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Phenotypic Effects of Chronic and Acute Use of Methiopropamine in a Mouse Model

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Phenotypic Effects of Chronic and Acute Use of Methiopropamine in a Mouse Model International Journal of Legal Medicine (2019) 133:811–820 https://doi.org/10.1007/s00414-018-1891-8 ORIGINAL ARTICLE Phenotypic effects of chronic and acute use of methiopropamine in a mouse model Federica Foti1 & Matteo Marti2 & Andrea Ossato1,3 & Sabrine Bilel3 & Eugenio Sangiorgi4 & Francesco Botrè5,6 & Bruna Cerbelli7 & Alfonso Baldi8 & Fabio De-Giorgio1 Received: 16 January 2018 /Accepted: 17 July 2018 /Published online: 28 July 2018 # Springer-Verlag GmbH Germany, part of Springer Nature 2018 Abstract Methiopropamine (MPA) is a structural analogue of methamphetamine and belongs to the category of the novel psychoactive substances. To the best of our knowledge, no experimental study has been performed to evaluate the organ damage evoked by MPA administration in an animal model. Therefore, the main purpose of the present study was to investigate the histological changes in CD-1 male mice following the chronic administration of MPA. MPA-chronically treated mice showed myocardial damage with features consistent with repeated episodes of ischemia and a pattern of kidney damage and gastrointestinal ischemia, with ischemic-necrotic lesions of variable extent. In agreement with the analogies between MPA and methamphetamine, we link organ damage secondary to MPA administration to the vasoconstrictive effect exhibited by both compounds. Chronically MPA- treated mice did not show changes in body weight, food intake, thermoregulation, muscular strength and motor coordination in the accelerod test. However, acute MPA administration significantly increased their heart rate and promoted vasoconstriction, which were associated with the sudden death of a subset of animals (40% of all chronically treated mice). In conclusion, the present study demonstrates that MPA consumption could induce health hazards, highlighting the risk of sudden catastrophic events; therefore, clinicians should be aware of these data and consider MPA screening when no other drug is identified by a urine drug screen. Keywords Methiopropamine . Novel psychoactive substances . Myocardium . Kidney . Gastrointestinal tract . Mice Abbreviations Introduction NPSs Novel psychoactive substances MPA Methiopropamine In the last 10 years, there has been an increase in the number METH Methamphetamine and types of novel psychoactive substances (NPSs) notified to MI Myocardial infarction the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). Such compounds are defined by EU Federica Foti and Matteo Marti contributed equally to this work. * Fabio De-Giorgio 5 Laboratorio Antidoping, Federazione Medica Sportiva Italiana, [email protected] Rome, Italy 1 Institute of Public Health, Section of Legal Medicine, Università 6 Department of Experimental Medicine, BSapienza^ University, Cattolica del Sacro Cuore, L.go F. Vito 1, 00168 Rome, Italy Rome, Italy 2 Department of Morphology, Surgery and Experimental Medicine, 7 Section of Legal Medicine, Università di Ferrara, Ferrara, Italy Department of Radiological, Oncological and Pathological Sciences, Università La Sapienza, Rome, Italy 3 Department of Life Sciences and Biotechnology (SVeB), Università di Ferrara, Ferrara, Italy 8 Department of Environmental, Biological and Pharmaceutical 4 Institute of Genomic Medicine, Università Cattolica del Sacro Cuore, Sciences and Technologies, Università della Campania L. Vanvitelli, Rome, Italy Caserta, Italy 812 Int J Legal Med (2019) 133:811–820 Council Decision 2005/387/JHA as new psychotropic drugs behavioural disturbances associated with psychosis and fea- in pure form or in a preparation that has not be scheduled in tures consistent with sympathomimetic toxicity (fever, sweat- the 1961 or in the 1971 United Nations Single Convention on ing, tachycardia, dilated pupils, increasing auditory and visual Narcotic Drugs/Psychotropic Substances and that may pose a hallucinations, agitation, aggression and insomnia) that may threat to public health comparable to the substances listed in be caused or contributed to by MPA, which was detected either schedule I, II, III or IV [1]. They are sold through the together with benzodiazepine. Even a case of sudden death Internet as Bbath salts^ or Blegal highs^ [2], and their market has been related to the use of MPA, as there were neither has a rapid turnover, making it difficult for laboratories and health problems nor other drugs or alcohol detected in the institutions to keep up with the appearance of these new com- toxicological post-mortem analysis: MPA was detected in pounds. Therefore, little is generally known about NPS’stox- the blood (38 mg/l) and urine. The autopsy showed non- icity when they enter the recreational drug scene. specific pulmonary oedema consistent with a fatal cardiac One of them is methiopropamine (MPA), which chemistry arrhythmia inducing cardiovascular collapse, with the same directly links to amphetamine and methamphetamine mechanism of action as METH [8]. However, the authors (METH) (http://www.who.int/medicines/areas/quality_ did not describe any microscopic feature consistent with spe- safety/4_23_review.pdf); similar to those stimulant drugs, cific organ damage. MPA inhibits dopamine and norepinephrine reuptake and, to Moreover, MPA’s side effects, such as vasoconstriction, a lesser extent, serotonin reuptake [3]. The use of MPA in cold extremities, Bracing heart^ and chest tightness, have been Europe has been recognised since January 2011. MPA’s widely discussed on informal Internet fora (https://www. stimulant properties include alertness and an increase in erowid.org/chemicals/methiopropamine/methiopropamine_ focus and energy, which are appealing to those needing to effects.shtml), thereby describing only acute toxicity. stay awake and alert for a long time, especially during night To the best of our knowledge, the literature contains no data hours, either, for instance, to work hard or to go out dancing. on health hazards secondary to chronic MPA consumption, This could be sufficient to broaden the Internet market for and no experimental studies evaluating its chronic toxicity misuse, especially among younger generations who consider have been performed. In light of recent scientific evidence the Internet an easier way to supply their needs. Consuming highlighting the risk of addiction-like behaviour induced by products containing NPSs can result in harmful behaviours, MPA consumption [9], we evaluated the effects of chronic such as violence, traffic accidents, self-injury or suicide at- MPA abuse on body tissues, using a mouse model. tempts; physical complications, such as liver or kidney injury; Moreover, to better understand the effects of the chronic and neuropsychiatric symptoms, such as agitation, anxiety, MPA treatment on mice behaviour, we investigated the effects fear, psychosis and panic attack [4]. At present, clinicians of chronic MPA on mouse body weight changes and food should already be aware that NPS abuse could be related to intake, body temperature, muscle strength and motor coordi- hospital emergencies and even cause death, but there is still nation. Finally, considering the cardiovascular effects caused limited information on the large amount of substances sold by MPA in humans, we studied the effects of acute MPA and consumed. In addition, most of them, including MPA, administration on cardiovascular function (heart rate and can only be detected by special tests, such as gas/liquid chro- vasoconstriction). matography mass spectrometry; therefore, a toxicological urine screen for routine psychostimulant drugs could be of little help in identifying such cases. Suspicions of NPS intox- Materials and methods ication should arise in the presence of patients with unex- plained psychiatric, neurological, cardiac or gastrointestinal Animals symptoms. In the scientific literature, the number of reported cases of acute toxicity (hospital admissions and deaths) direct- Sixty male ICR (CD-1®) mice, 25–30 g (Harlan Italy; S. ly attributed to MPA is very limited. The first was published in Pietro al Natisone, Italy), were group-housed (eight mice per 2014, regarding a young woman admitted in the emergency cage; the floor area per animal was 80 cm2; the minimum cage department with palpitations, Bchest tightness^, nausea and height was 12 cm) in a colony room under a constant temper- vomiting and a feeling of anxiety and euphoria with agitation ature (23–24 °C) and humidity (45–55%). Food (Diet 4RF25 and visual hallucinations. These alterations were reversible GLP; Mucedola, Settimo Milanese, Milan, Italy) and tap wa- upon diazepam administration and fluid replacement; MPA ter were available ad libitum the entire time the animals spent was detected in urine at a concentration of 400 μg/l [5]. in their home cages. The daylight cycle was maintained arti- Another case concerns a young man presenting with paranoid ficially (dark between 7 p.m. and 7 a.m.). The present study delusion, incoherent speech and auditory and visual halluci- was performed in accordance with the new European nations [6]. In the Identification Of Novel psychoActive sub- Communities Council Directive of September 2010 (2010/ stances (IONA) study [7], a patient presented with severe 63/EU), a revision of the Directive 86/609/EEC and approved Int J Legal Med (2019) 133:811–820 813 by the Italian Ministry of Health (licence no. 335/2016-PR) After 30 days, the surviving mice were sacrificed by cervi- and by the Ethics Committee of the University of Ferrara. cal dislocation and their organs were analysed. Pathologic
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