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Biomedical subjects

M Criscuoli

Publications and source records attributed to M Criscuoli.

67 records · Page 4Linked to original sources
PubMed1988

Catecholamines released from the adrenal medulla exert a compensatory, protective effect at beta 2-adrenoceptors against Paf-induced death in mice.

1. The effects of a number of drugs and experimental conditions, which inhibit or stimulate adrenergic function, were evaluated on platelet-activating factor (Paf)-induced death in conscious mice. 2. Adrenalectomy markedly potentiated Paf toxicity, while guanethidine and reserpine did not. However, reserpine, which produced a virtually complete depletion of catecholamines (CA) in cardiac tissue, was not able to reduce adrenal CA by more than 58%. Drugs which release noradrenaline from the adrenergic nerve terminals, such as tyramine and amphetamine, did not protect mice from Paf toxicity, while drugs or conditions which favour the release of CA from the adrenal medulla, such as urethane and cold-induced stress, did. 3. beta 2- and beta 1 + beta 2-adrenoceptor antagonists (ICI 118551, propranolol and nadolol), but not beta 1-antagonists (atenolol, practolol, metoprolol and CGP 20712 A), potentiated Paf toxicity at low doses; beta 2- and beta 1 + beta 2-agonists (salbutamol, fenoterol and isoprenaline), but not beta 1-agonists (prenalterol and tazolol) were potent inhibitors of Paf toxicity. alpha 1- and alpha 2-adrenoceptor agonists and antagonists did not exert significant effects. Propranolol did not appear to enhance the hypotensive action of Paf in pentobarbitone-anaesthetized mice. 4. It is concluded that manipulation of the release of CA from the adrenal medulla, but not from adrenergic nerves, has profound effects on Paf toxicity in mice. A number of considerations support the hypothesis that bronchoconstriction is a major determinant of Paf-induced death in mice.

Adrenal Cortex Hormones↗
PubMed1987

Paf-acether-induced death in mice: involvement of arachidonate metabolites and beta-adrenoceptors.

Intravenous Paf-acether (Paf, 15-80 micrograms kg-1) killed conscious Swiss mice in a dose-dependent manner, without causing platelet aggregation in the lung microvasculature, or pulmonary oedema. Propranolol (0.01-10 mg kg-1, i.p.) potentiated the effects of an LD20 of Paf dose-dependently, while the beta 1-adrenoceptor selective antagonist, metoprolol, was three orders of magnitude less potent in this respect. Salbutamol (1 mg kg-1, i.p.) provided complete protection against an LD80 of Paf. High doses of indomethacin, aspirin, benoxaprofen and FPL 55712 given i.p. failed to inhibit the effects of an LD80 of Paf, while BW 755C (50-100 mg kg-1) exerted a dose-dependent protection and benzydamine (50 mg kg-1) and nordihydroguaiaretic acid (200 mg kg-1) were partially active. Dexamethasone (1-5 mg kg-1, s.c.) exerted a dose-dependent protection, when administered at least 4 h before Paf. In mice anaesthetized with urethane, Paf (1-30 micrograms kg-1) produced hypotension which was not clearly dose-related. The effects of the highest dose were also tested on the resistance of the lungs to inflation and found to produce bronchoconstriction. It may be concluded that pharmacological manipulation of beta 2-adrenoceptors modulates Paf-induced death in mice, while arachidonate metabolites of the cyclo-oxygenase pathway and peptidoleukotrienes do not appear to be involved. However, lipoxygenase products, distinct from peptidoleukotrienes, may play a role in this phenomenon. It is suggested that bronchoconstriction, probably associated with cardiovascular effects, is a major determinant of the acute toxicity of Paf in mice.

Adrenergic beta-Agonists↗
PubMed1986

LG 30435 is a new bronchodilator agent with multiple sites of action.

LG 30435, a new quaternary derivative of the H1-histamine antagonist mequitazine, was evaluated against bronchospasm induced by different agonists. This compound inhibited equipotently methacholine- and histamine-induced contractions of isolated guinea-pig trachea. When administered to guinea-pig by the i.v. and/or the aerosol route, LG 30435 inhibited dose dependently the bronchospasm induced by acetylcholine and histamine and to a lesser degree that induced by 5-hydroxytryptamine and LTD4. When compared to that of mequitazine, its potency was higher in each case, up to 500-fold when tested in vitro against methacholine. LG 30435 also counteracted antigen-induced bronchospasm both in passively sensitized guinea-pigs and in actively sensitized rats. This compound had a rapid onset of action and an adequate duration after aerosol administration. It was poorly absorbed both by the oral and the aerosol routes and it did not appear to penetrate the blood-brain barrier. These results show that LG 30435 is a new aerosol bronchodilator agent, which, due to its multiple pharmacodynamic actions and to its suitable pharmacokinetics, is potentially useful in the therapy of obstructive airways disease.

Absorption↗
PubMed1986

LG 30435, a new bronchodilator/antiallergic agent, inhibits PAF-acether induced platelet aggregation and bronchoconstriction.

LG 30435 is a quaternary phenothiazinic antihistamine, endowed with bronchodilator and antiallergic activity. Since PAF-acether (PAF) is a potential mediator of asthma, LG 30435 was assayed for its ability to counteract PAF-induced platelet aggregation (PA) in rabbit platelet rich plasma and bronchoconstriction (BC) in anaesthetized guinea-pigs, in comparison with other antihistamines. LG 30435 was the most potent and selective inhibitor of PAF-induced PA (IC50: 66 microM), concentrations three and more than fifteen fold higher being needed to inhibit PA induced by collagen and arachidonic acid respectively. The other antihistamines, namely mepyramine, promethazine, mequitazine, thiazinamium methyl sulfate and ketotifen were less potent inhibitors of PAF-induced PA, while interfered at lower concentrations with collagen-induced PA. LG 30435 and thiazinamium, administered intravenously, inhibited dose-dependently PAF-induced BC, starting from the dose of 0.1 mumol/kg. The ED50 of LG 30435 was 0.28 mumol/kg, while the inhibition obtained with thiazinamium did not reach 50% even at 3 mumol/kg. Ketotifen and promethazine were partially active only at 3 mumol/kg, while mequitazine and mepyramine were inactive up to this dose. These results show that LG 30435 is endowed with a peculiar anti-PAF action, which may be advantageous in the treatment of asthma.

Animals↗
PubMed1985

Further assessment of glunicate hypolipidaemic activity in the rat.

The hypolipidaemic activity of glunicate administered orally to rats has been further evaluated. In the fasted normolipidaemic rat, glunicate, in single doses of 10-300 mg kg-1 (as nicotinic acid equivalents), exerted a dose-dependent reduction of plasma triglycerides and cholesterol. At the lower doses, the HDL: total cholesterol ratio was enhanced, but at higher doses it was depressed. Similar results were obtained in the fasted obese Zucker rat, but the acute effects of glunicate seemed less marked in this strain. When the same doses of glunicate were given for 7-8 consecutive days no alteration of the plasma lipid pattern was observed, the reason being that the hypocholesterolaemic action of single doses of glunicate is reduced or abolished in fed animals; this was not due to pharmacokinetic factors depending on feeding. The same lack of hypocholesterolaemic action in fed animals occurred with nicotinic acid.

Animals↗
PubMed1984

Glunicate (LG 13979) protects the arterial wall from cholesterol-induced atherosclerotic changes in the rabbit without affecting plasma lipids.

Glunicate is evaluated compared to nicotinic acid for effects on aortic atheromatous lesions, lipid parameters and factors involved in thrombosis and haemostasis in rabbits kept on a high-cholesterol diet for 12 weeks, using 2 doses of glunicate (0.17 and 0.69 g/day) and 1 of nicotinic acid (0.6 g/day). Glunicate afforded dose-dependent protection of the arterial wall from atheromatous lesions and from cholesterol and collagen accumulation, while nicotinic acid hardly had any effect. These effects were completely independent of plasma lipid-lowering action, the plasma levels of all lipids being indistinguishable in all cholesterol-fed groups. In addition to inducing the expected changes in the lipid pattern, the atherogenic diet increased platelet aggregation in response to collagen but not to ADP, prolonged the APTT and lowered the plasma fibrinogen levels. Both glunicate and nicotinic acid counteracted the effects of the diet on platelet aggregation and on APTT, but only glunicate normalised the fibrinogen levels. There was no change in PT or in prostacyclin-like activity release from the mesenteric artery after the diet or diet plus drugs.

Animals↗
PubMed1983

Acute effects on plasma lipids in the rat of a new long-acting nicotinic acid derivative: LG 13979.

The effects on plasma lipids and nicotinic acid concentrations of a single dose of 2-(3-pyridinecarbonylamino)-2-deoxy-1,3,4,6 dihydrogen-D-glucose tetra-3-pyridinecarboxylate (LG 13979) compared with the effects of nicotinic acid and of its known derivatives niceritrol and sorbinicate, at the same doses, were studied in the fasted rat. Results show that LG 13979 has more prolonged activity on plasma free fatty acids and triglycerides, with longer lasting and more intense activity on plasma cholesterol than these three reference standards. Free fatty acid rebound occurs after administration of nicotinic acid and niceritrol, but not after LG 13979. This pharmacodynamic profile may be explained on the basis of the kinetics of nicotinic acid plasma concentrations, which are low, constant and lasting after LG 13979 administration.

Animals↗
PubMed1982

On the absorption, distribution and excretion of sorbinicate in the rat and the monkey.

Absorption, distribution and excretion of 14C-D-glucitol hexanicotinate (sorbinicate, SN) were studied after oral dosing in the rat against 14C-nicotinic acid (NA). SN is absorbed in large quantities from the gastro-intestinal tract, even if to a lesser extent than NA. The serum 14C-radioactivity after SN presents a distinctly different trend from that after NA administration: peak at 8 h (against 15 min for NA), slow excretion, very low and constant levels (peak 1/10 of that induced by NA). The superior performance of SN is explained partly by the different absorption of the two drugs and partly by a strong tropism for the tissues, especially for the liver, of which SN gave proof in the distribution tests. The excretion of 14C after SN in the urine is about half of that after NA whereas excretion in the feces is several times greater. Some results obtained in the monkey substantially confirm the findings in the rat.

Animals↗
PubMedDate not supplied

Differential effect of dithiothreitol and DuP 753 on angiotensin II receptor subtypes in bovine cerebellar cortex.

Angiotensin II (AII) receptor subtypes were investigated in bovine cerebellar cortical membranes (BCCM) using agonists and antagonists. Differences were observed whether the tissue for the characterization was used fresh or frozen. In fresh BCCM, AII and angiotensin III (AIII) (not selective), p -aminophenylalanine6 -AII ([pNH2Phe6]AII) (AT2 selective), and DuP 753 (AT1 selective) interacted with two sites, at high and low affinity. In the presence of 10 mM dithiothreitol (DTT), the low-affinity site for AIII and [pNH2Phe6]AII and the high-affinity site for DuP 753 were no longer detectable. The same effect was obtained with 1 microM DuP 753, with only the low-affinity component of [pNH2Phe6]AII being resistant to this blocker. In frozen BCCM, DuP 753, PD 123319 (AT2 selective), and sarcosine1, isoleucine8-AII ([Sar1Ile8] AII) yielded monophasic curves. These data confirm the presence of multiple receptors (AT1 and AT2) for AII on BCCM and suggest the possibility that within the AT2 receptors, one subtype, DTT sensitive, may exist. Alternatively, a heterogeneity in the AT1 class, with respect to the sensitivity to DuP753, may be considered.

Angiotensin Receptor Antagonists↗
PubMedDate not supplied

Octylonium bromide, an antagonist of platelet-activating factor.

Octylonium bromide, a spasmolytic agent in clinical use for the treatment of increased tone and/or motility of the gastrointestinal tract, was examined for its ability to antagonize some biological actions of platelet-activating factor. It was found capable of inhibiting, in a concentration- or dose-dependent fashion, the platelet-activating factor-induced platelet aggregation of rabbit platelet-rich plasma, bronchoconstriction in guinea-pigs, hypotension in rats and lethality in mice, its potency being between 1/15 and 1/50 that of WEB 2086. On the other hand, octylonium bromide was not capable of inhibiting the platelet-activating factor-induced contraction of guinea-pig lung parenchymal strips, an effect which is inhibited by WEB 2086 only at high concentrations. It is worth mentioning that octylonium bromide antagonized endotoxin-induced gastrointestinal damage, known to be due to platelet-activating factor release, at doses comparable to those which exert a spasmolytic effect in man. The role of platelet-activating factor in human gastrointestinal disorders has not yet been clearly established and, therefore, the clinical implications of this property of octylonium bromide are at the moment unknown.

Animals↗
PubMedDate not supplied

Pharmacokinetics and pharmacodynamics of idrapril in rats, dogs, and humans.

Idrapril is the prototype of a new class of angiotensin converting enzyme (ACE) inhibitors. Its pharmacokinetics and pharmacodynamics (plasma ACE activity) were investigated in rats, dogs (after intravenous and oral doses), and human volunteers (after oral doses). Following intravenous administration (1 mg/kg) to rats and dogs, elimination half-lives were 96 and 52 min, systemic clearance 19.6 and 9.5 ml/min kg, and volume of distribution 2.7 and 0.8 liters/kg, respectively. Pharmacokinetics appeared linear in dogs, within the dose range of 0.1-10 mg/kg. After oral administration of similar doses (approximately 2 mg/kg) in the three species studied, peak plasma concentrations were 182, 567, and 726 ng/ml; AUCs 25, 85, and 182 micrograms min/ml; and elimination half-lives 82, 54, and 174 min in rats, dogs, and healthy volunteers, respectively. Absolute oral bioavailability was calculated to be approximately 24% in rats and dogs. Idrapril did not bind to plasma proteins of the species studied. Plasma ACE was fully inhibited following oral administration of approximately 2 mg/kg in rats and humans, but in dogs maximal inhibition did not exceed 85%. Duration of action, measured as time for ACE to recover to 70% of initial activity, was approximately 5, 3, and 22 hr in rats, dogs, and humans, respectively. Idrapril plasma levels appeared correlated in a saturable way with inhibition of plasma ACE in all three species, yielding ex vivo IC50 values of approximately 7 ng/ml for both the rat and humans, and 91 ng/ml for dogs.

Administration, Oral↗