Pharmacodynamic profile of isbufylline, a new antibronchospastic xanthine devoid of central excitatory actions.
1,3-Dimethyl-7-isobutylxanthine (isbufylline, TE/06; CAS 90162-60-0) is a newly synthetized xanthine derivative. This compound exhibits remarkable antibronchospastic properties both in in vitro and in vivo (after oral or intravenous administration) experimental models. Isbufylline is significantly more effective than theophylline in antagonizing bronchospasms elicited by spasmogens (capsaicin, arachidonic acid, PAF and antigen) which mainly act by a local release of biologically active substances proposed to be involved in the pathogenesis of asthma. Isbufylline, unlike theophylline, possesses little or no CNS excitatory properties. This reduced neuroexcitatory action is probably related to the poor affinity of isbufylline, as compared to theophylline, to A1 purinoceptor. Indeed, isbufylline is ineffective in antagonizing 2Cl-adenosine-induced EEG synchronization. In normotensive and hypertensive rats oral administration of isbufylline resulted in small and transient positive chronotropic and hypotensive response, markedly lower than those elicited by theophylline or enprofylline. Finally isbufylline exhibits phosphodiesterase inhibitory properties, although at concentration 50-100 times higher than those exerting spasmolytic effects in isolated bronchial tissues. As a whole the pharmacodynamic profile of isbufylline is promising and, in the clinical setting, this compound might exert enhanced antiasthma effects coupled to a low incidence of central and cardiovascular adverse effects.
Manzini
S
S
Istituto Farmacobiologico Malesci S.p.A., Pharmacology Department, Florence, Italy.
Meini
S
S
Giachetti
A
A
Beani
L
L
Borea
P A
PA
Antonelli
T
T
Ballati
L
L
Bacciarelli
C
C
D015056:1-Methyl-3-isobutylxanthine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants; D001794:Blood Pressure / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D001986:Bronchial Spasm / Q000139:chemically induced / Q000503:physiopathology; D001993:Bronchodilator Agents / Q000494:pharmacology*; D004569:Electroencephalography; D005260:Female; D005772:Gastrointestinal Transit / Q000187:drug effects; D006168:Guinea Pigs; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009197:Myenteric Plexus / Q000187:drug effects; D010276:Parasympatholytics / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains; D011983:Receptors, Purinergic / Q000187:drug effects; D012890:Sleep / Q000187:drug effects; D014132:Trachea / Q000187:drug effects
D000927:Anticonvulsants; D001993:Bronchodilator Agents; D010276:Parasympatholytics; D010726:Phosphodiesterase Inhibitors; D010972:Platelet Activating Factor; D011983:Receptors, Purinergic; C058878:isbufylline; D015056:1-Methyl-3-isobutylxanthine