Endothelin content, expression, and receptor type in normal and diseased human gallbladder.

The aims of this study were to characterize the endothelin (ET) system in human gallbladder by determining (1) the tissue content of ET-1 and ET-2 by ELISA; (2) the expression of mRNA of the ET precursors preproendothelin-1, -2, and -3; and (3) mRNA expression for the ETA and ETB receptors. Median content of ET-1/2 was significantly reduced in severely inflamed gallbladders compared to gallbladders with mild inflammation. There was an inverse correlation between content of ET-1/2 and inflammation score. mRNA for preproendothelin-2 was highly expressed in all samples, whereas mRNA for preproendothelin-1 was present in negligible quantities and mRNA for preproendothelin-3 was undetectable. mRNA for ETA receptors was expressed in all samples analyzed, whereas mRNA for ETB receptors was expressed at a much lower level. This study demonstrates the presence of ET-1/2 in human gallbladder. ET-1/2 content is decreased with increasing degrees of histological inflammation. ET-2 is likely to be the physiologically significant endothelin isopeptide expressed and ETA receptors appear to predominate in the human gallbladder.

Inadvertent diclofenac rechallenge from generic and non-generic prescribing, leading to liver transplantation for fulminant liver failure.

This case report describes fulminant hepatic failure in a 53-year-old female caused by inadvertent rechallenging with diclofenac, treated by orthotopic liver transplantation. The case also illustrates the hazards of using both generic and non-generic drug prescribing, with drugs that are known to be toxic. The literature on non-steroidal anti-inflammatory drugs and hepatoxicity is reviewed.

The differential effect of VIP and PACAP on guinea pig gallbladder in vitro.

OBJECTIVES: Pituitary adenylate cyclase-activating polypeptide (PACAP) is a recently identified member of the secretin/glucagon/vasoactive intestinal peptide (VIP) family. Like VIP, PACAP is largely inhibitory in the gastrointestinal tract. The aim of our work was to characterize the effects of PACAP on both contraction and relaxation of guinea pig gallbladder (GPGB) muscle. METHODS: Gallbladder muscle strips were obtained from male Dunkin-Hartley guinea pigs (250-350 g). Isometric tension was measured in strips suspended in gassed (95% O2, 5% CO2) Krebs' solution at 37 degrees C and equilibrated for 60 min. Cumulative additions of VIP or PACAP (10(-9)-10(-6) mol/l) were performed with strips at basal tone or with strips pre-contracted with cholecystokinin-octapeptide (CCK-8). RESULTS: VIP had no effect on basal tone, in contrast with PACAP which produced concentration-dependent contraction to a maximum of 57.9 +/- 24.3% of control (CCK 3 x 10(-7) mol/l). The highest concentration (10(-6) mol/l) of VIP produced a 32 +/- 6% relaxation of 3 x 10(-9) mol/l CCK-8-contracted GPGB. With 3 x 10(-8) mol/l CCK-contracted GPGB strips, VIP produced a 26.7 +/- 6.6% relaxation. PACAP produced a further concentration-dependent contraction of 3 x 10(-9) mol/l CCK-contracted strips which reached 17.5 +/- 9.9% at the maximal concentration used (10(-6) mol/l). PACAP produced a concentration-dependent relaxation of 3 x 10(-8) mol/l CCK-contracted strips which reached a maximum relaxation of 19 +/- 5% of the control. CONCLUSIONS: PACAP has a dual effect on guinea pig gallbladder motility in vitro, producing contraction in the basal state, and both contraction and relaxation in the CCK-contracted state. This is in contrast to the effects of VIP, a closely related peptide.

Differential effect of prostaglandins on gallstone-free and gallstone-containing human gallbladder.

Nonsteroidal antiinflammatory drugs, inhibitors of prostaglandin synthesis, have different effects on gallbladder contractility in normal and diseased human gallbladders in vivo. We investigated this differential effect by comparing the effects of prostaglandins PGE2 and PGF2alpha, the thromboxane A2 mimetic U46619, and PGI2 on in vitro contractility in gallstone-free and gallstone-containing human gallbladders. Isometric tension was measured in gallbladder muscle strips mounted in organ baths. EC50 was calculated for each agonist. The rank order of potency in gallstone-free gallbladders was PGE2 > CCK > U46619 > PGF2alpha and in gallstone-containing gallbladders was U46619 > PGE2 > CCK > PGF2alpha. PGI2 produced contraction of gallstone-free gallbladder and relaxation of gallstone-containing gallbladder in the basal state. Further, PGI2 produced no relaxation in gallstone-free muscle strips precontracted with CCK, but significant relaxation in CCK precontracted gallstone-containing strips. PGE2, PGF2alpha, and U46619 are potent contractors of gallstone-free and gallstone-containing gallbladders, whereas PGI2 relaxes only gallstone-containing gallbladders. Since gallbladders containing cholesterol-supersaturated bile produce increased PGI2, this PGI2-induced relaxation may be a determinant of the impaired gallbladder motility of gallstone disease.

Early experience with intrasphincteric botulinum toxin in the treatment of achalasia.

BACKGROUND: Recent reports have suggested that intrasphincteric injection of botulinum toxin is effective and long-lasting in the treatment of achalasia. AIM: To report our experience of botulinum toxin injection in a prospective series of consecutive patients with achalasia. METHODS: Eleven consecutive patients with achalasia (eight male, mean age 55 years, range 20-87) were treated with 60 units of botulinum toxin (Dysport; Speywood Pharmaceuticals Ltd, UK) into each of four quadrants at the lower oesophageal sphincter. Patients were assessed pre-treatment and 1 month after treatment using a symptom score and oesophageal manometry. Median follow-up was 12 months (range 6-28). RESULTS: The injection procedure was simple to perform and free of adverse effects. Although treatment had a beneficial effect on dysphagia (median pre-treatment score 3 [interquartile range 3-3]; post-treatment score 2 [0-3]: P=0.03) 1 month following therapy, there was no significant improvement in chest pain or regurgitation scores. Similarly, no significant reduction in median lower oesophageal sphincter pressure was observed (29.5 mmHg [21-42] pre-treatment, 28.5 [17.5-55.5] post-treatment P=0.67). Four patients (36%) required further therapy within 3 months and the overall relapse rate was 73% (eight of 11) within 2 years. CONCLUSION: Although botulinum toxin injection was well tolerated, these results using Dysport at a dose of 240 mouse units question its efficacy as a treatment for achalasia.

A double-blind randomized trial of low-dose versus high-dose topical anaesthesia in unsedated upper gastrointestinal endoscopy.

BACKGROUND: Upper gastrointestinal endoscopy is frequently performed on unsedated subjects. Pharyngeal anaesthesia is thought to improve patient tolerance to the procedure but the optimum dose of anaesthesia is not known. The aim of this study was to assess the benefits of low-dose vs. high-dose topical anaesthesia in unsedated gastroscopy. METHODS: One hundred and fourteen subjects attending for diagnostic gastroscopy were studied. Patients were randomized to receive either 30 mg or 100 mg of topical pharyngeal lidocaine spray prior to endoscopy in a double-blind fashion. Subjects completed a questionnaire before and after endoscopy. RESULTS: A similar proportion of patients in each group required intravenous sedation because of discomfort or anxiety during the procedure (P = 0.48). The high-dose group experienced less discomfort during endoscope insertion (P = 0.002) and throughout the examination (P = 0.01). Overall satisfaction was almost identical in the two groups (P = 0.85) and a similar percentage of the high-dose and low-dose groups stated that they would request sedation prior to future endoscopy (37 vs. 44%; P = 0.48). Further analysis showed that apprehensive patients and younger patients reported relatively high levels of discomfort, and that female subjects were more likely to express a preference for sedation at any future gastroscopy. CONCLUSION: High-dose pharyngeal anaesthesia reduces patient discomfort during unsedated upper gastrointestinal endoscopy. However, patient tolerance is also influenced by clinical features, which might be useful in deciding which patients are suitable for this procedure.

Eradication of Helicobacter pylori with clarithromycin and omeprazole.

Clarithromycin, a new and well tolerated, acid stable macrolide antibiotic, has a similar antimicrobial spectrum to erythromycin but a better in vitro MIC90 (0.03 microgram/l-1) against Helicobacter pylori (H pylori). This study aimed at determining the eradication rate using clarithromycin 500 mg thrice daily and omeprazole 40 mg daily for two weeks. Patients were given an endoscopy and H pylori status assessed by antral culture (microaerobic conditions, for up to 10 days), antral and corpus histology tests (haematoxylin and eosin/Gimenez stains), and 13C-urea breath test (13C-UBT, European standard protocol, positive result = excess delta 13CO2 excretion > 5 per mil). Compliance was assessed by returned tablet counts. H pylori clearance at the end of treatment and eradication four weeks after finishing treatment were assessed by the 13C-UBT. Seventy three patients (54 men, median age 45 years) with duodenal ulcers (n = 42) or duodenitis/non-ulcer dyspepsia (n = 31) all with a positive 13C-UBT (mean (SEM) excess delta-13CO2 excretion = 26.6 (4.9) per mil) and either positive antral histology (n = 72) or positive antral culture (n = 35) were studied. Before treatment 2/27 (7%) isolates of H pylori were resistant to clarithromycin and five isolates were resistant to metronidazole. In 70/73 (96%) the 13C-UBT was negative immediately after finishing treatment. Four weeks later the 13C-UBT was negative in 57/73 (mean (SEM) excess delta 13CO2 excretion = 1.2 (0.3) per mil, eradication rate = 78%). Forty eight (66%) patients experienced a metallic taste while taking the tablets. Although four (5%) patients, however, could not complete the course of treatment, in only one of these four was H pylori not eradicated. These results show that duel therapy with clarithromycin and omeprazole is well tolerated. With an eradication rate of 78% it is an effective treatment for metronidazole resistant H pylori and may be an alternative to standard triple therapy.