Hydrophilic but not hydrophobic bile acids prevent gallbladder muscle dysfunction in acute cholecystitis

The pathogenesis of acute cholecystitis (AC) is controversial. Bile acids may be involved in the pathogenesis of AC because the hydrophobic chenodeoxycholic acid (CDCA) reproduced in vitro the muscle dysfunction observed in AC and was prevented by the hydrophilic ursodeoxycholic acid (UDCA). The present study examined the in vivo effects of UDCA or CDCA on gallbladder muscle dysfunction caused by AC. Guinea pigs were treated with placebo, UDCA, or CDCA for 2 weeks before sham operation or induction of AC by bile duct ligation (BDL) for 3 days. Pretreatment with oral UDCA prevented the defective contraction in response to agonists (acetylcholine [ACh], cholecystokinin 8 [CCK-8], and KCl) that occurs after BDL. Prostaglandin (PG) E(2)-induced contraction remained normal in the placebo and UDCA-treated groups but was impaired in the CDCA-treated group. Treatment with UDCA also prevented the expected increase in the levels of H(2)O(2), lipid peroxidation, and PGE(2) content in the placebo-treated AC group, whereas CDCA caused further increases in these oxidative stress markers. The binding capacity of PGE(2) to its receptors and the activity of catalase were reduced after treatment with CDCA. Treatment with UDCA enriched gallbladder bile acids with its conjugates and reduced the percentage of CDCA conjugates. In contrast, treatment with CDCA significantly decreased the percentage of UDCA in bile. In conclusion, oral treatment with UDCA prevents gallbladder muscle damage caused by BDL, whereas oral treatment with CDCA worsens the defective muscle contractility and the oxidative stress.     

Co-administration of nitric oxide-aspirin (NCX-4016) and aspirin prevents platelet and monocyte activation and protects against gastric damage induced by aspirin in humans

OBJECTIVES: The goal of this study was to test the hypothesis that NCX-4016 may have broader anti-inflammatory and antithrombotic effects as well as better gastric tolerability than aspirin in humans. BACKGROUND: NCX-4016 is an aspirin derivative containing a nitric oxide-releasing moiety that prevents platelet activation and modulates tissue factor (TF) expression and cytokine release from lipopolysaccharide (LPS)-stimulated monocytes. METHODS: This was a blind-observer, placebo-controlled, parallel-group study in which 48 healthy subjects were randomized to receive NCX-4016 800 mg twice a day, NCX-4016 800 mg twice a day plus aspirin 325 mg, aspirin 325 mg, or placebo for 21 days. RESULTS: Similar to aspirin alone, NCX-4016 effectively inhibited platelet aggregation induced by 0.6 mmol/ arachidonic acid, clot-stimulated thromboxane (TX) B2 generation in whole blood, and urinary excretion of 11-dehydro-TXB2. Unlike aspirin alone, the administration of NCX-4016 significantly inhibited TF expression in monocytes stimulated ex vivo with 10 micromol/l LPS (determined by flow-cytometry analysis of TF on CD14 positive cells). NCX-4016 also inhibited the rapid TF expression induced in monocytes by a proteinase activated receptor agonist (thrombin receptor activator protein, 2 micromol/l) as well as LPS-induced expression of CD11b . Ex vivo, release of MCP-1 and interleukin-6 were significantly inhibited by NCX-4016, but not by aspirin. NCX-4016 was not associated with gastric damage, and significantly reduced gastric injury when co-administered with aspirin, although both drugs reduced gastric PGE2 production to the same extent. CONCLUSIONS: NCX-4016 is equally effective as aspirin in inhibiting cyclooxygenase activity. However, NCX-4016 causes less gastric damage and prevents monocyte activation. Larger multicenter trials are warranted to establish clinical efficacy and safety of NCX-4016.     

Visceral leishmaniasis: current status of control,diagnosis, and treatment,and a proposed research and development agenda

Visceral leishmaniasis is common in less developed countries, with an estimated 500000 new cases each year. Because of the diversity of epidemiological situations, no single diagnosis, treatment, or control will be suitable for all. Control measures through case finding, treatment, and vector control are seldom used, even where they could be useful. There is a place for a vaccine, and new imaginative approaches are needed. HIV co-infection is changing the epidemiology and presents problems for diagnosis and case management. Field diagnosis is difficult; simpler, less invasive tests are needed. Current treatments require long courses and parenteral administration, and most are expensive. Resistance is making the mainstay of treatment, agents based on pentavalent antimony, useless in northeastern India, where disease incidence is highest. Second-line drugs (pentamidine and amphotericin B) are limited by toxicity and availability, and newer formulations of amphotericin B are not affordable. The first effective oral drug, miltefosine, has been licensed in India, but the development of other drugs in clinical phases (paromomycin and sitamaquine) is slow. No novel compound is in the pipeline. Drug combinations must be developed to prevent drug resistance. Despite these urgent needs, research and development has been neglected, because a disease that mainly affects the poor ranks as a low priority in the private sector, and the public sector currently struggles to undertake the development of drugs and diagnostics in the absence of adequate funds and infrastructure. This article reviews the current situation and perspectives for diagnosis, treatment, and control of visceral leishmaniasis, and lists some priorities for research and development.     

Outcome of anti-HBe positive chronic hepatitis B in alpha-interferon treated and untreated patients: a long term cohort study

BACKGROUND/AIMS: We studied the influence of biochemical and virologic patterns and interferon on the outcome of anti-HBe positive chronic hepatitis B in 164 (103 treated) consecutive patients, followed-up prospectively for a mean of 6 years (21 months-12 years). METHODS: Histology, biochemical and virologic profiles were characterized by monthly monitoring during the first 12 months of follow-up. Thereafter patients underwent blood and clinical controls every 4 and 6 months, respectively. Cirrhosis at follow-up histology or end stage complications of cirrhosis served as end points for the analysis of factors influencing disease progression in patients with baseline chronic hepatitis or cirrhosis, respectively. RESULTS: Disease progression was associated with older age (P<0.001), absence of previous HBeAg history (P=0.017) and higher serum HBV-DNA levels (P=0.009) (more frequently observed in unremitting disease profile, P=0.012) at multivariate analysis. Fluctuations of IgM anti-HBc levels (associated with disease exacerbations, P=0.045) correlated with end stage complications in cirrhotics (P=0.011). Disease improved in 14.6 and 1.6% of treated and untreated patients, respectively (P=0.015): interferon slowed disease progression (P<0.001). CONCLUSIONS: The outcome of anti-HBe positive chronic hepatitis B is worsened by older age and persistent viral replication or hepatitis exacerbations in chronic hepatitis or in cirrhotic patients, respectively. Interferon reduces by 2.5-folds disease progression.     

Effect of plasma metformin concentrations on serum lipid levels in type II diabetic patients

Summary In this study we evaluated the relationships between plasma metformin levels, measured by reversed-phase high-performance liquid chromatography, and serum lipid levels in 20 metformintreated, type II diabetic patients. Mean fasting plasma metformin concentration was 490 ± 188 ng/ml. No correlation was found between daily dose of drug and lipid parameters. A significant correlation emerged between circulating metformin concentration and serum triglycerides (r=−0.574, p<0.01), HDL-cholesterol (r=0.583, p<0.01) and HDL₂-cholesterol (r=0.670, p<0.05). Multiple linear regression analysis showed that the correlation between plasma metformin concentration and serum triglycerides still remained significant after correction for other clinical and metabolic parameters. Total cholesterol and HDL₃-cholesterol were not correlated with metformin concentrations. These results demonstrate the clinical usefulness of measuring plasma metforminc concentrations and indicate that some effects of metformin on lipid metabolism depend on the drug plasma levels.     

Phagocytosis of Hemozoin (Native and Synthetic Malaria Pigment), and Plasmodium falciparum Intraerythrocyte-Stage Parasites by Human and Mouse Phagocytes

Hemozoin, the detoxification product of hemoglobin heme, piles up as electron-dense material in the food vacuole (FV) of intraerythrocytic malaria parasites (malaria pigment). In infected individuals, pigment is internalized by both circulating and resident phagocytes, thus modulating their functions. Synthetic beta-hematin, prepared in vitro from hematin (ferriprotoporphyrin IX hydroxide) in acidic condition, is spectroscopically identical to hemozoin. In this electron microscopy study, native and synthetic hemozoin also prove to be morphologically indistinguishable (large polygonal crystals with apparent transverse banding) and to undergo the same process when internalized by phagocytes (primarily a direct uptake of crystals, similar to what is described for asbestos fibers). On the contrary,whole parasites appear to follow a classical endocytic pathway. This suggests that there may be differences between the ingestion of free particles and whole parasites in terms of modulation of phagocytes' functions.