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Medicine Jun 2024The mortality rate related to variceal bleeding is high in patients with liver cirrhosis. Early detection and treatment of varices can reduce the risk of hemorrhage and...
The mortality rate related to variceal bleeding is high in patients with liver cirrhosis. Early detection and treatment of varices can reduce the risk of hemorrhage and thus decrease the mortality rate related to variceal bleeding. The study comprised 81 cirrhotic patients in training set, who were categorized into 2 groups: the patients with esophageal varices (EVs group) and the patients without esophageal varices (non-EVs group). The disparity in Cystatin C/albumin ratio (CAR) was assessed between these 2 groups. Subsequently, a regression model was constructed by generating a receiver operating characteristic (ROC) curve to calculate the area under the curve (AUC). Then an external validation was performed in 25 patients. Among patients with cirrhosis in training set, a statistically significant difference in CAR was observed between the EVs group and non-EVs group (P < .05). At the CAR cutoff value of 2.79*10-5, the AUC for diagnosing EVs were 0.666. Further, a multivariate logistic regression model was constructed, after adjusting the model, the AUC for EVs diagnosis were 0.855. And the external validation showed that the model could not be considered as a poor fit. CAR exhibits potential as an early detection marker for EVs in liver cirrhosis, and the regression model incorporating CAR demonstrates a strong capability for early EVs diagnosis.
Topics: Humans; Esophageal and Gastric Varices; Liver Cirrhosis; Cystatin C; Male; Female; Middle Aged; Early Diagnosis; Biomarkers; ROC Curve; Aged; Serum Albumin; Adult; Retrospective Studies; Area Under Curve
PubMed: 38941375
DOI: 10.1097/MD.0000000000038481 -
Health Care Science Aug 2023The coronavirus disease (COVID-19), which the World Health Organization classified as the Sixth Public Health Emergency Of International Concern (PHEIC) on January 30,... (Review)
Review
The coronavirus disease (COVID-19), which the World Health Organization classified as the Sixth Public Health Emergency Of International Concern (PHEIC) on January 30, 2020, is no longer a PHEIC. Millions were affected due to unawareness. The increase in fatalities and shortage of medicine was the first outrage of COVID-19. As per the Johns Hopkins COVID-19 resource center database, it was observed that the disease has spread dynamically across 200+ nations worldwide affecting more than 600 million people from 2019 to 2023, and over thousands of people were victimized regularly at a 2% mortality rate (approx.). In the midway, the mutant variants of concern like omicron, and delta have also created havoc and caused significant impact on public health, global economy, and lifestyle. Since 2019, 3 years now passed and the dynamic disease statistics seem decelerated; moreover, the prevalence of COVID-19 is also fading. The Johns Hopkins resource center has also stopped recording the data of the global pandemic recently from March 10, 2023. Hence, based on the facts, we are presenting a concise report on the pandemic from 2019 to 2023, which includes a brief discussion of the global pandemic. We have highlighted global epidemiology, emphasizing the Indian COVID scenario, vaccination across the globe, and the psychosocial and geopolitical consequences of COVID-19 with a brief background to pathology, clinical management, and the worldwide response against triage. A lot has changed and still needs to change after three tough years of COVID-19. Even though science has progressed and advanced research in medicine is pointing toward future generations, there is no standard care supplied for COVID-19-like calamities. COVID-19 cases might have declined but its influence on the society is still stagnant. This COVID experience has taught us that, despite our bleak beginnings, there is always hope for the future and that we must act with foresight to improve things for future generations.
PubMed: 38939523
DOI: 10.1002/hcs2.57 -
Simulated Target Attainment of Multidose Regimens of Dalbavancin for Prolonged Durations of Therapy.Open Forum Infectious Diseases Jun 2024Dalbavancin is a long-acting lipoglycopeptide antibiotic that is increasingly utilized for infections that require prolonged treatment durations despite the lack of Food... (Clinical Trial)
Clinical Trial
BACKGROUND
Dalbavancin is a long-acting lipoglycopeptide antibiotic that is increasingly utilized for infections that require prolonged treatment durations despite the lack of Food and Drug Administration approval for these indications. There is no consensus regarding optimal dosing of dalbavancin for these infections and no available pharmacokinetic studies to identify optimal dosing for long-term use.
METHODS
An in silico pharmacokinetic simulation was performed to assess the predicted dalbavancin concentration resulting from commonly utilized dosing regimens, in addition to modified regimens. The primary endpoint evaluated was days of median 24-hour free area under the curve over the minimum inhibitory concentration (AUC/MIC) >27.1, the established PK target.
RESULTS
A dosing regimen of 1500 mg on day 0 and day 7 resulted in median AUC/breakpoint value above the target for 57 days (lower 95% confidence interval [CI], 37 days). A modified regimen of 1500 mg on day 0 and day 21 resulted in an additional 11 days of median AUC/breakpoint target attainment. The other standard dosing regimen modeled was 1000 mg on day 0, then 500 mg weekly for 5 doses. This regimen achieved the AUC/breakpoint target for 76 days (lower 95% CI, 59 days). This regimen was modified to 1000 mg on day 0, then 500 mg on days 14 and 28, which shortened the median effective treatment duration by 14 days but required 3 fewer doses.
CONCLUSIONS
These simulated results, when combined with the favorable observational data, support the use of commonly reported dalbavancin regimens for prolonged therapy durations. In addition, these pharmacokinetic/pharmacodynamic data support extending the dosing interval beyond the frequently reported weekly regimens, which should be investigated further with a clinical trial.
PubMed: 38938895
DOI: 10.1093/ofid/ofae315 -
Frontiers in Neurology 2024Migraine, a prevalent neurological disorder, affects approximately 14.1% of the global population and disproportionately impacts females. This debilitating condition... (Review)
Review
Migraine, a prevalent neurological disorder, affects approximately 14.1% of the global population and disproportionately impacts females. This debilitating condition significantly compromises quality of life, productivity, and incurs high healthcare costs, presenting a challenge not only to individuals but to societal structures as a whole. Despite advances in our understanding of migraine pathophysiology, treatment options remain limited, necessitating ongoing research into effective therapies. This review delves into the complexity of migraine management, examining the roles of genetic predisposition, environmental influences, personalized treatment approaches, comorbidities, efficacy and safety of existing acute and preventive treatments. It further explores the continuum between migraine and tension-type headaches and discusses the intricacies of treating various migraine subtypes, including those with and without aura. We emphasize the recent paradigm shift toward trigeminovascular activation and the release of vasoactive substances, such as calcitonin gene-related peptide (CGRP), which offer novel therapeutic targets. We assess groundbreaking clinical trials, pharmacokinetic and pharmacodynamic perspectives, safety, tolerability, and the real-world application of CGRP monoclonal antibodies and gepants. In the face of persisting treatment barriers such as misdiagnosis, medication overuse headaches, and limited access to specialist care, we discuss innovative CGRP-targeted strategies, the high cost and scarcity of long-term efficacy data, and suggest comprehensive solutions tailored to Turkiye and developing countries. The review offers strategic recommendations including the formulation of primary care guidelines, establishment of specialized outpatient clinics, updating physicians on novel treatments, enhancing global accessibility to advanced therapies, and fostering patient education. Emphasizing the importance of lifestyle modifications and holistic approaches, the review underscores the potential of mass media and patient groups in disseminating critical health information and shaping the future of migraine management.
PubMed: 38938785
DOI: 10.3389/fneur.2024.1402569 -
TH Open : Companion Journal To... Apr 2024Recombinant von Willebrand factor (rVWF, vonicog alfa, Takeda Pharmaceuticals USA) is indicated in adults diagnosed with von Willebrand disease (VWD). In this study,...
Recombinant von Willebrand factor (rVWF, vonicog alfa, Takeda Pharmaceuticals USA) is indicated in adults diagnosed with von Willebrand disease (VWD). In this study, the exposure-response (ER) relationship between VWF activity (VWF:RCo) or factor VIII activity (FVIII:C) and spontaneous bleeding events (BEs) was evaluated in adults with severe VWD receiving rVWF prophylaxis for up to 1 year. This secondary analysis included 23 patients receiving rVWF prophylaxis in the open-label, phase 3 prophylaxis trial (NCT02973087). Population pharmacokinetic (PK) and PK/pharmacodynamic (PD) models were used to characterize VWF activity and endogenous FVIII:C, and PK/PD simulations were linked to spontaneous BEs to develop an ER model. None of the five patients with VWD types 1 or 2A/B experienced spontaneous BEs. Five of 18 patients with VWD type 3 experienced ≥1 spontaneous BEs. An ER relationship was observed whereby higher VWF:RCo levels were associated with a numerically lower spontaneous BE risk ( < 0.10). This relationship was independent of patients' pretrial VWF treatment. A statistically significant ER relationship was observed after accounting for relevant data (average ± standard error exposure estimate for VWF:RCo over 24 hours prior to the spontaneous BE: -0.043 ± 0.021, = 0.041). The model-generated hazard ratio for a 10 IU/dL increment in the average exposure of VWF:RCo 24 hours before a spontaneous BE was 0.651 (95% confidence interval: 0.431-0.982). This ER analysis suggests a causal association between VWF:RCo and spontaneous BEs, with an increase of VWF:RCo exposure leading to a decrease in spontaneous BE risk.
PubMed: 38938750
DOI: 10.1055/s-0044-1787815 -
International Journal of Analytical... 2024An ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed to determine the concentrations of Rhodojaponin II and Rhodojaponin...
An ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed to determine the concentrations of Rhodojaponin II and Rhodojaponin III in rat plasma, and their pharmacokinetic profiles were investigated. A UPLC HSS T3 (2.1 mm × 50 mm, 1.8 m) chromatographic column was employed at a temperature of 40°C. The mobile phase consisted of acetonitrile-0.1% formic acid in water, and a gradient elution method with an elution time of 6 min and flow rate of 0.4 mL/min was utilized for analysis purposes. Methodological investigations were conducted accordingly. The plasma concentrations of Rhodojaponin II and Rhodojaponin III exhibited excellent linearity within the range of 2 ng/mL-1250 ng/mL. Moreover, both intraday and interday precision were below 15%, while accuracy ranged from 88% to 115%. Additionally, matrix effect fell within the range of 90%-110%, and recoveries ranged from 78% to 87%. These results comply with relevant regulations for drug analysis in biological samples. Therefore, this method is deemed suitable for quantifying Rhodojaponin II and Rhodojaponin III levels in rats.
PubMed: 38938264
DOI: 10.1155/2024/6386570 -
Scientific Reports Jun 2024The purpose of this paper is to study the genetic polymorphisms of related gene loci (CYP2C9*3, VKORC1-1639G > A) based on demographic and clinical factors, and use...
The purpose of this paper is to study the genetic polymorphisms of related gene loci (CYP2C9*3, VKORC1-1639G > A) based on demographic and clinical factors, and use the maximum a posterior Bayesian method to construct a warfarin individualized dose prediction model in line with the Chinese Han population. Finally, the built model is compared and analyzed with the widely used models at home and abroad. In this study, a total of 5467 INR measurements are collected from 646 eligible subjects in our hospital, and the maximum a posterior Bayesian method is used to construct a warfarin dose prediction that conforms to the Chinese Han population on the basis of the Hamberg model. The model is verified and compared with foreign models. This study finds that body weight and concomitant use of amiodarone have a significant effect on the anticoagulant effect of warfarin. The model can provide an effective basis for individualized and rational dosing of warfarin in Han population more accurately. In the performance of comparison with different warfarin dose prediction models, the new model has the highest prediction accuracy, and the prediction percentage is as high as 72.56%. The dose predicted by the Huang model is the closest to the actual dose of warfarin. The population pharmacokinetics and pharmacodynamics model established in this study can better reflect the distribution characteristics of INR values after warfarin administration in the Han population, and performs better than the models reported in the literature.
Topics: Adult; Aged; Female; Humans; Male; Middle Aged; Anticoagulants; Bayes Theorem; China; Cytochrome P-450 CYP2C9; International Normalized Ratio; Vitamin K Epoxide Reductases; Warfarin; East Asian People
PubMed: 38937509
DOI: 10.1038/s41598-024-65048-7 -
The Journal of Pharmacology and... Jun 2024Estrogen receptors are essential pharmacological targets for treating hormonal disorders and estrogen-dependent malignancies. Selective activation of estrogen receptor...
Estrogen receptors are essential pharmacological targets for treating hormonal disorders and estrogen-dependent malignancies. Selective activation of estrogen receptor (ER) β is hypothesized to provide therapeutic benefit with reduced risk of unwanted estrogenic side-effects associated with ERα activity. However, activating ERβ without activating α is challenging due to the high sequence and structural homology between the receptor subtypes. We assessed the impact of structural modifications to the parent compound OSU-ERβ-12 on receptor subtype binding selectivity using cell-free binding assays. Functional selectivity was evaluated by transactivation in HEK-293 cells overexpressing human or murine estrogen receptors. selectivity was examined through the uterotrophic effects of the analogs after oral administration in estrogen-naïve female mice. Furthermore, we evaluated the pharmacokinetics of the analogs following single dose IV and oral administration. Regarding selectivity, a single compound exhibited greater functional selectivity than OSU-ERβ-12 for human ERβ. However, like others in the -carborane series, its poor pharmacokinetics limit its suitability for further development. Surprisingly, and at odds with their pharmacokinetic and human activity data, most analogs potently induced uterotrophic effects in estrogen-naïve female mice. Further investigation of activity in HEK293 cells expressing murine estrogen receptors revealed species-specific differences in the ER-subtype selectivity of these analogs. Our findings highlight species-specific receptor pharmacology and the challenges it poses to characterizing developmental therapeutics in preclinical species. This study investigates - and -substituted carborane analogs targeting estrogen receptors, revealing the greater selectivity of carborane analogs for human ERβ compared to the mouse homolog. These findings shed light on the intricacies of using preclinical species in drug development to predict human pharmacology. The report also provides insights for the refinement and optimization of carborane analogs as potential therapeutic agents for estrogen-related disease states.
PubMed: 38936980
DOI: 10.1124/jpet.123.001874 -
The Journal of Pharmacology and... Jun 2024Endocannabinoids, which are present throughout the central nervous system (CNS), can activate CB1 and CB2 receptors. CB1 and CB2 agonists exhibit broad...
Endocannabinoids, which are present throughout the central nervous system (CNS), can activate CB1 and CB2 receptors. CB1 and CB2 agonists exhibit broad anti-inflammatory properties, suggesting their potential to treat inflammatory diseases. However, careful evaluation of abuse potential is necessary. This study evaluated the abuse potential of lenabasum, a selective CB2 receptor agonist in participants (n=56) endorsing recreational cannabis use. Three doses of lenabasum (20, 60, and 120mg) were compared to placebo, and nabilone (3 and 6mg). The primary endpoint was the peak effect (Emax) on a bipolar Drug Liking visual analog scale (VAS). Secondary VAS and pharmacokinetic (PK) endpoints and adverse events were assessed. : Lenabasum was safe and well tolerated. Compared to placebo, a 20mg dose of lenabasum did not increase ratings of Drug Liking and had no distinguishable effect on other VAS endpoints. Dose-dependent increases in ratings of Drug Liking were observed with 60 and 120mg lenabasum. Drug Liking and all other VAS outcomes were greatest for nabilone 3mg and 6mg, which is a currently FDA-approved medication. : At a target therapeutic dose (20mg), lenabasum did not elicit subjective ratings of Drug Liking. However, supratherapeutic doses of lenabasum (60 and 120mg) did elicit subjective ratings of Drug Liking compared to placebo. Although both doses of lenabasum were associated with lower ratings of Drug Liking compared to 3mg and 6mg of nabilone, suggesting that lenabasum does have abuse potential and should be used cautiously in clinical settings. This work provides evidence that in people with a history of recreational cannabis use, lenabasum was safe and well-tolerated, although it did demonstrate abuse potential. This work supports further development of lenabasum for potential therapeutic indications.
PubMed: 38936978
DOI: 10.1124/jpet.124.002129 -
European Journal of Pharmacology Jun 2024The interleukin-1 receptor-associated kinase (IRAK) family is a group of serine-threonine kinases that regulates various cellular processes via toll-like receptor... (Review)
Review
The interleukin-1 receptor-associated kinase (IRAK) family is a group of serine-threonine kinases that regulates various cellular processes via toll-like receptor (TLR)/interleukin-1 receptor (IL1R)-mediated signaling. The IRAK family comprises four members, including IRAK1, IRAK2, IRAK3, and IRAK4, which play an important role in the expression of various inflammatory genes, thereby contributing to the inflammatory response. IRAKs are key proteins in chronic and acute liver diseases, and recent evidence has implicated IRAK family proteins (IRAK1, IRAK3, and IRAK4) in the progression of liver-related disorders, including alcoholic liver disease, non-alcoholic steatohepatitis, hepatitis virus infection, acute liver failure, liver ischemia-reperfusion injury, and hepatocellular carcinoma. In this article, we provide a comprehensive review of the role of IRAK family proteins and their associated inflammatory signaling pathways in the pathogenesis of liver diseases. The purpose of this study is to explore whether IRAK family proteins can serve as the main target for the treatment of liver related diseases.
PubMed: 38936453
DOI: 10.1016/j.ejphar.2024.176773