Poisoning by Anticoagulant Rodenticides in Humans and Animals: Causes and Consequences

Anticoagulant rodenticides (ARs) are a keystone of the management of rodent populations in the world. The widespread use of these molecules raises questions on exposure and intoxication risks, which define the safety of these products. Exposures and intoxications can affect humans, domestic animals and wildlife. Consequences are different for each group, from the simple issue of intoxication in humans to public health concern if farm animals are exposed. After a rapid presentation of the mechanism of action and the use of anticoagulant rodenticides, this chapter assesses the prominence of poisoning by anticoagulant rodenticides in humans, domestic animals and wildlife

Fecal Calprotectin Excretion in Preterm Infants during the Neonatal Period

Fecal calprotectin has been proposed as a non-invasive marker of intestinal inflammation in inflammatory bowel disease in adults and children. Fecal calprotectin levels have been reported to be much higher in both healthy full-term and preterm infants than in children and adults.To determine the time course of fecal calprotectin (f-calprotectin) excretion in preterm infants from birth until hospital discharge and to identify factors influencing f-calprotectin levels in the first weeks of life, including bacterial establishment in the gut.F-calprotectin was determined using an ELISA assay in 147 samples obtained prospectively from 47 preterm infants (gestational age, and birth-weight interquartiles 27–29 weeks, and 880–1320 g, respectively) at birth, and at 2-week intervals until hospital discharge. (p = 0.047).During the first weeks of life, the high f-calprotectin values observed in preterm infants could be linked to the gut bacterial establishment

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Etude multimodale in vivo des mécanismes de toxicité neurorespiratoire des opioïdes chez le rat

Opioids overdose may be responsible for respiratory depression. Nevertheless, two molecules exhibit particular toxicity patterns. Buprenorphine induces ceiling respiratory effects even at high doses. However, several deaths have been reported, mainly when buprenorphine was co-administered with benzodiazepines. Tramadol is a µ-opioid receptor agonist that induces seizures in 20% of poisoning cases. The exact mechanisms involved in both toxicity remain poorly understood. The aim of our investigation was to study the mechanisms involved in these two types of toxicity using a multimodal approach including pharmacodynamic data and in vivo brain neuropharmacokinetics. Regarding buprenorphine, we have shown that respiratory depression with diazepam does not result from neuropharmacokinetic/receptologic interaction (11C-buprenorphine PET imaging) Conversely, the study of respiratory parameters (plethysmography, blood gas, electromyogram) and their antagonization by opioid and gamma-aminobutyric acid (GABA) receptors antagonists supported interactions mediated by the addition of the pharmacodynamic effects of each molecule. Regarding tramadol, we showed that seizures did not involve the noradrenergic, dopaminergic, serotoninergic or opioidergic systems. Conversely, they involve the GABA-ergic system; tramadol acts as negative allosteric modulator of the benzodiazepine site of the GABA-A receptor (11C-flumazenil PET imaging). Using a multimodal in vivo approach in the rat, we have been able to determine that the interactions between opioids and the GABAergic system play a major role in mechanisms of toxicity of buprenorphine and tramadol.Les opioïdes peuvent être responsables, en cas d’intoxication, d’une dépression respiratoire mortelle. Deux opioïdes ont un profil de toxicité particulier. La buprénorphine, seule, a des effets respiratoires plafonnés alors qu’administrée avec des benzodiazépines elle peut être à l’origine d’une dépression respiratoire mortelle. Le tramadol, dans un contexte d’intoxication aigue, entraine dans 20% des cas des convulsions. Les mécanismes de ces toxicités sont inconnus.L’objectif de cette thèse était d’étudier de façon multimodale les mécanismes impliqués dans ces deux types de toxicité en incluant des données pharmacodynamiques et neuropharmacocinétiques in vivo. Pour la buprénorphine, nous avons montré que la dépression respiratoire observée avec le diazépam ne résultait pas d’une interaction neuropharmacocinétique/réceptologique centrale (imagerie TEP 11C- buprénorphine). En revanche, les données physiologiques respiratoires (pléthysmographie, gaz du sang, électromyographie) et leur réversion par les antagonistes des récepteurs opioïdes et de l’acide γ-aminobutyrique (GABA) étaient en faveur d’une interaction pharmacodynamique. Pour le tramadol, nous avons montré que les convulsions n’impliquaient pas les systèmes noradrénergiques, dopaminergiques, sérotoninergiques ou opioïdergiques. Le tramadol agissait comme un modulateur allostérique négatif du site de liaison des benzodiazépines des récepteurs GABA-A (imagerie TEP 11C-flumazénil). Par cette approche multimodale in vivo chez le rat, nous avons pu déterminer que les interactions entre les opioïdes et le système GABAergique jouent un rôle majeur dans les profils de toxicité spécifique de la buprénorphine et du tramadol

In vivo multimodal study of the neuro-respiratory toxicity of opioids

Les opioïdes peuvent être responsables, en cas d’intoxication, d’une dépression respiratoire mortelle. Deux opioïdes ont un profil de toxicité particulier. La buprénorphine, seule, a des effets respiratoires plafonnés alors qu’administrée avec des benzodiazépines elle peut être à l’origine d’une dépression respiratoire mortelle. Le tramadol, dans un contexte d’intoxication aigue, entraine dans 20% des cas des convulsions. Les mécanismes de ces toxicités sont inconnus.L’objectif de cette thèse était d’étudier de façon multimodale les mécanismes impliqués dans ces deux types de toxicité en incluant des données pharmacodynamiques et neuropharmacocinétiques in vivo. Pour la buprénorphine, nous avons montré que la dépression respiratoire observée avec le diazépam ne résultait pas d’une interaction neuropharmacocinétique/réceptologique centrale (imagerie TEP 11C- buprénorphine). En revanche, les données physiologiques respiratoires (pléthysmographie, gaz du sang, électromyographie) et leur réversion par les antagonistes des récepteurs opioïdes et de l’acide γ-aminobutyrique (GABA) étaient en faveur d’une interaction pharmacodynamique. Pour le tramadol, nous avons montré que les convulsions n’impliquaient pas les systèmes noradrénergiques, dopaminergiques, sérotoninergiques ou opioïdergiques. Le tramadol agissait comme un modulateur allostérique négatif du site de liaison des benzodiazépines des récepteurs GABA-A (imagerie TEP 11C-flumazénil). Par cette approche multimodale in vivo chez le rat, nous avons pu déterminer que les interactions entre les opioïdes et le système GABAergique jouent un rôle majeur dans les profils de toxicité spécifique de la buprénorphine et du tramadol.Opioids overdose may be responsible for respiratory depression. Nevertheless, two molecules exhibit particular toxicity patterns. Buprenorphine induces ceiling respiratory effects even at high doses. However, several deaths have been reported, mainly when buprenorphine was co-administered with benzodiazepines. Tramadol is a µ-opioid receptor agonist that induces seizures in 20% of poisoning cases. The exact mechanisms involved in both toxicity remain poorly understood. The aim of our investigation was to study the mechanisms involved in these two types of toxicity using a multimodal approach including pharmacodynamic data and in vivo brain neuropharmacokinetics. Regarding buprenorphine, we have shown that respiratory depression with diazepam does not result from neuropharmacokinetic/receptologic interaction (11C-buprenorphine PET imaging) Conversely, the study of respiratory parameters (plethysmography, blood gas, electromyogram) and their antagonization by opioid and gamma-aminobutyric acid (GABA) receptors antagonists supported interactions mediated by the addition of the pharmacodynamic effects of each molecule. Regarding tramadol, we showed that seizures did not involve the noradrenergic, dopaminergic, serotoninergic or opioidergic systems. Conversely, they involve the GABA-ergic system; tramadol acts as negative allosteric modulator of the benzodiazepine site of the GABA-A receptor (11C-flumazenil PET imaging). Using a multimodal in vivo approach in the rat, we have been able to determine that the interactions between opioids and the GABAergic system play a major role in mechanisms of toxicity of buprenorphine and tramadol

The desperate searching for reliable and convenient criteria of haemodialysis in the lithium‐poisoned patient

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Seizures induced by tramadol overdose: what is the respective contribution of tramadol and each of its metabolites?

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Defining predictive factors of severity and indications for extracorporeal toxin removal in lithium poisoning: not an easy objective!

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Does MARS™ beneficially affect hemodynamics in refractory vasoplegic shock due to calcium-channel blocker poisoning? Evidence is missing

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Are sodium nitrite exposures increasing in the United States?

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