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Serotonin syndrome (toxicity), resulting from an excessive accumulation of serotonin in the central nervous system, it can occur due to various factors such as the initiation of medication, overdose or drug interactions. Diagnosing serotonin toxicity presents challenges as there are no definitive criteria. This review delves into the pathophysiology, incidence, clinical assessment and management of serotonin toxicity, stressing the significance of promptly recognizing and managing severe cases. Diagnosis relies primarily relies on clinical assessment due to the absence of specific laboratory tests. The Hunter Serotonin Toxicity criteria are commonly utilized but have only been validated in the overdose setting. Assessing the severity of toxicity is crucial for guiding management decisions. Supportive care, discontinuation of causative agents and symptomatic treatment are prioritized in management. Mild toxicity often requires withdrawal or reduction of the serotonergic agent, while more severe toxicity requires more aggressive resuscitative and supportive care. Severe serotonin toxicity characterized by hyperthermia and rigidity requires aggressive supportive measures, including benzodiazepines, intubation, paralysis and active cooling. Animal studies suggest potential benefits of 5-HT2A receptor antagonists in preventing hyperthermia and fatalities, but only at high doses. Their clinical effectiveness remains uncertain, and evidence is predominately from case series and case reports. Although commonly used, serotonin antagonists like cyproheptadine lack conclusive evidence of efficacy. Other serotonin antagonists such as chlorpromazine and olanzapine have been explored but evidence is limited to case reports. Hence, the cornerstone of treating severe cases does not lie in 'antidote' administration or even diagnosis but in effective early resuscitative and supportive care.
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STUDY OBJECTIVE: Early detection of systemic envenoming is critical for early antivenom therapy to minimize morbidity and mortality from snakebite. We assessed the diagnostic utility of 3 serum biomarkers in the early detection of systemic envenoming in viper bites in rural Sri Lanka. METHODS: All confirmed snakebite patients admitted to Teaching Hospital Anuradhapura from July 2020 to June 2021 were included. On admission, blood was collected for venom concentrations, prothrombin time/international normalized ratio, fibrinogen concentration, serum creatinine concentration, and 3 serum biomarkers, namely secretory phospholipase A2 (sPLA2) activity, neutrophil gelatinase-associated lipocalin (sNGAL) concentration, and clusterin (sClu) concentration. Systemic envenoming was defined by the presence of venom-induced consumption coagulopathy, neurotoxicity, acute kidney injury, or the presence of nonspecific clinical effects. RESULTS: A total of 237 confirmed snakebite patients (Russell's viper, 72; hump-nosed viper, 80; nonvenomous snakes, 31; and unidentified bites, 54) with sufficient preantivenom serum samples were recruited [median age: 42 years (interquartile range [IQR] 29 to 53 years); 173 men (73%)]. Systemic envenoming occurred in 68 (94%) Russell's viper bites, 48 (60%) hump-nosed viper bites, and 45 (83%) unidentified bites. The median sPLA2 activity was 72 nmol/mL/min (IQR 30 to 164) for Russell's viper envenoming, 12 nmol/mL/min (IQR 9 to 16) for hump-nosed viper envenoming, and 11 nmol/mL/min (IQR 9 to 14) for nonvenomous bites. There was no difference in sNGAL and sCLu concentrations among the 3 groups. The median sPLA2 activity of patients with systemic envenoming was 16 nmol/min/mL (IQR 11 to 59) compared to 11 nmol/min/mL (IQR 9 to 14) in patients without systemic envenoming; the difference between medians was 5 nmol/min/mL (95% confidence interval [CI] 4 to 12). The area under the receiver operator characteristic curve (AUC-ROC) of admission sPLA2 activity was the best predictor of systemic envenoming in all snakebites (AUC-ROC 0.72, 95% CI 0.66 to 0.79), whereas sNGAL and sClu concentrations were poor predictors. sPLA2 activity was a better predictor of systemic envenoming in Russell's viper bites (AUC-ROC 0.90, 95% CI 0.76 to 1.00) and in those presenting within 2 hours of a bite. A sPLA2 activity more than 23.5 nmol/min/mL had a sensitivity of 41% (95% CI 34% to 49%), and a specificity of 97% (95% CI 91% to 99.5%) in predicting systemic envenoming. A sPLA2 activity of more than 46 nmol/min/mL on admission had a sensitivity of 67% (95% CI 55% to 77%) and a specificity of 100% (95% CI 51% to 100%) in predicting systemic envenoming in Russell's viper bites. CONCLUSIONS: sPLA2 activity is an early predictor of systemic envenoming following snakebite, particularly in Russell's viper bites and in those who present early.
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Snake venoms are heterogeneous mixtures of proteins and peptides used for prey subjugation. With modern proteomics there has been a rapid expansion in our knowledge of snake venom composition, resulting in the venom proteomes of 30% of vipers and 17% of elapids being characterised. From the reasonably complete proteomic coverage of front-fanged snake venom composition (179 species-68 species of elapids and 111 species of vipers), the venoms of vipers and elapids contained 42 different protein families, although 18 were only reported in < 5% of snake species. Based on the mean abundance and occurrence of the 42 protein families, they can be classified into 4 dominant, 6 secondary, 14 minor, and 18 rare protein families. The dominant, secondary and minor categories account for 96% on average of a snake's venom composition. The four dominant protein families are: phospholipase A2 (PLA2), snake venom metalloprotease (SVMP), three-finger toxins (3FTx), and snake venom serine protease (SVSP). The six secondary protein families are: L-amino acid oxidase (LAAO), cysteine-rich secretory protein (CRiSP), C-type lectins (CTL), disintegrins (DIS), kunitz peptides (KUN), and natriuretic peptides (NP). Venom variation occurs at all taxonomic levels, including within populations. The reasons for venom variation are complex, as variation is not always associated with geographical variation in diet. The four dominant protein families appear to be the most important toxin families in human envenomation, being responsible for coagulopathy, neurotoxicity, myotoxicity and cytotoxicity. Proteomic techniques can be used to investigate the toxicological profile of a snake venom and hence identify key protein families for antivenom immunorecognition.
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Proteómica , Toxinas Biológicas , Humanos , Proteómica/métodos , Venenos de Serpiente , Antivenenos , Proteoma , PéptidosRESUMEN
AIM: We aimed to describe the severity of clonidine poisonings in a paediatric population referred to a tertiary toxicology service. METHODS: We undertook a retrospective review of all presentations of clonidine poisoning in children or adolescents reported to a tertiary toxicology service from March 2014 to February 2020. Cases were divided into young children (0-6 years), older children (7-11 years) and adolescents (12-17 years). We report clinical effects: bradycardia, hypotension and abnormal Glasgow coma score (GCS), based on standard paediatric observation charts, interventions, length of emergency department stay, proportion admitted to a medical ward or paediatric intensive care unit. RESULTS: We identified 111 clonidine poisonings, 41 young children, 9 older children and 61 adolescents. There were more females in the adolescent group and slightly more males in the younger age groups. The median dose ingested was 13 mcg/kg (interquartile range: 7-38 mcg/kg), which varied across ages. Clonidine alone was ingested in 78 cases (70%) and co-ingestion was more common in adolescents (24/61; 39%). Thirty-seven patients (33%) were admitted and 23 (21%) were admitted to paediatric intensive care unit. Median length of emergency department stay was 16.4 h, longer for adolescents. At least one abnormal observation occurred in 101 of 111 (91%) cases: 76 of 106 (72%) bradycardia, 76 of 110 (69%) hypotension and 4 of 99 (4%) GCS < 9. Thirteen (12%) had severe bradycardia, more common in young children and 23 (21%) had severe hypotension, more common in adolescents. For 27 children (0-11 years) ingesting 5-10 mcg/kg, 3 (11%) had severe bradycardia or severe hypotension and 1 received naloxone (4%). No cases ingesting <5 mcg/kg developed moderate/severe bradycardia or hypotension. Four cases received naloxone with no significant change, two patients got atropine with a transient response. One patient was intubated to facilitate safe inter-hospital transfer. CONCLUSION: Paediatric clonidine poisoning commonly results in bradycardia, hypotension and decreased GCS, but rarely severe or requiring major interventions. Children ingesting <5 mcg/kg do not require admission.
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Hipotensión , Intoxicación , Masculino , Femenino , Niño , Humanos , Adolescente , Preescolar , Clonidina , Bradicardia/inducido químicamente , Atropina , Hipotensión/inducido químicamente , Naloxona , Estudios RetrospectivosRESUMEN
AIMS: The objectives were to determine the effect of NaHCO3 and/or mechanical ventilation on the biochemical profile and serum alkalinisation in tricyclic antidepressant (TCA) poisoning and investigate the impact of effective alkalinisation therapy on the QRS interval in TCA poisoning. METHODS: This was a retrospective review of TCA poisonings from three Australian toxicology units and a poisons information centre (Jan 2013 to Jan 2019). We included patients with TCA toxicity who ingested>10 mg/kg or had clinically significant toxicities consistent with TCA poisoning, and analysed patients' clinical, electrocardiogram and biochemical data. RESULTS: Of 210 patients, 84 received NaHCO3 and ventilation (dual therapy), 12 NaHCO3 , 46 ventilation and 68 supportive care treatment. When compared with single/supportive groups, patients who received dual therapy had taken a significantly higher median dose of TCA (1.5 g vs1.3 g, P < .001), a longer median maximum QRS interval (124 ms, interquartile ranges [IQR] 108-138 vs106 ms, IQR 98-115, P < .001) and were more likely to have seizures (14% vs3%, P = .006) and arrhythmias (17% vs1%, P < .001). The dual therapy group demonstrated greater increases in serum pH (median 0.11, IQR 0.04-0.17) compared to the single/supportive therapy group (median 0.03, IQR -0.01-0.09, p < .001). A greater proportion of patients reached the target pH 7.45-7.55 in the dual therapy group (59%) compared to the single/supportive therapy group (10%) (P < .001). For each 100 mmol bolus of NaHCO3 given, the median increase in serum sodium was 2.5 mmol/L (IQR 1.5-4.0). QRS narrowing occurred twice as quickly in the dual therapy vs single/supportive therapy group. CONCLUSIONS: A combination of NaHCO3 and mechanical ventilation was most effective in achieving serum alkalinisation and was associated with a more rapid narrowing of the QRS interval. We advise that the maximal dose of NaHCO3 should be <400 mmol (6 mmol/kg).
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Antidepresivos Tricíclicos , Intoxicación , Arritmias Cardíacas/inducido químicamente , Arritmias Cardíacas/tratamiento farmacológico , Australia/epidemiología , Electrocardiografía , Humanos , Estudios RetrospectivosRESUMEN
STUDY OBJECTIVE: Large doses of intramuscular (IM) naloxone are commonly used in out-of-hospital settings to reverse opioid toxicity; however, they are used less commonly in hospitals because of concerns about opioid withdrawal, particularly agitation. We aimed to determine the frequency of severe agitation following a single 1.6 mg IM naloxone dose. METHODS: We undertook a prospective study of adult (>15 years) patients treated by an Australian state ambulance service with 1.6 mg IM administration of naloxone for respiratory depression (respiratory rate <11 breaths/min and/or oxygen saturation <93% in room air) caused by presumed opioid poisoning. The primary outcome was the proportion of presentations with severe agitation (Sedation Assessment Tool score >1) within 1 hour of naloxone administration. Secondary outcomes were the proportion of presentations with acute opioid withdrawal (tachycardia [pulse rate >100 beats/min], hypertension [systolic >140 mm Hg], vomiting, agitation, seizure, myocardial infarction, arrhythmia, or pulmonary edema), and reversal of respiratory depression (respiratory rate >10 breaths/min and saturation >92% or Glasgow Coma Scale score 15). RESULTS: From October 2019 to July 2021, there were 197 presentations in 171 patients, with a median age of 41 years (range, 18 to 80 years); of the total patients, 119 were men (70%). The most common opioids were heroin (131 [66%]), oxycodone (14 [7%]), and morphine (11 [6%]). Severe agitation occurred in 14 (7% [95% confidence interval {CI} 4% to 12%]) presentations. Opioid withdrawal occurred in 76 presentations (39% [95% CI 32% to 46%]), most commonly in the form of tachycardia (18%), mild agitation/anxiety (18%) and hypertension (14%). Three presentations (1.5%) received chemical sedation for severe agitation within 1 hour of naloxone administration. A single 1.6 mg dose of naloxone reversed respiratory depression in 192 (97% [95% CI: 94% to 99%]) presentations. CONCLUSION: Severe agitation was uncommon following the administration of 1.6 mg IM naloxone and rarely required chemical sedation.
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Sobredosis de Droga , Hipertensión , Insuficiencia Respiratoria , Síndrome de Abstinencia a Sustancias , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Analgésicos Opioides/uso terapéutico , Australia , Sobredosis de Droga/tratamiento farmacológico , Femenino , Hospitales , Humanos , Hipertensión/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Naloxona , Antagonistas de Narcóticos/efectos adversos , Narcóticos , Estudios Prospectivos , Insuficiencia Respiratoria/inducido químicamente , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Adulto JovenRESUMEN
OBJECTIVE: To assess the accuracy and marginal value of quantitative D-dimer testing for diagnosing venom-induced consumption coagulopathy (VICC) in people bitten by Australian snakes. DESIGN, SETTING: Analysis of data for suspected and confirmed cases of snakebite collected prospectively by the Australian Snakebite Project, 2005-2019, from 200 hospitals across Australia. PARTICIPANTS: 1363 patients for whom D-dimer was quantitatively assessed within 24 hours of suspected or confirmed snakebite. MAIN OUTCOME MEASURES: Diagnostic performance of quantitative D-dimer testing for detecting systemic envenoming with VICC (area under the receiver operating characteristic curve, AUC); optimal D-dimer cut-off value (maximum sum of sensitivity and specificity). RESULTS: D-dimer values exceeded 2.5 mg/L within three hours of the bite for 95% of patients who developed VICC, and were lower than 2.5 mg/L for 95% of non-envenomed patients up to six hours after snakebite. The AUC for diagnosing envenoming with VICC on the basis of quantitative D-dimer testing within six hours of snakebite was 0.97 (95% CI, 0.96-0.98; 944 patients). Diagnostic performance increased during the first three hours after snakebite; for quantitative D-dimer testing at 2-6 hours, the AUC was 0.99 (95% CI, 0.99-1.0); with a cut-off of 2.5 mg/L, sensitivity was 97.1% (95% CI, 95.0-98.3%) and specificity 99.0% (95% CI, 97.6-99.6%) for VICC. For 36 patients with normal international normalised ratio (INR) and activated partial thromboplastin time (aPTT) values 2-6 hours after snakebite, the AUC was 0.97 (95% CI, 0.93-1.0); with a cut-off of 1.4 mg/L, sensitivity was 94% (95% CI, 82-99%) and specificity 96% (95% CI, 94-97%). In all but one of 84 patients who developed VICC-related acute kidney injury, D-dimer values exceeded 4 mg/L within 24 hours of the bite. CONCLUSION: D-dimer concentrations assessed 2-6 hours after snakebite, with a cut-off value of 2.5 mg/L, could be useful for diagnosing envenoming with VICC.
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Coagulación Intravascular Diseminada , Mordeduras de Serpientes , Antivenenos , Australia/epidemiología , Coagulación Intravascular Diseminada/diagnóstico , Coagulación Intravascular Diseminada/etiología , Venenos Elapídicos , Productos de Degradación de Fibrina-Fibrinógeno , Humanos , Estudios Prospectivos , Mordeduras de Serpientes/complicaciones , Mordeduras de Serpientes/diagnósticoRESUMEN
Paracetamol-induced hepatotoxicity is the leading cause of acute liver failure in many countries, including North America and the United Kingdom. Among the three dominant paracetamol metabolism pathways (i.e. glucuronidation, sulfation and oxidation), the importance of sulfation is often underestimated because of the general thinking that the sulfation pathway is saturated at therapeutic doses and ultimately accounts for a limited proportion of the fate of a paracetamol dose. We illustrate that insufficient sulfation leads to a shift in biotransformation of paracetamol to toxic oxidation pathways and patients with low sulfate reserves are at higher risk of paracetamol toxicity. Here, we propose that sulfation is of critical importance in understanding the risk of liver toxicity secondary to paracetamol overdose. Serum inorganic sulfate, a measurable substrate on the causal path of paracetamol-induced liver toxicity, should be considered a biomarker for potential toxicity as well as a target for treatment.
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Analgésicos no Narcóticos , Enfermedad Hepática Inducida por Sustancias y Drogas , Sobredosis de Droga , Acetaminofén/toxicidad , Analgésicos no Narcóticos/toxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Sobredosis de Droga/tratamiento farmacológico , Humanos , Sulfatos/uso terapéutico , Sulfatos/toxicidadRESUMEN
AIM: The aim of this study is to describe the epidemiology and health-care utilisation of paediatric emergency department (ED) presentations due to poisoning. METHODS: A retrospective review of all ED presentations of paediatric poisoning cases (<18 years) reported to a tertiary toxicology service from 2015 to 2016 was conducted. Cases were classified into three age groups: pre-school (0-6 years), primary school (7-11 years) and adolescent (12-17 years). Outcomes included patient transfer, length of ED stay (LOS) and proportion admitted to a medical ward, mental health unit or intensive care unit (ICU). RESULTS: From 764 consultations over a 2-year period, 87 were excluded as non-ED presentations. From these, there were 194 (29%; 47% female) pre-school aged, 34 (5%; 41% female) primary school aged and 449 (66%; 77% female) adolescent presentations. Deliberate self-poisoning was most common in 394 of 449 (88%) adolescents. Accidental exposures accounted for 159 (82%) of pre-school presentations and natural toxins occurred in all three age groups. Paracetamol, selective serotonin reuptake inhibitors, antipsychotics and ibuprofen were the most common toxins. Discharge from ED occurred in 147 of 194 (76%) pre-school, 24 of 34 (71%) primary school and 223 of 449 (50%) adolescent presentations. Of the 449 adolescents, 137 (31%) were admitted medically (median LOS 19.9 h), 19 were admitted to ICU (median LOS 71 h) and 70 (16%) admitted to mental health (median LOS 122 h). Five pre-school aged children were admitted to ICU. CONCLUSIONS: Adolescent deliberate self-poisoning has a significant impact on hospital resources, with mental health problems requiring extended length of stay. There were fewer pre-school accidental poisoning consultations, which were mainly discharged from ED.
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Servicio de Urgencia en Hospital , Intoxicación , Adolescente , Australia/epidemiología , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Unidades de Cuidados Intensivos , Tiempo de Internación , Masculino , Intoxicación/epidemiología , Estudios RetrospectivosRESUMEN
Cellular response to insults may result in the initiation of different cell death processes. For many cases the cell death process will result in an acute release of cellular material that in some circumstances provides valuable information about the process (i.e. may represent a biomarker). The characteristics of the biomarker release is often informative and plays critical roles in clinical practice and toxicology research. The aim of this study is to develop a general, semi-mechanistic model to describe cell turnover and biomarker release by injured tissue that can be used for estimation in pharmacokinetic and (toxicokinetic)-pharmacodynamic studies. The model included three components: (1) natural tissue turnover, (2) biomarker release from cell death and its movement from the cell through the tissue into the blood, (3) different target insult mechanisms of cell death. We applied the general model to biomarker release profiles for four different cell insult causes. Our model simulations showed good agreements with reported data under both delayed release and rapid release cases. Additionally, we illustrate the use of the model to provide different biomarker profiles. We also provided details on interpreting parameters and their values for other researchers to customize its use. In conclusion, our general model provides a basic structure to study the kinetic behaviour of biomarker release and disposition after cellular insult.
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Muerte Celular/fisiología , Modelos Biológicos , Acetaminofén/envenenamiento , Adulto , Anciano , Anciano de 80 o más Años , Alanina Transaminasa/metabolismo , Animales , Aspartato Aminotransferasas/metabolismo , Biomarcadores/metabolismo , Muerte Celular/efectos de los fármacos , Línea Celular , Senescencia Celular/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Niño , Simulación por Computador , Creatina Quinasa/metabolismo , Venenos de Crotálidos/toxicidad , Evaluación Preclínica de Medicamentos/métodos , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Infarto del Miocardio/patología , Daño por Reperfusión Miocárdica/patología , Toxicología/métodosRESUMEN
INTRODUCTION: To investigate whether there is an association between the blocking of cardiac potassium channels, which is characterised by a prolonged QTc interval and the frontal QRS-T angle after overdose by QT prolonging drugs. METHODS: We obtained patient medical records associated with QT prolonging drugs from 3 different hospitals: the Calvary Mater Newcastle Hospital (CMNH), Royal Prince Alfred Hospital (RPAH) and Prince of Wales Hospital (POWH). RPAH and POWH admissions were taken between 4/01/2017 to 1/11/2019, and CMNH admissions were taken between 4/01/2013 to 24/06/2018. Demographic information and details of overdose were collected. All admission ECGs were manually measured. Linear regression was used to assess the relationship between various QTc formulas and the frontal QRS-T angle. A Bland-Altman plot was used to examine agreement between manual and machine QT intervals. RESULTS: 144 patients met the inclusion criteria for analysis. None of the patients developed torsades de pointes (TdP). There was no linear association between the QRS-T angle and the various QTc formulas (For QRS-T angle: QTcRTH: p = 0.76, QTcB: p = 0.83, QTcFri: p = 0.90, QTcFra: p = 0.13, QTcH: p = 0.97; For square root transformation of the QRS-T angle: QTcRTH: p = 0.18, QTcB: p = 0.33, QTcFri: p = 0.95, QTcFra: p = 0.47, QTcH: p = 0.33). Agreement between machine and manual QT measurements was low. CONCLUSIONS: The frontal QRS-T angle cannot substitute the QTc in assessing the blockage of cardiac potassium channels in drug induced long QT syndrome. We also support the consensus that despite the availability of machine measurements of the QT interval, manual measurements should also be performed.
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Sobredosis de Droga , Síndrome de QT Prolongado , Profármacos , Torsades de Pointes , Sobredosis de Droga/diagnóstico , Electrocardiografía , Humanos , Torsades de Pointes/inducido químicamente , Torsades de Pointes/diagnósticoRESUMEN
BACKGROUND: The relative influence of diet and phylogeny on snake venom activity is a poorly understood aspect of snake venom evolution. We measured the activity of two enzyme toxin groups - phospholipase A2 (PLA2), and L-amino acid oxidase (LAAO) - in the venom of 39 species of Australian elapids (40% of terrestrial species diversity) and used linear parsimony and BayesTraits to investigate any correlation between enzyme activity and phylogeny or diet. RESULTS: PLA2 activity ranged from 0 to 481 nmol/min/mg of venom, and LAAO activity ranged from 0 to 351 nmol/min/mg. Phylogenetic comparative methods, implemented in BayesTraits showed that enzyme activity was strongly correlated with phylogeny, more so for LAAO activity. For example, LAAO activity was absent in both the Vermicella and Pseudonaja/Oxyuranus clade, supporting previously proposed relationships among these disparate taxa. There was no association between broad dietary categories and either enzyme activity. There was strong evidence for faster initial rates of change over evolutionary time for LAAO (delta parameter mean 0.2), but no such pattern in PLA2 (delta parameter mean 0.64). There were some exceptions to the phylogenetic patterns of enzyme activity: different PLA2 activity in the ecologically similar sister-species Denisonia devisi and D. maculata; large inter-specific differences in PLA2 activity in Hoplocephalus and Austrelaps. CONCLUSIONS: We have shown that phylogeny is a stronger influence on venom enzyme activity than diet for two of the four major enzyme families present in snake venoms. PLA2 and LAAO activities had contrasting evolutionary dynamics with the higher delta value for PLA2 Some species/individuals lacked activity in one protein family suggesting that the loss of single protein family may not incur a significant fitness cost.
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Venenos Elapídicos/enzimología , Elapidae/genética , L-Aminoácido Oxidasa/genética , Fosfolipasas A2/genética , Animales , Australia , Dieta , Elapidae/clasificación , Filogenia , Toxinas BiológicasRESUMEN
BACKGROUND & AIMS: Acetaminophen-protein adducts are specific biomarkers of toxic acetaminophen (paracetamol) metabolite exposure. In patients with hepatotoxicity (alanine aminotransferase [ALT] >1,000 U/L), an adduct concentration ≥1.0 nmol/ml is sensitive and specific for identifying cases secondary to acetaminophen. Our aim was to characterise acetaminophen-protein adduct concentrations in patients following acetaminophen overdose and determine if they predict toxicity. METHODS: We performed a multicentre prospective observational study, recruiting patients 14 years of age or older with acetaminophen overdose regardless of intent or formulation. Three serum samples were obtained within the first 24 h of presentation and analysed for acetaminophen-protein adducts. Acetaminophen-protein adduct concentrations were compared to ALT and other indicators of toxicity. RESULTS: Of the 240 patients who participated, 204 (85%) presented following acute ingestions, with a median ingested dose of 20 g (IQR 10-40), and 228 (95%) were treated with intravenous acetylcysteine at a median time of 6 h (IQR 3.5-10.5) post-ingestion. Thirty-six (15%) patients developed hepatotoxicity, of whom 22 had an ALT ≤1,000 U/L at the time of initial acetaminophen-protein adduct measurement. Those who developed hepatotoxicity had a higher initial acetaminophen-protein adduct concentration compared to those who did not, 1.63 nmol/ml (IQR 0.76-2.02, n = 22) vs. 0.26 nmol/ml (IQR 0.15-0.41; n = 204; p <0.0001), respectively. The AUROC for hepatotoxicity was 0.98 (95% CI 0.96-1.00; n = 226; p <0.0001) with acetaminophen-protein adduct concentration and 0.89 (95% CI 0.82-0.96; n = 219; p <0.0001) with ALT. An acetaminophen-protein adduct concentration of 0.58 nmol/ml was 100% sensitive and 91% specific for identifying patients with an initial ALT ≤1,000 U/L who would develop hepatotoxicity. Adding acetaminophen-protein adduct concentrations to risk prediction models improved prediction of hepatotoxicity to a level similar to that obtained by more complex models. CONCLUSION: Acetaminophen-protein adduct concentration on presentation predicted which patients with acetaminophen overdose subsequently developed hepatotoxicity, regardless of time of ingestion. An adduct threshold of 0.58 nmol/L was required for optimal prediction. LAY SUMMARY: Acetaminophen poisoning is one of the most common causes of liver injury. This study examined a new biomarker of acetaminophen toxicity, which measures the amount of toxic metabolite exposure called acetaminophen-protein adduct. We found that those who developed liver injury had a higher initial level of acetaminophen-protein adducts than those who did not. CLINICAL TRIAL REGISTRATION: Australian Toxicology Monitoring (ATOM) Study-Australian Paracetamol Project: ACTRN12612001240831 (ANZCTR) Date of registration: 23/11/2012.
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Acetaminofén/toxicidad , Analgésicos no Narcóticos/toxicidad , Benzoquinonas/sangre , Enfermedad Hepática Inducida por Sustancias y Drogas/sangre , Sobredosis de Droga/sangre , Iminas/sangre , Acetilcisteína/administración & dosificación , Administración Intravenosa , Adolescente , Adulto , Alanina Transaminasa/sangre , Australia/epidemiología , Biomarcadores/sangre , Enfermedad Hepática Inducida por Sustancias y Drogas/epidemiología , Sobredosis de Droga/tratamiento farmacológico , Sobredosis de Droga/epidemiología , Femenino , Humanos , Hígado/efectos de los fármacos , Hígado/lesiones , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
Snakebite is a major public health issue in the rural tropics. Antivenom is the only specific treatment currently available. We review the history, mechanism of action and current developments in snake antivenoms. In the late nineteenth century, snake antivenoms were first developed by raising hyperimmune serum in animals, such as horses, against snake venoms. Hyperimmune serum was then purified to produce whole immunoglobulin G (IgG) antivenoms. IgG was then fractionated to produce F(ab) and F(ab')2 antivenoms to reduce adverse reactions and increase efficacy. Current commercial antivenoms are polyclonal mixtures of antibodies or their fractions raised against all toxin antigens in a venom(s), irrespective of clinical importance. Over the last few decades there have been small incremental improvements in antivenoms, to make them safer and more effective. A number of recent developments in biotechnology and toxinology have contributed to this. Proteomics and transcriptomics have been applied to venom toxin composition (venomics), improving our understanding of medically important toxins. In addition, it has become possible to identify toxins that contain epitopes recognized by antivenom molecules (antivenomics). Integration of the toxinological profile of a venom and its composition to identify medically relevant toxins improved this. Furthermore, camelid, humanized and fully human monoclonal antibodies and their fractions, as well as enzyme inhibitors have been experimentally developed against venom toxins. Translation of such technology into commercial antivenoms requires overcoming the high costs, limited knowledge of venom and antivenom pharmacology, and lack of reliable animal models. Addressing such should be the focus of antivenom research.
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Antivenenos/historia , Antivenenos/inmunología , Biotecnología/historia , Serpientes , Animales , Antivenenos/farmacología , Biotecnología/tendencias , Historia del Siglo XIX , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Fragmentos de Inmunoglobulinas/sangre , Inmunoglobulina G/sangre , Proteómica , Mordeduras de Serpientes , TranscriptomaRESUMEN
AIMS: With rising use worldwide, pregabalin is increasingly implicated in poisoning deaths. We aimed to investigate the clinical effects and complications of pregabalin poisoning. METHODS: This is a retrospective review of patients presenting with pregabalin poisoning to two tertiary toxicology units from 1 July 2014 to 30 June 2019. Patients were identified from prospective databases maintained by both units and data were extracted from these in addition to medical records. RESULTS: There were 488 presentations in 413 patients (237 [57%] male) over the five-year period. The median age was 41 years (IQR 31-50 years). Deliberate self-poisonings accounted for 342 (70%) presentations, with 121 (25%) recreational exposures. Recreational exposures increased over the period from 2 (4%) in the first year to 54 (39%) presentations in the final year. The median dose of pregabalin was 1200 mg (IQR 600-3000 mg, range 75-16 800 mg). Co-ingestions occurred in 427 (88%) presentations, with sedating agents being co-ingested in 387 (79%)-most commonly opioids and benzodiazepines in 201 (41%) and 174 (36%) presentations respectively. Coma (GCS < 9) occurred in 89 (18%) cases, with 52 (11%) patients being intubated. Only one (0.2%) of these patients had not co-ingested a sedating agent. Hypotension occurred in 26 (5%) cases, all with co-ingestants. Seizures occurred in 11 (2%) cases, 3/59 (5%) in pregabalin-only overdoses. The median length of stay was 16.5 hours (IQR 10-25 hours). CONCLUSIONS: Pregabalin overdose does not cause severe toxicity, but rather mild sedation and, uncommonly, seizures. Coma is common in the presence of sedating co-ingestants. Recreational use is increasing.
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Analgésicos Opioides , Sobredosis de Droga , Intoxicación , Pregabalina , Adulto , Analgésicos Opioides/envenenamiento , Benzodiazepinas , Sobredosis de Droga/epidemiología , Femenino , Humanos , Masculino , Intoxicación/epidemiología , Pregabalina/envenenamiento , Estudios RetrospectivosRESUMEN
Redback spider envenoming causes severe pain lasting several days. A recent clinical trial found that antivenom is not effective. We investigated ketamine for pain in redback spider envenoming. Ten adult patients with severe pain from redback spider envenoming were administered 15 mg intravenous ketamine after standard analgesia, then up to 4 oral doses of ketamine 25- 50 mg. Three patients had a clinically significant improvement in pain compared to baseline after intravenous ketamine. Five patients had a minimal decrease in pain and 2 had no improvement. Eight patients received oral ketamine: 4 doses in 5 and 2 doses in 3. At 24 h, 3/6 patients assessed had clinically significant improvement in pain and 4/5 patients assessed at 48 h, had clinically significant improvement in pain. Six patients reported side effects, including dissociation (4) and hallucinations (2). Five patients required rescue opioids and 2 were readmitted to hospital. We found that ketamine provided no additional pain relief in redback spider envenoming, compared to standard analgesia, and resulted in unacceptable adverse effects.
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Analgésicos/administración & dosificación , Ketamina/administración & dosificación , Dolor/tratamiento farmacológico , Picaduras de Arañas/complicaciones , Adulto , Anciano , Analgésicos/efectos adversos , Analgésicos Opioides/administración & dosificación , Femenino , Humanos , Ketamina/efectos adversos , Masculino , Persona de Mediana Edad , Dolor/etiología , Proyectos Piloto , Venenos de Araña/toxicidad , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVES: To assess the numbers of paracetamol overdose-related hospital admissions and deaths in Australia since 2007-08, and the overdose size of intentional paracetamol overdoses since 2004. DESIGN, SETTING: Retrospective analysis of data on paracetamol-related exposures, hospital admissions, and deaths from the Australian Institute of Health and Welfare National Hospital Morbidity Database (NHMD; 2007-08 to 2016-17), the New South Wales Poisons Information Centre (NSWPIC; 2004-2017), and the National Coronial Information System (NCIS; 2007-08 to 2016-17). PARTICIPANTS: People who took overdoses of paracetamol in single ingredient preparations. MAIN OUTCOME MEASURES: Annual numbers of reported paracetamol-related poisonings, hospital admissions, and deaths; number of tablets taken in overdoses. RESULTS: The NHMD included 95 668 admissions with paracetamol poisoning diagnoses (2007-08 to 2016-17); the annual number of cases increased by 44.3% during the study period (3.8% per year; 95% CI, 3.2-4.6%). Toxic liver disease was documented for 1816 of these patients; the annual number increased by 108% during the study period (7.7% per year; 95% CI, 6.0-9.5%). The NSWPIC database included 22 997 reports of intentional overdose with paracetamol (2004-2017); the annual number increased by 77.0% during the study period (3.3% per year; 95% CI, 2.5-4.2%). The median number of tablets taken increased from 15 (IQR, 10-24) in 2004 to 20 (IQR, 10-35) in 2017. Modified release paracetamol ingestion report numbers increased 38% between 2004 and 2017 (95% CI, 30-47%). 126 in-hospital deaths were recorded in the NHMD, and 205 deaths (in-hospital and out of hospital) in the NCIS, with no temporal trends. CONCLUSIONS: The frequency of paracetamol overdose-related hospital admissions has increased in Australia since 2004, and the rise is associated with greater numbers of liver injury diagnoses. Overdose size and the proportion of overdoses involving modified release paracetamol have each also increased.
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Acetaminofén/envenenamiento , Analgésicos no Narcóticos/envenenamiento , Centros de Control de Intoxicaciones/estadística & datos numéricos , Intoxicación/mortalidad , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Australia/epidemiología , Niño , Preescolar , Bases de Datos Factuales , Femenino , Mortalidad Hospitalaria , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Medicamentos sin Prescripción , Estudios Retrospectivos , Adulto JovenRESUMEN
Snake venom α-neurotoxins potently inhibit rodent nicotinic acetylcholine receptors (nAChRs), but their activity on human receptors and their role in human paralysis from snakebite remain unclear. We demonstrate that two short-chain α-neurotoxins (SαNTx) functionally inhibit human muscle-type nAChR, but are markedly more reversible than against rat receptors. In contrast, two long-chain α-neurotoxins (LαNTx) show no species differences in potency or reversibility. Mutant studies identified two key residues accounting for this. Proteomic and clinical data suggest that paralysis in human snakebites is not associated with SαNTx, but with LαNTx, such as in cobras. Neuromuscular blockade produced by both subclasses of α-neurotoxins was reversed by antivenom in rat nerve-muscle preparations, supporting its effectiveness in human post-synaptic paralysis.
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Neurotoxinas/envenenamiento , Parálisis/fisiopatología , Mordeduras de Serpientes/fisiopatología , Venenos de Serpiente/envenenamiento , Transmisión Sináptica/efectos de los fármacos , Secuencia de Aminoácidos , Animales , Antivenenos/farmacología , Humanos , Unión Neuromuscular/efectos de los fármacos , Unión Neuromuscular/metabolismo , Neurotoxinas/genética , Parálisis/inducido químicamente , Proteómica/métodos , Ratas , Receptores Nicotínicos/genética , Receptores Nicotínicos/metabolismo , Homología de Secuencia de Aminoácido , Venenos de Serpiente/genética , Especificidad de la EspecieRESUMEN
Study objective: Although uncommon, children (<16 years) with acute behavioral disturbance are a significant issue for emergency medical service providers. In this study, we aimed to investigate the safety and effectiveness of droperidol in children with prehospital acute behavioral disturbance. Methods: This was a prospective observational study over 1 year investigating the use of droperidol (0.1-0.2 mg/kg) for children (< 16 years) with acute behavioral disturbance. Inclusion criteria for acute behavioral disturbance were defined by a sedation assessment tool score of ≥2 determined by the attending paramedic. The primary outcome was the proportion of adverse effects (need for airway intervention, oxygen saturation <90% and/or respiratory rate <12, systolic blood pressure <90 mmHg, sedation assessment tool score of -3 and dystonic reactions). Secondary outcomes included time to sedation (sedation assessment tool score decreased by 2 or more, or a score of zero), requirement for additional sedation, failure to sedate and proportion of sedation success defined as the number of patients successfully sedated who did not suffer any adverse events or receive additional sedation. Results: There were 96 patients (males 51 [53%], median age 14 years [range 7-15 years]) who presented on 102 occasions over the one year study period. Self-harm and/or harm to others was the commonest (74/105 [70%]) cause of acute behavioral disturbance followed by alcohol (16/105 [15%]). There were 9 adverse events in 8 patients (8/102 [8%]; 95% confidence intervals [CI]: 3-13%) Five patients had hypotension, all asymptomatic and only one required treatment; 2 dystonic reactions managed with benztropine and one patient with respiratory depression. Median time to sedation was 14 min (interquartile range (IQR): 10-20 min; range: 3-85 min). There was no requirement for prehospital additional sedation (0/102 [0%]; 95% CI: 0-4%) and additional sedation in the first hour of arrival to hospital was required by 4 patients (4/102 [4%]; 95% CI: 1-10%). Overall successful sedation was achieved in 89 (87%) patients. Conclusions: The use of droperidol in children for acute behavioral disturbance in the prehospital setting is both safe and effective.
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Antipsicóticos/uso terapéutico , Trastornos de la Conducta Infantil/tratamiento farmacológico , Droperidol/uso terapéutico , Servicios Médicos de Urgencia , Adolescente , Niño , Trastornos de la Conducta Infantil/diagnóstico , Femenino , Humanos , Masculino , Estudios ProspectivosRESUMEN
Massive metformin overdose can cause metabolic acidosis with hyperlactatemia. A 55-year-old woman presented 5 h after multidrug overdose, including 132 g extended-release metformin. Continuous venovenous haemodiafiltration (CVVHDF) and noradrenaline were commenced due to metabolic acidosis (pH 7.0, lactate 17 mmol l-1 ) and shock. Despite 3 h of CVVHDF, her acidosis worsened (pH 6.83, lactate 24 mmol l-1 ). Intermittent haemodialysis (IHD) improved acidosis (pH 7.13, lactate 26 mmol l-1 ) but again worsened (pH 6.91, lactate 30 mmol l-1 ) with CVVHDF recommencement. IHD (12 h), CVVHDF (26 h) and vasopressor support for 7 days resulted in survival. Measured metformin concentrations were extremely high with a peak of 292 µg ml-1 at 8 h postingestion. IHD, but not CVVHDF in this case, was associated with improvement in metabolic acidosis and hyperlactataemia. Pharmacokinetic analysis of metformin concentrations found a reduced apparent oral clearance of 8.2 l h-1 and a half-life of approximately 30 h. During IHD, the apparent oral clearance increased to 22.2 l h-1 with an approximate half-life of 10 h. The impact of prolonged oral absorption from a pharmacobezoar and redistribution of metformin from peripheral sites (including erythrocytes) on the pharmacokinetic profile cannot be determined from the data available.