Characterization of rimegepant drug-drug interactions using the cytochrome P450 probe drugs, itraconazole, rifampin, fluconazole, and midazolam.

OBJECTIVE: Reported here are the results of four rimegepant phase I studies, in healthy participants, aimed at determining the in vivo potential of rimegepant (75 mg) for cytochrome P450 (CYP) 3A4-related drug-drug interactions (DDIs). BACKGROUND: Rimegepant orally disintegrating tablet (Pfizer Inc., New York, NY, USA) is a calcitonin gene-related peptide receptor antagonist approved for acute treatment of migraine and preventive treatment of episodic migraine. People with migraine commonly use multiple drug treatments, with the potential for DDIs. METHODS: Each study was an open-label, single-arm, single-sequence, crossover study. Rimegepant was tested as a victim drug by separate co-administration of itraconazole (a strong CYP3A4 inhibitor and P-glycoprotein inhibitor) in Study 1, rifampin (a strong CYP3A4 inducer and moderate CYP2C9 inducer) in Study 2, and fluconazole (a strong CYP2C9 inhibitor and moderate CYP3A4 inhibitor) in Study 3, and as a perpetrator drug by co-administration with midazolam (a CYP3A4 substrate) in Study 4. RESULTS: Mean values of single-dose rimegepant maximum concentration (Cmax) and area under the curve from time 0 to infinity (AUC0-inf) increased with itraconazole co-administration (n = 22) by 1.42-fold (90% confidence interval [CI] 1.25-1.61) and by 4.14-fold (90% CI 3.87-4.44), respectively, and decreased with rifampin co-administration (n = 21) to 36% (90% CI 31.2-41.4%) and to 19% (90% CI 16.3-21.4%), respectively. Co-administration with fluconazole (n = 23) increased rimegepant mean AUC0-inf by 1.80-fold (90% CI 1.68-1.93), with no impact on Cmax (1.04-fold; 90% CI 0.94-1.15). Co-administration of rimegepant single dose (300 mg; n = 14) or multiple doses (150 mg/day; n = 14) increased the mean Cmax of midazolam by 1.38-fold (90% CI 1.13-1.67) and 1.53-fold (90% CI 1.32-1.78), respectively, and the AUC0-inf of midazolam by 1.86-fold (90% CI 1.58-2.19) and 1.91-fold (90% CI 1.63-2.25), respectively. CONCLUSIONS: Based on the magnitude of DDIs, these studies indicate the following: co-administration of rimegepant with a strong CYP3A4 inhibitor should be avoided; during co-administration with a moderate CYP3A4 inhibitor, another dose of rimegepant within 48 h should be avoided; co-administration of rimegepant with a strong or moderate CYP3A4 inducer should be avoided; CYP2C9 does not play a meaningful role in rimegepant metabolism; and there is no clinically meaningful CYP3A4 inhibition by rimegepant.

Open-Label Interventional Study in Healthy Volunteers to Evaluate NO-Mediated Vasodilation by Dermal Allyl Isothiocyanate Challenge and Whole-Body Heat Stress.

Dermal allyl isothiocyanate (AITC) administration and whole-body heat stress (WBHS) are two challenge models that are used to evaluate physiological mechanisms of vasodilation and pharmacological activity in humans. Their exact vasodilatory mechanisms in humans are not fully elucidated but are likely to be nitric oxide (NO)-mediated. This study aimed to evaluate whether there is overlap in the vasodilatory pathways of dermal AITC application and WBHS by combining the challenges. In this open-label interventional study, healthy volunteers underwent dermal administration of AITC twice: under basal conditions and during WBHS. Dermal blood flow (DBF) was non-invasively measured using laser speckle contrast imaging four times, once in each of the following situations: baseline, WBHS only, AITC only, and WBHS combined with AITC. A total of 12 male volunteers, aged 18-61 years, participated in the study. Compared to baseline, following AITC application, their DBF increased by 63.43 AU (baseline: 32.55, 95% CI [17.78, 47.31] AU, AITC only: 95.97, 95% CI [81.21, 110.7] AU, p < 0.0001). During WBHS, the increase in DBF after AITC was 42.76 AU (WBHS only: 87.25, 95% CI [72.49, 102.0] AU, WBHS+AITC: 130.0, 95% CI [115.2, 144.8] AU, p < 0.0001). The combination of WBHS and AITC resulted in a lower DBF than the sum of the DBF responses to AITC and WBHS when applied separately (ED 20.67, 95% CI [-3.532, 44.88], p = 0.0916). This might point towards the presence of an interaction in the vasodilatory mechanism of AITC application and WBHS, possibly indicating overlap in their NOS-driven vasodilatory pathways.

Clinical outcomes of guided tissue regeneration with carbonate apatite granules and poly(lactic acid/caprolactone) membrane for the treatment of intrabony defects and mandibular Class II furcation involvements: A 12-month prospective pilot clinical study.

Introduction: For deep intrabony defects or Class II furcation involvements (FI), periodontal tissue regenerative therapy combined with bone graft materials and a barrier membrane is recommended. The objective of this study was to assess the safety and efficacy of using carbonate apatite (CO3Ap) granules and absorbable poly(lactic acid/caprolactone) (PLCL) membranes for periodontal regeneration in the treatment of intrabony defects and mandibular Class II FI. Methods: This prospective pilot clinical study, conducted at a single center with a single-arm design, aimed to assess the safety and efficacy of CO3Ap and PLCL membranes in patients with periodontitis. A total of 9 patients with 10 teeth, including seven deep intrabony defects and three Class II FI, were treated with CO3Ap granules and PLCL membranes. Clinical parameters such as probing pocket depth (PPD), clinical attachment level (CAL), bleeding on probing (BOP), tooth mobility (Mo), Plaque Index (PI), and Gingival Index (GI) were assessed at baseline, 6 and 12 months post-surgery. Radiographic analysis was performed using dental X-rays and cone beam computed tomography (CBCT) images taken at baseline, 6, and 12 months post-surgery. Results: Postoperative healing was uneventful in most of the cases. In some cases, membrane exposures were observed. However, there were no signs of inflammation, such as abnormal bleeding, pain, swelling, or pus. These exposures eventually healed well in the end. The mean reductions in PPD at 6 and 12 months were 4.5 ± 1.6 mm and 4.9 ± 1.4 mm, respectively, while the mean gains in CAL were 4.4 ± 1.7 mm at 6 months and 4.6 ± 1.2 mm at 12 months. Radiographic analysis showed improvements in linear bone height within intrabony defects and in the vertical subclassification of FI in Class II FI. Conclusions: Despite the limitations of this study, periodontal regenerative therapy using CO3Ap granules and a PLCL membrane demonstrated promising clinical safety and efficacy for treating intrabony defects and mandibular Class II furcation involvement.

Utilising accessible and reproducible neurological assessments in clinical studies: Insights from use of the Neurological Impairment Scale in the multi-centre COVID-CNS study.

Reproducible and standardised neurological assessment scales are important in quantifying research outcomes. These scales are often performed by non-neurologists and/or non-clinicians and must be robust, quantifiable, reproducible and comparable to a neurologist's assessment. COVID-CNS is a multi-centre study which utilised the Neurological Impairment Scale (NIS) as a core assessment tool in studying neurological outcomes following COVID-19 infection. We investigated the strengths and weaknesses of the NIS when used by non-neurology clinicians and non-clinicians, and compared performance to a structured neurological examination performed by a neurology clinician. Through our findings, we provide practical advice on how non-clinicians can be readily trained in conducting reproducible and standardised neurological assessments in a multi-centre study, as well as illustrating potential pitfalls of these tools.

The potential of retinoic acid receptors as prognostic biomarkers and therapeutic targets in gastric cancer.

Background: Gastric cancer is a heterogeneous collection of tumors characterized by low survival rates. All-trans retinoic acid (retinoic-acid) is a clinically useful therapeutic agent belonging to the chemical family of retinoids, which consists of both natural and synthetic derivatives of vitamin-A. Retinoids are essential components of the normal diet and they regulate different physiological processes. From a therapeutic point of view, retinoic-acid is the first example of clinically useful differentiating agent. Indeed, the differentiating properties of this compound have promoted the use of retinoic-acid as a standard of care in Acute-Promyelocytic-Leukemia, a rare form of acute myeloid leukemia. In this study, we determine the RNA expression of the six isoforms of Retinoic-Acid-Receptors (RARα/RARß/RARγ/RXRα/RXRß/RXRγ) in view of their potential use as gastric cancer progression markers and/or therapeutic targets. In addition, we evaluate associations between the expression of these receptors and a simplified molecular classification of stomach tumors as well as the clinical characteristics of the cohort of patients analyzed. Finally, we define the prognostic value of the various Retinoic-Acid-Receptors in gastric cancer. Methods: In this single institution and retrospective RAR-GASTRIC study, we consider 55 consecutive gastric cancer patients. We extract total RNA from the pathological specimens and we perform a NanoString Assay using a customized panel of genes. This allows us to determine the expression levels of the RAR and RXR mRNAs as well as other transcripts of interest. Results: Our data demonstrate ubiquitous expression of the RAR and RXR mRNAs in gastric cancers. High levels of RARα, RARß, RXRα and RXRß show a significant association with stage IV tumors, "de novo" metastatic disease, microsatellite-stable-status, epithelial-to-mesenchymal-transition, as well as PIK3CA and TP53 expression. Finally, we observe a worse overall-survival in gastric cancer patients characterized by high RARα/RARß/RARγ/RXRß mRNA levels. Conclusions: In gastric cancer, high expression levels of RARα/RARß/RARγ/RXRß transcripts are associated with poor clinical and molecular characteristics as well as with reduced overall-survival. Our data are consistent with the idea that RARα, RARß, RARγ and RXRß represent potential prognostic markers and therapeutic targets of gastric cancer.

Does alveolar ridge preservation reduce the need for sinus floor elevation: A comparative study to spontaneous healing.

INTRODUCTION: In cases of atrophy in the maxillary posterior region, characterized by reduced vertical bone volume, implant placement becomes challenging. Augmentation procedures like sinus lifts are often needed to address insufficient bone volume. This study aims to explore if alveolar ridge preservation, using a bovine bone substitute and a porcine collagen membrane, significantly decreases the need for sinus lifts compared to natural wound healing after tooth extraction. MATERIALS AND METHODS: In this comparative clinical study, 40 patients requiring a total of 53 extractions were assigned to one of the following groups: a test group with bovine bone substitute material (Straumann® XenoFlex) and a porcine collagen membrane (Jason® membrane), or a control group with spontaneous socket healing. After 6 months, digital volume tomography was performed for implant planning. RESULTS: For seven patients from the control group (n = 22 extracted sites) sinus lift augmentations were performed while only four sinus lift procedures were performed in the test group (n = 31 extracted sites), indicating a higher need for sinus augmentation procedures in the control group, however not statistically different on a p value of 0.05 (p = 0.168). In the control group, the mean value of the radiographically measured bone height (mesial and distal) was 11.13 ± 2.12 mm preoperatively before tooth extraction, while it was 11.3 ± 2.17 mm postoperatively after implant placement. In contrast, the mean value in the test group was 11.78 ± 3.09 mm preoperatively and 11.92 ± 2.79 mm postoperatively. Statistical analysis revealed no significant difference between the two groups (odds ratio 0.32; 95% CI: 0.08, 1.26; p = 0.951). The implant survival rate in the control group was 100%, compared to 96.77% in the test group. CONCLUSION: Within the limits of this study, the use of bovine bone substitute and a porcine resorbable membrane after tooth extraction in the posterior maxilla seems to reduce the need for sinus augmentation in comparison to spontaneous healing although the difference was not statistically significant. Additionally, the Alveolar Ridge Preservation in the test group made external sinus floor elevation unnecessary compared to the control group. The change in radiographically measured bone height pre- and postoperatively showed no significant difference between the two groups.

Blood endocan as a biomarker for breast cancer recurrence.

BACKGROUND: Endocan was reported to affect breast cancer patients negatively and was able to be detected from patients' blood. OBJECTIVE: This study aimed to investigate if the measurement of blood endocan in breast cancer patients with high ESM1 expression could be an effective tool to detect postoperative recurrence compared with existing tumor markers. METHODS: Blood was collected before and after the tumor resection from the mouse models of breast cancer, and endocan levels were measured while visualizing metastatic recurrence with noninvasive luminescence imaging. In clinical settings, blood was withdrawn from 16 breast cancer patients before and after the tumor resection, and the effect of lumpectomy on blood endocan level was evaluated. Additionally, the blood endocan from 20 patients diagnosed with postoperative recurrence was measured, and their positivity rate for endocan was compared with that for serum carcinoembryonic antigen (CEA) or cancer antigen 15-3 (CA15-3). RESULTS: Our preclinical and clinical experiments revealed that blood endocan levels reflected tumor burden. Furthermore, over 60% of patients suffering from postoperative recurrence who tested negative for CEA or CA15-3 were positive for endocan. CONCLUSIONS: Our results support the clinical significance of endocan in breast cancer patients for detecting breast cancer recurrence.

Longevity and risk factors of CAD-CAM manufactured implant-supported all-ceramic crowns - A prospective, multi-center, practice-based cohort study.

OBJECTIVES: The aim of this prospective, multi-center, practice-based cohort study was to analyze factors associated with the success of implant supported all-ceramic single-unit crowns, made by computer-aided-design/computer-aided-manufacturing (CAD-CAM). METHODS: All-ceramic crowns placed in a private practice-based research network (Ceramic Success Analysis, AG Keramik) were analyzed. Data from 567patients with CAD-CAM implant supported all-ceramic crowns placed between 2008-2023 by 54dentists were evaluated. Firstly, all crowns with at least one follow-up control were included (n = 907). Secondly, all crowns being followed up for ≥ 5years and all failures were included (n = 151). At the latest follow-up visit, crowns were considered as successful (not failed) if they were still in function without the need for additional therapy. Multi-level Cox proportional hazards models were used to evaluate the association between a range of predictors and time of success. RESULTS: Within a mean follow-up period (SD) of 2.5 (2)years (first scenario) and 6.2 (1.2)years (second scenario) [maximum:12years], 27crowns failed (annual failure rate [AFR]:0.74 %). The main failure types were decementation, (n = 11), fracture of the ceramic (n = 4) or Ti-Base (n = 4). In 5-year-scenario, crowns fabricated in the laboratory had 26times lower failure rate than those fabricated chairside (95 %CI:0.0-0.7;p = 0.038). Furthermore, the use of a silane (HR:0.051;95 %CI:0.0-0.5;p = 0.014) and etching of the ceramic (HR:0.053;95 %CI:0.0-0.8;p = 0.035) resulted in a significantly higher risk for failure than their non-use. SIGNIFICANCE: For CAD-CAM manufactured implant supported all-ceramic crowns, high success rates were found in up to 12-year evaluation. Furthermore, after 5years, no patient-or implant-level factors, but operative-level factor (i.e.fabrication method, use of silane/etching) were significantly associated with failure. The study was registered in the German Clinical Trials Register (DRKS-ID: DRKS00020271).

Comparative Analysis of Two Different Techniques for Ridge Preservation Following Tooth Extraction: A Clinical and Radiographic Study.

Background: Ridge preservation following tooth extraction is essential for maintaining the alveolar bone structure and facilitating successful dental implant placement. Various techniques have been proposed for this purpose, but there remains a need for comparative analysis to determine their efficacy. Materials and Methods: This clinical and radiographic study compared two different techniques for ridge preservation: Technique A and Technique B. Fifty patients requiring tooth extraction were randomly assigned to either Technique A or Technique B group. Clinical parameters including pain, swelling, and soft tissue healing were evaluated postoperatively. Radiographic assessments were conducted to measure the dimensional changes in the alveolar ridge at baseline and after 3 months using cone-beam computed tomography (CBCT). Results: In the Technique A group, postoperative pain scores averaged 2.3 (±0.5) on a visual analog scale (VAS), while in the Technique B group, the average pain score was 2.5 (±0.6). The swelling was minimal in both groups with no significant difference. Soft tissue healing was satisfactory in both groups. Radiographically, the mean vertical bone loss was 1.2 mm (±0.3) in the Technique A group and 0.9 mm (±0.4) in the Technique B group, with a statistically significant difference (P < 0.05). Conclusion: Both Technique A and Technique B demonstrated favorable outcomes in terms of postoperative discomfort and soft tissue healing. However, Technique B showed superior preservation of vertical ridge dimensions compared to Technique A. Therefore, Technique B may be considered more effective for ridge preservation following tooth extraction.

Development of gallic acid loaded composite nanovesicles for the topical treatment of acne: optimization, characterization, and clinical investigation.

Gallic acid (GA) proved to produce desired effects topically in the treatment of acne, through its antibacterial, anti-inflammatory and antioxidant characteristics. In the current work, nanovesicular systems; aspasomes loaded with GA were prepared, and evaluated on in-vitro and ex-vivo levels. Formulations were coated with chitosan due to its mucoadhesive properties. Results indicated that the size of the formulations ranged between 273.20 and 855.00 nm, with positively charged zeta potential ranging between 30.60 and 34.40 mV, EE% ranging between 57.651% and 95.20% and good stability after 3-months storage. The formulae provided a sustained drug release of 98.22% over 24 h, 5.4-fold higher ex-vivo skin deposition compared to GA solution, and powerful antioxidant potential compared to the control solution and appeared as spherical bilayer vesicles on being examined using transmission electron microscope. A clinical study was carried out on patients suffering from acne, where the reduction percent of comedones, inflammatory, total acne lesions and infiltrate was calculated. Results revealed that aspasomes exhibited reduction percentages of 72.35%, 80.33%, 77.95% and 90.01% ± for comedones, inflammatory lesions, total lesions, and infiltrate, respectively compared to control solution providing an effective topical delivery system for the management of acne.