Pharmacodynamic profile of the new potent antibronchospastic agent 7-[(2,2-dimethyl)propyl]-1-methyl xanthine.
The pharmacodynamic profile of a new xanthine derivative, 7-[(2,2-dimethyl)propyl]-1-methyl xanthine (CAS 155006-67-0, MX2/120), was investigated in comparison with theophylline. The compound reduces in vitro the bronchospastic tone induced by carbachol or histamine in guinea-pig bronchi, with a potency 11 and 5 fold greater than theophylline, respectively. MX2/120 is significantly more active and long-lasting than theophylline in in vivo experiments toward spasmogens such as acetylcholine (ED50 over 5 h = 15 mumol/kg p.o. vs 230 mumol/kg p.o.) or histamine (ED50 over 5 h = 122 mumol/kg p.o. vs 500 mumol/kg p.o.) while being almost equiactive to theophylline toward antigen and capsaicin induced cough strokes. MX2/120, if administered by i.p. route reduces hyperresponsiveness to histamine induced by PAF and extravasation of protein into bronchoalveolar lavage fluid induced by capsaicin. These anti-inflammatory effects of MX2/120 are of similar extent when compared to theophylline. Unlike theophylline, MX2/120 up to 275 mumol/kg p.o. possesses little or no CNS excitatory effects in mice in terms of reduction of sleeping time induced by chlordiazepoxide, increase in mortality and convulsions induced by pentetrazol and increase in locomotor activity. This reduced neuroexcitatory action is probably related to its lack of affinity to adenosine receptors that could also explain the absence of effect on basal gastric secretion. Chronotropic effects of MX2/120 in conscious rats are similar to those of theophylline while the effects of both drugs on blood pressure are of minor extent. The overall pharmacodynamic properties of MX2/120 are superior to those of theophylline in relation to its antibronchospastic activity and lack of excitatory effects on CNS.
Evangelista
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S
Istituto Farmacobiologico Malesci S.p.A., Pharmacology Department, Florence, Italy.
Ballati
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L
Boni
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P
Castellucci
A
A
Perretti
F
F
Tramontana
M
M
Toja
E
E
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001986:Bronchial Spasm / Q000139:chemically induced / Q000188:drug therapy*; D016084:Bronchoconstriction / Q000187:drug effects; D001993:Bronchodilator Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000633:toxicity; D004347:Drug Interactions; D005122:Exudates and Transudates / Q000187:drug effects; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism; D005772:Gastrointestinal Transit / Q000187:drug effects; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010433:Pentylenetetrazole / Q000633:toxicity; D010972:Platelet Activating Factor / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012890:Sleep / Q000187:drug effects; D014970:Xanthines / Q000009:adverse effects / Q000494:pharmacology* / Q000633:toxicity
C092650:7-((2,2-dimethyl)propyl)-1-methylxanthine; D001993:Bronchodilator Agents; D010972:Platelet Activating Factor; D014970:Xanthines; D000109:Acetylcholine; D010433:Pentylenetetrazole