Nail penetration and predicted mycological efficacy of an innovative hydrosoluble ciclopirox nail lacquer vs. a standard amorolfine lacquer in healthy subjects.

BACKGROUND: In a previous study a new hydrosoluble nail lacquer (P-3051) containing 8% ciclopirox (CPX) showed higher nail penetration compared to a water-insoluble 5% amorolfine (MRF) lacquer. To our knowledge, in vivo human data on a similar topic are not available. OBJECTIVES: To compare fingernail penetration of P-3051 with that of MRF reference in humans and to evaluate their predicted efficacy against Trichophyton rubrum and Candida parapsilosis. METHODS: Single centre, randomized, multiple dose, open label, within subjects study. Test and reference were self-applied to all fingernails of either hand for 28 days. At baseline and after 15 and 25 days, the nail free edge was collected for analysis. Efficiency coefficients were calculated for T. rubrum and C. parapsilosis as ratios of nail concentration/minimum inhibitory concentration. The coefficients were classified as very high, high or poor. RESULTS: Nail concentrations after 15 days were 2.82 ± 0.58 µg/mg for CPX and 0.64 ± 0.11 µg/mg for MRF. At day 25 there was a non-significant decline (1.85 ± 0.31 µg/mg, P = 0.077) for CPX and a highly significant (0.13 ± 0.03 µg/mg, P = 0.0002) 80% decline for MRF. Efficiency coefficients were very high/high in all subjects treated with P-3051 against both T. rubrum and C. parapsilosis; they were significantly lower for MRF reference against both pathogens at both observation points. CONCLUSIONS: P-3051 exhibited better penetration and higher predicted efficacy after in vivo multiple application to human fingernails when compared to MRF reference. These in vivo data are in good agreement with our previous in vitro study.

Comparative evaluation of some pharmacological properties and side effects of D-glucitol hexanicotinate (sorbinicate) and nicotinic acid correlated with the plasma concentration of nicotinic acid.

In rabbits kept on a diet containing 1 g/day cholesterol for 12 weeks, the nicotinic acid derivative sorbinicate displayed greater hypolipemic and antiatherogenic activity than an equidose of plain nicotinic acid at much lower and more constant plasma nicotinic acid levels. In normocholesterolemic rats, nicotinic acid given at a level of 300 mg/kg per dose for 3 weeks induced plasma FFA and triglyceride rebound and triglyceride accumulation in the liver and possibly in the heart (all parameters determined 24 h after the last dosing), whereas an equidose of sorbinicate was free from these effects, potentially the two most dangerous side effects of nicotinic acid. By modulating the bioavailability of nicotinic acid, sorbinicate maintains and in some cases enhances the pharmacological activity of the acid, avoiding at least some of its major side effects.

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.

Synthesis and anticonvulsant activity of N-(benzoylalkyl)imidazoles and N-(omega-phenyl-omega-hydroxyalkyl)imidazoles.

A novel series of N-(benzoylalkyl)imidazoles and N-(omega-phenyl-omega-hydroxyalkyl)imidazoles was synthesized and evaluated for anticonvulsant activity in mice against maximal electroshock induced seizures. Some of the compounds showed an activity comparable to or better than phenytoin and phenobarbital. The N-[beta-[4-(beta-phenylethyl)phenyl]-beta-hydroxyethyl]imidazole (38) was selected for further studies; preclinical toxicology and additional efficacy evaluations are in progress. Structure-activity relationships are discussed.

N-3-substituted pyrimidinones as potent, orally active, AT1 selective angiotensin II receptor antagonists.

A novel series of nonpeptide angiotensin II (A II) antagonists containing a pyrimidinone ring which carries a C-linked biphenyltetrazole moiety and a carboxyheteroaryl group on the 3-position have been prepared. Their affinity for the AT1 receptor was determined in a binding assay on rat adrenal cortical membranes. The in vivo antihypertensive properties were tested by evaluating the inhibition of the pressor response to A II followed by iv and id administration. Extensive molecular modeling studies, including comparison of molecular electrostatic potential distributions, conformational analysis, and overlays on a computational pharmacophore model of A II, were used to evaluate structural parameters of the new compounds, in comparison to other known A II antagonists (e.g., DUP-753 and SK&F 108566). According to the modeling studies, the introduction of a (carboxyheteroaryl)methyl moiety at the 3-position of the pyrimidinone ring led to derivatives with increased potency. Methyl 2-[[4-butyl-2-methyl-6-oxo-5-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl ]- 4-yl]methyl]-1-(6H)-pyrimidinyl]methyl]-3-thiophenecarboxylate (3k, LR-B/081), one of the most potent compounds in the series (Ki = 1.4 nM), exhibited a marked antihypertensive activity on oral administration to conscious renal hypertensive rats, with long duration of action. It was selected for clinical evaluation in the treatment of hypertension in man.

4-Diazinyl- and 4-pyridinylimidazoles: potent angiotensin II antagonists. A study of their activity and computational characterization.

A series of N-[biphenylyl(tetrazolyl)methyl]-2-butylimidazoles containing variously substituted diazine or pyridine moieties either as their free bases or N-oxide derivatives attached to the 4-position of the imidazole ring was synthesized and tested for interaction with the AT1 receptors of rat adrenal cortex membranes (receptor binding assay). Some compounds were then chosen for further evaluation in vivo in the A II-induced pressor response in conscious normotensive rats. The most potent in the AT1 binding assay were found to be compounds in which the diazine or pyridine ring nitrogen is adjacent to the point of attachment between the two heteroaromatic rings such as 2-butyl-4-(3,6-dimethylpyrazin-2-yl)-1-[[2'-(1H-tetrazol-5-y l)-biphenyl-4- yl]methyl]-1H-imidazole (3b) or 2-butyl-4-[5-(methoxycarbonyl)pyrid-2-yl]-1-[[2'-(1H-tetrazol++ +-5- yl)biphenyl-4-yl]methyl]-1H-imidazole (6c). The binding affinities and oral activities of the pyridine N-oxide imidazoles in which a stabilizing group ortho to the pyridine ring nitrogen is present were markedly improved as in 2-butyl-4-[(3-methoxycarbonyl)-6-methyl-N-oxopyridin-2-yl]-1-[[2'- (1H- tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-imidazole 31b. Molecular modeling studies were carried out to determine the molecular electrostatic potential values of related model systems and to correlate their receptor interaction energies with the observed activities of our compounds.

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.

Experimental pharmacology of hirunorm: a novel synthetic peptide thrombin inhibitor.

Enhanced thrombin activity has been associated with coronary thrombosis and with acute and long-term complications following coronary balloon angioplasty. Blocking thrombin activity with specific inhibitors is proposed as a promising antithrombotic therapy. We describe the anticoagulant and antithrombotic properties of hirunorm, a novel synthetic 26-aminoacid peptide thrombin inhibitor, in comparison with r-hirudin and hirulog-1. Hirunorm was equipotent to hirulog-1 and 1/30 as potent as r-hirudin in blocking alpha-thrombin amidolytic activity (IC50 = 10 +/- 2, 15 +/- 1 and 0.3 +/- 0.1 nM, respectively), but it did not affect trypsin, plasmin and t-PA activities at 10 microM. All the compounds inhibited clot-bound thrombin to clots prepared by thrombin hydrolysis of purified fibrinogen in buffer. Hirunorm and hirulog-1 showed similar species-dependent potency in doubling basal in vitro clotting times of human, rat and rabbit plasma (EC200 varied 70 to 200 nM for TT, 0.7 to 16 microM for aPTT and 0.8 to 17 microM for PT), while r-hirudin was always at least three times more active. When assayed by HPLC or by bioassay of the intact peptide, hirunorm was stable against alpha-thrombin and plasma hydrolases, but it was catabolized by rat liver and kidney enzymes. Venous thrombosis was produced in anaesthetized rats by vena cava ligation following a procoagulant serum injection. Intravenous and subcutaneous hirunorm inhibited venous thrombosis at doses (< or = 0.3 mg/kg) two-three times higher than those of r-hirudin. Hirulog-1 was as active as hirunorm only after i.v. infusion. Arterial thrombosis was obtained in the anaesthetized rat by chemical (FeCl2) stimulation of a common carotid and i.v. infused hirunorm (1-3 mg/kg/30 min) inhibited it dose-dependently; r-hirudin was partly active only at 3 mg/kg, but hirulog-1 was inactive at either dose. Full antithrombotic doses of hirunorm did not affect the bleeding time as measured from punctured mesenteric vessels, in anaesthetized rats. In conclusion, hirunorm is a potent peptide thrombin inhibitor endowed with antithrombotic activity in models of venous and arterial thrombosis.

Human umbilical vein smooth muscle cells as a model to study thrombin generation and function: effect of thrombin inhibitors.

The aim of the present work was to study how human umbilical vein smooth muscle cells (HUVSMC) can initiate the coagulation process and to investigate the responses of these cells to thrombin. Exposure of HUVSMC to recalcified human plasma led to a time-dependent production of thrombin, measured both as amidolytic activity and as release of fibrinopeptide A. Thrombin activity was dose-dependently reduced by an anti-human tissue factor antibody (76 +/- 3% at 10 micrograms/ml) and by inhibitors like heparin, rec-hirudin, hirulog 1, Napap and hirunorm, a novel hirudin-like thrombin inhibitor (IC50 = 2 +/- 0.4, 8 +/- 1, 130 +/- 22, 199 +/- 29 and 68 +/- 8 nM, respectively). The release of fibrinopeptide A was similarly prevented (IC50 = 14 +/- 1, 132 +/- 25 and 50 +/- 8 nM for rec-hirudin, Napap and hirunorm, respectively). Exogenously added thrombin increased thymidine incorporation into HUVSMC to 240 +/- 30% of basal (EC50 = 0.49 +/- 0.09 nM) and thrombin inhibitors blocked this effect (IC50 = 10 +/- 3, 37 +/- 17, 343 +/- 165 and 1402 +/- 758 nM for rec-hirudin, hirunorm, Napap and hirulog-1, respectively). Also recalcified human plasma was mitogenic for HUVSMC and its effect was mainly due to endogenously generated thrombin, as shown by the use of thrombin inhibitors. In conclusion, HUVSMC are capable of initiating the extrinsic coagulation cascade, leading to the formation of thrombin which promotes clotting and stimulates DNA synthesis. Thrombin inhibitors prevent both coagulative and cellular effects of thrombin.

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.

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.

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.

Mechanism of the potentiation of neurally-induced bronchoconstriction by gallamine in the guinea-pig.

1. Electrical stimulation of the cervical vagi (15 Hz, 0.2 ms, 3 s, 7-15 V) produced a slight bronchoconstriction in the anaesthetized guinea-pig. This effect was fully abolished by atropine, while gallamine (0.1-10 mumol kg-1) produced a dose-dependent increase up to ten fold. 2. Gallamine-induced potentiation of neurally-mediated bronchoconstriction was not inhibited by depletion of sensory neuropeptides with capsaicin or by pretreatment with pyrilamine. In propranolol-pretreated guinea-pigs the potentiation induced by gallamine 3 and 10 mumol kg-1 was inhibited by 40 and 46%, respectively. 3. Physostigmine (0.5 mg kg-1) produced a very slight and slowly developing bronchoconstriction in the anaesthetized guinea-pig, which was also potentiated dose-dependently by gallamine (0.1-10 mumol kg-1). 4. Gallamine (10 mumol kg-1) potentiated the bronchial anaphylactic response induced by aerosol challenge with ovalbumin in actively sensitized guinea-pigs. 5. These results suggest that neither sensory neuropeptides nor histamine are involved in the gallamine-induced potentiation of neurally-mediated bronchoconstriction, while inhibition of the sympathetic nervous system may play a minor role. They are in general agreement with the hypothesis that gallamine antagonizes acetylcholine selectively at prejunctional muscarinic receptors in the guinea-pig airways, thus increasing its release from parasympathetic nerve terminals. These autoreceptors appear to be operant during anaphylactic bronchoconstriction.

Pharmacology of LR-B/081, a new highly potent, selective and orally active, nonpeptide angiotensin II AT1 receptor antagonist.

1. The pharmacological profile of LR-B/081, (methyl 2-[[4-butyl-2-methyl- 6-oxo-5-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1(6H)- pyrimidinyl]methyl]-3-thiophenecarboxylate), a novel antagonist at the angiotensin II (AII) AT1-receptor, was studied in vitro and in vivo. 2. In rabbit aortic strips incubated with LR-B/081 (1-1,000 nM), the concentration-response curve to AII was displaced to the right in a nonparallel fashion and the maximal contraction was progressively reduced, indicating that the compound is an insurmountable antagonist in this preparation (apparent pKB = 9.50 +/- 0.23). However, the interaction of LR-B/081 with AII receptors was found to be reversible, since the maximal response to AII was restored by coincubation with losartan, a surmountable AII AT1-antagonist. Contractions elicited by KCl or phenylephrine were not affected by 10 microM LR-B/081. 3. In rat isolated perfused kidney, LR-B/081 and losartan antagonized the AII-induced vasoconstriction [IC50 (95% confidence limits) = 17(13-24) and 39(32-54) nM, respectively]. The LR-B/081 antagonism was incompletely reversed by excess AII, while losartan was fully displaced. The IC50 values of LR-B/081 and losartan obtained against vasoconstriction induced by endothelin-1 and noradrenaline were two orders of magnitude higher. 4. In pithed rats, the intravenous administration of LR-B/081 (0.2-2 mumol kg-1) dose-dependently shifted to the right in a nonparallel fashion the dose-pressor response curve to AII. The maximal pressor response to AII was reduced by LR-B/081 in a dose-dependent fashion. The coadministration of losartan induced a progressive recovery of the maximal pressor response to All, indicating that in vivo the interaction of LR-B/081 with All receptors is reversible. LR-B/081 at 6 micromol kg-1, i.v. also did not affect the vasopressor response induced by noradrenaline in the pithed rat.5. In conscious normotensive rats, single oral administration of LR-B/081 at 6 micromol kg-1 markedly inhibited the All-induced pressor response; the inhibition lasted more than 24 h.6. In conscious renal hypertensive rats, intravenous LR-B/081 appeared as potent as losartan (ED40mmHg(95% confidence limits) = 0.50(0.36-0.70) and 0.86(0.57-1.3) micromol kg-1, respectively). A single intravenous(2 micromol kg-1) or oral (6 micromol kg-1) administration of LR-B/081 induced a marked fall in blood pressure which lasted for at least 12 h.7. In conscious spontaneously hypertensive rats, LR-B/081 at 20 micromol kg-1 , p.o., induced a marked and sustained fall in blood pressure. The duration of the antihypertensive effect was longer than 12 h.Heart rate was not modified by LR-B/081 treatment. Repeated oral administration of 17 micromol kg-1LR-B/081 for 16 days did not result in the development of tolerance.8 These results demonstrate that LR-B/081 is a potent, selective and orally active antagonist of All at the AT1-receptor subtype, which markedly lowers the blood-pressure in conscious renal and spontaneously hypertensive rats.

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.

Effects of spasmolytics on K+-induced contraction of rat intestine in vivo.

Eight spasmolytic drugs commonly used in the treatment of the irritable bowel syndrome were compared to verapamil with respect to their effects (all drugs injected i.v.) on the contraction of duodenum, ileum and colon induced by high K+ topical application in the anaesthetized rat. Verapamil greater than rociverine greater than papaverine greater than mebeverine greater than dicyclomine antagonized dose-dependently the contraction of duodenum and colon, the activity on duodenum being from 2 (rociverine) to 10 (verapamil) fold higher. Verapamil and rociverine, but not the other drugs mentioned above, were also active on ileum. N-Butylscopolammonium bromide, phloroglucinol and trimebutine were inactive against the contraction of the three intestinal tracts and prifinium bromide was inactive on duodenum and ileum, while it had remarkable activity on colon, unrelated to its antimuscarinic activity. The results are discussed briefly with reference to the pharmacological therapy of the irritable bowel syndrome.

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.

Ganglion-blocking agents enhance neurally mediated bronchoconstriction in the guinea-pig: possible role of sensory neuropeptides.

The effect of ganglion blockade by hexamethonium bromide (0.1-100 mumol.kg-1) and pentolinium tartrate (0.01-3 mumol.kg-1) on the bronchoconstriction induced by vagal nerve stimulation (15 Hz, 0.2 ms, 3 s, 7-20 V) was evaluated in the anaesthetized guinea-pig. Both ganglion-blocking agents potentiated this response dose dependently. When the neural bronchoconstriction was suppressed by atropine, hexamethonium restored this response dose dependently. Hexamethonium produced inhibitory effects on vagally induced bronchoconstriction in capsaicin-desensitized and in propranolol- or reserpine-pretreated guinea-pigs. Propranolol (0.03-3 mumol.kg-1) produced a marked dose-dependent increase of neural bronchoconstriction (which was markedly reduced, about 10 times) in capsaicin-desensitized animals. Our results show that ganglion-blocking agents potentiate neural bronchoconstriction in the guinea-pig and that sensory neuropeptides may have a role in this effect. Moreover, beta-adrenergic modulation of the release of neuropeptides from vagal sensory fibers is suggested.

Molecular pharmacology of LR-B/081, a new non-peptide angiotensin AT1 receptor antagonist.

This report describes the molecular pharmacological properties of LR-B/081 (methyl 2-[[4-butyl-2-methyl-6-oxo-5-[[2'-(1H-tetrazol-5- yl) [1,1'-biphenyl]-4-yl]methyl]-1 (6H)-pyrimidinyl]methyl]- 3-thiophenecarboxilate), a novel non-peptide angiotensin II receptor antagonist. This compound potently displaced [3H]angiotensin II from angiotensin AT1 (Ki = 1.4 nM, rat adrenal cortex), but not from angiotensin AT2 (Ki > 1 microM, bovine cerebellar cortex) receptors and did not show affinity for other receptor systems (Ki > 10 microM). In saturation studies, LR-B/081 both increased KD and decreased Bmax values in a dose-dependent fashion. The rate of dissociation of [3H]angiotenin II from angiotensin AT1 receptors was not affected by the presence of 1 microM LR-B/081 and the association rate of [3H]angiotensin II was not decreased by the presence of 1 or 30 nM LR-B/081, indicating that the Bmax reduction was not due to an allosteric interaction or to a delay in reaching the steady-state conditions. These data underline the complexity of the antagonistic nature of LR-B/081, presenting features of both competitive and noncompetitive antagonism.

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.