naphthoquinones and Diarrhea

This study examined the safety, tolerability, and pharmacokinetics (PK) of napabucasin in healthy Asian and non-Asian participants and investigated the potential for QT/QTc interval prolongation. This five-part (A-E) study proceeded in a stepwise manner, unless stopping criteria were met. Parts A-D were randomized, double-blind, placebo-controlled, and included healthy Asian male and female and non-Asian male participants. PK parameters were measured following single-dose napabucasin (80-1200 mg) in the fasted or fed state (Part D). Potential QT/QTc interval prolongation was assessed using digital 12-lead electrocardiogram (Parts B and C). Part E was open-label, and examined the PK of single-dose napabucasin (240-720 mg) in healthy non-Asian males. Safety and tolerability were measured in Parts A-E. Changes from baseline in the Fridericia-corrected QT interval (ΔQTcF) and other electrocardiogram parameters were analyzed using a linear mixed-effects model. Napabucasin was well-tolerated across the study (n = 70), and no serious adverse events or significant safety issues were reported when administered with or without food. The most frequent treatment-emergent adverse events were diarrhea and abdominal pain, and these were mild in severity. No prolongation of the QTcF interval was reported following single-dose napabucasin (240-1200 mg) and changes in other cardiac parameters were negligible. The PK profile of napabucasin was consistent with earlier studies. Single-dose napabucasin was tolerated in healthy male and female participants, and no significant safety (including no QTcF prolongation) or tolerability issues were identified, irrespective of food intake. Clinical studies of napabucasin in advanced cancers are ongoing.

Topics: Abdominal Pain; Antineoplastic Agents; Asian People; Benzofurans; Diarrhea; Double-Blind Method; Electrocardiography; Female; Healthy Volunteers; Heart Conduction System; Humans; Long QT Syndrome; Male; Naphthoquinones; Reactive Oxygen Species

Recent evidence has established the effectiveness of Malarone and primaquine for chemoprophylaxis against Plasmodium falciparum malaria. Both have the advantage of providing causal prophylaxis and therefore require continued dosing for only 1 wk after departure from a malaria endemic area. Canadian Forces aircrews are often placed in situations that put them at risk for malaria infection but the safety of these drugs for use in aircrew has not been ascertained. This study was undertaken to determine whether or not Malarone or primaquine impact psychomotor performance.. Twenty-eight subjects (20 men and 8 women) ranging from 21 to 52 yr of age were assessed for psychomotor performance on 2 psychomotor test batteries at the end of a 7-d dosing protocol for each of placebo, Malarone, and primaquine treatment, in a double-blind crossover design with counterbalanced treatment order. All subjects were also assessed for psychomotor performance once per week during the 3-wk washout intervals. The daily Malarone dose was atovaquone 250 mg/proguanil 100 mg and the daily primaquine dose was 30 mg of base. In order to verify subject compliance with the medication dosing protocol, blood samples were drawn from all subjects at the end of each of the three 7-d loading protocols. All three medications were packaged in identical gelatin capsules for blinding purposes. At each psychomotor test session, all subjects completed a drug side-effect questionnaire, a mood questionnaire, and a sleepiness/fatigue questionnaire.. There was no significant impact of Malarone or primaquine on serial reaction time, logical reasoning, serial subtraction, or multitask performance. With respect to drug adverse effects there were no significant main effects or interactions for the documented adverse effects of these medications (abdominal cramps, epigastric distress, nausea, vomiting, anorexia, headache, coughing and dizziness).. There was no impact of either Malarone or primaquine on psychomotor performance, mood, sleepiness, or fatigue. The usual adverse effects of these medications were not significantly manifested in our subjects. These findings support the possible use of either Malarone or primaquine in aircrew for malaria chemoprophylaxis.

Topics: Adult; Affect; Antimalarials; Atovaquone; Colic; Cross-Over Studies; Diarrhea; Double-Blind Method; Drug Combinations; Fatigue; Female; Headache; Humans; Male; Middle Aged; Naphthoquinones; Nausea; Patient Compliance; Primaquine; Proguanil; Psychomotor Performance

We previously reported that TU-100 suppresses irinotecan hydrochloride (CPT-11)-induced inflammatory cytokines and apoptosis. However, the mechanism underlying this effect has not been fully elucidated. The aim of this study was to further clarify the mechanism of CPT-11-induced bacterial translocation (BT) and the effect of TU-100 on BT.. Cell cytotoxicity was assessed in vitro by a WST-8 assay. For the in vivo experiments, rats were randomly divided into 3 groups: the control group, the CPT-11 group (250 mg/kg i.p. for 2 days), and the CPT-11 and TU-100 co-treated group (1000 mg/kg, p.o. for 5 days). All of the rats were sacrificed on day 6 and their tissues were collected.. CPT-11 and TU-100 co-treatment improved CPT-11 the related cytotoxicity in vitro. All CPT-11-treated rats developed different grades of diarrhea and BT was observed in 80% of the rats. CPT-11 caused a significant increase in the expression of TLR4, IL-6, TNF-α, IL-1β and caspase-3 mRNAs in the large intestine. The expression of tight junction (TJ) marker mRNAs (occludin, claudin-1 and 4, and ZO-1) was significantly decreased in comparison to the control group. TU-100 co-treatment significantly reversed diarrhea, BT, and the expression of TLR2, IL-6, TNF-α, IL-1β and caspase-3, and improved the expression of occludin, claudin-4 and ZO-1.. TU-100 can suppress the adverse effects associated with CPT-11 and improve the function of the TJ. It is possible that this occurs through the TLR pathway.

Topics: Animals; Antineoplastic Agents, Phytogenic; Bacterial Translocation; Camptothecin; Cells, Cultured; Claudin-4; Cytokines; Diarrhea; Humans; Inflammation Mediators; Irinotecan; Male; Naphthoquinones; Occludin; Phytotherapy; Rats, Wistar; Tight Junctions; Toll-Like Receptors; Zonula Occludens-1 Protein