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Biomedical subjects

M Criscuoli

Publications and source records attributed to M Criscuoli.

At least 55 records · Page 3Linked to original sources
PubMed1995

Effects of idrapril calcium on tissue angiotensin-converting enzyme in rats.

Tissue angiotensin-converting enzyme (ACE) inhibition was measured in rats after single intravenous (i.v.) and oral (p.o.) doses of idrapril calcium, and the correlation between peak inhibition and tissue concentration of the drug was investigated. Five minutes after idrapril calcium (3 mg/kg i.v. as free acid), ACE in the examined tissues (serum, lungs, kidneys, heart, aorta, adrenals, testes, and brain) showed > 50% inhibition, always associated with measurable amounts of idrapril. After 90 min, ACE activity was still inhibited only in serum, lungs, kidneys, and aorta, recovering to basal values by 8 h in all samples but serum. Oral idrapril calcium (30 mg/kg) produced > 50% peak ACE inhibition in serum, lungs, and kidneys, in which measurable levels of the drug were detected, and in the aorta, where idrapril was not detected. Other tissues showed neither marked inhibition nor measurable drug levels. Kinetics of ACE inhibition in affected tissue mirrored those observed after intravenous administration. Idrapril, despite its hydrophilic nature, is able to reach extravascular tissues and to inhibit local ACE. However, in no tissue did the effect on ACE last longer than in serum and the hypothesis of a peculiar role of tissue RAS in determining the hypotensive activity of idrapril calcium is not supported in rats.

Administration, Oral↗
PubMed1994

High-performance liquid chromatographic method with electrochemical detection for the determination of idrapril, a novel angiotensin-converting enzyme inhibitor, in biological matrices.

A reversed-phase high-performance liquid chromatographic method for the determination of idrapril in human and rat plasma and urine and in rat tissue homogenates is described. The method is based on the electrochemical detection of idrapril without prior derivatization. Sample preparation simply consists in deproteinization with acetonitrile for plasma and tissue homogenates and in passage through a Sep-Pak C18 cartridge for urine. The limit of quantification is 12.5 ng/ml for plasma, 125 ng/g for tissues and 2.5 micrograms/ml for urine. The method is suitable for monitoring idrapril plasma pharmacokinetics in humans and its tissue distribution and urinary excretion in rats.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1994

Angiotensins induce the release of prostacyclin from rabbit vas deferens: evidence for receptor heterogeneity.

Angiotensin II and angiotensin III stimulated prostacyclin release in a time- and dose-dependent manner in both the prostatic and the non-prostatic part of the rabbit vas deferens. Also, angiotensin I enhanced the production of prostacyclin and its effect was blocked by captopril. Losartan, a type 1 (angiotensin AT1)-selective receptor antagonist, prevented the angiotensin II-induced prostacyclin release. The agonist peptide, p-aminophenylalanine angiotensin II, and the type 2 (angiotensin AT2)-selective receptor antagonist, PD123319, were found active only in the prostatic portion, suggesting heterogeneity of the receptor population. In conclusion, an angiotensin AT1 receptor mostly mediates the angiotensin-induced release of prostacyclin in the rabbit vas deferens.

6-Ketoprostaglandin F1 alpha↗
PubMed1994

Endothelins induce prostacyclin release in both vascular and non-vascular tissue.

The effects of an i.v. administration of endothelin-1, -2 and -3 (0.25-3 nmol kg-1) or their corresponding proendothelins (1-20 nmol kg-1) on blood pressure and 6 keto-prostaglandin F1 alpha (6 keto-PGF1 alpha) release in the anaesthetized ganglion-blocked rat were evaluated. The same peptides were tested for their ability to release 6 keto-PGF1 alpha from the rat vas deferens in vitro. Endothelins and proendothelins showed a transient hypotensive effect followed by a potent, long lasting vasopressor response. Blood pressure increase induced by endothelins was found to be dose-dependently correlated with 6 keto-PGF1 alpha plasma level increases. On the other hand proendothelins produced similar pressor responses, but their effect on 6 keto-PGF1 alpha plasma levels was much less intense at equipressor doses. The effects of endothelins on arterial pressure and 6 keto-PGF1 alpha release were phosphoramidon-insensitive, while the activities of proendothelins were reduced by phosphoramidon (10 mg kg-1 i.v.). Both endothelins (5-15 nmol/l) and proendothelins (100-300 nmol/l) were able to increase to a similar extent 6 keto-PGF1 alpha levels in the rat vas deferens incubation buffer. The releasing activity of endothelins was not modified by the pretreatment with phosphoramidon (50 mumol/l). This pretreatment strongly inhibited proendothelin-1 and -2 effects, but not that of proendothelin-3.

6-Ketoprostaglandin F1 alpha↗
PubMed1994

Pharmacokinetics and biochemical efficacy of idrapril calcium, a novel ACE inhibitor, after multiple oral administration in humans.

The pharmacokinetic profile and biochemical efficacy of idrapril calcium, a novel angiotensin converting enzyme (ACE) inhibitor, were evaluated in healthy volunteers after multiple dosing for 5 days at the doses of 100, 200 and 400 mg twice daily. The study was conducted as a double-blind, cross-over comparison of idrapril calcium against placebo. Plasma concentrations of idrapril were determined by an indirect enzymatic method. Urinary concentrations were measured by reverse phase high performance liquid chromatography (h.p.l.c.). Plasma samples were also analysed for ACE activity. The pharmacokinetics of idrapril calcium did not change significantly between day 1 and day 5. The values of Cmax and AUC were dose-related over the range of doses tested; tmax was 3-4 h and apparent elimination half-life was 1.4-1.6 h. Plasma ACE activity was maximally inhibited (94-96%) at all dose levels and remained more than 80% depressed from 2 to at least 6 h after idrapril calcium. Although the maximum effect was not dose-related, the duration of inhibition showed some dose-dependency, ACE activity returning to 56, 45 and 29% of the basal value 12 h after the 100, 200 and 400 mg doses, respectively. There were no clinically significant adverse events experienced by the volunteers. No dose-related effects on blood pressure or heart rate were observed. There were no changes in clinical pathology tests, urine analyses or electrocardiograms after dosing with idrapril calcium. Idrapril calcium, the prototype of a new class of ACE inhibitors, appears to be well-tolerated.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1994

Angiotensin-converting enzyme inhibition by hydroxamic zinc-binding idrapril in humans.

The new angiotensin-converting enzyme (ACE) inhibitor idrapril acts by binding the catalytically important zinc ion to a hydroxamic group. We investigated its pharmacodynamic and pharmacokinetic properties in 8 healthy men: Increasing doses of 1, 5, and 25 mg idrapril as well as placebo or 5 mg captopril were administered intravenously (i.v.) at 1-week intervals. Six of the subjects received 100 mg idrapril orally (p.o.) last, and two ingested oral placebo as a double-blind control. Blood pressure (BP) and heart rate (HR) remained unchanged. No serious side effects were observed. ACE inhibition in vivo was evaluated by changes in the ratio of specifically measured plasma angiotensin II (AngII) and AngI concentrations determined by high-performance liquid chromatography/radioimmunoassay (HPLC/RIA) techniques. Plasma ACE activity in vitro was estimated by radioenzymatic assay; it was suppressed by > or = 93% at 15 min after injection of 25 mg idrapril or 5 mg captopril and by 96% 2 h after idrapril intake. Mean AngII levels were decreased dose dependently at 15 min after idrapril injections. At the same time, plasma renin activity (PRA) and AngI increased according to the doses. The AngII/AngI ratio was clearly related to plasma idrapril levels (r = -0.88, n = 60). Oral idrapril inhibited ACE maximally at 1-4 h after dosing, when < 7% of initial ACE activity was observed in vitro and in vivo. Idrapril is a safe and efficient ACE inhibitor in human subjects. It is well absorbed orally. Besides having a slightly slower onset of action, idrapril has pharmacodynamic effects comparable to those of captopril.

Adult↗
PubMed1993

Inhibition of rabbit lung angiotensin converting enzyme by idrapril.

Idrapril, the prototype of a new class of angiotensin converting enzyme (ACE) inhibitors, competitively inhibited, with nanomolar apparent Ki, the hydrolysis of hippuryl-glycyl-glycine by rabbit lung ACE. The pre-steady-state analysis of this tight-binding inhibition showed it to be characterized by slow kinetics, but at variance with what was found for enalaprilat in the same conditions, idrapril appeared to act through a simple, single step mechanism. Kinetic Ki and k(on) and k(off) values were 470 pM, 3.0 +/- 1.5 x 10(6) M-1 sec-1 and 1.4 +/- 0.3 x 10(-3) sec-1, respectively.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1993

1,2-Cyclomethylenecarboxylic monoamide hydroxamic derivatives. A novel class of non-amino acid angiotensin converting enzyme inhibitors.

A series of monoamidic derivatives of cis- and trans-1,2-cyclohexanedicarboxylic and 1,2-cyclopentanedicarboxylic acids bearing either a carboxylic, sulfhydrylic, or hydroxamic group in the side chain were synthesized and evaluated in vitro for their inhibitory activity against angiotensin converting enzyme. The compounds were designed as potential ACE inhibitors of novel structure, assuming that a monoamidic residue of an 1,2-cyclomethylenedicarboxylic acid could be an alternative structure to the acylproline moiety, the carboxyl-terminal portion common to various ACE inhibitors. The most active compounds were found in the hydroxamic derivatives of cyclohexane series; within this series of derivatives a marked increase of potency was caused by alkylation of the amidic nitrogen with a methyl or ethyl group. Therefore enantiomers of the selected hydroxamic derivatives of cis- and trans-1,2-cyclohexanedicarboxylic acid were prepared by two different chiral synthetic routes and evaluated in vitro for their ACE inhibitor potencies. The active enantiomers both of the cis series (21a, 21c) and trans series (16b, 16d) were found to have all R configuration at the C-2 and R or S configuration at the C-1, while in the classical ACE inhibitors S configuration at the terminal carboxylate (corresponding to the C-1 of our compounds) is strictly required for activity. The most potent compound of the series was (1S,2R)-cis-2[[[2-(hydroxyamino)-2-oxoethyl]methylamino]carbonyl] cyclohexanecarboxylic acid (21a) with an IC50 value of 7.0 nM compared with the value of 3.0 nM for captopril. Further 21a was shown to be highly selective and competitive ACE inhibitor. These results indicate that this non-amino acid structure of inhibitors meets the ACE active site requirements for the binding. The binding compatibility of the most active compounds with a model of ACE active site was evaluated by molecular modeling techniques.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1993

Effect of rociverine on P450-dependent monooxygenases and its N-deethylation metabolism in rat liver microsomes.

Rociverine [2-(diethylamino)-1-methylethyl cis-1-hydroxy [bicyclohexyl]-2-carboxylate] citrate (ROC) is an antispasmodic agent therapeutically active in humans at doses of 0.5-1 mg/kg. This study investigated the effect of acute administration of the drug on hepatic microsomal cytochrome P450 (P450)-catalysed drug metabolism. Only high doses (> or = 100 mg/kg) of ROC were able to induce in rats the hepatic microsomal pentoxyresorufin O-depenthylase (PROD) and 16 beta-testosterone hydroxylase activities both associated with P4502B1/2 and the erythromycin N-dimethylase (ErD) and 2 beta-testosterone hydroxylase activities both dependent on P4503A1/2. However, at 100 and 200 mg/kg of ROC, the 16 beta-testosterone hydroxylase and PROD were the most induced activities, suggesting that P4502B1/2 are the isoforms most sensitive to ROC induction. Accordingly, ROC treatment enhanced, in a dose-dependent manner, the amount of P4502B1/2 and 3A1/2 in microsomes as assayed by western blotting. The northern blot analysis of ROC-treated rat liver showed that the P4502B1/2 induction appears to be regulated at the mRNA level as in the induction by phenobarbital (PB). The oxidative metabolism of ROC with hepatic microsomes from control or PB- and ROC-induced rats resulted in a N-deethyl ROC derivative (major metabolite) and an unknown minor ROC derivative. The kinetic parameters for the N-deethylation of ROC were studied with purified P4502B1 and with microsomes from control or rats treated with various inducers (phenobarbital, ethanol, beta-naphthoflavone, dexamethasone and rociverine). It was found that phenobarbital-, dexamethasone- and rociverine-induced microsomes deethylated ROC with a Vmax about five times higher than that (0.9 nmol/min/mg protein) of control microsomes, although with a similar affinity (Km approximately 0.3 mM). In a reconstituted system, the purified P4502B1 metabolized ROC with a high deethylation rate (22 nmol/min/nmol P450). Moreover, the ROC deethylation was inhibited by compounds such as hexobarbital, metyrapone and triacetyloleandomicin, selective inhibitors for P4502B and/or P4503A enzymes. On the other hand ROC, when added in vitro, inhibited the 16 beta- and 2 beta-testosterone hydroxylases and the PROD and ErD activities. Taken together, these results indicate that the ROC-inducible P4502B and P4503A are involved in ROC deethylation. In conclusion, it has been demonstrated that ROC is a weak phenobarbital-like inducer of P450, probably able at high and reiterated doses to alter its own metabolism, at least in the rat liver.

Acetaldehyde↗
PubMed1992

[125I]His-neurokinin A binds selectively to NK2 receptors of the B-type in rat small intestine smooth muscle membranes.

The high-affinity, reversible binding of [125I]His-neurokinin A (NKA) to rat small intestine smooth muscle membranes was investigated. Endogenous neurokinin agonists, selective neurokinin analogues, both agonist and antagonist, were used to define the selectivity of the binding. Both the endogenous and selective neurokinin analogue agonists displayed orders of potency indicating that [125I]His-NKA was binding to NK2 receptors. The use of recently developed NK2-selective antagonists indicated that the NK2 receptors present in this preparation were similar to those described in hamster trachea preparations (NK2B), and not endothelium-denuded rabbit pulmonary artery (NK2A). The absence of NK2A receptors and the predominance of NK2B was confirmed by blocking experiments using MEN10376 and L659877. Low-affinity binding of NKA was also observed with this preparation, which was not sensitive to the NK2-selective agonist, [beta-Ala8]NKA4-10. This was shown not to be due to the presence of NK1 or NK3 receptors by using selective agonists for NK1 and NK3 to block any such receptors. (No evidence for the presence of these receptors was obtained during these blocking experiments.) Guanylylimidodiphosphate appears to discriminate between the high- and low-affinity binding sites for NKA. It was thus concluded that high-affinity binding of [125I]His-NKA to rat small intestine smooth muscle membranes was selective for NK2B receptors. No evidence was found for the binding of [125I]His-NKA to NK1, NK3 or NK2A receptors.

Animals↗
PubMed1992

Pharmacology of idrapril: a new class of angiotensin converting enzyme inhibitors.

Idrapril is the prototype of a new chemical class of angiotensin converting enzyme (ACE) inhibitors, the hydroxamic non-amino acid derivatives. Idrapril strongly inhibited rat and human plasma ACE and rabbit lung ACE (IC50: 7-12 nM) as well as the pressor response induced by angiotensin I in anesthetized rats (ED50: 63 nmol/kg i.v.). Idrapril (0.04-23 mumol/kg i.v.) lowered the blood pressure dose dependently, up to 20-35%, in different models of hypertension (sodium-depleted spontaneously hypertensive rat, two-kidney-one-clip renal hypertensive rat, and aortic-coarctated rat), its profile being similar to that of captopril in terms of potency and efficacy. Idrapril and captopril reduced the blood pressure and potentiated substance P-induced bronchoconstriction in the guinea pig to the same extent, suggesting a similar degree of ACE inhibition in the circulation. However, idrapril potentiated capsaicin-induced bronchoconstriction (a model that has been related to the liability of ACE inhibitors to produce cough in patients) less effectively than captopril. We conclude that effective ACE inhibition in vitro and in vivo can be obtained with this novel class of compounds.

Angiotensin I↗
PubMed1991

Characterization of NK-3 binding sites in rat and guinea pig cortical membranes by the selective ligand [3H]Senktide.

We have used [3H]Senktide, a selective Neurokinin B receptor ligand, for the characterization of NK-3 receptors in rat and guinea pig CNS membranes. Scatchard analysis of saturation binding studies in cerebral cortex membranes indicated that this ligand bound to a single site with apparent high affinity (KD = 4.6 +/- 1.6 and 3.1 +/- 0.37 nM, Bmax = 13.7 +/- 1.6 and 21.8 +/- 2.2 fmol/mg protein in rat and guinea pig membranes, respectively). However, in competition studies with a group of neurokinins and related peptides two different rank orders of affinities were obtained, as follows: NKB greater than [MePhe7]-NKB greater than or equal to Arg0-NKB greater than or equal to Senktide much greater than NKA greater than SP, in rat membranes, and [MePhe7]NKB greater than Senktide = NKB greater than Arg0-NKB much greater than SP greater than NKA, in guinea pig membranes.

Amino Acid Sequence↗
PubMed1990

High-affinity binding of mequitamium iodide (LG 30435) to muscarinic and histamine H1 receptors.

Mequitamium iodide (LG 30435) is a novel quaternary ammonium phenothiazine with potential as an anti-asthmatic agent. In vitro binding experiments were performed in order to clarify the molecular mechanisms underlying its biological activity. Mequitamium iodide was found to bind with high affinity only to histamine H1 receptors in rat brain membranes (Ki = 9 nM) and to muscarinic acetylcholine receptors in various tissues homogenates (Ki = 12-77 nM) with no clearcut selectivity for any of the known subtypes. The interaction with muscarinic receptors in rat cerebral cortex and lung parenchyma was competitive, as showed by saturation studies. Lower affinity values (Ki = 1-10 microM) were found for serotonin 5-HT2, platelet-activating factor (PAF), verapamil and beta-adrenergic agents. These results indicate that both the potent antimuscarinic and antihistamine and the relatively weak anti-PAF pharmacological effects of mequitamium iodide may be explained by the direct interaction of the substance with the respective receptors.

Animals↗
PubMed1990

Angiotensin converting enzyme inhibitors potentiate the bronchoconstriction induced by substance P in the guinea-pig.

1. The effects of intravenous captopril and enalaprilic acid on the increase in pulmonary inflation pressure induced by different bronchoconstrictor agents were evaluated in the anaesthetized guinea-pig. 2. Captopril and enalaprilic acid (1.6-200 micrograms kg-1) enhanced dose-dependently the bronchoconstriction (BC) induced by substance P. The threshold effective dose was 1.6 micrograms kg-1 and maximal potentiation over the control response was more than 400% for both agents. Enalaprilic acid was also assayed for serum and lung angiotensin converting enzyme (ACE) inhibition in anaesthetized guinea-pigs. This drug produced a dose-dependent inhibition of ACE in both tissues, with ED50 s of 7.6 and 9.4 micrograms kg-1, respectively: this inhibitory activity was positively correlated to substance P potentiation. 3. Captopril (8-1000 micrograms kg-1) enhanced dose-dependently the BC induced by capsaicin. The threshold effective dose was 40 micrograms kg-1 and maximal potentiation about 90%. 4. Captopril (200-1000 micrograms kg-1) did not affect BC induced by bradykinin. However, this response was markedly enhanced (about 200%) by captopril 200 micrograms kg-1 in propranolol-pretreated animals. 5. Captopril and enalaprilic acid (200-1000 micrograms kg-1) slightly (20-40%) but significantly enhanced the BC induced by 5-hydroxytryptamine. However, this response was potentiated to the same extent by a dose of prazosin, which produced a degree of hypotension similar to that observed after administration of the ACE inhibitors. 6. In conclusion, ACE inhibitors potentiate the BC induced by substance P and, to a minor extent, that induced by capsaicin in the anaesthetized guinea-pig. Potentiation of substance P is well correlated with ACE inhibition in guinea-pig serum and lungs. These experimental results may offer a mechanistic interpretation of cough and bronchial hyperreactivity observed in patients receiving treatment with ACE inhibitors.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1989

Study of inhibition of platelet aggregation of 1,8-naphthyridine derivatives.

The antiplatelet activity of some 1,8-naphthyridine derivatives was studied. The compounds displayed different abilities in blocking the effects of ADP, collagen and arachidonic acid. Four of them showed an in vitro remarkable activity similar to that of dipyridamole and papaverine.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1988

Effects of LG 30435 on different platelet activating factor-induced responses.

LG 30435 is a new potential anti-asthmatic agent with multiple sites of action. It can inhibit the bronchoconstriction induced by various agonists, including platelet activating factor (PAF). The effects of this compound on PAF-induced biological responses have now been investigated. LG 30435 inhibited both serotonin release from, and aggregation of, rabbit washed platelets evoked by PAF, being four times more potent on release than on aggregation. In contrast, it did not inhibit a number of the biological effects of PAF which are not platelet-mediated, such as contraction of guinea-pig lung parenchymal strips, hypotension in rats and lethality in mice. It may be concluded that, unless platelet PAF receptors are different from those in other tissues, LG 30435 is capable of inhibiting platelet-mediated effects of PAF by interfering with secondary mechanisms activated by this autacoid and not by direct antagonism of PAF at receptor sites.

Animals↗
PubMed1988

Effects of anti-asthma drugs on PAF-induced death in mice.

A number of anti-asthma drugs was assayed for the ability to protect mice from platelet-activating factor (PAF)-induced death, which has been suggested to be dependent on the bronchoconstrictive features of this autacoid. Salbutamol, dexamethasone, theophylline, ketotifen and zindotrine, administered parenterally, produced a dose-dependent protection, while forskolin, enprofylline, disodium cromoglycate, nedocromil, azelastine and antagonists of acetylcholine, histamine and serotonin were devoid of protective effects. Theophylline, contrary to salbutamol, lost its protective effects in adrenalectomized mice, suggesting that these effects are dependent on the release of adrenomedullary cathecolamines. Salbutamol, theophylline and dexamethasone, at doses capable of inhibiting PAF-induced death, did not affect PAF-induced haemoconcentration in mice, thus excluding widespread changes in vascular permeability as a major cause of death. These results are generally in agreement with the hypothesis that airway obstruction is an important determinant of PAF-induced death in mice.

Adrenalectomy↗