Josai International University

Static stretching, a common method used to improve flexibility, has traditionally involved repeated stretching until reaching the initial or pre-determined stretching angle or torque. However, recent recommendations suggest that stretching until reaching a new maximal angle may offer greater benefits owing to increased stretching intensity. This study aimed to examine the acute effects of resetting the static stretching intensity on flexibility.

In this randomized crossover trial, 14 healthy participants performed 300-s of static stretching of the right hamstrings randomly under two conditions: resetting the stretching intensity at new maximal knee extension angles every 30 s (10 × 30-s) or no-resetting (1 × 300-s). The outcomes assessed included range of motion (ROM), passive torque (PT) at pain onset, passive stiffness before and after stretching, and stretching angle during stretching.

During the 10 × 30-s condition, stretching angle was increased gradually (p < 0.05). Significant improvements were observed in ROM, PT at pain onset, and passive stiffness (p < 0.05) after stretching under both conditions. Moreover, the relative improvement in these parameters was greater under the 10 × 30-s condition than under the 1 × 300-s condition (p < 0.05).

These findings suggest that resetting stretching intensity can enhance flexibility, possibly due to the increased stretching intensity, underscoring the importance of individualized stretching approaches to optimize flexibility outcomes.

Dolutegravir is a clinically confirmed inhibitor of organic cation transporter 2 (OCT2)/SLC22A2; however, its in vitro IC₅₀ varies widely across studies. Using OCT2-expressing human embryonic kidney 293 cells, we investigated experimental conditions affecting IC₅₀ determination. Based on clinical drug-drug interaction (DDI) data, an inhibition constant (K_i) of 0.0890 μM was estimated through pharmacokinetic (PK) modeling using both plasma concentration and urinary excretion profiles of metformin. In vitro, dolutegravir was found to be a noncompetitive inhibitor of OCT2. IC₅₀ values increased with longer uptake times. A 2.9-fold difference was already observed between 1-minute and 5-minute uptake, and further extension to 30 minutes resulted in a 27-fold increase, attributable to the inhibition of both uptake and efflux processes. Preincubation of the cells with dolutegravir for 30 minutes additionally enhanced its inhibitory effect, resulting in a 5.8-fold decrease in IC₅₀. Similar uptake time dependency was observed with other inhibitors (cimetidine and pyrimethamine). However, the extent of variability differed among metformin, N¹-methylnicotinamide, atenolol, frovatriptan, and sumatriptan, likely reflecting differences in cellular kinetics. The lowest in vitro IC₅₀ of dolutegravir for metformin uptake (0.126 μM), obtained under a 1-minute uptake and 30-minute preincubation condition, closely matched the estimated in vivo K_i. DDI predictions using in vitro IC₅₀ values suggested repeated dolutegravir administration could raise the area under the curve of OCT substrates, such as atenolol, nadolol, and sulpiride beyond regulatory thresholds. In conclusion, we identified optimized in vitro conditions that yield IC₅₀ values consistent with in vivo K_i estimates, offering valuable guidance for predicting OCT2-mediated DDIs. SIGNIFICANCE STATEMENT: This study identified experimental conditions affecting the IC₅₀ variability of dolutegravir as an organic cation transporter 2 inhibitor. These findings offer valuable insights for improving in vitro to in vivo drug-drug interaction predictions and optimizing inhibition experiments for transporter-mediated drug-drug interactions.

We investigated the immediate effects of two types of self-stretching methods to clarify their efficacy on flexor digitorum longue (FDL) and tibialis posterior muscle (TP) stiffness. In 'conventional self-stretching', the subject used the strength of their own hands to dorsiflex the toes and dorsiflex and evert the ankle. In 'weight-bearing stretching', the participants instead weight-bearing to facilitate the dorsiflexion. In this crossover trial, the participants were 13 healthy men. They performed either conventional self-stretching, weight-bearing stretching, or a control trial on different days. Before and then after the intervention, we measured the shear modulus of the FDL and TP using shear wave elastography as an index of muscle stiffness. To compare the changes in the shear modulus following the different stretching methods, we performed a two-way repeated measures analysis of variance with Holm correction with type of intervention and time of measurement as variables. A significant interaction was found for the shear modulus of the FDL. After weight-bearing stretching, the shear modulus was significantly lower than before the intervention and at the same timing in the control trial (p < 0.05). Conversely, no significant differences in the shear modulus of the FDL were observed before or after the control trial and conventional self-stretching (p > 0.05). Neither the main effects nor interactions were observed for the shear modulus of the TP, and no effect was observed by any interventions (p > 0.05). Weight-bearing stretching is suggested by these results to have some efficacy for the stretching of the FDL.