High exposure compared with standard exposure to metoclopramide associated with a higher risk of parkinsonism: a nationwide population-based cohort study.

AIMS: We conducted a cohort study utilizing a nationwide health insurance database to assess the European Medicines Agency's restrictions on using metoclopramide and its association with the risk of parkinsonism. METHODS: New oral metoclopramide users aged ≥20 years, and age- and gender-matched non-users were recruited between 2001 and 2011. Users were divided into high-exposure (dose >30 mg day-1 and/or duration >5 days) and standard-exposure (dose ≤30 mg day-1 and duration ≤5 days) groups. The adjusted hazard ratio (aHR) with 95% confidence interval (CI) estimated the risk of parkinsonism. RESULTS: During a 1-year period, 122 of 218 931 (0.06%) users of metoclopramide vs. 56 of 218 931 (0.03%) non-users developed parkinsonism (P < 0.001). Among the 122 cases of parkinsonism in users, 64 (0.04%) were from 168 566 standard-exposure users and 58 (0.12%) from 50 365 high-exposure users. Compared with non-users, the risk of parkinsonism was higher in users (aHR 2.16; 95% CI 1.54, 3.02), including standard-exposure (aHR 1.73; 95% CI 1.11, 2.70), and high-exposure (aHR 3.15; 95% CI 1.78, 5.57) users. High-exposure users had a higher risk of parkinsonism than standard-exposure users (aHR 1.83; 95% CI 1.28, 2.63). Within the high-exposure group, 45 233 of 50 365 (89.81%) users and 55 of 58 (94.83%) parkinsonism were from long-duration exposure; 5 132 of 50 365 (10.19%) users and 3 of 58 (5.17%) parkinsonism were from high-dose exposure and long-duration + high-dose exposure. CONCLUSIONS: The risk of parkinsonism in metoclopramide users, although extremely low (0.06%), is 2.16-fold greater than in non-users. High-exposure users have a 1.83-fold higher risk than standard-exposure users. As users in high-exposure group had a higher risk of parkinsonism than in standard-exposure group, and the majority of users and parkinsonism in high-exposure group were from long-duration exposure; thus, physician are advised to avoid prescribing metoclopramide for >5 days, even if the daily dose is ≤30 mg.

Increased Fall Risk in Patients Receiving Androgen Deprivation Therapy for Prostate Cancer.

OBJECTIVE: To examine the relationship between the use of androgen deprivation therapy (ADT) and the subsequent risk of falls in men with prostate cancer (PC) by employing a population-based dataset. METHODS: We retrieved the study sample from the Taiwan Longitudinal Health Insurance Database 2005. We included 886 patients with PC who had received ADT as the study group, whereas 862 patients with PC who had not received ADT served as the comparison group. We then individually tracked each study patient for a 3-year period to identify those who subsequently received a diagnosis of a fall. We performed Cox proportional hazard regressions to calculate the hazard ratio (HR) and its corresponding 95% confidence interval (CI) for a fall during the 3-year follow-up period between these 2 groups. RESULTS: The incidence rates of falls per 1000 person-years were 13.37 (95% CI: 9.15~18.88) and 6.44 (95% CI: 3.61~10.63), respectively, for patients with PC who received ADT and those who did not receive ADT. Furthermore, the hazard ratio for a fall during the 3-year follow-up period for patients with PC who had received ADT was 1.95 (95% CI: 1.04~3.66, P = .037) compared to those who had not received ADT after censoring sampled patients who died during the 3-year follow-up period and adjusting for age, geographical location, monthly income, urbanization level, hypertension, diabetes, hyperlipidemia, coronary heart disease, Parkinson's disease, epilepsy, stroke, and mental illness. CONCLUSION: The present findings suggest that patients with PC who had received ADT had an increased risk of falls.

Synthesis of Canthardin Sulfanilamides and Their Acid Anhydride Analogues via a Ring-Opening Reaction of Activated Aziridines and Their Associated Pharmacological Effects.

The cantharidinimide derivatives, 5a-h, including sulfanilamides containing pyrimidyl, pyrazinyl, hydrogen, thiazolyl, and oxazolyl groups were synthesized. Modification of cantharidinimide by means of the reaction of activated aziridine ring opening led to the discovery of a novel class of antitumor compounds. The analogues 10i-k, 11l-n, 12o-p, and 16q-s were obtained from treating cantharidinimide 6 and analogues (7, 8, and 13) with activated aziridines, which produced a series of ring-opened products including normal and abnormal types. Some of these compounds showed cytotoxic effects in vitro against HL-60, Hep3B, MCF7, and MDA-MB-231 cancer cells. The most potent cytostatic compound, N-cantharidinimido-sulfamethazine (5a), exhibited anti-HL-60 and anti-Hep3B cell activities. Two compounds 5g and 5h displayed slight effects on the Hep3B cell line, while the other compounds produced no response in these four cell lines.

Radix Scrophulariae extracts (harpagoside) suppresses hypoxia-induced microglial activation and neurotoxicity.

BACKGROUND: Hypoxia could lead to microglia activation and inflammatory mediators' overproduction. These inflammatory molecules could amplify the neuroinflammatory process and exacerbate neuronal injury. The aim of this study is to find out whether harpagoside could reduce hypoxia-induced microglia activation. METHODS: In this study, primary microglia cells harvested from neonatal ICR mice were activated by exposure to hypoxia (1 % O2 for 3 h). Harpagoside had been shown to be no cytotoxicity on microglia cells by MTT assay. The scavenger effect of harpagoside on hypoxia-enhanced microglial cells proliferation, associated inflammatory genes expression (COX-II, IL-1ß and IL-6 genes) and NO synthesis were also examined. RESULTS: Hypoxia enhances active proliferation of microglial cells, while harpagoside can scavenge this effect. We find that harpagoside could scavenge hypoxia-enhanced inflammatory genes expression (COX-2, IL-1ß and IL-6 genes) and NO synthesis of microglial cells. Under 3 h' hypoxic stimulation, the nuclear contents of p65 and hypoxia inducible factor-1α (HIF-1α) significantly increase, while the cytosol IκB-α content decreases; these effects can be reversed by 1 h's pre-incubation of 10(-8) M harpagoside. Harpagoside could decrease IκB-α protein phosphorylation and inhibit p65 protein translocation from the cytosol to the nucleus, thus suppress NF-κB activation and reduce the HIF-1α generation. CONCLUSION: These results suggested that the anti-inflammatory mechanism of harpagoside might be associated with the NF-κB signaling pathway. Harpagoside protect against hypoxia-induced toxicity on microglial cells through HIF-α pathway.

Establishment of a two-dimensional chiral HPLC system for the simultaneous detection of lactate and 3-hydroxybutyrate enantiomers in human clinical samples.

A two-dimensional chiral high-performance liquid chromatography system was established for simultaneous detection of lactate (LA) and 3-hydroxybutyrate (3HB) enantiomers in human clinical samples. d-LA is increased upon kidney damage but 3HB protected against kidney injury. Therefore, determining the concentrations of D,L-LA and D,L-3HB simultaneously would be useful for evaluating pathological conditions. LA and 3HB were pre-column-derivatized with the fluorescent reagent 4-(N-chloroformylmethyl-N-methylamino)-7-nitro-2,1,3-benzoxadiazole (NBD-COCl) at 60 °C for 15 min and separated in the first dimension with a capillary monolithic octadecylsilane column. The mobile phase consisted of 13% acetonitrile and 0.05% tirfluoroacetic acid in water. Chiralpak QD-AX and KSAACSP-001S enantioselective columns were used in the second dimension to separate LA and 3HB enantiomers, respectively. Mobile phases were mixed solutions of methanol and acetonitrile containing formic acid. The separation factors were 1.14 and 1.08, respectively. The detection limit of LA and 3HB enantiomers was 10 fmol/injection. This method was applied to human clinical samples; intra- and inter-day relative standard deviations of LA and 3HB enantiomers were, respectively, 1.04-3.25% and 1.61-5.12% in plasma, 9.19-11.2% and 4.60-5.89% in urine, and 7.12-8.90% and 2.86-6.97% in saliva. This novel analytical method is a powerful tool for investigating variations in LA and 3HB enantiomers under disease conditions.

Arthropod steroid hormone (20-Hydroxyecdysone) suppresses IL-1ß-induced catabolic gene expression in cartilage.

BACKGROUND: In osteoarthritis (OA), the imbalance of chondrocytes' anabolic and catabolic factors can induce cartilage destruction. Interleukin-1 beta (IL-1ß) is a potent pro-inflammatory cytokine that is capable of inducing chondrocytes and synovial cells to synthesize MMPs. The hypoxia-inducible factor-2alpha (HIF-2alpha, encoded by Epas1) is the catabolic transcription factor in the osteoarthritic process. The purpose of this study is to validate the effects of ecdysteroids (Ecd) on IL-1ß-induced cartilage catabolism and the possible role of Ecd in treatment or prevention of early OA. METHODS: Chondrocytes and articular cartilage was harvested from newborn ICR mice. Ecd effect on chondrocytes viability was tested and the optimal concentration was determined by MTT assay. The effect of HIF-2α (EPAS1) in cartilage catabolism simulated by IL-1ß (5 ng/ml) was evaluated by articular cartilage explants culture. The effects of Ecd on IL-1ß-induced inflammatory conditions and their related catabolic genes expression were analyzed. RESULTS: Interleukin-1ß (IL-1ß) treatment on primary mouse articular cartilage explants enhanced their Epas1, matrix metalloproteinases (MMP-3, MMP-13) and ADAMTS-5 genes expression and down-regulated collagen type II (Col2a1) gene expression. With the pre-treatment of 10(-8) M Ecd, the catabolic effects of IL-1ß on articular cartilage were scavenged. CONCLUSION: In conclusions, Ecd can reduce the IL-1ß-induced inflammatory effect of the cartilage. Ecd may suppress IL-1ß-induced cartilage catabolism via HIF-2α pathway.

Osteoporosis is associated with antiepileptic drugs: a population-based study.

Controversy remains regarding the risk of bone abnormalities due to enzyme-inducing antiepileptic drugs (EIAEDs) and non-enzyme-inducing antiepileptic drugs (NEIAEDs). This case-control study aimed to investigate the possible association between osteoporosis and epilepsy disease and AEDs therapy using a population-based dataset in Taiwan. We first identified 48,102 cases, ≥ 18 years of age, who received a first-time diagnosis of osteoporosis, and then randomly selected 144,306 controls. We used conditional logistic regression analyses to compute the odds ratio (OR) and corresponding 95% confidence interval (CI) to compare a previous diagnosis of epilepsy between cases and controls. We found that of the 192,408 sampled subjects, epilepsy was found in 117 (0.24%) cases and 240 (0.17%) controls (p<0.001). Cases were found to be more likely to have previously been diagnosed with epilepsy than controls (OR: 1.41, 95% CI: 1.11 ≈ 1.78, p<0.01), after taking confounders into consideration. Furthermore, we found that, compared to controls, the adjusted OR of cases in which enzyme-inducing AEDs had been prescribed was 2.06 (95% CI: 1.43 ≈ 2.95). A higher proportion of cases with prescribed NEIAED was also found (OR: 2.09, 95% CI: 1.49 ≈ 2.92) compared to controls. This study demonstrates that patients with osteoporosis were more likely to have epilepsy and receive EIAED or NEIAED treatment. For patients with epilepsy who take AEDs, attention should be paid to the adverse effects of osteoporosis.

Biotransformation of dihydroisosteviol and the effects of transformed products on steroidogenic gene expressions.

The biotransformation of dihydroisosteviol with Absidia pseudocylindrospora ATCC 24169, Streptomyces griseus ATCC 10137, Mucor recurvatus MR36, and Aspergillus niger BCRC 31130 yielded 15 metabolites, eight of which were previously unknown. Structures of metabolites were established by 2D NMR techniques and HRMS data, two of which were further corroborated by chemical means, and another via single-crystal X-ray diffraction analysis. Subsequently, two steroidogenic cell lines (Y-1 mouse adrenal tumor and MA-10 mouse Leydig tumor cells) were used in a reverse transcription-PCR analysis to assess the effects of all compounds on steroidogenic gene expressions using forskolin as a positive control. The tested gene expressions included steroidogenic factor-1 (SF-1), steroidogenic acute regulatory protein (StAR), and cytochrome P450 side-chain cleavage (P450scc) enzyme. Gene expression profiles showed that ten of the tested compounds effectively suppressed P450SCC mRNA expression in both Y-1 and MA-10 cells. Several induced SF-1 gene expression and two enhanced StAR gene expression in Y-1 cells. By contrast, in MA-10 cells, one compound effectively suppressed StAR mRNA expression, whereas for others effectively suppressed SF-1 gene expression. The results suggest that analogs of dihydroisosteviol can be potential modulators to alter steroidogenic gene expressions and subsequent enzyme activities.

Biological characterization of oxidized hyaluronic acid/resveratrol hydrogel for cartilage tissue engineering.

Osteoarthritis is a type of arthritis that is caused by breakdown of cartilage, with eventual loss of the cartilage of the joints. The ability of self-repair in damaged cartilage tissue is limited; the aim of this work is to fabricate and characterize an oxidized hyaluronic acid/resveratrol (Oxi-HA/Res) hydrogel for future applications in cartilage tissue engineering. Under physiological conditions, the Oxi-HA/Res hydrogel was prepared by chemical crosslinking of Oxi-HA with resveratrol solution and characterized by Fourier transform infrared spectrometry assay; the biocompatibility and gene expression of chondrocytes within the Oxi-HA-Res hydrogel then analyzed. The cell viability and cytotoxicity assays showed that the Oxi-HA/Res hydrogel has good biocompatibility. Oxi-HA/Res hydrogel can upregulate expression of type II collagen, aggrecan, and Sox-9 genes; while down-regulating IL-1ß, MMP-1, MMP-3, MMP13 gene expression. It can also reduce LPS-induced inflammation and chondrocyte damage. The results of this study showed that the Oxi-HA/Res hydrogel is biocompatible with chondrocytes, allows for extracellular matrix synthesis, and also reduce LPS-induced inflammation and damage. These results suggest that Oxi-HA/Res hydrogel may be a potential suitable cell carrier for chondrocyte cells in the treatment of cartilage defect. However, further in vivo study is mandatory for future possible clinical applications.

A simple procedure for preparation of N-thiazol, thiadiazol, pyridyl and sulfanylamidocantharidinimines analogues and evaluation of their cytotoxicities against human HL-60, MCF7, Neuro-2a and A549 carcinoma cell.

The lab made an effort to prepare some biological active cantharidinimines by heating the reactant 1 and 2a-g, 5h-i and 7j-r amines to suitable temperature with ethanol to provide 18 N-thiazolyl-, sulfanyl-, aminopyridyl-, bromopyridyl-, alkylpyridyl- and hydroxypyridylcantharidinimines 3a-g, 4a-c, 6h-i and 8j-r in yield of 4-77% (Chart 1). These cantharidinimine derivatives were tested for their capabilities to suppress growth of the human carcinoma cell lines, HL-60, MCF7, Neuro-2a and A549, because the incidence rate is more prominent in Asian countries than western countries. Compounds 3c-d and 6h-i were found to have some antitumor activity in HL-60 but less activity in MCF cell and compounds 8j-l displayed some inhibition effects to A549 cell line, but less effect to Neuro-2a cell line. Compounds 8m-r had no cytotoxic effect against both cell lines. The cytotoxic effects of these cantharidinimine compounds seemed to be better than the cantharidinimide compounds which we had mentioned several years ago.