monooctanoin and methyl-tert-butyl-ether

Common duct calculi retained after gallbladder surgery continue to present a clinical challenge especially in the era of minimally invasive surgery. This review examines the strategy of dissolution therapy used throughout the history of biliary tract surgery and its use to the modern surgeon.. Original journal articles and reviews were identified using standard surgical textbooks and MEDLINE. Keywords for searching included choledocholithiasis, dissolution, mono-octanoin, common duct stones, MTBE, cholic acid, and gallstones.. Dissolution therapy used initially as an alternative to open surgery is now used more effectively as an adjunct to laparoscopic or endoscopic biliary tract surgery. The current review demonstrates a majority of patients with retained choledocholithiasis respond to dissolution and can be safely managed without choledochotomy.

Topics: Administration, Topical; Anesthetics, Local; Bile Acids and Salts; Calcium; Caprylates; Chelating Agents; Chloroform; Cholecystectomy, Laparoscopic; Expectorants; Gallstones; Glycerides; Heparin; Humans; Methyl Ethers; Sodium Chloride; Solubility; Solvents; Therapeutic Irrigation

Common bile duct stones are a common cause of morbidity and mortality in adults. An increasing number of surgical and medical therapies are available to manage them, with different success rates reported. The various medical treatment strategies were developed during the last decade, but these medical modalities should not be contemplated as a first-line alternative of treatment. A consensus from experts is that there is no primary indication to use solvents on common bile duct stones because they have a relatively high rate of adverse effects and their success is limited compared with lithotripsy. However, there is a subgroup of patients in whom invasive or surgical treatment is risky or may fail. In these patients stone dissolution by solvent may constitute a plausible therapeutic alternative or may help reduce the size of the stones sufficiently to facilitate subsequent endoscopic extraction. Solvents may also be indicated in settings where endoscopic techniques or lithotripsy are not available and the patient has a T-tube in the common bile duct. Even in this condition, however, it is probably quicker and more effective to refer the patient to a center with expertise and technologic support to practice stone removal.

Topics: Caprylates; Gallstones; Gastrointestinal Agents; Glycerides; Humans; Methyl Ethers; Solvents; Ursodeoxycholic Acid

Gallstones represent a major health problem in western society. For symptomatic gallstones, cholecystectomy is the gold standard. A considerable number of patients, however, cannot tolerate or are unwilling to undergo surgery and anaesthesia. For these patients, dissolution therapy, administered either systemically ('oral dissolution') or directly into the gallbladder ('contact dissolution'), might be preferable. In this review, the possibilities and limitations of dissolution therapy are discussed. It is concluded that dissolution is a good alternative in selected symptomatic patients and that it is useful as adjuvant therapy after lithotripsy (ESWL) of gall-bladder stones.

Topics: Caprylates; Chenodeoxycholic Acid; Cholelithiasis; Cyclohexenes; Edetic Acid; Ethers; Glycerides; Humans; Limonene; Methyl Ethers; Solvents; Terpenes; Ursodeoxycholic Acid

Endoscopic sphincterotomy and percutaneous approaches to the biliary tract have revolutionized the treatment of bile duct stones. Both the endoscopic and transhepatic approaches are less invasive than open surgery. This is an advantage for the mostly elderly and frail patients with common bile duct stones. Other patients with intrahepatic stones, e.g. young patients with oriental lithiasis, may also profit from the non-surgical approach. In this latter group it is often difficult for the surgeon to obtain access to the stone-bearing bile ducts. Due to the anatomical situation, size or impaction of stones the non-surgical approach, including mechanical disintegration, may primarily fail. Several techniques such as intracorporeal lithotripsy using electrohydraulic probes or laser light, extracorporeal shockwave lithotripsy or direct contact dissolution are now available and often allow complete clearance of the bile ducts. If a kidney lithotripter with radiographic devices is available, it should be used after an attempt at mechanical lithotripsy has failed (Figure 1). According to the literature, experience with this method is greater than with any other 'third-step approach'. The procedure is simple, relatively safe and successful in approximately 80% of patients. However, in at least one third of patients, several sessions have to be performed and further endoscopy is frequently required for extraction of fragments. Intracorporeal techniques may become the procedure of choice in the future, at least in patients with common bile duct stones. At the moment, however, the different devices are still not fully developed and too susceptible to damage. A further major drawback, especially with high-energy electrohydraulic intracorporeal lithotripsy, is the danger of bile duct injury or even perforation, so that most procedures must be performed under optical control. The use of contact dissolution cannot generally be recommended. Treatment with mono-octanoin or modified mono-octanoin solvents takes too long, is often not successful and has a high rate of side-effects. MTBE may shorten the procedure considerably, but is suitable only for cholesterol stones, and the danger of spill-over into the intestine with absorption and systemic side-effects has to be weighed against the probability of success.

Topics: Bile Acids and Salts; Bile Duct Diseases; Caprylates; Cholelithiasis; Cyclohexenes; Ethers; Glycerides; Humans; Laser Therapy; Limonene; Lithotripsy; Lithotripsy, Laser; Methyl Ethers; Solvents; Stents; Terpenes

It can be anticipated that most new therapies will generate considerable excitement and optimism when introduced. This is usually tempered with time as additional clinical experience is gained and therapeutic limitations and adverse effects are realized. All areas in the nonsurgical management of gallstones have experienced this course--some, such as ESWL, rather meteorically. Perspective, however, is important and may allow the appropriate use of each of these modalities in the correct clinical setting. For example, ursodiol when given in sufficient dose to nonobese patients with small radiolucent stones, could be expected to effect partial or complete dissolution in as many as 75% of patients, with minimal or no adverse effects and in a cost-effective manner. Contact dissolution using MTBE has been shown to be safe and generally effective but requires diligent characterization of stones to avoid those that are pigmented or heavily calcified. Similarly, ESWL combined with oral bile acids may be consistently effective if treatment is restricted to patients with acceptable cholesterol stone burdens and if treatment can be safely continued until fragments are substantially reduced. Continued experience with each of these treatment options, along with advances in research providing new solvents and technologies or in preventing recurrence, is likely to establish this field in an appropriately optimistic light.

Topics: Bile Acids and Salts; Caprylates; Cholelithiasis; Ethers; Glycerides; Humans; Methyl Ethers; Recurrence; Solvents

Contact dissolution of cholesterol gallstones with organic solvents is emerging as a rapid, safe, alternative treatment for symptomatic cholesterol gallbladder stones. Placement of a percutaneous transhepatic catheter into the gallbladder is a rapid and safe technique. The availability of safe, effective cholesterol solvents and solvent transfer devices means that cholesterol gallbladder stones can be eliminated rapidly and safely by CDOS, without the risk of general anesthesia or surgical dissection of the gallbladder bed. Patients with single gallstones are better candidates for CDOS than are patients with multiple gallstones because recurrence after dissolution is less common. Contact dissolution may well be judged the treatment of choice by the medical-surgical gallstone management team in some patients.

Topics: Caprylates; Cholelithiasis; Cholesterol; Ethers; Glycerides; Humans; Methyl Ethers; Solvents; Viscosity

Topics: Bile Acids and Salts; Caprylates; Cholelithiasis; Cholesterol; Ethers; Glycerides; Humans; Lithotripsy; Methyl Ethers; Ultrasonic Therapy

Topics: Bile Duct Diseases; Caprylates; Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Ethers; Glycerides; Humans; Lithotripsy; Methyl Ethers; Solvents; Ursodeoxycholic Acid

Topics: Animals; Caprylates; Chenodeoxycholic Acid; Cholecystectomy; Cholelithiasis; Cystic Duct; Electrocoagulation; Ethers; Glycerides; Humans; Lithotripsy; Methyl Ethers; Radio Waves; Solvents; Ultrasonic Therapy

Topics: Bile Acids and Salts; Bile Duct Diseases; Caprylates; Cholelithiasis; Cholesterol; Cyclohexenes; Edetic Acid; Ethers; Glycerides; Humans; Limonene; Methyl Ethers; Pigments, Biological; Recurrence; Solubility; Terpenes

Findings by several groups of investigators have provided a reliable data base that supports a nonoperative approach toward the management of so-called silent gallstones. Considerable progress has been made in the medical dissolution treatment of selected patients with cholesterol gallstones. Ursodeoxycholic acid, and, more recently, a combination of ursodeoxycholic and chenodeoxycholic acids have been shown to be both effective and safe in dissolving gallstones that are predominantly composed of cholesterol. A drawback of the bile acid dissolution therapy lies in a significant recurrence rate after treatment is discontinued. Currently, several new methods of gallstone treatment are under study, which involve either the injection of a cholelitholytic solution, such as methyl tert-butyl ether, into the gallbladder or the use of mechanical means, such as excorporeally induced shock waves, to disintegrate gallstones. These treatments, however, are effective only if the stones are composed mainly of cholesterol without significant admixtures of calcium salts, pigment, or mucus. Most of the treatment failures are probably related to the presence of calcifications that are not visible on conventional radiographs. Future improvements of gallstone dissolution therapy can be expected from the following possible developments: improvement in ability to predict gallstone composition; dissolution of calcium salt-, pigment-, and mucus-containing stones; early treatment, before calcifications occur; combination of chemical and mechanical methods of treatment; stimulation of gallbladder contraction; prevention of stone recurrence after dissolution; and synthesis of new cholelitholytic agents.

Topics: Bile Acids and Salts; Caprylates; Cholelithiasis; Ethers; Glycerides; Humans; Lithotripsy; Methyl Ethers

This in vitro study compared the gallstone dissolution rates of mono-octanoin, mono-octanoin plus 10% distilled water, and mono-octanoin plus methyl tert-butyl ether 2:1. Sixteen stones were treated with each solvent at a slow perfusion rate of 3-4 ml/h and a rapid perfusion rate of 2.5 ml/30 min with 20-sec instillation/aspiration cycles, both with and without bile. The stones were weighed before, and 3, 6, 12 and 24 hrs after the start of treatment: the solvent was changed every 30 min. After 24 hrs of instillation/aspiration without bile, the mono-octanoin/methyl tert-butyl ether mixture reduced the weight of the stones by 93%, mono-octanoin plus water by 63%, and mono-octanoin alone by 52%; with bile, the figures were, respectively, 86%, 42% and 40%. The mono-octanoin/methyl tert-butyl ether mixture thus took approximately half the time needed by the other two preparations to dissolve the stones to the same extent, a finding which may be relevant for the clinical dissolution of bile duct stones.

Topics: Caprylates; Cholelithiasis; Drug Combinations; Glycerides; Humans; In Vitro Techniques; Methyl Ethers; Solvents; Time Factors

The dissolution rates and solubilities of cholesterol monohydrate, palmitic acid, and their mixtures in the cholelitholytic solvents monooctanoin (MO) and methyl tert-butyl ether (MTBE) and mixtures of these two solvents were determined. The dissolution rates obtained were consistent with the diffusion-controlled two-component noninteracting model. The addition of MTBE as cosolvent to MO resulted in an increase in the solubility of both cholesterol monohydrate and palmitic acid; in the case of the former, the solubility peaked at 80% MTBE. Neither solute exhibited a log-linear solubility relationship on addition of MTBE as cosolvent. Furthermore the increases in the dissolution rates of both components were much larger than could be explained by the solubility increases alone. Mass transfer coefficients increased dramatically with increasing MTBE content of the solvent, were consistently higher for palmitic acid, and reflected the decline in solvent viscosity. Incorporation of relationships among solubility, viscosity, and cosolvent composition into the two-component noninteracting model gave good correlation between predicted and observed rates over nearly 3 orders of magnitude.

Topics: Caprylates; Cholelithiasis; Cholesterol; Chromatography, Gas; Diffusion; Ethers; Glycerides; Kinetics; Methyl Ethers; Models, Biological; Palmitic Acids; Solubility; Solvents; Viscosity

During contact dissolution of gallstones, solvents may escape from the gallbladder and damage the intestinal mucosa. In order to compare the extent of this potential injury, we developed a method to objectively quantify the effects of two commonly used cholesterol solvents, methyl tert-butyl ether and mono-octanoin, on mucosal transport function in the rat intestine. Two intestinal segments in each of 184 anesthetized rats were cannulated. Three milliliters of either solvent were instilled in one segment and left for varying periods of time, while saline was instilled in the other as control. The segments were then washed and perfused for 45 min with an isotonic solution containing [3H]polyethylene glycol 4000 (a nonabsorbable reference marker) and either [14C]alpha-aminoisobutyric acid (a marker for active absorption) or [14C]mannitol (a marker for passive permeability). Methyl tert-butyl ether caused more inhibition of alpha-aminoisobutyric acid absorption (64%) than mono-octanoin (48%) and a greater reduction of dry weight per centimeter of the perfused segment (22%) compared with mono-octanoin (10%). Such effects appeared after only 1 min of solvent exposure and did not appreciably increase with longer exposures. Permeation of mannitol increased by 26% after 1 min of exposure to mono-octanoin and by 54% after a similar period of exposure to methyl tert-butyl ether. Longer exposures to both solvents did not seem to cause progressive increases in mannitol permeation. The results indicate that brief exposure of the rat jejunum to either of the two solvents causes a reduction in active transport ([14C]alpha-aminoisobutyric acid absorption), an increase in passive permeability (mannitol permeation), and a loss of mucosal constituents. We conclude that the intestinal mucosa is susceptible to solvent damage and may be used as a selectively sensitive model that can characterize the biological injury of gallstone solvents. The study also suggests that escape of the currently available solvents into the small intestine in patients undergoing contact dissolution of gallbladder stones may cause injury to the small intestine.

Topics: Animals; Biological Transport; Caprylates; Cholelithiasis; Ethers; Glycerides; Intestinal Absorption; Intestinal Mucosa; Male; Methyl Ethers; Rats; Rats, Sprague-Dawley; Solvents

A new litholytic mixture of mono-octanoin (MO) and methyl tert-butyl ether (MTBE) in a ratio of 2:1 (v/v) was employed in 42 patients with bile duct stones, 29 of them failures after papillotomy. Twenty-two of these patients had complicated stones. The new solvent mixture was given for 4-6 h/day and 2-3 ml were instilled every 30 min. Gentle aspiration and instillation were alternated so as to "stir" the preparation around the stones. Perfusion was given for up to six days. The mixture contributed to success in 37 cases (88%), 19 of them with complicated stones. Total dissolution was attained in 18 cases, and in the other 19 cases clearance was achieved after partial lysis followed by easy crushing with a basket. The mean volume of solvent perfused (+/- SD) was 84.9 +/- 39 ml (range 25-150), the mean duration of treatment was 16.5 +/- 7.4 h (range 5-30). Hospital stay averaged 4.6 +/- 1.6 days (range 2-7). There were five failures: in one patient eight large concretions were eliminated only after extracorporeal shock wave lithotripsy (ESWL). Two were re-operated and pigment stones were found. The last two refused alternative treatments. Side effects were minimal and easily managed by withdrawal of a few ml of bile. Treatment with the new solvent may be indicated as first-instance therapy in place of ESWL, laser endoscopy, electrohydraulic or mechanical lithotripsy for patients with complicated biliary stones, or in cases in which endoscopic papillotomy has failed.

Topics: Adult; Aged; Aged, 80 and over; Bile Duct Diseases; Caprylates; Cholelithiasis; Drug Combinations; Ethers; Female; Follow-Up Studies; Glycerides; Humans; Male; Methyl Ethers; Middle Aged; Solvents

Extracorporeal shockwave lithotripsy (ESWL) of gall bladder stones leaves residual fragments that need to be dissolved by chemical solvents. In this study we compared the in vitro dissolving capacity of methyl tert-butyl ether (MTBE), mono-octanoin, limonene, and limonene/mono-octanoin (70%/30%). From nine sets of five human gall stones obtained at cholecystectomy, four stones were used for dissolution and the fifth was used for chemical analysis of cholesterol, calcium, and bilirubin contents. Eight sets were cholesterol stones with a mean (SD) cholesterol content of 89.9 (5.6)%. These stones dissolved completely in either solvent, often leaving sand-like debris, with the exception of one stone. MTBE dissolved cholesterol gall stones 100 times faster than mono-octanoin and 10 times faster than limonene or the limonene/mono-octanoin mixture (p less than 0.001). The combination of limonene and mono-octanoin was as effective as limonene alone. Of the four solvents, MTBE is the best one to evaluate for dissolution of residual fragments after ESWL treatment of gall bladder stones.

Topics: Bilirubin; Calcium; Caprylates; Cholelithiasis; Cholesterol; Cyclohexenes; Ethers; Glycerides; Humans; Limonene; Methyl Ethers; Solvents; Terpenes

Topics: Bile Acids and Salts; Caprylates; Cholelithiasis; Education, Nursing, Continuing; Endoscopy; Ethers; Glycerides; Humans; Lithotripsy; Methyl Ethers; Sphincterotomy, Transduodenal

Retained common bile duct stones in postcholecystectomy patients who have a T-tube in situ should be treated, preferably, by nonoperative means. Thus, we treated seven such patients with common bile duct perfusion (through T-tube) of methyl tertiary butyl ether, and 10 patients with perfusion of monooctanoin. However, successful dissolution was achieved in only one and three patients, respectively. Hence, endoscopic sphincterotomy (ES) was performed in the patients in whom solvent perfusion had failed, and in other subsequent patients with T-tube in situ. Of 28 patients thus treated, bile duct clearance could be achieved in 27 (96.5%) patients; minor bleeding occurred in only three patients. After sphincterotomy, the stones passed out spontaneously in 20 patients while the T-tube was still in situ, but in two patients, only after the T-tube was removed. Similarly, basketing of the stones could be done in four patients with the T-tube in position, but in one patient whose ductal stones were above the T-tube, the tube had to be removed to make basketing successful. Endoscopic sphincterotomy is an efficient method of treating retained common bile duct stones in patients with T-tube in situ. However, in those patients whose ductal stones are above or astride the T-tube, the T-tube may have to be removed to attain bile duct clearance.

Topics: Adolescent; Adult; Caprylates; Child; Cholangiopancreatography, Endoscopic Retrograde; Ethers; Female; Gallstones; Glycerides; Humans; Intubation; Male; Methyl Ethers; Middle Aged; Solvents; Sphincterotomy, Transduodenal; Therapeutic Irrigation

Groups of human cholesterol gallstones were subjected to monooctanoin with and without agitation, methyl-tert-butyl ether (MTBE) with and without agitation, and monooctanoin and MTBE used in succession with agitation. In this in vitro study, agitation greatly expedited the rate of dissolution with MTBE, by far the more potent of the two solvents. An additive effect was suggested when the solvents were used sequentially, monooctanoin followed by MTBE. Cholesterol-calcium stones were also dissolved by MTBE but at a slower rate, depending on the amount and distribution of calcium. Computed tomographic (CT) scans and mammographic images clearly delineated the amount and distribution of calcification, but plain radiographs did not. On the basis of these findings, the authors instituted two changes in their clinical protocol: All patients with gallstones are now examined by means of CT before chemical dissolution begins, and monooctanoin is instilled overnight before the MTBE procedure.

Topics: Caprylates; Cholelithiasis; Cholesterol; Ethers; Glycerides; Humans; In Vitro Techniques; Methyl Ethers; Tomography, X-Ray Computed

Percutaneous transhepatic removal of common bile duct stones was performed 54 times in 50 patients with a success rate of 93%. In all patients, a modified Dormia basket was inserted through a percutaneous transhepatic catheter, and the stones or fragments were advanced into the duodenum. All patients had contraindications to surgery or had undergone unsuccessful attempts at endoscopic retrograde cholangiopancreatography and sphincterotomy. Monooctanoin (25 patients) or methyl tertiary-butyl ether (four patients) was infused to reduce stone size or remove residual debris. The average time for complete stone removal was 8.6 days. Morbidity was 13% and mortality was 4%, results which compare favorably with those of surgery.

Topics: Aged; Caprylates; Catheterization; Cholangiopancreatography, Endoscopic Retrograde; Ethers; Gallstones; Glycerides; Humans; Methyl Ethers; Sphincterotomy, Transduodenal

The influence of different solvents on cholesterol and pigment stones was investigated in vitro. Stone analysis was performed chemically, with infrared spectroscopy (IRS), scanning electron microscopy, energy-dispersive X-microanalysis (EDXA) and wave-length-dispersive X-microanalysis (WDXA). Each set of stones came from one source: eight human calcified cholesterol stones (CHS), eight fragments of bovine radiopaque Ca-bilirubinate stones (BBIL), and two complete BBIL. CHS and BBIL fragments were treated with (1) a buffered, alkaline 1% ethylenediamine tetraacetate solution (BA-EDTA; pH 9.5); (2) with BA-EDTA and monooctanoin preparation (GMOC) alternately; (3) with GMOC alone, and (4) with methyl-tert-butyl ether (MTBE). The complete BBIL were treated with BA-EDTA and MTBE. Furthermore, two human black pigment stones (BPS) were incubated in BA-EDTA. Calcified cholesterol stones are not dissolved by GMOC alone, nor by alternating treatment with BA-EDTA. They are dissolved by MTBE. MTBE is unsuitable for complete Ca-bilirubinate stones but MTBE, GMOC and GMOC/BA-EDTA alternately disaggregate stone fragments. This means that stone fragments behave differently from complete Ca-bilirubinate stones, which is important for further in vitro investigations. Ca-bilirubinate and black pigment stones are disaggregated in BA-EDTA. These results were confirmed with six CHS, 12 BBIL and 12 BPS from 5 further patients, incubated in the most eligible solvent for any individual stone type.

Topics: Animals; Bilirubin; Caprylates; Cattle; Cholelithiasis; Cholesterol; Edetic Acid; Ethers; Glycerides; Humans; Methyl Ethers; Microscopy, Electron, Scanning; Solvents

The authors describe percutaneous treatment of gallbladder or bile duct stones in 18 patients who were poor surgical candidates or in whom conventional therapy failed. Dissolution was performed in most cases with methyl tert-butyl ether (MTBE) because of its potent dissolution properties; other solvents used included monooctanoin or chelating solutions. Gallbladder stones were eliminated in 11 of 13 patients (six of seven with dissolution alone, four of four with dissolution and basket extraction, one with basket removal alone). In five patients with stones in the common bile duct (n = 3), cystic duct remnant (n = 1), and intrahepatic bile ducts (n = 1), stones were eliminated with dissolution alone in two and with dissolution plus basket extraction in one. In two patients percutaneous therapy failed due to complications (vagal hypotension with bile peritonitis and transient respiratory arrest) that occurred during catheter placement. Preliminary results suggest that MTBE is effective for dissolution of many gallbladder stones and some bile duct stones. Noncholesterol solvents and adjuvant mechanical maneuvers are valuable adjuncts to achieve complete stone elimination.

Topics: Bile Duct Diseases; Bile Ducts, Intrahepatic; Caprylates; Chelating Agents; Cholelithiasis; Ethers; Female; Gallstones; Glycerides; Humans; Male; Methyl Ethers; Solvents

Topics: Caprylates; Cholelithiasis; Cyclohexenes; Edetic Acid; Ethers; Glycerides; Humans; Limonene; Methyl Ethers; Terpenes

Various gallstone solvents are compared to evaluate their efficacy. Cholesterol gallstones from 5 patients were weight matched and incubated in 5 different solutions at 37 degrees C. These solutions consisted of methyl-tertiary butyl ether (MTBE), 90% mono-octanoin (MO), absolute alcohol, normal saline, and water. Absolute alcohol and MTBE were found to induce faster stone dissolution than the mono-octanoin derivative. Concentrations of alcohol below 80%, normal saline, and water were not effective in dissolving stones. Newer agents such as MTBE may prove valuable in dissolution of stones in the human gallbladder or bile ducts.

Topics: Caprylates; Cholelithiasis; Ethanol; Ethers; Glycerides; Humans; Methyl Ethers; Sodium Chloride; Solvents; Water

We tested methyl tertiary butyl ether both in vitro and in vivo to evaluate its efficacy as a potential cholesterol gallstone solvent for direct instillation into the human gallbladder or bile duct. Like diethyl ether, methyl tertiary butyl ether is an aliphatic ether with an excellent cholesterol-solubilizing capacity. However, unlike diethyl ether which vaporizes at body temperature, methyl tertiary butyl ether remains a liquid having a boiling point of 55.2 degrees C. In vitro, methyl tertiary butyl ether dissolved human gallstones (40%-94% cholesterol) within 60-100 min. In contrast, monooctanoin, an established gallstone solvent, required greater than 50 h to dissolve similar stones. By direct catheter instillation in 6 dogs, methyl tertiary butyl ether required only 4-16 h to dissolve gallstones surgically implanted in the gallbladder. The dogs tolerated methyl tertiary butyl ether with only minor clinical, biochemical, or histologic effects. We conclude that further evaluation of methyl tertiary butyl ether for dissolution of human gallbladder and biliary duct cholesterol stones is warranted.

Topics: Animals; Caprylates; Cholelithiasis; Dogs; Drug Evaluation, Preclinical; Ethers; Female; Gallbladder; Glycerides; Humans; In Vitro Techniques; Methyl Ethers; Microscopy, Electron, Scanning; Solvents; Time Factors

Models of the common bile duct and gallbladder were constructed to study conditions that affect the rate of cholesterol gallstone dissolution by monooctanoin and other potential solvents. In the bile duct model, the rate of monooctanoin infusion was not an important factor in accelerating dissolution time. In contrast, the exclusion of bile from interfering with solvent-stone contact or the enhancement of solvent-stone contact by stirring significantly accelerated stone dissolution. The combination of both bile exclusion and stirring increased the dissolution rate of gallstones by monooctanoin 15-fold. When compared with two other ethers and with monooctanoin, methyl tert-butyl ether was found to be the most potent gallstone solvent. Methyl tert-butyl ether completely dissolved 219-mg cholesterol stones within 60 min. In the gallbladder model, in the absence of stirring both methyl tert-butyl ether and monooctanoin floated on bile, whereas the gallstones sank resulting in minimal stone-solvent contact. To increase the stone-solvent contact, we used a pump to create sufficient turbulence to mix the solvent with bile. Pump stirring of monooctanoin in the presence of bile achieved rates of stone dissolution approaching that of stirred monooctanoin without bile. Stirring of methyl tert-butyl ether and bile, however, did not achieve sufficient solvent-stone contact to appreciably accelerate dissolution in the presence of 50% bile. Stone-solvent contact was a critical factor in determining the rate of gallstone dissolution in both gallbladder and common bile duct models. Efforts to enhance contact include bile exclusion and intraluminal stirring--both of which are clinically applicable. Methyl tert-butyl ether is a potent new cholesterol gallstone solvent with excellent potential for use in humans. Even with this potent agent, however, rapid gallstone dissolution is likely to require removal of most of the bile from the dissolution medium.

Topics: Bile; Bile Ducts; Caprylates; Cholelithiasis; Cholesterol; Ethers; Gallbladder; Glycerides; Humans; In Vitro Techniques; Methyl Ethers; Models, Biological; Perfusion; Punctures; Solvents; Time Factors