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In anaesthetized ventilated guinea-pig, acetaldehyde (CAS 75-07-0) (40-80 mg/kg i.v.) elicits a dose-dependent increase in intratracheal pressure accompanied by an increase in circulating histamine. When acetaldehyde is injected repeatedly at 15 min intervals in capsaicin-desensitized animals, it already loses its activity at the second administration (50% reduction; p0.01); this does not happen in control animals. This phenomenon is even more marked when acetaldehyde is given at the dose of 80 mg/kg i.v., since at the third injection both the bronchoconstriction and the increase in blood histamine are almost completely reduced to baseline values. The increase in intratracheal pressure caused by acetaldehyde (20, 40, 80 mg/kg i.v.) is associated with a dose related increase in microvascular permeability and leakage of protein-bound Evans blue in lower tracheal tissue. This event and the bronchoconstrictor response caused by acetaldehyde (40 mg/kg i.v.) are 87% and 35% inhibited, respectively, (p0.01) in tachykinin-depleated animals. On the contrary, thiorphan (2 mg/kg i.v.) remarkably potentiates both the rise in intratracheal pressure (110%; p0.01) and Evans blue extravasation (215%; p0.01) induced by acetaldehyde (20 mg/kg i.v.) in normal guinea-pigs. Furthermore, treatment with CP-96,345, a selective tachykinin NK1-receptor antagonist, only prevents plasma extravasation in lower tracheal tissue (82% inhibition; p0.01) without affecting the bronchoconstriction caused by acetaldehyde (40 mg/kg i.v.).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaldehyde administered intravenously at various doses (20, 40 and 80 mg/kg) elicits a dose-dependent increase in intratracheal pressure (ITP) and a proportional rise in histamine blood concentration in anaesthetized guinea-pigs. Similar effects were observed in ovalbumin-sensitized guinea-pigs upon aerosol of acetaldehyde (20 mg/ml) which has been administered at the flow rate of 0.1 ml/min for 2 min. Theophylline (CAS 58-55-9) antagonized both the increase of ITP values and the rise of histamine in the blood caused by acetaldehyde given intravenously (ED50 = 5.8 mg/kg i.v.) or by aerosol (ED50 = 4.9 mg/kg i.v.). Furthermore, in animals where combined treatment with pyrilamine (2 mg/kg i.v.) and captopril (2 mg/kg i.v.) resulted in a remarkable potentiation of the bronchoconstrictor response to acetaldehyde (20 mg/kg i.v.), the administration of theophylline (5 mg/kg i.v.) or of the substance P (SP) receptor antagonist, [D-Pro4, D-Trp7.9] SP 4-11 (10 mg/kg i.v.) reduced the augmented action of acetaldehyde on respiratory airways induced by captopril by more than 50%. Moreover, the bronchoconstriction induced by acetaldehyde (40 mg/kg i.v.) was also associated with a significant increase of extravasation of Evans blue in tracheal tissue. Both these effects of acetaldehyde were inhibited by theophylline (10 mg/kg i.v.), whereas a NK1-TK (neurokinin 1-tachykinin) receptor antagonist (412 micrograms/kg i.v.) reduced (81%; p0.001) only the vascular permeability changes caused by acetaldehyde.(ABSTRACT TRUNCATED AT 250 WORDS)

The time to respiratory crisis in ovalbumin-sensitised guinea-pigs following exposure to aerosol administered antigen was dose dependently delayed by inhalation of nimesulide (0.1% to 1%), whereas indomethacin had no effect. At the same time, nimesulide significantly reduced blood histamine concentrations, in contrast to the slight increase observed with indomethacin. In human bronchial muscle preparations, nimesulide, but not indomethacin, antagonised H1-histamine-receptor activation by histamine and was without effect on acetylcholine-induced responses. Bronchoconstriction was also elicited in anaesthetised guinea-pigs by intravenous acetaldehyde (5% in saline, 1 ml/kg). This effect, which is paralleled by a rise in blood histamine concentrations, was significantly attenuated by inhaled nimesulide (0.1% to 1%), but not by indomethacin (1%). These data, which further support the antihistaminic and antiallergic activity of nimesulide, may have therapeutic relevance in patients who are affected by inflammation of the respiratory tract and who also have a history of allergic bronchoconstriction.

A series of 1-(3-substituted-5-isoxazolyl)-2-alkylaminoethanol derivatives was synthesized in order to evaluate the effectiveness of the isoxazole ring in replacing the catechol moiety of beta-adrenergic compounds. Among the investigated compounds, 1-(3-bromo-5-isoxazolyl)-2-tert-butyl aminoethanol hydrochloride, named broxaterol hydrochloride (laboratory code Z 1170), resulted to be the most potent and selective beta 2-agonist of the series. In vitro studies confirmed the beta 2-agonist profile of broxaterol, which showed a marked bronchodilating activity in different experimental models. Interestingly, besides its direct effect in relaxing bronchial smooth muscle, broxaterol was, also, very effective in inhibiting asthmogenic mediator release both in vitro and in vivo. The preclinical studies demonstrated that the similar potency observed in vitro for both broxaterol and salbutamol resulted in a higher effectiveness of broxaterol with respect to salbutamol, when the compounds were given by oral route. These findings account for a probably greater bioavailability of broxaterol after oral administration.

The effect of the inhibition of aminopeptidase and enkephalinase A on the pain threshold of mice and rats was investigated, using bestatin and thiorphan as selective peptidase inhibitors. The results indicate that both enzymes are relevant to the catabolism of enkephalins in vivo; however, their simultaneous activation requires particular conditions. These conclusions are based on the following observations: (1) Only concomitant intracerebral treatment with both inhibitors led to an increase in the threshold of animal pain, whereas, in the presence of exogenous peptides, the concomitant injection of both inhibitors in mice elicited an analgesic response greater than the sum of the effects of each single inhibitor. (2) This response could be seen only after acute trauma; in fact, when the drugs were injected through a plastic cannula, only enkephalinase A inhibition was effective in increasing analgesia induced by exogenous peptides.

Following oral administration of14C labelled chloramphenicol (CAP) in the rat (30 mg/Kg) the blood time curves obtained by gas chromatographic and radiochemical estimation appear to be strikingly divergent. Apparently this difference is due to a new CAP metabolite which is devoid of microbiological activity and whose chemical nature has yet to be defined; it is, however, characterized by the property of establishing covalent bonds to proteins. It may be interesting to point out that a methylsulphonyl analogue of CAP shows, under the same experimental conditions, blood concentration curves identical in terms both of radioactive or of gas chromatographically estimated material.

The injection of 0.15 to 0.2 mg/kg of muscimol intravenously, lowered the ED50 dose of morphine in mice and rats. Maximal tolerated doses of muscimol failed to cause alangesia when injected alone

Be statin [(2S,3R)-3-amino-2-hydroxy-4, phenyl-butanoyl]-L-leucine1, a strong inhibitor of aminopeptidase B and leucine aminopeptidase, icv administered in mice potentiates the analgesic effect of both Met-Enkephalin and Met-Enkephalinamide. Leu-Enkephalin icv administered in mice does not induce analgesia; when it is injected (100 μg/mouse) with Be statin (50 μg/mouse) a clear analgesic effect is found in all the animals tested. On the contrary the ED50 of D-Val2-Met-Enkephalin was not affected by Bestatin. The results we obtained suggest that, in our experimental conditions, aminopeptidase activity is relevant in determining the effect of enkephalins.

The synthesis of the stereoisomers of the centrally acting analgesic 1-[1-(2-chlorobenzyl)-pyrrol-2-yl]-2-di-sec.-butylamino-ethanol (viminol) is described. Their absolute configuration has been shown by comparing the circular dichroism (CD) curves with those of some phenyl analogs: for one of the viminol stereoisomers the postulated configurational assignment has been recently confirmed by an X-ray analysis. The pharmacological properties shared by the viminol stereoisomers are also described. The R,R configuration of the sec.-butyl groups and the S configuration of the hydroxy group appear to be essential for the agonistic effects: analgesia, tolerance and physical dependence in rodents. The S,R,R configurated viminol does not substitute, however, for morphine in monkeys, using the single dose suppression test. S,S or R,S(S,R) configurations of the sec.-butyl groups are associated with antagonistic properties. The binding capacity of the viminol stereoisomers to the opiate receptors and their influence on the acetylcholine release from the intestinal cholinergic terminals electrically stimulated are also described.

Opioids' modulation of beta-receptors' density and function has been investigated in a cultured cell line system. Rat C6 glioma cells do not have opioid receptors or, at least, the number of these receptors is very low, but cell exposure to desmethylimipramine (DMI) causes expression of functional opioid receptors as indicated by the increased [3H]DHM binding and by the acquired ability of opioids to inhibit ISO-stimulated cAMP accumulation. Cell exposure to DMI also causes beta-receptors' down-regulation as indicated by the decline in [3H]DHA binding coupled to a reduced ability of isoproterenol (ISO) to stimulate cAMP accumulation in intact cells. In the present paper we show that cell exposure to opioid agonists during DMI treatment counteracted DMI-induced beta-receptor loss. Similarly, opioid agonists added at the beginning of ISO exposure in DMI-pretreated cells, inhibited ISO-induced beta-receptor tachyphylaxis. These results suggest that opioids may exert a protective effect on beta-receptor function and this appears to be a common mechanism which is operant when overstimulation of beta-receptors takes place.

A series of 1-(3-subst-5-isoxazolyl)-2-alkylaminoethanol derivatives was synthesized and tested in order to evaluate the effectiveness of the isoxazole ring in replacing the catechol moiety of beta-adrenergic compounds. Direct binding studies and the influence on beta-receptors mediated responses in isolated guinea-pig atria and guinea-pig trachea were investigated to determine the pharmacological profile of the new derivatives. The results indicate that some derivatives with proper substitution in the isoxazole ring and in the aminoalcohol chain displayed a marked selectivity towards beta 2 tracheal receptors. In vivo studies confirmed this profile, and the derivative 1-(3-bromo-5-isoxazolyl)-2-tert.butyl aminoethanol hydrochloride was selected and further developed as a potential bronchodilatory agent.

Analgesia by enkephalins is of short duration probably due to rapid degradation by peptidases. An attempt was made to evaluate the action of either d-phenylalanine or β-phenylpropionic acid, two in vitro inhibitors of carboxypeptidase A activity, on the extent and duration of the analgesia elicited by exogenous methionine-enkephalin (Met-Enk) as well as by endogenously released peptides. The effect of d-phenylalanine added to the bath fluid on the inhibition of electrically stimulated guinea pig ileum contraction by methionine-enkephalin and morphine was also examined. In the present experiments, carboxypeptidase A inhibition did not affect per se either the pain threshold of mice or the electrically evoked contraction of guinea pig ileum, but it significantly increased the effect of enkephalins.

Publisher Summary This chapter focuses on bestatin, which is a selective and potent inhibitor of enkephalin aminopeptidase. At least two different enzymes are thought to be operative in the degradation of enkephalines released extraneurally: (1) an aminopeptidase which cleaves enkephalin at the amino terminus, and (2) a peptidyl dipeptidase that hydrolyzes the Gle-Phe bond. By generating Tyr-Gly-Gly, this enzyme seems to be more specific for the physiologic inactivation of enkephalins while the aminopeptidase activity appears dominant in crude brain homogenates and in soluble or unwashed particulate fractions. The chapter discusses the effect of bestatin on purified Carboxypeptidase A (CPA) activity, and on the Angiotensin Converting Enzyme (ACE) activity. ACE is a peptidyldipeptidase that cleaves a dipeptide from the C-terminal end of bradykinin and angiotensin I. Bestatin in concentration up to 10 -5 M did not affect the ACE activity. The chapter also discusses the effect of bestatin on the metabolism of enkephalins by aminopeptidase.

A series of pyrroles bearing an ethanol- or an iso-propanolamine side-chain in the beta-position was prepared and their adrenergic activity evaluated. The absence of any appreciable activity suggests that the pyrrole ring is not suitable for replacing the phenol nucleus in derivatives possessing an adrenergic activity. Noteworthy is the amphetamine-like activity observed in amino-ketone (XXIII).

The synthesis and pharmacological evaluation of a number of symmetrical bivalent ligand type beta-adrenolytics related to practolol are reported. The best results have been observed with N,N'-bis[3-[2-hydroxy-3-[1-methylethyl)amino]propoxy]phenyl] ethanediamide.