Sympathetic (electrodermal) activity during repeated maximal rectal distensions in patients with irritable bowel syndrome and constipation.

Irritable bowel syndrome (IBS) is associated with visceral hypersensitivity, stress and autonomic dysfunction. Sympathetic activity during repeated events indicates excitatory or inhibitory mechanisms such as sensitization or habituation. We investigated skin conductance (SC) during repetitive rectal distensions at maximal tolerable pressure in patients with IBS and chronic constipation. Twenty-seven IBS patients, 13 constipation patients and 18 controls underwent two sets of isobaric rectal distensions. First, maximal tolerable distension was determined and then it was repeated five times. Skin conductance was measured continuously. Subjective symptom assessment remained steady in all groups. The baseline values of SC were higher in IBS patients than in patients with constipation and significantly lower in constipation patients than in controls. The maximal SC response to repetitive maximal distensions was higher in IBS patients compared with constipation patients. The amplitude of the initial SC response decreased successively with increased number of distensions in patients with IBS and constipation but not in controls. Irritable bowel syndrome and constipation patients habituated to maximal repetitive rectal distensions with decreasing sympathetic activity. Irritable bowel syndrome patients had higher sympathetic reactivity and baseline activity than constipation patients. A lower basal SC in constipation patients compared with controls suggests an inhibition of the sympathetic drive in constipation patients.

Pre-experimental stress in patients with irritable bowel syndrome: high cortisol values already before symptom provocation with rectal distensions.

Stress is known to affect symptoms of irritable bowel syndrome (IBS) probably by an alteration of visceral sensitivity. We studied the impact of maximal tolerable rectal distensions on cortisol levels in patients with IBS, chronic constipation and controls, and evaluated the effect of the experimental situation per se. In twenty-four IBS patients, eight patients with chronic constipation and 15 controls salivary cortisol was measured before and after repetitive maximal tolerable rectal balloon distensions and at similar times in their usual environment. Rectal sensitivity thresholds were determined. IBS patients but not controls and constipation patients had higher cortisol levels both before and after the experiment compared with similar times on an ordinary day in their usual environment (P = 0.0034 and 0.0002). There was no difference in salivary cortisol level before compared with after rectal distensions. The IBS patients had significantly lower thresholds for first sensation, urge and maximal tolerable distension than controls (P = 0.0247, 0.0001 and <0.0001) and for urge and maximal tolerable distension than patients with constipation (P = 0.006 and 0.013). IBS patients may be more sensitive to expectancy stress than controls and patients with constipation according to salivary cortisol. Rectal distensions were not associated with a further significant increase in cortisol levels.

Pharmacokinetics of [14C]omeprazole in patients with impaired renal function.

Pharmacokinetics of [14C]omeprazole and its metabolites were studied after single intravenous and oral doses of 20 and 40 mg, respectively, to 12 patients with chronic renal insufficiency. Blood samples for determination of total radioactivity, omeprazole, OH-omeprazole, sulfone, and sulfide were taken for 24 hours. Urine was collected over 96 hours for determination of total radioactivity and during the first 24 hours for additional assay of omeprazole and metabolites. The mean systemic availability was 70%. The mean plasma t1/2 of omeprazole was 0.6 hours. Unchanged omeprazole was not measurable in urine. Derived pharmacokinetic constants of intact omeprazole were within the range of those reported in healthy individuals. The accumulated 24-hour excretion of radioactive metabolites was related significantly to creatinine clearance. The cumulative excretion of total radioactivity in urine over 96 hours in percent of given dose varied between 25% and 83%.

Pharmacokinetics of cimetidine after single doses and during continuous treatment.

The plasma concentration-time curve and urinary excretion of cimetidine were followed in 10 patients after single 200mg doses given intravenously, in 9 patients after 400 and 800mg single oral doses, and in 10 patients over a 24-hour period during continuous oral treatment with 1000mg daily. The bioavailability of cimetidine measured as the ratio between the areas under the plasma concentration-time curves (AUC) after oral and intravenous administration was 76%. The mean excretion of cimetidine in the urine as unchanged drug, expressed as a percentage of administered dose, was 58% after 200mg intravenously and between 37 and 41% after single oral doses of 200, 400 and 800mg and during continuous treatment with 1.0g/day. Since there were no significant differences between the oral doses, the relative bioavailability of cimetidine does not appear to be dose-dependent. The AUC after the 800mg dose was 2.1 times that of the 400mg dose. No dose-dependent kinetics were observed. There were also no significant differences in the AUCs after 200 and 400mg doses during continuous treatment compared with the AUCs after the same single doses. Thus, cimetidine does not appear to induce or inhibit its own metabolism during treatment. Following intravenous administration, the mean volume of distribution was 1.39L/kg and the mean total body clearance and the mean plasma renal clearance of cimetidine were 655 and 375ml/min, respectively. A renal clearance of cimetidine more than 3 times higher than the creatinine clearance demonstrates that the renal excretion of cimetidine is mainly by tubular secretion. Plasma concentrations of cimetidine during continuous treatment with 1.0g/day were above 1.0 microgram/ml-the plasma concentration associated with 50% inhibition of stimulated acid secretion in peptic ulcer patients-for 9 out of the 24 hours. A morning plasma concentration above 0.6 microgram/ml before the next morning dose has been taken during treatment with cimetidine 1.0g/day is only seen in patients with some degree of renal failure. Measurement of plasma half-life during continuous treatment shows that the plasma half-life is longer than the mean 1.79 hours estimated after intravenous administration of a single dose.

Steady-state kinetics and dosage requirements of cimetidine in renal failure.

25 patients with different degrees of chronic stable renal failure received oral treatment with cimetidine over 6 days and a final dose in the morning of day 7. The doses of cimetidine were reduced according to the degree of renal failure. Plasma concentrations of cimetidine were determined before the morning dose on days 2,3,6 and before the final morning dose and during the day on day 7. 24-hour excretions of cimetidine were measured during the study and on day 7, 6 to 9 hours after the final morning dose. There were significant linear relationships between the values of creatinine clearance and plasma elimination rate constant of cimetidine (p less than 0.0025) and between the values of creatinine clearance and renal clearance of cimetidine (p less than 0.05). On the basis of the morning plasma concentrations before and the plasma concentration curve after the final morning dose on day 7 the following dose recommendations according to pretrial values of creatinine clearance are recommended for cimetidine treatment in renal failure: 5 to 15ml/min 200mg 2 or 3 times daily, 15 to 30ml/min 200mg 3 times daily and 30 to 75ml/min 200mg 4 times daily.

A double-blind, randomized, placebo-controlled dose-ranging study to evaluate the efficacy of alosetron in the treatment of irritable bowel syndrome.

BACKGROUND: Irritable bowel syndrome is a common gastrointestinal disorder characterized by abdominal pain and discomfort and altered bowel habit. Antagonism at the 5-HT3 receptor may be of benefit in the treatment of irritable bowel syndrome. AIMS: To evaluate the effect of 12 weeks of treatment with alosetron, a 5-HT3 receptor antagonist at doses of 0.1 mg b.d., 0.5 mg b.d. and 2 mg b.d. in irritable bowel syndrome patients. METHODS: A double-blind, placebo-controlled, parallel-group study with a 2-week screening and a 12-week treatment period was conducted. A total of 462 patients (335 female) recorded details of the severity of their abdominal pain, and bowel function daily on a diary card throughout the study. At monthly clinic visits patients recorded the severity of their abdominal pain/discomfort and diarrhoea on a visual analogue scale. RESULTS: In the total population and in the female subpopulation (but not in males) alosetron 2 mg b.d. significantly increased the proportion of pain-free days and decreased the visual analogue scale score for diarrhoea compared with placebo. Alosetron at doses of 0.5 mg b.d. and 2 mg b.d. led to a significant hardening of stool, and a reduction in stool frequency in the total population. CONCLUSION: Alosetron at a dose of 2 mg b.d. is an effective treatment for female patients with irritable bowel syndrome.

Pain is temporally related to eating but not to defaecation in the irritable bowel syndrome (IBS). Patients' description of diarrhea, constipation and symptom variation during a prospective 6-week study.

OBJECTIVES: To study the intensity and variation of pain and its temporal relation to eating and defaecation. Furthermore, what irritable bowel (IBS) patients mean by constipation and diarrhea and how bowel symptoms vary. DESIGN: Prospective daily symptom recording over 6 weeks. SETTING: The primary catchment area of University Hospital of Linköping. PARTICIPANTS: Eighty consecutive patients fulfilling the Rome criteria; 63 finished the study. RESULTS: Fifty-nine of 63 patients recorded an average of 29 pain periods and 24 days with pain during the 6 weeks. Over-all pain burden decreased slightly over the study period. At inclusion 38 (64%) patients claimed that pain was relieved by defaecation. However, on average, only 10% of each patient's recorded pain periods were relieved by defaecation. At inclusion 29 (49%) patients claimed postprandial worsening of pain. On average, 50% of each patient's recorded pain periods worsened postprandially. The patients defined constipation as hard stools and diarrhea as loose stools and urgency. Stool frequency did not differ. Bowel symptoms varied within, but not between, fortnightly periods. CONCLUSIONS: Postprandial worsening of pain should be included as a criterion in the clinical definition of IBS while the criterion 'pain relieved by defaecation' should be re-evaluated. IBS patients can probably be divided into subgroups based on stool consistency, not frequency. Daily records are superior to structured clinical interviews or questionnaires for a detailed study of symptoms in IBS.

Air enema radiology compared with leukocyte scintigraphy for imaging inflammation in active ulcerative colitis.

OBJECTIVE: To compare air enema radiology with a leukocyte scintigraphy technique using technetium-99m-hexamethyl propylene amine oxime-labelled leukocytes for imaging colonic inflammation in ulcerative colitis. DESIGN: Prospective study in a University hospital. One radiologist and one nuclear physician independently graded the degree of inflammation in six colon segments per patient using radiographs and leukocyte scans. PATIENTS: Twenty consecutive patients with symptoms of active ulcerative colitis requiring corticosteroids, inflammation on rigid sigmoidoscopy and a positive leukocyte scan above the rectum. RESULTS: Using air enema radiology, inflammation above the rectum was observed in 17 of the 20 patients. Eleven patients had the same extent of disease with both imaging techniques (total n = 5; extensive n = 3; distal n = 3). Seven patients had more widespread colitis using leukocyte scintigraphy. In the remaining two patients with extensive inflammation at scintigraphy, air enema films showed total colitis. When the colon was subdivided into six different segments, prediction of the presence of inflammation in individual segments was 0.88 for air enema radiology compared with leukocyte scintigraphy and 0.60 for the prediction of absence of inflammation. All segments with an irregular mucosal contour or ulceration on air enema films had intense inflammation at scintigraphy. CONCLUSIONS: In patients with active ulcerative colitis, air enema radiology underestimates the extent of inflammation because this investigation shows secondary patho-anatomical changes, while leukocyte scintigraphy visualizes the acute cellular infiltrate. In patients with more severe inflammation, there is excellent agreement between the two methods.

Increased liver echogenicity at ultrasound examination reflects degree of steatosis but not of fibrosis in asymptomatic patients with mild/moderate abnormalities of liver transaminases.

AIMS: To investigate whether hyperechogenicity of liver can reliably be interpreted as liver steatosis and if any concomitant or isolated fibrosis can be disclosed. PATIENTS AND METHODS: A series of 165 patients with no signs or symptoms of liver disease referred because of slightly to moderately raised aminotransferases (alanine aminotransferase and/or aspartate aminotransferase 0.7-5.0 microkat/l) for more than 6 months were prospectively investigated with a comprehensive laboratory profile, ultrasound examination of liver and percutaneous liver biopsy Fibrosis was assessed quantitatively and according to Metavir. Steatosis was graded as none, mild, moderate or severe. RESULTS: Of 98 (59.4%) patients with raised echogenicity, 85 (86.7%) had liver steatosis of at least moderate degree, 9 patients with same degree of steatosis had normal echogenicity and 13 patients with no or only mild steatosis had a hyperechogenic liver (sensitivity 0.90, specificity 0.82, positive predictive value 0.87, negative predictive value 0.87). About the same relations were found regardless of body mass index and degree of fibrosis. With increased echogenicity together with high attenuation (n = 591 and reduced portal vessel wall distinction (n = 79), positive predictive value increased to 0.93 and 0.94, respectively. Quantitatively assessed fibrosis (mean +/- SD) was 3.2 +/- 4.6% of biopsy area with normal and 2.3 +/- 1.8% with raised echogenicity (ns). Echogenicity was normal in 5 out of 9 patients with septal fibrosis and in 4 out of 6 patients with cirrhosis. Any structural, non-homogenous findings at ultrasound were not associated with architectural fibrotic changes and none had nodular contours of liver surface. CONCLUSIONS: Assessment of liver echogenicity is of value for detection or exclusion of moderate to pronounced fatty infiltration (correct classification 86.6%) but cannot be relied upon in diagnosing fibrosis, not even cirrhosis in asymptomatic patients with mild to moderately elevated liver transaminases.

Influence of "outliers" on the association between laboratory data and histopathological findings in liver biopsy.

Discriminant analysis techniques were used to predict the histopathological findings in liver biopsy specimens in asymptomatic patients with slightly to moderately raised routine liver tests. Moderate to severe fibrosis and/or inflammation were treated as indication for biopsy. Two methods were used to classify patients. One was the dichotomous discrimination between "biopsy necessary" or "biopsy not necessary" groups of patients. The other involved combining two discriminant functions trained separately for recognition of fibrosis or inflammation, and then combined to predict the biopsy necessity. Detection of outliers by standard techniques, directly available in the SPSS-X package, was performed before starting discrimination procedures. Both "sharp" assignment rules and continuous scoring rules were applied to the classification problem. The correct classification rate reached over 85% for the algorithms tested. In the majority of cases the classification was found to be "non-doubtful". Elimination of outliers (especially by standardized residuals) improved the global correct classification rate, but only slightly improved assignment to the "biopsy necessary" group. Routine and complementary laboratory findings were found to be the most discriminating; answers to questionnaire and ultrasound examination were less important. Selection of the most diagnostic features based on "clean" data without outliers enabled us to find interesting medical associations, which were previously masked by extremely asymptomatic values outlying from the main body of the "biopsy necessary" group.

Low activities of disaccharidases associated with inflamed duodenal bulb mucosa.

In order to establish whether an enzymatic method (a "functional" test) could be used instead of the histological picture as an indicator of damage to enterocytes of duodenal mucosa, biopsies were taken from 39 patients with upper gastrointestinal symptoms suggestive of peptic ulcer disease, but without active ulcers at endoscopy. Eleven patients with a normal appearance of the duodenal bulb mucosa and twenty-eight patients with various degrees of endoscopic inflammation ("bulbitis") were evaluated. The histological degree of duodenitis was assessed, and the activities of maltase, invertase, trehalase and lactase in the biopsy specimens were measured. Disaccharidase activities were inversely proportional to severity in both endoscopic and histological scoring of degree of inflammation. Low disaccharidase activities were also present in patients with endoscopic inflammation of the duodenal bulb, but without histological duodenitis. Focal and especially widespread gastric metaplasia was, in itself, significantly associated with low disaccharidase activities. The correlation between endoscopic and histologic scoring of inflammation of duodenal mucosa was not significant as assessed by kappa statistics. A previous history of peptic ulcer disease was significantly more common in patients with, than in those without, endoscopic inflammation of the duodenal bulb.

[Irritable bowel syndrome. Survey of definitions, differential diagnosis and pathogenesis]. / Irriterade tarmens syndrom. Oversikt över definitioner, differentialdiagnostik och patogenes.

Abdominal pain/discomfort, bloating, need to rush to the toilet, straining, feeling of incomplete bowel emptying and alternating periods of diarrhea and constipation is the clinical definition of the irritable bowel syndrome. The internationally used syndrome definition is based on expert opinions and answers to patient questionnaires. When symptoms are registered prospectively, abdominal pain starts or worsens after meals and is not relieved by defecation. As in the general population patients with the syndrome define diarrhea as loose stools and constipation as hard stools regardless of stool frequencies. Variation in defecatory symptoms and discrepancies between these symptoms and stool consistency are the hallmarks of the syndrome, and the degree of variation per fortnight is relatively stable in the individual patient. Fermentation of carbohydrates by colonic bacteria, increased sensitivity to bowel distention by gas, gas-producing food, increased secretion of cholecystokinin after fatty meals and/or increased sympathetic nerve tone at stress can give rise to symptoms. Symptoms can start after a single period of bacterial gastroenteritis. Although patients seeking medical care for the syndrome are more often anxious, the syndrome itself is not psychosomatic. Symptoms are possibly mediated through partial degranulation of mast cells in bowel mucosa, but this does not make it an allergic disease. If bowel dysmotility can be measured, early stage or a mild case of intestinal pseudoobstruction should be considered. Hyperreactivity in the enteric nervous system and/or in the brain is the likely main cause of the symptoms. More widespread activity in the brain after exposure to stimuli originating from bowel nerves or less inhibition of this stimulation in the brain are possible mechanisms.

[Oral contraceptives and blood diseases are the most common causes of Budd-Chiari syndrome]. / P-piller och blodsjukdomar vanligaste orsakerna till Budd-Chiaris syndrom.

Two cases of young patients with the chronic form of Budd-Chiari syndrome are reported. The first concerns a 22-year-old woman with a 6-month history of hepatomegaly, who had used oral contraceptives almost continuously during the five years preceding diagnosis. In a thorough diagnostic work-up, thromboses were detected in all but one of the hepatic veins, and a possible non-occluding thrombosis in the retrohepatic portion of the inferior vena cava. In the blood and bone marrow, findings were compatible with polycythaemia rubra vera, and a high anti-cardiolipin antibody titre was found. The second case concerns a 25-year-old male smoker with normal bone marrow, who had thromboses in at least two of the hepatic veins, though the inferior vena cava was not occluded. In both cases a mesocaval shunt was interposed with synthetic grafts, and postoperatively the patients are doing well--at sixteen and five months, respectively. Both are maintained on anticoagulants, and even without diuretics there has been no recurrence of ascites. The woman takes a small dose of hydroxy-urea to control her hypercoagulability. To our knowledge, hers is the first case to be reported of Budd-Chiari syndrome with hypercoagulability due to the concomitant presence of oral contraceptives, polycythaemia rubra vera and anti-phospholipid antibodies.

PIP: The Budd-Chiari syndrome is a rare condition (0.4-.06 per cent in autopsy material) characterized by ascites, liver function disturbance and abdominal pain caused by thrombosis of the major hepatic veins. $ studies (N = 114) yield the following list of causes with percentages; Oral contraceptives, 18%; polycythemia vera, 13%; other myelo-proliferative disease, 4%; paroxysmal nocturnal hemoglobinuria, 5%; blood vessel malformation, 10%; malignancy, 6%; other simultaneous thrombosis, 3%, vasculitis, 2%; other (trauma, abscess, chronic active hepatitis, pregnancy) 5%; no known cause, 34%. The histories of 2 patients illustrate the difficulty of diagnosis, which is usually verified only by biopsy. One of the patients was a 20-year old woman who had used oral contraceptives for 5 years and presented changes consistent with myeloproliferative syndrome in the peripheral circulation and in the bone marrow, as well as a high cardiolipin antibody titer. Oral contraceptives have been cited as a cause of Budd- Chiari syndrome, but the proportion of oral contraceptives users among patients is no greater than among women in general. One recent French study (N = 33) gives a relative risk factor of 2.4 for women between 15 and 45 years old who have used oral contraceptives during the 12 months before onset of the disease. This risk factor parallels that for stroke, myocardial infarction, and venous thromboembolism. No cases of Budd- Chiari syndrome had been reported to the Swedish side-effects register through December 1988.

Does the choice of acute treatment influence future ulcer relapse?

Despite the fact that the direct effect of drugs used for healing of ulcers does not last longer than hours, or at most a few days, some clinical studies have indicated that the rate of new ulcers after short courses of treatment depends on the drug used for healing. Several studies have now shown that the development of new ulcers in the same, regardless whether active ulcers have been healed with antacids or histamine H2-receptor antagonists. This lack of difference in clinical outcome is very likely true also for sucralfate and omeprazole in comparison with histamine H2-antagonists. A bismuth compound can perhaps prolong the period of clinical remission in a subgroup of patients in whom campylobacter pylori do not recur after finalized ulcer healing treatment. Other factors, i.e. smoking, and not the choice of ulcer healing drug, are of importance to recurrencies of new ulcers.