The Inhibitory Effect of Kakkonto, Japanese Traditional (Kampo) Medicine, on Brain Penetration of Oseltamivir Carboxylate in Mice with Reduced Blood-Brain Barrier Function

Abstract

Oseltamivir phosphate (OP) is used to treat influenza virus infections. However, its use may result in central nervous system (CNS) adverse effects. In Japan, OP is used with Kampo formulations to improve clinical effectiveness. We evaluated the potential for using Kampo formulations to reduce CNS adverse effects by quantifying the CNS distribution of oseltamivir and its active metabolite oseltamivir carboxylate (OC) when administered with maoto and kakkonto. We administered lipopolysaccharide (LPS) by intraperitoneal injection to C57BL/6 mice to reduce blood-brain barrier function. Saline, maoto, and kakkonto were administered orally at the same time as LPS. OP was orally administered 4 hours after the last LPS injection and the migration of oseltamivir and OC was examined. Additionally, we examined the brain distribution of OC following intravenous administration. Changes in OC concentrations in the brain suggest that, in comparison to LPS-treated control mice, both Kampo formulations increased plasma levels of OC, thereby enhancing its therapeutic effect. Additionally, our findings suggest kakkonto may not only improve the therapeutic effect of oseltamivir but also reduce the risk of CNS-based adverse effects. Considering these findings, it should be noted that administration of kakkonto during periods of inflammation has led to increased OAT3 expression.

Effects of Traditional Kampo Drugs and Their Constituent Crude Drugs on Influenza Virus Replication In Vitro: Suppression of Viral Protein Synthesis by Glycyrrhizae Radix

“…It has also been reported that maoto inhibited influenza virus replication in the lungs of mice and exhibited antipyretic effects [13]. Although no direct inhibition of the growth of influenza viruses by kakkonto has been reported, toll-like receptor 4-dependent adjuvant activity of kakkonto [16] and the possibility of kakkonto inhibiting the onset of influenza encephalopathy by acting on the blood-brain barrier [17] have been reported. Jiinkokato and senkyuchachosan have not been reported to be associated with influenza viruses, and this is the first report about the effects of those Kampo drugs on influenza virus.…”

A Kanpó hagyományos orvoslás, ma is támogatott terápiás lehetőség Japánban.

“…Az utóbbi néhány évtizedben a természetes gyógymódokon belül a fitoterápia hatásosságának igazolására Japánban is arra törekszenek, hogy a növényi hatóanyagok és hatásmódok jobb megismerése érdekében komoly kísérletes, analitikai és molekuláris biológiai vizsgálatokban igazolják azok valódi értékét, és feltárják az esetleges mellékhatásokat vagy toxikus tulajdonságokat. Klinikai tanulmányokban igazolják a gyógynövények hasznosságát, létjogosultságát a szintetikus készítmények mellett [13,14]. A kutatások eredményei azonban csak nehezen jutnak el a felhasználókig, ezért célunk, hogy felhívjuk a figyelmet egyes készítmények esetében az óvatosságra.…”