Reactive oxygen-derived free radical species have been implicated in the pathogenesis and pathophysiology of inflammatory lung diseases. In a guinea pig model of aerosolized endotoxin-induced bronchial hyperresponsiveness to substance P, a possible involvement of oxidative lung injury was assessed by measuring the changes in membrane-bound neutral endopeptidase activity in the airway tissues and the level of lipid peroxides in the plasma. Vehicle-treated animals developed a neutrophilic airway inflammation, bronchial hyperresponsiveness to substance P associated with neutral endopeptidase hypoactivity, and elevation of lipid peroxides at 18 to 24 h after an exposure to endotoxin (75 microgram/ml, 40 min). A nonselective phosphodiesterase inhibitor, aminophylline, and selective phosphodiesterase isoenzyme inhibitors, SDZ-ISQ-844 (type III/IV) and SDZ-MKS-492 (type III), attenuated the neutrophilic airway inflammation induced by endotoxin. Aminophylline, SDZ-MKS-492, and a superoxide anion-generating NADPH-oxidase inhibitor apocynin inhibited bronchial hyperresponsiveness to substance P with attenuation of neutral endopeptidase inactivation induced by endotoxin. SDZ-ISQ-844, SDZ-MKS-492, and apocynin attenuated the elevation of lipid peroxides. The generation of hypochlorite (OCl-) from whole blood leukocytes was attenuated by aminophylline, SDZ-ISQ-844, SDZ-MKS-492, and apocynin at 1 to 2 h after exposure. These results suggest that reactive oxygen-derived free radical species-mediated oxidative lung injury may play an important role in endotoxin-induced bronchial hyperresponsiveness to substance P, and that phosphodiesterase isoenzyme inhibitors may be potentially useful as anti-inflammatory drugs.

01 Apr 1998·British Journal of Clinical PharmacologyQ2 · MEDICINE

Effect of selective phosphodiesterase 3 inhibition on the early and late asthmatic responses to inhaled allergen

Q2 · MEDICINE

Article

Author: Holgate, Stephen T. ; Franke, Brigitte ; Bardin, Philip G. ; Lampe, Fiona C. ; Dorward, Martina A.

Aims Phosphodiesterase isoenzymes may play an important role in the regulation of airway calibre and bronchial smooth muscle function. Immunomodulatory actions may also be important in allergic airway inflammation. We have examined the effect of a phosphodiesterase (PDE) 3 inhibitor (MKS492) on the early and late responses to inhaled allergen in 18 atopic asthmatic subjects.Methods On three separate occasions, 2–4 weeks apart, patients were administered either placebo, 20 mg or 40 mg of oral MKS492 as a single dose. After 90 min they inhaled a dose of allergen (grass pollen or D. pteronyssinus ) that had been demonstrated to produce a 20% decrease in FEV1. Measurements of FEV1 were repeated at 30 min intervals over the subsequent 7.5 h.Results After placebo, allergen inhalation produced bronchoconstriction with a maximum mean minimum FEV1 of 75.9% (12.7) (mean [s.d.]) of post‐saline baseline values and a late response developed in 13 subjects (decrease in FEV1≥15%). MKS492 (40 mg) increased the mean minimum % post‐saline FEV1 at 30 min from 81.6% (14.0) for placebo to 93.1% (13.8), difference 11.5, 95% CI (2.6, 20.4). The mean minimum % post‐saline FEV1 in the early response (0‐2 h) was also increased by the 40 mg dose to 86.5% (11.8) vs 77.9% (13.8) for placebo, but not by the 20 mg dose. Significant bronchodilatation was noted 90 min after dosing (pre‐allergen) in the MKS492 40 mg group. Late phase responses as assessed by 4 h % post‐saline FEV1 was significantly improved by MKS 492 40 mg to 90.0% (6.3) vs 83.0% (12.4) for placebo–difference 7.0, 95% CI (0.1, 13.9), but again not by the 20 mg dose. Analysis of the area under the FEV1 response‐time course curves showed non‐significant reduction in the late response after the 40 mg dose (placebo 159.0, 134.8) vs 128.1, [81.5] for 40 mg).Conclusions A novel PDE 3 inhibitor significantly decreases the early bronchoconstrictor response in asthma and attenuates the late response; effects that may be more marked at higher doses.

01 Jun 1995·Pediatric PulmonologyQ3 · MEDICINE

Intratracheal administration of phosphodiesterase III inhibitor attenuates bronchoconstriction in cats: A preliminary report

Q3 · MEDICINE

Article

Author: Michio Fujita ; Masao Takata ; Isao Kusakawa ; Hong Hu ; Katsuyuki Miyasaka

AbstractThe effects of intratracheal administration of MKS 492, selective phosphodiesterase (PDE) 111 inhibitor, were studied in five anesthetized bronchoconstricted cats. The animals were challenged by four repeated doses of intratracheal methacholine (67 μg/kg), and the degree of bronchoconstriction was assessed from increases in respiratory system resistance (Rrs). All animals demonstrated good bronchoconstrictive responses (i.e., 86–99% increases in Rrs) to methacholine without tachyphylaxis. On separate day, the cats received the same four doses of methacholine after being pretreated with either intratrachael saline or three different doses of MKS 492 (0.17, 1.7, and 17 μg/kg). The increases in Rrs with 1.7 μg/kg [;52.6 ± 8.4% (SE)] and 17 μg/kg of MKS 492 (44.4 ± 10.1%) were smaller than those with saline pretreatment (88.1 ± 16.8%) (P < 0.05). There were no treatment‐associated changes in mean arterial pressure or heart rate during administration of MKS 492. We conclude that intratracheal MKS 492 effectively reduced methacholine‐induced bronchoconstriction in dose‐dependent fashion without substantial systemic effects. These preliminary results suggest that inhalation of isozyme‐selective PDE inhibitors may deserve consideration for clinical trials provided that more extensive preclinical investigations justify such trials. © 1995 Wiley‐Liss, Inc.

100 Deals associated with SDZ-MKS-492

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Indication	Highest Phase	Country/Location	Organization	Date
Asthma	Phase 1	CH	Novartis AG	-
Asthma	Phase 1	-	Novartis Pharma AG	-
Asthma	Phase 1	GB	-	-
Anaphylaxis	Preclinical	JP	Gifu Pharmaceutical University	01 Jan 1993

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