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The structural identification of a methyl analog of methaqualone via 2-dimensional NMR techniques.

A submission to the Drug Enforcement Administration North Central Laboratory of a substance believed to be a structural analog of methaqualone hydrochloride precipitated an interest in being able to obtain a rapid and positive identification of such compounds. Both mass spectrometry and proton NMR spectroscopy (1-dimensional) provided evidence to suggest that the structural analog possessed a second methyl group in the molecule, relative to methaqualone, and that the methyl group was attached to the existing methyl-substituted phenyl ring. By application of proton 2-dimensional (2-D) NMR techniques, specifically the homonuclear shift correlation spectroscopy (COSY) and 2-D NOE (NOESY), the precise location of the methyl group in this unknown methaqualone analog was established and shown to have the structure 2.

Magnetic Resonance Spectroscopy↗

The effects of methaqualone on the temperature regulation of mice.

Methaqualone produces dose and time dependent changes in the rectal temperature of mice. More specifically, the drug produces poikilothermia. This effect appears to be produced by methaqualone itself rather than a liver metabolite since SKF525A, a compound known to block drug metabolizing enzymes in the liver, does not abolish the phenomenon. Tolerance to the temperature altering effects of methaqualone is also shown.

Animals↗

Correlation between dissolution characteristics and absorption of methaqualone from solid dosage forms.

A methaqualone tablet in two strengths, 150 and 300 mg, was developed. The dissolution rate of an experimental formulation in pH 7.0 phosphate buffer, measured by the resin flask method, was shown to correlate with bioavailability in humans. The dissolution rate criterion was used to develop the final tablet formulation. Bioavailability of this formulation in two strengths was compared with a commercial capsule formulation and a slowly dissolving tablet formulation. Correlation between dissolution rate and bioavailability was shown in freshly prepared methaqualone tablet formulations. Bioavailability of tablets under accelerated stability testing conditions remained unaltered, whereas the dissolution rates in pH 7 phosphate buffer decreased, using the resin flask method. A rotating-flask method was developed, and dissolution in 0.1 N HCl at 2 rpm correlated with the bioavailability of both new and aged tablet formulations.

Absorption↗

Comparison of in vitro dissolution and in vivo bioavailability of methaqualone tablets in humans.

Two methaqualone tablets that exhibited different in vitro dissolution rates were administered to 11 normal healthy male volunteers. Serial blood samples were withdrawn following administration of each tablet, and plasma methaqualone concentrations were determined by an established spectrophotofluormetric assay. Both tablets produced virtually identical plasma concentration versus time profiles in humans, and no statistically significant differences in either the rate or extent of drug absorbed were detected. The results indicate that there is no correlation between in vivo bioavailability and the modified NF in vitro dissolution test used.

Adult↗

Methaqualone: tolerance and physical dependence in mice.

Tolerance and physical dependence was produced in C57Bl/6 male mice that had been exposed, for 36 days, to methaqualone in food pellets via an automated system. Tolerance was revealed in the reduction of sleep-times following intraperitoneal injection of methaqualone. Physical dependence was manifested as an alteration in neural sensitivity to flurothyl-induced convulsions.

Animals↗

The metabolism of methaqualone in patients with biliary cirrhosis or secondary carcinoma of the liver.

The metabolism of methaqualone has been studied in three patients with secondary carcinoma of the liver and two with biliary cirrhosis. The urinary excretion of five C-monohydroxy metabolites and the N-oxide was studies in the 24 h period immediately after oral dosing with 250 mg methaqualone (Melsed). In both patients with biliary cirrhosis and one with primary carcinoma of the bile duct or pancreas with secondaries in the liver the pattern of metabolites was normal. In a patient with oat cell carcinoma with secondaries in the liver some metabolite patterns were disturbed and increased metabolite excretion occurred. A patient with primary carcinoma of the breast with secondaries in the liver gave a completely abnormal metabolite pattern.

Adult↗

The kinetics of the urinary excretion of the N-oxide and glucuronides of methaqualone in man.

The urinary excretion of the N-oxide and the glucuronides of five C-monohydroxy metabolites of methaqualone has been studied following the oral administration of a single dose of the drug. The apparent first order rate constants for the excretion of each metabolite (kme) were shown to be numerically smaller than the overall elimination rate constant for methaqualone (k10). The Kme values tended to be greater than or equal to the corresponding apparent first order rate constants for the formation of the metabolite (km) but corresponding kme and km values were always of the same order magnitude. The kme values for the glucuronides were much smaller than the literature kme value for paracetemol glucuronide. The rate of renal elimination of the metabolites was variably sensitive to urine flow but over a period of time of 8 hours or greater the total amount of metabolite recovered in the urine was was independent of the total urine volume.

Adult↗

The effect of age on the competitive C- and N-oxidative pathways of methaqualone in women.

The urinary excretion of the N-oxide and the glucuronides of five C-monohydroxy metabolizes of methaqualone has been studied in a group of young women aged 24-34 years and in a group of elderly women aged 85-87 years. The rate of appearance of the metabolites in the urine was slower in the elderly group but the relative importance of the six metabolites was the same in the two groups. There were differences in some metabolite ratios between the two groups, but only one difference approached statistical significance. The metabolite excretion in a 80 year old woman who had received methaqualone daily for over ten years was consistent with that of the elderly group. The results indicate that the ageing process per se and chronic weak hepatic enzyme induction in the elderly are not accompanied by changes in the relative importance of competitive metabolic pathways.

Adult↗

Variations in human metabolism of methaqualone given in therapeutic doses and in overdose cases studied by gas chromatography-mass spectrometry.

The individual variations in human metabolism of methaqualone were studied after oral administration of therapeutic doses. The effect of antabuse on the drug metabolism as well as metabolites in some autopsy cases were also studied. The metabolites were identified using the GC-MS computer technique, and the relative amounts of the indicated metabolites were calculated from the sum of the peak heights in the gas chromatogram. The results show that the individual variations were small in the cases of therapeutic doses and that antabuse did not interact with the metabolism of methaqualone. Large amounts of one single metabolite 2-methyl-3-[phenyl(2'-methyl-4-hydroxy)]-4(3H)-quinazolinone was found in the bile from the two autopsy cases where the bile was also collected.

Administration, Oral↗

Electroencephalographic studies with i.v. methaqualone in man.

Methaqualone injected i.v. has been reported to be a safe short-acting anaesthetic agent and a muscle relaxant in man. It has been employed in a variety of operative procedures and to modify convulsions in the management of tetanus and in electroconvulsive therapy. Safety, usefulness and the marked central effects of the drug led us to study its central effects by EEG in man. Discrepancies between clinical and EEG signs were thus seen. EEG patterns resembled those after barbiturates and the effect was dose dependent. Differences between methaqualone and barbiturates are discussed. The EEG patterns were potentiated by thioridazine and antagonised by imipramine.

Adult↗

Effect of methaqualone on plasma corticosterone in rats: possible sites of action.

Methaqualone produces large increases in plasma corticosterone in rats. This effect does not involve a direct stimulation of either the adrenal glands or pituitary, nor is it the result of a significant alteration in the clearance of circulating corticosterone. Methaqualone may therefore be influencing brain mechanisms which ultimately regulate hypothalamic CRH secretion, although a peripheral site of action has not yet been ruled out.

Adrenocorticotropic Hormone↗

Effects of d-amphetamine, methaqualone, and phencyclidine on the reaction time of pigeons.

The effects of acute administrations of d-amphetamine (0.56, 1.0, 1.78, 3.2, and 5.6 mg/kg), methaqualone (5.6, 10, 18, 32, and 56 mg/kg), and phencyclidine (0.3, 0.56, 1.0, and 1.78 mg/kg) on the reaction time of pigeons were examined. In the reaction time assay, birds were trained to depress and hold a foot treadle until a stimulus change occurred. Releases within 2 s of the stimulus change were reinforced with food; premature releases or releases occurring after the 2-s limited hold were not reinforced. At relatively high doses, each of the drugs decreased the percentage of responses that were reinforced. Methaqualone and phencyclidine usually increased median reaction times at these doses, whereas the effects of d-amphetamine on reaction time were less clear.

Animals↗

Comparison of methaqualone excretion patterns using Abuscreen ONLINE and EMIT II immunoassays and GC/MS.

A study was performed to compare the ONLINE and EMIT II immunoassays with gas chromatographic/mass spectrometric (GC/MS) analysis of methaqualone metabolites on urine using samples obtained from a clinical study. Urine was collected over a 72 h period from six healthy adults (4 male, 2 female) after oral dosing with 200 mg methaqualone (MTQ). Each urine sample was analyzed by ONLINE and EMIT II. The samples were then analyzed by GC/MS, hydrolyzed with beta-glucuronidase and again analyzed by GC/MS. Both immunoassays showed greater than 600 ng/ml concentrations of drug in each sample by the second void and remained highly positive for the rest of the 72 h. Unhydrolyzed samples analyzed by GC/MS showed both low concentrations of MTQ as well as its five major hydroxylated metabolites. The hydrolyzed samples analyzed by GC/MS showed high concentrations of the hydroxylated metabolites with the 2'-hydroxy and 3'-hydroxy metabolites being present at the highest concentrations, the 4'-hydroxy metabolite at a lower amount and the 6-hydroxy and 2-hydroxy metabolites at the lowest concentrations. The GC/MS data coupled with the antibody cross-reactivity data indicate that the major species in clinical samples that cross-react in both immunoassays are the conjugated forms of the hydroxylated metabolites of MTQ. Therefore when confirming by GC/MS after an immunoassay screen it would be prudent to confirm for the major hydroxylated metabolites as glucuronides of MTQ instead of the parent drug.

Adult↗

Synthesis and central nervous system activity of quinazolones related to 2-methyl-3-(o-tolyl)-4(3H)-quinazolone (methaqualone).

A number of derivatives of 2-methyl-3-(o-tolyl)-4(3H)-quinazolone bearing new substituents on the 2-methyl group have been synthesized. It was established that most substitutions at this position reduce or remove the CNS depressant activity of methaqualone. From the series prepared only the 2-fluoromethyl derivative or certain isothiouronium salts, which could be hydrolyzed in vivo to the 2-mercaptomethyl derivative, showed activity of the same magnitude as methaqualone.

Animals↗

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.

Amphetamines↗

EMIT-st screening for drugs of abuse: methaqualone.

The Emit-st (single test) drug detection system was determined, for methaqualone and several of its metabolites, to be reliable and simple to perform. Its sensitivity was 0.3 micrograms/mL for methaqualone and 0.4 micrograms/mL for the only methaqualolne metabolite (4-hydroxymethaqualone) known to be excreted unconjugated. This assay also detects mecloqualone, a Schedule I drug marketed in Europe and South Africa.

Humans↗

Effects of methaqualone on social behavior in monkeys (Macaca mulatta).

In an established social group of rhesus monkeys (macaca mulatta) consisting of 1 adult male, 6 adult females, 1 adolescent male and 2 infants, 3 subjects were selected to study the effects of intramuscular methaqualone (10 mg/kg) on behavioral changes in the treated animals, as well as the rest of the colony. Three drug trials alternating with saline controls given to the dominant male, a mid-ranking female and the adolescent male. 20 h of observations were made prior to treatment to serve as a baseline, using 40 discrete behaviors. For each drug and saline period, 2 h of continuous observation was directed towards each target animal (total 36 h), and 12-min behavioral samplings were carried out on each untreated subject in the colony (36 h). Dependent upon the sex and social rank of the subject, different behavioral changes occurred during drug treatment, which were consistent from trial to trial. New behaviors were observed, such as active grooming, autofellatio and masturbation in both males, while some previous behaviors disappeared or decreased. The mid-ranking female showed an increase in aggressive behavior. A biphasic action of the drug was also observed in all subjects. During the first 80--100 min, the males were mainly passive or engaged in grooming, but after this primary phase, they started either to masturbate or autofellate. After approximately 2 h, the social status and behavior of the animals returned to predrug levels. During the drug treatment, marked changes occurred in the behavior of other colony members, e.g. when the dominant male's vigilance was lowered, the highest ranking female replaced him in rank. In general, affiliative activities were increased under the influence of methaqualone, manifesting themselves mainly in grooming, hudding or sitting together: phenomena somewhat parallel to those described among humans taking the drug in group settings.

Agonistic Behavior↗