Pharmacokinetics, safety and tolerability of empagliflozin, a sodium glucose cotransporter 2 inhibitor, in patients with hepatic impairment.

AIMS: This open-label, parallel-group study investigated the effect of various degrees of hepatic impairment on the pharmacokinetics, safety and tolerability of the sodium glucose cotransporter 2 inhibitor empagliflozin. METHODS: Thirty-six subjects [8 each with mild, moderate or severe hepatic impairment (Child-Pugh classification), and 12 matched controls with normal hepatic function] received a single 50 mg dose of empagliflozin. RESULTS: Empagliflozin was rapidly absorbed. After reaching peak levels, plasma drug concentrations declined in a biphasic fashion. Compared with subjects with normal hepatic function, geometric mean ratios (90% confidence interval) of AUC(0-∞) and C(max) were 123.15% (98.89-153.36) and 103.81% (82.29-130.95), respectively, in patients with mild hepatic impairment, 146.97% (118.02-183.02) and 123.31% (97.74-155.55), respectively, in patients with moderate hepatic impairment, and 174.70% (140.29-217.55) and 148.41% (117.65-187.23), respectively, in patients with severe hepatic impairment. Adverse events, all mild or moderate in intensity, were reported in three subjects with moderate hepatic impairment, two subjects with severe hepatic impairment and six subjects with normal hepatic function. CONCLUSIONS: Empagliflozin was well tolerated in subjects with hepatic impairment. Increases in empagliflozin exposure were less than twofold in patients with hepatic impairment; therefore no dose adjustment of empagliflozin is required in patients with hepatic impairment.

Randomised clinical trial: macrogol/PEG 3350+electrolytes versus prucalopride in the treatment of chronic constipation -- a comparison in a controlled environment.

BACKGROUND: Constipation is a common condition for which PEG 3350 is an established treatment and prucalopride has recently been approved for this indication. AIM: To compare the efficacy, safety and impact on quality of life (QoL) of PEG 3350 plus electrolytes (PEG 3350+E) vs. prucalopride in females with chronic constipation (CC) in whom laxatives have previously failed to provide adequate relief. METHODS: In this single-centre, randomised, double-blind, double-dummy study, patients with CC [<3 spontaneous complete bowel movements (SCBM)/week] remained in a controlled environment and received either a 26 g split dose of PEG 3350+E (N = 120) or 1-2 mg prucalopride (N = 120) daily for 28 days following a 14-day run-in period. The primary endpoint was the proportion of patients having ≥3 SCBMs during the last treatment week. RESULTS: Non-inferiority of PEG 3350+E to prucalopride was demonstrated in the per-protocol population [difference, 10.1% (66.67% vs. 56.52%), 97.5% lower confidence interval (CI) -2.7%, above the preset margin of -20%] and approached superiority in the modified intent-to-treat population (difference, 9.8%, 97.5% lower CI, -3.1%). Statistically significant differences in favour of PEG 3350+E were observed for most secondary variables (bowel movements, stool weight, consistency, time to next SCBM, patient perception of straining and completeness of defecation). Colonic transit time was dramatically reduced in both arms. Both treatments were well tolerated. CONCLUSION: PEG 3350+E was at least as effective as and generally better tolerated than prucalopride as a treatment for chronic constipation in this study population (NCT01251822; http://www.clinicaltrials.gov).

Side-branch growth in two-dimensional dendrites. II. Phase-field model.

The development of side-branching in solidifying dendrites in a regime of large values of the Peclet number is studied by means of a phase-field model. We have compared our numerical results with experiments of the preceding paper and we obtain good qualitative agreement. The growth rate of each side branch shows a power-law behavior from the early stages of its life. From their birth, branches which finally succeed in the competition process of side-branching development have a greater growth exponent than branches which are stopped. Coarsening of branches is entirely defined by their geometrical position relative to their dominant neighbors. The winner branches escape from the diffusive field of the main dendrite and become independent dendrites.

Side-branch growth in two-dimensional dendrites. I. Experiments.

The dynamics of growth of dendrites' side branches is investigated experimentally during the crystallization of solutions of ammonium bromide in a quasi-two-dimensional cell. Two regimes are observed. At small values of the Peclet number a self-affine fractal forms. In this regime it is known that the mean lateral front grows as t(0.5). Here the length of each individual branch is shown to grow (before being screened off) with a power-law behavior t (alpha(n)). The value of the exponent alpha(n) (0.5< or = alpha(n) < or =1) is determined from the start by the strength of the initial disturbance. Coarsening then takes place, when the branches of small alpha(n) are screened off by their neighbors. The corresponding decay of the growth of a weak branch is exponential and defined by its geometrical position relative to its dominant neighbors. These results show that the branch structure results from a deterministic growth of initially random disturbances. At large values of the Peclet number, the faster of the side branches escape and become independent dendrites. The global structure then covers a finite fraction of the two-dimensional space. The crossover between the two regimes and the spacing of these independent branches are characterized.

Numerical study of the shape and integral parameters of a dendrite.

We present a numerical study of sidebranching of a solidifying dendrite by means of a phase-field model. Special attention is paid to the regions far from the tip of the dendrite, where linear theories are no longer valid. Two regions have been distinguished outside the linear region: a first one in which sidebranching is in a competition process and a second one further down where branches behave as independent of each other. The shape of the dendrite and integral parameters characterizing the whole dendrite (contour length and area of the dendrite) have been computed and related to the characteristic tip radius for both surface tension and kinetic dominated dendrites. Conclusions about the different behaviors observed and comparison with available experiments and theoretical predictions are presented.

Sidebranching induced by external noise in solutal dendritic growth.

We have studied sidebranching induced by fluctuations in dendritic growth. The amplitude of sidebranching induced by internal (equilibrium) concentration fluctuations in the case of solidification with solutal diffusion is computed. This amplitude turns out to be significantly smaller than values reported in previous experiments. The effects of other possible sources of fluctuations (of an external origin) are examined by introducing nonconserved noise in a phase-field model. This reproduces the characteristics of sidebranching found in experiments. Results also show that sidebranching induced by external noise is qualitatively similar to that of internal noise, and it is only distinguished by its amplitude.