Dose-response date

This consists of information from the complete clinical data package selected for its relevance to the new region. PK, PD and early dose-response date should all be included. If a bridging clinical study between the foreign data and the new region s population is needed, this may be a PK study, or PD demonstration of efficiency or a full... 

We can now proceed to demonstrate how scientific information and the regulatory defaults of Table 8.2 can be applied. It is useful and important to separate the dose-response evaluations into those used for substances that produce their toxic effects through threshold mechanisms, as these terms were described or used in Chapters 3 and 6, and those that may involve no-threshold mechanisms. As a practical matter, only carcinogens have, to date, been treated as belonging in the latter category. 

The limitations of the use of biomarkers in healthy volunteers must be recognised. For example, although there have been attempts to simulate migraine headache in volunteers, to date none of these models can be considered adequate to serve as a surrogate endpoint. Patients with migraine are not difficult to recruit and are usually healthy apart from their migraine. In this case, it maybe more appropriate to establish tolerability and pharmacokinetics in healthy volunteers and then to select a maximum well-tolerated dose with which to perform a small proof of principle clinical trial in patients. This will need to be followed by larger trials to establish the dose-response relationship. 

For example, in the two largest laboratory-controlled dose-response experiments conducted to date on the neurobehavioral effects of chronic sleep restriction, cumulative increases were evident in the average number of PVT lapses per 24 hr across days of sleep restricted to 3, 4, 5, and 6 hr per night... 

Absence of mechanistic understanding. Substantial understanding of the mechanisms by which most chemicals cause responses is not yet available. To date, virtually none of the models used to identify safe or acceptable doses of contaminants in air, water, or soil have been based on assessments that attempt to account for biological phenomena quantitatively (Andersen et al., 1987 Paustenbach, 1995). As a consequence, conservative approaches are usually employed, and this introduces an unknown uncertainty in the estimation of the dose-response relationship. 

US EPA (2005d). Science Issue Paper Mode of Carcinogenic Action for Cacodylic Acid (Dimethylarsinic Acid, DMA(V)) and Recommendations for Dose Response Extrapolation. Office of Pesticide Programs, Health Effects Div, http //www.epa.gov/oppsrrdl/reregistration/cacodylic acid/, 201p., July 26 (accession date, August 18, 2005). 

Animal disease models for acquired AT deficiency, such as Escherichia cofi-induced sepsis, were used to assess the biological consistency of the rhAT compared to hpAT. Although in these models the exact contributions of the anti-coagulant and anti-inflammatory properties of AT are still somewhat controversial [81], they do allow for some comparison of the properties of rhAT with hpAT. Human plasma-derived AT has been shown to prevent the lethal effects of experimentally induced sepsis in several animal models [82-89], and to block cytokine production in vitro. To date, several dose- response studies have been performed with rhAT in rats (GTC Biother-... 

Peptidoglycans have been postulated as a possible causative agent for pulmonary inflammation associated with inhalation of Gm+ bacteria. Peptidoglycans are components of the cell wall envelope of bacteria and are especially prevalent in the backbone of Gm+ bacteria. They may act as endotoxin-like molecules when inhaled. Muramic acid is an amino sugar component of peptidoglycans that does not appear elsewhere in nature and is a suitable marker for analytical assays (Black et al., 1994 Fox et al., 1993 Fox et al., 1995 Sonesson et al., 1988). Although peptidoglycans have been found in hospital and home air conditioner filters (Fox and Rosario, 1994), to date there have been no systematic dose-response studies to identify their potency. 

To date there has been relatively little work correlating the pattern of deposition with the therapentic outcome or pharmacodynamic effects (118,124, 133-135). This perhaps is not too surprising, as most p-agonists are administered at or close to supramaximal doses and therefore generally administered close to the plateau of the dose response curve, while the therapeutic effects of inhaled steroids are observed over weeks and indeed for bronchial hypersre-sponsiveness further benefits are still being observed after a couple of years of therapy. 

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