Poor tolerability of thalidomide in end-stage oesophageal cancer.

Oesophageal cancer cachexia is a significant clinical problem, resulting in excessive morbidity and mortality. In a pilot study, 10 patients with cachexia due to advanced cancer of the oesophagus gained weight, including lean tissue, after 14-day treatment with thalidomide. Here, we present randomised placebo controlled trial data over a 6-week period to test the hypothesis that thalidomide is superior to placebo in terms of weight gain in patients with cachexia caused by oesophageal cancer. Thalidomide, 200 mg daily, or an identical placebo was given to patients with advanced oesophageal cancer. Total body weight and lean body mass were assessed in addition to drug tolerability and performance indices. Thirty-four patients were recruited. Of these, six given thalidomide and 16 given placebo completed the protocol; all withdrawals were due to adverse drug reactions or complications of disease. Thalidomide showed no benefit over placebo in participants who completed the protocol. These data suggest that thalidomide is poorly tolerated in patients with advanced cancer of the oesophagus and may not ameliorate the progression of cachexia. In the absence of hard supportive evidence, off-licence treatment with thalidomide should be used with great caution as an adjunct to nutritional support in patients with advanced cancer.

Oesophageal cancer and cachexia: the effect of short-term treatment with thalidomide on weight loss and lean body mass.

BACKGROUND: Cachexia is common in patients with advanced cancer and has a direct impact on well-being and mortality. AIM: To test the hypothesis that thalidomide can promote weight gain and lean body mass in patients with advanced oesophageal cancer. METHODS: In an open-label study, 11 patients with non-obstructing and inoperable oesophageal cancer were established on an isocaloric diet for 2 weeks, followed by 2 weeks on thalidomide, 200 mg daily. The primary end-points were weight change and lean body mass. Secondary end-points were quality of life and changes in resting energy expenditure. RESULTS: Ten patients completed the study protocol. The average caloric intake remained the same throughout the study period in all patients. Nine of 10 patients (95% confidence interval, 0.60, 0.98) lost weight on diet alone. The mean weight gain on thalidomide in the following 2 weeks was 1.29 kg (median, 1.25 kg). A similar trend was shown in the lean body mass. Eight of nine patients (95% confidence interval, 0.57, 0.98) initially lost lean body mass on diet alone (missing data in one patient). The mean gain in lean body mass on thalidomide in the following 2 weeks was 1.75 kg (median, 1.33 kg). CONCLUSIONS: Thalidomide treatment appeared to reverse the loss of weight and lean body mass over the 2-week trial period.

Drug treatments in upper gastrointestinal bleeding: value of endoscopic findings as surrogate end points.

INTRODUCTION: Pharmacotherapy for upper gastrointestinal bleeding has been difficult to evaluate because clinical end points are infrequent and affected by other factors. AIMS: To evaluate whether blood in the stomach at endoscopy reflected severity of bleeding, predicted clinical outcomes, and could be altered by therapeutic agents. METHODS: We studied 414 consecutive admissions with suspected upper gastrointestinal bleeding. Patients were randomised to receive lansoprazole 60 mg followed by 30 mg four times daily, tranexamic acid 2 g followed by 1 g four times daily, both drugs, or placebo for four days, until discharge or a clinical end point occurred. Logistic regression analysis was used to determine predictors of endoscopic changes and clinical outcomes, and to investigate the effects of drug treatments on blood in the stomach. RESULTS: Of 414 patients with suspected upper gastrointestinal bleeding, 379 were endoscoped. Upper gastrointestinal bleeding was confirmed in 316. Sixteen required surgery within 30 days and 16 died on the index admission. Trial treatments were evaluable on a per protocol basis in 228 patients. The amount of blood in the stomach was found to reflect initial risk, with significant associations with high risk categorisation (odds ratio 3.7 (95% confidence interval 1.5-9.4) for more than a trace v none/trace), age (1.5 (1.1-1.9) per decade), and initial pulse (1.02 (1.00-1.04) per beat), and to predict rebleeding (9.2 (4.6-18.7)) and surgery (8.2 (2.9-22.9)). Other stigmata were less significant in these respects. The amount of blood in the stomach at endoscopy was reduced significantly by both lansoprazole (0.22 (0.07-0.63)) and tranexamic acid (0.27 (0.09-0.81)), although there was no evidence of synergy. CONCLUSIONS: Blood in the stomach reflects clinical features in patients with acute upper gastrointestinal bleeding and is reduced by treatment with lansoprazole and tranexamic acid.

Placement of esophageal self-expanding metallic stents without fluoroscopy.

BACKGROUND: Fluoroscopy is routinely used to guide the placement of self-expanding metallic stents for the palliative treatment of patients with esophageal malignancy. This is a description of a novel method of stent placement without fluoroscopy. METHODS: This technique relies on a clear endoscopic view of the proximal radiopaque marker on the stent. This was achieved by the application of an external white marker at this level. A gastroscope was passed, allowing guidewire deployment and measurement of stricture length. The endoscope was reinserted and placed alongside the guidewire giving direct visualization of the proximal margin of the stricture. The stent delivery device was positioned, keeping the white mark visible proximal to the stricture, and the stent was deployed. RESULTS: Thirty consecutive patients with inoperable esophageal malignancy underwent endoscopic placement of self-expanding metal stents. Deployment in satisfactory position without fluoroscopy was successful in 23 of 30 (77%); there were no complications. CONCLUSIONS: The majority of esophageal stents can be accurately positioned without fluoroscopy.

Protection of human gastric mucosa against aspirin-enteric coating or dose reduction?

BACKGROUND: Aspirin is widely used for cardiovascular prophylaxis. AIM: To compare the effectiveness of two widely-used strategies-dose reduction and enteric coating-for the minimization of gastric mucosal injury or toxicity. METHODS: Twelve healthy volunteers were studied. On four separate occasions each received, under blinded conditions, five daily doses of plain aspirin 300 mg, plain aspirin 75 mg, enteric-coated aspirin 300 mg or placebo. Ex vivo prostaglandin E2 synthesis was stimulated by the vortex mixing of gastric mucosal biopsies in Tris saline and measured by radioimmunoassay. Mucosal injury was quantified both by counting erosions and with a visual analogue scale. RESULTS: All three preparations reduced prostaglandin E2 synthesis by day five, by (median) 84% for plain aspirin 300 mg, by 80% for enteric coated aspirin 300 mg and by 63% for plain aspirin 75 mg. There was little mucosal injury prior to the start of each dose and period and no significant change with placebo. Plain aspirin caused a dose-dependent mucosal injury, with two (median, IQR 0-7) gastric erosions after five days of plain aspirin 75 mg, and 18 (2-26) after five days of plain aspirin 300 mg. With enteric-coated aspirin 300 mg there were 0 (0-1) gastric erosions (P = 0.003 compared to plain aspirin 300 mg P = 0.11, compared to plain aspirin 75 mg). CONCLUSION: Enteric coated aspirin reduces acute gastric mucosal injury to placebo levels, despite its inhibition of prostaglandin synthesis. Enteric coating is an appropriate strategy for the prevention of gastric mucosal damage induced by low-dose aspirin, which warrants systematic clinical evaluation.

Platelet responses to several agonists and combinations of agonists in whole blood: a placebo controlled comparison of the effects of a once daily dose of plain aspirin 300 mg, plain aspirin 75 mg and enteric coated aspirin 300 mg, in man.

Platelet responses to several agonists and combinations of agonists have been measured in whole blood from healthy volunteers. We have determined the effects of once daily treatment for five days with plain aspirin 300 mg, plain aspirin 75 mg, enteric coated aspirin 300 mg or placebo. Measurements were made of platelet aggregation (using a platelet counting technique) and the release reaction (14C-5HT release from pre-labelled platelets). The extents of these responses before aspirin administration depended on the agonist used. ADP, adrenaline and PAF failed to induce any 14C-5HT release in most subjects, but combinations of these agonists acted synergistically to produce extensive 14C-5HT release. All three aspirin preparations reduced the extent of the platelet responses to most agonists: platelet aggregation induced by collagen, ristocetin and arachidonate and 14C-5HT release induced by collagen, streptokinase, and various combinations of ADP, adrenaline and PAF. None of the preparations had any effect on the aggregation that occurred in the absence of an agonist (spontaneous aggregation), but they all reduced streptokinase-induced aggregation to control (spontaneous) levels, and abolished the 14C-5HT release induced by arachidonate and by ristocetin. All three aspirin preparations were equally effective after two daily doses. No further inhibition of platelet responses was obtained after five daily doses. Plain aspirin 300 mg achieved its maximal effect after only a single dose, but enteric coated aspirin 300 mg (and sometimes plain aspirin 75 mg) produced sub-maximal inhibition after only a single dose. Parallel investigations on the effects of these aspirin regimes on gastric mucosal prostaglandin E2 synthesis and gastroduodenal mucosal injury were performed. These results will be reported separately.

Effect of sucralfate on aspirin induced mucosal injury and impaired haemostasis in humans.

BACKGROUND: Sucralfate does not have potent anti-ulcerogenic actions in users of non-steroidal anti-inflammatory drugs (NSAIDs). However, sucralfate may influence intragastric haemostasis favourably. AIM: To investigate separately the effects of sucralfate on acute gastric and duodenal injury and on changes in intragastric bleeding induced by aspirin. METHOD: On three occasions, 24 healthy volunteers received three days' treatment with aspirin 900 mg twice daily together with placebo, sucralfate 2 g twice daily or sucralfate 1 g four times daily. Injury was assessed endoscopically and bleeding by spontaneous and biopsy induced bleeding intragastric washings. Ex vivo prostaglandin E2 (PGE2) synthesis and serum thromboxane were measured by using radioimmunoassay. RESULTS: Aspirin significantly inhibited ex vivo gastric mucosal PGE2 synthesis, reduced serum thromboxane, caused gastric erosions, and increased spontaneous and biopsy induced bleeding. Sucralfate had no significant effects on endoscopic injury but sucralfate 1 g four times daily significantly reduced spontaneous and biopsy induced bleeding. Similar trends were seen with sucralfate 2 g twice daily but the results were less consistent. CONCLUSION: Sucralfate does not affect aspirin induced acute gastric mucosal injury but reduces aspirin associated intragastric bleeding.

Mucosal factors inducing neutrophil movement in ulcerative colitis: the role of interleukin 8 and leukotriene B4.

BACKGROUND: The movement of neutrophils into the colonic mucosa in ulcerative colitis is induced by chemokines including interleukin 8 (IL8) and leukotriene B4 (LTB4). AIMS: To compare the ability of mucosa from ulcerative colitis patients and controls to stimulate neutrophil movement, to define the contribution of LTB4 to this, and to define the relative biological importance of LTB4 and IL8. PATIENTS: Resected mucosa was obtained from seven control patients and 10 patients with ulcerative colitis. METHODS: Mucosal homogenate supernatants were used to stimulate isolated neutrophils and the effect assessed by the neutrophil shape change response. Responses were inhibited with either the LTB4 receptor antagonist SC41930- or neutralising anti-IL8 antibody. LTB4 was extracted and assayed by RIA. RESULTS: Homogenate supernatants from inflamed mucosa were more bioactive (median 1.2 mg/ml-1 induced 50% response) than those from uninflamed mucosa (4.25 mg/ml-1 induced 50% response; difference 2.8 mg/ml-1 (96.5% CI 0.5 to 6.1, p < 0.05). Maximal inhibition by SC41930 of the response was significantly greater in inflamed mucosa (54% median) than in uninflamed mucosa (34%). This inhibition correlated with the level of immunoreactive LTB4 (r = 0.78). Anti-IL8 reduced bioactivity of homogenate supernatants from inflamed mucosa (at 1:10 dilution) by 11.4% (IQR 1.2 to 51.8, p = 0.021) whereas SC41930 reduced it by 54.8% (35.6 to 77.5, p = 0.008). CONCLUSIONS: Inflamed colonic mucosa releases more neutrophil movement inducing bioactivity than uninflamed mucosa, and has greater LTB4 dependent activity. It yields both IL8 and LTB4 dependent activity but greater LTB4 dependent activity.

Comparison of effects of calcium carbasalate and aspirin on gastroduodenal mucosal damage in human volunteers.

Calcium carbasalate is a therapeutically active salicylate which seems to cause less gastroduodenal mucosal damage than aspirin in laboratory animals. This endoscopist-blinded, randomised, cross over trial aimed to compare acute gastric mucosal damage in 20 healthy volunteers treated with acetyl salicylic acid (ASA) (650 mg three times daily) and effervescent calcium carbasalate (ECC) (826.8 mg three times daily) bioequivalent to 650 mg ASA over a five day period. Endoscopy was performed immediately before treatment and on day 5 of each treatment. Serum salicylate, thromboxane B2, and gastric mucosal prostaglandin E2 (PGE2) concentrations were measured after endoscopy. ECC caused fewer gastric mucosal erosions than ASA. The total number of gastric erosions was 23.8 (16.1) in the ASA treated subjects compared with 9.1 (8.7) in ECC treated subjects (p = 0.004). Differences between ASA and ECC were significant for both the gastric antrum and body, and for both haemorrhagic and non-haemorrhagic erosions. The mean gastric body Lanza score for mucosal damage was lower after ECC than ASA (p = 0.003). The visual analogue score for gastric body damage was lower for ECC (16.9 mm (15.9)) than for ASA (32.7 mm (20.8)), p = 0.008. Serum salicylate concentrations were similar after both preparations (ASA: 66 (23) mg/l, versus ECC: 58 (17) mg/l, NS). Serum thromboxane B2 was similarly reduced using both preparations-97.2 (3.5)% inhibition with ASA, 95.2 (5.5)% inhibition with calcium carbasalate (NS). Suppression of gastric mucosal PGE2 synthesis was similar with both preparations (ASA: 83.4 (17.1)%; ECC 84.3 (12.9)%; NS). It is concluded that ECC causes significantly less gastroduodenal mucosal damage than ASA administered at bioequivalent doses as judged by serum salicylate, serum thromboxane, and mucosal PGE2 values. ECC may therefore be a less harmful alternative treatment to plain ASA.

A flow cytometric method to measure shape change of human neutrophils.

1. We report a flow cytometric method in which changes in forward angle light scatter are shown to correlate with microscopically evaluated shape change in stimulated human neutrophils. Neutrophil movement and chemotaxis is conventionally measured using Boyden chambers, which is a laborious and exacting technique. Microscopic scoring of neutrophil shape change has been shown to correlate well with Boyden chamber measurements, and although less laborious, still requires manual counting. 2. We now show that measurement of forward angle light scatter in a benchtop flow cytometer correlates closely with microscopic evaluation of neutrophil shape change in dose-response stimulation experiments with leukotriene B4, N-formyl-methionine-leucine-phenylalanine or interleukin-8. The relationship between shape change and increased forward angle light scatter was confirmed using the fluorescence-activated cell sorter to separate partially stimulated neutrophils, followed by reanalysis by flow cytometry and microscopic examination. 3. This flow cytometric method provides a convenient, rapid and objective measure of neutrophil responses to external stimuli.

Low dose aspirin: selective inhibition of rectal dialysis thromboxane B2 in healthy volunteers.

AIM: To investigate the degree and selectivity of rectal thromboxane inhibition by low dose aspirin and there by investigate the contribution of platelet thromboxane to rectal thromboxane. METHODS: The study was a randomized double-blind placebo controlled crossover study. Twelve healthy volunteers were studied, each over four separate study periods with two weeks wash-out between each period. Changes in levels of thromboxane (TX) B2, prostaglandin (PG) E2 and leukotriene (LT) B4 in rectal dialysates were measured in response to 5 days oral low dose aspirin therapy in one of three once-daily formulations (plain 75 mg, plain 300 mg or enteric coated 300 mg), and compared to placebo. For each study period, rectal dialysates (4 h duration) were obtained at baseline and twice more after 5 days of aspirin or placebo therapy. Dialysate levels of thromboxane B2, leukotriene B4, prostaglandin E2, and serum thromboxane B2 were measured by radioimmunoassay. RESULTS: Dialysate thromboxane B2 levels were consistently inhibited by low dose aspirin (overall results of all formulations, 75 to 300 mg daily) from 1.06 ng/ml (geometric mean, 95% CI: 0.79-1.43 ng/ml) on placebo, by 29% (95% CI: 11-40%) to 0.75 ng/ml (0.56-1.01 ng/ml) (P = 0.046) on aspirin. In the absence of aspirin the level of prostaglandin E2 was 1.47 ng/ml (0.97-2.23 ng/ml) and in the presence of aspirin was not significantly changed. The dialysate level of leukotriene B4 was 0.45 ng/ml (0.34-0.61 ng/ml) in the absence of aspirin and there was no significant change on low dose aspirin. Serum thromboxane was inhibited by 80% to 20% of placebo values by plain aspirin 75 mg, by 95% by plain aspirin 300 mg, and by 82% by enteric coated aspirin 300 mg, respectively (P < 0.01). These results show that 29% of the rectal thromboxane, but none of the rectal prostaglandin E2 or leukotriene B4 is inhibited by low dose aspirin. We infer that 34% of the rectal thromboxane B2 is platelet-derived in our volunteers. CONCLUSION: Low dose aspirin will selectively inhibit a proportion of rectal thromboxane and may have prophylactic therapeutic potential in inflammatory bowel disease.

Treatment of inflammatory bowel disease from now to the millennium.

After decades of therapeutic stasis, treatment advances are occurring in inflammatory bowel disease. Recognition that mesalazine was the active moiety of sulphasalazine has led to a number of new methods of delivering mesalazine without sulphapyridine, with improved toxicity ratios. Current attempts to deliver topical steroids directly to the large bowel have yet to be established as therapeutically effective. Immunosuppressive treatment has been used for many years but recent evidence has firmly established its value and cyclosporin has recently been added to the therapeutic armamentarium. Increasing understanding of the basic processes of inflammation has yielded targets for anti-inflammatory treatments aimed both at the processes of immune activation and of attraction by chemotaxis of neutrophils from the circulation to the lamina propria. Some of these novel treatments, which will be assessed in forthcoming years, involve large molecular weight bioengineered peptides and antibodies that are likely to be expensive and difficult to administer. Other treatment, e.g. 5-lipoxygenase or thromboxane synthesis inhibitors or platelet-activating factor antagonists, are conventional lower molecular weight compounds that are easier to produce and are orally active. It is predicted that 5-lipoxygenase inhibitors will be the next therapeutic advance in inflammatory bowel disease. Such a prediction may founder if blanket suppression of multiple inflammatory mechanisms, rather than targeted actions, is required in inflammation.

Roles of leukotriene B4, prostaglandin E2, and cyclic AMP in Campylobacter jejuni-induced intestinal fluid secretion.

Infection of rabbit ileal loops with inflammatory Campylobacter jejuni strains caused elevation of cyclic AMP, prostaglandin E2, and leukotriene B4 levels in tissue and fluids. Incubation of cultured Caco-2 cells with loop fluids caused elevated cellular cyclic AMP levels, an effect which was inhibited by antiserum against prostaglandin E2.

Ranitidine bismuth citrate and aspirin-induced gastric mucosal injury.

The aim of this study was to investigate the protective action of a new compound, ranitidine bismuth citrate, in the prevention of aspirin-induced acute mucosal injury to the upper gastrointestinal tract of healthy human volunteers. In a double-blind randomized three-way cross-over study 24 male volunteers received placebo, 900 mg aspirin or 900 mg aspirin and 800 mg ranitidine bismuth citrate at 12-h intervals for nine doses with a 2-week wash-out period between each treatment. The median (interquartile range) number of erosions seen at endoscopy when ranitidine bismuth citrate was given with aspirin (1 [0-4]) was significantly lower than aspirin alone (24 [16-32]) (P < 0.001) and not significantly different from either baseline or placebo (0 [0-2]). These findings were similarly reflected in the effects on microbleeding following the ninth dose: 12.1 (7.1-21.0) microL/10 min following aspirin alone compared to levels with placebo of 1.2 (0.4-2.9), and with aspirin and ranitidine bismuth citrate of 1.6 (0.8-2.6) (P < 0.005). Ranitidine bismuth citrate conferred substantial protection from aspirin-induced injury to the gastric and duodenal mucosa as determined by both endoscopic assessment and microbleeding rates, reducing injury to placebo levels.

In vivo rectal inflammatory mediator changes with radiotherapy to the pelvis.

In vivo changes in the rectal values of eicosanoid inflammatory mediators induced by pelvic radiotherapy were measured to study the pathophysiology of the early radiation bowel reaction. Ten patients having pelvic radiotherapy, aged 57 to 78, had rectal dialysis. Values of the eicosanoids leukotriene B4 (LTB4), thromboxane B2 (TXB2), and prostaglandin E2 (PGE2) were measured before radiotherapy, at the end of radiotherapy, and at least four weeks after radiotherapy. Values of LTB4 rose with radiotherapy from 0.21 ng.ml-1 (median) to 1.14 ng.ml-1 (p = 0.012); PGE2 rose from 0.60 ng.ml-1 to 1.58 ng.ml-1 (p = 0.038), and TXB2 rose from 0.365 ng.ml-1 to 1.6 ng.ml-1 (p = 0.005). The rise in eicosanoid inflammatory mediators may have an important role in the pathophysiology of the early radiation bowel reaction.

Nitric oxide synthase activity in ulcerative colitis and Crohn's disease.

Excessive nitric oxide (NO) production by an isoform of NO synthase that can be induced by inflammatory stimuli leads to changes in vascular permeability and to tissue injury. We measured NO synthase activities in mucosa and muscle from the colons of control patients (n = 11) and patients with ulcerative colitis (6) or Crohn's disease (4). NO synthase activity in colonic mucosa of ulcerative colitis patients was 0.55 (median interquartile range 0.32-0.57) nmol/min per g tissue, which was about eightfold higher than the value in control mucosa, with no individual overlap (p < 0.001). With colonic muscle there was no difference in NO synthase activity between ulcerative colitis patients and controls. In the patients with Crohn's disease, mucosal NO synthase activity did not differ from control values and activity in the colonic muscle was low. Thus, induction of colonic NO synthase may be involved in the mucosal vasodilation and increased vascular permeability of active ulcerative colitis, and could also contribute to the impaired motility that accompanies toxic dilation.

Ranitidine: differential effects on gastric bleeding and mucosal damage induced by aspirin.

This study investigated the influence of ranitidine on mucosal injury and gastric bleeding in 20 normal volunteers taking 600 mg aspirin q.d.s. This study was a double-blind placebo controlled crossover study comparing ranitidine, as 150 mg b.d., 300 mg q.d.s. and 600 mg b.d. with placebo. Gastric mucosal injury was assessed at unsedated endoscopy by counting haemorrhagic and non-haemorrhagic erosions; bleeding was measured in gastric washings. Aspirin alone increased mucosal injury from 0 to 11.4 erosions (mean, P < 0.01) and bleeding from 1.77 to 9.11 microliters blood/10 min (mean P < 0.001). Ranitidine prophylaxis reduced bleeding to 5.34, 3.18 and 3.47 microliters/10 min with 150 mg b.d., 300 mg q.d.s. and 600 mg b.d. respectively (overall effect of ranitidine P < 0.001) and also reduced haemorrhagic erosions though it had no effect on the total number of erosions. Ranitidine is effective at reducing aspirin-induced gastric bleeding and whilst not reducing aspirin-induced gastric erosions, it does reduce the number that appear haemorrhagic. Ranitidine may have a role in the prophylaxis of aspirin-induced gastric bleeding.