Maximum well-tolerated dose

The limitations of the use of biomarkers in healthy volunteers must be recognised. For example, although there have been attempts to simulate migraine headache in volunteers, to date none of these models can be considered adequate to serve as a surrogate endpoint. Patients with migraine are not difficult to recruit and are usually healthy apart from their migraine. In this case, it maybe more appropriate to establish tolerability and pharmacokinetics in healthy volunteers and then to select a maximum well-tolerated dose with which to perform a small proof of principle clinical trial in patients. This will need to be followed by larger trials to establish the dose-response relationship. 

The tetracyclic compound (XXXI, R = Me) prepared by the action of hydrazine on (XXIX, R = Me) followed by acetic anhydride was also active and had selectivity ratios of 4 and 10 against two rhinovirus strains, but was inactive against the other two. In this paper, the maximum concentration of compound which permitted normal cell maintenance was determined for each compound and called the maximum well-tolerated dose. For (XXX, R = Me) this was 252 pg/ml and for (XXI, R = Me) was 42 pg/ml. 

Further work with (XXX, R = Me) established that it can inhibit 19 strains of rhinovirus at concentrations of 20-50 pg/ml and the maximum well-tolerated dose was 250 pg/ml. It was active orally in mice against vac-... 

Derivatives of 1 -piperazine carboxylic acid have been thoroughly examined for activity against influenza A (strain PR 8) in mice [175]. Of 100 compounds tested, 19 were found active after being given to mice orally in a single maximum well-tolerated dose. Virus was administered intranasally and activity was based on percentage survivors at 14 days after infection. It was found that the structural features of either (XXXII) or (XXXIII) were necessary for activity. 

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... 

Most work on saponins as immunological adjuvants has been done following parenteral inoculation. Saponins are more toxic by parenteral (i.p. or i.v.) administration than by the oral route, presumably because of a more complete uptake by the former. Toxicity associated with Quil A has limited its development to veterinary vaccines. The maximum well tolerated i.p. dose in mice was estimated to be 25 ig. Significantly lower toxicity was observed by subcutaneous, intradermal, and intramuscular routes of administration. The toxicity of individual saponins varies considerably. For example, the major peak saponin QS-18 (2) was found to be toxic in mice at low doses (80% mortality within three days after i.d. injection of 125 p,g) whereas QS-7 was non toxic (100% survival with 0.5 mg, the highest dose tested). A simple analogy between hemolytic activity and toxicity is not possible since QS-21 (3), which was shown to have a slightly higher hemolytic activity than QS-18 (2), was proven to be less toxic [9]. 

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. 

Nevertheless, this study had several limitations. Initial doses were not well tolerated because of exceedence of the Maximum Tolerated Dose (MTD) as indicated by excessive deaths. Doses were reduced 17-33% from initial doses once or twice during the experiment. During the final 75 days of treatment, high dose males received chlordecone on alternative weeks only. Doses above the MTD were used for 42-386 days. An unusually high mortality rate occurred in control animals also, and only pooled controls were used in this bioassay. 

CHF and chronic renal failure It has been suggested that doses as high as 2 to 2.5 g/day or more are well tolerated and effective in these patients. For IV bolus injections, the maximum should not exceed 1 g/day given over 30 minutes. 

The recommended starting dose of rivastigmine is 1.5 mg twice a day. If dose is well tolerated, after a minimum of 2 weeks of treatment, the dose may be increased to 3 mg twice a day. Subsequent increases to 4.5 and 6 mg twice/day should be attempted after a minimum of 2 weeks at the previous dose. If adverse effects (eg, nausea, vomiting, abdominal pain, loss of appetite) cause intolerance during treatment, instruct the patient to discontinue treatment for several doses and then restart at the same or next lower dose level. If treatment is interrupted for longer than several days, reinitiate treatment with the lowest daily dose and titrate as described above. The maximum dose is 6 mg twice/day (12 mg/day). 

Patients more than 12 years of age - The effective dose is 900 to 1800 mg/day in divided doses (3 times/day) using 300 or 400 mg capsules or 600 or 800 mg tablets. The starting dose is 300 mg 3 times/day. If necessary, the dose may be increased using 300 or 400 mg capsules or 600 or 800 mg tablets 3 times/day up to 1800 mg/day. Dosages up to 2400 mg/day have been well tolerated in long-term clinical studies. Doses of 3600 mg/day also have been administered to a small number of patients for a relatively short duration, and have been well tolerated. The maximum time between doses in the 3 times/day schedule should not exceed 12 hours. 

For adults, the maximum recommended dose is 10 mg/kg (600 mg), once weekly during the continuation phase. Data have suggested that a dose of 900 mg is well tolerated, but the clinical efficacy of this dose has not been established. 

PYA copolymer Bioavailability enhancer Single-dose toxicity (in rat and dog) and maximum tolerated dose/short-term (2wks—oral) (in rat and dog) toxicity as well as 2 in vitro and 1 in vivo genotoxicity studies. ADME studies with 14C-labelled material are underway and a 3-6 mo toxicity study in the rat is planned No adverse effects seen to date 41... 

This could normally be done in one strain provided the top dose used in the assay was well below the maximum tolerated dose, as this might be acutely toxic to a more sensitive strain. A lot of the increased sensitivity from using inbred strains comes from the reduced noise making it possible to detect subtle effects, not because the animals show more marked symptoms. 

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