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.

DARK Classics in Chemical Neuroscience: Methaqualone.

Commonly known as "Quaaludes," methaqualone (1) 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 (GABAAR). Following the discovery of the sedative and euphoric effects of methaqualone (1), 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 (1) 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 (1) addictive nature. In this review, the background, synthesis, pharmacology, metabolism, and pharmacokinetics of methaqualone (1) will be covered along with its discovery, history, and the derivatives that are currently available around the world through manufacture in clandestine laboratories.

Review of the experiences of users of methaqualone and methaqualone derivatives. An analysis of online forums.

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.

Rapid detection and speciation of illicit drugs via a thin-film microextraction approach for wastewater-based epidemiology study.

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-1 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-1, 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.

Mandrax use, sexual risk, and opportunities for pre-exposure prophylaxis among out-of-school adolescent girls and young women in Cape Town, South Africa.

BACKGROUND: In South Africa (SA), adolescent girls and young women (AGYW) aged 15 - 24 years account for nearly 25% of all new HIV infections in the country. The intersection of substance use and sexual risk continues to drive the HIV epidemic among AGYW. For example, methaqualone, also known as Mandrax, has sedative effects that may affect women's ability to negotiate condom use during sex, refuse sex without a condom, or consent to sex, thereby increasing their risk for HIV. Consequently, it is critical to understand how Mandrax use affects HIV risk among AGYW and to assess awareness of and willingness to use biomedical HIV prevention methods, such as pre-exposure prophylaxis (PrEP), among AGYW who use Mandrax. OBJECTIVES: To examine the role of Mandrax use in sexual behaviours and investigate the extent to which AGYW who use Mandrax are aware of and willing to initiate PrEP. METHODS: Data for this report were derived from baseline and 6-month follow-up data provided by 500 AGYW participating in a cluster-randomised trial assessing the efficacy of a young woman-focused intervention to reduce substance use and HIV risk. AGYW who self-identified as black African or coloured, reported using substances, reported condomless sex in the past 3 months, and had discontinued school early were recruited from 24 community clusters across Cape Town, SA. Following consent/assent, participants provided biological specimens to test for recent drug use (including Mandrax) and completed the self-report questionnaire. RESULTS: Logistic regression analysis revealed that the AGYW who had a positive test result for Mandrax use were less likely to use a condom with their main partner (p=0.01), and almost three times more likely to use alcohol and/or other drugs before or during their last act of sexual intercourse (p<0.001), compared with the AGYW who had a negative Mandrax test result. Mandrax use was not significantly related to PrEP awareness (p>0.10) or willingness to use PrEP (p>0.10), but 70% of AGYW who used Mandrax were willing to initiate PrEP. CONCLUSION: The study findings highlight how Mandrax use may contribute to HIV risk among SA AGYW. Key decision-makers should consider incorporating substance use prevention efforts into existing HIV reduction programmes and equip youth-friendly clinics with the resources to identify AGYW who use Mandrax and offer them PrEP.

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.

From Methaqualone and Beyond: Structure-Activity Relationship of 6-, 7-, and 8-Substituted 2,3-Diphenyl-quinazolin-4(3H)-ones and in Silico Prediction of Putative Binding Modes of Quinazolin-4(3H)-ones as Positive Allosteric Modulators of GABAA Receptors.

Methaqualone (2-methyl-3-(o-tolyl)-quinazolin-4(3H)-one, MTQ) is a moderately potent positive allosteric modulator (PAM) of GABAA receptors (GABAARs). In a previous structure-activity relationship (SAR) study probing the importance of 2- and 3-substituents in the quinazolin-4(3H)-one scaffold, several potent GABAAR PAMs were identified, including 2,3-diphenylquinazolin-4(3H)-one (PPQ) and 3-(2-chlorophenyl)-2-phenylquinazolin-4(3H)-one (Cl-PPQ). Here, PPQ was applied as lead in a SAR study of 6-, 7-, and 8-substituents in the quinazolin-4(3H)-one by synthesis and functional characterization of 36 PPQ analogs at various GABAAR subtypes. While none of the new analogs were significantly more potent than PPQ or displayed pronounced subtype selectivity across the GABAARs tested, several interesting SAR observations were extracted from the study. In an in silico study, the putative binding modes of MTQ, PPQ, and Cl-PPQ in the transmembrane ß2(+)/α1(-) interface of the α1ß2γ2S GABAAR were predicted. Several plausible binding modes were identified for the three PAMs, and rationalization of the molecular basis for their different modulatory potencies was attempted.

Functional properties and mechanism of action of PPTQ, an allosteric agonist and low nanomolar positive allosteric modulator at GABAA receptors.

The former sedative-hypnotic and recreational drug methaqualone (Quaalude) is a moderately potent, non-selective positive allosteric modulator (PAM) at GABAA receptors (GABAARs) (Hammer et al., 2015). In the present study, we have identified a novel methaqualone analog, 2-phenyl-3-(p-tolyl)quinazolin-4(3H)-one (PPTQ), in a screening of 67 analogs at five αß2γ2S GABAAR subtypes and delineated its functional properties and mechanism of action at wild-type and mutant GABAARs expressed in Xenopus laevis oocytes by two-electrode voltage clamp electrophysiology. PPTQ was found to be an allosteric agonist and a PAM (ago-PAM) at human α1ß2γ2S and α4ß2δ GABAARs, exhibiting intrinsic activity at micromolar concentrations and potentiating the GABA-evoked signaling through the receptors at concentrations down to the low-nanomolar range. Whereas PPTQ exclusively increased the potency of GABA at the α1ß2γ2S receptor, it increased both GABA potency and efficacy at α4ß2δ and displayed modest potency-based preference for α4ß2δ over α1ß2γ2S. In elaborate mutagenesis and competition experiments PPTQ was found to act through the same or an overlapping site as etomidate in the transmembrane ß(+)/α(-) subunit interfaces, whereas it did not seem to target the other three transmembrane interfaces in the GABAAR. Finally, the PPTQ site was shown to be allosterically linked with sites targeted by neurosteroids and barbiturates but not with the high-affinity benzodiazepine site in the α1ß2γ2S receptor. In conclusion, the development of a highly potent, bioavailable GABAAR ago-PAM by subtle modifications to the methaqualone scaffold demonstrates that derivatization of this infamous drug from the past can lead to modulators with distinct functional characteristics at the receptors.

Genitourinary syndrome of menopause in five Asian countries: results from the Pan-Asian REVIVE survey.

OBJECTIVES: The Pan-Asian REVIVE survey aimed to examine women's experiences with genitourinary syndrome of menopause (GSM) and their interactions with health-care professionals (HCPs). METHODS: Self-completed surveys were administered face-to-face to 5992 women (aged 45-75 years) in Indonesia, Malaysia, Singapore, Taiwan, and Thailand. RESULTS: Of 638 postmenopausal women with GSM symptoms, only 35% were aware of the GSM condition, most of whom first heard of GSM through their physician (32%). The most common symptoms were vaginal dryness (57%) and irritation (43%). GSM had the greatest impact on sexual enjoyment (65%) and intimacy (61%). Only 25% had discussed their GSM symptoms with a HCP, and such discussions were mostly patient-initiated (64%) rather than HCP-initiated (24%). Only 21% had been clinically diagnosed with GSM and only 24% had ever used treatment for their symptoms. Three-quarters of those who had used treatment for GSM had discussed their symptoms with a HCP compared to only 9% of those who were treatment-naïve. CONCLUSION: GSM is underdiagnosed and undertreated in Asia. As discussion of GSM with HCPs appears to be a factor influencing women's awareness and treatment status, a more active role by HCPs to facilitate early discussions on GSM and its treatment options is needed.

Synthesis and Anticonvulsant Activity of N-(Substituted)-1-methyl-2,4-dioxo-1,2-dihydroquinazoline-3(4H)-carboxamides.

A series of new N-(substituted)-1-methyl-2,4-dioxo-1,2-dihydroquinazoline-3(4H)-carboxamides were designed, synthesized, and evaluated for their anticonvulsant activity. Most of the synthesized compounds exhibited potent anticonvulsant activities in the maximal electroshock (MES) and pentylenetetrazol (PTZ) test. The most promising compound 4c showed significant anticonvulsant activity with a protective index value of 3.58. The compounds 4a-c were also found to have encouraging anticonvulsant activity in the MES and PTZ screen when compared with the standard drugs, valproate and methaqualone. The same compounds were found to exhibit advanced anticonvulsant activity as well as lower neurotoxicity than the reference drugs.

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.

A Multifaceted GABAA Receptor Modulator: Functional Properties and Mechanism of Action of the Sedative-Hypnotic and Recreational Drug Methaqualone (Quaalude).

In the present study, we have elucidated the functional characteristics and mechanism of action of methaqualone (2-methyl-3-o-tolyl-4(3H)-quinazolinone, Quaalude), an infamous sedative-hypnotic and recreational drug from the 1960s-1970s. Methaqualone was demonstrated to be a positive allosteric modulator at human α1,2,3,5ß2,3γ2S GABAA receptors (GABAARs) expressed in Xenopus oocytes, whereas it displayed highly diverse functionalities at the α4,6ß1,2,3δ GABAAR subtypes, ranging from inactivity (α4ß1δ), through negative (α6ß1δ) or positive allosteric modulation (α4ß2δ, α6ß2,3δ), to superagonism (α4ß3δ). Methaqualone did not interact with the benzodiazepine, barbiturate, or neurosteroid binding sites in the GABAAR. Instead, the compound is proposed to act through the transmembrane ß((+))/α((-)) subunit interface of the receptor, possibly targeting a site overlapping with that of the general anesthetic etomidate. The negligible activities displayed by methaqualone at numerous neurotransmitter receptors and transporters in an elaborate screening for additional putative central nervous system (CNS) targets suggest that it is a selective GABAAR modulator. The mode of action of methaqualone was further investigated in multichannel recordings from primary frontal cortex networks, where the overall activity changes induced by the compound at 1-100 µM concentrations were quite similar to those mediated by other CNS depressants. Finally, the free methaqualone concentrations in the mouse brain arising from doses producing significant in vivo effects in assays for locomotion and anticonvulsant activity correlated fairly well with its potencies as a modulator at the recombinant GABAARs. Hence, we propose that the multifaceted functional properties exhibited by methaqualone at GABAARs give rise to its effects as a therapeutic and recreational drug.

The 14-day repeated dose liver micronucleus test with methapyrilene hydrochloride using young adult rats.

The repeated dose liver micronucleus (RDLMN) assay using young adult rats has the potential to detect genotoxic hepatocarcinogens that can be integrated into a general toxicity study. The assay methods were thoroughly validated by 19 Japanese facilities. Methapyrilene hydrochloride (MP), known to be a non-genotoxic hepatocarcinogen, was examined in the present study. MP was dosed orally at 10, 30 and 100mg/kg/day to 6-week-old male Crl:CD (SD) rats daily for 14 days. Treatment with MP resulted in an increase in micronucleated hepatocytes (MNHEPs) with a dosage of only 100mg/kg/day. At this dose level, cytotoxicity followed by regenerative cell growth was noted in the liver. These findings suggest that MP may induce clastogenic effects indirectly on the liver or hepatotoxicity of MP followed by regeneration may cause increase in spontaneous incidence of MNHEPs.

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.

Mitochondrial triglyceride transfer protein inhibition: new achievements in the treatment of dyslipidemias.

Current lipid-lowering drugs are often unable to achieve low density lipoprotein cholesterol (LDL-C) goals. Moreover, despite LDL-C lowering mostly by statins, a considerable residual vascular risk remains. This is partly associated with atherogenic dyslipidemia where apolipoprotein (apo) B-containing lipoproteins predominate. Mitochondrial Triglyceride (TG) transfer protein (MTP) is a key enzyme for apoB-containing lipoprotein assembly and secretion. This is mostly attributed to its capacity to transfer lipid components (TGs, cholesterol esters and phospholipids) to the endoplasmic reticulum lumen, where these lipoproteins are assembled. Several agents were developed to inhibit MTP wherever it is expressed, namely the liver and/or the intestine. Liver-specific MTP inhibitors reduce secretion of very low density lipoproteins (VLDL) mostly containing apoB100, while the intestine-specific ones reduce secretion of chylomicrons containing apoB48. These drugs can significantly reduce total cholesterol, LDL-C, TGs, VLDL cholesterol, as well as apoB levels in vivo. They may also exert anti-atherosclerotic and insulin-sensitizing effects. Limited clinical data suggest that these compounds can also improve the serum lipid profile in patients with homozygous familial hypercholesterolemia (HoFH). The accumulation of unsecreted fat in the liver and intestinal lumen is associated with elevation of aminotransferases and steatorrhea. Liver steatosis can be avoided by the use of intestine-specific MTP inhibitors, while steatorrhea by low-fat diet. Future indications for these developing drugs may include dyslipidemia associated with insulin resistant states, familial combined hyperlipidemia and HoFH. Future clinical trials are warranted to assess the efficacy and safety of MTP inhibitors in various clinical states.

Synthesis and anticonvulsant evaluation of some new 2,3,8-trisubstituted-4(3H)-quinazoline derivatives.

A new series of 2,3,8-trisubstituted-4(3H)-quinazoline derivatives were synthesized, evaluated for their anticonvulsant activity against electrically (MES) and chemically (PTZ, picrotoxin and Strychnine) induced seizures and compared with the standard drugs methaqualone and sodium valproate. Compounds 3, 17 and 22 proved to be the most potent compounds of this series with relatively low neurotoxicity and low toxicity in the median lethal dose test as compared with the reference drugs. The obtained results showed that the most active compounds could be useful as a template for future design, modification and investigation to produce more active analogs.

Blockbusters and controlled substances: Miltown, Quaalude, and consumer demand for drugs in postwar America.

In 1955 Carter Products launched its new tranquilizer Miltown with a huge marketing blitz; Miltown soon became one of America's earliest "blockbuster" celebrity drugs. In 1981, federal agents shut down a network of "stress clinics" and arrested the owners, medical staff, and other personnel for illegally trafficking in the sedative Quaalude; Quaalude soon became a "Schedule I Controlled Substance." Both of these stories are familiar, indeed archetypal, moments from America's postwar medical system. As the Miltown example reminds us, this fundamentally commercial system was built on the creation and courting of consumer demand for medical products and services, particularly drugs. As the Quaalude example shows, however, this system also incorporated tools for reining in excessive consumer demand. Together the two episodes affirm an enduring irony of the American medical system: the need for regulatory campaigns to tame lively markets for drugs that had become popular, in part, because of advertising campaigns. This article uses the Miltown and Quaalude sagas to explore the issue of consumer demand for prescription medicines, arguing that efforts to stoke or quash that demand have shaped (and linked) America's medical system and its drug control regimes.