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Nature Communications Jun 2024Methaqualone, a quinazolinone marketed commercially as Quaalude, is a central nervous system depressant that was used clinically as a sedative-hypnotic, then became a...
Methaqualone, a quinazolinone marketed commercially as Quaalude, is a central nervous system depressant that was used clinically as a sedative-hypnotic, then became a notorious recreational drug in the 1960s-80s. Due to its high abuse potential, medical use of methaqualone was eventually prohibited, yet it persists as a globally abused substance. Methaqualone principally targets GABA receptors, which are the major inhibitory neurotransmitter-gated ion channels in the brain. The restricted status and limited accessibility of methaqualone have contributed to its pharmacology being understudied. Here, we use cryo-EM to localize the GABA receptor binding sites of methaqualone and its more potent derivative, PPTQ, to the same intersubunit transmembrane sites targeted by the general anesthetics propofol and etomidate. Both methaqualone and PPTQ insert more deeply into subunit interfaces than the previously-characterized modulators. Binding of quinazolinones to this site results in widening of the extracellular half of the ion-conducting pore, following a trend among positive allosteric modulators in destabilizing the hydrophobic activation gate in the pore as a mechanism for receptor potentiation. These insights shed light on the underexplored pharmacology of quinazolinones and further elucidate the molecular mechanisms of allosteric GABA receptor modulation through transmembrane binding sites.
Topics: Receptors, GABA-A; Binding Sites; Cryoelectron Microscopy; Humans; Animals; Etomidate; Propofol; Quinazolinones; Allosteric Regulation; HEK293 Cells; Hypnotics and Sedatives
PubMed: 38898000
DOI: 10.1038/s41467-024-49471-y -
The South African Journal of Psychiatry... 2024Epidemiological studies suggest that nyaope, a heroin-based drug, is widely used in South Africa. Yet few reliable research tools are available to assess treatment...
BACKGROUND
Epidemiological studies suggest that nyaope, a heroin-based drug, is widely used in South Africa. Yet few reliable research tools are available to assess treatment outcomes of users. The Opiate Treatment Index (OTI), a tool developed in Australia, could potentially facilitate research on context-specific South African treatment outcomes. However, we know little of its test-retest reliability.
AIM
This study aimed to assess the test-retest reliability of the OTI among a sample of nyaope users in Johannesburg.
SETTING
This study was conducted across three substance use treatment facilities in Johannesburg.
METHODS
The OTI was administered to 53 nyaope users at baseline and one week later. To determine the test-retest reliability of the OTI, the intra-class correlation coefficients (ICC) and the Brennan-Prediger coefficients of the two interviews were calculated.
RESULTS
The ICC of the Q-scores from the data sets along with the Brennan-Prediger coefficient for the substance use domain were calculated. The ICC for nyaope was 0.38. Brennan-Prediger coefficients were as follows: alcohol - 0.96, crack-cocaine - 0.89, cannabis - 0.92, methaqualone - 0.85 and crystal methamphetamine - 0.89.
CONCLUSION
A significant positive finding was the excellent test-retest reliability of the injecting and sexual behaviour domains and moderate reliability of the criminality, general health and social functioning domains.
CONTRIBUTION
The results of this study provide insight into the reliability of this tool and for its use in future studies in the South African context.
PubMed: 38444406
DOI: 10.4102/sajpsychiatry.v30i0.2087 -
Burns : Journal of the International... May 2024In South Africa, fire-related deaths are common, particularly within dense informal housing settlements. Published data on deaths from fire incidents in Cape Town is...
BACKGROUND
In South Africa, fire-related deaths are common, particularly within dense informal housing settlements. Published data on deaths from fire incidents in Cape Town is sparse. Additionally, little emphasis has been placed on the role of toxicological investigations in these deaths, despite the known risk of alcohol and drug impairment to burn injury.
METHODS
A retrospective, descriptive analysis of post-mortem case reports from Salt River Mortuary was conducted to investigate all deaths in which fires were involved in the west metropole of Cape Town, between 2006 to 2018. Demographic, circumstantial, and toxicological data were analyzed using R software.
RESULTS
In total 1370 fire deaths occurred over 13 years, with a mean of 106 (SD ± 18) cases per annum (≈3% of the annual caseload and a mortality rate of 5.5 per 100,000). Males (70.4%), adults (mean=30.7 years), and toddlers (1-4 years old) were notably at risk. Deaths typically occurred in the early morning (00h00 - 06h00) (45.7%), during winter (32.1%), and in lower socioeconomic areas with highly dense informal settlements (65.6%), with 29% of deaths occurring in multi-fatality incidents. Ethanol was detected (≥0.01 g/100 mL) in 55.1% of cases submitted for analysis (71.5%), with a mean of 0.18 g/100 mL, and with 93.8% of positive cases > 0.05 g/100 mL. Carboxyhaemoglobin (COHb) analysis was requested in 76.4% of cases, with 57% of cases having a %COHb of ≥ 20%. Toxicology results (for drugs other than ethanol) from the national laboratory were outstanding in 34.4% of the cases at the conclusion of the study. BAC and %COHb were significantly higher in deaths from burns and smoke inhalation (usually accidents) than deaths from combined trauma and burns (typically homicides). Fire deaths with high COHb levels were more likely to display cherry-red discoloration (OR=3.1) and soot in the airways (OR=2.7) at autopsy.
CONCLUSION
This article provides an updated description of fire deaths in the west metropole of Cape Town. The importance of BAC and COHb testing in these cases was noted, and the authors call for an investigation of the role of drug impairment (specifically frequently misused drugs methamphetamine and methaqualone) as a risk factor in these deaths. Areas of high-density informal settlements, where open flames are used to heat, light, and cook, were noted as high risk.
Topics: Humans; South Africa; Retrospective Studies; Male; Adult; Female; Burns; Fires; Infant; Child, Preschool; Child; Middle Aged; Adolescent; Young Adult; Carboxyhemoglobin; Aged; Blood Alcohol Content; Methamphetamine; Age Distribution; Ethanol; Sex Distribution; Smoke Inhalation Injury; Carbon Monoxide Poisoning; Seasons; Aged, 80 and over; Substance-Related Disorders; Central Nervous System Depressants
PubMed: 38290966
DOI: 10.1016/j.burns.2024.01.001 -
Archiwum Medycyny Sadowej I Kryminologii 2023The aim of this review article was to collect and analyze the available information on methaqualone and its derivatives reported by users in dedicated online forums.... (Review)
Review
The aim of this review article was to collect and analyze the available information on methaqualone and its derivatives reported by users in dedicated online forums. Methaqualone is a sedative-hypnotic drug that has been widely used for medical purposes in the past, but is now illegal in most countries due to its high abuse potential. The review collected information on doses, routes of administration, desirable and side effects of intoxication and other relevant aspects of the abuse of these compounds. The results of the study suggest that methaqualone and its derivatives continue to be used by some individuals despite their illicit status and potential health risks. The review, in the absence of other more reliable toxicological data, provides valuable insights from direct users on the use of these substances.
Topics: Humans; Methaqualone; Hypnotics and Sedatives
PubMed: 38186032
DOI: 10.4467/16891716AMSIK.22.003.18213 -
The International Journal of... Jun 2023Smoking of illicit drugs may lead to more rapid TB disease progression or late treatment presentation, yet research on this topic is scant. We examined the association...
Smoking of illicit drugs may lead to more rapid TB disease progression or late treatment presentation, yet research on this topic is scant. We examined the association between smoked drug use and bacterial burden among patients newly initiated on drug-susceptible TB (DS-TB) therapy. Data from 303 participants initiating DS-TB treatment in the Western Cape Province, South Africa, were analyzed. Smoked drug use was defined as self-reported or biologically verified methamphetamine, methaqualone and/or cannabis use. Proportional hazard and logistic regression models (adjusted for age, sex, HIV status and tobacco use) examined associations between smoked drug use and mycobacterial time to culture positivity (TTP), acid-fast bacilli sputum smear positivity and lung cavitation. People who smoked drugs (PWSD) comprised 54.8% ( = 166) of the cohort. TTP was faster for PWSD (hazard ratio 1.48, 95% CI 1.10-1.97; 0.008). Smear positivity was higher among PWSD (OR 2.28, 95% CI 1.22-4.34; = 0.011). Smoked drug use (OR 1.08, 95% CI 0.62-1.87; = 0.799) was not associated with increased cavitation. PWSD had a higher bacterial burden at diagnosis than those who do not smoke drugs. Screening for TB among PWSD in the community may facilitate earlier linkage to TB treatment and reduce community transmission.
Topics: Humans; Tuberculosis, Pulmonary; Smoke; Mycobacterium; Smoking; Tobacco Use; Sputum; HIV Infections
PubMed: 37231597
DOI: 10.5588/ijtld.22.0650 -
Forensic Toxicology Jul 2023
Topics: Humans; Methaqualone; Substance-Related Disorders
PubMed: 37169943
DOI: 10.1007/s11419-023-00665-x -
Forensic Toxicology Jan 2023The information on analytical methods for 4-quinazolinone recreational drugs, such as methaqualone, etaqualone and 2-methoxyqualone, is almost scant. In this study,...
The next addiction-causing drug class 4-quinazolinone derivatives: analyses of methaqualone analogs including recently discovered 2-methoxyqualone by different modes of mass spectrometry.
PURPOSE
The information on analytical methods for 4-quinazolinone recreational drugs, such as methaqualone, etaqualone and 2-methoxyqualone, is almost scant. In this study, product ion spectra of gas chromatography-tandem mass spectrometry (GC-MS/MS) with different collision energies were presented for these drugs. Because 2-methoxyqualone is a new recreational drug discovered in dubious tablets very recently, much more detailed data obtained by different types of mass spectrometry instruments, and quantification data of 2-methoxyqualone in the tablet together with its validation were demonstrated.
METHODS
The methods for analyses were GC-MS/MS, high-resolution ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry and liquid chromatography-tandem mass spectrometry.
RESULTS
The GC-MS/MS product ion spectra of the three compounds with different collision energies have not been reported before. They were very useful to tentatively identify unknown compounds. If a reference standard is available, the final identification and quantification can be achieved by measurements of product ion spectra and in selected reaction monitoring mode very easily by GC-MS/MS. The final identification and quantification for the new 2-methoxyqualone were performed in this way. The content of the compound was 69.8 ± 0.5% (w/w) in the tablet. Acetaminophen and caffeine coexisted in the tablet with approximate concentrations at 10 and 5%, respectively.
CONCLUSIONS
In this article, we have presented product ion spectra of methaqualone, etaqualone and 2-methoxyqualone at different collision energies by GC-MS/MS for the first time. In addition, this is the first paper to describe the details of quantification of 2-methoxyqualone in the authentic seized product.
Topics: Tandem Mass Spectrometry; Gas Chromatography-Mass Spectrometry; Methaqualone; Tablets
PubMed: 36652055
DOI: 10.1007/s11419-022-00631-z -
ACS Chemical Neuroscience Feb 2023Commonly known as "Quaaludes," methaqualone () is a sedative-hypnotic medication, with effects resembling barbiturates and other downers, that exerts its effects through... (Review)
Review
Commonly known as "Quaaludes," methaqualone () is a sedative-hypnotic medication, with effects resembling barbiturates and other downers, that exerts its effects through modulation of γ-aminobutyric acid type A receptors (GABAR). Following the discovery of the sedative and euphoric effects of methaqualone (), it was quickly adopted by pharmaceutical companies and promoted by clinicians around the world as a "safe" sleeping pill option, and for a period it was available over the counter. The popularity of methaqualone () soared worldwide, and many people began to use it recreationally for its sedative-hypnotic-like psychoactive effects. Not long after its introduction, many individuals began to misuse the drug leading to overdoses and drug dependence which brought to light methaqualone's () addictive nature. In this review, the background, synthesis, pharmacology, metabolism, and pharmacokinetics of methaqualone () will be covered along with its discovery, history, and the derivatives that are currently available around the world through manufacture in clandestine laboratories.
Topics: Humans; Methaqualone; Hypnotics and Sedatives; Substance-Related Disorders; Drug Overdose
PubMed: 36651763
DOI: 10.1021/acschemneuro.2c00697 -
Bioorganic & Medicinal Chemistry Letters Dec 2022Triazine-linked triazole compounds (4a-j) were designed, synthesized, and then examined for their anticonvulsant abilities. Compounds 4e, 4f, 4g, 4i, and 4j displayed...
Triazine-linked triazole compounds (4a-j) were designed, synthesized, and then examined for their anticonvulsant abilities. Compounds 4e, 4f, 4g, 4i, and 4j displayed significant anticonvulsant activity in both maximum electroshock seizure (MES) and pentylenetetrazole (PTZ) induced seizure during the preliminary screening. The phase II anticonvulsant activity statistics revealed that compounds 4e, 4f, 4g, 4i, and 4j demonstrated excellent activity as compared to the conventional drugs methaqualone and valproate, supporting the potential of these triazine-linked triazole analogues as novel anticonvulsant agents. To take use of the findings, computational parameters including docking analysis and drug-likeness prediction were carried out. Molecular modelling studies supported the essential pharmacophoric information that the structure activity relationship offered. The triazine-linked triazole analogues that were investigated might be viewed as helpful models for future research and derivatization.
Topics: Humans; Anticonvulsants; Molecular Docking Simulation; Triazines; Pentylenetetrazole; Seizures; Electroshock; Triazoles; Structure-Activity Relationship; Molecular Structure
PubMed: 36332884
DOI: 10.1016/j.bmcl.2022.129042 -
The Science of the Total Environment Oct 2022High detection frequency of illicit drugs in water samples urges the development of rapid detection method for wastewater-based epidemiology (WBE) study. Here, we first...
High detection frequency of illicit drugs in water samples urges the development of rapid detection method for wastewater-based epidemiology (WBE) study. Here, we first developed a fast, convenient, and cost-effective method by combining thin-film microextraction (TFME) with gas chromatography-mass spectrometry (GC-MS) for sensing illicit drugs in wastewater sample. A divinylbenzene particle-loaded membrane was prepared by dip coating on a copper mesh. The sampling conditions of three illicit drugs were optimized and the performance of the proposed method was evaluated. The limit of detection was 5.5 2.0, and 1.1 ng L for methamphetamine (MAMP), ketamine (KET), and methaqualone (MEQA), respectively, with acceptable precision (< 6.1 % for membrane to membrane reproducibility) and recovery from influent water (95 % - 111 %). Then, the proposed method was applied to study the occurrence and distribution of the target compounds in a wastewater treatment plant. The presence of methamphetamine, ketamine, and methaqualone was confirmed and their concentrations in the influent sample were 57 ± 8, 40 ± 4, and 75 ± 2 ng L, respectively. The speciation of the target compounds in different ponds was also investigated. Results showed that the content of organic matter and the pH of the sample significantly affected the binding state of the compounds. This work provides an efficient and accurate analytical protocol for WBE investigation of illicit drugs.
Topics: Illicit Drugs; Ketamine; Methamphetamine; Methaqualone; Reproducibility of Results; Wastewater; Wastewater-Based Epidemiological Monitoring; Water; Water Pollutants, Chemical
PubMed: 35753476
DOI: 10.1016/j.scitotenv.2022.156888