Analytically diagnosed intoxication by 2-methoxphenidine and flubromazepam mimicking an ischemic cerebral disease

Valli, A.; Lonati, Davide; Locatelli, Carlo; Buscaglia, Eleonora; Tuccio, Marcello Di; Papa, P.

doi:10.1080/15563650.2017.1286016

Cited by 18 publications

(11 citation statements)

References 4 publications

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“…Though flubromazepam has been marketed as a new psychoactive substance (NPS) for about 4 years (first EMCDDA report in 2013), there were only few reports on poisonings. Recently, a non‐fatal case of a combined 2‐methoxphenidine and flubromazepam overdose has been published showing half the serum level of flubromazepam of the presented case (412 ng/mL). In a study with drugged drivers, findings of flubromazepam were described among which the majority consumed other drugs as well.…”

Section: Discussionmentioning

confidence: 80%

Mixed intoxication by the synthetic opioid U‐47700 and the benzodiazepine flubromazepam with lethal outcome: Pharmacokinetic data

Koch

Auwärter

Hermanns-Clausen

et al. 2018

Drug Testing and Analysis

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Novel synthetic opioids and benzodiazepines are an emerging trend on the narcotic drugs market. We present a lethal case of U-47700 and flubromazepam poisoning. A 24-year-old man suffered apnoea after the consumption of the synthetic opioid U-47700 in combination with the benzodiazepine flubromazepam. After reanimation and hospital admission, hypoxic cerebral damage and severe brain oedema were stated. Six days after admission, mechanical ventilation was discontinued, and the patient died. Seven blood serum samples and one urine sample collected during the hospitalisation were analysed by liquid chromatography-tandem mass spectrometry. In the sample collected 42 minutes after admission, the concentrations of U-47700 and flubromazepam were 370 and 830 ng/mL, respectively. Three days later, the concentrations of U-47700 and flubromazepam dropped to 4.2 and 280 ng/mL, respectively. The resulting concentration-time-curves allowed calculating a U-47700 elimination half-life of approximately six hours and confirmed the previously reported flubromazepam elimination half-life of around 100 hours. In the presented case, intoxication by the synthetic opioid U-47700 with a contribution of flubromazepam can be assumed as the cause of death. The concentration-time curves allow an estimation of the clinical course of similar cases. Flubromazepam may lead to prolonged central-nervous depressant effects.

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Section: Discussionmentioning

confidence: 80%

Mixed intoxication by the synthetic opioid U‐47700 and the benzodiazepine flubromazepam with lethal outcome: Pharmacokinetic data

Koch

Auwärter

Hermanns-Clausen

et al. 2018

Drug Testing and Analysis

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“…Benzodiazepines were misused long before emerging as NPS and a recent report highlighted the increasing illicit availability and misuse of a clinically used benzodiazepine, alprazolam, often purchased from the dark web . The NPS benzodiazepines (referred to in this work as NPS‐benzodiazepines) have already been reported in a number of overdose cases, driving under the influence of drugs (DUID) cases, and hospital admissions . The lack of control over and safety of these NPS‐benzodiazepines is a prevalent issue and it is predicted that it will become an even more worrying trend as their misuse continues to spread.…”

Section: Introductionmentioning

confidence: 99%

“…4 The NPS benzodiazepines (referred to in this work as NPS-benzodiazepines) have already been reported in a number of overdose cases, driving under the influence of drugs (DUID) cases, and hospital admissions. [5][6][7][8] The lack of control over and safety of these NPS-benzodiazepines is a prevalent issue and it is predicted that it will become an even more worrying trend as their misuse continues to spread. A number of these compounds were originally prescription drugs such as phenazepam (Russia) as well as etizolam and flutazolam (Japan).…”

Section: Introductionmentioning

confidence: 99%

Experimental versus theoretical log D_7.4, pK_a and plasma protein binding values for benzodiazepines appearing as new psychoactive substances

Manchester

Maskell

Waters

2018

Drug Testing and Analysis

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The misuse of benzodiazepines as new psychoactive substances is an increasing problem around the world. Basic physicochemical and pharmacokinetic data is required on these substances to interpret and predict their effects upon humans. Experimental log D , pK and plasma protein binding values were determined for 11 benzodiazepines that have recently appeared as new psychoactive substances (3-hydroxyphenazepam, 4'-chlorodiazepam, desalkylflurazepam, deschloroetizolam, diclazepam, etizolam, flubromazepam, flubromazolam, meclonazepam, phenazepam, and pyrazolam) and compared with values generated by various software packages (ACD/I-lab, MarvinSketch, ADMET Predictor and PreADMET). ACD/I-LAB returned the most accurate values for log D and plasma protein binding while ADMET Predictor returned the most accurate values for pK . Large variations in predictive errors were observed between compounds. Experimental values are currently preferable and desirable as they may aid with the future 'training' of predictive models for these new psychoactive substances.

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“…Amnesia, loss of control, palpitations, hypertension tachycardia, and convulsions were reported . Moreover, rhabdomyolysis, acute kidney injury, and ischemic cerebral disease were observed with methoxphenidine .…”

Section: Resultsmentioning

confidence: 99%

“…The clinical cases reported in the literature concerned mainly methoxphenidine and diphenidine intoxications, with fatal outcome (death) related to methoxphenidine and diphenidine abuse in six cases [13][14][15][16][17][18][19][20]. These patients were always polysubstance consumers with associated intake of multiple NPS (synthetic cathinones, synthetic cannabinoids), with the exception of three cases of methoxphenidine intoxication, with high femoral blood concentrations of the drug (case 1: 24 mg/L, case 2: 2 mg/L, case 3: 1.36 mg/L) [17].…”

Section: R E S U L T Smentioning

confidence: 99%

Ephenidine, diphenidine, and methoxphenidine complications reported to the French Addictovigilance Network

Eiden¹,

Leone-Burgos²,

Serre³

et al. 2018

Fundamemntal Clinical Pharma

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Ephenidine, diphenidine, and methoxphenidine belong to the family of diarylethylamines that are psychoactive substances derived from lefetamine (N, N-di-methyl-1,2-diphenylethylamine, also called L-SPA). These dissociative anesthetic compounds act as potent and selective N-methyl-d-aspartate receptor antagonists and were recently classified as narcotic drugs in France. The available data suggest a significant risk of psychic and somatic complications. To obtain more information, this retrospective study analyzed all spontaneous notifications of serious cases of ephenidine, diphenidine, and methoxphenidine abuse collected by the French Addictovigilance Network from 2012 to 2016 and classified them as proven, probable, and possible. For each case, age, sex, concomitantly ingested substances, pattern of abuse of psychoactive drugs, and related complications (scored using the poisoning severity score) were collected. Eighteen cases were identified (one in 2013, five in 2015, and 12 in 2016) in 16 men (median age: 31.5 years [IQR 25-75% 27-34]). Ephenidine, diphenidine, and methoxphenidine were involved in four, seven, and 11 cases, respectively. No case was considered proven, 16 cases were considered possible, and two probable due to polysubstance abuse (co-ingestion of other new psychoactive substances). The reported clinical complications were minor in five cases, moderate in six cases, and serious in four cases, and included psychiatric, neurologic, and cardiovascular problems. This analysis indicates that the number of reported cases progressively increased from 2012 to 2016 and mainly concerned methoxphenidine. The addictive potential of these substances seems highly probable; but further investigations are needed to limit their harmful effects.

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Analytically diagnosed intoxication by 2-methoxphenidine and flubromazepam mimicking an ischemic cerebral disease

Cited by 18 publications

References 4 publications

Mixed intoxication by the synthetic opioid U‐47700 and the benzodiazepine flubromazepam with lethal outcome: Pharmacokinetic data

Mixed intoxication by the synthetic opioid U‐47700 and the benzodiazepine flubromazepam with lethal outcome: Pharmacokinetic data

Experimental versus theoretical log D_7.4, pK_a and plasma protein binding values for benzodiazepines appearing as new psychoactive substances

Ephenidine, diphenidine, and methoxphenidine complications reported to the French Addictovigilance Network

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Analytically diagnosed intoxication by 2-methoxphenidine and flubromazepam mimicking an ischemic cerebral disease

Cited by 18 publications

References 4 publications

Mixed intoxication by the synthetic opioid U‐47700 and the benzodiazepine flubromazepam with lethal outcome: Pharmacokinetic data

Mixed intoxication by the synthetic opioid U‐47700 and the benzodiazepine flubromazepam with lethal outcome: Pharmacokinetic data

Experimental versus theoretical log D7.4, pKa and plasma protein binding values for benzodiazepines appearing as new psychoactive substances

Ephenidine, diphenidine, and methoxphenidine complications reported to the French Addictovigilance Network

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Experimental versus theoretical log D_7.4, pK_a and plasma protein binding values for benzodiazepines appearing as new psychoactive substances