Maximum tolerated dose determination

Maximum tolerated dose (determined by 5-day toxicity tests in non-tumor-bearing mice). 

Nephrotoxicity is intrinsic to the pharmacological effect of certain anticancer drugs. Because anti-neoplastic drugs have a narrow therapeutic index, the amount of drug required to significantly reduce tumor burden usually induces significant nephrotoxicity. Furthermore, the dosage used in clinical trials often represents the maximum tolerated doses determined dur-... 

Dog or monkey (a) MTD, the maximum tolerated dose, determined with 2-4 animals at each dose level, spaced by twofold increments. In all instances individual doses which killed 0 and 100% were used. The highest dose killing 0% was considered the MTD (b) dose-related, hematopoietic effects, localized gastrointestinal hemorrhages, generalized hemorrhagic lesions, stimulation of the central nervous system, others. 

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. 

It is necessary to determine the toxicity of a drug. The maximum tolerable dose and area under the curve are established in rodents and nonrodents. There are two types of toxicity studies single dose and repeated dose. Single... 

Transitional cell bladder carcinomas and liver cell and cholangiomatous tumors were observed in hamsters fed a diet containing 0.3% 3,3 -dichlorobenzidine (300 mg/kg/day) (Sellakumar et al. 1969). This level was determined to be the maximum tolerated dose. In an earlier study, a diet eontaining 0.1%... 

The Phase I studies of vindesine determined the maximum tolerated dose of the compound to be 3-4 mg/m (body surface area) when given once weekly (i.v.) 78). Mild leukopenia ensues, reaching a nadir after about 4 days, and is accompanied by neurotoxicity. Several patients responded to drug treatment during this initial trial, including several complete responders with acute leukemias and partial responders with malignant melanoma and non-Hodgkin s lymphoma. Subsequent studies indicated that vindesine was active in vincristine-resistant childhood lymphocytic leukemia and, when combined with cisplatin, was effective in... 

Animals, usually rodents, are exposed to a test substance by an appropriate route (usually oral or intraperitoneal injection, other routes may be appropriate) followed by administration of bromodeoxyuridine (BrdU). At least five female and five male animals per experimental and control group should be used. For an initial assessment, one dose of the test substance may be used, the dose being the maximum tolerated dose or that producing some indication of toxicity as evidenced by animal morbidity (including death) or target cell toxicity. For determination of dose-response, at least three dose levels should be used. A compound known to produce SCE in vivo should be employed as the positive control. A spindle inhibitor (e.g., colchicine) is administered prior to sacrifice. After sacrifice, tissue is obtained and metaphase preparations made, stained, and scored for SCE. 

Choi NC, Herndon JEII, Rosenman J, et al. Phase I study to determine the maximum-tolerated dose of radiation in standard daily and hyperfractionated-accelerated twice-daily radiation schedules with concurrent chemotherapy for limited-stage small-cell lung cancer. J Clin Oncol 1998 16 3528-3536. 

Limonene and perillic acid remarkably reduced the lung metatastatic tumour nodule formation by 65 and 67%, respectively however, perillyl alcohol was considerably more potent than limonene against breast cancer [284, 302], rat mammary cancer and pancreatic tumours [288]. Phase 1 studies of d-limo-nene [303, 304] and phase I and phase II [305-311] studies of perillyl alcohol revealed dose-limiting toxicities nausea, vomiting, anorexia, unpleasant taste and eructation, and thus a maximum tolerated dose for perillyl alcohol was determined [305]. 

Thompson, E D. Hiles, R.A. (1981) A method for determining the maximum tolerated dose for in vivo cytogenetic analysis. Food Cosmet. Toxicol, 19, 347-351 Thompson, E.D., Coppinger, W.J., Piper, C.E., McCarroll, N., Oberly, T.J. Robinson, D. (1981) Mutageiucity of alkyl glycidyl ethers in three short-term assays. Mutat. Res., 90, 213-231... 

Acute toxicity Usually two species, two routes. Determine the no-effect dose and the maximum tolerated dose. In some cases, determine the acute dose that is lethal in approximately 50% of animals. 

Many toxicity studies, especially long-term bioassays carried out to determine potential carcinogenicity, use high-dose levels (e.g., maximum tolerated dose), and consequently, any hormetic response would be missed. To be properly evaluated, more doses and a wider dose response would have to be investigated. 

No studies were found in humans regarding the carcinogenic effect of chlorobenzene via inhalation. Since this is the primary route of environmental exposure, additional studies would be useful to assess potential risk to people who may be exposed to low levels of chlorobenzene in air near hazardous waste sites. There was no evidence for carcinogenicity in both sexes of mice or female rats following oral exposure to chlorobenzene. Since the animals were tested at the maximum tolerated dose and a no-effect level for tumors in rats and mice has been determined, additional oral studies are not warranted at this time. 

The usual daily dose ranges of antidepressants are shown in Table 30-4. Doses are almost always determined empirically the patient s acceptance of adverse effects is the usual limiting factor. Tolerance to some of the objectionable effects may develop, so that the usual pattern of treatment has been to start with small doses, increasing either to a predetermined daily dose, or to one that produces relief of depression, or to the maximum tolerated dose (except in the case of nortriptyline, which loses efficacy at plasma concentrations over 150 ng/mL). 

Notes Maximum tolerated dose (MTD) of inhibitor in cultured NIH 3T3 cells as determined by viable staining with MTT. 

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