Anticalcification effects of DS-1211 in pseudoxanthoma elasticum mouse models and the role of tissue-nonspecific alkaline phosphatase in ABCC6-deficient ectopic calcification.

Pseudoxanthoma elasticum (PXE) is a multisystem, genetic, ectopic mineralization disorder with no effective treatment. Inhibition of tissue-nonspecific alkaline phosphatase (TNAP) may prevent ectopic soft tissue calcification by increasing endogenous pyrophosphate (PPi). This study evaluated the anticalcification effects of DS-1211, an orally administered, potent, and highly selective small molecule TNAP inhibitor, in mouse models of PXE. Calcium content in vibrissae was measured in KK/HlJ and ABCC6-/- mice after DS-1211 administration for 13-14 weeks. Pharmacokinetic and pharmacodynamic effects of DS-1211 were evaluated, including plasma alkaline phosphatase (ALP) activity and biomarker changes in PPi and pyridoxal-phosphate (PLP). Anticalcification effects of DS-1211 through TNAP inhibition were further evaluated in ABCC6-/- mice with genetically reduced TNAP activity, ABCC6-/-/TNAP+/+ and ABCC6-/-/TNAP+/-. In KK/HlJ and ABCC6-/- mouse models, DS-1211 inhibited plasma ALP activity in a dose-dependent manner and prevented progression of ectopic calcification compared with vehicle-treated mice. Plasma PPi and PLP increased dose-dependently with DS-1211 in ABCC6-/- mice. Mice with ABCC6-/-/TNAP+/- phenotype had significantly less calcification and higher plasma PPi and PLP than ABCC6-/-/TNAP+/+ mice. TNAP plays an active role in pathomechanistic pathways of dysregulated calcification, demonstrated by reduced ectopic calcification in mice with lower TNAP activity. DS-1211 may be a potential therapeutic drug for PXE.

In Vitro and In Vivo Pharmacological Profiles of DS-1211, a Novel Potent, Selective, and Orally Bioavailable Tissue-Nonspecific Alkaline Phosphatase Inhibitor.

Inhibition of tissue-nonspecific alkaline phosphatase (TNAP) may prevent ectopic soft tissue calcification by increasing endogenous pyrophosphate (PPi). DS-1211 is a potent and selective novel small molecule TNAP inhibitor with well-characterized pharmacokinetics (PKs) in rodent and monkey. Herein, we report a comprehensive summary of studies establishing the pharmaceutical profile of DS-1211. In vitro studies characterized the mode of inhibition and inhibitory effects of DS-1211 on three human alkaline phosphatase (ALP) isozymes-TNAP, human intestinal ALP, human placental ALP-and on ALP activity across species in mouse, monkey, and human plasma. In vivo PK and pharmacodynamic (PD) effects of a single oral dose of DS-1211 in mice and monkeys were evaluated, including biomarker changes in PPi and pyridoxal 5'-phosphate (PLP). Oral bioavailability (BA) was determined through administration of DS-1211 at a 0.3-mg/kg dose in monkeys. In vitro experiments demonstrated DS-1211 inhibited ALP activity through an uncompetitive mode of action. DS-1211 exhibited TNAP selectivity and potent inhibition of TNAP across species. In vivo studies in mice and monkeys after single oral administration of DS-1211 showed linear PKs, with dose-dependent inhibition of ALP activity and increases in plasma PPi and PLP. Inhibitory effects of DS-1211 were consistent in both mouse and monkey. Mean absolute oral BA was 73.9%. Overall, in vitro and in vivo studies showed DS-1211 is a potent and selective TNAP inhibitor across species. Further in vivo pharmacology studies in ectopic calcification animal models and clinical investigations of DS-1211 in patient populations are warranted. © 2022 Daiichi Sankyo, Inc. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Discovery of DS-3801b, a non-macrolide GPR38 agonist with N-methylanilide structure.

Motilin is a 22-amino-acid gastrointestinal (GI) hormone and is involved in the regulation of GI motility through binding to GPR38, the motilin receptor which is expressed on smooth muscle cells in the GI tract. Therefore, GPR38 agonists are expected to be novel gastrointestinal prokinetic agents for the treatment of functional gastrointestinal disorders such as gastroparesis and chronic constipation. We identified a series of N-methylanilide derivatives as novel non-macrolide GPR38 agonists. Among them, 12 di-l-tartrate (DS-3801b) was selected as a clinical candidate for further evaluation.

Comparison of chest compression quality in walking versus straddling cardiopulmonary resuscitation during stretcher transportation: A prospective randomised crossover study using manikins.

The optimal strategy to ensure chest compression quality for patients being transported on a stretcher has not been established yet. We hypothesised that straddling cardiopulmonary resuscitation may improve chest compression quality in patients being transported on stretchers. We conducted a prospective randomised crossover study using manikins to investigate whether straddling cardiopulmonary resuscitation improves chest compression quality (depth, recoil, rate, correct hand position) performed on patients during stretcher transportation compared to walking cardiopulmonary resuscitation. Walking and straddling cardiopulmonary resuscitation were performed for 2 minutes each. The mean chest compression depth (mm) for 2 minutes was significantly greater in the straddling cardiopulmonary resuscitation group than in the walking cardiopulmonary resuscitation group (median, 51.3 [interquartile range, 46.7-55.5] versus 40.9 [34.6-50.1], P = 0.003). An adequate depth of chest compressions could not be achieved when walking cardiopulmonary resuscitation was performed by female participants, but the depth of chest compressions was within the acceptable range when female participants performed straddling cardiopulmonary resuscitation. On the other hand, the degree of deterioration was relatively small in male participants, even when they performed walking cardiopulmonary resuscitation. In patients with cardiac arrest being transported on a stretcher, straddling cardiopulmonary resuscitation improved the depth of chest compressions compared to walking cardiopulmonary resuscitation. Female rescuers, in particular, may consider using straddling cardiopulmonary resuscitation.

Abundant expression of KCNE1 in the left ventricle of the miniature pig.

Delayed rectifier potassium currents such as I (Kr) and I (Ks) play an important role in the repolarization phase of the action potential in cardiac myocytes. Electrophysiological studies have shown that the pig is a useful animal not only for clinical use as a good candidate for humans, but also for basic research in heart function or arrhythmia. However, no studies concerning the potassium channels on a molecular level have been done. To elucidate the expression level and distribution of delayed rectifier potassium channels in pigs, we quantitatively investigated the I (Kr) and I (Ks) channel subunits using the real-time polymerase chain reaction (PCR) method. The hearts from Clawn miniature pigs were separated into the apical and basal regions, and subsequently excised into transmural trisections within each of the left ventricular walls, epicardium, midcardium, and endocardium. After RNA extraction from these sites, real-time PCR was executed with reverse transcriptional products for quantitative analysis. The expression level of KCNE1 was significantly higher than those of KCNQ1, KCNH2, and KCNE2, which were comparable in all sites. Transmural heterogeneity of these potassium channel subunits was not detected on the mRNA level. These results indicate that KCNE1 is a dominant subunit on the post-transcriptional level in the miniature pig.