Phencyclidine - Effects on Human Performance and Behavior.

The history, symptoms, diagnosis and treatment of phencyclidine hydrochloride (PCP) intoxication, the pharmacology of PCP and the detection, identification and analysis of PCP are reviewed. The history of PCP from its synthesis in the early 1950s to the present is discussed. Intoxication with low to moderate doses of PCP resembles an acute, confusing state. High doses may cause serious neurological and cardiovascular complications and the patient is often comatose for several days. Treatment involves supportive psychological and medical measures, and acidification of the urine may further increase PCP clearance. The metabolism of PCP involves primarily hydroxylation followed by conjugation and elimination in the urine. Analysis can be accomplished by a number of instrumental methods, and several commercial test kits based on antigen-antibody interactions are available. PCP's effect on human performance and behaviour is due to its ability to alter the perception of reality in the user. PCP causes a range of effects that include hallucinations, delirium, disorientation, agitation, muscle rigidity, ataxia, nystagmus, seizures, and stupor. PCP has stimulant, depressant, hallucinogenic and analgesic effects. Which of these will be most pronounced is unpredictable and depends on the user's personality, psychological state and the environment of use. The impairment can manifest itself as over-aggressive or reckless driving behavior, or may mimic depressant effects due to PCP's anesthetic and depressant effect.

Katamine - Effects on Human Performance and Behavior.

Ketamine is a rapid-acting anesthetic commonly used during surgical procedures in both animals and humans, as an experimental drug in the treatment of chronic pain, and as a probe for the study of the cause of schizophrenia. When used medically as an anesthetic it is administered as an intravenous (IV) solution, but when diverted to the illicit market it can be injected, snorted, smoked, or consumed in drinks. Ketamine produces effects similar in some respects to phencyclidine (PCP) and lysergic acid (LSD), but of shorter duration. Psychedelic effects are produced quickly by low doses of the drug, although larger doses are frequently used in an attempt to produce "near-death" experiences. Convulsions and death can be caused by higher doses, although most deaths in which ketamine is detected are the result of poly-drug use or trauma. Reports of ketamine use at rave parties attended by young adults appear to be on the rise. The effects from ketamine last from 1-5 hours, and ketamine can be detected in the urine for a period of 1-2 days following use.

Distribution of topiramate in a medical examiner's case.

Topimarate (Topamax) is a novel antiepileptic drug. Its mode of action is multifactorial and involves blockage of voltage-dependent sodium channels. The drug was detected in a 15-year-old epileptic who died soon after switching seizure prescriptions. Topimarate was recovered by basic extraction with ethyl acetate and analyzed by gas chromatography-mass spectrometry using selected ion monitoring. Ions monitored were m/z 324 and m/z 110 for topiramate and m/z 98 for the internal standard mepivacane. The drug was quantitated in blood, vitreous humor, bile, stomach content, and liver: the concentrations were 8.9, 12.4, and 10.9 mg/L, 31 mg/total content, and 29 mg/kg, respectively. Topiramate was detected in urine but not quantitated. Other drugs identified in this case were 0.45 mg/L nordiazepam and 0.05 mg/L oxazepam in blood. No alcohol was detected in any of the specimens. The cause of death was seizure disorder with upper respiratory infection. The manner of death was determined as natural. To our knowledge, this is the first report of the presence of topiramate in postmortem specimens.

Distribution of 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) stereoisomers in a fatal poisoning.

This communication presents the quantitation and differential distribution of the enantiomers of 3,4-methylenedioxymethamphetamine (MDMA) and its physiologically active metabolite 3,4-methylenedioxyamphetamine (MDA) in a fatal poisoning following insufflation of MDMA, cocaine and heroin. Animal studies have demonstrated the stereoselective pharmacokinetics and neurotoxicity of these compounds; however, enantiomeric distributions have not been reported in humans. Quantitation of MDMA and MDA enantiomer was by gas chromatography/mass spectrometry (GC/MS) following chiral derivatization with N-trifluoroacetyl-L-triproyl chloride (LTPC). The decedents' blood concentration of S(+)-MDMA was slightly less than that of R(-)-MDMA (1.3 vs. 1.6 mg/l, respectively), while the S(+)- and R(-)-MDA blood concentrations were identical (0.8 mg/l). Both primary routes of excretion, bile and urine, had greater concentrations of R(-)-MDMA than the S(+) isomer. These fluids also contained twice the concentration of S(+)-MDA than the R(-)-isomer. These data indicate that S(+)-MDMA is metabolized and eliminated faster than R(-)-MDMA. The results appear to support the findings in animals regarding stereoselective metabolism of MDMA.

The detection of a metabolite of alpha-benzyl-N-methylphenethylamine synthesis in a mixed drug fatality involving methamphetamine.

A 37-year-old, white male collapsed at his home following a party. He reportedly had a history of unspecified cardiac arrhythmia. The ambulance crew found him unresponsive and an ECG revealed ventricular tachycardia/fibrillation. Following one hour of resuscitative efforts in the ambulance and emergency room of a local hospital, he was pronounced dead. An antemortem urine toxicology screen performed at the hospital was "positive" for benzodiazepines, cocaine and amphetamine/methamphetamine. At autopsy, there was generalized organ congestion with no evidence of trauma or other significant pathology except mild, left ventricular hypertrophy. Quantitation by gas chromatography/mass spectrometry (GC/MS) of methamphetamine in bile, blood, urine and gastric contents yielded 21.7, 0.7, 32.0 and 2.9 mg/L, respectively. Liver and brain contained 2.2 and 2.7 mg/kg, respectively. A trace amount of p-OH-alpha-benzyl-N-methylphenethylamine (p-OH-BNMPA), a metabolite of alpha-benzyl-N-methylphenethylamine (BNMPA), an impurity of illicit methamphetamine synthesis, was also detected in the urine. Since these impurities can be characteristic of a particular synthetic method, their presence in seized samples or their detection in biological samples from methamphetamine users can further be used to monitor the sales of precursor chemicals, group seized compounds to common sources of illicit production or provide links between manufacturers, dealers and users.

Distribution of metoprolol enantiomers in a fatal overdose.

The distribution of the racemic and the enantiomeric content of (+/-)-metoprolol was compared after ingestion of a massive fatal overdose of the racemic drug. Postmortem concentrations of the racemate in different tissues were assayed by gas chromatography after derivatization with trifluoroacetic acid anhydride. The distribution of the R- and S-enantiomers of metoprolol was analyzed by reversed-phase high-performance liquid chromatography. Metoprolol was extracted from postmortem specimens and derivatized with the chiral reagent 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl isothiocyanate. The concentrations of active S(-)-isomer in blood, liver, and stomach contents were 33 mg/L, 224 mg/kg, and 56 mg/61 g, respectively. The concentrations of inactive R(-)-enantiomer in blood, liver, and stomach contents were 33 mg/L, 222 mg/kg, and 55 mg/61 g, respectively. These results indicate that half the total postmortem tissue concentration of metoprolol is the R-enantiomer, which is devoid of any beta-blocker activity.

An overdose fatality in a child involving disopyramide and sulindac.

The results of an accidental overdose fatality in a child involving disopyramide and sulindac are reported in this paper. Quantitation of disopyramide was performed by gas chromatography using codeine as the internal standard. Sulindac was assayed by high- performance liquid chromatography using ketoprofen as the internal standard. The postmortem blood concentrations of disopyramide and sulindac were 41.3 and 12.2 mg/L, respectively. The concentrations of disopyramide and sulindac were also quantitated in the liver, in bile, and in urine.

Tissue levels and some pharmacological properties of an acetylated metabolite of phenelzine in the rat.

The metabolic generation of N2-acetylphenelzine by rats treated with phenelzine, and the activity of this metabolite as an inhibitor of monoamine oxidase enzymes in vivo were confirmed. The isomeric amide N1-acetylphenelzine was not a metabolic product of phenelzine and also did not inhibit monoamine oxidase enzymes. Levels of N2-acetylphenelzine in rat blood, after treatment with a dose (0.1 mmol.kg-1) of N2-acetylphenelzine sufficient to inhibit monoamine oxidase enzymes but not to increase brain levels of dopamine or noradrenaline, were higher than those generated metabolically from a higher dose (0.38 mmol.kg-1) of phenelzine which did increase brain levels of these biogenic amines. Metabolically derived N2-acetylphenelzine, therefore, probably does not contribute in any significant way to monoamine oxidase inhibition by phenelzine.

Synthesis and pharmacological evaluation of acyl derivatives of phenelzine.

Acyl derivatives of phenelzine were required for pharmacological evaluation. Eight mono- and di-acyl derivatives were synthesized and characterized by gas chromatography, mass spectrometry, nuclear magnetic resonance and infrared spectrophotometry. Selective acylation was observed with both acetic anhydride and ethyl chloroformate. In aqueous medium, monoacylation yielded N1-acetyl- and N1-(ethoxy-carbonyl)-phenelzine exclusively, whereas in non-aqueous medium only N2-acetyl and N2-(ethoxycarbonyl) products were obtained. NMR temperature studies were conducted to ascertain the presence of rotational isomers and their ratios. At room temperature, one ethoxy-carbonyl and four phenelzine acetate derivatives were present as mixtures of rotamers. Preliminary evaluations of the MAO-inhibiting properties of acylated phenelzines indicate that a hydrogen atom on the N1-position of phenelzine and its derivatives is essential for activity.

Recent studies on the MAO inhibitor phenelzine and its possible metabolites.

Although N2-acetylphenelzine (N2AcPLZ) appears to be only a minor metabolite of phenelzine (PLZ), other investigations have demonstrated that it may be worthy of study as an antidepressant in its own right. In the present report, the possibility of ring hydroxylation as a metabolic route for PLZ was investigated in the rat. Indirect evidence for such a route was obtained using iprindole, a drug known to block ring hydroxylation. Treatment of rats with iprindole followed by PLZ was demonstrated to result in increased brain levels of PLZ and beta-phenylethylamine (control rats were treated with vehicle and then PLZ). The possibility that hydroxylation in the para-position might be a metabolic route for PLZ has led to interest in the possible use of analogues in which this position is blocked with a substituent. In preliminary acute studies at a dose of 0.1 mmol/kg p-chloro-PLZ was found to have a similar effect to PLZ on the inhibition of MAO and to lead to an elevation of catecholamines and 5-hydroxytryptamine (5-HT) in rat whole brain.

Metabolic acetylation of phenelzine in rats.

1-Acetyl-2-(2-phenylethyl)hydrazine (N2-acetylphenelzine) is identified as an acetylated metabolite of phenelzine in the rat. One hour after intraperitoneal administration of a high dose of phenelzine sulfate to rats, the blood and brain of the animals were extracted and analyzed by combined gas chromatography/electron impact mass spectrometry in the total ion and selected ion modes. This procedure provided unequivocal proof of the presence of N2-acetylphenelzine in these tissues. The other possible monoacetylated metabolite of phenelzine, 1-acetyl-1-(2-phenylethyl)hydrazine (N1-acetylphenelzine), and the diacetylated derivative, 1,2-diacetyl-2-(2-phenylethyl)hydrazine, were sought, but were not detected.

Microbial metabolism of phenelzine and pheniprazine.

Phenelzine and pheniprazine were used as substrates for metabolic studies with Cunninghamella echinulata and Mycobacterium smegmatis. Metabolites were identified by means of gas-liquid chromatography and mass spectrometry. 1-Acetyl-2-(2-phenylethyl)-hydrazine and 1-acetyl-2-(1-methyl-2-phenylethyl)hydrazine were the major products of C. echinulata metabolism of phenelzine and pheniprazine, respectively. In addition, M. smegmatis produced a second metabolite from each substrate; these metabolites were unequivocally identified as N-acetylphenylethylamine and N-acetylamphetamine from phenelzine and pheniprazine, respectively.

Gas chromatographic analysis of monoalkylhydrazines.

A quantitative electron-capture gas chromatographic assay procedure was developed for the analysis of monoalkylhydrazines in biological samples. Application to the analysis of phenelzine was demonstrated. Four monoalkylhydrazines were analyzed in whole blood by reaction with pentafluorobenzaldehyde to form stable hydrazone derivatives which were extracted and subsequently reacted with pentafluoropropionic anhydride to give products which were very sensitive to electron-capture detection when analyzed by gas chromatography. Methylhydrazine, benzylhydrazine, phenelzine and pheniprazine each yielded single derivatives with this procedure suggesting that the analytical procedure has a broad application to the analysis of other monoalkylated hydrazines. The method was applied to monitor whole blood levels of phenelzine in rats treated intravenously with phenelzine sulphate.