Biological activity dose-effect relationships

The preclinical knowledge base is initially developed by designing studies to answer fundamental questions. The development of this knowledge base is generally applicable to most pharmaceuticals as well as biopharmaceuticals, and include data to support (1) the relationship of the dose to the biological activity, (2) the relationship of the dose to the toxicity, (3) the effect of route and/or schedule on activity or toxicity and (4) identification of the potential risks for subsequent clinical studies. These questions are considered in the context of indication and/or disease state. In addition there are often unique concerns related to the specific category or product class. 

In addition to the effect of biological variabihty in group response for a given exposure dose, the magnitude of the dose for any given individual also determines the severity of the toxic injury. In general, the considerations for dose—response relationship with respect to both the proportion of a population responding and the severity of the response are similar for local and systemic effects. However, if metabohc activation is a factor in toxicity, then a saturation level may be reached. 

The most recently reported UK results on surveillance for veterinary drug residues in meat and animal products show that traces of these compounds can, and sometimes do, arise in food. As all of these compounds are biologically potent in order to be effective in use, it is necessary to ensure that any residual activity in a food product does not present a risk to the consumer. The use of veterinary medicines inevitably leads to the presence of trace residues in food and the purpose of toxicological safety evaluation is to determine at what concentration the residues of a particular compound becomes a cause for concern with regard to human health. Thus, dose-response relationships have to be established and used to determine the concentration of a dmg at which the risks to human health become acceptable and are outweighed by the benefits from the use of the drug. This is in essence the process involved in the setting of Acceptable Daily Intakes (ADIs) and... 

However, some of the studies were limited by using 2,3,7,8-TCDD concentrations in excess of its solubility in water. Only two early studies reported positive results (Hussain et al. 1972 Seiler 1973). However, the results were limited by failure to demonstrate a dose-response relationship and by low bacterial survival rates. In addition, 2,3,7,8-TCDD exposure induced reverse mutations in Escherichia coli (Hussain et al. 1972) and in Saccharomyces cerevisiae (Bronzetti et al. 1983). The conflicting data obtained in the above studies may result from technical difficulties in testing 2,3,7,8-TCDD rather than from a lack of biological activity. Testing difficulties arise from an extreme insolubility of this compound and a high toxicity observed in some test systems, which would be anticipated to result in a very narrow window for effective genotoxic doses. 

The dose-response relationship measures the correlation that occurs as one modifies the amount (dose) of a chemical substance to which a living material is exposed and the severity of the effect (response). This is commonly used with pharmaceuticals to determine the most effective amount of medication to be administered to have the desired beneficial effect. If the amount of medicine administered is too small (below the therapeutic level), the intended beneficial effect does not occur if the dose is increased and the amount administered is too large (above therapeutic range) toxicity may become evident. Toxicologists hold that the dose-response relationship applies not only to therapeutic agents but also to all chemical substances, that is, the dose makes the poison . The underlying principal is that the biological effects (beneficial or deleterious) of chemicals are due to the amounts of active material at the site, or sites, of action and that the concentration or the amount of the substance at the site (internal dose) is related to the amount of chemical administered (external dose). 

A possible link between the effects of Cr(III) and Cr(VI) on carbohydrate metabolism and enzyme activation has been overlooked in the studies of Cr(III) as a nutrient (5). Treatment of rats with large doses of Cr(VI) (Na2Cr20v 20-40 mg kg subcutaneously) induced a severe, but short term, decrease in blood insulin levels (624). A significant insulin-independent stimulation of 3-0-methylglucose uptake by isolated rat adipocytes was achieved in the presence of Na2Cr207 [50-300 pM Cr(VI)] this effect was strictly ATP dependent, which implies a relationship to phosphorylation reactions (625). A detailed study of this effect by Yurkow and Kim (295, 626) showed that treatment of intact rat hepatoma cells with Cr(VI) (100 pM) induced the insulin-independent activation of certain types of protein kinases, which led to increased phosphorylation levels in various proteins these phosphorylated proteins could then participate in insulin signaling pathways. Treatment with Cr(VI) did not affect the insulin-dependent phosphorylation on p-subunits of insulin receptors. Thus, Cr(VI), similar to V(V) (618) but unlike the biologically active Cr(III) complexes (496, 497, 618), acts as an insulin mimetic rather than potentiator. Unlike V(V), however, the action of Cr(VI) resulted from kinase activation rather than... 

Good relationships between the retention in MLC and some biological activities of local anesthetics (bupivacaine, lidocaine, mepiva-caine, prilocaine, procaine and tetracaine), such as anesthetic potency, concentration of compound that produces an effect similar to a reference concentration of cocaine, duration of the action, toxicity and time taken to eliminate half the drug present in the body, have also b n reported [24]. Some anesthetic actions of barbiturates also correlated well with the retention minimum effective hypnotic dose in rabbits, molar drug concentration necessary to reduce cell division, and molar drug concentration required to reduce 50% the inhibition of oxygen respiration on the brain of a rat in vitro [25],... 

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