Research Landscape of Physiologically Based Pharmacokinetic Model Utilization in Different Fields: A Bibliometric Analysis (1999-2023).

PURPOSE: The physiologically based pharmacokinetic (PBPK) modeling has received increasing attention owing to its excellent predictive abilities. However, there has been no bibliometric analysis about PBPK modeling. This research aimed to summarize the research development and hot points in PBPK model utilization overall through bibliometric analysis. METHODS: We searched for publications related to the PBPK modeling from 1999 to 2023 in the Web of Science Core Collection (WoSCC) database. The Microsoft Office Excel, CiteSpace and VOSviewers were used to perform the analyses. RESULTS: A total of 4,649 records from 1999 to 2023 were identified, and the largest number of publications focused in the period 2018-2023. The United States was the leading country, and the Environmental Protection Agency (EPA) was the leading institution. The journal Drug Metabolism and Disposition published and co-cited the most articles. Drug-drug interactions, special populations, and new drug development are the main topics in this research field. CONCLUSION: We first visualize the research landscape and hotspots of the PBPK modeling through bibliometric methods. Our study provides a better understanding for researchers, especially beginners about the dynamization of PBPK modeling and presents the relevant trend in the future.

Photo-sonodynamic therapy mediated with OLI_NPs to induce HPV16E7-specific immune response and inhibit cervical cancer in a Tc-1-grafted murine model.

Cervical carcinoma is the fourth most common gynecological cancer. Here we reported the synthesis of oxygen-carried and lipopolysaccharide (LPS)/ indocyanine green (ICG)-loaded nanoparticles (OLI_NPs) for photo-sonodynamic therapy (PSDT) mediated combination therapy to induce systemic antitumor immune responses. We effectively built a new nanoparticle system, a multifunctional nanoagent that integrated the ability of dual-model imaging and therapy for tumors. In this study, we confirmed that OLI_NPs can act as a multifunctional platform that enables not only to diagnose tumors conveniently but also to efficiently provide treatment of in situ tumors, permitting simultaneous dual-mode imaging and localization of the therapy in combination with PSDT-mediated drug release. Furthermore, our combined strategy could effectively depress the tumor development and extend mouse life by the combination of inducing immunogenic cell death (ICD) with encapsulated LPS. In conclusion, combining therapy of OLI_NPs plus PSDT can induce anti-tumor immune responses and tumor antigen-specific immunity in a common TC-1 graft tumor model. Therefore, this combination therapy is a viable technique for cervical cancer treatment.

Ocular disorders associated with PCSK9 inhibitors: A pharmacovigilance disproportionality analysis.

AIMS: To identify and characterize ocular adverse events (oAEs) that are significantly associated with proprotein convertase subtilisin-like/kexin type 9 (PCSK9) inhibitors using the US Food and Drug Administration Adverse Event Reporting System (FAERS). METHODS: We conducted a disproportionality analysis of PCSK9 inhibitors in the FAERS (01/2004-12/2021). The association between PCSK9 inhibitors and oAEs was evaluated using the information component (IC) and the reporting odds ratio (ROR), and the difference in oAEs between evolocumab and alirocumab was compared using the ROR. Different sensitivity analyses were conducted to evaluate the robustness of results. RESULTS: A total of 103 531 reports involving at least 1 PCSK9 inhibitor were found in the FAERS. PCSK9 inhibitors were associated with higher reporting of increased lacrimation (IC 0.27 [95% confidence interval {CI} 0.02-0.45]; ROR 1.21 [95% CI 1.04-1.40]), seasonal allergy (IC 0.39 [95% CI 0.04-0.64]; ROR 1.32 [95% CI 1.07-1.62]) and eye operation (IC 0.66 [95% CI 0.04-1.10]; ROR 1.60 [95% CI 1.11-2.30]) compared with the full database, and there was no difference between evolocumab and alirocumab. Sensitivity analyses showed that the disproportionate signals of increased lacrimation disappeared after excluding cases with other lipid-lowering agents in the combined drugs. Except for eye operations, most of these adverse events occurred within 30 days of the first dose, and all 3 oAEs were mostly reported in women and individuals >65 years. CONCLUSION: This pharmacovigilance study identified a possible signal of ocular disorders associated with PCSK9 inhibitors and encourages paying attention to at-risk populations in PCSK9 inhibitors medication.

Photoacoustic mediated multifunctional tumor antigen trapping nanoparticles inhibit the recurrence and metastasis of ovarian cancer by enhancing tumor immunogenicity.

The hypoimmunogenicity of tumors is one of the main bottlenecks of cancer immunotherapy. Enhancing tumor immunogenicity can improve the efficacy of tumor immunotherapy by increasing antigen exposure and presentation, and establishing an inflammatory microenvironment. Here, a multifunctional antigen trapping nanoparticle with indocyanine green (ICG), aluminum hydroxide (Al(OH)3) and oxaliplatin (OXA) (PPIAO) has been developed for tumor photoacoustic/ultrasound dual-modality imaging and therapy. The combination of photothermal/photodynamic therapy and chemotherapy induced tumor antigen exposure and release through immunogenic death of tumor cells. A timely capture and storage of antigens by aluminum hydroxide enabled dendritic cells to recognize and present those antigens spatiotemporally. In an ovarian tumor model, the photoacoustic-mediated PPIAO NPs combination therapy achieved a transition from "cold tumor" to "hot tumor" that promoted more CD8+ T lymphocytes activation in vivo and intratumoral infiltration, and successfully inhibited the growth of primary and metastatic tumors. An in situ tumor vaccine effect was produced from the treated tumor tissue, assisting mice against the recurrence of tumor cells. This study provided a simple and effective personalized tumor vaccine strategy for better treatment of metastatic and recurrent tumors. The developed multifunctional tumor antigen trapping nanoparticles may be a promising nanoplatform for integrating multimodal imaging monitoring, tumor treatment, and tumor vaccine immunotherapy.

Metabolic effects of the dual SGLT 1/2 inhibitor sotagliflozin on blood pressure and body weight reduction in people with diabetes: An updated meta-analysis of randomized controlled trials.

AIM: To update the meta-analysis of the metabolic effects of a dual sodium-glucose co-transpoter-1/2 inhibitor, sotagliflozin, on blood pressure (BP) and body weight in people with diabetes. METHODS: An electronic search up to March 8, 2022, were conducted to determine eligible randomized-controlled trials of sotagliflozin-reporting BP and weight change outcomes in adults with diabetes. RESULTS: 16 trials were included, with a combined cohort of 19,140 patients. Compared with placebo, sotagliflozin had a mean systolic blood pressure reduction (weighted mean differences (WMDs) -2.60 mmHg, 95 % CI: -2.90 to -2.30), mean diastolic blood pressure reduction (WMD -0.96 mmHg, 95 % CI: -1.17 to -0.75), and mean weight loss (WMD -1.88 kg, 95 % CI: -2.16 to -1.59). Metabolic effects on BP-lowering and weight loss were observed across diabetes status, duration of follow-up, and chronic kidney disease comorbidity. Meanwhile sotagliflozin presented significant effects on people with type 1 diabetes and showed a dose-response relationship for BP-lowering and weight loss. CONCLUSION: This meta-analysis enriches the evidence on the metabolic benefits, including BP-lowering and weight loss, of sotagliflozin, and provide a reasonable therapeutic option for managing diabetes with metabolic syndrome. Further studies will be required to elucidate its long-term effects and role in metabolic syndrome management. PROSPERO REGISTRATION NUMBER: CRD42022323945.

Multifunctional Nanoparticles Co-Loaded with Perfluoropropane, Indocyanine Green, and Methotrexate for Enhanced Multimodal Imaging of Collagen-Induced Arthritis.

Rheumatoid arthritis (RA), a common chronic inflammatory joint disease with features of synovitis and pannus formation, may lead to irreparable joint damage and disability. Methotrexate (MTX) is known as the cornerstone of therapy for RA. However, the therapeutic effects of MTX are unsatisfactory due to its low retention in the inflammatory joints as well as systemic toxic effects. Fortunately, the use of multifunctional nanoparticles for diagnostics and in treatment shows potential for application as a strategy for traceable and targeted RA therapy. This research aims to develop novel nanoparticles that carry with perfluoropropane (PFP), indocyanine green (ICG), and MTX and investigate the corresponding enhancement in multimodal imaging both in vitro and in vivo. A modified double emulsion method was applied for the construction of encapsulated PFP-O2, ICG, and MTX (OIM@NPs), and the essential properties of the developed NPs were determined. The fluorescence and ultrasonic and photoacoustic imaging characteristics were experimentally evaluated both in in vitro and in vivo models. The OIM@NPs are stable and efficient nanoagents. They enable more targeted distribution in the inflammatory joints in RA rats. Moreover, the NPs play an important role as contrast agents for prominent ultrasound and photoacoustic imaging after laser and low-intensity focused ultrasound excitation, providing precision guidance and monitoring for subsequent treatment. This research may provide a novel and efficient strategy to better enable monitoring in inflammatory joints of RA patients and the developed NPs may be a promising nanoplatform for integrating multimodal image monitoring.

Microbiological Concordance in the Management of Diabetic Foot Ulcer Infections with Osteomyelitis, on the Basis of Cultures of Different Specimens at a Diabetic Foot Center in China.

OBJECTIVE: This study aimed to assess the microbiological concordance between swab and soft tissue cultures, and corresponding bone specimen cultures from patients with diabetic foot osteomyelitis (DFO). We aimed to analyze the bone specimens' antimicrobial susceptibilities, and to improve clinical management of diabetic foot ulcer infections by using proper antibiotics. METHODS: The microbial culture results of ulcer swabs, and soft tissue and bone tissue specimens, and the antimicrobial susceptibility tests of bone specimens from patients with DFO were analyzed in a single diabetic foot center. RESULTS: A total of 60 patients with results from three specimens were included. Staphylococcus aureus was the most common bacterium isolated from the three specimens. The microbiological results for the three specimens were identical in 12 cases, the culture results from swabs and bone tissue specimens were identical in 14 cases, and the results from soft tissue and bone tissue were identical in 46 cases. The concordance of the results of pathogens isolated between soft tissue and bone specimen cultures was higher than that between the swab and bone cultures. Gram-positive bacteria were more sensitive to moxifloxacin, linezolid, and vancomycin, while Gram-negative bacteria were more sensitive to piperacillin/tazobactam, cefoperazone/sulbactam, and carbapenems. CONCLUSION: Soft tissue culture results have more reliable microbiological concordance to identify DFO bacteria than swab culture results and targeted antibiotic therapy for DFO should be based on antimicrobial susceptibility testing in bone tissue specimen cultures.

Oxygen and oxaliplatin-loaded nanoparticles combined with photo-sonodynamic inducing enhanced immunogenic cell death in syngeneic mouse models of ovarian cancer.

Immunotherapy by stimulating the host immune system has been a promising therapeutic strategy for advanced ovarian cancer. Here we describe a treatment strategy that combines chemotherapy and photo-sonodynamic therapy (PSDT) to induce systemic antitumor immunity. We have successfully fabricated phase-changeable core-shell nanoparticles (OIX_NPs), which carry oxygen in the core and the photosensitizer indocyanine green (ICG)/oxaliplatin (OXP) in the shell for our combination therapy. In the present study, we demonstrated that OIX_NPs have great potential as contrast agents to enhance photoacoustic (PA) imaging. Furthermore, our combined strategy could induce immunogenic cell death (ICD) by promoting surface exposure of calreticulin (CRT) and passive release of high-mobility group box 1 (HMGB1). Importantly, it could inhibit the growth not only primary tumors but also distant tumors in a bilateral syngeneic mouse model by increasing intratumor infiltration of cytotoxic T lymphocytes. In conclusion, the combination of chemotherapy and PSDT has the potential to enhance antitumor immunity significantly and achieve the integration of diagnosis and treatment for ovarian cancer.

Long-term efficacy and safety of hypoxia-inducible factor prolyl hydroxylase inhibitors in anaemia of chronic kidney disease: A meta-analysis including 13,146 patients.

WHAT IS KNOWN AND OBJECTIVE: Previous studies based on small-sample clinical data proved that short-term use of hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) inhibitors increased haemoglobin levels in anaemic patients with chronic kidney disease (CKD). However, these studies reached conflicting conclusions on iron parameters and adverse event profiles. Our meta-analysis aimed to evaluate the long-term efficacy and safety of HIF-PHD inhibitors in renal anaemia. METHODS: Randomized controlled trials comparing treatment with HIF-PHD inhibitors versus placebo or erythropoiesis-stimulating agents (ESAs) were thoroughly searched in the PubMed, Embase, Cochrane Library and international clinical trial registries. Meta-analysis was performed on main outcomes with random effects models. RESULTS AND DISCUSSION: A total of 30 studies comprising 13,146 patients were included. The HIF-PHD inhibitors used included roxadustat, daprodustat, vadadustat, molidustat, desidustat and enarodustat. HIF-PHD inhibitors significantly increased haemoglobin levels in comparison with placebo [weighted mean difference (WMD) 1.53, 95% confidence interval (CI) 1.39 to 1.67] or ESAs (WMD 0.13, 95% CI 0.03 to 0.22). Hepcidin, ferritin and serum iron levels were decreased, while total iron binding capacity and transferrin levels were increased in the HIF-PHD inhibitor group versus those in placebo or ESAs group. Additionally, HIF-PHD inhibitors medication was associated with cholesterol-lowering effects. As for safety, the risk of serious adverse events in the HIF-PHD inhibitor group was increased in comparison with placebo group [risk ratio (RR) 1.07, 95% CI 1.01 to 1.13], but comparable to the ESAs group (RR 1.02, 95% CI 0.94 to 1.10). Compared with placebo, the agents increased the risk of diarrhoea (1.21, 1.00 to 1.47), nausea (1.46, 1.09 to 1.97), oedema peripheral (1.32, 1.01 to 1.59), hyperkalemia (1.27, 1.05 to 1.54) and hypertension (1.34, 1.02 to 1.76). Compared with ESAs, the drugs increased the risk of vomiting (1.30, 1.02 to 1.65), headache (1.27, 1.05 to 1.53) and thrombosis events (1.31, 1.05 to 1.63). WHAT IS NEW AND CONCLUSION: HIF-PHD inhibitors treatment effectively increased haemoglobin levels and promoted iron utilization in anaemic patients with CKD, and they were well tolerated for long-term use. In order to avoid unfavourable effects of excessive iron consumption, it was appropriate to administer HIF-PHD inhibitors in combination with iron supplements for long-term treatment.

Therapeutic drug monitoring-based dose optimization for imatinib-associated serious cutaneous reactions in a patient with gastrointestinal stromal tumours: A case report.

WHAT IS KNOWN AND OBJECTIVE: Imatinib mesylate (IM) is the first-line therapy for unresectable or metastatic gastrointestinal stromal tumours (GISTs). Here, we report a case of successful progressive dose optimization by therapeutic drug monitoring (TDM) for a patient with GISTs who developed IM-associated serious cutaneous reactions. CASE DESCRIPTION: A 72-year-old female patient received IM at a dose of 400 mg/day for GISTs. The patient developed serious eczematoid drug eruptions and desquamation, following which IM was discontinued. One year later, the GISTs recurred with metastasis, and IM was re-administered at a dose of 100 mg/day, and the dose was gradually increased on the basis of TDM. The final dose of IM was 200 mg/day, and the trough concentration (Ctrough ) of IM was 1457.76 ng/mL. The images obtained from follow-up computed tomography (CT) showed a marked anti-tumour response. IM was well tolerated and the patient developed tolerable IM-associated cutaneous reactions. WHAT IS NEW AND CONCLUSION: The strategy of TDM-guided dose optimization makes it possible to achieve optimal clinical efficacy for patients with GISTs who develop IM-associated serious cutaneous reactions.

The Destruction Of Laser-Induced Phase-Transition Nanoparticles Triggered By Low-Intensity Ultrasound: An Innovative Modality To Enhance The Immunological Treatment Of Ovarian Cancer Cells.

PURPOSE: Photodynamic therapy (PDT), sonodynamic therapy (SDT), and oxaliplatin (OXP) can induce immunogenic cell death (ICD) following damage-associated molecular patterns (DAMPs) exposure or release and can be united via the use of nanoplatforms to deliver drugs that can impart anti-tumor effects. The aim of this study was to develop phase-transition nanoparticles (OI_NPs) loaded with perfluoropentane (PFP), indocyanine green (ICG), and oxaliplatin (OXP), to augment anti-tumor efficacy and the immunological effects of chemotherapy, photodynamic therapy and sonodynamic therapy (PSDT). METHODS: OI_NPs were fabricated by a double emulsion method and a range of physicochemical and dual-modal imaging features were characterized. Confocal microscopy and flow cytometry were used to determine the cellular uptake of OI_NPs by ID8 cells. The viability and apoptotic rate of ID8 cells were investigated using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay and flow cytometry. Flow cytometry, Western blotting, and luminometric assays were then used to investigate the exposure or release of crucial DAMPs such as calreticulin (CRT), high mobility group box 1 (HMGB1), and adenosine-5'-triphosphate (ATP). Tumor rechallenge experiments were then used to investigate whether treated ID8 cells underwent ICD. Finally, cytotoxic T lymphocyte (CTL) activity was determined by a lactate dehydrogenase (LDH) assay. RESULTS: Spherical OI_NPs were able to carry OXP, ICG and PFP and were successfully internalized by ID8 cells. The application of OI_NPs significantly enhanced the phase shift ability of PFP and the optical characteristics of ICG, thus leading to a significant improvement in photoacoustic and ultrasonic imaging. When combined with near-infrared light and ultrasound, the application of OI_NPs led to improved anti-tumor effects on cancer cells, and significantly enhanced the expression of DAMPs, thus generating a long-term anti-tumor effect. CONCLUSION: The application of OI_NPs, loaded with appropriate cargo, may represent a novel strategy with which to increase anti-tumor effects, enhance immunological potency, and improve dual-mode imaging.

Folate-Targeted and Oxygen/Indocyanine Green-Loaded Lipid Nanoparticles for Dual-Mode Imaging and Photo-sonodynamic/Photothermal Therapy of Ovarian Cancer in Vitro and in Vivo.

We have successfully fabricated versatile folate-targeted and oxygen/indocyanine green-loaded lipid nanoparticles (FA-OINPs) for dual-mode imaging-guided therapy in ovarian cancer cells and subcutaneous xenograft models. FA-OINPs were demonstrated to have great potential as superb contrast agents to enhance ultrasound and photoacoustic (US/PA) imaging We have successfully fabricated versatile folate-targeted and oxygen/indocyanine green-loaded lipid nanoparticles (FA-OINPs) for dual-mode imaging-guided therapy in ovarian cancer cells and subcutaneous xenograft models. FA-OINPs were demonstrated to have great potential as superb contrast agents to enhance ultrasound and photoacoustic (US/PA) imaging in vitro and in vivo. Confocal laser scanning microscopy and flow cytometry analysis verified that FA-OINPs could specifically target SKOV3 ovarian cancer cells and be endocytosed with a remarkable efficiency. Compared with other therapeutic options, FA-OINPs exhibited an excellent therapeutic outcome after exposure to laser and ultrasound. The MTT assay and flow cytometry analysis confirmed that cytotoxicity effects and apoptosis/necrosis rates were significantly increased. The fluorescence microscopy and fluorescence microplate reader detection validated that the generation of intracellular reactive oxygen species (ROS) was dramatically improved. Immunohistochemical analyses of tumor tissues demonstrated the enhanced tumor apoptosis, the decreased vascular endothelial growth factor (VEGF) and microvascular density (MVD) expression, and the decreased expression of CD68 after treatment. The presented results suggest that photo-sonodynamic/photothermal mediated FA-OINPs could provide a promising strategy for synergistic therapy in ovarian cancer with the guidance of US/PA dual-mode imaging.

Risk factors and prevention for perioperative anaphylaxis: a nested case-control study.

Background Perioperative anaphylaxis is rare but often severe. Little is known about the risk factors regarding perioperative anaphylaxis and the effect of anti-allergy premedication on prevention of perioperative anaphylaxis. Objective To identify the risk factors of perioperative anaphylaxis and to evaluate the prophylactic effects of anti-allergy premedication on perioperative anaphylaxis and investigate the factors associated with anti-allergy premedication options in patients who previously experienced anaphylaxis with unidentified culprits. Setting Surgical operation unit of the University Hospital in Chongqing, China. Method We identified patients who underwent surgery between Oct. 2012 and Dec. 2017. The study included two parts: in part one, a retrospective nested case-control study was used to identify the risk factors of perioperative anaphylaxis by logistic regression with 1 in 4 matching between patients with and without perioperative anaphylaxis; in part two, patients with high-risk anaphylaxis were included, in which patients who previously experienced anaphylaxis with unidentified culprits had been given anti-allergy premedication prior to the operation according to the degree of risk and severity of anaphylaxis. The prophylactic effects of anti-allergy premedication were evaluated and the factors associated with anti-allergy premedication options were explored. Main outcome measure Perioperative anaphylaxis occurrence. Results In part one, in the multivariate logistic analysis, history of drug allergy (OR 6.78; 95% CI, 2.35-19.54; P < 0.01) and history of allergies to food or other substances (OR 40.56; 95% CI, 8.12-202.52; P < 0.01) were associated with a higher risk of perioperative anaphylaxis. In part two, none of these patients either who had avoided culprits or who had been given anti-allergy premedication developed anaphylaxis during the surgical procedure. In the multivariate logistic model, history of grade II or grade III perioperative anaphylaxis (OR 9.09; 95% CI, 1.34-61.55; P = 0.02) was identified as factor associated with anti-allergy premedication options in high-risk perioperative anaphylaxis patients. Conclusion In this study, history of drug allergy and history of allergies to food or other substances were significantly associated with perioperative anaphylaxis. Avoiding culprit drugs or taking rational anti-allergy premedication was critical to prevent perioperative anaphylaxis for surgical patients with high-risk factors.

Delirium induced by tigecycline treatment for Acinetobacter baumannii infection: A case report.

RATIONALE: Tigecycline is a broad-spectrum antimicrobial agent structurally belong to tetracyclines and covers against many multidrug-resistant organisms. Arising clinical cases reporting its adverse drug reactions have emerged alongside with the increasing off label use globally. By literature review, delirium caused by tigecycline has not been reported yet. We present what we believe to be the first case of tigecycline-induced delirium. PATIENT CONCERNS: A 77-year-old male patient with end-stage renal disease was hospitalized due to acute exacerbation of chronic obstructive pulmonary disease. DIAGNOSIS: The patient developed delirium after infused with a loading dose of tigecycline for pulmonary infection. INTERVENTIONS: All potential causes inducing delirium were evaluated and the symptoms improved soon after discontinuation of tigecycline. He experienced delirium once again after reusing tigecycline for the exacerbation of the pulmonary infection even without a loading dose. Tigecycline was discontinued and the symptoms quickly relieved. OUTCOMES: According to the Naranjo adverse drug reaction probability scale, tigecycline was the probable cause of his delirium. LESSONS: Clinicians should be aware of this potential adverse effect of tigecycline. We recommend that clinicians monitor patients for signs and symptoms of delirium during treatment with tigecycline.

A multifunctional-targeted nanoagent for dual-mode image-guided therapeutic effects on ovarian cancer cells.

PURPOSE: Nanomedicine has emerged as a novel therapeutic modality for cancer treatment and diagnosis. Lipid-polymer hybrid nanoparticles (LPHNPs) are core-shell nanoparticle (NP) structures comprising polymer cores and lipid shells, which exhibit complementary characteristics of both polymeric NPs and liposomes. However, it is difficult to wrap perfluoropentane (PFP) into core-shell NPs in the existing preparation process, which limits its application in the integration of diagnosis and treatment. METHODS: The folate-targeted LPHNPs-loaded indocyanine green/PFP-carrying oxygen (TOI_HNPs) using a combination of two-step method and solution evaporation technique for the first time. The essential properties and dual-mode imaging characteristics of developed NPs were determined. The cellular uptake of TOI_HNPs was detected by confocal microscopy and flow cytometry. The SKOV3 cell viability and apoptosis rate were evaluated by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay and flow cytometry. The ROS was demonstrated by fluorescence microplate reader and the expression of hypoxia-inducible factor 1-alpha (HIF-1α) and IL-6 was detected by Western blot. RESULTS: TOI_HNPs showed spherical morphology with particle size about (166.83±5.54) nm and zeta potential at -(30.57±1.36) mV. It exhibited better stability than lipid NPs and higher encapsulation efficiency as well as active targeting ability than poly (lactic-co-glycolic acid) (PLGA) NPs. In addition, the novel NPs could also act as the contrast agents for ultrasound and photoacoustic imaging, providing precision guidance and monitoring. Furthermore, TOI_HNPs-mediated photo-sonodynamic therapy (PSDT) caused more serious cell damage and more obvious cell apoptosis, compared with other groups. The PSDT mediated by TOI_HNPs induced generation of intracellular ROS and downregulated the expression of HIF-1α and IL-6 in SKOV3 cells. CONCLUSION: This kind of multifunctional-targeted nanoagent may provide an ideal strategy for combination of high therapeutic efficacy and dual-mode imaging guidance.

Synergistic in vitro effects of indocyanine green and ethylenediamine tetraacetate-mediated antimicrobial photodynamic therapy combined with antibiotics for resistant bacterial biofilms in diabetic foot infection.

BACKGROUND: Antibiotic resistance has emerged as one of the most important determinants in diabetic foot infections outcomes. Antimicrobial Photodynamic therapy(A-PDT) or Photodynamic antimicrobial chemotherapy (PACT) has been proposed as an alternative approach for inactivating bacteria, especially resistant bacterial biofilms. This research investigated the synergistic effects of PACT mediated by the photosensitizer indocyanine green (ICG) and ethylenediamine tetraacetate (EDTA) combined with antibiotics against common pathogens of diabetic foot ulcer infection, including Staphylococcus aureus and Pseudomonas aeruginosa, in vitro. METHODS: Planktonic bacteria and biofilms of S. aureus and P. aeruginosa were incubated with ICG and EDTA, and then exposed to laser treatment. Quantitative viable counting estimates the phototoxic effects on S. aureus and P. aeruginosa. The susceptibility of methicillin-resistant S. aureus (MRSA) and multidrug-resistant P. aeruginosa (MRPA) to PACT treatment was detected by disk diffusion and micro-broth dilution methods. Confocal microscopy was used to detect the morphology of biofilms treated with PACT and antibiotics. The resazurin assay was used to quantify the metabolic activity of bacteria in biofilms. RESULTS: PACT mediated by ICG and EDTA led to a more pronounced antibacterial effect in S. aureus and P. aeruginosa compared with ICG alone-mediated PACT. P. aeruginosa was more sensitive to ICG and EDTA-mediated PACT than S. aureus. After PACT treatment, the susceptibility of MRSA and MRPA to antibiotics increased. Furthermore, PACT combined with antibiotic treatment significantly contributed to killing bacteria in the biofilm and disrupting biofilm structure. CONCLUSIONS: ICG and EDTA-mediated PACT combined with antibiotics synergistically enhanced the effects of sterilization and biofilm destruction.

Dual-mode imaging and therapeutic effects of drug-loaded phase-transition nanoparticles combined with near-infrared laser and low-intensity ultrasound on ovarian cancer.

Chemotherapy and photo-sonodynamic therapy (PSDT) can be combined through drug delivery nano-platforms to enhance the anti-tumor efficacy, however, which is limited by hypoxia in tumor, thereby causing chemotherapy resistance. Perfluoropentane (PFP) has the ability to carry oxygen and to enhance ultrasound or photoacoustic imaging after vaporization. Herein, we constructed a kind of nanoparticles (PTX/ICG and oxygen loaded PLGA nanoparticles (PIO_NPs)), which had PFP core carrying oxygen and PLGA shell loaded indocyanine green (ICG) and paclitaxel (PTX). PIO_NPs harbored good optical stability and the ability to transit phase. Moreover, it could rapidly release PTX and generate ROS under the mediation by near-infrared laser and low-intensity ultrasound. The PIO_NPs enhanced contrast of the ultrasound and PA imaging. In particular, PIO_NPs may be used to monitor and guide treatment for the accumulation of PIO_NPs at tumor site can be observed by PA imaging. Compared with PTX or other nanoparticles, PIO_NPs combined with laser and ultrasound (L.U) significantly induced apoptosis of SKOV3 cells and inhibited SKOV3 tumor growth. Therefore, PIO_NPs are of great potential in cancer imaging and therapy.

Efficacy and feasibility of a collaborative multidisciplinary program for antibiotic prophylaxis in clean wound surgery.

Background Despite national and international guidelines and recommendations, inappropriate prophylactic antibiotic use for clean wound surgery remains a common phenomenon in many Chinese hospitals, causing higher medical costs and bacterial resistance. Objective To improve the prescribing behavior for antibiotic prophylaxis and decrease antibiotic abuse and/or misuse in clean wound surgery. Setting The teaching hospital of a medical university in Southwest China. Methods A collaborative multidisciplinary program involving educational, technical, and administrative strategies was undertaken. It was characterized by a monthly evaluation by clinical pharmacists for randomly selected cases of clean wound surgery, as well as a group discussion attended by correlative personnel, consisting of the administrative staff, experts from the Rational Drug Use Committee, clinical pharmacists and surgeons. Main outcome measure The overall incidence of antibiotic prophylaxis, appropriate antibiotics selection, appropriate initial dosage timing, proper drug combination and the duration of antibiotic prophylaxis were measured. Results from 2009 to 2014, the rate of antibiotic prophylaxis for clean wound surgery declined from nearly 100% to 20-30%. Improvements were also observed in drug selection, timing of the first dose, and dosage and duration for antibiotic prophylaxis. Broad-spectrum antibiotics and enzyme inhibitors have seldom been used after 2011. The medical cost for antibiotics also decreased. Conclusion A collaborative multidisciplinary program, together with a group discussion, is efficient for improving rational antibiotic prophylaxis for clean wound surgery. This study indicates that clinical pharmacists can play a pivotal role in providing the professional evaluation of medical cases, education, and intervention.

Efficacy of Indocyanine Green-Mediated Sonodynamic Therapy on Rheumatoid Arthritis Fibroblast-like Synoviocytes.

Sonodynamic therapy (SDT) has become a new therapeutic method because of its activation of certain sensitizers by ultrasound. Some studies have reported that indocyanine green (ICG) has the characteristics of a sonosensitizer and favorable fluorescence imaging in synovitis of early inflammatory arthritis. In this study, we aimed to investigate the cytotoxic effect of ICG-mediated SDT on MH7A cells in vitro and the potential mechanisms involved. ICG was found to be taken up mainly in cytoplasm, with maximal uptake in 4 h. Cell viability in ICG-mediated SDT (SDT-0.5 and SDT-1.0) groups decreased significantly to 73.09 ± 1.97% and 54.24 ± 4.66%, respectively; cell apoptosis increased significantly to 26.43 ± 0.91% and 45.93 ± 6.17%, respectively. Moreover, marked loss in mitochondrial membrane potential and greatly increased generation of reactive oxygen species were observed in ICG-mediated SDT groups. Interestingly, the loss in cell viability could be effectively rescued with pretreatment with the reactive oxygen species scavenger N-acetylcysteine. These results indicate that ICG-mediated SDT is cytotoxic to fibroblast-like synoviocytes and is a potential modality for targeted therapy of synovitis in rheumatoid arthritis.