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Development of a Synergistic Combination of Huperzia serrata, Convolvulus pluricaulis, and Celastrus paniculatus for Optimal Brain Health and Functions
Published in Abhai Kumar, Debasis Bagchi, Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
Imtiaz Ahmad, Deepanshi Dhar, Jagadeesh S. Rao, Anand Swaroop, Tariq Ahmad, Debasis Bagchi
Extensive research strategies are being pursued to include a wide variety of potential drug targets (Table 19.1). AD-based research is currently exploring the possibility of developing N-methyl-d-aspartate (NMDA) receptor antagonists, acetylcholinesterase inhibitors, antioxidants, radical scavengers, monoamine oxidase inhibitors, and Aβ and tau aggregation inhibitors/dissolver as likely candidates (Sureda et al. 2011, Bautista-Aguilera et al. 2014; Rafii and Aisen 2009). AD clinical trials have been recurrently dominated by anti-Aβ therapies, where 70 of 146 small molecules and immunotherapies are directed against Aβ compared with 13 compounds addressing tau-related mechanisms and 62 compounds assessing neuroprotective approaches (Cummings et al. 2014). Other approach under consideration as a potential target in AD is the inhibition of asparagine endopeptidase (protease responsible for the cleavage of its substrates after asparagine residues) with small molecular inhibitors due to its suggested role in the pathological processing of the amyloid precursor protein and tau proteins. Suggestive leads on its mechanisms and inhibition could be further exploited in other age-related neurological diseases such as PD, ALS, and frontotemporal lobar degeneration (Zhang et al. 2016). At present, of the five FDA-approved drugs marketed only for halting the disease progression, donepezil, galantamine, rivastigmine and tacrine are based on acetylcholinesterase inhibition, while memantine has an antagonist influence on NMDA receptor. Previously designed immunotherapies for AD using monoclonal antibodies such as gantenerumab, crenezumab, and aducanumab generated failed outcomes due to unsuccessful clinical efficacy and major safety problems when administered at higher doses. Ineffective attempts were also partly credited to a variation in their antibody epitopes and a high variability in recognition of the structural conformation of Aβ species along with a late intervention in patients post-excessive Aβ accumulation (Van Bulck et al. 2019). Accordingly, multifactorial drug design resulted in the development of combination therapies where certain drugs with the affinity for at least two molecular targets of AD, primarily AChE and BACE1, were tested for their efficacy, while other combinations displayed less toxicity and increased potential in metal-chelating and antioxidant properties. Major emphasis was placed on screening the combinations of AChE with GSK3β inhibitors, MAO (Monoamine oxidase) inhibitors, metal chelators, NMDAR (N-Methyl-D-aspartate receptor) inhibitors, 5-HT (5-hydroxytryptamine) receptor inhibitors, histaminic receptor inhibitors, and phosphodiesterase inhibitors. While a few combinations developed this way reported to alleviate AD, however, most of these combination agents were discontinued due to their adverse effects or dismal activity (Zhang et al. 2019).
Autoinjectors for large-volume subcutaneous drug delivery: a review of current research and future directions
Published in Expert Opinion on Drug Delivery, 2023
Andreas Schneider, Reto Jost, Christoph Jordi, Jakob Lange
Studies examining large-volume injections of monoclonal antibodies and immunoglobulins concluded that increasing the injection volume and rate did not affect serum concentrations [53,78,81,93,94]. Larger injection volumes (<50.0 mL) and rates (<0.028 mL/s) did not impact safety and tolerability of immunoglobulins, simplified overall administration, and reduced the number of injection sites and injection duration [78]. Cowan and colleagues [81] also concluded that increasing injection rates up to 0.033 mL/s did not change immunoglobulin serum levels. These findings were consistent for patient cohorts with manual push-type infusion and pump-assisted delivery [78,93,94]. Subcutaneous injection of crenezumab doses up to 40.0 mL (7200 mg) neither affected pharmacokinetics nor bioavailability parameters [53]. Adding recombinant hyaluronidase improved PK profiles compared with intravenous infusion and subcutaneous bioavailability [53]. The latter results have important implications for the development of large-volume injectors and show that adapting a formulation to meet the requirements of large-volume high-rate injections may affect PK equivalence.
Still grasping at straws: donanemab in Alzheimer’s disease
Published in Expert Opinion on Investigational Drugs, 2021
There are three treatments which will decrease Aβ deposition; β- and γ-secretase inhibitors reducing the production of Aβ and monoclonal antibodies that target Aβ. The secretase inhibitors do not improve cognition and have adverse effects in Alzheimer’s disease. To date, four monoclonal antibodies that target Aβ have been shown to have no benefit on cognition in their original phase 2/3 clinical trials in Alzheimer’s disease (bapinezumab, solanezumab, aducanumab, and crenezumab). Bapinezumab targeted the N-terminal Aβ peptide of soluble and fibrillar Aβ, triggering microglial phagocytosis of Aβ deposits. At high concentrations, bapinezumab was associated with amyloid-related imaging abnormalities (ARIA) edema and microhemorrhage. Solanezumab binds to the Aβ mid-domain, only in the soluble Aβ, not fibrillar or plaque-based Aβ, and did not reduce cerebral Aβ [3]. Aducanumab binds to amino terminus of Aβ at residues 3–7 in the aggregated of both insoluble fibrils and soluble oligomers [4]. Aducanumab did clear amyloid plaques but was ineffective in phase 3 [3]. Crenezumab targets the 13–16 residues of Aβ but does not alter Aβ burden in Alzheimer’s disease [5].
Grasping at straws: the failure of solanezumab to modify mild Alzheimer’s disease
Published in Expert Opinion on Biological Therapy, 2018
The Aβ cascade hypothesis is that reducing Aβ levels in the brain will be beneficial in Alzheimer’s disease. Consequently, many agents have been developed, or are being developed, to potentially reduce Aβ levels in the brain. This development includes passive immunotherapy using anti-Aβ monoclonal antibodies [3], but the results with some of these have been disappointing. Thus, despite reducing the levels of fibrillar Aβ [4], bapineuzumab, a humanized N-terminal-specific anti-Aβ antibody, did not improve cognition or function in subjects with mild-to-moderate Alzheimer’s disease. In addition, bapineuzumab increased amyloid-related imaging abnormalities with edema in these subjects [5]. Gantenerumab is a human anti-Aβ antibody that binds to the aggregated Aβ, which reduced brain amyloid load in subjects with mild-to-moderate Alzheimer’s disease in Phase 1, but also, at a higher dose, increased inflammation or vasogenic edema [6]. Thus, only a lower dose of gantenerumab was used in the Phase 3 trial in prodromal Alzheimer’s disease, and this was shown to have no effect on cognition, function, or brain amyloid load, while increasing amyloid-related imaging abnormalities [7]. Another humanized monoclonal antibody, crenezumab, binds to both the monomers and aggregated Aβ. In Phase 2, the effects of crenezumab on brain amyloid load were not reported, but it was shown to have no effect on cognition or function in 431 subjects with mild-to-moderate Alzheimer’s disease [8].