Dose effects

Hazard characterization and delineation of dose-effect or dose-response relationships. 3. Assessment of exposure 4. Risk characterization... 

The therapeutic ratio of antineoplastic agents, which is defined by the dose necessary to cause a significant anticancer effect divided by the dose effecting significant side effects, is generally low (near to one). 

The first dose effect may be minimized by decreasing the initial dose and administering the dose at bedtime The dosage can then be slowly increased every 2 weeks until a full therapeutic effect is achieved. If die patient experiences syncope, die nurse places die patient in a recumbent position and treats supportively. This effect is self-limiting and in most cases does not recur after the initial period of tiierapy. Light-headedness and dizziness are more common tiian loss of consciousness. The section below discusses these effects and provides interventions for management. 

Methadone is a p receptor agonist with special properties that make it particularly useful as a maintenance agent. Rehably absorbed orally, it does not reach peak concentration until about 4 hours after administration and maintains a large extravascular reservoir (Kreek 1979). These properties minimize acute euphoric effects. The reservoir results in a plasma half-life of 1—2 days, so there are usually no rapid blood level drops that could lead to withdrawal syndromes between daily doses. Effective blood levels are in the range of 200-500 ng/mL. Trough levels of 400 ng/mL are considered optimal (Payte and Khouri 1993). There is wide variability among individuals in blood levels with identical doses (Kreek 1979), and some have inadequate levels even with doses as high as 200 mg/day (Tennant 1987 Tenore 2003). 

Heishman SJ, Stitzer ML, Bigelow GE, et al Acute opioid physical dependence in postaddict humans naloxone dose effects after brief morphine exposure. J Pharmacol Exp Ther 248 127-134, 1989... 

Winters WD, Kott KS Continuum of sedation, activation and hypnosis or hallucinosis a comparison of low dose effects of pentobarbital, diazepam or gamma-hydroxy-butyrate in the cat. Neuropharmacology 18 877—884, 1979... 

Similar to alcohol and other CNS depressants, toluene has a biphasic dose-effect curve for the motor activity of rodents (Hinman 1987 Riegel and... 

Tin compound Species Test material Exposure period and dose Effects NOAEL/LOAEL (mg/kg body weight per day) Reference... 

Litchfield JJ, Wilcoxon F. 1949. A simplified method of evaluating dose-effect experiments. J Pharmacol Exp Ther 96 99-133. 

Buben JA, O Flaherty EJ. 1985. Delineation of the role of metabolism in the hepatotoxicity of trichloroethylene and perchloroethylene A dose-effect study. Toxicol Appl Pharmacol 78 105-122. 

Figure 7.8 Dopamine and motor function. When nigrostriatal dopamine activity is normal so is motor function. Any reduction in this DA activity, as in Parkinson s disease, results in reduced motor activity, i.e. akinesia. By contrast, too much DA activity, as in Huntington s Chorea, produces abnormal motor function, i.e. dyskinesia. The latter may be controlled by neuroleptic drugs (DA antagonists) but they can swing the balance in DA activity sufficiently to produce akinesia (Parkinsonism). DA agonists (and levodopa) may overcome akinesia but can induce DA overactivity and dyskinesia (peak dose effect) (see Chapter 15)...

C Low dose effects usually not measurable directly In human or animal observations Need to extrapolate observed high dose effects to low or zero dose range by theoretical dose-response models ... 

Both the development and application of bioindicators present a number of methodological considerations. One key requirement is to relate dose/effects studies in the laboratory, and residne levels/efifects studies in the field. For many years, these stndies were condncted by different groups of scientists, and the cotmections were not made (Eisler 1987). Ideally, we should use bioindicators where there are clear links between exposnre levels, tissue levels, and effects (Burger and Gochfeld 2003). The most nseful bioindicators of those we suggest are those where the cotmections have been clearly made. 

Owing to its ability to cause widespread T cell lysis after the first dose, OKT-3 has several severe adverse effects that manifest within 3 hours after administration.10,11,14 These adverse reactions often are referred to as the first-dose effect and usually are secondary to cytokine release. The adverse-reaction profile of OKT-3 includes fever (77%), chills (43%), dyspnea (16%), nausea (32%), vomiting (25%), diarrhea (37%), and tachycardia (26%). One of the major complications of OKT-3 is the development of severe pulmonary edema.11,15,16 In reported cases of this complication, patients were fluid overloaded at the time of the initial dose. Another problematic adverse reaction is the development of nephropathy.11,17... 

Sargramostim Neutrophil, 250 mcg/m2 per day First-dose effect (hypotension, flushing) Indicated for use following... 

Hasenfratz, M., Battig, K., Acute dose-effect relationships of caffeine and mental performance, EEG, cardiovascular and subjective parameters. Psychopharmacology 114(2), 281-287, 1994. 

Roache, J. and Griffiths, R., Interaction of diazepam and caffeie Behavioral and subjective dose effects in humans. Pharmacology, Biochemistry and Behavior 26(4), 801-812, 1987. 

Biological monitoring of exposure to coumarin derivatives can be performed by determination of the unchanged compound and/or its metabolites in blood and urine (Table 6). Analytical complexity and the lack of knowledge about the dose-effect relationship in exposed subjects are the primary limitations of this method. 

The database for lead is unusual in that it contains a great deal of data concerning dose-effect relationships in humans. These data come primarily from studies of occupationally exposed groups and the general population. However, the dose data for humans are generally expressed in terms of absorbed... 

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