Pharmaprojects No. 3498

Achieving Minimal-to-No Pain in Women with Endometriosis Treated with Relugolix Combination Therapy: SPIRIT Extension Trial.

Lukes Andrea S AS, Venturella Roberta R, Dynowski Krzysztof K, Wagman Rachel B RB et al.

Relugolix is an oral, non-peptide gonadotropin-releasing hormone receptor antagonist administered as once-daily combination therapy (relugolix-CT; 40 mg relugolix, 1 mg estradiol, 0.5 mg norethindrone acetate) to reduce endometriosis symptoms while potentially minimizing hypoestrogenic effects. In the 24-week SPIRIT1&2 studies, relugolix-CT significantly improved endometriosis-associated pain versus placebo, with improvements sustained over the 80-week open-label Long-Term Extension (LTE; all received relugolix-CT). This post hoc analysis of SPIRIT1, 2 and LTE data assessed temporal effects of relugolix-CT on minimal-to-no pain, amenorrhea, and analgesic-free status. This analysis included women who received relugolix-CT, delayed relugolix-CT, or placebo in SPIRIT 1 or 2 and entered the LTE. Cumulative probability and median time to minimal-to-no pain for dysmenorrhea and non-menstrual pelvic pain (NMPP), amenorrhea, and analgesic-free status were assessed. In SPIRIT1&2, 802/1261 women entered the LTE; 501/802 completed 104-week treatment. Median time to minimal-to-no pain for dysmenorrhea was 8 weeks for relugolix-CT and delayed relugolix-CT and was not reached with placebo within 24 weeks; cumulative probability of minimal-to-no dysmenorrhea at Week 24 was 82.5%, 86.4%, and 22.4%, respectively, increasing to 95.3%, 95.9%, and 94.9% at Week 104. Amenorrhea paralleled dysmenorrhea. Median time to minimal-to-no NMPP was 32, 28, and 40 weeks in the relugolix-CT, delayed relugolix-CT, and placebo groups, respectively; cumulative probability of minimal-to-no NMPP was 42.6%, 42.2%, and 28.9% at Week 24, increasing to 70.5%, 74.7%, and 74.3% at Week 104. In the relugolix-CT group, median time to analgesic-free status was 16 weeks; 68.8% and 94.9% were analgesic-free at Weeks 24 and 104. Delayed relugolix-CT results were similar. Analgesic-free status improved in the placebo group after relugolix-CT initiation. In this post hoc analysis, women receiving relugolix-CT for up to 104 weeks had rapid dysmenorrhea improvement with amenorrhea and reduced analgesic use, with longer treatment associated with further NMPP reduction.

Ribes fasciculatum Leaf Water Extract Enhances Macrophage Immune Responses via TLR4-Mediated JNK and NF-κB Activation in RAW264.7 Cells.

Park So Jung SJ, Choi Jeong Won JW, Choi Hyeok Jin HJ, Im Gyeong Eun GE et al.

This study investigated the immunostimulatory activity and underlying mechanism of Ribes fasciculatum leaf water extract in RAW264.7 macrophages. Among extracts prepared using water or ethanol-containing solvents, only the water extract induced NO production. Further evaluation of extraction temperature and time identified the extract prepared at 20°C for 24 h (RFL-DW20) as the most active sample under the tested conditions, with NO-inducing activity increasing after 12 h of extraction and reaching a plateau by 24 h. RFL-DW20 increased NO and PGE2 production, upregulated iNOS and COX-2 expression, and enhanced IL-6 and TNF-α production without cytotoxicity. RFL-DW20 also increased IL-1β mRNA expression but did not significantly alter extracellular IL-1β levels. RFL-DW20 also increased neutral red uptake, indicating enhanced macrophage functional activity. The immunostimulatory effects of RFL-DW20 were strongly inhibited by TAK-242, SP600125, and BAY 11-7082, suggesting the involvement of TLR4, JNK, and NF-κB signaling. RFL-DW20 activated MAPK and NF-κB signaling, including rapid IκBα phosphorylation/degradation and p65 phosphorylation, while pharmacological inhibition identified JNK and NF-κB as major functional mediators of the NO response. TAK-242 markedly suppressed RFL-DW20-induced JNK and p65 phosphorylation. Ethanol precipitation further enriched its NO-inducing activity. These findings suggest that RFL-DW20 activates macrophages through the TLR4/JNK/NF-κB signaling axis and may serve as a natural immune-stimulating material.

Medicines do no good if people don't take them.

Vargas-Parada Laura L

Efficacy and safety of anticoagulation for pediatric cerebral sinovenous thrombosis: systematic review and meta-analysis.

Azzam Muayad M, Kawtharany Hassan H, Betensky Marisol M, Alkhader Aseel A et al.

We performed this systematic review and meta-analysis to assess the efficacy and safety of anticoagulation therapy versus no anticoagulation in pediatric patients with cerebral sinovenous thrombosis (CSVT). Eligible studies included pediatric patients with CSVT that compared anticoagulation to no anticoagulation and reported on at least one relevant outcome (mortality, neurological deficit, thrombus resolution, recurrence, and bleeding). Meta-analysis reported risk ratios (RR) or differences (RD) (95% CIs) and absolute effects per 1000 patients. Risk of bias was assessed using ROBINS-I, and the certainty of evidence was evaluated with GRADE. After removing duplicates, we screened 8925 records independently and in duplicate, from which 12 nonrandomized studies of intervention were included. Compared with no anticoagulation, anticoagulation may be associated with lower risk of overall mortality RR 0.14 (0.05-0.39) (4 studies, n = 448), lower risk of neurological deficits RD -0.13 (-0.39 to 0.13) (6 studies, n = 462), and higher rates of complete and partial resolution RR 1.25 (0.94-1.66) (7 studies, n = 150). Recurrence RD 0 (-0.11 to 0.11) (2 studies, n = 56) and bleeding RD 0.03 (-0.09 to 0.15) (5 studies, n = 95) may be comparable between anticoagulation versus no anticoagulation. We judged outcomes to be very low to low certainty of evidence due to risk of bias, concerns from confounding, and imprecision from small sample sizes. To conclude, we show in this systematic review that anticoagulation therapy in pediatric patients with CSVT may be associated with better outcomes (reduced mortality, neurological deficits, and higher rate of thrombus resolution) with little to no effect on bleeding and recurrence.