Pralidoxime chloride

172.61

172.040344

4163981

200-080-9

38X7XS076H

759147|164614

DTXSID1023495

2933399090

36.5

-2.67680

white - off-white crystalline powder

1.3265 (rough estimate)

236.5 °C (decomp)

189.7ºC at760mmHg

68.5ºC

65.5 g/100 mL (25 ºC)

0-6°C

6.74X10-4 mm Hg at 25 °C (est)

LD50 in rats (mg/kg): 96 i.v. (Fleisher); LD50 in rabbits (mg/kg): 95 i.v.; LD50 in mice (mg/kg): 115 i.v., 205 i.p., 4100 orally (Ellin, Wills)

Henry's Law constant = 9.98X10-15 atm-cu m/mol at 25 °C (est)

pKa = 5.78 (pyridine) (est)|pKa = 7.63 (hydroxy group) (est)

White to pale yellow crystalline powder; odorless. Freely soluble in water /Pralidoxime chloride/|Odorless, white, nonhygroscopic, crystalline powder which is soluble in water to the extent of 1 g in less than 1mL. Stable in air ... melts between 215 and 225 °C, with decomposition /Pralidoxime chloride/|Hydroxyl radical reaction rate constant = 1.33X10-11 cu cm/molec-sec at 25 °C (est)

NONH for all modes of transport

3

20/21/22-36/37/38-20/22

36-37/39-26

UU4200000

Xn

No evidence of significant degradation products appears up to 48 hr after pralidoxime autoinjector discharge. Concentration without degradation of the solution was noted over time when the autoinjector needle caused coring of the vial closure ... Mark-1 autoinjectors are not suitable for administering pralidoxime to small children. However, the autoinjectors are a readily available source of concentrated pralidoxime for administering weight-adjusted doses in small children. The pralidoxime solution obtained in this manner remains chemically intact for at least 48 hr.|OBJECTIVES: Oximes such as pralidoxime (2-PAM) are essential antidotes for life-threatening organophosphate poisoning. Unfortunately, oximes are expensive, have limited use, and have short shelf lives. As such, maintaining large stockpiles in preparation for terrorist activity is not always possible. We have demonstrated that atropine is stable well beyond its labeled shelf life and that recently expired 2-PAM was clinically efficacious in a series of poisoned patients. Because 2-PAM is often dosed empirically, clinical improvement does not guarantee pharmacological stability. We therefore chose to analyze the chemical stability of expired 2-PAM. METHODS: Samples of lyophylized 2-PAM were maintained according to the manufacturer's recommendations for 20 years beyond the published shelf life. We studied 2-PAM contained in a MARK I autoinjector that was stored properly for 3 years beyond its expiration date. An Agilent LC/MSD 1100 with diode-array detector and an Agilent Sorbax SB-C-18, 4.6 x 150-mm, 5-um column were used with the following solvent systems: water with 0.01% trifluoroacetic acid and methanol with 0.01% trifluoroacetic acid. Fresh reagent grade 2-PAM was used as a standard. Results were repeated for consistency. RESULTS: Lyophylized 2-PAM was a white powder that was clear and colorless in solution. Liquid chromatography was identical to the standard and resulted in 2 isolated peaks with identical mass spectra, suggesting that they are stereoisomers. The autoinjector discharged a clear, yellowish solution. In addition to the 2 peaks identified for lyophylized 2-PAM, a small third peak was identified with a mass spectra corresponding to the reported N -methyl pyridinium carboxaldehyde degradation product. CONCLUSIONS: When properly stored, lyophylized 2-PAM appears to be chemically stable well beyond its expiration date. Although the relative amount of degradation product found in solubilized (autoinjector) 2-PAM was small, it is unclear whether this may be toxic and therefore is of concern. Further studies performed with lots of drug stored under varied conditions would be required to fully determine the stability of expired 2-PAM.|Stable under recommended storage conditions. /Pralidoxime Chloride/

P261-P280-P301 + P312 + P330

H302 + H312 + H332

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.|Product: Contact a licensed professional waste disposal service to dispose of this material. Offer surplus and non-recyclable solutions to a licensed disposal company. Contaminated packaging: Dispose of as unused product. /Pralidoxime Chloride/

Incompatible materials: Strong oxidizing agents, Strong bases. /Pralidoxime Chloride/

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including pralidoxime chloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Pralidoxime chloride/|The Generic Animal Drug and Patent Restoration act requires that each sponsor of an approved animal drug must submit to the FDA certain information regarding patents held for the animal drug or its method of use. The Act requires that this information, as well as a list of all animal drug products approved for safety and effectiveness, be made available to the public. Pralidoxime chloride is included on this list. /Pralidoxime chloride/|Implantation or injectable dosage form new animal drugs. ... It is used in horses, dogs, and cats as an antidote in the treatment of poisoning due to those pesticides and chemicals of the organophosphate class which have anticholinesterase activity in horses, dogs, and cats. ... Federal law restricts this drug to use by or on the order of a licensed veterinarian.

CDC; Cholinesterase Inhibitors: Including Insecticides and Chemical Warfare Nerve Agents Part 4 - Section 11 Management Strategy 3: Medications 2-PAM (2-Pyridine Aldoxime Methylchloride) (Pralidoxime)[Available from, as of November 13, 2018 https://www.atsdr.cdc.gov/csem/csem.asp?csem=11&po=23]|CHEMM; Pralidoxime - Medical Countermeasures Database (November, 2017)[Available from, as of November 13, 2018: https://chemm.nlm.nih.gov/countermeasure_pralidoxime.htm#eb]

|Warning|H302 (88.64%): Harmful if swallowed [Warning Acute toxicity, oral]|P261, P264, P270, P271, P280, P301+P312, P302+P352, P304+P312, P304+P340, P305+P351+P338, P312, P321, P322, P330, P332+P313, P337+P313, P362, P363, and P501|Aggregated GHS information provided by 44 companies from 4 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Eye/face protection: Safety glasses with side-shields conforming to EN166. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). /Pralidoxime Chloride/|Skin protection: Handle with gloves. /Pralidoxime Chloride/|Body Protection: Complete suit protecting against chemicals. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace. /Pralidoxime Chloride/|Respiratory protection: For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator. For higher level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). /Pralidoxime Chloride/

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. /Pralidoxime Chloride/|Advice for firefighters: Wear self-contained breathing apparatus for fire fighting if necessary. /Pralidoxime Chloride/

Hazardous decomposition products formed under fire conditions - Carbon oxides, Nitrogen oxides (NOx), Hydrogen chloride gas. /Pralidoxime Chloride/

ACCIDENT RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Avoid breathing dust. Environmental precautions: Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal. /Pralidoxime Chloride/

ACCIDENT RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Avoid breathing dust. Environmental precautions: Do not let product enter drains. /Pralidoxime Chloride/|Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols.Further processing of solid materials may result in the formation of combustible dusts. The potential for combustible dust formation should be taken into consideration before additional processing occurs. Provide appropriate exhaust ventilation at places where dust is formed. /Pralidoxime Chloride/|Appropriate engineering controls: Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday. /Pralidoxime Chloride/|Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands. /Pralidoxime Chloride/|SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

IDENTIFICATION AND USE: Pralidoxime is an antidote and cholinesterase reactivator used in the treatment of poisoning due to pesticides and chemicals which have anticholinesterase activity. It is also used to treatment overdoses by anticholinesterase drugs used in the treatment of myasthenia gravis. Pralidoxime chloride is used concomitantly with atropine for the treatment of nerve agent poisoning in the context of chemical warfare or terrorism. Pralidoxime chloride must be administered within minutes to hours following exposure to nerve agents to be effective. HUMAN STUDIES: Manifestations of overdosage in normal subjects include dizziness, blurred vision, diplopia, headache, impaired accommodation, nausea, and slight tachycardia. In therapy, it has been difficult to differentiate side effects due to the drug from those due to the effects of the poison. When atropine and pralidoxime chloride are used together, the signs of atropinization (flushing, mydriasis, tachycardia, dryness of the mouth and nose) may occur earlier than might be expected when atropine is used alone. ANIMAL STUDIES: Pralidoxime, used in the treatment of organophosphate poisoning, significantly increased cardiac output at all doses in open chest anesthetized dogs. A similar response was obtained in alpha-adrenergic blocked animals, but not with beta-adrenergic blocked or reserpine treated animals. All doses of pralidoxime significantly increased mean arterial pressure in control, beta-adrenergic blocked, and alpha-adrenergic blocked animals. Pralidoxime at 20 and 40 mg/kg also increased arterial pressure in reserpine treated animals. Heart rate was decreased in all but the alpha-adrenergic blocked animals with pralidoxime. The total peripheral resistance of the beta-blocked animals increased with every subsequent dose of pralidoxime although no significant increase was observed in controls. A smaller increase in total peripheral resistance was observed in reserpine-treated and alpha-adrenergic blocked animals. Significant increases in stroke volume and changes in stroke work were noted with all animals, each occurring at different atrial pressures depending on the treatment. The results suggest that pralidoxime directly stimulates the heart and vascular smooth muscle. Pralidoxime in dogs at high dosages, causes signs associated with its own anticholinesterase activity. Clinical signs of toxicity in dogs may be exhibited as muscle weakness, ataxia, vomiting, hyperventilation, seizures, respiratory arrest, and death.

The pharmacokinetics of 5 mg/kg IV pralidoxime chloride (Protopam; I) when administered one hr after continuous infusion of thiamine hydrochloride (II) are described in 6 males. Subjects were given I alone and while receiving an infusion of II. After the addition of II, the urinary excretion of oxime was the same but the amount excreted in the first 3 hr was smaller; the plasma half-life of oxime lengthened; the plasma concentrations of oxime rose; and the intercompartmental clearances and rate constant for elimination for oxime fell. It was concluded that II and oxime compete for a common renal secretory mechanism or that II alters the membrane transport of oxime.|BACKGROUND AND PURPOSE: Treatment of organophosphate poisoning with pralidoxime needs to be improved. Here we have studied the pharmacokinetics of pralidoxime after its intramuscular injection alone or in combination with avizafone and atropine using an auto-injector device. EXPERIMENTAL APPROACH: The study was conducted in an open, randomized, single-dose, two-way, cross-over design. At each period, each subject received either intramuscular injections of pralidoxime (700 mg), or two injections of the combination: pralidoxime (350 mg), atropine (2 mg), avizafone (20 mg). Pralidoxime concentrations were quantified using a validated LC/MS-MS method. Two approaches were used to analyse these data: (i) a non-compartmental approach; and (ii) a compartmental modelling approach. KEY RESULTS: The injection of pralidoxime combination with atropine and avizafone provided a higher pralidoxime maximal concentration than that obtained after the injection of pralidoxime alone (out of bioequivalence range), while pralidoxime AUC values were equivalent. Pralidoxime concentrations reached their maximal value earlier after the injection of the combination. According to Akaike and to goodness of fit criteria, the best model describing the pharmacokinetics of pralidoxime was a two-compartment with a zero-order absorption model. When avizafone and atropine were injected with pralidoxime, the best model describing pralidoxime pharmacokinetics becomes a two-compartment with a first-order absorption model. CONCLUSIONS AND IMPLICATIONS: The two approaches, non-compartmental and compartmental, showed that the administration of avizafone and atropine with pralidoxime results in a faster absorption into the general circulation and higher maximal concentrations, compared with the administration of pralidoxime alone.|We have recently shown that the pyridinium aldoximes, best-known as therapeutic antidotes for chemical warfare nerve-agents, could markedly detoxify the carcinogenic tetrachloro-1,4-benzoquinone (TCBQ) via an unusual double Beckmann fragmentation mechanism. However, it is still not clear why pralidoxime (2-PAM) cannot provide full protection against TCBQ-induced biological damages even when 2-PAM was in excess. Here we show, unexpectedly, that TCBQ can also activate pralidoxime to generate a reactive iminyl radical intermediate in two-consecutive steps, which was detected and unequivocally characterized by the complementary application of ESR spin-trapping, HPLC/MS and nitrogen-15 isotope-labeling studies. The same iminyl radical was observed when TCBQ was substituted by other halogenated quinones. The end product of iminyl radical was isolated and identified as its corresponding reactive and toxic aldehyde. Based on these data, we proposed that the reaction of 2-PAM and TCBQ might be through the following two competing pathways: a nucleophilic attack of 2-PAM on TCBQ forms an unstable transient intermediate, which can decompose not only heterolytically to form 2-CMP via double Beckmann fragmentation, but also homolytically leading to the formation of a reactive iminyl radical in double-steps, which then via H abstraction and further hydrolyzation to form its corresponding more toxic aldehyde. Analogous radical homolysis mechanism was observed with other halogenated quinones and pyridinium aldoximes. This study represents the first detection and identification of reactive iminyl radical intermediates produced under normal physiological conditions, which provides direct experimental evidence to explain only the partial protection by 2-PAM against TCBQ-induced biological damages, and also the potential side-toxic effects induced by 2-PAM and other pyridinium aldoxime nerve-agent antidotes.|When atropine and pralidoxime chloride are used together, the signs of atropinization (flushing, mydriasis, tachycardia, dryness of the mouth and nose) may occur earlier than might be expected when atropine is used alone. This is especially true if the total dose of atropine has been large and the administration of pralidoxime chloride has been delayed.|The following precautions should be kept in mind in the treatment of anticholinesterase poisoning, although they do not bear directly on the use of pralidoxime chloride: since barbiturates are potentiated by the anticholinesterases, they should be used cautiously in the treatment of convulsions; morphine, theophylline, aminophylline, reserpine, and phenothiazine-type tranquilizers should be avoided in patients with organophosphate poisoning. Prolonged paralysis has been reported in patients when succinylcholine is given with drugs having anticholinesterase activity; therefore, it should be used with caution.

LD50 Dog oral 190 mg/kg

Pralidoxime should be used with caution and in reduced dosage in patients with impaired renal function.|Pralidoxime should be used with caution in patients with myasthenia gravis who are receiving anticholinesterase agents, since the drug may precipitate a myasthenic crisis.

2-PAM's production and administration as an antidote to organophosphate pesticides and nerve agent chemicals(1,2) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 650(SRC), determined from a structure estimation method(2), indicates that 2-PAM is expected to have low mobility in soil(SRC). The estimated pKa of 2-PAM is 5.78(3), indicating that this compound will exist partially in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization from moist soil is not expected because the compound exists as a cation and cations do not volatilize. 2-PAM is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 6.7X10-4 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2018).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 650(SRC), determined from a structure estimation method(2), indicates that 2-PAM is expected to adsorb to suspended solids and sediment(SRC). An estimated pKa of 5.78(3) indicates 2-PAM will exist partially in the cation form at pH values of 5 to 9 and, therefore, volatilization from water or moist soil surfaces is not expected to be an important fate process(SRC). According to a classification scheme(4), an estimated BCF of 3(SRC), from an estimated log Kow of -1.29(2) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water were not available(SRC, 2018).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 2-PAM, which has an estimated vapor pressure of 6.7X10-4 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase 2-PAM is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 29 hrs(SRC), calculated from its rate constant of 1.3X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(2). Particulate-phase 2-PAM may be removed from the air by wet and dry deposition(SRC). 2-PAM does not contain chromophores that absorb at wavelengths >290 nm(3) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).

The rate constant for the vapor-phase reaction of 2-PAM with photochemically-produced hydroxyl radicals has been estimated as 1.3X10-11 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 29 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). 2-PAM is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(2). 2-PAM does not contain chromophores that absorb at wavelengths >290 nm(2) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).

An estimated BCF of 3 was calculated in fish for 2-PAM(SRC), using an estimated log Kow of -1.29(1) and a regression-derived equation(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of 2-PAM can be estimated to be 650(SRC). According to a classification scheme(2), this estimated Koc value suggests that pralidoxime is expected to have low mobility in soil. The estimated pKa of 2-PAM is 5.78(3), indicating that this compound will exist partially in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).

An estimated pKa of 5.78(1) indicates 2-PAM will exist partially in the cation at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process(SRC). 2-PAM is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 6.7X10-4 mm Hg(SRC), determined from a fragment constant method(2).

While data specific to 2-PAM were not located(SRC, 2018), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are, therefore, discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2).

Occupational exposure to 2-PAM may occur through inhalation and dermal contact with this compound at workplaces where 2-PAM is produced or used. The general public is not likely to be exposed to 2-PAM unless by direct medical treatment. (SRC)

Antidotes; Cholinesterase Reactivators|/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Pralidoxime is included in the database.|Protopam chloride is indicated as an antidote: 1. In the treatment of poisoning due to those pesticides and chemicals (e.g., nerve agents) of the organophosphate class which have anticholinesterase activity and 2. In the control of overdosage by anticholinesterase drugs used in the treatment of myasthenia gravis. The principal indications for the use of Protopam chloride are muscle weakness and respiratory depression. In severe poisoning, respiratory depression may be due to muscle weakness. /Included in US product label/|Pralidoxime chloride is used concomitantly with atropine for the treatment of nerve agent poisoning in the context of chemical warfare or terrorism. Pralidoxime chloride must be administered within minutes to hours following exposure to nerve agents to be effective. /Included in US product label/|For more Therapeutic Uses (Complete) data for 2-PAM (8 total), please visit the HSDB record page.

IM administration of pralidoxime may produce mild pain at the injection site.|Rapid IV injection of pralidoxime has produced tachycardia, laryngospasm, muscle rigidity, and transient neuromuscular blockade; therefore, the drug should be administered slowly, preferably by IV infusion. IV administration of pralidoxime reportedly may also cause hypertension which is related to the dose and rate of infusion. Some clinicians recommend that the patient's blood pressure be monitored during pralidoxime therapy. For adults, IV administration of 5 mg of phentolamine mesylate reportedly quickly reverses pralidoxime-induced hypertension.|Although pralidoxime is generally well-tolerated, dizziness, blurred vision, diplopia and impaired accommodation, headache, drowsiness, nausea, tachycardia, hyperventilation, maculopapular rash, and muscular weakness have been reported following administration of the drug. However, it is difficult to differentiate the toxic effects produced by atropine or organophosphates from those of pralidoxime, and the condition of patients suffering from organophosphate intoxication will generally mask minor signs and symptoms reported in normal subjects who receive pralidoxime. When atropine and pralidoxime are used concomitantly, signs of atropinism may occur earlier than when atropine is used alone, especially if the total dose of atropine is large and administration of pralidoxime is delayed. Excitement, confusion, manic behavior, and muscle rigidity have been reported following recovery of consciousness, but these symptoms have also occurred in patients who were not treated with pralidoxime.|The following precautions should be kept in mind in the treatment of anticholinesterase poisoning, although they do not bear directly on the use of pralidoxime chloride: since barbiturates are potentiated by the anticholinesterases, they should be used cautiously in the treatment of convulsions; morphine, theophylline, aminophylline, reserpine, and phenothiazine-type tranquilizers should be avoided in patients with organophosphate poisoning. Prolonged paralysis has been reported in patients when succinylcholine is given with drugs having anticholinesterase activity; therefore, it should be used with caution.|For more Drug Warnings (Complete) data for 2-PAM (11 total), please visit the HSDB record page.

Agents counteracting or neutralizing the action of POISONS. (See all compounds classified as Antidotes.)|Drugs used to reverse the inactivation of cholinesterase caused by organophosphates or sulfonates. They are an important component of therapy in agricultural, industrial, and military poisonings by organophosphates and sulfonates. (See all compounds classified as Cholinesterase Reactivators.)

It is not known if pralidoxime crosses the human placenta to the embryo or fetus. Pralidoxime chloride is a quaternary ammonium compound, but the molecular weight of the free base (about 137) is low enough for passage across the placenta. The rapid elimination of the drug should mitigate this transfer.|The specific mechanism by which the renal tubule handles pralidoxime, a quaternary ammonium compound used to reactivate organophosphate-inhibited cholinesterase, has been studied using 22 subjects. Each subject was placed under certain conditions in the course of the study. All 22 received pralidoxime (5 mg/kg, IV, over a 2-min interval) under conditions of forced hydration and bed rest to serve as controls. Eight subjects received pralidoxime under conditions of forced hydration and bed rest, one time after 36 hr of ammonium chloride acidification, and another time after sodium bicarbonate alkalinization. Nine subjects received pralidoxime under forced dehydration and bed rest, 20-30 min after thiamine (200 mg total, IM), organic base. Eight received pralidoxime under forced hydration and bed rest simultaneously with p-aminohippurate (900 mg total, IV), organic acid. Four received pralidoxime under bed rest, after 8-12 hr of fasting, NPO. The drug is rapidly cleared from the plasma by renal tubular secretion. Reduction of pralidoxime clearance rates and prolongation of the biologic half-life after thiamine administration as compared to those after PAH administration suggest that pralidoxime is secreted as an organic base. Reduction of the excretion of pralidoxime under conditions of both urine alkalinization and urine acidification implicates an active reabsorption of pralidoxime not heretofore described.|The pharmacokinetics of pralidoxime chloride (2-PAM) was studied in rats. Different groups of rats were given an intramuscular injection of 2-PAM at one of three doses (20, 40, or 80 mg/kg). This range of doses is used commonly in studies concerned with the efficacy of 2-PAM against poisoning by potent organophosphorus inhibitors of cholinesterase enzyme. Individual, sequential blood samples were collected during the course of the experiment. From these blood samples the plasma concentrations of 2-PAM were determined over time for each animal. Next the relationship of plasma concentration to time was expressed in terms of a standard pharmacokinetic model. Estimates of various pharmacokinetic parameters were calculated using an open, one-compartment model: volume of distribution (Vd), maximal plasma concentration (Cmax), elimination rate constant (k10), absorption rate constant (k01), area under the curve (AUC) and clearance (CL). Of the pharmacokinetic estimates, only Cmax and AUC were found to be statistically significant (p less than 0.0001) when compared across all the doses; these pharmacokinetic estimates were highly correlated with doses with r = 0.998 and r = 0.997, respectively. However, when AUC and Cmax were normalized by dividing through by dose, no significant differences were found in the transformed data. The results of this study in rat indicate that the pharmacokinetics of 2-PAM is linearly related to dose in a range employed in therapeutic studies of 2-PAM.|BACKGROUND: Current therapies for organophosphate poisoning involve administration of oximes, such as pralidoxime (2-PAM), that reactivate the enzyme acetylcholinesterase. Studies in animal models have shown a low concentration in the brain following systemic injection. METHODS: To assess 2-PAM transport, we studied transwell permeability in three Madin-Darby canine kidney (MDCKII) cell lines and stem cell-derived human brain microvascular endothelial cells (BC1-hBMECs). To determine whether 2-PAM is a substrate for common brain efflux pumps, experiments were performed in the MDCKII-MDR1 cell line, transfected to overexpress the P-gp efflux pump, and the MDCKII-FLuc-ABCG2 cell line, transfected to overexpress the BCRP efflux pump. To determine how transcellular transport influences enzyme reactivation, we developed a modified transwell assay where the inhibited acetylcholinesterase enzyme, substrate, and reporter are introduced into the basolateral chamber. Enzymatic activity was inhibited using paraoxon and parathion. RESULTS: The permeability of 2-PAM is about 2 x 10(-6) cm/s in MDCK cells and about 1 x 10(-6) cm/s in BC1-hBMECs. Permeability is not influenced by pre-treatment with atropine. In addition, 2-PAM is not a substrate for the P-gp or BCRP efflux pumps. CONCLUSIONS: The low permeability explains poor brain penetration of 2-PAM and therefore the slow enzyme reactivation. This elucidates one of the reasons for the necessity of sustained intravascular (IV) infusion in response to organophosphate poisoning.|For more Absorption, Distribution and Excretion (Complete) data for 2-PAM (10 total), please visit the HSDB record page.

Although the exact metabolic fate of pralidoxime has not been completely elucidated, the drug is believed to be metabolized in the liver. ... A recent study has suggested that active tubular secretion may be involved, although the specific mechanism has not been identified.|There is a trend towards increasing doses of pralidoxime to treat human organophosphate poisonings that may have relevance in subpopulations. Indeed, pralidoxime is eliminated unchanged by the renal route. This study assesses the effect of renal failure on the kinetics of pralidoxime in a rat model of acute renal failure induced by potassium dichromate administration. On the first day, Sprague-Dawley rats received subcutaneously potassium dichromate (study) or saline (control). Forty-eight hours post-injection, animals received pralidoxime methylsulfate (50 mg/kg of pralidoxime base) intramuscularly. Blood specimens were sampled during 180 min after the injection. Urine was collected daily during the 3 days of the study. Plasma pralidoxime concentrations were measured by liquid chromatography with electrochemical detection. There was a 2-fold increase in mean elimination half-life and a 2.5-fold increase in mean area under the curve in the study compared to the control group. The mean total body clearance was halved in the study compared to the control group. Our study showed acute renal failure does not modify the distribution of pralidoxime but significantly alters its elimination from plasma. These results suggest that dosages of pralidoxime should be adjusted in organophosphate-poisoned humans with renal failure when using high dosage regimen of pralidoxime.

The half-life of pralidoxime in patients with normal renal function varies and has been reported to range from 0.8-2.7 hours.

Other reported pharmacologic effects of pralidoxime include depolarization at the neuromuscular junction, anticholinergic action, mild inhibition of cholinesterase, sympathomimetic effects, potentiation of the depressor action of acetylcholine in nonatropinized animals, and potentiation of the pressor action of acetylcholine in atropinized animals. However, the contribution of these effects to the therapeutic action of the drug has not been established.|The principal pharmacologic effect of pralidoxime is reactivation of cholinesterase which has been recently inactivated by phosphorylation as the result of exposure to certain organophosphates. Pralidoxime removes the phosphoryl group from the active site of the inhibited enzyme by nucleophilic attack, regenerating active cholinesterase and forming an oxime complex. Pralidoxime also detoxifies certain organophosphates by direct chemical reaction and probably also reacts directly with cholinesterase to protect it from inhibition. Pralidoxime must be administered before aging of the inhibited enzyme occurs; after aging is completed, phosphorylated cholinesterase cannot be reactivated, and newly synthesized cholinesterase must replace the inhibited enzyme. Pralidoxime is not equally antagonistic to all anticholinesterases, partly because the time period required for aging of the inhibited enzyme varies and depends on the specific organophosphate bound to the cholinesterase.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) or lorazepam (Ativan) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/SIGNS AND SYMPTOMS/ Rapid IV injection of pralidoxime has produced tachycardia, laryngospasm, muscle rigidity, and transient neuromuscular blockade; therefore, the drug should be administered slowly, preferably by IV infusion. IV administration of pralidoxime reportedly may also cause hypertension which is related to the dose and rate of infusion. Some clinicians recommend that the patient's blood pressure be monitored during pralidoxime therapy. For adults, IV administration of 5 mg of phentolamine mesylate reportedly quickly reverses pralidoxime-induced hypertension.|/SIGNS AND SYMPTOMS/ There are no adequate and well-controlled clinical trials that establish the effectiveness of pralidoxime chloride in pediatric patients. Efficacy has been extrapolated from the adult population and is supported by nonclinical studies, pharmacokinetic studies in adults and experience in the pediatric population. As in adults, laryngospasm, cardiac arrest, tachycardia, and muscle rigidity or paralysis have been reported following rapid intravenous injection. Muscle fasciculations, apnea, and convulsions have also been reported.|/SIGNS AND SYMPTOMS/ Manifestations of Overdosage: Observed in normal subjects only: dizziness, blurred vision, diplopia, headache, impaired accommodation, nausea, slight tachycardia. In therapy, it has been difficult to differentiate side effects due to the drug from those due to the effects of the poison.

1-methylpyridinium-2-aldoxime ion

Table: Pralidoxime Chloride and Atropine Preparations [Table#8609]|Table: Pralidoxime Chloride Preparations [Table#8610]

An electrochemical method based on non-enzymatic inhibition for the determination of organophosphorus pesticide (OPPs) using pralidoxime chloride (PAM-Cl) as a universal electrochemical probe was reported. Cyclic voltammetry was performed to characterize the redox properties of pralidoxime and OPPs. Differential pulse voltammetry (DPV) was carried out to analyze the influence of anion (chloride and iodide ions), to optimize the pH of testing condition, and to explore the relationship between pralidoxime and OPPs. The results showed that iodide ion generated an anodic peak close to the peak of pralidoxime, which would interfere in the detection of OPPs. Phosphate buffer solution (pH 7.0) was chosen because of its high peak current and low peak potential when testing PAM-Cl by DPV. Chlorpyrifos, fenthion, and methyl parathion were examples of three existing OPPs detection methods. The peak current of PAM-Cl decreased along with the increase of concentration of OPPs in the solution. The limit of detection was 0.018 uM, 0.100 uM, and 0.215 uM, respectively. It was the first time for PAM-Cl to be used as a universal electrochemical probe to develop a simple, cheap and stable method for OPPs detection. /2-PAM Chloride/

Pralidoxime (2-PAM) is a monopyridinium oxime used as an antidote for the treatment of poisoning with organophosphorus (OP) compounds, for example, pesticides and nerve agents, reactivating OP-inhibited acetylcholinesterase. However, appropriate dosing and efficacy remains a matter of discussion requiring experimental data. Therefore, we developed and validated an ion pair chromatography-diode array detection (IPC-DAD) method suitable for quantitative analysis of 2-PAM in human and porcine urine. Before injection of 20 uL, urine was acidified with trichloroacetic acid, mixed with internal standard (pyridine-4-aldoxime, 4-PAO), and diluted with IPC solvent yielding a total dilution of 1:49.5 and a 100% recovery. Isocratic separation was carried out at 25 °C on a LiChrospher 60 RP-select B column (125x4.0 mm I.D.) using phosphate buffer (7.5 mM Na(2) HPO(4) , 7.5 mM KH(2) PO(4) , pH 2.6) mixed with octanesulfonate (2.5 mM) as ion pair reagent and acetonitrile (6% v/v) as organic modifier (1 mL/min). 2-PAM was detected at 293 nm and 4-PAO at 275 nm. The method is rugged, selective, and characterized by good intra-day and inter-day precision (RSD, 1.3-6.0%) and accuracy (88-100%) with a limit of detection at 4.9 ug/mL, a limit of quantification at 9.8 ug/mL, and a broad calibration range from 4.9-2500 ug/mL. The procedure was applied to urine samples obtained from dimethoate poisoned minipigs receiving 2-PAM therapy (intravenous bolus injection and infusion). Results indicate that 60-80% of infused 2-PAM is rapidly (within 1-2 hr) excreted in the urine.|BACKGROUND AND PURPOSE: Treatment of organophosphate poisoning with pralidoxime needs to be improved. Here we have studied the pharmacokinetics of pralidoxime after its intramuscular injection alone or in combination with avizafone and atropine using an auto-injector device. EXPERIMENTAL APPROACH: The study was conducted in an open, randomized, single-dose, two-way, cross-over design. At each period, each subject received either intramuscular injections of pralidoxime (700 mg), or two injections of the combination: pralidoxime (350 mg), atropine (2 mg), avizafone (20 mg). Pralidoxime concentrations were quantified using a validated LC/MS-MS method. Two approaches were used to analyse these data: (i) a non-compartmental approach; and (ii) a compartmental modelling approach. KEY RESULTS: The injection of pralidoxime combination with atropine and avizafone provided a higher pralidoxime maximal concentration than that obtained after the injection of pralidoxime alone (out of bioequivalence range), while pralidoxime AUC values were equivalent. Pralidoxime concentrations reached their maximal value earlier after the injection of the combination. According to Akaike and to goodness of fit criteria, the best model describing the pharmacokinetics of pralidoxime was a two-compartment with a zero-order absorption model. When avizafone and atropine were injected with pralidoxime, the best model describing pralidoxime pharmacokinetics becomes a two-compartment with a first-order absorption model. CONCLUSIONS AND IMPLICATIONS: The two approaches, non-compartmental and compartmental, showed that the administration of avizafone and atropine with pralidoxime results in a faster absorption into the general circulation and higher maximal concentrations, compared with the administration of pralidoxime alone.|HPLC determination in serum. /Pralidoxime chloride/

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