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The main toxicities were diarrhoea (dose limiting at 2500 mg once daily), nausea, dizziness, abdominal pain and vomiting.
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Delayed diarrhoea was dose limiting at an irinotecan dose level of 300 mg/m2 (dose level II) combined with 5-FU 425 mg/m2 and FA 20 mg/m.
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Neither myelosuppression nor diarrhoea was dose limiting in this study.
In phase I trials, skin rash and diarrhoea are dose limiting.
Hand-foot syndrome and diarrhoea were dose limiting with capecitabine 1250 mg/m2 twice daily.
One patient had prolonged grade 3 or 4 neutropenia and thrombocytopenia, and recurrent diarrhoea despite dose reduction.
Diarrhoea was dose limiting at 300 mg/m2 irinotecan in combination with 5-fluorouracil and folinic acid, and this was determined to be the maximum tolerated dose.
The correlation between the incidence of diarrhoea and dose, which was previously reported with lapatinib (Burris et al, 2009), was also examined in our study; a similar although smaller correlation was observed with TAK-285.
In the event of grade 3/4 neutropaenia or diarrhoea, the doses of irinotecan and 5-FU were reduced by 25%.
As shown in Figures 4(a) and 4(b), compared with vehicle-treated diarrhoea mice, doses of 125~500 mg/kg RTE markedly reduced the protein levels of AQPs 2 and 3 in the colon tissues of diarrhoea mice by western blot analysis (all P < 0.05).
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