Pharmacologically effective level

All intoxication cases described above demonstrate clearly that safety evaluation of pharmacologically active compounds to which consumers are exposed as residues in food must be based on both toxicological and pharmacological criteria. Consumption of 100 g liver containing clenbuterol in concentration levels as determined in liver samples contaminated with 160-500 ppb, would exceed the pharmacological effect level of 5 g per person (47). 

In order to interact with their target enzyme, the reverse transcriptase, pharmacologically effective levels of 2, 3 -dideoxynucleoside-5 -triphosphates have to be generated. This implies that the candidate 2, 3 -dideoxynucleoside has to enter the cell, using the nucleoside transport mechanisms or by passive diffusion. The 2, 3 -dideoxynucleoside must also be transformed to the corresponding 5 -triphosphate by cellular kinases, because HIV does not appear to encode for nucleoside kinases. The efficiency of this phosphorylation strongly depends on the type of compound and the nature of the cells. The susceptibility of the nucleosides and nucleotides involved in this process to metabolic enzymes such as deaminases, hydrolases and phosphatases is another important factor to reach and maintain effective levels of dideoxynucleoside triphosphates. 

Pharmacodynamics is a discipline within the broader topic of pharmacology, which focuses on how a drug brings about a particular response, and the effective levels that are required in order to elicit such a response. Some of these basic data will have emerged from the research-based activities that initiate the development of most drugs today. However, considerable additional studies are required to establish detailed dose-response curves so that the optimum therapeutic level can be chosen. 

The major drug interactions of antidepressants are shown in Table 35—6.9,19,30 Antidepressants cause both pharmacodynamic (e.g., additive pharmacologic effects) and pharmacokinetic (e.g., changes in drug levels) interactions with other medications. 

Caffeine is also effective in the antagonism of peripheral adenosine (type I) receptors, which are known to inhibit lipolysis by subduing adenylate cyclase activity.28 The appeal of this mechanism of action is that the majority of the pharmacological effects of adenosine on the central nervous system can be inhibited by doses of caffeine that are well within physiologically non-toxic levels comparable to only a couple of cups of coffee.5... 

Dihydroxybenzoic acid (DHB) is also a commonly used tool to measure the pharmacological effects of HIF-la stabilization via PHD inhibition. Recently, it was shown that mice pretreated with DHB (100 mg/kg, i.p.) showed a marked resistance to the neurotoxic effects of l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) via protection of dopaminergic cell loss and striatal denervation. Importantly, this protection was seen to coincide with HIF-la stabilization, and the prevention of the MPTP-induced loss of ferroportin and striatal iron. Additionally, in these studies, DHB was also observed to block MPTP-induced reduction in mitochondrial pyruvate dehydrogenase, at both the mRNA level and through the measurement of enzyme activity in midbrain substantia nigra [26]. 

Recently nicotinic acid has been found to lower serum cholesterol in hypercholesteremia, and also in normal persons and rabbits (A3, F2). It was shown that the hypercholesteremia, induced by a 48-hour fast, could be completely corrected by giving the animals large doses of nicotinic acid during the fast. In contrast to nicotinic acid, nicotinamide does not lower the cholesterol level (M10). Several explanations are offered for the action of nicotinic acid (1) it inhibits cholesterol biosynthesis, (2) it interferes with coenzyme A, and (3) it involves a hitherto unknown pharmacologic effect. The renewed clinical interest in nicotinic acid induced us to look for a more specific and sensitive assay for nicotinic acid (B7, M8). 

The goal of these efforts was to ensure that smokers obtained sufficient nicotine to support dependence. Cigarettes were developed and marketed on the premise that the primary motivation for smoking is to obtain the pharmacological effect of nicotine (Philip Morris 1969) and consequently, with the understanding that they must provide the appropriate levels of nicotine (Brown Williamson 1977). 

Some disease states or trial conditions militate in favour of a high placebo response rate and lend support for the inclusion of placebo in a comparative trial. These include long treatment periods, previous treatments and response to them, innate characteristics of the study subjects (e.g. social class, educational level and personality t)rpe), influence of medical staff, environment and supervision during the trial, appearance and taste of trial drugs, and presence (or absence) of imwanted pharmacological effects. 

Although nicotinic acid and nicotinamide function identically as vitamins, their pharmacologic effects differ. In large doses (up to 6 g/day), nicotinic acid is effective in reducing serum lipids (low-density lipoprotein [LDL], high-density lipoprotein [HDL], triglycerides, and lipoprotein A. Nicotinic acid produces vasodilation and increased blood flow due to histamine release. Nicotinamide does not affect blood lipid levels or the cardiovascular system. 

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