MET inhibitor tepotinib antagonizes multidrug resistance mediated by ABCG2 transporter: In vitro and in vivo study

Overexpression of ABCG2 transporter in cancer cells has been linked to the development of multidrug resistance (MDR), an obstacle to cancer therapy. Our recent study uncovered that the MET inhibitor, tepotinib, is a potent reversal agent for ABCB1-mediated MDR. In the present study, we reported for the first time that the MET inhibitor tepotinib can also reverse ABCG2-mediated MDR in vitro and in vivo by directly binding to the drug-binding site of ABCG2 and reversibly inhibiting ABCG2 drug efflux activity, therefore enhancing the cytotoxicity of substrate drugs in drug-resistant cancer cells. Furthermore, the ABCB1/ABCG2 double-transfected cell model and ABCG2 gene knockout cell model demonstrated that tepotinib specifically inhibits the two MDR transporters. In mice bearing drug-resistant tumors, tepotinib increased the intratumoral accumulation of ABCG2 substrate drug topotecan and enhanced its antitumor effect. Therefore, our study provides a new potential of repositioning tepotinib as an ABCG2 inhibitor and combining tepotinib with substrate drugs to antagonize ABCG2-mediated MDR.

Experiencia con idarucizumab como agente reversor de dabigatran / Experience with idarucizumab as a reverse agent of dabigatran

Resumen Los anticoagulantes orales directos (AOD), entre ellos dabigatrán, poseen un perfil riesgo-beneficio favorable comparados con warfarina y además no requieren monitoreo del efecto anticoagulante. Sin embargo, en ocasiones de sangrado con amenaza de vida o requerimiento de procedimiento quirúrgico de emergencia, es de gran utilidad revertir inmediatamente el efecto anticoagulante. Idarucizumab, fragmento de un anticuerpo monoclonal humanizado, revierte inmediatamente el efecto de dabigatrán y es actualmente el único agente reversor de un AOD disponible en Argentina. Presentamos una serie de 8 pacientes a los que se les administró idarucizumab para revertir el efecto de dabigatrán. Todos eran mayores de 65 años, recibían 110 o 150 mg cada 12 horas de dabigatrán y 7/8 estaban anticoagulados por fibrilación auricular; tres tenían indicación discutida para AOD y otro, una dosis mayor a la recomendada. Dos requirieron reversión debido a una cirugía de urgencia, y 6 tuvieron sangrado con amenaza de vida: tres hemorragias digestivas y tres sangrados intra-craneanos (en dos ocasiones traumático). En todos los casos se observó normalización de la hemostasia quirúrgica o control de sangrado crítico. No se observaron complicaciones trombóticas posteriores a la administración del antídoto. Dos fallecieron dentro de los 30 días de la administración por causas no relacionadas con la reversión. Ninguno de nuestros pacientes requirió administración de una segunda dosis de idarucizumab. Nuestro resultado es similar a lo informado en la literatura internacional.

Abstract Direct oral anticoagulants (DOACs), among them dabigatran, have a favorable benefit-risk profile compared with warfarin, and no monitoring of the anticoagulant effect is required. However, reversing the anticoagulant effect immediately is very useful in cases of life-threatening bleeding and emergency surgical procedure requirement. Idarucizumab, a humanized monoclonal antibody fragment, is currently the only reversal agent of a DOAC available in Argentina. Idarucizumab immediately reverse the effect of dabigatran. We present a series of 8 real-life clinical cases who received idarucizumab to reverse the effect of dabigatran. All of the patients were older than 65 years, were receiving 110 or 150 mg every 12 hours of dabigatran and 7/8 were anticoagulated because of atrial fibrillation. Three had a debatable indication for DOACs and another, a higher dose than recommended. Two required reversal due to emergency surgery, and 6 cases had life-threatening bleeding: three gastrointestinal hemorrhages and three intracranial bleeding (Two had a head trauma). In all cases normalization of surgical hemostasis or control of critical bleeding was observed. No hemorrhagic or thrombotic complications were observed after antidote administration. Two died within 30 days of administration of idarucizumab, due to causes unrelated to the reversal. None of our patients required administration of a second dose of idarucizumab. Our result is similar to that reported in international literature.

Rocuronium and sugammadex in a 3 days old neonate for draining an ovarian cyst. Neuromuscular management and review of the literature / Rocurônio e sugamadex em recém-nascido de 3 dias para drenagem de um cisto ovariano. Controle neuromuscular e revisão da literatura

Abstract A case is reported in which a 3-days old neonate with a giant ovarian cyst was scheduled for surgery. The patient received a dose of sugammadex to reverse a rocuronium-induced neuromuscular block. A fast and efficient recovery from neuromuscular block was achieved within 90 s. No adverse events or other safety concerns were observed. Furthermore, a review of the literature on the use of sugammadex in neonates was performed.

Resumo Relato do caso de uma criança recém-nascida de três dias de idade com um cisto ovariano gigante programada para a cirurgia. A paciente recebeu uma dose de sugamadex para reverter o bloqueio neuromuscular induzido por rocurônio. Uma recuperação rápida e eficiente do bloqueio neuromuscular foi obtida dentro de 90 segundos. Não foram observados efeitos adversos ou outros problemas de segurança. Além disso, uma revisão da literatura sobre o uso de sugamadex em recém-nascidos foi feita.

Reversal effect of vatalanib on BCRP-mediated multidrug resistance / 中国药理学通报

Aim To investigate the reversal effect of vatalanib, a novel kinase inhibitor, on multidrug re-sistance in cancer cells and its mechanism. Methods The cytotoxicity and reversal effects of vatalanib were evaluated in both resistant and sensitive tumor cell lines by MTS or SRB assays. The intracellular accumu-lation of fluorescence substrates ( Rh-123 , MX and ADR for P-gp, BCRP, MRP1, respectively) were ana-lysed by flow cytometry. Western blot or qRT-PCR was used to determine the protein or mRNA expression lev-el of BCRP. The effect of vatalanib on ATPase activity of BCRP was determined using crude membranes pre-pared from HEK293/ABCG2 cells. Results Vata-lanib at the nontoxic dose ( 5 μmol · L-1 ) potentially reversed BCRP-mediated MDR in cancer cells, howev-er it had no effect on P-gp or MRP1 mediated MDR. Vatalanib did not alter the intracellular accumulation of MX in HEK 2 9 3 / ABCG 2 , and had no influence on the BCRP-mediated drug efflux. The ATPase assay indica-ted that vatalanib may serve as a substrate of BCRP. Furthermore, vatalanib dramatically suppressed levels of both the protein and mRNA expression of BCRP in concentration-and time-dependent manners. However, reversal concentration of vatalanib had no influence on the total and phosphorylated forms of AKT and ERK1/ 2 in resistant cancer cells. Conclusion Vatalanib could significantly reverse BCRP-mediated MDR with specificity, and its mechanism may correlate with the down-regulation levels of BCRP both mRNA and pro-tein in resistant cancer cells.

Neuromuscular Block and Reversal

The Griffith and Johnson's report of the successful use of curare in 1942 brought a revolution in anesthetic care. The only depolarizing agent still in use is succinylcholine due to its rapid onset of action and rapid recovery. However, its use is limited by serious side effects (hyperkalemia, malignant hyperthermia, arrhythmia, etc). New non-depolarizing neuromuscular blocking agents have been studied to replace succinylcholine, which are still at a preclinical level. Rocuronium is an aminosteroid compound and has an intermediate duration of action, but the onset is shorter. A new method of reversing neuromuscular blockade has been advocated by the introduction of a cyclodextrin, sugammadex (Org 25969), which is still at the investigational stage in humans. It has a high affinity for rocuronium, with which it forms a complex. Sugammadex has a lower affinity for other steroidal neuromuscular blocking agents such as vecuronium and pancuronium, and does not bind benzylisoquinoline-type neuromuscular blocking agents. The ability to produce a rapid return of twitch height even at deep levels of paralysis and the lack of side effects make this compound a promising new agent for anesthesia.

Reversal of multidrug resistance in human liver cancer cells BEL-7402 by erythromycin / 中国药理学通报

AIM To study the reversal effect of erythromycin on multidrug resistance of human liver cancer cells BEL 7402. METHODS Cultivated the parental cells BEL 7402 in the presence of doxorubicin to obtain a multidrug resistant subline designated BEL 7402/ADM. The expression of P glycopro tein in BEL 7402 and BEL 7402/ADM cells was determined by using cell ELASA method. The cytotoxicity of drugs was determined by using MTT assay, and the intracellular concentration of doxorubicin in BEL 7402/ADM was determined using a spectrofluorometer. RESULTS After growing BEL 7402 cells in the presence of ADM for some time, the resulting cells (BEL 7402/ADM) became not only resistant to ADM but cross resistant to VCR and MMC, the P gp on the subline cells' surface was highly expresssed. Erythromycin, which is a lipophilic antibiotic, enhanced the anti tumor functions of ADM, VCR and MMC to BEL 7402/ADM cells and increased the intracellular concentration of ADM with no effect on the expression of the P gp in BEL 7402/ADM cells. CONCLUSUON Erythromycin can significantly reverse the multidrug resistance in BEL 7402/ADM cells, it may do so by saturating the P gp pathway to reduce the efflux of intracellular concentration of the drugs.