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Biomedical subjects

S Evangelista

Publications and source records attributed to S Evangelista.

At least 19 recordsLinked to original sources
PubMed2001

Cardioprotective effects of zofenopril, a new angiotensin-converting enzyme inhibitor, on doxorubicin-induced cardiotoxicity in the rat.

We have studied the effect of zofenopril, a new angiotensin-converting enzyme inhibitor in preventing cardiac injury induced by chronic doxorubicin treatment in rats. Cardiac function was assessed by measuring changes in electrocardiogram (ECG) tracings, haemodynamics and cardiac responses in vivo to isoprenaline, 4 weeks after suspension of doxorubicin treatment, in vehicle-treated rats and in animals receiving zofenopril (15 mg/kg/os/day) alone, doxorubicin (1.5 mg/kg i.v. once a week for 5 weeks) or zofenopril+doxorubicin treatment. Doxorubicin induced a significant lengthening of the QalphaT interval, which was completely prevented by zofenopril treatment. The cardiac positive inotropic effect induced by i.v. isoprenaline was selectively depressed by doxorubicin (no changes in chronotropic responses) and this adverse effect of doxorubicin was also prevented in zofenopril+doxorubicin pretreated rats. Doxorubicin induced a significant increase in relative heart weight, which was likewise prevented in zofenopril+doxorubicin treated rats. In separate experiments, zofenopril did not interfere with the antitumor activity of doxorubicin (inhibition of tumor growth in nude mice xenografted with A2780 human tumor line). In conclusion, the oral administration of zofenopril is able to significantly ameliorate, up to 4 weeks after the end of doxorubicin administration, doxorubicin-induced cardiotoxicity without affecting the antitumor activity of this anthracycline.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2001

Pro- and anti-inflammatory actions of ricinoleic acid: similarities and differences with capsaicin.

We have investigated the pro- and anti-inflammatory effects of ricinoleic acid (RA), the main active principle of castor oil, in an experimental model of blepharitis induced by intradermal injection of carrageenan in the guinea-pig eyelid and its possible capsaicin-like mode of action on acutely dissociated rat dorsal root ganglia (DRG) neurons in vitro. Topical treatment with RA (10-100 mg/guinea-pig) or capsaicin (1-10 mg/guinea-pig) caused eyelid reddening and oedema. At lower doses (0.3-3 mg/guinea-pig and 0.009-0.09 mg/guinea-pig for RA and capsaicin, respectively) both drugs significantly potentiated the eyelid oedema induced by carrageenan. The tachykinin NK1 receptor antagonist FK 888 (0.59 mg/kg s.c.) abolished the potentiation of carrageenan-induced eyelid oedema induced by either RA or capsaicin. The neutral endopeptidase inhibitor, thiorphan (1.3 mg/kg i.v.) significantly enhanced the potentiation of carrageenan-induced eyelid oedema produced by RA. This potentiating effect was abolished by FK 888. Repeated (8 days) topical application of RA (0.9 mg/guinea-pig) or capsaicin (0.09 mg/guinea-pig) inhibited the carrageenan-induced eyelid oedema. This anti-inflammatory effect was accompanied by a reduction (75%-80% of SP and 46%-51% of NKA) in tachykinin content of the eyelids, as determined by radioimmunoassay. In dissociated rat DRG neurons, RA (0.1 mM for 5 min) significantly inhibited the inward currents induced by application of capsaicin (1 microM) and/or low pH (5.8), without inducing any currents by itself or changing voltage-dependent currents. Moreover, after 24-h incubation, RA (0.1 mM) significantly decreased the capsaicin (1 microM)-induced calcitonin gene-related peptide (CGRP) release from rat DRG neurons, whereas acute drug superfusion did not evoke CGRP release by itself. Summarizing, RA possesses capsaicin-like dual pro-inflammatory and anti-inflammatory properties which are observed upon acute and repeated application, respectively. However, unlike capsaicin, RA does not induce inward current in DRG neurons and it is devoid of algesic properties in vivo.

Animals↗
PubMed2001

Involvement of tachykinins in intestinal inflammation.

The tachykinins, substance P, neurokinin A and neurokinin B are small peptides expressed in the extrinsic primary afferent nerve fibers and enteric neurons of the gut. Tachykinins exert a variety of biological actions mediated by three distinct receptors, termed NK1, NK2 and NK3, and at the gastrointestinal level these peptides influence motility, electrolyte and fluid secretion and tissue homeostasis. Several intestinal disorders are associated with changes in the expression of the tachykinin system. Thanks to biological studies and receptor cloning, new selective tachykinins antagonists are now available and have been shown to be active in experimental gut disorders. Some of them are now under clinical trial in inflammatory bowel diseases and the irritable bowel syndrome. The body of preclinical data so far available seems to indicate that tachykinin antagonists might be a new therapeutic tool in the treatment of gut disorders.

Animals↗
PubMed2001

Eziopitant. Pfizer.

Pfizer is developing ezlopitant, a neurokinin-1 antagonist, for the potential treatment of irritable bowel syndrome (IBS). The compound had undergone phase II trials in the US and Europe, and phase I in Japan for treatment of chemotherapy-induced emesis [290988], [320737], [329187]. A phase II, double-blind, randomized study was performed to assess the safety and efficacy of ezlopitant for the control of cisplatin-induced emesis. Treatment was well tolerated [290988]. Although the compound effectively controls emesis, it is less effective in controlling nausea, and development has been discontinued for the emesis indication [347367]. Ezlopitant has undergone a pilot study in 14 IBS patients [367631].

Animals↗
PubMed2000

Antinociceptive activity of ricinoleic acid, a capsaicin-like compound devoid of pungent properties.

The antinociceptive effect of ricinoleic acid ([R-(Z)]-12-hydroxy-9-octadecenoic acid) in comparison with capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) has been investigated in several "in vivo" tests. Acute topical application of capsaicin, but not ricinoleic acid, produced by itself an hyperalgesic effect detected as a decrease in paw withdrawal latency in response to a painful (heat) stimulus in mice. Capsaicin, but not ricinoleic acid at any dose tested, showed an irritant effect in the wiping test in guinea pig conjunctiva after local application and in the paw licking test in mice after intradermal injection. Whereas acute application of ricinoleic acid or capsaicin decreased paw withdrawal latency to heat in the presence of a pre-existing inflammation (injection of carrageenan in the mouse paw), the repeated local treatment for 8 days with either compounds markedly increased paw withdrawal latency. In a chronic model of inflammation (complete Freund's adjuvant arthritis in mice), the repeated topical and intradermal treatments with both ricinoleic acid and capsaicin increased paw withdrawal latency to heat, the antinociceptive effect of ricinoleic acid being more persistent than that of capsaicin. Antinociceptive effect of 8 days of treatment with ricinoleic acid and capsaicin was observed in acetic acid-induced writhing in mice, capsaicin-induced foot licking in mice and capsaicin-induced wiping movements in guinea pig conjunctiva. A decrease of substance P tissue levels in the mouse paw was found after repeated treatment with ricinoleic acid. In conclusion, ricinoleic acid seems to be a new antinociceptive agent lacking the pungent and acute hyperalgesic properties of capsaicin.

Administration, Topical↗
PubMed2000

Protective effect of the tachykinin NK2 receptor antagonist nepadutant in acute rectocolitis induced by diluted acetic acid in guinea-pigs.

We have evaluated the potential protective activity of nepadutant, a selective tachykinin NK2 receptor antagonist, in a model of acute rectocolitis induced by an enema with 7.5% acetic acid in guinea-pigs. The injury was quantified visually by using a macroscopic injury score, and histologically by using a necrosis score. In addition, changes in myeloperoxidase activity, a marker for neutrophil infiltration, and plasma protein extravasation were evaluated. The injury caused by 7.5% acetic acid was mild, affecting the superficial layers and producing a strong edema of the submucosa. A single administration of nepadutant (0.3-10 mg/kg s.c., 1 h before acetic acid) markedly reduced the macroscopic damage and necrosis score and the increase in plasma protein extravasation induced by 7.5% acetic acid in the early phase of the injury. Single administration of nepadutant (3 mg/kg s.c.) reduced the macroscopic score and myeloperoxidase activity at the top (24 h) of inflammation. Repeated administration (3 mg/kg s.c. three times during 24 h) or co-administration of the tachykinin NK1 receptor antagonist MEN 11467 (3 mg/kg s.c.) did not enhance the antiulcer effect obtained with the single treatment with nepadutant. These data suggest the involvement of tachykinin NK2 receptors in the first phases of inflammation induced by acetic acid.

Acetic Acid↗
PubMed2000

Effect of ricinoleic acid in acute and subchronic experimental models of inflammation.

Observational studies indicate that topical application of ricinoleic acid (RA), the main component of castor oil, exerts remarkable analgesic and anti-inflammatory effects. Pharmacological characterization has shown similarities between the effects of RA and those of capsaicin, suggesting a potential interaction of this drug on sensory neuropeptide-mediated neurogenic inflammation. The aim of this study was to assess RA anti-inflammatory activities in comparison with capsaicin in several models of acute and subchronic inflammation. The acute inflammation was induced by intradermal injection of carrageenan in the mouse or by histamine in the guinea-pig eyelid. In either experiment, the extent of the oedema thickness was measured. Subchronic oedema was induced by complete Freund's adjuvant injection in the ventral right paw of mice. Tissue substance P (SP) was measured in the carrageenan experiments by radioimmunoassay (RIA). It was found that the acute topical application of RA (0.9 mg/mouse) or capsaicin (0.09 mg/mouse) significantly increased the mouse paw oedema induced by carrageenan, while an 8-day repeated topical treatment with the same doses of both compounds resulted in a marked inhibition of carrageenan-induced paw oedema matched by a reduction in SP tissue levels. Similar effects were found against histamine-induced eyelid oedema in guinea-pigs after acute or repeated application of RA or capsaicin. RA and capsaicin given for 1-3 weeks reduced the established oedema induced by Freund's adjuvant, a subchronic model of inflammation, particularly if given by the intradermal route. Either in mouse paw or in guinea-pig eyelid, capsaicin but not RA by itself produced a slight hyperemia and activation of a behavioural response (e.g. scratching of the eyelids). On the basis of the present results, RA may be seen as a new capsaicin-like, non-pungent anti-inflammatory agent suitable for peripheral application.

Acute Disease↗
PubMed2000

A distribution study with (14)C-otilonium bromide in the rat: evidence for selective tropism for large intestine after oral administration.

The aim of this study was to determine the plasma levels and the tissue distribution of otilonium bromide, measured as total radioactivity, after oral administration of 2 mg/kg of (14)C-labeled drug to rats. Radioactivity levels were very low in the plasma (ranging from 2.7 ng Eq/ml at 1.5 h to 0.6 ng Eq/ml at 24 h) as compared with those found in the gastrointestinal (GI) tract, indicating negligible systemic otilonium bromide absorption. Results from both quantitative radioluminography of whole body tissue distribution and radioassay of dissected parts of the GI tract carried out with liquid scintillation counting clearly demonstrate the presence of radioactive compounds in the walls of the GI tract at all sacrifice times. In the other tissues and organs examined, radioactivity was only found in trace amounts in the liver. The presence of radioactivity in the GI walls reflected the transit kinetics of drug-enriched contents. The radioactivity in large intestine walls was measurable at otilonium bromide concentrations in the range of micromole equivalents/kg, from 4 to 8 h after drug administration. Total body radioactivity recovery was 95, 101, 24, and 9% at 1.5, 4, 8, and 24 h, respectively. In conclusion, orally administered (14)C-otilonium bromide is poorly absorbed systemically, as indicated by the very low plasma radioactivity levels, but it is able to effectively penetrate into the large intestine walls, a recognized target for drugs oriented toward irritable bowel syndrome therapy.

Administration, Oral↗
PubMed1999

Effect of MEN 11467, a new tachykinin NK1 receptor antagonist, in acute rectocolitis induced by acetic acid in guinea-pigs.

The aim of this study was to evaluate the effect of MEN 11467 (1R,2S)-2-N[1(H)indol-3-yl-carbonyl]-1-N{N-(p-tolylacetyl)-N-(meth yl)-D-3(2-Naphthyl)alanyl}diaminocyclohexane), a new potent tachykinin NK1 receptor antagonist, in an experimental model of acute rectocolitis induced by an enema with 7.5% acetic acid in guinea-pigs. This effect was compared to that of mesalazine (5-amino-2-hydroxybenzoic acid). The injury was quantified visually by using a macroscopic injury score and histologically by using a necrosis score. In addition, changes in myeloperoxidase activity, a marker for neutrophil infiltration, and plasma protein extravasation were evaluated. The injury caused by 7.5% acetic acid was mild, affecting the superficial layers and producing a strong edema of the submucosa. A single administration of MEN 11467 (0.3-10 mg/kg s.c., I h before acetic acid) reduced the macroscopic damage and necrosis score and the increase in plasma protein extravasation induced by 7.5% acetic acid in the early acute phase of the injury (death at 2.5 h). Mesalazine (100 mg/kg p.o., 1 h before) reduced the macroscopic score but not the plasma protein extravasation. Repeated administration of MEN 11467 (1-3 mg/kg s.c., -1, +6 and +23 h after 7.5% acetic acid) reduced the macroscopic score and myeloperoxidase activity but not the plasma protein extravasation induced in the late phase of acute injury (death at 24 h). At this time mesalazine markedly reduced the macroscopic score, myeloperoxidase activity and plasma protein extravasation induced by 7.5% acetic acid. These results suggest a greater involvement of tachykinin NK1 receptors in the early phase than in the late phase of colonic inflammation in response to chemical injury.

Acetic Acid↗
PubMed1998

Receptor binding profile of Otilonium bromide.

The interaction of Otilonium bromide (OB) with binding sites for 63 different receptors and ion channels in appropriate preparations has been investigated. Experiments were also performed in rat colon, the preferred tissue for OB 'in vivo' uptake after oral administration. Among the receptors investigated OB binds with sub microM affinity to muscarinic M1, M2, M4, M5 and PAF receptors and with microM affinity to the diltiazem binding site on L type Ca2+ channels. In the rat colon OB shows competitive interaction with the verapamil binding site on L type Ca2+ channels and with muscarinic M2 receptors with IC50 of 1020 and 1220 nM, respectively. These findings provide a molecular rationale to explain the spasmolytic action exerted by OB on intestinal smooth muscle. In particular, a combination of antimuscarinic and Ca2+ channel blocker properties seems to best account for the action of this compound.

Animals↗
PubMed1998

Antihistaminic and antiallergic properties of dextro-mequitamium iodide in upper and lower guinea pig airways: comparison with azelastine.

1. The ability of dextro-mequitamium iodide (d-Meq) to antagonize bronchomotor and inflammatory effects mediated by histamine and antigen challenge in the upper or lower guinea pig airways or both and its potential activity against the recruitment and activation of eosinophils in the bronchial wall have been evaluated in comparison with azelastine. 2. In receptor-binding studies, d-Meq displayed a nanomolar affinity for H1 and muscarinic receptors, and it was endowed with potent bronchodilating properties in the nanomolar range toward tonic contractions induced by histamine and carbachol. 3. d-Meq (100-1,000 nmol/guinea pig) and azelastine (100-5,000 nmol/guinea pig) administered by aerosol significantly inhibited histamine- and antigen-induced increases in insufflation pressure in sensitized animals. 4. d-Meq (1,000-6,000 nmol/kg i.v.) dose dependently inhibited the histamine- or antigen-induced increase in vascular permeability in the upper airways. 5. d-Meq was more effective against histamine than antigen challenge, and its potency was similar or greater than that of azelastine. 6. Aerosolized d-Meq (1,000 nmol/animal) reduced antigen-induced eosinophil accumulation in the bronchoalveolar lavage (BAL) fluid from sensitized guinea pigs. 7. Eosinophils recovered from the BAL fluid of antigen-challenged animals showed an increased chemotaxis in response to LTB4 or platelet-activating factor. Both d-Meq and azelastine (300 nmol/animal) reduced this increase without affecting direct chemotaxis induced by leukotriene B4 (LTB4). 8. These findings provide evidence that local administration of d-Meq might be useful in the treatment of allergic disorders, such as rhinitis and asthma.

Animals↗
PubMed1998

Endotoxin-mediated intestinal damage: protective effect of capsaicin in the rat.

BACKGROUND: Endotoxin provokes the disruption of intestinal mucosal architecture. To investigate whether afferent fibers of the enteric nervous system are involved in this damage, we have used capsaicin to induce a selective, long-lasting degeneration of these fibers in the rat. METHODS: The rats were divided in two groups, receiving subcutaneously either capsaicin or its vehicle. After 10 days the rats from each group were injected with nonlethal doses of endotoxin or with saline. The next day all the animals were killed, and the jejunum and ascending colon were collected for light and scanning electron microscopy analysis; morphometric analysis of jejunal villus height was also performed. RESULTS: The rats receiving endotoxin but not pretreated with capsaicin had severe morphologic alterations and a significant reduction in villus height. In contrast, the rats pretreated with capsaicin and then with endotoxin showed a preserved mucosa with normal mean villus height. CONCLUSIONS: Capsaicin pretreatment is able to prevent endotoxin-induced damage of intestinal mucosa; this result seems to indicate that afferent fibers of the enteric nervous system are involved in the pathogenesis of this damage.

Animals↗
PubMed1997

A protective role for calcitonin gene-related peptide in water-immersion stress-induced gastric ulcers in rats.

This study investigated the role of endogenous and exogenous calcitonin gene-related peptide (CGRP) in water immersion stress (WIS)-induced gastric ulcers in rats. WIS produced gastric ulcers which were inversely correlated to the decrease in CGRP-like immunoreactivity observed in the whole thickness of the corpus stomach but not in its mucosal layers. Systemic administration of CGRP (100 micrograms kg-1 s.c.) produced a significant decrease in lesion index of WIS-ulcers and this protection was inhibited by functional ablation of afferent neurons induced by capsaicin pretreatment (100 mg kg-1 s.c. in two days, a week before the experiments). These findings suggest that sensory endogenous CGRP plays a defensive role in WIS-ulcers.

Animals↗
PubMed1997

Involvement of tachykinin NK1 receptors in plasma protein extravasation induced by tachykinins in the guinea pig upper airways.

Plasma protein extravasation in the upper airways of anesthetized guinea pigs was measured with the FITC (Fluorescein isothiocyanate)-dextran technique. The effect of selective tachykinin (NK1 and NK2) receptor agonists and antagonists, capsaicin or antigen was studied. The tachykinin NK1 receptor agonist, [Sar9]substance P sulfone, induced an increase in FITC-dextran extravasation which was blocked by the nasal application (30-100 nmol/kg) of the tachykinin NK1 receptor antagonist FK888, but not by 1 micromol/kg of the tachykinin NK2 receptor antagonist, MEN10,627. The tachykinin NK2 receptor agonist, [betaAla8]neurokinin A-(4-10), had no effect on dye leakage. FK888 (30 nmol/kg intranasal) abolished the increase in the tracer recovery induced both by antigen and capsaicin. Conversely, the intranasal administration of MEN10,627 (0.1-1.0 micromol/kg) significantly reduced capsaicin-induced and only marginally inhibited antigen-induced increase in plasma protein extravasation. Pretreatment with the neutral endopeptidase inhibitor, phosphoramidon, increased the effect of all inflammatory agents. These findings show that the plasma extravasation of the upper airways induced by exogenous or endogenous tachykinins is primarily mediated by tachykinin NK1 receptors. This inflammatory response could be controlled by locally applied tachykinin NK1 receptor antagonist.

Animals↗
PubMed1997

Central and peripheral antiulcer and antisecretory effects of Ala5NKA(4-10), a tachykinin NK2 receptor agonist, in rats.

Analogs of NKA(4-10) which are selective tachykinin NK2 receptor agonists have been tested as anti-secretory and anti-ulcer agents in 2-h pylorus ligation in rats. Peripheral (500 micrograms/kg s.c.) or central (5 micrograms/rat i.c.v.) administration of Ala5NKA(4-10), but not NKA(4-10) or Ala5[beta Ala8]NKA(4-10), inhibited gastric ulcer and secretion. The same effective doses of Ala5NKA(4-10) did not influence gastric emptying. The anti-secretory and anti-ulcer effects of Ala5NKA(4-10) were antagonized by pretreatment with the tachykinin NK2 receptor antagonist MEN 10,627 at a dose (250 micrograms/kg s.c.) which did not affect gastric secretion and ulcers. These findings provide the first evidence that activation of central and peripheral tachykinin NK2 receptors affords protection against gastric ulcers induced by 2 h pylorus ligation in rats, by reducing gastric acid secretion.

Animals↗
PubMed1996

Down-regulation of substance P receptors during colitis induced by trinitrobenzene sulfonic acid in rats.

Neurochemical and functional studies were performed to investigate the role of substance P (SP) during trinitrobenzene sulfonic acid (TNB)-induced colitis. Time course studies showed that tissutal SP-like immunoreactivity levels decreased in acute or chronic phases of the experimental colitis. The affinity of SP was not significantly reduced up to 1 week after TNB-induced colitis but a decreased density of SP binding sites was observed at all times. The subcutaneous administration of neurokinin (NK)1 receptor antagonist RP 67580 (0.1-1 mumol/kg daily x 1 week) did not affect the injury induced by the hapten. These findings suggest that changes in SP seem to be the effect rather than the cause of colitis and differ from those observed in human inflammatory bowel diseases.

Animals↗