We aimed to evaluate the current nationwide trend, efficacy, safety, and quality of life (QoL) profiles of hormone treatment in real-world practice settings for prostate cancer (PCa) patients in Korea. A total of 292 men with any biopsy-proven PCa (TanyNanyMany) from 12 institutions in Korea were included in this multi-institutional, observational study of prospectively collected data. All luteinizing hormone-releasing hormone (LHRH) agonists were allowed to be investigational drugs. Efficacy was defined as (1) the rate of castration (serum testosterone ≤50 ng dl^-1) at 4-week visit and (2) breakthrough (serum testosterone >50 ng dl^-1 after castration). Safety assessments included routine examinations for potential adverse events, laboratory tests, blood pressure, body weight, and bone mineral density (BMD, at baseline and at the last follow-up visit). QoL was assessed using the Expanded Prostate Cancer Index Composite-26 (EPIC-26). The most common initial therapeutic regimen was LHRH agonist with anti-androgen (78.0%), and the most commonly used LHRH agonist for combination and monotherapy was leuprolide (64.0% for combination and 58.0% for monotherapy). The castration and breakthrough rates were 78.4% and 6.6%, respectively. The laboratory results related to dyslipidemia worsened after 4 weeks of hormone treatment. In addition, the mean BMD T-score was significantly lower at the last follow-up (mean: -1.950) compared to baseline (mean: -0.195). The mean total EPIC-26 score decreased from 84.8 (standard deviation [s.d.]: 12.2) to 78.3 (s.d.: 8.1), with significant deterioration only in the urinary domain (mean: 23.5 at baseline and 21.9 at the 4-week visit). These findings demonstrate the nationwide trend of current practice settings in hormone treatment for PCa in Korea.
Aged ; Androgen Antagonists/therapeutic use* ; Antineoplastic Agents, Hormonal/therapeutic use* ; Cholesterol/blood* ; Drug Therapy, Combination ; Humans ; Leuprolide/therapeutic use* ; Male ; Middle Aged ; Prostatic Neoplasms/pathology* ; Quality of Life ; Receptors, LHRH/agonists* ; Republic of Korea ; Testosterone/blood* ; Treatment Outcome ; Triglycerides/blood*

Exploring the transition from inter-ictal to ictal epileptiform discharges (IDs) and how GABA receptor-mediated action affects the onset of IDs will enrich our understanding of epileptogenesis and epilepsy treatment. We used Mg-free artificial cerebrospinal fluid (ACSF) to induce epileptiform discharges in juvenile mouse hippocampal slices and used a micro-electrode array to record the discharges. After the slices were exposed to Mg-free ACSF for 10 min-20 min, synchronous recurrent seizure-like events were recorded across the slices, and each event evolved from inter-ictal epileptiform discharges (IIDs) to pre-ictal epileptiform discharges (PIDs), and then to IDs. During the transition from IIDs to PIDs, the duration of discharges increased and the inter-discharge interval decreased. After adding 3 μmol/L of the GABA receptor agonist muscimol, PIDs and IDs disappeared, and IIDs remained. Further, the application of 10 μmol/L muscimol abolished all the epileptiform discharges. When the GABA receptor antagonist bicuculline was applied at 10 μmol/L, IIDs and PIDs disappeared, and IDs remained at decreased intervals. These results indicated that there are dynamic changes in the hippocampal network preceding the onset of IDs, and GABA receptor activity suppresses the transition from IIDs to IDs in juvenile mouse hippocampus.
Animals ; Animals, Newborn ; Bicuculline ; pharmacology ; Disease Models, Animal ; Epilepsy ; pathology ; GABA-A Receptor Agonists ; pharmacology ; GABA-A Receptor Antagonists ; therapeutic use ; Hippocampus ; drug effects ; metabolism ; physiopathology ; In Vitro Techniques ; Magnesium ; metabolism ; pharmacology ; Male ; Membrane Potentials ; drug effects ; Mice ; Mice, Inbred C57BL ; Muscimol ; pharmacology ; Nerve Net ; drug effects ; Receptors, GABA-A ; metabolism

Cyproheptadine (CPH), a first-generation antihistamine, enhances the delayed rectifier outward K current (I) in mouse cortical neurons through a sigma-1 receptor-mediated protein kinase A pathway. In this study, we aimed to determine the effects of CPH on neuronal excitability in current-clamped pyramidal neurons in mouse medial prefrontal cortex slices. CPH (10 µmol/L) significantly reduced the current density required to generate action potentials (APs) and increased the instantaneous frequency evoked by a depolarizing current. CPH also depolarized the resting membrane potential (RMP), decreased the delay time to elicit an AP, and reduced the spike threshold potential. This effect of CPH was mimicked by a sigma-1 receptor agonist and eliminated by an antagonist. Application of tetraethylammonium (TEA) to block I channels hyperpolarized the RMP and reduced the instantaneous frequency of APs. TEA eliminated the effects of CPH on AP frequency and delay time, but had no effect on spike threshold or RMP. The current-voltage relationship showed that CPH increased the membrane depolarization in response to positive current pulses and hyperpolarization in response to negative current pulses, suggesting that other types of membrane ion channels might also be affected by CPH. These results suggest that CPH increases the excitability of medial prefrontal cortex neurons by regulating TEA-sensitive I channels as well as other TEA-insensitive K channels, probably I and inward-rectifier Kir channels. This effect of CPH may explain its apparent clinical efficacy as an antidepressant and antipsychotic.
Animals ; Cyproheptadine ; pharmacology ; Female ; Histamine H1 Antagonists ; pharmacology ; Membrane Potentials ; drug effects ; physiology ; Mice, Inbred C57BL ; Patch-Clamp Techniques ; Potassium Channel Blockers ; pharmacology ; Potassium Channels ; metabolism ; Prefrontal Cortex ; drug effects ; physiology ; Pyramidal Cells ; drug effects ; physiology ; Receptors, sigma ; agonists ; metabolism ; Tetraethylammonium ; pharmacology ; Tissue Culture Techniques

β3-adrenoceptor (β3-AR) has been shown to promote myocardial apoptosis. However, the exact physiological role and importance of this receptor in the human myocardium, and its underlying mode of action, have not been fully elucidated. The present study aimed to determine the effects of β3-AR on the promotion of myocardial apoptosis and on norepinephrine (NE) injury. We analyzed NE-induced cardiomyocyte (CM) apoptosis by using a TUNEL and an annexin V/propidium iodide apoptosis assay. Furthermore, we investigated the NE-induced expression of the apoptosis marker genes Akt and p38MAPK, their phosphorylated counterparts p-Akt and p-p38MAPK, caspase-3, Bcl-2, and Bax. In addition, we determined the effect of a 48-h treatment with a β3-AR agonist and antagonist on expression of these marker genes. β3-AR overexpression was found to increase CM apoptosis, accompanied by an increased expression of caspase-3, bax/bcl-2, and p-p38MAPK. In contrast, the β3-blocker reduced apoptosis of CMs and the associated elevated Akt expression. We identified a novel and potent anti-apoptosis mechanism via the PI3K/Akt pathway and a pro-apoptosis pathway mediated by p38MAPK.
Adrenergic Agonists ; pharmacology ; Adrenergic Antagonists ; pharmacology ; Animals ; Apoptosis ; Cells, Cultured ; Myocytes, Cardiac ; drug effects ; metabolism ; Phosphatidylinositol 3-Kinases ; metabolism ; Proto-Oncogene Proteins c-akt ; metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, Adrenergic, beta-3 ; genetics ; metabolism ; Signal Transduction ; p38 Mitogen-Activated Protein Kinases ; metabolism

Adrenergic receptors are members of the G-protein coupled receptor superfamily. Recent studies revealed that these adrenergic receptors are playing an important role in the growth and metastasis of prostate cancer cells. The expression of adrenergic receptors rises significantly in prostate cancer cells and tissues. Agonists of these receptors promote the growth and mobility of prostate cancer cells, while antagonists may suppress their proliferation, trigger their apoptosis, and inhibit their metastasis. Clinically, receptor antagonists can significantly reduce the risk of prostate cancer and improve its prognosis after androgen depravation therapy. This article presents an overview on the roles of adrenergic receptors in prostate cancer.
Adrenergic Agonists ; pharmacology ; Adrenergic Antagonists ; pharmacology ; Apoptosis ; Humans ; Male ; Prostatic Neoplasms ; metabolism ; pathology ; Receptors, Adrenergic ; drug effects ; physiology

PURPOSE: Nociceptin/orphanin FQ (N/OFQ) as an endogeneous hexadecapeptide is known to exert antinociceptive effects spinally. The aims of this study were to demonstrate the antinociceptive effects of i.t. N/OFQ and to investigate the possible interaction between N/OFQ and endogenous opioid systems using selective opioid receptor antagonists in rat formalin tests. MATERIALS AND METHODS: I.t. N/OFQ was injected in different doses (1-10 nmol) via a lumbar catheter prior to a 50 microL injection of 5% formalin into the right hindpaw of rats. Flinching responses were measured from 0-10 min (phase I, an initial acute state) and 11-60 min (phase II, a prolonged tonic state). To observe which opioid receptors are involved in the anti-nociceptive effect of i.t. N/OFQ in the rat-formalin tests, naltrindole (5-20 nmol), beta-funaltrexamine (1-10 nmol), and norbinaltorphimine (10 nmol), selective delta-, micro- and kappa-opioid receptor antagonists, respectively, were administered intrathecally 5 min after i.t. N/OFQ. RESULTS: I.t. N/OFQ attenuated the formalin-induced flinching responses in a dose-dependent manner in both phases I and II. I.t. administration of naltrindole and beta-funaltrexamine dose-dependently reversed the N/OFQ-induced attenuation of flinching responses in both phases; however, norbinaltorphimine did not. CONCLUSION: I.t. N/OFQ exerted an antinociceptive effect in both phases of the rat-formalin test through the nociceptin opioid peptide receptor. In addition, the results suggested that delta- and micro-opioid receptors, but not kappa-opioid receptors, are involved in the antinociceptive effects of N/OFQ in the spinal cord of rats.
Analgesics/administration & dosage/*pharmacology ; Animals ; Formaldehyde/toxicity ; Injections, Spinal ; Male ; Naltrexone/administration & dosage/analogs & derivatives/pharmacology ; Narcotic Antagonists/administration & dosage/*pharmacology ; Opioid Peptides/administration & dosage/*pharmacology ; Pain Measurement ; Rats ; Rats, Sprague-Dawley ; Receptors, Opioid/*agonists/drug effects

In order to study effects of ginseng on the metabolism of drug belong to CYP3A4 substrate, screening of pregnane X receptor activation from ginsenosides was performed by reporter assay. Based on PXR-CYP3A stable translation cell lines, 13 ginsenosides were screened for pregnane X receptor activation by reporter assays, and RIF as the positive control. The effect of ginsenosides Rg1 onCYP3A4 mRNA expression was also investigated by RT-PCR. The PXR-CYP3A stable translation cell lines had good response to RIF, and the EC50 is 2.51 micro mol x L(-1). When the condition of final concentration was 10 micromol x L(-1), ginsenoside F2 and protopanaxatriol had moderate inductive effects on PXR. Panaxotriol, Rg2, pseudoginsenoside F11, Rg1, ginsenoside and Rb3 had inhibitory effects on PXR. Ginsenoside Rf1, Rg3, Rh2 and protopanaxdiol had no obvious effects on PXR. Rg1 down-regulated CYP3A4 mRNA expression in a concentration-dependent manner. Activation of pregnane X receptor by ginsenosides may influence the metabolism of drug belong to CYP3A4 substrate, and cause ginseng-drug interactions.
Cytochrome P-450 CYP3A ; genetics ; metabolism ; Drug Interactions ; Ginsenosides ; pharmacology ; Hep G2 Cells ; Humans ; RNA, Messenger ; metabolism ; Receptors, Steroid ; agonists ; antagonists & inhibitors ; genetics ; Sapogenins ; pharmacology ; Transfection

OBJECTIVETo investigate the role of N-Methyl-D-aspartic acid (NMDA)-type glutamate receptors in the central nucleus of the amygdale (CeA) in food and water intake.

METHODSMale Sprague-Dawley rats with stainless steel cannulae implanted unilaterally into the CeA were used. The prototypic NMDA receptor agonist NMDA, or the selective NMDA receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid (D-AP-5) was microinjected into the CeA of satiated and euhydrated rats.

RESULTSIntra-CeA injection of 8.50, 17.00, or 34.00 nmol NMDA did not alter food intake but significantly increased water intake 0-1 h after the injection (F(3,32)=3.191, P=0.037) independent of food intake. Without affecting the food intake, injection of 6.34, 12.70, or 25.40 nmol D-AP-5 into the CeA significantly decreased water intake 0-1 h after the injection (F(3,28)=3.118, P=0.042) independent of food intake.

CONCLUSIONNMDA receptors in the CeA may participate in the control of water intake rather than food intake.

2-Amino-5-phosphonovalerate ; pharmacology ; Amygdala ; drug effects ; Animals ; Drinking ; drug effects ; Eating ; drug effects ; Excitatory Amino Acid Agonists ; pharmacology ; Excitatory Amino Acid Antagonists ; pharmacology ; Injections, Intraventricular ; Male ; N-Methylaspartate ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate ; agonists ; antagonists & inhibitors

OBJECTIVETo investigate the role of cysteinyl leukotriene (CysLT) receptors in the differentiation of rat glioma C6 cells.

METHODSRat glioma C6 cells were treated with the agonist LTD(4), the CysLT(1) receptor antagonist montelukast and the differentiation inducer forskolin. Cell morphology and GFAP protein expression were determined after treatments.

RESULTForskolin (10 μmol/L) induced morphological changes and GFAP protein expression (cell differentiation) in C6 cells, but LTD(4) (0.1-100 nmol/L) did not induce these changes. Montelukast (1 μmol/L) alone did not affect C6 cell differentiation, while it induced the differentiation when combined with the LTD(4) (100 nmol/L).

CONCLUSIONThe CysLT(2) receptor may modulate the differentiation of rat glioma C6 cells.

Acetates ; pharmacology ; Animals ; Cell Differentiation ; drug effects ; Cell Line, Tumor ; Colforsin ; pharmacology ; Cysteine ; Glioma ; metabolism ; pathology ; Leukotriene Antagonists ; pharmacology ; Leukotriene D4 ; pharmacology ; Leukotrienes ; Quinolines ; pharmacology ; Rats ; Receptors, Leukotriene ; agonists

.This study is to investigate the analgesic effect produced by intrathecal injection (ith) of oxysophoridine (OSR) and the mechanism of GABAA receptor. Warm water tail-flick test was used to detect the analgesic effect of OSR (12.5, 6.25, and 3.13 mg.kg-1 ith) and to observe the influence of GABA (gamma aminobutyric acid) agonist or antagonist on the analgesic effect of OSR in mice. Immunohistochemistry method were used to detect the influence of OSR (12.5 mg.kg-1, ith) on the GABAARalpha1 protein expression in spinal cord. The results obtained covers that OSR (12.5 and 6.25 mg.kg-, ith) alleviates pain significantly with the warm water tail-flick test (P<0.05, P<0.01), the rate of pain threshold increases by 68.45%; GABA and muscimol (MUS) produces analgesic synergism together with the OSR, picrotoxin (PTX) and bicuculline (BIC) antagonize the analgesic effect of OSR; OSR (12.5 mg.kg-1, ith) significantly increase the positive number of GABAARalpha1 nerve cell in spinal cord (P<0.01) and significantly decrease the average grey levels (P<0.01). In conclusion, OSR intrathecal injection has significant analgesic effect. And GABAA receptor in spinal cord is involved in the analgesic mechanism.
Alkaloids ; administration & dosage ; pharmacology ; Analgesics ; administration & dosage ; pharmacology ; Animals ; Bicuculline ; pharmacology ; Female ; GABA-A Receptor Agonists ; pharmacology ; GABA-A Receptor Antagonists ; pharmacology ; Injections, Spinal ; Male ; Mice ; Muscimol ; pharmacology ; Pain Threshold ; drug effects ; Picrotoxin ; pharmacology ; Random Allocation ; Receptors, GABA-A ; metabolism ; Spinal Cord ; metabolism ; gamma-Aminobutyric Acid ; pharmacology