Safety pharmacology assessments

For the specific pharmacological assessment of inhibitors of gastric acid secretion, like H2-blockers, anticholinergics, H+/K+-ATPase inhibitors, this method reveals valid results with respect to the antisecretory potential of the candidate compound. Limitations of this methods with respect to safety pharmacological assessment of candidate compounds are (1) only parenteral administration of the candidate compound, preferentially i.v., is feasible and should be preferred, and (2) only antisecretory putative side effects can be investigated this method is of limited relevance to study secretory side effect potential of candidate compounds. 

For safety pharmacological assessment of a candidate compound with a totally different inherent primary indication, its antisecretory potential at supra-pharmacological doses has to be studied. Therefore, whether this method can be used for the safety evaluation depends on the solubility of... 

ICH-guideline S7A (2001 Section 2) recommended the use of unanesthetized animals for the safety pharmacological assessment of candidate compounds. Most of the techniques for collection of bile in rats use restrained or anesthetized animals. Such factors as well as the surgical intervention itself may profoundly influence the results. Therefore, Remie et al. (1990, 1991) developed a technique for a permanent double bile fistula in rats. The procedure is described in detail. 

The effect of a candidate compound on pancreas secretion can be measured in rats with acute pancreas fistula. For safety pharmacological assessment of candidate compounds the decrease of exocrine pancreatic secretion might be problematic due to the potential of induction of pancreatitis. 

Reynell and Spray (1956) described a method for the simultaneous measurements of gastric emptying and intestinal transit of test substances in the rat using phenol red as marker. This simple method can also be ideally used for safety pharmacological assessment of candidate compounds on their side effect potential on gastrointestinal motility. 

The enteropooling assay in rats has been developed by Robert et al. (1976) to test the diarrhoeic property of prostaglandins for prediction of this clinically relevant side effect of several synthetic prostaglandins. This method can also be used for the safety pharmacological assessment of candidate compounds on their side effect potential to induce diarrhoea. 

For the safety pharmacological assessment of candidate compounds to increase or reduce insulin resistance often long-term pre-treatment periods for 1 week or longer are necessary before an effect on insulin sensitivity can be detected. Candidate compounds causing an acute effect on lipolysis or andlipolysis of adipose tissue with subsequent changes in free fatty acids normally causes also a fast effect on peripheral insulin sensitivity, which can be measured after a relatively short (16h) pre-treatment period (Schoelch et al. 2004). 

S7A Safety Pharmacology Assessment of New Human Pharmaceuticals, Jime2001. 

Hablitz JJ (1984) Picrotoxin-induced epileptiform activity in hippocampus role of endogenous versus synaptic factors. J Neurophysiol 51 1011-1027 Htmmel HM (2008) Safety pharmacology assessment of central nervous system function in juvenile and adult rats effects of pharmacological reference compounds. J Pharmacol Toxicol Methods 58 129-156... 

Van der Linde HI, Deuren BV, Somers Y, Teisman A, Gallacher DJ (2011) The fentanyl/ etomidate-anesthetized beagle (FEAB) model in safety pharmacology assessment. Curr FYotoc Pharmacol 10 Unitl0.13... 

Table 3 Examples of safety pharmacology assessments suitable for incorporation into repeat-dose toxicology studies...

Amouzadeh HR, Vargas HM (2013) Safety pharmacology assessment of biopharmaceuticals. In Vogel HG et al (eds) Drag discovery and evaluation safety and pharmacokinetic assays. Springer, Berlin, pp 555-560... 

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