Interaction Between tropisétron / granisétron - paracétamol

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
University Hospital, Clermont-Ferrand
ClinicalTrials.gov Identifier:
NCT01226381
First received: October 14, 2010
Last updated: February 2, 2012
Last verified: February 2012
  Purpose

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


Condition Intervention Phase
Healthy Volunteers
Drug: Von Frey electronic
Phase 1

Study Type: Interventional
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

Resource links provided by NLM:


Further study details as provided by University Hospital, Clermont-Ferrand:

Primary Outcome Measures:
  • 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 ]

Secondary Outcome Measures:
  • 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 ]

Enrollment: 30
Study Start Date: July 2010
Study Completion Date: May 2011
Primary Completion Date: March 2011 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Von Frey electronic
    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
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.

  Eligibility

Ages Eligible for Study:   18 Years to 40 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Healthy volunteers
  • Aged 18 years and more than 40 years
  • Male
  • Weight and size within 80 to 120% of theoretical values determined from the Lorentz formula
  • Values of vital signs before administering the test products:
  • Oral temperature between 35 to 37.5 ° C
  • PAS between 100-140 mm Hg
  • PAD between 50-90 mm Hg
  • Radial pulse between 45-90 beats per minute
  • Free from any chronic treatment
  • Free of any active disease
  • Failure to take any medication within 7 days before enrollment in the study (including no use of analgesics or anti-inflammatory)
  • Cooperation and understanding to comply strictly with the requirements of the protocol
  • Acceptance to give written consent
  • Membership of the scheme of the French Social Security
  • Acceptance of registration or the national registry of volunteers participating in research

Exclusion Criteria:

  • Contraindications to the administration of paracetamol:
  • Known hypersensitivity to paracetamol
  • History of hepatitis B or C
  • Severe renal insufficiency
  • Liver failure
  • Contraindications to the administration of tropisetron or granisetron:
  • Known hypersensitivity to tropisetron, granisetron, and / or other antagonists of 5-HT3
  • Hypertension
  • Medical history and / or surgical judged by the investigator or his representative as being incompatible with the test.
  • Pathology evolving at the time of assessment for inclusion.
  • Excessive consumption of alcohol, tobacco (10 + cigarettes / day), coffee, tea or drinks containing caffeine (equivalent to more than 4 cups per day) or drug addiction.
  • Presence of any concurrent treatment (including prescription medicines, vitamins) or taking any medication within 2 weeks before the first administration of the test.
  • Topic lacking concentration during workouts nociceptive tests, or presenting training sessions after these tests a low reproducibility of the measured parameters (variability> 20%).
  • Topic participating in another clinical trial, or within the period of exclusion or who have received a total compensation of more than 4500 euros for the 12 months preceding the start of the test.
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01226381

Locations
France
CHU Clermont-Ferrand
Clermont-Ferrand, France, 63003
Sponsors and Collaborators
University Hospital, Clermont-Ferrand
Investigators
Principal Investigator: Claude DUBRAY University Hospital, Clermont-Ferrand
  More Information

No publications provided

Responsible Party: University Hospital, Clermont-Ferrand
ClinicalTrials.gov Identifier: NCT01226381     History of Changes
Other Study ID Numbers: CHU-0083, 2010-020509-34
Study First Received: October 14, 2010
Last Updated: February 2, 2012
Health Authority: France: Ministry of Health

Keywords provided by University Hospital, Clermont-Ferrand:
Paracetamol and setrons
No disease, healthy volunteers

Additional relevant MeSH terms:
Acetaminophen
Granisetron
Tropisetron
Antipyretics
Physiological Effects of Drugs
Pharmacologic Actions
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Central Nervous System Agents
Therapeutic Uses
Antiemetics
Autonomic Agents
Gastrointestinal Agents
Serotonin Antagonists
Serotonin Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 20, 2014