Explanations of Tolerance

The other factor affecting the use of organic nitrates is nitrate tolerance, the mechanism of which is unclear. An early explanation of tolerance was thiol depletion [68] but that now seems unlikely as their is an abundance of thiol in most tissue [69]. A more likely explanation is down regulation of the enzymes involved in the biotransformation but few details are available. An interesting suggestion is that GTN induces increased production of superoxide from the vascular wall and tolerance is caused by reaction of NO, produced enzymatically from GTN, with superoxide to give peroxynitrite and then nitrate [70] (Eq. (16)). 

Types of Tolerance Explanations of Tolerance Behavioral Pharmacology Reinforcement and Punishment Operant Principles and Drug Dependence Drug Discrimination Conflict Paradigm... 

Repeated administration of a given dose of a drug often results in reduced response to the drug (O Brien, 2001). This phenomenon, known as tolerance, was defined and briefly introduced in Chapter 1. Here we summarize the major principles and explanations of tolerance. Our discussion of tolerance follow s our overview of biological, psychological, and social/cnvironmental characteristics of the user because, as you will see, tolerance involves all three types of factors. 

One more aspect of compensatory reactions is that with repeated use of a given dose of a drug, they are thought to become stronger. You can see that we have the makings of an explanation of tolerance here, one that was made prominent over 30 years ago by two psychologists, Richard Solomon and John Corbit, when they published their opponent process theory of motivation (Solomon Corbit, 1974). 

The most essential question is why the CO-free sites are secured for H2 adsorption and oxidation. Watanabe and Motoo proposed a so-called bifunctional mechanism originally found at Pt electrodes with various oxygen-adsorbing adatoms (e.g., Ru, Sn, and As), which facilitate the oxidation of adsorbed COad at Pt sites [Watanabe and Motoo, 1975a Watanabe et al., 1985]. This mechanism has been adopted for the explanation of CO-tolerant HOR on Pt-Ru, Pt-Sn, and Pt-Mo alloys [Gasteiger et al., 1994, 1995], and recently confirmed by in sim FTIR spectroscopy [Yajima et al., 2004]. To investigate the role of such surface sites, we examined the details of the alloy surface states by various methods. 

All compounds used had equivalent purity (see Table 11). The test design was focused on the evaluation of histological differences after a tamponade time of 6 weeks. The density of the PFCLs used was 1.32 g/ml (perfluorobutylbutane), 1.62 g/ml (perfluorohexyl-ethane) and 1.78 g/ml (PFO). There was no dose-response relationship that means there is no evidence that a higher density creates more severe histological damage. Therefore, the simple explanation of the insufficient long-term tolerance for PFCLs could not be verified. 

Although there is no generally accepted explanation that accounts for these commonly observed clinical phenomena, it makes sense to consider the pharmacologic characteristics of the five SSRIs that differ one from another as candidates for explaining the broad range of individual patient reactions to different SSRIs. Now that the SSRIs have been in widespread clinical use for over a decade, pharmacologists have discovered that these five drugs have actions at receptors other than the serotonin transporter and at various enzymes that may be important to their overall actions, both therapeutically and in terms of tolerability. 

Many of us are currently fascinated with the possibilities of being happy or solving our problem by entering into various d-ASCs, using chemical or nonchemical means. We have not yet learned to estimate realistically the costs of this route. We know the costs of chronic alcohol use, but seem willing to tolerate them. We do not know the costs of other d-ASCs very well. Consensus realities can exist and be created in various d-ASCs. The explanation of ordinary consciousness as samsara may well apply in d-ASCs such as drunkenness or marijuana intoxication. In other d-ASCs, such as meditative states, samsaric illusion may be less common, but this has not yet been shown scientifically. 

Chronic alcohol ingestion causing enzyme induction is a likely explanation of the tolerance... 

One explanation for tolerance that has been around for more than 40 years is called the adaptation-homeostasis hypothesis (Cicero, 1980). This theory assumes that a drug acts on specific cells in the central nervous system (CNS). Because of the plasticity of the CNS, the cells become adapted to the presence of the drug with repeated exposure to it. The adaptation allows the cells to maintain normal functioning at a given drug dose. As a result, more drug is required to disrupt cell functioning. This required increase is called tolerance. 

Gentle reader, you have tolerated much to get to this point. Together we have made forays into almost every corner of mathematics in search of an explanation of the marvelous light of hydrogen. Will it pay I assure you it will pay, and handsomely. But do not hope for perfection, because that is not what science gives. Only mathematics can ever be perfect. In this chapter, we will explore the quantum number. The language will be that of the mathematician. You might want a translator, if you are more comfortable with the chemical or physical dialect. Later chapters will do this for you. 

According to Ladonin and Spesivtsev (1974), maize tolerant to chloro-5-triazines stores the triazine taken up in the cytoplasm and in the sensitive pea it is stored in the nucleus, chloroplasts and mitochondria. They assume that the triazines are thus incorporated into proteins and nucleic acids as antimetabolites during the biosynthesis of internuclear nucleic acids. This may also be one of the explanations of the different sensitivity of plants to triazines. Black currant is also tolerant to 4 ppm simazine. According to Shone and Wood (1972) triazine translocated into the leaves of black currant cannot get from the tissue system into the mesophyll. The simazine taken up remains in the leaf veins and does not enter the chloroplasts. 

The idiosyncratic nature of IDRs limits our ability to study them and presents a major challenge to elucidating the mechanisms involved. In vitro studies of IDRs cannot possibly mimic all the complex interactions that occur in vivo. Therefore, developing animal models with the potential to provide insight into the mechanisms of IDRs is essential to test mechanistic hypotheses and to study the sequence of events involved. Nevertheless, consistent with low incidence in humans, IDRs are also generally idiosyncratic in animals (Shenton et al. 2004). One explanation of why IDRs only occur in a minority of treated individuals is that in most cases the immune response is tolerance. If the danger hypothesis is correct, it should be... 

Yet another advantage of higher-MW materials over small molecules is their smaller polaron relaxation energies [99], so that the turn-over from polaron-like to band-Uke transport should, in principle, occur at a lower degree of interchain order. This provides an additional explanation of the higher mobilities in higher-MW polymers, as compared to more crystalline, but lower-MW materials longer chains tolerate more disorder. 

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