Akutno otrovanje cijanidima: klinička slika, dijagnoza i liječenje

Cyanide poisoning presents in many forms. Industrial intoxications occur due to extensive use of cyanide compounds as reaction products. Smoke inhalation, a polyintoxication, is most often responsible for domestic cyanide poisonings. Suicidal poisonings are rare. Cyanogenic compounds may produce acute or subacute toxicity. Signs of cyanide poisoning include headache, vertigo, agitation, confusion, coma, convulsions and death. Definitive laboratory confirmation is generally delayed. Elevated plasma lactate, associated with cardiovascular collapse, should suggest cyanide intoxication. Immediate treatment includes 100% oxygen, assisted ventilation, decontamination, correction of acidosis and blood pressure support. Antidotes include oxygen, hydroxocobalamin, di-cobalt EDTA and methaemoglobin-inducers. Hydroxocobalamin is an attractive antidote due to its rapid cyanide binding and its lack of serious side-effects, even in the absence of cyanide intoxication. Sodium thiosulphate acts more slowly than other antidotes and is indicated in subacute cyanogen poisoning and as an adjunct to acute cyanide poisoning. Initial evaluation of antidotal efficacy is based on correction of hypotension and lactic acidosis; the final analysis rests on the degree of permanent central nervous system injury.Otrovanje cijanidima može nastati na različite načine. Profesionalna otrovanja uzrokovana su širokom uporabom cijanidnih spojeva u kemijskoj sintezi. Udisanje dima u požarima najčešći je uzrok otrovanja cijanidima u kućnom okolišu. Otrovanja u svrhu samoubojstava su rijetka. Cijanogeni spojevi mogu uzrokovati akutna ill subakutna otrovanja. Znakovi otrovanja su glavobolja, vrtoglavica, nemir, smetenost, koma, konvulzije i smrt. Konačna laboratorijska potvrda uzroka otrovanja često dolazi sa zakašnjenjem. Povišenje laktata u plazmi praćeno zatajenjem srca i krvotoka upućuje na moguće otrovanje cijanidima. Hitno liječenje uključuje kisik, umjetno disanje, mjere dekontaminacije, suzbijanje acidoze i održavanje krvotoka. Kao antidoti rabe se kisik, hidroksikobalamin, dikobalt-EDTA i lijekovi koji dovode do methemoglobinemije. Hidroksikobalamin je antidot izbora zbog sposobnosti brzog vezanja cijanida, s malo ozbiljnih nuspojava čak i ako otrovanje nije uzrokovano cijanidima. Natrijev tiosulfat djeluje sporije od drugih antidota i indiciran je u subakutnim slučajevima otrovanja te kao pomoćni lijek za akutna otrovanja cijanidima. Početna procjena djelotvornosti antidota temelji se na sposobnosti suzbijanja hipotenzije i laktičke acidoze, dok se konačna ocjena temelji na procjeni stupnja trajnog oštećenja središnjeg živčanog sustava

Identification of Immunogenic Proteins of Waddlia chondrophila

Evidence is growing for a role of Waddlia chondrophila as an agent of adverse pregnancy outcomes in both humans and ruminants. This emerging pathogen, member of the order Chlamydiales, is also implicated in bronchiolitis and lower respiratory tract infections. Until now, the serological diagnosis of W. chondrophila infection has mainly relied on manually intensive tests including micro-immunofluorescence and Western blotting. Thus, there is an urgent need to establish reliable high throughput serological assays. Using a combined genomic and proteomic approach, we detected 57 immunogenic proteins of W. chondrophila, of which 17 were analysed by mass spectrometry. Two novel hypothetical proteins, Wim3 and Wim4, were expressed as recombinant proteins in Escherichia coli, purified and used as antigens in an ELISA test. Both proteins were recognized by sera of rabbits immunized with W. chondrophila as well as by human W. chondrophila positive sera but not by rabbit pre-immune sera nor human W. chondrophila negative sera. These results demonstrated that the approach chosen is suitable to identify immunogenic proteins that can be used to develop a serological test. This latter will be a valuable tool to further clarify the pathogenic potential of W. chondrophila

Intoxication with Calcium Channel Blockers and Other Highly Protein-Bound Drugs: Why Use MARS? Two Clinical Case Reports

Overdose with calcium channel blockers is often a life-threating condition that is frequently exacerbated by the availability of extended-release preparations with slow drug clearances. In the annual report of the American Association of Poison Control Centers, calcium channel inhibitor overdose is one of the most deadly poisonings. In addition, calcium channel blockers are highly bound to proteins, making them difficult to remove using standard dialysis techniques. We describe two cases of amlodipine overdose that presented with profound circulatory shock and were treated with the Molecular Adsorbent Recirculating System™ (MARS™). In this regard, the authors reviewed other cases reported in the literature to discuss the rationale for using albumin dialysis techniques in the setting of highly protein-bound drug intoxication

Case report : quantification of methadone-induced respiratory depression using toxicokinetic/toxicodynamic relationships

International audienceIntroduction: Methadone, the most widely delivered maintenance therapy for heroin addicts, may be responsible for life-threatening poisonings with respiratory depression. The toxicokinetics and the toxicokinetic/toxicodynamic (TK/TD) relationships of methadone enantiomers have been poorly investigated in acute poisonings. The aim of this study was to describe the relationships between methadone-related respiratory effects and their corresponding concentrations.Methods: We report a 44-year-old methadone-maintained patient who ingested a 240-mg dose of methadone. He was found comatose with pinpoint pupils and respiratory depression. He was successfully treated with intravenous naloxone infusion over the course of 31 hours at a rate adapted to maintain normal consciousness and respiratory rate. We performed a TK/TD analysis of the naloxone infusion rate needed to maintain his respiratory rate at more than 12 breaths per minute (as toxicodynamics parameter) versus plasma R,S- and R-methadone concentrations (as toxicokinetics parameter), determined using an enantioselective high-performance liquid chromatography assay.Results: Initial plasma R,S-methadone concentration was 1,204 ng/ml. Decrease in plasma R- and S-methadone concentrations was linear and demonstrated a first-order pharmacokinetics (maximal observed concentrations 566 and 637 ng/ml, half-lives 16.1 and 13.2 hours, respectively). TK/TD correlation between naloxone infusion rate and R,S- and R-methadone concentrations fitted well a sigmoidal Emax model (concentration associated with a half-maximum effect [EC50] 334 and 173 ng/ml, Hill coefficient 10.0 and 7.8, respectively). In our chronically treated patient, EC50 values were in the range of previously reported values regarding methadone analgesic effects, suggesting that plasma methadone concentrations to prevent withdrawal are lower than those associated with methadone analgesic effects.Conclusion: After the ingestion of a toxic dose of a racemic mixture, plasma R- and S-enantiomer concentrations decreased in parallel. Despite large inter-individual variability in methadone toxicokinetics and toxicodynamics, TK/TD relationships would be helpful for providing quantitative data regarding the respiratory response to methadone in poisonings. However, further confirmatory TK/TD data are needed

A Possible Hypophosphatemia-induced, Life-Threatening Encephalopathy in Diabetic Ketoacidosis: A Case Report

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Poisoning-related bowel infarction: Characteristics and outcomes

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Concentration-dependent mortality of chloroquine in overdose

International audienceHydroxychloroquine and chloroquine are used extensively in malaria and rheumatological conditions, and now in COVID-19 prevention and treatment. Although generally safe they are potentially lethal in overdose. In-vitro data suggest that high concentrations and thus high doses are needed for COVID-19 infections, but as yet there is no convincing evidence of clinical efficacy. Bayesian regression models were fitted to survival outcomes and electrocardiograph QRS durations from 302 prospectively studied French patients who had taken intentional chloroquine overdoses, of whom 33 died (11%), and 16 healthy volunteers who took 620 mg base chloroquine single doses. Whole blood concentrations of 13.5 µmol/L (95% credible interval 10.1–17.7) were associated with 1% mortality. Prolongation of ventricular depolarization is concentration-dependent with a QRS duration >150 msec independently highly predictive of mortality in chloroquine self-poisoning. Pharmacokinetic modeling predicts that most high dose regimens trialled in COVID-19 are unlikely to cause serious cardiovascular toxicity

Cell-cell fusion of mesenchymal cells with distinct differentiations triggers genomic and transcriptomic remodelling toward tumour aggressiveness

Cell-cell fusion is a physiological process that is hijacked during oncogenesis and promotes tumour evolution. The main known impact of cell fusion is to promote the formation of metastatic hybrid cells following fusion between mobile leucocytes and proliferating tumour cells. We show here that cell fusion between immortalized myoblasts and transformed fibroblasts, through genomic instability and expression of a specific transcriptomic profile, leads to emergence of hybrid cells acquiring dissemination properties. This is associated with acquisition of clonogenic ability by fused cells. In addition, by inheriting parental properties, hybrid tumours were found to mimic the histological characteristics of a specific histotype of sarcomas: undifferentiated pleomorphic sarcomas with incomplete muscular differentiation. This finding suggests that cell fusion, as macroevolution event, favours specific sarcoma development according to the differentiation lineage of parent cells