Pharmacokinetics of soy-derived lysophosphatidylcholine compared with that of glycerophosphocholine: a randomized controlled trial.

Lysophosphatidylcholine (LPC) is present in various foods and contains a choline moiety such as in glycerophosphocholine (GPC). However, the potential of LPC as a choline source remains unclear. This study investigated the single-dose pharmacokinetics of 480 mg soy-derived LPC in 12 healthy men compared with that of either soy oil with the same lipid amount (placebo) or GPC with the same choline amount. Both LPC and GPC supplementation increased plasma choline, serum phospholipid, and serum triglyceride concentrations, but neither of them significantly elevated plasma trimethylamine N-oxide concentration. In addition, although the intake of LPC slightly increased plasma LPC16:0, LPC18:2, and total LPC concentrations, their concentrations remained within physiological ranges. No adverse events were attributed to the LPC supplementation. To the best of our knowledge, this study is the first to compare LPC and GPC pharmacokinetics in humans and shows that LPC can be a source of choline.

Oral Administration of Egg- and Soy-Derived Lysophosphatidylcholine Mitigated Acetylcholine Depletion in the Brain of Scopolamine-Treated Rats.

Enzyme-modified lecithin that contains lysophosphatidylcholine (LPC) is generally recognized as safe. However, its potential as a functional ingredient has been less investigated than other choline (Ch)-containing compounds, such as glycerophosphocholine (GPC). Reports on the possibility of LPC functioning as a cholinergic precursor in vivo and on its kinetics are limited to docosahexaenoic acid-bound LPC. Herein, three experiments were performed to investigate these processes in scopolamine (SCO)-treated rats. First, an egg-derived LPC reagent was orally administered to rats, and brain acetylcholine (ACh), Ch, plasma Ch, and LPC were measured. Second, soy- and rapeseed-derived enzyme-modified lecithins and GPC were administered for comparison. Third, soy-derived enzyme-modified lecithins with different fat contents were administered for comparison. The LPC reagent mitigated SCO-induced ACh depletion at 500 mg/kg body weight and increased plasma Ch, but not LPC, concentrations. Additionally, soy-derived LPC-containing food additive counteracted brain ACh depletion similarly to GPC. Interestingly, plasma Ch and linoleoyl-LPC levels were higher when soy-derived LPC with a higher fat content was administered, whereas the plasma levels of palmitoyl-LPC decreased and those of total LPC remained constant. In conclusion, egg- and soy-derived LPC species function as cholinergic precursors in vivo, and future studies should explore this potential.

[A case of pembrolizumab responding to recurrent small bowel mucinous adenocarcinoma with Peutz-Jeghers syndrome].

An advanced small bowel mucinous adenocarcinoma with Peutz-Jeghers syndrome was resected, and we started capecitabine plus oxaliplatin (CapeOX) as adjuvant therapy. However, local recurrence was noted, and the tumor increased even after CapeOX plus bevacizumab and fluorouracil plus leucovorin plus irinotecan plus panitumumab (FOLFIRI plus panitumumab). Pembrolizumab was administered after confirming high-frequency microsatellite instability, and the tumor shrank markedly and remained shrunk for 20 months.

Novel and potent calcium-sensing receptor antagonists: discovery of (5R)-N-[1-ethyl-1-(4-ethylphenyl)propyl]-2,7,7-trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide monotosylate (TAK-075) as an orally active bone anabolic agent.

The calcium-sensing receptor antagonist (CaSR) has been recognized as a promising target of anabolic agents for treating osteoporosis. In the course of developing a new drug candidate for osteoporosis, we found tetrahydropyrazolopyrimidine derivative 1 to be an orally active CaSR antagonist that stimulated transient PTH secretion in rats. However, compound 1 showed poor physical and chemical stability. In order to work out this compound's chemical stability and further understand its in vivo efficacy, we focused on modifying the 2-position of the tetrahydropyrazolopyrimidine. As a result of chemical modification, we discovered (5R)-N-[1-ethyl-1-(4-ethylphenyl)propyl]-2,7,7-trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide monotosylate 10m (TAK-075), which showed improved solubility, chemical stability, and in vivo efficacy. Furthermore, we describe that evaluating the active metabolite is important during repeated treatment with short-acting CaSR antagonists.

Synthesis and evaluation of novel chalcone derivatives with (99m)Tc/Re complexes as potential probes for detection of ß-amyloid plaques.

Four (99m)Tc-labeled chalcone derivatives and their corresponding rhenium analogues were tested as potential probes for imaging ß-amyloid plaques. The chalcones showed higher affinity for Aß(1-42) aggregates than did (99m)Tc complexes. In sections of brain tissue from an animal model of AD, the four Re chalcones intensely stained ß-amyloid plaques. In biodistribution experiments using normal mice, (99m)Tc-BAT-chalcone ([(99m)Tc]17) displayed high uptake in the brain (1.48% ID/g) at 2 min postinjection. The radioactivity washed out from the brain rapidly (0.17% ID/g at 60 min), a highly desirable feature for an imaging agent. [(99m)Tc]17 may be a potential probe for imaging ß-amyloid plaques in Alzheimer's brains.

Synthesis and evaluation of radioiodinated (S,S)-2-(alpha-(2-iodophenoxy)benzyl)morpholine for imaging brain norepinephrine transporter.

PURPOSE: Abnormality of the brain norepinephrine transporter (NET) has been reported in several psychiatric and neuronal disorders. Since NET is an important target for the diagnosis of these diseases, the development of radiopharmaceuticals for imaging of brain NET has been eagerly awaited. In this study, we synthesized (S,S)-2-(alpha-(2-iodophenoxy)benzyl)morpholine [(S,S)-IPBM], a derivative of reboxetine iodinated at position 2 of the phenoxy ring, and evaluated its potential as a radiopharmaceutical for imaging brain NET using SPECT. METHODS: (S,S)-(123/125)I-IPBM was synthesized in a halogen exchange reaction. The affinity and selectivity of (S,S)-IPBM for NET was measured by assaying the displacement of (3)H-nisoxetine and (S,S)-(125)I-IPBM from the binding site in rat brain membrane, respectively. The biodistribution of (S,S)-(125)I-IPBM was also determined in rats. Furthermore, SPECT studies with (S,S)-(123)I-IPBM were carried out in the common marmoset. RESULTS: (S,S)-(125)I-IPBM was prepared with high radiochemical yields (65%) and high radiochemical purity (>98%). (S,S)-IPBM showed high affinity and selectivity for NET in the binding assay experiments. In biodistribution experiments, (S,S)-(125)I-IPBM showed rapid uptake in the brain, and the regional cerebral distribution was consistent with the density of NET. The administration of nisoxetine, a selective NET-binding agent, decreased the accumulation of (S,S)-(125)I-IPBM in the brain, but the administration of selective serotonin transporter and dopamine transporter binding agents caused no significant changes in the accumulation. Moreover, (S,S)-(123)I-IPBM allowed brain NET imaging in the common marmoset with SPECT. CONCLUSION: These results suggest that (S,S)-(123)I-IPBM is a potential SPECT radiopharmaceutical for imaging brain NET.

Novel inhibitor of p38 MAP kinase as an anti-TNF-alpha drug: discovery of N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (TAK-715) as a potent and orally active anti-rheumatoid arthritis agent.

The p38 mitogen-activated protein (MAP) kinase has been implicated in the proinflammatory cytokine signal pathway, and its inhibitors are potentially useful for the treatment of chronic inflammatory diseases such as rheumatoid arthritis (RA) and inflammatory bowel disease. To develop a new drug for RA, we synthesized a novel series of 4-phenyl-5-pyridyl-1,3-thiazoles and evaluated their inhibition of p38 MAP kinase, lipopolysaccharide (LPS)-stimulated release of tumor necrosis factor-alpha (TNF-alpha) from human monocytic THP-1 cells in vitro, and LPS-induced TNF-alpha production in vivo in mice. During the course of the study, we found that these compounds risk the inhibition of cytochrome P450 (CYP) isoforms by coordination of the 4-pyridyl nitrogen with heme iron. We therefore investigated the effects of substitution at the 2-position of the pyridyl ring on the inhibitory activity of p38 MAP kinase and CYPs in more detail. As a result, N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (8h, TAK-715) exhibited potent inhibitory activity in these assays (inhibition of p38alpha, IC50 = 7.1 nM; LPS-stimulated release of TNF-alpha from THP-1, IC50 = 48 nM; LPS-induced TNF-alpha production in mice, 87.6% inhibition at 10 mg/kg, po) and no inhibitory activity for major CYPs, including CYP3A4. This compound also showed good bioavailability in mice and rats and significant efficacy in a rat adjuvant-induced arthritis model. Compound 8h was selected as a clinical candidate and is now under clinical investigation for the treatment of RA.

Japanese herbal medicine, Saiko-keishi-to, prevents gut ischemia/reperfusion-induced liver injury in rats via nitric oxide.

AIM: To determine whether Saiko-keishi-to (TJ-10), a Japanese herbal medicine, could protect liver injury induced by gut ischemia/reperfusion (I/R), and to investigate the role of NO. METHODS: Male Wistar rats were exposed to 30-min gut ischemia followed by 60 min of reperfusion. Intravital microscopy was used to monitor leukocyte recruitment. Plasma tumor necrosis factor (TNF) levels and alanine aminotransferase (ALT) activities were measured. TJ-10 1 g/(kg.d) was intragastrically administered to rats for 7 d. A NO synthase inhibitor was administered. RESULTS: In control rats, gut I/R elicited increases in the number of stationary leukocytes, and plasma TNF levels and ALT activities were mitigated by pretreatment with TJ-10. Pretreatment with the NO synthase inhibitor diminished the protective effects of TJ-10 on leukostasis in the liver, and the increase of plasma TNF levels and ALT activities. Pretreatment with TJ-10 increased plasma nitrite/nitrate levels. CONCLUSION: TJ-10 attenuates the gut I/R-induced hepatic microvascular dysfunction and sequential hepatocellular injury via enhancement of NO production.

A novel oxyiminoalkanoic acid derivative, TAK-559, activates human peroxisome proliferator-activated receptor subtypes.

A novel oxyiminoalkanoic acid derivative, TAK-559, (E)-4-[4-[(5-methyl-2-phenyl-1, 3-oxazol-4-yl)methoxy]benzyloxyimino]-4-phenylbutyric acid, was synthesized as a candidate of a new type of insulin-sensitizing agent. We report here activation of human peroxisome proliferator-activated receptor (hPPAR) subtypes by TAK-559. In a transient transactivation assay, TAK-559 was a potent hPPARgamma1 and hPPARalpha agonist with EC50 values of 31 and 67 nM, respectively. Furthermore, TAK-559 was a partial agonist for hPPARgamma1 with about 68% of maximal activation obtained with rosiglitazone (5-(4-(2-(methyl(2-pyridinyl)amino)ethoxy) benzyl)-1,3-thiazolidine-2,4-dione), a thiazolidinedione derivative, which is known as a PPARgamma agonist. PPARdelta was significantly activated at a high concentration (10 microM) of TAK-559. Competition-binding assays using radiolabeled ligand indicated that the transactivation of all hPPAR subtypes by TAK-559 was due to direct binding of TAK-559 to each subtype. We also demonstrated that TAK-559 acts to recruit the coactivator SRC-1 to each of hPPARgamma1 and hPPARalpha, and to dissociate the corepressor NCoR from each of hPPARgamma1 and hPPARalpha. Taken together, we conclude that TAK-559 is a dual agonist for hPPARgamma1 and hPPARalpha with nearly equal EC50 values, a partial agonist for hPPARgamma1, and has a rather slight agonist activity for hPPARdelta.

The copper chelator trientine has an antiangiogenic effect against hepatocellular carcinoma, possibly through inhibition of interleukin-8 production.

Recent studies have revealed that copper is an important cofactor for several angiogenic agents. We examined the antiangiogenic effect against hepatocellular carcinoma (HCC) of the copper chelator trientine, especially focusing on the relationship between copper and interleukin-8 (IL-8), a potent angiogenic factor produced by hepatoma cells. HuH-7 hepatoma cells were transplanted into nude mice and the growth of xenograft tumors was compared to and without administration of trientine. Using the resected tumor, microvessel density, apoptotic potential and proliferative activity were analyzed histologically and IL-8 mRNA was semiquantified by RT-PCR. In addition, HuH-7 cells were cultured in control medium, medium supplemented with copper, medium supplemented with trientine and medium supplemented with both copper and trientine. Human IL-8 levels were measured in the supernatants by ELISA. Using the extracts from cultured cells, IL-8 mRNA was semiquantified by RT-PCR. Trientine suppressed the growth of xenograft tumors significantly. Histologically, apoptotic potential was increased significantly and microvessel density, decreased. The production of IL-8 from the tumor was suppressed by trientine. In vitro, IL-8 production by HuH-7 cells in copper-containing medium was significantly greater than that in copper-free medium, and this effect was weakened when trientine was added. However, no significant change was apparent when trientine was added to the medium alone. In conclusion, the chelating effect of trientine prevented copper from functioning as a cofactor in angiogenesis, which resulted in reduced IL-8 production from HuH-7 cells.