Dose-activity relationship

With the germanocene complexes no strong dose-activity relationship was manifest. The toxicity of all four metallocenes was low, the LD,0 values (lethal dose causing the death of 10% of the animals treated) of both stannocenes being 460 and 500 mg/kg, and those of both germanocenes higher than 700 mg/kg. For comparison purposes, the isolated hydrocar-... 

As compared to non-biotech NCEs, there are some additional hurdles to overcome with biopharmaceuticals there are often only a few clues for dose finding from pre-clinical data, since the dose-activity relationship is often not linear or sigmoidal and/or the pharmacokinetics do not always correlate with pharmacodynamics. 

The acute toxic effects of metals cannot be considered as isolated phenomena, but rather as a part of the complete spectmm of activity and/or dose-activity relationship of a metal in a biological system (Williams 1981b). 

In the case of the 1,1 -disubstituted dichloro complexes XXVI-XXIX and the 1,1 -bridged derivatives XXX-XXXTV, only sporadic cures without a strong dose-activity relationship occurred and 10-30% of the treated animals survived. 

On the other hand, the tumor inhibition effected by (CsH5)2MX2 compounds was distinctly dependent on the central metal atom M present within the molecules. Whereas the metallocene dichloro complexes I-III and V containing the first-row and second-row transition metals titanium, vanadium, niobium or molybdenum effected pronounced antitumor activity with distinct dose-activity relationships and with cure rates of 100% at optimum doses against Ehrlich ascites tumor the compounds IV and VI with... 

The aroma of fmit, the taste of candy, and the texture of bread are examples of flavor perception. In each case, physical and chemical stmctures ia these foods stimulate receptors ia the nose and mouth. Impulses from these receptors are then processed iato perceptions of flavor by the brain. Attention, emotion, memory, cognition, and other brain functions combine with these perceptions to cause behavior, eg, a sense of pleasure, a memory, an idea, a fantasy, a purchase. These are psychological processes and as such have all the complexities of the human mind. Flavor characterization attempts to define what causes flavor and to determine if human response to flavor can be predicted. The ways ia which simple flavor active substances, flavorants, produce perceptions are described both ia terms of the physiology, ie, transduction, and psychophysics, ie, dose-response relationships, of flavor (1,2). Progress has been made ia understanding how perceptions of simple flavorants are processed iato hedonic behavior, ie, degree of liking, or concept formation, eg, crispy or umami (savory) (3,4). However, it is unclear how complex mixtures of flavorants are perceived or what behavior they cause. Flavor characterization involves the chemical measurement of iadividual flavorants and the use of sensory tests to determine their impact on behavior. 

Side Effects and Toxicity. Adverse effects to the tricycHc antidepressants, primarily the result of the actions of these compounds on either the autonomic, cardiovascular, or central nervous systems, are summarized in Table 3. The most serious side effects of the tricycHcs concern the cardiovascular system. Arrhythmias, which are dose-dependent and rarely occur at therapeutic plasma levels, can be life-threatening. In order to prevent adverse effects, as weU as to be certain that the patient has taken enough dmg to be effective, the steady-state semm levels of tricycHc antidepressant dmgs are monitored as a matter of good practice. A comprehensive review of stmcture—activity relationships among the tricycHc antidepressants is available (42). 

In addition to the effect of biological variabihty in group response for a given exposure dose, the magnitude of the dose for any given individual also determines the severity of the toxic injury. In general, the considerations for dose—response relationship with respect to both the proportion of a population responding and the severity of the response are similar for local and systemic effects. However, if metabohc activation is a factor in toxicity, then a saturation level may be reached. 

Himnan DJ Tolerance and reverse tolerance to toluene inhalation effects on open-field behavior. Pharmacol Biochem Behav 21 625-631, 1984 Hinman DJ Biphasic dose-response relationship for effects of toluene inhalation on locomotor activity. Pharmacol Biochem Behav 26 65-69, 1987 Hormes JT, Filley CM, Rosenberg NL Neurologic sequelae of chronic solvent vapor abuse. Neurology 36 698—702, 1986... 

The database for monomethyltin is not conclusive for neurotoxic effects, and, therefore, a NOAEL could not be determined. However, on the basis of 90-day studies on monomethyltin/dimethyltin mixtures detailing histopathology, dose comparisons between studies on different mixtures suggest that dimethyltin is the predominant active ingredient, and, taking into account structure-activity relationships, it would be expected that the neurotoxicity of monomethyltin is lower than that of dimethyltin. 

A dose-response relationship was noted in dogs exposed to 0.03, 0.3, or 3.0 mg/kg/day methyl parathion in the diet for 13 weeks (Daly 1989). Significant reductions in erythrocyte cholinesterase activity (20-23%) and cholinesterase activity in the pons and cerebellum of the brain (43-54%) occurred in dogs... 

Despite the work of Overton and Meyer, it was to be many years before structure-activity relationships were explored further. In 1939 Ferguson [10] postulated that the toxic dose of a chemical is a constant fraction of its aqueous solubility hence toxicity should increase as aqueous solubility decreases. Because aqueous solubility and oil-water partition coefficient are inversely related, it follows that toxicity should increase with partition coefficient. Although this has been found to be true up to a point, it does not continue ad infinitum. Toxicity (and indeed, any biological response) generally increases initially with partition coefficient, but then tends to fall again. This can be explained simply as a reluctance of very hydrophobic chemicals to leave a lipid phase and enter the next aqueous biophase [11]. An example of this is shown by a QSAR that models toxicity of barbiturates to the mouse [12] ... 

Stages in hazard characterization according to the European Commission s Scientific Steering Committee are (1) establishment of the dose-response relationship for each critical effect (2) identification of the most sensitive species and strain (3) characterization of the mode of action and mechanisms of critical effects (including the possible roles of active metabolites) (4) high to low dose (exposure) extrapolation and interspecies extrapolation and (5) evaluation of factors that can influence severity and duration of adverse health effects. 

And it is certainly true that these compounds could well be hallueinogenic but fall outside what we understand the strueture-activity relationships of these compounds to be. For example, it may well be that MBDB in humans at some dose is hallueinogenie and is acting by some meehanism that is totally different from what we understand to be the mechanism of mescaline, DOM, or LSD. But at the present time, based on what we understand about strueture-aetivity relationships, it should not be. That remains to be seen. 

The earliest structure-activity relationships indicated that the transplatinum geometry is inactive— significantly higher doses must be given before any therapeutic effect is seen. In 1991, it was reported that alteration of amine structure and the introduction of sterically hindered amines produced cytotoxicity similar to that of cisplatin.162 The first examples used planar amines and a variety of tra s-[PtCl2(L)(L )] compounds have been synthesized and evaluated ((21)-(26), Figure 12).163... 

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