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Massive, Africanized honeybee attacks have increased in Brazil over the years. Humans and animals present local and systemic effects after envenomation, and there is no specific treatment for this potentially lethal event. This study evaluated the ability of a new ApilicApilic antivenom, which is composed of F(ab&rsquo, )2 fraction of specific immunoglobulins in heterologous and hyperimmune equine serum, to neutralize A. mellifera venom and melittin, in vitro and in vivo, in mice. Animal experiments were performed in according with local ethics committee license (UFRJ protocol no. DFBCICB072-04/16). Venom dose-dependent lethality was diminished with 0.25&ndash, 0.5 &mu, L of intravenous ApilicApilic antivenom/&mu, g honeybee venom. In vivo injection of 0.1&ndash, 1 &mu, g/g bee venom induced myotoxicity, hemoconcentration, paw edema, and increase of vascular permeability which were antagonized by ApilicApilic antivenom. Cytotoxicity, assessed in renal LLC-PK1 cells and challenged with 10 &mu, g/mL honeybee venom or melittin, was neutralized by preincubation with ApilicApilic antivenom, as well the hemolytic activity. Apilic antivenom inhibited phospholipase and hyaluronidase enzymatic activities. In flow cytometry experiments, ApilicApilic antivenom neutralized reduction of cell viability due to necrosis by honeybee venom or melittin. These results showed that this antivenom is effective inhibitor of honeybee venom actions. Thus, this next generation of ApilicApilic antivenom emerges as a new promising immunobiological product for the treatment of massive, Africanized honeybee attacks.

Made available in DSpace on 2018-12-11T17:10:38Z (GMT). No. of bitstreams: 0 Previous issue date: 2017-03-16. Added 1 bitstream(s) on 2021-07-15T15:21:48Z : No. of bitstreams: 1 S1678-91992017000100309.pdf: 628343 bytes, checksum: 154f2f153e36ae6b7b781823c75a2ab4 (MD5) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Background: Envenomation caused by multiple stings from Africanized honeybees Apis mellifera constitutes a public health problem in the Americas. In 2015, the Brazilian Ministry of Health reported 13,597 accidents (incidence of seven cases per 100,000 inhabitants) with 39 deaths (lethality of 0.25%). The toxins present in the venom, which include melittin and phospholipase A2, cause lesions in diverse organs and systems that may be fatal. As there has been no specific treatment to date, management has been symptomatic and supportive only. Methods: In order to evaluate the safety and neutralizing capacity of a new apilic antivenom, as well as to confirm its lowest effective dose, a clinical protocol was developed to be applied in a multicenter, non-randomized and open phase I/II clinical trial. Twenty participants with more than five stings, aged more than 18 years, of both sexes, who have not previously received the heterologous serum against bee stings, will be included for 24 months. The proposed dose was based on the antivenom neutralizing capacity and the number of stings. Treatment will be administered only in a hospital environment and the participants will be evaluated for a period up to 30 days after discharge for clinical and laboratory follow-up. Results: This protocol, approved by the Brazilian regulatory agencies for ethics (National Commission for Ethics on Research - CONEP) and sanitation (National Health Surveillance Agency - ANVISA), is a guideline constituted by specific, adjuvant, symptomatic and complementary treatments, in addition to basic orientations for conducting a clinical trial involving heterologous sera. Conclusions: This is the first clinical trial protocol designed specifically to evaluate the preliminary efficacy and safety of a new antivenom against stings from the Africanized honeybee Apis mellifera. The results will support future studies to confirm a new treatment for massive bee attack that has a large impact on public health in the Americas. São Paulo State University (UNESP - Univ Estadual Paulista) Department of Tropical Diseases Botucatu Medical School University of Arizona College of Medicine VIPER Institute Université d'Abomey-Calavi CERPAGE Faculté des Sciences de la Santé Université Paris Descartes UMR216 Mère et enfant face aux infections tropicales and PRES Sorbonne Paris Cité Faculté de Pharmacie São Paulo State University (UNESP - Univ Estadual Paulista) Clinical Research Unit (UPECLIN) Botucatu Medical School São Paulo State University (UNESP - Univ Estadual Paulista) Department of Internal Medicine Botucatu Medical School São Paulo State University (UNESP - Univ Estadual Paulista) Center for the Study of Venoms and Venomous Animals, Av. Jose Barbosa Barros, 1780,Fazenda Experimental Lageado São Paulo State University (UNESP - Univ Estadual Paulista) Department of Tropical Diseases Botucatu Medical School São Paulo State University (UNESP - Univ Estadual Paulista) Clinical Research Unit (UPECLIN) Botucatu Medical School São Paulo State University (UNESP - Univ Estadual Paulista) Department of Internal Medicine Botucatu Medical School São Paulo State University (UNESP - Univ Estadual Paulista) Center for the Study of Venoms and Venomous Animals, Av. Jose Barbosa Barros, 1780,Fazenda Experimental Lageado FAPESP: 2012/23466-2

Background: Envenomation caused by multiple stings from Africanized honeybees Apis mellifera constitutes a public health problem in the Americas. In 2015, the Brazilian Ministry of Health reported 13,597 accidents (incidence of seven cases per 100,000 inhabitants) with 39 deaths (lethality of 0.25%). The toxins present in the venom, which include melittin and phospholipase A(2), cause lesions in diverse organs and systems that may be fatal. As there has been no specific treatment to date, management has been symptomatic and supportive only. Methods: In order to evaluate the safety and neutralizing capacity of a new apilic antivenom, as well as to confirm its lowest effective dose, a clinical protocol was developed to be applied in a multicenter, non-randomized and open phase I/II clinical trial. Twenty participants with more than five stings, aged more than 18 years, of both sexes, who have not previously received the heterologous serum against bee stings, will be included for 24 months. The proposed dose was based on the antivenom neutralizing capacity and the number of stings. Treatment will be administered only in a hospital environment and the participants will be evaluated for a period up to 30 days after discharge for clinical and laboratory follow-up. Results: This protocol, approved by the Brazilian regulatory agencies for ethics (National Commission for Ethics on Research-CONEP) and sanitation (National Health Surveillance Agency-ANVISA), is a guideline constituted by specific, adjuvant, symptomatic and complementary treatments, in addition to basic orientations for conducting a clinical trial involving heterologous sera. Conclusions: This is the first clinical trial protocol designed specifically to evaluate the preliminary efficacy and safety of a new antivenom against stings from the Africanized honeybee Apis mellifera. The results will support future studies to confirm a new treatment for massive bee attack that has a large impact on public health in the Americas.