SUBJECTS toxic side effects

Of the toxic side effects, a major concern among clinicians is for dose-dependent bone marrow suppression (myelotoxicity), which occurs in 2. 6% of patients and can be fatal if not addressed properly. Study data suggest that a high incidence of secondary acute myeloid leukemia or brain cancer is correlated with low TPMT activity and high 6-TGN levels in children under immunosuppressive therapy. TPMT activity is subject to wide interindividual and interethnic variability due to TPMT gene polymorphism. In the Caucasian population, 0.3% of all individuals have no TPMT activity and 11% have intermediate activity, leading some to advocate additional monitoring of this activity in patients to help prevent unnecessary bone marrow toxicity from azathioprine treatment. 

Aminopyrine had been on the market as an antipyretic drug under the name of Pyramidon, but it was withdrawn after toxic side effects were found. Its use required a large loading dose and continuous intravenous infusion to match its clearance, and consequently it could not be used in human subjects. After 1975 tracer doses of [ " Cjaminopyrine were used in human studies, but in the meantime two British physiologists introduced the use of radioactive aniline clearance, which they demonstrated was equal to aminopyrine clearance if suitable analytical methods were used. ... 

Questions about the rapidity, extent, and duration of internal exposure to foreign chemicals are the province of the twin disciplines of pharmacokinetics and toxicokinetics. Pharmacokinetics is the study of foreign chemicals that act as therapeutic drugs. Their uptake, distribution, and elimination have been studied in detail in human subjects. Toxicokinetics is based on exactly the same principles as pharmacokinetics, but it is concerned with foreign chemicals with toxic, not therapeutic, effects. For obvious ethical reasons, toxicokinetic studies are limited to experimental animals. However, when dealing with the toxic ( side ) effects of therapeutic drugs, the line between pharmacokinetics and toxicokinetics becomes blurred and effectively disappears. 

Purpose Safety Pharmacology (pharmacokinetics, side effects tolerance assessment, evidence of toxicity, pharmacodynamics) Subjects 10-100 usually healthy males Duration <1 year... 

Phase 2 studies begin if Phase 1 studies don t reveal unacceptable toxicity. While the emphasis in Phase 1 is on safety, the emphasis in Phase 2 is on effectiveness. This phase aims to obtain preliminary data on whether the drug works in people who have a certain disease or condition. For controlled trials, patients receiving the drug are compared with similar patients receiving a different treatment—usually an inactive substance (placebo), or a different drug. Safety continues to be evaluated, and short-term side effects are studied. Typically, the number of subjects in Phase 2 studies ranges from a few dozen to about 300. 

D. Chemical Use Classes. This includes the toxicology aspects of the development of new chemicals for commercial use. In some of these use classes, toxicity, at least to some organisms, is a desirable trait in others, it is an undesirable side effect. Use classes are not composed entirely of synthetic chemicals many natural products are isolated and used for commercial and other purposes and must be subjected to the same toxicity testing as that required for synthetic chemicals. Examples of such natural products include the insecticide, pyrethrin, the clinical drug, digitalis, and the drug of abuse, cocaine. 

While the efficacy of an approved drug is extremely relevant, so too is its safety profile, sometimes referred to as its toxicity profile since every drug will have some unwanted side effects. Initial safety evaluations are conducted in healthy adult subjects in first time in human (FTTH) studies. The terms healthy volunteers or normal volunteers are often seen in this context, but they seem particularly unsuitable By definition, all participants in all clinical trials are volunteers, and the use of the word volunteer in just Fl IH trials could mistakenly be seen to imply that participants in other trials are not volunteers. Additionally, the word normal seems questionable in that it may mistakenly be seen to imply that subjects in other trials are abnormal in ways not related to having or not having the disease or condition of interest. The term healthy adult subjects circumvents such misperceptions. 

The lead optimization process introduces structural variations in the molecule in order to identify the best drug candidate. After a thorough evaluation of its toxicity and pharmacological activity in animal models, the molecule enters the clinical phases, when it is evaluated for tolerability, efficacy, and potential side effects on human subjects. After submittal of all the required documentation and registration to the appropriate authority (e.g. the U.S. Food and Drug Administration), the HIV protease inhibitor is ready for launching on the market. 

Elderly subjects have an enhanced sensitivity, particularly toward the CNS toxic manifestations. In this context, the diversity of drugs producing atropine-like side effects should be borne in mind e.g., tricyclic antidepressants, neuroleptics, antihistaminics, antiarrhythmics, antiparkinsonian agents. 

---