Paracetamol plasma and cerebrospinal fluid pharmacokinetics in children

Anderson, Brian J.; Holford, Nicholas H. G.; Woollard, Gerald A.; Chan, Phylinda L. S.

doi:10.1046/j.1365-2125.1998.00780.x

Cited by 95 publications

(76 citation statements)

References 42 publications

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“…These events include the pharmacokinetic processes for the drug to be absorbed and to reach the hypothalamus and the pharmacodynamic ones that alter temperature regulation leading to a decrease in heat production and an increase in heat loss. 13 The pharmacokinetic processes may be a limiting factor in rapidly obtaining the expected antipyretic efficacy. It has been shown that the plasma half-life of acetaminophen ranges between 2 and 10 hours in febrile children 5,11,14 ; con- sequently, acetaminophen steady-state plasma concentrations can be reached only approximately between 10 and 50 hours after the first administration.…”

Section: Discussionmentioning

confidence: 99%

Antipyretic Efficacy of an Initial 30-mg/kg Loading Dose of Acetaminophen Versus a 15-mg/kg Maintenance Dose

et al. 2001

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ABSTRACT. Objective. To compare the antipyretic efficacy of an initial 30-mg/kg acetaminophen loading dose versus a 15-mg/kg maintenance dose.Methods. A double-blind, parallel-group, randomized clinical trial was conducted. A total of 121 febrile (rectal temperature between 39°C and 40°C) but otherwise healthy outpatients who were 4 months to 9 years of age and weighed 4 to 26 kg were assigned randomly to 1 of the dose groups: 15 mg/kg (n ‫؍‬ 62) and 30 mg/kg (n ‫؍‬ 59).Results. In an "intention to treat" analysis, the time to obtain a temperature lower than 38.5°C was significantly shorter in the 30-mg/kg than in the 15-mg/kg group (110 ؎ 94 minutes vs 139 ؎ 113 minutes). The maximum temperature decrease was significantly higher in the 30-mg/kg than in the 15-mg/kg group (2.3 ؎ 0.7°C vs 1.7 ؎ 0.6°C). Duration of rectal temperature below 38.5°C was significantly longer in the 30-mg/kg than in the 15-mg/kg group (250 ؎ 92 minutes vs 185 ؎ 121 minutes, respectively). Adverse events were reported in 6 children in the 30-mg/kg group compared with 5 in the 15-mg/kg group (hyperthermia, hypothermia, vomiting). The difference was not statistically significant.Conclusion. An initial 30-mg/kg acetaminophen loading dose seemed to be more effective in reducing fever than a 15-mg/kg maintenance dose. No difference was observed regarding clinical tolerance. These data suggest that acetaminophen treatment of fever may be more efficient in an initial loading dose. Pediatrics 2001;108(4). URL: http://www.pediatrics.org/cgi/content/full/108/4/ e73; fever, loading dose, acetaminophen, children.ABBREVATIONS. Teff: time to obtain a rectal temperature below 38°C; Rmax, maximum temperature decrease; Tmax, time to maximum temperature decrease.

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Section: Discussionmentioning

confidence: 99%

Antipyretic Efficacy of an Initial 30-mg/kg Loading Dose of Acetaminophen Versus a 15-mg/kg Maintenance Dose

et al. 2001

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“…A tissue:plasma concentration ratio of unity is achieved in all tissues, except fat and cerebrospinal fluid (CSF). At equilibration, the CSF to plasma partition coefficient has been estimated as 1.18 (6,13).…”

Section: Pharmacokineticsmentioning

confidence: 99%

Paracetamol: New Vistas of an Old Drug

et al. 2006

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Paracetamol (acetaminophen) is one of the most popular and widely used drugs for the treatment of pain and fever. It occupies a unique position among analgesic drugs. Unlike NSAIDs it is almost unanimously considered to have no antiinflammatory activity and does not produce gastrointestinal damage or untoward cardiorenal effects. Unlike opiates it is almost ineffective in intense pain and has no depressant effect on respiration. Although paracetamol has been used clinically for more than a century, its mode of action has been a mystery until about one year ago, when two independent groups (Zygmunt and colleagues and Bertolini and colleagues) produced experimental data unequivocally demonstrating that the analgesic effect of paracetamol is due to the indirect activation of cannabinoid CB 1 receptors. In brain and spinal cord, paracetamol, following deacetylation to its primary amine (p-aminophenol), is conjugated with arachidonic acid to form N-arachidonoylphenolamine, a compound already known (AM404) as an endogenous cannabinoid. The involved enzyme is fatty acid amide hydrolase. N-arachidonoylphenolamine is an agonist at TRPV1 receptors and an inhibitor of cellular anandamide uptake, which leads to increased levels of endogenous cannabinoids; moreover, it inhibits cyclooxygenases in the brain, albeit at concentrations that are probably not attainable with analgesic doses of paracetamol. CB 1 receptor antagonist, at a dose level that completely prevents the analgesic activity of a selective CB 1 receptor agonist, completely prevents the analgesic ac- 250CNS Drug Reviews Vol. 12, No. 3-4, pp. 250-275 © 2006 tivity of paracetamol. Thus, paracetamol acts as a pro-drug, the active one being a cannabinoid. These findings finally explain the mechanism of action of paracetamol and the peculiarity of its effects, including the behavioral ones. Curiously, just when the first CB 1 agonists are being introduced for pain treatment, it comes out that an indirect cannabinomimetic had been extensively used (and sometimes overused) for more than a century.

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“…The pharmacokinetic parameters of the CSF compartment were estimated. 21 The structural parameters included in the model were the CSF distribution rate constant (k CSF ) and the partition coefficient (PC) corresponding to the ratio of the CSF over the plasma doripenem concentration at steady state. An exponential residual model was used for plasma and CSF concentrations.…”

Section: Pharmacokinetic Modelling and Simulationsmentioning

confidence: 99%

Pharmacokinetics of doripenem in CSF of patients with non-inflamed meninges

Nalda-Molina¹,

Dokoumetzidis²,

Charkoftaki³

et al. 2012

Journal of Antimicrobial Chemotherapy

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Objectives: To investigate intact blood-brain barrier (BBB) penetration by doripenem and characterize doripenem pharmacokinetics in CSF using a pharmacokinetic model. Patients and methods:Thirty-eight neurological patients with no active neurological disease or CNS infection received a single 500 mg doripenem dose before pump implantation surgery, or lumbar puncture, for intrathecal baclofen administration. In most cases single CSF and blood samples were collected per patient and analysed for doripenem with HPLC. A two-stage pharmacokinetic analysis was performed to estimate: (i) empirical Bayesian estimates (EBEs) of individual doripenem plasma pharmacokinetic parameters, using plasma doripenem concentrations and literature population priors for a two-compartment model; and (ii) doripenem CSF pharmacokinetic parameters using simulated plasma concentrations from stage (i) as a forcing function. The mean values of the structural model parameters, k CSF (distribution rate constant) and PC (CSF/plasma partition coefficient), and the residual variability were estimated. Results:The mean estimates of the parameters were k CSF ¼ 0.105 h 21 and PC ¼ 0.053, corresponding to mean steady-state doripenem CSF concentrations of 0.20 mg/L and 0.40 mg/L for regimens of 3× 500 mg daily and 3 × 1000 mg daily, respectively, and a mean equilibrium half-life of 6.6 h. The model was validated internally using a visual predictive check (VPC) and bootstrap. Simulating two dosing scenarios gave doripenem levels in the CSF above or close to the literature MIC values. Conclusions:The present NONMEM software analysis shows that doripenem crosses intact BBB significantly and suggests that the drug should be further evaluated as a candidate to treat certain CNS infections, since drug penetration through BBB is enhanced by meningeal inflammation.

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Paracetamol plasma and cerebrospinal fluid pharmacokinetics in children

Cited by 95 publications

References 42 publications

Antipyretic Efficacy of an Initial 30-mg/kg Loading Dose of Acetaminophen Versus a 15-mg/kg Maintenance Dose

Antipyretic Efficacy of an Initial 30-mg/kg Loading Dose of Acetaminophen Versus a 15-mg/kg Maintenance Dose

Paracetamol: New Vistas of an Old Drug

Pharmacokinetics of doripenem in CSF of patients with non-inflamed meninges

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