Single-Arm, Multicenter Phase I/II Clinical Trial for the Treatment of Envenomings by Massive Africanized Honey Bee Stings Using the Unique Apilic Antivenom

Abstract

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].

A new therapeutic approach for bone metastasis in colorectal cancer: intratumoral melittin

“…However, after seven days of a single dose, tumors start growing again ( Figure 4D ), suggesting that intratumoral injection, once a week, may be suitable for clinical therapy. In a recent paper melittin could be detected in patients up to 30 days after envenomation [ 61 ], clearly indicating bioaccumulation corroborating the effects of the single-dose treatment. Besides, melittin has the ability to improves systemic humoral [ 59 , 62 ] and cellular immune response [ 20 ].…”

Challenges and Opportunities in Clinical Diagnostic Routine of Envenomation Using Blood Plasma Proteomics

“…However, there is no specific diagnosis or protocol for monitoring the clinical condition of patients. During the multicenter phase I/II clinical trial of the first apilic antivenom for the treatment of Africanized bee stings, several clinical and biochemical parameters were taken into account to monitor treatment and therapeutic success [ 49 , 50 ]. The laboratory findings observed included the presence of stinging at the bite sites, hemodynamic changes, respiratory disorders, elevated levels of CK, C-reactive protein (CRP), fibrinogen, alanine transaminase (ALT), and leukocytosis.…”

“…The laboratory findings observed included the presence of stinging at the bite sites, hemodynamic changes, respiratory disorders, elevated levels of CK, C-reactive protein (CRP), fibrinogen, alanine transaminase (ALT), and leukocytosis. In addition, for the first time, plasma samples from patients were analyzed by mass spectrometry, through which it was possible to identify the presence of melittin in bee venom, suggesting that this tool can be used to identify biomarkers for envenomation [ 50 ].…”

Neuroactive venom compounds obtained from Phlogiellus bundokalbo as potential leads for neurodegenerative diseases: insights on their acetylcholinesterase and beta-secretase inhibitory activities in vitro

“…Therefore, the diverse pharmacological targets of spider and other animal venoms have been medically used as drugs to modulate pain and other neurological conditions. To some extent, other animal venoms were also applied to treat hypertension, diabetes, blood coagulation, pain and envenomation, which are commercially available as drugs such as exenatide from gila monsters ( Helodema suspectum ), captopril from Brazilian pit vipers ( Bothrops jararaca ), bivalirudin from medicinal leechs ( Hirudo medicinalis ), ziconitide from the cone snails ( Conus magus ), fibrin sealant from South American rattlesnakes ( Crotalus durissus ), and apilic antivenom from melittin and PLA 2 from Africanized honeybees ( Apis mellifera) [ 1 - 9 ].…”