Avizafone
Also known as: Ly-Gly-diazepam, Pro-diazepam, Prodiazepam, RS-44331
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Summary
Avizafone is a water‑soluble dipeptide prodrug of the benzodiazepine diazepam. It is being investigated for rapid seizure control in emergency settings such as status epilepticus or organophosphate poisoning. The compound is administered intramuscularly or intravenously, often together with an enzyme that converts it to active diazepam, and is also studied for intranasal delivery using a prodrug‑enzyme mixture.
Mechanism of Action
Avizafone itself is pharmacologically inactive; it is hydrolyzed by proteolytic enzymes (e.g., Aspergillus oryzae protease, human aminopeptidase B) to release diazepam. The liberated diazepam binds to the benzodiazepine site on the GABA_A receptor complex, enhancing the inhibitory effect of GABA and producing rapid anticonvulsant, anxiolytic, and sedative actions.
What the Research Shows
In vitro studies showed that avizafone combined with protease creates supersaturated diazepam solutions that cross MDCKII monolayers 2–17.6‑fold faster than saturated diazepam, suggesting rapid nasal absorption. Human pharmacokinetic trials demonstrated that intramuscular avizafone yields a higher Cmax and faster Tmax for diazepam compared with direct diazepam injection, both alone and when co‑administered with atropine‑pralidoxime auto‑injectors. Rat intranasal experiments using avizafone plus human aminopeptidase B reported plasma and brain Tmax of about 8 minutes and brain levels sufficient for seizure control. Military literature notes its adoption by French and UK forces as a water‑soluble anticonvulsant option, while newer intramuscular midazolam formulations are being compared as alternatives.
Reported Benefits
Avizafone’s water solubility enables aqueous injectable formulations and potential intranasal sprays without irritating organic solvents. Human studies show faster absorption and higher peak concentrations of diazepam than direct injection, which could translate to quicker seizure termination. The prodrug can be packaged in auto‑injector devices and combined with other antidotes (atropine, pralidoxime) for streamlined battlefield or emergency use.
Limitations of the Evidence
Evidence is limited to pharmacokinetic and early animal studies; no large‑scale clinical trials have demonstrated actual seizure‑control efficacy or superiority over standard benzodiazepines. Intranasal delivery requires co‑administration of an enzyme, adding formulation complexity. Long‑term stability and shelf‑life data are still being refined, and the compound remains investigational without regulatory approval for any indication.
Safety Considerations
Safety data in the cited human trials are limited to pharmacokinetic endpoints, with no major adverse events reported. As a diazepam prodrug, avizafone inherits the typical benzodiazepine risks of sedation, respiratory depression, and dependence, especially at high doses or in vulnerable populations. The effect of concurrent atropine‑pralidoxime administration appears minimal on diazepam exposure, but comprehensive safety profiling is still needed.
How It Is Administered
Avizafone is formulated as an aqueous solution for intramuscular or intravenous injection, often within auto‑injector devices. Research formulations for intranasal use mix the prodrug with a proteolytic enzyme (e.g., Aspergillus oryzae protease or human aminopeptidase B) immediately before administration to generate a supersaturated diazepam solution for rapid mucosal absorption.
Routes of Administration
Goals & Uses
- Seizure control in organophosphate/nerve agent poisoningEmergency Medicine / Military MedicineModerate
- Anxiolysis / SedationAnesthesia / PsychiatryLow
- Status epilepticus managementNeurology / Emergency MedicineModerate
Contraindications
- Severe respiratory depressionRespiratoryHigh
- Severe hepatic impairmentOrganModerateLiver function concerns
- Hypersensitivity to benzodiazepines or avizafone componentsAllergyHigh
- Acute narrow-angle glaucomaOphthalmologyModerate
- Myasthenia gravisNeuromuscular DiseaseHigh
Adverse Effects
- Injection site reactionsLocalUncommon
- HypotensionCardiovascularUncommonLow blood pressure
- Anterograde amnesiaNeurologicalCommon
- Respiratory depressionRespiratoryUncommon
- Dependence / Withdrawal on prolonged usePsychiatricUncommon
- CNS depression / SedationNeurologicalCommon
Drug Interactions
- CYP3A4 inhibitors (e.g., ketoconazole, erythromycin)Moderate
- Other CNS depressants (barbiturates, antipsychotics, antihistamines)Moderate
- Alcohol (ethanol)High
- OpioidsHigh
Population Constraints
- PregnancyReproductive SafetyRelative
- Hepatic impairmentOrgan FunctionRelative
- Neonates and infantsPediatricRelative
- Elderly patientsAgeRelative
Regulatory Status
- European UnionInvestigationalHas been used in French military medicine; not formally approved by EMA for civilian indications.
- United StatesInvestigationalNot FDA-approved; investigated in preclinical and early clinical contexts for nerve agent antidote use.
- United KingdomInvestigationalInvestigated for military and emergency anticonvulsant use; not listed as a standard approved medicinal product by MHRA.
Avizafone is not broadly approved for civilian clinical use by major regulatory agencies such as the FDA or EMA. It has been used or investigated in military medical contexts, particularly in France and the UK, as an injectable anticonvulsant for nerve agent casualties. Regulatory status varies by jurisdiction.
Evidence & Sources
- Journal ArticleLowKapoor M, et al.2014-01-01T00:00:00.000000Z
- Journal ArticleModerateAbbara C, et al.2010-01-01T00:00:00.000000Z
- Journal ArticleModerateGorecki L, et al.2024-01-01T00:00:00.000000Z
- Journal ArticleModerateSiegel RA, et al.2025-01-01T00:00:00.000000Z
- Journal ArticleModerateAbbara C, et al.2009-01-01T00:00:00.000000Z
- Journal ArticleModerateStojiljković MP, Jokanović M2006-01-01T00:00:00.000000Z
Frequently Asked Questions
How does avizafone differ from giving diazepam directly?
Avizafone is a water‑soluble prodrug that must be enzymatically converted to diazepam. Human studies show it reaches the bloodstream faster and achieves a higher peak concentration than direct diazepam injection, potentially offering quicker seizure control.
Can avizafone be used as a nasal spray?
Preclinical work demonstrates that mixing avizafone with a protease creates a supersaturated diazepam solution that is rapidly absorbed across nasal tissue in rats. Human nasal use has not yet been clinically validated.
Is avizafone approved for medical use?
No. Avizafone remains an investigational compound. It is used experimentally in military auto‑injector kits and studied in early‑phase human and animal trials, but it has not received regulatory approval for any indication.
What are the main safety concerns?
Because it releases diazepam, avizafone shares benzodiazepine risks such as sedation, respiratory depression, and potential dependence. Current studies provide limited safety data, so comprehensive adverse‑event monitoring is required before wider use.
Why is an enzyme needed for avizafone administration?
The prodrug is inactive until proteolytically cleaved. Adding an enzyme (e.g., Aspergillus oryzae protease or human aminopeptidase B) at the point of delivery converts avizafone to diazepam, creating a supersaturated solution that can be absorbed quickly.
What is Avizafone?
Avizafone is a water‑soluble dipeptide prodrug of the benzodiazepine diazepam. It is being investigated for rapid seizure control in emergency settings such as status epilepticus or organophosphate poisoning. The compound is administered intramuscularly or intravenously, often together with an enzyme that converts it to active diazepam, and is also studied for intranasal delivery using a prodrug‑enzyme mixture.
What is Avizafone used for?
Avizafone is educationally associated with: Seizure control in organophosphate/nerve agent poisoning, Anxiolysis / Sedation, Status epilepticus management. Educational only — not medical advice.
How is Avizafone administered?
Recorded routes of administration: Intramuscular, Intravenous.
What are the potential side effects of Avizafone?
Reported adverse effects include: Injection site reactions, Hypotension, Anterograde amnesia, Respiratory depression, Dependence / Withdrawal on prolonged use, CNS depression / Sedation. This list is not exhaustive — consult a qualified clinician.
Who should avoid Avizafone?
Recorded contraindications: Severe respiratory depression, Severe hepatic impairment, Hypersensitivity to benzodiazepines or avizafone components, Acute narrow-angle glaucoma, Myasthenia gravis. Consult a qualified clinician before use.