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Sankar J, Chauhan A, Singh R, Mahajan D. Isoniazid-historical development, metabolism associated toxicity and a perspective on its pharmacological improvement. Front Pharmacol 2024; 15:1441147. [PMID: 39364056 PMCID: PMC11447295 DOI: 10.3389/fphar.2024.1441147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 08/30/2024] [Indexed: 10/05/2024] Open
Abstract
Despite the extraordinary anti-tubercular activity of isoniazid (INH), the drug-induced hepatotoxicity and peripheral neuropathy pose a significant challenge to its wider clinical use. The primary cause of INH-induced hepatotoxicity is in vivo metabolism involving biotransformation on its terminal -NH2 group owing to its high nucleophilic nature. The human N-acetyltransferase-2 enzyme (NAT-2) exploits the reactivity of INH's terminal -NH2 functional group and inactivates it by transferring the acetyl group, which subsequently converts to toxic metabolites. This -NH2 group also tends to react with vital endogenous molecules such as pyridoxine, leading to their deficiency, a major cause of peripheral neuropathy. The elevation of liver functional markers is observed in 10%-20% of subjects on INH treatment. INH-induced risk of fatal hepatitis is about 0.05%-1%. The incidence of peripheral neuropathy is 2%-6.5%. In this review, we discuss the genesis and historical development of INH, and different reported mechanisms of action of INH. This is followed by a brief review of various clinical trials in chronological order, highlighting treatment-associated adverse events and their occurrence rates, including details such as geographical location, number of subjects, dosing concentration, and regimen used in these clinical studies. Further, we elaborated on various known metabolic transformations highlighting the involvement of the terminal -NH2 group of INH and corresponding host enzymes, the structure of different metabolites/conjugates, and their association with hepatotoxicity or neuritis. Post this deliberation, we propose a hydrolysable chemical derivatives-based approach as a way forward to restrict this metabolism.
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Affiliation(s)
- Jishnu Sankar
- Centre for Drug Discovery, BRIC-Translational Health Science and Technology Institute, Faridabad, Haryana, India
| | - Anjali Chauhan
- Centre for Drug Discovery, BRIC-Translational Health Science and Technology Institute, Faridabad, Haryana, India
- Centre for Tuberculosis Research, BRIC-Translational Health Science and Technology Institute, Faridabad, Haryana, India
| | - Ramandeep Singh
- Department of Pharmaceutical Chemistry, Delhi Institute of Pharmaceutical Sciences and Research, New Delhi, India
| | - Dinesh Mahajan
- Centre for Drug Discovery, BRIC-Translational Health Science and Technology Institute, Faridabad, Haryana, India
- Centre for Tuberculosis Research, BRIC-Translational Health Science and Technology Institute, Faridabad, Haryana, India
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Hepatoprotective Bile Acid Co-Drug of Isoniazid: Synthesis, Kinetics and Investigation of Antimycobacterial Potential. Pharm Chem J 2020. [DOI: 10.1007/s11094-020-02256-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Bhilare NV, Dhaneshwar SS, Mahadik KR, Dasgupta A. Co-drug of isoniazid and sulfur containing antioxidant for attenuation of hepatotoxicity and treatment of tuberculosis. Drug Chem Toxicol 2020; 45:850-860. [PMID: 32543916 DOI: 10.1080/01480545.2020.1778021] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
The prolonged use of isoniazid (INH) - a highly effective drug in the treatment of tuberculosis - causes fatal liver injury. In order to overcome this adverse effect, a unique amide codrug was designed by covalently linking INH with sulfur-containing antioxidant- alpha-lipoic acid for possible hepatoprotective and antimycobacterial effect. Co-drug LI was prepared by Schotten Baumann reaction and was characterized by spectroscopic analysis. To check the bioreversibility of LI, in vitro release tests were conducted in buffers of specific pH, stomach, and intestinal homogenates of rat employing HPLC. Male Wistar rats were used for the evaluation of the hepatoprotective activity. Liver function markers, oxidative stress markers, and biochemical parameters were estimated. The antimycobacterial efficacy of LI was examined in terms of its ability to decrease the lung bacillary load in Balb/c mice infected intravenously with Mycobacterium tuberculosis. LI resisted hydrolysis in buffers of pH 1.2 (acidic), pH 7.4 (basic), and stomach homogenate of the rat while displayed significant hydrolysis (88.19%) in intestinal homogenates over a period of 6 h. The effect of LI on liver function, antioxidant and biochemical paradigms was remarkable as it reestablished the enzyme levels and restored hepatic cytoarchitecture representing its abrogating effect. The findings of antimycobacterial activity assessment evidently demonstrated that LI was as potent as INH in lowering the mycobacterial load in mice. The outcome of this exploration confirmed that the described co-drug can offer desirable safety and therapeutic benefit in the management of tuberculosis.
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Affiliation(s)
- Neha V Bhilare
- Department of Pharmaceutical Chemistry, Arvind Gavali College of Pharmacy, Satara, India.,Department of Pharmaceutical Chemistry, Poona College of Pharmacy, Bharati Vidyapeeth University, Pune, India
| | | | - Kakasaheb R Mahadik
- Department of Pharmaceutical Chemistry, Poona College of Pharmacy, Bharati Vidyapeeth University, Pune, India
| | - Arunava Dasgupta
- Division of Microbiology, CSIR-Central Drug Research Institute, Lucknow, India
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González-Torres M, Guzmán-Beltrán S, Mata-Gómez MA, González-Valdez J, Leyva-Gómez G, Melgarejo-Ramírez Y, Brostow W, Velasquillo C, Zúñiga-Ramos J, Rodríguez-Talavera R. Synthesis, characterization, and in vitro evaluation of gamma radiation-induced PEGylated isoniazid. ELECTRON J BIOTECHN 2019. [DOI: 10.1016/j.ejbt.2019.07.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022] Open
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Srivastava P, Kakkar D, Kumar P, Tiwari AK. Modified benzoxazolone (ABO‐AA) based single photon emission computed tomography (SPECT) probes for 18 kDa translocator protein. Drug Dev Res 2019; 80:741-749. [DOI: 10.1002/ddr.21547] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2019] [Revised: 04/09/2019] [Accepted: 05/11/2019] [Indexed: 12/11/2022]
Affiliation(s)
- Pooja Srivastava
- Division of Cyclotron and Radiopharmaceutical SciencesInstitute of Nuclear Medicine and Allied Sciences Delhi India
- Molecular Neuroscience and Functional Genomic Laboratory, Department of BiotechnologyDelhi Technological University Delhi India
| | - Dipti Kakkar
- Division of Cyclotron and Radiopharmaceutical SciencesInstitute of Nuclear Medicine and Allied Sciences Delhi India
| | - Pravir Kumar
- Molecular Neuroscience and Functional Genomic Laboratory, Department of BiotechnologyDelhi Technological University Delhi India
| | - Anjani Kumar Tiwari
- Division of Cyclotron and Radiopharmaceutical SciencesInstitute of Nuclear Medicine and Allied Sciences Delhi India
- Department of Chemistry, School of Physical & Decision Sciences (SPDS)Babasaheb Bhimrao Ambedkar Central University Lucknow UP India
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Srivastava P, Kumari N, Kakkar D, Kaul A, Kumar P, Tiwari AK. Comparative evaluation of 99mTc-MBIP-X/11[C] MBMP for visualization of 18 kDa translocator protein. NEW J CHEM 2019. [DOI: 10.1039/c9nj00180h] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
An elevated translocator protein (18 kDa, TSPO) density is observed during inflammation in the brain and peripheral organs making it a viable target for imaging.
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Affiliation(s)
- Pooja Srivastava
- Division of Cyclotron and Radiopharmaceutical Sciences
- Institute of Nuclear Medicine and Allied Sciences
- Delhi 110054
- India
- Molecular Neuroscience and Functional Genomics Laboratory
| | - Neelam Kumari
- Division of Cyclotron and Radiopharmaceutical Sciences
- Institute of Nuclear Medicine and Allied Sciences
- Delhi 110054
- India
| | - Dipti Kakkar
- Division of Cyclotron and Radiopharmaceutical Sciences
- Institute of Nuclear Medicine and Allied Sciences
- Delhi 110054
- India
| | - Ankur Kaul
- Division of Cyclotron and Radiopharmaceutical Sciences
- Institute of Nuclear Medicine and Allied Sciences
- Delhi 110054
- India
| | - Pravir Kumar
- Molecular Neuroscience and Functional Genomics Laboratory
- Department of Biotechnology
- Delhi Technological University
- Delhi 110042
- India
| | - Anjani K. Tiwari
- Division of Cyclotron and Radiopharmaceutical Sciences
- Institute of Nuclear Medicine and Allied Sciences
- Delhi 110054
- India
- Department of Chemistry
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Bhilare NV, Dhaneshwar SS, Mahadik KR. Amelioration of hepatotoxicity by biocleavable aminothiol chimeras of isoniazid: Design, synthesis, kinetics and pharmacological evaluation. World J Hepatol 2018; 10:496-508. [PMID: 30079136 PMCID: PMC6068850 DOI: 10.4254/wjh.v10.i7.496] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2018] [Revised: 04/06/2018] [Accepted: 04/09/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To overcome the hazardous effects on liver caused by long-term use of antitubercular agent isoniazid (INH) by developing a novel hepatoprotective prodrug strategy by conjugating INH with aminothiols as antioxidant promoities for probable synergistic effect.
METHODS INH was conjugated with N-acetyl cysteine (NAC) and N-(2)-mercaptopropionyl glycine using the Schotten-Baumann reaction and with L-methionine using Boc-anhydride through a biocleavable amide linkage. Synthesized prodrugs were characterized by spectral analysis, and in vitro and in vivo release studies were carried out using HPLC. Their hepatoprotective potential was evaluated in male Wistar rats by performing liver function tests, measuring markers of oxidative stress and carrying out histopathology studies.
RESULTS Prodrugs were found to be stable in acidic (pH 1.2) and basic (pH 7.4) buffers and in rat stomach homogenates, whereas they were hydrolysed significantly (59.43%-94.93%) in intestinal homogenates over a period of 6 h. Upon oral administration of prodrug NI to rats, 52.4%-61.3% INH and 47.4%-56.8% of NAC were recovered in blood in 8-10 h. Urine and faeces samples pooled over a period of 24 h exhibited 1.3%-2.5% and 0.94%-0.9% of NAC, respectively, without any presence of intact NI or INH. Prodrugs were biologically evaluated for hepatoprotective activity. All the prodrugs were effective in abating oxidative stress and re-establishing the normal hepatic physiology. The effect of prodrug of INH with NAC in restoring the levels of the enzymes superoxide dismutase and glutathione peroxidase and abrogating liver damage was noteworthy especially.
CONCLUSION The findings of this investigation demonstrated that the reported prodrugs can add safety and efficacy to future clinical protocols of tuberculosis treatment.
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Affiliation(s)
- Neha Vithal Bhilare
- Department of Pharmaceutical Chemistry, Poona College of Pharmacy, Bharati Vidyapeeth University, Maharashtra 411038, India
| | - Suneela Sunil Dhaneshwar
- Department of Pharmaceutical Chemistry, Poona College of Pharmacy, Bharati Vidyapeeth University, Maharashtra 411038, India
| | - Kakasaheb Ramoo Mahadik
- Department of Pharmaceutical Chemistry, Poona College of Pharmacy, Bharati Vidyapeeth University, Maharashtra 411038, India
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Bhilare NV, Dhaneshwar SS, Mahadik KR. Phenolic acid-tethered isoniazid for abrogation of drug-induced hepatotoxicity: design, synthesis, kinetics and pharmacological evaluation. Drug Deliv Transl Res 2018; 8:770-779. [DOI: 10.1007/s13346-018-0500-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Natfji AA, Osborn HM, Greco F. Feasibility of polymer-drug conjugates for non-cancer applications. Curr Opin Colloid Interface Sci 2017. [DOI: 10.1016/j.cocis.2017.07.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Dumoga S, Dey N, Kaur A, Singh S, Mishra AK, Kakkar D. Novel biotin-functionalized lipidic nanocarriers for encapsulating BpT and Bp4eT iron chelators: evaluation of potential anti-tumour efficacy by in vitro, in vivo and pharmacokinetic studies in A549 mice models. RSC Adv 2016. [DOI: 10.1039/c6ra03079c] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
This work proposes a novel strategy for delivery of iron chelators to the tumour cells which is exemplified in A549 mice models by using lipidic nanocarriers and introducing biotin based targeting.
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Affiliation(s)
- Shweta Dumoga
- Institute of Nuclear Medicine and Allied Sciences
- Timarpur
- Delhi-110054
- Department of Chemistry
- University of Delhi
| | - Namit Dey
- Institute of Nuclear Medicine and Allied Sciences
- Timarpur
- Delhi-110054
| | - Anivind Kaur
- Institute of Nuclear Medicine and Allied Sciences
- Timarpur
- Delhi-110054
| | | | - Anil K. Mishra
- Institute of Nuclear Medicine and Allied Sciences
- Timarpur
- Delhi-110054
| | - Dipti Kakkar
- Institute of Nuclear Medicine and Allied Sciences
- Timarpur
- Delhi-110054
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Kakkar D, Dumoga S, Kumar R, Chuttani K, Mishra AK. PEGylated solid lipid nanoparticles: design, methotrexate loading and biological evaluation in animal models. MEDCHEMCOMM 2015. [DOI: 10.1039/c5md00104h] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The design of pegylated SLNs for efficient entrapment and delivery of methotrexate at tumour sites in order to overcome its bioavailability and blood retention issues.
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Affiliation(s)
- Dipti Kakkar
- Division of Cyclotron and Radiopharmaceutical Sciences
- Institute of Nuclear Medicine and Allied Sciences
- India
| | - Shweta Dumoga
- Division of Cyclotron and Radiopharmaceutical Sciences
- Institute of Nuclear Medicine and Allied Sciences
- India
| | - Rohit Kumar
- Division of Cyclotron and Radiopharmaceutical Sciences
- Institute of Nuclear Medicine and Allied Sciences
- India
| | - Krishna Chuttani
- Division of Cyclotron and Radiopharmaceutical Sciences
- Institute of Nuclear Medicine and Allied Sciences
- India
| | - Anil Kumar Mishra
- Division of Cyclotron and Radiopharmaceutical Sciences
- Institute of Nuclear Medicine and Allied Sciences
- India
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Singh C, Jodave L, Bhatt TD, Gill MS, Suresh S. Hepatoprotective agent tethered isoniazid for the treatment of drug-induced hepatotoxicity: Synthesis, biochemical and histopathological evaluation. Toxicol Rep 2014; 1:885-893. [PMID: 28962300 PMCID: PMC5598226 DOI: 10.1016/j.toxrep.2014.10.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2014] [Revised: 10/02/2014] [Accepted: 10/06/2014] [Indexed: 12/22/2022] Open
Abstract
The aim of the study was to investigate the protective effect of isoniazid–curcumin conjugate (INH–CRM) in INH-induced hepatic injury by biochemical analysis and histology examination of liver in Wistar rats. The biochemical analysis included determination of the levels of plasma cholesterol, triglycerides (TG), albumin content, and lipid peroxidation (MDA). INH–CRM administration resulted in a significant decrease in plasma cholesterol, TG, and MDA levels in the liver tissue homogenate with an elevation in albumin level indicating its hepatoprotective activity. Histology of the liver further confirmed the reduction in hepatic injury. The hepatoprotective with INH–CRM can be attributed to the antioxidant activity of curcumin. The conjugate probably stabilizes the curcumin molecule, preventing its presystemic metabolism thereby enhancing its bioavailability and therefore, its hepatoprotective activity. Thus, the novel INH–CRM has the potential to alleviate INH-induced liver toxicity in antitubercular treatment.
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Affiliation(s)
- Charan Singh
- Department of Pharmaceutical Technology (Formulations), National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar (Mohali) Punjab 160062 India
| | - Laxmikant Jodave
- Department of Pharmaceutical Technology (Formulations), National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar (Mohali) Punjab 160062 India
| | - Tara Datt Bhatt
- Technology Development Centre, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar (Mohali) Punjab 160062 India
| | - Manjinder Singh Gill
- Department of Pharmaceutical Technology (Process Chemistry), National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar (Mohali) Punjab160062 India
| | - Sarasija Suresh
- Department of Pharmaceutical Technology (Formulations), National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar (Mohali) Punjab 160062 India
- Corresponding author. Tel.: +0172 2292055; fax: +0172 2214692
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Thukral DK, Dumoga S, Arora S, Chuttani K, Mishra AK. Potential carriers of chemotherapeutic drugs: matrix based nanoparticulate polymeric systems. Cancer Nanotechnol 2014; 5:3. [PMID: 26561511 PMCID: PMC4631724 DOI: 10.1186/s12645-014-0003-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2013] [Accepted: 04/29/2014] [Indexed: 11/10/2022] Open
Abstract
In this work matrix based nanoparticulate polymer systems have been designed using the diacrylate derivative of the well-known biocompatible polymer, poly(ethylene glycol) (PEG). This has been crosslinked using bifunctional (ethyleneglycol dimethacrylate) and tetrafunctional (pentaerythritol tetraacrylate) crosslinkers in varied concentrations (10-90%) to result in a polymeric network. The crosslinked polymers thus obtained were characterized by spectroscopic techniques (NMR and FTIR) and then prepared nanoparticles by the nanoprecipitation technique. Particle size analysis showed sizes of ~150 nm (PDI < 1) (with tetrafunctional crosslinker) and ~300 nm (with bifunctional crosslinker). Both the systems however showed unimodal narrow particle size distributions with negative zeta potential values of -15.6 and -7.3 respectively. Cytotoxicity of these formulations was evaluated by MTT assay showing non-cytotoxic nature of these carrier systems. In vitro drug loading and release studies were carried out using a model chemotherapeutic drug, methotrexate(MTX). These MTX loaded nanoformulations have also been evaluated biologically with the help of in vivo studies using radiolabeling techniques (with 99mTc radionuclide). The blood kinetics profile of the formulations was studied on New Zealand Albino rabbits while the biodistribution studies were performed on balb/c mice (with EAT tumours), which revealed a hepatobiliary mode of elimination. These preliminary studies clearly demonstrated the ability of these multifunctional crosslinkers to result in tight nanosized networks with biocompatible polymers such as PEG and their potential to carry chemotherapeutic drugs.
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Affiliation(s)
- Dipti Kakkar Thukral
- Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, Defence Research & Development Organization(DRDO), Brig S. K. Mazumdar Road, Timarpur, Delhi 110054 India
| | - Shweta Dumoga
- Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, Defence Research & Development Organization(DRDO), Brig S. K. Mazumdar Road, Timarpur, Delhi 110054 India
| | - Shelly Arora
- Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, Defence Research & Development Organization(DRDO), Brig S. K. Mazumdar Road, Timarpur, Delhi 110054 India
| | - Krishna Chuttani
- Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, Defence Research & Development Organization(DRDO), Brig S. K. Mazumdar Road, Timarpur, Delhi 110054 India
| | - Anil K Mishra
- Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, Defence Research & Development Organization(DRDO), Brig S. K. Mazumdar Road, Timarpur, Delhi 110054 India
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