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©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
Superior gallstone dissolubility and safety of tert-amyl ethyl ether over methyl-tertiary butyl ether
Dong Do You, Suk Joon Cho, Ok-Hee Kim, Jin Sook Song, Kyu-Seok Hwang, Sang Chul Lee, Kee-Hwan Kim, Ho Joong Choi, Ha-Eun Hong, Haeyeon Seo, Tae Ho Hong, Jung Hyun Park, Tae Yoon Lee, Joseph Ahn, Jae-Kyung Jung, Kwan-Young Jung, Say-June Kim
Dong Do You, Department of Surgery, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul 16247, South Korea
Suk Joon Cho, Jae-Kyung Jung, College of Pharmacy, Chungbuk National University, Cheongju 28644, South Korea
Ok-Hee Kim, Ho Joong Choi, Tae Ho Hong, Tae Yoon Lee, Joseph Ahn, Say-June Kim, Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul 06591, South Korea
Ok-Hee Kim, Ha-Eun Hong, Haeyeon Seo, Say-June Kim, Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, the Catholic University of Korea, Seoul 06591, South Korea
Jin Sook Song, Kyu-Seok Hwang, Kwan-Young Jung, Bio and Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea
Sang Chul Lee, Department of Surgery, Daejeon St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul 34943, South Korea
Kee-Hwan Kim, Department of Surgery, Uijeongbu St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul 11765, South Korea
Ha-Eun Hong, Haeyeon Seo, Department of Biomedicine and Health Science, College of Medicine, the Catholic University of Korea, Seoul 06591, South Korea
Jung Hyun Park, Department of Surgery, Eunpyeong St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul 03312, South Korea
Kwan-Young Jung, Department of Medicinal Chemistry and Pharmacology, University of Science and Technology, Daejeon 34113, South Korea
Author contributions: Kim SJ was responsible for obtaining funds, planning the study, data interpretation and manuscript preparation; You DD and Kim SJ drafted the paper and participated in the animal experiments; Cho SJ and Jung KY developed contact litholytic agents (TAEE), and performed chemical experiments, such as thermogravimetric analysis; Song JS, Hwang KS, and Jung JK took responsibility of various in vitro and in vivo toxicity tests, including the measurement of zebrafish locomotor activity; Kim OH, Hong HE, and Seo HY principally involved in the in vitro experiments; Lee SC, Kim KH, Choi HJ, Hong TH, Park JH, Lee TY, and Ahn J were contributed to acquisition of human gallstones and participated in various in vivo experiments; all authors read and approved the manuscript.
Institutional review board statement: The study was approved by the Ethics Committee of Seoul St Mary’s hospital, the Catholic University of Korea (IRB code: KC18TESI0103).
Institutional animal care and use committee statement: This animal study was approved by the Institutional Animal Care and Use Committee of the Clinical Research Institute at Daejeon St. Mary’s Hospital at the Catholic University of Korea (IRB No. CMCDJ-AP-2016-004).
Conflict-of-interest statement: All the Authors have no conflict of interest related to the manuscript; Authors got grant from Catholic Medical Center Research Foundation.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Say-June Kim, MD, PhD, Professor, Surgeon, Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, South Korea. sayjunekim@gmail.com
Telephone: +82-10-87737616 Fax: +82-2-5350070
Received: July 2, 2019
Peer-review started: July 2, 2019
First decision: August 2, 2019
Revised: August 19, 2019
Accepted: September 11, 2019
Article in press: September 11, 2019
Published online: October 21, 2019
ARTICLE HIGHLIGHTS
Research background
Methyl tert-butyl ether (MTBE) has been the first choice of contact litholytic angents ever since its introduction in 1985. However, the use of MTBE to dissolve gallstones was limited by concerns about toxicity and widespread awareness of the safety of laparoscopic gallbladder surgery. MTBE has a relatively low boiling point (55 °C) and a higher evaporation rate, which could lead to the development of various side effects, including nausea, upper abdominal pain, duodenitis, mild-to-moderate anesthesia, and hemolysis
Research motivation
As westernized diets increase, cholelithiasis is increasing. 20%-30% of patients with asymptomatic gallstones eventually progress to symptomatic gallstones requiring aggressive treatment. Although laparoscopic cholecystectomy is a safe and efficient treatment for symptomatic gallstones, the removal of the entire functioning gallbladder has an exaggerated aspect. These considerations have led us to perform this experiment.
Research objectives
We performed this experiment to determine whether tert-amyl ethyl ether (TAEE), an MTBE analogue with a relatively higher boiling point (102 °C), could be used as an alternative to MTBE in terms of gallstone dissolubility and toxicity.
Research methods
To determine the dissolubility of TAEE, we compared the dissolubility of TAEE and MTBE in both in vitro and in vivo dissolubility tests, using human gallstones and hamster models with gallstones, respectively. Specifically, the in vitro dissolubility of each solvent was determined by measuring the dry weights of human gallstones at predetermined time intervals after placing them in glass containers with either of the two solvents. The in vivo dissolubility was determined by comparing the weights of solvent-treated gallstones and control (dimethyl sulfoxide)-treated gallstones, after the direct infusion of each solvent into the gallbladder of the hamsters with gallstones.
Research results
In both in vitro and in vivo models of gallstones, the TAEE consistently displayed better gallstone dissolubility than the MTBE. Specifically, in the in vitro experiments, TAEE showed a 1.2-, 1.4- and 1.3-fold higher dissolubility potentials for cholesterol, mixed, and pigmented gallstones, respectively, those of MTBE. In the in vivo tests, TAEE exhibited the 1.4 times and 1.9 times higher dissolubility potentials for cholesterol and pigment gallstones, respectively, than those of MTBE. In addition, TAEE had toxicities similar to or lesser than those of MTBE.
Research conclusions
Our results showed that TAEE has the higher gallstone-dissolubility and safety compared with that of MTBE. It should be noted that MTBE showed significantly higher dissolubility for pigmented gallstones because there is no efficient dissolving agents for pigmented gallstones so far. We assume that the low toxicities of TAEE could be considerably attributed to its lower evaporation causing from a relatively higher boiling point (102 °C) than that of MTBE. If consistent efficacy and safety parameters can be reproduced in the further studies, incorporating large animals and human patients, TAEE is expected to present an attractive alternative to MTBE.
Research perspectives
Currently, MTBE has been used for the purpose of dissolving gallstones worldwide, and its main indication is the patients who refuse surgery or are at high risk for surgery. However, if more effective and safe gallstone-dissolving agents are developed in the future, future therapeutic indications are expected to include the patients with asymptomatic gallstones, for a substantial proportion of them progress to have symptomatic gallstones.
