The use of anaerobic threshold in assessment of aerobic capacity was evaluated in 34 normal subjects and 47 patients with various kinds of chronic heart disease. Anaerobic threshold was determined as the oxygen consumption (W02) at which a linear relationship between pulmonary ventilation (yE) and V02 was lost during progressive treadmill exercise. Anaerobic threshold determined in this manner was validated with that determined by blood lactate measurements in eight normal subjects and nine cardiac patients (r = .962, p < .001). Thereafter, anaerobic threshold was determined only by respiratory measurements. In symptom-limited, maximal exercise, anaerobic threshold was reached well before maximal effort and corresponded to 70% of maximal V02 both in normal subjects and cardiac patients. Anaerobic threshold decreased as age progressed in normal subjects (r = -.70, p < .001). Anaerobic threshold in cardiac patients was lower than that in the normal subjects and decreased progressively as New York Heart Association functional classification advanced (normal, 32
Autotaxin, also known as ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2), is a secreted enzyme that has lysophospholipase D activity, which converts lysophosphatidylcholine to bioactive lysophosphatidic acid. Lysophosphatidic acid activates at least six G-protein coupled recpetors, which promote cell proliferation, survival, migration and muscle contraction. These physiological effects become dysfunctional in the pathology of cancer, fibrosis, and pain. To date, several autotaxin/ENPP2 inhibitors have been reported; however, none were able to completely and continuously inhibit autotaxin/ENPP2 in vivo. In this study, we report the discovery of a highly potent autotaxin/ENPP2 inhibitor, ONO-8430506, which decreased plasma lysophosphatidic acid formation.The IC50 values of ONO-8540506 for lysophospholipase D activity were 6.4–19 nM for recombinant autotaxin/ENPP2 proteins and 4.7–11.6 nM for plasma from various animal species. Plasma lysophosphatidic acid formation during 1-h incubation was almost completely inhibited by the addition of >300 nM of the compound to human plasma. In addition, when administered orally to rats at a dose of 30 mg/kg, the compound demonstrated good pharmacokinetics in rats and persistently inhibited plasma lysophosphatidic acid formation even at 24 h after administration.Smooth muscle contraction is a known to be promoted by lysophosphatidic acid. In this study, we showed that dosing rats with ONO-8430506 decreased intraurethral pressure accompanied by urethral relaxation. These findings demonstrate the potential of this autotaxin/ENPP2 inhibitor for the treatment of various diseases caused by lysophosphatidic acid, including urethral obstructive disease such as benign prostatic hyperplasia.
Lysophosphatidic
acid (LPA) is a bioactive lipid mediator that
elicits a number of biological functions, including smooth muscle
contraction, cell motility, proliferation, and morphological change.
LPA is endogenously produced by autotaxin (ATX) from extracellular
lysophosphatidylcholine (LPC) in plasma. Herein, we report our medicinal
chemistry effort to identify a novel and highly potent ATX inhibitor,
ONO-8430506 (20), with good oral availability. To enhance
the enzymatic ATX inhibitory activity, we designed several compounds
by structurally comparing our hit compound with the endogenous ligand
LPC. Further optimization to improve the pharmacokinetic profile and
enhance the ATX inhibitory activity in human plasma resulted in the
identification of ONO-8430506 (20), which enhanced the
antitumor effect of paclitaxel in a breast cancer model.
In this study, we systematically evaluated “bottom-up” physiologically based oral absorption modeling, focusing on free weak base drugs. The gastrointestinal unified theoretical framework (the GUT framework) was employed as a simple and transparent model. The oral absorption of poorly soluble free weak base drugs is affected by gastric pH. Alternation of bulk and solid surface pH by dissolving drug substances was considered in the model. Simple physicochemical properties such as pKa, the intrinsic solubility, and the bile micelle partition coefficient were used as input parameters. The fraction of a dose absorbed (Fa) in vivo was obtained by reanalyzing the pharmacokinetic data in the literature (15 drugs, a total of 85 Fa data). The AUC ratio with/without a gastric acid-reducing agent (AUCr) was collected from the literature (22 data). When gastric dissolution was neglected, Fa was underestimated (absolute average fold error (AAFE) = 1.85, average fold error (AFE) = 0.64). By considering gastric dissolution, predictability was improved (AAFE = 1.40, AFE = 1.04). AUCr was also appropriately predicted (AAFE = 1.54, AFE = 1.04). The Fa values of several drugs were slightly overestimated (less than 1.7-fold), probably due to neglecting particle growth in the small intestine. This modeling strategy will be of great importance for drug discovery and development.
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