RESUMO
To evaluate adherence to treatment, we developed and validated a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for baclofen quantification in hair.Twenty mg was washed twice with dichloromethane, incubated in phosphate buffer (pH 5) for 10 minutes at 95°C, then extracted by liquid-liquid extraction in alkaline condition. Baclofen-d4 was used as the internal standard. This method was applied to assess compliance in4 treated alcohol-dependent patients (3 dead and one living). Blood quantification of baclofen and ethanol were performed in the 4 cases. Hair ethylglucuronide (ethanol metabolite, EtG) measurement (2x3 cm) was associated in 1 patient. Baclofen quantification in hair was validated over the range 10-5000 pg/mg. The accuracy was within 96.0%-110.9% and the precision was less than 9.3%. Baclofen segmental (3x2cm) hair concentrations found in the living patient were 4420, 4260, and 4380 pg/mg, reflecting a regular exposure over the last 6 months and suggesting patient compliance. However, the high EtG level found in this patient in the analyzed segments (225 pg/mg and 215 pg/mg) showed excessive alcohol consumption during the same period, suggesting therapeutic failure. In the 3 deceased patients, the non-segmental analysis of hair showed baclofen concentrations of 15, 545, and 2475 pg/mg. The low concentrations in the 2 first cases are compatible either with a poor compliance or to a beginning of a treatment. This is the first measurement of baclofen in hair of alcohol dependent patients. It could be used as a monitoring biomarker to assess patient's compliance.
Assuntos
Alcoolismo/tratamento farmacológico , Baclofeno/análise , Agonistas dos Receptores de GABA-B/análise , Cabelo/química , Espectrometria de Massas em Tandem/métodos , Alcoolismo/sangue , Alcoolismo/diagnóstico , Baclofeno/sangue , Baclofeno/uso terapêutico , Biomarcadores/análise , Biomarcadores/sangue , Cromatografia Líquida/métodos , Monitoramento de Medicamentos/métodos , Etanol/análise , Etanol/sangue , Feminino , Agonistas dos Receptores de GABA-B/sangue , Agonistas dos Receptores de GABA-B/uso terapêutico , Glucuronatos/análise , Glucuronatos/sangue , Humanos , Limite de Detecção , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVES: Toxicodynetics aims at defining the time-course of major clinical events in drug overdose. We report the toxicodynetics in mono-intoxications with oxazepam and nordiazepam. METHODS: Cases of oxazepam or nordiazepam overdoses collected at the Paris poison control centre from 1999 to 2014 on the basis of self-report. A particular attention was paid to eliminate the concomitant alcohol or psychotropic co-ingestions. The toxicodynetic parameters were assessed as previously described. Results are expressed using 10-90 percentiles. In adults, the dose was normalized (TI, toxic Index) by dividing the supposed ingested dose by the maximal recommended dose. RESULTS: Two hundred and fifty-one and 74 cases of oxazepam and nordiazepam poisonings were included, respectively. The Emax for oxazepam and nordiazepam were sleepiness or obtundation in 106 and 36 cases, respectively. Coma was used to qualify only one oxazepam overdose. The median delay in onset of the Emax was 1.5h (0.33-15) in nordiazepam and 4h (0.5-15) in oxazepam overdose. In both overdoses, the onset of Emax occurred on an "on-off" mode. In adults, the greatest TIs in nordiazepam and oxazepam overdoses were 45 and 26.7, respectively. The TI in the oxazepam-induced coma was 26.7, the largest dose. CONCLUSION: Data collected in PCC allow determining a number of toxicodynetic parameters. Toxicodynetics showed that nordiazepam is not a cause of coma even in large overdose while oxazepam causes coma only at a very high dose. Deep coma in nordiazepam overdose whatever the dose and deep coma in overdose with oxazepam involving TI less than 20 result from unrecognized drug-drug interaction.
Assuntos
Overdose de Drogas/metabolismo , Moduladores GABAérgicos/efeitos adversos , Moduladores GABAérgicos/farmacocinética , Nordazepam/efeitos adversos , Nordazepam/farmacocinética , Oxazepam/efeitos adversos , Oxazepam/farmacocinética , Toxicocinética , Adolescente , Adulto , Envelhecimento/metabolismo , Depressores do Sistema Nervoso Central/efeitos adversos , Criança , Pré-Escolar , Etanol/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
OBJECTIVES: Regarding the different disciplines that encompass the pharmacology and the toxicology, none is specifically dedicated to the description and analysis of the time-course of relevant toxic effects both in experimental and clinical studies. The lack of a discipline devoted to this major field in toxicology results in misconception and even in errors by clinicians. MATERIAL AND METHODS: Review of the basic different disciplines that encompass pharmacology toxicology and comparing with the description of the time-course of effects in conditions in which toxicological analysis was not performed or with limited analytical evidence. RESULTS: Review of the literature clearly shows how misleading is the current extrapolation of toxicokinetic data to the description of the time-course of toxic effects. CONCLUSION: A new discipline entitled toxicodynetics should be developed aiming at a more systematic description of the time-course of effects in acute human and experimental poisonings. Toxicodynetics might help emergency physicians in risk assessment when facing a poisoning and contribute to a better assessment of quality control of data collected by poison control centres. Toxicodynetics would also allow a quantitative approach to the clinical effects resulting from drug-drug interaction.
Assuntos
Overdose de Drogas/terapia , Toxicologia/tendências , Overdose de Drogas/diagnóstico , Humanos , Centros de Controle de Intoxicações , Medição de Risco , Especialização , ToxicocinéticaRESUMO
We investigated the predictive factors for extended-spectrum beta-lactamase producing Enterobacteriaceae (ESBL-PE) causing infections among intensive care unit patients with prior documented ESBL-PE colonization. Using multivariate analysis, referral from medical ward, nursing home or rehabilitation center [Odds ratio (OR), 2.5; 95 % confidence interval (CI), [1.3-5.0]; p = 0.007], previous fluoroquinolone treatment (OR, 3.4; CI, [1.1-10.5]; p = 0.003), extracorporeal membrane oxygenation (OR, 4.6; CI, [1.3-15.9]; p = 0.02), and absence of prior positive ESBL-PE rectal swab culture (OR, 5.0; CI, [1.6-10.0]; p = 0.0009) were risk factors for ESBL-PE infection. Easily identifiable factors may help with targeting carbapenem prescriptions.
Assuntos
Proteínas de Bactérias/metabolismo , Portador Sadio/epidemiologia , Infecção Hospitalar/epidemiologia , Infecções por Enterobacteriaceae/epidemiologia , Enterobacteriaceae/enzimologia , beta-Lactamases/metabolismo , Idoso , Carbapenêmicos/uso terapêutico , Portador Sadio/microbiologia , Estado Terminal , Infecção Hospitalar/microbiologia , Enterobacteriaceae/isolamento & purificação , Infecções por Enterobacteriaceae/microbiologia , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
BACKGROUND: Human dichlorophen poisoning is rare. We aim to report a case of dichlorophen poisoning resulting in complete recovery despite life-threatening multiorgan failure and huge serum dichlorophen concentrations. METHODS: Description of features and management in one dichlorophen-poisoned patient. After liquid-liquid extraction, dichlorophen concentrations in the urine and the serum were measured using liquid chromatography-heated electrospray ionization-tandem mass spectrometry (LC-HESI-MS/MS). CASE REPORT: A 74-year-old female self-ingested an anti-moss dichlorophen solution (360 g/L) in a suicidal attempt. She rapidly developed caustic esophageal and gastric mucosal injuries, confusion, profuse diarrhea, and electrolyte disturbances. Initial elevation in serum aminotransferase and γ-glutamyltransferase concentrations resolved over 6 days. Serum dichlorophen concentration measured was 708.1 µg/L on admission, and its elimination was prolonged (serum apparent elimination half-life: 35.5 h), peaking in urine on day 2. Mild elevation in serum creatine phosphokinase concentration (peaking 48 h post-ingestion) and acute renal failure (requiring hemodialysis on day 8) occurred. The final outcome was favorable with supportive management. CONCLUSION: Dichlorophen ingestion results in life-threatening multiorgan dysfunction including rapid onset of caustic digestive lesions, diarrhea, liver enzyme disturbances, as well as acute kidney injury and rhabdomyolysis. Recovery can be complete if prompt supportive management is provided.
Assuntos
Diclorofeno/intoxicação , Idoso , Cromatografia Líquida , Diclorofeno/sangue , Diclorofeno/farmacocinética , Diclorofeno/urina , Overdose de Drogas/terapia , Feminino , Humanos , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
BACKGROUND/OBJECTIVES: Cardiotoxic drug poisoning can lead to severe cardiac shock (CS) and death. B-type natriuretic peptide (BNP) is a well-established diagnostic and prognostic marker in heart failure but has never been assessed in patients with cardiotoxic drug poisoning. The aim of the study was to determine whether BNP could be useful for early stratification of patients admitted to intensive care unit. METHODS: 30 consecutive patients experiencing shock and cardiotoxic drug exposure were enrolled in a prospective monocentric study and underwent at least two BNP measurements within the first 24 h after admission. RESULTS: While BNP values on admission were poorly informative, subsequent BNP measurements (11 ± 6 h after admission) were significantly increased in patients with CS compared to those with non-CS (756; [364-1130] versus 24; [15-65] pg/ml respectively; P = 0.008). This second BNP level was also significantly increased in non-survivor patients compared to survivor patients (784; [654-1028] versus 29; [15-104] pg/ml respectively; P = 0.05): BNP levels above 360 pg/ml predicted in-hospital mortality (sensitivity = 100%, specificity = 92%). In a multivariate analysis, BNP, SAPS II score and lactate blood level were associated with death. CONCLUSIONS: Serial BNP measurements after admission for cardiotoxic drug poisoning are useful to identify patients at the highest risk of CS as well as in-hospital death.
Assuntos
Cardiotoxinas/intoxicação , Peptídeo Natriurético Encefálico/sangue , Choque Cardiogênico/diagnóstico , Adulto , Biomarcadores/sangue , Feminino , França , Humanos , Unidades de Terapia Intensiva , Ácido Láctico/sangue , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Choque Cardiogênico/sangue , Choque Cardiogênico/induzido quimicamenteRESUMO
The widely used term "overdose" denotes a toxic effect: opioid-induced intoxication and a mechanism: the poisoning results only from an overdose. Surprisingly, our understanding of the pathophysiology of this deadly complication is limited. In drug users, we attempted to: (1) improve knowledge of drug-induced respiratory effects; (2) clarify the mechanisms of drug interactions; (3) identify factors of variability and vulnerability. A prospective study of opioid overdoses confirmed that poisonings involving buprenorphine do exist. However, the mechanisms of buprenorphine poisoning are more complex than only an overdose, particularly the severity is less than that induced by heroin. In contrast, methadone overdose is life-threatening. Experimental studies addressed several clinical questions and also showed limited discrepancies. At pharmacological doses, opioids decrease the ventilatory response to CO(2). However, this effect does not account for the morbimortality of opioid poisonings. The mechanisms of opioid-induced morbimortality are different. Buprenorphine at doses near its median lethal dose did not induce acute respiratory failure as defined by a decrease in the partial pressure of oxygen in arterial blood (PaO(2)). In contrast, the combination of buprenorphine with flunitrazepam results in a decrease in PaO(2). This harmful interaction does not exist with other benzodiazepines in the rat, except for very high doses of nordazepam. The interaction results from a pharmacokinetic process. In contrast, methadone causes a dose-dependent decrease in PaO(2,) even significant before hypercapnia. We are assessing the relationships between on one hand alterations of ventilatory pattern and of arterial blood gas and on the other hand the different types of opiate receptors in the rats.
Assuntos
Analgésicos Opioides/intoxicação , Overdose de Drogas/fisiopatologia , Animais , Buprenorfina/intoxicação , Interações Medicamentosas , Overdose de Drogas/epidemiologia , França/epidemiologia , Humanos , Metadona/intoxicação , Antagonistas de Entorpecentes/intoxicação , Entorpecentes/intoxicação , Transtornos Relacionados ao Uso de Opioides/patologia , Transtornos Relacionados ao Uso de Opioides/fisiopatologia , Sistema Respiratório/efeitos dos fármacos , Sistema Respiratório/fisiopatologiaRESUMO
The concern of a terrorist attack using cyanide, as well as the gradual awareness of cyanide poisoning in fire victims, has resulted in a renewed interest in the diagnosis and treatment of cyanide poisoning. The formerly academic presentation of cyanide poisoning must be replaced by more useful knowledge, which will allow emergency physicians and rescue workers to strongly suspect cyanide poisoning at the scene. Human cyanide poisonings may result from exposure to cyanide, its salts, or cyanogenic compounds, while residential fires are the most common condition of exposure. In fire victims, recognition of the cyanide toxidrome has been hampered by the short half-life in blood and poor stability of cyanide. In contrast, carboxyhemoglobin, as a marker of carbon monoxide poisoning, is easily measured and long-lasting. No evidence supports the assumption of the arbitrary fixed lethal thresholds of 50% for carboxyhemoglobin, and 3 mg/L for cyanide, in fire victims. Preliminary data, drawn when comparing pure carbon monoxide and pure cyanide poisonings, suggest that a cyanide toxidrome can be defined considering signs and symptoms induced by cyanide and carbon monoxide, respectively. Prospective studies in fire victims may provide value in clarifying signs and symptoms related to both toxicants. Cyanide can induce a life-threatening poisoning from which a full recovery is possible. A number of experimentally efficient antidotes to cyanide exist, whose clinical use has been hampered due to serious side effects. The availability of potentially safer antidotes unveils the possibility of their value as first-line treatment, even in a complex clinical situation, where diagnosis is rapid and presumptive.
Assuntos
Cianetos/intoxicação , Antídotos/uso terapêutico , Intoxicação por Monóxido de Carbono/diagnóstico , Humanos , Intoxicação/diagnóstico , Intoxicação/terapiaRESUMO
AIM: To describe the outcome of intensive care unit (ICU) patients admitted with a hyperglycaemic hyperosmolar non-ketotic syndrome (HHNS), with a specific analysis of precipitating conditions and complications including lower limb ischemia. METHODS: Retrospective review of patients admitted in a university-hospital ICU for HHNS. RESULTS: Seventeen consecutive patients (9F/8M, age: 75 years [57-81] (median [25-75% percentiles], Glasgow Coma score: 13 [12-14]) were admitted for HHNS over an 8-year period (1998-2005). On admission, the blood glucose level was 40.0 mmol/l [26.3-60.8], the corrected serum sodium concentration 167 mmol/l [158-174], and the calculated plasma osmolarity 384 mosmol/l [365-405]. All the patients presented with renal failure due to severe dehydration. An infection was identified as the precipitating factor in 8/17 cases. Three (18%) patients died in the ICU. Non-survivors were significantly older than survivors (P=0.02). Using univariate analysis, no other parameter measured on admission was related to mortality. Four patients (24%) presented with lower limb ischemia. They had a significantly more elevated blood urea nitrogen (P=0.03), creatinine phosphokinase level (P=0.04), and leukocyte count (P=0.02). The bilateral, symmetrical, and distal extremity involvement suggested diminished blood flow due to hyperviscosity, hypotension, vasoconstrictors, or cholesterol emboli rather than a proximal arterial obstruction as causative mechanisms. No patient was treated surgically. Ischemia reversed with fluid loading and resulted in toe dry digital necrosis. CONCLUSION: HHNS is a rare but life-threatening cause of ICU admission. There is a high incidence of lower limb ischemia in HHNS patients, which may be related to dehydration and blood hyperviscosity.
Assuntos
Pé Diabético/epidemiologia , Isquemia/epidemiologia , Perna (Membro)/irrigação sanguínea , Doença Aguda , Idoso , Idoso de 80 Anos ou mais , Pé Diabético/patologia , Feminino , Hospitais Universitários , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Necrose , Estudos Retrospectivos , Fatores SocioeconômicosRESUMO
AIMS: To assess the trends in the number, mortality and the nature of forensic cases involving toxicological detection of buprenorphine or methadone among toxicological investigations performed in Paris from June 1997 to June 2002. DESIGN: Retrospective, 5 year study with review of premortem data, autopsy, police reports, hospital data, and post-mortem toxicological analyses. SETTING AND PARTICIPANTS: 34 forensic cases of buprenorphine and 35 forensic cases of methadone detection among 1600 toxicological investigations performed at the Laboratory of Toxicology in the Medical Examiner's Office in Paris. MEASUREMENTS AND RESULTS: Therapeutic, toxic or lethal drug concentrations were defined based upon the results of blood analyses and the published literature. Drug concentrations were cross-referenced with other available ante- and post-mortem data. Subsequently, we classified a 'clear responsibility', 'possible responsibility' or 'not causative' role for buprenorphine or methadone in the death process, or 'no explanation of death'. Buprenorphine and methadone can be regarded as being directly implicated in, respectively, four of 34 death cases (12%) and three of 35 death cases (9%), and their participation in the lethal process is strongly plausible in eight (buprenorphine) and 11 (methadone) additional deaths. CONCLUSIONS: Analysis of causes of death reveals the difficulties in determining the role of substitution drugs in the death process, as many other factors may be involved, including circumstances surrounding death, past history, differential selection of subjects into either substitution modality and concomitant intake of other drugs (especially benzodiazepines and neuroleptics). The potential for synergistic or additive actions by other isolated molecules-particularly opioids, benzodiazepines, other psychotropes and alcohol-must be also considered.
Assuntos
Buprenorfina/intoxicação , Metadona/intoxicação , Entorpecentes/intoxicação , Adulto , Autopsia , Buprenorfina/sangue , Causas de Morte , Overdose de Drogas/mortalidade , Feminino , Humanos , Masculino , Metadona/sangue , Pessoa de Meia-Idade , Mortalidade/tendências , Entorpecentes/sangue , Estudos Retrospectivos , Transtornos Relacionados ao Uso de Substâncias/mortalidade , Transtornos Relacionados ao Uso de Substâncias/reabilitaçãoRESUMO
BACKGROUND: Serious delayed neuropsychological sequelae may complicate carbon monoxide intoxication. The existence of minor manifestations, especially memory disturbances, is not well documented. AIMS: To study several memory functions after carbon monoxide intoxication. METHODS: In a prospective study, 32 poisoned patients without risk factors for cognitive disturbances were compared to 32 paired control subjects one month after acute carbon monoxide intoxication (blood carbon monoxide concentration at least 1.0 mmol/l), who had been treated with standard conventional therapy. Psychometric tests included Buschke's verbal memory testing, verbal digit span, Corsi's visuospatial span, reaction times, Stroop's colours decoding test, and verbal fluency test. RESULTS: (1) Memory functions in poisoned subjects were not worse than in the control group and were even better in some areas: learning, word recall, and quality of learning by Buschke's verbal memory testing. Attention was also better in the patients, in whom visual reaction time was shorter than in controls. (2) Results of several memory functions-quality of learning and immediate visual memory-were positively correlated with the initial carbon monoxide level. CONCLUSIONS: In a highly selected subset of patients devoid of risk factors for memory impairment, memory, objectively evaluated by psychometric testing, was not worse one month after carbon monoxide intoxication in patients undergoing standard treatment than in paired control subjects.
Assuntos
Poluentes Atmosféricos/efeitos adversos , Intoxicação por Monóxido de Carbono/psicologia , Exposição Ambiental , Transtornos da Memória/induzido quimicamente , Doença Aguda , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Deficiências da Aprendizagem/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Estudos Prospectivos , Fatores de TempoRESUMO
AIMS: (1). To assess the trends in the number, mortality and the nature of severe opiate/opioid poisonings from 1995 to 1999 in north-east Paris and adjacent suburbs and (2). to examine the effects of the introduction of high-dose buprenorphine on these parameters. DESIGN: Retrospective, 5-year study with review of pre-hospital, hospital and post-mortem data. SETTING AND PARTICIPANTS: Eighty patients from the toxicological intensive care unit (TICU) in north-east Paris, 421 patients from the pre-hospital emergency medical service in a north-east suburb of Paris (SAMU 93) and 40 deaths from the coroner's office in Paris. MEASUREMENTS AND RESULTS: We found that the number of pre-hospital opiate/opioid poisonings and deaths decreased over 5 years. During the same time frame, opiate/opioid poisoning admissions to our TICU remained steady, but the number of deaths declined. From 1995 to 1999, the detection of buprenorphine among opiate/opioid-poisoned TICU patients increased from two to eight occurrences per year while detection of opiates diminished from 17 to 10 occurrences per year. Increased buprenorphine detection correlated directly with increasing sales over this time period. In spite of the increased use of buprenorphine, the mortality associated with opiate/opioid poisonings has diminished in the pre-hospital environment from 9% in 1995 to 0% in 1999, and in the TICU from 12% in 1995 to 0% in 1997 and thereafter. We found a high frequency of multiple opiate/opioid use in severe poisonings, as well as the frequent association of other psychoactive drugs including ethanol. CONCLUSIONS: The number and the mortality of opiate/opioid poisonings appear to be stable or decreasing in our region. The association of multiple opiates/ opioids appears nearly as common as the association with other psychoactive drugs. The introduction of high-dose buprenorphine coincides with a decrease in opiate/opioid poisoning mortality. Further study will be necessary to clarify this observation.
Assuntos
Transtornos Relacionados ao Uso de Opioides/epidemiologia , Adulto , Buprenorfina/uso terapêutico , Overdose de Drogas/epidemiologia , Feminino , Hospitalização/tendências , Humanos , Masculino , Antagonistas de Entorpecentes/uso terapêutico , Transtornos Relacionados ao Uso de Opioides/reabilitação , Paris/epidemiologia , Estudos RetrospectivosRESUMO
Opiates and substitution products are frequently abused, alone and in association with benzodiazepines. While this combination may result in severe respiratory depression and death, the quantitative relationship remains uncertain. We performed randomized, blinded intravenous median lethal dose (MLD) studies in Sprague-Dawley rats of morphine, buprenorphine, and methadone, alone and in combination with intraperitoneal flunitrazepam pretreatment. We employed the up-and-down method, performed in quadruplicate, comparing time to death following opioid injection. Results are expressed as median of four series (extremes). The MLDs of morphine, buprenorphine, and methadone alone were 64.0 (33.6:79.5), 234.6 (168.6:284.4), and 22.5 (19.3:24.1) mg/kg, respectively, and 60.6 (35.2:88.2), 38.4 (30.6:54.0), and 13.0 (9.7:13.8) mg/kg, respectively, after pretreatment with 40 mg/kg flunitrazepam. Times to death for morphine, buprenorphine, and methadone alone were 2.5 (0.8:24), 0.02 (0.0:24), and 2.0 (0.0:24) hours, respectively, and 13.5 (0.0:144), 24.0 (0.0:120), and 0.0 (0.0:24) hours, respectively, after pretreatment with flunitrazepam 40 mg/kg, ip. Flunitrazepam significantly altered methadone (P=0.02) and buprenorphine (P=0.02) but not morphine lethality (P=0.77). Flunitrazepam significantly prolonged time to death only for buprenorphine (P<0.01). Flunitrazepam-opioid drug-drug interactions are more complex than is generally believed. Mechanistic studies of flunitrazepam-opioid lethal interactions are needed.
Assuntos
Ansiolíticos/toxicidade , Flunitrazepam/toxicidade , Entorpecentes/toxicidade , Animais , Buprenorfina/toxicidade , Interações Medicamentosas , Injeções Intraperitoneais , Injeções Intravenosas , Dose Letal Mediana , Masculino , Metadona/toxicidade , Morfina/toxicidade , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVE: To assess the efficacy and safety of fomepizole, a competitive alcohol dehydrogenase inhibitor, in methanol poisoning and to test the hypothesis that fomepizole obviates the need for hemodialysis in selected patients. DESIGN AND SETTING: Retrospective clinical study in three intensive care units in university-affiliated teaching hospitals. PATIENTS: All methanol-poisoned patients admitted to these ICUs and treated with fomepizole from 1987-1999 (n=14). MEASUREMENTS AND RESULTS: The median plasma methanol concentration was 50 mg/dl (range 4-146), anion gap 22.1 mmol/l (11.8-42.2), arterial pH 7.34 (7.11-7.51), and bicarbonate 17.5 mmol/l (3.0-25.0). Patients received oral or intravenous fomepizole until blood methanol was undetectable. The median cumulative dose was 1250 mg (500-6000); the median number of twice daily doses was 2 (1-16). Four patients underwent hemodialysis for visual impairment present on admission. Four patients with plasma methanol concentrations of 50 mg/dl or higher and treated without hemodialysis recovered fully. Patients without pretreatment visual disturbances recovered, with no sequelae in any case. There were no deaths. Fomepizole was safe and well tolerated, even in the case of prolonged treatment. Analysis of methanol toxicokinetics in five patients demonstrated that fomepizole was effective in blocking methanol's toxic metabolism. CONCLUSIONS: Fomepizole appears safe and effective in the treatment of methanol-poisoned patients. If our results are confirmed in prospective analyses, hemodialysis may prove unnecessary in patients presenting without visual impairment or severe acidosis.
Assuntos
Álcool Desidrogenase/antagonistas & inibidores , Antídotos/uso terapêutico , Metanol/intoxicação , Pirazóis/uso terapêutico , Adolescente , Adulto , Antídotos/efeitos adversos , Antídotos/farmacologia , Qualidade de Produtos para o Consumidor , Feminino , Fomepizol , Meia-Vida , Humanos , Masculino , Metanol/sangue , Metanol/farmacocinética , Pessoa de Meia-Idade , Pirazóis/efeitos adversos , Pirazóis/farmacologia , Diálise Renal , Estudos Retrospectivos , Estatísticas não Paramétricas , Transtornos da Visão/induzido quimicamente , Transtornos da Visão/terapiaRESUMO
High dose buprenorphine, a potent semisynthetic agonist-antagonist for opiate receptors, is now used in substitution treatment of human heroin addiction. Deaths have been reported in addicts misusing buprenorphine. We determined the median lethal dose (LD(50)) and studied the effects of high doses of intravenous buprenorphine on arterial blood gases in rats. Male Sprague-Dawley rats were administered buprenorphine intravenously to determine the LD(50) using the up-and-down method. Subsequently, catheterized groups of 10 restrained rats received no drug, saline, acid-alcohol aqueous solvent (required to dissolve buprenorphine at a high concentration), or 3, 30, or 90 mg/kg of buprenorphine intravenously. Serial arterial blood gases were obtained over 3 h. The LD(50) determined in triplicate was 146.5 mg/kg (median of 3 series, range: 142.6-176.5). The mean dose received by surviving animals was 96.9 +/- 46.7 mg/kg. There was a significant effect of the acid-alcohol aqueous solvent on arterial blood gases. Excluding the solvent effect, 3, 30, and 90-mg/kg buprenorphine doses had no significant effects on arterial blood gases. The toxicity of intravenous buprenorphine in adult rats, assessed by the LD(50), is low. These data are consistent with a wide margin of safety of buprenorphine. The mechanism of death after the intravenous administration of a lethal dose of buprenorphine remains to be determined.
Assuntos
Buprenorfina/toxicidade , Dióxido de Carbono/sangue , Antagonistas de Entorpecentes/toxicidade , Oxigênio/sangue , Animais , Gasometria , Relação Dose-Resposta a Droga , Interações Medicamentosas , Artéria Femoral , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Injeções Intravenosas , Masculino , Nível de Efeito Adverso não Observado , Ratos , Ratos Sprague-Dawley , Solventes/farmacologia , Fatores de TempoRESUMO
The aim of this study was to determine whether respiratory acidosis favors the cerebral distribution of cyanide, and conversely, if respiratory alkalosis limits its distribution. The pharmacokinetics of a nontoxic dose of cyanide were first studied in a group of 7 rats in order to determine the distribution phase. The pharmacokinetics were found to best fit a 3-compartment model with very rapid distribution (whole blood T(1/2)alpha = 21.6 +/- 3.3 s). Then the effects of the modulation of arterial pH on the distribution of a nontoxic dose of intravenously administered cyanide into the brains of rats were studied by means of the determination of the permeability-area product (PA). The modulation of arterial blood pH was performed by variation of arterial carbon dioxide tension (PaCO2) in 3 groups of 8 anesthetized mechanically ventilated rats. The mean arterial pH measured 20 min after the start of mechanical ventilation in the acidotic, physiologic, and alkalotic groups were 7.07 +/- 0.03, 7.41 +/- 0.01, and 7.58 +/- 0.01, respectively. The mean PAs in the acidotic, physiologic, and alkalotic groups, determined 30 s after the intravenous administration of cyanide, were 0.015 +/- 0.002, 0.011 +/- 0.001, and 0.008 +/- 0.001 s(-1), respectively (one-way ANOVA; p < 0.0087). At alkalotic pH the mean permeability-area product was 43% of that measured at acidotic pH. This effect of pH on the rapidity of cyanide distribution does not appear to be limited to specific areas of the brain. We conclude that modulation of arterial pH by altering PaCO2 may induce significant effects on the brain uptake of cyanide.
Assuntos
Acidose Respiratória/metabolismo , Alcalose Respiratória/metabolismo , Encéfalo/metabolismo , Cianetos/farmacocinética , Animais , Pressão Sanguínea/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Dióxido de Carbono/farmacologia , Cianetos/administração & dosagem , Cianetos/sangue , Concentração de Íons de Hidrogênio , Hiperventilação/induzido quimicamente , Hipoventilação/induzido quimicamente , Oxigênio/farmacologia , Ratos , Ratos Sprague-Dawley , Sacarose/sangue , Fatores de TempoRESUMO
CASE REPORT: We report a case of mixed methanol and isopropanol poisoning in a patient who refused dialysis but agreed to treatment with intravenous fomepizole. The patient was asymptomatic on arrival, with initial blood methanol and isopropanol concentrations of 146 mg/dL and 39 mg/dL, respectively. Blood ethanol was undetectable. The patient was treated with fomepizole twice daily intravenously until blood methanol was undetectable. No side effects of therapy, other than transient eosinophilia, were observed. The evolution was uneventful and no metabolites of either alcohol were detected at any time during the hospitalization. The decay of plasma methanol and isopropanol under fomepizole treatment were well described by first-order kinetics. The plasma elimination half-lives of methanol and isopropanol were 47.6 hours and 27.7 hours, respectively. Fomepizole appears to have been effective in blocking the toxic metabolism of both methanol and isopropanol and was associated with a favorable outcome.
Assuntos
2-Propanol/intoxicação , Antídotos/uso terapêutico , Metanol/intoxicação , Pirazóis/uso terapêutico , 2-Propanol/sangue , 2-Propanol/farmacocinética , Adulto , Cromatografia Gasosa , Fomepizol , Meia-Vida , Humanos , Masculino , Taxa de Depuração Metabólica , Metanol/sangue , Metanol/farmacocinética , Tentativa de SuicídioRESUMO
BACKGROUND: The radiopacity of ingested substances may serve as a clue to the presence of particular compounds, as this characteristic varies considerably among medications and household products. Tablet conglomerations are also variably radiopaque. We report 4 cases of clomipramine poisoning associated with formation of radiopaque masses, believed to be clomipramine, in the area of the stomach. CASE REPORTS: Four patients were admitted to the Toxicological Intensive Care Unit after ingestions of, respectively, 8.5 g (180 tablets of mixed strength), 7.5 g (100 tablets), 10.5 g (140 tablets), and 4.5 g (60 tablets) of clomipramine, along with other sedatives and antipsychotics. In each case, a rounded density was observed in the gastric area on plain chest radiograph. The hospital courses of each patient were marked by tachycardia, hypotension, QRS and QT prolongation, seizures, and decreased mental status. Three of 4 patients underwent unsuccessful endoscopy to remove tablet fragments and subsequently suffered gastrointestinal hemorrhage requiring transfusion. All patients were discharged recovered from the hospital. DISCUSSION: Clomipramine, a potent tricyclic antidepressant, has been previously reported to be nonradiopaque, and has not been reported to induce formation of concretions. These cases suggest that massive ingestions of clomipramine may form bezoars which are radiopaque and may be associated with serious toxicity. Careful consideration should be given prior to the use of gastric endoscopy for the retrieval of tablet fragments since significant hemorrhage, attributed to the procedure itself rather than to clomipramine toxicity, may ensue.
Assuntos
Acepromazina/análogos & derivados , Antidepressivos Tricíclicos/intoxicação , Clomipramina/intoxicação , Estômago/diagnóstico por imagem , Acepromazina/química , Acepromazina/intoxicação , Adulto , Antidepressivos Tricíclicos/química , Antidepressivos Tricíclicos/farmacocinética , Compostos Azabicíclicos , Bromazepam/química , Bromazepam/intoxicação , Clomipramina/química , Clomipramina/farmacocinética , Mucosa Gástrica/metabolismo , Gastroscopia/métodos , Humanos , Lorazepam/química , Lorazepam/intoxicação , Masculino , Pessoa de Meia-Idade , Piperazinas/química , Piperazinas/intoxicação , Intoxicação/diagnóstico por imagem , Intoxicação/metabolismo , Prazepam/química , Prazepam/intoxicação , Piridinas/química , Piridinas/intoxicação , Radiografia , Comprimidos , ZolpidemRESUMO
In acute carbon monoxide intoxication the presence of altered consciousness, ranging from transient loss of consciousness to coma, represents a poor prognostic factor and modifies the approach to therapy. Transient loss of consciousness is, as a rule, contemporaneous to the exposure, generally occurring at the scene of the intoxication. We report an unusual case of delayed transient loss of consciousness, occurring in the absence of any other evident aetiology, in one member of an orchestra composed of 110 members after a mass carbon monoxide poisoning.