The Cerebrospinal Fluid Distribution of Postoperatively Administred Dexketoprofen and Etoricoxib and Their Effect on Pain and Inflammatory Markers in Patients Undergoing Hip Arthroplasty.

BACKGROUND AND OBJECTIVE: Based on earlier literature, etoricoxib may have a delayed analgesic effect in postoperative setting when analgesic efficacy of nonselective nonsteroidal anti-inflammatory drug dexketoprofen is rapid. This may be caused by slow penetration of etoricoxib into the central nervous system (CNS). Therefore we decided to determine the plasma and cerebrospinal fluid (CSF) pharmacokinetics and pharmacodynamics of dexketoprofen and etoricoxib in patients with hip arthroplasty. METHODS: A total of 24 patients, scheduled for an elective primary hip arthroplasty were enrolled. After surgery, 12 subjects were randomized to received a single intravenous dose of dexketoprofen, and 12 subjects were given oral etoricoxib. Paired blood and CSF samples were taken up to 24 h for measurement of drug concentrations, interleukin (IL)-6, IL-1ra and blood for interleukin 10. RESULTS: In CSF the highest measured concentration (C max) of dexketoprofen was 4.0 (median) ng/mL (minimum-maximum 1.9-13.9) and time to the highest concentration (t max) 3 h (2-5), and for etoricoxib C max 73 ng/mL (36-127) and t max 5 h (1-24), respectively. Opioid consumption during the first 24 postoperative hours was similar in the two groups. Dexketoprofen and etoricoxib had a similar effect on the postoperative inflammatory response. No significant differences considering pain relief or adverse events were found between the two groups. CONCLUSION: Dexketoprofen and etoricoxib entered the CNS readily, already at 30 min after administration dexketoprofen was detected in the CSF in most subjects and etoricoxib after 60 min. A single dose of dexketoprofen and etoricoxib provided a similar anti-inflammatory and analgesic response after major orthopaedic surgery.

Plasma and cerebrospinal fluid pharmacokinetics of naproxen in children.

The aim of this study was to characterize pediatric pharmacokinetics and central nervous system exposure of naproxen after oral administration. The pharmacokinetics of naproxen was studied in 53 healthy children aged 3 months to 12 years undergoing surgery with spinal anesthesia. Children received preoperatively a single dose of 10 mg/kg oral naproxen suspension. A single cerebrospinal fluid (CSF) sample (n = 52) was collected at the induction of anesthesia, and plasma samples (n = 270) were collected before, during, and after the operation (up to 51 hours after administration). A population pharmacokinetic model was built using the NONMEM software. Naproxen concentrations in plasma were well described by a 2-compartment model. The estimated oral clearance (CL/F) was 0.62 L/h when linearly scaled by weight to 70 kg. The apparent volume of distribution at steady state (Vss/F) was 12.5 L /70 kg. The findings are consistent with previously reported pharmacokinetic parameters for children older than 5 years. Naproxen permeated into the CSF and reached CSF concentrations that were 4 times higher than unbound plasma concentrations. Based on these data, weight can be used as a basis for naproxen dosing in children older than 3 months of age.

Modulation of anxiety behavior by intranasally administered vaccinia virus complement control protein and curcumin in a mouse model of Alzheimer's disease.

Widespread neuroinflammation in the central nervous system (CNS) of Alzheimer's disease (AD) patients, involving pro-inflammatory mediators such as complement components, might be responsible for AD associated behavioral symptoms such as anxiety. Vaccinia virus complement control protein (VCP) and curcumin (Cur) are the bioactive compounds of natural origin shown to inhibit the in-vitro complement activation. In order to develop complement regulatory compounds which could be delivered to the CNS by a non-invasive route, VCP, its truncated version (tVCP), and Cur were administered to Wistar rats intranasally. The distribution of these compounds in cerebrospinal fluid (CSF) was studied using an enzyme linked immunosorbent assay (ELISA), using VCP and tVCP as antigens and a modified fluorimetric method (Cur). VCP and tVCP were also detected in the olfactory lobes of the rat brain using immunohistochemical analysis. These compounds were then compared for their ability to attenuate the anxiety levels in APPswePS1δE9 mice using an elevated plus maze (EPM) apparatus. VCP treatment significantly improved the exploratory behavior and reduced the anxiety behavior in APPswePS1δE9 mice. tVCP however showed an opposite effect to VCP, whereas Cur showed no effect on the anxiety behavior of these mice. When these mice were subsequently tested for their cognitive performance in the Morris water maze (MWM), they showed tendencies to collide with the periphery of the walls of MWM. This unusual activity was termed "kissperi" behavior. This newly defined index of anxiety was comparable to the anxiety profile of the VCP and tVCP treated groups on EPM. VCP can thus be delivered to the CNS effectively via intranasal route of administration to attenuate anxiety associated with AD.

Diclofenac readily penetrates the cerebrospinal fluid in children.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Diclofenac, a nonselective nonsteroidal anti-inflammatory drug,, exerts analgesic action both in the peripheral tissues and in the central nervous system by inhibiting cyclooxygenase enzymes COX-1/2, but central nervous system penetration of diclofenac has not been evaluated in humans. WHAT THIS STUDY ADDS: Diclofenac penetrates the cerebrospinal fluid rapidly, and after a single intravenous dose of 1 mg kg(-1), sufficient concentrations to inhibit COX-1/2 are sustained for up to 4 h. AIMS: The primary aim was to study the cerebrospinal fluid (CSF) penetration of intravenous diclofenac in children. The secondary aim was to evaluate the plasma diclofenac concentration at the onset of wound pain after inguinal surgery in children. METHODS: A total of 31 children (24 boys) aged 3 months to 12 years received a single intravenous injection of diclofenac 1 mg kg(-1). Paired CSF and blood samples were obtained 5 min to 22 h (median 69 min) later. In children having inguinal surgery a second blood sample was obtained at the time that the children felt wound pain for the first time after surgery. Diclofenac concentrations in CSF, plasma and protein free plasma were measured by gas chromatography with mass spectrometric detection. RESULTS: In the 28 CSF samples obtained at 5 min to 3 h 43 min after injection, diclofenac concentrations ranged between 0.5 and 4.7 microg l(-1). At 5.5 h the CSF concentration was 0.1 microg l(-1), and no diclofenac was detected in the two CSF samples obtained at 22 h. The median of plasma diclofenac concentration at the time when pain returned after inguinal surgery was 104 microg l(-1) (range 70-272 microg l(-1)). No serious or unexpected adverse effects were reported. CONCLUSIONS: Diclofenac penetrates the CSF rapidly, and a sufficient concentration to inhibit cyclooxygenase enzymes is sustained for up to 4 h.

How readily does ketorolac penetrate cerebrospinal fluid in children?

Ketorolac is a potent nonsteroidal anti-inflammatory analgesic used in postoperative pain management. Ketorolac elicits its analgesic action by inhibiting the cyclo-oxygenase enzyme in peripheral tissues and in the spinal cord. Central nervous system penetration of parenteral ketorolac has been evaluated in adults but not in children. In the present study we investigated ketorolac cerebrospinal fluid penetration via spinal anesthesia in 30 healthy children undergoing surgery in the lower part of the body. A single cerebrospinal fluid and blood sample was obtained between 11 minutes and 6 hours after receiving ketorolac 0.5 mg x kg(-1) IV. Ketorolac concentrations were determined by gas chromatography with mass spectrometric detection. Ketorolac was detected from 22 of the 30 cerebrospinal fluid samples, and the concentrations ranged between 0.2 and 7.6 microg x L(-1) (median, 0.6 microg x L(-1)). The cerebrospinal fluid to unbound plasma concentration-ratio ranged between 0.01 and 0.69 (median, 0.08). These low concentrations indicate that ketorolac does not readily penetrate cerebrospinal fluid in children.

Comparison of drug concentrations in postmortem cerebrospinal fluid and blood specimens.

The concentration of drugs and metabolites in cerebrospinal fluid (CSF) and blood were determined in 282 autopsied cases using liquid-liquid extraction techniques and gas chromatographic analyses. All drugs were confirmed in one matrix by gas chromatography-mass spectrometry. CSF/blood ratios were used to compare the two biological fluids. Classes of drugs evaluated in this study included: benzodiazepines, anticonvulsants, sedatives, opioids, antidepressants, anesthetics, and antihistamines. The majority of the drugs tested were readily detected in CSF specimens. The average CSF/blood ratio for most drugs was in the range of 0.05-0.50. Interpretation of these results is difficult because protein binding, half-life, hydrophobic properties, and pKa of a drug, in addition to survival time after drug use, influence the CSF/blood ratio. While CSF specimens do provide a viable alternative testing matrix when blood specimens are not available, they should not be used to estimate blood drug concentrations.

Cerebrospinal fluid distribution of ibuprofen after intravenous administration in children.

BACKGROUND: Ibuprofen is the most commonly used nonsteroidal, antipyretic, antiinflammatory analgesic in children. Nonsteroidal, antipyretic, antiinflammatory analgesics act in both the peripheral tissues and the central nervous system. The central nervous system penetration of ibuprofen has been described in adults but not in children. OBJECTIVES: Our goals were to investigate the cerebrospinal fluid penetration of ibuprofen in children and evaluate the analgesic plasma concentration of ibuprofen after inguinal surgery in children. MATERIALS AND METHODS: A total 36 healthy children (25 boys) aged 3 months to 12 years received a single intravenous injection of ibuprofen (10 mg/kg). A paired cerebrospinal fluid and blood sample was obtained 10 minutes to 8 hours after the injection. In children having inguinal surgery, a second blood sample was obtained at the time that the child first had wound pain. RESULTS: The ibuprofen level was determined in all cerebrospinal fluid and plasma samples. Cerebrospinal fluid concentrations ranged between 15 and 541 microg/L, and the highest concentrations were measured 30 to 38 minutes after dosing. In all cerebrospinal fluid samples collected after 30 minutes, ibuprofen concentration exceeded that of unbound plasma. The plasma analgesic concentrations after inguinal surgery ranged between 10 and 25 mg/L. CONCLUSIONS: Ibuprofen penetrates the cerebrospinal fluid readily, with peak concentrations attained 30 to 40 minutes after intravenous injection of a 10 mg/kg dose. The plasma analgesic concentration after inguinal surgery with spinal anesthesia is 10 to 25 mg/L.

Plasma and cerebrospinal fluid concentrations of indomethacin in children after intravenous administration.

The objective of this study was to evaluate the cerebrospinal fluid (CSF) permeation of indomethacin in healthy children. The participants (n = 31, aged 4-144 months) received indomethacin (0.35 mg/kg) as a 10-minute intravenous infusion prior to surgery under spinal anaesthesia. A single CSF and plasma sample from each individual was collected 14 to 225 minutes after the infusion. Indomethacin concentrations were determined from the CSF, plasma, and protein-free plasma. Total plasma, protein-free plasma, and CSF concentrations of indomethacin ranged between 90 and 2200 ng/mL (median, 780 ng/mL), 0.3 and 0.8 ng/mL (median, 0.5 ng/mL), and 0.2 and 5.0 ng/mL (median, 1.4 ng/mL), respectively. The CSF to plasma concentration ratio remained less than 0.01. There was no correlation between the administration time and CSF concentrations. Eleven children developed 12 nonserious adverse effects, from which 5 were central nervous system (CNS) effects (agitation). In conclusion, indomethacin permeated into the CSF of children, which enables both desired and adverse CNS effects of indomethacin.

Cerebrospinal fluid distribution of ketoprofen after intravenous administration in young children.

OBJECTIVE: The purpose of this study was to evaluate the cerebrospinal fluid (CSF) distribution of an NSAID, ketoprofen, in children. Ketoprofen concentrations were determined from the CSF, plasma and protein-free plasma samples. METHODS: Children (n = 21), aged 13-94 months, were given intravenous ketoprofen (1 mg/kg) prior to surgery under spinal anaesthesia. Single venous blood and CSF samples from each patient were collected simultaneously 7-67 minutes after the drug administration. Ketoprofen concentrations in the samples were determined using gas chromatography-mass spectrometry. RESULTS: Ketoprofen entered the CSF and was detectable in all samples. However, CSF delivery was limited; the ratio of ketoprofen concentration in CSF to plasma remained below 0.006 at all times. Ketoprofen was highly bound (> 98%) to plasma proteins. The free ketoprofen fraction was not in equilibrium with the CSF, and no clear peak drug concentration in the CSF was observed. CONCLUSION: This study shows that ketoprofen is able to enter the CSF of children, which enables central analgesic effects of ketoprofen. However, the slow distribution of ketoprofen into the CSF and the apparently low absolute concentrations has to be taken into account when central analgesic effects are desired.

Diffusion of arylpropionate non-steroidal anti-inflammatory drugs into the cerebrospinal fluid: a quantitative structure-activity relationship approach.

A quantitative structure-activity relationship (QSAR) analysis of a series of arylpropionic acid non-steroidal anti-inflammatory drugs (NSAIDs) has been performed to determine which physicochemical properties of these compounds are involved in their diffusion into the cerebrospinal fluid (CSF). The penetration of eight arylpropionic acid derivatives into CSF was studied in male Wistar rats. After intraperitoneal administration of each compound (5 mg/kg), blood and CSF samples were collected at different times (0.5, 1, 3 and 6 h). The fraction unbound to plasma protein was determined using ultrafiltration. The areas under the curve of the free plasma (AUCF) and CSF (AUCCSF) concentrations were calculated according to the trapezoidal rule. The overall drug transit into CSF was estimated by the ratio RAUC (AUCCSF : AUCF). The lipophilicity was expressed as the chromatographic capacity factor (log kIAM) determined by high-performance liquid chromatography on an immobilized artificial membrane (IAM) column. A significant parabolic relationship was sought between lipophilicity (log kIAM) and the capacity of diffusion across the blood-brain barrier (log RAUC) (r = 0.928; P < 0.01). The arylpropionic acid NSAIDs exhibiting a lipophilicity value between 1.1 and 1.7 entered the CSF easily (RAUC > 1). The molecular weight (MW) was included in this parabolic relationship by means of a multiple regression analysis. This physicochemical parameter improved the correlation (r = 0.976; P < 0.005). Based on our findings, diffusion of arylpropionic acid NSAIDs into CSF appears to depend primarily on their lipophilicity and MW.

Simultaneous determination of nimesulide and hydroxynimesulide in rat plasma, cerebrospinal fluid and brain by liquid chromatography using solid-phase extraction.

A liquid chromatographic method with UV detection for the quantification of nimesulide (N) and hydroxynimesulide (M1) in rat plasma, cerebrospinal fluid (CSF) and brain tissue is reported. Plasma samples (250 microl) and brain homogenates added with the right amount of the internal standard (I.S., 2'-(cyclohexyloxy)-4'-nitrophenyl methanesulphonanilide, NS398) are extracted on C(18) disposable cartridges by solid-phase extraction (SPE), while CSF samples are analyzed without any extraction. The separation is performed at room temperature on a Waters Symmetry C(18) 3.5 microm (150x4.6 mm I.D.) column with acetonitrile-sodium citrate buffer pH 3.00 (53:47, v/v) as mobile phase, at a flow-rate of 1.1 ml/min and detection at 240 nm. The retention times are 3.3, 6.0 and 9.9 min for M1, N and I.S., respectively. The lower limits of quantitation for either nimesulide and M1 are 25 ng/ml for plasma, 20 ng/ml for CSF and 25 ng/g for brain tissue. The calibration curves are linear up to 10,000 ng/ml for plasma, 5000 ng/ml for CSF and 5000 ng/g for brain tissue. This new assay can be applied to the study of the role of nimesulide in the modulation of neuroinflammatory processes.

Diffusion of ketoprofen into the cerebrospinal fluid of young children.

BACKGROUND: The objective was to examine whether or not ketoprofen enters the cerebrospinal fluid after a single oral dose of 1 mg.kg-1 syrup, and to find out what is the lowest plasma concentration that will achieve a measurable level in the cerebrospinal fluid. METHODS: We measured ketoprofen concentrations both in plasma and cerebrospinal fluid of 10 young and healthy children (aged 9-86 months) after surgery with spinal anaesthesia. Samples of cerebrospinal fluid were collected 30 min after drug administration, at the same time as venous blood samples. A validated high-performance liquid chromatography method with a lower limit of 0.02 microg x ml(-1) was used to detect ketoprofen concentrations in cerebrospinal fluid and plasma. RESULTS: Ketoprofen was detectable in the cerebrospinal fluid only in the child who had the highest plasma concentration, 7.4 microg x ml(-1), while at plasma concentrations 6.5 microg x ml(-1) or less, cerebrospinal fluid (CSF) concentrations remained unmeasurable. The detected CSF/plasma ratio was 0.008. CONCLUSIONS: These results indicate that ketoprofen at a dose of 1 mg x kg(-1) is too low to produce measurable CSF levels within 30 min of oral administration.

Influence of molecular lipophilicity on the diffusion of arylpropionate non-steroidal anti-inflammatory drugs into the cerebrospinal fluid.

The diffusion of seven arylpropionic acid non-steroidal anti-inflammatory drugs (NSAIDs) into the cerebrospinal fluid (CSF) has been investigated in male Wistar rats by means of quantitative structure-activity relationship (QSAR) study. After intraperitoneal administration of each drug (5 mg/kg), blood and CSF samples were collected at different times (0.5, 1, 3, and 6 h). The fraction bound to plasma proteins (fb) was determined using ultracentrifugation. The total (CT) and free (CF) plasma concentrations and the concentrations in CSF (CCSF) were measured by a reversed-phase high performance liquid chromatographic (RP-HPLC) method. The areas under the curve of the free plasma (AUCF) and CSF (AUCCSF) concentrations were calculated according to the trapezoidal rule. The overall drug transit into CSF was estimated by the ratio RAUC (AUCCSF: AUCF). The lipophilicity of the compounds was expressed as their polycratic capacity factors (log k'w) measured in a RP-HPLC system. The RAUC ranged from 0.24 to 6.58 and fb from 91.4 to 99.8%. The compounds with an intermediate lipophilicity value (3 < logk'w < 3.6) easily entered the CSF (RAUC > 1). A parabolic relationship was found between log k'w and log RAUC, emphasizing the role of molecular lipophilicity in the diffusion into CSF. Considering the fb value of each drug in regard to this non-linear relationship, it can be hypothesized that the diffusion rate of NSAIDs into the CSF depends primarily on the lipophilicity.

Cerebrospinal fluid and plasma concentrations of dipyrone metabolites after a single oral dose of dipyrone.

OBJECTIVE: Dipyrone is a veteran analgesic and antipyretic drug. After oral administration it is rapidly converted by hydrolysis to 4-methylaminoantipyrine (MAA), which is further metabolized to 4-formylaminoantipyrine (FAA), 4-aminoantipyrine (AA) and 4-acetylaminoantipyrine (AAA). It is still debated whether the site of dipyrone action is in the central nervous system or in the periphery. The purpose of this study was to assess whether dipyrone metabolites cross the blood-brain barrier (BBB) when administered systemically. METHODS: Twenty-eight patients undergoing diagnostic lumbar puncture (LP) were randomly assigned to receive two 0.5-g dipyrone tablets either 30 min, 1, 1.5, 2, 4, 6, 8 h or 12 h before the lumbar tap. A 5-ml blood sample was drawn concomitantly. RESULTS: All four metabolites were found in the cerebrospinal fluid (CSF). Their appearance in the CSF lagged but followed that found in the plasma. Mean CSF/plasma ratios were 0.40 (for samples taken between 0.5-2 h) and 0.83 (for samples taken between 4-12 h) for MAA, 0.62 for AA, 0.55 for FAA and 0.40 for AAA (for all samples). Significant correlation was found between plasma and CSF concentrations for MAA, AA, FAA and AAA. CONCLUSION: The concentration-time course of dipyrone metabolite CSF concentrations are in agreement with that of their plasma concentrations and the analgesic effect of dipyrone.

The effect of alpha-trinositol (D-myo-inositol 1,2,6-trisphosphate) on formalin-evoked spinal amino acid and prostaglandin E2 levels.

The effect of the inositol trisphosphate analog alpha-trinositol on noxious-evoked behavior, amino acid and prostaglandin E2 (PGE2) release was examined in unanesthetized rats using intrathecal microdialysis probes. Subcutaneous injection of 50 microliters 5% formalin solution produced two phases of pain-like behavior and significant elevation of glutamate, aspartate, glycine, taurine and serine during phase 1. PGE2 concentrations were increased during both phases 1 and 2. Intraperitoneal delivery of 300 mg/kg alpha-trinositol significantly suppressed both phases 1 and 2 of formalin-induced behavior and the associated elevation of amino acids and PGE2. These data demonstrate that the antinociceptive effect of alpha-trinositol corresponds to suppression of noxious-evoked release of amino acids and PGE2 from the spinal cord.

Ketorolac penetration into the cerebrospinal fluid of humans.

STUDY OBJECTIVE: To determine the cerebrospinal fluid (CSF): total plasma concentration ratio of ketorolac tromethamine following a single intramuscular (IM) dose. DESIGN: Open, single-dose, IM-administration study. SETTING: General operating theaters of a medical school hospital. PATIENTS: 29 ASA physical status I and II patients scheduled to undergo elective surgery with spinal anesthesia. INTERVENTIONS: Patients were premedicated with ketorolac 90 mg IM formulated as 3 ml of a 3% solution. Between 1 and 4 1/2 hours later, an intravenous infusion of 500 ml of compound sodium lactate was begun. Lumbar puncture was then performed, and 2 ml of CSF was collected prior to administration of the spinal anesthetic. In addition, a 5 ml sample of venous blood was taken within 5 minutes of the CSF sample. MEASUREMENTS AND MAIN RESULTS: Simultaneous plasma and CSF concentrations of ketorolac were measured between 62 and 277 minutes following IM administration in 29 patients undergoing spinal anesthesia. The CSF concentrations were on the order of 1,000 times less than the total plasma concentrations; free concentrations of ketorolac in plasma were estimated to be about 10 times more than those in CSF. There appeared to be no constant time factor relating the appearance of ketorolac in the CSF to its plasma concentration following IM administration. CONCLUSION: Although the sensitivity of central prostaglandin synthetase systems to inhibition is unknown, it is unlikely from this pharmacokinetic data that there is a major central mechanism of analgesia for ketorolac.

Clinical pharmacokinetics of nonsteroidal anti-inflammatory drugs in the cerebrospinal fluid.

The pharmacokinetics of nonsteroidal anti-inflammatory drugs (NSAIDs) in the cerebrospinal fluid (CSF) is of clinical interest as it may be related to some of their properties and side-effects. Two types of NSAIDs can be described with respect to their concentration and time course in CSF: in the first type, the transfer across the blood-brain barrier seems to be controlled by simple physico-chemical factors. These drugs (oxyphenbutazone, indomethacin, ketoprofen) are characterized by a high lipophilicity. At steady state, their free plasma concentrations correspond to their CSF concentrations. The second group consists of more hydrophilic compounds (salicylates); there is no correlation between plasma concentrations and CSF concentration. Further investigation needs to be carried out on CNS side-effects and the antialgesic activity of salicylates in relation on their CSF distribution.

The diffusion of pirprofen into the cerebrospinal fluid in man.

We have measured the concentrations of pirprofen at various times in plasma and cerebrospinal fluid (CSF) samples, drawn during diagnostic myelography from 28 patients affected by sciatica. After intramuscular injection of 400 mg plasma concentrations of pirprofen reached a peak in 60 min then fell slowly. In contrast, the CSF concentration rose until 12 h and then fell. Pirprofen rapidly crossed the blood-brain barrier and was detectable in CSF at 15-30 min after injection. These results support the suggested hypothesis of a central analgesic action of pirprofen along with the known peripheral one. A new sensitive HPLC method was developed for measuring the concentration of pirprofen in the CSF.