Abstract Aims Ipragliflozin is a novel and highly selective sodium–glucose transporter 2 (SGLT2) inhibitor that reduces plasma glucose levels by enhancing urinary glucose excretion in patients with ...type 2 diabetes mellitus (T2DM). We examined the pharmacokinetic and pharmacodynamic characteristics of two oral doses of ipragliflozin in Japanese patients with T2DM. Methods In this randomized, placebo-controlled, double-blind study, patients were treated with placebo, 50 mg or 100 mg ipragliflozin once daily for 14 days. Plasma and urine pharmacodynamic parameters were measured on Days −1 and 14, and pharmacokinetic parameters on Day 14. Pharmacodynamic characteristics included area under the curve (AUC) for plasma glucose and insulin for 0–3 h (AUC0–3h ) and 0–24 h (AUC0–24h ). Pharmacokinetic characteristics included AUC0–24h , maximum ipragliflozin concentration ( Cmax ), and time to maximum plasma ipragliflozin concentration ( tmax ). Results Thirty patients were enrolled; 28 were included in pharmacokinetic/pharmacodynamic analyses and 30 in safety analyses. Administration of 50 and 100 mg ipragliflozin significantly reduced fasting plasma glucose, as well as the AUC0–3h and AUC0–24h for plasma glucose relative to placebo. Both doses of ipragliflozin also reduced AUC0–24h for insulin, body weight, and glycoalbumin, while urinary glucose excretion increased remarkably. Cmax and AUC0–24h were 1.7- and 1.9-fold higher, respectively, in the 100-mg group than in the 50-mg group. Conclusions Ipragliflozin increased urinary glucose excretion and improved fasting and postprandial glucose, confirming its pharmacokinetic/pharmacodynamic properties in Japanese patients with T2DM.
Abstract
Solifenacin succinate (YM905; Vesicare®, Astellas Pharma Inc., Tokyo, Japan) is a new once-daily, orally administered muscarinic receptor antagonist under investigation for the treatment of ...overactive bladder.
The aim of this study was to evaluate the effect of solifenacin on the pharmacokinetic (PK) parameters of an oral contraceptive (OC) containing ethinyl estradiol (EE) and levonorgestrel (LNG).
In a double-blind, placebo-controlled, 2-period, crossover study, 24 healthy, young, white women received a combined OC (EE 30 μg + LNG 150 μg) daily for two 21-day cycles, separated by a 7-day washout. On day 12 of each cycle, subjects began a 10-day regimen of solifenacin 10 mg QD, which is 2 times the suggested starting dose, or placebo. Subjects crossed over to the other treatment arm for the second cycle. Primary PK end points were C
max and AUC from time 0 to 24 hours (AUC
0–24h) for EE and LNG. Women ranged in age from 20 to 37 years and had a mean body weight of 64 kg, mean height of 167.4 cm, and mean body mass index of 23 kg/m
2. Seven women had never smoked, while 5 were former smokers and 12 were regular smokers. Safety assessments included the nature, frequency, and severity of spontaneously reported or observed adverse events, vital signs, electrocardiogram, laboratory values, and physical examination.
Statistical analysis of AUC
0–24h/product of baseline concentration and total blood sampling time, and C
max/baseline concentration ratios of solifenacin versus placebo for EE and LNG found the 90% CI to be within the predefined range of 0.8 to 1.25 (EE: 0.854–1.164 and 0.822–1.167; LNG: 0.920–1.125 and 0.910–1.139). The number of samples with non-quantifiable luteinizing hormone (LH) and folliclestimulating hormone (FSH) levels were comparable after administration of the OC with either solifenacin or placebo. The adverse event most frequently reported was dry mouth (solifenacin, n = 25 9 mild, 13 moderate, and 3 severe vs placebo, n = 1 moderate). There were no clinically relevant effects on vital signs, electrocardiogram, or laboratory parameters.
A PK interaction between solifenacin and the OC containing EE and LNG was not found in this study. Solifenacin was not found to have altered suppression of LH or FSH. The drug was well tolerated in these healthy, young, white, adult female volunteers.
Photoincorporation of the fluorescent probe 4,4′-bis(1-anilino-8-naphthalene sulfonic acid) (bis-ANS) can be used to locate solvent-exposed hydrophobic regions in proteins. We show that bis-ANS is ...specifically incorporated into the putative N-terminal domain of αB-crystallin. This incorporation diminishes the chaperone-like activity of αB-crystallin, suggesting that hydrophobic surfaces in the N-terminal domain are involved in the binding of unfolding proteins.
In IDDM, the development of microalbuminuria, which is associated with an elevation in blood pressure within the normal range, is a risk factor for future cardiovascular disease. Vascular stiffness ...might be one of the factors involved because it increases systolic blood pressure and the workload of the heart.
We investigated carotid artery stiffness with a noninvasive ultrasound method in 24 microalbuminuric and 53 normoalbuminuric IDDM patients and in 54 healthy control subjects.
The distensibility coefficient, a measure of intrinsic vascular wall elasticity, was decreased in microalbuminuric IDDM (21.6 x 10(-3)/kPa) as compared with normoalbuminuric IDDM (24.8 x 10(-3)/kPa) and control subjects (25.9 x 10(-3)/kPa; P = 0.02). This result was based on a higher blood pressure in microalbuminuric patients. After correction for the difference in blood pressure, the distensibility coefficients were similar in the three groups. In the two diabetic patient groups taken together, age, blood pressure, female sex, diabetes duration, and cigarette smoking were determinants of a decreased distensibility.
Blood pressure is a major determinant of increased arterial stiffness in microalbuminuric IDDM patients. Increased arterial stiffness may contribute to the accelerated progression of complications if concomitant hypertension exists.
Abstract
Background
Invasive pneumococcal disease (IPD) remains prevalent despite the use of conjugate vaccines over the past 20 years. Serotype replacement, limited efficacy for certain vaccine ...serotypes, and the incomplete coverage of disease in the elderly perpetuate the problem. Novel vaccines with broader serotype coverage are needed. To this end, a novel 24-valent pneumococcal vaccine, ASP3772, was developed based on a multiple antigen-presenting system (MAPS) platform. This platform takes advantage of the high affinity, noncovalent binding between biotin and rhizavidin to create a complex of 24 pneumococcal polysaccharides and a fusion of two pneumococcal proteins.
Methods
Healthy adults aged 18-64 years were randomized into this active-controlled, observer-blinded, dose-escalation study to evaluate the safety, tolerability, and immunogenicity of ASP3772 at three dose levels compared to Prevnar13 (PCV13) (target 30 per dose group). The primary endpoints were safety and reactogenicity. Immunogenicity was evaluated secondarily by measuring serotype-specific immunoglobulin G (IgG) and opsonophagocytic activity (OPA).
Results
Ninety-three subjects received ASP3772 at 1 of 3 doses and 33 received PCV13. Safety and reactogenicity were similar between the ASP3772 and PCV13 arms. Most frequently reported local reactions were tenderness and pain after injection occurring within the first 2 days. Most frequent systemic reactions were fatigue, headache, and myalgia, without a clear dose response. Treatment-emergent adverse events were few and most were mild to moderate in severity. No clinically relevant abnormalities were observed in vital signs, ECGs, and laboratory parameters. Robust IgG and OPA responses were observed for serotypes shared with PCV13, as well as serotypes unique to ASP3772.
Conclusion
ASP3772 vaccine was safe, well tolerated in adults aged 18-64 years, and exhibited robust immunogenicity that extended beyond serotypes shared with PCV13.
Disclosures
Gurunadh Chichili, PhD, Astellas Pharma Inc (Employee) Ronald Smulders, MD, PhD, Astellas Pharma Inc (Employee) Vicki Santos, n/a, Astellas Pharma Inc (Employee) Beth Cywin, n/a, Astellas Pharma Inc (Employee) Laura Kovanda, n/a, Astellas Pharma Inc (Employee) Frank J. Malinoski, MD, PhD, Affinivax Inc (Employee) Shite Sebastian, PhD, Affinivax Inc (Employee) George R. Siber, MD, Affinivax Inc (Consultant, Employee, Shareholder) Rick Malley, MD, Affinivax Inc (Board Member, Consultant, Employee)
Dysfunction of the vascular endothelium is considered an early step in the development of diabetic angiopathy. Hyperglycaemia results in endothelial dysfunction, both through direct effects of ...glucose and through formation of advanced glycosylation end-products (AGEs). We hypothesized that the effects of glucose and AGEs on endothelial function in insulin-dependent diabetes mellitus (IDDM) are distinct and are reflected by distinct plasma markers of endothelial function. We therefore measured plasma levels of von Willebrand factor (vWF), soluble (s) E-selectin and vascular cell adhesion molecule-1 (sVCAM-1), and evaluated the relationship with HbA1c and urinary excretion of pentosidine, an AGE product, in 56 patients with IDDM. Urinary pentosidine excretion was higher in the diabetic than in a control group (n = 60) of similar age (P < 0.0001) and showed a steeper increase with age (P < 0.02 vs controls). In the diabetic group, sE-selectin was correlated to HbA1c (r = 0.52, P < 0.0001), whereas sVCAM-1 was not (r = 0.11, P = 0.47). In contrast, sVCAM-1 showed a trend towards a correlation with log (pentosidine excretion) (r = 0.27, P = 0.06), whereas sE-selectin did not (r = -0.16, P = 0.27). Log(vWF) was correlated to HbA1c (r = 0.50, P < 0.0001) and tended to correlate with log (pentosidine excretion) (r = 0.25, P = 0.07). Multivariate analyses with both pentosidine and HbA1c as independent variables showed significant associations of sE-selectin with HbA1c, of sVCAM-1 with pentosidine, and of log(vWF) with both HbA1c and pentosidine (all P-values < 0.02). Our results imply that the effects of glucose and AGEs on the endothelium can be reflected by distinct endothelial markers. Plasma sE-selectin may reflect short-term effects of glucose on the endothelium, sVCAM-1 the effects of AGEs, and vWF the combined effect of glucose and AGEs.
Hsp20 is one of the newly described members of the mammalian small heat‐shock protein (sHsp) family. It occurs most abundantly in skeletal muscle and heart. We isolated clones for Hsp20 from a rat ...heart cDNA library, and expressed the protein in Escherichia coli to characterize this little known sHsp. Recombinant Hsp20 displayed similar far‐ultraviolet circular dichroism spectra as the most closely related sHsp, αB‐crystallin, but was less heat stable, denaturing upon heating to 50 +C. While other mammalian recombinant sHsps form large multimeric complexes, Hsp20 occurs in two complex sizes, 43‐kDa dimers and 470‐kDa multimers. The ratio between the two forms depends on protein concentration. Moreover, Hsp20 has a much lower chaperone‐like activity than αB‐crystallin, as indicated by its relatively poor capacity to diminish the reduction‐induced aggregation of insulin B chains. Hsp20 is considerably shorter at the C‐terminus and less polar than other sHsps, but 1H‐NMR spectroscopy reveals that the last 10 residues are flexible, as in the other sHsps. Our findings suggest that Hsp20 is a special member of the sHsp family in being less heat stable and tending to form dimers. These properties, together with the shorter and less polar C‐terminal extension, may contribute to the less effective chaperone‐like activity.
The rudimentary eyes of the mole rat Spalax ehrenbergi have lost their visual function, but are still required for the control of circadian rhythms. It has previously been found that αA-crystallin, a ...major eye lens protein in other mammals, evolved much faster in the mole rat than in rodents with normal vision. Yet, although mole rat αA-crystallin seems superfluous as a lens protein, its rate of change is still much slower than that of pseudogenes, suggesting some remaining function. The authors therefore studied the structure and function of recombinant mole rat αA-crystallin. Circular dichroism (CD), tryptophan fluorescence and gel permeation analyses indicated that the overall structure and stability of mole rat αA-crystallin are comparable to that of rat αA-crystallin. However, the chaperone-like activity of mole rat αA-crystallin is considerably lower than that of its rat orthologue. Two-dimensional NMR spectroscopy of mole rat αA-crystallin suggests that this may be in part due to a diminished flexibility of the C-terminal extension, which is thought to be important for the chaperoning capacity. Overall, mole rat αA-crystallin appears to still be a viable protein, confirming that it has some as yet elusive role, despite the loss of its primary lens function.
Background
Ipragliflozin (ASP1941), a potent selective sodium glucose co-transporter 2 inhibitor, is in development for the treatment of type 2 diabetes mellitus. Ipragliflozin is primarily ...eliminated via conjugation by the liver as five pharmacologically inactive metabolites (M1, M2, M3, M4 and M6). This study evaluated the effect of moderate hepatic impairment on the pharmacokinetics of ipragliflozin and its metabolites.
Methods
In an open-label, single-dose, parallel-group study, 16 subjects (eight with moderate hepatic impairment Child-Pugh score 7–9 and eight healthy, matched controls) received a single oral dose of 100-mg ipragliflozin. Plasma concentrations of ipragliflozin and its metabolites were determined. Adverse events (AEs) and other clinical laboratory parameters were monitored.
Results
All subjects completed the study. Least-squares geometric mean ratios (GMRs) (90 % confidence interval CI) for maximum plasma concentration (
C
max
) and area under the plasma concentration–time curve from time zero to infinity (AUC
∞
) of ipragliflozin were 127 % (93–173 %) and 125 % (94–166 %), respectively, in moderate hepatic impairment versus controls. No changes in elimination half-life and protein binding of ipragliflozin were observed in moderate hepatic impairment subjects. Least-squares GMRs for
C
max
and AUC
∞
of M2, the major metabolite, were respectively 95 % (68–133 %) and 100 % (77–130 %) in moderate hepatic impairment versus controls. No deaths, other serious AEs or AEs leading to discontinuation occurred.
Conclusions
Moderate hepatic impairment had no clinically relevant effects on the single-dose pharmacokinetics of ipragliflozin and its major metabolite, M2. A single oral dose of ipragliflozin, 100 mg, was well tolerated in both healthy subjects and those with moderate hepatic impairment.
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