Oxime-functionalized anti-insecticide fabric reduces insecticide exposure through dermal and nasal routes, and prevents insecticide-induced neuromuscular-dysfunction and mortality.

Farmers from South Asian countries spray insecticides without protective gear, which leads to insecticide exposure through dermal and nasal routes. Acetylcholinesterase plays a crucial role in controlling neuromuscular function. Organophosphate and carbamate insecticides inhibit acetylcholinesterase, which leads to severe neuronal/cognitive dysfunction, breathing disorders, loss of endurance, and death. To address this issue, an Oxime-fabric is developed by covalently attaching silyl-pralidoxime to the cellulose of the fabric. The Oxime-fabric, when stitched as a bodysuit and facemask, efficiently deactivates insecticides (organophosphates and carbamates) upon contact, preventing exposure. The Oxime-fabric prevents insecticide-induced neuronal damage, neuro-muscular dysfunction, and loss of endurance. Furthermore, we observe a 100% survival rate in rats when repeatedly exposed to organophosphate-insecticide through the Oxime-fabric, while no survival is seen when organophosphate-insecticide applied directly or through normal fabric. The Oxime-fabric is washable and reusable for at least 50 cycles, providing an affordable solution to prevent insecticide-induced toxicity and lethality among farmers.

Loading and Sustained Release of Pralidoxime Chloride from Swellable MIL-88B(Fe) and Its Therapeutic Performance on Mice Poisoned by Neurotoxic Agents.

Maintaining a long-term continuous and stable reactivator blood concentration to treat organophosphorus nerve agent poisoning using acetylcholinesterase (AChE) reactivator pralidoxime chloride (2-PAM) is very important yet difficult. Because the flexible framework of MIL-88B(Fe) nanoparticles (NPs) can swell in polar solvents, pralidoxime chloride (2-PAM) was loaded in MIL-88B(Fe) NPs (size: ca. 500 nm) by stirring and incubation in deionized water to obtain 2-PAM@MIL-88B(Fe), which had a maximum drug loading capacity of 12.6 wt %. The as-prepared composite was characterized by IR, powder X-ray diffraction (P-XRD), scanning electron microscopy (SEM), ζ-potential, Brunauer-Emmett-Teller (BET), and thermogravimetry/differential thermal analysis (TG/DTA). The results showed that under constant conditions, the maximum drug release rates of 2-PAM@MIL-88B(Fe) in absolute ethanol, phosphate-buffered saline (PBS) solution (pH = 7.4), and PBS solution (pH = 4) at 150 h were 51.7, 80.6, and 67.1%, respectively. This was because the composite showed different swelling behaviors in different solvents. In PBS solution with pH = 2, the 2-PAM@MIL-88B(Fe) framework collapsed after 53 h and released 100% of 2-PAM. For mice after intragastric poisoning with sarin (a neurotoxic agent), an atropine-assisted 2-PAM@MIL-88B(Fe) treatment experiment revealed that 2-PAM@MIL-88B(Fe) continuously released 2-PAM for more than 72 h so that poisoned AChE was continuously and steadily reactivated. The reactivation rate of AChE was 56.7% after 72 h. This composite is expected to provide a prolonged, stable therapeutic drug for the mid- and late-stage treatment of neurotoxic agent poisoning.

A delayed treatment model for the evaluation of scopolamine for VX nerve agent intoxication.

Most research on medical countermeasures for nerve agent exposure assumes a military scenario, in which (autoinjector) treatment is envisaged to be available immediately. In a civilian setting however, treatment is delayed until arrival of first-aid responders. This may significantly affect treatment efficacy and the requirements for secondary intensive care. The aim of the current study was to develop a guinea pig model to evaluate the efficacy of delayed treatment following nerve agent exposure. We identified a trigger-to-treat based on a progressive stage of the toxidrome following VX exposure, which was associated with the subsiding of clonic movements. This paradigm resulted in treatment consistently being administered between 15 and 25 min post-exposure. Using the model, we investigated the potential for the anticholinergic scopolamine to act as a delayed treatment either as a standalone treatment, or as an adjunct to delayed treatment with Standard of Care (SOC), containing atropine, 2-PAM, and midazolam. The study provides a framework for a small animal model for evaluating the efficacy of treatment administered at a specific stage of the toxidrome, when immediate treatment is absent. As an adjunct, scopolamine treatment did not result in improved survival, but did show a beneficial effect on recovery, in terms of general posture. As a standalone treatment, scopolamine showed a significant, dose-responsive, beneficial effect on survival and recovery. These promising results warrant additional studies to investigate which observed physiological improvements are relevant for the recovery process and residual injury.

Surface modification of pralidoxime chloride-loaded solid lipid nanoparticles for enhanced brain reactivation of organophosphorus-inhibited AChE: Pharmacokinetics in rat.

The nanotechnological approach is an innovative strategy of high potential to achieve reactivation of organophosphorus-inhibited acetylcholinesterase in central nervous system. It was previously shown that pralidoxime chloride-loaded solid lipid nanoparticles (2-PAM-SLNs) are able to protect the brain against pesticide (paraoxon) central toxicity. In the present work, we increased brain AChE reactivation efficacy by PEGylation of 2-PAM-SLNs using PEG-lipid N-(carbonyl-methoxypolyethylene glycol-2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine, sodium salt) (DSPE-PEG2000) as a surface-modifier of SLNs. To perform pharmacokinetic study, a simple, sensitive (LLOQ 1.0 ng/mL) high-performance liquid chromatography tandem mass spectrometry with atmospheric pressure chemical ionization by multiple reaction monitoring mode (HPLC-APCI-MS) was developed. The method was compared to mass spectrometry with electrospray ionization. The method was validated for linearity, accuracy, precision, extraction recovery, matrix effect and stability. Acetophenone oxime was used as the internal standard for the quantification of 2-PAM in rat plasma and brain tissue after intravenous administration. 2-PAM-DSPE-PEG2000-SLNs of mean size about 80 nm (PDI = 0.26), zeta-potential of -55 mV and of high in vitro stability, prolonged the elimination phase of 2-PAM from the bloodstream more than 3 times compared to free 2-PAM. An increase in reactivation of POX-inhibited human brain acetylcholinesterase up to 36.08 ± 4.3 % after intravenous administration of 2-PAM-DSPE-PEG2000-SLNs (dose of 2-PAM is 5 mg/kg) was achieved. The result is one of the first examples where this level of brain acetylcholinesterase reactivation was achieved. Thus, the implementation of different approaches for targeting and modifying nanoparticles' surface gives hope for improving the antidotal treatment of organophosphorus poisoning by marketed reactivators.

Effects of Different Doses of Pralidoxime Administered During Cardiopulmonary Resuscitation and the Role of α-Adrenergic Receptors in Its Pressor Action.

Background We previously reported that pralidoxime facilitated restoration of spontaneous circulation by potentiating the pressor effect of epinephrine. We determined the optimal dose of pralidoxime during cardiopulmonary resuscitation and evaluated the involvement of α-adrenoceptors in its pressor action. Methods and Results Forty-four pigs randomly received 1 of 3 doses of pralidoxime (40, 80, or 120 mg/kg) or saline placebo during cardiopulmonary resuscitation, including epinephrine administration. Pralidoxime at 40 mg/kg produced the highest coronary perfusion pressure, whereas 120 mg/kg of pralidoxime produced the lowest coronary perfusion pressure. Restoration of spontaneous circulation was attained in 4 (36.4%), 11 (100%), 9 (81.8%), and 3 (27.3%) animals in the saline, 40, 80, and 120 mg/kg groups, respectively (P<0.001). In 49 rats, arterial pressure response to 40 mg/kg of pralidoxime was determined after saline, guanethidine, phenoxybenzamine, or phentolamine pretreatment, and the response to 200 mg/kg pf pralidoxime was determined after saline, propranolol, or phentolamine pretreatment. Pralidoxime at 40 mg/kg elicited a pressor response. Phenoxybenzamine completely inhibited the pressor response, but guanethidine and phentolamine did not. The pressor response of pralidoxime was even greater after guanethidine or phentolamine pretreatment. Pralidoxime at 200 mg/kg produced an initial vasodepressor response followed by a delayed pressor response. Unlike propranolol, phentolamine eliminated the initial vasodepressor response. Conclusions Pralidoxime at 40 mg/kg administered with epinephrine improved restoration of spontaneous circulation rate by increasing coronary perfusion pressure in a pig model of cardiac arrest, whereas 120 mg/kg did not improve coronary perfusion pressure or restoration of spontaneous circulation rate. The pressor effect of pralidoxime was unrelated to α-adrenoceptors and buffered by its vasodepressor action mediated by sympathoinhibition.

Pharmacological and toxicological in vitro and in vivo effect of higher doses of oxime reactivators.

The major function of compounds with an oxime moiety attached to a quarternary nitrogen pyridinium ring is to reactivate acetylcholinesterase inhibited by organophosphorus agent (OP). However, other oxime mechanisms (e.g. modulation of cholinergic or glutamatergic receptor) may be involved in the recovery. The main disadvantage of positively charged reactivators is their low ability to penetrate into the brain although crossing the blood brain barrier could be supported via increasing the dose of administered oxime. Thus, this study presents maximal tolerated doses (MTD) for marketed oximes (TMB-4, MMB-4, LüH-6, HI-6, 2-PAM) and the most promising K-oximes (K027, K048, K203) which can be used in OP therapy in the future. No signs of sarin intoxication were observed in mice treated with 100% MTD of HI-6 in contrast to those treated with atropine and only 5% LD50 of HI-6. 100% MTD of HI-6 resulted in levels of 500 µM and 12 µM in plasma and brain, respectively. This concentration is by a far margin safe with respect to direct effects on neuronal cell viability and, on the other hand, does not have any effects on central NMDA receptors or central nACh receptors. However, a weak antimuscarinic activity in case of LüH-6 and a weak peripheral antinicotinic action in case of TMB-4 and 2-PAM could be observed at their respective 100% MTD dose. These high doses, represented by MTD, are, however, irrelevant to clinical practice since they led to mild to moderate toxic side effects. Therefore, we conclude that clinically used doses of marketed oxime reactivators have no significant direct pharmacological effect on the tested receptors.

Pyridostigmine Suicidal Attempt in a Myasthenia Gravis Patient.

BACKGROUND Pyridostigmine is a quaternary amine parasympathomymetic which inhibits acetylcholinesterase for the treatment of various conditions such as myasthenia gravis. Previously, no cases of pyridostigmine toxicity in human beings have been reported except the cases reported among the troops of Persian Gulf War. CASE REPORT A 47-year-old female intentionally ingested a high dose of pyridostigmine (Mestinon) and developed its toxic symptoms within 1 hour of ingestion. She was treated with injections of atropine and pralidoxime. The patient made an excellent recovery and responded to the classical treatment using atropine and pralidoxime. She was discharged on the second day of admission. CONCLUSIONS The authors demonstrated that pyridostigmine poisoning is self-limiting and well tolerated by young adults; however, unwanted effects of pyridostigmine on the heart has still to be considered which may become profound to the point of generating heart failure, syncope, or stress particularly in elderly patients. As the literature on human toxicity with pyridostigmine is scarce, not much data is available on its toxicity. However, prompt and specific management of pyridostigmine toxicity promises safety.

Oximes as pretreatment before acute exposure to paraoxon.

Organophosphates, useful agents as pesticides, also represent a serious danger due to their high acute toxicity. There is indication that oximes, when administered before organophosphate exposure, can protect from these toxic effects. We have tested at equitoxic dosage (25% of LD01 ) the prophylactic efficacy of five experimental (K-48, K-53, K-74, K-75, K-203) and two established oximes (pralidoxime and obidoxime) to protect from mortality induced by the organophosphate paraoxon. Mortalities were quantified by Cox analysis and compared with those observed after pretreatment with a strong acetylcholinesterase inhibitor (10-methylacridine) and after the FDA-approved pretreatment compound pyridostigmine. All nine tested substances statistically significantly reduced paraoxon-induced mortality. Best protection was conferred by the experimental oxime K-48, reducing the relative risk of death (RR) to 0.10, which was statistically significantly superior to pyridostigmine (RR = 0.31). The other oximes reduced the RR to 0.13 (obidoxime), 0.20 (K-203), 0.21 (K-74), 0.24 (K-75) and 0.26 (pralidoxime), which were significantly more efficacious than 10-methylacridine (RR = 0.65). These data support the hypothesis that protective efficacy is not primarily due to cholinesterase inhibition and indicate that the tested experimental oximes may be considered promising alternatives to the established pretreatment compound pyridostigmine.

Organophosphorus Compounds Poisoning in a Neonate: A Case Report.

Organophosphorus compounds (OPC) are widely used insecticides. Such poisoning is very rare in neonate. A 23 days old infant was admitted with severe respiratory distress, excessive secretion from nose and mouth, bluish discoloration of extremities and poor feeding for 4 hours. He was pale, cyanosed and lethargic with gasping respiration. Frothing was coming through mouth and nose. There was watering of eyes, pupils were pin pointed and light reflex was sluggish. The baby was hypothermic, hypotonic with altered sensorium. Capillary refill time was <3 sec. The neonate was gasping; there was crepitation over lung fields. Precordium and abdomen was normal. An odor of OPC was smelt on clothing and secretions of the infant. The baby was wrapped with a cloth that was ware during pesticide spraying in the field. In addition to general measures, decontamination of skin and clothing and gastric lavage was done. Empirical antibiotic, injection atropine and pralidoxime were given. Patient showed clinical improvement with disappearance of cholinergic signs. The baby was discharged on 7th day of admission after full recovery.

Atropine counteracts the depressive-like behaviour elicited by acute exposure to commercial chlorpyrifos in rats.

Acute organophosphate (OP) poisoning induces well-known signs of toxicosis related to acetylcholinesterase (AChE) inhibition. However, the relationship between acute OP poisoning and the onset of psychiatric disorders remains unclear. Thus, we investigated behavioural and biochemical consequences of acute exposure to the OP chlorpyrifos in male rats and also the effectiveness of the antidotes atropine and pralidoxime on reversing these changes. A sub-lethal dose of commercial chlorpyrifos (20 mg/kg, i.p.) elicited signs of acute toxicosis during the first hours after its injection in rats. Twenty-four hours after treatment, this single dose of chlorpyrifos induced a depressive-like behaviour in the rat forced swimming test without impairing locomotor activity. At this time (24 h), chlorpyrifos decreased plasma butyrylcholinesterase (BChE) activity and hippocampal, striatal and prefrontal cortical AChE activity in rats. The behavioural and biochemical consequences of acute chlorpyrifos poisoning do not seem to be long lasting, since 30 days later they were absent. We evaluated whether these behavioural and biochemical consequences of acute chlorpyrifos treatment would be reversed by the antidotes atropine (10 mg/kg i.p.) and/or pralidoxime (40 mg/kg; i.p.) given 1 h after poisoning. Pralidoxime partially reactivated the AChE activity in the prefrontal cortex, but not in the hippocampus and striatum. Atropine attenuated the depressive-like behaviour induced by chlorpyrifos in rats. Our results suggest that acute chlorpyrifos poisoning induces a transient depressive-like behaviour possible related to hippocampal AChE inhibition. They suggest that treatment with atropine and pralidoxime seems to be insufficient to counteract all the effects of OP acute poisoning, at least in rats.

Mixed cationic liposomes for brain delivery of drugs by the intranasal route: The acetylcholinesterase reactivator 2-PAM as encapsulated drug model.

New mixed cationic liposomes based on L-α-phosphatidylcholine and dihexadecylmethylhydroxyethylammonium bromide (DHDHAB) were designed to overcome the BBB crossing by using the intranasal route. Synthesis and self-assembly of DHDHAB were performed. A low critical association concentration (0.01 mM), good solubilization properties toward hydrophobic dye Orange OT and antimicrobial activity against gram-positive bacteria Staphylococcus aureus (MIC=7.8 µg mL-1) and Bacillus cereus (MIC=7.8 µg mL-1), low hemolytic activities against human red blood cells (less than 10%) were achieved. Conditions for preparation of cationic vesicles and mixed liposomes with excellent colloidal stability at room temperature were determined. The intranasal administration of rhodamine B-loaded cationic liposomes was shown to increase bioavailability into the brain in comparison to the intravenous injection. The cholinesterase reactivator, 2-PAM, was used as model drug for the loading in cationic liposomes. 2-PAM-loaded cationic liposomes displayed high encapsulation efficiency (∼ 90%) and hydrodynamic diameter close to 100 nm. Intranasally administered 2-PAM-loaded cationic liposomes were effective against paraoxon-induced acetylcholinesterase inhibition in the brain. 2-PAM-loaded liposomes reactivated 12 ± 1% of brain acetylcholinesterase. This promising result opens the possibility to use marketed positively charged oximes in medical countermeasures against organophosphorus poisoning for reactivation of central acetylcholinesterase by implementing a non-invasive approach, via the "nose-brain" pathway.

Evaluating the broad-spectrum efficacy of the acetylcholinesterase oximes reactivators MMB4 DMS, HLö-7 DMS, and 2-PAM Cl against phorate oxon, sarin, and VX in the Hartley guinea pig.

Organophosphorus (OP) compounds, including pesticides and chemical warfare nerve agents (CWNA), are threats to the general population as possible weapons of terrorism or by accidental exposure whether through inadvertent release from manufacturing facilities or during transport. To mitigate the toxicities posed by these threats, a therapeutic regimen that is quick-acting and efficacious against a broad spectrum of OPs is highly desired. The work described herein sought to assess the protective ratio (PR), median effective doses (ED50), and therapeutic index (TI = oxime 24-h LD50/oxime ED50) of MMB4 DMS, HLö-7 DMS, and 2-PAM Cl against the OPs sarin (GB), VX, and phorate-oxon (PHO). All OPs are representative of the broader classes of G and V chemical warfare nerve agents and persistent pesticides. MMB4 DMS and HLö-7 DMS were previously identified as comparative efficacy leads warranting further evaluations. 2-PAM Cl is the U.S. FDA-approved standard-of-care oxime therapy for OP intoxication. Briefly, PRs were determined in male guinea pigs by varying the subcutaneously (SC) delivered OP dose followed then by therapy with fixed levels of the oxime and atropine (0.4 mg/kg; administered intramuscularly [IM]). ED50s were determined using a similar approach except the OP dose was held constant at twice the median lethal dose (2 × LD50) while the oxime treatment levels were varied. The ED50 information was then used to calculate the TI for each OP/oxime combination. Both MMB4 DMS and HLö-7 DMS provided significant protection, i.e., higher PR against GB, VX, and PHO when compared to atropine controls, but significance was not readily demonstrated across the board when compared against 2-PAM Cl. The ED50 values of MMB4 DMS was consistently lower than that of the other oximes against all three OPs. Furthermore, based on those ED50s, the TI trend of the various oximes against both GB and VX was MMB4 DMS > HLö-7 DMS > 2-PAM Cl, while against PHO, MMB4 DMS > 2-PAM Cl > HLö-7 DMS.

Effect of administration method, animal weight and age on the intranasal delivery of drugs to the brain.

BACKGROUND: The intranasal route of administration has proven to be an effective method for bypassing the blood brain barrier and avoiding first pass hepatic metabolism when targeting drugs to the brain. Most small molecules gain rapid access to CNS parenchyma when administered intranasally. However, bioavailability is affected by various factors ranging from the molecular weight of the drug to the mode of intranasal delivery. COMPARISON WITH EXISTING METHODS: We examined the effects of animal posture, intranasal application method and animal weight and age on the delivery of radiolabeled pralidoxime (3H-2-PAM) to the brain of rats. RESULTS: We found that using upright vs. supine posture did not significantly affect 3H-2-PAM concentrations in different brain regions. Older animals with higher weights required increased doses to achieve the same drug concentration throughout the brain when compared to young animals with lower body weights. The use of an intranasal aerosol propelled delivery device mainly increased bioavailability in the olfactory bulbs, but did not reliably increase delivery of the drug to various other brain regions, and in some regions of the brain delivered less of the drug than simple pipette administration. CONCLUSION: In view of the emerging interest in the use of intranasal delivery of drugs to combat cognitive decline in old age, we tested effectiveness in very old rats and found the method to be as effective in the older rats.

Accidental Intrathecal Injection of Ionic Contrast: Case Report and Review of the Literature.

BACKGROUND: Ionic contrast, if accidentally injected into the intrathecal space during routine imaging studies or interventional procedures, may significantly interfere with neuronal activity, potentially causing ascending tonic-clonic seizure syndrome and even death. As a result, ionic contrast is strictly contraindicated for intrathecal use. Rapid recognition of the condition followed by prompt management, typically involving aggressive cerebrospinal fluid (CSF) drainage, is critical to improving patient outcome. Lumbar drain has previously been well described as a management strategy. CASE DESCRIPTION: We present a case of accidental intrathecal injection of an ionic contrast agent, iothalamate meglumine, in a patient undergoing cervical epidural steroid injection. This patient was managed successfully with drainage of CSF using an external ventricular drain alone. CONCLUSION: Our literature review and analysis of the previously published cases demonstrate that aggressive CSF drainage is essential to improve outcomes, and in some cases an external ventricular drain alone may be effectively used.

Intramuscular versus Intraosseous Delivery of Nerve Agent Antidote Pralidoxime Chloride in Swine.

OBJECTIVE: Exposure to nerve agents requires prompt treatment. We hypothesized that intraosseous (IO) injections of drug antidotes into the vascularized bone marrow will provide a more rapid and effective means to treat exposure to nerve agents than standard intramuscular (IM) injections. We compared the pharmacokinetics of IM and IO administration of pralidoxime chloride (2-PAM Cl) during normovolemia and hypovolemia, as well as their combined administration during normovolemia in swine. METHODS: Ten normovolemic swine were randomly administered 2 mL, 660 mg 2-PAM Cl via the IM or IO route and monitored for 180 minutes. IM versus IO also was compared in 8 hypovolemic swine bled to a mean arterial pressure of 50 mmHg. In a combined group, an IO injection was administered followed by an IM injection 60 minutes later. Blood samples were collected at times over a 180-minute period to calculate standard pharmacokinetic variables to compare the 2 routes of administration. RESULTS: In the normovolemic swine, IM injection achieved therapeutic levels (4 µg/mL) in 2 minutes, whereas IO infusion achieved these levels in less than 15 seconds. 2-PAM-Cl concentrations fell below these levels at 60 minutes post-injection in both groups. In the hypovolemic swine, IM injection achieved therapeutic levels in 4 minutes compared to less than 15 seconds in the IO group. 2-PAM-Cl concentrations fell below therapeutic levels at 12 and 90 minutes post-injection in the IM and IO groups, respectively. In the combined IO-IM treatment, plasma levels remained above therapeutic levels for the entire experiment and had two concentration peaks that corresponded to IO and IM injections. CONCLUSIONS: The IO route for the delivery of 2-PAM Cl provides a significant time and high initial blood concentrations advantage compared to the IM route for the prehospital treatment of nerve agent exposure even under hypovolemic conditions. The initial concentration peak associated with IO, but not IM, may provide greater initial therapy at the most critical time.

Brain-Targeting Chemical Delivery Systems and Their Cyclodextrin-Based Formulations in Light of the Contributions of Marcus E. Brewster.

Here, we present a brief review of brain-targeting chemical delivery systems (CDSs) and their cyclodextrin-based formulations. It is dedicated to the memory of Marcus E. Brewster (1957-2014) and highlights those aspects where he made particularly valuable contributions. During the first two decades of his scientific career that were dedicated to these fields (1978-1997), Marcus was involved in the development of several brain-targeted redox compounds, including design, activity assays, physicochemical characterization, computational modeling of theoretical aspects, and development of cyclodextrin-based formulation for increased stability and water solubility, as well as preclinical and clinical testing. CDSs are designed to provide site-specific or site-enhanced delivery through sequential, multistep enzymatic, and chemical transformations. Brain-targeting CDSs incorporate a redox targetor that undergoes enzymatic transformation resulting in a drastic change in physicochemical properties. They can not only increase central nervous system access by making the molecule more lipophilic and enabling its diffusion through the blood-brain barrier, but they can also provide more sustained release by "locking" it behind the blood-brain barrier by subsequently converting it into a hydrophilic intermediate. The origins of the concept (Pro-2-PAM, berberine), one of the most important representative (estradiol-CDS), and the introduction of 2-hydroxypropyl-ß-cyclodextrin for improved formulations are discussed in detail.

Efficacy of Recommended Prehospital Human Equivalent Doses of Atropine and Pralidoxime Against the Toxic Effects of Carbamate Poisoning in the Hartley Guinea Pig.

PURPOSE: Aldicarb and methomyl are carbamate pesticides commonly implicated in human poisonings. The primary toxic mechanism of action for carbamate poisoning is cholinesterase (ChE) inhibition. As such, it is logical to assume that the currently accepted therapies for organophosphate poisoning (muscarinic antagonist atropine and the oxime acetylcholinesterase reactivator pralidoxime chloride [2-PAM Cl]) could afford therapeutic protection. However, oximes have been shown to be contraindicated for poisoning by some carbamates. METHODS: A protective ratio study was conducted in guinea pigs to evaluate the efficacy of atropine and 2-PAM Cl. The ChE activity was determined in both the blood and the cerebral cortex. RESULTS: Coadministration of atropine free base (0.4 mg/kg) and 2-PAM Cl (25.7 mg/kg) demonstrated protective ratios of 2 and 3 against aldicarb and methomyl, respectively, relative to saline. The data reported here show that this protection was primarily mediated by the action of atropine. The reactivator 2-PAM Cl had neither positive nor negative effects on survival. Both blood acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities were significantly reduced at 15 minutes postchallenge but gradually returned to normal within 24 hours. Analysis of cerebral cortex showed that BChE, but not AChE, activity was reduced in animals that succumbed prior to 24 hours after challenge. CONCLUSION: The results suggest that coadministration of atropine and 2-PAM Cl at the currently recommended human equivalent doses for use in the prehospital setting to treat organophosphorus nerve agent and pesticide poisoning would likely also be effective against aldicarb or methomyl poisoning.

Pharmacokinetic and biodistribution study of eserine and pralidoxime chloride in rabbits following a single application of a transdermal patch.

In the present study, a simple reverse-phase high-performance liquid chromatography method with diode array detection has been developed and validated for the simultaneous determination and quantification of eserine and pralidoxime chloride in rabbit plasma and its application to pharmacokinetic study. The pharmacokinetic study was performed after transdermal application of single patch in rabbits. The plasma levels of both drugs following transdermal application of single patch were maintained for 72 h after removal of the patch. The maximal concentrations (C max) of both drugs were significantly reduced while the mean areas under the plasma concentration vs. time moment curve and mean residence times were evidently increased and extended, respectively. A sustained activity was observed over a period of 3 days. This sustained activity was due to the controlled release of drug into the systemic circulation following transdermal application. Linear correlation was also observed when fraction of drug permeated was correlated with the fraction of drug absorbed at the same time point. Gamma scintigraphy imaging on rabbit following transdermal patch application was performed to ascertain the localization of drugs in rabbit brain.

Clinical study of continuous micropump infusion of atropine and pralidoxime chloride for treatment of severe acute organophosphorus insecticide poisoning.

BACKGROUND: Our study sought to assess the effectiveness of a constant micropump infusion of atropine and pralidoxime chloride compared with repeated-bolus doses in patients with severe acute organophosphorus insecticide poisoning (AOPP). METHODS: A total of 60 patients with severe AOPP, defined as cholinergic crisis with respiratory failure or cerebral edema, were randomly divided into two groups of 30 patients each. In the experimental group, patients received a continuous micropump of atropine and pralidoxime chloride; in the control group, patients were given intermittent injections of atropine and pralidoxime chloride. Primary outcome measures were the dose of atropine required for atropinization, Acute Physiology and Chronic Health Evaluation II (APACHE II) score at atropinization, time to atropinization and acetylcholinesterase (AchE) recovery time. Additionally, the case fatality rate was measured as a secondary outcome. RESULTS: Compared to patients in the control group, the time to atropinization, AchE recovery time, dose of atropine when atropinization occurred, and APACHE II score in the experimental group showed a statistically significant therapeutic effect (p < 0.05), and the case fatality rate of the experimental group was lower than that of the control group (p < 0.05). CONCLUSION: Continuous micropump of atropine and pralidoxime chloride combined is more effective than the use of repeated-bolus injection in the treatment of severe acute organophosphorus insecticide poisoning.

Chronic Treatment with Naltrexone Prevents Memory Retention Deficits in Rats Poisoned with the Sarin Analog Diisopropylfluorophosphate (DFP) and Treated with Atropine and Pralidoxime.

Humans and rats poisoned with sarin develop chronic neurological disabilities that are not prevented with standardized antidotal therapy. We hypothesized that rats poisoned with the sarin analogue diisopropylfluorophosphate (DFP) and resuscitated with atropine and pralidoxime would have long-term memory deficits that were preventable with naltrexone treatment. Long Evans rats (250-275 g) were randomized to: DFP (N = 8): single subcutaneous (SC) injection of DFP (5 mg/kg). Treatment (N = 9): DFP (5 mg/kg) followed by chronic naltrexone (5 mg/kg/day × 12 weeks). Control (N = 12): single SC injection of isopropyl alcohol, (DFP vehicle) followed by chronic naltrexone (5 mg/kg/day). If toxicity developed after injection, antidotal therapy was initiated with atropine (2 mg/kg) and pralidoxime (25 mg/kg) and repeated as needed. After 12 weeks, rats underwent testing for place learning (acquisition) across 5 days of training using the Morris Water Maze. On day 6 a memory retention test was performed. Statistical analysis was performed using IBM SPSS Statistics. Rats receiving DFP rapidly developed toxicity requiring antidotal rescue. No differences in acquisition were seen between the DFP vs. DFP + naltrexone rats. During memory testing, DFP-poisoned rats spent significantly less time (29.4 ± 2.11 versus 38.5 ± 2.5 s, p < 0.05) and traveled less distance (267 ± 24.6 versus 370 ± 27.5 cm, p < 0.05) in the target quadrant compared to the treatment group. Treatment rats performed as well as control rats (p > 0.05) on the test for memory retention. Poisoning with DFP induced impaired memory retention. Deficits were not prevented by acute rescue with atropine and pralidoxime. Chronic naltrexone treatment led to preserved memory after DFP poisoning.