CMC Challenges and Solutions in Botanical IND & NDA Development: — Lessons Learned from Four Approved Botanical Drugs
Botanical INDs present unique challenges in chemistry, manufacturing, and controls (CMC) and quality assurance that distinguish them from conventional single-molecule drug development. Over more than two decades, the FDA has progressively constructed a fit-for-purpose regulatory pathway through two successive guidance documents (2004, 2016), the establishment of a dedicated Botanical Review Team within CDER, and the review of hundreds of botanical INDs. Central to this framework is the totality-of-evidence approach, which substitutes aggregate evidence from upstream raw material controls, chemical characterization, mechanistic bioassays, and multi-batch clinical data for the molecular certainty required of new chemical entity drugs. This review examines the four FDA-approved prescription botanical drugs, Veregen, Fulyzaq/Mytesi, NexoBrid, and Filsuvez, to illustrate their product-specific CMC challenges and the solutions that enabled their approvals, and the generalizable patterns that collectively define the totality-of-evidence framework as the governing regulatory architecture for botanical drug CMC development.
Astragaloside A Attenuates Oxaliplatin-Induced Cardiotoxicity, Oxidative Stress, Apoptosis, and Calcium Overload in H9c2 Cardiomyoblasts
Background: Oxaliplatin is a widely used platinum-based chemotherapeutic agent, and its cardiotoxicity remains an important safety concern during cancer treatment. Astragalus-derived saponins have been reported to exert cardioprotective effects; however, the specific active constituent responsible for protecting against oxaliplatin-induced myocardial injury has not been identified.
Methods: Several Astragalus saponins and related constituents were screened in oxaliplatin-treated H9c2 cardiomyoblasts. The lead compound was then evaluated in concentration-response experiments for protective efficacy and cytocompatibility. Oxidative stress, apoptosis, caspase-3 activation, calcium overload, and NCX-1 expression were assessed to explore the underlying mechanisms.
Results: Astragaloside A emerged as the most effective compound for restoring cell viability; at 1 and 2 μM, it significantly attenuated oxaliplatin-induced H9c2 cell injury without detectable cytotoxicity. Mechanistically, astragaloside A reduced intracellular reactive oxygen species accumulation, inhibited early and late apoptosis, decreased cleaved caspase-3 expression, alleviated oxaliplatin-induced calcium overload, and increased NCX-1 expression — consistent with enhanced calcium extrusion.
Conclusion: These findings demonstrate that astragaloside A protects H9c2 cardiomyoblasts against oxaliplatin-induced cardiotoxicity by suppressing oxidative stress, apoptosis, and calcium dysregulation. The results support further investigation of astragaloside A as a cardioprotective candidate in oxaliplatin-induced cardiotoxicity.
Plant-Derived Exosome-Like Nanoparticles: Advances in Therapeutic Applications and Drug Delivery
Background: Plant-derived exosome-like nanoparticles (PELNs) are nanoscale vesicles secreted by plant cells that contain lipids, proteins, RNAs, and secondary metabolites. Increasing evidence indicates that these vesicles can deliver plant-derived molecules into mammalian cells and modulate biological processes, including inflammation, oxidative stress, and immune responses.
Scope of the Review: This review summarizes current knowledge of PELNs, including their biogenesis, molecular composition, isolation and characterization strategies, cellular uptake mechanisms, and reported therapeutic applications. Representative examples from medicinal plants, such as ginger (Zingiber officinale), turmeric (Curcuma longa), and tea (Camellia sinensis), are discussed to illustrate their biological activity and their potential as natural nanocarriers. Their physicochemical stability, biocompatibility, and low immunogenicity support ongoing investigation for both oral and systemic delivery.
Challenges and Future Prospects: Despite growing interest, several challenges remain, including the lack of standardized isolation and purification protocols, variability in vesicle composition, and limited regulatory frameworks. Advances in omics-based analyses and functional validation will be essential to clarify mechanisms of action and improve reproducibility.
Conclusion: PELNs represent a rapidly developing research area at the interface of natural products and nanomedicine. Although current evidence is largely preclinical, these vesicles may contribute to the development of safe and effective therapeutic strategies with further validation.
Salidroside Improves Hyperuricemia by Simultaneously Regulating Uric Acid Production and Excretion
Background: Hyperuricemia is a common metabolic disease, which seriously affects the quality of life of patients. Salidroside (SAL) is a natural phenolic product extracted from Rhodiola rosea root, which is not only less toxic, but also beneficial for metabolic diseases.
Purpose: To investigate SAL's role in regulating hyperuricemia and explore the potential mechanism.
Methods: Molecular simulation was employed to predict the correlation between SAL and TLR4-NLRP3 pathway. The therapeutic effects of SAL were evaluated in cell model and hyperuricemia mice induced by potassium oxonate and hypoxanthine. Then, the mechanism was explored using Western blot assay.
Results: Prediction results showed that SAL bond stably to target proteins TLR4, NLRP3, Caspase-1, and IL-1β involved in the classical pathway of hyperuricemia TLR4-NLRP3. Further hyperuricemia cell and mice model all showed SAL treatment did decrease the uric acid, creatinine and blood urea nitrogen level. Importantly, pathological observation demonstrated liver and kidney injuries were rescued using HE examination and renal fibrosis ameliorated by Masson staining, which was superior to the positive allopurinol. In terms of mechanism, proteins related to uric acid production (XOD) and excretion (ABCG2, OAT1, OCT1, URAT1 and GLUT9) as well as TLR4-NLRP3 pathway in cell model and hyperuricemia mice were all recovered after SAL administration, which were consistent with the molecular docking prediction.
Conclusion: SAL may serve as a natural small molecule compound for improving hyperuricemia and its associated complications by inhibiting hepatic uric acid production and enhancing renal uric acid excretion. This discovery provides novel insights into hyperuricemia treatment.
