Organ system studies cardiovascular

The actual requirements of the November 8, 2000 ICH guidelines are broadly outlined. They call for the conduct of studies in a core battery to assess effects on the cardiovascular (Table 19.1), respiratory (Table 19.2), central nervous system (Table 19.3) and secondary organ system (Table 19.4) effects. Follow-up studies for the care battery are also required on a case-by-case basis for the three main organ systems. 

To assess the effects of the test substance on the central Anon.27 nervous system, peripheral nervous system, sensory organs, respiratory and cardiovascular systems, smooth muscles including uterus, peripheral organs, renal function, and adverse effects observed in clinical studies... 

Safety pharmacology studies have been subdivided into "core battery," "follow-up," and "supplemental" studies.25 The "core battery" studies are aimed to investigate the effects of NCEs on the cardiovascular, respiratory, and central nervous systems that are considered as vital organ systems based on the fact that acute failure of these systems would pose an immediate hazard to human life. In some instances, based on scientific rational, the "core battery" may or may not be supplemented.25 Additionally, ADRs may be either (1) suspected based on the pharmacological class, or the chemical class, or (2) identified... 

Table 13.10 illustrates examples of functional endpoints that have been successfully incorporated into toxicology studies. The examples cover primarily, but are not limited to, the vital organ systems (i.e., cardiovascular, respiratory, and central nervous systems). The repeat-dose toxicology studies offer an ideal opportunity to compare the pharmacological... 

The existing data indicate that, in humans, respiratory and hepatic effects result from inhalation exposure and that the liver, hematopoietic system and cardiovascular system are the target organs following intravenous injection of Thorotrast. Studies in animals have not reported effects in these... 

Whole animal studies are generally necessary to determine the effect of the drug on organ systems and disease models. Cardiovascular and renal function studies of all new drugs are generally first performed in normal animals. Where appropriate, studies on disease models are performed. For a candidate antihypertensive drug, animals with hypertension would be treated to see whether blood pressure was lowered in a dose-related manner and to characterize other effects of the compound. Evidence would be collected on duration of action and efficacy after oral and parenteral administration. 

The purpose of the safety pharmacology core battery is to investigate the effects of the test substance on vital functions. In this regard, the cardiovascular, respiratory and central nervous systems are usually considered the vital organ systems that should be studied in the core battery. In some instances, based on scientific rationale, the core battery may need to be supplemented (see also section 2.8) or may not need to be implemented (see also section 2.9). 

Effects of the compound on specific organ systems, i.e., cardiovascular, respiratory, and nervous, are evaluated. These are referred to as safety pharmacology studies and are intended to investigate the potential undesirable pharmacodynamic effects of a substance on physiological functions in relation to exposure. Parameters that are evaluated include blood pressure, heart rate, electrocardiogram, motor activity, behavioral changes, coordination, sensory/motor reflex responses, respiratory rate and depth (6,7). 

One aspect of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines that confuses some people is the tier system, or the division of organ systems into sequential groups to be evaluated. Core Tier I, which must be performed prior to first studies in man, includes evaluations of central nervous system, cardiovascular system, and respiratory/... 

A further characteristic of CNS safety pharmacology is that studies are almost exclusively carried out in vivo and must use conscious animals. In contrast to other organ systems, such as the cardiovascular system, CNS safety cannot rely on in vitro techniques, because the neurobiological mechanisms of CNS fimction are less well understood. 

However, most pathological conditions, believed to involve derangements in the thromboxane biosynthesis - or in the thromboxane/prostacyclin balance - concern the cardiovascular system. A large number of diseases affecting this organ system have been studied in this respect, i.e. atherosclerosis, myocardial infarction, coronary artery disease with angina of various etiologies, thrombotic disorders, hemostatic defects, circulatory shock, ulcerative diseases, and so on. The possible roles of thromboxane and prostacyclin in the cardiovascular system have been discussed in several reviews, e.g. refs. 32, 33, 348-354. 

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