Pharmacological Reports最新文献

Background: Fatigue, a prevalent symptom of chronic illness, impacts quality of life. This proof-of-concept, randomized, double-blind, crossover trial assessed the anti-fatigue effects of ketamine (0.5 mg/kg) versus midazolam (0.045 mg/kg), the active comparator.

Methods: Ten participants, who were cancer survivors, with fibromyalgia, myalgic encephalomyelitis/chronic fatigue syndrome, or systemic lupus erythematosus, were randomized into Arm 1 (n = 4, Period 1: ketamine to Period 2: midazolam) or Arm 2 (n = 6, Period 1: midazolam to Period 2: ketamine).

Results: The two periods were separately analyzed because of carryover effects with baseline fatigue scores, assessed by the fatigue visual analog scale (VAS), between the study periods (p = 0.03). Looking at changes in fatigue VAS scores from baseline (pre-infusion) to 3 days post-infusion, the ketamine group had a 21.0% decrease in Period 1 and 10.9% in Period 2, while the midazolam group showed a 17.7% decrease in Period 1 and 12.6% in Period 2. We did not observe a statistically significant difference in both periods. The largest fatigue score reduction for the ketamine group was at 1 day post-infusion, at - 38.7% in Period 1.

Conclusion: Despite no statistical significance, a reduction in real-time fatigue scores was observed, which exceeded the 20% efficacy threshold, the primary outcome, in the ketamine arm from pre-infusion to 3 days post-infusion. The carryover effects and the peak reduction in fatigue at 24 hours after ketamine administration suggest that future trials may need to consider a study design without cross-over and an optimal active placebo alternative.

Background: The pathology of Huntington's disease (HD) is marked by the aggregation of mutant huntingtin protein (mHTT), which results from expanded polyglutamine (polyQ) residues encoded by CAG repeats in the HTT gene. These repeats are differentially elongated in adult- and juvenile-onset HD. In striatal neurons, the mHTT disrupts cellular mechanisms such as store-operated calcium entry (SOCE), a process in which endoplasmic reticulum Ca²⁺ depletion triggers extracellular Ca²⁺ influx; however, this process can also be affected in peripheral cells. The aim of this study was to evaluate SOCE in fibroblasts derived from both HD onset patients and age-related controls.

Methods: We conducted SOCE analysis in dermal fibroblasts from 12 HD patients (including adult- and juvenile-onset subtypes) and age-related healthy controls using Fura-2 AM ratiometric imaging paired with EGTA-based extracellular calcium chelation protocols. To evaluate SOCE response, we administered two SOC channel inhibitors, 6-bromo-N-(2-phenylethyl)-2,3,4,9-tetrahydro-1 H-carbazol-1-amine hydrochloride (C₂₀H₂₂BrClN₂) and EVP4593, in premanifest HD fibroblasts.

Results: In healthy human fibroblast lines, a decline in SOCE was observed between juvenile and adult individuals. In fibroblast lines from adult-onset HD patients (premanifest, early manifest, and manifest stages), we observed increased SOC channel activity. Conversely, juvenile-onset HD fibroblast lines exhibited reduced SOC channel activity compared to controls. Notably, SOCE dysregulation was independent of CAG repeat length in HD lines. Both SOC channel inhibitors attenuated SOCE in adult-onset HD lines.

Conclusion: The mHTT upregulates SOCE in adult-onset HD fibroblasts and downregulates it in juvenile-onset HD fibroblast lines; however, SOCE levels do not correlate with the length of CAG repeats encoding mHTT. Despite opposing trends compared to age-related controls, similar levels of SOCE in both HD-onset fibroblasts were detected. Both C₂₀H₂₂BrClN₂ and EVP4593 show potential for stabilizing SOCE in adult-onset HD. These findings suggest that dysregulated SOCE could be investigated as a peripheral target for studying pathological processes potentially associated with Huntington's disease.

Background: The proper functioning of the nervous system determines the homeostasis of the entire body. There are many known approaches designed to positively stimulate the functions of the central nervous system by applying various plants and fungal extracts, but their course of action is poorly understood. Hericium erinaceus and Ganoderma lucidum are examples of fungi with medicinal properties and with a positive health-promoting effect. Therefore, the aim of our study was to evaluate the effect of H. erinaceus or G. lucidum M-CFS with their active metabolites alone and/or in co-treatment with CAY10464 [antagonist of aryl hydrocarbon receptor (AhR)] on the metabolic parameters, cell cycle, and selected protein expression.

Methods: The study was based on the use of the resazurin reduction assay, flow cytometry analyses, and Western blotting in the mouse hippocampal neuronal cell line (HT-22) in vitro.

Results: The obtained results proved no cytotoxicity of the tested metabolites towards the HT-22 cells in the concentration range of 2.5% - 10% of culture medium. The cells treated with the tested compounds were characterized by an increase in the protein expression of SQSTM/p62, PCNA, c-SRC, SOD1, AhR, Beclin 1, and ERK1/2. Moreover, a significant role of AhR in the mechanism of action of the tested metabolites was observed at the protein expression level.

Conclusion: The observed increase in the proliferation-related markers in the HT-22 cells proves the beneficial protective potential of these M-CFSs. Given the findings, we speculate their positive impact on the cognitive functions in the central nervous system.

Clinical trial registration date: Not applicable.

Clinical trial number: Not applicable.