naphthoquinones and Abdominal-Pain

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

Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) (PL) is a naturally occurring yellow pigment found in the plants of the Plumbaginaceae, Droseraceae, Ancistrocladaceae, and Dioncophyllaceae families. It has been reported that PL exhibits anticarcinogenic, anti-inflammatory, and analgesic activities. However, the mechanism underlying its anti-inflammatory action remains unknown. In the current study, we investigated and characterized the anti-inflammatory and analgesic effects of PL orally administrated in a range of dosages from 5 to 20 mg/kg. We also examined the role of nuclear factor κB (NF-κB) and proinflammatory cytokines and mediators in this effect. The results showed that PL significantly and dose-dependently suppressed the paw edema of rats induced by carrageenan and various proinflammatory mediators, including histamine, serotonin, bradykinin, and prostaglandin E(2). PL reduced the number of writhing episodes of mice induced by the intraperitoneal injection of acetic acid, but it did not reduce the writhing episode numbers induced by MgSO(4) in mice or prolong the tail-flick reaction time of rats to noxious thermal pain. Mechanistic studies showed that PL effectively decreased the production of the proinflammatory cytokines interleukin 1β, interleukin 6, and tumor necrosis factor α. It also inhibited the expression of the proinflammatory mediators inducible nitric-oxide synthase and cyclooxygenase 2, whereas it did not inhibit the expression of cyclooxygenase 1. Further studies demonstrated that PL suppressed inhibitor of κBα phosphorylation and degradation, thus inhibiting the phosphorylation of the p65 subunit of NF-κB. This study suggests that PL has a potential to be developed into an anti-inflammatory agent for treating inflammatory diseases.

Topics: Abdominal Pain; Acetic Acid; Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Carrageenan; Cyclooxygenase 2; Dinoprostone; Edema; Foot; Gene Expression; Histamine; Hot Temperature; I-kappa B Proteins; Inflammation; Interleukin-1beta; Interleukin-6; Magnesium Sulfate; Male; Mice; Mice, Inbred ICR; Naphthoquinones; NF-kappa B; NF-KappaB Inhibitor alpha; Nitric Oxide Synthase Type II; Pain Threshold; Phosphorylation; Rats; Rats, Sprague-Dawley; Serotonin; Transcription Factor RelA; Tumor Necrosis Factor-alpha

Topics: Abdominal Pain; Administration, Oral; Antimalarials; Atovaquone; Clinical Trials as Topic; Drug Combinations; Drug Interactions; Fees, Pharmaceutical; Humans; Malaria, Falciparum; Naphthoquinones; Nausea; Proguanil