Transmission Of Tuberculosis Among illicit drug use Linkages (TOTAL): A cross-sectional observational study protocol using respondent driven sampling.

People who use illicit drugs (PWUDs) have been identified as a key at-risk group for tuberculosis (TB). Examination of illicit drug use networks has potential to assess the risk of TB exposure and disease progression. Research also is needed to assess mechanisms for accelerated TB transmission in this population. This study aims to 1) assess the rate of TB exposure, risk of disease progression, and disease burden among PWUD; 2) estimate the proportion of active TB cases resulting from recent transmission within this network; and 3) evaluate whether PWUD with TB disease have physiologic characteristics associated with more efficient TB transmission. Our cross-sectional, observational study aims to assess TB transmission through illicit drug use networks, focusing on methamphetamine and Mandrax (methaqualone) use, in a high TB burden setting and identify mechanisms underlying accelerated transmission. We will recruit and enroll 750 PWUD (living with and without HIV) through respondent driven sampling in Worcester, South Africa. Drug use will be measured through self-report and biological measures, with sputum specimens collected to identify TB disease by Xpert Ultra (Cepheid) and mycobacterial culture. We will co-enroll those with microbiologic evidence of TB disease in Aim 2 for molecular and social network study. Whole genome sequencing of Mycobacteria tuberculosis (Mtb) specimens and social contact surveys will be done for those diagnosed with TB. For Aim 3, aerosolized Mtb will be compared in individuals with newly diagnosed TB who do and do not smoke illicit drug. Knowledge from this study will provide the basis for a strategy to interrupt TB transmission in PWUD and provide insight into how this fuels overall community transmission. Results have potential for informing interventions to reduce TB spread applicable to high TB and HIV burden settings. Trial registration: Clinicaltrials.gov Registration Number: NCT041515602. Date of Registration: 5 November 2019.

Return of the Quaaludes? Prolonged agitated delirium after intentional ingestion of the methaqualone analog SL-164 - a case report.

Background: A 22-year-old male with a known history of drug abuse presented to our department with prolonged agitated delirium, myocloni, tachycardia and subfebrile temperature after the deliberate ingestion of opium poppy tea (Papaver somniferum L.) together with the methaqualone analog SL-164 (5-chloro-3-(4-chloro-2-methylphenyl)-2-methyl-4(3H)-quinazolinone) which is sold online as a designer drug. Methods: SL-164 and its hydroxy metabolites were detected in serum and urine via liquid chromatography-quadrupole-time-of-flight mass spectrometry (LC-QTOF-MS). Results: The pronounced delirium was treated with benzodiazepines and neuroleptics; temporary medical restraint had to be applied. Symptoms completely resolved over the next 72 h and the patient was discharged on day three able to give consent. Conclusions: Although methaqualone was a popular and widespread sedative in the 1950s and 60 s before its discontinuation in the USA in 1985, derivatives of the methaqualone class have not previously played a large role as drugs of abuse in the rapidly growing market of new psychoactive substances. To our knowledge, this is the first case of agitated delirium with detection of SL-164 and hydroxylated metabolites in a patient's serum and urine.

Toxicological screening for drugs of abuse in samples adulterated with household chemicals.

OBJECTIVES: Urine samples that tested positive for two drugs of abuse, namely cannabis and methaqualone, were reassayed in the presence or absence of common household chemicals: Jik (sodium hypochlorite), Dettol (chloroxylenol), G-cide Plus (glutaraldehyde), Perle Hand Soap, ethanol, isopropanol and peroxide (20 volumes). These chemicals are frequently used for the adulteration of urine samples. SETTING: Department of Pharmacology, University of Stellenbosch. METHODS: Household chemicals, at three different concentrations, were added to urine samples that tested positive for methaqualone and cannabis. Samples were reanalysed on an ETS Plus Analyser (Syva Company, San Jose, Ca.) using Emit drugs-of-abuse urine test reagents. RESULTS: Most of the chemicals tested influenced the outcome of positive toxicological screening results for these drugs. G-cide (glutaraldehyde) and Perle Hand Soap had the largest effect (false-negative) on the methaqualone test. Dettol (chloroxylenol) and Perle Hand Soap had the largest effect on the cannabis test. Higher concentrations of the adulterant were not always an indication of the extent of modification of the test result. The addition of certain chemicals (ethanol, isopropanol and peroxide) to the urine samples tested for methaqualone interfered with the test to such an extent that it gave invalid test results.

Enantiomeric analysis of the five major monohydroxylated metabolites of methaqualone in human urine by chiral capillary electrophoresis.

Methaqualone (MQ; 2-methyl-3-o-tolylquinazolin-4(3H)-one) is a hypnotic and anticonvulsive drug in which the rotation about the nitrogen-to-aryl bond between the planar 2-methyl-quinazolin-4(3H)-one structure and the o-tolyl moiety is sterically hindered at body temperature. MQ and its five major monohydroxylated metabolites found in urine, 4'-hydroxymethaqualone (4'OH-MQ), 2'-hydroxymethaqualone (2'-OH-MQ), 3'-hydroxymethaqualone (3'OH-MQ), 2-hydroxymethaqualone (2OH-MQ) and 6-hydroxymethaqualone (6OH-MQ), are thus chiral substances whose enantiomers are shown to be separable by chiral capillary electrophoresis at pH 2.1 in the presence of 50 mM (2-hydroxypropyl)-beta-cyclodextrin (OHP-beta-CD). Other neutral derivatives of beta-CD, namely (2-hydroxypropyl)-gamma-CD, (2,3,6-trimethyl)-beta-CD, and (2,6-di-O-methyl)-beta-CD were found to be able to resolve the enantiomers of some but not all of these six components. With OHP-beta-CD, simultaneous analysis of the enantiomers of MQ and its five metabolites is hampered by the difficulty in separating MQ and 4'OH-MQ, the major urinary metabolite. A two-step solid phase extraction process is shown to permit discrimination between these two compounds and thus analysis of MQ enantiomers in unhydrolyzed urines that were collected overnight after administration of 250 mg of racemic MQ. Furthermore, analysis of liquid/liquid or solid-phase extracts of enzymatically hydrolyzed urines reveals the distribution of the enantiomers of the five hydroxymetabolites of MQ and, for the first time, insight into the stereoselectivity of the MQ metabolism. The major metabolite, 4'OH-MQ, is shown to be excreted almost exclusively as single enantiomer. The two urinary enantiomers of 6OH-MQ are present at about equal amounts, whereas unequal amounts are noted for the enantiomers of 3'OH-MQ, 2OH-MQ, and 2'OH-MQ.

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.

Solid-phase extraction and GC/MS confirmation of barbiturates from human urine.

A highly selective and sensitive procedure has been developed for isolating and identifying barbiturates in human urine. With a new disposable bonded silica gel solid-phase extraction (SPE) column and hexobarbital as an internal standard (IS), amobarbital, butabarbital, pentobarbital, phenobarbital, secobarbital, and methaqualone were selectively isolated from endogenous urine components. Capillary gas chromatography/ion trap mass spectrometry (GC/MS) analysis of the extracts generated a full mass spectrum for the detection, identification, and quantitation of barbiturates. Linear quantitative response curves for the drugs have been generated over a concentration range of 20-500 ng/mL. Overall extraction efficiencies for drugs averaged greater than 90%, and the quantitative response curves exhibited correlation coefficients of 0.996 to 0.999.

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.

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.

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.

Mass screening and confirmation of methaqualone and its metabolites in urine by radioimmunoassay-thin-layer chromatography.

A sensitive, rapid, and specific procedure is described for the mass screening and confirmation of methaqualone (Quaalude) in urine specimens. The method is sensitive to 1.0 microgram/ml levels of total methaqualone excretion products (free methaqualone, free hydroxylated methaqualone metabolites, and conjugated hydroxylated methaqualone metabolites). The raw urine is screened directly by radioimmunoassay, which is reactive to all the methaqualone excretion products. Specimens that are screened positive are confirmed by thin-layer chromatography using a solvent system of ethyl acetate-1,2-dichloroethane-chloroform (75:15:10) which separates methaqualone and its four major metabolites without interference from other drugs or urinary substances. The distinctive spot pattern produced by the methaqualone metabolites makes false positive results nearly impossible.

Analysis of therapeutic and commonly abused drugs in serum and urine by gas-liquid chromatography using a photoionization detector.

A simple, rapid and sensitive gas chromatographic procedure using the photoionization detector (PID) was developed for the detection and quantitation of several drugs in serum and urine. In order to evaluate the performance of the PID, the results were compared with those of the flame-ionization detector (FID). The data indicate that the PID is 8-16 times more sensitive than the FID for the drugs studied in the barbiturate group. Excellent reproducibility was found for samples quantitated with the PID on a routine basis. The PID and FID produced statistically similar results on extracted serum samples. The correlation coefficient was 0.99. The PID also produced chromatograms with less background than those obtained with the FID for many extracted serum samples. The advantages of the PID for drug analysis in biological fluids include simplicity of operation, lack of solvent response, universal drug response, non-destructive character and stability.

Deterrence of methaqualone abuse through mass urinalysis.

A temporary court-ordered cessation of urine testing in Europe and the widespread abuse of a detectable methaqualone-containing drug provided an opportunity with the resumption of testing for the evaluation of the possible effects of urinalysis on usage patterns. Evidence is presented suggesting that in this instance urinalysis acted to deter usage of this particular drug.

[Studies on the kinetics of methaqualone during the late stage of pregnancy (author's transl)]. / Untersuchungen zur Kinetik von Methaqualon in der Spätschwangerschaft.

After oral administration of 0.4 g of methaqualone to pregnant and non-pregnant women, the authors stated that the half-life of this drug was significantly reduced during the last trimester of pregnancy. The two experimental groups showed no significant differences in the volume of distribution and the fictitious initial concentration. The commonly used therapeutical dosages are not likely to produce increased blood levels during normal pregnancy.

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.

Radioimmunoassay of methaqualone in human urine compared with chromatographic methods.

The 125I-radioimmunoassay for methaqualone in human urine was evaluated by a comparison with newly modified gas-liquid chromatographic and thin-layer chromatographic methods. The statistically significant sensitivity value for the radioimmunoassay was at 2 microgram of methaqualone per liter of urine. The coefficient of variation was 2.88 +/- 0.39% interassay and 2.71 +/- 0.16% intraassay. There was cross-reactivity only with metabolites of methaqualone, 4'-hydroxymethaqualone being twice as sensitively measured as methaqualone. There was complete agreement between results by radioimmunoassay and by gas-liquid chromatography in 96.7% of the samples analyzed. Only 1.2% of the radioimmunoassay values were false positives, and 2.1% false negatives (phi = 0.8917, P less than 0.001). Comparisons between the thin-layer chromatographic data and the gas-liquid chromatographic or radioimmunoassay data showed less agreement because of the 50- to 200-fold higher sensitivity of the latter two techniques. Gas-liquid chromatography therefore appears to represent the best reference method for the evaluation of the radioimmunoassay, which appears to be a very sensitive and reliable technique for detecting methaqualone and its metabolites in human urine.

Metabolism of methaqualone in geriatric patients.

The urinary excretion of five C-monohydroxy metabolites and the N-oxide of methaqualone has been measured in a group of eleven geriatric patients aged 71--90 years. The total excretion of the six metabolites in 24 h after the oral administration of a single dose was approximately one-half of that in a group of young healthy adults. The relative importance of the six metabolites was 4'-hydroxy greater than N-oxide greater than 2'-hydroxymethyl = 3'-hydroxy greater than 6-hydroxy = 2-hydroxymethyl which was the same order as that in young adults. The ratio of C-to N-oxidation was also the same in the two groups. There was no impairment of conjugation of the C-hydroxy metabolites with glucuronic acid in the geriatric group but there was greater interindividual variation in metabolite excretion. There was also evidence for delayed metabolism in the geriatric patients.