Development of High-Throughput Experimentation Approaches for Rapid Radiochemical Exploration.

Positron emission tomography is a widely used imaging platform for studying physiological processes. Despite the proliferation of modern synthetic methodologies for radiolabeling, the optimization of these reactions still primarily relies on inefficient one-factor-at-a-time approaches. High-throughput experimentation (HTE) has proven to be a powerful approach for optimizing reactions in many areas of chemical synthesis. However, to date, HTE has rarely been applied to radiochemistry. This is largely because of the short lifetime of common radioisotopes, which presents major challenges for efficient parallel reaction setup and analysis using standard equipment and workflows. Herein, we demonstrate an effective HTE workflow and apply it to the optimization of copper-mediated radiofluorination of pharmaceutically relevant boronate ester substrates. The workflow utilizes commercial equipment and allows for rapid analysis of reactions for optimizing reactions, exploring chemical space using pharmaceutically relevant aryl boronates for radiofluorinations, and constructing large radiochemistry data sets.

Effects of gallstone solvents on commonly used catheters.

PURPOSE: To determine what interaction and effect different cholesterol gallstone solvents have on catheters used for gallstone chemolysis. MATERIALS AND METHODS: Five types of catheters used for biliary procedures were chosen: polyethylene, Percuflex, silicon, Silitek, and polyurethane. The solvents chosen were methyl tert-butyl ether, ethyl propionate, isopropyl acetate, and N-propyl acetate. After incubation of the catheters in the solvents for 72 hours, they were air dried. Weight and area changes were determined for each catheter. Additionally, carbon-13 nuclear magnetic resonance (NMR) spectroscopy was performed for analysis of composition changes. RESULTS: Three catheters--silicone, Silitek, and polyurethane--showed changes in their physical characteristics that would make them less desirable for stone chemolysis. The silicone catheter showed changes in elastic texture as well as marked weight reduction. The Silitek and polyurethane catheters had similar, but less dramatic changes. C-13 NMR analysis of collected solvents showed that commonly used plasticizers were leached out of some catheters. CONCLUSION: These results suggest that all catheters are not suitable for use with all solvents. The choice of catheter should be made based on the solvent in use. The polyethylene catheter performed best under the conditions and endpoints used in this study.

Pain control during interventional biliary procedures: epidural anesthesia vs i.v. sedation.

OBJECTIVE: We performed a study designed to compare epidural anesthesia with IV sedation for the control of pain during interventional biliary procedures. MATERIALS AND METHODS: Two hundred sixty-three biliary procedures were performed in 126 patients during a 3-year period. The transhepatic approach was used for all the procedures. Epidural anesthesia was used in 140 procedures and IV sedation was used in 123. Both epidural anesthesia and IV sedation were used in 31 patients who required multiple procedures. The efficacy of each method for control of pain was determined by a subjective rating of the patients' pain during the procedure: from 0 (no pain) to +3 (severe). The ratings were compiled and compared for each of the methods to ascertain which technique best achieved the desired effect. The pain control used depended on the urgency of the procedures and the availability of an anesthesiologist to administer epidural anesthetic. When an anesthesiologist was unavailable, IV sedation was used. The type and amount of drug administered depended on the patient's preference and history. RESULTS: Of the 140 procedures done with epidural anesthesia, patients had no pain to mild pain in 127 (91%) and moderate to severe pain in 13 (9%). All instances of moderate to severe pain were the result of unsuccessful attempts to establish or maintain anesthesia. Of the 123 procedures done with IV sedation, patients had no pain to mild pain in 62 (50%) and moderate to severe pain in 61 (50%). Complications were more frequent when IV sedation was used. Six (5%) occurred, and all were related to hypotension. The hypotensive episodes occurred early in the study, before monitoring of patients was improved; now, continuous updates on vital signs are provided throughout the interventional procedure. With epidural anesthesia, hypotension developed in only one patient (< 1%) and the patient responded to fluid administration. CONCLUSION: When it is successful, epidural anesthesia can completely eliminate moderate to severe pain in patients undergoing biliary procedures. IV sedation is only 50% effective in this regard. The greater efficacy of epidural anesthesia, coupled with the significantly lower prevalence of hypotension, justifies the additional cost and time associated with epidural anesthesia for pain management in biliary procedures.

Gallbladder ablation with gallstones in situ in an animal model.

RATIONALE AND OBJECTIVES: The authors evaluated a method of gallbladder sclerosis in the presence of cholelithiasis. METHODS: The study was performed in 20 pigs. The gallbladders of 16 pigs contained surgically placed human gallstones. Control groups included animals that had their gallbladders sclerosed in the absence of stones, as well as a surgical sham control. Sclerosis followed cystic duct ligation to prevent extravasation of the sclerosing agent (95% Ethanol with 2 mole% trifluoroacetic acid) into the biliary tree. After sclerosis, a pigtail catheter was placed in the gallbladder to drain any post-procedure fluid accumulations. Catheters were removed after all drainage had ceased. Animals were killed at either 8 weeks (n = 6) or 6 months (n = 14). RESULTS: Stones were enveloped within the sclerosed and fibrotic gallbladder remnant in 13 of 15 test animals (87%). CONCLUSIONS: Sclerosis of gallbladders with stones in situ was achievable. Total mucosal obliteration did not appear to be required to produce a dysfunctional gallbladder in the time frame of this study.

Accelerated destruction of large, calcified gallstone burdens by performing lithotripsy in the presence of methyl t-butyl ether: an in vitro study.

Numerous, large, or calcified gallstones hinder successful extracorporeal fragmentation. The purpose of this study was to investigate an in vitro method that could accelerate the destruction of these types of gallstone burdens. Matched sets of partially calcified gallstones, each set having a combined stone diameter greater than 3 cm, underwent lithotripsy while immersed in either 15 cc of bile, methyl t-butyl ether (MTBE), or dimethyl sulfoxide (DMSO), with a fourth set serving as a control. Results showed a 20% reduction in the relative weight of all fragments, an eightfold reduction of the relative weight of fragments greater than 3 mm, and a 50% reduction of the number of large fragments when the stones were immersed and shocked in MTBE rather than when shocked in bile. Dimethyl sulfoxide hindered gallstone destruction. These results indicate that large, partially calcified gallstone burdens can be more successfully destroyed if lithotripsy is performed in the presence of a small quantity of MTBE rather than in bile alone or in the presence of DMSO. If proven safe in vivo, this technique could expand the applicability of lithotripsy to those with larger, partially calcified stone burdens.

Simplified percutaneous gastrostomy.

By using 16-F self-retaining feeding catheters, fluoroscopically guided percutaneous gastrostomy was performed in 68 consecutive adult patients without the use of gastric fixation devices. Short-term (2-week) follow-up of all patients was available, with 30-day follow-up obtained in 94% of the study group (n = 64). Thirty-day mortality was 12%, with no procedure-related deaths. Major and minor morbidity rates were 4.7% and 7.8%, respectively. The mean procedure time was 7 minutes. These data compared favorably with those of series employing smaller catheters placed with and without the use of gastropexy, as well as surgical gastrostomy and gastropexy procedures. Percutaneous placement of large-caliber (16-F) gastrostomy catheters is safe, effective, and rapid in the adult population and can be accomplished routinely without the use of prior gastropexy.

The acceleration of gallstone destruction with synchronous biliary lithotripsy and contact dissolution in vitro using three cholesterol-solubilizing solvent.

In the first-known application of its kind, shockwave lithotripsy and contact-solvent dissolution of large, calcified gallstone burdens were performed simultaneously with three chemical solvents, each tested separately in an in vitro model, with the combined effects on gallstone eradication examined. Two solvents, ethyl propionate and isopropyl acetate, were chosen for their solubilizing ability and potentially high level of patient safety. The third solvent, a 70%:30% mixture of methyl tert-butyl ether (MTBE) and dimethyl sulfoxide (DMSO), was chosen for its known ability to accelerate the dissolution of calcium-containing gallstones. All stones were matched for size, weight, and number. Gallstone lithotripsy performed in ethyl propionate was significantly more effective (P less than .02) in the production of fragments less than 2 mm when compared with bile; lithotripsy with isopropyl acetate and the MTBE/DMSO mixture showed no statistically significant effect. Biliary lithotripsy performed in an ethyl propionate medium may enhance gallstone dissolution and the production of small fragments (diameter less than 2 mm).

Laparoscopic cholecystectomy: evolution, early results, and impact on nonsurgical gallstone therapies.

Laparoscopic cholecystectomy, a surgical technique first performed in France, has gained widespread acceptance among surgeons in the United States. The abdominal cavity is inflated by carbon dioxide, a video monitor is inserted via a laparoscope placed periumbilically, and the gallbladder is freed and removed from the liver bed by using small subcostal ports for access and dissection. Intraoperative cholangiography is routinely performed, but uncertainty exists about how best to manage choledocholithiasis. Compared with traditional cholecystectomy, initial reports describing laparoscopic cholecystectomy cite shorter recovery times because no large incisions are made, thus potentially reducing the cost and morbidity of cholecystectomy. A survey of 614 early cases supports these claims, with a reported complication rate of 1.5% and quick resumption of normal activities by patients. Because of its promise for reduced morbidity, laparoscopic cholecystectomy is challenging open cholecystectomy as the therapeutic gold standard for symptomatic cholelithiasis. Thus, the standard to which the nonsurgical gallstone therapies, such as lithotripsy and contact dissolution, will be compared may shift to laparoscopic cholecystectomy. As the laparoscopic complications are similar to those of traditional cholecystectomy, such as abscesses and bile leaks, their percutaneous treatment should not change.

In vitro cholesterol gallstone dissolution: comparison of methyl tert-butyl ether with three new ester solvents.

The in vitro effectiveness of three new cholesterol gallstone solvents that have a potential for clinical use--ethyl propionate, isopropyl acetate, and n-propyl acetate--was compared with that of the well-known cholesterol solvent methyl tert-butyl ether (MTBE). Ten sets of matched gallstones were initially weighed, imaged with radiography and computed tomography (CT), and analyzed for content. One stone from each set was incubated in one of the four solvents at 37 degrees C. Solvents were changed at 30-minute intervals. The study was stopped either when the stones were completely dissolved or at the end of 7 hours. Any residual fragments were weighed, reimaged, and reanalyzed for content. There were no statistical differences between dissolution times of the stones in MTBE compared with those in the three new solvents. Ethyl propionate and n-propyl acetate appear to be as efficacious as MTBE in dissolving cholesterol stones and could be attractive alternatives for gallstone chemolysis.

Percutaneous cholecystostomy in critically ill patients.

Sixteen critically ill patients underwent percutaneous cholecystostomy because of suspected acute cholecystitis. The procedure was technically successful, although 11 of 16 patients died subsequently because of various complications of their underlying primary disorders. We reviewed this series to reassess the value of percutaneous cholecystostomy. Four of 11 patients with definite acute cholecystitis (group 1) were cured by this technique, but three required surgery because of gallbladder wall necrosis. Two of these were among four cases which had demonstrated pericholecystic fluid collections on computed tomography (CT) or ultrasound of the abdomen. There were also five patients (group 2) in whom acute cholecystitis or its relationship to patients' symptoms were not fully determined, and four of them did not improve after percutaneous cholecystostomy. We conclude that this technique has a lower success rate in critically ill patients than reported previously.

Transhepatic cholangiography in patients with suspected biliary disease and nondilated intrahepatic bile ducts.

Transhepatic cholangiography (THC) was performed in 107 patients who had nondilated intrahepatic bile ducts on computed tomography (CT) or ultrasound. The cholangiogram was diagnostic in 72 patients (67%). Thirty-one (43%) of the 72 diagnostic studies were abnormal and showed poor emptying, stones, or strictures. Twenty-three (21%) complications occurred, including two deaths. Sixteen patients experienced acute pain, requiring additional narcotics. There was one case of peritonitis and pancreatitis, and two of bacteremia. We compared our success and complication rates to those of endoscopic retrograde cholangiography (ERC) reported in the literature. We conclude that when a bile duct abnormality is clinically suspected, the incidence of pathology is sufficiently high to warrant direct visualization of the ducts in order to make an anatomic diagnosis, even if the intrahepatic ducts are not dilated. However, ERC has a better success rate and fewer complications than THC and it should be the initial invasive procedure.

Percutaneous interventional gallbladder procedures: personal experience and literature review.

Our experience with 58 percutaneous gallbladder procedures in 48 patients are discussed. Diagnostic procedures consisted of needle aspiration of bile (n = 5) to evaluate the gallbladder as a source of infections and transcholecystic cholangiography (TCC) (n = 32) for bile duct visualization. Percutaneous cholecystostomy (PC) (n = 21) was performed for gallbladder or bile duct decompression or stone dissolution. Ultrasound and/or fluoroscopic guidance were used, and the procedures were successful in all but one patient. The overall complication rate was 13.8% (8/58 procedures) but only 5.2% were considered serious (three instances of bile peritonitis). No vasovagal reactions or hemorrhage occurred. We also reviewed the complications in 231 cases of PC that have been reported in the English literature. The overall complication rate was 7.8%, and the most significant problems were death (n = 1), peritonitis (n = 3), and severe vasovagal reactions (n = 4).

Large colonic neoplasms missed by endoscopy.

Endoscopy is commonly accepted as the gold standard in the evaluation of neoplastic colonic disease. The procedure is used to confirm or exclude lesions detected on barium enemas, with the assumption that the endoscopist was successful in reaching the appropriate segment of the colon. We collected 18 cases, all with proved colonic neoplasm 2-8 cm in diameter that were detected by barium enema but overlooked on initial endoscopy. All of the lesions were relatively flat with little intraluminal protuberance. Histologic examination showed malignant foci in six of 11 tumors that were resected. In two of the other seven patients, unresected lesions progressed to advanced carcinomas. This experience suggests that a repeat barium enema is indicated when endoscopy fails to detect a colonic tumor suspected on barium enema examination.

Ultrasound of hemobilia: a clinical and experimental study.

Clinical observations on patients with hemobilia secondary to percutaneous biliary procedures and laboratory studies on animals with experimentally induced hemobilia indicate that the presence of fresh blood or clot within the biliary tree may yield an erroneous impression of duct size in ultrasound examinations. Recognition of this potential source of error becomes increasingly important as the use of percutaneous procedures for the relief of biliary obstruction increases.

Common bile duct calculi: updated experience with dissolution with methyl tertiary butyl ether.

The authors describe their experience with methyl tertiary butyl ether (MTBE) in a larger series of patients than previously reported in order to acquaint physicians with both its effectiveness for dissolution of common bile duct calculi and the limitations of its use. Ten patients with 13 biliary calculi underwent percutaneous stone dissolution treatment with the experimental cholesterol solvent, MTBE. Three stones completely dissolved within 30 minutes, seven were reduced in size, and three were visibly unaffected. All stones not completely dissolved were easily extracted by means of a stone basket except for one in a patient taken to surgery. Although MTBE perfusion is an effective technique for management of biliary calculi, practitioners should be aware that its use is quite time consuming and its odor difficult to control.

Emphysematous cholecystitis: pitfalls in its plain film diagnosis.

The clinical and radiographic findings of emphysematous cholecystitis are usually characteristic. However, on occasion the radiographic findings may be simulated by other processes. In such circumstances accurate diagnosis can usually be rapidly established by a variety of simple radiographic maneuvers and procedures. Five illustrative cases are presented herein and the pertinent literature is reviewed.