Cumulation of active metabolites of levo-alpha-acetylmethadol in the rat fetus and neonate

Lichtblau, Leonard; Finkle, Bryan S.; Sparber, Sheldon B.

doi:10.1016/0024-3205(82)90513-6

Cited by 8 publications

(3 citation statements)

References 19 publications

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“…Dose-dependent increases of LAAM and metabolites in maternal and fetal plasma, liver and brain were demonstrated during this study. The ratio of analytes in tissue to maternal plasma were consistent with the previous studies (Lichtblau, Finkle, and Sparber 1982;Man et al 1980) and ranked as follows: maternal liver > fetal liver, fetal brain > maternal brain. Although we have not determined the mechanism for the differences in tissue-to-plasma ratios, we Borzelleca et al (1994) and Rosenkrantz and Fleischman (1988) described reduced weight gain in female rats chronically treated with LAAM; in both cases it was associated with reduced feed consumption.…”

Section: Discussionsupporting

confidence: 89%

“…The tissue and plasma concentrations of LAAM and metabolites substantiates that potential target organs were exposed to LAAM and pharmacodynamically active metabolites. Studies comparing fetal and maternal concentrations of LAAM and the metabolites norLAAM and dinorLAAM have previously been limited to chronic 0.2-and 2-mg/kg/day oral doses compared to an acute 2-mg/kg dose (Lichtblau, Finkle, and Sparber 1982) and a single 3 mg/kg subcutaneous dose (Man et al 1980). Dose-dependent increases of LAAM and metabolites in maternal and fetal plasma, liver and brain were demonstrated during this study.…”

Section: Discussionmentioning

confidence: 99%

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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: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

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

et al. 2002

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“…Pharmacokinetics of the different opioids differ greatly. For drugs with an elimination half-life longer than MOR, such as LAAM, daily dosing can lead to accumulation of the drug in fetal tissue, even when it does not accumulate in maternal tissue [32], Second, methodologies were dif ferent among studies. For example, neonatal guinea pigs were studied while awake, where as previous studies with newborn puppies [8] and human neonates [7] were done during quiet sleep.…”

Section: Discussionmentioning

confidence: 99%

Chronic Intermittent in utero Exposure to Morphine: Effects on Respiratory Control in the Neonatal Guinea Pig

Hunter¹,

Vangelisti²,

Olsen³

1997

Neonatology

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This study was done to determine if chronic intermittent in utero exposure to morphine (MOR) during the last half of gestation results in hypoventilation and decreased ventilatory sensitivity to CO₂ in the neonate. Pregnant guinea pigs were randomly assigned to once-daily treatment with saline and 1.5, 5.0, or 15.0mg/kg MOR. Neonates were studied for 3 weeks. Prenatal exposure to 5.0 and 15.0 mg/kg MOR significantly increased neonatal minute ventilation and central inspiratory drive on day 7 while breathing room air or 5% CO₂. The increase in minute ventilation was part of a withdrawal syndrome that included increased locomotor activity, but was not due to an increase in metabolic rate or sensitivity to CO₂. We conclude that neonatal guinea pigs exposed once daily to MOR during the last half of gestation hyperventilate during the 1 st week after birth. These changes are neither permanent nor followed by hypoventilation or depressed sensitivity to CO₂.

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