Jakub Pniak, Małgorzata Latocha

Tadalafil – less known effects of the drug and potential directions for its repositioning

 

2024-11-20

Subject of study. The paper concerns tadalafil, a drug used in erectile dysfunction in adult men and in the treatment of pulmonary arterial hypertension of the second and third degree in the four-stage NYHA classification. It demonstrates efficacy in both idiopathic pulmonary arterial hypertension and pulmonary arterial hypertension associated with systemic connective tissue diseases. It belongs to the phosphodiesterase 5 (PDE-5) enzyme inhibitors. It is distinguished by: high selectivity, rela-tively long duration of action, high efficacy and a relatively safe application profile. The results of studies on the properties of tadalafil published in recent years suggest that this drug may have significantly more therapeutic applications than are currently listed in the Characteristics of the Medicinal Product. Publications on tadalafil indicate that its action leads to an increase in the pool of cGMP in the natural places of synthesis and occurrence of this nucleotide in the body. The documented action of tadalafil on cGMP, and then the effect of cGMP on blood vessels, became the basis for the registration of this drug. However, disorders of cGMP metabolism appear in various diseases, and its presence and concentration may be important in the regulation and course of many processes and diseases. Molecular studies, which are rapidly developing and gaining popularity and commonness, have significantly expanded knowledge in this area.

Research Objective. The aim of this work is to present the properties of tadalafil and the molecular basis of its action in the body and the resulting possibilities of repositioning this drug in the future.

Literature search and selection methodology. The literature review was based on scientific materials from: PubMed, PubChem, Google Scholar, Wiley Online Library, Web of Science. The keywords used are: ‘tadalafil’, ‘phosphodiesterase (PDE)’, ‘PDE-5’ and combinations of ‘tadalafil’ and ‘PDE inhibitors’ with ‘PDE-5 inhibitors’, ‘drug repurposing’, ‘cancer’, ‘clinical trials’.

Results. The results presented in the publications prove the participation of cGMP in: regulation of smooth muscle tone changes in the gastrointestinal tract and urinary system, inhibition of platelet aggregation, presynaptic release of neurotransmitters, differentiation of myoblasts and osteoblasts, metabolism and enhancement of the action of some steroid hormones, activation of insulin signaling improving glucose management, activation of insulin dependent: Ras-Raf mitogen activated protein kinase (MAPK), protein kinase B/AKT (PKB/AKT), transcription factor c-Myc or glycogen synthase kinase 3-A (GSK3-A). It is also indicated that cGMP can inhibit the proliferation of rapidly dividing cells and their migration, and thus reduce the invasiveness of tumors. Tadalafil, by changing the pool of available cGMP, can therefore affect the course of all the above-mentioned processes and phenomena. There is also evidence that this drug may contribute to reducing inflammatory processes, restoring normal levels of glutathione, superoxide dismutase and catalase, activating the mitochondrial apoptosis pathway, changes in the amount and proportion of antiapoptotic proteins to proapoptotic proteins, increasing caspase 3 and 8 levels, reducing the expression of MDR1 and BCRP responsible for drug resistance, or even stimulating vascular endothelial growth factor VEGF responsible for angiogenesis. Improved sperm motility has also been described after prolonged use of tadalafil, as well as its effect on meiosis and the course of problematic pregnancies.

Conclusions. The review of the literature on the effects of tadalafil in vitro and in vivo conditions shows that there is a basis for conducting further research on the possibility of repositioning this drug and using it in indications other than those currently included in the Summary of Product Cha-racteristics. The justification for such work is knowledge of the importance of cGMP, discoveries regarding the presence of PDE-5 in various tissues and organs, intensively conducted research on phosphodiesterase inhibitors and the trend in recent years to reposition already available drugs. Based on the results described in the publications selected for the review, it can be concluded that tadalafil can be used to treat cardiovascular diseases, diseases related to age, dementia or muscle function, where tissue blood supply and the supply of appropriate nutrients and oxygen are very important. It seems that tadalafil may also support the therapy of diabetes, obesity or cancer in the future as a modulator of signaling pathways. Approval of new indications for the use of tadalafil requires comprehensive clinical trials on a sufficiently large population, of which there are currently few for this drug.

Keywords: drug repositioning, tadalafil, PDE-5 inhibitors.

© Farm Pol, 2024, 80(6): 375–387