NTP-CERHR Expert Panel Report on the reproductive and developmental toxicity of amphetamine and methamphetamine

Article (PDF Available)inBirth Defects Research Part B Developmental and Reproductive Toxicology 74(6):471-584 · December 2005with42 Reads
DOI: 10.1002/bdrb.20048 · Source: PubMed

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Available from: Andrew S Rowland
    • "Rats were assigned randomly to control or MAtreated groups based on body weights and likelihood of pregnancy (n = 13 for controls, n = 18 for MA treatments). MA abusers generally use a dose starting at 20 mg with a common MA dose being 30 mg (Golub et al., 2005 ). When extrapolating this dose back to a preclinical model, the use of an allometric scale (Reagan-Shaw et al., 2008) takes into account the body weight and the body surface area of the human and the animal. "
    [Show abstract] [Hide abstract] ABSTRACT: Many preclinical studies have aimed to elucidate the effects of methamphetamine (MA) exposure during pregnancy on the offspring in recent years. However, the severity of effects on the neonate may be related to the subcutaneous (sc) route of administration of the drug that is often employed (88% of preclinical studies) and consequently the delivered dose that the foetus is exposed to. To date there is a paucity of comparative studies investigating different routes of administration for MA during pregnancy and it is not known how these different routes compare when it comes to neonatal outcome. Thus, the aim of this study was to determine if the route of administration of MA (oral gavage or sc injection) during pregnancy at a pharmacological dose affects the magnitude of neurodevelopmental and behavioural effects in the resultant rat offspring. Pregnant Sprague-Dawley dams (n = 10 dams/group) received MA (3.75 mg/kg) or control (distilled water) via oral gavage or sc injection from gestation day 7–21. A range of well-recognised neurodevelopmental parameters were examined in the offspring. When administered sc, MA significantly reduced maternal weight gain and altered maternal behaviour; mothers spent less time in the nest with pups and spent less time nursing compared to controls. Significant impairments in neurodevelopmental parameters were evident in both MA treatment groups. Somatic development such as pinna unfolding, fur appearance and eye opening were all delayed after MA exposure but these impairments were more pronounced in the MA sc group. Other somatic parameters such as ano-genital distance and body length were only impeded by sc MA. Behavioural development in the surface righting, inclined plane and forelimb grip tests were also altered for both MA treatment groups. This study demonstrates that prenatal MA can have a profound effect on neonatal outcome, but this can be exacerbated if given via the subcutaneous route, as well as producing additional effects not seen with the oral gavage route. Consequently, the route of administration should be considered when interpreting preclinical studies investigating prenatal MA exposure.
    Full-text · Article · Dec 2015
    • "A variety of doses have been explored in prenatal and neonatal ATS exposure studies however, many of these studies fall into the neurotoxicological doses. When we look to the clinical situation we see many patterns of exposure (Table E.1) across each trimester of pregnancy but it has been shown that the most common frequency of MA use, for example, in pregnancy is generally almost every day/daily [58] and although there are a wide range of doses that are abused by these females (Table E.1), Golub et al. [19] reports that the most common MA dose is around 30 mg. The minimum doses of AMP, MDMA and MA examined in preclinical studies have been 0.5, 0.5 and 0.625 mg/kg [24,33,39] and the maximum doses have been 100, 20 and 40 mg/kg, respectively596061. "
    [Show abstract] [Hide abstract] ABSTRACT: The prevalence of drug use during pregnancy has increased in recent years and the amount of drug-exposed babies has therefore increased. In order to assess the risk associated with this there has been an increase in the amount of preclinical studies investigating the effects of prenatal and postnatal drug exposure on the offspring. There are many challenges associated with investigating the developmental and behavioural effects of drugs of abuse in animal models and ensuring that such models are appropriate and clinically relevant. The purpose of this review is to illustrate the variation in the design of preclinical studies investigating the effects of the amphetamine-type stimulants taken during pregnancy and/or lactation in animal models. Methamphetamine, methylendioxymethamphetamine and amphetamine were included in this review. The protocols used for exploring the effects of these drugs when taking during pregnancy and/or lactation were investigated and summarised into maternal experimental variables and offspring experimental variables. Maternal experimental variables include animals used, mating procedures and drug treatment and offspring experimental variables include litter standardisation, cross fostering, weaning and behaviours and parameters assessed. The findings in this paper suggest that there is a large diversity and little consistency among these studies and so the interpretation of these results may not be as clinically relevant as previously thought. For this reason, the importance of steering the preclinical studies in a direction that is most clinically relevant will be an important future recommendation. This will also allow us to be more confident in the results obtained and confident that the human situation is being replicated as closely as possible.
    Full-text · Article · Feb 2015
    • "However, in the clinical situation we know that the offspring are exposed indirectly to the drug through breast milk and not by direct exposure via injection and so, the same should be performed in preclinical studies. Methamphetamine abusers generally use a dose starting at 20 mg with a common MA dose being 30 mg (Golub et al., 2005). When extrapolating this dose back to a preclinical model, the use of an allometric scale (Reagan-Shaw et al., 2008) takes into account the body weight and the body surface area of the human and the animal. "
    [Show abstract] [Hide abstract] ABSTRACT: In recent years methamphetamine (MA) use has become more prevalent, and of particular concern is its growing popularity of MA among women of childbearing age. However, to date, studies examining MA effects on the developing offspring in laboratory animals are limited. Thus, the aim of this study was to determine if in utero MA exposure in rats at pharmacological doses can have a negative impact on neonatal neurodevelopment and behaviour. Pregnant Sprague-Dawley dams (n = 10 dams/group) received MA (0, 0.625, 1.25, 2.5) once daily via oral gavage from gestational day 7-21. Maternal body weight, food and water consumption were recorded daily. A range of standard neurodevelopment parameters were examined in the offspring during the neonatal period. There were no neurodevelopmental deficits observed with offspring exposed to 0.625 mg/kg MA, in fact, there were enhancements of neurodevelopment in some parameters at this low dose. However, exposure to the 1.25 mg/kg MA dose resulted in significant impairments in surface righting reflex and forelimb grip in both sexes. Exposure to the 2.5 mg/kg MA dose resulted in a significant reduction in ano-genital distance in males, and in both sexes resulted in delayed fur appearance and eye opening, impairments in surface righting reflex and negative geotaxis, and a reduction in body length. In conclusion, this study demonstrates that pharmacologically relevant doses of MA can have profound dose-related effects on neonatal outcome. If extrapolated to the clinical scenario this will give cause for concern regarding the risks associated with this drug of abuse at relatively low doses.
    Full-text · Article · Jun 2014
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