Protection patterns, drugs

FIGURE 20.7 Non-zero-asymptote model with natural history (thick line) offset pattern (thin line), and tu o types of protective pattern drug effects SSS, effect on steady-state burned out state (dashed line), and Tprog, effect on half-life of disease progress (dotted line). 

The 1996 Food Quality Protection Act (FQPA) now requires that an additional safety factor of 10 be used in the risk assessment of pesticides to ensure the safety of infants and children, unless the EPA can show that an adequate margin of safety is assured with out it (Scheuplein, 2000). The rational behind this additional safety factor is that infants and children have different dietary consumption patterns than adults and infants, and children are more susceptible to toxicants than adults. We do know from pharmacokinetics studies with various human pharmaceuticals that drug elimination is slower in infants up to 6 months of age than in adults, and therefore the potential exists for greater tissue concentrations and vulnerability for neonatal and postnatal effects. Based on these observations, the US EPA supports a default safety factor greater or less than 10, which may be used on the basis of reliable data. However, there are few scientific data from humans or animals that permit comparisons of sensitivities of children and adults, but there are some examples, such as lead, where children are the more sensitive population. It some cases qualitative differences in age-related susceptibility are small beyond 6 months of age, and quantitative differences in toxicity between children and adults can sometimes be less than a factor of 2 or 3. 

Figure 20.1 illustrates the offset and slope models and the combination of both types of effect. The offset pattern of drug effect provides an explicit definition of a temporary or symptomatic effect of a drug. In contrast, the slope pattern of drug effect defines a drug with a disease-modifying, protective effect. 

In addition, an exponentially progressing pattern of disease progress (parameterized by a half-life of progression) can reflect a protective benefit of drug treatment if the therapeutic intervention enhances the return to the normal state or shortens the half-life of the recovery process. Equation 20.10 describes the protective benefit ... 

Additional models for drug effects on the non-zero-asymptote model include two patterns of protective drug effects. These assume a drug effect changing either the burned out state, Sss ... 

Tablets may be formulated with coatings such as shellac, resin, or styrene-maleic acid copolymer. These coatings are insoluble in acid but dissolve readily at neutral or alkaline pH. Thus they are ideally suited to prevent drug release until the formulation has passed from the stomach into the small intestine. Preventing drug release in the stomach may protect drugs that are acid labile. It may also protect the patient from irritant substances like iron salts, diethylstilbo-estrol, and some anti-inflammatory agents. Release, and subsequent systemic availability of drugs from these formulations is likely to be highly sensitive to stomach emptying patterns.

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