Removal of baclofen with hemodialysis is negligible compared to intact kidney excretion in a pediatric overdose: a case report.

INTRODUCTION: Severe baclofen toxicity can result in respiratory failure, hemodynamic instability, bradycardia, hypothermia, seizures, coma, and death. While hemodialysis (HD) is well-described in treating acute baclofen toxicity in patients with end-stage kidney disease or acute kidney injury, the utility of HD for patients with normal kidney function is uncertain. Implementing HD to speed recovery after a large acute baclofen ingestion is appealing, considering: (a) potential for prolonged coma and ventilator-associated morbidity, and (b) baclofen's low protein-binding, low molecular-weight, and moderate volume of distribution. METHODS: We report a 51 kg, 14-year-old girl who presented to the emergency department (ED) with hypotension, obtundation, and status epilepticus after an intentional ingestion of 1200 mg baclofen. Her post-intubation neurologic examination was concerning for coma. A 14-hour post-ingestion baclofen concentration was 882 ng/mL (therapeutic range 80-400 ng/mL). Three urgent-HD sessions were performed to reduce her time on the ventilator. RESULTS: The total baclofen removed in the first three-hour HD session was 3.05 mg. The total urinary elimination of baclofen 42 mg over 24-hours on day one. She was discharged without neurologic deficits to psychiatry on day-14. CONCLUSION: In this case, the amount of baclofen recovered during HD is negligible in comparison to the amount cleared by kidney elimination in this patient with normal kidney function.

Baclofen overdose following recreational use in adolescents and young adults: A case report and review of the literature.

Over the past twenty years, psychotropic drug abuse by young people, especially by teenagers, has received special attention. Here, we present the case of baclofen overdose in a 16-year-old male who recreationally, and probably recurrently, self-administered baclofen. In addition, a review of other cases was conducted. The 16-year-old boy presented to emergency department with digestive signs followed by agitated confusion. Detection and determination of baclofen concentration were achieved using liquid chromatography tandem mass spectrometry. Baclofen was detected in plasma and urine, at 420 ng/mL and 64 900 ng/mL respectively. Further, an English exhaustive literature search was performed using several different scientific databases without any limiting period in order to identify scientific articles dealing with baclofen overdose following a recreational use among adolescent and young adults. Five publications describing baclofen overdoses following a recreational use among adolescents and young adults have been published reporting19 cases, all involving a non-fatal overdose, with baclofen concentrations ranging from less than 20-1322 ng/mL. Baclofen is a psychotropic drug and its recreational use among adolescents and young adults represent a serious problem and should be considered by healthcare professionals. Among young people, baclofen poisoning remains relatively infrequent or most likely underestimated and these observations highlight the importance of constructive communication and joining efforts of clinicians and analytical toxicologists.

Fabrication of water-compatible superparamagnetic molecularly imprinted biopolymer for clean separation of baclofen from bio-fluid samples: A mild and green approach.

A superparamagnetic molecularly imprinted biopolymer (SMIBP) was utilized as an eco-friendly and worth welting bio-sorbent and subsequently was applied for selective dispersive solid phase extraction (d-SPE) and selective separation of baclofen from urine samples. This effective solid phase was biopolymer network with imprinted cavities grafted on the surface of Fe3O4 cores possessing an influential SiO2 layer. The present sorbent easily achieved via co-precipitation and sol-gel processes followed by impressive bio-polymerization route under green and mild reaction conditions. The prepared SMIBP was subsequently characterized by different techniques including SEM, VSM, FT-IR, XRD, TEM and TGA verifying high suitability of the proposed solid phase for trapping and accumulation of target compound. Under optimized conditions recommended by experimental design, understudy SMIBP-d-SPE procedure supplied linear response over 1.0-2500.0µgL-1 with a satisfactory detection limit close to 0.26µgL-1, while repeatability assign to intra-day and inter-day precision as coefficients of variation was lower than 3.9% in both case. These appropriate validation imply high ability of proposed microextraction procedure for clean and effective enrichment of target analyte in complex human urine sample cause consequently leading to accurate analyses at ultra-trace levels.

Baclofen intoxication: a "fun drug" causing deep coma and nonconvulsive status epilepticus--a case report and review of the literature.

UNLABELLED: The number of reports on baclofen intoxication has increased in recent years. We report a 15-year-old boy who was referred in a state of deep coma (Glasgow Coma Scale = 3). On clinical examination, he showed sinus bradycardia with normal blood pressure. On admission to the hospital, he presented intermittent short episodes of generalized tonic-clonic seizures. While results of imaging procedures and initial toxicological screening (including standard HPLC analysis and urine test) were negative, a nonconvulsive status epilepticus was diagnosed by electroencephalography (EEG). Identification of baclofen as causative agent was possible after the boy's father reported abusive baclofen intake. Subsequent toxicological target analysis of blood and urine samples confirmed the excessive intake of baclofen and showed a typical elimination pattern with a secondary release. Following 112 h of mechanical ventilation, the boy rapidly regained consciousness and recovered normal neurological behavior. CONCLUSIONS: The present case demonstrates the importance of considering baclofen overdosage in cases of severe coma in combination with an abnormal EEG pattern and sinus bradycardia with normal blood pressure levels, in particular as the substance is popular in internet reports promoting baclofen as a rather harmless "fun drug." Furthermore, it underlines the difficulty to identify baclofen as a causative agent without anamnestic information. Nevertheless, by reviewing existing literature on oral baclofen overdosage, it is possible to picture a nearly specific pattern of clinical symptoms in baclofen intoxication.

Death due to baclofen and dipyrone ingestion.

A fatal suicidal intoxication with unusual drugs is reported. A 56-year-old man was found dead in his house; near by the corpse several empty drugs boxes were found. An autopsy was performed and the biological fluids were submitted to a full toxicological work-up. The analytical results supported the hypothesis of a death due to the acute baclofen (4-amino-3-(p-chlorophenyl)butyric acid) and dipyrone (sodium [N-(1,5-dimethyl-3-oxo-2-phenylpyrazolin-4-yl)-N-methylamino] methanesulfonate) intoxication.

Determination of baclofen in human plasma and urine by high-performance liquid chromatography with fluorescence detection.

An isocratic reversed-phase column liquid chromatographic assay for baclofen was developed. Prior to analysis, derivatization of urine or deproteinized plasma with 4-chloro-7-nitrobenzofurazan (NBD-CI) reagent was employed. After solid-phase extraction on a small silica gel column, the mixture was chromatographed on a 10 microns Bondapak C18 column using methanol-water (45 + 55 v/v) as the mobile phase. The NBD-baclofen derivative was detected spectrofluorimetrically by monitoring the emission at 524 nm with excitation at 463 nm. The method was tested for suitability in routine analysis. After a single oral dose of 20 mg of baclofen, the plasma concentration and the cumulative urinary excretion of the drug were determined. The average recoveries were 99.5 and 98.5% for plasma and urine, respectively.

Toxicological analysis of a fatal baclofen (Lioresal) ingestion.

A fatality following ingestion of the drug baclofen (Lioresal) is described. Baclofen was identified in urine by gas chromatography/mass spectrometry. After derivatization with trinitrobenzene sulfonic acid, baclofen was quantitated in serum and urine by high-performance liquid chromatography. The concentration of baclofen was 17 mg/L in serum and 760 mg/L in urine collected approximately 12 h after the overdose. To our knowledge, this is only the second reported fatality involving a baclofen overdose. The previous case did not include quantitation of baclofen in any biological fluid.

Determination of baclofen and alpha-baclofen in rat liver homogenate and human urine using solid-phase extraction, o-phthalaldehyde-tert.-butyl thiol derivatization and high-performance liquid chromatography with amperometric detection.

Methods were developed for the determination of the zwitterionic compounds baclofen and alpha-baclofen in complex biological samples (rat liver homogenates and human urine) in concentration ranges that would be suitable for pharmacokinetic studies of these compounds. In the procedure, the biological samples along with an internal standard were selectively concentrated using C18 solid-phase extraction cartridges, evaporated, derivatized with o-phthalaldehyde and tert.-butyl thiol at room temperature for 2 min, then subjected to high-performance liquid chromatographic analysis. The reversed-phase (C18) chromatographic analysis with amperometric detection (glassy carbon electrode in oxidative mode, +0.6 V vs. Ag/AgCl) was found to be useful for the measurement of both baclofen and alpha-baclofen from 10 ng/ml to 10 micrograms/ml in these complex biological samples. The primary advantage of the method was that the derivatives formed using tert.-butyl thiol were markedly more stable than the previously reported derivatives prepared using mercaptoethanol.

Plasma and urinary excretion kinetics of oral baclofen in healthy subjects.

Baclofen, a centrally acting muscle relaxant, is used in the treatment of spasticity. Its pharmacokinetics has been derived from plasma and urine data in four healthy subjects, whose renal function was simultaneously measured. After oral administration of a single 40 mg dose, baclofen was mainly excreted unchanged by the kidney, 69 (14)%. The half-life, calculated from extended least squares modelling (ELSMOS) both of plasma and urine data was 6.80 (0.68) h, which is longer than reported in most studies based solely on plasma data. The renal excretion rate constant had the high mean value of 0.35 (0.24) h-1, and the apparent renal clearance of baclofen equalled the creatinine clearance. Passive tubular reabsorption is relatively unimportant, since no dependence was observed on variables urine flow or pH. Although active tubular secretion may contribute to its renal clearance, as shown by the effect of co-administration of probenecid, glomerular filtration appears to be the dominant transport mechanism.

Comparison of the pharmacokinetics of intravenously administered rac-baclofen and its (-)-(R)- and (+)-(S)-enantiomers in dogs.

Baclofen is a centrally acting muscle relaxant marketed as the racemate. Since only the (-)-(R)-enantiomer is pharmacologically active, the pharmacokinetics of rac-baclofen and its enantiomers were studied individually in the same group of dogs to determine if there was any stereospecificity in the drug's kinetics after a single intravenous dose. High-pressure liquid chromatography was used to determine concentrations in plasma and urine. A major difference was found in the urinary recovery of the unchanged drug. Only about 50% of the dose of the clinically used racemate appeared as unchanged drug in the urine; whereas the active (-)-(R)-isomer was for the most part renally excreted (85%). Irrespective of isomeric composition, the renal clearance was dependent upon the creatinine clearance. Differences in non-renal clearance could not be explained by stereoselective formation of the gamma-hydroxymetabolite. It is concluded that in the dog, the active enantiomer is also pharmacokinetically preferred.

Determination of the S(+)- and R(-)-enantiomers of baclofen in plasma and urine by gas chromatography using a chiral fused-silica capillary column and an electron-capture detector.

A sensitive and enantiospecific gas chromatographic method for the determination of the S(+)- and R(-)-enantiomers of baclofen (I and II) in plasma and urine has been developed and validated. The method is based on the complete resolution of the derivatized enantiomers on a chiral fused-silica capillary column. The hydrochloride salt of a (-)-fluoro analogue of baclofen (III.HCl) was used as the internal standard in plasma, the hydrochloride salt of a (+)-fluoro analogue of baclofen (IV.HCl) as the internal standard in urine. Rapid and convenient isolation of the compounds was achieved using reversed-phase Bond-Elut C18 columns. After elution, the compounds were converted into isobutyl esters and purified by base-specific solvent extraction. The isobutyl esters were then N-acylated with heptafluorobutyric anhydride. The derivatives were quantitated after separation on the chiral column using electron-capture detection. The analysis of spiked plasma and urine samples demonstrated the good accuracy and precision of the method, with limits of quantitation of 25 nmol/l for I and II in plasma and of 2 mumol/l for I and II in urine. The method appears to be suitable for use in pharmacokinetic studies of the enantiomers in plasma and urine from animals and man after administration of the racemic baclofen.

Quantification of baclofen and its fluoro analogue in plasma and urine after fluorescent derivatisation with benoxaprofen chloride and thin-layer chromatographic separation.

An assay method for the quantification of the centrally acting muscle relaxant baclofen in human plasma and urine is described. Baclofen is separated from biological samples using Sep-Pak C18-cartridges. The liquid-solid extraction is followed by ion-pair extraction. The following procedure involves the formation of the baclofen butyl ester and an additional ion-pair extraction of the ester. Then a fluorescent derivatisation is performed, using the fluorescence marker benoxaprofen chloride. The resulting amide is separated from interfering compounds by TLC (silica gel) and quantified by directly measuring the fluorescence (313 nm/365 nm). The procedure described can also be applied for the determination of the fluoro analogue of baclofen. The lower limit of detection is 10 ng per 1 ml plasma and 20 ng per 0.1 ml urine. The applicability of the method was proved by investigating plasma and urine samples of 2 volunteers after oral administration of 20 mg baclofen as single dose.

The pharmacokinetics of baclofen derived from intestinal infusion.

The pharmacokinetics of baclofen, a centrally acting muscle relaxant, have been elucidated in man. The pharmacokinetic disposition was determined form plasma concentration-time data and urinary recovery after the administration of rate-limiting intestinal infusions and an oral bolus dose. Based on comparisons between the plasma concentration-time profiles from the intestinal infusions and the oral bolus doses, relative regression parameter assignments were made. The intestinal absorption of baclofen after intestinal infusion was very rapid, such that baclofen disposition was well characterized by an open two-compartment pharmacokinetic model with zero-order input. Intravenous administration of baclofen was precluded from this study because of the potential for severe adverse reactions. The average distribution phase constant (alpha) was 1.29 hours-1 and the average elimination phase constant (beta) was 0.191 hours-1. Average volume of the central compartment (Vc/F), volume of the body compartment (Varea/F), systemic clearance (CL/F), and renal clearance were 28.8 L, 59.0 L, 180 ml/min, and 103 ml/min, respectively. Pharmacokinetics were dose proportional in the dose range studied. The use of these pharmacokinetic parameters as determined in normal subjects in therapeutic management is particularly relevant, because baclofen is targeted to a patient population subject to renal dysfunction.

High-performance liquid chromatographic analysis of baclofen in plasma and urine of man after precolumn extraction and derivatization with o-phthaldialdehyde.

A reversed-phase high-performance liquid chromatographic method for the determination of the skeletal muscle relaxant baclofen in human plasma and urine is described. Cation-exchange extraction, precolumn derivatization with o-phthaldialdehyde, and on-column concentration precede fluorimetric detection (excitation at 340 nm, emission at 460 nm). The precision of the assay was always better than 6%. Recoveries of standards added to plasma and urine were 92% and 93%, respectively. With a sample size of 0.5 ml, a detection limit of a few nanograms, and the possibility of analysing up to four samples per hour, this method is suitable for pharmacokinetic studies. An example is presented.

Improved gas-liquid chromatographic method for the determination of baclofen in plasma and urine.

A simple, rapid and sensitive assay for baclofen analysis has been developed. Baclofen and the internal standard are analyzed by gas-liquid chromatography with electron-capture detection after esterification of the carboxyl group to the butyl ester and acylation of the amino group to the pentafluoropropionylamide. Recovery from biological matrixes is accomplished by ion-pair extraction. The limit of quantitation of the entire assay as stated is about 10 ng/ml baclofen in plasma.

Pharmacokinetics in baclofen overdose.

The pharmacokinetics of baclofen analyzed by gas chromatography mass spectrometry in a massive intoxication case (baclofen 1230 mg orally) is presented. In contrast to earlier reports, no increase in the plasma half-life of elimination of baclofen could be observed (t1/2 = 4.58 hours). On the contrary, we found an increased plasma clearance (Clpl = 0.368 l/kg) in this highly intoxicated patient compared to the kinetics usually found in healthy subjects.

The determination of gamma-amino-beta-(p-chlorophenyl)butyric acid (baclofen) in biological material by gas-liquid chromatography.

Baclofen and the internal standard are isolated from biological samples by adsorption on charcoal. After elution, the compounds are converted into butyl esters and purified by base-specific solvent extraction. The butyl esters are then N-acylated with heptafluorobutyrylimidazole, and the neutral derivatives are isolated by solvent extraction and subjected to gas-liquid chromarography, with use of an electron-capture detector. Baclofen can be determined in concentrations down to about 30 ng per sample.