Modeling approaches for reducing safety-related attrition in drug discovery and development: a review on myelotoxicity, immunotoxicity, cardiovascular toxicity, and liver toxicity

Tosca, Elena M.; Bartolucci, R.; Magni, Paolo; Poggesi, Italo

doi:10.1080/17460441.2021.1931114

Cited by 11 publications

(9 citation statements)

References 137 publications

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“…Another very interesting point is that some molecules do not seem to have immunotoxic potential (CP18, 20 and 21; Table 2 ). When a compound is immunotoxic, it can interfere with several signaling pathways, resulting in changes in cytokine production and marker expression [ 27 ].…”

Section: Resultsmentioning

confidence: 99%

Study of Genotoxicity, Activities on Caspase 8 and on the Stabilization of the Topoisomerase Complex of Isoeleutherin and Analogues

et al. 2023

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This study evaluated the genotoxicity of Ethanol Extract (EEEp), Dichloromethane Fraction (FDCMEp) and isoeleutherin isolated from Eleutherine plicata, using the micronucleus test and the impact of structural alterations on toxicity and molecular docking (topoisomerase II and DNA complex). The extract was obtained by maceration and fractionation in a chromatography column. The genotoxicity was evaluated by the micronucleus test in human hepatoma cells (HepG2). Isoeleutherin was the starting molecule in the search for analogues by structural similarity, using the ZINC and e-Molecules databases. Isoeleutherin and analogues were subjected to in silico toxicity prediction, and compounds free of toxicological risks (CP13, CP14, CP17 and isoeleutherin) were selected for molecular docking in Topoisomerase II (PDB: 1ZXM). In the micronucleus test, isoeleutherin was less genotoxic. Among the 22 isoeleutherin analogues there were variations in the toxicity profile. Molecular docking studies showed that the compounds have good complementarity in the active site with important hydrogens bonds. Therefore, the structural changes of isoeleutherin led to the obtaining of a molecule with a lower mutagenic potential, and the CP13 can be considered a prototype compound for the development of new molecules with pharmacological potential.

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Section: Resultsmentioning

confidence: 99%

Study of Genotoxicity, Activities on Caspase 8 and on the Stabilization of the Topoisomerase Complex of Isoeleutherin and Analogues

et al. 2023

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“…Another concern is that low in vitro IC50 (HFF) may not necessarily translate to high in vivo toxicity considering the complexity of the whole organism and the many varied tissues. 33 However, the overall cytostatic activity of the extract and fractions of T. diversifolia in the in vitro model and the corresponding antitrypanosomal activity in the in vivo/in vitro models have further validated the usefulness of this plant in folk medicine across Africa. In a biological activity-guided fractionation and separation of the methanol extract of T. diversifolia, the study identified the two STLrich VLC sub-fractions responsible for the tested activities.…”

Section: In Vitro Anti-tb Brucei and Cytotoxic Activitiesmentioning

confidence: 99%

Sesquiterpene Lactone-Rich Extract of Tithonia diversifolia (Hemsley) A. Gray (Asteraceae) suppresses Trypanosoma brucei brucei in both In Vivo and In Vitro Experimental Models

2022

TJNPR

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Tithonia diversifolia has continued to play vital roles in phytomedicine due to its ethnopharmacological relevance, medicinal properties and agricultural applications. Its richness in sesquiterpene lactones has also continued to generate interest due to its diverse pharmacological activities, structure-activity relationships, and pharmacokinetics. The study evaluated the anti-trypanosomal and cytotoxic activities of the sesquiterpene lactone (STL) constituents of Tithonia diversifolia using in vivo mouse and in vitro experimental models. The T. diversifolia methanol extract was fractionated by solvent-solvent partitioning in n-hexane, EtOAc, and n-butanol and further separated by the vacuum liquid chromatographic (VLC) method. The in vitro anti-trypanosomal and cytotoxic activities were evaluated using resazurinbased cell viability assays. The in vivo anti-trypanosomal activity was determined using a hematocrit-based packed cell volume analysis and rapid matching counting of Trypanosoma brucei brucei inhibition methods in a mouse model. The two STL-enriched sub-fractions (VLC-3 and VLC-4) obtained from the VLC separation displayed significant (p < 0.05) in vitro activity against Trypanosoma brucei with IC50 values of 0.88 and 0.52 µg/mL respectively and SI of 44 and 165 respectively. In the in vivo mouse model, a 400 mg/kg dose of VLC-3 and VLC-4 elicited a 100% clearance of the parasites within 16 and 14 days post-induction of parasitemia compared with a similar effect of the positive control drug, diminazene aceturate on day 12. The strong in vivo/in vitro anti-trypanosomal activity of T. diversifolia STL represents a promising starting point for discovering potent trypanocidal agents against T.b. brucei, the major cause of animal African trypanosomiasis.

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“…It is a twocompartments model with first-order absorption and elimination and WT effect on apparent clearance. Population and individual PK parameters are reported in Table S2 26,27 For each hematological parameter, the model consists of a proliferating cells compartment, three transit compartments for cell maturation, and a circulating cells compartment. A negative feedback loop links the circulating to the proliferating cell compartment.…”

Section: Givinostat Pk Model In Pv Patientsmentioning

confidence: 99%

In silico trial for the assessment of givinostat dose adjustment rules based on the management of key hematological parameters in polycythemia vera patients

Tosca,

De Carlo,

Bartolucci

et al. 2024

CPT Pharmacom & Syst Pharma

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Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by excessive levels of platelets (PLT), white blood cells (WBC), and hematocrit (HCT). Givinostat (ITF2357) is a potent histone‐deacetylase inhibitor that showed a good safety/efficacy profile in PV patients during phase I/II studies. A phase III clinical trial had been planned and an adaptive dosing protocol had been proposed where givinostat dose is iteratively adjusted every 28 days (one cycle) based on PLT, WBC, and HCT. As support, a simulation platform to evaluate and refine the proposed givinostat dose adjustment rules was developed. A population pharmacokinetic/pharmacodynamic model predicting the givinostat effects on PLT, WBC, and HCT in PV patients was developed and integrated with a control algorithm implementing the adaptive dosing protocol. Ten in silico trials in ten virtual PV patient populations were simulated 500 times. Considering an eight‐treatment cycle horizon, reducing/increasing the givinostat daily dose by 25 mg/day step resulted in a higher percentage of patients with a complete hematological response (CHR), that is, PLT ≤400 × 109/L, WBC ≤10 × 109/L, and HCT < 45% without phlebotomies in the last three cycles, and a lower percentage of patients with grade II toxicity events compared with 50 mg/day adjustment steps. After the eighth cycle, 85% of patients were predicted to receive a dose ≥100 mg/day and 40.90% (95% prediction interval = [34, 48.05]) to show a CHR. These results were confirmed at the end of 12th, 18th, and 24th cycles, showing a stability of the response between the eighth and 24th cycles.

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Modeling approaches for reducing safety-related attrition in drug discovery and development: a review on myelotoxicity, immunotoxicity, cardiovascular toxicity, and liver toxicity

Cited by 11 publications

References 137 publications

Study of Genotoxicity, Activities on Caspase 8 and on the Stabilization of the Topoisomerase Complex of Isoeleutherin and Analogues

Study of Genotoxicity, Activities on Caspase 8 and on the Stabilization of the Topoisomerase Complex of Isoeleutherin and Analogues

Sesquiterpene Lactone-Rich Extract of Tithonia diversifolia (Hemsley) A. Gray (Asteraceae) suppresses Trypanosoma brucei brucei in both In Vivo and In Vitro Experimental Models

In silico trial for the assessment of givinostat dose adjustment rules based on the management of key hematological parameters in polycythemia vera patients

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