A species comparison of the toxicity of nabilone, a new synthetic cannabinoid
Acute, subchronic, and chronic studies were conducted in various species to evaluate and compare the toxicity of nabilone, a new synthetic 9-ketocanna-binoid that is orally effective for the treatment of nausea and vomiting induced by cancer chemotherapy agents. The oral LD50 in mice and rats for na...
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Veröffentlicht in: | Fundamental and applied toxicology 1987-08, Vol.9 (2), p.185-197 |
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description | Acute, subchronic, and chronic studies were conducted in various species to evaluate and compare the toxicity of nabilone, a new synthetic 9-ketocanna-binoid that is orally effective for the treatment of nausea and vomiting induced by cancer chemotherapy agents. The oral LD50 in mice and rats for nabilone formulated as a polyvinylpyrrolidone (PVP) codispersion was in excess of 1000 mg/kg. Among nonrodents, rhesus monkeys had a higher tolerance to the CNS depression induced by single oral doses of nabilone-PVP than did dogs. Rats fed dietary mixtures of nabilone-PVP which provided approximate daily nabilone doses of 1 to 93 mg/kg tolerated treatment for 3 months with no deaths. Treatment-related changes (at doses ≥ 5 mg/kg) were limited to reduced body temperature, slight-to-moderate decreases in weight gain, and behavioral changes (e.g., hyperactivity, hyperirritability to touch, and hypoactivity). All dogs treated for 3 months with daily oral doses of up to 1.0 mg/kg survived; treatment-related effects were limited to transient episodes of ataxia and anorexia. Nabilone treatment of rats and dogs for 3 months produced no evidence of systemic toxicity in the clinical chemistry, hematology, or pathology parameters examined. Chronic treatment of dogs with daily oral doses of nabilone-PVP equal to 0.5, 1.0, or 2.0 mg of nabilone/kg produced cumulative toxicity; by the end of 7 months, 2, 6, and 7 dogs in the respective dose groups had died. In a number of instances, death was preceded by one or more convulsive episodes. In contrast to the dog, the toxic potential of nabilone was minimal in rhesus monkeys treated with nabilone-PVP for 1 year at daily oral nabilone doses of up to 2.0 mg/kg. The enzymatic reduction of the 9-keto group of nabilone to form carbinol metabolites was a major metabolic pathway for nabilone in dogs but not in rhesus monkeys. The carbinols were long-lived metabolites in the plasma of dogs and accumulated in the plasma compartment with time. Furthermore, the carbinol metabolites were found to concentrate in the brain tissues of treated dogs. Although the precise mechanism for this marked species difference in chronic toxicity is not known, the metabolic differences responsible for the presence of the carbinol metabolites at high concentrations in the plasma and brain over time may play a role in the toxicity observed in the dog. |
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The oral LD50 in mice and rats for nabilone formulated as a polyvinylpyrrolidone (PVP) codispersion was in excess of 1000 mg/kg. Among nonrodents, rhesus monkeys had a higher tolerance to the CNS depression induced by single oral doses of nabilone-PVP than did dogs. Rats fed dietary mixtures of nabilone-PVP which provided approximate daily nabilone doses of 1 to 93 mg/kg tolerated treatment for 3 months with no deaths. Treatment-related changes (at doses ≥ 5 mg/kg) were limited to reduced body temperature, slight-to-moderate decreases in weight gain, and behavioral changes (e.g., hyperactivity, hyperirritability to touch, and hypoactivity). All dogs treated for 3 months with daily oral doses of up to 1.0 mg/kg survived; treatment-related effects were limited to transient episodes of ataxia and anorexia. Nabilone treatment of rats and dogs for 3 months produced no evidence of systemic toxicity in the clinical chemistry, hematology, or pathology parameters examined. Chronic treatment of dogs with daily oral doses of nabilone-PVP equal to 0.5, 1.0, or 2.0 mg of nabilone/kg produced cumulative toxicity; by the end of 7 months, 2, 6, and 7 dogs in the respective dose groups had died. In a number of instances, death was preceded by one or more convulsive episodes. In contrast to the dog, the toxic potential of nabilone was minimal in rhesus monkeys treated with nabilone-PVP for 1 year at daily oral nabilone doses of up to 2.0 mg/kg. The enzymatic reduction of the 9-keto group of nabilone to form carbinol metabolites was a major metabolic pathway for nabilone in dogs but not in rhesus monkeys. The carbinols were long-lived metabolites in the plasma of dogs and accumulated in the plasma compartment with time. Furthermore, the carbinol metabolites were found to concentrate in the brain tissues of treated dogs. Although the precise mechanism for this marked species difference in chronic toxicity is not known, the metabolic differences responsible for the presence of the carbinol metabolites at high concentrations in the plasma and brain over time may play a role in the toxicity observed in the dog.</description><identifier>ISSN: 0272-0590</identifier><identifier>EISSN: 1095-6832</identifier><identifier>DOI: 10.1016/0272-0590(87)90042-X</identifier><identifier>PMID: 2888699</identifier><identifier>CODEN: FAATDF</identifier><language>eng</language><publisher>Boston, MA: Elsevier Science (USA)</publisher><subject>Animals ; Anti-Anxiety Agents - toxicity ; Biological and medical sciences ; Digestive system ; Dogs ; Dronabinol - analogs & derivatives ; Dronabinol - toxicity ; Female ; Lethal Dose 50 ; Macaca mulatta ; Male ; Medical sciences ; Mice ; Mice, Inbred ICR ; Pharmacology. Drug treatments ; Rats ; Rats, Inbred F344 ; Rats, Inbred Strains ; Species Specificity</subject><ispartof>Fundamental and applied toxicology, 1987-08, Vol.9 (2), p.185-197</ispartof><rights>1987</rights><rights>1988 INIST-CNRS</rights><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c417t-ffd70c73cdbdf5a671498ac20e4a19e125be1a58f813e3e603d8943b005832633</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=7522066$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/2888699$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hanasono, G.K.</creatorcontrib><creatorcontrib>Sullivan, H.R.</creatorcontrib><creatorcontrib>Gries, C.L.</creatorcontrib><creatorcontrib>Jordan, W.H.</creatorcontrib><creatorcontrib>Emmerson, J.L.</creatorcontrib><title>A species comparison of the toxicity of nabilone, a new synthetic cannabinoid</title><title>Fundamental and applied toxicology</title><addtitle>Fundam Appl Toxicol</addtitle><description>Acute, subchronic, and chronic studies were conducted in various species to evaluate and compare the toxicity of nabilone, a new synthetic 9-ketocanna-binoid that is orally effective for the treatment of nausea and vomiting induced by cancer chemotherapy agents. The oral LD50 in mice and rats for nabilone formulated as a polyvinylpyrrolidone (PVP) codispersion was in excess of 1000 mg/kg. Among nonrodents, rhesus monkeys had a higher tolerance to the CNS depression induced by single oral doses of nabilone-PVP than did dogs. Rats fed dietary mixtures of nabilone-PVP which provided approximate daily nabilone doses of 1 to 93 mg/kg tolerated treatment for 3 months with no deaths. Treatment-related changes (at doses ≥ 5 mg/kg) were limited to reduced body temperature, slight-to-moderate decreases in weight gain, and behavioral changes (e.g., hyperactivity, hyperirritability to touch, and hypoactivity). All dogs treated for 3 months with daily oral doses of up to 1.0 mg/kg survived; treatment-related effects were limited to transient episodes of ataxia and anorexia. Nabilone treatment of rats and dogs for 3 months produced no evidence of systemic toxicity in the clinical chemistry, hematology, or pathology parameters examined. Chronic treatment of dogs with daily oral doses of nabilone-PVP equal to 0.5, 1.0, or 2.0 mg of nabilone/kg produced cumulative toxicity; by the end of 7 months, 2, 6, and 7 dogs in the respective dose groups had died. In a number of instances, death was preceded by one or more convulsive episodes. In contrast to the dog, the toxic potential of nabilone was minimal in rhesus monkeys treated with nabilone-PVP for 1 year at daily oral nabilone doses of up to 2.0 mg/kg. The enzymatic reduction of the 9-keto group of nabilone to form carbinol metabolites was a major metabolic pathway for nabilone in dogs but not in rhesus monkeys. The carbinols were long-lived metabolites in the plasma of dogs and accumulated in the plasma compartment with time. Furthermore, the carbinol metabolites were found to concentrate in the brain tissues of treated dogs. Although the precise mechanism for this marked species difference in chronic toxicity is not known, the metabolic differences responsible for the presence of the carbinol metabolites at high concentrations in the plasma and brain over time may play a role in the toxicity observed in the dog.</description><subject>Animals</subject><subject>Anti-Anxiety Agents - toxicity</subject><subject>Biological and medical sciences</subject><subject>Digestive system</subject><subject>Dogs</subject><subject>Dronabinol - analogs & derivatives</subject><subject>Dronabinol - toxicity</subject><subject>Female</subject><subject>Lethal Dose 50</subject><subject>Macaca mulatta</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred ICR</subject><subject>Pharmacology. Drug treatments</subject><subject>Rats</subject><subject>Rats, Inbred F344</subject><subject>Rats, Inbred Strains</subject><subject>Species Specificity</subject><issn>0272-0590</issn><issn>1095-6832</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1987</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMFq3DAQhkVoSbdp3yAFHUpIoW5HsmVJl0AIbVJIyCWB3IQsj4mKLbmSN82-fezsssechuH_Zpj5CDlm8IMBq38Cl7wAoeFUyW8aoOLFwwFZMdCiqFXJ35HVHvlAPub8F4AxUcEhOeRKqVrrFbk5p3lE5zFTF4fRJp9joLGj0yPSKT5756fN0gfb-D4G_E4tDfif5k2Ykck76mxYwhB9-4m872yf8fOuHpH737_uLq6K69vLPxfn14WrmJyKrmslOFm6tmk7YWvJKq2s44CVZRoZFw0yK1SnWIkl1lC2SldlAyDmv-qyPCIn271jiv_WmCcz-Oyw723AuM6GVVIwrvgMVlvQpZhzws6MyQ82bQwDs1g0iyKzKDJKmleL5mEe-7Lbv24GbPdDO21z_nWX2-xs3yUbnM97TArOoa5n7GyL4eziyWMyeTYdHLY-oZtMG_3bd7wA98ONbg</recordid><startdate>19870801</startdate><enddate>19870801</enddate><creator>Hanasono, G.K.</creator><creator>Sullivan, H.R.</creator><creator>Gries, C.L.</creator><creator>Jordan, W.H.</creator><creator>Emmerson, J.L.</creator><general>Elsevier Science (USA)</general><general>Academic Press</general><scope>IQODW</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>7U7</scope><scope>C1K</scope></search><sort><creationdate>19870801</creationdate><title>A species comparison of the toxicity of nabilone, a new synthetic cannabinoid</title><author>Hanasono, G.K. ; Sullivan, H.R. ; Gries, C.L. ; Jordan, W.H. ; Emmerson, J.L.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c417t-ffd70c73cdbdf5a671498ac20e4a19e125be1a58f813e3e603d8943b005832633</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1987</creationdate><topic>Animals</topic><topic>Anti-Anxiety Agents - toxicity</topic><topic>Biological and medical sciences</topic><topic>Digestive system</topic><topic>Dogs</topic><topic>Dronabinol - analogs & derivatives</topic><topic>Dronabinol - toxicity</topic><topic>Female</topic><topic>Lethal Dose 50</topic><topic>Macaca mulatta</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred ICR</topic><topic>Pharmacology. Drug treatments</topic><topic>Rats</topic><topic>Rats, Inbred F344</topic><topic>Rats, Inbred Strains</topic><topic>Species Specificity</topic><toplevel>online_resources</toplevel><creatorcontrib>Hanasono, G.K.</creatorcontrib><creatorcontrib>Sullivan, H.R.</creatorcontrib><creatorcontrib>Gries, C.L.</creatorcontrib><creatorcontrib>Jordan, W.H.</creatorcontrib><creatorcontrib>Emmerson, J.L.</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><jtitle>Fundamental and applied toxicology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hanasono, G.K.</au><au>Sullivan, H.R.</au><au>Gries, C.L.</au><au>Jordan, W.H.</au><au>Emmerson, J.L.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A species comparison of the toxicity of nabilone, a new synthetic cannabinoid</atitle><jtitle>Fundamental and applied toxicology</jtitle><addtitle>Fundam Appl Toxicol</addtitle><date>1987-08-01</date><risdate>1987</risdate><volume>9</volume><issue>2</issue><spage>185</spage><epage>197</epage><pages>185-197</pages><issn>0272-0590</issn><eissn>1095-6832</eissn><coden>FAATDF</coden><abstract>Acute, subchronic, and chronic studies were conducted in various species to evaluate and compare the toxicity of nabilone, a new synthetic 9-ketocanna-binoid that is orally effective for the treatment of nausea and vomiting induced by cancer chemotherapy agents. The oral LD50 in mice and rats for nabilone formulated as a polyvinylpyrrolidone (PVP) codispersion was in excess of 1000 mg/kg. Among nonrodents, rhesus monkeys had a higher tolerance to the CNS depression induced by single oral doses of nabilone-PVP than did dogs. Rats fed dietary mixtures of nabilone-PVP which provided approximate daily nabilone doses of 1 to 93 mg/kg tolerated treatment for 3 months with no deaths. Treatment-related changes (at doses ≥ 5 mg/kg) were limited to reduced body temperature, slight-to-moderate decreases in weight gain, and behavioral changes (e.g., hyperactivity, hyperirritability to touch, and hypoactivity). All dogs treated for 3 months with daily oral doses of up to 1.0 mg/kg survived; treatment-related effects were limited to transient episodes of ataxia and anorexia. Nabilone treatment of rats and dogs for 3 months produced no evidence of systemic toxicity in the clinical chemistry, hematology, or pathology parameters examined. Chronic treatment of dogs with daily oral doses of nabilone-PVP equal to 0.5, 1.0, or 2.0 mg of nabilone/kg produced cumulative toxicity; by the end of 7 months, 2, 6, and 7 dogs in the respective dose groups had died. In a number of instances, death was preceded by one or more convulsive episodes. In contrast to the dog, the toxic potential of nabilone was minimal in rhesus monkeys treated with nabilone-PVP for 1 year at daily oral nabilone doses of up to 2.0 mg/kg. The enzymatic reduction of the 9-keto group of nabilone to form carbinol metabolites was a major metabolic pathway for nabilone in dogs but not in rhesus monkeys. The carbinols were long-lived metabolites in the plasma of dogs and accumulated in the plasma compartment with time. Furthermore, the carbinol metabolites were found to concentrate in the brain tissues of treated dogs. Although the precise mechanism for this marked species difference in chronic toxicity is not known, the metabolic differences responsible for the presence of the carbinol metabolites at high concentrations in the plasma and brain over time may play a role in the toxicity observed in the dog.</abstract><cop>Boston, MA</cop><cop>San Diego, CA</cop><cop>New York, NY</cop><pub>Elsevier Science (USA)</pub><pmid>2888699</pmid><doi>10.1016/0272-0590(87)90042-X</doi><tpages>13</tpages></addata></record> |
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subjects | Animals Anti-Anxiety Agents - toxicity Biological and medical sciences Digestive system Dogs Dronabinol - analogs & derivatives Dronabinol - toxicity Female Lethal Dose 50 Macaca mulatta Male Medical sciences Mice Mice, Inbred ICR Pharmacology. Drug treatments Rats Rats, Inbred F344 Rats, Inbred Strains Species Specificity |
title | A species comparison of the toxicity of nabilone, a new synthetic cannabinoid |
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