Acute neurotoxicity associated with recreational use of methylmethaqualone confirmed by liquid chromatography tandem mass spectrometry.

Methylmethaqualone is a sedative designer drug created by adding a methyl group to the 3-phenyl ring of methaqualone, and is at present not subject to restrictive regulation in many countries. To our knowledge, no case of methylmethaqualone abuse has been published to date in the scientific literature, and the only sources of information are users' reports on Web discussion forums and data from preclinical animal studies. We report a case of oral methylmethaqualone abuse confirmed by liquid chromatography tandem mass spectrometry in a 24-year-old previously healthy Caucasian male. Observed symptoms and signs such as central nervous system depression alternating with excitation, psychomotor agitation, muscle hyperactivity, and tachycardia were compatible with methaqualone-induced adverse effects. Except for the mild tachycardia (115 beats/min), other vital signs were normal: blood pressure 134/89 mmHg, body temperature 36.2°C (97.16°F), and peripheral oxygen saturation 99% while breathing room air. The ECG showed no prolongation of the QT interval and the QRS duration was normal. Laboratory analysis revealed a slight increase in creatine kinase (368 U/L) and alanine aminotransferase (90 U/L) serum concentrations. Blood alcohol concentration was 0.32 g/L. Methylmethaqualone was identified in a serum sample collected on admission which was analyzed by a liquid chromatography tandem mass spectrometry toxicological screening method using turbulent flow online extraction. After a few days the patient ingested the same amount of substance with identical symptoms. Based on the chemical structure and animal data, and according to this case report and users' Web reports, methylmethaqualone appears to have a similar acute toxicity profile to methaqualone, with marked psychomotor stimulation. Symptoms of acute toxicity can be expected to resolve with supportive care.

A case of lethal intoxication after ingestion of toquilone compositum.

A case of acute intoxication of both methaqualone and diphenhydramine is reported. The analysis of these compounds was performed by liquid-liquid extraction (Toxi-Lab DPC procedure) followed by gas chromatography/mass spectrometry determination; both substances are contained in the pharmaceutical formulation called Toquilone Compositum (Medichemie, Switzerland).

Solid-phase extraction and HPLC analysis of kebuzone and its metabolites in blood.

A HPLC method for quantification of kebuzone and its metabolites in whole blood was developed. The compounds and the internal standard were isolated from blood by solid-phase extraction on a C-18 cartridge. A blood sample was to be hemolyzed before extraction. HPLC was performed on a C-18 column with the mobile phase composed of methanol/water acidified to pH 2.7 and UV absorbance detection at 247 nm. This method has been successfully applied to a pharmacokinetic study of kebuzone and its metabolites in rabbits.

[Dangerous intoxication from extreme serum concentrations of methaqualone metabolites. Detection and quantification of biosynthesis with gas chromatography-mass spectrometry]. / Lebensbedrohliche Intoxikation durch extreme Serum-konzentration eines Methaqualonmetaboliten. Nachweis und Quantifizierung mittels Biosynthese und Gaschromatographie-Massenspektrometrie.

CLINICAL COURSE: We present a potentially fatal case of acute methaqualone (M) poisoning with very low serum concentrations of M but extremely high levels of its metabolite, 2-methyl-3-(2-hydroxymethyl-phenyl)-4 (3H)-chinazoline (Met-1). A 23-year-old man was admitted to the intensive care unit 2 days after ingestion of 4-5 g M in an suicidal attempt. On admission he was somnolent and poorly responsive to painful stimuli. Physical examination revealed a heart rate of 95 bpm, a blood pressure of 125/65 mmHg, and a normal body temperature. His chest was clear to auscultation, respirations were shallow, and the skin was cyanotic. The electrocardiogram was unremarkable. The chest radiograph showed a normal heart size without pulmonary infiltrates or venous congestion. The pupils were dilated but reactive to light. The neurologic examination was further remarkable for increased limb reflexes, myoclonia, and positive pyramidal signs. During the next 2 days the patient became comatose and developed respiratory insufficiency due to non-cardiogenic pulmonary oedema, which was confirmed by chest radiograph and haemodynamic investigations by means of right heart catheterisation. He required mechanical ventilation for 6 days. Finally, he recovered completely and was discharged in good condition. DIAGNOSTICS: A lumbar puncture revealed neither blood nor pleocytosis in the cerebrospinal fluid. Cranial computed tomography was carried out on an emergency basis, but no abnormality was disclosed. An electroencephalogram did not exhibit any significant pathological findings. Testing for infectious diseases or porphyria gave negative results. Toxicological screening based on enzyme immunoassays (ELISA) was negative for alcohol, tricyclic antidepressants, benzodiazepines, barbiturates, and morphine, but gave a positive result for M. From the moment of admission daily blood samples were taken and analysed by combined gas chromatography and mass spectrometry. These showed very low levels of M but extremely high levels of Met-1. THERAPY: After gastric lavage, continuous enteric lavage with activated charcoal and mannitol was initiated to minimise intestinal absorption. Since M was hardly detectable in the serum, haemoperfusion was not regarded as indicated for drug elimination and treatment was restricted to general supportive measures. To rule out a central anticholinergic syndrome, an anticholinesterase drug (physostigmine) was administered but remained without therapeutic effect. CONCLUSIONS: The presented case is the first report of a life-threatening intoxication after M ingestion primarily caused by Met-1. It supports the significance of this metabolite for the toxic effects of the drug. A toxicological screening test based on ELISA proved helpful due to its cross-reactivity with metabolites. In cases similar to ours, resin haemoperfusion may be indicated to remove the metabolites despite low detectable concentrations of the parent substance in the serum.

Quantification of dimethindene in plasma by gas chromatography-mass fragmentography using ammonia chemical ionization.

A gas chromatographic-mass fragmentographic method using ammonia chemical ionization for the determination of dimethindene in human plasma is described. The drug was isolated from plasma by liquid-liquid extraction with hexane-2-methylbutanol. Plasma components were separated on a capillary column coated with chemically bonded methyl silicone. For detection of dimethindene, its quasi-molecular ion (M + H+) was mass fragmentographically monitored after chemical ionization with ammonia as reagent gas. Dimethindene was quantified using methaqualone as the internal standard: the quantification limit in plasma was 0.2 ng/ml, the within-run precision was 8.0% and the inter-run precision 5.6%. The plasma concentration-time profile was established after a single dose of 4 mg of dimethindene with an average maximum concentration of 5.5 ng/ml, detectable up to 48 h post application.

Direct automated EMIT d.a.u. analysis of N,N-dimethylformamide-modified serum, plasma, and postmortem blood for amphetamines, barbiturates, methadone, methaqualone, phencyclidine, and propoxyphene.

The addition of two volumes of N,N-dimethylformamide (DMF) to serum, plasma, and postmortem blood with subsequent centrifugation resulted in supernatant that could be directly analyzed by EMIT d.a.u. urine reagents on the Syva autocarousel. Application of this method to the drugs below gave cutoff concentrations in milligrams of immunochemically cross-reactive analyte equivalents/L as follows: 0.05 for amphetamine, 0.05 for secobarbital, 0.075 for methadone, 0.05 for methaqualone, 0.025 for phencyclidine, and 0.05 for propoxyphene. Quantitative "false" negative/positive noncongruence between total EMIT cross-reactants and free-drug analyses by gas chromatography/mass spectrometry were 3/4 (n = 50) for amphetamines, 2/0 (n = 60) for barbiturates, 0/0 (n = 47) for methadone, 0/0 (n = 48) for methaqualone, 1/0 (n = 44) for phencyclidine, and 1/2 for propoxyphene (n = 53). Within-day precision, as indicated by the coefficient of variation, of quantitative estimates using low and high controls ranged from 3.7 to 11% and 1.8 to 10.3%, respectively. Using the same control levels, between-day precision of quantitative estimates varied from 5.8 to 30.3% and 3.0 to 11.8%, respectively.

Simultaneous determination of dextropropoxyphene, norpropoxyphene and methaqualone in plasma by gas chromatography with selective nitrogen detection.

A method for the identification and quantification of dextropropoxyphene, norpropoxyphene, and methaqualone in plasma by GC/NPD is presented. The procedure employs cyclizine as the internal standard and requires no derivatization. After a single-step extraction, analysis is achieved in 8 min. The lower limits of detection were found to be 6, 12, and 1 ng/ml for dextropropoxyphene, norpropoxyphene, and methaqualone, respectively. This method appears to be rapid, sensitive, and applicable to forensic and clinical toxicological analyses.

Simultaneous determination of mefloquine and chloroquine in biological fluids using high-performance liquid chromatography.

A high-performance liquid chromatography (HPLC) method for the simultaneous determination of mefloquine and chloroquine in biological fluids is described. Methaqualone is used as an internal standard. After a single-step extraction, achieved from alkalinized samples with diethyl ether, a separation is obtained using a mu-Bondapak phenyl column with a mobile phase of acetonitrile and sodium acetate buffer. Detection is done at 305 nm. The lower detection limits are 3 and 10 micrograms/l for mefloquine and chloroquine, respectively. Thus, this method appears to be simple, rapid, very sensitive and applicable in pharmaco-clinical, toxicological and forensic analyses.

Ethanol, marijuana, and other drug use in 600 drivers killed in single-vehicle crashes in North Carolina, 1978-1981.

Although the use of ethanol, marijuana, and other drugs may be detrimental to driving safety, this has been established by direct epidemiological evidence only for ethanol. In this study, the incidences of detection of ethanol (and other volatile substances), delta-9-tetrahydrocannabinol (THC), barbiturates, cocaine and benzoylecgonine, opiates, and phencyclidine were determined in an inclusive population of 600 verified single-vehicle operator fatalities that occurred in North Carolina in 1978 to 1981. The incidence of detection of amphetamines and methaqualone were determined for drivers accepted for study during the first two years (n = 340) and the last year (n = 260), respectively. Blood concentrations of 11-nor-deta-9-tetrahydrocannabinol-9-carboxylic acid (9-carboxy-THC) were determined in THC positive drivers. EMIT cannabinoid assays were performed on blood specimens from all drivers accepted for study during the third year, and the feasibility of using the EMIT cannabinoid assay as a screening method for cannabinoids in forensic blood specimens was investigated. The incidence of detection of ethanol (79.3%) was far greater than the incidences determined for THC (7.8%), methaqualone (6.2%), and barbiturates (3.0%). Other drugs were detected rarely, or were not detected. Blood ethanol concentrations (BECs) were usually high; 85.5% of the drivers whose bloods contained ethanol and 67.8% of all drivers had BECs greater than or equal to 1.0 g/L. Drug concentrations were usually within or were below accepted therapeutic or active ranges. Only a small number of drivers could have been impaired by drugs, and most of them had high BECs. Multiple drug use (discounting ethanol) was comparatively rare. Ethanol was the only drug tested for that appears to have a significantly adverse effect on driving safety.

Methaqualone-diphenhydramine interaction study in humans.

Twelve healthy subjects received three single oral doses (250 mg) of methaqualone alone or in combination with diphenhydramine (25 mg). Blood samples were collected for a 48-hr period after each dose and analyzed for methaqualone and its major metabolite, 2-methyl-3-(2'-hydroxymethylphenyl)-4(3H)-quinazolinone. Peak blood concentrations ranging from 1.0 to 2.7 micrograms/ml occurred approximately 1-2 hr after the oral dose. The area under the blood level-time curve, peak plasma level, and elimination half-life for methaqualone were not significantly different (three-way ANOVA, p greater than 0.05) when methaqualone was administered alone, in combination with a diphenhydramine elixir or as a commercial product (capsule) containing both methaqualone and diphenhydramine. Statistically significant intersubject differences in the area under the curve were eliminated if the area was corrected for subject differences in elimination. Blood levels of the metabolite reached an average peak of 314 ng/ml (+/- 107) between 4 and 8 hr after the dose and remained elevated for the 48-hr sampling period. The areas under the blood level time curve of the metabolite were not significantly different for the three treatments. Diphenhydramine administered at the dosage level used in therapeutic combination products did not alter the blood levels of methaqualone or its metabolite. In addition, no significant differences in methaqualone availability from the two commercial formulations tested could be detected.

[In vitro studies on the adsorption of various resins of the Wofatit type for drugs]. / In vitro-Untersuchungen zur Adsorption verschiedener Harze vom Typ Wofatit für Arzneimittel.

The capacities of the resins Wofatit Y 29, Y 55 and Y 56 (VEB Chemiekombinat Bitterfeld) to adsorb various medicaments were compared with that of the resin XAD-4. Methaquelone, diazepam, krotylbarbital, promazine phosphate and ethyloxamine were used as test substances. The resin Y 56 proved to have an adsorption capacity similar to that of XAD-4 (e.g. maximum saturation for methaquelone 98%, half-maximum saturation at 7 minutes). In further tests on various batches of this resin the best results were given by the resin Y 56/7. Adsorption was quite clearly shown to be dependent on concentration. At a blood-flow of 100 ml/min clearance values of 34.5 ml/min for krotylbarbitol and 22.1 ml/min for methaquelone were calculated. According to these findings the resin Y 56/7 is suitable for further testing in a haemoperfusion system with a view to clinical use.

A simple procedure for separating drugs from interfering lipids on special thin layer chromatographic media.

A method is reported for separating drugs from serum lipids on special thin layer chromatographic media with insertable sample application discs, using a double-development, single dimensional technique. Drugs whose detection normally was precluded by lipid were detected at therapeutic levels using the new procedure.

Incidence of methaqualone in driving-under-the-influence (DUI) cases in the state of Georgia.

A retrospective study was undertaken to assess the range of blood methaqualone levels, which should be considered sufficient to produce deterioration of driving ability. Data from 974 driving-under-the influence (DUI) cases were subdivided into five major catagories based on whether drugs other than methaqualone were discovered during the analytical procedures. The range of blood methaqualone levels, which appear to cause significant motor skill impairment, are discussed for each category. Also included are data from 20 of these cases indicating the symptoms of methaqualone intoxication which were reported by arresting officers.

Methaqualone ingestion: evaluation of present status.

Sixty cases of methaqualone ingestion have been reviewed from 1977 through 1980. Serum methaqualone concentrations, clinical information, and demographic data were studied in order to define the present status of abuse of this drug. The average user was a 27 year-old man who ingested Quaalude plus at least one additional drug (usually a narcotic analgesic, ethanol, a benzodiazepine, or a barbiturate, in that order). He was admitted to the emergency room with a depressed level of consciousness and a serum methaqualone concentration of 5 +/- 3 mg/L (mean +/- SD). Following a brief period of observation and supportive care, he was discharged from the hospital. Serum methaqualone concentrations showed no significant correlation with the physical findings, except that levels greater than or equal to 9 mg/L were always associated with a depressed level of consciousness, whether or not other drugs were present. Despite strict federal controls, methaqualone abuse appears to be a continuing problem, and analysis for this drug should be part of the toxicology screen.

A rapid procedure for the screening and quantitation of barbiturates, diazepam, desmethyldiazepam and methaqualone.

A procedure is presented for the concomitant identification and quantitation of certain commonly abused weak acid and natural drugs from whole blood. This procedure offers several advantages over other procedures in that: (A) a means of extraction of the drugs from blood using a very inexpensive source of diatomaceous earth (Celite 560) is presented, (B) the addition of three internal standards allows the quantitation of several drugs from blood with just one extraction of the blood sample, (C) the extracts are virtually free of any contaminants from biological sources or from biologically inert drug metabolites, and (D) the barbiturates and desmethyldiazepam are derivatized to enhance their limits of detection and reduce peak tailing frequently observed when using the nitrogen-phosphorous detector and gas chromatography (NPD/GC). Some 1000 positive driving-under-the-influence cases have been quantitated by this method.

Determination of methaqualone and its major metabolite in plasma and saliva after single oral doses.

A gas liquid chromatographic procedure for the determination of methaqualone and metabolite l (2-methyl-3(2-hydroxymethylphenyl)-4-(4H)-quinazoline) in plasma and saliva is described. The method requires 1.0 mL of sample and involves internal standard addition, extraction with butyl chloride, chromatography on a 1% SP-1,000 column packing using nitrogen phosphorous detectors. Within-run and day-to-day coefficient variations were less than 8% and the procedure has a sensitivity limit of 20 ng/mL. The method has been used to monitor both parent drug and metabolite in plasma and samples collected after a single oral dose.