| Humans |
Toxic doses for humans were determined to be located between 1-2 mg/kg. Symptoms occur between 15 and 120 mins after consumption and are characterised by seizures, respiratory depression, mydriasis, tachycardia, hypertension and hyperpnea. |
Borbély et al.189
|
| Hereford calves |
An increase in arterial blood pressure but no pulmonary side-effects after daily i.v. injections (0.25 mg/kg) for one month were reported. |
Byrne-Quinn & Grover28
|
| Sprague-Dawley rats |
A dose of 1.5 μmol/kg, administered i.v., elicited increased motor activity. Stereotypical behaviour was not detected in doses up to 112 μmol/kg. |
Costa et al.37
|
| Wistar rats |
After administration of 6.5 to 22mg/kg aminorex daily for 118 consecutive days, no anatomical differences of the pulmonary vessels were detectable. |
Engelhardt & Hort32
|
| Humans |
This retrospective study highlighted that anticoagulant therapy with warfarin in aminorex-caused pulmonary hypertension had beneficial effects on their survival time. |
Frank et al.190
|
| Rabbits |
Aminorex was found to be an efficient 5-HT releaser in platelets, similar in potency to amphetamine. |
Friström et al.191
|
| Human subjects |
Two studies (79 and 60 subjects) have proven aminorex (7.5 mg) to be an effective anorectic agent, similar to dextroamphetamine and diethylpropion but more effective than phenmetrazine. Side-effects concerning the CNS, the GI tract and the renal system, as well as leukopenia were reported. |
Hadler14
|
| Mongrel cats |
1.0 mg/kg i.p. caused a 90 % decrease in food intake and lead to 81.5 % of a 12 hour session being spent awake, 16.5 % in slow-wave sleep and 2.0 % in paradoxical sleep. |
Johnson et al.192
|
| Baboons |
Self-injection experiments showed for doses of 0.1 and 0.32 mg/kg/injection cyclical patterns of self-injection, with numbers of injections per day similar to cocaine, suggesting abuse potential. Food intake was decreased significantly at the highest concentration. |
Kaminski et al.193
|
| Wistar albino rats; beagle dogs |
Treatment with aminorex for 43 (rats) and 20 weeks (dogs) did not reveal evidence of pulmonary vascular disease. |
Kay et al.17
|
| Human subjects |
Aminorex was shown to be an effective anorectic drug and no relevant side-effects were reported after a daily intake of 10 mg for 120 days (20 patients). |
Kew194
|
| Beagle dogs |
Treatment of dogs with high doses of aminorex for 13 weeks led to no significant pulmonary and cardiac abnormalities. |
Leuschner et al.33
|
| Swine (young) |
Aminorex was given for three months but no significant cardiovascular and pulmonary side-effects could be detected. |
Mlczoch et al.195
|
| Swine |
Up to 15 mg/kg of aminorex per day was fed to swine for four months. No signs of pulmonary arterial hypertension could be detected but a slight decrease in cardiac and pulmonary function was noticeable. |
Orr et al.31
|
| Sprague-Dawley rats |
Aminorex was shown to be amongst the most potent amphetamine-type stimulants concerning its ability to evoke anorexia and stimulant activity. |
Paul et al.196
|
| CHO cells |
Aminorex inhibits hKv1.5 channels with a KD > 300 μM. |
Perchenet et al.39
|
| Rats |
Aminorex was shown to have an ED50 of 5.8 mg/kg. |
Poos et al.9
|
| Rats |
3 and 6 mg/kg were administered orally and motor activity was evaluated. Aminorex, when compared to 4-MAR and amphetamine, was shown to reach peak motor activity levels earlier (after 40 minutes) than the other compounds (4-MAR after 80 minutes and amphetamine after 130 minutes). |
Poos et al.197
|
| Sprague-Dawley rats |
Aminorex was shown to generalise for amphetamine and to have an ED50 of 3.0 μmol/kg. No stimulus generalisation could be obtained with rexamino. |
Russell et al.153
|
| Wistar rats |
Aminorex induced stereotyped behaviour, lasting three hours at 5.0 mg/kg, administered s.c. in rats pre-treated with α-methyl-p-tyrosine. |
Sayers & Handley198
|
| Patas monkeys |
Up to 4 mg/kg of aminorex was administered for 347 consecutive days and cardiac catheterization and autopsy results revealed no significant pulmonal and cardiac pathologies. |
Smith et al.29
|
| Mongrel dogs |
Administration of 1.0 to 1.5 mg/kg aminorex five times per week over two years lead to histologically detectable changes in the pulmonary arteries of 60% of the dogs. The changes were not as severe as those detected in humans suffering from pulmonary arterial hypertension. |
Stepanek & Zak34
|
| Chinese hamsters, V79 Chinese hamster cells, Saccharomyces cerevisiae, Escherichia coli, Salmonella typhimurium |
In contrast to other amino-oxazoline derivatives, mutagenic effects of aminorex could not be shown in vitro and vivo. Most of the other tested compounds were mutagenic but methylation of the oxazoline ring reduced the detrimental effects. |
Suter et al.199
|
| Sprague-Dawley rats |
Aminorex caused 5-HT release in rat hypothalamus in a dose-dependent manner. |
Tao et al.187
|
| Beagle dogs |
1.5 mg/kg aminorex was orally administered and transient increases of pulmonary and systemic arterial blood pressure but no formation of pulmonary hypertension were noted. |
Will & Bisgard30
|
| Rhesus monkeys, CF-1 mice, Sprague-Dawley rats |
Aminorex substituted for amphetamine in generalisation tests, served as a positive enforcer (both in monkeys), caused stimulant-mediated locomotor effects at 1.25 mg/kg (mice) and worsened signs of withdrawal (rats). |
Woolverton et al.200
|
| Sprague-Dawley rats |
Stimulus-generalisation tests revealed that aminorex is recognised by rats as an amphetamine-type stimulant (starting from doses of 0.5 mg/kg). |
Young201
|
| Sprague-Dawley rats |
4-MAR (ED50=1.11) was six times less potent than aminorex (ED50=0.22) in cocaine stimulus generalisation experiments. |
Young & Glennon202
|
| Sprague-Dawley rats |
Aminorex (1 μmol/kg) substituted for S-methcathinone in stimulus generalisation experiments with an ED50 of 0.27 mg/kg. |
Young & Glennon203
|
| CBA mice |
Between 25 mg/kg were injected intraperitoneally for three times in 24 hours. No significant changes in DOPAC or 5-HIAA, as well as no long-lasting depletion of monoamines could be detected. |
Zheng et al.155
|
| 4-methylaminorex |
| Sprague-Dawley rats |
The trans-4S,5S-isomer was the most potent isomer concerning a suppression of the basal firing rate of spontaneously active dopaminergic neurons (trans-4S,5S > cis-4R,5S = cis-4S,5R >>trans-4R,5R). This effect could be reversed by the addition of haloperidol and the D2 and D3 receptor antagonists eticlopride and sulpiride. The (pre-)treatment with pindolol, fluoxetine, granisetron and phentolamine (amongst others) did not change the effects, while pre-treatment with α-methyl-p-tyrosine and reserpine did. |
Ashby et al.150
|
| Sprague-Dawley rats |
The isomers of 4-MAR were ranked according to their ability to induce stereotyped behaviour at various doses: trans-4S,5S > cis-4R,5S = cis- 4S,5R >trans-4R,5R. This effect could be attenuated by administration of dopamine receptor antagonists, suggesting a dopaminergic neural causation of 4-MAR’s behavioural effects. |
Batsche et al.152
|
| Humans |
A case is described where aminorex was misrepresented as 4-MAR. |
Brewster & Davis128
|
| Sprague-Dawley rats |
Acute changes after administration of a single dose were determined. Between 5 and 20 mg/kg were administered. Tryptophan hydroxylase activity declined in a dose-dependent manner. Locomotor activity was dose-dependent and 20 mg/kg led to clonic seizures, oftentimes fatal. |
Bunker et al.204
|
| Humans |
A fatality involving 4-MAR is described (blood levels: 21.3 mg/L and urine levels: 12.3 mg/L). |
Davis & Brewster130
|
| Humans |
A case study is presented where three members of a family that produced and consumed 4-MAR, developed pulmonary hypertension. |
Gaine et al.131
|
| Sprague-Dawley rats |
Administration of the cis- and trans-racemate led to amphetamine stimulus generalisation with the trans-racemate being three times more potent than the cis-racemate (ED50: trans-4S,5S, 0.25 mg/kg > cis-4S,5R, 1.22 mg/kg = cis-4R,5S, 1.52 mg/kg > trans-4R,5R). |
Glennon & Misenheimer151
|
| CF-1 mice |
The seizure-causing properties of 4-MAR were evaluated. Its CD50 was determined to be 90μg and its CD97 110 μg, following intracerebroventricular injection. Thus, 4-MAR has a very steep dose-seizure curve. Onset of the seizures was intermediate (between 60-300 sec) and clonus duration was between 30 and 300 sec. After the termination of clonic activity, a second seizure episode followed after a short period of behavioural arrest. Flunarizine and valproate could be shown to be effective in preventing 4-MAR-caused seizures. |
Hanson et al.205
|
| Wistar rats |
The rank order of potency for elevating extracellular dopamine levels was trans-4S,5S > cis-4S,5R = cis-4R,5S >trans-4R,5R 4-MAR and for elevating 5-HT cis-4S,5R >trans-4S,5S = cis-4R,5S > trans-4R,5R. All isomers caused a decrease of extracellular concentrations of DOPAC and HVA. At lower doses (2.5 and 5.0 mg/kg), the isomers (except for trans-4R,5R) caused rises in locomotor activity and high doses (10 mg/kg) caused biphasic behaviour patterns, with initial rises in locomotor activity being followed by rapid declines and engagement in stereotyped behaviour, ataxia or catatonia. |
Kankaanpää et al.149
|
| Baboons, rhesus monkeys |
Self-administration experiments highlighted cyclical patterns of self-injection, where days with many injections (0.32 mg/kg/injection) were followed by low-rate days (in baboons). This behaviour lead to agitation, stereotypic movements, hypersensitivity and hallucinations. Rhesus monkeys had unlimited access to the compound for one hour and administered up to 100 injections (0.003 to 0.03 mg/kg/injection). The results were interpreted as 4-MAR having strong potential for abuse. |
Mansbach et al.206
|
| Wistar rats |
Conditioned place preference tests revealed that all isomers equipotently induced preference. This effect was, for some isomers, attenuated by the administration of dopamine receptor antagonists and lesions in the nucleus accumbens. Rewarding properties of 4-MAR consumption were revealed to be connected to the dopaminergic system. |
Meririnne et al.207
|
| Rats |
The ED50 of cis-4-MAR was determined to be 8.8 mg/kg. |
Poos et al.9
|
| Rats |
3 and 6 mg/kg were administered orally and motor activity was evaluated. 4-MAR caused peak motor activity levels earlier (after 80 minutes) than amphetamine (130 minutes) but later than aminorex (40 minutes). |
Poos et al.197
|
| Sprague-Dawley rats |
4S,5S-4-MAR was shown to generalise for amphetamine and to have an ED50 of 1.7 μmol/kg. |
Russell et al.153
|
| Mongrel dogs |
Sympathomimetic effects of the compound can be attributed to an increased release of catecholamines (published in 1963). |
Yelnosky & Katz179
|
| Sprague-Dawley rats |
4-MAR (ED50=1.11) was six times less potent than aminorex (ED50=0.22) in cocaine stimulus generalisation experiments. |
Young & Glennon202
|
| Sprague-Dawley rats |
Cis-4-MAR (2.3 μmol/kg) substituted for S-methcathinone in stimulus generalisation experiments with an ED50 of 0.49 mg/kg. |
Young & Glennon203
|
| CBA mice |
Between 5 and 30 mg/kg (depending on the stereoisomer) were injected intraperitoneally for three times in 24 hours. DOPAC levels were increased but no long-lasting depletion of monoamines could be detected. |
Zheng et al.155
|
| 4,4’-dimethylaminorex |
| Sprague-Dawley rats |
An extensive chemical analysis of 4,4'-DMAR was conducted (crystal structure analysis, mass spectrometry, chromatography and spectroscopy). Monoamine transporter assay results are mentioned in Table 1. |
Brandt et al.134
|
| -- |
A mini-review of 4,4'-DMAR. |
Coppola & Mondola208
|
| Humans |
4,4'-DMAR-caused fatalities were examined. Post-mortem concentrations of 4,4'-DMAR were between 0.20 to 3.75 mg/L. Liquid chromatography and mass spectrometry approaches of screening for 4,4'-DMAR were described. |
Cosbey et al.209
|
| -- |
A mini-review of 4,4'-DMAR. |
Glanville et al.210
|
| -- |
Drug fora were analysed to paint a picture of the way users discussed 4,4'-DMAR. |
Loi et al.144
|
| HEK293 cells, rPC12 cells, human striatal synaptic vesicles |
4,4'-DMAR was classified as a non-selective monoamine releasing agent and binding data was provided. Inhibition of VMAT2 hints at long-term neurotoxic effects in chronic abusers of the substance. |
Maier et al.135
|
| Sprague-Dawley rats |
An in-depth chemical analysis of MDMAR was provided. In addition, monoamine transporter assays comparing cis-MDMAR, trans-MDMAR, cis-4,4'-DMAR and trans-4,4'-DMAR are portrayed in Table 1. |
McLaughlin et al.148
|
| -- |
An internet snapshot survey was conducted to analyse the availability of 4,4'-DMAR and 4-MAR in April 2014. |
Nizar et al.143
|
