Minimum tolerated dose

Statistical models. A number of statistical dose-response extrapolation models have been discussed in the literature (Krewski et al., 1989 Moolgavkar et al., 1999). Most of these models are based on the notion that each individual has his or her own tolerance (absorbed dose that produces no response in an individual), while any dose that exceeds the tolerance will result in a positive response. These tolerances are presumed to vary among individuals in the population, and the assumed absence of a threshold in the dose-response relationship is represented by allowing the minimum tolerance to be zero. Specification of a functional form of the distribution of tolerances in a population determines the shape of the dose-response relationship and, thus, defines a particular statistical model. Several mathematical models have been developed to estimate low-dose responses from data observed at high doses (e.g., Weibull, multi-stage, one-hit). The accuracy of the response estimated by extrapolation at the dose of interest is a function of how accurately the mathematical model describes the true, but unmeasurable, relationship between dose and response at low doses. 

The maximum therapeutic index (tolerated dose/minimum effective dose) is highest when the two groups have a total of 6 to 10 carbons. Major drawbacks of their use are their habit formation and their high toxicity when alcohol is present in the bloodstream. 

Minimum tolerated dose. This concept is not so common as the one above, but it applies to longterm adrenocortical steroid therapy against inflammatory or immunological conditions, e.g. in asthma and some cases of rheumatoid arthritis, when the dose that provides symptomatic relief may be so high that serious adverse effects are inevitable if it is continued indefinitely. The patient must be persuaded to accept incomplete relief on the groxmds of safety. This can be difficult to achieve. 

Calcium chloride is found in the marine environment. The elemental composition of seawater is 400 ppm calcium, 18,900 ppm chlorine, and many organisms and aquatic species are tolerant of these concentrations. Toxicity arises either from the invasion of freshwater in otherwise saltwater environments or possible toxic doses of calcium chloride from spills, surface mnoff, or underground percolation into typically freshwater streams or aquifers. Various agencies have guidelines for calcium and chloride in potable water (41). The European Economic Community (EEC) is the only agency to have a minimum specification for calcium in softened water. 

Human toxicity data are limited to secondary citations. Because these citations provided no experimental details, they cannot be considered reliable. Deaths have occurred from aniline ingestion and skin absorption, but doses were unknown. Reviews of the older literature indicate that a concentration of 5 ppm was considered safe for daily exposures, concentrations of 7 to 53 ppm produced slight symptoms after several hours, a concentration of 40 to 53 ppm was tolerated for 6 h without distinct symptoms, a concentration of 130 ppm may be tolerated for 0.5 to 1 h without immediate or late sequalae, and 100 to 160 ppm was the maximum concentration that could be inhaled for 1 h without serious disturbance. In studies of accidents with unknown exposure concentrations, methemoglobin levels of up to 72% were measured. Recoveries occurred with a minimum of medical intervention following cessation of exposure. 

Livestock and small laboratory animals are comparatively resistant to zinc, as judged by their tolerance for extended periods to dietary loadings >100 times the minimum recommended daily zinc requirement (Table 9.8). Nevertheless, excessive zinc intake through inhalation or oral exposure can have dramatic effects on survival, metabolism, and well being. Sensitive species of mammals were affected at 90 to 300 mg Zn/kg diet, >300 mg Zn/L drinking water, >90 mg/kg BW daily, >350 mg Zn/kg BW as a single oral dose, and >0.8 mg Zn/m3 air (Table 9.8). 

Both enantiomers and the racemate of l-(3,4-dichlorophenyl)-3-azabicyclo [3.1.0]hexane, 27a-c, have been reported to be in development. The racemate, DOV 216,303, inhibits the reuptake of NE, 5-HT and DA with IC50 values of 20, 14 and 78 nM, respectively [85]. DOV 216,303 is active in tests predictive of antidepressant activity, including the mouse FST (minimum effective dose = lOmg/kg), reversal of tetrabenazine-induced ptosis and locomotor depression. DOV 216,303 was also reported to be well tolerated in phase I clinical trials [85,86], In a phase II study designed to explore safety and tolerability in depressed individuals, patients received either DOV 216,303 (50 mg, b.i.d.) or citalopram (20 mg, b.i.d.) for two weeks [85]. It was found that the side effect profile was not remarkably different between the two treatment groups. In addition, time-dependent reductions in Hamilton Depression Scores (HAM-D) were similar for both groups. 

The number of subjects per cohort needed for the initial study depends on several factors. If a well established pharmacodynamic measurement is to be used as an endpoint, it should be possible to calculate the number required to demonstrate significant differences from placebo by means of a power calculation based on variances in a previous study using this technique. However, analysis of the study is often limited to descriptive statistics such as mean and standard deviation, or even just recording the number of reports of a particular symptom, so that a formal power calculation is often inappropriate. There must be a balance between the minimum number on which it is reasonable to base decisions about dose escalation and the number of individuals it is reasonable to expose to a NME for the first time. To take the extremes, it is unwise to make decisions about tolerability and pharmacokinetics based on data from one or two subjects, although there are advocates of such a minimalist approach. Conversely, it is not justifiable to administer a single dose level to, say, 50 subjects at this early stage of ED. There is no simple answer to this, but in general the number lies between 6 and 20 subjects. 

IR Individually titrate on the basis of response and tolerance. Initiate with 150 mg every 8 hours (450 mg/day). Dosage may be increased at a minimum of 3 to 4 day intervals to 225 mg every 8 hours (675 mg/day) and, if necessary, to 300 mg every 8 hours (900 mg/day). The safety and efficacy of dosages exceeding 900 mg/day have not been established. In those patients in whom significant widening of the QRS complex or second- or third-degree AV block occurs, consider dose reduction. 

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). 

Starting dose is 4 mg twice/day (8 mg/day). After a minimum of 4 weeks of treatment, if well tolerated, increase the dose to 8 mg twice/day (16 mg/day). 

When discontinuing pregabalin, taper gradually over a minimum of 1 week. Neuropathic pain associated with diabetic peripherai neuropathy The maximum recommended dose of pregabalin is 100 mg 3 times a day (300 mg/day) in patients with creatinine clearance (Ccr) of at least 60 mUmin. Dosing should begin at 50 mg 3 times a day (150 mg/day) and may be increased to 300 mg/day within 1 week based on efficacy and tolerability. 

CT-based simulation is preferred whenever possible. Normal tissues (heart, lung, spinal cord) can then be contoured such that doses to these organs are kept to a minimum. If the tolerance dose is exceeded to any critical structure, alternate beam arrangements should be evaluated. 

Some clinicians adhere to the maxim never use two drugs when one will suffice and will prefer amoxapine. This is a reasonable strategy. However, amoxapine may be difficult for many patients to tolerate, and using a combination of two drugs may afford the clinician a finer ability to determine the amount of antipsychotic to the doses of the antidepressant and the antipsychotic for maximum efficacy and minimum toxicity. 

Extensive databases [see Table 24-1) have now shown that paroxetine and sertraline can reduce panic attacks to zero and prevent relapse. Paroxetine studies constitute the largest data set more than 700 patients have been treated for periods ranging from 10 to 36 weeks. In the placebo-controlled comparisons with clomipramine, paroxetine had an earlier onset of action and was better tolerated than clomipramine. Paroxetine was significantly better than placebo from week 4 onward, whereas no separation was seen between clomipramine and placebo until the end of the study. Fewer withdrawals occurred as a result of adverse events with paroxetine (7.3%) than with either clomipramine (14.9%) or placebo (11.4%). The minimum dose shown to be superior to placebo was 40 mg/day. 

Cell Dose The preclinical stage can be used to determine the specifications for the minimum effective and maximum tolerable number of viable and functional cells. The optimum dose of cells to be administered still needs to be established [20]. 

Every marketed product has a level of endotoxin tolerated based on the minimum pyrogenic dose and amount of the drug to be administered as per Food and Drug Administration (FDA) guidelines [19]. However, there are none for the more advanced chemical assays described here. Indeed there are only a few highly specialized university laboratories that currently have experience in trace chemical analysis of LPS and PG. There are no commercial testing laboratories. Simplification and automation will allow more widespread availability of these methods. 

Figure 1 Comparison of typical pharmacokinetic profiles seen for conventional versus controlled release formulations. Abbreviations. MEC, minimum effective concentration MTD, maximum tolerable dose.

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