RESUMO
Fluorescence imaging (FI) and photoacoustic imaging (PA) play important roles in the real-time assessment of cell-based therapies. However, the limitations of conventional organic fluorescence contrast agents and the narrow range of the emission wavelength in the first near-infrared (NIR-I) window (750-900â nm) hamper applications of fluorescence imaging in living subjects. Herein, we report the design and synthesis of a short-wave infrared FI contrast agent and PA contrast agent based on a conjugated polymer-poly{2,5-bis[(5-thiophen-2-yl)methylene]-3,6-bis(2-octyldodecyl)-2,5-dihydropyrazine}-and its use to construct multifunctional nanoparticles to simplify photothermal therapy.
Assuntos
Nanopartículas/química , Imagem Óptica/métodos , Técnicas Fotoacústicas/métodos , Fototerapia/métodos , Polímeros/química , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Fluorescência , Humanos , Hipertermia Induzida , Camundongos Nus , Microscopia Eletrônica de Transmissão , Nanopartículas/administração & dosagem , Nanopartículas/ultraestrutura , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Polímeros/administração & dosagem , Polímeros/síntese química , Espectrofotometria/métodosRESUMO
Near-infrared (NIR) fluorescent materials are considered to be the most promising labeling reagents for sensitive determination and biological imaging due to the advantages of lower background noise, deeper penetrating capacity, and less destructive effects on the biomatrix over those of UV and visible fluorophores. In the past decade, advances in biomedical fluorescence imaging in the NIR region have focused on the traditional NIR window (NIR-I; λ=700-900â nm), and have recently been extended to the second NIR window (NIR-II; λ=1000-1700â nm). In vivo NIR-II fluorescence imaging outperforms imaging in the NIR-I window as a result of further reduced absorption, tissue autofluorescence, and scattering. In this review, the applications of four types of NIR-II fluorescent materials, organic fluorophores, quantum dots, rare-earth compounds, and single-walled carbon nanotubes, are summarized and future trends are discussed. Some methods to enhance the NIR-II fluorescence quantum yield are also proposed.
Assuntos
Corantes Fluorescentes/química , Animais , Linhagem Celular Tumoral , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/efeitos da radiação , Humanos , Raios Infravermelhos , Metais Terras Raras/química , Metais Terras Raras/efeitos da radiação , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Nanotubos de Carbono/química , Nanotubos de Carbono/efeitos da radiação , Imagem Óptica/métodos , Pontos Quânticos/química , Pontos Quânticos/efeitos da radiaçãoRESUMO
BACKGROUND: Safe and effective therapies are needed for pediatric patients with psoriasis. OBJECTIVE: The purpose of this study was to evaluate ustekinumab in patients age 12 to 17 years who had moderate-to-severe psoriasis. METHODS: Patients (n = 110) were randomly assigned to ustekinumab standard dosing (SD; 0.75 mg/kg [≤60 kg], 45 mg [>60-≤100 kg], and 90 mg [>100 kg]) or half-standard dosing (HSD; 0.375 mg/kg [≤60 kg], 22.5 mg [>60-≤100 kg], and 45 mg [>100 kg]) at weeks 0 and 4 and every 12 weeks or placebo at weeks 0 and 4 with crossover to ustekinumab SD or HSD at week 12. Clinical assessments included the proportion of patients achieving a Physician's Global Assessment of cleared/minimal (PGA 0/1), at least 75% improvement in Psoriasis Area and Severity Index (PASI 75), and at least 90% in PASI (PASI 90). Adverse events (AEs) were monitored through week 60. RESULTS: At week 12, 67.6% and 69.4% of patients receiving ustekinumab HSD and SD, respectively, achieved PGA 0/1 versus 5.4% for placebo (P < .001). Significantly greater proportions receiving ustekinumab achieved PASI 75 (HSD, 78.4%; SD, 80.6%; placebo, 10.8%) or PASI 90 (HSD, 54.1%; SD, 61.1%; placebo, 5.4%) at week 12 (P < .001). Through week 12, 56.8% of placebo patients, 51.4% of HSD patients, and 44.4% of SD patients reported at least one AE; through week 60, 81.8% reported AEs. LIMITATIONS: The study was small relative to adult trials. CONCLUSIONS: In this patient population (12-17 years), the standard ustekinumab dose provided response comparable to that in adults with no unexpected AEs through 1 year.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Psoríase/diagnóstico , Psoríase/tratamento farmacológico , Ustekinumab/administração & dosagem , Adolescente , Fatores Etários , Criança , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Seguimentos , Humanos , Injeções Subcutâneas , Masculino , Medição de Risco , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
BACKGROUND AND OBJECTIVES: To evaluate in a phase 2 study the safety and efficacy of IV nipocalimab, a fully human, antineonatal Fc receptor monoclonal antibody, in patients with generalized myasthenia gravis (gMG). METHODS: Patients with gMG with inadequate response to stable standard-of-care (SOC) therapy were randomized 1:1:1:1:1 to receive either IV placebo every 2 weeks (Q2W) or one of 4 IV nipocalimab treatments: 5 mg/kg once every 4 weeks (Q4W), 30 mg/kg Q4W, 60 mg/kg Q2W each for 8 weeks, or a 60 mg/kg single dose, in addition to their background SOC therapy. Infusions (placebo or nipocalimab) were Q2W in all groups to maintain blinding. The primary safety endpoint was incidence of treatment-emergent adverse events (TEAEs), including serious adverse events and adverse events of special interest. The primary efficacy endpoint was change from baseline to day 57 in Myasthenia Gravis-Activities of Daily Living (MG-ADL) total scores. Dose response of change at day 57 was analyzed with a linear trend test over the placebo, nipocalimab 5 mg/kg Q4W, nipocalimab 30 mg/kg Q4W, and nipocalimab 60 mg/kg Q2W groups. RESULTS: Sixty-eight patients (nipocalimab: n = 54; placebo, n = 14) were randomized; 64 patients (94.1%) were positive for antiacetylcholine receptor autoantibodies, and 4 patients (6%) were positive for antimuscle-specific tyrosine kinase autoantibodies. Fifty-seven patients (83.8%) completed treatment through day 57. The combined nipocalimab group compared with the placebo group demonstrated similar incidences of TEAEs (83.3% vs 78.6%, respectively) and infections (33.3% vs 21.4%, respectively). No deaths or discontinuations due to TEAEs and no TEAEs of special interest (grade ≥3 infection or hypoalbuminemia) were observed with nipocalimab treatment. A statistically significant dose response was observed for change from baseline in MG-ADL at day 57 (p = 0.031, test of linear trend). DISCUSSION: Nipocalimab was generally safe, well-tolerated, and showed evidence of dose-dependent reduction in MG-ADL scores at day 57 in this phase 2 study. These results support further evaluation of nipocalimab for the treatment of gMG. TRIAL REGISTRATION INFORMATION: Clinical Trials Registration: NCT03772587; first submitted December 10, 2018; EudraCT Number: 2018-002247-28; first submitted November 30, 2018; date of first patient dosed April 10, 2019. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with gMG, nipocalimab was well-tolerated, and it did not significantly improve MG-ADL at any individual dose but demonstrated a significant dose response for improved MG-ADL across doses.
Assuntos
Atividades Cotidianas , Miastenia Gravis , Humanos , Miastenia Gravis/tratamento farmacológico , Anticorpos Monoclonais , Autoanticorpos , PacientesRESUMO
Theranostics has attracted great attention due to its ability to combine the real-time diagnosis of cancers with efficient treatment modalities. Activatable dual-functional molecular agents could be synthesized by covalently conjugating imaging agents, therapeutic agents, stimuli-responsive linkers and/or targeting molecules together. They could be selectively activated by overexpressed physiological stimuli or external triggers at the tumor sites to release imaging agents and cytotoxic drugs, thus offering many advantages for tumor imaging and therapy, such as a high signal-to-noise ratio, low systemic toxicity, and improved therapeutic effects. This review summarizes the recent advances of dual-functional molecular agents that respond to various physiological or external stimuli for cancer theranostics. The molecular designs, synthetic strategies, activatable mechanisms, and biomedical applications of these molecular agents are elaborated, followed by a brief discussion of the challenges and opportunities in this field.
Assuntos
Antineoplásicos , Neoplasias , Humanos , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Nanomedicina Teranóstica/métodosRESUMO
The compounding of polysaccharide macromolecules and antibacterial agents always has been the preferred strategy to prepare antibacterial products, attracting increasing interest. Herein, a novel acid-responsive oxidized dextran-based nanoplatform (OTP NP) has been fabricated for photodynamic antibacterial therapy by combing photosensitizer monoaminoporphyrin (TPP-NH2) with oxidized dextran (ODex) via the Schiff Base reaction. OTP NP of about 100 nm is composed of an inner hydrophobic core of 30 nm and peripheral polysaccharide macromolecules. The OTP NP killed 99.9 % of E. coli and S. aureus within 1.5 light cycles at a concentration of 200 µg/mL. Concurrently, OTP NP exhibited excellent cytocompatibility at a concentration of 1 mg/mL (about 5 folds bactericidal concentration). Particularly, except for the recognized antibacterial mechanism of photodynamic therapy, a novel mechanism of bacterial membrane damage was discovered: the bacterial cell membrane was peeled off and formed spherical particles that aggregated around the bacteria to accelerate bacterial apoptosis under the combined action of ROS and nanomaterials. Moreover, the slightly soluble drug levofloxacin (Lev) as a model drug was loaded into OTP NP to test its carrier function, providing a practicable strategy to design multifunctional polysaccharide-based photodynamic antibacterial materials.
Assuntos
Fotoquimioterapia , Staphylococcus aureus , Escherichia coli , Dextranos , Antibacterianos/farmacologia , Antibacterianos/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/químicaRESUMO
The great tissue penetration depth and low tissue autofluorescence of NIR-II fluorescence imaging make it attractive for in vivo diagnosis. However, the aggregation-caused quenching (ACQ) effect is among the dominant obstacles that weaken NIR-II imaging and restrict its application. Herein, the donor unit, 2,8-dibromo-6H,12H-5,11-methanodibenzo[b,f] [1,5]diazocine with a V-configuration, was introduced to prepare the donor-acceptor (D-A) polymer P-TB with a twisted backbone, while the planar D-A polymer P-TP was used as a control. P-TB and P-TP were prepared by Stille Coupling with DPP as the acceptor. The main absorption peaks of P-TB and P-TP are located at 610 nm and 640 nm, and the emission peaks of P-TB and P-TP are 1060 nm and 930 nm, respectively. Significantly, the V-shaped P-TB showed no obvious ACQ effect within 600 µM, and the same phenomenon was demonstrated during in vivo NIR-II imaging in mice, which proves that the introduction of V-configuration donor units is beneficial for weakening the ACQ effect. This work outlines a prospective tactic for the design of conventional NIR-II fluorescent polymers by modulating the configuration of the donor units.
Assuntos
Imagem Óptica , Polímeros , Animais , Camundongos , Estudos Prospectivos , Imagem Óptica/métodosRESUMO
Here, a D-A-D type fluorescent conjugated molecule with a high molar absorption coefficient and emission at 1120 nm in the near-infrared region was synthesized. Conjugated molecules and two polyethylene glycol polymers with different lipophilic ends are assembled into water-soluble nanoparticles to improve their biocompatibility. Then, their physical and chemical properties were studied and compared. Compared with phospholipid-based PEG, styrene-based PEG can reduce the π-π stacking between molecules and the quenching caused by molecular aggregation. It has more advantages in particle size and fluorescence performance and can be better used in biological imaging. In addition, the Nano-particles have good photo-thermal conversion efficiency; the temperature rises to 62.8°C after 980 nm irradiation for 6 min, which can be used as a potential near-infrared II photothermal therapeutic agent. In vivo imaging experiments confirmed that nanomaterials have fluorescence, photoacoustic dual-modal imaging and good biological safety. STATEMENT OF SIGNIFICANCE: In this work, we constructed D-A-D type dual donor fluorescent molecules using BBTD, CPDT and EDOT, and used amphiphilic polymers to improve their biocompatibility. Compared with DSPE NPs, PS-NPs can reduce intermolecular π-π stacking and increase quantum yield (QY = 0.98 %). Deep penetration and low biological toxicity make it have biomedical value and realize the integration of multi-functional collaborative imaging. This work can still be further improved and supplemented, and the molecular structure can be optimized to improve its application in biomedical imaging.
Assuntos
Nanopartículas , Técnicas Fotoacústicas , Terapia Fototérmica , Técnicas Fotoacústicas/métodos , Nanopartículas/uso terapêutico , Nanopartículas/química , Polímeros/química , Polietilenoglicóis/química , Imagem Óptica , Corantes , Fototerapia/métodosRESUMO
Traditional and single treatment strategies are difficult to achieve good results due to tumor resistance and complex mechanisms. Combination therapy through co-delivery systems is one of the methods to improve the effectiveness of cancer treatment. The polyprodrug platform has inherent advantages such as high drug loading and strong stability. Herein, a new reactive oxygen species (ROS)-responsive micelle composed of poly 10-hydroxycamptothecin (pHCPT) and PEG is reported, which loaded dexamethasone (DEX) as synergistic drugs. The micelles collapse in the complex microenvironment of tumor cells to release DEX. The first released DEX can increase the ROS level of tumor cells, thereby facilitating the cleavage of thioketal bonds to release intact HCPT molecules. Meanwhile, DEX can normalize tumor blood vessels, reduce adverse reactions, and further improve the efficacy of HCPT. This co-delivery system shows an ideal tumor suppressive effect in vivo and in vitro. Designing drugs into a modular multi-drug platform and selecting appropriate synergistic drugs according to the treatment plan provides a convenient strategy for future clinical treatment.
Assuntos
Nanopartículas , Neoplasias , Camptotecina/análogos & derivados , Linhagem Celular Tumoral , Dexametasona , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Micelas , Neoplasias/tratamento farmacológico , Espécies Reativas de OxigênioRESUMO
Ustekinumab (STELARA) is a human monoclonal antibody against interleukins-12 and -23 for the treatment of adult and adolescent (≥ 12 to < 18 years of age) patients with moderate-to-severe plaque psoriasis. A phase III study was recently completed in pediatric patients (≥ 6 to < 12 years of age) with psoriasis. The objectives of the current analysis were to develop a population pharmacokinetic (PK) model and a joint longitudinal exposure-response model using ordered categorial end points derived from Psoriasis Area and Severity Index (PASI) and Physician's Global Assessment (PGA) scores (namely a joint PASI response criteria (PRC) and PGA model) to characterize the PK and exposure-response relationship of ustekinumab in pediatric patients with psoriasis. The developed pediatric models reasonably predicted the PK of ustekinumab, as well as the PRC and PGA clinical response in pediatric patients with psoriasis. In addition, the joint PRC and PGA modeling framework was able to adequately extrapolate clinical response in pediatric patients using data collected from clinical studies in adult patients with psoriasis.
Assuntos
Psoríase/tratamento farmacológico , Ustekinumab/uso terapêutico , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/uso terapêutico , Criança , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pediatria/métodos , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Patients with psoriasis tend to be overweight, and the efficacy of fixed-dose biologics may be compromised by high body weight. OBJECTIVE: We sought to determine whether the optimal dose of ustekinumab is affected by weight in patients with psoriasis. METHODS: Patients were randomized in two phase III trials (PHOENIX 1 and 2) to receive 45 mg or 90 mg of ustekinumab every 12 weeks (n = 1331) or placebo with crossover to ustekinumab at week 12 (n = 665). Efficacy and serum ustekinumab concentrations were to be evaluated by 10-kg increments of body weight at week 28 (steady-state trough level). RESULTS: Mean baseline weight was 93.9 and 91.0 kg in PHOENIX 1 and 2, respectively. Based on the analyses by 10-kg increments, a cutoff of 100 kg was determined to best differentiate the dose response. The proportion of patients with at least 75% improvement from baseline in Psoriasis Area and Severity Index score was 74.2% for 90 mg and 54.6% for 45 mg in heavier patients (> 100 kg), but the proportion with a response of at least 75% improvement from baseline in Psoriasis Area and Severity Index score was similar between doses (80.8% vs 76.9%) in lighter patients (≤ 100 kg). Serum ustekinumab concentrations were also affected by weight, with lower serum concentrations observed in heavier patients at each dose. Safety was not affected by weight. LIMITATIONS: Low numbers of patients at the extremes of body weight may limit the analyses of these subgroups. CONCLUSION: Results of weight-based analyses of clinical and pharmacokinetic data indicate that fixed dosing of ustekinumab based on weight is appropriate for the treatment of patients with psoriasis.
Assuntos
Anticorpos Monoclonais/farmacocinética , Peso Corporal , Psoríase/tratamento farmacológico , Adulto , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Índice de Massa Corporal , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Seguimentos , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Psoríase/diagnóstico , Medição de Risco , Índice de Gravidade de Doença , Resultado do Tratamento , UstekinumabRESUMO
BACKGROUND: Ustekinumab, a fully human immunoglobulin (Ig) G1K monoclonal antibody directed against the p40 subunit of interleukin (IL)-12/23, has demonstrated efficacy in patients with moderate-to-severe psoriasis. OBJECTIVE: To evaluate the effect of IL-12/23 inhibition on immunocompetency by antigen-recall response in a preclinical multiple-dose toxicology study and three single-dose, phase 1 studies. METHODS: Cynomolgus monkeys (Mauritius; n = 32) treated with subcutaneous (s.c.) placebo or ustekinumab 22.5 or 45 mg/kg twice weekly for 26 weeks were assessed for antibody responsiveness to keyhole limpet hemocyanin (KLH). Patients with psoriasis or multiple sclerosis who received a single-dose of placebo (n = 8) or ustekinumab (n = 46) 0.09-4.5 mg/kg intravenous (i.v.) or 0.27-2.7 mg/kg s.c. were assessed by pneumococcal and tetanus antigen challenge. Primary T-cell response was not assessed in humans. RESULTS: Anti-KLH antibody responses in ustekinumab-treated cynomolgus monkeys were comparable to those observed in placebo-treated animals. A normal antibody response (> or = two-fold increase from baseline) to pneumococcal antigen was seen in 34/46 (73.9%) ustekinumab-treated versus 4/8 (50%) placebo-treated patients. A normal antigen-recall response (> or = four-fold increase from baseline) was seen in 12/20 (60%) ustekinumab- and 4/5 (80%) placebo-treated patients following tetanus toxoid exposure. Percentages of circulating immune cells were not affected by ustekinumab treatment. CONCLUSION: Results in nonhuman primates and human patients suggest that ustekinumab treatment does not significantly impair recall humoral immune system functions.
Assuntos
Anticorpos Monoclonais/farmacologia , Imunidade Humoral/efeitos dos fármacos , Memória Imunológica/efeitos dos fármacos , Animais , Anticorpos Monoclonais Humanizados , Hemocianinas/imunologia , Humanos , Macaca fascicularis , Vacinas Pneumocócicas/imunologia , Toxoide Tetânico/imunologia , UstekinumabRESUMO
This open-label, multicenter, phase I therapeutic protein-drug interaction study was designed to evaluate the potential effect of guselkumab, a fully human anti-interleukin-23 immunoglobulin G1 lambda monoclonal antibody, on the pharmacokinetics of a cocktail of representative cytochrome P450 (CYP) probe substrates (midazolam (CYP3A4), S-warfarin (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and caffeine (CYP1A2)). Fourteen participants with psoriasis received a single subcutaneous dose of guselkumab 200 mg on day 8 and an oral probe cocktail on days 1, 15, and 36. Blood samples were collected for measuring plasma concentrations of these probe substrates on days 1, 15, and 36. No consistent trends in observed maximum plasma concentration and area under the curve from time 0 to infinity values of each probe CYP-substrate before (day 1) and after guselkumab treatment (days 15 and 36) could be identified in each individual patient, suggesting that the use of guselkumab in patients with psoriasis is unlikely to influence the systemic exposure of drugs metabolized by CYP isozymes (CYP3A4, CYP2C9, CYP2C19, CYP2D6, and CYP1A2). The probe cocktail was generally well-tolerated when administered in combination with guselkumab in patients with psoriasis. Clinicaltrials.gov Identifiers: NCT02397382.
Assuntos
Anticorpos Monoclonais Humanizados/farmacocinética , Psoríase/tratamento farmacológico , Adolescente , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Área Sob a Curva , Cafeína/administração & dosagem , Cafeína/farmacocinética , Indutores das Enzimas do Citocromo P-450/administração & dosagem , Indutores das Enzimas do Citocromo P-450/farmacocinética , Inibidores das Enzimas do Citocromo P-450/administração & dosagem , Inibidores das Enzimas do Citocromo P-450/farmacocinética , Sistema Enzimático do Citocromo P-450/metabolismo , Interações Medicamentosas , Feminino , Humanos , Masculino , Taxa de Depuração Metabólica , Midazolam/administração & dosagem , Midazolam/farmacocinética , Pessoa de Meia-Idade , Omeprazol/administração & dosagem , Omeprazol/farmacocinética , Psoríase/sangue , Psoríase/diagnóstico , Índice de Gravidade de Doença , Varfarina/administração & dosagem , Varfarina/farmacocinética , Adulto JovemRESUMO
The population pharmacokinetics of ustekinumab are characterized in patients with moderate to severe plaque psoriasis in 2 Phase 3 studies (PHOENIX 1 and PHOENIX 2). Serum concentration data from 1937 patients are analyzed to determine pharmacokinetic characteristics of ustekinumab and to assess factors that may contribute to their variability. The population typical mean (percentage relative standard error) values for apparent clearance, apparent volume of distribution, and absorption rate constant from the final covariate model are 0.465 L.day(-1) (2.0%), 15.7 L (2.0%), and 0.354 day(-1) (16.2%), respectively. The interindividual variabilities for apparent clearance and apparent volume of distribution are 41.0% and 33.2%, respectively. Of the factors evaluated in this analysis, body weight, diabetes, and positive immune response (antibodies to ustekinumab) are important covariates affecting the apparent clearance and/or apparent volume of distribution of ustekinumab. To fully understand the clinical relevance of these results, the covariate findings need to be evaluated concurrently with the efficacy and safety data.
Assuntos
Anticorpos Monoclonais/farmacocinética , Interleucina-12/imunologia , Interleucina-23/imunologia , Psoríase/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados , Peso Corporal , Ensaios Clínicos Fase III como Assunto , Diabetes Mellitus/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Psoríase/complicações , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença , Distribuição Tecidual , Ustekinumab , Adulto JovemRESUMO
NIR-II fluorescence imaging has great potential in diagnosis, but the quantum efficiency of contrast agents is an urgent problem to be solved. We synthesized two new multifunctional polymers, P-TT and P-DPP, with a tetrahedral C (sp3) and branched alkyl chains in the main chain, which were beneficial to obtain high quantum efficiency. P-TT and P-DPP showed absorption peaks of 686 nm and 763 nm, respectively, and fluorescence emission peaks of 1071 nm and 1066 nm, respectively. The photothermal effect of P-DPP can reach 52 °C, and the quantum yield reaches 1.5%, which was three times higher than that of nanotube fluorophores (quantum yield 0.4%). P-DPP is used for stable fluorescence imaging of blood vessels and photoacoustic imaging of nude mice, and successfully applied to phototherapy of nude mouse tumours.
Assuntos
Antineoplásicos/uso terapêutico , Nanopartículas/uso terapêutico , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Polímeros/uso terapêutico , Tiofenos/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/efeitos da radiação , Antineoplásicos/toxicidade , Feminino , Corantes Fluorescentes , Células HeLa , Humanos , Hipertermia Induzida/métodos , Raios Infravermelhos , Fígado/diagnóstico por imagem , Camundongos Nus , Nanopartículas/efeitos da radiação , Nanopartículas/toxicidade , Técnicas Fotoacústicas/métodos , Fotoquimioterapia/métodos , Polímeros/síntese química , Polímeros/efeitos da radiação , Polímeros/toxicidade , Tiofenos/síntese química , Tiofenos/efeitos da radiação , Tiofenos/toxicidade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Psoriasis is a common inflammatory skin disorder that requires chronic treatment and is associated with multiple comorbidities. Guselkumab, a human immunoglobulin-G1-lambda monoclonal antibody, binds to interleukin-23 with high specificity and affinity and is effective in treating moderate to severe plaque psoriasis. As part of the guselkumab psoriasis clinical trial program, using a confirmatory approach, a population pharmacokinetics (PopPK) model was established using 13 014 PK samples from 1454 guselkumab-treated patients across 3 phase 2/3 trials. Observed serum guselkumab concentrations were adequately described by a 1-compartment linear PK model with first-order absorption and elimination. The final PK model was robust and stable, with apparent clearance (CL/F), apparent volume of distribution (V/F), and absorption rate constant (ka) estimates of 0.516 L/day, 13.5 L, and 1.11 day-1 , respectively. A model-derived elimination half-life of 18.1 days indicated achievement of steady-state serum guselkumab concentrations within 12-14 weeks. The primary covariate contributing to the observed PK variability was body weight, which accounted for only 28% (CL/F) and 32% (V/F) of the interindividual proportion of variance. Diabetes was identified to marginally reduce guselkumab exposure, owing to 12% higher CL/F in diabetic versus nondiabetic patients, but its contribution was not clinically relevant. None of the other covariates tested (eg, age, sex, ethnicity, immune response to guselkumab, or concomitant medications) had a clinically relevant effect on guselkumab exposure.
Assuntos
Anticorpos Monoclonais/farmacocinética , Modelos Biológicos , Psoríase/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Fármacos Dermatológicos/administração & dosagem , Fármacos Dermatológicos/farmacocinética , Feminino , Meia-Vida , Humanos , Interleucina-23/imunologia , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Psoríase/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença , Distribuição TecidualRESUMO
OBJECTIVE: To evaluate the efficacy and safety of ustekinumab through 2 years in adult patients with active psoriatic arthritis (PsA). METHODS: A total of 615 adult patients with active PsA were randomized to placebo, ustekinumab 45 mg, or ustekinumab 90 mg, at weeks 0, 4, and every 12 weeks through week 88 (last dose). At week 16, patients with <5% improvement in both tender and swollen joint counts entered blinded early escape (placebo to 45 mg, 45 mg to 90 mg, and 90 mg to 90 mg). All remaining placebo patients crossed over to ustekinumab 45 mg at week 24. Clinical efficacy measures included American College of Rheumatology criteria for 20% improvement (ACR20), Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP), and ≥75% improvement in the Psoriasis Area and Severity Index (PASI75). Radiographic progression was evaluated using the modified Sharp/van der Heijde score (SHS). RESULTS: At week 100, ACR20, DAS28-CRP moderate/good response, and PASI75 rates ranged from 56.7-63.6%, 71.9-76.7%, and 63.9-72.5%, respectively, across the 3 treatment groups. In both ustekinumab groups, the median percent improvement in dactylitis and enthesitis was 100% at week 100. The mean changes in SHS score from week 52 to week 100 were similar to those observed from week 0 to week 52 in the ustekinumab groups. Through week 108, 70.7% and 9.7% of patients had an adverse event (AE) or serious AE, respectively. The rates and type of AEs were similar between the dose groups. CONCLUSION: Clinical and radiographic benefits from ustekinumab treatment were maintained through week 100 in the PSUMMIT 1 study. No unexpected safety events were observed; the safety profile of ustekinumab in this population was similar to that previously observed in psoriasis patients treated with ustekinumab.
Assuntos
Artrite Psoriásica/tratamento farmacológico , Articulações/efeitos dos fármacos , Ustekinumab/uso terapêutico , Artrite Psoriásica/sangue , Artrite Psoriásica/diagnóstico por imagem , Artrografia , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Estudos Cross-Over , Avaliação da Deficiência , Método Duplo-Cego , Europa (Continente) , Humanos , Mediadores da Inflamação/sangue , América do Norte , Indução de Remissão , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Ustekinumab/efeitos adversos , Ustekinumab/farmacocinéticaRESUMO
The potential therapeutic activity of a human monoclonal antibody to the human interleukin-12 p40 subunit (anti-IL-12p40) has been established both in vitro and in vivo, warranting a first-in-human investigation in psoriasis. This phase I, first-in-human, non-randomized, open-label study evaluated the short-term safety, pharmacokinetics, and clinical response of single, ascending, intravenous (IV) doses of anti-IL-12p40 in subjects with moderate-to-severe psoriasis vulgaris. Eighteen subjects with at least 3% body surface area involvement were enrolled in four dose groups (0.1, 0.3, 1.0, and 5.0 mg per kg). Safety, pharmacokinetics, and clinical response (e.g., Psoriasis Area and Severity Index (PASI)) were monitored at baseline and at specific time points over a 16-wk follow-up period. Anti-IL-12p40 was generally well tolerated. No related serious adverse events or infusion reactions were reported, and most adverse events were mild. IV anti-IL-12p40 yielded linear pharmacokinetics, with a mean terminal half-life of approximately 24 d. Dose-dependent associations with both the rate and extent of clinical response were observed across the four dose groups. Twelve of 18 subjects (67%) achieved at least a 75% improvement in PASI between 8 and 16 wk after study agent administration. Significant and sustained concentration-dependent improvements in psoriatic lesions were observed in most subjects.
Assuntos
Imunoglobulinas Intravenosas/administração & dosagem , Imunoglobulinas Intravenosas/farmacocinética , Interleucina-12/imunologia , Subunidades Proteicas/imunologia , Psoríase/imunologia , Psoríase/terapia , Adulto , Feminino , Humanos , Imunoglobulinas Intravenosas/efeitos adversos , Subunidade p40 da Interleucina-12 , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do TratamentoAssuntos
Anticorpos Monoclonais Humanizados/imunologia , Anticorpos/sangue , Produtos Biológicos/imunologia , Reação no Local da Injeção/epidemiologia , Psoríase/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos/imunologia , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Produtos Biológicos/administração & dosagem , Produtos Biológicos/efeitos adversos , Feminino , Humanos , Incidência , Reação no Local da Injeção/imunologia , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Psoríase/sangue , Psoríase/diagnóstico , Psoríase/imunologia , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND AND OBJECTIVE: Ustekinumab, a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody against interleukin-12/23p40, has been reported to be significantly efficacious in treating patients with moderate-to-severe plaque psoriasis. Although the efficacy and safety of ustekinumab have been previously studied in Asian patients with psoriasis, the pharmacokinetics of ustekinumab has not been reported for Asian patients. The objective of this analysis was to compare the pharmacokinetics of ustekinumab in Chinese and non-Chinese subjects. SUBJECTS AND METHODS: Two Phase 1, open-label, single-period, inpatient/outpatient studies were conducted to evaluate the pharmacokinetics of ustekinumab following a single subcutaneous (SC) injection. In Study 1, non-Chinese healthy male subjects (n = 31) received a single SC injection of ustekinumab 90 mg. In Study 2, Chinese healthy male subjects (n = 24) were randomized (1:1) to receive a single SC injection of ustekinumab 45 mg or 90 mg. Serum ustekinumab concentrations were measured using validated immunoassays. The pharmacokinetic parameters were calculated using non-compartmental analyses. After data collection, a linear mixed model approach was used to compare the log-transformed maximum observed serum concentration (Cmax) and area under the serum concentration-time curves (AUCs) generated from the 90-mg dose groups in the two studies. The ratios of the geometric means of the Cmax and AUCs in Chinese subjects (Test) to those in non-Chinese subjects (Reference) along with the 90 % confidence intervals (CIs) were calculated. RESULTS: The mean body weight was 80.3 kg in non-Chinese (Caucasian: 77.4 %; black: 12.9 %; Asian: 0.0 %; other: 9.7 %) and 65.7 kg in Chinese subjects, with an overall mean of 74 kg. Across studies and dose groups, the median time corresponding to the Cmax (tmax) was 4.0-8.5 days, the mean terminal half-life (t½) was approximately 3 weeks, and the mean apparent volume of distribution based on the terminal phase (Vz/F) was 80.3-97.3 mL/kg. In the 90-mg groups, mean exposure parameters of ustekinumab were 1.1- to 1.3-fold higher in Chinese versus non-Chinese subjects. However, exposure parameters were not significantly different between the two study populations when individual parameters were adjusted to a subject weighing 74 kg: the 90 % CIs of the geometric mean ratios (Chinese versus non-Chinese) for weight-adjusted Cmax, AUC from time zero to time of last measurable concentration (AUClast), and AUC from time zero to infinity (AUC∞) were (0.76-1.09), (0.85-1.16) and (0.88-1.22), respectively. Ustekinumab was generally well tolerated, with no unexpected adverse events; one subject (non-Chinese) developed anti-drug antibodies to ustekinumab. CONCLUSION: The pharmacokinetics of ustekinumab were comparable between Chinese and non-Chinese healthy male subjects when exposure parameters were adjusted by subject body weight. CLINICAL TRIAL REGISTRATION: Study 1, conducted with non-Chinese subjects (March-July 2006), was completed before the 7th revision of the Declaration of Helsinki and was therefore exempt from registration under the existing guidelines. The clinical trial registration number for Study 2, conducted with Chinese subjects (October 2009-June 2010), is NCT01081704.