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Background: Opioids are effective for severe pain; however, the safety issue is also a primary concern. To better understand the opioid use in Taiwan, we conducted this study., Methods: Data on patients with opioid prescriptions, including morphine, fentanyl, pethidine, codeine, oxycodone, hydromorphone, and buprenorphine were collected using the Taiwan National Health Insurance Database (NHID)., Results: Our analysis of opioid prescriptions from 2008 to 2018 in Taiwan indicated that (1) A slow increase in prevalence of opioid prescription was found during the study period. Among the drugs studied, morphine accounted for the majority of the prescriptions written, with a gradual increase annually. Pethidine prescriptions showed a significant and rapid decline over the years; (2) medical centers prescribed the largest number of opioids, followed by regional hospitals, local hospitals, and clinics; (3) the number of prescriptions per year per capita in cancer group was much higher than that in noncancer group. In noncancer group, most of the prescriptions were used in acute pain service (98.7%); and (4) use of opioids increased with age in both cancer and noncancer patients., Conclusion: The total number of opioid prescriptions in Taiwan gradually increased annually, among which morphine was the most commonly used opioid. Cancer patients consumed more opioid prescriptions than noncancer patients and most of the prescriptions in noncancer patients were used in acute pain service. The number of prescriptions increased with the age of the patients in both cancer and noncancer patients. The low prescription rate of opioids in chronic pain in Taiwan is not similar as those in high opioid-consuming countries, such as United States., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2022, the Chinese Medical Association.)

Opioids are effective analgesics for pain relief, however, inappropriate use may cause risks. The aims of the study were to evaluate trends of opioid consumption for pain management in Taiwan and compare them among neighboring Asian countries. Opioid consumption data, including fentanyl, morphine, oxycodone, hydromorphone, codeine, and pethidine, were collected from the Controlled Drugs Management Information System of Taiwan Food and Drug Administration from 2008 to 2018. Data of different continents and neighboring Asian countries were retrieved from the WHO website. The major findings include: (1) In Taiwan, the total annual opioid consumption has gradually increased from 2008 to 2018, with fentanyl being the most frequently consumed opioid analgesic, followed by morphine. Codeine and pethidine consumption dropped significantly over the years. (2) In neighboring Asian countries, the opioid consumption in order from highest to lowest consumption were South Korea, Japan, Taiwan, Singapore, Hong Kong (China), and China. We concluded that, from 2008 to 2018, the total opioid consumption trend for pain management in Taiwan has slowly increased, with fentanyl and morphine being the most commonly used opioids. When compared with neighboring Asian countries, level of opioid consumption in Taiwan was between Japan and Singapore. The research results may provide a reference for healthcare professionals worldwide.

B-cell CLL/lymphoma 9 protein (BCL-9), a multi-functional co-factor in Wnt signaling, induced carcinogenesis as well as promoting tumor progression, metastasis and chemo-resistance in colorectal cancer (CRC). However, the mechanisms for increased BCL-9 expression in CRC were not well understood. Here, we report that hypoxia, a hallmark of solid tumors, induced BCL-9 mRNA expression in human CRC cells. Analysis of BCL-9 promoter revealed two functional hypoxia-responsive elements (HRE-B and HRE-C) that can be specifically bound with and be transactivated by hypoxia inducible factors (HIF) -1α but not HIF-2α. Consistently, ectopic expression of HIF-1α but not HIF-2α transcriptionally induced BCL-9 expression levels in cells. Knockdown of endogenous HIF-1α but not HIF-2α by siRNA largely abolished the induction of HIF by hypoxia. Furthermore, there was a strong association of HIF-1α expression with BCL-9 expression in human CRC specimens. In summary, results from this study demonstrated that hypoxia induced BCL-9 expression in human CRC cells mainly through HIF-1α, which could be an important underlying mechanism for increased BCL-9 expression in CRC.

The orexin system consists of orexin A/hypocretin 1 and orexin B/hypocretin 2, and OX1 and OX2 receptors. Our previous electrophysiological study showed that orexin A in the rat ventrolateral periaqueductal gray (vlPAG) induced antinociception via an OX1 receptor-initiated and endocannabinoid-mediated disinhibition mechanism. Here, we further characterized antinociceptive effects of orexins in the mouse vlPAG and investigated whether this mechanism in the vlPAG can contribute to stress-induced analgesia (SIA) in mice. Intra-vlPAG (i.pag.) microinjection of orexin A in the mouse vlPAG increased the hot-plate latency. This effect was mimicked by i.pag. injection of WIN 55,212-2, a CB1 agonist, and antagonized by i.pag. injection of the antagonist of OX1 (SB 334867) or CB1 (AM 251), but not OX2 (TCS-OX2-29) or opioid (naloxone), receptors. [Ala(11), D-Leu(15)]-orexin B (i.pag.), an OX2 selective agonist, also induced antinociception in a manner blocked by i.pag. injection of TCS-OX2-29, but not SB 334867 or AM 251. Mice receiving restraint stress for 30 min showed significantly longer hot-plate latency, more c-Fos-expressing orexin neurons in the lateral hypothalamus and higher orexin levels in the vlPAG than unrestrained mice. Restraint SIA in mice was prevented by i.pag. or intraperitoneal injection of SB 334867 or AM 251, but not TCS-OX2-29 or naloxone. These results suggest that during stress, hypothalamic orexin neurons are activated, releasing orexins into the vlPAG to induce analgesia, possibly via the OX1 receptor-initiated, endocannabinoid-mediated disinhibition mechanism previously reported. Although activating either OX1 or OX2 receptors in the vlPAG can lead to antinociception, only OX1 receptor-initiated antinociception is endocannabinoid-dependent., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

There exists a great need for repair grafts with similar volume to human skeletal muscle that can promote the innate ability of muscle to regenerate following volumetric muscle loss. Perfusion decellularization is an attractive technique for extracellular matrix (ECM) scaffold from intact mammalian organ or tissue which has been successfully used in tissue reconstruction. The perfusion-decellularization of skeletal muscle has been poorly assessed and characterized, but the bioactivity and functional capacity of the obtained perfusion skeletal muscle ECM (pM-ECM) to remodel in vivo is unknown. In the present study, pM-ECM was prepared from porcine rectus abdominis (RA). Perfusion-decellularization of porcine RA effectively removed cellular and nuclear material while retaining the intricate three-dimensional microarchitecture and vasculature networks of the native RA, and many of the bioactive ECM components and mechanical properties. In vivo, partial-thickness abdominal wall defects in rats repaired with pM-ECM showed improved neovascularization, myogenesis and functional recellularization compared to porcine-derived small intestinal submucosa (SIS). These findings show the biologic potential of RA pM-ECM as a scaffold for supporting site appropriate, tissue reconstruction, and provide a better understanding of the importance maintaining the tissue-specific complex three-dimensional architecture of ECM during decellularization and regeneration., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The present study aimed to investigate the effects of ursolic acid on the chloride channels and cell volume in nasopharyngeal carcinoma cells (CNE-2Z). The whole-cell patch clamp technique was used to detect the current, and cell imaging technique was applied to measure cell volume. The properties of the currents induced by ursolic acid were investigated by changing the extracellular osmotic pressure, replacing the extracellular anions and applying chloride channel blockers. The results showed that, under isotonic conditions, the background current was weak and stable. When perfusing the cells with ursolic acid (100 nmol/L), a large current (-59.86 pA/pF ± 4.86 pA/pF at -80 mV, 78.92 pA/pF ± 6.39 pA/pF at +80 mV) was induced. The chloride current showed outward rectification and negligible time- and voltage-dependent inactivation. The reversal potential (-4.83 mV ± 0.30 mV) of the current was close to the calculated equilibrium potential for Cl⁻ (-0.9 mV). The permeabilities of the channel to different anions were ranked in order as follows: Cl⁻ = I⁻ > Br⁻ > gluconate. Hypertonic solutions inhibited the current induced by ursolic acid. The chloride channel blockers, tamoxifen (20 μmol/L) and 5-nitro-2-(3-phenylpro-pylamino) benzoic acid (NPPB, 100 μmol/L), suppressed the current. Furthermore, ursolic acid decreased the cell volume by (11.78 ± 1.20)% in 1 h, and the effect was inhibited by NPPB. These results suggest that ursolic acid can activate chloride channels, resulting in outflow of Cl⁻ and decrease of cell volume in nasopharyngeal carcinoma cells.

Orexin A and B are hypothalamic peptides known to modulate arousal, feeding, and reward via OX1 and OX2 receptors. Orexins are also antinociceptive in the brain, but their mechanism(s) of action remain unclear. Here, we investigated the antinociceptive mechanism of orexin A in the rat ventrolateral periaqueductal gray (vlPAG), a midbrain region crucial for initiating descending pain inhibition. In vlPAG slices, orexin A (30-300 nm) depressed GABAergic evoked IPSCs. This effect was blocked by an OX1 [1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-yl urea (SB 334867)], but not OX2 [N-acyl 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (compound 29)], antagonist. Orexin A increased the paired-pulse ratio of paired IPSCs and decreased the frequency, but not amplitude, of miniature IPSCs. Orexin A-induced IPSC depression was mimicked by (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-napthalenylmethanone (WIN 55,212-2), a cannabinoid 1 (CB1) receptor agonist. 1-(2,4-Dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-(1-piperidyl)pyrazole-3-carboxamide (AM 251), a CB1 antagonist, reversed depressant effects by both agonists. Orexin A-induced IPSC depression was prevented by 1-[6-[[(17β)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione (U73122) and tetrahydrolipstatin, inhibitors of phospholipase C (PLC) and diacylglycerol lipase (DAGL), respectively, and enhanced by cyclohexyl[1,1'-biphenyl]-3-ylcarbamate (URB602), which inhibits enzymatic degradation of 2-arachidonoylglycerol (2-AG). Moderate DAGLα, but not DAGLβ, immunoreactivity was observed in the vlPAG. Orexin A produced an overall excitatory effect on evoked postsynaptic potentials and hence increased vlPAG neuronal activity. Intra-vlPAG microinjection of orexin A reduced hot-plate nociceptive responses in rats in a manner blocked by SB 334867 and AM 251. Therefore, orexin A may produce antinociception by activating postsynaptic OX1 receptors, stimulating synthesis of 2-AG, an endocannabinoid, through a Gq-protein-mediated PLC-DAGLα enzymatic cascade culminating in retrograde inhibition of GABA release (disinhibition) in the vlPAG.

The nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor is a non-opioid branch of the opioid receptor family implicated in several neurological and psychological disorders, such as pain, anxiety, depression, involuntary movement, addiction, seizure and dementia. Heterogeneity of NOP receptors has been proposed based on the findings of splicing variants and from binding and functional studies. We have previously reported that Ro 64-6198, a NOP receptor agonist, activated a subset, but not all, of N/OFQ-sensitive NOP receptors in midbrain ventrolateral periaqueductal grey (vlPAG). In this study, we found that a new NOP receptor ligand, (+)-5a Compound ((3aS, 6aR)-1-(cis-4-isopropylcyclohexyl)-5'-methyl-2'-phenylhexahydrospiro[piperidine-4,1'-pyrrolo[3, 4-c]pyrrole]), also activated a subset of NOP receptors in vlPAG neurons. (+)-5a Compound (0.1-30 μm) concentration-dependently activated G-protein-coupled inwardly-rectifying potassium (GIRK) channels mediated through the NOP receptors in about 35% of the recorded vlPAG neurons. (+)-5a Compound (EC50: 605 nm) was less potent (1/12) and efficacious (47%) than N/OFQ. In (+)-5a Compound-insensitive neurons, Ro 64-6198 was also ineffective, and vice versa, but N/OFQ activated GIRK channels through NOP receptors. In (+)-5a Compound-sensitive neurons, (+)-5a Compound precluded the effect of Ro 64-6198. Immunofluorecent and morphometric studies showed that most of the (+)-5a Compound-sensitive neurons were multipolar with intensive dendritic arborization and immunoreactive to glutamic acid decarboxylase-67. It is suggested that (+)-5a Compound activates a subset of NOP receptors, similar to the Ro 64-6198-sensitive subset, in the vlPAG neurons which are mostly GABAergic. These results further support the presence of functional heterogeneity of NOP receptors in the midbrain PAG.

One hundred and eighty-one 3,4-methylenedioxymethamphetamine (MDMA) containing tablets were sampled from confiscated drugs received by the Taiwan National Bureau of Controlled Drugs for testing from 2002 to February 2005. Sample tablets demonstrated various colors and logos. The appearances, contents of MDMA and other components in these tablets were analyzed in order to understand the characteristics and trends of MDMA use. Samples were analyzed using GC-MS methodology. Deuterated internal standards were used for drug quantification. The MDMA contents varied from 16 to 193 mg/tablet. 66-71% of the tablets seized each year contained only MDMA, and the content of MDMA in MDMA only tablets varied from 89 to 133 mg/tablet. There was a decreasing trend in MDMA content in these tablets over time. Other components commonly found besides MDMA included caffeine (18%), methamphetamine (7%), 3,4-methylenedioxyethylamphetamine (MDEA) (7%) and amphetamine (4%). 3,4-Methylenedioxyamphetamine (MDA), ketamine, ephedrine, diazepam, chlorzoxazone and nicotinamide were also detected. During the study period, the number of other drugs found as well as the combinations of different drugs detected in these tablets increased.

Harmine (3), 7-fluoro-1-methyl beta-carboline (35) and 1-(5-methyl-imidazol-4-yl) beta-carboline (41) were potent and specific inhibitors of cyclin-dependent kinases. The degree of aromaticity of the tricyclic ring and the positioning of substituents are important for inhibitory activity. While most beta-carbolines inhibited CDK2 and CDK5 to the same extent, selective inhibition against CDK2 was observed in 1-(2-chlorophenyl)- (12), 1-(2-fluorophenyl)- (15), and 1-(2-chloro-5-nitrophenyl)- (28) beta-carbolines.

A synthetic bifunctional ligand (22/8) comprising a triazine scaffold substituted with 3-aminophenol (22) and 4-amino-1-naphthol (8) has been designed, synthesised, characterised and immobilized on agarose beads to create a robust, highly selective affinity adsorbent for human immunoglobulin G (IgG). Scatchard analysis of the binding isotherm for IgG on immobilized 22/8 (90 micromol 22/8/g moist weight gel) indicated an affinity constant (Ka) of 1.4 x 10(5) M(-1) and a theoretical maximum capacity of 151.9 mg IgG/g moist weight gel. The adsorbent shows similar selectivity to immobilized protein A and binds IgG from a number of species. An apparent capacity of 51.9 mg human IgG/g moist weight gel was observed under the experimental conditions selected for adsorption. Human IgG was eluted with glycine-HCl buffer with a recovery of 67-69% and a purity of 97.3-99.2%, depending on the pH value of the buffer used for elution. Preparative chromatography of IgG from human plasma showed that under the specified conditions, 94.4% of plasma IgG was adsorbed and 60% subsequently eluted with a purity of 92.5%. The immobilized ligand was able to withstand incubation in 1 M NaOH for 7 days without loss of binding capacity for IgG.

An IgG-binding ligand library comprising 88 adsorbents based on a known lead compound (Li et al., 1998) was generated on an agarose solid phase. Individual members of the library were synthesized in two chemical steps using cyanuric chloride as the scaffold immobilized on the beaded support. The library was screened for binding of pure human IgG, whence selected ligands from the library were further assessed for specificity by the purification of IgG from human plasma. The potential of this strategy for the rapid identification and evaluation of chemical leads was demonstrated by the discovery of ligands with IgG binding capabilities. It was found that ligands comprising 3-aminophenol and an aminonaphthol moiety substituted on a triazine nucleus generally performed better than other ligands in the library. An immobilized ligand 22/8 adsorbent was able to purify IgG with high yield and a purity >99% from diluted human plasma., (Copyright 1999 John Wiley & Sons, Ltd.)