[A case of acute bromvalerylurea intoxication: clinical course and alteration in serum bromvalerylurea concentration].

Bromvalerylurea is one of the non-barbiturates products and has been used as analgesics and hypnotics in Japan. A 20-year-old woman was admitted to our hospital for loss of consciousness. She had a 6-month history of transient delirium and drunken gait. Physical examination revealed erythema less than thumb's head size at her face, shoulder and thigh. Neurologically, she had a state of coma and low muscle tonus. EEG showed the pattern of burst-suppression. The level of her serum chloride was not elevated. The erythema made us check up her state of acute bromvalerylurea intoxication. High blood concentration of bromvalerylurea led to diagnosis of the bromvalerylurea intoxication. The maximum value of her serum bromvalerylurea concentration was 107 microg/ml on the second hospital day, while the concentration in cerebrospinal fluid were also increased and remained for several days. She was treated with respiration control and drip infusions. She gradually improved and recovered to be alert. She was complicated severe liver dysfunction and disseminated intravascular coagulation resulting from bromvalerylurea intoxication, also treated with intensive care and gradually recovered. We should take notice to bromvalerylurea, easily available over the counter, as one of the drugs which may cause severe loss of consciousness or coma, and general complications. And if the bromvalerylurea intoxication is prospective, we should consider whether the option of gastric irrigation is available regardless of the elapsed time.

Simultaneous determination of bromvalerylurea and allylisopropylacetylurea in human blood and urine by gas chromatography-mass spectrometry.

We devised a sensitive and simple method to simultaneously determine bromvalerylurea and allylisopropylacetylurea in human blood and urine by gas chromatography-mass spectrometry. Bromvalerylurea and allylisopropylacetylurea were extracted using an Extrelut column with an internal standard, 2-bromohexanoylurea, followed by derivatization with heptafluorobutyric anhydride. The derivatized extract was submitted to GC-MS analysis of EI-SIM mode. The calibration curves of both compounds were linear in the concentration range from 0.01 to 10 microg/ml in both blood and urine samples. The lower limits of detection of bromvalerylurea and allylisopropylacetylurea were 0.005 and 0.005 microg/ml, respectively. This method proved most useful in accurately identifying these drugs in blood and urine from an autopsied individual.

Characterization of glutathione conjugation in humans: stereoselectivity in plasma elimination pharmacokinetics and urinary excretion of (R)- and (S)-2-bromoisovalerylurea in healthy volunteers.

Characterization of glutathione conjugation in vivo was performed in 12 healthy male volunteers by use of the racemic drug bromisovalum (bromisoval; 2-bromoisovalerylurea) as a model substrate. To study whether the pharmacokinetics of both bromisovalum enantiomers was related to the glutathione S-transferase class Mu phenotype, six subjects who were class Mu deficient and six subjects who were not class Mu deficient participated. After oral administration of 600 mg racemic bromisovalum, enantioselective measurement of unchanged bromisovalum (plasma and saliva) and the diastereomeric bromisovalum mercapturates (urine) showed a pronounced stereoselectivity in all subjects. The plasma clearance of R-bromisovalum was about 12 times higher than that of S-bromisovalum (9.3 +/- 3.7 and 0.78 +/- 0.38 L/min, respectively), which was in agreement with the higher urinary cumulative excretion for the mercapturate derived from R-bromisovalum: 26% +/- 4% of the dose versus 8% +/- 3% of the dose for the mercapturate derived from S-bromisovalum. Both the bromisovalum pharmacokinetics in general and the stereoselectivity in bromisovalum pharmacokinetics were not different for the subjects who were glutathione S-transferase class Mu deficient and the subjects who were not glutathione transferase class Mu deficient.

Rapid isolation with Sep-Pak C18 cartridges and wide-bore capillary gas chromatography of bromisovalum.

A simple and rapid method for isolation of bromisovalum with Sep-Pak C18 cartridges from human whole blood, plasma, and urine containing allylisopropylacetylurea as an internal standard, is presented. Detection of the drugs was made by nonpolar wide-bore capillary gas chromatography (GC) with flame ionization. The drug-containing samples, after mixing with water, were directly applied to the cartridges and eluted with chloroform-methanol (9:1). The recoveries of bromisovalum with use of the cartridges were excellent. Bromisovalum and internal standard allylisopropylacetylurea could be satisfactorily separated from each other and from impurities with the wide-bore capillary column. The detection limit for bromisovalum was 2-5 ng in an injected volume.

Simultaneous determination of bromvalerylurea, bromodiethylacetylurea, and allylisopropylacetylurea in serum and urine by high-performance liquid chromatography with a multiwavelength UV detector and thin-layer chromatography.

A method for rapid detection and identification of bromvalerylurea (BVU), bromodiethylacetylurea (BDU), and allylisopropylacetylurea (AIU) in serum and urine by high-performance liquid chromatography (HPLC) with a multiwavelength UV detector after Sep-Pak C18 cartridge extraction is reported. A Jasco Finepak C18 reversed-phase column was used for the separation. Acetonitrile-distilled water (1:1, v/v) was used as a mobile phase. There was no significant absorption of the three hypnotics in the UV spectra (210-350 nm). However, the absorption of each was higher at the shorter wavelengths. The quantifications for the three hypnotics detected at 210 nm by the chromatogram were linear over the range 0.2-4 micrograms/mL and the detection limits of BVU, BDU, and AIU were 5, 10, and 10 ng as absolute amounts, respectively. The mean recovery yields of BVU, BDU, and AIU by Sep-Pak C18 cartridge extraction were 85.7 +/- 4.1, 98.6 +/- 2.2, and 95.1 +/- 3.5% (n = 5) in serum and 79.5 +/- 3.8, 95.7 +/- 1.8, and 93.0 +/- 4.2% (n = 5) in urine, respectively. An optimal system of thin-layer chromatography for the identification of the hypnotics is also discussed.

Stereoselectivity in the urinary excretion of the mercapturates of (R-) and (S-) alpha-bromoisovalerylurea in man.

1. alpha-Bromoisovalerylurea (BIU) is a racemic drug that is metabolized by glutathione conjugation. The urinary excretion of the separate diastereomeric mercapturates formed from (S)- and (R)-BIU in healthy young human volunteers was investigated. 2. A pronounced stereoselectivity was observed: the mercapturate formed from R-BIU was excreted with a t1/2 of 1.5 +/- 0.4 h, while that from S-BIU showed a t1/2 of 3.1 +/- 1.3 h. Moreover, 22.5 +/- 4.3 and 5.7 +/- 1.6% of the dose, respectively, was excreted as each mercapturate diastereomer in 24 h. 3. This is the first example of stereoselectivity in the elimination of a substrate for glutathione conjugation in man.

Liquid chromatographic determination of diastereomeric glutathione conjugates and further derivatives of alpha-bromoisovalerylurea in rat bile and urine by electrochemically generated bromine.

To study the glutathione conjugation of alpha-bromoisovalerylurea in the rat in vivo, a reversed-phase liquid chromatographic assay of the thioether metabolites in bile and urine was developed. Since alpha-bromoisovalerylurea has a chiral centre, two diastereomeric glutathione conjugates (in bile) and two diastereomeric mercapturates (in urine) can be expected. The separation characteristics of these metabolites and the corresponding cysteine conjugates were investigated. Whereas all thioether metabolites could be separated in one run, optimal separation of the diastereomers required different mobile phases for the glutathione conjugates (in bile) and the mercapturates (in urine). The glutathione conjugates were analysed with the ion-pairing agent sodium decanesulphonate in the mobile phase, but the mercapturates were analysed without an ion-pair-forming agent. For detection, on-line generation of a constant bromine level (100%) was used; bromine-reactive compounds result in a decrease of the amperometric response from the 100% baseline. This technique could be used in continuous automated operation and required little clean-up of the sample. Thus, the diastereomeric glutathione conjugates and mercapturates were quantified in rat bile and urine samples, respectively, by direct injection of the (centrifuged and diluted) samples on the column. The limit of determination of the respective metabolites was 9 and 2.6 ng in bile and urine, respectively. Incubation mixtures of alpha-bromoisovalerylurea with a rat liver cytosolic fraction or with isolated rat hepatocytes were chromatographed after deproteinization with a double volume of methanol. The limit of determination of the diastereomeric glutathione conjugates in the deproteinized incubation samples was 2.0 ng.

[Post mortem determination of bromureides (author's transl)]. / Nachweis der Bromureide in Leichenorgranen.

Concentrations of carbromal, carbromide and bromisoval are determined in blood, urine, brain, kidney and muscle taken at autopsy from 41 fatal cases after overdosage of bromureides. In addition values of total bromine in blood are presented. Contents of total bromine can only lead to the deduction that a chronical abuse of bromureides is existent or not. Concentrations of bromureides and carbromide show a wide range according to the different time between taking the drug and death particularly in cases of pure carbromal intoxications which sometimes cause death after several days. In such cases quantitative determination of carbromide, a pharmacologically active metabolite of carbromal, is the only way to prove an acute carbromal intoxication. Especially in cases of additional foreign substances death may occur in early the phase of poisoning. Bromureides decompose post mortem by putrefaction a high degree so that the condition of the cadaver is important. Brain tissue is the most usable material for examination but other organs, particularly muscle and kidney, can be analysed with success. For differential diagnosis fatal cases are presented which were not caused by drug intake.