The development and use of immunotherapy in Africa

doi:10.1016/S0041-0101(98)00140-8

Toxicon

Volume 36, Issue 11, November 1998, Pages 1503-1506

https://doi.org/10.1016/S0041-0101(98)00140-8 Get rights and content

Abstract

The immunotherapy was recently developed due to the improvement of purification techniques of antivenoms and results of the research in toxicology and pharmacology. The utilisation of highly purified IgG fragments leads to a better tolerance and a higher efficacy. Snake envenomations constitute in Africa, as in many tropical countries, an important public health problem. The annual incidence of snakebites reaches 1 million and the annual mortality is about 20,000 deaths. Less than 25% of the antivenom needs are effectively covered and, probably in most of envenomations, used at insufficient doses. The treatment of snakebites would be improved by better knowledge on snakebite epidemiology, standardisation of treatment and training medical staff, and development of new financial procedures for antivenom supply.

Introduction

Since the discovery of immunotherapy one century ago, progress in this area has been moderate. Improvements have centered around the tolerance and the efficiency of antivenom. In contrast, notably in Africa, the availability of antivenom has decreased since the 70's and therapeutic protocols are non-existent or inappropriate. This is due to a lack of epidemiological data, disorganisation of health services and the high cost of antivenom with respect to the income of rural populations.

Section snippets

Immunotherapy: a new concept for an old tool

The objectives of immunotherapy are (i) to administer the smallest possible quantity of heterologous proteins to improve tolerance and ii) to use the greatest quantity of antibodies to increase efficiency.

This apparent contradiction can be avoided by improving the purification of the antivenom (precipitation, cleavage of IgG, filtration, chromatography) and by using more rigorous therapeutic protocols (intravenous administration of antivenom, standardisation of diagnosis and supervision

Immunotherapy in Africa: failure of a powerful treatment

The sale of antivenoms has declined by 60 to 80% during the last 20 years. Furthermore, the actual number of doses sold would not have covered even quarter of the estimated needs. Several causes could explain this.

The epidemiology of snake bites is poorly understood. The incidence is unknown and highly endemic regions have not been delimited. Consequently, real needs are not easily evaluated.

The treatment of envenomation is not standardised and practices are mostly empirical and irrational

Snake bites in Africa: appraisal of needs

According to surveys performed in rural areas, the number of snake bites (=incidence) ranges from 150 to 600 cases per 100,000 inhabitants per year. Variations can be attributed to the methodological and environmental differences. In addition, some human occupations induce the man–snake encounter. Approximately 50 to 75% of snake bites lead to an envenomation (=morbidity) necessitating antivenom therapy. Finally, depending on the delay before consultation and the efficiency of treatment

Treatment of snake bites in Africa: perspectives

Three kinds of measures can be suggested to improve the treatment of snake bites in Africa.

Acknowledgements

I thank Dr Amy Klion who corrected the English version of the manuscript.

References (0)

Cited by (46)

Snake antivenom: Challenges and alternate approaches
2020, Biochemical Pharmacology
Citation Excerpt :
Furthermore, adverse reactions triggered by animal proteins, such as polyvalent horse antibodies, is a major problem of antivenom therapy (Table 1) [11,12] which requires time consuming allergy testing prior to administration of antivenom therapy, in a situation where time is of concern [13]. Despite these limitations, the current treatment available in the market owes for conventional antivenoms that can neutralize the toxins [8,14]. Adverse reactions due to antivenom are classified by WHO as - early (anaphylactic reactions and pyrogenic reactions) which occur within 24 hrs of antivenom administration and late reactions (serum sickness) which develop between 5 and 24 days of treatment [15].
Snake envenomation is still a serious threat to many countries in the world. The only mainstay treatment depends on the administration of animal derived immunoglobulin based antivenom. Significant limitations to these antivenoms are a challenge in the treatment of snake envenomation. Many alternate approaches have been explored to overcome the limitations of antivenom. Exploring alternate approaches like use of bioactive components from plant sources, use of peptide and small molecule inhibitors are some aspects taken towards improving the current limitations of antivenom therapy. However, all these alternate approaches also have many drawbacks which should be improved by more in vitro and in vivo experiments. Here, we review some of the limitations of current antivenom therapy and developments as well as drawbacks of these alternate treatment strategies.
Terrestrial venomous snakes and snakebites in the Arab countries of the Middle East
2020, Toxicon
Citation Excerpt :
Snake bites are a medical concern in all these countries, where many cases are reported annually. The importance of snakebites in the Middle East has been emphasized in a number of publications (Swaroop and Grab, 1954; Warrell, 1995; Chippaux, 1998; Ismail and Memish, 2003; Kasturiratne et al., 2008; Fatani, 2015; Haidar and Deitch, 2015). The present study reviews the currently known venomous snakes, snake bite epidemiology, clinical manifestation of snake bites and antivenoms used for treatment in the Arab countries of the Middle East.
The 12 Arab countries of the Middle East are inhabited by 21 species of terrestrial venomous snakes of varying medical importance. This review considers these species, consisting of 16 viperids, 3 elapids and 2 atractaspidines. Iraq, Jordan, Lebanon, Oman, Saudi Arabia, and Yemen report the largest numbers of snakebites and envenomings. Accessible literature in English and Arabic on venomous snakes and snakebites and available antivenoms is reviewed. Clinical effects include potentially misleading symptoms attributable to anxiety and traditional pre-hospital treatments.
Pharmacokinetics of the Sri Lankan hump-nosed pit viper (Hypnale hypnale) venom following intravenous and intramuscular injections of the venom into rabbits
2014, Toxicon
Citation Excerpt :
The essential knowledge from which includes not only the venom's composition and toxic activities, but also its disposition in the body i.e. the pharmacological profile. Unfortunately, for over half a century, the management of snakebite is still confronted with various issues pertaining to antivenom supplies or uses (Williams et al., 2011), and the existing protocols for the therapeutic uses of antivenom are largely empirical (Chippaux, 1998). There is generally a lack of knowledge on the pharmacokinetics of individual snake venom and toxin, especially on the important aspects such as the venom's distribution and elimination half-lives, systemic clearance and bioavailability.
The knowledge of venom pharmacokinetics is essential to improve the understanding of envenomation pathophysiology. Using a double-sandwich ELISA, this study investigated the pharmacokinetics of the venom of hump-nosed pit viper (Hypnale hypnale) following intravenous and intramuscular injections into rabbits. The pharmacokinetics of the venom injected intravenously fitted a three-compartment model. There is a rapid (t_1/2π = 0.4 h) and a slow (t_1/2α = 0.8 h) distribution phase, followed by a long elimination phase (t_1/2β = 19.3 h) with a systemic clearance of 6.8 mL h⁻¹ kg⁻¹, consistent with the prolonged abnormal hemostasis reported in H. hypnale envenomation. On intramuscular route, multiple peak concentrations observed in the beginning implied a more complex venom absorption and/or distribution pattern. The terminal half-life, volume of distribution by area and systemic clearance of the venom injected intramuscularly were nevertheless not significantly different (p > 0.05) from that of the venom injected intravenously. The intramuscular bioavailability was exceptionally low (F_i.m. = 4%), accountable for the highly varied median lethal doses between intravenous and intramuscular envenomations in animals. The findings indicate that the intramuscular route of administration does not significantly alter the pharmacokinetics of H. hypnale venom although it significantly reduces the systemic bioavailability of the venom.
Paraspecificity of Vipera a. ammodytes-specific antivenom towards Montivipera raddei and Macrovipera lebetina obtusa venoms
2014, Toxicon
Citation Excerpt :
Although extrapolation of the results obtained in laboratory to real clinical setting has to be undertaken with caution because of physiological limitations of in vivo and in vitro tests (Theakston et al., 2003; WHO, 2010), determination of paraspecific immunoreactivity may have important implications for antivenom design and use, especially in medical situations with urgent need for extension of neutralisation coverage to species whose venom is not included in the immunisation mixture (Calvete et al., 2009; Calvete, 2010). Additionally, knowledge concerning paraspecificity also may be of great significance for accessibility and supply improvements in regions experiencing inadequate coverage or complete lack of antivenoms produced against medically important venoms, an issue often associated with lack of epidemiological data, disorganisation of health services and high manufacturing costs in developing countries (Chippaux, 1998a). Antivenom produced by hyperimmunisation of horses with the venom of nose-horned viper, Vipera ammodytes (V. a.) ammodytes (European viper venom antiserum, in the literature also known as Zagreb antivenom, Institute of Immunology Inc., Croatia), contains neutralising antibodies that are clinically successful against homologous venom, as well as against the venoms of several others medically important European snakes, as demonstrated by its continuous, over 30 years long use for the treatment of envenomings induced by Vipera aspis (Italy), Vipera berus (UK, Sweden), Macrovipera lebetina and Montivipera xanthina (Greece, Turkey).
Antivenom raised against the venom of nose-horned viper, Vipera ammodytes (V. a.) ammodytes (European viper venom antiserum, Zagreb antivenom), contains neutralising equine F(ab′)₂ fragments that are clinically successful against homologous venom, but also against the venoms of several others medically important European snakes due to its paraspecific action. In this work we demonstrated that Zagreb antivenom is preclinically effective in neutralising lethal toxicity and hemorrhagicity of venoms of Armenian mountain snakes – Montivipera raddei and Macrovipera lebetina obtusa as well. In order to better understand the biochemical basis of the observed paraspecificity, the ability of anti-V. a. ammodytes serum to recognise and neutralise proteinases of the two venoms was also investigated. Anti-V. a. ammodytes serum showed surprisingly low capacity to inhibit metalloproteinases of both venoms included in the study, probably due to weak immunorecognition of their P-I representatives. Also, it completely failed to abolish enzymatic action of serine proteinases from Macrovipera lebetina obtusa venom. Relevance of such finding is yet to be established.
Toxicokinetics of Naja sputatrix (Javan spitting cobra) venom following intramuscular and intravenous administrations of the venom into rabbits
2013, Toxicon
Existing protocols for antivenom treatment of snake envenomations are generally not well optimized due partly to inadequate knowledge of the toxicokinetics of venoms. The toxicokinetics of Naja sputatrix (Javan spitting cobra) venom was investigated following intravenous and intramuscular injections of the venom into rabbits using double-sandwich ELISA. The toxicokinetics of the venom injected intravenously fitted a two-compartment model. When the venom was injected intramuscularly, the serum concentration–time profile exhibited a more complex absorption and/or distribution pattern. Nevertheless, the terminal half-life, volume of distribution by area and systemic clearance of the venom injected intramuscularly were not significantly different (p > 0.05) from that of the venom injected intravenously. The systemic bioavailability of the venom antigens injected by intramuscular route was 41.7%. Our toxicokinetic finding is consistent with other reports, and may indicate that some cobra venom toxins have high affinity for the tissues at the site of injection. Our results suggest that the intramuscular route of administration doesn't significantly alter the toxicokinetics of N. sputatrix venom although it significantly reduces the systemic bioavailability of the venom.
Role of antivenoms in the treatment of snake envenomation
2013, Bulletin de l'Academie Nationale de Medecine
Après une longue période de rejet, la fabrication des sérums antivenimeux jugés peu efficaces, dangereux et d’utilisation difficile, a été significativement améliorée. Les anticorps, portés par les immunoglobulines G, sont désormais fragmentés, purifiés et leur qualité contrôlée, ce qui a permis d’augmenter considérablement leur tolérance et d’en simplifier l’utilisation en médecine d’urgence. L’envenimation se manifeste par des syndromes distincts en fonction de l’espèce de serpent responsable de la morsure : les Viperidae possèdent un venin fortement inflammatoire, hémorragique et nécrosant, les Elapidae entraînent une paralysie respiratoire parfois mortelle. Cependant, il existe des exceptions, le venin de certains Viperidae pouvant conduire à une asphyxie similaire à celle observée en cas de morsure par Elapidae et, inversement, des morsures d’Elapidae se compliquent par des hémorragies ou des nécroses, ce qui égare le diagnostic étiologique. Le traitement symptomatique est complexe, souvent insuffisant, et émaillé d’évènements indésirables. En revanche, neutralisant et accélérant l’élimination du venin, les antivenins — dénomination reflétant leurs nouvelles caractéristiques — constituent le traitement étiologique incontournable des envenimations, notamment dans les formations sanitaires isolées des pays en développement. Les préparations actuelles sont des antivenins polyvalents couvrant les espèces venimeuses d’une région. Le principal handicap reste leur coût élevé ; la priorité consiste désormais à développer de nouvelles stratégies de prise en charge des morsures de serpent, notamment en garantissant l’accessibilité d’antivenins appropriés, notamment dans les pays en développement où ils sont indispensables.
The production of antivenoms, which were long deemed ineffective, dangerous and difficult to use, has improved dramatically. These antibodies (immunoglobulin G) are now fragmented, purified and controlled for their quality, leading to significantly better safety and facilitating their emergency use. Envenomation can result in various syndromes depending on the snake species: Viperidae venoms are highly inflammatory, hemorrhagic and necrotising, while Elapidae venoms can cause fatal respiratory paralysis. However, some Viperidae venoms can lead to asphyxiation similar to that observed in Elapidae envenomation while, conversely, Elapidae bites may be complicated by hemorrhage or necrosis, thus complicating etiologic diagnosis. Symptomatic treatment is complex, often insufficient, and frequently associated with adverse events. In contrast, antivenoms neutralize the venom and accelerate its clearance, thus providing an etiological treatment for envenomation, particularly in remote healthcare facilities in developing countries. Current formulations consist of polyvalent antivenoms covering most of the venomous species present in a specific region. The main limitation is their high cost, and the priority should be to develop new treatment strategies, including more affordable antivenoms, especially in developing countries where they are most needed.

View all citing articles on Scopus

View full text