Recruitment or activation of mast cells in the liver aggravates the accumulation of fibrosis in carbon tetrachloride-induced liver injury.

Liver diseases caused by viral infections, alcoholism, drugs, or chemical poisons are a significant health problem: Liver diseases are a leading contributor to mortality, with approximately 2 million deaths per year worldwide. Liver fibrosis, as a common liver disease characterized by excessive collagen deposition, is associated with high morbidity and mortality, and there is no effective treatment. Numerous studies have shown that the accumulation of mast cells (MCs) in the liver is closely associated with liver injury caused by a variety of factors. This study investigated the relationship between MCs and carbon tetrachloride (CCl4)-induced liver fibrosis in rats and the effects of the MC stabilizers sodium cromoglycate (SGC) and ketotifen (KET) on CCl4-induced liver fibrosis. The results showed that MCs were recruited or activated during CCl4-induced liver fibrosis. Coadministration of SCG or KET alleviated the liver fibrosis by decreasing SCF/c-kit expression, inhibiting the TGF-ß1/Smad2/3 pathway, depressing the HIF-1a/VEGF pathway, activating Nrf2/HO-1 pathway, and increasing the hepatic levels of GSH, GSH-Px, and GR, thereby reducing hepatic oxidative stress. Collectively, recruitment or activation of MCs is linked to liver fibrosis and the stabilization of MCs may provide a new approach to the prevention of liver fibrosis.

Mitochondrial uptake of aristolactam I plays a critical role in its toxicity.

Aristolochic acid I (AAI), a component of aristolochic acids, can be converted to the toxic metabolite Aristolactam I (ALI) in vivo which forms aristolactam-nitrenium with delocalized positive charges. It is widely accepted that delocalized lipophilic cations can accumulate in mitochondria due to the highly negatively charged microenvironment of the mitochondrial matrix, but the uptake of ALI by mitochondria is not known. In this study, the cell uptake and mitochondrial localization of ALI, and its subsequent impact on mitochondrial function were investigated. Results show that ALI can rapidly penetrate HK-2 cells without relying on organic anion transporters 1/3 (OAT1/3). The cellular distribution of ALI was found to align with the observed distribution of a mitochondria-selective dye in HK-2 cells. Furthermore, the cell uptake and mitochondrial uptake of ALI were both inhibited by carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone, which induces mitochondrial membrane depolarization. These results suggest that ALI is selectively taken up by mitochondria. Consequently, mitochondrial dysfunction was observed after treatment with ALI. It should be noted that inhibiting OAT1/3 could result in an increased exposure of ALI in vivo and cause more seriously nephrotoxicity. In conclusion, this research reports the mitochondrial uptake of ALI and provides new insight on potential strategies for protection against AAI-induced nephrotoxicity.

Identification and characterization of endogenous biomarkers for hepatic vectorial transport (OATP1B3-P-gp) function using metabolomics with serum pharmacology.

The organic anion-transporting polypeptide 1B3 and P-glycoprotein (P-gp) provide efficient directional transport (OATP1B3-P-gp) from the blood to the bile that serves as a key determinant of hepatic disposition of the drug. Unfortunately, there is still a lack of effective means to evaluate the disposal ability mediated by transporters. The present study was designed to identify a suitable endogenous biomarker for the assessment of OATP1B3-P-gp function in the liver. We established stably transfected HEK293T-OATP1B3 and HEK293T-P-gp cell lines. Results showed that azelaic acid (AzA) was an endogenous substrate for OATP1B3 and P-gp using serum pharmacology combined with metabolomics. There is a good correlation between the serum concentration of AzA and probe drugs of rOATP1B3 and rP-gp when rats were treated with their inhibitors. Importantly, after 5-fluorouracil-induced rat liver injury, the relative mRNA level and expression of rOATP1B3 and rP-gp were markedly down-regulated in the liver, and the serum concentration of AzA was significantly increased. These observations suggest that AzA is an endogenous substrate of both OATP1B3 and P-gp, and may serve as a potential endogenous biomarker for the assessment of the function of OATP1B3-P-gp for the prediction of changes in the pharmacokinetics of drugs transported by OATP1B3-P-gp in liver disease states.

Identification and characterization of an endogenous biomarker of the renal vectorial transport (OCT2-MATE1).

The renal tubular organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1) mediate the vectorial elimination of many drugs and toxins from the kidney, and endogenous biomarkers for vectorial transport (OCT2-MATE1) would allow more accurate drug dosing and help to characterize drug-drug interactions and toxicity. Human serum uptake in OCT2-overexpressing cells and metabolomics analysis were carried out. Potential biomarkers were verified in vitro and in vivo. The specificity of biomarkers was validated in renal transporter overexpressing cells and the sensitivity was investigated by Km . The results showed that the uptake of thiamine, histamine, and 5-hydroxytryptamine was significantly increased in OCT2-overexpressing cells. In vitro assays confirmed that thiamine, histamine, and 5-hydroxytryptamine were substrates of both OCT2 and MATE1. In vivo measurements indicated that the serum thiamine level was increased significantly in the presence of the rOCT2 inhibitor cimetidine, and the level in renal tissue was increased significantly by the rMATE1 inhibitor pyrimethamine. There were no significant changes in the uptake or efflux of thiamine in cell lines overexpressed OAT1, OAT2, OAT3, MRP4, organic anion transporting polypeptide 4C1, P-gp, peptide transporter 2, urate transporter 1, and OAT4. The Km for thiamine with OCT2 and MATE1 were 71.2 and 10.8 µM, respectively. In addition, the cumulative excretion of thiamine at 2 and 4 h was strongly correlated with metformin excretion (R2  > 0.6). Thus, thiamine is preferentially secreted by the OCT2 and MATE1 in renal tubules and can provide a reference value for evaluating the function of the renal tubular OCT2-MATE1.

Effects of Early Versus Delayed Feeding in Patients With Acute Pancreatitis: A Systematic Review and Meta-analysis.

BACKGROUND: The aim of this study was to summarize the optimal strategy for early feeding in patients with acute pancreatitis. METHODS: The search was undertaken in electronic databases, which compared early with delayed feeding in acute pancreatitis. The primary outcome was the length of hospital stay (LOHS). The second outcomes were intolerance of refeeding, mortality, and total cost of each patient. This meta-analysis followed the "Preferred Reporting Items for Systematic Reviews and Meta-analyses" guideline. Research is registered by PROSPERO, CRD42020192133. RESULTS: A total of 20 trials involving 2168 patients were included, randomly assigned to the early feeding group (N = 1033) and delayed feeding group (N = 1135). The LOHS was significantly lower in the early feeding group than the delayed feeding group (mean difference: -2.35, 95% CI: -2.89 to -1.80; P < 0.0001), no matter the mild or severe subgroup ( Pint = 0.69). The secondary outcome of feeding intolerance and mortality were no significant difference (risk ratio: 0.96, 0.40 to 2.16, P = 0.87 and 0.91, 0.57 to 1.46, P = 0.69; respectively). Moreover, the hospitalization cost was significantly less in the early feeding group, resulting in an average savings of 50%. In patients with severe pancreatitis, early feeding after 24 hours may be beneficial ( Pint = 0.001). CONCLUSION: Early oral feeding can significantly reduce the LOHS and hospitalization costs in patients with acute pancreatitis without increasing feeding intolerance or mortality. In patients with severe pancreatitis, early feeding after 24 hours may be beneficial.

A rare case of hypertensive urgency caused by linezolid was reported: A case report.

RATIONALE: Linezolid itself is rarely reported to cause blood pressure elevation, and it is rare to report that linezolid causes hypertensive urgency. PATIENTS CONCERNS: This case report describes a 38-year-old man who developed acute hypertension after a postoperative foot infection that was treated with linezolid antitherapy. Hypertensive urgency occurred without obvious potential interaction between linezolid and drugs. After receiving appropriate treatment and stopping medication, the patient's blood pressure returned to normal and did not recur. DIAGNOSES: Hypertensive crises occurred during the treatment of linezolid. INTERVENTIONS: After stopping linezolid, the patient's blood pressure gradually returned to normal. OUTCOMES: The patient's blood pressure returned to normal on the 26th day after stopping linezolid, and no abnormal blood pressure was found in the follow-up 2 months after discharge. LESSONS: Linezolid is rarely reported to cause elevated blood pressure, even though it may occur in the absence of obvious drug interactions. Case reported fewer reasons may be for clinicians statistically insignificant or notice, and hypertensive urgency often lead to clinical risk, should be given enough attention to clinical. Pay attention to blood pressure monitoring during use, when there is abnormal increase in blood pressure, should consider adverse drug reactions, give timely discontinuation and give symptomatic treatment.

Albumin-bound kynurenic acid is an appropriate endogenous biomarker for assessment of the renal tubular OATs-MRP4 channel.

Renal tubular secretion mediated by organic anion transporters (OATs) and the multidrug resistance-associated protein 4 (MRP4) is an important means of drug and toxin excretion. Unfortunately, there are no biomarkers to evaluate their function. The aim of this study was to identify and characterize an endogenous biomarker of the renal tubular OATs-MRP4 channel. Twenty-six uremic toxins were selected as candidate compounds, of which kynurenic acid was identified as a potential biomarker by assessing the protein-binding ratio and the uptake in OAT1-, OAT3-, and MRP4-overexpressing cell lines. OAT1/3 and MRP4 mediated the transcellular vectorial transport of kynurenic acid in vitro. Serum kynurenic acid concentration was dramatically increased in rats treated with a rat OAT1/3 (rOAT1/3) inhibitor and in rOAT1/3 double knockout (rOAT1/3-/-) rats, and the renal concentrations were markedly elevated by the rat MRP4 (rMRP4) inhibitor. Kynurenic acid was not filtered at the glomerulus (99% of albumin binding), and was specifically secreted in renal tubules through the OAT1/3-MRP4 channel with an appropriate affinity (Km) (496.7 µM and 382.2 µM for OAT1 and OAT3, respectively) and renal clearance half-life (t1/2) in vivo (3.7 ± 0.7 h). There is a strong correlation in area under the plasma drug concentration-time curve (AUC0-t) between cefmetazole and kynurenic acid, but not with creatinine, after inhibition of rOATs. In addition, the phase of increased kynurenic acid level is earlier than that of creatinine in acute kidney injury process. These results suggest that albumin-bound kynurenic acid is an appropriate endogenous biomarker for adjusting the dosage of drugs secreted by this channel or predicting kidney injury.

Highly Efficient Light-Emitting Diodes Based on Self-Assembled Colloidal Quantum Wells.

Nanocrystal-based light-emitting diodes (Nc-LEDs) have immense potential for next-generation high-definition displays and lighting applications. They offer numerous advantages, such as low cost, high luminous efficiency, narrow emission, and long lifetime. However, the external quantum efficiency (EQE) of Nc-LEDs, typically employing isotropic nanocrystals, is limited by the out-coupling factor. Here efficient, bright, and long lifetime red Nc-LEDs based on anisotropic nanocrystals of colloidal quantum wells (CQWs) are demonstrated. Through modification of the substrate's surface properties and control of the interactions among CQWs, a self-assembled layer with an exceptionally high distribution of in-plane transitions dipole moment of 95%, resulting in an out-coupling factor of 37% is successfully spin-coated. The devices exhibit a remarkable peak EQE of 26.9%, accompanied by a maximum brightness of 55 754 cd m-2 and a long operational lifetime (T95 @100 cd m-2 ) over 15 000 h. These achievements represent a significant advancement compared to previous studies on Nc-LEDs incorporating anisotropic nanocrystals. The work is expected to provide a general self-assembly strategy for enhancing the light extraction efficiency of Nc-LEDs based on anisotropic nanocrystals.

Accumulation of Renal Fibrosis in Hyperuricemia Rats Is Attributed to the Recruitment of Mast Cells, Activation of the TGF-ß1/Smad2/3 Pathway, and Aggravation of Oxidative Stress.

Renal fibrosis is relentlessly progressive and irreversible, and a life-threatening risk. With the continuous intake of a high-purine diet, hyperuricemia has become a health risk factor in addition to hyperglycemia, hypertension, and hyperlipidemia. Hyperuricemia is also an independent risk factor for renal interstitial fibrosis. Numerous studies have reported that increased mast cells (MCs) are closely associated with kidney injury induced by different triggering factors. This study investigated the effect of MCs on renal injury in rats caused by hyperuricemia and the relationship between MCs and renal fibrosis. Our results reveal that hyperuricemia contributes to renal injury, with a significant increase in renal MCs, leading to renal fibrosis, mitochondrial structural disorders, and oxidative stress damage. The administration of the MCs membrane stabilizer, sodium cromoglycate (SCG), decreased the expression of SCF/c-kit, reduced the expression of α-SMA, MMP2, and inhibited the TGF-ß1/Smad2/3 pathway, thereby alleviating renal fibrosis. Additionally, SCG reduced renal oxidative stress and mitigated mitochondrial structural damage by inhibiting Ang II production and increasing renal GSH, GSH-Px, and GR levels. Collectively, the recruitment of MCs, activation of the TGF-ß1/Smad2/3 pathway, and Ang II production drive renal oxidative stress, ultimately promoting the progression of renal fibrosis in hyperuricemic rats.

Cardiac arrhythmias associated with anaplastic lymphoma kinase (ALK) inhibitors: an analysis of the FDA Adverse Event Reporting System (FAERS).

BACKGROUND: Anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) may provoke cardiac arrhythmias. We conducted this pharmacovigilance analysis to research cardiac arrhythmias associated with ALK-TKIs using the Food and Drug Administration Adverse Event Reporting System (FAERS). RESEARCH DESIGN AND METHODS: The first ALK-TKI, named crizotinib, was approved by the Food and Drug Administration (FDA) on 26 August 2011 for the treatment of ALK-rearranged non-small cell lung cancer (NSCLC). We evaluated ALK-TKIs-induced cardiac arrhythmias, by using the reporting odds ratio (ROR) and information component (IC) for mining the adverse event report signals in the FAERS database between January 2016 and June 2022. RESULTS: We identified a total of 362 ALK-TKIs-related cardiac arrhythmia reports which appeared to influence more men (64.44%) than women (30.76%), with a median age of 68 (interquartile range [IQR] 7-74) years. Compared with the full database, ALK-TKIs were detected with pharmacovigilance of cardiac arrhythmias (ROR025 = 1.26, IC025 = 0.26). Crizotinib and alectinib were found to be related to higher reporting of arrhythmias. The median time to onset (TTO) among five ALK-TKI therapies was significantly different (p = 0.044). CONCLUSION: ALK-TKIs present different frequencies of cardiac arrhythmias reporting, with only crizotinib and alectinib producing positive signals in high-level group term (HLGT) level arrhythmia. The time interval between the initial of drug treatment to the onset of arrhythmia varies greatly and cannot be predicted.

Proarrhythmia associated with antiarrhythmic drugs: a comprehensive disproportionality analysis of the FDA adverse event reporting system.

Objective: This study aimed to identify the different associations between antiarrhythmic drugs (AADs) and arrhythmias, and to determine whether pharmacokinetic drug interactions involving AADs increase the risk of AAD-related arrhythmias compared to using AADs alone. Materials and methods: The disproportionality analysis of AAD-associated cardiac arrhythmias, including AAD monotherapies and concomitant use of pharmacokinetic interacting agents involving AADs, was conducted by using reporting odds ratio (ROR) and information component (IC) as detection of potential safety signals based on FAERS data from January 2016 to June 2022. We compared the clinical features of patients reported with AAD-associated arrhythmias between fatal and non-fatal groups, and further investigated the onset time (TTO) following different AAD regimens. Results: A total of 11754 AAD-associated cardiac arrhythmias reports were identified, which was more likely to occur in the elderly (52.17%). Significant signals were detected between cardiac arrhythmia and all AAD monotherapies, with ROR ranging from 4.86 with mexiletine to 11.07 with flecainide. Regarding four specific arrhythmias in High Level Term (HLT) level, the AAD monotherapies with the highest ROR were flecainide in cardiac conduction disorders (ROR025 = 21.18), propafenone in rate and rhythm disorders (ROR025 = 10.36), dofetilide in supraventricular arrhythmias (ROR025 = 17.61), and ibutilide in ventricular arrhythmias (ROR025 = 4.91). Dofetilide/ibutilide, ibutilide, mexiletine/ibutilide and dronedarone presented no signal in the above four specific arrhythmias respectively. Compared with amiodarone monotherapy, sofosbuvir plus amiodarone detected the most significantly increased ROR in arrhythmias. Conclusion: The investigation showed the spectrum and risk of AAD-associated cardiac arrhythmias varied among different AAD therapies. The early identification and management of AAD-associated arrhythmias are of great importance in clinical practice.

Gentamicin alleviates cholestatic liver injury by decreasing gut microbiota-associated bile salt hydrolase activity in rats.

Intrahepatic cholestasis lacks effective therapeutic drugs. The gut microbiota-associated bile salt hydrolases (BSH) may be a potential therapeutic target. In this study, oral administration of gentamicin (GEN) decreased the serum and hepatic levels of total bile acid in 17α-ethynylestradiol (EE)-induced cholestatic male rats, significantly improved the serum levels of hepatic biomarkers and reversed the histopathological changes in the liver. In healthy male rats, the serum and hepatic levels of total bile acid were also decreased by GEN, the ratio of primary to secondary bile acids, and conjugated to unconjugated bile acids was significantly increased, and the urinary excretion of total bile acid was elevated. 16S rDNA sequencing of the ileal contents revealed that GEN treatment substantially reduced the abundance of Lactobacillus and Bacteroides both of which expressed BSH. Consistently, BSH activity analysis by the generation of d5-chenodeoxycholic acid from d5-taurochenodeoxycholic acid in situ showed BSH was significantly inhibited in the ileal contents of rats treated with GEN. This finding led to an increased proportion of hydrophilic conjugated bile acids and facilitated the urinary excretion of total bile acids, thereby decreasing serum and hepatic total bile acids and reversing liver injury related to cholestasis. Our results provide important evidence that BSH can be a potential drug target for treating cholestasis.

Multidisciplinary Guidelines for the Rational Use of Topical Non-Steroidal Anti-Inflammatory Drugs for Musculoskeletal Pain (2022).

(1) Background: Topical non-steroidal anti-inflammatory drugs (NSAIDs) are one of the primary drugs for treating musculoskeletal pain. However, there are currently no evidence-based recommendations about drug selection, drug administration, drug interactions, and use in special populations or other pharmacology-related content of such medications. To this end, the Chinese Pharmaceutical Association Hospital Pharmacy Professional Committee developed multidisciplinary guidelines on using topical NSAIDs to treat musculoskeletal pain. (2) Methods: The guidelines development process followed the World Health Organization guideline development handbook, the GRADE methodology, and the statement of Reporting Items for Practice Guidelines in Healthcare. The guideline panel used the Delphi method to identify six clinical questions to be addressed in the guidelines. An independent systematic review team conducted a systematic search and integration of evidence. (3) Results: Based on the balance between the benefits and harms of an intervention, the quality of the evidence, patient preferences and values, and resource utilization, the guideline panel developed 11 recommendations and nine expert consensuses on using topical NSAIDs to treat acute and chronic musculoskeletal pain. (4) Conclusions: Based on the effectiveness and overall safety of topical NSAIDs, we recommend patients with musculoskeletal pain use topical NSAIDs and suggest high-risk patients use topical NSAIDs, such as those with other diseases or receiving other concurrent treatments. The evidenced-based guidelines on topical NSAIDs for musculoskeletal pain incorporated a pharmacist perspective. The guidelines have the potential to facilitate the rational use of topical NSAIDs. The guideline panel will monitor the relevant evidence and update the recommendations accordingly.

Characterization of the renal tubular transport of creatinine by activity-based protein profiling and transport kinetics.

Serum creatinine is widely used to adjust the dosing of drugs eliminated by the kidney in patients with renal dysfunction, as it is a readily accessible indicator of kidney function. However, there are many limitations for drug dosage adjustment based on serum creatinine levels, one of which is the limited understanding of creatinine's tubular transport. Thus, we aimed to complement and advance the renal tubular transport of creatinine by activity-based protein profiling (ABPP) and transporter-overexpression technology. Renal tubular transporters were not identified via ABPP due to the low-affinity interaction between transporters and creatinine. The uptake of isotopically labeled d3-creatinine was significantly increased in OCT2-overexpressing cell lines (p<0.01), and the Km and Vmax of d3-creatinine uptake mediated by OCT2 was 3.1 mM and 408 pmol/mg protein/min, respectively. In the OCT2-overexpressing cell lines, the IC50 of creatinine for d3-creatinine uptake was 10.3 mM, and that of the OCT2 inhibitor cimetidine for d3-creatinine uptake was 99.04 µM. Different dosages of creatinine did not affect the renal excretion of d3-creatinine in mice (p>0.05), while cimetidine significantly reduced the renal excretion of d3-creatinine (p<0.01) without affecting the glomerular filtration rate. Molecular docking in silico showed that the OCT2 amino acid GLN242 could form a hydrogen bond of 2.5 Å with creatinine, and there may be a π-π interaction between TYR362 and creatinine. A site mutation experiment demonstrated that TYR362 and GLN242 were important sites for the OCT2-creatinine interaction. These results demonstrate that OCT2 mediates the renal tubular secretion of creatinine with low affinity and is a minor contributor to creatinine secretion.

7, 8-Dihydroxy-4-methyl coumarin alleviates cholestasis via activation of the Farnesoid X receptor in vitro and in vivo.

Cholestasis is primarily caused by bile acid homeostasis dysregulation, resulting in retention, aggregation, and accumulation of the toxic cholate in the hepatocytes. Existing therapies for cholestasis are limited, demanding the urgent development of novel drugs. As a result, targeting FXR specifically promises a unique treatment strategy for cholestasis. The current study aims to evaluate the influence of 7, 8-dihydroxy-4-methyl coumarin (DMC) against alpha-naphthyl isothiocyanate (ANIT)-induced liver injury in mice. The "Computer-Aided Drug Design" (CADD) and molecular docking study anticipated that DMC would proficiently bind and activate the FXR. Accordingly, the hepatoprotective activity of DMC against ANIT-induced hepatotoxicity and cholestasis was investigated in ANIT-treated HepaRG cells and the ANIT-induced cholestatic mouse model. Outcomes indicated the protective effects of DMC against ANIT toxicity in HepaRG cells after 24 h of intervention and animals after seven days of treatment. DMC partially blocks ANIT-induced increases in serum markers of hepatocellular injury, liver and gall bladder enlargement, and hepatic necrosis. Western blotting revealed that DMC alleviates ANIT-induced hepatotoxicity and cholestasis via activating the FXR receptor and regulating CYP7A1, the enzyme responsible for bile acid synthesis. DMC exhibited protective activity against cholestasis through activating FXR, suggesting it might be a promising strategy for preventing and treating cholestatic liver disease.

Uric acid accumulation in the kidney triggers mast cell degranulation and aggravates renal oxidative stress.

The accumulation of uric acid (UA) in the body can lead to the occurrence of hyperuricemia or uric acid nephropathy. Mast cells (MCs) increase oxidative stress and release renin to promote the production of Ang II. The aim of this study was to investigate the effect of UA on MCs in rat kidneys and the association between MCs and renal injury. Our results show that UA accumulation in the kidney stimulated the degranulation of MCs and the release of renin to promote Ang II production, resulting in renal oxidative stress, mitochondrial structural damage, and microvascular system damage. The expression of urate-related transporters was regulated by the UA level and serum urinary toxins levels were substantially elevated in hyperuricemia. Administration of the MCs membrane stabilizer sodium cromoglycate (SCG) or the angiotensin receptor antagonist Valsartan decreased the production of renin and Ang II and relieved renal oxidative stress, mitigated mitochondrial structural damage and microvascular system damage, and promoted the excretion of UA and urinary toxins by increasing the expression of urate-related transporters. These results demonstrate that the accumulation of UA in the kidney can trigger the degranulation of MCs and promote the development of renal oxidative stress. Administration of SCG and Valsartan ameliorated UA-induced renal injury by inhibiting MCs degranulation and reducing renal oxidative stress by inhibiting renin and Ang II production and accelerating renal clearance of UA and uremic toxins.

Enalapril increases the urinary excretion of metformin in rats by inducing multidrug and toxin excretion protein 1 in the kidney.

Two-thirds of patients with type 2 diabetes mellitus have hypertension, and thus the combination of two or more drugs to treat these diseases is common. It has been shown that the combination of metformin and enalapril has beneficial effects, but few studies have evaluated the interactions between these two drugs. This study investigated the effects of enalapril on the pharmacokinetics and urinary excretion of metformin in rats, with a focus on transporter-mediated drug interactions. Rats were dosed orally with metformin alone (100 mg/kg) or in combination with enalapril (4 mg/kg). The concentration of metformin was measured by high performance liquid chromatography and the level of organic cation transporters (rOCTs) and multidrug and toxin excretion protein 1 (rMATE1), which mediate the uptake and efflux of metformin, respectively, were evaluated by immunoblotting. After single and 7-day dosing, the plasma concentration of metformin in the co-administration group was significantly lower than that in the metformin-only group, and the CL/F and urinary excretion were increased in the co-administration group. Enalapril did not affect the Kp of metformin but reduced renal slice-uptake of metformin. The expression of rMATE1 was increased, whereas rOCT2 expression was decreased in rat kidney. Importantly, long-term co-administration of metformin and enalapril markedly decreased the level of lactic acid and uric acid in the blood. Enalapril increases the urinary excretion of metformin through the up-regulation of rMATE1. This reveals a new mechanism of drug interactions and provides a basis for drug dosage adjustment when these drugs are co-administered.

Cardiac arrhythmias associated with immune checkpoint inhibitors: A comprehensive disproportionality analysis of the FDA adverse event reporting system.

Introduction: With the widespread application of Immune checkpoint inhibitors (ICIs), it is important to explore the association between ICIs and cardiac arrhythmias and to characterize the clinical features of ICI-associated cardiac arrhythmias in real-world studies. Objective: The purpose of this study was to characterize the main features of ICI-related cardiac arrhythmias. Methods: From January 2017 to June 2021, data in the Food and Drug Administration Adverse Event Reporting System (FAERS) database were retrieved to conduct the disproportionality analysis. For the ICI-related cardiac arrhythmia detection, signals were detected by reporting odds ratio (ROR) and information component (IC), calculated using two-by-two contingency tables The clinical characteristics of patients reported with ICI-related cardiac arrhythmias were compared between fatal and non-fatal groups, and the time to onset (TTO) following different ICI regimens was further investigated. Multivariate logistic regression was used to evaluate the association between concurrent cardiotoxicities and ICI-associated arrhythmias. Results: We identified a total of 1957 ICI-associated cardiac arrhythmias reports which appeared to influence more men (64.44%) than women (30.76%), with a median age of 68 [interquartile range (IQR) 60-75] years. Cardiac arrhythmias were reported most often in patients with lung, pleura, thymus and heart cancers (38.02% of 1957 patients). Compared with the full database, ICIs were detected with pharmacovigilance of cardiac arrhythmias (ROR025 = 1.16, IC025 = 0.19). Anti-PD-1 and anti-PD-L1 monotherapies were found to be related to higher reporting of arrhythmias, corresponding to ROR025 = 1.03, IC025 = 0.06 and ROR025 = 1.27, IC025 = 0.29, respectively, with the exception of anti-CTLA-4 monotherapies (ROR025 = 0.57, IC025 = -1.21). The spectrum of arrhythmias induced by ICIs differed among therapeutic regimens. There was no significant difference in the onset time between monotherapy and combination regimen. Moreover, reports of ICI-associated arrhythmias were associated with other concurrent cardiotoxicity, including cardiac failure [ROR 2.61 (2.20-3.09)], coronary artery disorders [ROR 2.28 (1.83-2.85)], myocardial disorders [ROR 5.25 (4.44-6.22)], pericardial disorders [ROR 2.76 (2.09-3.64)] and cardiac valve disorders [ROR 3.21 (1.34-7.68)]. Conclusion: ICI monotherapy and combination therapy can lead to cardiac arrhythmias that can result in serious outcomes and tend to occur early. Our findings underscore the importance of early recognition and management of ICI-related cardiac arrhythmias.

Mycoplasma hominis and Ureaplasma urealyticum infections after knee arthroplasty: A case report.

RATIONALE: Artificial joint infection caused by Mycoplasma hominis and Ureaplasma urealyticum is rare and has not been reported. PATIENTS CONCERNS: A 59-year-old man underwent left total knee arthroplasty for 1 year of pain in the left knee joint. The indwelling urinary catheter was removed after 48 hour of the surgery. On day 8 after the surgery, the patient had fever, increased skin temperature, swelling and redness around the surgical site, and floating patella test (+). According to experience, Vancomycin, Ciprofloxacin and Linezolid were administrated. Evident decrease in C-reactive protein was observed after Linezolid administration, while there was no significant improvement in clinical symptoms. Microbiome sequencing was performed, resulting in diagnosis of positive M hominis and U urealyticum. The patient was then treated with Doxycycline in the following 3 months. During the 11-month outpatient follow-up, there was no evidence of recurrence of infection. DIAGNOSIS: Microbiome sequencing was performed, resulting in diagnosis of positive M hominis and Ureaplasma urealyticum. INTERVENTIONS: The patient recovered following with Doxycycline in the following 3 months. OUTCOMES: During the 11-month outpatient follow-up, there was no evidence of recurrence of infection. LESSONS: M hominis and U urealyticum are common pathogens of the urinary system infections but they are rare in osteoarticular infections. In cases of fever, swelling and heat pain around the surgical site, joint fluid, negative blood culture and being irresponsive to anti-bacterial agents against the cell wall, special bacteria-related infection should be highly suspected.