Biomedical subjects

C Blandizzi

Publications and source records attributed to C Blandizzi.

At least 37 records · Page 2Linked to original sources

PubMed1998

Gastric mucosal distribution and clinical efficacy of azithromycin in patients with Helicobacter pylori related gastritis.

The gastric mucosal distribution of azithromycin, the prototype of a new class of macrolide antibiotics named azalides, was studied in patients with duodenal ulcer and Helicobacter pylori-related gastritis. The time course of ulcer healing, H. pylori infection, and gastritis activity was also evaluated. Twenty patients (median age 50 years) received the following treatment for 1 month: three cycles of azithromycin (500 mg/day for 3 consecutive days) on days 1-3, 11-13 and 21-23 plus omeprazole (40 mg/day) for 30 consecutive days. Endoscopic biopsy specimens of gastric mucosa and blood samples were collected on days 0, 4, 7, 10, 20 and 30. An additional follow-up endoscopy was carried out on day 60. H. pylori infection was determined by both histology and rapid urease test. Azithromycin concentrations in both plasma and gastric mucosa were measured by a microbiological plate assay, using Micrococcus luteus NCTC 8440 as the reference organism. Azithromycin concentrations in plasma ranged between 0.17 mg/L (95% CI: 0.08-0.26; n = 5) and 0.32 mg/L (95% CI: 0.21-0.43; n = 5) throughout the treatment period. In addition, azithromycin concentrations in gastric mucosa were significantly higher than plasma concentrations at all times examined and ranged from 18.5 mg/kg (95% CI: 15-20; n = 20) to 24.6 mg/kg (95% CI: 16.8-32.4; n = 5), Indicating that the drug was highly retained in the target tissue. Accordingly, the ratio of azithromycin mucosal level to plasma concentration varied between 77.9 (95% CI: 56.5-99.3; n = 5) and 112.7 (95% CI: 100.2-125.2; n = 5). At the end of treatment (day 30) H. pylori was no longer detected in 16 of 20 patients (80%), and this finding was consistent with a marked decrease in the grading of gastritis activity. At the follow-up endoscopy (day 60) the infection was eradicated in only four patients (20%). These data indicate a favourable distribution of azithromycin into gastric mucosa of patients with H. pylori infection and suggest that this new macrolide antibiotic represents a valuable option for treatment regimens against H. pylori. However, the low eradication rate achieved with azithromycin plus omeprazole is a source of concern and requires further investigation.

Adult↗

PubMed1997

Suramin enhances ethanol-induced injury to gastric mucosa in rats.

Suramin is currently used in clinical practice as antineoplastic agent because of its complex interaction with the biological activity of various growth factors involved in tumor progression. The influence exerted by suramin on gastric injury induced in rats by intraluminal injection of absolute ethanol was investigated in the present study. The morphometric analysis of gastric histological sections revealed that suramin, 18 mg/kg, administered intraperitoneally for 14 days every other day, caused a marked enhancement of ethanol-induced mucosal damage. This effect was more pronounced 1-8 hr following ethanol administration, and it was still significant after 48 hr. In suramin-treated animals the evaluation of Alcian blue recovery from gastric-bound mucus showed that the levels of adherent mucus were significantly lower than those detected in untreated rats. In addition, pretreatment with suramin did not modify basal acid secretion, but caused potentiation of acid output stimulated by pylorus ligation or electrical vagal stimulation. Overall, the present results indicate that suramin exerts a negative influence on both gastric protective and repairing mechanisms. Due to the peculiar pharmacodynamic profile of suramin, it is suggested that interference with endogenous growth factors, endowed with physiological protective activity on gastric mucosa, might account for the damage-enhancing action of this drug.

Animals↗

PubMed1997

Periodontal tissue disposition of azithromycin.

The tissue penetration of azithromycin, the prototype of a new class of macrolide antibiotics named azalides, was studied in patients undergoing surgery for third-molar removal. Drug concentrations in plasma, saliva, and periodontal tissues were evaluated in 28 patients treated with azithromycin 500 mg/day per os for 3 consecutive days. Samples of blood, saliva, gingiva, and alveolar bone were collected during oral surgery, 12 hours, and 2.5, 4.5, and 6.5 days after the last dosing, and the azithromycin concentration was measured microbiologically by using Micrococcus luteus NCTC 8440 as the reference organism. The highest concentrations of azithromycin were observed 12 hours after the last dose in plasma, saliva, gingiva, and bone (0.33 +/- 0.04 mg/l, 2.14 +/- 0.30 mg/l, 6.47 +/- 0.57 mg/kg, and 1.86 +/- 0.15 mg/kg, respectively) and then declined gradually. However, consistent levels of the drug in saliva and periodontal tissues could be detected up to 6.5 days, indicating that azithromycin was retained in target tissues and fluids for a long time after the end of treatment. Among the samples examined, the highest concentration of azithromycin was found in the gingiva at each time studied. Moreover, the ratios of salivary or periodontal tissue levels versus plasma concentrations remained nearly unmodified from 12 hours up to 6.5 days. Overall, these results indicate a favorable disposition of azithromycin into saliva and periodontal tissues and suggest that this macrolide antibiotic represents a valuable option in the pharmacologic treatment of odontogenic infections.

Adult↗

PubMed1997

Positive modulation of pepsinogen secretion by gastric acidity after vagal cholinergic stimulation.

Parallel increments of gastric acid and pepsinogen secretion generally occur after the application of cholinergic stimuli. However, it still remains to be established whether the changes in acid output associated with cholinergic stimulation play a role in regulation of the concomitant peptic secretory activity. In the present study, an anesthetized rat model was used for the evaluation of pepsinogen secretion in order to pursue a dual purpose: 1) to assess the relative functional relevance of direct and acid-dependent control exerted by cholinergic pathways on pepsinogen output; 2) to characterize the mechanisms through which changes in acidity within the stomach lumen may affect the peptic secretory activity of gastric mucosa. Bethanechol, 2-deoxy-D-glucose or electrical vagal stimulation caused parallel and atropine-sensitive increments of peptic and acid secretions. Omeprazole, a selective inhibitor of gastric H+:K+-adenosintriphosphatase, blocked the increase in acid but not pepsinogen secretion induced by bethanechol. However, 2-deoxy-D-glucose or electrical vagal stimulation failed to increase either pepsinogen or acid secretion in omeprazole-pretreated rats. When tested in animals pretreated with both omeprazole and physostigmine (a drug able to prevent the enzymatic breakdown of vagally released ACh through the blockade of acetylcholinesterase), 2-deoxy-D-glucose or electrical vagal stimulation significantly increased pepsinogen secretion without affecting acid secretion. In omeprazole-pretreated rats, perfusion of the gastric lumen with acid solutions caused a pH-dependent and atropine-sensitive increase in peptic output only when applied in combination with electrical vagal stimulation. Functional ablation of capsaicin-sensitive sensory neurons did not modify the gastric secretory responses induced by bethanechol or electrical vagal stimulation. However, after topical application of lidocaine to the gastric mucosal surface, bethanechol stimulated both peptic and acid outputs, whereas electrical vagal stimulation only evoked acid secretion without affecting basal peptic output. The present results indicate that the activation of muscarinic receptors by vagally released ACh is not sufficient by itself to stimulate pepsinogen secretion and that a facilitatory action mediated by acid secretion is necessary to allow an increment of peptic output in response to vagal cholinergic stimuli. It is suggested that such facilitatory input is driven to chief cells by local intramural reflexes that involve capsaicin-insensitive intrinsic nerves.

Animals↗

PubMed1996

Determination on functional basis of presynaptic alpha 2-adrenoceptor subtypes in guinea-pig duodenum.

The effects of several alpha 2-adrenoceptor agonists and antagonists were examined on the cholinergic twitch contractions evoked by electrical field stimulation of guinea-pig duodenum. Oxymetazoline, xylazine, noradrenaline, alpha-methyl-noradrenaline or medetomidine (0.01-30 microM) were nearly equieffective in inhibiting duodenal twitch responses. The effects of xylazine were competitively counteracted by antagonists tested (0.03-10 microM) with the following order of potency: RX 821002 = idazoxan > rauwolscine = yohimbine = BRL 44408 >> prazosin = ARC 239 = BRL 41992. According to the current classification, it is suggested that alpha 2-heteroadrenoceptors involved in the modulation of duodenal cholinergic neurotransmission belong to the alpha ZD subtype.

Adrenergic alpha-2 Receptor Agonists↗

PubMed1995

Role of peripheral GABAB receptors in the regulation of pepsinogen secretion in anaesthetized rats.

The purpose of the present study was to investigate the role played by GABAB receptors in the regulation of gastric basal pepsinogen secretion in anaesthetized rats. Following parenteral administration, the GABAB receptor agonists (-)-baclofen and 3-aminopropylphosphinic acid (3-APPA) caused a dose-dependent increase in basal pepsinogen secretion which was associated with a parallel increment in acid output. The gastric stimulant effects induced by both agonists were not affected by intracerebroventricular injection of the GABAB receptor antagonists 2-hydroxy-saclofen, 3-aminopropyl(diethoxymethyl)phosphinic acid (CGP 35348) or phaclofen, whereas the excitatory actions were antagonized by intravenously administered 2-hydroxy-saclofen or CGP 35348, but not phaclofen. In addition, the (-)-baclofen-induced increases in both pepsinogen and acid output, were fully prevented by omeprazole or cimetidine, partly reduced by atropine and unaffected by pretreatment with capsaicin. When tested on rats undergoing bilateral cervical vagotomy, both (-)-baclofen and 3-APPA were still able to stimulate the basal pepsinogen and acid secretions, although at a lesser extent than in animals with intact vagus nerves. The stimulant actions elicited by (-)-baclofen in vagotomized rats were antagonized by 2-hydroxy-saclofen or CGP 35348, but not phaclofen. Moreover, these gastric excitatory effects were prevented by cimetidine or compound 48/80, while being unaffected by atropine. The present results show that peripheral GABAB receptors mediate an excitatory effect on gastric pepsinogen secretion which totally depends on an increase in acid output. It is also suggested that both vagal cholinergic and extravagal pathways, probably histaminergic in nature, take part in these GABAB receptor-mediated gastric stimulant actions.

Anesthesia↗

PubMed1995

Central administration of cholecystokinin stimulates gastric pepsinogen secretion from anaesthetized rats.

Intracerebroventricular administration of CCK-8S was associated with a stimulation of gastric pepsinogen secretion from anaesthetized rats; similar effects were induced by CCK-8S given intravenously. The excitatory effect of intracerebroventricular CCK-8S was not modified by central injection of L-364,718 or L-365,260, whereas both these antagonists, given by intravenous route, prevented the pepsigogue action of parenteral CCK-8S. Intracerebroventricular or intravenous CCK-8S also increased basal acid secretion, this latter effect being prevented by parenteral L-365,260 but not L-364,718. It is suggested that centrally applied CCK-8S evokes pepsinogen secretion through the activation of peripheral CCK-A and CCK-B receptors.

Anesthesia↗

PubMed1995

Characterization of alpha 2-adrenoceptor subtypes involved in the modulation of gastric acid secretion.

The effects of several alpha 2-adrenoceptor agonists and antagonists were examined on gastric acid secretion from reserpinized rats undergoing electrical stimulation of the left vagus nerve. Both detomidine and oxymetazoline inhibited vagal acid hypersecretion, their effects being fully prevented by idazoxan, 7,8-(methylenedioxy)-14-alpha-hydroxyalloberbane (CH 38083), or 2-(2-methoxy-1,4-benzodioxan-2-yl)-2-imidazoline (RX 821002), and partly antagonized by yohimbine or rauwolscine. 2-(2,4-(O-methoxy-phenyl)-piperazin-1-yl)-ethyl-4,4-dimethyl-1,3-( 2H,4H)-isoquinolindione (ARC 239) did not affect the antisecretory action of the two agonists, while prazosin at the highest dose was partly effective only against detomidine. Atropine markedly reduced vagally evoked acid output. It is suggested that acid secretion induced by vagal cholinergic stimulation is modulated by alpha 2A-like adrenoceptor subtypes.

Adrenergic alpha-2 Receptor Agonists↗

PubMed1995

Central GABA-A receptors exert a tonic inhibitory control on gastric pepsinogen secretion in anaesthetized rats.

1. The purpose of the present study was to analyse the role played by central gamma-aminobutyric acid (GABA-A) receptors in the regulation of gastric basal pepsinogen secretion in anaesthetized rats. 2. The central, but not parenteral, administration of the GABA-A receptor antagonist bicuculline or SR-95531 caused a significant and dose-dependent increase in basal pepsinogen secretion without changes in acid output. The stimulant effect exerted by bicuculline was prevented by atropine or pirenzepine, but not by vagotomy. 3. The central, but not parenteral, administration of the GABA-A receptor agonist muscimol or THIP induced a significant and dose-dependent stimulation of both basal pepsinogen and acid secretion. The excitatory effect exerted by muscimol was prevented by atropine, pirenzepine, or pretreatment with omeprazole, but not by vagotomy. 4. These results suggest that central GABA-A receptors mediate a tonic inhibitory control on gastric pepsinogen secretion, while their phasic activation leads to an excitatory effect on acid output. However, the agonist-induced pepsigogue action appears to be generated peripherally as an indirect consequence of the increase in acid secretion. 5. It is also suggested that central GABA-A receptors affect the gastric secretory functions through non-vagal pathways that are sensitive to the blockade of peripheral cholinergic receptors.

Anesthesia↗

PubMed1995

Mechanisms of protection by omeprazole against experimental gastric mucosal damage in rats.

In the present study, the protective effect of omeprazole on gastric mucosa injury induced by ethanol.HCl in rats and the putative mechanisms involved in this action were investigated. Misoprostol and ranitidine were used as reference drugs. The morphometric analysis of histological sections showed that omeprazole caused a significant reduction of mucosal necrotic damage, this effect being associated with a marked increase in Alcian blue recovery from gastric bound mucus. In addition, omeprazole elicited a significant inhibition of gastric acid secretion from pylorus-ligated rats. Misoprostol exerted similar effects to those obtained with omeprazole, even if the Alcian blue recovery and the acid output were affected to a lesser extent. By contrast, ranitidine failed to influence both the mucosal damage and the Alcian blue recovery, while it exerted a marked inhibition on acid secretion. The present results indicate that omeprazole is effective in protecting gastric mucosa from necrotic damage induced by ethanol.HCl and suggest that an enhancement of gastric mucus barrier may account for this protective action.

Animals↗

PubMed1994

Molecular cloning and structural analysis of the rabbit gastrin/CCKB receptor gene.

Gastrin and cholecystokinin exert a variety of physiological actions in the central nervous system and digestive tract that are mediated through one or more receptors exhibiting similar affinity for the two peptides. We isolated genomic clones encoding the rabbit gastrin/CCKB receptor by screening a rabbit EMBL phage library with a cDNA probe based on the nucleotide sequence of the human gastrin/CCKB receptor. The gene contained a putative 1356-bp open reading frame consisting of five exons interrupted by 4 introns and encoded a protein of 452 amino acids. The putative protein-coding region of the gene exhibits 93 to 97% amino acid similarity with corresponding cDNAs previously identified in human, canine and rodent brain or gastric tissues.

Alternative Splicing↗

PubMed1994

Functional evidence that alpha 2A-adrenoceptors are responsible for antilipolysis in human abdominal fat cells.

The effects of alpha 2-adrenoceptor agonists (dexmedetomidine, oxymetazoline), alone or in combination with various alpha-adrenoceptor subtype-selective antagonists (CH-38083, idazoxan, WB4101, BRL44408, ARC-239, prazosin), on noradrenaline- and isoprenaline-induced lipolysis were investigated in human isolated abdominal subcutaneous fat cells. The rank order of potency of antagonists in preventing dexmedetomidine- and oxymetazoline-evoked suppression of isoprenaline-induced lipolysis was (pA2-values): CH-38083 (7.69 and 7.48) congruent to idazoxan (7.5 and 7.41) > BRL44408 (7.23 and 7.19) congruent to WB4101 (7.13 and 7.12) > prazosin (5.18 and 5.17) > ARC-239 (4.72, 4.9). While CH-38083 and idazoxan, non-subtype selective alpha 2-adrenoceptor antagonists and BRL44408, a selective alpha 2A-adrenoceptor antagonist as well as WB4101 potentiated the lipolytic effect of noradrenaline, ARC-239, the selective alpha 2B-adrenoceptor antagonist failed to affect it. In addition since the alpha 2A-adrenoceptor selective agonist, oxymetazoline concentration dependently inhibited the lipolytic effect of isoprenaline, and WB4101 and BRL44408 (alpha 2A-adrenoceptor antagonists) antagonised the effect of oxymetazoline in a competitive manner, it is concluded that the alpha 2A-adrenoceptor subtype is involved in antilipolysis. In addition, functional evidence was obtained that there is an interaction between alpha 2A- and beta-adrenoceptors located on the cell surface of adipocytes, through which locally released noradrenaline and/or circulating circulating adrenaline influence lipolysis.

Abdomen↗

PubMed1994

Protective action of omeprazole against gastric mucosal injury induced by hemorrhagic shock in rats.

The efficacy of omeprazole in preventing gastric mucosal injury induced by hemorrhagic shock in rats and the putative mechanisms involved in this effect were investigated in the present study. Omeprazole did not affect mean arterial blood pressure under both basal conditions and induction of hemorrhagic shock, but it evoked a marked increase in Alcian blue recovery from gastric preepithelial mucus. The morphometric analysis of histological sections revealed that omeprazole caused a significant reduction of hemorrhagic shock-induced damage of gastric mucosa. Ranitidine, used as the reference drug, failed to affect mean arterial blood pressure, Alcian blue recovery from gastric mucus, or hemorrhagic shock-induced damage of gastric mucosa. Both omeprazole and ranitidine exerted a significant inhibition of gastric acid output from anesthetized pylorus-ligated rats. Overall, the present results indicate that omeprazole is effective in protecting gastric mucosa from necrotic damage induced by hemorrhagic shock and suggest that an enhancement of gastric mucus secretion contributes to this protective action.

Animals↗

PubMed1994

Regulation of gastrin release in the dog by alpha 2-adrenoceptors.

1. The purpose of the present study was to analyse the effects of the alpha 2-adrenoceptor agonist medetomidine and the antagonist yohimbine on gastrin release in conscious dogs. 2. Gastrin secretion was investigated under both basal conditions and stimulation by 2-deoxy-D-glucose, food or bombesin. 3. Basal gastrin under fasting conditions was significantly reduced by medetomidine and increased by yohimbine. 4. 2-deoxy-D-glucose-induced gastrin increase was fully inhibited by medetomidine; this effect was antagonized by yohimbine. 5. Medetomidine significantly inhibited food-induced increase in plasma gastrin; under these conditions yohimbine was without effect per se, but significantly antagonized the inhibitory action of medetomidine. 6. Gastrin release induced by bombesin was not affected by medetomidine or yohimbine. 7. These results suggest that alpha 2-adrenoceptors play an inhibitory role under conditions in which gastrin release is mainly mediated through cholinergic and non-cholinergic nervous pathways; in contrast, they do not indicate the presence of alpha 2-adrenoceptors on G cells of the dog stomach.

Adrenergic alpha-Agonists↗

PubMed1993

Macrolide antibiotics as antiinflammatory agents: roxithromycin in an unexpected role.

The antiinflammatory activity of a new 14-membered macrolide antibiotic, roxithromycin, was evaluated in various rat models including carrageenan- and poly-L-arginine-induced hind-paw oedema, croton oil inflamed ear assay and polyester sponge granuloma. When administered orally to animals, roxithromycin displayed an atypical profile in the assays utilized, including: (1) marked antioedema activity similar to that of indomethacin in poly-L-arginine assay, (2) significant inhibition of lambda-carrageenan hind-paw oedema and croton-oil-induced inflammation in the ear, although indomethacin was more effective, and (3) failure to reduce the development of granuloma induced by implanted polyester sponges, while indomethacin significantly reduced the chronic inflammatory reaction. Based on these results, it is concluded that roxithromycin is active in reducing the acute inflammatory reaction in rat models through mechanisms different from conventional nonsteroidal antiinflammatory agents such as indomethacin. Therefore, roxithromycin may have a favorable impact on skin inflammatory reactions accompanying microbial infections.

Analysis of Variance↗

PubMed1993

Inhibitory cholinergic effects of esaprazole on gastric secretion and plasma gastrin levels in the dog.

The effects of esaprazole, a novel antiulcer drug, on gastric acid secretion and plasma gastrin levels were investigated in dogs provided with a gastric fistula or Heidenhain pouch. Esaprazole affected in a different extent the tests performed on dogs with a gastric fistula. The greatest inhibitory effect was obtained against 2-deoxy-D-glucose-induced acid output and gastrin release. An intermediate inhibition by esaprazole was detected on bethanechol-evoked secretion, and the lowest activity was found versus histamine-stimulated secretion. All these responses were strongly inhibited by the antimuscarinic drug pirenzepine used as reference drug. Moreover, both esaprazole and pirenzepine prevented the acid secretory response to a test meal in dogs with a Heidenhain pouch, without significantly affecting plasma gastrin levels. The present results suggest that the depressant action of esaprazole on gastric secretion depends on its peripheral anticholinergic activity, consisting of a partial blockade of acid output and a main reduction of vagally mediated gastrin release. On the basis of these findings, the antiulcer activity of esaprazole might be in part ascribed to its inhibitory effects on gastric secretion.

Animals↗

PubMed1993

Functional evidence that [3H]acetylcholine and [3H]noradrenaline release from guinea pig ileal myenteric plexus and noradrenergic terminals is modulated by different presynaptic alpha-2 adrenoceptor subtypes.

The effects of a series of alpha-2 adrenoceptor agonists and antagonists were examined on the stimulation-evoked release of tritium from a myenteric plexus-longitudinal muscle preparation of guinea pig ileum preincubated with [3H]choline or [3H]noradrenaline. Oxymetazoline, xylazine, detomidine and alpha-methylnoradrenaline caused a significant and concentration-dependent inhibition of the stimulation-evoked release of [3H]acetylcholine, with calculated IC50 values of 1.22 microM, 0.88 microM, 0.93 microM and 0.83 microM, respectively. Idazoxan (1 microM), CH 38083 (1 microM), WB 4101 (1 microM), prazosin (1-10 microM) and ARC 239 (1-10 microM) did not significantly affect the evoked release of [3H]acetylcholine. However, idazoxan, CH 38083 and WB 4101 antagonized the inhibitory effect of all agonists tested on [3H]acetylcholine release with calculated KB values in the nanomolar range, whereas prazosin and ARC 239 were ineffective. After incubation of ileum strips with [3H]noradrenaline, the stimulation-evoked release of tritium was significantly inhibited by oxymetazoline (0.1-1000 microM), xylazine (0.1-100 microM), detomidine (0.1-100 microM) or alpha-methyl-noradrenaline (0.1-100 microM), whereas it was enhanced by idazoxan (0.1-100 microM), CH 38083 (0.1-100 microM), WB 4101 (0.1-100 microM), prazosin (0.1 microM) and ARC 239 (0.1-100 microM). The order of potency found for these drugs in affecting the evoked release of [3H]noradrenaline was: xylazine > or = detomidine > alpha-methyl-noradrenaline >> oxymetazoline for agonists and ARC 239 > or = idazoxan > CH 38083 > WB 4101 for antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗

PubMed1992

Peripheral 2-hydroxy-saclofen-sensitive GABA-B receptors mediate both vagal-dependent and vagal-independent acid secretory responses in rats.

1. The present study investigates the effects of peripherally administered baclofen on gastric acid secretion from the perfused stomach of anaesthetized rats. 2. Intravenous (i.v.) baclofen caused a marked dose-dependent increase in acid secretion which was antagonized by i.v. 2-hydroxy-saclofen, whereas intracerebroventricular (i.c.v.) 2-hydroxy-saclofen and i.c.v. or i.v. phaclofen and bicuculline were ineffective. In addition, 2-hydroxy-saclofen did not affect acid hypersecretion stimulated by histamine. 3. The secretagogue action of baclofen was fully prevented by cimetidine, but only partially attenuated by atropine, proglumide or bilateral cervical vagotomy. Moreover, the vagotomy-resistant excitatory effect of baclofen was abolished by 2-hydroxy-saclofen or cimetidine, but not by atropine or proglumide. 4. In vagotomized rats whose gastric secretion was maximally increased by electrical stimulation of the left vagus nerve, i.v. injection of baclofen further potentiated acid output, this action being prevented by cimetidine. 5. Taken together, the present results provide evidence that peripheral GABA-B receptors mediate the gastric hypersecretory effect of parenterally administered baclofen to anaesthetized rats, and suggest that both vagal cholinergic and extravagal pathways are involved in the stimulant effect.

Animals↗