Bee Venom

Scientific Name(s):Derived from Apis mellifera

Common Name(s): Bee venom , honeybee venom

Uses

Bee venom is used to hyposensitize individuals highly sensitive to bee stings. There is some evidence that it might also help inhibit or suppress arthritis and multiple sclerosis.

Dosing

There is no recent clinical evidence to guide dosage of bee venom.

Contraindications

Contraindications have not been identified.

Pregnancy/Lactation

Documented adverse reactions. Avoid use.

Interactions

None well documented.

Adverse Reactions

Various adverse reactions may occur to bee venom, the severity of which depends on the number of stings sustained.

Toxicology

A single bee sting can produce anaphylaxis in sensitive individuals. Regardless of history, monitor any patient with multiple stings.

Honeybee venom is obtained from A. mellifera , the common honeybee. Other venoms are derived from related members of the hymenoptera.

History

Anaphylaxis to insect stings is a relatively uncommon problem, affecting approximately 0.4% of the general United States population. It is the cause of an estimated 40 deaths per year in the United States. 1

The allergic reactions are mediated by immunoglobulin E (IgE) antibodies directed at constituents of honeybee, yellow jacket, hornet, and wasp venoms. In order to minimize allergic reactions, hyposensitization immunotherapy techniques have been developed in which small doses of the venom are administered under controlled conditions over a period of months to years. Patients allergic to honeybee venom may be particularly sensitive to hymenoptera venoms in general and have been found to be at a higher risk of developing systemic adverse reactions to venom immunotherapy than patients who are sensitive to yellow jacket venom. 2

More recently, it has been suggested that honeybee venom may alleviate the symptoms and slow the progression of immune-modulated diseases such as arthritis and multiple sclerosis.

Chemistry

Bee venoms are complex mixtures of enzymes and polysaccharides. They are collected from the insects and diluted to standardized concentrations. Melittin, a phospholipase activating protein in bee venom, has been shown to induce neutrophil degranulation 3 and to increase 3 or inhibit 4 the formation of superoxide. This variation in activity appears to depend upon the test method employed. Melittin induces neutrophil degranulation with subsequent superoxide formation in vitro 3 ; however, melittin binds to calmodulin, an effect associated with inhibition of superoxide production. 4

The polypeptide adolapin isolated from bee venom inhibits inflammation (carrageenan, prostaglandin, and adjuvant rat paw edema models) and appears to inhibit the prostaglandin synthase systems. 5

Uses and Pharmacology

Immunotherapy

Hypersensitivity to honeybee venom is mediated by a number of antibodies and immunomodulators, the most important of which appears to be IgE. Venom immunotherapy (VIT) reduces the likelihood of systemic response in patients with systemic allergic reactions to insect venom. Criteria to precisely identify the point in time when protection becomes persistent are unknown. In addition, despite the remote possibility of severe reaction, the supervised sting challenge test is the only current method for evaluating the efficacy of VIT. The identification of markers that can be used to predict protection is needed. 6

Animal data

No animal data exist regarding the use of bee venom in immunotherapy.

Clinical data

The infusion of beekeepers' plasma has been shown to protect patients against systemic reactions that can occur during active immunotherapy. 7 Following infusion of this plasma, a decrease in the sensitivity to honeybee venom has been noted; in one study, this was accompanied by increases in the levels of anti-idiotypic antibodies and decreases in specific antibodies to honeybee venom (immunoglobulin G and E). The study was conducted over a 76-week period of immunotherapy with the venom. These findings suggest that several mechanisms play an interrelated role in the development of immunity to honeybee venom. An upregulation of osteopontin expression associated with successful VIT has been reported, suggesting a potential role of osteopontin as a biomarker in VIT. In addition to its known regulatory role in bone metabolism, osteopontin has been postulated to be a T H 1 cytokine and is involved in T H 1-associated immune responses. 6

Arthritis therapy

It has been speculated that honeybee venom may prevent the development of or improve the status of patients with rheumatoid arthritis. This conclusion is based largely on anecdotal observations of a general lack of arthritis among beekeepers stung routinely during their lifetimes. In one survey of a random sampling of the general population, 83% of respondents believed that bee venom could be an effective treatment for arthritis based on information they had read in the lay press. 8

Animal data

Honeybee venom administered to rats with adjuvant arthritis resulted in a suppression of the disease. 9 Melittin has blocked the production of superoxide and hydrogen peroxide in human neutrophils. Melittin and other agents that bind calmodulin have decreased superoxide production. An elevated superoxide level has been suggested as a possible cause of oxidative damage to synovial fluid and other joint membranes. Therefore, agents that decrease the production of the superoxide may prevent or halt the progression of inflammatory diseases such as arthritis. Also, honeybee venom has decreased the production of the inflammatory mediator interleukin-1 in rat splenocytes. Honeybee venom treatment of rats with adjuvant arthritis inhibits certain macrophage activities and, thus, indirectly inhibits the activation of T and B cells. 10

Treatment with bee venom resulted in a reduction of tissue swelling and osteophyte formation in a model of chronic arthritis, as well as reduction of edema formation in a model of acute arthritis. 1

Bee venom inhibited lipopolysaccharide-induced prostaglandin E 2 and nitric oxide production in Raw 264.7 cells. The inhibitory actions of bee venom on the generation of inflammation mediators were also effective in synoviocytes from rheumatoid arthritis patients. The inhibitory effect of bee venom was consistent with that of indomethacin. 11

Clinical data

There is no clinical data regarding the use of bee venom to treat arthritis.

Multiple sclerosis (MS)

Uses for bee venom, although poorly substantiated, include the treatment of diseases of the locomotor system, 12 particularly MS. Despite widespread anecdotal reports, there is no scientific consensus as to the safety and effectiveness of bee venom in the management of this disorder. 13

Animal data

No animal data exist regarding the use of bee venom in MS.

Clinical data

In a study of 26 patients with relapsing-remitting or relapsing secondary progressive MS, bee sting therapy had no effect on disease activity as measured using gadolinium-enhanced magnetic resonance imaging of the brain. 13

Anti-inflammatory effects
Animal data

In a study using the mouse air pouch model, dilute bee venom (dBV) treatment produced a potent anti-inflammatory effect, as indicated by a marked reduction in leukocyte migration compared with that of saline pre-treatment.

Dilute bee venom's anti-inflammatory effect (dBVAI) is reversed by intrathecal pretreatment with atropine but not with hexamtehonium, indicating that dBV stimulated an increase in spinal acetylcholine, specifically activating spinal muscarinic receptors.

Intrathecal administration of a muscarinic type 2 (M 2 ) receptor antagonist (methoctramine), but not M 1 or M 3 receptor antagonists, abolished dBVAI, indicating that spinal M 2 receptors are specifically involved in dBVAI. 14

Systemic pretreatment with the beta-adrenergic receptor antagonist propranolol, but not the corticosteroid antagonist RU-486, inhibited dBVAI. This suggests that dBVAI is meditated by adrenal medullary catecholamines acting through beta-adrenoreceptors expressed by immune cells and that it is not dependent on corticosteroid release from the adrenal cortex. 15 A study in mice demonstrated that bee venom-induced anti-inflammatory effect is dependent on activation of capsaicin-insensitive primary afferent fibers and the central noradrenergic system, including the locus coeruleus.

These findings demonstrate the complex nature of the neuroimmune interactions that underlie the anti-inflammatory effect produced by subcutaneous bee venom administration.

Transection of the sciatic nerve completely eliminated BVAI on zymosan-induced inflammation, indicating that BVAI is dependent on peripheral nerve integrity and is not a locally mediated anti-inflammatory effect. 16

A study in Sprague-Dawley rats showed that sciatic nerve transaction, L4-L6 dorsal rhizotomy, and local treatment of the sciatic nerve with capsaicin produced a depression of subcutaneous injection of bee venom-induced inflammation, indicating that neurogenic components are involved in the bee venom-induced inflammatory response. Dorsal root reflex together with axon reflex conducted by capsaicin-sensitive primary afferents are the potential mechanisms underlying the generation of neurogenic inflammation.

It is further suggested that capsaicin-sensitive primary afferents may play differential roles in the development of dynamic and static mechanical allodynia in the bee venom test. 17

Clinical data

There is no clinical data regarding the use of bee venom to treat inflammation.

Other uses

A study of bee venom-induced apoptosis in human U937 leukemic cells showed that cells treated with more than 2 mcg/mL displayed a dose-dependent inhibition of proliferation, cell shrinkage, and nuclear condensation.

These results suggest that bee venom-induced apoptosis contributes to growth inhibition of U937 cells. Bee venom-induced apoptic cell death was accompanied by activation of caspase-3, caspase-8, and caspase-9, and subsequently upregulated cleavage of polyadenosine diphosphate-ribose polymerase. During apoptosis, caspase-3 is essential for the execution of cell death in response to various stimuli.

Bee venom also down-regulated antiapoptotic proteins such as Bcl-2. Moreover, down regulation of extracellular signal-regulated kinase and Akt may have an important role in bee venom-induced apoptosis. 18

Bee venom stimulation of the zusanli acupoint produced a antinociceptive effect in the second phase of the fomalin test that involves spinal neuronal transmission without detectable nociceptive behavior.

Peripheral capsaicin insensitive primary afferents were primarily involved in activating central catecholaminergic pathways associated with bee venom's antinoiceptive effect. 19

Dosage

There is no recent clinical evidence to guide dosage of bee venom.

Pregnancy/Lactation

Documented adverse reactions. Avoid use.

Interactions

None well documented.

Adverse Reactions

Immediate effects after multiple stings include localized pain, swelling, and erythema at individual sting sites. Stings to the eyes can result in corneal edema and ulceration. When bees are swallowed, life-threatening pharyngeal edema and respiratory obstruction may occur. Early systemic symptoms after large-volume envenomation include fatigue, dizziness, nausea, vomiting, and diarrhea. Within 24 hours, hemolysis, hemoglobinuria, rhabdomyolysis, and hepatic transaminase enzyme elevations may develop. Subendocardial damage and cardiac enzyme elevations seen in human case reports and animal studies may result from direct venom effects in the absence of anaphylaxis and hypotension. Renal insufficiency and electrolyte abnormalities such as hyperkalemia may occur secondary to rhabdomyolysis, hemolysis, and acute tubular necrosis. Nonanaphylactic responses to multiple stings often will be apparent within the first several hours; however, severe systemic signs and symptoms have been delayed for up to 24 hours or more. 20

Toxicology

Bee stings cause human reactions in 2 distinct patterns. One or a few stings may induce allergic responses that are sometimes severe or fatal. On the other hand, massive attacks with hundreds to thousands of stings can cause severe systemic injury affecting many different organs, resulting in high mortality. Melittin has been shown to be the main lethal component in bee venom.

Signs and symptoms of multiple stings include urticaria (hives), nausea, vomiting, diarrhea, hypotension, confusion, seizures, and renal failure. Treatment is supportive, with attention to blood pressure, renal function, and maintenance of an open airway. Stingers should be removed with gentle scraping to prevent further venom injection. 21 Mass inoculation of bee venom may induce acute renal failure (ARF), adult respiratory distress syndrome, liver injury, cardiac damage, pancreatitis, skin necrosis, shock hypertension, bleeding, thrombocytopenia, hemolysis, and rhabdomyolysis. Bee venom-induced ARF after multiple stinging has been sporadically reported in Europe, Africa, and Asia. 22

Animal studies have shown a decrease in glomerular filtration rate and urinary volume after bee venom infusion. In the same way, venom caused a sharp and immediate decrease in renal blood flow. Experimental injection of bee venom caused a reaction similar to that observed in patients with bee venom-induced ARF. 22

Because cardiac levels of noradrenaline have increased dramatically in animals following bee venom injection, it is suggested that all patients, regardless of sensitivity history, have cardiac monitoring if they are victims of multiple bee stings. 23 Rare cases of anuria and rhabdomyolysis/rhabdomyonecrosis have been reported. 24 , 25

Bibliography

1. Reisman RE . Stinging insect allergy . Med Clin North Am . 1992;76(4):883-894.
2. Muller U , Helbling A , Berchtold E . Immunotherapy with honeybee venom and yellow jacket venom is different regarding efficacy and safety . J Allergy Clin Immunol . 1992;89(2):529-535.
3. Bomalaski JS , Baker D , Resurreccion NV , Clark MA . Rheumatoid arthritis synovial fluid phospholipase A2 activating protein (PLAP) stimulates human neutrophil degranulation and superoxide ion production . Agents Actions . 1989;27(3-4):425-427.
4. Somerfield SD , Stach JL , Mraz C , Gervais F , Skamene E . Bee venom melittin blocks neutrophil O2- production . Inflammation . 1986;10(2):175-182.
5. Shkenderov S , Koburova K . Adolapin--a newly isolated analgetic and anti-inflammatory polypeptide from bee venom . Toxicon . 1982;20(1):317-321.
6. Konno S , Golden DB , Schroeder J , Hamilton RG , Lichtenstein LM , Huang SK . Increased expression of osteopontin is associated with long-term bee venom immunotherapy . J Allergy Clin Immunol . 2005;115(5):1063-1067.
7. Boutin Y , Jobin M , Bedard PM , Hebert M , Hebert J . Possible dual role of anti-idiotypic antibodies in combined passive and active immunotherapy in honeybee sting allergy . J Allergy Clin Immunol . 1994;93(6):1039-1046.
8. Price JH , Hillman KS , Toral ME , Newell S . The public's perceptions and misperceptions of arthritis . Arthritis Rheum . 1983;26(8):1023-1028.
9. Yiangou M , Konidaris C , Victoratos P , Hadjipetrou-Kourounakis L . Modulation of alpha 1-acid glycoprotein (AGP) gene induction following honey bee venom administration to adjuvant arthritic (AA) rats; possible role of AGP on AA development . Clin Exp Immunol . 1993;94(1):156-162.
10. Hadjipetrou-Kourounakis L , Yiangou M . Bee venom, adjuvant induced disease and interleukin production . J Rheumatol . 1988;15(7):1126-1128.
11. Park HJ , Lee SH , Son DJ , et al. Antiarthritic effect of bee venom: inhibition of inflammation mediator generation by suppression of NF-kappaB through interaction with the p50 subunit . Arthritis Rheum .2004;50(11):3504-3515.
12. Mund-Hoym WD . Bee venom containing Forapin in the treatment of mesenchymal diseases of the locomotor system. Report on treatment results in 211 patients [in German] . Med Welt . 1982;33(34):1174-1177.
13. Wesselius T , Heersema DJ , Mostert JP , et al. A randomized crossover study of bee sting therapy for multiple sclerosis . Neurology . 2005;65(11):1764-1768.
14. Yoon SY , Kim HW , Roh DH , et al. The anti-inflammatory effect of peripheral bee venom stimulation is mediated by central muscarinic type 2 receptors and activation of sympathetic preganglionic neurons . Brain Res . 2005;1049(2):210-216.
15. Kwon YB , Kim HW , Ham TW , et al. The anti-inflammatory effect of bee venom stimulation in a mouse air pouch model is mediated by adrenal medullary activity . J Neuroendocrinol . 2003;15(1):93-96.
16. Kwon YB , Yoon SY , Kim HW , et al. Substantial role of locus coeruleus-noradrenergic activation and capsaicin-insensitive primary afferent fibers in bee venom's anti-inflammatory effect . Neurosci Res . 2006;55(2):197-203.
17. Chen HS , Lei J , He X , et al. Pivotal involvement of neurogenic mechanism in subcutaneous bee venom-induced inflammation and allodynia in unanesthetized conscious rats . Exp Neurol . 2006;200(2):386-391.
18. Moon DO , Park SY , Heo MS , et al. Key regulators in bee venom-induced apoptosis are Bcl-2 and caspase-3 in human leukemic U937 cells through downregulation of ERK and Akt . Int Immunopharmacol . 2006;6(12):1796-1807.
19. Roh DH , Kim HW , Yoon SY , et al. Bee venom injection significantly reduces nociceptive behavior in the mouse formalin test via capsaicin-insensitive afferents . J Pain . 2006;7(7):500-512.
20. Betten DP , Richardson WH , Tong TC , Clark RF . Massive honey bee envenomation-induced rhabdomyolysis in an adolescent . Pediatrics . 2006;117(1):231-235.
21. Tunget CL , Clark RF . Invasion of the 'killer' bees. Separating fact from fiction . Postgrad Med . 1993;94(2):92-94, 97-98, 101-102.
22. Grisotto LS , Mendes GE , Castro I , et al. Mechanisms of bee venom-induced acute renal failure . Toxicon . 2006;48(1):44-54.
23. Ferreira DB , Costa RS , Oliveira JS , Muccillo G . Cardiac noradrenaline in experimental rat envenomation with Africanized bee venom . Exp Toxicol Pathol . 1994;45(8):507-511.
24. Azevedo-Marques MM , Ferreira DB , Costa RS . Rhabdomyonecrosis experimentally induced in Wistar rats by Africanized bee venom . Toxicon . 1992;30(3):344-348.
25. Beccari M , Castiglione A , Cavaliere G , et al. Unusual case of anuria due to African bee stings . Int J Artif Organs . 1992;15(5):281-283.

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