Passive leg movement (PLM) offers a robust method for assessing vascular function; however, the interactions among age, endothelial-mediated vasodilatory mechanisms, and exercise training-induced PLM modulation remain poorly understood. To address these gaps, the vasodilatory responses to PLM, quantified as leg vascular conductance (LVC) dynamics, were measured in younger (n = 9, 25 ± 4 yr) and older males (n = 9, 69 ± 5 yr) before and after 8 wk of single-leg knee-extension exercise training. Femoral arterial drug infusions pharmacologically dissected the contribution of the prostaglandin (PG) and epoxyeicosatrienoic acids (EETs) pathways to the residual, nitric oxide (NO)-independent component of the PLM vasodilatory response. Interrogation of these vasodilatory pathways was assessed by PLM under three conditions: control (CON), inhibition of nitric oxide synthase (NOS) alone (N[G]-monomethyl-l-arginine, l-NMMA), and combined inhibition of NOS, cyclooxygenase (ketorolac tromethamine, KET), and cytochrome P450 (fluconazole, FLUC) (l-NMMA + KET + FLUC). Exercise training improved the PLM vasodilatory (LVC area under the curve) response in younger (4.3 ± 1.4 to 7.1 ± 4.3 mL·mmHg[-1], P < 0.05) but not older (2.2 ± 1.4 to 2.4 ± 1.2 mL·mmHg[-1], P = 0.97) males. In younger males, both l-NMMA and l-NMMA + KET + FLUC elicited significant (both P < 0.05) and similar (P = 0.99) reductions in the PLM vasodilatory response, with no effect of exercise training (P = 0.90). Neither l-NMMA nor l-NMMA + KET + FLUC attenuated the PLM vasodilatory response in older males before or after exercise training (P = 0.68 and P = 0.51, respectively). Together, these results indicate 8 wk of single-leg knee-extension exercise training improves the vasodilatory response to PLM in younger, but not older males, and does not alter the contribution of NO or the combined contribution of PG and EETs to PLM-induced vasodilation.NEW & NOTEWORTHY This study examined the impact of age and exercise training on vasodilatory mechanisms associated with passive leg movement (PLM), including nitric oxide (NO), prostaglandins (PGs), and endothelial-derived hyperpolarizing factors (EDHFs) in younger and older adult males. Following 8 wk of single-leg knee-extension exercise training, PLM was improved in younger but not older males; however, the improvement was not associated with altered contribution from NO, PG, or EDHF, suggesting other vasodilatory mechanisms may be involved.

Ketorolac tromethamine (KT) is a potent nonsteroidal anti-inflammatory drug (NSAID) used for moderate to severe pain management. Its short elimination half-life necessitates frequent dosing, which can reduce patient compliance. The objective of this study was to formulate, develop, and optimize a novel biphasic-release tablet-in-tablet (TIT) system for KT to provide immediate pain relief followed by extended drug release. A TIT system was designed, comprising an immediate-release (IR) outer layer and an extended-release (ER) core matrix. The ER core was optimized using a 32 full factorial design, with the amounts of HPMC K100M and HPMC K4M as independent variables. Formulations were evaluated for pre- and post-compression parameters, drug-excipient compatibility, and in vitro drug release. The drug release kinetics and mechanism were analyzed using various mathematical models. The optimal ER core formulation (F1) exhibited a drug release of 4.6% at 0.5 h and 66.1% at 12 h, closely matching the theoretical profile (similarity factor f2 = 51). Release kinetics followed the first-order model and the Korsmeyer-Peppas model indicated an anomalous (non-Fickian) release mechanism (n = 0.831). The corresponding TIT formulation (F11) demonstrated desired physicochemical properties: hardness of 75 N, friability of 0.59%, and rapid outer layer disintegration (<50 s). The TIT provided an initial burst release (~30%) within 30 minutes, followed by sustained release exceeding 90% over 24 hours. This TIT system represents a promising alternative to conventional KT tablets for effective pain management.

Unicompartmental knee arthroplasty (UKA) serves as the primary surgical treatment for isolated unicompartmental knee osteoarthritis. Clinical data of 108 patients who underwent UKA at Yueyang People's Hospital from January 2020 to December 2024 were retrospectively screened. After strict case exclusion, 102 patients were categorized into Group A (ropivacaine combined with morphine and compound betamethasone, n = 52) and Group B (ropivacaine combined with ketorolac tromethamine and epinephrine, n = 50). Propensity score matching (PSM) was subsequently performed to balance baseline characteristics, resulting in 46 patients per group after matching. Primary outcomes consisted of resting and active visual analog scale (VAS) scores, 48 h postoperative opioid consumption, and inflammatory biomarkers, including C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), white blood cell (WBC), and neutrophil (NEUT) levels. Secondary outcomes covered knee range of motion (ROM), time to initial postoperative ambulation, Knee Injury and Osteoarthritis Outcome Score (KOOS), Barthel Index (BI), and postoperative adverse events. Baseline parameters were well balanced between the two groups following PSM (all P > 0.05). At 48 h postoperatively, Group B presented significantly decreased resting and active VAS scores, as well as lower 48 h opioid consumption (all P < 0.001). Milder elevations of CRP, ESR, WBC, and NEUT were observed in Group B (all P < 0.001). Additionally, Group B demonstrated superior knee functional recovery reflected by better ROM, higher KOOS and BI scores, and shorter time to first ambulation (all P < 0.001). No significant intergroup difference was detected in the incidence of adverse events (P = 0.503). In this single-center retrospective cohort, the ropivacaine-ketorolac-epinephrine cocktail demonstrates superior analgesic and anti-inflammatory properties with a noninferior safety profile. Limited by the single-center, retrospective design, this regimen is preliminarily considered a promising analgesic alternative for UKA patients, and further large-sample, multicenter, prospective studies are required for validation.

Pain is particularly intolerable for children, and the analgesic regimen must be carefully managed, as systemic delivery may lead to serious side effects to growth and development of children. Therefore, the research and development of pain-relieving formulations and administration routes specifically tailored for children are both meaningful and essential to enhance treatment compliance. In this study, ketorolac tromethamine (KT)-loaded hydrogel-forming microneedle (MN) were designed, prepared, and evaluated using methacrylic anhydride -modified hyaluronic acid as the MN matrix. Conical, tetrapyramidal and candle-like tip geometries with distinct profiles were fabricated. The relationship between tip geometry and mechanical strength was systematically evaluated, revealing that the candle-like MN (KT-TMN) exhibits superior mechanical performance. Comprehensive characterization was conducted on the morphology, mechanical properties, insertion capability, safety profile, and drug release kinetics of the MN system. Results from the acetic acid-induced writhing test and hot plate test demonstrated that KT-TMN significantly prolonged pain latency and reduced writhing responses in mice, exhibiting an analgesic efficacy comparable to intravenous administration of KT. In vivo pharmacokinetic studies revealed that KT-TMN enabled stable and sustained drug release, highlighting its potential for transdermal delivery of KT as a pediatric analgesic agent.

Introduction Postoperative pain is a common complication following root canal treatment (RCT) in teeth with symptomatic irreversible pulpitis and apical periodontitis. This study aimed to compare the effects of ketorolac tromethamine, 100% Moringa oleifera leaf extract, 50% Azadirachta indica leaf extract, and 5.25% sodium hypochlorite, as final root canal irrigants, on postoperative pain intensity and Substance P expression in patients with symptomatic irreversible pulpitis and apical periodontitis. Materials and methods In this prospective observational study, 84 patients with maxillary or mandibular molars diagnosed with symptomatic irreversible pulpitis and apical periodontitis were divided into four groups (21 patients each) based on the final irrigant used during single-visit RCT. Preoperative and postoperative Substance P levels were measured in pulp and periapical blood/exudate samples using enzyme-linked immunosorbent assay (ELISA). Pain intensity was assessed preoperatively and 24 hours postoperatively using a visual analog scale (VAS). Statistical analyses included paired t-tests, Wilcoxon signed-rank tests, one-way analysis of variance (ANOVA), Kruskal-Wallis tests, post-hoc comparisons, and Pearson correlation. Results All irrigants were associated with significant intragroup reductions in both Substance P levels and pain intensity at 24 hours (p = 0.001). Preoperative Substance P levels showed significant intergroup differences, which largely resolved postoperatively. Postoperative pain scores differed significantly between groups, with A. indica being associated with higher pain than the other three irrigants, which demonstrated comparable outcomes. No consistent correlation was found between Substance P levels and pain scores. Conclusion All tested irrigants effectively reduced postoperative pain and Substance P expression. Sodium hypochlorite, ketorolac tromethamine, and M. oleifera leaf extract provided similar analgesic efficacy, which was superior to that of A. indica. Alternative irrigants may serve as viable adjuncts in clinical practice, particularly when enhanced biocompatibility or anti-inflammatory effects are desired.