Biological & pharmaceutical bulletin
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The cardiotoxic effects of local anesthetics increase in cardiac ischemia which is characterized by the tissue pH lowering to 6.5 or less. Apart from the cardiac channel blockade, the membrane interaction has been referred to as another mode of their cardiotoxic action. By using biomimetic membranes, we verified the hypothesis that bupivacaine and lidocaine may increasingly interact with cardiac mitochondrial membranes under ischemia-like acidic conditions. ⋯ Such increases were greater in anionic phospholipid membranes which consisted of substantial amounts of cardiolipin and phosphatidylserine. Positively charged bupivacaine and lidocaine would form ion-pairs with the negatively charged head-groups of anionic phospholipids under acidic conditions, thereby increasing the induced membrane fluidization. The mitochondrial membrane interactions depending on pH lowering may be, at least in part, responsible for local anesthetic cardiotoxicity enhanced in acidosis associated with cardiac ischemia.
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Therapeutic drug monitoring of valproic acid (VPA) is essential to prevent toxicity, but the correlation between plasma ammonia level and serum VPA concentration remains unclear. We examined the correlation of plasma ammonia level with VPA dose and serum trough concentrations of total and free VPA in Japanese patients with epilepsy. Thirty-eight data sets from 19 Japanese patients with epilepsy were analyzed. ⋯ A significant positive correlation was observed between plasma ammonia level and VPA dose (r(s)=0.56, p=0.00062), serum trough total VPA concentration (r(s)=0.55, p=0.00086) and serum trough free VPA concentration (r(s)=0.58, p=0.00041). The breakpoints predicting hyperammonemia were VPA dose of 30.4 mg/kg, serum trough total VPA concentration of 90.9 µg/mL, and serum trough free VPA concentration of 8.65 µg/mL, with impurity reductions at 1.35, 1.35 and 2.02, respectively. These findings suggest that serum trough concentration of free VPA is the most reliable predictor for hyperammonemia, and that the risk of developing hyperammonemia may increase in patients with serum trough free VPA concentrations higher than 8.65 µg/mL.
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Neuropathic pain is a devastating neurological disease that seriously affects patients' quality of life. Despite a high level of incidence, the underlying mechanisms of neuropathic pain are still poorly understood. However, recent evidence supports the prominent role of spinal glial cells in neuropathic pain states. ⋯ In addition, the astrocyte activation was attenuated following najanalgesin treatment in the dorsal horn of neuropathic rats, as assessed by immunohistology and Western blotting. The tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) content of cerebral spinal fluid and cell culture supernatants changed significantly after najanalgesin administration. The results suggest that najanalgesin may exert its anti-allodynic effect by altering astrocyte cell function.
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One of the most significant conceptual changes brought about by the analysis of circadian clock-deficient mice is that abnormalities in the circadian clock are linked not only to sleep arousal disorder but also to a wide variety of common diseases, including hypertension, diabetes, obesity, and cancer. It has recently been shown that the disruption of the two cryptochrome genes Cry1 and Cry2-core elements of the circadian clock-induces salt-dependent hypertension due to abnormally high synthesis of the mineralocorticoid aldosterone by the adrenal gland. ⋯ Importantly, this enzyme is functionally conserved in humans, and the pathophysiologic condition of human idiopathic hyperaldosteronism resembles that of Cry1/2-deficient mice. This review highlights the potential utility of circadian clock-deficient mice as a tool for exploring hitherto unknown disease etiology linked to the circadian clock.
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Panax Notoginseng Saponins (PNS) have been well known to have anti-tumor activity and enhance cytotoxicity of some cancer chemotherapy agents, but the mechanisms underlying these effects are still unknown. This study investigates the effect of PNS on cytotoxicity of cisplatin and the relationship between this effect and the modulation of gap junctions (GJ) function by PNS in a transfected cell line. The cytotoxicity of cisplatin (0.25-1 µg/mL) was increased in the presence of GJ. ⋯ PNS (50-200 µg/mL) significantly enhanced cisplatin cytotoxicity, but this effect required functional gap junctions between the cells. Exposure of the cells to PNS (50-200 µg/mL) for 4 h leads to a significant enhance in dye coupling of GJ in a dose-dependent manner. These results suggest that PNS increases the cytotoxicity of cisplatin through enhancement of GJ activity.