Mikito Hirakata

Toxicological effect of emodin in mouse testicular gene expression profile.

Emodin (1,3,8‐trihydroxy‐6‐methyl‐anthraquinone) is a herbal medicine extracted from the rhizomes of Rheum palmatum, and is known as an inhibitor of casein kinase II (CK2). The CK2α′ knockout mice are known to be male‐infertile; however, there have been no reports on the toxicity of emodin in male reproductive organs/tissues. To evaluate the toxicological effects of emodin on differential gene expression profiles of the testis as compared with acrylamide, mice were orally administered emodin and acrylamide for 5 days at a dose of 1000 and 50 mg kg−1 per day, respectively, and euthanized 24 h after the final administration. Both chemicals induced hypospermatogenesis, eosinophilic change and apoptosis of germ cell. A DNA microarray analysis showed that the IGF‐1 receptor signaling was most closely related to the above testicular toxicity induced by emodin, and the RhoA regulation, TGF/WNT and cytoskeletal remodeling, TNFR1 signaling and adenosine A2A receptor signaling were commonly associated with the two chemicals. We selected 36 genes associated with CK2, apoptosis and spermatogenesis and determined their expression by quantitative reverse transcription‐polymerase chain reaction (qPCR). Both chemicals perturbed the expression of genes associated with CK2. Genes related to spermatogenesis were also affected, as evidenced by hypospermatogenesis, and eosinophilic change and apoptosis of germ cell. The results suggest that emodin causes testicular toxicity, including apoptosis with related the IGF‐1 receptor signaling pathway, and the two chemicals commonly affect CK2, spermatogenesis and sperm motility via four pathways, such as TNFR1 signaling. Copyright

Characteristics of TRK-130 (Naltalimide), a Novel Opioid Ligand, as a New Therapeutic Agent for Overactive Bladder

We characterized TRK-130 (N-[(5R,6R,14S)-17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxymorphinan-6-yl]phthalimide; naltalimide), an opioid ligand, to clarify the therapeutic potential for overactive bladder (OAB). In radioligand-binding assays with cells expressing human µ-opioid receptors (MORs), δ-opioid receptors (DORs), or κ-opioid receptors (KORs), TRK-130 showed high selectivity for MORs (Ki for MORs, DORs, and KORs = 0.268, 121, and 8.97 nM, respectively). In a functional assay (cAMP accumulation) with cells expressing each human opioid receptor subtype, TRK-130 showed potent but partial agonistic activity for MORs [EC50 (Emax) for MORs, DORs, and KORs = 2.39 nM (66.1%), 26.1 nM (71.0%), and 9.51 nM (62.6%), respectively]. In isovolumetric rhythmic bladder contractions (RBCs) in anesthetized guinea pigs, TRK-130 dose-dependently prolonged the shutdown time (the duration of complete cessation of the bladder contractions) (ED30 = 0.0034 mg/kg i.v.) without affecting amplitude of RBCs. Furthermore, TRK-130 ameliorated formalin-induced frequent urination at doses of higher than 0.01 mg/kg p.o. in guinea pigs under the freely moving condition. Meanwhile, TRK-130 showed only a negligible effect on the gastrointestinal transit at doses of up to 10 mg/kg s.c. in mice. These results indicate that TRK-130 is a potent and selective human MOR partial agonist without undesirable opioid adverse effects such as constipation and enhances the storage function by suppressing the afferent limb of the micturition reflex pathway, suggesting that TRK-130 would be a new therapeutic agent for OAB.

Nalfurafine hydrochloride, a selective κ opioid receptor agonist, has no reinforcing effect on intravenous self-administration in rhesus monkeys

Nalfurafine hydrochloride [(E)-N-[17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6β-yl]-3-(furan-3-yl)-N-methylprop-2-enamide monohydrochloride; nalfurafine] is used in Japan as an antipruritic for the treatment of intractable pruritus in patients undergoing hemodialysis or with chronic liver disease. It is a potent and selective agonist at the κ opioid receptor, but also has weak and partial agonist activity at μ opioid receptors. Opioids, especially those acting at μ receptors, carry a risk of abuse. This is an important factor in the consideration of therapeutic risk vs. benefit in clinical use and the potential for misuse as a public health problem. It is therefore necessary to carefully evaluate the reinforcing effects of nalfurafine. To this end, we investigated intravenous self-administration of nalfurafine in rhesus monkeys. The number of self-administration of nalfurafine at doses of 0.0625, 0.125 and 0.25 μg/kg/infusion was not higher than that of saline in rhesus monkeys that frequently self-administered pentazocine (0.25 mg/kg/infusion). These results indicate that nalfurafine has no reinforcing effect in rhesus monkeys in the intravenous self-administration paradigm.

Pregabalin Prescription for Neuropathic Pain and Fibromyalgia: A Descriptive Study Using Administrative Database in Japan

Objective To assess dose, characteristics, and coprescribed analgesics in patients newly prescribed pregabalin for neuropathic pain and fibromyalgia in Japan. Methods Based on the medical and prescription information present in the Medical Data Vision database, we analyzed the initial and maximum daily doses, prescription period, coprescribed analgesics, and neuropathic pain-related disorders of patients newly prescribed pregabalin between 01 July 2010 and 31 December 2013. Results A total of 45,331 patients (mean age 66.8 years, 48.7% men) were newly prescribed pregabalin during this period. The mean initial and maximum daily doses were 97.3 mg and 127.8 mg, respectively, and decreased yearly. The duration of the prescription period was 111.9 (mean) and 53 (median) days, and the frequently coprescribed analgesics included NSAIDs, opioids, and Neurotropin®. About one half of the patients had spinal disorders. Conclusion In Japan during the period examined, the number of newly prescribed pregabalin users increased, but the initial and maximum daily doses decreased yearly after pregabalin went on the market. The maximum daily dose in Japan was lower than those reported in the USA and Europe. These differences might be associated with patient age and physical status and with anxiety about possible adverse events.