RESUMO
Biologics are essential for treating inflammatory bowel disease (IBD); however, only a few studies have validated cost-effective treatment options and patient factors for biologic use using real-world data from Japanese patients with IBD. Here, we aimed to provide pharmacoeconomic evidence to support clinical decisions for IBD treatment using biologics. We assessed 183 cases (127 patients) of IBD treated with biologics between November 2004 and September 2021. Data on patient background, treatment other than biologics, treatment-related medical costs, and effectiveness index (ratio of the C-reactive protein-negative period to drug survival time) were analyzed using univariate and multivariate logistic regression analyses. Drug survival was determined using Kaplan-Meier survival curve analysis. The outcomes were to validate a novel assessment index and elucidate the following aspects using this index: the effectiveness-cost relationship of long-term biologic use in IBD and cost-effectiveness-associated patient factors. Body mass index ≥25 kg/m2 and duration of hypoalbuminemia during drug survival correlated significantly with the therapeutic effectiveness of biologics. There were no significant differences in surgical, granulocyte apheresis, or adverse-event costs per drug survival time. Biologic costs were significantly higher in the group showing lower effectiveness than in the group showing higher effectiveness. These findings hold major pharmacoeconomic implications for not only improving therapeutic outcomes through the amelioration of low albumin levels and obesity but also potentially reducing healthcare expenditure related to the use of biotherapeutics. To our knowledge, this is the first pharmacoeconomic study based on real-world data from Japanese patients with IBD receiving long-term biologic therapy.
Assuntos
Produtos Biológicos , Doenças Inflamatórias Intestinais , Humanos , Japão , Farmacoeconomia , Estudos Retrospectivos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Produtos Biológicos/uso terapêuticoRESUMO
BACKGROUND: Immune checkpoint inhibitors (ICI) and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) are key drugs for the treatment of EGFR mutation-positive lung cancer. While previous studies reported that the concomitant use of these drugs increases the risk of interstitial lung disease (ILD), the impact of sequential treatment on ILD risk is unknown. This study aimed to analyze the impact of EGFR-TKI pre-treatment on the risk of developing ILD after subsequent ICI administration. MATERIALS AND METHODS: We conducted a retrospective study using a Japanese health insurance claims database. ILD-naive lung cancer patients who had first ICI administration during the screening period from July 2014 to February 2019 were selected. Patients who had ILD within 1 year of receiving the first ICI dose were included in the ILD group. Multivariate logistic regression analysis was conducted to evaluate the effect of pre-treatment with EGFR-TKI on the development of ICI-associated ILD. RESULTS: A total of 353 patients were included, of which 61 were included in the ILD group. The median time to onset of ILD after ICI administration was 3 months. Multivariate logistic regression analysis revealed that pre-treatment with EGFR-TKI was not associated with ICI-associated ILD (odds ratio: 0.26, 95% confidence interval: 0.033 - 2.01). CONCLUSION: Although further analyses are required to confirm our findings, this study indicated that pre-treatment with EGFR-TKI might not increase the ILD risk after ICI treatment.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Doenças Pulmonares Intersticiais , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/complicações , Inibidores de Checkpoint Imunológico/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/complicações , Estudos Retrospectivos , Japão , Doenças Pulmonares Intersticiais/induzido quimicamente , Doenças Pulmonares Intersticiais/diagnóstico , Receptores ErbB , Inibidores de Proteínas Quinases/efeitos adversosRESUMO
In Japan, China, and Singapore, several studies have reported increased incidences of peripheral venous catheter-related bloodstream infection by Bacillus cereus during the summer. Therefore, we hypothesized that bed bathing with a B. cereus-contaminated "clean" towels increases B. cereus contact with the catheter and increases the odds of contaminating the peripheral parenteral nutrition (PPN). We found that 1) professionally laundered "clean" towels used in hospitals have B. cereus (3.3×104 colony forming units (CFUs) / 25cm2), 2) B. cereus is transferable onto the forearms of volunteers by wiping with the towels (n=9), and 3) B. cereus remain detectable (80â¼660 CFUs /50cm2) on the forearms of volunteers even with subsequent efforts of disinfection using alcohol wipes. We further confirmed that B. cereus grow robustly (102 CFUs /mL to more than 106 CFUs /mL) within 24hours at 30°C in PPN. Altogether we find that bed bathing with a towel contaminated with B. cereus leads to spore attachments to the skin, and that B. cereus can proliferate at an accelerated rate at 30°C compared to 20°C in PPN. We therefore highly recommend ensuring the use of sterile bed bath towels prior to PPN administration with catheter in patients requiring bed bathing.
Assuntos
Infecção Hospitalar , Sepse , Humanos , Bacillus cereus , Soluções de Nutrição Parenteral , Infecção Hospitalar/epidemiologia , Infecção Hospitalar/etiologia , Infecção Hospitalar/prevenção & controle , Hospitais , Nutrição Parenteral/efeitos adversos , Fatores de Risco , CatéteresRESUMO
The efficacy of biologics in psoriasis treatment is clinically proven; however, biologics are expensive. In this study, we assessed the real-world cost-effectiveness of biologics for psoriasis treatment by evaluating the relationship between biologic drug survival (DS) and total medical-treatment costs from a pharmacoeconomic viewpoint. Furthermore, the effects of patient factors on cost-effectiveness were investigated. We retrospectively reviewed the medical records of 135 cases who received either a tumor necrosis factor-alpha (TNF-α) monoclonal antibody (TNF-mab), interleukin (IL)-17 mab, or IL23p19-mab for psoriasis from January 2010 to June 2020 at Yamaguchi University Hospital. We compared the monthly medical-treatment costs according to biologic classification and found that costs of medical services, tests, and external preparations required for the treatment process were significantly higher in the TNF-mab group than in the other groups, and the total medical costs associated with TNF-mab treatment were significantly higher than those of IL17-mab treatment. The total monthly cost of medical care was lower in the long-term DS group than in the short-term group. The number of prescriptions for external preparations, comprising Vitamin D3 and corticosteroid, was significantly higher in the long-term DS group than in the short-term group; in the TNF-mab group, the proportion of patients without smoking habits was significantly higher in the long-term group as well. Our study indicated that when costly biologics are used for psoriasis treatment, the maintenance of long-term DS and appropriate patient guidance might improve the quality of medical care, thus allowing cost-effective medical care.
Assuntos
Produtos Biológicos , Psoríase , Anticorpos Monoclonais/uso terapêutico , Produtos Biológicos/uso terapêutico , Farmacoeconomia , Humanos , Psoríase/diagnóstico , Psoríase/tratamento farmacológico , Estudos RetrospectivosRESUMO
BACKGROUND AND AIM: Many patients are not satisfied with chronic constipation (CC) treatments. The aim of this study was to identify factors linked to CC treatment satisfaction or dissatisfaction. METHODS: Our study population included patients who received CC treatment at a clinic or hospital. CC was diagnosed by a physician based on the patient's complaint. Treatment satisfaction was evaluated using the 28th question of the Patient Assessment of Constipation Quality of Life questionnaire. RESULTS: We conducted this study at 28 facilities. We included 167 patients (mean age 66.7 ± 15.2 years, male:female ratio is 1:3.07). Sixty-eight (40.7%) of patients were satisfied with their constipation treatment. Treatment dissatisfaction of CC was significantly associated with frequency of bowel movement <3/week (odds ratio [OR] = 0.376, 95% confidence interval [CI]: 0.156-0.904, P = 0.029) or Bristol Stool Form Scale (BSFS) type 3 (OR = 0.401, 95% CI: 0.170-0.946, P = 0.037). CONCLUSIONS: Our study showed that CC patients with BSFS type3 were not satisfied with constipation treatment. In general, BSFS types 3-5 are defined as normal stools. Therefore, BSFS type 3 may be set as a treatment goal even though the patient is not satisfied. The pathophysiology of CC differs by region and patient background. Therefore, parameters used to define successful treatment will be different by patient or region. We should reconsider the positioning of BSFS type 3 to improve treatment satisfaction for CC.
Assuntos
Constipação Intestinal , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença Crônica , Constipação Intestinal/classificação , Constipação Intestinal/diagnóstico , Constipação Intestinal/terapia , Feminino , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Satisfação do Paciente , Qualidade de Vida , Índice de Gravidade de Doença , Inquéritos e Questionários , Adulto JovemRESUMO
Immunoglobulin A (IgA) is essential for defense of the intestinal mucosa against harmful pathogens. Previous studies have shown that Bacteroidetes, the major phylum of gut microbiota together with Firmicutes, impact IgA production. However, the relative abundances of species of Bacteroidetes responsible for IgA production were not well understood. In the present study, we identified some specific Bacteroidetes species that were associated with gut IgA induction by hsp60-based profiling of species distribution among Bacteroidetes The levels of IgA and the expression of the gene encoding activation-induced cytidine deaminase (AID) in the large intestine lamina propria, which is crucial for class switch recombination from IgM to IgA, were increased in soluble high-fiber diet (sHFD)-fed mice. We found that Bacteroides acidifaciens was the most abundant Bacteroidetes species in both sHFD- and normal diet-fed mice. In addition, the gut IgA levels were associated with the relative abundance of Bacteroides fragilis group species such as Bacteroides faecis, Bacteroides caccae, and Bacteroides acidifaciens Conversely, the ratio of B. acidifaciens to other Bacteroidetes species was reduced in insoluble high-fiber diet fed- and no-fiber diet-fed mice. To investigate whether B. acidifaciens increases IgA production, we generated B. acidifaciens monoassociated mice and found increased gut IgA production and AID expression. Collectively, soluble dietary fiber increases the ratio of gut Bacteroides fragilis group, such as B. acidifaciens, and IgA production. This might improve gut immune function, thereby protecting against bowel pathogens and reducing the incidence of inflammatory bowel diseases.IMPORTANCE Immunoglobulin A (IgA) is essential for defense of the intestinal mucosa against harmful pathogens. Gut microbiota impact IgA production, but the specific species responsible for IgA production remain largely elusive. Previous studies have shown that IgA and Bacteroidetes, the major phyla of gut microbiota, were increased in soluble high-fiber diet-fed mice. We show here that the levels of IgA in the gut and the expression of activation-induced cytidine deaminase (AID) in the large intestine lamina propria, which is crucial for class switch recombination from IgM to IgA, were correlated with the abundance of Bacteroides fragilis group species such as Bacteroides faecis, Bacteroides caccae, and Bacteroides acidifaciensB. acidifaciens monoassociated mice increased gut IgA production and AID expression. Soluble dietary fiber may improve gut immune function, thereby protecting against bowel pathogens and reducing inflammatory bowel diseases.
Assuntos
Bacteroides fragilis/fisiologia , Fibras na Dieta/metabolismo , Imunoglobulina A/biossíntese , Animais , Chaperonina 60 , Fibras na Dieta/administração & dosagem , Feminino , Perfilação da Expressão Gênica , Camundongos , Camundongos Endogâmicos C57BL , Proteínas MitocondriaisRESUMO
Cisplatin is classified as a drug with high emetic risk; thus, the use of aprepitant or fosaprepitant in addition to a 5-hydroxytryptamine-3 (5-HT3) receptor antagonist and dexamethasone is recommended for antiemetic therapy. Further, hydration is required to prevent renal dysfunction, and the use of magnesium has been proposed as a part of the hydration procedure. When fosaprepitant is chosen for antiemetic therapy because the patient has dysphagia, and magnesium is added to the hydration procedure, there may be an incompatibility between the two drugs that reduces the antiemetic effect. In our hospital, in a former regimen, these two drugs were administered concurrently as premedication for regimens containing cisplatin. We varied the conditions so that in a revised regimen the two drugs did not come into contact due to pharmaceutical support, and we conducted a retrospective study to determine the difference in the antiemetic effect. The observation period was 2 years (from October 2015 to September 2017) for the former regimen group (n = 89) and 2 years (from October 2017 to September 2019) for the revised regimen group (n = 177). Comparison of the former and revised regimen groups revealed sex (p = 0.012); anticancer drug dosage (p = 0.006); and variation of premedication condition (p = 0.043) as factors affected by the revised regimen. Optimization of the premedication regimen was a form of necessary pharmaceutical support to maintain the patient's QOL.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cisplatino/efeitos adversos , Náusea/prevenção & controle , Pré-Medicação/métodos , Vômito/prevenção & controle , Idoso , Antieméticos/uso terapêutico , Aprepitanto/uso terapêutico , Dexametasona/uso terapêutico , Quimioterapia Combinada/métodos , Neoplasias Esofágicas/tratamento farmacológico , Feminino , Humanos , Infusões Intravenosas , Sulfato de Magnésio/uso terapêutico , Masculino , Pessoa de Meia-Idade , Morfolinas/uso terapêutico , Náusea/induzido quimicamente , Qualidade de Vida , Estudos Retrospectivos , Antagonistas do Receptor 5-HT3 de Serotonina/uso terapêutico , Soluções , Resultado do Tratamento , Vômito/induzido quimicamenteRESUMO
Sunitinib is an orally administered tyrosine kinase inhibitor. Therapeutic drug monitoring is an important component of the follow-up of patients because of high interpatient variability in the pharmacokinetics of sunitinib and large variabilities in its efficacy and toxicity. The aim of the present study was to examine the light stability of sunitinib and confirm the effects of light exposure on sunitinib measurements by LC-MS/MS. Sunitinib and its active metabolite, SU12662, convert Z isomers to E isomers with exposure to light. The Z-E photoisomerization ratio reached a plateau at 35% for both E isomers in methanol within 15 min of normal light exposure (700 lx). However, the Z isomer of the sunitinib and SU12662 peak area ratios in plasma decreased by 10% within 15 min. These results suggest that sunitinib samples need to be handled without light exposure in all sample preparation steps. Alternatively, it should be measured sunitinib and SU12662 after the sample has reached photoisomerical equilibrium. These results suggest that the sunitinib therapeutic range changes depending on light conditions during sample handling in sunitinib and SU12662 measurements.
Assuntos
Cromatografia Líquida/métodos , Sunitinibe , Espectrometria de Massas em Tandem/métodos , Monitoramento de Medicamentos , Estabilidade de Medicamentos , Humanos , Indóis/sangue , Indóis/química , Indóis/efeitos da radiação , Processos Fotoquímicos , Pirróis/sangue , Pirróis/química , Pirróis/efeitos da radiação , Sunitinibe/sangue , Sunitinibe/química , Sunitinibe/efeitos da radiaçãoRESUMO
Folate receptors are overexpressed on the surface cancer cells. We successfully constructed a new gene delivery vector of methotrexate (MTX)-coated plasmid DNA-polyethylenimine (pDNA-PEI) complexes (PEI complexes) by electrostatic binding. The stable anionic nanoparticle was optimized at MTX charge ratios of 120 or more. pDNA-PEI-MTX complexes (MTX complexes) demonstrated gene expression efficiency as high as cationic pDNA-PEI complexes in the mouse melanoma cell line, B16-F10. The MTX complexes were taken up by the cell-specific uptake mechanisms via the folate receptor. MTX-coated complexes are useful as endocytosis ligands. The MTX120 complexes exhibited no blood aggregation. The transgene efficiency of MTX120 complexes in the liver and spleen after their intravenous administration was higher than that of PEI complexes. Therefore, MTX complexes are expected as a new gene vector in the future.
Assuntos
DNA , Terapia Genética , Vetores Genéticos , Melanoma/tratamento farmacológico , Metotrexato/administração & dosagem , Nanopartículas , Plasmídeos , Administração Intravenosa , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Endocitose , Expressão Gênica , Técnicas de Transferência de Genes , Fígado , Metotrexato/uso terapêutico , Camundongos , Polietilenoimina , Baço , Transfecção , TransgenesRESUMO
We developed and optimized a novel gene delivery vector constructed electrostatically with an anionic biological component and a cationic biological component. Cationic binary complexes of plasmid DNA (pDNA) with novo-protamine sulfate as a medical product (PRT complexes) demonstrated high gene expression with minimal cytotoxicity, likely related with its total cationic charge. Subsequently, anionic compounds were added to the PRT complexes to form ternary complexes with neutral or anionic charges. Among the anionic compounds examined, chondroitin sulfate sodium (CS) as a medical product encapsulated the PRT complexes to produce stable ternary complexes (CS complexes) at charge ratios of ≥4 with pDNA. CS complexes exhibited high gene expression without cytotoxicity in mouse melanoma cell line, B16-F10 cells, in vitro. An inhibition study with endocytosis inhibitors suggested that PRT complexes were mainly taken up by caveolae-mediated endocytosis, and CS complexes were mainly taken up by clathrin-mediated endocytosis in B16-F10 cells. We found that CS complexes including pDNA encoding Oplophorus gracilirostris luciferase induced selective gene expression in the spleen after intravenous administration into ddY male mice. Thus, we successfully constructed useful gene vectors with biological components as medical products.
Assuntos
Sulfatos de Condroitina/química , DNA/administração & dosagem , DNA/química , Técnicas de Transferência de Genes , Vetores Genéticos/química , Plasmídeos/administração & dosagem , Plasmídeos/química , Protaminas/química , Baço/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Endocitose/efeitos dos fármacos , Expressão Gênica , Hemaglutinação , Ácido Hialurônico/química , Luciferases/genética , Masculino , Melanoma Experimental/tratamento farmacológico , Camundongos , Tamanho da Partícula , Eletricidade EstáticaRESUMO
BACKGROUND/OBJECTIVES: Ethnic and racial differences in infant skin have not been well characterized. The purpose of this study was to establish whether there are ethnic differences and similarities in the stratum corneum (SC) functions of Thai and Chinese infants. METHODS: Healthy infants 6 to 24 months of age (N = 60; 30 Thai, 30 Chinese) who resided in Bangkok, Thailand, were enrolled. Transepidermal water loss (TEWL) and SC hydration (capacitance) on the thigh, buttock, and upper arm were measured. Ceramide content was determined in the SC on the upper arm. RESULTS: SC hydration was not remarkably different between the two ethnicities at any site measured, but TEWL was significantly higher in Chinese infants than in Thai infants at all sites. Hydration of the SC was not significantly correlated with age in either ethnicity. TEWL had significant but weak correlations with age on the thigh and upper arm in Thai infants. Ceramide content was significantly higher in Chinese SC than in Thai SC. No relationship between ceramide content and TEWL or hydration was observed in either ethnicity. CONCLUSION: The significant differences in TEWL and ceramide contents between Chinese and Thai infant skin could prove useful in designing skin care and diapering products that are best suited for each ethnicity.
Assuntos
Ceramidas/análise , Epiderme/fisiologia , Capacitância Vascular/fisiologia , Perda Insensível de Água/fisiologia , Povo Asiático , Água Corporal/fisiologia , Etnicidade , Feminino , Humanos , Lactente , Masculino , Tailândia/etnologiaRESUMO
Antiemetic prophylaxis with aprepitant, a 5-hydroxytryptamine3 (5-HT3) receptor antagonist and dexamethasone is recommended for patients receiving intravenous cisplatin chemotherapy. Whether the same antiemetic regime is superior for hepatic transcatheter arterial infusion chemotherapy with cisplatin (CDDP-TAI) is unknown. We conducted a retrospective study of antiemetic prophylaxis protection against chemotherapy-induced nausea and vomiting (CINV) in CDDP-TAI at Nagasaki University Hospital. The rate of complete response (CR) to antiemetics in the acute (<24 h) and delayed phases (24-120 h) was measured. Twenty-four patients were treated with a 5-HT3 receptor antagonist (granisetron or azasetron) and dexamethasone on the day of chemotherapy (day 1 only). There was a significant difference between the CR rates in the acute and delayed phases, 91.6, and 69.7%, respectively. Combination of a 5-HT3 antagonist and dexamethasone on day 1 is effective against acute CINV, but not delayed CINV during CDDP-TAI. These results may help guide the management of nausea and vomiting during CDDP-TAI to achieve better tolerance and compliance for fewer interventions and increased favorable therapeutic outcomes.
Assuntos
Antieméticos/uso terapêutico , Antineoplásicos , Cisplatino , Náusea/prevenção & controle , Antagonistas do Receptor 5-HT3 de Serotonina/uso terapêutico , Vômito/prevenção & controle , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Aprepitanto , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Cateterismo Periférico , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Cisplatino/uso terapêutico , Dexametasona/uso terapêutico , Quimioterapia Combinada , Feminino , Granisetron/uso terapêutico , Humanos , Isoquinolinas/uso terapêutico , Fígado , Neoplasias Hepáticas/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Morfolinas/uso terapêutico , Náusea/induzido quimicamente , Oxazinas/uso terapêutico , Palonossetrom , Quinuclidinas/uso terapêutico , Vômito/induzido quimicamenteRESUMO
Hypertension, hyperlipidemia, and diabetes are important precursors of cardiovascular disease. Here, we evaluated the antihypertensive, antihyperlipidemic, and antidiabetic potential of five types of sprouts in fructose-loaded spontaneously hypertensive rats (SHRs). Powdered sprouts (PSs) were produced from mung bean, broccoli, radish, and buckwheat sprouts and germinated soybeans by lyophilization. The PSs were analyzed for nutritional composition and bioactive agents (γ-aminobutyric acid [GABA], coenzyme Q10 [CoQ10], rutin, and myo-inositol-1,2,3,4,5,6-hexakisphosphate [IP6]) and functionally tested in SHRs given water containing 25 % fructose and diets containing 30 % PS for 46 days. All PSs were nutritionally rich in protein and dietary fiber. CoQ10, GABA/rutin, and GABA/IP6 were abundant in broccoli, buckwheat, and germinated soybean PSs, respectively. Mung bean, broccoli, and buckwheat PSs caused significant reductions in heart rates and/or serum triglycerides. Mung bean PS also significantly reduced serum total cholesterol. These data supported the antihypertensive and antihyperlipidemic potential of mung bean, broccoli, and buckwheat sprouts.
RESUMO
The recognition of phosphatidylserine on the erythrocyte membrane mediates erythrophagocytosis by resident spleen macrophages. The application of phosphatidylserine to a gene vector may be a novel approach for splenic drug delivery. Therefore, we chose 1,2-dioleoyl-sn-glycero-3-phospho-L-serin (DOPS) as an analogue of phosphatidylserine for splenic gene delivery of plasmid DNA (pDNA). In the present study, we successfully prepared a stable pDNA ternary complex using DOPS and polyethyleneimine (PEI) and evaluated its efficacy and safety. The pDNA/PEI complex had a positive charge and showed high transgene efficacy, although it caused cytotoxicity and agglutination. The addition of DOPS changed the ζ-potential of the pDNA/PEI complex to negative. It is known that anionic complexes are not taken up well by cells. Surprisingly, however, the pDNA/PEI/DOPS complex showed relatively high transgene efficacy in vitro. Fluorescence microscope observation revealed that the pDNA/PEI/DOPS complex internalized the cells while maintaining the complex formation. The injection of the pDNA/PEI complex killed most mice within 24 h at high doses, although all mice in the pDNA/PEI/DOPS complex group survived. The ternary complex with DOPS showed markedly better safety compared with the pDNA/PEI complex. The pDNA/PEI/DOPS complex showed high gene expression selectively in the spleen after intravenous injection into mice. Thus the ternary complex with DOPS can be used to deliver pDNA to the spleen, in which immune cells are abundant. It appears to have an excellent safety level, although further study to determine the mechanism of action is necessary.
Assuntos
DNA/administração & dosagem , Técnicas de Transferência de Genes , Fosfatidilserinas/administração & dosagem , Polietilenoimina/administração & dosagem , Baço/metabolismo , Animais , Linhagem Celular Tumoral , Sobrevivência Celular , DNA/química , Eritrócitos , Lipossomos , Masculino , Camundongos , Fosfatidilserinas/química , Plasmídeos , Polietilenoimina/químicaRESUMO
In this study, a novel liver-targeted gene delivery vector was developed by electrostatically coating the cationic complex of pDNA and polyethylenimine (PEI) with glycyrrhizin (GL). The ternary complex, pDNA/PEI/GL, had approximately 100 nm stable particles with a negative charge surface. pDNA/PEI/GL showed high gene expression comparable to that of the complex of pDNA and PEI (pDNA/PEI) in human hepatoma cell line HepG2 without cytotoxicity and agglutination. After intravenous injection of pDNA/PEI/GL into mice, the highest gene expression was observed in the liver. pDNA/PEI/GL showed significantly higher gene expression in parenchymal cells than in nonparenchymal cells. On the basis of these results, we evaluated the pharmacological activity of the ternary complex including the pDNA encoding insulin (pCMV-Ins). The pCMV-Ins/PEI/GL decreased blood glucose concentrations 24 h after its intravenous administration to mice. The ternary complex of pDNA, PEI, and GL may be a promising liver-targeted gene vector.
Assuntos
Ácido Glicirrízico/administração & dosagem , Ácido Glicirrízico/química , Animais , Portadores de Fármacos/efeitos adversos , Portadores de Fármacos/química , Técnicas de Transferência de Genes/efeitos adversos , Vetores Genéticos/efeitos adversos , Vetores Genéticos/química , Células Hep G2 , Humanos , Masculino , Células do Mesofilo/metabolismo , Camundongos , Polietilenoimina/química , Eletricidade EstáticaRESUMO
We developed a novel small interfering RNA (siRNA) delivery system using a ternary complex with polyethyleneimine (PEI) and γ-polyglutamic acid (γ-PGA), which showed silencing effect and no cytotoxicity. The binary complexes of siRNA with PEI were approximately 73-102 nm in particle size and 45-52 mV in ζ-potential. The silencing effect of siRNA/PEI complexes increased with an increase of PEI, and siRNA/PEI complexes with a charge ratio greater than 16 showed significant luciferase knockdown in a mouse colon carcinoma cell line regularly expressing luciferase (Colon26/Luc cells). However, strong cytotoxicity and blood agglutination were observed in the siRNA/Lipofectamine complex and siRNA/PEI16 complex. Recharging cationic complexes with an anionic compound was reported to be a promising method for overcoming these toxicities. We therefore prepared ternary complexes of siRNA with PEI (charge ratio 16) by the addition of γ-PGA to reduce cytotoxicity and deliver siRNA. As expected, the cytotoxicity of the ternary complexes decreased with an increase of γ-PGA content, which decreased the ζ-potential of the complexes. A strong silencing effect comparable to siRNA/Lipofectamine complex was discovered in ternary complexes including γ-PGA with an anionic surface charge. The high incorporation of ternary complexes into Colon26/Luc cells was confirmed with fluorescence microcopy. Having achieved knockdown of an exogenously transfected gene, the ability of the complex to mediate knockdown of an endogenous housekeeping gene, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), was assessed in B16-F10 cells. The ternary complex (siRNA/PEI16/γ-PGA12 complex) exhibited a significant GAPDH knockdown effect. Thus, we developed a useful siRNA delivery system.
Assuntos
Polietilenoimina/química , Ácido Poliglutâmico/análogos & derivados , RNA Interferente Pequeno/administração & dosagem , Animais , Linhagem Celular Tumoral , Sobrevivência Celular , Eritrócitos/fisiologia , Inativação Gênica , Testes de Hemaglutinação , Luciferases de Vaga-Lume/genética , Masculino , Camundongos , Ácido Poliglutâmico/química , RNA Interferente Pequeno/químicaRESUMO
The purpose of this study was to develop a ternary complex of plasmid DNA (pDNA) electrostatically assembled with polyamidoamine (PAMAM) dendrimer and chondroitin sulfate (CS) for effective and secure gene delivery. PAMAM dendrimers are new cationic polymers that are expected to be used as gene delivery vectors. However, cationic non-viral gene vectors showed cytotoxicity by binding to negative cellular membranes. We therefore prepared a ternary complex by adding CS, an anionic polymer, and examined its usefulness. The pDNA/PAMAM dendrimer complex (PAMAM dendriplex) and the PAMAM dendriplex coated by CS (CS complex) showed nanoparticles with positive ζ-potential and negative ζ-potential, respectively. The CS complex had no cytotoxicity against B16-F10 cells and no agglutination activity, although severe cytotoxicity and high agglutination were observed in the PAMAM dendriplex. As a result of an in vitro gene expression study of B16-F10 cells, not only the PAMAM dendriplex but also the CS complex showed high transfection efficiency. The transfection efficiency of the CS complex was significantly inhibited by clathrin-mediated endocytosis inhibitor (chlorpromazine), caveolae-mediated endocytosis inhibitor (genistein), and hypothermia. Tail-vein injection of the CS complex into mice led to significantly higher gene expression in the spleen than the PAMAM dendriplex. Thus, the ternary complex of pDNA electrostatically assembled with PAMAM denriplex and CS showed safe high gene expression in the spleen. This vector is expected to be useful for useful gene delivery.
Assuntos
Sulfatos de Condroitina/química , Dendrímeros/química , Técnicas de Transferência de Genes , Plasmídeos/química , Poliaminas/química , Eletricidade Estática , Aglutinação/efeitos dos fármacos , Animais , Células Cultivadas , Clorpromazina/farmacologia , Expressão Gênica/efeitos dos fármacos , Vetores Genéticos , Genisteína/farmacologia , Masculino , Camundongos , Nanopartículas/química , Baço/metabolismo , TransfecçãoRESUMO
In this study, we determined effects of an anionic siRNA delivery vector, siRNA ternary complex, which is constructed with biodegradable dendrigraft poly-L-lysine (DGL) and γ-polyglutamic acid (γ-PGA) on the melanoma cells and melanoma lung metastasis. The siRNA ternary complex showed high cellular uptake and silencing effect in melanoma cell line B16-F10/Luc cells. After intravenous administration of the siRNA ternary complex, high silencing effect was also observed in the lung of B16-F10/Luc melanoma metastasis model mice. Therefore, we applied vascular endothelial growth factor (VEGF)-siRNA on the siRNA ternary complex and determined the effect on the melanoma lung metastasis. The siRNA ternary complex containing VEGF-siRNA reduced VEGF protein levels significantly in in vitro and in vivo, and the complex successfully inhibited melanoma lung metastasis. This biodegradable and effective siRNA delivery vector, siRNA ternary complex, could be available for clinical trials.
Assuntos
Neoplasias Pulmonares , Melanoma Experimental , Ácido Poliglutâmico , Polilisina , RNA Interferente Pequeno , Fator A de Crescimento do Endotélio Vascular , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/farmacologia , Animais , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/patologia , Camundongos , Melanoma Experimental/patologia , Ácido Poliglutâmico/química , Ácido Poliglutâmico/análogos & derivados , Linhagem Celular Tumoral , Fator A de Crescimento do Endotélio Vascular/genética , Polilisina/química , Camundongos Endogâmicos C57BL , Inativação Gênica , Melanoma/patologia , Melanoma/genéticaRESUMO
Patients with autoimmune diseases treated with corticosteroids sometimes display feelings of anxiety regarding corticosteroid use. In this single-center prospective study, we aimed to evaluate the serial changes in anxiety levels related to corticosteroid use in 18 patients with autoimmune diseases. The degree of anxiety toward corticosteroid use was assessed using the visual analogue scale. Comprehension of drug characteristics and use was assessed using the Likert scale. To assess the patients' levels of depression and anxiety we used the State-Trait Anxiety Inventory. These surveys were conducted immediately before the initiation of corticosteroid therapy and just before discharge from the hospital. We observed a decrease in anxiety levels related to corticosteroid use and State-Trait Anxiety Inventory scores before discharge. However, we did not detect a correlation between these score changes. Additionally, we found that patients who had a poor understanding of the drugs showed little or no changes in their anxiety levels related to corticosteroid use at discharge. These results suggest that some aspects of anxiety related to corticosteroids might be groundless and substantiated by assumptions without a complete understanding of corticosteroid functioning. Patient education regarding corticosteroid use may lead to reductions in anxiety levels and improvement in quality of life of the patients.
Assuntos
Corticosteroides , Ansiedade , Humanos , Estudos Prospectivos , Feminino , Masculino , Ansiedade/tratamento farmacológico , Ansiedade/psicologia , Pessoa de Meia-Idade , Corticosteroides/uso terapêutico , Corticosteroides/administração & dosagem , Adulto , Idoso , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/psicologia , Depressão/tratamento farmacológico , Depressão/psicologia , Qualidade de VidaRESUMO
In this study, we examined the pharmacokinetics of nifedipine and investigated the maternal and foetal background factors that prolong pregnancy in pregnant women undergoing long-term tocolysis. This prospective observational study included 38 pregnant women hospitalised for threatened preterm labour and treated with nifedipine extended-release tablets in combination with an intravenous ritodrine infusion. Maternal plasma nifedipine concentrations were determined using high-performance liquid chromatography. All patients were administered 20 or 40 mg/dose of nifedipine every 6 h at the time of blood sampling. The plasma trough concentration (Ctrough ) was 22.6 ± 17.3 ng/mL, the maximum plasma concentration (Cmax ) was 30.9 ± 15.3 ng/mL and the time to maximum concentration (Tmax ) was 1.70 ± 1.10 h, as determined using noncompartmental analysis (NCA). The area under the curve for drug concentration (AUCtau ) was 152.3 ± 91.8 mg/Lã»h, and oral clearance (CL/F) was 0.17 ± 0.08 L/h. Using logistic regression analyses, we identified the factors that predicted term delivery from 37 weeks to <42 weeks of gestation. Gestational age at admission and the AUCtau of nifedipine can predict term delivery. The AUCtau of nifedipine is a valuable regulatory predictor of term delivery in pregnant women undergoing long-term tocolysis.