Development and assessment of the efficacy and safety of human lung-targeting liposomal methylprednisolone crosslinked with nanobody.
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ABSTRACT:
SUBMITTER: Weng D
PROVIDER: S-EPMC8259875 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:IntroductionThe administration of methylprednisolone (MP) is a component of perioperative multimodal analgesia that mitigates the potentially deleterious effects of postoperative pain and opioid consumption. However, a systematic evaluation of the efficacy and safety of MP is lacking. The present systematic review and meta-analysis was performed to quantify the potential clinical benefits and risks of perioperative MP in lung surgery.MethodsWe searched seven electronic databases for randomized controlled trials (RCTs) comparing MP with placebo. Coprimary outcomes were rest pain scores, dynamic pain scores, and cumulative morphine equivalent consumption within 24 h postoperatively.ResultsA total of 11 trials including 643 participants were selected for our meta-analysis. The results demonstrated that the MP group had a significant difference in coprimary outcomes (rest pain scores, dynamic pain scores, and cumulative morphine equivalent consumption) compared with the placebo group; nevertheless, the improvement was not clinically meaningful based on minimum clinically important differences (MCID). Notably, MP administration reduced serum levels of interleukin (IL)-6 at 6 h (weighted mean difference -20.49 pg/mL; 95% CI -29.94 to -11.04), and decreased the incidence rate of acute lung injury (rate ratio 0.18; 95% CI 0.03-0.98) and cognitive dysfunction (rate ratio 0.43; 95% CI 0.21-0.88) compared with the placebo group.ConclusionsOur findings suggest that the administration of MP contributed to an insignificant relief in acute postoperative pain for lung surgery in a clinical setting. Future studies should focus on exploring the role of MP in reducing pulmonary and surgical-related complications after lung surgery.Clinical trial numberPROSPERO registration number CRD42022314224.
| S-EPMC9845491 | biostudies-literature
Project description:BackgroundWe sought to determine the efficacy and safety of perioperative treatment with methylprednisolone on the development of lung injury after pulmonary thromboendarterectomy.MethodsThis was a randomized, prospective, double-blind, placebo-controlled study of 98 adult patients with chronic thromboembolic pulmonary hypertension who were undergoing pulmonary thromboendarterectomy at a single institution. The patients received either placebo (n = 47) or methylprednisolone (n = 51) (30 mg/kg in the cardiopulmonary bypass prime, 500 mg IV bolus following the final circulatory arrest, and 250 mg IV bolus 36 h after surgery). The primary end point was the presence of lung injury as determined by two independent, blinded physicians using prospectively defined criteria. The secondary end points included ventilator-free, ICU-free, and hospital-free days and selected levels of cytokines in the blood and in BAL fluid.ResultsThe incidence of lung injury was similar in both treatment groups (45% placebo, 41% steroid; P = .72). There were no statistical differences in the secondary clinical end points between treatment groups. Treatment with methylprednisolone, compared with placebo, was associated with a statistically significant reduction in plasma IL-6 and IL-8, a significant increase in plasma IL-10, and a significant reduction in postoperative IL-1ra and IL-6, but not IL-8 in BAL fluid obtained 1 day after surgery.ConclusionsPerioperative methylprednisolone does not reduce the incidence of lung injury following pulmonary thromboendarterectomy surgery despite having an antiinflammatory effect on plasma and lavage cytokine levels.
| S-EPMC3251267 | biostudies-literature
Project description:Hyper-inflammation associated with cytokine storm syndrome causes high mortality in patients with COVID-19. Glucocorticoids, such as methylprednisolone sodium succinate (MPSS), effectively inhibit this inflammatory response. However, frequent and chronic administration of glucocorticoids at high doses leads to hormone dependence and serious side effects. The aim of the present study was to combine nanoparticles with erythrocytes for the targeted delivery of MPSS to the lungs. Chitosan nanoparticles loading MPSS (MPSS-CSNPs) were prepared and adsorbed on the surface of red blood cells (RBC-MPSS-CSNPs) by non-covalent interaction. In vivo pharmacokinetic study indicated that RBC-hitchhiking could significantly reduce the plasma concentration of the drug and prolong the circulation time. The mean residence time (MRT) and area under the curve (AUC) of the RBC-MPSS-CSNPs group were significantly higher than those of the MPSS-CSNPs group and the MPSS injection group. Moreover, in vivo imaging and tissue distribution indicated that RBC-hitchhiking facilitated the accumulation of nanoparticles loading fluorescein in the lung, preventing uptake of these nanoparticles by the liver. Furthermore, compared with the MPSS-CSNPs and MPSS treatment groups, treatment with RBC-MPSS-CSNPs considerably inhibited the production of inflammatory cytokines such as TNF-α and IL-6, and consequently attenuated lung injury induced by lipopolysaccharide in rats. Therefore, RBC-hitchhiking is a potentially effective strategy for the delivery of nanoparticles to the lungs for the treatment of acute lung injury and acute respiratory distress syndrome.
| S-EPMC8684098 | biostudies-literature
Project description:Except for management of Pseudomonas aeruginosa (PA) in cystic fibrosis, there are no approved inhaled antibiotic treatments for any other diseases or for infections from other pathogenic microorganisms such as tuberculosis, non-tuberculous mycobacteria, fungal infections or potential inhaled biowarfare agents including Francisella tularensis, Yersinia pestis and Coxiella burnetii (which cause pneumonic tularemia, plague and Q fever, respectively). Delivery of an antibiotic formulation via the inhalation route has the potential to provide high concentrations at the site of infection with reduced systemic exposure to limit side effects. A liposomal formulation may improve tolerability, increase compliance by reducing the dosing frequency, and enhance penetration of biofilms and treatment of intracellular infections. Two liposomal ciprofloxacin formulations (Lipoquin(®) and Pulmaquin(®)) that are in development by Aradigm Corporation are described here.
| S-EPMC4810082 | biostudies-literature
Project description:BackgroundAcute respiratory distress syndrome (ARDS) is caused by an inflammatory injury to the lung. Dysregulated inflammation is the cardinal feature of ARDS. Methylprednisolone is an option for treating ARDS. However, the benefits and adverse effects of methylprednisolone have not been well assessed in patients with ARDS. This study aimed to evaluate the efficacy and safety of methylprednisolone against ARDS.Material and methodsThe electronic database of Embase, PubMed, the Cochrane Library, CNKI, and Wanfang were searched, and randomized controlled trials (RCTs) reporting the efficacy and safety of methylprednisolone for ARDS were included. Revman 5.3 and Stata 15.0 were used to conduct the analysis. The fixed-effects model was used to calculate summary odds ratios (ORs) and 95% confidence interval (CIs).ResultsTen RCTs studies involving 692 patients with ARDS. The summary results demonstrated that, compared with placebo, methylprednisolone had a statistically significant effect on mortality (OR = 0.64; 95% CI: 0.43-0.95, I2 = 42%); the time of mechanical ventilation (MD) = -2.70, 95% CI: -3.31 to -2.10; I2 = 0%) in patients with ARDS, but it was not associated with increased rates of adverse events (OR = 0.80; 95% CI: 0.34-1.86; I2 = 58%).ConclusionsThis systematic review and meta-analysis demonstrated that Methylprednisolone is safe against ARDS. It may reduce mortality and shorten the time of mechanical ventilation. However, well-designed and large-sample studies were required to fully characterize the efficacy and safety of methylprednisolone against ARDS.
| S-EPMC8036107 | biostudies-literature
Project description:Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease. The majority of patients are diagnosed with locally advanced or metastatic disease with a prognosis of short months. Therapeutic options are limited and until recently, there was no standard second-line chemotherapy option. Liposomal constructs have been engineered to encapsulate chemotherapy thereby preventing premature metabolism, improving distribution and minimizing toxicity. Favourable preclinical data on liposomal irinotecan and early phase trials, led to a recently published phase III trial of liposomal irinotecan in combination with fluorouracil and folinic acid in patients with metastatic PDAC, who progressed after gemcitabine-based chemotherapy. As a direct result, the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved the use of liposomal irinotecan in this setting. However, first-line treatment options for this disease now include the combination regimen, FOLFIRINOX, in patients with good performance status, and the role of second-line combination treatment with liposomal irinotecan in this setting is unclear. Recent advances have changed the therapeutic landscape, as clinicians are now able to choose a sequential approach to treatment tailored to the individual patient characteristics. This article reviews current treatment options for metastatic PDAC and focuses on the efficacy, safety and place in therapy of liposomal irinotecan.
| S-EPMC5349428 | biostudies-literature
Project description:Methylprednisolone (MP) is often used in the treatment of various kidney diseases, but overcoming the systemic side effects caused by its nonspecific distribution in the body is a challenge. This article reports the design, synthesis, and renal targeting of methylprednisolone-lysozyme (MPS-LZM). This conjugate was obtained by covalently linking MP with the renal targeting carrier LZM through a linker containing an ester bond, which could utilize the renal targeting of LZM to deliver MP to renal proximal tubular epithelial cells and effectively release MP. The reaction conditions for the preparation of the conjugate were mild, and the quality was controllable. The number of drug payloads per LZM was 1.1. Cell-level studies have demonstrated the safety and endocytosis of the conjugate. Further pharmacokinetic experiments confirmed that, compared with that of free MP, the conjugate increased the renal exposure (AUC0-t) of active MP from 17.59 to 242.18 h*ng/mL, and the targeting efficiency improved by approximately 14 times. Tissue and organ imaging further revealed that the conjugate could reach the kidneys quickly, and fluorescence could be detected in the kidneys for up to 12 h. This study preliminarily validates the feasibility of a renal targeting design strategy for MPS-LZM, which is expected to provide a new option for improving kidney-specific distribution of glucocorticoids.
| S-EPMC7139590 | biostudies-literature
Project description:Multidrug resistance (MDR) is a significant challenge to effective cancer chemotherapy treatment. However, the development of a drug delivery system that allows for the sustained release of combined drugs with improved vesicle stability could overcome MDR in cancer cells. To achieve this, we have demonstrated codelivery of doxorubicin (Dox) and paclitaxel (PTX) via a crosslinked multilamellar vesicle (cMLV). This combinatorial delivery system achieves enhanced drug accumulation and retention, in turn resulting in improved cytotoxicity against tumor cells, including drug-resistant cells. Moreover, this delivery approach significantly overcomes MDR by reducing the expression of P-glycoprotein (P-gp) in cancer cells, thus improving antitumor activity in vivo. Thus, by enhancing drug delivery to tumors and lowering the apoptotic threshold of individual drugs, this combinatorial delivery system represents a potentially promising multimodal therapeutic strategy to overcome MDR in cancer therapy.
| S-EPMC4201570 | biostudies-literature
Project description:A central treatment resistance mechanism in solid tumors is the maintenance of epithelial junctions between malignant cells that prevent drug penetration into the tumor. We have developed a small recombinant protein (JO-1) that triggers the transient opening of intercellular junctions and thus increases the efficacy of monoclonal antibodies and chemotherapeutic drugs without causing toxicity in mouse tumor models. Here, we provide data toward the clinical translation of an affinity-enhanced version of JO-1, which we call JO-4, in combination with PEGylated liposomal doxorubicin (PLD)/Doxil for ovarian cancer therapy. We have presented X-ray crystallography data suggesting a structural basis for the higher affinity of JO-4 to DSG2. We also confirmed JO-4 efficacy in a xenograft model with primary ovarian cancer cells showing that JO-4 can salvage Doxil therapy when given at a dose that was threefold lower than the therapeutic dose. Furthermore, we tested the safety of intravenous JO-4 alone and in combination with Doxil in Macaca fascicularis, an adequate animal model for predicting toxicity in humans. Our studies did not show critical JO-4-related toxicity or an increase of Doxil-related side effects. Our efficacy and safety data will help to support an Investigational new drug-filing for a JO-4/Doxil combination treatment.
| S-EPMC4445001 | biostudies-literature
Project description:Neonatal exposure to isoflavones improved bone health in thereafter in previous animal studies. However, since isoflavones possess hormonal activity, it may interfere with reproductive development. In the present study, we assessed the safety and efficiency of perinatal or peripubertal exposure to daidzein on bone and reproductive organ development at early adulthood in rats. Sprague-Dawley pregnant rats (n = 18) were divided into 3 groups: (1) dams and their offspring were fed the control diet. (2) Dams were fed the daidzein diet (0.5 g daidzein/kg diet) during pregnancy and then the control diet at postnatal day 13 and their offspring were fed the control diet. (3) Dams and their offspring were fed the daidzein diet through the experiment. While perinatal exposure to daidzein did not confer a positive effect on bone mineral density on postnatal day 35, peripubertal exposure to daidzein protected against a decline in bone mineral density. Meanwhile, exposure to daidzein during the perinatal or peripubertal period did not affect reproductive organ weights at early adulthood in rats. Further investigations should assess the mechanisms underlying these responses of bone metabolism to daidzein, as well as the safety of daidzein exposure during the perinatal period and throughout life.
| S-EPMC5598497 | biostudies-literature