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Biochemistry

Treatment for bee stings

In São Paulo and Rio de Janeiro, two compounds that reduce the effects of bee venom are undergoing initial tests

Like a needle: the stinger, at the end of the abdomen, is used to inject venom when the bee (Apis sp) feels threatened

STEVE GSCHMEISSNER / SCIENCE PHOTO LIBRARY Like a needle: the stinger, at the end of the abdomen, is used to inject venom when the bee (Apis sp) feels threatened STEVE GSCHMEISSNER / SCIENCE PHOTO LIBRARY

São Paulo researchers concluded another stage of the complex attempt to produce an antidote capable of protecting the body from the harm caused by bee venom. In tests with cells grown in the laboratory and in experiments with mice, the biochemist Mario Sérgio Palma and his group at Universidade Estadual Paulista (UNESP) in Rio Claro demonstrated that the serum they developed eliminated the most frequent damage of bee stings. “We were able to neutralize 95% of the harmful effects of the venom in the mice,” says Palma.

In the tests, the mice treated with the serum survived high doses of venom, which in humans would be equivalent to hundreds of stings, as is common in serious accidents. In these situations, the compound prevented the destruction of the blood cells that carry oxygen and carbon dioxide, one of the initial effects of the venom. Composed of antibodies extracted from the blood of horses, the serum also prevented damage to muscle cells, one of the first types of cells affected by bee venom, and protected the kidneys, liver and heart of the animals from the lesions that develop within 72 hours after an attack from a swarm of bees.

These results put the Brazilian candidate antidote at a stage that apparently has not been achieved by other groups. In the 1990s, teams in England and the United States began developing compounds from the blood of sheep and rabbits, but the research did not advance. Despite recent progress, there is still a long way to go before the serum is available for use in humans. “We need to develop a serum standardization process,” says Ricardo Palacios, manager of clinical research and development at the Butantan Institute, which is helping develop the antidote.

About two years ago, Palma’s group initiated a partnership with the Butantan Institute—one of the largest producers of antidotes and vaccines in Brazil—and with collaborators at the University of São Paulo (USP), São Francisco University and the Paraná Institute of Technology, to complete all test and production stages. “We have managed to produce the serum for laboratory tests,” comments physician Fan Hui Wen, from the Butantan Institute. “The challenge now is to transfer production from the workbench to an industrial scale.”

The Butantan researchers are currently repeating the tests with cells grown in the laboratory and in mice to confirm the effectiveness and safety of the compound. On the Butantan farm, the horses that will serve as serum factories for the next tests are already being selected and immunized. If all goes well, human trials should begin within two years. Criteria for administering the antidote, based on symptom severity, must also be defined. According to Wen, in principle the serum is only expected to work against the venom of Brazilian bees, the result of the crossing of European and African species, and should not be used to treat allergies or anaphylactic reactions. “They are different manifestations, which have to be treated with different strategies.”  She explains: the antidote will be used in the event of accidents involving swarms and multiple stings—there are 15,000 accidents involving bees every year in Brazil, of which about 750 are severe and, in theory, would benefit from the serum.

Even if it is efficient in humans, the serum alone is not expected to be able to counteract all of the effects of the venom. “The serum neutralizes the action of the venom, in other words, the cause of the damage,” explains Wen. “So the sooner it is administered, the less venom there will be in the blood.”  But, she concludes, the serum is not expected to eliminate the need for anti-inflammatories, antihistamines and other medications to combat the damage the tissues have already suffered.

Broad protection
Getting to this point was not simple. Palma and his team had to start by examining the unique elements in bee venom. In prior studies, researchers tried to imitate the chemical characteristics of the antidotes for snake bites. The two types of venom, however, have different purposes: snake venom paralyzes or kills prey that serve as food, while that of bees acts as a defense against the threat of a possible predator. Similarly, the effects of each venom are different. “A bee sting does not cause bleeding or gangrene,” explains Palma.

The next task was to identify the active molecules in bee venom and their possible effects (swelling, redness, muscle aches). Given that information, one can create an antidote with broad protection, with antibodies that neutralize each protein or peptide.

In parallel, at the Federal University of Rio de Janeiro (UFRJ), Paulo Melo’s team noted that a drug called suramin can help block the effects of bee venom. Developed almost a century ago, suramin is used to combat certain parasites and alleviates the effect of snake bites. The UFRJ tests were performed with cell cultures, isolated tissues and subsequently with mice, which received lethal doses of bee venom and then suramin. “We neutralized muscle lesions and swelling,” says Melo. He believes that suramin could be used as a complement to the serum developed by Unesp and the Butantan Institute, or as an isolated therapy if the patient is allergic to animal-based serums.

“In studies of this nature there are always scientific, technological and regulatory bottlenecks that must be overcome. But, if everything works out, Brazil, which is already a world leader in the production of various antidotes, may also become known for its expertise in treating accidents involving bees,” says Jorge Kalil, director of the Butantan Institute. He says that the Brazilian consortium that developed the bee venom antidote has already been contacted by a company that wants to put it on the market in the United States as soon as it is ready and approved.

Project
System biology as an experimental strategy for the discovery of novel natural products in the fauna of Venomous Arthropods in the State of São Paulo (No. 2011/51684-1); Grant Mechanism Thematic Project; Principal Investigator Mario Sérgio Palma – Unesp; Investment R$ 2,207,081.76 (Fapesp) and R$1,530,000.00 (CNPq and Finep)

Scientific articles
SANTOS, K.S. et al. Production of the first effective hyperimmune equine serum antivenom against africanized bees. PLOS One. Nov. 13, 2013.
EL-KIK, C.Z. et al. Neutralization of Apis mellifera bee venom activities by suramin. Toxicon. v. 1 (67), p. 55-62. 2013.

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