G. De Nucci

Chronic inhibition of nitric oxide synthesis. A new model of arterial hypertension.

Recent studies have indicated that acute inhibition of nitric oxide biosynthesis in the rat promotes arterial hypertension and renal vasoconstriction. We evaluated the renal and systemic effects of 4-6 weeks of nitric oxide blockade in Munich-Wistar rats receiving the nitric oxide inhibitor nitro-L-arginine orally. Age-matched untreated rats were used as controls. In an additional seven rats, nitric oxide blockade was carried out in conjunction with oral administration of the novel angiotensin II antagonist losartan potassium. Tail-cuff pressure rose progressively in nitro-L-arginine-treated rats, reaching 164 +/- 6 mm Hg at 4-6 weeks, compared with 108 +/- 3 mm Hg in controls. In rats concomitantly receiving losartan, tail-cuff pressure reached 125 +/- 6 mm Hg, still elevated compared with rats receiving losartan alone (98 +/- 3 mm Hg). Nitro-L-arginine-treated rats presented marked renal vasoconstriction and hypoperfusion, as well as a 30% fall in glomerular filtration rate and a 39% increase in filtration fraction. Treatment with Losartan normalized glomerular filtration rate, but not filtration fraction or renal vascular resistance. Plasma renin activity was elevated after nitro-L-arginine treatment. Renal histological examination revealed widespread arteriolar narrowing, focal arteriolar obliteration, and segmental fibrinoid necrosis in the glomeruli. In a separate group of rats, nitro-L-arginine administered for 1 week induced hypertension that was partially reversed by acute L-arginine, but not D-arginine or L-glycine, infusions. We conclude that chronic nitric oxide blockade may constitute a new model of severe arterial hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Expression of nitric oxide synthase isoforms and nitrotyrosine immunoreactivity by B-cell non-Hodgkin's lymphomas and multiple myeloma

Expression of nitric oxide synthase isoforms and nitrotyrosine immunoreactivity by B‐cell non‐Hodgkin’s lymphomas and multiple myeloma

Loss and Sprouting of Nitric Oxide Synthase Neurons in the Human Epileptic Hippocampus

Summary:  Purpose: Nitric oxide (NO) has been implicated in a variety of functions, including the control of synaptic plasticity and sensory signaling. Current evidence suggests that this unconventional neurotransmitter mediates N‐methyl‐d‐aspartate (NMDA) receptor–linked excitotoxicity. This study describes the expression of neuronal NO synthase (nNOS) immunoreactivity (IR) in hippocampi from patients with temporal lobe epilepsy (TLE).

Simultaneous determination of dextromethorphan, dextrorphan and doxylamine in human plasma by HPLC coupled to electrospray ionization tandem mass spectrometry: Application to a pharmacokinetic study

In the present study, a fast, sensitive and robust method to quantify dextromethorphan, dextrorphan and doxylamine in human plasma using deuterated internal standards (IS) is described. The analytes and the IS were extracted from plasma by a liquid-liquid extraction (LLE) using diethyl-ether/hexane (80/20, v/v). Extracted samples were analyzed by high performance liquid chromatography coupled to electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS). Chromatographic separation was performed by pumping the mobile phase (acetonitrile/water/formic acid (90/9/1, v/v/v) during 4.0min at a flow-rate of 1.5 mL min⁻¹ into a Phenomenex Gemini® C18, 5 μm analytical column (150 × 4.6 mm i.d.). The calibration curve was linear over the range from 0.2 to 200 ng mL⁻¹ for dextromethorphan and doxylamine and 0.05 to 10 ng mL⁻¹ for dextrorphan. The intra-batch precision and accuracy (%CV) of the method ranged from 2.5 to 9.5%, and 88.9 to 105.1%, respectively. Method inter-batch precision (%CV) and accuracy ranged from 6.7 to 10.3%, and 92.2 to 107.1%, respectively. The run-time was for 4 min. The analytical procedure herein described was used to assess the pharmacokinetics of dextromethorphan, dextrorphan and doxylamine in healthy volunteers after a single oral dose of a formulation containing 30 mg of dextromethorphan hydrobromide and 12.5mg of doxylamine succinate. The method has high sensitivity, specificity and allows high throughput analysis required for a pharmacokinetic study.

Prevalence peptic lesion in asymptomatic, healthy volunteers

Abstract Aim. To investigate the presence of lesions of the upper gastrointestinal tract of asymptomatic, healthy volunteers undergoing clinical pharmacology studies. Material and Methods. A series of 53 volunteers (45 male, 23 Helicobacter pylori negative and 30 Helicobacter pylori positive) underwent upper gastrointestinal endoscopy. Helicobacter pylori status was assessed using two methods (rapid urease test and histology) from antral and corpus biopsies. Results. Peptic lesions were found in 24 (45%) subjects: erosive oesophagitis, gastric/duodenal ulcers and gastric/duodenal erosions were found in 23%, 9% and 36% of these volunteers, respectively. Helicobacter plyori -positive subjects had significantly ( p Helicobacter pylori negative individuals ( 12 30 vs 3 23 ). The presence of peptic ulcers and erosive oesophagitis was similar in Helicobacter pylori -positive and -negative individuals. Conclusions. The possibility that peptic lesions might exist in otherwise asymptomatic, asymptomatic, healthy individuals cannot be ruled out. Helicobacter pylori -positive individuals have a significantly higher incidence of gastric and duodenal lesions than Helicobacter pylori negative subjects.

Acid suppression by omeprazole does not affect orally administered metronidazole bioavailability and metabolism in healthy male volunteers

The addition of omeprazole to classical triple therapy for eradication of H. pylori may enhance compliance through reducing ulcer symptoms and side‐effects. The aim of this study was to investigate the effects of a 5‐day administration of omeprazole on metronidazole pharmacokinetics.

Protective effects of exogenous and endogenous hydrogen sulfide in mast cell-mediated pruritus and cutaneous acute inflammation in mice

Graphical abstract Figure. No caption available. ABSTRACT The recently described ‘gasomediator’ hydrogen sulfide (H2S) has been involved in pain mechanisms, but its effect on pruritus, a sensory modality that similarly to pain acts as a protective mechanism, is poorly known and controversial. The effects of the slow‐releasing (GYY4137) and spontaneous H2S donors (Na2S and Lawessons reagent, LR) were evaluated in histamine and compound 48/80 (C48/80)‐dependent dorsal skin pruritus and inflammation in male BALB/c mice. Animals were intradermally (i.d.) injected with C48/80 (3 &mgr;g/site) or histamine (1 &mgr;mol/site) alone or co‐injected with Na2S, LR or GYY4137 (within the 0.3–100 nmol range). The involvement of endogenous H2S and KATP channel‐dependent mechanism were also evaluated. Pruritus was assessed by the number of scratching bouts, whilst skin inflammation was evaluated by the extravascular accumulation of intravenously injected 125I‐albumin (plasma extravasation) and myeloperoxidase (MPO) activity (neutrophil recruitment). Histamine or C48/80 significantly evoked itching behavior paralleled by plasma extravasation and increased MPO activity. Na2S and LR significantly ameliorated histamine or C48/80‐induced pruritus and inflammation, although these effects were less pronounced or absent with GYY4137. Inhibition of endogenous H2S synthesis increased both Tyrode and C48/80‐induced responses in the skin, whereas the blockade of KATP channels by glibenclamide did not. H2S‐releasing donors significantly attenuate C48/80‐induced mast cell degranulation either in vivo or in vitro. We provide first evidences that H2S donors confer protective effect against histamine‐mediated acute pruritus and cutaneous inflammation. These effects can be mediated, at least in part, by stabilizing mast cells, known to contain multiple mediators and to be primary initiators of allergic processes, thus making of H2S donors a potential alternative/complementary therapy for treating inflammatory allergic skin diseases and related pruritus.

Colo-rectal endoscopic full-thickness resection (EFTR) with the over-the-scope device (FTRD®): A multicenter Italian experience

BACKGROUND AND AIM Endoscopic full-thickness resection(EFTR) with FTRD® in colo-rectum may be useful for several indications.The aim was to assess its efficacy and safety. MATERIAL AND METHODS In this retrospective multicenter study 114 patients were screened; 110 (61M/49F, mean age 68 ± 11 years, range 20-90) underwent EFTR using FTRD®. Indications were:residual/recurrent adenoma (39), incomplete resection at histology (R1 resection) (26), non-lifting lesion (12), adenoma involving the appendix (2) or diverticulum (2), subepithelial lesions(10), suspected T1 carcinoma (16), diagnostic resection (3). Technical success (TS: lesion reached and resected), R0 resection (negative lateral and deep margins),EFTR rate(all layers documented in the specimen) and safety have been evaluated. RESULTS TS was achieved in 94.4% of cases. EFTR was achieved in 91% with lateral and deep R0 resection in 90% and 92%. Mean size of specimens was 20 mm (range 6-42). In residual/recurrent adenomas, final analysis revealed: low-risk T1 (11), adenoma with low-grade dysplasia (LGD) (24) and high-grade dysplasia (HGD) (3), scar tissue (1). Histology reports of R1 resections were: adenoma with LGD (6), with HGD (1), low-risk (6) and high-risk (1) T1, scar tissue (12). Non-lifting lesions were diagnosed as: adenoma with HGD (3), low-risk (7) and high risk (2) T1. Adverse clinical events occurred in 12 patients (11%),while adverse technical events in11%. Three-months follow-up was available in 100 cases and residual disease was evident in only seven patients. CONCLUSIONS EFTR using FTRD® seems to be a feasible, effective and safe technique for treating selected colo-rectal lesions. Comparative prospective studies are needed to confirm these promising results.

OC.07.5 HCV-ANTIVIRAL THERAPY DELAYS GASTRIC EMPTYING TIME AND MODIFIES CCK AND MOTILIN SERUM LEVELS

Background and aim: Digestive symptoms are common side effects of antiviral therapy in patients with HCV chronic hepatitis (CH). The occurrence of digestive symptoms significantly impairs quality of life and requires reduction or even suspension of the therapy in up to 15% of the cases. Recent advances in pathophisiology of functional dyspepsia indicate that delay of gastric emptying time (GET) likely depending on altered Cholecystokinin (CCK) and Motilin serum levels is implicated in the onset of symptoms. In this study we evaluated digestive symptoms, GET and CCK and motilin fasting and post-prandial serum levels in patients with HCV-related CH before, during and after standard antiviral therapy. Material and methods: Twenty-eight patients (M/F 11/17 male, age range 28-70 yrs) with histologically proven HCV-related CH and absence of digestive diseases were enrolled in the study. Baseline, during the therapy (3th month) and after a month by the end of therapy patients underwent: an oriented questionnaire evaluating digestive symptoms. 13C-octanoate breath test (13C-OBT) was performed to evaluate GET. Fasting and post-prandial CCK and Motilin serum levels were assessed ELISA. Antiviral therapy was performed according to standard protocols. Results: Baseline none of the patients complained of significant digestive symptoms. GET was normal (t/2 <120 min) in all cases but 3/28 (2%). Baseline and post-prandial CCK and Motilin levels were 0.6±0.4 and 1.57±0.5 and 5.9±5.2 and 1.7±0.9, respectively. At three-month therapy, epigastric burning, belching, epigastric pain, post-prandial fullness, early satiety, bloating, nausea and vomiting were reported by 31%, 57%, 7%, 60%, 57%, 53%, 46% and 14%, respectively. GET rate was significantly delayed in all cases (p <0.0001). CCK fasting and post-prandial serum levels significantly increased (p<0.0001) while Motilin decreased in respect to baseline values (p<0.003). Interestingly, there was a direct significant relation between GI symptom score, GET and CCK and Motilin serum level (p<0.05). After 1 month by the end of therapy, all patients were symptom-free and GET as well as CCK and Motilin serum levels returned to baseline values. Conclusions: Digestive symptoms caused by HCV-antiviral therapy depend on the delay of GET as well as deregulation of CCK/Motilin homeostasis.