Comparison of a high lipase pancreatic enzyme extract with a regular pancreatin preparation in adult cystic fibrosis patients.

BACKGROUND: Malabsorption due to exocrine pancreatic insufficiency is the main gastrointestinal problem in cystic fibrosis. Despite high doses of pancreatic enzyme supplements it is often not possible to normalize fat absorption. We compared a new high lipase pancreatic enzyme preparation (Pancrease-HL; Cilag, Brussels, Belgium), containing enteric coated microspheres with 25,000 U of lipase, 22,500 U of amylase and 1250 U of protease per capsule, with regular Pancrease capsules, containing 5000 U of lipase, 2900 U of amylase and 330 U of protease per capsule. METHODS: In a randomized double-blind crossover study, 13 cystic-fibrosis patients (6 male, 7 female, mean age 27.7 years) received either four capsules of Pancrease t.d.s. or one capsule of Pancrease-HL t.d.s. Patients took 20 mg omeprazole daily to raise intra-duodenal pH and thus optimize release of enzymes from the enteric coated microspheres. RESULTS: With four capsules of Pancrease t.d.s., mean fat excretion was 15.4% and mean nitrogen excretion was 19.9% vs. 15.5% fat and 19.9% nitrogen excretion with one capsule Pancrease-HL t.d.s. Fat and protein energy loss (as a percentage of total daily intake) was 18.3% with Pancrease and 18.2% with Pancrease-HL. The differences were not statistically significant. Pancrease-HL was well tolerated, with no difference in abdominal pain or general well-being scores. The number and average weight of stools passed remained the same. CONCLUSIONS: One capsule of Pancrease-HL appears to be equivalent to four capsules of regular Pancrease. Treatment with less capsules per day with the same efficacy may facilitate patient compliance.

In vitro dissolution profiles of enteric-coated microsphere/microtablet pancreatin preparations at different pH values.

OBJECTIVES: Enteric-coated microsphere/microtablet pancreatin should stay intact in the stomach and dissolve promptly on entering the duodenum. Postprandial intraluminal pH in the distal duodenum is 5.75 and is lower in exocrine pancreatic insufficiency. The aim of the study was to measure in vitro dissolution times in buffer solutions with pH 4.0-6.0 for five currently available enteric-coated microsphere/microtablet pancreatin preparations. METHODS: The following preparations were tested: Creon, Creon Forte, Pancrease, Pancrease HL and Panzytrat. Two capsules were placed in the buffer solution at 37 degrees C in a USP dissolution testing apparatus. Buffer solutions with pH between 4.0 and 6.0 were used. Solutions were stirred at 125 r.p.m. and the rate of dissolution was monitored by taking 2-mL samples at regular intervals and measuring extinction at 280 nm. Measurements were repeated six times. RESULTS: All preparations failed to dissolve at pH 4.0. At pH 5.0 Pancrease HL showed 43% dissolution within 30 min, all other preparations 15% or less. Panzytrat and Pancrease HL showed more than 50% dissolution within 30 min at pH 5.2. Panzytrat, Pancrease HL and Creon Forte had more than 90% dissolution within 30 min at pH 5.6, and all preparations more than 90% dissolution within 30 min at pH 5.8 and higher. CONCLUSIONS: For the treatment of exocrine pancreatic insufficiency conventional strength enteric-coated microsphere/microtablet pancreatin preparations do not have an optimal dissolution profile. The newer, high lipase preparations such as Pancrease HL perform better, although still not optimally, at pH 5.4 and lower.

Post-prandial intragastric and duodenal acidity are increased in patients with chronic pancreatitis.

OBJECTIVES: Patients with chronic pancreatitis and exocrine insufficiency have lower intraduodenal pH compared to controls. It has been assumed that abnormal low intraduodenal pH in these patients not only results from impaired pancreatic bicarbonate secretion but also from an increased gastric acid load to the duodenum. METHODS: We have tested this hypothesis by combined intragastric and intraduodenal 24 h pH monitoring in nine chronic pancreatitis patients with exocrine pancreatic insufficiency and nine healthy control subjects during standardized test conditions. Postprandial gastrin and cholecystokinin release were also determined. RESULTS: Median 24-h intraduodenal pH (5.90 vs. 6.00) and intragastric pH (1.60 vs. 1.70) were not significantly different between patients and controls. However, in the 2-h postprandial periods intraduodenal pH was below five for a significantly higher percentage of time in chronic pancreatitis patients compared to controls (lunch: 14.5% vs. 0.17%, P=0.011; dinner: 24.1% vs. 5.75%, P=0.05). The post-dinner intragastric pH was below three for a significantly higher percentage of time in chronic pancreatitis patients vs. controls (72.2 vs. 48.9%, P=0.04). Postprandial gastrin release was not significantly different between the two groups. Postprandial secretion of cholecystokinin (CCK), as enterogastrone, was significantly (P < 0.01) reduced in chronic pancreatitis patients (78 +/- 13 pmol/L, 120 min) compared to controls (155 +/- 14 pmol/L, 120 min). CONCLUSIONS: Median intraduodenal and intragastric pH are not significantly decreased in patients with chronic pancreatitis and exocrine insufficiency but the postprandial time with an acidic pH in the duodenum (pH < 5) and in the stomach (pH < 3) is significantly (P

Flavonol and anthraquinone glycosides from Rhamnus formosana.

Two new flavonol triglycosides, and a new anthraquinone glycoside, have been isolated from the roots of Rhamnus formosana. These compounds have been characterized as rhamnazin 3-O-[alpha-L-rhamopyranosyl(1----4)-alpha-L-rhamnopyranosyl(1----6 )]-beta-D-galactopyranoside (rhamnazin 3-isorhamninoside), rhamnocitrin 3-O-isorhamninoside and 1,6,8-trihydroxy-3-methylanthraquinone 1-O-rhamnosyl(1----2)glucoside, respectively.

Benzoquinones, a homoisoflavanone and other constitutents from Polygonatum alte-lobatum.

From the rhizomes of Polygonatum alte-lobatum, two new homologous series of 1,4-benzoquinones, polygonaquinones A and B, a novel homoisoflavanone, a new gentrogenin glycoside and 13 known compounds were isolated and characterized. The structures of the new compounds were determined as two homologous series of three 2,5-dihydroxy-3-methyl-6-alkyl-1,4-benzoquinones and three 2-hydroxy-3-methyl-6-alkyl-1,4-benzoquinones, with chain lengths C21 to C23, and 4',5,7-trihydroxy-6,8-dimethylhomoisoflavanone and gentrogenin 3-O-beta-D-glucopyranosyl(1-->2)-[beta-D-xylopyranosyl(1-->3)] -beta-D-glucopyranosyl(1-->4)-beta-D-galactopyranoside.

Antihepatotoxic principles of Solanum capsicastrum.

Two new steroidal alkaloids named capsimine and isocapsicastrine were isolated from the root bark of Solanum capsicastrum. Their structures were elucidated by chemical degradation and spectral data as (22R, 25R)-22,26-epiminocholest-5-ene-3 beta, 16 alpha-diol and (22S,25S)-O(3)-beta-D-glucopyranosyl-22,26-epiminocholest-5-ene-3 beta-16 alpha-diol, respectively. Capsicastrine, capsicastrine acetate, isoteinemine acetate, and etioline exhibited strong activity against liver damage induced by CCl4.

Cytotoxic principles and their derivatives of Formosan Solanum plants.

The new steroidal alkaloid capsimine-3-O-beta-D-glucoside [1] was isolated from the root bark of Solanum capsicastrum, and carpesterol [2], 3 beta-(p-hydroxy)-benzoyloxy-22 alpha-hydroxy-4 alpha-methyl-5 alpha-stigmast-7-en-6-one [3], and a new steroidal glycoside named indioside A [4] were isolated from the fruit of Solanum indicum. Indioside A was characterized as 3 beta-O-[alpha-L-rhamnopyranosyl-(1-->2), beta-D-glucopyranosyl-(1-->4), beta-D-glucopyranosyl-(1-->3)-]alpha-L-rhamnopyranosyl-(-->2)]-beta-D- glucopyranosyl]-diosgenin. Khasianine, dihydrosolasodine, capsimine, and capsimine-3-O-beta-D-glucoside exhibited strong activity against liver damage induced by CCl4. Capsimine and narigenin exhibited significant cytotoxic effect against human PLC/PRF/5 and KB cells in vitro, and capsicastrine and etioline exhibited significant cytotoxicity against human PLC/PRF/5 cells in vitro.

Genetic and clinical features of patients with cystic fibrosis diagnosed after the age of 16 years.

BACKGROUND: Cystic fibrosis is usually diagnosed in childhood, but a number of patients are not diagnosed until adulthood. The aim of this study was to investigate whether patients diagnosed at an older age had a different genetic constitution, manifestations of disease, and prognosis from those diagnosed at an early age. METHODS: Clinical data and results of lung function tests and DNA analysis of 143 adult patients with cystic fibrosis were entered into a computerised database. Patients diagnosed before their 16th birthday (early diagnosis, ED) were compared with those diagnosed at 16 years of age or older (late diagnosis, LD). RESULTS: Mean age of diagnosis of the ED group was 4.6 years compared with 27.7 years for the LD group. Mean (SD) percentage predicted pulmonary function was better for the LD group than for the ED group: forced expiratory volume in one second (FEV1) 72.5 (31.1)% and 52.0 (24.8)%, and forced vital capacity (FVC) 89.8 (25.7)% and 71.9 (23.0)%, respectively. Colonisation with Pseudomonas aeruginosa was present in 70% of the ED group and 24% of the LD group. In the ED group 81% had pancreatic insufficiency compared with only 12% of the LD group. None of the LD group was homozygous for delta F508 compared with 58% of the ED group. In the LD group 72% were compound AF508 heterozygotes and 28% had two non-delta F508 mutations. CONCLUSIONS: Among this group of 143 adult patients with cystic fibrosis late diagnosis is caused mainly by delayed expression and mild progression of clinical symptoms. Late diagnosis is associated with milder pulmonary disease, less pancreatic insufficiency, and different cystic fibrosis mutations. Since mortality in cystic fibrosis depends on the progression of pulmonary disease, patients with a late diagnosis have a better prognosis than those diagnosed early.

Effect of omeprazole 40 mg once daily on intraduodenal and intragastric pH in H. pylori-negative healthy subjects.

There is a lack of information about the effect of omeprazole or other antisecretory drugs on intraduodenal pH. Aim of the study was to document the variation over time of intraduodenal pH during a 24-hr period and to simultaneously study the effect of omeprazole 40 mg once daily on intragastric and intraduodenal pH in healthy H. pylori-negative subjects. In a randomized, placebo-controlled study, eight subjects (five women, three men, mean age 22.7 years) received oral 40 mg omeprazole or placebo once daily for eight days. On day 7, intragastric and intraduodenal pH was measured continuously for 24 hr, using two miniature glass-membrane electrodes placed in the stomach (fundus) and in the distal third of the duodenum. The 24-hr median intraduodenal pH was 5.95 with placebo and 5.85 with omeprazole. Median intragastric pH was 1.68 without and 4.93 with omeprazole. During omeprazole therapy, intragastric pH fell below 4.0 in five of eight subjects. In the 2- and 3-hr postprandial periods, the percentage of time with pH < 5 was significantly reduced with omeprazole. In healthy subjects, 24-hr median and postprandial pH in the distal part of the duodenum was lower than previously thought. Omeprazole significantly reduced the percentage of time with pH < 5 postprandially. At night, intragastric pH fell below 4.0 with omeprazole 40 mg once daily. Omeprazole does not change 24-hr median intraduodenal pH significantly.

Antiplatelet effects and vasorelaxing action of some constituents of Formosan plants.

Various xanthones as well as quercetin have been shown to exhibit antiplatelet activity. A series of anthraquinones analogues structurally related to xanthones and a series of quercetin-related compounds were tested for their antiplatelet effects. Emodin, frangulin B, kaempferol tetraacetate, quercetin-3-O-galactoside octaacetate, rhamnazin triacetate, and rhamnetin tetraacetate were found to be potent antiplatelet agents, and 1,8-dihydroxy-6-methoxy-3-methylanthraquinone 8-O-rhamnosyl-(1-->2)-glucoside, rhamnustrioside undecaacetate, rutin decaacetate, and quercetin-3-O-(6-O-alpha-L-arabinopyranosyl)-beta-D-galactopyranos ide decaacetate showed significant antiplatelet effects. Quercetin showed vasorelaxing action in rat thoracic aorta.

The cytotoxic principles of Solanum incanum.

In continuation of work on Solanum incanum a new steroidal alkaloid glycoside has been isolated from the fresh berries, which is named incanumine, and characterized as O(3)-[beta-D-xylopyranosyl-(1----3glu)-[beta-D-xylopyranosyl-(1--- -4rha)- alpha-L-rhamnopyranosyl-(1----4)]-beta-D-glucopyranosyl)-solasodine++ +. Solamargine, solasodine, ursolic acid, and ursolic acid derivatives (3-O-palmitoyl ursolic acid, 3-O-crotonyl ursolic acid, 3-O-propionyl ursolic acid) exhibited significant cytotoxic effects against human PLC/PRF/5 cells in vitro. Esterification of ursolic acid with aliphatic acids clearly enhanced the cytotoxic effects against human PLC/PRF/5 cells in vitro.

Mediation of the cytotoxicity of lanostanoids and steroids of Ganoderma tsugae through apoptosis and cell cycle.

A new lanostanoid ester glucoside, 3 alpha-acetoxy-5 alpha-lanosta-8,24-dien-21-oic acid ester beta-d-glucoside (1), and a known steroid, 2 beta,3 alpha,9 alpha-trihydroxy-5 alpha-ergosta-7,22-diene (2), were isolated from the fruit bodies of Ganoderma tsugae and their structures determined by spectroscopic methods. To study the cytotoxicity of 1 and 2, the changes of DNA content in human hepatocytes (Hep 3B) were studied. A sub-G1 cell stage was drastically increased after 24-h incubation with 1 (24 micrograms/mL). Compound 2 (100 micrograms/mL) inhibited the cell cycle progression of Hep 3B cells at the G2/M phase with an IC50 value of about 87.1 micrograms/mL. These results indicate that 1 causes cell death by apoptosis and 2 may possess the activity of cell cycle inhibition.

A cystic fibrosis mutation associated with mild lung disease.

BACKGROUND: Cystic fibrosis is the most common lethal autosomal recessive disorder among whites. Among Dutch patients with cystic fibrosis, delta F508 is the most common mutation and A455E the second most common mutation of the cystic fibrosis transmembrane conductance regulator gene on chromosome 7. A455E is associated with preserved pancreatic function and residual secretion of chloride across membranes. We investigated whether it is also associated with less severe pulmonary disease in patients with cystic fibrosis. METHODS: A total of 33 patients with compound heterozygosity for the A455E mutation were matched according to age and sex with patients who were homozygous for the delta F508 mutation. The pairs were analyzed with respect to the following outcome variables: age at diagnosis, pulmonary-function values, and the frequency of pseudomonas colonization, pancreatic sufficiency, and diabetes mellitus. RESULTS: Cystic fibrosis was diagnosed at a later age in the patients with the A455E mutation than in the delta F508 homozygotes (mean age at diagnosis, 15.0 vs. 3.1 years; P < 0.001). Fewer patients with the A455E mutation had pancreatic insufficiency (21.2 percent vs. 93.9 percent, P < 0.001), and none had diabetes mellitus (0 percent vs. 27.3 percent, P = 0.004). Forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) were significantly higher in the patients with the A455E mutation (mean FEV1, 73.9 percent of the predicted value vs. 54.3 percent of the predicted value; P = 0.002; mean FVC, 88.7 percent of the predicted value vs. 76.3 percent of the predicted value; P = 0.04). Fewer patients with the A455E mutation were colonized with Pseudomonas aeruginosa (33.3 percent vs. 60.6 percent, P = 0.02). CONCLUSIONS: A455E is a common mutation causing cystic fibrosis in the Netherlands. Although several mutations are known to be associated with less severe pancreatic disease, our findings demonstrate a correlation between the A455E mutation and mild pulmonary disease. Because mortality in this disease depends primarily on the progression of pulmonary disease, patients with the A455E mutation have a better prognosis than patients who are homozygous for the delta F508 mutation.