RESUMO
Mengen is an acute symptom that sometimes occurs after administration of a Kampo formula. It is a shortterm phenomenon and its onset indicates that the patient's clinical course will improve rapidly. It is important to distinguish it from other adverse events, which are not temporary. However, to date, detailed analysis of mengen characteristics such as its frequency, time of onset after Kampo administration, and duration have not been reported. Therefore, we report a precise analysis of mengen characteristics through a literature review of case reports published between 1945 and 2009 in Japan, and retrospective analyses of the cases in our institute.<br>The literature review revealed that 42% patients developed symptoms of mengen within a day of administration, and 79% developed symptoms within 3 days. In terms of mengen duration, the symptoms persisted for 1 day in 35% cases and 3 days in 63% cases. A diagnosis of mengen proved difficult in 39% cases that presented with atypical symptoms.<br>Overall, the retrospective analysis of the cases in our institute revealed that 11 patients (7.7%) developed mengen, among 143 patients treated with Kampo between May 2010 and November 2011.
RESUMO
CYT387 is an orally bioavailable, small molecule inhibitor of Janus family of tyrosine kinases (JAK) 1 and 2. It is currently undergoing Phase I/II clinical trials for the treatment of myelofibrosis and myeloproliferative neoplasms. We aimed to establish whether the multidrug efflux transporters P-glycoprotein (P-gp; MDR1; ABCB1) and breast cancer resistance protein (BCRP;ABCG2) restrict oral availability and brain penetration of CYT387. In vitro, CYT387 was efficiently transported by both human MDR1 and BCRP, and very efficiently by mouse Bcrp1 and its transport could be inhibited by specific MDR1 inhibitor, zosuquidar and/or specific BCRP inhibitor, Ko143. CYT387 (10 mg/kg) was orally administered to wild-type (WT), Bcrp1(-/-), Mdr1a/1b(-/-) and Bcrp1;Mdr1a/1b(-/-) mice and plasma and brain concentrations were analyzed. Over 8h, systemic exposure of CYT387 was similar between all the strains, indicating that these transporters do not substantially limit oral availability of CYT387. Despite the similar systemic exposure, brain accumulation of CYT387 was increased 10.5- and 56-fold in the Bcrp1;Mdr1a/1b(-/-) mice compared to the WT strain at 2 and 8h after CYT387 administration, respectively. In single Bcrp1(-/-) mice, brain accumulation of CYT387 was more substantially increased than in Mdr1a/1b(-/-) mice, suggesting that CYT387 is a slightly better substrate of Bcrp1 than of Mdr1a at the blood-brain barrier. These results indicate a marked and additive role of Bcrp1 and Mdr1a/1b in restricting brain penetration of CYT387, potentially limiting efficacy of this compound against brain (micro) metastases positioned behind a functional blood-brain barrier.