[GHB--dangerous, addictive and uncontrollable "party drug"]. / GHB--farlig, beroendeframkallande och svårkontrollerad "partydrog".

This report reviews the pharmacology, toxicity and abuse pattern of gamma-hydroxybutyrate (GHB). The legislative changes pertaining to this substance are also addressed. Examples of abuse, driving under the influence and fatal intoxication are given. It is concluded that GHB is widely abused, particularly among the younger generation, and that further cases of severe intoxication are likely to occur as long as the substance is easily available from countless sources, including via the Internet. Despite the classification of GHB as a narcotic in Sweden and several other countries, continued problems are expected since the precursors gamma-butyrolactone (GBL) and 1,4-butanediol (BD) are widely--and legally--available.

Increased levels of nitrogen oxides and lipid peroxidation in the rat brain after soman-induced seizures.

We have investigated the effect of soman-induced seizures on rat brain levels of nitrogen oxides (NOx) and lipid peroxidation (LPO) 30 min and 24 h after intoxication. Following administration of soman (90 microg/kg s.c.), acetylcholinesterase activity was reduced to <10% of control after 30 min, whereas some de novo synthesis had occurred after 24 h. Significant increases in the LPO products malondialdehyde (MDA) and (E)-4-hydroxy-2-nonenal (4-HNE) were seen in the cortex, hippocampus, striatum, thalamus and medulla-pons 30 min after administration. A significant increase in the brain NOx levels, suggesting an increase in NO production, was seen in the cortex after 30 min and in the hippocampus and the striatum after 24 h. No significant changes were observed in cerebellum. These data suggest the possibility that free radical reactions may be a primary cause of neuronal degeneration after soman intoxication.

Personal decontamination after exposure to stimulated liquid phase contaminants: functional assessment of a new unit.

OBJECTIVE: To evaluate the efficacy of a decontamination station following exposure of volunteers to liquids with physical characteristics comparable to sarin and mustard gas. DESIGN: Twenty-four volunteers participated in the experiment which was performed with all staff wearing personal protective equipment including respiratory protection. The clothes, skin, and hair of the volunteers were contaminated with the simulated liquid phase contaminants, ethyl lactate and methyl salicylate. Sulphur hexafluoride gas was used to confirm the ventilation efficacy. Decontamination followed guidelines using a two-stage procedure. In the first chamber, all volunteers received a 3-minute shower with water at 30 degrees C, and their clothes but not their respiratory masks were removed. In the second, they were twice washed thoroughly with soap and water. After decontamination, the volunteers entered a third chamber for first aid measures. RESULTS: The air concentration of sulphur hexafluoride was reduced by 1:10,000 between the first and the third chambers. Ethyl lactate and methyl salicylate were measured in low concentrations in the third chamber. The capacity was 16 volunteers per hour with two-thirds on stretchers. After self-decontamination of the staff, the concentration of ethyl lactate increased significantly in the third chamber, consistent with residual ethyl lactate adsorbed by their underwear. This observation revealed a deficiency in the guidelines for self-decontamination. CONCLUSION: The capacity of the decontamination unit was found to be 16 volunteers per hour. The ventilation system and guidelines of the decontamination unit were demonstrated to be effective under the conditions examined. The self-decontamination of the staff was not optimal.

Correlation between cortical EEG and striatal microdialysis in soman-intoxicated rats.

In vivo microdialysis and EEG recording have been used in order to study the combined neurochemical and electrophysiological events during intoxication with soman (o-1,2,2-trimethylpropyl methylphosphono-fluoridate), a potent inhibitor of acetylcholinesterase (AChE), in the freely moving rat. All rats exposed to soman exhibited signs of AChE inhibition. The duration of EEG recorded seizures after soman intoxication averaged 43 +/- 24 min. The extracellular striatal levels of dopamine and GABA, increased significantly during the EEG seizure periods. Using an EEG based differentiation between seizure and non-seizure conditions, we found that intrastriatal release of dopamine, but not glutamate, during soman intoxication is highly correlated with seizures. Our results suggest that excitatory amino acids (EAA) involvement in soman-induced seizures, as demonstrated in hippocampus, may not be relevant in the striatum. Our data, instead, may indicate the importance of dopamine as a neurotoxic agent.

Release of dopamine, GABA and EAA in rats during intrastriatal perfusion with kainic acid, NMDA and soman: a comparative microdialysis study.

There is an increasing amount of experimental evidence that excitatory amino acids (EAAs) are involved in the brain lesions observed after severe intoxication with the highly toxic organophosphorus compound soman. This study was undertaken to compare the acute actions of soman, and the glutamatergic receptor agonists kainic acid and N-methyl-D-aspartate (NMDA) on striatal release of dopamine and amino acids. The neurotoxic compounds were administered in high (10 mM) concentrations by unilateral intrastriatal microdialysis perfusion in freely moving rats. During the microdialysis the animals were observed for toxic signs related to convulsion. The glial fibrillary acidic protein (GFAP) was monitored as a marker of neurotoxicity in parts of prefrontal cortex, hippocampus, striatum and cerebellum. Acetylcholinesterase (AChE) inhibition in six brain regions was measured after soman perfusion in order to assess its cerebral distribution. We found that soman perfusion induced a major release of dopamine, GABA and aspartate in the striatum. Kainic acid also induced a release of dopamine and aspartate. NMDA was not as potent an inducer of striatal neurotransmitter release as soman and kainic acid. Soman and kainic acid perfusion produced convulsive behaviour in the rats. The main neurochemical event in the striatum during soman- and kainate-induced convulsions is the release of dopamine. We suggest that this major dopamine release might be as important as an increase in EAA in the cascade of pathological events leading to the brain damage in the striatum observed after soman intoxication.

Pharmacokinetics of HI-6 and atropine in anaesthetized pigs after administration by a new autoinjector.

A newly developed autoinjector (Astra Tech, Sweden) containing 500 mg HI-6 and 2 mg atropine sulphate was tested in anaesthetized normal pigs. The pharmacokinetics and pharmacodynamics of the drugs after administration by the autoinjector were compared with those after conventional needle and syringe delivery intramuscularly and intravenously. Cardiopulmonary parameters were monitored and serum concentrations of oxime, atropine, and acetylcholinesterase were determined in blood samples taken at intervals over a 6 h period postinjection. After injection in anaesthetized pigs, both HI-6 and atropine were absorbed rapidly and completely from the injection site. Therapeutic serum concentrations of HI-6, arbitrarily taken as 4 micrograms mL-1, were reached within 1 min of intravenous and autoinjector administration, and within 5 min of intramuscular injection. The concentrations remained above this level for 3-4 h. There were no significant changes in acetylcholinesterase activity, mean arterial blood pressure, or respiration frequency after injection of HI-6 and atropine sulphate. The heart rates increased significantly after administration of the two drugs (cardioacceleration defined as > or = 5% increase in heart rate), regardless of the technique employed. Our results show that HI-6 and atropine sulphate can be given intramuscularly by the new autoinjector with the same effectiveness and speed as when given intravenously. Irrespective of the injection technique, no overt signs of toxicity were observed at the drug concentrations used.

Treatment of organophosphate poisoning in pigs: antidote administration by a new binary autoinjector.

The therapeutic effectiveness of a new binary autoinjector containing 500 mg HI-6 and 2 mg atropine sulphate was tested in anesthetized pigs poisoned by a lethal dose of soman i.v. (9 micrograms/kg per 20 min). Pharmacokinetics and pharmacodynamics of HI-6 were studied concomitantly on administration of HI-6 alone, together with atropine sulphate, or together with atropine sulphate during soman intoxication. Cardiopulmonary parameters were monitored and serum concentrations of oxime and acetylcholinesterase (AChE) were measured in blood samples taken at intervals over a 6-h period postinjection. Five minutes after the start of soman infusion, mean AChE activity was decreased to 27 +/- 4.3% of baseline and signs of poisoning appeared. The antidotes, HI-6 and atropine sulphate, were then administered i.m. One minute after this injection there was a transient significant increase in AChE activity of 76 +/- 8.2% of baseline (p < 0.01). It then again decreased and remained suppressed throughout the experiment. Mean respiratory rate was significantly decreased (p < 0.01) to 20 +/- 3.2% of baseline after 20 min of soman infusion and remained low during the rest of the experiment. The poisoning signs were counteracted 15-20 min after antidote therapy and all pigs survived soman intoxication without ventilatory assistance. Administration of either atropine or atropine and soman had no significant effect on the pharmacokinetics of HI-6 in anesthetized pigs.

Effects of cyanide in vitro on the activity of monoamine oxidase in striatal tissue from rat and pig.

We have shown previously in the rat that lethal, acute cyanide intoxication dramatically decreased the levels of dopamine (DA) in the striatum, while the synthesis of DA was increased. The main brain metabolite of DA, homovanillic acid, was also diminished. However, the levels of the oxidatively deaminated metabolite of DA, 3,4-dihydroxyphenylacetic acid, were not significantly changed. In order to elucidate further these findings we examined the effects in vitro of sodium cyanide on rat and pig brain monoamine oxidase (MAO; EC 1.4.3.4). The MAO activity was measured radiochemically using [14C]5-hydroxytryptamine (5-HT; 100 microM), [14C]phenethylamine (PEA; 20 microM) and [14C]DA (100 microM) as substrates. The amounts of cyanide added were comparable to those tissue concentrations of cyanide usually considered to be fatal in rats. The effect of cyanide on MAO was immediate. In rat, as well as pig, striatal tissue we found that cyanide produced a dose-dependent increase in the activity of MAO-A (as measured with 5-HT), but not MAO-B (as measured with PEA). The change in MAO activity was also seen with DA as substrate (MAO-A and -B). Kinetic constants, Km and Vmax, were determined. In both rat and pig striatum the Vmax values for 5-HT were significantly increased, but the values for PEA were not affected. A significant decrease in the Km value for PEA was, however, found in the presence of high concentrations of cyanide.

Effects of cyanide on the striatal dopamine receptor binding in the rat.

In previous studies we have shown that sodium cyanide decreases the striatal dopamine levels within 60 s compared with the controls. Treatment with sodium cyanide also increases the naturally occurring 3,4-dihydroxy-L-phenylalanine (L-DOPA) in the striatum, but not in any other region studied. An increase in the in vivo synthesis of dopamine in cyanide-treated rats has also been observed. In order to further elucidate the effects on the central dopaminergic pathways the effects of sodium cyanide on the striatal dopamine D1 and dopamine D2 receptor binding were studied in vitro and after administration of sodium cyanide. In the rats injected with sodium cyanide (2.0 mg/kg, i.p.) the Bmax of the striatal dopamine D1 receptor binding was significantly decreased 15 min and 1 h after the treatment. The striatal dopamine D2 receptor binding was decreased only at 1 h after the cyanide administration. Neither sodium cyanide nor its metabolite sodium thiocyanate did significantly change the striatal dopamine D1 and D2 receptor binding in vitro. Accordingly sodium cyanide and sodium thiocyanate do not have direct effects on the dopamine receptors studied. The effects of cyanide on dopamine D1 and D2 receptors are probably in part due to the effect of cyanide on the release of dopamine.

Effects of acute lethal cyanide intoxication on central dopaminergic pathways.

In rats treated with sodium cyanide (NaCN), 20 mg/kg intraperitoneally, the striatal dopamine (DA) level was decreased within 60 sec. compared to controls injected with NaCl 0.9%. Treatment with NaCN also increased the naturally occurring L-DOPA in the striatum, but not in the other brain regions studied. Decreased DA levels but increased L-DOPA accumulation were also seen in cyanide-treated animals after inhibition of neuronal L-aromatic amino decarboxylase. In rats given a non-lethal dose of NaCN, 2.5 mg/kg intraperitoneally, 30 min. before sacrifice and L-DOPA, 100 mg/kg intraperitoneally, 25 min. before sacrifice, regional L-DOPA levels were not significantly changed, but the striatal DA levels were diminished compared to controls. Decreased DA levels might indicate that cyanide inhibits the synthesis of brain DA. However, both increased L-DOPA and increased accumulation of L-DOPA after neuronal decarboxylase were observed after cyanide. Furthermore, we have earlier reported that lethal doses of NaCN decreased the DA metabolite HVA in the striatum but did not significantly change the oxidatively deaminated metabolite of DA, DOPAC. Inhibition of L-aromatic amino acid decarboxylase appears to play a minor role in causing decreased striatal DA levels. However, our findings might be compatible with cyanide-produced inhibition of the energy-demanding granular uptake and/or release of DA.

Time-related changes in serum perphenazine, striatal 3H-spiperone binding and regional brain acid metabolites of dopamine and 5-hydroxy-tryptamine after a single dose of perphenazine.

A single dose of perphenazine (5.0 mg/kg) was administered intraperitoneally to male Wistar rats. The time-related alterations in serum levels of perphenazine, striatal 3H-spiperone binding ex vivo and the regional brain metabolism of dopamine and 5-hydroxy-tryptamine were studied. Low serum levels of perphenazine were observed together with increased Kd of 3H-spiperone. No significant changes in Bmax were observed. Since Kd of 3H-spiperone binding peaked several hours after the maximal serum levels of perphenazine, perphenazine in serum appeared not to directly reflect the events at the receptor level. The concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) and 3-methoxy, 4-hydroxyphenylacetic acid (HVA) in the striatum were increased after perphenazine. They were maximal 1-3 h after the drug administration and showed positive correlations (correlation coefficient 0.93 and 0.80, respectively) with the serum levels of perphenazine. Increased levels of HVA were also observed both in the olfactory tubercle and in the frontal cortex. However, in the olfactory tubercle, administration of perphenazine did not significantly increase the DOPAC concentrations. In the olfactory tubercle 5-hydroxyindoleacetic acid (5-HIAA) was decreased 1-24 h after administration of perphenazine. In the striatum and in the frontal cortex only slight changes in 5-HIAA were seen. Thus, in the olfactory tubercle 5-hydroxytryptaminergic mechanisms could modulate the dopaminergic neurotransmission.

Long-term carcinogenicity study in Syrian golden hamster of particulate emissions from coal- and oil-fired power plants.

Male Syrian golden hamsters were given 15 weekly intratracheal instillations with suspensions of coal fly ash or oil fly ash. Controls were instilled with saline containing gelatine (0.5 g/100 mL) or to check particle effects with suspensions of hematite (Fe2O3). The common weekly dose was 4.5 mg/hamster. In addition, one subgroup of hamsters was treated with oil fly ash at a weekly dose of 3.0 mg/hamster and another with coal fly ash at a weekly dose of 6.0 mg/hamster. Other groups of hamsters were treated with suspensions of benzo[a]pyrene (BaP) or with suspensions on coal fly ash, oil fly ash, or Fe2O3 coated with BaP. The mass median aerodynamic diameters of the coal and oil fly ashes were 4.4 microns and 28 microns, respectively. Hamsters treated with oil fly ash showed a higher frequency of bronchiolar-alveolar hyperplasia than hamsters in the other treatment groups. Squamous dysplasia and squamous metaplasia were most frequent in animals treated with suspensions of BaP or BaP-coated particles. The earliest appearance of a tumor, the highest incidence of tumors, and the highest incidence of malignant tumors were observed in hamsters treated with oil fly ash coated with BaP. Squamous cell carcinoma and adenosquamous carcinoma were the most frequent malignant tumors. No malignant tumors and only few benign tumors were observed in hamsters instilled with suspensions of fly ash not coated with BaP. The present study gives no indication that coal fly ash could create more serious health problems than oil fly ash.

Isolation and nephrotoxic studies of orellanine from the mushroom Cortinarius speciosissimus.

A nephrotoxic substance has been isolated from Cortinarius speciosissimus. The 1H-NMR and 13C-NMR mass spectra indicated the chemical structure to be 3,3',4,4'-tetrahydroxy-2,2'-bipyridine-N-N'-dioxide. The toxin was quantitated using reversed phase high performance liquid chromatography (HPLC) with electrochemical detection. The detection limit of this method was 500 pg, corresponding to a signal-to-noise ratio of 2.5. The toxin had an LD50 in mice of approximately 20 mg/kg i.p. Light microscopic examination of the kidneys of mice surviving treatment with the toxin showed interstitial nephritis and tubular necrosis.

Acute cyanide intoxication and central transmitter systems.

In rats treated with sodium cyanide (5-20 mg/kg, ip) dopamine was dose dependently decreased in the striatum within 60 sec. One of the main metabolites of dopamine in the central nervous system, 3-methoxy-4-hydroxyphenylacetic acid (HVA), was decreased in striatum, olfactory tubercle, and hippocampus. However, the oxidatively deaminated metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), was not significantly altered in any of the brain regions studied. Naturally occurring levels of 3,4-dihydroxy-L-phenylalanine (L-dopa), as well as L-dopa accumulated after inhibition of the neuronal L-aromatic amino acid decarboxylase, increased in cyanide-treated rats. The dopamine receptor antagonist spiperone (0.05 mg/kg, ip) slightly increased the survival in acute cyanide intoxication. Sodium cyanide increased the levels of glutamine in frontal cortex and striatum at all doses studied. Glutamic acid was increased in the cerebellum, striatum, and hippocampus after sodium cyanide (5-10 mg/kg, ip). Higher doses decreased glutamic acid in the cerebellum, the frontal cortex, and the striatum. gamma-Aminobutyric acid (GABA) concentrations were diminished at high doses in all regions studied. Cyanide increased the levels of cyclic GMP in the cerebellum. In the striatum cyclic GMP was decreased after sodium cyanide (10 and 20 mg/kg). No significant alterations in the concentrations of acetylcholine or choline were seen in the striatum of cyanide-treated rats. The acetylcholinesterase inhibitor physostigmine and the muscarinic receptor antagonist atropine decreased the survival of mice given sodium cyanide. Acute cyanide intoxication thus produces rapid and fairly specific changes in central dopaminergic and GABA-ergic pathways.

Partial denervation of the ovaries by transection of the suspensory ligament does not inhibit ovulation in rats treated with pregnant mare serum gonadotropin.

Adrenergic nerves reach the ovary via two routes: along the arteries to the ovary and via the suspensory ligament. Results from earlier investigations suggest that denervation of the nerves along the arteries does not influence the ovulatory process. In the present study we have examined whether denervation by transection of the ovarian suspensory ligament influences the ovulatory process. Partial denervation of the ovary by transection of the ovarian suspensory ligament, sham operation, or only anesthesia were performed on immature 25-day-old rats. To induce ovulation, pregnant mare serum gonadotropin (PMSG) was injected in the morning (0800-0930), when the rats were 26 days old. This PMSG treatment normally induces ovulation around 0200 in the early morning of day 29 with subsequent formation of corpora lutea. Rats were killed 5-8 hr, 3 days, and 5 days after this ovulation time. Ovarian interstitial norepinephrine levels were markedly decreased after transection of the suspensory ligament. Ovulations had occurred in all denervated, as well as sham-operated, and control rats. The various groups did not differ in the number of ovulations per rat. Thus, the adrenergic nerves in the suspensory ligament appear not to be necessary for ovulation. Whether catecholamines themselves play a role in the ovulatory process cannot be elucidated from this experiment, since the norepinephrine content in the ovary was not totally depleted. It seems unlikely that adrenergic nerves reach the corpus luteum via the suspensory ligament, since transection of this structure did not change the luteal content of norepinephrine.

Studies on interactions between striatal dopaminergic and cholinergic mechanisms in the early abstinence after chronic treatment with barbital in the rat.

Accumulation in the rat striatum of 3,4-dihydroxy-L-phenylalanine (DOPA) after inhibition of the neuronal decarboxylase was not significantly altered in the early abstinence after chronic treatment with barbital for 36-39 weeks in comparison with controls treated with water. Pilocarpine (10 mg/kg i.p.) increased the accumulation of DOPA in rats chronically treated with barbital and also in controls treated with water. Some weak correlations between striatal DOPA accumulation and changes in body weight or fluid consumption during the first three days of the abstinence were observed. There was also a highly significant, positive correlation (r = 0.85) between striatal DOPA accumulation and the number of convulsions in rats chronically treated with barbital and injected with NaCl. The corresponding correlation in rats chronically treated with barbital and injected with pilocarpine was positive but not significant (r = 0.50). No evidence for an increased sensitivity at muscarinic receptors in the striatum was found.

Morphine concentrations in serum, brain and cerebrospinal fluid in the rat after intravenous administration of a single dose.

Morphine has been determined in serum, cerebrospinal fluid (c.s.f.) and in five brain regions in the rat after a single intravenous dose, using high performance liquid chromatography with an electrochemical detector. In pure solution 50 pg morphine and 200 pg naloxone could be detected. Maximal concentrations of morphine were observed in serum and in most brain regions 5 min after administration of morphine. There was a rapid decline in morphine concentrations during the first 30 min, in serum and in all brian regions studied. The morphine concentration in the c.s.f. was constant for the first 30 min, but 30 min later there was a dramatic increase, suggesting that elimination through the c.s.f. could be an important way of eliminating morphine in the central nervous system.