Ralph E. Giles

Heterogeneity of leukotriene receptions in guinea-pig trachea

The selective leukotriene (LT) antagonist FPL 55712 antagonized the contractile activity of synthetic LTD4 and E4 on guinea-pig trachea. Schild analysis of the antagonism provided evidence for two distinct receptors for LTD4: one with significantly higher affinity for FPL 55712 than the other. LTE4 appears to interact preferentially with the high affinity receptor.

Biochemical and pharmacological characterization of ICI 198,615: a peptide leukotriene receptor antagonist

ICI 198,615 is one representative of a new chemical class of peptide leukotriene receptor antagonists that are the most potent and selective described to date. ICI 198,615 antagonized LTC4-, LTD4- and LTE4-induced increases in cutaneous vascular permeability in the guinea pig, with i.v. ED50 values of 0.083, 0.11 and 0.067 mumol/kg, respectively. Against LTD4, ICI 198,615 was 615 and 415 times more potent than LY 171883 and FPL 55712, respectively. L-Serine borate, an inhibitor of the metabolism of LTC4 to LTD4, did not influence the antagonism by ICI 198,615 of LTC4-induced increases in cutaneous vascular permeability. The compound both inhibited and reversed aerosol ovalbumin antigen-induced increases in pulmonary resistance in passively sensitized guinea pigs, but demonstrated little ability to inhibit or reverse ovalbumin antigen-induced decreases in dynamic lung compliance. At concentrations ranging from 10(-8) to 10(-5) M, ICI 198,615 had no significant effect on either the spontaneous or ovalbumin antigen-induced release of histamine, peptide leukotrienes, thromboxane B2 or 6-keto-prostaglandin F1 alpha from chopped guinea pig lung. At 10 microM, the compound did not inhibit 5-, 12- or 15-lipoxygenase. Finally, ICI 198,615 antagonized LTD4-induced increases in TxB2 release from chopped guinea-pig lung.

Biochemistry and Pharmacology of ICI 200,880, a Synthetic Peptide Inhibitor of Human Neutrophil Elastase

ICI 200,880 is representative of a new chemical class of inhibitors of human neutrophil elastase (HNE). The compound demonstrated competitive kinetics vs HNE with a Ki value of 5.0 x 10(-10) M. The selectivity of ICI 200,880 for HNE versus a variety of enzymes ranged from 150- (relative to porcine pancreatic elastase [PPE]) to greater than 360,000-fold in favor of HNE. In pharmacokinetic studies ICI 200,880 displayed a long retention time when administered directly to the lung and was rapidly eliminated when administered intravenously. Aerosol pretreatment of hamsters with ICI 200,880 before intratracheal administration of HNE produced a long-lasting inhibition of enzyme-induced increases in lung weight, total lavageable red cells, and total lavageable white cells. Subcutaneous administration of either 50 or 100 mumol/kg (twice/day) of ICI 200,880 for 14 or 28 days prevented the time-dependent increase in alveolar diameter produced by a single intratracheal dose of PPE when compound dosing was initiated 24 hours following the enzyme. Treatment of hamsters with ICI 200,880 using the same protocol and doses for 8 weeks prevented the destructive lesion induced by a single intratracheal dose of HNE. It is concluded that ICI 200,880 has biochemical, pharmacokinetic, and pharmacologic profiles that make it a useful therapeutic agent for understanding the role of HNE in various diseases. ICI 200,880 is presently being evaluated in man.

Physiological consequences of β-adrenoceptor desensitization in guinea pigs

Abstract The effects of repetitive doses of β-adrenoceptor stimulants on the resting tone and responsiveness of broncho-pulmonary smooth muscle were studied in guinea pigs. Collapse time was used to assess bronchospasm in conscious animals while resistance and compliance measurements were used in the anesthetized guinea pigs. Repetitive administration of either isoproterenol or salbutamol, at effective bronchodilator doses, caused an exacerbation of the histamine-induced bronchospasm in the presence or absence of anesthesia. Repetitive administration of either prostaglandin E 1 , 20 μg/kg i.m., or aminophylline, 400 μg/kg i.m. did not enhance histamine-induced bronchospasm. Furthermore, in guinea pigs preselected for lack of histamine sensitivity, treatment with salbutamol caused a decrease in both dynamic compliance values and peak expiratory flow rate as well as an increase in resistance values. Trachea removed from guinea pigs treated with isoproterenol or salbutamol retained normal responsiveness to histamine and dibutyryl cAMP while the responsiveness to isoproterenol was reduced. These studies indicate that repetitive administration of β-adrenoceptor stimulants can produce a specific desensitizatio of β-adrenoceptors in pulmonary tissue and an alteration of resting baseline values of pulmonary mechanics measurements.

The Therapeutic Effect of Progesterone in Papain-Induced Emphysema

Summary An emphysema-like lesion was produced in rats by the periodic administration of papain aerosol. Functional residual capacity (FRC) was measured at the completion of the papain treatments and at two week intervals during the next month. Progesterone (5 mg/kg sc) daily for one month after development of the papain lesion, caused a significant decrease in FRC values; untreated control emphysematous rats maintained elevated values. Measurements of (a) average intraalveolar distance (mean linear intercept) and (b) air spaces in histological sections prepared from the lungs of rats sacrificed at the end of the papain treatment period and rats sacrificed 4 weeks later, after progesterone therapy, also suggested a therapeutically beneficial effect by the hormone. In vitro, progesterone had no effect on casein hydrolysis by papain.

Pharmacology of aerosol leukotriene C4- and D4-induced alteration of pulmonary mechanics in anesthetized cynomolgus monkeys.

Aerosol administration of solutions of 900 micrograms/ml of leukotriene C4 (LT) or D4 to cynomolgus monkeys produced dose-dependent, equipotent increases in pulmonary resistance (Rp) and decreases in dynamic lung compliance (Cdyn). Time to peak response was, in part, related to dose and ranged from 4 to 20 min. Both LTC4 and LTD4 were less potent than histamine. Aerosol pretreatment with the cyclooxygenase inhibitor indomethacin had no significant effect on either LTC4 or LTD4 dose-response curves; however, at the highest doses of these agonists a notable, nonsignificant inhibition of effects on both Rp and Cdyn was seen. Intravenous dl-propranolol had no effect on responses to LTD4. Aerosol pretreatment with FPL 55712 significantly (P less than 0.05) inhibited airway responses to both LTC4 and D4. In contrast, an intravenous infusion of FPL 55712 failed to block the bronchospastic activity of LTD4. In conclusion, cynomolgus monkeys are responsive to aerosol administration of LTC4 and LTD4, and the pharmacology of their responses appears to resemble that of man.

Progesterone Antagonism of Papain Emphysema: Role of Sex, Estrogens and Serum Antitrypsin

Summary An emphysema-like lesion was produced in rats by periodic administration of papain aerosol. Progesterone (5 mg/kg/day) prevented the condition in males and ovariectomized females, but not in unaltered females. Estradiol-17β or diethylstilbestrol, at doses of 1 μg/rat/day, inhibited the protective action of progesterone. Neither of these estrogens alone had protective or deleterious effects in papain-treated rats. None of the hormones studied altered serum antitrypsin activity. Therefore, it is unlikely that either the beneficial effects of progesterone or the antagonistic effects of estradiol-17β or diethylstilbestrol were mediated through changes in this serum factor.

Effects of alprenolol, bunolol and propranolol on pulmonary resistance in the anaesthetized dog

Abstract The β-receptor antagonists alprenolol, bunolol and propranolol were evaluated for their effects on pulmonary resistance in anaesthetized dogs in the absence and presence of bronchoconstrictor agents. The effectiveness of the β-receptor antagonists in (a) blocking isoprenaline-induced bronchodilatation in animals receiving histamine aerosol and (b) potentiating histamine-induced bronchoconstriction was also assessed. Propranolol, given in increasing doses to dogs not previously given bronchoconstrictor substances, caused an increase in pulmonary resistance; bunolol had no apparent effect and alprenolol decreased resistance. Propranolol and bunolol, given 30 min after a histamine aerosol challenge, increased resistance whereas alprenolol decreased resistance. Bronchospasm induced by histamine after the administration of the β-receptor antagonists was not significantly altered from control. Alprenolol had less effect on isoprenaline-induced bronchodilatation than did the other two agents. When administered at the peak of pilocarpine-induced bronchoconstriction, bunolol or propranolol produced significant increases in pulmonary resistance whereas alprenolol had no effect. The different effects of these selected β-receptor antagonists on pulmonary resistance suggest that the actions of propranolol are not representative of the pulmonary effects of this class of compounds.