zaprinast and Asthma

We conducted a placebo controlled, double-blind trial on the effect of a single dose of zaprinast (M&B 22,948, an orally active mast cell stabilizer) on exercise-induced asthma in 15 children. We demonstrated no prophylactic effect on the whole group. A trend towards effectiveness was shown when the results for children whose asthma was not steroid dependent were analysed alone.

Topics: Adolescent; Asthma; Asthma, Exercise-Induced; Child; Clinical Trials as Topic; Double-Blind Method; Humans; Purinones

M&B 22,948 (2-o-propoxyphenyl-8-azapurin-6-one) is an orally absorbed mast cell stabilizer which is 30 times as potent as disodium cromoglycate in laboratory and animal studies. In a double-blind placebo-controlled cross-over trial we studied the protection afforded by a single oral dose of 10 mg of M&B 22,948 against asthma induced by histamine and exercise, each in 12 patients. Compared with placebo the drug had no significant effect on the response to inhaled histamine but significantly inhibited the fall in FEV1 induced by exercise on treadmill (P less than 0.005). The exercise-induced fall in FEV1 was less following M&B 22,948 than placebo in all patients and the fall was inhibited by more than 50% in five (42%) of 12 patients. The degree of inhibition was significantly correlated with the plasma drug concentration (r = 0.65, P less than 0.025). M&B 22,948 merits evaluation in the treatment of asthma.

Topics: Adolescent; Adult; Asthma; Asthma, Exercise-Induced; Bronchial Provocation Tests; Clinical Trials as Topic; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Physical Exertion; Purinones

We have characterised the mechanisms involved in the antiproliferative effect of NO in human airway smooth muscle cells (HASMC). S-Nitroso-N-acetyl penicillamine, a nitric oxide donor, inhibited proliferation in both G(1) and S phases of the cell cycle. Additionally, experiments with 8-bromo-cGMP, haemoglobin, a NO scavenger and zaprinast, a cGMP-specific phosphodiesterase inhibitor, showed that both effects were NO-mediated. The G(1) phase inhibition was cGMP-dependent whereas the S phase inhibition was due to a cGMP-independent inhibition of ribonucleotide reductase. These results demonstrate that NO inhibits HASMC proliferation by cGMP-dependent and -independent mechanisms acting at distinct points in the cell cycle.

Topics: 8-Bromo Cyclic Adenosine Monophosphate; Asthma; Bronchi; Cell Cycle; Cells, Cultured; Culture Media, Serum-Free; Deoxyadenosines; Deoxyguanosine; Hemoglobins; Humans; Methylene Blue; Muscle, Smooth; Nitric Oxide; Nitric Oxide Donors; Phosphodiesterase Inhibitors; Purinones; S-Nitroso-N-Acetylpenicillamine; Thymidine

Airway smooth muscle (ASM) hypertrophy and hyperplasia are important determinants of bronchial responsiveness in asthma, and agents that interfere with these processes may prevent airway remodeling. We tested the hypothesis that activators of soluble and particulate guanylyl cyclases would inhibit human ASM cell (HASMC) proliferation. We report that the nitric oxide (NO) donors S-nitroso-N-acetylpenicillamine (SNAP; 10(-6) to 10(-4) M) and sodium nitroprusside (10(-5) to 10(-3) M) and human atrial natriuretic peptide [ANP-(1-28); 10(-8) to 10(-6) M], which activate soluble and particulate guanylyl cyclases, respectively, inhibited serum- and thrombin-induced proliferation of cultured HASMCs. The antimitogenic effect of SNAP was reversed by hemoglobin (10(-5) M), an NO scavenger, suggesting that NO donation was involved. The antiproliferative effects of SNAP and ANP-(1-28) were potentiated by the cGMP-specific phosphodiesterase zaprinast and mimicked by 8-bromo-cGMP (10(-6) to 10(-3) M), suggesting that cGMP-dependent mechanisms were involved. However, first, ANP-(1-28) produced a smaller antiproliferative effect than SNAP in contrast to their abilities to elevate cGMP, and second, rat ANP-(104-126), which binds selectively to ANP clearance receptors without elevating cGMP, had a small antiproliferative effect, suggesting that cGMP-independent mechanisms were also involved. These results provide evidence for a novel antiproliferative effect of NO and ANP in HASMCs mediated through cGMP-dependent and cGMP-independent mechanisms.

Topics: Asthma; Atrial Natriuretic Factor; Blood Proteins; Cell Division; Cells, Cultured; Coloring Agents; Cyclic GMP; Diuretics; Hemoglobins; Hemostatics; Humans; Hyperplasia; Lung; Mitogens; Muscle, Smooth; Nitric Oxide; Nitric Oxide Donors; Nitroprusside; Penicillamine; Peptide Fragments; Phosphodiesterase Inhibitors; Purinones; Tetrazolium Salts; Thiazoles; Thrombin; Vasodilator Agents