Benserazide

Parkinson's disease is a debilitating neurodegenerative disorder that is primarily characterized by dopamine deficiency, which significantly impairs motor function and quality of life. Levodopa remains the gold standard treatment due to its efficacy in replenishing dopamine levels. However, its combination with decarboxylase inhibitors such as benserazide is necessary to increase bioavailability and reduce peripheral side effects. Despite this advantage, the inherent instability of benserazide under changing environmental conditions presents a significant challenge in formulating effective and long-lasting fixed-dose combinations. The objective of this study is to develop a stable fixed-dose tablet composition of levodopa and benserazide by formulating their granules separately to prevent degradation, an approach underexplored in existing literature. By granulating these active ingredients separately, the formulation exploits the stability and process advantages of both techniques while addressing the risks of degradation associated with their direct interaction. The wet granulation of levodopa ensures homogeneity and optimized powder compressibility, while the dry granulation of benserazide avoids moisture-induced instability. Extensive stability studies under accelerated and long-term conditions have demonstrated the superiority of this dual granulation strategy. These findings suggest that separate granulation improves the stability and efficacy of levodopa-benserazide formulations, offering a promising strategy for the long-term management of Parkinson's disease and addressing a critical gap in current pharmaceutical research. The formulation demonstrated consistent active ingredient content over time, minimized impurity formation, and exhibited stable physicochemical properties, going far beyond conventional single granulation methods.

KRAS Q61H is an aggressive oncogenic driver mutation rendering cancer cells drug resistant to SHP2 inhibitors (SHP2i). Some metastatic and chemoresistant non-small cell lung cancer (NSCLC) cells, exhibit a hybrid metabolic state in which both glycolysis and oxidative phosphorylation (OXPHOS) coexist. Hence, we evaluated the in vitro and in vivo efficacy of a combination of hexokinase 2 (HK2) and pyruvate dehydrogenase (PDH) inhibitors, benserazide (Benz) and CPI-613, respectively, against NSCLC NCI-H460 cells harboring the driver KRAS Q61H mutation. This combination synergistically disrupted the hybrid metabolic state, inhibited NCI-H460 cell proliferation in vitro, and markedly suppressed tumor growth in NCI-H460 cell xenograft model in mice. The molecular basis underlying this antitumor activity was apparently due to suppression of SHP2/SOS1/RAS/MAPK signaling pathways, leading to enhanced apoptosis. Moreover, this drug combination restored the sensitivity to SHP2i. Consistently, SHP2 overexpression in NCI-H460 cells abrogated the antitumor activity of this drug combination. These findings reveal that the combination of Benz and CPI-613 targets the metabolic vulnerability of KRAS Q61H mutant-bearing NSCLC tumors. These results offer a combination therapeutic strategy for the possible treatment of cancer cells displaying a hybrid metabolic state, thereby surmounting chemoresistance.