Phenylacetyl glutamine (PAGln) enhances cardiomyocyte death after myocardial infarction through ß1 adrenergic receptor.

This study aims to explore the roles of phenylacetyl glutamine (PAGln) on myocardial infarction (MI) pathogenesis. Here, using targeted metabolomics analysis, it was found that the plasma metabolite PAGln was upregulated in coronary artery disease (CAD) patients and MI mice and could be an independent risk factor for CAD. In vivo and in vitro functional experiments revealed that PAGln pretreatment enhanced MI-induced myocardial injury and cardiac fibrosis, as evident by the increased infarct size, cardiomyocyte death, and the upregulated expression of cardiac fibrosis markers (Col1a1 and α-SMA). Combined with RNA-sequencing analysis and G protein-coupled receptor (GPCR) inhibitor, we found that the GPCR signaling activation is essential for PAGln-mediated effects on cardiomyocyte death. Furthermore, drug affinity responsive target stability and cellular thermal shift assay demonstrated that PAGln could interact with ß1-adrenergic receptor (AR). Moreover, ß1-AR blocker treatment indeed extended the cardiac remodeling after PAGln-enhanced MI. These results suggest that PAGln might be a potential therapeutic target for extending the cardiac remodeling window in MI patients that signals via ß1-AR.

[Material basis of kidney Yang deficiency rats before and after salt processing of Dipsacus asper based on spectrum-effect relationship].

This paper aims to study the spectrum-effect relationship between the fingerprints before and after salt processing of Dipsacus asper and the efficacy of warming and tonifying kidney Yang and find the main active components against kidney Yang deficiency before and after salt processing of D. asper, so as to provide the basis for clarifying the effect of salt processing on kidney Yang deficiency. The HPLC fingerprint before and after salt processing of D. asper was established by the HPLC-DAD. 15 common peaks were obtained, and 11 components were identified. The content changes of various components in rat serum were detected, and the difference in efficacy before and after salt processing was compared. The results of pharmacological experiments showed that salt processing of D. asper could enhance the kidney index. At the same dose, there was a significant difference between the raw D. asper and D. asper after salt processing groups. Compared with the model group, the contents of ACTH, cAMP, CORT, E_2, GH, Na~+-K~+-ATPase, T, and T4 in the serum of rats in the administration group increased to a certain extent, and the contents of cGMP and TNF-α decreased to a certain extent. Among them, there were significant differences in the above indexes in the serum of rats in the high-dose group of raw D. asper, middle-dose group of D. asper after salt processing, high-dose group of D. asper after salt processing, and the positive drug group. The overall results showed that D. asper after salt processing was more effective than raw D. asper in preventing kidney yang deficiency. The efficacy of D. asper was evaluated by grey correlation analysis, entropy method, and Pearson correlation analysis, and the components of D. asper after salt processing against kidney yang deficiency were screened out. According to the results of correlation degree ranking, the components with increased ranking before and after salt processing of D. asper were loganin, chlorogenic acid, dipsacoside A, asperosaponin Ⅵ, caffeic acid, and isochlorogenic acid B. It was preliminarily speculated that these compounds may be the potential pharmacodynamic components for the treatment of kidney yang deficiency before and after salt processing of D. asper. The changing components before and after the salt processing of D. asper were determined, which proved that D. asper after salt processing was superior to D. asper in the treatment of kidney yang deficiency. The spectrum-effect relationship between the efficacy of D. asper before and after salt processing and the treatment of kidney yang deficiency was established, which laid a foundation for the subsequent study on the pharmacodynamic components and molecular mechanism of salt processing of D. asper.

Cerebrospinal fluid metabolic profiling reveals divergent modulation of pentose phosphate pathway by midazolam, propofol and dexmedetomidine in patients with subarachnoid hemorrhage: a cohort study.

BACKGROUND: Agitation is common in subarachnoid hemorrhage (SAH), and sedation with midazolam, propofol and dexmedetomidine is essential in agitation management. Previous research shows the tendency of dexmedetomidine and propofol in improving long-term outcome of SAH patients, whereas midazolam might be detrimental. Brain metabolism derangement after SAH might be interfered by sedatives. However, how sedatives work and whether the drugs interfere with patient outcome by altering cerebral metabolism is unclear, and the comprehensive view of how sedatives regulate brain metabolism remains to be elucidated. METHODS: For cerebrospinal fluid (CSF) and extracellular space of the brain exchange instantly, we performed a cohort study, applying CSF of SAH patients utilizing different sedatives or no sedation to metabolomics. Baseline CSF metabolome was corrected by selecting patients of the same SAH and agitation severity. CSF components were analyzed to identify the most affected metabolic pathways and sensitive biomarkers of each sedative. Markers might represent the outcome of the patients were also investigated. RESULTS: Pentose phosphate pathway was the most significantly interfered (upregulated) pathway in midazolam (p = 0.0000107, impact = 0.35348) and propofol (p = 0.00000000000746, impact = 0.41604) groups. On the contrary, dexmedetomidine decreased levels of sedoheptulose 7-phosphate (p = 0.002) and NADP (p = 0.024), and NADP is the key metabolite and regulator in pentose phosphate pathway. Midazolam additionally augmented purine synthesis (p = 0.00175, impact = 0.13481) and propofol enhanced pyrimidine synthesis (p = 0.000203, impact = 0.20046), whereas dexmedetomidine weakened pyrimidine synthesis (p = 0.000000000594, impact = 0.24922). Reduced guanosine diphosphate (AUC of ROC 0.857, 95%CI 0.617-1, p = 0.00506) was the significant CSF biomarker for midazolam, and uridine diphosphate glucose (AUC of ROC 0.877, 95%CI 0.631-1, p = 0.00980) for propofol, and succinyl-CoA (AUC of ROC 0.923, 95%CI 0.785-1, p = 0.000810) plus adenosine triphosphate (AUC of ROC 0.908, 95%CI 0.6921, p = 0.00315) for dexmedetomidine. Down-regulated CSF succinyl-CoA was also associated with favorable outcome (AUC of ROC 0.708, 95% CI: 0.524-0.865, p = 0.029333). CONCLUSION: Pentose phosphate pathway was a crucial target for sedatives which alter brain metabolism. Midazolam and propofol enhanced the pentose phosphate pathway and nucleotide synthesis in poor-grade SAH patients, as presented in the CSF. The situation of dexmedetomidine was the opposite. The divergent modulation of cerebral metabolism might further explain sedative pharmacology and how sedatives affect the outcome of SAH patients.

Methyleugenol Potentiates Central Amygdala GABAergic Inhibition and Reduces Anxiety.

The central amygdala (CeA) plays a critical role in the expression of emotional behaviors, including pathologic anxiety disorders. The present study demonstrated that GABAergic inhibition in CeA was significantly increased by methyleugenol (ME), a natural constituent isolated from the essential oils of several plants. The electrophysiologic recordings showed that ME increased both tonic and miniature inhibitory postsynaptic GABAergic currents in CeA slices, especially the tonic currents, while the miniature excitatory postsynaptic currents were not affected. In the fear-induced anxiety animal model, both intraperitoneal injection or CeA-specific infusion of ME reduced the anxiety-like behaviors in mice, likely by facilitating the activation of A-type GABA receptors (GABAARs). These results reveal that GABAAR in the CeA can be a potential therapeutic target for the treatment of anxiety and that ME is capable of enhancing the GABAergic inhibition in CeA neurons for the inhibition of neuronal excitability.

[Progress of regulation of leukemia stem cells of chronic myeloid leukemia by autophagy].

Leukemia stem cells (LSC) that were found in chronic myeloid leukemia (CML) responsible for the abnormal proliferation with the potential of self-renewal and multi-directional differentiation are involved in the pathophysiological process for drug resistance and relapse of CML. Autophagy, a conservative lysosomal degradation process that mediates cell degradation and recycling process, plays crucial roles in maintaining the homeostasis and function of intracellular environment. Recent studies suggested that autophagy is involved in the regulation of LSC differentiation and also closely related to the chemo-sensitivity of CML. In this review, we focused on the role of autophagy on chemotherapy sensitivity of CML as well as the leukemia stem cell function for the development of new anti-leukemia drugs.

[Analysis of different forms Linderae Radix based on HPLC and NIRS fingerprints].

Three different forms of Linderae Radix were evaluated by HPLC combined with NIRS fingerprint. The Linderae Radix was divided into three forms, including spindle root, straight root and old root. The HPLC fingerprints were developed, and then cluster analysis was performed using the SPSS software. The near-infrared spectra of Linderae Radix was collected, and then established the discriminant analysis model. The similarity values of the spindle root and straight root all were above 0.990, while the similarity value of the old root was less than 0.850. Two forms of Linderae Radix were obviously divided into three parts by the NIRS model and Cluster analysis. The results of HPLC and FT-NIR analysis showed the quality of Linderae Radix old root was different from the spindle root and straight root. The combined use of the two methods could identify different forms of Linderae Radix quickly and accurately.

Therapeutic effect of inulin on enteric hyperoxaluria in rats.

OBJECTIVE: To observe the therapeutic effect of inulin on enteric hyperoxaluria in rats. METHODS: In experimental A, 24 healthy male Sprague-Dawley rats received an oxalate-free diet on day 1, a high-oxalate diet (oxalate, 74.82 mg/100 g feed stuffs) on days 2 and 3, and plus 2 g inulin to each rat on day 3. The 24-hour urinary volume, concentrations of urinary oxalate and urine creatinine were measured, and 24-hour urinary oxalate excretion was calculated. In experimental B, 24 healthy male Sprague-Dawley rats were equally randomized into control group and inulin group, Each rat received a high oxalate diet (oxalate, 74.82 mg/100 g feedstuffs), and plus 2 g inulin in inulin group. The 24-hour urinary oxalate excretion was calculated in both two groups. RESULTS: In experimental A, the 24-hour urinary oxalate excretion varied with time (F=11.481, P=0.035). The 24-hour urinary oxalate excretion significantly increased on day 2 compared with that on day 1 (P=0.026) and day 3 (P=0.037); it significantly increased on day 3 compared with day 1 (P=0.004). In experimental B, the 24-hour urinary oxalate excretion significantly decreased in inulin group compared with the control (P=0.011). CONCLUSION: Inulin may have potential therapeutic effect on enteric hyperoxaluria in rats.

[Rapid Identification of Fresh-cut and Sulphur Fumigation Processed Fritillaria thunbergii Bulb Slices Based on Near-infrared Spectroscopy].

OBJECTIVE: A rapid identification model of the fresh-cut and sulphur fumigation processed Fritillaria thunbergii bulb slices was developed by near-infrared spectroscopy (NIR) with chemometrics method. METHODS: 186 batches of Fritillaria thunbergii bulb slices were collected from the two main producing areas Ningbo and Pan'an in Zhejiang Province, and the near-infrared spectrums were gathered to establish the qualitative identification model by discriminant analysis. RESULTS: The identification model was developed by choosing the spectrum of 9,881.46-4,119.20 cm(-1) and "MSC + spectrum + Ns" to the original spectral preprocessing, and then was verified by prediction set, with 100% identify accuracy. CONCLUSION: The rapid identification model of the fresh-cut and sulphur fumigation processed Fritillaria thunbergii bulb slices by NIR is feasible and efficient.

The Potential Application of Aloe Barbadensis Mill. as Chinese Medicine for Constipation: Mini-Review.

Aloe barbadensis Mill. has a long history of medicinal use in the annals of traditional Chinese medicine, wherein it has garnered considerable renown. Its multifaceted therapeutic properties, characterized by its anti-inflammatory and antibacterial attributes, alongside its established efficacy as a laxative agent, have been extensively documented. This review commences with an exploration of the nomenclature, fundamental characteristics, and principal constituents of Aloe barbadensis Mill. responsible for its laxative effects. Subsequently, we delve into an extensive examination of the molecular mechanisms underlying Aloe barbadensis Mill.'s laxative properties, types of constipation treatments, commercially available preparations, considerations pertaining to toxicity, and its clinical applications. This review aims to serve as a comprehensive reference point for healthcare professionals and researchers, fostering an enhanced understanding of the optimal utilization of Aloe barbadensis Mill. in the treatment of constipation.

[Determination of main active components in crude and processed Corydalis Rhizoma samples from different habitats].

OBJECTIVE: To compare the content of water, ethanol soluble extracts and tetrahydropalmatine in crude and processed Corydalis Rhizoma samples from different habitats. METHODS: Corydalis Rhizoma was processed according to the optimum processing of the Chinese Pharmacopoeia (2010 edition), and then, the difference of the content of water,ethanol soluble extracts and tetrahydropalmatine in crude and processed Corydalis Rhizoma samples were analyzed and compared. RESULTS: From 14 different batches of Corydalis Rhizoma studies, the content of water, ethanol soluble extracts and tetrahydropalmatine in crude Corydalis Rhizoma was 12.8%-14.8%, 16.5%-19.6% and 0.043%-0.075%, respectively; As for Corydalis Rhizoma after processing with vinegar,the content of water, ethanol soluble extracts and tetrahydropalmatine was 7.58%-11.7%, 17.8%-23.5% and 0.046%-0.079%, respectively. CONCLUSION: The content of water, ethanol soluble extracts and tetrahydropalmatine varies slightly in the same type of samples from different habitats,which might be due to the difference in soil and climate in each habitat.

The cost-effectiveness analysis of analgesic treatment options for postoperative pain following laparotomy surgeries.

BACKGROUND: Postoperative pain control remains unsatisfactory. Patients who underwent laparotomy may have moderate to severe acute postoperative pain. Comparative cost-effectiveness of the following postoperative pain treatment options remains to be investigated: patient-controlled intravenous analgesia (PCIA) with flurbiprofen therapy, flurbiprofen monotherapy, parecoxib monotherapy, or dezocine monotherapy. AIM: To provide a cost-effectiveness analysis (CEA) of four analgesic regimens for patients with postoperative pain following laparotomy surgeries. METHOD: Patients with postoperative pain following laparotomy were retrospectively reviewed from a postoperative pain management database created by pharmacists, and divided into four groups according to analgesic regimens. The clinical outcomes were visual analogue scale (VAS) scores and the incidence of adverse drug events. The CEA was conducted by developing a decision tree model based on retrospective data. The maximum incremental cost-effectiveness ratio (ICER) of the four regimens was used as the willingness-to-pay (WTP) value. Meanwhile, the uncertainty of the base-case results was examined by one-way and probabilistic sensitivity analyses. RESULTS: A total of 677 patients were included in the retrospective study. PCIA with flurbiprofen therapy had the lowest VAS scores at 6, 24, 48 h postoperatively. Based on the base-case results, PCIA plus flurbiprofen was the optimal regimen with the highest effectiveness, while flurbiprofen monotherapy had the lowest cost. PCIA plus flurbiprofen was the optimal regimen even with a WTP value of 0 dollars. CONCLUSION: PCIA plus flurbiprofen therapy was the optimal regimen. Parecoxib monotherapy was more cost-effective than flurbiprofen monotherapy. The findings may guide the selection of postoperative pain management.

Targeting abnormal lipid metabolism of T cells for systemic lupus erythematosus treatment.

Systemic lupus erythematosus (SLE) is an autoimmune disease in which the immune system attacks its own tissues and organs. However, the causes of SLE remain unknown. Dyslipidemia is a common symptom observed in SLE patients and animal models and is closely correlated to disease activity. Lipid metabolic reprogramming has been considered as a hallmark of the dysfunction of T cells in patients with SLE, therefore, manipulating lipid metabolism provides a potential therapeutic target for treating SLE. A better understanding of the underlying mechanisms for the metabolic events of immune cells under pathological conditions is crucial for tuning immunometabolism to manage autoimmune diseases such as SLE. In this review, we aim to summarize the cross-link between lipid metabolism and the function of T cells as well as the underlying mechanisms, and provide light on the novel therapeutic strategies of active compounds from herbals for the treatment of SLE by targeting lipid metabolism in immune cells.

Ticagrelor versus Clopidogrel in the Dual Antiplatelet Regimen for Unruptured Intracranial Aneurysm Treated with Stent-Assisted Coil Embolization: A Single-Center Cohort Study.

BACKGROUND: Dual antiplatelet therapy (DAPT) of aspirin plus clopidogrel is commonly used in patients with unruptured intracranial aneurysms treated with stent-assisted coil (SAC) embolization. However, the unpredictable clopidogrel efficacy of the 5%-55% nonresponders limits its use. Ticagrelor, as a potential alternative of clopidogrel, is an antiplatelet agent with low resistance rates but uncertain efficacy and safety in these patients. METHODS: A single-center cohort study was performed to compare the efficacy and safety of ticagrelor with clopidogrel in the DAPT regimen in patients with unruptured intracranial aneurysms and treated with SAC. The patients with clopidogrel resistance identified as inadequate adenosine diphosphate inhibition rate determined by thromboelastography were treated with ticagrelor instead, and both drugs achieved adequate suppression of platelet aggregation when stents were implanted. The occurrence of major adverse cardiovascular and cerebrovascular events (MACCE) and bleeding events was recorded through 6 months follow-up. RESULTS: Data from 86 patients with 99 unruptured intracranial aneurysms and treated by SAC with clopidogrel were compared with those from 108 patients with 111 aneurysms and treated with ticagrelor. Neither the baseline characteristics nor the incidence of the MACCE or bleeding events differed between the groups. Ticagrelor exerted significantly higher adenosine diphosphate inhibition rate than that of the clopidogrel. Multivariable logistic regression analysis showed that the incidence of MACCE was related to hematocrit and fibrinogen levels. CONCLUSIONS: Ticagrelor seemed to be as effective and safe as clopidogrel for SAC in unruptured intracranial aneurysms. Hematocrit and fibrinogen levels were independent risk factors for the incidence of MACCE.

Immune pathway activation in neurons triggers neural damage after stroke.

Ischemic brain injury is a severe medical condition with high incidences in elderly people without effective treatment for the resulting neural damages. Using a unilateral mouse stroke model, we analyze single-cell transcriptomes of ipsilateral and contralateral cortical penumbra regions to objectively reveal molecular events with single-cell resolution at 4 h and 1, 3, and 7 days post-injury. Here, we report that neurons are among the first cells that sense the lack of blood supplies by elevated expression of CCAAT/enhancer-binding protein ß (C/EBPß). To our surprise, the canonical inflammatory cytokine gene targets for C/EBPß, including interleukin-1ß (IL-1ß) and tumor necrosis factor α (TNF-α), are subsequently induced also in neuronal cells. Neuronal-specific silencing of C/EBPß or IL-1ß and TNF-α substantially alleviates downstream inflammatory injury responses and is profoundly neural protective. Taken together, our findings reveal a neuronal inflammatory mechanism underlying early pathological triggers of ischemic brain injury.

The Use of Oral Anticoagulation Is Not Associated With a Reduced Risk of Mortality in Patients With COVID-19: A Systematic Review and Meta-Analysis of Cohort Studies.

Background: Hypercoagulability and thromboembolic events are associated with poor prognosis in coronavirus disease 2019 (COVID-19) patients. Whether chronic oral anticoagulation (OAC) improve the prognosis is yet controversial. The present study aimed to investigate the association between the chronic OAC and clinical outcomes in COVID-19 patients. Methods: PubMed, Embase, Web of Science, and the Cochrane Library were comprehensively searched to identify studies that evaluated OAC for COVID-19 until 24 July 2021. Random-effects model meta-analyses were performed to pool the relative risk (RR) and 95% confidence interval (CI) of all-cause mortality and intensive care unit (ICU) admission as primary and secondary outcomes, respectively. According to the type of oral anticoagulants [direct oral anticoagulants (DOACs) or vitamin K antagonists (VKAs)], subgroup and interaction analyses were performed to compare DOACs and VKAs. Meta-regression was performed to explore the potential confounders on all-cause mortality. Results: A total of 12 studies involving 30,646 patients met the inclusion criteria. The results confirmed that chronic OAC did not reduce the risk of all-cause mortality (RR: 0.92; 95% CI 0.82-1.03; p = 0.165) or ICU admission (RR: 0.65; 95% CI 0.40-1.04; p = 0.073) in patients with COVID-19 compared to those without OAC. The chronic use of DOACs did not reduce the risk of all-cause mortality compared to VKAs (P interaction = 0.497) in subgroup and interaction analyses. The meta-regression failed to detect any potential confounding on all-cause mortality. Conclusion: COVID-19 patients with chronic OAC were not associated with a lower risk of all-cause mortality and ICU admission compared to those without OAC, and the results were consistent across DOACs and VKA subgroups. Systematic Review Registration: clinicaltrials.gov, identifier CRD42021269764.

Warfarin anticoagulation management during the COVID-19 pandemic: The role of internet clinic and machine learning.

Background: Patients who received warfarin require constant monitoring by hospital staff. However, social distancing and stay-at-home orders, which were universally adopted strategies to avoid the spread of COVID-19, led to unprecedented challenges. This study aimed to optimize warfarin treatment during the COVID-19 pandemic by determining the role of the Internet clinic and developing a machine learning (ML) model to predict anticoagulation quality. Methods: This retrospective study enrolled patients who received warfarin treatment in the hospital anticoagulation clinic (HAC) and "Internet + Anticoagulation clinic" (IAC) of the Nanjing Drum Tower Hospital between January 2020 and September 2021. The primary outcome was the anticoagulation quality of patients, which was evaluated by both the time in therapeutic range (TTR) and international normalized ratio (INR) variability. Anticoagulation quality and incidence of adverse events were compared between HAC and IAC. Furthermore, five ML algorithms were used to develop the anticoagulation quality prediction model, and the SHAP method was introduced to rank the feature importance. Results: Totally, 241 patients were included, comprising 145 patients in the HAC group and 96 patients in the IAC group. In the HAC group and IAC group, 73.1 and 69.8% (p = 0.576) of patients achieved good anticoagulation quality, with the average TTR being 79.9 ± 20.0% and 80.6 ± 21.1%, respectively. There was no significant difference in the incidence of adverse events between the two groups. Evaluating the five ML models using the test set, the accuracy of the XGBoost model was 0.767, and the area under the receiver operating characteristic curve was 0.808, which showed the best performance. The results of the SHAP method revealed that age, education, hypertension, aspirin, and amiodarone were the top five important features associated with poor anticoagulation quality. Conclusion: The IAC contributed to a novel management method for patients who received warfarin during the COVID-19 pandemic, as effective as HAC and with a low risk of virus transmission. The XGBoost model could accurately select patients at a high risk of poor anticoagulation quality, who could benefit from active intervention.

Intensive vs non-intensive statin pretreatment before percutaneous coronary intervention in Chinese patients: A meta-analysis of randomized controlled trials.

BACKGROUND: The results of intensive statin pretreatment before percutaneous coronary intervention (PCI) is inconsistent between Chinese and Western populations, and there are no corresponding meta-analyses involving hard clinical endpoints in the available published literature. AIM: To evaluate the efficacy and safety of high-dose statin loading before PCI in Chinese patients through a meta-analysis. METHODS: Relevant studies were identified by searching the electronic databases of PubMed, Embase and Cochrane's Library to December 2019. The outcomes included an assessment of major adverse cardiovascular event (MACE), non-fatal myocardial infarction (MI), cardiac death, target vessel revascularization (TVR), myalgia /myasthenia and abnormal alanine aminotransferase (ALT) in all enrolled patients. Random effect model and fixed effect model were applied to combine the data, which were further analyzed by χ 2 test and I 2 test. The main outcomes were then analyzed through the use of relative risks (RR) and its 95% confidence interval (95%CI). RESULTS: Eleven studies involving 3123 individuals were included. Compared with patients receiving placebo or no statin treatment before surgery, intensive statin treatment was associated with a clear reduction of risk of MACE (RR = 0.44, 95%CI: 0.31-0.61, P < 0.00001). However, compared with the patients receiving moderate-intensity statin before surgery, no advantage to intensive statin treatment was seen (RR = 1.04, 95%CI: 0.82-1.31, P = 0.74). In addition, no significant difference was observed between intensive statin therapy and non-intensive statin therapy on the incidence of TVR (RR = 0.43, 95%CI: 0.18-1.02, P = 0.06) , myalgia /myasthenia (RR = 1.35, 95%CI: 0.30-5.95, P = 0.69) and abnormal alanine aminotransferase (RR = 1.47, 95%CI: 0.54-4.02, P = 0.45) except non-fatal MI (RR = 0.54, 95%CI: 0.33-0.88, P = 0.01). CONCLUSION: Compared with placebo or no statin pretreatment, intensive statin before PCI displayed reduced incidence of MACE. However, there was no significant benefit between high and moderate-intensity statin. In addition, no significant difference was observed between intensive statin therapy and non-intensive statin therapy on the incidence of TVR, myalgia/myasthenia and abnormal alanine aminotransferase except non-fatal MI.

Prediction of Rivaroxaban-Rifampin Interaction After Major Orthopedic Surgery: Physiologically Based Pharmacokinetic Modeling and Simulation.

Rivaroxaban is commonly used for the prophylaxis of venous thromboembolism (VTE) for patients undergoing major orthopedic surgery. Rivaroxaban is primarily eliminated by hepatic CYP450 metabolism and renal excretion. Rifampin is a commonly used antibiotic for prosthetic joint infections (PJI) and a potent inducer of CYP450 enzymes. Clinical data about drug-drug interactions of rivaroxaban and rifampin are limited. The present study is to describe DDI of rivaroxaban and rifampin in several prosthetic joint infections patients undergoing major orthopedic surgery. We retrospectively identified six patients concomitantly administered with rivaroxaban and rifampin between 2019 and 2020. Plasma samples of these patients with accurate sampling time were chosen from the biobank and plasma levels of rivaroxaban were measured at each time point. A physiologically based pharmacokinetic model for the rivaroxaban-rifampin interaction was developed to predict the optimal dosing regimen of rivaroxaban in the case of co-medication with rifampin. The model was validated by the observed plasma concentration of rivaroxaban from the above patients. From this model, it could be simulated that when rifampin starts or stops, gradually changing rivaroxaban dose during the first few days would elevate the efficacy and safety of rivaroxaban.

Topical Diclofenac Solution for Osteoarthritis of the Knee: An Updated Meta-Analysis of Randomized Controlled Trials.

This study was performed to assess the efficacy and safety of a topical diclofenac solution in patients with knee osteoarthritis (OA). PubMed, Embase, Cochrane Library, Web of Science, and Scopus databases were searched for randomized controlled trials until June 2020. The WOMAC pain, stiffness, physical function subscales, pain on walking, and the occurrence of adverse events were pooled to comprehensively analyse the efficacy and safety of topical diclofenac solution. All statistical analyses were conducted using Review Manager 5.3 software. Five RCTs were included, which provided high-quality evidence. In comparison to the vehicle control, the mean differences for WOMAC pain, stiffness, and physical function subscales, as well as pain on walking, were all statistically significant in favor of topical diclofenac solution. The safety of topical diclofenac solution was similar to the vehicle control, apart from adverse events involving application-site skin reactions. Topical diclofenac solution is effective and safe for use in patients with knee OA, but may cause minor skin reactions.

Anticoagulation Resumption in a Patient With Mechanical Heart Valves, Antithrombin Deficiency, and Hemorrhagic Transformation Following Thrombectomy After Ischemic Stroke.

Anticoagulation is essential for patients undergoing mechanical heart valve replacement; however, the timing to reinitiate the anticoagulant could be a dilemma that imposes increased risk for bleeding events in patients suffering from the life-threatening hemorrhagic transformation (HT) after ischemic stroke. Such a situation was presented in this case report. A 71-year-old woman was transferred directly to the Neurocritical Care Unit because of a HT that occurred following the mechanical thrombectomy for ischemic stroke. Since she had a history of prosthetic metallic valve replacement, how the anticoagulating therapy could balance the hemorrhagic and thrombotic risks was carefully evaluated. On day 6 after the onset of hemorrhage transformation, the laboratory results of coagulation and fibrinolysis strongly suggested thrombosis as well as antithrombin deficiency. The short-acting and titratable anticoagulant argatroban was immediately initiated at low dose, and thrombosis was temporarily terminated. On day 3 of anticoagulation resumption, argatroban was discontinued for one dose when the prothrombin time and activated partial thromboplastin time significantly prolonged after argatroban infusion. Aortic valve thrombosis was detected the next day. The anticoagulation was then strengthened by dose adjustment to keep mitral valve intact, to stabilize the aortic valve thrombosis, and to decrease the aortic flow rate. The intravenous argatroban was transited to oral warfarin before the patient was discharged. This study is the first report of administering argatroban and titrating to its appropriate dose in the patient with valve thrombosis, antithrombin deficiency, and HT after mechanical thrombectomy for acute ischemic stroke. Notably, the fluctuations argatroban brings to the coagulation test results might not be interpreted as increased bleeding risk. This case also suggested that the reported timing (day 6 to day 14 after hemorrhage) of anticoagulant resumption in primary intracerebral hemorrhage with mechanical valves might be late for some patients with HT.