Biomedical subjects

Antonio Morelli

Publications and source records attributed to Antonio Morelli.

At least 19 recordsLinked to original sources

PubMed2007

Audit of constipation in a gastroenterology referral center.

This study was designed to assess the various subtypes of functional constipation in a referral gastrointestinal center of a Latino-American country. All patients referred for evaluation of constipation during a 10-year period were audited, and those with functional constipation according to Rome I criteria classified by physiologic tests of colonic transit, as well as tests of anorectal and pelvic floor function. More than 70% of patients with functional constipation had evidence of pelvic floor dysfunction, whereas those with slow transit and constipation-predominant irritable bowel syndrome subtypes were less frequently represented. Even in a setting different from those most frequently reported in the literature, pelvic floor dysfunction represents the most common cause of functional constipation. Simple, physiologic testing is needed and useful for the diagnosis. This fact has therapeutic implications, especially because many such patients may benefit from biofeedback.

Adult↗

PubMed2007

Comparison of three methods to assess enteric neuronal apoptosis in patients with slow transit constipation.

BACKGROUND: The pathophysiological basis of slow transit constipation are scarcely understood. Some recent evidence suggests that increased apoptotic phenomena in the colonic enteric neurons may play a role. However, the best method to assess these phenomena has not been evaluated. AIMS: To compare three different methods to detect enteric neuronal apoptosis in these patients. METHODS: Serial colonic tissue sections obtained in 10 patients with intractable slow transit constipation were evaluated with immunohistochemical methods aimed at evaluating apoptotic phenomena: the formamide-MAb method, the TUNEL, and the caspase-3. RESULTS: The highest yield of apoptotic neurons was obtained by means of the formamide-MAb method, compared to the other two, whereas the lowest yield was observed with the caspase-3. CONCLUSIONS: The formamide-MAb method, which is able to distinguish apoptosis from necrosis and is not influenced by DNA breaks, may prove useful to assess neuronal apoptotic phenomena in the human enteric nervous system. This represents a relevant method to detect enteric neuronal apoptosis.

Apoptosis↗

PubMed2006

Enteric neuropathology of the terminal ileum in patients with intractable slow-transit constipation.

Slow-transit constipation is usually considered a colonic motor disorder. However, there is some evidence that abnormalities may be present in locations other than the colon. In particular, several studies have reported abnormal motor activity of the small bowel in these patients. We evaluated the neuropathological aspects of the terminal ileum in patients with slow-transit constipation to see whether abnormalities are present that may explain an abnormal motility of the small intestine. Specimens of the terminal ileum were obtained from 16 female patients (age range, 42-76 years) with slow-transit constipation undergoing surgery for intractable symptoms. Fifteen age- and sex-matched controls were used for comparison. Histologic and immunohistochemical evaluation of the myenteric plexus and the smooth muscle of the proximal ileal resection margin was carried out by means of hematoxylin and eosin, trichrome and periodic acid-Schiff stain, neuron-specific enolase, S-100, CD117, CD34, anti-alpha-actin, desmin, and vimentin antibodies. The patient group displayed a significantly reduced number of glial cells, compared with controls, in both the submucosal and the myenteric plexus. Only 1 of the 3 populations of interstitial cells of Cajal (that associated with the deep muscular plexus) was decreased in patients. No differences were found between patients and controls concerning ganglia neurons, fibroblast-like cells, enteric neurons, apoptotic phenomena, and smooth muscle. Patients with slow-transit constipation display neuropathological abnormalities of the terminal ileum to a lesser extent than those we previously found in the colon, which might explain the abnormal motor aspects sometimes found in these patients.

Adult↗

PubMed2006

3alpha-6alpha-Dihydroxy-7alpha-fluoro-5beta-cholanoate (UPF-680), physicochemical and physiological properties of a new fluorinated bile acid that prevents 17alpha-ethynyl-estradiol-induced cholestasis in rats.

3alpha-6alpha-Dihydroxy-7alpha-fluoro-5beta-cholanoate (UPF-680), the 7alpha-fluorine analog of hyodeoxycholic acid (HDCA), was synthesized to improve bioavailability and stability of ursodeoxycholic acid (UDCA). Acute rat biliary fistula and chronic cholestasis induced by 17alpha-ethynyl-estradiol (17EE) models were used to study and compare the effects of UPF-680 (dose range 0.6-6.0 micromol/kg min) with UDCA on bile flow, biliary bicarbonate (HCO(3)(-)), lipid output, biliary bile acid composition, hepatic enzymes and organic anion pumps. In acute infusion, UPF-680 increased bile flow in a dose-related manner, by up to 40.9%. Biliary HCO(3)(-) output was similarly increased. Changes were observed in phospholipid secretion only at the highest doses. Treatment with UDCA and UPF-680 reversed chronic cholestasis induced by 17EE; in this model, UDCA had no effect on bile flow in contrast to UPF-680, which significantly increased bile flow. With acute administration of UPF-680, the biliary bile acid pool became enriched with unconjugated and conjugated UPF-680 (71.7%) at the expense of endogenous cholic acid and muricholic isomers. With chronic administration of UPF-680 or UDCA, the main biliary bile acids were tauro conjugates, but modification of biliary bile acid pool was greater with UPF-680. UPF-680 increased the mRNA for cytochrome P450 7A1 (CYP7A1) and cytochrome P450 8B (CYP8B). Both UDCA and UPF-680 increased the mRNA for Na(+) taurocholate co-transporting polypeptide (NCTP). In conclusion, UPF-680 prevented 17EE-induced cholestasis and enriched the biliary bile acid pool with less detergent and cytotoxic bile acids. This novel fluorinated bile acid may have potential in the treatment of cholestatic liver disease.

Animals↗

PubMed2006

Biofeedback is superior to laxatives for normal transit constipation due to pelvic floor dyssynergia.

BACKGROUND & AIMS: Uncontrolled trials suggest biofeedback is an effective treatment for pelvic floor dyssynergia (PFD), a type of constipation defined by paradoxical contraction, or inability to relax, pelvic floor muscles during defecation. The aim was to compare biofeedback to laxatives plus education. METHODS: Patients with chronic, severe PFD were first treated with 20 g/day fiber plus enemas or suppositories up to twice weekly. Nonresponders were randomized to either 5 weekly biofeedback sessions (n = 54) or polyethylene glycol 14.6-29.2 g/day plus 5 weekly counseling sessions in preventing constipation (n = 55). Satisfaction with treatment, symptoms of constipation, and pelvic floor physiology were assessed 6 and 12 months later. The biofeedback group was also assessed at 24 months. Laxative-treated patients were instructed to increase the dose of polyethylene glycol from 14.6 to 29.2 g/day after 6 months. RESULTS: At 6 months, major improvement was reported by 43 of 54 (80%) biofeedback patients vs 12 of 55 (22%) laxative-treated patients (P < .001). Biofeedback's benefits were sustained at 12 and 24 months. Biofeedback also produced greater reductions in straining, sensations of incomplete evacuation and anorectal blockage, use of enemas and suppositories, and abdominal pain (all P < .01). Stool frequency increased in both groups. All biofeedback-treated patients reporting major improvement were able to relax the pelvic floor and defecate a 50-mL balloon at 6 and 12 months. CONCLUSIONS: Five biofeedback sessions are more effective than continuous polyethylene glycol for treating PFD, and benefits last at least 2 years. Biofeedback should become the treatment of choice for this common and easily diagnosed type of constipation.

Adult↗

PubMed2006

Colonic propulsive and postprandial motor activity in patients with ulcerative colitis in remission.

BACKGROUND: Although it is known that colon motility is abnormal in ulcerative colitis, data are still scarce with regard to the underlying mechanisms. Recent evidence suggests that the propulsive activity is highly increased during the active phase of the disease, probably contributing to the diarrhoea. However, data are even scarcer in the quiescent phase of the disease. AIMS: To assess the colonic high-amplitude and low-amplitude propulsive activity and the colonic motor response to eating in patients with ulcerative colitis in remission. PATIENTS AND METHODS: Fourteen patients were recruited, all with the disease in remission as documented by clinical and endoscopic criteria. Twenty-four hour manometric recordings were obtained in these patients, and compared to those of 16 healthy controls. RESULTS: The high-amplitude propagated contractions were similar in both groups (5.8+/-2.6 events in ulcerative colitis patients and 5.5+/-0.8 in controls (P=0.13)), whereas patients tended to display a higher number of low-amplitude propagated events (134.4+/-34 vs. 60.9+/-16 in controls (P=0.058)). No differences were found in the colonic motor response to eating between patients and controls. CONCLUSIONS: Colonic propulsive activity in ulcerative colitis in remission is almost normal, even though the low-amplitude propagated activity tends to be similar to that observed in patients with the irritable bowel syndrome, thus possibly contributing to the persistence of abdominal symptoms in a subgroup of patients.

Adult↗

PubMed2005

Manometric assessment of idiopathic megarectum in constipated children.

AIM: Chronic constipation is a frequent finding in children. In this age range, the concomitant occurrence of megarectum is not uncommon. However, the definition of megarectum is variable, and a few data exist for Italy. We studied anorectal manometric variables and sensation in a group of constipated children with megarectum defined by radiologic criteria. Data from this group were compared with those obtained in a similar group of children with recurrent abdominal pain. METHODS: Anorectal testing was carried out in both groups by standard manometric technique and rectal balloon expulsion test. RESULTS: Megarectum patients displayed discrete abnormalities of anorectal variables and sensation with respect to controls. In particular, the pelvic floor function appeared to be impaired in most patients. CONCLUSION: Constipated children with megarectum have abnormal anorectal function and sensation. These findings may be helpful for a better understanding of the pathophysiological basis of this condition.

Case-Control Studies↗

PubMed2005

Evidence that hydrogen sulfide exerts antinociceptive effects in the gastrointestinal tract by activating KATP channels.

Hydrogen sulfide (H(2)S) functions as a neuromodulator, but whether it modulates visceral perception and pain is unknown. Cystathionine beta-synthase (CBS) and cystathionine-gamma-lyase (CSE) mediate enzymatic generation of H(2)S in mammalian cells. Here we have investigated the role of H(2)S in modulating nociception to colorectal distension, a model that mimics some features of the irritable bowel syndrome. Four graded (0.4-1.6 ml of water) colorectal distensions (CRDs) were produced in conscious rats (healthy and postcolitic), and rectal nociception was assessed by measuring the behavioral response during CRD. Healthy rats were administered with sodium hydrogen sulfide (NaHS) (as a source of H(2)S), L-cysteine, or vehicle. In a second model, we investigated nociception to CRD in rats recovering from a chemically induced acute colitis. We found that CBS and CSE are expressed in the colon and spinal cord. Treating rats with NaHS resulted in a dose-dependent attenuation of CRD-induced nociception with the maximal effect at 60 micromol/kg (p < 0.05). Administration of L-cysteine, a CSE/CBS substrate, reduced rectal sensitivity to CRD (p < 0.05). NaHS-induced antinociception was reversed by glibenclamide, a ATP-sensitive K(+) (K(ATP)) channel inhibitor, and N(omega)-nitro-L-arginine methyl ester hydrochloride (L-NAME), a nitric-oxide (NO) synthase inhibitor. The antinociceptive effect of NaHS was maintained during the resolution of colon inflammation induced by intrarectal administration of a chemical irritant. In summary, these data show that H(2)S inhibits nociception induced by CRD in both healthy and postcolitic rats. This effect is mediated by K(ATP) channels and NO. H(2)S-releasing drugs might be beneficial in treating painful intestinal disorders.

ATP-Binding Cassette Transporters↗

PubMed2005

Bio-feedback treatment of fecal incontinence: where are we, and where are we going?

Fecal incontinence is a disabling disease, often observed in young subjects, that may have devastating psycho-social consequences. In the last years, numerous evidences have been reported on the efficacy of bio-feedback techniques for the treatment of this disorder. Overall, the literature data claim a success rate in more than 70% of cases in the short term. However, recent controlled trials have not confirmed this optimistic view, thus emphasizing the role of standard care. Nonetheless, many authors believe that this should be the first therapeutic approach for fecal incontinence due to the efficacy, lack of side-effects, and scarce invasiveness. Well-designed randomized, controlled trial are eagerly awaited to solve this therapeutic dilemma.

Biofeedback, Psychology↗

PubMed2005

Cross-talk between farnesoid-X-receptor (FXR) and peroxisome proliferator-activated receptor gamma contributes to the antifibrotic activity of FXR ligands in rodent models of liver cirrhosis.

The nuclear receptors farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor (PPAR)gamma exert counter-regulatory effects on hepatic stellate cells (HSCs) and protect against liver fibrosis development in rodents. Here, we investigated whether FXR ligands regulate PPARgamma expression in HSCs and models of liver fibrosis induced in rats by porcine serum and carbon tetrachloride administration and bile duct ligation. Our results demonstrate that HSCs trans-differentiation associated with suppression of PPARgamma mRNA expression, whereas FXR mRNA was unchanged. Exposure of cells to natural and synthetic ligands of FXR, including 6-ethyl chenodeoxycholic acid (6-ECDCA), a synthetic derivative of chenodeoxycholic acid, reversed this effect and increased PPARgamma mRNA by approximately 40-fold. Submaximally effective concentrations of FXR and PPARgamma ligands were additive in inhibiting alpha1(I) collagen mRNA accumulation induced by transforming growth factor (TGF)beta1. Administration of 6-ECDCA in rats rendered cirrhotic by porcine serum and carbon tetrachloride administration or bile duct ligation reverted down-regulation of PPARgamma mRNA expression in HSCs. Cotreatment with 6-ECDCA potentiates the antifibrotic activity of rosiglitazone, a PPARgamma ligand, in the porcine serum model as measured by morphometric analysis of liver collagen content, hydroxyproline, and liver expression of alpha1(I) collagen mRNA, alpha-smooth muscle actin, fibronectin, TGFbeta1, and tissue inhibitor of metalloprotease 1 and 2, whereas it enhanced the expression of PPARgamma and uncoupling protein 2, a PPARgamma-regulated gene, by 2-fold. In conclusion, by using an in vitro and in vivo approach, we demonstrated that FXR ligands up-regulate PPARgamma mRNA in HSCs and in rodent models of liver fibrosis. A FXR-PPARgamma cascade exerts counter-regulatory effects in HSCs activation.

Animals↗

PubMed2005

Normal aspects of colorectal motility and abnormalities in slow transit constipation.

Human colonic motility is a relatively difficult topic to investigate. However, the refinement of manometric techniques in recent years enabled us to study both the proximal and distal segments of the viscus. The present paper reviews our knowledge about normal aspects of colorectal motility in man and the abnormalities found in slow transit constipation (STC), one of the most frequent and difficult to treat subtypes of constipation. An internet-based search strategy of the Medline and Science Citation Index was performed using the keywords colon, colonic, colorectal, constipation, slow transit, motility, rectal, rectum in various combinations with the Boolean operators AND, OR and NOT. Only articles related to human studies were used, and manual cross-referencing was also performed. Most of colonic motor activity is represented by single nonpropagated contractions, rarely organized in bursts; this activity is maximal during the day, especially after waking and following meals. In addition, a specialized propagated activity with propulsive features is detectable, represented by high- and low-amplitude propagated contractions. In the severe form of constipation represented by the slow transit type, the above motor activity is completely deranged. In fact, both basal segmental activity (especially in response to meals) and propagated activity (especially that of high amplitude) are usually decreased, and this may represent a physiologic marker of this disorder. Human colonic motor activity is quite a complex issue, still only partly understood and investigated, due to anatomic and physiological difficulties. In recent years, however, some more data have been obtained, even in proximal segments. These data have helped in elucidating, although only in part, some pathophysiological mechanisms of chronic constipation, and especially of the STC subtype.

Colon↗

PubMed2005

A farnesoid x receptor-small heterodimer partner regulatory cascade modulates tissue metalloproteinase inhibitor-1 and matrix metalloprotease expression in hepatic stellate cells and promotes resolution of liver fibrosis.

The farnesoid X receptor (FXR) is expressed by and regulates hepatic stellate cells (HSCs). In the present study, we investigated whether 6-ethyl chenodeoxycholic acid (6-ECDCA or INT-747), a semisynthetic derivative of chenodeoxycholic acid (CDCA), modulates tissue metalloproteinase inhibitor (TIMP)-1 and matrix metalloprotease (MMP)-2 expression/activity in HSCs and in the liver of rats rendered cirrhotic by 4-week administration of CCl(4). Exposure of HSCs to FXR ligands increases small heterodimer partner (SHP) mRNA by 3-fold and reduces basal and thrombin-stimulated expression of alpha1(I)collagen, alpha-smooth muscle actin (alpha-SMA), TIMP-1, and TIMP-2 by approximately 60 to 70%, whereas it increased matrix metalloprotease (MMP)-2 activity by 2-fold. In coimmunoprecipitation, electromobility shift, and transactivation experiments, FXR activation/overexpression caused a SHP-dependent inhibition of JunD binding to its consensus element in the TIMP-1 promoter. Inhibition of TIMP-1 expression by SHP overexpression enhanced the sensitivity of HSCs to proapoptogenic stimuli. Administration of 3 mg/kg 6-ECDCA, but not 15 mg/kg ursodeoxycholic acid, resulted in early (3-5-day) induction of SHP and prevention of early up-regulation of TIMP-1 mRNA induced by CCl(4). In the prevention protocol, 4-week administration of 6-ECDCA reduced alpha1(I)collagen, alpha-SMA, and TIMP-1 mRNA by 60 to 80%, whereas it increased MMP-2 activity by 5-fold. In the resolution protocol, administration of 3 mg/kg 6-ECDCA promoted liver fibrosis resolution and increased the apoptosis of nonparenchyma liver cells. By demonstrating that a FXR-SHP regulatory cascade promotes the development of a quiescent phenotype and increases apoptosis of HSCs, this study establishes that FXR ligands may be beneficial in treatment of liver fibrosis.

Actins↗

PubMed2005

Protective effects of 6-ethyl chenodeoxycholic acid, a farnesoid X receptor ligand, in estrogen-induced cholestasis.

The farnesoid X receptor (FXR), an endogenous sensor for bile acids, regulates a program of genes involved in bile acid biosynthesis, conjugation, and transport. Cholestatic liver diseases are a group of immunologically and genetically mediated disorders in which accumulation of endogenous bile acids plays a role in the disease progression and symptoms. Here, we describe the effect of 6-ethyl chenodeoxycholic acid (6-ECDCA or INT-747), a semisynthetic bile acid derivative and potent FXR ligand, in a model of cholestasis induced by 5-day administration of 17alpha-ethynylestradiol (E(2)17alpha) to rats. The exposure of rat hepatocytes to 1 microM 6-ECDCA caused a 3- to 5-fold induction of small heterodimer partner (Shp) and bile salt export pump (bsep) mRNA and 70 to 80% reduction of cholesterol 7alpha-hydroxylase (cyp7a1), oxysterol 12beta-hydroxylase (cyp8b1), and Na(+)/taurocholate cotransporting peptide (ntcp). In vivo administration of 6-ECDCA protects against cholestasis induced by E(2)17alpha. Thus, 6-ECDCA reverted bile flow impairment induced by E(2)17alpha, reduced secretion of cholic acid and deoxycholic acid, but increased muricholic acid and chenodeoxycholic acid secretion. In vivo administration of 6-ECDCA increased liver expression of Shp, bsep, multidrug resistance-associated protein-2, and multidrug resistance protein-2, whereas it reduced cyp7a1 and cyp8b1 and ntcp mRNA. These changes were reproduced by GW4064, a synthetic FXR ligand. In conclusion, by demonstrating that 6-ECDCA protects against E(2)17alpha cholestasis, our data support the notion that development of potent FXR ligands might represent a new approach for the treatment of cholestatic disorders.

Animals↗

PubMed2005

The third gas: H2S regulates perfusion pressure in both the isolated and perfused normal rat liver and in cirrhosis.

The regulation of sinusoidal resistance is dependent on the contraction of hepatic stellate cells (HSC) around sinusoidal endothelial cell (SEC) through paracrine cross-talk of vasoconstrictor and vasodilator agents. Hydrogen sulfide (H2S), a recently discovered gas neurotransmitter, is a putative vasodilator whose role in hepatic vascular regulation and portal hypertension is unexplored. Four-week bile duct-ligated (BDL) rats with cirrhosis and control rats were treated daily with NaHS (56 micromol/kg) for 5 days. Isolated livers were perfused first with NaHS for 20 minutes and then with norepinephrine (NE) and the intrahepatic resistance studied. In normal rats and animals with cirrhosis, administration of NE resulted in a dose-dependent increase of portal pressure. This effect was attenuated by H2S treatment (P < .05). The H2S-induced relaxation of hepatic microcirculation was attenuated by glibenclamide, an adenosine triphosphate (ATP)-sensitive K+ channel inhibitor. L-Cysteine, a substrate of cystathionine-gamma-lyase (CSE), decreased vasoconstriction in normal rat livers (P < .05) but failed to do so in livers with cirrhosis. BDL resulted in a downregulation of CSE mRNA/protein levels and activity (P < .05). Our in vitro data demonstrate that CSE is expressed in hepatocytes, HSCs, but not in sinusoidal endothelial cells (SEC). HSC activation downregulates CSE mRNA expression, resulting in a defective production of H2S and abrogation of relaxation induced by L-cysteine. In conclusion, CSE-derived H2S is involved in the maintenance of portal venous pressure. The reduction of CSE expression in the liver with cirrhosis contributes to the development of increased intrahepatic resistance and portal hypertension.

Animals↗

PubMed2005

Alterations in colonic motility and relationship to pain in colonic diverticulosis.

BACKGROUND AND AIMS: Although the pathophysiologic basis of colonic diverticular disease is understood incompletely, there is agreement that abnormal colon motility probably plays a major role. However, several different abnormalities have been reported in such patients. The purpose of this study was to assess whether patients with diverticulosis display an abnormal duration of regular colonic contractile patterns, which has been observed in other conditions characterized by spasticity of the viscus, such as the irritable bowel syndrome. METHODS: Twelve patients with symptomatic uncomplicated diverticular disease entered the study and underwent 24-hour colonic manometric recordings using a standard technique. The duration of regular contractile patterns was compared with that recorded in 20 healthy volunteers. RESULTS: Patients with diverticulosis had a significant increase of the duration of regular patterns of phasic pressure activity compared with healthy controls (31% vs. 6.4%, P < .001). In both groups, the 2- or 3-cycles-per-minute activity represented more than 80% of such activity, especially in the sigmoid colon. More than 30% of patients, but none of the controls, reported episodes of abdominal pain (cramping lower abdominal pain with characteristics similar to those experienced at home) during the occurrence of a regular colonic contractile pattern. This was significant by symptom association probability criteria. CONCLUSIONS: Patients with symptomatic uncomplicated colonic diverticulosis displayed increased duration of rhythmic, low-frequency, contractile activity, particularly in the segments bearing diverticula. These regular rhythms are associated significantly with reporting of abdominal pain.

Abdominal Pain↗

PubMed2005

Different sensitivity of lamina propria T-cell subsets to nitric oxide-induced apoptosis explains immunomodulatory activity of a nitric oxide-releasing derivative of mesalamine in rodent colitis.

BACKGROUND & AIMS: Uncontrolled T-cell activation plays a critical role in the pathogenesis of inflammatory bowel diseases. Therefore, pharmacological strategies directed toward restoring the normal responsiveness of the immune system could be effective in the treatment of these pathologic conditions. The addition of a nitric oxide-releasing moiety to conventional drugs, such as aspirin and other anti-inflammatory analgesic drugs, results in new chemical entities with potent immunomodulatory activities. The aim of this study was to investigate the immunomodulatory activity of a nitric oxide-releasing derivative of mesalamine (NCX-456), as compared with standard mesalamine, in 2,4,6-trinitrobenzene sulfonic acid-induced colitis in mice. METHODS: Cells and tissues from mice with 2,4,6-trinitrobenzene sulfonic acid-induced colitis and from interleukin 10-deficient mice with spontaneous chronic colitis receiving treatment with several doses of NCX-456 or mesalamine were analyzed for morphology, cytokine production, and apoptosis. RESULTS: NCX-456, but not mesalamine, administration resulted in a marked reduction in clinical, histological, and immunologic signs of colitis in both models. NCX-456 inhibited the release of T-helper type 1-derived cytokines and increased the release of the regulatory T cell-derived cytokines interleukin 10 and transforming growth factor beta. In vitro analyses showed that NCX-456 inhibited proliferation and caused selective apoptosis of the subset of activated lamina propria T-helper type 1 cells, whereas it was ineffective for regulatory T-cell function and survival. CONCLUSIONS: Collectively, these data show that NCX-456 inhibits lamina propria T-helper type 1 function and stimulates the activity of interleukin 10- and transforming growth factor beta-secreting cells, thus restoring mucosal immune homeostasis and suppressing intestinal inflammation.

Aminosalicylic Acids↗

PubMed2005

Inhibition of hydrogen sulfide generation contributes to gastric injury caused by anti-inflammatory nonsteroidal drugs.

BACKGROUND & AIMS: Hydrogen sulfide (H(2)S), an endogenous gaseous mediator that causes vasodilation, is generated in mammalian tissues by cystathionine beta-synthase (CBS) and cystathionine-gamma-lyase (CSE). Here, we have investigated the role of H(2)S in a rodent model of nonsteroidal anti-inflammatory drug (NSAID) gastropathy. METHODS: Rats were given acetyl salycilic acid (ASA) or an NSAID alone or in combination with NaHS, an H(2)S donor, and killed 3 hours later. Gastric blood flow was measured by laser-Doppler flowmetry, whereas intravital microscopy was used to quantify adhesion of leukocytes to mesenteric postcapillary endothelium. RESULTS: At a dose of 100 micromol/kg, NaHS attenuated by 60%-70% the gastric mucosal injury, and tumor necrosis factor (TNF)-alpha, intercellular adhesion molecule (ICAM)-1, and lymphocyte function-associated antigen (LFA)-1 mRNA up-regulation induced by NSAIDs (P < .05) NaHS administration prevented the associated reduction of gastric mucosal blood flow (P < .05) and reduced ASA-induced leukocyte adherence in mesenteric venules. NaHS did not affect suppression of prostaglandin E(2) (PGE(2)) synthesis by NSAIDs. Glibenclamide, a K(ATP) channel inhibitor, and DL-propargylglycine, a CSE inhibitor, exacerbated, whereas pinacidil, a K(ATP) opener, attenuated gastric injury caused by ASA. Exposure to NSAIDs reduced H(2)S formation and CSE expression (mRNA and protein) and activity by 60%-70%. By promoter deletion and mutation analysis, an Sp1 consensus site was identified in the CSE promoter. Exposure to NSAIDs inhibits Sp1 binding to its promoter and abrogates CSE expression in HEK-293 cells transfected with a vector containing the core CSE promoter. Exposure to NSAIDs inhibits Sp1 and ERK phosphorylation. CONCLUSIONS: These data establish a physiologic role for H(2)S in regulating the gastric microcirculation and identify CSE as a novel target for ASA/NSAIDs.

Animals↗

PubMed2005

Botulinum toxin treatment of oesophageal achalasia in the old old and oldest old: a 1-year follow-up study.

BACKGROUND: Intrasphincteric injection of botulinum toxin (BTX) has become one of the most frequent therapeutic approaches for the treatment of oesophageal achalasia. This treatment seems particularly effective in elderly patients who are not candidates for more invasive procedures. AIMS: There are few or no data on BTX treatment of achalasia in the old old and oldest old. Therefore, we evaluated BTX treatment in a group of patients with achalasia in the extreme age range who were too ill or frail to undergo surgery or pneumatic dilatation. PATIENTS AND METHODS: Twelve elderly achalasic patients (age range 81-94 years, average age 86 years) with American Society of Anesthesiologists (ASA) class III-IV status were recruited for the study. After baseline clinical and instrumental evaluations, BTX 100U was injected at time 0 and 1 month later. Clinical follow-up was carried out after 3, 6 and 12 months. RESULTS: A significant improvement in symptom score was documented at each follow-up step. On the basis of improvements in scores, approximately 70% of patients were considered responders at the end of follow-up. CONCLUSIONS: BTX treatment is an effective treatment in a substantial proportion of achalasic patients >80 years of age, in whom benefits are still detectable after 12 months. BTX is a therapeutic option in patients unsuitable for surgery or pneumatic dilatation.

Aged↗