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Development and characterization of two equine formulations towards SARS-CoV-2 proteins for the potential treatment of COVID-19
(2021-05-10) León Montero, Guillermo; Herrera Vega, María; Vargas Arroyo, Mariángela; Arguedas Gómez, Mauricio José; Sánchez Brenes, Andrés; Segura Ruiz, Álvaro; Gómez Argüello, Aarón; Solano Blanco, Gabriela; Corrales Aguilar, Eugenia; Risner, Kenneth; Narayanan, Aarthi; Bailey, Charles; Villalta Arrieta, Mauren; Hernández Bolaños, Andrés; Sánchez Sánchez, Adriana; Cordero Vasquez, Daniel; Solano Centeno, Daniela; Durán Blanco, Gina; Segura Agüero, Eduardo; Cerdas Solís, Maykel; Umaña Blanco, Deibid; Moscoso Suárez, Edwin; Estrada Umaña, Ricardo; Gutiérrez González, Jairo; Méndez Alvaro, Marcos; Castillo Mora, Ana Cecilia; Sánchez Céspedez, Laura; Sánchez Porras, Ronald; Gutiérrez, José María; Díaz Oreiro, Cecilia; Alape Girón, Alberto
In the current global emergency due to SARS-CoV-2 outbreak, passive immunotherapy emerges as a promising treatment for COVID-19. Among animal-derived products, equine formulations are still the cornerstone therapy for treating envenomations due to animal bites and stings. Therefore, drawing upon decades of experience in manufacturing snake antivenom, we developed and preclinically evaluated two anti-SARS-CoV-2 polyclonal equine formulations as potential alternative therapy for COVID-19. We immunized two groups of horses with either S1 (anti-S1) or a mixture of S1, N, and SEM mosaic (anti-Mix) viral recombinant proteins. Horses reached a maximum anti-viral antibody level at 7 weeks following priming, and showed no major adverse acute or chronic clinical alterations. Two whole-IgG formulations were prepared via hyperimmune plasma precipitation with caprylic acid and then formulated for parenteral use. Both preparations had similar physicochemical and microbiological quality and showed ELISA immunoreactivity towards S1 protein and the receptor binding domain (RBD). The anti-Mix formulation also presented immunoreactivity against N protein. Due to high anti-S1 and anti-RBD antibody content, final products exhibited high in vitro neutralizing capacity of SARS-CoV-2 infection, 80 times higher than a pool of human convalescent plasma. Pre-clinical quality profiles were similar among both products, but clinical efficacy and safety must be tested in clinical trials. The technological strategy we describe here can be adapted by other producers, particularly in low- and middle-income countries.
Viperid envenomation wound exudate contributes to increased vascular permeability via a DAMPs/TLR-4 mediated pathway
(2016-11-24) Rucavado Romero, Alexandra; Nicolau, Carolina; Escalante Muñoz, Teresa; Kim, Junho; Herrera Arias, Cristina; Gutiérrez, José María; Fox, Jay W.
Viperid snakebite envenomation is characterized by inflammatory events including increase in vascular permeability. A copious exudate is generated in tissue injected with venom, whose proteomics analysis has provided insights into the mechanisms of venom-induced tissue damage. Hereby it is reported that wound exudate itself has the ability to induce increase in vascular permeability in the skin of mice. Proteomics analysis of exudate revealed the presence of cytokines and chemokines, together with abundant damage associated molecular pattern molecules (DAMPs) resulting from both proteolysis of extracellular matrix and cellular lysis. Moreover, significant differences in the amounts of cytokines/chemokines and DAMPs were detected between exudates collected 1 h and 24 h after envenomation, thus highlighting a complex temporal dynamic in the composition of exudate. Pretreatment of mice with Eritoran, an antagonist of Toll-like receptor 4 (TLR4), significantly reduced the exudate-induced increase in vascular permeability, thus suggesting that DAMPs might be acting through this receptor. It is hypothesized that an “Envenomation-induced DAMPs cycle of tissue damage” may be operating in viperid snakebite envenomation through which venom-induced tissue damage generates a variety of DAMPs which may further expand tissue alterations.
Snakebite envenomation in the Caribbean: the role of medical and scientific cooperation
(2018-07-12) Resiere, Dabor; Mehdaoui, Hossein; Gutiérrez, José María
Snakebite envenomation by viperid species constitutes a significant public health problem in the Caribbean, causing local tissue damage, systemic complications, and in some cases, severe thrombotic events. Despite being a neglected tropical disease recently recognized by the WHO, snakebite management is hampered by limited access to antivenoms in several countries, leading to high morbidity and mortality. This review emphasizes the urgent need for a coordinated regional strategy to reduce the burden of envenomations, which should include scientific research on venom biology, preclinical evaluation of antivenoms, epidemiological studies, culturally tailored prevention programs, clinical investigations, health professional training, community education, and the establishment of poison control centers. Additionally, socioeconomic, ecological, and cultural factors affecting snake populations and human interactions must be addressed. Strengthening regional scientific and medical cooperation is essential for improving snakebite management, safeguarding public health, and promoting the conservation and study of venomous snakes as part of the Caribbean’s natural heritage.
Oral microbiota of the snake Bothrops lanceolatus in Martinique
(2018-09-27) Resiere, Dabor; Olive, Claude; Kallel, Hatem; Cabié, André; Neviere, Remi; Mégarbane, Bruno; Gutiérrez, José María; Mehdaoui, Hossein
In Martinique, Bothrops lanceolatus snakebite, although relatively uncommon (~30 cases/year), may result in serious complications such as systemic thrombosis and local infections. Infections have been hypothesized to be related to bacteria present in the snake’s oral cavity. In this investigation, we isolated, identified, and studied the susceptibility to beta-lactams of bacteria sampled from the oral cavity of twenty-six B. lanceolatus specimens collected from various areas in Martinique. Microbiota from B. lanceolatus oral cavity was polymicrobial. Isolated bacteria belonged to fifteen different taxa; the most frequent being Aeromonas hydrophyla (present in 50% of the samples), Morganella morganii, Klebsiella pneumoniae, Bacillus spp., and Enterococcus spp. Analysis of antibiotic susceptibility revealed that 66.7% of the isolated bacteria were resistant to amoxicillin/clavulanate. In contrast, the majority of isolated bacteria were susceptible to the third-generation cephalosporins (i.e., 73.3% with cefotaxime and 80.0% with ceftazidime). Microbiota from B. lanceolatus oral cavity is polymicrobial with bacteria mostly susceptible to third-generation cephalosporins but rarely to amoxicillin/clavulanate. In conclusion, our findings clearly support that first-line antibiotic therapy in the B. lanceolatus-bitten patients, when there is evidence of infection, should include a third-generation cephalosporin rather than amoxicillin/clavulanate.
Concurrent training increases serum brain-derived neurotrophic factor in older adults regardless of the exercise frequency
(2022-03-06) Canton Martínez, Ermilo; Rentería, Iván; García Suárez, Patricia Concepción; Moncada Jiménez, José; Machado Parra, Juan Pablo; Santos de Lira, Fábio; Johnson, David K.; Jiménez Maldonado, Alberto
Background: Human brain function declines with aging. In this sense, exercise-based interventions has a promising effect on brain plasticity for older adults. Serum brain-derived neurotrophic factor (BDNF) is a positive biomarker for brain neuroplasticity in healthy older adults also modified by exercise training. Selected features of the exercise prescription for improving brain health are missing; therefore, the aim of this study was to determine the effects of concurrent exercise training frequency on serum BDNF levels in healthy older adults. Methods: Nineteen volunteers (age: 65 ± 4 year; body mass index: 28.0 ± 4.5 kg/m2) completed either a three times/week (3-t/w) (n = 8) or five times/week (5-t/w) (n = 11) concurrent exercise program. The exercise program lasted 11 weeks and all exercise sessions were performed for 50 min at moderate intensity. Serum BDNF, body composition, cardiovascular, and physical fitness variables were assessed before and after the exercise training program. Results: Regardless of the group, the serum BDNF increased following the intervention (p < 0.001), and there were no significant group (p = 0.827) or interaction (p = 0.063) effects. The maximal oxygen consumption (VO2max) increased regardless of the group (p = 0.007), with a non-significant group (p = 0.722) or interaction (p = 0.223) effects. Upper- and lower-body strength increased in both groups (p = 0.003); however, there was no effect of the training frequency (p = 0.53). For the skeletal muscle mass, there was a trend in the interaction effect (p = 0.053). Finally, the body fat percentage was unchanged. Conclusion: Eleven weeks of combined exercise training increased serum BDNF levels in healthy older adults, a response independent of the training frequency. The overall fitness level improved similarly in both exercise groups. These data reveal that a minimal dosage of concurrent exercise enhance functional capacity and a brain health biomarker in older adults.