Small volume isosmotic polyethylene glycol electrolyte balanced solution (PMF-100) in treatment of chronic nonorganic constipation.

The present multicenter double-blind placebo-controlled trial evaluates the therapeutic effectiveness of small-volume daily doses of an isosmotic polyethylene glycol (PEG) electrolyte solution in the treatment of chronic nonorganic constipation. After a complete diagnostic investigation, patients still constipated at the end of a four-week placebo-treatment run-in period were enrolled and randomized to receive either placebo or PEG solution 250 ml twice a day for the following eight weeks. Patients were assessed at four and eight weeks of treatment, and they reported frequency and modality of evacuation, use of laxatives, and relevant symptoms daily on a diary card. Oroanal and segmental large-bowel transit times were assessed with radiopaque markers during the fourth week of the run-in period and the last week of the treatment period. During the study period, dietary fiber and liquids were standardized and laxatives were allowed only after five consecutive days without a bowel movement. Of the 55 patients enrolled, five dropped out, three because of adverse events and two for reasons unrelated to therapy; another two were excluded from the efficacy analysis because of protocol violation. Of the remaining 48 patients (37 women, age 42 +/- 15 years, mean +/- SD), 23 were assigned to placebo and 25 to PEG treatment. In comparison to placebo, PEG solution induced a statistically significant increase in weekly bowel frequency at four weeks and at the end of the study (PEG: 4.8 +/- 2.3 vs placebo: 2.8 +/- 1.6; P < 0.002) and a significant decrease in straining at defecation (P < 0.01), stool consistency (P < 0.02), and use of laxatives (P < 0.03). Oroanal, left colon, and rectal transit times were significantly shortened by PEG treatment. There was no difference between controls and PEG-treated patients as far as abdominal symptoms and side effects were concerned. In conclusion, PEG solution at 250 ml twice a day is effective in increasing bowel frequency, accelerating colorectal transit times, and improving difficult evacuation in patients with chronic nonorganic constipation and is devoid of significant side effects.

The effect of continuous enteral nutrition on gastric acidity in humans.

The effect of continuous intraduodenal enteral nutrition on gastric pH was compared with the effects of fasting and of parenteral and standard nutrition control regimens containing equal amounts of carbohydrate, protein, and lipid. Eleven healthy volunteers underwent four 24-hour intragastric pH-metry studies; serum glucose, calcium, immunoreactive insulin and gastrin levels were determined during fasting and enteral and parenteral regimens. Median 24-hour gastric pH during enteral nutrition (group median pH 1.4) was lower than during parenteral nutrition (pH 1.9; P = 0.0039 vs. enteral) but was not different from fasting (pH 1.4) or standard nutrition (pH 1.6) values. Median 24-hour serum glucose levels during enteral nutrition (group median, 4.8 mmol/L) were higher than during fasting (4.0 mmol/L; P = 0.00098 vs. enteral) and lower than during parenteral nutrition (5.3 mmol/L; P = 0.0039 vs. enteral). Median 24-hour serum insulin levels during enteral nutrition (group median, 22.9 mU/L) were higher than during fasting (group median, 9.2 mU/L; P = 0.00098 vs. enteral) but similar to levels during parenteral nutrition (23.3 mU/L). Neither median 24-hour gastrin levels nor calcium levels were affected by any nutrition regimen. Thus, continuous enteral nutrition produces gastric pH values similar to those seen with fasting or standard nutrition, suggesting that, under most physiological conditions, gastric acidity is subject to close feedback control. Parenteral nutrition increases gastric pH, suggesting that systemic nutrients may influence this feedback mechanism.

Reproducibility of long-term ambulatory esophageal combined pH/manometry.

Long-term ambulatory esophageal manometry is used increasingly, but normal values and data on the reproducibility of the method are not available. Thus, studies were conducted using paired 24-hour recordings, separated by 1-4 weeks, in 24 healthy volunteers (aged 19-50). Computerized analysis of each two-channel pressure recording (5 and 15 cm above lower esophageal sphincter) determined mean contraction amplitude, duration, area under the curve, contractility and propagation velocity, and the proportion of propagated contractions during day and night periods. A combined glass pH electrode (5 cm above lower esophageal sphincter) was used to register acid reflux. Visual analysis of the 24-hour contractility patterns showed marked intraindividual reproducibility but, although most subjects showed similar meal-associated increases and sleep-associated decreases in contraction frequency and amplitude, considerable interindividual variation was observed. This was confirmed by comparing the variation between subjects in the first and second recordings with the variation between recordings in the same subject; for all pH and manometry variables, the coefficient of variation was two to three times greater between subjects than between recordings in the same subject. The recordings were highly reproducible within subjects (nighttime contraction duration, P less than 0.05; all other variables, P less than 0.01). Thus, computerized ambulatory pH manometry is reproducible and because healthy volunteers have a characteristic individual pattern of esophageal motility, the method is perfectly suitable for repeated-measure design physiological and pharmacological studies. However, generally applicable normal values are difficult to define.

Reproducibility of ambulatory gastric pH recordings in the corpus and antrum. Effect of food, time, and electrode position.

The reproducibility of simultaneous, long-term, ambulatory gastric pH recordings in the antrum and corpus was investigated in nine healthy subjects who underwent three separate, 27-h gastric double pH-metries. Intraindividual reproducibility for the entire 27-h recording period was good in the corpus (Kendall's concordance coefficient, W' = 0.6393, p less than 0.025) but not in the antrum (W' = 0.4806, NS). Analysis of predefined time periods showed that non-meal daytime pH was reproducible in the corpus (W' = 0.6531, p less than 0.025) but not in the antrum (W' = 0.3395, NS), whereas mealtime pH was reproducible in the antrum (W' = 0.7159, p less than 0.005) but not in the corpus (W' = 0.4954, NS); nocturnal pH was not reproducible in either the antrum or the corpus. These results reflect the functional separation of corpus and antrum and their differing responses to food. Thus, studies of gastric acidity over long periods should be conducted in the corpus, whereas studies of gastric acidity over shorter, meal-related periods should be conducted with a second electrode in the antrum.

Twenty-four-hour pattern of esophageal motility in asymptomatic volunteers.

Diurnal variations in the pattern of esophageal motility and acidity were studied in 14 healthy volunteers. Data from a two-channel manometry and one-channel pH-metry recording were stored in a portable 1-MByte, solid-state data logger for subsequent computerised analysis. Comparison of predefined nighttime, mealtime and nonmeal daytime periods showed that propagated contractions predominated during mealtimes (56% of all contractions) and nonmeal daytime periods (53.5% of contractions) and that their propagation velocity (2.98 cm/sec) was at its lowest and the AUC of all contractions (134.6 hectoPascal.sec) at its greatest during mealtime periods. During the night, propagated contractions (0.136/min) and simultaneous contractions (0.025/min) were significantly less frequent than during both meal (1.31/min and 0.172/min, respectively) and nonmeal daytimes (0.665/min and 0.133/min, respectively), whereas the nocturnal segmental contraction frequency (0.181/min) was not significantly lower than the nonmeal daytime contraction frequency (0.243/min). Median reflux time was in the normal range (1.2%), although two subjects had prolonged reflux times (9.5% and 14.5%). In conclusion, all subjects showed similar patterns of diurnal esophageal contractory activity determined partly by meal intake and partly by a characteristic clustering of nocturnal contractions that could not be explained by episodes of nocturnal gastroesophageal reflux. It may, therefore, be speculated that nocturnal contraction clusters are associated with rhythmic phenomena such as MMC or specific sleep stages.

Fate of antacid gel in the stomach. Site of action and interaction with food.

The site of action of a high-power Al-Mg antacid gel (buffering capacity 70 meq/10 ml) and its interaction with food was examined in 10 healthy volunteers. Combined pH-metries in antrum and corpus were performed in each volunteer on four occasions. In a randomized study design, antacid or placebo were given 1 hr after either a protein or a carbohydrate pancake, of which only the former had any acid-buffering capacity. Before the meal, pH was higher in the antrum than in the corpus (median antrum: 3.2, corpus 1.5). In the corpus, a protein pancake but not a carbohydrate pancake raised the pH (median pH after protein pancake: 3.5; after carbohydrate pancake: 1.4). In the antrum, the protein pancake had no effect, but the carbohydrate pancake decreased the pH (median pH after protein pancake: 3.1; after carbohydrate pancake: 2.0). The antacid had no effect in the corpus after either pancake. It raised intraluminal pH markedly in the antrum after a carbohydrate pancake (median antral pH before antacid: 2.0; after antacid: 3.3), whereas its effect in the antrum was weak after a protein pancake. In vitro experiments were conducted to explain the in vivo results: in contrast to a carbohydrate pancake, a protein pancake reduced the buffering capacity of the antacid by direct interaction. In conclusion, the effect of an antacid gel on intragastric pH is predominantly localized in the antrum and is attenuated in the presence of proteins.(ABSTRACT TRUNCATED AT 250 WORDS)

[Is the measurement of carcinoembryonic antigen still indicated in digestive cancers?]. / Le dosage de l'antigène carcino-embryonnaire est-il encore indiqué dans les cancers digestifs?

Carcinoembryonic antigen (CEA) is not useful for detecting asymptomatic cancer. Its sensitivity and specificity are not high. For some cancers, antigen levels at the time of diagnosis provide more precise prognosis than staging alone. Regular determination of CEA is useful as a method of surveillance after surgery for cancer in the colon and in the rectum. Unfortunately the clinical gain of detecting postoperative relapses is low since curative surgical treatment is usually impossible.

[Pathogenic heterogeneity of Barrett's ulcers. Apropos of 38 case reports]. / Hétérogénéité pathogénique des ulcères de Barrett. A propos de 38 observations.

Barrett's ulcer is thought to develop in the columnar epithelium of Barrett's esophagus. In our series there is evidence that at least some Barrett's ulcers develop in squamous epithelium which may correspond to islets within Barrett's esophagus; in other cases Barrett's mucosa may surround a preexisting reflux-induced ulcer and thus transform it into Barrett's ulcer. In some individual cases of Barrett's ulcer development of the ulcer primarily in the columnar epithelium could not be ruled out. These ulcers may be produced by local acid secretion, by acid or alkaline gastroesophageal reflux in patients with reduced resistance of the columnar epithelium. Exceptionally, Barrett's ulcer may result from local irritation by medication (pill-induced ulcer) or by nasogastric intubation.

Combined esophageal and gastric pH-metry in healthy volunteers. Influence of cable through LES and effect of misoprostol.

In order to evaluate whether combined esophageal and gastric pH-metry is feasible without interference due to the transcardial cable, four 24-hr ambulatory esophageal pH-metries were carried out in seven healthy volunteers in a randomized order. In two studies only one glass electrode was used. It was placed 5 cm above the lower esophageal sphincter. In the two other studies an additional electrode was placed in the corpus region 10 cm below the lower esophageal sphincter. In order to obtain a wide range of pH values, misoprostol (400 micrograms) was given at 9 AM and 9:15 PM in two studies. In the two other studies placebo was given. Misoprostol exerted only a weak and short-lasting effect on gastric acidity. The four measuring conditions did not differ with respect to medians of esophageal reflux time and duration of single reflux episodes, Kendall's coefficient of concordance yielded a high reproducibility for both variables (P less than 0.0025). Thus, combined esophageal and gastric pH-metry is feasible and highly reproducible.

Subcellular changes and apoptosis induced by ethanol in rat liver.

The livers of rats given ethanol for 5 weeks showed marked structural alterations of hepatocytes of acinar zone 3 including mitochondrial pleomorphism, increased smooth endoplasmic reticulum and deposition of small (less than 0.5 micron) lipid droplets. In addition, apoptotic bodies involving altered parenchymal cells were frequently observed, together with prominent mononuclear infiltrates adjacent to the terminal hepatic veins. It is suggested that 'age' of liver cells may play a role in the preferential perivenular localization of early ethanol-induced liver damage.

Effect of a slow-release formula of trimoprostil on intragastric acidity in healthy volunteers.

We investigated the effect of a slow-release formula of trimoprostil, a prostaglandin E2 analogue, at a dose of 3 mg b.d. on circadian intragastric acidity in nine healthy volunteers using ambulatory pH-metry in a placebo-controlled study. The effect of trimoprostil was long lasting (8 hours during the night). However, it lowered gastric pH on average only by 0.4 pH units. In four of the six women severe side-effects occurred in the form of abdominal cramping, metrorrhagia, and/or diarrhoea. These disadvantages may limit the clinical use of this drug.

Does smoking interfere with the effect of histamine H2-receptor antagonists on intragastric acidity in man?

The interaction between smoking and the effect of histamine H2-antagonists on intragastric acidity was examined in a double blind double dummy placebo controlled study. Healthy volunteers, 11 smokers and 10 non-smokers, were given, on four separate days at least one week apart, either placebo or cimetidine 800 mg nocte or ranitidine 2 X 150 mg per day or ranitidine 300 mg nocte. Tablets were taken at 2115 and 0900 h. Smokers smoked a cigarette hourly from 0700 to 2300 h. Breakfast, lunch, and dinner were standardised. Intragastric acidity was measured with a combined intragastric glass electrode and a solid state recorder. The subjects were fully ambulatory. The three histamine H2-receptor antagonist regimens were less effective (p = 0.04) in smokers than in non-smokers, but the difference between acidity of smokers and non-smokers was small. Means of medians of pH during a 24-h period with placebo, cimetidine 800 mg, ranitidine 2 X 150 mg and ranitidine 300 mg were 1.6, 2.3, 3.1, and 2.7 in smokers and 1.5, 2.7, 3.2, and 3.1 in non-smokers, respectively. In a second part of the study seven chronic smokers were reexamined after acutely stopping smoking: inhibition of gastric acidity by histamine H2-receptor antagonists was similar before and after withdrawal. Smoking does not affect intragastric acidity in untreated volunteers and only slightly decreases the effectiveness of histamine H2-receptor antagonists on intragastric acidity. This effect best in part explains the unfavourable effect of smoking on healing of peptic ulcer in patients treated with these drugs.

Reduction of gastric acidity with ranitidine or famotidine: early evening dosage is more effective than late evening dosage.

The antisecretory effect of a once daily dose of ranitidine and famotidine was examined after administration of the drugs either immediately after dinner or 3 h after dinner. A placebo-controlled multiple cross-over study was performed in 7 healthy ambulatory volunteers. They were given, on 6 separate days at least 1 week apart, either placebo, ranitidine 300 mg or famotidine 40 mg, either immediately after dinner or 3 h later. Breakfast, lunch and dinner were standardized. 24-Hour intragastric acidity was measured with a combined glass electrode. Duration of secretory inhibition by a drug was defined as the nighttime period between the first rise of pH above and the final fall below 3.5. This value represents the 95% upper confidence limit of nighttime pH values during placebo treatment. Secretory inhibition with early and late administration of ranitidine lasted for 10.7 and 7.3 h, respectively (p = 0.012). With famotidine it lasted for 10.1 and 7.1 h, respectively (p = 0.005). Gastric acidity after dinner was decreased by early but not late intake of ranitidine and famotidine. Thus, both ranitidine and famotidine were more effective when taken early, immediately after dinner, than when taken late in the evening. This observation might affect the mode of ulcer treatment with these drugs.

[Continuous intragastric pH-metry]. / Die intragastrale Langzeit-pH-Metrie.

Ambulatory intragastric pH-metry is a suitable method of assessing gastric acidity under conditions of normal daily life. A detailed profile of intragastric acidity is given which is a reproducible individual characteristic. There is a circadian rhythm of gastric acidity in which pH rises during the night and after meals. pH-metry was used to determine the effects of H2-antagonists and antacids, and the results are the basis for the clinical use of intragastric pH-metry.

Long-term ambulatory gastric pH monitoring: validation of a new method and effect of H2-antagonists.

A new ambulatory monitoring system was evaluated for long-term measurements of gastric acidity. A close correlation was observed between values indicated by the pH electrode of the system and the pH of simultaneously aspirated gastric juice, suggesting that the electrode signaled the pH of the gastric fluid content. When the pH electrode was passed via an endoscope, and its bulb was placed against the corpus mucosa, a higher acidity was recorded as compared with gastric juice. To test whether the electrodes measured mucosal pH during ordinary test conditions, the readings of pH probes with mechanically shielded bulbs that did not come into direct contact with the mucosa were compared with those of nonshielded probes in identical positions. Similar results were observed, supporting the hypothesis that nonshielded probes measured the pH of gastric contents rather than that of the mucosa. The importance of a standardized electrode position and a fixed meal schedule was demonstrated in simultaneous recordings of antral and fundic pH. Under fasting conditions, acidity was similar in both regions. After ingestion of a meal, gastric contents were more alkaline in the fundus than in the antrum. A wide range of 24-h acidity (19-83 mmol/L) was detected in 25 healthy subjects. The day-to-day reproducibility of the method as revealed in two consecutive 24-h tests was good. The effect of cimetidine and ranitidine on gastric acidity was evaluated in 9 subjects in a double-blind, double-dummy trial. Mean 24-h H+ activity was 37.4 +/- 4.6 mmol/L under placebo medication. It was lower with cimetidine, two doses of 400 mg (23.8 +/- 4.0); cimetidine, four doses of 400 mg (10.2 +/- 3.0); ranitidine, two doses of 150 mg (10.3 +/- 3.6), and two doses of 300 mg (10.0 +/- 3.5), respectively. In conclusion, ambulatory long-term pH monitoring is a suitable method to assess the physiologic pattern of gastric acidity and the effect of antisecretory drugs.