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Cytotoxic drug safety

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https://www.readbyqxmd.com/read/28549369/safety-analysis-of-occupational-exposure-of-healthcare-workers-to-residual-contaminations-of-cytotoxic-drugs-using-fmeca-security-approach
#1
Laetitia Minh Mai Le, Delphine Reitter, Sophie He, Franck Té Bonle, Amélie Launois, Diane Martinez, Patrice Prognon, Eric Caudron
Handling cytotoxic drugs is associated with chemical contamination of workplace surfaces. The potential mutagenic, teratogenic and oncogenic properties of those drugs create a risk of occupational exposure for healthcare workers, from reception of starting materials to the preparation and administration of cytotoxic therapies. The Security Failure Mode Effects and Criticality Analysis (FMECA) was used as a proactive method to assess the risks involved in the chemotherapy compounding process. FMECA was carried out by a multidisciplinary team from 2011 to 2016...
May 22, 2017: Science of the Total Environment
https://www.readbyqxmd.com/read/28536971/selection-of-p-glycoprotein-inhibitor-and-formulation-of-combinational-nanoformulation-containing-selected-agent-curcumin-and-dox-for-reversal-of-resistance-in-k562-cells
#2
Tapan K Dash, V Badireenath Konkimalla
PURPOSE: To select P-glycoprotein (P-gp) inhibitor from natural source for reversal of DOX resistance in K562 cells and to develop selected one in to nanoformulation in combination with DOX. METHODS: DOX resistant K562 (K562R) cells were developed and reversal of resistance by P-gp inhibitor was validated by co-treatment with verapamil. The p-gp inhibitors were evaluated for their potential to inhibit P-gp (calcein assay) and to reverse drug resistance (XTT cell viability assay)...
May 23, 2017: Pharmaceutical Research
https://www.readbyqxmd.com/read/28532300/engineered-polymeric-amphiphiles-self-assembling-into-nanostructures-and-acting-as-efficient-gene-and-drug-carriers
#3
Ruby Bansal, Pradeep Kumar
Nonviral gene delivery systems are finding widespread use due to their safety, rapid and economical production, and ease of modification. In this work, series of N-alkyl-substituted linear polyethylenimine (CP) polymers have been synthesized, characterized, and investigated about how degree of substitution (hydrophobic-hydrophilic balance) (i.e. N-alkylation) influenced the transfection efficiency. Mobility shift assay demonstrated efficient binding of plasmid DNA (pDNA). Transfection efficiency and cytotoxicity of CP polymers were assessed in vitro, which revealed that all the formulations exhibited higher transfection activity than linear polyethylenimine (lPEI) and commercial transfection reagents, Lipofectamine and Superfect, with negligible toxicity (MTT assay)...
January 1, 2017: Journal of Biomaterials Applications
https://www.readbyqxmd.com/read/28532051/chitosan-folate-decorated-carbon-nanotubes-for-site-specific-lung-cancer-delivery
#4
Rahul Pratap Singh, Gunjan Sharma, Sonali, Sanjay Singh, Shreekant Bharti, Bajarangprasad L Pandey, Biplob Koch, Madaswamy S Muthu
The aim of this work was to formulate chitosan-folate conjugated multi-walled carbon nanotubes for the lung cancer targeted delivery of docetaxel. The chitosan-folate conjugate was synthesized and the conjugation was confirmed by Fourier transform infrared spectroscopy. The multi-walled carbon nanotubes were characterized for their particle size, polydispersity, zeta potential, surface morphology, drug encapsulation efficiency and in vitro release study. The in vitro cellular uptake, cytotoxicity, and cell cycle analysis of the docetaxel/coumarin-6 loaded multi-walled carbon nanotubes were carried out to compare the effectiveness of the formulations...
August 1, 2017: Materials Science & Engineering. C, Materials for Biological Applications
https://www.readbyqxmd.com/read/28531980/self-assembled-nanomicelles-of-damnacanthal-loaded-amphiphilic-modified-chitosan-preparation-characterization-and-cytotoxicity-study
#5
Pakin Sukamporn, Seung Joon Baek, Wandee Gritsanapan, Suwabun Chirachanchai, Thararat Nualsanit, Pleumchitt Rojanapanthu
Damnacanthal (Dam) is a phytochemical with many pharmacological properties including anticancer activity. However, its hydrophobicity, poor bioavailability and stability limit its application in many biological approaches. In this study, Dam nanomicelles as an emerging platform were developed to overcome limitations. The deoxycholic and poly(ethylene glycol) methyl ether grafted chitosan (DCA-CS-mPEG) was synthesized and characterized by FTIR and (1)H NMR and the degree of substitution (DS) was determined by elemental analysis (EA)...
August 1, 2017: Materials Science & Engineering. C, Materials for Biological Applications
https://www.readbyqxmd.com/read/28531278/cardiovascular-toxic-effects-of-targeted-cancer-therapy
#6
Kazuko Tajiri, Kazutaka Aonuma, Ikuo Sekine
Over the past decade, there has been a major shift in chemotherapy from non-specific cytotoxic drugs to molecular targeted drug therapies. As more molecular targeted therapies are developed, new types of cardiovascular toxicities induced by targeted therapies are a growing problem. Cardiotoxicity induced by the human epidermal growth factor receptor-2 inhibitor trastuzumab manifests as decreased left ventricular ejection fraction. In contrast to anthracycline treatment, most cardiac events occur during trastuzumab treatment, but are reversed quickly when treatment is interrupted and cardiac intervention is established...
May 20, 2017: Japanese Journal of Clinical Oncology
https://www.readbyqxmd.com/read/28529062/quantitative-targeted-bile-acid-profiling-as-new-markers-for-dili-in-a-model-of-methapyrilene-induced-liver-injury-in-rats
#7
Markus Slopianka, Anne Herrmann, Mira Pavkovic, Heidrun Ellinger-Ziegelbauer, Rainer Ernst, Angela Mally, Matthias Keck, Bjoern Riefke
Recently, bile acids (BAs) were reported as promising markers for drug-induced liver injury (DILI). BAs have been suggested to correlate with hepatocellular and hepatobiliary damage; however a clear connection of BA patterns with different types of DILI remains to be established. To investigate if BAs can improve the assessment of liver injury, 20 specific BAs were quantitatively profiled via LC-MS/MS in plasma and liver tissue in a model of methapyrilene-induced liver injury in rats. Methapyrilene, a known hepatotoxin was dosed daily over 14-days at doses of 30 and 80mg/kg, followed by a recovery phase of 10days...
May 19, 2017: Toxicology
https://www.readbyqxmd.com/read/28526447/toxicity-screening-of-a-novel-poly-methylmethacrylate-eudragit-nanocarrier-on-l929-fibroblasts
#8
Diogo Graça, Henriqueta Louro, Joana Santos, Kamila Dias, Lídia Gonçalves, António Almeida, Maria João Silva, Ana Bettencourt
Toxicity screening of a novel poly(methylmethacrylate)-Eudragit nanocarrier on L929 fibroblasts Translation of innovative drug delivery nanosystems into the market involves an early toxicity screening in the development phase. Previously, we showed that inclusion of the polymer (Eudragit, EUD) into poly(methylmethacrylate) (PMMA) nanoparticles (NP) resulted in a novel nanocarrier (PMMA-EUD) with an improved biomedical performance. The safety of this novel nanoparticulate system (PMMA-EUDNPs) was assessed in this work and compared to that of the original PMMANPs by using an integrated approach, comprising in vitro toxicity assessment and NPs physicochemical characterization in water and cell medium...
May 16, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/28524659/synthesis-molecular-docking-molecular-dynamics-studies-and-biological-evaluation-of-4h-chromone-1-2-3-4-tetrahydropyrimidine-5-carboxylate-derivatives-as-potential-antileukemic-agents
#9
Zahra Dolatkhah, Shahrzad Javanshir, Ahmad Shahir Sadr, Jaber Hosseini, Soroush Sardari
A series of 4H-chromone-1,2,3,4-tetrahydropyrimidine-5-carboxylates derivatives were synthesized via a three component one-pot condensation of chromone-3-carbaldehyde, alkyl acetoacetate, and urea or thiourea, using MCM-41-SO3H as efficient nanocatalysts and evaluated for their anticancer activity using a combined in silico docking and molecular dynamics protocol to estimate the binding affinity of the title compounds with the Bcr-Abl oncogene. Two programs, AutoDock 4 and AutoDock Vina software were applied to dock the target protein with synthesized compounds and ATP...
May 25, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28522587/preclinical-evaluation-of-medi0641-a-pyrrolobenzodiazepine-conjugated-antibody-drug-conjugate-targeting-5t4
#10
Jay Harper, Christopher Lloyd, Nazzareno Dimasi, Dorin Toader, Rose Marwood, Leeanne Lewis, David Bannister, Jelena Jovanovic, Ryan Fleming, Francois d'Hooge, Shenlan Mao, Allison M Marrero, Martin Korade, Patrick Strout, Linda Xu, Cui Chen, Leslie Wetzel, Shannon Breen, Lilian van Vlerken-Ysla, Sanjoo Jalla, Marlon Rebelatto, Helen Zhong, Elaine M Hurt, Mary Jane Hinrichs, Keven Huang, Philip W Howard, David A Tice, Robert E Hollingsworth, Ronald Herbst, Adeela Kamal
Antibody-drug conjugates (ADCs) are used to selectively deliver cytotoxic agents to tumors and have the potential for increased clinical benefit to cancer patients. 5T4 is an oncofetal antigen overexpressed on the cell surface in many carcinomas on both bulk tumor cells as well as cancer stem cells (CSCs), has very limited normal tissue expression, and can internalize when bound by an antibody. An anti-5T4 antibody was identified and optimized for efficient binding and internalization in a target-specific manner, and engineered cysteines were incorporated into the molecule for site-specific conjugation...
May 18, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28493985/photodynamic-antimicrobial-chemotherapy-with-the-novel-amino-acid-porphyrin-conjugate-4i-in-vitro-and-in-vivo-studies
#11
Yao Yuan, Zi-Quan Liu, Heng Jin, Shi Sun, Tian-Jun Liu, Xue Wang, Hao-Jun Fan, Shi-Ke Hou, Hui Ding
Photodynamic antimicrobial chemotherapy (PACT), as a novel and effective therapeutic modality to eradicate drug resistant bacteria without provoking multidrug resistance, has attracted increasing attention. This study examined the antimicrobial efficacy of the novel cationic amino acid-porphyrin conjugate 4I with four lysine groups against two different clinical isolated strains (drug sensitive and multidrug resistant) of the Acinetobacter baumannii species and its toxicity on murine dermal fibroblasts in vitro, as well as the therapeutic effect of PACT on acute, potentially lethal multidrug resistant strain excisional wound infections in vivo...
2017: PloS One
https://www.readbyqxmd.com/read/28493171/immunotherapy-in-urothelial-cancer-recent-results-and-future-perspectives
#12
REVIEW
Matthew S Farina, Kevin T Lundgren, Joaquim Bellmunt
Cytotoxic chemotherapy has been the only systemic treatment of locally advanced and metastatic urothelial carcinoma for decades. Long-term survival remains stagnant around 12-14 months for patients with advanced disease who have progressed on or recurred after receiving first-line platinum-based chemotherapy. Improving clinical outcomes for patients with urothelial carcinoma in all disease settings requires the development of novel treatments, especially for patients who failed on first-line chemotherapy. Since the discovery of intravesical Bacillus-Calmette Guerin (BCG) in the 1970s for non-muscle invasive disease, there have not been any major breakthrough drugs that exploit the immune-sensitivity of bladder cancer until recently...
May 11, 2017: Drugs
https://www.readbyqxmd.com/read/28481085/harnessing-phosphato-platinum-bonding-induced-supramolecular-assembly-for-systemic-cisplatin-delivery
#13
Yingqin Hou, Yaoyi Wang, Ruijue Wang, Weier Bao, Xiaobo Xi, Yunlong Sun, Sheng-Tao Yang, Wei Wei, Hua Lu
To improve the therapeutic index of cisplatin (CDDP), we present here a new paradigm of drug-induced self-assembly by harnessing phosphato-platinum complexation. Specifically, we show that a phosphato-platinum crosslinked micelle (PpY/Pt) can be generated by using a block copolymer methoxy-poly(ethylene glycol)-block-poly(L-phosphotyrosine) (mPEG-b-PpY). Coating of PpY/Pt with an R9-iRGD peptide by simple mixing affords a targeting micelle with near neutral-charged surface (iPpY/Pt). The micelles features in well-controlled sizes below 50 nm and high stability under physiological conditions, and can withstand various environmental stresses...
May 8, 2017: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/28471248/natural-killer-cells-as-a-promising-tool-to-tackle-cancer-a-review-of-sources-methodologies-and-potentials
#14
Senthilkumar Preethy, Vidyasagar Devaprasad Dedeepiya, Rajappa Senthilkumar, Mathaiyan Rajmohan, Ramalingam Karthick, Hiroshi Terunuma, Samuel J K Abraham
Immune cell-based therapies are emerging as a promising tool to tackle malignancies, both solid tumors and selected hematological tumors. Vast experiences in literature have documented their safety and added survival benefits when such cell-based therapies are combined with the existing treatment options. Numerous methodologies of processing and in vitro expansion protocols of immune cells, such as the dendritic cells, natural killer (NK) cells, NKT cells, αβ T cells, so-called activated T lymphocytes, γδ T cells, cytotoxic T lymphocytes, and lymphokine-activated killer cells, have been reported for use in cell-based therapies...
May 4, 2017: International Reviews of Immunology
https://www.readbyqxmd.com/read/28462502/mechanistically-elucidating-the-in-vitro-safety-and-efficacy-of-a-novel-doxorubicin-derivative
#15
Samaa Alrushaid, Yunqi Zhao, Casey L Sayre, Zaid H Maayah, M Laird Forrest, Sanjeewa N Senadheera, Kevin Chaboyer, Hope D Anderson, Ayman O S El-Kadi, Neal M Davies
Doxorubicin is an effective anticancer drug; however, it is cardiotoxic and has poor oral bioavazilability. Quercetin is a plant-based flavonoid with inhibitory effects on P-glycoprotein (P-gp) and CYP3A4 and also antioxidant properties. To mitigate these therapeutic barriers, DoxQ, a novel derivative of doxorubicin, was synthesized by conjugating quercetin to doxorubicin. The purpose of this study is to mechanistically elucidate the in vitro safety and efficacy of DoxQ. Drug release in vitro and cellular uptake by multidrug-resistant canine kidney (MDCK-MDR) cells were quantified by HPLC...
May 1, 2017: Drug Delivery and Translational Research
https://www.readbyqxmd.com/read/28454918/targeting-leishmania-amazonensis-amastigotes-through-macrophage-internalisation-of-a-hydroxymethylnitrofurazone-nanostructured-polymeric-system
#16
Lis Marie Monteiro, Raimar Löbenberg, Elizabeth Igne Ferreira, Paulo Cesar Cotrim, Edite Kanashiro, Mussya Rocha, Chung Man Chin, Nadia Bou-Chacra
Dextran-coated poly (n-butyl cyanoacrylate) nanoparticles (PBCA-NPs) were prepared and were evaluated for enhanced delivery of a promising anti-Leishmania drug candidate, hydroxymethylnitrofurazone (NFOH), to phagocytic cells. Currently available chemotherapy for leishmaniasis, such as pentavalent antimonials, presents low safety and efficacy. Furthermore, widespread drug resistance in leishmaniasis is rapidly emerging. To overcome these drawbacks, the use of nanosized delivery systems can reduce systemic drug toxicity and increase the drug concentration in infected macrophages, therefore improving treatment of leishmaniasis...
April 25, 2017: International Journal of Antimicrobial Agents
https://www.readbyqxmd.com/read/28440698/therapeutic-peg-ceramide-nanomicelles-synergize-with-salinomycin-to-target-both-liver-cancer-cells-and-cancer-stem-cells
#17
Meiping Wang, Fangyuan Xie, Xikai Wen, Han Chen, Hai Zhang, Junjie Liu, He Zhang, Hao Zou, Yuan Yu, Yan Chen, Zhiguo Sun, Xinxia Wang, Guoqing Zhang, Chuan Yin, Duxin Sun, Jie Gao, Beige Jiang, Yanqiang Zhong, Ying Lu
AIM: Salinomycin (SAL)-loaded PEG-ceramide nanomicelles (SCM) were prepared to target both liver cancer cells and cancer stem cells. MATERIALS & METHODS: The synergistic ratio of SAL/PEG-ceramide was evaluated to prepare SCM, and the antitumor activity of SCM was examined both in vitro and in vivo. RESULTS: SAL/PEG-ceramide molar ratio of 1:4 was chosen as the synergistic ratio, and SCM showed superior cytotoxic effect and increased apoptosis-inducing activity in both liver cancer cells and cancer stem cells...
May 2017: Nanomedicine
https://www.readbyqxmd.com/read/28438386/catabolism-of-antibody-drug-conjugates-and-characterization-methods
#18
REVIEW
Mohammad Shadid, Stephen Bowlin, Jayaprakasam Bolleddula
Antibody drug conjugates (ADCs) are large molecule therapeutics in which a cytotoxic payload is conjugated to a monoclonal antibody (mAb) via a linker. The molecules are designed to selectively bind to target-expressing cells, thus delivering therapeutic agents directly to the tumor. Chemical and enzymatic stability prior to reaching the target is an important factor for ADCs since it impacts their safety, efficacy, and pharmacokinetics (PK). One of the main reasons for off-target effects of ADCs is premature release of cytotoxic agents, either in the blood stream or at non-specific sites...
April 11, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28429938/high-resolution-accurate-mass-mass-spectrometry-enabling-in-depth-characterization-of-in-vivo-biotransformations-for-intact-antibody-drug-conjugates
#19
Jintang He, Dian Su, Carl Ng, Luna Liu, Shang-Fan Yu, Thomas H Pillow, Geoffrey Del Rosario, Martine Darwish, Byoung-Chul Lee, Rachana Ohri, Hongxiang Zhou, Xueji Wang, Jiawei Lu, Surinder Kaur, Keyang Xu
Antibody-drug conjugates (ADCs) represent a promising class of therapeutics for the targeted delivery of highly potent cytotoxic drugs to tumor cells to improve bioactivity while minimizing side effects. ADCs are composed of both small and large molecules and therefore have complex molecular structures. In vivo biotransformations may further increase the complexity of ADCs, representing a unique challenge for bioanalytical assays. Quadrupole-time-of-flight mass spectrometry (Q-TOF MS) with electrospray ionization has been widely used for characterization of intact ADCs...
May 3, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28428751/identification-of-nf-%C3%AE%C2%BAb-as-determinant-of-posttraumatic-stress-disorder-and-its-inhibition-by-the-chinese-herbal-remedy-free-and-easy-wanderer
#20
Chunlan Hong, Anja Schüffler, Ulrich Kauhl, Jingming Cao, Ching-Fen Wu, Till Opatz, Eckhard Thines, Thomas Efferth
Posttraumatic stress disorder (PTSD) is a mental disorder developing after exposure to traumatic events. Although psychotherapy reveals some therapeutic effectiveness, clinically sustainable cure is still uncertain. Some Chinese herbal formulae are reported to work well clinically against mental diseases in Asian countries, but the safety and their mode of action are still unclear. In this study, we investigated the mechanisms of Chinese remedy free and easy wanderer (FAEW) on PTSD. We used a reverse pharmacology approach combining clinical data to search for mechanisms of PTSD with subsequent in vitro verification and bioinformatics techniques as follows: (1) by analyzing microarray-based transcriptome-wide mRNA expression profiling of PTSD patients; (2) by investigating the effect of FAEW and the antidepressant control drug fluoxetine on the transcription factor NF-κB using reporter cell assays and western blotting; (3) by performing molecular docking and literature data mining based on phytochemical constituents of FAEW...
2017: Frontiers in Pharmacology
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