Bronchodilator prostaglandin-effect

Epinephrine and isoproterenol (via cAMP mechanisms) and theophylline (via cAMP or block of adenosine receptors) inhibit the release of mediators from mast cells and basophils and cause bronchodilation. Diphenhydramine competitively blocks histamine actions at H, receptors, actions that would otherwise cause bronchoconstriction and increased capillary permeability. Dexamethasone has multiple cellular effects, including inhibition of IgE-producing clone proliferation, block of T helper cell function, and anti-inflammatory actions. Most of the actions of glucocorticoids result from decreases in the synthesis of cytokines (eg, interleukins, platelet activating factor) or eicosanoids (leukotrienes, prostaglandins). 

Although the prostaglandin molecule has been subjected to one of the more intensive structure-activity studies in the history of medicinal chemistry, the significance of many of the structure variations has not been fully reported, and the effect on bronchodilator activity often remains unknown. In this review we will attempt to identify those structure-activity relationships that are apparent from our own studies as well as from those described in the literature. Recent discussions published concerning the effect of prostaglandins on the bronchial tree include those by Rosenthale (113) and by Karim and Adaikan (114). In addition, Schaaf has reviewed structure-activity relations in other areas of prostaglandin interest (115). 

For further evaluation, selected compounds are submitted to a dog assay (117,118) in which the prostaglandin is administered by aerosol to an anesthetized pilocarpine bronchoconstricted dog (n=3 to 6) and the decrease in airway resistance is recorded at the same time effects on the cardiovascular system (femoral pressure, pulmonary pressure, heart rate) are noted. This experiment is allowed to proceed for one hour, which also permits an assessment of the compound s ability to produce a prolonged bronchodilation. In this assay salbutamol maintains its effect for the entire hour, whereas isoproterenol and 1-PGEi lose theirs within the first twenty minutes. At the conclusion of the study a standard dose of isoproterenol is administered to determine the animal s maximum capacity to respond. 

The significance of the 11- and/or 15-hydroxy functions for bronchodilator activity is demonstrated in Table VI. Substantial activity clearly obtains in the 11-deoxy series, but the 15a-hy-droxy group apparently is an essential feature, although this requirement can be satisfied by a hydroxy group at Cje see section VIII F. Nevertheless it is noteworthy, that in the Konzett as well as other assays, even a primitive prostaglandin such as 11,15-bisdeoxy-PGEi produces a real PG-like effect, albeit with much diminished potency. 

A large number of prostaglandin esters and amides have been reported in the patent literature. Although little is known concerning the biology of these derivatives, it generally is accepted that at least the simple methyl ester usually produces effects equivalent to that of the parent acid. From our own experience we are able to confirm this view as it applies to our bronchodilator assays. In a limited study we have found that a decyl ester and certain amides retain activity, but of considerably diminished potency. 

Although Ci5-methylation has given prostaglandins with dramatically enhanced effects as orally active, long lasting inhibitors of gastric acid secretion (159) and to a lesser extent as abortifacients (160). this modification has proven to be a major dissapointment for the development of improved bronchodilators. 

In our Konzett assay, ll-deoxy-16-methyl derivatives showed exceptionally high potency (48), an observation also made by a Wyeth group (113). However, Turther examination of 11-deoxy-16(R/S)-methyl-PGEi (XXIV) in the pilocarpine dog assay indicated this compound to be relatively ineffective and of no interest. Another member of this series, 16(S)-methyl-20-methoxy-PGE2 (XXV, YPG-209), has been reported to be 230 times as potent as PGE2 in the guinea pig vs. histamine-induced spasms. It also is claimed to be orally effective in this model without concommitant hypotension or diarrhea (169). This is the first claim, that we are aware of, for oral activity for any prostaglandin bronchodilator and we await the results of further studies with this compound. 

Clearly the initial promise of the prostaglandins remains to be fulfilled. At least nine candidates have been submitted to clinical investigation and all but one have failed to produce a significant bronchodilator effect (Table XXIII). Furthermore, the one compound (entry 1) which appears to have been effective does not seem to possess any obvious advantages over the natural prostaglandins. 

Since all eight failures apparently were selected, at least in part, on the basis of data obtained from a guinea pig Konzett-Rossler assay, the question arises as to the predictive capability of this widely used model for the selection of effective prostaglandin bronchodilators. However, in point of fact, four of the failures (entries 2-5) provided relatively modest Konzett responses, about 1-20% that of 1-PGEi, and therefore only one of these compounds (3) can be considered to have been tested at an appropriate multiple of the apparent 1-PGEi minimally effective dose [(50-100 jq)10.11.1641. Accordingly, the possibility remains that "weak" candidates may not have been studied at sufficiently high dose levels. 

First, different PGs may have opposite effects on the same organ prostaglandins of the E type are bronchodilators whereas the F compounds are bronchoconstric-tors the cervix of the uterus is relaxed by PGEs but contracted by PGFs. 

Prostaglandins - PGEi and PGE2 are effective bronchodilators, capable of reversing the increased airway resistance and decreased airway compliance Induced by cholinergic stimulation in the cat. Administration by aerosol produces the greatest bronchodilating response with little or no cardiovascular effects of hypotension and tachycardia. The cardiovascular effects were most pronounced after intravenous administration. 

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