Safety, Tolerability, and Pharmacokinetics of the Novel Adenosine A Antagonist/Inverse Agonist KW-6356 Following Single and Multiple Oral Administration in Healthy Volunteers.

KW-6356 is an adenosine A receptor-selective antagonist and inverse agonist. We conducted 2 studies: study 6356-001 (no NCT number), a randomized, double-blind, placebo-controlled phase 1 trial of single ascending (1, 3, 10 mg) and multiple (6 mg once daily) oral doses of KW-6356 in healthy Japanese subjects; and study 6356-004 (NCT03830528), including a randomized, double-blind, placebo-controlled phase 1 trial of single ascending (21, 42, 60 mg) and multiple (24 mg once daily) oral doses of KW-6356, and a phase 1 open-label trial of multiple oral doses (6 mg once daily) of KW-6356 in healthy Japanese and White subjects, to evaluate the safety, tolerability, and pharmacokinetics of KW-6356. KW-6356 was well tolerated after administration of single doses of up to 60 mg and multiple doses of up to 24 mg once daily for 14 days.

Assessment of CYP-Mediated Drug Interactions for Evocalcet, a New Calcimimetic Agent, Based on In Vitro Investigations and a Cocktail Study in Humans.

Evocalcet is a novel calcimimetic agent for the treatment of secondary hyperparathyroidism (SHPT). This study evaluated the effects of evocalcet on inhibition and induction of cytochrome P450 (CYP) isozymes. Although drug interactions arising from reversible inhibition of CYP isozymes by evocalcet were considered unlikely based on the results of in vitro studies and static model analyses, the potential for evocalcet to cause time-dependent inhibition of CYP3A or induction of several CYP isozymes could not be ruled out.

Significant effect of the posterior tibial slope and medial/lateral ligament balance on knee flexion in total knee arthroplasty.

Purpose: The intra-operative femorotibial joint gap and ligament balance, the predictors affecting these gaps and their balances, as well as the postoperative knee flexion, were examined. These factors were assessed radiographically after a posterior cruciate-retaining total knee arthroplasty (TKA). The posterior condylar offset and posterior tibial slope have been reported as the most important intra-operative factors affecting cruciate-retaining-type TKAs.

Effect of a centrally active angiotensin converting enzyme inhibitor, perindopril, on cognitive performance in chronic cerebral hypo-perfusion rats.

We have previously demonstrated that perindopril, an angiotensin-converting enzyme (ACE) inhibitor, ameliorated the cognitive deficits in Alzheimer's disease model animals, independently of its anti-hypertensive effect. In this study, we again investigated the effects of perindopril on cognitive function in a vascular dementia model animal, comparing it with other ACE inhibitors. We also determined ACE activity in the brain and extracellular acetylcholine (ACh) concentration in the perirhinal cortex in order to elucidate the mechanism(s) responsible for the effects of these ACE inhibitors on cognitive function.

Effect of a centrally active angiotensin-converting enzyme inhibitor, perindopril, on cognitive performance in a mouse model of Alzheimer's disease.

Angiotensin-converting enzyme (ACE) inhibitors have clinically been widely used as anti-hypertensive agents. In the present study, we compared the effects of a centrally active ACE inhibitor, perindopril, with those of non-centrally active ACE inhibitors, imidapril and enalapril, on cognitive performance in amyloid beta(Abeta) (25-35)-injected mice, a rodent model of Alzheimer's disease. We also determined the brain ACE activity in order to elucidate the relationship between the cognitive function and ACE inhibition in the brain.

P-glycoprotein limits the brain penetration of olopatadine hydrochloride, H1-receptor antagonist.

Olopatadine, a new second-generation antihistamine, is widely used in the treatment of allergic disorders. The low levels of histamine H1 receptor occupancy in human brain by olopatadine, which is related to its minimal sedation, suggest its low penetration into the brain. The present study evaluates the impact of P-glycoprotein (P-gp) on brain penetration and plasma concentration of olopatadine.

Dislocation of the shoulder joint with ipsilateral humeral shaft fracture: two case reports.

Introduction: A combination of the shaft fracture of the humerus with shoulder dislocation is a rarely documented injury. Moreover, few reports describe a long-term outcome after a follow-up period over 10 years. The present article is the first report of long-term clinical results obtained with this combined injury.

The intestinal first-pass metabolism of substrates of CYP3A4 and P-glycoprotein-quantitative analysis based on information from the literature.

It is suggested that the bioavailability of CYP3A4 substrates might be low due to first-pass metabolism in the small intestine, and it is possible that P-glycoprotein (P-gp) may influence first-pass metabolism in a co-operative manner. We have collected information of the pharmacokinetics of CYP3A4 substrates to evaluate the fraction absorbed (Fa), intestinal availability (Fg) and hepatic availability (Fh) and have investigated the intestinal first-pass metabolism and the effect of P-gp on this. The pharmacokinetic data involved ten compounds metabolized by CYP3A4 in humans, with and without an inhibitor or inducer.

Involvement of rat organic anion transporter 3 in the uptake of an organic herbicide, 2,4-dichlorophenoxyacetate, by the isolated rat choroid plexus.

2,4-Dichlorophenoxyacetic acid (2,4-D) is an anionic herbicide. The purpose of the present study is to examine whether organic anion transporter 3 (Oat3; Slc22a8) is solely responsible for the uptake of 2,4-D by the isolated rat choroid plexus (CP). When expressed in LLC-PK1 cells, rOat3 was mainly localized to the basolateral membrane.

Carrier-mediated uptake of H2-receptor antagonists by the rat choroid plexus: involvement of rat organic anion transporter 3.

The choroid plexus (CP) acts as a site for the elimination of xenobiotic organic compounds from the cerebrospinal fluid (CSF). The purpose of the present study is to investigate the role of rat organic anion transporter 3 (rOat3; Slc22a8) in the uptake of H(2)-receptor antagonists (cimetidine, ranitidine, and famotidine) by the isolated rat CP. Saturable uptake of cimetidine and ranitidine was observed in rOat3-LLC with K(m) values of 80 and 120 microM, respectively, whereas famotidine was found to be a poor substrate.

Expression and functional involvement of organic anion transporting polypeptide subtype 3 (Slc21a7) in rat choroid plexus.

Purpose: It has been shown that transport(s) are involved in the uptake of estradiol 17beta glucuronide (E217betaG) by the choroid plexus (CP). The purpose of this study is to compare the substrate specificity of the transporter in the CP with those of rat organic anion transporting polypeptide 1 (rOatp1) and rOatp3.

Methods: The expression of rOatp1 and rOatp3 in rat CP was confirmed by RT-PCR and Western blot analyses.

Expression and functional characterization of rat organic anion transporter 3 (rOat3) in the choroid plexus.

We reported previously that an efficient efflux system for benzylpenicillin (PCG) is located on the choroid plexus (CP). In this study, we investigated the involvement of rat organic anion transporter 1 (rOat1; Slc22a6) and rOat3 (Slc22a8) in the uptake of PCG and p-aminohippurate (PAH) by the CP. Western blot analysis indicates the expression of rOat3, but not rOat1, on the CP, and immunohistochemical staining shows that rOat3 is localized on the brush border membrane of the choroid epithelial cells.