An exploration into CTEPH medications: Combining natural language processing, embedding learning, in vitro models, and real-world evidence for drug repurposing

Background In the modern era, the growth of scientific literature presents a daunting challenge for researchers to keep informed of advancements across multiple disciplines. Objective We apply natural language processing (NLP) and embedding learning concepts to design PubDigest, a tool that combs PubMed literature, aiming to pinpoint potential drugs that could be repurposed. Methods Using NLP, especially term associations through word embeddings, we explored unrecognized relationships between drugs and diseases. To illustrate the utility of PubDigest, we focused on chronic thromboembolic pulmonary hypertension (CTEPH), a rare disease with an overall limited number of scientific publications. Results Our literature analysis identified key clinical features linked to CTEPH by applying term frequency-inverse document frequency (TF-IDF) scoring, a technique measuring a term's significance in a text corpus. This allowed us to map related diseases. One standout was venous thrombosis (VT), which showed strong semantic links with CTEPH. Looking deeper, we discovered potential repurposing candidates for CTEPH through large-scale neural network-based contextualization of literature and predictive modeling on both the CTEPH and the VT literature corpora to find novel, yet unrecognized associations between the two diseases. Alongside the anti-thrombotic agent caplacizumab, benzofuran derivatives were an intriguing find. In particular, the benzofuran derivative amiodarone displayed potential anti-thrombotic properties in the literature. Our in vitro tests confirmed amiodarone's ability to reduce platelet aggregation significantly by 68% (p = 0.02). However, real-world clinical data indicated that CTEPH patients receiving amiodarone treatment faced a significant 15.9% higher mortality risk (p<0.001). Conclusions While NLP offers an innovative approach to interpreting scientific literature, especially for drug repurposing, it is crucial to combine it with complementary methods like in vitro testing and real-world evidence. Our exploration with benzofuran derivatives and CTEPH underscores this point. Thus, blending NLP with hands-on experiments and real-world clinical data can pave the way for faster and safer drug repurposing approaches, especially for rare diseases like CTEPH.