Backgound/Aim. Flumazenil is benzodiazepine receptor antagonist. It has been
studied for a various indications, including reversal of sedation after
surgery or diagnostic procedures, awakening of comatose patients in
benzodiazepine overdose, or for symptomatic treatment of hepatic
encephalopathy. Some drugs, like theophylline, may prolong its elimination
half-life. Considering the long half-life of diazepam and its metabolites,
concomitant use of theophylline may reduce the need for repeated dosing of
flumazenil in patients with acute diazepam poisoning. The aim of this study
was to introduce a reliable and accurate method for determining the
concentration of flumazenil after therapeutic application in patients with
acute poisoning, and using that method to assess whether the kinetics of
flumazenil change in the presence of aminophylline (combination of
theophylline and ethylenediamine in a 2 : 1 ratio) applied as concomitant
therapy. Methods. Blood samples from patients with acute diazepam poisoning
that received flumazenil at the dose of 0.5 mg, or the same dose with 3 mg/kg
of body weight of aminophylline, were collected 1, 3, 10, 30, 60, 120 and 240
min after its intravenous administration. Samples were prepared by
solid-phase extraction on Oasis HLB cartridges with ethylacetate as
extracting agens. Flumazenil was determined by liquid chromatography with
mass spectrometry (LC-MS) in single ion monitoring mode at m/z 304.
Separation of flumazenil from matrix compound was performed on Lichrospher
RP-8 column using the mixture of acidic acetonitrile and 20 mM of ammonium
acetate in water (55 : 45) as a mobile phase. Results. The applied analitycal
method showed excellent recovery (94.65%). The obtained extracts were much
cleaner than the extracts obtained by the same extractant in the process of
liquid-liquid extraction. The limit of detection of the LC-MS method
described in this paper was 0.5 ng/mL and the limit of quantitation was 1
ng/mL. In the patients treated with both flumazenil and aminophylline, the
elimination constant for flumazenil was significantly lower and the
elimination half-life was longer (p < 0.05) in comparison with the same
parameters in the patients who received flumazenil alone. Conclusion. The
applied LC-MS method for the determination of flumazenil in serum samples of
patients with acute diazepam poisoning is rapid, sensitive, precise and
specific. Concomitant use with theophylline significantly prolonged
elimination of flumazenil during the treatment of acute poisonings with
diazepam.
Pharmacokinetics of Pantoprazole and Pantoprazole Sulfone in Goats After Intravenous Administration: A Preliminary Report