Impact of Q141K on the Transport of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors by ABCG2.

The ATP-binding cassette transporter ABCG2 is expressed in various organs, such as the small intestine, liver, and kidney, and influences the pharmacokinetics of drugs that are its substrates. ABCG2 is also expressed by cancer cells and mediates resistance to anticancer agents by promoting the efflux of these drugs. In the present study, we investigated the interactions between epidermal growth factor receptor tyrosine kinase inhibitors and ABCG2 by MTT assay, intracellular drug accumulation assay, and FACS.

Discovery of novel 2-(3-phenylpiperazin-1-yl)-pyrimidin-4-ones as glycogen synthase kinase-3β inhibitors.

We herein describe the results of further evolution of glycogen synthase kinase (GSK)-3β inhibitors from our promising compounds containing a 2-phenylmorpholine moiety. Transformation of the morpholine moiety into a piperazine moiety resulted in potent GSK-3β inhibitors. SAR studies focused on the phenyl moiety revealed that a 4-fluoro-2-methoxy group afforded potent inhibitory activity toward GSK-3β.

Discovery of novel 2-(4-aryl-2-methylpiperazin-1-yl)-pyrimidin-4-ones as glycogen synthase kinase-3β inhibitors.

We herein describe the results of further evolution of glycogen synthase kinase (GSK)-3β inhibitors from our promising compounds containing a 3-methylmorpholine moiety. Transformation of the morpholine moiety into a piperazine moiety resulted in potent GSK-3β inhibitors. SAR studies focused on the nitrogen atom of the piperazine moiety revealed that a phenyl group afforded potent inhibitory activity toward GSK-3β.

Investigation of Bioequivalence Between Brand-name and Generic Irinotecan Products.

Background/aim: To investigate bioequivalence among generic and brand-name irinotecan products.

Materials And Methods: Products of Yakult and Daiichi-Sankyo (brand-name products), Sandoz, Nippon Kayaku, Taiho, and Sawai were compared with respect to their composition and antitumor activity.

Results: High-performance liquid chromatography demonstrated that related substances were within the acceptable range.

Discovery of novel 2-(alkylmorpholin-4-yl)-6-(3-fluoropyridin-4-yl)-pyrimidin-4(3H)-ones as orally-active GSK-3β inhibitors for Alzheimer's disease.

We herein describe the results of further evolution of GSK-3β inhibitors for Alzheimer's disease from our promising compounds with in vivo tau phosphorylation inhibitory activity by oral administration. Introduction of a low alkyl group instead of the phenyl group at the 3-position of the morpholine moiety aiming to improve pharmacokinetic profiles resulted in potent low molecular weight GSK-3β inhibitors with good in vitro pharmacokinetic profiles, which also showed in vivo tau phosphorylation inhibitory activity by oral administration. Effect of the stereochemistry of the alkyl moiety is also discussed using docking models.

2-(2-Phenylmorpholin-4-yl)pyrimidin-4(3H)-ones; a new class of potent, selective and orally active glycogen synthase kinase-3β inhibitors.

A series of 2-(2-phenylmorpholin-4-yl)pyrimidin-4(3H)-ones was synthesized and examined for their inhibitory activity against glycogen synthase kinase-3β (GSK-3β). We found 21, 29 and 30 to possess potent in vitro GSK-3β inhibitory activity with good in vitro PK profiles. 21 demonstrated significant decrease of tau phosphorylation after oral administration in mice and excellent PK profiles.

6-(4-Pyridyl)pyrimidin-4(3H)-ones as CNS penetrant glycogen synthase kinase-3β inhibitors.

The discovery of a series of 6-(4-pyridyl)pyrimidin-4(3H)-ones derived from a hit compound with low molecular weight and sufficient chemical space is reported. Transformation of substituents led to subnanomolar potent inhibitors with in vivo tau phoshorylation lowering activity.

Vascular malformations of the head and neck.

Objective: Vascular malformations may appear anywhere in the body; 14-65% are in the head and neck. There are several treatments (sclerotherapy, surgery, laser treatment, and embolization, etc.), but standardized guidelines for these treatments are lacking.

Efficacy and safety of additional 200-mg dose of celecoxib in adult patients with postoperative pain following extraction of impacted third mandibular molar: a multicenter, randomized, double-blind, placebo-controlled, phase II study in Japan.

Background: Although third mandibular molar extraction is a widely used and validated model of acute pain for evaluating analgesic efficacy, a large proportion of patients experience moderate or severe pain following this procedure and require analgesia. Current treatment options have been associated with safety concerns and alternative therapies are sought.

Objective: Our aim was to assess the efficacy and safety of an additional 200-mg dose of celecoxib, administered 5 to 12 hours after an initial 400-mg dose of the drug for the treatment of moderate or severe acute pain following extraction of an impacted third mandibular molar.

Prevalence of periodontitis and optimal timing of dental treatment in patients undergoing heart valve surgery.

We investigated the prevalence, risk factors, and optimal timing of treatment for advanced periodontitis in patients undergoing elective heart valve surgery. Dental examinations were given to 209 patients (aged 65 ± 10 years) scheduled for valve surgery. Patients with no or mild periodontitis were assigned as controls (n = 105).

Stereotactic radiosurgery/radiotherapy for pituitary adenomas: a review of recent literature.

The recent clinical results are reviewed of stereotactic radiosurgery/radiotherapy for the treatment of pituitary adenomas. The outcomes of pituitary adenomas treated by stereotactic radiosurgery/radiotherapy with gamma knife, CyberKnife, or linear accelerator (LINAC) radiosurgery were evaluated from articles published after 2004. Each study was evaluated for the number of patients, radiosurgical parameter (marginal dose), length of follow up, tumor growth control, rate of hormonal normalization in secretary adenomas, and adverse events.

MKC-231, a choline uptake enhancer: (3) Mode of action of MKC-231 in the enhancement of high-affinity choline uptake.

MKC-231, a putative cholinergic activity, is reported to improve learning and memory impaired in AF64A-treated animals. MKC-231 enhances high-affinity choline uptake (HACU) known as the rate-limiting step of acetylcholine (ACh) synthesis. We investigated the mode of action (MOA) of HACU enhancement by MKC-231.

MKC-231, a choline-uptake enhancer: (1) long-lasting cognitive improvement after repeated administration in AF64A-treated rats.

MKC-231 is reported to increase high-affinity choline uptake (HACU) in vitro and improve learning impairment on a single oral administration in AF64A-treated rats. In this study, we investigated the effects of repeated administration of MKC-231 (1 and 3 mg/kg, p.o.

MKC-231, a choline uptake enhancer: (2) Effect on synthesis and release of acetylcholine in AF64A-treated rats.

The effect of MKC-231 on acetylcholine (ACh) synthesis and release was studied in the hippocampus of normal and AF64A-treated rats. AF64A (3 nmol/brain, i.c.

Orally active neurotrophin-enhancing agent protects against dysfunctions of the peripheral nerves in hyperglycemic animals.

Biological substances with neurotrophic activities, such as nerve growth factor (NGF) and monosialoganglioside GM1, have been considered as agents for diabetic peripheral neuropathy. Because recent studies have suggested that decreased availability of these substances might contribute to the pathogenesis of diabetic peripheral neuropathy, some clinical trials of NGF for diabetic peripheral neuropathy have been conducted and have led to mixed conclusions. The major reasons were its limited delivery to the nervous system and adverse effects induced by subcutaneous injection, which was necessary because NGF is a polypeptide.

Pharmacological properties of traditional medicine (XXIX): effect of Hange-shashin-to and the combinations of its herbal constituents on rat experimental colitis.

Hange-shashin-to (HST) has been used as an herbal formula to treat inflammatory ulcerative gut diseases complicated with psychoneurosis in Japanese traditional Kampo medicine. The aim of the present study is to clarify anti-colitic effect of HST using a model of colitis induced by intracolonic instillation of 2,4,6-trinitrobenzene sulfonic acid (TNBS) in rats, and to evaluate the pharmaceutical properties of its herbal components. The colonic damage was elucidated by macroscopic damage scores, colon wet weight and area of mucosal necrosis.

Anti-stress effects of 3,4,5-trimethoxycinnamic acid, an active constituent of roots of Polygala tenuifolia (Onji).

3,4,5-trimethoxycinnamic acid (TMCA) is one of the constituents in Onji (roots of Polygala tenuifolia WILLD), an herbal medicine used for sedative in Japanese traditional Kampo medicine. Our previous study revealed that oral administration of this compound prolongs sleeping time induced by hexobarbital in mice to exhibit sedative action. In the present study, we investigate the effects of TMCA on the stress induced with repeated cold exposure or intracerebroventricular injection of corticotrophin-releasing hormone (CRH).

Anti-allergic effect of Perilla frutescens and its active constituents.

The leaves of Perilla frutescens Britton (Labiatae) are one of the most popular garnishes in Japan, used as an antidote for fi sh and crab meat allergy or as a food colorant. The present study was conducted to evaluate its anti-allergic effect and to identify its active constituents using mice ear-passive cutaneous anaphylaxis (PCA)-reaction. 48 h after the cutaneous injection of anti-ovalbumin serum into the ears of mice, ovalbumin and evansblue dye were intravenously injected.

Application of cyberknife for the treatment of juvenile nasopharyngeal angiofibroma: a case report.

Juvenile nasopharyngeal angiofibroma (JNA) tumors can be locally destructive when they spread submucosally. The purpose of this study was to present an image-guided, robotic radiotherapy (Cyberknife) to successfully treat a 12-year-old boy with Juvenile nasopharyngeal angiofibroma (JNA). He complained of progressive right nasal obstruction, intermittent epistaxis.

Pharmacological properties of traditional medicines (XXVII). Interaction between Ephedra Herb and Gypsum under hyperthermal conditions in rats.

There are many important considerations in the interactions among the herbal constituents in a prescription of traditional Chinese medicine (TCM). Ephedra Herb [Chinese characters: see text] (Eph) is described a warm and acrid agent in TCM. The combination of Eph and Gypsum [Chinese characters: see text] (Eph-Gyp) shows specific actions in patients with different body temperatures.

Effects of Kangen-karyu on coagulation system and platelet aggregation in mice.

Kangen-karyu (KGK) is a herbal formula created under the theory of traditional Chinese herbal medicine to invigorate the blood and dispel blood stasis. It contains 6 herbs: peony root, cnidium rhizome, safflower, cyperus rhizome, saussurea root (JP XIV), and Salvia miltiorrhiza root. The present study has been conducted to evaluate the in vivo anti-thrombotic activity of KGK using normal mice.