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1.
PLoS One ; 19(6): e0305868, 2024.
Article in English | MEDLINE | ID: mdl-38913661

ABSTRACT

The cannabinoid receptor type 1 (CB1R) is a promising therapeutic target for various neurodegenerative diseases, including HIV-1-associated neurocognitive disorder (HAND). However, the therapeutic potential of CB1R by direct activation is limited due to its psychoactive side effects. Therefore, research has focused on indirectly activating the CB1R by utilizing positive allosteric modulators (PAMs). Studies have shown that CB1R PAMs (ZCZ011 and GAT211) are effective in mouse models of Huntington's disease and neuropathic pain, and hence, we assess the therapeutic potential of ZCZ011 in a well-established mouse model of neuroHIV. The current study investigates the effect of chronic ZCZ011 treatment (14 days) on various behavioral paradigms and the endocannabinoid system in HIV-1 Tat transgenic female and male mice. Chronic ZCZ011 treatment (10 mg/kg) did not alter body mass, locomotor activity, or anxiety-like behavior regardless of sex or genotype. However, differential effects were noted in hot plate latency, motor coordination, and recognition memory in female mice only, with ZCZ011 treatment increasing hot plate latency and improving motor coordination and recognition memory. Only minor effects or no alterations were seen in the endocannabinoid system and related lipids except in the cerebellum, where the effect of ZCZ011 was more pronounced in female mice. Moreover, AEA and PEA levels in the cerebellum were positively correlated with improved motor coordination in female mice. In summary, these findings indicate that chronic ZCZ011 treatment has differential effects on antinociception, motor coordination, and memory, based on sex and HIV-1 Tat expression, making CB1R PAMs potential treatment options for HAND without the psychoactive side effects.


Subject(s)
Endocannabinoids , Mice, Transgenic , Receptor, Cannabinoid, CB1 , tat Gene Products, Human Immunodeficiency Virus , Animals , Female , Male , Endocannabinoids/metabolism , Receptor, Cannabinoid, CB1/metabolism , Receptor, Cannabinoid, CB1/genetics , Mice , tat Gene Products, Human Immunodeficiency Virus/genetics , tat Gene Products, Human Immunodeficiency Virus/metabolism , HIV-1/drug effects , Allosteric Regulation/drug effects , Behavior, Animal/drug effects , Motor Activity/drug effects , Disease Models, Animal
2.
Toxicol In Vitro ; 97: 105806, 2024 May.
Article in English | MEDLINE | ID: mdl-38432573

ABSTRACT

INTRODUCTION: Statins have demonstrated chondroprotective effects by reducing inflammation and mitigating extracellular matrix degradation. However, statins are also reported to be cytotoxic to several types of cells. Early-onset osteoarthritis (OA) is characterized by synovial inflammation, which adversely affects hyaluronan (HA) production in fibroblast-like synoviocytes (FLSs). Nevertheless, the precise effects of statins on the synovium remain unclear. METHODS: This study investigated the impact of lovastatin on human FLSs, and HA secretion-related genes, signaling pathways, and production were evaluated. RESULTS: The findings revealed that high doses of lovastatin (20 or 40 µM) decreased FLS viability and increased cell death. FLS proliferation ceased when cultured in a medium containing 5 or 10 µM lovastatin. mRNA expression analysis demonstrated that lovastatin (5 and 10 µM) upregulated the gene level of hyaluronan synthase 1 (HAS1), HAS2, and proteoglycan 4 (PRG4), but not HAS3. While the expression of multidrug resistance-associated protein 5 transporter gene remained unaffected, both inward-rectifying potassium channel and acid-sensing ion channel 3 were upregulated. Western blot further confirmed that lovastatin increased the production of HAS1 and PRG4, and activated the PKC-α, ERK1/2, and p38-MAPK signaling pathways. Additionally, lovastatin elevated intracellular cAMP levels and HA production in FLSs. CONCLUSION: Lovastatin impairs cellular proliferation but enhances HA production in human FLSs.


Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors , Synoviocytes , Humans , Synoviocytes/metabolism , Hyaluronic Acid/metabolism , Lovastatin/pharmacology , Lovastatin/metabolism , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Fibroblasts/metabolism , Cell Proliferation , Inflammation/metabolism , Cells, Cultured
3.
Int J Biol Macromol ; 264(Pt 1): 130479, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38431003

ABSTRACT

This work reports an improved enzyme-linked immunosorbent assay (ELISA) via the interaction between prussian blue nanoparticles (PBNPs) and amines for aflatoxin B1 (AFB1) detection. The effect of different amines on the structure and properties of PBNPs was systematically investigated. Amines with pKb < 7, like ethylenediamine (EDA), can decompose structure of PBNPs, leading to the reduction of extinction coefficient and photothermal effect. Whereas, amines with large pKb > 7, such as o-phenylenediamine (OPD), could undergo catalytic oxidation by PBNPs, resulting in the production of fluorescent and colored oxidation products. Accordingly, EDA and OPD were used to construct improved ELISA. Specifically, silica nanoparticles, on which AFB1 aptamer and amino binding agent (ethylenediaminetetraacetic acid disodium salt, EDTA•2Na) were previously assembled via carboxyl-amino linkage, are anchored to microplates by AFB1 and antibody. EDA concentration can be regulated by EDTA•2Na to affect extinction coefficient and photothermal effect of PBNPs, thereby achieving visual colorimetric and portable photothermal signal readout (Model 1). OPD concentration can also be controlled by EDTA•2Na, thus generating colorimetric and ultrasensitive fluorescent signals through PBNPs catalysis (Model 2). The proposed strategy not only opens new avenue for signal readout mode of biosensing, but also provides universal technique for hazards.


Subject(s)
Biosensing Techniques , Ferrocyanides , Nanoparticles , Aflatoxin B1/analysis , Amines , Nanoparticles/chemistry , Enzyme-Linked Immunosorbent Assay , Biosensing Techniques/methods , Limit of Detection
4.
Cannabis Cannabinoid Res ; 9(2): 581-590, 2024 Apr.
Article in English | MEDLINE | ID: mdl-36656312

ABSTRACT

Introduction: Cannabidiol (CBD) has gained considerable public and scientific attention because of its known and potential medicinal properties, as well as its commercial success in a wide range of products. Although CBD lacks cannabimimetic intoxicating side effects in humans and fails to substitute for cannabinoid type-1 receptor (CB1R) agonists in laboratory animal models of drug discrimination paradigm, anecdotal reports describe it as producing a "pleasant" subjective effect in humans. Thus, we speculated that this phytocannabinoid may elicit distinct subjective effects. Accordingly, we investigated whether mice would learn to discriminate CBD from vehicle. Additionally, we examined whether CBD may act as a CB1R allosteric and whether it would elevate brain endocannabinoid concentrations. Materials and Methods: C57BL/6J mice underwent discrimination training of either CBD or the high-efficacy CB1R agonist CP55,940 from vehicle. Additionally, we examined whether CBD or the CB1R-positive allosteric modulator ZCZ011 would alter the CP55,940 discriminative cue. Finally, we tested whether an acute CBD injection would elevate endocannabinoid levels in brain, and also quantified blood and brain levels of CBD. Results: Mice failed to discriminate high doses of CBD from vehicle following 124 training days, though the same subjects subsequently acquired CP55,940 discrimination. In a second group of mice trained to discriminate CP55,940, CBD neither elicited substitution nor altered response rates. A single injection of 100 or 200 mg/kg CBD did not affect brain levels of endogenous cannabinoids and related lipids and resulted in high drug concentrations in blood and whole brain at 0.5 h and continued to increase at 3 h. Discussion: CBD did not engender an interoceptive stimulus, did not disrupt performance in a food-motivated operant task, and lacked apparent effectiveness in altering brain endocannabinoid levels or modulating the pharmacological effects of a CB1R agonist. These findings support the assertions that CBD lacks abuse liability and its acute administration does not appear to play a functional role in modulating key components of the endocannabinoid system in whole animals.


Subject(s)
Cannabidiol , Humans , Mice , Animals , Cannabidiol/pharmacology , Endocannabinoids , Mice, Inbred C57BL , Cyclohexanols/pharmacology , Cannabinoid Receptor Agonists
5.
Ther Adv Chronic Dis ; 14: 20406223231189224, 2023.
Article in English | MEDLINE | ID: mdl-37841212

ABSTRACT

Background: Numerous first-line immune checkpoint inhibitors (ICI) were developed for patients with advanced non-small cell lung cancer (NSCLC) lacking driver gene mutations. However, this group consists of a heterogeneous patient population, for whom the optimal therapeutic choice is yet to be confirmed. Objective: To identify the best first-line immunotherapy regimen for overall advanced NSCLC patients and different subgroups. Design: Systematic review and Bayesian network meta-analysis (NMA). Methods: We searched several databases to retrieve relevant literature. We performed Bayesian NMA for the overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and treatment-related adverse events (tr-AEs) with a grade equal or more than 3 (grade ⩾ 3 tr-AEs). Subgroup analysis was conducted according to programed death ligand 1 (PD-L1) levels, histologic type, central nervous system (CNS) metastases and tobacco use history. Results: For the PD-L1 non-selective patients, sintilimab plus chemotherapy (sinti-chemo) provided the best OS [hazard ratio (HR) = 0.59, 95% confidence interval (CI):0.42-0.83]. Nivolumab plus bevacizumab plus chemotherapy (nivo-bev-chemo) was comparable to atezolizumab plus bevacizumab plus chemotherapy (atezo-bev-chemo) in prolonging PFS (HR = 0.99, 95% CI: 0.51-1.91). Atezo-bev-chemo remarkably elevated the ORR than chemotherapy (OR = 3.13, 95% CI: 1.51-6.59). Subgroup analysis showed pembrolizumab plus chemotherapy (pembro-chemo) ranked first in OS in subgroups of PD-L1 < 1%, non-squamous, no CNS metastases, with or without smoking history, and ranked second in OS in subgroups of PD-L1 ⩾ 1% and PD-L1 1-49%. Cemiplimab and sugemalimab plus chemotherapy ranked first in OS and PFS for squamous subgroup, respectively. For patients with CNS metastases, nivolumab plus ipilimumab plus chemotherapy (nivo-ipili-chemo) and camrelizumab plus chemotherapy provided the best OS and PFS, respectively. Conclusions: Sinti-chemo and nivo-bev-chemo were two effective first-line regimens ranked first in OS and PFS for overall patients, respectively. Pembro-chemo was favorable for patients in subgroups of PD-L1 < 1%, PD-L1 ⩾ 1%, PD-L1 1-49%, non-squamous, no CNS metastases, with or without smoking history. Addition of bevacizumab consistently provided with favorable PFS results in patients of all PD-L1 levels. Cemiplimab was the best option in squamous subgroup and nivo-ipili-chemo in CNS metastases subgroup due to their advantages in OS.


First-line PD-1/PD-L1 inhibitors for advanced NSCLC patients lacking driver gene mutations Patients with advance non-small cell lung cancer (NSCLC) lacking driver gene mutations are a group of heterogeneous people. Although numerous therapeutic regimens were developed, the optimal choice for advanced NSCLC patients and specific subgroups is yet to be identified.We conducted a Bayesian network meta-analysis with the currently available data, and performed subgroup analyses according to programed death ligand 1 (PD-L1) levels, histologic type, CNS metastases and tobacco use history.Our key findings were as follows: (1) in non-selective PD-L1 groups, sinti-chemo and pembro-chemo provided the best OS outcome; nivo-bev-chemo and atezo-bev-chemo resulted in the most prolonged PFS; atezo-bev-chemo and pembro-chemo yielded significantly improved ORR; (2) pembro-chemo was favorable for patients in subgroups of PD-L1 < 1%, PD-L1 ⩾ 1%, PD-L1 1­49%, non-squamous, no CNS metastases, with or without smoking history; (3) immunochemotherapies involving anti-PD-1 agents generally exhibited potential advantages over those with anti-PD-L1 drugs; (4) addition of anti-VEGF drugs to immunochemotherapies consistently provided with favorable PFS results in advanced NSCLC patients with or without PD-L1 selection; (5) in patients with squamous NSCLC, cemiplimab and suge-chemo were the optimal drugs for improving OS and PFS, respectively; in patients with non-squamous NSCLC, pembro-chemo provided the best OS, while nivo-bev-chemo, atezo-bev-chemo, sinti-chemo, and pembro-chemo showed comparable advantages in improving PFS; (6) for patients with CNS metastases, nivo-ipili-chemo and camre-chemo provided the best OS and PFS, respectively.Our findings provide evidence for a more precise selection of first-line immunotherapy regimen for advanced NSCLC patients.

6.
Heart Rhythm O2 ; 4(9): 538-548, 2023 Sep.
Article in English | MEDLINE | ID: mdl-37744936

ABSTRACT

Background: Coronary microvascular dysfunction (CMD) and hypertension (HTN) occur frequently in hypertrophic cardiomyopathy (HCM), but whether blood pressure (BP) influences CMD and outcomes is unknown. Objective: The purpose of this study was to test the hypothesis that HTN is associated with worse CMD and outcomes. Methods: This retrospective study included 690 HCM patients. All patients underwent cardiac magnetic resonance imaging, echocardiography, and rhythm monitoring; 127 patients also underwent rest/vasodilator stress 13NH3 positron emission tomography myocardial perfusion imaging. Patients were divided into 3 groups based on their rest systolic blood pressure (SBP) (group 1 ≤110 mm Hg; group 2 111-140; group 3 >140 mm Hg) and were followed for development of ventricular tachycardia (VT)/ventricular fibrillation (VF), heart failure (HF), death, and composite outcome. Results: Group 1 patients had the lowest age and left ventricular (LV) mass but the highest prevalence of nonobstructive hemodynamics and restrictive diastolic filling. LV scar was similar in the 3 groups. Group 1 had the lowest rest and stress myocardial blood flow (MBF) and highest SDS (summed difference score). Rest SBP was positively correlated with stress MBF and negatively correlated with SDS. Group 1 had the highest incidence of VT/VF, whereas the incidences of HF, death, and composite outcome were similar among the 3 groups. In multivariate analysis, rest SBP ≤110 mm Hg was independently associated with VT/VF (hazard ratio 2.6; 95% confidence interval 1.0-6.7; P = .04). Conclusion: SBP ≤110 mm Hg is associated with greater severity of CMD and coronary microvascular ischemia and higher incidence of ventricular arrhythmias in HCM.

7.
Int J Pharm ; 640: 123042, 2023 Jun 10.
Article in English | MEDLINE | ID: mdl-37178789

ABSTRACT

Currently there are no compendial assays for testing drug release from rectal suppositories. It is therefore essential to study different in vitro release testing (IVRT) and in vitro permeation testing (IVPT) methods for identifying a suitable technique to compare in vitro drug release and to predict in vivo performance of rectal suppositories. In the present study, three different rectal suppository formulations of mesalamine (CANASA, Generic, and In-house) were studied for in vitro bioequivalence. All the different suppository products were characterized by performing weight variation, content uniformity, hardness, melting time, and pH tests. Viscoelastic behavior of the suppositories was also tested both in presence and absence of mucin. Four different IVRT techniques such as Dialysis, Horizontal Ussing Chamber, Vertical Franz cell, and USP apparatus 4. IVPT studies were performed using Horizontal Ussing chamber and Vertical Franz cell methods. Q1/Q2 equivalent products (CANASA, Generic) and a half-strength product were studied to understand the reproducibility, bio relevance, and discriminatory ability of the IVRT and IVPT methods. This study is the first of its kind where molecular docking studies were performed to determine the potential interactions of drug (mesalamine) with mucin, IVRT studies were conducted with and without the presence of mucin, and porcine rectal mucosa was used to perform IVPT tests. The USP 4 method and Horizontal Ussing chamber methods were found to be suitable IVRT and IVPT techniques, respectfully, for rectal suppositories. RLD (Reference Listed Drug) and Generic rectal suppositories were found to exhibit similar release rate and permeation profiles obtained from USP 4, and the IVPT studies, respectfully. Wilcoxon Rank Sum/Mann-Whitney rank test, conducted for the IVRT profiles obtained using USP 4 method, proved the sameness of RLD and Generic suppository products.


Subject(s)
Mesalamine , Mucins , Animals , Swine , Suppositories , Reproducibility of Results , Molecular Docking Simulation
8.
Int J Cardiol Cardiovasc Risk Prev ; 16: 200166, 2023 Mar.
Article in English | MEDLINE | ID: mdl-36874040

ABSTRACT

Objective: Hypertensive response to exercise (HRE) is observed in patients with hypertrophic cardiomyopathy (HCM) with normal resting blood pressure (BP). However, the prevalence or prognostic implications of HRE in HCM remain unclear. Methods: In this study, normotensive HCM subjects were enrolled. HRE was defined as systolic BP > 210 mmHg in men or >190 mmHg in women, or diastolic BP > 90 mmHg, or an increase in diastolic BP > 10 mmHg during treadmill exercise. All participants were followed for subsequent development of hypertension, atrial fibrillation (AF), heart failure (HF), sustained ventricular tachycardia/fibrillation (VT/VF), and all-cause death. Six hundred and eighty HCM patients were screened. Results: 347 patients had baseline hypertension, and 333 patients were baseline normotensive. 132 (40%) of the 333 patients had HRE. HRE was associated with female sex, lower body mass index and milder left ventricular outflow tract obstruction. Exercise duration and metabolic equivalents were similar between patients with or without HRE, but the HRE group had higher peak heart rate (HR), better chronotropic response and more rapid HR recovery. Conversely, non-HRE patients were more likely to exhibit chronotropic incompetence and hypotensive response to exercise. After a mean follow-up of 3.4 years, patients with and without HRE had similar risks of progression to hypertension, AF, HF, sustained VT/VF or death. Conclusion: HRE is common in normotensive HCM patients during exercise. HRE did not carry higher risks of future hypertension or cardiovascular adverse outcomes. Conversely, the absence of HRE was associated with chronotropic incompetence and hypotensive response to exercise.

9.
Article in Chinese | WPRIM (Western Pacific) | ID: wpr-995276

ABSTRACT

Objective:To study the changes in long non-coding RNA C2dat1 expression in kidney tissues of rats at different stages of diabetic kidney disease (DKD) and its relationship with renal interstitial fibrosis.Methods:Forty-eight male SD rats were randomly divided into two groups with 24 rats in each group: control group and DKD group. The rats in the control group were fed with ordinary diet, while those in the DKD group were fed with high-fat diet and drank water freely. After eight weeks of feeding, the rats were fasted for 12 h with free access to water. Then, the DKD group was given a one-time intrabitoneal injection of streptozotocin and the control group was given an equal dose of sodium citrate buffer. After 72 h, the random peripheral blood glucose concentration (≥ 16.7 mmol/L for three consecutive days) and urine sugar (positive) were tested to assess the establishment of the diabetes model. Urine, blood and kidney samples were collected at 3, 6, 9 and 12 weeks. The urinary protein excretion rate within 24 h, urinary creatinine and serum total cholesterol were measured by automatic biochemical apparatus. Pathological changes in kidney tissues were observed by HE staining. The expression of calcium/calmodulin-dependent protein kinase Ⅱ delta (CaMK2D), p65, p50, α-SMA and E-cardherin was detected by immunohistochemistry. Quantitative real-time PCR (qPCR) was used to detect the expression of lncRNA C2dat1 and CaMK2D. The relationship of lncRNA C2dat1 with α-SMA, E-cardherin and CaMK2D was analyzed by correlation analysis. In in vitro experiment, renal tubular epithelial cells HK-2 were induced by high glucose. The expression of lncRNA C2dat1 and CaMK2D in HK-2 cells was detected by qPCR after 24, 48 and 72 h of intervention. Results:The rats in the DKD group showed typical symptoms such as polydipsia, polyphagia, significant weight loss and increased blood glucose as compared with the rats in the control group. Results of the biochemical tests revealed that compared with the control group, the DKD group had increased 24 h excretion rate of urinary protein, decreased urinary creatinine and up-regulated total cholesterol. HE staining showed that the rats in the control group had intact glomeruli, normal basement membrane and no mesangial hyperplasia or inflammatory cell infiltration. However, enlarged glomeruli and evenly thickened basement membrane were observed in the DKD group. Immunohistochemistry indicated that the expression of CaMK2D, p50 and α-SMA was higher in the DKD group than in the control group, while the expression of E-cardherin was lower in the DKD group. qPCR results showed that the expression of lncRNA C2dat1 and CaMK2D at mRNA level was higher in the DKD group than in the control group. In in vitro experiment, the expression of lncRNA C2dat1 and CaMK2D at mRNA level was also higher in HK-2 cells induced by high glucose than in the control group. Correlation analysis indicated that lncRNA C2dat1 was positively correlated with α-SMA and CaMK2D, but negatively correlated with E-cardherin. Conclusions:During the progression of DKD, the high expression of lncRNA C2dat1 might promote diabetic renal interstitial fibrosis by regulating the expression of CaMK2D to activate the NF-κB signaling pathway.

10.
Chinese Journal of Nephrology ; (12): 32-35, 2023.
Article in Chinese | WPRIM (Western Pacific) | ID: wpr-994947

ABSTRACT

The clinical data of maintenance hemodialysis (MHD) patients from twenty hemodialysis centers in Guizhou province from June to September 2020 were collected by cross-sectional study. The patients were divided into AFD group and non-AFD group according to whether AFD had occurred. LTI was measured by body composition monitor. The results showed that the incidence of AFD in 2 781 MHD patients was 30.0% (835/2 781). Median LTI level was 15.2 (13.2, 17.5) kg/m 2. The LTI level in the AFD group was higher than that in the non-AFD group ( P < 0.05). According to the tertiles of LTI, low LTI group (LTI ≤ 13.9 kg/m 2) had the highest incidence of AFD (35.5%, 334/940), and the high LTI group had the lowest incidence of AFD (26.3%, 241/916), and the difference among the three groups was statistically significant ( χ2=20.182, P < 0.001). Multivariate logistic regression analysis showed that low LTI group as the reference, the risk of AFD in moderate LTI group (13.9 kg/m 2 < LTI ≤ 16.6 kg/m 2) and high LTI group were associated with the 20.0% ( OR=0.800, 95% CI 0.650-0.986, P=0.036) and 22.8% ( OR=0.772, 95% CI 0.616-0.966, P=0.024) decrease, respectively. These results suggest that low LTI level is independently associated with an increased risk of AFD in MHD patients.

11.
Cancers (Basel) ; 14(22)2022 Nov 10.
Article in English | MEDLINE | ID: mdl-36428626

ABSTRACT

Neuroblastoma (NB) is a pediatric tumor of the peripheral nervous system. Approximately 80% of relapsed NB show RAS-MAPK pathway mutations that activate ERK, resulting in the promotion of cell proliferation and drug resistance. Ulixertinib, a first-in-class ERK-specific inhibitor, has shown promising antitumor activity in phase 1 clinical trials for advanced solid tumors. Here, we show that ulixertinib significantly and dose-dependently inhibits cell proliferation and colony formation in different NB cell lines, including PDX cells. Transcriptomic analysis revealed that ulixertinib extensively inhibits different oncogenic and neuronal developmental pathways, including EGFR, VEGF, WNT, MAPK, NGF, and NTRK1. The proteomic analysis further revealed that ulixertinib inhibits the cell cycle and promotes apoptosis in NB cells. Additionally, ulixertinib treatment significantly sensitized NB cells to the conventional chemotherapeutic agent doxorubicin. Furthermore, ulixertinib potently inhibited NB tumor growth and prolonged the overall survival of the treated mice in two different NB mice models. Our preclinical study demonstrates that ulixertinib, either as a single agent or in combination with current therapies, is a novel and practical therapeutic approach for NB.

12.
J Am Heart Assoc ; 11(17): e026016, 2022 09 06.
Article in English | MEDLINE | ID: mdl-36000438

ABSTRACT

Background Systemic vascular resistance (SVR) is an integral component of the hemodynamic profile. Previous studies have demonstrated a close correlation between an estimated SVR analog (eSVR) based on echocardiographic methods and SVR by direct hemodynamic measurement. However, the prognostic impact of eSVR remains unestablished. Methods and Results Study participants with established coronary artery disease from the Heart and Soul Study formed this study cohort. We defined Doppler-derived eSVR as the ratio of systolic blood pressure to left ventricular outflow tract velocity time integral. Study participants were separated based on baseline eSVR tertile: <5.6, 5.6 to <6.9, and ≧6.9. An elevated eSVR was defined as an eSVR in the third tertile (≧6.9). Follow-up eSVR was calculated at the fifth year of checkup. Cardiovascular outcomes included heart failure, major cardiovascular events, and all-cause death. Among the 984 participants (67±11 years old, 82% men), subjects with the highest baseline eSVR tertile were the oldest, with the highest systolic blood pressure and lowest left ventricular outflow tract velocity time integral. A higher eSVR was associated with increased risk of heart failure, major cardiovascular events, and death. The hazard ratio for major cardiovascular events was 1.38 (95% CI, 1.02-1.86, P=0.03) for subjects with the highest eSVR tertile compared with the lowest. In addition, those with a persistently elevated eSVR during follow-up had the most adverse outcomes. Conclusions An elevated eSVR, derived by the ratio of systolic blood pressure and left ventricular outflow tract velocity time integral, was more closely correlated with cardiovascular events than systolic blood pressure alone. Repeatedly elevated eSVR was associated with more adverse outcomes.


Subject(s)
Coronary Artery Disease , Heart Failure , Aged , Female , Heart Ventricles , Humans , Male , Middle Aged , Prognosis , Vascular Resistance
13.
J Pharm Sci ; 111(8): 2312-2321, 2022 08.
Article in English | MEDLINE | ID: mdl-35296412

ABSTRACT

The focus of present work was to synthesize prodrugs of dolutegravir (DTG) for ultra-long delivery purpose. The prodrug was synthesized by esterification of hydroxyl group with carboxyl group of fatty acid (lauric or myristic acid). The prodrugs were characterized by differential scanning calorimetry, X-ray powder diffraction, nuclear magnetic resonance, Fourier transformed infrared, near infrared-chemical imaging, pH-solubility, partition coefficient, and stability (solid and liquid). Stability studies were performed by exposing the powder drugs to 40°C/75% RH for three months and buffer solutions at room temperature for 72 h. The prodrugs and drug were formulated into in-situ implant using biodegradable polymer. Thermal, spectral, and diffractometric data indicated formation of new chemical and solid forms. Formation of prodrugs resulted in lowering of melting point of DTG from 191.1°C to 163.7 and 140.7°C for DTG-Laurate and DTG-Myristate prodrugs, respectively. A decrease in solubility of 18.2-115.9 and 124.5-1594.9 folds was observed for DTG-Laurate and DTG-Myristate, respectively compared to DTG. Similarly, the prodrugs were highly lipophilic compared to DTG. Solid-state and pH-stability profiles of DTG and prodrugs were comparable. Implant formulation released 60.1% in 77 days compared to 95.6% in 35 days in the case of DTG-Myristate and DTG, respectively. In summary, combining prodrug and drug delivery approaches can be utilized for delivering drug for ultra-long period.


Subject(s)
Prodrugs , Heterocyclic Compounds, 3-Ring , Laurates , Myristates , Myristic Acid , Oxazines , Piperazines , Powders , Prodrugs/chemistry , Pyridones , Solubility
14.
Echocardiography ; 39(2): 215-222, 2022 02.
Article in English | MEDLINE | ID: mdl-35060188

ABSTRACT

BACKGROUND: Transient ischemic dilation of the left ventricle (LV) during stress echocardiography indicates extensive myocardial ischemia. It remains unclear whether the change of LV end-systolic volume (ESV) or end-diastolic volume (EDV) better correlated with significant coronary artery disease (CAD). Meanwhile, the clinical significance of the extent of the volumetric change post-stress has not been investigated. METHODS: One hundred and five individuals (62 ± 12 years and 75% men) who underwent coronary angiography following exercise treadmill echocardiography were enrolled retrospectively. An additional 30 age- and sex-matched healthy subjects were included for comparison. LV dilation was defined as any increase in LV volume from rest to peak exercise. Patients who had at least two coronary arteries with significant stenosis were considered as having multi-vessel CAD. RESULTS: Thirty-four patients had ESV dilation during exercise echocardiography. On the contrary, ESV decreased at peak exercise in all healthy subjects. Forty-one patients had multi-vessel CAD, and its prevalence was higher in patients with ESV dilation (65% vs 27%, p = 0.001). The extent of ESV increase correlated with CAD severity. ESV dilation is associated with multi-vessel CAD (Odds ratio [OR] 5.02, 95% confidence interval [CI] 2.09 - 12.07, p < 0.001). After adjustment for EDV increase, clinical, electrocardiographic, and echocardiographic variables, the association remained significant (adjusted OR 5.57, 95% CI 1.37-22.64; p = 0.02). CONCLUSIONS: ESV dilation independently correlated with multi-vessel CAD, whereas EDV dilation did not. The amount of ESV increase correlated with the severity of CAD. Our findings provide a rationale for incorporating volume measurements into stress echocardiography practice.


Subject(s)
Coronary Artery Disease , Echocardiography, Stress , Coronary Artery Disease/complications , Coronary Artery Disease/diagnosis , Dilatation , Echocardiography , Female , Humans , Male , Retrospective Studies , Stroke Volume
15.
Elife ; 112022 01 25.
Article in English | MEDLINE | ID: mdl-35076018

ABSTRACT

Hypertrophic cardiomyopathy (HCM) is associated with risk of sudden cardiac death (SCD) due to ventricular arrhythmias (VAs) arising from the proliferation of fibrosis in the heart. Current clinical risk stratification criteria inadequately identify at-risk patients in need of primary prevention of VA. Here, we use mechanistic computational modeling of the heart to analyze how HCM-specific remodeling promotes arrhythmogenesis and to develop a personalized strategy to forecast risk of VAs in these patients. We combine contrast-enhanced cardiac magnetic resonance imaging and T1 mapping data to construct digital replicas of HCM patient hearts that represent the patient-specific distribution of focal and diffuse fibrosis and evaluate the substrate propensity to VA. Our analysis indicates that the presence of diffuse fibrosis, which is rarely assessed in these patients, increases arrhythmogenic propensity. In forecasting future VA events in HCM patients, the imaging-based computational heart approach achieved 84.6%, 76.9%, and 80.1% sensitivity, specificity, and accuracy, respectively, and significantly outperformed current clinical risk predictors. This novel VA risk assessment may have the potential to prevent SCD and help deploy primary prevention appropriately in HCM patients.


Subject(s)
Cardiomyopathy, Hypertrophic/diagnostic imaging , Computer Simulation , Magnetic Resonance Imaging , Tachycardia, Ventricular/etiology , Adult , Aged , Cardiomyopathy, Hypertrophic/complications , Cardiomyopathy, Hypertrophic/pathology , Cardiomyopathy, Hypertrophic/physiopathology , Death, Sudden, Cardiac/etiology , Death, Sudden, Cardiac/prevention & control , Female , Fibrosis , Humans , Logistic Models , Male , Middle Aged , Myocardium/pathology , Predictive Value of Tests , Retrospective Studies , Risk Assessment , Risk Factors , Tachycardia, Ventricular/diagnosis , Tachycardia, Ventricular/physiopathology , Tachycardia, Ventricular/therapy , Young Adult
16.
J Pharmacol Exp Ther ; 380(1): 1-14, 2022 01.
Article in English | MEDLINE | ID: mdl-34625464

ABSTRACT

Opioid use disorder reflects a major public health crisis of morbidity and mortality in which opioid withdrawal often contributes to continued use. However, current medications that treat opioid withdrawal symptoms are limited by their abuse liability or lack of efficacy. Although cannabinoid 1 (CB1) receptor agonists, including Δ9-tetrahydrocannabinol, ameliorate opioid withdrawal in both clinical and preclinical studies of opioid dependence, this strategy elicits cannabimimetic side effects as well as tolerance and dependence after repeated administration. Alternatively, CB1 receptor positive allosteric modulators (PAMs) enhance CB1 receptor signaling and show efficacy in rodent models of pain and cannabinoid dependence but lack cannabimimetic side effects. We hypothesize that the CB1 receptor PAM ZCZ011 attenuates naloxone-precipitated withdrawal signs in opioid-dependent mice. Accordingly, male and female mice given an escalating dosing regimen of oxycodone, a widely prescribed opioid, and challenged with naloxone displayed withdrawal signs that included diarrhea, weight loss, jumping, paw flutters, and head shakes. ZCZ011 fully attenuated naloxone-precipitated withdrawal-induced diarrhea and weight loss and reduced paw flutters by approximately half, but its effects on head shakes were unreliable, and it did not affect jumping behavior. The antidiarrheal and anti-weight loss effects of ZCZ0111 were reversed by a CB1 not a cannabinoid receptor type 2 receptor antagonist and were absent in CB1 (-/-) mice, suggesting a necessary role of CB1 receptors. Collectively, these results indicate that ZCZ011 completely blocked naloxone-precipitated diarrhea and weight loss in oxycodone-dependent mice and suggest that CB1 receptor PAMs may offer a novel strategy to treat opioid dependence. SIGNIFICANCE STATEMENT: Opioid use disorder represents a serious public health crisis in which current medications used to treat withdrawal symptoms are limited by abuse liability and side effects. The CB1 receptor positive allosteric modulator (PAM) ZCZ011, which lacks overt cannabimimetic behavioral effects, ameliorated naloxone-precipitated withdrawal signs through a CB1 receptor mechanism of action in a mouse model of oxycodone dependence. These results suggest that CB1 receptor PAMs may represent a viable strategy to treat opioid withdrawal.


Subject(s)
Antidiarrheals/therapeutic use , Cannabinoid Receptor Agonists/therapeutic use , Diarrhea/drug therapy , Indoles/therapeutic use , Substance Withdrawal Syndrome/drug therapy , Thiophenes/therapeutic use , Allosteric Regulation , Animals , Diarrhea/etiology , Female , Male , Mice , Mice, Inbred ICR , Naloxone/adverse effects , Narcotic Antagonists/adverse effects , Narcotics/toxicity , Opioid-Related Disorders/drug therapy , Opioid-Related Disorders/etiology , Oxycodone/toxicity , Receptor, Cannabinoid, CB1/metabolism , Substance Withdrawal Syndrome/etiology
17.
Eur Heart J Cardiovasc Imaging ; 23(4): 487-495, 2022 03 22.
Article in English | MEDLINE | ID: mdl-34687538

ABSTRACT

AIMS: Fabry cardiomyopathy (FC) is characterized by progressive left ventricular hypertrophy (LVH). Conventional echocardiography is not sensitive in detecting preclinical FC before the development of LVH. We aim to investigate whether myocardial deformation analysis is useful to detect preclinical FC before LVH. METHODS AND RESULTS: One hundred and sixty patients carrying mutated gene were prospectively enrolled, including 86 patients without LVH and 74 patients with LVH. Another 33 healthy individuals were also included for comparison. Standard transthoracic two-dimensional, Doppler, tissue Doppler echocardiography and deformation analysis were performed. The mean age of the overall 193 subjects was 48 ± 15 years, with 51% men. Fabry patients with LVH were older, more often to be men. They also had the worst diastolic function as evidenced by the largest left atrium, lowest E/A, and highest E/e' ratio. The global longitudinal strain (GLS) deteriorated with the development of LVH (control vs. LVH- patients vs. LVH+ patients = -21.2 ± 2.7 vs. -19.0 ± 2.9 vs. -16.5 ± 4.2%, P < 0.001). Despite similar LV systolic, diastolic function, and LV mass, LVH- Fabry patients still had a reduced GLS as well as regional longitudinal strains at mid-to-apical, anterior, and inferolateral wall when compared to healthy subjects. The basal longitudinal strain was consistently worse in male patients than in female patients, irrespective of LVH. CONCLUSION: Reduced GLS could be a marker of early FC before the development of LVH.


Subject(s)
Cardiomyopathies , Hypertrophy, Left Ventricular , Adult , Diastole , Echocardiography/methods , Echocardiography, Doppler , Female , Humans , Hypertrophy, Left Ventricular/diagnostic imaging , Hypertrophy, Left Ventricular/etiology , Male , Middle Aged
18.
Article in Chinese | WPRIM (Western Pacific) | ID: wpr-934243

ABSTRACT

Objective:To evaluate the safety and effectiveness of adventitial inversion technique for root repair in patients with acute type A aortic dissection(ATAAD).Methods:Between 2015 and 2018, ATAAD patients with dissected root and underwent open surgery were included. The exclusion criteria were as follows: previous root intervention, traumatic dissection and patient underwent root replacement(Bentall or David procedure). 490 ATAAD patients were included, 366(74.69%) male and 124(25.31%) female, aged(51.28±10.99) years(range 24-77 years). The clinical data were retrospectively analyzed with ANOVA/ nonparametric test and Chi- square test. Follow-up mortality and reoperation were displayed with Kaplan- Meier curve. Results:All patients were technically divided into three groups: adventitial inversion(A), direct suture(B) and Cabrol-shunt(C). The mean age in group A was(53.05±11.09) years, whereas worse cardiac and renal function occurred in group C. The mean duration of HCA, CPB and ACC were shortest, with a highest average of minimum rectal temperature during surgical interval in group A. Postoperative complications and early mortality were similar among groups. There were no significant differences of mid-term mortality and reoperation among these three techniques. Though no late reintervention for aortic root was found in both group A and B, the root diameter was more stable in group A during follow-up period[(33.14±3.74)mm vs.(34.51±3.83)mm vs.(33.89±3.89)mm, P=0.008]. Conclusion:Adventitial inversion technique is safe and effective for root repair in patients with ATAAD, achieving satisfactory short- and mid-term effects.

19.
Int J Pharm ; 607: 120889, 2021 Sep 25.
Article in English | MEDLINE | ID: mdl-34271151

ABSTRACT

The focus of present work was to characterize ultra-long acting prodrug of dolutegravir (DTG) and develop biodegradable microparticle formulation. Palmitic acid (PA) conjugated prodrug of DTG was prepared by esterification of hydroxyl group of DTG with the carboxyl group of PA. Physicochemical properties of the prodrug was characterize by MS, NMR, FTIR, SEM, DSC, NIR-CI, pH-solubility, and solid and liquid pH-stability. Comparative solid and liquid stability was performed by storing powder DTG and DTG-Palmitate at 40 °C/75% RH for three months and liquid solution pH 2-8 at room temperature for 24 h, respectively. Pharmacokinetic evaluation was performed in white albino New Zealand rabbits by subcutaneous injection (30 mg/Kg). Poly(lactide-co-glycolide) microparticle formulation was prepared by emulsification-evaporation method and characterized for particle size distribution, shape, drug loading and in-vitro release. MS, NMR, FTIR, SEM, DSC, NIR-CI indicated formation of prodrug. Melting point of the prodrug was lower than DTG but higher than PA. Shape of DTG crystals was irregular while DTG-Palmitate crystals was fine-needle. Solid and liquid stability profiles of the prodrug were similar to DTG. Plasma half-life, area under the curve, and mean-residence time of DTG-Palmitate were 8.8, 2.3 and 14.7 folds of DTG. D90 of DTG and DTG-Palmitate microparticles was 107.1 ± 2.7 and 94.3 ± 3.4 µm, respectively. The in-vitro drug release was almost complete in three weeks from DTG microparticles while it was <85% in six months from DTG-Palmitate microparticles. In conclusion, physicochemical and pharmacokinetic properties and biodegradable microparticles of the prodrug suggested that the prodrug has potential of sustaining DTG release for ultra-long period compared to DTG.


Subject(s)
Prodrugs , Animals , Drug Liberation , Heterocyclic Compounds, 3-Ring , Oxazines , Particle Size , Piperazines , Pyridones , Rabbits , Solubility
20.
J Chin Med Assoc ; 84(8): 778-782, 2021 08 01.
Article in English | MEDLINE | ID: mdl-34225335

ABSTRACT

BACKGROUND: Medical students in Taiwan start their clerkship in their fifth year. A lack of early clinical exposure can mean they have a lack of medical professionalism and collaborative practice. This study investigates whether early engagement in hospital-based clinical practice could improve their understanding of these requirements. METHODS: From 2017 to 2019, a total of 59 medical students at the end of their third year joined a 2-week summer camp at the hospital. Every participant was assigned to work with one patient and they accompanied this patient throughout their hospital course. The students were also asked to interview other medical professionals within the hospital and to write up interview reports. In addition, they had to complete pre- and postcamp questionnaires which included 10 questions to evaluate their recognition of professionalism, doctor-patient relationships, and interprofessional collaboration. Answers to the questions were all rated using a 5-score Likert scale. RESULTS: The total postcamp Likert scores were significantly increased after the 2-week training camp compared with the precourse scores (pre- vs postcourse: 44.08 ± 0.45 vs 46.66 ± 0.33, p < 0.001). In addition, the students' recognition of medical professionalism, the importance of communication with patients, and their respect for other medical professionals were significantly improved after the 2-week training. CONCLUSION: Our data showed that early clinical exposure through a preclerkship summer camp can help medical students improve their recognition of medical professionalism and interprofessional collaboration.


Subject(s)
Clinical Clerkship , Interprofessional Relations , Professionalism , Students, Medical , Humans , Physician-Patient Relations , Surveys and Questionnaires , Taiwan
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