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Asoxime chloride (also known as HI-6; HI6) is a potent oxime reactivator agent that can be used for counteracting intoxication by nerve agents. It is able to reactivate acetylcholinesterase (AChE) inhibited by cytotoxic nerve agents such as sarin or soman.
Asoxime chloride (HI-6) is a bispyridinium oxime compound developed as an antidote for organophosphate nerve agent poisoning, including sarin, soman, tabun, and VX. It acts by reactivating acetylcholinesterase (AChE) inhibited by these toxic agents, thereby restoring cholinergic neurotransmission. Due to the presence of two quaternary nitrogens, HI-6 has limited ability to cross the blood-brain barrier, acting primarily in the peripheral nervous system. Beyond its established role as an antidote, HI-6 also functions as an antagonist at both muscarinic and nicotinic acetylcholine receptors, including the α7 nicotinic receptor (α7 nAChR), which is involved in the cholinergic anti-inflammatory pathway. Preclinical studies in a BALB/c mouse model have demonstrated that HI-6 can enhance vaccine efficacy in a dose-dependent manner when administered with a low-dose antigen, achieving effects comparable to Freund’s complete adjuvant, while showing no inflammatory response or adverse effects at tested doses. [1]| Targets |
Acetylcholine receptors (AChRs), including nicotinic acetylcholine receptor α7 subunit (α7 nAChR). HI-6 acts as an antagonist at both muscarinic and nicotinic acetylcholine receptors. No specific IC₅₀ or Kᵢ values were reported in this study. [1]
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| ln Vivo |
Modulation of antibody production in mice: In BALB/c mice immunized with keyhole limpet hemocyanin (KLH) at a low dose (1 mg/kg), HI-6 (10 and 100 mg/kg, single intramuscular injection) significantly increased anti-KLH antibody levels in a dose-dependent manner. The effect was comparable to that of Freund’s complete adjuvant. At the higher KLH dose (10 mg/kg), HI-6 had no significant effect on antibody production. [1]
Effect of repeated HI-6 administration: When HI-6 was administered repeatedly on days 2 and 3 after the initial antigen injection (at doses of 0.1, 1, 10, and 100 mg/kg), no significant improvement in antibody production was observed compared to single-dose administration. [1] Memory immune response: In mice that received an initial immunization (with KLH 1 or 10 mg/kg, with or without HI-6) and were rechallenged with KLH (10 mg/kg) 60 days later, animals that had received HI-6 (10 or 100 mg/kg) along with low-dose KLH (1 mg/kg) during the initial immunization showed significantly higher antibody levels upon rechallenge compared to those that received KLH alone. HI-6 had no effect when combined with high-dose KLH (10 mg/kg). [1] Safety assessment: No alterations in mouse behavior or pathological manifestations were observed throughout the experiment. Interleukin-6 (IL-6) levels in plasma did not exceed 40 pg/mL in any group, indicating no inflammatory reaction. [1] Axime dichloride, administered intramuscularly into the hind limbs at 2% and 0.2% of LD50 (15.6 and 1.56 mg/kg) over 21 or 65 days, significantly increased vaccination effectiveness in a dose-dependent manner when KLH was 1 mg/kg. Freund's full adjuvant was nearly as efficacious as a vaccine made with HI-6 and keyhole limpet limpet hemocyanin (KLH) [1]. |
| Animal Protocol |
Animals: Female BALB/c mice (2 months old, weight 21 ± 3 g) were used. Animals were housed under controlled conditions (22 ± 2°C, 50 ± 10% humidity, 12-hour light/dark cycle) with food and water ad libitum. [1]
Dosing and administration: HI-6 was dissolved in saline and administered intramuscularly in a volume of 100 μL into the rear limb. KLH (keyhole limpet hemocyanin) was used as the antigen, and Freund’s complete adjuvant was used as a positive control. Doses of HI-6 ranged from 0.1 to 100 mg/kg, and KLH doses were 1 or 10 mg/kg. For repeated administration, HI-6 was injected on days 2 and 3 after the initial dose. [1] Experimental groups: A total of 320 animals were divided into 40 groups (8 animals per group). Various combinations of KLH, HI-6, and Freund’s complete adjuvant were tested. Euthanasia was performed at 21 or 65 days after initial treatment. [1] Sample collection: Animals were euthanized by carbon dioxide narcosis followed by carotid incision. Blood was collected into lithium heparin tubes, centrifuged at 1000 × g for 5 minutes, and plasma was stored at −80°C until analysis. [1] Antibody detection (ELISA): Plasma samples (diluted 100-fold) were incubated in 96-well plates coated with KLH (10 μg/mL). After blocking with 5% bovine albumin, secondary antibody (anti-mouse immunoglobulin conjugated with horseradish peroxidase) was added. Color was developed using tetramethylbenzidine and hydrogen peroxide, stopped with 2 M H₂SO₄, and optical density was measured at 650 nm. [1] IL-6 detection: Interleukin-6 levels in plasma were measured using a commercial ELISA kit according to the manufacturer’s instructions. [1] Animal/Disease Models: Balb/c mouse [1] Doses: 2% and 0.2% of the median lethal dose of 15.6 and 1.56 mg/kg. Route of Administration: intramuscularinjection in the hind limbs. Experimental Results: Improve the vaccination effect at the level of immune regulation of the nervous system. |
| ADME/Pharmacokinetics |
Half-life: In mice, the half-life of HI-6 is reported as 41.7 minutes (cited from Milic et al., 1996). [1]
Blood-brain barrier penetration: Due to the presence of two quaternary nitrogens, HI-6 has limited ability to cross the blood-brain barrier, making it more significant in the peripheral nervous system and blood. [1] |
| Toxicity/Toxicokinetics |
Dose safety: The doses of HI-6 used in this study (0.1–100 mg/kg) were below 2% and 0.2% of the median lethal dose (LD₅₀) for BALB/c mice (15.6 and 1.56 mg/kg, respectively). No adverse effects or pathological manifestations were observed. [1]
Inflammatory response: Plasma IL-6 levels remained below 40 pg/mL in all treatment groups, confirming the absence of an inflammatory reaction. [1] 135444627 mouse LD50 intravenous 168 mg/kg Fundamental and Applied Toxicology., 2(88), 1982 135444627 mouse LD50 intraperitoneal 295 mg/kg European Journal of Pharmacology., 48(377), 1978 [PMID:648582] 135444627 rat LD50 intramuscular 781 mg/kg Pharmacology and Toxicology, 84(41), 1999 [PMID:9974189] 135444627 guinea pig LD50 intramuscular 476 mg/kg Fundamental and Applied Toxicology., 4(S106), 1984 135444627 dog LD50 intramuscular 333 mg/kg Fundamental and Applied Toxicology., 4(S106), 1984 |
| References | |
| Additional Infomation |
Background and mechanism: HI-6 (asoxime) is an oxime used as an antidote for nerve agent poisoning, reactivating acetylcholinesterase inhibited by organophosphorus compounds. It also acts as an antagonist at acetylcholine receptors, including the α7 nicotinic acetylcholine receptor (α7 nAChR) involved in the cholinergic anti-inflammatory pathway. By antagonizing α7 nAChR on macrophages, HI-6 may modulate immune responses. [1]
Immunomodulatory effect: This study demonstrates that HI-6 can improve vaccine efficacy when the antigen is presented at a low dose, likely through modulation of the cholinergic anti-inflammatory pathway. The effect was dose-dependent and comparable to Freund’s complete adjuvant. Repeated administration of HI-6 did not enhance the effect, suggesting that the regulatory effect is needed immediately after antigen exposure. [1] Potential application: HI-6 may be useful as an adjuvant in vaccines where high doses of antigen are undesirable due to adverse effects, or when seroconversion is insufficient with standard antigen dosing. [1] |
| Molecular Weight |
359.20784
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| Exact Mass |
358.06
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| Elemental Analysis |
C, 46.81; H, 4.49; Cl, 19.74; N, 15.60; O, 13.36
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| CAS # |
34433-31-3
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| Related CAS # |
34433-31-3 (chloride); 82504-20-9 (chloride hydrate); 144252-71-1 (mesylate); 124051-64-5 (cation); Asoxime-d4 dichloride
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| PubChem CID |
135444627
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| Appearance |
White to off-white solid powder
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| Melting Point |
145-147ºC
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
23
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| Complexity |
356
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1=CC=[N+](C(=C1)/C=N/O)COC[N+]2=CC=C(C=C2)C(=O)N.[Cl-].[Cl-]
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| InChi Key |
QELSIJXWEROXOE-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C14H14N4O3.2ClH/c15-14(19)12-4-7-17(8-5-12)10-21-11-18-6-2-1-3-13(18)9-16-20;;/h1-9H,10-11H2,(H-,15,19);2*1H
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| Chemical Name |
1-[[2-[(E)-hydroxyiminomethyl]pyridin-1-ium-1-yl]methoxymethyl]pyridin-1-ium-4-carboxamide;dichloride
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| Synonyms |
Asoxime chloride; Transant; HI-6, HI 6, HI6, HI-6 Dichloride, HJ 6, Transant, WR 249655; WR-249655; WR249655; Asoxime dichloride; HUV88P6SJS; RefChem:114601;
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.7839 mL | 13.9194 mL | 27.8389 mL | |
| 5 mM | 0.5568 mL | 2.7839 mL | 5.5678 mL | |
| 10 mM | 0.2784 mL | 1.3919 mL | 2.7839 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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