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Cytotoxic drug safety

Albert Nguessan Ngo, Danielle Thomas, James Murowchick, Navid J Ayon, Archana Jaiswal, Bi-Botti Celestin Youan
It is hypothesized that a novel crystalline solid dispersion (CSD) of docetaxel (C-DXT) can be engineered by dispersing native docetaxel (DXT, a class II drug) in sodium acetate crystal (SA). DXT is dissolved in glacial acetic/SA solution and freeze-dried. The C-DXT is characterized by differential scanning calorimetry (DSC), powder X-ray analysis (PXRD), LC-MS/MS, scanning electron microscopy (SEM), transmission electron microscopy (TEM), Quartz crystal microbalance with dissipation monitoring (QCM-D) and dynamic light scattering (DLS)...
April 21, 2018: International Journal of Pharmaceutics
Shengyu Zhang, Yanjun Liu, Ye Gan, Nanqing Qiu, Yueqing Gu, Hongyan Zhu
The key for better anti-tumor efficacy is to improve the specificity of anti-tumor drugs for tumor cells and diminish their cytotoxicity to normal tissues. Targeted nanoparticles as anti-tumor drug delivery system can resolve this problem. In this study, we prepared folate and TAT (arginine-rich cell penetrating peptide) modified N-PEG-N'-octyl-chitosan to form the folate/TAT-PEG-OC micelles. Then the molecular structure, morphology, size distribution and bio-safety of the micelles were characterized. In order to investigate the drug loading capacity of folate/TAT-PEG-OC micelles, doxorubicin (DOX) was used as model drug to prepare DOX-loaded chitosan micelles...
April 24, 2018: Pharmaceutical Development and Technology
Tais Susane Pereira, Juliane Rocha de Sant'anna, Janicelle Fernandes Morais, Joana Paula Rocha de Sant'anna Yajima, Paulo Cezar de Freitas Mathias, Claudinéia Conationi da Silva Franco, Marialba Avezum Alves de Castro-Prado
Bendamustine, an anticancer drug with alkylating properties, is widely used to treat hematological malignancies. Since the nitrogen mustard family alkylators induce DNA damages and have been associated with an elevated risk of second malignancy, current study evaluates the cytotoxic, mutagenic, and recombinogenic effects of bendamustine by using, respectively the mitotic index assay, the in vitro mammalian cell micronucleus test (Mnvit) and the chromosome aberration (CA) test in human peripheral lymphocytes, and the in vivo homozygotization assay in Aspergillus nidulans, which detects the loss of heterozygosity (LOH) due to somatic recombination...
April 23, 2018: Drug and Chemical Toxicology
Kanika Thakur, Gajanand Sharma, Bhupinder Singh, Sanjay Chhibber, A B Patil, Om Prakash Katare
The current research study intends to explore the combined potential of lipid nanoparticles and chitosan as an optimum therapy for the management of wound infections. Fusidic acid (FA), a steroidal antibiotic employed for treatment of primary and secondary topical infections was encapsulated within the nanoengineered lipid-polymer hybrid nanoparticles (FA-LPHNs). A number of variables like lipid/polymer ratio, lipid, surfactant and chitosan concentration, stirring speed were optimized to get the desired particle size and % entrapment efficiency...
April 19, 2018: International Journal of Biological Macromolecules
Vincenzo De Leo, Silvia Ruscigno, Adriana Trapani, Sante Di Gioia, Francesco Milano, Delia Mandracchia, Roberto Comparelli, Stefano Castellani, Angela Agostiano, Giuseppe Trapani, Lucia Catucci, Massimo Conese
The aim of the present investigation was to evaluate the influence of liposome formulation on the ability of vesicles to penetrate a pathological mucus model obtained from COPD affected patients in order to assess the potential of such vesicles for the treatment of chronic respiratory diseases by inhalation. Therefore, Small Unilamellar Liposomes (PLAIN-LIPOSOMEs), Pluronic® F127-surface modified liposomes (PF-LIPOSOMEs) and PEG 2000PE-surface modified liposomes (PEG-LIPOSOMEs) were prepared using the micelle-to-vesicle transition (MVT) method and beclomethasone dipropionate (BDP) as model drug...
April 17, 2018: International Journal of Pharmaceutics
Pedro Fong, Cheng N Ao, Kai I Tou, Ka M Huang, Chi C Cheong, Li R Meng
The aim of this study was to investigate the inhibition effects of cordycepin and its derivatives on endometrial cancercell growth. Cytotoxicity MTT assays, clonogenic assays and flow cytometry were used to observe the effects on apoptosis and regulation of the cell cycle of Ishikawa cells under various concentrations of cordycepin, cisplatin and combinations of the two. Validated in silico docking simulations were performed on 31 cordycepin derivatives against adenosine deaminase (ADA) to predict their binding affinities and hence their potential tendency to be metabolized by ADA...
April 19, 2018: Oncology Research
Peter Herbener, Kurt Schönfeld, Martin König, Matthias Germer, Jude M Przyborski, Katrin Bernöster, Jörg Schüttrumpf
An increasing number of monoclonal antibodies and derivatives such as antibody-drug conjugates (ADC) are of the IgG1 and IgG4 isotype with distinct structural and functional properties. In cases where antibody-mediated cytotoxicity is not desired, IgG4 is often used, as its Fc region is relatively poor at inducing antibody-dependent cell-mediated or complement-dependent cytotoxicity. IgG4 ADCs with highly cytotoxic drugs against proliferating target cells but which lack or have diminished antibody effector functions against quiescent cells may have a favorable safety profile compared to IgG1...
2018: PloS One
Maneka Hoonjan, Geetanjali Sachdeva, Sudeshna Chandra, Prashant S Kharkar, Niteshkumar Sahu, Purvi Bhatt
The anticancer properties of arsenic trioxide (As2O3) are accompanied by highly cytotoxic effects on normal cells. This necessitates developing modalities towards the targeted delivery of As2O3. Albumins, on account of their large structure and presence of several interacting groups, are ideal for encapsulating or carrying various drugs. In the present study, human serum albumin (HSA) was chosen as a coating agent to increase the biocompatibility of As2O3. An in situ chemical precipitation method was adopted for the synthesis of HSA-coated As2O3 nanoparticles (HSA-As2O3NPs) that were further characterized by Fourier-transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), ultraviolet-visible (UV-vis) spectroscopy, inductively coupled plasma atomic emission spectrometry (ICP-AES), zeta potential and transmission electron microscopy (TEM)...
April 19, 2018: Nanoscale
Bethany Powell Gray, Linsley Kelly, Douglas P Ahrens, Ashley P Barry, Christina Kratschmer, Matthew Levy, Bruce A Sullenger
Therapies that can eliminate both local and metastatic prostate tumor lesions while sparing normal organ tissue are desperately needed. With the goal of developing an improved drug-targeting strategy, we turned to a new class of targeted anticancer therapeutics: aptamers conjugated to highly toxic chemotherapeutics. Cell selection for aptamers with prostate cancer specificity yielded the E3 aptamer, which internalizes into prostate cancer cells without targeting normal prostate cells. Chemical conjugation of E3 to the drugs monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF) yields a potent cytotoxic agent that efficiently kills prostate cancer cells in vitro but does not affect normal prostate epithelial cells...
April 16, 2018: Proceedings of the National Academy of Sciences of the United States of America
Mona Basha, Mona M AbouSamra, Ghada A Awad, Soheir S Mansy
Wound healing following skin injury is a natural phenomenon that usually lacks quality, rapidity, and aesthetics. Thus, the purpose of this study was to fabricate a new easily applied in situ gel of Cefadroxil (CDX) loaded with chitosan nanoparticles (CDX-CSNPs) that could promote wound healing, capable of inhibiting the possible accompanying bacterial infection. The nanoparticles were prepared by double emulsion technique and the influence of formulation parameters on drug entrapment efficiency (EE%), particle size (PS), polydispersity index (PDI) and zeta potential (ZP) were investigated using a full factorial design...
April 12, 2018: International Journal of Pharmaceutics
Kelly J Norsworthy, Chia-Wen Ko, Jee Eun Lee, Jiang Liu, Christy S John, Donna Przepiorka, Ann T Farrell, Richard Pazdur
On September 2, 2017, the U.S. Food and Drug Administration approved gemtuzumab ozogamicin (GO; Mylotarg; Pfizer, New York City, NY) for treatment of relapsed or refractory (R/R) CD33-positive acute myeloid leukemia (AML) in patients 2 years of age and older. GO is a CD33-directed antibody drug conjugate linked to the cytotoxic antibiotic calicheamicin. It originally received accelerated approval for treatment of older patients with relapsed CD33-positive AML in 2000, but it was withdrawn from the market in 2010 when the confirmatory trial failed to demonstrate clinical benefit among safety concerns, such as a higher rate of induction fatalities on the GO combination arm compared with chemotherapy alone...
April 12, 2018: Oncologist
Ralph Urbatzka, Sara Freitas, Andreia Palmeira, Tiago Almeida, João Moreira, Carlos Azevedo, Carlos Afonso, Marta Correia-da-Silva, Emilia Sousa, Madalena Pinto, Vitor Vasconcelos
Obesity is an increasing epidemic worldwide and novel treatments are urgently needed. Polyphenols are natural compounds derived from plants, which are known in particular for their antioxidant properties. However, some polyphenols were described to possess anti-obesity activities in vitro and in vivo. In this study, we aimed to screen a library of 85 polyphenol derivatives for their lipid reducing activity and toxicity. Compounds were analyzed at 5 μM with the zebrafish Nile red fluorescence fat metabolism assay and for general toxicity in vivo...
March 23, 2018: European Journal of Medicinal Chemistry
Meng Liu, Emily V Dressler
Molecular targeted therapies come often with lower toxicity profiles than traditional cytotoxic treatments, thus shifting drug development paradigm into establishing evidence of biological activity, target modulation, and pharmacodynamics effects of these therapies in early phase trials. Therefore, these trials need to address simultaneous evaluation of safety, proof-of-concept biological marker activity, or changes in continuous tumor size instead of binary response rate. Interim analyses are typically incorporated in the trial due to concerns regarding excessive toxicity and ineffective new treatment...
April 2, 2018: Statistics in Medicine
Samy Babai, Laurent Auclert, Hervé Le-Louët
BACKGROUND AND AIM: The occurrence of drug induced liver injury (DILI) is the most common reason of post-marketing withdrawals. DILI in humans is difficult to predict using in vitro cytotoxicity screening and animal studies. A review of hepatotoxicity data was performed with the aim of identifying relevant factors that could have predicted the occurrence of serious DILI. METHODS: The drugs withdrawn from the market due to hepatotoxicity in Europe and/or in USA either by marketing authorization holders or by Regulatory agencies from 1997 to 2016 were selected...
February 21, 2018: Thérapie
Elisabetta Bigagli, Cristina Luceri, Maria De Angioletti, Konstantin Chegaev, Mario D'Ambrosio, Chiara Riganti, Elena Gazzano, Simona Saponara, Mariangela Longini, Francesca Luceri, Lorenzo Cinci
Chemotherapy for castration-resistant prostate cancer (CRPC) is only temporarily effective due to the onset of chemoresistance. We investigated the efficacy of NO- and H2S-releasing doxorubicins (NitDox and H2SDox) in overcoming drug resistance and evaluated their safety. New and innovative NO- and H2 S-releasing doxorubicins (NitDox and H2 SDox) showed a good intracellular accumulation and high cytotoxic activity in vitro in an androgen-independent and doxorubicin-resistant DU-145 prostate cancer cell line...
April 2, 2018: Investigational New Drugs
Mingzhuo Liu, Huiqing Zhang, Xiangwei Song, Chaochao Wei, Zhenfang Xiong, Fen Yu, Chen Li, Fanrong Ai, Guanghua Guo, Xiaolei Wang
Background: As antibiotics progressively cease to be effective, silver based nanoparticles (SBNs), with broad antibacterial spectrum, might be the last line of defense against malicious bacteria. Unfortunately, there are still no proper SBNs-based strategies for in vivo antibacterial therapies. In this article, new carbon membrane packaged Ag nanoparticles (Ag-C) were synthesized. We assessed the effect of Ag-C with NaCl on size, cytotoxicity, antibacterial properties, metabolism and sepsis models...
2018: International Journal of Nanomedicine
Sylvia Natalie Kłodzińska, Natalia Molchanova, Henrik Franzyk, Paul Robert Hansen, Peter Damborg, Hanne Mørck Nielsen
Infections caused by Pseudomonas aeruginosa are associated with high morbidity and mortality, especially in immunocompromised patients. These bacteria frequently grow within a biofilm matrix, rendering therapy with conventional antibiotics inefficient; a fact that emphasizes the need for new treatment strategies. Antimicrobial peptidomimetics constitute potential alternatives to traditional antimicrobial agents, however, their application remains limited due to the lack of efficient delivery to their target site in vivo and the risk of high systemic toxicity...
March 29, 2018: European Journal of Pharmaceutics and Biopharmaceutics
Annette N Smith, Shawna Klahn, Brenda Phillips, Lisa Parshley, Peter Bennett, Andi Flory, Rosemary Calderon
The purpose of this report is to offer a consensus opinion of ACVIM oncology diplomates and technicians on the safe use of cytotoxic chemotherapeutics in veterinary practice. The focus is on minimizing harm to the personnel exposed to the drugs: veterinary practitioners, veterinary technicians, veterinary staff, and pet owners. The safety of the patient receiving these drugs is also of paramount importance, but is not addressed in this statement. Much of the information presented is based on national recommendations by Occupational Safety and Health Administration, National Institute for Occupational Safety and Health, United States Pharmacopeia, and other published regulations...
March 30, 2018: Journal of Veterinary Internal Medicine
Anna Maria Piras, Ylenia Zambito, Susi Burgalassi, Daniela Monti, Silvia Tampucci, Eleonora Terreni, Angela Fabiano, Federica Balzano, Gloria Uccello-Barretta, Patrizia Chetoni
The ocular bioavailability of lipophilic drugs, such as dexamethasone, depends on both drug water solubility and mucoadhesion/permeation. Cyclodextrins and chitosan are frequently employed to either improve drug solubility or prolong drug contact onto mucosae, respectively. Although the covalent conjugation of cyclodextrin and chitosan brings to mucoadhesive drug complexes, their water solubility is restricted to acidic pHs. This paper describes a straightforward grafting of methyl-β-cyclodextrin (MCD) on quaternary ammonium chitosan (QA-Ch60), mediated by hexamethylene diisocyanate...
March 30, 2018: Journal of Materials Science. Materials in Medicine
Kalishwaralal Kalimuthu, Bat-Chen Lubin, Andrii Bazylevich, Gary Gellerman, Ofer Shpilberg, Galia Luboshits, Michael A Firer
BACKGROUND: Peptide-drug-conjugates (PDCs) are being developed as an effective strategy to specifically deliver cytotoxic drugs to cancer cells. However one of the challenges to their successful application is the relatively low stability of peptides in the blood, liver and kidneys. Since AuNPs seem to have a longer plasma half-life than PDCs, one approach to overcoming this problem would be to conjugate the PDCs to gold nanoparticles (AuNPs), as these have demonstrated favorable physico-chemical and safety properties for drug delivery systems...
March 30, 2018: Journal of Nanobiotechnology
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