Interaction of dispersed cubic phases with blood components.

The interaction of aqueous nanoparticle dispersions, e.g. based on monoolein/poloxamer 407, with blood components is an important topic concerning especially the parenteral way of administration. Therefore, the influence of human and porcine plasma on dispersed cubic phases was investigated. Particle size measurements of mixtures with plasma indicated a decrease in particle size. In cryo-transmission electron micrographs, different structures could be found, which arose from the dispersed cubic phases under plasma contact. Non-cubic structures on the particle surface were decomposed first. Several phase transitions with the formation of smaller and sometimes larger particle fractions were observed beside remaining cubic structures. A very low but detectable hemolytic activity was found for the dispersed cubic phases based on monoolein and poloxamer 407, when compared to the hemolytic activity of cubic phases based on monoolein and poloxamer 188, on soy phosphatidylcholine, glycerol dioleate and polysorbate 80 or the parenteral fat emulsion Lipofundin MCT 20%.

Urinary excretion of polyethylene glycol 3350 during colonoscopy preparation.

BACKGROUND: Whole gut lavage with a polyethylene glycol electrolyte solution (PEG) is a common bowel cleansing method for diagnostic and therapeutic colon interventions. Absorption of orally administered PEG from the gastrointestinal tract in healthy human beings is generally considered to be poor. In patients with inflammatory bowel disease (IBD), intestinal permeability and PEG absorption were previously reported to be higher than in normal subjects. In the current study, we investigated the absorption of PEG 3350 in patients undergoing routine gut lavage. METHODS AND RESULTS: Urine specimens were collected for 8 hours in 24 patients undergoing bowel cleansing with PEG 3350 for colonoscopy. The urinary excretion of PEG 3350, measured by size exclusion chromatography, ranged between 0.01 and 0.51 % of the ingested amount, corresponding to 5.8 and 896 mg in absolute amounts, respectively. Mean PEG excretion in patients with impaired mucosa such as inflammation or ulceration of the intestine (0.24 % +/- 0.19, n = 11) was not significantly higher (p = 0.173) compared to that in subjects with macroscopically normal intestinal mucosa (0.13 % +/- 0.13, n = 13). CONCLUSION: The results indicate that intestinal absorption of PEG 3350 is higher than previously assumed and underlies a strong inter-individual variation. Inflammatory changes of the intestine do not necessarily lead to a significantly higher permeability of PEG.

Effect of oral administration of freshly pressed juice of Echinacea purpurea on the number of various subpopulations of B- and T-lymphocytes in healthy volunteers: results of a double-blind, placebo-controlled cross-over study.

BACKGROUND: In a recent double-blind placebo-controlled crossover-study the "immune stimulatory" effects (activation of macrophages leading to enhanced phagocytosis and production of several cytokines) of Echinacea purpurea preparations (EPP) which were observed in vitro experiments and following parenteral administration could not be confirmed following oral application of the drug in healthy volunteers. The aim of the present study was to investigate whether or not oral EPP has any effect on important lymphocyte-subpopulations. SUBJECTS AND METHODS: Forty healthy male volunteers (age range 20-40 years) participated in the study. They received either a commercially available pressed juice of E. purpurea herbs or placebo juice using a double-blind placebo-controlled cross-over design with two treatment periods of 14 days. The total number of lymphocytes and 12 subgroups of lymphocytes were determined by using Flow-cytometry. RESULTS: After 1 week of treatment with verum the mean value of the total number of lymphocytes decreased slightly (-6%, p = 0.033) compared to the initial value. Treatment for 1 and 2 weeks with EPP had only minor effects on two of the 12 subtypes of lymphocytes. No significant changes were observed in the verum period for the following types of cells: T- and B-lymphocytes, CD4 + - and CD8 + -T-lymphocytes including the subgroups of "naive" and "memory" CD4 + - and CD8 + -T-lymphocytes as well as the natural killer cells. Using a modified version of the Wilcoxon-Mann-Whitney-U-test, which is claimed to be optimal for the evaluation of the results of studies with a cross-over design, a significant difference was found for the number of CD8 + -T-lymphocytes and natural killer cells corresponding to either a decrease during treatment with verum or an increase in the number of these cells in the placebo period. CONCLUSION: Oral administration of EPP for 1 and 2 weeks has only minor effects on two out of 12 lymphocyte subpopulations determined in the study. The small differences observed in the number of CD8 + -T lymphocytes and natural killer cells are only of questionable physiological relevance.

Reversibility of increased formation of catecholamines in patients with alcoholic liver disease.

BACKGROUND: While chronic alcohol abuse has been shown to be associated with increased production of catecholamines, little is known about the reversibility of this increased sympathetic activity and the influence of severity of alcoholic liver disease (ALD). The aim of the present study was to investigate whether the increase in urinary excretion rates and plasma levels of catecholamines in alcohol-abusing patients are reversible during prolonged abstinence, especially with respect to the severity of ALD. METHODS: Urinary excretion rates and plasma levels of noradrenaline (NA), adrenaline (A) and dopamine (DA) were determined in 15 subjects with mild to moderate ALD (ALD1) and in 7 alcoholic cirrhotics (ALD2) on admission and after 2 and 12 weeks of abstinence. Eight healthy males, age-matched to ALD1, served as controls (HC). RESULTS: Urinary excretion rates (24 h) and resting plasma concentrations of NA and A were increased in ALD1 and ALD2 about 2-fold, while those of DA were elevated only moderately compared to HC. During exercise under a load of 100 watts, the increases in plasma levels of NA and A with reference to the resting values were nearly identical in all three groups. Already after 2 weeks of abstinence, the urinary excretion rate of NA had nearly normalized in ALD1 but remained unchanged in ALD2. CONCLUSION: The marked enhancement of catecholamine production, especially that of NA, observed in actively drinking alcoholics is reversible under abstinence within a few weeks in subjects with mild to moderate ALD but only partially reversible in alcoholic cirrhosis.

Nutritional deficiencies in German middle-class male alcohol consumers: relation to dietary intake and severity of liver disease.

OBJECTIVE: The purpose of the present study was to compare the nutrient intake and the nutritional status between German middle-class alcohol consumers and non-drinkers. DESIGN: Cross-sectional study using patients with different stages of alcoholic liver disease (ALD) and healthy volunteers. SETTING: Southern Germany. SUBJECTS: Seventy-six hospitalized German middle-class alcohol consumers with different stages of alcoholic liver disease (ALD) and 22 healthy control subjects. METHODS: Subjects and controls were nutritionally assessed and mineral and vitamin content was measured in blood and urine. RESULTS: When compared with controls, alcohol consumers had significantly higher intakes of total calories, but intake of non-alcoholic calories did not differ between groups (P<0.05). Among drinkers, there was a decrease in percentage of energy derived from protein and fat and a significant increase in carbohydrates (P<0.05). With the exception of vitamin E, micronutrient intake of alcoholics was equal to that of controls; however, blood vitamin (vitamin C, retinol, lycopene, alpha- and gamma-carotene) and trace element (selenium, zinc) concentrations of alcohol-drinking patients were lower than those of non-drinkers. CONCLUSION: From the results of this study it is concluded that in German middle-class male alcohol consumers the status of several micronutrients is disturbed, although dietary intake hardly differs from that in non-alcoholic controls.

Interstitial pneumonitis during combination therapy with interferon-alpha and ribavirin in a patient with chronic Hepatitis C.

After nine weeks of combination therapy with recombinant interferon-alpha and ribavirin for chronic hepatitis C a 62-year old woman complained of a dry cough and exertional dyspnea. An elevated erythrocyte sedimentation rate was noticed. Prior to treatment chest X-rays and physical examination revealed no pulmonary abnormalities. Inhalative steroids did not improve the symptoms and afer 12 weeks treatment chest X-ray and computed tomography showed bilateral reticonodular lung infiltration suggesting a diagnosis of interstitial pneumonitis. Cough and dyspnea resolved and abnormal lung shadows were reversible within two months following discontinuation of interferon-/ribavirin treatment. In the Japanese literature there are similar reports on pneumonitis occurring during high-dose IFN-alpha and concomitantly Chinese herbal medicine treatment. To our knowledge this is one of the first cases of interstitial pneumonitis due to combination therapy with IFN-alpha and ribavirin in chronic hepatitis C reported in the western world.

Models of alcoholic liver disease in rodents: a critical evaluation.

This article represents the proceedings of a workshop at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were J. Christian Bode and Hiroshi Fukui. The presentations were (1) Essentials and the course of the pathological spectrum of alcoholic liver disease in humans, by P. de la M. Hall; (2) Lieber-DeCarli liquid diet for alcohol-induced liver injury in rats, by C. S. Lieber and L. M. DeCarli; (3) Tsukamoto-French model of alcoholic liver injury, by S. W. French; (4) Animal models to study endotoxin-ethanol interactions, by K. O. Lindros and H. Järveläinen; and (5) Jejunoileal bypass operation in rats-A model for alcohol-induced liver injury? by Christiane Bode, Alexandr Parlesak, and J. Christian Bode.

Inhibition of retinol oxidation by ethanol in the rat liver and colon.

BACKGROUND: Epidemiological evidence has been presented for an increased risk of development of colon cancer after chronic alcohol abuse. Alcohol is degraded by cytosolic alcohol dehydrogenases that also are capable of retinol oxidation. Inhibition of retinol oxidation to retinoic acid has been shown to occur in parallel with profound impairment of intracellular retinoid signal transduction and loss of cell differentiation control. AIMS: In the present study, the change in cytosolic retinol oxidation and retinoic acid formation by ethanol concentrations that occur in body tissues in humans after social drinking was measured in cells from the liver, and small and large intestine of the rat. RESULTS: The specific catalytic efficiency V(max)/K(m) (ml/min/g) of cytosolic retinol oxidation in the large intestine (28.9) was found to be distinctly higher than that in the liver (3.4), while the efficiency in the small intestine was negligible (0.20). In the presence of increasing ethanol concentrations (9, 17, and 34 mM), V(max)/K(m) for retinol oxidation decreased in a dose dependent manner to 7.8% of the initial value in the large intestine and to 12% in the liver. The V(max)/K(m) of retinoic acid formation in the liver cytosol decreased to 15%. CONCLUSIONS: Our data demonstrate impairment of hepatic and intestinal cytosolic retinol oxidation and retinoic acid formation by ethanol at concentrations in body tissues after social drinking in humans. The results suggest that the increased risk of developing colorectal neoplasias after alcohol abuse may, at least in part, be caused by impaired retinoid signal transduction.

Thrombolytic therapy in patients with portal vein thrombosis: case report and review of the literature.

A 29-year-old male patient with Crohn's disease of the terminal ileum and previous abdominal surgery was admitted because of severe abdominal pain and signs of bacterial sepsis. The diagnosis of portal vein thrombosis and multiple liver abscesses due to Streptococcus intermedius septicaemia was made and antibiotic therapy was instituted immediately. As high-dose heparin therapy was ineffective, urokinase was administered intravenously over a total of 7 days. Within 2 days, the patient's symptoms completely subsided. Colour duplex ultrasonography revealed complete recanalization of the main stem of the portal vein; the right branch of the portal vein, however, remained occluded. Other case reports on thrombolytic therapy in patients with portal vein thrombosis are reviewed.

Increased intestinal permeability to macromolecules and endotoxemia in patients with chronic alcohol abuse in different stages of alcohol-induced liver disease.

BACKGROUND/AIMS: No information is yet available about the influence of alcohol abuse on the translocation of larger molecules (Mr>1200) through the intestinal mucosa in man. The present study aimed to determine the intestinal permeability to macromolecules in patients with chronic alcohol abuse and mild to more advanced stages of liver disease, and to measure the concentration of endotoxins in the plasma, as these compounds derive from the intestinal flora and are suspected to contribute to the development of alcoholic liver disease (ALD). METHODS: The permeability to polyethylene glycol Mr 400, Mr 1500, Mr 4000, and Mr 10,000 and endotoxin plasma concentrations were measured in 54 patients with alcoholic liver disease, 19 of them with cirrhosis, and in 30 non-alcoholic healthy controls. RESULTS: Permeability to polyethylene glycol Mr 400 was found to be unchanged in patients with ALD in comparison to healthy controls, whereas polyethylene glycol Mr 1500 and Mr 4000 were recovered in about twice as high concentrations in the urine of ALD patients (p<0.01). Polyethylene glycol Mr 10,000 was detected significantly less frequently in urine from healthy controls (0/30) than in urine of patients with alcoholic liver disease (20/54, p<0.01). Endotoxin concentrations in the plasma of alcoholics were increased more than 5-fold compared to healthy controls (p<0.01). CONCLUSIONS: The results of this study indicate that alcohol abuse impairs the function of the intestinal barrier, which might enhance the translocation of bacterial toxins, thereby contributing to inflammatory processes in alcoholic liver disease.

[Alcohol, the gastrointestinal tract and pancreas]. / Alkohol, Gastrointestinaltrakt und Pankreas.

The intake of larger quantities of alcoholic beverages leads to manifold functional disturbances and organ injury in the upper gastrointestinal tract. These damaging effects of alcohol are frequently the cause of complaints, such as heart burn, symptoms of dyspepsia and diarrhoea. Examples of more pronounced organ injury which can occur even following a single episode of heavy drinking are tears in the mucosa at the junction of the esophagus and the stomach (Mallory-Weiss-lesion) and hemorrhagic erosions in the stomach and/or the duodenum which may lead to massive bleeding. In the small intestine alcohol abuse interferes with the absorption of glucose, amino acids, lipids, water, sodium and vitamins (especially thiamine and folic acid). This inhibition of absorption of nutrients may contribute to nutritional deficiencies frequently observed in alcoholics. Acute alcohol ingestion can also damage the mucosa in the upper region of the small intestine and may lead to the disruption of the tips of the villi. Chronic alcohol abuse increases markedly the prevalence of bacterial overgrowth in the small intestine. The findings of human and animal studies suggest that the mucosal injury together with bacterial overgrowth favour the following sequence of events: Alcohol induced mucosal injury in the small intestine increases the permeability of the mucosa to macromolecules, such as endotoxin and/or other bacterial toxins, into the blood or lymph. This results in the release of potentially toxic cytokines and other mediators like Kupfer cells and other phagocytes. These cytokines and other mediators, in turn, exert multiple injurious effects on the microcirculation and membranes. The result is cell damage and even cell death (apoptosis, necrosis) in the liver and other organs. Chronic alcohol abuse is one of the most important risk factors for the development of cancers of the tongue, larynx, pharynx and esophagus. In many countries alcohol abuse is the most important cause for the development of chronic pancreatitis. In the initial phase the disease is frequently characterised by episodes of 'acute' pancreatitis. These episodes develop only on the basis of prolonged alcohol abuse leading to subclinical damage of the gland. The latter is found in about 20-50% of patients with chronic alcohol abuse while the clinically overt pancreatitis is observed in only 1%-3% of alcoholics. Despite numerous studies performed in animal experiments and man the pathogenesis of alcoholic pancreatitis until now has not been clarified.

Influence of the menstrual cycle on the LPS-induced cytokine response of monocytes.

We previously observed a gender difference in the cytokine response of peripheral blood monocytes (PBM). The study was performed to find out whether the gender-related difference might be due to hormonal changes during the menstrual cycle in healthy premenopausal females. The release of tumour necrosis factor a (TNF-alpha) was reduced in the premenopausal females during the luteal phase compared to the follicular phase. Compared to the male controls the release of TNF-alpha and of interleukin 6 (IL-6) during the luteal phase was also diminished. In premenopausal females the concentration of estradiol in plasma correlated with the release of TNF-alpha and IL-6 during the luteal phase.

[Does combination therapy of chronic viral hepatitis C with interferon-alpha and ribavirin approach financial limits?]. / Stösst die Kombinationstherapie der chronischen Virushepatitis C mit Interferon alpha und Ribavirin an die Grenze der Finanzierbarkeit?

Until April 1999, interferon alpha was the only licensed medication in Germany for chronic hepatitis C virus infection with proven effectiveness. In two large placebo-controlled studies the combination therapy with interferon alpha and ribavirin confirmed a major improvement of the sustained response compared to the treatment with interferon alone. These results led to the approval in Germany of the combination therapy for patients with chronic hepatitis C without prior interferon therapy and for patients who relapse after an initial response to therapy with interferon alone. The expenses for the two drugs of the combination therapy are, however, very high (about 40,000 DM for one year of treatment). Considering the large number of patients with chronic hepatitis C in Germany (about half a million), it is suggested that more detailed recommendations for the indication of the combination therapy should be elaborated by a group of experts. Using data from the published literature it is shown for two subgroups of patients with chronic hepatitis C that a more differentiated indication for the use of the combination therapy is possible and justified and might help to avoid a more dramatic increase of drug expenses without shortcomings for the patients.

Effects of chronic alcohol abuse on duodenal mononuclear cells in man.

The aim of this study was to investigate whether chronic alcohol abuse alters the number and distribution of mononuclear cells of the duodenal mucosa. The number of common leukocyte antigen (CLA)-positive interepithelial lymphocytes (IEL), B lymphocytes (BL), IgA-producing plasma cells (IgA-PC), and macrophages (MP) was quantitatively evaluated in biopsies of the duodenal mucosa of patients with alcohol abuse compared to subjects without alcohol abuse. Biopsies from the descending part of the duodenum were obtained by endoscopy from two groups of patients with chronic alcohol abuse (group A1, abstinence <5 days, N = 21) and group A2 abstaining 5-10 days (N = 6). Twenty-five subjects without alcohol abuse served as controls (C). Immunohistochemical staining was done by avidin-biotin-complex method. In addition, the content of IgA in the plasma cells was determined by using a TV-densitometric method. The number of B-lymphocytes in the lamina propria was increased by 37% in group A1 (P < 0.005). A distinct decrease was observed in group A1 compared to C in the number of IEL that were CLA positive (-50%, P < 0.025) and in the number of macrophages (-54%, P < 0.025). In group A2 the differences in the number of B lymphocytes and macrophages were no longer seen. In A1, there was no significant change in the number of IgA-producing plasma cells or in the number of interepithelial lymphocytes counted after H&E staining compared to the controls. There was no difference in content of IgA in the IgA-producing plasma cells. From these results it is concluded that chronic alcohol abuse significantly influences the gut-associated immune system, possibly by increasing the permeability of the gut mucosa to macromolecules that act as antigens.

Effect of the type of beverage and meat consumed by alcoholics with alcoholic liver disease.

We analyzed meat products and alcoholic beverage preference in patients with the three stages of alcoholic liver disease (ALD) compared with controls using diet history data. Daily consumption of total alcohol, types of alcoholic beverages, and types of meat and meat products in grams was obtained by dietary history taken from patients with biopsy proven stage of ALD. A strong association was found between the ALD subjects and total alcohol and beer consumption. There was a significant increase in the consumption of total pig products, pork, and offal in the ALD groups compared with controls. There was a significant positive correlation between beer consumption and pork in alcoholic hepatitis, total pork products in alcoholic hepatitis, and cirrhosis and offal in alcoholic hepatitis and cirrhosis. There was no correlation with the fatty liver stage of ALD. The strongest correlation was between beer and total pig products in the alcoholic hepatitis group. Wine consumption was negatively correlated with the consumption of pig products and beer in the alcoholic cirrhosis group. In conclusion, the association of total pig product consumption with cirrhosis mortality in various countries was validated by personal diet history data obtained from ALD patients in a tested clinical microcosm. The results suggest that this association may be modified by the type of alcoholic beverage that is preferentially consumed.

[Spontaneous bacterial peritonitis]. / Die spontane bakterielle Peritonitis.

BACKGROUND: Since the beginning of the eighties systematic investigations broadened our knowledge about the clinical picture of spontaneous bacterial peritonitis very much. Important insights into epidemiology, pathogenesis, symptomatology, diagnosis and therapy of this disease, which is a frequent complication in patients with cirrhosis of the liver and ascites, could be gained. Actual research work primarily deals with questions of therapy and prophylaxis. AIM: Aim of this review is a comprehensive presentation of the different aspects of this disease on the basis of the present literature. CONCLUSIONS: As on the one side the clinical symptoms may be very little and on the other side the prognosis is very bad, it is extremely important to take this entity into the differential considerations to make an early diagnosis and to start an adequate therapy early.

Free methionine supplementation limits alcohol-induced liver damage in rats.

Alcohol feeding to rats that were submitted to a jejunoileal bypass operation has been shown to result in liver damage being comparable with alcohol-induced liver disease in man. In the present study, a striking effect of free methionine consumption on histological liver injury, triglyceride accumulation, and energy-rich nucleoside content in the liver of rats with a jejunoileal bypass is demonstrated. The animals obtained 0, 30, and 120 mg of methionine in the control group and 0, 30, 120, and 240 mg in the alcohol-fed group per day and per kilogram of body weight for 12 weeks. Methionine was found to strongly improve the alcohol-induced histological changes in the liver. Triglyceride content of the liver was found to decrease in a dose-dependent manner with increasing methionine ingestion (from 255 +/- 20.7 to 49.7 +/- 6.1 micromol/g of protein in the control group and from 233 +/- 17.3 to 42.1 +/- 7.2 micromol/g of protein in the alcohol group). Hepatic adenosine triphosphate content increased significantly with higher methionine consumption (13.5 +/- 0.8 vs. 26.9 +/- 2.8 micromol/g of protein in the control group and 11.9 +/- 1.4 vs. 20.5 +/- 2.5 micromol/g of protein in the alcohol group), whereas no differences were found in the protein and DNA content of the liver. These results underscore the impairment of the transmethylation/transsulfuration pathway in the development of alcohol-induced liver diseases.