METHYL TERTIARY BUTYL ETHER CHOLELITHOLYSIS OF CALCULI IN THE GALLBLADDER AND BILE DUCTS*

Abstract Recent use of the cholelitholytic agent, methyl tertiary butyl ether (MTBE) has demonstrated its efficacy in the dissolution of cholesterol calculi. In three patients with retained stones in the bile duct, MTBE was instilled and aspirated through a T tube to effect dissolution. Stones dissolved completely in two patients, while in the third, partial dissolution permitted instrumental extraction through the T tube tract. In this third patient, dissolution of gallbladder stones in vitro was relatively slow. Patients tolerated the procedure well and there were no major complications. There was no evidence of duodenal inflammation in two patients who underwent duodenoscopy and biopsy before and after treatment. Four patients with cholesterol cholelithiasis underwent direct gallbladder perfusion with MTBE. The mean size of the gallstones was 0.8 cm (range 0.25–1.75 cm) and the mean number of stones per patient was four (range 1–13 stones). MTBE was instilled via a percutaneous gallbladder catheter inserted under local anesthesia with X-ray control. In three patients, the stone dissolution appeared to be complete after three to six hours of treatment. In the fourth patient, catheter displacement led to termination of dissolution therapy. Follow-up ultrasonograms in two patients demonstrated residual debris not visualised on the immediate post-dissolution films. Complications occurred in two patients and included catheter dislodgement and bile leakage after catheter withdrawal. Biliary perfusion with MTBE is a therapeutic option in patients with retained stones in whom instrumental retrieval has failed. It may also have a role in selected patients with symptomatic stones in the gallbladder.     

Dissolution of Cholesterol Gallbladder Stones with Methyl Tert-Butyl Ether in Patients with Increased Surgical Risk

The safety and efficacy of methyl fert-butyl ether (MTBE) dissolution of cholesterol gallbladder stones were evaluated in 25 patients with increased risk for surgery. Two patients were treated twice. The MTBE was infused and aspirated manually through a percutaneous transhepatic catheter to the gallbladder. The placement of the catheter failed in three patients (11%). In 19 of 24 patients (79%) there was complete dissolution of stones after a mean treatment time of 12.2 h (range, 4.3-19.5 h). In five patients treatment was discontinued before complete dissolution owing to technical problems or side effects. Side effects were nausea, pain, vasovagal reaction, and fever. Fifteen patients were followed up for a mean of 15.7 months after dissolution. Stone recurrence was found in eight patients, five of whom suffered symptomatic relapse. We conclude that dissolution therapy with MTBE is a safe and adequate alternative to surgery in selected high-risk patients.     

Gallbladder stones: Shockwave therapy

Within the past 7 years, gallbladder lithotripsy by shockwaves has been proven to be a safe and effective non-invasive therapy for selected patients with gallstone disease. While regulatory decisions prevent shockwave therapy from being used more frequently in the USA, the number of patients treated in Europe and Asia is increasing constantly. At our institution, a relatively constant number of about 250 new patients per year have been treated since 1988 (Figure 4).About 20% of patients with gallstones are suitable for shockwave therapy according to present criteria. The rate of evacuation of all fragments is determined by the initial stone number and stone size, the success at stone fragmentation, adjuvant bile acid dissolution therapy, and gallbladder contractility. In contrast to laparoscopic cholecystectomy (Dubois et al, 1989; Perissat et al, 1989; Southern Surgeons Club, 1991), shockwave therapy does not require general anaesthesia. And in contrast to direct contact dissolution therapy of gallbladder stones using MTBE (Thistle et al, 1989), lithotripsy is non-invasive. In the majority of patients, complete fragment disappearance takes several months. Preliminary analyses of the cost-effectiveness of lithotripsy have revealed that lithotripsy, including retreatments and bile acid medication for recurrent stones, costs about as much as open cholecystectomy (Rothschild et al, 1990; Bass et al, 1991).     

Transhepatic topical dissolution of gallbladder stones with MTBE and EDTA

Forty-two patients with symptomatic gallstones (28 women, 14 men, mean age 49.8±13.2 years) were recruited for contact dissolution therapy. Pretreatment CT scans of the gallbladder were obtained in every patient under standard conditions. For contact dissolution treatment of heterogeneous gallstones or gallstones with attenuation values of more than 50 Hounsfield units, methyltert-butyl ether and bile acid ethylene diaminetetraacetic acid were used in alternating administration at time intervals and durations adapted to the individual tolerance of the patients. In the case of gallstones with mean attenuation values under 50 Hounsfield units, the dissolution therapy was performed with methyltert-butyl ether alone. In 12 (28.6%) patients a complete dissolution of gallbladder stones could be achieved; 11 patients (26.2%) revealed gallbladder sludge but no radiologically or sonographically visualized residual stone debris. The remaining 19 (45.2%) patients had residual gallstone debris. Shell fragments in three of five rimmed gallstones, seven of eight laminated gallstones, and all densely calcified stones were refractory to contact dissolution therapy. Dissolution rates correlated well with mean attenuation values, whereas no significant correlation was found between stone number and dissolution rates or between stone diameter and dissolution rates respectively. The mean instillation time required for stones with a mean density of more than 50 HU was 17.7±11.5 hr of bile acid ethylene diaminetetraacetic acid and 5.8±3.2 hr of methyltert-butyl ether. In the case of isodense stones, the average instillation time of methyltert-butyl ether was 12.3±4.7 hr. There was a statistically significant difference in methyltert-butyl ether instillation time between the both groups (P<0.001), but the total instillation time required for stones with a mean density of more than 50 HU was significantly longer (P<0.0001); consequently, in these patients the incidence of severe complications was higher without reaching statistical significance. Mild complications occurred in 95.2% of patients and severe complications were observed in 16.8% of cases. Posttreatment CT examinations after intravenous application of contrast media revealed gallbladder mural hyperemia followed by edematous swelling of the pericystic tissue layer in 96.3% of patients. Eight of eleven patients (72.7%) with gallbladder sludge revealed gallstone recurrence in the course of a 12-month observation period. In the successfully treated group, only one patient experienced gallstone recurrence (P=0.0066). In principle, the use of bile acid ethylene diaminetetraacetic acid dissolution medium made the dissolution of calcified or pigment stones possible, although the side effects are greater than with cholesterol stones. More effective and safer solvents for these more difficult to dissolve stones should be sought.     

Endoscopy of the Gallbladder as Control of Gallstone Therapy with Methyl-tert-Butyl Ether

We report on a 36-yr-old woman with six gallstones measuring 2.1 cm each. Within 21 h of methyl-tert-butyl ether (MTBE) treatment, the stones had dissolved to a small amount of residue. As could be seen from cholesterol concentrations of samples of aspirated gallbladder bile and MTBE fractions, the dissolution process was slow to begin with, and gained momentum during hours 6-11, after which it decelerated. We discontinued treatment after 20 h, since the stone residue showed no change. Cholecystoscopy performed with an Edwards angioscope via a catheter showed that there were no stone remnants, but that there were flat polyps on the gallbladder wall. One hour later, we stopped the therapy. Cholecystoscopy is a useful method of assessing the results of MTBE treatment.     

Dissolution of cholesterol gallstones: comparison of solvents

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.     

Direct Dissolution of Gallstones with Methyl tert-Butyl Ether by Endoscopic Cannulation of the Gallbladder

Methyl tert -butyl ether (MTBE) rapidly and effectively dissolves cholesterol gallbladder stones. Due to the invasive nature of transhepatic catheterization, we studied the safety and efficacy of MTBE stone dissolution, delivered by endoscopic, retrograde cannulation of the gallbladder. Extracorporeal shock-wave lithotripsy (ESWL) was employed in patients with multiple stones, to increase contact surface area and facilitate dissolution. We successfully cannulated the gallbladder in 13/17 patients (76.5%) attempted, with no associated complications. After cannulation, MTBE lysis was then conducted on all patients, and 10/13 patients (77%) cannulated were either stone-free at completion, or had only residual gallbladder sludge. Predissolution ESWL successfully fragmented stones in 6/7 patients (86%) in which it was attempted. Both ESWL and MTBE were well tolerated by all patients. Endoscopic retrograde cannulation of the gallbladder and MTBE dissolution is a promising alternative for the treatment of gallbladder stones in patients who will not receive surgery.     

Contact chemical litholysis of gallbladder stones with methyl tert-butyl ether. Personal experience]

The purpose of the work is to estimate the efficiency and follow-ups of the contact chemical litholysis (CCL) of gallstones with methyl-tert-butyl ether (MTBE). The CCL has been carried to 5 women with plural (10-15) radiolucent gallstones, who refused from cholecystectomy. The percutaneous transhepatic puncture of the gallbladder has been executed to them under X-ray and ultrasonic control. Laboratory (general blood analysis, urine analysis, biochemical parameters of blood and bile) and tool (ultrasonic control, cholecystography) researches were carried out before the procedure, during dissolution, 2, 6, 9 months after the CCL. High litholytic activity of MTBE has been revealed by dissolution of cholesterol stones of the gallbladder with use of the above-mentioned agent. Local irritation, allergenic actions and essential collateral reactions were not observed. After the CCL, contractility function of the gallbladder has increased (before the procedure - 23,8 +/- 0,4%, after it - 37,5 +/- 0,8%, p < 0,001).     

Successful Topical Dissolution of Cholesterol Gallbladder Stones Using Ethyl Propionate

Topical dissolution of cholesterol gallbladderstones using methyl tert-butyl ether (MTBE) is useful insymptomatic patients judged too ill for surgery.Previous studies showed that ethyl propionate (EP), a C₅ ester, dissolves cholesterolgallstones rapidly in vitro, but differs from MTBE inbeing eliminated so rapidly by the liver that bloodlevels remain undetectable. Our aim was to test EP as atopical dissolution agent for cholesterol gallbladderstones. Five high-risk patients underwent topicaldissolution of gallbladder stones by EP. In threepatients, the solvent was instilled via acholecystostomy tube placed previously to treat acutecholecystitis; in two patients, a percutaneoustranshepatic catheter was placed in the gallbladderelectively. Gallstone dissolution was assessed bychromatography, by gravimetry, and by cathetercholecystography. Total dissolution of gallstones wasobtained in four patients after 6-10 hr of lavage; inthe fifth patient, partial gallstone dissolutionfacilitated basketing of the stones. In two patients, cholesteroldissolution was measured and averaged 30 mg/min. Sideeffects were limited to one episode of transienthypotension and pain at the infusion site; no patientdeveloped somnolence or nausea. Gallstone elimination wasassociated with relief of symptoms. EP is an acceptablealternative to MTBE for topical dissolution ofcholesterol gallbladder stones in high-risk patients. The lower volatility and rapid hepaticextraction of EP suggest that it may be preferable toMTBE in this investigational procedure.     

Oral dissolution therapy for cholelithiasis: mix and match

The authors conducted a prospective, randomized trial of chenodeoxycholic and ursodeoxycholic acid versus ursodeoxycholic acid alone in patients with cholelithiasis to determine their efficacy for dissolution of gallstones. One hundred and twenty patients with radiolucent gallstones, less than or equal to 15 mm and who had a functioning gallbladder were enrolled. The patients were divided into two groups based on the diameter of their largest stones. Seventy patients had stones larger than 5 mm but less than 15 mm, whereas 50 patients had stones that measured 5 mm or less. The patients were randomly assigned to treatment with chenodeoxycholic acid plus ursodeoxycholic acid (5 mm/kg of each) or ursodeoxycholic acid (10 mm/kg) alone. Oral cholecystography, plain abdominal x-rays, and ultrasonography of the gallbladder were done at 6, 12, and 24 months. Dissolution was deemed to be complete if not stones were visualized on two examinations. partial dissolution was defined as a 50% reduction in stone size and/or number. Stones that were not detected by cholecystography but still detected during ultrasonography were considered to be partially dissolved. Plasma triglycerides, serum cholesterol, HDL, and serologic liver function tests were determined at 1, 3, 6, 12, 18, and 24 months. In a select group of patients, bile-rich duodenal aspirates were aspirated and analyzed for biliary lipid contents. In the group with small stones, defined as less than or equal to 5 mm, complete stone dissolution occurred significantly more often utilizing combination therapy at 6 months (52% vs 24%), and this trend persisted, although no longer significant, at 12 and 24 months. Combination therapy also achieved an improved rate of dissolution for large stones within 6 months; however, this did not persist at 12 and 24 months. Although not statistically significant, stone calcification occurred less often with combined therapy. All treatment regimens were well tolerated, with only minor changes in bowel habits and mild elevations in serum transaminase levels. Serum lipid levels did not change with either therapy. The authors concluded that the combination of chenodeoxycholic acid and ursodeoxycholic acid was the preferred therapy for gallstone dissolution, because it dissolves stones more rapidly, with a lower incidence of stone calcifications, and thus might reduce the long-term cost of treatment.     

Gallstone recurrence after successful dissolution therapy

After successful dissolution therapy of cholesterol gallbladder stones bile again becomes supersaturated and recurrent gallstones may develop. Three different postdissolution treatments [500 mg ursodeoxycholic acid (UDCA) per day (N=14, group I), 100 mg aspirin per day (N=14, group II) and diet (N=15, group III) versus a control group (no treatment,N=15, group IV) aimed at preventing recurrence of gallstones were investigated in a prospective, randomized study in 58 gallstone patients (33 female, 25 male) after complete stone clearance. Bile samples (prior to dissolution therapy and at stone recurrence) were investigated for biliary cholesterol (C), phospholipids (PL), total bile acid concentration (BA), cholesterol saturation index (CSI), total lipid concentration (TLC), total biliary protein concentration (TP), and nucleation time (NT). In group IV multiple gallstones tended to recur more often than solitary stones (66.7% vs 16.7%) whereas in groups I–III only solitary stones recurred. Recurrent gallbladder stones were detectable in 10 patients (eight patients in group IV and one each in groups I and II, respectively) within one year after dissolution and in two patients (one each in groups III and IV, respectively) after 15 months. Furthermore, the probability of stone recurrence was significantly higher in untreated patients as compared to treated patients. In nine (group IV) of 12 patients with recurrent stones NT, C, CSI, PL, BA, TLC, TP, and bile acid spectrum remained nearly unchanged as compared to their pretreatment values, whereas in three (groups I–III) of 12 cases a decrease in C, CSI, and TP was observed during therapy. However, in each of these three patients, initial and after-treatment TP was significantly higher and NT shorter as compared to groups I–IV. Furthermore, in these cases (N=3) NT was prolonged, whereas no significant changes were found in PL, BA, TLC, and bile acid spectrum. Recurrence of gallstones, which seems to occur more likely in patients with multiple stones as compared to solitary stones, will happen in the early stage after stone clearance, again causing biliary pain. UDCA, aspirin or diet will reduce the probability for recurrent stones after complete gallstone dissolution.     

Chemical dissolution of gallstones in Taiwan: An in vitro study

Abstract To evaluate the potential for the chemical dissolution of gallstones, 480 stones from 214 patients were studied. The stones were obtained via surgery or endoscopically. They were classified into cholesterol-rich mixed stones, brown pigment stones and black stones. The composition of bilirubin and cholesterol was determined by Fourier transformed infrared spectroscopy. Two per cent tetrasodium ethylenediamine acetate (EDTA), dimethylsulfoxide (DMSO) or methyl-tert-butyl-ethylene (MTBE) were used to dissolve the stones. To enhance solubility, surfactant polysorbate-20 was used to mix two of the individual three solvents. Methyl-tert-butyl-ethylene was found to have the best dissolution ability (by dry weight) 94, 13.4 and 20% for mixed, brown and black stones, respectively. Dimethylsulfoxide resulted in 13, 14 and 25% dissolution and EDTA 9.5, 13 and 16.5%. In contrast, pure water dissolved 4, 6 and 10.4% of the stones, respectively. A combination of the dissolution agents did not enhance the dissolution rate. In fact, the combination of solvents unexpectedly reduced the solubility of the stones: EDTA/MTBE was 17.5, 6.7 and 16.0%; DMSO/MTBE 43.2, 21.9 and 18.0%; DMSO/EDTA 9.1, 7.0 and 9.6%. In conclusion, cholesterol-rich mixed stones were able to be dissolved using MTBE but results of contact dissolution for gallstones are still far from satisfactory.     

Percutaneous transhepatic dissolution of gallbladder stones.

The method of percutaneous transhepatic dissolution with methyl tert-butyl ether (MTBE) has been used at the Zagreb Clinical Hospital Department of Medicine since 1989. From December 1989 until December 1991, 69 patients, 51 (74%) females and 18 (26%) males, with symptomatic and cholesterol gallbladder stones were hospitalised at the Department. All patients preferred percutaneous transhepatic dissolution to surgical treatment of gallbladder stones. The gallbladder was successfully punctured and the catheter placed into the gallbladder lumen in 63 (91%) patients, whereas complete dissolution was achieved in 59 (85.5%) patients. In 21 (33.9%) of these 59 patients, after completed dissolution computer-processed roentgenograms and ultrasonic scan of the gallbladder revealed residual particles of debris sized up to 2 mm. Six patients in whom puncture, i.e. the placement of the catheter into the lumen was unsuccessful, were electively operated on the following day without any complications. The mean duration of hospitalisation for 63 patients was 4.5 days.     

Combined treatment of symptomatic gallbladder stones by extracorporeal shock-wave lithotripsy (ESWL) and instillation of methyl,Tert-butyl ether (MTBE)

Twenty-four patients with symptomatic gallbladder stones (12 radiolucent and 12 calcified) were treated by a combined approach of extracorporeal shock-wave lithotripsy (ESWL) and subsequent instillation of methyltert-butyl ether (MTBE). The patients received a mean of 1500±185 shock-wave discharges. The mean instillation time of MTBE was 13±4.2 hr. Treatment was tolerated without major adverse effects. Within a time period of three to five days eight of 12 patients with pure radiolucent stones and four of 12 with calcified stones became stone-free. After a median follow-up of five months (range: one week to 26 months), a total of 11 patients (92%) with radiolucent stones and of eight patients (66%) of those with calcified stones were free of stones, fragments, or debris. These clearence rates appear high when compared with reports on monotherapy with ESWL or MTBE, suggesting a positive effect of a combined approach in selected patients. Two patients exhibited recurrent stones after six and seven months respectively.Supported partly by a grant from the Koerber Foundation.     

Methyl tert-butyl ether fails to dissolve retained radiolucent common bile duct stones

Methyl tert-butyl ether (MTBE) has been recently proposed as a new therapeutic modality for the dissolution of cholesterol gallstones. To further evaluate efficacy and tolerability of this new litholytic agent, we have administered MTBE to 3 patients with nonobstructive radiolucent common bile duct stones after recent surgery. Methyl tert-butyl ether (8-11 ml/day) was infused after aspiration of bile via a Teflon catheter inserted through the postoperative T tube. Gentle aspiration and reinfusion were performed continuously to generate stirring. The total amount of MTBE retrieved during the entire procedure was equivalent to approximately 30% of the volume infused. In all cases, MTBE failed to dissolve the radiolucent stones, which were then dissolved with continuous infusion of monooctanoin via the biliary catheter. The characteristic odor of MTBE was detected on the breath of the patients, and nausea and somnolence developed during the treatment. Serum hepatic and pancreatic enzymes did not change after MTBE. In the third subject, who received 11 ml/day of MTBE for 2 consecutive days (total of 22 ml), histologic evidence of duodenitis was found around the papilla. In our opinion, the lack of efficacy of MTBE in dissolving retained radiolucent common bile duct stones was mainly related to its leakage from the common bile duct into the duodenum and the ensuing local chemical toxicity and systemic absorption. As MTBE needs a persistent stone-solvent contact to exert its litholytic action and, at the same time, its toxicity prevents the infusion of larger doses, MTBE use should be restricted to stones placed in closed chambers, such as the gallbladder.     

Influence of gallstones and ursodeoxycholic acid therapy on gallbladder emptying

Altered gallbladder motility could predispose to, or result from, gallstone formation and could also explain the alleged relief of biliary colic seen during bile acid therapy. Therefore, in 14 controls, 25 patients with radiolucent gallstones, and 14 patients with radiopaque gallstones, we used two techniques to measure gallbladder contraction--radionuclide imaging and real-time ultrasound--in response to one of two stimuli--a Lundh meal or intravenous cholecystokinin-octapeptide. Using the radionuclide technique, postprandial gallbladder emptying (t1/2) was prolonged (p less than 0.01) both in patients with radiopaque (26.7 +/- 3.1 min, mean +/- SEM) and radiolucent (21.7 +/- 3.1) gallstones when compared with controls (10.2 +/- 1.5). In patients with radiolucent stones, the t1/2 of gallbladder emptying became further prolonged (p less than 0.05) after 1 mo of therapy with 8-10 mg/kg body wt X day of ursodeoxycholic acid, to 32.1 +/- 4.4 min. A similar pattern of results was seen after cholecystokinin-octapeptide and also with real-time ultrasound. Thus, after both stimuli and using two independent techniques, gallbladder contraction was reduced in patients with gallstones. The slower and less complete gallbladder emptying with ursotherapy might explain the reduction in biliary colic noted during treatment.     

Cholesterol gallstone disease: the current status of nonsurgical therapy

Gallstone disease is a common disease that appears to be related to a Western diet. The underlying pathogenesis is a subtle alteration in the liver such that excessive cholesterol is extracted from the liver cell by bile acids undergoing an enterohepatic recirculation. Gallstone disease progresses through well-defined stages, beginning with a bile supersaturated with cholesterol and proceeding to crystal formation, stone growth, and finally symptoms caused by impaction of a stone in either the cystic duct or the common bile duct. The natural history is that most stones never cause symptoms. Stones that cause symptoms have been present for an average of 12 years. The treatment of truly asymptomatic stones should be observation. Ultrasonography of the right upper quadrant is the gold standard for the diagnosis of stones in the gallbladder. Endoscopic retrograde cholangiopancreatography (ERCP) is the gold standard for the diagnosis of stones in the common bile duct. Oral cholecystogram (OCG) helps select patients who have noncalcified, floating stones that may be dissolved with bile acids or methyl tertiary butyl ether (MTBE). Therapy with chenodiol has been a disappointment because of a low complete response rate. The ideal candidate for attempted dissolution with chenodiol would be a thin woman with hypercholesterolemia and a small number of symptomatic, small, floating, radiolucent gallstones. Ursodeoxycholic acid (Urso), when it is available, will have all of the attributes of chenodiol and virtually none of the side effects. Rapid dissolution of gallstones with MTBE shows great promise of being a generally available means of dissolving gallstones. Extracorporeal shock wave lithotripsy also shows promise, but its general availability may be limited by the cost of the equipment needed. As of now, the treatment of choice for symptomatic gallstones remains cholecystectomy, unless there is a compelling reason not to operate.     

Endoscopic retrograde cannulation of the gallbladder: direct dissolution of gallstones

Percutaneous transhepatic catheterization of the gallbladder for dissolution of cholesterol stones by instillation of methyl tert-butyl ether (MTBE) is an invasive therapeutic procedure. The only non-invasive alternative available to now, endoscopic retrograde cannulation of the cystic duct, was difficult because of the cystic duct's tortuosity and spiral valves. We therefore developed a catheter system which, using conventional duodenoscopes during a routine endoscopic retrograde cholangiography (ERC) procedure, permits reliable and safe catheterization of the gallbladder without the need for endoscopic sphincterotomy. In 18 of 22 patients (82%) we were able to place a cysto-nasal catheter, and in 14 patients MTBE dissolution therapy was then performed. Eight patients (57%) were completely free of stones after treatment; the other six (43%) had residual debris. In 4 of 22 patients (18%) cannulation attempts failed, in 3 patients due to cystic duct blockage by a calculus. Endoscopic retrograde cannulation of the gallbladder (ERCG) represents a promising alternative to the invasive percutaneous transhepatic catheterization procedure.     

Treatment of Cholesterol Gallstones with Chenic acid

Twenty-five patients were treated with chenie acid over the past three years. Asymptomatic or with mild nonspecific symptoms of "gallbladder dyspepsia" patients with radiolucent gallstones in functioning gallbladders were selected for this therapeutical trial. Clinical evaluation, liver tests and cholecystograms were performed periodically. In the functioning gallbladders the stone size (diameter of the largest stones) was measured during each standard cholecystography and classified as: smaller, less than 10 mm. and larger, more than 10 mm. Eight patients (with small gallstones) were treated less than six months and only one has had a partial dissolution. Of the 17 patients treated more than six months, the gallstones (small size) completely disappeared in nine (52.9%), most of them before 18 months of treatment and became partially smaller in three (17.6%) before 24 months of therapy. No change at all was observed in five patients between 18 and 24 months of treatment. In two of the nine patients in whom the cholecystograms demonstrated complete dissolution of gallstones, reappearance of small radiolucent gallstones was observed again six months after the drug was discontinued but reinstatement of chenic acid therapy again produced, after three months, complete dissolution of the gallstones. In our experience, therapy with chenie acid, with a daily dose of 750 mg. does not cause significant side-effects and offers a rational, effective, safe alternative to surgical treatment in a selected group of patients depending upon a reasonable clinical judgment.     

Experimental studies on dissolution of cholesterol gallstones using MTBE

Recently, methyl tertiary butyl ether (MTBE) has been evaluated as a new cholesterol gallstone dissolving agent. The dissolution rate of cholesterol monohydrate (ChM) by MTBE was measured and effective types of MTBE administration in vivo were studied. When the dissolution rate of ChM by MTBE was compared with that of d-limonene and monooctanoin used clinically at present, MTBE was found to be the most excellent dissolving agent. However, the dissolving effect of MTBE can be suppressed by water (a component of wet gallstones and 97% of bile) because MTBE is insoluble in water. Therefore, MTBE mixed with a small amount of surfactants (MTBEP) was prepared. The dissolving effect of MTBE alone and MTBEP on dry and wet gallstones were measured. The dissolving effect of MTBE alone on the wet stones was markedly decreased, while MTBEP suppressed the decrease of dissolving effect on wet stones significantly. Furthermore, the dissolving effect of MTBE alone and MTBEP on gallstones in water were measured. MTBEP significantly improved the decrease of dissolving effect on stones by MTBE alone, because the addition of a small amount of a surfactant suppressed the influence of water for dissolving effect of MTBE. MTBE emulsion, newly type of solvent, was prepared. Although the dissolution rate of ChM in MTBE emulsion was low, the dissolving effect of MTBE emulsion was also better than that of MTBE in animal experiments. In this study, emulsion type can be expected to become excellent dissolving agents, because emulsion type suppressed the influence of water for dissolving effect of solvent.