Maximal tolerable concentration

Gwynn and Salaman H tested a number of compounds, Including CN, as possible promoters of skin carcinogenesis when 9,10-dimethyl-1,2-benzanthracene (DMBA) was used as an initiator. Treatment consisted of 0.3 ml of a 0.1% or 0.15% acetone solution of DMBA on the clipped backs of mice, followed after a delay of 21 d by application of CN at a maximal tolerated concentration once or twice a week for 12-15 wk. There was a significant increase in tumors 22 wk after the start of secondary treatment. 

Table 3 summarizes different additives that have been proposed (1) as solubility enhancers, (2) to reduce adsorption or (3) to increase the biorelevance (pH, bile salts, sink conditions) in in ly r oabsorption models. The maximal tolerable concentration of each was determined by assessing the flux of a hydrophilic marker, the transepithelial electrical resistance (TEER) and/or the release of enzymes or the enzymatic status of the cell monolayers. 

The therapeutic window of an active substance is the blood concentration range within which the desired therapeutic effect will occur without serious side effects. The lower limit of the therapeutic window is the so-called minimal effective concentration (MEC). This is the lowest blood concentration of the active substance that exerts a therapeutic effect. The upper limit of the therapeutic window is the maximal tolerable concentration (MTC). When the MTC is reached or exceeded, unacceptable adverse effects of the active substance are likely to occur. 

TEL is not an irritant, and no unpleasant sensations are related to skin contact or inhalation. The ability to penetrate skin makes reliance on airborne concentrations impractical. Teratogenic effects have not been observed after exposure to maximally tolerated doses in mice or rats. Rodent embryos may serve as a poor model for human femses because the hepatic microsomal metabolizing... 

Single doses of 10 mg are tolerated by humans without any unwanted side effects. Maximal plasma concentrations are reached 2 h after either oral or subcutaneous ingestion. Elimination half-life is... 

Fiilliiwing oral administration, about 80% of the dose is vded.. Maximal plasma concentrations are achieved in I > hums. The drug is rapidly metabolized in Ihe liver in li liM pass. It is likely that some of the metabolites are. ->aii e. Praziquantel occurs as a white crystalline solid i It insoluble in water. It is available as 6(X)-mg film-K.iol lableis. The drug is generally well tolerated. 

Inhibitons of AChE. such as OPs. are fast acting and lethal it i.s therefore a surprise that a knockout animal for AChE can survive for almost 1 year. The animal must therefore have developed maximal tolerance to a high concentration of ACh. Investigation of the peripheral nerv-ous system using the phrenic nerve-hemidiaphragm. showed that the knockout animal had developed markedly greater twist tensions and slower rise and relaxation time. To compensate for the absence of AChE activity, the size of the endplate was reduced. This may provide some compensation because less ACh is provided. The juctional folds of the endplate and the number of nAChRs were heavily reduced. This allowed. smaller responses to ACh and also more ACh to diffuse out... 

Maximally tolerated dose and resulting plasma concentration in two species (rodent and nonrodent)... 

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