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.

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.

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.

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.

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.

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.

Analgesic Effect of Photobiomodulation on Bothrops Moojeni Venom-Induced Hyperalgesia: A Mechanism Dependent on Neuronal Inhibition, Cytokines and Kinin Receptors Modulation.

BACKGROUND: Envenoming induced by Bothrops snakebites is characterized by drastic local tissue damage that involves an intense inflammatory reaction and local hyperalgesia which are not neutralized by conventional antivenom treatment. Herein, the effectiveness of photobiomodulation to reduce inflammatory hyperalgesia induced by Bothrops moojeni venom (Bmv), as well as the mechanisms involved was investigated. METHODOLOGY/PRINCIPAL FINDINGS: Bmv (1 µg) was injected through the intraplantar route in the right hind paw of mice. Mechanical hyperalgesia and allodynia were evaluated by von Frey filaments at different time points after venom injection. Low level laser therapy (LLLT) was applied at the site of Bmv injection at wavelength of red 685 nm with energy density of 2.2 J/cm2 at 30 min and 3 h after venom inoculation. Neuronal activation in the dorsal horn spinal cord was determined by immunohistochemistry of Fos protein and the mRNA expression of IL-6, TNF-α, IL-10, B1 and B2 kinin receptors were evaluated by Real time-PCR 6 h after venom injection. Photobiomodulation reversed Bmv-induced mechanical hyperalgesia and allodynia and decreased Fos expression, induced by Bmv as well as the mRNA levels of IL-6, TNF-α and B1 and B2 kinin receptors. Finally, an increase on IL-10, was observed following LLLT. CONCLUSION/SIGNIFICANCE: These data demonstrate that LLLT interferes with mechanisms involved in nociception and hyperalgesia and modulates Bmv-induced nociceptive signal. The use of photobiomodulation in reducing local pain induced by Bothropic venoms should be considered as a novel therapeutic tool for the treatment of local symptoms induced after bothropic snakebites.

Cilengitide with metronomic temozolomide, procarbazine, and standard radiotherapy in patients with glioblastoma and unmethylated MGMT gene promoter in ExCentric, an open-label phase II trial.

Newly diagnosed glioblastoma multiforme with unmethylated MGMT promoter has a poor prognosis, with a median survival of 12 months. This phase II study investigated the efficacy and safety of combining the selective integrin inhibitor cilengitide with a combination of metronomic temozolomide and procarbazine for these patients. Eligible patients (newly diagnosed, histologically confirmed supratentorial glioblastoma with unmethylated MGMT promoter) were entered into this multicentre study. Cilengitide (2000 mg IV twice weekly) was commenced 1 week prior to radiotherapy combined with daily temozolomide (60 mg/m(2)) and procarbazine (50 or 100 mg) and, after 4 weeks' break, followed by six adjuvant cycles of temozolomide (50-60 mg/m(2)) and procarbazine (50 or 100 mg) on days 1-20, every 28 days. Cilengitide was continued for up to 12 months or until disease progression or unacceptable toxicity. The primary endpoint for efficacy was a 12-month overall survival rate of 65 %. Twenty-nine patients completed study treatment. Sixteen patients survived for 12 months or more, an overall survival rate of 55 %. The median overall survival was 14.5 months (95 % CI 11.1-19.6) and the median progression-free survival was 7.4 months (95 % CI 6.1-8). Cilengitide combined with metronomic temozolomide and procarbazine in MGMT-promoter unmethylated glioblastoma did not improve survival compared with historical data and does not warrant further investigation.

Snakebite in Korea: A Guideline to Primary Surgical Management.

PURPOSE: Snakebite is an emergency which causes local symptoms such as pain and edema around the bite. Systemic symptoms may also develop, such as dizziness or renal failure, and may even cause death. The purpose of this research was to assess the validity and safety of snakebite protocol for surgery when treating snakebite patients. MATERIALS AND METHODS: Retrospective research was performed on patients who were admitted after being treated at the emergency center from January 2008 to December 2012. When necessary, debridement was also performed, and 46 of 111 patients (41.4%) underwent debridement. Those who had received debridement without antivenom administration due to a positive skin reaction test were classified as group A, and group B received antivenom and delayed debridement. We reviewed the emergency and admission charts of the patients in each group and recorded and compared their age, sex, bite site, severity of local and general symptoms, time to receive antivenin, and complications. RESULTS: Of the ten patients (21.7%) in group A, two (66.6%) developed cellulites, and one of them experienced skin necrosis, resulting in a skin graft. In group B, there were 36 patients (78.2%), 19 (52.7%) of whom developed cellulitis. Skin necrosis occurred in two patients, and one of these patients received a skin graft. Compartment syndrome was found in one patient, and fasciotomy and a skin graft were performed. CONCLUSION: The treatment protocol implemented to treat snakebite patients admitted to the emergency center during this research was safely and properly followed during surgical treatment.

A phase I study of cediranib in combination with cilengitide in patients with recurrent glioblastoma.

BACKGROUND: Despite being a highly vascularized tumor, glioblastoma response to anti-vascular endothelial growth factor (VEGF) therapy is transient, possibly because of tumor co-option of preexisting blood vessels and infiltration into surrounding brain. Integrins, which are upregulated after VEGF inhibition, may play a critical role in this resistance mechanism. We designed a study of cediranib, a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor, combined with cilengitide, an integrin inhibitor. METHODS: This phase I study was conducted through the Adult Brain Tumor Consortium in patients with recurrent glioblastoma. Once the maximum tolerated dose was determined, 40 patients enrolled in a dose expansion cohort with 20 being exposed to anti-VEGF therapy and 20 being naive. The primary endpoint was safety. Secondary endpoints included overall survival, proportion of participants alive and progression free at 6 months, radiographic response, and exploratory analyses of physiological imaging and blood biomarkers. RESULTS: Forty-five patients enrolled, and no dose toxicities were observed at a dose of cediranib 30 mg daily and cilengitide 2000 mg twice weekly. Complete response was seen in 2 participants, partial response in 2, stable disease in 13, and progression in 21; 7 participants were not evaluable. Median overall survival was 6.5 months, median progression-free survival was 1.9 months, and progression-free survival at 6 months was 4.4%. Plasma-soluble VEGFR2 decreased with treatment and placental growth factor, carbonic anhydrase IX, and SDF1α, and cerebral blood flow increased. CONCLUSIONS: The combination of cediranib with cilengitide was well tolerated and associated with changes in pharmacodynamic blood and imaging biomarkers. However, the survival and response rates do not warrant further development of this combination.

Two cilengitide regimens in combination with standard treatment for patients with newly diagnosed glioblastoma and unmethylated MGMT gene promoter: results of the open-label, controlled, randomized phase II CORE study.

BACKGROUND: Survival outcomes for patients with glioblastoma remain poor, particularly for patients with unmethylated O(6)-methylguanine-DNA methyltransferase (MGMT) gene promoter. This phase II, randomized, open-label, multicenter trial investigated the efficacy and safety of 2 dose regimens of the selective integrin inhibitor cilengitide combined with standard chemoradiotherapy in patients with newly diagnosed glioblastoma and an unmethylated MGMT promoter. METHODS: Overall, 265 patients were randomized (1:1:1) to standard cilengitide (2000 mg 2×/wk; n = 88), intensive cilengitide (2000 mg 5×/wk during wk 1-6, thereafter 2×/wk; n = 88), or a control arm (chemoradiotherapy alone; n = 89). Cilengitide was administered intravenously in combination with daily temozolomide (TMZ) and concomitant radiotherapy (RT; wk 1-6), followed by TMZ maintenance therapy (TMZ/RT→TMZ). The primary endpoint was overall survival; secondary endpoints included progression-free survival, pharmacokinetics, and safety and tolerability. RESULTS: Median overall survival was 16.3 months in the standard cilengitide arm (hazard ratio [HR], 0.686; 95% CI: 0.484, 0.972; P = .032) and 14.5 months in the intensive cilengitide arm (HR, 0.858; 95% CI: 0.612, 1.204; P = .3771) versus 13.4 months in the control arm. Median progression-free survival assessed per independent review committee was 5.6 months (HR, 0.822; 95% CI: 0.595, 1.134) and 5.9 months (HR, 0.794; 95% CI: 0.575, 1.096) in the standard and intensive cilengitide arms, respectively, versus 4.1 months in the control arm. Cilengitide was well tolerated. CONCLUSIONS: Standard and intensive cilengitide dose regimens were well tolerated in combination with TMZ/RT→TMZ. Inconsistent overall survival and progression-free survival outcomes and a limited sample size did not allow firm conclusions regarding clinical efficacy in this exploratory phase II study.

Cisplatin, 5-fluorouracil, and cetuximab (PFE) with or without cilengitide in recurrent/metastatic squamous cell carcinoma of the head and neck: results of the randomized phase I/II ADVANTAGE trial (phase II part).

BACKGROUND: Recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M-SCCHN) overexpresses αvß5 integrin. Cilengitide selectively inhibits αvß3 and αvß5 integrins and is investigated as a treatment strategy. PATIENTS AND METHODS: The phase I/II study ADVANTAGE evaluated cilengitide combined with cisplatin, 5-fluorouracil, and cetuximab (PFE) in R/M-SCCHN. The phase II part reported here was an open-label, randomized, controlled trial investigating progression-free survival (PFS). Patients received up to six cycles of PFE alone or combined with cilengitide 2000 mg once (CIL1W) or twice (CIL2W) weekly. Thereafter, patients received maintenance therapy (cilengitide arms: cilengitide plus cetuximab; PFE-alone arm: cetuximab only) until disease progression or unacceptable toxicity. RESULTS: One hundred and eighty-two patients were treated. Median PFS per investigator read was similar for CIL1W + PFE, CIL2W + PFE, and PFE alone (6.4, 5.6, and 5.7 months, respectively). Accordingly, median overall survival and objective response rates were not improved with cilengitide (12.4 months/47%, 10.6 months/27%, and 11.6 months/36%, respectively). No clinically meaningful safety differences were observed between groups. None of the tested biomarkers (expression of integrins, CD31, Ki-67, vascular endothelial growth factor receptor 2, vascular endothelial-cadherin, type IV collagen, epidermal growth factor receptor, or p16 for human papillomavirus) were predictive of outcome. CONCLUSION: Neither of the cilengitide-containing regimens demonstrated a PFS benefit over PFE alone in R/M-SCCHN patients.

Randomized phase II study of three doses of the integrin inhibitor cilengitide versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer.

INTRODUCTION: This multicenter, open-label, phase II study was carried out to compare the efficacy and safety of cilengitide (EMD 121974), a selective inhibitor of the cell-surface integrins αVß3 and αVß5, with that of docetaxel in patients with advanced non-small-cell lung cancer (NSCLC). METHODS: Patients (n = 140) with advanced NSCLC who had failed first-line chemotherapy were randomized to cilengitide 240, 400, or 600 mg/m(2) twice weekly, or docetaxel 75 mg/m(2) once every 3 weeks for eight cycles. Non-progressing patients could continue cilengitide for up to 1 year. The primary endpoint was progression-free survival (PFS). No statistical tests were performed since the study was exploratory in nature and the number of patients enrolled was relatively small. RESULTS: Median PFS was 54, 63, 63, and 67 days for cilengitide 240, 400, and 600 mg/m(2), and docetaxel 75 mg/m(2), respectively. One-year survival rates were 13 %, 13 %, 29 %, and 27 %, respectively. The response rate (partial response only) with docetaxel was 15 %. No responses were reported in any cilengitide arm. The most frequent grade 3/4 treatment-related adverse events in the docetaxel group were leukopenia and neutropenia (experienced by 13 % of patients). Hematologic toxicity of this severity did not occur in cilengitide-treated patients. CONCLUSION: With the highest dose of cilengitide (600 mg/m(2)), median PFS and 1-year survival were similar to those in patients treated with docetaxel 75 mg/m(2) and there were fewer grade 3/4 treatment-related adverse events.

A randomized phase II study of cilengitide (EMD 121974) in patients with metastatic melanoma.

Cilengitide (EMD 121974) is a selective inhibitor of integrins αvß3 and αvß5. The αvß3 promotes the proliferation of tumor-associated endothelial cells and potentially the survival of melanoma cells. We conducted a randomized phase II trial in patients with metastatic melanoma to evaluate the clinical efficacy of cilengitide. Patients with stage IV or unresectable stage III melanoma who were either chemonaive or who had previously received one systemic therapy were enrolled. Patients were randomly assigned to either 500 or 2000 mg of cilengitide administered intravenously twice weekly. The primary aim of this study was to determine the progression-free survival rate at 8 weeks. Tumor samples and blood samples were collected for pharmacodynamic and pharmacokinetic studies. Twenty-nine patients were enrolled, of whom 26 were treated (14 at 500 mg and 12 at 2000 mg). Among those treated, only three were progression free at 8 weeks: two in the 500 mg arm and one in the 2000 mg arm. One patient in the 2000 mg arm showed a prolonged partial response after an initial 28% enlargement of her target lesions. The treatment was well tolerated without clinically significant adverse events. The sole responder and one of two patients with stable disease had no αvß3 expression at baseline. Overall, αvß3 expression was decreased by day 8 of the treatment (P=0.05). Cilengitide was well tolerated by patients in both the treatment arms but had minimal clinical efficacy as a single-agent therapy for metastatic melanoma, and the efficacy was not related to baseline αvß3 expression.

Phase II study of cilengitide (EMD 121974, NSC 707544) in patients with non-metastatic castration resistant prostate cancer, NCI-6735. A study by the DOD/PCF prostate cancer clinical trials consortium.

BACKGROUND: Integrins mediate invasion and angiogenesis in prostate cancer bone metastases. We conducted a phase II study of cilengitide, a selective antagonist of α(v)ß(3) and α(v)ß(5) integrins, in non-metastatic castration resistant prostate cancer with rising PSA. METHODS: Patients were observed for 4 weeks with PSA monitoring, and then treated with 2,000 mg IV of cilengitide twice weekly until toxicity/progression. PSA, circulating tumor cells (CTCs) and circulating endothelial cells (CECs) were monitored each cycle with imaging performed every three cycles. Primary end point was PSA decline by ≥ 50%. Secondary endpoints were safety, PSA slope, time to progression (TTP), overall survival (OS), CTCs, CECs and gene expression. RESULTS: 16 pts were enrolled; 13 were eligible with median age 65.5 years, baseline PSA 8.4 ng/mL and median Gleason sum 7. Median of three cycles was administered. Treatment was well tolerated with two grade three toxicities and no grade four toxicities. There were no PSA responses; 11 patients progressed by PSA after three cycles. Median TTP was 1.8 months and median OS has not been reached. Median pre- and on-treatment PSA slopes were 1.1 and 1.8 ng/mL/month. Baseline CTCs were detected in 1/9 patients. CTC increased (0 to 1; 2 pts), remained at 0 (2 pts) or decreased (23 to 0; 1 patient) at progression. Baseline median CEC was 26 (0-61) and at progression, 47 (15-148). Low cell counts precluded gene expression studies. CONCLUSIONS: Cilengitide was well tolerated but had no detectable clinical activity. CTCs are of questionable utility in non-metastatic prostate cancer.

A phase I study of continuous infusion cilengitide in patients with solid tumors.

BACKGROUND: Cilengitide (EMD121974) is a cyclized pentapeptide that is a potent and selective integrin antagonist which has shown activity in malignant gliomas. In all previous studies, cilengitide has been administered in an intermittent fashion. However, cilengitide has a short half-life of 3-5 h with no evidence of drug accumulation. These data prompted the initiation of this phase I study of continuous infusion cilengitide. METHODS: Cilengitide was administered as a continuous infusion without break in 4-week cycles. Plasma samples for pharmacokinetic studies were obtained weekly in cycle 1 immediately prior to and 2 h after infusion bag change. RESULTS: Thirty-five patients were treated (median age 56; 23 males) at dose levels of 1, 2, 4, 8, 12, 18, 27, and 40 mg/h. Toxicities were limited to grade ≤ 2 and showed no relation to dose. Fatigue was most common (17%), while all other toxicities were reported in <10% of patients. No dose-limiting toxicities were observed, and therefore the maximum tolerated dose was not reached. Pharmacokinetic analysis showed that values for clearance and volume of distribution were comparable across dose levels, and the steady-state concentration increased proportionally with dose. CONCLUSIONS: Cilengitide can be safely administered as a continuous infusion at doses up to at least 40 mg/h, which represents the maximum feasible dose due to drug solubility and delivery limitations. The pharmacokinetics of continuous infusion cilengitide are linear and consistent with the results obtained using a twice weekly infusion.

Cilengitide in patients with recurrent glioblastoma: the results of NABTC 03-02, a phase II trial with measures of treatment delivery.

Cilengitide is a cyclic pentapeptide that is a specific inhibitor of the αvß3 and αvß5 integrins. Preclinical studies demonstrate antiangiogenic activity and anti-invasive activity in a number of glioma models. This study was designed to evaluate the efficacy and tumor delivery of cilengitide in patients with recurrent glioblastoma. Patients with recurrent glioblastoma who require a surgical resection for optimal clinical care received 3 intravenous doses of cilengitide at either 500 or 2000 mg (day -8, -4, -1) prior to undergoing tumor resection with corresponding blood samples for plasma to tumor comparisons. After recovery from surgery, patients were treated with cilengitide (2000 mg i.v. twice weekly, maximum of 2 years of treatment). The study accrued 30 patients with recurrent glioblastoma, 26 were evaluable for efficacy. The 6-month progression free survival rate was 12%. Cilengitide was detected in all tumor specimens with higher levels in the group receiving 2000 mg dosing while corresponding plasma concentrations were low, often below the lower limit of detection. These results confirm drug delivery and possibly retention in tumor. This study provides evidence that with established dosing, cilengitide is adequately delivered to the tumor, although as a single agent, efficacy in recurrent glioblastoma is modest. However, these results demonstrating drug delivery to tumor do support continued investigation of this agent as preliminary results from recent studies combining cilengitide with cytotoxic therapies are promising.