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Biomedicine & Pharmacotherapy =... Jul 2024Globally, infections due to multi-drug resistant (MDR) Gram-negative bacterial (GNB) pathogens are on the rise, negatively impacting morbidity and mortality,...
Globally, infections due to multi-drug resistant (MDR) Gram-negative bacterial (GNB) pathogens are on the rise, negatively impacting morbidity and mortality, necessitating urgent treatment alternatives. Herein, we report a detailed bio-evaluation of an ultrashort, cationic lipopeptide 'SVAP9I' that demonstrated potent antibiotic activity and acted as an adjuvant to potentiate existing antibiotic classes towards GNBs. Newly synthesized lipopeptides were screened against ESKAPE pathogens and cytotoxicity assays were performed to evaluate the selectivity index (SI). SVAP9I exhibited broad-spectrum antibacterial activity against critical MDR-GNB pathogens including members of Enterobacteriaceae (MIC 4-8 mg/L), with a favorable CC value of ≥100 mg/L and no detectable resistance even after 50th serial passage. It demonstrated fast concentration-dependent bactericidal action as determined via time-kill analysis and also retained full potency against polymyxin B-resistant E. coli, indicating distinct mode of action. SVAP9I targeted E. coli's outer and inner membranes by binding to LPS and phospholipids such as cardiolipin and phosphatidylglycerol. Membrane damage resulted in ROS generation, depleted intracellular ATP concentration and a concomitant increase in extracellular ATP. Checkerboard assays showed SVAP9I's synergism with narrow-spectrum antibiotics like vancomycin, fusidic acid and rifampicin, potentiating their efficacy against MDR-GNB pathogens, including carbapenem-resistant Acinetobacter baumannii (CRAB), a WHO critical priority pathogen. In a murine neutropenic thigh infection model, SVAP9I and rifampicin synergized to express excellent antibacterial efficacy against MDR-CRAB outcompeting polymyxin B. Taken together, SVAP9I's distinct membrane-targeting broad-spectrum action, lack of resistance and strong in vitro andin vivopotency in synergism with narrow spectrum antibiotics like rifampicin suggests its potential as a novel antibiotic adjuvant for the treatment of serious MDR-GNB infections.
Topics: Animals; Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Microbial Sensitivity Tests; Mice; Lipopeptides; Cell Membrane; Gram-Negative Bacterial Infections; Drug Synergism; Female; Humans; Adjuvants, Pharmaceutic
PubMed: 38823276
DOI: 10.1016/j.biopha.2024.116810 -
Spectrochimica Acta. Part A, Molecular... Oct 2024Letrozole is an anticancer medication prescribed for the management of estrogen receptor-positive breast cancer in postmenopausal women. Chronic pain is prevalent in...
A highly sensitive first derivative synchronous spectrofluorimetric approach for the simultaneous analysis of the anti-breast cancer co-administered drugs, letrozole and tramadol in dosage forms and human plasma at nanogram levels.
Letrozole is an anticancer medication prescribed for the management of estrogen receptor-positive breast cancer in postmenopausal women. Chronic pain is prevalent in patients receiving chemotherapy, leading to the use of adjuvant analgesics such as tramadol. This work introduces the first analytical approach for the concurrent quantification of letrozole and tramadol, two co-administered drugs, employing a rapid, highly sensitive, eco-friendly, and cost-effective first derivative synchronous spectrofluorimetric technique. The fluorescence of tramadol and letrozole was measured at wavelengths of 235.9 nm and 241.9 nm, respectively using a wavelength difference (Δλ) of 60.0 nm. The developed approach demonstrated exceptional linearity (r ˃ 0.999) within the specified concentration ranges for tramadol (10.0-1200.0 ng/mL) and letrozole (1.0-140.0 ng/mL). The results demonstrated that the proposed technique exhibits a high level of sensitivity, with detection limits of 0.569 and 0.143 ng/mL for tramadol and letrozole, respectively, indicating the good bioanalytical applicability. The within-run precisions, both intra-day and inter-day, for both analytes, were less than 0.71 % RSD. The developed approach was effectively applied to simultaneously estimate the mentioned drugs in their tablets and human plasma samples, achieving high percentage recoveries and low % RSD values. In order to assess the environmental sustainability of the developed approach, Analytical GREEnnessNNESS (AGREE) and the Green Analytical Procedure Index (GAPI) metric tools were employed. Both tools revealed that the developed approach is excellent green, suggesting its usage as an environmentally-friendly alternative for the routine assayof the investigated pharmaceuticals. The developed approach was validated according to the ICHQ2 (R1) requirements.
Topics: Letrozole; Tramadol; Humans; Spectrometry, Fluorescence; Breast Neoplasms; Female; Limit of Detection; Antineoplastic Agents; Reproducibility of Results; Tablets
PubMed: 38820815
DOI: 10.1016/j.saa.2024.124532 -
Paediatric Anaesthesia Aug 2024Pediatric hypnosis is an extremely valuable adjuvant therapeutic tool to reduce pain and ameliorate anxiety in children undergoing procedures and pediatric anesthesia.... (Review)
Review
Pediatric hypnosis is an extremely valuable adjuvant therapeutic tool to reduce pain and ameliorate anxiety in children undergoing procedures and pediatric anesthesia. This perspective summarises; why Integrating hypnosis into practice has this potential, some techniques that are particularly useful in this setting, the training oppurtunities to learn more, and recommendations for future pediatric anesthesia hypnotic research. There is definite capacity for change by Integrating hypnosis into our practice. Not only will this ensure more capable, confident children who present for peri-operative care but also reduce costs and the environmental impact of the pharmaceutical agents we currently employ for sedation and anxiolysis.
Topics: Humans; Child; Anesthesia; Pediatrics; Anesthesiology; Anxiety; Hypnosis; Pediatric Anesthesia
PubMed: 38812464
DOI: 10.1111/pan.14942 -
Zhongguo Zhong Yao Za Zhi = Zhongguo... Apr 2024Panax ginseng, known as the "king of herbs", is a highly valued medicinal plant, and its medicinal parts include roots, stems, leaves, flowers, and fruits,... (Review)
Review
Panax ginseng, known as the "king of herbs", is a highly valued medicinal plant, and its medicinal parts include roots, stems, leaves, flowers, and fruits, among which the roots are the most commonly used. The main active components of this medicinal plant include triterpenoid saponins, polysaccharides, peptides, and volatile oils. The chemical components and active metabolites endow this herb with a variety of pharmacological effects, and thus this herb is used to treat various diseases and play healthcare roles. Currently, a wide range of preparations of P. ginseng have been officially registered and marketed, including tablets, oral liquids, and injections, which demonstrate good clinical efficacy in regulating immunity, adjuvant treatment of tumors, alleviating fatigue, delaying the aging process, improving glucose and lipid metabolism, treating cardiovascular diseases, and relieving inflammation and pain. The production process and quality standards of these drugs are of great significance to ensure their efficacy. According to the theory that Ginseng Radix et Rhizoma can greatly replenish original Qi, tonify the spleen and lung, promote fluid production to quench thirst, tranquilize mind and enrich the intelligence, this paper systematically summarized the clinical application progress of P. ginseng and rela-ted preparations on the market and prospected the further development of preparations from P. ginseng, providing a reference for further exploring the medicinal value and healthcare function of this herb. The above contents, as an important basis for the in-depth development of P. ginseng and related drugs, increase the possibilities for the application of P. ginseng.
Topics: Panax; Humans; Drugs, Chinese Herbal; Animals
PubMed: 38812184
DOI: 10.19540/j.cnki.cjcmm.20231124.301 -
Thoracic Cancer May 2024To elucidate the treatment and surgery outcomes with or without perioperative therapies in Japanese patients with clinical stage III non-small cell lung cancer (NSCLC)...
Treatment patterns and clinical outcomes of resectable clinical stage III non-small cell lung cancer in a Japanese real-world setting: Surgery cohort analysis of the SOLUTION study.
BACKGROUND
To elucidate the treatment and surgery outcomes with or without perioperative therapies in Japanese patients with clinical stage III non-small cell lung cancer (NSCLC) in real-world settings.
METHODS
We performed subset analyses of the SOLUTION study, a multicenter, noninterventional, observational study of Japanese patients diagnosed with clinical stage III NSCLC, for those who started first-line treatment (surgery±perioperative therapy) between January 2013 and December 2014 (study registration: UMIN000031385). Follow-up data were obtained using medical records from diagnosis to March 1, 2018.
RESULTS
Of 149 eligible patients, 67 underwent surgery alone (median age 71 years) and 82 underwent surgery+perioperative therapy (median age 63 years). Lung resection was performed in 137 patients and the others underwent exploratory thoracotomy or other procedures. Perioperative therapies included adjuvant therapy only (n = 41), neoadjuvant therapy only (n = 24), and neoadjuvant+adjuvant therapy (n = 17). The median overall survival (OS) and 3-year OS rate were 29.3 months and 44.0%, respectively, in patients who underwent surgery alone, and not reached and 61.1%, respectively, in patients who underwent surgery+perioperative therapy. The 3-year progression-free survival (PFS) and disease-free survival (DFS) rates were 42.4% and 47.1%, respectively, in patients who underwent surgery+perioperative therapy and 28.5% and 28.9%, respectively, in patients who underwent surgery alone. In multivariable Cox regression, perioperative therapy was associated with improved OS (hazard ratio [95% confidence interval] 0.49 [0.29-0.81]), PFS (0.62 [0.39-0.96]), and DFS (0.62 [0.39-0.97]) versus surgery alone.
CONCLUSIONS
Our study suggested that perioperative therapy may be associated with better survival among patients undergoing surgical treatment of clinical stage III NSCLC.
PubMed: 38812106
DOI: 10.1111/1759-7714.15305 -
Science Advances May 2024Viruses, bacteria, and parasites frequently cause infections in the gastrointestinal tract, but traditional vaccination strategies typically elicit little or no mucosal...
Viruses, bacteria, and parasites frequently cause infections in the gastrointestinal tract, but traditional vaccination strategies typically elicit little or no mucosal antibody responses. Here, we report a strategy to effectively concentrate immunogens and adjuvants in gut-draining lymph nodes (LNs) to induce gut-associated mucosal immunity. We prepared nanoemulsions (NEs) based on biodegradable oils commonly used as vaccine adjuvants, which encapsulated a potent Toll-like receptor agonist and displayed antigen conjugated to their surface. Following intraperitoneal administration, these NEs accumulated in gut-draining mesenteric LNs, priming strong germinal center responses and promoting B cell class switching to immunoglobulin A (IgA). Optimized NEs elicited 10- to 1000-fold higher antigen-specific IgG and IgA titers in the serum and feces, respectively, compared to free antigen mixed with NE, and strong neutralizing antibody titers against severe acute respiratory syndrome coronavirus 2. Thus, robust gut humoral immunity can be elicited by exploiting the unique lymphatic collection pathways of the gut with a lymph-targeting vaccine formulation.
Topics: Animals; Immunity, Humoral; Mice; Gastrointestinal Tract; Lymphoid Tissue; Immunity, Mucosal; SARS-CoV-2; COVID-19; Antibodies, Viral; Lymph Nodes; Immunoglobulin A; COVID-19 Vaccines; Antibodies, Neutralizing; Female; B-Lymphocytes; Adjuvants, Vaccine; Mice, Inbred C57BL; Humans
PubMed: 38809992
DOI: 10.1126/sciadv.adn7786 -
Journal of Biomedical Research May 2024Tumor vaccines are a promising avenue in cancer immunotherapy. Despite the progress in targeting specific immune epitopes, tumor cells lacking them can evade treatment....
Tumor vaccines are a promising avenue in cancer immunotherapy. Despite the progress in targeting specific immune epitopes, tumor cells lacking them can evade treatment. Here, we aimed to construct an efficient tumor vaccine Vac-SM, utilizing shikonin (SKN) to induce immunogenic cell death (ICD) and ( ) as an immune adjuvant to enhance tumor vaccine efficacy. SKN demonstrated a dose-dependent and time-dependent cytotoxic effect on the tumor cell line as seen using the CCK-8 assay and induced ICD in tumor cells by detecting the expression of relevant indicators respectively. Compared to that in the control groups, Vac-SM injection in mouse subcutaneous metastatic tumors significantly inhibited tumor growth and distant tumor growth and improved survival rates. effectively induced bone marrow-derived dendritic cells (DC) maturation and activation and tumor-draining lymph nodes showed increased maturation of DC and a higher proportion of effector memory T-cell subsets with Vac-SM treatment, based on flow cytometry analysis results.Collectively, Vac-SM vaccine effectively induces ICD, improves antigen presentation by DC, activates a specific systemic antitumor T-cell immune response, exhibits favorable safety profile, and holds promise for clinical translation for local tumor immunotherapy.
PubMed: 38807377
DOI: 10.7555/JBR.38.20240049 -
Frontiers in Immunology 2024None of the typhoid Vi Polysaccharide (ViPS) subunit vaccines incorporate adjuvants, and the immunogenicity of ViPS vaccines (e.g. Typbar TCV and Typhim Vi) is in part...
None of the typhoid Vi Polysaccharide (ViPS) subunit vaccines incorporate adjuvants, and the immunogenicity of ViPS vaccines (e.g. Typbar TCV and Typhim Vi) is in part due to associated TLR4 ligands such as endotoxin present in these vaccines. Since endotoxin content in vaccines is variable and kept very low due to inherent toxicity, it was hypothesized that incorporating a defined amount of a non-toxic TLR4-ligand such as monophosphoryl lipid A in ViPS vaccines would improve their immunogenicity. To test this hypothesis, a monophosphoryl lipid A-based adjuvant formulation named Turbo was developed. Admixing Turbo with Typbar TCV (ViPS-conjugated to tetanus toxoid) increased the levels of anti-ViPS IgM, IgG1, IgG2b, IgG2a/c, and IgG3 in inbred and outbred mice. In infant mice, a single immunization with Turbo adjuvanted Typbar TCV resulted in a significantly increased and durable IgG response and improved the control of bacterial burden compared to mice immunized without Turbo. Similarly, when adjuvanted with Turbo, the antibody response and control of bacteremia were also improved in mice immunized with Typhim Vi, an unconjugated vaccine. The immunogenicity of unconjugated ViPS is inefficient in young mice and is lost in adult mice when immunostimulatory ligands in ViPS are removed. Nevertheless, when adjuvanted with Turbo, poorly immunogenic ViPS induced a robust IgG response in young and adult mice, and this was observed even under antigen-limiting conditions. These data suggest that incorporation of Turbo as an adjuvant will make typhoid vaccines more immunogenic regardless of their intrinsic immunogenicity or conjugation status and maximize the efficacy across all ages.
Topics: Animals; Typhoid-Paratyphoid Vaccines; Mice; Toll-Like Receptor 4; Vaccines, Subunit; Antibodies, Bacterial; Adjuvants, Immunologic; Lipid A; Typhoid Fever; Immunoglobulin G; Female; Ligands; Polysaccharides, Bacterial; Immunogenicity, Vaccine; Adjuvants, Vaccine; Salmonella typhi; Mice, Inbred BALB C
PubMed: 38799439
DOI: 10.3389/fimmu.2024.1383476 -
Journal of Cancer Research and Clinical... May 2024Adjuvant immunotherapy with immune checkpoint blockade(ICB) has greatly reduced the risk of recurrence and metastatic spread in early and advanced melanoma. However, not...
PURPOSE
Adjuvant immunotherapy with immune checkpoint blockade(ICB) has greatly reduced the risk of recurrence and metastatic spread in early and advanced melanoma. However, not all patients benefit from adjuvant treatment: many patients show disease recurrence despite therapy, while those without recurrence harbor the risk for potentially irreversible adverse events. Biomarkers to select patients benefitting most from adjuvant therapy are currently lacking. As body composition assessment using CT images has shown promising results as a prognostic biomarker in stage IV melanoma, we aim to study the applicability of body composition parameters also in adjuvant melanoma treatment.
METHODS
We analyze body composition features via CT scans in a retrospective cohort of 109 patients with resected stage IIB-IV melanoma receiving an adjuvant first-line treatment with ICB in our department. In this analysis, we focus on the impact of body composition, especially the presence of low skeletal muscle mass (LSMM), on patients' survival and occurrence of adverse events (AEs).
RESULTS
In uni- and multivariate analyses, we identify an association between CT-measured LSMM and melanoma-specific survival in patients treated with adjuvant ICB. Furthermore, LSMM is associated with a lower risk for therapy-related AEs, especially hypothyroidism, fatigue, and xerostomia. Conventional serological biomarkers e.g. S100 and LDH and measures of adipose tissue compartments did not show a correlation with survival or the occurrence of AEs.
CONCLUSIONS
LSMM constitutes a novel biomarker for melanoma-specific survival in patients treated with adjuvant ICB.
Topics: Humans; Melanoma; Male; Female; Retrospective Studies; Middle Aged; Immune Checkpoint Inhibitors; Aged; Muscle, Skeletal; Adult; Body Composition; Chemotherapy, Adjuvant; Prognosis; Aged, 80 and over; Skin Neoplasms; Tomography, X-Ray Computed
PubMed: 38796605
DOI: 10.1007/s00432-024-05812-4 -
European Journal of Pharmaceutics and... Jul 2024Antimicrobial resistance is becoming more prominent day after day due to a number of mechanisms by microbes, especially the sophisticated biological barriers of...
Antimicrobial resistance is becoming more prominent day after day due to a number of mechanisms by microbes, especially the sophisticated biological barriers of bacteria, especially in Gram-negatives. There, the lipopolysaccharides (LPS) layer is a unique component of the outer leaflet of the outer membrane which is highly impermeable and prevents antibiotics from passing passively into the intracellular compartments. Biodynamers, a novel class of dynamically bio-responsive polymers, may open new perspectives to overcome this particular barrier by accommodating various secondary structures and form supramolecular structures in such bacterial microenvironments. Generally, bio-responsive polymers are not only candidates as bio-active molecules against bacteria but also carriers via their interactions with the cargo. Based on their dynamicity, design flexibility, biodegradability, biocompatibility, and pH-responsiveness, we investigated the potential of two peptide-based biodynamers for improving antimicrobial drug delivery. By a range of experimental methods, we discovered a greater affinity of Arg-biodynamers for bacterial membranes than for mammalian membranes as well as an enhanced LPS targeting on the bacterial membrane, opening perspectives for enhancing the delivery of antimicrobials across the Gram-negative bacterial cell envelope. This could be explained by the change of the secondary structure of Arg-biodynamers into a predominant β-sheet character in the LPS microenvironment, by contrast to the α-helical structure typically observed for most lipid membrane-permeabilizing peptides. In comparison to poly-L-arginine, the intrinsic antibacterial activity of Arg-biodynamers was nearly unchanged, but its toxicity against mammalian cells was >128-fold reduced. When used in bacterio as an antibiotic potentiator, however, Arg-biodynamers improved the minimum inhibitory concentration (MIC) against Escherichia coli by 32 times compared to colistin alone. Similar effect has also been observed in two stains of Pseudomonas aeruginosa. Arg-biodynamers may therefore represent an interesting option as an adjuvant for antibiotics against Gram-negative bacteria and to overcome antimicrobial resistance.
Topics: Lipopolysaccharides; Anti-Bacterial Agents; Gram-Negative Bacteria; Microbial Sensitivity Tests; Bacterial Outer Membrane; Humans; Escherichia coli; Polymers; Arginine; Drug Delivery Systems
PubMed: 38795784
DOI: 10.1016/j.ejpb.2024.114336