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.
解离常数：
pKa = 5.78 (pyridine) (est)
碰撞截面：
122.6 Ų [M]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]
亨利常数：
Henry's Law constant = 9.98X10-15 atm-cu m/mol at 25 °C (est)
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.
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.
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.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
背景：目前针对有机磷中毒的治疗方法包括使用拟除虫菊酯类药物，如普拉立多克斯（2-PAM），来重新激活乙酰胆碱酯酶。动物模型的研究表明，系统注射后大脑中的浓度较低。 方法：为了评估2-PAM的传输，我们研究了三种Madin-Darby犬肾（MDCKII）细胞系和干细胞来源的人脑微血管内皮细胞（BC1-hBMECs）的跨孔渗透性。为了确定2-PAM是否是常见大脑外排泵的底物，我们在MDCKII-MDR1细胞系中进行了实验，该细胞系被转染以过表达P-糖蛋白外排泵，以及在MDCKII-FLuc-ABCG2细胞系中进行了实验，该细胞系被转染以过表达BCRP外排泵。为了确定跨细胞传输如何影响酶的重新激活，我们开发了一种改进的跨孔实验，其中将抑制的乙酰胆碱酯酶酶、底物和报告分子引入基底外侧室。使用对氧磷和敌百虫来抑制酶活性。 结果：2-PAM在MDCK细胞中的渗透性约为2 x 10(-6) cm/s，在BC1-hBMECs中约为1 x 10(-6) cm/s。渗透性不受阿托品预处理的 影响。此外，2-PAM不是P-糖蛋白或BCRP外排泵的底物。 结论：较低的渗透性解释了2-PAM在大脑中的穿透性较差，因此酶的重新激活速度较慢。这阐明了在有机磷中毒反应中进行持续静脉（IV）输注的必要性之一。
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.
