Chronic cigarette smoke exposure is well known to cause mucus hypersecretion in experimental animals, but the alterations in mucus rheology have not been described. We studied mucus hypersecretion and viscoelasticity changes in nine tracheostomized beagle dogs exposed to cigarette smoke. The dogs were trained to stand quietly in a harness, and smoke was delivered via a cuffed tracheostomy tube. A 35-cm3 bolus was introduced to the inspiratory line each 20 s, using unfiltered 70-mm cigarettes (20 mg tar, 1.2 mg nicotine). Each dog smoked 10 cigarettes per day over 2.5 h, 5 days per week. Two dogs were exposed for 6 months; 7 dogs were exposed for 10 months. Five dogs served as sham-smoking controls. Mucus was collected twice weekly without drugs by resting a cytology brush on the lower trachea for 2-5 min. The rheological properties of the mucus samples were determined by magnetic rheometry, which yields elasticity and viscosity as a function of frequency. The mucus was also weighed, and the galactose content was determined by phenolsulfuric acid assay. The mucus collection rate served as an index of tracheal mucus flux, and the galactose assay as a marker of mucous glycoprotein content. The tracheal mucus linear velocity (TMV) was determined periodically under xylazine analgesia by observing charcoal particle transport bronchoscopically. Eight of 9 smoking dogs developed mucus hypersecretion (flux greater than 2 X control) versus 1 of 5 controls (p less than .01). TMV did not change significantly in 10 months of exposure. In the first 2-4 months of smoking, the elasticity and viscosity of the mucus both decreased (mean at 4 months = 42% control, p less than .001), as did the galactose content (mean at 4 months = 48% control, p less than .01). At this stage, according to model studies, the mucus should have been more easily clearable by ciliary action. After 6 months, the viscoelasticity returned toward the initial control level, while the galactose content remained low, suggesting an alteration in the nature of the mucous glycoprotein.

PRD-92-Ea [5,5-Dimethyl-11-oxo-5H, HH-(2) benzopyrano (4,3-g) (1) benzopyran-9-carboxylic acid ethanolamine], was an active antiallergic compound in rat and monkey experimental models of immediate hypersensitivity. It inhibited, in a dose-dependent manner, the rat PCA reaction after both intravenous and oral administration. It also inhibited the degranulation of rat peritoneal mast cells after antigenic challenge. PRD-92-Ea was also active in preventing bronchoconstriction in Ascaris-sensitive Rhesus monkeys after intravenous, topical and oral administration. Using chopped monkey tissues, it was found that PRD-92-Ea prevented histamine release from the respiratory mast cells, but not from the cutaneous mast cells. No reason for this dichotomy of effect is known. PRD-92-Ea showed antagonistic activity against the allergic mediators released from mast cells. In order of decreasing potency it was active against SRS-A (monkey lung), PGF_2α, PGE₂, serotonin, bradykinin and histamine. Apart from its antiallergic effects PRD-92-Ea had no other significant pharmacological activity.

DSCG and PRD-92-Ea showed tachyphylaxis in the rat PCA test when a large intravenous dose (40 mg/kg of DSCG and 20 mg/kg of PRD-92-Ea) was given 30 min before administering intravenously the expected effective doses at the time of antigen challenge. This predosing led to a marked loss of effectiveness. Cross-reacting tachyphylaxis was also demonstrated in this model. Predosing rats with DSCG led to a great loss of effectiveness of a subsequent expected active dose of PRD-92-Ea and predosing with PRD-92-Ea had the same effect in preventing the antiallergic action of a subsequent dose of DSCG. The Rhesus monkey (Macaca mulatto) did not exhibit this phenomenon of tachyphylaxis. PRD-92-Ea and DSCG were given intravenously 30 min before and the same dose of 20 mg/kg repeated just before Ascaris suum challenge in the Rhesus monkey asthma model with no loss of their expected effectiveness.