Recent Update on Pharmacokinetics and Drug Metabolism in CNS-based Drug
Discovery

Sanap, Sachin Nashik; Bisen, Amol Chhatrapati; Kedar, Ashwini; Agrawal, Sristi; Bhatta, Rabi Sankar

doi:10.2174/1381612829666230707121415

Cited by 12 publications

(1 citation statement)

References 103 publications

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“…It safeguards the brain against potentially harmful substances in the bloodstream by inhibiting their accumulation and transportation into the brain ( 6 ). Only small lipophilic compounds weighing <400 Da selectively pass across the BBB ( 7 ). This BBB hindrance has blocked the entry of almost 100% of all macromolecules, including recombinants peptides, protein, antibodies, gene therapies, plasmids, and RNAs into the brain, and <98% of all small therapeutic molecules are also unable to cross the BBB.…”

Section: Introductionmentioning

confidence: 99%

Navigating the brain: the role of exosomal shuttles in precision therapeutics

Fatima,

Qaiser,

Andleeb

et al. 2024

Front. Neurol.

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Brain diseases have become one of the leading roots of mortality and disability worldwide, contributing a significant part of the disease burden on healthcare systems. The blood-brain barrier (BBB) is a primary physical and biological obstacle that allows only small molecules to pass through it. Its selective permeability is a significant challenge in delivering therapeutics into the brain for treating brain dysfunction. It is estimated that only 2% of the new central nervous system (CNS) therapeutic compounds can cross the BBB and achieve their therapeutic targets. Scientists are exploring various approaches to develop effective cargo delivery vehicles to promote better therapeutics targeting the brain with minimal off-target side effects. Despite different synthetic carriers, one of the natural brain cargo delivery systems, “exosomes,” are now employed to transport drugs through the BBB. Exosomes are naturally occurring small extracellular vesicles (EVs) with unique advantages as a therapeutic delivery system for treating brain disorders. They have beneficial innate aspects of biocompatibility, higher stability, ability to cross BBB, low cytotoxicity, low immunogenicity, homing potential, targeted delivery, and reducing off-site target effects. In this review, we will discuss the limitations of synthetic carriers and the utilization of naturally occurring exosomes as brain-targeted cargo delivery vehicles and highlight the methods for modifying exosome surfaces and drug loading into exosomes. We will also enlist neurodegenerative disorders targeted with genetically modified exosomes for their treatment.

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Section: Introductionmentioning

confidence: 99%

Navigating the brain: the role of exosomal shuttles in precision therapeutics

Fatima,

Qaiser,

Andleeb

et al. 2024

Front. Neurol.

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Pirfenidone: A Promising Drug in Ocular Therapeutics

Bisen,

Agrawal,

Rayiti

et al. 2024

Chemistry & Biodiversity

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Pirfenidone, initially indicated for lung fibrosis, has gone beyond its original purpose, and shown promise in eye care. This detailed review tracks its evolution from lung treatment to aiding eye healing as evidenced by published literature. Pirfenidone's multifaceted attributes extend to mitigating corneal fibrosis, inflammation, and trauma. Through rigorous investigations, its efficacy emerges in diabetic retinopathy, macular degeneration, and postoperative glaucoma interventions. As an unheralded protagonist, pirfenidone reshapes ocular care paradigms, inviting renewed research opportunities.

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Hesperidin: Enrichment, forced degradation, and structural elucidation of potential degradation products using spectral techniques

Bisen,

Rawat,

Sharma

et al. 2023

Rapid Comm Mass Spectrometry

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RationaleHesperidin (HES) is a well‐known citrus bioflavonoid phyto‐nutraceutical agent with polypharmacological properties. After 2019, HES was widely used for prophylaxis and COVID‐19 treatment. Moreover, it is commonly prescribed for treating varicose veins and other diseases in routine clinical practice. Pharmaceutical impurities and degradation products (DP) impact the drug's quality and safety and thus its effectiveness. Therefore, forced degradation studies help study drug stability, degradation mechanisms, and their DPs. This study was performed because stress stability studies using detailed structural characterization of hesperidin are currently unavailable in the literature.MethodsIn the HES enrichment method crude HES was converted to its pure form (98% purity) using column chromatography and then subjected to forced degradation under acid, base, and neutral hydrolyses followed by oxidative, reductive, photolytic, and thermal stress testing (International Conference on Harmonization guidelines). The stability‐indicating analytical method (SIAM) was developed to determine DPs using reversed‐phase high‐performance liquid chromatography (C18 column with methanol and 0.1% v/v acetic acid in deionized water [70:30, v/v] at 284 nm). Further, structural characterization of DPs was performed using liquid chromatography‐electrospray ionization‐tandem mass spectrometry (LC‐ESI‐MS/MS) and nuclear magnetic resonance (NMR) spectroscopy. In addition, in silico toxicity predictions were performed using pKCSM and DataWarior freeware.ResultsHES was found to be susceptible to acidic and basic hydrolytic conditions and yielded three DPs in each, which were detected using designed SIAM. Of six DPs, three were pseudo‐DPs (short lived), and the remaining were characterized using LC–MS/MS and NMR spectroscopy. The tentative mechanism of the formation of proposed DPs was explained. The proposed DPs were found inactive from in silico toxicity predictions.ConclusionsHesperidin was labile under acidic and basic stress conditions. The potential DPs were characterized using LC‐ESI‐MS/MS and NMR spectral techniques. The proposed mechanism of formation was hypothesized. In addition, to identify and characterize the DPs, a SIAM, which has broad biomedical applications, was successfully developed.

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Recent Update on Pharmacokinetics and Drug Metabolism in CNS-based Drug Discovery

Cited by 12 publications

References 103 publications

Navigating the brain: the role of exosomal shuttles in precision therapeutics

Navigating the brain: the role of exosomal shuttles in precision therapeutics

Pirfenidone: A Promising Drug in Ocular Therapeutics

Hesperidin: Enrichment, forced degradation, and structural elucidation of potential degradation products using spectral techniques

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