Antivenom

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Antivenom
Snake Milking.jpg
Milking a snake for the production of antivenom
Clinical data
Other namesantivenin, antivenene
AHFS/Drugs.com Monograph
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]

Contents

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

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

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

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

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

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

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

AntivenomSpeciesCountry
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
AracmynAll species of Loxosceles and Latrodectus Mexico
Redback spider antivenom Redback spider Australia
Black widow spider (Latrodectus Mactans) antivenin (equine origin) Southern black widow spiderUnited States
SAIMR spider antivenom Button spider South Africa
Anti-Latrodectus antivenom Black widow spider Argentina

Acarids

AntivenomSpeciesCountry
Tick antivenom Paralysis tick Australia

Insects

AntivenomSpeciesCountry
soro antilonomico Lonomia obliqua caterpillarBrazil

Scorpions

AntivenomSpeciesCountry
Scorpion Venom Anti Serum (India) Purified lyophilized enzyme refined Equine ImmunoglobulinsButhus tamulus India
ANTISCORP - Premium (Scorpion Venom Antiserum North Africa) Purified lyophilized enzyme refined Equine ImmunoglobulinsAndroctonus 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 AntialacranCentruroides limpidus, C. noxius, C. suffusus Mexico
Tunisian polyvalent antivenomAll Iranian scorpions Tunisia
Anti-Scorpion Venom Serum I.P. (AScVS) Indian red scorpion India
Anti-scorpionique Androctonus spp., Buthus spp. Algeria
Scorpion antivenomBlack 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

AntivenomSpeciesCountry
CSL box jellyfish antivenom Box jellyfish Australia
CSL stonefish antivenom Stonefish Australia

Snakes

AntivenomSpeciesCountry
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 nigricollisSpain
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 antivenomSaw-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 antivenomAustralian snakes as listed aboveAustralia
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 antibotropicocrotalicoPit vipers and rattlesnakesBrazil
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 serumCoral snakesCosta Rica
AnticoralCoral snakesCosta Rica
Anti-mipartitus antivenomCoral snakesCosta Rica
Anticoral monovalentCoral snakesCosta Rica
AntimicrurusCoral snakesArgentina
CoralmynCoral snakesMexico
Anti-micruricoscoralesCoral snakesColombia
crotalidae immune F(ab')2 (equine)) (Anavip)North American species of Crotalinae US

Terminology

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]

Related Research Articles

An antidote is a substance that can counteract a form of poisoning. The term ultimately derives from the Greek term φάρμακον ἀντίδοτον (pharmakon antidoton), "(medicine) given as a remedy". Antidotes for anticoagulants are sometimes referred to as reversal agents.

<span class="mw-page-title-main">Snakebite</span> Injury caused by bite from snakes

A snakebite is an injury caused by the bite of a snake, especially a venomous snake. A common sign of a bite from a venomous snake is the presence of two puncture wounds from the animal's fangs. Sometimes venom injection from the bite may occur. This may result in redness, swelling, and severe pain at the area, which may take up to an hour to appear. Vomiting, blurred vision, tingling of the limbs, and sweating may result. Most bites are on the hands, arms, or legs. Fear following a bite is common with symptoms of a racing heart and feeling faint. The venom may cause bleeding, kidney failure, a severe allergic reaction, tissue death around the bite, or breathing problems. Bites may result in the loss of a limb or other chronic problems or even death.

<span class="mw-page-title-main">Snake venom</span> Highly modified saliva containing zootoxins

Snake venom is a highly toxic saliva containing zootoxins that facilitates in the immobilization and digestion of prey. This also provides defense against threats. Snake venom is usually injected by unique fangs during a bite, though some species are also able to spit venom.

<span class="mw-page-title-main">Vital Brazil</span> Brazilian physician, biomedical scientist, and immunologist (1865–1950)

Vital Brazil Mineiro da Campanha, known as Vital Brazil, was a Brazilian physician, biomedical scientist and immunologist, known for the discovery of the polyvalent anti-ophidic serum used to treat bites of venomous snakes of the Crotalus, Bothrops and Elaps genera. He went on to be also the first to develop anti-scorpion and anti-spider serums. He was the founder of the Butantan Institute, a research center located in São Paulo, which was the first in the world dedicated exclusively to basic and applied toxicology, the science of venomous animals.

<span class="mw-page-title-main">Inland taipan</span> Venomous snake native to Australia.

The inland taipan, also commonly known as the western taipan, small-scaled snake, or fierce snake, is a species of extremely venomous snake in the family Elapidae. The species is endemic to semiarid regions of central east Australia. Aboriginal Australians living in those regions named the snake dandarabilla. It was formally described by Frederick McCoy in 1879 and then by William John Macleay in 1882, but for the next 90 years, it was a mystery to the scientific community; no further specimens were found, and virtually nothing was added to the knowledge of this species until its rediscovery in 1972.

<span class="mw-page-title-main">Envenomation</span> Process of venom injection

Envenomation is the process by which venom is injected by the bite or sting of a venomous animal.

A snake-stone, also known as a viper's stone, snake's pearl, black stone, serpent-stone, or nagamani is an animal bone or stone used as folk medicine for snake bite in Africa, South America, India and Asia.

<i>Crotalus scutulatus</i> Species of snake

Crotalus scutulatus is known commonly as the Mohave Rattlesnake. Other common English names include Mojave Rattlesnake and, referring specifically to the nominate (northern) subspecies: Northern Mohave Rattlesnake and Mojave Green Rattlesnake, the latter name commonly shortened to the more colloquial “Mojave green”. Campbell and Lamar (2004) supported the English name “Mohave (Mojave) rattlesnake” with some reluctance because so little of the snake’s range lies within the Mojave Desert.

<span class="mw-page-title-main">Caspian cobra</span> Species of snake

The Caspian cobra, also called the Central Asian cobra or Russian cobra, is a species of highly venomous snake in the family Elapidae. The species is endemic to Central Asia. First described by Karl Eichwald, a German physician, in 1831, it was for many years considered to be a subspecies of the Naja naja until genetic analysis revealed it to be a distinct species.

Crotalidae polyvalent immune Fab (ovine), sold under the brandname CroFab, is a snake antivenin, indicated for North American crotalid (rattlesnake, copperhead and cottonmouth/water moccasin) snake envenomation.

<span class="mw-page-title-main">Spider bite</span> Bite caused by a spider

A spider bite, also known as arachnidism, is an injury resulting from the bite of a spider. The effects of most bites are not serious. Most bites result in mild symptoms around the area of the bite. Rarely they may produce a necrotic skin wound or severe pain.

<i>Naja</i> Genus of snakes

Naja is a genus of venomous elapid snakes commonly known as cobras. Members of the genus Naja are the most widespread and the most widely recognized as "true" cobras. Various species occur in regions throughout Africa, Southwest Asia, South Asia, and Southeast Asia. Several other elapid species are also called "cobras", such as the king cobra and the rinkhals, but neither is a true cobra, in that they do not belong to the genus Naja, but instead each belong to monotypic genera Hemachatus and Ophiophagus.

<span class="mw-page-title-main">Latrodectism</span> Illness from a Latrodectus spider bite

Latrodectism is the illness caused by the bite of Latrodectus spiders. Pain, muscle rigidity, vomiting, and sweating are the symptoms of latrodectism.

<i>Micrurus fulvius</i> Species of snake

Micrurus fulvius, commonly known as the eastern coral snake, common coral snake, American cobra, and more, is a species of highly venomous coral snake in the family Elapidae. The family also contains the cobras and sea snakes. The species is endemic to the southeastern United States. It should not be confused with the scarlet snake or scarlet kingsnake, which are harmless mimics. No subspecies are currently recognized.

A dry bite is a bite by a venomous animal in which no venom is released. Dry snake bites are called "venomous snake bite without envenoming". A dry bite from a snake can still be painful, and be accompanied by bleeding, inflammation, swelling and/or erythema. It may also lead to infection, including tetanus.

<span class="mw-page-title-main">Snake antivenom</span> Medication used to treat bites by venomous snakes

Snake antivenom is a medication made up of antibodies used to treat snake bites by venomous snakes. It is a type of antivenom.

<span class="mw-page-title-main">Epidemiology of snakebites</span>

Most snakebites are caused by non-venomous snakes. Of the roughly 3,700 known species of snake found worldwide, only 15% are considered dangerous to humans. Snakes are found on every continent except Antarctica. There are two major families of venomous snakes, Elapidae and Viperidae. 325 species in 61 genera are recognized in the family Elapidae and 224 species in 22 genera are recognized in the family Viperidae, In addition, the most diverse and widely distributed snake family, the colubrids, has approximately 700 venomous species, but only five genera—boomslangs, twig snakes, keelback snakes, green snakes, and slender snakes—have caused human fatalities.

Findlay Ewing Russell was an American internal medicine physician and toxicologist. He pursued a research interest in venomous and poisonous animals and the effects of toxins on the human nervous system and was widely acknowledged as one of the world's leading authorities on snakes and the pharmacology of snake venoms. Consulting work for the United Nations and various governmental agencies took him all over the world.

Venomics is the study of proteins associated with venom, a toxic substance secreted by animals, which is typically injected either offensively or defensively into prey or aggressors, respectively.

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