Complementary studies of the gastrointestinal safety of the cyclo-oxygenase-2-selective inhibitor etoricoxib.

BACKGROUND: Cyclo-oxygenase-2-selective non-steroidal anti-inflammatory drugs are intended to preserve cyclo-oxygenase-1-mediated gastroprotection and platelet function, whilst inhibiting cyclo-oxygenase-2-mediated inflammation. AIM: To assess the gastrointestinal safety of the cyclo-oxygenase-2-selective inhibitor etoricoxib vs. non-selective non-steroidal anti-inflammatory drugs. METHODS: Two randomized, double-blind, placebo- and active-controlled studies were performed: (i) daily faecal red blood cell loss was measured in 62 subjects receiving etoricoxib (120 mg once daily), ibuprofen (800 mg t.d.s.) or placebo for 28 days; (ii) the incidence of endoscopically detectable gastric/duodenal ulcers was determined in 742 osteoarthritis or rheumatoid arthritis patients receiving etoricoxib (120 mg once daily), naproxen (500 mg b.d.) or placebo over 12 weeks. RESULTS: In the first study, the between-treatment ratio of faecal blood loss for etoricoxib vs. placebo (1.06) was not significantly different from unity; however, the ratios for ibuprofen vs. placebo (3.26) and etoricoxib (3.08) were significantly greater than unity (P < 0.001). In the second study, the incidence of ulcers of > or = 3 mm with naproxen (25.3%) was significantly higher than that with etoricoxib (7.4%) or placebo (1.4%; P < 0.001); the results were similar for ulcers of > or = 5 mm. CONCLUSIONS: The reduced toxicity of etoricoxib (less faecal blood loss and fewer endoscopically detectable lesions) suggests that use of this drug will may be associated with a reduced incidence of gastrointestinal perforations, ulcers and bleeds.

Local plants as repellents against Anopheles arabiensis, in Mpumalanga Province, South Africa.

OBJECTIVE: To assess the repellency effect of three local plants; fever tea (Lippia javanica), rose geranium (Pelargonium reniforme) and lemon grass (Cymbopogon excavatus) against laboratory reared Anopheles arabiensis mosquitoes. DESIGN: A laboratory experimental study. SETTING: Mpumalanga Province, South Africa. SUBJECTS: Three adult male volunteers. MAIN OUTCOME MEASURES: Affordable alternatives to synthetic repellents against biting of Anopheles arabiensis mosquitoes. RESULTS: All three alcohol plant extracts provided significantly more protection (p = 0.012) than alcohol control. The alcohol plant extract of L. javanica provided 76.7% protection against An. arabiensis after a four hour period, and C. excavatus and P. reniforme provided 66.7% and 63.3% protection for three hours, respectively. At five hours post application only L. javanica alcohol extract provided appreciable protection (59.3%) against An. arabiensis. CONCLUSION: The results of this study indicate that L. javanica, P. reniforme and C. excavatus protect against An. arabiensis mosquito bites with the repellent effect of L. javanica lasting significantly longer than that of the other two plants.

Adding once-daily omeprazole 20 mg to metronidazole/amoxicillin treatment for Helicobacter pylori gastritis: a randomized, double-blind trial showing the importance of metronidazole resistance.

OBJECTIVE: We compared the Helicobacter pylori eradication rate after a 14-day treatment with amoxicillin 500 mg t.i.d. and metronidazole 500 mg t.i.d. with or without omeprazole 20 mg once daily. METHODS: This was a randomized, controlled trial in which omeprazole was given in double-blind fashion. Patients with H. pylori-associated gastritis were enrolled in four centers in Canada from July 1991 to January 1994. Eradication of H. pylori was assessed by histological evaluation and culture of endoscopic biopsies obtained from the antrum and corpus of the stomach. RESULTS: The H. pylori eradication rate was 73% (33 of 45) in the omeprazole-amoxicillin-metronidazole group, compared with 66% (31 of 47) in the amoxicillin-metronidazole group. This 7% difference was not statistically significant (p = 0.43, 95% confidence interval for difference -11% to 26%). Metronidazole primary resistance in the prestudy cultures was found more frequently in the omeprazole-amoxicillin-metronidazole group than in the amoxicillin-metronidazole group. Resistance to metronidazole was an important predictor of treatment failure. The H. pylori eradication rate was 61% (19 of 31) for patients infected with metronidazole-resistant H. pylori strains, compared with 91% (30 of 33) eradication for those infected with metronidazole-sensitive strains (p < 0.01). Vaginal candidiasis was reported in four patients. CONCLUSIONS: The H. pylori eradication rate was higher (73%) for omeprazole-amoxicillin-metronidazole than for the dual antibiotic therapy given without omeprazole (66%); however, this difference was not statistically significant. Metronidazole resistance significantly reduces H. pylori eradication rates.

Mucosal damage during intestinal anaphylaxis in the rat. Effect of betamethasone and disodium cromoglycate.

In this study, two antiallergic compounds, betamethasone and disodium cromoglycate were tested in an animal model of intestinal anaphylaxis. Rats, immunized with Nippostrongylus brasiliensis, were challenged intravenously with whole worm antigen or saline. Antigen challenge resulted in significant abnormalities: epithelial damage with shorter villi, decreased activity of digestive enzymes, decreased levels of mucosal histamine, a mast cell mediator, and increased blood uptake of [51Cr]EDTA from the lumen. Low-dose betamethasone, 24 and 48 hr before antigen, was not effective in preventing the effects: villus damage and increased [51Cr]EDTA uptake were seen, although mucosal mast cell numbers were significantly reduced by the drug. High-dose betamethasone completely prevented intestinal anaphylaxis: villus height, digestive function, and [51Cr]EDTA recovery in antigen-challenged animals were not significantly different from controls. Mucosal histamine levels and mast cells were significantly reduced in the high dose betamethasone group. Oral disodium cromoglycate did not prevent the abnormalities but provided a slight beneficial effect.

The effect of acupuncture on gastrointestinal function and disorders.

Acupuncture has been used empirically in clinical practice in China for several millenia and has recently drawn interest as a mode of anesthesia. Despite extensive investigation, the exact mechanisms of its analgesic action are unknown, but are thought to involve endogenous opioid peptides. Only recently have studies attempted to evaluate the effect of acupuncture on gastrointestinal function and disease. A review of studies from both the Chinese and Western literature supports the efficacy of acupuncture in the regulation of gastrointestinal motor activity and secretion through opioid and other neural pathways. However, no firm conclusion can be drawn about the effectiveness of acupuncture in the treatment of specific gastrointestinal disorders because of the lack of properly randomized controlled trials.

Effect of acupuncture on gastric acid secretion in healthy male volunteers.

Six randomized, placebo controlled studies were performed to investigate the effect of electroacupuncture on gastric acid output in 38 healthy males. Electroacupuncture decreased basal acid output when compared to placebo acupuncture [from 3.50 +/- 0.59 mmol/hr to 2.54 +/- 0.56 mmol/hr (P < 0.05)] as well as sham feeding-stimulated acid output [from 18.52 +/- 2.25 mmol/hr to 5.38 +/- 2.11 mmol/hr (P < 0.005)], but had no effect on the pentagastrin stimulated acid output. The inhibitory effect of acupuncture on sham feeding-stimulated acid output was not affected by local anesthesia of the acupoint, but was prevented by a prior intravenous naloxone injection. Acupuncture did not alter plasma gastrin levels (20.7 +/- 7.6 micrograms/liter, vs control 21.2 +/- 7.2 micrograms/liter) but naloxone increased it (26.1 +/- 14.5 micrograms/liter) (P < 0.05). We conclude that the antisecretory effects of electroacupuncture do not result from decreased gastrin release or decreased parietal cell sensitivity to gastrin, but are mediated through naloxone-sensitive opioid neural pathways and vagal efferent pathways.

Effects of chronic left vagal stimulation on visceral vagal function in man.

We examined the effects of chronic left vagal electrostimulation on afferent and efferent gastrointestinal vagal function in eight patients. Afferent function was assessed using cortical evoked responses to electrical stimulation of the esophagus and to direct vagal stimulation using the implanted left vagal electrode. Efferent gastrointestinal vagal function was measured by examining the basal, maximal, and sham fed stimulated gastric acid output prior to and with chronic left vagal electrostimulation. Esophageal electrostimulation produced a cortical evoked response consisting of three negative and three positive peaks within 400 msec after stimulation. Prior to vagal electrostimulation the mean conduction velocity of the afferent signal was measured at 8.72 +/- 3.39 m/sec, compatible with A-delta fibers involvement. Basal, maximal, and sham fed acid output were 1.11, 21.87, and 9.37 mmol/hour, respectively. The evoked response to esophageal electrical stimulation was not changed with chronic left vagal electrostimulation. Direct vagal stimulation also produced evoked potentials that were comparable to those obtained with esophageal stimulation. The mean conduction velocity was 6.26 +/- 2.72 m/sec (NS) so that there was no evidence of loss of myelinated fibers with chronic stimulation. No differences were detected in basal (1.29 mmol/h), maximal (21.64 mmol/h), or sham fed stimulated (8.03 mmol/h) acid output, showing that vagal electrostimulation has no effect on either total or vagally mediated acid output, an efferent vagal function. In conclusion, chronic left vagal electrostimulation has no significant adverse effect on gastrointestinal vagal function.

Prospective comparison of double contrast barium enema plus flexible sigmoidoscopy v colonoscopy in rectal bleeding: barium enema v colonoscopy in rectal bleeding.

Rectal bleeding often heralds serious colonic disease. The literature suggests that colonoscopy is superior to barium enema plus sigmoidoscopy, although no good comparative studies exist. Seventy one patients with overt rectal bleeding had prospectively flexible sigmoidoscopy, double contrast barium enema and colonoscopy completed independently. Against the gold standard, the sensitivity and specificity of colonoscopy were 0.69 and 0.78 respectively for a spectrum of colonic lesions, while for combined flexible sigmoidoscopy and double contrast barium enema these values were 0.80 and 0.56, respectively. When assessing adenoma or carcinoma, colonoscopy was more sensitive at 0.82 v 0.73, while flexible sigmoidoscopy plus double contrast barium enema was superior for detecting diverticular disease. The positive predictive value for colonoscopy was 0.87 against 0.81 for flexible sigmoidoscopy and double contrast barium enema. This study confirms that colonoscopy should be a first line investigation in subjects likely to require biopsy or therapeutic intervention.

Omeprazole (20 mg daily) versus cimetidine (1200 mg daily) in duodenal ulcer healing and pain relief.

We conducted a double-blind, randomized, parallel group study in 169 patients with acute duodenal ulcers to compare omeprazole, 20 mg daily, with cimetidine, 600 mg twice daily. After 2 wk, 58% of the omeprazole-treated patients and 46% of the cimetidine-treated patients were completely healed (p = 0.056). After 4 and 6 wk 84% and 88% healed with omeprazole, and 80% and 89% healed with cimetidine (p = NS). After 2 wk, pain was completely gone in 62% of the omeprazole-treated patients versus 46% of the cimetidine-treated patients (p = 0.04). Clinical or laboratory adverse events were reported in 6 (7%) of the omeprazole-treated patients and 11 (13%) of the cimetidine-treated patients (p = NS). An adverse event caused withdrawal of 1 patient on omeprazole (anxiety and depression) and 2 patients on cimetidine (diarrhea and fall in hemoglobin). We conclude that omeprazole (20 mg daily) resulted in a trend toward more rapid ulcer healing compared with a relatively high dose of cimetidine (600 mg b.i.d.), and was preferred by patients for relief of ulcer pain.

The role of colonoscopy in complicated diverticular disease. A review.

Colonoscopy in complicated diverticular disease may assist the clinician in establishing the diagnosis of associated strictures. A review of the literature shows that carcinoma was identified in 21 (17%) of 125 patients and that an additional diagnosis was made in 40 (32%) patients. Although colonoscopy may be a difficult procedure in patients with diverticular disease the caecum was reached in 27 (61%) of 44 patients and took no longer than routine colonoscopic orpcedures. Further analysis of these results confirms that the barium enema frequently produces both false positive and false negative diagnoses of carcinoma and polyps. The presence of bleeding strongly suggests the presence of a concomitant lesion. Fifteen (11%) carcinomas were identified in a group of 135 patients with persistent rectal bleeding whose barium enema showed only diverticular disease and an additional diagnosis was made in 50 (37%) of these patients. Colonoscopy is an important investigation in patients with complicated diverticular disease.

Controlled comparison of cimetidine and carbenoxolone sodium in gastric ulcer.

Fifty-four outpatients with endoscopically diagnosed benign gastric ulcer were allocated at random to treatment with either cimetidine 800 mg daily for six weeks or carbenoxolone sodium 300 mg daily for one week then 150 mg daily for five weeks. Ulcers were reassessed by endoscopy at the end of the trial. The endoscopist was unaware of the treatment and did not take part in the clinical care of the patients. Twenty-one of the 27 patients (78%) given cimetidine and 14 of the 27 (52%) given carbenoxolone had healed ulcers. Symptomatic response occurred earlier with cimetidine but was not significantly better. Unwanted effects were more common in the carbenoxolone group: 12 patients developed hypokalaemia, four of whom needed oral potassium supplements. The results suggest that histamine H2-receptor blockade is at least as effective as carbenoxolone sodium for benign gastric ulcer and produces fewer side effects.