LY303366 exhibits rapid and potent fungicidal activity in flow cytometric assays of yeast viability.

LY303366 is a semisynthetic analog of the antifungal lipopeptide echinocandin B that inhibits (1,3)-beta-D-glucan synthase and exhibits efficacy in animal models of human fungal infections. In this study, we utilized flow cytometric analysis of propidium iodide uptake, single-cell sorting, and standard microbiological plating methods to study the antifungal effect of LY303366 on Saccharomyces cerevisiae and Candida albicans. Our data indicate that an initial 5-min pulse treatment with LY303366 caused yeasts to take up propidium iodide and lose their ability to grow. Amphotericin B and cilofungin required longer exposure periods (30 and 180 min, respectively) and higher concentrations to elicit these fungicidal effects. These two measurements of fungicidal activity by LY303366 were highly correlated (r > 0.99) in concentration response and time course experiments. As further validation, LY303366-treated yeasts that stained with propidium iodide were unable to grow in single-cell-sorted cultures. Our data indicate that LY303366 is potent and rapidly fungicidal for actively growing yeasts. The potency and rapid action of this new fungicidal compound suggest that LY303366 may be useful for antifungal therapy.

Development of an objective method for assessing viscosity of formulated foods and beverages for the dysphagic diet.

OBJECTIVE: To develop and validate a practical, economical, and objective viscosity assessment tool, the line-spread test, for foods and beverages formulated for the dysphagic diet. The line-spread test is based on the measure of product dispersion over a flat surface. DESIGN: Viscosity-altering formulations for a selection of soups and beverages commonly served to patients with dysphagia at a local hospital were developed under controlled conditions. The samples were presented to a trained sensory panel for evaluation by quantitative descriptive analysis and were measured by the line-spread test. Numeric results of the two tests were compared. SETTING: The Food Research Laboratory with private sensory booths at Mount Saint Vincent University. MAIN OUTCOME MEASURES: Results of the sensory evaluation and the line-spread test would strongly correlate, indicating predictive validity, but the line-spread test would be more reliable and show variability in measurement. STATISTICAL ANALYSES PERFORMED: Correlation, analysis of variance (ANOVA), and standard deviations (calculated from the within-group mean square error of the ANOVAs). RESULTS: ANOVA showed that both the sensory panel results and the line-spread test values indicated significant differences among the samples. Standard deviations indicated less variability in line-spread values. There was a strong positive correlation (r = .90 to .97) between the two types of results, which indicated strong predictive validity for the line-spread test. APPLICATIONS: The line-spread test is a reliable and valid tool to assess viscosity of formulated foods and beverages for the dysphagic diet and can be readily and economically adapted to any dietary department for product development and quality control.

Blockade of human neutrophil activation by 2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5- hydroxyphenoxy]propoxy]phenoxy]benzoic acid (LY293111), a novel leukotriene B4 receptor antagonist.

Leukotriene B4 (LTB4), a naturally occurring pro-inflammatory product of arachidonic acid metabolism, has been associated with human inflammatory disease. This study compares the abilities of two LTB4 receptor antagonists, 2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]- propoxy]phenoxy]benzoic acid (LY293111) and 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)-propoxy]- 3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid (SC-41930), to displace LTB4 binding and their functional blockade of human neutrophil activation. LY293111 inhibited the binding of [3H]LTB4 with a Ki of 25 nM; SC-41930 displayed a similar potency (Ki = 17 nM). In contrast, LY293111 prevented LTB4-induced calcium mobilization with an IC50 = 20 nM, or 40 times more effectively than SC-41930 (IC50 = 808 nM). LY293111 was 300 times more potent than SC-41930 in blocking LTB4-induced CD11b up-regulation on isolated neutrophils. LY293111 also arrested LTB4-induced up-regulation of CD11b on neutrophils in whole human blood. LY293111 was not effective in blocking human neutrophil activation responses induced by N-formyl-methionyl-leucyl-phenylalanine (fMLP), platelet-activating factor (PAF), human recombinant endothelial interleukin-8 (IL-8) or human recombinant complement component 5a (C5a).

Antibiotics in infections of the biliary tract.

The combination of a penicillin and an aminoglycoside has been recommended as the initial treatment of choice for patients with infections of the biliary tract. However, elderly, septic, patients with jaundice have a high incidence of renal problems. For this reason, amingolycoside treatment of these patients must be reevaluated as newer less nephrotoxic agents become available. We, therefore, performed a prospective, randomized trial of ampicillin plus tobramycin, cefoperazone and piperacillin in patients with biliary tract infections. During a 20 month period, 106 patients with acute cholecystitis (53) or cholangitis (53), or both, received one of these antibiotic regimens for a minimum of five days. In patients with acute cholecystitis, ampicillin plus tobramycin, cefoperazone and piperacillin had clinical cure rates of 85, 95 and 95 per cent, respectively. In patients with cholangitis, however, cure rates for the three regimens were 85, 56 (p less than 0.05 versus ampicillin plus tobramycin) and 60 per cent (not significant versus ampicillin plus tobramycin), respectively. Moreover, 13 per cent of the patients receiving cefoperazone had an increased prothrombin time and three of 39 patients receiving this antibiotic had clinical problems with bleeding. Nephrotoxicity was greatest in patients with cholangitis receiving ampicillin plus tobramycin, 10 per cent, as compared with 3 per cent in those who did not receive an aminoglycoside. This difference, however, was not statistically significant. It was concluded that piperacillin should be considered for antibiotic management of patients with acute cholecystitis and that further studies are necessary in patients with cholangitis to determine whether or not newer agents should replace penicillin and aminoglycoside combinations.

Proximal bile duct cancer. Quality of survival.

A retrospective study of 97 patients with proximal bile duct cancer treated at the University of California, Los Angeles Medical Center was conducted to determine the benefits of different operative treatments. Eighty-nine patients were divided into three treatment groups: Group I, curative resection (29 patients); Group II, palliative resection (13 patients) and bypasses (8 patients); and Group III, operative intubation (39 patients). Two patients died before operation and six patients were treated without operation by percutaneous biliary decompression. High morbidity rate (53.8%) and mortality rate (69.2%) were encountered in 13 patients who had hepatic resection. Survival rates of the three treatment groups were comparable. For the 64 patients closely monitored after discharge, quality of survival was assessed according to six parameters: frequency of hospitalization for cholangitis; catheter-related problems; the percentage of days hospitalized; duration of jaundice; antibiotic requirements; and analgesic needs. Group I patients had the best qualitative survival, whereas Group II patients had the worst result when compared with either Group I (p less than 0.001) or Group III (p less than 0.005). Curative resection is recommended when it can be done without a concomitant hepatic resection. When noncurable disease is found on examination, operative intubation after dilatation is the preferred palliative measure.

Chronic intestinal pseudo-obstruction. Management with total parenteral nutrition and a venting enterostomy.

A variety of remedies have been suggested for patients with chronic intestinal pseudo-obstruction. However, none of these treatments have been particularly effective, and many of these patients have died of malnutrition. Therefore, in an effort to maintain nutrition and avoid repetitive nasogastric intubation, 22 patients (12 adults and ten children) with chronic intestinal pseudo-obstruction were managed with long-term total parenteral nutrition (TPN), and 20 also received a "venting" enterostomy. Only two patients had to undergo revision of their gastrostomies. Prior to referral, these 22 patients required 56 admissions for obstruction (1.2 admissions per patient-year). Since the initiation of TPN and placement of a venting enterostomy, these 22 patients required only 17 hospitalizations for obstruction in a total of 80 patient years (0.2 admissions per patient-year). We conclude that patients with chronic intestinal pseudo-obstruction who receive TPN at home and have a venting enterostomy can be safely managed for prolonged periods and require fewer hospitalizations for obstruction.

Does preoperative percutaneous biliary drainage reduce operative risk or increase hospital cost?

Despite recent advances in perioperative support care, surgery for obstructive jaundice is still associated with significant morbidity and mortality. For this reason, preoperative percutaneous transhepatic drainage (PTD) has been recommended for these patients. This method of management, however, has only been supported by retrospective and nonrandomized studies. Therefore, a prospective, randomized study was performed to determine the effect of preoperative PTD on operative mortality, morbidity, hospital stay, and hospital cost. Thirty-day mortality was 8.1% among 37 patients undergoing preoperative PTD, compared to 5.3% for 38 patients who went to surgery without preoperative drainage. Overall morbidity was also slightly, but not significantly, higher in patients who underwent preoperative PTD, (57% versus 53%). However, total hospital stay was significantly longer (p less than 0.005) in the PTD group (31.4 days versus 23.1 days). The cost of this excess hospitalization and the PTD procedure at our university medical center was over +8000 per patient. The authors conclude that preoperative PTD does not reduce operative risk but does increase hospital cost and, therefore, should not be performed routinely.

Percutaneous transhepatic drainage. Risks and benefits.

We evaluated the risks and benefits of percutaneous transhepatic biliary drainage (PTD) in 44 patients. Patients were divided into two groups, palliative and preoperative, each of which had 22 patients. Major complications included bacteremia, hemobilia, and liver abscess and occurred in ten patients (23%). A liver abscess along the catheter tract may have contributed to the death of one patient with an advanced malignant neoplasm. Major complications were more likely to develop in palliative-group patients (36% v 9%) and those patients were more likely to die within 30 days of the procedure (27% v 0%). Four (57%) of seven palliative-group patients and none of six preoperative-group patients with pre-PTD bilirubin levels higher than 20 mg/dL died within 30 days after PTD. Liver function test results improved within seven days in approximately 85% of the patients. Twenty-one patients (95%) in the preoperative group survived surgery. We concluded that the risk of PTD may outweigh the benefit in the subset of patients with advanced malignant neoplasms and a bilirubin level higher than 20 mg/dL. Even then, however, PTD may be justified if pruritus is incapacitating. Pending results of further randomized trials, we have continued performing PTD preoperatively in patients whose bilirubin levels exceed 10 mg/dL.

Increased risk of gallstones in children receiving total parenteral nutrition.

Twenty-one children receiving long-term total parenteral nutrition were prospectively evaluated for the presence of gallstones. Using ultrasonography, nine children (43%) were found to have cholelithiasis, and five have since undergone cholecystectomy. Only children with ileal disorders or previous resection developed stones. In the select group of patients with ileal disorders or previous resection, the prevalence of stones was 64%, nearly twice that which has been observed in similarly defined adults not receiving total parenteral nutrition. Data from this study suggest that the prolonged administration of parenteral nutrition significantly enhances the risk of gallstone formation already imposed by a previous ileal resection or disorder. Periodic ultrasonograms provide a safe and accurate means of monitoring high-risk patients during and after prolonged total parenteral nutrition therapy.

Gallbladder disease in patients on long-term parenteral nutrition.

Recent anecdotal reports suggest that total parenteral nutrition may be associated with an increased incidence of both acalculous cholecystitis and cholelithiasis. The validity of this association, however, has not been tested in a large population of patients on long-term total parenteral nutrition. Therefore, we assessed the incidence of gallbladder disease among our patients 15 yr and older who had received a minimum of 3 mo of total parenteral nutrition. Of the patients meeting these criteria, 128 were on total parenteral nutrition a mean of 13.5 mo. Nineteen had gallbladder disease before receiving total parenteral nutrition, leaving 109 patients at risk. Of these patients, 25 (23%) developed gallbladder disease after the initiation of total parenteral nutrition. Because of their known propensity for cholelithiasis, 94 of our patients with ileal disorders (Crohn's disease or ileal resection, or both) were considered separately. The 40% incidence of gallbladder disease in these 94 patients was significantly higher than expected from a series of similarly defined patients with ileal disorders not receiving total parenteral nutrition (p less than 0.05). We propose that the enhanced risk of gallbladder disease among patients on long-term total parenteral nutrition results from multiple factors working in concert to promote gallbladder stasis.

Increased risk of cholelithiasis with prolonged total parenteral nutrition.

Patients who receive hyperalimentation undergo prolonged periods of fasting which may alter bile composition and lead to gallbladder stasis, both important factors in gallstone formation. Therefore, we tested the hypothesis that patients who receive long-term TPN are at increased risk for cholelithiasis by performing cholecystosonography on adult patients who had received a minimum of 3 months of intravenous hyperalimentation during 1981. Seventy-one patients whose mean age was 41.9 years, 41 percent of whom were men, met these criteria. Gallstones had been diagnosed in 11 of the 71 patients (15 percent) before the initiation of parenteral nutrition. Twenty-one of the remaining 60 at risk patients (35 percent) were discovered to have cholelithiasis after hyperalimentation was started. The 45 percent prevalence of gallstones in our 71 patients was significantly higher (p less than 0.001) than predicted from autopsy data. In addition, the 49 percent prevalence of cholelithiasis in our 53 patients with ileal disorders was significantly greater (p less than 0.02) than predicted from a study of patients with similarly defined ileal disorders. This analysis strongly suggests that patients who receive long-term TPN are at increased risk for the development of cholelithiasis.