Current research into snake antivenoms, their mechanisms of action and applications.

Snakebite is a major public health issue in the rural tropics. Antivenom is the only specific treatment currently available. We review the history, mechanism of action and current developments in snake antivenoms. In the late nineteenth century, snake antivenoms were first developed by raising hyperimmune serum in animals, such as horses, against snake venoms. Hyperimmune serum was then purified to produce whole immunoglobulin G (IgG) antivenoms. IgG was then fractionated to produce F(ab) and F(ab')2 antivenoms to reduce adverse reactions and increase efficacy. Current commercial antivenoms are polyclonal mixtures of antibodies or their fractions raised against all toxin antigens in a venom(s), irrespective of clinical importance. Over the last few decades there have been small incremental improvements in antivenoms, to make them safer and more effective. A number of recent developments in biotechnology and toxinology have contributed to this. Proteomics and transcriptomics have been applied to venom toxin composition (venomics), improving our understanding of medically important toxins. In addition, it has become possible to identify toxins that contain epitopes recognized by antivenom molecules (antivenomics). Integration of the toxinological profile of a venom and its composition to identify medically relevant toxins improved this. Furthermore, camelid, humanized and fully human monoclonal antibodies and their fractions, as well as enzyme inhibitors have been experimentally developed against venom toxins. Translation of such technology into commercial antivenoms requires overcoming the high costs, limited knowledge of venom and antivenom pharmacology, and lack of reliable animal models. Addressing such should be the focus of antivenom research.

Zvonimir Maretic (1921-1989): The History of Discovery of the First European Antilatrodectic Serum and its Preparator in the Occasion Of the 30th Anniversary of His Death

Zvonimir Maretic was the pioneer of the study of venomous animals and plants, toxicology, and tourism medicine. His achievements have been recognized, but insufficiently researched. His work covers a broad range of biomedical sciences: from public health, ecology, and environmental protection, to epidemiology and infectology. Maretic was one of the founding members of the International Society on Toxinology and the Toxicon journal's first Editorial Board. He was the first in Europe to prepare the antilatrodectic serum and to successfully apply the weever and scorpionfish antiserum on humans. This brief note tries to commemorate the achievements of Maretic, up to now poorly recognized and insufficiently researched.

The history of antivenoms development: Beyond Calmette and Vital Brazil.

This review presents the main contributions to our knowledge regarding the development of antivenoms for therapeutic use in victims of venomous animal bites. We cover the progress of serum therapy since tetanus and diphtheria antitoxins in Germany and France until the current scenario of antivenom production worldwide. During these more than 120 years of antivenom development, many researchers contributed to establish what are nowadays the antivenoms used for therapeutic purpose. The history of antivenoms development is fascinating! This review aims to recognize all those who contributed to the establishment of new sera, new methodologies and saving lives: much more than Calmette and Vital Brazil.

Evolution of alternative methodologies of scorpion antivenoms production.

Scorpionism represents a serious public health problem resulting in the death of children and debilitated individuals. Scorpion sting treatment employs various strategies including the use of specific medicines such as antiserum, especially for patients with severe symptoms. In 1909 Charles Todd described the production of an antiserum against the venom of the scorpion Buthus quinquestriatus. Based on Todd's work, researchers worldwide began producing antiserum using the same approach i.e., immunization of horses with crude venom as antigen. Despite achieving satisfactory results using this approach, researchers in this field have developed alternative approaches for the production of scorpion antivenom serum. In this review, we describe the work published by experts in toxinology to the development of scorpion venom antiserum. Methods and results describing the use of specific antigens, detoxified venom or toxins, purified toxins and or venom fractions, native toxoids, recombinant toxins, synthetic peptides, monoclonal and recombinant antibodies, and alternative animal models are presented.

History of scorpion antivenom: one Arizonan's view.

This paper was originally presented as the Elsevier Lecture in July, 2012 at the International Society on Toxinology/Venom Week combined meeting in Honolulu, Hawaii. In it, the author addresses the ancient history of venom and immunity, from the Silurian Era to the 1890s; the development of the first antivenoms; the impact of shifting political and economic pressures; the special case of Arizona; the relative stability of the 1960s through 1990s; the transition to regulatory compliance that took place at the time of the author's own research; and concluding thoughts regarding the instability of apparent success.

Toxinology in Brazil: A big challenge for a rich biodiversity.

Toxinology in Brazil developed specially during the 19th and 20th centuries. A very brief description of the main contributions made by pioneer toxinologists is presented here in an attempt to give an idea of the evolution of toxinology in our country, from its first steps until the XVI World Congress of the International Society on Toxinology, held in Recife, Brazil in March of 2009.

'Watch out for these KILLERS!': newspaper coverage of the Sydney funnel web spider and its impact on antivenom research.

Based on a content analysis of treatments of the funnel web spider in the Sydney Morning Herald between 1955 and 1985, this paper argues that negative attitudes towards the funnel web were encouraged throughout this period in news stories, commentary, and advertisements and were demonstrated in the reported words and actions of members of the general public. Despite this opprobrium, research into a funnel web antivenom was able to proceed because of the willingness of individuals to collect the spiders and forward them to researchers. Negative attitudes towards the funnel web were able to be directed to a positive action which eventually helped to bring about the development of an antivenom, lessening the real threat posed by the spider.

Twentieth century toxinology and antivenom development in Australia.

It was not until the last decade of the 19th century that an experimental approach (led by Bancroft in Queensland and Martin in Sydney and Melbourne) brought a higher plane of scientific objectivity to usher in the modern era of Australian toxinology. This Australia era, 1895-1905, coincided with and in some respects was the result of the new knowledge emerging from Europe and the Americas of the therapeutic effects of antitoxins. The subsequent systematic study of Australian venoms and toxins through to the 1930s and beyond, by Tidswell, Fairley, Ross, Kellaway and Cleland, set the foundation for Australia's leading reputation in venom research. As elsewhere, this development was to revolutionise the medical management of those victims who in the past had died in Australia from our venomous and toxic fauna. Morgan, Graydon, Weiner, Lane and Baxter at the Commonwealth Serum Laboratories emphasised the importance of cooperation between those expert at catching and milking the venomous creatures and those developing the antivenoms. Commercial antivenom manufacture began in Australia in 1930 with the tiger snake antivenom. This was followed by other antivenoms for the other important species (1955: taipan; 1956: brown snake; 1958: death adder; 1959: Papuan black snake; 1961: sea snake; 1962: polyvalent) including the first marine antivenoms in the world (1956: stonefish antivenom; 1970: box jellyfish) culminating, in 1980, with the release of the funnel web spider antivenom. More recent activity has focused on veterinary antivenoms and production of new generation human antivenoms for export (CroFab and ViperaTAB). This paper reviews some of the milestones of Australian toxinology, and antivenom development in particular, during the 20th century.

The pioneers of venom production for Australian antivenoms.

Before the introduction of the first Australian antivenom was the era of the self-styled 'snakemen' and their diverse snakebite remedies. Many received multiple bites from highly dangerous snakes, some of which were deliberately taken to either prove a certain treatment or liven up their show. The mortality rate among these handlers and showmen was high. Production of the first effective Australian antivenom, the tiger snake antivenom, in 1930, began the scientific approach to treating snakebite and opened new frontiers for professional and amateur snake people. Collecting venoms in the development and early production of antivenoms was carried out by a number of professional herpetologists often with little or no reward and in some instances at the ultimate cost of their lives. This paper reviews the most important of those late nineteenth and twentieth century snakemen and their contributions to venom research, antivenom production and current toxinological knowledge.

Struan Sutherland--Doyen of envenomation in Australia.

Struan Sutherland (1936-2002) was the doyen of medical research in the field of envenomation and the ultimate authority on the medical management of envenomated victims in Australia for almost 3 decades. In 1981 as Head of Immunology Research of Commonwealth Serum Laboratories (CSL), he produced an antivenom against the Sydney Funnel-web Spider (Atrax robustus)-an accomplishment that had defied numerous previous attempts. Struan also invented the pressure-immobilisation technique of first-aid for snake bite. This ingenious, simple but safe and effective technique revolutionised first-aid management of snake bite and of some other types of envenomation. It made redundant the use of tourniquets and other dangerous first-aid treatments. Similarly, he helped to develop a snake venom detection kit, which enables doctors working at a victim's bedside to ascertain which snake was responsible and which antivenom should be administered. He had a very wide range of research interests and was a prodigious researcher publishing over 200 scientific and medical articles, numerous chapters in books and the standard Australian medical textbook on the management of envenomation, Australian Animal Toxins. He made major contributions to the understanding of the venoms of Australia's remarkable range of fauna including snakes, spiders, Blue-ringed octopus, ants, jellyfish and stinging fish. Struan served the medical fraternity and the public selflessly. He was always available to doctors, or to anybody, to give advice at any hour of the day or night, on management of envenomated victims. Members of the Australian Venom Research Unit, which he founded in 1994 at The University of Melbourne, now continue this 24-h advisory service.

Las experiencias de José Celestino mutis sobre el uso del guaco como antiofídico

Este artículo busca explorar el germinal proceso de validación y de legitimación de un saber indígena con fines terapéuticos. Se trata de una corriente práctica curativa tradicional: la "cura" contra la mordedura de serpiente mediante la inoculación del zumo de una planta llamada guaco. Participan en este proceso varios representantes de la élite cultural neogranadina, pregoneros de la razón ilustrada en el virreinato de la Nueva Granada a finales del siglo XVIII (AU)

Bartisch on theriac.

George Bartisch is best known as the German ophthalmologist who wrote the mammoth textbook Ophthalmodouleia, printed in 1583. He wrote several other books, most of which were never published. One that he self-published is on Venice Theriac of Andromachus. Common theriac has a long history in medicine from just after Hippocrates. It initially was used for venomous snake bites but later was used for poisonings too. By Bartisch's time it was considered a nearly universal cure-all. In the book, a multitude of ophthalmic and general diseases are listed and then the dose of Theriac is given. Bartisch warned against the many inferior types of theriac available through unscrupulous traveling salespeople. He offered the superior Venice Theriac for sale, compounded by himself in Dresden, Germany, where he resided.

Poul Agerholm Christensen MD (1912-1991): antivenom production at the South African Institute for Medical Research.

Dr Christensen arrived in Cape Town in June 1940 as ship's surgeon on a Danish cargo-liner. Denmark was under German control, and the ship came under command of the South African government for use in war operations. In October 1941, Christensen left the ship to become assistant to Dr Edmond Grasset of the South African Institute for Medical Research in Johannesburg. Later, Christensen was head of department and associate director. Grasset produced the Institute's first concentrated Bitis arietans-Naja nivea antivenom in 1932. When Grasset resigned in 1946, Christensen took over the venom research projects. He introduced changes and produced antisera of high quality. As the paraspecificity of the polyvalent antivenom was limited, Christensen increased the number of immunising antigens to allow treatment against the bite of the many species of viperid and elapid snakes in southern and equatorial Africa. Using pepsin-refined antiserum, Christensen isolated three toxic fractions from Naja nivea venom and showed how the presence of multiple toxins affected antivenom neutralisation curves and estimates of antivenom potency. A member of a WHO Expert Committee, he raised and tested for suitability, the first reference antivenom. Dr Christensen was acclaimed internationally for his expertise, and for his dedicated service to the treatment of snakebite.

Doctor Albert Calmette 1863-1933: founder of antivenomous serotherapy and of antituberculous BCG vaccination.

In 1891 in Saigon (now Ho Chi Minh City), Dr. Albert Calmette established the first daughter Pasteur Institute for the protection of the local population against rabies and smallpox. Inspired by the discovery of diphtheria antitoxin by Behring, Calmette studied ways of raising serum against cobra venom. In 1895, now in Lille at the second daughter institute that he established, Calmette produced anticobra serum for therapeutic use that was to revolutionize the treatment of snakebite worldwide. The incidence of tuberculosis in the working class of the industrial north shocked Calmette. In response, firstly he organized an antituberculous dispensary to provide assistance to the sick and help limit the spread of the disease by improving social hygiene and secondly he devoted himself, with the assistance of Camille Guérin, to obtaining an attenuated live strain of tubercle bacilli with fixed biological characteristics for use as a vaccine. Such a strain developed during repeated passage of a culture of Mycobacterium bovis grown on a bile potato medium. In 1919, Dr. Albert Calmette took up the appointment of Sub-Director of the Pasteur Institute of Paris. Prolonged trials of BCG (Bacille Calmette-Guérin) vaccine showed it to be safe and vaccination of very young infants born of tuberculous mothers commenced in 1921. The use of BCG vaccine as a prophylactic against tuberculosis spread world-wide and has remained important in combatting this scourge.