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A Calignano

Publications and source records attributed to A Calignano.

At least 37 records · Page 2Linked to original sources
PubMed1997

NO-naproxen vs. naproxen: ulcerogenic, analgesic and anti-inflammatory effects.

BACKGROUND: A novel class of nitric oxide-releasing nonsteroidal anti-inflammatory drug (NO-NSAID) derivatives has recently been described which exert anti-inflammatory activities but produce significantly less gastrointestinal injury than the parent NSAID from which they are derived. The present studies were performed to determine if a nitroxybutylester derivative of naproxen was less ulcerogenic to the gastrointestinal tract than its parent NSAID, and if it exerted comparable analgesic and anti-inflammatory properties to the parent NSAID. METHODS: The two drugs were compared in an acute gastric injury model, an antral ulcer model and after twice-daily administration for 18 days (small intestinal damage model). Anti-inflammatory activity was examined in the carrageenan-induced paw oedema model, while analgesia was examined in the acetic acid-induced writhing model. The pharmacokinetic profiles of naproxen vs. NO-naproxen were compared by HPLC analysis. RESULTS: NO-naproxen was found to produce significantly less gastric damage despite inducing similar increases in plasma TNF alpha to naproxen. With chronic administration, small intestinal damage was markedly less with NO-naproxen than with the parent NSAID. However, NO-naproxen exerted superior analgesic and comparable anti-inflammatory effects to naproxen. NO-naproxen was not completely converted to naproxen, but the reduced plasma levels of the latter was not the underlying reason for reduced gastrointestinal toxicity of NO-naproxen. CONCLUSION: NO-naproxen represents a novel, gastrointestinal-sparing NSAID derivative with superior analgesic and comparable anti-inflammatory properties to naproxen.

Analgesics↗
PubMed1997

Synthesis and in vitro activities of NK-1 antagonists derived from L-tryptophan.

A study of structure-activity relationships of a series of L-tryptophan derivative NK-1 antagonist was performed using 3,5-bis(trifluoromethyl)benzyl ester of N-acetyl-L-Tryptophan (IV) as a starting point. The ester moiety was replaced with several amidic functions while the N-acetyl group (Ac-) was retained (compounds 1-8) or changed into a benzyloxycarbonyl group (Z-) (compounds 9-16). The compounds were tested on guinea pig ileum longitudinal muscle, rat colon muscolaris mucosae, and rat everted portal vein, representative of tachykinin NK-1, NK-2 and NK-3 receptors, respectively. Both, Ac- and Z-series showed generally moderate antagonist activity on tachykinin NK-1 receptors with respect to the reference drug IV. The most potent term was compound 2 (Ac-Trp-N(CH3)CH(CH3)Ph with S-configuration at the C-terminus) which exhibited pA2 values of 7.0, 4.2 and 4.4 on NK-1, NK-2 and NK-3 sites, respectively.

Animals↗
PubMed1997

One-step synthesis and pharmacological activity of new (N-substituted)amino-spiroalkan-dione derivatives.

The synthesis of (N-substituted)amino-spiroalkan-dione derivatives 3 is described starting from enamines 1 and carbon suboxide 2, and their inhibitory effects on blood coagulation in vivo and on platelet aggregation in vitro are determined. Some of synthesized compounds showed a strong anticoagulant activity. A comparative pharmacological study of the anticoagulant effects of the new compounds versus Warfarin suggests that their behaviour is analogous, though the action mechanism is different.

Adenosine Diphosphate↗
PubMed1996

Inhibition of zymosan-induced air-pouch inflammation by rat seminal vesicle protein and by its spermidine derivative.

The anti-inflammatory effect of one of the major proteins secreted by rat seminal vesicles (SVIV) and of its spermidine derivative (Spd2-SVIV) was evaluated by measuring polymorphonuclear leukocyte migration, protein release, platelet-activating factor (PAF) and prostaglandin E2 levels in the mouse air-pouch exudate following zymesan treatment. Both proteins were found to markedly reduce dose dependently PAF and prostaglandin E2 levels in the exudate as well as the other parameters. Concurrent injection of either arachidonic acid or PAF, directly into the pouch, significantly counteracted the anti-inflammatory effect of SVIV and of its polyaminated derivative. These results support the notion that the molecular mechanism of the anti-inflammatory activity of SVIV and Spd2-SVIV is linked to the inhibition of both phospholipase A2 and acetyl:lyso-PAF acetyltransferase.

Animals↗
PubMed1996

Increase in the basal tone of guinea pig thoracic aorta induced by ouabain is inhibited by spironolactone canrenone and potassium canrenoate.

Guinea pig aorta rings repeatedly stimulated with phenylephrine (1 microM) in the presence of Krebs solution containing ouabain (0.8 microM) or low K+ (0.5 mM) concentration produced an increase in basal tone. This effect is due to an increase in intracellular Ca2+ as a consequence of Na(+)-K+ATPase pump inhibition induced by receptorial (ouabain) or ion imbalance (low K+) mechanism. We investigated the effect of spironolactone and its metabolites canrenone and potassium canrenoate on the increase in basal tone of guinea pig aorta rings. Spironolactone, canrenone, and potassium canrenoate, in a concentration-dependent manner (3-30 microM), inhibited the increase in basal tone induced by ouabain, most likely acting as antagonist for ouabain binding site on Na(+)-K+ATPase pump. Indeed, this effect appears to be a feature of these drugs since structurally related drugs, such as aldosterone and hydrocortisone, were ineffective. Conversely, all the drugs tested reduced, to a certain degree, the increase in basal tone produced by low K+ Krebs solution, implying that this could be a non-specific effect. Our results may indicate that spironolactone, canrenone, and potassium canrenoate act in hypertension by interfering with mechanisms in which an ouabain-like factor is involved.

Animals↗
PubMed1996

Modification of the potent peptide FK888 with unusual aminoacids: effects on activity on neurokinin receptors.

We report on the synthesis and the pharmacological properties of a new series of tachykinin antagonists based on the peptide N2-[(4R)-4-hydroxy-1-[(1-methyl-1H-indol-3-yl) carbonyl]-L-prolyl]-N-methyl-N-(phe-nylmethyl)-3-(2-naphthyl)-L-al aninamide (FK888) modified on the (2-naphthyl)-L-alanine and the [(1-methyl-1H-indol-3-yl)carbonyl] moieties. The compounds were tested on guinea pig ileum for NK-1, rat colon for NK-2 and rat portal vein for NK-3 receptors. The two most potent peptides of this series, 1b and 2b, were selective for the NK-2 receptor (pA2 = 7.5 and 7.3, respectively).

Amino Acid Sequence↗
PubMed1995

Synthesis and biological activity of tripeptide FR113680 analogues containing unconventional amino acids.

In order to further develop structure-activity relationships and to get information about the biological active conformations we synthetized analogues tripeptide to the FR 113680 [Ac-Thr-D-Trp(CHO)-PheNMeBzl; Ac: acethyl], in which the phenylalanine residue was replaced by unconventional amino acids [1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic); (3aS, 7aS)-octahydroindole-2-carboxylic acid (Oic); (S,S,S)-2-azabiciclo[3.3.0]octane-3-carboxylic acid (Aoc); 3-(1'-naphthyl)alanine (Nap); phenylglicine (Phg); thienylalanine (Thi)]. The biological activity of the peptides was performed on guinea pig ileum for neurokinin 1 (NK-1) and on rat colon for neurokinin 2 (NK-2). In particular, the replacement of the Phe3 by the Oic (8a) gave an higher antagonist activity in both NK-1 and NK-2 receptors, but no improvement in selectivity with respect to reference tripeptide (FR113680). The compound (8a) represent the first example of highly potent peptides that do not contain an aromatic amino acid of the third position as had been previously considered essential.

Amino Acid Sequence↗
PubMed1995

Neurokinin receptors could be differentiated by their capacity to respond to the transglutaminase-synthesized gamma-(glutamyl5)spermine derivative of substance P.

Four different gamma-(glutamyl5)amine derivatives of substance P (SP) were synthesized in vitro in the presence of purified guinea pig liver transglutaminase and Ca2+. The 1,3-diaminopropane, spermidine, spermine (Spm), and monodansylcadaverine adducts of the neuropeptide were purified by HPLC on a reversed-phase column and characterized by fast atom bombardment mass spectrometry. The gamma-(glutamyl5)Spm derivative of SP (Spm-SP) was found to be able, like the parent neuropeptide, to provoke rabbit aorta relaxation, to decrease rat arterial blood pressure, and to inhibit collagen-induced platelet aggregation. Unlike SP, only a weak inflammatory response was observed when Spm-SP was injected in the rat hind limb. All these effects were found to be prevented by N omega-nitro-L-arginine methyl ester, a well-known nitric oxide synthesis inhibitor. In contrast, Spm-SP was completely ineffective in contracting guinea pig ileal segments, thus confirming our preliminary observations indicating that Spm-SP does not evoke SP-like spasmogenic effects on isolated smooth muscle preparations. The specificity of the effects due to the selective introduction of a Spm moiety at the glutamine5 level was demonstrated by the SP agonist pharmacological profile of the other gamma-(glutamyl5)amine derivatives tested. These results suggest that neurokinin receptors could be differentiated by their capacity to respond to Spm-SP.

Animals↗
PubMed1995

Synthesis and in vitro activities of highly potent and selective tripeptide antagonists of the neurokinin NK-1 receptor.

We report on the synthesis and the pharmacological properties of a new series of tachykinin antagonists based on the tripeptide Ac-Thr-D-Trp(CHO)-Phe-N(Me)-Bzl (1, FR113680) partly modified on the C-terminal amide part. Stereochemistry around the benzilic carbon, as well as nitrogen substitution was investigated. Selected compounds were tested on guinea pig ileum for NK-1, rat colon and rat portal vein for NK-2 and NK-3 receptors, respectively. Two of these peptides were shown to have higher tachykinin antagonist activity (pA2 > 8.8) and selectivity for NK-1 receptors compared with compound 1 taken as reference (Table 2). In addition we investigated the stability of compounds 2 and 3 on guinea pig plasma and liver homogenate.

Amino Acid Sequence↗
PubMed1994

Endogenous nitric oxide modulates behavioural effects elicited by substance P in rat.

Several studies have shown that the undecapeptide, substance P, alters behaviour following central or peripheral administration in the rat. Here we report that L-arginine administration increases substance P-induced locomotion and changes in food intake in rats. NG-Nitro-L-arginine methyl ester, a specific inhibitor of nitric oxide synthase, reduces substance P-induced effects. These results suggest that endogenous nitric oxide plays a role in the modulation of the catecholaminergic effect of substance P on motor behaviour. They also clarify the mechanism underlying food intake induced by substance P.

Amino Acid Oxidoreductases↗
PubMed1994

(+/-)-Gelliusines A and B, two diastereomeric brominated tris-indole alkaloids from a deep water new caledonian marine sponge (Gellius or Orina sp.).

Two new diastereomeric brominated tris-indole alkaloids occurring as enantiomeric pairs, (+/-)-gelliusines A [1] and B [2], have been isolated from a deep water New Caledonian sponge (Gellius or Orina sp.), whose crude extract exhibited cytotoxicity against KB cells. Their structures were elucidated by spectroscopic methods including one- and two-dimensional nmr spectroscopy. The major compound, (+/-) gelliusine A [1], which showed very weak cytotoxicity, proved to be active at the serotonin receptor.

Animals↗
PubMed1994

Modulation of morphine antinociception in the mouse by endogenous nitric oxide.

1. L-Arginine (100-1000 mg kg-1) administered orally (p.o.) or intraperitoneally (i.p.), but not intracerebroventricularly (i.c.v., 0.08 mg per mouse), reduced the antinociceptive effect of morphine (0.5-10 mg kg-1 s.c.) assessed in mice using three different tests: hot plate, tail-flick and acetic acid-induced writhing. D-Arginine (up to 1000 mg kg-1 p.o. or i.p.) was ineffective. 2. NG-Monomethyl-L-arginine (L-NMMA, 5-50 mg kg-1 i.p.) and NG-nitro-L-arginine methyl ester (L-NAME, 5- 30 mg kg-1 i.p.), but not NG-nitro-D-arginine methyl ester (D-NAME, 30 mg kg-1 i.p.), reversed in all assays the effect of L-arginine on morphine-induced antinociception. 3. Morphine (10 mg kg-1 s.c.), L-arginine (1000 mg kg-1 p.o.) or L-NAME (30 mg kg-1 i.p.), either alone or in combination, did not produce changes in locomotor activity or sensorimotor performance of animals. 4. These results suggest that the L-arginine-nitric oxide pathway plays a modulating role in the morphine-sensitive nociceptive processes.

Acetates↗
PubMed1993

Protective effect of SV-IV on platelet-activating factor-induced hypotension, bronchoconstriction and gastric mucosal injury.

The inhibitory effect of one of the major proteins secreted by the rat seminal vesicles (SV-IV) on platelet-activating factor (PAF)-induced biological activities was investigated in vivo. SV-IV was found to prevent dose dependently both hypotension and acute bronchospasm caused by PAF administration in guinea-pigs. In addition, SV-IV inhibited both PAF- and ethanol-induced gastric mucosal injury in a dose-dependent manner.

Animals↗
PubMed1993

Involvement of NK receptors and beta-adrenoceptors in nitric oxide-dependent relaxation of rabbit aorta rings following electrical-field stimulation.

Electrical-field stimulation caused an endothelium-dependent relaxation in rabbit aorta rings precontracted by phenylephrine. The relaxation was reduced in a dose-dependent manner by morphine, benzalkonium, [D-Pro2,D-Trp7,9]substance P and an beta-adrenoceptor antagonist, propranolol. The vasodilatation was enhanced by superoxide dismutase and abolished by haemoglobin and NG-monomethyl-L-arginine. The inhibitory effect of NG-monomethyl-L-arginine was reversed by L-arginine, the precursor of nitric oxide biosynthesis, but not by its enantiomer, D-arginine. These data show that the electrically induced relaxation is independent on nitric oxide released by NK receptors and beta-receptors. Moreover, morphine, by reducing substance P release, decreased the magnitude of electrically induced relaxation, suggesting an indirect role of opioids in the regulation of the peripheral circulation through the control of nitric oxide release. Furthermore our observations confirm the hypothesis that subtypes of beta-adrenoceptors releasing nitric oxide participate in the regulation of vascular tone.

Adrenergic beta-Antagonists↗
PubMed1993

Endogenous nitric oxide modulates morphine-induced changes in locomotion and food intake in mice.

Opioids increase the dopaminergic turnover in nucleus striatum and nucleus accumbens of mice, causing behavioural changes such as increased locomotion and food intake. We have now shown that L-arginine administration increases morphine-induced locomotion and changes in food intake in mice. D-Arginine had no effect, suggesting a stereospecific mechanism. Furthermore NG-nitro-L-arginine methyl ester, a specific inhibitor of nitric oxide synthase, reduced the morphine-induced effects. These results suggest that endogenous nitric oxide could play a role in the modulation of dopaminergic effects elicited by morphine.

Animals↗
PubMed1993

L-arginine modulates morphine-induced changes in locomotion in mice.

In mice opioids increase dopaminergic turnover in nucleus striatum and nucleus accumbens, causing behavioural changes such as increased locomotion. In this study we have shown that L-arginine administration increases morphine-induced locomotion in mice. D-Arginine had not effect, suggesting a stereospecific mechanism. Furthermore NG-nitro-L-arginine methyl ester, a specific inhibitor of nitric oxide synthase, reduced morphine-induced effect. These results suggest that endogenous nitric oxide could play a role in the modulation of dopaminergic effects elicited by morphine.

Animals↗
PubMed1992

Involvement of endogenous nitric oxide in the regulation of rat intestinal motility in vivo.

The effect of the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) on the motility of the small intestine in an acute model in the anaesthetised rat was determined by changes in jejunal intraluminal pressure. L-NAME (0.5-10 mg kg-1 i.v.) caused a dose-dependent increase in intraluminal pressure and initiated phasic intestinal contractions. These responses were inhibited by concurrent administration of L-arginine (200 mg kg-1 i.v.) but not by D-arginine (200 mg kg-1). The increase in jejunal motility induced by L-NAME was attenuated by atropine (4 mg kg-1), although even high doses of atropine (16 mg kg-1) did not abolish these responses. This indicates that although there are interactions between NO and muscarinic cholinergic mechanisms, other processes are also involved in these contractile events following administration of L-NAME. These observations in the rat suggest that endogenous NO plays a role in the modulation of intestinal motility in vivo.

Animals↗