Emerging drugs of abuse: current perspectives on substituted cathinones.

Substituted cathinones are synthetic analogs of cathinone that can be considered as derivatives of phenethylamines with a beta-keto group on the side chain. They appeared in the recreational drug market in the mid-2000s and now represent a large class of new popular drugs of abuse. Initially considered as legal highs, their legal status is variable by country and is rapidly changing, with government institutions encouraging their control. Some cathinones (such as diethylpropion or pyrovalerone) have been used in a medical setting and bupropion is actually indicated for smoking cessation. Substituted cathinones are widely available from internet websites, retail shops, and street dealers. They can be sold under chemical, evocative or generic names, making their identification difficult. Fortunately, analytical methods have been developed in recent years to solve this problem. Available as powders, substituted cathinones are self-administered by snorting, oral injestion, or intravenous injection. They act as central nervous system stimulants by causing the release of catecholamines (dopamine, noradrenaline, and serotonin) and blocking their reuptake in the central and peripheral nervous system. They may also decrease dopamine and serotonin transporter function as nonselective substrates or potent blockers and may inhibit monoamine oxidase effects. Nevertheless, considerable differences have been found in the potencies of the different substituted cathinones in vitro. Desired effects reported by users include increased energy, empathy, and improved libido. Cardiovascular (tachycardia, hypertension) and psychiatric/neurological signs/symptoms (agitation, seizures, paranoia, and hallucinations) are the most common adverse effects reported. Severe toxicity signs compatible with excessive serotonin activity, such as hyperthermia, metabolic acidosis, and prolonged rhabdomyolysis, have also been observed. Reinforcing potential observed in animals predicts a high potential for addiction and abuse in users. In case of overdose, no specific antidote exists and no curative treatment has been approved by health authorities. Therefore, management of acute toxic effects is mainly extrapolated from experience with cocaine/amphetamines.

Effects of three therapeutic doses of codeine/paracetamol on driving performance, a psychomotor vigilance test, and subjective feelings.

RATIONALE: Some recent pharmacoepidemiological studies revealed an elevated risk of driving accidents after opioid analgesics uses. Among analgesics, codeine is often associated with paracetamol in numerous pharmaceutical specialties. OBJECTIVES: The objective of this study was to evaluate the dose-effect relationship of three usual therapeutic doses of codeine/paracetamol on driving ability, psychomotor performance, subjective alertness, in link with blood concentrations in healthy young volunteers. METHODS: Driving performance, responses to psychomotor vigilance tests, and scales reflecting alertness were evaluated during the morning after drug intake in a double-blind, randomized, placebo-controlled study. Sixteen healthy volunteers (23.4 ± 2.7 years old, 8 men and 8 women) participated in this balanced, cross-over study. Three doses of codeine/paracetamol (20/400, 40/800, 60/1200 mg) were evaluated against placebo. Two blood samples were collected, 1 and 4 h after drug intake. In serum, codeine and morphine concentrations were determined in serum using high-performance liquid chromatography electrospray ionization-tandem mass spectrometry, and paracetamol concentrations using fluorescence polarization immunoassay. RESULTS: Driving and psychomotor performance were not affected by any of the three codeine/paracetamol doses. However, significant, though modest, correlations were observed between the driving parameters and both morphine and codeine blood concentrations. CONCLUSIONS: This study did not reveal any significant impairment in performance due to the three therapeutic doses used in healthy young volunteers. However, the relationships between drug blood concentration and behavioral measures suggest that an inter-subject variability in blood concentration may influence the power of the observed drug effect.

Zolpidem and zopiclone impair similarly monotonous driving performance after a single nighttime intake in aged subjects.

RATIONALE: Although hypnotics are primarily used by older people, the residual effects the morning after a single nighttime intake of the two most commonly prescribed hypnotics, zolpidem (Zp) and zopiclone (Zc), on older middle-aged drivers have not been evaluated and compared. METHODS: Sixteen healthy subjects, 55 to 65 years of age, participated in this double-blind, balanced, cross-over study. Zc (7.5 mg), Zp (10 mg) and flunitrazepam (Fln) (1 mg) or a placebo was administered at each subject's home at 11.00 pm. The next morning, at 9.00 am, the subjects had to drive in a simulated monotonous driving environment for 1 h. During each morning session, two blood samples were collected, and subjective feelings of alertness were completed three times. RESULTS: In comparison to placebo, Zp and Zc equivalently and significantly impaired the standard deviation of lateral position, the standard deviation of speed and the number of road exits. Detectable blood concentrations were found with Zp in 11 subjects at 8.30 am and at 1.30 pm. The subjective alertness factor was significantly impaired with Zp. CONCLUSIONS: This is the first study revealing residual effects of Zp on driving performance in ageing drivers which are similar to that of Zc. Studying the effects of medication in different age ranges appears useful to complete the studies on behavioural-pharmacological effects of medication. To reduce the incidence of driving accidents due to prescription drugs, patients should be warned at the time of treatment initiation that they should avoid driving.

[Comparison between analytic and anamnestic data about drug consumption among opiate addicts with substitutes therapy. A feasibility study]. / Comparaison des données analytiques et anamnestiques des consommations de drogues et psychotropes chez des usagers d'opiacés en traitement de substitution. Etude de faisabilité

In this feasibility study of an observational nature, we used the protocol 'AnalyTox-Op' to compare analytical data with anamnestic reports gathered from specialized drug addiction treatment centers. These data were collected from 32 drug addicts who were patients undergoing treatment with addictive drug substitutes or prescribed psychotropic drugs. Urine toxicology screens were performed using immunological methods followed by confirmation with more specific techniques, i.e. gas chromatography coupled with mass spectrometry (GC-MS) and liquid chromatography with diode array detection (HPLC-DB). While complete agreement between patient reports of drug consumption (obtained from a questionnaire) and analytical data was only observed in 13 out of the 32 cases, a very good concordance was seen with opiate substitutes (88% with methadone and high-dosage buprenorphine, combined) and legally prescribed psychotropic drugs. Of note, however, was the omission of illicit drug use in patient questionnaires, especially with cocaine (22%) and recreational opiates (22%), causing discordance in the comparison. This study is currently being expanded to include a large number of participants across the country with the aim of obtaining data under homogeneous conditions, verifying the discordance we found and determining its significance.

Novel aminoethylbiphenyls as 5-HT7 receptor ligands.

The synthesis of a series of aminoethylbiphenyls as novel 5-HT(7) receptor ligands is described. The novel derivatives exhibit high affinity for the 5-HT(7) receptor with selectivity toward 5-HT(1A) receptor.

Molecular modeling studies focused on 5-HT7 versus 5-HT1A selectivity. Discovery of novel phenylpyrrole derivatives with high affinity for 5-HT7 receptors.

The present study discusses the well-known 5-HT7/5-HT1A selectivity issue through a new series of phenylpyrrole derivatives. The first hits emerged from a virtual screening performed on a chemolibrary. Further study led to an optimization of a preliminary 5-HT7 pharmacophore model. The importance of each pharmacophoric feature is confirmed, but these characteristics have to be coupled to geometric constraints in order to achieve a 5-HT7 selectivity. Indeed, 5-HT1A affinity probably arises from extended conformations, whereas a bent one appears to be best suited for 5-HT7 selectivity.

Phenylpyrroles, a new chemolibrary virtual screening class of 5-HT7 receptor ligands.

Virtual screening studies have identified a series of phenylpyrroles as novel 5-HT7 receptor ligands. The synthesis and the affinity for the 5-HT7 receptor of these phenylpyrroles are described. Some of these compounds exhibited high affinity for the 5-HT7 receptors.