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1.
Acta Gastroenterol Belg ; 82(3): 407-415, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31566329

RESUMO

OBJECTIVE: To assess the efficacy adjunction of oral simethicone to polyethylene glycol as bowel preparation agent on cecal intubation rate. METHODS: We searched EMBASE, PubMed and Cochrane library for randomized controlled trials regarding simeticone plus polyethylene glycol as oral drinking agents before gastroscopy,we used the soft RevMan5.3 to perform statistical analysis and stata12.0 for publication bias. RESULTS: 12 randomized trials that met the inclusion criteria were therefore pooled into a meta-analysis, which included a total of 5,112 patients. There were no significant differences on cecal intubation rate in two groups(RR=1.0,95%CI : 0.99-1.01, P=0.93) with moderate level of evidence;Subgroups analysis of 2LPEG+ Simethicone VS 2LPEG(RR =1.0, 95% CI : 0.98,1.01), 2LPEG+ Simethicone VS 4L PEG (RR=1.00, 95% CI : 0.98,1.02), PEG+ Simethicone with bisacodyl vs PEG (RR =1.00, 95% CI : 0.99,1.02), PEG+Simethicone without bisacodyl vs PEG (RR =1.00, 95% CI : 0.98,1.02) showed no difference on cecal intubation rate.There was aslo no significant difference on cecal intubation time.Abdominal bloating incidence was lower in PEG+Simethicone group than that in PEG group (RR=0.53, 95%CI : 0.31, 0.91, P=0.02). The meta-analysis result also showed a better acceptability in PEG+Simethicone group (RR=1.28, 95% CI : 1.01, 1.49, P=0.001). CONCLUSION: Adjunction of oral simethicone to polyethylene glycol as bowel preparation agent dose not improve cecal intubation rate on colonoscopy,but with better gastrointestinal tolerability and acceptability.


Assuntos
Catárticos/administração & dosagem , Colonoscopia/métodos , Polietilenoglicóis/administração & dosagem , Simeticone/administração & dosagem , Catárticos/efeitos adversos , Humanos , Intubação Intratraqueal , Polietilenoglicóis/efeitos adversos , Simeticone/efeitos adversos
2.
Expert Opin Drug Metab Toxicol ; 15(10): 779-785, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31593639

RESUMO

Introduction: Interferon (IFN) had both antiviral and immunomodulatory effects, and was one of the approved treatments for hepatitis B virus (HBV). Herein, we reviewed the pharmacokinetics and pharmacodynamics of pegylated IFN-α (PegIFN-α) for the treatment of HBV. Areas covered: The steady-state serum levels of PegIFN-α were reached within 5 to 8 weeks, and the week 48 mean trough concentrations were approximately 2-fold higher than week 1. There was also no difference of the pharmacokinetics in male or female, healthy volunteers or patients with hepatitis B or C infection. PegIFN-α did not affect the metabolism of the cytochrome P450 (CYP) isozymes, except inhibition of CYP1A2. There was also no pharmacokinetic interaction between PegIFN-α and HBV nucleot(s)ide analogues (NUCs). Forty-eight weeks of PegIFN-α achieved 32% of HBeAg seroconversion, 32-43% of HBV DNA suppression, 41-59% of ALT normalization, and 3% of HBsAg seroconversion rate with a post-treatment durable response up to 80% in the initial responders. Expert opinion: On-treatment HBsAg titer guided the treatment of HBV with PegIFN-α. The recommendation of PegIFN-α and NUC combination or switch remained controversial. New immunotherapeutic agents are now in development. Although, PegIFN-α should continue to play a role in the treatment of HBV.


Assuntos
Hepatite B Crônica/tratamento farmacológico , Interferon alfa-2/administração & dosagem , Interferon-alfa/administração & dosagem , Polietilenoglicóis/administração & dosagem , Animais , Antivirais/administração & dosagem , Antivirais/farmacocinética , Antivirais/farmacologia , DNA Viral/efeitos dos fármacos , Interações de Medicamentos , Feminino , Antígenos E da Hepatite B/sangue , Humanos , Interferon alfa-2/farmacocinética , Interferon alfa-2/farmacologia , Interferon-alfa/farmacocinética , Interferon-alfa/farmacologia , Masculino , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/farmacologia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/farmacologia
3.
Toxicol Lett ; 317: 120-129, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31580884

RESUMO

PEGylation is considered a safe mechanism to enhance the pharmacokinetics (PK) and pharmacodynamics (PD) of biotherapeutics. Previous studies using PEGylation as a PK enhancement tool have reported benign PEG-related vacuolation in multiple tissues. This paper establishes a threshold for PEG burden beyond which there are alterations in tissue architecture that could potentially lead to dysfunction. As part of the nonclinical safety assessment of Compound A, a 12 kDa protein conjugated to a 40 kDa branched PEG molecule, monkeys were dosed subcutaneously twice weekly for 3 months at protein doses resulting in weekly PEG doses of 8, 24, 120, or 160 mg/kg. Consistent with previous reports with PEGylated biomolecules, Compound A administration resulted in intracellular vacuoles attributed to the PEG moiety in macrophages in numerous tissues and epithelial cells in the choroid plexus and kidney. Vacuolation occurred at all doses with dose-dependent severity and no evidence of recovery up to 2 months after dosing cessation. The vacuolation was considered nonadverse at PEG doses ≤120 mg/kg/week. However, at 160 mg/kg/week PEG, the vacuolation in choroid plexus, pituitary gland, kidney, and choroid of the eye was considered adverse due to significant alterations of tissue architecture that raised concern for the possibility of compromised tissue function. To our knowledge, this is the first report of potentially adverse cellular consequences of PEG accumulation in tissues other than kidney. Furthermore, the lack of reversibility of vacuolation coupled with the lack of a biomarker for intracellular PEG accumulation highlights a potential risk that should be weighed against the benefits of PK/PD enhancement for long-term administration of PEGylated compounds at high doses.


Assuntos
Células Epiteliais/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Polietilenoglicóis/toxicidade , Proteínas/toxicidade , Vacúolos/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Esquema de Medicação , Composição de Medicamentos , Células Epiteliais/patologia , Feminino , Injeções Subcutâneas , Macaca fascicularis , Macrófagos/patologia , Masculino , Polietilenoglicóis/administração & dosagem , Proteínas/administração & dosagem , Medição de Risco , Fatores de Tempo , Vacúolos/patologia
4.
Bone Joint J ; 101-B(9): 1115-1121, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31474138

RESUMO

AIMS: The aim of this study was to explore risk factors for complications associated with dural tear (DT), including the types of DT, and the intra- and postoperative management of DT. PATIENTS AND METHODS: Between 2012 and 2017, 12 171 patients with degenerative lumbar diseases underwent primary lumbar spine surgery. We investigated five categories of potential predictors: patient factors (sex, age, body mass index, and primary disease), surgical factors (surgical procedures, operative time, and estimated blood loss), types of DT (inaccessible for suturing/clipping and the presence of cauda equina/nerve root herniation), repair techniques (suturing, clipping, fibrin glue, polyethylene glycol (PEG) hydrogel, and polyglycolic acid sheet), and postoperative management (drainage duration). Postoperative complications were evaluated in terms of dural leak, prolonged bed rest, headache, nausea/vomiting, delayed wound healing, postoperative neurological deficit, surgical site infection (SSI), and reoperation for DT. We performed multivariable regression analyses to evaluate the predictors of postoperative complications associated with DT. RESULTS: In total, 429/12 171 patients (3.5%) had a DT. Multivariable analysis revealed that PEG hydrogel significantly reduced the incidence of dural leak and prolonged bed rest, and that patients treated with sealants (fibrin glue and PEG hydrogel) significantly less frequently suffered from headache. A longer drainage duration significantly increased the incidence of headache, nausea/vomiting, and delayed wound healing. Headache and nausea/vomiting were significantly more prevalent in younger female patients. Postoperative neurological deficit and reoperation for DT significantly depended on the presence of cauda equina/nerve root herniation. A longer operative time was the sole independent risk factor for SSI and was also a risk factor for dural leak, prolonged bed rest, and nausea/vomiting. CONCLUSION: Sealants, particularly PEG hydrogel, may be useful in reducing symptoms related to cerebrospinal fluid leakage, whereas prolonged drainage may be unnecessary. Younger female patients should be carefully treated when DT occurs. Cite this article: Bone Joint J 2019;101-B:1115-1121.


Assuntos
Vazamento de Líquido Cefalorraquidiano/terapia , Dura-Máter/lesões , Dura-Máter/cirurgia , Vértebras Lombares/cirurgia , Procedimentos Ortopédicos/efeitos adversos , Doenças da Coluna Vertebral/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Vazamento de Líquido Cefalorraquidiano/etiologia , Drenagem , Feminino , Adesivo Tecidual de Fibrina/administração & dosagem , Humanos , Hidrogel de Polietilenoglicol-Dimetacrilato/administração & dosagem , Complicações Intraoperatórias/etiologia , Complicações Intraoperatórias/terapia , Masculino , Pessoa de Meia-Idade , Procedimentos Ortopédicos/métodos , Polietilenoglicóis/administração & dosagem , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/terapia , Prognóstico , Reoperação , Estudos Retrospectivos , Fatores de Risco , Técnicas de Sutura , Adesivos Teciduais/administração & dosagem , Adulto Jovem
5.
Lancet ; 394(10201): 840-848, 2019 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-31402112

RESUMO

BACKGROUND: Decreased surgical site infections (SSIs) and morbidity have been reported with mechanical and oral antibiotic bowel preparation (MOABP) compared with no bowel preparation (NBP) in colonic surgery. Several societies have recommended routine use of MOABP in patients undergoing colon resection on the basis of these data. Our aim was to investigate this recommendation in a prospective randomised context. METHODS: In this multicentre, parallel, single-blinded trial, patients undergoing colon resection were randomly assigned (1:1) to either MOABP or NBP in four hospitals in Finland, using a web-based randomisation technique. Randomly varying block sizes (four, six, and eight) were used for randomisation, and stratification was done according to centre. The recruiters, treating physicians, operating surgeons, data collectors, and analysts were masked to the allocated treatment. Key exclusion criteria were need for emergency surgery; bowel obstruction; colonoscopy planned during surgery; allergy to polyethylene glycol, neomycin, or metronidazole; and age younger than 18 years or older than 95 years. Study nurses opened numbered opaque envelopes containing the patient allocated group, and instructed the patients according to the allocation group to either prepare the bowel, or not prepare the bowel. Patients allocated to MOABP prepared their bowel by drinking 2 L of polyethylene glycol and 1 L of clear fluid before 6 pm on the day before surgery and took 2 g of neomycin orally at 7 pm and 2 g of metronidazole orally at 11 pm the day before surgery. The primary outcome was SSI within 30 days after surgery, analysed in the modified intention-to-treat population (all patients who were randomly allocated to and underwent elective colon resection with an anastomosis) along with safety analyses. The trial is registered with ClinicalTrials.gov, NCT02652637, and EudraCT, 2015-004559-38, and is closed to new participants. FINDINGS: Between March 17, 2016, and Aug 20, 2018, 738 patients were assessed for eligibility. Of the 417 patients who were randomised (209 to MOABP and 208 to NBP), 13 in the MOABP group and eight in the NBP were excluded before undergoing colonic resection; therefore, the modified intention-to-treat analysis included 396 patients (196 for MOABP and 200 for NBP). SSI was detected in 13 (7%) of 196 patients randomised to MOABP, and in 21 (11%) of 200 patients randomised to NBP (odds ratio 1·65, 95% CI 0·80-3·40; p=0·17). Anastomotic dehiscence was reported in 7 (4%) of 196 patients in the MOABP group and in 8 (4%) of 200 in the NBP group, and reoperations were necessary in 16 (8%) of 196 compared with 13 (7%) of 200 patients. Two patients died in the NBP group and none in the MOABP group within 30 days. INTERPRETATION: MOABP does not reduce SSIs or the overall morbidity of colon surgery compared with NBP. We therefore propose that the current recommendations of using MOABP for colectomies to reduce SSIs or morbidity should be reconsidered. FUNDING: Vatsatautien Tutkimussäätiö Foundation, Mary and Georg Ehrnrooth's Foundation, and Helsinki University Hospital research funds.


Assuntos
Antibacterianos/administração & dosagem , Cefuroxima/administração & dosagem , Colectomia/métodos , Metronidazol/administração & dosagem , Cuidados Pré-Operatórios/métodos , Infecção da Ferida Cirúrgica/prevenção & controle , Administração Intravenosa , Idoso , Catárticos/administração & dosagem , Procedimentos Cirúrgicos Eletivos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/administração & dosagem , Estudos Prospectivos , Método Simples-Cego
6.
Anticancer Res ; 39(8): 4379-4383, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366533

RESUMO

BACKGROUND/AIM: Dose-dense doxorubicin and cyclophosphamide (ddAC) followed by dose-dense paclitaxel (ddP) (ddAC-P) has improved disease-free survival of patients with breast cancer. The aim of this study was to evaluate the safety and relative dose intensity (RDI) of ddAC-P administered together with pegfilgrastim. PATIENTS AND METHODS: Between May 2015 and Aug 2017, 44 patients were retrospectively reviewed; they were administered 4 cycles of ddAC, followed by 4 cycles of ddP. Pegfilgrastim (3.6 mg) was administered in every cycle. RESULTS: The mean RDIs for ddAC-P, ddAC, and ddP were 95.0%, 94.5%, and 93.3%, respectively. The prevalence of high RDIs (≥85%) for ddAC-P, ddAC, and ddP was 90.9%, 84.1%, and 88.6%, respectively. Seven of the 10 patients with low RDIs experienced grade 1 or 2 fever. CONCLUSION: DdAC-P administered together with pegfilgrastim (3.6 mg) appears to be feasible and maintains RDI in most of Japanese patients with breast cancer. Rapid evaluation and proper management of fever may prevent low RDI.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Paclitaxel/administração & dosagem , Adulto , Idoso , Neoplasias da Mama/patologia , Ciclofosfamida/efeitos adversos , Relação Dose-Resposta a Droga , Doxorrubicina/efeitos adversos , Feminino , Filgrastim/administração & dosagem , Humanos , Pessoa de Meia-Idade , Paclitaxel/efeitos adversos , Polietilenoglicóis/administração & dosagem
7.
Int J Nanomedicine ; 14: 4895-4909, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31456636

RESUMO

Introduction: Insulin is given by injection, because when administered orally, it would be destroyed by enzymes in the digestive system, hence only about 0.1% reaches blood circulation. The purpose of the present study was to use pH sensitive polyelectrolyte methyl methacrylate (MMA)/itaconic acid (IA) nanogels as carriers in an attempt to improve absorption of insulin administered orally. Methods: Insulin (Ins) was incorporated into the MMA/IA nanogels (NGs) using the polyelectrolyte complexation (PEC) method to form Ins/NGs-PEC. Several parameters, including Ins:NGs ratio, pH, incubation time and stirring rate were optimized during preparation of InsNGs-PEC. The prepared formulations were characterized in terms of particle size (PS), polydispersity index (PdI), zeta potential (ZP) and percent entrapment efficiency (% EE). Results: The optimized InF12 nanogels had a PS, PdI, ZP and %EE of 190.43 nm, 0.186, -16.70 mV and 85.20%, respectively. The InF12 nanogels were lyophilized in the presence of different concentrations of trehalose as cryoprotectant. The lyophilized InF12 containing 2%w/v trahalose (InF12-Tre2 nanogels) was chosen as final formulation which had a PS, PdI, ZP and %EE of 430.50 nm, 0.588, -16.50 mv and 82.10, respectively. The in vitro release of insulin from InF12-Tre2 nanogels in the SGF and SIF were 28.71% and 96.53%, respectively. The stability study conducted at 5±3°C for 3 months showed that lnF12-Tre2 nanogels were stable. The SDS-PAGE assay indicated that the primary structure of insulin in the lnF12-Tre2 nanogels was intact. The in-vivo study in the diabetic rats following oral administration of InF12-Tre2 nanogels at a dose of 100 IU/kg body weight reduced blood glucose level significantly to 51.10% after 6 hours compared to the control groups. Conclusions: The pH sensitive MMA/IA nanogels are potential carriers for oral delivery of insulin as they enhanced the absorption of the drug.


Assuntos
Liofilização , Insulina/administração & dosagem , Polieletrólitos/química , Polietilenoglicóis/administração & dosagem , Polietilenoimina/administração & dosagem , Administração Oral , Animais , Crioprotetores/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Concentração de Íons de Hidrogênio , Ponto Isoelétrico , Masculino , Ratos Sprague-Dawley , Espectroscopia de Infravermelho com Transformada de Fourier , Temperatura Ambiente , Fatores de Tempo
9.
Expert Opin Investig Drugs ; 28(8): 667-673, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31353973

RESUMO

Introduction: A PEGylated form of irinotecan, a topoisomerase I inhibitor, is now available in commerce; its safety and efficacy have been tested in platinum resistant/refractory ovarian cancer (PROC) patients. This novel agent is known as Etirinotecan Pegol (EP). EP, like irinotecan, exerts its action through its principal metabolite SN-38. Areas covered: This drug evaluation article focuses on the most recent investigations and clinical progress regarding EP, a long-acting polymer conjugate of irinotecan for the treatment of PROC. Expert opinion: EP provides prolonged and continuous exposure of SN-38 in tumors, when compared to its parent drug irinotecan. Results from phase II studies are comparable in terms of efficacy to other agents of proven use in PROC. A limitation of the use of EP is the schedule-dependent toxicities (mainly diarrhea and dehydration). In the future, EP could be investigated in association with other agents, even in attempts to restore sensitivity to other treatments. PROC remains a very difficult setting and EP might be a valid agent for patients with good performance status that have exhausted therapeutic options. In such a setting, participation in clinical trials is strongly encouraged.


Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Neoplasias Ovarianas/tratamento farmacológico , Polietilenoglicóis/administração & dosagem , Inibidores da Topoisomerase I/administração & dosagem , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Humanos , Irinotecano/administração & dosagem , Irinotecano/efeitos adversos , Recidiva Local de Neoplasia , Neoplasias Ovarianas/patologia , Polietilenoglicóis/efeitos adversos , Inibidores da Topoisomerase I/efeitos adversos , Inibidores da Topoisomerase I/farmacologia
10.
Pan Afr Med J ; 32: 205, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31312317

RESUMO

To test the hypothesis claimed in recent studies that quality of bowel preparation for colonoscopy could be influenced by the time of the day colonoscopy is performed. Do patients in morning list have better bowel preparation than those on the afternoon list? Retrospective analysis of 736 consecutive patients who had colonoscopy from 1st August to 31st December 2012. Patients with poor bowel preparation (Boston Bowel Prep Score 6 or less) were identified (n = 242). Colonoscopy reports of these patients analysed. Patients were stratified into two groups (am and pm) and results compared. Mean patient age 63.9 years (range 19-89). Male to female ratio 1:1. 92% of patients were given Moviprep. for bowel preparation. 32.9% (242/736) of patients were identified as having inadequate bowel preparation. 37.7% of morning list patients had poor bowel preparation. 26.7% of afternoon list patients had poor bowel preparation. 14.7% (108/736) had incomplete colonoscopy, of which 26.9% (29/108) were due to poor bowel preparation. The commonest reasons for incomplete examination were patient discomfort & bowel looping. Our study demonstrates that morning session patients had poorer bowel preparation than the afternoon session patients in contrast to published evidence in recent literature. This implies that timing of bowel preparation is probably more important than timing of colonoscopy. Poor bowel preparation does not seem to have a significant impact on the colonoscopy failure rate in this series.


Assuntos
Catárticos/administração & dosagem , Colonoscopia/métodos , Polietilenoglicóis/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cuidados Pré-Operatórios/métodos , Estudos Retrospectivos , Fatores de Tempo , Falha de Tratamento , Adulto Jovem
11.
Nat Commun ; 10(1): 2717, 2019 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-31222048

RESUMO

Hepatic steatosis develops when lipid influx and production exceed the liver's ability to utilize/export triglycerides. Obesity promotes steatosis and is characterized by leptin resistance. A role of leptin in hepatic lipid handling is highlighted by the observation that recombinant leptin reverses steatosis of hypoleptinemic patients with lipodystrophy by an unknown mechanism. Since leptin mainly functions via CNS signaling, we here examine in rats whether leptin regulates hepatic lipid flux via the brain in a series of stereotaxic infusion experiments. We demonstrate that brain leptin protects from steatosis by promoting hepatic triglyceride export and decreasing de novo lipogenesis independently of caloric intake. Leptin's anti-steatotic effects are generated in the dorsal vagal complex, require hepatic vagal innervation, and are preserved in high-fat-diet-fed rats when the blood brain barrier is bypassed. Thus, CNS leptin protects from ectopic lipid accumulation via a brain-vagus-liver axis and may be a therapeutic strategy to ameliorate obesity-related steatosis.


Assuntos
Leptina/metabolismo , Fígado/metabolismo , Bulbo/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Triglicerídeos/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Humanos , Infusões Intraventriculares , Injeções Intraventriculares , Leptina/administração & dosagem , Lipogênese/fisiologia , Lipoproteínas VLDL , Fígado/inervação , Masculino , Hepatopatia Gordurosa não Alcoólica/etiologia , Polietilenoglicóis/administração & dosagem , Ratos , Ratos Sprague-Dawley , Técnicas Estereotáxicas , Simpatectomia , Nervo Vago/fisiologia , Nervo Vago/cirurgia
12.
Ann Hematol ; 98(9): 2035-2044, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31236667

RESUMO

BAY 94-9027 is an extended-half-life, recombinant factor VIII (rFVIII) product conjugated with a 60-kDa branched polyethylene glycol (PEG) molecule indicated for use in previously treated patients (aged ≥ 12 years) with hemophilia A. This randomized, open-label, two-way crossover study compared the pharmacokinetics (PK) of BAY 94-9027 and rFVIII Fc fusion protein (rFVIIIFc) in patients with hemophilia A. Patients aged 18-65 years with FVIII < 1% and ≥ 150 exposure days to FVIII were randomized to receive intravenous single-dose BAY 94-9027 60 IU/kg followed by rFVIIIFc 60 IU/kg or vice versa, with ≥ 7-day wash-out between doses. FVIII activity was measured by one-stage assay. PK parameters, including area under the curve from time 0 to the last data point (AUClast, primary parameter), half-life, and clearance were calculated. Eighteen patients were randomized and treated. No adverse events were observed. In the analysis set excluding one outlier, geometric mean (coefficient of variation [%CV, 95% confidence interval {CI}]) AUClast was significantly higher for BAY 94-9027 versus rFVIIIFc (2940 [37.8, 2440-3550] IU h/dL versus 2360 [31.8, 2010-2770] IU h/dL, p = 0.0001). A population PK model was developed to simulate time to reach FVIII threshold levels; median time to 1 IU/dL was approximately 13 h longer for BAY 94-9027 versus rFVIIIFc after a single infusion of 60 IU/kg. In conclusion, BAY 94-9027 had a superior PK profile versus rFVIIIFc. ClinicalTrials.gov : NCT03364998.


Assuntos
Fator VIII , Hemofilia A , Polietilenoglicóis , Proteínas Recombinantes de Fusão , Adolescente , Adulto , Idoso , Estudos Cross-Over , Fator VIII/administração & dosagem , Fator VIII/farmacocinética , Hemofilia A/sangue , Hemofilia A/tratamento farmacológico , Hemofilia A/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/farmacocinética , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/farmacocinética
13.
AAPS PharmSciTech ; 20(5): 218, 2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-31187334

RESUMO

The aim of this study was to develop a self-microemulsifying drug delivery system (SMEDDS) for enhancement of the oral bioavailability of isoliquiritigenin (ISL) as well as evaluate its in vivo anti-hyperuricemic effect in rats. The ISL-loaded self-microemulsifying drug delivery system (ISL-SMEDDS) was comprised of ethyl oleate (EO, oil phase), Tween 80 (surfactant), and PEG 400 (co-surfactant). The ISL-SMEDDS exhibited an acceptable narrow size distribution (44.78 ± 0.35 nm), negative zeta potential (- 10.67 ± 0.86 mV), and high encapsulation efficiency (98.17 ± 0.24%). The in vitro release study indicated that the release rates of the formulation were obviously higher in different release media (HCl, pH 1.2; PBS, pH 6.8; double-distilled water, pH 7.0) compared with the ISL solution. The oral bioavailability of the ISL-SMEDDS was enhanced by 4.71 times in comparison with the free ISL solution. More importantly, ISL-SMEDDS significantly reduced uric acid level by inhibiting xanthine oxidase (XOD) activity in the model rats. Collectively, the prepared ISL-SMEDDS proved to be potential carriers for enhancing the solubility and oral bioavailability of ISL, as well as ameliorating its anti-hyperuricemic effect.


Assuntos
Chalconas/administração & dosagem , Chalconas/sangue , Sistemas de Liberação de Medicamentos/métodos , Hiperuricemia/sangue , Hiperuricemia/tratamento farmacológico , Administração Oral , Animais , Disponibilidade Biológica , Emulsões , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/sangue , Masculino , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/metabolismo , Ratos , Ratos Sprague-Dawley , Solubilidade , Tensoativos/administração & dosagem , Tensoativos/metabolismo
14.
Biol Pharm Bull ; 42(6): 996-1003, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31155597

RESUMO

A small interfering RNA (siRNA) delivery system using dioleylphosphate-diethylenetriamine conjugate (DOP-DETA)-based liposomes (DL) was assessed for systemic delivery of siRNA to tumors. DL carrying siRNA capable of inducing efficient gene silencing with low doses of siRNA were modified with polyethylene glycol (PEG-DL/siRNA) for systemic injection of siRNA. The biodistribution of DL and siRNA in the PEG-DL/siRNA was studied by using radiolabeled DL and fluorescence-labeled siRNA, respectively. DL in the PEG-DL/siRNA showed a high retention in the plasma, accumulation in the tumor, and low accumulation in the liver and spleen after intravenous injection. The in vivo effects of PEGylation were observed only when distearoylphosphatidylethanolamine (DSPE)-PEG but not distearoylglycerol (DSG)-PEG were used. This result suggests that the electrostatic interaction between lipid molecules on the surface of PEG-DL/siRNA was a critical determinant for the in vivo effect of PEGylation. When PEG-DL/siRNA (0.1 mg/kg siRNA) was intravenously injected into tumor-bearing mice, in vivo gene silencing was observed in subcutaneous tumors. These results indicate that PEG-DL/siRNA designed in this study is a promising formulation for systemic use of siRNA.


Assuntos
Neoplasias/genética , Fosfatidiletanolaminas/administração & dosagem , Polietilenoglicóis/administração & dosagem , RNA Interferente Pequeno/administração & dosagem , Animais , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Inativação Gênica , Vetores Genéticos , Humanos , Lipossomos , Fígado/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neoplasias/metabolismo , Fosfatidiletanolaminas/química , Fosfatidiletanolaminas/farmacocinética , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , RNA Interferente Pequeno/sangue , RNA Interferente Pequeno/química , RNA Interferente Pequeno/farmacocinética , Baço/metabolismo , Distribuição Tecidual
15.
BMC Gastroenterol ; 19(1): 65, 2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31046700

RESUMO

BACKGROUND: Pegylated interferon (PEG-IFN) alfa-2b is recommended for chronic hepatitis B (CHB). We aimed to investigate the sustainability of off-treatment responses among Chinese HBeAg-positive CHB patients treated with PEG-IFN alfa-2b from a randomized trial. METHODS: Eligible Chinese patients (n = 322) were followed up by one visit after a median of 6 years (LTFU) following their participation in a randomized trial evaluating the efficacy of three PEG-IFN alfa-2b dosing regimens (1.0 or 1.5 µg/kg/wk. 24 weeks or 1.5 µg/kg/wk. 48 weeks). Primary endpoints at the LTFU were sustained SR and CR (SR/CR at the end of original study [EOS] and at the LTFU). SR was defined as HBeAg loss and seroconversion to anti-HBe and CR as HBeAg loss and seroconversion to anti-HBe and HBV-DNA < 2000 IU/mL. RESULTS: The proportions of patients achieving sustained SR among patients who had SR at EOS were high in three treatment groups (61.9, 65.5, 76.5%, respectively, p = 0.46); treatment with PEG-IFN alfa-2b 1.5 µg/kg/wk. 48 weeks had the highest proportion of a sustained CR among patients who had CR at EOS (75.0%, p = 0.05). A considerable number of patients achieved sustained SR (18.2-29.9%) and sustained CR (14.8-18.3%) after EOS despite no further NA treatment. At the LTFU, rates of SR and CR were less than 70.0 and 50.0%, respectively, among all enrolled patients regardless of additional nucleos(t)ide analogs before the LTFU. CONCLUSIONS: PEG IFN alfa-2b therapy had considerable off-treatment sustainability in Chinese HBeAg positive chronic hepatitis B patients with serological and complete responses.


Assuntos
Antivirais/uso terapêutico , Antígenos E da Hepatite B/sangue , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/virologia , Interferon alfa-2/uso terapêutico , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Resposta Viral Sustentada , Adulto , Antivirais/administração & dosagem , China , Feminino , Seguimentos , Hepatite B Crônica/sangue , Humanos , Interferon alfa-2/administração & dosagem , Interferon-alfa/administração & dosagem , Masculino , Polietilenoglicóis/administração & dosagem , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Adulto Jovem
16.
BMC Plant Biol ; 19(1): 221, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138155

RESUMO

BACKGROUND: Drought stress negatively affects plant growth and productivity. Plants sense soil drought at the root level but the underlying mechanisms remain unclear. At the cell level, we aim to reveal the short-term root perception of drought stress through membrane dynamics. RESULTS: In our study, 15 Medicago truncatula accessions were exposed to a polyethylene glycol (PEG)-induced drought stress, leading to contrasted ecophysiological responses, in particular related to root architecture plasticity. In the reference accession Jemalong A17, identified as drought susceptible, we analyzed lateral roots by imaging of membrane-localized fluorescent probes using confocal microscopy. We found that PEG stimulated endocytosis especially in cells belonging to the growth differentiation zone (GDZ). The mapping of membrane lipid order in cells along the root apex showed that membranes of root cap cells were more ordered than those of more differentiated cells. Moreover, PEG triggered a significant increase in membrane lipid order of rhizodermal cells from the GDZ. We initiated the membrane analysis in the drought resistant accession HM298, which did not reveal such membrane modifications in response to PEG. CONCLUSIONS: Our data demonstrated that the plasma membranes of root cells from a susceptible genotype perceived drought stress by modulating their physical state both via a stimulation of endocytosis and a modification of the degree of lipid order, which could be proposed as mechanisms required for signal transduction.


Assuntos
Secas , Endocitose , Medicago truncatula/fisiologia , Lipídeos de Membrana/metabolismo , Genótipo , Medicago truncatula/genética , Células Vegetais/metabolismo , Células Vegetais/fisiologia , Polietilenoglicóis/administração & dosagem , Rizoma/metabolismo , Rizoma/fisiologia , Estresse Fisiológico
17.
AAPS PharmSciTech ; 20(5): 188, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31093777

RESUMO

Mannose receptor (CD206) and E-selectin are selectively expressed in M2-like tumor-associated macrophages (M2-TAMs) and activated endothelial cells of vessels surrounding tumor tissues. With the knowledge that D-mannose is the natural ligand of mannose receptors and L-fucose is the key calcium chelator for tumor-associated carbohydrate antigens (TACAs) binding to E-selectin, herein, we firstly reported D-mannose polyethylene glycol (PEG) conjugates (Man-PEG) and L-fucose PEG conjugates (Fuc-PEG) co-modified liposomal doxorubicin (DOX-MFPL) to improve tumor-targeting ability. The dual-ligand modified PEGylated liposomes (DOX-MFPL) were assessed by both in vitro and in vivo trials. Compared with the single-ligand D-mannose- or L-fucose-modified liposomes (DOX-MPL or DOX-FPL), DOX-MFPL achieved an increased distribution of DOX in tumor tissues. The antitumor study based on S180 tumor-bearing mice was conducted and the superior tumor inhibitory rate was shown with DOX-MFPL, probably owing to the superior tumor-targeting effect of DOX-MFPL and the modulation of the tumor microenvironment with the exhaustion of TAMs. In general, the dual-ligand drug delivery systems are expected to be promising in the development of specific and efficient methods for tumor treatment.


Assuntos
Doxorrubicina/análogos & derivados , Sistemas de Liberação de Medicamentos , Fucose/química , Manose/química , Polietilenoglicóis/química , Animais , Linhagem Celular Tumoral , Doxorrubicina/administração & dosagem , Humanos , Ligantes , Masculino , Camundongos , Polietilenoglicóis/administração & dosagem , Células RAW 264.7
18.
Int J Clin Oncol ; 24(10): 1284-1291, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31127479

RESUMO

PURPOSE: To compare the efficacy, safety, and tolerability profiles of pegylated liposomal doxorubicin and carboplatin (PLDC) with those of gemcitabine and carboplatin (GC) for the treatment of patients with platinum-sensitive recurrent ovarian cancer. METHODS: Ovarian cancer patients with recurrence > 6 months after first-line platinum and taxane-based therapies were randomly assigned to PLDC [pegylated liposomal doxorubicin 30 mg/m2 plus carboplatin area under the curve (AUC) 5 mg/mL/min on day 1] every 4 weeks or GC (gemcitabine 1000 mg/m2 on days 1 and 8 plus carboplatin AUC 4 mg/mL/min on day 1) every 3 weeks for at least 6 cycles. The primary endpoint was progression-free survival, and overall response rate, overall survival, toxicity, and dose administration were secondary endpoints. RESULTS: One-hundred patients (49 PLDC; 51 GC) were randomly assigned. Over a median follow-up of 24 months, the median progression-free survival was 12.0 months (95% CI 9.2-15.0) for PLDC and 9.8 months (8.9-12.3) for GC [HR 0.69 (0.455-1.047)] with a difference of 2.2 months. The response rate was 57.1% (41.0-72.3) for PLDC and 56.4% (39.6-72.2) for GC. No obvious differences in toxicity (G3/4) were noted between arms. The median relative dose intensity of planned dose per week was 88.9% for pegylated liposomal doxorubicin and 53.1% for gemcitabine (p < 0.0001). CONCLUSIONS: PLDC and GC are both good treatment candidates for platinum-sensitive recurrent ovarian cancer patients; however, the dose intensity was lower for GC than for PLDC. PLDC had a more favorable risk-benefit profile than that of GC for patients.


Assuntos
Adenocarcinoma de Células Claras/tratamento farmacológico , Adenocarcinoma Mucinoso/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Adenocarcinoma de Células Claras/patologia , Adenocarcinoma Mucinoso/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carboplatina/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Neoplasias Ovarianas/patologia , Polietilenoglicóis/administração & dosagem , Prognóstico , Taxa de Sobrevida , Adulto Jovem
19.
Yakugaku Zasshi ; 139(4): 629-633, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-30930398

RESUMO

The combination of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin with rituximab (DA-EPOCH-R) is used for non-Hodgkin lymphoma patients. Febrile neutropenia (FN) is a common complication of treatment with myelo-suppressive chemotherapy, so preventing FN is important for maintaining chemotherapy dosage. Recently, pegfilgrastim has been used as the primary prophylaxis of FN in Japan, but there have been few cases reported using pegfilgrastim for the primary prophylaxis in DA-EPOCH-R. In this study, we retrospectively compared the efficacy of pegfilgrastim with that of filgrastim in patients receiving DA-EPOCH-R in Hiroshima University Hospital. Efficacy assessment was based on incidence of FN and serious neutropenia (neutrophil count <500/µL), hospitalization days and chemotherapy dosage level. Ten patients met the inclusion criteria: pegfilgrastim (n=5, 30 cycles) or filgrastim (n=5, 16 cycles). No difference in efficacy existed between pegfilgrastim and filgrastim in the first cycle; however, 2 of 5 patients in filgrastim group reduced dose level in the total cycles of chemotherapy, no patients in pegfilgrastim group reduced. In conclusion, pegfilgrastim seemed better than filgrastim for the primary prophylaxis in DA-EPOCH-R.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neutropenia Febril/induzido quimicamente , Neutropenia Febril/prevenção & controle , Filgrastim/administração & dosagem , Polietilenoglicóis/administração & dosagem , Rituximab/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Humanos , Linfoma não Hodgkin/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Estudos Retrospectivos , Resultado do Tratamento , Vincristina/administração & dosagem
20.
Recenti Prog Med ; 110(3): 6e-9e, 2019 Mar.
Artigo em Italiano | MEDLINE | ID: mdl-30968858

RESUMO

Oncologic patients on opioid therapy due to pain may have several side effects, including respiratory depression (in about 1% of cases), pruritus (up to 10% of cases), nausea (in 25-32% of cases), sedation (in 20- 60% of cases); but the most far-reaching side effect (up to 95% of cases) that can occur is constipation. The socalled "opioid-induced constipation" (OIC) can develop at the start of opioid therapy and can last as long as continued use. The OIC is a real change in intestinal habits that occurs when opioid treatment is started; it is noted with a reduced frequency of episodes of defecation, with a development or worsening of the effort to defecation, with a feeling of incomplete emptying and a perception on the part of the patient to live in a stressful way the act of defecation. Also because of this, the OIC can induce to tolerate the dose of opioids routinely causing inadequate pain management. Continuous therapy with opioids lasting at least two weeks and resistance to the treatment of constipation with osmotic laxatives for more than three days in patients with terminal disease (Nota 90 AIFA) allow the prescription of naloxegol, a PEGylated derivative of the naloxone. Naloxegol belongs to the PAMORA family (peripheral mu-opioid receptor antagonists) which does not generally cross the blood-brain barrier and therefore does not interfere with the central nervous system-mediated analgesic efficacy. The reported clinical case tends to show how the use of the drug under examination (naloxegol) solves the problem of the OIC in a oncologic patient, improving her quality of life.


Assuntos
Analgésicos Opioides/efeitos adversos , Dor do Câncer/tratamento farmacológico , Constipação Intestinal/tratamento farmacológico , Morfinanos/administração & dosagem , Polietilenoglicóis/administração & dosagem , Analgésicos Opioides/administração & dosagem , Constipação Intestinal/induzido quimicamente , Feminino , Humanos , Pessoa de Meia-Idade , Antagonistas de Entorpecentes/administração & dosagem , Qualidade de Vida
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