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We report the details of an accidental overdosage of haloperidol in 24 children in one hospital in Kyushu, Japan. Evidence of acute toxicity included disturbances in consciousness (24/24), tremors in the extremities (16/24), an oculogyric or similar crisis (14/24), dysarthria (9/17), drooling (8/24), akathisia (6/20), hyperreflexia (6/24) and opisthotonos (3/24). Laboratory examinations revealed late-onset transient thrombocytosis (5/24), elevated AST and GPT (1/24) and abnormal ECG with prolonged QT interval in 2 of 8 children. We detected haloperidol in 11 of 18 children whose blood was specifically examined within four days after the final haloperidol administration. The maximum serum haloperidol level was 28.9 ng/ml. The mean half-life of haloperidol in the serum of five children (age range 2-10 years) was 18.6 +/- 12.2 h (mean +/- SD) (range 9.1-39.4 h).

To elucidate the dose-effect relationship of neurotoxicity of allyl chloride (AC) in Donryu rats, 5 animals each were exposed to 10, 50 and 100 ppm AC for 8 h/d and 5 d/wk for a period of 34 wk. Nerve conduction velocities of the tail nerve in rats were determined before and after 4, 8, 12, 16, 22, 28 and 34 wk of exposure, and the width of landing foot-spread after 8, 12, 16, 28 and 34 wk. Animals subjected to 100 ppm AC showed significant (p less than 0.01) reduction of motor and sensory nerve conduction velocities and nerve action potentials (NAP) after 28 wk when clinical signs of neuropathy were observed, i.e., weakness of hindlimbs and significantly (p less than 0.01) extended landing foot-spreads. Motor distal latency was retarded in rats exposed to 100 ppm AC at the last period of exposure. In rats exposed to 50 and 100 ppm AC, no remarkable electrophysiological findings or abnormal clinical signs were observed except for depressed amplitude of NAP in 50 ppm-exposed rats when compared with those exposed to 10 ppm.

Using unit recording and microelectrophoresis, influence of pipecolic acid (PA), a major metabolite of lysine in the brain, on GABA and glycine responses was studied in the cerebral cortical and hippocampal pyramidal neurons of rats. With small currents, PA had no effect on the single neuron activities but enhanced GABA response without affecting glycine response. The finding provides a new evidence that PA may have a connection with central GABA system.

Pyrrolidine, one of biogenic volatile amines, possesses nicotine-like synaptotropic actions on the nervous systems. In the present study, pyrrolidine levels in the tissues were examined by using mass fragmentographic technique. High concentrations of pyrrolidine were found in the seminal vesicle and lung of rabbits. Only trace amounts of pyrrolidine existed in the brain of mice and rats, although higher concentrations were detected in the brain of rabbits. In the rat brain, however, high levels of pyrrolidine were found in the pineal gland, pituitary gland and corpus striatum.

Pipecolic acid (PA) is an intermediate of lysine metabolism in the mammalian brain. Recent findings suggest a functional connection of PA as neuromodulator in GABAergic transmission. Since many drugs are postulated to produce their effects by interaction with the central GABA system, the influence of PA on the anticonvulsant activity of phenobarbital was examined. Pretreatment of mice with 50 mg . kg-1 of PA potentiated the suppressing effects of the barbiturate on electrically and chemically induced convulsions. However, there was no potentiation of the behavioral effects and hypothermia induced by phenobarbital. PA itself had no or only little effect on the convulsions, motor function and rectal temperature when given in i.p. doses up to 500 mg . kg-1. Intraventricular administration of 500 microgram of PA also did not suppress either type of convulsion, although it produced ptosis, hypotonia, sedation and hypothermia. The results are discussed in relation to GABA system.

Imino acid and related alicyclic amine concentrations in blood and urine of mammals including humans were concurrently determined by a selected ion monitoring technique. Nanomole levels of proline and pipecolic acid, and pyrrolidine and piperidine as well, were found in human urine. Proline levels but not pipecolic acid levels were higher in blood of humans than in urine. Pyrrolidine and piperidine levels in blood of humans were picomole levels and much lower than those in urine. Similar tendencies were also recognized when these 4 compounds were analyzed using animal blood and urine, although the levels were generally higher in animals than in humans. Significantly high concentrations of the imino acids and the amines were found also in animal semen.

The reaction of sulfinic acid (1) with methanol in the presence of NCS-DMS gave methyl sulfinate (2) and methyl sulfonate (3) in 22% and 45% yields, respectively. Similarly, 1 reacted with morpholine under the same conditions to give the corresponding sulfinamide (5) and sulfonamide (6) in 23% and 50% yields. In these reactions, the disulfone (4) was also obtained as a minor product in some cases. The formation of sulfonic acid derivatives and disulfone was found to proceed through the intermediate formation of the sulfonyl chloride (7). The formation mechanism of sulfinic acid derivatives is also discussed.

Using unit recording and electrophoretic techniques, pharmacological properties of pipecolic acid (PA) were studied in the brain neurons of rats. PA response was blocked by bicuculline more effectively than GABA response but not blocked by strychnine. Stereochemical findings obtained using the HGS-model demonstrated that PA structure is almost the same as a part of bicuculline structure. The present results suggest that PA might be a new type of substance possessing bicuculline-sensitive action. The site of the action of PA was also discussed.

A method for the analysis of 5-hydroxypipecolic acid and 4-hydroxyproline in mammalian brain and blood is reported. The identification and quantification of the two hydroxyimino acids were accomplished with gas chromatography/mass spectrometry including a selected ion-monitoring technique following HPLC prepurification. The lower limit of detection for the method is 2 to 10 pmol. The amounts of 5-hydroxypipecolic acid and 4-hydroxyproline in blood were 20 to 30 pmol/ml and 3 to 6 nmol/ml, respectively. Their concentrations in the rabbit whole brain were determined to be 5 and 120 pmol/g, respectively.

Piperidine is a biogenic alicyclic amine possessing potent pharmacological activity. Interest has recently been focussed on its possible role as an endogenous hypnogenic substance. Using a mass fragmentographic technique with deuterium-labelled piperidine as an internal standard, the time relations of the change in brain levels of piperidine and the anesthetic activity of urethane were determined in mice. The brain piperidine level increased prior to the loss of the righting reflex and the elevated level declined prior to the reappearance of the reflex. The change in brain piperidine level correlated with neither that in spontaneous motility nor that in body temperature. The findings favor the idea that piperidine might at least partly regulate the level of consciousness.

The therapeutic effect of Vitamin B12 or Vitamin B6 on 2,5-hexanedione induced-neuropathy in animals was examined by using our electrodiagnostic technique in order to investigate the mechanism of the development of the neuropathy. Pyridoxal phosphate and two forms of Vitamin B12 were administered to rats intoxicated by the neurotoxin for a period of 18 weeks, and the sensory and motor fiber conduction velocity and the motor distal latency of the tail nerve were periodically determined. None of the groups treated with the therapeutic drugs exhibited a definite improvement in the nerve fiber conduction velocity and motor distal latency of the rat tail nerve, as compared with those of the 2,5-hexanedione-treated controls.

The reaction of sulfinic acid (1) with methanol in the presence of NCS-DMS gave methyl sulfinate (2) and methyl sulfonate (3) in 22% and 45% yields, respectively. Similarly, 1 reacted with morpholine under the same conditions to give the corresponding sulfinamide (5) and sulfonamide (6) in 23% and 50% yields. In these reactions, the disulfone (4) was also obtained as a minor product in some cases. The formation of sulfonic acid derivatives and disulfone was found to proceed through the intermediate formation of the sulfonyl chloride (7). The formation mechanism of sulfinic acid derivatives is also discussed.

A method for the simultaneous analysis of pipecolic acid and proline in the brain is developed. The qualification and quantification of pipecolic acid and proline are accomplished with gas chromatography/mass spectrometry including a selected ion-monitoring technique by using deuterium-labeled proline as an internal standard, after the amino and carboxylic groups of these cyclic amino acids are derivatized with boron trifluoride methanol complex and heptafluorobutyric anhydride. The lower limit of quantification for the method is picomole levels and the concentration of pipecolic acid and proline in rat whole brain is determined to be 1.05 and 71.50 nmol/g of tissue, respectively.

Piperidine levels in the brain and adrenal gland of rats during development were determined by mass fragmentography with deuterium-labeled piperidine as an internal standard. The levels in both organs showed distinct developmental changes, and two peaks were observed in association with the development of each organ. The initial peaks appeared in the early stage of development, that is, at the 19th day of gestation for the brain and 1 week after birth for the adrenal gland. The second peaks appeared at the age of sexual maturation (10 weeks after birth). The significance of the finding is discussed with respect to a presumed role of piperidine as a neuroendocrine modulator.

A specific and sensitive method for analysis of brain pyrrolidine, a volatile amine with potent synaptotropic actions on the peripheral and central nervous systems, was devised. The method involves the isolation of volatile amines by steam distillation and the qualification and quantification of pyrrolidine by gas chromatography/mass spectrometry (gcms) including a selected ion monitoring technique with deuterium-labeled pyrrolidine as an internal standard. The lower limit of quantification for the method was 2 pmol, and the mean concentration of pyrrolidine in the rat whole brain was determined to be 95 pmol/g of tissue.