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1.
Theranostics ; 11(12): 5700-5712, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33897876

RESUMO

Rationale: Increasing the bioavailable drug level in a tumor is the key to enhance efficacy of chemotherapy. Thermosensitive smart drug delivery systems (SDDS) in combination with local hyperthermia facilitate high local drug levels, thus improving uptake in the tumor. However, inability to rapidly and efficiently absorb the locally released drug results in reduced efficacy, as well as undesired redistribution of the drug away from the tumor to the system. Methods: Based on this paradigm we propose a novel approach in which we replaced doxorubicin (DXR), one of the classic drugs for nanocarrier-based delivery, with idarubicin (IDA), a hydrophobic anthracycline used solely in the free form for treatment hematologic cancers. We established a series of in vitro and in vivo experiments to in depth study the kinetics of SDDS-based delivery, drug release, intratumor biodistribution and subsequent cell uptake. Results: We demonstrate that IDA is taken up over 10 times more rapidly by cancer cells than DXR in vitro. Similar trend is observed in in vivo online imaging and less drug redistribution is shown for IDA, together resulting in 4-times higher whole tumor drug uptake for IDA vs. DXR. Together his yielded an improved intratumoral drug distribution for IDA-SDDS, translating into superior tumor response compared to DXR-SDDS treatment at the same dose. Thus, IDA - a drug that is not used for treatment of solid cancers - shows superior therapeutic index and better outcome when administered in externally triggered SDDS. Conclusions: We show that a shift in selection of chemotherapeutics is urgently needed, away from the classic drugs towards selection based on properties of a chemotherapeutic in context of the nanoparticle and delivery mode, to maximize the therapeutic efficacy.


Assuntos
Idarubicina/farmacologia , Idarubicina/farmacocinética , Neoplasias/tratamento farmacológico , Animais , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/farmacologia , Transporte Biológico/efeitos dos fármacos , Linhagem Celular Tumoral , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Hipertermia Induzida/métodos , Cinética , Camundongos , Nanopartículas/química , Neoplasias/metabolismo , Distribuição Tecidual/efeitos dos fármacos
2.
Int J Nanomedicine ; 14: 543-556, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30666113

RESUMO

PURPOSE: Nanoparticle (NP)-based drug delivery approaches have tremendous potential for enhancing treatment efficacy and decreasing doses of chemotherapeutics. Idarubicin (IDA) is one of the most common chemotherapeutic drugs used in the treatment of acute myeloid leukemia (AML). However, severe side effects and drug resistance markedly limit the application of IDA. METHODS: In this study, we encapsulated IDA in polymeric NPs and validated their antileukemia activity in vitro and in vivo. RESULTS: NPs with an average diameter of 84 nm was assembled from a methoxy poly(ethylene glycol)-b-poly(l-lactide-co-glycolide) (mPEG-PLGA). After loading of IDA, IDA-loaded mPEG-PLGA NPs (IDA/mPEG-PLGA NPs) were formed. The in vitro release data showed that the IDA/mPEG-PLGA NPs have excellent sustained release property. IDA/mPEG-PLGA NPs had exhibited the lower IC50 than pure IDA. Moreover, IDA/mPEG-PLGA NPs in the same concentration substantially induced apoptosis than did pure IDA. Most importantly, IDA/MPEG-PLGA NPs significantly decreased the infiltration of leukemia blasts and improved the overall survival of MLL-AF9-induced murine leukemia compared with free IDA. However, the blank NPs were nontoxic to normal cultured cells in vitro, suggesting that NPs were the safe carrier. CONCLUSION: Our data suggest that IDA/mPEG-PLGA NPs might be a suitable carrier to encapsulate IDA. Low dose of IDA/mPEG-PLGA NPs can be used as a conventional dosage for antileukemia therapy to reduce side effect and improve survival.


Assuntos
Sistemas de Liberação de Medicamentos , Idarubicina/farmacologia , Leucemia/tratamento farmacológico , Nanopartículas/administração & dosagem , Poliésteres/química , Polietilenoglicóis/química , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/farmacologia , Transporte Biológico , Humanos , Idarubicina/administração & dosagem , Idarubicina/farmacocinética , Leucemia/patologia , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/química , Distribuição Tecidual , Células Tumorais Cultivadas
3.
Future Oncol ; 14(26): 2761-2772, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29953255

RESUMO

Transarterial chemoembolization (TACE) combines intra-arterial delivery of a chemotherapeutic agent with selective embolization to obtain a synergistic effect. TACE is recognized as the standard treatment of hepatocellular carcinoma patients at an intermediate stage. If conventional TACE, defined as the injection of an emulsion of a drug with ethiodized oil, still has a role to play, the development of drug-eluting beads has allowed many improvements and optimization of the technique. TANDEM® microspheres are second-generation drug-loadable microspheres. This device raised a special interest due to its tightly calibrated spherical microspheres, with small sizes down to 40 µm available. In this review, we describe the technical characteristics of these microspheres, analyze the scientific literature and hypothesize on the future perspectives.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica/métodos , Portadores de Fármacos/química , Neoplasias Hepáticas/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/patologia , Quimioembolização Terapêutica/instrumentação , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacocinética , Liberação Controlada de Fármacos , Humanos , Idarubicina/administração & dosagem , Idarubicina/farmacocinética , Fígado/diagnóstico por imagem , Fígado/patologia , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/patologia , Microesferas , Tamanho da Partícula , Ensaios Clínicos Controlados Aleatórios como Assunto , Tomografia Computadorizada por Raios X , Resultado do Tratamento
4.
Eur Radiol ; 26(2): 601-9, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26060065

RESUMO

OBJECTIVES: To investigate the relationship between the improved stability of an anticancer drug-lipiodol emulsion and pharmacokinetic (PK) profile for transarterial chemoembolisation (TACE) of hepatocellular carcinoma (HCC). METHODS: The stability of four doxorubicin- or idarubicin-lipiodol emulsions was evaluated over 7 days. PK and clinical data were recorded after TACE with the most stable emulsion in eight unresectable HCC patients, after institutional review board approval. RESULTS: The most stable emulsion was the one that combined idarubicin and lipiodol (1:2 v:v). At 7 days, the percentages of aqueous, persisting emulsion and oily phases were 50-0-50, 33-0-67, 31-39-30, and 10-90-0 for the doxorubicin-lipiodol (1:1 v:v), doxorubicin-lipiodol (1:2 v:v), idarubicin-lipiodol (1:1 v:v), and the idarubicin-lipiodol (1:2 v:v) emulsion, respectively. After TACE, mean idarubicin Cmax and AUC0-24h were 12.5 ± 9.4 ng/mL and 52 ± 16 ng/mL*h. Within 24 h after injection, 40% of the idarubicin was in the liver, either in vessels, tumours, or hepatocytes. During the 2 months after TACE, no clinical grade >3 adverse events occurred. One complete response, five partial responses, one stabilisation, and one progression were observed at 2 months. CONCLUSION: This study showed a promising and favourable PK and safety profile for the idarubicin-lipiodol (1:2 v:v) emulsion for TACE. KEY POINTS: • Transarterial chemoembolisation (TACE) regimens that improve survival in hepatocellular carcinoma are needed. • Improved emulsion stability for TACE resulted in a favourable pharmacokinetic profile. • Preliminary safety and efficacy data for the idarubicin-lipiodol emulsion for TACE were encouraging.


Assuntos
Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica/métodos , Óleo Etiodado/administração & dosagem , Idarubicina/administração & dosagem , Idarubicina/farmacocinética , Neoplasias Hepáticas/terapia , Idoso , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/farmacocinética , Feminino , Humanos , Masculino , Estudos Prospectivos , Resultado do Tratamento
5.
J Vasc Interv Radiol ; 26(2): 262-70, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25311967

RESUMO

PURPOSE: To present in vitro loading and release characteristics of idarubicin with ONCOZENE (CeloNova BioSciences, Inc, San Antonio, Texas) drug-eluting embolic (DEE) agents and in vivo pharmacokinetics data after transarterial chemoembolization with idarubicin-loaded ONCOZENE DEE agents in patients with hepatocellular carcinoma. MATERIALS AND METHODS: Loading efficacy of idarubicin with ONCOZENE DEE agents 100 µm and DC Bead (Biocompatibles UK Ltd, Farnham, United Kingdom) DEE agents 100-300 µm was monitored at 10, 20, and 30 minutes loading time by high-pressure liquid chromatography. A T-apparatus was used to monitor the release of idarubicin from the two types of DEE agents over 12 hours. Clinical and 24-hour pharmacokinetics data were recorded after transarterial chemoembolization with idarubicin-loaded ONCOZENE DEE agents in four patients with unresectable hepatocellular carcinoma. RESULTS: Idarubicin loading in ONCOZENE DEE agents was > 99% at 10 minutes. Time to reach 75% of the release plateau level was 37 minutes ± 6 for DC Bead DEE agents and 170 minutes ± 19 for ONCOZENE DEE agents both loaded with idarubicin 10 mg/mL. After transarterial chemoembolization with idarubicin-loaded ONCOZENE DEE agents, three partial responses and one complete response were observed with only two asymptomatic grade 3 biologic adverse events. Median time to maximum concentration for idarubicin in patients was 10 minutes, and mean maximum concentration was 4.9 µg/L ± 1.7. Mean area under the concentration-time curve from 0-24 hours was equal to 29.5 µg.h/L ± 20.5. CONCLUSIONS: ONCOZENE DEE agents show promising results with very fast loading ability, a favorable in vivo pharmacokinetics profile with a sustained release of idarubicin during the first 24 hours, and encouraging safety and responses. Histopathologic and clinical studies are needed to evaluate idarubicin release around the DEE agents in tumor tissue and to confirm safety and efficacy.


Assuntos
Carcinoma Hepatocelular/sangue , Quimioembolização Terapêutica/métodos , Preparações de Ação Retardada/química , Hemostáticos/administração & dosagem , Idarubicina/farmacocinética , Neoplasias Hepáticas/sangue , Idoso , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/farmacocinética , Carcinoma Hepatocelular/terapia , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Difusão , Hemostáticos/química , Humanos , Idarubicina/administração & dosagem , Neoplasias Hepáticas/terapia , Masculino , Taxa de Depuração Metabólica , Ácidos Polimetacrílicos/administração & dosagem , Ácidos Polimetacrílicos/química , Resultado do Tratamento
6.
Leuk Res ; 37(8): 868-71, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23726414

RESUMO

Daunorubicin has historically been considered the anthracycline of choice at many cancer centers for the treatment of acute myeloid leukemia (AML). Drug shortages have required the substitution of daunorubicin with idarubicin. Randomized studies have shown idarubicin (10-12mg/m(2)) to be comparable or superior to standard dose daunorubicin (45-60mg/m(2)) for achieving complete remission (CR). Whether these results can be extrapolated to dose-intense daunorubicin (90mg/m(2)), recently shown to improve CR rates when compared to standard daunorubicin doses remains uncertain. This observational study was conducted at Northwestern Memorial Hospital (NMH) to compare CR rates. The results suggest idarubicin is equivalent to daunorubicin, and for some subsets of patients, idarubicin may have superior CR rates.


Assuntos
Daunorrubicina/uso terapêutico , Idarubicina/uso terapêutico , Leucemia Mieloide/tratamento farmacológico , Doença Aguda , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Disponibilidade Biológica , Daunorrubicina/administração & dosagem , Daunorrubicina/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Humanos , Idarubicina/administração & dosagem , Idarubicina/farmacocinética , Estimativa de Kaplan-Meier , Leucemia Mieloide/metabolismo , Leucemia Mieloide/patologia , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Indução de Remissão , Adulto Jovem
7.
Blood ; 122(1): 37-43, 2013 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-23704089

RESUMO

Outcomes of patients with acute myeloid leukemia (AML) improve significantly by intensification of induction. To further intensify anthracycline dosage without increasing cardiotoxicity, we compared potentially less cardiotoxic liposomal daunorubicin (L-DNR) to idarubicin at a higher-than-equivalent dose (80 vs 12 mg/m(2) per day for 3 days) during induction. In the multicenter therapy-optimization trial AML-BFM 2004, 521 of 611 pediatric patients (85%) were randomly assigned to L-DNR or idarubicin induction. Five-year results in both treatment arms were similar (overall survival 76% ± 3% [L-DNR] vs 75% ± 3% [idarubicin], Plogrank = .65; event-free survival [EFS] 59% ± 3% vs 53% ± 3%, Plogrank = .25; cumulative incidence of relapse 29% ± 3% vs 31% ± 3%, P(Gray) = .75), as were EFS results for standard (72% ± 5% vs 68% ± 5%, Plogrank = .47) and high-risk (51% ± 4% vs 46% ± 4%, Plogrank = .45) patients. L-DNR resulted in significantly better probability of EFS in patients with t(8;21). Overall, treatment-related mortality was lower with L-DNR than idarubicin (2/257 vs 10/264 patients, P = .04). Grade 3/4 cardiotoxicity was rare after induction (4 L-DNR vs 5 idarubicin). Only 1 L-DNR and 3 idarubicin patients presented with subclinical or mild cardiomyopathy during follow-up. In conclusion, at the given dose, L-DNR has overall antileukemic activity comparable to idarubicin, promises to be more active in subgroups, and causes less treatment-related mortality. This trial was registered at www.clinicaltrials.gov as #NCT00111345.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Daunorrubicina/administração & dosagem , Idarubicina/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Lipossomos/administração & dosagem , Adolescente , Antibióticos Antineoplásicos/efeitos adversos , Antibióticos Antineoplásicos/farmacocinética , Medula Óssea/efeitos dos fármacos , Medula Óssea/patologia , Criança , Pré-Escolar , Daunorrubicina/efeitos adversos , Daunorrubicina/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Cardiopatias/induzido quimicamente , Cardiopatias/mortalidade , Humanos , Idarubicina/efeitos adversos , Idarubicina/farmacocinética , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Lipossomos/farmacocinética , Masculino , Análise Multivariada , Segunda Neoplasia Primária/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Modelos de Riscos Proporcionais , Fatores de Risco , Resultado do Tratamento
8.
Invest New Drugs ; 31(4): 1023-34, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23397500

RESUMO

Survivin is expressed in tumor cells, including acute myeloid leukemia (AML), regulates mitosis, and prevents tumor cell death. The antisense oligonucleotide sodium LY2181308 (LY2181308) inhibits survivin expression and may cause cell cycle arrest and restore apoptosis in AML. In this study, the safety, pharmacokinetics, and pharmacodynamics/efficacy of LY2181308 was examined in AML patients, first in a cohort with monotherapy (n = 8) and then post-amendment in a cohort with the combination of cytarabine and idarubicin treatment (n = 16). LY2181308 was administered with a loading dosage of three consecutive daily infusions of 750 mg followed by weekly intravenous (IV) maintenance doses of 750 mg. Cytarabine 1.5 g/m(2) was administered as a 4-hour IV infusion on Days 3, 4, and 5 of Cycle 1, and idarubicin 12 mg/m(2) was administered as a 30-minute IV infusion on Days 3, 4, and 5 of Cycle 1. Cytarabine and idarubicin were administered on Days 1, 2, and 3 of each subsequent 28-day cycle. Reduction of survivin was evaluated in peripheral blasts and bone marrow. Single-agent LY2181308 was well tolerated and survivin was reduced only in patients with a high survivin expression. In combination with chemotherapy, 4/16 patients had complete responses, 1/16 patients had incomplete responses, and 4/16 patients had cytoreduction. Nine patients died on study: 6 (monotherapy), 3 (combination). LY2181308 alone is well tolerated in patients with AML. In combination with cytarabine and idarubicin, LY2181308 does not appear to cause additional toxicity, and has shown some clinical benefit needing confirmation in future clinical trials.


Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citarabina/uso terapêutico , Idarubicina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Oligonucleotídeos/efeitos adversos , Oligonucleotídeos/farmacocinética , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Citarabina/efeitos adversos , Citarabina/sangue , Citarabina/farmacocinética , Demografia , Feminino , Humanos , Idarubicina/efeitos adversos , Idarubicina/sangue , Idarubicina/farmacocinética , Proteínas Inibidoras de Apoptose/metabolismo , Leucemia Mieloide Aguda/sangue , Masculino , Pessoa de Meia-Idade , Oligonucleotídeos/sangue , Oligonucleotídeos/uso terapêutico , Oligonucleotídeos Antissenso/efeitos adversos , Oligonucleotídeos Antissenso/sangue , Oligonucleotídeos Antissenso/farmacocinética , Oligonucleotídeos Antissenso/uso terapêutico , Recidiva , Survivina , Resultado do Tratamento
9.
J Vet Intern Med ; 26(3): 608-13, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22404399

RESUMO

BACKGROUND: Idarubicin, a PO bioavailable anthracycline antibiotic-class chemotherapeutic, could have substantial convenience advantages over currently available similar class agents in use that require IV delivery. OBJECTIVES: The primary objective of this study was to determine the maximally tolerated dose (MTD), dose-limiting toxicities (DLTs), and basic pharmacokinetic parameters of oral idarubicin exposure in dogs with lymphoma after a single oral dose. A secondary objective was to document preliminary antitumor efficacy in an expanded treatment cohort using the established MTD. ANIMALS: Client-owned dogs with measurable lymphoma. METHODS: Dogs (n = 31) were enrolled in a prospective open label phase I study of oral idarubicin. By means of a 3 + 3 cohort design, dose escalations were made with 3 dogs per dose level, and the MTD was established based on the number of patients experiencing a DLT. Plasma concentrations of idarubicin and idarubicinol were determined by postdose sampling. Assessment of antitumor efficacy focused on evaluation of accessible, measurable lymph nodes and skin lesions by modified RECIST guidelines. RESULTS: The MTD in dogs > 15 kg body weight was 22 mg/m(2) . Adverse hematologic events (neutropenia and thrombocytopenia) were the predominant DLT and generally correlated with higher plasma concentrations of idarubicin and idarubicinol. CONCLUSIONS AND CLINICAL IMPORTANCE: PO administered idarubicin was generally well-tolerated and had preliminary antitumor activity in dogs with lymphoma. Furthermore, the potential clinical advantage of a safe and efficacious oral anthracycline alternative supports further investigations of this agent in repeated-dose, randomized clinical trials.


Assuntos
Antibióticos Antineoplásicos/efeitos adversos , Doenças do Cão/patologia , Idarubicina/efeitos adversos , Linfoma/veterinária , Administração Oral , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/farmacocinética , Estudos de Coortes , Doenças do Cão/tratamento farmacológico , Doenças do Cão/metabolismo , Cães , Feminino , Idarubicina/administração & dosagem , Idarubicina/farmacocinética , Linfoma/tratamento farmacológico , Linfoma/metabolismo , Linfoma/patologia , Masculino , Dose Máxima Tolerável , Estudos Prospectivos
11.
Mol Pharm ; 9(1): 14-28, 2012 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-22047066

RESUMO

As 95% of all prescriptions are for orally administered drugs, the issue of oral absorption is central to the development of pharmaceuticals. Oral absorption is limited by a high molecular weight (>500 Da), a high log P value (>2.0) and low gastrointestinal permeability. We have designed a triple action nanomedicine from a chitosan amphiphile: quaternary ammonium palmitoyl glycol chitosan (GCPQ), which significantly enhances the oral absorption of hydrophobic drugs (e.g., griseofulvin and cyclosporin A) and, to a lesser extent, the absorption of hydrophilic drugs (e.g., ranitidine). The griseofulvin and cyclosporin A C(max) was increased 6- and 5-fold respectively with this new nanomedicine. Hydrophobic drug absorption is facilitated by the nanomedicine: (a) increasing the dissolution rate of hydrophobic molecules, (b) adhering to and penetrating the mucus layer and thus enabling intimate contact between the drug and the gastrointestinal epithelium absorptive cells, and (c) enhancing the transcellular transport of hydrophobic compounds. Although the C(max) of ranitidine was enhanced by 80% with the nanomedicine, there was no appreciable opening of tight junctions by the polymer particles.


Assuntos
Quitosana/análogos & derivados , Ciclosporina/administração & dosagem , Portadores de Fármacos/administração & dosagem , Griseofulvina/administração & dosagem , Absorção Intestinal , Nanopartículas/química , Compostos de Amônio Quaternário/química , Adesividade , Animais , Antiulcerosos/administração & dosagem , Antiulcerosos/sangue , Antiulcerosos/metabolismo , Antiulcerosos/farmacocinética , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/metabolismo , Antibióticos Antineoplásicos/farmacocinética , Antifúngicos/administração & dosagem , Antifúngicos/sangue , Antifúngicos/metabolismo , Antifúngicos/farmacocinética , Células CACO-2 , Quitosana/química , Ciclosporina/sangue , Ciclosporina/metabolismo , Ciclosporina/farmacocinética , Portadores de Fármacos/análise , Portadores de Fármacos/metabolismo , Portadores de Fármacos/farmacocinética , Griseofulvina/sangue , Griseofulvina/metabolismo , Griseofulvina/farmacocinética , Humanos , Interações Hidrofóbicas e Hidrofílicas , Idarubicina/administração & dosagem , Idarubicina/metabolismo , Idarubicina/farmacocinética , Mucosa Intestinal/citologia , Mucosa Intestinal/metabolismo , Intestino Delgado/citologia , Intestino Delgado/metabolismo , Masculino , Nanopartículas/ultraestrutura , Ranitidina/administração & dosagem , Ranitidina/sangue , Ranitidina/metabolismo , Ranitidina/farmacocinética , Ratos , Ratos Wistar
12.
J Control Release ; 158(2): 215-23, 2012 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-22063001

RESUMO

We investigated anticancer therapy with a novel combination of D-penicillamine (D-pen) and Idarubicin (Ida) in a synthetic dual drug conjugate (DDC). D-pen and Ida were covalently linked to poly(α)-L-glutamic acid (PGA) via reducible disulfide and acid-sensitive hydrazone bonds, respectively. The DDCs showed cell uptake and sustained release of the bound drugs in conditions mimicking the intracellular release media (10mM glutathione and pH 5.2). The in-vitro cytotoxicity of DDCs was comparable to unconjugated Ida in several sensitive and resistant cancer cell lines and correlated with the rate of cell uptake. In a single equivalent-dose pharmacokinetic study, DDCs enhanced the drug exposure by 7-fold and prolonged the plasma circulation half-life (t(1/2)) by 5-fold over unconjugated Ida. The therapeutic index of DDCs was 2-3-fold higher than unconjugated drugs. DDCs caused 89% tumor growth inhibition compared to 60% by unconjugated Ida alone and led to significant enhancement in the median survival (17%) of athymic nu/nu mice bearing NCI-H460 tumor xenografts.


Assuntos
Antineoplásicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Idarubicina/administração & dosagem , Penicilamina/administração & dosagem , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Humanos , Idarubicina/química , Idarubicina/farmacocinética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Penicilamina/química , Penicilamina/farmacocinética , Peptídeos , Ácido Poliglutâmico/química , Distribuição Tecidual , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
13.
J Control Release ; 146(1): 68-75, 2010 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-20510316

RESUMO

The purpose of this study was to design a new stable liposomal formulation for the anticancer drug idarubicin. Idarubicin is a relatively hydrophobic member of the anthracycline family. It exhibits pronounced bilayer interactions leading to rapid in vivo drug release from liposomes. This rapid drug leakage is due to the presence of cholesterol and charged lipids in the liposomal bilayer. Therefore, a novel method of remote drug loading was developed to prevent rapid drug release from PEGylated cholesterol-containing liposomes. This method uses EDTA disodium or diammonium salt as an agent to form low solubility complexes between the drug and EDTA molecules inside the liposomes, thus yielding improved drug retention. The efficiency of idarubicin encapsulation is close to 98% at a drug to lipid molar ratio of 1:5. An in vitro long-term storage experiment confirmed the high stability of the liposomes. The in vivo studies also showed the superiority of the new idarubicin formulation over the recently used remote loading methods. The plasma level of idarubicin was much higher when EDTA liposomes were used. The presented results fully demonstrate the superiority of the proposed method of idarubicin encapsulation over existing methods. The method offers the possibility of encapsulating not only all the anthracyclines, but also other weakly amphiphilic bases within the liposomes.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Colesterol/química , Portadores de Fármacos/química , Ácido Edético/química , Idarubicina/administração & dosagem , Animais , Antibióticos Antineoplásicos/sangue , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacocinética , Cromatografia Líquida de Alta Pressão , Microscopia Crioeletrônica , Preparações de Ação Retardada , Composição de Medicamentos , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Humanos , Concentração de Íons de Hidrogênio , Idarubicina/sangue , Idarubicina/química , Idarubicina/farmacocinética , Técnicas In Vitro , Lipossomos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Solubilidade , Propriedades de Superfície
14.
Pharm Res ; 27(7): 1224-36, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20354767

RESUMO

PURPOSE: To determine if solid lipid nanoparticles represent a viable strategy for local delivery of poorly water soluble and unstable chemopreventive compounds to human oral tissues. METHODS: Nanoparticle uptake and compound retention evaluations employed monolayer-cultured human oral squamous cell carcinoma (OSCC) cell lines and normal human oral mucosal explants. Feasibility of nanoparticle delivery was also evaluated with respect to the presence of phase-III efflux transporters in normal oral mucosal tissue and OSCC tissues. RESULTS: Functional uptake assays confirmed significantly greater internalization of nanoparticle-delivered fluorescent probe relative to free-fluorescent probe delivery, while concurrently demonstrating nanoparticle uptake rate differences among the OSCC cell lines and the phagocytic control human monocyte cell line. Mucosal explants exhibited nanoparticle penetration and internalization in the spinous and basal epithelial layers (7/10 specimens), and also exhibited the presence of the phase-III efflux transporters multidrug resistance-associated protein 1 (MRP1) and breast cancer resistance protein (BCRP). CONCLUSIONS: These data confirm nanoparticle internalization by OSCC cells and support the premise that nanoparticle-based delivery provides higher final intracellular levels relative to bolus administration. Furthermore, the penetration and subsequent internalization of nanoparticles within the proliferating basal layer cells demonstrates the feasibility of nanoparticle formulations for local delivery and stabilization of oral chemopreventive compounds.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Compostos de Boro/administração & dosagem , Idarubicina/administração & dosagem , Mucosa Bucal , Nanopartículas/administração & dosagem , Antibióticos Antineoplásicos/farmacocinética , Western Blotting , Compostos de Boro/farmacocinética , Carcinoma de Células Escamosas/prevenção & controle , Células Cultivadas , Sistemas de Liberação de Medicamentos , Corantes Fluorescentes/administração & dosagem , Corantes Fluorescentes/farmacocinética , Humanos , Idarubicina/farmacocinética , Imuno-Histoquímica , Mucosa Bucal/metabolismo , Mucosa Bucal/patologia
15.
Eur J Clin Pharmacol ; 65(12): 1179-86, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19820921

RESUMO

AIMS: To study anthracycline-induced apoptosis in leukemic cells isolated from patients with acute myelogenous leukemia (AML) in vitro and to compare intracellular anthracycline concentrations causing apoptosis in vitro with those obtained in vivo during anthracycline treatment. METHODS: Mononuclear blood cells from AML patients were isolated before (n = 20) and after anthracycline infusion (n = 24). The pre-treated cells were incubated in vitro with daunorubicin (DNR) and/or idarubicin (IDA). Anthracycline concentrations were determined by high-performance liquid chromatography, and apoptosis was detected by propidium iodine staining using a flow cytometer. RESULTS: There was a clear concentration-response relationship between intracellular anthracycline levels and apoptosis albeit with a large interindividual variation. Intracellular levels >1200 muM always led to high apoptosis development (>60%) in vitro. The intracellular concentrations of DNR in vivo (n = 24) were more than tenfold lower than the concentrations needed to induce effective apoptosis in vitro, although a significant relation between in vivo concentrations and clinical remission was found. We also found a significant relation between apoptosis induction in leukemic cells by IDA in vitro and clinical remission. CONCLUSIONS: Our results indicate that intracellular anthracycline levels in vivo are suboptimal and that protocols should be used that increase intracellular anthracycline levels.


Assuntos
Antraciclinas/farmacologia , Antraciclinas/farmacocinética , Apoptose/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antraciclinas/sangue , Daunorrubicina/sangue , Daunorrubicina/farmacocinética , Daunorrubicina/farmacologia , Relação Dose-Resposta a Droga , Feminino , Citometria de Fluxo , Humanos , Idarubicina/sangue , Idarubicina/farmacocinética , Idarubicina/farmacologia , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/patologia , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Células Tumorais Cultivadas , Adulto Jovem
16.
Anticancer Drugs ; 19(7): 729-32, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18594215

RESUMO

Although idarubicin is one of the most important anthracyclines and liposomal formulations seemed less cardiotoxic than free drug formulations, there are no definite data on cardiac uptake of liposomal encapsulated idarubicin. This study has been designed to determine uptake and negative inotropic action of liposomal idarubicin in the single-pass isolated perfused rat heart. Idarubicin-bearing liposomes, composed of 1,2-distearoyl-sn-glicero-phosphocholine, 1,2-distearoyl-sn-glicero-phosphoethanolamine-N-[poly(ethylene glycol)2000], and cholesterol were administered as a 10-min constant infusion of 1 mg followed by a 70-min washout period. Outflow concentration and left ventricular-developed pressure were measured and compared with data of free idarubicin observed previously under the same experimental conditions. Liposomal encapsulation significantly reduced cardiac uptake of idarubicin to about 15% and extensively diminished its negative inotropic action to less than 5% of the values observed for free idarubicin.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Idarubicina/administração & dosagem , Idarubicina/farmacocinética , Miocárdio/metabolismo , Animais , Técnicas In Vitro , Lipossomos , Perfusão , Ratos
17.
Leuk Lymphoma ; 49(4): 809-14, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18398750

RESUMO

Severe myelosuppression is one of the major adverse effects of Idarubicin (IDA). Especially, after two sequential therapy courses, IDA showed a stronger myelosuppression than after the first course. IDA was metabolized in liver by carbonyl reducing enzymes (CRE) to its 13-OH metabolite, idarubicinol(IDAol),which is more active compared with IDA. RLN-B2, a rat liver cell line, precultured in the presence of IDA showed higher CRE activity compared with non-precultured cells. A crude extract of the enzyme obtained from the livers of F344 rats preadministered IDA 7 days before they were sacrificed showed higher enzymatic activity than that from non-preadministered rats. At 4 h after IDA i.v., the production of IDAol was facilitated in the preadministered group compared with the non-preadministered group. In conclusion, CRE was induced by IDA pretreatment in vitro and vivo, resulting in increased IDAol, which could cause self-potentiation of the myelosuppressive and probably antitumor effects of IDA.


Assuntos
Oxirredutases do Álcool/genética , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Idarubicina/farmacocinética , Oxirredutases do Álcool/metabolismo , Animais , Antraciclinas , Linhagem Celular , Idarubicina/metabolismo , Fígado/citologia , Fígado/enzimologia , Farmacocinética , Ratos
18.
Cancer Chemother Pharmacol ; 59(6): 771-9, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17256136

RESUMO

OBJECTIVE: High dose (HD) Ara-C combined with a single HD idarubicin dose (IDA) is an efficient and safe salvage regimen for patients with refractory or relapsed acute lymphoblastic leukemia as indicated by phase II studies. No data are available on the pharmacokinetics of IDA after a rapid HD intravenous infusion. An open phase II pharmacokinetic and clinical study was performed to evaluate antileukemic efficacy, IDA pharmacokinetics and to investigate the presence of IDA and its reduced metabolite idarubicinol (IDAol) in cerebrospinal fluid (CSF) of patients treated with HD-IDA. PATIENTS AND METHODS: Twenty-five patients with refractory or relapsed acute lymphoblastic leukemia received Ara-C 3 g/m2 from days 1-5, idarubicin (HD-IDA) 40 mg/m2 as rapid intravenous (i.v.) infusion on day 3 and subcutaneous G-CSF 5 microg/kg from day 7 until PMN recovery. Pharmacokinetics of IDA was evaluated after HD idarubicin administration in nine of these patients. CSF samples were collected in 15 patients at different times. IDA and IDAol concentrations were quantified by a validated HPLC assay described in detail elsewhere. RESULTS: Eleven patients (44%, 95% CI: 23-65%) achieved complete remission with median disease free survival for 6 months. After administration of HD-IDA i.v. bolus of 40 mg/m2, plasma level profiles of unchanged drug and IDAol were similar to those previously described after standard dose and measured with the same analytical method. The mean terminal half-life measured for IDA in this group of patients (14.9 h) was not significantly different from the mean value observed after standard dose (13.9 h, P=0.72). IDAol t1/2 was also similar after HD-IDA (46.2 h) and standard dose (39.4 h, P=0.79). Pharmacokinetic data reveal that in our series of patients IDA and IDAol clearances are significantly higher than those observed in patients treated with 12 mg/m2 of IDA but, although the administered dose (mg/m2) of the drug is 3.3 times higher, IDA exposure (measured in terms of AUC) is only 2.3 times and IDAol exposition 2.1 times greater. Furthermore, HD infusion resulted in a ratio between the AUC of parent drug and idarubicinol not different from the value observed with the standard-dose. IDA and IDAol were measurable only in 3 of the 15 cerebrospinal fluid samples collected. CONCLUSION: Responses observed in our series are comparable to those reported with other salvage regimens. The IDA exposure lower than expected may explain the safety of the single i.v. administration of 40 mg/m2 of IDA, combined with HD Ara-C, with a degree of myelosuppression equivalent to that reported with this agent administered in standard doses. Our data do not allow us to clearly attribute this behavior to a pharmacokinetic non-linearity since the baseline creatinine clearance, even within normal values, and patient age are significantly different in the two groups. Cerebrospinal fluid penetration was poor, reaching levels not considered as cytotoxic.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citarabina/administração & dosagem , Idarubicina/administração & dosagem , Adolescente , Adulto , Citarabina/farmacocinética , Intervalo Livre de Doença , Feminino , Humanos , Idarubicina/farmacocinética , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Recidiva , Indução de Remissão , Análise de Sobrevida
19.
J Control Release ; 105(1-2): 89-105, 2005 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-15878792

RESUMO

Idarubicin has been successfully encapsulated in cholesterol-free liposomes, however, little is known about how the rate of drug release from circulating liposomes influences therapeutic activity. The studies described herein assess the attributes of a liposome formulation required to significantly increase the plasma levels of idarubicin and further establish whether increases in the circulation longevity of the drug mediate improved antitumor activity. Pharmacokinetic assessments of 6 different 3[H]-labelled liposome formulations were compared to free idarubicin. The highest idarubicin plasma concentrations were observed with DSPC/DSPE-PEG2000 liposomes formulated with 2 mol% DSPE-PEG2000 and 150 mM (iso-osmotic) internal citrate concentration. It was shown that increased levels of PEG-lipid incorporation augmented IDA release and the optimal liposomal formulation needed to be prepared under iso-osmotic conditions. For efficacy studies in a murine leukemia model, groups of 12-14 mice were treated i.v. with saline or equivalent doses (1, 2, 3 mg/kg) of free or liposomal IDA. Liposomal treatment groups exhibited a higher % increase in life span (ILS) as compared to equivalent doses of free drug. Efficacy studies completed in two drug resistant models, P388/ADR and MDA435LCC6/MDR1, demonstrated that neither the free nor liposomal formulation of idarubicin was therapeutically active. Encapsulation of IDA in liposomes increased antitumor activity in an IDA sensitive model, however, the significant increase in plasma drug levels was not sufficient to overcome multidrug resistance.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/uso terapêutico , Idarubicina/administração & dosagem , Idarubicina/uso terapêutico , Animais , Antibióticos Antineoplásicos/farmacocinética , Área Sob a Curva , Soluções Tampão , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Colesterol , Portadores de Fármacos , Composição de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Humanos , Concentração de Íons de Hidrogênio , Idarubicina/farmacocinética , Lipossomos , Camundongos , Transplante de Neoplasias , Neoplasias Experimentais/tratamento farmacológico , Veículos Farmacêuticos , Polietilenoglicóis , Sais de Tetrazólio , Tiazóis , Transplante Heterólogo
20.
Leuk Res ; 29(3): 263-71, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15661261

RESUMO

This study was conducted to define the maximum tolerated dose (MTD), dose limiting toxicity (DLT), and pharmacokinetics of idarubicin when administered with and without the P-glycoprotein inhibitor PSC-833 in combination with cytarabine, and etoposide. Fifteen patients with relapsed and refractory acute leukemia were enrolled and received cytarabine as a 7-day continuous infusion, with etoposide and idarubicin administered for any three consecutive days during the cytarabine infusion. Two hours prior to the second dose of idarubicin, PSC-833 administration was initiated. The pharmacokinetics of idarubicin alone and with PSC-833 was assessed at three idarubicin dose levels (6, 8 and 10 mg/m(2)). The MTD of idarubicin in this combination was 8 mg/(m(2) day) with a DLT of oral mucositis. The complete remission rate (on an intent-to-treat basis) for this regimen was 33%, with a median duration of 6 months. The clearance of idarubicin was 140 +/- 200 and 181 +/- 94.3 l/h for idarubicin alone and with PSC-833, respectively. The volume of distribution of the central compartment was 423 +/- 443 and 337 +/- 394 l for idarubicin alone and in combination with PSC-833, respectively. This combination including PSC-833 was well tolerated. Although a pharmacokinetic interaction might have been expected, PSC-833 did not significantly alter the disposition of idarubicin.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Ciclosporinas/administração & dosagem , Ciclosporinas/farmacocinética , Citarabina/administração & dosagem , Citarabina/farmacocinética , Interações Medicamentosas , Resistencia a Medicamentos Antineoplásicos , Etoposídeo/administração & dosagem , Etoposídeo/farmacocinética , Feminino , Humanos , Idarubicina/administração & dosagem , Idarubicina/farmacocinética , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Resultado do Tratamento
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