Primary pulmonary arterial hypertension: Protocol to assess comprehensively in the rat the response to pharmacologic treatments

Deborah Novelli; Francesca Fumagalli; Lidia Staszewsky; Giuseppe Ristagno; Davide Olivari; Serge Masson; Daria De Giorgio; Sabina Ceriani; Roberta Massafra; Francesco De Logu; Romina Nassini; Marco Milioli; Fabrizio Facchinetti; Silvia Cantoni; Marcello Trevisani; Teresa Letizia; Ilaria Russo; Monica Salio; Roberto Latini

doi:10.1016/j.mex.2019.100771

Primary pulmonary arterial hypertension: Protocol to assess comprehensively in the rat the response to pharmacologic treatments

MethodsX. 2019 Dec 19:7:100771. doi: 10.1016/j.mex.2019.100771. eCollection 2020.

Authors

Deborah Novelli¹, Francesca Fumagalli¹, Lidia Staszewsky¹, Giuseppe Ristagno¹, Davide Olivari¹, Serge Masson¹, Daria De Giorgio¹, Sabina Ceriani¹, Roberta Massafra¹, Francesco De Logu², Romina Nassini², Marco Milioli³, Fabrizio Facchinetti³, Silvia Cantoni³, Marcello Trevisani³, Teresa Letizia⁴, Ilaria Russo¹, Monica Salio¹, Roberto Latini¹

Affiliations

¹ Department of Cardiovascular Medicine, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156, Milan, Italy.
² Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, 50139, Florence, Italy.
³ Chiesi Farmaceutici S.p.A., Corporate Pre-Clinical R&D, Largo F. Belloli 11/A, 43122, Parma, Italy.
⁴ Endocrinology Laboratory, Luigi Sacco Hospital, Via Giovanni Battista Grassi 74, 20157, Milan, Italy.

Abstract

The identification of new treatments for primary pulmonary arterial hypertension (PAH) is a critical unmet need since there is no a definitive cure for this disease yet. Due to the complexity of PAH, a wide set of methods are necessary to assess the response to a pharmacological intervention. Thus, a rigorous protocol is crucial when experimental studies are designed. In the present experimental protocol, a stepwise approach was followed in a monocrotaline-induced PAH model in the rat, moving from the dose finding study of treatment compounds to the recognition of the onset of disease manifestation, in order to identify when to start a curative treatment. A complete multidimensional evaluation of treatment effects represented the last step. The primary study endpoint was the change in right ventricular systolic pressure after 14 days of treatment; echocardiographic and biohumoral markers together with heart and pulmonary arterial morphometric parameters were considered as secondary efficacy and/or safety endpoints and for the evaluation of the biologic coherence in the different results.

Keywords: Alanine transaminase; Blood pressure; Cardiac biomarkers; Creatinine; Echocardiography; Heart histology; Monocrotaline; Morphometric analysis of pulmonary arteries; Randomization; Right ventricular systolic pressure; Sample size.