‘New/Designer Benzodiazepines’: An Analysis of the Literature and Psychonauts’ Trip Reports

Author(s): Laura Orsolini*, John M. Corkery, Stefania Chiappini, Amira Guirguis, Alessandro Vento, Domenico De Berardis, Duccio Papanti, Fabrizio Schifano

Journal Name: Current Neuropharmacology

Volume 18 , Issue 9 , 2020

Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Background: NPS belonging to the benzodiazepine (BZD) class, e.g., ‘legal/designer BZDs’/‘research chemicals’, have recently emerged in the drug (mainly online/virtual) market.

Objective: While certain NPS belonging to the BZD class possess pharmacological profiles similar to controlled pharmaceutical BZDs, clinical and pharmacological profiles of current emerging BZDs are still not well-described. Therefore, there is a need to increase clinicians’/public health knowledge/awareness, to incentive harm reduction strategies.

Method: A comprehensive overview was carried out by using the EMCDDA/EDND database regularly monitored by our research team, by specifically looking at the ‘new BZDs’ so far notified. Furthermore, given the limitation of peer-reviewed data published so far, a nonparticipant multilingual qualitative netnographic study was conducted to obtain further clinical/pharmacological/ toxicological data, including psychonauts’ online trip reports.

Results: First designer BZDs appeared as NPS around 2007. So far, 29 designer BZDs have been notified to the EMCDDA, being some of them extremely powerful, also at lower dosages. They are sold as tablets/powder/pellets/capsules/blotters/liquids, at very affordable prices, and variably administered. Some are also sold on the illicit drugmarket as counterfeit forms of traditional BZDs or as either adulterants or diluents in heroin or other synthetic opioids/cannabinoids. Nowadays, there is no guarantee of the quality of designer BZDs composition/purification and, hence, most NPS consumers may be inadvertently exposed to unsafe and harmful compounds.

Conclusion: Given the limited information on their pharmacology/toxicity, variations in dosage, onset of effects, combination of substances, potency, and general patient or individual variability, the concomitant use of these substances with other drugs entails several and unpredictable risks.

Keywords: New benzodiazepines, NPS, novel psychoactive substances, benzodiazepines, designer benzodiazepines, synthetic benzodiazepines.

Stahl, S. Stahl’s Essential Psychopharmacology: Neuroscientific Basis & Practical Applications, 4th ed; Cambridge University Press, 2013.
Tan, K.R.; Rudolph, U.; Lüscher, C. Hooked on benzodiazepines: GABAA receptor subtypes and addiction. Trends Neurosci., 2011, 34(4), 188-197.
[http://dx.doi.org/10.1016/j.tins.2011.01.004] [PMID: 21353710]
Bellantuono, C.; Balestrieri, M. Psicofarmacoterapia; Il Pensiero Scientifico Editore: Roma, 2014.
Greenblatt, H.K.; Greenblatt, D.J. Designer Benzodiazepines: A Review of Published Data and Public Health Significance. Clin. Pharmacol. Drug Dev., 2019, 8(3), 266-269.
[http://dx.doi.org/10.1002/cpdd.667] [PMID: 30730611]
Fukasawa, T.; Suzuki, A.; Otani, K. Effects of genetic polymorphism of cytochrome P450 enzymes on the pharmacokinetics of benzodiazepines. J. Clin. Pharm. Ther., 2007, 32(4), 333-341.
[http://dx.doi.org/10.1111/j.1365-2710.2007.00829.x] [PMID: 17635335]
Dear, J.W.; Bateman, D.N. Benzodiazepines. Medicine (Baltimore), 2016, 44, 145.
Moosmann, B.; Bisel, P.; Auwärter, V. Characterization of the designer benzodiazepine diclazepam and preliminary data on its metabolism and pharmacokinetics. Drug Test. Anal., 2014, 6(7-8), 757-763.
[http://dx.doi.org/10.1002/dta.1628] [PMID: 24604775]
Moosmann, B.; King, L.A.; Auwärter, V. Designer benzodiazepines: A new challenge. World Psychiatry, 2015, 14(2), 248.
[http://dx.doi.org/10.1002/wps.20236] [PMID: 26043347]
United Nations Office on Drugs and Crimes (UNODC). Global SMART Update Volume 18, Non-medical use of benzodiazepines: a growing threat to public health? (2019). Https://www.unodc.org/documents/scientific/Global_SMART_Update_2017_Vol_18.pdf (Accessed Oct 6, 2019)
European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). European Drug Report 2019: Trends and Developments (2019). Publications Office of the European Union, Luxembourg. . Http://www.emcdda.europa.eu/system/files/publications/11364/20191724_TDAT19001ENN_PDF.pdf (Accessed Oct 6, 2019)
European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) The misuse of benzodiazepines among high-risk opioid users in Europe (2015). Publications Office of the European Union, Luxembourg.. Http://www.emcdda.europa.eu/system/files/publications/2733/Misuse%20of%20benzos_POD2015.pdf (Accessed Oct 6, 2019).
World Health Organization (WHO). Critical Revie Report: flualprazolam. Expert Committee on Drug Dependence Forty-Second Meeting. Geneva, 21-25 October 2019. . Https://www.who.int/medicines/access/controlled substances/Final_Flualprazolam.pdf?ua=1 (Accessed Oct 15, 2019)
Darbinian, T.M.; Papin, A.A.; Vagina, M.A.; Petrov, O.V. [Comparative study of the sedative and tranquilizing effect of phenazepama and seduxen and their influence on human evoked brain potentials]. Farmakol. Toksikol., 1979, 42(6), 592-597.
[PMID: 40816]
Zakusov, V.V. New psychotropic phenazepam preparation. Pharm Chem J (Ussr), 1979, 13, 1094-1097.
Sozinov, V.A.; Rudenko, O.P.; Zinkovskii, V.G.; Golovenko, N.Y.; Lisitsyna, A.L. Synthesis of hydrogenated analog of phenazepam. Pharm Chem J (Ussr), 1984, 18, 721-725.
Rafstedt, K.; Hultén, P.; Brusiu, K. Phenazepam as a drug of abuse high frequency of prolonged symptoms. Clin. Toxicol. (Phila.), 2009, 47, 436-510.
Johnson, W. Phenazepam in Wisconsin drivers. Annual meeting of the Society of Forensic Toxicologist, 2010.Richmond, Virginia, USA
Baselt, R.C. Disposition of toxic drugs and chemicals in man, 5th ed; Biomedical Publications: Seal Beach, California, 2011, pp. 1320-1321.
Maskell, P.D.; Paoli, G.D.; Seetohul, L.N.; Pounder, D.J. Phenazepam is currently being misused in the UK. BMJ, 2011, 343, d4207.
[http://dx.doi.org/10.1136/bmj.d4207] [PMID: 21729984]
European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). Country Overview: Moldova (2009). Publications Office of the European Union, Luxembourg.. Http://www.emcdda.europa.eu/publications/country-overviews/md (Accessed Oct 6, 2019)
European Monitoring Centre for Drugs and Drug Addiction. European Legal Database on Drugs (2011). Publications Office of the European Union, Luxembourg. . http://www.emcdda.europa.eu/eldd (Accessed Oct 6, 2019)
Drugs-Forum. Legal status of phenazepam around the world (2019). Https://drugs-forum.com/forum/showwiki.php?title1 (Accessed Oct 6, 2019)
Advisory Council on the Misuse of Drugs (ACMD). Phenazepam advice. Letter from chair of ACMD to Minister of State for Crime Prevention and ASB reduction (2011). . Http://www.homeoffice.gov.uk/publications/agencies-public bodies/acmd1/acmd- (Accessed Oct 6, 2019)
Home Office (2011). Import ban of new 'legal high' phenazepam introduced. Home Office, London. . Https://www.gov.uk/government/news/import-ban-of-new-legal- (Accessed Oct 6, 2019)
Home Office (2012). Circular: a change to the Misuse of Drugs Act 1971. Home Office circular 014/2012 A Change to the Misuse of Drugs Act 1971: control of pipradrol-related compounds and phenazepam. Https://www.gov.uk/government/publications/a change-to-the-misuse-of-drugs-act-1971- (Accessed Oct 6, 2019)
Lillsunde, P.; Gunnar, T. Drugs and driving: the Finnish perspective. Bull Narc, , 2005, 57(1 and 2 ), 213-219.
Gjerde, H.; Christophersen, A.S.; Normann, P.T.; Mørland, J. Toxicological investigations of drivers killed in road traffic accidents in Norway during 2006-2008. Forensic Sci. Int., 2011, 212(1-3), 102-109.
[http://dx.doi.org/10.1016/j.forsciint.2011.05.021] [PMID: 21665393]
Kriikku, P.; Wilhelm, L.; Rintatalo, J.; Hurme, J.; Kramer, J.; Ojanperä, I. Phenazepam abuse in Finland: findings from apprehended drivers, post-mortem cases and police confiscations. Forensic Sci. Int., 2012, 220(1-3), 111-117.
[http://dx.doi.org/10.1016/j.forsciint.2012.02.006] [PMID: 22391477]
Zherdev, V.P.; Caccia, S.; Garattini, S.; Ekonomov, A.L. Species differences in phenazepam kinetics and metabolism. Eur. J. Drug Metab. Pharmacokinet., 1982, 7(3), 191-196.
[http://dx.doi.org/10.1007/BF03189565] [PMID: 7173273]
Mykkanen, S.; Gunnar, T.; Ariniem, K.; Lillsunde, P.; Krasnova, R. Quantitation of phenazepam in blood by GC-eMS in positive drug-driving cases in Finland. The annual meeting of the Society of Forensic Toxicologists,, 2004.Washington DC, USA .
Mrozkowska, J.; Vinge, E.; Boma, C. Missbruk av fenazepam - ny företeelse i Sverige Abuse of phenazepam - new phenomenon in Sweden. Larkartidningen., 2009, 106, 516-517.
Bailey, K.; Richards-Waugh, L.; Clay, D.; Gebhardt, M.; Mahmoud, H.; Kraner, J.C. Fatality involving the ingestion of phenazepam and poppy seed tea. J. Anal. Toxicol., 2010, 34(8), 527-532.
[http://dx.doi.org/10.1093/jat/34.8.527] [PMID: 21819799]
Volgram, J.; Khdasevitsch, T. A fatal case due to phenazepam. Bull Int Assoc Forensic Toxicologists., 1999, 29(4), 13.
Boone, C. Exotic drug leaves Cherokee teen dead, 3 friends hospitalized. (2010). Cherokee County News (20 September 2010).. Http://www.ajc.com/news/news/local/exotic-drug-leaves-cherokee-teen-dead-3-friends- ho/nQkNR/ (Accessed Oct 6, 2019)
Corkery, J.M.; Schifano, F.; Ghodse, H. UK fatality involving phenazepam. BMJ, 2011, 343, d4207.
Yip, T.; Martin, A.; Scott, K.S. Phenazepam abuse in the West of Scotland 2009-2011. In: UKIAFT Annual Meeting, , Aberdeen, Scotland. . 2011.
Corkery, J.M.; Schifano, F.; Ghodse, A.H. Phenazepam abuse in the UK: an emerging problem causing serious adverse health problems, including death. Hum. Psychopharmacol., 2012, 27(3), 254-261.
[http://dx.doi.org/10.1002/hup.2222] [PMID: 22407587]
Corkery, J.; Claridge, H.; Loi, B.; Goodair, C.; Schifano, F. Drug related deaths in the UK: January-December 2012. Annual Report 2013, National Programme on Substance Abuse Deaths (NPSAD).(2013). St George's, University of London.. Http://www.sgul.ac.uk/research/population-health/our projects/national-programme-on-substance-abuse-deaths (Accessed Oct 6, 2019)
Dargan, P.I.; Davies, S.; Puchnarewicz, M.; Johnston, A.; Wood, D.M. First reported case in the UK of acute prolonged neuropsychiatric toxicity associated with analytically confirmed recreational use of phenazepam. Eur. J. Clin. Pharmacol., 2013, 69(3), 361-363.
[http://dx.doi.org/10.1007/s00228-012-1361-z] [PMID: 22843017]
National Records of Scotland. (2014). Drug-related deaths in Scotland in 2013. . http://www.gro-scotland.gov.uk/statistics-and data/statistics/statistics-by-theme/vital-events/deaths/drug-related-deaths-in-scotland/2013 (Accessed Oct 6, 2019)
Barnsdale, L.; Gordon, R.; McAuley, A. The National Drug- Related Deaths Database (Scotland) Report: Analysis of deaths occurringin 2013. (2015). Http://www.isdscotland.org/Health-Topics/Drugs-and-Alcohol-Misuse/Publications/2015- 04-28/2015-04-28-NDRDD-Report.pdf (Accessed Oct 6, 2019)
McAuley, A.; Hecht, G.; Barnsdale, L.; Thomson, C.S.; Graham, L.; Priyadarshi, S.; Robertson, J.R. Mortality related to novel psychoactive substances in Scotland, 2012: an exploratory study. Int. J. Drug Policy, 2015, 26(5), 461-467.
[http://dx.doi.org/10.1016/j.drugpo.2014.10.010] [PMID: 25477285]
Shearer, K.; Bryce, C.; Parsons, M.; Torrance, H. Phenazepam: A review of medico-legal deaths in South Scotland between 2010 and 2014. Forensic Sci. Int., 2015, 254, 197-204.
[http://dx.doi.org/10.1016/j.forsciint.2015.07.033] [PMID: 26254627]
Luzhnikov, E.A.; Sukhodolova, G.N.; Ostapenko, Y.N.; Kovalenko, L.A.; Dolginov, D.M. Clinical toxicometry of acute poisonings by fenazepam in older children. Clin. Toxicol. (Phila.), 2010, 48, 282.
Aleksandrovskiy, Y.A.; Kraznov, V.N.; Neznanov, L.V.; Romasenko, L.V. Efficacy of etifoxine versus phenazepam in treatment of patients with adjustment disorders (open-label randomized controlled trial). Russian J Psychiatry., 2010, 1, 74-78.
Ali, A.; Jerry, J.M.; Khawam, E.A. Delirium induced by a new synthetic legal intoxicating drug: phenazepam. Psychosomatics, 2015, 56(4), 414-418.
[http://dx.doi.org/10.1016/j.psym.2014.05.018] [PMID: 25555294]
Bogatskiĭ, A.V.; Golovenko, N.Ia.; Zin’kovskiĭ, V.G. [Intrahepatic circulation of 14C-phenazepam and its metabolites in albino rats]. Biull. Eksp. Biol. Med., 1980, 89(1), 27-29.
[http://dx.doi.org/10.1007/BF00835494] [PMID: 7378565]
Kopanitsa, M.V.; Zbarska, S.M.; Boychuk, Y.; Krishtal, O.A. Modulation of GABA-activated currents by phenazepam and its metabolites in isolated rat Purkinje neurons. Neurophysiology, 2000, 32(3), 192.
Dorofeyeva, O.A.; Syunyakov, S.A.; Neznamov, G.G. Comparative analysis of different phenazepam formulations.Regional congress of the World Psychiatric Association; Petersburg, 2010, p. 83.
Maskell, P.D.; De Paoli, G.; Nitin Seetohul, L.; Pounder, D.J. Phenazepam: the drug that came in from the cold. J. Forensic Leg. Med., 2012, 19(3), 122-125.
[http://dx.doi.org/10.1016/j.jflm.2011.12.014] [PMID: 22390996]
Bluelight.org . Https://www.bluelight.org (Accessed Oct 6, 2019).
Erowid.org . Https://www.erowid.org (Accessed Oct 6, 2019)
Golovenko, N.Y.; Kravchenko, I.A.; Zin’kovskii, V.G.; Andronati, S.A.; Aleksandrova, A.I.; Ovcharenko, N.V.; Larionov, V.B. Biokinetics of transdermal therapeutic medicinal form of phenazepam. Bull. Exp. Biol. Med., 2000, 130(12), 1153-1155.
[http://dx.doi.org/10.1023/A:1017519731950] [PMID: 11276308]
Drugs-Forum.com. . Https://drugs-forum.com (Accessed Oct 6, 2019)
European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). EMCDDA–Europol 2007. Annual Report on the Implementation of Council Decision 2005/387/JHA, 2007. Lisbon, Portugal,. Http://www.emcdda.europa.eu/system/files/publications/503/2007_Implementation_report_281403.pdf (Accessed Oct 6, 2019)
Couch, R.A.; Madhavaram, H. Phenazepam and cannabinomimetics sold as herbal highs in New Zealand. Drug Test. Anal., 2012, 4(6), 409-414.
[http://dx.doi.org/10.1002/dta.349] [PMID: 22924168]
Lee, C.; Lee, H.; Pyo, J.; Jo, J.; Lee, J.; Choi, H.; Kim, S.; Seon, R.; Yonghoon, H.; Bang, P.; Hwang, H.; Choe, S.; Jung, J.H. Identification of a new synthetic cannabinoid in a herbal mixture: 1-butyl-3-(2-methoxybenzoyl)indole. Forensic Toxicol., 2013, 31(2), 187-196.
Tripsit Http. ://.drugs.tripsit.me/ (Accessed Oct 6, 2019)
European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). EMCDDA–Europol 2011. Annual Report on the Implementation of Council Decision 2005/387/JHA, 2011. Lisbon, Portugal . Http://www.emcdda.europa.eu/system/files/publications/689/EMCDDA-Europol_Annual_Report_2011_2012_final_335568.pdf (Accessed Oct 6, 2019).
Fracasso, C.; Confalonieri, S.; Garattini, S.; Caccia, S. Single and multiple dose pharmacokinetics of etizolam in healthy subjects. Eur. J. Clin. Pharmacol., 1991, 40(2), 181-185.
[PMID: 2065698]
Nakamae, T.; Shinozuka, T.; Sasaki, C.; Ogamo, A.; Murakami-Hashimoto, C.; Irie, W.; Terada, M.; Nakamura, S.; Furukawa, M.; Kurihara, K. Case report: Etizolam and its major metabolites in two unnatural death cases. Forensic Sci. Int., 2008, 182(1-3), e1-e6.
[http://dx.doi.org/10.1016/j.forsciint.2008.08.012] [PMID: 18976871]
National Records of Scotland (2019). Table SUB2 - Substances which were reported for drug-related deaths on the basis of the Office for National Statistics (ONS) ‘wide’ definition, Scotland, 2000 to 2018. 16 July, Edinburgh: National Records of Scotland. Available at: . https://www.nrscotland.gov.uk/files//statistics/drug-related-deaths/2018/drug-related deaths-sub2-18.xlsx (Accessed 6 October 2019)
Moosmann, B.; Hutter, M.; Huppertz, L.M.; Ferlaino, S.; Redlingshöfer, L.; Auwärter, V. Characterization of the designer benzodiazepine pyrazolam and its detectability in human serum and urine. Forensic Toxicol., 2013, 31(2), 263-271.
European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). EMCDDA-Europol 2012. Annual Report on the Implementation of Council Decision 2005/387/JHA, 2012. Lisbon, Portugal, . Http://www.emcdda.europa.eu/system/files/publications/734/EMCDDA-Europol_2012_Annual_Report_final_439477.pdf (Accessed Oct 6, 2019)
Sternbach, L.H.; Fryer, R.Y.; Metlesics, W.; Reeder, E.; Sach, G.; Saucy, G.; Stempel, G. Quinazolines and 1,4-Benzodiazepines. VI.1a Halo-, Methyl-, and Methoxy-substituted 1,3-Dihydro-5-phenyl-2H-1,4- benzodiazepin-2-ones1b,c. J. Org. Chem., 1962, 27, 3788.
Carter, M.C.; Alber, D.G.; Baxter, R.C.; Bithell, S.K.; Budworth, J.; Chubb, A.; Cockerill, G.S.; Dowdell, V.C.L.; Henderson, E.A.; Keegan, S.J.; Kelsey, R.D.; Lockyer, M.J.; Stables, J.N.; Wilson, L.J.; Powell, K.L. 1,4-Benzodiazepines as inhibitors of respiratory syncytial virus. J. Med. Chem., 2006, 49(7), 2311-2319.
[http://dx.doi.org/10.1021/jm051185t] [PMID: 16570927]
Koch, K.; Auwärter, V.; Hermanns-Clausen, M.; Wilde, M.; Neukamm, M.A. Mixed intoxication by the synthetic opioid U-47700 and the benzodiazepine flubromazepam with lethal outcome: Pharmacokinetic data. Drug Test. Anal., 2018.
[http://dx.doi.org/10.1002/dta.2391] [PMID: 29637722]
Pettersson Bergstrand, M.; Helander, A.; Hansson, T.; Beck, O. Detectability of designer benzodiazepines in CEDIA, EMIT II Plus, HEIA, and KIMS II immunochemical screening assays. Drug Test. Anal., 2017, 9(4), 640-645.
[http://dx.doi.org/10.1002/dta.2003] [PMID: 27366870]
Bäckberg, M.; Pettersson Bergstrand, M.; Beck, O.; Helander, A. Occurrence and time course of NPS benzodiazepines in Sweden - results from intoxication cases in the STRIDA project. Clin. Toxicol. (Phila.), 2019, 57(3), 203-212.
[http://dx.doi.org/10.1080/15563650.2018.1506130] [PMID: 30348014]
Carpenter, J.E.; Murray, B.P.; Dunkley, C.; Kazzi, Z.N.; Gittinger, M.H. Designer benzodiazepines: a report of exposures recorded in the National Poison Data System, 2014-2017. Clin. Toxicol. (Phila.), 2019, 57(4), 282-286.
[http://dx.doi.org/10.1080/15563650.2018.1510502] [PMID: 30430874]
Ligon, E.S.; Nawyn, J.; Jones, L.V.; Allred, B.M.; Reinhardt, D.V., Jr; France, S. Synthesis of Flubromazepam Positional Isomers for Forensic Analysis. J. Org. Chem., 2019, 84(16), 10280-10291.
[http://dx.doi.org/10.1021/acs.joc.9b01433] [PMID: 31328518]
European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). EMCDDA-Europol, 2013. Annual Report on the Implementation of Council Decision 2005/387/JHA, 2013. Lisbon, Portugal.. Http://www.emcdda.europa.eu/system/files/publications/814/TDAN14001ENN_475519.pdf (Accessed Oct 6, 2019)
Manchester, K.R.; Maskell, P.D.; Waters, L. Experimental versus theoretical log D7.4, pKa and plasma protein binding values for benzodiazepines appearing as new psychoactive substances. Drug Test. Anal., 2018.
[http://dx.doi.org/10.1002/dta.2387] [PMID: 29582576]
Sternbach, L.H.; Fryer, R.I.; Metlesics, W.; Sach, G.; Stempel, A. Quinazolines and 1,4-Benzodiazepines. V. o-Aminobenzophenones. J. Org. Chem., 1962, 27(11), 3781-3788.
Babbini, M.; Gaiardi, M.; Bartoletti, M. Anxiolytic versus sedative properties in the benzodiazepines series: differencies in structure activity relationships. Life Sci., 1979, 25(1), 15-22.
[http://dx.doi.org/10.1016/0024-3205(79)90484-3] [PMID: 39212]
Sternbach, L.H.; Randall, L.O.; Banziger, R.; Lehr, H. Structure activity relationships in the 1,3-benzodiazepine series. Drugs Affecting the Central Nervous System; Burger, A., Ed.; Edward Arnold: London, 1968.
Bradley, C.M.; Nicholson, A.N. Activity of the chloro- and triazolo-benzodiazepines. Behavioural studies in the monkey (Macaca mulatta). Neuropharmacology, 1984, 23(3), 327-331.
[http://dx.doi.org/10.1016/0028-3908(84)90195-3] [PMID: 6145112]
Cho, M.J.; Sethy, V.H.; Haynes, L.C. Sequentially labile water soluble prodrugs of alprazolam. J. Med. Chem., 1986, 29(8), 1346-1350.
[http://dx.doi.org/10.1021/jm00158a004] [PMID: 3016261]
European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). EMCDDA-Europol, 2014. Annual Report on the Implementation of Council Decision 2005/387/JHA, 2014. Lisbon, Portugal.. Http://www.emcdda.europa.eu/system/files/publications/1018/TDAN15001ENN.pdf Accessed Oct 6, 2019.
Thibaut, J.P.; Monteiro, L.M.; Leite, L.C.; Menezes, C.M.; Lima, L.M.; Noël, F. The effects of 3-methylclonazepam on Schistosoma mansoni musculature are not mediated by benzodiazepine receptors. Eur. J. Pharmacol., 2009, 606(1-3), 9-16.
[http://dx.doi.org/10.1016/j.ejphar.2009.01.021] [PMID: 19374857]
Vikingsson, S.; Wohlfarth, A.; Andersson, M.; Gréen, H.; Roman, M.; Josefsson, M.; Kugelberg, F.C.; Kronstrand, R. Identifying Metabolites of meclonazepam by high-resolution mass spectrometry using human liver microsomes, hepatocytes, a mouse model, and authentic urine samples. AAPS J., 2017, 19(3), 736-742.
[http://dx.doi.org/10.1208/s12248-016-0040-x] [PMID: 28091881]
Baard, A.P.; Sommers, D.K.; Honiball, P.J.; Fourie, E.D.; du Toit, L.E. Preliminary results in human schistosomiasis with Ro 11-3128. S. Afr. Med. J., 1979, 55(16), 617-618.
[PMID: 380021]
Ansseau, M.; Doumont, A.; Thiry, D.; von Frenckell, R.; Collard, J. Initial study of methylclonazepam in generalized anxiety disorder. Evidence for greater power in the cross-over design. Psychopharmacology (Berl.), 1985, 87(2), 130-135.
[http://dx.doi.org/10.1007/BF00431795] [PMID: 3931136]
Abdul-Ghani, R.A.; Loutfy, N.; Hassan, A. Experimentally promising antischistosomal drugs: a review of some drug candidates not reaching the clinical use. Parasitol. Res., 2009, 105(4), 899-906.
[http://dx.doi.org/10.1007/s00436-009-1546-2] [PMID: 19588166]
O’Boyle, C.; Lambe, R.; Darragh, A. Central effects in man of the novel schistosomicidal benzodiazepine meclonazepam. Eur. J. Clin. Pharmacol., 1985, 29(1), 105-108.
[http://dx.doi.org/10.1007/BF00547377] [PMID: 4054198]
Coassolo, P.; Aubert, C.; Cano, J.P. Plasma determination of 3-methylclonazepam by capillary gas chromatography. J. Chromatogr. A, 1985, 338(2), 347-355.
[http://dx.doi.org/10.1016/0378-4347(85)80105-5] [PMID: 3998022]
Ameline, A.; Richeval, C.; Gaulier, J.M.; Raul, J.S.; Kintz, P. Characterization of flunitrazolam, a new designer benzodiazepine, in oral fluid after a controlled single administration. J. Anal. Toxicol., 2018, 42(6), e58-e60.
[http://dx.doi.org/10.1093/jat/bky012] [PMID: 29462316]
Huppertz, L.M.; Bisel, P.; Westphal, F.; Franz, F.; Auwärter, V.; Moosmann, B. Characterization of the four designer benzodiazepines clonazolam, deschloroetizolam, flubromazolam, and meclonazepam, and identification of their in vitro metabolites. Forensic Toxicol., 2015, 33, 388-395.
Abe, M.; Mikashima, H.; Moriwaki, M.; Tahara, T. Thieno(- triazolo)diazepine compound and medicinal application of the same Patent WO1988009333A1, . 1988.
Huppertz, L.M.; Moosmann, B.; Auwärter, V. Flubromazolam - Basic pharmacokinetic evaluation of a highly potent designer benzodiazepine. Drug Test. Anal., 2018, 10(1), 206-211.
[http://dx.doi.org/10.1002/dta.2203] [PMID: 28378533]
Noble, C.; Mardal, M.; Bjerre, H.N.; Stybe, J.S.; Linnet, K. In vitro studies on flubromazolam metabolism and detection of its metabolites in authentic forensic samples. Drug Test. Anal., 2017, 9(8), 1182-1191.
[http://dx.doi.org/10.1002/dta.2146] [PMID: 27935260]
Wohlfarth, A.; Vikingsson, S.; Roman, M.; Andersson, M.; Kugelberg, F.C.; Green, H.; Kronstrand, R. Looking at flubromazolam metabolism from four different angles: Metabolite profiling in human liver microsomes, human hepatocytes, mice and authentic human urine samples with liquid chromatography high-resolution mass spectrometry. Forensic Sci. Int., 2017, 274, 55-63.
[http://dx.doi.org/10.1016/j.forsciint.2016.10.021] [PMID: 27863836]
Bohnenberger, K.; Liu, M.T. Flubromazolam overdose: A review of a new designer benzodiazepine and the role of flumazenil. Ment Health Clin, 2019, 9(3), 133-137.
[http://dx.doi.org/10.9740/mhc.2019.05.133] [PMID: 31123661]
Łukasik-Głębocka, M.; Sommerfeld, K.; Teżyk, A.; Zielińska-Psuja, B.; Panieński, P.; Żaba, C. Flubromazolam--A new life threatening designer benzodiazepine. Clin. Toxicol. (Phila.), 2016, 54(1), 66-68.
[http://dx.doi.org/10.3109/15563650.2015.1112907] [PMID: 26585557]
Katselou, M.; Papoutsis, I.; Nikolaou, P.; Spiliopoulou, C.; Athanaselis, S. Metabolites replace the parent drug in the drug arena. The cases of fonazepam and nifoxipam. Forensic Toxicol., 2017, 35(1), 1-10.
[http://dx.doi.org/10.1007/s11419-016-0338-5] [PMID: 28127407]
Hester, J.B., Jr; Rudzik, A.D.; Kamdar, B.V. 6-phenyl-4H-s triazolo[4,3-a][1,4]benzodiazepines which have central nervous system depressant activity. J. Med. Chem., 1971, 14(11), 1078-1081.
[http://dx.doi.org/10.1021/jm00293a015] [PMID: 5165540]
Advisory Council on the Misuse of Drugs (ACMD). Circular 008/2017: a Change to the Misuse of Drugs Act 1971 to Control U- 47,700, Twelve Methylphenidate Related Substances and Sixteen ‘designer’ Benzodiazepines . Https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/616781/misuse_of_drugs_act_circular_008_2017.pdf (Accessed Oct 6, 2019)
Shapiro, A.P.; Krew, T.S.; Vazirian, M.; Jerry, J.; Sola, C. Novel ways to acquire designer benzodiazepines: a case report and discussion of the changing role of the internet. Psychosomatics., , 2019, 14S0033-3182(19), 30046-5.
Robertson, M.; Raymon, L. Rohypnol VR and other benzodiazepines. Drug-facilitated sexual assault: a forensic handbook; LeBeau, M.A; Mozayani, A., Ed.; Academic Press: London, 2001, pp. 89-106.
DeVane, C.L.; Ware, M.R.; Lydiard, R.B. Pharmacokinetics, pharmacodynamics, and treatment issues of benzodiazepines: alprazolam, adinazolam, and clonazepam. Psychopharmacol. Bull., 1991, 27(4), 463-473.
[PMID: 1687613]
Bird, M. Abuse potential of adinazolam: A comparison with diazepam, lorazepam and placebo. In: Problems of Drug Dependence 1987, , Proceedings of the 49th Annual Scientific Meeting. The Committee on Problems of Drug Dependence, Inc. NIDA Research Monograph(81) .
Sethy, V.H.; Collins, R.J.; Daniels, E.G. Determination of biological activity of adinazolam and its metabolites. J. Pharm. Pharmacol., 1984, 36(8), 546-548.
[http://dx.doi.org/10.1111/j.2042-7158.1984.tb04449.x] [PMID: 6148400]
Fraser, A.D.; Isner, A.F.; Bryan, W. Urinary screening for adinazolam and its major metabolites by the Emit d.a.u. and FPIA benzodiazepine assays with confirmation by HPLC. J. Anal. Toxicol., 1993, 17(7), 427-431.
[http://dx.doi.org/10.1093/jat/17.7.427] [PMID: 8309217]
Lahti, R.A.; Sethy, V.H.; Barsuhn, C.; Hester, J.B. Pharmacological profile of the antidepressant adinazolam, a triazolobenzodiazepine. Neuropharmacology, 1983, 22(11), 1277-1282.
[http://dx.doi.org/10.1016/0028-3908(83)90200-9] [PMID: 6320036]
File, S.E.; Pellow, S. Triazolobenzodiazepines antagonize the effects of anxiogenic drugs mediated at three different central nervous system sites. Neurosci. Lett., 1985, 61(1-2), 115-119.
[http://dx.doi.org/10.1016/0304-3940(85)90410-0] [PMID: 2867497]
Venkatakrishnan, K.; Culm, K.E.; Ehrenberg, B.L.; Harmatz, J.S.; Corbett, K.E.; Fleishaker, J.C.; Greenblatt, D.J. Kinetics and dynamics of intravenous adinazolam, N-desmethyl adinazolam, and alprazolam in healthy volunteers. J. Clin. Pharmacol., 2005, 45(5), 529-537.
[http://dx.doi.org/10.1177/0091270004269105] [PMID: 15831776]
Dunner, D.; Myers, J.; Khan, A.; Avery, D.; Ishiki, D.; Pyke, R. Adinazolam--a new antidepressant: findings of a placebo controlled, double-blind study in outpatients with major depression. J. Clin. Psychopharmacol., 1987, 7(3), 170-172.
[http://dx.doi.org/10.1097/00004714-198706000-00010] [PMID: 3298327]
Venkatakrishnan, K.; von Moltke, L.L.; Duan, S.X.; Fleishaker, J.C.; Shader, R.I.; Greenblatt, D.J. Kinetic characterization and identification of the enzymes responsible for the hepatic biotransformation of adinazolam and N-desmethyladinazolam in man. J. Pharm. Pharmacol., 1998, 50(3), 265-274.
[http://dx.doi.org/10.1111/j.2042-7158.1998.tb06859.x] [PMID: 9600717]
Cornett, E.M.; Novitch, M.B.; Brunk, A.J.M.; Davidson, K.S.; Menard, B.L.; Urman, R.D.; Kaye, A.D. New benzodiazepines for sedation. Best Pract. Res. Clin. Anaesthesiol., 2018, 32(2), 149-164.
[http://dx.doi.org/10.1016/j.bpa.2018.06.007] [PMID: 30322456]
European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). EMCDDA-Europol, 2015. Annual Report on the Implementation of Council Decision 2005/387/JHA (2016). Lisbon, Portugal. . Http://www.emcdda.europa.eu/system/files/publications/1018/TDAN15001ENN.pdf (Accessed Oct 6, 2019)
Dowling, G.; Kavanagh, P.V.; Eckhardt, H.G.; Twamley, B.; Hessman, G.; McLaughlin, G.; O’Brien, J.; Brandt, S.D. An approach to shortening the timeframe between the emergence of new compounds on the drugs market and the availability of reference standards: The microscale syntheses of nitrazolam and clonazolam for use as reference materials, utilizing polymer-supported reagents. Drug Test. Anal., 2018. [Epub a head of print].
[http://dx.doi.org/10.1002/dta.2383] [PMID: 29542872]
Hester, J.B. "Patent US3987052 - 6-Phenyl-4H-striazolo[ 4,3a][1,4]benzodiazepines.” (1976). Https://patents.google.com/patent/US3987052A/en (Accessed Oct 6, 2019).
Chaslot, M.; El Balkhi, S.; Robin, T.; Morichon, J.; Picard, N.; Saint‐Marcoux, F. Exploration des métabolites de 8 benzodiazépines de synthèse. Toxicol Anal Clin., 2016, 28(2), S32.
Høiseth, G.; Tuv, S.S.; Karinen, R. Blood concentrations of new designer benzodiazepines in forensic cases. Forensic Sci. Int., 2016, 268, 35-38.
[http://dx.doi.org/10.1016/j.forsciint.2016.09.006] [PMID: 27685473]
Meyer, M.R.; Bergstrand, M.P.; Helander, A.; Beck, O. Identification of main human urinary metabolites of the designer nitrobenzodiazepines clonazolam, meclonazepam, and nifoxipam by nano-liquid chromatography-high-resolution mass spectrometry for drug testing purposes. Anal. Bioanal. Chem., 2016, 408(13), 3571-3591.
[http://dx.doi.org/10.1007/s00216-016-9439-6] [PMID: 27071765]
Reddit.com . Https://www.reddit.com (Accessed Oct 7, 2019)
Kintz, P.; Richeval, C.; Jamey, C.; Ameline, A.; Allorge, D.; Gaulier, J.M.; Raul, J.S. Detection of the designer benzodiazepine metizolam in urine and preliminary data on its metabolism. Drug Test. Anal., 2017, 9(7), 1026-1033.
[http://dx.doi.org/10.1002/dta.2099] [PMID: 27671107]
Moosmann, B.; Bisel, P.; Franz, F.; Huppertz, L.M.; Auwärter, V. Characterization and in vitro phase I microsomal metabolism of designer benzodiazepines - an update comprising adinazolam, cloniprazepam, fonazepam, 3-hydroxyphenazepam, metizolam and nitrazolam. J. Mass Spectrom., 2016, 51(11), 1080-1089.
[http://dx.doi.org/10.1002/jms.3840] [PMID: 27535017]
Mortelé, O.; Vervliet, P.; Gys, C.; Degreef, M.; Cuykx, M.; Maudens, K.; Covaci, A.; van Nuijs, A.L.N.; Lai, F.Y. In vitro Phase I and Phase II metabolism of the new designer benzodiazepine cloniprazepam using liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. J. Pharm. Biomed. Anal., 2018, 153, 158-167.
[http://dx.doi.org/10.1016/j.jpba.2018.02.032] [PMID: 29494888]
Schukin, S.I.; Zinkovsky, V.G.; Zhuk, O.V. Elimination kinetics of the novel prodrug cinazepam possessing psychotropic activity in mice. Pharmacol. Rep., 2011, 63(5), 1093-1100.
[http://dx.doi.org/10.1016/S1734-1140(11)70628-4] [PMID: 22180351]
Kerrigan, S.; Mellon, M.B.; Hinners, P. Detection of phenazepam in impaired driving. J. Anal. Toxicol., 2013, 37(8), 605-610.
[http://dx.doi.org/10.1093/jat/bkt075] [PMID: 24022117]
Crichton, M.L.; Shenton, C.F.; Drummond, G.; Beer, L.J.; Seetohul, L.N.; Maskell, P.D. Analysis of phenazepam and 3-hydroxyphenazepam in post-mortem fluids and tissues. Drug Test. Anal., 2015, 7(10), 926-936.
[http://dx.doi.org/10.1002/dta.1790] [PMID: 25847502]
Ekonomov, A.L.; Zherdev, V.P. Method of quantitative gas-chromatographic determination of phenazepam and its metabolite 3-hydroxyphenazepam in plasma. Pharm. Chem. J., 1980, 14, 579-582.
Golovenko, N.Y.; Larionov, V.B.; Kravchenko, I.A.; Ovcharenko, N.V.; Aleksandrova, A.I. Biokinetics of transdermal 3-hydroxyphenazepam. Bull. Exp. Biol. Med., 2002, 134(3), 254-256.
[http://dx.doi.org/10.1023/A:1021503417490] [PMID: 12511995]
Voronina, T.A.; Larionov, V.B.; Golovenko, N.Ia.; Nerobkova, L.N. Peculiarities of hypnotic effect and pharmacokinetics of hemisuccinate 3-hydroxyphenazepam (levana). Eksp. Klin. Farmakol., 2014, 77(1), 3-6.
[PMID: 24649593]
World Health Organization (WHO)- Expert Committee on Drug Dependence (ECDD) 2015 . Http://www.who.int/medicines/access/controlled-substances/5.8_Phenazepam_PreRev.pdf(Accessed Oct 7, 2019)
Lomas, E.C.; Maskell, P.D. Phenazepam: More information coming in from the cold. J. Forensic Leg. Med., 2015, 36, 61-62.
[http://dx.doi.org/10.1016/j.jflm.2015.08.017] [PMID: 26408390]
Mei, V.; Concheiro, M.; Pardi, J.; Cooper, G. Validation of an LC-MS/MS Method for the Quantification of 13 Designer Benzodiazepines in Blood. J. Anal. Toxicol., 2019, 43(9), 688-695.
[http://dx.doi.org/10.1093/jat/bkz063] [PMID: 31436813]
Golovenko, N.Y.; Larionov, V.B. Pharmacodynamical and neuroreceptor analysis of the permeability of the blood-brain barrier for Derivatives of 1, 4-Benzodiazepine. Neurophysiology, 2014, 46(3), 199-205.
Hallifax, D.; Galetin, A.; Houston, J.B. Prediction of metabolic clearance using fresh human hepatocytes: comparison with cryopreserved hepatocytes and hepatic microsomes for five benzodiazepines. Xenobiotica, 2008, 38(4), 353-367.
[http://dx.doi.org/10.1080/00498250701834665] [PMID: 18340561]
Sternbach, L.H.; Fryer, R.I.; Keller, O.; Metlesics, W.; Sach, G.; Steiger, N. Quinazolines and 1, 4-Benzodiazepines. X. 1 Nitro-Substituted 5-Phenyl-1, 4-benzodiazepine Derivatives2. J. Med. Chem., 1963, 6(3), 261-265.
[http://dx.doi.org/10.1021/jm00339a010] [PMID: 14185980]
de Silva, J.A.; Bekersky, I.; Puglisi, C.V.; Brooks, M.A.; Weinfeld, R.E. Determination of 1,4-benzodiazepines and -diazepin-2-ones in blood by electron-capture gas-liquid chromatography. Anal. Chem., 1976, 48(1), 10-19.
[http://dx.doi.org/10.1021/ac60365a037] [PMID: 1244754]
Maddalena, D.J.; Johnston, G.A. Prediction of receptor properties and binding affinity of ligands to benzodiazepine/GABAA receptors using artificial neural networks. J. Med. Chem., 1995, 38(4), 715-724.
[http://dx.doi.org/10.1021/jm00004a017] [PMID: 7861419]
So, S.S.; Karplus, M. Genetic neural networks for quantitative structure-activity relationships: improvements and application of benzodiazepine affinity for benzodiazepine/GABAA receptors. J. Med. Chem., 1996, 39(26), 5246-5256.
[http://dx.doi.org/10.1021/jm960536o] [PMID: 8978853]
European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). EMCDDA-Europol, 2017. Annual Report on the Implementation of Council Decision 2005/387/JHA (2017). Lisbon, Portugal ; Http://www.emcdda.europa.eu/system/files/publications/9282/20183924_TDAN18001ENN_PDF.pdf(Accessed Oct 6, 2019). .
Moosmann, B.; Auwärter, V. Designer Benzodiazepines: Another Class of New Psychoactive Substances. Handb. Exp. Pharmacol., 2018, 252, 383-410.
[http://dx.doi.org/10.1007/164_2018_154] [PMID: 30367253]
Earl, R.; Henryk, S.L. inventors; Hoffmann, La Roche, assignee. Amino substituted benzophenone oximes and derivatives thereof. United States patent US 3,136,815. .
Skerritt, J.H.; Werz, M.A.; McLean, M.J.; Macdonald, R.L. Diazepam and its anomalous p-chloro-derivative Ro 5-4864: comparative effects on mouse neurons in cell culture. Brain Res., 1984, 310(1), 99-105.
[http://dx.doi.org/10.1016/0006-8993(84)90013-1] [PMID: 6478244]
Schoemaker, H.; Boles, R.G.; Horst, W.D.; Yamamura, H.I. Specific high-affinity binding sites for [3H]Ro 5-4864 in rat brain and kidney. J. Pharmacol. Exp. Ther., 1983, 225(1), 61-69.
[PMID: 6132001]
Marangos, P.J.; Patel, J.; Boulenger, J.P.; Clark-Rosenberg, R. Characterization of peripheral-type benzodiazepine binding sites in brain using [3H]Ro 5-4864. Mol. Pharmacol., 1982, 22(1), 26-32.
[PMID: 6289073]
Gavioli, E.C.; Duarte, F.S.; Bressan, E.; Ferrara, P.; Farges, R.C.; De Lima, T.C. Antidepressant-like effect of Ro5-4864, a peripheral-type benzodiazepine receptor ligand, in forced swimming test. Eur. J. Pharmacol., 2003, 471(1), 21-26.
[http://dx.doi.org/10.1016/S0014-2999(03)01789-8] [PMID: 12809948]
DalBó, S.; Nardi, G.M.; Ferrara, P.; Ribeiro-do-Valle, R.M.; Farges, R.C. Antinociceptive effects of peripheral benzodiazepine receptors. Pharmacology, 2004, 70(4), 188-194.
[http://dx.doi.org/10.1159/000075547] [PMID: 15001819]
Leonelli, E.; Yague, J.G.; Ballabio, M.; Azcoitia, I.; Magnaghi, V.; Schumacher, M.; Garcia-Segura, L.M.; Melcangi, R.C. Ro5-4864, a synthetic ligand of peripheral benzodiazepine receptor, reduces aging-associated myelin degeneration in the sciatic nerve of male rats. Mech. Ageing Dev., 2005, 126(11), 1159-1163.
[http://dx.doi.org/10.1016/j.mad.2005.06.001] [PMID: 16045970]
Solhjoo, S.; O’Rourke, B. Mitochondrial instability during regional ischemia-reperfusion underlies arrhythmias in monolayers of cardiomyocytes. J. Mol. Cell. Cardiol., 2015, 78, 90-99.
[http://dx.doi.org/10.1016/j.yjmcc.2014.09.024] [PMID: 25268650]
Veiga, S.; Azcoitia, I.; Garcia-Segura, L.M. Ro5-4864, a peripheral benzodiazepine receptor ligand, reduces reactive gliosis and protects hippocampal hilar neurons from kainic acid excitotoxicity. J. Neurosci. Res., 2005, 80(1), 129-137.
[http://dx.doi.org/10.1002/jnr.20430] [PMID: 15696538]
Mills, C.; Makwana, M.; Wallace, A.; Benn, S.; Schmidt, H.; Tegeder, I.; Costigan, M.; Brown, R.H., Jr; Raivich, G.; Woolf, C.J. Ro5-4864 promotes neonatal motor neuron survival and nerve regeneration in adult rats. Eur. J. Neurosci., 2008, 27(4), 937-946.
[http://dx.doi.org/10.1111/j.1460-9568.2008.06065.x] [PMID: 18333964]
Soustiel, J.F.; Zaaroor, M.; Vlodavsky, E.; Veenman, L.; Weizman, A.; Gavish, M. Neuroprotective effect of Ro5-4864 following brain injury. Exp. Neurol., 2008, 214(2), 201-208.
[http://dx.doi.org/10.1016/j.expneurol.2008.08.008] [PMID: 18789929]
Arbo, B.D.; Hoppe, J.B.; Rodrigues, K.; Garcia-Segura, L.M.; Salbego, C.G.; Ribeiro, M.F. 4′-Chlorodiazepam is neuroprotective against amyloid-beta in organotypic hippocampal cultures. J. Steroid Biochem. Mol. Biol., 2017, 171, 281-287.
[http://dx.doi.org/10.1016/j.jsbmb.2017.04.010] [PMID: 28442392]
Ma, B.; Liu, X.; Huang, X.; Ji, Y.; Jin, T.; Ma, K. Translocator protein agonist Ro5-4864 alleviates neuropathic pain and promotes remyelination in the sciatic nerve. Mol. Pain, 2018, 14, 1744806917748019
[http://dx.doi.org/10.1177/1744806917748019] [PMID: 29212402]
Ameline, A.; Arbouche, N.; Raul, J.S.; Kintz, P. Documentation of a little-studied designer benzodiazepine after a controlled single administration: ii. concentration profile of deschloroetizolam in saliva. Ther. Drug Monit., 2018, 40(6), 759-761.
[http://dx.doi.org/10.1097/FTD.0000000000000557] [PMID: 30048379]
Moosmann, B.; Bisel, P.; Westphal, F.; Wilde, M.; Kempf, J.; Angerer, V.; Auwärter, V. Characterization and in vitro phase I microsomal metabolism of designer benzodiazepines: An update comprising flunitrazolam, norflurazepam, and 4′-chlorodiazepam (Ro5-4864). Drug Test. Anal., 2019, 11(3), 541-549.
[http://dx.doi.org/10.1002/dta.2561] [PMID: 30578721]
Manchester, K.R.; Lomas, E.C.; Waters, L.; Dempsey, F.C.; Maskell, P.D. The emergence of new psychoactive substance (NPS) benzodiazepines: A review. Drug Test. Anal., 2017, 1-17.
[http://dx.doi.org/10.1002/dta.2211] [PMID: 28471096]
Hester, J.B., Jr; Von Voigtlander, P. 6-Aryl-4H-s-triazolo[4,3-a][1,4]benzodiazepines. Influence of 1-substitution on pharmacological activity. J. Med. Chem., 1979, 22(11), 1390-1398.
[http://dx.doi.org/10.1021/jm00197a021] [PMID: 42799]
Vogt, S.; Kempf, J.; Buttler, J.; Auwärter, V.; Weinmann, W. Desalkylflurazepam found in patients’ samples after high-dose midazolam treatment. Drug Test. Anal., 2013, 5(9-10), 745-747.
[http://dx.doi.org/10.1002/dta.1484] [PMID: 23713025]
Maskell, P.D.; Wilson, N.E. Designer benzodiazepines: new challenges and treatment Options.Roman-Urrestarazu. In: Handbook of Novel Psychoactive Substances: What Clinicians Should Know about NPS; Corazza, O., Ed.; Taylor & Francis, 2019. 978-1-138- 06830-8
Akatsu, M. Benzodiazepine derivatives. Jpn. Kokai Tokkyo Koho, , 1972. JP 47030683 B 19721109.
Winkler, A.D.; Burden, F.R.; Watkins, A.J.R. Atomistic topological indices applied to benzodiazepines using various regression methods. Quantitative Structure-Activity Relationships, 1998, 17(1), 14-19.
Reeder, E. inventor. Process for preparing 5-phenyl-1,2-dihydro- 3H-1,4-benzodiazepines. United States patent US 3,109,843, 1963 Nov;5..
Anjaneyulu, Y.; Marayya, D.; Linga, R.D.; Krishna, R.P. High performance thin layer chromatographic determination of the related substances in alprazolam drug. Asian J. Chem., 2007, 19(5), 3375.
Baumann, M.; Baxendale, I.R.; Ley, S.V.; Nikbin, N. An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals. Beilstein J. Org. Chem., 2011, 7, 442-495.
[http://dx.doi.org/10.3762/bjoc.7.57] [PMID: 21647262]
Borrey, D.; Meyer, E.; Lambert, W.; Van Calenbergh, S.; Van Peteghem, C.; De Leenheer, A.P. Sensitive gas chromatographic--mass spectrometric screening of acetylated benzodiazepines. J. Chromatogr. A, 2001, 910(1), 105-118.
[http://dx.doi.org/10.1016/S0021-9673(00)01177-8] [PMID: 11263563]
Wilhelm, M.; Battista, H.J.; Obendorf, D. HPLC with simultaneous UV and reductive electrochemical detection at the hanging mercury drop electrode: a highly sensitive and selective tool for the determination of benzodiazepines in forensic samples. J. Anal. Toxicol., 2001, 25(4), 250-257.
[http://dx.doi.org/10.1093/jat/25.4.250] [PMID: 11386638]
Bugey, A.; Rudaz, S.; Staub, C. A fast LC-APCI/MS method for analyzing benzodiazepines in whole blood using monolithic support. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2006, 832(2), 249-255.
[http://dx.doi.org/10.1016/j.jchromb.2006.01.009] [PMID: 16483857]
Ueki, S.; Gomita, Y.; Ataki, Y.; Yamada, K.; Yoshimura, H. Behavioral effects of 5-(o-chlorophenyl)-1-methyl-7-nitro-1,3-dihydro-2H-1,4-benzodiazepin-2-one (ID-690). Nippon Yakurigaku Zasshi, 1977, 73(2), 243-255.
[http://dx.doi.org/10.1254/fpj.73.243] [PMID: 560343]
Fukuda, H.; Kudo, Y.; Ono, H.; Togari, A.; Tanaka, Y. Pharmacological study on 5-(o-chlorophenyl)-1-methyl-7-nitro-1,3-dihydro-2H-1,4-benzodiazepin-2-one (ID-690), with special reference to the effects on motor systems. Nippon Yakurigaku Zasshi, 1977, 73(1), 123-134.
[http://dx.doi.org/10.1254/fpj.73.123] [PMID: 558942]
Fukuda, H.; Kudo, Y.; Takeuchi, E. Effects of benzodiazepine derivatives on γ-motor system in rats (author’s transl). Nippon Yakurigaku Zasshi, 1979, 75(4), 315-319.
[http://dx.doi.org/10.1254/fpj.75.315] [PMID: 535826]
Watanabe, S.; Kawasaki, H.; Nishi, H.; Ueki, S. Electroencephalographic effects of ID-690 [5-(o-chlorophenyl)-1-methyl-7-nitro-1,3-dihydro-2H-1,4-benzodiazepin-2-one] in rabbits with chronic electrode implants. Nippon Yakurigaku Zasshi, 1974, 70(4), 531-542.
[http://dx.doi.org/10.1254/fpj.70.531] [PMID: 4155395]
Tsuchiya, T.; Fukushima, H. Effects of 5-(o-chlorophenyl)-1-methyl-7-nitro-1, 3-dihydro-2HO1, 4-benzodiazepin-2-one (ID-390) as compared to nitrazepam on the sleep-wakefulness cycle in cats (author’s transl). Nippon Yakurigaku Zasshi, 1977, 73(4), 437-447.
[http://dx.doi.org/10.1254/fpj.73.437] [PMID: 198344]
Hellerbach, J. Thienotriazolodiazepine. 1974. DE 2405682. Hoffmann-La Roche Inc. . Https://worldwide.espacenet.com/publicationDetails/originalDocument?CC=DE&NR=2405682A1&KC=A1&FT=D&ND=3&date=19740815&DB=EPODOC&locale=en_EP# (Accessed Oct 7, 2019)
Zawilska, J.B.; Wojcieszak, J. An expanding world of new psychoactive substances-designer benzodiazepines. Neurotoxicology, 2019, 73, 8-16.
[http://dx.doi.org/10.1016/j.neuro.2019.02.015] [PMID: 30802466]
ukchemicalresearch.org. Https://www.ukchemicalresearch.org (Accessed Oct 7, 2019)
Zsila, F.; Gergely, A.; Horvath, P.; Szasz, G. Separation and identification of tofisopam stereoisomers by hyphenated HPLC-CD technique. J Liq Chrom Relat Tech., 1999, 22(5), 713-719.
Foroughbakhshfasaei, M.; Szabó, Z.I.; Mirzahosseini, A.; Horváth, P.; Tóth, G. Enantiomeric quality control of R-Tofisopam by HPLC using polysaccharide-type chiral stationary phases in polar organic mode. Electrophoresis, 2018, 39(20), 2566-2574.
[http://dx.doi.org/10.1002/elps.201800220] [PMID: 29999177]
Bond, A.; Lader, M. A comparison of the psychotropic profiles of tofisopam and diazepam. Eur. J. Clin. Pharmacol., 1982, 22(2), 137-142.
[http://dx.doi.org/10.1007/BF00542458] [PMID: 6124424]
Bernard, P.; Dufresne-Favetta, C.; Favetta, P.; Do, Q.T.; Himbert, F.; Zubrzycki, S.; Scior, T.; Lugnier, C. Application of drug repositioning strategy to TOFISOPAM. Curr. Med. Chem., 2008, 15(30), 3196-3203.
[http://dx.doi.org/10.2174/092986708786848488] [PMID: 19075663]
Murthy, V.S.; Mangot, A.G. Psychiatric aspects of phosphodiesterases: An overview. Indian J. Pharmacol., 2015, 47(6), 594-599.
[http://dx.doi.org/10.4103/0253-7613.169593] [PMID: 26729948]
Tominaga, K.; Fujikawa, Y.; Tsumoto, C.; Kadouchi, K.; Tanaka, F.; Kamata, N.; Yamagami, H.; Tanigawa, T.; Watanabe, T.; Fujiwara, Y.; Arakawa, T. Disorder of autonomic nervous system and its vulnerability to external stimulation in functional dyspepsia. J. Clin. Biochem. Nutr., 2016, 58(2), 161-165.
[http://dx.doi.org/10.3164/jcbn.15-140] [PMID: 27013784]
Pellow, S.; File, S.E. Is tofisopam an atypical anxiolytic? Neurosci. Biobehav. Rev., 1986, 10(2), 221-227.
[http://dx.doi.org/10.1016/0149-7634(86)90026-6] [PMID: 2874535]
Petócz, L. Pharmacologic effects of tofizopam (Grandaxin). Acta Pharm. Hung., 1993, 63(2), 79-82.
[PMID: 8100112]
Srivastava, S.; Bhatia, M.S.; Gupta, K.; Rajdev, K. Current update on evidence based literature of tofisopam. Delhi Psychiatry J., 2014, 17, 154-159.
Chopin, P.; Stenger, A.; Couzinier, J.P.; Briley, M. Indirect dopaminergic effects of tofisopam, a 2,3-benzodiazepine, and their inhibition by lithium. J. Pharm. Pharmacol., 1985, 37(12), 917-919.
[http://dx.doi.org/10.1111/j.2042-7158.1985.tb05003.x] [PMID: 2868105]
Szegó, J.; Somogyi, M.; Papp, E. Excerpts from the clinical pharmacologic and clinical studies of Grandaxin. Acta Pharm. Hung., 1993, 63(2), 91-98.
[PMID: 8100114]
Rundfeldt, C.; Socała, K.; Wlaź, P. The atypical anxiolytic drug, tofisopam, selectively blocks phosphodiesterase isoenzymes and is active in the mouse model of negative symptoms of psychosis. J. Neural Transm. (Vienna), 2010, 117(11), 1319-1325.
[http://dx.doi.org/10.1007/s00702-010-0507-3] [PMID: 20967473]
Bihel, F.J.; Justiniano, H.; Schmitt, M.; Hellal, M.; Ibrahim, M.A.; Lugnier, C.; Bourguignon, J.J. New PDE4 inhibitors based on pharmacophoric similarity between papaverine and tofisopam. Bioorg. Med. Chem. Lett., 2011, 21(21), 6567-6572.
[http://dx.doi.org/10.1016/j.bmcl.2011.08.036] [PMID: 21920746]
Vakhrushev, IaM.; Belova, E.V.; Efremova, L.I. Use of grandaxine in the treatment of patients with erosive-ulcerative stomach and gastroduodenal lesions. Eksp. Klin. Gastroenterol., 2004, (4), 21-24.
[PMID: 15568662]
Plotnikova, E.Iu.; Beloborodova, E.I. Use of grandaxin in hypermotor dysfunction of the biliary ducts in young people. Eksp. Klin. Gastroenterol., , 2005, (6), 65-70. 113-114.
[PMID: 17378391]
Leventer, S.M.; Raudibaugh, K.; Frissora, C.L.; Kassem, N.; Keogh, J.C.; Phillips, J.; Mangel, A.W. Clinical trial: dextofisopam in the treatment of patients with diarrhoea-predominant or alternating irritable bowel syndrome. Aliment. Pharmacol. Ther., 2008, 27(2), 197-206.
[http://dx.doi.org/10.1111/j.1365-2036.2007.03566.x] [PMID: 17973974]
Manabe, N.; Rao, A.S.; Wong, B.S.; Camilleri, M. Emerging pharmacologic therapies for irritable bowel syndrome. Curr. Gastroenterol. Rep., 2010, 12(5), 408-416.
[http://dx.doi.org/10.1007/s11894-010-0124-1] [PMID: 20694841]
Klebovich, I.; Abermann, M. Pharmacokinetics and metabolism of tofizopam (Grandaxin). Acta Pharm. Hung., 1993, 63(2), 83-90.
[PMID: 8100113]
Tomori, E.; Elekes, I.; Láng, T.; Horváth, G. Investigation of metabolites of tofizopam in man and animals. Pol. J. Pharmacol. Pharm., 1984, 36(4), 423-430.
[PMID: 6152052]
Hatayama, M.; Sumida, C.; Kurajoh, M.; Shiraishi, J.; Okazaki, H.; Shoji, T.; Koyama, H.; Tsutsumi, Z.; Moriwaki, Y.; Namba, M.; Yamamoto, T. Acute effects of oral tofisopam on plasma concentration and urinary excretion of uric acid and oxypurinol “preliminary communication”. Curr. Clin. Pharmacol., 2015, 10(2), 160-164.
[http://dx.doi.org/10.2174/1574884710666150126143421] [PMID: 25619490]
Veĭn, A.V.; Artemenko, A.R.; Oknin, V.Iu.; Pomortseva, I.V. Effectiveness of grandaxin in the treatment of somatoform disorders. Klin. Med. (Mosk.), 1999, 77(6), 41-45.
[PMID: 10459219]
Osipenko, M.F.; Khramov, IuA.; Makarova, T.A.; Vdovenko, E.G. Role of grandaxin in the treatment of functional gastrointestinal diseases. Ter. Arkh., 2000, 72(10), 23-27.
[PMID: 11220871]
Kato, R.; Ooi, K.; Ueno, K. A case in which tofisopam was effective for treatment of paroxysmal supraventricular tachycardia. Yakugaku Zasshi, 2003, 123(5), 365-368.
[http://dx.doi.org/10.1248/yakushi.123.365] [PMID: 12772593]
Fustero, S.; González, J.; del Pozo, C. 1,4-Benzodiazepine N nitrosoamidines: useful intermediates in the synthesis of tricyclic benzodiazepines. Molecules, 2006, 11(8), 583-588.
[http://dx.doi.org/10.3390/11080583] [PMID: 17971730]
Kaliszan, R.; Kaliszan, A.; Noctor, T.A.; Purcell, W.P.; Wainer, I.W. Mechanism of retention of benzodiazepines in affinity, reversed-phase and adsorption high-performance liquid chromatography in view of quantitative structure retention relationships. J. Chromatogr. A, 1992, 609(1-2), 69-81.
Garzone, P.D.; Kroboth, P.D. Pharmacokinetics of the newer benzodiazepines. Clin. Pharmacokinet., 1989, 16(6), 337-364.
[http://dx.doi.org/10.2165/00003088-198916060-00002] [PMID: 2567646]
Qian, Z.; Liu, C.; Huang, J.; Deng, Q.; Hua, Z. Identification of the designer benzodiazepine 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (flualprazolam) in an anesthesia robbery case. Forensic Toxicol., 2019.
Drug-café ; https://drug.cafe/(Accessed Oct 8, 2019) .
Vejdelek, Z.; Protiva, M. Synthesis of two 1-substituted 8-bromo-6-(2-chlorophenyl)-4H-s-triazolo[4,3-a]-1,4-benzodiazepines. Collect. Czech. Chem. Commun., 1983, 48(5), 1477-1482.
Gonzalez López, F.; Mariño, E.L.; Dominguez-Gil, A. Pharmacokinetics of tiadipone: a new anxiolytic. Int. J. Clin. Pharmacol. Ther. Toxicol., 1986, 24(9), 482-484.
[PMID: 2877954]
CIMA. Medicine Online Information Center of AEMPS (from the Spanish: Centro de Información Online de Medicamentos de la Agencia española de medicamentos y productos sanitarios). . Https://hes32-ctp.trendmicro.com:443/wis/clicktime/v1/query?url=https%3a%2f%2fcima.aemps.es%2fcima%2fpublico%2fhome.html&umid=7cec72cc-7e38-4174-a2ab-f34a2ce0e3fe&auth=768f192bba830b801fed4f40fb360f4d1374fa7c-400a686fb11df4fef2d673976f3bd27783f37b2d (Accessed Oct 8, 2019)
Andrade, R.J.; Lucena, M.I.; Alcantara, R.; Fraile, J.M. Bentazepam-associated chronic liver disease. Lancet, 1994, 343(8901), 860.
[http://dx.doi.org/10.1016/S0140-6736(94)92065-6] [PMID: 7908109]
de-la-Serna, C.; Gil-Grande, L.A.; Sanromán, A.L.; Gonzalez, M.; Ruiz-del-Arbol, L.; Garcia Plaza, A. Bentazepam-induced hepatic bridging necrosis. J. Clin. Gastroenterol., 1997, 25(4), 710-711.
[http://dx.doi.org/10.1097/00004836-199712000-00042] [PMID: 9451703]
Andrade, R.J.; Lucena, M.I.; Aguilar, J.; Lazo, M.D.; Camargo, R.; Moreno, P.; García-Escaño, M.D.; Marquez, A.; Alcántara, R.; Alcáin, G. Chronic liver injury related to use of bentazepam: an unusual instance of benzodiazepine hepatotoxicity. Dig. Dis. Sci., 2000, 45(7), 1400-1404.
[http://dx.doi.org/10.1023/A:1005520523502] [PMID: 10961721]
Andrade, R.J.; López-Torres, E.; Lucena, M.I. Fernández, Mdel.C. Acute hepatitis due to bentazepam. Med. Clin. (Barc.), 2003, 120(17), 678-679.
[http://dx.doi.org/10.1157/13047311] [PMID: 12747823]
Andrade, R.J.; Lucena, M.I.; Kaplowitz, N.; García-Muņoz, B.; Borraz, Y.; Pachkoria, K.; García-Cortés, M.; Fernández, M.C.; Pelaez, G.; Rodrigo, L.; Durán, J.A.; Costa, J.; Planas, R.; Barriocanal, A.; Guarner, C.; Romero-Gomez, M.; Muņoz-Yagüe, T.; Salmerón, J.; Hidalgo, R. Outcome of acute idiosyncratic drug-induced liver injury: Long-term follow-up in a hepatotoxicity registry. Hepatology, 2006, 44(6), 1581-1588.
[http://dx.doi.org/10.1002/hep.21424] [PMID: 17133470]
Baumeister, D.; Tojo, L.M.; Tracy, D.K. Legal highs: staying on top of the flood of novel psychoactive substances. Ther. Adv. Psychopharmacol., 2015, 5(2), 97-132.
[http://dx.doi.org/10.1177/2045125314559539] [PMID: 26240749]
Schifano, F.; Orsolini, L.; Duccio, P.G.; Corkery, J.M. Novel psychoactive substances of interest for psychiatry. World Psychiatry, 2015, 14(1), 15-26.
[http://dx.doi.org/10.1002/wps.20174] [PMID: 25655145]
Pope, J.D.; Choy, K.W.; Drummer, O.H.; Schneider, H.G. Novel benzodiazepines (clonazolam and flubromazolam) identified in candy-like pills. J. Appl. Lab. Med., 2018, 3(1), 48-55.
Griffin, C.E., III; Kaye, A.M.; Bueno, F.R.; Kaye, A.D. Benzodiazepine pharmacology and central nervous system-mediated effects. Ochsner J., 2013, 13(2), 214-223.
[PMID: 23789008]
Broséus, J.; Gentile, N.; Esseiva, P. The Cutting of Cocaine and Heroin: A Critical Review. For Sci Intern, , 2016, 262, 73-83.
El Balkhi, S.; Chaslot, M.; Picard, N.; Dulaurent, S.; Delage, M.; Mathieu, O.; Saint-Marcoux, F. Characterization and identification of eight designer benzodiazepine metabolites by incubation with human liver microsomes and analysis by a triple quadrupole mass spectrometer. Int. J. Legal Med., 2017, 131(4), 979-988.
[http://dx.doi.org/10.1007/s00414-017-1541-6] [PMID: 28160051]
Orsolini, L.; Papanti, G.D.; Francesconi, G.; Schifano, F. Mind navigators of chemicals’ experimenters? A web-based description of e-psychonauts. Cyberpsychol. Behav. Soc. Netw., 2015, 18(5), 296-300.
[http://dx.doi.org/10.1089/cyber.2014.0486] [PMID: 25965863]
Corkery, J.M.; Orsolini, L.; Papanti, D.; Schifano, F. From concept( ion) to life after death/the grave: The ‘natural’ history and life cycle(s) of novel psychoactive substances (NPS). Hum. Psychopharmacol.,, 2017, 32(3) Review.
[http://dx.doi.org/10.1002/hup.2566] [PMID: 28657188]
Orsolini, L.; Papanti, D.; Corkery, J.; Schifano, F. An insight into the deep web; why it matters for addiction psychiatry? Hum. Psychopharmacol., 2017, 32(3)
[http://dx.doi.org/10.1002/hup.2573] [PMID: 28657187]
Vinkers, C.H.; Tijdink, J.K.; Luykx, J.J.; Vis, R. Choosing the correct benzodiazepine: mechanism of action and pharmacokinetics. Ned. Tijdschr. Geneeskd., 2012, 155(35), A4900.
[PMID: 22929751]
Turner, S.; Mota, N.; Bolton, J.; Sareen, J. Self-medication with alcohol or drugs for mood and anxiety disorders: A narrative review of the epidemiological literature. Depress. Anxiety, 2018, 35(9), 851-860.
[http://dx.doi.org/10.1002/da.22771] [PMID: 29999576]
Jones, J.D.; Mogali, S.; Comer, S.D. Polydrug abuse: a review of opioid and benzodiazepine combination use. Drug Alcohol Depend., 2012, 125(1-2), 8-18.
[http://dx.doi.org/10.1016/j.drugalcdep.2012.07.004] [PMID: 22857878]

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Published on: 05 October, 2020
Page: [809 - 837]
Pages: 29
DOI: 10.2174/1570159X18666200110121333
Price: $65

Article Metrics

PDF: 21