RESUMO
Poor aqueous solubility, chemical instability, and indiscriminate cytotoxicity have limited clinical development of camptothecin (CPT) as potent anticancer therapeutic. This research aimed at fabricating thermoresponsive nanocomposites that enhance solubility and stability of CPT in aqueous milieu and enable stimulus-induced drug release using magnetic hyperthermia. 1,2-Dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and l-α-dipalmitoylphosphatidyl glycerol (DPPG) (1:1, mol/mol) were immobilized on the surface of superparamagnetic Fe3O4 nanoparticles (SPIONs) via high affinity avidin-biotin interactions. Heating behavior was assessed using the MFG-1000 magnetic field generator. Encapsulation efficiency and drug release were quantified by fluorescence spectroscopy. Anticancer efficacy of medicated nanoparticles was measured in vitro using Jurkat cells. The results revealed that drug incorporation did not significantly alter particle size, zeta potential, magnetization, and heating properties of lipid-coated SPIONs. Drug loading efficiency was 93.2⯱â¯5.1%. Drug release from medicated nanoparticles was significantly faster at temperatures above the lipid transition temperature, reaching 37.8⯱â¯2.6% of incorporated payload after 12â¯min under therapeutically relevant hyperthermia (i.e., 42⯰C). Medicated SPIONs induced greater cytotoxicity than CPT in solution suggesting synergistic activity of magnetically-induced hyperthermia and drug-induced apoptosis. These results underline the opportunity for thermoresponsive phospholipid-coated SPIONs to enable clinical development of highly lipophilic and chemically unstable drugs such as CPT for stimulus-induced cancer treatment.
Assuntos
Hipertermia Induzida , Nanopartículas de Magnetita/administração & dosagem , 1,2-Dipalmitoilfosfatidilcolina/administração & dosagem , 1,2-Dipalmitoilfosfatidilcolina/análogos & derivados , 1,2-Dipalmitoilfosfatidilcolina/química , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Humanos , Células Jurkat , Nanopartículas de Magnetita/química , Neoplasias/terapia , Fosfatidilgliceróis/administração & dosagem , Fosfatidilgliceróis/químicaRESUMO
BACKGROUND: Surfactant replacement therapy (SRT) has been demonstrated to be both safe and highly effective in the treatment of preterm infants with respiratory distress syndrome (RDS). However, administration of the various available suspensions has required endotracheal intubation and its inherent risks. Delivery of aerosolized SRT would be a laudable goal. OBJECTIVE: To review the chemistry, pharmacodynamics, clinical efficacy and safety of aerosolized lucinactant for the prevention/treatment of RDS in the preterm infant. METHODS: Laboratory and clinical experience with aerosolized lucinactant are reviewed. RESULTS/CONCLUSIONS: Laboratory studies confirm the ability of lucinactant to withstand the aerosolization process and to maintain its biological activity. A small clinical pilot trial demonstrated safety and feasibility and provided a signal to suggest proof of concept and the justification for a larger Phase III trial.
Assuntos
Álcoois Graxos/administração & dosagem , Álcoois Graxos/uso terapêutico , Fosfatidilgliceróis/administração & dosagem , Fosfatidilgliceróis/uso terapêutico , Proteínas/administração & dosagem , Proteínas/uso terapêutico , Surfactantes Pulmonares/administração & dosagem , Surfactantes Pulmonares/uso terapêutico , Síndrome do Desconforto Respiratório do Recém-Nascido/tratamento farmacológico , Administração por Inalação , Aerossóis , Pressão Positiva Contínua nas Vias Aéreas , Combinação de Medicamentos , Humanos , Recém-Nascido , Intubação IntratraquealRESUMO
In patients with hematologic malignancy, invasive aspergillosis continues to be associated with high mortality even when treated with conventional antifungal therapy. To investigate novel antifungal agents, we compared 53 patients who received posaconazole salvage therapy to 52 contemporary control patients who received high-dose lipid formulation of amphotericin B (HD-LPD/AMB at > or = 7.5 mg kg(-1) per day) and 38 other control patients who received caspofungin plus HD-LPD/AMB. Patients in the three groups had similar. The overall response rate to salvage therapy was 40% for posaconazole, 8% for HD-LPD/AMB (P < or = 0.001) and 11% for combination therapy (P < 0.002). Aspergillosis contributed to the death of 40% of posaconazole group, 65% of the HD-LPD/AMB group and 68% of the combination group (P < or = 0.008). By multivariate analysis, posaconazole therapy independently improved response (9.5; 95% confidence interval, 2.8-32.5; P < 0.001). HD-LPD/AMB alone or in combination was associated with a significantly higher rate of nephrotoxicity (P < or = 0.02) and hepatotoxicity (P < 0.03). In conclusion, posaconazole salvage therapy demonstrated greater efficacy and safety than HD-LPD/AMB alone or in combination with caspofungin in the salvage therapy of invasive aspergillosis in hematologic malignancy.
Assuntos
Antifúngicos/uso terapêutico , Aspergilose/tratamento farmacológico , Fungemia/tratamento farmacológico , Neoplasias Hematológicas/complicações , Terapia de Salvação , Triazóis/uso terapêutico , Adulto , Anfotericina B/administração & dosagem , Anfotericina B/uso terapêutico , Antifúngicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Aspergilose/etiologia , Caspofungina , Terapia Combinada , Combinação de Medicamentos , Quimioterapia Combinada , Equinocandinas/administração & dosagem , Equinocandinas/uso terapêutico , Feminino , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/cirurgia , Transplante de Células-Tronco Hematopoéticas , Humanos , Itraconazol/administração & dosagem , Itraconazol/uso terapêutico , Lipopeptídeos , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Neutropenia/complicações , Fosfatidilcolinas/administração & dosagem , Fosfatidilcolinas/uso terapêutico , Fosfatidilgliceróis/administração & dosagem , Fosfatidilgliceróis/uso terapêutico , Pirimidinas/administração & dosagem , Pirimidinas/uso terapêutico , Resultado do Tratamento , Triazóis/administração & dosagem , VoriconazolRESUMO
Nebulized liposomal amphotericin B (20-15 mg twice daily by nebulizer) was combined with high dose intravenous liposomal amphotericin B (10 mg/kg/day) and high dose caspofungin (100 mg/m(2)) for the treatment of severe, recurrent pulmonary aspergillosis following allogeneic hematopoietic stem cell transplantation from alternative donor in a patient with mitochondrial disease (Pearson's syndrome). This combined treatment was administered for 8 days. Nebulized liposomal amphotericin B was well tolerated. Since severe transplant complications developed, nebulized administration was withdrawn and intravenous doses of liposomal amphotericin B and caspofungin were tapered to usual schedules. Pulmonary aspergillosis responded well to 45 days of combined intravenous antifungal therapies which were maintained for 2 years with secondary prophylaxis, because of persistent immunosuppressive treatment.
Assuntos
Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Aspergilose/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Pneumopatias Fúngicas/tratamento farmacológico , Doenças Mitocondriais/terapia , Fosfatidilcolinas/uso terapêutico , Fosfatidilgliceróis/uso terapêutico , Administração por Inalação , Anfotericina B/administração & dosagem , Antifúngicos/administração & dosagem , Caspofungina , Combinação de Medicamentos , Quimioterapia Combinada , Equinocandinas , Feminino , Humanos , Injeções Intravenosas , Lipopeptídeos , Peptídeos Cíclicos/uso terapêutico , Fosfatidilcolinas/administração & dosagem , Fosfatidilgliceróis/administração & dosagem , Síndrome , Transplante HomólogoRESUMO
BACKGROUND: Patients with fungal infections who are treated with amphotericin B lipid complex (ABLC) often receive dosages less than that recommended in the product information (5 mg/kg.d). This occurs despite the described safety and increased efficacy in select patients treated with higher ABLC dosages. OBJECTIVE: The purpose of this study was to compare the renal effects of high-dosage/long-duration (HDos/LDur) ABLC therapy (>5 mg/kg.d for >12 days) with those of low-dosage/short-duration (LDos/SDur) ABLC therapy (
Assuntos
Anfotericina B/administração & dosagem , Antifúngicos/administração & dosagem , Creatinina/metabolismo , Taxa de Filtração Glomerular , Micoses/tratamento farmacológico , Fosfatidilcolinas/administração & dosagem , Fosfatidilgliceróis/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Aminoglicosídeos/uso terapêutico , Antibacterianos/uso terapêutico , Inibidores de Calcineurina , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Esquema de Medicação , Combinação de Medicamentos , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sistema de Registros , Estudos Retrospectivos , Vancomicina/uso terapêuticoRESUMO
Children with acute lymphoblastic leukemia (ALL) are at risk for serious electrolyte abnormalities. The authors report their experience in managing a child with ALL who developed severe hyperphosphatemia as a consequence of a large exogenous load of phosphorus from high-dose liposomal amphotericin B. Health care providers need to recognize this potentially life-threatening complication of liposomal amphotericin B, since early detection and intervention can prevent significant morbidity.
Assuntos
Anfotericina B/efeitos adversos , Antifúngicos/efeitos adversos , Aspergilose/tratamento farmacológico , Candidíase/tratamento farmacológico , Celulite (Flegmão)/tratamento farmacológico , Lipossomos/efeitos adversos , Mucormicose/tratamento farmacológico , Doenças Orbitárias/tratamento farmacológico , Fosfatos/sangue , Fosfatidilcolinas/efeitos adversos , Fosfatidilgliceróis/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Sinusite/tratamento farmacológico , Anfotericina B/administração & dosagem , Antifúngicos/administração & dosagem , Aspergilose/complicações , Carbonato de Cálcio/uso terapêutico , Candidíase/complicações , Celulite (Flegmão)/microbiologia , Criança , Portadores de Fármacos/efeitos adversos , Feminino , Cefaleia/etiologia , Humanos , Hiperparatireoidismo Secundário/etiologia , Hospedeiro Imunocomprometido , Itraconazol/uso terapêutico , Lipossomos/química , Mucormicose/complicações , Doenças Orbitárias/microbiologia , Hormônio Paratireóideo/sangue , Fosfatidilcolinas/administração & dosagem , Fosfatidilgliceróis/administração & dosagem , Recidiva , Convulsões/etiologia , Sinusite/microbiologia , Vitamina D/sangueRESUMO
We compared four doses of amphotericin B lipid complex (ABLC) with three doses of fluconazole in temporarily neutropenic mice in a murine model of disseminated candidiasis due to four different isolates of Candida tropicalis. The mice were infected with a 90% lethal dose of four strains of C. tropicalis for which the fluconazole MICs ranged from 1 to >125 mg/liter 3 days after receiving 200 mg of cyclophosphamide/kg of body weight. Treatment was started 18 h after infection and lasted for 7 days. ABLC (1, 2, 5, and 10 mg/kg) was administered once a day intravenously, fluconazole was administered by oral gavage once daily (25 and 50 mg/kg/day) or twice daily (125 mg/kg). MICs determined in five different ways with 24- and 48-h endpoints were also compared. The overall survival rates were controls, 14%; fluconazole, 64%; and ABLC, 82%. Treatment with ABLC at 2 to 10 mg/kg increased survival compared to controls (P = <0.0001) and was also superior to fluconazole at 25 and 50 mg/kg (P = 0.006). In the fluconazole-resistant C. tropicalis model (MIC, 128 microg/ml), ABLC at 2 to 10 mg/kg was superior to fluconazole at 250 mg/kg and ABLC at 10 mg/kg was superior to all fluconazole doses (P = <0.05). Fluconazole at 250 mg/kg daily was superior to both 25 and 50 mg/kg at reducing mortality with most isolates. ABLC was superior to fluconazole (P = <0.01), and fluconazole at 250 mg/kg was superior to fluconazole at both 25 and 50 mg/kg (P = 0.02) in all models at reducing C. tropicalis counts in the kidneys. Neither drug consistently sterilized the brain or kidneys. A 48-h endpoint reading with the NCCLS susceptibility testing microtiter variation overestimates resistance to fluconazole. ABLC is an effective treatment for fluconazole-resistant C. tropicalis at all doses tested.
Assuntos
Anfotericina B/uso terapêutico , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Candida/efeitos dos fármacos , Candidíase/tratamento farmacológico , Fluconazol/farmacologia , Hospedeiro Imunocomprometido/imunologia , Fosfatidilcolinas/uso terapêutico , Fosfatidilgliceróis/uso terapêutico , Anfotericina B/administração & dosagem , Animais , Antifúngicos/administração & dosagem , Antifúngicos/sangue , Candidíase/microbiologia , Candidíase/mortalidade , Contagem de Colônia Microbiana , Combinação de Medicamentos , Resistência Microbiana a Medicamentos , Fluconazol/sangue , Fluconazol/uso terapêutico , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Fosfatidilcolinas/administração & dosagem , Fosfatidilgliceróis/administração & dosagemRESUMO
This paper presents a sequence of tests for experimental evaluation of potential substitutes for pulmonary surfactant. Differential thermal analysis and the pulsating bubble technique were applied to identify an emulsified mixture of synthetic lipids with properties similar to those of natural surfactant. Instilled into the airways of premature newborn rabbits, this emulsion improved pulmonary pressure-volume characteristics and enhanced lung-thorax compliance during artificial ventilation. However, the in vivo effect was inferior to that of natural surfactant, especially as the emulsion failed to prevent the development of bronchiolar epithelial lesions.