Investigation of the Experimental Pharmacokinetics of the Bis-Chlorinated Bis-pyridinium Mono-aldoxime Cholinesterase Reactivator K-868 in Rats

Background: The widespread use of organophosphorus compounds in agriculture and their existence in some military arsenals present continuous threats. Quaternary bis-pyridinium aldoximes are potent, highly polar cholinesterase reactivators and the most intensively studied candidate antidotes against poisoning with organophosphorus compounds. Objective: The in vivo experimental pharmacokinetic properties of K-868, a novel bis-chlorinated, bis-pyridinium mono-aldoxime are detailed and put in context with regard to similar compounds described earlier. Methods: Rats received 30 µmol K-868 i.m. and were sacrificed at various time points following treatment. Blood, cerebrospinal fluid and tear were collected, while the brains, eyes, kidneys, livers, lungs and testes were removed, dissected and homogenized. K-868 concentrations were determined using high performance liquid chromatography with ultraviolet absorption detection. Results: K-868 was detected in the eyes, kidneys, lungs and tear within 5 minutes in maximal serum concentrations attained 15 minutes following administration. Elimination was slow for K-868 which remained detectable at 120 minutes in the blood and the kidneys, and at 60 minutes in the eyes, lungs and tear following its administration. Nevertheless, its distribution was overall poor with areas under the 120-minute concentration curves (AUC120) showing close similarity in the blood and the kidneys, while reaching just approximately 5% of serum AUC120 in the eyes and lungs. Conclusion: K-868 is a potent candidate antidote against organophosphate poisoining with a prolonged presence in the circulation.

Modulation of Tularemia Disease Progress by the Bisquaternary Pyridinium Oxime HI-6

Cholinesterase reactivator HI-6 is a drug commonly used to treat individuals exposed to nerve agents. Recent experiments proved HI-6 impact on parasympathetic response and impact on the nervus vagus associated cholinergic anti-inflammatory pathway is hypothesized here. The modulation effect of HI-6 was studied on BALB/c mice infected with Francisella tularensis, the bacteria causing tularemia. Cultivation test in vitro confirmed weak bacteriostatic effects of HI-6. Results in experiments revealed intriguing effect differences resulting from HI-6 administration to mice. While the HI-6 dose of 7 mg per animal (pro toto) had no significant effects on infection progress, lower dose of 8 μg of HI-6 pro toto reduced mice mortality caused by tularemia infection compared to control group of mice infected only with F. tularensis (survival curves were compared by the logrank test, chi square = 4.335, df = 1, P = 0.0373). The effect observed in mice exceeded the effect provided in vitro on bacterial cultures. Though the exact molecular mechanism of HI-6 modulation during infection should be investigated, HI-6 is seems to be suitable as immunomodulans.