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Paracetamol CSF Pharmacokinetics Study

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ClinicalTrials.gov Identifier: NCT01821872
Recruitment Status : Completed
First Posted : April 1, 2013
Last Update Posted : April 4, 2013
Sponsor:
Information provided by (Responsible Party):
Barts & The London NHS Trust

Brief Summary:

Despite its use for decades all over the world, the exact mechanism of action of paracetamol is not fully understood and essentially involves a combination of hypotheses. It is known to have an effect via the central nervous system, and of the many mechanisms proposed, one hypothesis is that it may have indirectly activate CB1 (cannabinoid) receptors, through its novel metabolite AM404.

This study aims to elucidate cerebrospinal levels of paracetamol and to measure the concentration of its metabolites, including AM404 in CSF. This may, in turn, give us useful information on the mechanism of action of paracetamol.


Condition or disease Intervention/treatment Phase
Paracetamol Drug: Administration of paracetamol Phase 4

Detailed Description:

Patients undergoing spinal blockade for urological surgery were administered 1g paracetamol intravenously at varying intervals prior to spinal anaesthesia, at which time 5mls of cerebrospinal fluid and 10mls of blood were sampled, and analysed for concentrations of paracetamol, paracetamol glucuronide, paracetamol sulphate, and AM404, a known endocannabinoid reuptake inhibitor, and metabolite of paracetamol.

Paracetamol readily penetrates into the cerebrospinal fluid in animal studies and in children. This could account for the rapid central analgesic and antipyretic action of intravenous paracetamol however this remains to be studied in adults. AM404 has never before been identified in humans, and its presence in CSF following paracetamol supports the hypothesis of a central mechanism of action of paracetamol via AM404.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: A Single Centre Prospective Randomised Study to Investigate the Cerebrospinal Fluid (CSF) Pharmacokinetics of Intravenous Paracetamol in Humans
Study Start Date : May 2011
Actual Primary Completion Date : August 2011
Actual Study Completion Date : November 2011

Arm Intervention/treatment
Active Comparator: Sampling at approx 15 minutes
Plasma and CSF samples to be taken at 15 minutes post administration of intravenous paracetamol
Drug: Administration of paracetamol
Administration of 1g intravenous paracetamol
Other Name: Perfalgan

Active Comparator: Sampling at approx 30 minutes
Plasma and CSF samples to be taken at 30 minutes post administration of intravenous paracetamol
Drug: Administration of paracetamol
Administration of 1g intravenous paracetamol
Other Name: Perfalgan

Active Comparator: Sampling at approx 120minutes
Plasma and CSF samples to be taken at 120 minutes post administration of intravenous paracetamol
Drug: Administration of paracetamol
Administration of 1g intravenous paracetamol
Other Name: Perfalgan




Primary Outcome Measures :
  1. Measurement of AM404 in CSF [ Time Frame: 5-211 minutes post-administration of paracetamol ]
    AM404 is a metabolite of paracetamol thought to be formed in the brain.


Secondary Outcome Measures :
  1. Measurement of paracetamol in plasma and CSF [ Time Frame: 5-211 minutes post administration of paracetamol ]
    Concentrations of paracetamol measured in plasma and CSF following intravenous paracetamol administration.

  2. Measurement of paracetamol glucuronide and sulphate conjugates in plasma and CSF. [ Time Frame: 5-211 minutes post administration of paracetamol ]
    Concentrations of glucuronide and sulphate conjugates of paracetamol measured in plasma and CSF following intravenous paracetamol administration.



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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Adult subjects aged 18 to 80 years
  • Subjects undergoing surgery who require a spinal anaesthetic and paracetamol as part of their routine anaesthetic plan
  • Subjects with an American Society of Anesthesiology score of I-III

Exclusion Criteria:

  • Subjects with any contraindication to spinal anaesthesia
  • Subjects with known clotting abnormalities
  • Pregnant or lactating women
  • Subjects with known hypersensitivity to paracetamol
  • Patients with severe hepatocellular insufficiency
  • Patients already taking regular doses of paracetamol
  • Any subjects deemed medically unsuitable by the investigator

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01821872


Locations
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United Kingdom
St Bartholomew's Hospital
London, United Kingdom, EC1A
Sponsors and Collaborators
Barts & The London NHS Trust
Investigators
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Study Director: Vivek Mehta, MD Pain and Anaesthesia Research Centre, Barts Health NHS Trust

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Responsible Party: Barts & The London NHS Trust
ClinicalTrials.gov Identifier: NCT01821872     History of Changes
Other Study ID Numbers: 7258
First Posted: April 1, 2013    Key Record Dates
Last Update Posted: April 4, 2013
Last Verified: April 2013
Keywords provided by Barts & The London NHS Trust:
paracetamol
acetaminophen
AM404
CSF
pharmacokinetics
Additional relevant MeSH terms:
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Acetaminophen
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Antipyretics