Overcoming apathy in research on organophosphate poisoning
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《英国医生杂志》
1 South Asian Clinical Toxicology Research Collaboration, Department of Clinical Pharmacology and Toxicology, Canberra Hospital, PO Box 11, Woden, ACT 2606, Australia, 2 Ox-Col Collaboration, Department of Clinical Medicine, University of Colombo, Colombo, Sri Lanka
Correspondence to: N A Buckley Nick.Buckley@act.gov.au
High rates of pesticide poisoning in developing countries and increasing risk of nerve gas attacks in the West mean effective antidotes for organophosphates should be a worldwide priority
Introduction
Thus organophosphates are of worldwide interest. Their toxicity is well understood.10 Current treatment for organophosphate poisoning is to give atropine, an oxime such as pralidoxime, and benzodiazepines. However, no evidence exists that either oximes or benzodiazepines are effective at reducing morbidity or mortality in humans.5 No good quality clinical research has been performed on these antidotes in humans.
Newer, more effective antidotes are needed. The currently recommended antidotes are the tip of a therapeutic iceberg that could be mobilised. Animal studies have shown many beneficial compounds, yet no new treatment has reached the bedside in the past 30 years, and no new treatment is in clinical trials. Potential new treatments identified in animal models include organophosphate hydrolases, which break down organophosphates and speed up reactivation of acetyl cholinesterase; reversible anticholinesterases (such as the carbamate pyridostigmine), which reduce re-inhibition of acetyl cholinesterase; and glutamate antagonists and agonists for adenosine and -2 adrenergic receptors, which limit damage to the central nervous system.11
Information on these potential treatments has been available for years,11 but neither the military nor the pharmaceutical industry has attempted to test them or develop new drugs. Arguments that new antidotes for organophosphate nerve agents should be approved without human safety or efficacy data have been heeded,4 with the recent registration of pyridostigmine by the FDA without trials.12 The controversy surrounding the role of pyridostigmine prophylaxis in Gulf war syndrome13 shows the dangers of this approach.13 Lack of human studies before wide scale use of pyridostigmine in military staff and the failure to gather prospective data during this experimental mass treatment make the association difficult to refute.13
Much of the research on treatment for nerve gas poisoning has concentrated on prophylaxis. However, in all recent reported exposures treatment, and usually diagnosis, of nerve gas poisoning has been delayed.14 15 Thus the situation is similar to that faced with pesticide poisoning. Patients with pesticide poisoning require the same treatment as those poisoned by nerve gases.10 11Ample opportunity exists for clinical trials because at least two million people are poisoned by organophosphate pesticides each year in the developing world.16 17 Yet little evidence exists to guide treatment.5 The problems are compounded by the conditions in which most patients with pesticide poisoning are seen—in hospitals without sufficient doctors, nurses, ventilators, or antidotes to offer a good service.17 18 This scenario may well be one that occurs in industrialised countries after a large scale chemical attack.
Collaboration and support are needed
Terrorism preparedness in state health departments—United States, 2001-2003. JAMA 2003;290: 3190.
Lee EC. Clinical manifestations of sarin nerve gas exposure. JAMA 2003;290: 659-62.
Brown MA, Brix KA. Review of health consequences from high-, intermediate- and low-level exposure to organophosphorus nerve agents. J Appl Toxicol 1998;18: 393-408.
Marino MT. Use of surrogate markers for drugs of military importance. Military Med 1998;163: 743-6.
Eddleston M, Singh S, Buckley N. Acute organophosphorus poisoning. Clinical Evidence 2003;10: 1652-63.
Eddleston M, Sheriff MH, Hawton K. Deliberate self harm in Sri Lanka: an overlooked tragedy in the developing world. BMJ 1998;317: 133-5.
Eddleston M. Patterns and problems of deliberate self-poisoning in the developing world. Q J Med 2000;93: 715-31.
Phillips MR, Li X, Zhang Y. Suicide rates in China, 1995-99. Lancet 2002;359: 835-40.
Buckley NA, Karalliedde L, Dawson A, Senanayake N, Eddleston M. Where is the evidence for the management of pesticide poisoning—is clinical toxicology fiddling while the developing world burns? J Toxicol Clin Toxicol 2004;42: 1-4.
Ballantyne B, Marrs TC. Overview of the biological and clinical aspects of organophosphates and carbamates. In: Ballantyne B, Marrs TC, eds. Clinical and experimental toxicology of organophosphates and carbamates. Oxford: Butterworth Heinemann, 1992: 3-14.
Johnson MK, Jacobsen D, Meredith TJ, Eyer P, Heath AJ, Ligtenstein DA, et al. Evaluation of antidotes for poisoning by organophosphorus pesticides. Emerg Med 2000;12: 22-37.
US Food and Drug Administration. FDA approves pyridostigmine bromide as a pretreatment against nerve gas. www.fda.gov/bbs/topics/NEWS/2003/NEW00870.html (accessed 15 Oct 2004).
Lashof JC, Cassells JS. Illness among Gulf War veterans: risk factors, realities, and future research. JAMA 1998;280: 1010-1.
Okumura T, Takasu N, Ishimatsu S, Miyanoki S, Mitsuhashi A, Kumada K. Report on 640 victims of the Tokyo subway sarin attack. Ann Emerg Med 1996;28: 129-35.
Balali-Mood M, Shariat M. Treatment of organophosphate poisoning. Experience of nerve agents and acute pesticide poisoning on the effects of oximes. J Physiol (Paris) 1998;92: 375-8.
Gunnell D, Eddleston M. Suicide by intentional ingestion of pesticides: a continuing tragedy in developing countries. Int J Epidemiol 2003;32: 902-9.
Eddleston M, Phillips MR. Self poisoning with pesticides. BMJ 2004;328: 42-4.
Eddleston M, Karalliedde L, Buckley N, Fernando R, Hutchinson G, Isbister G, et al. Pesticide poisoning in the developing world—a minimum pesticides list. Lancet 2002;360: 1163-7.
Roberts DM, Karunarathna A, Buckley NA, Manuweera G, Sheriff MHR, Eddleston M. Influence of pesticide regulation on acute poisoning deaths in Sri Lanka. Bull World Health Organ 2003;81: 789-98.(Nick A Buckley, director )
Correspondence to: N A Buckley Nick.Buckley@act.gov.au
High rates of pesticide poisoning in developing countries and increasing risk of nerve gas attacks in the West mean effective antidotes for organophosphates should be a worldwide priority
Introduction
Thus organophosphates are of worldwide interest. Their toxicity is well understood.10 Current treatment for organophosphate poisoning is to give atropine, an oxime such as pralidoxime, and benzodiazepines. However, no evidence exists that either oximes or benzodiazepines are effective at reducing morbidity or mortality in humans.5 No good quality clinical research has been performed on these antidotes in humans.
Newer, more effective antidotes are needed. The currently recommended antidotes are the tip of a therapeutic iceberg that could be mobilised. Animal studies have shown many beneficial compounds, yet no new treatment has reached the bedside in the past 30 years, and no new treatment is in clinical trials. Potential new treatments identified in animal models include organophosphate hydrolases, which break down organophosphates and speed up reactivation of acetyl cholinesterase; reversible anticholinesterases (such as the carbamate pyridostigmine), which reduce re-inhibition of acetyl cholinesterase; and glutamate antagonists and agonists for adenosine and -2 adrenergic receptors, which limit damage to the central nervous system.11
Information on these potential treatments has been available for years,11 but neither the military nor the pharmaceutical industry has attempted to test them or develop new drugs. Arguments that new antidotes for organophosphate nerve agents should be approved without human safety or efficacy data have been heeded,4 with the recent registration of pyridostigmine by the FDA without trials.12 The controversy surrounding the role of pyridostigmine prophylaxis in Gulf war syndrome13 shows the dangers of this approach.13 Lack of human studies before wide scale use of pyridostigmine in military staff and the failure to gather prospective data during this experimental mass treatment make the association difficult to refute.13
Much of the research on treatment for nerve gas poisoning has concentrated on prophylaxis. However, in all recent reported exposures treatment, and usually diagnosis, of nerve gas poisoning has been delayed.14 15 Thus the situation is similar to that faced with pesticide poisoning. Patients with pesticide poisoning require the same treatment as those poisoned by nerve gases.10 11Ample opportunity exists for clinical trials because at least two million people are poisoned by organophosphate pesticides each year in the developing world.16 17 Yet little evidence exists to guide treatment.5 The problems are compounded by the conditions in which most patients with pesticide poisoning are seen—in hospitals without sufficient doctors, nurses, ventilators, or antidotes to offer a good service.17 18 This scenario may well be one that occurs in industrialised countries after a large scale chemical attack.
Collaboration and support are needed
Terrorism preparedness in state health departments—United States, 2001-2003. JAMA 2003;290: 3190.
Lee EC. Clinical manifestations of sarin nerve gas exposure. JAMA 2003;290: 659-62.
Brown MA, Brix KA. Review of health consequences from high-, intermediate- and low-level exposure to organophosphorus nerve agents. J Appl Toxicol 1998;18: 393-408.
Marino MT. Use of surrogate markers for drugs of military importance. Military Med 1998;163: 743-6.
Eddleston M, Singh S, Buckley N. Acute organophosphorus poisoning. Clinical Evidence 2003;10: 1652-63.
Eddleston M, Sheriff MH, Hawton K. Deliberate self harm in Sri Lanka: an overlooked tragedy in the developing world. BMJ 1998;317: 133-5.
Eddleston M. Patterns and problems of deliberate self-poisoning in the developing world. Q J Med 2000;93: 715-31.
Phillips MR, Li X, Zhang Y. Suicide rates in China, 1995-99. Lancet 2002;359: 835-40.
Buckley NA, Karalliedde L, Dawson A, Senanayake N, Eddleston M. Where is the evidence for the management of pesticide poisoning—is clinical toxicology fiddling while the developing world burns? J Toxicol Clin Toxicol 2004;42: 1-4.
Ballantyne B, Marrs TC. Overview of the biological and clinical aspects of organophosphates and carbamates. In: Ballantyne B, Marrs TC, eds. Clinical and experimental toxicology of organophosphates and carbamates. Oxford: Butterworth Heinemann, 1992: 3-14.
Johnson MK, Jacobsen D, Meredith TJ, Eyer P, Heath AJ, Ligtenstein DA, et al. Evaluation of antidotes for poisoning by organophosphorus pesticides. Emerg Med 2000;12: 22-37.
US Food and Drug Administration. FDA approves pyridostigmine bromide as a pretreatment against nerve gas. www.fda.gov/bbs/topics/NEWS/2003/NEW00870.html (accessed 15 Oct 2004).
Lashof JC, Cassells JS. Illness among Gulf War veterans: risk factors, realities, and future research. JAMA 1998;280: 1010-1.
Okumura T, Takasu N, Ishimatsu S, Miyanoki S, Mitsuhashi A, Kumada K. Report on 640 victims of the Tokyo subway sarin attack. Ann Emerg Med 1996;28: 129-35.
Balali-Mood M, Shariat M. Treatment of organophosphate poisoning. Experience of nerve agents and acute pesticide poisoning on the effects of oximes. J Physiol (Paris) 1998;92: 375-8.
Gunnell D, Eddleston M. Suicide by intentional ingestion of pesticides: a continuing tragedy in developing countries. Int J Epidemiol 2003;32: 902-9.
Eddleston M, Phillips MR. Self poisoning with pesticides. BMJ 2004;328: 42-4.
Eddleston M, Karalliedde L, Buckley N, Fernando R, Hutchinson G, Isbister G, et al. Pesticide poisoning in the developing world—a minimum pesticides list. Lancet 2002;360: 1163-7.
Roberts DM, Karunarathna A, Buckley NA, Manuweera G, Sheriff MHR, Eddleston M. Influence of pesticide regulation on acute poisoning deaths in Sri Lanka. Bull World Health Organ 2003;81: 789-98.(Nick A Buckley, director )