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After acute and 7\u2010day pilot studies to define dose levels appropriate for use in longer term evaluations, Sprague\u2010Dawley rats (20 of each sex per group) were gavaged with doses of 4.4\u201325.9 mg kg<jats:sup>\u22121<\/jats:sup> day<jats:sup>\u22121<\/jats:sup> for 30 days followed by a 14\u2010day recovery period. Treatment\u2010related effects included dose\u2010dependent CNS depression paralleled by changes in food consumption, body weight gain and fecal output, as well as reddish urine and abdominal staining. Tolerance developed by day 7. The spectrum of activity observed differed from the parent compound primarily in its time course. Cage\u2010biting and gnawing behavior were observed only with NorLAAM. Mortality was dose\u2010dependent, with deaths occurring predominantly during the first week. At day 30, all male\u2010treated groups exhibited statistically significant, dose\u2010dependent decreases in body weight gain and increases in serum cholesterol that returned to the control range following recovery. Increases in brain\/body weight and testes\/body weight ratios and decreases in kidney\/brain, liver\/brain, spleen\/brain and heart\/brain ratios, as well as decreases in kidney, liver, spleen and heart absolute weights, achieved statistical significance only for males. At terminal sacrifice, histological findings in the kidneys included increased incidences of tubular mineral deposition in mid\u2010 and high\u2010dose groups of both sexes and of corticomedullary mineral deposition in females. Hepatic centrilobular hypertrophy was evident in male and female mid\u2010 and high\u2010dose groups. Histopathological changes abated following the recovery period. In summary, acute and repeated administration of NorLAAM produced a pharmacodynamic profile commensurate with its role as the primary <jats:italic>N<\/jats:italic>\u2010demethylated metabolite of LAAM, which is more potent and less lipophilic than the parent compound; this was reflected in the toxicological outcomes observed. Like LAAM, NorLAAM's overall pattern of activity is consistent with its activity as a \u03bc\u2010agonist, which stimulates hepatic microsomal enzymes in rodents.<\/jats:p>","DOI":"10.1002\/jat.2550150503","type":"journal-article","created":{"date-parts":[[2006,10,17]],"date-time":"2006-10-17T13:52:59Z","timestamp":1161093179000},"page":"339-355","source":"Crossref","is-referenced-by-count":0,"title":["Toxicological evaluation of \u03bc\u2010agonists. Part II: Assessment of toxicity following 30 days of repeated oral dosing of male and female rats with <i>levo<\/i>\u2010alpha\u2010noracetylmethadol hcl (norlaam)"],"prefix":"10.1002","volume":"15","author":[{"given":"Joseph F.","family":"Borzelleca","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"suffix":"Jr","given":"John L.","family":"Egle","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Louis S.","family":"Harris","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jo Ann Nuite","family":"Belleville","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2006,1,11]]},"reference":[{"key":"e_1_2_1_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/jat.2550140609"},{"key":"e_1_2_1_3_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1948.tb27252.x"},{"key":"e_1_2_1_4_2","doi-asserted-by":"publisher","DOI":"10.1021\/jo01136a022"},{"key":"e_1_2_1_5_2","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1016\/S0022-3565(25)05099-2","article-title":"Action and addiction liabilities of alpha\u2010acetylmethadol in man","volume":"105","author":"Fraser H. 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