Pharmacokinetics and metabolism of mirogabalin, a novel αδ ligand, in rats and monkeys.

The purpose of this study was to investigate the pharmacokinetic behaviour of mirogabalin in rats and monkeys.Pharmacokinetic parameters of mirogabalin after its oral and intravenous administration were determined. Distribution study, mass balance study, and metabolite identification were also conducted after the oral administration of [C]mirogabalin.

Metabolism, excretion, and pharmacokinetics of [C]mirogabalin, a novel αδ ligand, in healthy volunteers following oral administration.

The metabolism, excretion, and pharmacokinetics of mirogabalin were investigated following a single oral administration of [C]mirogabalin at 30 mg/5.55 MBq to six healthy male subjects.The mean recovery values of radioactivity in urine and faeces were 96.

A Phase I, Single-Ascending-Dose Study in Healthy Subjects to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DS-2969b, a Novel GyrB Inhibitor.

DS-2969b is a novel GyrB inhibitor in development for the treatment of Clostridium difficile infection. The aim of this study was to assess the safety, tolerability, pharmacokinetics, and effects on normal gastrointestinal microbiota groups of single daily oral ascending doses of DS-2969b in healthy subjects. The study enrolled 6 sequential ascending dose cohorts (6 mg, 20 mg, 60 mg, 200 mg, 400 mg, and 600 mg).

Urotensin II upregulates migration and cytokine gene expression in leukocytes of the African clawed frog, Xenopus laevis.

Urotensin II (UII) exhibits diverse physiological actions including vasoconstriction, locomotor activity, osmoregulation, and immune response via the UII receptor (UTR) in mammals. However, in amphibians the function of the UII-UTR system remains unknown. In the present study, we investigated the potential immune function of UII using leukocytes isolated from the African clawed frog, Xenopus laevis.

Cloning and expression of the epithelial sodium channel and its role in osmoregulation of aquatic and estivating African lungfish Protopterus annectens.

The epithelial sodium channel (ENaC) is a sodium (Na(+))-selective aldosterone-stimulated ion channel involved in Na(+) transport homeostasis of tetrapods. We examined full-length cDNA sequences and tissue distributions of ENaCα, ENaCβ, and ENaCγ subunits in the African lungfish Protopterus annectens. Protopterus ENaC (pENaC) comprises 3 subunits: pENaCα, pENaCβ, and pENaCγ.

Identification, tissue distribution and functional characterization of the ghrelin receptor in West African lungfish, Protopterus annectens.

We identified two ghrelin receptor isoforms, the ghrelin receptor type-1a (GHS-R1a) and its alternative splice form (GHS-R1b) for West African lungfish, Protopterus annectens. Lungfish GHS-R1a and 1b comprised 361 and 281 amino acids, respectively. Lungfish GHS-R1a showed the highest identity to coelacanth GHS-R1a (80.

Changes in plasma angiotensin II, aldosterone, arginine vasotocin, corticosterone, and electrolyte concentrations during acclimation to dry condition and seawater in the crab-eating frog.

The crab-eating frog Fejervarya cancrivora inhabits mangrove swamps and marshes in Southeast Asia. In the present study, circulating angiotensin II (Ang II), aldosterone (Aldo), arginine vasotocin (AVT), and corticosterone (Cort) concentrations as well as various blood parameters were studied under osmotically stressful conditions. Following acclimation to hyperosmotic seawater and dry condition for 5days, body weight was significantly decreased.

Urotensin II receptor (UTR) exists in hyaline chondrocytes: a study of peripheral distribution of UTR in the African clawed frog, Xenopus laevis.

Urotensin II (UII) and UII-related peptide (URP) exhibit diverse physiological actions including vasoconstriction, locomotor activity, osmoregulation, and immune response through UII receptor (UTR), which is expressed in the central nervous system and peripheral tissues of fish and mammals. In amphibians, only UII has been identified. As the first step toward elucidating the actions of UII and URP in amphibians, we cloned and characterized URP and UTR from the African clawed frog Xenopus laevis.

Gonadotropin-releasing hormone 2 suppresses food intake in the zebrafish, Danio rerio.

Gonadotropin-releasing hormone (GnRH) is an evolutionarily conserved neuropeptide with 10 amino acid residues, of which several structural variants exist. A molecular form known as GnRH2 ([His(5) Trp(7) Tyr(8)]GnRH, also known as chicken GnRH II) is widely distributed in vertebrates except for rodents, and has recently been implicated in the regulation of feeding behavior in goldfish. However, the influence of GnRH2 on feeding behavior in other fish has not yet been studied.

The epithelial sodium channel in the Australian lungfish, Neoceratodus forsteri (Osteichthyes: Dipnoi).

Epithelial sodium channel (ENaC) is a Na(+)-selective, aldosterone-stimulated ion channel involved in sodium transport homeostasis. ENaC is rate-limiting for Na(+) absorption in the epithelia of osmoregulatory organs of tetrapods. Although the ENaC/degenerin gene family is proposed to be present in metazoans, no orthologues or paralogues for ENaC have been found in the genome databases of teleosts.

The fifth neurohypophysial hormone receptor is structurally related to the V2-type receptor but functionally similar to V1-type receptors.

The neurohypophysial peptides of the vasopressin (VP) and oxytocin (OT) families regulate salt and water homeostasis and reproduction through distinct G protein-coupled receptors. The current thinking is that there are four neurohypophysial hormone receptors (V1aR, V1bR, V2R, and OTR) in vertebrates, and their evolutionary history is still debated. We report the identification of a fifth neurohypophysial hormone receptor (V2bR) from the holocephalan elephant fish.

Polymorphism of somatolactin-producing cells in the goldfish pituitary: immunohistochemical investigation for somatolactin-α and -β.

Somatolactin (SL) is a pituitary hormone belonging to the growth hormone/prolactin family of adenohypophyseal hormones. In teleost fish, SL is encoded by one or two paralogous genes, namely SL-α and -β. Our previous studies have revealed that pituitary adenylate-cyclase-activating polypeptide stimulates SL release from cultured goldfish pituitary cells, whereas melanin-concentrating hormone suppresses this release.

Neuropeptide Y in tiger puffer (Takifugu rubripes): distribution, cloning, characterization, and mRNA expression responses to prandial condition.

Neuropeptide tyrosine (NPY) is a potent orexigenic neuropeptide implicated in feeding regulation in rodents. However, the involvement of NPY in feeding behavior has not well been studied in fish. Therefore, we investigated the role of NPY in food intake using a tiger puffer (Takifugu rubripes) model.

Inhibitory effect of corticotropin-releasing factor on food intake in the bullfrog, Aquarana catesbeiana.

Corticotropin-releasing factor (CRF) and CRF-related peptides exert hypophysiotropic and anorexigenic effects in mammals and teleost fish. In anuran amphibians, CRF acts as a potent stimulator of thyrotropin release from the pituitary. According to our recent study, CRF also acts as an anorexigenic factor for the cessation of food intake in the metamorphosing bullfrog larvae.

Stimulatory effect of intracerebroventricular administration of orexin A on food intake in the zebrafish, Danio rerio.

Orexin is a potent orexigenic neuropeptide implicated in feeding regulation of mammals. However, except for the case of goldfish, the involvement of orexin in the feeding behavior of teleost fish has not well been studied. Therefore, we investigated the role of orexin on food intake using a zebrafish (Danio rerio) model.

Immunohistological classification of ionocytes in the external gills of larval Japanese black salamander, Hynobius nigrescens Stejneger.

In this cytological and immunohistological study, we clarified the localization of the membrane transporters Na(+) , K(+) -ATPase (NKA), vacuolar-type H(+) -ATPase (VHA), and epithelial sodium channel (ENaC) and distinguished ionocyte subtypes in the gill of the Japanese salamander (Hynobius nigrescens). In larvae (IY stages 43-65), NKA immunoreactivity was observed on the basolateral plasma membrane in more than 60% cells and less than 20% cells in the primary filaments and secondary lamellae of the external gills, respectively. VHA immunoreactivity was observed on the apical membrane of some epithelial cells in the secondary lamellae of the external gills.

In vitro metabolism of rivoglitazone, a novel peroxisome proliferator-activated receptor γ agonist, in rat, monkey, and human liver microsomes and freshly isolated hepatocytes.

The in vitro metabolism of rivoglitazone, (RS)-5-{4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl)methoxy]benzyl}-1,3-thiazolidine-2,4-dione monohydrochloride, a novel thiazolidinedione (TZD) peroxisome proliferator-activated receptor γ selective agonist, was studied in liver microsomes and freshly isolated hepatocytes of rat, monkey, and human as well as cDNA-expressed human cytochrome P450 (P450) and UDP-glucuronosyltransferase (UGT) enzymes. Fourteen metabolites were detected, and these structures were elucidated by liquid chromatography-tandem mass spectrometry. Five initial metabolic pathways of rivoglitazone consisting of four oxidation pathways and one N-glucuronidation pathway were predicted in correspondence with those proposed for in vivo studies using rats and monkeys.

Ontogeny of ENaC expression in the gills and the kidneys of the Japanese black salamander (Hynobius nigrescens Stejneger).

A full-length cDNA cloning and tissue distribution of epithelial sodium channel (ENaC) protein were studied during ontogeny by immunohistochemistry in the external gills, and the kidney, pronephros and mesonephros, of the Japanese black salamander, Hynobius nigrescens (Family Hynobiidae; a primitive caudate species). The amino acid sequence of Hynobius ENaCα is 64 and 63% identical to Bufo ENaCα and Rat ENaCα, respectively. In aquatic larva salamander at the digit differentiation stage, Hynobius ENaCα mRNA was expressed in the external gills and pronephros.

Ghrelin Receptor in Two Species of Anuran Amphibian, Bullfrog (Rana catesbeiana), and Japanese Tree Frog (Hyla japonica).

We have identified cDNA encoding a functional growth hormone secretagogue-receptor 1a (GHS-R1a, ghrelin receptor) in two species of anuran amphibian, the bullfrog (Rana catesbeiana), and the Japanese tree frog (Hyla japonica). Deduced receptor protein for bullfrog and Japanese tree frog (tree frog) was comprised of 374- and 371-amino acids, respectively. The two receptors shared 86% identity, and are grouped to the clade of the tetrapod homologs by phylogenetic analysis.

Pharmacokinetics, metabolism, and disposition of rivoglitazone, a novel peroxisome proliferator-activated receptor γ agonist, in rats and monkeys.

The pharmacokinetics, metabolism, and excretion of rivoglitazone [(RS)-5-{4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl)methoxy]benzyl}-1,3-thiazolidine-2,4-dione monohydrochloride], a novel thiazolidinedione (TZD) peroxisome proliferator-activated receptor γ selective agonist, were evaluated in male F344/DuCrlCrlj rats and cynomolgus monkeys. The total body clearance and volume of distribution of rivoglitazone were low in both animals (0.329-0.

Gonadotropin-releasing hormone II (GnRH II) mediates the anorexigenic actions of α-melanocyte-stimulating hormone (α-MSH) and corticotropin-releasing hormone (CRH) in goldfish.

Intracerebroventricular (ICV) administration of gonadotropin-releasing hormone II (GnRH II), which plays a crucial role in the regulation of reproduction in vertebrates, markedly reduces food intake in goldfish. However, the neurochemical pathways involved in the anorexigenic action of GnRH II and its interaction with other neuropeptides have not yet been identified. Alpha-melanocyte-stimulating hormone (α-MSH), corticotropin-releasing hormone (CRH) and CRH-related peptides play a major role in feeding control as potent anorexigenic neuropeptides in goldfish.

Central angiotensin II stimulates cutaneous water intake behavior via an angiotensin II type-1 receptor pathway in the Japanese tree frog Hyla japonica.

Angiotensin II (Ang II) stimulates oral water intake by causing thirst in all terrestrial vertebrates except anurans. Anuran amphibians do not drink orally but absorb water osmotically through ventral skin. In this study, we examined the role of Ang II on the regulation of water-absorption behavior in the Japanese tree frog (Hyla japonica).

Molecular cloning and characterization of V2-type receptor in two ray-finned fish, gray bichir, Polypterus senegalus and medaka, Oryzias latipes.

In tetrapods, vasopressin (VP) and vasotocin (VT) are involved in various aspects of physiology and behavior including osmoregulation, cardiovascular function, reproduction, stress response and social behavior. Pharmacological and molecular studies have identified three types of VP/VT receptors, V1a-type (V1aR), V1b-type (V1bR) and V2-type (V2R). On the other hand, only V1aR has so far been identified in teleosts.

The anorexigenic action of the octadecaneuropeptide (ODN) in goldfish is mediated through the MC4R- and subsequently the CRH receptor-signaling pathways.

Intracerebroventricular (ICV) administration of the octadecaneuropeptide (ODN), a peptide derived from diazepam-binding inhibitor, reduces food intake in goldfish as in rodents. However, the neurochemical pathways involved in the anorexigenic action of ODN have not yet been identified in goldfish. Alpha-melanocyte-stimulating hormone (alpha-MSH), corticotropin-releasing hormone (CRH), and CRH-related peptides play a major role in the control of food consumption in goldfish.

Identification of novel metabolic pathways of pioglitazone in hepatocytes: N-glucuronidation of thiazolidinedione ring and sequential ring-opening pathway.

The metabolism of [(14)C]pioglitazone was studied in vitro in incubations with freshly isolated human, rat, and monkey hepatocytes. Radioactivity detection high-performance liquid chromatography analysis of incubation extracts showed the detection of 13 metabolites (M1-M13) formed in incubations with human hepatocytes. An identical set of metabolites (M1-M13) was also detected in monkey hepatocytes.