Safety Pharmacology in Drug Discovery and Development

Morimoto, Bruce H.; Castelloe, Erin; Fox, Anthony W.

doi:10.1007/978-3-662-46943-9_3

Cited by 13 publications

(9 citation statements)

References 14 publications

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“…Since the pharmacological activity does not depend only on the pharmacodynamic properties, but also on the pharmacokinetic properties. Moreover, as the drug safety, the assessment of drug-likeness probability, and the synthetic accessibility are important issues [78], the identification of the best A. nilotica's phytochemical constituents will be attained by the assessment of those issues collectively.…”

Section: -D-alanine D-alanine Ligase Enzymementioning

confidence: 99%

Ellagic Acid, Kaempferol, and Quercetin from Acacia nilotica: Promising Combined Drug With Multiple Mechanisms of Action

2019

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The pharmacological activity of Acacia nilotica's phytochemical constituents was confirmed with evidence-based studies, but the determination of exact targets that they bind and the mechanism of action were not done; consequently, we aim to identify the exact targets that are responsible for the pharmacological activity via the computational methods. Furthermore, we aim to predict the pharmacokinetics (ADME) properties and the safety profile in order to identify the best drug candidates. To achieve those goals, various computational methods were used including the ligand-based virtual screening and molecular docking. Moreover, pkCSM and SwissADME web servers were used for the prediction of pharmacokinetics and safety. The total number of the investigated compounds and targets was 25 and 61, respectively. According to the results, the pharmacological activity was attributed to the interaction with essential targets. Ellagic acid, Kaempferol, and Quercetin were the best A. nilotica's phytochemical constituents that contribute to the therapeutic activities, were non-toxic as well as non-carcinogen. The administration of Ellagic acid, Kaempferol, and Quercetin as combined drug via the novel drug delivery systems will be a valuable therapeutic choice for the treatment of recent diseases attacking the public health including cancer, multidrug-resistant bacterial infections, diabetes mellitus, and chronic inflammatory systemic disease.

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Section: -D-alanine D-alanine Ligase Enzymementioning

confidence: 99%

Ellagic Acid, Kaempferol, and Quercetin from Acacia nilotica: Promising Combined Drug With Multiple Mechanisms of Action

2019

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“…Treatment with nicotinamide (NAM), a precursor of NAD + , increases circulating NAD + and is protective in models of RGC degeneration [ 18 , 20 , 21 , 22 ] and is being tested in a glaucoma clinical trial [ 23 ]. The maximal efficacy in models was achieved only at doses that, by human equivalent dose (HED), may be above a good safety profile, and was not protective in a significant portion of the treated cohorts [ 24 , 25 , 26 ]. Thus, though maintaining NAD + levels by treatment with precursors is potentially therapeutic, NAD + precursors in addition to NAM should be considered.…”

Section: Introductionmentioning

confidence: 99%

Systemic Treatment with Nicotinamide Riboside Is Protective in Two Mouse Models of Retinal Ganglion Cell Damage

Zhang

Chrenek

et al. 2021

Pharmaceutics

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Glaucoma etiology often includes retinal ganglion cell (RGC) death associated with elevated intraocular pressure (IOP). However, even when IOP is managed well, disease can progress. It is thus important to develop therapeutic approaches that directly protect RGCs in an IOP-independent manner. Compromised nicotinamide adenine dinucleotide (NAD+) metabolism occurs in neurodegenerative diseases, including models of glaucoma. Here we report testing the protective effects of prophylactically systemically administered nicotinamide riboside (NR), a NAD+ precursor, in a mouse model of acute RGC damage (optic nerve crush (ONC)), and in a chronic model of RGC degeneration (ocular hypertension induced by intracameral injection of microbeads). For both models, treatment enhanced RGC survival, assessed by counting cells in retinal flatmounts immunostained for Brn3a+. In the ONC model, treatment preserved RGC function, as assessed by pattern electroretinogram, and suppressed retinal inflammation, as assessed by immunofluorescence staining of retinal fixed sections for glial fibrillary acidic protein (GFAP). This is the first study to demonstrate that systemic treatment with NR is protective in acute and chronic models of RGC damage. The protection is significant and, considering that NR is highly bioavailable in and well-tolerated by humans, may support the proposition of prospective human subject studies.

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“…Prior to first-in-human studies, pre-clinical safety pharmacology assays, tests, and models are positioned to predict the clinical risk profile of NCEs. More importantly, properly conducted safety pharmacology studies are important given the necessity to reduce the number of late-stage failures by way of triaging drug candidates early and allowing for advancement of the best drug candidates based on a balance between efficacy and safety (Morimoto et al, 2015 ). While most pre-clinical in vivo safety pharmacology models employ quantitative and objective measurements of organ function (e.g., blood pressure in telemetry-instrumented rodents), CNS functional profiling is more difficult to quantify as assessments are typically performed with the use of behavioral models that are largely, albeit not exclusively, dependent on multiple subjective endpoints.…”

Section: Resultsmentioning

confidence: 99%

Physical Properties and Effect in a Battery of Safety Pharmacology Models for Three Structurally Distinct Enteric Polymers Employed as Spray-Dried Dispersion Carriers

et al. 2016

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Establishing a wide therapeutic index (TI) for pre-clinical safety is important during lead optimization (LO) in research, prior to clinical development, although is often limited by a molecules physiochemical characteristics. Recent advances in the application of the innovative vibrating mesh spray-drying technology to prepare amorphous solid dispersions may offer an opportunity to achieve high plasma concentrations of poorly soluble NCEs to enable testing and establishment of a wide TI in safety pharmacology studies. While some of the amorphous solid dispersion carriers are generally recognized as safe for clinical use, whether they are sufficiently benign to enable in vivo pharmacology studies has not been sufficiently demonstrated. Thus, the physical properties, and effect in a battery of in vivo safety pharmacology models, were assessed in three classes of polymers employed as spray-dried dispersion carriers. The polymers (HPMC-AS, Eudragit, PVAP) displayed low affinity with acetone/methanol, suitable for solvent-based spray drying. The water sorption of the polymers was moderate, and the degree of hysteresis of HPMC-AS was smaller than Eudragit and PVAP indicating the intermolecular interaction of water-cellulose molecules is weaker than water-acrylate or water-polyvinyl molecules. The polymer particles were well-suspended without aggregation with a mean particle size less than 3 μm in an aqueous vehicle. When tested in conscious Wistar Han rats in safety pharmacology models (n = 6–8/dose/polymer) investigating effects on CNS, gastrointestinal, and cardiovascular function, no liabilities were identified at any dose tested (30–300 mg/kg PO, suspension). In brief, the polymers had no effect in a modified Irwin test that included observational and evoked endpoints related to stereotypies, excitation, sedation, pain/anesthesia, autonomic balance, reflexes, and others. No effect of the polymers on gastric emptying or intestinal transit was observed when measured using a barium sulfate tracer material. Finally, in telemetry-instrumented rats the polymers had no effect on acute or 24-h mean blood pressure and heart rate values at doses up to 300 mg/kg. Thus, the properties of the three enteric polymers are appropriate as spray-dried dispersion carriers and were benign in a battery of safety pharmacology studies, demonstrating their applicability to enable in vivo safety pharmacology profiling of poorly soluble molecules during LO.

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Safety Pharmacology in Drug Discovery and Development

Cited by 13 publications

References 14 publications

Ellagic Acid, Kaempferol, and Quercetin from Acacia nilotica: Promising Combined Drug With Multiple Mechanisms of Action

Ellagic Acid, Kaempferol, and Quercetin from Acacia nilotica: Promising Combined Drug With Multiple Mechanisms of Action

Systemic Treatment with Nicotinamide Riboside Is Protective in Two Mouse Models of Retinal Ganglion Cell Damage

Physical Properties and Effect in a Battery of Safety Pharmacology Models for Three Structurally Distinct Enteric Polymers Employed as Spray-Dried Dispersion Carriers

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