Matti Vuoristo

Long-term treatment of ulcerative colitis with ciprofloxacin: A prospective, double-blind, placebo-controlled study

BACKGROUND & AIMS Although bacterial bowel flora may be one of the contributing factors in the pathogenesis of chronic mucosal inflammation, antibiotic treatment has no established role in ulcerative colitis. The aim of the study was to evaluate the role of ciprofloxacin in the induction and maintenance of remission in ulcerative colitis in patients responding poorly to conventional therapy with steroids and mesalamine. METHODS Ciprofloxacin (n = 38; 500-750 mg twice a day) or placebo (n = 45) was administered for 6 months in a double-blind, randomized study with a high but decreasing dose of prednisone and maintenance treatment with mesalamine including follow-up for the next 6 months. Clinical assessment and colonoscopic evaluation were performed at 0, 3, 6, and 12 months. Treatment failure, the primary end point, was defined as both symptomatic and endoscopic failure to respond. RESULTS During the first 6 months, the treatment-failure rate was 21% in the ciprofloxacin-treated group and 44% in the placebo group (P = 0.02). Endoscopic and histological findings were used as secondary end points and showed better results in the ciprofloxacin group at 3 months but not at 6 months. CONCLUSIONS Addition of a 6-month ciprofloxacin treatment for ulcerative colitis improved the results of conventional therapy with mesalamine and prednisone.

A placebo-controlled trial of primary biliary cirrhosis treatment with colchicine and ursodeoxycholic acid

BACKGROUND/AIMS Ursodeoxycholic acid (UDCA) and colchicine have beneficial effects in primary biliary cirrhosis (PBC). The efficacy of colchicine and UDCA in PBC was compared in a 2-year placebo-controlled study (n = 90). METHODS Clinical events, laboratory test results, and liver histology were recorded at the beginning and end of the trial. RESULTS There were significantly fewer dropouts for hepatic reasons with UDCA than with placebo. Pruritus was reduced by both active drugs. Colchicine improved liver function test results only modestly, whereas UDCA significantly decreased the serum activities of aminotransferases, alkaline phosphatase, and gamma-glutamyltransferase compared with colchicine and placebo. Serum total bilirubin levels were decreased only by UDCA. Both colchicine and UDCA reduced serum cholesterol levels, and UDCA also reduced high-density lipoprotein cholesterol levels. Furthermore, UDCA reduced the serum levels of immunoglobulin (Ig) M and IgG, and colchicine reduced IgG levels compared with placebo. The elevated serum level of aminoterminal propeptide of type III procollagen remained unchanged by colchicine or UDCA, whereas the serum level of carboxyterminal propeptide of type I procollagen was significantly decreased by UDCA. UDCA significantly decreased ductular proliferation compared with colchicine or placebo. CONCLUSIONS These data suggest that UDCA frequently is superior to colchicine and especially to placebo in the treatment of PBC.

Prospective study of Helicobacter pylori seropositivity and cardiovascular diseases in a general elderly population.

Case-control and cross sectional studies have suggested that chronic infection with Helicobacter pylori is a risk factor for cardiovascular disease.1 2 No prospective studies have examined this association in elderly people–those usually with the highest prevalence of H pylori infection.3 We performed a prospective study on people from the Helsinki aging study. From the Helsinki census register random cohorts of people alive in July 1988 and born in 1904, 1909, and 1914 (300 in each group, 11.2% of the total population of 8035) were invited to participate; 795 people were alive and still living in the city of Helsinki. Altogether 144 refused to participate, leaving 651 (81.9%) people to be examined clinically up to April 1990. H pylori IgG, IgA, and IgM antibodies were tested by enzyme immunoassays3 in 624 subjects (repeatibility of the …

Biliary lipid composition in monozygotic and dizygotic pairs of twins

The relative contribution of genetic factors to biliary and serum lipid composition was studied in 17 monozygotic and 18 dizygotic middle aged male pairs of twins. Cholesterol precursors, squalene and Methylated sterols which reflect the activity of cholesterol synthesis were also measured. Pairwise intraclass correlations were determined for monozygotic and dizygotic twin pairs and heritability estimates were calculated. Molar % of biliary cholesterol and percentage distribution of biliary cholic acid and particularly deoxycholic acid showed significant pairwise correlations within the monozygotic but not the dizygotic pairs. Similar correlations were found for total biliary methylsterols and of the methylsterol subfractions for the two methostenols but not for squalene, lanosterol and dimethylsterols. In serum, the precursor sterols, but not squalene, showed even higher pairwise correlations in the monozygotic twins than the corresponding precursors in bile. Molar per cent of bile acids and phospholipids and cholesterol saturation index were not correlated significantly in either twin pairs, but the pairwise correlations tended to be higher in the monozygotic than in the dizygotic pairs. Gall stones were found in seven monozygotic and three dizygotic subjects. Two monozygotic twin pairs were concordant for gall stones; all the dizygotic pairs were discordant. Overall, these data suggest that molar percentage of biliary cholesterol, bile acid composition, cholesterol synthesis, bile cholesterol saturation, and gall stone formation may be under a significant genetic control.

Cholesterol malabsorption in pancreatic insufficiency: Effects of enzyme substitution

Defective lipolysis, steatorrhea, and hypocholesterolemia characterize pancreatic insufficiency. Lipid metabolism in pancreatic insufficiency was studied by measuring serum lipoproteins, cholesterol absorption with double labels and serum plant sterols, and bile acid and cholesterol synthesis with fecal and dietary steroid analysis and cholesterol precursor sterols before and during exogenous pancreatic enzyme substitution. Baseline fecal fat, masses, bile acids and neutral steroids, and cholesterol synthesis were increased, whereas cholesterol absorption was markedly reduced. In fact, the present data suggest that sterol absorption may be disturbed more sensitively than fat absorption in pancreatic insufficiency. Enzyme substitution significantly reduced fecal fat, masses, bile acids and neutral steroids, and synthesis of cholesterol and improved cholesterol absorption in relation to serum cholesterol, although normal values were not obtained. Serum level of high-density lipoprotein cholesterol was significantly elevated by exogenous enzymes, whereas levels of cholesterol or triglycerides in other lipoproteins remained unchanged. Improved sterol absorption increased also serum levels of plant sterols and reduced levels of cholesterol precursors and cholesterol synthesis and precursor sterol-plant sterol ratios. Thus, reduced intestinal lipolysis with expanded oil phase appears to be a major reason for impaired cholesterol absorption, causing enhanced cholesterol and, consequently, bile acid synthesis and reduced serum cholesterol level. Exogenous enzyme substitution seems partly to correct these abnormalities, improvements of which can be monitored by the gas-liquid chromatographic determination of serum plant sterols or cholesterol precursor-plant sterol ratios.

Increased Biliary Lipid Secretion in Celiac Disease

Direct measurements of biliary lipid outputs, cholesterol absorption, and fecal steroids were carried out in celiac patients before and during a gluten-free diet to show whether an enhanced flux of cholesterol into the gut (found earlier in these patients) is due to increased biliary output or mucosal secretion of cholesterol, or both. The bile flow rate and the secretion of biliary cholesterol, phospholipids, and bile acids were significantly increased in celiac disease and appeared to be normalized by effective gluten-free diet. A significant amount of cholesterol originated from the intestinal mucosa, but the amount was not consistently increased in the celiac patients. Fractional absorption of cholesterol was low, but due to enhanced biliary secretion the amount of cholesterol absorbed was mostly within the normal limits so that fecal neutral steroids of biliary origin and cholesterol synthesis were markedly increased in celiac disease. Despite high biliary bile acid secretion, fractional absorption of bile acids was enhanced. Thus, the effective ileal conservation of bile acids could have contributed to increased bile acid-dependent secretion of biliary cholesterol. The enhanced biliary and fecal output of cholesterol should ultimately be balanced by augmented cholesterol synthesis, but the closer site of the synthesis and regulatory mechanisms between cholesterol and lipoprotein metabolism need further exploration.

Serum plant sterols and lathosterol related to cholesterol absorption in coeliac disease

The concentrations of the plant sterols, campesterol and beta-sitosterol in serum, normally correlate with the efficiency of cholesterol absorption, whereas the concentration of lathosterol, a cholesterol precursor sterol, closely parallels changes in cholesterol synthesis. In this study we explored whether the plant sterol concentrations in serum in coeliac disease are determined by cholesterol absorption and whether they alone or with the serum lathosterol concentration, could be used for screening the activity of coeliac disease. In six patients the plant sterol concentrations in serum were significantly lower than in 17 control subjects, the reduction being more marked for campesterol than for beta-sitosterol: the serum lathosterol concentration was significantly higher than in the control subjects. The opposite changes in serum plant sterols and lathosterol were recorded in patients on a gluten-free diet. The plant sterol concentrations in serum (nmol/mg of cholesterol) were positively correlated with each other, and with the percentage absorption of cholesterol and with xylose absorption; they were negatively correlated with faecal fat, but not with faecal plant sterols. Thus, the low plant sterol concentrations in serum in coeliac disease were attributable to their impaired absorption, which in turn was closely associated with the absorption of cholesterol. The serum campesterol concentration clearly distinguished the untreated patients from the controls, whereas the use of serum beta-sitosterol, and the serum ratios of lathosterol/plant sterol resulted in some overlapping with the controls. It is suggested that the plant sterols in serum might be worth of determining when screening patients for coeliac disease and especially when testing their adherence to the gluten-free diet.

Impaired absorption of cholesterol and bile acids in patients with an ileoanal anastomosis

Background—No data exist on cholesterol absorption in patients with an ileoanal anastomosis (IAA). Aims—To study cholesterol absorption and its effects on cholesterol and bile acid metabolism in patients with an IAA. Patients and methods—Cholesterol absorption, and serum, biliary, and faecal lipids were studied in 24 patients with an IAA and 20 controls. Results—Fractional cholesterol absorption was significantly lower in the patients (36% versus 47% in controls). Surprisingly, the calculated intestinal influx of endogenous cholesterol was reduced so that the absolute absorption of cholesterol was decreased; elimination of cholesterol as faecal neutral steroids remained normal. Thus, the slightly increased cholesterol synthesis was mainly due to increased faecal bile acid excretion, which, in turn, was associated with reduced absorption and biliary secretion of bile acids. Serum total and low density lipoprotein (LDL) cholesterol and LDL triglycerides were lower in the patients. Molar percentage and saturation index of biliary cholesterol were slightly higher in patients with an IAA. Proportions of secondary bile acids in bile and faeces were diminished, and faecal unidentified bile acids were higher in patients. Conclusions—Cholesterol absorption is significantly impaired in patients with an IAA, and is closely related to changes in serum and biliary lipids observed in these patients.

Rhabdomyolysis in a patient receiving atorvastatin and fluconazole

The hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are widely used hypolipidemic agents which decrease cardiovascular morbidity and mortality in both primary and secondary prevention. Lovastatin, simvastatin, atorvastatin, fluvastatin, pravastatin and rosuvastatin are globally available. In general, statins are well tolerated, and serious adverse effects are rare. The most important adverse effect of statins is myopathy [1–3]. Clinically relevant myopathy is often defined as a proximal or generalised pain and/or weakness in skeletal muscles, and a creatine phosphokinase (CK) value higher than ten times the upper limit of the normal range. Statin-associated myopathy may also occur with normal CK levels [4]. Statin myopathy can progress to necrosis of muscle cells (rhabdomyolysis) which may lead to myoglobinuria and acute renal failure [1–3]. CYP3A4 catalyses the biotransformation of lovastatin, simvastatin and atorvastatin [5]. Erythromycin, clarithromycin, itraconazole and ketoconazole are examples of widely used drugs that inhibit CYP3A4. The concomitant use of these drugs with lovastatin, simvastatin or atorvastatin leads to increased bioavailability and reduced elimination of the statin, thereby greatly increasing the potential for myotoxicity [2, 5, 6]. One case of rhabdomyolysis after concomitant use of fluconazole and simvastatin has been reported [7], but, to our knowledge, there are no reported cases of rhabdomyolysis associated with concomitant intake of fluconazole and atorvastatin. We describe a fatal case of rhabdomyolysis in a 76-year-old male after use of this drug combination.

Cholesterol absorption, elimination and synthesis in coeliac disease

Abstract. Hypocholesterolaemia and high faecal elimination of cholesterol was explored by measuring the percentage of cholesterol absorbed, faecal steroids, serum cholesterol and dietary cholesterol in patients with coeliac disease before and after a gluten free diet. From these data, the total and endogenous flux of cholesterol into the gut and the amount of cholesterol absorbed could be calculated.