Bromoderma mimicking pyoderma gangrenosum caused by commercial sedatives.

Bromoderma is a rare skin disorder caused by bromide intake. It presents as single or multiple papillomatous nodules or plaques, and ulcers studded with small pustules on the face or limbs. The clinical features of bromoderma are similar to those of pyoderma gangrenosum. A 41-year-old Japanese woman was diagnosed with pyoderma gangrenosum 11 years prior to presentation. Pyoderma had repeatedly appeared over her entire body despite treatment. She also frequently complained of syncopal episodes. She was admitted to our hospital after loss of consciousness and an episode of generalized convulsion. Laboratory tests revealed a negative serum anion gap and hyperchloremia. Her serum bromide level was significantly elevated, suggesting bromide intoxication. The patient had a 10-year history of high serum bromide levels. After the intake of bromide-containing sedatives was stopped, there was no recurrence of pyoderma in the absence of treatment. In conclusion, this case was diagnosed as bromoderma with commercial sedative-induced bromide intoxication. Although the US Food and Drug Administration have banned the use of bromides, over-the-counter (OTC) treatments containing bromides are still used in Japan and other countries. Long-term use of OTC medicines containing bromvalerylurea may result in the development of bromoderma. If unclarified neurological or psychiatric symptoms are associated with pyoderma, we propose measurement of the patient's serum chloride concentration. Determination of hyperchloremia is helpful for the diagnosis of chronic intoxication with bromides.

[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.

Determination of plasma bromvalerylurea and its main metabolite by a simple high-performance liquid chromatographic method and quantitation of bromide by energy dispersive X-ray spectrometry in carbon tetrachloride-intoxicated rats.

In the present study, small volumes of plasma were used for the measurement of bromvalerylurea (BVU), its metabolite, 3-methylbutyrylurea (MVU), and bromide in carbon tetrachloride (CCl4)-treated rats by HPLC-UV and energy dispersive X-ray spectrometry. A liquid-liquid extraction system was also investigated. BVU and MVU were extracted from 100 microl plasma samples in a single-step involving deproteination with 1 M hydrochloric acid using ethenzamide as internal standard. Samples were separated by HPLC in an acetonitrile-8 mM potassium dihydrogenphosphate buffer (35:65, v/v) mobile phase at a flow-rate of 0.4 ml/min on a 15 cm octadecylsilyl column at room temperature. Analytes were detected at a wavelength of 210 nm. The limits of quantitation for BVU, MVU and bromide are 0.1, 0.1 and 50 microg/ml, respectively. The intra-day accuracies over the range of concentrations were 95.8 to 121.1%, 97.2 to 119.7% and 96.2 to 105.8% for BVU, MVU and bromide, respectively. The inter-day accuracies were 97.7 to 115.1%, 98.3 to 111.6% and 98.3 to 102.9% for BVU, MVU and bromide, respectively. The absolute recoveries using tert.-butyl methyl ether are 96-98% for BVU and 95-98% for MVU. The decline in the plasma concentrations of BVU in olive oil-treated rats fitted a one-compartment model and the plasma MVU level reached a peak at around 1.5-2 h and then decreased gradually. The elimination of BVU in CCl4 (1 ml/kg)-treated rats was delayed and MVU production was less than that in the olive oil-treated group. However, there was no difference in the plasma levels of bromide between CCl4-treated rats and control rats. rights reserved.

Determination of (+)- and (-)-bromoisovalerylurea in sera of overdosed subjects.

Bromoisovalerylurea (bromisovalum) is a sedative-hypnotic given orally as a racemic mixture of optical isomers (i.e., (+)- and (-)-enantiomer) and frequently taken in overdose in order to commit suicide. Sera from 16 overdosed subjects were analyzed for each enantiomer by high-performance liquid chromatography on chiral stationary phases. The (+)-enantiomer concentration was lower than the (-)-enantiomer concentration in all specimens, that is, the ratio of the (+)-enantiomer to the total concentration ranged from about 50% to 0%. The ratio of the (+)-enantiomer was continuously decreasing in each subject. The data indicate that the drug in gastrointestinal tract was absorbed into blood nonstereoselectively and that the drug in blood was eliminated stereoselectively. The enantioselective determination of this drug will give useful information on absorption and elimination.

Enantioselective determination of bromoisovalerylurea by liquid chromatography on chiral stationary phase in reversed- or normal-phase partition mode.

Bromoisovalerylurea (bromvalerylurea) is a sedative-hypnotic given orally as a racemate. Enantiomers of this drug could be separated by high-performance liquid chromatography on the three chiral stationary phases (a vancomycin-bonded, beta-cyclodextrin derivative-bonded, or urea derivative-bonded phase). Biological fluids of human subjects who had ingested toxic or therapeutic doses of the racemate were chromatographed after liquid-liquid extraction. The (+)-enantiomer concentration was almost equal to the (-)-enantiomer concentration in the serum of one overdosed patient. In all the other subjects, the (+)-enantiomer was less than the (-)-enantiomer in their sera and saliva. The data suggest that the drug is absorbed non-stereoselectively from the gastrointestinal tract and eliminated from the blood stereoselectively.

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.

[Toxicology in legal medicine].

The purpose of toxicology in legal medicine is to determine the presence of chemicals effecting the human body in biological samples and to interpret the concentrations of chemicals. Analytical methods and medico-legal interpretations of the results of poisoning cases were discussed. 1. "Yusho," PCB poisoning "Yusho" was determined to be PCB poisoning by the detection of PCB in Rice-oil used by a "Yusho" family. My toxicological works were based on the study of "Yusho," which taught me the importance of the collaboration between faculties, the moral of the co-worker, and the PCB contamination in the laboratory. 2. Drugs In order to interpret the concentration of bromvalerylurea in blood, a very sensitive method was developed using a Florisil mini-column for cleaning up, and ECD-GC for analysis. GC/MS is used to determine the concentrations of other drugs in biological samples as well. 3. Pesticides In the first case of fatal ethyl parathion poisoning, only ethyl parathion in the stomach contents was analyzed by ECD-GC, and the cause of death was determined to be ethyl parathion poisoning. In the second case, parathion in the blood, brain, and stomach contents was analyzed. Both cases, however, were not reported in detail in the journal. Joint study on pesticides with the Division of Emergency Medicine is carrying on now. 4. Thinner Male rats were exposed to toluene vapor in pure oxygen, air, and 10%-O2 air. Anesthetic death from thinner vapor was confirmed. It seems that inhalation of toluene in a hypoxic atmosphere, such as from a plastic bag, is very dangerous.(ABSTRACT TRUNCATED AT 250 WORDS)

Selected ion monitoring for the determination of bromovalerylurea in human plasma.

A gas chromatography-selected ion monitoring procedure with chemical ionization is described for the determination of bromovalerylurea (BVU) in human plasma. BVU was extracted with ether after addition of 2-bromo-2-methylpropylurea as an internal standard. The lower limit of BVU quantification by this method was 2 ng/0.1 ml plasma volume. This procedure was used to determine the sequential plasma levels of BVU in a human volunteer following a single oral dose of a commercial analgesic.

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.

Enantioselective determination of R- and S-(alpha-bromoisovaleryl)urea in plasma using high-performance liquid chromatography after solid-phase extraction.

A stereoselective method has been developed for the determination of R- and S-(alpha-bromoisovaleryl)urea in plasma and saliva after oral administration. The chiral separation was carried out on Chiralcel OJ or OD columns with hexane--2-propanol as the mobile phase. The poor detection properties of the analyte required the development of an effective sample pretreatment procedure to enable ultraviolet detection at 210 nm. Solid-phase extraction using hydrophobic Amberlite XAD-2 in combination with washing steps at alkaline and acidic pH completely removed interfering components of the biological matrix and allowed the detection of the optical isomers at concentrations down to 10 ng/ml (0.05 microM). The method was validated by determining the recovery, linearity, accuracy and within-day and between-day repeatability at 50, 200 and 2000 ng/ml. Application to the analysis of plasma and saliva samples is demonstrated.

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 of glutathione conjugation: blood elimination of alpha-bromoisovalerylurea enantiomers and biliary excretion of the conjugates in unanesthetized normal or congenitally jaundiced rats.

Stereoselectivity of glutathione conjugation was studied in unanesthetized normal and congenitally jaundiced rats (Groningen Yellow), using the separate enantiomers of alpha-bromoisovalerylurea (BIU) as substrates. The blood elimination half-lives of (R)- or (S)-BIU were 8 and 38 min, respectively. The excretion half-lives of the GSH conjugates in bile in normal rats showed a similar difference: (R)-BIU yielded exclusively (S)-IU-S-G with a T1/2 of 12 min, and (S)-BIU yielded only (R)-IU-S-G with a T1/2 of 36 min. In normal rats 45-47% of the dose of (R)-BIU and (S)-BIU was found in bile as glutathione (GSH) conjugate, and 19-25% was excreted in urine as mercapturates. Similar values in the mutant rats indicated that BIU elimination by GSH conjugation was unimpaired, but the GSH conjugates were absent from bile. In the urine twice as much mercapturates was found as in normal rats. The GSH content and the activity of the glutathione-S-transferases in the liver were similar in mutant and controls. The data on blood elimination of the BIU enantiomers and biliary excretion of the GSH conjugates suggest that for (S)-BIU the conjugation step is rate-limiting, whereas for (R)-BIU a transport step into bile may be rate-limiting.

Efficacy of hemoperfusion in the therapy of bromvalerylurea (bromural) intoxication.

We have found that charcoal hemoperfusion is effective in removing bromvalerylurea (BVU) from circulation. A patient poisoned with BVU showed a marked lightening of coma after 3 h of hemoperfusion. The BVU concentration in the patient's serum was decreased significantly by hemoperfusion. In an experiment with dogs without hemoperfusion, the BVU concentration had its peak at the fourth hour after oral administration and decreased in 24 h. In an experiment with hemoperfusion, BVU concentration in dogs decreased markedly during hemoperfusion. After hemoperfusion a rebound of concentration was observed.