Association between road traffic accidents and drugs belonging to the antiseizure medications class: A pharmacovigilance analysis in VigiBase.

AIMS: Due to their central mechanism of action, antiseizure medications (ASMs) could lead to adverse effects likely to impair driving skills. Their extended use to neuropsychiatric disorders makes it a class of drugs to monitor for their road traffic accidental (RTA) potential. We aimed to assess the reporting association between ASMs and RTAs using the World Health Organization pharmacovigilance database (VigiBase). METHODS: We performed a disproportionality analysis to compute adjusted reporting odds ratios to evaluate the strength of reporting association between ASMs and RTAs. A univariate analysis using the reporting odds-ratio was used to assess drug-drug interactions between ASMs and RTAs. RESULTS: There were 1 341 509 reports associated with at least 1 ASM in VigiBase of whom 2.91‰ were RTAs reports. Eight ASMs were associated with higher reporting of RTAs compared to others (ranging from 1.35 [95% confidence interval 1.11-1.64] for lamotrigine to 4.36 [95% confidence interval 3.56-5.32] for cannabis). Eight significant drug-drug interactions were found between ASMs and the onset of RTA, mainly involving CYP450 induction. CONCLUSION: A significant safety signal between RTAs and some ASMs was identified. Association of several ASMs might further increase the occurrence of RTA. ASMs prescription in patients with identified risk factors of RTA should be considered with caution. Study number: ClinicalTrials.gov, NCT04480996.

An Investigation of O-Demethyl Tramadol/Tramadol Ratio for Cytochrome P450 2D6 Phenotyping: The CYTRAM Study.

Cytochrome P450 2D6 (CYP2D6) gene polymorphisms influence the exposure to tramadol (T) and its pharmacologically active metabolite, O-demethyl tramadol (O-dT). Tramadol has been considered as a candidate probe drug for CYP2D6 phenotyping. The objective of the CYTRAM study was to investigate the value of plasma O-dT/T ratio for CYP2D6 phenotyping. European adult patients who received IV tramadol after surgery were included. CYP2D6 genotyping was performed and subjects were classified as extensive (EM), intermediate (IM), poor (PM), or ultra-rapid (UM) CYP2D6 metabolizers. Plasma concentrations of tramadol and O-dT were determined at 24 h and 48 h. The relationship between O-dT/T ratio and CYP2D6 phenotype was examined in both a learning and a validation group. Genotype data were obtained in 301 patients, including 23 PM (8%), 117 IM (39%), 154 EM (51%), and 7 UM (2%). Tramadol trough concentrations at 24 h were available in 297 patients. Mean value of O-dT/T ratio was significantly lower in PM than in non-PM individuals (0.061 ± 0.031 versus 0.178 ± 0.09, p < 0.01). However, large overlap was observed in the distributions of O-dT/T ratio between groups. Statistical models based on O-dT/T ratio failed to identify CYP2D6 phenotype with acceptable sensitivity and specificity. Those results suggest that tramadol is not an adequate probe drug for CYP2D6 phenotyping.

Pharmacokinetics of 300 mg/d Intraperitoneal Daptomycin: New Insight from the DaptoDP Study.

The DaptoDP (NCT 2012-005699-33) study aimed to evaluate the pharmacokinetic parameters of daptomycin (DAP) in peritoneal dialysis-related peritonitis (PDRP) patients following intraperitoneal (IP) administration. The authors have already reported the findings on the 200-mg dosing and present here the follow-up results of the 300-mg dosing. The primary endpoint was a dialysate concentration of DAP above the effective concentration in situ during 6 hours of dwell time i.e., 16 mg/L. Secondary endpoints were to avoid the toxic threshold of 120 mg/L DAP and to be above 16 mg/L DAP for 2 hours in plasma. Pharmacokinetic parameters were evaluated on days 1 and 5. Safety data were evaluated on days 1 to 14 based on clinical and biological parameters. Daptomycin was administered in Nutrineal during 6 hours of dwell time for 14 days plus the usual antibiotic therapy in a separate dwell. Because the 200-mg dosing objectives were not reached, a higher DAP dose of 300 mg was tested in the next 3 patients. Effective dialysate and plasma concentrations were achieved at the 300-mg DAP dose with the plasma concentration well below the toxic threshold, even at steady state, during which the accumulation factor never exceeded 3. The optimal DAP dose of 300 mg daily by the IP route, as determined by the pharmacokinetic data, needs to be clinically confirmed prior to routine use. The peritoneal bioavailability of DAP supports using the IP route as an alternative to the intravenous route for peritonitis and systemic infections.

Pharmacokinetics of Intraperitoneal Daptomycin in Patients with Peritoneal Dialysis-Related Peritonitis.

♦ BACKGROUND: Antibiotics are preferentially delivered via the peritoneal route to treat peritoneal dialysis-related peritonitis (PDRP) to ensure that maximal concentrations are delivered to the site of infection. Our study focused on the pharmacokinetics of daptomycin (DAP) administered via the intraperitoneal (IP) route in patients with PDRP. ♦ METHODS: According to the DaptoDP protocol (Clinical Trial No. 2012-005699-33), IP DAP was administered daily, i.e., during the 6-h Nutrineal (Baxter Healthcare Corporation, Deerfield, IL, USA) dwell time period, for 14 days, in addition to administration of the antibiotics used for the usual care of patients with PDRP. The plasma and IP levels of DAP were measured on days 1 and 5. The tested dose was 200 mg/day. The principal endpoint was the dialysate concentration after 6 hours of dwell time > 16 mg/L (corresponding to 4 x minimum inhibitory concentration [MIC] for E. faecalis). ♦ RESULTS: Three participants were evaluated. On day 5, the IP concentrations after 6 hours of dwell time were between 6.3 and 23.4 mg/L, and the peak plasma concentrations were between 13.0 and 15.3 mg/L. ♦ CONCLUSION: The results suggest that 200 mg/day is very likely sufficient for the treatment of PDRP by Staphylococci or Streptococci whereas it could be insufficient to treat PRDP by Enterococci. The good peritoneal bioavailability of DAP was quantitatively established, suggesting that IP administration could also be used as an alternate route for patients with damaged venous access. No DAP accumulation that could lead to toxic concentrations after repeated administration is expected, even in anuric patients. The protocol will further continue to assess whether a higher dose achieves the pharmacokinetic objectives.

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.

Patterns of adherence to raltegravir-based regimens and the risk of virological failure among HIV-infected patients: the RALTECAPS cohort study.

Adherence patterns and their influence on virologic outcome are well characterized for protease inhibitor (PI)- and non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens. We aimed to determine how patterns of adherence to raltegravir influence the risk of virological failure. We conducted a prospective multicenter cohort following 81 HIV-infected antiretroviral-naive or experienced subjects receiving or starting twice-a-day raltegravir-based antiretroviral therapy. Their adherence patterns were monitored using the Medication Events Monitoring System. During follow-up (188 days, ±77), 12 (15%) of 81 subjects experienced virological failure. Longer treatment interruption [adjusted odds ratio per 24-hour increase: 2.4; 95% confidence interval: 1.2 to 6.9; P < 0.02] and average adherence (odds ratio per 5% increase: 0.68; 95% confidence interval: 0.46 to 1.00, P < 0.05) were both independently associated with virological failure controlling for prior duration of viral suppression. Timely interdose intervals and high levels of adherence to raltegravir are both necessary to control HIV replication.

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.

[Therapeutic drug monitoring of clonazepam]. / 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.

[Not Available]. / 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 µg/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.

[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.