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Antivenom serum production in Ecuador

Antivenom serum production in Ecuador : 작성자, 카테고리, 작성일, 조회수, 원문,출처, 정보 제공
작성자 관리자 카테고리 전문가 인사이트
작성일 2016-11-03 조회수 3,675
원문
출처

Antivenom serum production in Ecuador

전문가
글 Esteban Ortiz Prado
GPKOL위원
컨설팅 분야
  • R&D Planning
  • Clinical Trial
  • GMP, GCP and Regulatory Affairs
  • Project management
주요 약력
  • 2015-Present: TID/ Chief research and development executive officer
  • 2013-2015: ENFARMA/Manager
  • 2012-2013: Minister of Higher Education/ Senior Adviser
  • 2011-2012: Tom Banker Cancer Centre/ Clinical Research Coordinator
  • 2006-2010: University of Galgary/Department of Radiology/Research Associate

ABSTRACT

Ecuador is a country where snake anti-venom serum was produced by the National Institute of Hygiene “Izquieta Perez” until 2012. During the partition of this institute in the National Institute of Health (INSPI) and The National Agency for Regulation and Control Health Surveillance (ARCSA), the antivenom facility became isolated from the two institutions, leading Ecuador to a pitfall regarding snake antivenom. In 2014, Enfarma EP, the only publicly funded pharmaceutical company in Ecuador tries to produce this biologic product, however and due to several political and administrative problems, Enfarma EP could not keep their production. In Ecuador the needs for this type of product are growing everyday, several number of cases are treated with imported snake anti-venom serum, leading in some adverse events reported to the Minister of Public Health. The goal of this review is to offer an insight to potential Korean Pharmaceutics and investors whom might be willing to invest in Ecuador.

Keywords: Antivenom serum, pharmaceutical market, vaccine facility, snake

INTRODUCTION

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Poisoning by snake bites is a global health problem that requires attention of health authorities at regional and global levels. Accidents caused by snakebites are considered an occupational and environmental disease affecting farmers or their family, mainly in developing countries in Latin America, Africa and Oceania (1). Despite its importance and risk, this disease is qualified by WHO as one of the neglected diseases, since it has been developed little innovation in healthcare and pharmaceutical research about it, compared to other diseases(1). Up to the present, the Anti-venom serum is the only specific treatment for poisoning by snake bites. Therefore, their production is crucial in the treatment of these snakebites. The function of Anti-venom serum is to neutralize poisons used in its production to avoid toxicity in the organism(2). Several decades ago, researchers have shown that these poisons are important sources of pharmacologically active molecules and promising compounds (3).The importance of Anti-venom serum is that their effectiveness helps to reduce situations that pose a threat of life for the population (4). Therefore, we consider relevant to carry out a review of the Anti-venom serum in terms of its development, history, epidemiology, mechanisms of action and production methods.

HISTORICAL REVIEW

Anti Venom Production History

The first Anti-venom serum for human use was developed by Dr. Albert Calmette in 1895, at the Pasteur Institute of Lille in France (5).This serum anti-cobra revolutionized the treatment of snakebites worldwide(2).

Figure 1. Milestones in the discovery and development of antivenoms

Figure 1. Milestones in the discovery and development of antivenoms.

Dr. Calmette was the first to extract the venom of the glands of snakes and store with glycerol to maintain its lethal activity(5).Calmette studied the physiology of snakebite poisoning and the effectiveness of various antiseptic substances such as treatment. During his trials, Calmette noted that gold chloride 1% was an agent capable of preventing poisoning cobra venom because the poison adhered to this agentforming a solid precipitate.This fact gave a clue that effective treatment against snake bite poisoning was related to the use of antiserum. Calmette began to conduct experiments with successive inoculations cobra venom heat inactivated or mixed with gold chloride(5).
In 1894, Calmette injected to rabbits a dose of 2mg. cobra venom diluted in a solution of calcium hypochlorite at regular intervals on 5 days. After a monthwas achieved to immunize rabbits against a dose of 2mgof pure poison(5).Additionally, the sera of animals immunized neutralized the cobra venom toxicity in vitro, and allowed preventive immunization in vivo. Calmette presented his discovery at the meeting of the Society of Biology on 10 February 1894(6). He noted that inject a rabbit with the serum of another immunized against 20 lethal doses of venom; the first will not show signs of poisoning when you inject twice the lethal dose of a poison. He added that this effect of immunization is even greater if the antivenom is injected 24 hours before. The same dose of venom injected into an animal that hasn’t received the antiserum previously would kill it in about 3 hours. (5). This experiment was the basis of immunization with antivenom against snake bite poisoning. Calmette recommended at this conference that the poisoning symptoms appear, it should be injected into the peritoneum or under the skin of the animal in different areas of its body 6cc or 8cc of immunizing serum.
This serum produces fever, but in 48 hours the animal returns to normal. The demonstration of Calmette on the effectiveness of theanti-cobra serotherapy revolutionized the treatment for snake bites in humans and domesticanimals worldwide(5).
Once demonstrated the effectiveness of the serotherapy, it was important to know the mechanism of action toxin-antitoxin. Calmette and Massol showed that the poison/antivenom complex can be ruptures by strong acids, alcohol or temperatures higher than 75° C, suggesting an interaction of proteins. It was also shown that the toxicity of the genus Crotalus, was due to the high content ofhemorrhagic protein, against which the anti-Naja serum has no activity, resulting ineffective. These events strengthened the idea of the specificity of the serum against proteins that compose it. Therefore, Calmette immediately beganof polyspecific sera horses involving all neurotoxins and hemolytic proteins(5).
Similarly, several experiments around the world contributed to the development of the first antivenom. In 1877, Fornara performed the first successful experiment of immunization inoculating a dog with secretions from frogs. In 1887, Sewall used the same methodology to immunize pigeons against the venom of a rattlesnake. In 1890 Behring and Kitasato developed tetanus antitoxin and later in 1891 Behring developed an antitoxin against diphtheria. These experiments supported the effectiveness of the immunization of animals to obtain specific antibodies that can be used for passive immunization or serotherapy.Finally, in 1895 Calmette commercially prepared the antivenom for the cobra India Naja naja, by immunization of horse(4)(2).
Another pioneer researcher in the development of antivenom was Dr. Vital Brazil in Sao Paulo.In 1897, Dr. Brazil showed that the serum anti-cobra Naja naja developed by Calmette was not effective against the species Crotalus durissus terrificus and Bothrops jararaca of their country.This was the first evidence of the specificity of the antivenoms.Vital Brazil studied the physiology of poisoning by Bothrops jaraca and Crotalus durissus terrificus. The first species cause intense local reaction with a swelling of the area of the bite due to hemorrhagic edema.On the other hand, the second species cause a mild local reaction, but there are signs of neurotoxicity as ptosis and asphyxia(7).
In 1889, Vital Brazil increased the evidence relating to the specificity of antivenoms, to observe that the dogs immunized against B. jararca were not protected against the poison of C. d. terrificus. Brazil then suggested the need to develop polyspecific antivenoms to treat snake bites;and in 1901 began to inject venom from C. d. terrificus or a mixture of poisons from B. jararca. B. atrox and B. alternatus on horses and mules for antivenom. In the same year the first scientific publications about serum therapy for the treatment of snakebites were made.Brazil showed that the serum produced by Calmette was effective against neurotoxicvenom and very little effective againstpoisons with hemorrhagic action. Therefore, it announced the production of a polyspecific antivenom, which consisted of a mixture of anti-rattlesnake serum and bothropic antivenom, which were the most common poisonous species in natural accidents snakebites. (7).

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In 1903, Vital Brazil and his team were devoted to the study the proteolytic activity, hemolytic, and coagulant of poisons in vitro and in vivo in dogs as animal models.They also studied methods to increase the potency of monospecific and polyspecific antivenoms.They developed methods for determining the power and showed that the antivenom should be administered up to 6 hours after the snakebite, for best results. In addition, Brazil began studying herpetology of snakes in his country(7).In 1915, the specificity of the antivenom was demonstrated when a patient bitten by Crotalus atrox was treated with an anti-rattlesnake antivenom from C. d. terrificus. An important discovery of Brazil was the fact that the antitoxins were in the fraction of serum globulins, therefore was introduced in the process of purification and concentration of antivenoms(7).
In parallel, in other countries several scientists also showed the lack of effectiveness of the serum developed by Calmette against the poison of local species. In the United States, in 1899 Mc Farland began experiments to develop sera for the venoms from Crotalus, Agkistrodon and Cerastes species, because the antivenom Calmette was not effective against the venom of Crotalus an American.
In Australia, Tidswell and Mastin noticed the lack of action of antivenom of calmette and began to inject horses with the venom of Notechis scutatus, developing the first Australian experimental poison in 1901(8).And the first antivenom for human use in 1930. Subsequently, were developed other antivenoms for snakes Taipan, snake coffee, death adder, Papuan black snake, is snake and polyspecific in 1962(8).
In India, the experiments carried out by Lamb also showed that poisons should be specific depending on whether they are bleeding or neurotoxic. Lamb pointed outsome of the drawbacks in the production of antivenom, such as collecting snakes and poisons and the difficulty in identifying the type of poisoning in the person. Meanwhile Vital Brazil, tried to solve these problems, training people on the therapeutic effectiveness of antivenom and exchanging snake antivenom and injections as a source of poison snakes(7).
The introduction of the antivenom by Albert Calmette in 1895 was acknowledged as an important treatment after their effectiveness in clinical trials was demonstrated(3).The antivenoms developed by Calmette and Brazil, its used for a long time. These consisted of separating the blood serum of horses hyperimmunecompared to poison of snakes. Subsequently, it was demonstrated that the immunoglobulins were the molecules responsible for the activity of the Serum.Therefore, nowadays are used only immunoglobulins or its fragments purified and not serum; however, his name remains antivenom.

Epidemiology of Snake Bites

Snake bites are a serious health problem worldwide. Every year, 5 million people suffer snake bites, 2.4 million poisonings occur through them and between 94 000 and 125 000 deaths. The aftermath of snake bites also presents alarming figures. Are reported annually 400 000 amputations and other serious consequences for the health, such as infections, tetanus, deformations, scars, contractures and psychological sequelae. When the access to health care is poor and there is a shortage of the antitoxin, increases the severity of injuries and their results(9).

Among Latin A merican countries, Ecuador presents a high incidence of 1400 to 1600 cases per year of snake bites. The 70% of the Ecuadorian territory has tropical and subtropical characteristics which has led to the development of various species of snakes, the highest incidence of accidents of snake bites are in the rural area especially farmers, laborers, miners and native(11).
In the country there is a stable trend, which on average is 13.21 cases of bites per 100,000 inhabitants. The most frequent cases are those of bites by gender Brothrops(12).
In the country were recorded 1,759 accidents by snake bites during 2013. These cases are generally presented at altitudes lower than 2,500 meters above sea level, in tropical and subtropical climates, in the months which has greater presence of rains, from January to May on the coast and from May to August in the Amazon(12).

Figure 2. Incidence of cases and rate per 100,000 population of snakebites in Ecuador from 1994-2014.
[From: Anuario de Vigilancia Epidemiológica(12)]

The region with the highest incidence of snake bites in the country is the Amazon region, secondly the Coast and the region with the lowest incidence is the Sierra. In the year 2013 there was a high number of snake bites in the Amazon Region (Figure 3).

Figure 3. Cases and rate per 100,000 population of snakebites by province in Ecuador from 2011 to 2014.
[From: Anuario de Vigilancia Epidemiológica(12)]

Mechanism of Action

The antivenom is composed of immunoglobulins (Ig). Immunoglobulins are also called antibodies. These are proteins (amino acids composed macromolecules) involved in the adaptive immune response.
The adaptive immune response occurs when the body detects a threat against which induces the production of immunoglobulins through highly regulated biological processes. These processes are regulated by activation of proteins signaling cascadesand the activation of cells of the immune system, among which are the antibody-producing cells (B lymphocytes).
Immunoglobulins specifically recognize the structure of a strange molecule that may be pathogenic microorganisms or toxins,bind to these specifically and neutralize the activity that they could exercise. (13).
The immunoglobulins that make up the antivenomrecognize and bind to the proteins that are part of the venom of the serpent, this way neutralize the toxic activity of the venom.
Applying antivenom is defined as passive immunization(14), i.e. the antibodies are produced by immunizing animals in which resistance to the toxicity of the venom has been generated.These antibodies are obtained through standardized processes of production, purification and formulation which will be detailed in the next section.In this way, when necessary application in subjects who have had some bite, antibodies are transferred to the subject by intravenousapplication.The antibodies used in the serum correspond to the IgG.

For the serum achieve neutralize the venom of the serpent, two conditions are necessary a priori:

  1. 1. The antibodies that contain the serum must specifically recognize all toxic substances from the poison and neutralize them.
  2. 2. The antibodies must be in sufficient quantity to neutralize the venom

From the above highlights the importance of the compatibility of the poison used for the elaboration of the serum, with the poison of snakes that are in circulation in the environment. It should be noted, that the antivenom should display the same properties than any other medicine, because it depends on its clinical effectiveness. Serum must have appropriate characteristics of pharmacokinetics (changes of the concentration of the medicine in the body with respect to its absorption, distribution, metabolism and excretion) and pharmacodynamics (mechanism of action based on the interaction of the medicine with its target or the receiver, as the basis of its therapeutic activity and toxicity)(16). The recurrence of the effects of the poison because of the snakebite, despite treatment with the antivenom, may occur as a result of the gap between poison and Serum pharmacokinetic(16 ,17). It is to say that the speed of removal of antibodies may be higher that the serum elimination rate, keeping this in the body for longer than the antivenom. Modifications within the production of serum, as well as structural changes and dose regimen may improve the pharmacological characteristics.

Anti venom Production

Anti-venom serum production is a process that involves several steps as shown in Figure 4. Each step involves a large number of controls in accordance with the standards of Good Manufacturing Practices and the guides in the World Health Organization.

Figure 4. Diagram of the production process of Anti-venom serum (WHO GuidelinesfortheProduction,
Control and Regulation of Snake AntivenomImmunoglobulins) (2)

In Ecuador, the production of Anti-venom serum (bothropic antivenom) was in charge of the Instituto Nacional de Higiene y Medicina Tropical Leopoldo Izquieta Pérez (INH), which through a transition process became part of the Instituto Nacional de Investigación en Salud Pública (INSPI) and subsequently to Empresa Pública de Fármacos ENFARMA EP(18).
In Ecuador 63,149 vials single doses of Anti-venom serum have been produced during the years 2000 to 2012. However, the production of Anti-venom serum is suspended from April 8 of 2013 to the present.

Selection of the poisons

The selection of poisons is the first step in the production of Anti-venom serum. Poisons are very complete matrices that have high variability between species and even within the same species because its composition is impacted by diet and environmental conditions on which the poisonous snake develops (2) (19). The first factor to consider is the region in which the serum going to be used, due to the serum should confer protection against poisonous snake’s major medical and epidemiological relevance in the area of interest. It is important that the serum be representative in relation to all the variability of poisons present in the region, which should be maintained constant control profiles poisons. Finally, it is crucial to know whether serum can offer cross-protection between different types of poisons, neutralizing poisons from more than one species (20).
In order to ensure the greatest possible variability, it is necessary to create a sample made of snake venoms from different places in the region, several backgrounds (wild or in captivity) and ages. This sample must be at least 20 to 50 specimens to be representative of the region and the species that are going to be neutralized. When obtained serum from this sample is necessary preclinical testing the same in which is shown by a power test the ability of cross-neutralization and scope having the serum against poisons in the region. Tests should not be limited to in vitro tests to demonstrate cross-reactivity to different poisons used to make the serum (21).
When the collection of the poison is carried out it is necessary to record all information concerning: the species, location, origin, size (indicative of age), amount of collected poison, whether it is an endangered species (CITES), and all precautions taken to avoid collecting venom for snakes sick. It is recommended freeze the poison quickly to prevent protein degradation. If you go store for long periods the poison freeze-drying it is important. Additionally, poison characterization should be performed to determine the uniformity from batch to batch (22).
Some of the tests used for the characterization of poison are: concentration of the protein, gel electrophoresis of polyacrylamide (SDS-PAGE), profiles of chromatography (example HPLC), enzyme activity and toxicity (example lethal dose LD50). These analyzes can be outsourced if they could not do directly on the ground (23).
Due to the high variability of the poison above mentioned, it should draw up a national standard that encompasses it. This standard should include all information about the species, subspecies and location of the specimens used for processing. Together with the standard, a quality control serum must be performed, which includes poison potency tests by agglutination tests in vitro and in vivo tests confrontation (24).

Types of serum

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The serums may be monospecific or polyspecific, which differ in their scope of protection range. Monospecific serums were produced by using the serum of a particular specie; therefore, they provide direct protection against that species or cross-protection against closely related species. The polyspecific serums were produced using the poison of various species and give a greater range of protection, but their power may be reduced (2)
Monospecific serums are recommended when in the region only exist one kind of interest specie or can only be found very interrelated species. This type of serums is recommended when it is easy to identify the species which produced poisoning, either because symptoms are easy to differentiate, or are available for simple and rapid identification of the toxin test. Because in Ecuador can be found several species of snakes and do not have quick access to identification tests effectively, these types of serums are not recommended (11).
The polyspecific serums may be obtained by immunizing animals with a mixture of venoms. An advantage of immunize the animal with various poisons is that the antibody title obtained is higher because greater stimulation of the immune system occurs. A second method is the immunization of various animals with a specific serum, then mixing the plasma of each and generates the final serum. In either case, the power of the poison to each of the target species should be checked to ensure that power for a specific poison is not reduced. This control should be carried out rigorously for a sufficient activity of serum is taken and is not necessary to inject several doses that increase the risk of occurrence of side effects (11).

Obtaining poison

The snakes that will enter in the vivarium must go through a quarantine period of at least two months in an exclusive area for this purpose. At the time of capture and during quarantine an ophidian's specialized veterinarian should examine all specimens to determine that they don't have ectoparasites or pentastomes. It is important to verify that snakes have no infectious disease and if so, they are treated in the quarantine area. If snakes are found sick in the vivarium these must not be moved, but must be treated in situ, and milking will be postponed until four weeks after recovery (23).
The cages that host snakes must be ventilated and have an adequate size relative to the specimen. They should be washed and disinfected at least once a week. Drinking water should be changed regularly and have UV disinfection treatments. The area where the cages are placed should be broad and kept clean permanently. Disinfectant must be available in a tray at the entrance to disinfect the soles of shoes and prevent the entry of infectious agents. Food depends on the specie and the age, but varies from twice a week to once a month. You can use live or dead prey depending on the preferences of the species (22).
For milking, the snake must be removed from its cage by using a hook to hold it from behind the head. For very dangerous species can be used anesthesia or moderate cooling (15 ° C). The poison should be collected in sterile containers and must indicate all the information mentioned in the previous sections. It is possible to collect the venom of several snakes in the same container as long as the cold chain, between milking, is maintained. All poisons that are mixed should be considered part of the same batch. During milking the specimen can be examined by ectoparasites. After the milking, you should be careful not to damage the teeth or dentures of the snakes. It is important to have standard procedures for milking that consider all precautions and all necessary personal protective equipment (2).

conditions, the country´s most sold prescribed product on a private level during 2012 was a medicine for the treatment of asthma and the most commercialized over the counter product was an anti-inflammatory medicine (14).
One must consider that the spending on health is 40%, despite the strong intervention in health from the State. Although the price of drugs in the last five years has increased 12% globally (12.5% brand name and 0.86% generic), this economical stimuli for the consumer seems not be and incentive for the consumption in general (1, 10, 15, 20).

Animal care and handling

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You can use any mammal for immunization with poison, but it is important to consider the amount of plasma that can be obtained from the asset because bigger animals will allow to obtain higher volumes of plasma. Horses are animals commonly used for commercial production because they are docile and allow to obtain greater volumes of plasma in comparison with other animals. The use of sheep is restricted due to the risk of prions contamination in serum (2).
The animals used for immunization programs must go into quarantine and habituation of at least 3 months. Each animal should be clearly identified for the effects of traceability. It is important keep a proper veterinary surveillance in which it is included vaccination programs against tetanus and other possible diseases of interest such as rabies, brucellosis, anthrax among others. Also, animals should be dewormed regularly for helminths and other parasites of interest. Animal’s health should always be monitored with biochemical tests such as hemogram and coagulation tests (2) (25).
Animals’ diet should only be of vegetable matter or be added with vitamins, folic acid, iron or other necessary supplements. Vegetable contamination, from materials derived from ruminants to prevent possible transmission of prions, should be avoided. It is important to constantly monitor the quality of food and water (25). The poison preparation should be performed in laminar flow booths, with the necessary protective equipment to prevent accidents of personnel handling the poison. The dilution of the poison must be adequate in order to prevent overdoses in animals that could generate signs of poisoning and death. Calculations of dilution must be corroborated by another person and must maintain a constant record of equipment calibration. In case that the poison is lyophilized it should be taken into account that the dust produced is highly allergenic (26).
The inoculation of the poison should be done in a designated area for this process. The area of the animal should be shaved and disinfected before injecting the venom. The areas of an animal body preferably used for immunization are those near to the lymph nodes, near the neck or back. The administration should be subcutaneously to induce a better immune response. In case there are only small doses of poison, these could be mixed with substances that stimulate the response as Freund adjuvant (27).

Extraction of blood and purification of plasma

The extraction of blood must be performed in a dedicated area for this purpose, possessing all the necessary controls. Always check the health status of the animal before and several days after the bleeding. The puncture should be performed in the external jugular vein. The blood volume obtained depends on the species and weight of the animal. Some studies recommend a dose of 13 to 15 milliliters per kilogram of body weight on average in order to obtain from 3 to 6 liters d from horses qualified horses (2). It is important to the addition of anticoagulant in the ratio 1: 9 and blood should be constantly mixed to prevent clot formation. Sessions can last 30 to 45 minutes. The separated plasma must be recovered under aseptic conditions for 24 hours so that it can perform manual infusion of donor erythrocytes in animals (28). Currently, there are specialized apparatus to perform plasmapheresis, automatically separating plasma from red blood cells for return to the animal body. This process produces higher yields and is less likely to occur in anemia donor animal. However, time is higher (1 to 4 hours) and the cost of the apparatus and handling thereof is high (2).
Before the fractionation is performed, quality control plasma is required to determine that the process that is used does not dramatically reduce the horsepower. It is important that the plasma’s total amount of protein present is measured and tests are performed to detect the presence of pyrogens. Phenol or cresol can be placed as a preservatives and should be stored at 2 ° to 8 ° C. In case they are planned to be stored for longer time, it is important to perform 6 months stability tests (11).
It is possible to obtain three types of serums containing: the fracciónesF (ab ') 2, Fab or intact IgG fractions. For fractions F (ab ') 2 or Fab serum should be treated with proteolytic enzymes, for the first ones use pepsin, and for the latter to use papain. In the case of intact IgG any treatment should be done. The use of enzymes facilitates the degradation of unwanted proteins in the final product which facilitates its purification usinf either of both methods: using ammonium sulfate or caprylic acid (2).
The ammonium sulfate method consists of two steps of precipitation in which two different concentrations of salt are used. Ammonium sulfate precipitates the antibodies (whether intact IgG fractions F (ab ') the 2nd Fab) and left in the supernatant to all small proteins and other globulins. The yield is 40 is 50%, however, a relatively high proportion of other proteins like albumin (2) is obtained.
The method of caprylic acid precipitation produces small proteins in the supernatant and leave to immunoglobulins (IgG is intact, fractions F (ab ') the 2nd Fab). After the addition of caprylic acid, the supernatant from the precipitate must be separated by filtration or centrifugation. The performance of this method reaches between 60 and 70% and obtains less contaminating proteins (2)

Formulation, packaging and labeling

Once immunoglobulins have been purified, the final formulation must be done. Here the osmolarity is corrected, and preservatives and other excipients to improve product stability and maintain the pH between 6.5 and 7.5 are added, because values higher pH stability of proteins is compromised, while lower values may occur the formation of agglutination (11).
The bulk obtained must be analyzed to determine purity, potency, sterility and pyrogenicity. Once you have surpassed the quality control, it is ready to be passed to the container container. The packaging must be made in Class A laminar under aseptic filling to ensure product stability and flow. Once it is hermetic sealed, the vials or ampoules can pass the labeling process. The label must include at least the name of the product and the producer, the animal species used to produce the serum, the batch number, presentation, volume, specificity (which poisons can be neutralized using the serum), power, the route of administration, storage conditions and the expiration date (2).

CONCLUSIONS

The development of the first Anti-venom in 1895 by Dr. Alberte Calmette was a milestone in the treatment of snakebite poisoning. Calmette showed that it is possible to immunize an animal against the venom of a snake and then obtain their serum to treat another victim of poisoning by the same snake specie. This was the first biological therapeutic alternative for snakebites. Subsequently, Dr. Vital Brazil demonstrated the specificity of the Anti-venom , suggesting the subsequent development of polyspecific sera species representative of each region.
Understanding the mechanism of action allows us to acknowledge the need to develop Anti-venom in accordance with the population of snakes in circulation. This should be supported by a clinical point of view with drug information of Anti-venom , which would optimize treatment.
It is very important for the serum production to make an analysis of the diversity of poisonous snakes in Ecuador species, as well as an analysis of poisons to determine the level of variability between species and within the same species. This is the information that should be used in order to start the selection of poisons for serums production. Because Ecuador has a large number of ecosystems and different regions, it is important to resume domestic production of serum using local poisons and generating the necessary national standards for their quality control.

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