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.

Correlates of Mandrax use and condom beliefs in preventing sexually transmitted infections among a cohort of South African prison inmates.

BACKGROUND: This study was designed to identify the extent to which self-reported Mandrax use impacts condom-use beliefs amongst South African prison inmates. METHODS: Participants were inmates from four prisons in the provinces of KwaZulu-Natal and Mpumalanga. In total, 357 inmates participated in the parent study of which 121 are included in this analysis based on their self-reported use of Mandrax. The questionnaire was developed in English, translated into Zulu, and back translated into English. Age significantly predicted the use of Mandrax: younger prison inmates reported higher use. Linear regression analysis was conducted to determine whether the use of Mandrax was associated with length of incarceration and other demographic variables, as well as participants' self-reported condom use beliefs behavior. RESULTS: Regression results indicated that two factors operationalizing condom-use beliefs were impacted by Mandrax use: 1) it is important to use condoms every time you have sex (p<0.01); 2) condoms work well to prevent the spread of HIV (p<0.02). Both factors were also inversely related to Mandrax use. CONCLUSION: STI prevention programs among prison inmates that seek to promote safer sex behaviors among men must address attitudes to condom use, specifically consistent and correct use of latex condoms and reducing substance misuse.

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.

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.

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.

Induction of hepatic UDP-glucuronyltransferase by oral methaqualone consumption.

Repeated oral administration of methaqualone (100 mg/kg/day) to rats for 6 consecutive days evoked approximately two and a half fold increase in p-nitrophenol glucuronidation by hepatic microsomes. Interestingly, the magnitude of UDP-glucuronyltransferase stimulation by methaqualone, when assessed in crude liver homogenate, was comparable to that obtained with isolated microsomes.

Dose-response studies on tolerance to multiple doses of secobarbital and methaqualone in a polydrug abuse population.

Patients from a polydrug abuse treatment program were titrated with either secobarbital or methaqualone, their primary drug of abuse, to a state of mild intoxication, consisting of lateral and vertical nystagmus, ataxia, slurred speech, and drownsiness. The mean dose required to produce each sign was compared to that determined in a similarly treated control group. Tolerance to secobarbital was more easily demonstrated than tolerance to methaqualone, and nystagmus was the least sensitive indicator of patient tolerance. The individual signs were also cumulated into a graded rating scale of central nervous system depression which would be related to the dose administered. Tolerence was easily demonstrated at the higher stages of toxicity for secobarbital in the overall patient population, but tolerance to methaqualone was only unequivocal in the subjects indicating a relatively high frequency of abuse. Tolerance to methaqualone occurred at the lower stages of toxicity, suggesting that there is a difference between tolerance to secobarbital and tolerance to methaqualone. There was no indication that patients who also abuse alcohol are more tolerant than their patient counterparts. The patients who also had a history of amphetamine abuse, however, were less tolerant than the nonusers of these drugs.

One man's poison.

In an unrandomised uncontrolled study on boats and trains, capsules of flurazepam (30 mg) and temazepam (20 mg), when chewed, but not when swallowed whole (even with the ends pricked), gave a better night's sleep than 'Mandrax' (methaqualone 250 mg/diphenhydramine 50 mg) and a better night's sleep than nitrazepam 7.5 mg.

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.

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.

Simultaneous identification and quantitation of diphenhydramine and methaqualone.

Methods for the simulataneous identification and quantitation of diphenhydramine and methaqualone in urine have been investigated. Suitable thin-layer and gas chromatographic techniques have been developed. The extraction techniques were evaluated by extracting human urine after the ingestion of therapeutic dosages of the two drugs. A charcoal cartridge technique proved to be superior to direct solvent extraction. Although enzyme hydrolysis gave slightly better recoveries than the charcoal cartridge technique, it is a time-consuming procedure.

[The problem of polyneuropathy in methaqualone medication]. / Zur Problematik einer Polyneuropathie bei Methaqualon-Medikation.

Thirteen years after the introduction of methaqualone into therapy, investigators (namely, Finke, Spiegelberg, and Suchenwirth), by reference to individual cases, pointed out the possible development of polyneuropathies. This has not so far been confirmed despite worldwide use of the drug. Experiments on rats, which were conducted by the present authors, show a statistically significant decrease in maximum motor conduction speed, which is believed to be functional disorder. Clinical symptoms or nervous structural variations in the sense of polyneuropathy could not be observed.

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.