China
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12
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Pharmacokinetics and Toxicokinetics of Artemisinin-Hydroxychloroquine Sulfate Tablets in Rats and Dogs. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:6830459. [PMID: 34721641 PMCID: PMC8553450 DOI: 10.1155/2021/6830459] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 08/12/2021] [Accepted: 09/22/2021] [Indexed: 11/18/2022]
Abstract
Artemisinin-hydroxychloroquine sulfate tablets (AH) are relatively inexpensive and a novel combination therapy for the treatment of all forms of malaria, especially aminoquinine drug-resistant strains of P. falciparum. Our aim was to assess the pharmacokinetics (PK) and toxicokinetics (TK) of AH following oral administration in Sprague Dawley rats and Beagle dogs by using the liquid chromatography tandem mass spectrometry methods (LC-MS/MS). The PK studies were carried out in eighteen rats at three doses and six dogs at three rounds of three doses after a single oral administration of AH. The TK studies in rats and dogs were accompanied by the 14-day repeated dosing studies. The PK results revealed that artemisinin was absorbed and cleared rapidly in rats with obvious gender difference and interindividual variability, and the systemic exposure with regard to AUC was positively correlated with the dosage in female rats. However, the kinetics parameters of artemisinin in dogs were not obtained because the plasma concentration was undetectable. The absorption and elimination of hydroxychloroquine in dogs and rats were relatively slow, and no gender difference was observed. The AUC of hydroxychloroquine showed a linear correlation with the dosage, but C max varied significantly among individuals. After 14-day repeated oral administration of AH, hydroxychloroquine shows an increase in systemic exposure and accumulation in rats and dogs, whereas the AUC and C max of artemisinin remarkably decreased in female rats due to its autoinduction metabolism. The TK results were basically consistent with the dose- and time-dependent toxic reaction in 14-day repeated dosing studies of AH in rats and dogs. The information from our studies could be helpful for further pharmacological and toxicological research and clinical application of AH.
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13
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Kumar R, Sharma A, Srivastava JK, Siddiqui MH, Uddin MS, Aleya L. Hydroxychloroquine in COVID-19: therapeutic promises, current status, and environmental implications. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2021; 28:40431-40444. [PMID: 33447984 PMCID: PMC7808930 DOI: 10.1007/s11356-020-12200-1] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 12/22/2020] [Indexed: 04/16/2023]
Abstract
The outbreak of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected the entire world with its infectious spread and mortality rate. The severe cases of coronavirus disease 2019 (COVID-19) are characterized by hypoxia and acute respiratory distress syndrome. In the absence of any specific treatment, just the preventive and supportive care options are available. Therefore, much focus is given to assess the available therapeutic options not only to avoid acute respiratory failure and hypoxia but also to reduce the viral load to control the severity of the disease. The antimalarial drug hydroxychloroquine (HCQ) is among the much-discussed drugs for the treatment and management of COVID-19 patients. This article reviews the therapeutic potential of HCQ in the treatment of COVID-19 based on the available in vitro and clinical evidence, current status of registered HCQ-based clinical trials investigating therapeutic options for COVID-19, and environmental implications of HCQ.
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Affiliation(s)
- Rajnish Kumar
- Amity Institute of Biotechnology, Amity University Uttar Pradesh Lucknow Campus, Uttar Pradesh, India.
| | - Anju Sharma
- Department of Applied Science, Indian Institute of Information Technology, Allahabad, Uttar Pradesh, India
| | - Janmejai Kumar Srivastava
- Amity Institute of Biotechnology, Amity University Uttar Pradesh Lucknow Campus, Uttar Pradesh, India
| | | | - Md Sahab Uddin
- Department of Pharmacy, Southeast University, Dhaka, Bangladesh.
- Pharmakon Neuroscience Research Network, Dhaka, Bangladesh.
| | - Lotfi Aleya
- Chrono-Environnement Laboratory, UMR CNRS 6249, Bourgogne Franche-Comté University, Besançon, France.
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14
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Askarian F, Firoozi Z, Ebadollahi-Natanzi A, Bahrami S, Rahimi HR. A review on the pharmacokinetic properties and toxicity considerations for chloroquine and hydroxychloroquine to potentially treat coronavirus patients. Toxicol Res 2021; 38:137-148. [PMID: 34306523 PMCID: PMC8286988 DOI: 10.1007/s43188-021-00101-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 04/10/2021] [Accepted: 06/07/2021] [Indexed: 02/06/2023] Open
Abstract
The SARS-CoV-2 virus, caused a novel emerged coronavirus disease, is growing rapidly worldwide. Few studies have evaluated the efficacy and safety of Chloroquine (CQ), an old antimalarial drug, and Hydroxychloroquine (HCQ) in the treatment of COVID-19 infection. HCQ is derived from CQ by adding a hydroxyl group into it and is a less toxic derivative of CQ for the treatment of COVID-19 infection because it is more soluble. This article summarizes pharmacokinetic properties and toxicity considerations for CQ and HCQ, drug interactions, and their potential efficacy against COVID-19. The authors also look at the biochemistry changes and clinical uses of CQ and HCQ, and supportive treatments following toxicity occurs. It was believed that CQ and HCQ may provide few benefits to COVID-19 patients. A number of factors should be considered to keep the drug safe, such as dose, in vivo animal toxicological findings, and gathering of metabolites in plasma and/or tissues. The main conclusion of this review is that CQ and HCQ with considered to their ADMET properties has major shortcomings and fully irresponsible.
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Affiliation(s)
- Fatemeh Askarian
- Student Research Committee, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran
| | - Zahra Firoozi
- Department of Medical Genetics, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Alireza Ebadollahi-Natanzi
- Medicinal Plants Department, Imam Khomeini Higher Education Center, Agricultural Research, Education and Extension Organization (AREEO), Karaj, Iran
| | - Solmaz Bahrami
- Department of Institutional Research, Westcliff University, Irvine, CA 92614 USA
| | - Hamid-Reza Rahimi
- Student Research Committee, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran.,Department of Pharmacology and Toxicology, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran
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15
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Deb S, Reeves AA, Hopefl R, Bejusca R. ADME and Pharmacokinetic Properties of Remdesivir: Its Drug Interaction Potential. Pharmaceuticals (Basel) 2021; 14:ph14070655. [PMID: 34358081 PMCID: PMC8308800 DOI: 10.3390/ph14070655] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 06/24/2021] [Accepted: 06/28/2021] [Indexed: 02/07/2023] Open
Abstract
On 11 March 2020, the World Health Organization (WHO) classified the Coronavirus Disease 2019 (COVID-19) as a global pandemic, which tested healthcare systems, administrations, and treatment ingenuity across the world. COVID-19 is caused by the novel beta coronavirus Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Since the inception of the pandemic, treatment options have been either limited or ineffective. Remdesivir, a drug originally designed to be used for Ebola virus, has antiviral activity against SARS-CoV-2 and has been included in the COVID-19 treatment regimens. Remdesivir is an adenosine nucleotide analog prodrug that is metabolically activated to a nucleoside triphosphate metabolite (GS-443902). The active nucleoside triphosphate metabolite is incorporated into the SARS-CoV-2 RNA viral chains, preventing its replication. The lack of reported drug development and characterization studies with remdesivir in public domain has created a void where information on the absorption, distribution, metabolism, elimination (ADME) properties, pharmacokinetics (PK), or drug-drug interaction (DDI) is limited. By understanding these properties, clinicians can prevent subtherapeutic and supratherapeutic levels of remdesivir and thus avoid further complications in COVID-19 patients. Remdesivir is metabolized by both cytochrome P450 (CYP) and non-CYP enzymes such as carboxylesterases. In this narrative review, we have evaluated the currently available ADME, PK, and DDI information about remdesivir and have discussed the potential of DDIs between remdesivir and different COVID-19 drug regimens and agents used for comorbidities. Considering the nascent status of remdesivir in the therapeutic domain, extensive future work is needed to formulate safer COVID-19 treatment guidelines involving this medication.
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16
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Akın A, Şen V, Yılmaz K, Aktar F, Türe M, Mermutluoğlu Ç, Gözü Pirinççioğlu A. Electrocardiographic Ventricular Repolarization Variables in Children Diagnosed With COVID-19. Turk Arch Pediatr 2021; 56:394-395. [PMID: 35005737 PMCID: PMC8655970 DOI: 10.5152/turkarchpediatr.2021.21092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 05/08/2021] [Indexed: 11/22/2022]
Affiliation(s)
- Alper Akın
- Department of Pediatric Cardiology, Dicle University School of Medicine, Diyarbakır, Turkey
| | - Velat Şen
- Department of Pediatrics, Dicle University School of Medicine, Diyarbakır, Turkey
| | - Kamil Yılmaz
- Department of Pediatrics, Dicle University School of Medicine, Diyarbakır, Turkey
| | - Fesih Aktar
- Department of Pediatrics, Dicle University School of Medicine, Diyarbakır, Turkey
| | - Mehmet Türe
- Department of Pediatric Cardiology, Dicle University School of Medicine, Diyarbakır, Turkey
| | - Çiğdem Mermutluoğlu
- Department of Infectious Disease and Clinical Microbiology, Dicle University School of Medicine, Diyarbakır, Turkey
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Jain A, Prajapati SK, Tripathi M, Raichur AM, Kanwar JR. Exploring the room for repurposed hydroxychloroquine to impede COVID-19: toxicities and multipronged combination approaches with pharmaceutical insights. Expert Rev Clin Pharmacol 2021; 14:715-734. [PMID: 33769888 DOI: 10.1080/17512433.2021.1909473] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Introduction: SARS-CoV-2 has fatally affected the whole world with millions of deaths. Amidst the dilemma of a breakthrough in vaccine development, hydroxychloroquine (HCQ) was looked upon as a prospective repurposed candidate. It has confronted numerous controversies in the past few months as a chemoprophylactic and treatment option for COVID-19. Recently, it has been withdrawn by the World Health Organization for its use in an ongoing pandemic. However, its benefit/risk ratio regarding its use in COVID-19 disease remains poorly justified. An extensive literature search was done using Scopus, PubMed, Google Scholar, www.cdc.gov, www.fda.gov, and who.int.Areas covered: Toxicity vexations of HCQ; pharmaceutical perspectives on new advances in drug delivery approaches; computational modeling (PBPK and PD modeling) overtures; multipronged combination approaches for enhanced synergism with antiviral and anti-inflammatory agents; immuno-boosting effects.Expert commentary: Harnessing the multipronged pharmaceutical perspectives will optimistically help the researchers, scientists, biotech, and pharmaceutical companies to bring new horizons in the safe and efficacious utilization of HCQ alone or in combination with remdesivir and immunomodulatory molecules like bovine lactoferrin in a fight against COVID-19. Combinational therapies with free forms or nanomedicine based targeted approaches can act synergistically to boost host immunity and stop SARS-CoV-2 replication and invasion to impede the infection.
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Affiliation(s)
- Ankit Jain
- Department of Materials Engineering, Indian Institute of Science, Bangalore - Karnataka, India
| | - Shiv Kumar Prajapati
- Department of Pharmaceutical Sciences, Ram-Eesh Institute of Vocational and Technical Education, Greater Noida, Uttar Pradesh, India
| | - Madhavi Tripathi
- Department of Materials Engineering, Indian Institute of Science, Bangalore - Karnataka, India
| | - Ashok M Raichur
- Department of Materials Engineering, Indian Institute of Science, Bangalore - Karnataka, India
| | - Jagat R Kanwar
- Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), Bhopal, Madhya Pradesh, India
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Hammoudeh SM, Hammoudeh AM, Bhamidimarri PM, Mahboub B, Halwani R, Hamid Q, Rahmani M, Hamoudi R. Insight into molecular mechanisms underlying hepatic dysfunction in severe COVID-19 patients using systems biology. World J Gastroenterol 2021; 27:2850-2870. [PMID: 34135558 PMCID: PMC8173390 DOI: 10.3748/wjg.v27.i21.2850] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 03/30/2021] [Accepted: 05/10/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The coronavirus disease 2019 (COVID-19), a pandemic contributing to more than 105 million cases and more than 2.3 million deaths worldwide, was described to be frequently accompanied by extrapulmonary manifestations, including liver dysfunction. Liver dysfunction and elevated liver enzymes were observed in about 53% of COVID-19 patients.
AIM To gain insight into transcriptional abnormalities in liver tissue of severe COVID-19 patients that may result in liver dysfunction.
METHODS The transcriptome of liver autopsy samples from severe COVID-19 patients against those of non-COVID donors was analyzed. Differentially expressed genes were identified from normalized RNA-seq data and analyzed for the enrichment of functional clusters and pathways. The differentially expressed genes were then compared against the genetic signatures of liver diseases including cirrhosis, fibrosis, non-alcoholic fatty liver disease (NAFLD), and hepatitis A/B/C. Gene expression of some differentially expressed genes was assessed in the blood samples of severe COVID-19 patients with liver dysfunction using qRT-PCR.
RESULTS Analysis of the differential transcriptome of the liver tissue of severe COVID-19 patients revealed a significant upregulation of transcripts implicated in tissue remodeling including G-coupled protein receptors family genes, DNAJB1, IGF2, EGFR, and HDGF. Concordantly, the differential transcriptome of severe COVID-19 liver tissues substantially overlapped with the disease signature of liver diseases characterized with pathological tissue remodeling (liver cirrhosis, Fibrosis, NAFLD, and hepatitis A/B/C). Moreover, we observed a significant suppression of transcripts implicated in metabolic pathways as well as mitochondrial function, including cytochrome P450 family members, ACAD11, CIDEB, GNMT, and GPAM. Consequently, drug and xenobiotics metabolism pathways are significantly suppressed suggesting a decrease in liver detoxification capacity. In correspondence with the RNA-seq data analysis, we observed a significant upregulation of DNAJB1 and HSP90AB1 as well as significant downregulation of CYP39A1 in the blood plasma of severe COVID-19 patients with liver dysfunction.
CONCLUSION Severe COVID-19 patients appear to experience significant transcriptional shift that may ensue tissue remodeling, mitochondrial dysfunction and lower hepatic detoxification resulting in the clinically observed liver dysfunction.
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Affiliation(s)
- Sarah Musa Hammoudeh
- Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Arabella Musa Hammoudeh
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
- General Surgery Department, Tawam Hospital, SEHA, Al-Ain 15258, United Arab Emirates
| | - Poorna Manasa Bhamidimarri
- Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Bassam Mahboub
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
- Rashid Hospital, 315 Umm Hurair Second, Dubai Health Authority, Dubai 4545, United Arab Emirates
| | - Rabih Halwani
- Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Qutayba Hamid
- Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
- Meakins-Christie Laboratories, McGill University, Quebec H4A 3J1, Montreal, Canada
| | - Mohamed Rahmani
- Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Rifat Hamoudi
- Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
- Division of Surgery and Interventional Science, University College London, London W1W 7TY, United Kingdom
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Attah AF, Fagbemi AA, Olubiyi O, Dada-Adegbola H, Oluwadotun A, Elujoba A, Babalola CP. Therapeutic Potentials of Antiviral Plants Used in Traditional African Medicine With COVID-19 in Focus: A Nigerian Perspective. Front Pharmacol 2021; 12:596855. [PMID: 33981214 PMCID: PMC8108136 DOI: 10.3389/fphar.2021.596855] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 01/20/2021] [Indexed: 12/12/2022] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic is caused by an infectious novel strain of coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which was earlier referred to as 2019-nCoV. The respiratory disease is the most consequential global public health crisis of the 21st century whose level of negative impact increasingly experienced globally has not been recorded since World War II. Up till now, there has been no specific globally authorized antiviral drug, vaccines, supplement or herbal remedy available for the treatment of this lethal disease except preventive measures, supportive care and non-specific treatment options adopted in different countries via divergent approaches to halt the pandemic. However, many of these interventions have been documented to show some level of success particularly the Traditional Chinese Medicine while there is paucity of well reported studies on the impact of the widely embraced Traditional African Medicines (TAM) adopted so far for the prevention, management and treatment of COVID-19. We carried out a detailed review of publicly available data, information and claims on the potentials of indigenous plants used in Sub-Saharan Africa as antiviral remedies with potentials for the prevention and management of COVID-19. In this review, we have provided a holistic report on evidence-based antiviral and promising anti-SARS-CoV-2 properties of African medicinal plants based on in silico evidence, in vitro assays and in vivo experiments alongside the available data on their mechanistic pharmacology. In addition, we have unveiled knowledge gaps, provided an update on the effort of African Scientific community toward demystifying the dreadful SARS-CoV-2 micro-enemy of man and have documented popular anti-COVID-19 herbal claims emanating from the continent for the management of COVID-19 while the risk potentials of herb-drug interaction of antiviral phytomedicines when used in combination with orthodox drugs have also been highlighted. This review exercise may lend enough credence to the potential value of African medicinal plants as possible leads in anti-COVID-19 drug discovery through research and development.
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Affiliation(s)
- Alfred Francis Attah
- Department of Pharmacognosy and Drug Development, Faculty of Pharmaceutical Sciences, University of Ilorin, Ilorin, Nigeria
| | - Adeshola Adebayo Fagbemi
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ibadan, Ibadan, Nigeria
| | - Olujide Olubiyi
- Department of Pharmaceutical Chemistry, Obafemi Awolowo University, Ile-Ife, Nigeria
- Institute of Biological Information Processing, Structural Biochemistry (IBI-7), Forschungszentrum Jülich, Jülich, Germany
| | - Hannah Dada-Adegbola
- Department of Medical Microbiology and Parasitology, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | | | - Anthony Elujoba
- Department of Pharmacognosy, Faculty of Pharmacy, Obafemi Awolowo University, Ile-Ife, Nigeria
| | - Chinedum Peace Babalola
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ibadan, Ibadan, Nigeria
- Centre for Drug Discovery, Development and Production, University of Ibadan, Ibadan, Nigeria
- College of Basic Medical Sciences, Chrisland University, Abeokuta, Nigeria
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20
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Tecen‐Yucel K, Aras‐Atik E, Bayraktar‐Ekincioglu A. Does therapeutic drug monitoring of hydroxychloroquine improve treatment outcome in intensive care unit patients with COVID-19? Int J Clin Pract 2021; 75:e13894. [PMID: 33752299 PMCID: PMC8250044 DOI: 10.1111/ijcp.13894] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Affiliation(s)
- Kamer Tecen‐Yucel
- Department of Clinical PharmacyFaculty of PharmacyHacettepe UniversityAnkaraTurkey
| | - Elif Aras‐Atik
- Department of Clinical PharmacyFaculty of PharmacyHacettepe UniversityAnkaraTurkey
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21
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Shah SB, Hariharan U, Chawla R. Common anti-COVID-19 drugs and their anticipated interaction with anesthetic agents. J Anaesthesiol Clin Pharmacol 2021; 37:160-170. [PMID: 34349362 PMCID: PMC8289657 DOI: 10.4103/joacp.joacp_461_20] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 09/21/2020] [Accepted: 11/29/2020] [Indexed: 12/24/2022] Open
Abstract
The corona virus disease 2019 (COVID-19) pandemic has till date (26/7/20) affected 1crore 62 lac 73 thousand 638 people globally with almost 6.5 lakh mortalities. COVID-19 has invaded the operation theatre and intensive care unit (ICU) in a short span of 6 months. It appears inevitable that all of us, as anesthesiologists, have to treat COVID-positive patients, either in the ICU or the operation theatre. Many asymptomatic, presumably noninfected people including frontline health care workers are also consuming potential anticorona viral drugs (such as hydroxychloroquine) prophylactically and may present for surgery. Detailed knowledge of which anesthetic and perioperative care drugs can interact with anti-COVID drugs would be very valuable for pre, intra-, and postoperative management of such patients and COVID-19 positive patients requiring intubation, mechanical ventilation, and ICU-sedation. Powered with this knowledge, anesthesiologists and intensivists can minimize the adverse effects of drug interactions. An extensive literature search using different search engines including Cochrane, Embase, Google Scholar, Scopus, and PubMed for all indexed review articles, original articles, case reports, and referenced webpages was performed to extract the most current and relevant literature on drug-drug interactions for clinicians.
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Affiliation(s)
- Shagun B. Shah
- Rajiv Gandhi Cancer Institute and Research Centre, Sector-5, Rohini, India
| | - Uma Hariharan
- Dr. Ram Manohar Lohia Hospital and PGIMER, CHS, New Delhi, India
| | - Rajiv Chawla
- Rajiv Gandhi Cancer Institute and Research Centre, Sector-5, Rohini, India
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22
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Baburaj G, Thomas L, Rao M. Potential Drug Interactions of Repurposed COVID-19 Drugs with Lung Cancer Pharmacotherapies. Arch Med Res 2021; 52:261-269. [PMID: 33257051 PMCID: PMC7670900 DOI: 10.1016/j.arcmed.2020.11.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Revised: 11/03/2020] [Accepted: 11/12/2020] [Indexed: 12/13/2022]
Abstract
Lung cancer patients are at heightened risk for developing COVID-19 infection as well as complications due to multiple risk factors such as underlying malignancy, anti-cancer treatment induced immunosuppression, additional comorbidities and history of smoking. Recent literatures have reported a significant proportion of lung cancer patients coinfected with COVID-19. Chloroquine, hydroxychloroquine, lopinavir/ritonavir, ribavirin, oseltamivir, remdesivir, favipiravir, and umifenovir represent the major repurposed drugs used as potential experimental agents for COVID-19 whereas azithromycin, dexamethasone, tocilizumab, sarilumab, famotidine and ceftriaxone are some of the supporting agents that are under investigation for COVID-19 management. The rationale of this review is to identify potential drug-drug interactions (DDIs) occurring in lung cancer patients receiving lung cancer medications and repurposed COVID-19 drugs using Micromedex and additional literatures. This review has identified several potential DDIs that could occur with the concomitant treatments of COVID-19 repurposed drugs and lung cancer medications. This information may be utilized by the healthcare professionals for screening and identifying potential DDIs with adverse outcomes, based on their severity and documentation levels and consequently design prophylactic and management strategies for their prevention. Identification, reporting and management of DDIs and dissemination of related information should be a major consideration in the delivery of lung cancer care during this ongoing COVID-19 pandemic for better patient outcomes and updating guidelines for safer prescribing practices in this coinfected condition.
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Affiliation(s)
- Gayathri Baburaj
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Levin Thomas
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Mahadev Rao
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India.
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23
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Eh-Haj BM. Metabolic N-Dealkylation and N-Oxidation as Elucidators of the Role of Alkylamino Moieties in Drugs Acting at Various Receptors. Molecules 2021; 26:1917. [PMID: 33805491 PMCID: PMC8036657 DOI: 10.3390/molecules26071917] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 03/22/2021] [Accepted: 03/24/2021] [Indexed: 12/16/2022] Open
Abstract
Metabolic reactions that occur at alkylamino moieties may provide insight into the roles of these moieties when they are parts of drug molecules that act at different receptors. N-dealkylation of N,N-dialkylamino moieties has been associated with retaining, attenuation or loss of pharmacologic activities of metabolites compared to their parent drugs. Further, N-dealkylation has resulted in clinically used drugs, activation of prodrugs, change of receptor selectivity, and providing potential for developing fully-fledged drugs. While both secondary and tertiary alkylamino moieties (open chain aliphatic or heterocyclic) are metabolized by CYP450 isozymes oxidative N-dealkylation, only tertiary alkylamino moieties are subject to metabolic N-oxidation by Flavin-containing monooxygenase (FMO) to give N-oxide products. In this review, two aspects will be examined after surveying the metabolism of representative alkylamino-moieties-containing drugs that act at various receptors (i) the pharmacologic activities and relevant physicochemical properties (basicity and polarity) of the metabolites with respect to their parent drugs and (ii) the role of alkylamino moieties on the molecular docking of drugs in receptors. Such information is illuminative in structure-based drug design considering that fully-fledged metabolite drugs and metabolite prodrugs have been, respectively, developed from N-desalkyl and N-oxide metabolites.
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Affiliation(s)
- Babiker M Eh-Haj
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, University of Science and Technology of Fujairah, Emirate of Fujairah, Fujairah 2022, United Arab Emirates
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24
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Salem Hareedy M, Rashad SM, Hetta HF, Hassanien SM, Abdellatif H, Hassanien M. CYP2D6 and CYP3A4 variants influence the risk and outcome of COVID-19 infection among rheumatoid arthritis patients maintained on hydroxychloroquine. Drug Metab Pers Ther 2021; 0:dmdi-2020-0164. [PMID: 33770833 DOI: 10.1515/dmdi-2020-0164] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Accepted: 01/19/2021] [Indexed: 12/27/2022]
Abstract
OBJECTIVES Hydroxychloroquine (HCQ) has been used as an off label for the management of coronavirus disease (Covid-19) infection with other drugs. However, different genetic variants can affect the metabolism of HCQ leading to inter-individual differences in its efficacy. In this study, we investigated the effects of variants in CYP2D6, CYP3A4 and CYP3A5 on the risk of Covid-19 infection among patients receiving HCQ for controlling rheumatoid arthritis (RA). METHODS A total of 60 patients were genotyped for CYP2D6*2XN, CYP2D6*4, CYP3A4*1B and CYP3A5*2. They were receiving HCQ for the treatment of RA. The patients were evaluated clinically for fever and dry cough, radiologically via chest computed tomography (CT) and immunologically via anti-Covid-19 IgG and IgM titers. RESULTS Variants in CYP2D6 significantly affected the grade of ground glass (CYP2D6*4 AA carriers showed the higher risk for grade 3) and the risk of positive anti-Covid-19 IgM (CYP2D6*2XN CC and CYP3A4*1B AA had the lowest risk), the duration of HCQ, the use of corticosteroids or gender did not affect the Covid-19 status significantly. CONCLUSIONS In general, the outcome of the studied patients receiving HCQ was good (no deaths, no intubation needed). CYP2D6 variants could affect the outcome of Covid-19 infection.
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Affiliation(s)
- Mohammad Salem Hareedy
- Department of Medical Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | | | - Helal F Hetta
- Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | | | | | - Manal Hassanien
- Department of Rheumatology and Rehabilitation, Assuit University, Assiut, Egypt
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25
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Nishiyama T, Kondo Y, Tsuboi H, Noma H, Tabuchi D, Sugita T, Okamoto S, Terasaki T, Shimizu M, Honda F, Ohyama A, Kurata I, Yagishita M, Abe S, Takahashi H, Osada A, Hagiwara S, Matsumoto I, Sumida T. QTc interval prolongation in patients with systemic lupus erythematosus treated with hydroxychloroquine. Mod Rheumatol 2021; 31:1107-1112. [PMID: 33496215 DOI: 10.1080/14397595.2021.1879368] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
OBJECTIVES The primary objective is to reveal the effect of hydroxychloroquine (HCQ) treatment on corrected QT (QTc) interval in patients with systemic lupus erythematosus (SLE). The secondary objective is to investigate factors that affect QTc prolongation. METHODS SLE patients who had electrocardiograms between 2015 and 2020 were recruited and assigned to two groups based on whether they were treated with HCQ (HCQ group) or not (control group). Change of QTc before and after HCQ administration in the HCQ group was measured and compared with the control group. Patients treated with HCQ were further divided into two groups based on presence or absence of QTc prolongation and the characteristics were compared. RESULTS In total, 126 patients were recruited, of whom 42 were treated with HCQ. In the HCQ group, the mean QTc significantly increased (p < .001), while there was no significant difference of mean QTc in the control group. Moreover, those in the HCQ group with QTc prolongation showed a significantly higher proportion of hypertension and longer SLE duration compared to those without QTc prolongation. However, the multiple logistic regression analysis showed that there were no significant differences among them. CONCLUSION HCQ could induce QTc prolongation in SLE patients. It might be better that the possibility of QTc prolongation was taken into consideration when HCQ was administered in the patients with longer disease duration of SLE and coincidence of hypertension.
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Affiliation(s)
- Taihei Nishiyama
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Yuya Kondo
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Hiroto Tsuboi
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Hisashi Noma
- Department of Data Science, The Institute of Statistical Mathematics, Tokyo, Japan
| | - Daiki Tabuchi
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Toshiki Sugita
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Shota Okamoto
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Toshihiko Terasaki
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Masaru Shimizu
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Fumika Honda
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Ayako Ohyama
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Izumi Kurata
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Mizuki Yagishita
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Saori Abe
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Hiroyuki Takahashi
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Atsumu Osada
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Shinya Hagiwara
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Isao Matsumoto
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Takayuki Sumida
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
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26
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Liu X, Jusko WJ. Physiologically Based Pharmacokinetics of Lysosomotropic Chloroquine in Rat and Human. J Pharmacol Exp Ther 2021; 376:261-272. [PMID: 33277347 PMCID: PMC7841423 DOI: 10.1124/jpet.120.000385] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 12/01/2020] [Indexed: 11/22/2022] Open
Abstract
A semimechanistic physiologically based pharmacokinetic (PBPK) model for chloroquine (CQ), a highly lysosomotropic weak base, was applied to digitized rat and human concentration versus time data. The PBPK model in rat featured plasma and red blood cell (RBC) concentrations, extensive and apparent nonlinear tissue distribution, fitted hepatic and renal intrinsic clearances, and a plasma half-life of about 1 day. Tissue-to-plasma CQ ratios at 50 hours after dosing were highest in lung, kidney, liver, and spleen (182-318) and lower in heart, muscle, brain, eye, and skin (11-66). The RBC-to-plasma ratio of 11.6 was assumed to reflect cell lipid partitioning. A lysosome-based extended model was used to calculate subcellular CQ concentrations based on tissue mass balances, fitted plasma, interstitial and free cytosol concentrations, and literature-based pH and pKa values. The CQ tissue component concentrations ranked as follows: lysosome > > acidic phospholipid > plasma = interstitial = cytosol ≥ neutral lipids. The extensive lysosome sequestration appeared to change over time and was attributed to lowering pH values caused by proton pump influx of hydrogen ions. The human-to-rat volume of distribution (Vss) ratio of 7 used to scale rat tissue partitioning to human along with estimation of hepatic clearance allowed excellent fitting of oral-dose PK (150-600 mg) of CQ with a 50-day half-life in humans. The prolonged PK of chloroquine was well characterized for rat and human with this PBPK model. The calculated intratissue concentrations and lysosomal effects have therapeutic relevance for CQ and other cationic drugs. SIGNIFICANCE STATEMENT: Sequestration in lysosomes is a major factor controlling the pharmacokinetics and pharmacology of chloroquine and other cationic drugs. This report provides comprehensive physiologic modeling of chloroquine distribution in tissues and overall disposition in rat and human that reveals expected complexities and inferences related to its subcellular association with various tissue components.
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Affiliation(s)
- Xin Liu
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, New York
| | - William J Jusko
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, New York
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27
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Rezaee H, Pourkarim F, Pourtaghi‐Anvarian S, Entezari‐Maleki T, Asvadi‐Kermani T, Nouri‐Vaskeh M. Drug-drug interactions with candidate medications used for COVID-19 treatment: An overview. Pharmacol Res Perspect 2021; 9:e00705. [PMID: 33421347 PMCID: PMC7796804 DOI: 10.1002/prp2.705] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 11/20/2020] [Accepted: 11/30/2020] [Indexed: 02/06/2023] Open
Abstract
Drug-drug interaction (DDI) is a common clinical problem that has occurred as a result of the concomitant use of multiple drugs. DDI may occur in patients under treatment with medications used for coronavirus disease 2019 (COVID-19; i.e., chloroquine, lopinavir/ritonavir, ribavirin, tocilizumab, and remdesivir) and increase the risk of serious adverse reactions such as QT-prolongation, retinopathy, increased risk of infection, and hepatotoxicity. This review focuses on summarizing DDIs for candidate medications used for COVID-19 in order to minimize the adverse reactions.
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Affiliation(s)
- Haleh Rezaee
- Infectious Diseases and Tropical Medicine Research CenterTabriz University of Medical SciencesTabrizIran
- Department of Clinical PharmacyFaculty of PharmacyTabriz University of Medical SciencesTabrizIran
| | - Fariba Pourkarim
- Department of Clinical PharmacyFaculty of PharmacyTabriz University of Medical SciencesTabrizIran
| | | | - Taher Entezari‐Maleki
- Department of Clinical PharmacyFaculty of PharmacyTabriz University of Medical SciencesTabrizIran
| | - Touraj Asvadi‐Kermani
- Department of SurgeryFaculty of MedicineTabriz University of Medical SciencesTabrizIran
| | - Masoud Nouri‐Vaskeh
- Immunology Research CenterTabriz University of Medical SciencesTabrizIran
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMAUniversal Scientific Education and Research Network (USERNTehranIran
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Rendic S, Guengerich FP. Metabolism and Interactions of Chloroquine and Hydroxychloroquine with Human Cytochrome P450 Enzymes and Drug Transporters. Curr Drug Metab 2021; 21:1127-1135. [PMID: 33292107 DOI: 10.2174/1389200221999201208211537] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 09/24/2020] [Accepted: 10/08/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND In clinical practice, chloroquine and hydroxychloroquine are often co-administered with other drugs in the treatment of malaria, chronic inflammatory diseases, and COVID-19. Therefore, their metabolic properties and the effects on the activity of cytochrome P450 (P450, CYP) enzymes and drug transporters should be considered when developing the most efficient treatments for patients. METHODS Scientific literature on the interactions of chloroquine and hydroxychloroquine with human P450 enzymes and drug transporters, was searched using PUBMED.Gov (https://pubmed.ncbi.nlm.nih.gov/) and the ADME database (https://life-science.kyushu.fujitsu.com/admedb/). RESULTS Chloroquine and hydroxychloroquine are metabolized by P450 1A2, 2C8, 2C19, 2D6, and 3A4/5 in vitro and by P450s 2C8 and 3A4/5 in vivo by N-deethylation. Chloroquine effectively inhibited P450 2D6 in vitro; however, in vivo inhibition was not apparent except in individuals with limited P450 2D6 activity. Chloroquine is both an inhibitor and inducer of the transporter MRP1 and is also a substrate of the Mate and MRP1 transport systems. Hydroxychloroquine also inhibited P450 2D6 and the transporter OATP1A2. CONCLUSIONS Chloroquine caused a statistically significant decrease in P450 2D6 activity in vitro and in vivo, also inhibiting its own metabolism by the enzyme. The inhibition indicates a potential for clinical drug-drug interactions when taken with other drugs that are predominant substrates of the P450 2D6. When chloroquine and hydroxychloroquine are used clinically with other drugs, substrates of P450 2D6 enzyme, attention should be given to substrate-specific metabolism by P450 2D6 alleles present in individuals taking the drugs.
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Affiliation(s)
| | - Frederick Peter Guengerich
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, United States
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Lei ZN, Wu ZX, Dong S, Yang DH, Zhang L, Ke Z, Zou C, Chen ZS. Chloroquine and hydroxychloroquine in the treatment of malaria and repurposing in treating COVID-19. Pharmacol Ther 2020; 216:107672. [PMID: 32910933 PMCID: PMC7476892 DOI: 10.1016/j.pharmthera.2020.107672] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 08/28/2020] [Accepted: 08/31/2020] [Indexed: 12/14/2022]
Abstract
Chloroquine (CQ) and Hydroxychloroquine (HCQ) have been commonly used for the treatment and prevention of malaria, and the treatment of autoimmune diseases for several decades. As their new mechanisms of actions are identified in recent years, CQ and HCQ have wider therapeutic applications, one of which is to treat viral infectious diseases. Since the pandemic of the coronavirus disease 2019 (COVID-19), CQ and HCQ have been subjected to a number of in vitro and in vivo tests, and their therapeutic prospects for COVID-19 have been proposed. In this article, the applications and mechanisms of action of CQ and HCQ in their conventional fields of anti-malaria and anti-rheumatism, as well as their repurposing prospects in anti-virus are reviewed. The current trials and future potential of CQ and HCQ in combating COVID-19 are discussed.
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Affiliation(s)
- Zi-Ning Lei
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
| | - Zhuo-Xun Wu
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
| | - Shaowei Dong
- Key Laboratory of medical electrophysiology of education ministry, School of Pharmacy, Southwest Medical University, China; Shenzhen Public Service Platform on Tumor Precision Medicine and Molecular Diagnosis, Southern University of Science and Technology, Shenzhen 518020, Guangdong, China
| | - Dong-Hua Yang
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
| | - Litu Zhang
- Department of Research, Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Zunfu Ke
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Guangdong, China.
| | - Chang Zou
- Key Laboratory of medical electrophysiology of education ministry, School of Pharmacy, Southwest Medical University, China; Shenzhen Public Service Platform on Tumor Precision Medicine and Molecular Diagnosis, Southern University of Science and Technology, Shenzhen 518020, Guangdong, China.
| | - Zhe-Sheng Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
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Baralić K, Jorgovanović D, Živančević K, Antonijević Miljaković E, Antonijević B, Buha Djordjevic A, Ćurčić M, Đukić-Ćosić D. Safety assessment of drug combinations used in COVID-19 treatment: in silico toxicogenomic data-mining approach. Toxicol Appl Pharmacol 2020; 406:115237. [PMID: 32920000 PMCID: PMC7483129 DOI: 10.1016/j.taap.2020.115237] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 07/11/2020] [Accepted: 09/08/2020] [Indexed: 12/28/2022]
Abstract
Improvement of COVID-19 clinical condition was seen in studies where combination of antiretroviral drugs, lopinavir and ritonavir, as well as immunomodulant antimalaric, chloroquine/hydroxychloroquine together with the macrolide-type antibiotic, azithromycin, was used for patient's treatment. Although these drugs are "old", their pharmacological and toxicological profile in SARS-CoV-2 - infected patients are still unknown. Thus, by using in silico toxicogenomic data-mining approach, we aimed to assess both risks and benefits of the COVID-19 treatment with the most promising candidate drugs combinations: lopinavir/ritonavir and chloroquine/hydroxychloroquine + azithromycin. The Comparative Toxicogenomics Database (CTD; http://CTD.mdibl.org), Cytoscape software (https://cytoscape.org) and ToppGene Suite portal (https://toppgene.cchmc.org) served as a foundation in our research. Our results have demonstrated that lopinavir/ritonavir increased the expression of the genes involved in immune response and lipid metabolism (IL6, ICAM1, CCL2, TNF, APOA1, etc.). Chloroquine/hydroxychloroquine + azithromycin interacted with 6 genes (CCL2, CTSB, CXCL8, IL1B, IL6 and TNF), whereas chloroquine and azithromycin affected two additional genes (BCL2L1 and CYP3A4), which might be a reason behind a greater number of consequential diseases. In contrast to lopinavir/ritonavir, chloroquine/hydroxychloroquine + azithromycin downregulated the expression of TNF and IL6. As expected, inflammation, cardiotoxicity, and dyslipidaemias were revealed as the main risks of lopinavir/ritonavir treatment, while chloroquine/hydroxychloroquine + azithromycin therapy was additionally linked to gastrointestinal and skin diseases. According to our results, these drug combinations should be administrated with caution to patients suffering from cardiovascular problems, autoimmune diseases, or acquired and hereditary lipid disorders.
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Affiliation(s)
- Katarina Baralić
- Department of Toxicology "Akademik Danilo Soldatović", Center for Toxicological Risk Assessment, University of Belgrade - Faculty of Pharmacy, Serbia.
| | - Dragica Jorgovanović
- Department of Toxicology "Akademik Danilo Soldatović", Center for Toxicological Risk Assessment, University of Belgrade - Faculty of Pharmacy, Serbia
| | - Katarina Živančević
- Department of Toxicology "Akademik Danilo Soldatović", Center for Toxicological Risk Assessment, University of Belgrade - Faculty of Pharmacy, Serbia
| | - Evica Antonijević Miljaković
- Department of Toxicology "Akademik Danilo Soldatović", Center for Toxicological Risk Assessment, University of Belgrade - Faculty of Pharmacy, Serbia.
| | - Biljana Antonijević
- Department of Toxicology "Akademik Danilo Soldatović", Center for Toxicological Risk Assessment, University of Belgrade - Faculty of Pharmacy, Serbia.
| | - Aleksandra Buha Djordjevic
- Department of Toxicology "Akademik Danilo Soldatović", Center for Toxicological Risk Assessment, University of Belgrade - Faculty of Pharmacy, Serbia.
| | - Marijana Ćurčić
- Department of Toxicology "Akademik Danilo Soldatović", Center for Toxicological Risk Assessment, University of Belgrade - Faculty of Pharmacy, Serbia.
| | - Danijela Đukić-Ćosić
- Department of Toxicology "Akademik Danilo Soldatović", Center for Toxicological Risk Assessment, University of Belgrade - Faculty of Pharmacy, Serbia.
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Peng H, Chen Z, Wang Y, Ren S, Xu T, Lai X, Wen J, Zhao M, Zeng C, Du L, Zhang Y, Cao L, Hu J, Wei X, Hong T. Systematic Review and Pharmacological Considerations for Chloroquine and Its Analogs in the Treatment for COVID-19. Front Pharmacol 2020; 11:554172. [PMID: 33192503 PMCID: PMC7655531 DOI: 10.3389/fphar.2020.554172] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 08/31/2020] [Indexed: 01/07/2023] Open
Abstract
COVID-19 has been announced pandemic by WHO and over 17,000,000 people infected (Till April 21st 2020). The disease is currently under control in China, with a curative rate of 86.8%. Chloroquine (CQ) is an old anti-malarial drug with good tolerability, which had proved to be effective in previous SARS-coronavirus, which spread and disappeared between 2002-2003. In vitro studies demonstrated the efficacy of CQ in curing COVID-19. Consequently, via analytical PBPK modeling, a further preliminary clinical trial has proved the efficacy and safety of CQ in China., and multiple clinical trials were registered and approved to investigate the activity of other analogs of CQ against COVID-19. We have listed all the clinical trials and made a meta-analysis of published data of hydroxychloroquine (HCQ). HCQ could increase the CT improvement and adverse reactions (ADRs) significantly though there was considerable heterogeneity among current researches. Actually, CQ and its analogs have unique pharmacokinetic characteristics, which would induce severe side effects in some circumstances. We have then summarized pharmacological considerations for these drugs so as to provide to the busy clinicians to avoid potential side effects when administered CQ or its analogs to COVID-19 patients, especially in the elderly, pediatrics, and pregnancies.
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Affiliation(s)
- Hongwei Peng
- Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Zhangren Chen
- Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yunyun Wang
- Academic Affairs Office, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Simei Ren
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Chinese Academy of Medical Sciences, Beijing, China,Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China,Graduate School, Chinese Academy of Medical Sciences and Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Tiantian Xu
- Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Xin Lai
- Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jinhua Wen
- Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Mengjun Zhao
- The First Clinical Medical College of Nanchang University, Nanchang, China
| | - Chuanfei Zeng
- The First Clinical Medical College of Nanchang University, Nanchang, China
| | - Lijuan Du
- The First Clinical Medical College of Nanchang University, Nanchang, China
| | - Yanmei Zhang
- The First Clinical Medical College of Nanchang University, Nanchang, China
| | - Li Cao
- Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jinfang Hu
- Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang, China,*Correspondence: Xiaohua Wei, ; Jinfang Hu, ; Tao Hong, ;
| | - Xiaohua Wei
- Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang, China,*Correspondence: Xiaohua Wei, ; Jinfang Hu, ; Tao Hong, ;
| | - Tao Hong
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, China,*Correspondence: Xiaohua Wei, ; Jinfang Hu, ; Tao Hong, ;
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Babayeva M, Loewy Z. Repurposing Drugs for COVID-19: Pharmacokinetics and Pharmacogenomics of Chloroquine and Hydroxychloroquine. PHARMACOGENOMICS & PERSONALIZED MEDICINE 2020; 13:531-542. [PMID: 33122936 PMCID: PMC7591012 DOI: 10.2147/pgpm.s275964] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 10/06/2020] [Indexed: 12/27/2022]
Abstract
Background A new coronavirus SARS-CoV-2 has been identified as the etiological agent of the severe acute respiratory syndrome, COVID-19, the source and cause of the 2019–20 coronavirus pandemic. Hydroxychloroquine and chloroquine have gathered extraordinary attention as therapeutic candidates against SARS-CoV-2 infections. While there is growing scientific data on the therapeutic effect, there is also concern for toxicity of the medications. The therapy of COVID-19 by hydroxychloroquine and chloroquine is off-label. Studies to analyze the personalized effect and safety are lacking. Methods A review of the literature was performed using Medline/PubMed/Embase database. A variety of keywords were employed in keyword/title/abstract searches. The electronic search was followed by extensive hand searching using reference lists from the identified articles. Results A total of 126 results were obtained after screening all sources. Mechanisms underlying variability in drug concentrations and therapeutic response with chloroquine and hydroxychloroquine in mediating beneficial and adverse effects of chloroquine and hydroxychloroquine were reviewed and analyzed. Pharmacogenomic studies from various disease states were evaluated to elucidate the role of genetic variation in drug response and toxicity. Conclusion Knowledge of the pharmacokinetics and pharmacogenomics of chloroquine and hydroxychloroquine is necessary for effective and safe dosing and to avoid treatment failure and severe complications.
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Affiliation(s)
| | - Zvi Loewy
- Touro College of Pharmacy, New York, NY, USA.,New York Medical College, Valhalla, NY, USA
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Elucidating the Pivotal Immunomodulatory and Anti-Inflammatory Potentials of Chloroquine and Hydroxychloroquine. J Immunol Res 2020; 2020:4582612. [PMID: 33062720 PMCID: PMC7533005 DOI: 10.1155/2020/4582612] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Accepted: 08/03/2020] [Indexed: 12/30/2022] Open
Abstract
Chloroquine (CQ) and hydroxychloroquine (HCQ) are derivatives of 4-aminoquinoline compounds with over 60 years of safe clinical usage. CQ and HCQ are able to inhibit the production of cytokines such as interleukin- (IL-) 1, IL-2, IL-6, IL-17, and IL-22. Also, CQ and HCQ inhibit the production of interferon- (IFN-) α and IFN-γ and/or tumor necrotizing factor- (TNF-) α. Furthermore, CQ blocks the production of prostaglandins (PGs) in the intact cell by inhibiting substrate accessibility of arachidonic acid necessary for the production of PGs. Moreover, CQ affects the stability between T-helper cell (Th) 1 and Th2 cytokine secretion by augmenting IL-10 production in peripheral blood mononuclear cells (PBMCs). Additionally, CQ is capable of blocking lipopolysaccharide- (LPS-) triggered stimulation of extracellular signal-modulated extracellular signal-regulated kinases 1/2 in human PBMCs. HCQ at clinical levels effectively blocks CpG-triggered class-switched memory B-cells from differentiating into plasmablasts as well as producing IgG. Also, HCQ inhibits cytokine generation from all the B-cell subsets. IgM memory B-cells exhibits the utmost cytokine production. Nevertheless, CQ triggers the production of reactive oxygen species. A rare, but serious, side effect of CQ or HCQ in nondiabetic patients is hypoglycaemia. Thus, in critically ill patients, CQ and HCQ are most likely to deplete all the energy stores of the body leaving the patient very weak and sicker. We advocate that, during clinical usage of CQ and HCQ in critically ill patients, it is very essential to strengthen the CQ or HCQ with glucose infusion. CQ and HCQ are thus potential inhibitors of the COVID-19 cytokine storm.
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Modulation of CYP2C9 activity and hydrogen peroxide production by cytochrome b 5. Sci Rep 2020; 10:15571. [PMID: 32968106 PMCID: PMC7511354 DOI: 10.1038/s41598-020-72284-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Accepted: 08/28/2020] [Indexed: 11/09/2022] Open
Abstract
Cytochromes P450 (CYP) play a major role in drug detoxification, and cytochrome b5 (cyt b5) stimulates the catalytic cycle of mono-oxygenation and detoxification reactions. Collateral reactions of this catalytic cycle can lead to a significant production of toxic reactive oxygen species (ROS). One of the most abundant CYP isoforms in the human liver is CYP2C9, which catalyzes the metabolic degradation of several drugs including nonsteroidal anti-inflammatory drugs. We studied modulation by microsomal membrane-bound and soluble cyt b5 of the hydroxylation of salicylic acid to gentisic acid and ROS release by CYP2C9 activity in human liver microsomes (HLMs) and by CYP2C9 baculosomes. CYP2C9 accounts for nearly 75% of salicylic acid hydroxylation in HLMs at concentrations reached after usual aspirin doses. The anti-cyt b5 antibody SC9513 largely inhibits the rate of salicylic acid hydroxylation by CYP2C9 in HLMs and CYP2C9 baculosomes, increasing the KM approximately threefold. Besides, soluble human recombinant cyt b5 stimulates the Vmax nearly twofold while it decreases nearly threefold the Km value in CYP2C9 baculosomes. Regarding NADPH-dependent ROS production, soluble recombinant cyt b5 is a potent inhibitor both in HLMs and in CYP2C9 baculosomes, with inhibition constants of 1.04 ± 0.25 and 0.53 ± 0.06 µM cyt b5, respectively. This study indicates that variability in cyt b5 might be a major factor underlying interindividual variability in the metabolism of CYP2C9 substrates.
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Lee CH, Franchi F, Angiolillo DJ. Clopidogrel drug interactions: a review of the evidence and clinical implications. Expert Opin Drug Metab Toxicol 2020; 16:1079-1096. [PMID: 32835535 DOI: 10.1080/17425255.2020.1814254] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Patients with cardiovascular disease are commonly affected by a number of comorbidities leading to a high prevalence of polypharmacy. Polypharmacy increases the probability of drug-drug interactions (DDIs). Amongst these, DDIs involving clopidogrel, the most commonly utilized platelet P2Y12 inhibitor, is a topic of potential clinical concern. AREAS COVERED This article reviews DDIs between clopidogrel and drugs which are widely used in clinical practice. In particular, drugs shown to interfere with the pharmacodynamic and pharmacokinetic effects of clopidogrel and the clinical implications of these findings are reviewed. These drugs include inhibitors of gastric acid secretion, statins, calcium channel blockers, antidiabetic agents, and antimicrobial agents. For the references, we searched PubMed, EMBASE, or the Cochrane Library. EXPERT OPINION Clopidogrel-drug interactions are common. Most of these DDIs are limited to laboratory findings showing an impact on clopidogrel-induced antiplatelet effects. While variability in clopidogrel-induced antiplatelet effects is known to affect clinical outcomes, with high platelet reactivity being associated with thrombotic complications among patients undergoing coronary stenting, most studies assessing the clinical implications of clopidogrel-drug interactions have not shown to significantly affect outcomes. However, awareness of these DDIs remains important for optimizing the selection of concomitant therapies.
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Affiliation(s)
- Chang Hoon Lee
- Division of Cardiology, University of Florida College of Medicine-Jacksonville , Jacksonville, FL, USA.,Division of Cardiology, Department of Internal Medicine, Veterans Health Service Medical Center , Seoul, Korea
| | - Francesco Franchi
- Division of Cardiology, University of Florida College of Medicine-Jacksonville , Jacksonville, FL, USA
| | - Dominick J Angiolillo
- Division of Cardiology, University of Florida College of Medicine-Jacksonville , Jacksonville, FL, USA
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Siripanthong B, Nazarian S, Muser D, Deo R, Santangeli P, Khanji MY, Cooper LT, Chahal CAA. Recognizing COVID-19-related myocarditis: The possible pathophysiology and proposed guideline for diagnosis and management. Heart Rhythm 2020; 17:1463-1471. [PMID: 32387246 PMCID: PMC7199677 DOI: 10.1016/j.hrthm.2020.05.001] [Citation(s) in RCA: 494] [Impact Index Per Article: 98.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Human coronavirus-associated myocarditis is known, and a number of coronavirus disease 19 (COVID-19)-related myocarditis cases have been reported. The pathophysiology of COVID-19-related myocarditis is thought to be a combination of direct viral injury and cardiac damage due to the host's immune response. COVID-19 myocarditis diagnosis should be guided by insights from previous coronavirus and other myocarditis experience. The clinical findings include changes in electrocardiogram and cardiac biomarkers, and impaired cardiac function. When cardiac magnetic resonance imaging is not feasible, cardiac computed tomographic angiography with delayed myocardial imaging may serve to exclude significant coronary artery disease and identify myocardial inflammatory patterns. Because many COVID-19 patients have cardiovascular comorbidities, myocardial infarction should be considered. If the diagnosis remains uncertain, an endomyocardial biopsy may help identify active cardiac infection through viral genome amplification and possibly refine the treatment risks of systemic immunosuppression. Arrhythmias are not uncommon in COVID-19 patients, but the pathophysiology is still speculative. Nevertheless, clinicians should be vigilant to provide prompt monitoring and treatment. The long-term impact of COVID-19 myocarditis, including the majority of mild cases, remains unknown.
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Affiliation(s)
| | - Saman Nazarian
- Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Daniele Muser
- Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Rajat Deo
- Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Pasquale Santangeli
- Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Mohammed Y Khanji
- Department of Cardiology, Newham University Hospital and Barts Heart Centre, Barts Health NHS Trust, London, United Kingdom; NIHR Barts Biomedical Research Centre, William Harvey Research Institute, Queen Mary University of London, London UK
| | | | - C Anwar A Chahal
- Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania; Mayo Clinic, Rochester, Minnesota; Royal Papworth Hospital, Cambridge, United Kingdom.
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Song Y, Fields E. Pharmacological Advances of Chloroquine and Hydroxychloroquine: From Antimalarials to Investigative Therapies in COVID-19. Nat Prod Commun 2020. [DOI: 10.1177/1934578x20953648] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
During the coronavirus disease 2019 (COVID-19) pandemic, numerous existing chemicals have been screened for antiviral potential against the emerging coronavirus severe acute respiratory syndrome coronavirus 2. Chloroquine and hydroxychloroquine, after exhibiting potent in vitro efficacy, have gained tremendous attention. Both therapeutics are derivatives of natural alkaloid quinine and were first synthesized to treat malaria. Thereafter, the pharmaceutical applications of the agents have expanded to many new areas. In this article, the medicinal history and pharmacological activities of chloroquine and hydroxychloroquine are summarized. Antimalarial, anti-inflammatory, antitumor, antiviral properties, and therapeutic potential in the emerging viral infection COVID-19 are discussed. Pharmacokinetics, adverse effects, and toxicities are reviewed.
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Affiliation(s)
- Yang Song
- Department of Pharmacy Services, CHI Franciscan Health, St. Joseph Medical Center, Tacoma, WA, USA
| | - Elise Fields
- Department of Pharmacy Services, CHI Franciscan Health, St. Joseph Medical Center, Tacoma, WA, USA
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Al Rihani SB, Smith MK, Bikmetov R, Deodhar M, Dow P, Turgeon J, Michaud V. Risk of Adverse Drug Events Following the Virtual Addition of COVID-19 Repurposed Drugs to Drug Regimens of Frail Older Adults with Polypharmacy. J Clin Med 2020; 9:E2591. [PMID: 32785135 PMCID: PMC7463624 DOI: 10.3390/jcm9082591] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 07/27/2020] [Accepted: 08/04/2020] [Indexed: 12/16/2022] Open
Abstract
Determination of the risk-benefit ratio associated with the use of novel coronavirus disease 2019 (COVID-19) repurposed drugs in older adults with polypharmacy is mandatory. Our objective was to develop and validate a strategy to assess risk for adverse drug events (ADE) associated with COVID-19 repurposed drugs using hydroxychloroquine (HCQ) and chloroquine (CQ), alone or in combination with azithromycin (AZ), and the combination lopinavir/ritonavir (LPV/r). These medications were virtually added, one at a time, to drug regimens of 12,383 participants of the Program of All-Inclusive Care for the Elderly. The MedWise Risk Score (MRSTM) was determined from 198,323 drug claims. Results demonstrated that the addition of each repurposed drug caused a rightward shift in the frequency distribution of MRSTM values (p < 0.05); the increase was due to an increase in the drug-induced Long QT Syndrome (LQTS) or CYP450 drug interaction burden risk scores. Increases in LQTS risk observed with HCQ + AZ and CQ + AZ were of the same magnitude as those estimated when terfenadine or terfenadine + AZ, used as positive controls for drug-induced LQTS, were added to drug regimens. The simulation-based strategy performed offers a way to assess risk of ADE for drugs to be used in people with underlying medical comorbidities and polypharmacy at risk of COVID-19 infection without exposing them to these drugs.
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Affiliation(s)
- Sweilem B. Al Rihani
- Tabula Rasa HealthCare Precision Pharmacotherapy Research & Development Institute, Orlando, FL 32827, USA; (S.B.A.R.); (M.K.S.); (R.B.); (M.D.); (P.D.); (J.T.)
| | - Matt K. Smith
- Tabula Rasa HealthCare Precision Pharmacotherapy Research & Development Institute, Orlando, FL 32827, USA; (S.B.A.R.); (M.K.S.); (R.B.); (M.D.); (P.D.); (J.T.)
| | - Ravil Bikmetov
- Tabula Rasa HealthCare Precision Pharmacotherapy Research & Development Institute, Orlando, FL 32827, USA; (S.B.A.R.); (M.K.S.); (R.B.); (M.D.); (P.D.); (J.T.)
| | - Malavika Deodhar
- Tabula Rasa HealthCare Precision Pharmacotherapy Research & Development Institute, Orlando, FL 32827, USA; (S.B.A.R.); (M.K.S.); (R.B.); (M.D.); (P.D.); (J.T.)
| | - Pamela Dow
- Tabula Rasa HealthCare Precision Pharmacotherapy Research & Development Institute, Orlando, FL 32827, USA; (S.B.A.R.); (M.K.S.); (R.B.); (M.D.); (P.D.); (J.T.)
| | - Jacques Turgeon
- Tabula Rasa HealthCare Precision Pharmacotherapy Research & Development Institute, Orlando, FL 32827, USA; (S.B.A.R.); (M.K.S.); (R.B.); (M.D.); (P.D.); (J.T.)
- Faculty of Pharmacy, Université de Montréal, Montreal, QC H3C 3J7, Canada
| | - Veronique Michaud
- Tabula Rasa HealthCare Precision Pharmacotherapy Research & Development Institute, Orlando, FL 32827, USA; (S.B.A.R.); (M.K.S.); (R.B.); (M.D.); (P.D.); (J.T.)
- Faculty of Pharmacy, Université de Montréal, Montreal, QC H3C 3J7, Canada
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Rani S, Grover S, Mehra A, Sahoo S. Psychiatric implications of the use of hydroxychloroquine in COVID-19 patients. Indian J Pharmacol 2020; 52:229-231. [PMID: 32874009 PMCID: PMC7446676 DOI: 10.4103/ijp.ijp_595_20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Revised: 07/16/2020] [Accepted: 07/16/2020] [Indexed: 11/05/2022] Open
Affiliation(s)
- Seema Rani
- Department of Psychiatry, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Sandeep Grover
- Department of Psychiatry, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Aseem Mehra
- Department of Psychiatry, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Swapnajeet Sahoo
- Department of Psychiatry, Post Graduate Institute of Medical Education and Research, Chandigarh, India
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Kang Y, Chen T, Mui D, Ferrari V, Jagasia D, Scherrer-Crosbie M, Chen Y, Han Y. Cardiovascular manifestations and treatment considerations in COVID-19. Heart 2020; 106:1132-1141. [PMID: 32354800 PMCID: PMC7211105 DOI: 10.1136/heartjnl-2020-317056] [Citation(s) in RCA: 258] [Impact Index Per Article: 51.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Revised: 04/13/2020] [Accepted: 04/15/2020] [Indexed: 02/06/2023] Open
Abstract
Since its recognition in December 2019, covid-19 has rapidly spread globally causing a pandemic. Pre-existing comorbidities such as hypertension, diabetes, and cardiovascular disease are associated with a greater severity and higher fatality rate of covid-19. Furthermore, COVID-19 contributes to cardiovascular complications, including acute myocardial injury as a result of acute coronary syndrome, myocarditis, stress-cardiomyopathy, arrhythmias, cardiogenic shock, and cardiac arrest. The cardiovascular interactions of COVID-19 have similarities to that of severe acute respiratory syndrome, Middle East respiratory syndrome and influenza. Specific cardiovascular considerations are also necessary in supportive treatment with anticoagulation, the continued use of renin-angiotensin-aldosterone system inhibitors, arrhythmia monitoring, immunosuppression or modulation, and mechanical circulatory support.
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Affiliation(s)
- Yu Kang
- Cardiovascular Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Tiffany Chen
- Cardiovascular Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - David Mui
- University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Victor Ferrari
- Cardiovascular Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Dinesh Jagasia
- Cardiovascular Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Marielle Scherrer-Crosbie
- Cardiovascular Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Yucheng Chen
- Department of Cardiology, West China Hospital, Sichuan University, Chengdu, China
| | - Yuchi Han
- Cardiovascular Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
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Della Porta A, Bornstein K, Coye A, Montrief T, Long B, Parris MA. Acute chloroquine and hydroxychloroquine toxicity: A review for emergency clinicians. Am J Emerg Med 2020; 38:2209-2217. [PMID: 33071096 PMCID: PMC7369162 DOI: 10.1016/j.ajem.2020.07.030] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 07/11/2020] [Accepted: 07/11/2020] [Indexed: 02/08/2023] Open
Abstract
Background Acute chloroquine and hydroxychloroquine toxicity is characterized by a combination of direct cardiovascular effects and electrolyte derangements with resultant dysrhythmias and is associated with significant morbidity and mortality. Objective This review describes acute chloroquine and hydroxychloroquine toxicity, outlines the complex pathophysiologic derangements, and addresses the emergency department (ED) management of this patient population. Discussion Chloroquine and hydroxychloroquine are aminoquinoline derivatives widely used in the treatment of rheumatologic diseases including systemic lupus erythematosus and rheumatoid arthritis as well as for malaria prophylaxis. In early 2020, anecdotal reports and preliminary data suggested utility of hydroxychloroquine in attenuating viral loads and symptoms in patients with SARS-CoV-2 infection. Aminoquinoline drugs pose unique and significant toxicological risks, both during their intended use as well as in unsupervised settings by laypersons. The therapeutic range for chloroquine is narrow. Acute severe toxicity is associated with 10–30% mortality owing to a combination of direct cardiovascular effects and electrolyte derangements with resultant dysrhythmias. Treatment in the ED is focused on decontamination, stabilization of cardiac dysrhythmias, hemodynamic support, electrolyte correction, and seizure prevention. Conclusions An understanding of the pathophysiology of acute chloroquine and hydroxychloroquine toxicity and available emergency treatments can assist emergency clinicians in reducing the immediate morbidity and mortality associated with this disease.
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Affiliation(s)
- Alessandra Della Porta
- University of Miami Miller School of Medicine, Miami, Florida, USA; Department of Emergency Medicine, Jackson Memorial Health System, Miami, Florida, USA; Department of Emergency Medicine, Brooke Army Medical Center, San Antonio, TX, USA; Emergency Department, Jackson South Medical Center, Miami, Florida, USA
| | - Kasha Bornstein
- University of Miami Miller School of Medicine, Miami, Florida, USA; Department of Emergency Medicine, Jackson Memorial Health System, Miami, Florida, USA; Department of Emergency Medicine, Brooke Army Medical Center, San Antonio, TX, USA; Emergency Department, Jackson South Medical Center, Miami, Florida, USA
| | - Austin Coye
- University of Miami Miller School of Medicine, Miami, Florida, USA; Department of Emergency Medicine, Jackson Memorial Health System, Miami, Florida, USA; Department of Emergency Medicine, Brooke Army Medical Center, San Antonio, TX, USA; Emergency Department, Jackson South Medical Center, Miami, Florida, USA
| | - Tim Montrief
- University of Miami Miller School of Medicine, Miami, Florida, USA; Department of Emergency Medicine, Jackson Memorial Health System, Miami, Florida, USA; Department of Emergency Medicine, Brooke Army Medical Center, San Antonio, TX, USA; Emergency Department, Jackson South Medical Center, Miami, Florida, USA
| | - Brit Long
- University of Miami Miller School of Medicine, Miami, Florida, USA; Department of Emergency Medicine, Jackson Memorial Health System, Miami, Florida, USA; Department of Emergency Medicine, Brooke Army Medical Center, San Antonio, TX, USA; Emergency Department, Jackson South Medical Center, Miami, Florida, USA.
| | - Mehruba Anwar Parris
- University of Miami Miller School of Medicine, Miami, Florida, USA; Department of Emergency Medicine, Jackson Memorial Health System, Miami, Florida, USA; Department of Emergency Medicine, Brooke Army Medical Center, San Antonio, TX, USA; Emergency Department, Jackson South Medical Center, Miami, Florida, USA.
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Chary MA, Barbuto AF, Izadmehr S, Hayes BD, Burns MM. COVID-19: Therapeutics and Their Toxicities. J Med Toxicol 2020; 16:284-294. [PMID: 32356252 PMCID: PMC7192319 DOI: 10.1007/s13181-020-00777-5] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 04/09/2020] [Accepted: 04/09/2020] [Indexed: 02/07/2023] Open
Abstract
SARS-CoV-2 is a novel coronavirus that emerged in 2019 and is causing the COVID-19 pandemic. There is no current standard of care. Clinicians need to be mindful of the toxicity of a wide variety of possibly unfamiliar substances being tested or repurposed to treat COVID-19. The United States Food and Drug Administration (FDA) has provided emergency authorization for the use of chloroquine and hydroxychloroquine. These two medications may precipitate ventricular dysrhythmias, necessitating cardiac and electrolyte monitoring, and in severe cases, treatment with epinephrine and high-doses of diazepam. Recombinant protein therapeutics may cause serum sickness or immune complex deposition. Nucleic acid vaccines may introduce mutations into the human genome. ACE inhibitors and ibuprofen have been suggested to exacerbate the pathogenesis of COVID-19. Here, we review the use, mechanism of action, and toxicity of proposed COVID-19 therapeutics.
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Affiliation(s)
- Michael A Chary
- Division of Emergency Medicine, Harvard Medical Toxicology Fellowship, Boston Children's Hospital, Boston, MA, USA.
- Regional Center for Poison Control and Prevention Serving Massachusetts and Rhode Island, Boston, MA, USA.
- Department of Emergency Medicine, Brigham and Women's Hospital, Boston, MA, USA.
| | - Alexander F Barbuto
- Division of Emergency Medicine, Harvard Medical Toxicology Fellowship, Boston Children's Hospital, Boston, MA, USA
- Regional Center for Poison Control and Prevention Serving Massachusetts and Rhode Island, Boston, MA, USA
- Department of Emergency Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Sudeh Izadmehr
- Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Bryan D Hayes
- Department of Pharmacy, Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Michele M Burns
- Division of Emergency Medicine, Harvard Medical Toxicology Fellowship, Boston Children's Hospital, Boston, MA, USA
- Regional Center for Poison Control and Prevention Serving Massachusetts and Rhode Island, Boston, MA, USA
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Cui C, Zhang M, Yao X, Tu S, Hou Z, Jie En VS, Xiang X, Lin J, Cai T, Shen N, Song C, Qiao J, Zhang S, Li H, Liu D. Dose selection of chloroquine phosphate for treatment of COVID-19 based on a physiologically based pharmacokinetic model. Acta Pharm Sin B 2020; 10:1216-1227. [PMID: 32834950 PMCID: PMC7252145 DOI: 10.1016/j.apsb.2020.04.007] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 03/24/2020] [Accepted: 03/25/2020] [Indexed: 01/05/2023] Open
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 (e.g., 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.
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Affiliation(s)
- Cheng Cui
- Drug Clinical Trial Center, Peking University Third Hospital, Beijing 100191, China
| | - Miao Zhang
- Drug Clinical Trial Center, Peking University Third Hospital, Beijing 100191, China
| | - Xueting Yao
- Drug Clinical Trial Center, Peking University Third Hospital, Beijing 100191, China
| | - Siqi Tu
- Drug Clinical Trial Center, Peking University Third Hospital, Beijing 100191, China
| | - Zhe Hou
- Drug Clinical Trial Center, Peking University Third Hospital, Beijing 100191, China
| | - Valerie Sia Jie En
- Drug Clinical Trial Center, Peking University Third Hospital, Beijing 100191, China
| | - Xiaoqiang Xiang
- Department of Clinical Pharmacy, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Jing Lin
- Key Laboratory of Diagnosis and Treatment of Digestive System Tumors of Zhejiang Province, HwaMei Hospital, University of Chinese Academy of Sciences (Ningbo No.2 Hospital), Ningbo 315010, China
| | - Ting Cai
- Key Laboratory of Diagnosis and Treatment of Digestive System Tumors of Zhejiang Province, HwaMei Hospital, University of Chinese Academy of Sciences (Ningbo No.2 Hospital), Ningbo 315010, China
| | - Ning Shen
- Department of Respirator, Peking University Third Hospital, Beijing 100191, China
| | - Chunli Song
- Department of Orthopedics, Peking University Third Hospital, Beijing 100191, China
| | - Jie Qiao
- Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China
| | - Shun Zhang
- Key Laboratory of Diagnosis and Treatment of Digestive System Tumors of Zhejiang Province, HwaMei Hospital, University of Chinese Academy of Sciences (Ningbo No.2 Hospital), Ningbo 315010, China
| | - Haiyan Li
- Drug Clinical Trial Center, Peking University Third Hospital, Beijing 100191, China
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing 100191, China
| | - Dongyang Liu
- Drug Clinical Trial Center, Peking University Third Hospital, Beijing 100191, China
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Influence of CYP2C8, CYP3A4, and CYP3A5 Host Genotypes on Early Recurrence of Plasmodium vivax. Antimicrob Agents Chemother 2020; 64:AAC.02125-19. [PMID: 32366712 DOI: 10.1128/aac.02125-19] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Accepted: 04/25/2020] [Indexed: 11/20/2022] Open
Abstract
Cytochrome P450 (CYP) enzymes are involved in the biotransformation of chloroquine (CQ), but the role of the different profiles of metabolism of this drug in relation to Plasmodium vivax recurrences has not been properly investigated. To investigate the influence of the CYP genotypes associated with CQ metabolism on the rates of P. vivax early recurrences, a case-control study was carried out. The cases included patients presenting with an early recurrence (CQ-recurrent individuals), defined as a recurrence during the first 28 days after initial infection and plasma concentrations of CQ plus desethylchloroquine (DCQ; the major CQ metabolite) higher than 100 ng/ml. A control group with no parasite recurrence over the follow-up (the CQ-responsive group) was also included. CQ and DCQ plasma levels were measured on day 28. CQ-metabolizing CYP (CYP2C8, CYP3A4, and CYP3A5) genotypes were determined by real-time PCR. An ex vivo study was conducted to verify the efficacy of CQ and DCQ against P. vivax isolates. The frequency of alleles associated with normal and slow metabolism was similar between the cases and the controls for the CYP2C8 (odds ratio [OR] = 1.45, 95% confidence interval [CI] = 0.51 to 4.14, P = 0.570), CYP3A4 (OR = 2.38, 95% CI = 0.92 to 6.19, P = 0.105), and CYP3A5 (OR = 4.17, 95% CI = 0.79 to 22.04, P = 1.038) genes. DCQ levels were higher than CQ levels, regardless of the genotype. Regarding the DCQ/CQ ratio, there was no difference between groups or between those patients who had a normal genotype and those patients who had a mutant genotype. DCQ and CQ showed similar efficacy ex vivo CYP genotypes had no influence on early recurrence rates. The similar efficacy of CQ and DCQ ex vivo could explain the absence of therapeutic failure, despite the presence of alleles associated with slow metabolism.
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Smit C, Peeters MYM, van den Anker JN, Knibbe CAJ. Chloroquine for SARS-CoV-2: Implications of Its Unique Pharmacokinetic and Safety Properties. Clin Pharmacokinet 2020; 59:659-669. [PMID: 32306288 PMCID: PMC7165255 DOI: 10.1007/s40262-020-00891-1] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Since in vitro studies and a preliminary clinical report suggested the efficacy of chloroquine for COVID-19-associated pneumonia, there is increasing interest in this old antimalarial drug. In this article, we discuss the pharmacokinetics and safety of chloroquine that should be considered in light of use in SARS-CoV-2 infections. Chloroquine is well absorbed and distributes extensively resulting in a large volume of distribution with an apparent and terminal half-life of 1.6 days and 2 weeks, respectively. Chloroquine is metabolized by cytochrome P450 and renal clearance is responsible for one third of total clearance. The lack of reliable information on target concentrations or doses for COVID-19 implies that for both adults and children, doses that proved effective and safe in malaria should be considered, such as 'loading doses' in adults (30 mg/kg over 48 h) and children (70 mg/kg over 5 days), which reported good tolerability. Here, plasma concentrations were < 2.5 μmol/L, which is associated with (minor) toxicity. While the influence of renal dysfunction, critical illness, or obesity seems small, in critically ill patients, reduced absorption may be anticipated. Clinical experience has shown that chloroquine has a narrow safety margin, as three times the adult therapeutic dosage for malaria can be lethal when given as a single dose. Although infrequent, poisoning in children is extremely dangerous where one to two tablets can potentially be fatal. In conclusion, the pharmacokinetic and safety properties of chloroquine suggest that chloroquine can be used safely for an acute virus infection, under corrected QT monitoring, but also that the safety margin is small, particularly in children.
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Affiliation(s)
- Cornelis Smit
- Pediatric Pharmacology and Pharmacometrics Research Center, University of Basel Children's Hospital, Basel, Switzerland
- Department of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
| | - Mariska Y M Peeters
- Department of Clinical Pharmacy, St. Antonius Hospital, Koekoekslaan 1, 3435 CM, Nieuwegein, The Netherlands
| | - John N van den Anker
- Pediatric Pharmacology and Pharmacometrics Research Center, University of Basel Children's Hospital, Basel, Switzerland
- Division of Clinical Pharmacology, Children's National Hospital, Washington, DC, USA
| | - Catherijne A J Knibbe
- Department of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
- Department of Clinical Pharmacy, St. Antonius Hospital, Koekoekslaan 1, 3435 CM, Nieuwegein, The Netherlands.
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Abena PM, Decloedt EH, Bottieau E, Suleman F, Adejumo P, Sam-Agudu NA, Muyembe TamFum JJ, Seydi M, Eholie SP, Mills EJ, Kallay O, Zumla A, Nachega JB. Chloroquine and Hydroxychloroquine for the Prevention or Treatment of COVID-19 in Africa: Caution for Inappropriate Off-label Use in Healthcare Settings. Am J Trop Med Hyg 2020; 102:1184-1188. [PMID: 32323646 PMCID: PMC7253100 DOI: 10.4269/ajtmh.20-0290] [Citation(s) in RCA: 96] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 04/16/2020] [Indexed: 12/21/2022] Open
Abstract
The novel severe acute respiratory syndrome-coronavirus-2 pandemic has spread to Africa, where nearly all countries have reported laboratory-confirmed cases of novel coronavirus disease (COVID-19). Although there are ongoing clinical trials of repurposed and investigational antiviral and immune-based therapies, there are as yet no scientifically proven, clinically effective pharmacological treatments for COVID-19. Among the repurposed drugs, the commonly used antimalarials chloroquine (CQ) and hydroxychloroquine (HCQ) have become the focus of global scientific, media, and political attention despite a lack of randomized clinical trials supporting their efficacy. Chloroquine has been used worldwide for about 75 years and is listed by the WHO as an essential medicine to treat malaria. Hydroxychloroquine is mainly used as a therapy for autoimmune diseases. However, the efficacy and safety of CQ/HCQ for the treatment of COVID-19 remains to be defined. Indiscriminate promotion and widespread use of CQ/HCQ have led to extensive shortages, self-treatment, and fatal overdoses. Shortages and increased market prices leave all countries vulnerable to substandard and falsified medical products, and safety issues are especially concerning for Africa because of its healthcare system limitations. Much needed in Africa is a cross-continental collaborative network for coordinated production, distribution, and post-marketing surveillance aligned to low-cost distribution of any approved COVID-19 drug; this would ideally be piggybacked on existing global aid efforts. Meanwhile, African countries should strongly consider implementing prescription monitoring schemes to ensure that any off-label CQ/HCQ use is appropriate and beneficial during this pandemic.
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Affiliation(s)
- Pascale M. Abena
- Infectious Diseases Outpatient Clinic, Cameroon and Infectious Diseases Society of Cameroon, Yaoundé, Douala, Cameroon
| | - Eric H. Decloedt
- Division of Clinical Pharmacology, Department of Medicine, Stellenbosch University, Cape Town, South Africa
| | - Emmanuel Bottieau
- Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium
| | - Fatima Suleman
- Discipline of Pharmaceutical Sciences, University of Kwazulu-Natal, Durban, South Africa
| | - Prisca Adejumo
- Department of Nursing, University of Ibadan, Ibadan, Nigeria
| | - Nadia A. Sam-Agudu
- Institute of Human Virology and Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland
- International Research Center of Excellence, Institute of Human Virology Nigeria, Abuja, Nigeria
- Department of Paediatrics, University of Cape Coast School of Medical Sciences, Cape Coast, Ghana
| | - Jean-Jacques Muyembe TamFum
- Department of Medical Microbiology and Virology, National Institute of Biomedical Research (INRB), Faculty of Medicine, University of Kinshasa, Kinshasa, Democratic Republic of the Congo
| | - Moussa Seydi
- Service de Maladies Infectieuses et Tropicales, Centre Hospitalo-Universitaire de Fann, Université Cheik Anta-Diop, Dakar, Sénégal
| | - Serge P. Eholie
- Unit of Infectious Diseases, Treichville University Teaching Hospital, Abidjan, Côte d’Ivoire
- Unité de Dermatologie et Infectiologie, Unité de Formation et de Recherche, Université Félix Houphouet Boigny, Abidjan, Côte d’Ivoire
| | - Edward J. Mills
- University of Kigali School of Public Health, Kigali, Rwanda
| | - Oscar Kallay
- Erasme Hospital, Free University of Brussels, Brussels, Belgium
| | - Alimuddin Zumla
- Department of Infection, Division of Infection and Immunity, Centre for Clinical Microbiology, University College London, London, United Kingdom
- National Institute for Health Research Biomedical Research Centre, University College London Hospitals, London, United Kingdom
| | - Jean B. Nachega
- Center for Infectious Diseases, at Stellenbosch University, Cape Town, South Africa
- Department of International Health and Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
- University of Pittsburgh Graduate School of Public Health and Center for Global Health, Pittsburgh, Pennsylvania
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Pharmacologic Treatment of Transplant Recipients Infected With SARS-CoV-2: Considerations Regarding Therapeutic Drug Monitoring and Drug-Drug Interactions. Ther Drug Monit 2020; 42:360-368. [PMID: 32304488 PMCID: PMC7188032 DOI: 10.1097/ftd.0000000000000761] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
COVID-19 is a novel infectious disease caused by the severe acute respiratory distress (SARS)-coronavirus-2 (SARS-CoV-2). Several therapeutic options are currently emerging but none with universal consensus or proven efficacy. Solid organ transplant recipients are perceived to be at increased risk of severe COVID-19 because of their immunosuppressed conditions due to chronic use of immunosuppressive drugs (ISDs). It is therefore likely that solid organ transplant recipients will be treated with these experimental antivirals.
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Damle B, Vourvahis M, Wang E, Leaney J, Corrigan B. Clinical Pharmacology Perspectives on the Antiviral Activity of Azithromycin and Use in COVID-19. Clin Pharmacol Ther 2020; 108:201-211. [PMID: 32302411 PMCID: PMC7262099 DOI: 10.1002/cpt.1857] [Citation(s) in RCA: 112] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 04/15/2020] [Indexed: 12/19/2022]
Abstract
Azithromycin (AZ) is a broad-spectrum macrolide antibiotic with a long half-life and a large volume of distribution. It is primarily used for the treatment of respiratory, enteric, and genitourinary bacterial infections. AZ is not approved for the treatment of viral infections, and there is no well-controlled, prospective, randomized clinical evidence to support AZ therapy in coronavirus disease 2019 (COVID-19). Nevertheless, there are anecdotal reports that some hospitals have begun to include AZ in combination with hydroxychloroquine or chloroquine (CQ) for treatment of COVID-19. It is essential that the clinical pharmacology (CP) characteristics of AZ be considered in planning and conducting clinical trials of AZ alone or in combination with other agents, to ensure safe study conduct and to increase the probability of achieving definitive answers regarding efficacy of AZ in the treatment of COVID-19. The safety profile of AZ used as an antibacterial agent is well established.1 This work assesses published in vitro and clinical evidence for AZ as an agent with antiviral properties. It also provides basic CP information relevant for planning and initiating COVID-19 clinical studies with AZ, summarizes safety data from healthy volunteer studies, and safety and efficacy data from phase II and phase II/III studies in patients with uncomplicated malaria, including a phase II/III study in pediatric patients following administration of AZ and CQ in combination. This paper may also serve to facilitate the consideration and use of a priori-defined control groups for future research.
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Affiliation(s)
- Bharat Damle
- Pfizer Global Research and Development, New York, New York, USA
| | | | - Erjian Wang
- Pfizer Global Research and Development, San Diego, California, USA
| | - Joanne Leaney
- Pfizer Global Research and Development, Sandwich, Kent, UK
| | - Brian Corrigan
- Pfizer Global Research and Development, Groton, Connecticut, USA
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Naksuk N, Lazar S, Peeraphatdit T(B. Cardiac safety of off-label COVID-19 drug therapy: a review and proposed monitoring protocol. EUROPEAN HEART JOURNAL. ACUTE CARDIOVASCULAR CARE 2020; 9:215-221. [PMID: 32372695 PMCID: PMC7235441 DOI: 10.1177/2048872620922784] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 04/09/2020] [Indexed: 02/06/2023]
Abstract
More than 2,000,000 individuals worldwide have had coronavirus 2019 disease infection (COVID-19), yet there is no effective medical therapy. Multiple off-label and investigational drugs, such as chloroquine and hydroxychloroquine, have gained broad interest due to positive pre-clinical data and are currently used for treatment of COVID-19. However, some of these medications have potential cardiac adverse effects. This is important because up to one-third of patients with COVID-19 have cardiac injury, which can further increase the risk of cardiomyopathy and arrhythmias. Adverse effects of chloroquine and hydroxychloroquine on cardiac function and conduction are broad and can be fatal. Both drugs have an anti-arrhythmic property and are proarrhythmic. The American Heart Association has listed chloroquine and hydroxychloroquine as agents which can cause direct myocardial toxicity. Similarly, other investigational drugs such as favipiravir and lopinavir/ritonavir can prolong QT interval and cause Torsade de Pointes. Many antibiotics commonly used for the treatment of patients with COVID-19, for instance azithromycin, can also prolong QT interval. This review summarizes evidenced-based data regarding potential cardiac adverse effects due to off-label and investigational drugs including chloroquine and hydroxychloroquine, antiviral therapy, monoclonal antibodies, as well as common antibiotics used for the treatment of COVID-19. The article focuses on practical points and offers a point-of-care protocol for providers who are taking care of patients with COVID-19 in an inpatient and outpatient setting. The proposed protocol is taking into consideration that resources during the pandemic are limited.
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Affiliation(s)
- Niyada Naksuk
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Division of Cardiology, University of Illinois at Chicago, USA
| | - Sorin Lazar
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Division of Cardiology, University of Illinois at Chicago, USA
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50
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Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol 2020; 16:155-166. [PMID: 32034323 DOI: 10.1038/s41584-020-0372-x] [Citation(s) in RCA: 869] [Impact Index Per Article: 173.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/09/2020] [Indexed: 12/15/2022]
Abstract
Despite widespread clinical use of antimalarial drugs such as hydroxychloroquine and chloroquine in the treatment of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and other inflammatory rheumatic diseases, insights into the mechanism of action of these drugs are still emerging. Hydroxychloroquine and chloroquine are weak bases and have a characteristic 'deep' volume of distribution and a half-life of around 50 days. These drugs interfere with lysosomal activity and autophagy, interact with membrane stability and alter signalling pathways and transcriptional activity, which can result in inhibition of cytokine production and modulation of certain co-stimulatory molecules. These modes of action, together with the drug's chemical properties, might explain the clinical efficacy and well-known adverse effects (such as retinopathy) of these drugs. The unknown dose-response relationships of these drugs and the lack of definitions of the minimum dose needed for clinical efficacy and what doses are toxic pose challenges to clinical practice. Further challenges include patient non-adherence and possible context-dependent variations in blood drug levels. Available mechanistic data give insights into the immunomodulatory potency of hydroxychloroquine and provide the rationale to search for more potent and/or selective inhibitors.
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