Effective dose comparison with

In a study by Stresser and co-workers, the effect on tumor modulation by 227 has been investigated. HPLC on liver extracts from Fisher 344 rats revealed two major compounds, 3,3 -bisindolylmefliane (133) and a linear trimer, together with a < l(KX)-fold lower content of 4 in comparison with the two major substances. The HPLC isolate was derivatized with /V-methyl-/V-bis(trifluoroacetamide) that, upon MS detection, gave a compound identical to /V,W -ditrifluoroacetylindolo-[3,2-()]carbazole. The content of 4 in this system was estimated to be 0.(XKX)13% of the total dose of 227 given. Thus, it was concluded that the beneficial effect of oral distribution of 227 is due to the total content of derivatives formed (95MI5). 

Comparison with other Studies. How do the results of our investigation compare with similar studies Our results corroborate the data provided in a similar study of the effect of UV-B on primary productivity in the southeastern Pacific Ocean (35). In the latter study, it was noted that enhanced UV-B radiation caused significant decreases in the productivity of surface and deep samples. Compared to ambient, primary productivity decreased with increasing doses of UV-B. In another study in which in situ experiments using natural Antarctic phytoplankton populations, it was noted that incident solar radiation significantly depressed photosynthetic rates in the upper 10-15 meters of the water column (36). It was also found that the spectral region between 305 and 350 nm was responsible for approximately 75 percent of the overall inhibitory effect. 

The comparison of fish bioassays (6) with the calculated effective doses indicate that the two most potent brevetoxins, PbTx-1 and PbTx-7, also are most effective at displacing tritiated probe from its specific site of action. The considerably lower potency of brevetoxins PbTx-5 and PbTx-6 in the rat system suggest that these two toxins may bind with lesser affinity to site 5. In a general sense, this is indicated in Table II, and is summmarized in Table III. 

Co-payment is an instrument that should not be used on its own. Neither efficiency in drag use nor equity nor the control of pharmaceutical expenditure can rest solely on co-payment. Its effectiveness is reinforced when it is combined with other instruments and incentives. In fact, all European countries combine, in different doses and proportions, multiple instruments that influence the behaviour of the industry, prescribes and patients. It is sufficient to recall that pharmaceutical expenditure is the product of price by quantity, and to consider the enormous international variability of drag prices,35 in order to understand the limitations of co-payment regulation in comparison with other policies that influence prices. Policies aimed at price control can be as effective as co-payment - or more so - for purposes of cost containment. 

The second study, which included 2924 postmenopausal women with osteoporosis, had to be cancelled after 10 months due to a marked increase in adverse uterine effects induced by the two doses of levormeloxifene under study in comparison with the placebo arm leukorrhea (30% versus 3%),... 

A possible explanation for these results may be twofold. First, the raloxifene doses were too low to reduce or reverse the proliferative effect of serum estradiol in normal ovulatory women. In fact, in postmenopausal women serum estradiol levels are about tenfold lower in comparison with normally cycled premenopausal women. Second, it is possible that in postmenopausal women ERs have a different intratumoral pattern in terms of concentration, expression, and affinity in comparison with premenopausal women. 

The critical effect of intermediate-duration exposure to -hexane in humans is neurotoxicity, specifically peripheral neuropathy. No inhalation MRL was derived for this duration because the reports of neurological effects in humans were predominantly case reports with inadequate documentation of exposure levels or comparison with unexposed groups. A large database on neurological effects in rats exists for this duration however, the design of these experiments precluded documentation of clear dose-response relationships within a single study. Because of the limited database for oral exposure to -hexane and the lack of toxicokinetic data for this route, no MRL was derived for oral exposure to -hexane. 

Risk characterisation Comparison of information on hazardous properties and effective dose levels/ concentrations with exposure levels in order to characterise the degree of risk posed by the substance to human health or to the environment ... 

The criterion employed for a positive response in this assay is a reproducible statistically significant increase in mutation frequency (weighted mean for duplicate treated cultures) over the concurrent vehicle control value (weighted mean for four independent control cultures). Ideally, the response should show evidence of a dose-response relationship. When a small isolated significant increase in mutation frequency is observed in only one of the two duplicate experiments, then a third test should be carried out. If the third test shows no significant effects, the initial increase is likely to be a chance result. In cases where an apparent treatment-related increase is thought to be a result of unusually low variability or a low control frequency, comparison with the laboratory historical control frequency may be justified. 

When examined together, these values provide mathematical profiles of the drugs we studied and allow numerically precise comparisons with other agents. The use of operational definitions not only makes it simpler to characterize a drug, but allows accurate predictions of its effects at various doses. Obviously, such predictions have practical as well as academic significance. 

Many studies reviewed by Tanda and Goldberg (2000) have found evidence for interactions of nicotine with caffeine and drug discrimination studies have further expanded these investigations (Sect. 6.6). The bidirectional, dose-dependent nature of caffeine effects on nicotine discrimination invites comparisons with parallel studies of nicotine self-adminisfration. However, whereas very large chronic doses of caffeine that were much above those obtained by consumers of caffeinated beverages potentiated nicotine self-administration (Shoaib et al. 1999), there is a... 

An alternative approach to a quantitative assessment is to divide the highest dose at which there is no observed increase in tumor incidence in comparison with controls by a large composite UF, for example 5000 as suggested by Wed (1972). The magnimde of the factor could be a function of the weight of evidence, e.g., numbers of species in which the mmors have been observed or namre of the mmors (WHO/IPCS 1994). The adequacy of this approach, which is sometimes used when data on dose-response are limited, must be judged by criteria similar to those used in developing a tolerable intake for threshold effects this is addressed in detail in Chapter 5. 

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