Dose-effect correlations

The basic model for ascertaining dose-effect relationships is derived from the sigmoidal effect model, which correlates maximal response (E ), placebo (Eg), and the dose producing 50% of effect (EDjq) ... 

Corticosteroids suppress both humoral and cellular immunity. Single doses produce a redistribution of lymphocytes with a concentration dependent decrease of CD4 and CDS positive cells. This in vivo lymphopenic effect correlates with the in vitro inhibition of stimulated T-cell proliferation. Furthermore, corticosteroids are able to inhibit the expression of genes coding for IL-1, IL-2, IL-6, interferon a, and tumor necrosis factor, TNE-a. Chronic administration decreases the size and also the cellu-larity of lymphoid tissues like lymph nodes, spleen, and thymus. Corticosteroids have more effect on the primary immune response and are less effective against previously sensitized immune responses. Their suppressive effects are more pronounced for T-cell immune responses than for the humoral immune response. 

In 138 Japanese patients with West syndrome treated with low-dose tetracosactide, the initial effects on seizures and long-term outcome were not related to dose (daily dose 0.005-0.032 mg/kg, 0.2-1.28 IU/kg total dose 0.1-0.87 mg/kg, 4—35 IU/kg) (7). There were moderate or severe adverse effects in 30% of the patients. There was slight loss of brain volume on CT/MRI scans in 64% of the patients, moderate loss in 23%, and severe loss in 4%. The severity of adverse effects correlated with the total dose of corticotropin, and the severity of brain volume loss due to corticotropin correlated well with the daily and total doses. The authors recommended a reduction in the dose of corticotropin in order to avoid serious adverse effects. 

Fig. 4. Dose-response correlation in cats of the effects of U-74006F on post-traumatic (compression injury) spinal cord lipid peroxidation (i.e., loss of reduced vitamin E) and on progressive white matter ischemia at 4 hours post-injury (data from ref. [24]) versus chronic (4-week) neurological recovery (data from ref. [46]). Doses indicated were administered at 30 minutes post-injury. Doses in parentheses under the chronic recovery dose-response curve indicate the total 48-hour dosing regimen that these cats received. All values are mean standard error. Numbers of animals are given in parentheses in each bar. Asterisks indicate p < 0.05 vs vehicle-injured animals by ANOVA.

Plasma concentration must exceed the minimum inhibitory concentration but cannot be accurately predicted from the dose. Toxic effects of overdose are serious. Retrospective studies suggest that toxic effects correlate better with high trough than with high peak concentrations. 

Uranium is in essentially all food, water, and air, so everyone is exposed to some levels. In a study reported by NIOSH (Thun et al. 1981, 1985), enhanced levels of P2-microglobulin levels were observed in the urine of uranium workers. It was postulated that enhanced excretion of P2-niicroglobulin might be used as an indication of uranium exposure however, Thun et al. (1981, 1985) were unable to establish a dose response correlation between level of exposure and excretion of the P2-microglobulin. Limson-Zamora et al. (1996) identified changes in several potential biomarkers of effect following exposure to uranium, in which each individual biomarker could be affected by a range of chemicals, but the results... 

In another study investigating the dose-effect and dose-response relationship between the Cd concentration in rice and urinary concentrations/prevalence of abnormal levels of markers of renal dysfunction, significant correlations between Cd concentration in rice and concentrations as well as prevalence rates of abnormal urinary p2-microglobulin, metallothionein, glucose and amino-nitrogen levels were found. The highest maximum allowable concentration of Cd in rice calculated for these indicators was 0.34 mg/kg when the uncorrected urinary value was used and 0.29 mg/kg when the creatinine corrected value was used. Both values are lower than 0.4 mg/kg, the tentative limit prescribed by the Japanese government [103]. 

The most frequent difficulty in environmental toxicology is to demonstrate a true effect at very low concentrations of the substance. It is relatively easy to draw so-called dose-effect relationship for SO2 (Rondia, 1970), even if the ordinate of the effects is somewhat subjective and if mathematical artifice (log or probit transformation) has been used to make the relationship a nearly straight line. We meet no problem in the high concentrations zone we can drive experiments and repeat them showing that increasing concentrations of SO2, preferably associated with an inert aerosol (sodium chloride, haematite, etc—) results in correlated increases in lung or bronchial irritation (Amdur, 1968). 

With chronic exposure, side effects may include rash, thrombocytopenia, leukopenia, and a lupus-like disorder. Chronic therapy is likely to result in tolerance, and withdrawal symptoms if primidone therapy is abruptly stopped. Doses in excess of 1500 mg (twice the maximum recommended daily dose) should be considered toxic. Less common side effects are hypotension, hypothermia, and dermal bullae. Encephalopathy has been observed in an epileptic patient with high plasma levels and poor renal function. With plasma concentrations exceeding 80pgml primidone may precipitate and cause crystalluria. Plasma levels >10 rgpml are associated with toxic effects. The therapeutic range is reportedly 5-10pgml , but clinical effects correlate more closely with phenobarbital blood levels. 

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