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Aim of the study: Our hypothesis is that nirmatrelvir can penetrate the blood‒brain barrier and reach effective concentrations in the brain. Furthermore, herbal formulations can help maintain nirmatrelvir levels in the body, suggesting potential interactions between these medications. Materials and methods: To investigate this hypothesis, an animal model combining multisite microdialysis, ultrahigh-performance liquid chromatography and tandem mass spectrometry (UHPLC-MS/MS) methods was developed to monitor nirmatrelvir levels in the blood and brain of rats. Results: The pharmacokinetic results showed that the area under the curve (AUC) of nirmatrelvir in the blood and brain was 798.3 ± 58.56 and 187.2 ± 23.46 min μg/mL, respectively, after the administration of nirmatrelvir alone (15 mg/kg, iv). When the Scutellaria baicalensis formulations were administered for five consecutive days prior to drug administration, the AUC of nirmatrelvir in the blood increased. Conclusions: These results provide constructive preclinical information that the concentrations of nirmatrelvir in the blood and brain were greater than the effective concentration (EC90) for more than 6 h, and the Scutellaria baicalensis formulations had synergistic pharmacokinetic effects by increasing the concentration of nirmatrelvir in the blood.

Background: Ritonavir is one of the most potent CYP3A4 inhibitor currently on the market, and is often used together with other antiviral drugs to increase their bioavailability and efficacy. Paxlovid, consisting of nirmatrelvir and ritonavir, was approved for the treatment of COVID-19. As previous studies regarding the use of ritonavir during pregnancy were limited to ex-vivo experiments and systemic safety data, to fully explore the detailed pharmacokinetics of ritonavir in pregnant rats’ blood and conceptus, an analytical method consisted of multi-microdialysis coupled with UHPLC-MS/MS were developed to analyze the pharmacokinetics of ritonavir, both as a component of Paxlovid and by itself. 17 days pregnant female Sprague-Dawley rats were randomly split into three experimental group: normal dosage of ritonavir alone (7 mg kg−1), normal dosage of Paxlovid (ritonavir 7 mg kg−1 + nirmatrelvir 15 mg kg−1), and 3× dosage of ritonavir (21 mg kg−1). Results: 3× dosage of ritonavir produced a more than 3× increase in rats’ blood and placenta. Transfer rate of ritonavir to the placenta, amniotic fluid, and fetus were determined to be 20.7%, 13.8%, and 4.7% respectively. Concentration of ritonavir in the placenta, amniotic fluid, and fetus did not significantly go down after 8 h. Significance: Overall, ritonavir's metabolism was not influenced by the presence of nirmatrelvir in pregnant rats. A 3× increase in dosage produced a concentration of roughly 4×, most likely a result of ritonavir's auto-inhibition effect on cytochrome P450 proteins. Accumulation of ritonavir is possible in placenta, amniotic fluid, and fetus.

Abstract Current rat alveolar ridge preservation models have not been well standardized. In this study, we proposed decoronation-induced infected alveolar socket model of rat. The bilateral maxillary first molars (M1) of twenty-four rats were decoronized or extracted. After 2, 6, 10, and 14 weeks, bone and soft tissue changes at M1 and periodontal conditions of maxillary second (M2) and third molars (M3) were evaluated by micro-computed tomography and histological analysis. Additional eighteen rats with standardized size defects were grafted with Bio-Oss Collagen to compare with unmanipulated contralateral side. Decoronation preserved greater bone and soft tissue dimensions at M1, provided larger three-dimensional (3D) bone contour volume, but also promoted periodontal breakdown of M2 Histological results showed intense inflammatory cell infiltrations and severe bone resorption within M1 socket and at mesial aspect of M2. The critical dimensions to accommodate largest standardized defect at M1 were 2.2–2.3 mm at vertical bone height and 2.8–3.2 mm at alveolar crestal width. Bio-Oss Collagen could not fully preserve buccal or palatal bone height but could be beneficial in preserving ridge width in large alveolar defects. Collectively, if periodontally-involved alveolar bone defect is preferred, we suggest extracting M1 roots 6 weeks after decoronation to allow periodontitis to occur at M2. If standardized critical dimension defect is preferred, we suggest extracting M1 roots 2 weeks after decoronation, and creating defect in the middle of M1 site with size no larger than 2.7 mm diameter to its full depth.

Osteoarthritis is a prevalent musculoskeletal disorder in the elderly, which leads to high rates of morbidity. Mesenchymal stem cells (MSCs) are a promising approach to promote tissue regeneration in the absence of effective long-term treatments. Small molecules are relatively inexpensive and can selectively alter stem cell behavior during their differentiation, making them an attractive option for clinical applications. In this study, we developed an extracellular matrix (ECM)-based biphasic scaffold (BPS) loaded with two small-molecule drugs, kartogenin (KGN) and metformin (MET). This cell-free biomimetic biphasic scaffold consists of a bone (gelatin/hydroxyapatite scaffold embedded with metformin [GHSM]) and cartilage (nano-gelatin fiber embedded with kartogenin [NGFK]) layer designed to stimulate osteochondral regeneration. Extracellular matrix (ECM)-based biomimetic scaffolds can promote native cell recruitment, infiltration, and differentiation even in the absence of additional growth factors. The biphasic scaffold (BPS) showed excellent biocompatibility in vitro, with mesenchymal stem cells (MSCs) adhering, proliferating, and differentiated on the biomimetic biphasic scaffolds (GHSM and NGFK layers). The biphasic scaffolds upregulated both osteogenic and chondrogenic gene expression, sulfated glycosaminoglycan (sGAG), osteo- and chondrogenic biomarker, and relative mRNA gene expression. In an in vivo rat model, histo-morphological staining showed effective regeneration of osteochondral defects. This novel BPS has the potential to enhance both subchondral bone repair and cartilage regeneration, demonstrating excellent effects on cell homing and the recruitment of endogenous stem cells.

Abstract Introduction We examined the associations among instrumental activities of daily living (IADL), cortical amyloid, and cognition in cognitively normal (CN) older adults. Methods CN participants screening for the A4 Study (n = 4486) underwent florbetapir (amyloid) positron emission tomography. IADL were assessed using the Alzheimer's Disease Cooperative Study Activities of Daily Living Prevention Instrument. Separate logistic regression models were run with cortical amyloid or cognition as independent variable and IADL as dependent variable, adjusting for age and sex. Results IADL difficulties were endorsed infrequently (≤16%). Overall IADL and four select IADL item difficulties (“remembering appointments,” “finding belongings,” “following TV programs,” and “remembering current events”) reported by both participant and study partner were significantly associated with greater amyloid burden and worse cognition. Discussion Although IADL deficits were infrequent in this CN cohort, greater participant and study partner report of overall IADL deficits and subtle difficulties in specific IADL items were associated with mildly higher amyloid burden and worse cognition.

Abstract Introduction Possession of the apolipoprotein E (APOE) ε4 allele advances amyloid β (Aβ) deposition and symptomatic onset of Alzheimer's disease (AD), whereas its effect on the rate of cognitive decline remained controversial. We examined the effects of APOE ε4 allele on cognition in biomarker‐confirmed late mild cognitive impairment (LMCI) and mild AD subjects in the Japanese Alzheimer's Disease Neuroimaging Initiative (J‐ADNI) and North American ADNI (NA‐ADNI). Methods The “early AD” (ie, combined LMCI and mild AD) cohort of 649 subjects from J‐ADNI and NA‐ADNI were selected based on positivity of Aβ confirmed by amyloid positron emission tomography (PET) or cerebrospinal fluid testing. The rates of cognitive decline in the Mini Mental State Examination (MMSE), the Clinical Dementia Rating Sum of Boxes (CDR‐SB), and the Alzheimer's Disease Assessment Scale‐cognitive subscale 13 (ADAS‐Cog) from baseline were examined using mixed‐effects model. The effect of ε4 on time to conversion to dementia was also analyzed in LMCI using the Kaplan‐Meier estimator and log‐rank test. Results The rates of cognitive decline were not significantly different between ε4 carriers and ε4 non‐carriers in the total early AD cohort, which were affected neither by region nor by the number of ε4 alleles. In LMCI, ε4 carriers showed almost the same progression rates as ε4 non‐carriers, except for a significantly faster decline in MMSE (P = .0282). Time to conversion to demenita was not significantly different between ε4 carriers and ε4 non‐carriers. In ε4‐positive mild AD, the rates of decline in MMSE (P = .003) and CDR‐SB (P = .0071) were slower than those in ε4 non‐carriers. DISCUSSION The APOE ε4 allele had little effect on the rates of cognitive decline in the overall biomarker‐confirmed early AD, regardless of region and number of ε4 alleles, with a slight variability in different clinical stages, the ε4 allele being slightly accelerative in LMCI, while decelerative in mild AD.