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  October, 2006

PhaseZERO® Drug Discovery Services –
Human Tissue Pharmacology

Despite the major technological developments in drug discovery processes and our ever-increasing understanding of how the human body works, the identification and subsequent development of new, safe and effective medicines remains extremely difficult, time-consuming and expensive. PhaseZERO® is a collection of in vitro human tissue-based capabilities that serves to identify the distribution, regulation and function of drug targets, and also provide information on the actions and metabolism of compounds of interest.

Effects, both desirable and potential side effects, of compounds of interest can be assessed by measuring contractile function of both smooth and cardiac muscle preparations from appropriately consented human tissue.

At Asterand we obtain fresh human tissue from all regions of the body, the cardiovascular, gastrointestinal, genitourinary and respiratory systems. From these human tissues, isolated muscle preparations are used in our laboratories in Royston, U.K. to assess novel compounds for the treatment of, for example, migraine, COPD, irritable bowel and urinary incontinence.

Human Urinary Bladder

Compounds of interest can be profiled for either agonist or antagonist activity, and their potency and magnitude of effect can be measured. When required, both onset and duration of action times can be determined, as can investigation into the compound’s mechanism of action.



Concentration-effect curves to carbachol in the absence or presence of ipratropium in
human bronchus



Antagonism of PGE2 vasodilatation by Merck’s EP4 receptor antagonist, EP4 A, in
human middle meningeal artery



Inhibition of electrical field stimulation-induced contractions by
atropine and isoprenaline in human bladder wall. Note that isoprenaline
also causes relaxation of the basal level of tone



Contractile effects of 5-hydroxytryptamine and the 5-HT1B receptor agonist, sumatriptan,
in human coronary artery. Note that 5-HT is ~3-fold more potent than sumatriptan,
and also causes a much larger contraction, presumably due to a additional action at 5-HT
2A receptors



Compounds of interest can also be assessed for potential side effects by looking at their effects in non-target tissues. For example, does an anti-migraine compound have the potential to also cause coronary vasoconstriction or bronchoconstriction? The likelihood of this occurring can be assessed in human isolated coronary artery and human isolated bronchus, respectively.

In addition to profiling compounds, isolated muscle preparations from fresh human tissue can also be used for target validation, allowing assessment of potential species differences in target expression, localisation and function. Confirmation that the target is functional in fresh human tissue will give confidence to any pre-clinical program.

Isolated muscle preparations from fresh human tissue can also be used for assay validation. Many screening programmes use human recombinant assays but, unless receptor expression levels are at a level similar to that found in human native systems, misleading results can be obtained. For example, receptor over expression can result in low efficacy compounds exhibiting marked agonist activity. Therefore, assessing the compound’s activity in fresh human tissue allows interpretation of the appropriateness of the human recombinant assay.

In conclusion, Asterand uses a broad range of muscle function assays to profile compounds of interest and validate drug targets and assays. The list (click here) gives examples of the fresh human muscle assays available at Asterand.

Why do human tissue functional pharmacology?

Compound profiling
  • Agonist & antagonist potency
  • Magnitude of effect
  • Onset & duration
  • Mechanism of action
  • Side-effect liability
    		• Target validation
  • Assess species differences: animal vs. human
  • Assay validation: human recombinant vs. human native

    • Why work with Asterand?

    Asterand has:
  • Proven capability, expertise and experience in human tissue muscle function
  • Excellent access to regular supplies of high quality human tissue
  • A team of experienced human tissue pharmacologists that perform these experiments 24/7, every day of the year
  • More than 10 years experience in delivering bespoke studies to its clients


    • ASTERAND SUPPORTS HUMAN DRUG DISCOVERY AND TRANSLATIONAL MEDICINE THROUGH THE PROVISION OF HIGH QUALITY WELL CHARACTERIZED HUMAN BIOMATERIALS AND PRECLINICAL RESEARCH SERVICES
    Visit us at www.Asterand.com