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Pharmacokinetics of obidoxime in patients poisoned with organophosphorus compounds
H Thiermann1, F Eyer, N Felgenhauer
1Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstrasse 11, 80937 Munich, Germany. HorstThiermann@bundeswehr.org
Objectives:
Reactivation of inhibited acetylcholinesterase (AChE) with oximes is a causal therapy of intoxication with organophosphorus compounds (OPs). Maximal oxime effects are expected when effective doses are administered as soon as possible and as long as reactivation can be anticipated. An obidoxime plasma level in the range of 10-20 microM was estimated as appropriate. The achievement of this target was assessed in 34 severely OP-poisoned patients.
Methods:
After admission to the intensive care unit (ICU) the obidoxime regimen (250 mg i.v. as bolus, followed by 750 mg/24h) was started and maintained as long as reactivation was possible. Plasma concentrations of obidoxime were determined by HPLC.
Results:
A total amount of 2269+/-1726 mg obidoxime was infused over 65 h+/-55 h resulting in a steady state plasma concentration of 14.5+/-7.3 microM. Obidoxime was eliminated with t(1/2(1)) 2.2 and t(1/2(2)) 14 h. The volumes of distribution amounted to 0.32+/-0.1L/kg (V((1))) and 0.28+/-0.12 (V((2)))L/kg. Postmortem examination of tissue in one patient showed obidoxime accumulation in cartilage, kidney and liver and pointed to brain concentrations similar to plasma concentration.
Conclusions:
Using the suggested obidoxime regimen, the targeted plasma concentration could be achieved. Obidoxime was eliminated biphasically and was well tolerated. This result allows the recommendation of using this definite regimen for adults also in case of mass casualties.
Insights
This study shows that a specific obidoxime regimen effectively achieves therapeutic plasma levels for organophosphorus poisoning treatment. The treatment was well-tolerated and suitable for mass casualty events.
Area of Science:
- Pharmacology
- Toxicology
- Emergency Medicine
Background:
- Organophosphorus (OP) compounds inhibit acetylcholinesterase (AChE), leading to poisoning.
- Oximes are crucial for reactivating inhibited AChE, serving as a causal therapy for OP intoxication.
- Optimal oxime therapy requires prompt administration of effective doses to maximize reactivation potential.
Purpose of the Study:
- To assess the achievement of a target obidoxime plasma concentration (10-20 microM) in severely OP-poisoned patients.
- To evaluate the efficacy and tolerability of a specific obidoxime regimen in achieving therapeutic levels.
Main Methods:
- A cohort of 34 severely OP-poisoned patients received an obidoxime regimen (250 mg IV bolus, then 750 mg/24h) in the ICU.
- Plasma obidoxime concentrations were monitored using High-Performance Liquid Chromatography (HPLC).
- The regimen was maintained as long as AChE reactivation was possible.
Main Results:
- The regimen resulted in a mean steady-state plasma obidoxime concentration of 14.5+/-7.3 microM, within the target range.
- A total of 2269+/-1726 mg of obidoxime was infused over 65+/-55 hours.
- Obidoxime exhibited biphasic elimination (t1/2(1)=2.2h, t1/2(2)=14h) and accumulated in tissues like cartilage, kidney, and liver.
Conclusions:
- The proposed obidoxime regimen successfully achieved the targeted therapeutic plasma concentrations in OP-poisoned patients.
- Obidoxime demonstrated biphasic elimination and was well-tolerated, indicating a favorable safety profile.
- This regimen is recommended for adults, even in mass casualty scenarios involving OP poisoning.
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