Trends in the incidence of urothelial carcinoma in Taiwan after the ban on aristolochic acid-containing Chinese herbal preparations, 2001-2018: a national population-based cohort study.

PURPOSE: Urothelial carcinoma (UC) of the bladder (BUC) and the upper urinary tract (UTUC) are the two most common UCs. The incidence of UTUC in Taiwan is the highest worldwide. Aristolochic acid (AA) was identified as the main cause of UTUC in Taiwan. To explore trends in the incidence of UC in Taiwan after the ban on Chinese herbal preparations containing AA in 2003. METHODS: We used data from the Taiwanese National Health Insurance Research Database-linked Taiwanese National Cancer Registry for 2001-2018. UC was defined in accordance with the International Classification of Disease for Oncology. The age-standardized incidence was calculated on the basis of the World Health Organization standard population. Trends in the incidence were calculated as the annual percent change (APC) by using the Joinpoint regression program. RESULTS: Over the investigated period, the incidence of UC decreased at an average annual percent change (AAPC) of - 1.19% (95% CI - 1.47 ~ - 0.91, P < 0.001). However, the incidence in UTUC significantly increased, with the AAPC being 1.47% (95% CI 1.03 ~ 1.90, P < 0.001). In contrast, the incidence of BUC significantly decreased, with the overall AAPC being - 1.92% (95% CI - 2.3 ~ - 1.54, P < 0. 001). From 2001 to 2018, the overall incidence of UCs and BUC decreased in Taiwan, but the incidence of UTUC significantly increased. CONCLUSION: We suggest to apply the same review standards of new drug development process to herbal preparations and incorporate them into the adverse drug reaction or poison surveillance system. Most importantly, raise public awareness of the potential toxicity of phytotherapy.

Effects of Denosumab and Calcitriol on Severe Secondary Hyperparathyroidism in Dialysis Patients With Low Bone Mass.

CONTEXT: Secondary hyperparathyroidism (SHPT) may worsen with administration of denosumab in chronic renal failure patients with low bone mass. OBJECTIVE: This study aimed to evaluate the short-term effect of coadministration of calcitriol and denosumab on PTH secretion and parathyroid structure and the incidence of adverse effects in patients with SHPT and low bone mass. DESIGN AND SETTING: This was a 24-week, open-label study at Kaohsiung Veterans General Hospital in Kaohsiung, Taiwan. PATIENTS: Dialysis patients with SHPT (intact parathyroid hormone [iPTH] > 800 pg/mL) and low bone mass (T score < -2.5) were enrolled. INTERVENTION: Patients received denosumab (60 mg) and doses of calcitriol adjusted to achieve iPTH < 300 pg/mL. MAIN OUTCOME MEASURES: Parathyroid gland volume was assessed upon study initiation and completion. Serum calcium, phosphate, alkaline phosphatase, iPTH, and adverse effects were assessed at each visit (Day 7, 14, and 21, and every month thereafter). RESULTS: iPTH significantly decreased (mean decrease, 58.28 ± 6.12%) with denosumab/calcitriol administration (P < .01) but not in the controls (patients not receiving denosumab). Parathyroid gland volume decreased (mean decrease, 21.98 ± 5.54%) with denosumab/calcitriol administration (P < .01) and progressively increased (20.58 ± 4.48%) in the controls (P < .05). Serum alkaline phosphatase and iPTH levels were significantly correlated to decreased iPTH and regression of parathyroid hyperplasia (P < .05). The most common adverse events were hypocalcemia (33.33%) and respiratory tract infection (4.17%). Hypocalcemia rapidly resolved with calcium and calcitriol supplements. CONCLUSIONS: Denosumab allows for supra-physiologic doses of calcitriol resulting in decreased parathyroid secretion and parathyroid hyperplasia. Supervised administration and weekly laboratory and clinical monitoring of serum calcium are recommended during the first month to prevent hypocalcemia.

A novel poly-naphthol compound ST104P suppresses angiogenesis by attenuating matrix metalloproteinase-2 expression in endothelial cells.

Angiogenesis, the process of neovascularization, plays an important role in physiological and pathological conditions. ST104P is a soluble polysulfated-cyclo-tetrachromotropylene compound with anti-viral and anti-thrombotic activities. However, the functions of ST104P in angiogenesis have never been explored. In this study, we investigated the effects of ST104P in angiogenesis in vitro and in vivo. Application of ST104P potently suppressed the microvessels sprouting in aortic rings ex vivo. Furthermore, ST104P treatment significantly disrupted the vessels' development in transgenic zebrafish in vivo. Above all, repeated administration of ST104P resulted in delayed tumor growth and prolonged the life span of mice bearing Lewis lung carcinoma. Mechanistic studies revealed that ST104P potently inhibited the migration, tube formation and wound closure of human umbilical endothelial cells (HUVECs). Moreover, ST104P treatment inhibited the secretion and expression of matrix metalloproteinase-2 (MMP-2) in a dose-dependent manner. Together, these results suggest that ST104P is a potent angiogenesis inhibitor and may hold potential for treatment of diseases due to excessive angiogenesis including cancer.

Novel action of lignans isolated from Hernandia nymphaeifolia on Ca(2+) signaling in renal tubular cells.

The effect of five lignans, epi-aschantin, epi-magnolin, epi-yangambin, deoxypodophyllotoxin and yatein, isolated from Hernandia nymphaeifolia on Ca(2+) signaling in Madin-Darby canine kidney cells was examined using fura-2 as a Ca(2+) indicator. These lignans at concentrations between 10 and 100 microM increased [Ca(2+)](i) in a concentration-dependent manner. Removal of extracellular Ca(2+) abolished the Ca(2+) signals evoked by 50 microM of the lignans. La(3+)(50 microM) abolished the Ca(2+) signals induced by 100 microM of epi-aschantin, epi-magnolin and epi-yangambin, and 20 microM deoxypodophyllotoxin, but inhibited by 60% 50 microM yatein-induced responses. All five lignans (50-100 microM) inhibited by 42-65% thapsigargin-induced capacitative Ca(2+) entry, and inhibited by 23-61% thapsigargin-induced intracellular Ca(2+) release. Epi-yangambin (100 microM), epi-magnolin (100 microM), and epi-aschantin (100 microM) inhibited by 8-38% 10 microM ATP-induced Ca(2+) release. Trypan blue exclusion revealed that incubation with deoxypodophyllotoxin or yatein (but not the other lignans) decreased cell viability in a concentration-dependent manner. Together, the results suggest that, in renal tubular cells, these lignans exert multiple actions on Ca(2+) signaling. They caused Ca(2+) influx but reduced thapsigargin-induced capacitative Ca(2+) entry and also thapsigargin- and ATP-induced Ca(2+) release. Additionally, deoxypodophyllotoxin and yatein may be cytotoxic.

Novel action of lignans isolated from Hernandia nymphaeifolia on Ca2+ signaling in human neutrophils.

The effects of five lignans (epi-aschantin, epi-magnolin, epi-yangambin, deoxypodophyllotoxin, yatein) isolated from Hernandia nymphaeifolia (Presl.) Kubitzki (Hernandiaceae) on intracellular Ca2+ levels ([Ca2+]i) in human neutrophils were investigated by using fura-2 as a fluorescent probe. In both Ca2+-containing and Ca2+-free media, the lignans (50-100 microM) did not alter basal [Ca2+]i but inhibited the [Ca2+]i increase induced by platelet activating factor (PAF, 10 microM), leukotriene B4 (LTB4, 0.2 microM), and thapsigargin (1 microM) to different extents. In Ca2+-free medium, after depleting stores of Ca2+ with PAF, LTB4 or thapsigargin, addition of 3 mM Ca2+ induced Ca2+ influx. Each of the lignans (50-100 microM) caused 39-89% inhibition of PAF-induced Ca2+ influx; whereas only epi-aschantin was able to inhibit LTB4- and thapsigargin-induced Ca2+ influx by 54-79%. Together, the results suggest that in human neutrophils, these lignans did not alter basal [Ca2+]i but inhibited Ca2+ movement induced by Ca2+ mobilizing agents.