Enhancement of target toxin neutralization effect in vivo by PEGylation of multifunctionalized lipid nanoparticles.

Protein-protein (e.g., antibody-antigen) interactions comprise multiple weak interactions. We have previously reported that lipid nanoparticles (LNPs) bind to and neutralize target toxic peptides after multifunctionalization of the LNP surface (MF-LNPs) with amino acid derivatives that induce weak interactions; however, the MF-LNPs aggregated after target capture and showed short blood circulation times. Here we optimized polyethylene glycol (PEG)-modified MF-LNPs (PEG-MF-LNPs) to inhibit the aggregation and increase the blood circulation time. Melittin was used as a target toxin, and MF-LNPs were prepared with negatively charged, hydrophobic, and neutral amino-acid-derivative-conjugated functional lipids. In this study, MF-LNPs modified with only PEG5k (PEG5k-MF-LNPs) and with both PEG5k and PEG2k (PEGmix-MF-LNPs) were prepared, where PEG5k and PEG2k represent PEG with a molecular weight of 5000 and 2000, respectively. PEGylation of the MF-LNPs did not decrease the melittin neutralization ability of nonPEGylated MF-LNPs, as tested by hemolysis assay. The PEGmix-MF-LNPs showed better blood circulation characteristics than the PEG5k-MF-LNPs. Although the nonPEGylated MF-LNPs immediately aggregated when mixed with melittin, the PEGmix-MF-LNPs did not aggregate. The PEGmix-MF-LNPs dramatically increased the survival rate of melittin-treated mice, whereas the nonPEGylated MF-LNPs increased slightly. These results provide a fundamental strategy to improve the in vivo toxin neutralization ability of MF-LNPs.

Positron emission tomography studies of organophosphate chemical threats and oxime countermeasures.

There is a unique in vivo interplay involving the mechanism of inactivation of acetylcholinesterase (AChE) by toxic organophosphorus (OP) compounds and the restoration of AChE activity by oxime antidotes. OP compounds form covalent adducts to this critical enzyme target and oximes are introduced to directly displace the OP from AChE. For the most part, the in vivo inactivation of AChE leading to neurotoxicity and antidote-based therapeutic reversal of this mechanism are well understood, however, these molecular-level events have not been evaluated by dynamic imaging in living systems at millimeter resolution. A deeper understanding of these critically, time-dependent mechanisms is needed to develop new countermeasures. To address this void and to help accelerate the development of new countermeasures, positron-emission tomography (PET) has been investigated as a unique opportunity to create platform technologies to directly examine the interdependent toxicokinetic/pharmacokinetic and toxicodynamic/pharmacodynamic features of OPs and oximes in real time within live animals. This review will cover two first-in-class PET tracers representing an OP and an oxime antidote, including their preparation, requisite pharmacologic investigations, mechanistic interpretations, biodistribution and imaging.

Efficacy of Oral Administration of Sodium Thiosulfate and Glycine in a Large, Swine Model of Oral Cyanide Toxicity.

STUDY OBJECTIVE: Cyanide is a deadly poison, particularly with oral exposure, in which larger doses can occur before any symptoms develop. Multiple governmental agencies highlight oral cyanide as an agent that can be used in a terrorist attack because it can be easily weaponized and is readily available. Currently, there are no Food and Drug Administration-approved antidotes specifically for oral cyanide. An oral countermeasure that can neutralize and prevent absorption of cyanide from the gastrointestinal tract after oral exposure is needed. The objective of this study is to determine if the combination of glycine and sodium thiosulfate administered orally is effective in reducing mortality in a large, swine model of oral cyanide toxicity. METHODS: Nine swine (45 to 55 kg) were instrumented, sedated, and stabilized. Potassium cyanide (at 8 mg/kg) in saline solution was delivered as a onetime bolus through an orogastric tube. Three minutes after cyanide administration, animals that were randomized to the treatment group received sodium thiosulfate (508.2 mg/kg, 3.25-M solution) and glycine (30 mg/kg, 3.5-M solution) through an orogastric tube. Survival at 60 minutes was the primary outcome. We compared survival between groups by log-rank Mantel-Cox analysis and trended laboratory results and vital signs. RESULTS: At baseline and treatment, all animals were similar. Survival at 60 minutes was 100% in treated animals compared with 0% in the control group (P=.003). By the study end, defined as death or 60 minutes after cyanide administration, there was a significant difference in the lactate concentration between the treatment and control groups (control 9.43 mmol/L [SD 4.08]; treatment 1.66 mmol/L [SD 0.82]; difference between means 7.69 mmol/L [SD 2.07]; 95% confidence interval difference -14.05 to -1.32). Mean arterial pressure was significantly different between the treatment and control groups at study end (control 26 mm Hg [SD 6.7]; treatment 81 mm Hg [SD 14]; difference between means 55.2 mm Hg [SD 7.1]; 95% confidence interval difference 37.8 to 72.6). pH and oxygen saturation were also significantly different between the treatment and control groups at study end. CONCLUSION: The combination of oral sodium thiosulfate and glycine significantly improved survival and physiologic parameters in a large-animal model of oral cyanide toxicity.

Computational framework for predictive PBPK-PD-Tox simulations of opioids and antidotes.

The primary goal of this work was to develop a computational tool to enable personalized prediction of pharmacological disposition and associated responses for opioids and antidotes. Here we present a computational framework for physiologically-based pharmacokinetic (PBPK) modeling of an opioid (morphine) and an antidote (naloxone). At present, the model is solely personalized according to an individual's mass. These PK models are integrated with a minimal pharmacodynamic model of respiratory depression induction (associated with opioid administration) and reversal (associated with antidote administration). The model was developed and validated on human data for IV administration of morphine and naloxone. The model can be further extended to consider different routes of administration, as well as to study different combinations of opioid receptor agonists and antagonists. This work provides the framework for a tool that could be used in model-based management of pain, pharmacological treatment of opioid addiction, appropriate use of antidotes for opioid overdose and evaluation of abuse deterrent formulations.

Prediction of Human Pharmacokinetics of Fomepizole from Preclinical Species Pharmacokinetics Based on Normalizing Time Course Profiles.

Fomepizole is used as an antidote to treat methanol poisoning due to its selectivity towards alcohol dehydrogenase. In the present study, the goal is to develop a method to predict the fomepizole human plasma concentration versus time profile based on the preclinical pharmacokinetics using the assumption of superimposability on simulated time course profiles of animals and humans. Standard allometric equations with/without correction factors were also assimilated in the prediction. The volume of distribution at steady state (Vss) predicted by simple allometry (57.55 L) was very close to the reported value (42.17 L). However, clearance (CL) prediction by simple allometry was at least 3-fold higher to the reported value (33.86 mL/min); hence, multiple correction factors were used to predict the clearance. Both brain weight and maximum life span potential could predict the CL with 1.22- and 1.01-fold difference. Specifically, the predicted Vss and CL values via interspecies scaling were used in the prediction of series of human intravenous pharmacokinetic parameters, while the simulation of human oral profile was done by the use of absorption rate constant (Ka) from dog following the applicability of human bioavailability value scaled from dog data. In summary, the findings indicate that the utility of diverse allometry approaches to derive the human pharmacokinetics of fomepizole after intravenous/oral dosing.

Naloxone nasal spray - bioavailability and absorption pattern in a phase 1 study. / Naloksonnesespray ­ biotilgjengelighet og opptaksmønster i en fase 1-studie.

BACKGROUND: Bystander administration with naloxone nasal spray can prevent deaths from opioid overdose. To achieve optimal nasal absorption of naloxone, the spray must be administered at low volume with high concentration of the drug. The study aimed to investigate the bioavailability and absorption pattern for a new naloxone nasal spray. MATERIAL AND METHOD: In an open, randomised, two-way crossover study undertaken in five healthy men, naloxone 2 mg (20 mg/ml) in nasal spray was compared with 1 mg intravenously administered naloxone. A total of 15 blood samples were taken over a period of six hours after administration. The drug concentration was determined using liquid chromatography tandem-mass spectrometry. Pharmacokinetic variables were calculated using non-compartmental analysis. RESULTS: Bioavailability for intranasal naloxone was 47 % (minimum-maximum values 24-66 %). Maximum concentration (Cmax) was 4.2 (1.5-7.1) ng/ml, and this was achieved (Tmax ) after 16 (5-25) minutes. INTERPRETATION: The nasal spray resulted in a rapid systemic absorption with higher serum concentrations than intravenous naloxone 10-240 minutes after intake. The pilot study indicated that the highly concentrated nasal spray may provide a therapeutic dose of naloxone with a single spray actuation. The findings led to further commercial development of the medication.

Emerging applications of aptamers for anticoagulation and hemostasis.

PURPOSE OF REVIEW: Since the selection of the first thrombin-binding aptamer in 1992, the use of nucleic acid aptamers to target specific coagulation factors has emerged as a valuable approach for generating novel anticoagulant and procoagulant therapeutics. Herein, we highlight the most recent discoveries involving application of aptamers for those purposes. RECENT FINDINGS: Learning from the successes and pitfalls of the FIXa-targeting aptamer pegnivacogin in preclinical and clinical studies, the latest efforts to develop antidote-controllable anticoagulation strategies for cardiopulmonary bypass that avoid unfractionated heparin involve potentiation of the exosite-binding factor X (FX)a aptamer 11F7t by combination with either a small molecule FXa catalytic site inhibitor or a thrombin aptamer. Recent work has also focused on identifying aptamer inhibitors of contact pathway factors such as FXIa and kallikrein, which may prove to be well tolerated and effective antithrombotic agents in certain clinical settings. Finally, new approaches to develop procoagulant aptamers to control bleeding associated with hemophilia and other coagulopathies involve targeting activated protein C and tissue plasminogen activator. SUMMARY: Overall, these recent findings exemplify the versatility of aptamers to modulate a variety of procoagulant and anticoagulant factors, along with their capacity to be used complementarily with other aptamers or drugs for wide-ranging applications.

Pharmacology, Pharmacokinetics, and Tissue Disposition of Zwitterionic Hydroxyiminoacetamido Alkylamines as Reactivating Antidotes for Organophosphate Exposure.

In the development of antidotal therapy for treatment of organophosphate exposure from pesticides used in agriculture and nerve agents insidiously employed in terrorism, the alkylpyridinium aldoximes have received primary attention since their early development by I. B. Wilson in the 1950s. Yet these agents, by virtue of their quaternary structure, are limited in rates of crossing the blood-brain barrier, and they require administration parenterally to achieve full distribution in the body. Oximes lacking cationic charges or presenting a tertiary amine have been considered as alternatives. Herein, we examine the pharmacokinetic properties of a lead ionizable, zwitterionic hydroxyiminoacetamido alkylamine in mice to develop a framework for studying these agents in vivo and generate sufficient data for their consideration as appropriate antidotes for humans. Consequently, in vitro and in vivo efficacies of immediate structural congeners were explored as leads or backups for animal studies. We compared oral and parenteral dosing, and we developed an intramuscular loading and oral maintenance dosing scheme in mice. Steady-state plasma and brain levels of the antidote were achieved with sequential administrations out to 10 hours, with brain levels exceeding plasma levels shortly after administration. Moreover, the zwitterionic oxime showed substantial protection after gavage, whereas the classic methylpyridinium aldoxime (2-pyridinealdoxime methiodide) was without evident protection. Although further studies in other animal species are necessary, ionizing zwitterionic aldoximes present viable alternatives to existing antidotes for prophylaxis and treatment of large numbers of individuals in terrorist-led events with nerve agent organophosphates, such as sarin, and in organophosphate pesticide exposure.

Fluorescent MUA-stabilized Au nanoclusters for sensitive and selective detection of penicillamine.

In this study, we have developed a facile method for preparation of highly fluorescent Au nanoclusters (AuNCs) using 11-mercaptoundecanoic acid (MUA) as both the reducing and stabilizing agent. The as-prepared MUA functionalized AuNCs (MUA-AuNCs) have good water solubility, excellent photostability, and strong fluorescence emission at 610 nm with a quantum yield of 7.28% in water. The fluorescence of MUA-AuNCs was first quenched by copper ions through electron transfer, subsequently caused obvious restoration by competitive effect after adding penicillamine, making it a potential fluorescent sensor for penicillamine with a detection limit of 0.08 µM. Furthermore, the newly designed fluorescence "on-off-on" assay was explored for the measurement of penicillamine in complex real water and urine samples with satisfactory results.

Behavioral, Pharmacokinetic, and Cardiovascular Evaluation of Candidate Oximes in African Green Monkeys.

Oxime reactivators are critical antidotes after organophosphate pesticide or nerve agent poisoning, directly restoring the function of inhibited acetylcholinesterase. In the continuing search for more broad-spectrum acetylcholinesterase reactivators, this study evaluated one of the leading next-generation oxime reactivators: methoxime, (1,1'-trimethylene bis[4-(hydroxyimino)methyl]pyridinium dichloride (MMB-4). The pharmacokinetics of both salts of MMB-4 (dichloride [2Cl] and dimethanesulphonate [DMS]) were characterized across a range of relevant doses (19, 58, and 116 µmol/kg, intramuscular) in a nonhuman primate model (male African green monkeys), and only subtle differences were observed between the salts. Additionally, the behavioral and cardiovascular safety of these MMB-4 salts was compared directly to other available oximes (HI-6 2Cl, HI-6 DMS, and pyridine-2-aldoxime chloride (2-PAM Cl)) at comparable projected doses. Automated operant behavioral tests were used to examine attention, motivation, visual discrimination, concept execution, and fine motor coordination after high doses of all oxime salts, and of all oximes studied, only the highest dose of 2-PAM Cl (447 µmol/kg) disrupted behavioral performance. Likewise, the effects of a range of doses of MMB-4 2Cl or DMS, HI-6 2Cl or DMS, or 2-PAM Cl on cardiovascular parameters were measured in African green monkeys implanted with telemetry devices. Only a small transient decrease in pulse pressure was observed following administration of the highest dose of MMB-4 DMS (116 µmol/kg). Thus, MMB-4 salts, up to the 9× equivalent of a projected autoinjector dose in humans, did not produce behavioral or cardiovascular toxicity in African green monkeys in the current study, and the pharmacokinetic parameters were orderly and predictable.

An assessment of the variation in the concentration of acetylcysteine in infusions for the treatment of paracetamol overdose.

BACKGROUND: Intravenous acetylcysteine is the treatment of choice for paracetamol poisoning. A previous UK study in 2001 found that 39% of measured acetylcysteine infusion concentrations differed by >20% from anticipated concentrations. In 2012, the UK Commission on Human Medicines made recommendations for the management of paracetamol overdose, including provision of weight-based acetylcysteine dosing tables. The aim of this study was to assess variation in acetylcysteine concentrations in administered infusions following the introduction of this guidance. METHODS: A 6-month single-centre prospective study was undertaken at a UK teaching hospital. After preparation, 5-ml samples were taken from the first, second and third/any subsequent acetylcysteine infusions. Acetylcysteine was measured in diluted (1:50) samples by high-performance liquid chromatography. Comparisons between measured and expected concentrations based on prescribed weight-based dose and volume were made for each infusion. RESULTS: Ninety samples were collected. There was a variation of ≤10% in measured compared to expected concentration for 45 (50%) infusions, of 10-20% for 27 (30%) infusions, 20.1-50% for 14 (16%) infusions and >50% for four (4%) infusions. There was a median (interquartile range) variation in measured compared to expected concentration of -3.6 mg ml-1 (-6.7 to -2.3) for the first infusion, +0.2 mg ml-1 (-0.9 to +0.4) for the second infusion and -0.3 mg ml-1 (-0.6 to +0.2) for third and fourth infusions. CONCLUSION: There has been a moderate improvement in the variation in acetylcysteine dose administered by infusion. Further work is required to understand the continuing variation and consideration should be given to simplification of acetylcysteine regimes to decrease the risk of administration errors.

Neutralization of EP217609, a new dual-action FIIa/FXa anticoagulant, by its specific antidote avidin: a phase I study.

INTRODUCTION: EP217609 is a representative of a new class of synthetic parenteral anticoagulants with a dual mechanism of action. It combines in a single molecule a direct thrombin inhibitor and an indirect factor Xa inhibitor. EP217609 can be neutralized by a specific antidote avidin, which binds to the biotin moiety of EP217609. PURPOSE: The primary objective was to assess the neutralization of EP217609 by avidin in healthy subjects. Secondary objectives were to define the optimal avidin monomer/EP217609 molar ratio to achieve an adequate neutralization of EP217609 and to assess the safety and tolerability of EP217609 and avidin. METHODS: Healthy subjects (n = 36) were randomized to a 3 by 3 replicated Latin square design between 3 EP217609 doses (4, 8, 12 mg) and 3 avidin monomer/EP217609 molar ratios (1:1; 2:1; 3:1). EP217609 was administered as a single intravenous bolus, and avidin as a 30-min intravenous infusion, starting 90 min after EP217609 administration. RESULTS: Overall, EP217609 and avidin were well tolerated. One subject experienced a benign and transient typical pseudo-allergic reaction. The administration of EP217609 resulted in dose-dependent increases in pharmacodynamic markers. Avidin triggered a rapid and irreversible neutralization of EP217609 without rebound effect. Adequate neutralization of the anticoagulant activity was achieved with both 2:1 and 3:1 avidin monomer/EP217609 molar ratios. All safety parameters did not show any treatment-emergent clinically relevant changes or abnormalities in any dose group. CONCLUSIONS: These results will allow further investigation in patients requiring a neutralizable anticoagulant as those undergoing cardiac surgery. STUDY REGISTRATION: EudraCT number 2010-020216-10.

Effects of Chitosan Derivative N-[(2-Hydroxy-3-Trimethylammonium)Propyl]Chloride on Anticoagulant Activity of Guinea Pig Plasma.

Intravenous injection of protamine sulfate or quarternized chitosan derivative to guinea pigs after injection of 70 aIIa U/kg non-fractionated heparin shortened plasma clotting time (shown by partial activated thromboplastin time, thrombin time, and prothrombin time). Intravenous injection of protamine sulfate or quarternized chitosan derivative to guinea pigs after injection of 1 mg/kg (100 aXa U/kg) low-molecular-weight heparin (clexane) led to shortening of plasma clotting time in the ReaClot Heparin test and to prolongation of plasma amidolytic activity in the factor Xa chromogenic substrate test.

Sequential use of hemoperfusion and single-pass albumin dialysis can safely reverse methotrexate nephrotoxicity.

BACKGROUND: High-dose methotrexate therapy (HDMTX) is a common form of chemotherapy used in children with high-grade malignancy such as osteosarcoma. Treatment with HDMTX requires careful monitoring of drug levels with folinic acid (leucovorin) rescue therapy. Toxicity from methotrexate is not uncommon and sometimes causes significant morbidity and mortality. CASE-DIAGNOSIS/TREATMENT: We report an 11-year-old child whose 24-h post-HDMTX serum level was 651.8 µmol/L (recommended level <20 µmol/L), which was complicated by septic shock and progressive renal and liver failure. As carboxypeptidase (glucarpidase) was not available locally, she was treated with the sequential use of charcoal hemoperfusion (CHP) and single-pass albumin dialysis (SPAD). The patient recovered without complications. Both liver and renal function recovered with no significant late sequelae. CONCLUSION: CHP and SPAD are effective extracorporeal methods of removing methotrexate. They provide alternative treatment options for critical care nephrologists in the management of methotrexate toxicity.

Universal, class-specific and drug-specific reversal agents for the new oral anticoagulants.

Although there is controversy about the absolute need for a reversal agent for the new direct oral anticoagulants (DOACs), the absence of such an agent is a barrier to more widespread use of these agents. For the management of major life-threatening bleeding with the DOACs, most authorities recommend the use of four factor prothrombin complex concentrates, although the evidence to support their use in terms of improving outcomes is meager. At the present time, there are three antidotes in development and poised to enter the market. Idarucizumab is a drug-specific antidote targeted to reverse the direct thrombin inhibitor, dabigatran. Andexanet alfa is a class-specific antidote targeted to reverse the oral direct factor Xa inhibitors as well as the indirect inhibitor, enoxaparin. Ciraparantag is a universal antidote targeted to reverse the direct thrombin and factor Xa inhibitors as well as the indirect inhibitor, enoxaparin.

Who, when, and how to reverse non-vitamin K oral anticoagulants.

Non-vitamin K oral anticoagulants (NOACs) have been a major addition to our therapeutic armamentarium. They are at least as effective as warfarin in the thromboprophylaxis of non-valvular atrial fibrillation and management of thromboembolic disease, with a more favorable safety profile. Their predictable pharmacokinetics and pharmacodynamics allow for a fixed oral dosing without the need for anticoagulation monitoring. A major concern regarding NOACs is the lack of a readily available antidote to reverse their anticoagulation effect in case of life-threatening bleeding or need for emergent surgery. In this review, we summarize preclinical and clinical data on (a) hemostatic agents used to reverse NOACs, and (b) novel, target-specific NOACs reversal agents under development. The prothrombin complex concentrates, activated prothrombin complex concentrates and recombinant activated factor VII are hemostatic agents that have been assessed in reversing NOACs. Preclinical studies with hemostatic agents report variable results and there is only limited clinical data available to date. Idarucizumab and andexanet alfa are NOAC-specific reversal agents designed to reverse dabigatran and factor Xa inhibitors accordingly. Aripazine is a universal anticoagulation reversal agent. Preclinical studies show promising results and these agents are already in different stages of clinical development. Phase I and II clinical trials demonstrate efficacy in reversing NOACs without major side effects. Until these agents become commercially available, management of patients receiving NOACs who present with major bleeding or require emergent surgery should focus on (a) immediate discontinuation of NOACs, (b) supportive measures or postponing surgery for 12-24 h after the last NOAC dose, and/or

Why develop antidotes and reversal agents for non-vitamin K oral anticoagulants?

Over the past several years, non-vitamin K oral anticoagulants (NOACs) have been introduced into clinical practice for the treatment of venous thromboembolism and prevention of stroke in patients with nonvalvular atrial fibrillation. Clinical trials have shown these agents to have similar or less risk of major bleeding as compared to warfarin therapy. Moreover, when patients do experience a major bleeding event administration of advanced factor products is rare, and post-bleed outcomes are similar in those receiving a NOAC compared to those receiving warfarin. However, there are situations where urgent reversal of NOAC anticoagulation would be desirable. The following review focuses on the outcomes and management strategies for patients experiencing a major bleed with warfarin or NOAC agents and describes the rationale for the development of therapies capable of targeted NOAC-reversal.

Widening the path and window of opportunity for FDA approval of non-vitamin K oral anticoagulant specific antidotes and reversal agents.

There remains a need for safe, immediately effective, and easy to administer antidotes for patients taking novel oral anticoagulants (NOACs) in the settings of major bleeding, need for emergency surgery, and accidental overdose. We review considerations for the successful safety and effectiveness evaluation of potential antidotes currently under development. These compounds are in expedited regulatory approval programs aimed at accelerating the preclinical and clinical evaluation and approval processes for treatments of serious conditions. We review the features of these expedited programs as well as the FDA's efforts to broadly advance the efficiency of drug development and increase the number of new compounds brought to market. The critical path initiative and regulatory science initiative have resulted in numerous successful programs to address current challenges such as a paucity of validated biomarkers and surrogate endpoints as well as unreliable animal models of toxicity. The FDA has also advocated for increased use of pharmacokinetic/pharmacodynamic modeling and adaptive trial design. These efforts foster collaboration between academia, industry and the public sector across interdisciplinary sciences and may continue to widen the pathway for NOAC-specific reversal agents and other novel compounds.

Preclinical and first-in-human evaluation of PRX-105, a PEGylated, plant-derived, recombinant human acetylcholinesterase-R.

PRX-105 is a plant-derived recombinant version of the human 'read-through' acetylcholinesterase splice variant (AChE-R). Its active site structure is similar to that of the synaptic variant, and it displays the same affinity towards organophosphorus (OP) compounds. As such, PRX-105 may serve as a bio-scavenger for OP pesticides and chemical warfare agents. To assess its potential use in prophylaxis and treatment of OP poisoning we conducted several preliminary tests, reported in this paper. Intravenous (IV) PRX-105 was administered to mice either before or after exposure to an OP toxin. All mice who received an IV dose of 50nmol/kg PRX-105, 2min before being exposed to 1.33×LD50 and 1.5×LD50 of toxin and 10min after exposure to 1.5×LD50 survived. The pharmacokinetic and toxicity profiles of PRX-105 were evaluated in mice and mini-pigs. Following single and multiple IV doses (50 to 200mg/kg) no deaths occurred and no significant laboratory and histopathological changes were observed. The overall elimination half-life (t½) in mice was 994 (±173) min. Additionally, a first-in-human study, to assess the safety, tolerability and pharmacokinetics of the compound, was conducted in healthy volunteers. The t½ in humans was substantially longer than in mice (average 26.7h). Despite the small number of animals and human subjects who were assessed, the fact that PRX-105 exerts a protective and therapeutic effect following exposure to lethal doses of OP, its favorable safety profile and its relatively long half-life, renders it a promising candidate for treatment and prophylaxis against OP poisoning and warrants further investigation.

Mini review on blood-brain barrier penetration of pyridinium aldoximes.

This paper reviews the blood-brain barrier (BBB) penetration of newly developed pyridinium aldoximes. Pyridinium aldoximes are highly charged hydrophilic compounds used in the treatment of subjects exposed to organophosphonates because they are effective as acetylcholinesterase reactivators. Pyridinium aldoximes have antidotal effects against poisoning with cholinesterase inhibitors, a frequent problem affecting people working with organophosphate-based insecticides and pesticides. Toxic organophosphonate products such as sarin and tabun can be used by terrorists as chemical warfare agents. This poses a severe challenge to all innocent and peace-loving people worldwide. This review gives a brief summary of BBB transporters and description of the current in vitro and in vivo methods for the characterization of BBB penetration of established and novel pyridinium aldoximes. The authors provide a putative mechanism of penetration, outline some future ways of formulation and discuss the possible advantages and disadvantages of increasing BBB penetration.