Optimal assessment of gastrointestinal side effects induced by non-steroidal anti-inflammatory drugs. Endoscopic lesions, faecal blood loss, and symptoms not necessarily correlated, as observed after naproxen and oxindanac in healthy volunteers

Gastrointestinal side effects caused by naproxen and oxindanac (a developmental non-steroidal anti-inflammatory drug) were compared by combined endoscopy and determination of faecal blood loss in 16 healthy male volunteers in a randomized, double-blind, crossover study. Individual daily faecal blood loss was determined by means of 51Cr-labelled erythrocytes. Gastroduodenoscopy was performed before and after administration of naproxen, 750 mg/day, and oxindanac, 600 mg/day, for 1 week each. A washout period of at least 3 weeks was inserted between drug periods. Visual analogue scales (VAS) were used for endoscopic assessment of lesions and subjective complaints. Mean faecal blood loss increased from a base line 0.48 ml/24 h to 1.59 ml/24 h with naproxen (p less than 0.01) and from 0.56 ml/24 h to 1.31 ml/24 h with oxindanac (p less than 0.01). VAS scores for gastroduodenal lesions increased significantly with both drugs. Naproxen caused a significantly greater increase than oxindanac (p less than 0.05). There was no correlation between gastrointestinal blood loss and endoscopic findings. Subjective symptoms were correlated to faecal blood loss with naproxen, but not to endoscopic findings. No such correlations were observed for oxindanac. Naproxen caused a significant prolongation of bleeding time (p less than 0.01), whereas the increase caused by oxindanac was not significant (p = 0.09).     

Gastric mucosal damage caused by plain and microencapsulated acetylsalicylic acid tablets in healthy subjects: a gastrocamera study.

In a randomized, cross-over study plain acetylsalicylic acid (ASA) tablet and microencapsulated ASA tablets were given in doses of 1 gram 3 times a day for 3 days to 8 healthy subjects with no previous gastrointestinal disturbances. Gastrocamera examinations were performed before the ASA treatment and 1--2 hours after the last dose of ASA. The gastric mucosa appeared macroscopically normal at all the control examinations; whereas musocal bleeding was evident in all the subjects after the ASA treatment. There was no statistically significant difference between the plain ASA and the microencapsulated ASA preparations. No correlation could be found between the ASA concentration in plasma and the gastric mucosal damage.     

Occult faecal blood loss determined by a 51Cr method and chemical tests in patients referred for upper gastrointestinal endoscopy

In 119 patients referred for upper gastrointestinal endoscopy, the faecal blood loss was determined by a 51Cr method and 7 chemical tests. For patients with negative upper endoscopy (no. = 8), atrophic gastritis (no. = 30), gastric ulcer (no. = 31), or gastric cancer (no. = 23), the median 51Cr-determined faecal blood loss was 0.51, 0.61, 0.83, and 2.68 ml/24 h, respectively. For all chemical tests, the results were highly influenced by the upper time limit for positive reaction. Mixing of faecal specimens before testing did not prove essential. By repeated analyses of faecal samples stored for 3 days, the benzidine test showed a decreased sensitivity (p less than 0.01), whereas Fecatwin and Fecatwin sensitive showed an increased number of positive tests (p less than 0.01). Of cases of gastric cancer, tetramethylbenzidine tests including Hemo-Fec Test, benzidine test, Fecatwin sensitive, Hemoccult II, and Fecatwin could detect about 85%, 80%, 60%, 55%, and 30%, respectively.     

Does sucralfate reduce acetylsalicylic-acid-induced gastric mucosal bleeding?

We studied the possible protection of sucralfate with regard to acetylsalicylic acid (ASA)-induced gastric mucosal bleeding as measured by a radiochromium assay of faecal blood loss in a double-blind crossover study involving 16 healthy male volunteers. Medication was given in two combinations during the 2nd and 5th week of the study: 1 g ASA and 1 g sucralfate four times daily, or 1 g ASA four times daily and placebo tablets. Mean faecal blood loss (+/- SEM) was 0.38 +/- 0.04 ml/day in the 1st week (no drugs administered), 7.17 +/- 1.60 ml/day during treatment with ASA + sucralfate, and 9.59 +/- 1.76 ml/day during treatment with ASA + placebo, the difference being not statistically significant. Individual bleeding values registered during sucralfate treatment correlated with those measured in the placebo period. However, three persons with pronounced bleeding after ASA + placebo had minimal bleeding after ASA + sucralfate. Sucralfate may have a protective potential by reducing ASA-induced gastric mucosal bleeding, but further studies are required to evaluate its protective mechanisms and to identify the groups of patients that could benefit from this.     

Prevention of aspirin-induced faecal blood loss by prostaglandin E2.

Prostaglandins have been shown in animal laboratory studies to be capable of protecting the gastrointestinal tract against injury by exogenous agents. This study was conducted to determine if prostaglandin E2 (PGE2), which is native to the human gastric mucosa, could influence the increase in faecal blood loss associated with the ingestion of aspirin (ASA). A randomised double-blind study was performed on 27 healthy men. Faecal blood loss was measured by the 51Cr labelled red cell technique. ASA (600 mg four times daily) caused a significant increase in faecal blood loss. PGE2 (1 mg four times daily) had no effect on faecal blood loss when administered alone. When given in addition to ASA it resulted in a faecal blood loss not significantly different from control. No significant alteration in intestinal transit occurred. It is concluded that PGE2 protects man from the gastrointestinal injury associated with ASA.     

Occult faecal blood loss determined by a 51Cr method and chemical tests in patients referred for colonoscopy

In 67 patients referred for colonoscopy the faecal blood loss was determined by a 51Cr method and 7 chemical tests. For patients with negative colonoscopy (no. = 10), colorectal polyps (no. = 24), rectal cancer (no. = 8), or colonic cancer (no. = 12), the median 51Cr-determined faecal blood loss was 0.67, 0.74, 1.26, and 2.18 ml/24 h, respectively. For all chemical tests the results were highly influenced by the upper time limit for a positive reaction. Mixing of faecal specimens before testing proved unimportant. Fecatwin sensitive showed more positive tests in delayed compared with immediate analyses (p less than 0.01). Of cases of colorectal polyps, tetramethylbenzidine (TMB) tests including Hemo-Fec Test could detect half, the benzidine test 2 of 5. Fecatwin sensitive and Hemoccult II 1 of 4, and Fecatwin 1 of 24. Of cases of colorectal cancer, TMB tests, the benzidine test, Fecatwin sensitive, Hemoccult, and Fecatwin could detect about 85%, 85%, 85%, 80%, and 45%, respectively. All chemical tests detected faecal blood loss from colorectal lesions more easily than from gastric lesions.     

Faecal blood loss during administration of acetylsalicylic acid, ketoprofen and two new ketoprofen sustained-release compounds

The influence of one week's treatment with acetylsalicylic acid, ketoprofen, ketoprofen sustained-release capsules (Biovail capsules), and ketoprofen sustained-release tablets (IBP tablet) on gastrointestinal bleeding was investigated in 41 healthy male volunteers by means of a radiochromium assay. The physiological faecal bleeding was 0.10 to 0.90 ml/day (99% confidence limits). It appeared that faecal bleeding during treatment with acetylsalicylic acid medication was greater than bleeding during medication with ketoprofen capsules in equipotent dosage, the latter being in turn causing significantly more bleeding than during medication with the newly developed Biovail capsules. The most modest faecal bleeding (0.8 ml/day) was seen with IBP tablets.     

Gastrointestinal Blood Loss with Low Dose (325 mg) Plain and Enteric-Coated Aspirin Administration

Objectives : The purpose of this study was to assess gastrointestinal blood loss with low dose (325 mg) plain and enteric-coated aspirin. Methods : A total of 47 healthy volunteers participated in randomized, controlled acute and chronic trials. Seventeen participated in a repeated measures acute trial, and 30 participated in an independent sample chronic trial. Gastrointestinal blood loss was determined by obtaining 72-hour stool collections and quantitating Chromium-51 labeled erythrocytes Results : Acute phase trials: gastrointestinal blood loss during base line was 0.47 (±0.11) mL/day, 0.96 (±0.12) mL/day with enteric-coated aspirin ( p < 0.0006), and 1.82 (±0.35) mL/day with plain aspirin ( p < 0.0001 vs . base line, p = 0.0476 vs . enteric-coated aspirin). Chronic phase trials: gastrointestinal blood loss was 1.12 (±0.31) mL/day with enteric-coated aspirin ( p = 0.0024 vs . control) and 2.60 (±0.68) with plain aspirin ( p < 0.0001 vs. control, p = 0.0364 vs . enteric-coated aspirin). Conclusions : During acute and chronic ingestion, plain aspirin at a dose of 325 mg/day significantly increased gastrointestinal blood loss when compared to control or enteric-coated aspirin values, although enteric-coated aspirin values were also significantly increased compared to control. Gastric adaptation does not decrease blood loss with low dose aspirin consumption.     

Sodium homeostasis after small-bowel resection

In 16 small-bowel-resected patients, 8 with ileostomy and 8 with at least half of the colon in function, plasma volume, plasma aldosterone concentration, plasma renin activity, and the 4-day excretion of sodium and potassium in urine and stools were determined. Patients with ileostomy had a high faecal loss of sodium: 85-181 (median, 149) mmol/24 h, and were all more or less sodium-depleted with decreased plasma volume of 1.4-2.5 (median, 2.0) l/175 cm (normal range, 2.3-3.8l/175 cm), increased plasma aldosterone of 742-2250 (median, 1131) pg/ml (normal range, 33-220 pg/ml), and extremely low sodium excretion in the urine of 0-3 (median, 1) mmol/24 h. Patients with similar small-bowel resection but with at least half of the colon in function had a much smaller faecal sodium loss of 1-66 (median, 8) mmol/24 h. They showed significantly higher plasma volume, 2.2-3.7 (median, 2.6) l/175 cm; normal plasma aldosterone, 25-232 (median, 124) pg/ml; and normal or almost normal sodium excretion in the urine, 49-168 (median, 118) mmol/24 h. Six jejunostomy patients, who sustained a normal or almost normal sodium balance thanks to parenteral saline, had intravenous infusion over 6 h of 1000 ml isotonic sodium chloride with or without aldosterone added. During aldosterone infusion plasma aldosterone increased to the level in the sodium-depleted ileostomy patients. Urinary sodium excretion decreased significantly. Stomal sodium loss did not change. It is concluded that small-bowel resection in ileostomized patients causes excessive faecal sodium loss and results in chronic sodium depletion with severe secondary hyperaldosteronism.(ABSTRACT TRUNCATED AT 250 WORDS)     

Investigation of normal flatus production in healthy volunteers.

Flatulence can cause discomfort and distress but there are few published data of normal patterns and volumes. Twenty four hour collections were made using a rectal catheter in 10 normal volunteers taking their normal diet plus 200 g baked beans. Total daily volume ranged from 476 to 1491 ml (median 705 ml). Women and men (both n = 5) expelled equivalent amounts. The median daily flatus hydrogen volume was 361 ml/24 h (range 42-1060) and the carbon dioxide volume 68 ml/24 h (range 25-116), three volunteers produced methane (3, 26, and 120 ml/24 h), and the remaining unidentified gas (presumably nitrogen) or gases contributed a median 213 ml/24 h (range 61-476). Larger volumes of flatus were produced after meals than at other times. Flatus produced at a faster rate tended to contain more fermentation gases. Flatus was produced during the sleeping period, but the rate was significantly lower than the daytime rate (median 16 and 34 ml/h respectively). Ingestion of a 'fibre free' diet (Fortisip) for 48 hours significantly reduced the total volume collected in 24 hours (median 214 ml/24 h), reduced the carbon dioxide volume (median 6 ml/24 h), and practically eradicated hydrogen production. The volume of unidentified gas was not significantly affected (median 207 ml/24 h). Thus fermentation gases make the highest contribution to normal flatus volume. A 'fibre free' diet eliminates these without changing residual gas release of around 200 ml/24 h.     

Pharmacokinetic interaction study between ranitidine and metoclopramide

The pharmacokinetics of metoclopramide in healthy volunteers was evaluated to determine if previously repeated doses of ranitidine inhibit the metabolism of the gastrointestinal prokinetic drug. Metoclopramide 20 mg (tablets) in combination with ranitidine 150 mg (tablets) were administered to 14 healthy human volunteers in a two treatment study design, separated by 5 days in which the ranitidine alone was administrated in single p.o. doses twice daily. Plasma concentrations of metoclopramide were determined during a 24 hour period following drug administration. Metoclopramide plasma concentrations were determined by a validated RP-HPLC method. Pharmacokinetic parameters were calculated with compartmental and non-compartmental analysis. In the two periods of treatments, the mean peak plasma concentrations Cmax were 44 ng/ml (metoclopramide alone) and 49.2 ng/ml (metoclopramide and ranitidine). The time taken to reach the peak, Tmax, was 1.15 hrs, and 1.21 hrs, respectively. The total areas under the curve (AUC) was 314.3 ng.hr/ml and 354.06 ng.hr/ml, respectively. The half-life (T 1/2) was 5.6 hr and 6.7 hr. A statistically significant difference was observed for both AUC and half-life of metoclopramide when administered alone or after 5 days of treatment with ranitidine. The experimental data proved the pharmacokinetic interaction between ranitidine of metoclopramide, and suggest monitoring adverse effects in patients.     

Effects of microencapsulated vs. enteric-coated acetylsalicylic acid on gastric and duodenal mucosa: an endoscopic study

Two preparations of acetylsalicylic acid (ASA) were tested for their effects on gastroduodenal mucosa in a randomized crossover double-blind study that involved 12 healthy volunteers. Medication M (Monobeltin) consisted of 1,050 mg ASA provided with an enteric coat and medication C (Colfarit) consisted of 1,000 mg of a microencapsulated ASA preparation. Both drugs were taken for 6 consecutive days each. Upper gastrointestinal endoscopy was performed before and 2 and 6 days after each medication. An interval of 10 days elapsed between one treatment and the other. Gastric lesions occurred in 10 of 12 subjects taking medication M and in 11 of 12 subjects taking medication C after 2 days and were present in all subject after 6 days. Duodenal lesions were seen only in subjects taking medication C. The degree of gastric mucosal lesions based on two grading scales was not significantly different between the two treatments. Neither of the two pharmaceutical formulations of ASA provided sufficient protection for the gastric mucosa.     

Influence of acetylsalicylic acid on plasma glucose, insulin, glucagon, and growth hormone levels following tolbutamide stimulation in man.

The effects of acetylsalicylic acid (ASA), a known inhibitor of prostaglandin (PG) synthesis, on plasma glucose, insulin, glucagon and growth hormone (GH) responses to tolbutamide were examined in ten normal volunteers. Treatment with 3.2 g ASA daily for 3 days caused a significant reduction in basal plasma glucose levels (p less than 0.05); by contrast, basal insulin rose from 23 +/- 2 to 31 +/- 2 microU/ml (p less than 0.01). No significant changes in the basal concentrations of glucagon and GH were found after ASA. Insulin response to tolbutamide was significantly augmented after ASA (p less than 0.01) while GH response to hypoglycemia was reduced (p less than 0.05). The pattern of plasma glucose and glucagon was not significantly modified by the treatment. Since ASA seems to have an action opposite to PGE on insulin and GH secretion, it is possible that the ASA may work through inhibition of PG synthesis.     

The Effects of Enteric Coating of Aspirin Tablets on Occult Gastrointestinal Blood Loss

The effects of enteric coating of aspirin tablets on occult gastrointestinal blood loss. The effect of enteric coating of aspirin tablets on the gastrointestinal blood loss associated with high dose aspirin therapy was investigated in 12 patients with rheumatoid arthritis. Occult blood loss was measured after labelling the patients' red blood cells with Cr ⁵¹. Three salicylate preparations were used: enteric coated tablets of aspirin (“Rhusal”, G.P, Laboratories, 7 × 650 mg per day), uncoated tablet cores of aspirin from the same batch (7×650 mg per day) and enteric coated tablets of sodium salicylate (7 × 600 mg and 1 × 300 mg per day). Daily blood loss during a salicylate-free period was (0.7±0.15ml, mean±SE). Blood loss was significantly increased during dosage with all three salicylate preparations. Daily blood loss during dosage with the uncoated tablets of aspirin (5.3 ± 0.3 ml) was significantly greater than during dosage with the enteric coated tablets of aspirin (2.3 ± 0.3 ml) and enteric coated tablets of sodium salicylate (2.1 ± 0.4 ml). The bioavailability of the salicylate preparations was studied in seven of the 12 patients. Mean plasma salicylate concentration two hours after the second daily dose during dosage with the enteric coated tablets of aspirin was 118±15 μg/ml compared to 131 ± 16 μg/ml during dosage with the uncoated tablets. Urinary recoveries of the daily dosage of aspirin in the two formulations were also similar.     

Comparison of two nimodipine formulations in healthy volunteers

The objective of this study was to assess the pharmacokientic parameters of regular nimodipine (Bayer), 30 mg, given every 6 h and nimodipine AP (nimodipine in micro particles with programmed action contained in tablets, developed by Biocontrolled-Leti Group Laboratories), 120 mg, given every 24 h. Subjects (19 healthy volunteers, five female; 14 male: age: 21 +/- 0.7 years) received one formulation over 5 days. Then, after a washout period of 7 days, the other formulation was given. The analyst was blinded to the relationship in formulation received. Antecubital blood samples were taken before the first tablet was taken and after 15, 45, 60 min and 2, 4, 6, 8, 12, 13, 18 and 24 h on day 1 and five of each formulation. Nimodipine blood levels were analysed by HPLC. At steady-state regular nimodipine reached a C-max of 10.208 +/- 0.317 ng/ml, at a t-max of 1 h; minimum concentration 6 h after dosage was 1.2929 +/- 0.411 ng/ml, half-life was estimated in 2.9 h. Meanwhile nimodipine AP 120 mg reach a C-max of 11.885 +/- 0.403 ng/ml; a t-max of 1 h with a minimum concentration 24 h after the last dose of 4.2387 +/- 0.353 ng/ml (P < 0.001). Apparent half-life was calculated in 17.8 h (P < 0.001). Area under the curve for the 24 h period was 143.76 ng/ml/min for regular nimodipine and 183.7 ng/ml/min for nimodipine AP 120 mg (P < 0.001), indicating better bioavailability. In conclusion nimodipine in AP formulation 120 mg produced similar peak plasma levels (C-max) than regular nimodipine, but with higher trough (C-min) values and stable plasma levels with one administration every 24 h. This formulation would be more suitable when nimodipine chronic therapy is indicated.     

Occult gastrointestinal bleeding due to aspirin: comparison of two compounds.

Occult gastrointestinal bleeding as measured by the faecal 51Cr-labelled red-cell loss was compared in eight healthy volunteers while on therapeutic doses of soluble aspirin and a new slow-release formulation of aspirin (Deskoval). While both preparations led to increased faecal blood loss, this was significantly less during administration of Deskoval than when soluble aspirin was taken.     

Platelet aggregatory responses to low-dose collagen are maintained in hirudin-anticoagulated whole blood for 24 h when stored at room temperature

Whole blood from 15 volunteers was anticoagulated with hirudin (200 U/l) and the response to a known submaximal concentration of collagen (0.6 w g/ml) was tested by impedance aggregometry. In 8 volunteers platelet counts were also taken before and after the maximum aggregatory response. These tests were repeated when the samples had rested for 24 h at room temperature. The median [interquartile range] aggregatory response immediately after sampling was 17.3 [16.7-18.4] ohms. At 24 h it was 17.7 [15.8-19.3] ohms ( p = 0.88) although variance was increased ( p = 0.006). The immediate platelet count before collagen exposure was 438 [381-510] 2 10 9 /l and 258 [227-297] 2 10 9 /l post-collagen. At 24 h the platelet count was 448 [443-473] 2 10 9 /l ( p = 0.224 versus immediate count) but variance was not increased ( p = 0.215). After full aggregation the count fell to 284 [234-304] 2 10 9 /l ( p = 0.592 versus early post-collagen). Variances were similar ( p = 0.558). Aggregate response ratios increased non-significantly after 24 h from 0.59 [0.53-0.62] to 0.64 [0.51-0.68] although variance was increased ( p = 0.021). Full macroaggregatory responses by impedance aggregometry were seen after 24 h storage of whole blood with hirudin at room temperature. This suggests both that distant assessment of platelet function using a standardized method is possible and a potential role of thrombin inhibition for platelet storage.     

OCCULT GASTROINTESTINAL BLEEDING DUE TO ASPIRIN: COMPARISON OF TWO COMPOUNDS

Occult gastrointestinal bleeding as measured by the faecal ⁵¹Cr-labelledred-cell loss was compared in eight healthy volunteers whileon therapeutic doses of soluble aspirin and a new slow-releaseformulation of aspirin (Deskoval). While both preparations led to increased faecal blood loss,this was significantly less during administration of Deskovalthan when soluble aspirin was taken.     

A controlled study of faecal distribution in ulcerative colitis and proctitis

The object of this study was to assess faecal distribution and faecal stasis in patients with ulcerative colitis and healthy control subjects and to relate the findings to the activity and extent of the disease. Each subject ingested 10 radiopaque markers daily for 13 days and attended for a plain abdominal roentgenogram on the 14th day. Patients with active ulcerative proctocolitis retained significantly fewer markers in the whole colon (median values, 11 versus 24 markers) due to a decrease of markers in the left colon (median values, 3 versus 13 markers) compared with the control group (p less than 0.05). Patients with either proctitis or colitis in remission and control subjects retained similar numbers of markers. The results of this study suggest that, as a group, patients with proctocolitis do not have proximal faecal stasis.     

The long-acting somatostatin analogue SMS 201-995 causes malabsorption

Somatostatin and its long-acting analogue SMS 201-995 (Sandostatin) have been suspected of causing steatorrhoea. The aim of this study was to examine the effect of SMS 201-995 on fat assimilation in healthy subjects, using 14C-triolein and 3H-oleic acid as tracers of dietary triglycerides and free fatty acids, respectively, and 51CrCl3 as non-absorbable marker. Six healthy male volunteers participated in the double-blinded, randomized, crossover study. In each test period either 1 ml of SMS 201-995, containing 200 micrograms, or 1 ml of isotone saline was given subcutaneously three times within 16 h. Faeces were collected for 3 days, every stool separately. The faecal 14C-triolein and 3H-oleic acid excretion was calculated from two aliquots of faeces. In addition, the mean daily faecal fat excretion was estimated. When placebo was given, the median 14C-triolein excretion was 1% (range, 0.9-1.6%), the median 3H-oleic acid excretion was 5% (range, 3-10%), and the daily faecal fat excretion was 4 g/day (range, 1-6 g/day), all within normal limits. When SMS 201-995 was given, the faecal 14C-triolein excretion increased to a median of 75% (range, 43-119%), the 3H-oleic acid excretion increased to a median of 82% (range, 46-126%), and the faecal fat excretion increased to a median of 22 g/day (range, 4-34 g/day), all clearly above normal. The faecal 14C-triolein/3H-oleic acid test showed triglycerides and free fatty acids to be equally malassimilated, which indicates malabsorption.