Critical Human Action Profile

This is accomplished using the ECFC and the Critical Human Achon Profile (CHAP), a fask analysis-based method used to identify the most critical actions necessary for the performance of the task. Change Analysis is a technique for investigating the role of change in accident causation. It will be described in Section 6.8.6. 

Relating the Time-Course of Plasma Concentrations to the Time-Course of Effect A critical decision to be made after the first human study is whether the compound s speed of onset and duration of action are likely to be consistent with the desired clinical response. Speed of onset is clearly of interest for treatments which are taken intermittently for symptoms rehef, for example, acute treatments for migraine, analgesics, or antihistamines for hay fever. Duration of action phase I is particularly important when the therapeutic effect needs to be sustained continuously, such as for anticonvulsants. The first information on the probable time course of action often comes from the plasma pharmacokinetic profile. However, it has become increasingly evident that the kinetic profile alone may be misleading, with the concentration-time and the effect-time curves being substantially different. Some reasons for this, with examples, include... 

Once the human safety and pharmacokinetic profiles are established the focus shifts to the design and conduct of early clinical trials that will confirm the hypothesized mechanism of drug action and characterize the differentiating features of the drug. These trials to establish mechanism of action and differentiation profile are the "killer experiments" that need to be conducted early in the program to provide the data to support a critically important Go/No-Go decision. It is essential to have answered the following four questions before proceeding to more extensive clinical trials in patients with the illness to be treated ... 

A mode by which cannabinoids may exert their multiplicity of effects may be through the modulation of the expression of chemokines and cytokines which cross-signal among immune cells and play a critical role in pro-inflammatory versus anti-inflammatory activities. Blanchard et al. (1986) and Cabral et al. (1986a) reported that induction of IFN-a/ was suppressed by chronic treatment of mice with THC. Watzl et al. (1991) indicated that cytokine activity also was modulated in human peripheral blood mononuclear cell cultures by THC. However, the non-psychoactive CBD also modulated cytokine production and/or secretion, suggesting that a non-cannabinoid receptor-mediated mode of action could also be involved. The investigators indicated that a possible explanation for the capacity of cannabinoids to act through cannabinoid receptors so as to exert a broad spectrum of immune function effects was that exposure to these compounds resulted in the expression of a differential profile of cytokines. 

---