Placental barrier

Specific barriers may serve to limit dmg distribution. The placental barrier is of obvious importance to dmg action in the fetus. Dmg transfers across the placenta primarily by Hpid solubiHty. Hence, this barrier is not particularly restrictive. Similarly, the Hpid solubiHty of a dmg is a primary deterrninant in access to the brain and cerebrospinal fluid. Generally, hydrophilic or charged dmgs can also penetrate to these latter areas, but the result is slow and incomplete. The blood brain barrier is composed of cells having tight junctions which are much less permeable to solutes than are the endotheHal cells of other tissues. 

Myxedema and goiter are the main conditions for which thyroid preparations are indicated. The treatment of cretinism is difficult because it is recognized only at or after birth. Even if this disease could be diagnosed m utero, thyroid hormones do not readily cross the placental barrier. In addition, the fetus, as does a premature infant, rapidly deactivates the thyroid hormones. The halogen-free analogue DlMlT [26384-44-7] (3), which is resistant to fetal deiodinases, may prove useful for fetal hypothyroidism (cretinism). 

Hewitt M et al. (2007) Structure-based modelling in reproductive toxicology (Q)SARs for the placental barrier. SAR QSAR Environ Res 18(l-2) 57-76 Mekenyan O et al. (2003) In silico modelling of hazard endpoints current problems and perspectives. SAR QSAR Environ Res 14(5-6) 361-371... 

Discuss characteristics that affect drug transfer across the placental barrier and into breast milk. 

Describe the roles and functions of the blood-brain and placental barriers. 

No studies addressing developmental or reproductive effects following acute inhalation exposure to aniline were located. However, because effects on development and reproduction arise after systemic uptake, oral administration of aniline can be considered for evaluating potential developmental and reproductive toxicity. Aniline (administered as aniline hydrochloride) readily crosses the placental barrier in rodents (Price et al. 1985). 

Grossly elevated concentrations of dissolved copper produce teratogenicity in fish embryos. A significant number of malformed fish larvae came from eggs treated with 500 pg Cu/L (Birge and Black 1979). In studies with laboratory animals and elevated concentrations of copper salts, copper penetrates the placental barrier into the fetus intramuscular injection of 4 mg Cu/kg BW early in pregnancy adversely affects fetal central nervous system development (Aaseth and Norseth 1986). In humans, no definitive data are available on whether copper can cause birth defects however, incubation of human spermatozoa with metallic copper results in loss of sperm motility (Aaseth and Norseth 1986). 

Arsenic can traverse placental barriers as little as 1.7 mg As+5/kg body weight at critical stages of hamster embryogenesis, for example, can produce fetal death and malformation. 

In Vitro Models and Multidrug Resistance Mechanisms of the Placental Barrier... 

Figure 16.1 Illustration of the anatomical arrangement of the syncytiotrophoblast (placental barrier) and the fetal capillaries as would appear in a cross section of a human placental villus. Reprinted from Audus [10] with permission from Elsevier B.V.

C. Ampasavate, G.A. Chandorkar, D.G. Vande Velde, J.F. Stobaugh, and K.L. Audus. Transport and metabolism of opioid peptides across BeWo cells, an in vitro model of the placental barrier. Int I Pharm. 233 85-98 (2002). 

M. Molsa, T. Heikkinen, J. Hakkola, K. Hakala, O. Wallerman, M. Wadelius, C. Wadelius, and K. Laine. Functional role of P-glycoprotein in the human blood-placental barrier. Clin Pharmacol Ther. 78 123-131 (2005). 

Placental Barrier The placental barrier consists of several layers of cells between the maternal and fetal circulatory systems. Diffusion of polar drugs is limited. However, lipid-soluble drugs can pass through the barrier. Fetuses are rich in lipids and may form a reservoir for sequestering lipid-soluble drugs. 

However, it had not been discovered that the thalidomide drug molecule could cross the placental barrier and affect fetal development. As a result, thousands of babies were born with crippled extremities, disfigurement, and disabilities. Numerous fetuses were stillborn or died soon after birth. 

Neonatal Cocaine freely crosses the placental barrier, and prenatal exposure to cocaine alters neurobehavioral development in rat pups (Sobrian et al. 1990). The effects on humans exposed prenatally to cocaine is a complicated matter, because so many other concurrent factors contribute to development. Common confounds are prenatal care and maternal polydrug use. Prenatal cocaine use is associated with reduced gestational age, birth weight, body length, and head circumference (Richardson et al. 1999). In children exposed prenatally to cocaine, some studies have shown behavioral differences evident at 1 to 3 years of age (Richardson et al. 1993 Richardson 1998). Associations are also made with impulsivity and attention deficits at age 6 (Leech et al. 1999). 

Harmala alkaloids are potent inhibitors of monoamine oxidase (Callaway and Grob 1998). Thus, if combined with other antidepressants, such as selective serotonin reuptake inhibitors, there is potential for serious side effects. Harmaline or its metabolites also cross the placental barrier (Okonmah et al. 1988). 

A small number of fetal cells cross the placental barrier and circulate in the mother s bloodstream. These can be isolated from a sample of the mother s blood using cell-sorting techniques, and DNA can be amplified by PCR for genetic diagnosis. Although still experimental, this technique offers the advantage that there is no risk of fetal loss as a result of the procedure. 

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