Separation of hepatic n-demethylase-inducing and opioid dependence-producing doses of levo-alpha-acetylmethadol in the pregnant rat

Mercurio, Steven D.; Lichtblau, Leonard; Sparber, Sheldon B.

doi:10.1016/0024-3205(83)90016-4

Cited by 6 publications

(3 citation statements)

References 17 publications

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“…Previous examinations for physical end points of developmental toxicity have been limited to doses of LAAM no greater than 2 mg/kg/day (Lichtblau and Sparber 1981, 1983, where evidence for behavioral de cits and physical developmental toxicity in the offspring was found. We have now explored much higher doses.…”

Section: Discussionmentioning

confidence: 99%

“…As the tapering occurred in the high-dose group that was still undergoing dose escalation, this along with the similar maximum across dose groups, indicates that dose was not a sole contributing factor. LAAM is known to induce P450-dependent metabolism after both short-term treatment in the rat and mouse (Bellward 1977;Masten, Price, and Burnett 1978), and after prolonged treatment in the rat (Mercurio 1983). In the mouse this includes induction of LAAM N -demethylation (Masten, Price, and Burnett 1978).…”

Section: Discussionmentioning

confidence: 99%

“…Original developmental toxicity work conducted in the 1970s, focused on behavior, and was therefore restricted to relatively low doses (e.g., 0.2 to 2 mg/kg/day). Although some evidence of behavioral or functional toxicity was found for rats prenatally exposed to LAAM, no evidence of gross teratogenicity was reported at these doses (Lichtblau and Sparber 1981, 1983. The objective of this study was to elaborate on this earlier work and determine the developmental toxicity, including the teratogenic potential of LAAM at higher doses.…”

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confidence: 95%

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Developmental Toxicity of Levo-Alpha-Acetylmethadol (LAAM) in Tolerant Rats

et al. 2002

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Mated Crl:CD VAF/Plus female rats, in a range-finding study (n = 5-6 per dose) and a subsequent definitive study (n = 30 per dose) were used to determine the developmental toxicity, including the teratogenic potential of levo-alpha-acetylmethadol (LAAM) hydrochloride, in tolerant rats. Tolerance was induced by initially administering the drug by gavage (10 ml/kg) at 2 mg/kg/day and increasing the dose every 2 weeks for 12 weeks until the doses of 2, 6, 9, 12, and 15, or 2, 6, and 12 mg/kg/day were achieved in the range-finding or definitive study, respectively. Females were then mated to stock males and treated throughout mating and gestation. Controls received distilled water on a similar regimen. The range-finding experiment was used for initial clinical evaluations and to determine tissue concentrations of LAAM and metabolites. In plasma, liver, and brain collected from dams and fetuses pooled by litter on gestation day 20, LAAM and its two N-demethylated metabolites, norLAAM and dinorLAAM, showed dose-dependent increases in concentration and in tissue to plasma ratios. Tissue to dam plasma ratios were highest in dam liver (17-60), intermediate in fetal liver (3-16), and fetal brain (3-14), and lowest in dam brain (0.8-5.6) and fetal plasma (0.3-2.1). In the definitive study, caesarean section examinations were performed following euthanization on gestation day 20 on all surviving females followed by teratologic examination of the fetuses. Drug-related outcomes, including increased activity, secondary hair loss, scabbing, focal swelling, and material around the nose, were exhibited by all groups receiving LAAM. Maternal toxicity was evident as decreased body weights, with maximum reduction at the 6-mg/kg/day dose, and reduction in feed consumption. There was also evidence of developmental toxicity in the form of postimplantation losses at all doses of LAAM. There were no deaths attributable to LAAM. No grossly observable visceral or skeletal anomalies related to LAAM were observed in the fetuses. In conclusion, the no-observable-effect level when administered to tolerant rats was less than 2 mg/kg/day with regard to clinical signs, body weight, body weight gain, and feed consumption, and with regard to developmental toxicity as reflected by postimplantation losses. Despite maternal and developmental toxicity, there was no evidence of selective fetal toxicity or teratogenic activity attributable to LAAM.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 95%

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Developmental Toxicity of Levo-Alpha-Acetylmethadol (LAAM) in Tolerant Rats

et al. 2002

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Toxicological evaluation of μ‐agonists part I: Assessment of toxicity following 30 days of repeated oral dosing of male and female rats with levo‐alpha‐acetylmethadol HCl (LAAM)

Borzelleca

Egle

Harris

et al. 1994

J of Applied Toxicology

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This study evaluated levo-alpha-acetylmethadol hydrochloride (LAAM), a long-acting morphine-like (mu) agonist approved in 1993 to treat opiate dependence. Sprague-Dawley rate (20/sex/group) were gavaged with doses of 3.0-33.5 mg kg-1 for 30 days followed by a 14-day drug-free recovery period. Treatment-related effects included dose-dependent CNS depression, decreased food consumption and body weight gain, reddish urine and abdominal staining. Tolerance developed by day 7. Mortality was dose-dependent; deaths occurred predominantly during the first week. Increased alanine aminotransferase (SGOT, AST) and lactate dehydrogenase (LDH), observed only in high-dose males, were associated with findings in liver. Decreases in spleen/brain weight and increases in brain/body weight ratios were seen in both sexes. Decreases in weights of heart, liver and kidney achieved statistical significance only for high-dose groups. Kidneys of mid- and high-dose groups displayed intertubular mineral/crystal deposition, focal corticomedullary mineralization and focal regenerative tubular epithelium. Centrilobular hypertrophy was observed in livers of high-dose males and mid- and high-dose females. Following the recovery period, decreased body weights and increased brain/body weight ratios occurred in mid-dose males and low-dose females. Weights of liver and kidney and organ/brain weight ratios were decreased in mid-dose males. Histopathological findings observed in kidneys and livers had abated. In summary, acute and repeated administration of LAAM produced a spectrum of activity consistent with its profile as a long-acting pure mu-agonist which stimulates microsomal enzymes in rodents. Renal and hepatic effects seen in initially drug-naive rats treated with morphine-type agonists are not observed in tolerant individuals stabilized on mu-agonists to treat opiate dependence.

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Substance Abuse

Kenepp¹,

Chatwani²

Anesthetic and Obstetric Management of High-Risk Pregnancy

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Separation of hepatic n-demethylase-inducing and opioid dependence-producing doses of levo-alpha-acetylmethadol in the pregnant rat

Cited by 6 publications

References 17 publications

Developmental Toxicity of Levo-Alpha-Acetylmethadol (LAAM) in Tolerant Rats

Developmental Toxicity of Levo-Alpha-Acetylmethadol (LAAM) in Tolerant Rats

Toxicological evaluation of μ‐agonists part I: Assessment of toxicity following 30 days of repeated oral dosing of male and female rats with levo‐alpha‐acetylmethadol HCl (LAAM)

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