Dihydroergotamine Mesylate

Dihydroergotamine mesylate suppressed the proliferation of liver cancer cells by inhibiting STAT3 activation, an effect observed across multiple cell lines including Huh7, Hep3B, HepG2, and PLC/PRF/5. The drug reduced STAT3 phosphorylation at both Tyr705 and Ser727 residues in a concentration-dependent manner. However, DHE simultaneously activated the ERK signaling pathway, which led to enhanced protein stability of Mcl-1, an anti-apoptotic protein. This ERK-Mcl-1 activation partially counteracted the pro-apoptotic effect of STAT3 inhibition, limiting the efficacy of DHE as a single agent.
When combined with sorafenib, DHE produced synergistic anti-tumor effects: sorafenib enhanced DHE-induced STAT3 suppression while inhibiting DHE-mediated ERK-Mcl-1 pathway activation. In a xenograft mouse model, the combination of sorafenib and DHE significantly suppressed tumor growth and increased apoptosis compared to either agent alone, as confirmed by TUNEL staining and Western blot analysis of cleaved caspase-3.

Fig. 1 Anti-cancer mechanism of Dihydroergotamine mesylate. (He M.; et al. 2023)

Dihydroergotamine mesylate delivered via the nasal route offers rapid absorption and gastrointestinal avoidance, but traditional nasal devices deposit less than 5% of the drug into the upper nasal space (UNS), with most reaching the lower nasal space where absorption is poor and drug loss occurs via nasal drip or mucociliary clearance. In contrast, the UNS provides a permeable, richly vascularized epithelium and reduced drug clearance. Precision Olfactory Delivery is a handheld, propellant-powered device that specifically targets the UNS. The DHE mesylate product INP104, utilizing this technology, achieves favorable pharmacokinetics, rapid and consistent systemic absorption, good safety and tolerability on the upper nasal mucosa, and high patient acceptance.

Fig. 2 Traditional Nasal Delivery versus Precision Olfactory Delivery. (Cooper W.; et al. 2022)