Paracetamol CSF Pharmacokinetics Study

Paracetamol Clinical Trial

Official title:

A Single Centre Prospective Randomised Study to Investigate the Cerebrospinal Fluid (CSF) Pharmacokinetics of Intravenous Paracetamol in Humans

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01821872
• Other study ID #: 7258
• Status: Completed
• Phase: Phase 4
• First received: March 27, 2013
• Last updated: April 2, 2013
• Start date: May 2011
• Est. completion date: November 2011

Study information

• Verified date: April 2013
• Source: Barts & The London NHS Trust
• Contact: n/a
• Is FDA regulated: No
• Health authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: November 2011
• Est. primary completion date: August 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Paracetamol

Intervention

Drug:
• Administration of paracetamol
Administration of 1g intravenous paracetamol

Locations

Country	Name	City	State
United Kingdom	St Bartholomew's Hospital	London

Sponsors (1)

Lead Sponsor	Collaborator
Barts & The London NHS Trust

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Measurement of AM404 in CSF	AM404 is a metabolite of paracetamol thought to be formed in the brain.	5-211 minutes post-administration of paracetamol	No
Secondary	Measurement of paracetamol in plasma and CSF	Concentrations of paracetamol measured in plasma and CSF following intravenous paracetamol administration.	5-211 minutes post administration of paracetamol	No
Secondary	Measurement of paracetamol glucuronide and sulphate conjugates in plasma and CSF.	Concentrations of glucuronide and sulphate conjugates of paracetamol measured in plasma and CSF following intravenous paracetamol administration.	5-211 minutes post administration of paracetamol	No