[Diffuse cerebral atrophy and reversible polyneuropathy in a patient with chronic Bromvalerylurea intoxication: a case report].

A 37-year-old man who had been on bromvalerylurea (BU) medication for 11 years at a maximum dose of 2,400 mg per day for headache therapy was admitted to our hospital due to gait disturbance. He had weight loss and exanthema all over his body. Cognitive dysfunction, intellectual deterioration, attention disturbance, decreased muscle strength, and decreased vibratory sense in the lower limbs were observed. Brain MRI showed diffuse brain atrophy, and a peripheral nerve conduction examination revealed decreased nerve conduction velocity and action potential amplitude in the extremities. We diagnosed him with chronic BU intoxication based on pseudohyperchloremia, BU detected in the blood, and bromide elevation. By discontinuing BU and performing intravenous infusion, neurological symptoms and exanthema were improved, and peripheral nerve conduction examination findings also improved. There are few reports of peripheral neuropathy cases of chronic BU intoxication; herein we report one such case along with previously reported cases.

Application of energy dispersive X-ray fluorescent spectrometry (EDXRF) in drug-related cases.

We applied here energy dispersive X-ray fluorescent spectrometry (EDXRF) to two medico-legal autopsy cases of bromvalerylurea ingestion. Rapid elemental analysis using EDXRF identified bromide in blood, urine and stomach contents of victims during autopsy. The present cases indicate that screening with EDXRF, an instrument suitable for non-destructive, rapid elemental analysis, provides useful information for identification of drugs.

Myoclonic jerks due to acute bromovalerylurea intoxication.

BACKGROUND: Bromides are still sold as sedatives, antitussives, and anticonvulsants in many countries. Bromovalerylurea is a bromide-containing sedative-hypnotic that is occasionally combined with non-steroidal anti-inflammatory drugs in over-the-counter products. Chronic intake of excessive bromovalerylurea can produce bromide intoxication, but acute bromovalerylurea intoxication presenting with myoclonic jerks has never been described. CASE REPORT: A 23-year-old woman was brought to our emergency department with unusual drowsiness. Her physical examination was normal except for frequent myoclonic jerks in all extremities that could be triggered by moving the patient or by noxious stimuli. Initial blood tests results were normal; the serum bromide concentration was 81.0 mg/L (reference <10 mg/L). Treatment with intravenous normal saline and furosemide resulted in gradual improvement in her drowsiness and myoclonic jerks. By the second hospital day, she was normal. A brain magnetic resonance imaging (MRI) was normal. At a 2-month follow-up visit, the patient had no neurological sequelae. DISCUSSION: Chronic bromide intoxication caused by long-term abuse of bromovalerylurea may present as psychiatric or neurologic abnormalities. Our case of acute bromovalerylurea intoxication presented with severe myoclonic jerks and lethargy. The serum bromide concentration was similar to the reported concentrations in acute bromide intoxications. Treatment with normal saline and diuretics results in increased clearance of bromide and an improvement in clinical effects. CONCLUSION: Myoclonic jerks may be one of the major presentations of acute bromovalerylurea intoxication. Physicians should consider bromide intoxication in the differential diagnosis of the causes of myoclonic jerks.

[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.

Method for screening and quantitative determination of serum levels of salicylic Acid, acetaminophen, theophylline, phenobarbital, bromvalerylurea, pentobarbital, and amobarbital using liquid chromatography/electrospray mass spectrometry.

We investigated a method for the simultaneous screening, identification, and quantitative determination of salicylic acid, acetaminophen, theophylline, barbiturates, and bromvalerylurea, drugs that frequently cause acute poisoning in Japan and therefore require rapid analysis for effective treatment in the clinical setting. The method employs liquid chromatography/electrospray mass spectrometry (LC/MS) of solid-phase extracted serum samples. For LC/MS ionization, the electrospray-ionization method was used, with acetaminophen in the positive-ion mode, and salicylic acid, theophylline, phenobarbital, bromvalerylurea, pentobarbital, amobarbital, and o-acetamidophenol (internal standard) in the negative-ion mode, the base ions were used in each case for quantitative analysis. Quantitation was possible for the following sample concentration ranges: salicylic acid and acetaminophen, 100 to 5 microg/ml; theophylline, 100 to 0.5 microg/ml; and phenobarbital, bromvalerylurea, pentobarbital, and amobarbital, 100 to 1 microg/ml. Using full-scan mass spectrometry, the lower detection limits of 1 microg/ml for salicylic acid and acetaminophen, 0.1 microg/ml for theophylline, and 0.5 microg/ml for phenobarbital, bromvalerylurea, pentobarbital, and amobarbital were adequate for identifying acute poisoning. When each compound was added to serum to a final concentration of 5 microg/ml and solid-phase extraction was performed using Oasis HLB 1-cc (30-mg), the mean recovery rate of each compound was 89.2 to 96.1% (n=5), and the coefficients of variation of the intraday and interday assays were 3.55 to 6.05% (n=5) and 3.68 to 6.38% (n=5), respectively, which are acceptable. When this method of analysis was applied in testing the sera of a female patient who had consumed a large amount of an unknown commercial drug, salicylic acid and bromvalerylurea were identified, and the treatment strategy could be determined in accordance with the serum concentration of those drugs.

Bromide intoxication by the combination of bromide-containing over-the-counter drug and dextromethorphan hydrobromide.

A 30-year old woman was presented to the emergency room with marked lethargy and fever. Her physical examination showed an acneiform eruption on the face. Blood biochemistry showed a high chloride level and a negative anion gap. High blood bromide level measurements on an ion-selective electrode was noted later to cause spurious hyperchloremia with a negative anion gap. After receiving saline hydration and diuretic treatment, her serum chloride returned to normal range on hospital day nine. Slow resolution of her mental status occurred over 2 months. Her skin lesions disappeared about 5 months later. In conclusion, in face of an unusual high chloride level and a negative anion gap in a patient of long-term use of over-the-counter (OTC) agents, bromide intoxication should be included in the differential diagnosis.

[A case of chronic bromvalerylurea intoxication due to habitual use of commercially available nonsteroidal anti-inflammatory drugs presenting an indefinite hyperchloremia].

A 75-year-old man was admitted to our hospital with disorientation and progression of speech disturbance and gait disturbance. He had been given a diagnosis of cervical spondylosis about four years previously, and gait disturbance and numbness in his extremities have been gradually increasing. Hyperchloremia and a careful history taking, which led to the discovery of habitual use of an analgesic containing bromvalerylurea, suggested bromism. A high level of bromide in serum yielded a diagnosis of bromism. Disorientation and speech disturbance were treated and improved by infusion diuresis. Gait disturbance only partly improved. There is a possibility that not only cervical spondylosis, but also chronic bromvalerylurea intoxication, may have contributed to the neurological disturbance resulting in gait disturbance and numbness. Bromvalerylurea, which is contained in many commercially available analgesics, should be noted as a possible cause of neurological disturbance.

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.

[A case of the cerebellar atrophy and pseudo-hyperchloremia as a clue to diagnose chronic bromvalerylurea intoxication].

A 36-year-old woman was admitted to our hospital because of walking disturbance and dizziness. Her neurological examination showed psychiatric disturbance, truncal and limb ataxia, wide-based gait. She has taken 3 g of bromvalerylurea daily. The laboratory test revealed elevated levels of serum chloride (201 mEq/L) and bromide (105 mg/dl), and decreased (-43 mEq/L) anion gap. Brain MRI revealed atrophy of upper part of the vermis and cerebellar hemisphere, and widening of the primary fissure and dilatation of the forth ventricle. Bromvalerylurea, which is an easily available sedative, should be still noted as a cause of cerebellar ataxia. Increased level of serum chloride was useful information for early diagnosis of chronic bromide intoxication.

Chronic bromvalerylurea intoxication: dystonic posture and cerebellar ataxia due to nonsteroidal anti-inflammatory drug abuse.

Nalon-Ace and other nonsteroidal anti-inflammatory drugs (NSAID) containing bromvalerylurea (BVU) are sold as over-the-counter (OTC) drugs and are obtainable without prescription in Japan. A 32-year-old woman was diagnosed as having chronic BVU intoxication due to habitual use of Nalon-Ace. In addition to cerebellar ataxia and pyramidal signs well known in this condition, she showed an as yet non-described dystonic posture of the neck. Laboratory tests revealed an elevated concentration of serum organic bromide, iron deficiency anemia, and hyperchloremia. Brain magnetic resonance imaging (MRI) revealed definite cerebellar atrophy. We should consider the possibility of chronic BVU intoxication in peculiar neurological cases like ours.

Detection of bromisovalum from the bone marrow of skeletonized human remains: a case report with a comparison between gas chromatography/mass spectrometry (GC/MS) and high-performance liquid chromatography/mass spectrometry (LC/MS).

We report a case of totally skeletonized human remains in which a considerable amount of a hypnotic, bromisovalum (bromovalerylurea), was detected from the bone marrow. The unknown skeletal remains were found in a bush, together with empty vials of bromisovalum and a water bottle. The body was identified as a 46-year-old male, who had died about seven months previously. There was no evidence of trauma. The dried bone marrow of both femurs was separately collected and toxicologically analysed by gas chromatography/mass spectrometry (GC/MS) and a high-performance liquid chromatography/mass spectrometry (LC/MS). Bromisovalum was identified from the femurs. The concentration along with the circumstantial evidence suggested possible contribution of bromisovalum to the fatality. However, a considerable quantitative difference was observed between the left and right femur, showing significant post-mortem interference to toxicological evidence. The result showed that multiple sampling at least would be required for quantitative evaluation of post-mortem toxicological evidence. Moreover, the diagnostic value should also be considered with caution in relation to the load to bone marrow ratio of each drug concentration.

[A suicidal case of electrocution with hypnotic drug poisoning: an autopsy report].

A 28-year-old male was found dead on a bed in a hotel. He had two electric wires, the ends of which were fastened to each coin (50 and 100 yen); the coins were attached to a left hypochondrial region and a left side of the chest. The other ends of the wires were connected to a time switch, which had been connected to a plug top (100 V, 60 Hz alternating current). An empty box of a commercially available hypnotic (bromvalerylurea), a suicide note and a manual book for suicide were found at the spot. As autopsy findings, both burns on the left hypochondrial region and on the left side of the chest were carbonized at their central parts and erythemas were also noted around them. Histological findings were consistent with electric marks and the burns showed vital reactions. Copper stain was slightly positive; iron stain was negative. Bromvalerylurea concentrations in blood, urine, brain, liver and kidney samples were 14.5, 37.7, 5.8, 5.2 and 6.2 micrograms/ml or g, respectively. The blood level showed that he had been moderately intoxicated by the drug, but not fatal. The cause of death was thus judged to be suicidal electrocution. It seems that suicide was influenced by a "Manual Book of Suicide", which was found in his bag.