Action potential duration testing

Studies to assess the effects of compound and any known metabolites on ECG and cardiac action potentials are recommended. Changes in action potential duration and other parameters measured are a functional consequence of effects on the ion channels which contribute to the action potential. This in vitro test is considered to provide a reliable risk assessment of the potential for a compound to prolong Q-T interval in humans. 

Hondeghem, L.M. and Hoffmann, P. (2003) Blinded test in isolated female rabbit heart reliably identifies action potential duration prolongation and proarrhythmic drugs importance of triangulation, reverse use dependence, and instability. Journal of Cardiovascular Pharmacology, 41, 14—24. 

Shen and Crain [13] tested the effects of biphalin on naive and chronic morphine-treated dorsal root ganglion (DRG) neurons in cell culture. At low (pM-nM) concentrations, most mu, delta, or kappa opioid peptides as well as morphine and other opioid alkaloids elicit dose-dependent excitatory prolongation of the calcium-dependent component of the action potential duration (APD) of many mouse sensory DRG neurons. In contrast, application of the same opioids at higher (pM) concentrations results in inhibitory shortening of the APD [14]. Biphalin at a low concentration elicits only dose-... 

Fig. 2 An early version of the ICH S7B testing strategy, Step 2 circulated for comment included an evaluation of the action potential duration (repolarization assay) as a primary test with regard to assessing risk. This assay was moved to a secondary role by the time of the Step 2 revision to the draft guidance document...

Stimulation of the peripheral nerve trunk of intact animals leads to generation of muscle action potentials of three types. According to the duration of latent periods, they fall into the following order M-response (the result of the direct stimulation of a-motor neuron axons), Fl-response (the monosynaptic response), and polysynaptic responses with the variable latent period from 8-12 up to about 40 ms. In test animals of the III group, the changes of temporal parameters refer mainly to the latent period and duration of M-response (Table 7.4). Polysynaptic responses occur at all intensities of excitation and have a more pronounced character than in intact rats. A marked level and more distinct differentiation of the peaks of the complex action potential were noted. 

In vivo tests for drug activity provide information for two purposes firstly, to obtain data on the potency and duration of action of novel compounds and, secondly, animal models of disease states may be used in order to predict potential therapeutic uses. Models for both of these purposes have been established for agents which interact with the 5-HT3 receptor. 

Although it is not normally feasible to include comprehensive psychological or psychophysiological testing during the first tolerability trials, because medical aspects have to be paramount at this stage, it is possible to determine with considerable reliability any pronounced central actions of a substance as well as the approximate duration of such effects. Examples are effects on vigilance, attention, concentration and potential side effects such as sedation, stimulation, euphoric effects, etc. Further data also will be available as to the effects of the preparation on vital functions such as ECG, respiration and circulation, as well as on biochemical laboratory tests, liver enzyme and renal functions. 

The objectives of preclinical testing to support development of new medicines are to detect and characterize unwanted actions, whether inherently toxic or secondary to pharmacological effects of the substance and its pharmacokinetics, to exclude predicted harmful effects, and as far as possible to reveal other, potentially valuable actions. All this must be done in such a way that the results are both scientifically and administratively useful, as GLP and GMP considerations are essential, and the duration and costs of the of the studies are minimized. In this way the necessary resources of scientists, experimental animals, and laboratory facilities can be minimized in order to make the development of products to treat sick patients as efficient, humane, speedy, and economical as possible. 

This sensitivity toward lateral attacks explains the four times shorter duration of action of sila-meprobamate compared to its carbon isostere on a model of tranquiUizing activity in mice (rotarod test, potentiation of hexobarbital-induced sleep, and intraperitoneal injection). " On the other hand, when given orally, sila-meprobamate is practically inactive. One of the first metabolites formed has been characterized as being a di-siloxane (Figure 15.67). For the two phenyl-trimethylsilyl-derived AChE inhibitors, the rather positively charged trimethyl-silyl group mimics the trimethyl-ammonium function present in acetylcholine. Eor these compound metabolic oxidation does not take place on the silicon, but on one of methyl groups (S1-CH3 Si—CH2—OH). ... 

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