Changes of Propofol Concentration in Cerebrospinal Fluid During Continuous Infusion

Dawidowicz, Andrzej L.; Kalitynski, Rafal; Nestorowicz, Andrzej; Fijałkowska, Anna

doi:10.1097/00000539-200211000-00033

Cited by 14 publications

(15 citation statements)

References 10 publications

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“…Using the same pharmacokinetic model as the Diprofusor software (Dawidowicz et al, 2002), total effect site propofol concentration in Engdahl et al (1998) is estimated to be 2.75-2.80 mg/ml and 3.25-3.30 mg/ml by , both of which are in good agreement with the observed values. Our modeling is based on a 30-year-old man, with height of 178 cm and weight of 75 kg.…”

Section: Methodssupporting

confidence: 63%

“…2,6-DTBP does not potentiate GABA A -Rs nor is it a general anesthetic at concentrations equivalent to those that are hypnotic for propofol (James and Glen, 1980;Engdahl et al, 1998;Krasowski et al, 2001;Dawidowicz et al, 2002Dawidowicz and Kalitynski, 2003). Thus, if potentiation of GABA A -Rs represents a critical aspect of propofol's efficacy as a neuropathic pain-selective analgesic, then 2,6-DTBP would be expected to be ineffective.…”

Section: Resultsmentioning

confidence: 99%

“…a The fixed-rate dosing regimens in Engdahl et al (1998) and yield comparable total propofol plasma levels as the target controlled infusion regimens utilized in Dawidowicz et al (2002) and Dawidowicz and Kalitynski (2003). Using the same pharmacokinetic model as the Diprofusor software (Dawidowicz et al, 2002), total effect site propofol concentration in Engdahl et al (1998) is estimated to be 2.75-2.80 mg/ml and 3.25-3.30 mg/ml by , both of which are in good agreement with the observed values.…”

Section: Methodsmentioning

confidence: 99%

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HCN1 Channels as Targets for Anesthetic and Nonanesthetic Propofol Analogs in the Amelioration of Mechanical and Thermal Hyperalgesia in a Mouse Model of Neuropathic Pain

Tibbs

Rowley

Sanford

et al. 2013

J Pharmacol Exp Ther

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Chronic pain after peripheral nerve injury is associated with afferent hyperexcitability and upregulation of hyperpolarizationactivated, cyclic nucleotide-regulated (HCN)-mediated I H pacemaker currents in sensory neurons. HCN channels thus constitute an attractive target for treating chronic pain. HCN channels are ubiquitously expressed; analgesics targeting HCN1-rich cells in the peripheral nervous system must spare the cardiac pacemaker current (carried mostly by HCN2 and HCN4) and the central nervous system (where all four isoforms are expressed). The alkylphenol general anesthetic propofol (2,6-diiso-propylphenol) selectively inhibits HCN1 channels versus HCN2-HCN4 and exhibits a modest pharmacokinetic preference for the periphery. Consequently, we hypothesized that propofol, and congeners, should be antihyperalgesic. Alkyl-substituted propofol analogs have different rank-order potencies with respect to HCN1 inhibition, GABA A receptor (GABA A -R) potentiation, and general anesthesia. Thus, 2,6-and 2,4-di-tertbutylphenol (2,6-and 2,4-DTBP, respectively) are more potent HCN1 antagonists than propofol, whereas 2,6-and 2,4-di-sec-butylphenol (2,6-and 2,4-DSBP, respectively) are less potent. In contrast, DSBPs, but not DTBPs, enhance GABA A -R function and are general anesthetics. 2,6-DTBP retained propofol's selectivity for HCN1 over HCN2-HCN4. In a peripheral nerve ligation model of neuropathic pain, 2,6-DTBP and subhypnotic propofol are antihyperalgesic. The findings are consistent with these alkylphenols exerting analgesia via non-GABA A -R targets and suggest that antagonism of central HCN1 channels may be of limited importance to general anesthesia. Alkylphenols are hydrophobic, and thus potential modifiers of lipid bilayers, but their effects on HCN channels are due to direct drug-channel interactions because they have little bilayer-modifying effect at therapeutic concentrations. The alkylphenol antihyperalgesic target may be HCN1 channels in the damaged peripheral nervous system.

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Section: Methodssupporting

confidence: 63%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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HCN1 Channels as Targets for Anesthetic and Nonanesthetic Propofol Analogs in the Amelioration of Mechanical and Thermal Hyperalgesia in a Mouse Model of Neuropathic Pain

Tibbs

Rowley

Sanford

et al. 2013

J Pharmacol Exp Ther

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“…It was deemed that only the free or unbound fraction of the drug enters across the choroid plexus and exits in CSF. Therefore there is about 60-fold difference in the concentration of propofol in CSF and in plasma (Engdahl et al, 1998;Dawidowicz et al, 2001b;Dawidowicz et al, 2003a). In contrast to the above founding, the results presented by Dawidowicz et al(2003b) showed that free propofol concentration in blood was lower than the total drug concentration in CSF.…”

Section: Discussionmentioning

confidence: 75%

“…The concentration of propofol in and surrounding the cells of the human brain during clinical anaesthesia is unknown. The propofol concentration in human CSF had been measured (Engdahl et al, 1998;Dawidowicz et al, 2001b) infrequently because of limited accessibility to the CSF. Knowledge of propofol concentration in human CSF is useful for delineating the molecular and cellular mechanisms of propofol anaesthesia.…”

Section: Introductionmentioning

confidence: 99%

Cerebrospinal fluid and plasma propofol concentration during total intravenous anaesthesia of patients undergoing elective intracranial tumor removal

Luo

Yang

et al. 2005

J. Zhejiang Univ. Sci.

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Luo et al. / J Zhejiang Univ SCI 2005 6B(9)Abstract: Objective: The aim of this paper is to compare the propofol concentration in plasma and cerebrospinal fluid (CSF) in patients scheduled for intracranial tumor removal and anaesthetized using propofol as part of a total intravenous anaesthesia technique. Methods: Twenty-seven patients (ASA I-II) scheduled for elective intracranial tumor removal were studied. Anesthesia was induced with 2 mg/kg propofol for 5 min and infused at 10 mg/(kg⋅h) for 5 min and then stopped. CSF and arterial blood were collected simultaneously before infusion of propofol and at different time points after infusion of propofol according to bispectral index (BIS) values. Concentrations of propofol in plasma and CSF were measured by HPLC with fluorescence detection. The correlation coefficient and regression equation between plasma and CSF concentration of propofol were worked out by linear simple regression. Results: The propofol CSF concentration that we measured was 1.46% of the plasma concentration. The coefficient of relation between plasma and CSF concentration was 76.7%. Conclusions: The propofol CSF concentration was positively correlated with and much lower than the plasma concentration. Discrepancies may result from high plasma protein binding of propofol, intracranial pathology and sampling volume.

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HPLC investigation of free and bound propofol in human plasma and cerebrospinal ﬂuid

Dawidowicz

Kalitynski

2003

Biomedical Chromatography

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The paper compares the total propofol concentration in the cerebrospinal fluid (CSF) with the free drug concentration in plasma measured in 35 humans scheduled for elective neurosurgical procedures during propofol anaesthesia. The concentrations of total and free propofol in the blood and CSF samples were measured by means of HPLC using liquid-liquid extraction and ultrafiltration in the sample preparation procedure. The arterial blood and CSF samples (collected from intraventricular drainage) were taken at the same time. According to the obtained results, the usually expected equality between free drug concentration in plasma and its total concentration in CSF is not valid for propofol: the unbound propofol concentration in plasma is not equal to its total concentration in CSF (p < 0.05). This difference suggests a substantial contribution of active transport in propofol transfer from blood into CSF. Moreover, the paper shows the presence of bound propofol in CSF, which is a novel finding.

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Changes of Propofol Concentration in Cerebrospinal Fluid During Continuous Infusion

Cited by 14 publications

References 10 publications

HCN1 Channels as Targets for Anesthetic and Nonanesthetic Propofol Analogs in the Amelioration of Mechanical and Thermal Hyperalgesia in a Mouse Model of Neuropathic Pain

HCN1 Channels as Targets for Anesthetic and Nonanesthetic Propofol Analogs in the Amelioration of Mechanical and Thermal Hyperalgesia in a Mouse Model of Neuropathic Pain

Cerebrospinal fluid and plasma propofol concentration during total intravenous anaesthesia of patients undergoing elective intracranial tumor removal

HPLC investigation of free and bound propofol in human plasma and cerebrospinal ﬂuid

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