| 2021 | "That's Not His Regular Formula": A Case of Organophosphate Poisoning in an Infant. | Pediatr Emerg Care | Organophosphates (OPs) are the basis of many insecticides and herbicides and are also used as nerve agents. Approximately 1 million unintentional and 2 million suicidal poisonings as well as more than 300,000 fatalities that are reportedly due to OPs are reported each year worldwide. The mortality rate from OP toxicity is reported as approximately 20%. We present a rare pediatric exposure to OPs.This is an unintentional OP poisoning in an infant who presented to a pediatric emergency department with obtundation, respiratory distress, and copious secretions. The infant was intubated, treated with atropine and pralidoxime after resuscitation, and eventually recovered with no neurologic sequelae.Symptoms from OP toxicity are secondary to effects on muscarinic and nicotinic cholinergic receptors in the autonomic and central nervous systems. Symptoms include diaphoresis, diarrhea, urination, miosis, bradycardia, bronchospasm, bronchorrhea, emesis, lethargy, lacrimation, and salivation. Treatment starts with titrated doses of atropine and oximes (eg, pralidoxime) after resuscitation and decontamination. Severity of toxicity and recovery can be monitored via plasma and whole blood acetylcholinesterase levels, respectively. Once aging has occurred, oximes will not be able to reverse acetylcholinesterase inhibition. Despite early treatment, rare cases may result in delayed neurologic complications associated with sensory and motor axonal degeneration of the peripheral nerves and spinal cord known as OP-induced delayed neuropathy.This case highlights the importance of safety education for families. It also demonstrates how to recognize and treat OP toxicity in an infant. It emphasizes starting treatment early to avoid complications secondary to aging. |
| 2014 | Acute and Long-Term Impact of Chemical Weapons: Lessons from the Iran-Iraq War. | Forensic Sci Rev | Chemical weapons have given the human experience of warfare a uniquely terrifying quality that has inspired a general repugnance and led to periodic attempts to ban their use. Nevertheless, since ancient times, toxic agents have been consistently employed to kill and terrorize target populations. The evolution of these weapons is examined here in ways that may allow military, law enforcement, and scientific professionals to gain a perspective on conditions that, in the past, have motivated their use - both criminally and as a matter of national policy during military campaigns. Special emphasis is placed on the genocidal use of chemical weapons by the regime of Saddam Hussein, both against Iranians and on Kurdish citizens of his own country, during the Iran-Iraq War of 1980-88. The historical development of chemical weapons use is summarized to show how progressively better insight into biochemistry and physiology was adapted to this form of warfare. Major attributes of the most frequently used chemical agents and a description of how they affected military campaigns are explained. Portions of this review describing chemical-casualty care devote particular focus to Iranian management of neurotoxic (nerve) agent casualties due to the unique nature of this experience. Both nerve and blistering "mustard" agents were used extensively against Iranian forces. However, Iran is the only nation in history to have sustained large-scale attacks with neurotoxic weapons. For this reason, an understanding of the successes and failures of countermeasures to nerve-agent use developed by the Iranian military are particularly valuable for future civil defense and military planning. A detailed consideration of these strategies is therefore considered. Finally, the outcomes of clinical research into severe chronic disease triggered by mustard-agent exposure are examined in the context of the potential of these outcomes to determine the etiology of illness among US and Allied veterans of the 1991 Persian Gulf War. |
| 2013 | Colonic perforation associated with neostigmine administration. | J Surg Case Rep | Neostigmine is an acetylcholinesterase inhibitor that is increasingly used as a medical treatment in cases of pseudo-obstruction. It has a well-recognized side-effect profile that includes bradycardia and bronchospasm. We present a case of colonic perforation after administration of neostigmine in the treatment of pseudo-obstruction. |
| 2012 | Structure-activity relationship and efficacy of pyridinium oximes in the treatment of poisoning with organophosphorus compounds: a review of recent data. | Curr Top Med Chem | During more than five decades, pyridinium oximes have been developed as therapeutic agents used in the medical treatment of poisoning with organophosphorus compounds. Their mechanism of action is reactivation of acetylcholinesterase (AChE) inhibited by organophosphorus agents. Organophosphorus compounds (OPC) are used as pesticides and developed as warfare nerve agents such as tabun, soman, sarin, VX and others. Exposure to even small amounts of an OPC can be fatal and death is usually caused by respiratory failure resulting from paralysis of the diaphragm and intercostal muscles, depression of the brain respiratory center, bronchospasm, and excessive bronchial secretions. The mechanism of OPC poisoning involves phosphorylation of the serine hydroxyl group at the active site of AChE leading to the inactivation of this essential enzyme, which has an important role in neurotransmission. AChE inhibition results in the accumulation of acetylcholine at cholinergic receptor sites, producing continuous stimulation of cholinergic fibers throughout the central and peripheral nervous systems. Presently, a combination of an antimuscarinic agent, e.g. atropine, AChE reactivator such as one of the standard pyridinium oximes (pralidoxime, trimedoxime, obidoxime, HI-6) and diazepam are used for the treatment of organophosphate poisoning in humans. Despite of enormous efforts devoted to synthesis and development of new pyridinium oximes as potential antidotes against poisoning with OPC, only four compounds have found their application in human medicine so far. However, they differ in their activity in poisoning with warfare nerve agents and pesticides and there is still no universal broad-spectrum oxime capable of protecting against all known OPC. In this article the latest data on structure-activity relationship of pyridinium oximes including their efficacy in treatment of poisoning with organophosphorus compounds are reviewed. |
| 2009 | Pyridinium oximes as cholinesterase reactivators. Structure-activity relationship and efficacy in the treatment of poisoning with organophosphorus compounds. | Curr Med Chem | During more than five decades, pyridinium oximes have been developed as therapeutic agents used in the medical treatment of poisoning with organophosphorus compounds. Their mechanism of action is reactivation of acetylcholinesterase (AChE) inhibited by organophosphorus agents. Organophosphorus compounds (OPC) are used as pesticides and developed as warfare nerve agents such as tabun, soman, sarin, VX and others. Exposure to even small amounts of an OPC can be fatal and death is usually caused by respiratory failure resulting from paralysis of the diaphragm and intercostal muscles, depression of the brain respiratory center, bronchospasm, and excessive bronchial secretions. The mechanism of OPC poisoning involves phosphorylation of the serine hydroxyl group at the active site of AChE leading to the inactivation of this essential enzyme, which has an important role in neurotransmission. AChE inhibition results in the accumulation of acetylcholine at cholinergic receptor sites, producing continuous stimulation of cholinergic fibers throughout the central and peripheral nervous systems. Presently, a combination of an antimuscarinic agent, e.g. atropine, AChE reactivator such as one of the standard pyridinium oximes (pralidoxime, trimedoxime, obidoxime, HI-6) and diazepam has been used for the treatment of organophosphate poisoning in humans. Despite enormous efforts devoted to synthesis and development of new pyridinium oximes as potential antidotes against poisoning with OPC, only four compounds have found their application in human medicine so far. However, they differ in their activity in poisoning with warfare nerve agents and pesticides and there is still no universal broad-spectrum oxime capable of protecting against all known OPC. In this article, we review data on structure-activity relationship of pyridinium oximes and discuss their pharmacological and toxicological significance. |
| 2005 | Mechanisms of airway smooth muscle relaxation during maturation. | Can J Physiol Pharmacol | Greater airway responsiveness in healthy juveniles is considered a factor in the higher asthma prevalence at a young age compared with adults. We have developed a guinea pig maturational model that utilizes tracheal strips from 1-week-, 3-week-, and 3-month-old guinea pigs to study the role of airway smooth muscle (ASM) in juvenile airway hyperresponsiveness. Because a reduced ability of ASM to spontaneously relax may contribute to airway hyperresponsiveness by maintaining bronchospasm and thus high airway resistance, we have employed this model to study ASM spontaneous relaxation during electrical field stimulation (EFS). Since relaxation during EFS had been neither described nor quantified during maturation, we developed new indices that allowed an appropriate comparison of the relaxing response from strips of different age animals. Using these indices we found that, whereas strips from adult animals relax to a level of tension similar to that found in the absence of stimulation, this ability to spontaneously relax is essentially absent in trachealis from infant animals. These results confirmed that maturation of ASM relaxation may play a role in juvenile airway hyperresponsiveness and that our maturational model is suitable to study the mechanisms regulating spontaneous relaxation in physiological conditions. We investigated the role of prostanoids in ASM relaxation and showed that cyclooxygenase inhibition increases relaxation in infant ASM to levels similar to adults. These results suggest that prostanoids regulate the ability of ASM to spontaneously relax, i.e., they reduce relaxation. We have produced preliminary data suggesting a maturational change in the level of prostanoids. Moreover, the possible action of acetylcholinesterase on maturation of ASM relaxation is discussed here on the basis of a preliminary study. We suggest that impairment of ASM relaxation likely contributes to increased airway responsiveness. |
| 2005 | Organic phosphorus compounds--nerve agents. | Crit Care Clin | The organic phosphorous compounds (OPC) include both the military grade nerve agents and the organic phosphorous pesticides. The major mechanism of OPC toxicity is through inhibition of acetylcholinesterase in neuronal synapses leading to excess acetylcholine and overstimulation of target organs. Signs and symptoms depend on the affinity of the OPC for muscarinic versus nicotinic receptors, and are likely to include both. Muscarinic symptoms may include diarrhea, urination, bronchospasm, bronchorrhea, emesis, and salivation. Nicotinic symptoms such as paralysis and fasciculations may also occur. Central nervous system toxicity may include seizures, altered mental status, and apnea, and require prompt intervention. Treatment includes early airway and ventilatory support as well as antidotal therapy with atropine, pralidoxime, and diazepam. Goals of therapy include prevention and rapid treatment of hypoxia and seizures, as these are linked to patient outcome. |
| 2002 | [Galantamine: a novel cholinergic agent for Alzheimer's disease]. | Neurologia | Galantamine has been recently approved for the symptomatic treatment of Alzheimer's disease (AD). Apart from inhibiting acetylcholinesterase, galantamine modulates the nicotinic receptors, although the clinical significance of this action remains uncertain. Through a broad research program, it has been shown that galantamine produces a cognitive, functional and behavioral benefit in patients with either mild or moderate AD. Initially, the maintenance dose must be 16 mg a day. Later on, 24 mg dose attempts are justified on an individual patient basis. A clinical stabilization for almost one year is observed. After that time, treated patients deteriorate at a similar pace than the non-treated ones, but they remain above the non-treated during at least one more year. Additional data suggest that positive effects of galantamine spread both caregiver burden and pharmacoeconomic areas. Tolerability is good, provided that titration is made slowly. The only contraindications of this drug are atrioventricular blockade and uncontrolled bronchospasm. Galantamine has also shown efficacy in mixed dementia. New possible indications are mild cognitive impairment and vascular dementia. |
| 2000 | [Acute neurotoxic organophosphate poisoning: insecticides and chemical weapons]. | Ann Fr Anesth Reanim | To review clinical and therapeutic bases of an organophosphate poisoning, either with insecticide or nerve agent.References were obtained from computerized bibliographic research (Medline), from personal data (academic memoir, documents under approbation of the National Defense Office), from Internet's data.Generally, organophosphate poisoning occurs during accidental exposure with agricultural insecticide or suicide. The effects of organophosphate compounds are due to the inhibition of the enzyme acetylcholinesterase. The intoxication symptoms can be divided into muscarine-like, nicotine-like effects, effects on the central nervous system and symptoms related to the dysfunction of the neuromuscular junction. The interest of biological acetylcholinesterase's measuring is minimal because it is weakly specific or sensitive. The immediate severity is due to hypoxia. Respiratory failure results from the lack of central drive inflated with excessive bronchial secretions, bronchospasm and respiratory muscles paralysis. The secondary complications are early myopathies whose gravity is correlated with the decrease of acetylcholinesterases, or later neuropathies induced by a different mechanism. Beside the symptomatic measures, atropine is the specific anticholinergic treatment. When promptly used, oximes can regenerate cholinesterases. The attempted effects of the treatment are mouth dryness, pupilar dilatation and flushing of the skin. Nerve agents are lethal toxics which have a short onset time and produce severe neurological pathology. In a terrorist incident, it is as important to identify rapidly the toxic agent and provide emergency decontamination as to manage medical care. An effective response must be multidisciplinary, involving clinicians, toxicologists, Emergency Medical Service and public's health personnel. |
| 1992 | Physiological mechanisms mediating enhanced force generation during development and immune sensitization. | Can J Physiol Pharmacol | We examined the development of acetylcholinesterase (AChase) activity and tracheal smooth muscle (TSM) contraction elicited by acetylcholine (ACh) in a swine model of maturation and a dog model of allergic bronchospasm. Strips of TSM were tethered isometrically at optimal length and responses were expressed as a percentage of the maximum to KCl-substituted perfusate (% KCl). Maximal contraction (ATmax) to ACh in 2-week-old swine (168 +/- 8% KCl) was greater than in 10-week-old swine (142 +/- 2% KCl; p less than 0.02). The AChase inhibitor, physostigmine, augmented ACh-elicited ATmax in 10-week-old (27% increase; p less than 0.01) but not in 2-week-old swine (2% increase; p is NS) and caused a greater increase in sensitivity to muscarinic activation in 2 versus 10 week-old swine (p less than 0.02), thus demonstrating increased contraction of TSM in 2 versus 10-week-old swine, which results at least in part from reduced AChase activity in immature animals. In another study, TSM from ragweed-sensitized dogs demonstrated augmented efficacy to ACh-elicited contraction (180 +/- 6% KCl) compared with TSM from sham-sensitized, littermate controls (163 +/- 4% KCl; p less than 0.05). In the presence of physostigmine, ATmax was not different between ragweed-sensitized and control TSM.(ABSTRACT TRUNCATED AT 250 WORDS) |
| 1991 | Roles of neutral endopeptidase in airways. | Am J Physiol | In recent years, studies of the regulation of the airways have focused to an increasing degree on the roles of neuropeptides. Several peptides have been shown to be present in airways and mediate such diverse responses as ion transport, mucus secretion, bronchospasm or relaxation, edema, cough, changes in vascular permeability, and neutrophil chemotaxis. More recently, studies have described the roles of peptidases, most notably neutral endopeptidase (NEP, also known as enkephalinase, or E.C. 3.4.24.11) and kininase II (also known as angiotensin-converting enzyme, or E.C. 3.4.15.1) in modulating peptide-induced responses. The enzymes cleave a wide variety of peptides, generating metabolites that are inactive in the systems studied to date. Thus inhibitors of NEP potentiate responses to peptides that are cleaved by it. Therefore, NEP plays roles in modulating peptide-induced effects analogous to the role of acetylcholinesterase in modulating cholinergic neurotransmission. In several experimental respiratory diseases, the activity of neutral endopeptidase is decreased, resulting in increased responses to peptides. The therapeutic application of recombinant NEP protects the airways from the adverse actions of stimuli that release inflammatory peptides, and induction of the NEP gene expression by glucocorticoids suggest a possible mechanism for the action of these steroids in treating airway diseases such as asthma, chronic bronchitis, or cystic fibrosis. |
| 1983 | [Histochemical characteristics of the neural apparatus of the bronchi in different states of tonus]. | Arkh Patol | Composite histoenzymochemical characteristics of the nervous apparatus of bronchi in vagotomy, desympathetization, histamine shock, and development of pneumonia experimentally and clinically were obtained. The development of bronchospasm under the above effects and in pneumonia was found to be accompanied by decreases in the activity of acetylcholinesterase, the content of noradrenaline, a high content of nucleoproteins, polysaccharides, a high activity of oxidoreductases in different structures of the nervous apparatus of the bronchi. Bronchodilatation was accompanied by a decrease of all the above-mentioned indicators of the status of the nervous apparatus as well as destructive changes in its elements. The condition of production and utilization of the cholinergic and adrenergic mediators is discussed on the basis of the data obtained. |
| 1979 | Effects of dichlorvos (DDVP) inhalation on the activity of acetylcholinesterase in the bronchial tissue of rats. | Arch Toxicol | The experiments presented here deal with the effects of the inhalation of dichlorvos [dimethyl-(2,2 dichlorvinyl)-phosphate, DDVP] vapor on acetylcholinesterase (ACHE) activity in rat bronchial tissue. Exposure to DDVP concentrations of 0.8 and 1.8 micrograms/l for 3 days reduced ACHE activity in the bronchial tissue (62.8 +/- 0.8 and 51.6 +/- 1.6% of the control), but did not elicit any changes in blood ACHE activity (101 +/- 4.5% of the control each). Higher concentrations (4.3 micrograms/l) induced a decline in ACHE activity also in the blood (38.2 +/- 1.1% of the control). In the histochemical preparations used to demonstrate ACHE activity in bronchial tissue (thiolacetic acid method), a staining of the bronchial glands and smooth muscles characteristic of the enzyme activity was strongly reduced after exposure of the animals to even the lowest dose applied (0.2 microgram/l). The question of whether localized inhibition of ACHE in the bronchial tissue might cause increases in airway resistance due to activation of a broncho-bronchial reflex is discussed. This efferent cholinergic mechanism has been found to be at least partly responsible for maintenance of bronchospasm and hypersecretion in chronic obstructive diseases of the respiratory system. |