In vitro i in vivo farmakološka karakterizacija atipičnog simpatomimetika lerimazolina

Abstract

Dekongestivi su lijekovi sa simpatomimetskim djelovanjem. Obično se izdaju bez ljekarskog recepta i široko su zastupljeni u svakodnevnoj ambulantnoj i apotekarskoj praksi. Kontrakcija krvnih sudova sluznice nosa može simptomatski pomoći pacijenatima sa alergijskim rinitisom, rinosinusitisom, prehladom i drugim stanjima respiratornih puteva, kod kojih se javlja osjećaj "zapušenosti nosa". Postoje dvije klase nazalnih dekongestiva: simpatomimetski amini (fenilefrin, pseudoefedrin, efedrin, fenilpropanolamin) i imidazolini (oksimetazolin, ksilometazolin, nafazolin, lerimazolin). Dok je sistemska primjena dekongestivne terapije povezana sa rizicima od neželjenih efekata na srce i krvne sudove, lokalna primjena može dovesti do razvoja medikamentoznog rinitisa, što ukazuje na potrebu usavršavanja terapijskih mogućnosti u ovoj oblasti. Pored monokomponentnih, postoji nekoliko nazalnih preparata sa kombinacijom dvije aktivne supstance, od kojih samo jedna ima dekongestivno dejstvo. Jedina kombinacija dva dekongestiva prisutna na tržištu lijekova sadrži standardni vazokonstriktor fenilefrin i lerimazolin, dekongestiv strukture slične ksilometazolinu i oksimetazolinu. In vitro ispitivanja vazokonstriktorne aktivnosti lerimazolina oskudna, a in vivo dejstva još uvijek nepoznata. Ciljevi ovog istraživanja su bili ispitivanje mehanizama kontraktilnog dejstva lerimazolina, prirode interakcije sa fenilefrinom, kao i uticaja na ponašanje oglednih životinja. Radioaktivno obilježenim visoko selektivnim ligandima za pojedine podtipove receptora mjeren je afinitet vezivanja lerimazolina na α1, 5-HT2A, 5-HT1A i dopaminskim D2 receptorima, čime su upotpunjeni literaturni podaci o vezivanju za 5-HT1B i 5-HT1D receptore. Najveće afinitete lerimazolin ima za 5-HT1D i 5-HT1A receptore, a najmanji za α1 receptor. Ispitivanjem vazoaktivnosti lerimazolina na isječcima torakalne arterije pacova u vodenom kupatilu, uz korišćenje većeg broja supstanci u kombinaciji (antagonist α1 adrenoceptora prazosin, antagonisti α2 adrenoceptora RX 821002 i rauvolscin, antagonist α2C adrenoceptora JP 1302, neselektivni antagonist 5-HT receptora metiotepin, antagonist 5-HT1B receptora SB 224289, antagonist 5-HT1D receptora BRL 15572, antagonist 5-HT2A receptora ketanserin) utvrđeno je da se vazokonstriktorno dejstvo lerimazolina primarno ispoljava putem 5-HT2A receptora, dok je u većim koncentracijama i posljedica aktivacije α1 receptora...

Decongestants are drugs with sympathomimetic properties, commonly dispensed without a prescription and widely used in everyday out-of-hospital and community pharmacy settings. The contraction of the blood vessels of nasal mucosa can symptomatically help patients with allergic rhinitis, rhinosinusitis, colds and other respiratory tract infections in which the feeling of "nasal congestion" appears. There are two classes of nasal decongestants: sympathomimetic amines (phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine) and the imidazolines (oxymetazoline, xylometazoline, naphazoline, lerimazoline). While oral administration of decongestant therapy is associated with the risks of adverse effects on the heart and blood vessels, topical administration can lead to the development of rhinitis medicamentosa, underlying the need for improvement of therapeutic strategies in this field. Besides the monocomponent preparations, there are several nasal preparations that combine two active compounds, only one of which exerts the decongestant action. The only combination of two decongestants available in the drug market contains the standard vasoconstrictive agent phenylephrine and lerimazoline, a decongestant structurally similar to xylometazoline and oxymetazoline. As the in vitro actions of lerimazoline were scarcely examined, and its in vivo effects are generally unknown, the current research aimed at the elucidation of mechanisms of contractile actions of lerimazoline, the nature of its interaction with phenylephrine, as well as its influence on behavior of the experimental animals. Specific binding affinities were determined by measuring the extent of displacement of [3H] labelled specific ligands for α1, 5-HT2A, 5-HT1A and dopamine D2 receptors, and these data complemented the literature findings on binding of lerimazoline to 5-HT1B and 5-HT1D receptors. The highest affinity of lerimazoline was for 5-HT1D and 5-HT1A receptors, and the lowest for the α1 receptor. Examination of lerimazoline vasoconstrictive activity in rat aortic rings mounted in an organ bath, with use of several ligands in combination (α1 adrenoceptor antagonist prazosin, α2 adrenoceptor antagonists RX 821002 and rauwolscine, α2C adrenoceptor antagonist JP 1302, non-selective 5-HT receptor antagonist methiothepin, 5- HT1B receptor antagonist SB 224289, 5-HT1D receptor antagonist BRL 15572, and 5-HT2A receptor antagonist ketanserin) has revealed that the vasoconstrictor effect of lerimazoline was primarily mediated by 5-HT2A receptor, while in higher concentrations it is also contributed to by the α1 receptor...