Mechanisms of the pH- and Oxygen-Dependent Oxidation Activities of Artesunate.

Artemisinin was discovered in 1971 as a constituent of the wormwood genus plant (Artemisia annua). This plant has been used as an herbal medicine to treat malaria since ancient times. The compound artemisinin has a sesquiterpene lactone bearing a peroxide group that offers its biological activity. In addition to anti-malarial activity, artemisinin derivatives have been reported to exert antitumor activity in cancer cells, and have attracted attention as potential anti-cancer drugs. Mechanisms that might explain the antitumor activities of artemisinin derivatives reportedly induction of apoptosis, angiogenesis inhibitory effects, inhibition of hypoxia-inducible factor-1α (HIF-1α) activation, and direct DNA injury. Reactive oxygen species (ROS) generation is involved in many cases. However, little is known about the mechanism of ROS formation from artemisinin derivatives and what types of ROS are produced. Therefore, we investigated the iron-induced ROS formation mechanism by using artesunate, a water-soluble artemisinin derivative, which is thought to be the underlying mechanism involved in artesunate-mediated cell death. The ROS generated by the coexistence of iron(II), artesunate, and molecular oxygen was a hydroxyl radical or hydroxyl radical-like ROS. Artesunate can reduce iron(III) to iron(II), which enables generation of ROS irrespective of the iron valence. We found that reduction from iron(III) to iron(II) was activated in the acidic rather than the neutral region and was proportional to the hydrogen ion concentration.

[Efficacy and safety of low-dose matrix-type transdermal fentanyl applied for opioid initiation].

Minimum-size matrix-type transdermal fentanyl(TDF)(Durotep®MTPatch 2.1mg), with a dose equivalent to half of a minimum-size conventional-type TDF(Durotep Patch 2.5mg), was newly produced. Now, the use of minimum-size matrix-type TDF at the early stage of opioid initiation has become possible. For several reasons, we sometimes encounter clinical cases where clinicians are inclined to use the minimum-size matrix-type TDF first without prior use of other opioids. In order to evaluate the efficacy and safety of minimum-size matrix-type TDF, we analyzed 49 patients, retrospectively for whom minimum-size matrix-type TDF was initiated. We used the Wong-Baker faces pain rating scale to assess the effect of matrix-type TDF. The rate of effective and ineffective cases were 55% and 37%, respectively, and 8% of cases could not be evaluated. The frequency of side effects such as nausea, somnolence, sense of fatigue and constipation was 20%, 16%, 4% and 2%, respectively. However, respiration depression was not documented at all. The score of the palliative prognostic index was significantly higher in ineffective cases compared with effective cases. Patients who were judged ineffective tended to have poor prognoses. One of the reasons matrix-type TDF was thought to be ineffective in such patients was that a rapid increase of the dose according to dynamic changes of symptoms was difficult. These findings suggest that we can use a matrix-type TDF as opioid initiation relatively safely, but in cases with poor prognoses, we should use it under appropriate and sufficient rescue setting only when other opioids cannot be prescribed.