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Clinical Pharmacokinetics

, Volume 42, Issue 8, pp 721–741 | Cite as

Pharmacokinetic-Pharmacodynamic Relationships of Immunoglobulin Therapy for Envenomation

  • José María GutiérrezEmail author
  • Guillermo León
  • Bruno Lomonte
Review Article

Abstract

Parenteral administration of horse- and sheep-derived antivenoms constitutes the cornerstone in the therapy of envenomations induced by animal bites and stings. Depending on the type of neutralising molecule, antivenoms are made of: (i) whole IgG molecules (150 kDa), (ii) F(ab′)2 immunoglobulin fragments (100 kDa) or (iii) Fab immunoglobulin fragments (50 kDa). Because of their variable molecular mass, these three types of antivenoms have different pharmacokinetic profiles. Fab fragments have the largest volume of distribution and readily reach extravascular compartments. They are catabolised mainly by the kidney, having a more rapid clearance than F(ab′)2 fragments and IgG. On the other hand, IgG molecules have a lower volume of distribution and a longer elimination half-life, showing the highest cycling through the interstitial spaces in the body. IgG elimination occurs mainly by extrarenai mechanisms. F(ab′)2 fragments display a pharmacokinetic profile intermediate between those of Fab fragments and IgG molecules.

Such diverse pharmacokinetic properties have implications for the pharmacodynamics of these immunobiologicals, since a pronounced mismatch has been described between the pharmacokinetics of venoms and antivenoms. Some venoms, such as those of scorpions and elapid snakes, are rich in low-molecular-mass neurotoxins of high diffusibility and large volume of distribution that reach their tissue targets rapidly after injection. In contrast, venoms rich in high-molecular-mass toxins, such as those of viperid snakes, have a pharmacokinetic profile characterised by a rapid initial absorption followed by a slow absorption process from the site of venom injection. Such delayed absorption has been linked with recurrence of envenomation when antibody levels in blood decrease.

This heterogeneity in pharmacokinetics and mechanism of action of venom components requires a detailed analysis of each venom-antivenom system in order to determine the most appropriate type of neutralising molecule for each particular venom. Besides having a high affinity for toxicologically relevant venom components, an ideal antivenom should possess a volume of distribution as similar as possible to that of the toxins being neutralised. Moreover, high levels of neutralising antibodies should remain in blood for a relatively prolonged time to assure neutralisation of toxins reaching the bloodstream later in the course of envenomation, and to promote redistribution of toxins from extravascular compartments to blood. Additional studies are required on different venoms and antivenoms in order to further understand the pharmacokinetic-pharmacodynamic relationships of antibodies and their fragments and to optimise the immunotherapy of envenomations.

Keywords

Snake Venom Scorpion Venom Venom Component Extravascular Compartment Scorpion Envenomations 
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.

Notes

Acknowledgements

The authors thank their coworkers at Instituto Clodomiro Picado for valuable discussions and suggestions, and Vicerrectoría de Investigación, Universidad de Costa Rica, and the International Foundation for Science (IFS) for financial support. The authors have provided no information on conflicts of interest directly relevant to the content of this review.

References

  1. 1.
    Warrell DA. Clinical features of envenoming from snake bites. In: Bon C, Goyffon M, editors. Envenomings and their treatment. Lyon: Fondation Marcel Mérieux, 1996: 63–76Google Scholar
  2. 2.
    White J. Poisonous and venomous animals: the physician’s view. In: Meier J, White J, editors. Handbook of clinical toxicology of animal venoms and poisons. Boca Raton (FL): CRC Press, 1995: 9–26Google Scholar
  3. 3.
    Chippaux JP. Snake-bites: appraisal of the global situation. Bull World Health Org 1998; 76: 515–24PubMedGoogle Scholar
  4. 4.
    White J, Cardoso JL, Fan HW. Clinical toxicology of spider bites. In: Meier J, White J, editors. Handbook of clinical toxicology of animal venoms and poisons. Boca Raton (FL): CRC Press, 1995: 259–329Google Scholar
  5. 5.
    Dehesa-Dávila M, Alagón AC, Possani LD. Clinical toxicology of scorpion stings. In: Meier J, White J, editors. Handbook of clinical toxicology of animal venoms and poisons. Boca Raton (FL): CRC Press, 1995: 221–38Google Scholar
  6. 6.
    Meier J, White J, editors. Handbook of clinical toxicology of animal venoms and poisons. Boca Raton (FL): CRC Press, 1995Google Scholar
  7. 7.
    Endo T, Tamiya N. Structure-function relationships of postsynaptic neurotoxins from snake venoms. In: Harvey AL, editor. Snake toxins. New York: Pergamon Press, 1991: 165–222Google Scholar
  8. 8.
    Possani LD, Merino E, Corona M, et al. Peptides and genes coding for scorpion toxins that affect ion-channels. Biochimie 2000; 82: 861–8PubMedCrossRefGoogle Scholar
  9. 9.
    Rosenberg P. Phospholipases. In: Shier WT, Mebs D, editors. New York: Marcel Dekker, 1990: 67–277Google Scholar
  10. 10.
    Kini RM. Phospholipase A2: a complex multifunctional protein puzzle. In: Kini RM, editor. Venom phospholipase A2 enzymes: structure, function and mechanism. Chichester: John Wiley & Sons, 1997: 1–28Google Scholar
  11. 11.
    Ushkaryov Y. α-Latrotoxin: from structure to some functions. Toxicon 2002; 40: 1–5PubMedCrossRefGoogle Scholar
  12. 12.
    Bjarnason JB, Fox JW. Hemorrhagic metalloproteinases from snake venoms. Pharmacol Ther 1994; 62: 325–72PubMedCrossRefGoogle Scholar
  13. 13.
    Gutiérrez JM, Rucavado A. Snake venom metalloproteinases: their role in the pathogenesis of local tissue damage. Biochimie 2000; 82: 841–50PubMedCrossRefGoogle Scholar
  14. 14.
    Warrell DA. The global problem of snake bite: its prevention and treatment. In: Gopalakrishnakone P, Tan CK, editors. Recent advances in toxinology research. Vol. 1. Singapore: National University of Singapore, 1992: 121–53Google Scholar
  15. 15.
    Bon C. Serum therapy was discovered 100 years ago. In: Bon C, Goyffon M, editors. Envenomings and their treatment. Lyon: Fondation Marcel Mérieux, 1996: 3–9Google Scholar
  16. 16.
    Raw I, Guidolin R, Higashi HG, et al. Antivenins in Brazil: preparation. In: Tu AT, editor. Handbook of natural toxins, vol 5, reptile venoms and toxins. New York: Marcel Dekker, 1991: 557–81Google Scholar
  17. 17.
    Theakston RDG, Warrell DA. Antivenoms: a list of hyperimmune sera currently available for the treatment of envenoming by bites and stings. Toxicon 1991; 29: 1419–70PubMedCrossRefGoogle Scholar
  18. 18.
    Meier J. Commercially-available antivenoms (“hyperimmune sera”, “antivenins”, “antisera”) for antivenom therapy. In: Meier J, White J, editors. Handbook of clinical toxicology of animal venoms and poisons. Boca Raton (FL): CRC Press, 1995: 689–721Google Scholar
  19. 19.
    Heard K, O’Malley GF, Dart RC. Antivenom therapy in the Americas. Drugs 1999; 58: 5–15PubMedCrossRefGoogle Scholar
  20. 20.
    Thalley BS, Carroll SB. Rattlesnake and scorpion antivenoms from the egg yolks of immunized hens. Biotechnology (N Y) 1990; 8: 934–8CrossRefGoogle Scholar
  21. 21.
    Carroll SB, Thalley BS, Theakston RDG, et al. Comparison on the purity and efficacy of affinity purified avian antivenoms with commercial equine crotalid antivenoms. Toxicon 1992; 30: 1017–25PubMedCrossRefGoogle Scholar
  22. 22.
    Ménez A. Immunology of snake toxins. In: Harvey AL, editor. Snake toxins. New York: Pergamon Press, 1991: 35–90Google Scholar
  23. 23.
    Lomonte B, Kahan L. Production and partial characterization of monoclonal antibodies to Bothrops asper (terciopelo) myotox-in. Toxicon 1988; 26: 675–89PubMedCrossRefGoogle Scholar
  24. 24.
    Licea AF, Becerril B, Possani LD. Fab fragments of the monoclonal antibody BCF2 are capable of neutralizing the whole soluble venom from the scorpion Centruroides noxius Hoffman. Toxicon 1996; 34: 843–7PubMedCrossRefGoogle Scholar
  25. 25.
    Guilherme P, Fernandes I, Barbaro KC. Neutralization of dermonecrotic and lethal activities and differences among 32-35 kDa toxins of medically important Loxosceles spider venoms in Brazil revealed by monoclonal antibodies. Toxicon 2001; 39: 1333–42PubMedCrossRefGoogle Scholar
  26. 26.
    Organizatión Panamericana de la Salud. Manual de procedimientos. Producción y pruebas de control en la preparation de antisueros diftérico, tetánico, botulínico, antivenenos y de la gangrena gaseosa. Oficina Sanitaria Panamericana 1977, 141Google Scholar
  27. 27.
    Rojas G, Jiménez JM, Gutiérrez JM. Caprylic acid fractionation of hyperimmune horse plasma: description of a simple procedure for antivenom production. Toxicon 1994; 32: 351–63PubMedCrossRefGoogle Scholar
  28. 28.
    Gronski P, Seiler FR, Schwick HG. Discovery of antitoxins and development of antibody preparations for clinical uses from 1890 to 1990. Mol Immunol 1991; 28: 1321–32PubMedCrossRefGoogle Scholar
  29. 29.
    Landon J, Smith DC. Development of novel antivenoms based on specific ovine Fab. In: Bon C, Goyffon M, editors. Envenomings and their treatments. Lyon: Fondation Marcel Mérieux, 1996, 180Google Scholar
  30. 30.
    Grandgeorge M, Véron JL, Lutsch C, et al. Preparation of improved F(ab′)2 antivenoms: an example, new polyvalent European viper antivenom (equine). In: Bon C, Goyffon M, editors. Envenomings and their treatment. Lyon: Fondation Marcel Mérieux, 1996, 172Google Scholar
  31. 31.
    Saetang T, Treamwattana N, Suttijitpaisal P, et al. Quantitative comparison on the refinement of horse antivenom by salt fractionation and ion-exchange chromatography. J Chromatogr B Biomed Sci Appl 1997; 700: 233–9PubMedCrossRefGoogle Scholar
  32. 32.
    Smith DC, Reddi KR, Laing G, et al. An affinity purified ovine antivenom for the treatment of Vipera berus envenoming. Toxicon 1992; 30: 865–71PubMedCrossRefGoogle Scholar
  33. 33.
    Sutherland SK. Serum reactions: an analysis of commercial antivenoms and the possible role of anticomplementary activity in de-novo reactions to antivenoms and antitoxins. Med J Aust 1977; 1: 613–5PubMedGoogle Scholar
  34. 34.
    Malasit P, Warrell DA, Chanthavanich P, et al. Prediction, prevention, and mechanism of early (anaphylactic) antivenom reactions in victims of snake bites. BMJ 1986; 292: 17–20PubMedCrossRefGoogle Scholar
  35. 35.
    Ismail M, Abd-Elsalam MA. Serotherapy of scorpion envenoming: pharmacokinetics of antivenoms and a critical assessment of their usefulness. In: Bon C, Goyffon M, editors. Envenomings and their treatment. Lyon: Fondation Marcel Mérieux, 1996: 135–53Google Scholar
  36. 36.
    Ismail M, Abd-Elsalam MA, Al-Ahaidib MS. Pharmacokinetics of 125I-labelled Walterinnesia aegyptia venom and its specific antivenins: flash absorption and distribution of the venom and its toxin versus slow absorption and distribution if IgG, F(ab′)2 and Fab of the antivenin. Toxicon 1998; 36: 93–114PubMedCrossRefGoogle Scholar
  37. 37.
    Thwin MM, Mee KM, Kyin MM, et al. Kinetics of envenomation with Russell’s viper (Vipera russelli) venom and of antivenom use in mice. Toxicon 1988; 26: 373–8CrossRefGoogle Scholar
  38. 38.
    Rivière G, Choumet V, Audebert F, et al. Effect of antivenom on venom pharmacokinetics in experimentally envenomed rabbits: toward an optimization of antivenom therapy. J Pharmacol Exp Ther 1997; 281: 1–8PubMedGoogle Scholar
  39. 39.
    Pépin-Covatta S, Lutsch C, Grandgeorge M, et al. Immunoreactivity and pharmacokinetics of horse anti-scorpion venom F(ab′)2-scorpion venom interactions. Toxicol Appl Pharmacol 1996; 141: 272–7PubMedGoogle Scholar
  40. 40.
    Ho M, Silamut K, White NJ, et al. Pharmacokinetics of three commercial antivenoms in patients envenomed by the Malayan pit viper, Calloselasma rhodostoma, in Thailand. Am J Trop Med Hyg 1990; 42: 260–6PubMedGoogle Scholar
  41. 41.
    Theakston RDG, Fan HW, Warrell DA, et al. Use of enzyme immunoassays to compare the effect and assess the dosage regimens of three brazilian Bothrops antivenoms. Am J Trop Med Hyg 1992; 47: 593–604PubMedGoogle Scholar
  42. 42.
    Ariaratnam CA, Meyer WP, Perera G, et al. A new monospecific ovine Fab fragment antivenom for treatment of envenoming by the Sri Lankan Russell’s viper (Daboia russellirusselli): a preliminary dose-finding and pharmacokinetic study. Am J Trop Med Hyg 1999; 61: 259–65PubMedGoogle Scholar
  43. 43.
    Thanh-Barthet CV, Urtizberea M, Sabouraud AE, et al. Development of a sensitive radioimmunoassay for Fab fragments: application to Fab pharmacokinetics in humans. Pharmacol Res 1993; 10: 692–6CrossRefGoogle Scholar
  44. 44.
    Meyer WP, Habib AG, Onayade AA, et al. First clinical experiences with a new ovine Fab Echis ocellatus snake bite antivenom in Nigeria: randomized comparative trial with Institute Pasteur serum (IPSER) Africa antivenom. Am J Trop Med Hyg 1997; 56: 291–300PubMedGoogle Scholar
  45. 45.
    Ariaratnam CA, Sjostrom L, Raziek Z, et al. An open, randomized comparative trial of two antivenoms for the treatment of envenoming by Sri Lankan Russell’s viper (Daboia russellirusselli). Trans R Soc Trop Med Hyg 2001; 95: 74–80PubMedCrossRefGoogle Scholar
  46. 46.
    Schaumann W, Kaufmann B, Neubert P, et al. Kinetics of the Fab fragments of digoxin antibodies and of bound digoxin in patients with severe digoxin intoxication. Eur J Clin Pharmacol 1986; 30: 527–33PubMedCrossRefGoogle Scholar
  47. 47.
    Smith BL, Lloyd N, Spicer N, et al. Immunogenicity and kinetics of distribution and elimination of sheep digoxin-spe-cific IgG and Fab fragments in the rabbit and baboon. Clin Exp Immunol 1979; 36: 384–96PubMedGoogle Scholar
  48. 48.
    Than T, Thein K, Thwin MM. Plasma clearance time of Russell’s viper (Vipera russelli) antivenom in human snake bite victims. Trans R Soc Trop Med Hyg 1985; 79: 262–3CrossRefGoogle Scholar
  49. 49.
    Seifert SA, Boyer LV. Recurrence phenomena after immunoglobulin therapy for snake envenomations: pharmacokinetics and pharmacodynamics of immunoglobulin antivenoms and related antibodies. Ann Emerg Med 2001; 37 (Pt 1): 189–95PubMedCrossRefGoogle Scholar
  50. 50.
    Scherrmann JM. Antibody treatment of toxin poisoning: recent advances. Clin Toxicol 1994; 32: 363–75CrossRefGoogle Scholar
  51. 51.
    Pepin S, Lutsch C, Grandgeorge M, et al. Snake F(ab′)2 antivenom from hyperimmunized horse: pharmacokinetics following intravenous and intramuscular administration in rabbits. Pharmacol Res 1995; 12: 1470–3CrossRefGoogle Scholar
  52. 52.
    Ismail M, Abd-Elsalam MA. Pharmacokinetics of 125I-labelled IgG, F(ab′)2 and Fab fractions of scorpion and snake antivenins: merits and potential for therapeutic use. Toxicon 1998; 36: 1523–8PubMedCrossRefGoogle Scholar
  53. 53.
    Covell DG, Barbet J, Holton OD, et al. Pharmacokinetics of monoclonal immunoglobulin G1, F(ab′)2, and Fab’ in mice. Cancer Res 1986; 46: 3969–78PubMedGoogle Scholar
  54. 54.
    Gutiérrez JM, Lomonte B. Phospholipase A2 myotoxins from Bothrops snake venoms. In: Kini RM, editor. Venom phospholipase A2 enzymes: structure, function and mechanism. Chichester: John Wiley & Sons, 1997, 352Google Scholar
  55. 55.
    Rivière G, Choumet V, Salious B, et al. Absorption and elimination of viper venom after antivenom administration. J Pharmacol Exp Ther 1998; 285: 490–5PubMedGoogle Scholar
  56. 56.
    Timsina MP, Hewick DS. The plasma disposition and renal elimination of digoxin-specific Fab fragments and digoxin in the rabbit. J Pharm Pharmacol 1992; 44: 796–800PubMedCrossRefGoogle Scholar
  57. 57.
    Timsina MP, Hewick DS. Digoxin-specific Fab fragments impair renal function in the rabbit. J Pharm Pharmacol 1992; 44: 867–9PubMedCrossRefGoogle Scholar
  58. 58.
    Dart RC, Seifert SA, Boyer LV, et al. A randomized multicenter trial of Crotalinae polyvalent immune Fab (ovine) antivenom for the treatment for crotaline snakebite in the United States. Arch Intern Med 2001; 161: 2030–6PubMedCrossRefGoogle Scholar
  59. 59.
    Warrell DA. Clinical toxicology of snakebite in Asia. In: Meier J, White J, editors. Handbook of clinical toxicology of animal venoms and poisons. Boca Raton (FL): CRC Press, 1995: 493–594Google Scholar
  60. 60.
    Sancho J, González E, Escanero JF, et al. Binding kinetics of monomeric and aggregated IgG to Kuppfer cells and hepatocytes of mice. Immunology 1984; 53: 283–9PubMedGoogle Scholar
  61. 61.
    Bazin-Readureau M, Gires P, Chapelle P, et al. Immunoglobulin G, F(ab′)2, and Fab fragment uptake kinetics in isolated perfused rat liver and rat hepatic cells. Drug Metab Dispos 1995; 23: 1400–6Google Scholar
  62. 62.
    Henderson LA, Baynes JW, Thorpe SR. Identification of the sites of IgG catabolism in the rat. Arch Biochem Biophys 1982; 215: 1–11PubMedCrossRefGoogle Scholar
  63. 63.
    Ownby CL. Locally acting agents: myotoxins, hemorrhagic toxins and dermonecrotic factors. In: Shier WT, Mebs D, editors. Handbook of toxinology. New York: Marcel Dekker, 1990: 602–54Google Scholar
  64. 64.
    Lomonte B, Lundgren J, Johansson B, et al. The dynamics of local tissue damage induced by Bothrops asper snake venom and myotoxin II on the mouse cremaster muscle: an intravital and electron microscopic study. Toxicon 1994; 32: 41–55PubMedCrossRefGoogle Scholar
  65. 65.
    Leon G, Monge M, Rojas E, et al. Comparison between IgG and F(ab′)2 polyvalent antivenoms: neutralization of systemic effects induced by Bothrops asper venom in mice, extravasation to muscle tissue, and potential for induction of adverse reactions. Toxicon 2001; 39: 793–801PubMedCrossRefGoogle Scholar
  66. 66.
    Leon G, Stiles B, Alape A, et al. Comparative study on the ability of IgG and F(ab′)2 antivenoms to neutralize lethal and myotoxic effects induced by Micrurus nigrocinctus (coral snake) venom. Am J Trop Med Hyg 1999; 61: 266–71PubMedGoogle Scholar
  67. 67.
    Rovira ME, Cannona E, Lomonte B. Immunoenzymatic quantitation of antibodies to myotoxins after polyvalent antivenom administration in mice. Braz J Med Biol Res 1992; 25: 23–33PubMedGoogle Scholar
  68. 68.
    Boulain JC, Ménez A. Neurotoxin-specific immunoglobulins accelerate dissociation of the neurotoxin-acetylcholine receptor complex. Science 1982; 217: 732–3PubMedCrossRefGoogle Scholar
  69. 69.
    Gatineau E, Lee CY, Fromageot P, et al. Reversal of snake neurotoxin binding to mammalian acetylcholine receptor by specific antiserum. Eur J Biochem 1988; 171: 535–9PubMedCrossRefGoogle Scholar
  70. 70.
    Alape-Girón A, Stiles BG, Gutiérrez JM. Antibody-mediated neutralization and binding-reversal studies on α-neurotoxins from Micrurus nigrocinctus nigrocinctus (coral snake) venom. Toxicon 1996; 34: 369–80PubMedCrossRefGoogle Scholar
  71. 71.
    Pepin-Covatta S, Lutsch C, Lang J, et al. Preclinical assessment of immunoreactivity of a new purified equine F(ab′)2 against European viper venom. J Pharm Sci 1998; 87: 221–5PubMedCrossRefGoogle Scholar
  72. 72.
    World Health Organization. Progress in the characterization of venoms and standardization of antivenoms. Geneva: WHO Offset Publication No. 58, 1981Google Scholar
  73. 73.
    Gutiérrez JM, Rojas G, Lomonte B, et al. Standardization of assays for testing the neutralizing ability of antivenoms. Toxicon 1990; 28: 1127–9PubMedCrossRefGoogle Scholar
  74. 74.
    Gutiérrez JM, Rojas G, Bogarín G, et al. Evaluation of the neutralizing ability of antivenoms for the treatment of snake bite envenomation in Central America. In: Bon C, Goyffon M, editors. Envenomings and their treatment. Lyon: Fondation Marcel Mérieux, 1996: 223–31Google Scholar
  75. 75.
    Bogarín G, Morais JF, Yamaguchi IK, et al. Neutralization of crotaline snake venoms from Central and South America by antivenoms produced in Brazil and Costa Rica. Toxicon 2000; 38: 1429–41PubMedCrossRefGoogle Scholar
  76. 76.
    Theakston RDG, Laing GD, Fielding CM, et al. Treatment of snake bites by Bothrops species and Lachesis muta in Ecuador: laboratory screening of candidate antivenoms. Trans R Soc Trop Med Hyg 1995; 89: 550–4PubMedCrossRefGoogle Scholar
  77. 77.
    Theakston RGD. Characterization of venoms and standardization of antivenoms. In: Harris JB, editor. Natural toxins: animal, plant and microbial. Oxford: Clarendon Press, 1986: 287–303Google Scholar
  78. 78.
    Ismail M, Abd-Elsalam MA. Are the toxicological effects of scorpion envenomation related to tissue venom concentration? Toxicon 1988; 26: 233–56PubMedCrossRefGoogle Scholar
  79. 79.
    Santana GC, Freire ACT, Ferreira APL, et al. Pharmacokinetics of Tityus serrulatus scorpion venom determined by enzymelinked immunosorbent assay in the rat. Toxicon 1996; 34: 1963–066Google Scholar
  80. 80.
    Calderón-Aranda ES, Rivière G, Choumet V, et al. Pharmacokinetics of the toxic fraction of Centruroides limpidus limpidusvenom in experimentally envenomed rabbits and effects of immunotherapy with specific F(ab′)2. Toxicon 1999; 37: 771–82PubMedCrossRefGoogle Scholar
  81. 81.
    Ismail M, Amal J, Fatani Y, et al. Experimental treatment protocols for scorpion envenomation: a review of common therapies and an effect of kallikrein-kinin inhibitors. Toxicon 1992; 30: 1257–79PubMedCrossRefGoogle Scholar
  82. 82.
    Krifi MN, Miled K, Abderrazek M, et al. Effects of antivenom on Buthus occitanus tunetanus (Bot) scorpion venom pharmacokinetics: towards an optimization of antivenom immunotherapy in a rabbit model. Toxicon 2001; 39: 1317–26PubMedCrossRefGoogle Scholar
  83. 83.
    Amuy E, Alape-Girón A, Lomonte B, et al. Development of immunoassays for determination of circulating venom antigens during envenomation by coral snakes (Micrurus species). Toxicon 1997; 35: 1605–16PubMedCrossRefGoogle Scholar
  84. 84.
    Amarai CFS, Campolina D, Dias MB, et al. Time factor in the detection of circulating whole venom and crotoxin and efficacy of antivenom therapy in patients envenomed by Crotalus durissus. Toxicon 1997; 35: 699–704CrossRefGoogle Scholar
  85. 85.
    Barral-Neto M, von Sohstein RL. Serum kinetics of crotoxin from Crotalus durissus terrificus venom in mice: evidence for a rapid clearance. Toxicon 1991; 29: 527–31CrossRefGoogle Scholar
  86. 86.
    Kornalik F. The influence of snake venom proteins on blood coagulation. In: Harvey AL, editor. New York: Pergamon Press, 1991: 323–83Google Scholar
  87. 87.
    Cardoso JLC, Fan HW, Franca FOS, et al. 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: 315–25PubMedGoogle Scholar
  88. 88.
    Otero R, Gutiérrez JM, Núñez V, et al. A randomized doubleblind clinical trial of two antivenoms in patients bitten by Bothrops atrox in Colombia. Trans R Soc Trop Med Hyg 1996; 90: 696–700PubMedCrossRefGoogle Scholar
  89. 89.
    Audebert F, Urtizberea M, Sabouraud A, et al. Pharmacokinetics of Vipera aspis venom after experimental envenomation in rabbits. J Pharmacol Exp Ther 1994; 268: 1512–7PubMedGoogle Scholar
  90. 90.
    Barral-Neto M, Schriefer A, Vinhas V, et al. Enzyme-linked immunosorbent assay for the detection of Bothrops jararacavenom. Toxicon 1990; 28: 1053–61CrossRefGoogle Scholar
  91. 91.
    Theakston RDG. Snake bite: the kinetics of envenoming and therapy. In: Bon C, Goyffon M, editors. Envenomings and their treatment. Lyon: Fondation Marcel Mérieux, 1996: 117–26Google Scholar
  92. 92.
    Smith TW. Review of clinical experience with digoxin immune Fab. Am J Emerg Med 1991; 9 Suppl. 1: 1–6PubMedCrossRefGoogle Scholar
  93. 93.
    Eddleston M, Rajapakse S, Rajakanthan S, et al. Anti-digoxin Fab fragments incardiotoxicity induced by ingestion of yellow oleander: a randomised controlled trial. Lancet 2000; 355: 967–72PubMedCrossRefGoogle Scholar
  94. 94.
    Leon G, Rojas G, Lomonte B, et al. Immunoglobulin G and F(ab′)2 polyvalent antivenoms do not differ in their ability to neutralize hemorrhage, edema and myonecrosis induced by Bothrops asper (terciopelo) snake venom. Toxicon 1997; 35: 1627–37PubMedCrossRefGoogle Scholar
  95. 95.
    Leon G, Valverde JM, Rojas G, et al. Comparative study on the ability of IgG and Fab sheep antivenoms to neutralize local hemorrhage, edema and myonecrosis induced by Bothrops asper (terciopelo) snake venom. Toxicon 2000; 38: 233–44PubMedCrossRefGoogle Scholar
  96. 96.
    Morais JF, de Freitas MCW, Yamaguchi IK, et al. Snake antivenom from hyperimmune horses: comparison of the antivenom activity and biological properties of their whole IgG and F(ab′)2 fragments. Toxicon 1994; 32: 725–34PubMedCrossRefGoogle Scholar
  97. 97.
    Fernandes I, Tavares FL, Sano-Martins IS, et al. Efficacy of bothropic antivenom and its IgG(T) fraction in restoring fibrinogen levels of Bothrops jararaca envenomed mice. Toxicon 2000; 38: 995–8PubMedCrossRefGoogle Scholar
  98. 98.
    Rezende NA, Dias MB, Campolina D, et al. Efficacy of antivenom therapy for neutralizing circulating venom antigens in patients stung by Tityus serrulatus scorpions. Am J Trop Med Hyg 1995; 52: 277–80PubMedGoogle Scholar
  99. 99.
    Ismail M. The scorpion envenoming syndrome. Toxicon 1995; 33: 825–58PubMedCrossRefGoogle Scholar
  100. 100.
    Gutiérrez JM, Lomonte B. Local tissue damage induced by Bothrops snake venoms: a review. Mem Inst Butantan 1989; 51: 211–23Google Scholar
  101. 101.
    Gutiérrez JM, Leon G, Rojas G, et al. Neutralization of local tissue damage induced by Bothrops asper (terciopelo) snake venom. Toxicon 1998; 36: 1529–38PubMedCrossRefGoogle Scholar
  102. 102.
    Rucavado A, Lomonte B. Neutralization of myonecrosis, hemorrhage, and edema induced by Bothrops asper snake venom by homologous and heterologous pre-existing antibodies in mice. Toxicon 1996; 34: 567–77PubMedCrossRefGoogle Scholar
  103. 103.
    Lomonte B, Leon G, Hanson LA. Similar effectiveness of Fab and F(ab′)2 antivenoms in the neutralization of hemorrhagic activity of Vipera berus snake venom in mice. Toxicon 1996; 34: 1197–202PubMedCrossRefGoogle Scholar
  104. 104.
    Gutiérrez JM, Ownby CL, Odell GV. Pathogenesis of myonecrosis induced by crude venom and a myotoxin of Bothropsasper. Exp Mol Pathol 1984; 40: 367–79PubMedCrossRefGoogle Scholar
  105. 105.
    Moreira L, Gutiérrez JM, Borkow G, et al. Ultrastructural alterations in mouse capillary blood vessels after experimental injection of venom from the snake Bothrops asper (terciopelo). Exp Mol Pathol 1992; 57: 124–33PubMedCrossRefGoogle Scholar
  106. 106.
    Gutiérrez JM, Chaves F, Bolaños R, et al. Neutralización de los efectos locales del veneno de Bothrops asper por un antiveneno polivalente. Toxicon 1981; 19: 493–500PubMedCrossRefGoogle Scholar
  107. 107.
    Gómez HF, Miller MJ, Trachy JW, et al. Intradermal anti Loxosceles Fab fragments attenuate dermonecrotic arachnidism. Acad Emerg Med 1999; 6: 1195–202PubMedCrossRefGoogle Scholar
  108. 108.
    Gutiérrez JM, Rucavado A, Ovadia M. Metalloproteinase inhibitors in snakebite envenomations. Drug Discov Today 1999; 4: 532–3PubMedCrossRefGoogle Scholar
  109. 109.
    Escalante T, Franceschi A, Rucavado A, et al. Effectiveness of batimastat, a synthetic inhibitor of matrix metalloproteinases, in neutralizing local tissue damage induced by BaP1, a hemorrhagic metalloproteinase from the venom of the snake Bothrops asper. Biochem Pharmacol 2000; 60: 269–74PubMedCrossRefGoogle Scholar
  110. 110.
    Rucavado A, Escalante T, Franceschi A, et al. Inhibition of local hemorrhage and dermonecrosis induced by Bothrops asper snake venom: effectiveness of early in situ administration of the peptidomimetic metalloproteinase inhibitor batimastat and the chelating agent CaNa2EDTA. Am J Trop Med Hyg 2000; 63: 313–9PubMedGoogle Scholar
  111. 111.
    Gutiérrez JM, Rojas G, Pérez A, et al. Neutralization of coral snake Micrurus nigrocinctus venom by a monovalent antivenom. Braz J Med Biol Res 1991; 24: 701–10PubMedGoogle Scholar
  112. 112.
    Warrell DA, Looareesuwan S, Theakston RDG, et al. Randomized comparative trial of three monospecific antivenoms for bites by the Malayan pit viper (Calloselasma rhodostoma) in southern Thailand: clinical and laboratory correlations. Am J Trop Med Hyg 1986; 35: 1235–47PubMedGoogle Scholar
  113. 113.
    Otero-Patiño R, Cardoso JLC, Higashi HG, et al. 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: 183–9PubMedGoogle Scholar
  114. 114.
    Bucher B, Canonge D, Thomas L, et al. Clinical indicators of envenoming and serum levels of venom antigens in patients bitten by Bothrops lanceolatus in Martinique. Trans R Soc Trop Med Hyg 1997; 91: 186–90PubMedCrossRefGoogle Scholar
  115. 115.
    Ho M, Warrell DA, Looareesuwan S, et al. Clinical significance of venom antigen levels in patients envenomed by the Malayan pit viper (Calloselasma rhodostoma). Am J Trop Med Hyg 1986; 35: 579–87PubMedGoogle Scholar
  116. 116.
    Audebert F, Sorkine M, Bon C. Envenomings by viper bites in France: clinical gradation and biological quantification by ELISA. Toxicon 1992; 30: 599–609PubMedCrossRefGoogle Scholar
  117. 117.
    Gillissen A, Theakston RDG, Barth J, et al. Neurotoxicity, haemostatic disturbances and haemolytic anaemia after a bite by a Tunisian saw-scled or carpet viper (Echis ‘pyramidum’-complex). Toxicon 1994; 32: 937–44PubMedCrossRefGoogle Scholar
  118. 118.
    Phillips RE, Theakston RDG, Warrell DA, et al. Paralysis, rhabdomyolysis and haemolysis caused by bites of Russell’s viper (Vipera russelli pulchella) in Sri Lanka: failure of Haffkine antivenom. Q J Med 1988; 68: 691–716PubMedGoogle Scholar
  119. 119.
    Silveira JN, Heneine IF, Beirao PSL. Reversion by polyclonal antibodies of a effects of Tityus serrulatus venom on frog sciatic nerve. Toxicol Lett 1995; 76: 187–93PubMedCrossRefGoogle Scholar
  120. 120.
    Harris JB. Phospholipases in snake venoms and their effects on nerve and muscle. In: Harvey AL, editor. New York: Pergamon Press, 1991: 91–129Google Scholar
  121. 121.
    Boyer LV, Seifert SA, Clark RF, et al. Recurrent and persistent coagulopathy following pit viper envenomation. Arch Intern Med 1999; 159: 706–10PubMedCrossRefGoogle Scholar
  122. 122.
    Boyer LV, Seifert SA, Cain JS. Recurrence phenomena after immunoglobulin therapy for snake envenomations: guidelines for clinical management with crotaline Fab antivenom. Ann Emerg Med 2001; 37 (Pt 2): 196–201PubMedCrossRefGoogle Scholar
  123. 123.
    Bogdan GM, Dart RC, Falbo SC, et al. Recurrent coagulopathy after antivenom treatment of crotalid snakebite. South Med J 2000; 93: 562–6PubMedGoogle Scholar
  124. 124.
    Wilde H, Thipkong P, Sitprija V, et al. Heterologous antisera and antivenins are essential biologicals: perspectives on a worldwide crisis. Ann Intern Med 1996; 125: 233–6PubMedGoogle Scholar
  125. 125.
    Chippaux JP. The development and use of immunotherapy in Africa. Toxicon 1998; 36: 1503–6PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2003

Authors and Affiliations

  • José María Gutiérrez
    • 1
    Email author
  • Guillermo León
    • 1
  • Bruno Lomonte
    • 1
  1. 1.Instituto Clodomiro Picado, Facultad de MicrobiologíaUniversidad de Costa RicaSan JoséCosta Rica

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