A systematic review and meta-analysis of new-onset atrial fibrillation in the context of COVID-19 infection.

New-onset atrial fibrillation (NOAF) in COVID-19 raises significant clinical and public health issues. This systematic review and meta-analysis aims to compile and analyze the current literature on NOAF in COVID-19 and give a more comprehensive understanding of the prevalence and outcomes of NOAF in COVID-19. A comprehensive literature search was carried out using several databases. The random effect model using inverse variance method and DerSimonian and Laird estimator of Tua2 was used to calculate the pooled prevalence and associated 95% confidence interval (CI). Results for outcome analysis were presented as odds ratios (ORs) with 95% CI and pooled using the Mantel-Haenszel random-effects model. The pooled prevalence of NOAF in COVID-19 was 7.8% (95% CI: 6.54%-9.32%),a pooled estimate from 30 articles (81 929 COVID-19 patients). Furthermore, our analysis reported that COVID-19 patients with NOAF had a higher risk of developing severe disease compared with COVID-19 patients without a history of atrial fibrillation (OR = 4.78, 95% CI: 3.75-6.09) and COVID-19 patients with a history of pre-existing atrial fibrillation (OR = 2.75, 95% CI: 2.10-3.59). Similarly, our analysis also indicated that COVID-19 patients with NOAF had a higher risk of all-cause mortality compared with, COVID-19 patients without a history of atrial fibrillation (OR = 3.83, 95% CI: 2.99-4.92) and COVID-19 patients with a history of pre-existing atrial fibrillation (OR = 2.32, 95% CI: 1.35-3.96). The meta-analysis did not reveal any significant publication bias. The results indicate a strong correlation between NOAF and a higher risk of severe illness and mortality. These results emphasize the importance of careful surveillance, early detection, and customized NOAF management strategies to improve clinical outcomes for COVID-19 patients.

Relevance of preclinical rodent pharmacokinetics in the selection of a companion antibiotic for combining with beta-lactamase inhibitor.

Recent approvals of beta-lactamase inhibitor (BLI) drug in combination with cephalosporins/penems have provided the right impetus for novel BLIs. One important research question, hitherto not addressed, is pertaining to the relevance of preclinical pharmacokinetics for pairing the antibiotic with existing/novel BLI.Two BLI combination drugs: (a) approved (i.e. ceftazidime/avibactam); (b) clinical development (i.e. cefepime/zidebactam) were explored to provide insights to address the research question.Individual intravenous dosing of ceftazidime, avibactam, cefepime and zidebactam was done at 1 mg/kg by intravenous route in Balb/c mice and Wistar rats. Serial blood samples were collected and analysed by LC-MS/MS method.Examination of the ratios of pharmacokinetic parameters (CL, VSS and T1/2) for individual drugs in combinations (for instance, CL (ceftazidime)/CL (avibactam); CL (cefepime)/CL (zidebactam)) suggested that the pharmacokinetic data gathered in rats were generally within 0.5- to 2-fold; but mouse data revealed larger disparity for VSS (0.11- to 8.25-fold) or CL (0.49- to 4.03-fold).The observed ratio for CL/VSS observed in rats agreed with corresponding human ratios for the pairwise comparison of the individual drugs in the combinations.Retrospectively, current pharmacokinetic findings suggest rat pharmacokinetic data may aid the combination of BLI with an appropriate antibiotic.

Transcanal infrapromontorial approach for internal auditory canal surgery and cochlear implantation.

OBJECTIVE: To demonstrate the feasibility of a transcanal infrapromontorial approach for vestibular schwannoma surgery through an anatomical dissection study and the description of a clinical case. METHODS: A microscopic and endoscopic dissection of cadaveric heads was undertaken through a transcanal infrapromontorial approach to the internal auditory canal (IAC), preserving the cochlea and the cochlear nerve. Description of the anatomy and surgical steps is reported as well as presentation of a clinical case in which a transcanal infrapromontorial approach was performed. RESULTS: In all of the cadaveric dissections, a transcanal infrapromontorial route with near total cochlea preservation was performed, removing only the most posterior portion of the basal turn of the cochlea. The IAC was opened through removal of "cochlear-vestibular bone". At the end of the dissection a cochlear implant array was placed. A transcanal infrapromontorial approach was also performed in a patient to allow a concurrent cochlear implant placement, with good postoperative results. CONCLUSION: The transcanal infrapromontorial approach permits the preservation of the cochlea and the cochlear nerve. This approach may be considered as an option in case of a small intracanalicular schwannoma removal (< 0.5 cm cerebellopontine angle spread), when concurrent cochlear implantation is indicated.

Impact of collagen-induced arthritis on the pharmacokinetic disposition of voriconazole, a widely used antifungal agent: in vitro and in vivo investigations in DBA/1J mice.

Pharmacokinetics of voriconazole, an anti-fungal agent, was determined in collagen-induced arthritic (CIA) and healthy DBA/1J mice. CIA was confirmed in DBA/1J mice by clinical scoring and histological analysis. In vivo oral pharmacokinetic study (3 mg/kg) and in vitro stability assessment in liver microsomes were performed in CIA vs. healthy DBA/1J mice. Additionally, hepatic portal vein cannulated (HPVC) CIA and healthy mice were used to clarify the role of gut first-pass effect. Voriconazole/N-oxide metabolite was measured in plasma and in vitro samples using liquid chromatography tandem-mass spectrometry method. Voriconazole exposure was reduced in CIA by 27% as compared to healthy mice. Formation of voriconazole N-oxide was higher in CIA mice as evidenced by higher molar Cmax ratio (i.e. metabolite/parent) of 2.08 vs. 1.66 in healthy mice. Because voriconazole was stable in microsomes, involvement of presystemic gut metabolism was suspected for decreased voriconazole exposure and formation of higher molar ratio of metabolite. HPVC work revealed higher formation of voriconazole N-oxide in CIA relative to healthy mice resulting in Cmax/AUC ratios of 0.41/0.54 and 0.08/0.17, respectively, confirming first-pass effect. The findings may have implications in the clinical therapy of arthritis patients who are concomitantly given voriconazole for the management of fungal infections.

Assessment of the in vitro cytochrome P450 (CYP) inhibition potential of ZYTP1, a novel poly (ADP-ribose) polymerase inhibitor.

ZYTP1 is a novel Poly (ADP-ribose) polymerase protein inhibitor being developed for cancer indications. The focus of the work was to determine if ZYTP1 had a perpetrator role in the in vitro inhibition of cytochrome P450 (CYP) enzymes to aid dosing decisions during the clinical development of ZYTP1. ZYTP1 IC50 for CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4/5 was determined using human liver microsomes and LC-MS/MS detection. CYP3A4/5 IC50 of depropylated metabolite of ZYTP1 was also determined. Time dependent inhibition of CYP3A4/5 by ZYTP1 was also assessed using substrates, testosterone and midazolam. The mean IC50 values of ZYTP1 were >100 µM for CYP1A2, 2B6 and 2D6, while 56.1, 24.5, 39.5 and 23.3-58.7 µM for CYP2C8, 2C9, 2C19 and 3A4/5, respectively. The CYP3A4/5 IC50 of depropylated metabolite was 11.95-24.51 µM. Time dependent CYP3A4/5 inhibition was noted for testosterone and midazolam with IC50 shift of 10.9- and 39.9-fold, respectively. With midazolam, the kinact and KI values of ZYTP1 were 0.075 min-1 and 4.47 µM for the CYP3A4/5 time dependent inhibition, respectively. Because of potent inhibition of CYP3A4/5, drugs that undergo metabolism via CYP3A4/5 pathway should be avoided during ZYTP1 therapy.

Incurred sample reanalysis in drug discovery bioanalysis.

Bioanalysis plays a key role during the drug discovery process to generate the pharmacokinetic data to facilitate unbiased evaluation of leads, optimized leads and drug candidates. Such pharmacokinetic data are used to enable key decisions in the drug discovery process. The aim of the work is to put forward a new strategy of performing the incurred sample reanalysis for select small molecule novel chemical entities at different stages of drug discovery prior to candidate selection. Three discovery programs representing hits, leads and optimized lead candidates were selected for the incurred sample reanalysis (ISR) analysis. From each discovery program, two novel chemical entities were selected for the ISR analysis. The time points considered for ISR generally varied among the programs; however, samples coinciding with drug absorption, distribution and elimination were considered in the ISR assessment. With the exception of a single ISR value that gave a high deviation (about 63%), the observed ISR values supported the discovery bioanalytical assays. While the individual bioanalytical laboratory can draw an algorithm for selecting novel chemical entities and fixing the acceptance criteria for the ISR data, it is proposed that the percentage difference between ISR vs. original concentration for 67% of the repeat samples is contained within ±30% for discovery bioanalysis.

Consequences of daily corticosteroid dosing with or without pre-treatment with quinidine on the in vivo cytochrome P450 2D (CYP2D) enzyme in rats: effect on O-demethylation activity of dextromethorphan and expression levels of CYP2D1 mRNA.

1. Present investigation was carried out in rats to study influence of corticosteroids after repeated dosing with/without pre-treatment with CYP2D inhibitor quinidine on the CYP2D1 mRNA levels and CYP2D enzyme activity using dextromethorphan as probe substrate. 2. CYP2D1 mRNA was measured in liver homogenate using quantitative real-time polymerase chain reaction [qRT-PCR] and enzymatic reaction was studied ex vivo in liver S-9 fractions of rats treated with oral 10 mg/kg dexamethasone or prednisolone for five days or pre-treated with quinidine and followed by treatment with oral 10 mg/kg corticosteroids for five days. 3. Five days repeat dosing of dexamethasone or prednisolone decreased the activity of the rat liver CYP2D by 37% and 34%, at 30 min incubation and decreased CYP2D1 mRNA levels by 62% and 61%, respectively. 4. Pre-treatment of quinidine decreased the enzymatic activity of rat CYP2D by 58% and did not potentiate CYP2D inhibition by corticosteroids. This observation was further complemented by qRT-PCR data. 5. Corticosteroids caused CYP2D inhibition in rats vs. literature evidence of CYP2D induction in human hepatocytes/pregnant humans demonstrating lack of concordance. In vivo inhibition should be factored for interpretation of pharmacokinetic data of CYP2D substrates when treated with corticosteroids in rats.

Sensitive and specific LC-ESI-MS/MS method for determination of ZYDPLA1, a novel long-acting dipeptidyl peptidase 4 inhibitor in rat plasma: An application for toxicokinetic study in rats.

A rapid and highly specific assay was developed and validated for the estimation of ZYDPLA1 in rat plasma using liquid chromatography coupled to tandem mass spectrometry with positive electrospray ionization. Method validation comprised of parameters such as specificity, matrix effect, precision, accuracy, recovery, stability, etc. The assay procedure involved a simple protein precipitation of ZYDPLA1 and alprazolam (internal standard) from rat plasma using acetonitrile. Chromatographic separation was achieved with a gradient mobile phase comprising: (A) 0.2% ammonia in purified water; (B) 0.1% formic acid in isopropyl alcohol/methanol (1: 1 v/v); and (C) acetonitrile at a flow rate of 1 mL/min on an ACE-5, C18 (4.6 × 50 mm) column with a run time of 5.5 min. The quantitation of ZYDPLA1 was achieved by the summation of four multiple reaction mode transitions (m/z 399.7 → 383.0, 399.7 → 276.10, 399.7 → 153.20 and 399.7 → 127.20), while that of the internal standard was by a single multiple reaction mode transition (m/z 309.10 → 281.00). The lower limit of quantitation achieved was 0.01 µg/mL and the method showed linearity from 0.01 to 25 µg/mL. The intra- and inter-day precision (%CV) of the quality control samples was within 8.81% and accuracy was ±10% of nominal values. This novel method was applied for evaluation of toxicokinetics of ZYDLA1 in rats.

Round window chamber and fustis: endoscopic anatomy and surgical implications.

The round window region is of critical importance in the anatomy of the middle ear. The aim of this paper is to describe its anatomy from an endoscopic point of view, emphasizing structures that have important surgical implications, in particular the fustis and the subcochlear canaliculus. The fustis, a smooth bony structure that forms the floor of the round window region, is a constant and important structure. It seems to indicate the round window membrane and the correct position of scala tympani. A structure connecting the round window region to the petrous apex, named the subcochlear canaliculus, is also described. A retrospective review of video recordings of endoscopic dissection and surgical procedures, carried out between June 2014 and February 2015, was conducted across two Tertiary university referral centers. A total of 42 dissections were analyzed in the study. We observed the fustis in all the cases and we identify two different anatomical conformations. The subcochlear canaliculus was found in 81.0 %, with a pneumatization direct to the petrous apex in 47.7 %. Conformation and limits of the round window niche may influence the surgical view of the round window membrane. Endoscopic approaches allow a very detailed view, which enables a comprehensive exploration of the round window region. Accurate knowledge of the anatomical relationships of this region has important advantages during middle ear surgery.

Assessing the Quality of Patient Information for Cholesteatoma on the Video Sharing Platform YouTube.

INTRODUCTION: Cholesteatoma is common chronic ear condition that usually requires surgical treatment and long-term follow-up. The Internet helps patients find information about their medical conditions and assists in shared clinical decision making. This work aims to assess the quality of information on YouTube for cholesteatoma. We aim to assess the quality of the most popular cholesteatoma videos on YouTube using recognized scoring systems and determine if quality correlated with video likes and views. METHODS: The YouTube website was systematically searched on separate days with a formal search strategy to identify videos relevant to cholesteatoma. Each video was viewed and scored by three independent assessors using a novel Essential and Ideal Video Completeness criteria for cholesteatoma and the validated DISCERN tool. Popularity metrics were analyzed and compared with video popularity. RESULTS: A total of 90 YouTube videos were analyzed with an average 55,292 views per video with an average of 271 likes and 22 dislikes. The interrater correlation was moderate with Fleiss kappa score 0.42 ( p < 0.01) using the Essential and Ideal Video Completeness criteria for cholesteatoma and interrater correlation coefficient was 0.78 (95% confidence interval, 0.58-0.90), indicating good reliability for DISCERN scores. The overall video quality was poor with higher DISCERN scores found from academic institutions. CONCLUSION: YouTube content with regard to cholesteatoma is of poor quality. Videos with unclassified sources or more dislikes correlated with poor quality. Otology societies should be encouraged to publish high-quality YouTube videos on cholesteatoma and other ear conditions.

Cochlear Implantation in Far Advanced Otosclerosis: A Systematic Review and Meta-Analysis.

OBJECTIVE: To evaluate speech outcomes and facial nerve stimulation (FNS) rates in patients with far advanced otosclerosis (FAO) after cochlear implantation. METHODS: A systematic review was performed using standardized methodology of Medline, EMBASE, PubMed, Cochrane, and Web of Science databases. Studies were included if adults with FAO underwent cochlear implantation. Exclusion criteria included concurrent otologic history (e.g., Meniere's disease, superior canal dehiscence), non-English-speaking implant users, case reports, abstracts, and letters/commentaries. Bias was assessed using the Newcastle-Ottawa Scale for cohort studies and the National Institute of Health Scale for case series. The primary outcome measure was speech discrimination and the secondary outcomes were rates of partial insertion and FNS. RESULTS: Twenty-seven studies evaluated cochlear implantation in FAO. Due to the heterogeneity of testing methods, statistical pooling of speech discrimination was not feasible, but qualitative synthesis indicated a positive effect of implantation. Pooled rates of FNS were 18% (95% confidence interval, CI 12%-27%) and the rate of partial insertion was 10% (95% CI 7%-15%). CONCLUSION: Cochlear implantation in FAO demonstrates significant gains in speech discrimination scores with higher rates of FNS and partial insertion. Laryngoscope, 133:1288-1296, 2023.

Anorexia Nervosa: Evaluating Disparities in Places of Death in the United States Over 22 Years Using the CDC WONDER Database.

INTRODUCTION: Anorexia nervosa is a severe and occasionally fatal eating disorder characterized by extreme weight loss and a distorted body image in which the affected individuals typically exhibit a strong fear of gaining weight, leading to rigid dietary restrictions and excessive activity. This condition can cause severe health problems, such as hunger, cardiovascular issues, and organ destruction. Anorexia nervosa is a key subject for research in the context of end-of-life care disparities due to its psychological and physical challenges.  Aims: This study examines differences in the places of death for people with anorexia nervosa during a 22-year period in the USA, taking into account four important factors: age group, gender, race, and U.S. census region. METHODOLOGY: Data were collected from the CDC WONDER website on August 31, 2023, and spans years 1999 to 2020, using the particular ICD-11 code F50.0 for anorexia nervosa. The study aims to uncover the important determinants impacting the location of death within this specific population using sophisticated statistical methods, including univariate logistic regression. RESULTS: The analysis of aggregate data yielded notable findings. The patient's principal site of death was at home or in hospice care. Other sites were less prevalent, with medical facilities or nursing homes ranking second. The place of death was highly influenced by age groups with diverse patterns. Gender had no significant impact; however, geographical inequalities were noticeable. Individuals in the Northeast, Midwest, and South were less likely than those in the West to die at home or in hospice care. The location of death was unaffected by race. CONCLUSIONS: In conclusion, this study found that death in home and hospice was more common than in medical or hospital nursing facilities in all four analyzed groups. These findings highlight the critical need for significant advancements in end-of-life care, particularly in home and hospice settings.

Analyzing Instagram Posts on Hypothyroidism: Characteristics, Information Types, Quality, and Reliability.

Background and aims In the age of social media, a vast amount of information is widely and easily accessible. Platforms such as Instagram allow its users to post pictures and videos that can reach millions of users. This could be utilized by healthcare providers to provide education to a vast number of the population about a disease such as hypothyroidism with an easily digestible infographic. However, this easy accessibility comes with the risk of rampant misinformation. This study aimed to evaluate the characteristics of Instagram posts, the type of information, and the quality and reliability of information posted about hypothyroidism. Methodology This is a cross-sectional observational study that was conducted over the course of days on Instagram. Top posts meeting inclusion criteria under seven different hypothyroidism-related hashtags were surveyed for content and social media metrics by the authors utilizing Google Forms. The quality and reliability of the posts were analyzed using the global quality scale and DISCERN scales, respectively. The data were exported to an Excel sheet and analyzed using the SPSS software version 21.0 (Armonk, NY: IBM Corp.). Results A total of 629 posts met the inclusion criteria of which 62.5% were images and 37.5% were reels. The content heavily focused on the medical aspect of hypothyroidism with posts about symptoms (46.1%), prevention (39.59%), cause/etiology (36.41%), and treatment (34.34%). The median DISCERN score which reflects the reliability of the posts uploaded was highest for doctors at 3 and the least reliable posts were uploaded by dieticians, naturopathic doctors, and patients. This study found that the quality of posts uploaded by nutritionists and naturopathic doctors with a median Global Quality Score (GQS) score of 3. Conclusions There is a need to establish a quality control body that regulates the quality and reliability of the posts to curb misinformation and help patients gain easy access to reliable resources that will aid their decision-making.

Futuristic Novel Therapeutic Approaches in the Treatment of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by systemic inflammation and joint destruction, leading to significant morbidity and reduced quality of life. Although significant progress has been made in the management of RA over the past few decades, many patients still fail to respond adequately to currently available therapies. This article aims to review the current landscape of RA treatment and explore potential novel therapeutic approaches that hold promise for the future. Advances in our understanding of the underlying pathogenesis of the disease have led to the identification of new targets and the development of innovative treatment strategies. This review focuses on emerging therapies including small molecule inhibitors, targeted biologics, cell-based therapies, and gene editing technologies that have shown potential in preclinical and early clinical trials. Additionally, we discuss the challenges and opportunities associated with the use of these new approaches in the treatment of RA. By elucidating the future of novel therapeutic approaches, this article provides insights that can guide clinicians and researchers in their efforts to improve outcomes for patients with RA.

Caution in Transnasal Balloon Dilation of the Eustachian Tube: Middle Ear Penetration of Catheter Tip in a Cadaveric Model.

OBJECTIVE: To investigate the degree to which transnasal eustachian tube (ET) dilation balloon catheters are able to be passed through the ET in a cadaver model. PATIENTS AND INTERVENTIONS: A cadaveric study of 8 cadaver heads (16 ears), which underwent transnasal ET insertion with a 3 × 20-mm balloon catheter with transtympanic endoscopic visualization and grading. RESULTS: Catheter tip incursion into the protympanum or mesotympanum occurred in all ears. Radiological validation was obtained with correlation to published ET length data. CONCLUSION: Middle ear incursion of balloon catheter tips can be demonstrated in a cadaver model and highlights the ongoing need for both caution in novel surgical techniques and evolution in device design.

Incidence and trends of middle ear cholesteatoma surgery and mastoidectomy in Australia-A national hospital morbidity database analysis.

OBJECTIVE: To investigate the incidence of middle ear cholesteatoma surgery and assess trends in mastoidectomy procedures in Australia. STUDY DESIGN: Cross-sectional population-based study using data from the National Hospital Morbidity Database. METHODS: Admitted care episodes containing the principal diagnosis of middle ear cholesteatoma were analyzed for two 12-month periods of 2007-2008 and 2017-2018. Surgical admissions involving mastoidectomy were identified by procedure codes. Incidence rate per 100,000 person-years were compared between study periods. RESULTS: Of the 3855 middle ear cholesteatoma admissions, 3558 (92.3%) involved surgery, with the incidence rate for cholesteatoma surgical admissions estimated at 8.6 per 100,000 (95% CI: 8.2-9.0) and 8.1 per 100,000 (95% CI: 7.7-8.5) for 2017-2018 and 2007-2008, respectively. Population aged 10-19 years had the highest age-specific incidence rate at 12.5 per 100,000 (95% CI: 11.3-13.9) for 2017-2018. The 60 years and over age groups had the highest decennial percentage increase. Mastoidectomy procedures were consistently used in over half of all surgical admissions. An increase in the rate of canal wall up (CWU) mastoidectomy procedure related admissions was observed (rate ratio of 1.62 [95%CI: 1.41-1.86], P <.001) and was offset by a decreased rate of canal wall down (CWD) procedure associated admissions (0.69 [95% CI: 0.61-0.78], P <.001]). CONCLUSIONS: The incidence rate of cholesteatoma surgery in Australia is estimated at 8.6 per 100,000. Mastoidectomy continues to play an essential role in cholesteatoma surgery with a trend favoring CWU over CWD mastoidectomy. Level of evidence: 4.

Assessing the Quality of Patient Information for Vestibular Schwannoma on the Open Source Video Sharing Platform YouTube.

BACKGROUND: Patients frequently use the internet to gain information and make decisions about their health conditions. This work aims to assess the quality of information about Vestibular Schwannoma on a popular video sharing platform, YouTube (Alphabet Inc.). OBJECTIVES: To assess quality of the most popular vestibular schwannoma videos using recognized scoring systems and whether video quality metrics correlated with video popularity based on metadata analysis. SETTING: Public domain. STUDY DESIGN: Cross-sectional Study. METHODS: The YouTube website was systematically searched on separate days with a formal search strategy to identify videos relevant to vestibular schwannoma. Each video was viewed and scored by three independent assessors, using scores for quality and disease specific accuracy. Popularity metrics were analyzed and compared to video quality. Patient surveys were conducted to further assess their perspectives of the included videos. RESULTS: A total of 23 YouTube videos were included. In terms of Essential and Ideal Video Completeness Criteria, the mean scores ranged from 4.8 to 5.0 (out of 12), indicating moderate video quality. The average DISCERN score ranged from 30.0 to 36.7, indicating lower reliability. The mean JAMA scores ranged from 1.96 to 2.48, indicating average quality. Based on metrics including DISCERN and JAMA instruments, the information in the YouTube videos were of low to average quality and reliability. Rater scoring was reliable. Viewer engagement correlated poorly with video quality except for JAMA metrics. CONCLUSION: Video quality on YouTube with respect to Vestibular Schwannoma is of low to average quality. Viewer engagement and popularity correlated poorly with video quality. Clinicians should direct their patients to high quality videos and should consider uploading their own high-quality videos.

ZY12201, A Potent TGR5 Agonist: Identification of a Novel Pan CYP450 Inhibitor Tool Compound for In-Vitro Assessment.

BACKGROUND: Identification of clinical drug-drug interaction (DDI) risk is an important aspect of drug discovery and development owing to poly-pharmacy in present-day clinical therapy. Drug metabolizing enzymes (DME) plays important role in the efficacy and safety of drug candidates. Hence evaluation of a New Chemical Entity (NCE) as a victim or perpetrator is very crucial for DDI risk mitigation. ZY12201 (2-((2-(4-(1H-imidazol-1-yl) phenoxy) ethyl) thio)-5-(2-(3, 4- dimethoxy phenyl) propane-2-yl)-1-(4-fluorophenyl)-1H-imidazole) is a novel and potent Takeda-G-protein-receptor-5 (TGR-5) agonist. ZY12201 was evaluated in-vitro to investigate the DDI liabilities. OBJECTIVE: The key objective was to evaluate the CYP inhibition potential of ZY12201 for an opportunity to use it as a tool compound for pan CYP inhibition activities. METHOD: In-vitro drug metabolizing enzymes (DME) inhibition potential of ZY12201 was evaluated against major CYP isoforms (1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4/5), aldehyde oxidase (AO), monoamine oxidase (MAO), and flavin-containing monooxygenase (FMO in human liver cytosol/mitochondrial preparation/ microsomes using probe substrates and Liquid Chromatography with tandem mass spectrometry (LC-MS-MS) method. RESULTS: The study conducted on ZY12201 at 100 µM ZY12201 was found to reduce the metabolism of vanillin (AO probe substrate), tryptamine (MAO probe substrate), and benzydamine (FMO probe substrate) by 49.2%, 14.7%, and 34.9%, respectively. ZY12201 Ki values were 0.38, 0.25, 0.07, 0.01, 0.06, 0.02, 7.13, 0.03 and 0.003 µM for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5 (substrate: testosterone) and CYP3A4/5 (substrate: midazolam), respectively. Time-dependant CYP inhibition potential of ZY12201 was assessed against CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4/5 and no apparent IC50 shift was observed. CONCLUSIONS: ZY12201, at 100 µM concentration showed low inhibition potential of AO, MAO, and FMO. ZY12201 was found as a potent inhibitor of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5 while moderately inhibits to CYP2E1. Inhibition of CYP1A2, CYP2B6, CYP2C19, and CYP2E1 by ZY12201 was competitive, while inhibition of CYP2C8, CYP2C9, CYP2D6, and CYP3A4/5 was of mixed-mode. ZY12201 is a non-time-dependent inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5. In summary, the reported Ki values unequivocally support that ZY12201 has a high potential to inhibit all major CYP isoforms. ZY12201 can be effectively used as a tool compound for in-vitro evaluation of CYP-based metabolic contribution to total drug clearance in the lead optimization stage of Drug Discovery Research.

Endoscopic Repair of a Temporal Bone Pneumatocele.

OBJECTIVE: Pneumatoceles of the temporal bone are rare entities. A symptomatic external auditory canal pneumatocele repaired endoscopically is demonstrated. METHODS: A 79-year-old man presented with fluctuating hearing loss and difficulty wearing in-ear hearing aids. The patient had two previous tube insertions which both failed within days. Examination of the left ear revealed a cyst filling the superior aspect of the lateral canal and obscuring the view of the majority of the tympanic membrane. Pre-op audiogram demonstrated a symmetric bilateral mild to moderate sensorineural hearing loss. The patient underwent a transcanal endoscopic composite cartilage myringoplasty. On incising the pneumatocele, a pars flaccida defect was identified in continuity with the pneumatocele. After excising the pneumatocele, a posterosuperior based tympanomeatal flap was raised and the defect repaired with a composite tragal cartilage perichondrial graft. RESULTS: The patient had an uneventful recovery. On first postoperative review, the tympanomeatal flap had healed and the cartilage graft was intact with partial integration and epithelialization. There was no evidence of pneumatocele recurrence and his existing hearing aids were able to be worn with satisfactory amplification. The formation of the pneumatocele was presumed secondary to a ball-valve effect of skin through the pars flaccida defect and progressive raising of the epithelial layer in continuity with the canal skin. CONCLUSION: Surgical repair of temporal bone pneumatoceles is warranted in symptomatic patients. Identifying and addressing the underlying cause of their development is essential to surgical management.SDC video link: http://links.lww.com/MAO/B267.