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Molecular Pharmaceutics Dec 2022Traditional approaches to vaccines use whole organisms to trigger an immune response, but they do not typically generate robust cellular-mediated immunity and have...
Traditional approaches to vaccines use whole organisms to trigger an immune response, but they do not typically generate robust cellular-mediated immunity and have various safety risks. Subunit vaccines composed of proteins and/or peptides represent an attractive and safe alternative to whole organism vaccines, but they are poorly immunogenic. Though there are biological reasons for the poor immunogenicity of proteins and peptides, one other key to their relative lack of immunogenicity could be attributed to the poor pharmacokinetic properties of exogenously delivered proteins and peptides. For instance, peptides often aggregate at the site of injection and are not stable in biological fluids, proteins and peptides are rapidly cleared from circulation, and both have poor cellular internalization and endosomal escape. Herein, we developed a delivery system to address the lack of protein immunogenicity by overcoming delivery barriers as well as codelivering immune-stimulating adjuvants. The glycopolymeric nanoparticles (glycoNPs) are composed of a dual-stimuli-responsive block glycopolymer, poly[2-(diisopropylamino)ethyl methacrylate]--poly[(pyridyl disulfide ethyl methacrylate)--(methacrylamidoglucopyranose)] (p[DPA--(PDSMA--MAG)]). This polymer facilitates protein conjugation and cytosolic release, the pH-responsive release of lipophilic adjuvants, and pH-dependent membrane disruption to ensure cytosolic delivery of antigens. We synthesized p[DPA--(PDSMA--MAG)] by reversible addition-fragmentation chain transfer (RAFT) polymerization, followed by the formation and physicochemical characterization of glycoNPs using the p[DPA--(PDSMA--MAG)] building blocks. These glycoNPs conjugated the model antigen ovalbumin (OVA) and released OVA in response to elevated glutathione levels. Moreover, the glycoNPs displayed pH-dependent drug release of the model hydrophobic drug Nile Red while also exhibiting pH-responsive endosomolytic behavior as indicated by a red blood cell hemolysis assay. GlycoNPs coloaded with OVA and the toll-like receptor 7/8 (TLR-7/8) agonist Resiquimod (R848) activated DC 2.4 dendritic cells (DCs) significantly more than free OVA and R848 and led to robust antigen presentation of the OVA epitope SIINFEKL on major histocompatibility complex I (MHC-I). In sum, the dual-stimuli-responsive glycopolymer introduced here overcomes major protein and peptide delivery barriers and could vastly improve the immunogenicity of protein-based vaccines.
Topics: Animals; Mice; Antigens; Adjuvants, Immunologic; Ovalbumin; Nanoparticles; Vaccines, Subunit; Adjuvants, Pharmaceutic; Methacrylates; Dendritic Cells; Mice, Inbred C57BL
PubMed: 36374992
DOI: 10.1021/acs.molpharmaceut.2c00750 -
The Journal of Maternal-fetal &... Dec 2023There is ongoing interest in glucocorticoid treatment during oocyte stimulation to treat infertility in women who have undergone Assisted Reproductive Technology (ART). (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
There is ongoing interest in glucocorticoid treatment during oocyte stimulation to treat infertility in women who have undergone Assisted Reproductive Technology (ART).
OBJECTIVE
This meta-analysis was performed to evaluate the efficiency and safety of adjuvant glucocorticoid therapy on pregnancy outcomes in infertile women undergoing ART cycles.
STUDY DESIGN
A literature search was performed in PubMed, EMBASE, Web of Science, and the Cochrane Library up to December 2022. To assess the efficacy and safety of additional glucocorticoid treatment during ovulation induction in women who underwent IVF or ICSI treatment, only randomized controlled trials were included.
RESULTS
Overall, glucocorticoid therapy during ovulation showed a nonsignificant effect of prednisolone improving the live birth rate (OR = 1.03, 95% CI [.75, 1.43], I = .0%, = .84), abortion rate (OR = 1.14, 95% CI [.62, 2.08], I = 31%, = .68), and implantation rate (OR = 1.1, 95% CI [.82, 1.5], I = 8%, = .52) of infertile women compared to the control group. The present meta-analysis revealed that the clinical pregnancy rate per cycle tended to increase after glucocorticoid treatment (OR = 1.29, 95% CI [1.02, 1.63], I = 8%, = .52).
CONCLUSIONS
The present meta-analysis suggested that ovarian stimulation prednisolone therapy does not significantly improve clinical outcomes in women undergoing IVF/ICSI. Although the results indicated that adjuvant glucocorticoid therapy during ovarian stimulation may increase the clinical pregnancy rate, subgroup analysis showed that it was affected by infertility factors, dose schedules, and length of treatment. Therefore, these results should be interpreted with caution.
Topics: Female; Pregnancy; Humans; Glucocorticoids; Infertility, Female; Ovulation Induction; Prednisolone; Adjuvants, Pharmaceutic; Dietary Supplements
PubMed: 37385781
DOI: 10.1080/14767058.2023.2227310 -
International Journal of Molecular... Aug 2016Because diabetes mellitus (DM) is a multifactorial metabolic disease, its prevention and treatment has been a constant challenge for basic and clinical investigators... (Review)
Review
Because diabetes mellitus (DM) is a multifactorial metabolic disease, its prevention and treatment has been a constant challenge for basic and clinical investigators focused on translating their discoveries into clinical treatment of this complex disorder. In this review, we highlight recent experimental and clinical evidences of potential coadjuvants in the management of DM, such as polyphenols (quercetin, resveratrol and silymarin), cultured probiotic microorganisms and drugs acting through direct/indirect or pleiotropic effects on glycemic control in DM. Among several options, we highlight new promising therapeutic coadjuvants, including chemical scavengers, the probiotic kefir and the phosphodiesterase 5 inhibitors, which besides the reduction of hyperglycemia and ameliorate insulin resistance, they reduce oxidative stress and improve endothelial dysfunction in the systemic vascular circulation. In the near future, experimental studies are expected to clear the intracellular pathways involving coadjuvants. The design of clinical trials may also contribute to new strategies with coadjuvants against the harmful effects of diabetic complications.
Topics: Adjuvants, Pharmaceutic; Biological Products; Diabetes Complications; Dietary Supplements; Humans; Hyperglycemia; Hypoglycemic Agents
PubMed: 27527163
DOI: 10.3390/ijms17081273 -
PloS One 2020Ever decreasing efficiency of antibiotic treatment due to growing antibiotic resistance of pathogenic bacteria is a critical issue in clinical practice. The two...
Ever decreasing efficiency of antibiotic treatment due to growing antibiotic resistance of pathogenic bacteria is a critical issue in clinical practice. The two generally accepted major approaches to this problem are the search for new antibiotics and the development of antibiotic adjuvants to enhance the antimicrobial activity of known compounds. It was therefore the aim of the present study to test whether alkylresorcinols, a class of phenolic lipids, can be used as adjuvants to potentiate the effect of various classes of antibiotics. Alkylresorcinols were combined with 12 clinically used antibiotics. Growth-inhibiting activity against a broad range of pro- and eukaryotic microorganisms was determined. Test organisms did comprise 10 bacterial and 2 fungal collection strains, including E. coli and S. aureus, and clinical isolates of K. pneumoniae. The highest adjuvant activity was observed in the case of 4-hexylresorcinol (4-HR), a natural compound found in plants with antimicrobial activity. 50% of the minimal inhibitory concentration (MIC) of 4-HR caused an up to 50-fold decrease in the MIC of antibiotics of various classes. Application of 4-HR as an adjuvant revealed its efficiency against germination of bacterial dormant forms (spores) and prevented formation of antibiotic-tolerant persister cells. Using an in vivo mouse model of K. pneumoniae-induced sepsis, we could demonstrate that the combination of 4-HR and polymyxin was highly effective. 75% of animals were free of infection after treatment as compared to none of the animals receiving the antibiotic alone. We conclude that alkylresorcinols such as 4-HR can be used as an adjuvant to increase the efficiency of several known antibiotics. We suggest that by this approach the risk for development of genetically determined antibiotic resistance can be minimized due to the multimodal mode of action of 4-HR.
Topics: Adjuvants, Pharmaceutic; Animals; Anti-Bacterial Agents; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Drug Synergism; Drug Therapy, Combination; Escherichia coli; Female; Hexylresorcinol; Humans; Klebsiella Infections; Klebsiella pneumoniae; Mice; Microbial Sensitivity Tests; Polymyxins; Sepsis; Staphylococcus aureus
PubMed: 32960928
DOI: 10.1371/journal.pone.0239147 -
The Journal of Infectious Diseases Sep 2023NVX-CoV2373 is an efficacious coronavirus disease 2019 (COVID-19) vaccine comprising full-length recombinant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
NVX-CoV2373 is an efficacious coronavirus disease 2019 (COVID-19) vaccine comprising full-length recombinant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (rS) glycoprotein and Matrix-M adjuvant. Phase 2 of a randomized, placebo-controlled, phase 1/2 trial in healthy adults (18-84 years of age) previously reported good safety/tolerability and robust humoral immunogenicity.
METHODS
Participants were randomized to placebo or 1 or 2 doses of 5-µg or 25-µg rS with 50 µg Matrix-M adjuvant 21 days apart. CD4+ T-cell responses to SARS-CoV-2 intact S or pooled peptide stimulation (with ancestral or variant S sequences) were measured via enzyme-linked immunosorbent spot assay and intracellular cytokine staining.
RESULTS
A clearly discernable spike antigen-specific CD4+ T-cell response was induced after 1 dose, but markedly enhanced after 2 doses. Counts and fold increases in cells producing Th1 cytokines exceeded those secreting Th2 cytokines, although both phenotypes were clearly present. Interferon-γ responses to rS were detected in 93.5% of 2-dose 5-µg recipients. A polyfunctional CD4+ T-cell response was cross-reactive and of equivalent magnitude to all tested variants, including Omicron BA.1/BA.5.
CONCLUSIONS
NVX-CoV2373 elicits a moderately Th1-biased CD4+ T-cell response that is cross-reactive with ancestral and variant S proteins after 2 doses.
CLINICAL TRIALS REGISTRATION
NCT04368988.
Topics: Adult; Humans; CD4-Positive T-Lymphocytes; COVID-19; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Cytokines; Adjuvants, Immunologic; Adjuvants, Pharmaceutic; Antibodies, Viral
PubMed: 37210741
DOI: 10.1093/infdis/jiad163 -
Journal of Pain and Symptom Management Nov 1994Local anesthetics administered to block nerve conduction for surgical anesthesia and to provide analgesia in management of acute pain have become a standard of... (Review)
Review
Local anesthetics administered to block nerve conduction for surgical anesthesia and to provide analgesia in management of acute pain have become a standard of anesthesiology practice. These drugs have had an important role in the multimodality management of chronic pain as well, and this role is expanding since the revival of systemic administration. Local anesthetics are analgesics, albeit not in the traditional clinical and pharmacologic sense. Evidence suggests that intravenous administration is an effective treatment in chronic neuropathic pain syndromes. There is also evidence that intravenous local anesthetics can relieve acute pain. Furthermore, the novel idea that acute procedural and postprocedural pain control with local anesthetics could prevent the development of chronic pain syndromes, including chronic neuropathic pain syndromes, adds another important potential dimension to the role of local anesthetics in pain management.
Topics: Adjuvants, Pharmaceutic; Analgesics; Anesthetics, Local; Chronic Disease; Clinical Trials as Topic; Humans; Palliative Care
PubMed: 7531734
DOI: 10.1016/0885-3924(94)90110-4 -
Oncotarget Sep 2023Patient-derived organoids (PDOs) and xenografts (PDXs) have been extensively studied for drug-screening. However, their usage is limited due to lengthy establishment...
BACKGROUND
Patient-derived organoids (PDOs) and xenografts (PDXs) have been extensively studied for drug-screening. However, their usage is limited due to lengthy establishment time, high engraftment failure rates and different tumor microenvironment from original tumors. To overcome the limitations, we developed real time-live tissue sensitivity assay (RT-LTSA) using fresh tumor samples.
METHODS
Tissue slices from resected pancreatic cancer samples were placed in 96-well plates, and the slices were treated with chemotherapeutic agents. The correlation between the chemo-sensitivity of tissue slices and each patient's clinical outcome was analyzed.
RESULTS
The viability and tumor microenvironment of the tissue slices are well-preserved over 5 days. The drug sensitivity assay results are available within 5 days after tissue collection. While all 4 patients who received RT-LTSA sensitive adjuvant regimens did not develop recurrence, 7 of 8 patients who received resistant adjuvant regimens developed recurrence. We observed significantly improved disease-free survival in the patients who received RT-LTSA sensitive adjuvant regimens (median: not reached versus 10.6 months, = 0.02) compared with the patient who received resistant regimens. A significant negative correlation between RT-LTSA value and relapse-free survival was observed (Somer's D: -0.58; = 0.016).
CONCLUSIONS
RT-LTSA which maintains the tumor microenvironment and architecture as found in patients may reflect clinical outcome and could be used as a personalized strategy for pancreatic adenocarcinoma. Further, studies are warranted to verify the findings.
Topics: Humans; Adenocarcinoma; Pancreatic Neoplasms; Neoplasm Recurrence, Local; Adjuvants, Immunologic; Adjuvants, Pharmaceutic; Tumor Microenvironment
PubMed: 37713330
DOI: 10.18632/oncotarget.28508 -
Frontiers in Immunology 2023Currently licensed vaccine adjuvants offer limited mucosal immunity, which is needed to better combat respiratory infections such as influenza. Mast cells (MCs) are...
Currently licensed vaccine adjuvants offer limited mucosal immunity, which is needed to better combat respiratory infections such as influenza. Mast cells (MCs) are emerging as a target for a new class of mucosal vaccine adjuvants. Here, we developed and characterized a nanoparticulate adjuvant composed of an MC activator [mastoparan-7 (M7)] and a TLR ligand (CpG). This novel nanoparticle (NP) adjuvant was co-formulated with a computationally optimized broadly reactive antigen (COBRA) for hemagglutinin (HA), which is broadly reactive against influenza strains. M7 was combined at different ratios with CpG and tested for immune responses and cytotoxicity. We observed significantly higher cytokine production in dendritic cells and MCs with the lowest cytotoxicity at a charge-neutralizing ratio of nitrogen/phosphate = 1 for M7 and CpG. This combination formed spherical NPs approximately 200 nm in diameter with self-assembling capacity. Mice were vaccinated intranasally with COBRA HA and M7-CpG NPs in a prime-boost-boost schedule. Vaccinated mice had significantly higher antigen-specific antibody responses (IgG and IgA) in serum and mucosa compared with controls. Splenocytes from vaccinated mice had significantly increased cytokine production upon antigen recall and the presence of central and effector memory T cells in draining lymph nodes. Finally, co-immunization with NPs and COBRA HA induced influenza H3N2-specific HA inhibition antibody titers across multiple strains and partially protected mice from a challenge against an H3N2 virus. These results illustrate that the M7-CpG NP adjuvant combination can induce a protective immune response with a broadly reactive influenza antigen mucosal vaccination.
Topics: Animals; Mice; Humans; Influenza, Human; Influenza Vaccines; Orthomyxoviridae Infections; Adjuvants, Vaccine; Influenza A Virus, H3N2 Subtype; Antibodies, Viral; Adjuvants, Immunologic; Vaccination; Adjuvants, Pharmaceutic; Hemagglutinins; Cytokines
PubMed: 37033992
DOI: 10.3389/fimmu.2023.1103765 -
The Brazilian Journal of Infectious... 2013Cerebral malaria is the most severe and rapidly fatal neurological complication of Plasmodium falciparum infection and responsible for more than two million deaths... (Review)
Review
Cerebral malaria is the most severe and rapidly fatal neurological complication of Plasmodium falciparum infection and responsible for more than two million deaths annually. The current therapy is inadequate in terms of reducing mortality or post-treatment symptoms such as neurological and cognitive deficits. The pathophysiology of cerebral malaria is quite complex and offers a variety of targets which remain to be exploited for better therapeutic outcome. The present review discusses on the pathophysiology of cerebral malaria with particular emphasis on scope and promises of curcumin as an adjunctive therapy to improve survival and overcome neurological deficits.
Topics: Adjuvants, Pharmaceutic; Antimalarials; Curcumin; Humans; Malaria, Cerebral
PubMed: 23906771
DOI: 10.1016/j.bjid.2013.03.004 -
PloS One 2023This study investigated the oncological and functional outcomes of robot-assisted radical prostatectomy (RaRP) in high-risk and very high-risk prostate cancer patients.
PURPOSE
This study investigated the oncological and functional outcomes of robot-assisted radical prostatectomy (RaRP) in high-risk and very high-risk prostate cancer patients.
MATERIALS AND METHODS
One hundred localized prostate cancer patients receiving RaRP from August 2015 to December 2020 were retrospectively enrolled. According to NCCN risk classification, patients were classified into two groups, below high-risk group, and high-risk/very high-risk group, to analyze continence outcome within postoperative year one and biochemical recurrence-free survival.
RESULTS
The mean age of the cohort was 69.7 ± 7.4 years with a median follow-up of 26.4 (range 3.3-71.3) months. Among them, 53%, and 47% patients were below high-risk group, and high-risk/very high-risk group, respectively. The median biochemical recurrence-free survival of the entire cohort was 53.1 months. The high-risk/very high-risk group without adjuvant treatment had significantly worse biochemical recurrence-free survival than the high-risk/very high-risk group with adjuvant treatment (19.6 vs. 60.5 months, p = 0.029). Rates of postoperative stress urinary incontinence at 1 week, 1 month, and 12 months were 50.7%, 43.7%, and 8.5%, respectively. High-risk/very high-risk patients had significantly higher rates of stress urinary incontinence at postoperative week 1 (75.8% vs. 28.9%) and month 1 (63.6% vs. 26.3%) than the below high-risk group (both p < 0.01). Rates of stress urinary incontinence after RaRP did not differ between two groups from postoperative 3 months to 12 months. The factor of high-risk / very high-risk group was a predictor of immediate but not for long-term postoperative stress urinary incontinence.
CONCLUSIONS
High-risk and very high-risk prostate cancer patients receiving a combination of RaRP and adjuvant treatment had comparable biochemical recurrence-free survival to below high-risk prostate cancer patients. The high-risk/very high-risk factor impeded early but not long-term postoperative recovery of continence. RaRP can be considered a safe and feasible option for high-risk and very high-risk prostate cancer patients.
Topics: Male; Humans; Infant; Child, Preschool; Retrospective Studies; Robotics; Urinary Incontinence, Stress; Prostatectomy; Prostatic Neoplasms; Adjuvants, Immunologic; Adjuvants, Pharmaceutic
PubMed: 36867638
DOI: 10.1371/journal.pone.0282494