zolpidem tartrate (Intermezzo / zolpidem, TransOral)

Periodontitis aggravates high-fat diet-induced MASLD via gut microbiota dysbiosis and metabolic dysfunction in mice.

Liu Xinchan X, Che Zhenzhen Z, Hou Yubo Y, Yu Weixian W et al.

Periodontitis has been recognized as a contributing factor in the development of metabolic dysfunction-associated steatotic liver disease (MASLD). However, the precise mechanisms through which periodontitis influences the pathogenesis of MASLD remain unclear. This study aimed to investigate the association between experimental periodontitis and MASLD severity and to explore the potential underlying mechanisms using a ligature-induced periodontitis model under low-fat diet (LFD) and high-fat diet (HFD) conditions. A total of 40 mice were divided into four groups: low-fat diet control group (LFD-Ctrl), low-fat diet with periodontitis group (LFD-Perio), high-fat diet control group (HFD-Ctrl), and high-fat diet with periodontitis group (HFD-Perio), with 10 mice initially assigned to each group. Mice were fed an HFD for 12 weeks to establish the MASLD model, followed by ligature-induced periodontitis for 4 weeks. Periodontal inflammation and alveolar bone loss were assessed using micro-computed tomography (Micro-CT), hematoxylin and eosin (H&E) staining, and tartrate-resistant acid phosphatase (TRAP) staining, while MASLD severity was evaluated via hepatic H&E staining, Oil Red O staining, periodic acid-Schiff (PAS) staining, Masson's Trichrome staining, nonalcoholic fatty liver disease activity score (NAS), alpha-smooth muscle actin (α-SMA) expression, pericellular fibrosis, and serum lipid and liver enzyme measurements. Compared with HFD-Ctrl mice, HFD-Perio mice exhibited aggravated MASLD-related phenotypes, including elevated fasting blood glucose, significantly increased homeostatic model assessment for insulin resistance (HOMA-IR) (2.89 ± 0.67 vs. 1.93 ± 0.26, P < 0.0001), higher nonalcoholic fatty liver disease activity score (NAS) (4.57 ± 0.71 vs. 2.30 ± 0.33, P < 0.01), and more pronounced pericellular fibrosis. Gut microbiota analysis showed that the Firmicutes/Bacteroidota ratio was further increased in HFD-Perio mice compared with HFD-Ctrl mice (9.39 ± 2.82 vs. 5.48 ± 1.98, P < 0.05), accompanied by enrichment of the genus Helicobacter. These findings indicate that experimental periodontitis aggravates HFD-induced MASLD phenotypes, potentially via metabolic dysregulation, liver inflammation and fibrosis, and gut microbiota dysbiosis, highlighting the need for further studies to clarify whether periodontal health influences MASLD progression.

Zolpidem for Severe Insomnia Associated With Delirium in Critical Illness.

Gunther Matthew M, Maldonado Jose R JR, Jiang Shixie S

Hot-water extract of defatted Perilla frutescens seed residue suppresses osteoclast differentiation and improves bone-related parameters in ovariectomized mice.

Asano Hiroyuki H, Nishimoto Sogo S

The defatted residue of Perilla frutescens seeds, a by-product of edible oil production, remains largely underutilized in food applications. This study investigated the effects of a hot-water extract derived from this residue on osteoclast differentiation and bone-related changes. In bone marrow-derived macrophages, the extract inhibited receptor activator of nuclear factor-κB ligand-induced osteoclast differentiation, as evidenced by the reduced formation of tartrate-resistant acid phosphatase-positive multinucleated cells and decreased tartrate-resistant acid phosphatase activity, without significantly affecting cell viability. In ovariectomized mice, the extract increased trabecular region length and cortical bone thickness. In a separate experiment, it enhanced femoral mechanical strength in a three-point bending test. High-performance liquid chromatography analysis identified rosmarinic acid and salviaflaside in the extract. These findings suggest that defatted Perilla frutescens seed residue may be a functional resource for improving bone health.

TAR-0520, a new candidate in oncodermatology: Results of a phase 1 program in healthy volunteers.

Andres Philippe P, Winckle Gareth G, Lamquin Alexandra A, Czernielewski Janusz J

TAR-0520 gel is a new topical formulation of brimonidine tartrate designed to prevent chemotherapy-induced skin toxicities. We report here the main outcomes of the phase 1 program which included two double-blind, randomized trials in healthy volunteers (TAR006 and TAR012) and were performed to evaluate the safety, local tolerability, pharmacokinetics, and pharmacodynamics (PD) of TAR-0520 gel. In TAR006, participants received four concentrations of TAR-0520 gel (0.5%, 0.75%, 1% and 1.5% of Brimonidine tartrate), placebo, or active comparator (Mirvaso® Galderma International, France) applied daily to the chest for 21 days, while TAR012 evaluated TAR-0520 gel 1% and 1.5% on the chest and face over the same duration. Local tolerance was assessed daily in both studies using mean cumulative irritation index and maximum irritation score as key endpoints. Skin blanching was assessed via chromameter-measured reductions in skin redness as a marker of vasoconstriction and product potency. In TAR006, systemic exposure to brimonidine tartrate was assessed from blood samples collected in a separate cohort treated with TAR-0520 gel 1%. Overall, 28 participants were randomized in TAR006 and 26 were randomized in TAR012. Both studies showed excellent local tolerance with 50 healthy volunteers reporting no evidence of irritation with any treatment and four patients reporting barely perceptible minimal erythema. No adverse events related to TAR-0520 gel were reported. Minimal systemic absorption was observed that was not considered to be clinically relevant. PD studies indicated dose-dependent vasoconstriction with once-daily use lasting over 24 h. Under the conditions of these studies, TAR-0520 gel presents a very favorable safety profile with little to no local irritation and insignificant systemic exposure. Allowing a superficial skin vasoconstriction over a period of 24 h, it offers a safe, patient-friendly, and adaptable topical solution. The 1.5% concentration was selected for further development and phase II trials for managing chemotherapy-related skin toxicities are in progress. - TARIAN 006, 2023-504178-39-00 approved 24/08/203. - TARIAN 012, 2324CMCL096 approved 28/05/2024.