Mordeduras de ofidios en mano pediátrica y sus complicaciones locales / Snake bites in pediatric hand and their local complications / Mordidas de serpentes de mão pediátricas e suas complicações locais

Introducción: el envenenamiento por mordedura de ofidios es reconocido como un problema de salud pública según la Organización Mundial de la Salud. La baja incidencia sumada a la diversidad de presentaciones clínicas, edades, topografías afectadas, así como los diferentes protocolos en la bibliografía existente sobre algunos aspectos del tratamiento, hacen difícil el manejo sistematizado de estos pacientes. El objetivo de este trabajo es realizar una revisión sistemática de la literatura sobre mordedura de serpientes en pacientes pediátricos con afectación en mano y miembro superior, haciendo hincapié en la conducta frente las complicaciones loco-regionales. Por importancia y frecuencia destacamos al síndrome compartimental, las flictenas y las infecciones. Metodología: se realizó una búsqueda bibliográfica en MedLine/PubMed con las palabras clave: "Snake Bite hand Children" y "Snake Bite compartimental syndrome". Se incluyeron los artículos publicados en los últimos 10 años (2012 al 2022). Resultados: la búsqueda de artículos ante las palabras "Snake Bite hand Children" resultó en 20 articulos y la busqueda ante las palabras "Snake Bite compartimental syndrome" derivó en 34. Luego de aplicar los criterios de inclusión y exclusión se obtuvieron 30 artículos para el análisis. Conclusiones: la población pediátrica se encuentra más expuesta a las mordeduras por serpientes y a su vez a presentar lesiones más severas. El tratamiento del síndrome compartimental continúa siendo un tema de debate. El veneno inoculado puede simular un síndrome compartimental que puede revertir sin fasciotomías con el tratamiento adecuado. Igualmente, ante síntomas y signos claros de síndrome compartimental se sugiere realizar fasciotomías frente a las graves secuelas potenciales. Ante la aparición de flictenas, el destechado cuidadoso de la misma es un tratamiento adecuado. La mayoría de los autores coinciden con el tratamiento profiláctico con antibioticoterapia.

Introduction: Ophidian bite poisoning is recognized as a public health problem by the World Health Organization. The low incidence added to the diversity of clinical presentations, ages, affected topographies, as well as the different protocols in the existing literature on some aspects of treatment, make the systematized management of these patients difficult. The aim of this work is to carry out a systematic review of the literature on snakebite in pediatric patients with hand and upper limb involvement, with emphasis on the management of loco-regional complications. In terms of importance and frequency, we highlight compartment syndrome, phlyctenas and infections. Methodology: a literature search was carried out in MedLine/PubMed with the keywords: "Snake Bite hand Children" and "Snake Bite compartment syndrome". Articles published in the last 10 years (2012 to 2022) were included. Results: the search for articles with the words "Snake Bite hand Children" resulted in 20 articles and the search for the words "Snake Bite compartment syndrome" resulted in 34 articles. After applying the inclusion and exclusion criteria, 30 articles were obtained for the analysis. Conclusions: the pediatric population is more exposed to snake bites and in turn to present more severe lesions. The treatment of compartment syndrome continues to be a subject of debate. Inoculated venom can simulate a compartment syndrome that can be reversed without fasciotomies with proper treatment. Likewise, in the presence of clear symptoms and signs of compartment syndrome, fasciotomies are suggested because of the serious sequelae generated. In the event of the appearance of phlyctenas, careful unroofing of the phlyctenas would be an appropriate treatment. Most authors agree with prophylactic treatment with antibiotic therapy.

Introdução: O envenenamento por mordidas ofídias é reconhecido como um problema de saúde pública pela Organização Mundial da Saúde. A baixa incidência, juntamente com a diversidade de apresentações clínicas, idades, topografias afetadas, bem como os diferentes protocolos da literatura existente sobre alguns aspectos do tratamento, tornam difícil o gerenciamento sistemático desses pacientes. O objetivo deste trabalho é realizar uma revisão sistemática da literatura sobre mordida de cobra em pacientes pediátricos com envolvimento de mãos e membros superiores, com ênfase no gerenciamento de complicações loco-regionais. Em termos de importância e freqüência, destacamos a síndrome compartimental, as flectenas e as infecções. Metodologia: foi realizada uma pesquisa bibliográfica no MedLine/PubMed com as palavras-chave: "Snake Bite hand Children" e "Snake Bite compartment syndrome". Os artigos publicados nos últimos 10 anos (2012 a 2022) foram incluídos. Resultados: a busca de artigos usando as palavras "Snake Bite hand Children" resultou em 20 artigos e a busca das palavras "Snake Bite compartment syndrome" resultou em 34 artigos. Após a aplicação dos critérios de inclusão e exclusão, foram obtidos 30 artigos para análise. Conclusões: a população pediátrica está mais exposta às picadas de cobra e, por sua vez, a lesões mais graves. O tratamento da síndrome compartimental continua a ser motivo de debate. O veneno inoculado pode simular uma síndrome de compartimento que pode ser revertida sem fasciotomias com tratamento apropriado. Da mesma forma, se houver sinais e sintomas claros de síndrome compartimental, são sugeridas fasciotomias por causa das severas seqüelas. Se as flectenas aparecerem, o desenrolamento cuidadoso das flectenas seria um tratamento apropriado. A maioria dos autores concorda com o tratamento profilático com a antibioticoterapia.

Venenos de serpentes do gênero Bothrops: impacto da glicosilação na complexidade dos proteomas e função de toxinas / Bothrops snake venoms: impact of glycosylation on the complexity of proteomes and toxins function

A variabilidade estrutural é uma característica das proteínas de venenos de serpentes, e a glicosilação é uma das principais modificações pós-traducionais que contribui para a diversificação de seus proteomas. Recentes estudos de nosso grupo demonstraram que venenos do gênero Bothrops são marcadamente definidos pelo seu conteúdo de glicoproteínas, e que a maioria das estruturas de N-glicanos dos tipos híbrido e complexo identificados em oito venenos deste gênero contêm unidades de ácido siálico. Em paralelo, em glicoproteínas do veneno de B. cotiara foi identificada a presença de uma estrutura de N-acetilglicosamina bissecada. Assim, com o objetivo de investigar a variação do conteúdo de glicoproteínas, assim como os mecanismos envolvidos na geração dos diferentes venenos de Bothrops, neste estudo foram analisados comparativamente os glicoproteomas de nove venenos do gênero Bothrops (B. atrox, B. cotiara, B. erythromelas, B. fonsecai, B. insularis, B. jararaca, B. jararacussu, B. moojeni e B. neuwiedi). As abordagens glicoproteômicas envolveram cromatografia de afinidade e ensaio de pull-down utilizando, respectivamente, as lectinas SNA (aglutinina de Sambucus nigra) e MAL I (lectina de Maackia amurensis), que mostram afinidade por unidades de ácido siálico nas posições, respectivamente, α2,6 e α2,3; e cromatografia de afinidade com a lectina PHA-E (eritroaglutinina de Phaseolus vulgaris), que reconhece N-acetilglicosamina bissecada. Ainda, eletroforese de proteínas, blot de lectina, e identificação de proteínas por espectrometria de massas foram empregadas para caracterizar os glicoproteomas. As lectinas geraram frações dos venenos enriquecidas de diferentes componentes, onde as principais classes de glicoproteínas identificadas foram metaloprotease, serinoprotease, e L-amino ácido oxidase, além de outras enzimas pouco abundantes nos venenos. Os diferentes conteúdos de proteínas reconhecidas por essas lectinas, com especificidades distintas, ressaltaram novos aspectos da variabilidade dos subproteomas de glicoproteínas desses venenos, dependendo da espécie. Ainda, considerando que metaloproteases e serinoproteases são componentes abundantes nesses venenos e fundamentais no quadro de envenenamento botrópico, e que estas enzimas contêm diversos sítios de glicosilação, o papel das unidades de ácido siálico na atividade proteolítica das mesmas foi avaliado. Assim, a remoção enzimática de ácido siálico (i) alterou o padrão de gelatinólise em zimografia da maioria dos venenos, (ii) diminuiu a atividade proteolítica de alguns venenos sobre o fibrinogênio e a atividade coagulante do plasma humano de todos os venenos, e (iii) alterou o perfil de hidrólise de proteínas plasmáticas pelo veneno de B. jararaca, indicando que este carboidrato pode desempenhar um papel na interação das proteases com seus substratos proteicos. Em contraste, o perfil da atividade amidolítica dos venenos não se alterou após a remoção de ácido siálico e incubação com o substrato Bz-Arg-pNA, indicando que ácido siálico não é essencial em N-glicanos de serinoproteases atuando sobre substratos não proteicos. Em conjunto, esses resultados expandem o conhecimento sobre a variabilidade de proteomas de venenos do gênero Bothrops e apontam a importância das cadeias de carboidratos contendo ácido siálico nas atividades enzimáticas das proteases desses venenos

Structural variability is a feature of snake venom proteins, and glycosylation is one of the main post-translational modifications that contributes to the diversification of venom proteomes. Recent studies by our group have shown that Bothrops venoms are markedly defined by their glycoprotein content, and that most hybrid and complex N-glycan structures identified in eight venoms of this genus contain sialic acid units. In parallel, the presence of a bisected N-acetylglucosamine structure was identified in B. cotiara venom glycoproteins. Thus, with the aim of investigating the variation in the content of glycoproteins, as well as the mechanisms involved in the generation of different Bothrops venoms, in this study the glycoproteomes of nine Bothrops venoms (B. atrox, B. cotiara, B. erythromelas, B. fonsecai, B. insularis, B. jararaca, B. jararacussu, B. moojeni e B. neuwiedi) were comparatively analyzed. The glycoproteomic approaches involved affinity chromatography and pulldown using, respectively, the lectins SNA (Sambucus nigra agglutinin) and MAL I (Maackia amurensis lectin), which show affinity for sialic acid units at positions, respectively, α2,6 and α2,3, and affinity chromatography with PHA-E (Phaseolus vulgaris erythroagglutinin), which recognizes bisected N-acetylglucosamine. In addition, protein electrophoresis, lectin blot, and protein identification by mass spectrometry were employed for glycoproteome characterization. The lectins generated venom fractions enriched with different components, where the main classes of glycoproteins identified were metalloprotease, serine protease, and L-amino acid oxidase, in addition to other low abundant enzymes. The different contents of proteins recognized by these lectins of distinct specificities highlighted new aspects of the variability of the glycoprotein subproteomes of these venoms, depending on the species. Furthermore, considering that metalloproteases and serine proteases are abundant components of these venoms and essential in Bothrops envenomation, and that these enzymes contain several glycosylation sites, the role of sialic acid units in their proteolytic activities was evaluated. Thus, enzymatic removal of sialic acid (i) altered the pattern of gelatinolysis in zymography of most venoms, (ii) decreased the proteolytic activity of some venoms on fibrinogen and the clotting activity of human plasma of all venoms, and (iii) altered the hydrolysis profile of plasma proteins by B. jararaca venom, indicating that this carbohydrate may play a role in the interaction of proteases with their protein substrates. In contrast, the profile of amidolytic activity of the venoms did not change after removal of sialic acid and incubation with the substrate Bz-Arg-pNA, indicating that sialic acid is not essential in N-glycans of serine proteases acting on small substrates. Together, these results expand the knowledge about the variability of proteomes of Bothrops venoms and point to the importance of carbohydrate chains containing sialic acid in the enzymatic activities of venom proteases

Animal Venom for Medical Usage in Pharmacopuncture in Korean Medicine: Current Status and Clinical Implication.

Animal venoms, widespread throughout the world, are complex mixtures, the composition of which depends on the venom-producing species. The objective of this study was to contribute to the development of animal venom-based medicines by investigating the use of animal venom pharmacopuncture in Korean medicine (KM) institutions. We surveyed 256 public health centers from 1 through 31 October 2019 as guided by the Ministry of Health and Welfare (MoHW). A questionnaire developed by an expert group was distributed and collected for statistical analysis. The survey identified three types of animal venom-based pharmacopuncture: bee, snake, and toad venoms. The medications are based on a single animal venom ingredient and produced in 11 external herbal dispensaries (EHDs). Each animal venom is processed, refined, and freeze-dried in a cleanroom to produce a powder formulation that is later measured, diluted, filtered, filled, sealed, sterilized, and packaged as pharmacopuncture injections used in KM institutions. Bee venom therapy is effective in treating musculoskeletal pain, snake venom therapy is effective in controlling bleeding during surgery, and toad venom therapy is effective in cancer treatment. The study suggests that bee, snake, and toad venoms could be used in medical institutions and have the potential for drug development.

Snakebite Envenoming a Challenging Diagnosis for the Forensic Pathologist: A Systematic Review.

Snakebite envenoming (SBE) is a public health issue in developing countries. The estimated annual global incidence of snakebites is about 5.4 million snakebites per year, resulting from 1.8 to 2.7 million cases of SBE and from 81,000 to 138,000 deaths with 400,000 survivors suffering permanent physical and psychological disabilities. There are more than 3000 species of snakes around the world: 600 are venomous and over 200 are considered to be medically important because of their clinical effects. The severity of SBE depends on several factors among which bite localization, snake's size, condition of glands and teeth, bite angle and bite duration, the microflora of the snake's mouth and victim's skin, age of the victim, weight, health status, and victim's activity after a bite. Snake venoms are mixtures of protein families, and each of these families contains many different toxins or toxin isoforms. Based on their effects, snake venoms can be classified as hemotoxic, neurotoxic, or cytotoxic and they can all act together involving multiple tissues and organs. When the bite is fatal, the mechanism of death is primarily related to the paralysis of respiratory muscles, which causes asphyxia and hypoxic-ischemic encephalopathy, but also anaphylactic shock, hemorrhagic shock, cardiomyopathy, acute tubular necrosis (ATN). The purpose of this literature review is to evaluate epidemiological and post-mortem examination findings in fatal SBEs in order to better understand the pathophysiological mechanisms, thus helping pathologists in defining the correct diagnosis.

Boomslang (Dispholidus typus) envenomation in a patient on warfarin therapy.

The venom of the boomslang (Dispholidus typus) has potent effects on the coagulation system. It is known to produce a venom-induced consumptive coagulopathy (VICC) through the proposed activation of clotting factor II (prothrombin), factor X, and possibly factor IX. Warfarin, an anticoagulant medication, decreases the circulating vitamin K-dependent clotting factors II, VII, IX and X. We report a unique case of a boomslang bite in a patient on warfarin therapy. During the patient's hospital stay he developed abnormal clotting profiles indicating an underlying VICC, but without major bleeding. He received monovalent antivenom and recovered with no complications. We discuss two possible outcomes of a boomslang bite in a patient on warfarin therapy, exploring the underlying pathophysiology that could lead to the presentation of a reduced risk of overall bleeding or, alternatively, that the bleeding could be compounded and exacerbated. It is possible that in our case the anticoagulant effect of warfarin was wholly obscured by the VICC of the boomslang venom. The composition of the snake venom may have been a contributory factor in the reduced clinical bleeding observed.

Capacitação para diagnóstico e tratamento em acidentes ofídicos

2º aula 20/08/2020: Painel sobre A situação epidemiológica dos acidentes ofídicos no RN e as espécies de serpentes predominantes no RN com a enfermeira Luanna Roberta Paiva De Oliveira

Capacitação para diagnóstico e tratamento em acidentes ofídicos

1º aula 19/08/2020: Acidente Botrópico e Crotálico - Diagnóstico e Tratamento com o palestrante Adebal de Andrade Filho

Endocrine and Metabolic Manifestations of Snakebite Envenoming.

Snakebite envenoming is a neglected, public health problem in tropical and subtropical regions. Local tissue necrosis, neurotoxic, and hemo-vasculotoxic effects are well-recognized features, whereas the endocrine and metabolic derangements are not as well known. In addition to contributing to morbidity, some of these manifestations can be potentially life-threatening if not recognized early. The most prominent endocrine manifestation is hypopituitarism (HP), which can manifest acutely or remain asymptomatic and present years later. Unexplained recurrent hypoglycemia and refractory hypotension are early clinical clues to suspect corticotroph axis involvement in acute settings. Chronic pituitary failure may present, like Sheehan's syndrome, several years after the bite. The occurrence of acute kidney injury, capillary leak syndrome, and disseminated intravascular coagulation are predictors of HP. Adrenal hemorrhages are documented in autopsy series; however, primary adrenal insufficiency is very rare and confounded by the presence of HP. Hyponatremia, hypokalemia or hyperkalemia, and dysglycemia can occur, but the mechanisms involved are only partially understood. Awareness, a high index of suspicion, correct interpretation of hormonal parameters, and timely treatment of these abnormalities can be lifesaving.

Epidemiology and Outcomes of Early Morning Neuroparalytic Syndrome Following Snake Bite-A Retrospective Study.

OBJECTIVE: Snake envenomation has been poorly studied in developing countries. 'Early morning neuroparalytic syndrome' (EMNS), the classical clinical constellation caused by krait bites, refers to nighttime, indoor bites where nonspecific symptoms progress to neuroparalysis. Literature regarding EMNS in children is scarce. This study was planned to describe the clinical profile, intensive care needs and predictors of outcome in children with EMNS. METHODS: It is a retrospective study of children below 12 years admitted with a clinical diagnosis of snake envenomation to the pediatric intensive care unit (PICU) of a tertiary care hospital in North India. Patient records were reviewed from the electronic patient database manager. Comparison was made between the EMNS group and the non-EMNS group and between survivors and nonsurvivors within the EMNS group. RESULTS: Of the 111 children with snake envenomation, 76 had neuroparalysis (68%) and 51 had EMNS. In the EMNS cohort, 37 (72.5%) belonged to rural areas, 46 (90.2%) had indoor bites and 39 (76.5%) were witnessed. Patients with EMNS were more likely to have absent fang marks, hypoxemia at admission, bulbar palsy and need for PICU admission. Mortality rate was 13.7% in EMNS; predictors included younger age, presence of ptosis, cardiac arrest at admission and nonavailability of PICU bed (univariable analysis) but none of them independently predicted mortality. CONCLUSION: Younger age, presence of ptosis, cardiac arrest at admission and nonavailability of intensive care beds increase the risk of mortality in children with EMNS. Timely recognition and respiratory support may reduce mortality in these children.

Effect of Bitis gabonica and Dendroaspis angusticeps snake venoms on apoptosis-related genes in human thymic epithelial cells

Certain environmental toxins permanently damage the thymic epithelium, accelerate immune senescence and trigger secondary immune pathologies. However, the exact underlying cellular mechanisms and pathways of permanent immune intoxication remain unknown. The aim of the present study was to demonstrate gene expressional changes of apoptosis-related cellular pathways in human thymic epithelial cells following exposure to snake venom from Bitis gabonica and Dendroaspis angusticeps. Methods: Snake venoms were characterized by analytical methods including reversed phase high-performance liquid chromatography and sodium dodecyl sulphate-polyacrylamide gel electrophoresis, then applied on human thymic epithelial cells (1889c) for 24 h at 10 μg/mL (as used in previous TaqMan Array study). Gene expressional changes restricted to apoptosis were assayed by TaqMan Array (Human Apoptosis Plate). Results: The most prominent gene expressional changes were shown by CASP5 (≈ 2.5 million-fold, confirmed by dedicated quantitative polymerase chain reaction) and CARD9 (0.016-fold) for B. gabonica, and BIRC7 (6.46-fold) and CASP1 (0.30-fold) for D. angusticeps. Conclusion: The observed apoptotic environment suggests that pyroptosis may be the dominant pathway through which B. gabonica and D. angusticeps snake venoms trigger thymic epithelial apoptosis following envenomation.(AU)

Enzymes modulation by dried grape pomace from the manufacture of wines and juices

The processing of grapes for the manufacture of juices and wines, generates large quantities of by-products rich in metabolites with antioxidant, antimicrobial, anti-inflammatory and cicatrizing activities. The high homology between human enzymes and snake venoms makes the latter valuable laboratory tools for the study of pathophysiological processes. Proteases and phospholipases A2 act in processes related to hemostasis and inflammatory response. Thus, in this work, dried pomace obtained from grape (Isabel, Niagara, Bordô, BRS Violeta and Blend cultivars) processing were evaluated on phospholipase, proteolytic, hemolytic and thrombolytic activities induced by snakes venoms and the content of phenolic compounds and minerals was evaluated. The dried pomace exerted inhibitory and potentiating actions in all analyzed activities. The enzymatic modulators present in the evaluated dried pomace have potential for therapeutic use, although their broad characterization is still necessary, in order to define adequate amounts and formulations to obtain efficacy and safety in their use.

Perspective on the Therapeutics of Anti-Snake Venom.

Snakebite envenomation is a life-threatening disease that was recently re-included as a neglected tropical disease (NTD), affecting millions of people in tropical and subtropical areas of the world. Improvement in the therapeutic approaches to envenomation is required to palliate the morbidity and mortality effects of this NTD. The specific therapeutic treatment for this NTD uses snake antivenom immunoglobulins. Unfortunately, access to these vital drugs is limited, principally due to their cost. Different ethnic groups in the affected regions have achieved notable success in treatment for centuries using natural sources, especially plants, to mitigate the effects of snake envenomation. The ethnopharmacological approach is essential to identify the potential metabolites or derivatives needed to treat this important NTD. Here, the authors describe specific therapeutic snakebite envenomation treatments and conduct a review on different strategies to identify the potential agents that can mitigate the effects of the venoms. The study also covers an increased number of literature reports on the ability of natural sources, particularly plants, to treat snakebites, along with their mechanisms, drawbacks and future perspectives.

Snake Eyes: Coral Snake Neurotoxicity Associated With Ocular Absorption of Venom and Successful Treatment With Exotic Antivenom.

BACKGROUND: Coral snake bites from Micrurus fulvius and Micrurus tener account for < 1% of all snake bites in North America. Coral snake envenomation may cause significant neurotoxicity, including respiratory insufficiency, and its onset may be delayed up to 13 h. CASE REPORT: We present a unique patient encounter of M. tener venom exposure through the ocular mucous membranes and a small cutaneous bite, resulting in neurotoxicity. To our knowledge, this is the first reported case of systemic neurotoxicity associated with ocular contact with coral snake venom. Our patient developed rapid-onset skeletal muscle weakness, which is very uncommon for M. tener, along with cranial nerve deficits. Acquisition of antivenom was challenging, but our patient provides a rare report of resolution of suspected M. tener neurotoxicity after receiving Central American coral snake (Micrurus nigrocinctus) antivenom. Our patient subsequently developed serum sickness, a known delayed complication of antivenom. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: The emergency physician should be aware that coral snake venom may be absorbed through different routes. Neurotoxicity and respiratory insufficiency may be fatal and onset may be delayed up to 13 h. North American Coral Snake Antivenom is in very limited supply, so non-Food and Drug Administration-approved alternative coral snake antivenoms may be used for patients demonstrating neurotoxicity. Emergency physicians should be proactive in contacting a toxicologist to procure antivenom, as well as consideration of adjunctive treatments, such as neostigmine. Furthermore, whole immunoglobulin G products, such as antivenom, may result in immediate and delayed reactions.

Knowledge of venomous snakes, snakebite first aid, treatment, and prevention among clinicians in northern Nigeria: a cross-sectional multicentre study.

Background: Snakebite envenoming causes considerable morbidity and mortality in northern Nigeria. The clinician's knowledge of snakebite impacts outcome. We assessed clinicians' knowledge of snakebite envenoming to highlight knowledge and practice gaps for possible intervention to improve snakebite outcomes. Methods: This was a cross-sectional multicentre study of 374 doctors selected from the accident and emergency, internal medicine, family medicine/general outpatient, paediatrics and surgery departments of nine tertiary hospitals in northern Nigeria using a multistage sampling technique. A self-administered questionnaire was used to assess their sociodemographics, knowledge of common venomous snakes, snakebite first aid, snake antivenom treatment and prevention. Results: The respondents' mean age was 35.6±5.8 y. They were predominantly males (70.6%) from urban hospitals (71.9%), from the northwest region (35.3%), in family medicine/general outpatient departments (33.4%), of <10 years working experience (66.3%) and had previous experience in snakebite management (78.3%). Although their mean overall knowledge score was 70.2±12.6%, only 52.9% had an adequate overall knowledge score. Most had adequate knowledge of snakebite clinical features (62.3%), first aid (75.7%) and preventive measures (97.1%), but only 50.8% and 25.1% had adequate knowledge of snake species that caused most injuries/deaths and anti-snake venom treatment, respectively. Overall knowledge predictors were ≥10 y working experience (odd ratio [OR] 1.72 [95% confidence interval {CI} 1.07 to 2.76]), urban hospital setting (OR 0.58 [95% CI 0.35 to 0.96]), surgery department (OR 0.44 [95% CI 0.24 to 0.81]), northwest/north-central region (OR 2.36 [95% CI 1.46 to 3.82]) and previous experience in snakebite management (OR 2.55 [95% CI 1.49 to 4.36]). Conclusions: Overall knowledge was low. Improvements in overall knowledge may require clinicians' exposure to snakebite management and training of accident and emergency clinicians in the region.

Continuous Infusion of Cilengitide Plus Chemoradiotherapy for Patients With Stage III Non-Small-cell Lung Cancer: A Phase I Study.

INTRODUCTION: Because of our previous preclinical results, we conducted a phase I study associating the specific αvß3/αvß5 integrin inhibitor cilengitide, given as a continuous infusion, with exclusive chemoradiotherapy for patients with stage III non-small-cell lung cancer. PATIENTS AND METHODS: A standard 3+3 dose escalation design was used. Cilengitide was given as a continuous infusion (dose levels of 12, 18, 27, and 40 mg/h), starting 2 weeks before and continuing for the whole course of chemoradiotherapy (66 Gy combined with platinum/vinorelbine), and then at a dose of 2000 mg twice weekly in association with chemotherapy. 2-Deoxy-2-[fluorine-18]fluoro-d-glucose positron emission tomography (PET) and computed tomography scans were performed before and after the first 2 weeks of cilengitide administration and then every 3 months. RESULTS: Of the 14 patients included, 11 were evaluable for evaluation of the dose-limiting toxicities (DLTs). One DLT, a tracheobronchial fistula, was reported with the 40 mg/h dose. No relevant adverse events related to cilengitide were observed overall. At the PET evaluation 2 months after chemoradiotherapy, 4 of 9 patients had a complete response and 4 had a partial response. The median progression-free and overall survival was 14.4 months (95% confidence interval [CI], 8.4 to not reached) and 29.4 months (95% CI, 11.73 to not reached), respectively. CONCLUSION: Cilengitide, given continuously with chemoradiotherapy, showed acceptable toxicity and gave encouraging clinical results.

A Human Study to Evaluate Safety, Tolerability, and Cyclic GMP Activating Properties of Cenderitide in Subjects With Stable Chronic Heart Failure.

Cenderitide is a novel designer natriuretic peptide (NP) composed of C-type natriuretic peptide (CNP) fused to the C-terminus of Dendroaspis natriuretic peptide (DNP). Cenderitide was engineered to coactivate the two NP receptors, particulate guanylyl cyclase (pGC)-A and -B. The rationale for its design was to achieve the renal-enhancing and antifibrotic properties of dual receptor activation, but without clinically significant hypotension. Here we report the first clinical trial on the safety, tolerability, and cyclic guanosine monophosphate (cGMP) activating properties of Cenderitide in subjects with stable heart failure (HF). Four-hour infusion of Cenderitide was safe, well-tolerated, and significantly increased plasma cGMP levels and urinary cGMP excretion without adverse effects with no change in blood pressure. Thus, Cenderitide has a favorable safety profile and expected pharmacological effects in stable human HF. Our results support further investigations of Cenderitide in HF as a potential future cGMP-enhancing therapeutic strategy.