Biomedical subjects

Antonio Morelli

Publications and source records attributed to Antonio Morelli.

At least 37 records · Page 2Linked to original sources

PubMed2004

A beta-oxidation-resistant lipoxin A4 analog treats hapten-induced colitis by attenuating inflammation and immune dysfunction.

Lipoxins and aspirin-triggered 15-epi-lipoxins (ATL) are counter-regulatory eicosanoids with potent antiinflammatory actions. Oral efficacy and mechanism of action of ZK-192, a beta-oxidation-resistant 3-oxa-ATL analog, were examined in trinitrobenzenesulphonate (TNBS)-induced colitis. When dosed orally once daily, 300 and 1,000 mug/kg ZK-192 markedly attenuated TNBS colitis in rodents both in preventive and therapeutic regimens. ZK-192 attenuated weight loss, macroscopic and histologic colon injury, mucosal neutrophil infiltration, and colon wall thickening. ZK-192 was as effective as 3-10 mg/kg oral prednisolone. ZK-192 decreased mucosal mRNA levels for several inflammatory mediators: inducible nitric oxide synthase, cyclooxygenase 2, and macrophage inflammatory protein 2. ZK-192 also decreased mucosal mRNA and protein levels of T helper 1 effector cytokines: tumor necrosis factor alpha, IL-2, and IFN-gamma. Systemic levels of these cytokines were also dramatically attenuated. CD3/CD28-mediated costimulation of T helper 1 effector cytokine release in lamina propria mononuclear cells was markedly inhibited by ZK-192 ex vivo and in vitro. ZK-192 also prevented colitis in lymphocyte-deficient severe combined immunodeficient mice, with approximately 75% inhibition of mucosal tumor necrosis factor alpha and IL-2 levels. The results are further evidence that innate immune cells function as triggers for hapten-induced colitis. The combined antiinflammatory and immunomodulatory effects of ZK-192 in TNBS colitis suggest that ATL analogs may be an attractive oral treatment approach for inflammatory bowel diseases.

Animals↗

PubMed2004

Toward a definition of colonic inertia.

Chronic constipation is a relatively frequent symptom; among its subtypes, the so called-colonic inertia represents a disease condition that is often considered for surgery. However, to date, there has been no agreement on definition of colonic inertia, and a literature review showed that this definition was given to numerous entities that differ from each other. In this paper these concepts are reviewed and a more stringent definition of colonic inertia is proposed.

Chronic Disease↗

PubMed2004

Nitric oxide (NO)-releasing naproxen (HCT-3012 [(S)-6-methoxy-alpha-methyl-2-naphthaleneacetic Acid 4-(nitrooxy)butyl ester]) interactions with aspirin in gastric mucosa of arthritic rats reveal a role for aspirin-triggered lipoxin, prostaglandins, and NO in gastric protection.

Administration of selective and nonselective cyclooxygenase (COX)-2 inhibitors to rheumatoid arthritis patients taking low doses of acetylsalicylic acid (ASA) for cardiovascular prevention associates with increased risk of gastrointestinal bleeding. The present study was undertaken to investigate whether administration of HCT-3012 [(S)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid 4-(nitrooxy)butyl ester], a nitric oxide (NO)-releasing derivative of naproxen, exacerbates gastric mucosal injury in arthritic rats administered low doses of ASA. Our results demonstrated that while treating arthritic rats with a dose of 30 mg/kg/day ASA causes detectable mucosal injury, but had no effect on arthritis score and interleukin-6 plasma levels, coadministration of naproxen (10 mg/kg/day) and celecoxib (30 mg/kg/day), in combination with ASA from day 7 to day 21, attenuates arthritis development (P <0.01 versus arthritis alone), but markedly enhanced gastric mucosal damage caused by ASA (P <0.01 versus ASA alone). In contrast, coadministration of HCT-3012 (15 mg/kg/day) significantly attenuated arthritis development, because HCT-3012 was equally or more effective than naproxen and celecoxib in attenuating local and systemic inflammation (P >0.001 versus arthritis) without exacerbating gastric mucosal injury caused by ASA. Arthritis development associates with gastric COX-2 induction, mRNA and protein, and enhanced gastric prostaglandin E2 (PGE2) synthesis (P <0.01 versus control rats). Although all treatments, including celecoxib, were effective in reducing gastric PGE2 synthesis, administering arthritic rats with ASA resulted in a significant increase in gastric content of aspirin-triggered lipoxin (ATL), a COX-2-derived lipid mediator that regulates proinflammatory responses at the neutrophils/endothelial interface. Administering arthritic rats with naproxen and celecoxib abrogates ATL formation induced by ASA although enhanced neutrophils accumulate into the gastric mucosa (P <0.01 versus ASA alone). In contrast, whereas HCT-3012 inhibited ATL formation, it did not increase neutrophil recruitment into the gastric microcirculation. Collectively, these data indicate that HCT-3012 derived from NO has the potential to compensate for inhibition of PGE2 and ATL and to protect the gastric mucosa by limiting the recruitment of neutrophils. These data suggest that HCT-3012 might be a safer alternative to nonsteroidal anti-inflammatory drugs and coxibs in rheumatic patients that take low doses of ASA.

Animals↗

PubMed2004

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.

Administration, Oral↗

PubMed2004

Empirical antibiotic treatment with piperacillin-tazobactam in patients with microbiologically-documented biliary tract infections.

AIM: To report our experience with empiric antimicrobial monotherapy (piperacillin/tazobactam, of which no data are available in such specific circumstances) in microbiologically-documented infections in patients with benign and malignant conditions of the biliary tract. METHODS: Twenty-three patients, 10 with benign and 13 with malignant conditions affecting the biliary tree and microbiologically-documented infections were recruited and the efficacy of empirical antibiotic therapy was assessed. RESULTS: The two groups featured similar demographic and clinical data. Overall, the infective episodes were most due to Gram negative agents, more than 60% of such episodes (mostly in malignant conditions) were preceded by invasive instrumental maneuvers. Empirical antibiotic therapy with a single agent (piperacillin/tazobactam) was effective in more than 80% of cases. No deaths were reported following infections. CONCLUSION: An empiric therapeutic approach with piperacillin/tazobactam is highly effective in biliary tract infections due to benign or malignant conditions.

Adult↗

PubMed2004

Nitric oxide regulates immune cell bioenergetic: a mechanism to understand immunomodulatory functions of nitric oxide-releasing anti-inflammatory drugs.

The 2-(acetyloxy)benzoic acid 3-(nitrooxymethyl)phenyl ester (NCX-4016) is a NO-releasing derivative of aspirin. In this study, we provide evidence that NCX-4016 delivered to PMBC-derived T lymphocytes and monocytes causes a transitory inhibition of cell respiration and approximately 50% reduction of cellular ATP, which translates in a time-reversible inhibition of cell proliferation and IL-2, IL-4, IL-5, and IFN-gamma secretion. Exposure of lymphocytes and monocytes to aspirin, 2-(acetyloxy)benzoic acid 3-(hydroxymethyl)phenyl ester (NCX-4017), a non-NO-releasing analog of NCX-4016, and cyclooxygenase inhibitors, reduced PG formation, but has no effect on cytokine/chemokine release. In contrast, delivering NO with (z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino] diazen-1-ium-1,2 diolate (DETA-NO) reproduced most of the metabolic and anti-cytokine activities of NCX-4016. Scavenging NO with hemoglobin or adding selective substrates of complex II, III, and IV of the mitochondrial respiratory chain reverses NCX-4016' inhibitory activities. Exposure to DETA-NO and NCX-4016 enhances glucose uptake, glycolytic rate, and lactate generation in CD3/CD28-costimulated lymphocytes, while reduced citric acid cycle intermediates. These effects were not reproduced by selective and nonselective cyclooxygenase 2 inhibitors. In summary, we demonstrated that exposure of lymphocytes to NCX-4016 causes a metabolic hypoxia that inhibits lymphocyte reactivity to costimulatory molecules, providing a potential counteregulatory mechanism to control activated immune system.

Adenosine Triphosphate↗

PubMed2004

Twenty-four-hour manometric study of colonic propulsive activity in patients with diarrhea due to inflammatory (ulcerative colitis) and non-inflammatory (irritable bowel syndrome) conditions.

BACKGROUND: Little is known concerning colonic motility and almost nothing is known concerning propulsive activity in pathological conditions characterized by diarrhea of both inflammatory and non-inflammatory origin. AIMS: The purpose of the present study was to investigate colonic propulsive activity in ulcerative colitis and diarrhea-predominant irritable bowel syndrome (IBS) patients. PATIENTS AND METHODS: Seven patients with active, moderate ulcerative colitis and nine diarrhea-predominant IBS patients entered the study. Sixteen healthy volunteers were recruited as a control group. In all subjects, 24-h colonic motility was recorded by a colonoscopically positioned manometric catheter. Both high- (mass movements) and low-amplitude propagated contractions were analyzed. RESULTS: High-amplitude propagated contractions were significantly increased in ulcerative colitis with respect to controls; no significant differences were found with respect to IBS patients, and between IBS and controls. Concerning amplitude, no significant difference was found between groups, although IBS patients approached the statistical difference with respect to controls. Low-amplitude propagated contractions were significantly increased in ulcerative colitis with respect to controls; no significant differences were found compared with IBS patients. The latter, however, displayed a trend toward an increase with respect to controls that approached but did not reach statistical significance. CONCLUSIONS: Both inflammatory and non-inflammatory diarrheal conditions are characterized by an overall increase of colonic propulsive activity. This observation may be useful for a better understanding of the pathophysiologic mechanisms of these disorders.

Adult↗

PubMed2004

Cooperation between aspirin-triggered lipoxin and nitric oxide (NO) mediates antiadhesive properties of 2-(Acetyloxy)benzoic acid 3-(nitrooxymethyl)phenyl ester (NCX-4016) (NO-aspirin) on neutrophil-endothelial cell adherence.

2-(Acetyloxy)benzoic acid 3-(nitrooxymethyl)phenyl ester (NCX-4016) is a nitric oxide (NO)-releasing derivative of aspirin that inhibits cyclooxygenase (COX) activity and releases NO. Acetylation of COX-2 by aspirin activates a transcellular biosynthetic pathway that switches eicosanoid biosynthesis from prostaglandin E(2) to 15-epi-lipoxin (LX)A(4) or aspirin-triggered lipoxin (ATL). Here, we demonstrate that exposure of neutrophil (PMN)/human umbilical vein endothelial cell (HUVEC) cocultures to aspirin and NCX-4016 triggers ATL formation and inhibits cell-to-cell adhesion induced by endotoxin (LPS) and interleukin (IL)-1beta by 70 to 90%. However, although selective and nonselective COX-2 inhibitors (celecoxib, rofecoxib, and naproxen) or N-t-butoxycarbonylmethionine-leucine-phenylalanine (Boc-1), an LXA(4) receptor antagonist, reduced the antiadhesive properties of aspirin by approximately 70%, antiadhesive effects of NCX-4016 were only marginally affected ( approximately 30%) by COX inhibitors and Boc-1, implying that COX-independent mechanisms mediate the antiadhesive properties of NCX-4016. Indeed, NCX-4016 causes a long-lasting (up to 12 h) release of NO and cGMP accumulation in HUVEC. Scavenging NO with 10 mM hemoglobin, in the presence of celecoxib, reduced the antiadhesive properties of NCX-4016 by approximately 80%. Confirming a role for NO, the NO donor diethylenetriamine-NO also inhibited PMN/HUVEC adhesion by approximately 80%. NCX-4016, but not aspirin, decreased DNA binding of nuclear factor-kappaB (NF-kappaB) on gel shift analysis and HUVEC's overexpression of CD54 and CD62E induced by LPS/IL-1beta. Reduction of binding of the two NF-kappaB subunits p50-p50 and p50-p65 was reversed by dithiothreitol, implying S-nitrosylation as mechanism of inhibition. In summary, our results support that ATL and NO are formed at the PMN/HUVEC interface after exposure to NCX-4016 and mediate the antiadhesive properties of this compound.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2004

Long-term study on the effects of visual biofeedback and muscle training as a therapeutic modality in pelvic floor dyssynergia and slow-transit constipation.

PURPOSE: Biofeedback training has been shown as an effective therapeutic measure in patients with pelvic floor dyssynergia, at least in the short term. Long-term effects have received less attention. Moreover, its effects in patients with slow-transit constipation have been scarcely investigated. This study was designed to assess in an objective way the medium- and long-term effects of biofeedback and muscle training in patients with pelvic floor dyssynergia and slow-transit constipation. METHODS: Twenty-four patients (14 with pelvic floor dyssynergia and 10 with slow transit) meeting the Rome II criteria for constipation, and unresponsive to conventional treatments, entered the study. Clinical evaluation and anorectal manometry were performed basally and three months after a cycle of electromyographic biofeedback and muscle training; moreover, a clinical interview was obtained one year after biofeedback. Patients with slow-transit constipation also had colonic transit time reassessed at one year. RESULTS: Clinical variables (abdominal pain, straining, number of evacuations/week, use of laxatives) all significantly improved in both groups at three-month assessment; anorectal manometric variables remained unchanged, apart from a significant decrease of sensation threshold in the pelvic floor dyssynergia group and of the maximum rectal tolerable volume in the slow-transit constipation group. At one-year control, 50 percent of patients with pelvic floor dyssynergia still maintained a beneficial effect from biofeedback, whereas only 20 percent of those complaining of slow-transit constipation did so. Moreover, the latter displayed no improvement in colonic transit time. CONCLUSIONS: In our experience, patients with pelvic floor dyssynergia are likely to have continued benefit from biofeedback training in the time course, whereas its effects on slow-transit constipation seems to be maximal in the short-term course.

Adult↗

PubMed2004

PAR1 antagonism protects against experimental liver fibrosis. Role of proteinase receptors in stellate cell activation.

In fibroblasts, thrombin induces collagen deposition through activation of a G-protein-coupled receptor, proteinase-activated receptor 1 (PAR(1)). In the current study, we examined whether PAR(1) antagonism inhibits hepatic stellate cell (HSC) activation in vitro and whether it protects against fibrosis development in a rodent model of cirrhosis. A rat HSC line was used for in vitro studies whereas cirrhosis was induced by bile duct ligation (BDL). The current results demonstrated that HSCs express PAR(1), as well as proteinase-activated receptors 2 (PAR(2)) and 4 (PAR(4)), and that all three PARs were up-regulated in response to exposure to growth factor in vitro. Exposure to thrombin and to SFLLRN-(SF)-NH(2), a PAR(1) agonist, and GYPGKF (GY)-NH(2), a PAR(4) agonist, triggered HSC proliferation and contraction, as well as monocyte chemotactic protein-1 (MCP-1) production and collagen I synthesis and release. These effects were inhibited by the PAR(1) antagonist. Administration of this antagonist, 1.5 mg/kg/d, to BDL rats reduced liver type I collagen messenger RNA (mRNA) expression and surface collagen by 63%, as measured by quantitative morphometric analysis. Similarly, hepatic and urinary excretion of hydroxyproline was reduced significantly by the PAR(1) antagonist. In conclusion, PAR(s) regulates HSC activity; development of PAR antagonists might be a feasible therapeutic strategy for protecting against fibrosis in patients with chronic liver diseases.

Adaptor Proteins, Signal Transducing↗

PubMed2004

One-year follow-up study on the effects of electrogalvanic stimulation in chronic idiopathic constipation with pelvic floor dyssynergia.

BACKGROUND: Constipation is a commonly reported symptom, and pelvic floor dyssynergia is frequently documented in constipated patients. The standard therapeutic approach for pelvic floor dyssynergia is biofeedback training, but long-term studies show that a significant percentage of patients remain symptomatic. Alternative or adjunctive therapeutic options are needed. AIMS: The purpose of this study was to evaluate the long-term effects of electrogalvanic stimulation in patients with pelvic floor dyssynergia and severe constipation, to see whether this treatment may be of some benefit. PATIENTS AND METHODS: Thirty consecutive constipated patients with clinical and instrumental evidence of pelvic floor dyssynergia entered the study and were treated with a standard high-frequency galvanic electrostimulation protocol. Clinical and instrumental (colon transit time, anorectal manometry, defecography, rectal balloon expulsion) assessment evaluations were performed basally and one year after the treatment. RESULTS: Overall, approximately 50 percent of patients showed significant improvement after electrogalvanic treatment, from both a clinical and an instrumental point of view, as shown by the objective measurements obtained through manometry, defecography, and the balloon expulsion test. The benefit was limited to normal transit constipation patients. CONCLUSIONS: Because of the relatively simple, painless and effective nature of electrogalvanic stimulation, we concluded that it may represent a useful adjunct to the therapeutic armamentarium for pelvic floor dyssynergia in normal transit constipation.

Adult↗

PubMed2004

Liver delivery of NO by NCX-1000 protects against acute liver failure and mitochondrial dysfunction induced by APAP in mice.

1. NCX-1000, (3alpha, 5beta, 7beta)-3,7-dihydroxycholan-24oic acid[2-methoxy-4-[3-[4-(nitroxy)butoxy]-3-oxo-1-propenyl]phenyl ester, is a nitric oxide (NO)-derivative of ursodeoxyxholic acid (UDCA) that selectively release NO in the liver. 2. Here, we demonstrated that administering mice with 40 micromol kg(-1) NCX-1000, but not UDCA, improves liver histopathology and reduces mortality caused by 330 micromol kg(-1) APAP from 60 to 25% (P<0.01). Administration of NCX-1000, in a therapeutic manner, that is, 2 h after acetaminophen (APAP) intoxication reduced mortality, improved liver histopathology and prevented liver IFN-gamma, TNF-alpha, Fas/Fas ligand and inducible nitric oxide synthase (iNOS) mRNA accumulation caused by APAP. 3. In vitro exposure of primary cultures of mouse hepatocytes to APAP, 6.6 mm, resulted in apoptosis followed by necrosis. Loss of cell viability correlates with early mitochondrial membrane potential (Deltapsi(m)) hyperpolarization followed by depolarization and cytochrome c translocation from mitochondria to cytosol. APAP-induced apoptosis associated with procaspase-3 and -9 cleavage, appearance of truncated Bid and activation of poly(ADP-ribose) polymerase (PARP). 4. Treating primary culture of hepatocytes with 5 microm cyclosporine and 10 microm trifluoperazine for eight resulted in significant reduction of apoptosis induced by APAP suggesting that loss of Deltapsim was mechanistically involved in apoptosis induced by APAP in vitro. 5. NCX-1000, but not UDCA, concentration-dependently (ED(50)=16 microm) protected against Deltapsi(m) depolarization and reduced transition from apoptosis to necrosis caused by 6.6 mm APAP. 6. Treating primary cultures of hepatocytes with the NO-donor DETA-NO, 100 microm, reduced apoptosis induced by APAP and prevented caspase activation. 7. In conclusion, NCX-1000 is effective in protecting against APAP-induced hepatotoxicity when administered in a therapeutic manner. This protection may involve the inhibition of apoptosis and the maintenance of mitochondrial integrity.

Acetaminophen↗

PubMed2004

The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis.

BACKGROUND AND AIMS: The farnesoid X receptor (FXR) is an endogenous sensor for bile acids and inhibits bile acid synthesis by inducing small heterodimer partner (SHP) gene expression. The aim of this study was to investigate whether FXR is expressed by and modulates function of hepatic stellate cells (HSCs). METHODS: The antifibrotic activity of FXR ligand was tested in 2 rodent models: the porcine serum and bile duct ligation (BDL). RESULTS: Twelve-week administration of 1-10 mg/kg 6-ethyl chenodeoxycholic acid (6-ECDCA), a synthetic FXR ligand, to porcine serum-treated rats prevented liver fibrosis development and reduced liver expression of alpha1(I) collagen, TGF-beta1 and alpha-SMA mRNA by approximately 90%. Therapeutic administration of 6-ECDCA, 3 mg/kg, to BDL rats reduced liver fibrosis and alpha1(I) collagen, transforming growth factor (TGF)-beta1, alpha-SMA, and tissue metalloproteinase inhibitor (TIMP)-1 and 2 messenger RNA (mRNA) by 70%-80%. No protection was observed in BDL rats treated with CDCA, 3 mg/kg, and ursodeoxycholic acid, 15 mg/kg. FXR expression was detected in HSCs. Exposure of HSCs to FXR ligands caused a 3-fold increase of SHP, reduced alpha1(I)collagen and TGF-beta1 by approximately 60%-70% and abrogates alpha1(I) collagen mRNA up-regulation induced by thrombin and TGF-beta1. By retrovirus infection and small interference RNA, we generated SHP overexpressing and SHP-deficient HSC-T6. Using these cell lines, we demonstrated that SHP binds JunD and inhibits DNA binding of adaptor protein (AP)-1 induced by thrombin. CONCLUSIONS: By demonstrating that an FXR-SHP regulatory cascade promotes resolution of liver fibrosis, this study establish that FXR ligands might represent a novel therapeutic option to treat liver fibrosis.

Animals↗

PubMed2004

Colonic regular contractile frequency patterns in irritable bowel syndrome: the 'spastic colon' revisited.

BACKGROUND: Irritable bowel syndrome is a frequent gastrointestinal disorder of which the pathophysiological basis is still not completely understood. Among the various proposed mechanisms, colonic motility may play a role, at least in a subset of patients. AIMS: To investigate the regular colonic contractile patterns in patients with irritable bowel syndrome. Our working hypothesis was that an increase of these patterns in such condition might represent a motility equivalent of the so-called 'spastic colon'. PATIENTS AND METHODS: Twelve patients of both genders were investigated by means of 24 h colonic manometry, and the results were compared to those from 20 healthy controls. Regular contractile patterns (with frequencies ranging from 2 to 8 per min) were calculated for the entire recording period and in single colonic segments. RESULTS: Overall, colonic frequency patterns were significantly more frequent in patients than controls (12.6% vs 6.4% of the total contractile activity, P < 0.001); in both groups, the 3 cycles/min frequency was predominant, especially in the sigmoid colon. More than 40% patients displayed a correlation between abdominal pain and occurrence of regular contractile frequencies. CONCLUSIONS: Abnormal colonic motility may play some role in the pathogenesis of symptoms related to irritable bowel syndrome, with an excess of regular contractile activity related to the so-called 'spastic colon'.

Adult↗

PubMed2004

Pseudo-pseudo-obstruction.

Chronic intestinal pseudo-obstruction is a clinical syndrome characterised by symptoms and signs of intestinal obstruction in the absence of a mechanical lesion of the intestinal lumen. The diagnosis is often difficult and relies on clinical, radiological and manometric grounds. We present here a case in which such a diagnosis was suspected, but a thorough in-depth evaluation revealed that the symptoms were due to a treatable cause--abdominopelvic adhesions.

Abdominal Pain↗

PubMed2004

Treatment of portal hypertension with NCX-1000, a liver-specific NO donor. A review of its current status.

Portal hypertension, a life threatening complication of liver cirrhosis, results from increased intrahepatic resistance and increased portal blood inflow through a hyperdynamic splanchnic system. The increased intrahepatic vascular tone is the result of an enhanced activity of endogenous vasoconstrictors and a deficiency of nitric oxide (NO) release by sinusoidal endothelial cells. These pathophysiological events provide the rational basis for using NO-based therapies for the treatment of portal hypertension. Clinical studies have demonstrated that nitrate therapy results in a significant reduction of portal pressure as assessed by hepatic venous portal gradient but causes vasodilation in both systemic arterial and venous vascular beds, aggravating the progression of the vasodilatory syndrome of cirrhotic patients. For this reason, the ideal drug for the treatment of portal hypertension should act by decreasing intrahepatic vascular resistance, without worsening the splanchnic/systemic vasodilatation. NCX-1000 is the prototype of a family of NO-releasing derivatives of ursodeoxycholic acid (UDCA). These compounds are releasing selectively, from parenchymal and non-parenchymal hepatic cells, biologically active NO into the liver microcirculation with no detectable effect on systemic circulation. Preclinical studies have shown that long- and short-term administration of NCX-1000 to rodents with chronic liver injury protects against the development of portal hypertension and reduces the intrahepatic hyperreactivity to alpha1-adrenoceptor agonists. The finding of increased liver nitrite/nitrate content in NCX-1000-treated animals together with an increase in cGMP levels in their liver homogenates suggests that this nitro-compound behaves as a liver-selective NO donor. In contrast to conventional NO-donors such as isosorbide mono- and di-nitrate, which are also used for primary and secondary prevention of gastrointestinal bleeding, NCX-1000 has no effect on mean arterial pressure in either normal or cirrhotic animals indicating the absence of adverse systemic effect. In summary, these data suggest that NCX-1000 may provide a novel therapy for the treatment of patients with portal hypertension.

Animals↗

PubMed2003

Abnormal colonic propagated activity in patients with slow transit constipation and constipation-predominant irritable bowel syndrome.

BACKGROUND: The pathophysiological basis of constipation is still unclear, and the role of colonic dysfunction is debated, especially in irritable bowel syndrome. Objective data are quite scarce, especially concerning colonic propulsive activity. AIMS: To evaluate high- and low-amplitude colonic propulsive activity in constipated patients (slow-transit type and irritable bowel syndrome) in comparison with normal controls. PATIENTS AND METHODS: Forty-five constipated patients (35 with slow-transit constipation and 10 with constipation-predominant irritable bowel syndrome) were recruited, and their data compared to those of 18 healthy subjects. Twenty-four-hour colonic manometric recordings were obtained in the three groups of subjects, and data concerning high- and low-amplitude colonic propulsive activity were then compared. RESULTS: High-amplitude propagated contractions were significantly (p < 0.05) decreased in patients with slow-transit constipation and constipation-predominant irritable bowel syndrome with respect to controls (1.5 +/- 0.4, 3.7 +/- 2, and 6 +/- 1 events/subject/day, respectively). In slow-transit constipation, a significant decrease of contractions' amplitude was also observed. Concerning low-amplitude propagated contractions, patients with slow-transit constipation had significantly less events with respect to patients with constipation-predominant irritable bowel syndrome (46 +/- 7 vs. 87.4 +/- 19, p = 0.015); no differences were found between patients with slow-transit constipation and controls and between patients with constipation-predominant irritable bowel syndrome and controls. All three groups displayed a significant increase of low-amplitude propagated contractions after meals (6.3 +/- 2 vs. 18.2 +/- 5 for controls, p < 0.005; 6.4 +/- 1.4 vs. 16.3 +/- 2.4 for slow-transit constipation, p < 0.005; 10.5 +/- 3.2 vs. 32.6 +/- 7 for constipation-predominant irritable bowel syndrome, p = 0.001). CONCLUSIONS: Low-amplitude propagated contractions may represent an important physiologic motor event in constipated patients, reducing the severity of constipation in patients with irritable bowel syndrome and preserving a residual colonic propulsive activity in patients with slow-transit constipation.

Adult↗

PubMed2003

Interaction of a selective cyclooxygenase-2 inhibitor with aspirin and NO-releasing aspirin in the human gastric mucosa.

In addition to inhibiting cyclooxygenase (COX)-1-derived prostanoid biosynthesis, aspirin acetylates COX-2, enabling the conversion of arachidonic acid to 15(R)-epi lipoxin A4, or aspirin-triggered lipoxin (ATL). Selective COX-2 inhibitors block ATL formation and exacerbate mucosal injury in rats treated with aspirin. In the present study, we have examined whether inhibition of COX-2 activity in healthy volunteers taking aspirin exacerbates gastric mucosal injury and if such an effect would be prevented by NCX-4016, a NO-releasing derivative of aspirin. Thirty-two volunteers were randomized to receive 2 wk of treatment with NCX-4016 (800 mg twice a day) or aspirin (100 mg once a day) alone or in combination with 200 mg of celecoxib twice a day. Mucosal damage was assessed by endoscopy. The mean mucosal injury score was 5.8 +/- 1.8 in subjects treated with aspirin and 2.4 +/- 0.7 (P < 0.01 vs. aspirin) in subjects treated with NCX-4016. Administration of celecoxib increased the injury score in volunteers treated with aspirin (9.9 +/- 1.9) but not in subjects taking NCX-4016 (1.5 +/- 0.8). Aspirin and NCX-4016 caused a comparable suppression of serum thromboxane B2 levels and increased urinary excretion of ATL. Celecoxib inhibited endotoxin-induced prostaglandin E2 generation in whole blood by approximately 80% and abolished ATL formation. These findings suggests that (i) aspirin and NCX-4016 trigger ATL formation in humans, (ii) celecoxib inhibits ATL formation and exacerbates the mucosal injury caused by low doses of aspirin, and (iii) the NO-donating moiety of NCX-4016 protects the gastric mucosa even in the presence of suppression of COX-1 and COX-2.

Adult↗