PK/PD and safety of a single dose of TMX-67 (febuxostat) in subjects with mild and moderate renal impairment.

A single oral dose of 20 mg febuxostat was administered to subjects with normal, mild or moderate impairment in renal function. There was less than a 2-fold difference in AUC of plasma unchanged febuxostat among the renal function groups, and changes in plasma urate levels from pre-dose levels were not significant. A total of five adverse events were reported with all mild in severity. The results indicate that renal impairment will have little clinical impact on the pharmacokinetics (PK), pharmacodynamics (PD) and safety of the study drug.

Pharmacokinetics and pharmacodynamics of febuxostat (TMX-67), a non-purine selective inhibitor of xanthine oxidase/xanthine dehydrogenase (NPSIXO) in patients with gout and/or hyperuricemia.

The diurnal change of sUA and the effect of febuxostat on this change were investigated in 10 patients with gout and/or hyperuricemia. The diurnal sUA change after the last dose during the 4-week treatment phase (20 mg, QD) was almost the same as the pre-treatment value. Considering the dose, the AUC(obs) and Cmax of unchanged drug in patients with gout and/or hyperuricemia were estimated to be similar to those of healthy male adults. The results show that a 6-week treatment with febuxostat is safe and well-tolerated in the target patient population for this drug.

catena-Poly

The two title compounds, [Cu(3)(C(6)H(11)O(2))(6)(C(7)H(9)N)(2)](n), (I), and [Cu(2)(C(5)H(9)O(2))(4)(C(7)H(9)N)(2)], (II), have chain and finite-molecular structures, respectively. In (I), binuclear cage units and mononuclear 2,6-dimethylpyridine complexes, both of which have inversion centres, are arranged alternately and are linked by the carboxylate ions to form one-dimensional chains along the a axis. In (II), the binuclear cage unit has an inversion centre and the coordination geometry around the Cu atom is typical square pyramidal, with 2,6-dimethylpyridine at the apical position.

[1,2-Diphenyl-N,N'-bis(salicylidene)-(RR,SS)-1,2-ethanediyldiaminato]nitridomanganese(V).

The title compound, [MnN(C(28)H(22)N(2)O(2))], has a distorted square-pyramidal coordination with an Mn[triple-bond]N bond length of 1.516 (2) A at the apical position. The five-membered chelate ring adopts a gauche conformation with the two phenyl groups in equatorial orientations.

The exo and endo isomers of [N,N'-bis(salicylidene)-1,2-diphenyl-(RS,SR)-1,2-ethanediyldiaminato]oxovanadium(IV).

The title complexes, exo- and endo-[VO(C(28)H(22)N(2)O(2))], show monomeric structures with a distorted square-pyramidal coordination. The two phenyl groups on the five-membered N,N'-chelate ring are both on the same side as the oxo ligand for the exo isomer and on opposite sides for the endo isomer.

exo-[N,N'-Bis(3-tert-butylsalicylidene)-1,2-diphenyl-(RS,SR)-1,2-ethanediyldiaminato]oxovanadium(IV).

The title mononuclear oxovanadium(IV) complex, [VO(C(36)H(38)N(2)O(2))], has a distorted square-pyramidal coordination. The complex was shown to be the exo isomer.

Tetra-micro-acetato-O:O'-bis[(7-azaindole-N)copper(II)].

The title complex, [Cu(2)(C(2)H(3)O(2))(4)(C(7)H(6)N(2))(2)], shows a binuclear cage structure having an inversion centre. There are intramolecular N-H.O hydrogen bonds between the 7-azaindole ligands and the bridging acetate O atoms.

[N,N'-Bis(3-carboxysalicylidene)-1,2-diphenyl-(RR,SS)-1,2-ethanediyldiaminato-O,N,N',O'](methanol-O)oxovanadium(IV) and [N,N'-bis(3-carboxysalicylidene)-2,3-dimethyl-2,3-butanediyldiaminato-O,N,N',O']oxovanadium(IV) monohydrate.

The two title mononuclear oxovanadium (IV) complexes, [VO(C(30)H(22)N(2)O(6))(CH(3)OH)] and [VO(C(22)H(22)N(2)O(6))].H(2)O, respectively, have distorted square-pyramidal coordination and the 3-carboxy groups form intramolecular hydrogen bonds with the coordinated salicyl O atoms. In (I), methanol coordinates to the vanadium atom trans with respect to the oxo ligand.

[N,N'-Bis(salicylidene)-1,2-diphenyl-(RS,SR)-1,2-ethanediaminato]nickel(II).

In crystals of the title compound, [Ni(C(28)H(22)N(2)O(2))], the coordination geometry around the Ni atom is square planar with a slight tetrahedral distortion. The five-membered N,N'-chelate ring adopts a distorted gauche conformation with the two phenyl groups in axial and equatorial orientations.

trans-Diaquabis(N-acetylanthranilato-O,O')copper(II).

The title monomeric copper(II) complex, [Cu(C(9)H(8)NO(3))(2)(H(2)O)(2)], (I), shows a square-planar coordination and has an inversion centre at the Cu atom. The carboxylate group of the N-acetylanthranilate ion acts as a monodentate donor ligand to copper and as an acceptor of an intramolecular O-H.O hydrogen bond from the coordinated water molecule, with an O.O distance of 2.581 (2) A.

catena-Poly[[tetrakis(micro-2,2-dimethylpropionato-O:O')dicopper(II)]-micro-dioxane-O:O'] and catena-poly[[tetrakis(micro-3,3-dimethylbutyrato-O:O')dicopper(II)]-micro-dioxane-O,O'].

The title two compounds, [Cu(2)(C(5)H(9)O(2))(4)(C(4)H(8)O(2))](n), (I), and [Cu(2)(C(6)H(11)O(2))(4)(C(4)H(8)O(2))](n), (II), are isomorphous. The binuclear Cu(II) units have a cage structure and are linked by the dioxane molecules to form a zigzag chain along the c axis. The binuclear copper unit and the dioxane ligand each have a centre of symmetry.

Nitric oxide, histamine, and sensory nerves in the acid secretory response in rat stomach after damage.

The stomach normally responds to mucosa-damaging agents by decreasing acid secretion, but this acid response turn from "inhibition" into "stimulation" when the production of nitric oxide (NO) is inhibited by NG-nitro-L-arginine methyl ester (L-NAME). We investigated the mechanism underlying stimulation of acid secretion in the stomach after damage with taurocholate (TC) in the presence of L-NAME. A rat stomach was mounted in an ex vivo chamber and perfused with saline, and the potential difference (PD), luminal pH, and acid secretion were measured before and after application of 20 mM TC for 30 min. Exposure of the stomach to TC caused a reduction in PD, an increase in luminal pH, and a decrease in acid secretion. Pretreatment with L-NAME did not affect basal acid secretion but significantly increased secretion after damage with TC, without any effect on PD. This effect of L-NAME was antagonized by co-administration of L-arginine but not D-arginine. The luminal appearance of NO was also increased after exposure of the stomach to TC, a phenomenon completely blocked by L-NAME, or when EGTA was applied together with TC. The enhanced acid secretory response in the presence of L-NAME was inhibited by prior administration of cimetidine, FPL-52694 (a mast cell stabilizer), spantide (a substance P antagonist), or by chemical ablation of capsaicin-sensitive sensory neurons. Mucosal exposure to TC increased histamine output in the lumen and decreased the number of mucosal mast cells in the stomach. These changes were prevented by FPL-52694 or sensory neuronal ablation. These results suggest that (a) damage in the stomach may activate acid stimulation in addition to an NO-dependent inhibitory mechanism but that the latter effect overcomes the former, resulting in a decrease in acid secretion, (b) acid stimulation in the damaged stomach may be mediated by histamine released from the mucosal mast cells, a process that may interact with capsaicin-sensitive sensory nerves, and (c) L-NAME unmasks the acid stimulatory response by suppressing the inhibitory mechanism.

Tacalcitol (1,24(OH)2D3, TV-02) inhibits phorbol ester-induced epidermal proliferation and cutaneous inflammation, and induces epidermal differentiation in mice.

In this study, we examined the cutaneous effects of tacalcitol [1,24(R)(OH)2D3] on epidermal proliferation, differentiation, and skin inflammation in vivo using hairless mice. Tacalcitol was shown to inhibit epidermal proliferation using TPA-induced ornithine decarboxylase activity and DNA synthesis as indices, and the induction of epidermal differentiation using type I transglutaminase activity as an index. Tacalcitol also displayed an antiinflammatory effect on TPA-induced inflammatory changes histopathologically. These results confirm the clinical efficacy of tacalcitol in psoriasis, and suggest that it may be efficacious in the treatment of other inflammatory skin diseases.

Alendronate distributed on bone surfaces inhibits osteoclastic bone resorption in vitro and in experimental hypercalcemia models.

Alendronate is an aminobisphosphonate that acts as a potent inhibitor of osteoclastic bone resorption. To understand the mechanism of action of alendronate in vivo, in this study we investigated the relationship between distribution of [14C]-alendronate in rat bone and its effects on bone resorption in vitro or in rat hypercalcemic models. A single IV dose of 0.05 approximately 1.25 mg/kg inhibited the increase in plasma calcium level induced by bovine PTH or 1 alpha(OH)D3. The minimal effective dose of pamidronate (1.25 mg/kg) and etidronate (over 31.25 mg/kg) were at least 5 times and 25 times, respectively, higher than the dose of alendronate in the rat hypercalcemic model prepared by 1 alpha(OH)D3. The relative potencies of compounds in the hypercalcemic rat models reflected those of inhibitory effects on bone resorption in vitro. We conducted the ivory-slice assay under two conditions: (a) addition of a given bisphosphonate after adherence of the osteoclasts; and (b) preincubation of the ivory slices with a given bisphosphonate. The inhibitory IC50 values of alendronate under condition (b) were similar to those under condition (a). To evaluate the interaction between osteoclasts and alendronate in bone, we investigated the localization of [14C]-alendronate in the tibia of growing rats (4-day-old rats). Alendronate did not distribute uniformly in the tibia. At 1 day after injection (0.05 mg SC), dense labeling was seen primarily under osteoclasts. We injected 0.05 mg/kg of [14C]-alendronate (single i.v.) into rats [14C]-alendronate was rapidly eliminated from plasma, and mainly distributed to the bone in rats. These data suggest that alendronate which distributed on bone surface mainly contributed to the antihypercalcemic action in vivo.

Alendronate modulates osteogenesis of human osteoblastic cells in vitro.

The bisphosphonates, which are carbon-substituted pyrophosphates, have been studied extensively both in vivo and in vitro to elucidate their effects on bone tissues and cells. However, because these agents were shown to have a potent inhibitory effect on bone resorption, the majority of studies have focused on only this aspect of bone metabolism. There appears to be less information regarding the direct effect of bisphosphonates on bone formation, so thus we undertook experiments to investigate the effects of bisphosphonates, especially alendronate, on the mineralization and matrix protein synthesis of human osteoblastic cells in vitro. The data show that the bisphosphonates, alendronate, etidronate and pamidronate, suppressed 1,25-dihydroxycholecalciferol (1,25(OH)2D3)-stimulated mineralization of human osteoblastic cells at high concentrations, while relatively lower concentrations of alendronate and etidronate potentiated mineralization of the cells in the presence of 1,25(OH)2D3. The potentiation of mineralization with alendronate was accompanied by increased synthesis of bone matrix proteins, osteocalcin and collagen, and the mRNA of pro alpha(I) collagen. These findings show that in addition to their well-known effects on bone resorption, bisphosphonates have significant and direct effects on osteogenesis in osteoblasts in vitro. The actual mechanism remains to be further investigated.

Hypouricemic effect of the novel xanthine oxidase inhibitor, TEI-6720, in rodents.

We investigated the xanthine oxidase/xanthine dehydrogenase inhibitory activity and hypouricemic effect of a newly synthesized xanthine oxidase/xanthine dehydrogenase inhibitor, TEI-6720, 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazole-carboxylic acid, and compared its effects with those of allopurinol in rodents. TEI-6720 was found to inhibit bovine milk xanthine oxidase, and mouse liver and rat liver xanthine oxidase/xanthine dehydrogenase with IC50 values of 1.4, 1.8 and 2.2 nM, respectively. On bovine milk xanthine oxidase, TEI-6720 exhibited mixed-type inhibition and the Ki value was 0.7 nM. TEI-6720 displayed prolonged urate-lowering activity in normal mice and rats. We evaluated the hypouricemic effect of TEI-6720 on hyperuricemia induced by the uricase inhibitor, potassium oxonate (250 mg/kg s.c., 1 h before the test drugs), and measured the total molarity of both serum allantoin and urate in rats. Oral TEI-6720 and allopurinol had a hypouricemic effect 2 h after their administration to oxonate-pretreated rats with ED50 values of 1.5 and 5.0 mg/kg, respectively. Both compounds also reduced the combined molarity of uric acid and allantoin in rats. The ED50 values of TEI-6720 and allopurinol were 2.1 and 6.9 mg/kg p.o., respectively. These results suggest that TEI-6720 may be useful for the treatment of hyperuricemia.

1,25-Dihydroxyvitamin D3 inhibits thromboxane release from activated macrophages.

1,25-Dihydroxyvitamin D3 (1,25-(OH)2D3) in concentrations from 0.1 to 10 nM suppressed immunoreactive thromboxane B2 (iTXB2) release from Propionibacterium acnes (P. acnes)-elicited liver adherent cells stimulated with lipopolysaccharide (LPS, 1 microgram/ml). These suppressive effects of 1,25-(OH)2D3 were also observed in oyster glycogen-elicited peritoneal macrophages. On the contrary, it did not inhibit iTXB2 release from both resident Kupffer cells and peritoneal macrophages stimulated with the same concentration of LPS. Furthermore, 1,24(R)-dihydroxyvitamin D3 (1,24(R)-(OH)2D3), a vitamin D3 analogue, also inhibited iTXB2 release from liver adherent cells, but, another synthesized vitamin D3 analogue, 1 alpha-hydroxyvitamin D3 (1 alpha-OH-D3) tended to decrease iTXB2 release only at higher concentrations. These results suggest that active vitamin D3 analogues inhibit iTXB2 release from activated macrophages.