Effects of anti-ulcer agents on ethanol-induced gastric mucosal lesions in D-galactosamine-induced hepatitis rats

Patients with hepatic injury have an increased incidence of gastric ulcers and erosions. In this study, the effect of D-galactosamine(GalN)-induced hepatitis on ethanol-induced gastric mucosal lesions and the protective effect of anti-ulcer agents in rats were examined. Subcutaneous injection of GalN (1 g/kg) remarkably increased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities suggesting induction of hepatic injury. Gastric mucosal lesions induced by ethanol were significantly aggravated in GalN-induced hepatitis rats. Orally administered ecabet (CAS 86408-72-2; 20-200 mg/kg) dose dependently inhibited ethanol-induced gastric mucosal lesions in GalN-induced hepatitis rats. Sucralfate (CAS 54182-58-0) tended to inhibit the gastric mucosal lesions at a dose of 200 mg/kg but teprenone (CAS 6809-52-5), cimetidine (CAS 51481-61-9) and rebamipide (CAS 90098-04-7) had little effect. All anti-ulcer agents had no effect on the serum ALT and AST activities increased by GalN pretreatment. These results indicate that the gastric mucosa of GalN-induced hepatitis rats is more susceptible to injury induced by luminal irritants such as ethanol. Ecabet potently inhibited gastric mucosal lesions suggesting its clinical utility for the gastric mucosal damage in patients with hepatic injury.     

Val-Tyr as a natural antihypertensive dipeptide can be absorbed into the human circulatory blood system

1. Intact absorption of the bioactive dipeptide Val-Tyr (VY), with in vivo antihypertensive ability in normotensive human subjects, was investigated. 2. As a result of a single oral administration of VY, the VY absorption curve occurred maximally over the second hour postprandially; a greater than 10-fold higher increment of VY following a dose of 12 mg was observed in the plasma at 2 h compared with the baseline concentration of VY at 0 h (1934 +/- 145 vs 159 +/- 11 fmol/mL plasma, respectively). 3. Plasma VY levels increased with dose administered (3, 6 and 12 mg), suggesting that exogenous VY could be absorbed intact into the human blood depending on the dose. The elimination half time (t1/2) of VY was estimated to be 3.1 h. The area under the curve for the 12 mg VY dose was 9185 +/- 688 fmol small middle doth/mL plasma.     

Bacteria isolated from surgical infections and their susceptibilities to antimicrobial agents--special references to bacteria isolated between April 2000 and March 2001

Tendency of isolated bacteria from infections in general surgery and their antimicrobial susceptibilities during the period from April 2000 to March 2001 were investigated in a multicenter study in Japan, and the following results were obtained. The number of cases investigated as objectives was 234 for one year. A total of 388 strains (136 strains from primary infections and 252 strains from postoperative infections) were isolated from 165 cases (70.5% of total cases). In primary infections, anaerobic Gram-positive bacteria were predominant, while from postoperative infections, aerobic Gram-positive bacteria were predominant. Among aerobic Gram-positive bacteria, the isolation rate of Enterococcus faecalis was the highest, followed by that of Staphylococcus aureus from postoperative infections. Among anaerobic Gram-positive bacteria, the isolation rate of Peptostreptococcus spp. was the highest from both types of infections. Among aerobic Gram-negative bacteria, Escherichia coli was the most predominantly isolated from primary infections, followed by Klebsiella pneumoniae and Pseudomonas aeruginosa in this order, and from postoperative infections, P. aeruginosa was the most predominantly isolated, followed by Enterobacter spp. and Klebsiella spp. Among anaerobic Gram-negative bacteria, the isolation rate of Bacteroides fragilis group was the highest from both types of infections. There was no vancomycin-resistant S. aureus nor Enterococcus spp. Among anaerobic bacteria, there were many resistant strains against penicillins and cephems with MICs higher than 100 micrograms/ml, and the same trend was observed among other Bacteroides spp. and Prevotella spp.     

How is "coverage" defined for occupational health services?

The proportion of workers receiving occupational health services (OHS), or OHS coverage, is considered an important indicator in the evaluation of the national OHS levels. Although the term "coverage" is used in some papers, the definition of the term appears to vary from author to author. Despite vague definitions of the term, the issue has not been much studied. It appears that this vagueness has not led to attempts to establish a clear definition of the term. This study, was undertaken to clarify the meaning of "coverage" when used in relation to OHS. Papers using "coverage" as an indicator of the OHS levels or discussing the issue were collected and analyzed. The first aspect examined concerned the definition of "coverage." Next, the denominator (the target population), and methods for estimating the numerator (the number of workers provided with OHS) were described according to this definition. Few papers dealing with OHS coverage provided an explicit definition: none of the papers stated clearly the OHS functions encompassed when considering coverage, using simply the term in the context. Nor was the worker category to be represented in the denominator discussed, e.g. employees only, or the entire working population. The method for estimating the numerator was generally undefined. This study makes it clear that the term "coverage" in relation to OHS is currently used without clear definition. To permit objective assessments of the national OHS levels, "coverage" must be defined in terms of three elements: OHS functions, the numerator and the denominator of the proportion representing the extent of OHS coverage.     

Novel mode of action of ribavirin (Rebetol), a drug for the treatment of chronic hepatitis C: inducting the mutation of RNA viruses

Ribavirin (Rebetol) is an antiviral agent used in combination with interferon alpha-2b (IFN alpha-2b) for the treatment of chronic hepatitis C. Ribavirin has been reported to have a broad-spectrum antiviral activity mainly against RNA viruses. The effect of ribavirin was potentiated when administered in combination with IFN alpha-2b in an antiviral assay using bovine viral diarrhea virus as a surrogate for hepatitis C virus (HCV). Inhibition of host inosine monophosphate dehydrogenase and inhibition of RNA-dependent RNA polymerase (RdRp) of RNA viruses have been reported as the modes of action of ribavirin. Recently, ribavirin has been shown to induce mutation as template for newly generated RNA after uptake in RNA by RdRp of poliovirus, which is an RNA virus as in the case of HCV. It has also been shown that the infectivity of viruses is drastically reduced by the very slight increase in mutations induced by ribavirin. This effect as a mutagen on RNA viruses is a novel mode of ribavirin, and it is thought necessary to classify ribavirin into a new antiviral drug class.     

Effects of anions on ATP-induced [Ca2+], increase in NG108-15 cells

We investigated the effects of anions on different P2 receptors by measuring ATP-induced increase in intracellular Ca2+ concentration ([Ca2+]i) in fura-2-loaded NG108-15 and PC12 cells. In NG108-15 cells, ATP at 100 microM and 1 mM induced a transient and a sustained [Ca2+]i increase, respectively. The former, but not the latter, was inhibited by U-73122, indicating that the former was via the P2Y2 receptor and the latter via the P2X7 receptor. When external Cl- was replaced by other anions, the [Ca2+]i increase mediated by the P2Y2 receptor was not changed, but that mediated by the P2X7 receptor varied in the order of aspartate- > methanesulfonate > Cl- > Br > or = I-. In PC12 cells, transient [Ca2+]i increases mediated by the P2Y2 and P2X2 receptors were not affected by various anions. These results suggest that modulation by anions is unique to the P2X7 receptor and does not occur in P2Y2 and P2X2 receptors. This may be because the mechanism of ATP binding to the P2X7 receptor may be different than that to other P2 receptors.     

Pharmacological characterisation of [(pX)Phe4]nociceptin(1-13)amide analogues. 1. In vitro studies

Phe(4) in the nociceptin (NC) sequence has been identified as the most critical residue for receptor interaction. In the present study, we investigated the pharmacological activity of a series of NC(1-13)NH(2) analogues, in which the hydrogen atom in the para position of Phe(4) was substituted with F, NO(2), CN, Cl, Br, I, CH(3), OH or NH(2).In receptor binding studies, performed using CHO cells expressing the recombinant human NC receptor (CHO(hOP4)) and in rat cerebral cortex membranes, [(pF)Phe(4)]NC(1-13)NH(2), [(pNO(2))Phe(4)]NC(1-13)NH(2), and [(pCN)Phe(4)]NC(1-13)NH(2) displayed higher affinity than NC(1-13)NH(2). The affinity of [(pCl)Phe(4)]NC(1-13)NH(2) was essentially identical to that of NC(1-13)NH(2), while the remaining compounds displayed reduced affinity. In a series of functional assays (stimulation of GTPgammaS binding in CHO(hOP4)cells and rat cerebral cortex membranes and inhibition of cAMP accumulation in CHO(hOP4) cells), the para substituted analogues behaved as full agonists (with the exception of [(pOH)Phe(4)]NC(1-13)NH(2) which acted as a partial agonist in the GTPgammaS binding assays) with the following rank order potency:[(pF)Phe(4)]NC(1-13)NH(2) and [(pNO(2))Phe(4)]NC(1-13)NH(2) were either inactive or displayed micromolar potencies in cAMP accumulation experiments performed on cells expressing classical opioid receptors. All compounds were full agonists in isolated tissues from various species (guinea pig ileum, mouse colon and mouse/rat vas deferens) with the exception of [(pOH)Phe(4)]NC(1-13)NH(2) which displayed partial agonist/weak antagonist activities. The rank order of potency was similar to that found in the other assays. The effects of all analogues were not modified by naloxone. The selective OP(4) receptor antagonist [Nphe(1)]NC(1-13)NH(2), tested in all preparations against one or both of the highly potent derivatives [(pF)Phe(4)]NC(1-13)NH(2) and [(pNO(2))Phe(4)]NC(1-13)NH(2), showed pA(2) values similar to those found against NC, the pA(2) in the GTPgammaS binding/rat cerebral cortex assay being much higher (ca. 7.5) than in the other functional assays (ca. 6).This study further supports the notion that Phe(4) of NC is the critical residue for receptor occupation and activation. Moreover, as part of this study, we have identified two novel, highly potent and selective agonists for the OP(4) receptor, [(pF)Phe(4)]NC(1-13)NH(2) and [(pNO(2))Phe(4)]NC(1-13)NH(2).     

Effect of replacing the aspartic acid/glutamic acid residues of bullfrog sialic acid binding lectin with asparagine/glutamine and arginine on the inhibition of cell proliferation in murine leukemia P388 cells

The sialic acid binding lectin from bullfrog oocytes (cSBL) is known to have anti-tumor activity. In a previous report, to elucidate the relationship between the net charge and anti-tumor activity of cSBL, we examined the effect of chemical modifications of cSBL with a water-soluble carbodiimide in the presence of various nucleophiles. The results suggested that the anti-tumor activity and internalization into tumor cells increased with an increase in the net charge of cSBL. However, in the chemically modified cSBL, a modification site was observed on average in two of the carboxyl groups of cSBL. To confirm these previous results and to determine which modified carboxyl group contributes to the increase in anti-tumor activity, we prepared mutants with substitutions of Asn/Gln and Arg at three acidic amino acid residues of cSBL and studied their anti-tumor activity and internalization efficiency. The results showed the enhancing effect of charge on anti-tumor activity and internalization, and suggested that the replacement of D24 and E88 of cSBL with arginine is more effective than that of E97. The double mutant D24RE88R showed comparable anti-tumor activity to the ethylenediamine-modified cSBL reported previously. The mutant was well-characterized as a pure cSBL derivative suitable for studying the mechanism of the anti-tumor action of cSBL.     

Inhibition of the antibody production by acetaminophen independent of liver injury in mice

The causal relationship between the inhibition of antibody production and liver injury induced by single doses of acetaminophen (APAP) was investigated in mice. The liver injury and antibody production were evaluated using the serum transaminase activity and the number of antibody forming cells against sheep red blood cells (SRBC), respectively. The relevance of APAP hepatotoxicity with inhibiting antibody production was elucidated in fasted and fed mice treated with a single oral administration of APAP. In fasted mice, the oral administration of APAP produced serious liver injury, while it was not the case in the fed mice. As the antibody production was measured under these conditions, APAP significantly depressed the antibody production in fed mice as well as in fasted mice. The rate of B220 positive cells in the splenocytes was significantly decreased by APAP administration in both the fasted and fed mice. Splenocytes proliferative responses following mitogenic stimulation with concanavalin A or lipopolysaccharide were inhibited by APAP. Moreover, APAP added directly to the splenocyte culture also inhibited the in vitro antibody-producing response to SRBC. These findings indicate that the APAP-induced depression of antibody production may not be a secondary response to APAP-hepatitis, but may be a primary response to APAP.     

Increased hepatocyte growth factor level in cerebrospinal fluid in Alzheimer's disease

BACKGROUND & OBJECTIVE: Hepatocyte growth factor (HGF), also known as the scatter factor, is a potent mitogen for mature hepatocytes, and also has multifunctional effects on some cells in various organs. Recently, we have found expression and localization of HGF in white matter astrocytes in human brain tissues. Furthermore, immunohistochemistry using anti-HGF antibody revealed more intense immunolabeling in Alzheimer's disease (AD) than control brains. The aim of the study is to investigate the level of HGF in cerebrospinal fluid (CSF) from patients with AD. MATERIAL AND METHODS: We examined the level of HGF in CSF from 34 AD and 15 age-matched disease control patients by highly sensitive enzyme-linked immunoabsorbent assay (ELISA) system. RESULTS: Consistent with the immunohistochemical data, a significantly higher concentration of HGF in AD CSF was found as compared with controls. A significant correlation was also seen between CSF HGF levels and white matter high-signal foci determined on brain magnetic resonance imaging (MRI) in AD patients. CONCLUSION: These results indicate that CSF HGF levels correspond with the white matter damage in AD brain.