Interaction Between tropisétron / granisétron - paracétamol
|Study Design:||Allocation: Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
|Official Title:||Comparative Study of the Influence of Two Antagonist Receptors 5-HT3, tropisétron and granisétron, on the Analgesic Effect of Paracétamol|
- Change in pain threshold testing mechanical stimulation (von Frey electronic) [ Time Frame: Time 0 + 1h, time0 +3h, time 0 +3h30, timet0+12h30, time 0+14h, time0+14h30, time0+23h30, time0+25h, timt0+25h30, time0+34h30, time0+36h, time0+36h30 ] [ Designated as safety issue: Yes ]
- Assays setrons, paracetamol and its metabolites [ Time Frame: Time 0 + 1h, time0 +3h, time 0 +3h30, timet0+12h30, time 0+14h, time0+14h30, time0+23h30, time0+25h, timt0+25h30, time0+34h30, time0+36h, time0+36h30 ] [ Designated as safety issue: Yes ]
|Study Start Date:||July 2010|
|Study Completion Date:||May 2011|
|Primary Completion Date:||March 2011 (Final data collection date for primary outcome measure)|
Drug: Von Frey electronic
Although the mechanism of action of paracetamol is far from being elucidated, data from the literature suggest that its action would be rather central, without excluding an associated peripheral action. Thus, various studies have shown that paracetamol easily passed the blood-brain barrier. After administration in humans systemically, paracetamol was found in the cerebrospinal fluid.
Various mechanisms have been suggested for the central action. In 1992, Vane and Feirrera have considered the involvement of cyclooxygenase plants, but their conclusions seem to have been invalidated by more recent work showing that, compared to NSAIDs, acetaminophen is a weak inhibitor of these enzymes. Another hypothesized mechanism of action of acetaminophen involves central serotonergic system have demonstrated a reduction of the effect of paracetamol after lesion of descending serotonergic pathways. The inhibition of serotonin synthesis by p-chlorophenylalanine reduced the antinociceptive effect of paracetamol in the hot plate test and formalin test. In addition, paracetamol increases serotonin levels in the cortex and the deck and reduces the number of cortical 5-HT2 receptors, without changing the number of 5-HT1A receptors.
Work done in animals in our laboratory showed a total inhibition of analgesic effects of paracetamol administered orally, intravenously or intrathecally after intrathecal administration of tropisetron, a 5 HT3 receptor antagonist. This suggests a role of 5-HT3 receptor in the mechanism of action of paracetamol, despite the absence of binding of acetaminophen to this receptor.
A clinical trial was conducted in our laboratory in 2004 in 24 healthy volunteers. In this protocol, pain thresholds were measured using a who had been psychophysical test of an electrical nature, the PainMatcher previously validated in our laboratory. This essay has highlighted the pharmacodynamic interaction expected with tropisetron, but also with granisetron.
This difference between the preclinical and clinical results should be studied to determine whether it is due to differences in the mechanism of the analgesic action of paracetamol in humans and animals, or if this is the result administration in clinical doses of granisetron for which it loses its specificity for the 5-HT3 receptor, as in animal studies.
This study is thus complementary to previous work which helped to demonstrate, in humans, the reversion of the analgesic effect of acetaminophen by tropisetron and granisetron.
This protocol is based on a study of the interaction setron -paracetamol at 4 different levels of plasma concentrations, by repeating the tests at set intervals, while concentrations of setrons down gradually (half-life of 8 to 10 am ) after a single administration. In addition, the interindividual variability of the effects of paracetamol will be studied, and linking with certain genetic polymorphisms reported by the subjects tested.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01226381
|Clermont-Ferrand, France, 63003|
|Principal Investigator:||Claude DUBRAY||University Hospital, Clermont-Ferrand|