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Context: Increased use of organophosphate insecticides (OPI) and possibility of terror groups using stocks of nerve agents underscore the need to develop effective and safe antidotes. While intramuscular administration of antidotes like atropine sulphate (AS) has certain lacunae, intravenous route may not be always feasible in emergency field conditions., Objective: Objective was (a) to develop a novel inhalable submicronic-AS respiratory fluid as potential antidote for OPI poisoning, (b) in-vitro and in-vivo evaluation in terms of respiratory fraction, and (c) clinical study to assess drug bioavailability in blood and atropinization pattern post-inhalation., Methods: Formulation was optimized on the basis of particle size of aerosolized droplets and in-vitro nebulization rate. Anderson cascade impaction (ACI) studies were carried out to validate the advantage of test formulation in terms of respirable fraction. Six healthy volunteers were inhaled the test formulation and blood bioavailability and atropinization were noted serially. Gamma scintigraphy was used to quantify total and regional lung deposition of nebulized AS in-vivo., Results: The formulation was optimized using 30% ethanol-saline with particle size in the range of 350-500 nm. In-vitro ACI data showed high respirable fraction (82.6 ± 3.1%) for the test formulation. In-vivo scintigraphy suggested whole lung deposition of 80.2 ± 6.8% of the total inhaled dose. Early blood bioavailability and atropinization pattern confirmed that therapeutic concentration of the drug in blood was reached within 5 min., Conclusions: 3% submicronic-AS respiratory fluid might be used as potential prophylactic/therapeutic option against OPI poisoning with several advantages over intramuscular injection, including early blood bioavailability and atropinization.

Poisoning is the most common mode of unnatural death in South East Asia, causing hundreds of thousand deaths per year. Organophosphorus (OP) compounds are commonly used as pesticides. Easy availability and widespread use has increased the likelihood of poisoning with these compounds. The present study was done to predict severity in acute organophosphate poisoning with clinical scoring and serum pseudocholinesterase levels. Total 60 patients of acute organophosphorus poisoning patients are enrolled in the study after fulfilling inclusion and exclusion criteria. The study was done at IGMC Shimla, Himachal Pradesh in the period of June 2018 to July 2019. POP score was applied and serum pseudocholine esterase levels are estimated. Suitable statistical methods applied to assess correlation and variables. Majority of patients were aged between 21 to 40 years, with M:F ratio of 2:1. Most common consumed compound was chlorpyriphos and mainly for suicidal intent. Bradycardia was the most common clinical feature. There was significant correlation between the severity of poisoning categorized by the POP scale and the serum cholinesterase at the time of initial presentation of the patients, requirements of atropine on the first day of admission, the total amount of dose of atropine, atropine needed and the average duration of hospital stay(<0.01) . We concluded that POP score scale is useful for determining the severity of the poisoning. POP scale can be used to treat OP poisoning patients in terms of need of ventilator, hospital stay and atropine dose; at the same time being important indicator of mortality. POP scale can be used readily in all level of health care from primary to tertiary level health care. [ABSTRACT FROM AUTHOR]

Background: Organophosphorus poisoning (OPP) is a major global public health problem. Pralidoxime has been used in a complimentary role to atropine for the management of OPP. World Health Organization (WHO) recommends use of pralidoxime but studies regarding its role have been inconclusive, ranging from being ineffective to harmful or beneficial. Materials and Methods: The present study was undertaken to evaluate the effectiveness of pralidoxime. Eddleston′s study was the most compelling factor for our study, as he showed worst outcomes using pralidoxime. Our practice of continuous use of pralidoxime was based on the WHO guidelines and the study by Pawar (2006), which showed better outcome with higher doses of pralidoxime. These conflicting results suggested that a re-evaluation of its use in our clinical practice was indicated. Results: There was no difference in mortality rates, hemodynamic parameters and atropine requirements between the AP and A groups. Mean duration of ventilation (3.6 ± 4.6 in AP group vs. 3.6 ± 4.4 in A group) and Intensive Care Unit stay (7.1 ± 5.4 in AP group vs. 6.8 ± 4.7 in A group) was comparable. Serum sodium concentrations showed a correlation with mortality, with lower concentrations associated with better outcomes. Conclusion: The study suggests that add-on WHO-recommended pralidoxime therapy does not provide any benefit over atropine monotherapy. Adding pralidoxime does not seem to be beneficial and at the same time does not result in increased mortality rates. Our practice changed after completion of this study, and it has proven to be of significant benefit to patients who had to bear the expense of treatment.

Background: Organophosphorus poisoning (OPP) is a major global public health problem. Pralidoxime has been used in a complimentary role to atropine for the management of OPP. World Health Organization (WHO) recommends use of pralidoxime but studies regarding its role have been inconclusive, ranging from being ineffective to harmful or beneficial. Materials and Methods: The present study was undertaken to evaluate the effectiveness of pralidoxime. Eddleston’s study was the most compelling factor for our study, as he showed worst outcomes using pralidoxime. Our practice of continuous use of pralidoxime was based on the WHO guidelines and the study by Pawar (2006), which showed better outcome with higher doses of pralidoxime. These conflicting results suggested that a re-evaluation of its use in our clinical practice was indicated. Results: There was no difference in mortality rates, hemodynamic parameters and atropine requirements between the AP and A groups. Mean duration of ventilation (3.6 ± 4.6 in AP group vs. 3.6 ± 4.4 in A group) and Intensive Care Unit stay (7.1 ± 5.4 in AP group vs. 6.8 ± 4.7 in A group) was comparable. Serum sodium concentrations showed a correlation with mortality, with lower concentrations associated with better outcomes. Conclusion: The study suggests that add-on WHO-recommended pralidoxime therapy does not provide any benefit over atropine monotherapy. Adding pralidoxime does not seem to be beneficial and at the same time does not result in increased mortality rates. Our practice changed after completion of this study, and it has proven to be of significant benefit to patients who had to bear the expense of treatment. [ABSTRACT FROM AUTHOR]

Introduction: The increased use of organophosphate (OP) insecticides and the ever increasing possibility of terror groups using nerve agents underscore the need to develop effective and safe antidotes against OP poisoning. While intramuscular administration of nerve gas antidotes like atropine sulphate has certain lacunae, intravenous route is neither practical nor feasible in the field conditions for mass casualties. The objective was to develop a novel atropine sulphate nasal drop formulation, evaluate and characterize it using scintigraphy and to carry out safety–efficacy study in human volunteers with a view to obtain early pharmacological effects in comparison to the existing options, particularly the conventional intramuscular route. Methods: Permeability studies were done using atropine sulphate solution containing variable amount of chitosan. Radiometric method was developed for scintigraphy studies while standard spectroscopy was used for the quantification of atropine sulphate in fluids. Concentration of atropine sulphate in nasal drops to produce therapeutic concentration in blood was calculated. Six volunteers (age range 18–53 years) were administered the formulation delivering 6mg of atropine sulphate each. Bioavailability and atropinization were noted serially. Results: Based on the results of in vitro, human scintigraphy and analytical data, 1% atropine sulphate–0.5% chitosan was chosen as the final nasal formulation. Human bioavailability curve was created which showed that the therapeutic concentration of the drug in blood was reached within 5min with nasal drops suggesting that drug delivery through the nasal route is significantly better than the intramuscular route. Unpaired t-test between the means of baseline value of heart rate and that of each time interval showed that increase in heart rate of all the volunteers became significant at 15min (P <0.01) and extremely significant at 30min (P <0.001). Correlation was evident from 5min (c >0.7). Pupil diameter showed maximal increase at 30min (P <0.01). Conclusions: This novel product, 1% atropine sulphate–0.5% chitosan nasal drops might be a safe and efficacious emergency treatment of organophosphorous poisoning with several advantages over the present management, including early atropinization and capability of mass treatment in least amount of time. [Copyright &y& Elsevier]

Abstract: The aim of the work was to develop, characterize, and carry out a clinical trial with nano–atropine sulfate (nano-AS) dry powder inhaler (DPI), because this route may offer several advantages over the conventional intramuscular route as an emergency treatment, including ease of administration and more rapid bioavailability. Different batches of nanoparticles of AS were produced using variants of nanoprecipitation method. The influence of the process parameters, such as the types and quantity of solvent and nonsolvent, the stirring speed, the solvent-to-nonsolvent volume ratio, and the drug concentration, was investigated. The methodology resulted in optimally sized particles. Bulk properties of the particles made by the chosen methodology were evaluated. A clinical trial was conducted in six healthy individuals using a single DPI capsule containing 6 mg nano-AS DPI in lactose. Early blood bioavailability and atropinization pattern confirmed its value as a potential replacement to parenteral atropine in field conditions. The formulation seems to have the advantage of early therapeutic drug concentration in blood due to absorption through the lungs as well as sustained action due to absorption from the gut of the remaining portion of the drug. [Copyright &y& Elsevier]

There is a wide variation and lack of evidence in current recommendations for atropine dosing schedules leading to subsequent variation in clinical practice. Therefore, we sought to examine the safety and effectiveness of a titrated vs. ad hoc atropine treatment regimen in a cohort of patients with acute cholinesterase inhibitor pesticide poisoning. A prospective cohort study was conducted in three district secondary referral hospitals in Sri Lanka using a structured data collection form that collected details of clinical symptoms and outcomes of cholinesterase inhibitor pesticide poisoning, atropine doses, and signs of atropinization. We compared two hospitals that used a titrated dosing protocol based on a structured monitoring sheet for atropine infusion with another hospital using an ad hoc regime. During the study, 272 symptomatic patients with anticholinesterase poisoning requiring atropine were admitted to the three hospitals. Outcomes of death and ventilation were analyzed for all patients, 226 patients were prospectively assessed for atropine toxicity. At baseline, patients in the titrated dose cohort had clinical signs consistent with greater toxicity. This in part may be due to ingestion of more toxic organophosphates. They received less pralidoxime and atropine, and were less likely to develop features of atro- pine toxicity, such as delirium (1% vs. 17%), hallucinations (1% vs. 35%), or either (1% vs. 35%) and need for patient restraint (3% vs. 48%) compared with the ad hoc dose regime. After adjusting for the pesticides ingested, there was no difference in mortality and ventilatory rates between protocols. Ad hoc high dose atropine regimens are associated with more frequent atropine toxicity without any obvious improvement in patient outcome compared with doses titrated to clinical effect. Atropine doses should be titrated against response and toxicity. Further education and the use of a structured monitoring sheet may assist in more appropriate atropine use in anti-cholinesterase pesticide poisoning. [ABSTRACT FROM AUTHOR]