Danièle Debruyne

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.

Emerging drugs of abuse: current perspectives on synthetic cannabinoids

New psychoactive drugs that have appeared over the last decade are typically dominated by cathinones and synthetic cannabinoids (SCs). SCs have been emerging as recreational drugs because they mimic the euphoria effect of cannabis while still being legal. Sprayed on natural herb mixtures, SCs have been primarily sold as “herbal smoking blends” or “herbal incense” under brand names like “Spice” or “K2”. Currently, SCs pure compounds are available from websites for the combination with herbal materials or for the use in e-cigarettes. For the past 5 years, an ever increasing number of compounds, representative of different chemical classes, have been promoted and now represent a large assortment of new popular drugs of abuse, which are difficult to properly identify. Their legal status varies by country with many government institutions currently pushing for their control. The in vitro binding to CB1/CB2 receptors is usually well-known and considerable differences have been found in the CB1 versus CB2 selectivity and potency within the different SCs, with several structure-activity relations being evident. Desired effects by CB1 agonist users are relaxation/recreative, however, cardiovascular, gastrointestinal, or psychiatric/neurological side effects are commonly reported. At present there is no specific antidote existing if an overdose of designer drugs was to occur, and no curative treatment has been approved by health authorities. Management of acute toxic effects is mainly symptomatic and extrapolated from experience with cannabis.

Focus on cannabinoids and synthetic cannabinoids

The recent emergence of a multitude of synthetic cannabinoids (SCs) has generated a wealth of new information, suggesting the usefulness of state‐of‐the‐art on lato sensu cannabinoids. By modulating a plurality of neurotransmission pathways, the endocannabinoid system is involved in many physiological processes that are increasingly explored. SCs desired and adverse effects are considered to be more intense than those observed with cannabis smoking, which is partly explained by the full agonist activity and higher affinity for cannabinoid receptors. Neurological and cardiovascular side effects observed after cannabinoid poisoning generally respond to conventional supportive care, but severe outcomes may occur in a minority of cases, mainly observed with SCs. The likelihood of severe abuse and addiction produced by SCs are of concern for the scientific community also interested in the potential therapeutic value of cannabinoids.

Daptomycin compatibility in peritoneal dialysis solutions.

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Suivi thérapeutique pharmacologique du clonazépam

Clonazepam is a 1-4 benzodiazepine mainly used to treat epilepsy and epileptiform convulsion state. Rapidly absorbed after oral administration, it is widely distributed in the organism and is extensively converted in metabolites, poorly or not active, eliminated mainly in urine (70%) and feces. Elimination half-life is long, around 40 h. In adult and child, several studies showed a concentration-effect relation. Meanwhile, a large inter-individual variability in the dose-concentration relation was observed. A 15-50 microg/L range of clonazepam blood concentrations appears to be retained as an acceptable target to control a majority of epileptic seizures. The Therapeutic Drug Monitoring (TDM) of clonazepam can be considered as possibly useful in case of association with CYP450 inducers or inhibitors, suspicion of poor observance, or toxicity signs.

Comment on “A Unique Case of Cardiac Arrest following K2 Abuse”

We appreciated reading the paper by Ibrahim et al. [1] describing the impact of K2 abuse on sudden cardiac death (SCD). This paper, although it provides interesting information about synthetic cannabinoid (SC), it also presents several limitations. Notably, the authors formally connected the K2 abuse and the SCD. In contrast to Ibrahim et al., we think that the SCD is mainly related to the cardiac history of the patient. Substantial evidence supports our point of view. First, the patient had a past cardiological history with a previous myocardial infarction (MI) and four-vessel coronary artery bypass graft 10 years ago. Authors did not specify where the MI was located but we can suppose, from the electrocardiogram (ECG) in sinus rhythm, that it was an inferior MI (Q wave in inferior derivations). Moreover, authors did not specify the exact coronary lesions in native vessels. It would be interesting to know if one vessel (right coronary artery) was occluded. All these elements are important because it is well established that most of SCD cases in coronary artery disease patients occur on previous myocardial scar (which is the consequence of a coronary artery occlusion and results in the presence of Q wave in a coronary artery territory) and typically 10 years after MI [2–4]. Another element that supports our hypothesis is that authors declare that “the cardiac arrest was not associated with an acute coronary occlusion” [1] which is largely in favor of our theory. So it seems more reasonable to think that cardiac arrest is the consequence of a malignant reentrant ventricular arrhythmia than K2 abuse [2, 3]. It seems also difficult to conclude a myocardial necrosis based on moderate troponin T elevation (0.632). It would be helpful to specify the laboratory standards for the troponin T. The moderate elevation seems more likely due to the resuscitation (drugs, defibrillation, cardiac massage…) than a real myocardial necrosis which usually leads to major troponin T elevations [5]. Second, we have serious concerns regarding some cardiological interpretation of this observation. In fact, authors interpreted the ECG on admission [1] as a sinus tachycardia. It is wrong. This ECG shows a typical atrial flutter with a 2/1 ventricular conduction. We can recognize the atrial flutter with a regular and typical atrial activation near 240/min, uniform and continuous in all leads, with the typical “sawtooth” pattern in the inferior leads (manifested by a notching of the end of the QRS complex, clearly visible in V1 derivation and disappears during sinus rhythm in the second ECG presented by Ibrahim et al.). There is a classically 2 : 1 ventricular response [6]. The very long PR interval observed during tachycardia and absent in sinus rhythm also indicated that the rhythm cannot be sinusal in the first ECG. Atrial flutter following a cardiac arrest is classical when using drugs such as epinephrine or adrenaline and disappears most frequently in few hours or a day [7]. Regarding ECGs, we agree that cannabinoids have an impact on several ion channels but it seems difficult to directly link these properties to ECG changes, especially since the patient already has changes on his baseline ECG due to his coronary artery disease (and possibly antiarrhythmic drugs). Third, evidence supports that cannabis is now a well-known trigger for MI [8, 9]. However, the challenge remains to link clearly the cardiac event to cannabinoids consumption and case reports are most often published without a clear etiology, with conclusions which are therefore most speculative. Conversely, the SC impact on serious cardiac events remains to date unknown, even if there are serious concerns [10–15]. The increasing use of SC as drug of abuse and their consequences in terms of public health have, therefore, to be closely monitored, especially considering pharmacological properties as the higher affinity for cannabinoid receptors than natural cannabinoid delta-9 THC resulting in higher pharmacological activity, early demonstrated with first SC [16, 17]. This present case report by Ibrahim et al. is therefore consistent with previously published reports but, to our knowledge, cannot reliably connect SC and SCD. In conclusion, there are several evidences [10–15] to think that cannabis and SC can lead to serious cardiac disorders but we think that this case report is speculative rather than affirmative (because of the study limitations described above) and therefore, conclusions should be more modulated.

Radiosynthesis and ex vivo evaluation of [11C]-SIB-1553A as a PET radiotracer for β4 selective subtype nicotinic acetylcholine receptor

[11C]-SIB-1553A ((+/-)-4-[2-((N-[11C]-methyl)-2-pyrrolidinyl)ethyl]thiophenol) was labelled with carbon-11 (t1/2=20.4 min) and evaluated in vivo as potential radiotracer for noninvasive assessment of the beta4 subunit nicotinic acetylcholine neurotransmission system with positron emission tomography (PET). The labelling precursor was obtained within five steps from N-Boc-prolinal in 45-56% overall yields. The radiosynthesis of [11C]-SIB-1553A was achieved by a selective N-[11C]-methylation in 32 min with a radiochemical purity greater than 97%, 7.5-30 GBq/micromol of specific radioactivity and 55-65% radiochemical yield (decay corrected, based on [11C]methyl iodide). The ex vivo pharmacological profile of [11C]-SIB-1553A was evaluated in rats with biodistribution studies in organs and in brain structures by autoradiography. The radiotracer uptake in the brain reached 0.49 %ID/g at 10 min and no brain radiometabolite was detected 40 min after intravenous injection. The quantification of radioactivity in various cerebral structures indicated a significantly higher radioactivity level at 15 min than at 30 min. Among the beta4 nAChR subunit-rich structures studied in the rat brain, only the thalamus at 15 and 30 min and the hippocampus at 30 min showed significantly higher uptake. Moreover, competition studies performed with SIB-1553A (15 min before the radiotracer injection) revealed only a low specific binding estimated to 7% of the total binding at 15 min and 13% at 30 min.

Le syndrome de la poche à urine violette : à propos d’un cas avec identification des substances colorantes

The report of purple discoloration in an urinary drainage system known as purple urine bag syndrome, is primarily described in elderly female patient with chronic urinary catheterization. Some factors are frequently associated: constipation, insanity, alkaline urine, urinary tract infection and indicanuria. The aetiology remains elusive. The discoloration would be secondary to the presence of indigo and indirubin dissolved in the plastic of the catheterbag.Wereportthecaseofa71year-oldwomanwithtwoepisodesofthistype.Usingagaschromatography- mass spectrometry original method, we have formally identified, from plastic bag, indigo and, for the first time, indirubin.

Synthetic cannabinoid (K2) use in pediatric patients and cardiovascular events: A place for pericarditis and myopericarditis?

To the Editor: We read with interest the article by Clark et al assessing the link between synthetic cannabinoids andmyocardial ischemia in pediatrics. Evidence supports cannabis as a trigger for myocardial ischemia. Cannabinoid 1/cannabinoid 2 receptors are widely distributed in the cardiovascular system, which could explain cardiac disorders linked to intake of synthetic cannabinoids, even if they do not all bind the cannabinoid receptors with greater affinity than D9-tetrahydrocannibol. Today the challenge remains to link with certainty cardiac events to synthetic cannabinoid consumption. This relationship is based primarily on chronological criteria, with the limitations that implies. Myocardial ischemia and infarction are the most frequently implicated cardiac events; however, we believe that pericarditis and myopericarditis should be considered in this context as well. Pericarditis and myopericarditis are very frequent cardiovascular events, particularly in male pediatric patients. This patient category is also the greatest consumer cannabis and synthetic cannabinoids. These elements could introduce a bias in causality assessment. The presence of pericardial effusion and the rise in troponin level may be insufficient for a diagnosis, given the occurrence of dry pericarditis. Therefore, in this series of pediatric patients, it would have been interesting to use cardiac myocardial magnetic resonance imaging, which is the most powerful diagnostic tool for acute myocarditis, based on delayed enhancement imaging findings, to confirm such a diagnosis with confidence.

Suivi thérapeutique pharmacologique du clobazam

Clobazam is a 1,5 benzodiazepine available in France since 1975, used in add-on with the other anticonvulsant drugs in the treatment of refractory epilepsies of child and adult and for the treatment of anxiety of adult. It is mainly metabolized in desmethylclobazam, or norclobazam, active metabolite, present in a concentration approximately eight times superior to that of the parent drug, but with an activity of the order of 20 to 40% of that of clobazam. Elimination half-life of clobazam is of 18 h while that of norclobazam is from 40 to 50 h. There is a large interindividual variability in the plasma concentrations. Furthermore, clobazam being prescribed in add-on with the other anticonvulsant drugs in resistant epilepsies, concentration-effect relationship is difficult to bring to light, since, in many studies, the patients who did not answer received the highest doses. Adverse reactions are moderated, appearing more often for the highest concentrations; also the phenomenon of tolerance seems more frequent in high concentrations. However, because of the kinetic interactions, a dosage of clobazam and norclobazam can be useful in certain cases. There is no validated therapeutic range, but the usual concentrations are in the range of 100-300 μg/L for the parent drug and about ten times more for the metabolite. The level of proof of the interest of the Therapeutic Drug Monitoring for this molecule is estimated in: rather useless.