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Salvi de Souza G, Liu W, Mossel P, Somsen JF, Bartels AL, Furini CRG, Lammertsma AA, Tsoumpas C, Luurtsema G. Exploratory Study of Sex Differences in P-Glycoprotein Function at the Blood-Brain Barrier. Clin Transl Sci 2025; 18:e70196. [PMID: 40207685 PMCID: PMC11983324 DOI: 10.1111/cts.70196] [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: 01/13/2025] [Revised: 02/27/2025] [Accepted: 02/28/2025] [Indexed: 04/11/2025] Open
Abstract
Permeability-glycoprotein (P-gp), a crucial efflux pump transporter encoded by the ABCB1 gene, plays a pivotal role in drug disposition at the blood-brain barrier (BBB) and is involved in the pharmacokinetics of numerous therapeutic agents. This study investigates differences in P-gp function at the BBB between males and females in a cohort of older (55+) healthy volunteers (HV) using [18F]MC225 and PET. Twenty HV (11 males and 9 females), free from medications that affect P-gp function and without a history of neurological or psychiatric disorders, underwent [18F]MC225 PET scans with manual arterial blood sampling. Tissue time-activity curves (TAC) were extracted using the Hammers maximum-probability atlas. Whole-blood TAC was derived from the internal carotid arteries, calibrated using manual arterial samples, and adjusted for the plasma-to-whole blood ratio and plasma parent fraction to obtain the image-derived input function. The volume of distribution (VT) was estimated using a reversible two-tissue compartment model, yielding the parameter of interest. Statistical analysis revealed no significant differences in P-gp function between sexes, based on VT values across various brain regions (Cohen's d < 0.2). Furthermore, the arterial blood concentration, plasma parent fraction, and microparameters demonstrated no statistical differences between male and female participants. These findings suggest that P-gp function at the BBB does not exhibit substantial sex-related variability in healthy older adults (55+). For future [18F]MC225 PET studies, a mixed-sex population can serve as an appropriate age-matched control group for neurodegenerative studies. Further research is needed to explore sex-related differences in younger populations, particularly with respect to hormonal cycles.
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Affiliation(s)
- Giordana Salvi de Souza
- Department of Nuclear Medicine and Molecular ImagingUniversity of Groningen, University Medical Center GroningenGroningenthe Netherlands
- School of Medicine, PUCRSPorto AlegreBrazil
| | - Wanling Liu
- Department of Nuclear Medicine and Molecular ImagingUniversity of Groningen, University Medical Center GroningenGroningenthe Netherlands
| | - Pascalle Mossel
- Department of Nuclear Medicine and Molecular ImagingUniversity of Groningen, University Medical Center GroningenGroningenthe Netherlands
- Department of RadiologyLeiden University Medical CenterLeidenthe Netherlands
| | - Joost F. Somsen
- Department of Nuclear Medicine and Molecular ImagingUniversity of Groningen, University Medical Center GroningenGroningenthe Netherlands
| | - Anna L. Bartels
- Department of NeurologyOmmelander Ziekenhuis GroningenScheemdathe Netherlands
| | - Cristiane R. G. Furini
- School of Medicine, PUCRSPorto AlegreBrazil
- Laboratory of Cognition and Memory Neurobiology, Brain Institute, PUCRSPorto AlegreBrazil
| | - Adriaan A. Lammertsma
- Department of Nuclear Medicine and Molecular ImagingUniversity of Groningen, University Medical Center GroningenGroningenthe Netherlands
| | - Charalampos Tsoumpas
- Department of Nuclear Medicine and Molecular ImagingUniversity of Groningen, University Medical Center GroningenGroningenthe Netherlands
| | - Gert Luurtsema
- Department of Nuclear Medicine and Molecular ImagingUniversity of Groningen, University Medical Center GroningenGroningenthe Netherlands
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Fuchs DI, Serio LD, Balaji S, Sprenger KG. Investigating how HIV-1 antiretrovirals differentially behave as substrates and inhibitors of P-glycoprotein via molecular dynamics simulations. Comput Struct Biotechnol J 2024; 23:2669-2679. [PMID: 39027651 PMCID: PMC11254953 DOI: 10.1016/j.csbj.2024.06.025] [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: 04/15/2024] [Revised: 06/18/2024] [Accepted: 06/18/2024] [Indexed: 07/20/2024] Open
Abstract
HIV-1 can rapidly infect the brain upon initial infection, establishing latent reservoirs that induce neuronal damage and/or death, resulting in HIV-Associated Neurocognitive Disorder. Though anti-HIV-1 antiretrovirals (ARVs) suppress viral load, the blood-brain barrier limits drug access to the brain, largely because of highly expressed efflux proteins like P-glycoprotein (P-gp). While no FDA-approved P-gp inhibitor currently exists, HIV-1 protease inhibitors show promise as partial P-gp inhibitors, potentially enhancing drug delivery to the brain. Herein, we employed docking and molecular dynamics simulations to elucidate key differences in P-gp's interactions with several antiretrovirals, including protease inhibitors, with known inhibitory or substrate-like behaviors towards P-gp. Our results led us to hypothesize new mechanistic details of small-molecule efflux by and inhibition of P-gp, where the "Lower Pocket" in P-gp's transmembrane domain serves as the primary initial site for small-molecule binding. Subsequently, this pocket merges with the more traditionally studied drug binding site-the "Upper Pocket"-thus funneling small-molecule drugs, such as ARVs, towards the Upper Pocket for efflux. Furthermore, our results reinforce the understanding that both binding energetics and changes in protein dynamics are crucial in discerning small molecules as non-substrates, substrates, or inhibitors of P-gp. Our findings indicate that interactions between P-gp and inhibitory ARVs induce bridging of transmembrane domain helices, impeding P-gp conformational changes and contributing to the inhibitory behavior of these ARVs. Overall, insights gained in this study could serve to guide the design of future P-gp-targeting therapeutics for a wide range of pathological conditions and diseases, including HIV-1.
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Affiliation(s)
- Daisy I. Fuchs
- Department of Chemical and Biological Engineering, University of Colorado Boulder, Boulder, CO 80303, USA
| | - Lauren D. Serio
- Department of Chemical and Biological Engineering, University of Colorado Boulder, Boulder, CO 80303, USA
| | - Sahana Balaji
- Department of Chemical and Biological Engineering, University of Colorado Boulder, Boulder, CO 80303, USA
| | - Kayla G. Sprenger
- Department of Chemical and Biological Engineering, University of Colorado Boulder, Boulder, CO 80303, USA
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Decaix T, Kemache K, Gay P, Ketz F, Laprévote O, Pautas É. Pharmacokinetics and pharmacodynamics of drug‒drug interactions in hospitalized older adults treated with direct oral anticoagulants. Aging Clin Exp Res 2024; 36:113. [PMID: 38776005 PMCID: PMC11111557 DOI: 10.1007/s40520-024-02768-w] [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: 01/31/2024] [Accepted: 04/26/2024] [Indexed: 05/25/2024]
Abstract
PURPOSE Polypharmacy is a frequent situation in older adults that increases the risk of drug-drug interactions (DDIs), both pharmacokinetic (PK) and pharmacodynamic (PD). Direct oral anticoagulants (DOACs) are frequently prescribed in older adults, mainly because of the high prevalence of atrial fibrillation (AF). DOACs are subject to cytochrome P450 3A4 (CYP3A4)- and/or P-glycoprotein (P-gp)-mediated PK DDIs and PD DDIs when co-administered with drugs that interfere with platelet function. The aim of our study was to assess the prevalence of DDIs involving DOACs in older adults and the associated risk factors at admission and discharge. METHODS This was a cross-sectional study conducted in an acute geriatric unit between January 1, 2018 and December 31, 2022, including patients over 75 years of age treated with DOACs at admission and/or discharge, for whom a comprehensive collection of co-medications was performed. RESULTS From 909 hospitalizations collected, the prevalence of PK DDIs involving DOACs was 16.9% at admission and 20.7% at discharge, and the prevalence of PD DDIs was 20.7% at admission and 20.2% at discharge. Factors associated with DDIs were bleeding history [adjusted odds ratio (ORa) 1.74, 95% confidence interval (CI) 1.13-2.68], number of drugs > 6 (ORa 2.54, 95% CI 1.88-3.46) and reduced dose of DOACs (ORa 0.39, 95% CI 0.28-0.54) at admission and age > 87 years (ORa 0.74, 95% CI 0.55-0.99), number of drugs > 6 (ORa 2.01, 95% CI 1.48-2.72) and reduced dose of DOACs (ORa 0.41, 95% CI 0.30-0.57) at discharge. CONCLUSION This study provides an indication of the prevalence of DDIs as well as the profile of DDIs and patients treated with DOACs.
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Affiliation(s)
- Théodore Decaix
- Geriatrics department, APHP Paris Cité University, Lariboisière-Fernand Widal Hospital, Paris, France.
- Paris-Cité University, CNRS, Paris, F-75006, CitCoM, France.
- Faculty of Pharmacy, Paris-Cité University, 4 avenue de l'Observatoire, Paris, 75006, France.
| | - Kenza Kemache
- Acute Geriatrics Unit, Charles Foix Hospital, APHP Sorbonne University, Ivry-sur-Seine, France
| | - Pierre Gay
- Acute Geriatrics Unit, Charles Foix Hospital, APHP Sorbonne University, Ivry-sur-Seine, France
| | - Flora Ketz
- Acute Geriatrics Unit, Charles Foix Hospital, APHP Sorbonne University, Ivry-sur-Seine, France
| | - Olivier Laprévote
- Paris-Cité University, CNRS, Paris, F-75006, CitCoM, France
- Department of biology, National Hospital Center Of ophthalmology, 15-20, F-75012, Paris, France
| | - Éric Pautas
- Acute Geriatrics Unit, Charles Foix Hospital, APHP Sorbonne University, Ivry-sur-Seine, France
- Therapeutic innovations in hemostasis, Paris-Cité University, UMR-S 1140, Inserm, Paris, France
- Medical school, Sorbonne University, Paris, France
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Wang Y, Wang J, Ye R, Jin Q, Yin F, Liu N, Wang Y, Zhang Q, Gao T, Zhao Y. Cancer Cell-Mimicking Prussian Blue Nanoplatform for Synergistic Mild Photothermal/Chemotherapy via Heat Shock Protein Inhibition. ACS APPLIED MATERIALS & INTERFACES 2024. [PMID: 38624164 DOI: 10.1021/acsami.4c00873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/17/2024]
Abstract
Combined mild-temperature photothermal/chemotherapy has emerged as a highly promising modality for tumor therapy. However, its therapeutic efficacy is drastically compromised by the heat-induced overexpression of heat shock proteins (HSPs) by the cells, which resist heat stress and apoptosis. The purpose of this study was to downregulate HSPs and enhance the mild-temperature photothermal/chemotherapy effect. In detail, the colon cancer cell membrane (CT26M)-camouflaged HSP90 inhibitor ganetespib and the chemotherapeutic agent doxorubicin (DOX)-coloaded hollow mesoporous Prussian blue (HMPB) nanoplatform (named PGDM) were designed for synergistic mild photothermal/chemotherapy via HSP inhibition. In addition to being a photothermal agent with a high efficiency of photothermal conversion (24.13%), HMPB offers a hollow hole that can be filled with drugs. Concurrently, the cancer cell membrane camouflaging enhances tumor accumulation through a homologous targeting mechanism and gives the nanoplatform the potential to evade the immune system. When exposed to NIR radiation, HMPB's photothermal action (44 °C) not only causes tumor cells to undergo apoptosis but also causes ganetespib to be released on demand. This inhibits the formation of HSP90, which enhances the mild photothermal/chemotherapy effect. The results confirmed that the combined treatment regimen of mild photothermal therapy (PTT) and chemotherapy showed a better therapeutic efficacy than the individual treatment methods. Therefore, this multimodal nanoparticle can advance the development of drugs for the treatment of malignancies, such as colon cancer, and has prospects for clinical application.
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Affiliation(s)
- Yun Wang
- Department of Gastroenterology, Jiamusi Central Hospital, Jiamus 154003, P. R. China
- Department of Internal Medicine, School of Clinical Medicine, Jiamusi University, Jiamusi 154007, P. R. China
| | - Jinling Wang
- Department of Emergency and Critical Care Center, The Second Affiliated Hospital of Guangdong Medical University, No.12 Minyou Road, Xiashan, Zhanjiang, Guangdong 524003, P. R. China
| | - Roumei Ye
- Department of Pharmacy, Medical College of Guangxi University, Nanning 530004, P. R. China
| | - Quanyi Jin
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361005, P. R. China
| | - Fengyue Yin
- Department of Pharmacy, Medical College of Guangxi University, Nanning 530004, P. R. China
| | - Nian Liu
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361005, P. R. China
| | - Yubo Wang
- Department of Biomedical Engineering, Medical College of Guangxi University, Nanning 530004, P. R. China
| | - Quan Zhang
- Department of Gastroenterology, Jiamusi Central Hospital, Jiamus 154003, P. R. China
- Department of Internal Medicine, School of Clinical Medicine, Jiamusi University, Jiamusi 154007, P. R. China
| | - Ting Gao
- Department of Pharmaceutical Preparation, General Hospital of Ningxia Medical University, Yinchuan 750004, P. R. China
| | - Yilin Zhao
- Department of Oncology and Vascular Interventional Radiology, Zhongshan Hospital of Xiamen University, Xiamen 361004, P. R. China
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Briki M, Murisier A, Guidi M, Seydoux C, Buclin T, Marzolini C, Girardin FR, Thoma Y, Carrara S, Choong E, Decosterd LA. Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) methods for the therapeutic drug monitoring of cytotoxic anticancer drugs: An update. J Chromatogr B Analyt Technol Biomed Life Sci 2024; 1236:124039. [PMID: 38490042 DOI: 10.1016/j.jchromb.2024.124039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 01/26/2024] [Accepted: 01/31/2024] [Indexed: 03/17/2024]
Abstract
In the era of precision medicine, there is increasing evidence that conventional cytotoxic agents may be suitable candidates for therapeutic drug monitoring (TDM)- guided drug dosage adjustments and patient's tailored personalization of non-selective chemotherapies. To that end, many liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) assays have been developed for the quantification of conventional cytotoxic anticancer chemotherapies, that have been comprehensively and critically reviewed. The use of stable isotopically labelled internal standards (IS) of cytotoxic drugs was strikingly uncommon, accounting for only 48 % of the methods found, although their use could possible to suitably circumvent patients' samples matrix effects variability. Furthermore, this approach would increase the reliability of cytotoxic drug quantification in highly multi-mediated cancer patients with complex fluctuating pathophysiological and clinical conditions. LC-MS/MS assays can accommodate multiplexed analyses of cytotoxic drugs with optimal selectivity and specificity as well as short analytical times and, when using stable-isotopically labelled IS for quantification, provide concentrations measurements with a high degree of certainty. However, there are still organisational, pharmacological, and medical constraints to tackle before TDM of cytotoxic drugs can be more largely adopted in the clinics for contributing to our ever-lasting quest to improve cancer treatment outcomes.
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Affiliation(s)
- M Briki
- Laboratory of Clinical Pharmacology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland; Service of Clinical Pharmacology, Department of Medicine, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland; Bio/CMOS Interfaces Laboratory, École Polytechnique Fédérale de Lausanne-EPFL, 2002 Neuchâtel, Switzerland
| | - A Murisier
- Laboratory of Clinical Pharmacology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland
| | - M Guidi
- Service of Clinical Pharmacology, Department of Medicine, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland; Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, University of Lausanne, 1206 Geneva, Switzerland; Centre for Research and Innovation in Clinical Pharmaceutical Sciences, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland
| | - C Seydoux
- Internal Medicine Service, Department of Medicine, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland
| | - T Buclin
- Service of Clinical Pharmacology, Department of Medicine, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland
| | - C Marzolini
- Laboratory of Clinical Pharmacology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland
| | - F R Girardin
- Laboratory of Clinical Pharmacology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland; Service of Clinical Pharmacology, Department of Medicine, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland
| | - Y Thoma
- School of Engineering and Management Vaud, HES-SO University of Applied Sciences and Arts Western Switzerland, 1401 Yverdon-les-Bains, Switzerland
| | - S Carrara
- Bio/CMOS Interfaces Laboratory, École Polytechnique Fédérale de Lausanne-EPFL, 2002 Neuchâtel, Switzerland
| | - E Choong
- Laboratory of Clinical Pharmacology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland
| | - L A Decosterd
- Laboratory of Clinical Pharmacology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland.
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Gong L, Hu G, Xu L, Chen Y, Wang N. Association between the MDR1 rs1045642 polymorphism and breast cancer risk: An updated meta‑analysis. Oncol Lett 2024; 27:178. [PMID: 38464339 PMCID: PMC10921258 DOI: 10.3892/ol.2024.14312] [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: 10/23/2023] [Accepted: 01/31/2024] [Indexed: 03/12/2024] Open
Abstract
Multidrug resistance 1 (MDR1) is a transmembrane transporter on the cell membrane. As an ATP-dependent efflux pump, MDR1 is mainly responsible for the adsorption, distribution, metabolism, excretion and transportation of anticancer drugs to cancer cells. Mutations of the MDR1 gene may be associated with the incidence of cancer. In the past decade, associations found between the MDR1 rs1045642 polymorphism and breast cancer have been inconsistent and inconclusive. Therefore, the present study performed a meta-analysis including studies published up until August 16, 2023 to systematically evaluate the association between the MDR1 rs1045642 polymorphism and breast cancer risk. A total of 21 published case studies involving 6,815 patients with breast cancer and 9,227 healthy participants were included in the meta-analysis. Overall, the MDR1 rs1045642 polymorphism was not significantly associated with breast cancer-associated risk. However, in the subgroup analysis, the MDR1 rs1045642 polymorphism was found to be notably associated with a higher risk of breast cancer among Asian populations in recessive models [TT vs. CT + CC; odds ratio (OR)=1.393; 95% confidence interval (CI), 1.143-1.698; P=0.001; I2<25%]. The MDR1 C3435T polymorphism was also associated with a notable decrease in the incidence of breast cancer in mixed ethnicity populations (TT and CT + CC; OR=0.578; 95% CI, 0.390-0.856; P=0.006; I2<25%). In Caucasian populations, the MDR1 rs1045642 polymorphism was not associated with breast cancer risk. In conclusion, the present meta-analysis demonstrated that the MDR1 rs1045642 polymorphism may increase the risk of breast cancer in Asian populations, is associated with a reduced risk of breast cancer in mixed populations but has no notable effect in Caucasian populations.
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Affiliation(s)
- Lili Gong
- Department of Breast Surgery Center, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430016, P.R. China
| | - Gang Hu
- Department of Breast Surgery Center, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430016, P.R. China
| | - Lihua Xu
- Department of Breast Surgery Center, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430016, P.R. China
| | - Yajuan Chen
- Department of Breast Surgery Center, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430016, P.R. China
| | - Na Wang
- Department of Breast Surgery Center, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430016, P.R. China
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Jara-Prado A, Guerrero-Camacho JL, Ángeles-López QD, Ochoa-Morales A, Dávila-Ortiz de Montellano DJ, Ramírez-García MÁ, Breda-Yepes M, Durón RM, Delgado-Escueta AV, Barrios-González DA, Martínez-Juárez IE. Association of variants in the ABCB1, CYP2C19 and CYP2C9 genes for Juvenile Myoclonic Epilepsy. Neurol Sci 2024; 45:1635-1643. [PMID: 37875597 DOI: 10.1007/s10072-023-07124-w] [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: 06/15/2023] [Accepted: 10/06/2023] [Indexed: 10/26/2023]
Abstract
Juvenile myoclonic epilepsy (JME) is the most common of the generalized genetic epilepsies, with multiple causal and susceptibility genes; however, its etiopathogenesis is mainly unknown. The toxic effects caused by xenobiotics in cells occur during their metabolic transformation, mainly by enzymes belonging to cytochrome P450. The elimination of these compounds by transporters of the ABC type protects the central nervous system, but their accumulation causes neuronal damage, resulting in neurological diseases. The present study has sought the association between single nucleotide genetic variants of the CYP2C9, CYP2C19, and ABCB1 genes and the development of JME in patients compared to healthy controls. The CC1236 and GG2677 genotypes of ABCB1 in women; allele G 2677, genotypes GG 2677 and CC 3435 in men; the CYP2C19*2A allele, and the CYP2C19*3G/A genotype in both sexes were found to be risk factors for JME. Furthermore, carriers of the TTGGCC genotype combination of the ABCB1 gene (1236/2677/3435) have a 10.5 times higher risk of developing JME than non-carriers. Using the STRING database, we found an interaction between the proteins encoded by these genes and other possible proteins. These findings indicate that the CYP450 system and ABC transporters could interact with other genes in the JME.
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Affiliation(s)
- Aurelio Jara-Prado
- Genetics Department, National Institute of Neurology and Neurosurgery, Mexico City, Mexico
| | | | | | - Adriana Ochoa-Morales
- Genetics Department, National Institute of Neurology and Neurosurgery, Mexico City, Mexico
| | | | | | - Michelle Breda-Yepes
- National Institute of Neurology and Neurosurgery, Epilepsy Clinic, Mexico City, Mexico
| | - Reyna M Durón
- Universidad Tecnológica Centroamericana (UNITEC), Tegucigalpa, Honduras
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Scherf-Clavel M, Baumann P, Hart XM, Schneider H, Schoretsanitis G, Steimer W, Zernig G, Zurek G. Behind the Curtain: Therapeutic Drug Monitoring of Psychotropic Drugs from a Laboratory Analytical Perspective. Ther Drug Monit 2024; 46:143-154. [PMID: 36941240 DOI: 10.1097/ftd.0000000000001092] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/23/2023]
Abstract
PURPOSE Therapeutic drug monitoring (TDM) is a well-established tool for guiding psychopharmacotherapy and improving patient care. Despite their established roles in the prescription of psychotropic drugs, the "behind the curtain" processes of TDM requests are invariably obscure to clinicians, and literature addressing this topic is scarce. METHODS In the present narrative review, we provide a comprehensive overview of the various steps, starting from requesting TDM to interpreting TDM findings, in routine clinical practice. Our goal was to improve clinicians' insights into the numerous factors that may explain the variations in TDM findings due to methodological issues. RESULTS We discussed challenges throughout the TDM process, starting from the analyte and its major variation forms, through sampling procedures and pre-analytical conditions, time of blood sampling, sample matrices, and collection tubes, to analytical methods, their advantages and shortcomings, and the applied quality procedures. Additionally, we critically reviewed the current and future advances in the TDM of psychotropic drugs. CONCLUSIONS The "behind the curtain" processes enabling TDM involve a multidisciplinary team, which faces numerous challenges in clinical routine. A better understanding of these processes will allow clinicians to join the efforts for achieving higher-quality TDM findings, which will in turn improve treatment effectiveness and safety outcomes of psychotropic agents.
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Affiliation(s)
- Maike Scherf-Clavel
- Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Germany
- Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) Work Group on "Therapeutic Drug Monitoring" (Chair: Prof. Dr Med. Dipl.-Psych. Stefan Unterecker, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Germany)
| | - Pierre Baumann
- Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) Work Group on "Therapeutic Drug Monitoring" (Chair: Prof. Dr Med. Dipl.-Psych. Stefan Unterecker, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Germany)
- German Society for Clinical Chemistry and Laboratory Medicine e. V. (DGKL), Section Therapeutic Drug Monitoring and Clinical Toxicology, Berlin/Bonn, Germany
| | - Xenia M Hart
- Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) Work Group on "Therapeutic Drug Monitoring" (Chair: Prof. Dr Med. Dipl.-Psych. Stefan Unterecker, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Germany)
- Department of Molecular Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Heike Schneider
- Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) Work Group on "Therapeutic Drug Monitoring" (Chair: Prof. Dr Med. Dipl.-Psych. Stefan Unterecker, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Germany)
- Institute of Clinical Chemistry and Pathobiochemistry, Technical University Munich, Munich, Germany
- German Society for Clinical Chemistry and Laboratory Medicine e. V. (DGKL), Section Therapeutic Drug Monitoring and Clinical Toxicology, Berlin/Bonn
- INSTAND e.V. Society for Promoting Quality Assurance in Medical Laboratories, Duesseldorf, Germany
- German Society for Clinical Chemistry and Laboratory Medicine e. V. (DGKL), Section Therapeutic Drug Monitoring and Clinical Toxicology, Berlin/Bonn, Germany
| | - Georgios Schoretsanitis
- Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) Work Group on "Therapeutic Drug Monitoring" (Chair: Prof. Dr Med. Dipl.-Psych. Stefan Unterecker, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Germany)
- Department of Psychiatry, The Zucker Hillside Hospital, Northwell Health, Glen Oaks, New York
- Department of Psychiatry, Zucker School of Medicine at Northwell/Hofstra, Hempstead, New York
- Department of Psychiatry, Psychotherapy and Psychosomatics, Hospital of Psychiatry, University of Zurich, Zurich, Switzerland
| | - Werner Steimer
- Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) Work Group on "Therapeutic Drug Monitoring" (Chair: Prof. Dr Med. Dipl.-Psych. Stefan Unterecker, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Germany)
- Institute of Clinical Chemistry and Pathobiochemistry, Technical University Munich, Munich, Germany
- German Society for Clinical Chemistry and Laboratory Medicine e. V. (DGKL), Section Therapeutic Drug Monitoring and Clinical Toxicology, Berlin/Bonn
| | - Gerald Zernig
- Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) Work Group on "Therapeutic Drug Monitoring" (Chair: Prof. Dr Med. Dipl.-Psych. Stefan Unterecker, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Germany)
- Department of Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
- Private Practice for Psychotherapy and Court-certified Expert Witness, Hall in Tirol, Austria; and
| | - Gabriela Zurek
- Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) Work Group on "Therapeutic Drug Monitoring" (Chair: Prof. Dr Med. Dipl.-Psych. Stefan Unterecker, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Germany)
- Medical Laboratory Bremen, Bremen, Germany
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Singh H, Dhotre K, Shyamveer, Choudhari R, Verma A, Mahajan SD, Ali N. ABCG2 polymorphisms and susceptibility to ARV-associated hepatotoxicity. Mol Genet Genomic Med 2024; 12:e2362. [PMID: 38451012 PMCID: PMC10955225 DOI: 10.1002/mgg3.2362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 12/05/2023] [Accepted: 01/04/2024] [Indexed: 03/08/2024] Open
Abstract
BACKGROUND The ABCG2 421C/A polymorphism contributes significantly to the distribution and absorption of antiretroviral (ARV) regimens and is associated with the undesirable side effects of efavirenz. METHODS To investigate this, we examined ABCG2 34G/A (rs2231137) and 421C/A (rs2231142) genetic variations in 149 HIV-infected patients (116 without hepatotoxicity, 33 with ARV-induced hepatotoxicity) and 151 healthy controls through the PCR-restriction fragment length polymorphism (PCR-RFLP) technique. RESULTS AND DISCUSSION The ABCG2 34GA genotype and 34A allele indicated a risk for antiretroviral therapy-associated hepatotoxicity development (p = 0.09, OR = 1.58, 95% CI: 0.93-2.69; p = 0.06, OR = 1.50, 95% CI: 0.98-2.30). The haplotype GA was associated with hepatotoxicity (p = 0.042, OR = 2.37, 95% CI: 1.04-5.43; p = 0.042, OR = 2.49, 95% CI: 1.04-5.96). Moreover, when comparing HIV patients with hepatotoxicity to healthy controls, the haplotype GA had an association with an elevated risk for the development of hepatotoxicity (p = 0.041, OR = 1.73, 95% CI: 1.02-2.93). Additionally, the association of the ABCG2 34GA genotype with the progression of HIV (p = 0.02, OR = 1.97, 95% CI: 1.07-3.63) indicated a risk for advanced HIV infection. Furthermore, the ABCG2 421AA genotype was linked to tobacco users and featured as a risk factor for the progression of HIV disease (p = 0.03, OR = 11.07, 95% CI: 1.09-270.89). CONCLUSION The haplotype GA may enhance the risk of hepatotoxicity development and its severity. Individuals with the ABCG2 34A allele may also be at risk for the development of hepatotoxicity. Additionally, individuals with an advanced stage of HIV and the ABCG2 34GA genotype may be at risk for disease progression.
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Affiliation(s)
- HariOm Singh
- Department of Molecular BiologyNational AIDS Research InstitutePuneIndia
| | - Kishore Dhotre
- Department of Molecular BiologyNational AIDS Research InstitutePuneIndia
| | - Shyamveer
- Department of Molecular BiologyNational AIDS Research InstitutePuneIndia
| | - Ranjana Choudhari
- Department of Molecular BiologyNational AIDS Research InstitutePuneIndia
| | - Amita Verma
- Bioorganic and Medicinal Chemistry Research Laboratory, Department of Pharmaceutical SciencesSam Higginbottom University of Agriculture, Technology and SciencesAllahabadIndia
| | - Supriya D. Mahajan
- Department of Medicine, Jacobs School of Medicine & Biomedical SciencesUniversity at Buffalo's Clinical Translational Research CenterBuffaloNew YorkUSA
| | - Nemat Ali
- Department of Pharmacology and Toxicology, College of PharmacyKing Saud UniversityRiyadhSaudi Arabia
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10
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Gareri P, Gallelli L, Gareri I, Rania V, Palleria C, De Sarro G. Deprescribing in Older Poly-Treated Patients Affected with Dementia. Geriatrics (Basel) 2024; 9:28. [PMID: 38525745 PMCID: PMC10961769 DOI: 10.3390/geriatrics9020028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Revised: 02/18/2024] [Accepted: 02/19/2024] [Indexed: 03/26/2024] Open
Abstract
Polypharmacy is an important issue in older patients affected by dementia because they are very vulnerable to the side effects of drugs'. Between October 2021 and September 2022, we randomly assessed 205 old-aged outpatients. The study was carried out in a Center for Dementia in collaboration with a university center. The primary outcomes were: (1) deprescribing inappropriate drugs through the Beers and STOPP&START criteria; (2) assessing duplicate drugs and the risk of iatrogenic damage due to drug-drug and drug-disease interactions. Overall, 69 men and 136 women (mean age 82.7 ± 7.4 years) were assessed. Of these, 91 patients were home care patients and 114 were outpatient. The average number of the drugs used in the sample was 9.4 drugs per patient; after the first visit and the consequent deprescribing process, the average dropped to 8.7 drugs per patient (p = 0.04). Overall, 74 potentially inappropriate drugs were used (36.1%). Of these, long half-life benzodiazepines (8.8%), non-steroidal anti-inflammatory drugs (3.4%), tricyclic antidepressants (3.4%), first-generation antihistamines (1.4%), anticholinergics (11.7%), antiplatelet drugs (i.e., ticlopidine) (1.4%), prokinetics in chronic use (1.4%), digoxin (>0.125 mg/day) (1.4%), antiarrhythmics (i.e., amiodarone) (0.97%), and α-blockers (1.9%) were included. The so-called "duplicate" drugs were overall 26 (12.7%). In total, ten potentially dangerous prescriptions were found for possible interactions (4.8%). We underline the importance of checking all the drugs taken periodically and discontinuing drugs with the lowest benefit-to-harm ratio and the lowest probability of adverse reactions due to withdrawal. Computer tools and adequately trained teams (doctors, nurses, and pharmacists) could identify, treat, and prevent possible drug interactions.
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Affiliation(s)
- Pietro Gareri
- Department of Frailty, Center for Cognitive Disorders and Dementia (CDCD) Catanzaro Lido—ASP Catanzaro, Magna Graecia University, 88100 Catanzaro, Italy
| | - Luca Gallelli
- Unit of Clinical Pharmacology and Pharmacovigilance, “Renato Dulbecco” University Hospital, 88100 Catanzaro, Italy; (L.G.); (V.R.); (G.D.S.)
- Department of Health Science, Magna Graecia University, 88100 Catanzaro, Italy; (I.G.); (C.P.)
- Research Center FAS@UMG, Department of Health Science, Magna Graecia University, 88100 Catanzaro, Italy
| | - Ilaria Gareri
- Department of Health Science, Magna Graecia University, 88100 Catanzaro, Italy; (I.G.); (C.P.)
| | - Vincenzo Rania
- Unit of Clinical Pharmacology and Pharmacovigilance, “Renato Dulbecco” University Hospital, 88100 Catanzaro, Italy; (L.G.); (V.R.); (G.D.S.)
| | - Caterina Palleria
- Department of Health Science, Magna Graecia University, 88100 Catanzaro, Italy; (I.G.); (C.P.)
- Research Center FAS@UMG, Department of Health Science, Magna Graecia University, 88100 Catanzaro, Italy
| | - Giovambattista De Sarro
- Unit of Clinical Pharmacology and Pharmacovigilance, “Renato Dulbecco” University Hospital, 88100 Catanzaro, Italy; (L.G.); (V.R.); (G.D.S.)
- Department of Health Science, Magna Graecia University, 88100 Catanzaro, Italy; (I.G.); (C.P.)
- Research Center FAS@UMG, Department of Health Science, Magna Graecia University, 88100 Catanzaro, Italy
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11
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Merabet N, Ramoz N, Boulmaiz A, Bourefis A, Benabdelkrim M, Djeffal O, Moyse E, Tolle V, Berredjem H. SNPs-Panel Polymorphism Variations in GHRL and GHSR Genes Are Not Associated with Prostate Cancer. Biomedicines 2023; 11:3276. [PMID: 38137497 PMCID: PMC10741232 DOI: 10.3390/biomedicines11123276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 12/05/2023] [Accepted: 12/09/2023] [Indexed: 12/24/2023] Open
Abstract
Prostate cancer (PCa) is a major public health problem worldwide. Recent studies have suggested that ghrelin and its receptor could be involved in the susceptibility to several cancers such as PCa, leading to their use as an important predictive way for the clinical progression and prognosis of cancer. However, conflicting results of single nucleotide polymorphisms (SNPs) with ghrelin (GHRL) and its receptor (GHSR) genes were demonstrated in different studies. Thus, the present case-control study was undertaken to investigate the association of GHRL and GHSR polymorphisms with the susceptibility to sporadic PCa. A cohort of 120 PCa patients and 95 healthy subjects were enrolled in this study. Genotyping of six SNPs was performed: three tag SNPs in GHRL (rs696217, rs4684677, rs3491141) and three tag SNPs in the GHSR (rs2922126, rs572169, rs2948694) using TaqMan. The allele and genotype distribution, as well as haplotypes frequencies and linked disequilibrium (LD), were established. Multifactor dimensionality reduction (MDR) analysis was used to study gene-gene interactions between the six SNPs. Our results showed no significant association of the target polymorphisms with PCa (p > 0.05). Nevertheless, SNPs are often just markers that help identify or delimit specific genomic regions that may harbour functional variants rather than the variants causing the disease. Furthermore, we found that one GHSR rs2922126, namely the TT genotype, was significantly more frequent in PCa patients than in controls (p = 0.040). These data suggest that this genotype could be a PCa susceptibility genotype. MDR analyses revealed that the rs2922126 and rs572169 combination was the best model, with 81.08% accuracy (p = 0.0001) for predicting susceptibility to PCa. The results also showed a precision of 98.1% (p < 0.0001) and a PR-AUC of 1.00. Our findings provide new insights into the influence of GHRL and GHSR polymorphisms and significant evidence for gene-gene interactions in PCa susceptibility, and they may guide clinical decision-making to prevent overtreatment and enhance patients' quality of life.
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Affiliation(s)
- Nesrine Merabet
- Laboratory of Applied Biochemistry and Microbiology, Department of Biochemistry, Faculty of Sciences, Badji Mokhtar University, Annaba 23000, Algeria; (A.B.); (A.B.); (M.B.)
- Unit 85 PRC (Physiology of Reproduction and Behavior), Centre INRAe of Tours, University of Tours, 37380 Nouzilly, France;
| | - Nicolas Ramoz
- University Paris Cité, INSERM U1266, Institute of Psychiatry and Neuroscience of Paris (IPNP), 75014 Paris, France; (N.R.); (V.T.)
| | - Amel Boulmaiz
- Laboratory of Applied Biochemistry and Microbiology, Department of Biochemistry, Faculty of Sciences, Badji Mokhtar University, Annaba 23000, Algeria; (A.B.); (A.B.); (M.B.)
| | - Asma Bourefis
- Laboratory of Applied Biochemistry and Microbiology, Department of Biochemistry, Faculty of Sciences, Badji Mokhtar University, Annaba 23000, Algeria; (A.B.); (A.B.); (M.B.)
| | - Maroua Benabdelkrim
- Laboratory of Applied Biochemistry and Microbiology, Department of Biochemistry, Faculty of Sciences, Badji Mokhtar University, Annaba 23000, Algeria; (A.B.); (A.B.); (M.B.)
| | - Omar Djeffal
- Private Medical Uro-Chirurgical Cabinet, Cité SafSaf, BatR02 n°S01, Annaba 23000, Algeria;
| | - Emmanuel Moyse
- Unit 85 PRC (Physiology of Reproduction and Behavior), Centre INRAe of Tours, University of Tours, 37380 Nouzilly, France;
| | - Virginie Tolle
- University Paris Cité, INSERM U1266, Institute of Psychiatry and Neuroscience of Paris (IPNP), 75014 Paris, France; (N.R.); (V.T.)
| | - Hajira Berredjem
- Laboratory of Applied Biochemistry and Microbiology, Department of Biochemistry, Faculty of Sciences, Badji Mokhtar University, Annaba 23000, Algeria; (A.B.); (A.B.); (M.B.)
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12
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Decaix T, Magny R, Gouin‐Thibaut I, Delavenne X, Mismetti P, Salem J, Narjoz C, Blanchard A, Pépin M, Auzeil N, Loriot M, Laprévote O. Plasma lipidomic analysis to investigate putative biomarkers of P-glycoprotein activity in healthy volunteers. Clin Transl Sci 2023; 16:1935-1946. [PMID: 37529981 PMCID: PMC10582668 DOI: 10.1111/cts.13601] [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: 06/08/2023] [Revised: 06/21/2023] [Accepted: 06/23/2023] [Indexed: 08/03/2023] Open
Abstract
P-glycoprotein (P-gp) is an efflux transporter involved in the bioavailability of many drugs currently on the market. P-gp is responsible for several drug-drug interactions encountered in clinical practice leading to iatrogenic hospital admissions, especially in polypharmacy situations. ABCB1 genotyping only reflects an indirect estimate of P-gp activity. Therefore, it would be useful to identify endogenous biomarkers to determine the P-gp phenotype to predict in vivo activity prior to the initiation of treatment and to assess the effects of drugs on P-gp activity. The objective of this study was to assess changes in plasma lipidome composition among healthy volunteers selected on the basis of their ABCB1 genotype and who received clarithromycin, a known inhibitor of P-gp. Untargeted lipidomic analysis based on liquid chromatography-tandem mass spectrometry was performed before and after clarithromycin administration. Our results revealed changes in plasma levels of some ceramides (Cers) {Cer(d18:1/22:0), Cer(d18:1/22:1), and Cer(d18:1/20:0) by ~38% (p < 0.0001), 13% (p < 0.0001), and 13% (p < 0.0001), respectively} and phosphatidylcholines (PCs) {PC(17:0/14:1), PC(16:0/18:3), and PC(14:0/18:3) by ~24% (p < 0.001), 10% (p < 0.001), and 23.6% (p < 0.001)} associated with both ABCB1 genotype and clarithromycin intake. Through the examination of plasma lipids, our results highlight the relevance of untargeted lipidomics for studying in vivo P-gp activity and, more generally, to safely phenotyping transporters.
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Affiliation(s)
| | | | | | - Xavier Delavenne
- Clinical Pharmacology DepartmentUniversity Hospital of Saint‐EtienneSaint EtienneFrance
- INSERM, U1059Vascular Dysfunction and HemostasisSaint‐EtienneFrance
| | - Patrick Mismetti
- INSERM, U1059Vascular Dysfunction and HemostasisSaint‐EtienneFrance
- Vascular and Therapeutic Medicine DepartmentSaint‐Etienne University Hospital CenterSaint‐EtienneFrance
| | - Joe‐Elie Salem
- Pharmacology Department, APHP, Pitié‐Salpétrière HospitalGHU Sorbonne UniversityParisFrance
- CIC‐1421 and Institut de Cardiométabolisme et Nutrition (ICAN) UMR ICAN_1166INSERMParisFrance
| | - Céline Narjoz
- Department of Clinical Chemistry, APHP, GHU Paris‐CentreEuropean Georges Pompidou HospitalParisFrance
- INSERM U1138, Team 26Research Center of CordeliersParisFrance
| | - Anne Blanchard
- Sorbonne Paris CitéParis Descartes UniversityParisFrance
- Centre d'Investigation Clinique, APHP, INSERM CIC‐1418Européen Georges Pompidou HospitalParisFrance
| | - Marion Pépin
- Department of Geriatrics, APHPGHU Paris‐Saclay University, Ambroise Paré HospitalBoulogne‐BillancourtFrance
- Clinical Epidemiology, UVSQ, Inserm U1018, CESPParis‐Saclay UniversityVillejuifFrance
| | | | - Marie‐Anne Loriot
- Department of Clinical Chemistry, APHP, GHU Paris‐CentreEuropean Georges Pompidou HospitalParisFrance
- INSERM U1138, Team 26Research Center of CordeliersParisFrance
- Sorbonne Paris CitéParis Descartes UniversityParisFrance
| | - Olivier Laprévote
- CNRS, CiTCoMParis‐Cité UniversityParisFrance
- Department of Clinical Chemistry, APHP, GHU Paris‐CentreEuropean Georges Pompidou HospitalParisFrance
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13
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Magadmi R, Alyoubi R, Moshrif T, Bakhshwin D, Suliman BA, Kamel F, Jamal M, Burzangi AS, Basit S. Polymorphisms in the Drug Transporter Gene ABCB1 Are Associated with Drug Response in Saudi Epileptic Pediatric Patients. Biomedicines 2023; 11:2505. [PMID: 37760947 PMCID: PMC10526247 DOI: 10.3390/biomedicines11092505] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 09/03/2023] [Accepted: 09/09/2023] [Indexed: 09/29/2023] Open
Abstract
Epilepsy is one of the most common chronic neurodisorders in the pediatric age group. Despite the availability of over 20 anti-seizure medications (ASMs) on the market, drug-resistant epilepsy still affects one-third of individuals. Consequently, this research aimed to investigate the association between single-nucleotide polymorphisms (SNPs) of the ATP-binding cassette subfamily B member 1 (ABCB1) gene in epileptic pediatric patients and their response to ASMs. This multicentric, cross-sectional study was conducted among Saudi children with epilepsy in Jeddah, Saudi Arabia. The polymorphism variants of ABCB1 rs1128503 at exon 12, rs2032582 at exon 21, and rs1045642 at exon 26 were genotyped using the Sanger sequencing technique. The study included 85 children with epilepsy: 43 patients demonstrated a good response to ASMs, while 42 patients exhibited a poor response. The results revealed that good responders were significantly more likely to have the TT genotypes at rs1045642 and rs2032582 SNPs compared to poor responders. Additionally, haplotype analysis showed that the T-G-C haplotype at rs1128503, rs2032582, and rs1045642 was only present in poor responders. In conclusion, this study represents the first pharmacogenetic investigation of the ABCB1 gene in Saudi epileptic pediatric patients and demonstrates a significant association between rs1045642 and rs2032582 variants and patient responsiveness. Despite the small sample size, the results underscore the importance of personalized treatment for epileptic patients.
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Affiliation(s)
- Rania Magadmi
- Department of Clinical Pharmacology, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (T.M.); (D.B.); (F.K.); (M.J.); (A.S.B.)
| | - Reem Alyoubi
- Pediatric Department, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
| | - Tahani Moshrif
- Department of Clinical Pharmacology, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (T.M.); (D.B.); (F.K.); (M.J.); (A.S.B.)
- Clinical Pharmacy Department, King Abdullah Medical Complex, Jeddah 23816 , Saudi Arabia
| | - Duaa Bakhshwin
- Department of Clinical Pharmacology, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (T.M.); (D.B.); (F.K.); (M.J.); (A.S.B.)
| | - Bandar A. Suliman
- College of Applied Medical Sciences, Taibah University, Madinah 42353, Saudi Arabia;
| | - Fatemah Kamel
- Department of Clinical Pharmacology, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (T.M.); (D.B.); (F.K.); (M.J.); (A.S.B.)
| | - Maha Jamal
- Department of Clinical Pharmacology, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (T.M.); (D.B.); (F.K.); (M.J.); (A.S.B.)
| | - Abdulhadi S. Burzangi
- Department of Clinical Pharmacology, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (T.M.); (D.B.); (F.K.); (M.J.); (A.S.B.)
| | - Sulman Basit
- Biochemistry and Molecular Medicine Department, College of Medicine, Taibah University, Madinah 42353, Saudi Arabia;
- Centre for Genetics and Inherited Diseases, College of Medicine, Taibah University, Madinah 42353, Saudi Arabia
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14
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El Gazzar WB, Albakri KA, Hasan H, Badr AM, Farag AA, Saleh OM. Poly(ADP-ribose) polymerase inhibitors in the treatment landscape of triple-negative breast cancer (TNBC). J Oncol Pharm Pract 2023; 29:1467-1479. [PMID: 37559370 DOI: 10.1177/10781552231188903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/11/2023]
Abstract
OBJECTIVE Chemotherapy is the mainstay for triple-negative breast cancer (TNBC) patients. Over the years, the use of chemotherapy for these patients has demonstrated many adversities, including toxicity and resistance, which suggested the need to develop novel alternative therapeutic options, such as poly(ADP-ribose) polymerase inhibitors (PARPi). Herein, we provide an overview on PARPi, mechanisms of action and the role of biomarkers in PARPi sensitivity trials, clinical advances in PARPi therapy for TNBC patients based on the most recent studies and findings of clinical trials, and challenges that prevent PARP inhibitors from achieving high efficacy such as resistance and overlapping toxicities with other chemotherapies. DATA SOURCES Searching for relevant articles was done using PubMed and Cochrane Library databases by using the keywords including TNBC; chemotherapy; PARPi; BRCA; homologous recombination repair (HRR). Studies had to be published in full-text in English in order to be considered. DATA SUMMARY Although PARPi have been used in the treatment of local/metastatic breast malignancies that are HER2 negative and has a germline BRCA mutation, several questions are still to be answered in order to maximize the clinical benefit of PARP inhibitors in TNBC treatment, such as questions related to the optimal use in the neoadjuvant and metastatic settings as well as the best combinations with various chemotherapies. CONCLUSIONS PARPi are emerging treatment options for patients with gBRCA1/2 mutations. Determining patients that are most likely to benefit from PARPi and identifying the optimal treatment combinations with high efficacy and fewer side effects are currently ongoing.
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Affiliation(s)
- Walaa Bayoumie El Gazzar
- Department of Anatomy, Physiology and Biochemistry, Faculty of Medicine, The Hashemite University, Zarqa, Jordan
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Benha University, Benha City, Egypt
| | | | - Hanan Hasan
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, The University of Jordan, Amman, Jordan
| | - Amira M Badr
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
- Department of Pharmacology and Toxicology, College of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Amina A Farag
- Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Benha University, Benha City, Egypt
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15
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Radic Savic Z, Coric V, Vidovic S, Vidovic V, Becarevic J, Milovac I, Reljic Z, Mirjanic-Azaric B, Skrbic R, Gajanin R, Matic M, Simic T. GPX3 rs8177412 Polymorphism Modifies Risk of Upper Urothelial Tumors in Patients with Balkan Endemic Nephropathy. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1421. [PMID: 37629712 PMCID: PMC10456338 DOI: 10.3390/medicina59081421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 07/29/2023] [Accepted: 07/31/2023] [Indexed: 08/27/2023]
Abstract
Current data suggest that aristolochic acid (AA) exposure is a putative cause of Balkan endemic nephropathy (BEN), a chronic kidney disease strongly associated with upper tract urothelial carcinoma. The cellular metabolism of AA is associated with the production of reactive oxygen species, resulting in oxidative distress. Purpose: Therefore, the aim of this study was to analyze individual, combined and cumulative effect of antioxidant gene polymorphisms (Nrf2 rs6721961, KEAP1 rs1048290, GSTP1AB rs1695, GSTP1CD rs1138272, GPX3 rs8177412 and MDR1 rs1045642), as well as GSTP1ABCD haplotypes with the risk for BEN development and associated urothelial cell carcinoma in 209 BEN patients and 140 controls from endemic areas. Experimental method: Genotyping was performed using polymerase chain reaction (PCR) and PCR with confronting two-pair primers (PCR-CTTP) methods. Results: We found that female patients carrying both variant GPX3 rs8177412 and MDR1 rs1045642 genotypes in combination exhibited significant risk towards BEN (OR 1 = 3.34, 95% CI = 1.16-9.60, p = 0.025; OR 2 = 3.79, 95% CI = 1.27-11.24, p = 0.016). Moreover, significant association was determined between GPX3rs8174412 polymorphism and risk for urothelial carcinoma. Carriers of variant GPX3*TC + CC genotype were at eight-fold increased risk of BEN-associated urothelial tumors development. There was no individual or combined impact on BEN development and BEN-associated tumors among all examined polymorphisms. The haplotype consisting of variant alleles for both polymorphisms G and T was associated with 1.6-fold increased risk although statistically insignificant (OR = 1.64; 95% CI = 0.75-3.58; p = 0.21). Conclusions: Regarding GPX3 rs8177412 polymorphism, the gene variant that confers lower expression is associated with significant increase in upper urothelial carcinoma risk. Therefore, BEN patients carrying variant GPX3 genotype should be more frequently monitored for possible upper tract urothelial carcinoma development.
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Affiliation(s)
- Zana Radic Savic
- Department of Medical Biochemistry, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and Herzegovina; (Z.R.S.); (B.M.-A.)
- Centre for Biomedical Research, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and Herzegovina; (S.V.); (V.V.); (J.B.); (I.M.)
| | - Vesna Coric
- Institute of Medical and Clinical Biochemistry, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
- Center of Excellence for Redox Medicine, Biotech Place, 2W-017, 575 North Patterson Avenue, Winston-Salem, NC 27157, USA
| | - Stojko Vidovic
- Centre for Biomedical Research, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and Herzegovina; (S.V.); (V.V.); (J.B.); (I.M.)
- Department of Human Genetics, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and Herzegovina
| | - Vanja Vidovic
- Centre for Biomedical Research, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and Herzegovina; (S.V.); (V.V.); (J.B.); (I.M.)
- Department of Human Genetics, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and Herzegovina
| | - Jelena Becarevic
- Centre for Biomedical Research, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and Herzegovina; (S.V.); (V.V.); (J.B.); (I.M.)
| | - Irina Milovac
- Centre for Biomedical Research, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and Herzegovina; (S.V.); (V.V.); (J.B.); (I.M.)
- Department of Human Genetics, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and Herzegovina
| | - Zorica Reljic
- Medical Laboratory “PAN LAB”, 36000 Kraljevo, Serbia;
| | - Bosa Mirjanic-Azaric
- Department of Medical Biochemistry, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and Herzegovina; (Z.R.S.); (B.M.-A.)
| | - Ranko Skrbic
- Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and Herzegovina;
- Academy of Sciences and Arts of the Republic of Srpska, 78000 Banja Luka, The Republic of Srpska, Bosnia and Herzegovina
| | - Radoslav Gajanin
- Department of Pathological Anatomy, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and Herzegovina;
| | - Marija Matic
- Institute of Medical and Clinical Biochemistry, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
- Center of Excellence for Redox Medicine, Biotech Place, 2W-017, 575 North Patterson Avenue, Winston-Salem, NC 27157, USA
| | - Tatjana Simic
- Institute of Medical and Clinical Biochemistry, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
- Center of Excellence for Redox Medicine, Biotech Place, 2W-017, 575 North Patterson Avenue, Winston-Salem, NC 27157, USA
- Serbian Academy of Sciences and Arts, 11000 Belgrade, Serbia
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16
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Wang SSY, Jie YE, Cheng SW, Ling GL, Ming HVY. PARP Inhibitors in Breast and Ovarian Cancer. Cancers (Basel) 2023; 15:cancers15082357. [PMID: 37190285 DOI: 10.3390/cancers15082357] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 04/12/2023] [Accepted: 04/13/2023] [Indexed: 05/17/2023] Open
Abstract
Poly (ADP-ribose) polymerase (PARP) inhibitors are one of the most successful examples of clinical translation of targeted therapies in medical oncology, and this has been demonstrated by their effective management of BRCA1/BRCA2 mutant cancers, most notably in breast and ovarian cancers. PARP inhibitors target DNA repair pathways that BRCA1/2-mutant tumours are dependent upon. Inhibition of the key components of these pathways leads to DNA damage triggering subsequent critical levels of genomic instability, mitotic catastrophe and cell death. This ultimately results in a synthetic lethal relationship between BRCA1/2 and PARP, which underpins the effectiveness of PARP inhibitors. Despite the early and dramatic response seen with PARP inhibitors, patients receiving them often develop treatment resistance. To date, data from both clinical and preclinical studies have highlighted multiple resistance mechanisms to PARP inhibitors, and only by understanding these mechanisms are we able to overcome the challenges. The focus of this review is to summarise the underlying mechanisms underpinning treatment resistance to PARP inhibitors and to aid both clinicians and scientists to develop better clinically applicable assays to better select patients who would derive the greatest benefit as well as develop new novel/combination treatment strategies to overcome these mechanisms of resistance. With a better understanding of PARP inhibitor resistance mechanisms, we would not only be able to identify a subset of patients who are unlikely to benefit from therapy but also to sequence our treatment paradigm to avoid and overcome these resistance mechanisms.
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Affiliation(s)
- Samuel S Y Wang
- Medical Oncology, Tan Tock Seng Hospital, Singapore 308433, Singapore
| | - Yeo Ee Jie
- Medical Oncology, Tan Tock Seng Hospital, Singapore 308433, Singapore
| | - Sim Wey Cheng
- Molecular Diagnostic Laboratory, Tan Tock Seng Hospital, Singapore 308433, Singapore
| | - Goh Liuh Ling
- Molecular Diagnostic Laboratory, Tan Tock Seng Hospital, Singapore 308433, Singapore
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Justesen S, Bilde K, Olesen RH, Pedersen LH, Ernst E, Larsen A. ABCB1 expression is increased in human first trimester placenta from pregnant women classified as overweight or obese. Sci Rep 2023; 13:5175. [PMID: 36997557 PMCID: PMC10063677 DOI: 10.1038/s41598-023-31598-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 03/14/2023] [Indexed: 04/01/2023] Open
Abstract
Obesity has become a global health challenge also affecting reproductive health. In pregnant women, obesity increases the risk of complications such as preterm birth, macrosomia, gestational diabetes, and preeclampsia. Moreover, obesity is associated with long-term adverse effects for the offspring, including increased risk of cardiovascular and metabolic diseases and neurodevelopmental difficulties. The underlying mechanisms are far from understood, but placental function is essential for pregnancy outcome. Transporter proteins P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) are important for trans-placental transport of endogenous substances like lipids and cortisol, a key hormone in tissue maturation. They also hold a protective function protecting the fetus from xenobiotics (e.g. pharmaceuticals). Animal studies suggest that maternal nutritional status can affect expression of placental transporters, but little is known about the effect on the human placenta, especially in early pregnancy. Here, we investigated if overweight and obesity in pregnant women altered mRNA expression of ABCB1 encoding P-gp or ABCG2 encoding BCRP in first trimester human placenta. With informed consent, 75 first trimester placental samples were obtained from women voluntarily seeking surgical abortion (< gestational week 12) (approval no.: 20060063). Villous samples (average gestational age 9.35 weeks) were used for qPCR analysis. For a subset (n = 38), additional villi were snap-frozen for protein analysis. Maternal BMI was defined at the time of termination of pregnancy. Compared to women with BMI 18.5-24.9 kg/m2 (n = 34), ABCB1 mRNA expression was significantly increased in placenta samples from women classified as overweight (BMI 25-29.9 kg/m2, n = 18) (p = 0.040) and women classified as obese (BMI ≥ 30 kg/m2, n = 23) (p = 0.003). Albeit P-gp expression did not show statistically significant difference between groups, the effect of increasing BMI was the same in male and female pregnancies. To investigate if the P-gp increase was compensated, we determined the expression of ABCG2 which was unaffected by maternal obesity (p = 0.291). Maternal BMI affects ABCB1 but not ABCG2 mRNA expression in first trimester human placenta. Further studies of early placental function are needed to understand how the expression of placental transport proteins is regulated by maternal factors such as nutritional status and determine the potential consequences for placental-fetal interaction.
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Affiliation(s)
- Signe Justesen
- Department of Biomedicine, Aarhus University, Høegh-Guldbergs Gade 10, 8000, Aarhus C, Denmark
| | - Katrine Bilde
- Department of Biomedicine, Aarhus University, Høegh-Guldbergs Gade 10, 8000, Aarhus C, Denmark
| | - Rasmus H Olesen
- Department of Biomedicine, Aarhus University, Høegh-Guldbergs Gade 10, 8000, Aarhus C, Denmark
- Department of Obstetrics and Gynecology, Randers Regional Hospital, 8930, Randers, Denmark
| | - Lars H Pedersen
- Department of Biomedicine, Aarhus University, Høegh-Guldbergs Gade 10, 8000, Aarhus C, Denmark
- Department of Clinical Medicine, Aarhus University, 8200, Aarhus N, Denmark
- Department of Obstetrics and Gynecology, Aarhus University Hospital, 8200, Aarhus N, Denmark
| | - Erik Ernst
- Department of Biomedicine, Aarhus University, Høegh-Guldbergs Gade 10, 8000, Aarhus C, Denmark
- Department of Obstetrics and Gynecology, Horsens Regional Hospital, 8700, Horsens, Denmark
| | - Agnete Larsen
- Department of Biomedicine, Aarhus University, Høegh-Guldbergs Gade 10, 8000, Aarhus C, Denmark.
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Sohail A, Arshad A, Tariq T, Bibi A, Aslam S, Irfan M. Role of MDR1 Gene Polymorphisms in Human Male Infertility: A Meta-Analysis. Am J Mens Health 2023; 17:15579883231166645. [PMID: 37081725 PMCID: PMC10126615 DOI: 10.1177/15579883231166645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/22/2023] Open
Abstract
The present meta-analysis is performed to determine the association of C1236T and C3435T polymorphisms in the MDR1 gene. Google Scholar, PubMed, and Science Direct were searched. A total of 47 studies were retrieved, of which only three case-control studies, consisting of 490 cases and 423 controls, met the selection criteria. Odds ratios (ORs) for MDR1 C1236T were as follows: Allelic model (T vs. C): OR = 1.06 [0.83, 1.35]; Additive model (TT vs. CC): OR = 0.91 [0.53, 1.56]; Dominant model (TT+CT vs. CC): OR = 0.83 [0.55, 1.24]; and Recessive model (TT vs. CT+CC): OR = 1.43 [0.95, 2.17]. However, for MDR1 C3435T: Allelic model (T vs. C): OR = 1.06 [0.83, 1.35]; Additive model (TT vs. CC): OR = 1.18 [0.75, 1.88]; Dominant model (TT+CT vs. CC): OR = 1.42 [0.99, 2.04]; and Recessive model (TT vs. CT+CC): OR = 0.90 [0.61, 1.33]. None of the four models presented a significant association of either polymorphism with the risk of infertility in men (p >.05). The present study indicates that MDR1 gene polymorphisms might not be a risk factor for male infertility. Further studies with a larger sample size are needed to be conducted to confirm the findings of the present study.
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Affiliation(s)
- Anam Sohail
- Department of Zoology, Wildlife, and Fisheries, Pir Mehr Ali Shah, Arid Agriculture University, Rawalpindi, Pakistan
| | - Adina Arshad
- Department of Zoology, Wildlife, and Fisheries, Pir Mehr Ali Shah, Arid Agriculture University, Rawalpindi, Pakistan
| | - Tamjeed Tariq
- Department of Zoology, Wildlife, and Fisheries, Pir Mehr Ali Shah, Arid Agriculture University, Rawalpindi, Pakistan
| | - Ayesha Bibi
- Department of Zoology, Wildlife, and Fisheries, Pir Mehr Ali Shah, Arid Agriculture University, Rawalpindi, Pakistan
| | - Shaista Aslam
- Department of Biological Sciences, National University of Medical Sciences, Rawalpindi, Pakistan
| | - Muhammad Irfan
- Department of Zoology, Wildlife, and Fisheries, Pir Mehr Ali Shah, Arid Agriculture University, Rawalpindi, Pakistan
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The Role of Silver Nanoparticles in the Diagnosis and Treatment of Cancer: Are There Any Perspectives for the Future? Life (Basel) 2023; 13:life13020466. [PMID: 36836823 PMCID: PMC9965924 DOI: 10.3390/life13020466] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 02/02/2023] [Accepted: 02/03/2023] [Indexed: 02/10/2023] Open
Abstract
Cancer is a fatal disease with a complex pathophysiology. Lack of specificity and cytotoxicity, as well as the multidrug resistance of traditional cancer chemotherapy, are the most common limitations that often cause treatment failure. Thus, in recent years, significant efforts have concentrated on the development of a modernistic field called nano-oncology, which provides the possibility of using nanoparticles (NPs) with the aim to detect, target, and treat cancer diseases. In comparison with conventional anticancer strategies, NPs provide a targeted approach, preventing undesirable side effects. What is more, nanoparticle-based drug delivery systems have shown good pharmacokinetics and precise targeting, as well as reduced multidrug resistance. It has been documented that, in cancer cells, NPs promote reactive oxygen species (ROS) production, induce cell cycle arrest and apoptosis, activate ER (endoplasmic reticulum) stress, modulate various signaling pathways, etc. Furthermore, their ability to inhibit tumor growth in vivo has also been documented. In this paper, we have reviewed the role of silver NPs (AgNPs) in cancer nanomedicine, discussing numerous mechanisms by which they render anticancer properties under both in vitro and in vivo conditions, as well as their potential in the diagnosis of cancer.
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Nanomedicine based strategies for oligonucleotide traversion across the blood-brain barrier. J Control Release 2023; 354:554-571. [PMID: 36649742 DOI: 10.1016/j.jconrel.2023.01.031] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 01/10/2023] [Accepted: 01/12/2023] [Indexed: 01/19/2023]
Abstract
Neurological disorders are considered the most prominent cause of disability worldwide. The major hurdle in the management of neurological disorders is the existence of the blood-brain barrier (BBB), which hinders the entry of several therapeutic moieties. In recent years, oligonucleotides have gained tremendous attention for their target specificity, diminished dose and adverse effects, thereby halting disease progression. However, enzymatic degradation, rapid clearance, limited circulation and availability at the bio-active site, etc., limit its clinical translation. Nanomedicine has opened up a breadth of opportunities in the delivery of oligonucleotides across the BBB. This review addresses the pitfalls associated with oligonucleotide delivery in traversing the BBB via nanotherapeutics for the management of brain disorders. Regulatory perspectives pertaining to hastening the clinical translation of oligonucleotide-loaded nanocarriers for brain delivery have been highlighted.
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Kubanov A, Asoskova AВ, Zastrozhin M, Sozaeva Z, Sychev D. Influence of ABCB1 3435C>T polymorphism on methotrexate safety in patients with psoriasis. VESTNIK DERMATOLOGII I VENEROLOGII 2023. [DOI: 10.25208/vdv1321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Introduction:
Methotrexate is a highly effective systemic treatment for moderate to severe psoriasis, but drug toxicity may limit its use. Recent evidence suggests that it is necessary to take into account the individual characteristics of methotrexate pharmacokinetics, which are determined by the presence of polymorphisms of genes encoding methotrexate carrier proteins, to predict the risk of methotrexate-induced toxicity.
Goal:
To identify associations of ABCB1 rs1045642 polymorphism with methotrexate safety in patients with psoriasis.
Materials and methods:
The study included 75 patients diagnosed with psoriasis who received methotrexate. Data on adverse drug reactions were collected using a clinically structured questionnaire, complete and biochemical blood tests, and urinalysis. The severity of adverse drug reactions was assessed using visual analog scales and the CTCAE toxicity scale. The severity of gastrointestinal ADR was assessed using the GSRS questionnaire. Genotyping was carried out by real-time PCR.
Results:
Gastrointestinal toxicity was detected in 38 patients (50.67%). The mean GSRS score was 7.979.18. Analysis of differences in the incidence of adverse drug reactions showed the presence of statistically significant differences in the frequency of adverse drug reactions in the gastrointestinal tract: the toxic effect of methotrexate was more often observed in carriers of the T allele of the ABCB1 rs1045642 polymorphism (3435CT), (CC - 2 (14.3%), TC - 18 (52.9%), TT - 18 (66.7%), p=0.006). Binomial regression demonstrated the presence of a statistically significant effect of the rs1045642 polymorphism of the ABCB1 gene on the incidence of ADR from the gastrointestinal tract: estimation -2.16, OR = 8.64, 95% CI OR: 1.78 - 42.01, p -value = 0.008.
Conclusion:
An association of ABCB1 rs1045642 polymorphism with the safety of gastrointestinal methotrexate therapy in patients with moderate and severe forms of psoriasis was revealed. The data obtained can be used to personalize the prescription of methotrexate to patients with psoriasis.
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Sharma P, Singh N, Sharma S. Impact of ABCB1, ABCC1, ABCC2, and ABCG2 variants in predicting prognosis and clinical outcomes of north Indian lung cancer patients undergoing platinum-based doublet chemotherapy. J Gene Med 2023; 25:e3460. [PMID: 36314103 DOI: 10.1002/jgm.3460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 09/12/2022] [Accepted: 10/23/2022] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND ABC transporters are membrane proteins expressed in the lungs and are crucial for efflux of various chemotherapeutic agents. Polymorphisms of ABC transporters have a certain impact on the transporter activity because their expression levels may influence the extent and longevity of chemotherapeutic drug outflow, affecting patient outcomes. The present study aimed to assess the impact of ABCB1, ABCC1/2, and ABCG2 gene variants in predicting prognosis and clinical outcomes in lung carcinoma patients. METHODS In total, 502 lung cancer patients undergoing platinum-based chemotherapy were recruited in this prospective study. Genotyping of ABCB1 (C1236 T, C3435 T, and G2677 T/A), ABCC1 (G3173 A and G2168 A), ABCC2 (G4544 A), and ABCG2 (C421 A) polymorphisms in Northern Indian lung carcinoma patients were evaluated using polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS Poor survival outcomes were noted in patients carrying a heterozygous genotype (CT) for the ABCB1 C1236 T polymorphism compared to the wild-type genotype (CC) (p = 0.04). The mutant genotype (AA) for ABCC1 G3173 A exhibited a lower median survival time compared to the reference genotype (GG) (p = 0.009). Lower survival was observed in individuals carrying a heterozygous genotype (GA) for ABCC2 G4544 A polymorphism compared to the wild-type genotype (GG) (p = 0.017). Small cell lung cancer patients with the ABCB1 G2677 A polymorphism having a heterozygous genotype (GA) showed poor survival compared to the wild-type genotype (GG) (p = 0.03). For ABCC1 G3173 A, adenocarcinoma patients having a mutant genotype (AA) had reduced survival compared to the wild-type (GG) genotype (p = 0.03). For ABCB1 C3435 T, individuals carrying a heterozygous (CT) (p = 0.018) and mutant (TT) genotype (p = 0.007) had poor survival compared to the wild-type (CC) genotype in patients treated with pemetrexed and cisplatin. The patients administered cisplatin and irinotecan and having mutant alleles (AA) for the ABCB1 G2677 A polymorphism showed a lower survival compared to the individuals carrying wild-type alleles (GG) (p = 0.009). CONCLUSIONS Our findings suggest that ABCB1 C1236 T, ABCB1 C3435 T, ABCB1 G2677 A, ABCC1 G3173 A, and ABCC2 G4544 A are involved in predicting prognosis. Genotyping of the ABC polymorphism is essential for predicting prognosis in lung carcinoma patients.
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Affiliation(s)
- Parul Sharma
- Department of Biotechnology, Thapar Institute of Engineering & Technology, Patiala, India
| | - Navneet Singh
- Department of Pulmonary Medicine, Post Graduate Institute of Medical Education & Research, Chandigarh, India
| | - Siddharth Sharma
- Department of Biotechnology, Thapar Institute of Engineering & Technology, Patiala, India
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Annisa N, Barliana MI, Santoso P, Ruslami R. Transporter and metabolizer gene polymorphisms affect fluoroquinolone pharmacokinetic parameters. Front Pharmacol 2022; 13:1063413. [PMID: 36588725 PMCID: PMC9798452 DOI: 10.3389/fphar.2022.1063413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 11/28/2022] [Indexed: 12/14/2022] Open
Abstract
Tuberculosis (TB) is an infectious disease that occurs globally. Treatment of TB has been hindered by problems with multidrug-resistant strains (MDR-TB). Fluoroquinolones are one of the main drugs used for the treatment of MDR-TB. The success of therapy can be influenced by genetic factors and their impact on pharmacokinetic parameters. This review was conducted by searching the PubMed database with keywords polymorphism and fluoroquinolones. The presence of gene polymorphisms, including UGT1A1, UGT1A9, SLCO1B1, and ABCB1, can affect fluoroquinolones pharmacokinetic parameters such as area under the curve (AUC), creatinine clearance (CCr), maximum plasma concentration (Cmax), half-life (t1/2) and peak time (tmax) of fluoroquinolones.
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Affiliation(s)
- Nurul Annisa
- Department of Biological Pharmacy, Biotechnology Pharmacy Laboratory, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang, Indonesia,Unit of Clinical Pharmacy and Community, Faculty of Pharmacy, Universitas Mulawarman, Samarinda, Indonesia
| | - Melisa I. Barliana
- Department of Biological Pharmacy, Biotechnology Pharmacy Laboratory, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang, Indonesia,Center of Excellence for Pharmaceutical Care Innovation, Universitas Padjadjaran, Sumedang, Indonesia,*Correspondence: Melisa I. Barliana,
| | - Prayudi Santoso
- Division of Respirology and Critical Care, Department of Internal Medicine, Faculty of Medicine, Universitas Padjadjaran-Hasan Sadikin Hospital, Bandung, Indonesia
| | - Rovina Ruslami
- Division of Pharmacology and Therapy, Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia
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Daikohara K, Akanuma SI, Kubo Y, Hosoya KI. Lipopolysaccharide-Induced Functional Alteration of P-glycoprotein in the Ex Vivo Rat Inner Blood-Retinal Barrier. Int J Mol Sci 2022; 23:ijms232415504. [PMID: 36555148 PMCID: PMC9779076 DOI: 10.3390/ijms232415504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 12/02/2022] [Accepted: 12/03/2022] [Indexed: 12/13/2022] Open
Abstract
At the inner blood-retinal barrier (BRB), P-glycoprotein (P-gp) contributes to maintaining the homeostasis of substance concentration in the retina by transporting drugs and exogenous toxins from the retina to the circulating blood. Under inflammatory conditions, P-gp activities have been reported to be altered in various tissues. The purpose of this study was to clarify the alterations in P-gp activity at the inner BRB due to lipopolysaccharide (LPS), an inflammatory agent, and the molecular mechanisms of the alterations induced by LPS. Ex vivo P-gp activity was evaluated as luminal accumulation of 7-nitro-2,1,3-benzoxadiazole-cyclosporin A (NBD-CSA), a fluorescent P-gp substrate, in freshly prepared rat retinal capillaries. The luminal NBD-CSA accumulation was significantly decreased in the presence of LPS, indicating that P-gp activity at the inner BRB is reduced by LPS. This LPS-induced attenuation of the luminal NBD-CSA accumulation was abolished by inhibiting toll-like receptor 4 (TLR4), a receptor for LPS. Furthermore, an inhibitor/antagonist of tumor necrosis factor receptor 1, endothelin B receptor, nitric oxide synthase, or protein kinase C (PKC) significantly restored the LPS-induced decrease in the luminal NBD-CSA accumulation. Consequently, it is suggested that the TLR4/PKC pathway is involved in the reduction in P-gp function in the inner BRB by LPS.
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Affiliation(s)
- Kiyotaka Daikohara
- Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
| | - Shin-ichi Akanuma
- Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
- Correspondence: ; Tel.: +81-76-434-7508
| | - Yoshiyuki Kubo
- Laboratory of Drug Disposition and Pharmacokinetics, Faculty of Pharma-Sciences, Teikyo University, Kaga 2-11-1, Tokyo 173-8605, Japan
| | - Ken-ichi Hosoya
- Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
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Assessment of Aging-Related Function Variations of P-gp Transporter in Old-Elderly Chinese CHF Patients Based on Modeling and Simulation. Clin Pharmacokinet 2022; 61:1789-1800. [PMID: 36378486 DOI: 10.1007/s40262-022-01184-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/21/2022] [Indexed: 11/16/2022]
Abstract
BACKGROUND AND OBJECTIVES P-glycoprotein (P-gp) is one of the most intensely studied transporters owing to its broad tissue distribution and substrate specificity. Existing research suggests that the risk of systemic exposure to dabigatran etexilate (DABE) and digoxin, two P-gp probe substrates in vivo, has significantly increased in elderly patients. We applied a model-based quantitative pharmacological approach to assess aging-related P-gp changes in the Chinese old-elderly population. METHODS Population pharmacokinetic (PopPK) modeling was first performed using clinical pharmacokinetic data to explore the effect of age on the pharmacokinetic characteristics of dabigatran (DAB, the active principle of DABE) and digoxin in elderly Chinese patients. Corresponding physiologically based pharmacokinetic (PBPK) models were established to further explain the elevated systemic exposure to these two drugs. Eventually, standard dosing regimens of DABE and digoxin were assessed in Chinese old-elderly patients with chronic heart failure (CHF) with different stages of renal impairment. RESULTS PopPK analysis suggested that age as a covariate had an additional effect on the apparent clearance of these two drugs after correcting for creatinine clearance. PBPK simulation results suggested that disease-specific pathophysiological changes could explain DAB exposure in the young elderly. In the elderly population, 17.1% of elevated DAB exposure remained unexplained, and 25.5% of the reduced P-gp function associated with aging was ultimately obtained using sensitivity analysis. This value was further validated using digoxin data obtained by PBPK modeling. The simulation results suggest that CHF patients with advanced age and moderate-to-severe renal impairment require heightened vigilance for elevated exposure risk during the use of DABE and digoxin. CONCLUSIONS Aging might be a significant risk factor for elevated systemic exposure to DAB and digoxin by reducing P-gp-mediated efflux in the Chinese old elderly population.
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Influence of ABCB1, CYP3A5 and CYP3A4 gene polymorphisms on prothrombin time and the residual equilibrium concentration of rivaroxaban in patients with non-valvular atrial fibrillation in real clinical practice. Pharmacogenet Genomics 2022; 32:301-307. [PMID: 36256705 DOI: 10.1097/fpc.0000000000000483] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE The study of ABCB1 and CYP3A4/3A5 gene polymorphism genes is promising in terms of their influence on prothrombin time variability, the residual equilibrium concentration of direct oral anticoagulants (DOACs) in patients with atrial fibrillation and the development of new personalized approaches to anticoagulation therapy in these patients. The aim of the study is to evaluate the effect of ABCB1 (rs1045642) C>T; ABCB1 (rs4148738) C>T and CYP3A5 (rs776746) A>G, CYP3A4*22(rs35599367) C>T gene polymorphisms on prothrombin time level and residual equilibrium concentration of rivaroxaban in patients with atrial fibrillation. METHODS In total 86 patients (42 men and 44 female), aged 67.24 ± 1.01 years with atrial fibrillation were enrolled in the study. HPLC mass spectrometry analysis was used to determine rivaroxaban residual equilibrium concentration. Prothrombin time data were obtained from patient records. RESULTS The residual equilibrium concentration of rivaroxaban in patients with ABCB1 rs4148738 CT genotype is significantly higher than in patients with ABCB1 rs4148738 CC (P = 0.039). The analysis of the combination of genotypes did not find a statistically significant role of combinations of alleles of several polymorphic markers in increasing the risk of hemorrhagic complications when taking rivaroxaban. CONCLUSION Patients with ABCB1 rs4148738 CT genotype have a statistically significantly higher residual equilibrium concentration of rivaroxaban in blood than patients with ABCB1 rs4148738 CC genotype, which should be considered when assessing the risk of hemorrhagic complications and risk of drug-drug interactions. Further studies of the effect of rivaroxaban pharmacogenetics on the safety profile and efficacy of therapy are needed.
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Chen Y, Wang P, Zhang Y, Du XY, Zhang YJ. Comparison of effects of aminosalicylic acid, glucocorticoids and immunosuppressive agents on the expression of multidrug-resistant genes in ulcerative colitis. Sci Rep 2022; 12:20656. [PMID: 36450761 PMCID: PMC9712546 DOI: 10.1038/s41598-022-19612-8] [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: 01/15/2022] [Accepted: 08/31/2022] [Indexed: 12/05/2022] Open
Abstract
To compare the effects of aminosalicylic acid, glucocorticoids and immunosuppressants on the expression levels of multidrug resistance genes in patients with ulcerative colitis (UC), with the aim of providing a theoretical and therapeutic basis for the diagnosis, treatment, and prevention of UC. Fresh colonic mucosal tissues or postoperative pathological biopsies from 148 UC patients were collected, and the distribution sites and morphology of P-glycoprotein (P-gp) were detected using immunohistochemical staining. RT-PCR was used to quantify the expression levels of multidrug resistance gene (MDR1) mRNA before and after the corresponding treatment, and the effects of aminosalicylic acid, glucocorticoids and immunosuppressive drugs on P-gp were compared. In addition, the effects of the three drugs on MDR1 mRNA were analyzed. Administration of 5-aminosalicylic acid (5-ASA) drugs did not correlate with MDR1 expression in UC, whereas administration of glucocorticoids and immunosuppressive drugs was positively correlated with MDR1 expression profile. The expression levels of MDR1 mRNA and its product P-gp were significantly upregulated in patients who did not respond to glucocorticoids and immunosuppressive drugs. 5-ASA had no effect on the expression levels of MDR1 and its product P-gp in patients with a confirmed diagnosis of UC. However, the use of glucocorticoids and immunosuppressants can increase the expression level of MDR1.
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Affiliation(s)
- Yan Chen
- grid.453074.10000 0000 9797 0900Department of Gastroenterology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, No. 24 Jinghua Road, Luoyang, 471003 Henan China
| | - Ping Wang
- grid.453074.10000 0000 9797 0900Department of Public Health, School of Medicine, Henan University of Science and Technology, Luoyang, 471003 Henan China
| | - Yin Zhang
- grid.453074.10000 0000 9797 0900Department of Gastroenterology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, No. 24 Jinghua Road, Luoyang, 471003 Henan China
| | - Xiao-Yu Du
- grid.453074.10000 0000 9797 0900Department of Gastroenterology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, No. 24 Jinghua Road, Luoyang, 471003 Henan China
| | - Ying-Jian Zhang
- grid.453074.10000 0000 9797 0900Department of Gastroenterology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, No. 24 Jinghua Road, Luoyang, 471003 Henan China
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Mishra A, Oliinyk P, Lysiuk R, Lenchyk L, Rathod SSS, Antonyak H, Darmohray R, Dub N, Antoniv O, Tsal O, Upyr T. Flavonoids and stilbenoids as a promising arsenal for the management of chronic arsenic toxicity. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2022; 95:103970. [PMID: 36067934 DOI: 10.1016/j.etap.2022.103970] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 08/29/2022] [Accepted: 09/01/2022] [Indexed: 06/15/2023]
Abstract
Rapid industrial and technological development has impacted ecosystem homeostasis strongly. Arsenic is one of the most detrimental environmental toxins and its management with chelating agents remains a matter of concern due to associated adverse effects. Thus, safer and more effective alternative therapy is required to manage arsenic toxicity. Based on existing evidence, native and indigenous plant-based active biomolecules appear as a promising strategy to mitigate arsenic-induced toxicity with an acceptable safety profile. In this regard, various phytochemicals (flavonoids and stilbenoids) are considered important classes of polyphenolic compounds with antioxidant and chelation effects, which may facilitate the removal of arsenic from the body more effectively and safely with regard to conventional approaches. This review presents an overview of conventional chelating agents and the potential role of flavonoids and stilbenoids in ameliorating arsenic toxicity. This report may provide a roadmap for identifying novel prophylactic/therapeutic strategies for managing arsenic toxicity.
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Affiliation(s)
- Awanish Mishra
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER) - Guwahati, Changsari, Kamrup, Assam 781101, India.
| | - Petro Oliinyk
- Danylo Halytsky Lviv National Medical University, Lviv, Ukraine.
| | - Roman Lysiuk
- Danylo Halytsky Lviv National Medical University, Lviv, Ukraine.
| | | | - Suraj Singh S Rathod
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara 144411, India.
| | | | - Roman Darmohray
- Danylo Halytsky Lviv National Medical University, Lviv, Ukraine.
| | - Natalia Dub
- Andrei Krupynskyi Lviv Medical Academy, Lviv, Ukraine.
| | - Olha Antoniv
- Danylo Halytsky Lviv National Medical University, Lviv, Ukraine.
| | - Oksana Tsal
- Danylo Halytsky Lviv National Medical University, Lviv, Ukraine.
| | - Taras Upyr
- National University of Pharmacy, Kharkiv, Ukraine.
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Yamasaki Y, Moriwaki T, Ogata S, Ito S, Ohtsuki S, Minegishi G, Abe S, Ohta Y, Kazuki K, Kobayashi K, Kazuki Y. Influence of MDR1 gene polymorphism (2677G>T) on expression and function of P-glycoprotein at the blood-brain barrier: utilizing novel P-glycoprotein humanized mice with mutation. Pharmacogenet Genomics 2022; 32:288-292. [PMID: 35997049 DOI: 10.1097/fpc.0000000000000481] [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: 11/26/2022]
Abstract
P-glycoprotein, the encoded product of the MDR1 / ABCB1 gene in humans, is expressed in numerous tissues including brain capillary endothelial cells and restricts the distribution of xenobiotics into the brain as an efflux pump. Although a large number of single nucleotide polymorphisms in the MDR1 gene have been identified, the influence of the nonsynonymous 2677G>T/A single nucleotide polymorphism on P-glycoprotein at the blood-brain barrier has remained unclear. In the present study, we developed a novel P-glycoprotein humanized mouse line carrying the 2677G>T mutation by utilizing a mouse artificial chromosome vector constructed by genetic engineering technology and we evaluated the influence of 2677G>T on the expression and function of P-glycoprotein at the blood-brain barrier in vivo . The results of this study showed that the introduction of the 2677G>T mutation does not alter the expression levels of P-glycoprotein protein in the brain capillary fraction. On the other hand, the brain penetration of verapamil, a representative substrate of P-glycoprotein, was increased by the introduction of the 2677G>T mutation. These results suggested that the 2677G>T single nucleotide polymorphism may attenuate the function of P-glycoprotein, resulting in increased brain penetration of P-glycoprotein substrates, without altering the expression levels of P-glycoprotein protein in the blood-brain barrier. This mutant mouse line is a useful model for elucidating the influence of an MDR1 gene single nucleotide polymorphism on the expression and function of P-glycoprotein at the blood-brain barrier.
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Affiliation(s)
- Yuki Yamasaki
- Graduate School of Pharmaceutical Sciences, Chiba University, Chiba
| | - Takashi Moriwaki
- Department of Chromosome Biomedical Engineering, School of Life Science, Faculty of Medicine, Tottori University
| | - Seiryo Ogata
- Graduate School of Pharmaceutical Sciences, Kumamoto University
| | - Shingo Ito
- Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto
| | - Sumio Ohtsuki
- Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto
| | - Genki Minegishi
- Graduate School of Pharmaceutical Sciences, Chiba University, Chiba
- Department of Biopharmaceutics, Graduate School of Clinical Pharmacy, Meiji Pharmaceutical University, Tokyo
| | - Satoshi Abe
- Chromosome Engineering Research Center, Tottori University, Tottori, Japan
| | - Yumi Ohta
- Department of Chromosome Biomedical Engineering, School of Life Science, Faculty of Medicine, Tottori University
| | - Kanako Kazuki
- Chromosome Engineering Research Center, Tottori University, Tottori, Japan
| | - Kaoru Kobayashi
- Graduate School of Pharmaceutical Sciences, Chiba University, Chiba
- Department of Biopharmaceutics, Graduate School of Clinical Pharmacy, Meiji Pharmaceutical University, Tokyo
| | - Yasuhiro Kazuki
- Department of Chromosome Biomedical Engineering, School of Life Science, Faculty of Medicine, Tottori University
- Chromosome Engineering Research Center, Tottori University, Tottori, Japan
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Yao N, Huang S, Huang A, Song H. Analysis of influencing factors on monohydroxylated derivative of oxcarbazepine plasma concentration in children with epilepsy. Eur J Clin Pharmacol 2022; 78:1667-1675. [PMID: 36006433 DOI: 10.1007/s00228-022-03373-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 08/12/2022] [Indexed: 11/26/2022]
Abstract
PURPOSE This study aimed to investigate the factors affecting the plasma concentration of monohydroxylated derivative (MHD) of oxcarbazepine (OXC) in children with epilepsy. METHODS We recruited 125 children with epilepsy who received OXC monotherapy. Among them, 16 single nucleotide polymorphisms were detected by MassARRAY genotyping technology to evaluate the influence of related factors on the plasma concentration of OXC monotherapy. MHD is the main active metabolite of OXC, and its plasma concentration was measured by high-performance liquid chromatography (HPLC). RESULTS Bivariate correlation analysis revealed that concentration-dose ratio (CDR) increased with weight, and the corresponding maintenance dose decreased with weight (r=0.317, P=0.001 for CDR; r=-0.285, P=0.000 for OXC maintenance dose). The duration of seizure was found to be associated with CDR (0.90 ± 0.36 vs 0.74 ± 0.26 μg·kg/mg/mL for ≥6 years vs <1 year, P=0.028; 0.90 ± 0.36 vs 0.64 ± 0.21 μg·kg/mg/mL for ≥6 years vs 1-3 years, P=0.004; 0.90 ± 0.36 vs 0.69 ± 0.18 μg·kg/mg/mL for ≥6 years vs 3-6 years, P=0.031). The CDR of patients with ABCB1 rs1045642 mutation homozygous GG type is higher than heterozygous AG type (0.79 ± 0.30 vs 0.68 ± 0.20 μg·kg/mg/mL for AG vs GG, P=0.032). CONCLUSION This study clarified the association of weight, duration of seizure, and gene polymorphisms of ABCB1 rs1045642 with MHD plasma concentration in children with epilepsy.
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Affiliation(s)
- Nannan Yao
- Department of Pharmacy, 900TH Hospital of Joint Logistics Support Force, Fuzhou, China
| | - Shan Huang
- Department of Pharmacy, 900TH Hospital of Joint Logistics Support Force, Fuzhou, China
| | - Aiwen Huang
- Department of Pharmacy, 900TH Hospital of Joint Logistics Support Force, Fuzhou, China.
| | - Hongtao Song
- Department of Pharmacy, 900TH Hospital of Joint Logistics Support Force, Fuzhou, China.
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Bisht P, Kumar VU, Pandey R, Velayutham R, Kumar N. Role of PARP Inhibitors in Glioblastoma and Perceiving Challenges as Well as Strategies for Successful Clinical Development. Front Pharmacol 2022; 13:939570. [PMID: 35873570 PMCID: PMC9297740 DOI: 10.3389/fphar.2022.939570] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 06/10/2022] [Indexed: 11/13/2022] Open
Abstract
Glioblastoma multiform is the most aggressive primary type of brain tumor, representing 54% of all gliomas. The average life span for glioblastoma multiform is around 14-15 months instead of treatment. The current treatment for glioblastoma multiform includes surgical removal of the tumor followed by radiation therapy and temozolomide chemotherapy for 6.5 months, followed by another 6 months of maintenance therapy with temozolomide chemotherapy (5 days every month). However, resistance to temozolomide is frequently one of the limiting factors in effective treatment. Poly (ADP-ribose) polymerase (PARP) inhibitors have recently been investigated as sensitizing drugs to enhance temozolomide potency. However, clinical use of PARP inhibitors in glioblastoma multiform is difficult due to a number of factors such as limited blood-brain barrier penetration of PARP inhibitors, inducing resistance due to frequent use of PARP inhibitors, and overlapping hematologic toxicities of PARP inhibitors when co-administered with glioblastoma multiform standard treatment (radiation therapy and temozolomide). This review elucidates the role of PARP inhibitors in temozolomide resistance, multiple factors that make development of these PARP inhibitor drugs challenging, and the strategies such as the development of targeted drug therapies and combination therapy to combat the resistance of PARP inhibitors that can be adopted to overcome these challenges.
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Affiliation(s)
- Priya Bisht
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER-Hajipur), Hajipur, India
| | - V. Udaya Kumar
- Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research (NIPER-Hajipur), Hajipur, India
| | - Ruchi Pandey
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER-Hajipur), Hajipur, India
| | - Ravichandiran Velayutham
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER-Hajipur), Hajipur, India
| | - Nitesh Kumar
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER-Hajipur), Hajipur, India
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Naz F, Malik A, Riaz M, Mahmood Q, Mehmood MH, Rasool G, Mahmood Z, Abbas M. Bromocriptine Therapy: Review of mechanism of action, safety and tolerability. Clin Exp Pharmacol Physiol 2022; 49:903-922. [DOI: 10.1111/1440-1681.13678] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 05/24/2022] [Accepted: 05/25/2022] [Indexed: 11/28/2022]
Affiliation(s)
- Faiza Naz
- Punjab University College of Pharmacy University of the Punjab Lahore Pakistan
| | - Abdul Malik
- College of Pharmacy University of Sargodha Sargodha Pakistan
| | - Muhammad Riaz
- Department of Allied Health Sciences University of Sargodha Sargodha Pakistan
| | - Qaisar Mahmood
- College of Pharmacy University of Sargodha Sargodha Pakistan
| | - Malik Hassan Mehmood
- Department of Pharmacology, Faculty of Pharmaceutical Sciences Government College University Faisalabad Pakistan
| | - Ghulam Rasool
- Department of Allied Health Sciences University of Sargodha Sargodha Pakistan
| | - Zahed Mahmood
- Department of Biochemistry Government College University Faisalabad Pakistan
| | - Mazhar Abbas
- Department of Biochemistry College of Veterinary and Animal Sciences, University of Veterinary and Animal Sciences (Jhang Campus) Lahore Pakistan
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Guerrero Camacho JL, Corona Vázquez T, Flores Rivera JJ, Ochoa Morales A, Martínez Ruano L, Torres Ramírez de Arellano I, Dávila Ortiz de Montellano DJ, Jara Prado A. ABCB1 gene variants as risk factors and modulators of age of onset of demyelinating disease in Mexican patients. NEUROLOGÍA (ENGLISH EDITION) 2022; 38:65-74. [PMID: 35256320 DOI: 10.1016/j.nrleng.2020.05.021] [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: 01/30/2020] [Accepted: 05/05/2020] [Indexed: 11/16/2022] Open
Abstract
INTRODUCTION The C1236T, G2677T/A, and C3435T variants of the ABCB1 gene alter the functioning of P-glycoprotein and the transport of endogenous and exogenous substances across the blood-brain barrier, and act as risk factors for some neurodegenerative diseases. This study aimed to determine the association between demyelinating disease and the C1236T, G2677T/A, and C3435T variants of ABCB1 and its haplotypes and combinations of genotypes. METHODS Polymerase chain reaction with restriction fragment length polymorphism analysis (PCR-RFLP) and Sanger sequencing were used to genotype 199 patients with demyelinating disease and 200 controls, all Mexicans of mixed race; frequencies of alleles, genotypes, haplotypes, and genotype combinations were compared between patients and controls. We conducted a logistic regression analysis and calculated chi-square values and 95% confidence intervals (CI); odds ratios (OR) were calculated to evaluate the association with demyelinating disease. RESULTS The TTT and CGC haplotypes were most frequent in both patients and controls. The G2677 allele was associated with demyelinating disease (OR: 1.79; 95% CI, 1.12-2.86; P = .015), as were the genotypes GG2677 (OR: 2.72; 95% CI, 1.11-6.68; P = .025) and CC3435 (OR: 1.82; 95% CI, 1.15-2.90; P = .010), the combination GG2677/CC3435 (OR: 2.02; 95% CI, 1.17-3.48; P = .010), and the CAT haplotype (OR: 0.21; 95% CI, 0.05-0.66; P = .001). TTTTTT carriers presented the earliest age of onset (23.0 ± 7.7 years, vs 31.6 ± 10.7; P = .0001). CONCLUSIONS The GG2677/CC3435 genotype combination is associated with demyelinating disease in this sample, particularly among men, who may present toxic accumulation of P-glycoprotein substrates. In our study, the G2677 allele of ABCB1 may differentially modulate age of onset of demyelinating disease in men and women.
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Affiliation(s)
- J L Guerrero Camacho
- Departamento de Genética, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, Mexico
| | - T Corona Vázquez
- Laboratorio Clínico de Enfermedades Neurodegenerativas, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, Mexico
| | - J J Flores Rivera
- Laboratorio Clínico de Enfermedades Neurodegenerativas, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, Mexico
| | - A Ochoa Morales
- Departamento de Genética, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, Mexico
| | - L Martínez Ruano
- Departamento de Genética, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, Mexico
| | - I Torres Ramírez de Arellano
- Departamento de Genética, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, Mexico
| | - D J Dávila Ortiz de Montellano
- Departamento de Genética, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, Mexico
| | - A Jara Prado
- Departamento de Genética, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, Mexico.
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Zhao W, Meng H. Effects of genetic polymorphism of drug-metabolizing enzymes on the plasma concentrations of antiepileptic drugs in Chinese population. Bioengineered 2022; 13:7709-7745. [PMID: 35290166 PMCID: PMC9278974 DOI: 10.1080/21655979.2022.2036916] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/24/2022] [Accepted: 01/26/2022] [Indexed: 11/02/2022] Open
Abstract
As a chronic brain disease, epilepsy affects ~50 million people worldwide. The traditional antiepileptic drugs (AEDs) are widely applied but showing various problems. Although the new AEDs have partially solved the problems of traditional AEDs, the current clinical application of traditional AEDs are not completely replaced by new drugs, particularly due to the large individual differences in drug plasma concentrations and narrow therapeutic windows among patients. Therefore, it is still clinically important to continue to treat patients using traditional AEDs with individualized therapeutic plans. To date, our understanding of the molecular and genetic mechanisms regulating plasma concentrations of AEDs has advanced rapidly, expanding the knowledge on the effects of genetic polymorphisms of genes encoding drug-metabolizing enzymes on the plasma concentrations of AEDs. It is increasingly imperative to summarize and conceptualize the clinical significance of recent studies on individualized therapeutic regimens. In this review, we extensively summarize the critical effects of genetic polymorphisms of genes encoding drug-metabolizing enzymes on the plasma concentrations of several commonly used AEDs as well as the clinical significance of testing genotypes related to drug metabolism on individualized drug dosage. Our review provides solid experimental evidence and clinical guidance for the therapeutic applications of these AEDs.
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Affiliation(s)
- Weixuan Zhao
- Department of Neurology, the First Hospital of Jilin University, Jilin University, Changchun, China
| | - Hongmei Meng
- Department of Neurology, the First Hospital of Jilin University, Jilin University, Changchun, China
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Bairova TA, Nemchinova NV, Belyaeva EV, Sambyalova AY, Ershova OA, Rychkova LV. The Prevalence of Polymorphic Variants of ABCB1 Gene among Indigenous Populations of Siberia. RUSS J GENET+ 2022. [DOI: 10.1134/s1022795421110028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Zhang J, Dong ZF, Bian CX, Zhang X, Xin XB, Chen F. The Correlation Between MDR1 Gene Polymorphism and Clopidogrel Resistance in People of the Hui and Han Nationalities. Clin Appl Thromb Hemost 2022; 28:10760296211073272. [PMID: 35068171 PMCID: PMC8793376 DOI: 10.1177/10760296211073272] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
To investigate the differences in the correlation between multidrug resistance protein 1 ( MDR1) ( ABCB1) gene polymorphism and clopidogrel resistance in patients of the Hui and Han nationalities with percutaneous coronary intervention (PCI). A total of 377 subjects (154 people of Hui nationality, 223 people of Han nationality) with PCI were enrolled in the study. Each patient's platelet aggregation rate was induced by adenosine diphosphate and measured using light turbidimetry. Based on the results, the patients were divided into two groups: a clopidogrel resistance (CR) group and a non-clopidogrel resistance (NCR) group. Restrictive fragment-length polymorphism polymerase chain reaction technology was then used to determine the genotype and alleles at two loci (C3435 T[rs1045642] and C1236 T[rs1128503]), calculate the frequencies of the genotype and alleles at these two loci, and conduct correlation analysis. The incidence rate of clopidogrel resistance was 23.4%, and the frequencies of the TT genotype and T allele at C3435 T for patients of both nationalities were significantly higher in the CR group than in the NCR group (P < 0.05). There were no significant differences between the two groups in genotype or allele frequency at C1236 T. There was a significant difference in the distribution of C1236 T polymorphism between the two nationalities (P < 0.05), but there was no significant difference between the two nationalities in C3435 T polymorphism. Patients with a T allele at MDR1 C3435 T are more likely to show clopidogrel resistance, and no significant differences were identified in C3435 T gene polymorphism between the two nationalities.
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Affiliation(s)
- Jing Zhang
- Yantai Yuhuangding Hospital Affiliated to Qingdao Medical University, Yantai, China
| | - Zhi-Feng Dong
- The First People’s Hospital of Yinchuan, Yinchuan, China
| | | | - Xuan Zhang
- Xi’An International Medical Centre, Xi’An, China
| | - Xiang-Bin Xin
- Zhangye People’s Hospital Affiliated to Hexi University, Zhangye, China
| | - Fang Chen
- The First People’s Hospital of Yinchuan, Yinchuan, China
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Melikoglu MA, Balkan E. Can we predict unresponsiveness to methotrexate in rheumatoid arthritis? A pharmacogenetic study. Inflammopharmacology 2022; 30:193-197. [PMID: 35043269 DOI: 10.1007/s10787-021-00921-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 12/27/2021] [Indexed: 11/05/2022]
Abstract
OBJECTIVE Methotrexate (MTX) is the anchor drug in the treatment of rheumatoid arthritis (RA) and the therapeutic response to MTX has been observed to vary widely among these patients. The aim of this study was to investigate ABCB1 gene (the multidrug resistant 1 gene; MDR1 gene) polymorphism in patients with RA and to evaluate the relation between MTX unresponsiveness and this polymorphism. METHODS Forty-five patients with RA administered MTX were included in this pharmacogenetic cross-sectional study. The gender, age, body mass index (BMI), rheumatoid factor (RF) positivity, anti-cyclic citrullinated peptide (anti-CCP) positivity, doses of MTX and glucocorticoids were recorded. In addition, initial and third month disease activity (DAS28, Simplified and Clinical Disease Activity Index; SDAI and CDAI) scores were evaluated. We also examined frequencies of two single-nucleotide polymorphisms (SNPs), G2677T and C3435T, within the gene encoding ABCB1. RESULTS 22 patient's responsive and 20 patients unresponsive to MTX were enrolled. Initial demographic and disease related factors were similar between patients responsive or nonresponsive to MTX. In the third month evaluation, disease activity scores were significantly higher in patients unresponsive to MTX (p < 0.05). In addition, almost all patients unresponsive to MTX (19 of the 20 patients) presented heterozygosity in C3435T (p < 0.000). CONCLUSION We determined heterozygosity in C3435T SNP of ABCB1 gene (multidrug resistant 1 gene) in almost all patients with RA who were non-responders to MTX. This result may contribute to predict unresponsiveness to MTX in RA. Individualized treatment strategies based on the pharmacogenetic characteristics of MTX may lead to optimization of the treatment.
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Affiliation(s)
- Meltem Alkan Melikoglu
- Rheumatology Department, Ataturk University School of Medicine, Faculty of Medicine, Physical Medicine and Rehabilitation, Ataturk University, Ataturk University Campus, 25050, Erzurum, Turkey.
| | - Eda Balkan
- Faculty of Medicine, Medical Biology, Ataturk University, Erzurum, Turkey
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Rodeiro Guerra I, Herrea J, Cuétara E, Garrido G, Reyes E, Martínez I, Pérez CL, Fernández G, Hernández-Balmaseda I, Delgado R, Stingl JC, Berghe WV. Prevalence of ABCB1 3435C>T polymorphism in the Cuban population. Drug Metab Pers Ther 2021; 37:141-148. [PMID: 34860473 DOI: 10.1515/dmpt-2020-0156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 09/15/2021] [Indexed: 01/18/2023]
Abstract
OBJECTIVES ABCB1 gene polymorphisms can modify P-glycoprotein function with clinical consequences. METHODS The 3435C>T polymorphism prevalence was analyzed using oligonucleotide probes and next-generation sequencing in 421 unrelated healthy individuals living in Cuba. Data were stratified by gender, ethnic background and residence. The genotype and allelic frequencies were determined. RESULTS The genotype distribution met the Hardy-Weinberg equilibrium assumption. The allelic frequency was 63.5% for the 3435C variant. The genotype frequencies were 41.1% for CC, 44.9% for CT and 14.0% for TT. The allele and genotype distributions differed between individuals living in La Habana and Santiago de Cuba (p<0.05) when ethnic background was analyzed. The allelic distribution was similar among Admixed and Black subjects, and they differed from Caucasians. The CC genotype was equally distributed among Admixed and Black subjects, and they differed from Caucasians. The TT genotype frequency differed between Caucasians and Admixed. The CT genotype was distributed differently among the three groups. Similar distribution was obtained in Brazilians, whereas some similarities were observed in African, Spanish and Chinese populations, consistent with the mixed Cuban ethnic origin. CONCLUSIONS This is the first report on allele and genotype frequencies of the 3435C>T polymorphism in Cuba, which may support personalized medicine programs.
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Affiliation(s)
- Idania Rodeiro Guerra
- Departamento de Farmacología, Instituto de Ciencias del Mar (ICIMAR), La Habana, Cuba
| | - Jose Herrea
- Instituto de Ciencia y Tecnología de Materiales, IMRE, Universidad de La Habana, La Habana, Cuba
| | - Elizabeth Cuétara
- Departamento de Farmacología, Instituto Nacional de Oncología y Radiobiología (INOR), La Habana, Cuba
| | - Gabino Garrido
- Departamento de Ciencias Farmacéuticas, Facultad de Ciencias, Universidad de Católica del Norte, Antofagasta, Chile
| | - Elizabeth Reyes
- Departamento de Farmacología, Instituto Nacional de Oncología y Radiobiología (INOR), La Habana, Cuba
| | - Ioanna Martínez
- Instituto de Ciencias Básicas y Preclínicas Victoria de Girón (ICBP), Universidad de Ciencias Médicas de La Habana (UCMH), La Habana, Cuba
| | - Carlos L Pérez
- Instituto de Ciencias Básicas y Preclínicas Victoria de Girón (ICBP), Universidad de Ciencias Médicas de La Habana (UCMH), La Habana, Cuba
| | - Gisselle Fernández
- Instituto de Ciencias Básicas y Preclínicas Victoria de Girón (ICBP), Universidad de Ciencias Médicas de La Habana (UCMH), La Habana, Cuba
| | | | - René Delgado
- Instituto de Farmacia y Alimentos (IFAL), Universidad de La Habana, La Habana, Cuba.,Facultad de Ciencias Naturales y Agropecuarias, Universidad de Santander (UDES), Bucaramanga, Colombia
| | - Julia C Stingl
- Institute of Clinical Pharmacology, University Hospital of RWTH Aachen, Aachen, Germany
| | - Wim Vanden Berghe
- Laboratory of Protein Science, Proteomics and Epigenetic Signaling (PPES), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium
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van Eerden RAG, van Doorn L, de Man FM, Heersche N, Doukas M, van den Bosch TPP, Oomen-de Hoop E, de Bruijn P, Bins S, Ibrahim E, Nikkessen S, Friberg LE, Koolen SLW, Spaander MCW, Mathijssen RHJ. Tissue Type Differences in ABCB1 Expression and Paclitaxel Tissue Pharmacokinetics in Patients With Esophageal Cancer. Front Pharmacol 2021; 12:759146. [PMID: 34858183 PMCID: PMC8632367 DOI: 10.3389/fphar.2021.759146] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Accepted: 10/28/2021] [Indexed: 12/27/2022] Open
Abstract
Background: Data from previous work suggests that there is no correlation between systemic (plasma) paclitaxel exposure and efficacy in patients treated for esophageal cancer. In this trial, we investigated ATP-binding cassette efflux transporter expression and intratumoral pharmacokinetics of paclitaxel to identify changes which could be a first sign of chemoresistance. Methods: Patients with esophageal cancer treated with paclitaxel and carboplatin (± concomitant radiotherapy) were included. During the first and last cycle of weekly paclitaxel, blood samples and biopsies of esophageal mucosa and tumor tissue were taken. Changes in paclitaxel exposure and expression of ABCB1 (P-glycoprotein) over time were studied in both tumor tissue and normal appearing esophageal mucosa. Results: ABCB1 was significantly higher expressed in tumor tissue compared to esophageal tissue, during both the first and last cycle of paclitaxel (cycle 1: p < 0.01; cycle 5/6: p = 0.01). Interestingly, ABCB1 expression was significantly higher in adenocarcinoma than in squamous cell carcinoma (p < 0.01). During the first cycle, a trend towards a higher intratumoral paclitaxel concentration was observed compared to the esophageal mucosa concentration (RD:43%; 95%CI: −3% to 111% p = 0.07). Intratumoral and plasma paclitaxel concentrations were significantly correlated during the first cycle (AUC0–48 h: r = 0.72; p < 0.01). Conclusion: Higher ABCB1 expression in tumor tissue, and differences between histological tumor types might partly explain why tumors respond differently to systemic treatment. Resistance by altered intratumoral paclitaxel concentrations could not be demonstrated because the majority of the biopsies taken at the last cycle of paclitaxel did contain a low amount of tumor cells or no tumor.
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Affiliation(s)
- Ruben A G van Eerden
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, Netherlands
| | - Leni van Doorn
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, Netherlands
| | - Femke M de Man
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, Netherlands
| | - Niels Heersche
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, Netherlands
| | - Michail Doukas
- Department of Pathology, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands
| | | | - Esther Oomen-de Hoop
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, Netherlands
| | - Peter de Bruijn
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, Netherlands
| | - Sander Bins
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, Netherlands
| | - Eman Ibrahim
- Department of Pharmacy, Uppsala University, Uppsala, Sweden
| | - Suzan Nikkessen
- Department of Gastroenterology and Hepatology Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Lena E Friberg
- Department of Pharmacy, Uppsala University, Uppsala, Sweden
| | - Stijn L W Koolen
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, Netherlands.,Department of Pharmacy, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Manon C W Spaander
- Department of Gastroenterology and Hepatology Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Ron H J Mathijssen
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, Netherlands
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Foley SE, Loew EB, McCormick BA. Recent advances in understanding microbial regulation of host multi-drug resistance transporters. CURRENT OPINION IN PHYSIOLOGY 2021. [DOI: 10.1016/j.cophys.2021.100469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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Petryszyn P, Dudkowiak R, Gruca A, Jaźwińska-Tarnawska E, Ekk-Cierniakowski P, Poniewierka E, Wiela-Hojeńska A, Głowacka K. C3435T Polymorphism of the ABCB1 Gene in Polish Patients with Inflammatory Bowel Disease: A Case-Control and Meta-Analysis Study. Genes (Basel) 2021; 12:genes12091419. [PMID: 34573401 PMCID: PMC8465101 DOI: 10.3390/genes12091419] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 09/05/2021] [Accepted: 09/11/2021] [Indexed: 12/30/2022] Open
Abstract
P-glycoprotein encoded by the ABCB1 gene constitutes a molecular barrier in the small and large bowel epithelium, and its different expression may influence susceptibility to inflammatory bowel disease (IBD). We aimed to assess the contribution of the C3435T polymorphism to disease risk in the Polish population. A total of 100 patients (50 Crohn's disease (CD), 50 ulcerative colitis (UC)) and 100 healthy controls were genotyped for the single nucleotide polymorphism (SNP) C3435T by using the PCR-RFLP method. Patients were classified on the basis of disease phenotype and the specific treatment used. A meta-analysis was carried out of our results and those from previously published Polish studies. There was no significant difference in allele and genotype frequencies in IBD patients compared with controls. For CD patients, a lower frequency of TT genotype in those with colonic disease, a lower frequency of T allele, and a higher frequency of C allele in those with luminal disease were observed, whereas for UC patients, a lower frequency of CT genotype was observed in those with left-sided colitis. A meta-analysis showed a tendency towards higher prevalence of CC genotype in UC cases. These results indicate that the C3435T variants may confer a risk for UC and influence disease behaviour.
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Affiliation(s)
- Paweł Petryszyn
- Department of Clinical Pharmacology, Wroclaw Medical University, 50-571 Wroclaw, Poland; (A.G.); (E.J.-T.); (A.W.-H.); (K.G.)
- Correspondence: ; Tel.: +48-717840601
| | - Robert Dudkowiak
- Department of Gastroenterology and Hepatology, Wroclaw Medical University, 50-571 Wroclaw, Poland; (R.D.); (E.P.)
| | - Agnieszka Gruca
- Department of Clinical Pharmacology, Wroclaw Medical University, 50-571 Wroclaw, Poland; (A.G.); (E.J.-T.); (A.W.-H.); (K.G.)
| | - Ewa Jaźwińska-Tarnawska
- Department of Clinical Pharmacology, Wroclaw Medical University, 50-571 Wroclaw, Poland; (A.G.); (E.J.-T.); (A.W.-H.); (K.G.)
| | | | - Elżbieta Poniewierka
- Department of Gastroenterology and Hepatology, Wroclaw Medical University, 50-571 Wroclaw, Poland; (R.D.); (E.P.)
| | - Anna Wiela-Hojeńska
- Department of Clinical Pharmacology, Wroclaw Medical University, 50-571 Wroclaw, Poland; (A.G.); (E.J.-T.); (A.W.-H.); (K.G.)
| | - Krystyna Głowacka
- Department of Clinical Pharmacology, Wroclaw Medical University, 50-571 Wroclaw, Poland; (A.G.); (E.J.-T.); (A.W.-H.); (K.G.)
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Gardouh AR, Srag El-Din ASG, Salem MSH, Moustafa Y, Gad S. Starch Nanoparticles for Enhancement of Oral Bioavailability of a Newly Synthesized Thienopyrimidine Derivative with Anti-Proliferative Activity Against Pancreatic Cancer. DRUG DESIGN DEVELOPMENT AND THERAPY 2021; 15:3071-3093. [PMID: 34305395 PMCID: PMC8292977 DOI: 10.2147/dddt.s321962] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 07/08/2021] [Indexed: 01/02/2023]
Abstract
Purpose This research aimed to improve water solubility and oral bioavailability of a newly synthesized thienopyrimidine derivative (TPD) with anti-pancreatic cancer activity by loading on starch nanoparticles (SNPs). Methods TPD was synthesized, purified and its ADME behavior was predicted using Swiss ADME software. A UV spectroscopy method was developed and validated to measure TPD concentration at various dosage forms. SNPs loaded with TPD (SNPs-TPD) were prepared, characterized for particle size, polydispersity index, zeta potential, transmission electron microscopy, Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), entrapment efficiency, in-vitro release, and in-vivo animal study. Results The Swiss ADME results showed that TPD can be administered orally; however, it has low oral bioavailability (0.55) and poor water solubility. The significant regression coefficient of the calibration curve (r2 = 0.9995), the precision (%RSD < 0.5%) and the accuracy (99.46−101.72%) confirmed the efficacy of the developed UV method. SNPs-TPD had a spherical monodispersed (PDI= 0.12) shape, nanoparticle size (22.98 ± 4.23) and good stability (−21 ± 4.72 mV). Moreover, FT-IR and DSC revealed changes in the physicochemical structure of starch resulting in SNPs formation. The entrapment efficiency was 97% ± 0.45%, and the in-vitro release showed that the SNPs enhanced the solubility of the TPD. The in-vivo animal study and histopathology showed that SNPs enhanced the oral bioavailability of TPD against solid Ehrlich carcinoma. Conclusion SNPs-TPD were superior in drug solubility and oral bioavailability than those obtained from TPD suspension.
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Affiliation(s)
- Ahmed R Gardouh
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.,Department of Pharmaceutical Sciences, Faculty of Pharmacy, Jadara University, Irbid, 21110, Jordan
| | - Ahmed S G Srag El-Din
- Department of Pharmaceutics, Faculty of Pharmacy, Delta University for Science & Technology, Gamasa City, Egypt
| | - Mohamed S H Salem
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia, 41522, Egypt.,The Institute of Scientific and Industrial Research (ISIR), Osaka University, Ibaraki-shi, Osaka, 567-0047, Japan
| | - Yasser Moustafa
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.,Department of Pharmacology and Toxicology, Faculty of Pharmacy, Badr University in Cairo, Badr City, Cairo, Egypt
| | - Shadeed Gad
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt
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Shoily SS, Ahsan T, Fatema K, Sajib AA. Common genetic variants and pathways in diabetes and associated complications and vulnerability of populations with different ethnic origins. Sci Rep 2021; 11:7504. [PMID: 33820928 PMCID: PMC8021559 DOI: 10.1038/s41598-021-86801-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Accepted: 03/15/2021] [Indexed: 01/04/2023] Open
Abstract
Diabetes mellitus is a complex and heterogeneous metabolic disorder which is often pre- or post-existent with complications such as cardiovascular disease, hypertension, inflammation, chronic kidney disease, diabetic retino- and nephropathies. However, the frequencies of these co-morbidities vary among individuals and across populations. It is, therefore, not unlikely that certain genetic variants might commonly contribute to these conditions. Here, we identified four single nucleotide polymorphisms (rs5186, rs1800795, rs1799983 and rs1800629 in AGTR1, IL6, NOS3 and TNFA genes, respectively) to be commonly associated with each of these conditions. We explored their possible interplay in diabetes and associated complications. The variant allele and haplotype frequencies at these polymorphic loci vary among different super-populations (African, European, admixed Americans, South and East Asians). The variant alleles are particularly highly prevalent in different European and admixed American populations. Differential distribution of these variants in different ethnic groups suggests that certain drugs might be more effective in selective populations rather than all. Therefore, population specific genetic architectures should be considered before considering a drug for these conditions.
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Affiliation(s)
- Sabrina Samad Shoily
- Department of Genetic Engineering and Biotechnology, University of Dhaka, Dhaka, Bangladesh
| | - Tamim Ahsan
- Department of Genetic Engineering & Biotechnology, Bangabandhu Sheikh Mujibur Rahman Maritime University, Dhaka, Bangladesh
| | - Kaniz Fatema
- Department of Genetic Engineering and Biotechnology, University of Dhaka, Dhaka, Bangladesh
| | - Abu Ashfaqur Sajib
- Department of Genetic Engineering and Biotechnology, University of Dhaka, Dhaka, Bangladesh.
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Munisamy M, Munisamy S, Kumar JP, Jose A, Thomas L, Baburaj G, Subbiah V. Pharmacogenetics of ATP binding cassette transporter MDR1(1236C>T) gene polymorphism with glioma patients receiving Temozolomide-based chemoradiation therapy in Indian population. THE PHARMACOGENOMICS JOURNAL 2021; 21:262-272. [PMID: 33589792 DOI: 10.1038/s41397-021-00206-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 12/18/2020] [Accepted: 01/15/2021] [Indexed: 01/31/2023]
Abstract
Temozolomide (TMZ), an alkylating agent with a broad-spectrum antitumor activity, ability to cross blood-brain barrier (BBB), shown to be effective against malignant glioma. This study aims to investigate the effect of 1236C>T (rs1128503) single-nucleotide gene polymorphisms of ABCB1 (MDR1) in north-Indian patients diagnosed with glioma undergoing TMZ-based chemoradiotherapy. Genotyping was performed in 100 patients diagnosed with malignant glioma (50 anaplastic astrocytoma (AA) patients and 50 glioblastoma multiforme (GBM) patients) and 150 age and sex-matched controls by polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP) method, followed by sanger sequencing. TMZ plasma levels were analyzed by reverse phase HPLC method. Glioma patient's survival time was analyzed by Kaplan-Meier's curve. Results of MDR1 gene 1236C>T polymorphism showed significant allelic and genotypic frequency association between glioma patients and controls. The plasma TMZ levels between metabolizers group in Grade III and Grade IV were found to be statistically significant (p < 0.05). The mutant genotype (TT) has less survival benefit compared with other genotypes (CT/CC) and the survival difference between AA and GBM was found to be statistically significant (p < 0.05). Though CT and TT polymorphisms have significant association with lower TMZ levels in both Grade III (AA) and IV (GBM) tumors, the survival difference seems to be mainly among patients with Grade III tumors. Our findings suggest that the MDR1 gene polymorphism plays a role in plasma TMZ levels and in survival time of glioma patients and, hence, TMZ therapy in malignant glioma can be predicted by genotyping MDR1 (1236C>T) gene polymorphism.
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Affiliation(s)
- Murali Munisamy
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India.,Department of Neuro Biochemistry, Neuroscience Centre, All India Institute of Medical Sciences, New Delhi, India
| | - Srinivasan Munisamy
- Department of Neuro Biochemistry, Neuroscience Centre, All India Institute of Medical Sciences, New Delhi, India
| | - Julka Pramod Kumar
- Department of Radiotherapy, Dr. B.R.A Institute-Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | - Anmi Jose
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Levin Thomas
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Gayathri Baburaj
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Vivekanandhan Subbiah
- Department of Neuro Biochemistry, Neuroscience Centre, All India Institute of Medical Sciences, New Delhi, India.
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Elmagid DSA, Abdelsalam M, Magdy H, Tharwat N. The association between MDR1 C3435T genetic polymorphism and the risk of multidrug-resistant epilepsy in Egyptian children. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2021. [DOI: 10.1186/s43042-021-00152-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Epilepsy is a chronic disease affecting about 2% of the population and is considered a serious neurological disease. Despite its good prognosis, 20–30% of epileptic patients were not cured of their seizures even with the many trials of antiepileptic drug (AED) therapy. The resistance mechanism is still unclear, maybe due to the effect of the genetic factors on the bioavailability of the drugs. Consequently, the association between therapy resistance and the presence of a gene called “multidrug resistance 1 (MDR1)” had been proposed. Thus, the present study aimed to understand the relationship between the genetic polymorphism of MDR1C3435T and the resistance to AEDs.
Result
A non-significant association was found between MDR1 C3435T single-nucleotide polymorphism (SNP) and drug-resistant epilepsy. However, there was statistical significance in the association between the drug type and the genotype distribution, in cases that were maintained on sodium valproate and MDR1C3435T genotype.
Conclusion
Possible involvement of the MDR1 gene C 3435T polymorphism with sodium valproate resistance clarifies the importance of genetic variability in response to the drug and may help to find novel genetic therapy for epilepsy, by targeting the biological mechanisms responsible for epilepsy in each specific individual. Future studies with bigger sample sizes and in other racial populations will be necessary.
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Baba SM, Pandith AA, Shah ZA, Geelani SA, Mir MM, Bhat JR, Bhat GM. Impact of ABCB1 Gene (C3435T/A2677G) Polymorphic Sequence Variations on the Outcome of Patients with Chronic Myeloid Leukemia and Acute Lymphoblastic Leukemia in Kashmiri Population: A Case-Control Study. Indian J Hematol Blood Transfus 2021; 37:21-29. [PMID: 33707832 DOI: 10.1007/s12288-020-01289-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 05/06/2020] [Indexed: 11/30/2022] Open
Abstract
Inherited polymorphic sequence variations in drug transport genes like ABCB1 impact a portion of patients with hematologic malignancies that show intrinsic or acquire resistance to treatment. Keeping in view inter-individual sensitivities for such drugs, we through this case-control study tested whether ABCB1 C3435T and G2677T polymorphisms have any influence on the risk and treatment response in patients with chronic myeloid leukemia (CML) and B-acute lymphoblastic leukemia (B-ALL). Genotyping for ABCB1 polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism in 100 CML and 80 B-ALL patients along with 100 age and gender matched healthy controls. ABCB1 C3435T and G2677T polymorphism showed no association with CML. Genotype distribution revealed significant higher frequency of TT genotype for both SNPs in B-ALL cases and associated with increased B-ALL risk (OR 2.5, p = 0.04 for 3435TT; OR 2.4, p = 0.04 for 2677TT). There was no significant difference in genotype frequency of 3435C > T and 2677G > T among resistant and responsive groups for the two leukemia types. Kaplan-Meier survival plots revealed significantly lower event free survival in CML and B-ALL patients that were carriers of 3435TT genotype (p < 0.05). Multivariate analysis considered 3435TT genotype as independent risk factor for imatinib resistance in CML cases (HR 6.24, p = 0.002) and increased relapse risk in B-ALL patients (HR 4.51, p = 0.03). The current study provides preliminary evidence of a significant association between variant TT genotype and increased B-ALL risk. Also, results suggest that ABCB1 3435TT genotype increases imatinib resistance in CML and influence therapeutic outcome in B-ALL.
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Affiliation(s)
- Shahid M Baba
- Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, J&K 190011 India
| | - Arshad A Pandith
- Advanced Centre for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, J&K India
| | - Zafar A Shah
- Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, J&K 190011 India
| | - Sajad A Geelani
- Department of Clinical Hematology, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, J&K India
| | - Mohammad Muzaffar Mir
- Department of Basic Medical Sciences, College of Medicine, University of Bisha, Bisha, Kingdom of Saudi Arabia
| | - Javid Rasool Bhat
- Advanced Centre for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, J&K India
| | - Gul Mohammad Bhat
- Department of Medical Oncology, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, J&K India
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Janysek DC, Kim J, Duijf PHG, Dray E. Clinical use and mechanisms of resistance for PARP inhibitors in homologous recombination-deficient cancers. Transl Oncol 2021; 14:101012. [PMID: 33516088 PMCID: PMC7847957 DOI: 10.1016/j.tranon.2021.101012] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 12/14/2020] [Accepted: 12/31/2020] [Indexed: 12/11/2022] Open
Abstract
Cells are continuously subjected to DNA damaging agents. DNA damages are repaired by one of the many pathways guarding genomic integrity. When one or several DNA damage pathways are rendered inefficient, cells can accumulate mutations, which modify normal cellular pathways, favoring abnormal cell growth. This supports malignant transformation, which can occur when cells acquire resistance to cell cycle checkpoints, apoptosis, or growth inhibition signals. Mutations in genes involved in the repair of DNA double strand breaks (DSBs), such as BRCA1, BRCA2, or PALB2, significantly increase the risk of developing cancer of the breast, ovaries, pancreas, or prostate. Fortunately, the inability of these tumors to repair DNA breaks makes them sensitive to genotoxic chemotherapies, allowing for the development of therapies precisely tailored to individuals' genetic backgrounds. Unfortunately, as with many anti-cancer agents, drugs used to treat patients carrying a BRCA1 or BRCA2 mutation create a selective pressure, and over time tumors can become drug resistant. Here, we detail the cellular function of tumor suppressors essential in DNA damage repair pathways, present the mechanisms of action of inhibitors used to create synthetic lethality in BRCA carriers, and review the major molecular sources of drug resistance. Finally, we present examples of the many strategies being developed to circumvent drug resistance.
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Affiliation(s)
- Dawn C Janysek
- School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
| | - Jennifer Kim
- School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
| | - Pascal H G Duijf
- Queensland University of Technology, IHBI at the Translational Research Institute, Brisbane, QLD, Australia; Centre for Data Science, Queensland University of Technology, Brisbane, QLD, Australia; University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia
| | - Eloïse Dray
- Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States; Mays Cancer Center, UT Health San Antonio MD Anderson, San Antonio, TX, United States.
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Yang R, Chen Z, Xie F, Xie M, Liu N, Su Z, Gu J, Zhao R. (+/-)-Borneol Reverses Mitoxantrone Resistance against P-Glycoprotein. J Chem Inf Model 2020; 61:252-262. [PMID: 33378196 DOI: 10.1021/acs.jcim.0c00892] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
P-Glycoprotein (Pgp) is a main factor contributing to multidrug resistance and the consequent failure of chemotherapy. Overcoming Pgp efflux is a strategy to improve the efficacy of drugs. (+)-Borneol (BNL1) and (-)-borneol (BNL2) interfere and inhibit Pgp, and thus, the accumulation of drugs increases in cells. However, it is not clear yet how they play the inhibitory effect against Pgp. In this work, the effect and molecular mechanism of borneol enantiomers in reversing mitoxantrone (MTO) resistance against Pgp were explored by in vitro and in silico approaches. Chemosensitizing potential tests showed that BNLs could enhance the efficacy of MTO in MES-SA/MX2 cells, and BNL2 exhibited a stronger potential. The protein expression of Pgp was decreased to some extent by the administration of BNLs. Molecular docking revealed that BNLs could reduce the binding affinity between MTO and Pgp. The results were consistent with the chemosensitizing potential test and were supported by molecular dynamics (MD) simulations. Molecular docking also suggested that BNLs preferred to bind in the drug-binding pocket rather than the nucleotide-binding domain of inward-facing Pgp. The occupied space of BNLs had an evident distance from that of MTO, which was further verified by the conformational analysis after MD simulations. The decomposition of binding free energies revealed the key amino acid residues (GLN195, SER196, TRP232, PHE343, SER344, GLY346, and GLN347) for BNLs to reverse MTO resistance. The results provide an insight into the mechanism through which BNLs reduce the MTO resistance against inward-facing Pgp in the drug-binding pocket through noncompetitive inhibition.
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Affiliation(s)
- Rong Yang
- Research Centre for Integrative Medicine, School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Zhenxing Chen
- College of Basic Medicine, Guangxi University of Chinese Medicine, Nanning 530200, China.,The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Fuda Xie
- Research Centre for Integrative Medicine, School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Mingxiang Xie
- Research Centre for Integrative Medicine, School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Na Liu
- Research Centre for Integrative Medicine, School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Ziren Su
- Mathematical Engineering Academy of Chinese Medicine, Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Jiangyong Gu
- Research Centre for Integrative Medicine, School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Ruizhi Zhao
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510006, China.,Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
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Pagnotta PA, Melito VA, Lavandera JV, Parera VE, Rossetti MV, Zuccoli JR, Buzaleh AM. Role of ABCB1 and glutathione S-transferase gene variants in the association of porphyria cutanea tarda and human immunodeficiency virus infection. Biomed Rep 2020; 14:22. [PMID: 33335728 PMCID: PMC7739863 DOI: 10.3892/br.2020.1398] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 10/13/2020] [Indexed: 12/11/2022] Open
Abstract
In Argentina, porphyria cutanea tarda (PCT) is strongly associated with infection with human immunodeficiency virus (HIV); however, whether the onset of this disease is associated with HIV infection and/or the antiretroviral therapy has not been determined. The ABCB1 gene variants c.1236C>T, c.2677G>T/A and c.3435C>T affect drug efflux. The GSTT1 null, GSTM1 null and GSTP1 (c.313A>G) gene variants alter Glutathione S-transferase (GST) activity, modifying the levels of xenobiotics. The aim of the present study was to evaluate the role of genetic variants in initiation of PCT and to analyze the genetic basis of the PCT-HIV association. Control individuals, and HIV, PCT and PCT-HIV patients were recruited, PCR-restriction fragment length polymorphism was used to genotype the ABCB1 and GSTP1 variants, and multiplex PCR was used to study the GSTM1 and GSTT1 variants. The high frequency of c.3435C>T (PCT and PCT-HIV) and c.1236C>T (PCT) suggested that the onset of PCT were not specifically related to HIV infection or antiretroviral therapy for these variants. c.2677G>T/A frequencies in the PCT-HIV patients were higher compared with the other groups, suggesting that a mechanism involving antiretroviral therapy served a role in this association. PCT-HIV patients also had a high frequency of GSTT1 null and low frequency for GSTM1 null variants; thus, the genetic basis for PCT onset may involve a combination between the absence of GSTT1 and the presence of GSTM1. In conclusion, genes encoding for proteins involved in the flow and metabolism of xenobiotics may influence the PCT-HIV association. The present study is the first to investigate the possible role of GST and ABCB1 gene variants in the triggering of PCT in HIV-infected individuals, to the best of our knowledge, and may provide novel insights into the molecular basis of the association between PCT and HIV.
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Affiliation(s)
- Priscila Ayelén Pagnotta
- Centro de Investigaciones sobre Porfirinas y Porfirias, Universidad de Buenos Aires, Argentina-National Scientific and Technical Research Council, Hospital de Clínicas José de San Martín, Buenos Aires 1120, Argentina.,Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires 1428, Argentina
| | - Viviana Alicia Melito
- Centro de Investigaciones sobre Porfirinas y Porfirias, Universidad de Buenos Aires, Argentina-National Scientific and Technical Research Council, Hospital de Clínicas José de San Martín, Buenos Aires 1120, Argentina.,Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires 1428, Argentina
| | - Jimena Verónica Lavandera
- Cátedra de Bromatología y Nutrición, Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Santa Fe 3000, Argentina
| | - Victoria Estela Parera
- Centro de Investigaciones sobre Porfirinas y Porfirias, Universidad de Buenos Aires, Argentina-National Scientific and Technical Research Council, Hospital de Clínicas José de San Martín, Buenos Aires 1120, Argentina
| | - María Victoria Rossetti
- Centro de Investigaciones sobre Porfirinas y Porfirias, Universidad de Buenos Aires, Argentina-National Scientific and Technical Research Council, Hospital de Clínicas José de San Martín, Buenos Aires 1120, Argentina
| | - Johanna Romina Zuccoli
- Centro de Investigaciones sobre Porfirinas y Porfirias, Universidad de Buenos Aires, Argentina-National Scientific and Technical Research Council, Hospital de Clínicas José de San Martín, Buenos Aires 1120, Argentina
| | - Ana Maria Buzaleh
- Centro de Investigaciones sobre Porfirinas y Porfirias, Universidad de Buenos Aires, Argentina-National Scientific and Technical Research Council, Hospital de Clínicas José de San Martín, Buenos Aires 1120, Argentina.,Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires 1428, Argentina
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Rowsell L, Wu JGA, Yee BJ, Wong KKH, Sivam S, Somogyi AA, Grunstein RR, Wang D. The effect of acute morphine on sleep in male patients suffering from sleep apnea: Is there a genetic effect? An RCT Study. J Sleep Res 2020; 30:e13249. [PMID: 33319444 DOI: 10.1111/jsr.13249] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 11/12/2020] [Accepted: 11/12/2020] [Indexed: 01/11/2023]
Abstract
Questionnaire-based studies have suggested genetic differences in sleep symptoms in chronic opioid users. The present study aims to investigate if there is a genetic effect on sleep architecture and quantitative electroencephalogram (EEG) in response to acute morphine. Under a randomized, double-blind, placebo-controlled, crossover design, 68 men with obstructive sleep apnea undertook two overnight polysomnographic studies conducted at least 1 week apart. Each night they received either 40 mg of controlled-release morphine or placebo. Sleep architecture and quantitative EEG were compared between conditions. Blood was sampled before sleep and on the next morning for genotyping and pharmacokinetic analyses. We analysed three candidate genes (OPRM1 [rs1799971, 118 A > G], ABCB1[rs1045642, 3435 C > T] and HTR3B [rs7103572 C > T]). We found that morphine decreased slow wave sleep and rapid eye movement sleep and increased stage 2 sleep. Those effects were less in subjects with HTR3B CT/TT than in those with CC genotype. Similarly, sleep onset latency was shortened in the ABCB1 CC subgroup compared with the CT/TT subgroup. Total sleep time was significantly increased in ABCB1 CC but not in CT/TT subjects. Sleep apnea and plasma morphine and metabolite concentration were not confounding factors for these genetic differences in sleep. With morphine, patients had significantly more active/unstable EEG (lower delta/alpha ratio) during sleep. No genetic effects on quantitative EEG were detected. In summary, we identified two genes (HTR3B and ABCB1) with significant variation in the sleep architecture response to morphine. Morphine caused a more active/unstable EEG during sleep. Our findings may have relevance for a personalized medicine approach to targeted morphine therapy.
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Affiliation(s)
- Luke Rowsell
- Centre for Integrated Research and Understanding of Sleep (CIRUS), Woolcock Institute of Medical Research, Sydney Medical School, the University of Sydney, Sydney, Australia
| | - Justin Guang-Ao Wu
- Centre for Integrated Research and Understanding of Sleep (CIRUS), Woolcock Institute of Medical Research, Sydney Medical School, the University of Sydney, Sydney, Australia
| | - Brendon J Yee
- Centre for Integrated Research and Understanding of Sleep (CIRUS), Woolcock Institute of Medical Research, Sydney Medical School, the University of Sydney, Sydney, Australia.,Department of Respiratory and Sleep Medicine, Royal Prince Alfred Hospital (work performed), Sydney Local Health District, Camperdown, Australia
| | - Keith K H Wong
- Centre for Integrated Research and Understanding of Sleep (CIRUS), Woolcock Institute of Medical Research, Sydney Medical School, the University of Sydney, Sydney, Australia.,Department of Respiratory and Sleep Medicine, Royal Prince Alfred Hospital (work performed), Sydney Local Health District, Camperdown, Australia
| | - Sheila Sivam
- Centre for Integrated Research and Understanding of Sleep (CIRUS), Woolcock Institute of Medical Research, Sydney Medical School, the University of Sydney, Sydney, Australia.,Department of Respiratory and Sleep Medicine, Royal Prince Alfred Hospital (work performed), Sydney Local Health District, Camperdown, Australia
| | - Andrew A Somogyi
- Discipline of Pharmacology, Adelaide Medical School, University of Adelaide, Adelaide, Australia
| | - Ronald R Grunstein
- Centre for Integrated Research and Understanding of Sleep (CIRUS), Woolcock Institute of Medical Research, Sydney Medical School, the University of Sydney, Sydney, Australia.,Department of Respiratory and Sleep Medicine, Royal Prince Alfred Hospital (work performed), Sydney Local Health District, Camperdown, Australia
| | - David Wang
- Centre for Integrated Research and Understanding of Sleep (CIRUS), Woolcock Institute of Medical Research, Sydney Medical School, the University of Sydney, Sydney, Australia.,Department of Respiratory and Sleep Medicine, Royal Prince Alfred Hospital (work performed), Sydney Local Health District, Camperdown, Australia
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