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The patient, a male newborn, was admitted to the hospital 2 hours after birth due to prematurity (gestational age 27+5 weeks) and respiratory distress occurring 2 hours postnatally. After admission, the infant developed fever and elevated C-reactive protein levels. On the fourth day after birth, metagenomic next-generation sequencing of cerebrospinal fluid indicated a positive result for Mycoplasma hominis (9 898 reads). On the eighth day, a retest of cerebrospinal fluid metagenomics confirmed Mycoplasma hominis (56 806 reads). The diagnosis of purulent meningitis caused by Mycoplasma hominis was established, and the antibiotic treatment was switched to moxifloxacin [5 mg/(kg·day)] administered intravenously for a total of 4 weeks. After treatment, the patient's cerebrospinal fluid tests returned to normal, and he was discharged as cured on the 76th day after birth. This article focuses on the diagnosis and treatment of neonatal Mycoplasma hominis purulent meningitis, introducing the multidisciplinary diagnosis and treatment of the condition in extremely preterm infants.

Is the current therapeutic dosage of nadroparin adequate for neonates and infants under 8 months with thromboembolic disease? a population pharmacokinetic study from a national children's medical center.

Objectives: Nadroparin, a low-molecular-weight-heparin is commonly used off-label in neonates and infants for thromboembolic events prevention. However, the recommended dosing regimen often fails to achieve therapeutic target ranges. This study aimed to develop a population pharmacokinetic (PK) model of nadroparin to determine an appropriate dosing regimen for neonates and infants less than 8 months. Methods: A retrospective chart review was conducted on patients treated with nadroparin at Children's Hospital of Fudan University between July 2021 and December 2023. A population PK model was developed using anti-Xa levels, and its predictive performance was evaluated internally. Monte Carlo simulations were performed to design an initial dosing schedule targeting anti-Xa levels between 0.5 and 1 IU/mL. Results: A total of 40 neonates and infants aged less than 8 months with gestational age ranging from 25 to 41 weeks treated with nadroparin were enrolled in the study for analysis. A one-compartment PK model with first order absorption and elimination was adequately fitted to the data. Creatinine clearance was identified as a significant factor contributing to inter-individual variability in clearance. The typical population parameter estimates of clearance, distribution volume and absorption rate in this population were 0.211 L/h, 1.55 L and 0.495 h-1, respectively. Our findings suggest that current therapeutic doses of nadroparin (150-200 IU/kg q12 h) may result in subtherapeutic exposure, thus higher doses might be required. Conclusion: The present study offers the first estimation of PK parameters for nadroparin in preterm or term neonates and infants less than 8 months utilizing the model. Our findings have potential implications for recommending initial personalized dosages, particularly among patient populations exhibiting similar characteristics.

Acetylenic spiroketal enol ethers from Artemisia rupestris and their synergistic antibacterial effects on methicillin-resistant Staphylococcus aureus.

Synergistic bioassay-guided isolation of the extracts of Artemisia rupestris L, which belongs to the family Asteraceae, afforded two acetylenic spiroketal enol ethers, namely rupesdiynes A (1) and B (2). Their structures were determined based on spectroscopic analysis and experimental and calculated ECD investigations. The two compounds exhibited synergistic activity and were able to reduce the minimum inhibitory concentration (MIC) of oxacillin four-fold, with a fractional inhibitory concentration index (FICI) of 0.5 in combination with oxacillin against the oxacillin-resistant EMRSA-16. Biofilm formation inhibitory and Ethidium bromide (EtBr) efflux assay were further employed to verify the possible mechanism of the synergistic antibacterial effect. Additionally, molecular docking studies were conducted to investigate the binding affinities of the two compounds with penicillin-binding protein 2a (PBP2a) of EMRSA-16. Taken together, rupesdiynes A (1) and rupesdiyne B (2) showed moderate synergistic activity against EMRSA-16 with oxacillin via inhibiting biofilm formation and efflux pump activity, respectively.

Initial sirolimus dosage recommendations for pediatric patients with PIK3CD mutation-related immunodeficiency disease.

Sirolimus is used to treat pediatric patients with PIK3CD mutation-related immunodeficiency disease. However, the initial dosages of sirolimus remain undecided. The present study aims to explore initial dosages in pediatric patients with PIK3CD mutation-related immunodeficiency disease. Pediatric patients with this disease were analyzed using the population pharmacokinetic (PPK) model and the Monte Carlo simulation. Body weight and concomitant use of posaconazole were included in the final PPK model, where, under the same weight, clearances of sirolimus were 1 : 0.238 between children without and children with posaconazole. Without posaconazole, the initial dosages of sirolimus were 0.07, 0.06, 0.05, and 0.04 mg/kg/day for body weights of 10-14, 14-25, 25-50, and 50-60 kg, respectively. With posaconazole, the initial dosages of sirolimus were 0.02 mg/kg/day for body weights of 10-60 kg. This is the first attempt to build a sirolimus PPK model for recommending initial dosages in children with PIK3CD mutation-related immunodeficiency disease, thereby providing a reference for individualized clinical drug administration.

Antidiarrheal activity of the extracts of Valeriana jatamansi Jones on castor oil-induced diarrhea mouse by regulating multiple signal pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Valeriana jatamansi Jones, a traditional medicine, is used for various medicinal purposes worldwide. This species is popular for its gastro-protective properties and has been verified to exert antidiarrheal effects. Qiuxieling mixture, an oral liquid preparation used to treat diarrhea in children in clinical practice, was extracted from V. jatamansi Jones. AIM OF THE STUDY: Although Qiuxieling mixture has a good preventive effect on diarrhea children, the disgusting smell makes it intolerable. Therefore, we extracted odorless products from V. jatamansi Jones and Qiuxieling mixture. The present study is aimed to investigate the protective effects of two ethanolic extracts of V. jatamansi Jones and Qiuxieling mixture against castor oil-induced diarrhea and their possible mechanisms in mice. MATERIALS AND METHODS: The two extracts of V. jatamansi Jones and Qiuxieling mixture were detected by HPLC. A castor oil-induced diarrheal model was used to evaluate the antidiarrheal effects. The expression of Occludin in the small intestine was measured by IHC. Western blotting and immunofluorescence were used to detect the expression of proteins related to the oxidative stress and GSDMD-mediated pyroptosis signaling pathways. ELISA was used to detect the expression of IL-6 and IL-1ß in the small intestine of mice with diarrhea. RESULTS: The two extracts of V. jatamansi Jones and Qiuxieling mixture dose-dependently reduced the diarrhea index and the diarrhea rate, delayed the onset of diarrhea, and decreased the weight of the intestinal content. Meanwhile, they reversed the decreased expression of Occludin and restored the activity of Na+-K+-ATPase in the intestines of diarrheal mice. In addition, they reversed the depletion of GSH, attenuated the activation of the ERK/JNK pathway, promoted the Nrf2/SOD1 signaling pathways, and decreased the release of ROS in the intestines of diarrheal mice. Moreover, they suppressed GSDMD-mediated pyroptosis by downregulating the NLRP3/caspase-1/GSDMD signaling pathway. CONCLUSIONS: The two extracts of V. jatamansi Jones and Qiuxieling mixture exerted protective effects on castor oil-induced diarrhea in mice through a variety of mechanisms, including antioxidant stress, restoration of tight junctions between intestinal mucosal cells and regulation of the GSDMD-mediated pyroptosis pathway.

Effects of voriconazole on population pharmacokinetics and optimization of the initial dose of tacrolimus in children with chronic granulomatous disease undergoing hematopoietic stem cell transplantation.

BACKGROUND: This study aimed to explore the effects of voriconazole on population pharmacokinetics and optimization of the initial dose of tacrolimus in children with chronic granulomatous disease (CGD) undergoing hematopoietic stem cell transplantation (HSCT). METHODS: Thirty-four children with CGD undergoing HSCT were assessed to establish a population pharmacokinetic model (PPM) using the non-linear mixed effect. Tacrolimus concentrations were simulated by the Monte Carlo method in children weighing <25 kg at different doses. RESULTS: In the final model, weight and concomitant use of voriconazole were included as covariates. With the same weight, the relative value of tacrolimus clearance was 1:0.388 in children not taking voriconazole: children taking voriconazole. Compared with children not taking voriconazole, the measured tacrolimus concentrations were all higher in children taking voriconazole (P<0.01); however, these were not corrected by dose or body weight for concentration differences. Thus, we simulated the tacrolimus concentrations using different body weights (5-25 kg) and different dose regimens (0.1-0.8 mg/kg/day) for the same body weight and dose. Tacrolimus concentrations in children taking voriconazole were higher than those in children not taking voriconazole (P<0.01). Also, in children with CGD undergoing HSCT who were not taking voriconazole, the initial dose regimen of 0.5 mg/kg/day was recommended for body weights of 5-10 kg, and 0.4 mg/kg/day was recommended for body weights of 10-25 kg. In children with CGD undergoing HSCT who were taking voriconazole, an initial dose regimen of 0.3 mg/kg/day was recommended for body weights of 5-25 kg. CONCLUSIONS: We established, for the first time, a PPM of tacrolimus in children with CGD undergoing HSCT in which voriconazole significantly increased tacrolimus concentrations. In addition, the initial dose of tacrolimus in children with CGD undergoing HSCT was recommended.

Exposure levels of mycophenolic acid are associated with comorbidities in children with systemic lupus erythematosus.

INTRODUCTION: Little is known about the relationship between exposure levels of mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), and comorbidities of systemic lupus erythematosus (SLE) in children. This study aims to explore this association. METHODS: Longitudinal data from SLE children, who were taking MMF for immunosuppression and under therapeutic drug monitoring (TDM), were retrospectively collected. Area under the concentration-time curve of mycophenolic acid (MPA) over 24 hours (AUC0-24h) was estimated with Bayesian methods. Logistic regression and random forest models were used to explore the association between comorbidities and MPA exposure levels. RESULTS: This study included 107 children with 358 times of follow-up (median age 169.02 months). The incidence of diabetes, acute kidney injury (AKI), or pneumonia was significantly associated with AUC0-24h (odds ratio [OR] 0.991, 95% confidence interval [CI] 0.982-0.999), SLE duration (OR 1.012, 95% CI 1.002-1.022), lymphocyte percentage (OR 0.959, 95% CI 0.925-0.991), plasma albumin levels (OR 0.891, 95% CI 0.843-0.940), use of aspirin (OR 0.292, 95% CI 0.126-0.633) and hydroxychloroquine (OR 0.407, 95% CI 0.184-0.906). The random forest model showed that albumin and AUC0-24h were two important predictors. The case group (with the three comorbidities) had a mean AUC0-24h of 73.63 mg · h/L, while the control group had a mean AUC0-24h of 100.39 mg · h/L. CONCLUSIONS: Increased levels of MPA exposure are associated with decreased incidence odds of diabetes, AKI or pneumonia in SLE children. An AUC0-24h of 100.39 mg · h/L or an AUC0-12h of 50.20 mg · h/L could be used as the targeted exposure level for clinical practice.

Mycophenolic Acid Exposure Optimization Based on Vitamin D Status in Children with Systemic Lupus Erythematosus: A Single-Center Retrospective Study.

INTRODUCTION: Systemic lupus erythematosus (SLE) can affect bone metabolism and homeostasis of serum electrolytes that are associated with abnormal levels of vitamin D. Mycophenolate mofetil (MMF) is a commonly used immunosuppressant with the active metabolite mycophenolic acid (MPA). The area under the plasma concentration-time curve (AUC) of MPA is often monitored during the treatment to assess the exposure levels. This study aims to explore the association between exposure levels of MPA and 25-hydroxyvitamin D [25(OH)D] levels in children with SLE. METHODS: Repeated measured data of children with SLE who were treated with MMF and under therapeutic drug monitoring (TDM) were retrospectively collected from the electronic medical records. MPA exposure levels were reflected by the area under the concentration-time curve over 24 h (AUC0-24h). Univariate and multivariate linear regression models were employed to analyze factors associated with 25(OH)D levels. Hierarchical linear models were developed to analyze the intra- and inter-individual effects of AUC0-24h on the variance of 25(OH)D levels. RESULTS: Data from 184 children with SLE (142 female and 42 male) with 518 follow-ups were collected. The median age was 14 years (range 3-18 years) at TDM. Children with normal 25(OH)D levels had significantly higher AUC0-24h than children with low 25(OH)D levels (98.71 vs. 84.05 mg·h/L, P = 0.004). Intra- and inter-individual effects of AUC0-24h on 25(OH)D levels were similar ([Formula: see text] = 0.034 vs. [Formula: see text] = 0.037) but only the intra-individual effect was significant (P = 0.001) in hierarchical models. Other associated factors include age, sex, season at measurement, glucocorticoid daily dose, and external vitamin D3 supplements. CONCLUSION: 25(OH)D levels are associated with MPA exposure levels, and may serve as a potential indicator to optimize the exposure level of MPA during treatment. AUC0-24h of 98.71 mg·h/L or AUC0-12h of 49.36 mg·h/L could be the targeted exposure level for children with SLE.

Safety survey by clinical pharmacists on COVID-19 vaccination from a single center in China.

This study explored the safety of COVID-19 vaccine (Aikewei) and the role of clinical pharmacists in the implementation of COVID-19 vaccination. A total of 2305 hospital employees in Children's Hospital of Fudan University in Shanghai, China received the COVID-19 vaccine. The whole process of vaccination was monitored by clinical pharmacists, and the occurrence, types, severity of adverse reactions were recorded in detail. Through the investigation and analysis on the safety of COVID-19 vaccination of the 2305 people, the important role and value of clinical pharmacists in the vaccination process was elaborated. Common adverse reactions included local pain, dizziness and fatigue, with the incidence rates of 2.09%, 0.67% and 0.49%, respectively. Others such as headache, nausea, skin itching, cough, palpitation, dry mouth, hand anesthesia, local induration, muscle soreness, local rash, and chill had incidence rates of less than 0.30%. Three cases of serious adverse events that occurred in this vaccination returned to normal after treatment, with no subsequent discomfort. Clinical pharmacists played an important role in the safety monitoring of COVID-19 vaccination. The safety of the inactivated COVID-19 vaccine is good. Most of the common adverse reactions were mild and tolerable, with generally low incidence. The work of clinical pharmacists is important and can be expanded in the future to ensure the safety of vaccination and to provide better health care service.

Flavonoids from Artemisia rupestris and their synergistic antibacterial effects on drug-resistant Staphylococcus aureus.

This study seeks to discover flavonoids from a traditional Chinese herb, Artemisia rupestris L., with synergistic antibacterial effects against multidrug-resistant Staphylococcus aureus. Five flavonoids, artemetin (1), chrysosplenetin (2), pachypodol (3), penduletin (4) and chrysoeriol (5) were obtained by various column chromatographic methods. Their chemical structures were determined on the basis of comprehensive spectroscopic analysis and comparison with literature data. Three of the compounds (2, 4 and 5) exhibited synergistic activity when combined with norfloxacin against SA1199B, an effluxing fluoroquinolone-resistant strain. The fractional inhibitory concentration indices (FICIs) of 2, 4 and 5 in combination with norfloxacin were 0.375, 0.079 and 0.266 respectively, suggesting synergy. Compound 5 also showed synergistic effects against EMRSA-15 and EMRSA-16 when combined with ciprofloxacin and oxacillin exhibiting FICIs of 0.024 and 0.375 respectively. Real time ethidium bromide (EtBr) efflux assay, qRT-PCR and molecular docking were employed to explore the mechanisms of the synergistic effects.

Synergism of sophoraflavanone G with norfloxacin against effluxing antibiotic-resistant Staphylococcus aureus.

Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), remains a challenge in hospital and community settings. The design and discovery of new compounds to deal with resistant bacteria has become one of the most important areas of anti-infective research today. The aim of this study was to address the problem of MRSA by searching for synergistic natural antibacterial products from traditional Chinese herbs that are not substrates for the efflux mechanisms of MRSA and that overcome bacterial drug resistance by other, as yet undescribed, mechanisms. In vitro synergistic activity was determined using the standard chequerboard method, and mechanistic studies were performed by an ethidium bromide efflux assay. Using in vivo experiments, the efficacies of different concentrations of the combinations were compared in a murine model of pyaemia. The natural product sophoraflavanone G showed specific synergistic antibacterial effects both in vitro and in vivo and may serve as a template for agents with antibiotic-potentiating activity for use against infections caused by S. aureus, including MRSA.

High-Speed Counter-Current Chromatography with an Online Storage Technique for the Preparative Isolation and Purification of Dihydroflavonoids from Sophora alopecuroides L.

INTRODUCTION: High-speed counter-current chromatography (HSCCC) is an efficient and non-absorption separation technique, but limitations still exist in simultaneous isolation of complex structures of natural products. Moreover, particular methods are various for different kinds of natural products. OBJECTIVE: A novel HSCCC strategy combined with an online storage recycling elution (OSR-CCC) technique was developed for the quick separation of naturally occurring dihydroflavonoids from the extract of the herb Sophora alopecuroides L. METHODOLOGY: In the separation procedure, a storage loop and two six-port valves were connected to a HSCCC system. Effluent A was subjected to an online storage loop and then to recycling separation three times after effluent B was collected in head-to-tail mode. After completion of the recycling separation of effluent A, the elution was switched to tail-to-head mode to collect effluent C. A biphasic solvent system of n-hexane/ethyl acetate/methanol/water (9:6:6:8, v/v/v/v) was used as the separation solvent during the whole elution. RESULTS: Six constituents were isolated simultaneously from the extract (200 mg) of S. alopecuroides by running HSCCC non-stop, and their purities were higher than 95.0%. Their structures were determined as the pterocarpan glycoside sophoratonkin (1) (10.0 mg) and five dihydroflavonoids, alopecurone F (2) (5.4 mg), lehmannin (3) (11.0 mg), alopecurone A (4) (35.0 mg), sophoraflavanone G (5) (21.0 mg), alopecurone B (6) (31.0 mg). CONCLUSION: This recycling HSCCC method combined with an online storage technique could be a rapid, effective and simple approach to isolate stilbene-dihydroflavonoids from herbs of the Sophora genus simultaneously. Copyright © 2017 John Wiley & Sons, Ltd.