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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 -
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 -
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 -
Cell Jun 2024Interleukin (IL)-23 and IL-17 are well-validated therapeutic targets in autoinflammatory diseases. Antibodies targeting IL-23 and IL-17 have shown clinical efficacy but...
Interleukin (IL)-23 and IL-17 are well-validated therapeutic targets in autoinflammatory diseases. Antibodies targeting IL-23 and IL-17 have shown clinical efficacy but are limited by high costs, safety risks, lack of sustained efficacy, and poor patient convenience as they require parenteral administration. Here, we present designed miniproteins inhibiting IL-23R and IL-17 with antibody-like, low picomolar affinities at a fraction of the molecular size. The minibinders potently block cell signaling in vitro and are extremely stable, enabling oral administration and low-cost manufacturing. The orally administered IL-23R minibinder shows efficacy better than a clinical anti-IL-23 antibody in mouse colitis and has a favorable pharmacokinetics (PK) and biodistribution profile in rats. This work demonstrates that orally administered de novo-designed minibinders can reach a therapeutic target past the gut epithelial barrier. With high potency, gut stability, and straightforward manufacturability, de novo-designed minibinders are a promising modality for oral biologics.
PubMed: 38936360
DOI: 10.1016/j.cell.2024.05.052 -
Heliyon Jun 2024(PC) is a traditional Chinese medicine (TCM) and food as well as an important essential oil plant in China. PC essential oil exerts pharmacological effects such as...
GC-MS method for simultaneous determination and pharmacokinetic investigation of five volatile components in rat plasma after oral administration of the essential oil extract of .
(PC) is a traditional Chinese medicine (TCM) and food as well as an important essential oil plant in China. PC essential oil exerts pharmacological effects such as anti-inflammatory, anti-oxidant, anti-platelet, anti-thrombotic, and anti-depressant. This study established a reliable and sensitive gas chromatography-mass spectrometry (GC-MS) method for the simultaneous determination of the pharmacokinetics of patchouli alcohol, β-elemene, β-caryophyllene, caryophyllene oxide, and farnesol in the plasma of rats after oral administration of PC essential oil extract. Using ethyl acetate to prepare the plasma samples, and p-menthone was used as the internal standard (IS). An HP5-MS column (0.25 μm × 0.25 mm × 30 m) was used for chromatographic separation, and detection was performed in selected ion monitoring (SIM) mode. The accuracies of intra-day and inter-day for all analytes displayed a range of -6.7 %-9.2 %, with precision below 12.5 %. Extraction recoveries for analytes ranged from 74.0 to 106.4 % and matrix effects ranged from 92.4 to 106.9 %. Stability results have demonstrated that the relative standard deviations (RSD) of analytes were below 12.1 %. Therefore, the developed GC-MS method successfully evaluated the pharmacokinetics of five volatile components in PC essential oil extract administered orally to rats.
PubMed: 38933986
DOI: 10.1016/j.heliyon.2024.e32444 -
Frontiers in Pharmacology 2024Heart failure is the most costly cardiovascular disorder. New treatments are urgently needed. This study aims to evaluate the safety, pharmacokinetics, and...
Safety, tolerability, pharmacokinetics, and pharmacodynamics of a soluble guanylate cyclase stimulator, HEC95468, in healthy volunteers: a randomized, double-blinded, placebo-controlled phase 1 trial.
Heart failure is the most costly cardiovascular disorder. New treatments are urgently needed. This study aims to evaluate the safety, pharmacokinetics, and pharmacodynamic profile of HEC95468, a soluble guanylate cyclase (sGC) stimulator, in healthy volunteers. Sixty-two, eighteen, and forty-eight participants were enrolled in the single ascending dose (SAD) study, the food effect (FE) study, and the multiple ascending dose (MAD) study, respectively. The study conforms to good clinical practice and the Declaration of Helsinki. Overall, HEC95468 was safe and tolerable; a higher proportion of HEC95468-treated participants reported mild headaches, dizziness, decreased blood pressure, increased heart rate, and gastrointestinal-related treatment-emergent adverse events (TEAEs), similar to the sGC stimulators riociguat and vericiguat. In terms of pharmacokinetic parameters, the maximum observed plasma concentration (C) and the area under the concentration-time curve (AUC) were dose-proportional over the dose range. Moderate accumulation was observed after multiple administrations of HEC95468. Systolic blood pressure (SBP) and diastolic blood pressure decreased, while 3',5'-cyclic guanosine monophosphate (cGMP) concentration in plasma increased and heart rate was induced. Vasoactive hormones (renin, angiotensin II, and norepinephrine) in plasma were compensatorily elevated after oral administration. These data supported further clinical trials of HEC95468 in the treatment of heart failure and pulmonary arterial hypertension. http://www.chinadrugtrials.org.cn, identifier CTR20210064.
PubMed: 38933676
DOI: 10.3389/fphar.2024.1359939 -
Frontiers in Pharmacology 2024Mefunidone is a novel synthetic compound and is better when compared to pirfenidone for the anti-fibrotic treatment of renal fibrosis in end-stage renal disease. We...
BACKGROUND
Mefunidone is a novel synthetic compound and is better when compared to pirfenidone for the anti-fibrotic treatment of renal fibrosis in end-stage renal disease. We conducted this first-in-human, phase I clinical trial to determine the safety, tolerability, and pharmacokinetic (PK) (including food effect) profiles of mefunidone administered orally as single and multiple ascending doses in healthy subjects.
METHODS
Part A assessed single ascending doses of mefunidone from 25 mg to 800 mg or placebo once daily in the fasting state. Part A also assessed the effect of food on tolerability and PK in the 100 mg cohort. Part B consisted of three treatment groups who received 100 mg, 200 mg, or 400 mg of mefunidone or placebo twice daily (BID, ) on days 1-6 and once in the morning on day 7.
RESULTS
Single oral doses of mefunidone up to 800 mg and multiple doses of mefunidone up to 400 mg BID were all well-tolerated. Mefunidone behaved with ideal dose proportionality within the single-dose range of 50 mg-600 mg and the multiple-dose range of 100 mg BID to 400 mg BID by day 7. High-fat fed conditions led to a delay in T by approximately 1 h and a slight reduction of approximately 20% in C compared to that in fasting conditions, but it did not significantly affect systemic exposure.
CONCLUSION
Mefunidone exhibited favorable pharmacokinetics and safety profiles. The present study informed and supported further developmental clinical studies of mefunidone.
CLINICAL TRIAL REGISTRATION
clinicaltrials.gov, identifier CXHL1900206.
PubMed: 38933669
DOI: 10.3389/fphar.2024.1414066 -
Cureus May 2024Paediatric patients frequently encounter medication errors caused by the requirement for individualised drug dose estimates based on weight, age variance, and drug...
BACKGROUND
Paediatric patients frequently encounter medication errors caused by the requirement for individualised drug dose estimates based on weight, age variance, and drug pharmacokinetics. One thing contributing to drug dosing errors is the lack of healthcare personnel's knowledge of paediatric drug dosing. The present study aimed to evaluate the knowledge and perception regarding the workshop on paediatric drug dosing among undergraduate pharmacy students.
METHOD
A prospective pre-post study was conducted. A virtual workshop on paediatric drug dosing was designed and developed by the clinical pharmacy lecturer from Universiti Sultan Zainal Abidin (UniSZA) for pharmacy students. An online questionnaire with 15 questions regarding knowledge of paediatric drug dosing and perception of the virtual workshop on paediatric drug dosing was used to evaluate pharmacy students' knowledge pre- and post-workshop.
RESULT
Twenty-six students took part in the study (100%). In the pre-workshop on paediatric drug dosing calculation, most students had poor knowledge of the paediatric drug dosing calculation, scored 8 out of 15, 26.92% between 9 to 11 and only 11.54% scored ≥ 12. There was a statistically significant difference in median knowledge score between pre- and post-workshop (p< 0.05). Among the students, 73.08% stated that they strongly agreed that the online workshop attracted their attention and 76.92% of students strongly agreed that they were able to calculate paediatric drug dosing after joining the online workshop.
CONCLUSION
Results demonstrate that pharmacy students have insufficient knowledge of paediatric drug dosing calculations. Virtual workshop is one strategy that could improve the pharmacy students' knowledge.
PubMed: 38933608
DOI: 10.7759/cureus.61140