Interaction Between tropisétron / granisétron - paracétamol
Condition: Healthy Volunteers
Study type: Interventional
Phase: Phase 1

Summary: 
      This is a Crossover study, double-blind, randomized, controlled versus placebo.
    

Detailed description: 
      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.
    

Intervention name(s): Von Frey electronic
Intervention type(s): Drug
Intervention description(s): 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
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Paracetamol and setrons; No disease, healthy volunteers