Correlations between heart sound components and hemodynamic variables.

Although the esophageal stethoscope is used for continuous auscultation during general anesthesia, few studies have investigated phonocardiographic data as a continuous hemodynamic index. In this study, we aimed to induce hemodynamic variations and clarify the relationship between the heart sounds and hemodynamic variables through an experimental animal study. Changes in the cardiac contractility and vascular resistance were induced in anesthetized pigs by administering dobutamine, esmolol, phenylephrine, and nicardipine. In addition, a decrease in cardiac output was induced by restricting the venous return by clamping the inferior vena cava (IVC). The relationship between the hemodynamic changes and changes in the heart sound indices was analyzed. Experimental data from eight pigs were analyzed. The mean values of the correlation coefficients of changes in S1 amplitude (ΔS1amp) with systolic blood pressure (ΔSBP), pulse pressure (ΔPP), and ΔdP/dt during dobutamine administration were 0.94, 0.96, and 0.96, respectively. The mean values of the correlation coefficients of ΔS1amp with ΔSBP, ΔPP, and ΔdP/dt during esmolol administration were 0.80, 0.82, and 0.86, respectively. The hemodynamic changes caused by the administration of phenylephrine and nicardipine did not correlate significantly with changes in the heart rate. The S1 amplitude of the heart sound was significantly correlated with the hemodynamic changes caused by the changes in cardiac contractility but not with the variations in the vascular resistance. Heart sounds can potentially provide a non-invasive monitoring method to differentiate the cause of hemodynamic variations.

Bento: a toolkit for subcellular analysis of spatial transcriptomics data.

The spatial organization of molecules in a cell is essential for their functions. While current methods focus on discerning tissue architecture, cell-cell interactions, and spatial expression patterns, they are limited to the multicellular scale. We present Bento, a Python toolkit that takes advantage of single-molecule information to enable spatial analysis at the subcellular scale. Bento ingests molecular coordinates and segmentation boundaries to perform three analyses: defining subcellular domains, annotating localization patterns, and quantifying gene-gene colocalization. We demonstrate MERFISH, seqFISH + , Molecular Cartography, and Xenium datasets. Bento is part of the open-source Scverse ecosystem, enabling integration with other single-cell analysis tools.

16α-OHE1 alleviates hypoxia-induced inflammation and myocardial damage via the activation of ß2-Adrenergic receptor.

OBJECTIVE: Myocardial injuries resulting from hypoxia are a significant concern, and this study aimed to explore potential protective strategies against such damage. Specifically, we sought to investigate the cardioprotective effects of 16α-hydroxyestrone (16α-OHE1). METHODS: Male Sprague‒Dawley (SD) rats were subjected to hypoxic conditions simulating high-altitude exposure at 6000 m in a low-pressure chamber for 7 days. Before and during hypoxic exposure, estradiol (E2) and various doses of 16α-OHE1 were administered for 14 days. Heart weight/body weight (HW/BW), myocardial structure, Myocardial injury indicators and inflammatory infiltration in rats were measured. H9C2 cells cultured under 5% O2 conditions received E2 and varying doses of 16α-OHE1; Cell viability, apoptosis, inflammatory infiltration, and Myocardial injury indicators were determined. Expression levels of ß2AR were determined in rat hearts and H9C2 cells. The ß2AR inhibitor, ICI 118,551, was employed to investigate ß2AR's role in 16α-OHE1's cardioprotective effects. RESULTS: Hypoxia led to substantial myocardial damage, evident in increased heart HW, CK-MB, cTnT, ANP, BNP, structural myocardial changes, inflammatory infiltration, and apoptosis. Pre-treatment with E2 and 16α-OHE1 significantly mitigated these adverse changes. Importantly, the protective effects of E2 and 16α-OHE1 were associated with the upregulation of ß2AR expression in both rat hearts and H9C2 cells. However, inhibition of ß2AR by ICI 118,551 in H9C2 cells nullified the protective effect of 16α-OHE1 on myocardium. CONCLUSION: Our findings suggest that 16α-OHE1 can effectively reduce hypoxia-induced myocardial injury in rats through ß2ARs, indicating a promising avenue for cardioprotection.

Survival in pregnancy-associated breast cancer patients compared to non-pregnant controls.

BACKGROUND: Pregnancy-associated breast cancer (PABC) is a rare entity whose prognosis has previously been studied and is subject to controversy. METHODS: Survival of patients with PABC diagnosed between 2009 and 2021 with breast cancer during pregnancy or until 1 year after childbirth was compared with non-pregnant patients with breast cancer from the same period at La Paz University Hospital. Cox proportional hazards regression was used to compare disease-free (DFS) and overall (OS) survival between the groups, adjusting for grade and pathologic stage. RESULTS: Among the 89 included patients with breast cancer, 34 were diagnosed during pregnancy, and 55 were not pregnant. The pregnant patients were more likely to have grade 3 tumors (61.3% vs 37%, p = 0.023) and an advanced stage (pathologic stage III-IV: 44.1% vs 17.6%, p = 0.008). Median follow-up was 47 months for the pregnant group and 46 months for the control group. After adjustments for tumor grade and pathologic stage, OS was comparable between the groups (HR 2.03; 95% CI 0.61 to 6.79; P = 0.25). CONCLUSIONS: The outcome of women diagnosed with PABC is comparable to young non-pregnant controls. However, it should be taken into account that PABC has a more aggressive phenotype.

MRI of the Lactating Breast.

The breasts undergo marked physiologic changes during lactation that can make conventional imaging evaluation with mammography and US challenging. MRI can be a valuable diagnostic aid to differentiate physiologic and benign processes from malignancy in patients who are lactating. In addition, MRI may allow more accurate delineation of disease involvement than does conventional imaging and assists in locoregional staging, screening of the contralateral breast, assessment of response to neoadjuvant chemotherapy, and surgical planning. Although the American College of Radiology recommends against patients undergoing contrast-enhanced MRI during pregnancy because of fetal safety concerns, contrast-enhanced MRI is safe during lactation. As more women delay childbearing, the incidence of pregnancy-associated breast cancer (PABC) and breast cancer in lactating women beyond the 1st year after pregnancy is increasing. Thus, MRI is increasingly being performed in lactating women for diagnostic evaluation and screening of patients at high risk. PABC is associated with a worse prognosis than that of non-PABCs, with delays in diagnosis contributing to an increased likelihood of advanced-stage disease at diagnosis. Familiarity with the MRI features of the lactating breast and the appearance of various pathologic conditions is essential to avoid diagnostic pitfalls and prevent delays in cancer diagnosis and treatment. The authors review clinical indications for breast MRI during lactation, describe characteristic features of the lactating breast at MRI, and compare MRI features of a spectrum of benign and malignant breast abnormalities. ©RSNA, 2024 Test Your Knowledge questions for this article are available in the supplemental material. See the invited commentary by Chikarmane in this issue.

Pregnancy-related breast cancer: 14-year experience in a tertiary institution in Hong Kong.

BACKGROUND: The incidence of pregnancy-associated breast cancer (PABC) is increasing. Its tumor characteristics and overall survival compared with those in nonpregnant patients remain controversial. While there have been suggestions that PABC patients have a 40 % increase in the risk of death compared to non-pregnant patients, other studies suggested similar disease outcomes. This study aims to review our local experience with PABC. METHODS: Twenty-eight patients diagnosed with PABC and twenty-eight patients diagnosed at premenopausal age randomly selected by a computer-generated system during the same period were recruited. Background characteristics, tumor features, and survival were compared. RESULTS: Among the twenty-eight pregnant patients, seventeen were diagnosed during pregnancy, and eleven were diagnosed in the postpartum period. Compared to the non-pregnant breast cancer patients, they presented with less progesterone receptor-positive tumor (35.7 % vs. 64.2 %, p = 0.03). Although there was no statistically significant difference in tumor size (p = 0.44) and nodal status (p = 0.16), the tumor tended to be larger in size (2.94 +/- 1.82 vs 2.40 +/- 1.69 cm) and with more nodal involvement (35.7 % vs 25.0 %). There was also a trend of delayed presentation to medical attention, with a mean duration of 13.1 weeks in the PABC group and 8.6 weeks in the control group. However, the overall survival did not differ (p = 0.63). CONCLUSION: PABC is increasing in incidence. They tend to have more aggressive features, but overall survival remains similar. A multidisciplinary approach is beneficial for providing the most appropriate care.

Unexpectedly stable homopurine parallel triplex of SNA:RNA*SNA and L-aTNA:RNA*L-aTNA.

Homopurine strands are known to form antiparallel triplexes stabilized by G*G and A*A Hoogsteen pairs, which have two hydrogen bonds. But there has been no report on the parallel triplex formation of homopurine involving both adenosine and guanosine to the duplex. In this paper, we first report parallel triplex formation between a homopurine serinol nucleic acid (SNA) strand and an RNA/SNA duplex. Melting profiles revealed that the parallel SNA:RNA*SNA triplex was remarkably stable, even though the A*A pair has a single hydrogen bond. An L-acyclic threoninol nucleic acid (L-aTNA) homopurine strand also formed a stable parallel triplex with an L-aTNA/RNA duplex.

Blocking brown adipocyte ß3-adrenoceptor attenuates blood-spinal cord barrier impairment and chronic postsurgical pain in a rat model of preoperative stress.

Preoperative stress has been recognized as an independent risk factor for chronic postsurgical pain (CPSP). However, the underlying mechanisms of CPSP influenced by preoperative stress remain elusive. Previous studies indicated that excessive stress could induce disruption of the blood-spinal cord barrier (BSCB). We wondered whether and how BSCB involves in CPSP by using a single prolonged stress (SPS) combining plantar incision model in male rats to mimic preoperative stress-related postsurgical pain. Here, we observed that preoperative SPS-exposed rats exhibited relentless incisional pain, which was accompanied by impairment of BSCB and persistent elevation of serum IL-6. Intraperitoneal injections of Tocilizumab (an IL-6 receptor monoclonal antibody) not only mitigated BSCB breakdown but also alleviated pain behaviors. In addition, intervening ß3-adrenoceptor (ADRB3) signaling in brown adipocytes by SR59230a (a specific ADRB3 antagonist) treatment or removal of brown adipose tissues could effectively decrease serum IL-6 levels, ameliorate BSCB disruption, and alleviate incisional pain. Further results displayed that SI-exposed rats also showed markedly spinal microglia activation. And exogenous His-tagged IL-6 could pass through the disrupted BSCB, which might contribute to microglia activation. Injection of SR59230a or ablation of brown adipose tissues could effectively reduce the activation of spinal microglia. Thus, our findings suggest that serum IL-6 induced by brown adipocyte ADRB3 signaling contributed to BSCB disruption and spinal microglia activation, which might be involved in preoperative stress mediated CPSP. This work indicates a promising treatment strategy for preoperative stress induced CPSP by blocking ADRB3.

Comparative analysis of machine learning vs. traditional modeling approaches for predicting in-hospital mortality after cardiac surgery: temporal and spatial external validation based on a nationwide cardiac surgery registry.

AIMS: Preoperative risk assessment is crucial for cardiac surgery. Although previous studies suggested machine learning (ML) may improve in-hospital mortality predictions after cardiac surgery compared to traditional modeling approaches, the validity is doubted due to lacking external validation, limited sample sizes, and inadequate modeling considerations. We aimed to assess predictive performance between ML and traditional modelling approaches, while addressing these major limitations. METHODS AND RESULTS: Adult cardiac surgery cases (n = 168 565) between 2013 and 2018 in the Chinese Cardiac Surgery Registry were used to develop, validate, and compare various ML vs. logistic regression (LR) models. The dataset was split for temporal (2013-2017 for training, 2018 for testing) and spatial (geographically-stratified random selection of 83 centers for training, 22 for testing) experiments, respectively. Model performances were evaluated in testing sets for discrimination and calibration. The overall in-hospital mortality was 1.9%. In the temporal testing set (n = 32 184), the best-performing ML model demonstrated a similar area under the receiver operating characteristic curve (AUC) of 0.797 (95% CI 0.779-0.815) to the LR model (AUC 0.791 [95% CI 0.775-0.808]; P = 0.12). In the spatial experiment (n = 28 323), the best ML model showed a statistically better but modest performance improvement (AUC 0.732 [95% CI 0.710-0.754]) than LR (AUC 0.713 [95% CI 0.691-0.737]; P = 0.002). Varying feature selection methods had relatively smaller effects on ML models. Most ML and LR models were significantly miscalibrated. CONCLUSION: ML provided only marginal improvements over traditional modelling approaches in predicting cardiac surgery mortality with routine preoperative variables, which calls for more judicious use of ML in practice.

Which should you choose for post operative atrial fibrillation, carvedilol or metoprolol? A systemic review and meta-analysis.

BACKGROUND: Postoperative atrial fibrillation (POAF) is the most common arrhythmic complication following cardiac surgery. Current guidelines suggest beta-blockers for the prevention of POAF. In comparing metoprolol succinate with carvedilol, the later has sparked interest in its usage as an important medication for POAF prevention. METHODS: We considered randomized controlled studies (RCTs) and retrospective studies that evaluated the efficacy of carvedilol versus metoprolol for the prevention of POAF. After literature search, data extraction, and quality evaluation, pooled data were analyzed using either the fixed-effect or random-effect model using Review Manager 5.3. The Cochrane risk of bias tool was used to assess the bias of included studies. The incidence of POAF was the primary endpoint, while mortality rate and bradycardia were secondary outcomes. RESULTS: In meta-analysis 5 RCTs and 2 retrospective studies with a total of 1000 patients were included. The overall effect did not favor the carvedilol over metoprolol groups in terms of mortality rate [risk ratio 0.45, 95 % CI (0.1-1.97), P=0.29] or incidence of bradycardia [risk ratio 0.63, 95 % CI (0.32-1.23), P=0.17]. However, the incidence of POAF was lower in patients who received carvedilol compared to metoprolol [risk ratio 0.54, 95 % CI (0.42-0.71), P < 0.00001]. CONCLUSION: In patients undergoing cardiac surgery, carvedilol may minimize the occurrence of POAF more effectively than metoprolol. To definitively establish the efficacy of carvedilol compared to metoprolol and other beta-blockers in the prevention of POAF, a large-scale, well-designed randomized controlled trials are required.

Developmental and reproductive toxicity hazard characterization of 2-amino-2-methyl-1-propanol (AMP).

2-Amino-2-methyl-1-propanol (AMP™) is a widely used pH stabilizer in personal care products (PCPs); thus, the safety implications of dermal AMP exposure remain of interest. We have previously reported that exposure to AMP in PCPs when used as intended is not anticipated to result in an increased risk of hepatotoxicity (primarily steatosis and altered phospholipid homeostasis). The current study focuses on AMP in PCP's potential for developmental and reproductive toxicity (DART) in humans, based on data from animal studies. Animal studies suggest that exposure to AMP can result in post-implantation loss. However, such effects occur at maternally toxic doses, posing a challenge for determining appropriate hazard classifications in the context of relevant consumer use scenarios. Our assessment concluded that human exposure to AMP in PCPs is not anticipated to result in DART at non-maternally toxic doses. Further, mode of action (MOA) analysis elucidated the potential biological pathways underlying DART effects observed in high-dose animal studies, such that perturbation of uterine choline synthesis was the most well-supported MOA hypothesis. Downstream uterine effects might reflect choline-dependent changes in epigenetic control of pathways important for implantation maintenance and uterine cell energetics. Since AMP-induced post-implantation loss occurs at doses higher than pathology related to liver toxicity, maintaining AMP exposures from exceeding the onset dose for maternal liver effects will also be protective of DART effects. Furthermore, dermal exposure to AMP expected from the use of PCPs is highly unlikely to result in toxicologically significant systemic AMP concentrations; thus, DART is not anticipated.

Sentinel lymph node biopsy for breast cancer during pregnancy: A comprehensive update.

BACKGROUND: Pregnant patients diagnosed with breast cancer (PrBC) may receive substantially different treatments compared to general population, considering that certain treatment options cannot be applied during pregnancy due to their potential harmful effects to the foetus. Regarding the use of sentinel lymph node biopsy (SLNB) in pregnant patients, potential concerns include foetal harm from radiation exposure, possible teratogenic effects of blue dyes and maternal anaphylaxis to isosulfan. OBJECTIVE: The main objective of the present systematic review is to summarize and present current knowledge and up-to-date evidence about the safety and efficacy of SLNB in PABC. METHODS: MEDLINE, Google Scholar and UpToDate databases were searched up to 22 January 2023. Articles studying the safety and effectiveness of SLNB in patients for PrBC were eligible for inclusion in the present review. RESULTS: In total, 63 articles that met the inclusion criteria were included in this study. Forty-seven articles were strongly in favour of performing SLNB in PABC, 4 articles were partially in favour, 10 articles were strongly against and 2 articles were partially against performing SLNB in PABC. Sub-categorization based on type of study showed that the majority of studies in favour were of higher level of evidence than those against. Furthermore, there were overall 12 studies reporting on outcomes. There were overall 382 women with PrBC that underwent SLNB. Full data were reported for 237 cases. Overall live birth rate was 95.8%, while overall neonatal complication rate was 3.4%. No case of maternal side effects or anaphylactic reaction, maternal death, stillbirth and neonatal death was reported (0%). CONCLUSIONS: Sentinel lymph node biopsy seems to be safe and effective technique for breast cancer during pregnancy.

The ß-Blocker Carvedilol and Related Aryloxypropanolamines Promote ERK1/2 Phosphorylation in HEK293 Cells with K A Values Distinct From Their Equilibrium Dissociation Constants as ß 2-Adrenoceptor Antagonists: Evidence for Functional Affinity.

The determination of affinity by using functional assays is important in drug discovery because it provides a more relevant estimate of the strength of interaction of a ligand to its cognate receptor than radioligand binding. However, empirical evidence for so-called, "functional affinity" is limited. Herein, we determined whether the affinity of carvedilol, a ß-adrenoceptor antagonist used to treat heart failure that also promotes extracellular signal-regulated kinases 1 and 2 (ERK1/2) phosphorylation, differed between these two pharmacological activities. Four structurally related ß-adrenoceptor antagonists (alprenolol, carazolol, pindolol, propranolol) that also activated ERK1/2 were included as comparators to enhance our understanding of how these drugs work in the clinical setting. In HEK293 cells stably expressing the human ß 2-adrenoceptor carvedilol and related aryloxypropanolamines were partial agonists of ERK1/2 phosphorylation with potencies ([A]50s) that were lower than their equilibrium dissociation constants (K Bs) as ß 2-adrenoceptor antagonists. As the [A]50 of a partial agonist is a good approximation of its K B, then these data indicated that the affinities of carvedilol and related ligands for these two activities were distinct. Moreover, there was a significant negative rank order correlation between the [A]50 of each ligand to activate ERK1/2 and their intrinsic activities (i.e., as intrinsic activity for ERK1/2 phosphorylation increased, so did affinity). Genome editing revealed that the transducer that coupled the ß 2-adrenoceptor to ERK1/2 phosphorylation in response to carvedilol and other ß 2-adrenoceptor antagonists was Gαs. Collectively, these data support the concept of "functional affinity" and indicate that the ability of the ß 2-adrenoceptor to recruit Gαs may influence the affinity of the activating ligand. SIGNIFICANCE STATEMENT: In HEK293 cells overexpressing the human ß2-adrenoceptor carvedilol and four related aryloxypropanolamines behaved as ß2-adrenoceptor antagonists and partial agonists of ERK1/2 phosphorylation with rank orders of affinity that were distinct. These data imply that carvedilol and other ß-blockers can stabilize the ß2-adrenoceptor in different affinity conformations that are revealed when functionally distinct responses are measured. This is the basis for the pharmacological concept of "functional affinity."

Synthesis of ionically imprinted Poly(Alylthiourea) in the presence of 1-(2-Pyridylazo)-2-Napthol (PAN) for preconcentration in magnetic dispersive solid phase of nickel ions in water and food samples.

In the present study, a magnetic ion-imprinted polymer based on n-allylthiourea in the presence of 1-(2-pyridylazo)-2-naphthol (MIIP-PAN) was synthesized, characterized, and applied in the preconcentration of nickel ions by dispersive magnetic solid phase extraction (DMSPE) with FAAS detection. For comparison, non-imprinted polymer (MNIP-PAN) and imprinted polymer without PAN were synthesized. The characterization of the polymers was performed by FT-IR, DRX, TEM, TGA, VSM, and BET. Selectivity studies were performed comparing the competitive adsorption of Ni2+ with other cations on MIIP-PAN and MNIP-PAN, achieving higher relative selectivity coefficients for MIIP-PAN than for MNIP-PAN and NIP. Under optimized conditions, the method provided a preconcentration factor of 76.70, detection limit of 0.25 µg/L and intra-day (2.06 - 2.33 %) and inter-day (1.82 - 4.90 %) precision. The developed method was applied to samples of water, teas, and chocolate powder, and its precision was evaluated through tests of recovery and analysis of certified materials.

Discovery of novel isopropanolamine inhibitors against MoTPS1 as potential fungicides with unique mechanisms.

The resistance and ecotoxicity of fungicides seriously restrict our ability to effectively control Magnaporthe oryzae. Discovering fungicidal agents based on novel targets, including MoTPS1, could efficiently address this situation. Here, we identified a hit VS-10 containing an isopropanolamine fragment as a novel MoTPS1 inhibitor through virtual screening, and forty-four analogs were synthesized by optimizing the structure of VS-10. Utilizing our newly established ion-pair chromatography (IPC) and leaf inoculation methods, we found that compared to VS-10, its analog j11 exhibited substantially greater inhibitory activity against both MoTPS1 and the pathogenicity of M. oryzae. Molecular simulations clarified that the electrostatic interactions between the bridging moiety of isopropanolamine and residue Glu396 of contributed significantly to the binding of j11 and MoTPS1. We preliminarily revealed the unique fungicidal mechanism of j11, which mainly impeded the infection of M. oryzae by decreasing sporulation, killing a small portion of conidia and interfering with the accumulation of turgor pressure in appressoria. Thus, in this study, a novel fungicide candidate with a unique mechanism targeting MoTPS1 was screened and discovered.

Hospital-based health technology assessment of innovative medical devices: insights from a nationwide survey in France.

OBJECTIVES: To better understand the process of hospital acquisition of innovative medical devices (MDs) and the hospital-based health technology assessment (HB-HTA) pathways in France, an in-depth study based on a quantitative approach is needed. The aim of the present study was to assess through a national survey how HB-HTA is currently implemented in French hospitals and to identify its level of formalization. METHODS: A quantitative online survey was conducted among hospitals performing HB-HTA in France, with a focus on the acquisition of innovative MDs for individual use. The survey, conducted between March and June 2022, was developed by a scientific board composed of members of the French-speaking Society for HB-HTA. RESULTS: Sixty-seven out of 131 surveyed hospitals with HB-HTA activities responded, including 29 university hospitals, 24 nonprofit private hospitals, and 14 local hospitals. Sixty-one respondents (91 percent) reported the existence of a process dedicated to evaluating innovative MDs; of these, 16 declared that their hospitals had a formalized unit with HB-HTA activity. These units were more frequently found in larger hospitals with more than 500 inpatient beds (n = 16, p = 0.0160) and in university hospitals (n = 12, p = 0.0158). No hospital reported any collaboration with HAS, the French national HTA agency. CONCLUSION: A diverse range of HB-HTA organizations with different structural levels exist in France for MD procurement linked to the category of hospitals. The study highlights the need for recognition of HB-HTA activity at the regulatory level in France and for direct collaboration between HTA activities performed at local and national levels.

Population Pharmacokinetic-Pharmacodynamic Modeling of Carvedilol to Evaluate the Effect of Cytochrome P450 2D6 Genotype on the Heart Rate Reduction.

BACKGROUND: Carvedilol is a beta-adrenergic receptor antagonist primarily metabolized by cytochromes P450 (CYP) 2D6. This study established a carvedilol population pharmacokinetic (PK)-pharmacodynamic (PD) model to describe the effects of CYP2D6 genetic polymorphisms on the inter-individual variability of PK and PD. METHODS: The PK-PD model was developed from a clinical study conducted on 21 healthy subjects divided into three CYP2D6 phenotype groups, with six subjects in the extensive metabolizer (EM, *1/*1, *1/*2), seven in the intermediate metabolizer-1 (IM-1, *1/*10, *2/*10), and eight in the intermediate metabolizer-2 (IM-2, *10/*10) groups. The PK-PD model was sequentially developed, and the isoproterenol-induced heart rate changes were used to establish the PD model. A direct effect response and inhibitory Emax model were used to develop a carvedilol PK-PD model. RESULTS: The carvedilol PK was well described by a two-compartment model with zero-order absorption, lag time, and first-order elimination. The carvedilol clearance in the CYP2D6*10/*10 group decreased by 32.8% compared with the other groups. The inhibitory concentration of carvedilol estimated from the final PK-PD model was 16.5 ng/mL regardless of the CYP2D6 phenotype. CONCLUSION: The PK-PD model revealed that the CYP2D6 genetic polymorphisms were contributed to the inter-individual variability of carvedilol PK, but not PD.

Tuning the Metabolic Stability of Visual Cycle Modulators through Modification of an RPE65 Recognition Motif.

In the eye, the isomerization of all-trans-retinal to 11-cis-retinal is accomplished by a metabolic pathway termed the visual cycle that is critical for vision. RPE65 is the essential trans-cis isomerase of this pathway. Emixustat, a retinoid-mimetic RPE65 inhibitor, was developed as a therapeutic visual cycle modulator and used for the treatment of retinopathies. However, pharmacokinetic liabilities limit its further development including: (1) metabolic deamination of the γ-amino-α-aryl alcohol, which mediates targeted RPE65 inhibition, and (2) unwanted long-lasting RPE65 inhibition. We sought to address these issues by more broadly defining the structure-activity relationships of the RPE65 recognition motif via the synthesis of a family of novel derivatives, which were tested in vitro and in vivo for RPE65 inhibition. We identified a potent secondary amine derivative with resistance to deamination and preserved RPE65 inhibitory activity. Our data provide insights into activity-preserving modifications of the emixustat molecule that can be employed to tune its pharmacological properties.