Tolerance dose

For carckiogen pesticides (70,71), animal testkigs are subject to maximum tolerated doses (M I L)). M I D is the maximum amount of a substance that can be administered to an experimental animal without causkig extreme health consequences, such as death, to occur but while continuing to produce some measurable toxic effects. Current regulatory theory holds that carckiogen effects do not have a threshold and caimot be related to reference doses. 

Savolainen, K. M. (1997). The use of maximum tolerated dose in rodent carcinogenicity bioas says and its relevance to human risk assessment. Hum. Exp. Toxicol. 16, 190-192. 

The drug should be administered at three levels by the route proposed for humans. The high dose level should be set so as to have relevance in humans. For drugs that display significant toxic effects, this may be related to the maximally tolerated dose in the toxicity tests, for example, the dose causing less than 10% deviation in body weight versus controls. If there is little evidence of toxicity it may be more appropriate to base the dose level on a multiple (usually 25-fold) of the maximum therapeutic dosage recommended in humans. 

Numerous experimental therapeutics have shown potency in vitro however, when they are tested in vivo, they often lack significant efficacy. This is often attributed to unfavorable pharmacokinetic properties and systemic toxicity, which limit the maximum tolerated dose. These limitations can be overcome by use of drug carriers. Two general types of carrier systems have been designed drug conjugation to macromolecular carriers, such as polymers and proteins and drug encapsulation in nanocarriers, such as liposomes, polymersomes and micelles. 

Experiments were conducted in which purified trichloroethylene (1 mg in acetone) was applied to the shaved backs of female ICR/Ha Swiss mice (Van Duuren et al. 1979). In an initiation-promotion study, a single application of trichloroethylene was followed by repeated application of phorbol myristate acetate (PMA) promoter. In a second study, mice were treated with trichloroethylene three times per week without a promoter. No significant tumor incidences were observed in these studies. Doses used in these studies were well below the maximum tolerated dose, which is often not reached in dermal studies. 

In practice it is obviously difficult to actually determine the toxic and effective dose in 50% of treated patients in the same population but the concept of a maximum tolerated dose compared with an effective dose is of great importance. 

Is the patient at goal or maximally tolerated doses of vasodilator and P-blocker therapy ... 

Treatment should begin as early as possible in patients with a diagnosis of AD.30 Figure 32-2 provides a recommended treatment algorithm for AD.31 Patients should be switched to another ChE inhibitor from their initial ChE inhibitor if they show an initial lack of efficacy initially respond to treatment, but lose clinical benefit or experience safety/tolerability issues. This switch should not be attempted until the patient has been on a maximally tolerated dose for a period of 3 to 6 months. The switch should also be based on realistic expectations of the patient and/or caregiver.32 ChE inhibitor therapy should be discontinued in patients who experience poor tolerance or compliance, who show a lack of clinical improvement after 3 to 6 months at optimal dosing, who continue to deteriorate at the pretreatment rate, or who demonstrate dramatic clinical deterioration following initiation of treatment.33... 

FIGURE 69-3. Treatment algorithm3 for acute bacterial rhinosinusitis in patients with mild disease without recent antibiotic exposure.31 aAntibiotics are listed in order of predicted efficacy based on predicted clinical and bacteriologic efficacy rates, clinical studies, safety, and tolerability. Doses can be found in Table 69-4. 6Cephalosporins should be considered for patients with non-type I hypersensitivity to penicillins they are more likely to be effective than the alternative agents. cHigh doses (90 mg/kg per day) are recommended for most children, especially those with day-care contacts or frequent infections. 

Mitotane—if well-tolerated, dose may be doubled on day 3 then, from day 5 onwards, may increase dose by 500 mg every 2-3 days until maximum tolerated dose (8-12 grams daily) has been reached glucocorticoid and mineralocorticoid replacement necessary to prevent adrenal insufficiency increased steroid doses may be needed at times of physiologic stress... 

Repeat every 4-6 weeks for 2 cycles, then adjust to maximum tolerated dose (1 -2 mg/M2/d CIV X 5 days) every 4-8 weeks to a maximum of 12 cycles... 

Doses should be doubled no more often than every 2 weeks, as tolerated, until the target dose or the maximally tolerated dose is reached. Patients... 

In general, very dilute solutions are given initially once or twice per week. The concentration is increased until the maximum tolerated dose is achieved. This maintenance dose is continued every 2 to 6 weeks, depending on clinical response. Better results are obtained with year-round rather than seasonal injections. 

Oxybutynin IR is best tolerated when the dose is gradually escalated from less than or equal to 2.5 mg twice daily to 2.5 mg three times daily after 1 month. Oxybutynin IR can be further increased in 2.5-mg/day increments every 1 to 2 months until the desired response, maximum recommended dose of 5 mg three times daily, or maximum tolerated dose is attained. 

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