Short‐term toxicity assessment of combined use of zidovudine, lamivudine and lopinavir/ritonavir in vitro and in vivo
Introduction A combination of zidovudine (AZT), lamivudine (3TC) and lopinavir/ritonavir (LPV/r) is one of the most effective drugs for preventing mother‐to‐child transmission (PMTCT) of HIV. However, limited information is available regarding its systemic toxicity. This study aimed to investigate i...
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| Veröffentlicht in: | Basic & clinical pharmacology & toxicology 2023-07, Vol.133 (1), p.82-97 |
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| creator | Wen, Pingjing Ge, Xianmin Wang, Yanwu Ge, Yun Lan, Guanghua Li, Bin Qin, Guangqiu Zhu, Qiuying Chen, Huanhuan Zhu, Jinhui Qin, Huiyan Yang, Hui Luo, Hailan Gao, Yuqiu Meng, Qin Luo, Liuhong Liu, Shuaifeng Wu, Xiuling Li, Shanshan Deng, Yueqin |
| description | Introduction
A combination of zidovudine (AZT), lamivudine (3TC) and lopinavir/ritonavir (LPV/r) is one of the most effective drugs for preventing mother‐to‐child transmission (PMTCT) of HIV. However, limited information is available regarding its systemic toxicity. This study aimed to investigate its potential toxicity.
Method
An acute oral toxicity test was conducted to assess the potential acute toxicity of AZT + 3TC + LPV/r. Bacterial reverse mutation, mammalian erythrocyte micronucleus and mouse spermatogonia chromosomal aberration tests were conducted to assess its potential genotoxicity. A 28‐day feeding test was conducted to assess the potential subacute toxicity.
Results
In mice, the LD50 of the AZT + 3TC + LPV/r mixture was greater than 2000 mg/kg body weight (BW). The rate of micronucleated polychromatic erythrocytes (PCEs) increased in a dose‐dependent manner in mice (P |
| doi_str_mv | 10.1111/bcpt.13870 |
| format | Article |
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A combination of zidovudine (AZT), lamivudine (3TC) and lopinavir/ritonavir (LPV/r) is one of the most effective drugs for preventing mother‐to‐child transmission (PMTCT) of HIV. However, limited information is available regarding its systemic toxicity. This study aimed to investigate its potential toxicity.
Method
An acute oral toxicity test was conducted to assess the potential acute toxicity of AZT + 3TC + LPV/r. Bacterial reverse mutation, mammalian erythrocyte micronucleus and mouse spermatogonia chromosomal aberration tests were conducted to assess its potential genotoxicity. A 28‐day feeding test was conducted to assess the potential subacute toxicity.
Results
In mice, the LD50 of the AZT + 3TC + LPV/r mixture was greater than 2000 mg/kg body weight (BW). The rate of micronucleated polychromatic erythrocytes (PCEs) increased in a dose‐dependent manner in mice (P < 0.01). After treatment with AZT + 3TC + LPV/r for 28 days, the BW gain of male and female rats in the high‐dose group was lower than that in the control group (P < 0.05); the relative weights of the liver, kidney, spleen and brain increased (P < 0.05); and pathological abnormalities appeared in the thyroid and spleen of male and female rats in the high‐dose group. The haemoglobin (HGB) and red blood cells (RBCs) count in male and female rats decreased, but the white blood cells (WBCs) and lymphocyte apoptosis rates in male and female rats in the high‐dose group increased (P < 0.05). The total protein, albumin, cholesterol and blood glucose levels of male and female rats in the high‐dose group were significantly decreased (P < 0.05). The alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), creatinine (Cr) and blood urea nitrogen (BUN) levels of male and female rats in the medium‐ and high‐dose groups increased significantly (P < 0.05).
Conclusion
The results suggest that AZT + 3TC + LPV/r may exhibit genotoxicity and subacute toxicity under experimental conditions.]]></description><identifier>ISSN: 1742-7835</identifier><identifier>EISSN: 1742-7843</identifier><identifier>DOI: 10.1111/bcpt.13870</identifier><identifier>PMID: 37016497</identifier><language>eng</language><publisher>England: Wiley Subscription Services, Inc</publisher><subject>Abnormalities ; Acute toxicity ; Alanine ; Alanine transaminase ; Alkaline phosphatase ; Animals ; Anti-HIV Agents - therapeutic use ; Anti-HIV Agents - toxicity ; Apoptosis ; AZT + 3TC + LPV/r ; Biocompatibility ; Body weight ; Cholesterol ; Chromosome aberrations ; Creatinine ; Disease transmission ; Erythrocytes ; Female ; Females ; Genotoxicity ; Hemoglobin ; HIV ; HIV Infections - drug therapy ; Human immunodeficiency virus ; In vivo methods and tests ; Infectious Disease Transmission, Vertical - prevention & control ; Kidneys ; L-Lactate dehydrogenase ; Lactate dehydrogenase ; Lamivudine ; Lamivudine - toxicity ; Leukocytes ; Lopinavir ; Lopinavir - toxicity ; Lymphocytes ; Male ; Males ; Mammals ; Mice ; PMTCT ; Rats ; Ritonavir ; Spermatogonia ; Spleen ; Subacute toxicity ; Thyroid ; Toxicity testing ; Urea ; Zidovudine ; Zidovudine - therapeutic use ; Zidovudine - toxicity</subject><ispartof>Basic & clinical pharmacology & toxicology, 2023-07, Vol.133 (1), p.82-97</ispartof><rights>2023 The Authors. published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).</rights><rights>2023 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).</rights><rights>2023. This article is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c3520-d78316295d37c4e8308d3f84dbd2b246feb6930734739eba08712daaa43db6713</cites><orcidid>0000-0003-0888-9281</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fbcpt.13870$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fbcpt.13870$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>314,776,780,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37016497$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wen, Pingjing</creatorcontrib><creatorcontrib>Ge, Xianmin</creatorcontrib><creatorcontrib>Wang, Yanwu</creatorcontrib><creatorcontrib>Ge, Yun</creatorcontrib><creatorcontrib>Lan, Guanghua</creatorcontrib><creatorcontrib>Li, Bin</creatorcontrib><creatorcontrib>Qin, Guangqiu</creatorcontrib><creatorcontrib>Zhu, Qiuying</creatorcontrib><creatorcontrib>Chen, Huanhuan</creatorcontrib><creatorcontrib>Zhu, Jinhui</creatorcontrib><creatorcontrib>Qin, Huiyan</creatorcontrib><creatorcontrib>Yang, Hui</creatorcontrib><creatorcontrib>Luo, Hailan</creatorcontrib><creatorcontrib>Gao, Yuqiu</creatorcontrib><creatorcontrib>Meng, Qin</creatorcontrib><creatorcontrib>Luo, Liuhong</creatorcontrib><creatorcontrib>Liu, Shuaifeng</creatorcontrib><creatorcontrib>Wu, Xiuling</creatorcontrib><creatorcontrib>Li, Shanshan</creatorcontrib><creatorcontrib>Deng, Yueqin</creatorcontrib><title>Short‐term toxicity assessment of combined use of zidovudine, lamivudine and lopinavir/ritonavir in vitro and in vivo</title><title>Basic & clinical pharmacology & toxicology</title><addtitle>Basic Clin Pharmacol Toxicol</addtitle><description><![CDATA[Introduction
A combination of zidovudine (AZT), lamivudine (3TC) and lopinavir/ritonavir (LPV/r) is one of the most effective drugs for preventing mother‐to‐child transmission (PMTCT) of HIV. However, limited information is available regarding its systemic toxicity. This study aimed to investigate its potential toxicity.
Method
An acute oral toxicity test was conducted to assess the potential acute toxicity of AZT + 3TC + LPV/r. Bacterial reverse mutation, mammalian erythrocyte micronucleus and mouse spermatogonia chromosomal aberration tests were conducted to assess its potential genotoxicity. A 28‐day feeding test was conducted to assess the potential subacute toxicity.
Results
In mice, the LD50 of the AZT + 3TC + LPV/r mixture was greater than 2000 mg/kg body weight (BW). The rate of micronucleated polychromatic erythrocytes (PCEs) increased in a dose‐dependent manner in mice (P < 0.01). After treatment with AZT + 3TC + LPV/r for 28 days, the BW gain of male and female rats in the high‐dose group was lower than that in the control group (P < 0.05); the relative weights of the liver, kidney, spleen and brain increased (P < 0.05); and pathological abnormalities appeared in the thyroid and spleen of male and female rats in the high‐dose group. The haemoglobin (HGB) and red blood cells (RBCs) count in male and female rats decreased, but the white blood cells (WBCs) and lymphocyte apoptosis rates in male and female rats in the high‐dose group increased (P < 0.05). The total protein, albumin, cholesterol and blood glucose levels of male and female rats in the high‐dose group were significantly decreased (P < 0.05). The alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), creatinine (Cr) and blood urea nitrogen (BUN) levels of male and female rats in the medium‐ and high‐dose groups increased significantly (P < 0.05).
Conclusion
The results suggest that AZT + 3TC + LPV/r may exhibit genotoxicity and subacute toxicity under experimental conditions.]]></description><subject>Abnormalities</subject><subject>Acute toxicity</subject><subject>Alanine</subject><subject>Alanine transaminase</subject><subject>Alkaline phosphatase</subject><subject>Animals</subject><subject>Anti-HIV Agents - therapeutic use</subject><subject>Anti-HIV Agents - toxicity</subject><subject>Apoptosis</subject><subject>AZT + 3TC + LPV/r</subject><subject>Biocompatibility</subject><subject>Body weight</subject><subject>Cholesterol</subject><subject>Chromosome aberrations</subject><subject>Creatinine</subject><subject>Disease transmission</subject><subject>Erythrocytes</subject><subject>Female</subject><subject>Females</subject><subject>Genotoxicity</subject><subject>Hemoglobin</subject><subject>HIV</subject><subject>HIV Infections - drug therapy</subject><subject>Human immunodeficiency virus</subject><subject>In vivo methods and tests</subject><subject>Infectious Disease Transmission, Vertical - prevention & control</subject><subject>Kidneys</subject><subject>L-Lactate dehydrogenase</subject><subject>Lactate dehydrogenase</subject><subject>Lamivudine</subject><subject>Lamivudine - toxicity</subject><subject>Leukocytes</subject><subject>Lopinavir</subject><subject>Lopinavir - toxicity</subject><subject>Lymphocytes</subject><subject>Male</subject><subject>Males</subject><subject>Mammals</subject><subject>Mice</subject><subject>PMTCT</subject><subject>Rats</subject><subject>Ritonavir</subject><subject>Spermatogonia</subject><subject>Spleen</subject><subject>Subacute toxicity</subject><subject>Thyroid</subject><subject>Toxicity testing</subject><subject>Urea</subject><subject>Zidovudine</subject><subject>Zidovudine - therapeutic use</subject><subject>Zidovudine - toxicity</subject><issn>1742-7835</issn><issn>1742-7843</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>EIF</sourceid><recordid>eNp9kctKxDAUhoMo3jc-gATciDhObm3apQ7eYEDBcR3SJsVI29QkrY4rH8Fn9EnsTEcXLswm_zl8_OdwfgAOMDrD_RtneRPOME04WgPbmDMy4gmj67-aRltgx_tnhAhnGG2CLcoRjlnKt8Hrw5N14evjM2hXwWDfTG7CHErvtfeVrgO0BcxtlZlaK9h6vajfjbJdq_rWKSxlZQYNZa1gaRtTy864sTPBLhU0NexMcHYJLIvO7oGNQpZe76_-XfB4dTmb3Iymd9e3k_PpKKcRQSPVb49jkkaK8pzphKJE0SJhKlMkIywudBanFHHKOE11JlHCMVFSSkZVFnNMd8Hx4Ns4-9JqH0RlfK7LUtbatl4QnsY4SiIS9-jRH_TZtq7utxMkIXgxAfOeOhmo3FnvnS5E40wl3VxgJBZxiEUcYhlHDx-uLNus0uoX_bl_D-ABeDWlnv9jJS4m97PB9Bv-_pcZ</recordid><startdate>202307</startdate><enddate>202307</enddate><creator>Wen, Pingjing</creator><creator>Ge, Xianmin</creator><creator>Wang, Yanwu</creator><creator>Ge, Yun</creator><creator>Lan, Guanghua</creator><creator>Li, Bin</creator><creator>Qin, Guangqiu</creator><creator>Zhu, Qiuying</creator><creator>Chen, Huanhuan</creator><creator>Zhu, Jinhui</creator><creator>Qin, Huiyan</creator><creator>Yang, Hui</creator><creator>Luo, Hailan</creator><creator>Gao, Yuqiu</creator><creator>Meng, Qin</creator><creator>Luo, Liuhong</creator><creator>Liu, Shuaifeng</creator><creator>Wu, Xiuling</creator><creator>Li, Shanshan</creator><creator>Deng, Yueqin</creator><general>Wiley Subscription Services, Inc</general><scope>24P</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7TK</scope><scope>7U7</scope><scope>C1K</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-0888-9281</orcidid></search><sort><creationdate>202307</creationdate><title>Short‐term toxicity assessment of combined use of zidovudine, lamivudine and lopinavir/ritonavir in vitro and in vivo</title><author>Wen, Pingjing ; Ge, Xianmin ; Wang, Yanwu ; Ge, Yun ; Lan, Guanghua ; Li, Bin ; Qin, Guangqiu ; Zhu, Qiuying ; Chen, Huanhuan ; Zhu, Jinhui ; Qin, Huiyan ; Yang, Hui ; Luo, Hailan ; Gao, Yuqiu ; Meng, Qin ; Luo, Liuhong ; Liu, Shuaifeng ; Wu, Xiuling ; Li, Shanshan ; Deng, Yueqin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3520-d78316295d37c4e8308d3f84dbd2b246feb6930734739eba08712daaa43db6713</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Abnormalities</topic><topic>Acute toxicity</topic><topic>Alanine</topic><topic>Alanine transaminase</topic><topic>Alkaline phosphatase</topic><topic>Animals</topic><topic>Anti-HIV Agents - therapeutic use</topic><topic>Anti-HIV Agents - toxicity</topic><topic>Apoptosis</topic><topic>AZT + 3TC + LPV/r</topic><topic>Biocompatibility</topic><topic>Body weight</topic><topic>Cholesterol</topic><topic>Chromosome aberrations</topic><topic>Creatinine</topic><topic>Disease transmission</topic><topic>Erythrocytes</topic><topic>Female</topic><topic>Females</topic><topic>Genotoxicity</topic><topic>Hemoglobin</topic><topic>HIV</topic><topic>HIV Infections - drug therapy</topic><topic>Human immunodeficiency virus</topic><topic>In vivo methods and tests</topic><topic>Infectious Disease Transmission, Vertical - prevention & control</topic><topic>Kidneys</topic><topic>L-Lactate dehydrogenase</topic><topic>Lactate dehydrogenase</topic><topic>Lamivudine</topic><topic>Lamivudine - toxicity</topic><topic>Leukocytes</topic><topic>Lopinavir</topic><topic>Lopinavir - toxicity</topic><topic>Lymphocytes</topic><topic>Male</topic><topic>Males</topic><topic>Mammals</topic><topic>Mice</topic><topic>PMTCT</topic><topic>Rats</topic><topic>Ritonavir</topic><topic>Spermatogonia</topic><topic>Spleen</topic><topic>Subacute toxicity</topic><topic>Thyroid</topic><topic>Toxicity testing</topic><topic>Urea</topic><topic>Zidovudine</topic><topic>Zidovudine - therapeutic use</topic><topic>Zidovudine - toxicity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wen, Pingjing</creatorcontrib><creatorcontrib>Ge, Xianmin</creatorcontrib><creatorcontrib>Wang, Yanwu</creatorcontrib><creatorcontrib>Ge, Yun</creatorcontrib><creatorcontrib>Lan, Guanghua</creatorcontrib><creatorcontrib>Li, Bin</creatorcontrib><creatorcontrib>Qin, Guangqiu</creatorcontrib><creatorcontrib>Zhu, Qiuying</creatorcontrib><creatorcontrib>Chen, Huanhuan</creatorcontrib><creatorcontrib>Zhu, Jinhui</creatorcontrib><creatorcontrib>Qin, Huiyan</creatorcontrib><creatorcontrib>Yang, Hui</creatorcontrib><creatorcontrib>Luo, Hailan</creatorcontrib><creatorcontrib>Gao, Yuqiu</creatorcontrib><creatorcontrib>Meng, Qin</creatorcontrib><creatorcontrib>Luo, Liuhong</creatorcontrib><creatorcontrib>Liu, Shuaifeng</creatorcontrib><creatorcontrib>Wu, Xiuling</creatorcontrib><creatorcontrib>Li, Shanshan</creatorcontrib><creatorcontrib>Deng, Yueqin</creatorcontrib><collection>Wiley-Blackwell Open Access Titles</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>MEDLINE - Academic</collection><jtitle>Basic & clinical pharmacology & toxicology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wen, Pingjing</au><au>Ge, Xianmin</au><au>Wang, Yanwu</au><au>Ge, Yun</au><au>Lan, Guanghua</au><au>Li, Bin</au><au>Qin, Guangqiu</au><au>Zhu, Qiuying</au><au>Chen, Huanhuan</au><au>Zhu, Jinhui</au><au>Qin, Huiyan</au><au>Yang, Hui</au><au>Luo, Hailan</au><au>Gao, Yuqiu</au><au>Meng, Qin</au><au>Luo, Liuhong</au><au>Liu, Shuaifeng</au><au>Wu, Xiuling</au><au>Li, Shanshan</au><au>Deng, Yueqin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Short‐term toxicity assessment of combined use of zidovudine, lamivudine and lopinavir/ritonavir in vitro and in vivo</atitle><jtitle>Basic & clinical pharmacology & toxicology</jtitle><addtitle>Basic Clin Pharmacol Toxicol</addtitle><date>2023-07</date><risdate>2023</risdate><volume>133</volume><issue>1</issue><spage>82</spage><epage>97</epage><pages>82-97</pages><issn>1742-7835</issn><eissn>1742-7843</eissn><abstract><![CDATA[Introduction
A combination of zidovudine (AZT), lamivudine (3TC) and lopinavir/ritonavir (LPV/r) is one of the most effective drugs for preventing mother‐to‐child transmission (PMTCT) of HIV. However, limited information is available regarding its systemic toxicity. This study aimed to investigate its potential toxicity.
Method
An acute oral toxicity test was conducted to assess the potential acute toxicity of AZT + 3TC + LPV/r. Bacterial reverse mutation, mammalian erythrocyte micronucleus and mouse spermatogonia chromosomal aberration tests were conducted to assess its potential genotoxicity. A 28‐day feeding test was conducted to assess the potential subacute toxicity.
Results
In mice, the LD50 of the AZT + 3TC + LPV/r mixture was greater than 2000 mg/kg body weight (BW). The rate of micronucleated polychromatic erythrocytes (PCEs) increased in a dose‐dependent manner in mice (P < 0.01). After treatment with AZT + 3TC + LPV/r for 28 days, the BW gain of male and female rats in the high‐dose group was lower than that in the control group (P < 0.05); the relative weights of the liver, kidney, spleen and brain increased (P < 0.05); and pathological abnormalities appeared in the thyroid and spleen of male and female rats in the high‐dose group. The haemoglobin (HGB) and red blood cells (RBCs) count in male and female rats decreased, but the white blood cells (WBCs) and lymphocyte apoptosis rates in male and female rats in the high‐dose group increased (P < 0.05). The total protein, albumin, cholesterol and blood glucose levels of male and female rats in the high‐dose group were significantly decreased (P < 0.05). The alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), creatinine (Cr) and blood urea nitrogen (BUN) levels of male and female rats in the medium‐ and high‐dose groups increased significantly (P < 0.05).
Conclusion
The results suggest that AZT + 3TC + LPV/r may exhibit genotoxicity and subacute toxicity under experimental conditions.]]></abstract><cop>England</cop><pub>Wiley Subscription Services, Inc</pub><pmid>37016497</pmid><doi>10.1111/bcpt.13870</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0003-0888-9281</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Basic & clinical pharmacology & toxicology, 2023-07, Vol.133 (1), p.82-97 |
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| subjects | Abnormalities Acute toxicity Alanine Alanine transaminase Alkaline phosphatase Animals Anti-HIV Agents - therapeutic use Anti-HIV Agents - toxicity Apoptosis AZT + 3TC + LPV/r Biocompatibility Body weight Cholesterol Chromosome aberrations Creatinine Disease transmission Erythrocytes Female Females Genotoxicity Hemoglobin HIV HIV Infections - drug therapy Human immunodeficiency virus In vivo methods and tests Infectious Disease Transmission, Vertical - prevention & control Kidneys L-Lactate dehydrogenase Lactate dehydrogenase Lamivudine Lamivudine - toxicity Leukocytes Lopinavir Lopinavir - toxicity Lymphocytes Male Males Mammals Mice PMTCT Rats Ritonavir Spermatogonia Spleen Subacute toxicity Thyroid Toxicity testing Urea Zidovudine Zidovudine - therapeutic use Zidovudine - toxicity |
| title | Short‐term toxicity assessment of combined use of zidovudine, lamivudine and lopinavir/ritonavir in vitro and in vivo |
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