Primary prophylaxis of gastroesophageal variceal bleeding: consensus recommendations of the Asian Pacific Association for the Study of the Liver.

The Asian Pacific Association for the Study of the Liver (APASL) set up a Working Party on Portal Hypertension in 2002, with a mandate to develop consensus guidelines on various clinical aspects of portal hypertension relevant to disease patterns and clinical practice in the Asia-Pacific region. Variceal bleeding is a consequence of portal hypertension, which, in turn, is the major complication of liver cirrhosis. Primary prophylaxis to prevent the first bleed from varices is one of the most important strategies for reducing the mortality in cirrhotic patients. Experts predominantly from the Asia-Pacific region were requested to identify the different aspects of primary prophylaxis and develop the consensus guidelines. The APASL Working Party on Portal Hypertension evaluated the various therapies that have been used for the prevention of first variceal bleeding. A 2-day meeting was held on January 12 and 13, 2007, at New Delhi, India, to discuss and finalize the consensus statements. Only those statements that were unanimously approved by the experts were accepted. These statements were circulated to all the experts and were subsequently presented at the annual conference of the APASL at Kyoto, Japan, in March 2007.

Ten years' follow-up of 472 patients following transjugular intrahepatic portosystemic stent-shunt insertion at a single centre.

BACKGROUND: Transjugular intrahepatic portosystemic stent-shunt (TIPSS) is increasingly used for the management of portal hypertension. We report on 10 years' experience at a single centre. METHODS: Data held in a dedicated database was retrieved on 497 patients referred for TIPSS. The efficacy of TIPSS and its complications were assessed. RESULTS: Most patients were male (59.4%) with alcoholic liver disease (63.6%), and bleeding varices (86.8%). Technical success was achieved in 474 (95.4%) patients. A total of 13.4% of patients bled at portal pressure gradients < or = 12 mmHg, principally from gastric and ectopic varices. Procedure-related mortality was 1.2%. The mean follow-up period of surviving patients was 33.3 +/- 1.9 months. Primary shunt patency rates were 45.4% and 26.0% at 1 and 2 years, respectively, while the overall secondary assisted patency rate was 72.2%. Variceal rebleeding rate was 13.7%, with all episodes occurring within 2 years of TIPSS insertion, and almost all due to shunt dysfunction. The overall mortality rate was 60.4%, mainly resulting from end-stage liver failure (42.5%). Patients who bled from gastric varices had lower mortality than those from oesophageal varices (53.9% versus 61.5%, P < 0.01). The overall rate of hepatic encephalopathy was 29.9% (de novo encephalopathy was 11.5%), with pre-TIPSS encephalopathy being an independent predicting variable. Refractory ascites responded to TIPSS in 72% of cases, although the incidence of encephalopathy was high in this group (36.0%). CONCLUSIONS: TIPSS is effective in the management of variceal bleeding, and has a low complication rate. With surveillance, good patency can be achieved. Careful selection of patients is needed to reduce the encephalopathy rate.

Chronic administration of losartan, an angiotensin II receptor antagonist, is not effective in reducing portal pressure in patients with preascitic cirrhosis.

OBJECTIVES: Plasma angiotensin II (ANG II) concentrations are elevated in cirrhosis and have been implicated as a cause of portal hypertension. We aimed to study both the systemic and portal hemodynamics, and tolerability after chronic administration of losartan, an ANG II receptor antagonist. METHODS: Twelve patients with preascitic cirrhosis were studied: mean age of 53.8 +/- 3.3 yr; average Child-Pugh score of 5.8 +/- 0.3; alcohol etiology (5), hepatitis B/C (1/3), primary biliary cirrhosis (3). No patients were on diuretics or vasoactive medication. Hemodynamic measurements were performed at baseline and 4 weeks after daily administration of 25 mg losartan. RESULTS: There was no significant change in the hepatic venous pressure gradient (15.4 +/- 1.5 to 13.6 +/- 1.6 mmHg, -11.7%, p = NS), despite a significant reduction in the wedge hepatic venous pressure (20.3 +/- 1.8 to 17.3 +/- 1.8 mmHg, -14.8%, p < 0.05). Cardiac output, hepatic blood flow, systemic vascular resistance, creatinine clearance, and natriuresis were unaffected. The plasma renin activity increased significantly from 2.7 +/- 0.4 to 5.2 +/- 1.1 ng/ml/h (p < 0.05). There was a significant reduction in the mean arterial pressure from 96.9 +/- 3.3 to 89.3 +/- 3.5 mmHg, -7.8 +/- 3.0% (p = 0.02), with 1 patient experiencing symptomatic hypotension. CONCLUSIONS: Chronic administration of low-dose losartan does not lead to a significant reduction in the portal pressure gradient. Losartan is unlikely to be useful in the management of patients with early cirrhosis, who are at risk of variceal bleeding.

Oral amino acid load mimicking hemoglobin results in reduced regional cerebral perfusion and deterioration in memory tests in patients with cirrhosis of the liver.

This study tests the hypothesis that administration of an oral amino acid load mimicking hemoglobin in patients with cirrhosis of the liver causes deterioration in neuropsychological function and a reduction in regional cerebral perfusion. Eight overnight fasted, metabolically stable cirrhotic patients with no evidence of overt hepatic encephalopathy were studied prior to and 4 h after simulating an upper gastrointestinal bleed by oral administration of 75 g of a solution mimicking the amino acid composition of hemoglobin. Neuropsychological function was measured using a test battery. Peripheral venous blood was collected for the measurement of ammonia and amino acid concentrations. Regional cerebral perfusion was measured using a head SPECT scanner following intravenous administration of technetium-99m hexamethyl propylamineoxime. The amino acid solution resulted in significant deterioration in the immediate and delayed story recall tests. Ammonia concentration increased from a median of 87 (range 67-94) micromol/L to 105 (98-112) micromol/L at 4 h after the simulated bleed (p < 0.01). The concentration of almost all amino acids increased; only isoleucine levels decreased following the upper gastrointestinal bleed. SPECT analysis showed a significant reduction in cerebral perfusion after the simulated bleed in both temporal lobes, left superior frontal gyrus, and right parietal and cingulate gyrus. An oral amino acid load mimicking hemoglobin in cirrhotic patients produces hyperammonemia and hypoisoleucinemia and causes a significant deterioration in memory tests, probably due to a reduction in regional cerebral perfusion. The model of simulating the metabolic effects of an upper gastrointestinal bleed in patients with cirrhosis of the liver seems to be useful in studying the metabolism of hepatic encephalopathy.

Primary prophylaxis of variceal hemorrhage: a randomized controlled trial comparing band ligation, propranolol, and isosorbide mononitrate.

BACKGROUND & AIMS: This randomized controlled trial compared variceal band ligation (VBL), propranolol (PPL), and isosorbide-5-mononitrate (ISMN) in the prevention of first esophageal variceal bleed. METHODS: Over a 6-year period, 172 patients with cirrhosis, grade II or III esophageal varices that had never bled, were recruited; 44 into VBL, 66 into PPL, and 62 into ISMN. Baseline patient characteristics: age, 55 +/- 11 years; Child-Pugh score, 8 +/- 2; 65% alcohol-induced cirrhosis; follow-up period, 19.7 +/- 17.6 months (range, 0.13-72.1 months), were comparable in the 3 groups. RESULTS: On intention-to-treat analysis, variceal bleeding occurred in 7% of patients randomized to VBL, 14% to PPL, and 23% to ISMN. The 2-year actuarial risks for first variceal bleed were 6.2% (95% confidence interval [CI], 0.0%-15.0%) for VBL, 19.4% (95% CI, 0.1%-32.4%) for PPL, and 27.7% (95% CI, 14.2%-41.2%) for ISMN. A significant number of patients reported side effects with drug treatment (45% PPL and 42% ISMN vs. 2% VBL; P = 0.00), resulting in withdrawal from treatment in 30% of PPL and 21% of ISMN patients. There were no statistically significant differences in mortality rates in the 3 groups. In as-treated analysis, there was a statistically significant difference in actuarial risk for bleeding at 2 years between VBL and ISMN (7.5%, 95% CI, 2.5%-10.6% vs. 33.0%, 95% CI, 15%-49%, respectively, log rank test P = 0.03) but not between VBL and PPL. CONCLUSIONS: VBL was equivalent to PPL and superior to ISMN in preventing first variceal bleed. The side-effect profile for pharmacotherapy was considerable.

Impact of transjugular intrahepatic portosystemic stent-shunt for secondary prophylaxis of oesophageal variceal haemorrhage: a single-centre study over an 11-year period.

AIMS: The role of various treatments for variceal haemorrhage is currently being evaluated. The purpose of this study was to analyse the impact of the use of endoscopic variceal sclerotherapy (EVS), variceal band ligation (VBL) and transjugular intrahepatic portosystemic stent-shunt (TIPSS) for secondary prophylaxis on the outcome of cirrhotic patients with the first episode of variceal haemorrhage presenting to a single centre. METHODS: Between 1986 and 1996, data from 225 consecutive patients with the first episode of variceal haemorrhage were analysed. The modality of treatment for secondary prophylaxis between 1986 and 1991 was EVS (group I: n = 83; Child class C, 29%; mean follow-up 36 +/- 3 months), between 1991 and 1993 VBL (group II: n = 56; Child class C, 38%; mean follow-up 24 +/- 3 months), and between 1995 and 1996 TIPSS (group III: n = 86; Child class C, 60%; mean follow-up 17 +/- 1 months). Half of the patients between 1993 and 1995 underwent VBL and the other half had TIPSS. Data regarding rebleeding, mortality and encephalopathy were analysed using the Kaplan-Meier method. Cox's proportional hazard regression was used to test the significance of prognostic factors. RESULTS: Seventy-five per cent of patients re-bled in group I, 40% in group II, and 16% in group III (P < 0.0001). Mortality was significantly lower in the patients with Child class C disease in group III patients compared with those in groups I and II (P < 0.02). TIPSS was associated independently with reduced early mortality and re-bleeding. CONCLUSION: The results of this study suggest that TIPSS improves survival in patients with advanced liver disease and variceal haemorrhage, and should be considered for secondary prophylaxis in high-risk patients.

Occurrence of Salmonella enterica serovar Dublin in Austria.

In Austria, Salmonella enterica subsp. enterica serovar Dublin, a bovine-adapted serovar, rarely causes infections in humans. In 2000, Austria was within the European mean with an incidence of 0.1 per million inhabitants. Our data show that the vast majority of all serovar Dublin infections (human and non-human) can be traced epidemiologically to two districts in the Tyrol. This concentration of cases can be explained by a particularly traditional aspect of cattle farming in this area, the alpine pasture. There is an increased risk of cross infection due to the communal keeping of animals from various farms. Infected cattle are a source of infection for humans, and transmission usually occurs from eating beef and drinking cows milk. Using pulsed field gel electrophoresis and automated ribotyping, three out of five isolates from human infections could be traced to characteristic Tyrolean Dublin clones. Bacteriological screening for faecal carriage before the transfer of cattle from risk-herds to the alpine pastures and before the return from risk-pastures to the farms would be a possible starting point to prevent cross-contamination of large mixed herds and contamination of pasture through latently infected cattle. Appropriate research is necessary.

7-Methyl-6,7,8,9,14,15-hexahydro-5H-benz[d]indolo[2,3-g]azecine: a new heterocyclic system and a new lead compound for dopamine receptor antagonists.

Partially hydrogenated derivatives of the new heterocyclic ring systems benz[d]indolo[2,3-g]azecine and bisindolo[3,2-d][2, 3-g]azecine were synthesized starting from lactones and amines via the described synthetic methods. In binding assays with rat striatal receptors, 7-methyl-6,7,8,9,14,15-hexahydro-5H-benz[d]indolo[2, 3-g]azecine (LE 300) proved to be of high affinity for the D(1) binding site (K(i) = 0.08 nmol for displacement of [(3)H]SCH23390), being superior in this assay to standards such as butaclamol and SCH23390. This compound was characterized as a dopamine antagonist by conditioned avoidance response test with mice. Thus, LE 300 represents the lead of a new class of dopamine antagonists for future investigations.

Intracellular pH regulation in bovine aortic endothelial cells: evidence of both Na+/H+ exchange and Na+-dependent Cl-/HCO3- exchange.

Regulation of intracellular pH (pHi) was studied in cultured bovine aortic endothelial cells, an important cell system for cardiovascular research. Suspended cells were acidified by the NH4Cl prepulse technique as well as by exposure to CO2/HCO3-. Subsequent rates of pHi recovery were monitored using the fluorescent dye 2',7'-bis(2-carboxyethyl)-5-(6)-carboxyfluorescein (BCECF). In HCO3(-)-free solutions, an EIPA-sensitive, Na+-dependent mechanism fully accounted for realkalinization, namely the Na+/H+ exchanger (NHE). In the presence of HCO3-, an additional acid efflux mechanism was found. This one was dependent on Na+ and intracellular Cl-, EIPA-insensitive but DIDS-sensitive, and therefore represented a Na+-dependent Cl-/HCO3- exchanger (NCBE). In summary, two acid-extruding mechanisms were identified in bovine aortic endothelial cells: NHE and NCBE.

Therapeutic approaches for memory impairments.

Pharmacological treatment strategies for the treatment in dementia disorders were described. A selection of the 15 different classes described by Fröstl and Maitre was made. In the paper there were included and described in detail the following classes: piracetam-type compounds, co-dergocrine-type compounds, vasodilators and haemorheological agents, cholinesterase inhibitors, ACTH and vasopressin analogs and angiotensin II and angiotensin converting enzyme inhibitors. Some compounds e.g. propentofylline, vincamine, THA and RA-octil were described in more detail.

Involvement of nitric oxide-formation in the action of losartan (DuP 753): effects in an inhibitory avoidance model.

The potent and selective orally active ANG II receptor antagonist losartan (DuP 753) enhanced the retentions in an inhibitory (passive) avoidance test after scopolamine amnesia. In addition, the influence of the specific NO-synthase inhibitor NG-nitro-L-arginine (L-NNA) in combination with losartan was tested. L-NNA itself shows no effect. The combination of losartan with L-NNA did not produce any prolongation of step-through latencies.

Mnemogenic effects of injecting RA-octil, a CE-inhibitor derivate, systemically or into the basal forebrain.

The aim of this study was to investigate the effects of systemically or intracerebrally administered RA-octil, a derivative of the angiotensin converting enzyme (CE)-inhibitor ramipril, on memory and reinforcement and to compare its effectiveness with that of the neurokinin substance P (SP). In the first experiment systemic post-trial application of RA-octil and SP in the rat enhanced habituation, a learning task which does not require motivational treatments. Unlike SP, injection of RA-octil did not have reinforcing effects as measured with a conditioned place preference task. In the second experiment, a facilitation of inhibitory avoidance learning was obtained by injection of RA-octil or SP unilaterally into the basal forebrain immediately after the learning trial. In contrast, a 5 h delayed injection of RA-octil had no effects on learning. The results demonstrate memory-enhancing effects of RA-octil after systemic application as well as after injection into the basal forebrain. Furthermore, the mnemogenic effects of SP after central and peripheral administration were confirmed. Since RA-octil, although being structurally closely related to CE-inhibitors, does not affect plasma CE, yet exhibits mnemogenic effects, it is possible that "cognition-enhancing" actions of CE-inhibitors are dissociable from their action within the renin-angiotensin system.

Hoe 140 a new potent and long acting bradykinin-antagonist: in vitro studies.

1. Hoe 140 (D-Arg-[Hyp3, Thi5, D-Tic7, Oic8]bradykinin) is a new bradykinin (BK)-antagonist. It was tested in several in vitro assays and compared with D-Arg-[Hyp2,Thi5,8,D-Phe7]BK. 2. In receptor binding studies in guinea-pig ileum preparations, Hoe 140 showed an IC50 of 1.07 x 10(-9) mol l-1 and a KI value of 7.98 x 10(-10) mol l-1. 3. In isolated organ preparations Hoe 140 and D-Arg-[Hyp2,Thi5,8, D-Phe7]BK inhibited bradykinin-induced contractions concentration dependently, with IC50-values in the guinea-pig ileum preparation of 1.1 x 10(-8) mol l-1 and 3 x 10(-5) mol l-1, respectively. pA2 values in this tissue were 8.42 and 6.18, respectively. In the rat uterus preparation the IC50 value was 4.9 x 10(-9) mol l-1 for Hoe 140. D-Arg-[Hyp2, Thi5,8, D-Phe7]BK showed an IC50 of 4.0 x 10(-6) mol l-1. The IC50 values in the guinea-pig isolated pulmonary artery were 5.4 x 10(-9) mol l-1 and 6.4 x 10(-6) mol l-1, respectively. In the rabbit aorta no inhibitory effects on Des-Arg9-BK induced contractions were observed. 4. In cultured bovine endothelial cells, Hoe 140 antagonized (IC50 = 10(-8) mol l-1) bradykinin-induced endothelium-derived relaxing factor (EDRF) release and the bradykinin-induced increase in cytosolic free calcium (IC50 = 10(-9) mol l-1). 5. Hoe 140 (10 -7mol I1) totally suppressed the bradykinin-induced (10 8 to 10- mol I') prostacyclin (PGI2) release from cultured endothelial cells of bovine aorta. D-Arg-[Hyp2, Thi5'8, D-Phe7]BK (10- 7 mol I1- ) showed a weaker antagonism. 6. Taken together these results show that Hoe 140 is a highly potent bradykinin antagonist. It was two to three orders of magnitude more potent than D-Arg-[Hyp2, Thi5 8, D-Phe7]BK.

Hoe 140 a new potent and long acting bradykinin-antagonist: in vivo studies.

1. The potency, duration of action and tolerability of Hoe 140, a novel and highly potent bradykinin (BK) antagonist in vitro, has been tested in different in vivo models and compared with the well-known BK antagonist D-Arg-[Hyp2, Thi5,8, D-Phe7]BK. 2. Hoe 140 is highly potent and long acting in inhibiting BK-induced hypotensive responses in the rat. Four hours after s.c. administration of 20 nmol kg-1, inhibition still amounted to 60% whereas the effect of 200 nmol kg-1 of D-Arg-[Hyp2, Thi5,8, D-Phe7]BK was not significant. 3. BK-induced bronchoconstriction in guinea-pigs was strongly inhibited by Hoe 140. The magnitude and duration of inhibition confirmed the findings obtained in the blood pressure experiments in the rat. 4. Carrageenin-induced inflammatory oedema of the rat paw was considerably inhibited at i.v. doses between 0.1 and 1 mg kg-1. 5. In conscious dogs, intravenous doses of 0.01 and 0.1 mg kg-1 of Hoe 140 and D-Arg-[Hyp2, Thi5,8, D-Phe7]BK were well tolerated. At doses of 1 mg kg-1 adverse effects occurred that were attributed to the residual BK agonistic activity of both compounds. 6. Hoe 140 has been shown to be a highly potent and long acting BK antagonist in vivo in different animal species and models. This makes it appropriate to investigate further the physiological and pathophysiological role of BK.

Interaction between catecholaminergic and opioid systems in an active avoidance task.

Male NMRI mice were given intravenous injections of the noradrenergic neurotoxin DSP4 or the vehicle 24 to 72 h prior behavioral testing. Animals were given 2 days of training on a one-way active avoidance task. Naloxone was given in one of three doses prior to training on Day 1 and Day 2 or prior to training on Day 1 only (saline was given prior to training on Day 2). There was a dose-dependent impairment of acquisition by naloxone in the vehicle-pretreated groups; 10 mg/kg naloxone produced a significant impairment of acquisition. Naloxone also modulated retention (Day 2) performance of the active avoidance task. For vehicle-pretreated mice, 1 mg/kg naloxone facilitated and 10 mg/kg naloxone-impaired performance on Day 2. DSP4 alone produced an impairment of acquisition of this task but had no effect on retention; Day 2 scores were slightly higher in the DSP4-pretreated group than in the vehicle-pretreated group. Naloxone produced somewhat different effects in DSP4-pretreated animals than in vehicle-pretreated animals. Naloxone (1 mg/kg) ameliorated the DSP4-induced impairment of acquisition; 10 mg/kg naloxone did not significantly alter the acquisition performance of this group. For the DSP4-pretreated mice that received naloxone before training on both days, the dose-response characteristics for retention scores were similar to those of vehicle-pretreated mice; 1 mg/kg naloxone was the facilitatory dose. However, for DSP4-treated mice that received naloxone before training on Day 1 only, there was a shift to the right in the effective facilitatory dose of naloxone. For these animals, 10 mg/kg naloxone but not 1 mg/kg naloxone significantly enhanced retention performance. We discuss these results in the context of a possible state-dependent modulation by naloxone in the DSP4-treated animals.

Effects of the novel compound, Hoe 065, upon impaired learning and memory in rodents.

The effects of Hoe 065 (n-octyl 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S, 5S)-2-azabicyclo [3.3.0]octane-3-carboxylate maleate salt) were studied on the performance of mice and rats in different learning tasks. Hoe 065 prevented the disruption of memory induced by scopolamine administered before training. The results indicate that Hoe 065 improves cognitive function in different tasks.

Effects of Hoe 065, a compound structurally related to inhibitors of angiotensin converting enzyme, on acetylcholine metabolism in rat brain.

Hoe 065, a compound structurally related to inhibitors of angiotensin converting enzyme, caused a fall in the content of acetylcholine (ACh) in different brain areas of the rat following i.p. administration in the range 0.03-30 mg/kg. This effect occurred 0.5 h after a single injection and lasted for at least 6 h. Simultaneous administration of the choline uptake inhibitor hemicholinium-3 (HC-3) with Hoe 065 potentiated the decrease in ACh content induced by HC-3. In the same dose range Hoe 065 acutely enhanced the activity of the enzyme choline acetyltransferase as well as the capacity of the high-affinity choline uptake system which is considered as the rate-limiting step in the synthesis of ACh. Cholinesterase activity in vivo was not altered by the compound. Hoe 065 produced a concurrent elevation of brain cyclic GMP content. Taken together, these results suggest that Hoe 065 acutely increases cholinergic activity within its physiological range, probably by means of an enhanced release of ACh.

Neurochemical effects of the synthetic ACTH4-9-analog Hoe 427 (Ebiratide) in rat brain.

The ACTH4-9-analog Hoe 427 systemically injected in a dose range from 0.01-10 micrograms/kg caused a fall in acetylcholine (ACh) content in different brain areas of the rat. This effect occurred 0.5 hour after a single administration and lasted up to 24 hours. The decrease in ACh content induced by Hoe 427 was more pronounced when the animals were pretreated with dexamethasone (over 7 days 1 mg/kg SC, daily). Coadministration of the choline uptake inhibitor hemicholinium-3 (HC-3) and Hoe 427 potentiated the decrease in ACh content induced by HC-3. In the same dose range Hoe 427 acutely evoked an increase of the activity of the enzyme choline acetyltransferase as well as an elevation of brain cyclic GMP content. These data indicate that Hoe 427 enhances ACh metabolism in rat brain after systemic administration.

Learning and memory processes of an ACTH4-9 analog (ebiratide; Hoe 427) in mice and rats.

These experiments investigated the effects of the new ACTH4-9 analog ebiratide (Hoe 427) [H-Met(O2)-Glu-His-Phe-D-Lys-Phe-NH-(CH2)8-NH2 X 3 CH3COOH] on memory processes in mice and rats in five training tasks. With all five training and testing procedures (inhibitory avoidance test with ECS- or scopolamine-induced amnesia, up-hill avoidance, one-way shuttle box avoidance and eight-arm radial maze) ebiratide was most effective in a dose range of 1-10 micrograms/kg SC.

Drug influences on learning and memory in aged animals and humans.

In this article the effects of neurotransmitter systems or specific drugs on cognitive functions of aged animals and humans are reviewed. While there have been used many different pharmacologic and behavioral approaches to treat and test cognitive deficits in aged animals and geriatric or demented patients, there is still the question of the validity of animal models of human disorders. Attempts are made to show that there are parallels and similarities. These similarities suggest that the neurological and neurochemical changes observed may play common roles in similar behavioral deficits observed in aged animals and humans.