Efficacy and safety of a novel topical agent for gallstone dissolution: 2-methoxy-6-methylpyridine

Abstract

Background Although methyl-tertiary butyl ether (MTBE) is the only clinical topical agent for gallstone dissolution, its use is limited by its side effects mostly arising from a relatively low boiling point (55 °C). In this study, we developed the gallstone-dissolving compound containing an aromatic moiety, named 2-methoxy-6-methylpyridine (MMP) with higher boiling point (156 °C), and compared its effectiveness and toxicities with MTBE. Methods The dissolubility of MTBE and MMP in vitro was determined by placing human gallstones in glass containers with either solvent and, then, measuring their dry weights. Their dissolubility in vivo was determined by comparing the weights of solvent-treated gallstones and control (dimethyl sulfoxide)-treated gallstones, after directly injecting each solvent into the gallbladder in hamster models with cholesterol and pigmented gallstones. Results In the in vitro dissolution test, MMP demonstrated statistically higher dissolubility than did MTBE for cholesterol and pigmented gallstones (88.2% vs. 65.7%, 50.8% vs. 29.0%, respectively; P < 0.05). In the in vivo experiments, MMP exhibited 59.0% and 54.3% dissolubility for cholesterol and pigmented gallstones, respectively, which were significantly higher than those of MTBE (50.0% and 32.0%, respectively; P < 0.05). The immunohistochemical stains of gallbladder specimens obtained from the MMP-treated hamsters demonstrated that MMP did not significantly increase the expression of cleaved caspase 9 or significantly decrease the expression of proliferation cell nuclear antigen. Conclusions This study demonstrated that MMP has better potential than does MTBE in dissolving gallstones, especially pigmented gallstones, while resulting in lesser toxicities. Electronic supplementary material The online version of this article (10.1186/s12967-019-1943-y) contains supplementary material, which is available to authorized users.

Bisphenol A enhances apoptosis, fibrosis, and biochemical fluctuations in the liver of adult male rats with possible regression after recovery

“…Alkaline phosphatase (ALP) activity was estimated in serum according to Burtis et al (2012). Additionally, serum total protein and albumin were measured according to Ruot et al's (2000) method, and total bilirubin was measured following Choi et al's (2019) protocol. The total serum levels of cholesterol and triglycerides were assessed using standard enzymatic methods.…”

Gallbladder Drainage: IR and GI Perspective

“…31 However, recent work to find safer alternatives have been reported. 32,33 Photothermal stone destruction including the use of laser fibers to turn gallstones to dust are another option, so that resulting stone fragments are smaller and less basketing is required to clear stone fragments. While this has been common for years in GI and urologic endoscopy, 22,34 there is reported use in IR trails given the higher capital and technical requirements compared to EHL, and the only recent democratization of disposable endoscopes for widespread use in IR.…”

In-vitro Dissolution Study of Gallstone with Medicinal Plant Extracts

“…The plant extracts were changed every day to minimize any effect due to saturation of the solution by dissolved components of the stone [23]. The stones were taken out of the extract by filtration through filter paper (Whatman No1), washed with distilled water, transferred into a pre-weighed crucible, dried at 60 °C in an incubator for two days to get constant weight, and the weight reduced was noted [11,24]. To determine the gallstone dissolution capacity of each extract and solvent, we recorded the dry weight of the stone samples at three different time points (4, 94, and 190 h) after they were directly immersed in the solution.…”

“…First of all, the weight dissolved by negative control at every time point was subtracted from the weight reduction value recorded for each of the preparations at respective time points to calculate the actual weight dissolved by the preparations. Then the percentage dissolution was calculated by using the following formula [11,24]:…”

“…The treatment of gallstone disease can be done through surgery or non-surgical methods. Nonsurgical methods include taking bile acids like chenodeoxycholic acid (CDCA) and ursodeoxycholic acid (UDCA) orally (oral dissolution therapy) [9] or installing litholytic solvent like methyl tert-butyl ether (MTBE) [10], 2-methoxy-6-methylpyridine (MMP) [11], or ethylenediaminetetraacetic acid (EDTA) [12], directly into the gallbladder through a percutaneous transhepatic catheter (contact dissolution therapy) [13]. However, these methods have limitations due to side effects, toxicity, low efficiency [14], incomplete dissolution [15], and gallstone reoccurrence is common [16].…”