Drug compounds therapeutic monitoring

In drug development, it is important to know that the compound has reached its intended target as well as to understand the absorption, excretion, bioavailability, metabolism, and distribution (e.g., the pharmacodynamics and pharmacokinetics) of the compound. Direct monitoring of human in vivo drug and metabolite concentrations in the target organs or in adverse event-related organs, such as the brain, liver, or heart, is often needed to understand the therapeutic impact, potential adverse events, or other effects. 

Phase II investigates the compound s efficacy and safety in controlled clinical trials for a specific therapeutic indication. To eliminate as many competing factors as possible, Phase II trials are narrowly controlled. They are characterized as small—several hundred subjects with the indicated disease or symptoms—and are closely monitored. The control may be either a placebo study arm or an active control arm. The endpoint measured may be the clinical outcome of interest or a surrogate. Phase II trials may last for several months or even several years. Early pilot trials to evaluate safety and efficacy are called Phase Ila. Later trials, called Phase lib, are important tests of the compound s efficacy. These trials may constitute the pivotal trials used to establish the drug s safety and efficacy. At least one pivotal trial (most frequently a large, randomized Phase III study) is done. Only about one third of compounds entered into Phase II will begin Phase III studies [61],... 

During the first half of the century, there was virtually an exclusive reliance on animal testing as the primary model for drug discovery and development. New chemical entities were administered to rodents in the primary screen assay, and the appropriate responses were monitored for indications of therapeutic potential. Compounds meeting the appropriate potency and efficacy criteria were promoted to more diverse and sophisticated animal models to characterize their pharmacological profile. The responses that were monitored included blood pressure (hypotensives), latency to respond to painful stimuli (analgesics), attenuation of seizure propensity (antiepileptics) and other responses that were intuitively and pharmacologically valid indicators of medicinal potential or toxicity. Some of these methods were semiautomated and quite sophisticated for their time, particularly for cardiovascular indications [1]. 

Therapeutic application of AChE inhibitors requires the need to monitor the activity of this enzyme on the periphery. Since the brain is the target organ for all potential cholinergic drugs, any peripheral measures can provide important information about a compound efficacy and mechanism of action. Such studies are relatively non-invasive and simple. The reliable correlation between peripheral and central cholinesterase inhibition in humans depend on many factors, clearly vary from drug to drug, and require detailed pharmacokinetic studies. 

Theophylline, 1011 in sport, 98 (metabolite), 421 quantification in plasma, 26 therapeutic drug monitoring, 110 Theophylline, anhydrous, 1011 Theophylline cholinate, 1011 Theophylline ethylenediamine compound, 1011 Theophylline hydrate, 1011 Theophylline monoethanolamine, 1011 Theophylline monohydrate, 1011 Theophylline olamine, 1011 Theophylline sodium aminoacetate, 1011 Theophylline sodium glycinate, 1011 Theophylline-7-acetic acid, 310 Theophylline-aminoisobutanol, 408 Theospan, 1011 Theovent, 1011 Thephorin, 880 Theralax, 397 Theralene, 1046 Therapav, 848... 

Side Effects a.nd Toxicity. Adverse effects to the tricyclic 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 tricyclics 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 well as to be certain that the patient has taken enough drug to be effective, the steady-state semm levels of tricyclic antidepressant dmgs are monitored as a matter of good practice. A comprehensive review of structure—activity relationships among the tricyclic antidepressants is available (42). 

Although therapeutic drug monitoring may seem an ideal application for HPLC it is not uncommon to find that an HPLC assay is developed in the first instance sinee this ean be done relatively rapidly but if the assay proves clinieally useful then an immunoassay whieh will take mueh longer to develop will be perfected. This same scenario has also been observed with other assays sueh as specifie proteins sinee immunoassays are considered preferable when high throughput is necessary. When more than one compound is required, sueh as a drug and its metabolites or all of the 20 plus amino aeids in plasma, or the three prineipal eatecholamines. 

In any case, both biosensors and biosensing devices have been coupled to microdialysis and are considered among the non-separation-based methods [83]. The drawback of biosensing approaches is that they are usually able to measure just one analyte at a time, in contrast with separation-based methods such as chromatography and electrophoresis, which allow the detection of several analytes. However, if the primary interest is not the identification of unknown compounds, but, for example, the monitoring of variations in a single metabolite or drug, the optimization of therapeutic responses, or the control of a bioprocess via a marker analyte, the use of a specific sensor, which can be employed in a continuous manner, can provide useful information, and can also help to avoid the analysis of hundreds of samples or to reduce the number of animals necessary for a study. 

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