The evaluation of thioridazine as a hematopoietic progenitor cell mobilizing agent in healthy human subjects

Chigaev, Alexandre; Sklar, Larry A.; Schrader, Ronald M.; Stephens, Nicole; Raissy, Hengameh H.; Winter, Stuart S.

doi:10.1002/jcph.448

Cited by 3 publications

(2 citation statements)

References 25 publications

(40 reference statements)

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“…Phenothiazines also displayed notable toxicity against primary human granulocytes and to a lesser extent, lymphocytes. TDZ exhibited greater toxicity than PCZ, but this was not surprising given that agranulocytosis is a noted adverse effect of TDZ. − For this reason, TDZ is perhaps unsuitable for clinical use as a dynII-inhibiting adjuvant therapy in cancer patients undergoing combination chemotherapy with drugs that cause leukopenia. The white cell toxicity exhibited in the present study may, however, be a consequence of the low in vitro concentration (5%) of FCS used.…”

Section: Discussionmentioning

confidence: 99%

Dose-Dependent Effect of Phenothiazines as Dynamin II Inhibitors on the Uptake of PEGylated Liposomes by Endocytic Cells and In Vivo Pharmacokinetics of PEGylated Liposomal Doxorubicin in Rats

et al. 2023

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Dynamin II (dynII) plays a significant role in the internalization pathways of endocytic cells, by allowing membrane invaginations to "bud off". An important class of dynII inhibitors that are used clinically are phenothiazines, such as prochlorperazine (PCZ). PCZ is an antipsychotic drug but is also currently in clinical trials at higher concentrations as an adjuvant in cancer patients that increases the efficacy of monoclonal antibodies at high intravenous doses. It is unknown, however, whether high-dose dynII inhibitors have the potential to alter the pharmacokinetics of co-administered chemotherapeutic nanomedicines that are largely cleared via the mononuclear phagocyte system. This work therefore sought to investigate the impact of clinically relevant concentrations of phenothiazines, PCZ and thioridazine, on in vitro liposome endocytosis and in vivo liposome pharmacokinetics after PCZ infusion in rats. The uptake of fluorescently labeled PEGylated liposomes into differentiated and undifferentiated THP-1 and RAW246.7 cells, and primary human peripheral white blood cells, was investigated via flow cytometry after co-incubation with dynII inhibitors. The IV pharmacokinetics of PEGylated liposomes were also investigated in rats after a 20 min infusion with PCZ. Phenothiazines and dyngo4a reduced the uptake of PEGylated liposomes by THP-1 and RAW264.7 cells in a concentrationdependent manner in vitro. However, dynII inhibitors did not alter the mean uptake of liposomes by human peripheral white blood cells, but endocytic white cells from some donors exhibited sensitivity to phenothiazine exposure. When a clinically relevant dose of PCZ was co-administered with PEGylated liposomal doxorubicin (Caelyx/Doxil) in rats, the pharmacokinetics and biodistribution of liposomes were unaltered. These data suggest that while clinically relevant doses of dynII inhibitors can inhibit the uptake of liposomes by endocytic cells in vitro, they are unlikely to significantly affect the pharmacokinetics of long-circulating, coadministered liposomes.

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Section: Discussionmentioning

confidence: 99%

Dose-Dependent Effect of Phenothiazines as Dynamin II Inhibitors on the Uptake of PEGylated Liposomes by Endocytic Cells and In Vivo Pharmacokinetics of PEGylated Liposomal Doxorubicin in Rats

et al. 2023

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“…It has been effective in vitro by inhibiting CSC spheroid formation and inducing apoptosis and in vivo by reducing xenograft tumor volume in mice. The plasma peak concentration (C Max ) of thioridazine after a single oral dose of 50 mg reaches 280 nM( Chigaev et al., 2015 ). We have shown in this work that synergy between thioridazine and gemcitabine occurs in a wide range of concentrations of both drugs, including at 100nM and 300nM of thioridazine.…”

Section: Discussionmentioning

confidence: 99%

Prediction and identification of synergistic compound combinations against pancreatic cancer cells

et al. 2021

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Summary Resistance to current therapies is common for pancreatic cancer and hence novel treatment options are urgently needed. In this work, we developed and validated a computational method to select synergistic compound combinations based on transcriptomic profiles from both the disease and compound side, combined with a pathway scoring system, which was then validated prospectively by testing 30 compounds (and their combinations) on PANC-1 cells. Some compounds selected as single agents showed lower GI50 values than the standard of care, gemcitabine. Compounds suggested as combination agents with standard therapy gemcitabine based on the best performing scoring system showed on average 2.82–5.18 times higher synergies compared to compounds that were predicted to be active as single agents. Examples of highly synergistic in vitro validated compound pairs include gemcitabine combined with Entinostat, thioridazine, loperamide, scriptaid and Saracatinib. Hence, the computational approach presented here was able to identify synergistic compound combinations against pancreatic cancer cells.

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New agents in HSC mobilization

2016

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The evaluation of thioridazine as a hematopoietic progenitor cell mobilizing agent in healthy human subjects

Cited by 3 publications

References 25 publications

Dose-Dependent Effect of Phenothiazines as Dynamin II Inhibitors on the Uptake of PEGylated Liposomes by Endocytic Cells and In Vivo Pharmacokinetics of PEGylated Liposomal Doxorubicin in Rats

Dose-Dependent Effect of Phenothiazines as Dynamin II Inhibitors on the Uptake of PEGylated Liposomes by Endocytic Cells and In Vivo Pharmacokinetics of PEGylated Liposomal Doxorubicin in Rats

Prediction and identification of synergistic compound combinations against pancreatic cancer cells

New agents in HSC mobilization

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