Advertisement

Snakebite Envenomingin Latin America and the Caribbean

  • José María GutiérrezEmail author
Living reference work entry

Abstract

Envenomings induced by snakebites constitute a serious public health problem in Latin America. This condition affects predominantly vulnerable rural populations and has a high impact in regions where the provision of health services is deficient. Most envenomings are provoked by species of the genera Bothrops and Crotalus, classified in the family Viperidae, whereas about 1 % of cases are due to Micrurus species (family Elapidae). There are laboratories in several countries in the region which manufacture antivenoms. Scientific and biotechnological research has generated a significant body of knowledge on snakes and their venoms and on antivenoms. Despite important advances in the control of these envenomings in Latin America, it is necessary to strengthen regional efforts in order to (a) improve the knowledge on snakes and their venoms; (b) acquire information on the incidence and mortality of snakebite envenomings; (c) increase the volume of antivenom produced and, in some cases, the quality of antivenoms; (d) improve the regulatory work of national quality control laboratories; (e) develop knowledge-based strategies of distribution of antivenoms; (f) consolidate continuous education programs for the health staff in charge of the treatment of these envenomings; (g) ensure support to people that suffer physical or psychological sequelae as a consequence of these envenomings; and (h) strengthen community programs aimed at improving the prevention and adequate management of snakebites. The development of inter-programmatic and inter-sectorial projects in this field should be promoted in the region, involving multiple actors and institutions, within a frame of regional cooperation programs.

Keywords

Geographical Information System Snake Venom Cold Chain Snake Species Psychological Sequela 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Introduction

Snakebite envenoming constitutes a highly relevant public health problem, particularly in Africa, Asia, and Latin America (Kasturiratne et al. 2008; Gutiérrez et al. 2010a). This pathology, which largely affects impoverished populations in rural settings (Harrison et al. 2009), has been largely neglected by health authorities, research agendas, and pharmaceutical companies. As a consequence, the World Health Organization (WHO ) has included snakebite envenoming in its list of neglected tropical diseases (www.who.int/neglected_diseases/diseases/en/). A renewed interest in this subject has been raised in the last years, resulting in a number of initiatives; publications; scientific events; regional workshops; the publication of the WHO Guidelines for the Production, Control and Regulation of Snake Antivenom Immunoglobulins (WHO 2010); and the birth of the Global Snakebite Initiative (GSI; www.snakebiteinitiative.org) (Williams et al. 2010). In Latin America, a number of initiatives have been developed aimed at increasing the awareness of the seriousness of this pathology and at promoting regional cooperative efforts to confront it (www.paho.org/spanish/ad/dpc/vp/poisonous-animals.htm; Gutiérrez et al. 2007).

An effective attention to this public health problem demands concerted efforts in the frame of an integrated and holistic strategy, taking into consideration its complexity and multifactorial nature (Williams et al. 2010; Gutiérrez et al. 2010a). This demands actions in scientific research, technological development and innovation, production of sufficient volumes of safe and effective antivenoms, programs for acquisition and distribution of antivenoms to regions where they are needed, permanent education programs for health personnel, effective prevention platforms, and adequate attention to people suffering from sequelae secondary to snakebites. This chapter discusses snakebite envenomings in Latin America and the Caribbean and highlights some of the tasks that need to be undertaken in this region in order to significantly reduce the impact of this disease.

Epidemiology

Incidence and Mortality

Information on the incidence of snakebite envenomings is rather incomplete in many regions of the world (WHO 2010). The majority of the studies have been based on hospital statistics, which are often incomplete, for various reasons. In some cases, only a fraction of snakebitten patients attend hospitals and health centers for attention, and also the collection of hospital records by epidemiological surveillance units is often deficient. When more precise estimations have been performed, such as in community- and household-based studies, the actual dimension of incidence and mortality is evident. The problem of poor or incomplete epidemiological records on snakebites also occurs in Latin America (Gutiérrez 2011). Therefore, it is necessary to develop national and regional efforts in this region aimed at gathering robust epidemiological data on snakebite envenomings by integrating hospital-based information with community-based studies, in order to have a more precise estimation of the magnitude of this public health problem. An aspect that will contribute to this goal is the introduction of compulsory report of snakebites; this has been achieved in some countries (Gutiérrez et al. 2007), but needs to be generalized to the whole region.

Despite the limitations of currently available data, a rough estimation of the incidence and mortality of snakebite envenomings in Latin America and the Caribbean can be obtained by using records emanating from hospitals and ministries of health. Such estimations indicate that there are at least 70,000 cases of snakebites in the region (Table 1) . Such estimation corresponds to the lower limit of a study in which the global burden of snakebites was investigated (Kasturiratne et al. 2008). In this work, the annual number of snakebites in the region was estimated to be in the range of 80,329–129,084. Likewise, data on mortality are also incomplete, although there is reliable information for some countries. The mortality rates (expressed per 100,000 population per year) described for various countries are Costa Rica, 0.02–0.15; Panama, 0.5 (Hildaura Acosta, personal communication); Venezuela, 0.1–0.2; Brazil, 0.05; and Ecuador, 0.05 (Gutiérrez 2011 and references therein). Kasturiratne et al. (2008) estimated the total number of deaths due to snakebite envenomings in Latin America to be in the range of 540–2,298, although this is likely to represent an underestimation due to the problems discussed above.
Table 1

Estimated number of snakebites per year per country in Latin America and the Caribbean and species of highest medical impact in each country (From Gutiérrez (2011) and references therein)

Country

Estimated number of snakebites per year

Species of highest medical impacta

North America

Mexico

27,000

Agkistrodon bilineatus

Agkistrodon taylori

Bothrops asper

Crotalus atrox

Crotalus scutulatus

Crotalus simus

Crotalus totonacus

Central America

Belize

50

Bothrops asper

Costa Rica

500–600

Bothrops asper

Crotalus simus

El Salvador

50

Crotalus simus

Guatemala

500

Bothrops asper

Crotalus simus

Honduras

500

Bothrops asper

Nicaragua

600

Bothrops asper

Crotalus simus

Panamá

1,300–1,800

Bothrops asper

The Caribbean

Aruba

Information not found

Crotalus durissus

Martinique

20

Bothrops lanceolatus

Saint Lucia

12

Bothrops caribbaeus

Trinidad and Tobago

Information not found

Bothrops atrox

South America

Argentina

270

Bothrops alternatus

Bothrops diporus b

Crotalus durissus

Bolivia

1,000

Bothrops atrox

Bothrops mattogrossensis b

Crotalus durissus

Brazil

26,000–29,000

Bothrops atrox

Bothrops jararaca

Bothrops jararacussu

Bothrops leucurus

Bothrops moojeni

Crotalus durissus

Colombia

3,000

Bothrops asper

Bothrops atrox

Bothrops bilineatus

Crotalus durissus

Ecuador

1,400–1,600

Bothrops asper

Bothrops atrox

Bothrops bilineatus

Lachesis muta

Guiana

200

Bothrops atrox

Bothrops bilineatus

Bothrops brazili

Crotalus durissus

French Guiana

100

Bothrops atrox

Bothrops bilineatus

Bothrops brazili

Crotalus durissus

Paraguay

400–500

Bothrops alternatus

Crotalus durissus

Peru

1,400–1,500

Bothrops atrox

Bothrops bilineatus

Bothrops pictus

Crotalus durissus

Lachesis muta

Suriname

Information not found

Bothrops atrox

Bothrops bilineatus

Bothrops brazili

Crotalus durissus

Uruguay

50–60

Bothrops alternatus

Crotalus durissus

Venezuela

7,000

Bothrops atrox

Bothrops colombiensis

Bothrops venezuelensis

Crotalus durissus

aThe species having the highest medical impact are those classified within category 1 in the WHO Guidelines for the Production, Control and Regulation of Snake Antivenom Immunoglobulins (WHO 2010). In the case of Venezuela, the species Bothrops colombiensis is added

bFormerly classified as subspecies of Bothrops neuwiedi

Snakebites affect predominantly young adult agricultural workers, especially males, although a significant number of cases also occur in women, as well as in children and adolescents, most of whom are affected when working in the fields (de Oliveira et al. 2009). Most of the accidents occur when people are performing agricultural duties (de Oliveira et al. 2009; Gutiérrez 2010, 2011). Incidence varies during the year, with peaks generally occurring during the rainy season, associated with agricultural work (Sasa and Vázquez 2003; de Oliveira et al. 2009). For some snake species, the invasion of natural habitats by agricultural activities and the development of human settlements provokes a close contact between snakes and people, which increases the likelihood of accidents, as occurs in the case of the viperid species Bothrops asper (Gutiérrez 2010) and other species that also adapt to altered environments. Likewise, the effect of natural disasters on snakebite incidence needs to be considered, as floods or other natural phenomena might increase the incidence of snakebites. However, presenting general data on incidence per country does not allow the identification of specific regions where the magnitude of this problem is very high. Thus, there is a need to assess incidence and mortality on a regional basis within countries, in order to detect highly vulnerable regions and human groups that require particular attention of public health programs, such as indigenous populations. The use of Geographical Information Systems (GIS) methodologies should be fostered, with the aim of analyzing spatial patterns of distribution of incidence, snake species, location of health services, and transportation facilities, among other parameters. These technologies have been used in Argentina (Leynaud and Reati 2009) and Costa Rica (Hansson et al. 2013) and have allowed the identification of vulnerable regions in which provision of health care for snakebitten patients should be improved.

Sequelae of Snakebite Envenomings: The Need to Know Their Impact

The impact of snakebite envenomings in Latin America should be viewed from a wide perspective, considering the consequences in terms of permanent sequelae and of social and economic implications. An unknown percentage of viperid snakebite cases end up in permanent physical sequelae associated with tissue loss or dysfunction (Warrell 2004; Cardoso et al. 2009; Gutiérrez et al. 2010a). Moreover, psychological sequelae occur after snakebite envenomings, as has been described in Sri Lanka (Williams et al. 2011). Although this subject has not been investigated in Latin America, the severity and complications of many of these envenomings strongly suggest that psychological effects occur. The issue of physical and psychological sequelae after snakebite envenomings should be analyzed in terms of DALYs (disability adjusted life years) lost, a valuable tool to assess the impact of diseases. Likewise, the social and economic impacts of this disease have not been properly assessed. Since the large majority of cases occur in young agricultural workers, including women and children, the impact of this pathology in household and community economics and social life is considerable, especially since snakebites occur predominantly in impoverished rural areas. There is an urgent need to assess the impact of snakebite envenoming from this broader perspective, using research tools of the social sciences. The adequate understanding on the physical, economic, social, and psychological consequences of snakebites is required for a knowledge-based allocation of resources and for developing robust advocacy to combat this neglected problem in Latin America and elsewhere in the world.

Snake Species Responsible for the Highest Burden of Envenomings

The medically most important snake species in Latin America and the Caribbean belong to the families Viperidae and Elapidae (Cardoso et al. 2009). Species of the family Colubridae (sensu lato) cause a number of bites and are able to inject venom, although the severity of these cases is generally mild (Prado-Franceschi and Hyslop 2002). The vast majority of snakebites in the region are inflicted by species of the family Viperidae, especially of the genus Bothrops, followed by species of the genus Crotalus (Warrell 2004; de Oliveira et al. 2009; Gutiérrez 2010, 2011). Envenomings caused by coral snakes (family Elapidae, genus Micrurus) represent 1 % of the total number of bites (de Oliveira et al. 2009; Gutiérrez 2010, 2011). The species causing the highest number of bites vary depending on the country and are enlisted in Table 1. Some species having a high impact are Bothrops asper in Central America and northern regions of South America, Bothrops atrox in the Amazon, Bothrops jararaca and B. alternatus in southern South America, and the rattlesnake Crotalus durissus in South America (Warrell 2004; Cardoso et al. 2009; Gutiérrez 2010; WHO 2010) (Table 1; Fig. 1).
Fig. 1

Representatives of venomous snake species in Latin America . (a) Bothrops atrox (family Viperidae), responsible for a large number of snakebites in South America. It induces drastic local and systemic effects associated with tissue necrosis (see Fig. 2) and systemic bleeding and hemodynamic disturbances. Specimen from Brazil (Photo by Giuseppe Puorto). (b) Bothrops alternatus (family Viperidae), distributed in the southern parts of South America. Specimen from Brazil (Photo by Giuseppe Puorto). (c) Crotalus simus (family Viperidae), a rattlesnake distributed in Mexico and Central America. Envenomings provoked by adult specimens are characterized by local tissue damage, coagulopathy, systemic hemorrhage, and cardiovascular alterations, although venoms of adult specimens of the subspecies C. s. simus from Mexico and of neonate specimens of C. s. simus from Central America induce neurotoxic effects. Specimen from Mexico (Photo by Edgar Neri Castro). (d) Crotalus durissus terrificus (family Viperidae), the medically most important rattlesnake in South America, which induces severe envenomings associated with neurotoxicity, myotoxicity, and acute kidney injury. Specimen from Brazil (Photo by Giuseppe Puorto). (e) Micrurus diastema (family Elapidae), a coral snake distributed in Mexico and northern Central America, which provokes neurotoxic envenomings. Specimen from Mexico (Photo by Edgar Neri Castro)

Clinical Aspects of Envenomings

Envenomings by Species of the Family Viperidae

The majority of envenomings provoked by species of the family Viperidae are characterized by a complex combination of local and systemic pathological and pathophysiological alterations. Local effects are characterized by edema, pain, hemorrhage, dermonecrosis, blistering, and myonecrosis (Warrell 2004; Cardoso et al. 2009; Otero-Patiño 2009; Gutiérrez 2010) (Fig. 2). The magnitude of these effects varies according to the severity of envenoming. Mild cases are characterized mostly by local edema and pain, whereas severe envenomings are associated with prominent necrosis which might result in tissue loss resulting in permanent sequelae (Otero et al. 2002; Warrell 2004; Cardoso et al. 2009). Local infection often occurs in the affected tissue, and venom-induced muscle tissue damage promotes colonization by bacteria (Otero et al. 2002; Otero-Patiño 2009). Systemic manifestations of envenomings by viperid snakes are characterized by bleeding; coagulopathy associated with defibrinogenation and incoagulability, together with thrombocytopenia and platelet hypoaggregation; hypovolemia leading to hypotension and cardiovascular shock; and acute kidney injury (Warrell 2004; Cardoso et al. 2009; Otero-Patiño 2009; Gutiérrez 2010). The severity of viperid envenomings depends on a number of factors, mostly the volume of venom injected, but also the site of the bite and the size and physiological constitution of the victim. Snake venoms present notorious inter- and intraspecies variations in their composition due to geographical and ontogenetic factors (Calvete 2011); such variation might influence the clinical outcome of envenomings.
Fig. 2

Local tissue pathology characteristic of envenomings by Bothrops sp. snakes . This 12-year-old boy was bitten by a specimen of Bothrops atrox (upper photograph) in a rural area of Peru. Severe local tissue damage developed, and the necrotic arm was amputated. The delay in medical attention of snakebitten people in many rural regions of Latin America results in complications which might lead to permanent sequelae, like in this case. Deployment of antivenom to rural health posts and proper use of this immunotherapeutic agent by trained health staff should be strengthened in the region. Photos by David A. Warrell (Reprinted from Gutiérrez et al. (2010a) Toxicon 56: 1223–1235, with permission from Elsevier)

There are several exceptions to this predominant clinical picture of viperid envenomings. Bites by South American rattlesnakes classified within the species Crotalus durissus, as well as by other species of rattlesnakes distributed in North America, such as the Mojave rattlesnake C. scutulatus, induce envenomings characterized by the absence of local tissue damage, and instead by neurotoxic manifestations resulting in respiratory paralysis. In addition, these venoms provoke systemic myotoxicity, i.e., rhabdomyolysis, and coagulopathy (Warrell 2004; Azevedo-Marques et al. 2009). On the other hand, envenomings by Bothrops lanceolatus and B. caribbaeus, endemic species in the Lesser Caribbean islands of Martinique and Saint Lucia, respectively, are characterized, in addition to local tissue pathology, by severe thrombotic effects, often resulting in myocardial or cerebral infarctions (Thomas and Tyburn 1996). Patients suffering envenomings by bushmasters (Lachesis sp.) develop, in addition to local tissue damage and systemic hemorrhage, coagulopathy and cardiovascular shock, a unique syndrome characterized by bradycardia, hypotension, abdominal colic, diarrhea, sweating, and vomiting of possible autonomic or autopharmacological origin (Warrell 2004).

Envenomings by Species of the Family Elapidae

Envenomings by coral snakes (genus Micrurus) are scarce (approximately 1 % of the cases in Latin America). These envenomings are characterized by the absence of local effects, except for pain, and by a predominant neurotoxic picture secondary to neuromuscular blockade induced by neurotoxins present in these venoms. Thus, signs and symptoms include palpebral ptosis, diplopia, ophthalmoplegia, dysarthria, and, eventually, respiratory paralysis (Warrell 2004; da Silva and Bucaretchi 2009). However, few clinical reports suggest that some coral snake venoms might induce additional effects, including myotoxicity and mild clotting disturbances, which might complicate the differential diagnosis in snakebite cases. Bites by the only species of the subfamily Hydrophiinae distributed in the Americas, the yellow-bellied sea snake Pelamis platurus, are very infrequent, and antivenoms against its venom are not produced in the region. On the basis of clinical observations performed in bites by other sea snakes, it would be expected that envenomings by P. platurus would be characterized by neurotoxicity and myotoxicity.

Bites by Species of the Family Colubridae (sensu lato)

Colubrid snakes are diverse and abundant in Latin America and induce bites in humans. In South America, cases inflicted by species of the genus Philodryas have been reported to induce mostly local effects, i.e., bruising, edema, and pain, with a low frequency of systemic manifestations. Predominantly local effects have been also described after bites by species of other genera (Prado-Franceschi and Hyslop 2002). Regardless of the low severity usually associated with colubrid bites, care should be taken since there is growing evidence on the biochemical and pharmacological complexity and toxicity of colubrid venoms.

Snake Venoms : Unveiling their Biochemical and Pharmacological Complexity

Since the first decades of the twentieth century, a large body of knowledge on the composition and toxicological profile of snake venoms has developed in Latin America. Many venom components have been isolated and characterized, and the last decade has witnessed the application of proteomic tools in the study of venoms, a field known as “venomics” (Calvete 2011). Proteomic analysis of viperid venoms in the region has unveiled the great complexity of these toxic secretions (Gutiérrez et al. 2009a; Calvete 2011). Viperid venoms are comprised by many different proteins, grouped in a relatively limited number of families. Predominant components are zinc-dependent metalloproteinases (SVMPs), phospholipases A2 (PLA2s), and serine proteinases, followed by other types of proteins which are present in lower amounts, such as C-type lectin-like proteins, disintegrins, cysteine-rich secretory proteins (CRISPs), l-amino acid oxidases, and a number of vasoactive peptides, among others (Alape-Girón et al. 2008; Calvete 2011) (Fig. 3). P-III SVMPs play a key role in local and systemic pathology and pathophysiology associated with hemorrhage, coagulopathy, and cardiovascular disturbances (Gutiérrez et al. 2010b). PLA2s and PLA2 homologues are responsible for the local myonecrosis characteristic of these envenomings, as well as for inflammation and pain (Gutiérrez and Lomonte 2009; Teixeira et al. 2009). In the case of the venoms of some rattlesnakes, such as the South American species Crotalus durissus, a PLA2 heterodimer, known as “crotoxin,” induces neurotoxic and myotoxic effects and is responsible for the predominant alterations characteristic of envenomings by this species (Bon 1997; Gopalakrishnakone et al. 1984) (Fig. 3). Serine proteinases induce clotting disturbances, especially enzymes exerting a “thrombin-like”effect, and also contribute to hemodynamic alterations (Serrano and Maroun 2005). In addition, some C-type lectin-like proteins induce thrombocytopenia (Rucavado et al. 2001), and there are other venom components exerting deleterious actions in viperid envenomings. In the case of Micrurus sp. venoms, proteomic analyses have identified predominantly low molecular mass neurotoxins of the three-finger family, together with abundant PLA2s which contribute to the pathophysiology of envenoming (Corrêa-Neto et al. 2011) (Fig. 3). Short-chain neurotoxins bind to the cholinergic receptor at the motor end plate in muscle fibers and induce neuromuscular blockade, whereas PLA2s induce myotoxicity and, in some cases, neurotoxicity. The venom of Pelamis platurus, the only sea snake in the Americas, contains a postsynaptically acting neurotoxin of the three-finger family (Tu et al. 1975). In resemblance to other sea snakes, it is likely that the venom of P. platurus also presents myotoxic PLA2s.
Fig. 3

Relative occurrence of components from different protein families in the venoms of the viperid snakes Bothrops asper from Costa Rica (a), Crotalus durissus terrificus from Brazil (b), and of the elapid snake Micrurus corallinus from Brazil (c). The proteomic analyses of these venoms were described in detail by Alape-Girón et al. (2008), Calvete et al. (2010), and Corrêa-Neto et al. (2011), respectively. PLA 2 phospholipases A2, SVMP snake venom metalloproteinases, SP serine proteinases, LAO L-amino acid oxidases, Dis disintegrins, CRISP cysteine-rich secretory proteins, CTL C-type lectin-like proteins, VAP vasoactive peptides, 3FT neurotoxins of the three-finger family

Proteomic and pharmacological analysis has shown evidence of a conspicuous pattern of inter- and intraspecies venom variability. The venoms of some species having a wide geographical distribution range, such as Bothrops atrox and species of Crotalus sp., are characterized by conspicuous intraspecies variation (Alape-Girón et al. 2008; Calvete et al. 2010; Calvete 2011). In addition, a complex pattern of ontogenetic venom variation has been also described for various species, such as Crotalus simus (Saravia et al. 2002; Calvete et al. 2010), Bothrops asper (Alape-Girón et al. 2008), Bothrops jararaca (Zelanis et al. 2011), and Lachesis stenophrys (Madrigal et al. 2012). Some venoms present a “paedomorphic” pattern in which the characteristics of the venoms of neonate specimens are maintained in the adults (this is the case of Crotalus durissus in South America), whereas other species are characterized by an “ontogenetic” pattern of venom development in which prominent changes occur during the maturation of individuals to become adults, as occurs in the venom of Crotalus simus from Central America (Calvete et al. 2010). The large variability in venom composition should be considered when designing venom mixtures for immunization of animals for antivenom production, as to ensure that representative venom pools are prepared (Gutiérrez et al. 2009a).

Antivenoms in Latin America: Production and Quality Control

The parenteral administration of antivenoms constitutes the only scientifically validated therapy for snakebite envenoming on a worldwide basis (WHO 2010; Gutiérrez et al. 2011). Vital Brazil and coworkers were the pioneers in the production of these immunobiologicals in Latin America by generating bothropic and crotalid antivenoms at Instituto Butantan in the first decade of the twentieth century. Further developments in the region have resulted in a conglomerate of antivenom manufacturers, both in the public and private realms, in Argentina, Uruguay, Brazil, Peru, Ecuador, Bolivia, Colombia, Venezuela, Costa Rica, and Mexico (Gutiérrez et al. 2007). Detailed information on manufacturers, types of products, and species coverage are included in the WHO webpage devoted to antivenoms (http://apps.who.int/bloodproducts/snakeantivenoms/database/).

The majority of antivenoms produced in the region are polyspecific , i.e., they are generated by immunizing animals (mostly horses) with mixtures of venoms from two or more snake species. In some cases, monospecific antivenoms are produced by immunizing animals with a venom pool from only one snake species (Gutiérrez et al. 2011). Various polyspecific venoms are produced against venoms of Bothrops sp. For instance, in Brazil, a bothropic antivenom of wide distribution and use is prepared by immunizing horses with a mixture of the venoms of Bothrops jararaca, B. jararacussu, B. moojeni, B. neuwiedi, and B. alternatus. In Central America and in Mexico, polyspecific antivenoms are prepared by immunization with a mixture of venoms of Bothrops sp. and Crotalus sp. and in some cases including Lachesis sp. venoms. In addition, monospecific crotalic antivenoms are manufactured in South America, to treat envenomings by the rattlesnake Crotalus durissus. Moreover, various laboratories in Brazil, Colombia, Costa Rica, and Mexico manufacture either monospecific or polyspecific antivenoms for the treatment of envenomings by coral snakes (Micrurus sp.). In addition to these antivenoms manufactured in the region, Sanofi Pasteur produces a monospecific anti-Bothrops lanceolatus antivenom which is used in Martinique for the treatment of envenomings by this endemic species (Thomas and Tyburn 1996).

Antivenoms manufactured in Latin America are of two basic types, depending on the nature of the active neutralizing substance . Some laboratories generate antivenoms composed of whole IgG molecules. These are produced either by salting-out procedures using various concentrations of ammonium sulfate or, alternatively, by caprylic acid precipitation of non-IgG plasma proteins (Rojas et al. 1994; WHO 2010; Gutiérrez et al. 2011). Other laboratories produce antivenoms made of F(ab′)2 antibody fragments, generated by pepsin digestion of plasma proteins, followed by ammonium sulfate precipitation of antibody fragments; in few cases, ion-exchange chromatography is used to further purify the active substance(WHO 2010; Gutiérrez et al. 2011). The WHO has issued guidelines for the production, regulation, and control of antivenom, which constitutes a highly useful document for manufacturers and regulators (WHO 2010). After fractionation of hyperimmune plasma with the methods described, antivenoms are formulated and standardized as to have a specific neutralizing potency against the venoms for which they are produced. The vast majority of antivenom manufacturers use horses for immunization, although donkeys and llamas are used in La Paz, Bolivia (Gutiérrez et al. 2007).

Some countries produce the volume of antivenom required to fulfill the national needs, such as the case of Mexico, Costa Rica, Brazil, and Argentina. On the other hand, Colombia, Venezuela, Peru, Bolivia, and Ecuador have laboratories that generate a volume of antivenom which covers the national demand only to a partial extent, thus having to rely on producers from other countries to fill their national needs. In the cases of countries which do not have antivenom-producing laboratories, their requirements for this product are fulfilled by importing antivenoms from other countries in the region. Antivenom requirements for the Martinique are covered by a French manufacturer.

The quality control of antivenoms is performed both by manufacturer laboratories and regulatory bodies in the ministries of health. They involve a set of biological, chemical, and physical tests, such as neutralizing potency tests in mice, pyrogen test, sterility test, determination of the concentration of protein, preservatives, sodium chloride, excipients of various sorts, and pH, together with tests for turbidity and visual inspection of the product. A complete description of the methodologies for the quality control of antivenoms is provided in the WHO guidelines (WHO 2010). The quality control of locally produced or imported antivenoms is weak in the ministries of health of some countries in Latin America; therefore, it is necessary to promote regional programs and workshops aimed at improving the regional capacity to ensure the efficacy and safety of antivenoms being produced or imported in every country.

The Preclinical Assessment of Antivenom Efficacy

Owing to the large variation in the composition of snake venoms, both within and between species, the assessment of the efficacy of antivenoms to neutralize medically relevant snake venoms is highly relevant to ensure that antivenoms to be used in a specific setting are indeed effective. In general, preclinical testing of antivenoms involves the incubation of a “challenge dose” of venom with various dilutions of the antivenom, following by assessing the toxicity of the mixtures in standard laboratory tests. The single most important test to confirm antivenom efficacy is the neutralization of lethality using mice (WHO 2010; Gutiérrez et al. 2013). However, due to the complexity of the pathophysiological manifestations induced by viperid snake venoms, it has been proposed that a more comprehensive evaluation of preclinical efficacy should include the neutralization of additional effects, such as hemorrhagic, myotoxic, coagulant, and defibrinogenating activities (WHO 2010; Gutiérrez et al. 2013). In the case of coral snake (Micrurus sp.) venoms, the neutralization of lethality properly evaluates the most relevant toxic effect, i.e., neuromuscular paralysis.

Many studies have been performed in Latin America to assess the preclinical efficacy of antivenoms produced in various countries (see, e.g., de Roodt et al. 1998; Bogarín et al. 2000; Camey et al. 2002). Recently, a large collaborative regional project evaluated several antivenoms against the venoms of the medically most important Bothrops species in the region (Segura et al. 2010). In general, these studies have shown a notorious cross-neutralization by antivenoms against heterologous viperid snake venoms, thus supporting the use of some antivenoms in countries different from where they are produced, facilitating regional cooperation in antivenom distribution. On the other hand, there are cases where antivenoms are not effective against venoms from different geographical settings. For example, crotalic antivenoms manufactured in Central America do not neutralize lethality of Crotalus sp. venoms from South America, and antivenoms prepared against C. durissus from South America are not effective in the neutralization of hemorrhagic activity of C. simus from Central America (Saravia et al. 2002). Such observations are explained by the different venom composition, since C. durissus is rich in the neurotoxic PLA2 complex crotoxin, which is largely absent in the venoms of adult specimens of C. simus. On the other hand, the latter contains hemorrhagic metalloproteinases, which are absent in South American C. durissus (Calvete et al. 2010). Likewise, bothropic antivenoms are not effective in the neutralization of coagulant and defibrinogenating effects induced by Lachesis sp. venoms (Colombini et al. 2001). Moreover, there is limited cross-reactivity between species in the case of antivenoms against Micrurus sp. venoms.

Evaluation of Antivenom Efficacy and Safety at the Clinical Level

After the demonstration of efficacy at the preclinical level, the introduction of a new antivenom for clinical use in a particular geographical setting should be preceded by appropriate clinical assessment of its efficacy and safety, as established by the WHO (2010). In many instances in Latin America, clinical evidence in support of the use of some antivenoms derives from nonsystematic observations of many years on the efficacy and safety of antivenoms. In the last decades, however, efforts have been implemented to perform controlled, randomized clinical trials (see, e.g., Cardoso et al. 1993; Otero et al. 1999; Otero-Patiño et al. 1998). The efficacy of antivenoms manufactured in Brazil, Colombia, Ecuador, México, and Costa Rica has been demonstrated, and novel findings concerning antivenom safety have been made. For instance, it has been shown that ammonium sulfate-fractionated whole IgG antivenoms induce a higher incidence of early adverse reactions than caprylic acid-fractionated whole IgG antivenoms (Otero-Patiño et al. 1998; Otero et al. 1999). Likewise, some of these studies demonstrated that the incidence of early adverse reactions is similar in whole IgG antivenoms manufactured by caprylic acid precipitation of plasma and in F(ab′)2 antivenoms prepared by pepsin digestion and ammonium sulfate fractionation (Otero-Patiño et al. 1998). It is necessary to further explore the clinical profile of safety and efficacy of antivenoms produced in Latin America through international cooperative projects, on the basis of the expertise developed in some countries in the region. Moreover, it is important to assess specific aspects of the therapy of snakebite envenomings, such as the time required, after administration of the antivenom, to correct the main clinical manifestations of envenoming, i.e., bleeding and coagulopathies in the case of viperid snakebite envenomings (Cardoso et al. 1993; Otero et al. 1999).

Beyond Science and Technology: The Issue of Antivenom Distribution

Even if antivenom production in Latin America is improved, with the consequent increment in the volume of antivenom available for public health systems, and with the generation of products if high efficacy and safety, this does not ensure that antivenoms will be accessible to people suffering snakebite envenomings. Additional factors within the public health realm determine whether these products are available and accessible to the people that need them. Some factors relevant for the distribution of antivenoms, and which should be considered by health authorities, are the following:
  1. 1.

    The distribution of antivenoms should be based on a meticulous knowledge of the epidemiology of envenomings. A proper understanding on the incidence of these accidents in different regions, and the species of snakes responsible for the accidents, is necessary to estimate the number of antivenom doses that need to be deployed to various regions in a country. Unfortunately, such information is scarce in many countries; moreover, even when the information is available, the decisions on antivenom distribution are not necessarily based on these data. It is therefore necessary to improve the epidemiological records of snakebite envenomings in the region and to ensure that this information is properly used for the design of antivenom distribution policies. The use of novel tools, such as geographical information system (GIS) methods, should contribute to a better understanding of vulnerable areas that demand attention regarding antivenom accessibility (Leynaud and Reati 2009; Hansson et al. 2013). Likewise, distribution systems must ensure that antivenoms will be allocated to the rural health posts where the majority of snakebites occur.

     
  2. 2.

    The policies and procedures for antivenom acquisition by public health authorities are often cumbersome, bureaucratic, and slow, thus precluding a rapid response to cope with antivenom needs. Novel schemes for the purchase of antivenoms should be devised to ensure that the required volumes of effective antivenoms are available. Advocacy should be promoted to ensure that governments will allocate the necessary resources for the purchase of the needed volume of antivenom to avoid shortages of this precious drug in some regions or some times of the year. Moreover, it is necessary to keep the antivenom prices at a level that guarantees the acquisition of the required volumes to cover the needs of the various countries.

     
  3. 3.

    The maintenance of a functional “cold chain” has to be guaranteed to ensure that liquid antivenoms, which should be kept at 2–8 °C (Gutiérrez et al. 2009b; WHO 2010), are properly transported and stored. This issue is of concern in many regions of Latin America, where power supply often fails and where conditions to keep the cold chain are not always present. Investment in the cold chain system should be promoted, together with the use of cold chain channels already developed for vaccines in the region. In addition, the staff in charge of antivenom transportation and storage should be trained in the basic aspects of the cold chain. Several antivenoms manufactured in Latin America are freeze-dried, thus avoiding the need of a cold chain (Gutiérrez et al. 2009b); however, the majority of the products available in the region are liquid antivenoms. There have been efforts to increase the thermal stability of liquid antivenoms, for example, by using excipients such as sorbitol (Segura et al. 2009). Technological development projects in this subject should be promoted.

     
  4. 4.

    The lack of health centers in many rural regions of Latin America where snakebites are frequent represents a serious drawback in the efforts to reduce the impact of this pathology. The deficient investment, over several decades, in public health systems in many countries, has had serious implications for an effective attention of health problems. This structural constraint demands renewed political efforts at many levels, from the central government to local community organizations and health advocacy groups of various sorts.

     

How to Ensure the Adequate Use of Antivenoms

Even if antivenoms are available and accessible at the health posts where most snakebites occur in Latin America, there is a need to guarantee that the health personnel in charge of attending snakebite victims is well trained in the diagnosis of envenomings and in the proper treatment of this pathology, including the use of antivenoms (correct dose, management of adverse reactions, need of an additional dose, etc.) and the ancillary treatment of snakebite envenomings. This task includes the coverage of this subject in the programs of study of medicine and nursing in universities. Moreover, continuous education programs for health personnel, especially in rural areas, should be designed and implemented. These activities should come together with the publication and distribution of national and regional guidelines for the diagnosis and management of envenomings, such as the ones that have been prepared in Brazil, Costa Rica, Panamá, Argentina, Venezuela, and Paraguay, among other countries (Gutiérrez 2011 and references therein). It is also necessary to develop novel methodologies, taking advantage of the possibilities offered by communication and information technologies, aimed at extending the scope of training programs for health personnel in the region.

People Suffering from Sequelae: A Poorly Attended Aspect of Snakebite Envenoming

Viperid snakebites in Latin America are often characterized by prominent tissue damage at the site of venom injection, i.e., necrosis, blistering, and hemorrhage (Gutiérrez and Lomonte 2009). Antivenom is only partially effective in the neutralization of these effects, since they develop very rapidly, thus generating significant tissue damage before antivenom is administered. As a consequence, people suffering from severe viperid bites often end up with permanent tissue damage, which have a notorious impact in their quality of life. Since the majority of affected people are agricultural young workers or children, these sequelae have evident deleterious effects from the economic and social standpoints. Moreover, it is very likely that people suffering from snakebite envenomings in Latin America develop psychological sequelae , as has been described in Sri Lanka (Williams et al. 2011). In the vast majority of cases, there is no follow-up of snakebitten patients after they leave hospitals and other health facilities, and, consequently, there is a lack of attention to the sequelae that affect them. This demands renewed efforts to understand the magnitude of this aspect of the problem and to establish intervention programs aimed at providing these people with resources to confront the long-term consequences of envenomings.

Prevention of Snakebites and Improvement of the Early Attention of Victims

Public campaigns aimed at the prevention of snakebites constitute a key component of the regional strategy to reduce the impact of this health problem. Such campaigns should involve diverse stakeholders, including health authorities, community groups of various sorts (health advocacy associations, art groups, youth groups, teachers, etc.), and other actors. The participation of local authorities and community organizations is required to ensure that the campaigns will be designed and performed on the basis of local cultural, social, economic, and political contexts. Since the large majority of snakebites occur in the feet and hands, preventive measures such as wearing shoes while doing agricultural duties, and using a stick to avoid hand exposure, can reduce the incidence of snakebites. Information campaigns on snakebite prevention in primary and high schools in rural areas, as well as in agricultural associations and other groups at risk, need to be reinforced. Particular attention has to be given to vulnerable groups often excluded from the provision of health services, such as indigenous communities and remote rural localities. In this regard, the involvement of both public and private sector organizations, in addition to governmental agencies, is necessary through diverse innovative and cooperative programs.

A key aspect for the reduction of the impact of these envenomings is the appropriate early attention to snakebite victims. Once a person has suffered a snakebite, he or she should be immediately transported to the nearest health post to receive antivenom and other aspects of medical care. Thus, communities should be organized in such a way that people receive rapid attention after a snakebite; this involves implementing transport systems, which have to be designed on the basis of the local contexts. In some cases, this can be achieved by ambulance transportation, whereas in others by the use of private cars, motorcycles, boats, or other means. In this regard, a common problem in the region is the implementation of actions at the local level which might worsen the cases, such as the use of harmful first aid interventions (application of tourniquets or ligatures, incisions, administration of toxic substances, etc.). Besides their direct deleterious effects, these interventions result in a delay in the transportation of the patient to health facilities. It is necessary to develop campaigns to promote a dialogue between health staff and people working in traditional medicine, with the aim of reducing the use of harmful practices and promoting the rapid deployment of patients to health facilities. A successful project, supported by the Pan American Health Organization (PAHO), was developed in Nicaragua, in which traditional healers and staff from the Ministry of Health established a fruitful dialogue and agreed on policies of intervention for the benefit of people affected by snakebites (Luz Marina Lozano, personal communication).

Conclusions and Future Directions

Snakebite envenoming represents a serious public health problem in Latin America and in few Caribbean islands. The majority of cases are inflicted by species of the family Viperidae, which provoke envenomings characterized by local and systemic pathological alterations that may provoke lethality or permanent tissue damage and psychological sequelae. A large body of knowledge has been built in the region on the biochemical and pharmacological characteristics of snake venoms, as well as on the clinical manifestations of envenomings. Toxinological research, both basic and clinical, should be fostered in the region. There are antivenom manufacturing laboratories in many Latin American countries. Regional cooperative networks are necessary to improve the regional production and quality control of antivenoms, in order to guarantee the availability of safe and effective products throughout Latin America. Despite important advances in confronting this problem, there are still vulnerable regions where the provision of health services and the proper medical attention of snakebitten patients, including the administration of antivenoms, are deficient. Likewise, there is a need to improve the epidemiological information on snakebites in order to design knowledge-based policies of antivenom distribution, training of health personnel, and deployment of medical services. The medical management of cases has to be also improved through the provision of health services to the population, the training of health staff in the diagnosis and treatment of snakebite envenomings, and the access to safe and effective antivenoms. The social, psychological, and economic consequences of snakebite envenomings are largely unknown, and therefore, renewed efforts should be implemented to gain a better understanding of these aspects of the problem. Finally, people suffering from permanent sequelae, both physical and psychological, as a consequence of envenomings should receive proper attention, and preventive campaigns have to be implemented and strengthened, with the involvement of diverse participants, including local community organizations. All these pending tasks demand the development of integrated multisectorial strategies at the national and regional levels, with the long-term goal of reducing the impact of this neglected pathology in the region.

Cross-References

References

  1. Alape-Girón A, Sanz L, Escolano J, Flores-Díaz M, Madrigal M, Sasa M, Calvete JJ. Snake venomics of the lancehead pitviper Bothrops asper: geographic, individual, and ontogenetic variations. J Proteome Res. 2008;7(8):3556–71.PubMedCrossRefGoogle Scholar
  2. Azevedo-Marques MM, Hering SE, Cupo P. Acidente crotálico. In: Cardoso JLC, França FOS, Wen FH, Málaque CMS, Haddad Jr V, editors. Animais Peçonhentos no Brasil. Biologia, Clínica e Terapêutica dos Acidentes. 2nd ed. São Paulo: Sarvier; 2009.Google Scholar
  3. Bogarín G, Morais JF, Yamaguchi IK, Stephano MA, Marcelino JR, Nishikawa AK, Guidolin R, Rojas G, Higashi HG, Gutiérrez JM. Neutralization of crotaline snake venoms from Central and South America by antivenoms produced in Brazil and Costa Rica. Toxicon. 2000;38:1429–41.PubMedCrossRefGoogle Scholar
  4. Bon C. Multicomponent neurotoxic phospholipases A2. In: Kini RM, editor. Venom phospholipase A2 enzymes: structure, function and mechanism. Chichester: Wiley; 1997.Google Scholar
  5. Calvete JJ. Proteomic tools against the neglected pathology of snake bite envenoming. Expert Rev Proteomics. 2011;8:739–58.PubMedCrossRefGoogle Scholar
  6. Calvete JJ, Sanz L, Cid P, de la Torre P, Flores-Díaz M, dos Santos MC, Borges A, Bremo A, Angulo Y, Lomonte B, Alape-Girón A, Gutiérrez JM. Snake venomics of the Central American rattlesnake Crotalus simus and the South American Crotalus durissus complex points to neurotoxicity as an adaptive paedomorphic trend along Crotalus dispersal in South America. J Proteome Res. 2010;9:528–44.PubMedCrossRefGoogle Scholar
  7. Camey KU, Velarde DT, Sanchez EF. Pharmacological characterization and neutralization of the venoms used in the production of Bothropic antivenom in Brazil. Toxicon. 2002;40:501–9.PubMedCrossRefGoogle Scholar
  8. Cardoso JL, Fan HW, França FOS, Jorge MT, Leite RP, Nishioka SA, Avila A, Sano-Martins IS, Tomy SC, Santoro ML, Chudzinski AM, Castro SCB, Kamiguti AS, Kelen EMA, Hirata MH, Mirandola RMS, Theakston RDG, Warrell DA. Randomized comparative trial of three antivenoms in the treatment of envenoming by lance-headed vipers (Bothrops jararaca) in Sao Paulo, Brazil. Q J Med. 1993;86:315–25.PubMedGoogle Scholar
  9. Cardoso JLC, França FOS, Wen FH, Málaque CMS, Haddad Jr V. Animais Peçonhentos no Brasil. Biologia, Clínica e Terapêutica dos Acidentes. 2nd ed. São Paulo: Sarvier; 2009.Google Scholar
  10. Colombini M, Fernandes I, Cardoso DF, Moura-da-Silva AM. Lachesis muta muta venom: immunological differences compared with Bothrops atrox venom and importance of specific antivenom therapy. Toxicon. 2001;39:711–9.PubMedCrossRefGoogle Scholar
  11. Corrêa-Neto C, Junqueira-de Azevedo IL, Silva DA, Ho PL, Leitao-de-Araújo M, Alves ML, Sanz L, Foguel D, Zingali RB, Calvete JJ. Snake venomics and venom gland transcriptomic analysis of Brazilian coral snakes, Micrurus altirostris and M. corallinus. J Proteomics. 2011;74:1795–809.CrossRefGoogle Scholar
  12. da Silva NJ, Bucaretchi F. Mecanismo de ação do veneno elapídico e aspectos clínicos dos accidentes. In: Cardoso JLC, França FOS, Wen FH, Málaque CMS, Haddad Jr V, editors. Animais Peçonhentos no Brasil. Biologia, Clínica e Terapêutica dos Acidentes. 2nd ed. São Paulo: Sarvier; 2009.Google Scholar
  13. de Oliveira RC, Wen FH, Sifuentes DN. Epidemiologia dos accidentes por animais peçonhentos. In: Cardoso JLC, França FOS, Wen FH, Málaque CMS, Haddad Jr V, editors. Animais Peçonhentos no Brasil. Biologia, Clínica e Terapêutica dos Acidentes. 2nd ed. São Paulo: Sarvier; 2009.Google Scholar
  14. de Roodt A, Dolab JA, Fernández T, Segre L, Hajos EE. Cross-reactivity and heterologous neutralisation of crotaline antivenoms used in Argentina. Toxicon. 1998;36:1025–38.PubMedCrossRefGoogle Scholar
  15. Gopalakrishnakone P, Dempster DW, Hawgood BJ, Elder HY. Cellular and mitochondrial changes induced in the structure of murine skeletal muscle by crotoxin, a neurotoxic phospholipase A2 complex. Toxicon. 1984;22:85–98.PubMedCrossRefGoogle Scholar
  16. Gutiérrez JM. Snakebite envenomation in Central America. In: Mackessy SP, editor. Handbook of venoms and toxins of reptiles. Boca Raton: CRC Press; 2010.Google Scholar
  17. Gutiérrez JM. Envenenamientos por mordeduras de serpientes en América Latina y el Caribe: Una visión integral de carácter regional. Boletín de Malariología y Salud Ambiental. 2011;51:1–16.Google Scholar
  18. Gutiérrez JM, Lomonte B. Efectos locales en el envenenamiento ofídico en América Latina. In: Cardoso JLC, França FOS, Wen FH, Málaque CMS, Haddad Jr V, editors. Animais Peçonhentos no Brasil. Biologia, Clínica e Terapêutica dos Acidentes. 2nd ed. São Paulo: Sarvier; 2009.Google Scholar
  19. Gutiérrez JM, Higashi HG, Wen FH, Burnouf T. Strengthening antivenom production in Central and South American public laboratories: report of a workshop. Toxicon. 2007;49:30–5.PubMedCrossRefGoogle Scholar
  20. Gutiérrez JM, Lomonte B, León G, Alape-Girón A, Flores-Díaz M, Sanz L, Angulo Y, Calvete JJ. Snake venomics and antivenomics: proteomic tools in the design and control of antivenoms for the treatment of snakebite envenoming. J Proteomics. 2009a;72:165–82.PubMedCrossRefGoogle Scholar
  21. Gutiérrez JM, Fan HW, Silvera CL, Angulo Y. Stability, distribution and use of antivenoms for snakebite envenomation in Latin America: report of a workshop. Toxicon. 2009b;53:625–30.PubMedCrossRefGoogle Scholar
  22. Gutiérrez JM, Williams D, Fan HW, Warrell DA. Snakebite envenoming from a global perspective: towards an integrated approach. Toxicon. 2010a;56:1223–35.PubMedCrossRefGoogle Scholar
  23. Gutiérrez JM, Rucavado A, Escalante T. Snake venom metalloproteinases. Biological roles and participation in the pathophysiology of envenomation. In: Mackessy SP, editor. Handbook of venoms and toxins of reptiles. Boca Raton: CRC Press; 2010b.Google Scholar
  24. Gutiérrez JM, León G, Lomonte B, Angulo Y. Antivenoms for snakebite envenomings. Inflamm Allergy Drug Targets. 2011;10:369–80.PubMedCrossRefGoogle Scholar
  25. Gutiérrez JM, Solano G, Pla D, Herrera M, Segura Á, Villalta M, Vargas M, Sanz L, Lomonte B, Calvete JJ. Assessing the preclinical efficacy of antivenoms: from the lethality neutralization assay to antivenomics. Toxicon. 2013;69:168–79.PubMedCrossRefGoogle Scholar
  26. Hansson E, Sasa M, Mattisson K, Robles A, Gutiérrez JM. Using geographical information systems to identify populations in need of improved accessibility to antivenom treatment for snakebite envenoming in Costa Rica. PLoS Negl Trop Dis. 2013;7:e2009.PubMedCentralPubMedCrossRefGoogle Scholar
  27. Harrison RA, Hargreaves A, Wagstaff SC, Faraguer B, Lalloo DG. Snake envenoming: a disease of poverty. PLoS Negl Trop Dis. 2009;3:e569.PubMedCentralPubMedCrossRefGoogle Scholar
  28. Kasturiratne A, Wickremasinghe AR, de Silva N, Gunawardena NK, Pathmeswaran A, Premaratna R, Savioli L, Lalloo DG, de Silva HJ. The global burden of snakebite: a literature analysis and modeling based on regional estimates of envenoming and deaths. PLoS Negl Trop Dis. 2008;5:e218.Google Scholar
  29. Leynaud GC, Reati GJ. Identificación de las zonas de riesgo ofídico en Córdoba, Argentina, mediante el programa SIGEpi. Rev Panam Salud Publica. 2009;26:64–9.PubMedCrossRefGoogle Scholar
  30. Madrigal M, Sanz L, Flores-Díaz M, Sasa M, Núñez V, Alape-Girón A, Calvete JJ. Snake venomics across genus Lachesis. Ontogenetic changes in the venom composition of Lachesis stenophrys and comparative proteomics of the venoms of adult Lachesis melanocephala and Lachesis acrochorda. J Proteomics. 2012;77:280–97.PubMedCrossRefGoogle Scholar
  31. Otero R, Gutiérrez JM, Rojas G, Núñez V, Díaz A, Miranda E, Uribe AF, Silva JF, Ospina JG, Medina Y, Toro MF, García ME, León G, García M, Lizano S, de la Torre J, Márquez J, Mena Y, González N, Arenas LC, Puzón A, Blanco N, Sierra A, Espinal ME, Arboleda M, Jiménez JC, Ramírez P, Díaz M, Guzmán MC, Barros J, Henao S, Ramírez A, Macea U, Lozano R. A randomized blinded clinical trial of two antivenoms, prepared by caprylic acid or ammonium sulphate fractionation of IgG in Bothrops and Porthidium snake bites in Colombia: correlation between safety and biochemical characteristics of antivenoms. Toxicon. 1999;37:895–908.PubMedCrossRefGoogle Scholar
  32. Otero R, Gutiérrez J, Mesa MB, Duque E, Rodriguez O, Arrange JL, Gómez F, Toro A, Cano F, Rodriguez LM, Caro E, Martínez J, Cornejo W, Gómez LM, Uribe FL, Cárdenas S, Núñez V, Díaz A. Complications of Bothrops, Porthidium, and Bothriechis snakebites in Colombia. A clinical and epidemiological study of 39 cases attended in a university hospital. Toxicon. 2002;40:1107–14.PubMedCrossRefGoogle Scholar
  33. Otero-Patiño R. Epidemiological, clinical and therapeutic aspects of Bothrops asper bites. Toxicon. 2009;54:998–1011.PubMedCrossRefGoogle Scholar
  34. Otero-Patiño R, Cardoso JLC, Higashi HG, Núñez V, Díaz A, Toro MF, García ME, Sierra A, García LF, Moreno AM, Medina MC, Castañeda N, Silva-Díaz JF, Murcia M, Cárdenas SY, Dias-da-Silva W. A randomized, blinded, comparative trial of one pepsin-digested and two whole IgG antivenoms for Bothrops snake bites in Uraba, Colombia. Am J Trop Med Hyg. 1998;58:183–9.PubMedGoogle Scholar
  35. Prado-Franceschi J, Hyslop S. South American colubrid envenomations. J Toxicol Toxin Rev. 2002;21:117–58.CrossRefGoogle Scholar
  36. Rojas G, Jiménez JM, Gutiérrez JM. Caprylic acid fractionation of hyperimmune horse plasma: description of a simple procedure for antivenom production. Toxicon. 1994;32:351–63.PubMedCrossRefGoogle Scholar
  37. Rucavado A, Soto M, Kamiguti AS, Theakston RDG, Fox JW, Escalante T, Gutiérrez JM. Characterization of aspercetin, a platelet aggregating component from the venom of the snake Bothrops asper which induces thrombocytopenia and potentiates metalloproteinase-induced hemorrhage. Thromb Haemost. 2001;85:710–5.PubMedGoogle Scholar
  38. Saravia P, Rojas E, Arce V, Guevara C, López JC, Chaves E, Velásquez R, Rojas G, Gutiérrez JM. Geographic and ontogenic variability in the venom of the neotropical rattlesnake Crotalus durissus: pathophysiological and therapeutic implications. Rev Biol Trop. 2002;50:337–46.PubMedGoogle Scholar
  39. Sasa M, Vázquez S. Snakebite envenomation in Costa Rica: a revision of incidence in the decade 1990–2000. Toxicon. 2003;41:19–22.PubMedCrossRefGoogle Scholar
  40. Segura A, Herrera M, González E, Vargas M, Solano G, Gutiérrez JM, León G. Stability of equine IgG antivenoms obtained by caprylic acid precipitation: towards a liquid formulation stable at tropical room temperature. Toxicon. 2009;53:609–15.PubMedCrossRefGoogle Scholar
  41. Segura A, Castillo MC, Núñez V, Yarlequé A, Gonçalves LRC, Villalta M, Bonilla C, Herrera M, Vargas M, Fernández M, Yano MY, Araújo HP, Boller MA, León P, Tintaya B, Sano-Martins IS, Gómez A, Fernández GP, Geoghegan P, Higashi HG, León G, Gutiérrez JM. Preclinical assessment of the neutralizing capacity of antivenoms produced in six Latin American countries against medically-relevant Bothrops snake venoms. Toxicon. 2010;56:980–9.PubMedCrossRefGoogle Scholar
  42. Serrano SM, Maroun RC. Snake venom serine proteinases: sequence homology vs. substrate specificity, a paradox to be solved. Toxicon. 2005;45:1115–32.PubMedCrossRefGoogle Scholar
  43. Teixeira C, Cury Y, Moreira V, Picolo G, Chaves F. Inflammation induced by Bothrops asper venom. Toxicon. 2009;54:988–97.PubMedCrossRefGoogle Scholar
  44. Thomas L, Tyburn B. Research group on snake bite in Martinique. Bothrops lanceolatus bites in Martinique: clinical aspects and treatment. In: Bon C, Goyffon M, editors. Envenomings and their treatments. Lyon: Fondation Marcel Mérieux; 1996.Google Scholar
  45. Tu AT, Lin TS, Bieber L. Purification and chemical characterization of the major neurotoxin from the venom of Pelamis platurus. Biochemistry. 1975;14:3408–13.PubMedCrossRefGoogle Scholar
  46. Warrell DA. Snakebites in Central and South America: epidemiology, clinical features, and clinical management. In: Campbell JA, Lamar WW, editors. The venomous reptiles of the western hemisphere, vol. I. Ithaca: Cornell University Press; 2004.Google Scholar
  47. Williams D, Gutiérrez JM, Harrison R, Warrell DA, White J, Winkel KD, Gopalakrishnakone P. The Global Snake Bite Initiative: an antidote for snake bite. Lancet. 2010;375:89–91.PubMedCrossRefGoogle Scholar
  48. Williams SS, Wijesinghe CA, Jayamanne SF, Buckley NA, Dawson AH, Lalloo DG, de Silva HJ. Delayed psychological morbidity associated with snakebite envenoming. PLoS Negl Trop Dis. 2011;5:e1255.PubMedCentralPubMedCrossRefGoogle Scholar
  49. World Health Organization. Guidelines for the production, control and regulation of snake antivenom immunoglobulins. Geneva: WHO; 2010. Available from: www.who.int/bloodproducts/snakeantivenoms.Google Scholar
  50. Zelanis A, Tashima AK, Pinto AF, Leme AF, Stuginski DR, Furtado MFD, Sherman NE, Ho PL, Fox JW, Serrano SMT. Bothrops jararaca venom proteome rearrangement upon neonate to adult transition. Proteomics. 2011;11:4218–28.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  1. 1.Facultad de Microbiología, Instituto Clodomiro PicadoUniversidad de Costa RicaSan JoséCosta Rica

Personalised recommendations