Single-arm, multicenter phase I/II clinical trial for the treatment of envenomings by massive africanized honey bee stings using the unique apilic antivenom

We evaluated the safety, optimal dose, and preliminary effectiveness of a new-approach Africanized honeybee (Apis mellifera) Antivenom (AAV) in a phase I/II, multicenter, non-randomized, single-arm clinical trial involving 20 participants with multiple stings. Participants received 2 to 10 vials of AAV depending on the number of stings they suffered, or a predefined adjuvant, symptomatic, and complementary treatment. The primary safety endpoint was the occurrence of early adverse reactions within the first 24 h of treatment. Preliminary efficacy based on clinical evolution, including laboratory findings, was assessed at baseline and at various time points over the four following weeks. ELISA assays and mass spectrometry were used to estimate venom pharmacokinetics before, during, and after treatment. Twenty adult participants, i.e., 13 (65%) men and 7 (35%) women, with a median age of 44 years and a mean body surface area of 1.92 m2 (median = 1.93 m2) were recruited. The number of stings ranged from 7 to > 2,000, with a median of 52.5. Symptoms of envenoming were classified as mild, moderate, or severe in 80% (16), 15% (3), and 5% (1) of patients, respectively; patients with mild, moderate, or severe envenoming received 2, 6, and 10 vials of AAV as per the protocol. None of the patients had late reactions (serum sickness) within 30 d of treatment. There was no discontinuation of the protocol due to adverse events, and there were no serious adverse events. One patient had a moderate adverse event, transient itchy skin, and erythroderma. All participants completed the intravenous antivenom infusion within 2 h, and there was no loss to follow-up after discharge. ELISA assays showed venom (melittin and PLA2) concentrations varying between 0.25 and 1.479 ng/mL prior to treatment. Venom levels decreased in all patients during the hospitalization period. Surprisingly, in nine cases (45%), despite clinical recovery and the absence of symptoms, venom levels increased again during outpatient care 10 d after discharge. Mass spectrometry showed melittin in eight participants, 30 d after treatment. Considering the promising safety results for this investigational product in the treatment of massive Africanized honeybee attack, and its efficacy, reflected in the clinical improvements and corresponding immediate decrease in blood venom levels, the AAV has shown to be safe for human use. Clinical Trial Registration: UTN: U1111-1160-7011, identifier [RBR-3fthf8].

Human platelet antigen-3 polymorphism as a risk factor for rheumatological manifestations in hepatitis C

Abstract INTRODUCTION: Hepatitis C virus (HCV) infection is involved in the pathogenesis of autoimmune and rheumatic disorders. Although the human platelet antigens (HPA) polymorphism are associated with HCV persistence, they have not been investigated in rheumatological manifestations (RM). This study focused on verifying associations between allele and genotype HPA and RM in patients with chronic hepatitis C. METHODS: Patients (159) with chronic hepatitis C of both genders were analyzed. RESULTS: Women showed association between HPA-3 polymorphisms and RM. CONCLUSIONS: An unprecedented strong association between rheumatological manifestations and HPA-3 polymorphism, possibly predisposing women to complications during the disease course, was observed.

A clinical trial protocol to treat massive Africanized honeybee (Apis mellifera) attack with a new apilic antivenom

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.(AU)

A clinical trial protocol to treat massive Africanized honeybee (Apis mellifera) attack with a new apilic antivenom

Abstract 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.

Análise de associações de polimorfismos HPA, indicadores de autoimunidade e manifestações reumatológicas na Hepatite C / Associations analysis HPA polymorphism, autoimmunity indicators and rheumatologic manifestatios in Hepatitis C

A Hepatite C tem sido associada a várias manifestações extra-hepáticas como comprometimento articular. Em 90 pacientes VHC positivos, foram encontradas manifestações reumatológicas em 31%. A artralgia é mais comum, porém a artrite aparece em 4% dos casos. Clinicamente, a artrite relacionada ao VHC, pode ser indistinguível da artrite tradicional e a maioria dos doentes cumprem com os critérios diagnósticos para a doença preconizados pelo Colégio Americano de Reumatologia (ACR), tornando-se um desafio diagnóstico. O fator reumatóide e as crioglobulinas são os autoanticorpos mais presentes em cerca de 40% a 70% dos pacientes com VHC, portanto não auxiliam no diagnóstico diferencial . Anticorpos antipeptídeo citrulinado cíclico (anti-ccp), são considerados anticorpos com grande especificidade e sensibilidade para AR, assim, são capazes de distinguir atrite relacionada ao vírus e AR. Fatores genéticos do hospedeiro também foram associados à infecção pelo VHC, como os polimorfismos dos antígenos plaquetários humanos (HPAs). A avaliação de polimorfismos genéticos pode ser útil na identificação de maior suscetibilidade dos indivíduos infectados ao desenvolvimento de manifestações reumatológicas e/ou de alguns desses serem indicativos de um curso mais grave da doença. Assim, o objetivo deste estudo foi verificar possíveis associações de indicadores de autoimunidade e polimorfismos do HPA com manifestações reumatológicas em pacientes com Hepatite C...

Hepatitis C has been associated with various extrahepatic manifestations such as joint involvement. In 90 HCV positive patients, rheumatological manifestations were found in 31%. Arthralgia is the most common, however the arthritis appears in 4% of the cases. Clinically, HCV related to arthritis may be indistinguishable from RA, since the majority of patients fulfilling the criteria of the American College of Rheumatology for the diagnosis of RA, making it diagnostic challenge. The rheumatoid factor and crioglobulines may be present in about 40 to 70% of patients with chronic HCV, which does not help in the differential diagnosis. The cyclic citrullinated peptide antibodies (anti-CCP) are considered good markers for RA, due to their high specificity and sensitivity, they can be useful in distinguishing between HCV arthritis and RA. The genetic factors of the host were also related to virus C infection like polymorphisms of human platelet antigens (HPAs). The evaluation of these genetic polymorphisms may reflect greater susceptibility to rheumatological manifestations and/or one of them be indicative of a more severe disease. So the goal of this study was evaluate possible associations of autoimmunity indicators and HPA polymorphisms with rheumatological manifestations in patients with Hepatitis C...