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Tramontano D, Bini S, Maiorca C, Di Costanzo A, Carosi M, Castellese J, Arizaj I, Commodari D, Covino S, Sansone G, Minicocci I, Arca M, D'Erasmo L. Renal Safety Assessment of Lipid-Lowering Drugs: Between Old Certainties and New Questions. Drugs 2025; 85:755-775. [PMID: 40106181 PMCID: PMC12098426 DOI: 10.1007/s40265-025-02158-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/09/2025] [Indexed: 03/22/2025]
Abstract
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in patients with chronic kidney disease (CKD). Quantitative and qualitative changes in plasma lipoprotein profiles are frequently associated with CKD and represent a significant risk factor for CVD in patients with CKD. Guidelines from the European Society of Cardiology and the European Atherosclerosis Society classify CKD as a condition with high or very high cardiovascular risk and set specific low-density lipoprotein cholesterol targets. Conventional lipid-lowering therapies (LLTs), such as statins, ezetimibe, and fibrates, can control CKD-associated dyslipidemia and, to some extent, prevent major atherosclerotic events in patients with CKD, but their use in clinical practice presents challenges because of the potential renal safety concerns. In recent years, novel therapies with the ability to lower both low-density lipoprotein cholesterol and triglycerides have been introduced to the market (e.g., proprotein convertase subtilisin/kexin type 9 inhibitors, bempedoic acid, lomitapide, volanesorsen) to improve our ability to control lipid abnormalities. However, their impact on kidney functionality has not been fully elucidated. The aim of this review was to examine the renal safety profiles of various LLTs, with special reference to novel medications, and to highlight important considerations and guidance for the use of these medications in overt CKD or in patients with some degree of renal function impairment. We underscore the lack of a comprehensive understanding of kidney safety, particularly for novel LLT therapies, and strongly emphasize the importance of future dedicated research to fully assess the safety and efficacy of these agents in patients with kidney abnormalities.
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Affiliation(s)
- Daniele Tramontano
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy.
| | - Simone Bini
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Carlo Maiorca
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Alessia Di Costanzo
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Martina Carosi
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Jacopo Castellese
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Ina Arizaj
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Daniela Commodari
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Stella Covino
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Giorgia Sansone
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Ilenia Minicocci
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Marcello Arca
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Laura D'Erasmo
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
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Krohmer E, Rohr BS, Stoll F, Gümüs KS, Bergamino M, Mikus G, Sauter M, Burhenne J, Weiss J, Meid AD, Czock D, Blank A, Haefeli WE. Influence of a Short Course of Ritonavir Used as Booster in Antiviral Therapies Against SARS-CoV-2 on the Exposure of Atorvastatin and Rosuvastatin. Cardiovasc Drugs Ther 2025; 39:325-335. [PMID: 38112932 PMCID: PMC11954719 DOI: 10.1007/s10557-023-07538-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/04/2023] [Indexed: 12/21/2023]
Abstract
PURPOSE Early antiviral treatment with nirmatrelvir/ritonavir is recommended for SARS-CoV-2-infected patients at high risk for severe courses. Such patients are usually chronically ill and susceptible to adverse drug interactions caused by ritonavir. We investigated the interactions of short-term low-dose ritonavir therapy with atorvastatin and rosuvastatin, two statins commonly used in this population. METHOD We assessed exposure changes (area under the concentration-time curve (AUC∞) and maximum concentration (Cmax)) of a single dose of 10 mg atorvastatin and 10 mg rosuvastatin before and on the fifth day of ritonavir treatment (2 × 100 mg/day) in healthy volunteers and developed a semi-mechanistic pharmacokinetic model to estimate dose adjustment of atorvastatin during ritonavir treatment. RESULTS By the fifth day of ritonavir treatment, the AUC∞ of atorvastatin increased 4.76-fold and Cmax 3.78-fold, and concurrently, the concentration of atorvastatin metabolites decreased to values below the lower limit of quantification. Pharmacokinetic modelling indicated that a stepwise reduction in atorvastatin dose during ritonavir treatment with a stepwise increase up to 4 days after ritonavir discontinuation can keep atorvastatin exposure within safe and effective margins. Rosuvastatin pharmacokinetics were only mildly modified; ritonavir significantly increased the Cmax 1.94-fold, while AUC∞ was unchanged. CONCLUSION Atorvastatin doses should likely be adjusted during nirmatrelvir/ritonavir treatment. For patients on a 20-mg dose, we recommend half of the original dose. In patients taking 40 mg or more, a quarter of the dose should be taken until 2 days after discontinuation of nirmatrelvir/ritonavir. Patients receiving rosuvastatin do not need to change their treatment regimen. TRIAL REGISTRATION EudraCT number: 2021-006634-39. DRKS00027838.
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Affiliation(s)
- Evelyn Krohmer
- Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Medical Faculty of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
| | - Brit Silja Rohr
- Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Medical Faculty of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
| | - Felicitas Stoll
- Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Medical Faculty of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
| | - Katja S Gümüs
- Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Medical Faculty of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
| | - Mariano Bergamino
- Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Medical Faculty of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
| | - Gerd Mikus
- Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Medical Faculty of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
| | - Max Sauter
- Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Medical Faculty of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
| | - Jürgen Burhenne
- Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Medical Faculty of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
| | - Johanna Weiss
- Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Medical Faculty of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
| | - Andreas D Meid
- Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Medical Faculty of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
| | - David Czock
- Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Medical Faculty of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
| | - Antje Blank
- Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Medical Faculty of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
| | - Walter E Haefeli
- Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Medical Faculty of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
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Miletic B, Schneiter S, Lygkoni S. Progressive Muscle Weakness: Identifying Necrotizing Autoimmune Myopathy as a Rare Culprit. Cureus 2025; 17:e79164. [PMID: 40109791 PMCID: PMC11921991 DOI: 10.7759/cureus.79164] [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] [Accepted: 02/17/2025] [Indexed: 03/22/2025] Open
Abstract
Statin-induced necrotizing autoimmune myopathy (SINAM) is a rare but critical complication of statin therapy that leads to progressive muscle weakness. The complicated mechanisms underlying it make both diagnosis and treatment difficult. It is essential to recognize the condition early, especially in people who have had muscle problems treated with statins in the past. A 73-year-old woman arrived at the emergency department due to increasingly severe symmetrical muscle weakness accompanied by markedly elevated liver enzymes, creatine kinase (CK), and cardiac troponins. Although an acute cardiac event was ruled out, further tests indicated progressive myositis, necessitating hospitalization. A muscle biopsy subsequently confirmed myopathy with complement deposition, and anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR) antibodies were detected. With treatment that included corticosteroids, intravenous immunoglobulin, and rehabilitation, the patient showed remarkable improvement. This case undeniably highlights the critical importance of early detection of SINAM and intervention and emphasizes the absolute need for further research into causes and treatment strategies.
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Affiliation(s)
- Bojan Miletic
- Department of Geriatrics and Rehabilitation, Lucerne Cantonal Hospital Wolhusen, Wolhusen, CHE
- Clinical Medical Science, Faculty of Health Studies, University of Rijeka, Rijeka, HRV
| | - Simon Schneiter
- Department of Internal Medicine, Lucerne Cantonal Hospital Wolhusen, Wolhusen, CHE
| | - Stavroula Lygkoni
- Department of Cardiology, University Hospital of Zürich, Zürich, CHE
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Hafner S, Reins J, Baader C, Balling F, Eff S. Use of Hemoadsorption and Continuous Venovenous Hemodialysis With Enhanced Middle Molecule Clearance in Drug-Induced Rhabdomyolysis. Case Rep Crit Care 2025; 2025:3968057. [PMID: 39872682 PMCID: PMC11772059 DOI: 10.1155/crcc/3968057] [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: 05/29/2024] [Accepted: 01/08/2025] [Indexed: 01/30/2025] Open
Abstract
Drug-induced rhabdomyolysis has become increasingly prevalent due to the rising use of medications such as statins, antidepressants, and antipsychotics. These can lead to muscle cell destruction and the release of myoglobin, potentially causing kidney damage. Recent advancements include the use of CytoSorb hemoadsorption as a promising therapy to remove myoglobin and other potentially toxic substances from the bloodstream. A 47-year-old male with a complex medical history presented with weakness, pain, and dizziness. Lab results indicated severe rhabdomyolysis, most likely of medication-induced etiology. He developed acute kidney injury (AKI) and underwent continuous venovenous hemodialysis (CVVHD) combined with CytoSorb hemoadsorption. Despite initial stabilization, rhabdomyolysis parameters surged, necessitating the use of an additional high-flux filter with enhanced middle molecule clearance. CytoSorb therapy was administered for nine consecutive sessions, resulting in decreased creatine kinase (CK) and myoglobin levels. Due to persistent kidney injury, the patient required permanent dialysis and was transferred to a kidney disease center. This case highlights the complexity and severity of drug-induced rhabdomyolysis with hemoadsorption playing a pivotal role in reducing myoglobin levels and improving the patient's condition. Combining hemoadsorption and filters with enhanced middle molecule clearance holds even more promise for improved myoglobin removal.
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Affiliation(s)
- Sebastian Hafner
- Department of Anesthesiology and Intensive Care Medicine, Sana Klinikum Landkreis Biberach, Biberach, Germany
| | - Johannes Reins
- Department of Anesthesiology and Intensive Care Medicine, Kreiskliniken Günzburg-Krumbach, Krumbach, Germany
| | - Christoph Baader
- Department of Anesthesiology and Intensive Care Medicine, Kreiskliniken Günzburg-Krumbach, Krumbach, Germany
| | - Florian Balling
- Department of Anesthesiology and Intensive Care Medicine, Kreiskliniken Günzburg-Krumbach, Krumbach, Germany
| | - Sebastian Eff
- Department of Anesthesiology and Intensive Care Medicine, Kreiskliniken Günzburg-Krumbach, Krumbach, Germany
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Ferri N, Corsini A. Statin-associated muscle symptoms: Not simply a genetic predisposition. Atherosclerosis 2025; 400:119047. [PMID: 39550243 DOI: 10.1016/j.atherosclerosis.2024.119047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Accepted: 11/05/2024] [Indexed: 11/18/2024]
Affiliation(s)
- Nicola Ferri
- Department of Medicine, University of Padova, 35100, Padua, Italy; Veneto Institute of Molecular Medicine, 35129, Padua, Italy.
| | - Alberto Corsini
- Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", University of Milan, Italy; Centro di Ricerca Coordinata sulle Interazioni Farmacologiche, Milan, Italy
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Bellosta S, Corsini A. Drug interactions in cardiology: focus on statins and their combination with other lipid-lowering drugs. Expert Opin Drug Metab Toxicol 2024; 20:1013-1021. [PMID: 39252198 DOI: 10.1080/17425255.2024.2402493] [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: 05/20/2024] [Revised: 08/12/2024] [Accepted: 09/05/2024] [Indexed: 09/11/2024]
Abstract
INTRODUCTION Statins are the primary therapeutic approach for treating hypercholesterolemia in hyperlipidemic high cardiovascular-risk patients, as stated by the recent European and American guidelines. However, in some patients, statin treatment is not sufficient to achieve the recommended plasma LDL-C levels, and the addition of a second hypolipidemic drug becomes mandatory. Concomitant administration of multiple medications may increase the risk of adverse events, potentially leading to statin-associated muscle or liver symptoms and non-adherence or discontinuation of statin therapy, such as in women. The addition of a second hypolipidemic drug (such as ezetimibe, anti-PCSK9 monoclonal antibodies, bempedoic acid, and inclisiran) may lead to drug-drug interactions (DDIs). The evaluation of the different pharmacokinetic profiles may improve and personalize the treatment. AREAS COVERED We aimed to give an update on the potential DDIs between statins and other hypolipidemic drugs currently used to treat high-risk hyperlipidemic patients. EXPERT OPINION It is fundamental to understand the risk associated with DDIs to manage better the addition of a concomitant hyperlipidemic drug to a statin-treated patient. Many health agencies have published specific guidelines for assessing DDIs, but these mainly apply to in vitro studies. New predictive approaches are being proposed and may help evaluate and manage DDIs.
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Affiliation(s)
- Stefano Bellosta
- Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", Centro di Ricerca Coordinata sulle Interazioni Farmacologiche, Università degli Studi di Milano, Milan, Italy
| | - Alberto Corsini
- Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", Centro di Ricerca Coordinata sulle Interazioni Farmacologiche, Università degli Studi di Milano, Milan, Italy
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Chen J, Wu J, Guo N, Song Y, Li L, Wang B, Li J, Hou M, Yin H, Zhang M, Kong Y, Wu X, Li R, Wu L, Gao Q, Dong R. Evaluation of drug-drug interactions of a novel potent FLT3 inhibitor SKLB1028 in healthy subjects. Clin Transl Sci 2024; 17:e70063. [PMID: 39533673 PMCID: PMC11557726 DOI: 10.1111/cts.70063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 09/23/2024] [Accepted: 10/16/2024] [Indexed: 11/16/2024] Open
Abstract
SKLB1028 is a novel multi-target protein kinase inhibitor under investigation for the treatment of FLT3-ITD mutated acute myeloid leukemia. Based on the preclinical characterization of SKLB1028 metabolism, three drug-drug interaction clinical studies were performed to investigate the effects of itraconazole, rifampin (CYP3A4 inhibitor and inducer, respectively), and gemfibrozil (CYP2C8 inhibitor) on the metabolism of SKLB1028. Fourteen healthy Chinese male subjects were enrolled in each study. In Study 1, subjects were administered a single dose of SKLB1028 (100 mg on days 1 and 11) and multiple doses of itraconazole (200 mg twice daily on day 8 and 200 mg once daily from days 9 to 18). Itraconazole was given with a loading dose on Day 8 and the total administration of itraconazole was 11 days. In Study 2, subjects were administered a single dose of SKLB1028 (100 mg on days 1 and 12) and multiple doses of gemfibrozil (600 mg twice daily from days 8 to 19). In Study 3, subjects were administered a single dose of SKLB1028 (150 mg on days 1 and 15) and multiple doses of rifampin (600 mg once daily from day 8 to 22). Itraconazole increased the AUC and Cmax of SKLB1028 by approximately 28% and 41%, respectively. Compared to the single drug, co-administration with gemfibrozil increased the AUC of SKLB1028 by ~26% and the Cmax by ~21%. Co-administration with rifampin reduced the AUC of SKLB1028 by ~30%, while the Cmax did not change significantly. All treatments were well tolerated in all three studies.
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Affiliation(s)
- Jingcheng Chen
- Beijing Friendship HospitalCapital Medical UniversityBeijingChina
| | - Jingxuan Wu
- Beijing Friendship HospitalCapital Medical UniversityBeijingChina
| | - Nini Guo
- CSPC Zhongqi Pharmaceutical Technology (SJZ) Co., Ltd.ShijiazhuangHebei ProvinceChina
| | - Yuqin Song
- Beijing Friendship HospitalCapital Medical UniversityBeijingChina
| | - Lijun Li
- Beijing Friendship HospitalCapital Medical UniversityBeijingChina
| | - Bingyan Wang
- Beijing Friendship HospitalCapital Medical UniversityBeijingChina
| | - Jiangshuo Li
- Beijing Friendship HospitalCapital Medical UniversityBeijingChina
| | - Mengyu Hou
- Beijing Friendship HospitalCapital Medical UniversityBeijingChina
| | - Hang Yin
- Beijing Friendship HospitalCapital Medical UniversityBeijingChina
| | - Meijuan Zhang
- Beijing Friendship HospitalCapital Medical UniversityBeijingChina
| | - Yanhong Kong
- Beijing Friendship HospitalCapital Medical UniversityBeijingChina
| | - Xiaofang Wu
- Beijing Friendship HospitalCapital Medical UniversityBeijingChina
| | - Ran Li
- Beijing Friendship HospitalCapital Medical UniversityBeijingChina
| | - Le Wu
- Beijing Friendship HospitalCapital Medical UniversityBeijingChina
| | - Qiannan Gao
- Beijing Friendship HospitalCapital Medical UniversityBeijingChina
| | - Ruihua Dong
- Beijing Friendship HospitalCapital Medical UniversityBeijingChina
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Wang Y, Lilienfeldt N, Hekimi S. Understanding coenzyme Q. Physiol Rev 2024; 104:1533-1610. [PMID: 38722242 PMCID: PMC11495197 DOI: 10.1152/physrev.00040.2023] [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: 10/16/2023] [Revised: 04/08/2024] [Accepted: 05/01/2024] [Indexed: 08/11/2024] Open
Abstract
Coenzyme Q (CoQ), also known as ubiquinone, comprises a benzoquinone head group and a long isoprenoid side chain. It is thus extremely hydrophobic and resides in membranes. It is best known for its complex function as an electron transporter in the mitochondrial electron transport chain (ETC) but is also required for several other crucial cellular processes. In fact, CoQ appears to be central to the entire redox balance of the cell. Remarkably, its structure and therefore its properties have not changed from bacteria to vertebrates. In metazoans, it is synthesized in all cells and is found in most, and maybe all, biological membranes. CoQ is also known as a nutritional supplement, mostly because of its involvement with antioxidant defenses. However, whether there is any health benefit from oral consumption of CoQ is not well established. Here we review the function of CoQ as a redox-active molecule in the ETC and other enzymatic systems, its role as a prooxidant in reactive oxygen species generation, and its separate involvement in antioxidant mechanisms. We also review CoQ biosynthesis, which is particularly complex because of its extreme hydrophobicity, as well as the biological consequences of primary and secondary CoQ deficiency, including in human patients. Primary CoQ deficiency is a rare inborn condition due to mutation in CoQ biosynthetic genes. Secondary CoQ deficiency is much more common, as it accompanies a variety of pathological conditions, including mitochondrial disorders as well as aging. In this context, we discuss the importance, but also the great difficulty, of alleviating CoQ deficiency by CoQ supplementation.
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Affiliation(s)
- Ying Wang
- Department of Biology, McGill University, Montreal, Quebec, Canada
| | - Noah Lilienfeldt
- Department of Biology, McGill University, Montreal, Quebec, Canada
| | - Siegfried Hekimi
- Department of Biology, McGill University, Montreal, Quebec, Canada
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Hoshi RA, Alotaibi M, Liu Y, Watrous JD, Ridker PM, Glynn RJ, Serhan CN, Luttmann-Gibson H, Moorthy MV, Jain M, Demler OV, Mora S. One-Year Effects of High-Intensity Statin on Bioactive Lipids: Findings From the JUPITER Trial. Arterioscler Thromb Vasc Biol 2024; 44:e196-e206. [PMID: 38841856 PMCID: PMC11209760 DOI: 10.1161/atvbaha.124.321058] [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: 04/08/2024] [Accepted: 05/22/2024] [Indexed: 06/07/2024]
Abstract
BACKGROUND Statin effects extend beyond low-density lipoprotein cholesterol reduction, potentially modulating the metabolism of bioactive lipids (BALs), crucial for biological signaling and inflammation. These bioactive metabolites may serve as metabolic footprints, helping uncover underlying processes linked to pleiotropic effects of statins and yielding a better understanding of their cardioprotective properties. This study aimed to investigate the impact of high-intensity statin therapy versus placebo on plasma BALs in the JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin; NCT00239681), a randomized primary prevention trial involving individuals with low-density lipoprotein cholesterol <130 mg/dL and high-sensitivity C-reactive protein ≥2 mg/L. METHODS Using a nontargeted mass spectrometry approach, over 11 000 lipid features were assayed from baseline and 1-year plasma samples from cardiovascular disease noncases from 2 nonoverlapping nested substudies: JUPITERdiscovery (n=589) and JUPITERvalidation (n=409). The effect of randomized allocation of rosuvastatin 20 mg versus placebo on BALs was examined by fitting a linear regression with delta values (∆=year 1-baseline) adjusted for age and baseline levels of each feature. Significant associations in discovery were analyzed in the validation cohort. Multiple comparisons were adjusted using 2-stage overall false discovery rate. RESULTS We identified 610 lipid features associated with statin randomization with significant replication (overall false discovery rate, <0.05), including 26 with annotations. Statin therapy significantly increased levels of 276 features, including BALs with anti-inflammatory activity and arterial vasodilation properties. Concurrently, 334 features were significantly lowered by statin therapy, including arachidonic acid and proinflammatory and proplatelet aggregation BALs. By contrast, statin therapy reduced an eicosapentaenoic acid-derived hydroxyeicosapentaenoic acid metabolite, which may be related to impaired glucose metabolism. Additionally, we observed sex-related differences in 6 lipid metabolites and 6 unknown features. CONCLUSIONS Statin allocation was significantly associated with upregulation of BALs with anti-inflammatory, antiplatelet aggregation and antioxidant properties and downregulation of BALs with proinflammatory and proplatelet aggregation activity, supporting the pleiotropic effects of statins beyond low-density lipoprotein cholesterol reduction.
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Affiliation(s)
- Rosangela Akemi Hoshi
- Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Division of Preventive Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Center for Lipid Metabolomics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Mona Alotaibi
- Department of Medicine, University of California San Diego, La Jolla, CA 92037, USA
- Division of Pulmonary, Critical Care and Sleep Medicine, University of California San Diego, La Jolla, CA, USA
| | - Yanyan Liu
- Division of Preventive Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Center for Lipid Metabolomics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Jeramie D. Watrous
- Department of Medicine, University of California San Diego, La Jolla, CA 92037, USA
| | - Paul M Ridker
- Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Division of Preventive Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Robert J. Glynn
- Division of Preventive Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Charles N. Serhan
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Heike Luttmann-Gibson
- Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Division of Preventive Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Center for Lipid Metabolomics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
| | - M. Vinayaga Moorthy
- Division of Preventive Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Mohit Jain
- Department of Medicine, University of California San Diego, La Jolla, CA 92037, USA
| | - Olga V. Demler
- Division of Preventive Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Center for Lipid Metabolomics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Department of Computer Science, ETH Zurich, Zurich 8092, Switzerland
| | - Samia Mora
- Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Division of Preventive Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Center for Lipid Metabolomics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
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Oliai SF, Shippy DC, Ulland TK. Mitigation of CXCL10 secretion by metabolic disorder drugs in microglial-mediated neuroinflammation. J Neuroimmunol 2024; 391:578364. [PMID: 38718558 PMCID: PMC11165694 DOI: 10.1016/j.jneuroim.2024.578364] [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: 02/13/2024] [Revised: 04/26/2024] [Accepted: 05/02/2024] [Indexed: 05/12/2024]
Abstract
Metabolic disorders are associated with several neurodegenerative diseases. We previously identified C-X-C motif chemokine ligand 10 (CXCL10), also known as interferon gamma-induced protein 10 (IP-10), as a major contributor to the type I interferon response in microglial-mediated neuroinflammation. Therefore, we hypothesized FDA-approved metabolic disorder drugs that attenuate CXCL10 secretion may be repurposed as a treatment for neurodegenerative diseases. Screening, dose curves, and cytotoxicity assays in LPS-stimulated microglia yielded treprostinil (hypertension), pitavastatin (hyperlipidemia), and eplerenone (hypertension) as candidates that significantly reduced CXCL10 secretion (in addition to other pro-inflammatory mediators) without impacting cell viability. Altogether, these data suggest metabolic disorder drugs that attenuate CXCL10 as potential treatments for neurodegenerative disease through mitigating microglial-mediated neuroinflammation.
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Affiliation(s)
- Sophia F Oliai
- Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI, USA
| | - Daniel C Shippy
- Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI, USA
| | - Tyler K Ulland
- Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI, USA; Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
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Fayol A, Schiele F, Ferrières J, Puymirat E, Bataille V, Tea V, Chamandi C, Albert F, Lemesle G, Cayla G, Weizman O, Simon T, Danchin N. Association of Use and Dose of Lipid-Lowering Therapy Post Acute Myocardial Infarction With 5-Year Survival in Older Adults. Circ Cardiovasc Qual Outcomes 2024; 17:e010685. [PMID: 38682335 DOI: 10.1161/circoutcomes.123.010685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 03/18/2024] [Indexed: 05/01/2024]
Abstract
BACKGROUND Older people are underrepresented in randomized trials. The association between lipid-lowering therapy (LLT) and its intensity after acute myocardial infarction and long-term mortality in this population deserves to be assessed. METHODS The FAST-MI (French Registry of Acute ST-Elevation or Non-ST-Elevation Myocardial Infarction) program consists of nationwide French surveys including all patients admitted for acute myocardial infarction ≤48 hours from onset over a 1- to 2-month period in 2005, 2010, and 2015, with long-term follow-up. Numerous data were collected and a centralized 10-year follow-up was organized. The present analysis focused on the association between prescription of LLT (atorvastatin ≥40 mg or equivalent, or any combination of statin and ezetimibe) and 5-year mortality in patients aged ≥80 years discharged alive. Cox multivariable analysis and propensity score matching were used to adjust for baseline differences. RESULTS Among the 2258 patients aged ≥80 years (mean age, 85±4 years; 51% women; 39% ST-segment elevation myocardial infarction; 58% with percutaneous coronary intervention), 415 were discharged without LLT (18%), 866 with conventional doses (38%), and 977 with high-dose LLT (43%). Five-year survival was 36%, 47.5%, and 58%, respectively. Compared with patients without LLT, high-dose LLT was significantly associated with lower 5-year mortality (adjusted hazard ratio, 0.78 [95% CI, 0.66-0.92]), whereas conventional-intensity LLT was not (adjusted hazard ratio, 0.93 [95% CI, 0.80-1.09]). In propensity score-matched cohorts (n=278 receiving high-intensity LLT and n=278 receiving no statins), 5-year survival was 52% with high-intensity LLT at discharge and 42% without statins (hazard ratio, 0.78 [95% CI, 0.62-0.98]). CONCLUSIONS In these observational cohorts, high-intensity LLT at discharge after acute myocardial infarction was associated with reduced all-cause mortality at 5 years in an older adult population. These results suggest that high-intensity LLT should not be denied to patients on the basis of old age. REGISTRATION URL: https://www.clinicaltrials.gov; Unique identifiers: NCT00673036, NCT01237418, and NCT02566200.
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Affiliation(s)
- Antoine Fayol
- Assistance Publique-Hôpitaux de Paris, Departement of Cardiology, Hôpital Européen Georges-Pompidou, France (A.F., E.P., V.T., C.C., O.W., N.D.)
- University Paris Cité, France (A.F., E.P., V.T., C.C., O.W., N.D.)
| | - François Schiele
- Department of Cardiology, University Hospital Jean-Minjoz, Besançon, France (F.S.)
| | - Jean Ferrières
- Department of Cardiology, Toulouse Rangueil University Hospital, Institut National pour la Santé Et la Recherche Médicale Unité Mixte de Recherche, Toulouse cedex, France Emergency Department, Rangueil Hospital, Toulouse (J.F., V.B.)
| | - Etienne Puymirat
- Assistance Publique-Hôpitaux de Paris, Departement of Cardiology, Hôpital Européen Georges-Pompidou, France (A.F., E.P., V.T., C.C., O.W., N.D.)
- University Paris Cité, France (A.F., E.P., V.T., C.C., O.W., N.D.)
| | - Vincent Bataille
- Department of Cardiology, Toulouse Rangueil University Hospital, Institut National pour la Santé Et la Recherche Médicale Unité Mixte de Recherche, Toulouse cedex, France Emergency Department, Rangueil Hospital, Toulouse (J.F., V.B.)
| | - Victoria Tea
- Assistance Publique-Hôpitaux de Paris, Departement of Cardiology, Hôpital Européen Georges-Pompidou, France (A.F., E.P., V.T., C.C., O.W., N.D.)
- University Paris Cité, France (A.F., E.P., V.T., C.C., O.W., N.D.)
| | - Chekrallah Chamandi
- Assistance Publique-Hôpitaux de Paris, Departement of Cardiology, Hôpital Européen Georges-Pompidou, France (A.F., E.P., V.T., C.C., O.W., N.D.)
- University Paris Cité, France (A.F., E.P., V.T., C.C., O.W., N.D.)
| | - Franck Albert
- Department of Cardiology, Hospital of Chartres, France (F.A.)
| | - Gilles Lemesle
- Department of Cardiology, Heart and Lung Institute, University Hospital of Lille, France (G.L.)
- University of Lille, France (G.L.)
- Institut Pasteur de Lille, France (G.L.)
- FACT (French Alliance for Cardiovascular Trials), Paris (G.L.)
| | - Guillaume Cayla
- Department of Cardiology, University Hospital of Nimes, University of Montpellier, France (G.C.)
| | - Orianne Weizman
- Assistance Publique-Hôpitaux de Paris, Departement of Cardiology, Hôpital Européen Georges-Pompidou, France (A.F., E.P., V.T., C.C., O.W., N.D.)
- University Paris Cité, France (A.F., E.P., V.T., C.C., O.W., N.D.)
| | - Tabassome Simon
- Department of Pharmacology and Clinical Research Platform of East of Paris (Unité de Recherche Clinique des hopitaux EST parisiens, Comité de Recherche Clinique des hopitaux EST parisiens, Centre de Ressources Biologiques), Hôpital St Antoine, Sorbonne University, and FACT (T.S.)
| | - Nicolas Danchin
- Assistance Publique-Hôpitaux de Paris, Departement of Cardiology, Hôpital Européen Georges-Pompidou, France (A.F., E.P., V.T., C.C., O.W., N.D.)
- University Paris Cité, France (A.F., E.P., V.T., C.C., O.W., N.D.)
- Hôpital Paris St Joseph, and FACT (N.D.)
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12
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Lho Y, Kim GO, Kim BY, Son EJ, Kang SH. Effects of Administration and Intensity of Statins on Mortality in Patients Undergoing Hemodialysis. Pharmaceuticals (Basel) 2024; 17:498. [PMID: 38675457 PMCID: PMC11054991 DOI: 10.3390/ph17040498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 04/08/2024] [Accepted: 04/10/2024] [Indexed: 04/28/2024] Open
Abstract
(1) Background: Few studies have investigated the association between the intensity of statins and patient survival rates in patients undergoing hemodialysis (HD) as primary outcomes. This study aimed to evaluate patient survival rates according to the intensity of statins using a large sample of patients undergoing maintenance HD. (2) Methods: Data from a national HD quality assessment program were used in this study (n = 53,345). We divided the patients into four groups based on the administration and intensity of statins: Group 1, patients without a prescription of statins (n = 37,944); Group 2, patients with a prescription of a low intensity of statins (n = 700); Group 3, patients with a prescription of a moderate intensity of statins (n = 14,160); Group 4, patients with a prescription of a high intensity of statins (n = 541). (3) Results: Significant differences in baseline characteristics were observed among the four groups. Group 1 had the best patient survival among the four groups in the univariate Cox regression analyses. However, multivariable Cox regression analyses showed that the patient survival rate was higher for Group 3 than for Group 1. Cox regression analyses using data of a balanced cohort showed that, on univariate analyses, the HRs were 0.93 (95% CI, 0.91-0.95, p < 0.001) in Group 2 and 0.95 (95% CI, 0.93-0.96, p < 0.001) in Group 3 compared to that in Group 1. Group 4 had a higher mortality rate than Groups 2 or 3. The results from the cohort after balancing showed a similar trend to those from the multivariable Cox regression analyses. Young age and less comorbidities in Group 1 were mainly associated with favorable survival in Group 1 in the univariate analysis using cohort before balancing. Among the subgroup analyses based on sex, age, presence of diabetes mellitus, and heart disease, most multivariable analyses showed significantly higher patient survival rates in Group 3 than for Group 1. (4) Conclusions: Our study exhibited significant differences in baseline characteristics between the groups, leading to limitations in establishing a robust association between statin intensity and clinical outcomes. However, we conducted various statistical analyses to mitigate these differences. Some results, including multivariable analyses controlling for baseline characteristics and analyses of a balanced cohort using propensity score weighting, indicated improved patient survival in the moderate-intensity statin group compared to non-users. These findings suggest that moderate statin use may be associated with favorable patient survival.
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Affiliation(s)
- Yunmee Lho
- Senotherapy-Based Metabolic Disease Control Research Center, Yeungnam University, Daegu 42415, Republic of Korea;
| | - Gui Ok Kim
- Quality Assessment Department, Health Insurance Review and Assessment Service, Wonju 26465, Republic of Korea
| | - Bo Yeon Kim
- Healthcare Review and Assessment Committee, Health Insurance Review and Assessment Service, Wonju 26465, Republic of Korea
| | - Eun Jung Son
- Quality Assessment Department, Health Insurance Review and Assessment Service, Wonju 26465, Republic of Korea
| | - Seok Hui Kang
- Division of Nephrology, Department of Internal Medicine, College of Medicine, Yeungnam University, Daegu 42415, Republic of Korea
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13
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Ferri N, Ruscica M, Fazio S, Corsini A. Low-Density Lipoprotein Cholesterol-Lowering Drugs: A Narrative Review. J Clin Med 2024; 13:943. [PMID: 38398257 PMCID: PMC10889346 DOI: 10.3390/jcm13040943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2024] [Revised: 01/26/2024] [Accepted: 02/02/2024] [Indexed: 02/25/2024] Open
Abstract
The modern history of cholesterol-lowering drugs started in 1972 when Dr. Akira Endo identified an active compound (compactin) that inhibited cholesterol biosynthesis from the culture broth of blue-green mold (Penicillium citrinum Pen-51). Since 1987, statins have represented the milestone for the treatment of atherosclerotic cardiovascular disease. A new therapy for the treatment of hypercholesterolemia since the discovery of statins is ezetimibe, the first and only agent inhibiting intestinal cholesterol absorption. Ezetimibe was approved by the FDA in October 2002. A year later, the association between gain-of-function PCSK9 genetic mutations and hypercholesterolemia was reported, and this discovery opened a new era in lipid-lowering therapies. Monoclonal antibodies and small-interfering RNA approaches to reduce PCSK9 were developed and approved for clinical use in 2015 and 2022, respectively. Finally, the newly approved bempedoic acid, an oral adenosine triphosphate citrate lyase inhibitor that lowers LDL-C, is able to reduce major adverse cardiovascular events in both primary and secondary prevention. In the present narrative review, we summarize the pharmacological properties and the clinical efficacy of all these agents currently used for a tailored therapy of hypercholesterolemia in patients with atherosclerotic cardiovascular disease.
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Affiliation(s)
- Nicola Ferri
- Department of Medicine (DIMED), University of Padova, 35122 Padova, Italy
- Veneto Institute of Molecular Medicine (VIMM), 35129 Padua, Italy
| | - Massimiliano Ruscica
- Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, University of Milan, 20133 Milan, Italy;
- Department of Cardio-Thoracic-Vascular Diseases, Foundation IRCCS Cà Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Sergio Fazio
- Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA;
| | - Alberto Corsini
- Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, University of Milan, 20133 Milan, Italy;
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14
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Ghorbannezhad G, Mehrabadi S, Golampour-Shamkani N, Barjasteh A, Etesamizadeh P, Tayyebi M, Khazaei M, Hassanian SM, Ferns GA, Avan A. Genetic Determinants of Response to Statins in Cardiovascular Diseases. Curr Cardiol Rev 2024; 20:20-28. [PMID: 38204221 PMCID: PMC11107471 DOI: 10.2174/011573403x267793231220114042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Revised: 10/28/2023] [Accepted: 11/15/2023] [Indexed: 01/12/2024] Open
Abstract
Despite extensive efforts to identify patients with cardiovascular disease (CVD) who could most benefit from the treatment approach, patients vary in their benefit from therapy and propensity for adverse drug events. Genetic variability in individual responses to drugs (pharmacogenetics) is considered an essential determinant in responding to a drug. Thus, understanding these pharmacogenomic relationships has led to a substantial focus on mechanisms of disease and drug response. In turn, understanding the genomic and molecular bases of variables that might be involved in drug response is the main step in personalized medicine. There is a growing body of data evaluating drug-gene interactions in recent years, some of which have led to FDA recommendations and detection of markers to predict drug responses (e.g., genetic variant in VKORC1 and CYP2C9 genes for prediction of drug response in warfarin treatment). Also, statins are widely prescribed drugs for the prevention of CVD. Atorvastatin, fluvastatin, rosuvastatin, simvastatin, and lovastatin are the most common statins used to manage dyslipidemia. This review provides an overview of the current knowledge on the pharmacogenetics of statins, which are being used to treat cardiovascular diseases.
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Affiliation(s)
- Ghazaleh Ghorbannezhad
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Shima Mehrabadi
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Negar Golampour-Shamkani
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Barjasteh
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Poorya Etesamizadeh
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Tayyebi
- Department of Cardiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Khazaei
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Mahdi Hassanian
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Brighton & Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex BN1 9PH, UK
| | - Amir Avan
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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15
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Sadowska A, Osiński P, Roztocka A, Kaczmarz-Chojnacka K, Zapora E, Sawicka D, Car H. Statins-From Fungi to Pharmacy. Int J Mol Sci 2023; 25:466. [PMID: 38203637 PMCID: PMC10779115 DOI: 10.3390/ijms25010466] [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: 11/30/2023] [Revised: 12/22/2023] [Accepted: 12/23/2023] [Indexed: 01/12/2024] Open
Abstract
Statins have been used in the treatment of hyperlipidemia, both as monotherapy and in combination therapy. Natural fermentation processes of fungi such as Monascus spp., Penicillium spp., Aspergillus terreus, and Pleurotus ostreatus have given rise to natural statins. Compactin (mevastatin), the original naturally occurring statin, is the primary biotransformation substrate in the manufacturing process of marketed drugs. Statins are classified into natural, semi-synthetic derivatives of natural statins, and synthetic ones. Synthetic statins differ from natural statins in their structural composition, with the only common feature being the HMG-CoA-like moiety responsible for suppressing HMG-CoA reductase. Statins do not differ significantly regarding their pleiotropic and adverse effects, but their characteristics depend on their pharmacokinetic parameters and chemical properties. This paper focuses on describing the processes of obtaining natural statins, detailing the pharmacokinetics of available statins, divided into natural and synthetic, and indicating their pleiotropic effects.
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Affiliation(s)
- Anna Sadowska
- Department of Experimental Pharmacology, Medical University of Bialystok, Szpitalna 37, 15-295 Bialystok, Poland; (D.S.); (H.C.)
| | - Patryk Osiński
- Student’s Pharmacological Club, Lazarski University, Świeradowska 43, 02-662 Warsaw, Poland; (P.O.); (A.R.); (K.K.-C.)
| | - Alicja Roztocka
- Student’s Pharmacological Club, Lazarski University, Świeradowska 43, 02-662 Warsaw, Poland; (P.O.); (A.R.); (K.K.-C.)
| | - Karolina Kaczmarz-Chojnacka
- Student’s Pharmacological Club, Lazarski University, Świeradowska 43, 02-662 Warsaw, Poland; (P.O.); (A.R.); (K.K.-C.)
| | - Ewa Zapora
- Department of Silviculture and Forest Use, Institute of Forest Sciences, Bialystok University of Technology, Wiejska 45E, 15351 Bialystok, Poland;
| | - Diana Sawicka
- Department of Experimental Pharmacology, Medical University of Bialystok, Szpitalna 37, 15-295 Bialystok, Poland; (D.S.); (H.C.)
| | - Halina Car
- Department of Experimental Pharmacology, Medical University of Bialystok, Szpitalna 37, 15-295 Bialystok, Poland; (D.S.); (H.C.)
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16
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Kumar N, He J, Rusling JF. Electrochemical transformations catalyzed by cytochrome P450s and peroxidases. Chem Soc Rev 2023; 52:5135-5171. [PMID: 37458261 DOI: 10.1039/d3cs00461a] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/01/2023]
Abstract
Cytochrome P450s (Cyt P450s) and peroxidases are enzymes featuring iron heme cofactors that have wide applicability as biocatalysts in chemical syntheses. Cyt P450s are a family of monooxygenases that oxidize fatty acids, steroids, and xenobiotics, synthesize hormones, and convert drugs and other chemicals to metabolites. Peroxidases are involved in breaking down hydrogen peroxide and can oxidize organic compounds during this process. Both heme-containing enzymes utilize active FeIVO intermediates to oxidize reactants. By incorporating these enzymes in stable thin films on electrodes, Cyt P450s and peroxidases can accept electrons from an electrode, albeit by different mechanisms, and catalyze organic transformations in a feasible and cost-effective way. This is an advantageous approach, often called bioelectrocatalysis, compared to their biological pathways in solution that require expensive biochemical reductants such as NADPH or additional enzymes to recycle NADPH for Cyt P450s. Bioelectrocatalysis also serves as an ex situ platform to investigate metabolism of drugs and bio-relevant chemicals. In this paper we review biocatalytic electrochemical reactions using Cyt P450s including C-H activation, S-oxidation, epoxidation, N-hydroxylation, and oxidative N-, and O-dealkylation; as well as reactions catalyzed by peroxidases including synthetically important oxidations of organic compounds. Design aspects of these bioelectrocatalytic reactions are presented and discussed, including enzyme film formation on electrodes, temperature, pH, solvents, and activation of the enzymes. Finally, we discuss challenges and future perspective of these two important bioelectrocatalytic systems.
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Affiliation(s)
- Neeraj Kumar
- Department of Chemistry, University of Connecticut, Storrs, CT 06269-3136, USA.
| | - Jie He
- Department of Chemistry, University of Connecticut, Storrs, CT 06269-3136, USA.
- Institute of Materials Science, University of Connecticut, Storrs, CT 06269-3136, USA
| | - James F Rusling
- Department of Chemistry, University of Connecticut, Storrs, CT 06269-3136, USA.
- Institute of Materials Science, University of Connecticut, Storrs, CT 06269-3136, USA
- Department of Surgery and Neag Cancer Center, Uconn Health, Farmington, CT 06030, USA
- School of Chemistry, National University of Ireland at Galway, Galway, Ireland
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17
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Puttarat N, Kasorn A, Vitheejongjaroen P, Chantarangkul C, Tangwattanachuleeporn M, Taweechotipatr M. Beneficial Effects of Indigenous Probiotics in High-Cholesterol Diet-Induced Hypercholesterolemic Rats. Nutrients 2023; 15:2710. [PMID: 37375614 DOI: 10.3390/nu15122710] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 05/27/2023] [Accepted: 06/07/2023] [Indexed: 06/29/2023] Open
Abstract
Hypercholesterolemia is a significant risk factor for cardiovascular disease and metabolic disorders. Probiotics are the essential constituents of the gastrointestinal microbiota that provide health-promoting effects. Cholesterol-lowering activity is a specific property of probiotics, improving the cholesterol metabolism without adverse effects. Thus, the purpose of this study was to investigate the hypocholesterolemic effect of single and mixed cholesterol-lowering probiotic strains (including Limosilactobacillus reuteri TF-7, Enterococcus faecium TF-18, and Bifidobacterium animalis TA-1) in high-cholesterol diet (HCD)-induced hypercholesterolemic rats. The results showed that the administration of single probiotics contributed to a reduction in the body weight gain, visceral organ indexes, hyperlipidemia, and hepatic steatosis and also an improvement in the gastrointestinal microbiota. Besides the effect of single cholesterol-lowering probiotics, three probiotics strains could also synergize their hypocholesterolemic effect when administered simultaneously. These findings indicate that three cholesterol-lowering probiotic strains are suitable for development as probiotic supplements to reduce the risk of diseases caused by cholesterol and exert health benefits with synergistic effect when administered simultaneously.
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Affiliation(s)
- Narathip Puttarat
- Center of Excellence in Probiotics, Srinakharinwirot University, Bangkok 10110, Thailand
- Department of Microbiology, Faculty of Medicine, Srinakharinwirot University, Bangkok 10110, Thailand
| | - Anongnard Kasorn
- Department of Biomedical Science, Faculty of Medicine, Vajira Hospital, Navamindradhiraj University, Bangkok 10300, Thailand
| | - Porntipha Vitheejongjaroen
- Center of Excellence in Probiotics, Srinakharinwirot University, Bangkok 10110, Thailand
- Department of Microbiology, Faculty of Medicine, Srinakharinwirot University, Bangkok 10110, Thailand
| | - Chantanapa Chantarangkul
- Center of Excellence in Probiotics, Srinakharinwirot University, Bangkok 10110, Thailand
- Department of Microbiology, Faculty of Medicine, Srinakharinwirot University, Bangkok 10110, Thailand
| | - Marut Tangwattanachuleeporn
- Faculty of Allied Health Sciences, Burapha University, Chonburi 20131, Thailand
- Research Unit for Sensor Innovation (RUSI), Burapha University, Chonburi 20131, Thailand
| | - Malai Taweechotipatr
- Center of Excellence in Probiotics, Srinakharinwirot University, Bangkok 10110, Thailand
- Department of Microbiology, Faculty of Medicine, Srinakharinwirot University, Bangkok 10110, Thailand
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18
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Gudiwada MCVB, Gaddam V, Rahman M, Jasti JR, Bhalodia P, Jitta SR. High-Intensity Statin Therapy and Associated Rhabdomyolysis in Chronic Liver Disease: A Case Report and Review of Literature. Cureus 2023; 15:e39150. [PMID: 37378115 PMCID: PMC10292103 DOI: 10.7759/cureus.39150] [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] [Accepted: 05/17/2023] [Indexed: 06/29/2023] Open
Abstract
Current literature suggests an increased incidence of rhabdomyolysis in patients with chronic liver disease (CLD) compared to the general population. We present a case of a 60-year-old female with a history of non-alcoholic fatty liver disease and cirrhosis who developed rhabdomyolysis and acute kidney injury after starting high-intensity atorvastatin therapy. This case highlights the potential risks associated with high-intensity statin therapy in patients with CLD, particularly those with advanced liver dysfunction, emphasizing the need for cautious prescribing and thorough risk-benefit assessment in this vulnerable patient population.
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Affiliation(s)
| | - Vinuthna Gaddam
- Internal Medicine, Advocate Illinois Masonic Medical Center, Chicago, USA
| | - Maheen Rahman
- Internal Medicine, Advocate Illinois Masonic Medical Center, Chicago, USA
| | - Jaswanth R Jasti
- Internal Medicine, University of South Dakota Sanford School of Medicine, Sioux Falls, USA
| | - Paritaben Bhalodia
- Internal Medicine, Advocate Illinois Masonic Medical Center, Chicago, USA
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19
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Tariq S, Goriparthi L, Ismail D, Kankeu Tonpouwo G, Thapa M, Khalid K, Cooper AC, Jean-Charles G. Correlates of Myopathy in Diabetic Patients Taking Statins. Cureus 2023; 15:e37708. [PMID: 37206522 PMCID: PMC10191392 DOI: 10.7759/cureus.37708] [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] [Accepted: 04/16/2023] [Indexed: 05/21/2023] Open
Abstract
Diabetes is one of the most common chronic ailments; its incidence has reached epidemic proportions in the 21st century. Diabetes significantly increases micro and macrovascular complications, which are effectively managed with statins. Therefore, statins' pharmacokinetics, pharmacodynamics, and pharmacogenetics have been extensively studied. Although statins act as a keystone in preventing cardiovascular complications, at the same time, they pose a threat to the quality of life of diabetics due to the resulting muscular side effects. This article summarizes the prevalence, clinical manifestations, pathophysiology, and risk factors of statin-induced myopathy in diabetic patients. Among the diverse predisposing risk factors, the primary variables identified for causing myopathy in diabetic patients include age, gender, ethnicity, duration and severity of illness, comorbid conditions, level of physical activity, alcohol use, cholecalciferol (vitamin D3) levels, type and dose of statins, and anti-diabetic drugs or other drugs used concomitantly. In addition, cardiovascular risk quotients also potentially impact diabetic patients making them more vulnerable to developing myopathy from statins. Therefore, this study highlights the importance of managing statin-associated myopathic side effects by providing consensus guidelines on diagnostic, monitoring, and treatment strategies. We also discussed statins' prognostic value in reducing cardiovascular events in diabetic individuals.
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Affiliation(s)
- Sara Tariq
- Internal Medicine, Mayo Hospital, Lahore, PAK
- Internal Medicine, JC (Jean-Charles) Medical Center, Orlando, USA
| | - Lakshmi Goriparthi
- General Surgery, Osmania Medical College, Hyderabad, IND
- Internal Medicine, JC (Jean-Charles) Medical Center, Orlando, USA
| | - Dina Ismail
- Internal Medicine, JC (Jean-Charles) Medical Center, Orlando, USA
- Family Medicine, University Hassan II of Casablanca Faculty of Medicine and Pharmacy, Casablanca, MAR
| | - Gauvain Kankeu Tonpouwo
- Internal Medicine, Faculty of Medicine, University of Lubumbashi, Plaine Tshombé, Lubumbashi, COD
| | - Milan Thapa
- Internal Medicine, Monmouth Medical Center, Long Branch, USA
| | - Khizer Khalid
- Internal Medicine, JC (Jean-Charles) Medical Center, Orlando, USA
| | | | - Gutteridge Jean-Charles
- Internal Medicine, AdventHealth Orlando Hospital, Orlando, USA
- Internal Medicine, JC (Jean-Charles) Medical Center, Orlando, USA
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20
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Weber CM, Moiz B, Zic SM, Alpízar Vargas V, Li A, Clyne AM. Induced pluripotent stem cell-derived cells model brain microvascular endothelial cell glucose metabolism. Fluids Barriers CNS 2022; 19:98. [PMID: 36494870 PMCID: PMC9733016 DOI: 10.1186/s12987-022-00395-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 11/27/2022] [Indexed: 12/13/2022] Open
Abstract
Glucose transport from the blood into the brain is tightly regulated by brain microvascular endothelial cells (BMEC), which also use glucose as their primary energy source. To study how BMEC glucose transport contributes to cerebral glucose hypometabolism in diseases such as Alzheimer's disease, it is essential to understand how these cells metabolize glucose. Human primary BMEC (hpBMEC) can be used for BMEC metabolism studies; however, they have poor barrier function and may not recapitulate in vivo BMEC function. iPSC-derived BMEC-like cells (hiBMEC) are readily available and have good barrier function but may have an underlying epithelial signature. In this study, we examined differences between hpBMEC and hiBMEC glucose metabolism using a combination of dynamic metabolic measurements, metabolic mass spectrometry, RNA sequencing, and Western blots. hiBMEC had decreased glycolytic flux relative to hpBMEC, and the overall metabolomes and metabolic enzyme levels were different between the two cell types. However, hpBMEC and hiBMEC had similar glucose metabolism, including nearly identical glucose labeled fractions of glycolytic and TCA cycle metabolites. Treatment with astrocyte conditioned media and high glucose increased glycolysis in both hpBMEC and hiBMEC, though hpBMEC decreased glycolysis in response to fluvastatin while hiBMEC did not. Together, these results suggest that hiBMEC can be used to model cerebral vascular glucose metabolism, which expands their use beyond barrier models.
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Affiliation(s)
| | - Bilal Moiz
- University of Maryland, College Park, MD, 20742, USA
| | - Sophia M Zic
- University of Maryland, College Park, MD, 20742, USA
| | | | - Andrew Li
- University of Maryland, College Park, MD, 20742, USA
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Arrout A, El Ghallab Y, El Otmani IS, Said AAH. Ethnopharmacological survey of plants prescribed by herbalists for traditional treatment of hypercholesterolemia in Casablanca, Morocco. J Herb Med 2022. [DOI: 10.1016/j.hermed.2022.100607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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22
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Huang M, Prayson RA, Li Y. Genvoya-Associated and Simvastatin-Associated Noninflammatory and Nonautoimmune Myopathy: A Case Report and Literature Review. J Clin Neuromuscul Dis 2022; 24:75-79. [PMID: 36409337 DOI: 10.1097/cnd.0000000000000386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Patients with HIV have a higher incidence of rhabdomyolysis compared with the HIV negative population because of medication-related myotoxicity and drug-drug interactions. Statins and antiretroviral therapy have been previously reported to cause myopathy in patients with HIV when used alone or in combination. In this study, we describe a case of biopsy-proven noninflammatory and nonautoimmune myopathy associated with the use of simvastatin and Genvoya (elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide fumarate) and review 3 previously reported similar cases. Our patient presented with acute proximal limb weakness and significantly elevated serum creatine kinase. Muscle biopsy revealed scattered degenerating and regenerating muscle fibers without evidence for an inflammatory process. She did not respond to empiric treatment with high-dose intravenous steroids and intravenous immunoglobulin. Her creatine kinase only began to downtrend after discontinuation of both simvastatin and Genvoya, and she returned to baseline function at 2-month follow-up. Our case highlights the importance of recognizing drug-drug interactions between HIV and statin medications in causing significant noninflammatory myopathy. In these patients, both categories of medications need to be discontinued for recovery.
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Affiliation(s)
- Merry Huang
- Department of Neurology, Neurological Institute, Cleveland Clinic, Cleveland, OH; and
| | | | - Yuebing Li
- Department of Neurology, Neurological Institute, Cleveland Clinic, Cleveland, OH; and
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Achievement of Low-Density Lipoprotein Cholesterol Targets in Cardiac Rehabilitation: Impact of the 2019 ESC/EAS Dyslipidaemia Guidelines. J Clin Med 2022; 11:jcm11237057. [PMID: 36498631 PMCID: PMC9740039 DOI: 10.3390/jcm11237057] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 11/20/2022] [Accepted: 11/24/2022] [Indexed: 12/05/2022] Open
Abstract
In 2019 the European Society of Cardiology (ESC) lowered the target values for low-density lipoprotein cholesterol (LDL-C) from <1.8 mmol/L to <1.4 mmol/L for secondary prevention of cardiovascular disease (CVD). The aim of this study was to determine the clinical impact of the 2019 ESC/EAS dyslipidaemia guidelines on lipid-lowering therapies and achievement rates of LDL-C targets in a contemporary cohort of CAD patients participating in an ambulatory cardiac rehabilitation (CR) program.We conducted a retrospective analysis of prospectively collected data from the Swiss Secondary Prevention Registry (SwissPR) in patients with Coronary Artery Disease (CAD), who completed the ambulatory cardiovascular rehabilitation program (CR) of the University Hospital Basel, Switzerland from January 2017 to April 2021. To evaluate the impact of the guideline publication, the cohort was split into a pre-Guideline 2019 group (A) and a post-Guideline 2019 group (B). In total 1320 patients were screened leaving 875 patients for analysis. At discharge, more patients in group B were on maximal statin doses (20% vs. 9%, p < 0.0001) and on combination therapy with ezetimibe (51% vs. 17%, p < 0.0001) than in group A, which resulted in 53% of patients reaching the LDL-C target of <1.4 mmol/L in group B. Regression analysis revealed that dyslipidaemia and positive smoking history represent independent predictors for intensified lipid-lowering medication, whereas absolving CR after publication of the 2019 guidelines was the only significant predictor for reduced LDL-C at CR discharge. We found a significant difference in prescription rates of lipid-lowering medication, especially combination therapies and statin doses, after publication of the 2019 ESC/EAS dyslipidaemia guidelines resulting in an achievement rate of >50% of the LDL-C target <1.4 mmol/L in CAD patients participating in ambulatory CR.
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Al Quran TM, Bataineh ZA, Al-Mistarehi AH, Zein Alaabdin AM, Allan H, Al Qura’an A, Weshah SM, Alanazi AA, Khader YS. Prevalence and Pattern of Dyslipidemia and Its Associated Factors Among Patients with Type 2 Diabetes Mellitus in Jordan: A Cross-Sectional Study. Int J Gen Med 2022; 15:7669-7683. [PMID: 36217367 PMCID: PMC9547589 DOI: 10.2147/ijgm.s377463] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 09/22/2022] [Indexed: 11/29/2022] Open
Abstract
Background Dyslipidemia and type 2 diabetes mellitus (T2DM) are growing health problems, particularly in developing countries. This study aimed to determine the prevalence and pattern of dyslipidemia and its associated factors among patients with T2DM. Methods A cross-sectional study was conducted among patients with T2DM attending Family Medicine Clinics in Jordan between August 2017 and March 2019. The socio-demographics, clinical features, medications, and laboratory findings were collected. These laboratory findings included high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs). Results A total of 870 patients with T2DM were included. The prevalence of dyslipidemia among patients with T2DM was 91.4%. The most common patterns of dyslipidemia were low HDL-C (66.2%), high LDL-C (62.1%), and hypertriglyceridemia (58.2%). Female gender, obesity, and hypertension were associated with diabetic dyslipidemia patterns. T2DM duration and poor glycemic control were associated with high LDL-C and hypercholesterolemia. Hypertriglyceridemia was associated with poor glycemic control and smoking. Conclusion Dyslipidemia is highly prevalent among patients with T2DM. Evidence -based interventions are needed to prevent and control dyslipidemia among patients with T2DM in Jordan.
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Affiliation(s)
- Thekraiat M Al Quran
- Department of Public Health and Family Medicine, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan
| | - Ziad A Bataineh
- Department of General Surgery, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan
| | - Abdel-Hameed Al-Mistarehi
- Department of Public Health and Family Medicine, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan
| | - Anas M Zein Alaabdin
- Department of Public Health and Family Medicine, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan
| | - Hadeel Allan
- Department of Public Health and Family Medicine, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan
| | - Anood Al Qura’an
- Department of Internal Medicine, Jordanian Royal Medical Services, Amman, Jordan
| | - Shatha M Weshah
- Department of Public Health and Family Medicine, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan
| | - Anfal A Alanazi
- Family Medicine Academy, E1-Eastern Health Cluster, Dammam, Saudi Arabia
| | - Yousef S Khader
- Department of Public Health and Family Medicine, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan
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Impact of Prior Statin Therapy on In-Hospital Outcome of STEMI Patients Treated with Primary Percutaneous Coronary Intervention. J Clin Med 2022; 11:jcm11185298. [PMID: 36142948 PMCID: PMC9502753 DOI: 10.3390/jcm11185298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 09/06/2022] [Indexed: 11/18/2022] Open
Abstract
Background: Prior statin therapy has a cardioprotective effect in patients undergoing elective or urgent percutaneous coronary intervention (PCI). However, data on patients with ST-elevation myocardial infarction (STEMI) undergoing primary PCI are still controversial. We retrospectively evaluated the effect of prior statin therapy on in-hospital clinical outcomes in consecutive STEMI patients undergoing primary PCI. Methods: A total of 1790 patients (mean age 67 ± 11 years, 1354 men) were included. At admission, all patients were interrogated about prior (>6 months) statin therapy. The primary endpoint of the study was the composite of in-hospital mortality, acute pulmonary edema, and cardiogenic shock in patients with or without prior statin therapy. Results: A total of 427 patients (24%) were on prior statin therapy. The incidence of the primary endpoint was similar in patients with or without prior statin therapy (15% vs. 16%; p = 0.38). However, at multivariate analysis, prior statin therapy was associated with a lower risk of the primary endpoint, after adjustment for major prognostic predictors (odds ratio 0.61 [95% CI 0.39−0.96]; p = 0.03). Conclusions: This study demonstrated that prior statin therapy is associated with a better in-hospital clinical outcome in patients with STEMI undergoing primary PCI compared to those without prior statin therapy.
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Kunakorntham P, Pattanaprateep O, Dejthevaporn C, Thammasudjarit R, Thakkinstian A. Detection of statin-induced rhabdomyolysis and muscular related adverse events through data mining technique. BMC Med Inform Decis Mak 2022; 22:233. [PMID: 36064346 PMCID: PMC9446837 DOI: 10.1186/s12911-022-01978-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 08/31/2022] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND AND OBJECTIVE Rhabdomyolysis (RM) is a life-threatening adverse drug reaction in which statins are the one commonly related to RM. The study aimed to explore the association between statin used and RM or other muscular related adverse events. In addition, drug interaction with statins were also assessed. METHODS All extracted prescriptions were grouped as lipophilic and hydrophilic statins. RM outcome was identified by electronically screening and later ascertaining by chart review. The study proposed 4 models, i.e., logistic regression (LR), Bayesian network (BN), random forests (RF), and extreme gradient boosting (XGBoost). Features were selected using multiple processes, i.e., bootstrapping, expert opinions, and univariate analysis. RESULTS A total of 939 patients who used statins were identified consisting 15, 9, and 19 per 10,000 persons for overall outcome prevalence, using statin alone, and co-administrations, respectively. Common statins were simvastatin, atorvastatin, and rosuvastatin. The proposed models had high sensitivity, i.e., 0.85, 0.90, 0.95 and 0.95 for LR, BN, RF, and XGBoost, respectively. The area under the receiver operating characteristic was significantly higher in LR than BN, i.e., 0.80 (0.79, 0.81) and 0.73 (0.72, 0.74), but a little lower than the RF [0.817 (95% CI 0.811, 0.824)] and XGBoost [0.819 (95% CI 0.812, 0.825)]. The LR model indicated that a combination of high-dose lipophilic statin, clarithromycin, and antifungals was 16.22 (1.78, 148.23) times higher odds of RM than taking high-dose lipophilic statin alone. CONCLUSIONS The study suggested that statin uses may have drug interactions with others including clarithromycin and antifungal drugs in inducing RM. A prospective evaluation of the model should be further assessed with well planned data monitoring. Applying LR in hospital system might be useful in warning drug interaction during prescribing.
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Affiliation(s)
- Patratorn Kunakorntham
- Department of Clinical Epidemiology and Biostatistics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, 270 Rama VI Rd, Ratchathewi, Bangkok, 10400, Thailand
| | - Oraluck Pattanaprateep
- Department of Clinical Epidemiology and Biostatistics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, 270 Rama VI Rd, Ratchathewi, Bangkok, 10400, Thailand.
| | - Charungthai Dejthevaporn
- Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, 270 Rama VI Rd, Ratchathewi, Bangkok, 10400, Thailand.
| | - Ratchainant Thammasudjarit
- Department of Clinical Epidemiology and Biostatistics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, 270 Rama VI Rd, Ratchathewi, Bangkok, 10400, Thailand
| | - Ammarin Thakkinstian
- Department of Clinical Epidemiology and Biostatistics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, 270 Rama VI Rd, Ratchathewi, Bangkok, 10400, Thailand
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Saberianpour S, Abolbashari S, Modaghegh MHS, Karimian MS, Eid AH, Sathyapalan T, Sahebkar A. Therapeutic effects of statins on osteoarthritis: A review. J Cell Biochem 2022; 123:1285-1297. [PMID: 35894149 DOI: 10.1002/jcb.30309] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 06/05/2022] [Accepted: 07/13/2022] [Indexed: 11/11/2022]
Abstract
Osteoarthritis (OA) is a progressive joint disease. The etiology of OA is considered to be multifactorial. Currently, there is no definitive treatment for OA, and the existing treatments are not very effective. Hypercholesterolemia is considered a novel risk factor for the development of OA. Statins act as a competitive inhibitor of the β-hydroxy β-methylglutaryl-CoA (HMG-CoA) reductase and are widely used to manage hypercholesterolemia. Inhibition of HMG-CoA reductase results in reduced synthesis of a metabolite named mevalonate, thereby reducing cholesterol biosynthesis in subsequent steps. By this mechanism, statins such as atorvastatin and simvastatin could potentially have a preventive impact on joint cartilage experiencing osteoarthritic deterioration by reducing serum cholesterol levels. Atorvastatin can protect cartilage degradation following interleukin-1β-stimulation. Atorvastatin stimulates the STAT1-caspase-3 signaling pathway that was shown to be responsible for its anti-inflammatory effects on the knee joint. Simvastatin had chondroprotective effects on OA in vitro by reducing matrix metalloproteinases expression patterns. In this study, we tried to review the therapeutic effects of statins on OA.
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Affiliation(s)
- Shirin Saberianpour
- Vascular and Endovascular Surgery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Samaneh Abolbashari
- Vascular and Endovascular Surgery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohamad H S Modaghegh
- Vascular and Endovascular Surgery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Maryam S Karimian
- International UNESCO center for Health Related Basic Sciences and Human Nutrition, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali H Eid
- Department of Basic Medical Sciences, QU Health, Qatar University, Doha, Qatar
| | - Thozhukat Sathyapalan
- Department of Academic Diabetes, Endocrinology and Metabolism, Hull York Medical School, University of Hull, Hull, UK
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,School of Medicine, The University of Western Australia, Perth, Australia.,Department of Biotechnology, Mashhad University of Medical Sciences, Mashhad, Iran
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Drug-Drug Interactions of Direct Oral Anticoagulants (DOACs): From Pharmacological to Clinical Practice. Pharmaceutics 2022; 14:pharmaceutics14061120. [PMID: 35745692 PMCID: PMC9229376 DOI: 10.3390/pharmaceutics14061120] [Citation(s) in RCA: 64] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 05/20/2022] [Accepted: 05/23/2022] [Indexed: 12/24/2022] Open
Abstract
The direct oral anticoagulants (DOACs), dabigatran, rivaroxaban, apixaban, and edoxaban, are becoming the most commonly prescribed drugs for preventing ischemic stroke in patients with non-valvular atrial fibrillation (NVAF) and for the treatment and prevention of venous thromboembolism (VTE). Rivaroxaban was also recently approved for the treatment of patients with a recent acute coronary syndrome (ACS). Their use demonstrated to have a favorable risk-benefit profile, with significant reductions in stroke, intracranial hemorrhage, and mortality compared to warfarin, but with increased gastrointestinal bleeding. Nevertheless, their safety profile is compromised in multimorbidity patients requiring contemporary administration of several drugs. Comorbidity and polypharmacy have a high prevalence in elderly patients, who are also more susceptible to bleeding events. The combination of multiple treatments can cause relevant drug–drug interactions (DDIs) by affecting the exposure or the pharmacological activities of DOACs. Although important differences of the pharmacokinetic (PK) properties can be observed between DOACs, all of them are substrate of P-glycoprotein (P-gp) and thus may interact with strong inducers or inhibitors of this drug transporter. On the contrary, rivaroxaban and, to a lower extent, apixaban, are also susceptible to drugs altering the cytochrome P450 isoenzyme (CYP) activities. In the present review, we summarize the potential DDI of DOACs with several classes of drugs that have been reported or have characteristics that may predict clinically significant DDIs when administered together with DOACs. Possible strategies, including dosage reduction, avoiding concomitant administration, or different time of treatment, will be also discussed to reduce the incidence of DDI with DOACs. Considering the available data from specific clinical trials or registries analysis, the use of DOACs is associated with fewer clinically relevant DDIs than warfarin, and their use represents an acceptable clinical choice. Nevertheless, DDIs can be significant in certain patient conditions so a careful evaluation should be made before prescribing a specific DOAC.
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Liu TW, Chen CM, Chang KH. Biomarker of Neuroinflammation in Parkinson's Disease. Int J Mol Sci 2022; 23:ijms23084148. [PMID: 35456966 PMCID: PMC9028544 DOI: 10.3390/ijms23084148] [Citation(s) in RCA: 83] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Revised: 04/02/2022] [Accepted: 04/05/2022] [Indexed: 02/04/2023] Open
Abstract
Parkinson's disease (PD) is caused by abnormal accumulation of α-synuclein in dopaminergic neurons of the substantia nigra, which subsequently causes motor symptoms. Neuroinflammation plays a vital role in the pathogenesis of neurodegeneration in PD. This neuroinflammatory neurodegeneration involves the activation of microglia, upregulation of proinflammatory factors, and gut microbiota. In this review, we summarized the recent findings on detection of PD by using inflammatory biomarkers, such as interleukin (IL)-1β, IL-2, IL-6, IL-10, tumor necrosis factor (TNF)-α; regulated upon activation, normal T cell expressed and presumably secreted (RANTES) and high-sensitivity c-reactive protein (hsCRP); and radiotracers such as [11C]PK11195 and [18F]-FEPPA, as well as by monitoring disease progression and the treatment response. Many PD-causing mutations in SNCA, LRRK2, PRKN, PINK1, and DJ-1 are also associated with neuroinflammation. Several anti-inflammatory medications, including nonsteroidal anti-inflammatory drugs (NSAID), inhibitors of TNF-α and NLR family pyrin domain containing 3 (NLRP3), agonists of nuclear factor erythroid 2-related factor 2 (NRF2), peroxisome proliferator-activated receptor gamma (PPAR-γ), and steroids, have demonstrated neuroprotective effects in in vivo or in vitro PD models. Clinical trials applying objective biomarkers are required to investigate the therapeutic potential of anti-inflammatory medications for PD.
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Affiliation(s)
- Tsai-Wei Liu
- Linkou Medical Center, Department of Neurology, Chang Gung Memorial Hospital, Tauoyan 333, Taiwan; (T.-W.L.); (C.-M.C.)
| | - Chiung-Mei Chen
- Linkou Medical Center, Department of Neurology, Chang Gung Memorial Hospital, Tauoyan 333, Taiwan; (T.-W.L.); (C.-M.C.)
- School of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Kuo-Hsuan Chang
- Linkou Medical Center, Department of Neurology, Chang Gung Memorial Hospital, Tauoyan 333, Taiwan; (T.-W.L.); (C.-M.C.)
- School of Medicine, Chang Gung University, Taoyuan 333, Taiwan
- Correspondence: ; Tel.: +886-3-3281200 (ext. 8729); Fax: +886-3-3288849
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Lactobacillus reuteri CCFM8631 Alleviates Hypercholesterolaemia Caused by the Paigen Atherogenic Diet by Regulating the Gut Microbiota. Nutrients 2022; 14:nu14061272. [PMID: 35334930 PMCID: PMC8953203 DOI: 10.3390/nu14061272] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 03/10/2022] [Accepted: 03/15/2022] [Indexed: 12/13/2022] Open
Abstract
Cardiovascular disease has one of the highest global incidences and mortality rates. Atherosclerosis is the main cause of cardiovascular disease, and hypercholesterolaemia and hyperlipidaemia are the main risk factors for the development of atherosclerosis. Decreasing serum cholesterol and triglyceride concentrations is considered to be an effective strategy to prevent atherosclerotic cardiovascular disease. Previous studies have shown that many diseases are related to gut microbiota dysbiosis. The positive regulation of the gut microbiota by probiotics may prevent or treat certain diseases. In this study, Lactobacillus reuteri CCFM8631 treatment was shown to decrease plasma total cholesterol (TC), low-density lipoprotein–cholesterol, aspartate transaminase, alanine transaminase and trimethylamine N-oxide concentrations, decrease liver TC and malondialdehyde concentrations and recover liver superoxide dismutase concentrations in mice fed a Paigen atherogenic diet. In addition, L. reuteri increased the faecal short-chain fatty acid content (acetate, propionate and butyrate), which was accompanied by an increase in the relative abundance of faecal Deferribacteres, Lachnospiraceae NK4A136 group, Lactobacillus and Dubosiella; a decrease in the relative abundance of Erysipelatoclostridium and Romboutsia and the activation of butanoate and vitamin B6 metabolism, leading to the alleviation of hypercholesterolaemia.
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Tjandrawinata RR, Kartawijaya M, Hartanti AW. In vitro Evaluation of the Anti-hypercholesterolemic Effect of Lactobacillus Isolates From Various Sources. Front Microbiol 2022; 13:825251. [PMID: 35295304 PMCID: PMC8920493 DOI: 10.3389/fmicb.2022.825251] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 01/19/2022] [Indexed: 01/28/2023] Open
Abstract
The anti-hypercholesterolemic effect of 11 Lactobacillus isolates was investigated in vitro by measuring remaining cholesterol in growth media, growth ability in media supplemented with cholesterol, and BSH activity. Among the selected isolates, DLBSH104, DLBSH122, and DLBSK207 have demonstrated outstanding potential as cholesterol-lowering cultures. The three isolates showed high cholesterol removal by growing cells, whereas resting and dead cells showed less cholesterol removal. Furthermore, visualization of those isolates in growing and non-growing states by SEM showed the ability of DLBSH104 to attach cholesterol to their cell surface. In contrast, alteration of DLBSH122 and DLBSK207 cells did not involve surface attachment of cholesterol. Thus, the isolates’ ability to remove cholesterol is mainly attributed to the cells’ metabolically active state that assimilates and incorporates cholesterol into the cell membrane as reflected by a significantly higher cholesterol removal in a growing state than a non-growing state. Only in DLBSH104 did cholesterol removal also involve attachment on the cell surface. Moreover, DLBSH104 has beneficially affected the host cell by a significant reduction of NPC1L1 mRNA levels that are responsible for intestinal cholesterol absorption. In hepatic cells, cell-free supernatant (CFS) from DLBSH104 and DLBSK207 were able to reduce LDLR and HMGCR mRNA at the transcription level. To sum up, L. helveticus DLBSH104 and L. plantarum DLBSK207 are confirmed as isolates with an anti-hypercholesterolemic effect.
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Affiliation(s)
- Raymond Rubianto Tjandrawinata
- Dexa Laboratories of Biomolecular Sciences, PT Dexa Medica, Cikarang, Indonesia
- Faculty of Biotechnology, Atma Jaya Catholic University of Indonesia, Jakarta, Indonesia
- *Correspondence: Raymond Rubianto Tjandrawinata,
| | - Medicia Kartawijaya
- Dexa Laboratories of Biomolecular Sciences, PT Dexa Medica, Cikarang, Indonesia
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Producing personalized statin treatment plans to optimize clinical outcomes using big data and machine learning. J Biomed Inform 2022; 128:104029. [PMID: 35182785 DOI: 10.1016/j.jbi.2022.104029] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 01/18/2022] [Accepted: 02/11/2022] [Indexed: 11/23/2022]
Abstract
Almost half of Americans 65 years of age and older take statins, which are highly effective in lowering low-density lipoprotein cholesterol, preventing atherosclerotic cardiovascular disease (ASCVD), and reducing all-cause mortality. Unfortunately, ∼50% of patients prescribed statins do not obtain these critical benefits because they discontinue use within one year of treatment initiation. Therefore, statin discontinuation has been identified as a major public health concern due to the increased morbidity, mortality, and healthcare costs associated with ASCVD. In clinical practice, statin-associated symptoms (SAS) often result in dose reduction or discontinuation of these life-saving medications. Currently, physician decision-making in statin prescribing typically relies on only a few patient data elements. Physicians then employ reactive strategies to manage SAS concerns after they manifest (e.g., offering an alternative statin treatment plan or a statin holiday). A preferred approach would be a proactive strategy to identify the optimal treatment plan (statin agent + dosage) to prevent/minimize SAS and statin discontinuation risks for a particular individual prior to initiating treatment. Given that using a single patient's data to identify the optimal statin regimen is inadequate to ensure that the harms of statin use are minimized, alternative tactics must be used to address this problem. In this proof-of-concept study, we explore the use of a machine-learning personalized statin treatment plan (PSTP) platform to assess the numerous statin treatment plans available and identify the optimal treatment plan to prevent/minimize harms (SAS and statin discontinuation) for an individual. Our study leveraged de-identified administrative insurance claims data from the OptumLabs® Data Warehouse, which includes medical and pharmacy claims, laboratory results, and enrollment records for more than 130 million commercial and Medicare Advantage (MA) enrollees, to successfully develop the PSTP platform. In this study, we found three results: (1) the PSTP platform recommends statin prescription with significantly lower risks of SAS and discontinuation compared with standard-practice, (2) because machine learning can consider many more dimensions of data, the performance of the proactive prescription strategy with machine-learning support is better, especially the artificial neural network approach, and (3) we demonstrate a method of incorporating optimization constraints for individualized patient-centered medicine and shared decision making. However, more research into its clinical use is needed. These promising results show the feasibility of using machine learning and big data approaches to produce personalized healthcare treatment plans and support the precision-health agenda.
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Noh S, Mai K, Shaver M, Yong S, Mostaghimi M, Oh G, Radwan MM. Emerging Cholesterol Modulators for Atherosclerotic Cardiovascular Disease. Am J Med Sci 2022; 363:373-387. [DOI: 10.1016/j.amjms.2021.12.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 08/07/2021] [Accepted: 12/07/2021] [Indexed: 12/01/2022]
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Zanin-Silva DC, Santana-Gonçalves M, Kawashima-Vasconcelos MY, Oliveira MC. Management of Endothelial Dysfunction in Systemic Sclerosis: Current and Developing Strategies. Front Med (Lausanne) 2021; 8:788250. [PMID: 35004754 PMCID: PMC8727451 DOI: 10.3389/fmed.2021.788250] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 11/29/2021] [Indexed: 12/12/2022] Open
Abstract
Systemic Sclerosis (SSc) is an autoimmune disease marked by dysregulation of the immune system, tissue fibrosis and dysfunction of the vasculature. Vascular damage, remodeling and inadequate endothelial repair are hallmarks of the disease. Since early stages of SSc, damage and apoptosis of endothelial cells (ECs) can lead to perivascular inflammation, oxidative stress and tissue hypoxia, resulting in multiple clinical manifestations. Raynaud's phenomenon, edematous puffy hands, digital ulcers, pulmonary artery hypertension, erectile dysfunction, scleroderma renal crisis and heart involvement severely affect quality of life and survival. Understanding pathogenic aspects and biomarkers that reflect endothelial damage in SSc is essential to guide therapeutic interventions. Treatment approaches described for SSc-associated vasculopathy include pharmacological options to improve blood flow and tissue perfusion and, more recently, cellular therapy to enhance endothelial repair, promote angiogenesis and heal injuries. This mini-review examines the current knowledge on cellular and molecular aspects of SSc vasculopathy, as well as established and developing therapeutic approaches for improving the vascular compartment.
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Affiliation(s)
- Djúlio César Zanin-Silva
- Center for Cell-Based Therapy, Regional Hemotherapy Center of the Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
- Basic and Applied Immunology Graduate Program, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Maynara Santana-Gonçalves
- Center for Cell-Based Therapy, Regional Hemotherapy Center of the Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
- Oncology, Stem Cell and Cell-Therapy Graduate Program, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Marianna Yumi Kawashima-Vasconcelos
- Center for Cell-Based Therapy, Regional Hemotherapy Center of the Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
- Internal Medicine Graduate Program, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Maria Carolina Oliveira
- Center for Cell-Based Therapy, Regional Hemotherapy Center of the Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
- Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
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Vinci P, Panizon E, Tosoni LM, Cerrato C, Pellicori F, Mearelli F, Biasinutto C, Fiotti N, Di Girolamo FG, Biolo G. Statin-Associated Myopathy: Emphasis on Mechanisms and Targeted Therapy. Int J Mol Sci 2021; 22:11687. [PMID: 34769118 PMCID: PMC8583847 DOI: 10.3390/ijms222111687] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 10/10/2021] [Accepted: 10/13/2021] [Indexed: 12/25/2022] Open
Abstract
Hyperlipidemia is a major risk factor for cardiovascular morbidity and mortality. Statins are the first-choice therapy for dyslipidemias and are considered the cornerstone of atherosclerotic cardiovascular disease (ASCVD) in both primary and secondary prevention. Despite the statin-therapy-mediated positive effects on cardiovascular events, patient compliance is often poor. Statin-associated muscle symptoms (SAMS) are the most common side effect associated with treatment discontinuation. SAMS, which range from mild-to-moderate muscle pain, weakness, or fatigue to potentially life-threatening rhabdomyolysis, are reported by 10% to 25% of patients receiving statin therapy. There are many risk factors associated with patient features and hypolipidemic agents that seem to increase the risk of developing SAMS. Due to the lack of a "gold standard", the diagnostic test for SAMS is based on a clinical criteria score, which is independent of creatine kinase (CK) elevation. Mechanisms that underlie the pathogenesis of SAMS remain almost unclear, though a high number of risk factors may increase the probability of myotoxicity induced by statin therapy. Some of these, related to pharmacokinetic properties of statins and to concomitant therapies or patient characteristics, may affect statin bioavailability and increase vulnerability to high-dose statins.
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Affiliation(s)
- Pierandrea Vinci
- Clinica Medica, Cattinara Hospital, Department of Medical Surgical ad Health Science, University of Trieste, 34149 Trieste, Italy; (E.P.); (L.M.T.); (C.C.); (F.P.); (F.M.); (N.F.); (F.G.D.G.); (G.B.)
| | - Emiliano Panizon
- Clinica Medica, Cattinara Hospital, Department of Medical Surgical ad Health Science, University of Trieste, 34149 Trieste, Italy; (E.P.); (L.M.T.); (C.C.); (F.P.); (F.M.); (N.F.); (F.G.D.G.); (G.B.)
| | - Letizia Maria Tosoni
- Clinica Medica, Cattinara Hospital, Department of Medical Surgical ad Health Science, University of Trieste, 34149 Trieste, Italy; (E.P.); (L.M.T.); (C.C.); (F.P.); (F.M.); (N.F.); (F.G.D.G.); (G.B.)
| | - Carla Cerrato
- Clinica Medica, Cattinara Hospital, Department of Medical Surgical ad Health Science, University of Trieste, 34149 Trieste, Italy; (E.P.); (L.M.T.); (C.C.); (F.P.); (F.M.); (N.F.); (F.G.D.G.); (G.B.)
| | - Federica Pellicori
- Clinica Medica, Cattinara Hospital, Department of Medical Surgical ad Health Science, University of Trieste, 34149 Trieste, Italy; (E.P.); (L.M.T.); (C.C.); (F.P.); (F.M.); (N.F.); (F.G.D.G.); (G.B.)
| | - Filippo Mearelli
- Clinica Medica, Cattinara Hospital, Department of Medical Surgical ad Health Science, University of Trieste, 34149 Trieste, Italy; (E.P.); (L.M.T.); (C.C.); (F.P.); (F.M.); (N.F.); (F.G.D.G.); (G.B.)
| | - Chiara Biasinutto
- SC Assistenza Farmaceutica, Cattinara Hospital, Azienda Sanitaria Universitaria Integrata di Trieste, 34149 Trieste, Italy;
| | - Nicola Fiotti
- Clinica Medica, Cattinara Hospital, Department of Medical Surgical ad Health Science, University of Trieste, 34149 Trieste, Italy; (E.P.); (L.M.T.); (C.C.); (F.P.); (F.M.); (N.F.); (F.G.D.G.); (G.B.)
| | - Filippo Giorgio Di Girolamo
- Clinica Medica, Cattinara Hospital, Department of Medical Surgical ad Health Science, University of Trieste, 34149 Trieste, Italy; (E.P.); (L.M.T.); (C.C.); (F.P.); (F.M.); (N.F.); (F.G.D.G.); (G.B.)
- SC Assistenza Farmaceutica, Cattinara Hospital, Azienda Sanitaria Universitaria Integrata di Trieste, 34149 Trieste, Italy;
| | - Gianni Biolo
- Clinica Medica, Cattinara Hospital, Department of Medical Surgical ad Health Science, University of Trieste, 34149 Trieste, Italy; (E.P.); (L.M.T.); (C.C.); (F.P.); (F.M.); (N.F.); (F.G.D.G.); (G.B.)
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Muñoz AE, Pollarsky FD, Marino M, Cartier M, Vázquez H, Salgado P, Romero G. Addition of statins to the standard treatment in patients with cirrhosis: Safety and efficacy. World J Gastroenterol 2021; 27:4639-4652. [PMID: 34366626 PMCID: PMC8326251 DOI: 10.3748/wjg.v27.i28.4639] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 02/26/2021] [Accepted: 07/05/2021] [Indexed: 02/06/2023] Open
Abstract
This review summarizes the safety and efficacy of statins in patients with cirrhosis. Due to concerns about the safety of statins in patients with impaired liver function, they have recently been investigated as a potential treatment option in cirrhosis. The most clinically significant adverse event is statin-related myopathy, and this may be related to the high serum statin concentrations in the setting of severely impaired liver function. Rhabdomyolysis is the most serious and potentially life-threatening manifestation. It has recently been demonstrated that the recommended dose of simvastatin in patients with decompensated cirrhosis would be 20 mg/d because higher values, such as 40 mg/d, are associated with many adverse events, especially muscle injury. Likewise, simvastatin should not be administered to patients with Model for End-stage Liver Disease score > 12 and/or Child-Pugh class C because of the high risk of severe muscle injury. Due to the pleiotropic effects, the focus on statins has shifted from being considered harmful to something useful. Through these effects, statins could prevent liver-related morbidity and mortality in cirrhotic patients. Observational studies in large populations of patients with cirrhosis have shown that treatment with statins to decrease high cholesterol levels was associated with a reduced risk of hepatic decompensation, hepatocellular carcinoma development and death. The few randomized controlled trials in patients with cirrhosis and portal hypertension showed that statins lower portal pressure, quite likely through a reduction in hepatic resistance. Another large randomized controlled trial in patients with variceal bleeding showed that simvastatin in addition to standard of care did not prevent rebleeding but improved survival rate. Despite these encouraging outcomes, the quality of the evidence regarding the use of statins is low or very low due to the observational characteristics of most of the studies involved. Therefore, it is advisable to perform further randomized controlled trials on a large series of patients with hard clinical endpoints, using different statin types and varying doses. The objectives would be to prevent liver-related morbidity and mortality rather than treating cirrhosis complications to take additional information that makes it possible to add statins to the standard of care of these patients.
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Affiliation(s)
- Alberto E Muñoz
- Sección Hepatología, Hospital de Gastroenterología Dr. Carlos Bonorino Udaondo, Facultad de Medicina, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires 1264, Argentina
- Instituto de Investigaciones en Salud Pública, Facultad de Odontología, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires 1122, Argentina
| | - Florencia D Pollarsky
- Sección Hepatología, Hospital de Gastroenterología Dr. Carlos Bonorino Udaondo, Facultad de Medicina, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires 1264, Argentina
| | - Mónica Marino
- Sección Hepatología, Hospital de Gastroenterología Dr. Carlos Bonorino Udaondo, Facultad de Medicina, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires 1264, Argentina
| | - Mariano Cartier
- Sección Hepatología, Hospital de Gastroenterología Dr. Carlos Bonorino Udaondo, Facultad de Medicina, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires 1264, Argentina
| | - Horacio Vázquez
- Unidad Clínica, Hospital de Gastroenterología Dr. Carlos Bonorino Udaondo, Investigador Asociado del Gobierno de la Ciudad Autónoma de Buenos Aires, Ciudad Autónoma de Buenos Aires 1264, Argentina
| | - Pablo Salgado
- Instituto de Investigaciones en Salud Pública, Facultad de Odontología, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires 1122, Argentina
| | - Gustavo Romero
- Sección Hepatología, Hospital de Gastroenterología Dr. Carlos Bonorino Udaondo, Facultad de Medicina, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires 1264, Argentina
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Ding Z, Hani A, Li W, Gao L, Ke W, Guo X. Influence of a cholesterol-lowering strain Lactobacillus plantarum LP3 isolated from traditional fermented yak milk on gut bacterial microbiota and metabolome of rats fed with a high-fat diet. Food Funct 2021; 11:8342-8353. [PMID: 32930686 DOI: 10.1039/d0fo01939a] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
L. plantarum LP3 isolated from traditinal fermented Tibetan yak milk has been identified as a potential probiotic candidate strain with high cholesterol-lowering activity. In this study, thirty Sprague-Dawley (SD) rats were randomly divided into three groups, including normal diet (NC), high-fat diet (HC), and high-fat diet + L. plantarum LP3 (HLp). The effects of L. plantarum LP3 on plasma lipid profile, gut bacterial microbiota, and metabolome induced by high-fat diet in rats were investigated. Results shown that L. plantarum LP3 administration was found to reduce the levels of total cholesterol, triglyceride, and low-density lipoprotein cholesterol (LDL-C) and atherogenic index in the serum of high-fat diet rats. It also controlled the decrease of Bacteroidetes and increase of Firmicutes at the phylum level in gut microbiota induced by high-fat diet in SD rats and increased the diversity and relative abundance of intestinal flora in obese rats. In particular, the LP3 strain controlled the changes induced by the high-fat diet in the abundance of for Lachnospiraceae and Erysipelotrichaceae. We also further observed the beneficial regulatory effects of L. plantarum LP3 on changes in the levels of obesity-related metabolites. The biosynthesis of fatty acids, steroids, and bile acids and metabolism of linoleic acid, linolenic acid, and arachidonic acid were the main metabolic pathways adjusted by L. plantarum LP3 in obese rats, and the metabolic rates were similar to those observed in normal diet rats levels. The findings of this study provided useful information on the mechanism underlying the hypocholesterolemic effects of L. plantarum LP3 in the high-fat induced SD rat model with the perspective of modulation of gut microbiota and metabolites.
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Affiliation(s)
- Zitong Ding
- State Key Laboratory of Grassland and Agro-Ecosystems, School of Life Sciences, Lanzhou University, Lanzhou 730000, PR China. and Probiotics and biological Feed Research Center, Lanzhou University, Lanzhou 730000, PR China
| | - Anum Hani
- State Key Laboratory of Grassland and Agro-Ecosystems, School of Life Sciences, Lanzhou University, Lanzhou 730000, PR China. and Probiotics and biological Feed Research Center, Lanzhou University, Lanzhou 730000, PR China
| | - Wenyuan Li
- State Key Laboratory of Grassland and Agro-Ecosystems, School of Life Sciences, Lanzhou University, Lanzhou 730000, PR China. and Probiotics and biological Feed Research Center, Lanzhou University, Lanzhou 730000, PR China
| | - Li'e Gao
- State Key Laboratory of Grassland and Agro-Ecosystems, School of Life Sciences, Lanzhou University, Lanzhou 730000, PR China. and Probiotics and biological Feed Research Center, Lanzhou University, Lanzhou 730000, PR China
| | - Wencan Ke
- State Key Laboratory of Grassland and Agro-Ecosystems, School of Life Sciences, Lanzhou University, Lanzhou 730000, PR China. and Probiotics and biological Feed Research Center, Lanzhou University, Lanzhou 730000, PR China
| | - Xusheng Guo
- State Key Laboratory of Grassland and Agro-Ecosystems, School of Life Sciences, Lanzhou University, Lanzhou 730000, PR China. and Probiotics and biological Feed Research Center, Lanzhou University, Lanzhou 730000, PR China
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Fuah KW, Lim C. First Reported Case of Rhabdomyolysis Associated with Concomitant Use of Cyclosporin, Diltiazem, and Simvastatin. Indian J Nephrol 2021; 31:173-175. [PMID: 34267441 PMCID: PMC8240945 DOI: 10.4103/ijn.ijn_5_20] [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: 01/18/2020] [Revised: 02/16/2020] [Accepted: 04/02/2020] [Indexed: 11/05/2022] Open
Abstract
Rhabdomyolysis is a syndrome with a wide range of symptoms ranging from asymptomatic raised serum creatinine kinase to life-threatening metabolic disturbances and acute kidney injury. A careful history taking and high clinical suspicion on drug-drug interaction are crucial to identify the etiology of rhabdomyolysis. Here, we present a case of rhabdomyolysis due to a rare drug-to-drug interaction of simvastatin, diltiazem, and cyclosporin in a patient with IgA nephropathy. Early renal replacement therapy was initiated, and the insulting agents were withheld. Despite the metabolic disturbances were corrected, the patient succumbed to possible venous thromboembolism event during the prolonged hospital stay. Therefore, heightened awareness is required in dealing with patients with glomerulonephritis who are frequently prescribed on polypharmacy, in order to reduce unwarranted adverse events.
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Affiliation(s)
- Kar Wah Fuah
- Department of Medicine, Hospital Tengku Ampuan Afzan, Kuantan, Pahang, Malaysia
| | - Christopher Lim
- Unit of Nephrology, Department of Medicine, Universiti Putra Malaysia, Malaysia
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Cai T, Abel L, Langford O, Monaghan G, Aronson JK, Stevens RJ, Lay-Flurrie S, Koshiaris C, McManus RJ, Hobbs FDR, Sheppard JP. Associations between statins and adverse events in primary prevention of cardiovascular disease: systematic review with pairwise, network, and dose-response meta-analyses. BMJ 2021; 374:n1537. [PMID: 34261627 PMCID: PMC8279037 DOI: 10.1136/bmj.n1537] [Citation(s) in RCA: 124] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVE To assess the associations between statins and adverse events in primary prevention of cardiovascular disease and to examine how the associations vary by type and dosage of statins. DESIGN Systematic review and meta-analysis. DATA SOURCES Studies were identified from previous systematic reviews and searched in Medline, Embase, and the Cochrane Central Register of Controlled Trials, up to August 2020. REVIEW METHODS Randomised controlled trials in adults without a history of cardiovascular disease that compared statins with non-statin controls or compared different types or dosages of statins were included. MAIN OUTCOME MEASURES Primary outcomes were common adverse events: self-reported muscle symptoms, clinically confirmed muscle disorders, liver dysfunction, renal insufficiency, diabetes, and eye conditions. Secondary outcomes included myocardial infarction, stroke, and death from cardiovascular disease as measures of efficacy. DATA SYNTHESIS A pairwise meta-analysis was conducted to calculate odds ratios and 95% confidence intervals for each outcome between statins and non-statin controls, and the absolute risk difference in the number of events per 10 000 patients treated for a year was estimated. A network meta-analysis was performed to compare the adverse effects of different types of statins. An Emax model based meta-analysis was used to examine the dose-response relationships of the adverse effects of each statin. RESULTS 62 trials were included, with 120 456 participants followed up for an average of 3.9 years. Statins were associated with an increased risk of self-reported muscle symptoms (21 trials, odds ratio 1.06 (95% confidence interval 1.01 to 1.13); absolute risk difference 15 (95% confidence interval 1 to 29)), liver dysfunction (21 trials, odds ratio 1.33 (1.12 to 1.58); absolute risk difference 8 (3 to 14)), renal insufficiency (eight trials, odds ratio 1.14 (1.01 to 1.28); absolute risk difference 12 (1 to 24)), and eye conditions (six trials, odds ratio 1.23 (1.04 to 1.47); absolute risk difference 14 (2 to 29)) but were not associated with clinically confirmed muscle disorders or diabetes. The increased risks did not outweigh the reduction in the risk of major cardiovascular events. Atorvastatin, lovastatin, and rosuvastatin were individually associated with some adverse events, but few significant differences were found between types of statins. An Emax dose-response relationship was identified for the effect of atorvastatin on liver dysfunction, but the dose-response relationships for the other statins and adverse effects were inconclusive. CONCLUSIONS For primary prevention of cardiovascular disease, the risk of adverse events attributable to statins was low and did not outweigh their efficacy in preventing cardiovascular disease, suggesting that the benefit-to-harm balance of statins is generally favourable. Evidence to support tailoring the type or dosage of statins to account for safety concerns before starting treatment was limited. SYSTEMATIC REVIEW REGISTRATION PROSPERO CRD42020169955.
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Affiliation(s)
- Ting Cai
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK
| | - Lucy Abel
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK
| | - Oliver Langford
- Alzheimer's Therapeutic Research Institute, University of Southern California, Los Angeles, USA
| | - Genevieve Monaghan
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK
| | - Jeffrey K Aronson
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK
| | - Richard J Stevens
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK
| | - Sarah Lay-Flurrie
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK
| | | | - Richard J McManus
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK
| | - F D Richard Hobbs
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK
| | - James P Sheppard
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK
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Fleming MR, Xiao L, Jackson KD, Beckman JA, Barac A, Moslehi JJ. Vascular Impact of Cancer Therapies: The Case of BTK (Bruton Tyrosine Kinase) Inhibitors. Circ Res 2021; 128:1973-1987. [PMID: 34110908 PMCID: PMC10185355 DOI: 10.1161/circresaha.121.318259] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Novel targeted cancer therapies have revolutionized oncology therapies, but these treatments can have cardiovascular complications, which include heterogeneous cardiac, metabolic, and vascular sequelae. Vascular side effects have emerged as important considerations in both cancer patients undergoing active treatment and cancer survivors. Here, we provide an overview of vascular effects of cancer therapies, focusing on small-molecule kinase inhibitors and specifically inhibitors of BTK (Bruton tyrosine kinase), which have revolutionized treatment and prognosis for B-cell malignancies. Cardiovascular side effects of BTK inhibitors include atrial fibrillation, increased risk of bleeding, and hypertension, with the former 2 especially providing a treatment challenge for the clinician. Cardiovascular complications of small-molecule kinase inhibitors can occur through either on-target (targeting intended target kinase) or off-target kinase inhibition. We will review these concepts and focus on the case of BTK inhibitors, highlight the emerging data suggesting an off-target effect that may provide insights into development of arrhythmias, specifically atrial fibrillation. We believe that cardiac and vascular sequelae of novel targeted cancer therapies can provide insights into human cardiovascular biology.
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Affiliation(s)
- Matthew R Fleming
- Division of Cardiovascular Medicine (M.R.F., J.A.B., J.J.M.), Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
| | - Ling Xiao
- Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston (L.X.)
| | - Klarissa D Jackson
- UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill (K.D.J.)
| | - Joshua A Beckman
- Division of Cardiovascular Medicine (M.R.F., J.A.B., J.J.M.), Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
| | - Ana Barac
- Georgetown University and MedStar Heart and Vascular Institute, MedStar Washing Hospital Center, DC (A.B.)
| | - Javid J Moslehi
- Division of Cardiovascular Medicine (M.R.F., J.A.B., J.J.M.), Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
- Cardio-Oncology Program (J.J.M.), Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
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Wang H, Wang T, Zhang Z, Fan Y, Zhang L, Gao K, Luo S, Xiao Q, Sun C. Simvastatin inhibits oral squamous cell carcinoma by targeting TMEM16A Ca 2+-activated chloride channel. J Cancer Res Clin Oncol 2021; 147:1699-1711. [PMID: 33755783 DOI: 10.1007/s00432-021-03575-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 02/18/2021] [Indexed: 12/17/2022]
Abstract
PURPOSE Ca2+-activated chloride channel TMEM16A has been found to be overexpressed in many cancers including head and neck squamous cell carcinoma (HNSCC). Nevertheless, the role of TMEM16A in oral squamous cell carcinoma (OSCC) remains unclear. Although simvastatin is known to produce anti-tumor effect, the mechanisms by which simvastatin inhibits cancer remain unclear. METHODS In this study, we explored the role of TMEM16A expression in human OSCC tissues using both TCGA dataset and immunohistochemistry. CCK-8 assay was applied to evaluate cell proliferation. Patch clamp technique was applied to record TMEM16A Cl- currents. RESULTS We found that high TMEM16A expression is related with large tumor size, lymph node metastasis, and poor clinical outcome in patients with OSCC. In addition, TMEM16A overexpression could promote cell proliferation, and inhibition of TMEM16A channel activities could suppress cell proliferation in OSCC cells. Furthermore, simvastatin could suppress TMEM16A channel activities, and inhibited cell proliferation in OSCC cells via TMEM16A. CONCLUSION Our findings identify a novel anti-tumor mechanism of simvastatin by targeting TMEM16A. Simvastatin may represent an innovative strategy for treating OSCC with high TMEM16A expression.
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Affiliation(s)
- Hechen Wang
- Liaoning Provincial Key Laboratory of Oral Diseases, Department of Oromaxillofacial-Head and Neck Surgery, School and Hospital of Stomatology, China Medical University, 117 Nanjing Bei Jie, Heping District, Shenyang,, 110002, Liaoning, China.,Department of Ion Channel Pharmacology, School of Pharmacy, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, 110122, Liaoning Province, China
| | - Tianyu Wang
- Department of Ion Channel Pharmacology, School of Pharmacy, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, 110122, Liaoning Province, China
| | - Zeying Zhang
- Liaoning Provincial Key Laboratory of Oral Diseases, Department of Oromaxillofacial-Head and Neck Surgery, School and Hospital of Stomatology, China Medical University, 117 Nanjing Bei Jie, Heping District, Shenyang,, 110002, Liaoning, China
| | - Yu Fan
- Liaoning Provincial Key Laboratory of Oral Diseases, Department of Pathology, School and Hospital of Stomatology, China Medical University, Shenyang, China
| | - Lan Zhang
- Liaoning Provincial Key Laboratory of Oral Diseases, Hospital Infection Management Office, School and Hospital of Stomatology, China Medical University, Shenyang, China
| | - Kuan Gao
- Department of Ion Channel Pharmacology, School of Pharmacy, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, 110122, Liaoning Province, China
| | - Shuya Luo
- Department of Ion Channel Pharmacology, School of Pharmacy, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, 110122, Liaoning Province, China
| | - Qinghuan Xiao
- Department of Ion Channel Pharmacology, School of Pharmacy, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, 110122, Liaoning Province, China.
| | - Changfu Sun
- Liaoning Provincial Key Laboratory of Oral Diseases, Department of Oromaxillofacial-Head and Neck Surgery, School and Hospital of Stomatology, China Medical University, 117 Nanjing Bei Jie, Heping District, Shenyang,, 110002, Liaoning, China.
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Kuba JO, Yu Y, Klauda JB. Estimating localization of various statins within a POPC bilayer. Chem Phys Lipids 2021; 236:105074. [PMID: 33676920 DOI: 10.1016/j.chemphyslip.2021.105074] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 02/20/2021] [Accepted: 03/02/2021] [Indexed: 11/29/2022]
Abstract
As a class of drugs prescribed to heart disease patients, statins are among the most popular prescription drugs in the world. Over the years, statins have been shown to have beneficial effects on patients via pathways independent of their effect on cholesterol. These pleiotropic effects vary across the different statins, and a growing hypothesis is that they are related to the localization of the statins in and their effect on the membrane. In this study, we use molecular dynamics (MD) simulations with the CHARMM36 all-atom force field to investigate the localization of statins (atorvastatin, cerivastatin, lovastatin, and pravastatin) in a POPC bilayer and how they affect the acyl chain order parameters (SCD), surface area per lipid (APL), and thicknesses of the bilayer. The data obtained from 500 ns simulations suggests that lovastatin is localized deepest in the membrane, mostly interacting with the hydrophobic core, cerivastatin is slightly closer to the bilayer/solvent interface than lovastatin and interacts with the headgroups via its dihydroxy acid group, and pravastatin is found closest to the bilayer/solvent interface, its hydrophobic rings interacting mostly with the region around the acyl's carbonyl and its dihydroxy acid interacting with the solvent and the headgroups. Consistent binding of atorvastatin to the bilayer is not observed during our simulation due to self-aggregation. The statins differentially alter the SCD and APL and most of the bilayer thicknesses, but these effects are modest. Overall, as expected, the localization of statins seems to follow their hydrophilicity, and given previous data showing the relationship between statins' hydrophobicity and pleiotropic effects, one would expect statins that localize and interact with different regions of the membrane to have different effects. This research provides some important insight into statin localization in a simplified model of a cellular membrane.
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Affiliation(s)
- Jacob Olondo Kuba
- Department of Chemical and Biomolecular Engineering, University of Maryland, College Park, MD, 20742, USA
| | - Yalun Yu
- Biophysics Graduate Program, University of Maryland, College Park, MD, 20742, USA
| | - Jeffery B Klauda
- Department of Chemical and Biomolecular Engineering, University of Maryland, College Park, MD, 20742, USA; Biophysics Graduate Program, University of Maryland, College Park, MD, 20742, USA.
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Camerino GM, Tarantino N, Canfora I, De Bellis M, Musumeci O, Pierno S. Statin-Induced Myopathy: Translational Studies from Preclinical to Clinical Evidence. Int J Mol Sci 2021; 22:ijms22042070. [PMID: 33669797 PMCID: PMC7921957 DOI: 10.3390/ijms22042070] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 02/14/2021] [Accepted: 02/15/2021] [Indexed: 02/07/2023] Open
Abstract
Statins are the most prescribed and effective drugs to treat cardiovascular diseases (CVD). Nevertheless, these drugs can be responsible for skeletal muscle toxicity which leads to reduced compliance. The discontinuation of therapy increases the incidence of CVD. Thus, it is essential to assess the risk. In fact, many studies have been performed at preclinical and clinical level to investigate pathophysiological mechanisms and clinical implications of statin myotoxicity. Consequently, new toxicological aspects and new biomarkers have arisen. Indeed, these drugs may affect gene transcription and ion transport and contribute to muscle function impairment. Identifying a marker of toxicity is important to prevent or to cure statin induced myopathy while assuring the right therapy for hypercholesterolemia and counteracting CVD. In this review we focused on the mechanisms of muscle damage discovered in preclinical and clinical studies and highlighted the pathological situations in which statin therapy should be avoided. In this context, preventive or substitutive therapies should also be evaluated.
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Affiliation(s)
- Giulia Maria Camerino
- Section of Pharmacology, Department of Pharmacy and Drug Sciences, University of Bari “Aldo Moro”, 70125 Bari, Italy; (G.M.C.); (N.T.); (I.C.); (M.D.B.)
| | - Nancy Tarantino
- Section of Pharmacology, Department of Pharmacy and Drug Sciences, University of Bari “Aldo Moro”, 70125 Bari, Italy; (G.M.C.); (N.T.); (I.C.); (M.D.B.)
| | - Ileana Canfora
- Section of Pharmacology, Department of Pharmacy and Drug Sciences, University of Bari “Aldo Moro”, 70125 Bari, Italy; (G.M.C.); (N.T.); (I.C.); (M.D.B.)
| | - Michela De Bellis
- Section of Pharmacology, Department of Pharmacy and Drug Sciences, University of Bari “Aldo Moro”, 70125 Bari, Italy; (G.M.C.); (N.T.); (I.C.); (M.D.B.)
| | - Olimpia Musumeci
- Unit of Neurology and Neuromuscular Disorders, Department of Clinical and Experimental Medicine, University of Messina, 98122 Messina, Italy;
| | - Sabata Pierno
- Section of Pharmacology, Department of Pharmacy and Drug Sciences, University of Bari “Aldo Moro”, 70125 Bari, Italy; (G.M.C.); (N.T.); (I.C.); (M.D.B.)
- Correspondence:
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Zhao J, Chow RP, McLeese RH, Hookham MB, Lyons TJ, Yu JY. Modelling preeclampsia: a comparative analysis of the common human trophoblast cell lines. FASEB Bioadv 2021; 3:23-35. [PMID: 33521587 PMCID: PMC7805545 DOI: 10.1096/fba.2020-00057] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 09/08/2020] [Accepted: 09/28/2020] [Indexed: 12/03/2022] Open
Abstract
Preeclampsia remains a challenge without an effective therapy. Evidence supports targetability of soluble fms‐like tyrosine kinase‐1 (sFlt‐1) and soluble endoglin (sEng), which are released excessively from the placenta under ischemic and hypoxic stresses. We compared four trophoblast cell lines, BeWo, Jar, Jeg‐3, and HTR‐8/SVneo, in order to identify a suitable model for drug screening. Cultured trophoblasts were exposed to 1% oxygen vs. normoxia for 24‐48 hr; human umbilical vein and aortic endothelial cells were included for comparison. Supernatant sFlt‐1 and sEng concentrations were measured by ELISA, and sFlt‐1 mRNA expression determined by RT‐PCR. Cellular responses to experimental therapeutics were explored. All four trophoblast lines secreted sEng, which did not increase by hypoxia. BeWo, Jar, and Jeg‐3 exhibited significantly enhanced expression of sFlt‐1 i13 and e15a mRNA in response to hypoxia; however, only BeWo released a detectable level of sFlt‐1 protein, which was doubled by hypoxia. In contrast, hypoxia decreased sFlt‐1 mRNA expression and protein release in HTR‐8/SVneo, similarly to endothelial cells. The cellular mechanism involved HIFα. BeWo responded to representative agents similarly to human primary placental tissues in the literature. These data support that the BeWo‐hypoxia model mimics a key pathogenic mechanism of preeclampsia and has potential value for translational drug discovery.
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Affiliation(s)
- Jiawu Zhao
- Wellcome-Wolfson Institute for Experimental Medicine School of Medicine, Dentistry and Biomedical Sciences Queen's University Belfast Belfast UK
| | - Rebecca P Chow
- Wellcome-Wolfson Institute for Experimental Medicine School of Medicine, Dentistry and Biomedical Sciences Queen's University Belfast Belfast UK.,Division of Endocrinology, Diabetes and Metabolic Diseases Department of Medicine Medical University of South Carolina Charleston SC USA
| | - Rebecca H McLeese
- Wellcome-Wolfson Institute for Experimental Medicine School of Medicine, Dentistry and Biomedical Sciences Queen's University Belfast Belfast UK.,Division of Endocrinology, Diabetes and Metabolic Diseases Department of Medicine Medical University of South Carolina Charleston SC USA
| | - Michelle B Hookham
- Wellcome-Wolfson Institute for Experimental Medicine School of Medicine, Dentistry and Biomedical Sciences Queen's University Belfast Belfast UK
| | - Timothy J Lyons
- Wellcome-Wolfson Institute for Experimental Medicine School of Medicine, Dentistry and Biomedical Sciences Queen's University Belfast Belfast UK.,Division of Endocrinology, Diabetes and Metabolic Diseases Department of Medicine Medical University of South Carolina Charleston SC USA
| | - Jeremy Y Yu
- Wellcome-Wolfson Institute for Experimental Medicine School of Medicine, Dentistry and Biomedical Sciences Queen's University Belfast Belfast UK.,Division of Endocrinology, Diabetes and Metabolic Diseases Department of Medicine Medical University of South Carolina Charleston SC USA
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Kadir NAAA, Azlan A, Abas F, Ismail IS. Hepatoprotective Effect of Supercritical Carbon Dioxide Extracted Dabai Pulp Oil and Its Defatted Pulp. Molecules 2021; 26:molecules26030671. [PMID: 33525363 PMCID: PMC7865250 DOI: 10.3390/molecules26030671] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 01/25/2021] [Accepted: 01/26/2021] [Indexed: 02/01/2023] Open
Abstract
All food scientists must utilize plants for their application as functional foods to reduce hypercholesterolemia incidence through diet. Canarium odontophyllum (dabai) is a novel source for new healthy oil and functional foods. In this work, we evaluate the hepatoprotective effects of supercritical carbon dioxide (SC-CO2) extracted dabai pulp oil (DPO) and defatted dabai pulp (DDP) against hypercholesterolemia elicited by a high-cholesterol diet in rats. Our results show that DPO and DDP supplementation exerted beneficial hypocholesterolemic effects against the high-cholesterol diet-fed rat. Nevertheless, supplementation with DDP revealed superior total cholesterol, low-density lipoprotein, and HMG-CoA reductase lowering efficacy (p < 0.05). Supplementation of either DPO or DDP did not significantly affect AST and ALT levels than normal rats (p > 0.05). Therefore, DDP and DPO are considered as having no toxicological significance. The histological section of rats treated with DPO and DDP showed improved steatosis in hepatocytes. HPLC analysis revealed that DPO and DDP contained syringic acid, which plays an important role in the beneficial effect. In conclusion, our results support the hypocholesterolemic and hepatoprotective effects of DPO and DDP in the hypercholesterolemic rats model.
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Affiliation(s)
- Noor Atiqah Aizan Abdul Kadir
- Department of Nutrition, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia;
| | - Azrina Azlan
- Department of Nutrition, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia;
- Research Centre for Excellence for Nutrition and Non-Communicable Disease, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia
- Halal Products Research Institute, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia
- Correspondence: ; Tel.: +60-3-97692466
| | - Faridah Abas
- Department of Food Science, Faculty of Food Science and Technology, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia;
| | - Intan Safinar Ismail
- Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia;
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Avram VF, Chamkha I, Åsander-Frostner E, Ehinger JK, Timar RZ, Hansson MJ, Muntean DM, Elmér E. Cell-Permeable Succinate Rescues Mitochondrial Respiration in Cellular Models of Statin Toxicity. Int J Mol Sci 2021; 22:E424. [PMID: 33401621 PMCID: PMC7796258 DOI: 10.3390/ijms22010424] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 12/25/2020] [Accepted: 12/29/2020] [Indexed: 02/06/2023] Open
Abstract
Statins are the cornerstone of lipid-lowering therapy. Although generally well tolerated, statin-associated muscle symptoms (SAMS) represent the main reason for treatment discontinuation. Mitochondrial dysfunction of complex I has been implicated in the pathophysiology of SAMS. The present study proposed to assess the concentration-dependent ex vivo effects of three statins on mitochondrial respiration in viable human platelets and to investigate whether a cell-permeable prodrug of succinate (complex II substrate) can compensate for statin-induced mitochondrial dysfunction. Mitochondrial respiration was assessed by high-resolution respirometry in human platelets, acutely exposed to statins in the presence/absence of the prodrug NV118. Statins concentration-dependently inhibited mitochondrial respiration in both intact and permeabilized cells. Further, statins caused an increase in non-ATP generating oxygen consumption (uncoupling), severely limiting the OXPHOS coupling efficiency, a measure of the ATP generating capacity. Cerivastatin (commercially withdrawn due to muscle toxicity) displayed a similar inhibitory capacity compared with the widely prescribed and tolerable atorvastatin, but did not elicit direct complex I inhibition. NV118 increased succinate-supported mitochondrial oxygen consumption in atorvastatin/cerivastatin-exposed platelets leading to normalization of coupled (ATP generating) respiration. The results acquired in isolated human platelets were validated in a limited set of experiments using atorvastatin in HepG2 cells, reinforcing the generalizability of the findings.
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Affiliation(s)
- Vlad F. Avram
- Department of Internal Medicine-Diabetes, Nutrition and Metabolic Diseases, “Victor Babeș” University of Medicine and Pharmacy Timișoara, Romania, Eftimie Murgu Sq. No. 2, 300041 Timișoara, Romania; (V.F.A.); (R.Z.T.)
- Center for Translational Research and Systems Medicine, “Victor Babeș” University of Medicine and Pharmacy Timișoara, Romania, Spl. Tudor Vladimirescu No. 14, 300173 Timișoara, Romania
| | - Imen Chamkha
- Mitochondrial Medicine, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, BMC A13, 221 84 Lund, Sweden; (I.C.); (E.Å.-F.); (J.K.E.); (M.J.H.)
- Abliva AB, Medicon Village, 223 81 Lund, Sweden
| | - Eleonor Åsander-Frostner
- Mitochondrial Medicine, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, BMC A13, 221 84 Lund, Sweden; (I.C.); (E.Å.-F.); (J.K.E.); (M.J.H.)
- Abliva AB, Medicon Village, 223 81 Lund, Sweden
| | - Johannes K. Ehinger
- Mitochondrial Medicine, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, BMC A13, 221 84 Lund, Sweden; (I.C.); (E.Å.-F.); (J.K.E.); (M.J.H.)
- Abliva AB, Medicon Village, 223 81 Lund, Sweden
| | - Romulus Z. Timar
- Department of Internal Medicine-Diabetes, Nutrition and Metabolic Diseases, “Victor Babeș” University of Medicine and Pharmacy Timișoara, Romania, Eftimie Murgu Sq. No. 2, 300041 Timișoara, Romania; (V.F.A.); (R.Z.T.)
- Center for Translational Research and Systems Medicine, “Victor Babeș” University of Medicine and Pharmacy Timișoara, Romania, Spl. Tudor Vladimirescu No. 14, 300173 Timișoara, Romania
| | - Magnus J. Hansson
- Mitochondrial Medicine, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, BMC A13, 221 84 Lund, Sweden; (I.C.); (E.Å.-F.); (J.K.E.); (M.J.H.)
- Abliva AB, Medicon Village, 223 81 Lund, Sweden
| | - Danina M. Muntean
- Center for Translational Research and Systems Medicine, “Victor Babeș” University of Medicine and Pharmacy Timișoara, Romania, Spl. Tudor Vladimirescu No. 14, 300173 Timișoara, Romania
- Department of Functional Sciences-Pathophysiology, 2Center for Translational Research and Systems Medi-cine, “Victor Babeș” University of Medicine and Pharmacy Timișoara, Romania, Eftimie Murgu Sq. No. 2, 300041 Timișoara, Romania
| | - Eskil Elmér
- Mitochondrial Medicine, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, BMC A13, 221 84 Lund, Sweden; (I.C.); (E.Å.-F.); (J.K.E.); (M.J.H.)
- Abliva AB, Medicon Village, 223 81 Lund, Sweden
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Eltellawy YA, El-Kayal M, Abdel-Rahman RF, Salah S, Shaker DS. Optimization of transdermal atorvastatin calcium - Loaded proniosomes: Restoring lipid profile and alleviating hepatotoxicity in poloxamer 407-induced hyperlipidemia. Int J Pharm 2020; 593:120163. [PMID: 33309831 DOI: 10.1016/j.ijpharm.2020.120163] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 11/28/2020] [Accepted: 12/05/2020] [Indexed: 01/22/2023]
Abstract
In an attempt to optimize the anti- hyperlipidemic effect and reduce statins induced hepatotoxicity, Atorvastatin Calcium (ATC) transdermal proniosomal gel (PNG) was developed. Different non-ionic surfactants (NISs) (Spans, Tweens, Cremophor RH 40 and Brij 52) were incorporated in the vesicle's lipid bilayer, in combination with lecithin. PNG formulae were characterized for encapsulation efficiency percent (% EE), vesicle size, polydispersity index (PDI) and zeta potential (ZP). Ex-vivo permeation study was performed using full thickness rat skin measuring drug flux and skin permeability coefficients. The pharmacodynamic performance of optimized transdermal ATC- PNG on both lipid profile and liver biomarkers was assessed and compared to oral ATC administration in poloxamer 407-induced hyperlipidemic rats. The liver tissues were subjected to histological examination as well. The results revealed nano-size range vesicles with relatively high ATC entrapment efficiency. Ex-vivo results demonstrated the permeation superiority of ATC proniosomes over free drug. Pharmacodynamic study revealed that transdermal administration of ATC- PNG succeeded in retaining the anti-hyperlipidemic efficacy of orally administered ATC without elevating liver biomarkers. The histological examination signified the role of optimized ATC-PNG in hindering statin- induced hepatocellular damage. The obtained results suggested a promising, easy-to-manufacture and effective ATC proniosomal gel for safe treatment of hyperlipidemia.
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Affiliation(s)
- Yasmin A Eltellawy
- Department of Pharmaceutics & Pharmaceutical Technology, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University in Egypt (FUE), Cairo, Egypt.
| | - Maha El-Kayal
- Department of Pharmaceutics & Pharmaceutical Technology, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University in Egypt (FUE), Cairo, Egypt
| | | | - Salwa Salah
- Department of Pharmaceutics & Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
| | - Dalia S Shaker
- Department of Pharmaceutics & Pharmaceutical Technology, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University in Egypt (FUE), Cairo, Egypt.
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Robertson JA, Guzman DSM, Graham JL, Stanhope KL, Douglas JM, Havel PJ, Beaufrère H, Knych H, Tully TN, Paul-Murphy JR. Evaluation of Orally Administered Atorvastatin on Plasma Lipid and Biochemistry Profiles in Hypercholesterolemic Hispaniolan Amazon Parrots ( Amazona ventralis). J Avian Med Surg 2020; 34:32-40. [PMID: 32237680 DOI: 10.1647/1082-6742-34.1.32] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Atorvastatin is a synthetic statin administered in its active form and used for the treatment of dyslipidemias. In the current study, the effects of atorvastatin were evaluated on plasma lipid profiles and the potential for adverse effects after once daily PO dosing of atorvastatin for 30 days in Hispaniolan Amazon parrots (Amazona ventralis). Sixteen adult parrots (10 female, 6 male) with hypercholesterolemia were used for this study. Birds were assigned to 2 groups (treatment and control) of 8 parrots each (3 male, 5 female) after balancing for age, sex, originating institution, and baseline plasma cholesterol values. Compounded atorvastatin oral suspension (10 mg/kg) was administered PO once daily via gavage into the crop. Equivalent volumes of placebo suspension were administered to the control group. Plasma biochemistry and plasma lipid profile analysis (total cholesterol, high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], and triglycerides [TGs]) were analyzed on days 0, 14, and 30. Plasma samples and HDL-C fractions were evaluated for cholesterol and TG concentrations via enzymatic assays. Subtraction of HDL-C values from total cholesterol yielded the non-HDL-C concentration for each bird. Birds were routinely assessed for appetite, activity, and urofeces. Plasma atorvastatin concentrations were obtained from 7 of 8 birds in the treatment group from banked samples. Those samples were obtained on days 14 and 30, with drug administration 6 to 8 hours before collection. No significant differences were observed in total cholesterol, HDL-C, non-HDL-C, or TG between treatment and control groups at days 0, 14, and 30. Plasma atorvastatin concentrations were variable on day 14 (0.54-5.41 ng/ mL for 6 of 7 samples, with 1 outlier of 307 ng/mL) and on day 30 (0.79-6.74 ng/mL). No adverse effects were noted in any of the birds during the study period. When dosed PO at 10 mg/kg once daily, atorvastatin did not result in significant changes to plasma lipid profiles (eg, lowering of plasma total or non-HDL-C concentrations) at any time point during this study. Future studies to investigate pharmacokinetic and pharmacodynamic properties of atorvastatin in parrots may require increased doses and/or frequency of administration.
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Affiliation(s)
- Jessica A Robertson
- William R. Pritchard Veterinary Medical Teaching Hospital, School of Veterinary Medicine, University of California, Davis, Davis, CA 95616, USA
| | - David Sanchez-Migallon Guzman
- Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California, Davis, Davis, CA 95616, USA,
| | - James L Graham
- Department of Nutrition, School of Veterinary Medicine, University of California, Davis, Davis, CA 95616, USA
| | - Kimber L Stanhope
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, Davis, CA 95616, USA
| | - Jamie M Douglas
- Department of Veterinary Clinical Sciences, Auburn University, College of Veterinary Medicine, Auburn, AL 36849, USA
| | - Peter J Havel
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, Davis, CA 95616, USA.,Department of Nutrition, School of Veterinary Medicine, University of California, Davis, Davis, CA 95616, USA
| | - Hugues Beaufrère
- Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada, N1G 2W1
| | - Heather Knych
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, Davis, CA 95616, USA
| | - Thomas N Tully
- Department of Veterinary Clinical Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA 70803-8410, USA
| | - Joanne R Paul-Murphy
- Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California, Davis, Davis, CA 95616, USA
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The Role of Structure and Biophysical Properties in the Pleiotropic Effects of Statins. Int J Mol Sci 2020; 21:ijms21228745. [PMID: 33228116 PMCID: PMC7699354 DOI: 10.3390/ijms21228745] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 11/12/2020] [Accepted: 11/16/2020] [Indexed: 12/13/2022] Open
Abstract
Statins are a class of drugs used to lower low-density lipoprotein cholesterol and are amongst the most prescribed medications worldwide. Most statins work as a competitive inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGR), but statin intolerance from pleiotropic effects have been proposed to arise from non-specific binding due to poor enzyme-ligand sensitivity. Yet, research into the physicochemical properties of statins, and their interactions with off-target sites, has not progressed much over the past few decades. Here, we present a concise perspective on the role of statins in lowering serum cholesterol levels, and how their reported interactions with phospholipid membranes offer a crucial insight into the mechanism of some of the more commonly observed pleiotropic effects of statin administration. Lipophilicity, which governs hepatoselectivity, is directly related to the molecular structure of statins, which dictates interaction with and transport through membranes. The structure of statins is therefore a clinically important consideration in the treatment of hypercholesterolaemia. This review integrates the recent biophysical studies of statins with the literature on the physiological effects and provides new insights into the mechanistic cause of statin pleiotropy, and prospective means of understanding the cholesterol-independent effects of statins.
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50
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Medicinal Chemistry Friendliness of Pigments from Monascus-Fermented Rice and the Molecular Docking Analysis of Their Anti-Hyperlipidemia Properties. FERMENTATION-BASEL 2020. [DOI: 10.3390/fermentation6040111] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
In this study, the physicochemical properties, pharmacokinetics properties, and drug-likeness of pigments from Monascus-fermented rice (Monascus pigments, MPs) were predicted in silico using SwissADME tool. In silico prediction of physicochemical properties showed that MPs had desirable lipophilic drug-like physicochemical properties including molecular weight (236 to 543), TPSA (44.76 to 179.77), lipophilicity (−0.81 to 4.14), and water solubility (−4.94 to −0.77). The pharmacokinetic properties of MPs (i.e., GIA, P-glycoprotein substrate, and CYP3A4 inhibitor) illustrated that most MPs had high intestinal absorption and bioavailability, but some MPs might cause pharmacokinetics-related drug–drug interactions. Following this, six main well-known MPs (monascin, ankaflavin, rubropunctatin, monascorubrin, rubropunctamine, monascorubramine) were selected for molecular docking with some enzyme receptors. The docking results were shown with the best molecular docking poses, and the interacting residues, number and distance of hydrogen bonds of the MPs and monacolin K (for docking with 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMG-CoA reductase)), or MPs and oleic acid (for docking with lipase). Dissociation constants showed that MPs had lower inhibitory potential for HMGR (compared with Monacolin K), and higher inhibitory potential for lipase. Individual pigments from Monascus-fermented rice, therefore, have the potential to be developed as drug candidates for controlling hyperlipidemia.
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