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Antivenom

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For the comics character, see Anti-Venom.

Antivenom
Milking a snake for the production of antivenom
Clinical data
Other namesantivenin, antivenene
AHFS/Drugs.comMonograph
Routes of
administration		injection
ATC code
Identifiers
ChemSpider
  • none

Antivenom, also known as antivenin, venom antiserum, and antivenom immunoglobulin, is a specific treatment for envenomation. It is composed of antibodies and used to treat certain venomous bites and stings.[1] Antivenoms are recommended only if there is significant toxicity or a high risk of toxicity.[1] The specific antivenom needed depends on the species involved.[1] It is given by injection.[1]

Side effects may be severe.[1] They include serum sickness, shortness of breath, and allergic reactions including anaphylaxis.[1] Antivenom is traditionally made by collecting venom from the relevant animal and injecting small amounts of it into a domestic animal.[2] The antibodies that form are then collected from the domestic animal's blood and purified.[2]

Versions are available for spider bites, snake bites, fish stings, and scorpion stings.[3] Due to the high cost of producing antibody-based antivenoms and their short shelf lives when not refrigerated, alternative methods of production of antivenoms are being actively explored.[4] One such different method of production involves production from bacteria.[5] Another approach is to develop targeted drugs (which, unlike antibodies, are usually synthetic and easier to manufacture at scale).[6]

Antivenom was first developed in the late 19th century and came into common use in the 1950s.[2][7] It is on the World Health Organization's List of Essential Medicines.[8]

Medical uses

[edit]

Antivenom is used to treat certain venomous bites and stings.[1] They are recommended only if there is significant toxicity or a high risk of toxicity.[1] The specific antivenom needed depends on the venomous species involved.[1]

In the US, approved antivenom, including for pit viper (rattlesnake, copperhead and water moccasin) snakebite, is based on a purified product made in sheep known as CroFab.[9] It was approved by the FDA in October 2000. U.S. coral snake antivenom ceased production, and remaining stocks of in-date antivenom for coral snakebite expired in fall 2009, leaving the U.S. without a coral snake antivenom. However, as of July 2021, Pfizer has indicated that antivenom is available.[10] Efforts are being made to obtain approval for a coral snake antivenom produced in Mexico which would work against U.S. coral snakebite, but such approval remains speculative.[11][12]

As an alternative when conventional antivenom is not available, hospitals sometimes use an intravenous version of the antiparalytic drug neostigmine to delay the effects of neurotoxic envenomation through snakebite.[13] Some promising research results have also been reported for administering the drug nasally as a "universal antivenom" for neurotoxic snakebite treatment.[14]

A monovalent antivenom is specific for one toxin or species, while a polyvalent one is effective against multiple toxins or species.[15]

The majority of antivenoms (including all snake antivenoms) are administered intravenously; however, stonefish and redback spider antivenoms are given intramuscularly. The intramuscular route has been questioned in some situations as not uniformly effective.[16]

Side effects

[edit]

Antivenoms are purified from animal serum by several processes and may contain other serum proteins that can act as immunogens. Some individuals may react to the antivenom with an immediate hypersensitivity reaction (anaphylaxis) or a delayed hypersensitivity (serum sickness) reaction, and antivenom should, therefore, be used with caution. Although rare, severe hypersensitivity reactions including anaphylaxis to antivenom are possible.[17] Despite this caution, antivenom is typically the sole effective treatment for a life-threatening condition, and once the precautions for managing these reactions are in place, an anaphylactoid reaction is not grounds to refuse to give antivenom if otherwise indicated. Although it is a popular myth that a person allergic to horses "cannot" be given antivenom, the side effects are manageable, and antivenom should be given rapidly as the side effects can be managed.[18]

Method of preparation

[edit]

Most antivenoms are prepared by freeze drying (also called cryodesiccation or lyophilization). The process involves freezing the antisera, followed by application of high vacuum. This causes frozen water to sublimate. Sera is reduced to powder with no water content. In such an environment, microorganisms and enzymes cannot degrade the antivenom, and it can be stored for up to 5 years [at normal temperatures]. Liquid antivenoms may also be stored for 5 years, but they must be stored at low temperatures (below 8 °C/46 °F).[19]

Mechanism

[edit]

Antivenoms act by binding to and neutralizing venoms. The principle of antivenom is based on that of vaccines, developed by Edward Jenner; however, instead of inducing immunity in the person directly, it is induced in a host animal and the hyperimmunized serum is transfused into the person.[20] The host animals may include horses, donkeys, goats, sheep, rabbits, chickens, llamas, and camels.[21] In addition, opossums are being studied for antivenom production.[22] Antivenoms for medical use are often preserved as freeze-dried ampoules, but some are available only in liquid form and must be kept refrigerated. They are not immediately inactivated by heat, however, so a minor gap in the cold chain is not disastrous.

History

[edit]

The use of serum from immunized animals as a treatment for disease was pioneered in 1890 by Emil von Behring and Shibasaburo Kitasato, who first demonstrated that the infectious diseases diphtheria and tetanus could be prevented or cured using transfusions from an immune animal to a susceptible one.[23] On February 10, 1894, Albert Calmette at the Pasteur Institute, and independently Césaire Auguste Phisalix and Gabriel Bertrand at the National Museum of National History in France, announced that they had achieved the same result—treatment of a vulnerable animal with serum from an immunized one—this time using snake venom as the source of protection and disease.[24] Calmette went on subsequently to immunize horses using venom from Indian cobras, and the resulting Serum Antivenimeux (antivenomous serum) became the first commercially-available antivenom product.[25][26]

Natural immunity of snakes to their own venom was observed at least as long ago as 1767, by Felice Fontana in his work Ricerche Fisiche sopra il Veleno della Vipera (Physical Research on the Venom of the Viper).[27] Surgeon-Major Edward Nicholson wrote in the November 1870 Madras Medical Journal that he had witnessed a Burmese snake-catcher inoculating himself with cobra venom. However, the snake-catcher was unsure whether this was actually effective and therefore continued to treat his snakes with care. Nicholson, along with other Britons, began to consider that venom might provide its own cure. Although Scottish surgeon Patrick Russell had noted in the late 18th century that snakes were not affected by their own venom,[28] it was not until the late 19th century that Joseph Fayrer, Lawrence Waddell, and others began to consider venom-based remedies again. However, they and other naturalists working in India did not have the funding to fully develop their theories. In 1895 Sir Thomas Fraser, Professor of Medicine at the University of Edinburgh, picked up Fayrer and Waddell's research to produce a serum to act against cobra venom. His "antivenene" was effective in the laboratory, but failed to make an impact as the public were focused on contemporary Pasteurian discoveries.[29]

In 1901, Vital Brazil, working at the Instituto Butantan in São Paulo, Brazil, developed the first monovalent and polyvalent antivenoms for Central and South American Crotalus and Bothrops genera,[30] as well as for certain species of venomous spiders, scorpions, and frogs. In Mexico in 1905, Daniel Vergara Lope developed an antivenom against scorpion venom, by immunizing dogs.[31] In Australia, the Commonwealth Serum Laboratories (CSL) began antivenom research in the 1920s. CSL has developed antivenoms for the redback spider, funnel-web spiders and all deadly Australian snakes.[32] In the USA, the H.K. Mulford company began producing "Nearctic Crotalidae antivenin"[33] in 1927, via a consortium called the Antivenin Institute of America.[34]

Over time, a variety of improvements have been made in the specificity, potency, and purity of antivenom products, including "salting out" with ammonium sulphate or caprylic acid,[35] enzymatic reduction of antibodies with papain or with pepsin, affinity purification, and a variety of other measures.[36] Many equine facilities now use plasmapheresis to collect blood plasma instead of blood serum.[37][38]

Availability

[edit]

There is an overall shortage of antivenom to treat snakebites. Because of this shortage, clinical researchers are considering whether lower doses may be as effective as higher doses in severe neurotoxic snake envenoming.[39]

Antivenom undergoes successive price markups after manufacturing, by licencees, wholesalers and hospitals.[40] When weighed against profitability (especially for sale in poorer regions), the result is that many snake antivenoms, world-wide, are very expensive. Availability, from region to region, also varies.[41]

Internationally, antivenoms must conform to the standards of pharmacopoeia and the World Health Organization (WHO).[21][42]

In 2024 researchers have discovered a synthetic antibody that can neutralize a key type of neurotoxin produced by four different deadly snake species from South Asia, Southeast Asia, and Africa. This might be a step toward an antivenom that could be used on any of the 200 or so dangerous venomous snakes throughout the world.[43][44]

Antivenoms have been developed for the venoms associated with the following animals:[45]

Spiders

[edit]
Antivenom Species Country
Funnel web spider antivenom Sydney funnel-web spider Australia
Soro antiaracnidico Brazilian wandering spider Brazil
Soro antiloxoscelico Recluse spider Brazil
Suero antiloxoscelico Chilean recluse Chile
Aracmyn All species of Loxosceles and Latrodectus Mexico
Redback spider antivenom Redback spider Australia
Black widow spider (Latrodectus Mactans) antivenin (equine origin) Southern black widow spider United States
SAIMR spider antivenom Button spider South Africa
Anti-Latrodectus antivenom Black widow spider Argentina

Acarids

[edit]
Antivenom Species Country
Tick antivenom Paralysis tick Australia

Insects

[edit]
Antivenom Species Country
soro antilonomico Lonomia obliqua caterpillar Brazil

Scorpions

[edit]
Antivenom Species Country
Scorpion Venom Anti Serum (India) Purified lyophilized enzyme refined Equine Immunoglobulins Buthus tamulus India
ANTISCORP - Premium (Scorpion Venom Antiserum North Africa) Purified lyophilized enzyme refined Equine Immunoglobulins Androctonus amoerexi and Leiurus quinquestraiatus India
INOSCORPI MENA (Middle East and North Africa) Androctonus australis, Androctonus mauritanicus, Androctonus crassicauda, Buthus occitanus mardochei, Buthus occitanus occitanus, Leiurus quinquestriatus quinquestriatus, Leiurus quinquestriatus hebreus Spain
Alacramyn Centruroides limpidus, C. noxius, C. suffusus Mexico
Suero Antialacran Centruroides limpidus, C. noxius, C. suffusus Mexico
Tunisian polyvalent antivenom All Iranian scorpions Tunisia
Anti-Scorpion Venom Serum I.P. (AScVS) Indian red scorpion India
Anti-scorpionique Androctonus spp., Buthus spp. Algeria
Scorpion antivenom Black scorpion, Buthus occitanus Morocco
Soro antiscorpionico Tityus spp. Brazil
SAIMR scorpion antivenin Parabuthus spp. South Africa
Purified prevalent Anti-Scorpion Serum (equine source) Leiurus spp. and Androctonus scorpions Egypt

Marine animals

[edit]
Antivenom Species Country
CSL box jellyfish antivenom Box jellyfish Australia
CSL stonefish antivenom Stonefish Australia

Snakes

[edit]
Antivenom Species Country
PANAF PREMIUM (Sub-Sahara Africa) Purified lyophilized enzyme refined Equine Immunoglobulins [46] Echis ocellatus, Echis leucogaster, Echis carinatus, Bitis arietans, Bitis rhinoceros, Bitis nasicornis, Bitis gabonica, Dendroaspis polylepis, Dendroaspis viridis, Dendroaspis angusticeps, Dendroaspis jamesoni, Naja nigricollis, Naja melanoleuca and Naja haje India
Snake Venom Antiserum (India) Purified lyophilized enzyme refined Equine Immunoglobulins Naja naja, Vipera russelii and Echis carinatus India
INOSERP MENA (Middle East and North Africa) Bitis arietans, Cerastes cerastes, Cerastes gasperettii,Cerastes vipera, Daboia deserti, Daboia mauritanica, Daboia palaestinae, Echis carinatus sochureki, Echis coloratus, Echis khosatzkii, Echis leucogaster, Echis megalocephalus, Echis omanensis, Echis pyramidum, Macrovipera lebetina obtusa, Macrovipera lebetina transmediterranea, Macrovipera lebetina turanica, Montivipera bornmuelleri, Montivipera raddei kurdistanica, Pseuocerastes fieldi, Pseudocerastes persicus, Vipera latastei, Naja haje, Naja nubiae, Naja pallida and Walterinnesia aegyptia Spain
INOSERP PAN-AFRICA (Sub-Sahara Africa) Echis ocellatus, Bitis arietans, Dendroaspis polylepis and Naja nigricollis Spain
EchiTAbG (Sub-Sahara Africa)[47] Echis ocellatus, Echis pyramidum Wales, UK
Polyvalent snake antivenom Anavip South American rattlesnake Crotalus durissus and fer-de-lance Bothrops asper Mexico (Instituto Bioclon); South America
Polyvalent snake antivenom Saw-scaled viper Echis carinatus, Russell's viper Daboia russelli, spectacled cobra Naja naja, common krait Bungarus caeruleus (These are the "Big Four" snakes which account for nearly 75% of snakebites in India). India
Death adder antivenom Death adder Australia
Taipan antivenom Taipan Australia
Black snake antivenom Pseudechis spp. Australia
Tiger snake antivenom Australian copperheads, tiger snakes, Pseudechis spp., rough-scaled snake Australia
Brown snake antivenom Brown snakes Australia
Polyvalent snake antivenom Australian snakes as listed above Australia
Sea snake antivenom Sea snakes Australia
Vipera tab Vipera spp. UK
Polyvalent crotalid antivenin (CroFab—Crotalidae Polyvalent Immune Fab (Ovine)) North American pit vipers (all rattlesnakes, copperheads, and cottonmouths) North America
Soro antibotropicocrotalico Pit vipers and rattlesnakes Brazil
Antielapidico Coral snakes Brazil
SAIMR polyvalent antivenom Mambas, cobras, Rinkhalses, puff adders (Unsuitable small adders: B. worthingtoni, B. atropos, B. caudalis, B. cornuta, B. heraldica, B. inornata, B. peringueyi, B. schneideri, B. xeropaga) South Africa[48]
SAIMR echis antivenom Saw-scaled vipers South Africa
SAIMR Boomslang antivenom Boomslang South Africa
Panamerican serum Coral snakes Costa Rica
Anticoral Coral snakes Costa Rica
Anti-mipartitus antivenom Coral snakes Costa Rica
Anticoral monovalent Coral snakes Costa Rica
Antimicrurus Coral snakes Argentina
Coralmyn Coral snakes Mexico
Anti-micruricoscorales Coral snakes Colombia
crotalidae immune F(ab')2 (equine)) (Anavip) North American species of Crotalinae US

Terminology

[edit]

The name "antivenin" comes from the French word venin, meaning venom, which in turn was derived from Latin venenum, meaning poison.[49]

Historically, the term antivenin was predominant around the world, its first published use being in 1895.[50] In 1981, the World Health Organization decided that the preferred terminology in the English language would be venom and antivenom rather than venin and antivenin or venen and antivenene.[51]

References

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