Developmental toxicity assessment of d,l-Methylphenidate and d-Methylphenidate in rats and rabbits
BACKGROUND: Previous investigations reported no teratogenicity for methylphenidate (MPH). These studies investigated potential teratogenicity of d‐MPH and d,l‐MPH as commitments to the FDA. METHODS: Rabbits received 15, 50, 150 mg/kg/day (mkd) d‐MPH or 20, 60, 200, 300 mkd d,l‐MPH on gestation days...
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| Veröffentlicht in: | Birth defects research. Part B. Developmental and reproductive toxicology 2008-10, Vol.83 (5), p.489-501 |
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| container_title | Birth defects research. Part B. Developmental and reproductive toxicology |
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| creator | Beckman, David A. Schneider, Marilynn Youreneff, Maureen Tse, Francis L.S. |
| description | BACKGROUND: Previous investigations reported no teratogenicity for methylphenidate (MPH). These studies investigated potential teratogenicity of d‐MPH and d,l‐MPH as commitments to the FDA. METHODS: Rabbits received 15, 50, 150 mg/kg/day (mkd) d‐MPH or 20, 60, 200, 300 mkd d,l‐MPH on gestation days 7–20. Rats received 2.5, 10, 40 mkd d‐MPH, or 7, 25, 75, 80 mkd d,l‐MPH on gestation days 6–17. RESULTS: d‐MPH—In rabbits, mortality occurred at 150 mkd. Dilated pupils, increased activity, biting/chewing, respiration, and salivation occurred at ≥15 mkd in rabbits and ≥10 mkd in rats. Decreased food consumption occurred at 40 mkd in rats. Decreased body weight parameters occurred at 150 mkd in rabbits and ≥10 mkd in rats. There were no fetal findings in rabbits. In rats, skeletal variations occurred at 40 mkd. d,l‐MPH—In rabbits, mortality occurred at ≥200 mkd. Dilated pupils, increased activity, biting/chewing, respiration, and salivation occurred at ≥20 mkd in rabbits and ≥25 mkd in rats. Decreased food consumption occurred at ≥200 mkd in rabbits and ≥25 mkd in rats. Decreased body weight parameters occurred at ≥200 mkd in rabbits and ≥25 mkd in rats. In rabbits, two fetuses (separate litters) had spina bifida and malrotated hindlimbs at 200 mkd. In rats, skeletal variations occurred at ≥75 mkd. CONCLUSIONS: There was no teratogenicity with d‐MPH. There was a low teratogenic risk with d,l‐MPH in only the rabbit. Higher Cmax may explain differences in results from previous studies. Birth Defects Res (Part B) 83:489‐501, 2008. © 2008 Wiley‐Liss, Inc. |
| doi_str_mv | 10.1002/bdrb.20168 |
| format | Article |
| fullrecord | <record><control><sourceid>wiley_cross</sourceid><recordid>TN_cdi_crossref_primary_10_1002_bdrb_20168</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>BDRB20168</sourcerecordid><originalsourceid>FETCH-LOGICAL-c3658-3b10bc3e4f66b9e655518f280dd5a2a5d38b05627889a168a78c2a1f7eb2cb3e3</originalsourceid><addsrcrecordid>eNp9kF9LwzAUxYMoTqcvfgDps9jZJM2fPbpNp7IpiOLwJSRNyqJdW5Kq67e3W-d8EHy6l3N_58A9AJzAqAejCF0o7VQPRZDyHXAASYzCPovh7nbHuAMOvX9rWMwY3wcdyPsohjE7AGpkPk1WlAuTVzILqmJpE1vVgfTeeL9SgyIN9HkWTk01r7NybnKrZWUCmetA_1FtHjhZ-fXVSaVs5Y_AXiozb443swuer6-ehjfh5GF8O7ychAmmhIdYwUgl2MQppapvKCEE8hTxSGsikSQacxURihjnfdn8KhlPkIQpMwolChvcBWdtbuIK751JRensQrpawEisihKrosS6qAY-beHyQy2M_kU3zTQAbIEvm5n6nygxGD0OfkLD1mN9ZZZbj3TvgjLMiHi5H4sZha93s8FUQPwNxcWDvQ</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Developmental toxicity assessment of d,l-Methylphenidate and d-Methylphenidate in rats and rabbits</title><source>MEDLINE</source><source>Wiley Online Library Journals Frontfile Complete</source><creator>Beckman, David A. ; Schneider, Marilynn ; Youreneff, Maureen ; Tse, Francis L.S.</creator><creatorcontrib>Beckman, David A. ; Schneider, Marilynn ; Youreneff, Maureen ; Tse, Francis L.S.</creatorcontrib><description>BACKGROUND: Previous investigations reported no teratogenicity for methylphenidate (MPH). These studies investigated potential teratogenicity of d‐MPH and d,l‐MPH as commitments to the FDA. METHODS: Rabbits received 15, 50, 150 mg/kg/day (mkd) d‐MPH or 20, 60, 200, 300 mkd d,l‐MPH on gestation days 7–20. Rats received 2.5, 10, 40 mkd d‐MPH, or 7, 25, 75, 80 mkd d,l‐MPH on gestation days 6–17. RESULTS: d‐MPH—In rabbits, mortality occurred at 150 mkd. Dilated pupils, increased activity, biting/chewing, respiration, and salivation occurred at ≥15 mkd in rabbits and ≥10 mkd in rats. Decreased food consumption occurred at 40 mkd in rats. Decreased body weight parameters occurred at 150 mkd in rabbits and ≥10 mkd in rats. There were no fetal findings in rabbits. In rats, skeletal variations occurred at 40 mkd. d,l‐MPH—In rabbits, mortality occurred at ≥200 mkd. Dilated pupils, increased activity, biting/chewing, respiration, and salivation occurred at ≥20 mkd in rabbits and ≥25 mkd in rats. Decreased food consumption occurred at ≥200 mkd in rabbits and ≥25 mkd in rats. Decreased body weight parameters occurred at ≥200 mkd in rabbits and ≥25 mkd in rats. In rabbits, two fetuses (separate litters) had spina bifida and malrotated hindlimbs at 200 mkd. In rats, skeletal variations occurred at ≥75 mkd. CONCLUSIONS: There was no teratogenicity with d‐MPH. There was a low teratogenic risk with d,l‐MPH in only the rabbit. Higher Cmax may explain differences in results from previous studies. Birth Defects Res (Part B) 83:489‐501, 2008. © 2008 Wiley‐Liss, Inc.</description><identifier>ISSN: 1542-9733</identifier><identifier>EISSN: 1542-9741</identifier><identifier>DOI: 10.1002/bdrb.20168</identifier><identifier>PMID: 18924147</identifier><language>eng</language><publisher>Hoboken: Wiley Subscription Services, Inc., A Wiley Company</publisher><subject>Abnormalities, Drug-Induced - etiology ; Administration, Oral ; Animals ; Body Weight - drug effects ; Central Nervous System Stimulants - chemistry ; Central Nervous System Stimulants - toxicity ; developmental toxicity ; Dose-Response Relationship, Drug ; Eating - drug effects ; embryo/fetal development ; Embryonic Development - drug effects ; Female ; Hindlimb - drug effects ; Hindlimb - embryology ; Hindlimb - pathology ; Male ; Methylphenidate ; Methylphenidate - chemistry ; Methylphenidate - toxicity ; rabbit ; Rabbits ; rat ; Rats ; Rats, Wistar ; Respiration - drug effects ; Salivation - drug effects ; Spinal Dysraphism - embryology ; Spinal Dysraphism - pathology ; teratogen</subject><ispartof>Birth defects research. Part B. Developmental and reproductive toxicology, 2008-10, Vol.83 (5), p.489-501</ispartof><rights>2008 Wiley‐Liss, Inc.</rights><rights>(c) 2008 Wiley-Liss, Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3658-3b10bc3e4f66b9e655518f280dd5a2a5d38b05627889a168a78c2a1f7eb2cb3e3</citedby><cites>FETCH-LOGICAL-c3658-3b10bc3e4f66b9e655518f280dd5a2a5d38b05627889a168a78c2a1f7eb2cb3e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fbdrb.20168$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fbdrb.20168$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18924147$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Beckman, David A.</creatorcontrib><creatorcontrib>Schneider, Marilynn</creatorcontrib><creatorcontrib>Youreneff, Maureen</creatorcontrib><creatorcontrib>Tse, Francis L.S.</creatorcontrib><title>Developmental toxicity assessment of d,l-Methylphenidate and d-Methylphenidate in rats and rabbits</title><title>Birth defects research. Part B. Developmental and reproductive toxicology</title><addtitle>Birth Defects Research Part B: Developmental and Reproductive Toxicology</addtitle><description>BACKGROUND: Previous investigations reported no teratogenicity for methylphenidate (MPH). These studies investigated potential teratogenicity of d‐MPH and d,l‐MPH as commitments to the FDA. METHODS: Rabbits received 15, 50, 150 mg/kg/day (mkd) d‐MPH or 20, 60, 200, 300 mkd d,l‐MPH on gestation days 7–20. Rats received 2.5, 10, 40 mkd d‐MPH, or 7, 25, 75, 80 mkd d,l‐MPH on gestation days 6–17. RESULTS: d‐MPH—In rabbits, mortality occurred at 150 mkd. Dilated pupils, increased activity, biting/chewing, respiration, and salivation occurred at ≥15 mkd in rabbits and ≥10 mkd in rats. Decreased food consumption occurred at 40 mkd in rats. Decreased body weight parameters occurred at 150 mkd in rabbits and ≥10 mkd in rats. There were no fetal findings in rabbits. In rats, skeletal variations occurred at 40 mkd. d,l‐MPH—In rabbits, mortality occurred at ≥200 mkd. Dilated pupils, increased activity, biting/chewing, respiration, and salivation occurred at ≥20 mkd in rabbits and ≥25 mkd in rats. Decreased food consumption occurred at ≥200 mkd in rabbits and ≥25 mkd in rats. Decreased body weight parameters occurred at ≥200 mkd in rabbits and ≥25 mkd in rats. In rabbits, two fetuses (separate litters) had spina bifida and malrotated hindlimbs at 200 mkd. In rats, skeletal variations occurred at ≥75 mkd. CONCLUSIONS: There was no teratogenicity with d‐MPH. There was a low teratogenic risk with d,l‐MPH in only the rabbit. Higher Cmax may explain differences in results from previous studies. Birth Defects Res (Part B) 83:489‐501, 2008. © 2008 Wiley‐Liss, Inc.</description><subject>Abnormalities, Drug-Induced - etiology</subject><subject>Administration, Oral</subject><subject>Animals</subject><subject>Body Weight - drug effects</subject><subject>Central Nervous System Stimulants - chemistry</subject><subject>Central Nervous System Stimulants - toxicity</subject><subject>developmental toxicity</subject><subject>Dose-Response Relationship, Drug</subject><subject>Eating - drug effects</subject><subject>embryo/fetal development</subject><subject>Embryonic Development - drug effects</subject><subject>Female</subject><subject>Hindlimb - drug effects</subject><subject>Hindlimb - embryology</subject><subject>Hindlimb - pathology</subject><subject>Male</subject><subject>Methylphenidate</subject><subject>Methylphenidate - chemistry</subject><subject>Methylphenidate - toxicity</subject><subject>rabbit</subject><subject>Rabbits</subject><subject>rat</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Respiration - drug effects</subject><subject>Salivation - drug effects</subject><subject>Spinal Dysraphism - embryology</subject><subject>Spinal Dysraphism - pathology</subject><subject>teratogen</subject><issn>1542-9733</issn><issn>1542-9741</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kF9LwzAUxYMoTqcvfgDps9jZJM2fPbpNp7IpiOLwJSRNyqJdW5Kq67e3W-d8EHy6l3N_58A9AJzAqAejCF0o7VQPRZDyHXAASYzCPovh7nbHuAMOvX9rWMwY3wcdyPsohjE7AGpkPk1WlAuTVzILqmJpE1vVgfTeeL9SgyIN9HkWTk01r7NybnKrZWUCmetA_1FtHjhZ-fXVSaVs5Y_AXiozb443swuer6-ehjfh5GF8O7ychAmmhIdYwUgl2MQppapvKCEE8hTxSGsikSQacxURihjnfdn8KhlPkIQpMwolChvcBWdtbuIK751JRensQrpawEisihKrosS6qAY-beHyQy2M_kU3zTQAbIEvm5n6nygxGD0OfkLD1mN9ZZZbj3TvgjLMiHi5H4sZha93s8FUQPwNxcWDvQ</recordid><startdate>200810</startdate><enddate>200810</enddate><creator>Beckman, David A.</creator><creator>Schneider, Marilynn</creator><creator>Youreneff, Maureen</creator><creator>Tse, Francis L.S.</creator><general>Wiley Subscription Services, Inc., A Wiley Company</general><scope>BSCLL</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></search><sort><creationdate>200810</creationdate><title>Developmental toxicity assessment of d,l-Methylphenidate and d-Methylphenidate in rats and rabbits</title><author>Beckman, David A. ; Schneider, Marilynn ; Youreneff, Maureen ; Tse, Francis L.S.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3658-3b10bc3e4f66b9e655518f280dd5a2a5d38b05627889a168a78c2a1f7eb2cb3e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Abnormalities, Drug-Induced - etiology</topic><topic>Administration, Oral</topic><topic>Animals</topic><topic>Body Weight - drug effects</topic><topic>Central Nervous System Stimulants - chemistry</topic><topic>Central Nervous System Stimulants - toxicity</topic><topic>developmental toxicity</topic><topic>Dose-Response Relationship, Drug</topic><topic>Eating - drug effects</topic><topic>embryo/fetal development</topic><topic>Embryonic Development - drug effects</topic><topic>Female</topic><topic>Hindlimb - drug effects</topic><topic>Hindlimb - embryology</topic><topic>Hindlimb - pathology</topic><topic>Male</topic><topic>Methylphenidate</topic><topic>Methylphenidate - chemistry</topic><topic>Methylphenidate - toxicity</topic><topic>rabbit</topic><topic>Rabbits</topic><topic>rat</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>Respiration - drug effects</topic><topic>Salivation - drug effects</topic><topic>Spinal Dysraphism - embryology</topic><topic>Spinal Dysraphism - pathology</topic><topic>teratogen</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Beckman, David A.</creatorcontrib><creatorcontrib>Schneider, Marilynn</creatorcontrib><creatorcontrib>Youreneff, Maureen</creatorcontrib><creatorcontrib>Tse, Francis L.S.</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Birth defects research. Part B. Developmental and reproductive toxicology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Beckman, David A.</au><au>Schneider, Marilynn</au><au>Youreneff, Maureen</au><au>Tse, Francis L.S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Developmental toxicity assessment of d,l-Methylphenidate and d-Methylphenidate in rats and rabbits</atitle><jtitle>Birth defects research. Part B. Developmental and reproductive toxicology</jtitle><addtitle>Birth Defects Research Part B: Developmental and Reproductive Toxicology</addtitle><date>2008-10</date><risdate>2008</risdate><volume>83</volume><issue>5</issue><spage>489</spage><epage>501</epage><pages>489-501</pages><issn>1542-9733</issn><eissn>1542-9741</eissn><abstract>BACKGROUND: Previous investigations reported no teratogenicity for methylphenidate (MPH). These studies investigated potential teratogenicity of d‐MPH and d,l‐MPH as commitments to the FDA. METHODS: Rabbits received 15, 50, 150 mg/kg/day (mkd) d‐MPH or 20, 60, 200, 300 mkd d,l‐MPH on gestation days 7–20. Rats received 2.5, 10, 40 mkd d‐MPH, or 7, 25, 75, 80 mkd d,l‐MPH on gestation days 6–17. RESULTS: d‐MPH—In rabbits, mortality occurred at 150 mkd. Dilated pupils, increased activity, biting/chewing, respiration, and salivation occurred at ≥15 mkd in rabbits and ≥10 mkd in rats. Decreased food consumption occurred at 40 mkd in rats. Decreased body weight parameters occurred at 150 mkd in rabbits and ≥10 mkd in rats. There were no fetal findings in rabbits. In rats, skeletal variations occurred at 40 mkd. d,l‐MPH—In rabbits, mortality occurred at ≥200 mkd. Dilated pupils, increased activity, biting/chewing, respiration, and salivation occurred at ≥20 mkd in rabbits and ≥25 mkd in rats. Decreased food consumption occurred at ≥200 mkd in rabbits and ≥25 mkd in rats. Decreased body weight parameters occurred at ≥200 mkd in rabbits and ≥25 mkd in rats. In rabbits, two fetuses (separate litters) had spina bifida and malrotated hindlimbs at 200 mkd. In rats, skeletal variations occurred at ≥75 mkd. CONCLUSIONS: There was no teratogenicity with d‐MPH. There was a low teratogenic risk with d,l‐MPH in only the rabbit. Higher Cmax may explain differences in results from previous studies. Birth Defects Res (Part B) 83:489‐501, 2008. © 2008 Wiley‐Liss, Inc.</abstract><cop>Hoboken</cop><pub>Wiley Subscription Services, Inc., A Wiley Company</pub><pmid>18924147</pmid><doi>10.1002/bdrb.20168</doi><tpages>13</tpages></addata></record> |
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| ispartof | Birth defects research. Part B. Developmental and reproductive toxicology, 2008-10, Vol.83 (5), p.489-501 |
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| source | MEDLINE; Wiley Online Library Journals Frontfile Complete |
| subjects | Abnormalities, Drug-Induced - etiology Administration, Oral Animals Body Weight - drug effects Central Nervous System Stimulants - chemistry Central Nervous System Stimulants - toxicity developmental toxicity Dose-Response Relationship, Drug Eating - drug effects embryo/fetal development Embryonic Development - drug effects Female Hindlimb - drug effects Hindlimb - embryology Hindlimb - pathology Male Methylphenidate Methylphenidate - chemistry Methylphenidate - toxicity rabbit Rabbits rat Rats Rats, Wistar Respiration - drug effects Salivation - drug effects Spinal Dysraphism - embryology Spinal Dysraphism - pathology teratogen |
| title | Developmental toxicity assessment of d,l-Methylphenidate and d-Methylphenidate in rats and rabbits |
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