Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 1.400
Filter
1.
J Clin Rheumatol ; 2024 Jun 17.
Article in English | MEDLINE | ID: mdl-38880959

ABSTRACT

OBJECTIVE: To evaluate the predictive value of the LFA-REAL ClinRO (Lupus Foundation of America Rapid Evaluation of Activity in Lupus clinician-reported outcome) on damage accrual in systemic lupus erythematosus patients. METHODS: Data from a prevalent lupus cohort were used. The LFA-REAL ClinRO includes 9 domains: mucocutaneous (global and 3 subdomains), musculoskeletal (global and 2 subdomains), cardiorespiratory, neuropsychiatric, renal, hematological, constitutional, vasculitis, and other (it allows for other or rare manifestations). For each domain, a 0- to 100-mm visual analog scale is used, and global domains are included except for the mucocutaneous and musculoskeletal domains where the subdomains are included; it allows for 3 manifestations under "other," so the score ranges from 0 to 1400 (sum of 14 in the visual analog scale). Damage was assessed with the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index. Generalized estimating equations were performed, being the outcome the increase in the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index; confounders from the previous visit were included; adjusted multivariable models were done. Incidence rate ratios per 10-unit increase in the LFA-REAL ClinRO were reported. Similar models were performed to evaluate the impact of the SLEDAI-2K (SLE Disease Activity Index) and physician global assessment on damage to determine which measure would better predict damage accrual. RESULTS: Three-hundred thirty-one patients and 1425 visits were included, 1.9 (SD 1.2) years of follow-up. Disease duration at baseline was 10.7 (7.4) years. The mean LFA-REAL ClinRO was 18.2 (SD 30.7). During the follow-up visits, 63 (17.9%) patients accrued damage once; 4 (1.1%) accrued damage twice. The LFA-REAL ClinRO was predictive of damage accrual even after adjustment for possible confounders (incidence rate ratio 1.10 (95% confidence interval 1.04-1.16; p < 0.001). Similar results were obtained using the SLEDAI-2K and the physician global assessment. CONCLUSION: The LFA-REAL ClinRO is predictive of damage accrual, even after adjusting for possible confounders.

3.
Eur J Heart Fail ; 2024 May 09.
Article in English | MEDLINE | ID: mdl-38721803

ABSTRACT

AIMS: The effects of initiating sacubitril/valsartan in patients with stable heart failure with reduced ejection fraction (HFrEF) on response to fluid and sodium expansion are unknown. METHODS AND RESULTS: We have explored changes in natriuresis, diuresis, and congestion in response to the administration of intravenous fluid/sodium load in patients with HFrEF before as compared to after the initiation of sacubitril/valsartan. At baseline (before sacubitril/valsartan initiation) and 2 and 3 months after the initiation, patients underwent an evaluation that consisted of three phases of 3 h: the rest phase (0-3 h), the load phase (3-6 h) in which 1 L of intravenous Ringer solution was administered, and the diuretic phase (6-9 h) at the beginning of which furosemide was administered. Overall, 216 patients completed the study. In comparison to baseline values, at 2 and 3 months after sacubitril/valsartan initiation, patients' diuresis and natriuresis in response to Ringer administration significantly increased (mean difference: 38.8 [17.38] ml, p = 0.0040, and 9.6 [2.02] mmol, p < 0.0001, respectively). Symptoms and signs of congestion after the fluid/sodium challenge were significantly decreased at months 2 and 3 compared to baseline. Compared to baseline, there was also an increment of natriuresis after furosemide administration on sacubitril/valsartan (9.8 [5.13] mmol, p = 0.0167). There was a significant decrease in body weight in subsequent visits when compared to baseline values (-0.50 [-12.7, 7.4] kg at 2 months, and -0.75 [-15.9, 7.5] kg at 3 months; both p < 0.0001). CONCLUSIONS: The initiation of sacubitril/valsartan in HFrEF patients was associated with improvements in natriuresis, diuresis, and weight loss and better clinical adaptation to potentially decongestive stressors.

5.
J Oral Biol Craniofac Res ; 14(3): 339-341, 2024.
Article in English | MEDLINE | ID: mdl-38699685

ABSTRACT

The growing popularity of soft tissue filler injections has brought attention to the associated risks, particularly vascular complications, and their treatments. This case report focuses on a 34-year-old female who developed nasal skin necrosis following hyaluronic acid (HA) filler injection for nasolabial fold (NLF) enhancement. Despite the careful procedure, complications emerged rapidly, emphasizing the critical importance of prompt diagnosis and intervention. A total of 10,000 turbidity reducing units (TRU) of hyaluronidase (HSE) were administered in a high-dose pulsed manner, alongside hyperbaric oxygen therapy. The patient experienced a gradual but significant improvement over 60 days. This case underscores the need for constant vigilance in aesthetic medicine and the potential consequences of even minute HA amounts, exceeding zero, in causing severe vascular events.

6.
Healthcare (Basel) ; 12(10)2024 May 11.
Article in English | MEDLINE | ID: mdl-38786403

ABSTRACT

Advances in anti-retroviral therapy (ART) have decreased mortality rates and subsequently led to a rise in the number of HIV-positive people living longer. The housing experiences of this new population of interest-older adults (50 years and older) living with HIV-are under-researched. Understanding the housing experiences and unmet needs of older people with HIV can better provide comprehensive care services for them. This study's systematic review evaluated the peer-reviewed literature reporting housing access/insecurity/assistance/options, housing impact, and unmet needs of older individuals living with HIV in North America from 2012 to 2023. Furthermore, Latent Semantic Analysis (LSA), a text-mining technique, and Singular Value Decomposition (SVD) for text clustering were utilized to examine unstructured data from the abstracts selected from the review. The goal was to allow for a better understanding of the relationships between terms in the articles and the identification of emerging public health key themes affecting older adults living with HIV. The results of text clustering yielded two clusters focusing on (1) improvements to housing and healthcare services access and policies and (2) unmet needs-social support, mental health, finance, food, and sexuality insecurities. Topic modeling demonstrated four topics, which we themed to represent (1) a holistic care approach; (2) insecurities-food, financial, sexuality, and other basic needs; (3) access to housing and treatment/care; and (4) homelessness and HIV-related health outcomes. Stable housing, food, and healthcare services access and availability are critical elements to incorporating comprehensive, holistic healthcare for older adults living with HIV. The aging population requires high-priority policies for accessible and equitable healthcare. Clinicians and policymakers should address individual barriers, adopt a patient-centered approach, increase doctor visits, provide competency training, ensure long-term follow-up, involve families, and improve patient education in care management, contributing to HIV/AIDS geriatric care models.

7.
Br J Haematol ; 2024 May 12.
Article in English | MEDLINE | ID: mdl-38735682

ABSTRACT

The pathophysiology and genetic risk for sickle cell disease (SCD)-related chronic kidney disease (CKD) are not well understood. In 70 adults with SCD-related CKD and without APOL1 inherited in a high-risk pattern, 24 (34%) had pathogenic variants in candidate genes using KidneySeq™. A moderate impact INF2 variant was observed in 20 (29%) patients and those with 3 versus 0-2 pathogenic or moderate impact glomerular genetic variants had higher albuminuria and lower estimated glomerular filtration rate (adjusted p ≤ 0.015). Using a panel of preselected genes implicated in kidney health, we observed several variants in people with sickle cell nephropathy.

8.
bioRxiv ; 2024 Mar 14.
Article in English | MEDLINE | ID: mdl-38559183

ABSTRACT

Circulating Tumor Cells (CTCs), interrogated by sampling blood from patients with cancer, contain multiple analytes, including intact RNA, high molecular weight DNA, proteins, and metabolic markers. However, the clinical utility of tumor cell-based liquid biopsy has been limited since CTCs are very rare, and current technologies cannot process the blood volumes required to isolate a sufficient number of tumor cells for in-depth assays. We previously described a high-throughput microfluidic prototype utilizing high-flow channels and amplification of cell sorting forces through magnetic lenses. Here, we apply this technology to analyze patient-derived leukapheresis products, interrogating a mean blood volume of 5.83 liters from patients with metastatic cancer, with a median of 2,799 CTCs purified per patient. Isolation of many CTCs from individual patients enables characterization of their morphological and molecular heterogeneity, including cell and nuclear size and RNA expression. It also allows robust detection of gene copy number variation, a definitive cancer marker with potential diagnostic applications. High-volume microfluidic enrichment of CTCs constitutes a new dimension in liquid biopsies.

9.
Cardiovasc Res ; 2024 Apr 13.
Article in English | MEDLINE | ID: mdl-38613511

ABSTRACT

BACKGROUND: Atrial fibrillation (AF) and concomitant cardiometabolic disease processes interact and combine to lead to adverse events such as stroke, heart failure, myocardial infarction, and cardiovascular death. Circulating biomolecules provide quantifiable proxies for cardiometabolic disease processes. Their role in defining subphenotypes of AF is not known. METHODS AND RESULTS: This prespecified analysis of the EAST-AFNET4 biomolecule study assigned patients to clusters using polytomous variable latent class analysis (poLCA) based on baseline concentrations of thirteen precisely-quantified biomolecules potentially reflecting ageing, cardiac fibrosis, metabolic dysfunction, oxidative stress, cardiac load, endothelial dysfunction, and inflammation. In each cluster, rates of cardiovascular death, stroke, or hospitalization for heart failure or acute coronary syndrome, the primary outcome of EAST-AFNET 4, were calculated and compared between clusters over median 5.1 years follow-up. Findings were independently validated in a prospective cohort of 748 patients with AF (BBC-AF; median follow up 2.9 years).Unsupervised biomolecule analysis assigned 1586 patients (71 years old, 46% women) into four clusters. The highest-risk cluster was dominated by elevated BMP10, IGFBP7, NT-proBNP, ANGPT2 and GDF15. Patients in the lowest-risk cluster showed low concentrations of these biomolecules. Two intermediate-risk clusters differed by high or low concentrations of hsCRP, IL-6, and D-dimer. Patients in the highest-risk cluster had a 5-fold higher cardiovascular event rate than patients in the low-risk cluster. Early rhythm control was effective across clusters (pinteraction = 0.63). Sensitivity analyses and external validation in BBC-AF replicated clusters and risk gradients. CONCLUSIONS: Biomolecule concentrations identify cardiometabolic subphenotypes in patients with atrial fibrillation at high and low cardiovascular risk.

10.
J Oral Biol Craniofac Res ; 14(3): 280-283, 2024.
Article in English | MEDLINE | ID: mdl-38586285

ABSTRACT

Background: While effective, DAc injections for submental fat (SMF) reduction carry risks, including vascular damage and skin necrosis when improperly administered. This study presents a novel approach to SMF reduction using blunt microcannulas for DAc injections, coupled with 3D stereophotogrammetry quantification (3D-SQ). Clinical presentation: A 47-year-old female with SMF underwent two DAc applications. 3D-SQ was performed before and after each treatment using a 3D-SQ system. The patient experienced a substantial total volume reduction of 14.81 mL in the submental area after two DAc applications. 3D-SQ analysis showed a gradual reduction in submental volume over time. Importantly, no serious adverse events were reported, with only minor pain and warmth at the treated site. The reduction of SMF through DAc injections involves adipocyte cell lysis, emphasizing the importance of proper injection technique to avoid adverse events. The use of blunt microcannulas offers a safer alternative, minimizing the risk of skin necrosis, ulceration, and intra-arterial injections. Additionally, cannulas reduce bruising due to their blunt design and fan technique, enhancing patient comfort and safety. Conclusion: This case report highlights the efficacy of a novel cannula approach for DAc SMF reduction, assessed by 3D-SQ. Blunt microcannulas may represent a safer option compared to hypodermic needles, reducing the likelihood of severe complications.

11.
Cancer Discov ; 2024 Apr 03.
Article in English | MEDLINE | ID: mdl-38564707

ABSTRACT

Activating point mutations in the MET tyrosine kinase domain (TKD) are oncogenic in a subset of papillary renal cell carcinomas (PRCC). Here, using comprehensive genomic profiling among >600,000 patients, we identify activating MET TKD point mutations as putative oncogenic driver across diverse cancers, with a frequency of ~0.5%. The most common mutations in the MET TKD defined as oncogenic or likely oncogenic according to OncoKB resulted in amino acid substitutions at positions H1094, L1195, F1200, D1228, Y1230, M1250, and others. Preclinical modeling of these alterations confirmed their oncogenic potential, and also demonstrated differential patterns of sensitivity to type I and type II MET inhibitors. Two patients with metastatic lung adenocarcinoma harboring MET TKD mutations (H1094Y, F1200I) and no other known oncogenic drivers achieved confirmed partial responses to a type I MET inhibitor. Activating MET TKD mutations occur in multiple malignancies and may confer clinical sensitivity to currently available MET inhibitors.

12.
Blood ; 143(14): 1326-1327, 2024 Apr 04.
Article in English | MEDLINE | ID: mdl-38573609
13.
Environ Pollut ; 349: 123904, 2024 May 15.
Article in English | MEDLINE | ID: mdl-38565392

ABSTRACT

The indiscriminate and, very often, incorrect use of pesticides in Brazil, as well as in other countries, results in severe levels of environmental pollution and intoxication of human life. Herein, we studied plasma membrane models (monolayer and bilayer) of the phospholipid Dioleoyl-sn-glycerol-3-phosphocholine (DOPC) using Langmuir films, and large (LUVs) and giant (GUVs) unilamellar vesicles, to determine the effect of the pesticides chlorantraniliprole (CLTP), isoxaflutole (ISF), and simazine (SMZ), used in sugarcane. CLTP affects the lipid organization of the bioinspired models of DOPC π-A isotherms, while ISF and SMZ pesticides significantly affect the LUVs and GUVs. Furthermore, the in vivo study of the gill tissue in fish in the presence of pesticides (2.0 × 10-10 mol/L for CLTP, 8.3 × 10-9 mol/L for ISF, and SMZ at 9.9 × 10-9 mol/L) was performed using optical and fluorescence images. This investigation was motivated by the gill lipid membranes, which are vital for regulating transporter activity through transmembrane proteins, crucial for maintaining ionic balance in fish gills. In this way, the presence of phospholipids in gills offers a model for understanding their effects on fish health. Histological results show that exposure to CLTP, ISF, and SMZ may interfere with vital gill functions, leading to respiratory disorders and osmoregulation dysfunction. The results indicate that exposure to pesticides caused severe morphological alterations in fish, which could be correlated with their impact on the bioinspired membrane models. Moreover, the effect does not depend on the exposure period (24h and 96h), showing that animals exposed to pesticides for a short period suffer irreparable damage to gill tissue. In summary, we can conclude that the harm caused by pesticides, both in membrane models and in fish gills, occurs due to contamination of the aquatic system with pesticides. Therefore, water quality is vital for the preservation of ecosystems.


Subject(s)
Gills , Pesticides , Phospholipids , Tilapia , ortho-Aminobenzoates , Animals , Gills/drug effects , Gills/metabolism , Phospholipids/metabolism , Pesticides/toxicity , Tilapia/metabolism , ortho-Aminobenzoates/toxicity , Water Pollutants, Chemical/toxicity , Cell Membrane/drug effects , Brazil
14.
Lancet Haematol ; 11(5): e345-e357, 2024 May.
Article in English | MEDLINE | ID: mdl-38554715

ABSTRACT

BACKGROUND: Although nitric oxide based therapeutics have been shown in preclinical models to reduce vaso-occlusive events and improve cardiovascular function, a clinical trial of a phosphodiesterase 5 inhibitor increased rates of admission to hospital for pain. We aimed to examine if riociguat, a direct stimulator of the nitric oxide receptor soluble guanylate cyclase, causes similar increases in vaso-occlusive events. METHODS: This was a phase 1-2, randomised, double blind, placebo-controlled trial. Eligible patients were 18 years or older, had confirmed sickle cell disease documented by haemoglobin electrophoresis or HPLC fractionation (haemoglobin SS, SC, Sß-thalassemia, SD, or SO-Arab), and stage 1 hypertension or proteinuria. Participants were randomly assigned 1:1 to receive either riociguat or matching placebo via a web-based system to maintain allocation concealment. Both treatments were administered orally starting at 1·0 mg three times a day up to 2·5 mg three times a day (highest tolerated dose) for 12 weeks. Dose escalation by 0·5 mg was considered every 2 weeks if systolic blood pressure was greater than 95 mm Hg and the participant had no signs of hypotension; otherwise, the last dose was maintained. The primary outcome was the proportion of participants who had at least one adjudicated treatment-emergent serious adverse event. The analysis was performed by the intention-to-treat. This trial is registered with ClinicalTrials.gov (NCT02633397) and was completed. FINDINGS: Between April 11, 2017, and Dec 31, 2021, 165 participants were screened and consented to be enrolled into the study. Of these, 130 participants were randomly assigned to either riociguat (n=66) or placebo (n=64). The proportion of participants with at least one treatment-emergent serious adverse event was 22·7% (n=15) in the riociguat group and 31·3% (n=20) in the placebo group (difference -8·5% [90% CI -21·4 to 4·5]; p=0·19). A similar pattern emerged in other key safety outcomes, sickle cell related vaso-occlusive events (16·7 [n=11] vs 21·9% [n=14]; difference -5·2% [-17·2 to 6·5]; p=0·42), mean pain severity (3·18 vs 3·32; adjusted mean difference -0·14 [-0·70 to 0·42]; p=0·69), and pain interference (3·15 vs 3·12; 0·04 [-0·62 to 0·69]; p=0·93) at 12 weeks were similar between groups. Regarding the key clinical efficacy endpoints, participants taking riociguat had a blood pressure of -8·20 mm Hg (-10·48 to -5·91) compared with -1·24 (-3·58 to 1·10) in those taking placebo (-6·96 mm Hg (90% CI -10·22 to -3·69; p<0·001). INTERPRETATION: Riociguat was safe and had a significant haemodynamic effect on systemic blood pressure. The results of this study provide measures of effect and variability that will inform power calculations for future trials. FUNDING: Bayer Pharmaceuticals.


Subject(s)
Anemia, Sickle Cell , Hypertension , Proteinuria , Pyrazoles , Pyrimidines , Humans , Anemia, Sickle Cell/drug therapy , Anemia, Sickle Cell/complications , Male , Female , Double-Blind Method , Pyrazoles/therapeutic use , Pyrazoles/adverse effects , Adult , Pyrimidines/therapeutic use , Pyrimidines/adverse effects , Pyrimidines/administration & dosage , Hypertension/drug therapy , Proteinuria/drug therapy , Middle Aged , Treatment Outcome
15.
J Ophthalmol ; 2024: 4003914, 2024.
Article in English | MEDLINE | ID: mdl-38468717

ABSTRACT

Purpose: The aim of the study is to describe the genotype and phenotype of a Mexican cohort with PCARE-related retinal disease. Methods: The study included 14 patients from 11 unrelated pedigrees with retinal dystrophies who were demonstrated to carry biallelic pathogenic variants in PCARE. Visual assessment methods included best corrected visual acuity, color fundus photography, Goldmann visual field test, kinetic perimetry, dark/light adapted chromatic perimetry, full-field electroretinography, autofluorescence imaging, and spectral domain-optical coherence tomography imaging. Genetic screening was performed either by gene panel sequencing or by exome sequencing. Results: According to the results of multimodal imaging and functional tests, all 14 patients were diagnosed with cone-rod dystrophy. Six different PCARE pathogenic alleles were identified in our cohort, including three novel mutations: c.3048_3049del (p.Tyr1016∗), c.3314_3315del (p.Ser1105∗), and c.551A > G (p.His184Arg). Notably, alleles p.His184Arg, p.Arg613∗, and p.Arg984∗ were present in 18 of the 22 (82%) PCARE alleles from probands in our cohort. Conclusion: Our work expands the PCARE mutational profile by identifying three novel pathogenic variants causing retinal dystrophy. While phenotypic variations occurred among patients, a cone-rod dystrophy pattern was observed in all affected individuals.

16.
BMC Health Serv Res ; 24(1): 291, 2024 Mar 06.
Article in English | MEDLINE | ID: mdl-38448911

ABSTRACT

BACKGROUND: Adults with sickle cell disease (SCD) suffer early mortality and high morbidity. Many are not affiliated with SCD centers, defined as no ambulatory visit with a SCD specialist in 2 years. Negative social determinants of health (SDOH) can impair access to care. HYPOTHESIS: Negative SDOH are more likely to be experienced by unaffiliated adults than adults who regularly receive expert SCD care. METHODS: Cross-sectional analysis of the SCD Implementation Consortium (SCDIC) Registry, a convenience sample at 8 academic SCD centers in 2017-2019. A Distressed Communities Index (DCI) score was assigned to each registry member's zip code. Insurance status and other barriers to care were self-reported. Most patients were enrolled in the clinic or hospital setting. RESULTS: The SCDIC Registry enrolled 288 Unaffiliated and 2110 Affiliated SCD patients, ages 15-45y. The highest DCI quintile accounted for 39% of both Unaffiliated and Affiliated patients. Lack of health insurance was reported by 19% of Unaffiliated versus 7% of Affiliated patients. The most frequently selected barriers to care for both groups were "previous bad experience with the healthcare system" (40%) and "Worry about Cost" (17%). SCD co-morbidities had no straightforward trend of association with Unaffiliated status. The 8 sites' results varied. CONCLUSION: The DCI economic measure of SDOH was not associated with Unaffiliated status of patients recruited in the health care delivery setting. SCDIC Registrants reside in more distressed communities than other Americans. Other SDOH themes of affordability and negative experiences might contribute to Unaffiliated status. Recruiting Unaffiliated SCD patients to care might benefit from systems adopting value-based patient-centered solutions.


Subject(s)
Anemia, Sickle Cell , Social Determinants of Health , Adult , Humans , Cross-Sectional Studies , Emotions , Anemia, Sickle Cell/epidemiology , Anemia, Sickle Cell/therapy , Registries
17.
Am J Hematol ; 99(5): 900-909, 2024 May.
Article in English | MEDLINE | ID: mdl-38450756

ABSTRACT

The cause of death in people affected by sickle cell disease (SCD) is often challenging to define as prior studies have used retrospective or administrative data for analysis. We used a prospective longitudinal registry to assess mortality and clinical co-morbidities among subjects enrolled in the Sickle Cell Disease Implementation Consortium (SCDIC) registry. At enrollment, we collected the following data: patient-reported demographics, SCD phenotype, baseline laboratory values, comorbidities, and current medications. Subjects were followed for a median of 4.7 years before the present analysis. The relationship of clinical co-morbidities (at time of enrollment) to mortality was determined using survival analysis, adjusting for SCD phenotype and gender. There was a total of 2439 people with SCD enrolled in the SCDIC registry. One hundred and twenty-eight participants (5%) died during the observation period (2017-2022). Six people died from trauma and were excluded from further analysis. Proximate cause of death was unwitnessed in 17% of the deaths, but commonest causes of death include cardiac (18%), acute chest or respiratory failure (11%), sudden unexplained death (8%). Enrollment characteristics of the individuals who died (n = 122) were compared to those of survivors (n = 2317). Several co-morbidities at enrollment increased the odds of death on univariate analysis. All co-morbidities were included in a multivariable model. After backward elimination, iron overload, pulmonary hypertension, and depression, remained statistically significant predictors of the risk of death. SCD reduces life expectancy. Improved comprehensive and supportive care to prevent end-organ damage and address comorbidities is needed for this population.


Subject(s)
Anemia, Sickle Cell , Hypertension, Pulmonary , Adult , Humans , Prospective Studies , Retrospective Studies , Anemia, Sickle Cell/drug therapy , Research Design
18.
Bioresour Technol ; 399: 130572, 2024 May.
Article in English | MEDLINE | ID: mdl-38492651

ABSTRACT

Aqueous phase reforming has been explored for renewable H2 production from waste biomass. Promising results have been reported for pyrolysis bio-oil aqueous fractions (AFB), but economical assessments are needed to determine process feasibility, which requires both energy consumption minimization and optimal H2 valorization. This work compares different alternatives using process simulation and economic evaluation computational tools. Experimental results and a specific thermodynamic model are used to set mass balances. An adequate heat integration allows to reduce the process energy demand, covering the 100 % of the reactor duty. Optimal H2 unit cost is achieved if part of the produced H2 is valorized for energy self-covering and the rest is commercialized. Renewable H2 net production of c.a. 3.3 kgH2/m3 of treated AFB at a preliminary 1-2 €/kg unit cost is estimated, which can be considered as competitive with green H2, even though a case of diluted AFB is considered.


Subject(s)
Hydrogen , Polyphenols , Pyrolysis , Rivers , Plant Oils , Water , Biomass
19.
J Med Chem ; 67(5): 3571-3589, 2024 Mar 14.
Article in English | MEDLINE | ID: mdl-38385264

ABSTRACT

PAR4 is a promising antithrombotic target with potential for separation of efficacy from bleeding risk relative to current antiplatelet therapies. In an effort to discover a novel PAR4 antagonist chemotype, a quinoxaline-based HTS hit 3 with low µM potency was identified. Optimization of the HTS hit through the use of positional SAR scanning and the design of conformationally constrained cores led to the discovery of a quinoxaline-benzothiazole series as potent and selective PAR4 antagonists. The lead compound 48, possessing a 2 nM IC50 against PAR4 activation by γ-thrombin in platelet-rich plasma (PRP) and greater than 2500-fold selectivity versus PAR1, demonstrated robust antithrombotic efficacy and minimal bleeding in the cynomolgus monkey models.


Subject(s)
Fibrinolytic Agents , Thrombosis , Animals , Fibrinolytic Agents/pharmacology , Fibrinolytic Agents/therapeutic use , Macaca fascicularis , Quinoxalines/pharmacology , Quinoxalines/therapeutic use , Receptors, Thrombin , Thrombin , Hemorrhage , Thrombosis/drug therapy , Thrombosis/prevention & control , Receptor, PAR-1 , Blood Platelets , Platelet Aggregation
20.
Respir Physiol Neurobiol ; 323: 104229, 2024 May.
Article in English | MEDLINE | ID: mdl-38307440

ABSTRACT

This study investigated the respiratory activity in adult Wistar rats across different behavioral seizure severity induced by pentylenetetrazole (PTZ). Animals underwent surgery for electrodes implantation, allowing simultaneous EEG and diaphragm EMG (DIAEMG) recordings and the respiratory frequency and DIAEMG amplitude were measured. Seizures were acutely induced through PTZ injection and classified based on a pre-established score, with absence-like seizures (spike wave discharge (SWD) events on EEG) representing the lowest score. The respiratory activity was grouped into the different seizure severities. During absence-like and myoclonic jerk seizures, the breathing frequency decreased significantly (∼50% decrease) compared to pre- and post-ictal periods. Pronounced changes occurred with more severe seizures (clonic and tonic) with periods of apnea, especially during tonic seizures. Apnea duration was significantly higher in tonic compared to clonic seizures. Notably, during PTZ-induced tonic seizures the apnea events were marked by tonic DIAEMG contraction (tonic-phase apnea). In the majority of animals (5 out of 7) this was a fatal event in which the seizure-induced respiratory arrest preceded the asystole. In conclusion, we provide an assessment of the respiratory activity in the PTZ-induced acute seizures and showed that breathing dysfunction is more pronounced in seizures with higher severity.


Subject(s)
Apnea , Pentylenetetrazole , Rats , Animals , Pentylenetetrazole/toxicity , Rats, Wistar , Seizures/chemically induced , Respiratory Rate
SELECTION OF CITATIONS
SEARCH DETAIL
...