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Adverse drug reaction profile of nanoparticle versus conventional formulation of paclitaxel: An observational study
Brahmachari Ballari,Hazra Avijit,Majumdar Anup
Indian Journal of Pharmacology , 2011,
Abstract: Objectives : Conventional polyethoxylated castor oil (PCO)-based paclitaxel is associated with major adverse drug reactions (ADRs). Nanoxel, a nanoparticle-based formulation, may improve its tolerability by removing the need for PCO vehicle, and also permit its use in a higher dose. We conducted intensive monitoring of the ADR profile of Nanoxel in comparison with conventional paclitaxel in a public tertiary care set-up. Materials and Methods : ADR data were collected from 10 patients receiving Nanoxel and 10 age-matched controls receiving conventional paclitaxel in this longitudinal observational study, conducted in a medical oncology ward over 18 months. Severity was graded as per US National Cancer Institute Common Terminology Criteria for Adverse Events. Results : The groups had comparable demography at baseline. The median disease duration and per cycle median dose of paclitaxel were greater in the Nanoxel arm. Total 119 ADRs were noted with Nanoxel and 123 with conventional paclitaxel. Of these, 25 (21.0%, 95% CI 13.69-28.33%) in the Nanoxel and 20 (16.2%, 95% CI 9.74-22.78%) in paclitaxel group were of grade 3/4 severity. Common events included myalgia, nausea, anemia, paresthesia, alopecia, diarrhea, and vomiting with Nanoxel, and paresthesia, anemia, myalgia, anorexia, alopecia, vomiting, diarrhea, stomatitis, and nausea with paclitaxel. Of the less common events (<5%), grade 2 or 3 arthralgia was seen exclusively with Nanoxel while motor neuropathy with muscular weakness was more frequent and severe with conventional paclitaxel. Hypersensitivity reactions were not encountered in either arm, although no antiallergy premedication was employed for Nanoxel. Conclusions : Despite its ADR profile being statistically comparable to conventional paclitaxel, this observational study suggests that Nanoxel tolerability could be better, considering that a significantly higher dose was employed. This hypothesis needs confirmation through an interventional study.
Enabling Anticancer Therapeutics by Nanoparticle Carriers: The Delivery of Paclitaxel  [PDF]
Yongjin Liu,Bin Zhang,Bing Yan
International Journal of Molecular Sciences , 2011, DOI: 10.3390/ijms12074395
Abstract: Anticancer drugs, such as paclitaxel (PTX), are indispensable for the treatment of a variety of malignancies. However, the application of most drugs is greatly limited by the low water solubility, poor permeability, or high efflux from cells. Nanoparticles have been widely investigated to enable drug delivery due to their low toxicity, sustained drug release, molecular targeting, and additional therapeutic and imaging functions. This review takes paclitaxel as an example and compares different nanoparticle-based delivery systems for their effectiveness in cancer chemotherapy.
Nanoparticle Albumin Bound Paclitaxel in the Treatment of Human Cancer: Nanodelivery Reaches Prime-Time?  [PDF]
Iole Cucinotto,Lucia Fiorillo,Simona Gualtieri,Mariamena Arbitrio,Domenico Ciliberto,Nicoletta Staropoli,Anna Grimaldi,Amalia Luce,Pierfrancesco Tassone,Michele Caraglia,Pierosandro Tagliaferri
Journal of Drug Delivery , 2013, DOI: 10.1155/2013/905091
Abstract: Nanoparticle albumin bound paclitaxel (nab-paclitaxel) represents the first nanotechnology-based drug in cancer treatment. We discuss the development of this innovative compound and report the recent changing-practice results in breast and pancreatic cancer. A ground-breaking finding is the demonstration that nab-paclitaxel can not only enhance the activity and reduce the toxicity of chromophore-diluted compound, but also exert activity in diseases considered refractory to taxane-based treatment. This is the first clinical demonstration of major activity of nanotechnologically modified drugs in the treatment of human neoplasms. 1. Introduction Current development of cancer treatment mainly relies on three avenues:(a)the identification of molecular targets for selective blockade of driver pathways in cancer cells or in tumour microenvironment,(b)immunemodulatory approaches which might enhance the antitumor specific immune response,(c)new delivery approaches in order to achieve higher bioavailability of anticancer agents. The topic of the current review is the nanoparticle albumin bound paclitaxel (nab-paclitaxel) development, which has opened a novel scenario in cancer treatment by the enhancement of paclitaxel delivery by the use of nanotechnology. 2. Taxane (First) Revolution of Cancer Therapy Taxanes are an important class of antitumor agents using solvent-based delivery vehicles. Paclitaxel (Bristol-Myers Squibb (New York, NY)) was identified in 1966, as an extract from Taxus brevifolia, obtained in a pure form in 1969 but its structure was published in 1971. Investigators faced several problems due to low concentration and structure complexities for low water solubility [1, 2] (Figure 1). Figure 1: Structure of paclitaxel (5 ,20-epoxy-1,2 ,4,7 ,13 -hex-ahydroxytan-11-en-9-one-4,10-diacetate2-benzoate-13-ester with (2 R.3 S)- N-benzoyl-3-phenyllioserine). In fact, only in 1979 Susan Horwitz discovered that paclitaxel has a unique mechanism of action and interest which was additionally stimulated when impressive activity was demonstrated in NCI tumor screening [3]. Paclitaxel is a diterpenoid pseudoalkaloid with formula C47H51NO14 ( ?Da) whose activity was demonstrated in different preclinical models. For antitumor activity the presence of the entire taxane molecule is required (Figure 2) for the inactivity of the ester and the tetraol formed by a low temperature cleavage of paclitaxel [4]. Figure 2: Taxane nucleus. Although the development of paclitaxel was hampered by limited availability of its primary source and the difficulties inherent to
Superior Antitumor Activity of Nanoparticle Albumin-Bound Paclitaxel in Experimental Gastric Cancer  [PDF]
Changhua Zhang, Niranjan Awasthi, Margaret A. Schwarz, Stefan Hinz, Roderich E. Schwarz
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0058037
Abstract: Gastric cancer is the second common cause of cancer related death worldwide and lacks highly effective treatment for advanced disease. Nab-paclitaxel is a novel microtubule-inhibitory cytotoxic agent that has not been tested in gastric cancer as of yet. In this study, human gastric cancer cell lines AGS, NCI-N87 and SNU16 were studied. Nab-paclitaxel inhibited cell proliferation with an IC50 of 5 nM in SNU16, 23 nM in AGS and 49 nM in NCI-N87 cells after 72-hour treatment, which was lower than that of oxaliplatin (1.05 μM to 1.51 μM) and epirubicin (0.12 μM to 0.25 μM). Nab-paclitaxel treatment increased expression of the mitotic-spindle associated phospho-stathmin irrespective of the baseline total or phosphorylated stathmin level, and induced mitotic cell death as confirmed through increased expression of cleaved-PARP and caspase-3. After a two-week nab-paclitaxel, oxaliplatin or epirubicin treatment, the average in vivo local tumor growth inhibition rate was 77, 17.2 and 21.4 percent, respectively (p = 0.002). Effects of therapy on tumoral proliferative and apoptotic indices corresponded with tumor growth inhibition data, while expression of phospho-stathmin also increased in tissues. There was an increase in median animal survival after nab-paclitaxel treatment (93 days) compared to controls (31 days, p = 0.0007), oxaliplatin (40 days, p = 0.0007) or to docetaxel therapy (81 days, p = 0.0416). The strong antitumor activity of nab-paclitaxel in experimental gastric cancer supports such microtubule-inhibitory strategy for clinical application. Nab-paclitaxel benefits were observed independent from phosphorylated stathmin expression at baseline, putting into question the consideration of nab-paclitaxel use in gastric cancer based on this putative biomarker.
Paclitaxel Loaded Niosome Nanoparticle Formulation Prepared via Reverse Phase Evaporation Method: An in vitro Evaluation  [PDF]
M. Zarei,D. Norouzian,B. Honarvar,M. Mohammadi
Pakistan Journal of Biological Sciences , 2013,
Abstract: Niosoms are nanoparticles used in drug delivery systems. Niosomes are prepared by various methods. In this research niosoms were prepared by reverse phase evaporation and the factors affecting the niosomes formation were studied. Percent of paclitaxel pegylated and non-pegylated prepared with Span 60 were 95 and 92, respectively while for those of pegylated and non-pegylated niosomes with Span 20, 94 and 90, respectively. In addition, the average diameters of pegylated and no-pegylated prepared with Span 60 and 20 were determined to be 191, 214, 244 and 284 nm, respectively. The amount of released drug (48 h) from pegylated and non pegylated formulations in the presence of Spans 60 and 20 were 8, 10, 6, 7%, respectively. Cytotoxicities of paclitaxel niosom polyethyleneglycol, paclitaxel niosome and free paclitaxel on MCF-7 cell line after 48 hours were studied by MTT assay. The results showed the formulation prepared with Span 60 is more effective than that of Span 20 and the IC50 of the former was decreased twice while IC50 of the later decreased 1.5 times.
Construction of paclitaxel-loaded poly (2-hydroxyethyl methacrylate)-g-poly (lactide)- 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine copolymer nanoparticle delivery system and evaluation of its anticancer activity
Ma X, Wang H, Jin S, Wu Y, Liang XJ
International Journal of Nanomedicine , 2012, DOI: http://dx.doi.org/10.2147/IJN.S29371
Abstract: nstruction of paclitaxel-loaded poly (2-hydroxyethyl methacrylate)-g-poly (lactide)- 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine copolymer nanoparticle delivery system and evaluation of its anticancer activity Original Research (3241) Total Article Views Authors: Ma X, Wang H, Jin S, Wu Y, Liang XJ Published Date March 2012 Volume 2012:7 Pages 1313 - 1328 DOI: http://dx.doi.org/10.2147/IJN.S29371 Received: 21 December 2011 Accepted: 24 January 2012 Published: 07 March 2012 Xiaowei Ma*, Huan Wang*, Shubin Jin, Yan Wu, Xing-Jie Liang Laboratory of Nanomedicine and Nanosafety, Division of Nanomedicine and Nanobiology, National Center for Nanoscience and Technology, People’s Republic of China; and CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Chinese Academy of Sciences, Beijing, People’s Republic of China *These authors contributed equally to this work Background: There is an urgent need to develop drug-loaded biocompatible nanoscale packages with improved therapeutic efficacy for effective clinical treatment. To address this need, a novel poly (2-hydroxyethyl methacrylate)-poly (lactide)-1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine [PHEMA-g-(PLA-DPPE)] copolymer was designed and synthesized to enable these nanoparticles to be pH responsive under pathological conditions. Methods: The structural properties and thermal stability of the copolymer was measured and confirmed by Fourier transform infrare d spectroscopy, nuclear magnetic resonance, and thermogravimetric analysis. In order to evaluate its feasibility as a drug carrier, paclitaxel-loaded PHEMA-g-(PLA-DPPE) nanoparticles were prepared using the emulsion-solvent evaporation method. Results: The PHEMA-g-(PLA-DPPE) nanoparticles could be efficiently loaded with paclitaxel and controlled to release the drug gradually and effectively. In vitro release experiments demonstrated that drug release was faster at pH 5.0 than at pH 7.4. The anticancer activity of the PHEMA-g-(PLA-DPPE) nanoparticles was measured in breast cancer MCF-7 cells in vivo and in vitro. In comparison with the free drug, the paclitaxel-loaded PHEMA-g-(PLA-DPPE) nanoparticles could induce more significant tumor regression. Conclusion: This study indicates that PHEMA-g-(PLA-DPPE) nanoparticles are promising carriers for hydrophobic drugs. This system can passively target cancer tissue and release drugs in a controllable manner, as determined by the pH value of the area in which the drug accumulates.
Targeted delivery of albumin bound paclitaxel in the treatment of advanced breast cancer  [cached]
Francesco Di Costanzo,Silvia Gasperoni,Virginia Rotella,Federica Di Costanzo
OncoTargets and Therapy , 2009,
Abstract: Francesco Di Costanzo,1 Silvia Gasperoni,1 Virginia Rotella,1 Federica Di Costanzo21Struttura Complessa Oncologia Medica, Azienda Ospedaliero Universitaria Careggi, Florence; 2Servizio di Oncologia: Ospedale S: Maria della Stella, Orvieto, ItalyAbstract: Taxanes are chemotherapeutic agents with a large spectrum of antitumor activity when used as monotherapy or in combination regimens. Paclitaxel and docetaxel have poor solubility and require a complex solvent system for their commercial formulation, Cremophor EL (CrEL) and Tween 80 respectively. Both these biological surfactants have recently been implicated as contributing not only to the hypersensitivity reactions, but also to the degree of peripheral neurotoxicity and myelosuppression, and may antagonize the cytotoxicity. Nab-paclitaxel, or nanoparticle albumin-bound paclitaxel (ABI-007; Abraxane ), is a novel formulation of paclitaxel that does not employ the CrEL solvent system. Nab-paclitaxel demonstrates greater efficacy and a favorable safety profile compared with standard paclitaxel in patients with advanced disease (breast cancer, non-small cell lung cancer, melanoma, ovarian cancer). Clinical studies in breast cancer have shown that nab-paclitaxel is significantly more effective than standard paclitaxel in terms of overall objective response rate (ORR) and time to progression. Nab-paclitaxel in combination with gemcitabine, capecitabine or bevacizumab has been shown to be very active in patients with advanced breast cancer. An economic analysis showed that nab-paclitaxel would be an economically reasonable alternative to docetaxel or standard paclitaxel in metastatic breast cancer. Favorable tumor ORR and manageable toxicities have been reported for nab-paclitaxel as monotherapy or in combination treatment in advanced breast cancer.Keywords: breast cancer, nab-paclitaxel, chemotherapy
Nab-paclitaxel for the treatment of breast cancer: efficacy, safety, and approval
Yamamoto Y, Kawano I, Iwase H
OncoTargets and Therapy , 2011, DOI: http://dx.doi.org/10.2147/OTT.S13836
Abstract: b-paclitaxel for the treatment of breast cancer: efficacy, safety, and approval Review (6101) Total Article Views Authors: Yamamoto Y, Kawano I, Iwase H Published Date July 2011 Volume 2011:4 Pages 123 - 136 DOI: http://dx.doi.org/10.2147/OTT.S13836 Yutaka Yamamoto1, Ichiro Kawano2, Hirotaka Iwase1 1Department of Breast and Endocrine Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; 2Department of Surgery, Asahino General Hospital, Kumamoto, Japan Abstract: Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a novel formulation of paclitaxel that does not require solvents such as polyoxyethylated castor oil and ethanol. Use of these solvents has been associated with toxic response, including hypersensitivity reactions and prolonged sensory neuropathy, as well as a negative impact in relation to the therapeutic index of paclitaxel. nab-paclitaxel displays greater antitumor activity and less toxicity than solvent-base paclitaxel. In a phase I trial of single nab-paclitaxel, the maximum tolerated dose was 300 mg/m2 with the dose limiting toxicities being sensory neuropathy, stomatitis, and superficial keratopathy. In the metastatic setting, a pivotal comparative randomized phase III study demonstrated that nab-paclitaxel (at 260 mg/m2 over 30 minutes infusion without premedication every 3 weeks) mediated a superior objective response rate and prolonged time to progression compared with solvent-based paclitaxel (at 175 mg/m2 over a 3-hour injection with standard premedication). The nab-paclitaxel-treated group showed a higher incidence of sensory neuropathy than the solvent-based paclitaxel group. However, these adverse side effects rapidly resolved after interruption of treatment and dose reduction. Weekly administration of nab-paclitaxel was also more active and displayed less toxicity compared with 100 mg/m2 docetaxel given triweekly. Nab-paclitaxel has already been approved in 42 countries for the treatment of metastatic breast cancer previously treated with anthracycline, based on confirmation of the efficacy and manageable toxicity in the metastatic setting. This review summarizes the most relevant knowledge on nab-paclitaxel for treating breast cancer in terms of clinical usefulness including efficacy and safety of this new agent.
Nab-paclitaxel for the treatment of breast cancer: efficacy, safety, and approval
Yamamoto Y,Kawano I,Iwase H
OncoTargets and Therapy , 2011,
Abstract: Yutaka Yamamoto1, Ichiro Kawano2, Hirotaka Iwase11Department of Breast and Endocrine Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; 2Department of Surgery, Asahino General Hospital, Kumamoto, JapanAbstract: Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a novel formulation of paclitaxel that does not require solvents such as polyoxyethylated castor oil and ethanol. Use of these solvents has been associated with toxic response, including hypersensitivity reactions and prolonged sensory neuropathy, as well as a negative impact in relation to the therapeutic index of paclitaxel. nab-paclitaxel displays greater antitumor activity and less toxicity than solvent-base paclitaxel. In a phase I trial of single nab-paclitaxel, the maximum tolerated dose was 300 mg/m2 with the dose limiting toxicities being sensory neuropathy, stomatitis, and superficial keratopathy. In the metastatic setting, a pivotal comparative randomized phase III study demonstrated that nab-paclitaxel (at 260 mg/m2 over 30 minutes infusion without premedication every 3 weeks) mediated a superior objective response rate and prolonged time to progression compared with solvent-based paclitaxel (at 175 mg/m2 over a 3-hour injection with standard premedication). The nab-paclitaxel-treated group showed a higher incidence of sensory neuropathy than the solvent-based paclitaxel group. However, these adverse side effects rapidly resolved after interruption of treatment and dose reduction. Weekly administration of nab-paclitaxel was also more active and displayed less toxicity compared with 100 mg/m2 docetaxel given triweekly. Nab-paclitaxel has already been approved in 42 countries for the treatment of metastatic breast cancer previously treated with anthracycline, based on confirmation of the efficacy and manageable toxicity in the metastatic setting. This review summarizes the most relevant knowledge on nab-paclitaxel for treating breast cancer in terms of clinical usefulness including efficacy and safety of this new agent.Keywords: nab-paclitaxel, breast cancer, toxicity profile
An Italian cost-effectiveness analysis of paclitaxel albumin (nab-paclitaxel) versus conventional paclitaxel for metastatic breast cancer patients: the COSTANza study  [cached]
Lazzaro C,Bordonaro R,Cognetti F,Fabi A
ClinicoEconomics and Outcomes Research , 2013,
Abstract: Carlo Lazzaro,1 Roberto Bordonaro,2 Francesco Cognetti,3 Alessandra Fabi,3 Sabino De Placido,4 Grazia Arpino,4 Paolo Marchetti,5 Andrea Botticelli,5 Paolo Pronzato,6 Elisa Martelli7 1Studio di Economia Sanitaria, Milan, Italy; 2Public Hospital Trust Garibaldi, Catania, Italy; 3Istituto dei Tumori Regina Elena, Rome, Italy; 4School of Medicine, Federico II University, Naples, Italy; 5Department of Medical Oncology, School of Medicine, Sapienza University Hospital, Rome, Italy; 6Istituto di Ricovero e Cura a Carattere Scientifico, Azienda Ospedaliera Universitaria San Martino – Isituto Scientifico Tumori, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy; 7Health Economics and Outcomes Research, Celgene Srl, Milan, Italy Purpose: Paclitaxel albumin (nab-paclitaxel) is a nanoparticle albumin-bound paclitaxel formulation aimed at increasing therapeutic index in metastatic breast cancer. When compared to conventional paclitaxel, nab-paclitaxel has a reported longer time to progression, higher response, lower incidence of neutropenia, no need for premedication, shorter time of administration, and in pretreated metastatic breast cancer patients, extended overall survival. This study investigates the cost-effectiveness of nab-paclitaxel versus conventional paclitaxel for pretreated metastatic breast cancer patients in Italy. Materials and methods: A Markov model with progression-free, progressed, and dead states was developed to estimate costs, outcomes, and quality adjusted life years over 5 years from the Italian National Health Service viewpoint. Patients were assumed to receive nab-paclitaxel 260 mg/m2 three times weekly or conventional paclitaxel 175 mg/m2 three times weekly. Data on health care resource consumption was collected from a convenience sample of five Italian centers. Resources were valued at Euro (€) 2011. Published utility weights were applied to health states to estimate the impact of response, disease progression, and adverse events on quality adjusted life years. Three sensitivity analyses tested the robustness of the base case incremental cost-effectiveness ratio (ICER). Results and conclusion: Compared to conventional paclitaxel, nab-paclitaxel gains an extra 0.165 quality adjusted life years (0.265 life years saved) and incurs additional costs of €2506 per patient treated. This translates to an ICER of €15,189 (95% confidence interval: €11,891–€28,415). One-way sensitivity analysis underscores that ICER for nab-paclitaxel remains stable despite varying taxanes cost. Threshold analysis shows that ICER for nab-paclitaxel exceeds
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