Fetus restriction

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. 

If the genetic lesion is understood and a specific probe is available, prenatal diagnosis is possible. DNA from cells collected from as little as 10 mL of amniotic fluid (or by chorionic villus biopsy) can be analyzed by Southern blot transfer. A fetus with the restriction pattern AA in Figure 40-10 does not have sickle cell disease, nor is it a carrier. A fetus with the SS pattern will develop the disease. Probes are now available for this type of analysis of many genetic diseases. 

The degree of exposure of the fetus to a particular substance can be best assessed in human subjects, but concerns of fetal safety have restricted the use of this approach. Moreover, clinical studies cannot elucidate the various mechanisms that contribute to transplacental transport of a particular compound. There are many structural differences between the human placenta and the placenta of other mammalian species, which complicates extrapolation of data obtained from in vivo animal models to humans [7], Thus, several ex vivo and in vitro techniques have been developed to study the placental role in drug transfer and metabolism during pregnancy and there are some excellent articles that discuss these systems in detail [7], Both isolated tissues and various cell culture techniques are currently in use and these have been summarized below. 

Topical formulations of nystatin and of amphotericin B are useful in the management of Candida albicans infections of the skin. Both antibiotics are ineffective against dermatophytes. The use of nystatin is limited to topical treatment of cutaneous and mucosal Candida infections because of its narrow spectrum and its negligible absorption from the gastrointestinal tract. Hypersensitivity reactions are rare. It is not known whether topical nystatin can cause fetal harm when used by a pregnant woman. Amphotericin B has broader antifungal activity but its topical use is restricted to Candida. Topical use of amphotericin B has shown minimal absorption through the skin and is well tolerated. Limited human surveillance data do not indicate any harm to mother or fetus, but relative safety is still unknown. 

For most substances, however, a preliminary study is advisable to avoid the use of inappropriate (i.e., either too high or too low) dose levels. The design would be as described below for a main study but with typically five or six animals per dose level and fetal evaluation restricted to an external examination and weight. Sexing of fetuses is not needed, although many laboratories will sex fetuses as routine. 

This decision drew a rapid response from defenders of women s reproductive privacy, who saw it as part of a trend to undermine Roe v. Wade by acknowledging fetuses as persons and restricting women s rights correspondingly. 

Fetal DNA shows only fragment "b" when DNA is digested with the same restriction endonuclease. This means that the fetus is affected because it has inherited two abnormal genes from its parents and shows the genotype "bb."... 

Tin does not appear to readily cross the placenta. At 10 days of gestation, tin was not found in the uterine horns or combined fetuses and placentas in rats following daily ingestion of 20 mg tin/kg/day as SnF2 or SnF (Hiles 1974). Flowever, at 21 days, fetuses of dams administered 20 mg/kg/day as SnF2 contained very low levels of tin. The detection of low levels and the absence of developmental effects suggest placental restriction of tin transfer to the fetus. 

In the immediate future, many other common problems of pregnancy and the fetus are likely to be reexamined by proteomics and metabolomics, ultimately identifying the best predictive biomarkers for disease and adverse neonatal outcome. As we have begun to see, pregnancy-induced hypertension (PIH), growth restriction in utero, diabetic pregnancy, and placental insufficiency are but a few of the situations in which early proteomic assessment is likely to play a prominent role in the next several years (Figure 8). 

Since morning sickness of pregnancy occurs during the time when the fetus is vulnerable, it is specially important to restrict drug therapy of this symptom to a minimum but severe vomiting with its accompanying biochemical changes may itself harm the fetus. 

Prasad and Oberleas (90) provided evidence that decreased activity of deoxythymidine kinase may be responsible for this early reduction in DNA synthesis. As early as six days after the animals were placed on the dietary treatment, the activity of deoxythymidine kinase was reduced in rapidly regenerating connective tissue of zinc-deficient rats, compared with pair-fed controls. These results recently have been confirmed by Dreosti and Hurley (94), The activity of deoxythymidine kinase in 12-day-old fetuses taken from females exposed to a dietary zinc deficiency during pregnancy was significantly lower than in adlibitum and restricted-fed controls. Activity of the enzyme was not restored by in vitro addition of zinc, whereas addition of copper severely aflFected the enzyme activity adversely. Recently zinc has been shown to be an essential constituent for the DNA polymerase of E. coli (95). Whether or not this enzyme is affected adversely in animal model, because of deficiency of zinc, is not known. 

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