Dose normalization

The properties of such materials are not measurably altered until subjected to doses in excess of a million rads. At these higher doses, the principal changes are due to chem decompn which, with very few exceptions, resnlt in a decrease in sensitivity to mechanical stimulus and also in a dimunition of expl output. The radiation doses normally encountered in neutron activation procedures range from a few rads for 14 MeV fast neutron activation to several thousand rads for thermal neutron activations in a nuclear reactor. Thus, such doses are well under the limit at which measurable changes can occur... 

Consumption of fish oil in excess can generate immunotoxic effects in laboratory animals. Rats fed a 17% fish oil diet had reduced wound-healing responses when compared to com oil [59], In a mouse model of bacterial resistance to S. typhimurium, lower survival rates were reported for those animals that ingested a 20% fish oil diet over 15 days [59], Similar fish oil-induced effects in guinea pigs were noted in a study of experimental tuberculosis leading the authors to conclude that this treatment resulted in decreased resistance to infectious disease. The consumption of fish oil has also been reported to result in alterations of hemostatic parameters such as platelet production and function. However, there is no indication that at doses normally consumed by humans, immunotoxicity will occur. 

An adverse drug reaction is defined by WHO as A response to a dmg which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological... 

Figure 9 Tumor growth inhibition study in nude mice implanted with human colon cancer cells. The mean tumor volume from each group was blotted against the number of days. Each group involved eight animals. For clarity, error bars were omitted. Note that after 1.5 weeks the dose, normalized for paclitaxel, was tripled in all treatment groups. Source. From Ref. 43...

Fig. 17. Unlike BZ, EA 3443 effeets on heart rate are minimal. In this ehart, the low dose of 1.0 meg/kg appears to eause a heart rate deerease at 15 hours. The higher initial rate may be an artifaet, not seen in the HR at the mueh larger dose, whieh remains essentially level. It is probable that low doses normally eause a reduetion in rate, as is seen with seopolamine, and is attributable to a dominant effeet on medullary eenters.

Children-240 mg/kg/day of anhydrous cholestyramine resin in 2 to 3 divided doses, normally not to exceed 8 g/day with dosage titration based on response and tolerance. 

Acute mania Optimal patient response is usually established and maintained with 600 mg 3 times/day or 900 mg twice/day for the slow release form. Such doses normally produce an effective serum lithium level ranging between 1 and 1.5 mEq/L. 

Side effect Any unintended effect of a pharmaceutical product occurring at doses normally used in man which is related to the pharmacological properties of the drug. 

Cohen et al. (1999) reported an absence of a clinically significant pharmacokinetic interaction between DMI and stimulants in children. In their study, 403 serum concentrations from 142 subjects were examined. Pharmacokinetic parameters were similar for both the DMI and DMI + stimulant groups, including the mean weight-corrected dose (mg/kg), weight and dose-normalized DMI serum concentrations [( ig/L)/ mg/kg], and DMI clearance (L/kg)/hr. 

Adverse drug reaction is an undesired or unintended effect of the drug, occurs at dose normally used by human being. The adverse drug reaction requires treatment or decrease in dose if it is due to poisoning or overdose. 

EDS0 The median effective dose (normally expressed as mg/kg or mg/g of body weight) producing a designated effect in 50 percent of the exposed test organism population. 

The adrenal glands are sensitive to the toxic effects of suramin both glucocorticoid and mineralocorticoid functions can be impaired at doses normally used, necessitating replacement therapy (1081). 

Assuming that a drug can be characterized by linear pharmacokinetics, the standard approach to determining absolute bioavailability F is based on plasma AUCs of oral data relative to IV data, dose normalized [58]. Accordingly, F would be calculated using the following equation ... 

Both the dose normalized AUC of the plasma concentration for two hours after administration and the maximum plasma concentration exhibited nonlinearity, when cefadroxil, a (1-lactam antibiotic, was administered at different oral doses from 5 to 30 mg/kg orally (357). Coadministration of cephalexin (15 mg/kg) reduced both the AUC and C max of cephadroxil (357). Since cefadroxil and cephalexin are substrates of PEPT1 (358), this interaction may be accounted for by an interaction at the binding site of PEPT1(357). 

In case that an essential part of dose is excreted via urine, an estimation of absorption is often done giving the ratio of urine excretion (oral/intravenous) as absorption rate. It should be compared with the ratio of the dose-normalized plasma AUCs (oral/intravenous). 

The estimation of absorption via the ratio of dose-normalized plasma AUCs after oral and intravenous administration is based on the assumption that ... 

The estimation of absorption based on the urine excretion ratio (oral/intravenous) should be compared with the ratio of dose-normalized plasma AUCs after iv. and oral administration from the rat radiokinetic study. In case of major differences between both methods of absorption determination, a thorough investigation/discussion of a route of administration-dependent metabolism and/or volume of distribution might help to explain the apparent discrepancy. 

Investigate the time course of radioactivity concentrations in blood and plasma with the aim to getting information about the absorption process, the AUC, Cmax and the elimination half-life of radioactivity in blood and plasma. Possibly indices for enterohepatic cycle or for metabolites with very different volume of distribution from the original compound may be found. An estimate of the absorption rate comparing dose normalized AUCs after iv and oral (or any other) administration can be done and a major binding to formed blood elements can be noticeable by comparison of blood and plasma concentrations. 

Explorative dose-proportionality was to be investigated in parallel to the progress of the dose escalation, using dose normalized values (on a dose per body weight basis) for AUC, Cmax, and Ae (characterized by an additional suffix norm ) and/or by adequate regression analyses of all parameters. Predictions for the next dose steps were to be derived, based on these findings. 

Table 1 Synopsis of key PK parameters. AUQnf, Cnlax (including dose normalization to 100 mg), and the terminal half-life.

Comparing the data from the seven dose groups synoptically, it can be seen that the dose normalized exposure [AUCinf] shows much fewer differences for the medians than the dose normalized peak values [Cmax] (see Table 1). The variability [CV %] is greater than 50 % for nearly all of these observations. 

Since the adverse effects of clozapine may be more common in children than adults, perhaps reflecting developmental pharmacokinetic differences, clozapine and its metabolites, norclozapine and clozapine-N-oxide, have been studied in six youths aged 9-16 years, with childhood onset schizophrenia (222). Dose-normalized concentrations of clozapine did not vary with age and were similar to reported adult values. Clinical improvement in five patients correlated with serum clozapine concentrations, and clinical response and total number of common adverse effects (sialorrhea, n = 5 tachycardia, n = 4 sedation, n = 1 enuresis, n = 1) correlated with norclozapine concentrations. One child had a reduced neutrophil count (1.1 x 109/1) and another child had increased hepatic transaminases. 

Scopolamine in therapeutic doses normally causes drowsiness, euphoria, amnesia, fatigue, and dreamless sleep with a reduction in rapld-eye-movement (REM) sleep. However, the same doses of scopola ne occasionally cause excitement, restlessness, hallucinations, or delirium, especially in the presence of severe pain. 

Adverse effects are infrequent at doses normally Report 1993 Chloroquine poisoning. Lancet 307 49. 

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