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Esaprazole, N-cyclohexyl-1-piperazineacetamide monohydrochloride, was studied for its activity to prevent gastric mucosal damage induced by several necrotizing agents in the rat. Its effects on acid gastric secretion and the role of gastric mucosal prostaglandin generation were also investigated. Esaprazole, given orally, dose dependently prevented the formation of mucosal damage induced by absolute ethanol, 0.2 N NaOH or 0.6 N HCl. This activity occurred at doses lower than the antisecretory doses. Esaprazole was also found to increase the gastric mucosal prostaglandin content but at doses that exceeded the cytoprotective doses. The failure of indomethacin to impair the gastric mucosal protection provided by esaprazole suggests that mechanisms other than mobilization of endogenous prostaglandins may be involved.

The (±)-3′-hydroxyfarrerol (IdB 1031) is a new drug endowed with an interesting mucokinetic activity. In this study the effectiveness of IdB 1031 has been verified in a model of airway hyperreactivity and lung inflammation induced in anaesthetized guinea pig by active cigarette smoke exposure. IdB 1031 (500 mg/kg per os) completely inhibited the capacity of cigarette smoke to induce airway hyperreactivity. IdB 1031 also inhibited the recruitment of proinflammatory cells within the airway lumen as showed in bronchoalveolar lavage fluids. In line with these experiments IdB 1031 inhibited 5-lipoxygenase with an lC50 of 7.36×10−6 M in human leukocytes challenged by A-23187 (2 μM). A significant reduction of the above parameters was observed also in animals exposed to smoke after repeated treatment with IdB 1031 at 200 mg/kg per os for 15 days. These results show that IdB 1031 is a promising drug with a favourable spectrum of activities on the respiratory tract.

1 The formation and release of PGE2-like material (PGE2-lm) from guinea-pig isolated trachea and human bronchi following relaxation with isoprenaline (I) was investigated. 2 When airway smooth muscle precontracted with pilocarpine is relaxed by I, PGE2-lm is released in the bathing fluid. Under conditions of β-adrenoreceptor desensitization, a greater amount of PGE2-lm is formed and the responsiveness of guinea-pig tracheal spirals to cumulative doses of I is diminished. 3 Inhibition of cyclo-oxygenase with indomethacin does not modify the relaxation induced by I but prevents the occurrence of refractoriness to I as well as formation and release of PGE2-lm. Addition of exogenous PGE2 to guinea-pig tracheas which were treated with indomethacin is able to restore the capacity of I to cause tachyphylaxis. 4 It is concluded that PGE2 which does not mediate the relaxation induced by I in airway smooth muscle, is responsible for the onset of desensitization of the β-adrenoreceptor.

Various doses of histamine, bradykinin and leukotriene C 4 caused bronchoconstriction in anaesthetized guinea-pigs which were breathing spontaneously or artificially ventilated; there was a simultaneous, dose-related increase of circulating TXA 2 . The animals were prepared for continuous recording of extracororeal circulation in order to detect the appearance in the blood of bioassayable levels of TXA 2 -like substance. Furthermore, a TXA 2 derivative, the mono-O-Me-TXB 2 , was radioimmunoassayed. Atropine, oxytropium bromide and ipratropium bromide given in μmol doses prevented both the increased airway resistance and the release of TXA 2 -like substance in the blood. Pirenzepine dihydrochloride was the least active of the drugs tested. The protecting activity of anticholinergics and the relationship with their ability to affect TXA 2 -like substance generation suggest a new site of action for these drugs besides the blockade of muscarinic receptors.

Angiotensin II (AII) induces generation of prostacyclin (PGI2) in rabbit lung in vitro at different ages, i.e., fetus, newborn and adult. Particularly, neonatal rabbit lungs display a pattern of sensitivity to AII in producing PGI2, measured as 6-oxo-PGF1 alpha, which seems to be higher than that observed in fetal lungs. The PGI2 release appears to be specific for AII stimulation since the vasoconstriction induced by noradrenaline and ergotamine was not associated with generation of this lipidic material. The inability of PGI2 to relax the extralobar pulmonary artery in the newborn suggests that the lung microcirculation is the most likely site where the vasodilating and antiaggregatory functions of PGI2 may have a physiological role.

Ro 21-7634 has previously been shown to inhibit histamine and SRS-A release from actively-sensitized guinea pig lung fragments upon antigen challenge. In the studies described herein, it was observed that Ro 21-7634 does not decrease SRS-A release but instead acts to inhibit the synthesis of this mediator. This was confirmed by studying SRS-A synthesis in vitro in rat peritoneal cells after challenge with ionophore A23187. In the peritoneal cell system, Ro 21-7634 exhibited an IC50 of 500 microM, in comparison with 5.8,11,14-eicosatetraynoic acid, phenidone and BW755C (IC50's of 2, 100, and 100 microM, respectively). When studied at 10(-4) and 10(-3) M in perfused guinea pig lung, Ro 21-7634 inhibited antigen-induced thromboxane A2 production by 68 and 96%, respectively. In this system, antigen is believed to induce thromboxane A2 production through the release of histamine and SRS-A from lung tissue. These mediators then interact at receptor sites in the lung parenchyma to induce thromboxane A2 synthesis. Ro 21-7634 could thus be inhibiting thromboxane A2 production by preventing the release of histamine and synthesis of SRS-A in the perfused lung system. Such a mechanism is suggested by the fact that although Ro 21-7634 was effective in inhibiting antigen-induced thromboxane production, it was ineffective in inhibiting thromboxane A2 production induced in the guinea pig lung system by the direct perfusion of histamine or SRS-A through the lung.

S-(+)-2-(4-Fluorophenyl)-alpha-methyl-5-benzoxazolacetic acid (flunoxaprofen, Priaxim is a new antiinflammatory compound, which in various biological systems interferes with the generation and release of arachidonic acid metabolites of the cyclo-oxygenase pathways without affecting the formation of 5- and 12-lipoxygenase products. Flunoxaprofen reduces the concentration of thromboxane (TX)B2 (ED50 = 35.4 mg/kg p.o.) and prostaglandin (PG)E2-like activity (ED50 = 39.9 mg/kg p.o.) in the inflammatory exudate of rats 8 h after implantation of sponges soaked with carrageenan, whereas the concentration of leukotriene (LT)B4 remains in the range of that of the untreated animals (3.1 ng/ml). Flunoxaprofen inhibits cell infiltration in the exudate and this suggests that LTB4 does not initiate cell recruitment but may represent a mechanism for amplifying the inflammatory response. Using human platelets challenged with collagen, flunoxaprofen only at higher concentration (10(-4) mol/l) reduces TXB2 formation without altering generation of 12-hydroxy-5,8,10,14-eicosatetraenoic acid. This suggests a low capacity of flunoxaprofen of affecting platelet aggregation regulated by arachidonic acid metabolites. Flunoxaprofen prevents pulmonary changes due to secondary release of TXA2 in the guinea-pig. In fact this drug prevents changes due to immunological reaction and antagonizes bronchoconstriction due to exogenous administration of histamine and LTC4.(ABSTRACT TRUNCATED AT 250 WORDS)

Tiaramide hydrochloride (THC) is a benzothiazoline derivative with a remarkable antianaphylactic activity: in anaesthetized guinea-pig it shows protecting effects against histamine (H)- and bradykinin (Bk)-induced bronchoconstriction, preventing increase of lung resistance and decrease of dynamic compliance. At the same time THC inhibits formation of circulating thromboxane A2 brought about by H and Bk. THC is also able to antagonize the contractions induced by CaCl2 on isolated guinea-pig tracheal spirals and its mode of action seems to be of the competitive type. Furthermore THC abolishes the "tonic" phase of K+-induced contractions of guinea-pig taenia coli which are dependent on inward movement of calcium, whereas the "phasic" component of the contractions is left unaltered. THC is a very weak inhibitor of 3'-5' cyclic adenosine monophosphate phosphodiesterase which is affected only at very high dosage (10(-2) M). The calcium antagonistic activity of THC may explain both its bronchodilating and antianaphylactic properties.

Defibrotide, a polydeoxyribonucleotide obtained from mammalian lungs, reduced in a dose-dependent fashion the ischemic contracture due to low perfusion (0.2 ml/min) of isovolumic left heart of rabbit and abolished the irregular rhythm of the heart, thereby restoring the cardiomechanical activity upon reperfusion (20 ml/min). Defibrotide stimulated the release of PG-like material from the heart in a dose-dependent manner without modifying the basal contractility. Both PGE2 and PGI2 (10 ng/ml) have an antiischemic activity on this preparation as shown by the partial reduction of the ischemic contracture and by the improvement of heart contractility upon reperfusion. Indomethacin infusion (1 microgram/ml) completely removed both the antiischemic activity of Defibrotide (400 micrograms/ml) and its ability to increase the generation of prostaglandins in the rabbit heart. These results suggest that Defibrotide has a beneficial influence on ischemic rabbit heart through an increase in prostaglandin synthesis. However other mechanisms not necessarily related to prostaglandin generation, such as a direct effect on membrane function deactivation and mitochondrial Ca2+ overload, should be considered in explaining the antiischemic activity of Defibrotide in the rabbit heart.

Summary Tiaramide hydrochloride (THC), a benzothiazolinone derivative, displays a direct bronchodilating activity associated with anti-anaphylactic properties. The smooth muscle relaxing capacity of this compound is not related to increased levels of cyclic AMP. The anti-anaphylactic activity has been investigated using isolated lungs from ovoalbumin sensitized guinea-pigs. THC prevents histamine and TXA 2 release from lungs during antigen exposure. In addition to this THC antagonizes the direct effect of histamine on TXA 2 generation in guinea-pig lungs without affecting the cyclo-oxygenase system. Our results indicate that THC can control the anphylactic reaction through at least two different mechanisms: 1) inhibition of mediator release, 2) direct antagonism of their spasmogenic activity.

Defibrotide, a polydeoxyribonucleotide extracted from mammalian organs (laboratory code Fraction P), displays antithrombotic activity after oral administration on different animal species. This activity is also demonstrated in a typical local thrombonecrotic hemorrhagic lesion caused by endotoxin in rabbit (Shwartzman reaction). Defibrotide prevents and antagonizes this kind of lesion in a dose dependent and in a long lasting way. The ability of Defibrotide to increase generation of PGI2 from vascular tissue following oral administration, is demonstrated and the mechanism of this phenomenon discussed.

Histamine 2.5, 5, 10 or 20 μg/kg i.v. induce a pronounced bronchospasm in guinea-pigs, accompanied by a dose-related increase of TXA 2 in arterial blood, as revealed by contraction of rabbit isolated aorta and by radioimmunoassay. Aspirin 10 mg/kg prevented formation of TXA 2 like material without significantly modifying the severity of the bronchospasm. Bradykinin 0.5, 1 or 2 μg/kg i.v. acted similarly, except that pretreatment with aspirin blocked both the increased airway resistance and release of TXA 2 . Aspirin also blocked the increase in blood pressure and heart rate caused by histamine or bradykinin.

Summary The selectivity of procaterol for β 2 -adrenoceptors vs β 1 -adrenoceptors in animals has been already described. In these studies the ability of procaterol to protect guinea-pig against bronchoconstriction induced by various spasmogens such as histamine, LTC 4 and acetylcholine is demonstrated. The results obtained both in anaesthetized animals and in perfused lungs clearly show that procaterol antagonizes not only the direct effect of the bronchoconstrictors quoted above but also their ability to activate arachidonic acid metabolism and to augment the generation of TXA 2 . Procaterol (0,3-3 μg/Kg i.v.) is more potent than salbutamol in protecting passively sensitized guinea-pig from massive bronchoconstriction following antigen challenge: a phenomenon which is paralleled by an increment of the circulating TXA 2 . The possibility that the adenylate-cyclase-stimulating properties of procaterol may explain its antiasthmatic activity is discussed.

1 Histamine (0.5 to 5 micrograms) and slow reacting substance of anaphylaxis (SRS-A, 0.05 to 0.3 u), injected in the isolated, perfused lungs of normal and ovalbumin-sensitized guinea-pigs, promote formation and release of thromboxane A2(TXA2) and other arachidonate metabolites, the effect being more pronounced in sensitized lungs. 2 Carbachol injected (1 to 10 micrograms) or perfused (1 micrograms ml-1 min-1) through normal or sensitized lungs does not elicit formation of TXA2 and prostaglandins. Furthermore the increased generation of arachidonate metabolites due to histamine is not altered by carbachol. 3 Atropine and ipratropium bromide (1 microgram ml-1 min-1) reduce significantly the increased rate of production of TXA2 caused by histamine and SRS-A both in normal and sensitized lungs, whereas hexamethonium (10 to 25 micrograms ml-1 min-1) is ineffective. 4 The mechanism of action of atropine in inhibiting the increased generation of TXA2 is clearly not related to its antimuscarinic or antihistaminic properties. The drug might act at the early events, involved in the activation of arachidonic acid metabolism. The results suggest new sites of action for atropine which, besides the control of the vagal bronchomotor tone, interferes directly with the primary mediators of anaphylaxis.