RESUMEN
Loperamide, a potent µ-opioid receptor agonist used as an antidiarrheal drug, exhibits increased bioavailability at supratherapeutic doses, causing potential central nervous system effects. Its misuse for opioid withdrawal relief and euphoria can lead to dangerously elevated blood levels, causing severe cardiac dysrhythmias and death. This study aimed to compare loperamide positive autopsy cases in Sweden and Finland after the introduction of postmortem toxicological analysis of loperamide, focusing on loperamide's role in fatalities and identifying common characteristics among those affected. All cases with detected loperamide in femoral blood at forensic autopsies in Sweden (2012-2022) and Finland (2017-2022) were included. In Sweden, loperamide was detected in 126 individuals, and in Finland, in 111 individuals. The incidence of individuals positive for loperamide in postmortem femoral blood increased steadily over the study duration in both Sweden and Finland. Loperamide related fatalities were observed exclusively in Sweden (n=80), predominantly involving younger males with histories of substance abuse, typically classified as accidental deaths. The group of loperamide nonrelated deaths in Sweden mirrored the entirety of cases in Finland. The concentration of loperamide in postmortem femoral blood was significantly higher in cases where loperamide was considered the cause of death (median 0.140⯵g/g) compared to cases where loperamide contributed (median 0.080⯵g/g), as well as in deaths unrelated to loperamide in both countries (Sweden: median 0.029⯵g/g; Finland: median 0.010⯵g/ml). The high limit of quantification for loperamide in Sweden may underestimate therapeutic users in epidemiological assessments. This study underscores the absence of loperamide misuse in Finland and indicates a rising trend of loperamide abuse in Sweden.
Asunto(s)
Loperamida , Loperamida/sangre , Loperamida/envenenamiento , Humanos , Suecia/epidemiología , Finlandia/epidemiología , Masculino , Adulto , Femenino , Persona de Mediana Edad , Adulto Joven , Anciano , Antidiarreicos/sangre , Adolescente , Distribución por Sexo , Distribución por Edad , Trastornos Relacionados con Sustancias/mortalidad , Trastornos Relacionados con Sustancias/sangre , Accidentes/mortalidadRESUMEN
Diagnosing anaphylactic shock postmortem is challenging since differential diagnoses exist and the forensic pathologist often faces subtle findings and lacks relevant information which prevents reaching an opinion of certainty. This review provides an overview of the literature covering research and existing recommendations on the postmortem diagnosis of anaphylactic shock. In order to harmonize the approach and provide guidance for diagnosing deaths from anaphylactic shock in the six forensic centers in Sweden, a guidance protocol aligned with the notion of a holistic view in the approach was devised. Areas in need of further studies include both immunohistological and biochemical investigations to stratify quantitative approaches based on condition and anaphylactic trigger and to lay the ground for and possibly establish alternative matrices.
RESUMEN
The neurotrophin brain-derived neurotrophic factor (BDNF) occurs in elevated levels during airway inflammation, including asthma and hypoxic lung injury, and has been suggested to be associated with airway hyperresponsiveness in these conditions. The aim of the present study was to examine whether airway responses to histamine challenge and levels of exhaled nitric oxide (NO) in vivo might be altered upon BDNF treatment. Pulmonary resistance, lung compliance, insufflation pressure, and levels of exhaled NO were measured in anaesthetized guinea pigs exposed to BDNF prior to challenge with histamine and with intact or inhibited endogenous NO production. BDNF pretreatment significantly enhanced histamine-evoked increase in pulmonary resistance and insufflation pressure, as well as the decrease in lung compliance. BDNF markedly accentuated the reduction in exhaled NO following histamine challenge. In animals with inhibited endogenous NO production BDNF induced a significantly earlier histamine-evoked increase in airway responses. The present data show that BDNF can induce an augmentation of histamine-evoked airway responses and reduce levels of NO in exhaled air in vivo. Endogenous NO seems to exert a braking action on BDNF-induced enhancement of airway responses and a reduced ability to release NO may be one mechanism for increased airway response during elevated BDNF levels. Taken together this indicates that BDNF may be of importance for airway hyperresponsiveness in vivo. The interaction between BDNF and airway NO formation, and its relation to airway responses, merit further investigation.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Broncoconstricción/efectos de los fármacos , Broncoconstrictores/administración & dosificación , Espiración , Histamina/administración & dosificación , Pulmón/efectos de los fármacos , Óxido Nítrico/metabolismo , Administración por Inhalación , Animales , Factor Neurotrófico Derivado del Encéfalo/administración & dosificación , Hiperreactividad Bronquial/metabolismo , Hiperreactividad Bronquial/fisiopatología , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Cobayas , Infusiones Intravenosas , Inyecciones Intravenosas , Pulmón/irrigación sanguínea , Pulmón/metabolismo , Pulmón/fisiopatología , Rendimiento Pulmonar/efectos de los fármacos , Masculino , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/metabolismo , Presión , Factores de Tiempo , Resistencia Vascular/efectos de los fármacosRESUMEN
The neurotrophin nerve growth factor (NGF) is elevated in serum and locally in the lung in asthmatics and has been suggested to evoke airway hyperresponsiveness. The aim of this study was to explore mechanisms behind NGF-evoked changes in airway responsiveness. We studied if NGF could evoke increased airway responsiveness to tachykinins, such as neurokinin A (NKA), in a similar way as for histamine and, if so, whether an NGF-evoked increase in NKA airway responsiveness could involve a histamine receptor-dependent mechanism. Contractile responses to cumulative doses of histamine or NKA were studied in guinea-pig tracheal rings in vitro in organ baths. Furthermore, insufflation pressure (IP), pulmonary resistance, lung compliance and exhaled NO (FeNO) were measured in vivo in anaesthetised guinea-pigs challenged with histamine or NKA. NGF pre-treatment in vitro increased the contractile response evoked by histamine, but not by NKA, in tracheal rings. NGF pre-treatment in vivo increased IP, pulmonary resistance and levels of FeNO, and further decreased lung compliance, upon histamine and NKA challenge. The NGF-evoked enhancement of IP, pulmonary resistance, lung compliance as well as FeNO in response to NKA was reversed by the histamine receptor antagonist mepyramine. We suggest that NGF can induce an increase in tachykinin-evoked airway responses and NO formation via a histamine receptor-dependent pathway. This points to an important role for the mast cell in neurotrophin-evoked airway hyperresponsiveness and changes in exhaled NO.
Asunto(s)
Histamina/fisiología , Factor de Crecimiento Nervioso/farmacología , Neuroquinina A/farmacología , Óxido Nítrico/metabolismo , Sistema Respiratorio/efectos de los fármacos , Animales , Hiperreactividad Bronquial/fisiopatología , Cobayas , Histamina/farmacología , Antagonistas de los Receptores Histamínicos H1/farmacología , Técnicas In Vitro , Rendimiento Pulmonar/efectos de los fármacos , Masculino , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Pirilamina/farmacología , Receptores Histamínicos/efectos de los fármacos , Receptores Histamínicos/fisiología , Mecánica Respiratoria/efectos de los fármacos , Tráquea/efectos de los fármacosRESUMEN
Nitric oxide (NO) is a marker of airway inflammation in humans, despite not having effects on basal bronchial tone. Inhibition of NO synthesis can lead to enhanced airway reactivity in humans and it is therefore of importance to understand how bronchial provocation can affect endogenous NO. Presently, we have studied the role of exhaled nitric oxide in airway reactivity by measuring changes in pulmonary mechanics in response to histamine in anaesthetized guinea pigs. Two groups were challenged i.v. and four groups were challenged by aerosol at different doses. One of the i.v. and one of the aerosol groups received an inhibitor of NO synthesis, N(omega)-nitro-L-arginine methyl ester (L-NAME), to reduce endogenous production of NO before histamine challenge. All animals with intact NO production showed a decrease in exhaled nitric oxide after challenge. There were positive correlations between the peak in exhaled nitric oxide and pulmonary resistance, and between the decrease in exhaled nitric oxide and lung compliance. L-NAME pretreatment increased the reactivity to aerosolized histamine but not to i.v. histamine. We conclude that the different ways of administration elicit different response patterns of exhaled nitric oxide, resistance, and compliance, even when compared at similar insufflation pressure changes. The effects of L-NAME suggest that, although different mechanisms might be responsible for the changes in pulmonary mechanics, inhibition of endogenous NO enhances decrements in pulmonary function when histamine is administered in an aerosol. The close relationship between changes in exhaled nitric oxide and changes in lung compliance and pulmonary resistance merits further studies on the relationship between NO and airway reactivity.