Margaret O'Donnell

An in vivo model for measuring antigen-induced SRS-A-mediated bronchoconstriction and plasma S RS- A levels in the guinea-pig

1 Pharmacological modulation of antigen‐induced anaphylaxis in actively sensitized guinea‐pigs with intravenously administered indomethacin (10 mg/kg), pyrilamine (2.0 mg/kg) and propranolol (0.1 mg/kg) resulted in a delayed onset, slowly developing bronchoconstriction indicative of a slow‐reacting substance of anaphylaxis (SRS‐A) response. 2 Measurements of pulmonary mechanics on the drug‐pretreated animals challenged with ovalbumin demonstrated a more prominent effect on dynamic compliance than resistance. This is consistent with the more potent effects of SRS‐A on peripheral rather than central airways. 3 The slowly developing bronchoconstriction obtained after treatment with indomethacin, pyrilamine and propranolol was inhibited by the standard SRS‐A antagonist, FPL 55712 and the SRS‐A synthesis inhibitors, phenidone, BW 755C and nordihydroguaiaretic acid. 4 Plasma SRS‐A levels were determined in guinea‐pigs following antigen challenge. The appearance of SRS‐A in the plasma preceded the onset of bronchoconstriction and SRS‐A levels remained elevated throughout its development. Coincident with the inhibition of bronchoconstriction by the SRS‐A synthesis inhibitor, phenidone, was a dose‐dependent reduction in plasma SRS‐A. The intravenous ED50 in each case was 4 mg/kg. 5 This model of antigen‐induced SRS‐A‐mediated bronchoconstriction should prove useful for the in vivo evaluation and development of therapeutics which regulate the synthesis of SRS‐A.

Pentadienyl carboxamide derivatives as antagonists of platelet activating factor

A series of N-[4-(3-pyridinyl)butyl]-5,5-disubstituted-pentadienamides was prepared and evaluated for PAF-antagonist activity. Compounds were assayed in vitro in a PAF-binding assay employing washed, whole dog platelets as the receptor source and in vivo after intravenous or oral administration for their ability to prevent PAF-induced bronchoconstriction in guinea pigs. Criteria required for good oral activity in the latter model include an (E,-E)-5-phenyl-2,4-pentadienamide, a second phenyl or a four- or five-carbon alkyl moiety in the 5-position of the diene, and an (R)-[1-alkyl-4-(3-pyridinyl)butyl] substituent on the carboxamide nitrogen atom. The alkyl substituent on this side chain can be methyl, ethyl, or cyclopropyl. Two members of this series, [R-(E)]-5,5-bis(4-methoxy-phenyl)-N- [1-methyl-4-(3-pyridinyl)butyl]- 2,4-pentadienamide (31) and [R-(E,E)]-5-(4-methoxyphenyl)-N-[1-methyl-4- (3-pyridinyl)butyl]-2,4-decadienamide (58), were selected for further pharmacological evaluation. Both were found to be substantially longer acting after oral administration than the corresponding S enantiomers in the guinea pig bronchoconstriction assay. A second in vivo model used to evaluate PAF antagonists determines the ability of test compounds to decrease the area of skin wheals induced by an intradermal injection of PAF. In this model, using both rats and guinea pigs, compounds 31 and 58 were found to be as active as the reference PAF antagonist 3-[4-(2-chlorophenyl)-9-methyl-6H- 1-(4-morpholinyl)-1-propanone (45).

Relaxant activity of atriopeptins in isolated guinea pig airway and vascular smooth muscle

Atriopeptins are circulating peptide hormones which are secreted by atrial tissue and act at the kidney. Because the atriopeptins survive passage through the pulmonary circulation, they also may be involved in the modulation of airway or pulmonary vascular smooth muscle tone. Using in vitro organ bath techniques, atriopeptins were found to induce potent concentration-dependent relaxation of isolated guinea pig trachea, and pulmonary artery with a rank order of potency: atriopeptin III greater than atriopeptin II greater than atriopeptin I. Atriopeptin-induced smooth muscle relaxation was observed to be a direct response since it was not mediated by activation of relaxant VIP receptors, beta-adrenergic receptors, or H2 receptors nor affected by cyclooxygenase inhibition or denuding of the vasculature or trachea of endothelial and epithelial cells. The time course of atriopeptin II-induced relaxation of the pulmonary artery was transient in contrast to the prolonged relaxations on the trachea. The transient relaxant responses of atriopeptin II on pulmonary artery were not due to metabolism of atriopeptin II to atriopeptin I by angiotensin-converting enzyme since pretreatment with captopril did not augment the response. These results seem to indicate that distinct atriopeptin receptors may exist in airway and pulmonary arterial smooth muscle and that activation of these relaxant receptors may play an important role in the regulation of pulmonary vascular and bronchomotor tone.

Pharmacologic properties of FPL 55712 administered by aerosol

FPL 55712 was investigated by the aerosol route of administration for efficacy at protecting against leukotriene-induced bronchoconstrictions in guinea pigs and for mediator release inhibitory activity in passively sensitized rats. In the studies to investigate leukotriene antagonism; anesthetized, spontaneously breathing guinea pigs were pretreated with propranolol and were exposed via tracheal cannula to aerosols generated by a Monaghan nebulizer. Subsequently, the animals were artificially ventilated and challenged with LTD4 or LTE4 (25 μg/kg, i.v.). FPL 55712 produced a concentration-dependent inhibition of LTD4 and LTE4-induced bronchoconstriction (IC50s 0.5% and 0.8%, respectively). Although the biologic half-life of FPL 55712, administered intravenously, was very short (1.7 minutes against LTD4 and 1.2 minutes against LTE4) after aerosol administration the biological half-life was surprisingly long (120 minutes against LTD4 and 90 minutes against LTE4). Aerosolized FPL 55712 also possessed weak antiallergic activity in comparison to disodium cromoglycate when measured as an inhibitor of IgE-mediated anaphylactic bronchoconstriction in rats (IC50s of 2.0% and 0.01%, respectively). Thus, these studies demonstrate that, when administered by aerosol, FPL 55712 is effective at protecting against leukotriene-induced bronchoconstrictions, exhibits a long duration of action and also possesses weak antiallergic activity.

Chapter 7. Pulmonary and Antiallergy Agents

Publisher Summary This chapter discusses the researches made during the past year on pulmonary and antiallergy agents. Clinical tests have proved that several leukotriene D 4 (LTD 4 ), the “first generation” compounds are not potent enough to fully test their role in treating asthmatics. More potent, orally-active compounds have recently been reported. LTB 4 is hypothesized to be a potential mediator of lung eosinophilia in asthmatics. For this reason, LTB 4 antagonists may be useful in treating asthma. Of special interest with regard to future antiasthmatic therapy are reports of new, orally-active, selective 5-LO inhibitors. ICI 207, 968 has been reported to be 200-times more potent an inhibitor of 5-LO than CO. The thromboxane (TXA 2 ) antagonist, GR 32191, has been reported to decrease allergen-induced bronchoconstriction in man. Phospholipases in the signal transduction mechanisms found in key cells are associated with the initiation of asthmatic disease. Two β 2 -adrenoceptor agonists, salmeterol, and formoterol have been evaluated clinically by inhalation. Recent progress in the cloning of the subunits of the human IgE receptor may allow the future development of high flux in vitro screens for non-peptide antagonists. In addition, histamine release inhibitory factors have been identified and may be novel tools in the development of mediator release inhibitors (MRI). Vasoactive intestinal peptide (VIP) has been postulated to be the peptide mediator of the non-adrenergic, non-cholinergic, inhibitory pathway. Thus, VIP may be an important endogenous bronchodilator in man. Pirenzepine, an orally-active specific M1 antagonist, increased lung volume in both large and small airways in asthmatics. These results indicated the functional role of M1 receptors in human airways and suggest the potential for the development of anticholinergic drugs based on pirenzepine.

The Physiology and Biochemistry of Normal and Diseased Lung

Publisher Summary This chapter presents the knowledge of the cellular composition and anatomy, the physiological properties, and the biochemical mechanisms associated with normal lung function. This information provides the basis for describing the pathophysiology associated with various obstructive, restrictive, and vascular disease states of the lung. The diagnostic tests used to detect the lung diseases and the biochemical mechanisms associated with the therapeutic treatment of these diseases are described in the chapter. The lungs are innervated along the tracheobronchial tree by the autonomic nervous system. Afferent autonomic nerve fibers from “stretch receptors” in the alveoli, “irritant receptors” in the bronchi, bronchioles, and trachea, and “cough receptors” in the larynx transmit signals to the central nervous system via the vagus nerve. The lung is equipped with two arterial blood systems because of the unique function of the lung to supply oxygen to the circulatory system of the body. The primary function of the lung is to exchange oxygen and carbon dioxide between the gaseous atmosphere in which man lives and the blood that transmits oxygen to and removes carbon dioxide from the cells of the body.