Publications by authors named "Lucie Chevillard"

38 Publications

L-carnitine does not improve valproic acid poisoning management: a cohort study with toxicokinetics and concentration/effect relationships.

Ann Intensive Care 2022 Jan 29;12(1). Epub 2022 Jan 29.

Department of Medical and Toxicological Critical Care, Federation of Toxicology APHP, Lariboisière Hospital, 2 Rue Ambroise Paré, 75010, Paris, France.

Background: Valproic acid (VPA) poisoning is responsible for life-threatening neurological and metabolic impairments. Despite only low-level evidence of effectiveness, L-carnitine has been used for years to prevent or reverse VPA-related toxicity. We aimed to evaluate the effects of L-carnitine used to treat acute VPA poisoning on the time-course of plasma VPA concentrations and VPA-related toxicity. We designed a single-center cohort study including all VPA-poisoned patients admitted to the intensive care unit. We studied VPA toxicokinetics using a nonlinear mixed-effects model-based population approach and modeled individual plasma VPA/blood lactate concentration relationships. Then, we evaluated L-carnitine-attributed effects by comparing VPA elimination half-lives and time-courses of blood lactate levels and organ dysfunction [assessed by the Sequential Organ Failure Assessment (SOFA) score] between matched L-carnitine-treated and non-treated patients using a multivariate analysis including a propensity score.

Results: Sixty-nine VPA-poisoned patients (40F/29 M; age, 41 years [32-47]) (median [25th-75th percentiles]; SOFA score, 4 [1-6]) were included. The presumed VPA ingested dose was 15 g [10-32]. Plasma VPA concentration on admission was 231 mg/L [147-415]. The most common manifestations were coma (70%), hyperlactatemia (3.9 mmol/L [2.7-4.9]) and hyperammonemia (127 mmol/L [92-159]). VPA toxicokinetics well fitted a one-compartment linear model with a mean elimination half-life of 22.9 h (coefficient of variation, 28.1%). Plasma VPA (C)/blood lactate concentration (E) relationships were well described by an exponential growth equation [[Formula: see text]; with baseline E = 1.3 mmol/L (43.9%) and rate constant of the effect, k = 0.003 L/mg (59.5%)]. Based on a multivariate analysis, peak blood lactate concentration was the only factor independently associated with L-carnitine administration (odds ratio, 1.9, 95% confidence interval, 1.2-2.8; P = 0.004). We found no significant contribution of L-carnitine to enhancing VPA elimination, accelerating blood lactate level normalization and/or preventing organ dysfunction.

Conclusions: VPA poisoning results in severe toxicity. While L-carnitine does not contribute to enhancing VPA clearance, its impact on accelerating blood lactate level normalization and/or preventing organ dysfunction remains uncertain. Investigating VPA toxicokinetics and concentration/effect relationships may help understanding how to improve VPA-poisoned patient management.
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http://dx.doi.org/10.1186/s13613-022-00984-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8800998PMC
January 2022

Case series of massive direct oral anticoagulant ingestion-Treatment and pharmacokinetics data.

Eur J Clin Invest 2022 Jun 12;52(6):e13746. Epub 2022 Jan 12.

Department of Medical and Toxicological Critical Care, AP-HP Lariboisière Hospital, Paris, France.

Background: Direct oral anticoagulants (DOAC) are widely used due to favourable benefit/risk ratio. However, consequences of massive ingestion have been poorly investigated.

Objectives: We aimed to report outcome and pharmacokinetic parameters in patients who massively ingested DOACs.

Methods: We conducted a 5-year cohort study including consecutive massive DOAC ingestion patients admitted to two critical care departments. Patients were managed in accordance with standards of care. We collected the main history, clinical, laboratory, management and outcome data. The time-course of plasma DOAC concentrations measured using specific assays was modelled.

Results: Twelve patients (3F/9M; age, 55 years [41-63], median [25th-75th percentiles]) were included. Ingestions involved rivaroxaban (n = 7), apixaban (n = 3) and dabigatran (n = 2), with presumed doses of 9.4-fold [5.0-22.0] the full daily dose. Six patients received activated charcoal but no antidote nor blood-derived product. No bleeding was observed. One patient died due to refractory cardiogenic shock related to bisoprolol co-intoxication. Highest observed peak plasma concentrations were 1720 ng/ml (rivaroxaban), 750 ng/ml (apixaban) and 644 ng/ml (dabigatran). Times to reach DOAC concentration below 50 ng/ml were ~20-45 h (rivaroxaban), ~125 h (apixaban) and ~30-50 h (dabigatran). Elimination half-lives were 2.5-25.5 h (rivaroxaban), 22.0 and 36.5 h (apixaban), and 5.8 and 15.5 h (dabigatran), with substantial interindividual variability and prolongation in case of cardiovascular failure related to co-intoxicants. Charcoal administration, even if delayed, may have contributed to limit toxicity, possibly by reducing absorption and/or enteroenteric recycling.

Conclusion: No bleeding was observed in this series of massive DOAC ingestions despite elevated plasma concentrations. No patient required specific haemostatic agents. Charcoal administration should be considered to limit toxicity.
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http://dx.doi.org/10.1111/eci.13746DOI Listing
June 2022

Mechanisms of respiratory depression induced by the combination of buprenorphine and diazepam in rats.

Br J Anaesth 2022 03 4;128(3):584-595. Epub 2021 Dec 4.

Université Paris-Saclay - CEA - CNRS - Inserm - BioMaps, Orsay, France.

Background: The safety profile of buprenorphine has encouraged its widespread use. However, fatalities have been attributed to benzodiazepine/buprenorphine combinations, by poorly understood mechanisms of toxicity. Mechanistic hypotheses include (i) benzodiazepine-mediated increase in brain buprenorphine (pharmacokinetic hypothesis); (ii) benzodiazepine-mediated potentiation of buprenorphine interaction with opioid receptors (receptor hypothesis); and (iii) combined effects of buprenorphine and benzodiazepine on respiratory parameters (pharmacodynamic hypothesis).

Methods: We studied the neuro-respiratory effects of buprenorphine (30 mg kg, i.p.), diazepam (20 mg kg, s.c.), and diazepam/buprenorphine combination in rats using arterial blood gas analysis, plethysmography, and diaphragm electromyography. Pretreatments with various opioid and gamma-aminobutyric acid receptor antagonists were tested. Diazepam impact on brain C-buprenorphine kinetics and binding to opioid receptors was studied using positron emission tomography imaging.

Results: In contrast to diazepam and buprenorphine alone, diazepam/buprenorphine induced early-onset sedation (P<0.05) and respiratory depression (P<0.001). Diazepam did not alter C-buprenorphine brain kinetics or binding to opioid receptors. Diazepam/buprenorphine-induced effects on inspiratory time were additive, driven by buprenorphine (P<0.0001) and were blocked by naloxonazine (P<0.01). Diazepam/buprenorphine-induced effects on expiratory time were non-additive (P<0.001), different from buprenorphine-induced effects (P<0.05) and were blocked by flumazenil (P<0.01). Diazepam/buprenorphine-induced effects on tidal volume were non-additive (P<0.01), different from diazepam- (P<0.05) and buprenorphine-induced effects (P<0.0001) and were blocked by naloxonazine (P<0.05) and flumazenil (P<0.05). Compared with buprenorphine, diazepam/buprenorphine decreased diaphragm contraction amplitude (P<0.01).

Conclusions: Pharmacodynamic parameters and antagonist pretreatments indicate that diazepam/buprenorphine-induced respiratory depression results from a pharmacodynamic interaction between both drugs on ventilatory parameters.
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http://dx.doi.org/10.1016/j.bja.2021.10.029DOI Listing
March 2022

Gliclazide disposition in overdose - a case report with pharmacokinetic modeling.

Clin Toxicol (Phila) 2022 04 26;60(4):541-542. Epub 2021 Oct 26.

Paris University, Paris, France.

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http://dx.doi.org/10.1080/15563650.2021.1993245DOI Listing
April 2022

Pharmacokinetics of Baclofen in a Full-Term Newborn after Intrauterine Exposure: A Case Report.

Neonatology 2021 23;118(5):624-627. Epub 2021 Sep 23.

Inserm, UMRS-1144, Optimisation Thérapeutique en Neuropsychopharmacologie, Université de Paris, Paris, France.

Intrauterine exposure to baclofen can lead to syndrome of withdrawal during the first days of the newborn. We report the case of a full-term baby exposed to baclofen during pregnancy. The mother was treated with baclofen 10 mg 4 times daily. Blood samples were collected from the mother before entering labor and from the baby at H0, H11, H31, and H102 after birth to measure baclofen concentrations and monitor its elimination. Baclofen maternal and neonate pharmacokinetics (PK) and placental transfer were assessed using a physiologically based PK model. Baclofen PK in the neonate after birth followed a monoexponential elimination with a half-life of 10 h, 3-fold longer than that in adults. The newborn was monitored for 11 days without experiencing any symptoms of withdrawal. Reducing baclofen dosing regimen of the mother to the lowest and therefore reducing fetal exposure to baclofen is essential. This case reports for the first time the baclofen pharmacokinetic profile in a newborn.
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http://dx.doi.org/10.1159/000518657DOI Listing
November 2021

Bleeding and Thrombosis: Insights into Pathophysiology of Venom-Related Hemostasis Disorders.

Int J Mol Sci 2021 Sep 6;22(17). Epub 2021 Sep 6.

INSERM, UMRS-1144, Paris University, 75006 Paris, France.

Toxins from venoms targeting hemostasis are responsible for a broad range of clinical and biological syndromes including local and systemic bleeding, incoagulability, thrombotic microangiopathy and macrothrombosis. Beyond hemostais disorders, toxins are also involved in the pathogenesis of edema and in most complications such as hypovolemia, cardiovascular collapse, acute kidney injury, myonecrosis, compartmental syndrome and superinfection. These toxins can be classified as enzymatic proteins (snake venom metalloproteinases, snake venom serine proteases, phospholipases A and L-amino acid oxidases) and non-enzymatic proteins (desintegrins and C-type lectin proteins). Bleeding is due to a multifocal toxicity targeting vessels, platelets and coagulation factors. Vessel damage due to the degradation of basement membrane and the subsequent disruption of endothelial cell integrity under hydrostatic pressure and tangential shear stress is primarily responsible for bleeding. Hemorrhage is promoted by thrombocytopenia, platelet hypoaggregation, consumption coagulopathy and fibrin(ogen)olysis. Onset of thrombotic microangiopathy is probably due to the switch of endothelium to a prothrombotic phenotype with overexpression of tissue factor and other pro-aggregating biomarkers in association with activation of platelets and coagulation. Thrombosis involving large-caliber vessels in envenomation remains a unique entity, which exact pathophysiology remains poorly understood.
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http://dx.doi.org/10.3390/ijms22179643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8431793PMC
September 2021

Pharmacodynamic and pharmacokinetic profiles of a neurotensin receptor type 2 (NTS2) analgesic macrocyclic analog.

Biomed Pharmacother 2021 Sep 3;141:111861. Epub 2021 Jul 3.

Institut de Pharmacologie de Sherbrooke, Department of Pharmacology and Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada. Electronic address:

The current opioid crisis highlights the urgent need to develop safe and effective pain medications. Thus, neurotensin (NT) compounds represent a promising approach, as the antinociceptive effects of NT are mediated by activation of the two G protein-coupled receptor subtypes (i.e., NTS1 and NTS2) and produce potent opioid-independent analgesia. Here, we describe the synthesis and pharmacodynamic and pharmacokinetic properties of the first constrained NTS2 macrocyclic NT(8-13) analog. The Tyr residue of NT(8-13) was replaced with a Trp residue to achieve NTS2 selectivity, and a rationally designed side-chain to side-chain macrocyclization reaction was applied between Lys and Trp to constrain the peptide in an active binding conformation and limit its recognition by proteolytic enzymes. The resulting macrocyclic peptide, CR-01-64, exhibited high-affinity for NTS2 (K 7.0 nM), with a more than 125-fold selectivity over NTS1, as well as an improved plasma stability profile (t > 24 h) compared with NT (t ~ 2 min). Following intrathecal administration, CR-01-64 exerted dose-dependent and long-lasting analgesic effects in acute (ED = 4.6 µg/kg) and tonic (ED = 7.1 µg/kg) pain models as well as strong mechanical anti-allodynic effects in the CFA-induced chronic inflammatory pain model. Of particular importance, this constrained NTS2 analog exerted potent nonopioid antinociceptive effects and potentiated opioid-induced analgesia when combined with morphine. At high doses, CR-01-64 did not cause hypothermia or ileum relaxation, although it did induce mild and short-term hypotension, all of which are physiological effects associated with NTS1 activation. Overall, these results demonstrate the strong therapeutic potential of NTS2-selective analogs for the management of pain.
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http://dx.doi.org/10.1016/j.biopha.2021.111861DOI Listing
September 2021

Pharmacodynamic and pharmacokinetic profiles of a neurotensin receptor type 2 (NTS2) analgesic macrocyclic analog.

Biomed Pharmacother 2021 Sep 3;141:111861. Epub 2021 Jul 3.

Institut de Pharmacologie de Sherbrooke, Department of Pharmacology and Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada. Electronic address:

The current opioid crisis highlights the urgent need to develop safe and effective pain medications. Thus, neurotensin (NT) compounds represent a promising approach, as the antinociceptive effects of NT are mediated by activation of the two G protein-coupled receptor subtypes (i.e., NTS1 and NTS2) and produce potent opioid-independent analgesia. Here, we describe the synthesis and pharmacodynamic and pharmacokinetic properties of the first constrained NTS2 macrocyclic NT(8-13) analog. The Tyr residue of NT(8-13) was replaced with a Trp residue to achieve NTS2 selectivity, and a rationally designed side-chain to side-chain macrocyclization reaction was applied between Lys and Trp to constrain the peptide in an active binding conformation and limit its recognition by proteolytic enzymes. The resulting macrocyclic peptide, CR-01-64, exhibited high-affinity for NTS2 (K 7.0 nM), with a more than 125-fold selectivity over NTS1, as well as an improved plasma stability profile (t > 24 h) compared with NT (t ~ 2 min). Following intrathecal administration, CR-01-64 exerted dose-dependent and long-lasting analgesic effects in acute (ED = 4.6 µg/kg) and tonic (ED = 7.1 µg/kg) pain models as well as strong mechanical anti-allodynic effects in the CFA-induced chronic inflammatory pain model. Of particular importance, this constrained NTS2 analog exerted potent nonopioid antinociceptive effects and potentiated opioid-induced analgesia when combined with morphine. At high doses, CR-01-64 did not cause hypothermia or ileum relaxation, although it did induce mild and short-term hypotension, all of which are physiological effects associated with NTS1 activation. Overall, these results demonstrate the strong therapeutic potential of NTS2-selective analogs for the management of pain.
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http://dx.doi.org/10.1016/j.biopha.2021.111861DOI Listing
September 2021

The role of brain barriers in the neurokinetics and pharmacodynamics of lithium.

Pharmacol Res 2021 04 4;166:105480. Epub 2021 Feb 4.

Université de Paris, Inserm, UMRS-1144, Optimisation Thérapeutique en Neuropsychopharmacologie, F-75006 Paris, France; Biologie du Médicament, AP-HP, Hôpital Cochin, 27 rue du Faubourg, St. Jacques, 75679 Paris Cedex 14, France. Electronic address:

Lithium (Li) is the most widely used mood stabilizer in treating patients with bipolar disorder. However, more than half of the patients do not or partially respond to Li therapy, despite serum Li concentrations in the serum therapeutic range. The exact mechanisms underlying the pharmacokinetic-pharmacodynamic (PK-PD) relationships of lithium are still poorly understood and alteration in the brain pharmacokinetics of lithium may be one of the mechanisms explaining the variability in the clinical response to Li. Brain barriers such as the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) play a crucial role in controlling blood-to-brain and brain-to-blood exchanges of various molecules including central nervous system (CNS) drugs. Recent in vivo studies by nuclear resonance spectroscopy revealed heterogenous brain distribution of Li in human that were not always correlated with serum concentrations, suggesting regional and variable transport mechanisms of Li through the brain barriers. Moreover, alteration in the functionality and integrity of brain barriers is reported in various CNS diseases, as a cause or a consequence and in this regard, Li by itself is known to modulate BBB properties such as the expression and activity of various transporters, metabolizing enzymes, and the specialized tight junction proteins on BBB. In this review, we will focus on recent knowledge into the role of the brain barriers as key-element in the Li neuropharmacokinetics which might improve the understanding of PK-PD of Li and its interindividual variability in drug response.
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http://dx.doi.org/10.1016/j.phrs.2021.105480DOI Listing
April 2021

The neurobehavioral effects of the designer drug naphyrone - an experimental investigation with pharmacokinetics and concentration/effect relationship in mice.

Psychopharmacology (Berl) 2020 Jul 12;237(7):1943-1957. Epub 2020 May 12.

Inserm, UMR-S 1144, Paris University, Paris, France.

Rationale: The recreational use of naphyrone, a potent synthetic cathinone with a pyrovalerone structure, has raised questions about possible deleterious neurobehavioral consequences.

Objective: To investigate naphyrone-induced neurobehavioral effects and alterations in brain monoamines using two patterns of abuse, i.e., single and repeated (binge) use.

Methods: We studied naphyrone dose/induced locomotor activity relationship at 3, 10, 30, and 100 mg/kg in mice. We investigated the effects of single (30 mg/kg; acute injection) versus repeated (30 mg/kg ×3/day for 3 days; binge injection) intraperitoneal naphyrone administration on locomotor activity, anxiety-like behavior, spatial recognition memory, anhedonia, behavioral despair, and social interaction. We measured post-mortem prefrontal cortex levels of monoamines and modeled naphyrone pharmacokinetics and concentration/locomotor effect relationship.

Results: Both naphyrone administration patterns induced time-dependent increases in locomotor activity (p < 0.001 and p < 0.0001, respectively) and social interaction (p < 0.05 and p < 0.001, respectively) but did not alter spatial recognition memory or anhedonia. Acute naphyrone injection induced anxiety-like behavior (p < 0.01) and reduced resignation (p < 0.01) whereas binge administration induced non-anxiety-like behavior (p < 0.05) and did not alter behavioral despair. Both patterns increased the prefrontal cortex dopamine (p < 0.0001) and norepinephrine (p < 0.05 and p < 0.01, respectively) but not serotonin content. Naphyrone pharmacokinetics followed a two-compartment model with an overall elimination half-life of 0.3 h. The naphyrone concentration/locomotor effect relationship was described by an additive E model with an EC of 672 μg/L.

Conclusions: Single naphyrone administration increases locomotor activity according to a direct concentration/effect relationship. The neurobehavioral effects after binge differs from those after single administration and are not explained by drug accumulation given the relatively fast elimination.
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http://dx.doi.org/10.1007/s00213-020-05510-2DOI Listing
July 2020

Naloxone should remain the appropriate antidote to treat opioid overdose.

Crit Care 2020 04 28;24(1):173. Epub 2020 Apr 28.

INSERM UMRS-1144, Paris University, Paris, France.

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http://dx.doi.org/10.1186/s13054-020-2835-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187523PMC
April 2020

Higher Atazanavir Plasma Exposure in Rats is Associated with Gut Microbiota Changes Induced by Cotrimoxazole.

Curr Drug Metab 2019 ;20(11):898-906

EA4065 Intestinal Ecosystem, Probiotics, Antibiotics, Paris Descartes University SPC, Paris, France.

Background: Cotrimoxazole (TMP-SMX) is concomitantly used as a primary prophylaxis of opportunistic infections with antiretroviral agents, such as Atazanavir (ATV). Results from an ex vivo study showed changes in intestinal absorption of ATV when rats were pretreated with TMP-SMX. The objective of this in vivo study is to determine the effect of TMP-SMX on the pharmacokinetics of ATV in rats. We also studied changes in gut microbiota induced by TMP-SMX.

Methods: We used the non-compartment analysis to compare the pharmacokinetics of ATV in a parallel group of rats treated with a low or therapeutic dose of TMP-SMX for nine days to untreated control rats. Gut microbiota was characterized using qPCR and High Throughput Sequencing of 16S rDNA.

Results: Rats treated with TMP-SMX showed a much broader exposure to ATV compared to the control group (AUC0-8h (ng.mL-1.h), 25975.9±4048.7 versus 2587.6±546.9, p=0.001). The main observation regarding the gut microbiota was a lower proportion of enterobacteria related to the administration of TMP-SMX. Moreover, the Total Gastrointestinal Transit Time (TGTT) was longer in the TMP-SMX treated group.

Conclusion: Concomitant administration of TMP-SMX and ATV significantly increased ATV exposure in rats. This increase could be the result of a prolonged TGTT leading to an increase in the intestinal residence time of ATV favoring its absorption. Gut microbiota changes induced by TMP-SMX could be at the origin of this prolonged TGTT. If demonstrated in humans, this potential interaction could be accompanied by an increase in the adverse effects of ATV.
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http://dx.doi.org/10.2174/1389200220666191023105609DOI Listing
May 2020

Pharmacokinetics and Pharmacodynamics of Once-daily Prolonged-release Tacrolimus in Liver Transplant Recipients.

Clin Ther 2019 05 17;41(5):882-896.e3. Epub 2019 Apr 17.

Département de Pharmacocinétique et Pharmacochimie, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France; UMR8638 CNRS, UFR Pharmacie, Université Paris Descartes, PRES Sorbonne Paris Cité, Paris, France. Electronic address:

Purpose: Limited published data are available regarding the pharmacokinetic (PK) and pharmacodynamic (PD) variables of prolonged-release tacrolimus (PRT) after liver transplantations. The goal of this study was to compare the PK and PD profiles of PRT in early and stable liver transplant recipients by developing a population PK model of PRT and investigating the profile of calcineurin activity (CNA) in the peripheral blood mononuclear cells.

Methods: A conversion from BID immediate-release tacrolimus (IRT) to once-daily PRT based on a one-to-one daily dose was performed at day 7 (D7) and D90 posttransplantation in groups A (n = 12) and B (n = 12), respectively. Extensive PK samplings, including whole-blood tacrolimus (TAC) concentration, and CNA assessments were performed at D14 and D104 in groups A and B, respectively. TAC concentration-time data (N = 221) were analyzed by using nonlinear mixed effects modeling.

Findings: A 2-compartment model with linear elimination and a delayed first-order absorption characterized by 2 transit compartments best described the PK data. Model-predicted dose-normalized (6.0 mg/d) area under the TAC concentration-time curve over the dosing interval in groups A and B was similar (geometric mean, 235.6 ng/mL · h [95% CI, 139.6-598.7] vs 224.6 ng/mL · h [95% CI, 117.6-421.5], respectively; P = 0.94). Area under the CNA versus time curve over the dosing interval did not differ between groups (4897 [3437] and 4079 [1008] pmol/min/10 cells; P = 0.50). In group A, trough CNA at D14 posttransplantation was statistically higher than that measured just before the switch to PRT (ie, D7 posttransplantation) (198 [92] vs 124 [72] pmol/min/10cells, n = 8; P = 0.048); no statistical difference in TAC concentration was observed (P = 0.11). In group B, no statistical difference between D90 and D104 was observed in either trough CNA (149 [78] vs 172 [82] pmol/min/10 cells, n = 6; P = 0.18) or TAC (P = 0.17) concentration. No graft rejection was observed in either of the groups.

Implications: This study suggests that one-to-one dosage conversion to once-daily PRT during the early posttransplantation period could result in significant CNA variations but without causing graft rejection. Further investigations in larger cohorts are warranted to confirm these results. ClinicalTrials.gov identifier: NCT02105155.
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http://dx.doi.org/10.1016/j.clinthera.2019.03.006DOI Listing
May 2019

Tramadol: Distinguishing the Pathophysiology of Serotonin Syndrome and Seizures.

Am J Med 2018 11 26;131(11):e487. Epub 2018 Oct 26.

INSERM UMRS-1144, Paris-Descartes University,Paris, France.

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http://dx.doi.org/10.1016/j.amjmed.2018.07.005DOI Listing
November 2018

Is the 3,4-methylendioxypyrovalerone/mephedrone combination responsible for enhanced stimulant effects? A rat study with investigation of the effect/concentration relationships.

Psychopharmacology (Berl) 2019 Mar 3;236(3):891-901. Epub 2018 Jul 3.

Inserm, UMR-S 1144, Paris-Descartes and Paris-Diderot Universities, Paris, France.

Rationale: The use of synthetic cathinones as recreational drugs frequently sold in combination has been increasing exponentially. However, the consequences of combining cathinones on the resulting stimulant effects and the pharmacokinetics have been poorly investigated.

Objective And Methods: To study 3,4-methylenedioxypyrovalerone (MDPV; 3 mg/kg) and mephedrone (4-MMC; 30 mg/kg)-induced effects on rat locomotor activity and pharmacokinetics, administered alone or in combination by the intragastric route. The pharmacokinetic parameters were determined using non-compartmental analysis and the relationships between the locomotor activity and drug concentrations using sigmoidal E modeling.

Results: Locomotor activity significantly increased during the first hour post-administration with the MDPV/4-MMC combination in comparison to MDPV (p < 0.001) and 4-MMC (p < 0.01) alone. The pharmacokinetic profile of MDPV, but not 4-MMC, was significantly modified with the combination resulting in decreases in C (16.4 ± 5.5 versus 62.2 ± 14.2 μg/L, p < 0.05) and AUC (708 ± 91 versus 3316 ± 682 μg/L/min, p < 0.01) and increases in V/F (582.6 ± 136.8 versus 115.9 ± 42.7 L/kg, p < 0.05) and Cl/F (4.6 ± 0.7 versus 1.2 ± 0.4 L/kg/min, p < 0.01) in comparison to MDPV alone. The sigmoidal E model fitted the observed data well; MDPV being markedly more potent than 4-MMC (EC, 0.043 versus 0.7 μmol/L). The enhancing factor representing the MDPV contribution to the alteration in the relationships between locomotor activity and 4-MMC concentrations was 0.3.

Conclusion: An MDPV/4-MMC combination results in enhanced stimulant effects in the rat, despite significant reduction in MDPV bioavailability. Enhanced effects could be explained by increased MDPV distribution and/or possible complementation at the brain dopaminergic targets. However, the exact consequences of the MDPV/4-MMC combination in humans remain to be clarified.
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http://dx.doi.org/10.1007/s00213-018-4962-0DOI Listing
March 2019

Baclofen-Induced Neuro-Respiratory Toxicity in the Rat: Contribution of Tolerance and Characterization of Withdrawal Syndrome.

Toxicol Sci 2018 07;164(1):153-165

Inserm, UMRS-1144, Paris-Descartes University, 75006 Paris, France.

Baclofen, a γ-amino-butyric acid type-B receptor agonist with exponentially increased use at high-dose to facilitate abstinence in chronic alcoholics, is responsible for increasing poisonings. Tolerance and withdrawal syndromes have been reported during prolonged treatment but their contribution to the variability of baclofen-induced neurotoxicity in overdose is unknown. We studied baclofen-induced effects on rat sedation, temperature, and ventilation and modeled baclofen pharmacokinetics and effect/concentration relationships aiming to investigate the consequences of repeated baclofen pretreatment and to characterize withdrawal syndrome. Baclofen-induced dose-dependent sedation (p <0.01), hypothermia (p <.001) and respiratory depression (p <.01) were altered in repeatedly baclofen-pretreated rats (p <.05). Repeatedly baclofen-pretreated rats did not exhibit respiratory depression following baclofen overdose due to limitations on baclofen-induced increase in inspiratory (p <.01) and expiratory times (p <.01). Only slight hypoxemia without respiratory acidosis was observed. Baclofen discontinuation resulted in hyperlocomotion and non-anxiogenic withdrawal symptoms. Regarding pharmacokinetics, repeated baclofen pretreatment increased the peak concentration (p <.05) and absorption constant rate (p <.05) and reduced the distribution volume (p <.0001) and elimination half-life (p <.05). Analysis of the effect/concentration relationships indicated that plasma baclofen concentration decreases more rapidly than all studied neuro-respiratory effects, in tolerant and non-tolerant rats. Taken together, our findings supported the role of brain distribution in baclofen-induced neurotoxicity expression and its probable involvement in tolerance-related attenuation in addition to physiological adaptations of ventilation. In conclusion, repeated pretreatment attenuates baclofen-attributed neurotoxicity in overdose and results in post-discontinuation withdrawal syndrome. Our findings suggest both pharmacodynamic and pharmacokinetic mechanisms whose relative contributions to the variability of baclofen-induced neurotoxicity in overdose remain to be established.
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http://dx.doi.org/10.1093/toxsci/kfy073DOI Listing
July 2018

Baclofen-induced encephalopathy in overdose - Modeling of the electroencephalographic effect/concentration relationships and contribution of tolerance in the rat.

Prog Neuropsychopharmacol Biol Psychiatry 2018 08 18;86:131-139. Epub 2018 May 18.

Inserm UMRS-1144, Paris-Descartes University, Paris, France.

Baclofen, a γ-amino-butyric acid type-B receptor agonist with exponentially increased use at high-dose to facilitate abstinence in chronic alcoholics, is responsible for increasing poisonings. Baclofen overdose may induce severe encephalopathy and electroencephalographic (EEG) abnormalities. Whether prior prolonged baclofen treatment may influence the severity of baclofen-induced encephalopathy in overdose has not been established. We designed a rat study to characterize baclofen-induced encephalopathy, correlate its severity with plasma concentrations and investigate the contribution of tolerance. Baclofen-induced encephalopathy was assessed using continuous EEG and scored based on a ten-grade scale. Following the administration by gavage of 116 mg/kg baclofen, EEG rapidly and steadily impaired resulting in the successive onset of deepening sleep followed by generalized periodic epileptiform discharges and burst-suppressions. Thereafter, encephalopathy progressively recovered following similar phases in reverse. Periodic triphasic sharp waves, non-convulsive status epilepticus and even isoelectric signals were observed at the most critical stages. Prior repeated baclofen administration resulted in reduced severity (peak: grade 7 versus 9; peak effect length: 382 ± 40 versus 123 ± 14 min, P = 0.008) and duration of encephalopathy (18 versus > 24 h, P = 0.0007), supporting the acquisition of tolerance. The relationship between encephalopathy severity and plasma baclofen concentrations fitted a sigmoidal E model with an anticlockwise hysteresis loop suggesting a hypothetical biophase site of action. The baclofen concentration producing a response equivalent to 50% of E was significantly reduced (8947 μg/L, ±11.3% versus 12,728 μg/L, ±24.0% [mean, coefficient of variation], P = 0.03) with prior prolonged baclofen administration. In conclusion, baclofen overdose induces early-onset and prolonged marked encephalopathy that is significantly attenuated by prior repeated baclofen treatment. Our findings suggest a possible role for the blood-brain barrier in the development of tolerance; however, its definitive involvement remains to be demonstrated.
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http://dx.doi.org/10.1016/j.pnpbp.2018.05.016DOI Listing
August 2018

Is naloxone the best antidote to reverse tramadol-induced neuro-respiratory toxicity in overdose? An experimental investigation in the rat.

Clin Toxicol (Phila) 2018 08 17;56(8):737-743. Epub 2017 Nov 17.

a Inserm UMR-S 1144, Paris-Descartes and Paris-Diderot Universities , Paris , France.

Context: Since the banning of dextropropoxyphene from the market, overdoses, and fatalities attributed to tramadol, a WHO step-2 opioid analgesic, have increased markedly. Tramadol overdose results not only in central nervous system (CNS) depression attributed to its opioid properties but also in seizures, possibly related to non-opioidergic pathways, thus questioning the efficiency of naloxone to reverse tramadol-induced CNS toxicity.

Objective: To investigate the most efficient antidote to reverse tramadol-induced seizures and respiratory depression in overdose.

Materials And Methods: Sprague-Dawley rats overdosed with 75 mg/kg intraperitoneal (IP) tramadol were randomized into four groups to receive solvent (control group), diazepam (1.77 mg/kg IP), naloxone (2 mg/kg intravenous bolus followed by 4 mg/kg/h infusion), and diazepam/naloxone combination. Sedation depth, temperature, number of seizures, and intensity, whole-body plethysmography parameters and electroencephalography activity were measured.

Results: Naloxone reversed tramadol-induced respiratory depression (p < .05) but significantly increased seizures (p < .01) and prolonged their occurrence time. Diazepam abolished seizures but significantly deepened rat sedation (p < .05) without improving ventilation. Diazepam/naloxone combination completely abolished seizures, significantly improved rat ventilation by reducing inspiratory time (p < .05) but did not worsen sedation. None of these treatments significantly modified rat temperature.

Conclusions: Diazepam/naloxone combination is the most efficient antidote to reverse tramadol-induced CNS toxicity in the rat.
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http://dx.doi.org/10.1080/15563650.2017.1401080DOI Listing
August 2018

Population pharmacokinetics of oral baclofen at steady-state in alcoholic-dependent adult patients.

Fundam Clin Pharmacol 2018 Apr 23;32(2):239-248. Epub 2017 Nov 23.

Inserm, UMR-S 1144, Université Paris Descartes - Paris Diderot, Variabilité de Réponse Aux Psychotropes, Paris, F-75006, France.

Baclofen has been proposed for few years to help treating alcohol dependence at higher doses than those used in neurology. Baclofen pharmacokinetics has been previously well described at low oral or intravenous doses but remains poorly investigated with such high oral doses. We here describe dose regimens of baclofen in 143 alcohol-dependent patients treated with steady-state oral doses of baclofen. Plasma baclofen levels were measured in blood samples using liquid chromatography coupled with tandem mass spectrometry. One hundred and forty-nine baclofen concentrations were sampled 30 min to 15 h after the last dose, and baclofen pharmacokinetics was determined using population pharmacokinetics approach. Our population, whose average age and BMI were 51.5 years and 25.5 kg/m , respectively, was composed of two-thirds of men. Daily baclofen doses ranged from 15 to 250 mg and 26% were higher than 120 mg. A one-compartment model with first-order absorption and elimination allowed to determine mean values for clearance (CL/F), volume of distribution (V/F) and absorption rate constant at 8.0 L/h, 44.5 L and 2.23 h , respectively. Inter-individual variability on CL/F and V/F was 27.4 and 86% for the parameters. None of the demographic and biological covariates significantly decreased inter-individual variability. A proportional relationship between oral dose and plasma baclofen exposure indicated a linear pharmacokinetics of baclofen even at doses over 120 mg/day. Our large population study evidenced a linear pharmacokinetics of oral baclofen even at high daily doses with an inter-individual variability of baclofen exposure that could not be explained by demographic and biological data.
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http://dx.doi.org/10.1111/fcp.12330DOI Listing
April 2018

Investigation of lithium distribution in the rat brain ex vivo using lithium-7 magnetic resonance spectroscopy and imaging at 17.2 T.

NMR Biomed 2017 Nov 13;30(11). Epub 2017 Jul 13.

NeuroSpin, Institut Frédéric Joliot, CEA, Université Paris-Saclay, Gif-sur-Yvette, France.

Lithium is the first-line mood stabilizer for the treatment of patients with bipolar disorder. However, its mechanisms of action and transport across the blood-brain barrier remain poorly understood. The contribution of lithium-7 magnetic resonance imaging ( Li MRI) to investigate brain lithium distribution remains limited because of the modest sensitivity of the lithium nucleus and the expected low brain concentrations in humans and animal models. Therefore, we decided to image lithium distribution in the rat brain ex vivo using a turbo-spin-echo imaging sequence at 17.2 T. The estimation of lithium concentrations was performed using a phantom replacement approach accounting for B inhomogeneities and differential T and T weighting. Our MRI-derived lithium concentrations were validated by comparison with inductively coupled plasma-mass spectrometry (ICP-MS) measurements ([Li]  = 1.18[Li] , R = 0.95). Overall, a sensitivity of 0.03 mmol/L was achieved for a spatial resolution of 16 μL. Lithium distribution was uneven throughout the brain (normalized lithium content ranged from 0.4 to 1.4) and was mostly symmetrical, with consistently lower concentrations in the metencephalon (cerebellum and brainstem) and higher concentrations in the cortex. Interestingly, low lithium concentrations were also observed close to the lateral ventricles. The average brain-to-plasma lithium ratio was 0.34 ± 0.04, ranging from 0.29 to 0.39. Brain lithium concentrations were reasonably correlated with plasma lithium concentrations, with Pearson correlation factors ranging from 0.63 to 0.90.
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http://dx.doi.org/10.1002/nbm.3770DOI Listing
November 2017

Intoxication by gamma hydroxybutyrate and related analogues: Clinical characteristics and comparison between pure intoxication and that combined with other substances of abuse.

Toxicol Lett 2017 Aug 1;277:84-91. Epub 2017 Jun 1.

Department of Clinical Toxicology, Klinikum rechts der Isar, Technical University of Munich, Germany.

Objective: To study the profile of European gamma-hydroxybutyrate (GHB) and gammabutyrolactone (GBL) intoxication and analyse the differences in the clinical manifestations produced by intoxication by GHB/GBL alone and in combination with other substances of abuse.

Method: We prospectively collected data on all the patients attended in the Emergency Departments (ED) of the centres participating in the Euro-DEN network over 12 months (October 2013 to September 2014) with a primary presenting complaint of drug intoxication (excluding ethanol alone) and registered the epidemiological and clinical data and outcomes.

Results: We included 710 cases (83% males, mean age 31 years), representing 12.6% of the total cases attended for drug intoxication. Of these, 73.5% arrived at the ED by ambulance, predominantly during weekend, and 71.7% consumed GHB/GBL in combination with other substances of abuse, the most frequent additional agents being ethanol (50%), amphetamine derivatives (36%), cocaine (12%) and cannabis (8%). Among 15 clinical features pre-defined in the project database, the 3 most frequently identified were altered behaviour (39%), reduced consciousness (34%) and anxiety (14%). The severity ranged from mild cases requiring no treatment (308 cases, 43.4%) to severe cases requiring admission to intensive care (103 cases, 14.6%) and mechanical ventilation (49 cases, 6.9%). No deaths were reported. In comparison with only GHB/GBL consumption, patients consuming GHB/GBL with co-intoxicants presented more vomiting (15% vs. 3%, p<0.001) and cardiovascular symptoms (5.3% vs. 1.5%, p<0.05), a greater need for treatment (59.8% vs. 48.3%, p<0.01) and a longer ED stay (11.3% vs. 3.6% patients with ED stay >12h, p<0.01).

Conclusions: The profile of the typical GHB/GBL-intoxicated European is a young male, requiring care for altered behaviour and reduced level of consciousness, mainly during the weekend. The clinical features are more severe when GHB is consumed in combination with other substances of abuse.
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http://dx.doi.org/10.1016/j.toxlet.2017.05.030DOI Listing
August 2017

Electroencephalographic patterns of lithium poisoning: a study of the effect/concentration relationships in the rat.

Bipolar Disord 2017 03 20;19(2):135-145. Epub 2017 Apr 20.

Inserm, UMR-S1144, Paris, France.

Objectives: Lithium overdose may result in encephalopathy and electroencephalographic abnormalities. Three poisoning patterns have been identified based on the ingested dose, previous treatment duration and renal function. Whether the severity of lithium-induced encephalopathy depends on the poisoning pattern has not been established. We designed a rat study to investigate lithium-induced encephalopathy and correlate its severity to plasma, erythrocyte, cerebrospinal fluid and brain lithium concentrations previously determined in rat models mimicking human poisoning patterns.

Methods: Lithium-induced encephalopathy was assessed and scored using continuous electroencephalography.

Results: We demonstrated that lithium overdose was consistently responsible for encephalopathy, the severity of which depended on the poisoning pattern. Acutely poisoned rats developed rapid-onset encephalopathy which reached a maximal grade of 2/5 at 6 h and disappeared at 24 h post-injection. Acute-on-chronically poisoned rats developed persistent and slightly fluctuating encephalopathy which reached a maximal grade of 3/5. Chronically poisoned rats developed rapid-onset but gradually increasing life-threatening encephalopathy which reached a maximal grade of 4/5. None of the acutely, 20% of the acute-on-chronically and 57% of the chronically lithium-poisoned rats developed seizures. The relationships between encephalopathy severity and lithium concentrations fitted a sigmoidal E model based on cerebrospinal fluid concentrations in acute poisoning and brain concentrations in acute-on-chronic poisoning. In chronic poisoning, worsening of encephalopathy paralleled the increase in plasma lithium concentrations.

Conclusions: The severity of lithium-induced encephalopathy is dependent on the poisoning pattern, which was previously shown to determine lithium accumulation in the brain. Our data support the proposition that electroencephalography is a sensitive tool for scoring lithium-related neurotoxicity.
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http://dx.doi.org/10.1111/bdi.12482DOI Listing
March 2017

Neurobehavioral effects of lithium in the rat: Investigation of the effect/concentration relationships and the contribution of the poisoning pattern.

Prog Neuropsychopharmacol Biol Psychiatry 2017 06 20;76:124-133. Epub 2017 Mar 20.

Inserm, UMR-S1144, Paris, France; Paris-Descartes University, Paris, France; Paris-Diderot University, Paris, France; Assistance Publique - Hôpitaux de Paris, Lariboisière Hospital, Department of Medical and Toxicological Critical Care, Paris, France. Electronic address:

Severity of lithium poisoning depends on the ingested dose, previous treatment duration and renal function. No animal study has investigated neurobehavioral differences in relation to the lithium poisoning pattern observed in humans, while differences in lithium pharmacokinetics have been reported in lithium-pretreated rats mimicking chronic poisonings with enhanced brain accumulation in rats with renal failure. Our objectives were: 1)-to investigate lithium-related effects in overdose on locomotor activity, anxiety-like behavior, spatial recognition memory and anhedonia in the rat; 2)-to model the relationships between lithium-induced effects on locomotion and plasma, erythrocyte, cerebrospinal fluid and brain concentrations previously obtained according to the poisoning pattern. Open-field, elevated plus-maze, Y-maze and sucrose consumption tests were used. In acutely lithium-poisoned rats, we observed horizontal (p<0.001) and vertical hypolocomotion (p<0.0001), increased anxiety-like behavior (p<0.05) and impaired memory (p<0.01) but no altered hedonic status. Horizontal (p<0.01) and vertical (p<0.001) hypolocomotion peaked more markedly 24h after lithium injection and was more prolonged in acute-on-chronically vs. acutely lithium-poisoned rats. Hypolocomotion in chronically lithium-poisoned rats with impaired renal function did not differ from acutely poisoned rats 24h after the last injection. Interestingly, hypolocomotion/concentration relationships best fitted a sigmoidal E model in acute poisoning and a linear regression model linked to brain lithium in acute-on-chronic poisoning. In conclusion, lithium overdose alters rat behavior and consistently induces hypolocomotion which is more marked and prolonged in repeatedly lithium-treated rats. Our data suggest that differences between poisoning patterns regarding lithium-induced hypolocomotion are better explained by the duration of lithium exposure than by its brain accumulation.
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http://dx.doi.org/10.1016/j.pnpbp.2017.03.005DOI Listing
June 2017

Bifunctional peptide-based opioid agonist/nociceptin antagonist ligand for dual treatment of nociceptive and neuropathic pain.

Pain 2017 03;158(3):505-515

Inserm, UMR-S 1144, Paris, France.

Drugs able to treat both nociceptive and neuropathic pain effectively without major side effects are lacking. We developed a bifunctional peptide-based hybrid (KGNOP1) that structurally combines a mu-opioid receptor agonist (KGOP1) with antinociceptive activity and a weak nociceptin receptor antagonist (KGNOP3) with anti-neuropathic pain activity. We investigated KGNOP1-related behavioral effects after intravenous administration in rats by assessing thermal nociception, cold hyperalgesia in a model of neuropathic pain induced by chronic constriction injury of the sciatic nerve, and plethysmography parameters including inspiratory time (TI) and minute ventilation (VM) in comparison to the well-known opioid analgesics, tramadol and morphine. Time-course and dose-dependent effects were investigated for all behavioral parameters to determine the effective doses 50% (ED50). Pain-related effects on cold hyperalgesia were markedly increased by KGNOP1 as compared to KGNOP3 and tramadol (ED50: 0.0004, 0.32, and 12.1 μmol/kg, respectively), whereas effects on thermal nociception were significantly higher with KGNOP1 as compared to morphine (ED50: 0.41 and 14.7 μmol/kg, respectively). KGNOP1 and KGOP1 produced a larger increase in TI and deleterious decrease in VM in comparison to morphine and tramadol (ED50(TI): 0.63, 0.52, 12.2, and 50.9 μmol/kg; ED50(VM): 0.57, 0.66, 10.6, and 50.0 μmol/kg, respectively). Interestingly, the calculated ratios of anti-neuropathic pain/antinociceptive to respiratory effects revealed that KGNOP1 was safer than tramadol (ED50 ratio: 5.44 × 10 vs 0.24) and morphine (ED50 ratio: 0.72 vs 1.39). We conclude that KGNOP1 is able to treat both experimental neuropathic and nociceptive pain, more efficiently and safely than tramadol and morphine, respectively, and thus should be a candidate for future clinical developments.
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http://dx.doi.org/10.1097/j.pain.0000000000000790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5302413PMC
March 2017

Editor's Highlight: Neurorespiratory Effects of Buprenorphine and Ethanol in Combination: A Mechanistic Study of Drug-Drug Interactions in the Rat.

Toxicol Sci 2017 02 1;155(2):389-399. Epub 2016 Nov 1.

Inserm, U1144, Paris, France;

Respiratory depression and fatalities have been attributed to ethanol/buprenorphine (BUP) combination in drug addicts maintained with BUP/naloxone or BUP alone. The exact mechanisms of the ethanol/BUP interaction and the contribution to the toxicity of norbuprenorphine (NBUP), the main BUP metabolite with respiratory depressant properties are unknown. We investigated the sedative and plethsymographic effects resulting from the co-administration of intragastric ethanol (3 g/kg) and intravenous BUP (30 mg/kg) in Sprague-Dawley rats. We determined the whole blood pharmacokinetics of ethanol (using gas chromatography coupled to mass spectrometry), BUP and its metabolites (using liquid chromatography coupled to tandem mass spectrometry) and investigated the mechanisms of drug-drug interactions in the presence or absence of naloxone (7.5 mg/kg). Ethanol/BUP and ethanol/BUP/naloxone combinations significantly deepened sedation in comparison to BUP alone (P < .01) and BUP/naloxone (P < .05), respectively. Ethanol/BUP combination significantly increased the inspiratory time and decreased the minute volume in comparison to BUP alone (P < .01 and P < .01, respectively) and ethanol/BUP/naloxone (P < .05 and P < .01, respectively). Neither naloxone nor flumazenil reversed ethanol/BUP-induced sedation and respiratory depression. In the presence of ethanol, the area under the BUP concentration-time curve was significantly decreased (P < .05), BUP volume of distribution increased (P < .05) and the metabolic ratios of NBUP and norbuprenorphine-3-glucuronide increased (P < .01). In conclusion, the ethanol/BUP combination results in marked sedation and respiratory depression in the rat, prevented but not reversed by naloxone. Ethanol/BUP interactions are mainly pharmacokinetic resulting in increased NBUP production. Despite the non-reversal by naloxone and flumazenil of the effects attributed to the ethanol/BUP combination, protection provided by naloxone suggests an additional pharmacodynamic interaction.
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http://dx.doi.org/10.1093/toxsci/kfw221DOI Listing
February 2017

Mechanisms of tramadol-related neurotoxicity in the rat: Does diazepam/tramadol combination play a worsening role in overdose?

Toxicol Appl Pharmacol 2016 Nov 16;310:108-119. Epub 2016 Sep 16.

Inserm, U1144, Paris, France; UMR-S 1144, Paris-Descartes University, Paris, France; UMR-S 1144, Paris-Diderot University, Paris, France; Assistance Publique - Hôpitaux de Paris, Lariboisière Hospital, Department of Medical and Toxicological Critical Care, Paris, France. Electronic address:

Poisoning with opioid analgesics including tramadol represents a challenge. Tramadol may induce respiratory depression, seizures and serotonin syndrome, possibly worsened when in combination to benzodiazepines. Our objectives were to investigate tramadol-related neurotoxicity, consequences of diazepam/tramadol combination, and mechanisms of drug-drug interactions in rats. Median lethal-doses were determined using Dixon-Bruce's up-and-down method. Sedation, seizures, electroencephalography and plethysmography parameters were studied. Concentrations of tramadol and its metabolites were measured using liquid-chromatography-high-resolution-mass-spectrometry. Plasma, platelet and brain monoamines were measured using liquid-chromatography coupled to fluorimetry. Median lethal-doses of tramadol and diazepam/tramadol combination did not significantly differ, although time-to-death was longer with combination (P=0.04). Tramadol induced dose-dependent sedation (P<0.05), early-onset seizures (P<0.001) and increase in inspiratory (P<0.01) and expiratory times (P<0.05). The diazepam/tramadol combination abolished seizures but significantly enhanced sedation (P<0.01) and respiratory depression (P<0.05) by reducing tidal volume (P<0.05) in addition to tramadol-related increase in respiratory times, suggesting a pharmacodynamic mechanism of interaction. Plasma M1 and M5 metabolites were mildly increased, contributing additionally to tramadol-related respiratory depression. Tramadol-induced early-onset increase in brain concentrations of serotonin and norepinephrine was not significantly altered by the diazepam/tramadol combination. Interestingly neither pretreatment with cyproheptadine (a serotonin-receptor antagonist) nor a benserazide/5-hydroxytryptophane combination (enhancing brain serotonin) reduced tramadol-induced seizures. Our study shows that diazepam/tramadol combination does not worsen tramadol-induced fatality risk but alters its toxicity pattern with enhanced respiratory depression but abolished seizures. Drug-drug interaction is mainly pharmacodynamic but increased plasma M1 and M5 metabolites may also contribute to enhancing respiratory depression. Tramadol-induced seizures are independent of brain serotonin.
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http://dx.doi.org/10.1016/j.taap.2016.09.013DOI Listing
November 2016

Bifunctional Peptide-Based Opioid Agonist-Nociceptin Antagonist Ligands for Dual Treatment of Acute and Neuropathic Pain.

J Med Chem 2016 04 14;59(8):3777-92. Epub 2016 Apr 14.

Research Group of Organic Chemistry, Departments of Chemistry and Bio-engineering Sciences, Vrije Universiteit Brussel , Pleinlaan 2, 1050 Brussels, Belgium.

Herein, the opioid pharmacophore H-Dmt-d-Arg-Aba-β-Ala-NH2 (7) was linked to peptide ligands for the nociceptin receptor. Combination of 7 and NOP ligands (e.g., H-Arg-Tyr-Tyr-Arg-Ile-Lys-NH2) led to binding affinities in the low nanomolar domain. In vitro, the hybrids behaved as agonists at the opioid receptors and antagonists at the nociceptin receptor. Intravenous administration of hybrid 13a (H-Dmt-d-Arg-Aba-β-Ala-Arg-Tyr-Tyr-Arg-Ile-Lys-NH2) to mice resulted in potent and long lasting antinociception in the tail-flick test, indicating that 13a was able to permeate the BBB. This was further supported by a cell-based BBB model. All hybrids alleviated allodynia and hyperalgesia in neuropathic pain models. Especially with respect to hyperalgesia, they showed to be more effective than the parent compounds. Hybrid 13a did not result in significant respiratory depression, in contrast to an equipotent analgesic dose of morphine. These hybrids hence represent a promising avenue toward analgesics for the dual treatment of acute and neuropathic pain.
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http://dx.doi.org/10.1021/acs.jmedchem.5b01976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4850106PMC
April 2016

[Novel psychoactive substances: a review].

Presse Med 2015 Apr 29;44(4 Pt 1):383-91. Epub 2015 Jan 29.

Université Paris-Diderot, hôpital Bichat, service de psychiatrie et d'addictologie, 75018 Paris, France.

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http://dx.doi.org/10.1016/j.lpm.2014.09.020DOI Listing
April 2015

Study of blood and brain lithium pharmacokinetics in the rat according to three different modalities of poisoning.

Toxicol Sci 2015 Jan 28;143(1):185-95. Epub 2014 Oct 28.

*Inserm, U1144, Paris, France, Université Paris Descartes, UMR-S 1144, Paris, France, Université Paris Diderot, UMR-S 1144, Paris, France, Assistance Publique - Hôpitaux de Paris, Hôpital Lariboisière, Laboratoire de Toxicologie biologique, Paris, France, Assistance Publique - Hôpitaux de Paris, Hôpital Lariboisière, Laboratoire de Biochimie et Biologie moléculaire, Paris, France, and Assistance Publique - Hôpitaux de Paris, Hôpital Lariboisière, Réanimation Médicale et Toxicologique, Paris, France *Inserm, U1144, Paris, France, Université Paris Descartes, UMR-S 1144, Paris, France, Université Paris Diderot, UMR-S 1144, Paris, France, Assistance Publique - Hôpitaux de Paris, Hôpital Lariboisière, Laboratoire de Toxicologie biologique, Paris, France, Assistance Publique - Hôpitaux de Paris, Hôpital Lariboisière, Laboratoire de Biochimie et Biologie moléculaire, Paris, France, and Assistance Publique - Hôpitaux de Paris, Hôpital Lariboisière, Réanimation Médicale et Toxicologique, Paris, France *Inserm, U1144, Paris, France, Université Paris Descartes, UMR-S 1144, Paris, France, Université Paris Diderot, UMR-S 1144, Paris, France, Assistance Publique - Hôpitaux de Paris, Hôpital Lariboisière, Laboratoire de Toxicologie biologique, Paris, France, Assistance Publique - Hôpitaux de Paris, Hôpital Lariboisière, Laboratoire de Biochimie et Biologie moléculaire, Paris, France, and Assistance Publique - Hôpitaux de Paris, Hôpital Lariboisière, Réanimation Médicale et Toxicologique, Paris, France *Inserm, U1144, Paris, France, Université Paris Descartes, UMR-S 1144, Paris, France, Université Paris Diderot, UMR-S 1144, Paris, France, Assistance Publique - Hôpitaux de Paris, Hôpital Lariboisière, Laboratoire de Toxicologie biologique, Paris, France, Assistance Publique - Hôpitaux de Paris, Hôpital Lariboisière, Laboratoire de Biochimie et Biologie moléculaire, Paris, France, and Assistance Publique - Hôpitaux de Paris, Hôpita

Lithium-induced neurotoxicity may be life threatening. Three patterns have been described, including acute, acute-on-chronic, and chronic poisoning, with unexplained discrepancies in the relationship between clinical features and plasma lithium concentrations. Our objective was to investigate differences in plasma, erythrocyte, cerebrospinal fluid, and brain lithium pharmacokinetics using a multicompartmental approach in rat models mimicking the three human intoxication patterns. We developed acute (intraperitoneal administration of 185 mg/kg Li₂CO₃ in naive rats), acute-on-chronic (intraperitoneal administration of 185 mg/kg Li₂CO₃ in rats receiving 800 mg/l Li₂CO₃ in water during 28 days), and chronic poisoning models (intraperitoneal administration of 74 mg/kg Li₂CO₃ during 5 days in rats with 15 mg/kg K₂Cr₂O₇-induced renal failure). Delayed absorption (4.03 vs 0.31 h), increased plasma elimination (0.65 vs 0.37 l/kg/h) and shorter half-life (1.75 vs 2.68 h) were observed in acute-on-chronically compared with acutely poisoned rats. Erythrocyte and cerebrospinal fluid kinetics paralleled plasma kinetics in both models. Brain lithium distribution was rapid (as early as 15 min), inhomogeneous and with delayed elimination (over 78 h). However, brain lithium accumulation was more marked in acute-on-chronically than acutely poisoned rats [area-under-the-curve of brain concentrations (379 ± 41 vs 295 ± 26, P < .05) and brain-to-plasma ratio (45 ± 10 vs 8 ± 2, P < .0001) at 54 h]. Moreover, brain lithium distribution was increased in chronically compared with acute-on-chronically poisoned rats (brain-to-plasma ratio: 9 ± 1 vs 3 ± 0, P < .01). In conclusion, prolonged rat exposure results in brain lithium accumulation, which is more marked in the presence of renal failure. Our data suggest that differences in plasma and brain kinetics may at least partially explain the observed variability between human intoxication patterns.
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http://dx.doi.org/10.1093/toxsci/kfu224DOI Listing
January 2015

Lithium-related neurotoxicity despite serum concentrations in the therapeutic range: risk factors and diagnosis.

Shanghai Arch Psychiatry 2014 Aug;26(4):243-4

Inserm, U1144, Paris, France ; Université Paris Descartes, Paris, France ; Université Paris Diderot, Paris, France.

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http://dx.doi.org/10.3969/j.issn.1002-0829.2014.04.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4194008PMC
August 2014
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