Organizational safety culture/climate and worker compliance with hazardous drug guidelines: lessons from the blood-borne pathogen experience.

PubMed

McDiarmid, Melissa A; Condon, Marian

2005-07-01

The health risks posed to health care workers (HCW) handling antineoplastic and other hazardous drugs (HDs) are well established. However, despite nearly 20 years of professional practice standards, compliance with safe handling procedures is poor. We present documentation of undercompliance with recommended safety procedures for HDs. Then, we examine a similar problem, HCW compliance with blood-borne pathogen universal precautions (UP) and its partial solution tied to the strength of a facility's safety culture. Lessons learned here may be applicable to the HD issue. It is proposed that analyzing a facility's safety culture may enlarge our understanding of the barriers contributing to HD under-compliance and suggest strategies to improve it. The Safety Culture paradigm offers many targets for intervention to enhance and promote worker compliance with safe HD handling practices thus mitigating internal exposure.

Antineoplastic agents: comparing off-label uses among authoritative drug compendia.

PubMed

Thompson, D F; Keefe, C C

1993-07-01

Unlabeled indications for antineoplastic drugs listed in the American Hospital Formulary-Drug Information, United States Pharmacopeia Dispensing Information-Drug Information for the Health Care Professional (Volume 1), and the American Medical Association-Drug Evaluations were evaluated. Specifically, the total number of unlabeled and unique uses (ie, not listed in either of the other two compendia) of 35 antineoplastic drugs were compared. Using a nonparametric analysis of variance to evaluate the results, significant differences in both the average unlabeled indications per drug and unique unlabeled indications per drug were found among the resources checked. The implications of the study results on reimbursement by private insurance carriers of unlabeled antineoplastic drug use is discussed in this article.

Injectable-antineoplastic-drug practices in Michigan hospitals.

PubMed

Cohen, I A; Newland, S J; Kirking, D M

1987-05-01

Practices related to parenteral (injectable) antineoplastic drugs (PADs) in Michigan hospitals were surveyed. All hospitals in Michigan were surveyed to assess compliance with American Society of Hospital Pharmacists (ASHP) and Occupational Safety and Health Administration (OSHA) recommendations related to PADs. Other PAD-related practice issues not covered within those guidelines were also studied. Surveys were mailed to the pharmacy directors of the state's 192 acute-care hospitals. Included were questions concerning policies and procedures for ordering, storing, preparing, handling, labeling, transporting, administering, and disposing of PADs. Questions concerning staff education, spill cleanup, and personnel issues were also included. A total of 169 questionnaires were returned, yielding a response rate of 88%. Of those respondents, 132 indicated that they prepare PAD doses for inpatients. Adherence rates were high for several of the PAD-preparation recommendations, including handwashing (97%) and gloving (98.5%). Rates for gowning (71.2%), labeling of PAD doses as biohazards (chemical hazards) (73.5%), and use of Class II biological-safety cabinets (71.2%) were less favorable. Practice areas with relatively poor adherence rates included use of plastic-backed absorbent pads under PAD preparation areas (53.8%), storing PADs separately from other drugs (48.5%), informing prospective employees of potential risks of handling PADs (36.4%), availability of spill kits (36.4%), and attaching and priming i.v. tubing before adding PADs to i.v. containers (5.4%). Many pharmacy departments in Michigan hospitals can substantially improve their adherence to ASHP and OSHA recommendations related to PADs.

Important exposure controls for protection against antineoplastic agents: Highlights for oncology health care workers.

PubMed

Alehashem, Maryam; Baniasadi, Shadi

2018-01-01

A great number of antineoplastic drugs (ANPDs) are used globally in cancer treatment. Due to their adverse health effects, occupational exposure to ANPDs is considered a potential health risk to health care workers. The current study aimed to evaluate safe-handling practices of ANPDs, exposure controls, and adverse health implications for health care providers exposed to ANDPs. Prevention measures, including engineering, administrative, and work practice controls, as well as personal protective equipment (PPE), were recorded daily through a questionnaire for six weeks. Acute adverse health effects experienced by health care workers were also documented. The implemented exposure controls for preparation, administration, cleaning, and waste disposal were not in accordance with the safe handling guidelines. Central nervous system disorders (26.33%) were the most frequent acute adverse effects reported by health care workers. A significant correlation was found between the number of experienced adverse effects and handling characteristics, including the number of preparations (r = 0.38, p < 0.05), dose, and the number of prepared drugs (r = 0.46, p < 0.01 and 0.39, p < 0.05), and working hours in different locations of oncology setting for six weeks (preparation room: r = 0.38, P < 0.05, treatment room: r = 0.46, P < 0.01, patient room: r = 0.63, P < 0.01, and station: r = 0.68, P < 0.01). Due to inadequate control measures, oncology health care workers were in danger of exposure to ANPDs and experienced acute adverse health effects. Implementation of appropriate exposure controls is required to prevent occupational exposure to ANPDs.

Exposure to antineoplastic drugs outside the hospital environment.

PubMed

Meijster, T; Fransman, W; Veldhof, R; Kromhout, H

2006-10-01

The objectives were (i) to identify occupational populations outside hospitals working with antineoplastic drugs, (ii) to determine the size of the populations 'at risk', (iii) to identify major determinants and routes of exposure outside hospitals and (iv) to estimate exposure levels and frequencies relative to levels found in hospitals. The survey consisted of two phases; (i) identification of activities with potential exposure to antineoplastic drugs by literature review, interviews, questionnaires and workplace visits, (ii) exploratory measurements of exposure and surface contamination in selected sectors. Eight sectors were identified with potential exposure to antineoplastic drugs: pharmaceutical industry, pharmacies, universities, veterinary medicine, nursing homes, home care, laundry facilities, and waste treatment. Four sectors were of primary concern: veterinary medicine, home care, nursing homes and industrial laundries. The populations potentially exposed in these sectors vary considerably (from several tens to thousands of workers), as do their levels of exposure. Exposure measurements collected in the veterinary medicine sector showed that workers are indeed exposed to antineoplastic drugs and, in some cases (on gloves after administration), levels were 15 times higher than levels measured during administration in hospitals. Workers sorting contaminated hospital laundry in industrial laundry facilities were exposed to antineoplastic drugs through inhalation. For the home care and nursing homes sectors the highest exposure levels were found when cleaning toilets and washing treated patients. These two sectors are expected to have the largest exposed population (5,000-10,000 individuals). This study has resulted in a comprehensive overview of populations with potential exposure to antineoplastic drugs. Exposure levels can potentially be high compared with the hospital environment, because exposure routes are complex and awareness of the hazard (and therefore use of protective measures) is low. The number of individuals outside hospitals in The Netherlands exposed to antineoplastic drugs is estimated to be between 5,000 and 15,000.

Electrochemical sensors and biosensors for the analysis of antineoplastic drugs.

PubMed

Lima, Handerson Rodrigues Silva; da Silva, Josany Saibrosa; de Oliveira Farias, Emanuel Airton; Teixeira, Paulo Ronaldo Sousa; Eiras, Carla; Nunes, Lívio César Cunha

2018-06-15

Cancer is a leading cause of death worldwide, often being treated with antineoplastic drugs that have high potential for toxicity to humans and the environment, even at very low concentrations. Therefore, monitoring these drugs is of utmost importance. Among the techniques used to detect substances at low concentrations, electrochemical sensors and biosensors have been noted for their practicality and low cost. This review brings, for the first time, a simplified outline of the main electrochemical sensors and biosensors developed for the analysis of antineoplastic drugs. The drugs analyzed and the methodology used for electrochemical sensing are described, as are the techniques used for drug quantification and the analytical performance of each sensor, highlighting the limit of detection (LOD), as well as the linear range of quantification (LR) for each system. Finally, we present a technological prospection on the development and use of electrochemical sensors and biosensors in the quantification of antineoplastic drugs. A search of international patent databases revealed no patents currently submitted under this topic, suggesting this is an area to be further explored. We also show that the use of these systems has been gaining prominence in recent years, and that the quantification of antineoplastic drugs using electrochemical techniques could bring great financial and health benefits. Copyright © 2018. Published by Elsevier B.V.

Geographic Variations and Time Trends in Cancer Treatments in Taiwan.

PubMed

Hsu, Jason C; Chang, Sheng-Mao; Lu, Christine Y

2017-08-02

Targeted therapies have become important treatment options for cancer care in many countries. This study aimed to examine recent trends in utilization of antineoplastic drugs, particularly the use of targeted therapies for treatment of cancer, by geographic region in Taiwan (northern, midwestern, southern, and eastern regions and the outer islands). This was a retrospective observational study of antineoplastic agents using 2009-2012 quarterly claims data from Taiwan's National Health Insurance Research Database. Yearly market shares by prescription volume and costs for targeted therapies among total antineoplastic agents by region were estimated. We used multivariate regression model and ANOVA to examine variations in utilization of targeted therapies between geographic regions and used ARIMA models to estimate longitudinal trends. Population-adjusted use and costs of antineoplastic drugs (including targeted therapies) were highest in the southern region of Taiwan and lowest in the outer islands. We found a 4-fold difference in use of antineoplastic drugs and a 49-fold difference in use of targeted therapies between regions if the outer islands were included. There were minimal differences in use of antineoplastic drugs between other regions with about a 2-fold difference in use of targeted therapies. Without considering the outer islands, the market share by prescription volume and costs of targeted therapies increased almost 2-fold (1.84-1.90) and 1.5-fold (1.26-1.61) respectively between 2009 and 2012. Furthermore, region was not significantly associated with use of antineoplastic agents or use of targeted therapies after adjusting for confounders. Region was associated with costs of antineoplastic agents but it was not associated with costs of targeted therapies after confounding adjustments. Use of antineoplastic drugs overall and use of targeted therapies for treatment of cancer varied somewhat between regions in Taiwan; use was notably low in the outer islands. Strategies might be needed to ensure access to cancer care in each region as economic burden of cancer care increase due to growing use of targeted therapies.

Intravesical antineoplastic therapy following transurethral resection of bladder tumors: nursing implications from the operating room to discharge.

PubMed

Washburn, Donna J

2007-08-01

An aging population and latent effects from exposure to carcinogens will likely augment the current trend of increased incidence of urinary bladder cancer. Intravesical antineoplastic therapy is a common treatment for urinary bladder cancer. Transurethral resection of bladder tumors often is followed immediately by the instillation of an antineoplastic agent in the operating room or postanesthesia care unit. Oncology nurses, who have a unique knowledge of safe handling and patient care, can improve staff safety and patient outcomes in several areas of healthcare organizations, as well as reduce the mortality and morbidity of urinary bladder cancer by learning more about the disease and intravesical antineoplastic therapy.

Inductively coupled plasma mass-spectrometric determination of platinum in excretion products of client-owned pet dogs.

PubMed

Janssens, T; Brouwers, E E M; de Vos, J P; de Vries, N; Schellens, J H M; Beijnen, J H

2015-06-01

Residues of antineoplastic drugs in canine excretion products may represent exposure risks to veterinary personnel, owners of pet dogs and other animal care-takers. The aim of this study was to measure the extent and duration of platinum (Pt) excretion in pet dogs treated with carboplatin. Samples were collected before and up to 21 days after administration of carboplatin. We used validated, ultra-sensitive, inductively coupled plasma-mass spectrometry assays to measure Pt in canine urine, faeces, saliva, sebum and cerumen. Results showed that urine is the major route of elimination of Pt in dogs. In addition, excretion occurs via faeces and saliva, with the highest amounts eliminated during the first 5 days. The amount of excreted Pt decreased over time but was still quantifiable at 21 days after administration of carboplatin. In conclusion, increased Pt levels were found in all measured excretion products up to 21 days after administration of carboplatin to pet dogs, with urine as the main route of excretion. These findings may be used to further adapt current veterinary guidelines on safe handling of antineoplastic drugs and treated animals. © 2013 Blackwell Publishing Ltd.

Medicinal electronomics bricolage design of hypoxia-targeting antineoplastic drugs and invention of boron tracedrugs as innovative future-architectural drugs.

PubMed

Hori, Hitoshi; Uto, Yoshihiro; Nakata, Eiji

2010-09-01

We describe herein for the first time our medicinal electronomics bricolage design of hypoxia-targeting antineoplastic drugs and boron tracedrugs as newly emerging drug classes. A new area of antineoplastic drugs and treatments has recently focused on neoplastic cells of the tumor environment/microenvironment involving accessory cells. This tumor hypoxic environment is now considered as a major factor that influences not only the response to antineoplastic therapies but also the potential for malignant progression and metastasis. We review our medicinal electronomics bricolage design of hypoxia-targeting drugs, antiangiogenic hypoxic cell radiosensitizers, sugar-hybrid hypoxic cell radiosensitizers, and hypoxia-targeting 10B delivery agents, in which we design drug candidates based on their electronic structures obtained by molecular orbital calculations, not based solely on pharmacophore development. These drugs include an antiangiogenic hypoxic cell radiosensitizer TX-2036, a sugar-hybrid hypoxic cell radiosensitizer TX-2244, new hypoxia-targeting indoleamine 2,3-dioxygenase (IDO) inhibitors, and a hypoxia-targeting BNCT agent, BSH (sodium borocaptate-10B)-hypoxic cytotoxin tirapazamine (TPZ) hybrid drug TX-2100. We then discuss the concept of boron tracedrugs as a new drug class having broad potential in many areas.

Measurement of surface contamination by certain antineoplastic drugs using high-performance liquid chromatography: applications in occupational hygiene investigations in hospital environments.

PubMed

Rubino, F M; Floridia, L; Pietropaolo, A M; Tavazzani, M; Colombi, A

1999-01-01

Within the context of continuing interest in occupational hygiene of hospitals as workplaces, the authors report the results of a preliminary study on surface contamination by certain antineoplastic drugs (ANDs), recently performed in eight cancer departments of two large general hospitals in Milan, Italy. Since reliable quantitative information on the exposure levels to individual drugs is mandatory to establish a strong interpretative framework for correctly assessing the health risks associated with manipulation of ANDs and rationally advise intervention priorities for exposure abatement, two automated analytical methods were set up using reverse-phase high-performance liquid chromatography for the measurement of contamination by 1) methotrexate (MTX) and 2) the three most important nucleoside analogue antineoplastic drugs (5-fluorouracil 5FU, Cytarabin CYA, Gemcytabin GCA) on surfaces such as those of preparation hoods and work-benches in the pharmacies of cancer wards. The methods are characterized by short analysis time (7 min) under isocratic conditions, by the use of a mobile phase with a minimal content of organic solvent and by high sensitivity, adequate to detect surface contamination in the 5-10 micrograms/m2 range. To exemplify the performance of the analytical methods in the assessment of contamination levels from the target analyte ANDs, data are reported on the contamination levels measured on various surfaces (such as on handles, floor surfaces and window panes, even far from the preparation hood). Analyte concentrations corresponding to 0.8-1.5 micrograms of 5FU were measured on telephones, 0.85-28 micrograms/m2 of CYA were measured on tables, 1.2-1150 micrograms/m2 of GCA on furniture and floors. Spillage fractions between 1-5% of the used ANDs (daily use 5FU 7-13 g; CYA 0.1-7.1 g; GCA 0.2-5 g) were measured on the disposable polythene-backed paper cover sheet of the preparation hood.

List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings 2012

MedlinePlus

... inorganic arsenic compounds, which include the antineoplastic drug ar- senic trioxide [29 CFR 1910.1018; NIOSH 2004; ... an established safety program [McDiarmid et al. 1991; Ar- rington and McDiarmid 1993]. The criteria are prioritized ...

Combined cyto/genotoxic activity of a selected antineoplastic drug mixture in human circulating blood cells.

PubMed

Gajski, Goran; Gerić, Marko; Domijan, Ana-Marija; Garaj-Vrhovac, Vera

2016-12-01

Antineoplastic drugs are highly cytotoxic chemotherapeutic agents that can often interfere directly or indirectly with the cell's genome. In an environmental or medical setting simultaneous exposure may occur. Such multiple exposures may pose a higher risk than it could be assumed from the studies evaluating the effect of a single substance. Therefore, in the present study we tested the combined cyto/genotoxicity of a mixture of selected antineoplastic drugs with different mechanisms of action (5-fluorouracil, etoposide, and imatinib mesylate) towards human lymphocytes in vitro. The results suggest that the selected antineoplastic drug mixture is potentially cyto/genotoxic and that it can induce cell and genome damage even at low concentrations. Moreover, the changes in the measured oxidative stress parameters suggest the participation of reactive oxygen species in the cyto/genotoxicity of the selected mixture. The obtained results indicate not only that such mixtures may pose a risk to cell and genome integrity, but also that single compound toxicity data are not sufficient for the predicting toxicity in a complex environment. Altogether, the results emphasise the need for further toxicological screening of antineoplastic drug mixtures, especially at low environmentally relevant concentrations, as to avoid any possible adverse effects on the environment and human health. Copyright © 2016 Elsevier Ltd. All rights reserved.

Antineoplastic compounds in the environment-substances of special concern.

PubMed

Kümmerer, Klaus; Haiß, Annette; Schuster, Armin; Hein, Arne; Ebert, Ina

2016-08-01

Antineoplastic drugs are important in the treatment of cancer. Some interact directly with the deoxyribonucleic acid (DNA) and are of utmost importance in terms of risk. As highly active compounds, antineoplastics and their metabolites are largely excreted into wastewater and are found in the aquatic environment up to the lower μg/L range. Their predicted environmental concentrations are often below the action limit set in the European Medicines Agency (EMA) guideline. An in-depth risk assessment regarding their presence and effects in the aquatic environment is often not performed, and there is a lack of knowledge. This study considered whether there is an underestimation of possible risks associated with the presence of antineoplastic drugs with regard to trigger value stated in the EMA and FDA guidelines. In a balance, we identified a total of 102 active pharmaceutical ingredients of the ATC-group L01 (antineoplastic agents), which are environmentally relevant. In Germany, 20.7 t of antineoplastic agents was consumed in 2012. The share of drugs with DNA-damaging properties increased within the last 6 years from 24 up to 67 %. Solely, capecitabine and 5-fluorouracil amount together 8 t-which corresponds to 39 % of the total antineoplastic consumption. Around 80 % of the total mass consumed could be attributed to prescriptions issued by office-based practitioners and is mostly excreted at home. Based on the different mode of actions, a case-by-case evaluation of the risk connected to their presence in the environment is recommended. DNA-damaging drugs should be assessed independently as no action limit can be assumed.

Antineoplastic Drugs.

ERIC Educational Resources Information Center

Morris, Sara; Michael, Nancy, Ed.

This module on antineoplastic drugs is intended for use in inservice or continuing education programs for persons who administer medications in long-term care facilities. Instructor information, including teaching suggestions, and a listing of recommended audiovisual materials and their sources appear first. The module goal and objectives are then…

Evaluation of real-time data obtained from gravimetric preparation of antineoplastic agents shows medication errors with possible critical therapeutic impact: Results of a large-scale, multicentre, multinational, retrospective study.

PubMed

Terkola, R; Czejka, M; Bérubé, J

2017-08-01

Medication errors are a significant cause of morbidity and mortality especially with antineoplastic drugs, owing to their narrow therapeutic index. Gravimetric workflow software systems have the potential to reduce volumetric errors during intravenous antineoplastic drug preparation which may occur when verification is reliant on visual inspection. Our aim was to detect medication errors with possible critical therapeutic impact as determined by the rate of prevented medication errors in chemotherapy compounding after implementation of gravimetric measurement. A large-scale, retrospective analysis of data was carried out, related to medication errors identified during preparation of antineoplastic drugs in 10 pharmacy services ("centres") in five European countries following the introduction of an intravenous workflow software gravimetric system. Errors were defined as errors in dose volumes outside tolerance levels, identified during weighing stages of preparation of chemotherapy solutions which would not otherwise have been detected by conventional visual inspection. The gravimetric system detected that 7.89% of the 759 060 doses of antineoplastic drugs prepared at participating centres between July 2011 and October 2015 had error levels outside the accepted tolerance range set by individual centres, and prevented these doses from reaching patients. The proportion of antineoplastic preparations with deviations >10% ranged from 0.49% to 5.04% across sites, with a mean of 2.25%. The proportion of preparations with deviations >20% ranged from 0.21% to 1.27% across sites, with a mean of 0.71%. There was considerable variation in error levels for different antineoplastic agents. Introduction of a gravimetric preparation system for antineoplastic agents detected and prevented dosing errors which would not have been recognized with traditional methods and could have resulted in toxicity or suboptimal therapeutic outcomes for patients undergoing anticancer treatment. © 2017 The Authors. Journal of Clinical Pharmacy and Therapeutics Published by John Wiley & Sons Ltd.

77 FR 41190 - Revised Document Posted: NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-12

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Centers for Disease Control and Prevention [Docket Number NIOSH-190] Revised Document Posted: NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings 2012, Correction AGENCY: National Institute for Occupational Safety and Health (NIOSH) of the...

Cardiotoxicity of copper-based antineoplastic drugs casiopeinas is related to inhibition of energy metabolism

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hernandez-Esquivel, Luz; Marin-Hernandez, Alvaro; Pavon, Natalia

2006-04-01

Isolated rat hearts were perfused with glucose, octanoate or glucose + octanoate and different concentrations of the copper-based antineoplastic drugs casiopeina II-gly (CSII) or casiopeina III-i-a (CSIII). In isolated perfused hearts with glucose + octanoate, both casiopeinas induced diminution in cardiac work and O{sub 2} consumption with half-maximal inhibitory concentrations (IC{sub 5}) of 4 (CSII) and 4.6 (CSIII) {mu}M, after 1 h of perfusion. Strong inhibition of the pyruvate and 2-oxoglutarate dehydrogenases as well as total creatine kinase by casiopeinas suggested that ATP generation by oxidative phosphorylation and its transfer towards myofibrils were targets for these drugs. In consequence, themore » cellular contents of ATP and phosphocreatine were also lowered by casiopeinas. Remarkably, casiopeinas were less toxic than adriamycin (IC{sub 5} = 2.6 {mu}M), a well-known potent cardiotoxic and antineoplastic drug, which has a wide clinical use. In an open-chest animal, which is a more physiological model than the isolated heart, femoral administration of 1 {mu}M drug revealed that CSII was innocuous very likely due to strong binding to serum albumin, whereas adriamycin induced again a potent cardiotoxic effect (diminution in heart rate and severe depression of systolic blood pressure). Thus, it seems that casiopeinas are a group of new antineoplastic drugs with milder secondary toxic effects than proven drugs such as adriamycin.« less

Pharmacists' perceived knowledge of and confidence in dispensing oral antineoplastic agents.

PubMed

Dayer, Lindsey; Dunn, Eddie; Pace, Anne; Flowers, Schwanda

2016-01-01

To assess community pharmacists' perceived confidence with counseling patients about oral antineoplastic agents, in identifying drug and/or herbal interactions with these agents, and with identifying adverse drug events. Four hundred pharmacists were contacted and asked to take an anonymous survey regarding 11 oral antineoplastic agents (OAAs) and the oral antineoplastic market place in general. With a response rate of 61.5%, there was variation with perceived overall confidence in counseling patients, identifying drug and/or herbal interactions (DHIs), and identifying adverse drug events (ADEs) with each oral antineoplastic agent (OAA). There was a trend toward more confidence in identifying DHI and ADE in those agents dispensed within the past 6 months. The majority of pharmacists reported the main barrier to counseling to be a lack of training or knowledge. Only about 22% of pharmacists who participated in this survey reported confidence in their ability to manage an influx of OAAs. Overall, there was a lack of perceived confidence among pharmacists in counseling patients and identifying DHIs as well as with identifying ADEs with the 11 OAAs chosen for this survey. One of the main barriers identified was the lack of knowledge or training. These data provide preliminary information needed to launch educational programs in the student pharmacist curriculum (e.g., elective courses) and continuing education programs to improve overall confidence among pharmacists. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Safe Handling of Oral Antineoplastic Medications: Focus on Targeted Therapeutics in the Home Setting

PubMed Central

Cass, Yaakov; Connor, Thomas H.; Tabachnik, Alexander

2017-01-01

Introduction With the growing number of oral targeted therapies being approved for use in cancer therapy, the potential for long-term administration of these drugs to cancer patients is expanding. The use of these drugs in the home setting has the potential to expose family members and caregivers to them either through direct contact with the drugs or indirectly by exposure to the parent compounds and/or their active metabolites in contaminated patient's waste. Methods A systematic literature review was performed and the known adverse health effect of 32 oral targeted therapeutics is summarized. In particular, the carcinogenicity, genotoxicity, and embryo-foetal toxicity, along with the route of excretion were evaluated. Results Carcinogenicity testing has not been performed on most of the oral targeted therapeutics and the genotoxicity data are mixed. However, the majority of these drugs exhibit adverse reproductive effects, some of which are severe. Currently available data does not permit the possibility of a health hazard from inappropriate handling of drugs and contaminated patients waste to be ignored, especially in a long-term home setting. Further research is needed to understand these issues. Conclusions With the expanding use of targeted therapies in the home setting, family members and caregivers, especially those of reproductive risk age, are, potentially at risk. Overall basic education and related precautions should be taken to protect family members and caregivers from indirect or direct exposure from these drugs. Further investigations and discussion on this subject is warranted. PMID:27009803

Protection behaviors for cytotoxic drugs in oncology nurses of chemotherapy centers in Shiraz hospitals, South of Iran.

PubMed

Abbasi, Khadijeh; Hazrati, Maryam; Mohammadbeigi, Abolfazl; Ansari, Jasem; Sajadi, Mahboubeh; Hosseinnazzhad, Azam; Moshiri, Esmail

2016-01-01

The use of antineoplastic agents for the treatment of cancer is an increasingly common practice in hospitals. As a result, workers involved with handling antineoplastic drugs may be accidentally exposed to these agents, placing them at potential risk for long-term adverse effects. This study aimed to determine the occupational protection status of clinical nursing staff exposed to cytotoxic drugs. The study was designed as an analytic descriptive survey. The research settings took place in six centers of chemotherapy in Shiraz, Iran. The participants were 86 nurses who worked in oncology units and administered cytotoxic drugs. Data were collected using a questionnaire and a checklist which was developed by the investigators to determine occupational protection status of clinical nursing staff exposed to cytotoxic drugs. Percentage calculations and the independent samples t -test were used to see the general distribution and analysis of data. To statistically analyze of the data, SPSS software (version 16) was applied. The mean age of participants was 30.52 ± 6.50 years and 66.27% of the nurses worked on inpatient oncology wards. The mean practice score was 21.1 ± 3.76 that ranged from 12.5 to 31. The independent samples t -test showed the outpatient nurses were weaker in practice (17.2 ± 2.52) in comparison with university hospitals (23.35 ± 3.02, P < 0.001). Occupational protection status of clinical nursing staff exposed to cytotoxic drugs especially during administration and disposal of medicines was poor and rarely trained with this subject and was observed under the standard conditions. There is deficiency in the understanding and related protection practices of clinical nursing staff vocationally exposed to cytotoxic drugs. It is recommended that all clinical nursing staff should receive full occupational protection training about these matters and the authorities provide standard conditions of oncology wards.

75 FR 57044 - NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings 2010

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-17

...-167/ . Background: The NIOSH Alert: Preventing Occupational Exposures to Antineoplastic and Other... the 2004 list in Appendix A of the Alert. This guidance document does not have the force and effect of...

Impact of Robotic Antineoplastic Preparation on Safety, Workflow, and Costs

PubMed Central

Seger, Andrew C.; Churchill, William W.; Keohane, Carol A.; Belisle, Caryn D.; Wong, Stephanie T.; Sylvester, Katelyn W.; Chesnick, Megan A.; Burdick, Elisabeth; Wien, Matt F.; Cotugno, Michael C.; Bates, David W.; Rothschild, Jeffrey M.

2012-01-01

Purpose: Antineoplastic preparation presents unique safety concerns and consumes significant pharmacy staff time and costs. Robotic antineoplastic and adjuvant medication compounding may provide incremental safety and efficiency advantages compared with standard pharmacy practices. Methods: We conducted a direct observation trial in an academic medical center pharmacy to compare the effects of usual/manual antineoplastic and adjuvant drug preparation (baseline period) with robotic preparation (intervention period). The primary outcomes were serious medication errors and staff safety events with the potential for harm of patients and staff, respectively. Secondary outcomes included medication accuracy determined by gravimetric techniques, medication preparation time, and the costs of both ancillary materials used during drug preparation and personnel time. Results: Among 1,421 and 972 observed medication preparations, we found nine (0.7%) and seven (0.7%) serious medication errors (P = .8) and 73 (5.1%) and 28 (2.9%) staff safety events (P = .007) in the baseline and intervention periods, respectively. Drugs failed accuracy measurements in 12.5% (23 of 184) and 0.9% (one of 110) of preparations in the baseline and intervention periods, respectively (P < .001). Mean drug preparation time increased by 47% when using the robot (P = .009). Labor costs were similar in both study periods, although the ancillary material costs decreased by 56% in the intervention period (P < .001). Conclusion: Although robotically prepared antineoplastic and adjuvant medications did not reduce serious medication errors, both staff safety and accuracy of medication preparation were improved significantly. Future studies are necessary to address the overall cost effectiveness of these robotic implementations. PMID:23598843

French Health Technology Assessment of Antineoplastic Drugs Indicated in the Treatment of Solid Tumours: Perspective for Future Trends.

PubMed

Chouaid, Christos; Borget, Isabelle; Braun, Eric; Bazil, Marie-Laure; Schaetz, Dominique; Rémuzat, Cécile; Toumi, Mondher

2016-08-01

France is one of the European countries that spend the most on oncology drugs. To keep pharmaceutical expenditure under control, Health Authorities highly scrutinize market access of costly medicines. To assess current and future trends in French health technology assessment (HTA) of antineoplastic drugs indicated in the treatment of solid tumours. A review of the SMR and ASMR drivers of the Transparency Committee (CT) opinions issued for antineoplastic drugs indicated in the treatment of solid tumours and approved between 2009 and 2014 was performed to assess current trends in French health technology assessment (HTA), complemented by an expert board consultation to capture the critical issues on the future of antineoplastic drugs HTA. Thirty-one drugs indicated for the treatment of solid tumours were identified (77 % targeted therapies). Initial CT assessments were available for 26 drugs. Four key items in the CT assessment were identified: 1) Clinical trial methodology; 2) Acceptance of progression-free survival (PFS) as a valuable endpoint; 3) Transferability of clinical trials in clinical practice; 4) Unpredictability of CT decisions. Experts raised the important development of personalised medicines in oncology and key challenges for oncology products to generate information expected from HTA perspective. The French system remains committed to its values and philosophy (access of all innovations for everybody) which are threatened by the increasing launch of innovative therapies and budget constraint. Both HTA decision framework evolution and revision of the current pricing process should be considered in France to cope with these new challenges.

[Applying dose banding to the production of antineoplastic drugs: a narrative review of the literature].

PubMed

Pérez Huertas, Pablo; Cueto Sola, Margarita; Escobar Cava, Paloma; Borrell García, Carmela; Albert Marí, Asunción; López Briz, Eduardo; Poveda Andrés, José Luis

2015-07-01

The dosage of antineoplastic drugs has historically been based on individualized prescription and preparation according to body surface area or patient´s weight. Lack of resources and increased assistance workload in the areas where chemotherapy is made, are leading to the development of new systems to optimize the processing without reducing safety. One of the strategies that has been proposed is the elaboration by dose banding. This new approach standardizes the antineoplastic agents doses by making ranges or bands accepting a percentage of maximum variation. It aims to reduce processing time with the consequent reduction in waiting time for patients; to reduce errors in the manufacturing process and to promote the rational drug use. In conclusion, dose banding is a suitable method for optimizing the development of anticancer drugs, obtaining reductions in oncologic patients waiting time but without actually causing a favorable impact on direct or indirect costs. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

Where Are the Opportunities for Reducing Health Care Spending Within Alternative Payment Models?

PubMed

Rocque, Gabrielle B; Williams, Courtney P; Kenzik, Kelly M; Jackson, Bradford E; Halilova, Karina I; Sullivan, Margaret M; Rocconi, Rod P; Azuero, Andres; Kvale, Elizabeth A; Huh, Warner K; Partridge, Edward E; Pisu, Maria

2018-06-01

The Oncology Care Model (OCM) is a highly controversial specialty care model developed by the Centers for Medicare & Medicaid aimed to provide higher-quality care at lower cost. Because oncologists will be increasingly held accountable for spending as well as quality within new value-based health care models like the OCM, they need to understand the drivers of total spending for their patients. This retrospective cohort study included patients ≥ 65 years of age with primary fee-for-service Medicare insurance who received antineoplastic therapy at 12 cancer centers in the Southeast from 2012 to 2014. Medicare administrative claims data were used to identify health care spending during the prechemotherapy period (from cancer diagnosis to antineoplastic therapy initiation) and during the OCM episodes of care triggered by antineoplastic treatment. Total health care spending per episode includes all types of services received by a patient, including nononcology services. Spending was further characterized by type of service. Average total health care spending in the three OCM episodes of care was $33,838 (n = 3,427), $23,811 (n = 1,207), and $19,241 (n = 678). Antineoplastic drugs accounted for 27%, 32%, and 36% of total health care spending in the first, second, and third episodes. Ten drugs, used by 31% of patients, contributed 61% to drug spending ($18.8 million) in the first episode. Inpatient spending also substantially contributed to total costs, representing 17% to 20% ($30.5 million) of total health care spending. Health care spending was heavily driven by both antineoplastic drugs and hospital use. Oncologists' ability to affect these types of spending will determine their success under alternative payment models.

Detection and measurement of surface contamination by multiple antineoplastic drugs using multiplex bead assay

PubMed Central

Smith, Jerome P; Sammons, Deborah L; Robertson, Shirley A; Pretty, Jack; Debord, D Gayle; Connor, Thomas H; Snawder, John

2015-01-01

Objectives Contamination of workplace surfaces by antineoplastic drugs presents an exposure risk for healthcare workers. Traditional instrumental methods to detect contamination such as liquid chromatography-tandem mass spectrometry (LC-MS/MS) are sensitive and accurate but expensive. Since immunochemical methods may be cheaper and faster than instrumental methods, we wanted to explore their use for routine drug residue detection for preventing worker exposure. Methods In this study we examined the feasibility of using fluorescence covalent microbead immunosorbent assay (FCMIA) for simultaneous detection and semi-quantitative measurement of three antineoplastic drugs (5-fluorouracil, paclitaxel, and doxorubicin). The concentration ranges for the assay were 0–1000 ng/ml for 5-fluorouracil, 0–100 ng/ml for paclitaxel, and 0–2 ng/ml for doxorubicin. The surface sampling technique involved wiping a loaded surface with a swab wetted with wash buffer, extracting the swab in storage/blocking buffer, and measuring drugs in the extract using FCMIA. Results There was no significant cross reactivity between these drugs at the ranges studied indicated by a lack of response in the assay to cross analytes. The limit of detection (LOD) for 5-fluorouracil on the surface studied was 0.93 ng/cm2 with a limit of quantitation (LOQ) of 2.8 ng/cm2, the LOD for paclitaxel was 0.57 ng/cm2 with an LOQ of 2.06 ng/cm2, and the LOD for doxorubicin was 0.0036 ng/cm2 with an LOQ of 0.013 ng/cm2. Conclusion The use of FCMIA with a simple sampling technique has potential for low cost simultaneous detection and semi-quantitative measurement of surface contamination from multiple antineoplastic drugs. PMID:25293722

Drug interactions between antineoplastic and antidepressant agents: analysis of patients seen at an oncology clinic at a general hospital.

PubMed

Reinert, Camila de Araújo; Ribas, Marcelo Rodrigues; Zimmermann, Paulo Roberto

2015-01-01

To determine the prevalence of depressive symptoms among oncology patients and identify simultaneous use of antineoplastic and antidepressant agents. This was a cross-sectional study that interviewed 56 oncology patients using two data collection instruments: a questionnaire covering clinical and sociodemographic data and the Beck Depression Inventory-II (BDI-II), for assessment of depressive symptoms. For data analysis, descriptive statistics were used to determine the prevalence of depressive symptoms and the chi-square test was used to evaluate associations between sociodemographic and clinical variables and depressive symptoms. A 26.7% (15 patients) prevalence of depression was detected. Just eight of these 15 patients (53.3%) were receiving treatment for depression. In the sample as a whole, 13 of the patients interviewed (23.2%) were taking antidepressants and 11 of these 13 patients (19.6%) were taking antidepressive and antineoplastic agents simultaneously. A total of five (8.9% of the sample) contraindicated drug interactions were detected. Depressive symptoms are more prevalent among cancer patients than in the general population, but they are generally under-diagnosed and under-treated. Simultaneous use of antidepressant and antineoplastic agents is common and so, in order to reduce the number of harmful adverse effects, possible drug interactions must be identified before antidepressants are prescribed to cancer patients.

Mesenchymal Stromal Cells for Antineoplastic Drug Loading and Delivery.

PubMed

Petrella, Francesco; Rimoldi, Isabella; Rizzo, Stefania; Spaggiari, Lorenzo

2017-11-23

Mesenchymal stromal cells are a population of undifferentiated multipotent adult cells possessing extensive self-renewal properties and the potential to differentiate into a variety of mesenchymal lineage cells. They express broad anti-inflammatory and immunomodulatory activity on the immune system and after transplantation can interact with the surrounding microenvironment, promoting tissue healing and regeneration. For this reason, mesenchymal stromal cells have been widely used in regenerative medicine, both in preclinical and clinical settings. Another clinical application of mesenchymal stromal cells is the targeted delivery of chemotherapeutic agents to neoplastic cells, maximizing the cytotoxic activity against cancer cells and minimizing collateral damage to non-neoplastic tissues. Mesenchymal stem cells are home to the stroma of several primary and metastatic neoplasms and hence can be used as vectors for targeted delivery of antineoplastic drugs to the tumour microenvironment, thereby reducing systemic toxicity and maximizing antitumour effects. Paclitaxel and gemcitabine are the chemotherapeutic drugs best loaded by mesenchymal stromal cells and delivered to neoplastic cells, whereas other agents, like pemetrexed, are not internalized by mesenchymal stromal cells and therefore are not suitable for advanced antineoplastic therapy. This review focuses on the state of the art of advanced antineoplastic cell therapy and its future perspectives, emphasizing in vitro and in vivo preclinical results and future clinical applications.

Mycelial antineoplastic activity of Agaricus blazei.

PubMed

Bertéli, Míria Benetati Delgado; Umeo, Suzana Harue; Bertéli, André; do Valle, Juliana Silveira; Linde, Giani Andrea; Colauto, Nelson Barros

2014-08-01

Basidiocarp of Agaricus blazei (=Agaricus brasiliensis; =Agaricus subrufescens) is used as teas or capsules due to its antineoplastic effect but there are few reports of using mycelium for this purpose. The objective of this study was to evaluate the antineoplastic activity on sarcoma 180 cells implanted in mice of two forms of preparation of the mycelium from two A. blazei strains grown in culture medium with different concentrations of isolated soy protein. Mycelia were grown in Pontecorvo medium with different concentrations of isolated soybean protein (ISP). Mycelial hot water extract, moistened mycelial powder, hot water extract of green tea, Ifosfamida(®) (ifosfamide drug), and saline solution were administered daily by gavage in mice with sarcoma 180 cells to evaluate antineoplastic activity. It was concluded that antineoplastic activity was the same for both strains, except when used as moistened mycelial powder, which rules out the use of mycelial powder in capsules. Mycelial hot water extract had high antineoplastic activity with lower metabolic demand on the spleen and maintenance of normal blood parameters. Mycelial growth in different ISP concentrations had the same antineoplastic activity. Also the vegetative mycelium was as effective as the basidiocarp for sarcoma 180 tumor inhibition. Green tea was as effective as mycelial hot water extract.

To Take or Not to Take With Meals? Unraveling Issues Related to Food Effects Labeling for Oral Antineoplastic Drugs.

PubMed

Deng, Jiexin; Brar, Satjit S; Lesko, Lawrence J

2017-12-02

There has been controversy regarding whether bioavailability of certain oral oncology drugs should be maximized by taking these medications with food, irrespective of label instructions in the dosing and administration section. To provide insight into this controversy, we conducted an in-depth analysis for oral antineoplastic drugs approved by the Food and Drug Administration in 2000-2016 and identified important issues influencing food labeling decisions. Furthermore, a case study involving sonidegib, a drug approved for locally advanced basal cell carcinoma with a significant food effect on exposure, was used to demonstrate the consequences of failure to adhere to food label recommendations using drug-specific population pharmacokinetic and exposure-toxicity models. In 2000-2009, 80% (4 out of 5) of all approved oral antineoplastics with increased bioavailability in the fed state were labeled as "take on empty stomach." In contrast, we found that in 2010-2016 there is a greater diversity in food recommendations for drugs with increased bioavailability in the fed state. Currently, many oral oncology drugs are given with food to maximize their bioavailability; however, as seen from our case study of sonidegib, failure to fully adhere to label recommendations to either take with food or not could lead to adverse consequences in terms of safety and efficacy. © 2017, The American College of Clinical Pharmacology.

Repurposing psychiatric drugs as anti-cancer agents.

PubMed

Huang, Jing; Zhao, Danwei; Liu, Zhixiong; Liu, Fangkun

2018-04-10

Cancer is a major public health problem and one of the leading contributors to the global disease burden. The high cost of development of new drugs and the increasingly severe burden of cancer globally have led to increased interest in the search and development of novel, affordable anti-neoplastic medications. Antipsychotic drugs have a long history of clinical use and tolerable safety; they have been used as good targets for drug repurposing. Being used for various psychiatric diseases for decades, antipsychotic drugs are now reported to have potent anti-cancer properties against a wide variety of malignancies in addition to their antipsychotic effects. In this review, an overview of repurposing various psychiatric drugs for cancer treatment is presented, and the putative mechanisms for the anti-neoplastic actions of these antipsychotic drugs are reviewed. Copyright © 2018 Elsevier B.V. All rights reserved.

Examining factors that influence the effectiveness of cleaning antineoplastic drugs from drug preparation surfaces: a pilot study.

PubMed

Hon, Chun-Yip; Chua, Prescillia Ps; Danyluk, Quinn; Astrakianakis, George

2014-06-01

Occupational exposure to antineoplastic drugs has been documented to result in various adverse health effects. Despite the implementation of control measures to minimize exposure, detectable levels of drug residual are still found on hospital work surfaces. Cleaning these surfaces is considered as one means to minimize the exposure potential. However, there are no consistent guiding principles related to cleaning of contaminated surfaces resulting in hospitals to adopt varying practices. As such, this pilot study sought to evaluate current cleaning protocols and identify those factors that were most effective in reducing contamination on drug preparation surfaces. Three cleaning variables were examined: (1) type of cleaning agent (CaviCide®, Phenokil II™, bleach and chlorhexidine), (2) application method of cleaning agent (directly onto surface or indirectly onto a wipe) and (3) use of isopropyl alcohol after cleaning agent application. Known concentrations of antineoplastic drugs (either methotrexate or cyclophosphamide) were placed on a stainless steel swatch and then, systematically, each of the three cleaning variables was tested. Surface wipes were collected and quantified using high-performance liquid chromatography-tandem mass spectrometry to determine the percent residual of drug remaining (with 100% being complete elimination of the drug). No one single cleaning agent proved to be effective in completely eliminating all drug contamination. The method of application had minimal effect on the amount of drug residual. In general, application of isopropyl alcohol after the use of cleaning agent further reduced the level of drug contamination although measureable levels of drug were still found in some cases.

Restrained management of copper level enhances the antineoplastic activity of imatinib in vitro and in vivo.

PubMed

Hassan, Iftekhar; Khan, Azmat Ali; Aman, Shazia; Qamar, Wajhul; Ebaid, Hossam; Al-Tamimi, Jameel; Alhazza, Ibrahim M; Rady, Ahmed M

2018-01-26

The present study was designed to investigate if elevated copper level can be targeted to enhance the efficacy of a significant anticancer drug, imatinib (ITB). The antineoplastic activity of this drug was assessed in the HepG2, HEK-293, MCF-7 and MDA-MD-231 cells targeting elevated copper level as their common drug target. The cell lines were treated with the different doses of copper chloride (Cu II) and disulfiram (DSF) alone as well as in their combinations with the drug for 24 h in standard culture medium and conditions. The treated cells were subjected to various assays including MTT, PARP, p-53, caspase-7, caspase-3, LDH and single cell electrophoresis. The study shows that DSF and Cu (II) synergizes the anticancer activity of ITB to a significant extent in a dose-specific way as evidenced by the combinations treated groups. Furthermore, the same treatment strategy was employed in cancer-induced rats in which the combinations of ITB-DSF and ITB-Cu II showed enhanced antineoplastic activity as compared to ITB alone. However, DSF was more effective than Cu (II) as an adjuvant to the drug. Hence, restrained manipulation of copper level in tumor cells can orchestrate the redox and molecular dispositions inside the cells favoring the induction of apoptosis.

[Implementation of a robot for the preparation of antineoplastic drugs in the Pharmacy Service].

PubMed

Pacheco Ramos, María de la Paz; Arenaza Peña, Ainhoa Elisa; Santiago Pérez, Alejandro; Bilbao Gómez-Martino, Cristina; Zamora Barrios, María Dolores; Arias Fernández, María Lourdes

2015-05-01

To describe the implementation of a robot for the preparation of antineoplastic drugs in the Pharmacy Service and to be able to analyze the added value to pharmacotherapy. The implementation was carried out in June 2012 at a tertiary level Hospital, taking place in two periods: 1- test period with the installation of the robot, with technical configuration of the equipment and validation of 29 active ingredients and the integration of electronic prescribing software with the robot application (9 months). 2- Usage period (22 months). On the other hand, training was given to pharmacists and nurses. The robot uses image recognition, barcode identification and gravimetric controls for proper operation. These checks provide information about the error ratio in the preparation, with a margin of ± 10%, which after a pilot study was restricted to a range of ±4%. The robot was programmed to recognize bags, infusion pumps, syringes and vials. The added value was assessed for 31 months by identifying preparation's errors. 11,865 preparations were made by the robot, which meant approximately 40% of all antineoplastic prepared from 29 different active ingredients. 1.12% (n=133) of the errors were identified by the robot and therefore didn't reach the patient (negative desviation - 4%). These errors were corrected manually. The implementation of a robot in the preparation of antineoplastic drugs allows to identify errors therefore preventing them to arrive to the patient. This promotes safety and quality of the process, reducing the exposure to cytotoxic drugs from the manipulator. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

NIOSH health and safety practices survey of healthcare workers: training and awareness of employer safety procedures.

PubMed

Steege, Andrea L; Boiano, James M; Sweeney, Marie H

2014-06-01

The Health and Safety Practices Survey of Healthcare Workers describes current practices used to minimize chemical exposures and barriers to using recommended personal protective equipment for the following: antineoplastic drugs, anesthetic gases, high level disinfectants, surgical smoke, aerosolized medications (pentamidine, ribavirin, and antibiotics), and chemical sterilants. Twenty-one healthcare professional practice organizations collaborated with NIOSH to develop and implement the web-based survey. Twelve thousand twenty-eight respondents included professional, technical, and support occupations which routinely come in contact with the targeted hazardous chemicals. Chemical-specific safe handling training was lowest for aerosolized antibiotics (52%, n = 316), and surgical smoke (57%, n = 4,747). Reported employer procedures for minimizing exposure was lowest for surgical smoke (32%, n = 4,746) and anesthetic gases (56%, n = 3,604). Training and having procedures in place to minimize exposure to these chemicals is one indication of employer and worker safety awareness. Safe handling practices for use of these chemicals will be reported in subsequent papers. © 2014 Wiley Periodicals, Inc.

Effects of antineoplastic drugs on Lactobacillus casei and radioisotopic assays for serum folate

DOE Office of Scientific and Technical Information (OSTI.GOV)

Carmel, R.

1978-02-01

Microbiologic assay, usually employing Lactobacillus casei, remains the standard assay for serum folate to date. Among its disadvantages have been falsely low results in patients receiving bacteriostatic agents such as antibiotics. This study examined whether commonly used antineoplastic drugs had similar effect. Methotrexate and 5-fluorouracil depressed microbiologic serum folate levels. No effect was found for adriamycin, bleomycin, BCNU, cyclophosphamide, cytosine arabinoside, vincristine, vinblastine, mechlorethamine, mithramycin, hydroxyurea, and hydrocortisone. None of the drugs affected radioassay except methotrexate, which produced falsely high folate results. Thus, it appears that L. casei assay for folate becomes unreliable in patients receiving 5-fluorouracil and radioisotopic assaymore » becomes unreliable in those receiving methotrexate.« less

77 FR 38297 - Revised Document Posted: NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-27

.../2012-150 . Background: The NIOSH Alert: NIOSH published Preventing Occupational Exposures to.../docs/2004-165/ ). Appendix A of this Alert defined hazardous drugs and provided a list of drugs that...

Evaluation of new antiemetic agents and definition of antineoplastic agent emetogenicity--an update.

PubMed

Grunberg, Steven M; Osoba, David; Hesketh, Paul J; Gralla, Richard J; Borjeson, Sussanne; Rapoport, Bernardo L; du Bois, Andreas; Tonato, Maurizio

2005-02-01

Development of effective antiemetic therapy depends upon an understanding of both the antiemetic agents and the emetogenic challenges these agents are designed to address. New potential antiemetic agents should be studied in an orderly manner, proceeding from phase I to phase II open-label trials and then to randomized double-blind phase III trials comparing new agents and regimens to best standard therapy. Use of placebos in place of antiemetic therapy against highly or moderately emetogenic chemotherapy is unacceptable. Nausea and vomiting should be evaluated separately and for both the acute and delayed periods. Defining the emetogenicity of new antineoplastic agents is a challenge, since such data are often not reliably recorded during early drug development. A four-level classification system is proposed for emetogenicity of intravenous antineoplastic agents. A separate four-level classification system for emetogenicity of oral antineoplastic agents, which are often given over an extended period of time, is also proposed.

Occupational exposure to antineoplastic agents induces a high level of chromosome damage. Lack of an effect of GST polymorphisms

DOE Office of Scientific and Technical Information (OSTI.GOV)

Testa, Antonella; Giachelia, Manuela; Palma, Selena

The aim of our study was to investigate whether occupational exposure to antineoplastic drugs (AND) resulted in genetic damage, possibly indicative of adverse health effects in the long term. We performed a chromosomal aberrations (CA) analysis in peripheral blood lymphocytes (PBL) of a group of 76 trained nurses occupationally exposed to AND. Furthermore, we analysed whether genetic polymorphisms in four metabolic genes of the glutathione S-transferase (GST) family involved in antineoplastic drugs detoxification (GSTM1, GSTT1, GSTP1, GSTA1) had any effect on the yield of chromosomal aberrations in nurses exposed to antineoplastic agents. The exposed group showed a very significant increasemore » of genetic damage (p < 0.0001) potentially indicative of an increased risk of cancer. Unexpectedly, besides the elevated level of chromatid-type aberrations usually related to exposure to chemical agents, we found also severe chromosome damages such as chromosome deletions and dicentric chromosomes, usually related to radiation exposure. No significant association was detected between all GSTs genotypes and chromosome damage. In conclusion, our data show how the occupational exposure to AND is associated to a potential cancer risk, suggesting that current prevention methods do not completely eliminate opportunities for exposure and supporting the need to improve the actual safety practices.« less

[Trends in drug-induced liver injury based on reports of adverse reactions to PMDA in Japan].

PubMed

Sudo, Chie; Maekawa, Keiko; Segawa, Katsunori; Hanatani, Tadaaki; Sai, Kimie; Saito, Yoshiro

2012-01-01

Reports on drug-related adverse reactions from manufacturing/distributing pharmaceutical companies or medical institutions/pharmacies are regulated under the Pharmaceutical Affairs Law of Japan, and this system is important for post-marketing safety measures. Although association between the medicine and the adverse event has not been clearly evaluated, and an incidence may be redundantly reported, this information would be useful to roughly grasp the current status of drug-related adverse reactions. In the present study, we analyzed the incidence of drug-induced liver injury by screening the open-source data publicized by the homepage of Pharmaceutical and Medical Devices Agency from 2005 to 2011 fiscal years. Major drug-classes suspected to cause general drug-induced liver injury were antineoplastics, anti-inflammatory agents/common cold drugs, chemotherapeutics including antituberculous drugs, antidiabetics, antiulcers and antiepileptics. In addition, reported cases for fulminant hepatitis were also summarized. We found that antituberculous isoniazid and antineoplastic tegafur-uracil were the top two suspected drugs. These results might deepen understanding of current situations for the drug-induced liver injury in Japan.

PubMed

Poupeau, Céline; Roland, Christel; Bussières, Jean-François

2016-01-01

There is increasing evidence that traces of hazardous drugs occur in the urine of health care professionals who are exposed to these drugs. To review the scientific literature regarding urinary monitoring of health care professionals exposed to antineoplastic drugs through their work. A search of PubMed using the Medical Subject Headings 'occupational exposure' and 'antineoplastic agents' and of Google Scholar using the terms 'antineoplastic', 'urine', and 'occupational exposure'. The analysis covered all articles in English or French pertaining to health care professionals exposed to hazardous drugs in the workplace, published from January 1, 2010, to December 31, 2015. Articles that did not discuss the results of urine tests and those concerning veterinarians, as well as literature reviews, editorials, letters to the editor, and conference abstracts, were excluded. Twenty-four articles were retained. The studies were conducted in 52 health care institutions in 7 countries. They included 826 workers exposed to hazardous drugs and 175 controls, specifically nurses ( n = 16 studies), pharmacists ( n = 10), pharmacy technicians ( n = 8), physicians ( n = 7), health care aides ( n = 2), and others ( n = 8). Various analytical methods were used to quantify the presence of 13 hazardous drugs, primarily cyclophosphamide ( n = 16 studies), platinum-based drugs ( n = 7), and alpha-fluoro-beta-alanine, a urine metabolite derived from 5-fluorouracil ( n = 3). The proportion of workers with positive results ranged from 0% ( n = 10 studies) to 100% ( n = 4). Considering only those studies that allowed calculation of the rate of workers with at least one positive urine sample ( n = 23), the total proportion was 21% (173/809 workers, for all methods and drugs combined). Twenty-four studies on urine monitoring were conducted in 7 countries between 2010 and 2015. In several studies, no traces of drugs were detected in urine.

From Molecular Mechanisms to Clinical Management of Antineoplastic Drug-Induced Cardiovascular Toxicity: A Translational Overview.

PubMed

Tocchetti, Carlo Gabriele; Cadeddu, Christian; Di Lisi, Daniela; Femminò, Saveria; Madonna, Rosalinda; Mele, Donato; Monte, Ines; Novo, Giuseppina; Penna, Claudia; Pepe, Alessia; Spallarossa, Paolo; Varricchi, Gilda; Zito, Concetta; Pagliaro, Pasquale; Mercuro, Giuseppe

2017-05-15

Antineoplastic therapies have significantly improved the prognosis of oncology patients. However, these treatments can bring to a higher incidence of side-effects, including the worrying cardiovascular toxicity (CTX). Substantial evidence indicates multiple mechanisms of CTX, with redox mechanisms playing a key role. Recent data singled out mitochondria as key targets for antineoplastic drug-induced CTX; understanding the underlying mechanisms is, therefore, crucial for effective cardioprotection, without compromising the efficacy of anti-cancer treatments. CTX can occur within a few days or many years after treatment. Type I CTX is associated with irreversible cardiac cell injury, and it is typically caused by anthracyclines and traditional chemotherapeutics. Type II CTX is generally caused by novel biologics and more targeted drugs, and it is associated with reversible myocardial dysfunction. Therefore, patients undergoing anti-cancer treatments should be closely monitored, and patients at risk of CTX should be identified before beginning treatment to reduce CTX-related morbidity. Genetic profiling of clinical risk factors and an integrated approach using molecular, imaging, and clinical data may allow the recognition of patients who are at a high risk of developing chemotherapy-related CTX, and it may suggest methodologies to limit damage in a wider range of patients. The involvement of redox mechanisms in cancer biology and anticancer treatments is a very active field of research. Further investigations will be necessary to uncover the hallmarks of cancer from a redox perspective and to develop more efficacious antineoplastic therapies that also spare the cardiovascular system. Antioxid. Redox Signal. 00, 000-000.

PTTG1 Attenuates Drug-Induced Cellular Senescence

PubMed Central

Tong, Yunguang; Zhao, Weijiang; Zhou, Cuiqi; Wawrowsky, Kolja; Melmed, Shlomo

2011-01-01

As PTTG1 (pituitary tumor transforming gene) abundance correlates with adverse outcomes in cancer treatment, we determined mechanisms underlying this observation by assessing the role of PTTG1 in regulating cell response to anti-neoplastic drugs. HCT116 cells devoid of PTTG1 (PTTG1−/−) exhibited enhanced drug sensitivity as assessed by measuring BrdU incorporation in vitro. Apoptosis, mitosis catastrophe or DNA damage were not detected, but features of senescence were observed using low doses of doxorubicin and TSA. The number of drug-induced PTTG1−/− senescent cells increased ∼4 fold as compared to WT PTTG1-replete cells (p<0.001). p21, an important regulator of cell senescence, was induced ∼3 fold in HCT116 PTTG1−/− cells upon doxorubicin or Trichostatin A treatment. Binding of Sp1, p53 and p300 to the p21 promoter was enhanced in PTTG1−/− cells after treatment, suggesting transcriptional regulation of p21. p21 knock down abrogated the observed senescent effects of these drugs, indicating that PTTG1 likely suppresses p21 to regulate drug-induced senescence. PTTG1 also regulated SW620 colon cancer cells response to doxorubicin and TSA mediated by p21. Subcutaneously xenografted PTTG1−/− HCT116 cells developed smaller tumors and exhibited enhanced responses to doxorubicin. PTTG1−/− tumor tissue derived from excised tumors exhibited increased doxorubicin-induced senescence. As senescence is a determinant of cell responses to anti-neoplastic treatments, these findings suggest PTTG1 as a tumor cell marker to predict anti-neoplastic treatment outcomes. PMID:21858218

Early Diagnosis and Prediction of Anticancer Drug-induced Cardiotoxicity: From Cardiac Imaging to "Omics" Technologies.

PubMed

Madonna, Rosalinda

2017-07-01

Heart failure due to antineoplastic therapy remains a major cause of morbidity and mortality in oncological patients. These patients often have no prior manifestation of disease. There is therefore a need for accurate identification of individuals at risk of such events before the appearance of clinical manifestations. The present article aims to provide an overview of cardiac imaging as well as new "-omics" technologies, especially with regard to genomics and proteomics as promising tools for the early detection and prediction of cardiotoxicity and individual responses to antineoplastic drugs. Copyright © 2017 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

Access to Cytotoxic Medicines by Children With Cancer: A Focus on Low and Middle Income Countries.

PubMed

Barr, Ronald; Robertson, Jane

2016-02-01

The Essential Medicines Working Group of the International Society of Pediatric Oncology (SIOP) has proposed a list of antineoplastic drugs that should be available in low and middle income countries. Data were extracted on the listing of 18 essential and 8 ancillary antineoplastic medicines in the national essential medicines lists (NEMLs) or national reimbursable medicines lists (NRMLs) of 135 countries with gross national income (GNI) per capita of less than US $25,000. Correlations between numbers of medicines listed and GNI per capita, annual government health expenditure (AGHE) per capita, and the number of physicians per million people were examined. Listing of the 18 essential antineoplastic drugs ranged from 27% (thioguanine) to 95% (methotrexate). The median number of medicines listed was 7 (0-18) in low income countries (n = 26) and 14 in lower-middle (n = 42), upper-middle (n = 44), and high income countries (n = 20). For the ancillary eight medicines, the median was one (0-8) across the 135 countries. Correlations with GNI per capita (r = 0.17, P = 0.0266) and physician density (r = 0.25, P = 0.0017) were statistically significant; not so for AGHE per capita (r = 0.00, P = 0.5000). There was large variability within income groups in numbers of antineoplastic agents identified as essential in NEMLs and NRMLs. While not a direct measure of availability, listing is an important step, guiding procurement for the public sector. These results focus attention on deficits in NEMLs and NMRLs as a step to improving access to effective antineoplastic medicines for cancers in children in low and middle income countries. © 2015 Wiley Periodicals, Inc.

Interaction of human organic anion transporter 2 (OAT2) and sodium taurocholate cotransporting polypeptide (NTCP) with antineoplastic drugs.

PubMed

Marada, Venkata V V R; Flörl, Saskia; Kühne, Annett; Müller, Judith; Burckhardt, Gerhard; Hagos, Yohannes

2015-01-01

The ability of an antineoplastic drug to exert its cytostatic effect depends largely on the balance between its uptake into and extrusion from the cancer cells. ATP driven efflux transporter proteins drive the export of antineoplastic drugs and play a pivotal role in the development of chemoresistance. As regards uptake transporters, comparably less is known on their impact in drug action. In the current study, we characterized the interactions of two uptake transporter proteins, expressed mainly in the liver; the organic anion transporter 2 (OAT2, encoded by the SLC22A7 gene) and the sodium taurocholate cotransporting polypeptide (NTCP, encoded by the SLC10A1 gene), stably transfected in human embryonic kidney cells, with some antineoplastic agents that are routinely being used in cancer chemotherapy. Whereas NTCP did not show any strong interactions with the cytostatics tested, we observed a very strong inhibition of OAT2 mediated [(3)H] cGMP uptake in the presence of bendamustine, irinotecan and paclitaxel. The Ki values of OAT2 for bendamustine, irinotecan and paclitaxel were determined to be 43.3±4.33μM, 26.4±2.34μM and 10.4±0.45μM, respectively. Incubation of bendamustine with OAT2 expressing cells increased the caspase-3 activity, and this increase was inhibited by simultaneous incubation with bendamustine and probenecid, a well-known inhibitor of OATs, suggesting that bendamustine is a substrate of OAT2. A higher accumulation of irinotecan was observed in OAT2 expressing cells compared to control pcDNA cells by HPLC analysis of cell lysates. The accumulation was diminished in the presence of cGMP, the substrate we used to functionally characterize OAT2, suggesting specificity of this uptake and the fact that OAT2 mediates uptake of irinotecan. Copyright © 2014 Elsevier Ltd. All rights reserved.

Ecotoxicity of disinfectant benzalkonium chloride and its mixture with antineoplastic drug 5-fluorouracil towards alga Pseudokirchneriella subcapitata

PubMed Central

Ženko, Maja

2018-01-01

Background Benzalkonium chloride (BAC) is one of the most common ingredients of the disinfectants. It is commonly detected in surface and wastewaters where it can interact with the residues of pharmaceuticals that are also common wastewater pollutants. Among the latter, the residues of antineoplastic drugs are of particular concern as recent studies showed that they can induce adverse effect in aquatic organisms at environmentally relevant concentrations. Methods Ecotoxicity of BAC as an individual compound and in a binary mixture with an antineoplastic drug 5-fluorouracil (5-FU) was determined towards alga Pseudokirchneriella subcapitata, a representative of primary producers. The toxicity of the BAC+5-FU binary mixture was predicted by the two basic models: concentration addition (CA) and independent action (IA), and compared to the experimentally determined toxicity. Additionally combination index (CI) was calculated to determine the type of interaction. Results After 72 h exposure to BAC a concentration dependent growth inhibition of P. subcapitata was observed with an EC50 0.255 mg/L. Comparing the predicted no effect concentration to the measured concentrations in the surface waters indicate that BAC at current applications and occurrence in aquatic environment may affect algal populations. The measured toxicity of the mixture was higher from the predicted and calculated CI confirmed synergistic effect on the inhibition of algal growth, at least at EC50 concentration. The observed synergism may have impact on the overall toxicity of wastewaters, whereas it is less likely for general environments because the concentrations of 5-FU are several orders of magnitude lower from its predicted no effect concentration. Discussion These results indicate that combined effects of mixtures of disinfectants and antineoplastic drugs should be considered in particular when dealing with environmental risk assessment as well as the management of municipal and hospital wastewaters. PMID:29938131

Occupational exposures among nurses and risk of spontaneous abortion.

PubMed

Lawson, Christina C; Rocheleau, Carissa M; Whelan, Elizabeth A; Lividoti Hibert, Eileen N; Grajewski, Barbara; Spiegelman, Donna; Rich-Edwards, Janet W

2012-04-01

We investigated self-reported occupational exposure to antineoplastic drugs, anesthetic gases, antiviral drugs, sterilizing agents (disinfectants), and X-rays and the risk of spontaneous abortion in US nurses. Pregnancy outcome and occupational exposures were collected retrospectively from 8461 participants of the Nurses' Health Study II. Of these, 7482 were eligible for analysis using logistic regression. Participants reported 6707 live births, and 775 (10%) spontaneous abortions (<20 weeks). After adjusting for age, parity, shift work, and hours worked, antineoplastic drug exposure was associated with a 2-fold increased risk of spontaneous abortion, particularly with early spontaneous abortion before the 12th week, and 3.5-fold increased risk among nulliparous women. Exposure to sterilizing agents was associated with a 2-fold increased risk of late spontaneous abortion (12-20 weeks), but not with early spontaneous abortion. This study suggests that certain occupational exposures common to nurses are related to risks of spontaneous abortion. Published by Mosby, Inc.

Ontology-based systematic representation and analysis of traditional Chinese drugs against rheumatism.

PubMed

Liu, Qingping; Wang, Jiahao; Zhu, Yan; He, Yongqun

2017-12-21

Rheumatism represents any disease condition marked with inflammation and pain in the joints, muscles, or connective tissues. Many traditional Chinese drugs have been used for a long time to treat rheumatism. However, a comprehensive information source for these drugs is still missing, and their anti-rheumatism mechanisms remain unclear. An ontology for anti-rheumatism traditional Chinese drugs would strongly support the representation, analysis, and understanding of these drugs. In this study, we first systematically collected reported information about 26 traditional Chinese decoction pieces drugs, including their chemical ingredients and adverse events (AEs). By mostly reusing terms from existing ontologies (e.g., TCMDPO for traditional Chinese medicines, NCBITaxon for taxonomy, ChEBI for chemical elements, and OAE for adverse events) and making semantic axioms linking different entities, we developed the Ontology of Chinese Medicine for Rheumatism (OCMR) that includes over 3000 class terms. Our OCMR analysis found that these 26 traditional Chinese decoction pieces are made from anatomic entities (e.g., root and stem) from 3 Bilateria animals and 23 Mesangiospermae plants. Anti-inflammatory and antineoplastic roles are important for anti-rheumatism drugs. Using the total of 555 unique ChEBI chemical entities identified from these drugs, our ChEBI-based classification analysis identified 18 anti-inflammatory, 33 antineoplastic chemicals, and 9 chemicals (including 3 diterpenoids and 3 triterpenoids) having both anti-inflammatory and antineoplastic roles. Furthermore, our study detected 22 diterpenoids and 23 triterpenoids, including 16 pentacyclic triterpenoids that are likely bioactive against rheumatism. Six drugs were found to be associated with 184 unique AEs, including three AEs (i.e., dizziness, nausea and vomiting, and anorexia) each associated with 5 drugs. Several chemical entities are classified as neurotoxins (e.g., diethyl phthalate) and allergens (e.g., eugenol), which may explain the formation of some TCD AEs. The OCMR could be efficiently queried for useful information using SPARQL scripts. The OCMR ontology was developed to systematically represent 26 traditional anti-rheumatism Chinese drugs and their related information. The OCMR analysis identified possible anti-rheumatism and AE mechanisms of these drugs. Our novel ontology-based approach can also be applied to systematic representation and analysis of other traditional Chinese drugs.

Occupational exposures to antineoplastic drugs and ionizing radiation in Canadian veterinary settings: findings from a national surveillance project.

PubMed

Hall, Amy L; Davies, Hugh W; Demers, Paul A; Nicol, Anne-Marie; Peters, Cheryl E

2013-11-01

Although veterinary workers may encounter various occupational health hazards, a national characterization of exposures is lacking in Canada. This study used secondary data sources to identify veterinary exposure prevalence for ionizing radiation and antineoplastic agents, as part of a national surveillance project. For ionizing radiation, data from the Radiation Protection Bureau of Health Canada were used to identify veterinarians and veterinary technicians monitored in 2006. This was combined with Census statistics to estimate a prevalence range and dose levels. For antineoplastic agents, exposure prevalence was estimated using statistics on employment by practice type and antineoplastic agent usage rates, obtained from veterinary licensing bodies and peer-reviewed literature. In 2006, 7,013 (37% of all) Canadian veterinary workers were monitored for ionizing radiation exposure. An estimated 3.3% to 8.2% of all veterinarians and 2.4% to 7.2% of veterinary technicians were exposed to an annual ionizing radiation dose above 0.1 mSv, representing a total of between 536 and 1,450 workers. All monitored doses were below regulatory limits. For antineoplastic agents, exposure was predicted in up to 5,300 (23%) of all veterinary workers, with an estimated prevalence range of 22% to 24% of veterinarians and 20% to 21% of veterinary technicians. This is the first national-level assessment of exposure to ionizing radiation and antineoplastic agents in Canadian veterinary settings. These hazards may pose considerable health risks. Exposures appeared to be low, however our estimates should be validated with comprehensive exposure monitoring and examination of determinants across practice areas, occupations, and tasks.

Off-label prescription of antineoplastic drugs: an Italian prospective, observational, multicenter survey.

PubMed

Roila, Fausto; Ballatori, Enzo; Labianca, Roberto; De Braud, Filippo; Borgonovo, Karen; Martelli, Olga; Gallo, Ciro; Tinazzi, Angelo; Perrone, Francesco

2009-01-01

An appropriate use of drugs should follow the registered indications. Different reasons can induce oncologists to prescribe drugs off-label. The aim of this study was to describe incidence and characteristics of these prescriptions in Italy. Patients submitted to chemotherapy in 15 Italian oncology centers were evaluated for two randomized non-consecutive days of two weeks in May 2006. The study enrolled 644 patients receiving 1,053 drugs. Overall, 199 of 1053 (18.9%) prescriptions were off-label. In 92 of 199 cases (46.2%), the drugs were used for a neoplasm for which they were not approved, but there was scientific evidence (one or more randomized clinical trials or more phase II studies published in a major oncology journal) justifying the prescription. In 27 cases (13.6%), the drugs were prescribed for a rare neoplasm (cisplatin and gemcitabine in mesothelioma). In 20/21 cases (10.1%/10.5%), drugs were used in association/alone in contrast with the approved use (capecitabine in association in colorectal cancer). In 28/11 cases (14.0%/5.6%), the drugs were used in lines of chemotherapy subsequent/previous to that approved. Off-label use of antineoplastic drugs, in this observational survey, represents less than 20% of the prescriptions, and most of them are based on scientific evidence of efficacy.

Thyroid Dysfunction from Antineoplastic Agents

PubMed Central

Larsen, P. Reed; Marqusee, Ellen

2011-01-01

Unlike cytotoxic agents that indiscriminately affect rapidly dividing cells, newer antineoplastic agents such as targeted therapies and immunotherapies are associated with thyroid dysfunction. These include tyrosine kinase inhibitors, bexarotene, radioiodine-based cancer therapies, denileukin diftitox, alemtuzumab, interferon-α, interleukin-2, ipilimumab, tremelimumab, thalidomide, and lenalidomide. Primary hypothyroidism is the most common side effect, although thyrotoxicosis and effects on thyroid-stimulating hormone secretion and thyroid hormone metabolism have also been described. Most agents cause thyroid dysfunction in 20%–50% of patients, although some have even higher rates. Despite this, physicians may overlook drug-induced thyroid dysfunction because of the complexity of the clinical picture in the cancer patient. Symptoms of hypothyroidism, such as fatigue, weakness, depression, memory loss, cold intolerance, and cardiovascular effects, may be incorrectly attributed to the primary disease or to the antineoplastic agent. Underdiagnosis of thyroid dysfunction can have important consequences for cancer patient management. At a minimum, the symptoms will adversely affect the patient’s quality of life. Alternatively, such symptoms can lead to dose reductions of potentially life-saving therapies. Hypothyroidism can also alter the kinetics and clearance of medications, which may lead to undesirable side effects. Thyrotoxicosis can be mistaken for sepsis or a nonendocrinologic drug side effect. In some patients, thyroid disease may indicate a higher likelihood of tumor response to the agent. Both hypothyroidism and thyrotoxicosis are easily diagnosed with inexpensive and specific tests. In many patients, particularly those with hypothyroidism, the treatment is straightforward. We therefore recommend routine testing for thyroid abnormalities in patients receiving these antineoplastic agents. PMID:22010182

To create a cleanroom controlled environment using a mobile air decontamination unit for the preparation of antineoplastic drugs.

PubMed

Lecordier, Julien; Plivard, Claire; Gardeux, Michel; Daouadi, Karim; Lahet, Jean-Jacques

2016-02-01

To use a mobile air decontamination unit (MADU) for a microbial destruction and decreased particle burden making a cleanroom controlled environment in a Centralized Chemotherapy Preparation Unit (CCPU). Good manufacturing practices (GMP) in France specify that the ambient air in the vicinity of a class III biosafety cabinet (isolator) complies with air cleanliness ISO 8 level in CCPU. This guideline has a significant impact because implementing a dedicated air handling unit (AHU) brings some engineering constraints and generates substantial additional costs. Authors have previously studied some technical and economical aspects to evaluate the feasibility of the MADU option. Using a MADU was the chosen option. Qualification of the CCPU showed that results were in compliance with the French GMP. After one year of use, the efficiency of the MADU was confirmed. According to these results, using a MADU constitutes a beneficial option for CCPU previously equipped with an isolator when compared to renovation work involving a standard built-in AHU. © The Author(s) 2014.

Azelaic acid was sensitizing effect in the chemotherapeutic treatment of several melanoma cell lines.

PubMed

Rodriguez-Vicente, J; Vicente-Ortega, V; Canteras-Jordana

1996-12-01

Chemotherapy for melanoma results in low response and must be reinforced with sensitizer compounds. We believed that azelaic acid (AZA) could modulate melanomas' resistance to antineoplastics. Therefore we tried to compare in vitro treatment with antineoplastics alone versus AZA treatment followed by antineoplastics. We carried out MTT assays to evaluate the cytotoxicity of melphalan, lomustine (CCNU), fotemustine, and 4-Hydroxyanisole (4-HA) on three melanoma lines (B16F10, SK-MEL-28, and SK-MEL-1), and the modulating effect of pretreatment with AZA (1 mM). AZA showed a dose-dependent antineoplastic activity on the three lines. Melphalan was the most active drug followed by CCNU, fotemustine, and 4-HA. The most sensitive line was B16F10 and the least sensitive was SK-meL-1. Previous treatment with AZA of B16F10 reinforced the effect of melphalan (2.5 times), CCNU (10 times), and fotemustine (14 times); whereas for SK-MEL-28 and SK-MEL-1, only the cytotoxicity of CCNU and fotemustine increased. An antagonist effect was produced by 4-HA on all three lines. We concluded that AZA enhances in vitro cytotoxicity of CCNU and fotemustine.

Occupational exposures among nurses and risk of spontaneous abortion

PubMed Central

LAWSON, Christina C; ROCHELEAU, Carissa M.; WHELAN, Elizabeth A; LIVIDOTI HIBERT, Eileen N.; GRAJEWSKI, Barbara; SPIEGELMAN, Donna; RICH-EDWARDS, Janet W.

2015-01-01

Objective We investigated self-reported occupational exposure to antineoplastic drugs, anesthetic gases, antiviral drugs, sterilizing agents (disinfectants), and X-rays and the risk of spontaneous abortion in U.S. nurses. Study Design Pregnancy outcome and occupational exposures were collected retrospectively from 8,461 participants of the Nurses’ Health Study II. Of these, 7,482 were eligible for analysis using logistic regression. Results Participants reported 6,707 live births, and 775 (10%) spontaneous abortions (<20 weeks). After adjusting for age, parity, shift work, and hours worked, antineoplastic drug exposure was associated with a 2-fold increased risk of spontaneous abortion, particularly with early spontaneous abortion before the 12th week, and 3.5-fold increased risk among nulliparous women. Exposure to sterilizing agents was associated with a 2-fold increased risk of late spontaneous abortion (12–20 weeks), but not with early spontaneous abortion. Conclusion This study suggests that certain occupational exposures common to nurses are related to risks of spontaneous abortion. PMID:22304790

Stereocomplex micelle from nonlinear enantiomeric copolymers efficiently transports antineoplastic drug

NASA Astrophysics Data System (ADS)

Wang, Jixue; Shen, Kexin; Xu, Weiguo; Ding, Jianxun; Wang, Xiaoqing; Liu, Tongjun; Wang, Chunxi; Chen, Xuesi

2015-05-01

Nanoscale polymeric micelles have attracted more and more attention as a promising nanocarrier for controlled delivery of antineoplastic drugs. Herein, the doxorubicin (DOX)-loaded poly(D-lactide)-based micelle (PDM/DOX), poly(L-lactide)-based micelle (PLM/DOX), and stereocomplex micelle (SCM/DOX) from the equimolar mixture of the enantiomeric four-armed poly(ethylene glycol)-polylactide (PEG-PLA) copolymers were successfully fabricated. In phosphate-buffered saline (PBS) at pH 7.4, SCM/DOX exhibited the smallest hydrodynamic diameter ( D h) of 90 ± 4.2 nm and the slowest DOX release compared with PDM/DOX and PLM/DOX. Moreover, PDM/DOX, PLM/DOX, and SCM/DOX exhibited almost stable D hs of around 115, 105, and 90 nm at above normal physiological condition, respectively, which endowed them with great potential in controlled drug delivery. The intracellular DOX fluorescence intensity after the incubation with the laden micelles was different degrees weaker than that incubated with free DOX · HCl within 12 h, probably due to the slow DOX release from micelles. As the incubation time reached to 24 h, all the cells incubated with the laden micelles, especially SCM/DOX, demonstrated a stronger intracellular DOX fluorescence intensity than free DOX · HCl-cultured ones. More importantly, all the DOX-loaded micelles, especially SCM/DOX, exhibited potent antineoplastic efficacy in vitro, excellent serum albumin-tolerance stability, and satisfactory hemocompatibility. These encouraging data indicated that the loading micelles from nonlinear enantiomeric copolymers, especially SCM/DOX, might be promising in clinical systemic chemotherapy through intravenous injection.

Recent insights in nanotechnology-based drugs and formulations designed for effective anti-cancer therapy.

PubMed

Piktel, Ewelina; Niemirowicz, Katarzyna; Wątek, Marzena; Wollny, Tomasz; Deptuła, Piotr; Bucki, Robert

2016-05-26

The rapid development of nanotechnology provides alternative approaches to overcome several limitations of conventional anti-cancer therapy. Drug targeting using functionalized nanoparticles to advance their transport to the dedicated site, became a new standard in novel anti-cancer methods. In effect, the employment of nanoparticles during design of antineoplastic drugs helps to improve pharmacokinetic properties, with subsequent development of high specific, non-toxic and biocompatible anti-cancer agents. However, the physicochemical and biological diversity of nanomaterials and a broad spectrum of unique features influencing their biological action requires continuous research to assess their activity. Among numerous nanosystems designed to eradicate cancer cells, only a limited number of them entered the clinical trials. It is anticipated that progress in development of nanotechnology-based anti-cancer materials will provide modern, individualized anti-cancer therapies assuring decrease in morbidity and mortality from cancer diseases. In this review we discussed the implication of nanomaterials in design of new drugs for effective antineoplastic therapy and describe a variety of mechanisms and challenges for selective tumor targeting. We emphasized the recent advantages in the field of nanotechnology-based strategies to fight cancer and discussed their part in effective anti-cancer therapy and successful drug delivery.

Effects of open-air temperature on air temperature inside biological safety cabinet.

PubMed

Umemura, Masayuki; Shigeno, Katsuro; Yamamura, Keiko; Osada, Takashi; Soda, Midori; Yamada, Kiyofumi; Ando, Yuichi; Wakiya, Yoshifumi

2011-02-14

In Japan, biological safety cabinets (BSCs) are normally used by medical staff while handling antineoplastic agents. We have also set up a class II B2 BSC at the Division of Chemotherapy for Outpatients. The air temperature inside this BSC, however, decreases in winter. We assumed that this decrease is caused by the intake of open-air. Therefore, we investigated the effects of low open-air temperature on the BSC temperature and the time of admixtures of antineoplastic agents. The studies were conducted from January 1 to March 31, 2008. The outdoor air temperature was measured in the shade near the intake nozzle of the BSC and was compared with the BSC temperature. The correlation between the outdoor air temperature and the BSC temperature, the dissolution time of cyclophosphamide (CPA) and gemcitabine (GEM), and accurate weight measurement of epirubicin (EPI) solution were investigated for low and normal BSC temperatures. The BSC temperature was correlated with the open-air temperature for open-air temperatures of 5-20°C (p < 0.0001). The dissolution of CPA and GEM at these temperatures was significantly delayed as compared to that at 25°C (p < 0.01 and p < 0.0001, respectively). The weight measurement of EPI solution using a syringe method lacks accuracy because of its high coefficient of viscosity at low temperatures (p < 0.01). These results suggest that the BSC temperature decreases below room temperature in winter when air is drawn from outdoors. We showed that the BSC temperature affects the dissolution rate of antineoplastic agents. Further, we suggested that the BSC temperature drop might delay the affair of the admixtures of antineoplastic agents and increase the waiting time of outpatients for chemotherapy.

New solid state forms of antineoplastic 5-fluorouracil with anthelmintic piperazine

NASA Astrophysics Data System (ADS)

Moisescu-Goia, C.; Muresan-Pop, M.; Simon, V.

2017-12-01

The aim of the present study was to asses the formation of solid forms between the 5-fluorouracil chemotherapy drug and the anthelmintic piperazine. Two new solid forms of antineoplastic agent 5-fluorouracil with anthelmintic piperazine were obtained by liquid assisted ball milling and slurry crystallization methods. The Nsbnd H hydrogen bonding donors and C = O hydrogen bonding acceptors of 5-fluorouracil allow to form co-crystals with other drugs delivering improved properties for medical applications, as proved for other compounds of pharmaceutical interest. Both new solid forms were investigated using X-ray powder diffraction (XRD), differential thermal analysis (DTA) and Fourier transform infrared (FTIR) spectroscopy. The XRD results show that by both methods were successfully synthesized new solid forms of 5-fluorouracil with piperazine. According to FTIR results the form prepared by lichid assisted grinding process was obtained as co-crystal and the other one, prepared by slurry method, resulted as a salt.

Optimal Anti-cancer Drug Profiles for Effective Penetration of the Anti-cancer Drug Market by Generic Drugs in Japan.

PubMed

Shibata, Shoyo; Matsushita, Maiko; Saito, Yoshimasa; Suzuki, Takeshi

2017-01-01

The increased use of generic drugs is a good indicator of the need to reduce the increasing costs of prescription drugs. Since there are more expensive drugs compared with other therapeutic areas, "oncology" is an important one for generic drugs. The primary objective of this article was to quantify the extent to which generic drugs in Japan occupy each level of the Anatomical Therapeutic Chemical (ATC) classification system. The dataset used in this study was created from publicly available information obtained from the IMS Japan Pharmaceutical Market database. Data on the total amount of sales and number of prescriptions for anti-cancer drugs between 2010 and 2016 in Japan were selected. The data were categorized according to the third level of the ATC classification system. All categories of the ATC classification system had increased market shares in Japan between 2010 and 2016. The barriers to market entry were relatively low in L01F (platinum anti-neoplastics), L01C (plant-based neoplastics), L02B (cytostatic hormone antagonists), and L01D (anti-neoplastic antibiotics) but were high in L02A (cytostatic hormones), L01H (protein kinase inhibitors), and L01B (anti-metabolites). Generic cancer drugs could bring savings to Japanese health care systems. Therefore, their development should be directed toward niche markets, such as L02A, L01H, and L01B, and not competitive markets.

Application and assessment of a regular environmental monitoring of the antineoplastic drug contamination level in pharmacies - the MEWIP project.

PubMed

Kiffmeyer, Thekla K; Tuerk, Jochen; Hahn, Moritz; Stuetzer, Hartmut; Hadtstein, Claudia; Heinemann, André; Eickmann, Udo

2013-05-01

A large-scale study was carried out in order to determine the contamination level of antineoplastic drugs in pharmacies and to investigate the suitability and effects of wipe sample monitoring at regular intervals. A specific study design was developed. The 130 participating pharmacies were divided into a study and a control group, carrying out five and two wipe sampling cycles, respectively. The work practice was analyzed using questionnaires to identify factors that influence the contamination level. From 1269 wipe samples, 774 (61%) were contaminated with at least one of the analyzed cytotoxic drugs: cyclophosphamide, docetaxel, etoposide, 5-fluorouracil, gemcitabine, ifosfamide, methotrexate, and paclitaxel. A significant decrease of the contamination with cyclophosphamide and 5-fluorouracil was observed in the study group. The Monitoring-Effect Study of Wipe Sampling in Pharmacies method has proven to be a reliable and affordable tool for contamination control. Based on the 90th percentile of the contamination values, a substance-independent performance-based guidance value of 0.1ng cm(-2) has been derived.

Effects of various antineoplastic agents on an established human melanoma cell line (G-361).

PubMed

García Reverte, J M; Bernabeu Esclapez, A; Muñoz Ramos, J; Vicente Ortega, V; Canteras Jordana, M

1995-01-01

An established human melanoma cell line was treated with several concentrations of three antineoplastic drugs: melphalan (0.016, 0.032, 0.16 microns), CCNU (1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea) (0.04, 0.21, 0.42 microM), and 4-OHA (4-hydroxyanisole) (4.01 x 10(-4), 1.20 x 10(-3), 2.4 x 10(-3) microM), and the effects on cell growth and viability were compared. 24 hours after treatment, 4-OHA (ID50 = 2.4 x 10(-3) microM) was more cytotoxic than melphalan (ID50 = 0.016 microM) and CCNU (ID50 = 0.21 microM). However, after 96 hours exposure, the most effective drug was CCNU (growth rate = -1.277), which caused the death of the culture. This was followed by melphalan (growth rate = -1.024) and finally 4-OHA (growth rate = -0.69). Similar ultrastructural cell injuries were observed after the use of the three drugs: the dilation of endoplasmic reticulum vesicles and the nuclear membrane; mitochondria swelling; and the existence of lamellar structures and cytoplasmic vacuoles.

[Current movements of four serious adverse events induced by medicinal drugs based on spontaneous reports in Japan].

PubMed

Sudo, Chie; Azuma, Yu-ichiro; Maekawa, Keiko; Kaniwa, Nahoko; Sai, Kimie; Saito, Yoshiro

2011-01-01

Spontaneous reports on suspected serious adverse events caused by medicines from manufacturing/distributing pharmaceutical companies or medical institutions/pharmacies are regulated by the Pharmaceutical Affairs Law of Japan, and this system is important for post-marketing safety features. Although causal relationship between the medicine and the adverse event is not evaluated, and one incidence may be redundantly reported, this information would be useful to roughly grasp the current movements of drug-related serious adverse events, We searched open-source data of the spontaneous reports publicized by Pharmaceutical and Medical Devices Agency for 4 serious adverse events (interstitial lung disease, rhabdomyolysis, anaphylaxis, and Stevens-Johnson syndrome/toxic epidermal necrolysis) from 2004 to 2010 fiscal year (for 2010, from April 1 st to January 31th). Major drug-classes suspected to the adverse events were antineoplastics for interstitial lung disease, hyperlipidemia agents and psychotropics for rhabdomyolysis, antibiotics/chemotherapeutics, antineoplastics and intracorporeal diagnostic agents for anaphylaxis (anaphylactic shock, anaphylactic reactions, anaphylactoid shock and anaphylactoid reactions), and antibiotics/chemotherapeutics, antipyretics and analgesics, anti-inflammatory agents/common cold drugs, and antiepileptics for Stevens-Johnson syndrome/toxic epidermal necrolysis. These results would help understanding of current situations of the 4 drug-related serious adverse events in Japan.

Improvements in Clinical Trials Information Will Improve the Reproductive Health and Fertility of Cancer Patients.

PubMed

Dauti, Angela; Gerstl, Brigitte; Chong, Serena; Chisholm, Orin; Anazodo, Antoinette

2017-06-01

There are a number of barriers that result in cancer patients not being referred for oncofertility care, which include knowledge about reproductive risks of antineoplastic agents. Without this information, clinicians do not always make recommendations for oncofertility care. The objective of this study was to describe the level of reproductive information and recommendations that clinicians have available in clinical trial protocols regarding oncofertility management and follow-up, and the information that patients may receive in clinical trials patient information sheets or consent forms. A literature review of the 71 antineoplastic drugs included in the 68 clinical trial protocols showed that 68% of the antineoplastic drugs had gonadotoxic animal data, 32% had gonadotoxic human data, 83% had teratogenic animal data, and 32% had teratogenic human data. When the clinical trial protocols were reviewed, only 22% of the protocols reported the teratogenic risks and 32% of the protocols reported the gonadotoxic risk. Only 56% of phase 3 protocols had gonadotoxic information and 13% of phase 3 protocols had teratogenic information. Nine percent of the protocols provided fertility preservation recommendations and 4% provided reproductive information in the follow-up and survivorship period. Twenty-six percent had a section in the clinical trials protocol, which identified oncofertility information easily. When gonadotoxic and teratogenic effects of treatment were known, they were not consistently included in the clinical trial protocols and the lack of data for new drugs was not reported. Very few protocols gave recommendations for oncofertility management and follow-up following the completion of cancer treatment. The research team proposes a number of recommendations that should be required for clinicians and pharmaceutical companies developing new trials.

Accelerator mass spectrometry analysis of 14C-oxaliplatin concentrations in biological samples and 14C contents in biological samples and antineoplastic agents

NASA Astrophysics Data System (ADS)

Toyoguchi, Teiko; Kobayashi, Takeshi; Konno, Noboru; Shiraishi, Tadashi; Kato, Kazuhiro; Tokanai, Fuyuki

2015-10-01

Accelerator mass spectrometry (AMS) is expected to play an important role in microdose trials. In this study, we measured the 14C concentration in 14C-oxaliplatin-spiked serum, urine and supernatant of fecal homogenate samples in our Yamagata University (YU) - AMS system. The calibration curves of 14C concentration in serum, urine and supernatant of fecal homogenate were linear (the correlation coefficients were ⩾0.9893), and the precision and accuracy was within the acceptance criteria. To examine a 14C content of water in three vacuum blood collection tubes and a syringe were measured. 14C was not detected from water in these devices. The mean 14C content in urine samples of 6 healthy Japanese volunteers was 0.144 dpm/mL, and the intra-day fluctuation of 14C content in urine from a volunteer was little. The antineoplastic agents are administered to the patients in combination. Then, 14C contents of the antineoplastic agents were quantitated. 14C contents were different among 10 antineoplastic agents; 14C contents of paclitaxel injection and docetaxel hydrate injection were higher than those of the other injections. These results indicate that our quantitation method using YU-AMS system is suited for microdosing studies and that measurement of baseline and co-administered drugs might be necessary for the studies in low concentrations.

Effects of outside air temperature on the preparation of antineoplastic drug solutions in biological safety cabinets.

PubMed

Umemura, Masayuki; Itoh, Akio; Ando, Yuichi; Yamada, Kiyofumi; Wakiya, Yoshifumi; Nabeshima, Toshitaka

2015-08-01

In Japan, biological safety cabinets are commonly used by medical staff to prepare antineoplastic agents. At the Division of Chemotherapy for Outpatients, Nagoya University Hospital, a class II B2 biological safety cabinet is used. The temperature inside this biological safety cabinet decreases in winter. In this study, we investigated the effect of low outside air temperature on the biological safety cabinet temperature, time required to admix antineoplastic agents, and accuracy of epirubicin weight measurement. Studies were conducted from 1 January to 31 March 2008 (winter). The outside air temperature near the biological safety cabinet intake nozzle was compared with the biological safety cabinet temperature. The correlation between the outside air temperature and the biological safety cabinet temperature, time for cyclophosphamide and gemcitabine solubilization, and accuracy of epirubicin weight measurement were investigated at low and high biological safety cabinet temperatures. The biological safety cabinet temperature correlated with the outside air temperature of 5-20℃ (p < 0.0001). Compared to cyclophosphamide and gemcitabine solubilization in the biological safety cabinet at 25℃, solubilization at 10℃ was significantly delayed (p < 0.01 and p < 0.0001, respectively). Measurement of epirubicin weight by using a syringe lacked accuracy because of epirubicin's high viscosity at low temperatures (p < 0.01). These results suggest that the biological safety cabinet temperature decreases when cool winter air is drawn into the biological safety cabinet, affecting the solubilization of antineoplastic agents. We suggest that a decrease in biological safety cabinet temperature may increase the time required to admix antineoplastic agents, thereby increasing the time for which outpatients must wait for chemotherapy. © The Author(s) 2014.

Delving into cornerstones of hypersensitivity to antineoplastic and biological agents: value of diagnostic tools prior to desensitization.

PubMed

Alvarez-Cuesta, E; Madrigal-Burgaleta, R; Angel-Pereira, D; Ureña-Tavera, A; Zamora-Verduga, M; Lopez-Gonzalez, P; Berges-Gimeno, M P

2015-07-01

Evidence regarding drug provocation test (DPT) with antineoplastic and biological agents is scarce. Our aim was to assess the usefulness of including DPT as a paramount gold standard diagnostic tool (prior to desensitization). Prospective, observational, longitudinal study with patients who, during a 3-year period, were referred to the Desensitization Program at Ramon y Cajal University Hospital. Patients underwent a structured diagnostic protocol by means of anamnesis, skin tests (ST), risk assessment, and DPT. Oxaliplatin-specific IgE was determined in oxaliplatin-reactive patients (who underwent DPT regardless of oxaliplatin-specific IgE results). Univariate analysis and multivariate analysis were used to identify predictors of the final diagnosis among several variables. A total of 186 patients were assessed. A total of 104 (56%) patients underwent DPT. Sixty-four percent of all DPTs were negative (i.e., hypersensitivity was excluded). Sensitivity for oxaliplatin-specific IgE (0.35 UI/l cutoff point) was 34%, specificity 90.3%, negative predictive value 45.9%, positive predictive value 85%, negative likelihood ratio 0.7, and positive likelihood ratio 3.5. These are the first reported data based on more than 100 DPTs with antineoplastic and biological agents (paclitaxel, oxaliplatin, rituximab, infliximab, irinotecan, and other drugs). Implementation of DPT in diagnostic protocols helps exclude hypersensitivity (in 36% of all referred patients), and avoids unnecessary desensitizations in nonhypersensitive patients (30-56% of patients, depending on culprit-drug). Drug provocation test is vital to validate diagnostic tools; consequently, quality data are shown on oxaliplatin-specific IgE and oxaliplatin-ST in the largest series of oxaliplatin-reactive patients reported to date (74 oxaliplatin-reactive patients). Identifying phenotypes and predictors of a diagnosis of hypersensitivity may be helpful for tailored plans. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Wipe Sampling Method and Evaluation of Environmental Variables for Assessing Surface Contamination of 10 Antineoplastic Drugs by Liquid Chromatography/Tandem Mass Spectrometry.

PubMed

Colombo, Manuel; Jeronimo, Matthew; Astrakianakis, George; Apte, Chirag; Hon, Chun-Yip

2017-10-01

This paper describes a novel wipe sampling and high-performance liquid chromatography/tandem mass spectrometry (HPLC-MS/MS) method capable of simultaneously detecting 10 antineoplastic drugs (5-fluorouracil, oxaliplatin, methotrexate, vindesine, ifosfamide, cyclophosphamide, vincristine, vinblastine, docetaxel, and paclitaxel). The good overall recoveries and sensitivity values of this method along with the comparatively short run time (8 min) allows for its use in routine monitoring in health care facilities. The long-term behavior of the studied drugs on contaminated surfaces and the effect of surface roughness on drug recoveries were studied to gain insights about how these environmental variables influence the detection, cleaning, and occupational exposure of these drugs. Surfaces with higher roughness parameter (Ra) values (rougher) had the lowest recoveries while those with lower Ra (smoother) presented the highest recoveries. Long-term assessments evidence distinctive drug behaviors with oxaliplatin, vindesine, vincristine, and vinblastine being the less persistent drugs (~20% was recovered after 24 h) and docetaxel and paclitaxel the most persistent drugs with recoveries of 40% and 80% after 1 month. This information indicates the importance of collecting ancillary information about drug usage (throughput, timing, cleaning procedures, etc.) to interpret the results in the context of potential exposure. Finally, the method was successfully applied to evaluate trace surface contamination down to the single picogram per square centimeter in multiple work areas within three local health care centers on Vancouver Island, Canada. © The Author 2017. Published by Oxford University Press on behalf of the British Occupational Hygiene Society.

Marketed nonsteroidal anti-inflammatory agents, antihypertensives, and human immunodeficiency virus protease inhibitors: as-yet-unused weapons of the oncologists’ arsenal

PubMed Central

Papanagnou, Panagiota; Baltopoulos, Panagiotis; Tsironi, Maria

2015-01-01

Experimental data indicate that several pharmacological agents that have long been used for the management of various diseases unrelated to cancer exhibit profound in vitro and in vivo anticancer activity. This is of major clinical importance, since it would possibly aid in reassessing the therapeutic use of currently used agents for which clinicians already have experience. Further, this would obviate the time-consuming process required for the development and the approval of novel antineoplastic drugs. Herein, both pre-clinical and clinical data concerning the antineoplastic function of distinct commercially available pharmacological agents that are not currently used in the field of oncology, ie, nonsteroidal anti-inflammatory drugs, antihypertensive agents, and anti-human immunodeficiency virus agents inhibiting viral protease, are reviewed. The aim is to provide integrated information regarding not only the molecular basis of the antitumor function of these agents but also the applicability of the reevaluation of their therapeutic range in the clinical setting. PMID:26056460

The Utility of the Small Rodent Electrocardiogram in Toxicology

EPA Science Inventory

Extensive research has lead to a growing appreciation that the heart is acutely sensitive to a broad array of toxicants via multiple routes of exposure. These agents are as diverse as the anti-neoplastic drug doxorubicin and various components of ambient air pollution. Adverse ef...

Occult nodal metastasis in solid carcinomata

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moloy, P.J.; Nicolson, G.L.

1987-01-01

This book contains 23 selections. Some of the titles are: Rationale for radiotherapy in subclinical nodal disease; rationale of chemotherapy for nodal disease: The stabilization of topoisomerase II-DNA complexes as a mechanism of antineoplastic drug action; magnetic resonance imaging of malignant cervical adenopathy; and local and regional immune function in cancer patients.

76 FR 46299 - NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings 2012: Proposed...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-02

... National Institute for Occupational Safety and Health (NIOSH) of the Centers for Disease Control and..., Director, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention... DEPARTMENT OF HEALTH AND HUMAN SERVICES Centers for Disease Control and Prevention [Docket Number...

Orally administered rapamycin, dacarbazine or both for treatment of human melanoma evaluated in severe combined immunodeficiency mice.

PubMed

Thallinger, Christiane; Skorjanec, Sophie; Soleiman, Afschin; Tzaneva, Stanislava; Griss, Johannes; Rous, Wolfgang; Poeppl, Wolfgang; Weinlich, Georg; Karimian-Teherani, Daniela; Joukhadar, Christian

2008-01-01

In this experimental study, the antineoplastic potential of orally administered rapamycin in human melanoma was evaluated and compared with dacarbazine (DTIC) as well as with the antineoplastic effect of the combination of both drugs. The substances were tested using 2 human melanoma cell lines, 518A2, which is highly susceptible to DTIC, and 607B, which is moderately susceptible. A human melanoma severe combined immunodeficiency mouse xenotransplantation model was used. After development of palpable tumors, mice received oral rapamycin or saline over 18 days. Additionally, from treatment day 4 to 8, mice were randomly chosen to receive either DTIC or saline treatment. The oral rapamycin treatment (1.5, 7.5, 15 and 30 mg/kg body weight) had an antineoplastic effect, ranging from 35 to 78% tumor weight reduction compared with the saline group. In DTIC less sensitive 607B tumors, rapamycin treatment (15 and 30 mg/kg body weight) was superior to DTIC treatment (p < 0.05). DTIC monotreatment reduced tumor weight in 518A2 tumors by 85% on average, whereas in 607B xenografts, no significant tumor weight reduction was observed compared with the saline group (p > 0.05). The combination of rapamycin and DTIC was not superior to rapamycin monotreatment in any cell line. These data indicate that oral rapamycin exerts a relevant antineoplastic effect on human melanoma cells. This effect appeared to be more pronounced in DTIC less sensitive melanoma xenografts. Copyright 2008 S. Karger AG, Basel.

Effectiveness of oxaliplatin desensitization protocols.

PubMed

Cortijo-Cascajares, Susana; Nacle-López, Inmaculada; García-Escobar, Ignacio; Aguilella-Vizcaíno, María José; Herreros-de-Tejada, Alberto; Cortés-Funes Castro, Hernán; Calleja-Hernández, Miguel-Ángel

2013-03-01

Hypersensitivity reaction (HSR) to antineoplastic drugs can force doctors to stop treatment and seek other alternatives. These alternatives may be less effective, not as well tolerated and/or more expensive. Another option is to use desensitization protocols that induce a temporary state of tolerance by gradually administering small quantities of the antineoplastic drug until the therapeutic dosage is reached. The aim of this study is to assess the effectiveness of oxaliplatin desensitization protocols. A retrospective observational study was carried out between January 2006 and May 2011. The inclusion criteria were patients undergoing chemotherapy treatment with oxaliplatin who had developed an HSR to the drug and who were candidates for continuing the treatment using a desensitization protocol. The patients' clinical records were reviewed and variables were gathered relating to the patient, the treatment, the HSR, and the desensitization protocol administered. The data were analysed using version 18.0 of the statistics program SPSS. A total of 53 desensitization protocols were administered to 21 patients. In 89 % of these cases, no new reactions occurred while the drug was being administered. New reactions of mild severity only occurred in 11 % of cases, and none of these reactions were severe enough for treatment to be stopped. All patients were able to complete the desensitization protocol. This study confirms that oxaliplatin desensitization protocols are safe and effective and allow patients to continue with the treatment that initially caused an HSR.

Hypertension in malignancy–an underappreciated problem

PubMed Central

Małyszko, Jolanta; Małyszko, Maciej; Kozlowski, Leszek; Kozlowska, Klaudia; Małyszko, Jacek

2018-01-01

Hypertension is one of the most common comorbidities in cancer patients with malignancy, in particular, in the elderly. On the other hand, hypertension is a long-term consequence of antineoplastic treatment, including both chemotherapy and targeted agents. Several chemotherapeutics and targeted drugs may be responsible for development or worsening of the hypertension. The most common side effect of anti-VEGF (vascular endothelial growth factor) treatment is hypertension. However, pathogenesis of hypertension in patients receiving this therapy appears to be associated with multiple pathways and is not yet fully understood. Development of hypertension was associated with improved antitumor efficacy in patients treated with anti-antiangiogenic drugs in some but not in all studies. Drugs used commonly as adjuvants such as steroids, erythropoietin stimulating agents etc, may also cause rise in blood pressure or exacerbate preexisiting hypertension. Hypotensive therapy is crucial to manage hypertension during certain antineoplastic treatment. The choice and dose of antihypertensive drugs depend upon the presence of organ dysfunction, comorbidities, and/or adverse effects. In addition, severity of the hypertension and the urgency of blood pressure control should also be taken into consideration. As there are no specific guidelines on the hypertension treatment in cancer patients we should follow the available guidelines to obtain the best possible outcomes and pay the attention to the individualization of the therapy according to the actual situation. PMID:29755695

Peroxisome Proliferator-Activated Receptors (PPARs) as Potential Inducers of Antineoplastic Effects in CNS Tumors

PubMed Central

Tatenhorst, Lars; Hahnen, Eric; Heneka, Michael T.

2008-01-01

The peroxisome proliferator-activated receptors (PPARs) are ligand-inducible transcription factors which belong to the superfamily of nuclear hormone receptors. In recent years it turned out that natural as well as synthetic PPAR agonists exhibit profound antineoplastic as well as redifferentiation effects in tumors of the central nervous system (CNS). The molecular understanding of the underlying mechanisms is still emerging, with partially controverse findings reported by a number of studies dealing with the influence of PPARs on treatment of tumor cells in vitro. Remarkably, studies examining the effects of these drugs in vivo are just beginning to emerge. However, the agonists of PPARs, in particular the thiazolidinediones, seem to be promising candidates for new approaches in human CNS tumor therapy. PMID:18725982

The FDA approved PI3K inhibitor GDC-0941 enhances in vitro the anti-neoplastic efficacy of Axitinib against c-myc-amplified high-risk medulloblastoma.

PubMed

Ehrhardt, Michael; Craveiro, Rogerio B; Velz, Julia; Olschewski, Martin; Casati, Anna; Schönberger, Stefan; Pietsch, Torsten; Dilloo, Dagmar

2018-04-01

Aberrant receptor kinase signalling and tumour neovascularization are hallmarks of medulloblastoma development and are both considered valuable therapeutic targets. In addition to VEGFR1/2, expression of PDGFR α/β in particular has been documented as characteristic of metastatic disease correlating with poor prognosis. Therefore, we have been suggested that the clinically approved multi-kinase angiogenesis inhibitor Axitinib, which specifically targets these kinases, might constitute a promising option for medulloblastoma treatment. Indeed, our results delineate anti-neoplastic activity of Axitinib in medulloblastoma cell lines modelling the most aggressive c-myc-amplified Non-WNT/Non-SHH and SHH-TP53-mutated tumours. Exposure of medulloblastoma cell lines to Axitinib results in marked inhibition of proliferation and profound induction of cell death. The differential efficacy of Axitinib is in line with target expression of medulloblastoma cells identifying VEGFR 1/2, PDGFR α/β and c-kit as potential markers for drug application. The high specificity of Axitinib and the consequential low impact on the haematopoietic and immune system render this drug ideal multi-modal treatment approaches. In this context, we demonstrate that the clinically available PI3K inhibitor GDC-0941 enhances the anti-neoplastic efficacy of Axitinib against c-myc-amplified medulloblastoma. Our findings provide a rational to further evaluate Axitinib alone and in combination with other therapeutic agents for the treatment of most aggressive medulloblastoma subtypes. © 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

In vitro antineoplastic effects of auranofin in canine lymphoma cells.

PubMed

Zhang, Hong; Rose, Barbara J; Pyuen, Alex A; Thamm, Douglas H

2018-05-03

The orally available gold complex auranofin (AF) has been used in humans, primarily as an antirheumatic/immunomodulatory agent. It has been safely administered to healthy dogs to establish pharmacokinetic parameters for oral administration, and has also been used as a treatment in some dogs with immune-mediated conditions. Multiple in vitro studies have recently suggested that AF may possess antineoplastic properties. Spontaneous canine lymphoma may be a very useful translational model for the study of human lymphoma, prompting the evaluation of AF in canine lymphoma cells. We investigated the antineoplastic activity of AF in 4 canine lymphoid tumor derived cell lines through measurements of proliferation, apoptosis, thioredoxin reductase (TrxR) activity and generation of reactive oxygen species (ROS), and detected the effects of AF when combined with conventional cytotoxic drugs using the Chou and Talalay method. We also evaluated the antiproliferative effects of AF in primary canine lymphoma cells using a bioreductive fluorometric assay. At concentrations that appear clinically achievable in humans, AF demonstrated potent antiproliferative and proapoptotic effects in canine lymphoid tumor cell lines. TrxR inhibition and increased ROS production was observed following AF treatment. Moreover, a synergistic antiproliferative effect was observed when AF was combined with lomustine or doxorubicin. Auranofin appears to inhibit the growth and initiate apoptosis in canine lymphoma cells in vitro at clinically achievable concentrations. Therefore, this agent has the potential to have near-term benefit for the treatment of canine lymphoma, as well as a translational model for human lymphoma. Decreased TrxR activity and increasing ROS production may be useful biomarkers of drug exposure.

5-AZA-2'-DEOXYCYTIDINE INDUCED CYTOTOXICITY AND LONG BONE REDUCTION DEFECTS IN THE MURINE LIMB

EPA Science Inventory

The antineoplastic drug 5-aza-2'-deoxycytidine (dAZA) is a DNA hypomethylating agent that can be used to induce hind limb phocomelia in the offspring of CD-1 Swiss Webster mice. Previously, our laboratory investigated the possibility that dAZA induced alterations in gene express...

REPEATED TREATMENTS WITH DOXORUBICIN CAUSES ELECTROCARDIOGRAM (ECG) CHANGES AND INCREASED VENTRICULAR PREMATURE BEATS IN WISTAR-KYOTO (WKY) RATS

EPA Science Inventory

Doxorubicin (DOX) is a widely used anthracycline anti-neoplastic drug used to treat tumors. However it has been implicated in irreversible cardiac toxicity via the generation of a proxidant semiquinone free radical, which often results in cardiomyopathy and changes in the ECG. Ac...

Platinum anti-cancer drugs: Free radical mechanism of Pt-DNA adduct formation and anti-neoplastic effect.

PubMed

Fong, Clifford W

2016-06-01

The literature on the anti-neoplastic effects of Pt drugs provides substantial evidence that free radical may be involved in the formation of Pt-DNA adducts and other cytotoxic effects. The conditions specific to cancerous tumours are more conducive to free radical mechanisms than the commonly accepted hydrolysis nucleophilic-electrophilic mechanism of Pt-DNA adduct formation. Molecular orbital studies of the adiabatic attachment of hydrated electrons to Pt drugs reveal that there is a significant lengthening of the Pt-X bond (where X is Cl, O in cisplatin, carboplatin and some pyrophosphate-Pt drugs but not oxaliplatin) in the anion radical species. This observation is consistent with a dissociative electron transfer (DET) mechanism for the formation of Pt-DNA adducts. A DET reaction mechanism is proposed for the reaction of Pt drugs with guanine which involves a quasi-inner sphere 2 electron transfer process involving a transient intermediate 5 co-ordinated activated anion radical species {R2Pt---Cl(G)(Cl)•}*(-) (where R is an ammine group, and G is guanine) and the complex has an elongated Pt---Cl (or Pt---O) bond. A DET mechanism is also proposed when Pt drugs are activated by reaction with free radicals such as HO•, CO3•(-), O2•(-) but do not react with DNA bases to form adducts, but form Pt-protein adducts with proteins such ezrin, FAS, DR5, TNFR1 etc. The DET mechanism may not occur with oxaliplatin. Copyright © 2016 Elsevier Inc. All rights reserved.

Response of Human Prostate Cancer Cells to Mitoxantrone Treatment in Simulated Microgravity Environment

NASA Astrophysics Data System (ADS)

Zhang, Ye; Wu, Honglu

2012-07-01

RESPONSE OF HUMAN PROSTATE CANCER CELLS TO MITOXANTRONE TREATMENT IN SIMULATED MICROGRAVITY ENVIRONMENT Ye Zhang1,2, Christopher Edwards3, and Honglu Wu1 1 NASA-Johnson Space Center, Houston, TX 2 Wyle Integrated Science and Engineering Group, Houston, TX 3 Oregon State University, Corvallis, OR This study explores the changes in growth of human prostate cancer cells (LNCaP) and their response to the treatment of an antineoplastic agent, mitoxantrone, under the simulated microgravity condition. In comparison to static 1g, microgravity and simulated microgravity have been shown to alter global gene expression patterns and protein levels in various cultured cell models or animals. However, very little is known about the effect of altered gravity on the responses of cells to the treatment of drugs, especially chemotherapy drugs. To test the hypothesis that zero gravity would result in altered regulations of cells in response to antineoplastic agents, we cultured LNCaP cells in either a High Aspect Ratio Vessel (HARV) bioreactor at the rotating condition to model microgravity in space or in the static condition as control, and treated the cells with mitoxantrone. Cell growth, as well as expressions of oxidative stress related genes, were analyzed after the drug treatment. Compared to static 1g controls, the cells cultured in the simulated microgravity environment did not present significant differences in cell viability, growth rate, or cell cycle distribution. However, after mitoxantrone treatment, a significant proportion of bioreactor cultured cells became apoptotic or was arrested in G2. Several oxidative stress related genes also showed a higher expression level post mitoxantrone treatment. Our results indicate that simulated microgravity may alter the response of LNCaP cells to mitoxantrone treatment. Understanding the mechanisms by which cells respond to drugs differently in an altered gravity environment will be useful for the improvement of cancer treatment on the ground. This study explores the changes in growth of human prostate cancer cells (LNCaP) and their response to the treatment of an antineoplastic agent, mitoxantrone, under the simulated microgravity condition. In comparison to static 1g, microgravity and simulated microgravity have been shown to alter global gene expression patterns and protein levels in various cultured cell models or animals. However, very little is known about the effect of altered gravity on the responses of cells to the treatment of drugs, especially chemotherapy drugs. To test the hypothesis that zero gravity would result in altered regulations of cells in response to antineoplastic agents, we cultured LNCaP cells in either a High Aspect Ratio Vessel (HARV) bioreactor at the rotating condition to model microgravity in space or in the static condition as control, and treated the cells with mitoxantrone. Cell growth, as well as expressions of oxidative stress related genes, were analyzed after the drug treatment. Compared to static 1g controls, the cells cultured in the simulated microgravity environment did not present significant differences in cell viability, growth rate, or cell cycle distribution. However, after mitoxantrone treatment, a significant proportion of bioreactor cultured cells became apoptotic or was arrested in G2. Several oxidative stress related genes also showed a higher expression level post mitoxantrone treatment. Our results indicate that simulated microgravity may alter the response of LNCaP cells to mitoxantrone treatment. Understanding the mechanisms by which cells respond to drugs differently in an altered gravity environment will be useful for the improvement of cancer treatment on the ground.

Assessment of toxicity and genotoxicity of low doses of 5-fluorouracil in zebrafish (Danio rerio) two-generation study.

PubMed

Kovács, Róbert; Csenki, Zsolt; Bakos, Katalin; Urbányi, Béla; Horváth, Ákos; Garaj-Vrhovac, Vera; Gajski, Goran; Gerić, Marko; Negreira, Noelia; López de Alda, Miren; Barceló, Damià; Heath, Ester; Kosjek, Tina; Žegura, Bojana; Novak, Matjaž; Zajc, Irena; Baebler, Špela; Rotter, Ana; Ramšak, Živa; Filipič, Metka

2015-06-15

Residues of anti-neoplastic drugs represent new and emerging pollutants in aquatic environments. Many of these drugs are genotoxic, and it has been postulated that they can cause adverse effects in aquatic ecosystems. 5-Fluorouracil (5-FU) is one of the most extensively used anti-neoplastic drugs in cancer therapy, and this article describes the results of the first investigation using a two-generation toxicity study design with zebrafish (Danio rerio). Exposure of zebrafish to 5-FU (0.01, 1.0 and 100 μg/L) was initiated with adult zebrafish (F0 generation) and continued through the hatchings and adults of the F1 generation, and the hatchings of the F2 generation, to day 33 post-fertilisation. The exposure did not affect survival, growth and reproduction of the zebrafish; however, histopathological changes were observed in the liver and kidney, along with genotoxic effects, at all 5-FU concentrations. Increases in DNA damage determined using the comet assay were significant in the liver and blood cells, but not in the gills and gonads. In erythrocytes, a significant, dose-dependent increase in frequency of micronuclei was observed at all 5-FU concentrations. Whole genome transcriptomic analysis of liver samples of F1 generation zebrafish exposed to 0.01 μg/L and 1 μg/L 5-FU revealed dose-dependent increases in the number of differentially expressed genes, including up-regulation of several DNA-damage-responsive genes and oncogenes (i.e., jun, myca). Although this chronic exposure to environmentally relevant concentrations of 5-FU did not affect the reproduction of the exposed zebrafish, it cannot be excluded that 5-FU can lead to degenerative changes, including cancers, which over long-term exposure of several generations might affect fish populations. The data from this study contribute to a better understanding of the potential consequences of chronic exposure of fish to low concentrations of anti-neoplastic drugs, and they demonstrate that further studies into multi-generation toxicity are needed. Copyright © 2015. Published by Elsevier Ltd.

Effectiveness of a Closed-System Transfer Device in Reducing Surface Contamination in a New Antineoplastic Drug-Compounding Unit: A Prospective, Controlled, Parallel Study

PubMed Central

Pinturaud, Marine; Soichot, Marion; Richeval, Camille; Humbert, Luc; Lebecque, Michèle; Sidikou, Ousseini; Barthelemy, Christine; Bonnabry, Pascal; Allorge, Delphine; Décaudin, Bertrand; Odou, Pascal

2016-01-01

Background The objective of this randomized, prospective and controlled study was to investigate the ability of a closed-system transfer device (CSTD; BD-Phaseal) to reduce the occupational exposure of two isolators to 10 cytotoxic drugs and compare to standard compounding devices. Methods and Findings The 6-month study started with the opening of a new compounding unit. Two isolators were set up with 2 workstations each, one to compound with standard devices (needles and spikes) and the other using the Phaseal system. Drugs were alternatively compounded in each isolator. Sampling involved wiping three surfaces (gloves, window, worktop), before and after a cleaning process. Exposure to ten antineoplastic drugs (cyclophosphamide, ifosfamide, dacarbazine, 5-FU, methotrexate, gemcitabine, cytarabine, irinotecan, doxorubicine and ganciclovir) was assessed on wipes by LC-MS/MS analysis. Contamination rates were compared using a Chi2 test and drug amounts by a Mann-Whitney test. Significance was defined for p<0.05. Overall contamination was lower in the “Phaseal” isolator than in the “Standard” isolator (12.24% vs. 26.39%; p < 0.0001) although it differed according to drug. Indeed, the contamination rates of gemcitabine were 49.3 and 43.4% (NS) for the Standard and Phaseal isolators, respectively, whereas for ganciclovir, they were 54.2 and 2.8% (p<0.0001). Gemcitabine amounts were 220.6 and 283.6 ng for the Standard and Phaseal isolators (NS), and ganciclovir amounts were 179.9 and 2.4 ng (p<0.0001). Conclusion This study confirms that using a CSTD may significantly decrease the chemical contamination of barrier isolators compared to standard devices for some drugs, although it does not eliminate contamination totally. PMID:27391697

78 FR 33097 - NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings 2014: Proposed...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-03

... comments should be formatted as Microsoft Word. Please make reference to CDC-2013-0007 and Docket Number... DEPARTMENT OF HEALTH AND HUMAN SERVICES Centers for Disease Control and Prevention [CDC-2013-0007... effect of law. Public Comment Period: Comments must be received by August 2, 2013. ADDRESSES: You may...

Preventing medication errors in cancer chemotherapy.

PubMed

Cohen, M R; Anderson, R W; Attilio, R M; Green, L; Muller, R J; Pruemer, J M

1996-04-01

Recommendations for preventing medication errors in cancer chemotherapy are made. Before a health care provider is granted privileges to prescribe, dispense, or administer antineoplastic agents, he or she should undergo a tailored educational program and possibly testing or certification. Appropriate reference materials should be developed. Each institution should develop a dose-verification process with as many independent checks as possible. A detailed checklist covering prescribing, transcribing, dispensing, and administration should be used. Oral orders are not acceptable. All doses should be calculated independently by the physician, the pharmacist, and the nurse. Dosage limits should be established and a review process set up for doses that exceed the limits. These limits should be entered into pharmacy computer systems, listed on preprinted order forms, stated on the product packaging, placed in strategic locations in the institution, and communicated to employees. The prescribing vocabulary must be standardized. Acronyms, abbreviations, and brand names must be avoided and steps taken to avoid other sources of confusion in the written orders, such as trailing zeros. Preprinted antineoplastic drug order forms containing checklists can help avoid errors. Manufacturers should be encouraged to avoid or eliminate ambiguities in drug names and dosing information. Patients must be educated about all aspects of their cancer chemotherapy, as patients represent a last line of defense against errors. An interdisciplinary team at each practice site should review every medication error reported. Pharmacists should be involved at all sites where antineoplastic agents are dispensed. Although it may not be possible to eliminate all medication errors in cancer chemotherapy, the risk can be minimized through specific steps. Because of their training and experience, pharmacists should take the lead in this effort.

RB1 status in triple negative breast cancer cells dictates response to radiation treatment and selective therapeutic drugs.

PubMed

Robinson, Tyler J W; Liu, Jeff C; Vizeacoumar, Frederick; Sun, Thomas; Maclean, Neil; Egan, Sean E; Schimmer, Aaron D; Datti, Alessandro; Zacksenhaus, Eldad

2013-01-01

Triple negative breast cancer (TNBC) includes basal-like and claudin-low subtypes for which only chemotherapy and radiation therapy are currently available. The retinoblastoma (RB1) tumor suppressor is frequently lost in human TNBC. Knockdown of RB1 in luminal BC cells was shown to affect response to endocrine, radiation and several antineoplastic drugs. However, the effect of RB1 status on radiation and chemo-sensitivity in TNBC cells and whether RB1 status affects response to divergent or specific treatment are unknown. Using multiple basal-like and claudin-low cell lines, we hereby demonstrate that RB-negative TNBC cell lines are highly sensitive to gamma-irradiation, and moderately more sensitive to doxorubicin and methotrexate compared to RB-positive TNBC cell lines. In contrast, RB1 status did not affect sensitivity of TNBC cells to multiple other drugs including cisplatin (CDDP), 5-fluorouracil, idarubicin, epirubicin, PRIMA-1(met), fludarabine and PD-0332991, some of which are used to treat TNBC patients. Moreover, a non-biased screen of ∼3400 compounds, including FDA-approved drugs, revealed similar sensitivity of RB-proficient and -deficient TNBC cells. Finally, ESA(+)/CD24(-/low)/CD44(+) cancer stem cells from RB-negative TNBC lines were consistently more sensitive to gamma-irradiation than RB-positive lines, whereas the effect of chemotherapy on the cancer stem cell fraction varied irrespective of RB1 expression. Our results suggest that patients carrying RB-deficient TNBCs would benefit from gamma-irradiation as well as doxorubicin and methotrexate therapy, but not necessarily from many other anti-neoplastic drugs.

HDACs and HDAC inhibitors in urothelial carcinoma - perspectives for an antineoplastic treatment.

PubMed

Pinkerneil, Maria; Hoffmann, Michèle J; Schulz, Wolfgang A; Niegisch, Günter

2017-01-11

Histone deacetylases (HDACs) influence diverse cellular processes and may contribute to tumor development and progression by multiple mechanisms. Class I HDACs are often overexpressed in cancers contributing to a genome-wide epigenetic state permitting increased proliferation, and diminished apoptosis and cell differentiation. Class IIA and IIB isoenzymes may likewise contribute to tumorigenesis as components of specific intranuclear repressor complexes or regulators of posttranslational protein modifications. As HDAC inhibitors may counteract these tumorigenic effects several of these compounds are currently tested in clinical trials. HDAC inhibitors are also considered for urothelial carcinoma, where novel therapeutic drugs are urgently required. However, only modest antineoplastic activity has been observed with isoenzyme-unspecific pan-HDAC inhibitors. Therefore, inhibition of specific HDAC isoenzymes might be more efficacious and tumor-specific. Here, we systematically review knowledge on the expression, function and suitability as therapeutic targets of the 11 classical HDACs in UC. Overall, the class I HDACs HDAC1 and HDAC2 are the most promising targets for antineoplastic treatment. In contrast, targeting HDAC8 and HDAC6 is likely to be of minor relevance in urothelial carcinoma. Class IIA HDACs like HDAC4 require further study, since their downregulation rather than upregulation could be involved in urothelial carcinoma pathogenesis.

[The Necessity and the Current Status of Safe Handling of Anticancer Drugs].

PubMed

Kanda, Kiyoko

2017-07-01

Number of people who handle anticancer drugs in their profession is increasing. Anticancer drugs, which are hazardous drugs(HD), exert cytocidal effects on cancer cells, but many have also been shown to have mutagenicity, teratogenicity and carcinogenicity; therefore, safe handling of anticancer drugs is necessary. In July 2015, the first Japanese guidelines for exposure control measures, namely, the "Joint Guidelines for Safe Handling of Cancer Chemotherapy Drugs", were published jointly by 3 societies. Our guideline is the creation of the Japanese Society of Cancer Nursing(JSCN), Japanese Society of Medical Oncology(JSMO)and Japanese Society of Pharmaceutical Oncology(JASPO)and has a historical significance. This paper states the necessity of safe handling of anticancer drugs, Japan's recent movement of safe handling, the introduction of joint guidelines of safe handling of anticancer drugs, and new movement of safe handling of USP chapter 800 in the United States.

Use of liposomes as injectable-drug delivery systems.

PubMed

Ostro, M J; Cullis, P R

1989-08-01

The formation of liposomes and their application as delivery systems for injectable drugs are described. Liposomes are microscopic vesicles composed of one or more lipid membranes surrounding discrete aqueous compartments. These vesicles can encapsulate water-soluble drugs in their aqueous spaces and lipid-soluble drugs within the membrane itself. Liposomes release their contents by interacting with cells in one of four ways: adsorption, endocytosis, lipid exchange, or fusion. Liposome-entrapped drugs are distributed within the body much differently than free drugs; when administered intravenously to healthy animals and humans, most of the injected vesicles accumulate in the liver, spleen, lungs, bone marrow, and lymph nodes. Liposomes also accumulate preferentially at the sites of inflammation and infection and in some solid tumors; however, the reason for this accumulation is not clear. Four major factors influence liposomes' in vivo behavior and biodistribution: (1) liposomes tend to leak if cholesterol is not included in the vesicle membrane, (2) small liposomes are cleared more slowly than large liposomes, (3) the half-life of a liposome increases as the lipid dose increases, and (4) charged liposomal systems are cleared more rapidly than uncharged systems. The most advanced application of liposome-based therapy is in the treatment of systemic fungal infections, especially with amphotericin B. Liposomes are also under investigation for treatment of neoplastic disorders. Liposomes' uses in cancer therapy include encapsulation of known antineoplastic agents such as doxorubicin and methotrexate, delivery of immune modulators such as N-acetylmuramyl-L-alanine-D-isoglutamine, and encapsulation of new chemical entities that are synthesized with lipophilic segments tailored for insertion into lipid bilayers. Liposomal formulations of injectable antimicrobial agents and antineoplastic agents already are undergoing clinical testing, and most probably will receive approval for marketing in the early 1990s. Liposomal encapsulation of drugs represents a new drug delivery system that appears to offer important therapeutic advantages over existing methods of drug delivery.

Polypharmacology of Approved Anticancer Drugs.

PubMed

Amelio, Ivano; Lisitsa, Andrey; Knight, Richard A; Melino, Gerry; Antonov, Alexey V

2017-01-01

The major drug discovery efforts in oncology have been concentrated on the development of selective molecules that are supposed to act specifically on one anticancer mechanism by modulating a single or several closely related drug targets. However, a bird's eye view on data from multiple available bioassays implies that most approved anticancer agents do, in fact, target many more proteins with different functions. Here we will review and systematize currently available information on the targets of several anticancer drugs along with revision of their potential mechanisms of action. Polypharmacology of the current antineoplastic agents suggests that drug clinical efficacy in oncology can be achieved only via modulation of multiple cellular mechanisms. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Photo-Fenton and Fenton-like processes for the treatment of the antineoplastic drug 5-fluorouracil under simulated solar radiation.

PubMed

Koltsakidou, Α; Antonopoulou, M; Sykiotou, M; Εvgenidou, Ε; Konstantinou, I; Lambropoulou, D A

2017-02-01

In the present study, photo-Fenton and Fenton-like processes were investigated for the degradation and mineralization of the antineoplastic drug 5-fluorouracil (5-FU). For the optimization of photo-Fenton treatment under simulated solar light (SSL) radiation, the effects of several operating parameters (i.e., 5-FU concentration, Fe 3+ , and oxidant concentration) on the treatment efficiency were studied. According to the results, SSL/[Fe(C 2 Ο 4 ) 3 ] 3- /Η 2 Ο 2 process was the most efficient, since faster degradation of 5-FU and higher mineralization percentages were achieved. All the applied processes followed quite similar transformation routes which include defluorination-hydroxylation as well as pyrimidine ring opening, as demonstrated by the transformation products identified by high resolution mass spectrometry analysis. The toxicity of the treated solutions was evaluated using the Microtox assay. In general, low toxicity was recorded for the initial solution and the solution at the end of the photocatalytic treatment, while an increase in the overall toxicity was observed only at the first stages of SSL/Fe 3+ /Η 2 Ο 2 and SSL/Fe 3+ /S 2 O 8 2- processes.

Characterizing interspecies uncertainty using data from studies of anti-neoplastic agents in animals and humans

DOE Office of Scientific and Technical Information (OSTI.GOV)

Price, Paul S.; Keenan, Russell E.; Swartout, Jeffrey C.

For most chemicals, the Reference Dose (RfD) is based on data from animal testing. The uncertainty introduced by the use of animal models has been termed interspecies uncertainty. The magnitude of the differences between the toxicity of a chemical in humans and test animals and its uncertainty can be investigated by evaluating the inter-chemical variation in the ratios of the doses associated with similar toxicological endpoints in test animals and humans. This study performs such an evaluation on a data set of 64 anti-neoplastic drugs. The data set provides matched responses in humans and four species of test animals: mice,more » rats, monkeys, and dogs. While the data have a number of limitations, the data show that when the drugs are evaluated on a body weight basis: 1) toxicity generally increases with a species' body weight; however, humans are not always more sensitive than test animals; 2) the animal to human dose ratios were less than 10 for most, but not all, drugs; 3) the current practice of using data from multiple species when setting RfDs lowers the probability of having a large value for the ratio. These findings provide insight into inter-chemical variation in animal to human extrapolations and suggest the need for additional collection and analysis of matched toxicity data in humans and test animals.« less

Nail toxicity induced by cancer chemotherapy.

PubMed

Gilbar, Peter; Hain, Alice; Peereboom, Veta-Marie

2009-09-01

To provide a comprehensive literature review of chemotherapy-induced nail toxicity, including clinical presentation, implicated drugs and approaches for prevention and management. A search of MEDLINE and EMBASE (1966-2008) databases was conducted using the terms (and variations of the terms) antineoplastic agents, nails, nail toxicity, onycholysis, and paronychia. Bibliographies from selected articles were reviewed for appropriate references. The retrieved literature was reviewed to include all articles relevant to the clinical presentation, diagnosis, incidence, prevention, and treatment of chemotherapy-induced nail toxicity. Nail toxicity is a relatively uncommon adverse effect linked to a number of chemotherapeutic agents. Clinical presentation varies, depending on which nail structure is affected and the severity of the insult. Nail changes may involve all or some nails. Toxicity may be asymptomatic and limited to cosmetic concerns, however, more severe effects, involving pain and discomfort can occur. Taxanes and anthracyclines are the antineoplastic drug groups most commonly implicated. It is suggested that the administration schedule may influence the incidence of nail abnormalities, for example reported cases linked to the weekly administration of paclitaxel.Before instituting chemotherapy, patients should be educated regarding potential nail toxicities and strategies for prevention implemented. Management includes appropriate nail cutting, avoiding potential irritants, topical, or oral antimicrobials, and possibly cessation or dose reduction of the offending agent. Cryotherapy, through the application of frozen gloves or socks, has been beneficial in reducing docetaxel-induced nail toxicity and may be effective for other drugs.

[Mitoguazone (methylglyoxal bis(guanylhydrazone))--its status and prospects].

PubMed

Hoffmann, H; Gutsche, W; Amlacher, R; Schulze, W; Werner, W; Lenk, H; Wohlrab, W; Haupt, E

1989-01-01

Because of its severe side effects, initial clinical trials of the antineoplastic compound mitoguazone (Methyl-GAG, M-G) were ceased in the middle of 1960s. One decade later pharmacokinetically guided dose schedules as well as new experimental data on the antiproliferative mechanism of action stimulated new clinical studies. First results indicated that M-G had single-agent activity against various tumors such as acute leukemia and malignant lymphoma connected with acceptable tolerance. M-G seems to be effective especially in combination with other antineoplastic drugs. Its final evaluation may be reserved to further randomized trials. Recently, the psoriasis vulgaris is expected to be an additional field of the application of M-G. In this minireview data on synthesis, preclinical pharmacology, pharmacokinetics, biochemical effects and toxicology of M-G are given. Furthermore, clinical findings on M-G concerning its pharmacokinetic behaviour, antitumor and antipsoriatic activities are described.

Cisplatin Therapy Does Not Worsen Renal Function in Severe Antenatal Bartter Syndrome.

PubMed

Welch, Thomas R; Shaffer, David R; Feldman, Darren R

2017-01-01

A 30-year-old man with severe antenatal Bartter syndrome, diagnosed and treated in infancy, developed testicular carcinoma. Despite the known renal complications of cisplatin, this drug was used for his chemotherapy because of its superior antineoplastic effect. Nonsteroidal anti-inflammatory drug administration was continued during cisplatin therapy. Despite an increase in his oral potassium requirement, renal function was maintained following completion of chemotherapy. In spite of its significant associated nephrotoxicity, cisplatin can be used in patients with severe antenatal Bartter syndrome if required for therapy of malignancy.

Development of dihydrochalcone-functionalized gold nanoparticles for augmented antineoplastic activity

PubMed Central

Moolani, Harsh V; Tockstein, Sarah; Thompson, David H; Dakshinamurthy, Rajalingam

2018-01-01

Background Phloridzin, an antidiabetic and antineoplastic agent usually found in fruit trees, is a dihydrochalcone constituent that has a clinical/pharmaceutical significance as a sodium-glucose linked transport 2 (SGLT2) inhibitor. While the aglycone metabolite of phloridzin, phloretin, displays a reduced capacity of SGLT2 inhibition, this nutraceutical displays enhanced antineoplastic activity in comparison to phloridzin. Purpose The objective of this study was to develop gold nanoparticle (AuNP) mediated delivery of phloridzin and phloretin and explore their anticancer mechanism through conjugation of the dihydrochalcones and the AuNP cores. Methods Phloridzin and phloretin conjugated AuNPs (Phl-AuNP and Pht-AuNP) were synthesized in single-step, rapid, biofriendly processes. The synthesized AuNPs morphology was characterized via transmission electron microscopy and ultraviolet-visible spectroscopy. The presence of phloridzin or phloretin was confirmed using scanning electron microscopy-energy dispersive x-ray spectroscopy. The percentage of organic component (phloridzin/phloretin) onto AuNPs surface was characterized using thermogravimetric analysis. Assessment of the antineoplastic potency of the dihydrochalcones conjugated AuNPs against cancerous cell lines (HeLa) was accomplished through monitoring via flow cytometry. Results The functionalized AuNPs were synthesized via a single-step method that relied only upon the redox potential of the conjugate itself and required no toxic chemicals. The synthesized Phl-AuNPs were found to be in the size range of 15±5 nm, whereas the Pht-AuNP were found to be 8±3 nm, placing both conjugated AuNPs well within the size range necessary for successful pharmaceutical applications. These assays demonstrate a significant increase in the cancerous cell toxicities as a result of the conjugation of the drugs to AuNPs, as indicated by the 17.45-fold increase in the efficacy of Pht-AuNPs over pure phloretin, and the 4.49-fold increase in efficacy of Phl-AuNP over pure phloridzin. Conclusion We report a simple, biofriendly process using the reducing and capping potential of the dihydrochalcones, phloridzin and phloretin, to synthesize stable AuNPs that have promising futures as potential antineoplastic agents. PMID:29636609

Development of dihydrochalcone-functionalized gold nanoparticles for augmented antineoplastic activity.

PubMed

Payne, Jason N; Badwaik, Vivek D; Waghwani, Hitesh K; Moolani, Harsh V; Tockstein, Sarah; Thompson, David H; Dakshinamurthy, Rajalingam

2018-01-01

Phloridzin, an antidiabetic and antineoplastic agent usually found in fruit trees, is a dihydrochalcone constituent that has a clinical/pharmaceutical significance as a sodium-glucose linked transport 2 (SGLT2) inhibitor. While the aglycone metabolite of phloridzin, phloretin, displays a reduced capacity of SGLT2 inhibition, this nutraceutical displays enhanced antineoplastic activity in comparison to phloridzin. The objective of this study was to develop gold nanoparticle (AuNP) mediated delivery of phloridzin and phloretin and explore their anticancer mechanism through conjugation of the dihydrochalcones and the AuNP cores. Phloridzin and phloretin conjugated AuNPs (Phl-AuNP and Pht-AuNP) were synthesized in single-step, rapid, biofriendly processes. The synthesized AuNPs morphology was characterized via transmission electron microscopy and ultraviolet-visible spectroscopy. The presence of phloridzin or phloretin was confirmed using scanning electron microscopy-energy dispersive x-ray spectroscopy. The percentage of organic component (phloridzin/phloretin) onto AuNPs surface was characterized using thermogravimetric analysis. Assessment of the antineoplastic potency of the dihydrochalcones conjugated AuNPs against cancerous cell lines (HeLa) was accomplished through monitoring via flow cytometry. The functionalized AuNPs were synthesized via a single-step method that relied only upon the redox potential of the conjugate itself and required no toxic chemicals. The synthesized Phl-AuNPs were found to be in the size range of 15±5 nm, whereas the Pht-AuNP were found to be 8±3 nm, placing both conjugated AuNPs well within the size range necessary for successful pharmaceutical applications. These assays demonstrate a significant increase in the cancerous cell toxicities as a result of the conjugation of the drugs to AuNPs, as indicated by the 17.45-fold increase in the efficacy of Pht-AuNPs over pure phloretin, and the 4.49-fold increase in efficacy of Phl-AuNP over pure phloridzin. We report a simple, biofriendly process using the reducing and capping potential of the dihydrochalcones, phloridzin and phloretin, to synthesize stable AuNPs that have promising futures as potential antineoplastic agents.

Multicenter evaluation of a new closed system drug-transfer device in reducing surface contamination by antineoplastic hazardous drugs.

PubMed

Bartel, Sylvia B; Tyler, Timothy G; Power, Luci A

2018-02-15

Results of a study to evaluate the effectiveness of a recently introduced closed system drug-transfer device (CSTD) in reducing surface contamination during compounding and simulated administration of antineoplastic hazardous drugs (AHDs) are reported. Wipe samples were collected from 6 predetermined surfaces in compounding and infusion areas of 13 U.S. cancer centers to establish preexisting levels of surface contamination by 2 marker AHDs (cyclophosphamide and fluorouracil). Stainless steel templates were placed over the 6 previously sampled surfaces, and the marker drugs were compounded and infused per a specific protocol using all components of the CSTD. Wipe samples were collected from the templates after completion of tasks and analyzed for both marker AHDs. Aggregated results of wipe sampling to detect preexisting contamination at the 13 study sites showed that overall, 66.7% of samples (104 of 156) had detectable levels of at least 1 marker AHD; subsequent testing after CSTD use per protocol found a sample contamination rate of 5.8% (9 of 156 samples). In the administration areas alone, the rate of preexisting contamination was 78% (61 of 78 samples); with use of the CSTD protocol, the contamination rate was 2.6%. Twenty-six participants rated the CSTD for ease of use, with 100% indicating that they were satisfied or extremely satisfied. A study involving a rigorous protocol and 13 cancer centers across the United States demonstrated that the CSTD reduced surface contamination by cyclophosphamide and fluorouracil during compounding and simulated administration. Participants reported that the CSTD was easy to use. Copyright © 2018 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

In vitro antineoplastic effects of brivaracetam and lacosamide on human glioma cells.

PubMed

Rizzo, Ambra; Donzelli, Sara; Girgenti, Vita; Sacconi, Andrea; Vasco, Chiara; Salmaggi, Andrea; Blandino, Giovanni; Maschio, Marta; Ciusani, Emilio

2017-06-06

Epilepsy is a frequent symptom in patients with glioma. Although treatment with antiepileptic drugs is generally effective in controlling seizures, drug-resistant patients are not uncommon. Multidrug resistance proteins (MRPs) and P-gp are over-represented in brain tissue of patients with drug-resistant epilepsy, suggesting their involvement in the clearance of antiepileptic medications. In addition to their anticonvulsant action, some drugs have been documented for cytotoxic effects. Aim of this study was to evaluate possible in vitro cytotoxic effects of two new-generation antiepileptic drugs on a human glioma cell line U87MG. Cytotoxicity of brivaracetam and lacosamide was tested on U87MG, SW1783 and T98G by MTS assay. Expression of chemoresistance molecules was evaluated using flow cytometry in U87MG and human umbilical vein endothelial cells (HUVECs). To investigate the putative anti-proliferative effect, apoptosis assay, microRNA expression profile and study of cell cycle were performed. Brivaracetam and lacosamide showed a dose-dependent cytotoxic and anti-migratory effects. Cytotoxicity was not related to apoptosis. The exposure of glioma cells to brivaracetam and lacosamide resulted in the modulation of several microRNAs; particularly, the effect of miR-195-5p modulation seemed to affect cell cycle, while miR-107 seemed to be implicated in the inhibition of cells migration. Moreover, brivaracetam and lacosamide treatment did not modulate the expression of chemoresistance-related molecules MRPs1-3-5, GSTπ, P-gp on U87MG and HUVECs. Based on antineoplastic effect of brivaracetam and lacosamide on glioma cells, we assume that patients with glioma could benefit by the treatment with these two molecules, in addition to standard therapeutic options.

Astemizole Synergizes Calcitriol Antiproliferative Activity by Inhibiting CYP24A1 and Upregulating VDR: A Novel Approach for Breast Cancer Therapy

PubMed Central

Barrera, David; Santos, Nancy; Avila, Euclides; Ordaz-Rosado, David; Rivas-Suárez, Mariana; Halhali, Ali; Rodríguez, Pamela; Gamboa-Domínguez, Armando; Medina-Franco, Heriberto; Camacho, Javier; Larrea, Fernando; Díaz, Lorenza

2012-01-01

Background Calcitriol antiproliferative effects include inhibition of the oncogenic ether-à-go-go-1 potassium channel (Eag1) expression, which is necessary for cell cycle progression and tumorigenesis. Astemizole, a new promising antineoplastic drug, targets Eag1 by blocking ion currents. Herein, we characterized the interaction between calcitriol and astemizole as well as their conjoint antiproliferative action in SUM-229PE, T-47D and primary tumor-derived breast cancer cells. Methodology/Principal Findings Molecular markers were studied by immunocytochemistry, Western blot and real time PCR. Inhibitory concentrations were determined by dose-response curves and metabolic activity assays. At clinically achievable drug concentrations, synergistic antiproliferative interaction was observed between calcitriol and astemizole, as calculated by combination index analysis (CI <1). Astemizole significantly enhanced calcitriol’s growth-inhibitory effects (3–11 folds, P<0.01). Mean IC20 values were 1.82±2.41 nM and 1.62±0.75 µM; for calcitriol (in estrogen receptor negative cells) and astemizole, respectively. Real time PCR showed that both drugs alone downregulated, while simultaneous treatment further reduced Ki-67 and Eag1 gene expression (P<0.05). Astemizole inhibited basal and calcitriol-induced CYP24A1 and CYP3A4 mRNA expression (cytochromes involved in calcitriol and astemizole degradation) in breast and hepatoma cancer cells, respectively, while upregulated vitamin D receptor (VDR) expression. Conclusions/Significance Astemizole synergized calcitriol antiproliferative effects by downregulating CYP24A1, upregulating VDR and targeting Eag1. This study provides insight into the molecular mechanisms involved in astemizole-calcitriol combined antineoplastic effect, offering scientific support to test both compounds in combination in further preclinical and clinical studies of neoplasms expressing VDR and Eag1. VDR-negative tumors might also be sensitized to calcitriol antineoplastic effects by the use of astemizole. Herein we suggest a novel combined adjuvant therapy for the management of VDR/Eag1-expressing breast cancer tumors. Since astemizole improves calcitriol bioavailability and activity, decreased calcitriol dosing is advised for conjoint administration. PMID:22984610

Does the use of melatonin overcome drug resistance in cancer chemotherapy?

PubMed

Asghari, Mohammad Hossein; Ghobadi, Emad; Moloudizargari, Milad; Fallah, Marjan; Abdollahi, Mohammad

2018-03-01

Our knowledge regarding the implications of melatonin in the therapy of numerous medical conditions, including cancer is constantly expanding. Melatonin can variably affect cancer pathology via targeting several key aspects of any neoplastic condition, including the very onset of carcinogenesis as well as tumor growth, differentiation, and dissemination. Numerous studies have examined the effects of melatonin in the context of various cancers reporting the enhanced efficacy of chemo/radiotherapy in combination with this compound. Reduced sensitivity and also resistance of cancer cells to antineoplastic agents are common events which might arise as a result of genomic instability of the malignant cells. Genetic mutations provide numerous mechanisms for these cells to resist cytotoxic therapies. Melatonin, due to its pleitropic effects, is able to correct these alterations in favour of sensitization to antineoplastic agents as evident by increased response to treatment via modulating the expression and phosphorylation status of drug targets, the reduced clearance of drugs by affecting their metabolism and transport within the body, decreased survival of malignant cells via altering DNA repair and telomerase activity, and enhanced responsiveness to cell death-associated mechanisms such as apoptosis and autophagy. These effects are presumably governed by melatonin's interventions in the main signal transduction pathways such as Akt and MAPK, independent of its antioxidant properties. Possessing such a signaling altering nature, melatonin can considerably affect the drug-resistance mechanisms employed by the malignant cells in breast, lung, hepatic, and colon cancers as well as different types of leukemia which are the subject of the current review. Copyright © 2018 Elsevier Inc. All rights reserved.

Environmental and biological monitoring on an oncology ward during a complete working week.

PubMed

Koller, Michael; Böhlandt, Antje; Haberl, Christopher; Nowak, Dennis; Schierl, Rudolf

2018-05-05

Workplace exposure to antineoplastic drugs (AD) is still of evident concern to all occupationally exposed persons in the healthcare sector as residues in relevant concentrations continue to be present. With respect to the carcinogenic and mutagenic potential of ADs and their toxicity on reproduction, occupational exposure should be kept as low as reasonably achievable (ALARA). In the oncology patient care, the medical staff is involved both in chemotherapy administration and handling of AD-contaminated body fluids of the patients. For this purpose, in this study, surface monitoring on an oncology ward and concurrent urine monitoring of the complete healthcare staff was performed during five consecutive days for 5-fluorouracil (5-FU), cyclophosphamide (CP) and platinum (Pt). Contamination was detected on all surfaces in various ranges (5-FU 0.7-12,600 pg/cm 2 , Pt 0.2-181,800 pg/cm 2 , CP (

Nanotechnology-Based Drug Delivery Systems for Melanoma Antitumoral Therapy: A Review

PubMed Central

Rigon, Roberta Balansin; Oyafuso, Márcia Helena; Fujimura, Andressa Terumi; do Prado, Alice Haddad; Gremião, Maria Palmira Daflon

2015-01-01

Melanoma (MEL) is a less common type of skin cancer, but it is more aggressive with a high mortality rate. The World Cancer Research Fund International (GLOBOCAN 2012) estimates that there were 230,000 new cases of MEL in the world in 2012. Conventional MEL treatment includes surgery and chemotherapy, but many of the chemotherapeutic agents used present undesirable properties. Drug delivery systems are an alternative strategy by which to carry antineoplastic agents. Encapsulated drugs are advantageous due to such properties as high stability, better bioavailability, controlled drug release, a long blood circulation time, selective organ or tissue distribution, a lower total required dose, and minimal toxic side effects. This review of scientific research supports applying a nanotechnology-based drug delivery system for MEL therapy. PMID:26078967

A targeted drug delivery system based on dopamine functionalized nano graphene oxide

NASA Astrophysics Data System (ADS)

Masoudipour, Elham; Kashanian, Soheila; Maleki, Nasim

2017-01-01

The cellular targeting property of a biocompatible drug delivery system can widely increase the therapeutic effect against various diseases. Here, we report a dopamine conjugated nano graphene oxide (DA-nGO) carrier for cellular delivery of the anticancer drug, Methotrexate (MTX) into DA receptor positive human breast adenocarcinoma cell line. The material was characterized using scanning electron microscopy, atomic force microscopy, Fourier transform infrared spectroscopy and UV-vis spectroscopy. Furthermore, the antineoplastic action of MTX loaded DA-nGO against DA receptor positive and negative cell lines were explored. The results presented in this article demonstrated that the application of DA functionalized GO as a targeting drug carrier can improve the drug delivery efficacy for DA receptor positive cancer cell lines and promise future designing of carrier conjugates based on it.

Nanotechnology-Based Drug Delivery Systems for Melanoma Antitumoral Therapy: A Review.

PubMed

Rigon, Roberta Balansin; Oyafuso, Márcia Helena; Fujimura, Andressa Terumi; Gonçalez, Maíra Lima; do Prado, Alice Haddad; Gremião, Maria Palmira Daflon; Chorilli, Marlus

2015-01-01

Melanoma (MEL) is a less common type of skin cancer, but it is more aggressive with a high mortality rate. The World Cancer Research Fund International (GLOBOCAN 2012) estimates that there were 230,000 new cases of MEL in the world in 2012. Conventional MEL treatment includes surgery and chemotherapy, but many of the chemotherapeutic agents used present undesirable properties. Drug delivery systems are an alternative strategy by which to carry antineoplastic agents. Encapsulated drugs are advantageous due to such properties as high stability, better bioavailability, controlled drug release, a long blood circulation time, selective organ or tissue distribution, a lower total required dose, and minimal toxic side effects. This review of scientific research supports applying a nanotechnology-based drug delivery system for MEL therapy.

Environmental contamination, product contamination and workers exposure using a robotic system for antineoplastic drug preparation.

PubMed

Sessink, Paul J M; Leclercq, Gisèle M; Wouters, Dominique-Marie; Halbardier, Loïc; Hammad, Chaïma; Kassoul, Nassima

2015-04-01

Environmental contamination, product contamination and technicians exposure were measured following preparation of iv bags with cyclophosphamide using the robotic system CytoCare. Wipe samples were taken inside CytoCare, in the clean room environment, from vials, and prepared iv bags including ports and analysed for contamination with cyclophosphamide. Contamination with cyclophosphamide was also measured in environmental air and on the technicians hands and gloves used for handling the drugs. Exposure of the technicians to cyclophosphamide was measured by analysis of cyclophosphamide in urine. Contamination with cyclophosphamide was mainly observed inside CytoCare, before preparation, after preparation and after daily routine cleaning. Contamination outside CytoCare was incidentally found. All vials with reconstituted cyclophosphamide entering CytoCare were contaminated on the outside but vials with powdered cyclophosphamide were not contaminated on the outside. Contaminated bags entering CytoCare were also contaminated after preparation but non-contaminated bags were not contaminated after preparation. Cyclophosphamide was detected on the ports of all prepared bags. Almost all outer pairs of gloves used for preparation and daily routine cleaning were contaminated with cyclophosphamide. Cyclophosphamide was not found on the inner pairs of gloves and on the hands of the technicians. Cyclophosphamide was not detected in the stationary and personal air samples and in the urine samples of the technicians. CytoCare enables the preparation of cyclophosphamide with low levels of environmental contamination and product contamination and no measurable exposure of the technicians. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

[Polymeric drug carriers activated by ultrasounds energy].

PubMed

Kik, Krzysztof; Lwow, Felicja; Szmigiero, Leszek

2007-01-01

In the last two decades an extensive research on the employment of ultrasounds in anticancer therapy has been noticed. So far ultrasounds have been widely used in medicine for diagnostic purposes (ultrasonography), but their great therapeutic potential and the development of polymer based antineoplastic drug carriers have persuaded many investigators to start research on the employment of ultrasounds in anticancer therapy. A new therapeutic concept based on the controlled drug's molecules release from their transporting polymer carriers has been proposed. Cavitation, a phenomenon characteristic for the action of ultrasounds, is used to destroy polymeric drug carriers and for drug release in target sites. The sonodynamic therapy (SDT) which utilizes ultrasonic waves for "acoustic drug activation" leading to the enhancement of cytotoxic activity of some drugs has also been developed. Furthermore, a long standing research on ultrasounds resulted in a new concept based on hyperthermia. This method of cancer treatment does not require any chemotherapeutic agent to be applied.

Covalent conjugation of graphene oxide with methotrexate and its antitumor activity

NASA Astrophysics Data System (ADS)

Wojtoniszak, M.; Urbas, K.; Perużyńska, M.; Kurzawski, M.; Droździk, M.; Mijowska, E.

2013-05-01

Here, we have functionalized graphene oxide with anticancer drug methotrexate through amide bonding. A kinetics of the drug release from graphene oxide in physiological solution - phosphate buffered saline (PBS) containing different biocompatible polymers have been investigated. Dispersion of MTX-GO in poly sodium-4-styrene sulfonate and poly ethylene glycol resulted in increase of the release time. The material was characterized with transmission electron microscopy, atomic force microscopy, Raman spectroscopy, Fourier transform infrared spectroscopy and UV-vis spectroscopy. Furthermore, antineoplastic action against human breast adenocarcinoma cell line MCF7 of MTX-GO and empty graphene oxide was explored.

Nuclear Transcription Factor Kappa B Downregulation Reduces Chemoresistance in Bone Marrow-derived Cells Through P-glycoprotein Modulation.

PubMed

Loaiza, Brenda; Hernández-Gutierrez, Salomon; Montesinos, Juan Jose; Valverde, Mahara; Rojas, Emilio

2016-02-01

Nuclear transcription factor kappa B (NF-κB) is associated with many types of refractory cancer. However, despite multiple strategies to treat cancer and novel target drugs, multidrug resistance still causes relapses. The best-characterized mechanism responsible for multidrug resistance involves the expression of the MDR-1 gene product, P-glycoprotein (P-gp). Because the direct inhibition of this protein is very toxic, other methods of multidrug resistance (MDR) regulation have been proposed. The MDR-1 promoter sequence contains a κB site, which is recognized by NF-κB. The aim of this work was to characterize whether NF-κB modulation changes the response of bone marrow-derived cells (BMDCs) to chemotherapy. We exposed BMDCs to etoposide and doxorubicin, two of the most used antineoplastic drugs. BMDCs presented high tolerance to these drugs, which correlated with high intrinsic P-gp activity and strong protein expression of NF-κB. To determine the mechanism behind the poor sensitivity of BMDCs to chemotherapy, we blocked the activity of the heterodimer protein NF-κB using the pharmacological inhibitor Bay 11-7085 and through the transfection of an adenovirus negative mutant of I kappa B alpha. The multidrug resistance phenotype of BMDCs was reversed by inhibiting the NF-κB pathway, and this change was accompanied by a decrease in P-gp activity. NF-κB is a possible target for improving the antineoplastic response. Copyright © 2016 IMSS. Published by Elsevier Inc. All rights reserved.

Antineoplastic activity of the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine in anaplastic large cell lymphoma

PubMed Central

Hassler, Melanie R.; Klisaroska, Aleksandra; Kollmann, Karoline; Steiner, Irene; Bilban, Martin; Schiefer, Ana-Iris; Sexl, Veronika; Egger, Gerda

2012-01-01

DNA methylation is an epigenetic mechanism establishing long-term gene silencing during development and cell commitment, which is maintained in subsequent cell generations. Aberrant DNA methylation is found at gene promoters in most cancers and can lead to silencing of tumor suppressor genes. The DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (5-aza-CdR) is able to reactivate genes silenced by DNA methylation and has been shown to be a very potent epigenetic drug in several hematological malignancies. In this report, we demonstrate that 5-aza-CdR exhibits high antineoplastic activity against anaplastic large cell lymphoma (ALCL), a rare CD30 positive non-Hodgkin lymphoma of T-cell origin. Low dose treatment of ALCL cell lines and xenografted tumors causes apoptosis and cell cycle arrest in vitro and in vivo. This is also reflected in genome-wide expression analyses, where genes related to apoptosis and cell death are amongst the most affected targets of 5-aza-CdR. Furthermore, we observed demethylation and re-expression of p16INK4A after drug administration and senescence associated β-galactosidase activity. Thus, our data provide evidence that 5-aza-CdR is highly efficient against ALCL and warrants further clinical evaluation for future therapeutic use. PMID:22687603

Removal of polycyclic synthetic musks and antineoplastic drugs in ozonated wastewater: Quantitation based on the data of differential spectroscopy.

PubMed

Li, Wei; Nanaboina, Venkateswarlu; Chen, Fang; Korshin, Gregory V

2016-03-05

This study examined the degradation behavior of polycyclic musks (PMs) and antineoplastic drugs (ADs) and the absorbance spectra of effluent organic matter (EfOM) in municipal wastewater by ozone. Specific ozone doses used in the experiments ranged from 0 to 1mg O3/mg dissolved organic matter (DOC). The examined PMs included galaxolide, tonalide, celestolide, traseolide and phantolide. ADs included busulfan, chlorambucil, cyclophosphamide, dacarbazine, flutamide, ifosfamide, tamoxifen and methotrexate. Strong monotonic albeit nonlinear correlations were found to exist between relative changes of EfOM absorbance at 254 nm (i.e. ΔA254/A(0)254) and the degradation of the selected PMs and ADs. This result was interpreted based on the concept of the simultaneous oxidation of EfOM and, on the other hand, PMs and ADs. This interpretation showed that PMs were degraded primarily via OH radical attack, with tonalide and phantolide being less reactive compared with the other PMs. ADs such as cyclophosphamide, ifosfamide and busulfan were also determined to undergo oxidation by OH radicals. Comparison of the behavior of the radical probe para-chlorobenzoic acid and the examined ADs and PMs allowed evaluating corresponding reaction rate constants for reactions between these species and OH radicals. Copyright © 2015 Elsevier B.V. All rights reserved.

Pharmacological Modulation of Lung Carcinogenesis in Smokers: Preclinical and Clinical Evidence

PubMed Central

De Flora, Silvio; Ganchev, Gancho; Iltcheva, Marietta; La Maestra, Sebastiano; Micale, Rosanna T.; Steele, Vernon E.; Balansky, Roumen

2016-01-01

Many drugs in common use possess pleiotropic properties that make them capable of interfering with carcinogenesis mechanisms. We discuss here the ability of pharmacological agents to mitigate the pulmonary carcinogenicity of mainstream cigarette smoke. The evaluated agents included antiinflammatory drugs (budesonide, celecoxib, aspirin, naproxen, licofelone), antidiabetic drugs (metformin, pioglitazone), antineoplastic agents (lapatinib, bexarotene, vorinostat), and other drugs and supplements (phenethyl isothiocyanate, myo-inositol, N-acetylcysteine, ascorbic acid, berry extracts). The drugs have been evaluated in mouse models mimicking interventions either in current smokers or in ex-smokers or a prenatal chemoprevention. They displayed a broad spectrum of activities by attenuating either smoke-induced preneoplastic lesions or benign tumors and/or malignant tumors. Together with epidemiological data, these findings provide useful information to predict the potential effects of pharmacological agents in smokers. PMID:26726119

Pathophysiology of Chemotherapy-Induced Peripheral Neuropathy

PubMed Central

Starobova, Hana; Vetter, Irina

2017-01-01

Chemotherapy-induced neuropathy is a common, dose-dependent adverse effect of several antineoplastics. It can lead to detrimental dose reductions and discontinuation of treatment, and severely affects the quality of life of cancer survivors. Clinically, chemotherapy-induced peripheral neuropathy presents as deficits in sensory, motor, and autonomic function which develop in a glove and stocking distribution due to preferential effects on longer axons. The pathophysiological processes are multi-factorial and involve oxidative stress, apoptotic mechanisms, altered calcium homeostasis, axon degeneration and membrane remodeling as well as immune processes and neuroinflammation. This review focusses on the commonly used antineoplastic substances oxaliplatin, cisplatin, vincristine, docetaxel, and paclitaxel which interfere with the cancer cell cycle—leading to cell death and tumor degradation—and cause severe acute and chronic peripheral neuropathies. We discuss drug mechanism of action and pharmacokinetic disposition relevant to the development of peripheral neuropathy, the epidemiology and clinical presentation of chemotherapy-induced neuropathy, emerging insight into genetic susceptibilities as well as current understanding of the pathophysiology and treatment approaches. PMID:28620280

Uptake and metabolism of cisplatin by rat kidney.

PubMed

Safirstein, R; Miller, P; Guttenplan, J B

1984-05-01

Cisplatin, an effective antineoplastic agent, is toxic to the kidney. Since the kidney's vulnerability to cisplatin may originate in its ability to accumulate and retain platinum to a greater degree than other organs, we studied the characteristics of the renal accumulation of platinum and investigated the nature of intracellular platinum. Cisplatin and ethylenediamminedichloroplatinum, nephrotoxic and antineoplastic liganded platinum compounds, were concentrated in rat renal cortical slices fivefold above medium concentration. Platinum uptake was energy- and temperature-dependent and could be inhibited by drugs which inhibit base transport. The organic anions para-aminohippurate and pyrazinoate did not reduce renal slice platinum uptake. Unbound platinum in the blood and urine was predominantly cisplatin but unbound platinum in kidney cytosol was not. This latter compound, in contrast to cisplatin, was not active as a mutagen. These studies suggest that the kidney accumulates platinum in part by transport or specific binding to the base transport system in the kidney and biotransforms it intracellularly. Unbound platinum in the cell is not cisplatin and may no longer be toxic.

The Antineoplastic Effect of Nitric Oxide-Donating Acetylsalicylic Acid (NO-ASA) in Chronic Lymphocytic Leukemia (CLL) Cells is Highly Dependent on its Positional Isomerism.

PubMed

Gehrke, Iris; Razavi, Regina; Poll-Wolbeck, Simon Jonas; Berkessel, Albrecht; Hallek, Michael; Kreuzer, Karl-Anton

2011-10-01

Chronic Lymphocytic Leukemia (CLL) is not curable in patients that are not eligible for allogeneic stem cell transplantation. Therefore, new treatment options are highly desirable. Chemically modified nonsteroidal anti-inflammatory drugs (NSAIDs), such as nitric-oxide-donating acetylsalicylic acid (NO-ASA), have been described to possess antineoplastic capacity. Recently, we could demonstrate a potent apoptosis induction in primary CLL cells in vitro and tumor growth inhibition by para-NO-ASA in a xenograft mouse model. However, little is known about the impact of positional isomerism of NO-ASA on its antineoplastic capacity in CLL. Primary CLL cells were treated with the meta-or para-isomer of NO-ASA at varying concentrations and durations. Viability was assessed flow cytometrically by annexin V-FITC/PI staining and by CellTiter-Glo luminescence cell viability assay. Caspase and PARP cleavage as well as involvement of β-catenin/Lef-1 signaling was determined by immunoblotting. For caspase inhibition, BD™ ApoBlock was used. Nude mice were xenografted with JVM3 cells and treated with meta-NO-ASA, para-NO-ASA or vehicle control. The meta-isomer was entirely ineffective in inducing CLL cell apoptosis in concentrations up to 100 μM, while para-NO-ASA acted in the low micromolar range. meta-NO-ASA, in contrast to para-NO-ASA, did not alter caspase activity. While para-NO-ASA action involved inhibition of β-catenin/Lef-1 signaling, meta-NO-ASA did not show any impact on this signaling pathway. Further, meta-NO-ASA did not significantly reduce tumor growth in a CLL xenograft mouse model, while para-NO-ASA was highly potent. We conclude that positional isomerism is crucial for the antineoplastic effect of NO-ASA in CLL. It can be suggested that the para-isomer, but not the meta-isomer, generates a chemical structure which is essential for the neoplastic effect of NO-ASA.

The Antineoplastic Effect of Nitric Oxide-Donating Acetylsalicylic Acid (NO-ASA) in Chronic Lymphocytic Leukemia (CLL) Cells is Highly Dependent on its Positional Isomerism

PubMed Central

Gehrke, Iris; Razavi, Regina; Poll-Wolbeck, Simon Jonas; Berkessel, Albrecht; Hallek, Michael; Kreuzer, Karl-Anton

2011-01-01

Background: Chronic Lymphocytic Leukemia (CLL) is not curable in patients that are not eligible for allogeneic stem cell transplantation. Therefore, new treatment options are highly desirable. Chemically modified nonsteroidal anti-inflammatory drugs (NSAIDs), such as nitric-oxide-donating acetylsalicylic acid (NO-ASA), have been described to possess antineoplastic capacity. Recently, we could demonstrate a potent apoptosis induction in primary CLL cells in vitro and tumor growth inhibition by para-NO-ASA in a xenograft mouse model. However, little is known about the impact of positional isomerism of NO-ASA on its antineoplastic capacity in CLL. Methods: Primary CLL cells were treated with the meta-or para-isomer of NO-ASA at varying concentrations and durations. Viability was assessed flow cytometrically by annexin V-FITC/PI staining and by CellTiter-Glo luminescence cell viability assay. Caspase and PARP cleavage as well as involvement of β-catenin/Lef-1 signaling was determined by immunoblotting. For caspase inhibition, BD™ ApoBlock was used. Nude mice were xenografted with JVM3 cells and treated with meta-NO-ASA, para-NO-ASA or vehicle control. Results: The meta-isomer was entirely ineffective in inducing CLL cell apoptosis in concentrations up to 100 μM, while para-NO-ASA acted in the low micromolar range. meta-NO-ASA, in contrast to para-NO-ASA, did not alter caspase activity. While para-NO-ASA action involved inhibition of β-catenin/Lef-1 signaling, meta-NO-ASA did not show any impact on this signaling pathway. Further, meta-NO-ASA did not significantly reduce tumor growth in a CLL xenograft mouse model, while para-NO-ASA was highly potent. Conclusion: We conclude that positional isomerism is crucial for the antineoplastic effect of NO-ASA in CLL. It can be suggested that the para-isomer, but not the meta-isomer, generates a chemical structure which is essential for the neoplastic effect of NO-ASA. PMID:23556096

21 CFR 878.5070 - Air-handling apparatus for a surgical operating room.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Air-handling apparatus for a surgical operating room. 878.5070 Section 878.5070 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND....5070 Air-handling apparatus for a surgical operating room. (a) Identification. Air-handling apparatus...

21 CFR 878.5070 - Air-handling apparatus for a surgical operating room.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Air-handling apparatus for a surgical operating room. 878.5070 Section 878.5070 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND....5070 Air-handling apparatus for a surgical operating room. (a) Identification. Air-handling apparatus...

Treatment, overall survival, and costs in patients with ALK-positive non-small-cell lung cancer after crizotinib monotherapy.

PubMed

Guérin, A; Sasane, M; Wakelee, H; Zhang, J; Culver, K; Dea, K; Nitulescu, R; Galebach, P; Macalalad, A R

2015-08-01

Limited post-crizotinib treatment options for ALK-positive non-small cell lung cancer (NSCLC) might lead to poor survival and high economic burden. To evaluate real-world treatment patterns, overall survival (OS), and costs following crizotinib discontinuation. This study used chart review and claims data. First, 27 participating US oncologists reviewed medical records of ALK-positive NSCLC patients who discontinued crizotinib monotherapy and reported patient demographic and clinical information, including post-crizotinib treatment and mortality. OS was estimated using Kaplan-Meier analyses. Second, three large administrative US claims databases were pooled. NSCLC patients were selected if they discontinued crizotinib monotherapy. Post-crizotinib costs were analyzed separately for patients who did or did not discontinue antineoplastic treatment after crizotinib monotherapy. All data were collected prior to ceritinib approval for this patient population. A total of 119 ALK-positive NSCLC patients discontinued crizotinib monotherapy. Upon discontinuation, 42% had no additional antineoplastic treatment and 13% received radiation therapy only. The median OS post-crizotinib was 61 days; patients with brain metastases had shorter OS than those who did not (44 vs. 69 days, P = 0.018), and patients without further antineoplastic treatment had shorter OS than those who did (17 vs. 180 days, P < 0.001). From claims data, 305 ALK-positive NSCLC patients discontinued crizotinib monotherapy. After discontinuation, 72% had no additional antineoplastic treatment. Among patients who continued antineoplastic treatment, monthly healthcare costs averaged $22,160, driven by pharmacy ($9202), inpatient ($6419), and outpatient radiotherapy ($2888) and imaging ($1179) costs. Among patients who discontinued any antineoplastic treatment, monthly healthcare costs averaged $3423, mostly driven by inpatient costs ($2074). After crizotinib monotherapy, most patients either received radiotherapy only or discontinued antineoplastic treatment altogether. OS after discontinuing crizotinib was poor and shorter among those with brain metastases than without, and among those without subsequent antineoplastic treatment than with. Patients who continued antineoplastic treatment incurred substantial healthcare costs.

The anti-neoplastic activity of Vandetanib against high-risk medulloblastoma variants is profoundly enhanced by additional PI3K inhibition

PubMed Central

Velz, Julia; Olschewski, Martin; Goetz, Barbara; Pietsch, Torsten; Dilloo, Dagmar

2017-01-01

Medulloblastoma is comprised of at least four molecular subgroups with distinct clinical outcome (WHO classification 2016). SHH-TP53-mutated as well as MYC-amplified Non-WNT/Non-SHH medulloblastoma show the worst prognosis. Here we present evidence that single application of the multi-kinase inhibitor Vandetanib displays anti-neoplastic efficacy against cell lines derived from high-risk SHH-TP53-mutated and MYC-amplified Non-WNT/Non-SHH medulloblastoma. The narrow target spectrum of Vandetanib along with a favourable toxicity profile renders this drug ideal for multimodal treatment approaches. In this context our investigation documents that Vandetanib in combination with the clinically available PI3K inhibitor GDC-0941 leads to enhanced cytotoxicity against MYC-amplified and SHH-TP53-mutated medulloblastoma. In line with these findings we show for MYC-amplified medulloblastoma a profound reduction in activity of the oncogenes STAT3 and AKT. Furthermore, we document that Vandetanib and the standard chemotherapeutic Etoposide display additive anti-neoplastic efficacy in the investigated medulloblastoma cell lines that could be further enhanced by PI3K inhibition. Of note, the combination of Vandetanib, GDC-0941 and Etoposide results in MYC-amplified and SHH-TP53-mutated cell lines in complete loss of cell viability. Our findings therefore provide a rational to further evaluate Vandetanib in combination with PI3K inhibitors as well as standard chemotherapeutics in vivo for the treatment of most aggressive medulloblastoma variants. PMID:28159923

The anti-neoplastic activity of Vandetanib against high-risk medulloblastoma variants is profoundly enhanced by additional PI3K inhibition.

PubMed

Craveiro, Rogerio B; Ehrhardt, Michael; Velz, Julia; Olschewski, Martin; Goetz, Barbara; Pietsch, Torsten; Dilloo, Dagmar

2017-07-18

Medulloblastoma is comprised of at least four molecular subgroups with distinct clinical outcome (WHO classification 2016). SHH-TP53-mutated as well as MYC-amplified Non-WNT/Non-SHH medulloblastoma show the worst prognosis.Here we present evidence that single application of the multi-kinase inhibitor Vandetanib displays anti-neoplastic efficacy against cell lines derived from high-risk SHH-TP53-mutated and MYC-amplified Non-WNT/Non-SHH medulloblastoma. The narrow target spectrum of Vandetanib along with a favourable toxicity profile renders this drug ideal for multimodal treatment approaches. In this context our investigation documents that Vandetanib in combination with the clinically available PI3K inhibitor GDC-0941 leads to enhanced cytotoxicity against MYC-amplified and SHH-TP53-mutated medulloblastoma. In line with these findings we show for MYC-amplified medulloblastoma a profound reduction in activity of the oncogenes STAT3 and AKT. Furthermore, we document that Vandetanib and the standard chemotherapeutic Etoposide display additive anti-neoplastic efficacy in the investigated medulloblastoma cell lines that could be further enhanced by PI3K inhibition. Of note, the combination of Vandetanib, GDC-0941 and Etoposide results in MYC-amplified and SHH-TP53-mutated cell lines in complete loss of cell viability. Our findings therefore provide a rational to further evaluate Vandetanib in combination with PI3K inhibitors as well as standard chemotherapeutics in vivo for the treatment of most aggressive medulloblastoma variants.

Expression of NK Cell Surface Receptors in Breast Cancer Tissue as Predictors of Resistance to Antineoplastic Treatment

PubMed Central

Mariel, Garcia-Chagollan; Edith, Carranza-Torres Irma; Pilar, Carranza-Rosales; Elena, Guzmán-Delgado Nancy; Humberto, Ramírez-Montoya; Guadalupe, Martínez-Silva María; Ignacio, Mariscal-Ramirez; Alfredo, Barrón-Gallardo Carlos; Laura, Pereira-Suárez Ana; Adriana, Aguilar-Lemarroy; Felipe, Jave-Suárez Luis

2018-01-01

Background: Currently, one of the most used strategies for the treatment of newly diagnosed patients with breast cancer is neoadjuvant chemotherapy based on the application of taxanes and anthracyclines. However, despite the high number of patients who develop a complete pathological clinical response, resistance and relapse following this therapy continue to be a clinical challenge. As a component of the innate immune system, the cytotoxic function of Natural Killer (NK) cells plays an important role in the elimination of tumor cells. However, the role of NK cells in resistance to systemic therapy in breast cancer remains unclear. The present project aims to evaluate the gene expression profile of human NK cells in breast cancer tissue resistant to treatment with taxanes–anthracyclines. Methods: Biopsies from tumor tissues were obtained from patients with breast cancer without prior treatment. Histopathological analysis and ex vivo exposure to antineoplastic chemotherapeutics were carried out. Alamar blue and lactate dehydrogenase release assays were performed for quantitative analysis of tumor viability. Gene expression profiles from tumor tissues without prior exposure to therapeutic drugs were analyzed by gene expression microarrays and verified by polymerase chain reaction. Results: A significant decrease in gene expression of cell-surface receptors related to NK cells was observed in tumor samples resistant to antineoplastic treatment compared with those that were sensitive to treatment. Conclusion: A decrease in NK cell infiltration into tumor tissue might be a predictive marker for failure of chemotherapeutic treatment in breast cancer. PMID:29558872

Expression of NK Cell Surface Receptors in Breast Cancer Tissue as Predictors of Resistance to Antineoplastic Treatment.

PubMed

Mariel, Garcia-Chagollan; Edith, Carranza-Torres Irma; Pilar, Carranza-Rosales; Elena, Guzmán-Delgado Nancy; Humberto, Ramírez-Montoya; Guadalupe, Martínez-Silva María; Ignacio, Mariscal-Ramirez; Alfredo, Barrón-Gallardo Carlos; Laura, Pereira-Suárez Ana; Adriana, Aguilar-Lemarroy; Felipe, Jave-Suárez Luis

2018-01-01

Currently, one of the most used strategies for the treatment of newly diagnosed patients with breast cancer is neoadjuvant chemotherapy based on the application of taxanes and anthracyclines. However, despite the high number of patients who develop a complete pathological clinical response, resistance and relapse following this therapy continue to be a clinical challenge. As a component of the innate immune system, the cytotoxic function of Natural Killer (NK) cells plays an important role in the elimination of tumor cells. However, the role of NK cells in resistance to systemic therapy in breast cancer remains unclear. The present project aims to evaluate the gene expression profile of human NK cells in breast cancer tissue resistant to treatment with taxanes-anthracyclines. Biopsies from tumor tissues were obtained from patients with breast cancer without prior treatment. Histopathological analysis and ex vivo exposure to antineoplastic chemotherapeutics were carried out. Alamar blue and lactate dehydrogenase release assays were performed for quantitative analysis of tumor viability. Gene expression profiles from tumor tissues without prior exposure to therapeutic drugs were analyzed by gene expression microarrays and verified by polymerase chain reaction. A significant decrease in gene expression of cell-surface receptors related to NK cells was observed in tumor samples resistant to antineoplastic treatment compared with those that were sensitive to treatment. A decrease in NK cell infiltration into tumor tissue might be a predictive marker for failure of chemotherapeutic treatment in breast cancer.

pH-sensitive liposomes for drug delivery in cancer treatment.

PubMed

Ferreira, Diego Dos Santos; Lopes, Sávia Caldeira de Araújo; Franco, Marina Santiago; Oliveira, Mônica Cristina

2013-09-01

In recent years, liposomes have been employed with growing success as pharmaceutical carriers for antineoplastic drugs. One specific strategy used to enhance in vivo liposome-mediated drug delivery is the improvement of intracytoplasmic delivery. In this context, pH-sensitive liposomes (pHSLip) have been designed to explore the endosomal acidification process, which may lead to a destabilization of the liposomes, followed by a release of their contents into the cell cytoplasm. This review considers the current status of pHSLip development and its applicability in cancer treatment, focusing on the mechanisms of pH sensitivity and liposomal composition of pHSLip. The final section will discuss the application of these formulations in both in vitro and in vivo studies of antitumor efficacy.

Extravasation of antineoplastic agents: prevention and treatments.

PubMed

Boschi, Rita; Rostagno, Elena

2012-07-31

The extravasation of antineoplastic agents is an unwanted and distressing situation that can easily occur. It may cause severe and irreversible local injuries. Left untreated, vesicant chemotherapy extravasation can potentially cause tissue necrosis, functional impairment and permanent disfigurement. This article provides a review of current literature regarding recommendations on the prevention and treatment of extravasation of antineoplastic agents.

Handling of hazardous drugs - Effect of an innovative teaching session for nursing students.

PubMed

Zimmer, Janine; Hartl, Stefanie; Standfuß, Katrin; Möhn, Till; Bertsche, Astrid; Frontini, Roberto; Neininger, Martina P; Bertsche, Thilo

2017-02-01

Imparting knowledge and practical skills in hazardous drug handling in nursing students' education is essential to prevent hazardous exposure and to preserve nurses' health. This study aimed at comparing routine nursing education with an additional innovative teaching session. A prospective controlled study in nursing students was conducted in two study periods: (i) a status-quo period (routine education on handling hazardous drugs) followed by (ii) an intervention period (additional innovative teaching session on handling hazardous drugs). Nursing students at a vocational school were invited to participate voluntarily. In both study periods (i) and (ii), the following factors were analysed: (a) knowledge of hazardous drug handling by questionnaire, (b) practical skills in hazardous drug handling (e.g. cleaning) by a simulated handling scenario, (c) contamination with drug residuals on the work surface by fluorescent imaging. Fifty-three nursing students were enrolled. (a) Median knowledge improved from status-quo (39% right answers) to intervention (65%, p<0.001), (b) practical skills improved from status-quo (53% of all participants cleaned the work surface) to intervention (92%, p<0.001). (c) Median number of particles/m 2 decreased from status-quo to intervention (932/97, p<0.001). Compared with routine education, knowledge and practical skills in hazardous drug handling were significantly improved after an innovative teaching session. Additionally, the amount of residuals on the work surface decreased. This indicates a lower risk for hazardous drug exposure. Copyright © 2016 Elsevier Ltd. All rights reserved.

Acid-mediated Lipinski's second rule: application to drug design and targeting in cancer.

PubMed

Omran, Ziad; Rauch, Cyril

2014-05-01

With a predicted 382.4 per 100,000 people expected to suffer from some form of malignant neoplasm by 2015, and a current death toll of 1 out of 8 deaths worldwide, improving treatment and/or drug design is an essential focus of cancer research. Multi-drug resistance is the leading cause of chemotherapeutic failure, and delivery of anticancer drugs to the inside of cancerous cells is another major challenge. Fifteen years ago, in a completely different field in which improving drug delivery is the objective, the bioavailability of oral compounds, Christopher Lipinski formulated some rules that are still used by the pharmaceutical industry as rules of thumb to improve drug delivery to their target. Although Lipinski's rules were not formulated to improve delivery of antineoplastic drugs to the inside of cancer cells, it is interesting to note that the problems are similar. On the basis of the strong similarity between the fields, we discuss how they can be connected and how new drug targets can be defined in cancer.

Network Analysis of Drug-target Interactions: A Study on FDA-approved New Molecular Entities Between 2000 to 2015.

PubMed

Lin, Hui-Heng; Zhang, Le-Le; Yan, Ru; Lu, Jin-Jian; Hu, Yuanjia

2017-09-25

The U.S. Food and Drug Administration (FDA) approves new drugs every year. Drug targets are some of the most important interactive molecules for drugs, as they have a significant impact on the therapeutic effects of drugs. In this work, we thoroughly analyzed the data of small molecule drugs approved by the U.S. FDA between 2000 and 2015. Specifically, we focused on seven classes of new molecular entity (NME) classified by the anatomic therapeutic chemical (ATC) classification system. They were NMEs and their corresponding targets for the cardiovascular system, respiratory system, nerve system, general anti-infective systemic, genito-urinary system and sex hormones, alimentary tract and metabolisms, and antineoplastic and immunomodulating agents. To study the drug-target interaction on the systems level, we employed network topological analysis and multipartite network projections. As a result, the drug-target relations of different kinds of drugs were comprehensively characterized and global pictures of drug-target, drug-drug, and target-target interactions were visualized and analyzed from the perspective of network models.

Bacterial inactivation of the anticancer drug doxorubicin.

PubMed

Westman, Erin L; Canova, Marc J; Radhi, Inas J; Koteva, Kalinka; Kireeva, Inga; Waglechner, Nicholas; Wright, Gerard D

2012-10-26

Microbes are exposed to compounds produced by members of their ecological niche, including molecules with antibiotic or antineoplastic activities. As a result, even bacteria that do not produce such compounds can harbor the genetic machinery to inactivate or degrade these molecules. Here, we investigated environmental actinomycetes for their ability to inactivate doxorubicin, an aminoglycosylated anthracycline anticancer drug. One strain, Streptomyces WAC04685, inactivates doxorubicin via a deglycosylation mechanism. Activity-based purification of the enzymes responsible for drug inactivation identified the NADH dehydrogenase component of respiratory electron transport complex I, which was confirmed by gene inactivation studies. A mechanism where reduction of the quinone ring of the anthracycline by NADH dehydrogenase leads to deglycosylation is proposed. This work adds anticancer drug inactivation to the enzymatic inactivation portfolio of actinomycetes and offers possibilities for novel applications in drug detoxification. Copyright © 2012 Elsevier Ltd. All rights reserved.

New Antimicrobial Approaches: Reuse of Old Drugs.

PubMed

Savoia, Dianella

2016-01-01

The global situation of antibiotic resistance and the reduction of investments in antibiotics research by the pharmaceutical industry suggest the need for specific cost-effective approaches in order to identify drugs for the therapy of many microbial infections. Among the viable alternative anti-infective compounds, drug repurposing, i.e. to find new uses for previously approved medicines, revealed some encouraging in vitro and in vivo results. In this article the reader has a panoramic view of the updated references on the strategies encountered during the repositioning process. New findings are reported about the anti-microbial efficacy of antipsychotic, cardiovascular, anti-inflammatory and anti-neoplastic drugs. This approach may enhance the portfolio of pharmaceutical companies reducing the need for pharmacokinetic and toxicity studies; the development of new uses of old drugs for different infectious diseases, leading to better health for patients, also in poor, tropical countries, appears to be having better results.

21 CFR 820.140 - Handling.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Handling. 820.140 Section 820.140 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES..., contamination, or other adverse effects to product do not occur during handling. ...

Levetiracetam mitigates doxorubicin-induced DNA and synaptic damage in neurons.

PubMed

Manchon, Jose Felix Moruno; Dabaghian, Yuri; Uzor, Ndidi-Ese; Kesler, Shelli R; Wefel, Jeffrey S; Tsvetkov, Andrey S

2016-05-11

Neurotoxicity may occur in cancer patients and survivors during or after chemotherapy. Cognitive deficits associated with neurotoxicity can be subtle or disabling and frequently include disturbances in memory, attention, executive function and processing speed. Searching for pathways altered by anti-cancer treatments in cultured primary neurons, we discovered that doxorubicin, a commonly used anti-neoplastic drug, significantly decreased neuronal survival. The drug promoted the formation of DNA double-strand breaks in primary neurons and reduced synaptic and neurite density. Pretreatment of neurons with levetiracetam, an FDA-approved anti-epileptic drug, enhanced survival of chemotherapy drug-treated neurons, reduced doxorubicin-induced formation of DNA double-strand breaks, and mitigated synaptic and neurite loss. Thus, levetiracetam might be part of a valuable new approach for mitigating synaptic damage and, perhaps, for treating cognitive disturbances in cancer patients and survivors.

Levetiracetam mitigates doxorubicin-induced DNA and synaptic damage in neurons

PubMed Central

Manchon, Jose Felix Moruno; Dabaghian, Yuri; Uzor, Ndidi-Ese; Kesler, Shelli R.; Wefel, Jeffrey S.; Tsvetkov, Andrey S.

2016-01-01

Neurotoxicity may occur in cancer patients and survivors during or after chemotherapy. Cognitive deficits associated with neurotoxicity can be subtle or disabling and frequently include disturbances in memory, attention, executive function and processing speed. Searching for pathways altered by anti-cancer treatments in cultured primary neurons, we discovered that doxorubicin, a commonly used anti-neoplastic drug, significantly decreased neuronal survival. The drug promoted the formation of DNA double-strand breaks in primary neurons and reduced synaptic and neurite density. Pretreatment of neurons with levetiracetam, an FDA-approved anti-epileptic drug, enhanced survival of chemotherapy drug-treated neurons, reduced doxorubicin-induced formation of DNA double-strand breaks, and mitigated synaptic and neurite loss. Thus, levetiracetam might be part of a valuable new approach for mitigating synaptic damage and, perhaps, for treating cognitive disturbances in cancer patients and survivors. PMID:27168474

Interactions of ozone and antineoplastic drugs on rat lung fibroblasts and Walker rat carcinoma cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wenzel, D.G.; Morgan, D.L.

Cultured rat lung fibroblasts (F-cells) and Walker rat carcinoma cells (WRC-cells) labeled with /sup 51/Cr were exposed to the following antitumor drugs alone or with O/sub 3/: carmustine (BCNU), doxorubicin (Dox), cisplatin (CPt), mitomycin C (Mit C) or vitamin K/sub 3/ (Vit K). Release of /sup 51/Cr (cell injury) was greater for F-cells than WRC-cells with any single treatment. Pretreatment with any drug (400 microM), except for Vit K with WRC-cells, did not significantly increase O/sub 3/-induced loss of /sup 51/Cr. Co-exposure of F-cells to drugs and O/sub 3/ resulted in a marked potentiation of O/sub 3/-induced injury with Vitmore » K, and an inhibition with Dox.« less

A prospective three-step intervention study to prevent medication errors in drug handling in paediatric care.

PubMed

Niemann, Dorothee; Bertsche, Astrid; Meyrath, David; Koepf, Ellen D; Traiser, Carolin; Seebald, Katja; Schmitt, Claus P; Hoffmann, Georg F; Haefeli, Walter E; Bertsche, Thilo

2015-01-01

To prevent medication errors in drug handling in a paediatric ward. One in five preventable adverse drug events in hospitalised children is caused by medication errors. Errors in drug prescription have been studied frequently, but data regarding drug handling, including drug preparation and administration, are scarce. A three-step intervention study including monitoring procedure was used to detect and prevent medication errors in drug handling. After approval by the ethics committee, pharmacists monitored drug handling by nurses on an 18-bed paediatric ward in a university hospital prior to and following each intervention step. They also conducted a questionnaire survey aimed at identifying knowledge deficits. Each intervention step targeted different causes of errors. The handout mainly addressed knowledge deficits, the training course addressed errors caused by rule violations and slips, and the reference book addressed knowledge-, memory- and rule-based errors. The number of patients who were subjected to at least one medication error in drug handling decreased from 38/43 (88%) to 25/51 (49%) following the third intervention, and the overall frequency of errors decreased from 527 errors in 581 processes (91%) to 116/441 (26%). The issue of the handout reduced medication errors caused by knowledge deficits regarding, for instance, the correct 'volume of solvent for IV drugs' from 49-25%. Paediatric drug handling is prone to errors. A three-step intervention effectively decreased the high frequency of medication errors by addressing the diversity of their causes. Worldwide, nurses are in charge of drug handling, which constitutes an error-prone but often-neglected step in drug therapy. Detection and prevention of errors in daily routine is necessary for a safe and effective drug therapy. Our three-step intervention reduced errors and is suitable to be tested in other wards and settings. © 2014 John Wiley & Sons Ltd.

Comparison of Decontamination Efficacy of Cleaning Solutions on a Biological Safety Cabinet Workbench Contaminated by Cyclophosphamide

PubMed Central

Adé, Apolline; Chauchat, Laure; Frève, Johann-François Ouellette; Gagné, Sébastien; Caron, Nicolas; Bussières, Jean-François

2017-01-01

Background Several studies have compared cleaning procedures for decontaminating surfaces exposed to antineoplastic drugs. All of the cleaning products tested were successful in reducing most of the antineoplastic drug quantities spilled on surfaces, but none of them completely removed residual traces. Objective To assess the efficacy of various cleaning solutions for decontaminating a biological safety cabinet workbench exposed to a defined amount of cyclophosphamide. Methods In this pilot study, specific areas of 2 biological safety cabinets (class II, type B2) were deliberately contaminated with a defined quantity of cyclophosphamide (10 μg or 107 pg). Three cleaning solutions were tested: quaternary ammonium, sodium hypochlorite 0.02%, and sodium hypochlorite 2%. After cleaning, the cyclophosphamide remaining on the areas was quantified by wipe sampling. Each cleaning solution was tested 3 times, with cleaning and wipe sampling being performed 5 times for each test. Results A total of 57 wipe samples were collected and analyzed. The average recovery efficiency was 121.690% (standard deviation 5.058%). The decontamination efficacy increased with the number of successive cleaning sessions: from 98.710% after session 1 to 99.997% after session 5 for quaternary ammonium; from 97.027% to 99.997% for sodium hypochlorite 0.02%; and from 98.008% to 100% for sodium hypochlorite 2%. Five additional cleaning sessions performed after the main study (with detergent and sodium hypochlorite 2%) were effective to complete the decontamination, leaving no detectable traces of the drug. Conclusions All of the cleaning solutions reduced contamination of biological safety cabinet workbenches exposed to a defined amount of cyclophosphamide. Quaternary ammonium and sodium hypochlorite (0.02% and 2%) had mean efficacy greater than 97% for removal of the initial quantity of the drug (107 pg) after the first cleaning session. When sodium hypochlorite 2% was used, fewer cleaning sessions were required to complete decontamination. Further studies should be conducted to identify optimal cleaning strategies to fully eliminate traces of hazardous drugs. PMID:29298999

Detection of teratogens in human serum using rat embryo culture: cancer and epilepsy treatments. [Detecting teratogenicity of anticonvulsant and antineoplastic drugs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chatot, C. L.

1979-01-01

Growth (protein and DNA contents) of headfold stage rat embryos cultured for 48 hrs on human serum was enhanced by glucose supplementation. Embryo growth varied with the source of the serum. Sera from 3 of the 19 control subjects produced abnormal embryos. Sera from 5 subjects undergoing cancer chemotherapy and 6 subjects receiving anticonvulsants were either lethal or teratogenic to cultured rat embryos.

Drug repurposing in cancer.

PubMed

Sleire, Linda; Førde, Hilde Elise; Netland, Inger Anne; Leiss, Lina; Skeie, Bente Sandvei; Enger, Per Øyvind

2017-10-01

Cancer is a major health issue worldwide, and the global burden of cancer is expected to increase in the coming years. Whereas the limited success with current therapies has driven huge investments into drug development, the average number of FDA approvals per year has declined since the 1990s. This unmet need for more effective anti-cancer drugs has sparked a growing interest for drug repurposing, i.e. using drugs already approved for other indications to treat cancer. As such, data both from pre-clinical experiments, clinical trials and observational studies have demonstrated anti-tumor efficacy for compounds within a wide range of drug classes other than cancer. Whereas some of them induce cancer cell death or suppress various aspects of cancer cell behavior in established tumors, others may prevent cancer development. Here, we provide an overview of promising candidates for drug repurposing in cancer, as well as studies describing the biological mechanisms underlying their anti-neoplastic effects. Copyright © 2017 Elsevier Ltd. All rights reserved.

The continuing search for antitumor agents from higher plants

PubMed Central

Pan, Li; Chai, Heebyung; Kinghorn, A. Douglas

2009-01-01

Plant secondary metabolites and their semi-synthetic derivatives continue to play an important role in anticancer drug therapy. In this short review, selected single chemical entity antineoplastic agents from higher plants that are currently in clinical trials as cancer chemotherapy drug candidates are described. These compounds are representative of a wide structural diversity. In addition, the approaches taken toward the discovery of anticancer agents from tropical plants in the laboratory of the authors are summarized. The successful clinical utilization of cancer chemotherapeutic agents from higher plants has been evident for about half a century, and, when considered with the promising pipeline of new plant-derived compounds now in clinical trials, this augurs well for the continuation of drug discovery research efforts to elucidate additional candidate substances of this type. PMID:20228943

Near-infrared fluorescence imaging and photodynamic therapy with indocyanine green lactosome has antineoplastic effects for hepatocellular carcinoma.

PubMed

Tsuda, Takumi; Kaibori, Masaki; Hishikawa, Hidehiko; Nakatake, Richi; Okumura, Tadayoshi; Ozeki, Eiichi; Hara, Isao; Morimoto, Yuji; Yoshii, Kengo; Kon, Masanori

2017-01-01

Anticancer agents and operating procedures have been developed for hepatocellular carcinoma (HCC) patients, but their prognosis remains poor. It is necessary to develop novel diagnostic and therapeutic strategies for HCC to improve its prognosis. Lactosome is a core-shell-type polymeric micelle, and enclosing labeling or anticancer agents into this micelle enables drug delivery. In this study, we investigated the diagnostic and therapeutic efficacies of indocyanine green (ICG)-loaded lactosome for near-infrared fluorescence (NIF) imaging and photodynamic therapy (PDT) for HCC. The human HCC cell line HuH-7 was treated with ICG or ICG-lactosome, followed by PDT, and the cell viabilities were measured (in vitro PDT efficiency). For NIF imaging, HuH-7 cells were subcutaneously transplanted into BALB/c nude mice, followed by intravenous administration of ICG or ICG-lactosome. The transplanted animals were treated with PDT, and the antineoplastic effects were analyzed (in vivo PDT efficiency). PDT had toxic effects on HuH-7 cells treated with ICG-lactosome, but not ICG alone. NIF imaging revealed that the fluorescence of tumor areas in ICG-lactosome-treated animals was higher than that of contralateral regions at 24 h after injection and thereafter. PDT exerted immediate and continuous phototoxic effects in the transplanted mice treated with ICG-lactosome. Our results demonstrate that ICG-lactosome accumulated in xenograft tumors, and that PDT had antineoplastic effects on these malignant implants. NIF imaging and PDT with ICG-lactosome could be useful diagnostic and/or therapeutic strategies for HCC.

21 CFR 58.47 - Facilities for handling test and control articles.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 1 2010-04-01 2010-04-01 false Facilities for handling test and control articles. 58.47 Section 58.47 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... for handling test and control articles. (a) As necessary to prevent contamination or mixups, there...

Combination of capecitabine and phenytoin may cause phenytoin intoxication: a case report.

PubMed

Ciftci, Rumeysa; Tas, Faruk; Karabulut, Senem; Ciftci, Serkan

2015-01-01

Capecitabine is an oral antineoplastic agent, and phenytoin is an anticonvulsant drug with a narrow therapeutic index. Although the interaction between capecitabine and phenytoin is rare, it may be potentially fatal. This interaction is thought to be at the level of CYP2C9 isoenzyme system in the liver. Here, we present a patient with metastatic breast cancer who developed phenytoin intoxication when using capecitabine and phenytoin together. Closely monitoring plasma phenytoin levels is essential if capecitabine is used with phenytoin concurrently.

The effects of pharmacist interventions on adult outpatients with cancer: A systematic review.

PubMed

Colombo, L R P; Aguiar, P M; Lima, T M; Storpirtis, S

2017-08-01

Most antineoplastic drugs are highly toxic and have low therapeutic indexes, which can result in drug-related problems. In this context, pharmacist interventions may play an important role in the success of the treatment. The objective of this study was to examine the effects of pharmacist interventions on adult outpatients with cancer using antineoplastic drugs. A literature search was performed using PubMed, ISI Web of Science and LILACS databases from January 1990 to April 2016, using MeSH terms or text words related to pharmacist interventions, cancer and outpatient care. Studies published in English, Portuguese or Spanish on the effects of pharmacist interventions in outcome measures in adult outpatients with cancer were included. Two independent authors performed study selection and data extraction with a consensus process. The articles were analysed according to previously established criteria, such as country, study design, setting, population, type of cancer, description of the intervention and control groups, outcomes, main conclusions and study limitations. A total of 874 records were identified, of which 11 satisfied the inclusion criteria. The studies were conducted mainly in the United States and included patients aged >50 years. Most studies had a before-after design. Pharmacist interventions primarily included educating and counselling patients on the management of adverse events. Rates of nausea and vomiting control, medication adherence and patient satisfaction were the most common outcome measures; a significant benefit in these parameters as a result of pharmacist interventions was noted in most studies. The findings from this systematic review indicate that pharmacist interventions can improve outcome measures in outpatients with cancer. However, the collective quality of the studies was poor and gaps identified indicate that further research is needed to provide more robust results. © 2017 John Wiley & Sons Ltd.

Introduction for Design of Nanoparticle Based Drug Delivery Systems.

PubMed

Edgar, Jun Yan Chan; Wang, Hui

2017-01-01

Conventional drug delivery systems contain numerous limitations such as limited targeting, low therapeutic indices, poor water solubility, and the induction of drug resistances. In order to overcome the drawbacks of conventional pathway of drug delivery, nanoparticle delivery systems are therefore designed and used as the drug carriers. Nanoparticle based drug delivery systems have been rapidly growing and are being applied to various sections of biomedicine. Drug nanocarriers based on dendrimers, liposomes, self-assembling peptides, watersoluble polymers, and block copolymer micelles are the most extensively studied types of drug delivery systems and some of them are being used in clinical therapy. In particular for cancer therapy, antineoplastic drugs are taking advantage of nanoparticulate drug carriers to improve the cure efficacy. Nanoparticle based drug carriers are capable of improving the therapeutic effectiveness of the drugs by using active targeting for the site-specific delivery, passive targeting mechanisms such as enhanced permeability and retention (EPR), de novo synthesis and uptake of low density liposome in cancer cells or by being water-soluble to improve the suboptimal pharmacokinetics in limited water-soluble delivery methods. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

21 CFR 203.32 - Drug sample storage and handling requirements.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 4 2010-04-01 2010-04-01 false Drug sample storage and handling requirements. 203.32 Section 203.32 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... contamination, deterioration, and adulteration. (b) Compliance with compendial and labeling requirements...

[Effect of free and polymer carrier encapsulated doxorubicin towards HCT116 cells of human colorectal carcinoma].

PubMed

Sen'kiv, Iu V; Heffeter, P; Riabtseva, A O; Boĭko, N M; Mitina, N Ie; Zaichenko, O S; Berger, W; Stoĭka, R S

2013-01-01

Development of novel nanoscale functionalized carriers is nowadays one of the most urgent problems in cancer treatment. The aim of our study was to compare the antineoplastic effect of free doxorubicin and its complex with a nanoscale polymeric carrier towards HTC116 colorectal carcinoma cells. It was established that application of the complex of poly(5-tret-butylperoxy)-5-methyl-1-hexene-3-in-co-glycydyl metacrylat)-graft-polyethyleneglycol (poly(VEP-GMA-PEG)-graft-PEG), where VEP--5-tret-butylperoxy)-5-methyl-1-hexene-3-in; GMA--glycydyl metacrylat; graft-PEG--graft-polyethyleneglycol accordingly, functionalized with phosphatidylcholine for doxorubicin delivery increased 10 times the efficiency of cytotoxic action of this drug, as compared wich such efficiency in case of the action of free doxorubicin. The encapsulated form of doxorubicin caused more intensive cleavage of the reparation enzyme PARP and longer delay in G2/M cell cycle arrest, compared to such effects of free doxorubicin. The developed carrier itself is non-toxic to the used mammalian cells and does not cause impairment in their cell cycle. A deletion in both alleles of p53 gene did not affect the antineoplastic action of doxorubicin that was immobilized on the nanoscale carrier. Thus, p53-dependent signaling pathways are not involved in the cytotoxic action of doxorubicin-carrier complex. It is suggested that novel nanoscale polymeric carrier poly(VEP-GMA-PEG)-graft-PEG functionalized with phosphatidylcholine could be a promising carrier for targeted delivery of anticancer drugs.

Evaluation of the anti-neoplastic effect of sorafenib on liver cancer through bioluminescence tomography

NASA Astrophysics Data System (ADS)

Liang, Qian; Ye, Jinzuo; Du, Yang; Chi, Chongwei; Tian, Jie

2017-03-01

Hepatocellular carcinoma (HCC) is one of the most important leading causes of cancer-related deaths worldwide. In this study, we evaluated the efficacy of sorafenib on hepatocellular carcinoma through bioluminescence tomography (BLT) based on Micro-CT/BLT multi-modal system. Initially, the human hepatocellular carcinoma cell line HepG2-Red-FLuc, which was transfected with luciferase gene, was cultured. And then, the orthotopic liver tumor mouse model was established on 4 5 weeks old athymic male Balb/c nude mice by inoculating the HepG2-Red-FLuc cell suspension into the liver lobe under isoflurane anesthesia. 15 20 days after tumor cells implantation, the mice were divided into two groups including the sorafenib treatment group and the control group. The mice in the treatment group were treated with sorafenib with dosage of 62 mg/kg/day by oral gavage for continuous 14 days, and the mice in the control group were treated with sterile water at equal volume. The tumor growth and drug treatment efficacy were dynamically monitored through BLT. The results in this study showed that the growth of liver cancer can be dynamically monitored from very early stage, and also the sorafenib treatment efficacy can be reliably and objectively assessed using BLT imaging method. Our experimental result demonstrated sorafenib can inhibit the tumor growth effectively. BLT enabled the non-invasive and reliable assessment of anti-neoplastic drug efficacy on liver cancer.

Screening and evaluation of anticancer agents.

PubMed

Zee-Cheng, R K; Cheng, C C

1988-02-01

The screening and evaluation procedures for the development of anticancer agents indicated that the entire process is a rather difficult task. This is particularly true in choosing screening models and criteria for activity. If the criteria were set too low, then some clinically false-positive results may be faced; and if the criteria were set too high, some agents could be missed which might be effective against certain types of human cancer. Presently, active compounds are selected by prescreening and screening against transplanted mouse tumors and human tumor xenografts as well as by the in vitro systems. Xenografts of human tumor in athymic nude animals represent metabolic characteristics of human malignant disease which appear to be of value in the preclinical screening. Human tumor cloning assays have gained increased attention as a promising in vitro test system for the screening as well as for the prediction of patient responses. Application of chemosensitivity tests in the prediction of the responses of individuals to chemotherapy, especially in the identification of drug resistant tumors are, in general, quite reliable. Human tumor xenografts, human tumor cloning assays and chemosensitivity tests may be regarded as the major impetus in screening during the past decade. After promising agents are selected from the screening procedures, before the filing of an investigational new drug application, the preclinical toxicology and pharmacology should be completed. Information on the nature of toxicity, dose-response effects, and dose schedule are necessary for predicting the effects of the drug in man. The new drugs then go through three phases of clinical trials to assure safety, effectiveness, and reliability of the drugs. During the past fifteen years eight-three antineoplastic drugs were evaluated clinically under the NCI sponsorship and twenty-four are active in at least one disease. Among these active drugs, eleven possess novel clinical structure, the remaining thirteen are analogues of known active compounds already in clinical trials. After an investigational anticancer drug is approved by the U.S. Food and Drug Administration it becomes a commercial product on the market and the benefits can be shared by the general public. The time required for evaluation and development from the first discovery of activity to final FDA approval for fifty-two therapeutic drugs are tabled. The average interval is 8.8 years, but in the 1950s the average was only 2.8 years, in the 1960s, 6.5 years; in the 1970s, 13.9 years; and in the 1980s, 16.0 years. This reflects the increasing stricter requirements for an antineoplastic drug to be officially recognize

Evaluation of clay/poly (L-lactide) microcomposites as anticancer drug, 6-mercaptopurine reservoir through in vitro cytotoxicity, oxidative stress markers and in vivo pharmacokinetics.

PubMed

Kevadiya, Bhavesh D; Chettiar, Shiva Shankaran; Rajkumar, Shalini; Bajaj, Hari C; Gosai, Kalpeshgiri A; Brahmbhatt, Harshad

2013-12-01

Intercalation of 6-mercaptopurine (6-MP), an antineoplastic drug in interlayer gallery of Na(+)-clay (MMT) was further entrapped in poly (L-lactide) matrix to form microcomposite spheres (MPs) in order to reduce the cell toxicity and enhance in vitro release and pharmacokinetic proficiency. The drug-clay hybrid was fabricated via intercalation by ion-exchange method to form MPs from hybrid. In vitro drug release showed controlled pattern, fitted to kinetic models suggested controlled exchange and partial diffusion through swollen matrix of clay inter layered gallery. The in vitro efficacy of formulated composites drug was tested in Human neuroblastoma cell line (IMR32) by various cell cytotoxic and oxidative stress marker indices. In vivo pharmacokinetics suggested that the intensity of formulated drug level in plasma was within remedial borders as compared to free drug. These clay based composites therefore have great potential of becoming a new dosage form of 6-MP. Copyright © 2013 Elsevier B.V. All rights reserved.

21 CFR 205.50 - Minimum requirements for the storage and handling of prescription drugs and for the establishment...

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 4 2013-04-01 2013-04-01 false Minimum requirements for the storage and handling of prescription drugs and for the establishment and maintenance of prescription drug distribution records. 205.50 Section 205.50 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL...

Synergistic cytogenetic and antineoplastic effects by the combined action of esteric steroidal derivatives of nitrogen mustards.

PubMed

Mourelatos, Constantinos; Nikolaropoulos, Sotiris; Fousteris, Manolis; Pairas, Georgios; Argyraki, Maria; Kareli, Dimitra; Dafa, Evaggelia; Mourelatos, Dionisios; Lialiaris, Theodore

2012-06-01

We studied the effect of five newly synthesized steroidal derivatives of nitrogen mustards. These derivatives have as alkylators either P-N, N-bis(2-chloroethyl)aminophenyl-butyrate (CHL) or P-N, N-bis(2-chloroethyl)aminophenyl-acetate (PHE) groups esterified with different modified steroidal nuclei. We examined them alone or in combination, on sister chromatid exchange rates and on human lymphocyte proliferation kinetics. The antitumor activity of these compounds, alone or in combination, was also tested on Leukemia P388-bearing mice. A pronounced cytogenetic and antineoplastic action was demonstrated by the compounds that contain either PHE or CHL as alkylators and are esterified with a steroidal nucleus having added a cholestene group in the 17 position of the D-ring. The exocyclical insertion of an -NHCO- group in the D-ring of the steroidal nucleus esterified with PHE (amide ester of PHE) yielded a compound demonstrating a distinct cytogenetic and antineoplastic effect. In contrast, the ketone group in the D-ring being inserted endocyclically in the steroidal nucleus (androstene) esterified with either CHL or with PHE gave negative cytogenetic and antineoplastic effects. However, the combined action of cholestene esterified with either CHL or with PHE in combination with either the androstene ester of PHE or with the androstene ester of CHL, respectively, gave synergistic cytogenetic and antineoplastic effects. Also the amide ester of PHE in combination with the androstene ester of CHL gave distinct cytogenetic and antineoplastic effects in a synergistic manner.

21 CFR 1250.32 - Food-handling operations.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Food-handling operations. 1250.32 Section 1250.32 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) REGULATIONS UNDER CERTAIN OTHER ACTS ADMINISTERED BY THE FOOD AND DRUG ADMINISTRATION INTERSTATE CONVEYANCE...

21 CFR 1250.32 - Food-handling operations.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Food-handling operations. 1250.32 Section 1250.32 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) REGULATIONS UNDER CERTAIN OTHER ACTS ADMINISTERED BY THE FOOD AND DRUG ADMINISTRATION INTERSTATE CONVEYANCE...

21 CFR 1250.32 - Food-handling operations.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Food-handling operations. 1250.32 Section 1250.32 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) REGULATIONS UNDER CERTAIN OTHER ACTS ADMINISTERED BY THE FOOD AND DRUG ADMINISTRATION INTERSTATE CONVEYANCE...

21 CFR 1250.32 - Food-handling operations.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Food-handling operations. 1250.32 Section 1250.32 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) REGULATIONS UNDER CERTAIN OTHER ACTS ADMINISTERED BY THE FOOD AND DRUG ADMINISTRATION INTERSTATE CONVEYANCE...

21 CFR 1250.32 - Food-handling operations.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Food-handling operations. 1250.32 Section 1250.32 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) REGULATIONS UNDER CERTAIN OTHER ACTS ADMINISTERED BY THE FOOD AND DRUG ADMINISTRATION INTERSTATE CONVEYANCE...

Ion channels and neuronal hyperexcitability in chemotherapy-induced peripheral neuropathy

PubMed Central

Goldstein, Peter A

2017-01-01

Cancer is the second leading cause of death worldwide and is a major global health burden. Significant improvements in survival have been achieved, due in part to advances in adjuvant antineoplastic chemotherapy. The most commonly used antineoplastics belong to the taxane, platinum, and vinca alkaloid families. While beneficial, these agents are frequently accompanied by severe side effects, including chemotherapy-induced peripheral neuropathy (CPIN). While CPIN affects both motor and sensory systems, the majority of symptoms are sensory, with pain, tingling, and numbness being the predominant complaints. CPIN not only decreases the quality of life of cancer survivors but also can lead to discontinuation of treatment, thereby adversely affecting survival. Consequently, minimizing the incidence or severity of CPIN is highly desirable, but strategies to prevent and/or treat CIPN have proven elusive. One difficulty in achieving this goal arises from the fact that the molecular and cellular mechanisms that produce CPIN are not fully known; however, one common mechanism appears to be changes in ion channel expression in primary afferent sensory neurons. The processes that underlie chemotherapy-induced changes in ion channel expression and function are poorly understood. Not all antineoplastic agents directly affect ion channel function, suggesting additional pathways may contribute to the development of CPIN Indeed, there are indications that these drugs may mediate their effects through cellular signaling pathways including second messengers and inflammatory cytokines. Here, we focus on ion channelopathies as causal mechanisms for CPIN and review the data from both pre-clinical animal models and from human studies with the aim of facilitating the development of appropriate strategies to prevent and/or treat CPIN. PMID:28580836

Functional differentiation of cytotoxic cancer drugs and targeted cancer therapeutics.

PubMed

Winkler, Gian C; Barle, Ester Lovsin; Galati, Giuseppe; Kluwe, William M

2014-10-01

There is no nationally or internationally binding definition of the term "cytotoxic drug" although this term is used in a variety of regulations for pharmaceutical development and manufacturing of drugs as well as in regulations for protecting medical personnel from occupational exposure in pharmacy, hospital, and other healthcare settings. The term "cytotoxic drug" is frequently used as a synonym for any and all oncology or antineoplastic drugs. Pharmaceutical companies generate and receive requests for assessments of the potential hazards of drugs regularly - including cytotoxicity. This publication is intended to provide functional definitions that help to differentiate between generically-cytotoxic cancer drugs of significant risk to normal human tissues, and targeted cancer therapeutics that pose much lesser risks. Together with specific assessments, it provides comprehensible guidance on how to assess the relevant properties of cancer drugs, and how targeted therapeutics discriminate between cancer and normal cells. The position of several regulatory agencies in the long-term is clearly to regulate all drugs regardless of classification, according to scientific risk based data. Despite ongoing discussions on how to replace the term "cytotoxic drugs" in current regulations, it is expected that its use will continue for the near future. Copyright © 2014 Elsevier Inc. All rights reserved.

HDAC inhibitor-loaded bone cement for advanced local treatment of osteosarcoma and chondrosarcoma.

PubMed

Tonak, Marcus; Becker, Marc; Graf, Claudine; Eckhard, Lukas; Theobald, Matthias; Rommens, Pol-Maria; Wehler, Thomas C; Proschek, Dirk

2014-11-01

The treatment of osteosarcoma, especially wide resection, is challenging. An additional local drug therapy after resection using anti-neoplastic bone cement (Polymethylmethacrylate (PMMA)) could help improve the outcome of therapy. In this study, we evaluated the effects of PMMA loaded with valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA) on the cell activity of a SaOs-2 cell culture, as well as the elution rate of the drugs out of the bone cement. In our experiments, we used the SaOs-2 osteosarcoma and the SW1353 chondrosarcoma cell line. Bone cement clots (5 g) were prepared and loaded with different drug concentrations of VPA (25 mg and 50 mg) and SAHA (1 mg, 2.5 mg and 5 mg). Two control groups were established, one with a native cement clot, the other with human mesenchymal stem cells, in order to evaluate toxicity on non tumor-cells. Cell activity was measured using an Alamar Blue assay on days 1, 2, 3, 4 and 7. The cement clots were additionally examined in a material testing unit for biomechanical and structural changes. Tumor cells showed a significant and complete reduction of activity under therapy with VPA and SAHA. Drug release of VPA was extensive between days 0 and 3 and decreased progressively to day 7. Cumulative drug concentration in the medium continuously increased. Biomechanical testing of the cement clots showed no differences in stability and architecture compared to the control group. SaOs-2 and SW1353 cells with medium from native cement clots without drug therapy presented a cell activity of 100% in all groups and during all measurements. Human mesenchymal stem cells were not significantly affected during therapy with VPA and low concentrations of SAHA. In contrast, cell activity of human mesenchymal stem cells was significantly reduced under therapy with higher concentrations of SAHA, with an approximately linear decrease between days 0-3 and a rapidly decreasing activity between days 4-7. A local cytotoxic therapy in the treatment of osteosarcoma and chondrosarcoma might improve the rate of metastasis and survival of patients. Our results present an encouraging approach to loading PMMA with anti-neoplastic drugs. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

21 CFR 1250.35 - Health of persons handling food.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Health of persons handling food. 1250.35 Section 1250.35 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) REGULATIONS UNDER CERTAIN OTHER ACTS ADMINISTERED BY THE FOOD AND DRUG ADMINISTRATION INTERSTATE CONVEYANCE...

21 CFR 1250.35 - Health of persons handling food.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Health of persons handling food. 1250.35 Section 1250.35 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) REGULATIONS UNDER CERTAIN OTHER ACTS ADMINISTERED BY THE FOOD AND DRUG ADMINISTRATION INTERSTATE CONVEYANCE...

21 CFR 1250.28 - Source and handling of ice.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Source and handling of ice. 1250.28 Section 1250.28 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) REGULATIONS UNDER CERTAIN OTHER ACTS ADMINISTERED BY THE FOOD AND DRUG ADMINISTRATION INTERSTATE CONVEYANCE...

76 FR 50740 - Draft Guidance for Industry and Food and Drug Administration Staff; Procedures for Handling...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-16

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2011-D-0514] Draft Guidance for Industry and Food and Drug Administration Staff; Procedures for Handling Section 522 Postmarket Surveillance Studies; Availability AGENCY: Food and Drug Administration, HHS. ACTION: Notice...

Evaluation of Nephroprotective and Immunomodulatory Activities of Antioxidants in Combination with Cisplatin against Murine Visceral Leishmaniasis

PubMed Central

Sharma, Meenakshi; Sehgal, Rakesh; Kaur, Sukhbir

2012-01-01

Background Most available drugs against visceral leishmaniasis are toxic, and growing limitations in available chemotherapeutic strategies due to emerging resistant strains and lack of an effective vaccine against visceral leishmaniasis deepens the crisis. Antineoplastic drugs like miltefosine have in the past been effective against the parasitic infections. An antineoplastic drug, cisplatin (cis-diamminedichloroplatinum II; CDDP), is recognized as a DNA-damaging drug which also induces alteration of cell-cycle in both promastigotes and amastigotes leading to cell death. First in vivo reports from our laboratory revealed the leishmanicidal potential of cisplatin. However, high doses of cisplatin produce impairment of kidney, which can be reduced by the administration of antioxidants. Methodology/Principal Findings The present study was designed to evaluate the antileishmanial effect of cisplatin at higher doses (5 mg and 2.5 mg/kg body weight) and its combination with different antioxidants (vitamin C, vitamin E and silibinin) so as to eliminate the parasite completely and reduce the toxicity. In addition, various immunological, hematological and biochemical changes induced by it in uninfected and Leishmania donovani infected BALB/c mice were investigated. Conclusion/Significance A significant reduction in parasite load, higher IgG2a and lower IgG1 levels, enhanced DTH responses, and greater concentration of Th1 cytokines (IFN-γ, IL-2) with a concomitant down regulation of IL-10 and IL-4 pointed towards the generation of the protective Th1 type of immune response. A combination of cisplatin with antioxidants resulted in successful reduction of nephrotoxicity by normalizing the enzymatic levels of various liver and kidney function tests. Reduction in parasite load, increase in Th1 type of immune responses, and normalization of various biochemical parameters occurred in animals treated with cisplatin in combination with various antioxidants as compared to those treated with the drug only. The above results are promising as antioxidants reduced the potential toxicity of high doses of cisplatin, making the combination a potential anti-leishmanial therapy, especially in resistant cases. PMID:22563510

Factors associated with prescribing restriction on oncology formulary drugs in Malaysia.

PubMed

Fatokun, Omotayo; Olawepo, Michael N

2016-10-01

Background Drugs listed on formularies are often subjected to a variety of utilization restriction measures. However, the degree of restriction is influenced by multiple factors, including the characteristics and attributes of the listed drugs. Objective To identify the factors that are associated with the levels of prescribing restriction on oncology formulary drugs in Malaysia. Setting Oncology formulary in Malaysia. Method The Malaysia Drug Code assigned to each of the drug products on the Malaysia Ministry of Health (MOH) drug formulary was used to identify oncology drugs belonging to WHO ATC class L (antineoplastic and immunomodulating agents). Main outcome measures Categories of prescribing restrictions, therapeutic class, drug type, administration mode, number of sources and the post-approval use period. Results Oncology drugs having a shorter post-approval use period (p < 0.001), biologic oncology drugs (p = 0.01) and oncology drugs belonging to immunosuppressant therapeutic class (p = 0.03) were all significantly associated with a greater likelihood of being subjected to a higher level of prescribing restriction. Conclusion This study suggests that safety concerns, costs and potentials for inappropriate use were the important considerations influencing a higher level of prescribing restriction placement on oncology drugs in the Malaysia MOH drug formulary.

Cytotoxicity and Antineoplastic Activities of Alkylamines and Their Borane Derivatives

PubMed Central

Tse, Elaine Y.; Muhammad, Rosallah A.

1996-01-01

The alkylamines and their related boron derivatives demonstrated potent cytotoxicity against the growth of murine and human tissue cultured cells. These agents did not necessarily require the boron atom to possess potent cytotoxic action in certain tumor lines. Their ability to suppress tumor cell growth was based on their inhibition of DNA and protein syntheses. DNA synthesis was reduced because purine synthesis was blocked at the enzyme site of IMP dehydrogenase by the agents. In addition ribonucleotide reductase and nucleoside kinase activities were reduced by the agents which would account for the reduced d[NTP] pools. The DNA template or molecule may be a target of the drugs with regard to binding of the drug to nucleoside bases or intercalaction of the drug between DNA base pairs. Only some Of the agents caused DNA fragmentation with reduced DNA viscosity. These effects would contribute to overall cell death afforded by the agents. PMID:18472803

Halloysite clay nanotubes for resveratrol delivery to cancer cells.

PubMed

Vergaro, Viviana; Lvov, Yuri M; Leporatti, Stefano

2012-09-01

Halloysite is natural aluminosilicate clay with hollow tubular structure which allows loading with low soluble drugs using their saturated solutions in organic solvents. Resveratrol, a polyphenol known for having antioxidant and antineoplastic properties, is loaded inside these clay nanotubes lumens. Release time of 48 h is demonstrated. Spectroscopic and ζ-potential measurements are used to study the drug loading/release and for monitoring the nanotube layer-by-layer (LbL) coating with polyelectrolytes for further release control. Resveratrol-loaded clay nanotubes are added to breast cell cultures for toxicity tests. Halloysite functionalization with LbL polyelectrolyte multilayers remarkably decrease nanotube self-toxicity. MTT measurements performed with a neoplastic cell lines model system (MCF-7) as function of the resveratrol-loaded nanotubes concentration and incubation time indicate that drug-loaded halloysite strongly increase of cytotoxicity leading to cell apoptosis. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

ATP-binding cassette transporters in tumor endothelial cells and resistance to metronomic chemotherapy.

PubMed

Hida, Kyoko; Kikuchi, Hiroshi; Maishi, Nako; Hida, Yasuhiro

2017-08-01

Drug resistance is a major problem in anticancer therapy. ATP-binding cassette (ABC) transporters have a role in the multidrug resistance. A new regimen of chemotherapy has been proposed, called "metronomic chemotherapy". Metronomic chemotherapy is the frequent, regular administration of drug doses designed to maintain low, but active, concentrations of chemotherapeutic drugs over prolonged periods of time, without causing serious toxicities. Metronomic chemotherapy regimens were developed to optimize the antitumor efficacy of agents that target the tumor vasculature instead of tumor cells, and to reduce toxicity of antineoplastic drugs [1]. Nevertheless, recent studies revealed that ABC transporters are expressed at a higher level in the endothelium in the tumor. To avoid resistance to metronomic anti-angiogenic chemotherapy, ABC transporter inhibition of tumor endothelial cells may be a promising strategy. In this mini-review, we discuss the possible mechanism of resistance to metronomic chemotherapy from the viewpoint of tumor endothelial cell biology, focusing on ABC transporters. Copyright © 2017. Published by Elsevier B.V.

Magneto-electric Nanoparticles to Enable Field-controlled High-Specificity Drug Delivery to Eradicate Ovarian Cancer Cells

PubMed Central

Guduru, Rakesh; Liang, Ping; Runowicz, Carolyn; Nair, Madhavan; Atluri, Venkata; Khizroev, Sakhrat

2013-01-01

The nanotechnology capable of high-specificity targeted delivery of anti-neoplastic drugs would be a significant breakthrough in Cancer in general and Ovarian Cancer in particular. We addressed this challenge through a new physical concept that exploited (i) the difference in the membrane electric properties between the tumor and healthy cells and (ii) the capability of magneto-electric nanoparticles (MENs) to serve as nanosized converters of remote magnetic field energy into the MENs' intrinsic electric field energy. This capability allows to remotely control the membrane electric fields and consequently trigger high-specificity drug uptake through creation of localized nano-electroporation sites. In in-vitro studies on human ovarian carcinoma cell (SKOV-3) and healthy cell (HOMEC) lines, we applied a 30-Oe d.c. field to trigger high-specificity uptake of paclitaxel loaded on 30-nm CoFe2O4@BaTiO3 MENs. The drug penetrated through the membrane and completely eradicated the tumor within 24 hours without affecting the normal cells. PMID:24129652

Magneto-electric nanoparticles to enable field-controlled high-specificity drug delivery to eradicate ovarian cancer cells.

PubMed

Guduru, Rakesh; Liang, Ping; Runowicz, Carolyn; Nair, Madhavan; Atluri, Venkata; Khizroev, Sakhrat

2013-10-16

The nanotechnology capable of high-specificity targeted delivery of anti-neoplastic drugs would be a significant breakthrough in Cancer in general and Ovarian Cancer in particular. We addressed this challenge through a new physical concept that exploited (i) the difference in the membrane electric properties between the tumor and healthy cells and (ii) the capability of magneto-electric nanoparticles (MENs) to serve as nanosized converters of remote magnetic field energy into the MENs' intrinsic electric field energy. This capability allows to remotely control the membrane electric fields and consequently trigger high-specificity drug uptake through creation of localized nano-electroporation sites. In in-vitro studies on human ovarian carcinoma cell (SKOV-3) and healthy cell (HOMEC) lines, we applied a 30-Oe d.c. field to trigger high-specificity uptake of paclitaxel loaded on 30-nm CoFe₂O₄ @BaTiO₃ MENs. The drug penetrated through the membrane and completely eradicated the tumor within 24 hours without affecting the normal cells.

[Research and pharmaceutical development on the subject of communicable diseases in the intertropical region].

PubMed

Trouiller, P

1996-01-01

The development of the antimalarial drugs mefloquine and halofantrine in 1988 by American military research teams marked a start in the decline in investment in tropical disease research and drug development. The globalization of the market, increased clinical costs, and constraints on public health spending caused the pharmaceutical industry to concentrate on more profitable market segments (cardiovascular drugs, antineoplastics, anti-infection drugs, etc.). The market in developing countries represents a large volume, but a very low return because the added value is small, generic drugs are used and the state of the populations is impoverished. The ten or so drugs that have been developed recently result from chance (eflornithine), veterinary research (ivermectin), fortuitous analysis of traditional pharmacopoeia (artemether) or reevaluations of former drugs (amopyroquine). The deficiency of research and drug development for diseases of the intertropical zone has a direct negative effect on public health and also reveals health policy inconsistencies, particularly the incompatibility of the pharmaceutical industry's interests and international health priorities. The problem is also aggravated by the closed approach of external health assistance (official development aid) which aims to minimize costs by favoring primary health care.

Documentation forms for monitoring occupational surveillance of healthcare workers who handle cytotoxic drugs.

PubMed

Parillo, V L

1994-01-01

To develop a procedure for medical surveillance of healthcare workers who handle cytotoxic drugs. Literature review and guidelines published by the Occupational Safety and Health Administration and the National Institute for Occupational Safety and Health. INFORMATION SELECTION: Studies of possible exposure screening tests, congenital defects in offspring, and case studies. Some degree of risk exists in handling cytotoxic drugs, but no reliable screening test for cytotoxic drug exposure has been developed. Reproductive hazards are possible when protective equipment is not used. Areas to be addressed when devising surveillance procedures include who to cover, what baseline data to gather, what periodic monitoring will be necessary (and at what interval it will be conducted), how to handle exposure incidents, and what documentation system will be used. A procedure using a baseline risk factor form and a yearly monitoring questionnaire was devised and implemented. Forms contain documentation of worker teaching. Most often, nurses are the healthcare workers who handle cytotoxic drugs. A consistent approach to monitoring healthcare workers is facilitated by using a defined procedure and standardized forms.

Benzimidazole condensed ring systems 10 (1). Synthesis and cytotoxic activity of some pyrido[1,2-a]benzimidazoles.

PubMed

Badawey, E S; Kappe, T

1995-01-01

As a part of research project on the synthesis of a number of pyrido[1,2-a]benzimidazole derivatives with possible antineoplastic activity and as a result of the interesting antineoplastic activity recorded for one such compounds (NSC 649900), some new pyrido[1,2-a]benzimidazoles were prepared and evaluated for such activity. Compound (11, NSC 660334) exhibited a moderate in vitro antineoplastic activity especially against most of the leukemia cell lines, while compound (10, VM30309) showed a good cytotoxic activity against Artina salina larvae (IC50 = 1.75 micrograms/ml).

Anti-Neoplastic Cytotoxicity of Gemcitabine-(C4-amide)-[anti-EGFR] in Dual-combination with Epirubicin-(C3-amide)-[anti-HER2/neu] against Chemotherapeutic-Resistant Mammary Adenocarcinoma (SKBr-3) and the Complementary Effect of Mebendazole

PubMed Central

Coyne, CP; Jones, Toni; Bear, Ryan

2015-01-01

Aims Delineate the feasibility of simultaneous, dual selective “targeted” chemotherapeutic delivery and determine if this molecular strategy can promote higher levels anti-neoplastic cytotoxicity than if only one covalent immunochemotherapeutic is selectively “targeted” for delivery at a single membrane associated receptor over-expressed by chemotherapeutic-resistant mammary adenocarcinoma. Methodology Gemcitabine and epirubicin were covalently bond to anti-EGFR and anti-HER2/neu utilizing a rapid multi-phase synthetic organic chemistry reaction scheme. Determination that 96% or greater gemcitabine or epirubicin content was covalently bond to immunoglobulin fractions following size separation by micro-scale column chromatography was established by methanol precipitation analysis. Residual binding-avidity of gemcitabine-(C4-amide)-[anti-EG-FR] applied in dual-combination with epirubicin-(C3-amide)-[anti-HER2/neu] was determined by cell-ELIZA utilizing chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3) populations. Lack of fragmentation or polymerization was validated by SDS-PAGE/immunodetection/chemiluminescent autoradiography. Anti-neoplastic cytotoxic potency was determined by vitality stain analysis of chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3) monolayers known to uniquely over-express EGFR (2 × 105/cell) and HER2/neu (1 × 106/cell) receptor complexes. The covalent immunochemotherapeutics gemcitabine-(C4-amide)-[anti-EGFR] and epirubicin-(C3-amide)-[anti-HER2/neu] were applied simultaneously in dual-combination to determine their capacity to collectively evoke elevated levels of anti-neoplastic cytotoxicity. Lastly, the tubulin/microtubule inhibitor mebendazole evaluated to determine if it’s potential to complemented the anti-neoplastic cytotoxic properties of gemcitabine-(C4-amide)-[anti-EGFR] in dual-combination with epirubicin-(C3-amide)-[anti-HER2/neu]. Results Dual-combination of gemcitabine-(C4-amide)-[anti-EGFR] with epirubicin-(C3-amide)-[anti-HER2/neu] produced greater levels of anti-neoplastic cytotoxicity than either of the covalent immunochemotherapeutics alone. The benzimidazole microtubule/tubulin inhibitor, mebendazole complemented the anti-neoplastic cytotoxicity of gemcitabine-(C4-amide)-[anti-EGFR] in dual-combination with epirubicin-(C3-amide)-[anti-HER2/neu]. Conclusions The dual-combination of gemcitabine-(C4-amide)-[anti-EGFR] with epirubicin-(C3-amide)-[anti-HER2/neu] produced higher levels of selectively “targeted” anti-neoplastic cytotoxicity against chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3) than either covalent immunochemotherapeutic alone. The benzimidazole tubulin/microtubule inhibitor, mebendazole also possessed anti-neoplastic cytotoxicity against chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3) and complemented the potency and efficacy of gemcitabine-(C4-amide)-[anti-EGFR] in dual-combination with epirubicin-(C3-amide)-[anti-HER2/neu]. PMID:25844392

Applicability of the comet assay in evaluation of DNA damage in healthcare providers' working with antineoplastic drugs: a systematic review and meta-analysis.

PubMed

Zare Sakhvidi, Mohammad Javad; Hajaghazadeh, Mohammad; Mostaghaci, Mehrdad; Mehrparvar, Amir Houshang; Zare Sakhvidi, Fariba; Naghshineh, Elham

2016-01-01

Unintended occupational exposure to antineoplastic drugs (ANDs) may occur in medical personnel. Some ANDs are known human carcinogens and exposure can be monitored by genotoxic biomarkers. To evaluate the obstacles to obtaining conclusive results from a comet assay test to determine DNA damage among AND exposed healthcare workers. We systematically reviewed studies that used alkaline comet assay to determine the magnitude and significance of DNA damage among health care workers with potential AND exposure. Fifteen studies were eligible for review and 14 studies were used in the meta-analysis. Under random effect assumption, the estimated standardized mean difference (SMD) in the DNA damage of health care workers was 1.93 (95% CI: 1.15-2.71, p < 0.0001). The resulting SMD was reduced to 1.756 (95% CI: 0.992-2.52, p < 0.0001) when the analysis only included nurses. In subgroup analyses based on gender and smoking, heterogeneity was observed. Only for studies reporting comet moment, I2 test results, as a measure of heterogeneity, dropped to zero. Heterogeneity analysis showed that date of study publication was a possible source of heterogeneity (B = -0.14; p < 0.0001). A mixture of personal parameters, comet assay methodological variables, and exposure characteristics may be responsible for heterogenic data from comet assay studies and interfere with obtaining conclusive results. Lack of quantitative environmental exposure measures and variation in comet assay protocols across studies are important obstacles in generalization of results.

Cisplatin loaded PMMA: mechanical properties, surface analysis and effects on Saos-2 cell culture.

PubMed

Özben, Hakan; Eralp, Levent; Baysal, Gökhan; Cort, Ayşegül; Sarkalkan, Nazli; Özben, Tomris

2013-01-01

Despite wide resection and systemic chemotherapy, bone tumors may present with local recurrences, metastases and pathological fractures. Application of bone cement containing antineoplastic drug to fill the defect after resection of metastatic lesions and to support implants has been suggested to prevent local tumor growth and implant failures. In this study, we aimed to demonstrate the effects of the addition of cisplatin which is a widely used antineoplastic drug for osteosarcoma, on the mechanical properties of bone cement, and to evaluate the cytotoxic effects of eluted cisplatin on Saos-2 cell culture. Two cement samples were prepared by mixing 100 mg and 300 mg of cisplatin powder with 40 g cement powder. The bone cement of the control group did not contain cisplatin. Mechanical analyses included 4-point bending, compression and shear testing. For cytotoxicity analysis, samples were incubated in Dulbecco's Modified Eagle's medium for 15 days. Mediums were applied to Saos-2 cell culture and cell viability was measured. Surface analyses were performed by scanning electron microscope (SEM). The addition of cisplatin did not alter the mechanical properties of bone cement. It was observed that the eluted cisplatin had cytotoxic effects on Saos-2 cells. SEM analyses demonstrated cisplatin granules on the surface of cement samples. Cisplatin maintains its cytotoxic property when released from bone cement without compromising the mechanical stability. Application of cisplatin loaded bone cement may help local control of tumor growth. We believe that our study will shed light on to these new practices for the treatment of bone cancers and will encourage future studies.

Apoptosis induction and anti-cancer activity of LeciPlex formulations.

PubMed

Dhawan, Vivek V; Joshi, Ganesh V; Jain, Ankitkumar S; Nikam, Yuvraj P; Gude, Rajiv P; Mulherkar, Rita; Nagarsenker, Mangal S

2014-10-01

Cationic agents have been reported to possess anti-neoplastic properties against various cancer cell types. However, their complexes with lipids appear to interact differently with different cancer cells. The purpose of this study was to (i) design and generate novel cationic lecithin nanoparticles, (ii) assess and understand the mechanism underlying their putative cytotoxicity and (iii) test their effect on cell cycle progression in various cancer-derived cell lines. In addition, we aimed to evaluate the in vivo potential of these newly developed nanoparticles in oral anti-cancer delivery. Cationic lecithin nanoparticles were generated using a single step nanoprecipitation method and they were characterized for particle size, zeta potential, stability and in vitro release. Their cytotoxic potential was assessed using a sulforhodamine B assay, and their effect on cell cycle progression was evaluated using flow cytometry. The nanoparticle systems were also tested in vivo for their anti-tumorigenic potential. In contrast to cationic agents alone, the newly developed nanoformulations showed a specific toxicity against cancer cells. The mechanism of toxic cell death included apoptosis, S and G2/M cell cycle phase arrest, depending on the type of cationic agent and the cancer-derived cell line used. Both blank and drug-loaded systems exhibited significant anti-cancer activity, suggesting a synergistic anti-tumorigenic effect of the drug and its delivery system. Both in vitro and in vivo data indicate that cationic agents themselves exhibit broad anti-neoplastic activities. Complex formation of the cationic agents with phospholipids was found to provide specificity to the anti-cancer activity. These formulations thus possess potential for the design of effective anti-cancer delivery systems.

Radiation induction of drug resistance in RIF-1: Correlation of tumor and cell culture results

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moulder, J.E.; Hopwood, L.E.; Volk, D.M.

1991-02-01

The RIF-1 tumor line contains cells that are resistant to various anti-neoplastic drugs, including 5-fluorouracil (5FU), methotrexate (MTX), adriamycin (ADR), and etoposide (VP16). The frequency of these drug-resistant cells is increased after irradiation. The frequency of drug-resistant cells and the magnitude of radiation-induced drug resistance are different in cell culture than in tumors. The dose-response and expression time relationships for radiation induction of drug resistance observed in RIF-1 tumors are unusual.We hypothesize that at high radiation doses in vivo, we are selecting for cells that are both drug resistant and radiation resistant due to microenvironmental factors, whereas at low radiationmore » doses in vivo and all radiation doses in vitro, we are observing true mutants. These studies indicate that there can be significant differences in drug-resistance frequencies between tumors and their cell lines of origin, and that radiation induction of drug resistance depends significantly on whether the induction is done in tumors or in cell culture. These results imply that theories about the induction of drug resistance that are based on cell culture studies may be inapplicable to the induction of drug resistance in tumors.« less

Study of Efficacy and Safety of LEE011 in Men and Postmenopausal Women With Advanced Breast Cancer.

ClinicalTrials.gov

2017-10-12

Breast Neoplasms; Breast Diseases; Neoplasms; Neoplasms by Site; Fulvestrant; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Estrogen Receptor Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Therapeutic Use

Clinical practice

PubMed Central

Mulder, W. M. C.

2010-01-01

Immediate type allergic reactions to medication are potentially life threatening and can hamper drug therapy of several medical conditions. Exact incidence and prevalence data for these reactions in children are lacking. If no alternative drug treatment is available, a desensitization procedure may secure the continuation of necessary therapy. Desensitization is only appropriate in case of a strong suspicion of an IgE-mediated allergic reaction. It should be performed by trained clinicians (allergy specialists) in a hospital setting where treatment of a potential anaphylactic reaction can be done without any delay. In this article, literature describing desensitization procedures for several antibiotics, antineoplastic agents, and vaccines in children is reviewed. In general, desensitization schemes for children differ only in final dose from schemes for adults. Contradictory data were found regarding the protective effects of premedication with antihistamines and glucocorticoids. PMID:20571825

Dacarbazine.

PubMed

Al-Badr, Abdullah A; Alodhaib, Mansour M

2016-01-01

Dacarbazine is a cell cycle nonspecific antineoplastic alkylating agent used in the treatment of metastatic malignant melanoma. This chapter contains the descriptions of the drug: nomenclature, formulae, chemical structure, elemental composition, and appearance. The uses and applications of dacarbazine and the methods that were used for its preparation are reported. The methods which were used for the physical characterization of the drug are ionization constant, solubility, X-ray powder diffraction pattern, crystal structure, melting point, and differential scanning calorimetry. The profile contains the spectra of the drug: ultraviolet spectrum, vibrational spectrum, nuclear magnetic resonance spectra, and mass spectrum. The compendial methods of analysis for dacarbazine include the United States Pharmacopeia methods, British Pharmacopeia methods, and International Pharmacopeia methods. Other reported methods that are used for the analysis of the drug are high-performance liquid chromatography, high-performance liquid chromatography-mass spectrometry, and polarography. Metabolism, pharmacokinetics, and stability studies on dacarbazine are also included. Reviews of some analytical methods and physicochemical properties of the drug as well as the most important enzymes that are involved in the prodrug activation are provided. Sixty-four references are listed at the end of this monograph. © 2016 Elsevier Inc. All rights reserved.

Host-guest interaction of ZnBDC-MOF + doxorubicin: A theoretical and experimental study

NASA Astrophysics Data System (ADS)

Vasconcelos, Iane B.; Wanderley, Kaline A.; Rodrigues, Nailton M.; da Costa, Nivan B.; Freire, Ricardo O.; Junior, Severino A.

2017-03-01

The incorporation of drugs in biodegradable polymeric particles is one of many processes that controllably and significantly increase their release and action. In this paper, we describe the synthesis and physicochemical characterization of ZnBDC-MOF + doxorubicin (DOXO@ZnBDC) and the system's effectiveness in the sustained release of the drug doxorubicin. An experimental and theoretical study is presented of the interaction between the [Zn(BDC)(H2O)2]n MOF and the drug doxorubicin (DOXO). The synthesis was characterized by elemental analysis and X-ray powder diffraction (XRPD). The experimental incorporation was accomplished and analyzed by Fourier transform infrared spectroscopy (FTIR), XRPD and UV-Vis (ultraviolet-visible) spectrophotometry. Based on an analysis of the doxorubicin release profile, our results suggest that the drug delivery system showed slower release than other systems under development. Studies of cytotoxicity by the MTT method showed good results for the system developed with antineoplastic doxorubicin, and together with the other results of this study, suggest the successful development of a MOF-based drug delivery system.

Experiments and synthesis of bone-targeting epirubicin with the water-soluble macromolecular drug delivery systems of oxidized-dextran.

PubMed

Yu, Li; Cai, Lin; Hu, Hao; Zhang, Yi

2014-05-01

Epirubicin (EPI) is a broad spectrum antineoplastic drug, commonly used as a chemotherapy method to treat osteosarcoma. However, its application has been limited by many side-effects. Therefore, targeted drug delivery to bone has been the aim of current anti-bone-tumor drug studies. Due to the exceptional affinity of Bisphosphonates (BP) to bone, 1-amino-ethylene-1, 1-dephosphate acid (AEDP) was chosen as the bone targeting moiety for water-soluble macromolecular drug delivery systems of oxidized-dextran (OXD) to transport EPI to bone in this article. The bone targeting drug of AEDP-OXD-EPI was designed for the treatment of malignant bone tumors. The successful conjugation of AEDP-OXD-EPI was confirmed by analysis of FTIR and (1)H-NMR spectra. To study the bone-seeking potential of AEDP-OXD-EPI, an in vitro hydroxyapatite (HAp) binding assay and an in vivo experiment of bone-targeting capacity were established. The effectiveness of AEDP-OXD-EPI was demonstrated by inducing apoptosis and necrosis of MG-63 tumor cell line. The obtained experimental data indicated that AEDP-OXD-EPI is an ideal bone-targeting anti-tumor drug.

21 CFR 1250.45 - Food handling facilities on railroad conveyances.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Food handling facilities on railroad conveyances. 1250.45 Section 1250.45 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... facilities on railroad conveyances. (a) Both kitchens and pantries of cars hereafter constructed or...

21 CFR 58.107 - Test and control article handling.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 1 2010-04-01 2010-04-01 false Test and control article handling. 58.107 Section 58.107 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL... designed to preclude the possibility of contamination, deterioration, or damage. (c) Proper identification...

10 CFR 707.12 - Specimen collection, handling and laboratory analysis for drug testing.

Code of Federal Regulations, 2011 CFR

2011-01-01

... drug testing. 707.12 Section 707.12 Energy DEPARTMENT OF ENERGY WORKPLACE SUBSTANCE ABUSE PROGRAMS AT DOE SITES Procedures § 707.12 Specimen collection, handling and laboratory analysis for drug testing... collection to final disposition of specimens, and testing laboratories shall use appropriate cutoff levels in...

10 CFR 707.12 - Specimen collection, handling and laboratory analysis for drug testing.

Code of Federal Regulations, 2010 CFR

2010-01-01

... drug testing. 707.12 Section 707.12 Energy DEPARTMENT OF ENERGY WORKPLACE SUBSTANCE ABUSE PROGRAMS AT DOE SITES Procedures § 707.12 Specimen collection, handling and laboratory analysis for drug testing... collection to final disposition of specimens, and testing laboratories shall use appropriate cutoff levels in...

10 CFR 707.12 - Specimen collection, handling and laboratory analysis for drug testing.

Code of Federal Regulations, 2014 CFR

2014-01-01

... drug testing. 707.12 Section 707.12 Energy DEPARTMENT OF ENERGY WORKPLACE SUBSTANCE ABUSE PROGRAMS AT DOE SITES Procedures § 707.12 Specimen collection, handling and laboratory analysis for drug testing... collection to final disposition of specimens, and testing laboratories shall use appropriate cutoff levels in...

10 CFR 707.12 - Specimen collection, handling and laboratory analysis for drug testing.

Code of Federal Regulations, 2012 CFR

2012-01-01

... drug testing. 707.12 Section 707.12 Energy DEPARTMENT OF ENERGY WORKPLACE SUBSTANCE ABUSE PROGRAMS AT DOE SITES Procedures § 707.12 Specimen collection, handling and laboratory analysis for drug testing... collection to final disposition of specimens, and testing laboratories shall use appropriate cutoff levels in...

10 CFR 707.12 - Specimen collection, handling and laboratory analysis for drug testing.

Code of Federal Regulations, 2013 CFR

2013-01-01

... drug testing. 707.12 Section 707.12 Energy DEPARTMENT OF ENERGY WORKPLACE SUBSTANCE ABUSE PROGRAMS AT DOE SITES Procedures § 707.12 Specimen collection, handling and laboratory analysis for drug testing... collection to final disposition of specimens, and testing laboratories shall use appropriate cutoff levels in...

21 CFR 1250.38 - Toilet and lavatory facilities for use of food-handling employees.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Toilet and lavatory facilities for use of food-handling employees. 1250.38 Section 1250.38 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) REGULATIONS UNDER CERTAIN OTHER ACTS ADMINISTERED BY THE FOOD AND DRUG ADMINISTRATION INTERSTATE CONVEYANCE...

[Molecular fundamentals of drug interactions in the therapy of colorectal cancer].

PubMed

Regulska, Katarzyna; Stanisz, Beata; Regulski, Miłosz; Gieremek, Paulina

2014-03-04

Rapid advances in the field of chemotherapy have resulted in the introduction of numerous antineoplastic drugs into clinical practice, which increased the efficiency of patient management. Also the prevalent use of combination treatment based on drug action synergy contributed to the improved clinical effect associated with cytotoxic drug administration. It seems, however, obvious that the multidirectional pharmacotherapy in oncology requires a thorough knowledge of drugs' pharmaceutical behavior in order to maximize their collective action and prevent the occurrence of unintended drug interactions that could potentially impair treatment effectiveness. In fact, drug interactions constitute a serious problem for current oncology primarily resulting from a narrow therapeutic index specific for the majority of anticancer drugs. This, in turn, indicates that even slight deviations of their pharmacokinetics could cause significant clinical consequences, manifested by alteration of the toxicological profile or reduction of therapeutic efficiency. Hence, the investigation of molecular aspects underlying the mechanisms of various drug interactions seems to be essential for proper and safe patient management. The present article is devoted to the extensive subject of drug interactions occurring in the therapy of colorectal cancer. It presents the available literature data on both positive and negative effects of interactions and it discusses their mechanisms complying with their classification into pharmacokinetic and pharmacodynamic ones.

Serine deprivation enhances antineoplastic activity of biguanides.

PubMed

Gravel, Simon-Pierre; Hulea, Laura; Toban, Nader; Birman, Elena; Blouin, Marie-José; Zakikhani, Mahvash; Zhao, Yunhua; Topisirovic, Ivan; St-Pierre, Julie; Pollak, Michael

2014-12-15

Metformin, a biguanide widely used in the treatment of type II diabetes, clearly exhibits antineoplastic activity in experimental models and has been reported to reduce cancer incidence in diabetics. There are ongoing clinical trials to evaluate its antitumor properties, which may relate to its fundamental activity as an inhibitor of oxidative phosphorylation. Here, we show that serine withdrawal increases the antineoplastic effects of phenformin (a potent biguanide structurally related to metformin). Serine synthesis was not inhibited by biguanides. Instead, metabolic studies indicated a requirement for serine to allow cells to compensate for biguanide-induced decrease in oxidative phosphorylation by upregulating glycolysis. Furthermore, serine deprivation modified the impact of metformin on the relative abundance of metabolites within the citric acid cycle. In mice, a serine-deficient diet reduced serine levels in tumors and significantly enhanced the tumor growth-inhibitory actions of biguanide treatment. Our results define a dietary manipulation that can enhance the efficacy of biguanides as antineoplastic agents that target cancer cell energy metabolism. ©2014 American Association for Cancer Research.

Does applying technology throughout the medication use process improve patient safety with antineoplastics?

PubMed

Bubalo, Joseph; Warden, Bruce A; Wiegel, Joshua J; Nishida, Tess; Handel, Evelyn; Svoboda, Leanne M; Nguyen, Lam; Edillo, P Neil

2014-12-01

Medical errors, in particular medication errors, continue to be a troublesome factor in the delivery of safe and effective patient care. Antineoplastic agents represent a group of medications highly susceptible to medication errors due to their complex regimens and narrow therapeutic indices. As the majority of these medication errors are frequently associated with breakdowns in poorly defined systems, developing technologies and evolving workflows seem to be a logical approach to provide added safeguards against medication errors. This article will review both the pros and cons of today's technologies and their ability to simplify the medication use process, reduce medication errors, improve documentation, improve healthcare costs and increase provider efficiency as relates to the use of antineoplastic therapy throughout the medication use process. Several technologies, mainly computerized provider order entry (CPOE), barcode medication administration (BCMA), smart pumps, electronic medication administration record (eMAR), and telepharmacy, have been well described and proven to reduce medication errors, improve adherence to quality metrics, and/or improve healthcare costs in a broad scope of patients. The utilization of these technologies during antineoplastic therapy is weak at best and lacking for most. Specific to the antineoplastic medication use system, the only technology with data to adequately support a claim of reduced medication errors is CPOE. In addition to the benefits these technologies can provide, it is also important to recognize their potential to induce new types of errors and inefficiencies which can negatively impact patient care. The utilization of technology reduces but does not eliminate the potential for error. The evidence base to support technology in preventing medication errors is limited in general but even more deficient in the realm of antineoplastic therapy. Though CPOE has the best evidence to support its use in the antineoplastic population, benefit from many other technologies may have to be inferred based on data from other patient populations. As health systems begin to widely adopt and implement new technologies it is important to critically assess their effectiveness in improving patient safety. © The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Anticancer activity and tissue distribution of platinum (II) complex with lignin-derived polymer of benzene-poly-carboxylic acids.

PubMed

Solovyev, Nikolay D; Fedoros, Elena I; Drobyshev, Evgenii J; Ivanenko, Natalya B; Pigarev, Sergey E; Tyndyk, Margarita L; Anisimov, Vladimir N; Vilpan, Yury A; Panchenko, Andrey V

2017-09-01

Platinum-containing antineoplastic agents with physiologically active ligands seem to be a promising direction in anticancer drug design. PDBA is a novel promising antineoplastic agent, containing polymer ligand of natural origin (international patent WO2013/143549 A1). Polymer ligand of PDBA has a highly functionalised polyphenolic backbone, which exerts its own pharmacological effect via immune modulation and regulation of gene expression. PDBA is a cis-diammineplatinum(II) complex, containing mono-deprotonated benzene-poly-carboxylic acids, derived from lignin, and hydroxyl group as O-donor ligands (approximate bulk formula C 83 H 70 N 2 O 27 Pt). The agent is being evaluated in Phase II controlled clinical trials in metastatic breast cancer patients. In the present study, tissue distribution and tumour growth inhibition effects of PDBA, cisplatin and carboplatin were compared in SHR female mice, bearing inoculated solid Ehrlich carcinoma. The agents were administered subcutaneously every second day for the period of 10days (5 injections) at 62.5mg/kg, 3.0mg/kg and 18.5mg/kg for PDBA, cisplatin and carboplatin, respectively. Experimental animals were sacrificed on the Days 11, 16 and 23 after the inoculation of the tumour. The doses of all studied drugs were selected to obtain similar antitumour efficacy with ca. 50% growth inhibition of the Ehrlich tumour at the end of the study. The efficacy of a single platinum reactive moiety [cis-diammineplatinum(II)] was shown to be the highest for cisplatin, followed by PDBA and finally carboplatin. However, the toxicity of PDBA was considerably lower than that of carboplatin and especially cisplatin. The drugs were mainly distributed in lungs, kidneys, liver, spleen and tumour tissue. PDBA showed quite high accumulation in the tumour tissue, possibly, owing to the effect of the lignin-derived ligand. Copyright © 2016 Elsevier GmbH. All rights reserved.

From growing plants to killing tumors.

PubMed

Flinn, E D

2000-04-01

A technique called photodynamic therapy, originally developed for commercial plant growth research on the Space Shuttle, has been used by surgeons in two successful operations for brain tumors. The device uses pin-head-size light emitting diodes (LEDs) that release long, cool, wavelengths of light which activate photosensitive antineoplastic drugs. The device is being adapted to non-space uses through a Small Business Innovation Research grant. The LEDs also are used to treat skin cancer, psoriasis, and rheumatoid arthritis. Research is being conducted regarding LED use in wound healing, tissue growth, and prevention of muscle and bone atrophy in astronauts.

Flavonoids from Heliotropium subulatum exudate and their evaluation for antioxidant, antineoplastic and cytotoxic activities II.

PubMed

Singh, Bharat; Sahu, Pooran M; Sharma, Ram A

2017-02-01

The flavonoids are the largest group of phenolic compounds isolated from a wide range of higher plants. These compounds work as antimicrobials, anti-insect agents and protect plants from other types of biotic and abiotic stresses. Various researchers have suggested that flavonoids possessed antioxidant, antineoplastic and cytotoxic activities. The main objective of this study was to test dichloromethane fraction of resinous exudate of Heliotropium subulatum for their antioxidant, antineoplastic and cytotoxic activities, as well as to search new antioxidant and antineoplastic agents for pharmaceutical formulations. Five flavonoids were isolated from resinous exudate of this plant species and screened for their in vitro and in vivo antioxidant models (DPPH radical scavenging, reducing power, superoxide anion scavenging, metal chelating scavenging systems, catalase and lipid peroxidation), antineoplastic (Sarcoma 180), and cytotoxic (Chinese hamster V79 cells) activities. Tricetin demonstrated maximum antioxidant activity against both in vitro and in vivo experimental systems while galangin exhibited maximum inhibition (78.35%) at a dose of 10 µg/kg/day against Sarcoma 180. Similarly, it was found that galangin also showed highest activity (21.1 ± 0.15%) at a concentration of 70 µg/ml to Chinese hamster V79 cells. The observed results suggest that tricetin has a potential to scavenge free radicals in both in vitro and in vivo models while the galangin could be considered as antitumor and cytotoxic agent.

21 CFR 1250.35 - Health of persons handling food.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Health of persons handling food. 1250.35 Section 1250.35 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... SANITATION Food Service Sanitation on Land and Air Conveyances, and Vessels § 1250.35 Health of persons...

21 CFR 1250.35 - Health of persons handling food.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Health of persons handling food. 1250.35 Section 1250.35 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... SANITATION Food Service Sanitation on Land and Air Conveyances, and Vessels § 1250.35 Health of persons...

21 CFR 1250.35 - Health of persons handling food.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Health of persons handling food. 1250.35 Section 1250.35 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... SANITATION Food Service Sanitation on Land and Air Conveyances, and Vessels § 1250.35 Health of persons...

21 CFR 878.5070 - Air-handling apparatus for a surgical operating room.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Air-handling apparatus for a surgical operating room. 878.5070 Section 878.5070 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES GENERAL AND PLASTIC SURGERY DEVICES Therapeutic Devices § 878...

21 CFR 878.5070 - Air-handling apparatus for a surgical operating room.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Air-handling apparatus for a surgical operating room. 878.5070 Section 878.5070 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES GENERAL AND PLASTIC SURGERY DEVICES Therapeutic Devices § 878...

21 CFR 878.5070 - Air-handling apparatus for a surgical operating room.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Air-handling apparatus for a surgical operating room. 878.5070 Section 878.5070 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES GENERAL AND PLASTIC SURGERY DEVICES Therapeutic Devices § 878...

New drugs, new toxicities: severe side effects of modern targeted and immunotherapy of cancer and their management.

PubMed

Kroschinsky, Frank; Stölzel, Friedrich; von Bonin, Simone; Beutel, Gernot; Kochanek, Matthias; Kiehl, Michael; Schellongowski, Peter

2017-04-14

Pharmacological and cellular treatment of cancer is changing dramatically with benefits for patient outcome and comfort, but also with new toxicity profiles. The majority of adverse events can be classified as mild or moderate, but severe and life-threatening complications requiring ICU admission also occur. This review will focus on pathophysiology, symptoms, and management of these events based on the available literature.While standard antineoplastic therapy is associated with immunosuppression and infections, some of the recent approaches induce overwhelming inflammation and autoimmunity. Cytokine-release syndrome (CRS) describes a complex of symptoms including fever, hypotension, and skin reactions as well as lab abnormalities. CRS may occur after the infusion of monoclonal or bispecific antibodies (MABs, BABs) targeting immune effectors and tumor cells and is a major concern in recipients of chimeric antigen receptor (CAR) modified T lymphocytes as well. BAB and CAR T-cell treatment may also be compromised by central nervous system (CNS) toxicities such as encephalopathy, cerebellar alteration, disturbed consciousness, or seizures. While CRS is known to be induced by exceedingly high levels of inflammatory cytokines, the pathophysiology of CNS events is still unclear. Treatment with antibodies against inhibiting immune checkpoints can lead to immune-related adverse events (IRAEs); colitis, diarrhea, and endocrine disorders are often the cause for ICU admissions.Respiratory distress is the main reason for ICU treatment in cancer patients and is attributable to infectious agents in most cases. In addition, some of the new drugs are reported to cause non-infectious lung complications. While drug-induced interstitial pneumonitis was observed in a substantial number of patients treated with phosphoinositol-3-kinase inhibitors, IRAEs may also affect the lungs.Inhibitors of angiogenetic pathways have increased the antineoplastic portfolio. However, vessel formation is also essential for regeneration and tissue repair. Therefore, severe vascular side effects, including thromboembolic events, gastrointestinal bleeding or perforation, hypertension, and congestive heart failure, compromise antitumor efficacy.The limited knowledge of the pathophysiology and management of life-threatening complications relating to new cancer drugs presents a need to provide ICU staff, oncologists, and organ specialists with evidence-based algorithms.

E-Combretastatin and E-Resveratrol Structural Modifications: Antimicrobial and Cancer Cell Growth Inhibitory Beta-E-Nitrostyrenes

USDA-ARS?s Scientific Manuscript database

As part of a broad-based SAR investigation of E-resveratrol (strong sirtuin activator and antineoplastic) and the anticancer vascular-targeting combretastatin-type stilbenes, a series of twenty-three beta-E-nitrostyrenes was synthesized in order to evaluate potential antineoplastic, antitubulin poly...

Current challenges in European oncology pharmacy practice.

PubMed

Hoppe-Tichy, Torsten

2010-03-01

The demand for pharmacy cancer services is expected to at least double over the next 10 years, as the population ages and new treatments are introduced. Safe and efficient handling of cytotoxic products minimises risks to staff and reduces medication errors. To identify and describe strategies for coping safely and effectively with heavier workloads in the hospital oncology pharmacy, currently and in the future. The PubMed database was searched for literature on approaches to safe handling of antineoplastic agents and to decreasing medication errors in the hospital pharmacy. Articles that were judged to be of prime importance to the hospital oncologist were reviewed. These safety concepts are put into the context of contemporary hospital oncology pharmacy practice through discussion of key issues, including increased demand, the role of the pharmacist in determining the hospital formulary, and growth in patient preferences for oral chemotherapy. Recommendations on best practices are also provided, based on relevant literature and author experience. Efficient, safe hospital pharmacy operations can be aided by capacity planning, dose banding, and knowledge of novel products and procedures that can reduce risks to health while increasing the number of patients who are safely treated. Consideration may also be given to the economic role of oncology pharmacists in formulary development.

Application of electrolysis for inactivation of an antiviral drug that is one of possible selection pressure to drug-resistant influenza viruses.

PubMed

Kobayashi, Toyohide; Hirose, Jun; Wu, Hong; Sano, Kouichi; Katsumata, Takahiro; Tsujibo, Hiroshi; Nakano, Takashi

2013-12-01

The recent development of antiviral drugs has led to concern that the release of the chemicals in surface water due to expanded medical use could induce drug-resistant mutant viruses in zoonosis. Many researchers have noted that the appearance of an oseltamivir (Tamiflu(®))-resistant avian influenza mutant virus, which may spread to humans, could be induced by oseltamivir contamination of surface water. Although past studies have reported electrolysis as a possible method for degradation of antineoplastics and antibacterials in water, the validity of the method for treatment of antiviral drugs is unknown. In this study, electrolysis was used to degrade an antiviral prodrug, oseltamivir, and a stable active form, oseltamivir carboxylate, and the degradation process was monitored with HPLC-UV and the neuraminidase inhibitory assay. HPLC-UV-detectable oseltamivir and oseltamivir carboxylate were decomposed by electrolysis within 60 min, and inhibitory activity of neuraminidase decreased below the detection limit of the assay used. Cytotoxic and genotoxic activity were not detected in electrolyzed fluid. These results indicate that electrolysis is a possible treatment for inactivation of the antiviral drug oseltamivir. Copyright © 2013 Elsevier B.V. All rights reserved.

Drug Delivery Systems, CNS Protection, and the Blood Brain Barrier

PubMed Central

Upadhyay, Ravi Kant

2014-01-01

Present review highlights various drug delivery systems used for delivery of pharmaceutical agents mainly antibiotics, antineoplastic agents, neuropeptides, and other therapeutic substances through the endothelial capillaries (BBB) for CNS therapeutics. In addition, the use of ultrasound in delivery of therapeutic agents/biomolecules such as proline rich peptides, prodrugs, radiopharmaceuticals, proteins, immunoglobulins, and chimeric peptides to the target sites in deep tissue locations inside tumor sites of brain has been explained. In addition, therapeutic applications of various types of nanoparticles such as chitosan based nanomers, dendrimers, carbon nanotubes, niosomes, beta cyclodextrin carriers, cholesterol mediated cationic solid lipid nanoparticles, colloidal drug carriers, liposomes, and micelles have been discussed with their recent advancements. Emphasis has been given on the need of physiological and therapeutic optimization of existing drug delivery methods and their carriers to deliver therapeutic amount of drug into the brain for treatment of various neurological diseases and disorders. Further, strong recommendations are being made to develop nanosized drug carriers/vehicles and noninvasive therapeutic alternatives of conventional methods for better therapeutics of CNS related diseases. Hence, there is an urgent need to design nontoxic biocompatible drugs and develop noninvasive delivery methods to check posttreatment clinical fatalities in neuropatients which occur due to existing highly toxic invasive drugs and treatment methods. PMID:25136634

Prevention of cytotoxic drug induced skin ulcers with dimethyl sulfoxide (DMSO) and alpha-tocopherole.

PubMed

Ludwig, C U; Stoll, H R; Obrist, R; Obrecht, J P

1987-03-01

Accidental subcutaneous extravasation of several antineoplastic agents may provoke skin ulcerations for which there has been no simple and effective treatment. Since January 1983 we have treated all patients in our institution sustaining extravasation by a cytotoxic drug with a combination of DMSO and alpha-Tocopherole. During the first 48 hr after extravasation a mixture of 10% alpha-Tocopherole acetate and 90% DMSO was topically applied. The bandage was changed every 12 hr. So far eight patients with extravasation of an anthracycline or Mitomycin were treated on this protocol. No skin ulceration, functional or neurovascular impairment occurred in any of these patients. The only toxic effect observed by this treatment was a minor skin irritation. The combination of DMSO and alpha-Tocopherole seems to prevent skin ulceration induced by anthracyclines and Mitomycin.

Insights into defibrotide: an updated review.

PubMed

Morabito, F; Gentile, M; Gay, F; Bringhen, S; Mazzone, C; Vigna, E; Musto, P; Di Raimondo, F; Palumbo, A

2009-06-01

Defibrotide is a polydisperse oligonucleotide with antiatherosclerotic, anti-inflammatory, anti-ischaemic, pro-fibrinolytic and antithrombotic actions without significant systemic anticoagulant effects. It has been used in the treatment of various cardiovascular disorders, and especially in endothelial complications of allogeneic stem-cell transplantation. We reviewed the published work for the mechanism of action and clinical use of defibrotide to consolidate data and to describe new applications of this drug. We reviewed the most relevant papers on defibrotide published from November 1982 to January 2008. (selected through PubMed), and used recent meeting abstracts as sources for this review. Reports have suggested that defibrotide has clinical efficacy for treatment and prophylaxis of hepatic sinusoidal obstruction syndrome occurring after stem-cell transplantation. Animal models have clearly shown the potential antineoplastic effect of this drug. Further clinical investigations are needed to clarify this new application.

[Training of pharmacy personnel in the management of a centralized unit: the Oncolor network experience].

PubMed

Henn-Ménétré, Sophie; Noirez, Véronique; Husson, Julien; Vallance, Catherine; Lestreit, Jean-Michel; Llorens, Anne-Marie; May, Isabelle; Grandhaye, Jean-Pierre; Bey, Pierre

2003-10-01

The network of cancer care units in Lorraine area (Oncolor) developed management training for people working in chemotherapy units, and cytotoxic drug preparation. The programme was framed both for staff of executives (pharmacists), and technicians. Firstly, comparison between practices and theoretical recommendations lead to the elaboration of standardized operating procedures. Secondly, we elaborated a specific handbook for this education programme. A series of four-days independent sessions were organized for pharmacists and technicians. Each session combined theoretical and technical teaching for preparing antineoplastic drugs. Participants passing a successful final examination received a certificate from the Oncolor's network attesting their capacity to manage a chemotherapy unit. Four sessions were performed, with 35 participants. Only 31 passed at final examination. This preliminary experience will be enlarged to all members of the network and regularly brought up to date.

Comparative Analysis of the Antineoplastic Activity of C60 Fullerene with 5-Fluorouracil and Pyrrole Derivative In Vivo

NASA Astrophysics Data System (ADS)

Lynchak, O. V.; Prylutskyy, Yu I.; Rybalchenko, V. K.; Kyzyma, O. A.; Soloviov, D.; Kostjukov, V. V.; Evstigneev, M. P.; Ritter, U.; Scharff, P.

2017-01-01

The antitumor activity of pristine C60 fullerene aqueous solution (C60FAS) compared to 5-fluorouracil (5-FU) and pyrrole derivative 1-(4-Cl-benzyl)-3-Cl-4-(CF3-fenylamino)-1H-pyrrol-2.5-dione (MI-1) cytostatic drugs was investigated and analyzed in detail using the model of colorectal cancer induced by 1.2-dimethylhydrazine (DMH) in rats. The number, size, and location of the tumors were measured, and the pathology was examined. It was found that the number of tumors and total lesion area decreased significantly under the action of C60FAS and MI-1. Because these drugs have different mechanisms of action, their simultaneous administration can potentially increase the effectiveness and significantly reduce the side effects of antitumor therapy.

Downregulation of PI3-K/Akt/PTEN pathway and activation of mitochondrial intrinsic apoptosis by Diclofenac and Curcumin in colon cancer.

PubMed

Rana, Chandan; Piplani, Honit; Vaish, Vivek; Nehru, Bimla; Sanyal, S N

2015-04-01

Phosphatidylinositol 3-kinase (PI3-K)/PTEN/Akt signaling is over activated in various tumors including colon cancer. Activation of this pathway regulates multiple biological processes such as apoptosis, metabolism, cell proliferation, and cell growth that underlie the biology of a cancer cell. In the present study, the chemopreventive effects have been observed of Diclofenac, a preferential COX-2 inhibitory non-steroidal anti-inflammatory drugs, and Curcumin, a natural anti-inflammatory agent, in the early stage of colorectal carcinogenesis induced by 1,2-dimethylhydrazine dihydrochloride in rats. The tumor-promoting role of PI3-K/Akt/PTEN signal transduction pathway and its association with anti-apoptotic family of proteins are also observed. Both Diclofenac and Curcumin downregulated the PI3-K and Akt expression while promoting the apoptotic mechanism. Diclofenac and Curcumin administration significantly increased the expression of pro-apoptotic Bcl-2 family members (Bad and Bax) while decreasing the anti-apoptotic Bcl-2 protein. An up-regulation of cysteine protease family apoptosis executioner, such as caspase-3 and -9, is seen. Diclofenac and Curcumin inhibited the Bcl-2 protein by directly interacting at the active site by multiple hydrogen bonding, as also evident by negative glide score of Bcl-2. These drugs stimulated apoptosis by increasing reactive oxygen species (ROS) generation and simultaneously decreasing the mitochondrial membrane potential (ΔΨ M). Diclofenac and Curcumin showed anti-neoplastic effects by downregulating PI3-K/Akt/PTEN pathway, inducing apoptosis, increasing ROS generation, and decreasing ΔΨ M. The anti-neoplastic and apoptotic effects were found enhanced when both Diclofenac and Curcumin were administered together, rather than individually.

Applicability of the comet assay in evaluation of DNA damage in healthcare providers’ working with antineoplastic drugs: a systematic review and meta-analysis

PubMed Central

Zare Sakhvidi, Mohammad Javad; Hajaghazadeh, Mohammad; Mostaghaci, Mehrdad; Mehrparvar, Amir houshang; Zare Sakhvidi, Fariba; Naghshineh, Elham

2016-01-01

Background Unintended occupational exposure to antineoplastic drugs (ANDs) may occur in medical personnel. Some ANDs are known human carcinogens and exposure can be monitored by genotoxic biomarkers. Objective To evaluate the obstacles to obtaining conclusive results from a comet assay test to determine DNA damage among AND exposed healthcare workers. Methods We systematically reviewed studies that used alkaline comet assay to determine the magnitude and significance of DNA damage among health care workers with potential AND exposure. Fifteen studies were eligible for review and 14 studies were used in the meta-analysis. Results Under random effect assumption, the estimated standardized mean difference (SMD) in the DNA damage of health care workers was 1.93 (95% CI: 1.15–2.71, p < 0.0001). The resulting SMD was reduced to 1.756 (95% CI: 0.992–2.52, p < 0.0001) when the analysis only included nurses. In subgroup analyses based on gender and smoking, heterogeneity was observed. Only for studies reporting comet moment, I2 test results, as a measure of heterogeneity, dropped to zero. Heterogeneity analysis showed that date of study publication was a possible source of heterogeneity (B = −0.14; p < 0.0001). Conclusions A mixture of personal parameters, comet assay methodological variables, and exposure characteristics may be responsible for heterogenic data from comet assay studies and interfere with obtaining conclusive results. Lack of quantitative environmental exposure measures and variation in comet assay protocols across studies are important obstacles in generalization of results. PMID:27110842

Novel Polymyxin Combination With Antineoplastic Mitotane Improved the Bacterial Killing Against Polymyxin-Resistant Multidrug-Resistant Gram-Negative Pathogens.

PubMed

Tran, Thien B; Wang, Jiping; Doi, Yohei; Velkov, Tony; Bergen, Phillip J; Li, Jian

2018-01-01

Due to limited new antibiotics, polymyxins are increasingly used to treat multidrug-resistant (MDR) Gram-negative bacteria, in particular carbapenem-resistant Acinetobacter baumannii , Pseudomonas aeruginosa , and Klebsiella pneumoniae . Unfortunately, polymyxin monotherapy has led to the emergence of resistance. Polymyxin combination therapy has been demonstrated to improve bacterial killing and prevent the emergence of resistance. From a preliminary screening of an FDA drug library, we identified antineoplastic mitotane as a potential candidate for combination therapy with polymyxin B against polymyxin-resistant Gram-negative bacteria. Here, we demonstrated that the combination of polymyxin B with mitotane enhances the in vitro antimicrobial activity of polymyxin B against 10 strains of A. baumannii , P. aeruginosa , and K. pneumoniae , including polymyxin-resistant MDR clinical isolates. Time-kill studies showed that the combination of polymyxin B (2 mg/L) and mitotane (4 mg/L) provided superior bacterial killing against all strains during the first 6 h of treatment, compared to monotherapies, and prevented regrowth and emergence of polymyxin resistance in the polymyxin-susceptible isolates. Electron microscopy imaging revealed that the combination potentially affected cell division in A. baumannii . The enhanced antimicrobial activity of the combination was confirmed in a mouse burn infection model against a polymyxin-resistant A. baumannii isolate. As mitotane is hydrophobic, it was very likely that the synergistic killing of the combination resulted from that polymyxin B permeabilized the outer membrane of the Gram-negative bacteria and allowed mitotane to enter bacterial cells and exert its antimicrobial effect. These results have important implications for repositioning non-antibiotic drugs for antimicrobial purposes, which may expedite the discovery of novel therapies to combat the rapid emergence of antibiotic resistance.

PPAR-γ Agonists As Antineoplastic Agents in Cancers with Dysregulated IGF Axis

PubMed Central

Vella, Veronica; Nicolosi, Maria Luisa; Giuliano, Stefania; Bellomo, Maria; Belfiore, Antonino; Malaguarnera, Roberta

2017-01-01

It is now widely accepted that insulin resistance and compensatory hyperinsulinemia are associated to increased cancer incidence and mortality. Moreover, cancer development and progression as well as cancer resistance to traditional anticancer therapies are often linked to a deregulation/overactivation of the insulin-like growth factor (IGF) axis, which involves the autocrine/paracrine production of IGFs (IGF-I and IGF-II) and overexpression of their cognate receptors [IGF-I receptor, IGF-insulin receptor (IR), and IR]. Recently, new drugs targeting various IGF axis components have been developed. However, these drugs have several limitations including the occurrence of insulin resistance and compensatory hyperinsulinemia, which, in turn, may affect cancer cell growth and survival. Therefore, new therapeutic approaches are needed. In this regard, the pleiotropic effects of peroxisome proliferator activated receptor (PPAR)-γ agonists may have promising applications in cancer prevention and therapy. Indeed, activation of PPAR-γ by thiazolidinediones (TZDs) or other agonists may inhibit cell growth and proliferation by lowering circulating insulin and affecting key pathways of the Insulin/IGF axis, such as PI3K/mTOR, MAPK, and GSK3-β/Wnt/β-catenin cascades, which regulate cancer cell survival, cell reprogramming, and differentiation. In light of these evidences, TZDs and other PPAR-γ agonists may be exploited as potential preventive and therapeutic agents in tumors addicted to the activation of IGF axis or occurring in hyperinsulinemic patients. Unfortunately, clinical trials using PPAR-γ agonists as antineoplastic agents have reached conflicting results, possibly because they have not selected tumors with overactivated insulin/IGF-I axis or occurring in hyperinsulinemic patients. In conclusion, the use of PPAR-γ agonists in combined therapies of IGF-driven malignancies looks promising but requires future developments. PMID:28275367

FDA-approved medications that impair human spermatogenesis.

PubMed

Ding, Jiayi; Shang, Xuejun; Zhang, Zhanhu; Jing, Hua; Shao, Jun; Fei, Qianqian; Rayburn, Elizabeth R; Li, Haibo

2017-02-07

We herein provide an overview of the single-ingredient U.S. Food and Drug Administration (FDA)-approved drugs that affect human spermatogenesis, potentially resulting in a negative impact on male fertility. To provide this information, we performed an in-depth search of DailyMed, the official website for FDA-approved drug labels. Not surprisingly, hormone-based agents were found to be the drugs most likely to affect human spermatogenesis. The next category of drugs most likely to have effects on spermatogenesis was the antineoplastic agents. Interestingly, the DailyMed labels indicated that several anti-inflammatory drugs affect spermatogenesis, which is not supported by the peer-reviewed literature. Overall, there were a total of 65 labels for drugs of various classes that showed that they have the potential to affect human sperm production and maturation. We identified several drugs indicated to be spermatotoxic in the drug labels that were not reported in the peer-reviewed literature. However, the details about the effects of these drugs on human spermatogenesis are largely lacking, the mechanisms are often unknown, and the clinical impact of many of the findings is currently unclear. Therefore, additional work is needed at both the basic research level and during clinical trials and post-marketing surveillance to fill the gaps in the current knowledge. The present findings will be of interest to physicians and pharmacists, researchers, and those involved in drug development and health care policy.

HG-829 Is a Potent Noncompetitive Inhibitor of the ATP-Binding Cassette Multidrug Resistance Transporter ABCB1

PubMed Central

Caceres, Gisela; Robey, Robert W.; Sokol, Lubomir; McGraw, Kathy L.; Clark, Justine; Lawrence, Nicholas J.; Sebti, Said M.; Wiese, Michael; List, Alan F.

2015-01-01

Transmembrane drug export mediated by the ATP-binding cassette (ABC) transporter P-glycoprotein contributes to clinical resistance to antineoplastics. In this study, we identified the substituted quinoline HG-829 as a novel, noncompetitive, and potent P-glycoprotein inhibitor that overcomes in vitro and in vivo drug resistance. We found that nontoxic concentrations of HG-829 restored sensitivity to P-glycoprotein oncolytic substrates. In ABCB1-overexpressing cell lines, HG-829 significantly enhanced cytotoxicity to daunorubicin, paclitaxel, vinblastine, vincristine, and etoposide. Coadministration of HG-829 fully restored in vivo antitumor activity of daunorubicin in mice without added toxicity. Functional assays showed that HG-829 is not a Pgp substrate or competitive inhibitor of Pgp-mediated drug efflux but rather acts as a noncompetitive modulator of P-glycoprotein transport function. Taken together, our findings indicate that HG-829 is a potent, long-acting, and noncompetitive modulator of P-glycoprotein export function that may offer therapeutic promise for multidrugresistant malignancies. PMID:22761337

Focus on Fotemustine.

PubMed

De Rossi, A; Rossi, L; Laudisi, A; Sini, V; Toppo, L; Marchesi, F; Tortorelli, G; Leti, M; Turriziani, M; Aquino, A; Bonmassar, E; De Vecchis, L; Torino, F

2006-12-01

Fotemustine is a cytotoxic alkylating agent, belonging to the group of nitrosourea family. Its mechanism of action is similar to that of other nitrosoureas, characterized by a mono-functional/bi-functional alkylating activity. Worth of consideration is the finding that the presence of high levels of the DNA repair enzyme O6-methylguanine-DNA-methyltransferase (MGMT) in cancer cells confers drug resistance. In different clinical trials Fotemustine showed a remarkable antitumor activity as single agent, and in association with other antineoplastic compounds or treatment modalities. Moreover, its toxicity is generally considered acceptable. The drug has been employed in the treatment of metastatic melanoma, and, on the basis of its pharmacokinetic properties, in brain tumors, either primitive or metastatic. Moreover, Fotemustine shows pharmacodynamic properties similar to those of mono-functional alkylating compounds (e.g. DNA methylating drugs, such as Temozolomide), that have been recently considered for the management of acute refractory leukaemia. Therefore, it is reasonable to assume that this agent could be a good candidate to play a potential role in haematological malignancies.

Multifunctional enveloped mesoporous silica nanoparticles for subcellular co-delivery of drug and therapeutic peptide.

PubMed

Luo, Guo-Feng; Chen, Wei-Hai; Liu, Yun; Lei, Qi; Zhuo, Ren-Xi; Zhang, Xian-Zheng

2014-08-14

A multifunctional enveloped nanodevice based on mesoporous silica nanoparticle (MSN) was delicately designed for subcellular co-delivery of drug and therapeutic peptide to tumor cells. Mesoporous silica MCM-41 nanoparticles were used as the core for loading antineoplastic drug topotecan (TPT). The surface of nanoparticles was decorated with mitochondria-targeted therapeutic agent (Tpep) containing triphenylphosphonium (TPP) and antibiotic peptide (KLAKLAK)2 via disulfide linkage, followed by coating with a charge reversal polyanion poly(ethylene glycol)-blocked-2,3-dimethylmaleic anhydride-modified poly(L-lysine) (PEG-PLL(DMA)) via electrostatic interaction. It was found that the outer shielding layer could be removed at acidic tumor microenvironment due to the degradation of DMA blocks and the cellular uptake was significantly enhanced by the formation of cationic nanoparticles. After endocytosis, due to the cleavage of disulfide bonds in the presence of intracellular glutathione (GSH), pharmacological agents (Tpep and TPT) could be released from the nanoparticles and subsequently induce specific damage of tumor cell mitochondria and nucleus respectively with remarkable synergistic antitumor effect.

Exposure of pharmacy personnel to mutagenic antineoplastic drugs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nguyen, T.V.; Theiss, J.C.; Matney, T.S.

1981-01-01

The Salmonella reversion test was used to measure the mutagenic activities of urine concentrates from individuals preparing cancer chemotherapy agents for intravenous administration. Longitudinal studies were performed in which the total urine produced in 24 hour periods was collected, starting on a Sunday at 7:00 p.m. after a duty-free weekend and extending over an eight day period. There was no detectable increase in mutagenic activity in the urine concentrates of three pharmacy administrators who had no contact with these drugs. All six individuals admixing drugs in open-faced, horizontal laminar flow hoods displayed a two-fold increase in mutagenesis by the fourthmore » day with peak values of 2.7 to 24-fold occurring on days five and six, reduced values by day seven with a return to the spontaneous level by day eight. When four of the six positive individuals in the preceding experiment admixed comparable amounts of chemotherapeutic drugs in a closed-faced, vertical laminar flow hood, no increase in mutagenic activity was detected in their urine concentrates over the eight day period.« less

Monitoring occupational exposure to cancer chemotherapy drugs

NASA Technical Reports Server (NTRS)

Baker, E. S.; Connor, T. H.

1996-01-01

Reports of the health effects of handling cytotoxic drugs and compliance with guidelines for handling these agents are briefly reviewed, and studies using analytical and biological methods of detecting exposure are evaluated. There is little conclusive evidence of detrimental health effects from occupational exposure to cytotoxic drugs. Work practices have improved since the issuance of guidelines for handling these drugs, but compliance with the recommended practices is still inadequate. Of 64 reports published since 1979 on studies of workers' exposure to these drugs, 53 involved studies of changes in cellular or molecular endpoints (biological markers) and 12 described chemical analyses of drugs or their metabolites in urine (2 involved both, and 2 reported the same study). The primary biological markers used were urine mutagenicity, sister chromatid exchange, and chromosomal aberrations; other studies involved formation of micronuclei and measurements of urinary thioethers. The studies had small sample sizes, and the methods were qualitative, nonspecific, subject to many confounders, and possibly not sensitive enough to detect most occupational exposures. Since none of the currently available biological and analytical methods is sufficiently reliable or reproducible for routine monitoring of exposure in the workplace, further studies using these methods are not recommended; efforts should focus instead on wide-spread implementation of improved practices for handling cytotoxic drugs.

Radiation induction of drug resistance in RIF-1 tumors and tumor cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hopwood, L.E.; Moulder, J.E.

1989-11-01

The RIF-1 tumor cell line contains a small number of cells (1-20 per 10(6) cells) that are resistant to various single antineoplastic drugs, including 5-fluorouracil (5FU), methotrexate (MTX), and adriamycin (ADR). For 5FU the frequency of drug resistance is lower for tumor-derived cells than for cells from cell culture; for MTX the reverse is true, and for ADR there is no difference. In vitro irradiation at 5 Gy significantly increased the frequency of drug-resistant cells for 5FU, MTX, and ADR. In vivo irradiation at 3 Gy significantly increased the frequency of drug-resistant cells for 5FU and MTX, but not formore » ADR. The absolute risk for in vitro induction of MTX, 5FU, and ADR resistance, and for in vivo induction of 5FU resistance, was 1-3 per 10(6) cells per Gy; but the absolute risk for in vivo induction of MTX resistance was 54 per 10(6) cells per Gy. The frequency of drug-resistant cells among individual untreated tumors was highly variable; among individual irradiated tumors the frequency of drug-resistant cells was significantly less variable. These studies provide supporting data for models of the development of tumor drug resistance, and imply that some of the drug resistance seen when chemotherapy follows radiotherapy may be due to radiation-induced drug resistance.« less

Drug delivery systems based on biocompatible imino-chitosan hydrogels for local anticancer therapy.

PubMed

Ailincai, Daniela; Tartau Mititelu, Liliana; Marin, Luminita

2018-11-01

A series of drug delivery systems were prepared by chitosan hydrogelation with citral in the presence of an antineoplastic drug: 5-fluorouracil. The dynamic covalent chemistry of the imine linkage allowed the obtaining of supramolecular tridimensional architectures in which the drug has been homogenously dispersed. Fourier-transform infrared spectroscopy (FTIR), wide-angle X-ray diffraction (WXRD) and polarized light microscopy (POM) measurements were used in order to follow the hydrogelation and drug encapsulation processes. The ability of the prepared systems to release the drug has been investigated by UV-Vis spectroscopy using a calibration curve and by fitting the results with different mathematic models. To mimic the behavior of the hydrogel matrix in bio-environmental conditions in view of applications, their enzymatic degradability was monitored in the presence of lysozyme. The in vivo side effects of the systems, in terms of their influence on the blood elements, biochemical and immune parameters were monitored on white Swiss mice by intraperitoneal administration of the injectable obtained hydrogels. All the characteristics of the obtained systems, such as micro-porous morphology, uniform drug encapsulation, enzymatic degradability, lack of side effects, other than the one of the drug itself, along with their ability to release the drug in a sustained manner proved that these material meet the requirements for the development of drug delivery systems, making them suitable for being applied in intraperitoneal chemotherapy.

Assessment of surface concentrations in resorbable ocular implants: controlled drug delivery devices for 5-fluorouracil (5-FU)

NASA Astrophysics Data System (ADS)

Milne, Peter J.; Gautier, Sandrine; Parel, Jean-Marie A.; Jallet, Valerie

1997-05-01

The antineoplastic drug 5-fluorouracil (5-fluoro- 2,4,(1H,3H)-pyrimidinedione; 5-FU) has been used to control proliferation of penetrating fibroblasts and to prevent channel closure following glaucoma filtration surgery (trabeculectomy) or laser sclerectomy. Because of the toxicity of the drug, administration of low dosages slowly over time, at the site of the desired treatment, is indicated for optimum efficacy. Repeated injections of low dosages of the drug represent an undesirable intervention and may also result in unwanted toxicity to the corneal epithelium. A suitable biocompatible and resorbable polymer matrix composed of a poly (D,L-lactic-co-glycolic acid: PLGA) has been admixed with varying amounts of 5-FU and cast as shapes suitable for intracorneal implantation. Slow biodegradation of this polymer over a one to two week period has been shown to result in an acceptably slow drug release mechanism. An issue arising during the clinical evaluation of the efficacy of this drug delivery system was how best to quantify the concentration of 5-FU and its distribution spatially in the solid implant. FT-IR and FT-Raman spectroscopies distinguishes between the drug and the polymer matrix and were used to differentiate and quantitate the 5-FU concentration of the implants.

The importance of monitoring adverse drug reactions in pediatric patients: the results of a national surveillance program in Italy.

PubMed

Carnovale, Carla; Brusadelli, Tatiana; Zuccotti, GianVincenzo; Beretta, Silvia; Sullo, Maria Giuseppa; Capuano, Annalisa; Rossi, Francesco; Moschini, Martina; Mugelli, Alessandro; Vannacci, Alfredo; Laterza, Marcella; Clementi, Emilio; Radice, Sonia

2014-09-01

To gain information on safety of drugs used in pediatrics through a 4-year post-marketing active pharmacovigilance program. The program sampled the Italian population and was termed 'Monitoring of the Adverse Effects in Pediatric population' (MEAP). Adverse drug reactions (ADRs) were collected for individuals aged 0 - 17 years treated in hospitals and territorial health services in Lombardy, Tuscany, Apulia and Campania; located to gain an appropriate sampling of the population. ADRs were evaluated using the Adverse Drug Reaction Probability Scale (Naranjo) and analyzed with respect to time, age, sex, category of ADR, seriousness, suspected medicines, type of reporter and off-label use. We collected and analyzed reports from 3539 ADRs. Vaccines, antineoplastic and psychotropic drugs were the most frequently pharmacotherapeutic subgroups involved. Seventeen percent of reported ADRs were serious; of them fever, vomiting and angioedema were the most frequently reported. Eight percent of ADRs were associated with off-label use, and 10% were unknown ADRs. Analysis of these revealed possible strategies of therapy optimization. The MEAP project demonstrated that active post-marketing pharmacovigilance programs are a valid strategy to increase awareness on pediatric pharmacology, reduce underreporting and provide information on drug actions in pediatrics. This information enhances drug therapy optimization in the pediatric patients.

Investigation of the host-guest complexation between 4-sulfocalix[4]arene and nedaplatin for potential use in drug delivery

NASA Astrophysics Data System (ADS)

Fahmy, Sherif Ashraf; Ponte, Fortuna; Abd El-Rahman, Mohamed K.; Russo, Nino; Sicilia, Emilia; Shoeib, Tamer

2018-03-01

Macromolecules including macrocyclic species have been reported to have the potential to encapsulate biologically active compounds such as drugs through host-guest complexation to increase their solubility, stability and bioavailability. In this paper the first experimental and theoretical investigation of the complexation between nedaplatin, a second generation antineoplastic drug, and p-4-sulfocalix[4]arene, a macromolecule possessing a bipolar amphiphilic structure with good biocompatibility and relatively low haemolytic toxicity for potential use as a drug delivery system is presented. Data from 1H NMR, UV, Job's plot analysis, HPLC and DFT calculations are detailed and suggest the formation of a 1:1 complex. The stability constant of the complex was experimentally estimated to be 3.6 × 104 M- 1 and 2.1 × 104 M- 1 which correspond to values of - 6.2 and - 5.9 kcal mol- 1, respectively for the free energy of complexation while the interaction free energy is calculated to be - 4.9 kcal mol- 1. The formed species is shown to be stabilised in solution through hydrogen bonding between the host and the guest which may allow for this strategy to be effective for potential use in drug delivery.

Thrombotic microangiopathy associated with Valproic acid toxicity.

PubMed

Hebert, Sean A; Bohan, Timothy P; Erikson, Christian L; Swinford, Rita D

2017-08-03

Thrombotic microangiopathy (TMA) is a serious, sometimes life-threatening disorder marked by the presence of endothelial injury and microvascular thrombi. Drug-induced thrombotic microangiopathy (DI-TMA) is one specific TMA syndrome that occurs following drug exposure via drug-dependent antibodies or direct tissue toxicity. Common examples include calcineurin inhibitors Tacrolimus and Cyclosporine and antineoplastics Gemcitabine and Mitomycin. Valproic acid has not been implicated in DI-TMA. We present the first case of a patient meeting clinical criteria for DI-TMA following admission for valproic acid toxicity. An adolescent male with difficult to control epilepsy was admitted for impaired hepatic function while on valproic acid therapy. On the third hospital day, he developed severe metabolic lactic acidosis and multiorgan failure, prompting transfer to the pediatric intensive care unit. Progressive anemia and thrombocytopenia instigated an evaluation for thrombotic microangiopathy, where confirmed by concomitant hemolysis, elevated lactate dehydrogenase (LDH), low haptoglobin, and concurrent oliguric acute kidney injury. Thrombotic thrombocytopenic purpura was less likely with adequate ADAMTS13. Discontinuing valproic acid reversed the anemia, thrombocytopenia, and normalized the LDH and haptoglobin, supporting a drug-induced cause for the TMA. To the best of our knowledge, this is the first report of drug-induced TMA from valproic acid toxicity.

Drug Monographs: Avelumab and Ribociclib.

PubMed

Waddell, J Aubrey; Solimando, Dominic A

2017-07-01

The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparation, dispensing, and administration of antineoplastic therapy, and the agents, both commercially available and investigational, used to treat malignant diseases. Questions or suggestions for topics should be addressed to Dominic A. Solimando, Jr, President, Oncology Pharmacy Services, Inc, 4201 Wilson Blvd #110-545, Arlington, VA 22203, email: OncRxSvc@comcast.net; or J. Aubrey Waddell, Professor, University of Tennessee College of Pharmacy; Oncology Pharmacist, Pharmacy Department, Blount Memorial Hospital, 907 E. Lamar Alexander Parkway, Maryville, TN 37804, e-mail: waddfour@charter.net.

Drug Monographs: Ixazomib and Necitumumab.

PubMed

Lawson, Fern E; Waddell, J Aubrey; Solimando, Dominic A

2016-05-01

The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparation, dispensing, and administration of antineoplastic therapy, and the agents, both commercially available and investigational, used to treat malignant diseases. Questions or suggestions for topics should be addressed to Dominic A. Solimando, Jr, President, Oncology Pharmacy Services, Inc., 4201 Wilson Blvd #110-545, Arlington, VA 22203, e-mail: OncRxSvc@comcast.net; or J. Aubrey Waddell, Professor, University of Tennessee College of Pharmacy; Oncology Pharmacist, Pharmacy Department, Blount Memorial Hospital, 907 E. Lamar Alexander Parkway, Maryville, TN 37804, e-mail: waddfour@charter.net.

Antimicrobial and anticancer efficacy of antineoplastic agent capped gold nanoparticles.

PubMed

Selvaraj, V; Grace, A Nirmala; Alagar, M; Hamerton, I

2010-04-01

Synthesis of thioguanine (TG)-capped Au nanoparticles (Au@TG) and their enhanced in vitro antimicrobial and anticancer efficacy against Micrococcus luteus, Staphylococcus aureus, Pseudomonas aeruginosa, E. coli, Aspergillus fumigatus, Aspergillus niger and Hep2 cancer cell (Human epidermiod cell) have been reported. The nature of binding between 6-TG and the gold nanoparticles via complexation is investigated using ultraviolet-visible spectrum, cyclic voltammetry, transmission electron microscopy, fluorescence and Fourier transform infrared (FT-IR) spectroscopy. The present experimental studies suggests that Au@TG are more potential than TG towards antimicrobial and anticancer activities. Hence, gold nanoparticles have the potential to be used as effective carriers for anticancer drug.

A dose-ranging study of the pharmacokinetics and pharmacodynamics of the selective apoptotic antineoplastic drug (SAAND), OSI-461, in patients with advanced cancer, in the fasted and fed state

PubMed Central

O’Bryant, C. L.; Lieu, C. H.; Leong, S.; Boinpally, R.; Basche, M.; Gore, L.; Leonardi, K.; Schultz, M. K.; Hariharan, S.; Chow, L.; Diab, S.; Gibbs, A.; Eckhardt, S. G.

2010-01-01

Purpose To evaluate the safety, pharmacokinetics and determine the recommended dose of the selective apoptotic antineoplastic drug, OSI-461 administered on a twice-daily regimen to patients with advanced solid malignancies. Methods In this phase I trial, 33 patients were treated with OSI-461 doses ranging from 400 to 1,200 mg given twice daily in 4-week cycles. Pharmacokinetic studies were performed to characterize the plasma disposition of OSI-461 and the effect of food intake on OSI-461 absorption. Secondary biomarker studies were performed to assess the biologic activity of OSI-461 including the measurement of pGSK-3β, a PKG substrate, and pharmacogenetic studies to identify polymorphisms of CYP3A that influence drug metabolism and of ABCG2, involved in drug resistance. Results Thirty-three patients were treated with 86 courses of OSI-461. The dose-limiting toxicities were grade 3 abdominal pain, found in one patient at the 1,000 mg BID fed dose level and all patients at the 1,200 mg BID fed dose level. There was also one episode each of grade 3 fatigue and grade 3 constipation at the 1,000 and 1,200 mg BID fed dose levels, respectively. Other common toxicities included mild to moderate fatigue, nausea, anorexia and mild elevation in bilirubin. Pharmacokinetic studies of OSI-461 revealed approximately a twofold increase in AUC0–24 when OSI-461 was administered with food. An increase in pGSK-3β post-dose was seen in the majority of patients and was greater at higher dose levels. No patients exhibited CYP3A4 polymorphisms, while 100% of patients were found to have the CYP3A5*3/CYP3A5*3 polymorphism. Two known polymorphisms of the ABCG2 gene, G34 → A34 and C421 → A421, occurred at frequencies of 11.76 and 29%, respectively. Conclusions Toxicity and pharmacodynamic data show that the recommended oral dose of OSI-461 is 800 mg twice daily administered with food. The drug appears to be well-tolerated, and overall bioavailability appears to be markedly increased when the drug is administered with food. These results support further disease-directed evaluations of OSI-461 at a dose of 800 mg BID in combination with other chemotherapeutic agents. PMID:18509645

Incidence of infusion reactions to anti-neoplastic agents in early phase clinical trials: The MD Anderson Cancer Center experience.

PubMed

Bupathi, Manojkumar; Hajjar, Joud; Bean, Stacie; Fu, Siqing; Hong, David; Karp, Daniel; Stephen, Bettzy; Hess, Kenneth; Meric-Bernstam, Funda; Naing, Aung

2017-02-01

Infusion reactions (IRs) to anti-neoplastic agents require prompt recognition and immediate treatment to avert significant complications. We conducted a retrospective review of the medical records of consecutive patients who received anti-neoplastic therapy in the outpatient treatment center of the Department of Investigational Cancer Therapeutics from January 1, 2013 to November 30, 2013. Of the 597 patients who received treatment, 9 (1.5 %) had IRs (all ≤ grade 2). The most common IRs observed on first occurrence were chills (n = 5), itching, rash, and facial flushing (n = 3 each). There were no IR-related deaths. All the IRs were reversible with appropriate symptomatic treatment and the therapy was completed after temporary cessation of infusion in 7 of the 9 patients. The infusion was stopped in 2 patients due to symptoms suggestive of IgE-mediated allergic reaction and cytokine storm. Five of the 8 patients who were re-challenged with the same therapy developed a similar reaction. However, the infusion was completed in 4 of the 5 patients after administration of intravenous diphenhydramine and/or hydrocortisone, or slowing the rate of infusion. And, subsequent cycles with the same agents were uneventful. IRs to anti-neoplastic agents are rare. Though the clinical presentations are overlapping, most IRs are not IgE-mediated allergic reactions. Appropriate premedication and slow rate of infusion facilitates uneventful administration of the anti-neoplastic agents in subsequent cycles. Further study in a larger cohort of patients to identify biomarkers of hypersensitivity is warranted.

Cost-benefit analysis of prophylactic granulocyte colony-stimulating factor during CHOP antineoplastic therapy for non-Hodgkin's lymphoma.

PubMed

Dranitsaris, G; Altmayer, C; Quirt, I

1997-06-01

Several randomised comparative trials have shown that granulocyte colony-stimulating factor (G-CSF) reduces the duration of neutropenia, hospitalisation and intravenous antibacterial use in patients with cancer who are receiving high-dosage antineoplastic therapy. However, one area that has received less attention is the role of G-CSF in standard-dosage antineoplastic regimens. One such treatment that is considered to have a low potential for inducing fever and neutropenia is the CHOP regimen (cyclophosphamide, doxorubicin, vincristine and prednisone) for non-Hodgkin's lymphoma. We conducted a cost-benefit analysis from a societal perspective in order to estimate the net cost or benefit of prophylactic G-CSF in this patient population. This included direct costs for hospitalisation with antibacterial support, as well as indirect societal costs, such as time off work and antineoplastic therapy delays secondary to neutropenia. The findings were then tested by a comprehensive sensitivity analysis. The administration of G-CSF at a dosage of 5 micrograms/kg/day for 11 doses following CHOP resulted in an overall net cost of $Can1257. In the sensitivity analysis, lowering the G-CSF dosage to 2 micrograms/kg/day generated a net benefit of $Can6564, indicating a situation that was cost saving to society. The results of the current study suggest that the use of G-CSF in patients receiving CHOP antineoplastic therapy produces a situation that is close to achieving cost neutrality. However, low-dosage (2 micrograms/kg/day) G-CSF is an economically attractive treatment strategy because it may result in overall savings to society.

Venetoclax (ABT-199) Might Act as a Perpetrator in Pharmacokinetic Drug-Drug Interactions.

PubMed

Weiss, Johanna; Gajek, Thomas; Köhler, Bruno Christian; Haefeli, Walter Emil

2016-02-24

Venetoclax (ABT-199) represents a specific B-cell lymphoma 2 (Bcl-2) inhibitor that is currently under development for the treatment of lymphoid malignancies. So far, there is no published information on its interaction potential with important drug metabolizing enzymes and drug transporters, or its efficacy in multidrug resistant (MDR) cells. We therefore scrutinized its drug-drug interaction potential in vitro. Inhibition of cytochrome P450 enzymes (CYPs) was quantified by commercial kits. Inhibition of drug transporters (P-glycoprotein (P-gp, ABCB1), breast cancer resistance protein (BCRP), and organic anion transporting polypeptides (OATPs)) was evaluated by the use of fluorescent probe substrates. Induction of drug transporters and drug metabolizing enzymes was quantified by real-time RT-PCR. The efficacy of venetoclax in MDR cells lines was evaluated with proliferation assays. Venetoclax moderately inhibited P-gp, BCRP, OATP1B1, OATP1B3, CYP3A4, and CYP2C19, whereas CYP2B6 activity was increased. Venetoclax induced the mRNA expression of CYP1A1, CYP1A2, UGT1A3, and UGT1A9. In contrast, expression of ABCB1 was suppressed, which might revert tumor resistance towards antineoplastic P-gp substrates. P-gp over-expression led to reduced antiproliferative effects of venetoclax. Effective concentrations for inhibition and induction lay in the range of maximum plasma concentrations of venetoclax, indicating that it might act as a perpetrator drug in pharmacokinetic drug-drug interactions.

Towards the use of non-psychoactive cannabinoids for prostate cancer

PubMed Central

Pacher, Pál

2013-01-01

The palliative effects of Cannabis sativa (marijuana), and its putative main active ingredient, Δ9-tetrahydrocannabinol (THC), which include appetite stimulation, attenuation of nausea and emesis associated with chemo- or radiotherapy, pain relief, mood elevation, and relief from insomnia in cancer patients, are well-known. Because of the adverse psychoactive effects of THC, numerous recent preclinical studies have been focused on investigating other non-psychoactive constituents of C. sativa, such as cannabidiol, for potential therapeutic use. In this issue of the British Journal of Pharmacology, De Petrocellis and colleagues present comprehensive evidence that plant-derived cannabinoids, especially cannabidiol, are potent inhibitors of prostate carcinoma viability in vitro. They also showed that the extract was active in vivo, either alone or when administered with drugs commonly used to treat prostate cancer (the anti-mitotic chemotherapeutic drug docetaxel (Taxotere) or the anti-androgen bicalutamide (Casodex)) and explored the potential mechanisms behind these antineoplastic effects. PMID:22849856

Osteonecrosis of the jaw - prevention and treatment strategies for oral health professionals.

PubMed

Hinchy, Nicole V; Jayaprakash, Vijayvel; Rossitto, Rachael A; Anders, Patrick L; Korff, Kathryn C; Canallatos, Paul; Sullivan, Maureen A

2013-09-01

Patients diagnosed with multiple myeloma and metastatic breast, prostate and renal cancers have a better opportunity for longer survival due to a myriad of chemotherapies regimens that attempt to manage disease progression while decreasing treatment-related side effects. Osteonecrosis of the jaws (ONJ) is a known side effect of bisphosphonates and other anti-neoplastic drugs. This complication can lead to oncologic treatment interruptions as well as diminished quality of life. Most recommendations for treatment of ONJ are based on position papers and case reports, while evidence-based treatment paradigms are lacking. With cancer survivorship on the rise, long-term chemotherapeutic side effects are becoming more prevalent and attention to untoward oral complications cannot be understated. In this review, the accepted recommendations for dental clearance prior to head and neck chemo-radiation therapy are put forth as a means of possibly preventing and treating drug induced ONJ. Copyright © 2013 Elsevier Ltd. All rights reserved.

[The significance of extravasation in oncological care].

PubMed

Zatkóné Puskás, Gabriella

2008-03-01

The treatment of cancer may be associated with various chemotherapy-induced mucocutaneous reactions. One of the mucocutaneous adverse effects of antineoplastic drugs is the toxic local tissue reaction, the extravasation, which occurs in less than 1-2% of cytotoxic infusions. The standard management of vesicant extravasation includes: discontinuing all local infusions, aspiration of any residual drug, elevating the involved limb, local cooling or warm compresses, local anesthesia, antidotes (sodium thiosulfate for alkylating agents, dimethylsulfoxide (DMSO) for anthracyclines and mitomycin, and hyaluronidase for the vinca alkaloids), and finally surgical debridement with plastic surgery reconstruction. Because the anthracyclines are topoisomerase II poisons that are antagonized by topoisomerase II catalytic inhibitors such as dexrazoxane, it seems to be the treatment of choice immediately after extravasation of doxorubicin, epirubicin, daunorubicin, etc. One systemic dose of dexrazoxane after the accident may significantly reduce the toxic tissue lesions. Repeated intralesional injections of GM-CSF may accelerate the wound healing without the need of skin grafts.

Drug Monographs: Olaratumab and Rucaparib.

PubMed

Solimando, Dominic A; Waddell, J Aubrey

2017-04-01

The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparation, dispensing, and administration of antineoplastic therapy, and the agents, both commercially available and investigational, used to treat malignant diseases. Questions or suggestions for topics should be addressed to Dominic A. Solimando, Jr, President, Oncology Pharmacy Services, Inc., 4201 Wilson Blvd #110-545, Arlington, VA 22203, e-mail: OncRxSvc@comcast.net; or J. Aubrey Waddell, Professor, University of Tennessee College of Pharmacy; Oncology Pharmacist, Pharmacy Department, Blount Memorial Hospital, 907 E. Lamar Alexander Parkway, Maryville, TN 37804, e-mail: waddfour@charter.net. The information presented in this review is based on published data and clinical expertise and includes information not included in the product labeling. Incorporation of such published data provides a more robust assessment of the drugs and assists pharmacists in evaluation of orders for off-label use of these agents.

Challenges beyond elimination in leprosy.

PubMed

Naaz, Farah; Mohanty, Partha Sarathi; Bansal, Avi Kumar; Kumar, Dilip; Gupta, Umesh Datta

2017-01-01

Every year >200,000 new leprosy cases are registered globally. This number has been fairly stable over the past 8 years. The World Health Organization has set a target to interrupt the transmission of leprosy globally by 2020. It is important, in terms of global action and research activities, to consider the eventuality of multidrug therapy (MDT) resistance developing. It is necessary to measure disease burden comprehensively, and contact-centered preventive interventions should be part of a global elimination strategy. Drug resistance is the reduction in effectiveness of a drug such as an antimicrobial or an antineoplastic in curing a disease or condition. MDT has proven to be a powerful tool in the control of leprosy, especially when patients report early and start prompt treatment. Adherence to and its successful completion is equally important. This paper has reviewed the current state of leprosy worldwide and discussed the challenges and also emphasizes the challenge beyond the elimination in leprosy.

Environmental contamination with methotrexate in Canadian community pharmacies.

PubMed

Merger, Delphine; Tanguay, Cynthia; Langlois, Éric; Lefebvre, Michel; Bussières, Jean-François

2013-01-01

To evaluate environmental contamination with methotrexate, cyclophosphamide, and ifosfamide in Quebec, Canada, community pharmacies and to describe hazardous drug handling practices in these pharmacies. Three standardized sites were sampled in each participating community pharmacy. Samples were analyzed for the presence of cyclophosphamide, ifosfamide, and methotrexate by high-performance liquid chromatography tandem mass spectrometry. The limits of detection were 0.10, 0.12, and 0.41 ng/mL for cyclophosphamide, ifosfamide, and methotrexate, respectively. Nine working practices were assessed. 20 community pharmacies participated in the study, and 60 samples were analyzed. No traces of cyclophosphamide or ifosfamide were detected. Traces of methotrexate were found in 12 of 20 pharmacies (60%). Of the 20 pharmacies, 8 (40%) had a storage space reserved for hazardous drugs and none had a preparation area reserved for handling methotrexate tablets. All of the participating community pharmacies had a tablet counter reserved for the handling of hazardous drugs, and all pharmacies cleaned their tablet counter reserved for handling hazardous drugs after use. None of the pharmacies cut or crushed methotrexate tablets. The growing number of hazardous drugs represents a challenge for community pharmacies. Community pharmacists must be made aware of their presence and the need to comply with personal protection measures to reduce staff occupational exposure to hazardous drugs.

USP <800> Adds Significant Safety Standards: Facility Upgrades Needed to Protect Employees From Hazardous Drugs.

PubMed

Beans, Bruce E

2017-05-01

The new USP standard for handling hazardous drugs (HDs) will require millions of dollars in capital outlays for facility and equipment upgrades and also requires in-depth assessments of each HD that facilities handle, significant workflow and work practice changes, and thorough staff training.

DGIdb 3.0: a redesign and expansion of the drug-gene interaction database.

PubMed

Cotto, Kelsy C; Wagner, Alex H; Feng, Yang-Yang; Kiwala, Susanna; Coffman, Adam C; Spies, Gregory; Wollam, Alex; Spies, Nicholas C; Griffith, Obi L; Griffith, Malachi

2018-01-04

The drug-gene interaction database (DGIdb, www.dgidb.org) consolidates, organizes and presents drug-gene interactions and gene druggability information from papers, databases and web resources. DGIdb normalizes content from 30 disparate sources and allows for user-friendly advanced browsing, searching and filtering for ease of access through an intuitive web user interface, application programming interface (API) and public cloud-based server image. DGIdb v3.0 represents a major update of the database. Nine of the previously included 24 sources were updated. Six new resources were added, bringing the total number of sources to 30. These updates and additions of sources have cumulatively resulted in 56 309 interaction claims. This has also substantially expanded the comprehensive catalogue of druggable genes and anti-neoplastic drug-gene interactions included in the DGIdb. Along with these content updates, v3.0 has received a major overhaul of its codebase, including an updated user interface, preset interaction search filters, consolidation of interaction information into interaction groups, greatly improved search response times and upgrading the underlying web application framework. In addition, the expanded API features new endpoints which allow users to extract more detailed information about queried drugs, genes and drug-gene interactions, including listings of PubMed IDs, interaction type and other interaction metadata.

‘One-pot’ synthesis of multifunctional GSH-CdTe quantum dots for targeted drug delivery

NASA Astrophysics Data System (ADS)

Chen, Xiaoqin; Tang, Yajun; Cai, Bing; Fan, Hongsong

2014-06-01

A novel quantum dots-based multifunctional nanovehicle (DOX-QD-PEG-FA) was designed for targeted drug delivery, fluorescent imaging, tracking, and cancer therapy, in which the GSH-CdTe quantum dots play a key role in imaging and drug delivery. To exert curative effects, the antineoplastic drug doxorubicin hydrochloride (DOX) was loaded on the GSH-CdTe quantum dots through a condensation reaction. Meanwhile, a polyethylene glycol (PEG) shell was introduced to wrap the DOX-QD, thus stabilizing the structure and preventing clearance and drug release during systemic circulation. To actively target cancer cells and prevent the nanovehicles from being absorbed by normal cells, the nanoparticles were further decorated with folic acid (FA), allowing them to target HeLa cells that express the FA receptor. The multifunctional DOX-QD-PEG-FA conjugates were simply prepared using the ‘one pot’ method. In vitro study demonstrated that this simple, multifunctional nanovehicle can deliver DOX to the targeted cancer cells and localize the nanoparticles. After reaching the tumor cells, the FA on the DOX-QD-PEG surface allowed folate receptor recognition and increased the drug concentration to realize a higher curative effect. This novel, multifunctional DOX-QD-PEG-FA system shows great potential for tumor imaging, targeting, and therapy.

Simultaneous Dual Selective Targeted Delivery of Two Covalent Gemcitabine Immunochemotherapeutics and Complementary Anti-Neoplastic Potency of [Se]-Methylselenocysteine

PubMed Central

Coyne, C. P.; Jones, Toni; Bear, Ryan

2015-01-01

The anti-metabolite chemotherapeutic, gemcitabine is relatively effective for a spectrum of neoplastic conditions that include various forms of leukemia and adenocarcinoma/carcinoma. Rapid systemic deamination of gemcitabine accounts for a brief plasma half-life but its sustained administration is often curtailed by sequelae and chemotherapeutic-resistance. A molecular strategy that diminishes these limitations is the molecular design and synthetic production of covalent gemcitabine immunochemotherapeutics that possess properties of selective “targeted” delivery. The simultaneous dual selective “targeted” delivery of gemcitabine at two separate sites on the external surface membrane of a single cancer cell types represents a therapeutic approach that can increase cytosol chemotherapeutic deposition; prolong chemotherapeutic plasma half-life (reduces administration frequency); minimize innocent exposure of normal tissues and healthy organ systems; and ultimately enhance more rapid and thorough resolution of neoplastic cell populations. Materials and Methods: A light-reactive gemcitabine intermediate synthesized utilizing succinimidyl 4,4-azipentanoate was covalently bound to anti-EGFR or anti-HER2/neu IgG by exposure to UV light (354-nm) resulting in the synthesis of covalent immunochemotherapeutics, gemcitabine-(C4-amide)-[anti-EGFR] and gemcitabine-(C4-amide)-[anti-HER2/neu]. Cytotoxic anti-neoplastic potency of gemcitabine-(C4-amide)-[anti-EGFR] and gemcitabine-(C4-amide)-[anti-HER2/neu] between gemcitabine-equivalent concentrations of 10−12 M and 10−6 M was determined utilizing chemotherapeutic-resistant mammary adenocarcinoma (SKRr-3). The organoselenium compound, [Se]-methylselenocysteine was evaluated to determine if it complemented the anti-neoplastic potency of the covalent gemcitabine immunochemotherapeutics. Results: Gemcitabine-(C4-amide)-[anti-EGFR], gemcitabine-(C4-amide)-[anti-HER2/neu] and the dual simultaneous combination of gemcitabine-(C4-amide)-[anti-EGFR] with gemcitabine-(C4-amide)-[anti-HER2/neu] all had anti-neoplastic cytotoxic potency against mammary adenocarcinoma. Gemcitabine-(C4-amide)-[anti-EGFR] and gemcitabine-(C4-amide)-[anti-HER2/neu] produced progressive increases in anti-neoplastic cytotoxicity that were greatest between gemcitabine-equivalent concentrations of 10−9 M and 10−6 M. Dual simultaneous combinations of gemcitabine-(C4-amide)-[anti-EGFR] with gemcitabine-(C4-amide)-[anti-HER2/neu] produced levels of anti-neoplastic cytotoxicity intermediate between each of the individual covalent gemcitabine immunochemotherapeutics. Total anti-neoplastic cytotoxicity of the dual simultaneous combination of gemcitabine-(C4-amide)-[anti-EGFR] and gemcitabine-(C4-amide)-[anti-HER2/neu] against chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3) was substantially higher when formulated with [Se]-methylsele-nocysteine. PMID:25821636

Comparison of oncology drug approval between Health Canada and the US Food and Drug Administration.

PubMed

Ezeife, Doreen A; Truong, Tony H; Heng, Daniel Y C; Bourque, Sylvie; Welch, Stephen A; Tang, Patricia A

2015-05-15

The drug approval timeline is a lengthy process that often varies between countries. The objective of this study was to delineate the Canadian drug approval timeline for oncology drugs and to compare the time to drug approval between Health Canada (HC) and the US Food and Drug Administration (FDA). In total, 54 antineoplastic drugs that were approved by the FDA between 1989 and 2012 were reviewed. For each drug, the following milestones were determined: the dates of submission and approval for both the FDA and HC and the dates of availability on provincial drug formularies in Canadian provinces and territories. The time intervals between the aforementioned milestones were calculated. Of 54 FDA-approved drugs, 49 drugs were approved by HC at the time of the current study. The median time from submission to approval was 9 months (interquartile range [IQR], 6-14.5 months) for the FDA and 12 months (IQR, 10-21.1 months) for HC (P < .0006). The time from HC approval to the placement of a drug on a provincial drug formulary was a median of 16.7 months (IQR, 5.9-27.2 months), and there was no interprovincial variability among the 5 Canadian provinces that were analyzed (P = .5). The time from HC submission to HC approval takes 3 months longer than the same time interval for the FDA. To the authors' knowledge, this is the first documentation of the time required to bring an oncology drug from HC submission to placement on a provincial drug formulary. © 2015 American Cancer Society.

Apoptosis and TRAF-1 cleavage in Epstein-Barr virus-positive nasopharyngeal carcinoma cells treated with doxorubicin combined with a farnesyl-transferase inhibitor.

PubMed

Vicat, Jean Michel; Ardila-Osorio, Hector; Khabir, Abdelmajid; Brezak, Marie Christine; Viossat, Isabelle; Kasprzyk, Philip; Jlidi, Rachid; Opolon, Paule; Ooka, Tadamassa; Prevost, Grégoire; Huang, Dolly P; Busson, Pierre

2003-02-01

Epstein-Barr virus (EBV)-associated nasopharyngeal carcinomas (NPC) are much more sensitive to chemotherapy than other head and neck carcinomas. Spectacular regressions are frequently observed after induction chemotherapy. However, these favorable responses are difficult to predict and often of short duration. So far there have been only few experiments to investigate the mechanisms which underline the cytotoxic effects of anti-neoplastic drugs against NPC cells. In addition, these studies were performed almost entirely on EBV-negative cell lines therefore not truly representative of NPC cells. For the first time, we have used two EBV-positive NPC tumor lines derived from a North African (C15) and a Chinese (C666-1) patient as in vitro targets for a panel of anti-neoplastic agents. Doxorubicin, taxol and in a lesser extent cis-platinum efficiently inhibited NPC cell proliferation at clinically relevant concentrations, but all three agents failed to induce apoptosis. However, massive apoptosis of C15 cells was achieved when doxorubicin (1 microM) was combined with a farnesyl-transferase inhibitor, BIM 2001 (5 microM). Moreover, this apoptotic process was associated with a caspase-dependent early cleavage of the TNF-receptor associated factor 1 (TRAF-1) molecule, a signaling adaptor which is specifically expressed in latently EBV-infected cells. TRAF-1 cleavage might become a useful indicator of chemo-induced apoptosis in EBV-associated NPCs.

Relevance of the OCT1 transporter to the antineoplastic effect of biguanides

DOE Office of Scientific and Technical Information (OSTI.GOV)

Segal, Eric D.; Yasmeen, Amber; Beauchamp, Marie-Claude

2011-11-04

Highlights: Black-Right-Pointing-Pointer siRNA knockdown of OCT1 reduced sensitivity of EOC cells to metformin, but not to another biguanide, phenformin. Black-Right-Pointing-Pointer Suppression of OCT1 also affects the activation of AMP kinase in response to metformin, but not to phenformin. Black-Right-Pointing-Pointer Direct actions of metformin may be limited by low OCT1 expression in EOC tumors. Black-Right-Pointing-Pointer Phenformin could be used as an alternative biguanide. -- Abstract: Epidemiologic and laboratory data suggesting that metformin has antineoplastic activity have led to ongoing clinical trials. However, pharmacokinetic issues that may influence metformin activity have not been studied in detail. The organic cation transporter 1 (OCT1)more » is known to play an important role in cellular uptake of metformin in the liver. We show that siRNA knockdown of OCT1 reduced sensitivity of epithelial ovarian cancer cells to metformin, but interestingly not to another biguanide, phenformin, with respect to both activation of AMP kinase and inhibition of proliferation. We observed that there is heterogeneity between primary human tumors with respect to OCT1 expression. These results suggest that there may be settings where drug uptake limits direct action of metformin on neoplastic cells, raising the possibility that metformin may not be the optimal biguanide for clinical investigation.« less

The modification of high-dose therapy shortens the duration of neutropaenia by delay of leucocyte nadir.

PubMed

Kiefer, T; Krüger, W H; Schüler, F; Lotze, C; Hirt, C; Dölken, G

2006-06-01

Infections during neutropaenia contribute still significantly to mortality and morbidity after high-dose therapy and autologous stem cell transplantation. Further acceleration of haemopoietic recovery seems impossible for biological reasons. Another approach to shorten neutropaenia could be to remove drugs from high-dose therapy protocols with strong contribution to immunosuppression and neutropaenia and unproven antineoplastic activity. In this retrospective matched-pair analysis, conventional busulphan/cyclophosphamide (Bu/Cy) high-dose therapy was compared to single-agent busulphan conditioning before autologous stem cell transplantation. This modification led to a significant shorter neutropaenic interval by protraction of cell decrease and to a significant mitigation of neutropaenia. After single-agent busulphan conditioning, leucocytes dropped below 1/nl at median 1.5 days later when compared to the patients from the busulphanBu/Cy control group (P=0.001). In a significant percentage of patients (n=6, 60%) leucocytes did not fall below 0.5 cells/nl at any time. In contrast, all patients from the Bu/Cy control group experienced deep neutropaenia (P=0.004). Thrombocytopaenia and requirement for transfusions of platelets or red cells were not influenced. Antineoplastic activity seemed to be preserved as determined by survival analysis. In conclusion, modification of high-dose regimen with the intention to shorten neutropaenia with preserved antitumour activity could be an approach to reduce infection-related morbidity and mortality and to consider economic necessities.

21 CFR 58.107 - Test and control article handling.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 1 2014-04-01 2014-04-01 false Test and control article handling. 58.107 Section... GOOD LABORATORY PRACTICE FOR NONCLINICAL LABORATORY STUDIES Test and Control Articles § 58.107 Test and control article handling. Procedures shall be established for a system for the handling of the test and...

21 CFR 58.107 - Test and control article handling.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 1 2011-04-01 2011-04-01 false Test and control article handling. 58.107 Section... GOOD LABORATORY PRACTICE FOR NONCLINICAL LABORATORY STUDIES Test and Control Articles § 58.107 Test and control article handling. Procedures shall be established for a system for the handling of the test and...

21 CFR 58.107 - Test and control article handling.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 1 2012-04-01 2012-04-01 false Test and control article handling. 58.107 Section... GOOD LABORATORY PRACTICE FOR NONCLINICAL LABORATORY STUDIES Test and Control Articles § 58.107 Test and control article handling. Procedures shall be established for a system for the handling of the test and...

21 CFR 58.107 - Test and control article handling.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 1 2013-04-01 2013-04-01 false Test and control article handling. 58.107 Section... GOOD LABORATORY PRACTICE FOR NONCLINICAL LABORATORY STUDIES Test and Control Articles § 58.107 Test and control article handling. Procedures shall be established for a system for the handling of the test and...

Longitudinal trends in use and costs of targeted therapies for common cancers in Taiwan: a retrospective observational study

PubMed Central

Hsu, Jason C; Lu, Christine Y

2016-01-01

Objectives Some targeted therapies have improved survival and overall quality of cancer care generally, but these increasingly expensive medicines have led to increases in pharmaceutical expenditure. This study examined trends in use and expenditures of antineoplastic agents in Taiwan, and estimated market shares by prescription volume and costs of targeted therapies over time. We also determined which cancer types accounted for the highest use of targeted therapies. Design This is a retrospective observational study focusing on the utilisation of targeted therapies for treatment of cancer. Setting The monthly claims data for antineoplastic agents were retrieved from Taiwan's National Health Insurance Research Database (2009–2012). Main outcome measures We calculated market shares by prescription volume and costs for each class of antineoplastic agent by cancer type. Using a time series design with Autoregressive Integrated Moving Average (ARIMA) models, we estimated trends in use and costs of targeted therapies. Results Among all antineoplastic agents, use of targeted therapies grew from 6.24% in 2009 to 12.29% in 2012, but their costs rose from 26.16% to 41.57% in that time. Monoclonal antibodies and protein kinase inhibitors contributed the most (respectively, 23.84% and 16.12% of costs for antineoplastic agents in 2012). During 2009–2012, lung (44.64% of use; 28.26% of costs), female breast (16.49% of use; 27.18% of costs) and colorectal (12.11% of use; 13.16% of costs) cancers accounted for the highest use of targeted therapies. Conclusions In Taiwan, targeted therapies are increasingly used for different cancers, representing a substantial economic burden. It is important to establish mechanisms to monitor their use and outcomes. PMID:27266775

Safe procedure development to manage hazardous drugs in the workplace.

PubMed

Gaspar Carreño, Marisa; Achau Muñoz, Rubén; Torrico Martín, Fátima; Agún Gonzalez, Juan José; Sanchez Santos, Jose Cristobal; Cercos Lletí, Ana Cristina; Ramos Orozco, Pedro

2017-03-01

To develop a safety working procedure for the employees in the Intermutual Hospital de Levante (HIL) in those areas of activity that deal with the handling of hazardous drugs (MP). The procedure was developed in six phases: 1) hazard definition; 2) definition and identification of processes and development of general correct work practices about hazardous drugs' selection and special handling; 3) detection, selection and set of specific recommendations to handle with hazardous drugs during the processes of preparation and administration included in the hospital GFT; 4) categorization of risk during the preparation/administration and development of an identification system; 5) information and training of professionals; 6) implementation of the identification measures and prevention guidelines. Six processes were detected handling HD. During those processes, thirty HD were identified included in the hospital GFT and a safer alternative was found for 6 of them. The HD were classified into 4 risk categories based on those measures to be taken during the preparation and administration of each of them. The development and implementation of specific safety-work processes dealing with medication handling, allows hospital managers to accomplish effectively with their legal obligations about the area of prevention and provides healthcare professional staff with the adequate techniques and safety equipment to avoid possible dangers and risks of some drugs. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

Chemoselective synthesis of ketones and ketimines by addition of organometallic reagents to secondary amides

NASA Astrophysics Data System (ADS)

Bechara, William S.; Pelletier, Guillaume; Charette, André B.

2012-03-01

The development of efficient and selective transformations is crucial in synthetic chemistry as it opens new possibilities in the total synthesis of complex molecules. Applying such reactions to the synthesis of ketones is of great importance, as this motif serves as a synthetic handle for the elaboration of numerous organic functionalities. In this context, we report a general and chemoselective method based on an activation/addition sequence on secondary amides allowing the controlled isolation of structurally diverse ketones and ketimines. The generation of a highly electrophilic imidoyl triflate intermediate was found to be pivotal in the observed exceptional functional group tolerance, allowing the facile addition of readily available Grignard and diorganozinc reagents to amides, and avoiding commonly observed over-addition or reduction side reactions. The methodology has been applied to the formal synthesis of analogues of the antineoplastic agent Bexarotene and to the rapid and efficient synthesis of unsymmetrical diketones in a one-pot procedure.

New antineoplastic agent based on a dibenzoylmethane derivative: Cytotoxic effect and direct interaction with DNA.

PubMed

Nascimento, Fernanda R; Moura, Tiago A; Baeta, Jefferson V P B; Publio, Bruno C; Ferreira, Pollyanna M F; Santos, Anésia A; França, Andressa A P; Rocha, Marcio S; Diaz-Muñoz, Gaspar; Diaz, Marisa A N

2018-08-01

Melanoma accounts for only 4% of all skin cancers but is among the most lethal cutaneous neoplasms. Dacarbazine is the drug of choice for the treatment of melanoma in Brazil through the public health system mainly because of its low cost. However, it is an alkylating agent of low specificity and elicits a therapeutic response in only 20% of cases. Other drugs available for the treatment of melanoma are expensive, and tumor cells commonly develop resistance to these drugs. The fight against melanoma demands novel, more specific drugs that are effective in killing drug-resistant tumor cells. Dibenzoylmethane (1,3-diphenylpropane-1,3-dione) derivatives are promising antitumor agents. In this study, we investigated the cytotoxic effect of 1,3-diphenyl-2-benzyl-1,3-propanedione (DPBP) on B16F10 melanoma cells as well as its direct interaction with the DNA molecule using optical tweezers. DPBP showed promising results against tumor cells and had a selectivity index of 41.94. Also, we demonstrated the ability of DPBP to interact directly with the DNA molecule. The fact that DPBP can interact with DNA in vitro allows us to hypothesize that such an interaction may also occur in vivo and, therefore, that DPBP may be an alternative to treat patients with drug-resistant melanomas. These findings can guide the development of new and more effective drugs. Published by Elsevier B.V.

USSR and Eastern Europe Scientific Abstracts, Biomedical and Behavioral Sciences, Number 84

DTIC Science & Technology

1977-12-28

36 Molecular Biology 4° Pharmacology ^2 Physiology • 46 Plant Biochemistry • 5^ Public Health. 56 Radiobiology ->9 Therapy 60...Tyagunenko) USSR UDC 615.332 (Oxycarminomycinum) SYNTHESIS OF II+-OXYCARMINOMYCIN AND STUDY OF ITS ANTINEOPLASTIC ACTIVITY Moscow ANTIBIOTIKI in...antineoplastic activity and toxicity as carminomycin. It suppressed tumor growth by 90% in doses that did not exceed the maximum tolerable (LD10). Figure 1

Assessment of new drugs in a tertiary hospital using a standardized tool.

PubMed

González-Bueno, J; Chamorro-de-Vega, E; Alfaro-Lara, E R; Galván-Banqueri, M; Santos-Ramos, B

2013-01-01

To describe the profile of new drugs evaluated by the Pharmacy and Therapeutics committee in a tertiary hospital using a standardized tool, the Guideline for the Introduction of New Drugs in the Formulary (GINF form), as main objective. Retrospective observational study of drugs was assessed during 2008-2011. Variables related to the drug, the request, and the result of the evaluation were collected based on information contained in the GINF form and in the assessment reports. 63 of 75 assessed drugs (84%) were included in the hospital formulary. Only one drug (1%) was included without any restrictions. The rest of them were included as therapeutic equivalents (23%) or under specific recommendations (61%). Half of the drugs (6) not included had insufficient evidence of effectiveness compared with current treatments. Haematology and Medical Oncology were found to be the most active medical services in the application process. There was a high prevalence of drugs that had more than one advanced clinical trial (phase III and/or phase IV). Furthermore, 28% of assessed drugs were associated with a financial burden of more than ?10,000 per year for our hospital. Highquality information was provided by applicants to the P&T committee for drugs that were finally included. However, the relationship between the information provided to the P&T committee and its decision was not statistical significance. The requests received were primarily related to drugs intended for parenteral use and most of them were antineoplastic drugs. The medical departments most heavily represented were Haematology and Oncology. Copyright © 2013 SEFH. Published by AULA MEDICA. All rights reserved.

Equitable Prices of Single-Source Drugs in Thailand.

PubMed

Ngorsuraches, Surachat; Chaiyakan, Kanokkan

2015-08-01

In Thailand, total drug expenditure has grown rapidly. Recently, the Thai government has addressed the issue of drug pricing, but the prices of single-source drugs remain a major challenge. To examine equitable prices of single-source drugs in Thailand. A total of 98 single-source and high-expenditure drugs were examined. Unit prices from the Drug and Medical Supplies Information Center (DMSIC) and National Average Drug Acquisition Cost (NADAC) were used to represent drug prices at the provider level in Thailand and the U.S., respectively. Data for measuring drug affordability, e.g., dose and poverty line, were obtained from Micromedex online and the National Statistical Office (NSO). The U.S. drug prices were adjusted by the Human Development Index (HDI) to be equitable prices for Thailand. Purchasing Power Parity (PPP) was used to convert US currency into Thai baht. All prices in this study were based on the year 2012. Catastrophic, Impoverishment, and WHO/Health Action International (HAI) approaches were used to determine Thai citizens' ability to afford the study drugs. Finally, uncertainty analyses were conducted. From all study drugs, 55 single-source drugs were priced higher than their equitable prices, ranging from 0.38 to 422.36% higher. Among these, 28 items were antineoplastic drugs. The prices of drugs outside the National List of Essential Medicines (NLEM), as well as the country's newer drugs, tended to be higher than their calculated equitable prices. The majority of drugs in Thailand priced higher than equitable prices were unaffordable for most Thai citizens. The uncertainty analyses revealed that almost all results were relatively robust. Most single-source drug prices in Thailand were higher than their equitable prices, and were likely to be unaffordable to Thai citizens.

Obesity: an endocrine tumor?

PubMed

Dizdar, Omer; Alyamaç, Evrim

2004-01-01

Obesity is one of the most common disorders in clinical practice. The prevalance of obesity has increased by more than 60% since 1990. Adipose tissue acts as an endocrine organ secreting many factors into the blood, known as adipokines, including leptin, adipsin, acylation-stimulating protein, adiponectin, etc. This article examines the hypothesis that obesity may be evaluated as an endocrine tumor, regarding its genetic basis, hyperplasia and hypertrophy of adipocytes, neovascularisation within the adipose tissue associated with growth, and beneficisal metabolic effects of surgical removal of excess adipose tissue by liposuction. Assuming obesity as an endocrine tumor may bring out new treatment modalities. Liposuction as "cytoreductive surgery", antiangiogenic teraphy or anti-neoplastic drugs may be important components of obesity treatment in future.

Design, synthesis and biological evaluation of bisthiazole-based trifluoromethyl ketone derivatives as potent HDAC inhibitors with improved cellular efficacy.

PubMed

Gong, Chao-Jun; Gao, An-Hui; Zhang, Yang-Ming; Su, Ming-Bo; Chen, Fei; Sheng, Li; Zhou, Yu-Bo; Li, Jing-Ya; Li, Jia; Nan, Fa-Jun

2016-04-13

Histone deacetylases (HDACs) are a class of epigenetic modulators with complex functions in histone post-translational modifications and are well known targets for antineoplastic drugs. We have previously developed a series of bisthiazole-based hydroxamic acids as novel potent HDAC inhibitors. In the present work, a new series of bisthiazole-based compounds with different zinc binding groups (ZBGs) have been designed and synthesized. Among them is compound 7, containing a trifluoromethyl ketone as the ZBG, which displays potent inhibitory activity towards human HDACs and improved antiproliferative activity in several cancer cell lines. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

An empirical analysis of primary and secondary pharmaceutical patents in Chile.

PubMed

Abud, María José; Hall, Bronwyn; Helmers, Christian

2015-01-01

We analyze the patent filing strategies of foreign pharmaceutical companies in Chile distinguishing between "primary" (active ingredient) and "secondary" patents (patents on modified compounds, formulations, dosages, particular medical uses, etc.). There is prior evidence that secondary patents are used by pharmaceutical originator companies in the U.S. and Europe to extend patent protection on drugs in length and breadth. Using a novel dataset that comprises all drugs registered in Chile between 1991 and 2010 as well as the corresponding patents and trademarks, we find evidence that foreign originator companies pursue similar strategies in Chile. We find a primary to secondary patents ratio of 1:4 at the drug-level, which is comparable to the available evidence for Europe; most secondary patents are filed over several years following the original primary patent and after the protected active ingredient has obtained market approval in Chile. This points toward effective patent term extensions through secondary patents. Secondary patents dominate "older" therapeutic classes like anti-ulcer and anti-depressants. In contrast, newer areas like anti-virals and anti-neoplastics (anti-cancer) have a much larger share of primary patents.

Cationic Albumin Nanoparticles for Enhanced Drug Delivery to Treat Breast Cancer: Preparation and In Vitro Assessment

PubMed Central

Abbasi, Sana; Paul, Arghya; Shao, Wei; Prakash, Satya

2012-01-01

Most anticancer drugs are greatly limited by the serious side effects that they cause. Doxorubicin (DOX) is an antineoplastic agent, commonly used against breast cancer. However, it may lead to irreversible cardiotoxicity, which could even result in congestive heart failure. In order to avoid these harmful side effects to the patients and to improve the therapeutic efficacy of doxorubicin, we developed DOX-loaded polyethylenimine- (PEI-) enhanced human serum albumin (HSA) nanoparticles. The formed nanoparticles were ~137 nm in size with a surface zeta potential of ~+15 mV, prepared using 20 μg of PEI added per mg of HSA. Cytotoxicity was not observed with empty PEI-enhanced HSA nanoparticles, formed with low-molecular weight (25 kDa) PEI, indicating biocompatibility and safety of the nanoparticle formulation. Under optimized transfection conditions, approximately 80% of cells were transfected with HSA nanoparticles containing tetramethylrhodamine-conjugated bovine serum albumin. Conclusively, PEI-enhanced HSA nanoparticles show potential for developing into an effective carrier for anticancer drugs. PMID:22187654

Nanostructured delivery system for Suberoylanilide hydroxamic acid against lung cancer cells.

PubMed

Sankar, Renu; Karthik, Selvaraju; Subramanian, Natesan; Krishnaswami, Venkateshwaran; Sonnemann, Jürgen; Ravikumar, Vilwanathan

2015-06-01

With the objective to provide a potential approach for the treatment of lung cancer, nanotechnology based Suberoylanilide hydroxamic acid (SAHA)-loaded Poly-d, l-lactide-co glycolide (PLGA) nanoparticles have been formulated using the nanoprecipitation technique. The acquired nanoparticles were characterized by various throughput techniques and the analyses showed the presence of smooth and spherical shaped SAHA-loaded PLGA nanoparticles, with an encapsulation efficiency of 44.8% and a particle size of 208nm. The compatibility between polymer and drug in the formulation was tested using FT-IR, Micro-Raman spectrum and DSC thermogram analyses, revealing a major interaction between the drug and polymer. The in vitro drug release from the SAHA-loaded PLGA nanoparticles was found to be biphasic with an initial burst followed by a sustained release for up to 50h. In experiments using the lung cancer cell line A549, SAHA-loaded PLGA nanoparticles demonstrated a superior antineoplastic activity over free SAHA. In conclusion, SAHA-loaded PLGA nanoparticles may be a useful novel approach for the treatment of lung cancer. Copyright © 2015. Published by Elsevier B.V.

Nanoengineered mesoporous silica nanoparticles for smart delivery of doxorubicin

NASA Astrophysics Data System (ADS)

Mishra, Akhilesh Kumar; Pandey, Himanshu; Agarwal, Vishnu; Ramteke, Pramod W.; Pandey, Avinash C.

2014-08-01

The motive of the at hand exploration was to contrive a proficient innovative pH-responsive nanocarrier designed for an anti-neoplastic agent that not only owns competent loading capacity but also talented to liberate the drug at the specific site. pH sensitive hollow mesoporous silica nanoparticles ( MSN) have been synthesized by sequence of chemical reconstruction with an average particle size of 120 nm. MSN reveal noteworthy biocompatibility and efficient drug loading magnitude. Active molecules such as Doxorubicin (DOX) can be stocked and set free from the pore vacuities of MSN by tuning the pH of the medium. The loading extent of MSN was found up to 81.4 wt% at pH 7.8. At mild acidic pH, DOX is steadily released from the pores of MSN. Both, the nitrogen adsorption-desorption isotherms and X-ray diffraction patterns reflects that this system holds remarkable stable mesostructure. Additionally, the outcomes of cytotoxicity assessment further establish the potential of MSN as a relevant drug transporter which can be thought over an appealing choice to a polymeric delivery system.

Multifunctional Enveloped Mesoporous Silica Nanoparticles for Subcellular Co-delivery of Drug and Therapeutic Peptide

PubMed Central

Luo, Guo-Feng; Chen, Wei-Hai; Liu, Yun; Lei, Qi; Zhuo, Ren-Xi; Zhang, Xian-Zheng

2014-01-01

A multifunctional enveloped nanodevice based on mesoporous silica nanoparticle (MSN) was delicately designed for subcellular co-delivery of drug and therapeutic peptide to tumor cells. Mesoporous silica MCM-41 nanoparticles were used as the core for loading antineoplastic drug topotecan (TPT). The surface of nanoparticles was decorated with mitochondria-targeted therapeutic agent (Tpep) containing triphenylphosphonium (TPP) and antibiotic peptide (KLAKLAK)2 via disulfide linkage, followed by coating with a charge reversal polyanion poly(ethylene glycol)-blocked-2,3-dimethylmaleic anhydride-modified poly(L-lysine) (PEG-PLL(DMA)) via electrostatic interaction. It was found that the outer shielding layer could be removed at acidic tumor microenvironment due to the degradation of DMA blocks and the cellular uptake was significantly enhanced by the formation of cationic nanoparticles. After endocytosis, due to the cleavage of disulfide bonds in the presence of intracellular glutathione (GSH), pharmacological agents (Tpep and TPT) could be released from the nanoparticles and subsequently induce specific damage of tumor cell mitochondria and nucleus respectively with remarkable synergistic antitumor effect. PMID:25317538

Roles of dextrans on improving lymphatic drainage for liposomal drug delivery system.

PubMed

Feng, Linglin; Zhang, Lei; Liu, Min; Yan, Zhiqiang; Wang, Chenyu; Gu, Bing; Liu, Yu; Wei, Gang; Zhong, Gaoren; Lu, Weiyue

2010-04-01

Our aim was to develop a novel liposomal drug delivery system containing dextrans to reduce undesirable retention of antineoplastic agents and thus alleviate local tissue damage. At the cell level, diethylaminoethyl-dextran (DEAE-Dx) showed the strongest inhibiting effect on liposome uptake by macrophages among tested dextrans. The distribution of radiolabeled liposomes mixed with dextrans in injection site and draining lymph node was investigated in rats after subcutaneous injection. DEAE-Dx substantially reduced the undesired local retention and promoted the draining of liposome into lymphatics, which was further confirmed by confocal microscopy images revealing the substantial prevention of rhodamine B-labelled liposome sequestration by macrophages in normal lymph node in rats. Pharmacokinetic data indicated the accelerated drainage of liposome through lymphatics back to systemic circulation by mixing with DEAE-Dx. In the toxicological study in rabbits, DEAE-Dx alleviated the local tissue damage caused by liposomal doxorubicin. In conclusion, dextrans, particularly DEAE-Dx, could efficiently enhanced liposomes drainage into lymphatics, which proves themselves as promising adjuvants for lymphatic-targeted liposomal drug delivery system.

Recent Progress on C-4-Modified Podophyllotoxin Analogs as Potent Antitumor Agents

PubMed Central

Liu, Ying-Qian; Tian, Jing; Qian, Keduo; Zhao, Xiao-Bo; Morris-Natschke, Susan L.; Yang, Liu; Nan, Xiang; Tian, Xuan; Lee, Kuo-Hsiung

2015-01-01

Podophyllotoxin (PPT), as well as its congeners and derivatives, exhibits pronounced biological activities, especially antineoplastic effects. Its strong inhibitory effect on tumor cell growth led to the development of three of the most highly prescribed anticancer drugs in the world, etoposide, teniposide, and the water-soluble prodrug etoposide phosphate. Their clinical success as well as intriguing mechanism of action stimulated great interest in further modification of PPT for better antitumor activity. The C-4 position has been a major target for structural derivatization aimed at either producing more potent compounds or overcoming drug resistance. Accordingly, numerous PPT derivatives have been prepared via hemisynthesis and important structure–activity relationship (SAR) correlations have been identified. Several resulting compounds, including GL-331, TOP-53, and NK611, reached clinical trials. Some excellent reviews on the distribution, sources, applications, synthesis, and SAR of PPT have been published. This review focuses on a second generation of new etoposide-related drugs and provides detailed coverage of the current status and recent development of C-4-modified PPT analogs as anticancer clinical trial candidates. PMID:24827545

The JAK2/STAT5 signaling pathway as a potential therapeutic target in canine mastocytoma

PubMed Central

Keller, Alexandra; Wingelhofer, Bettina; Peter, Barbara; Bauer, Karin; Berger, Daniela; Gamperl, Susanne; Reifinger, Martin; Cerny-Reiterer, Sabine; Moriggl, Richard; Willmann, Michael; Valent, Peter; Hadzijusufovic, Emir

2018-01-01

Background Mastocytoma are frequently diagnosed cutaneous neoplasms in dogs. In non-resectable mastocytoma patients, novel targeted drugs are often applied. The transcription factor STAT5 has been implicated in the survival of human neoplastic mast cells (MC). Our study evaluated the JAK2/STAT5 pathway as a novel target in canine mastocytoma. Materials and Methods We employed inhibitors of JAK2 (R763, TG101348, AZD1480, ruxolitinib) and STAT5 (pimozide, piceatannol) and evaluated their effects on 2 mastocytoma cell lines, C2 and NI-1. Results Activated JAK2 and STAT5 were detected in both cell lines. The drugs applied were found to inhibit proliferation and survival in these cells with the following rank-order of potency: R763 > TG101348 > AZD1480 > pimozide > ruxolitinib > piceatannol. Moreover, synergistic anti-neoplastic effects were obtained by combining pimozide with KIT-targeting drugs (toceranib, masitinib, nilotinib, midostaurin) in NI-1 cells. Conclusion The JAK2/STAT5 pathway is a novel potential target of therapy in canine mastocytoma. PMID:28397975

Venetoclax (ABT-199) Might Act as a Perpetrator in Pharmacokinetic Drug–Drug Interactions

PubMed Central

Weiss, Johanna; Gajek, Thomas; Köhler, Bruno Christian; Haefeli, Walter Emil

2016-01-01

Venetoclax (ABT-199) represents a specific B-cell lymphoma 2 (Bcl-2) inhibitor that is currently under development for the treatment of lymphoid malignancies. So far, there is no published information on its interaction potential with important drug metabolizing enzymes and drug transporters, or its efficacy in multidrug resistant (MDR) cells. We therefore scrutinized its drug–drug interaction potential in vitro. Inhibition of cytochrome P450 enzymes (CYPs) was quantified by commercial kits. Inhibition of drug transporters (P-glycoprotein (P-gp, ABCB1), breast cancer resistance protein (BCRP), and organic anion transporting polypeptides (OATPs)) was evaluated by the use of fluorescent probe substrates. Induction of drug transporters and drug metabolizing enzymes was quantified by real-time RT-PCR. The efficacy of venetoclax in MDR cells lines was evaluated with proliferation assays. Venetoclax moderately inhibited P-gp, BCRP, OATP1B1, OATP1B3, CYP3A4, and CYP2C19, whereas CYP2B6 activity was increased. Venetoclax induced the mRNA expression of CYP1A1, CYP1A2, UGT1A3, and UGT1A9. In contrast, expression of ABCB1 was suppressed, which might revert tumor resistance towards antineoplastic P-gp substrates. P-gp over-expression led to reduced antiproliferative effects of venetoclax. Effective concentrations for inhibition and induction lay in the range of maximum plasma concentrations of venetoclax, indicating that it might act as a perpetrator drug in pharmacokinetic drug–drug interactions. PMID:26927160

Impact of the new handling recommendations for hazardous drugs in a hospital pharmacy service.

PubMed

García-Alcántara, Beatriz G; Perelló Alomar, Catalina; Moreno Centeno, Elena; Modamio, Pilar; Mariño, Eduardo L; Delgado Sánchez, Olga

2017-03-01

To describe the actions taken by the Pharmacy Unit in a tertiary hospital in order to adapt to the recommendations established by NIOSH 2014 for handling Hazardous Drugs. Method: A retrospective observational study. A list was prepared including all hazardous drugs according to NIOSH 2014 that were available at the hospital as marketed or foreign drugs, or used in clinical trials, and there was a review of the processes of acquisition, repackaging, preparation, circuits, organizational, dispensing and identification. Results: After the analysis, a report including all needs was prepared and sent to the Hospital Management. Any relevant information about the handling and administration of hazardous drugs was included in the prescription computer program. There were changes in the acquisition process of two drugs, in order to avoid splitting and multi-dose formulations. An alternative or improvement was found for 35 253 of the 75 779 units of hazardous drugs repackaged in one year. The Pharmacy Unit took over the preparation of four non-sterile medications, as well as the preparation of all sterile parenteral medications included in Lists 1 and 2 that were not previously prepared there, as well as one from List 3. Information was also included about the preparation processes of Magistral Formulations that involved hazardous drugs from Lists 2 or 3. The adaptation to the recommendations by NIOSH 2014 has represented a change, but also a significant reduction in the handling process of hazardous drugs by the healthcare staff, therefore reducing the risk of occupational exposure. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

Repositioning approved drugs for the treatment of problematic cancers using a screening approach

PubMed Central

Kuttler, Fabien; Banfi, Damiano; Turcatti, Gerardo; Dyson, Paul J.

2017-01-01

Advances in treatment strategies together with an earlier diagnosis have considerably increased the average survival of cancer patients over the last four decades. Nevertheless, despite the growing number of new antineoplastic agents introduced each year, there is still no adequate therapy for problematic malignancies such as pancreatic, lung and stomach cancers. Consequently, it is important to ensure that existing drugs used to treat other types of cancers, and potentially other diseases, are not overlooked when searching for new chemotherapy regimens for these problematic cancer types. We describe a screening approach that identifies chemotherapeutics for the treatment of lung and pancreatic cancers, based on drugs already approved for other applications. Initially, the 1280 chemically and pharmacologically diverse compounds from the Prestwick Chemical Library® (PCL) were screened against A549 (lung cancer) and PANC-1 (pancreatic carcinoma) cells using the PrestoBlue fluorescent-based cell viability assay. More than 100 compounds from the PCL were identified as hits in one or both cell lines (80 of them, being drugs used to treat diseases other than cancer). Selected PCL hits were further evaluated in a dose-response manner. Promising candidates for repositioning emanating from this study include antiparasitics, cardiac glycosides, as well as the anticancer drugs vorinostat and topotecan. PMID:28166232

The Role of Therapeutic Drugs on Acquired Mitochondrial Toxicity.

PubMed

Morén, Constanza; Juárez-Flores, Diana Luz; Cardellach, Francesc; Garrabou, Glòria

2016-01-01

Certain therapeutic drugs used in medical practice may trigger mitochondrial toxicity leading to a wide range of clinical symptoms including deafness, neuropathy, myopathy, hyperlactatemia, lactic acidosis, pancreatitis and lipodystrophy, among others, which could even compromise the life of the patient. The aim of this work is to review the potential mitochondrial toxicity derived from drugs used in health care, including anesthetics, antiepileptics, neuroleptics, antidepressants, antivirals, antibiotics, antifungals, antimalarics, antineoplastics, antidiabetics, hypolipemiants, antiarrhythmics, anti-inflammatories and nitric oxide. We herein have reviewed data from experimental and clinical studies to document the molecular mitochondrial basis, potential biomarkers and putative clinical symptoms associated to secondary effects of drugs. One hundred and forty-five articles were selected and the information was organized by means of the primary target to which pharmacologic drugs were directed. Adverse toxic events were classified depending on the mitochondrial offtarget effect and whether they had been demonstrated in the experimental or clinical setting. Since treatment of acquired mitochondriopathies remains supportive and therapeutic interventions cannot be avoided, information of molecular and clinical consequences of toxic exposure becomes fundamental to assess riskbenefit imbalance of treatment prescription. Additionally, there is a crucial need to develop less mitochondrial toxic compounds, novel biomarkers to follow up mitochondrial toxicity (or implement those already proposed) and new approaches to prevent or revert unintended mitochondrial damage.

Statistical evaluation for stability studies under stress storage conditions.

PubMed

Gil-Alegre, M E; Bernabeu, J A; Camacho, M A; Torres-Suarez, A I

2001-11-01

During the pharmaceutical development of a new drug, it is necessary to select as soon as possible the formulation with the best stability characteristics. The current International Commission for Harmonisation (ICH) regulations regarding stability testing requirements for a Registration Application provide the stress testing conditions with the aim of assessing the effect of severe conditions on the drug product. In practice, the well-known Arrhenius theory is still used to make a rapid stability prediction, to estimate a drug product shelf life during early stages of its pharmaceutical development. In this work, both the planning of a stress stability study to obtain a correct stability prediction from a temperature extrapolation and the suitable data treatment to discern the reliability of the stability results are discussed. The study was focused on the early formulation step of a very stable drug, Mitonafide (antineoplastic agent), formulated in a parenteral solution and in tablets. It was observed, for the solid system, that the extrapolated results using Arrhenius theory might be statistically good, but far from the real situation if the stability study is not designed in a correct way. The statistical data treatment and the stress-stability test proposed in this work are suitable to make a reliable stability prediction of different formulations with the same drug, within its pharmaceutical development.

E phage gene transfection associated to chemotherapeutic agents increases apoptosis in lung and colon cancer cells.

PubMed

Rama, Ana R; Prados, Jose; Melguizo, Consolacion; Alvarez, Pablo J; Ortiz, Raúl; Madeddu, Roberto; Aranega, Antonia

2011-01-01

The limited ability of conventional therapies to achieve the long-term survival of metastatic lung and colon cancer patients suggests the need for new treatment options. In this respect, genes encoding cytotoxic proteins have been proposed as a new strategy to enhance the activity of drugs, and combined therapies involving such genes and classical antitumoral drugs have been studied intensively. The E gene from phiX174 encodes a membrane protein with a toxic domain that leads to a decrease in tumour cell growth rates. Therefore, in order to improve the anti-tumour effects of currently used chemotherapeutic drugs on cancer cells, we investigated the association of the E suicide gene with these antineoplastic drugs. The E gene has antitumoral effects in both lung and colon cancer cells. In addition, expression of this gene induces ultrastructural changes in lung cancer transfected cells (A-549), although the significance of these changes remains unknown. The effect of combined therapy (gene and cytotoxic therapy) enhances the inhibition of tumour cell proliferation in comparison to single treatments. Indeed, our in vitro results indicate that an experimental therapeutic strategy based on this combination of E gene therapy and cytotoxic drugs may result in a new treatment strategy for patients with advanced lung and colon cancer.

Comparison of new nitrosoureas esters with modified steroidal nucleus for cytogenetic and antineoplastic activity.

PubMed

Hussein, A; Mioglou-Kalouptsi, E; Papageorgiou, A; Karapidaki, I; Iakovidou-Kritsi, Z; Lialiaris, T; Xrysogelou, E; Camoutsis, C; Mourelatos, D

2007-01-01

Nitrosourea is decomposed under physiological conditions to react with biological macromolecules by two mechanisms: alkylation (with proteins and nucleic acids) and carbamoylation (with proteins but not nucleic acids). It has been suggested that the alkylating action is responsible for the therapeutic effects of nitrosoureas, and that the carbamoylation activity leads to toxicity effects. In order to reduce systemic toxicity and improve specificity and distribution for cancer therapy, 2-haloethyl nitrosourea has been esterified with modified steroids, which are used as biological platforms for transporting the alkylating agent to the tumor site in a specific manner. The cytogenetic and antineoplastic effect were studied of seven newly synthesized esters of N,N-bis(2-chloroethyl)alanyl carboxyl derivatives with a modified steroidal nucleus (compounds 1-7). As a very sensitive indicator of genotoxicity the Sister Chromatid Exchange (SCE) assay was used and as a valuable marker of cytostatic activity the cell Proliferation Rate Index (PRI) in cultures of normal human lymphocytes was used. The order of magnitude of the cytogenetic activity on a molar basis (15, 30, 120 microM) of the compounds was 7>6>3>5>2>4>1. The most active compound 7 has an enlarged (seven carbon atoms) A ring modified with a lactam group (-NHCO-) with the nitrosourea moiety esterified at position 17 In the group of seven substances a correlation was observed between the magnitude of SCE response and the depression in PRI (r=-O, 65, p<0.001). According to the criterion of activity of National Cancer Institute (NCI), the order of antineoplastic activity of compounds on lymphoid L1210 leukemia is 7>6>2>5>4>3>1 and on lympocytic P388 leukemia cells is 7>2>6>5>4>3>1. The present results are in agreement with previous suggestions that the effectiveness in cytogenetic activity may well be correlated with antitumor effects [T/C: 248% for the compound 7 in 250 mg/kg b.w.; T/C: mean survival time of drug-treated animals (T) (excluding long term survivals) vs. corn-oil-treated controls (C)].

Projecting future drug expenditures in U.S. nonfederal hospitals and clinics--2013.

PubMed

Hoffman, James M; Li, Edward; Doloresco, Fred; Matusiak, Linda; Hunkler, Robert J; Shah, Nilay D; Vermeulen, Lee C; Schumock, Glen T

2013-03-15

Factors likely to influence drug expenditures, drug expenditure trends in 2012, and projected drug expenditures for U.S. nonfederal hospitals and clinics in 2013 are discussed. Prescription drug expenditure data for 2011 through September 2012 were obtained from the IMS Health National Sales Perspectives database. Expenditure projections were based on a combination of quantitative and qualitative analyses, combined with expert opinion. Total prescription sales in the United States for the 12-month period ending September 2012 were $326.0 billion, a 0.8% increase from the previous 12 months. This rate of growth was the lowest in recent history and can be attributed to modest increases in expenditures for new products (3.3%) and the prices of existing products (5.9%), coupled with a marked decline in overall volume and mix (-8.4%). For the 9 months ending in September 2012, total prescription expenditures grew 2.7% when compared with the same period in 2011. Oncology products remained important expenditures for hospitals and clinics. Antineoplastic agents were the top medication class for expenditures in nonfederal hospitals, and oncology products accounted for 32.2% of drug expenditures in the clinic setting in the first 9 months of 2012. For 2013, we project a 1-3% increase in total drug expenditures across all settings, a 2-4% increase in expenditures for clinic-administered drugs, and a 0.5% decline to 1.5% increase in hospital drug expenditures. Health-system pharmacy leaders should carefully examine their own local drug-utilization patterns to determine their own organization's drug expenditure forecast.

How do drug users define their progress in harm reduction programs? Qualitative research to develop user-generated outcomes

PubMed Central

Ruefli, Terry; Rogers, Susan J

2004-01-01

Background Harm reduction is a relatively new and controversial model for treating drug users, with little formal research on its operation and effectiveness. In order to advance the study of harm reduction programs and our understanding of how drug users define their progress, qualitative research was conducted to develop outcomes of harm reduction programming that are culturally relevant, incremental, (i.e., capable of measuring change), and hierarchical (i.e., capable of showing how clients improve over time). Methods The study used nominal group technique (NGT) to develop the outcomes (phase 1) and focus group interviews to help validate the findings (phase 2). Study participants were recruited from a large harm-reduction program in New York City and involved approximately 120 clients in 10 groups in phase 1 and 120 clients in 10 focus groups in phase 2. Results Outcomes of 10 life areas important to drug users were developed that included between 10 to 15 incremental measures per outcome. The outcomes included ways of 1) making money; 2) getting something good to eat; 3) being housed/homeless; 4) relating to families; 5) getting needed programs/benefits/services; 6) handling health problems; 7) handling negative emotions; 8) handling legal problems; 9) improving oneself; and 10) handling drug-use problems. Findings also provided insights into drug users' lives and values, as well as a window into understanding how this population envisions a better quality of life. Results challenged traditional ways of measuring drug users based solely on quantity used and frequency of use. They suggest that more appropriate measures are based on the extent to which drug users organize their lives around drug use and how much drug use is integrated into their lives and negatively impacts other aspects of their lives. Conclusions Harm reduction and other programs serving active drug users and other marginalized people should not rely on institutionalized, provider-defined solutions to problems in living faced by their clients. PMID:15333130

Targeting Brain Tumors with Nanomedicines: Overcoming Challenges of Blood Brain Barrier.

PubMed

Ningaraj, Nagendra S; Reddy, Polluru L; Khaitan, Divya

2018-04-12

This review elucidates ongoing research, which show improved delivery of anticancer drugs alone and/ or enclosed in carriers collectively called nanomedicines to cross the Blood brain barrier (BBB) / blood-brain tumor barrier (BTB) to kill tumor cells and impact patient survival. We highlighted various advances in understanding the mechanism of BTB function that impact on anticancer therapeutics delivery. We discussed latest breakthroughs in developing pharmaceutical strategies, including nanomedicines and delivering them across BTB for brain tumor management and treatment. We highlight various studies on regulation of BTB permeability regulation with respect to nanotech-based nanomedicines for targeted treatment of brain tumors. We have reviewed latest literature on development of specialized molecules and nanospheres for carrying pay load of anticancer agents to brain tumor cells across the BBB/ BTB and avoid drug efflux systems. We discuss identification and development of distinctive BTB biomarkers for targeted anti-cancer drug delivery to brain tumors. In addition, we discussed nanomedicines and multimeric molecular therapeutics that were encapsulated in nanospheres for treatment and monitoring of brain tumors. In this context, we highlight our research on calcium-activated potassium channels (KCa) and ATP-sensitive potassium channels (KATP) as portals of enhanced antineoplastic drugs delivery. This review might interest both academic and drug company scientists involved in drug delivery to brain tumors. We further seek to present evidence that BTB modulators can be clinically developed as combination drug or/ and as stand-alone anticancer drugs. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Nanoparticle strategies for cancer therapeutics: Nucleic acids, polyamines, bovine serum amine oxidase and iron oxide nanoparticles (Review).

PubMed

Agostinelli, Enzo; Vianello, Fabio; Magliulo, Giuseppe; Thomas, Thresia; Thomas, T J

2015-01-01

Nanotechnology for cancer gene therapy is an emerging field. Nucleic acids, polyamine analogues and cytotoxic products of polyamine oxidation, generated in situ by an enzyme-catalyzed reaction, can be developed for nanotechnology-based cancer therapeutics with reduced systemic toxicity and improved therapeutic efficacy. Nucleic acid-based gene therapy approaches depend on the compaction of DNA/RNA to nanoparticles and polyamine analogues are excellent agents for the condensation of nucleic acids to nanoparticles. Polyamines and amine oxidases are found in higher levels in tumours compared to that of normal tissues. Therefore, the metabolism of polyamines spermidine and spermine, and their diamine precursor, putrescine, can be targets for antineoplastic therapy since these naturally occurring alkylamines are essential for normal mammalian cell growth. Intracellular polyamine concentrations are maintained at a cell type-specific set point through the coordinated and highly regulated interplay between biosynthesis, transport, and catabolism. In particular, polyamine catabolism involves copper-containing amine oxidases. Several studies showed an important role of these enzymes in developmental and disease-related processes in animals through the control of polyamine homeostasis in response to normal cellular signals, drug treatment, and environmental and/or cellular stress. The production of toxic aldehydes and reactive oxygen species (ROS), H2O2 in particular, by these oxidases suggests a mechanism by which amine oxidases can be exploited as antineoplastic drug targets. The combination of bovine serum amine oxidase (BSAO) and polyamines prevents tumour growth, particularly well if the enzyme has been conjugated with a biocompatible hydrogel polymer. The findings described herein suggest that enzymatically formed cytotoxic agents activate stress signal transduction pathways, leading to apoptotic cell death. Consequently, superparamagnetic nanoparticles or other advanced nanosystem based on directed nucleic acid assemblies, polyamine-induced DNA condensation, and bovine serum amine oxidase may be proposed for futuristic anticancer therapy utilizing nucleic acids, polyamines and BSAO. BSAO based nanoparticles can be employed for the generation of cytotoxic polyamine metabolites.

Global patterns of adverse drug reactions over a decade: analyses of spontaneous reports to VigiBase™.

PubMed

Aagaard, Lise; Strandell, Johanna; Melskens, Lars; Petersen, Paw S G; Holme Hansen, Ebba

2012-12-01

Although systems to collect information about suspected adverse drug reactions (ADRs) were established in many countries and by the WHO in the 1960s, few studies have examined reported ADRs related to national income. The aim of the study was to characterize ADRs reported to the WHO-ADR database, VigiBase™, and to relate data to national income. We analysed ADR reports submitted to VigiBase™ from 2000 to 2009 with respect to reporting rate, age and sex of patient, type, seriousness and medications. Reports were also analysed with respect to national income level, classified in accordance with the World Bank definition: low, lower-middle, upper-middle and high. We analysed 1,359,067 ADR reports including 3,013,074 ADRs. Overall, 16% of reports were serious and 60% were reported for females. High-income countries had the highest ADR reporting rates (range 3-613 reports/million inhabitants/year) and low-income countries the lowest (range 0-21). Distribution of ADRs across income groups with respect to age group, seriousness and sex was non-significant. Overall, the majority of ADRs were reported for nervous system medications, followed by cardiovascular medicines. Low-income countries reported relatively more ADRs for antiinfectives for systemic use than high-income countries, and high-income countries reported more ADRs for antineoplastic and immunomodulating agents than lower-income groups. This study showed that high-income countries had the highest ADR reporting rates and low-income countries the lowest, with large variations across countries in each group. Significant differences in ADR reporting rates were only found for ADRs of the type 'skin and subcutaneous tissue disorders' and for the therapeutic groups 'antiinfectives for systemic use' and 'antineoplastic and immunomodulation agents'. To strengthen ADR reporting rates, especially in low-income countries, more research is needed about the impact of organizational structures and economic resources of national pharmacovigilance centres and ADR reporting practices on the large variations in ADR reporting rates within income groups.

Apatinib (YN968D1) reverses multidrug resistance by inhibiting the efflux function of multiple ATP-binding cassette transporters

PubMed Central

Mi, Yan-jun; Liang, Yong-ju; Huang, Hong-bing; Zhao, Hong-yun; Wu, Chung-Pu; Wang, Fang; Tao, Li-yang; Zhang, Chuan-zhao; Dai, Chun-Ling; Tiwari, Amit K.; Ma, Xiao-xu; Wah To, Kenneth Kin; Ambudkar, Suresh V.; Chen, Zhe-Sheng; Fu, Li-wu

2010-01-01

Apatinib, a small-molecule multi-targeted tyrosine kinase inhibitor, is in phase III clinical trial for treatment of patients with non-small cell lung cancer and gastric cancer in China. In this study, we determined the effect of apatinib on the interaction of specific antineoplastic compounds with P-glycoprotein (P-gp, ABCB1), multidrug resistance protein 1 (MRP1, ABCC1) and breast cancer resistance protein (BCRP, ABCG2). Our results showed that apatinib significantly enhanced the cytotoxicity of ABCB1 or ABCG2 substrate drugs in KBv200, MCF-7/adr and HEK293/ABCB1 cells overexpressing ABCB1 and S1-M1-80, MCF-7/FLV1000 and HEK293/ABCG2-R2 cells overexpressing ABCG2 (wild-type). In contrast, apatinib did not alter the cytotoxicity of specific substrates in the parental cells and cells overexpressing ABCC1. Apatinib significantly increased the intracellular accumulation of rhodamine 123 and doxorubicin in the multidrug resistance (MDR) cells. Furthermore, apatinib significantly inhibited the photolabeling of both ABCB1 and ABCG2 with [125I]-iodoarylazidoprazosin in a concentration-dependent fashion. The ATPase activity of both ABCB1 and ABCG2 was significantly increased by apatinib. However, apatinib, at a concentration the produced a reversal of MDRl, did not significantly alter the expression of the ABCB1 or ABCG2 protein or mRNA levels or the phosphorylation of AKT and ERK1/2. Importantly, apatinib significantly enhanced the effect of paclitaxel against the ABCB1 resistant KBv200 cancer cell xenografts in nude mice. In conclusion, apatinib reverses ABCB1- and ABCG2-mediated MDR by inhibiting their transport function, but not by blocking AKT or ERK1/2 pathway or downregulating ABCB1 or ABCG2 expression. Apatinib may be useful in circumventing MDR to other conventional antineoplastic drugs. PMID:20876799

Preclinical development of G1T38: A novel, potent and selective inhibitor of cyclin dependent kinases 4/6 for use as an oral antineoplastic in patients with CDK4/6 sensitive tumors

PubMed Central

Jordan, Jamie L.; Darr, David D.; Roberts, Patrick J.; Tavares, Francis X.; Strum, Jay C.

2017-01-01

Inhibition of the p16INK4a/cyclin D/CDK4/6/RB pathway is an effective therapeutic strategy for the treatment of estrogen receptor positive (ER+) breast cancer. Although efficacious, current treatment regimens require a dosing holiday due to severe neutropenia potentially leading to an increased risk of infections, as well as tumor regrowth and emergence of drug resistance. Therefore, a next generation CDK4/6 inhibitor that can inhibit proliferation of CDK4/6-dependent tumors while minimizing neutropenia could reduce both the need for treatment holidays and the risk of inducing drug resistance. Here, we describe the preclinical characterization and development of G1T38; a novel, potent, selective, and orally bioavailable CDK4/6 inhibitor. In vitro, G1T38 decreased RB1 (RB) phosphorylation, caused a precise G1 arrest, and inhibited cell proliferation in a variety of CDK4/6-dependent tumorigenic cell lines including breast, melanoma, leukemia, and lymphoma cells. In vivo, G1T38 treatment led to equivalent or improved tumor efficacy compared to the first-in-class CDK4/6 inhibitor, palbociclib, in an ER+ breast cancer xenograft model. Furthermore, G1T38 accumulated in mouse xenograft tumors but not plasma, resulting in less inhibition of mouse myeloid progenitors than after palbociclib treatment. In larger mammals, this difference in pharmacokinetics allowed for 28 day continuous dosing of G1T38 in beagle dogs without producing severe neutropenia. These data demonstrate G1T38 has unique pharmacokinetic and pharmacodynamic properties, which result in high efficacy against CDK4/6 dependent tumors while minimizing the undesirable on-target bone marrow activity, thus potentially allowing G1T38 to be used as a continuous, daily oral antineoplastic agent. PMID:28418845

Free radicals generated by tantalum implants antagonize the cytotoxic effect of doxorubicin.

PubMed

Chen, Muwan; Hein, San; Le, Dang Q S; Feng, Wenzhou; Foss, Morten; Kjems, Jørgen; Besenbacher, Flemming; Zou, Xuenong; Bünger, Cody

2013-05-01

Little is known about the interaction between antineoplastic drugs and implants in bone cancer patients. We investigated the interaction between commercially available porous tantalum (Ta) implants and the chemotherapeutic drug, Doxorubicin (DOX). DOX solutions were prepared in the presence of Ta implant. The changes in fluorescence intensity of the DOX chromophore were measured by spectrofluorometry and the efficacy of DOX was evaluated by viability of rabbit rectal tumor cells (VX2). After 5 min interaction of the DOX solution (5 μg/ml) with the Ta implant, the fluorescent intensity of the DOX solution was 85% degraded, and only 20% the drug efficacy to kill VX2 cells was retained. However, after adding a reducing agent, Dithiothreitol (DTT, 10 μg/ml), 80% of the original fluorescence and 50% of the drug efficacy were restored while UV irradiation enhanced drug degradation in the presence of Ta implant. The action of DTT and UV irradiation indicated that reactive oxygen species (ROS) were involved in the drug degradation mechanism. We detected that Ta implants in aqueous medium produced hydroxyl radicals. Cells showed higher intracellular ROS activity when culture medium was incubated with the Ta implant prior to cell culture. It is concluded that the porous Ta implant antagonizes the cytotoxicity of DOX via ROS generation of the porous Ta implant. Copyright © 2013 Elsevier B.V. All rights reserved.

[Analysis of prescriptions associated to hormone replacement therapy in Midi-Pyrénées region].

PubMed

Gass-Jégu, Florence; Damase-Michel, Christine; Hurault-Delarue, Caroline; Bourrel, Robert; Montastruc, Jean-Louis

2012-01-01

The aim of the present study was 1- to describe hormone replacement therapy (HRT) prescription in Midi-Pyrénées region (South West France) and 2- to compare the prescriptions of associated drugs to those of women who took HRT with prescriptions to women who did not take HRT. From 2004 to 2008, HRT prescription decreased for women aged 50 to 59 years in Midi-Pyrénées: 13.95% to 10.33% estradiol/progestin association consumers. During the first 6 months of 2008, 20,161 women took the association estradiol/progestin. Transdermal/percutaneous forms of estradiol (71.21%) and natural progesterone were mainly prescribed. The number of different dispensed drugs was significantly higher in the HRT group: 5.18 versus 2.82 in the control group (p < 0.0001). All classes were concerned except antineoplastic drugs and immunomodulators, drugs for diabetes and raloxifene which were more prescribed to controls. In the period of the study, 7,035 patients took estrogen alone (25.87% of HRT consumers). The same phenomena were observed in this group. Women exposed to HRT in Midi-Pyrénées, great consumers of drugs, represent a population who require particular medical supervision, because of the risks of HRT and pathologies and/or numerous associated drugs. © 2012 Société Française de Pharmacologie et de Thérapeutique.

Anacardic acid enhances the anticancer activity of liposomal mitoxantrone towards melanoma cell lines – in vitro studies

PubMed Central

Legut, Mateusz; Lipka, Dominik; Filipczak, Nina; Piwoni, Adriana; Kozubek, Arkadiusz; Gubernator, Jerzy

2014-01-01

This paper describes a novel formulation of antineoplastic drug: mitoxantrone loaded into liposomal carriers enriched with encapsulated anacardic acid in the liposomal bilayer using a vitamin C gradient. Anacardic acid is a potent epigenetic agent with anticancer activity. This is the first liposomal formulation to combine an actively encapsulated drug and anacardic acid. The liposomes were characterized in terms of basic parameters, such as size, zeta potential, optimal drug-to-lipid ratio, loading time and temperature, and stability at 4°C and in human plasma in vitro. The formulation was found to be stable, and the loading process was rapid and efficient (drug-to-lipid ratio of up to 0.3 with over 90% efficiency in 5 minutes). The cytotoxicity of these formulations was assessed using the human melanoma cell lines A375 and Hs294T and the normal human dermal fibroblast line. The results showed that anacardic acid and to a smaller extent vitamin C significantly increased the cytotoxicity of the drug towards melanoma compared to ammonium sulfate liposomes. On the other hand, vitamin C and anacardic acid both protected normal cells from damage caused by the drug. The formulation combining anacardic acid, vitamin C, and mitoxantrone showed promising results in terms of cytotoxicity and cytoprotection. Therefore, it has potential for anticancer treatment. PMID:24489469

Nanomedicine to Deal With Cancer Cell Biology in Multi-Drug Resistance.

PubMed

Tekchandani, Pawan; Kurmi, Balak Das; Paliwal, Shivani Rai

2017-01-01

Today Cancer still remains a major cause of mortality and death worldwide, in humans. Chemotherapy, a key treatment strategy in cancer, has significant hurdles such as the occurrence of chemoresistance in cancer, which is inherent unresponsiveness or acquired upon exposure to chemotherapeutics. The resistance of cancer cells to an antineoplastic agent accompanied to other chemotherapeutic drugs with different structures and mechanisms of action called multi-drug resistance (MDR) plays an important role in the failure of chemo- therapeutics. MDR is primarily based on the overexpression of drug efflux pumps in the cellular membrane, which belongs to the ATP-binding cassette (ABC) superfamily of proteins, are P-gp (P-glycoprotein) and multidrug resistance-associated protein (MRP). Over the years, various strategies have been evaluated to overcome MDR, based not only on the use of MDR modulators but also on the implementation an innovative approach and advanced nanosized drug delivery systems. Nanomedicine is an emerging tool of chemotherapy that focuses on alternative drug delivery for improvement of the treatment efficacy and reducing side effects to normal tissues. This review aims to focus on the details biology, reversal strategies option with the limitation of MDR and various advantages of the present medical science nanotechnology with intracellular delivery aspects for overcoming the significant potential for improving the treatment of MDR malignancies. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Influence of Alternative Tubulin Inhibitors on the Potency of a Epirubicin-Immunochemotherapeutic Synthesized with an Ultra Violet Light-Activated Intermediate: Influence of incorporating an internal/integral disulfide bond structure and Alternative Tubulin/Microtubule Inhibitors on the Cytotoxic Anti-Neoplastic Potency of Epirubicin-(C3-amide)-Anti-HER2/neu Synthesized Utilizing a UV-Photoactivated Anthracycline Intermediate.

PubMed

Coyne, C P; Jones, Toni; Bear, Ryan

2012-11-01

Immunochemotherapeutics, epirubicin-(C 3 - amide )-SS-[anti-HER2/ neu ] with an internal disulfide bond, and epirubicin-(C 3 - amide )-[anti-HER2/ neu ] were synthesized utilizing succinimidyl 2-[(4,4'-azipentanamido) ethyl]-1,3'-dithioproprionate or succinimidyl 4,4-azipentanoate respectively. Western blot analysis was used to determine the presence of any immunoglobulin fragmentation or IgG-IgG polymerization. Retained HER2/ neu binding characteristics of epirubicin-(C 3 - amide )-[anti-HER2/ neu ] and epirubicin-(C 3 - amide )-SS-[anti-HER2/ neu ] were validated by cell-ELISA using a mammary adenocarcinoma (SKBr-3) population that highly over-expresses trophic HER2/ neu receptor complexes. Cytotoxic anti-neoplastic potency of epirubicin-(C 3 - amide )-[anti-HER2/ neu ] and epirubicin-(C 3 - amide )-SS-[anti-HER2/ neu ] between epirubicin-equivalent concentrations of 10 -10 M and 10 -6 M was determined by measuring the vitality/proliferation of chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3 cell type). Cytotoxic anti-neoplastic potency of benzimidazoles (albendazole, flubendazole, membendazole) and griseofulvin were assessed between 0-to-2 μg/ml and 0-to-100 μg/ml respectively while mebendazole and griseofulvin were analyzed at fixed concentrations of 0.35 μg/ml and 35 g/ml respectively in dual combination with gradient concentrations of epirubicin-(C 3 - amide )-[anti-HER2/ neu ] and epirubicin-(C 3 - amide )-SS-[anti-HER2/ neu ]. Cytotoxic anti-neoplastic potency for epirubicin-(C 3 - amide )-[anti-HER2/ neu ] and epirubicin-(C 3 - amide )-SS-[anti-HER2/ neu ] against chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3) was nearly identical at epirubicin-equivalent concentrations of 10 -10 M and 10 -6 M. The benzimadazoles also possessed cytotoxic anti-neoplastic activity with flubendazole and albendazole being the most and least potent respectively. Similarly, griseofulvin had cytotoxic anti-neoplastic activity and was more potent than methylselenocysteine. Both mebendazole and griseofulvin when applied in dual combination with either epirubicin-(C 3 - amide )-[anti-HER2/ neu ] or epirubicin-(C 3 - amide )-SS-[anti-HER2/ neu ] produced enhanced levels of cytotoxic anti-neoplatic potency.

A Comparative Study on the Cost of New Antibiotics and Drugs of Other Therapeutic Categories

PubMed Central

Falagas, Matthew E.; Fragoulis, Konstantinos N.; Karydis, Ioannis

2006-01-01

Background Drug treatment is becoming more expensive due to the increased cost for the introduction of new drugs, and there seems to be an uneven distribution of medication cost for different therapeutic categories. We hypothesized that the cost of new antimicrobial agents may differ from that of other therapeutic categories and this may play a role in the stagnation of development of new antibiotics. Methodology/Principal Findings We performed a pharmaco-economical comparative analysis of the drug cost of treatment for new agents introduced in the United States drug market in various therapeutic categories. We calculated the drug cost (in US dollars) of a ten-day treatment of all new drugs approved by the FDA during the period between January 1997 and July 2003, according to the 2004 Red Book Pharmacy's Fundamental Reference. New anti-neoplastic agents were found to be the most expensive drugs in comparison to all other therapeutic categories, with a median ten-day drug-treatment cost of US$848 compared to the median ten-day drug-treatment costs of all other categories ranging from US$29 to US$301. On the other hand, new antimicrobial drugs were found to be much less expensive, with a median ten-day drug-treatment cost of US$137 and $US85 for all anti-microbial agents and for anti-microbial agents excluding anti-HIV medications, respectively. Conclusions/Significance The drug-treatment cost of new medications varies considerably by different therapeutic categories. This fact may influence industry decisions regarding the development of new drugs and may play a role in the shortage of new antimicrobial agents in the fight against the serious problem of antimicrobial resistance. PMID:17183637

A comparative study on the cost of new antibiotics and drugs of other therapeutic categories.

PubMed

Falagas, Matthew E; Fragoulis, Konstantinos N; Karydis, Ioannis

2006-12-20

Drug treatment is becoming more expensive due to the increased cost for the introduction of new drugs, and there seems to be an uneven distribution of medication cost for different therapeutic categories. We hypothesized that the cost of new antimicrobial agents may differ from that of other therapeutic categories and this may play a role in the stagnation of development of new antibiotics. We performed a pharmaco-economical comparative analysis of the drug cost of treatment for new agents introduced in the United States drug market in various therapeutic categories. We calculated the drug cost (in US dollars) of a ten-day treatment of all new drugs approved by the FDA during the period between January 1997 and July 2003, according to the 2004 Red Book Pharmacy's Fundamental Reference. New anti-neoplastic agents were found to be the most expensive drugs in comparison to all other therapeutic categories, with a median ten-day drug-treatment cost of US$848 compared to the median ten-day drug-treatment costs of all other categories ranging from US$29 to US$301. On the other hand, new antimicrobial drugs were found to be much less expensive, with a median ten-day drug-treatment cost of US$137 and $US85 for all anti-microbial agents and for anti-microbial agents excluding anti-HIV medications, respectively. The drug-treatment cost of new medications varies considerably by different therapeutic categories. This fact may influence industry decisions regarding the development of new drugs and may play a role in the shortage of new antimicrobial agents in the fight against the serious problem of antimicrobial resistance.

Safety Management Status among Nurses Handling Anticancer Drugs: Nurse Awareness and Performance Following Safety Regulations.

PubMed

Jeong, Kyeong Weon; Lee, Bo-Young; Kwon, Myung Soon; Jang, Ji-Hye

2015-01-01

This study identified the actual conditions for safe anticancer drug management among nurses and the relationship between level of awareness and performance of anticancer drug safety regulations in terms of preparation, administration, and disposal. The respondents were 236 nurses working with chemotherapy in wards and outpatient clinics in five hospitals in and near Seoul. Safety regulations provided for the anticancer drug the Occupational Safety Health Administration (OSHA, 1999), as modified for an earlier study, were used. The results showed that the level of awareness and performance on the anticancer drug safety regulations indicate their preparation (3.38±0.55, 2.38±0.98), administration (3.52±0.46, 3.17±0.70), general handling and disposal (3.33±0.54, 2.42±0.90) on a scale 0 to 5. Also, there were significant differences in job positions, work experience, type of preparation, and continuing education and a positive relationship between the level of awareness and nursing performance. Thus, nurses should receive continuing education on the handling of anticancer drugs to improve the level of performance following safety regulations.

Ameliorative action of Vernonia cinerea L. on cyclophosphamide-induced immunosuppression and oxidative stress in mice.

PubMed

Pratheeshkumar, P; Kuttan, Girija

2010-08-01

Cyclophosphamide (CTX) is a widely used antineoplastic drug, which could cause toxicity to normal cells due to its toxic metabolites. The use of CTX in treating cancer patients is limited due to its severe toxicity induced mainly by oxidative stress. The present study reports the protective role of Vernonia cinerea L. against the CTX-induced toxicity in Balb/c mice. Intraperitoneal administration of the extract significantly increased the total WBC Count, bone marrow cellularity, alpha-esterase positive cells, and weights of lymphoid organs in CTX-treated animals, when compared with CTX control mice. Administration of V. cinerea was found to reduce the enhanced level of alkaline phosphatase, glutamate pyruvate transaminase, lipid peroxidation, and also significantly increased the reduced glutathione level in CTX-treated animals. Histopathological analysis of small intestine also suggests that extract could reduce the CTX-induced intestinal damage. The level of proinflammatory cytokine TNF-alpha, which was elevated during CTX administration, was significantly reduced by the V. cinerea extract administration. The lowered levels of other cytokines like IFN-gamma, IL-2, GM-CSF, after CTX treatment were also found to be increased by extract administration. Administration of V. cinerea did not compromise the anti-neoplastic activity of CTX. Infact, there was a synergistic action of CTX and V. cinerea in reducing the solid tumors in mice. Methanolic extract of V. cinerea given intraperitoneally (i.p.) showed a significant chemoprotective activity without compromising the chemotherapeutic efficacy of CTX, indicating its possible use as an adjuvant during chemotherapy.

Treatment algorithm in 2014 for advanced non-small cell lung cancer: therapy selection by tumour histology and molecular biology.

PubMed

Manegold, Christian

2014-09-01

The availability of antineoplastic monoclonal antibodies, small molecules and newer cytotoxics such as pemetrexed, the EGFR-tyrosine kinase inhibitors erlotinib, gefitinib, afatinib as well as the anti-angiogenic bevacizumab and the ALK-inhibitor crizotinib has recently changes the treatment algorithm of advanced non-small cell lung cancer. Decision making in 2014 is characterized by customizing therapy, by selecting a specific therapeutic regimen based on the histotype and the genotype of the tumour. This refers to first-line induction therapy and maintenance therapy as well, but also to subsequent lines of therapy since anti-neoplastic drugs and regimens used upfront clinically influence the selection of agents/regimes considered for second-/third-line treatment. Consequently, therapy customization through tumour histology and molecular markers has significantly influenced the work of pathologists around the globe and the process of obtaining an extended therapeutically relevant tumour diagnosis. Not only histological sub-typing became standard but molecular information is also considered of increasing importance for treatment selection. Routine molecular testing in certified laboratories must be established, and the diagnostic process should ideally be performed under the guidance of evidence based recommendation. The process of investigating and implementing medical targeting in lung cancer therefore, requires advanced diagnostic techniques and expertise and because of its large dimension is costly and influenced by the limitation of financial and clinical resources. Copyright © 2014. Published by Elsevier Urban & Partner Sp. z o.o.

Prophylaxis for mucositis induced by ambulatory chemotherapy: systematic review.

PubMed

Manzi, Natália de Melo; Silveira, Renata Cristina de Campos Pereira; dos Reis, Paula Elaine Diniz

2016-04-01

The aim of this study was to perform a systematic review of clinical trials covering interventions used as prophylaxis for oral mucositis induced by ambulatory antineoplastic chemotherapy. Oral mucositis in patients undergoing chemotherapy is a side effect that can impact the quality of treatment and can interfere with eating and therapeutic adherence. Quantitative systematic review. Relevant databases were searched, from January 2002-July 2013, by using the combination of the keywords mucositis, stomatitis, neoplasms, antineoplastic agents, drug therapy, prevention and control and chemotherapy. Two researchers independently read the titles and abstracts from every cross-reference. The quality of the included studies was analysed by the Jadad Scale and the Cochrane Collaboration Risk of Bias Tool. Data were extracted from the selected studies with a data collection form developed specifically for this purpose. Of the 23 controlled clinical trials that were identified in this study, five articles evaluated the use of oral cryotherapy to prevent oral mucositis and three studies analysed the prophylactic use of glutamine. Interventions of protocols for oral care, palifermin, allopurinol and chlorhexidine were evaluated by two articles each. Interventions of zinc sulphate, amifostine, chewing gum, sucralfate, recombination human intestinal trefoil factor, kefir and vitamin E were evaluated by one article each. There is strong evidence that cryotherapy can prevent oral mucositis arising from ambulatory treatment with 5-flurouracil chemotherapy. Other interventions, although showing positive results in preventing oral mucositis, require further study to confirm their conclusions. © 2015 John Wiley & Sons Ltd.

Activation of microbubbles by low-intensity pulsed ultrasound enhances the cytotoxicity of curcumin involving apoptosis induction and cell motility inhibition in human breast cancer MDA-MB-231 cells.

PubMed

Li, Yixiang; Wang, Pan; Chen, Xiyang; Hu, Jianmin; Liu, Yichen; Wang, Xiaobing; Liu, Quanhong

2016-11-01

Ultrasound and microbubbles-mediated drug delivery has become a promising strategy to promote drug delivery and its therapeutic efficacy. The aim of this research was to assess the effects of microbubbles (MBs)-combined low-intensity pulsed ultrasound (LPUS) on the delivery and cytotoxicity of curcumin (Cur) to human breast cancer MDA-MB-231 cells. Under the experimental condition, MBs raised the level of acoustic cavitation and enhanced plasma membrane permeability; and cellular uptake of Cur was notably improved by LPUS-MBs treatment, aggravating Cur-induced MDA-MB-231 cells death. The combined treatment markedly caused more obvious changes of cell morphology, F-actin cytoskeleton damage and cell migration inhibition. Our results demonstrated that combination of MBs and LPUS may be an efficient strategy for improving anti-tumor effect of Cur, suggesting a potential effective method for antineoplastic therapy. Copyright © 2016 Elsevier B.V. All rights reserved.

Towards the use of non-psychoactive cannabinoids for prostate cancer.

PubMed

Pacher, Pál

2013-01-01

The palliative effects of Cannabis sativa (marijuana), and its putative main active ingredient, Δ(9) -tetrahydrocannabinol (THC), which include appetite stimulation, attenuation of nausea and emesis associated with chemo- or radiotherapy, pain relief, mood elevation, and relief from insomnia in cancer patients, are well-known. Because of the adverse psychoactive effects of THC, numerous recent preclinical studies have been focused on investigating other non-psychoactive constituents of C. sativa, such as cannabidiol, for potential therapeutic use. In this issue of the British Journal of Pharmacology, De Petrocellis and colleagues present comprehensive evidence that plant-derived cannabinoids, especially cannabidiol, are potent inhibitors of prostate carcinoma viability in vitro. They also showed that the extract was active in vivo, either alone or when administered with drugs commonly used to treat prostate cancer (the anti-mitotic chemotherapeutic drug docetaxel (Taxotere) or the anti-androgen bicalutamide (Casodex)) and explored the potential mechanisms behind these antineoplastic effects. Published 2012. This article is a U.S. Government work and is in the public domain in the USA.

[Farnesyl transferase inhibitors (anti-Ras). A new class of anticancer agents].

PubMed

Levy, R

Ras genes are frequently activated in human tumours. The role of their product, the P21 proteins, in the transduction of the mitogenic signal makes them attractive targets for an anti-neoplastic therapy. The p21 ras proteins are linked to the plasma membrane and transformed into an active form for signal transmission. Their effect is to mediate the effects of growth factors. Two drug families, the Benzodiazepine peptidomimetics and the CAAX tetrapeptides which inhibit the farnesylation of P21-Ras proteins abolish the transforming properties of mutated P21. These promising drugs could rapidly have clinical applications. They have been shown to be highly active at precise concentrations on ras-transformed cells but at the same concentrations are not toxic for untransformed cells. They do not effect other similar enzyme systems within the cell, underlining their selective capacity. Theoretically anti-ras therapy could only suspend cell transformation although it might be possible that if given long enough, a lethal threshold could be reached.

Effects of Handling and Vehicle Injections on Adrenocorticotropic and Corticosterone Concentrations in Sprague–Dawley Compared with Lewis Rats

PubMed Central

Deutsch-Feldman, Molly; Picetti, Roberto; Seip-Cammack, Katharine; Zhou, Yan; Kreek, Mary Jeanne

2015-01-01

The hypothalamic–pituitary–adrenal (HPA) axis is a key factor in the trajectory of the addiction-like cycle (a pattern of behavior characterized by escalating drug use, withdrawal, and relapse) in preclinical and clinical studies. Concentrations of HPA hormones change in laboratory animals in response to standard experimental procedures, including handling and vehicle injections. We compared HPA activity in adult male Lewis (inbred) and Sprague–Dawley (outbred) rats, 2 common strains in rodent models of addiction, after different schedules of handling and saline injections, to explore the extent to which HPA responses differ by strain and whether interindividual differences underlie addiction vulnerability. The 4 treatment conditions were no, short, or long handling and saline injections. In handled groups, rats were handled for 1 to 2 min for 3 times daily and were euthanized after 7 d (short handling) or 14 d (long handling). The injection schedule in the saline injection group mimicked that in a model of binge-like cocaine exposure. Across all treatment groups, concentrations of adrenocorticotropic hormone were higher in Sprague–Dawley than in Lewis rats. In Sprague–Dawley rats, corticosterone concentrations decreased after continued handling but remained constant in Lewis rats. Interindividual variability in hormone levels was greater in Sprague–Dawley than Lewis rats, although corticosterone variability decreased after continued handling. Prolactin did not differ between groups of either Sprague–Dawley and Lewis rats before or after handling. This study underscores the importance of prolonged handling before experimenter-provided drug-administration paradigms and of strain-associated differences that may affect study outcomes. PMID:25651089

Spontaneous and bilateral avascular necrosis of the navicula: Müller-Weiss disease.

PubMed

Aktaş, Erdem; Ayanoğlu, Tacettin; Hatipoğlu, Yasin; Kanatlı, Ulunay

2016-12-01

Although, trauma, foot deformity (pesplanovalgus), systemic diseases such as diabetes mellitus and lupus, drugs (steroids, antineoplastic) and excessive alcohol consumption have all been accused in the etiology of avascular necrosis of the tarsal bones, spontaneous avascular necrosis of the navicular bone, especially in adults, is a rare entity. In this article, we report a 50-year-old female patient with bilateral, spontaneous avascular necrosis of the navicular bone and related severe talonavicular arthrosis. Clinical and radiological findings were concordant with Müller-Weiss disease, which is a rare disease with complex idiopathic foot condition of the adult tarsal navicular bone characterized by progressive navicular fragmentation and talonavicular joint destruction. The patient was successfully treated with two-staged bilateral talonavicular arthrodesis.

Endophytic Fungus from Sinopodophyllum emodi (Wall.) Ying that Produces Podophyllotoxin.

PubMed

Liang, Zizhen; Zhang, Jia; Zhang, Xuan; Li, Jinjie; Zhang, Xiaoqian; Zhao, Changqi

2016-02-01

The aryltetralin lactone podophyllotoxin, which exhibits pronounced antineoplastic activity, is used as the precursor of the following three clinical anticancer drugs: Etoposide™, Etopophos™ and Teniposide™. The natural occurrence of this arylnaphthalene lignan is scarce and unable to meet the ever-rising demand in the medical industry. Thus, developing alternative sources for the production of podophyllotoxin is extremely urgent. This is the first report of the production of podophyllotoxin from endophytic Alternaria tenuissima isolated from Sinopodophyllum emodi (Wall.) Ying. The identification of podophyllotoxin was performed using high-performance liquid chromatography and liquid chromatography-mass spectrometry (MS)-MS and confirmed by comparison with authentic standards. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Heparin: Past, Present, and Future.

PubMed

Oduah, Eziafa I; Linhardt, Robert J; Sharfstein, Susan T

2016-07-04

Heparin, the most widely used anticoagulant drug in the world today, remains an animal-derived product with the attendant risks of adulteration and contamination. A contamination crisis in 2007-2008 increased the impetus to provide non-animal-derived sources of heparin, produced under cGMP conditions. In addition, recent studies suggest that heparin may have significant antineoplastic activity, separate and distinct from its anticoagulant activity, while other studies indicate a role for heparin in treating inflammation, infertility, and infectious disease. A variety of strategies have been proposed to produce a bioengineered heparin. In this review, we discuss several of these strategies including microbial production, mammalian cell production, and chemoenzymatic modification. We also propose strategies for creating "designer" heparins and heparan-sulfates with various biochemical and physiological properties.

Uso del Registro de Solicitudes de Medicamentos no Incluidos en el Listado de Medicamentos Esenciales como Nueva Fuente de Información en los Sistemas Nacionales de Farmacovigilancia.

PubMed

Buendía, Jefferson Antonio; Zuluaga Salazar, Andrés Felipe; Vacca González, Claudia Patricia

2013-12-01

To describe the frequency of adverse drugs events (ADEs) as possible causes of request of drugs not included in national essential Medicines list in Colombia. This was a descriptive study developed in a private medical insurance company in Bogota, Colombia. Data were obtained from drug request form of drugs not included in a national essential Medicines list. We analyzed the content of the notes to identify the records related to the occurrence of ADEs in the period 2008 to 2009. Information concerning the adverse event and the drug involved was recorded in a data collection instrument developed by the researchers. The pharmacological classification of drugs was performed according to the Anatomical Therapeutic Chemical Classification System (ATC). We study 3,336 request forms of drugs not included in a national essential Medicines list. The level 1 groups of the ATC of drugs with greater frequency of ADEs were the cardiovascular agents (47%), nervous system agents (24%) and antineoplastic and immunomodulating agents (15%). The great majority was cases of light severity (62.7%) and classified as possible (48.4%). The results of this study support the innovative approach of using request form of drug not included in national essential Medicines list to obtain information regarding ADEs in developing countries; recognizing the importance of looking for new sources of report of adverse reactions to diminish the under-notification of ADEs. © 2013 International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Published by International Society for Pharmacoeconomics and Outcomes Research (ISPOR) All rights reserved.

Drug repurposing for the treatment of glioblastoma multiforme.

PubMed

Abbruzzese, Claudia; Matteoni, Silvia; Signore, Michele; Cardone, Luca; Nath, Kavindra; Glickson, Jerry D; Paggi, Marco G

2017-11-28

Glioblastoma Multiforme is the deadliest type of brain tumor and is characterized by very poor prognosis with a limited overall survival. Current optimal therapeutic approach has essentially remained unchanged for more than a decade, consisting in maximal surgical resection followed by radiotherapy plus temozolomide. Such a dismal patient outcome represents a compelling need for innovative and effective therapeutic approaches. Given the development of new drugs is a process presently characterized by an immense increase in costs and development time, drug repositioning, finding new uses for existing approved drugs or drug repurposing, re-use of old drugs when novel molecular findings make them attractive again, are gaining significance in clinical pharmacology, since it allows faster and less expensive delivery of potentially useful drugs from the bench to the bedside. This is quite evident in glioblastoma, where a number of old drugs is now considered for clinical use, often in association with the first-line therapeutic intervention. Interestingly, most of these medications are, or have been, widely employed for decades in non-neoplastic pathologies without relevant side effects. Now, the refinement of their molecular mechanism(s) of action through up-to-date technologies is paving the way for their use in the therapeutic approach of glioblastoma as well as other cancer types. The spiraling costs of new antineoplastic drugs and the long time required for them to reach the market demands a profoundly different approach to keep lifesaving therapies affordable for cancer patients. In this context, repurposing can represent a relatively inexpensive, safe and fast approach to glioblastoma treatment. To this end, pros and cons must be accurately considered.

Development and optimization of locust bean gum and sodium alginate interpenetrating polymeric network of capecitabine.

PubMed

Upadhyay, Mansi; Adena, Sandeep Kumar Reddy; Vardhan, Harsh; Pandey, Sureshwar; Mishra, Brahmeshwar

2018-03-01

The objective of the study was to develop interpenetrating polymeric network (IPN) of capecitabine (CAP) using natural polymers locust bean gum (LBG) and sodium alginate (NaAlg). The IPN microbeads were optimized by Box-Behnken Design (BBD) to provide anticipated particle size with good drug entrapment efficiency. The comparative dissolution profile of IPN microbeads of CAP with the marketed preparation proved an excellent sustained drug delivery vehicle. Ionotropic gelation method utilizing metal ion calcium (Ca 2+ ) as a cross-linker was used to prepare IPN microbeads. The optimization study was done by response surface methodology based Box-Behnken Design. The effect of the factors on the responses of optimized batch was exhibited through response surface and contour plots. The optimized batch was analyzed for particle size, % drug entrapment, pharmacokinetic study, in vitro drug release study and further characterized by FTIR, XRD, and SEM. To study the water uptake capacity and hydrodynamic activity of the polymers, swelling studies and viscosity measurement were performed, respectively. The particle size and % drug entrapment of the optimized batch was 494.37 ± 1.4 µm and 81.39 ± 2.9%, respectively, closer to the value predicted by Minitab 17 software. The in vitro drug release study showed sustained release of 92% for 12 h and followed anomalous drug release pattern. The derived pharmacokinetic parameters of optimized batch showed improved results than pure CAP. Thus, the formed IPN microbeads of CAP proved to be an effective extended drug delivery vehicle for the water soluble antineoplastic drug.

Handling Kids in Crisis with Care

ERIC Educational Resources Information Center

Bushinski, Cari

2018-01-01

The Handle with Care program helps schools help students who experience trauma. While at the scene of an event like a domestic violence call, drug raid, or car accident, law enforcement personnel determine the names and school of any children present. They notify that child's school to "handle ___ with care" the next day, and the school…

Controllable fabrication and characterization of biocompatible core-shell particles and hollow capsules as drug carrier

NASA Astrophysics Data System (ADS)

Hao, Lingyun; Gong, Xinglong; Xuan, Shouhu; Zhang, Hong; Gong, Xiuqing; Jiang, Wanquan; Chen, Zuyao

2006-10-01

SiO 2@CdSe core-shell particles were fabricated by controllable deposition CdSe nanoparticles on silica colloidal spheres. Step-wise coating process was tracked by the TEM and XRD measurements. In addition, SiO 2@CdSe/polypyrrole(PPy) multi-composite particles were synthesized based on the as-prepared SiO 2@CdSe particles by cationic polymerization. The direct electrochemistry of myoglobin (Mb) could be performed by immobilizing Mb on the surface of SiO 2@CdSe particles. Immobilized with Mb, SiO 2@CdSe/PPy-Mb also displayed good bioelectrochemical activity. It confirmed the good biocompatible property of the materials with protein. CdSe hollow capsules were further obtained as the removal of the cores of SiO 2@CdSe spheres. Hollow and porous character of CdSe sub-meter size capsules made them becoming hopeful candidates as drug carriers. Doxorubicin, a typical an antineoplastic drug, was introduced into the capsules. A good sustained drug release behavior of the loading capsules was discovered via performing a release test in the PBS buffer (pH 7.4) solution at 310 k. Furthermore, SiO 2@CdSe/PPy could be converted to various smart hollow capsules via selectively removal of their relevant components.

Exploring novel pharmacotherapeutic applications and repurposing potential of sodium glucose CoTransporter 2 (SGLT2) inhibitors.

PubMed

Madaan, Tushar; Husain, Ibraheem; Akhtar, Mohamad; Najmi, Abul Kalam

2018-05-11

Sodium glucose cotransporter 2 (SGLT2) inhibitors are a relatively new class of anti-hyperglycemic drugs with a distinctive mechanism of action focusing on renal absorption ofglucose. Apart from its anti-hyperglycemic effects, a multitude of research studies on this classhave revealed that these drugs have far more versatile and comprehensive pharmacologicaleffects than previously believed. Approximately 30% of FDA approved drugs are repurposedand used for indications other than those they were initially intended for. Repurposing alreadyapproved drugs leads to significant reduction in pre-clinical and clinical R&D costs as well as minimizes the burden with respect to obtaining regulatory approval. SGLT2 inhibitors have been found to exhibit cardioprotective, renoprotective, anti-hyperlipidemic, anti-atherosclerotic, anti- obesity, anti-neoplastic, hepatoprotective, and renoprotective effects in in vitro, pre-clinical, and clinical studies. The pleiotropic effects of this class have been attributed to a variety of itspharmacodynamic actions such as natriuresis, hemoconcentration, deactivation of RAAS, ketone body formation, alterations in energy homeostasis, glycosuria, lipolysis, anti-inflammatory, andanti-oxidative actions. These favorable observations encourage further research on this multifaceted class in order to effectively explore and harness its full potential and consequently lead to clinical outcomes. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

21 CFR 579.12 - Incorporation of regulations in part 179.

Code of Federal Regulations, 2014 CFR

2014-04-01

... (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS IRRADIATION IN THE PRODUCTION, PROCESSING, AND HANDLING.... Regulations providing for irradiation in the production, processing, and handling of food in part 179 of this...

21 CFR 579.12 - Incorporation of regulations in part 179.

Code of Federal Regulations, 2012 CFR

2012-04-01

... (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS IRRADIATION IN THE PRODUCTION, PROCESSING, AND HANDLING.... Regulations providing for irradiation in the production, processing, and handling of food in part 179 of this...

21 CFR 579.12 - Incorporation of regulations in part 179.

Code of Federal Regulations, 2010 CFR

2010-04-01

... (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS IRRADIATION IN THE PRODUCTION, PROCESSING, AND HANDLING.... Regulations providing for irradiation in the production, processing, and handling of food in part 179 of this...

21 CFR 579.12 - Incorporation of regulations in part 179.

Code of Federal Regulations, 2011 CFR

2011-04-01

... (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS IRRADIATION IN THE PRODUCTION, PROCESSING, AND HANDLING.... Regulations providing for irradiation in the production, processing, and handling of food in part 179 of this...

21 CFR 579.12 - Incorporation of regulations in part 179.

Code of Federal Regulations, 2013 CFR

2013-04-01

... (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS IRRADIATION IN THE PRODUCTION, PROCESSING, AND HANDLING.... Regulations providing for irradiation in the production, processing, and handling of food in part 179 of this...

Surface-enhanced Raman spectroscopy of the anti-cancer drug irinotecan in presence of human serum albumin.

PubMed

Vicario, A; Sergo, V; Toffoli, G; Bonifacio, A

2015-03-01

The development of nanotechnological devices and their clinical application in medicine has become increasingly important, especially in the context of targeted and personalized therapy. This is particularly important in cancer therapy, where antitumor drugs are highly cytotoxic and often exert their therapeutic effect at concentrations close to systemic toxicity. In the last years a growing number of studies has started to report the use of plasmonic nanoprobes in the field of theranostics, broadening the application of vibrational spectroscopies like Raman scattering and surface enhanced Raman scattering (SERS) in biomedicine. The present work aims to identify and characterize the vibrational profiles of a widely used anticancer drug, irinotecan (CPT-11). With a rational approach, SERS experiments have been performed on this analyte employing both Au and Ag colloids, starting from simple aqueous solutions up to albumin mixtures. A major step forward for drug detection in albumin solutions has been taken with the adoption of a simple deproteinization strategy, and a two-in-one-step separation and identification by coupling thin layer chromatography, TLC, with SERS (TLC-SERS). The latter has revealed to be a valid system for protein separation and simultaneous analyte detection, showing a potential to become an innovative, sensitive and low cost method for antineoplastic drug profiling in patients' body fluids. Copyright © 2015 Elsevier B.V. All rights reserved.

Changes in the chemical composition of mineralised teeth in children after antineoplastic treatment.

PubMed

Krasuska-Sławińska, Ewa; Dembowska-Bagińska, Bożenna; Brożyna, Agnieszka; Olczak-Kowalczyk, Dorota; Czarnowska, Elżbieta; Sowińska, Agnieszka

2018-01-01

Chemotherapy, neoplasms, and their complications linked to malabsorption, malnutrition, and metabolic disorders may lead to improper tooth development and frequent severe caries in patients during/after antineoplastic treatment and to a more frequent improper tooth development in patients undergoing chemotherapy during odontogenesis. However, the causes of these abnormalities remain unknown; there are no studies on the impact of antineoplastic treatment and its complications on the chemical composition of mineralised teeth. To compare the chemical composition of mineralised teeth extracted due to complicated caries in children after chemotherapy, and of teeth extracted due to orthodontic treatment in generally healthy children. The treatment group included five teeth extracted due to complicated caries in children after antineoplastic treatment. The control group included five teeth extracted due to orthodontic treatment in generally healthy children. The chemical composition of enamel, dentine, cementum, interior of the canal, and enamel abnormalities in teeth extracted from patients after chemotherapy and in generally healthy patients were assessed with energy-dispersive X-ray spectroscopy. Results were analysed statistically. The magnesium (Mg) and zinc (Zn) mass contents in the enamel of patients after chemotherapy increased and so did the calcium (Ca) to phosphorus (P) ratio when compared to controls. Areas with abnormal enamel in patients after chemotherapy had lower concentrations of Ca and P, and higher concentrations of trace elements (Mg, Cl, and Na). The levels of the assessed elements in dentine, cementum, and inside the canal were similar in both groups of teeth.

Activation of PPARγ mediates icaritin-induced cell cycle arrest and apoptosis in glioblastoma multiforme.

PubMed

Liu, Yongji; Shi, Ling; Liu, Yuan; Li, Peng; Jiang, Guoping; Gao, Xiaoning; Zhang, Yongbin; Jiang, Chuanwu; Zhu, Weiping; Han, Hongxing; Ju, Fang

2018-04-01

Glioblastoma multiforme (GBM) is the most prevalent primary malignancy of the brain. This study was designed to investigate whether icaritin exerts anti-neoplastic activity against GBM in vitro. Cell Counting Kit-8 (CCK-8) assay was utilized to examine the viability of GBM cells. The apoptotic cell population was measured by flow cytometry analysis. Cell cycle distribution was detected by flow cytometry as well. Western blot analysis was performed to examine the level of biomarker proteins in GBM cells. Levels of PPARγ mRNA and protein were detected by qPCR and western blot analysis, respectively. To examine the role of PPARγ in the anti-neoplastic activity of icaritin, PPARγ antagonist GW9662 or PPARγ siRNA was used. The activity of PPARγ was determined by DNA binding and luciferase assays. Our findings revealed that icaritin markedly suppresses cell growth in a dose-dependent and time-dependent fashion. The cell population at the G0/G1 phase of the cell cycle was significantly increased following icaritin treatment. Meanwhile, icaritin promoted apoptotic cell death in T98G and U87MG cells. Further investigation showed upregulation of PPARγ played a key role in the anti-neoplastic activities of icaritin. Moreover, our result demonstrated activation of AMPK signaling by icaritin mediated the modulatory effect of icaritin on PPARγ. Our results suggest the PPARγ may mediate anti-neoplastic activities against GBM. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Cocaine-induced locomotor activity is increased by prior handling in adolescent but not adult female rats

PubMed Central

Maldonado, Antoniette M.; Kirstein, Cheryl L.

2017-01-01

Adolescence is a period of transition that is associated with increased levels of stress and a heightened propensity to initiate drug use. Neuronal development is still occurring during this transitional period, which includes the continued development of the dopamine system during the adolescent period. In the present study, the effects of pre-test handling on cocaine-induced locomotor activity were investigated among female adolescent and young adult rats upon presentation to a novel environment. On postnatal days (PND) 41–44 and 56–59 animals were handled (b.i.d.) in the colony room for 3 min. On PND 45 or PND 60, animals were removed from the colony room, weighed, and administered an acute injection of either cocaine or saline and presented to a novel environment where behavior was recorded for 30 min. Adolescent females (PND 45) that were handled prior to cocaine administration demonstrated elevated levels of cocaine-induced activity relative to their age-matched non-handled counterparts and also to their handled-adult counterparts. In contrast, among non-handled animals, young adults (PND 60) exhibited elevated drug-induced locomotion at several time points during the trial. Non-handled adolescent animals demonstrated the previously described “hyporesponsive” behavioral profile relative to their non-handled adult counterparts. The results from the present experiment indicate that adolescent animals may be more sensitive to basic laboratory manipulations such as pre-test handling, and care must be taken when utilizing adolescent animals in behavioral testing. Handling appears to be a sensitive manipulation in elucidating differences in cocaine-induced behavioral activation between ages. PMID:16176824

21 CFR 58.47 - Facilities for handling test and control articles.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 1 2012-04-01 2012-04-01 false Facilities for handling test and control articles... for handling test and control articles. (a) As necessary to prevent contamination or mixups, there shall be separate areas for: (1) Receipt and storage of the test and control articles. (2) Mixing of the...

21 CFR 58.47 - Facilities for handling test and control articles.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 1 2011-04-01 2011-04-01 false Facilities for handling test and control articles... for handling test and control articles. (a) As necessary to prevent contamination or mixups, there shall be separate areas for: (1) Receipt and storage of the test and control articles. (2) Mixing of the...

21 CFR 58.47 - Facilities for handling test and control articles.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 1 2013-04-01 2013-04-01 false Facilities for handling test and control articles... for handling test and control articles. (a) As necessary to prevent contamination or mixups, there shall be separate areas for: (1) Receipt and storage of the test and control articles. (2) Mixing of the...

21 CFR 58.47 - Facilities for handling test and control articles.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 1 2014-04-01 2014-04-01 false Facilities for handling test and control articles... for handling test and control articles. (a) As necessary to prevent contamination or mixups, there shall be separate areas for: (1) Receipt and storage of the test and control articles. (2) Mixing of the...

Chloroquine analogues in drug discovery: new directions of uses, mechanisms of actions and toxic manifestations from malaria to multifarious diseases.

PubMed

Al-Bari, Md Abdul Alim

2015-01-01

Antimalarial drugs (e.g. chloroquine and its close structural analogues) were developed primarily to treat malaria; however, they are beneficial for many dermatological, immunological, rheumatological and severe infectious diseases, for which they are used mostly today. Chloroquine and hydroxychloroquine, two of the most fascinating drugs developed in the last 50 years, are increasingly recognized for their effectiveness in myriad non-malarial diseases. In advanced research, chloroquine and hydroxychloroquine have been shown to have various immunomodulatory and immunosuppressive effects, and currently have established roles in the management of rheumatic diseases, lupus erythematosus (different forms) and skin diseases, and in the treatment of different forms of cancer. Recently, chloroquine analogues have also been found to have metabolic, cardiovascular, antithrombotic and antineoplastic effects. This review is concerned with the lysosomotropic, anti-inflammatory and immunomodulatory mechanisms of chloroquine, hydroxychloroquine, quinacrine and related analogues, and the current evidence for both their beneficial effects and potential adverse manifestations in various diseases. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

An Empirical Analysis of Primary and Secondary Pharmaceutical Patents in Chile

PubMed Central

Abud, María José; Hall, Bronwyn; Helmers, Christian

2015-01-01

We analyze the patent filing strategies of foreign pharmaceutical companies in Chile distinguishing between “primary” (active ingredient) and “secondary” patents (patents on modified compounds, formulations, dosages, particular medical uses, etc.). There is prior evidence that secondary patents are used by pharmaceutical originator companies in the U.S. and Europe to extend patent protection on drugs in length and breadth. Using a novel dataset that comprises all drugs registered in Chile between 1991 and 2010 as well as the corresponding patents and trademarks, we find evidence that foreign originator companies pursue similar strategies in Chile. We find a primary to secondary patents ratio of 1:4 at the drug-level, which is comparable to the available evidence for Europe; most secondary patents are filed over several years following the original primary patent and after the protected active ingredient has obtained market approval in Chile. This points toward effective patent term extensions through secondary patents. Secondary patents dominate “older” therapeutic classes like anti-ulcer and anti-depressants. In contrast, newer areas like anti-virals and anti-neoplastics (anti-cancer) have a much larger share of primary patents. PMID:25915050

New estradiol-linked nitrosoureas: can the pharmacokinetic properties help to explain the pharmacodynamic activities?

PubMed

Betsch, B; Berger, M R; Spiegelhalder, B; Eisenbrand, G; Schmähl, D

1989-01-01

The pharmacokinetics of 1-(2-chloroethyl)-1-nitrosocarbamoyl-L-alanine-estradiol-17-ester (CNC-alanine-estradiol-17-ester) a new estradiol-linked anticancer drug and the unlinked DNA-crosslinking agent 1-(2-chloroethyl)-1-nitrosocarbamoyl-L-alanine (CNC-alanine) have been studied in methylnitrosourea-induced female Sprague-Dawley rats after equimolar intravenous and oral administration. In comparison with the unlinked single agent, the CNC-alanine-estradiol-17-ester showed a 3-fold longer halflife in plasma and a three times larger volume of distribution. The distribution after intravenous administration was nearly three times faster. The absorption after peroral administration was likewise two times faster. The bioavailability of the estradiol-linked drug was determined to be 52%. After application of CNC-alanine-estradiol-17-ester the cytostatic metabolite CNC-alanine was found, indicating the cleavage of the ester bond. CNC-alanine generated from CNC-alanine-estradiol-17-ester showed a 50% longer halflife than when applied directly. The results indicate that linking 2-chloroethyl-nitrosoureas to estradiol can result in new anticancer agents with modified properties in comparison to the unlinked single agent. The higher antineoplastic activity of the hormone-linked drug can mainly be attributed to differences in the pharmacokinetic behaviour.

Cancer preventive and curative attributes of plants of the Cactaceae family: a review.

PubMed

Harlev, Eli; Nevo, Eviatar; Solowey, Elaine; Bishayee, Anupam

2013-06-01

The ever-increasing occurrence of cancer and the severe side effects and limited efficacy of current cancer chemotherapy based on chemical drugs shift the attention toward drugs of plant origin. The Cactaceae family comprises more than 1500 species, but until recently only a few of them have been tested for their chemopreventive and anticancer attributes, leaving a wide unexplored area still waiting for researchers to investigate. Considering this fact, and also the promising results obtained with the relatively few plants of this family already tested, it should justly be expected that some plants of the Cactaceae family yet unexplored might possess outstanding anticancer attributes, exceeding those displayed by the plants already tested. This review presents in vitro and in vivo experimental evidence on cancer chemopreventive and therapeutic potential of bioactive phytoconstituents and extracts derived from cactus plants. It also examines the underlying biochemical and molecular mechanisms involved in the antineoplastic effects of plants of the Cactaceae family. Current limitation and future directions of research towards effective use of cacti to develop efficient and side effect-free future cancer-preventive and anticancer drugs are also discussed. Georg Thieme Verlag KG Stuttgart · New York.

Frequencies of 23 Functionally Significant Variant Alleles Related with Metabolism of Antineoplastic Drugs in the Chilean Population: Comparison with Caucasian and Asian Populations

PubMed Central

Roco, Ángela; Quiñones, Luis; Agúndez, José A. G.; García-Martín, Elena; Squicciarini, Valentina; Miranda, Carla; Garay, Joselyn; Farfán, Nancy; Saavedra, Iván; Cáceres, Dante; Ibarra, Carol; Varela, Nelson

2012-01-01

Cancer is a leading cause of death worldwide. The cancer incidence rate in Chile is 133.7/100,000 inhabitants and it is the second cause of death, after cardiovascular diseases. Most of the antineoplastic drugs are metabolized to be detoxified, and some of them to be activated. Genetic polymorphisms of drug-metabolizing enzymes can induce deep changes in enzyme activity, leading to individual variability in drug efficacy and/or toxicity. The present research describes the presence of genetic polymorphisms in the Chilean population, which might be useful in public health programs for personalized treatment of cancer, and compares these frequencies with those reported for Asian and Caucasian populations, as a contribution to the evaluation of ethnic differences in the response to chemotherapy. We analyzed 23 polymorphisms in a group of 253 unrelated Chilean volunteers from the general population. The results showed that CYP2A6*2, CYP2A6*3, CYP2D6*3, CYP2C19*3, and CYP3A4*17 variant alleles are virtually absent in Chileans. CYP1A1*2A allele frequency (0.37) is similar to that of Caucasians and higher than that reported for Japanese people. Allele frequencies for CYP3A5*3(0.76) and CYP2C9*3(0.04) are similar to those observed in Japanese people. CYP1A1*2C(0.32), CYP1A2*1F(0.77), CYP3A4*1B(0.06), CYP2D6*2(0.41), and MTHFR T(0.52) allele frequencies are higher than the observed either in Caucasian or in Japanese populations. Conversely, CYP2C19*2 allelic frequency (0.12), and genotype frequencies for GSTT1 null (0.11) and GSTM1 null (0.36) are lower than those observed in both populations. Finally, allele frequencies for CYP2A6*4(0.04), CYP2C8*3(0.06), CYP2C9*2(0.06), CYP2D6*4(0.12), CYP2E1*5B(0.14), CYP2E1*6(0.19), and UGT2B7*2(0.40) are intermediate in relation to those described in Caucasian and in Japanese populations, as expected according to the ethnic origin of the Chilean population. In conclusion, our findings support the idea that ethnic variability must be considered in the pharmacogenomic assessment of cancer pharmacotherapy, especially in mixed populations and for drugs with a narrow safety range. PMID:23130019

Nurses' use of hazardous drug-handling precautions and awareness of national safety guidelines.

PubMed

Polovich, Martha; Martin, Susan

2011-11-01

To determine patterns of personal protective equipment (PPE) used by oncology nurses while handling hazardous drugs (HDs) and to assess knowledge of the 2004 National Institute for Occupational Safety and Health (NIOSH) Alert and its effect on precaution use. Descriptive, correlational. The Oncology Nursing Society 31st Annual Congress in Boston, MA, in 2006. 330 nurses who prepared and/or administered chemotherapy. Nurses described HD safe-handling precaution use by self-report survey. The availability and use of biologic safety cabinets and PPE. Respondents were well educated (57% had a bachelor's degree or more), experienced (X = 19, SD = 10.2 years in nursing and X = 12, SD = 7.9 years in oncology), and certified (70%; majority OCN®). Forty-seven percent of respondents were aware of the NIOSH Alert. Thirty-five percent of all participants and 93% of nurses in private practice settings reported preparing chemotherapy. Glove use (95%-100%) was higher than that reported in earlier studies, and gown use for drug preparation (65%), drug administration (50%), and handling excretions (23%) have remained unchanged. Double-gloving was rare (11%-18%). Nurses in private practices were less likely to have chemotherapy-designated PPE available, use PPE, and use spill kits for HD spills. Nurses have adopted glove use for HD handling; however, gown use remains comparatively low. Chemotherapy-designated PPE is not always provided by employers. Nurses lack awareness of current safety guidelines. Nurses must know about the risks of HD exposure and ways to reduce exposure. Employers must provide appropriate PPE and encourage its use. Alternative methods of disseminating safety recommendations are needed.

Closed-system drug-transfer devices plus safe handling of hazardous drugs versus safe handling alone for reducing exposure to infusional hazardous drugs in healthcare staff.

PubMed

Gurusamy, Kurinchi Selvan; Best, Lawrence Mj; Tanguay, Cynthia; Lennan, Elaine; Korva, Mika; Bussières, Jean-François

2018-03-27

Occupational exposure to hazardous drugs can decrease fertility and result in miscarriages, stillbirths, and cancers in healthcare staff. Several recommended practices aim to reduce this exposure, including protective clothing, gloves, and biological safety cabinets ('safe handling'). There is significant uncertainty as to whether using closed-system drug-transfer devices (CSTD) in addition to safe handling decreases the contamination and risk of staff exposure to infusional hazardous drugs compared to safe handling alone. To assess the effects of closed-system drug-transfer of infusional hazardous drugs plus safe handling versus safe handling alone for reducing staff exposure to infusional hazardous drugs and risk of staff contamination. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, OSH-UPDATE, CINAHL, Science Citation Index Expanded, economic evaluation databases, the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov to October 2017. We included comparative studies of any study design (irrespective of language, blinding, or publication status) that compared CSTD plus safe handling versus safe handling alone for infusional hazardous drugs. Two review authors independently identified trials and extracted data. We calculated the risk ratio (RR) and mean difference (MD) with 95% confidence intervals (CI) using both fixed-effect and random-effects models. We assessed risk of bias according to the risk of bias in non-randomised studies of interventions (ROBINS-I) tool, used an intracluster correlation coefficient of 0.10, and we assessed the quality of the evidence using GRADE. We included 23 observational cluster studies (358 hospitals) in this review. We did not find any randomised controlled trials or formal economic evaluations. In 21 studies, the people who used the intervention (CSTD plus safe handling) and control (safe handling alone) were pharmacists or pharmacy technicians; in the other two studies, the people who used the intervention and control were nurses, pharmacists, or pharmacy technicians. The CSTD used in the studies were PhaSeal (13 studies), Tevadaptor (1 study), SpikeSwan (1 study), PhaSeal and Tevadaptor (1 study), varied (5 studies), and not stated (2 studies). The studies' descriptions of the control groups were varied. Twenty-one studies provide data on one or more outcomes for this systematic review. All the studies are at serious risk of bias. The quality of evidence is very low for all the outcomes.There is no evidence of differences in the proportion of people with positive urine tests for exposure between the CSTD and control groups for cyclophosphamide alone (RR 0.83, 95% CI 0.46 to 1.52; I² = 12%; 2 studies; 2 hospitals; 20 participants; CSTD: 76.1% versus control: 91.7%); cyclophosphamide or ifosfamide (RR 0.09, 95% CI 0.00 to 2.79; 1 study; 1 hospital; 14 participants; CSTD: 6.4% versus control: 71.4%); and cyclophosphamide, ifosfamide, or gemcitabine (RR not estimable; 1 study; 1 hospital; 36 participants; 0% in both groups).There is no evidence of a difference in the proportion of surface samples contaminated in the pharmacy areas or patient-care areas for any of the drugs except 5-fluorouracil, which was lower in the CSTD group than in the control (RR 0.65, 95% CI 0.43 to 0.97; 3 studies, 106 hospitals, 1008 samples; CSTD: 9% versus control: 13.9%).The amount of cyclophosphamide was lower in pharmacy areas in the CSTD group than in the control group (MD -49.34 pg/cm², 95% CI -84.11 to -14.56, I² = 0%, 7 studies; 282 hospitals, 1793 surface samples). Additionally, one interrupted time-series study (3 hospitals; 342 samples) demonstrated a change in the slope between pre-CSTD and CSTD (3.9439 pg/cm², 95% CI 1.2303 to 6.6576; P = 0.010), but not between CSTD and post-CSTD withdrawal (-1.9331 pg/cm², 95% CI -5.1260 to 1.2598; P = 0.20). There is no evidence of difference in the amount of the other drugs between CSTD and control groups in the pharmacy areas or patient-care areas.None of the studies report on atmospheric contamination, blood tests, or other measures of exposure to infusional hazardous drugs such as urine mutagenicity, chromosomal aberrations, sister chromatid exchanges, or micronuclei induction.None of the studies report short-term health benefits such as reduction in skin rashes, medium-term reproductive health benefits such as fertility and parity, or long-term health benefits related to the development of any type of cancer or adverse events.Five studies (six hospitals) report the potential cost savings through the use of CSTD. The studies used different methods of calculating the costs, and the results were not reported in a format that could be pooled via meta-analysis. There is significant variability between the studies in terms of whether CSTD resulted in cost savings (the point estimates of the average potential cost savings ranged from (2017) USD -642,656 to (2017) USD 221,818). There is currently no evidence to support or refute the routine use of closed-system drug transfer devices in addition to safe handling of infusional hazardous drugs, as there is no evidence of differences in exposure or financial benefits between CSTD plus safe handling versus safe handling alone (very low-quality evidence). None of the studies report health benefits.Well-designed multicentre randomised controlled trials may be feasible depending upon the proportion of people with exposure. The next best study design is interrupted time-series. This design is likely to provide a better estimate than uncontrolled before-after studies or cross-sectional studies. Future studies may involve other alternate ways of reducing exposure in addition to safe handling as one intervention group in a multi-arm parallel design or factorial design trial. Future studies should have designs that decrease the risk of bias and enable measurement of direct health benefits in addition to exposure. Studies using exposure should be tested for a relevant selection of hazardous drugs used in the hospital to provide an estimate of the exposure and health benefits of using CSTD. Steps should be undertaken to ensure that there are no other differences between CSTD and control groups, so that one can obtain a reasonable estimate of the health benefits of using CSTD.

Drugs: What You Should Know (For Teens)

MedlinePlus

... need. Several kinds of treatment are available for drug addiction . The two main types are behavioral (helping a ... handling relapses. It can be hard to overcome drug addiction without professional help and treatment. It takes time ...

21 CFR 1.406 - How will FDA handle classified information in an informal hearing?

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 1 2014-04-01 2014-04-01 false How will FDA handle classified information in an... Animal Consumption What Is the Appeal Process for A Detention Order? § 1.406 How will FDA handle... disclosure in the interest of national security (“classified information”), FDA will not provide you with...

21 CFR 1.406 - How will FDA handle classified information in an informal hearing?

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 1 2011-04-01 2011-04-01 false How will FDA handle classified information in an... Animal Consumption What Is the Appeal Process for A Detention Order? § 1.406 How will FDA handle... disclosure in the interest of national security (“classified information”), FDA will not provide you with...

21 CFR 1.406 - How will FDA handle classified information in an informal hearing?

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 1 2012-04-01 2012-04-01 false How will FDA handle classified information in an... Animal Consumption What Is the Appeal Process for A Detention Order? § 1.406 How will FDA handle... disclosure in the interest of national security (“classified information”), FDA will not provide you with...

21 CFR 1.406 - How will FDA handle classified information in an informal hearing?

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 1 2010-04-01 2010-04-01 false How will FDA handle classified information in an... Animal Consumption What Is the Appeal Process for A Detention Order? § 1.406 How will FDA handle... disclosure in the interest of national security (“classified information”), FDA will not provide you with...

21 CFR 1.406 - How will FDA handle classified information in an informal hearing?

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 1 2013-04-01 2013-04-01 false How will FDA handle classified information in an... Animal Consumption What Is the Appeal Process for A Detention Order? § 1.406 How will FDA handle... disclosure in the interest of national security (“classified information”), FDA will not provide you with...

[Preparation and administration of cytotoxic drugs: prickly innovation].

PubMed

Mullot, H; Simon, L; Payen, C; Gentes, P

2005-06-01

The requirement for safe and optimal administration of cytotoxic drugs led us to test a new product manufactured by Codan. The transfer set (CONNECT SET) and the administration set (CYTO-AD-SET) were assessed successively by pharmacist assistance within a centralized unit for cytotoxic drug preparation and by the nursing staff in an ambulatory unit. Transfer sets can be handled in the centralized units without using needles, but with an increased sterilization load and production cost. Assessment of the administration sets demonstrated time saving for the nursing staff. These materials require significant expenditures, careful training, and a change in treatment routine, but provide important time savings for the nursing staff and considerable improvement in the safety of handling cytotoxic drugs.

Influence of Alternative Tubulin Inhibitors on the Potency of a Epirubicin-Immunochemotherapeutic Synthesized with an Ultra Violet Light-Activated Intermediate

PubMed Central

Coyne, C. P.; Jones, Toni; Bear, Ryan

2015-01-01

Immunochemotherapeutics, epirubicin-(C3-amide)-SS-[anti-HER2/neu] with an internal disulfide bond, and epirubicin-(C3-amide)-[anti-HER2/neu] were synthesized utilizing succinimidyl 2-[(4,4′-azipentanamido) ethyl]-1,3′-dithioproprionate or succinimidyl 4,4-azipentanoate respectively. Western blot analysis was used to determine the presence of any immunoglobulin fragmentation or IgG-IgG polymerization. Retained HER2/neu binding characteristics of epirubicin-(C3-amide)-[anti-HER2/neu] and epirubicin-(C3-amide)-SS-[anti-HER2/neu] were validated by cell-ELISA using a mammary adenocarcinoma (SKBr-3) population that highly over-expresses trophic HER2/neu receptor complexes. Cytotoxic anti-neoplastic potency of epirubicin-(C3-amide)-[anti-HER2/neu] and epirubicin-(C3-amide)-SS-[anti-HER2/neu] between epirubicin-equivalent concentrations of 10−10 M and 10−6 M was determined by measuring the vitality/proliferation of chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3 cell type). Cytotoxic anti-neoplastic potency of benzimidazoles (albendazole, flubendazole, membendazole) and griseofulvin were assessed between 0-to-2 μg/ml and 0-to-100 μg/ml respectively while mebendazole and griseofulvin were analyzed at fixed concentrations of 0.35 μg/ml and 35 g/ml respectively in dual combination with gradient concentrations of epirubicin-(C3-amide)-[anti-HER2/neu] and epirubicin-(C3-amide)-SS-[anti-HER2/neu]. Cytotoxic anti-neoplastic potency for epirubicin-(C3-amide)-[anti-HER2/neu] and epirubicin-(C3-amide)-SS-[anti-HER2/neu] against chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3) was nearly identical at epirubicin-equivalent concentrations of 10−10 M and 10−6 M. The benzimadazoles also possessed cytotoxic anti-neoplastic activity with flubendazole and albendazole being the most and least potent respectively. Similarly, griseofulvin had cytotoxic anti-neoplastic activity and was more potent than methylselenocysteine. Both mebendazole and griseofulvin when applied in dual combination with either epirubicin-(C3-amide)-[anti-HER2/neu] or epirubicin-(C3-amide)-SS-[anti-HER2/neu] produced enhanced levels of cytotoxic anti-neoplatic potency. PMID:26225190

Treatment patterns among breast cancer patients in the United States using two national surveys on visits to physicians' offices and hospital outpatient departments.

PubMed

Wittayanukorn, Saranrat; Qian, Jingjing; Westrick, Salisa C; Billor, Nedret; Johnson, Brandon; Hansen, Richard A

2015-01-01

Despite the availability of previous studies, little research has examined how types of anti-neoplastic agents prescribed differ among various populations and health care characteristics in ambulatory settings, which is a primary method of providing care in the U.S. Understanding treatment patterns can help identify possible disparities and guide practice or policy change. To characterize patterns of anti-neoplastic agents prescribed to breast cancer patients in ambulatory settings and identify factors associated with receipt of treatment. A cross-sectional analysis using the National Ambulatory Medical Care Survey data in 2006-2010 was conducted. Breast cancer treatments were categorized by class and further grouped as chemotherapy, hormone, and targeted therapy. A visit-level descriptive analysis using visit sampling weights estimated national prescribing trends (n = 2746 breast cancer visits, weighted n = 28,920,657). Multiple logistic regression analyses identified factors associated with anti-neoplastic agent used. The proportion of visits in which anti-neoplastic agent(s) was/were documented remained stable from 2006 to 2010 (20.47% vs. 24.56%; P > 0.05). Hormones were commonly prescribed (29.69%) followed by mitotic inhibitors (9.86%) and human epidermal growth factor receptor2 inhibitors (5.34%). Patients with distant stage were more likely than patients with in-situ stage to receive treatment (Adjusted Odds Ratio [OR] = 2.79; 95% CI, 1.04-7.77), particularly chemotherapy and targeted therapy. Patients with older age, being ethnic minorities, having comorbid depression, and having U.S. Medicaid insurance were less likely to receive targeted therapy (P < 0.05). Patients with older age, having comorbid obesity and osteoporosis were less likely to receive chemotherapy, while patients seen in hospital-based settings and settings located in metropolitan areas were more likely to receive chemotherapy (P < 0.05). Anti-neoplastic treatment patterns differ among breast cancer patients treated in ambulatory settings. Factors predicting treatment include certain socio-demographics, cancer stages, comorbidities, metropolitan areas, and setting. Copyright © 2015 Elsevier Inc. All rights reserved.

Role of Oxidative Stress in the Induction of Metallothionein-2A and Heme Oxygenase-1 Gene Expression by the Antineoplastic Agent Gallium Nitrate in Human Lymphoma Cells

PubMed Central

Yang, Meiying; Chitambar, Christopher R.

2008-01-01

The mechanisms of action of gallium nitrate, an antineoplastic drug, are only partly understood. Using a DNA microarray to examine genes induced by gallium nitrate in CCRF-CEM cells, we found that gallium increased metallothionein-2A (MT2A) and heme oxygenase-1 (HO-1) gene expression and altered the levels of other stress-related genes. MT2A and HO-1 were increased after 6 and 16 h of incubation with gallium nitrate. An increase in oxidative stress, evidenced by a decrease in cellular GSH and GSH/GSSG ratio, and an increase in dichlorodihydrofluoroscein (DCF) fluorescence, was seen after 1 – 4 h incubation of cells with gallium nitrate. DCF fluorescence was blocked by the mitochondria-targeted antioxidant mitoquinone. N-acetyl-L-cysteine blocked gallium-induced MT2A and HO-1 expression and increased gallium’s cytotoxicity. Studies with a zinc-specific fluoroprobe suggested that gallium produced an expansion of an intracellular labile zinc pool, suggesting an action of gallium on zinc homeostasis. Gallium nitrate increased the phosphorylation of p38 mitogen-activated protein kinase and activated Nrf-2, a regulator of HO-1 gene transcription. Gallium-induced Nrf-2 activation and HO-1 expression were diminished by a p38 MAP kinase inhibitor. We conclude that gallium nitrate induces cellular oxidative stress as an early event which then triggers the expression of HO-1 and MT2A through different pathways. PMID:18586083

Chemotherapy and Cardiotoxicity in Hematologic Malignancies.

PubMed

Stellitano, Antonio; Fedele, Roberta; Barilla, Santina; Iaria, Antonino; Rao, Carmelo Massimiliano; Martino, Massimo

2017-01-01

Antineoplastic agents affect the cardiovascular system, and the incidence of cardiotoxicity is continuously growing in patients with hematologic malignancies and treated with antineoplastic therapy. In this mini-review, we analyzed existing literature which evaluates the likelihood of cardiotoxicity related to the main agents employed in the treatment of hematologic malignancies. There is a significant need to optimize the early identification of patients who are at risk of cardiotoxicity. The conventional echocardiographic measurements used to detect cardiac alterations, such as LVEF, fractional shortening, diameters and volumes, allow only a late diagnosis of cardiac dysfunction, which might be already irreversible. The early identification of patients at risk for rapid progression towards irreversible cardiac failure has a primary purpose, the opportunity for them to benefit from early preventive and therapeutic measures. A useful imaging technique that points in this direction detecting subclinical LVD may be the speckle tracking echocardiography, that has demonstrated a previous detection of myocardial contractile dysfunction compared to the traditional left ventricular ejection fraction. In this view, the discovery of new biomarkers to identify patients at a high risk for the development of these complications is another priority. Cardiotoxicity induced by anticancer drugs is always the outcome of several concurrent factors. It is plausible that an asymptomatic dysfunction precedes clinical events. During this asymptomatic phase, an early treatment prepares the patient for cardiovascular "safety" conditions; on the other hand, a late or missing treatment paves the ground for the development of future cardiac events. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Matched pairs dosimetry: 124I/131I metaiodobenzylguanidine and 124I/131I and 86Y/90Y antibodies.

PubMed

Lopci, Egesta; Chiti, Arturo; Castellani, Maria Rita; Pepe, Giovanna; Antunovic, Lidija; Fanti, Stefano; Bombardieri, Emilio

2011-05-01

The technological advances in imaging and production of radiopharmaceuticals are driving an innovative way of evaluating the targets for antineoplastic therapies. Besides the use of imaging to better delineate the volume of external beam radiation therapy in oncology, modern imaging techniques are able to identify targets for highly specific medical therapies, using chemotherapeutic drugs and antiangiogenesis molecules. Moreover, radionuclide imaging is able to select targets for radionuclide therapy and to give the way to in vivo dose calculation to target tissues and to critical organs. This contribution reports the main studies published on matched pairs dosimetry with (124)I/(131)I- and (86)Y/(90)Y-labelled radiopharmaceuticals, with an emphasis on metaiodobenzylguanidine (MIBG) and monoclonal antibodies.

The cancer theory of pulmonary arterial hypertension

PubMed Central

Boucherat, Olivier; Vitry, Geraldine; Trinh, Isabelle; Paulin, Roxane; Provencher, Steeve; Bonnet, Sebastien

2017-01-01

Pulmonary arterial hypertension (PAH) remains a mysterious killer that, like cancer, is characterized by tremendous complexity. PAH development occurs under sustained and persistent environmental stress, such as inflammation, shear stress, pseudo-hypoxia, and more. After inducing an initial death of the endothelial cells, these environmental stresses contribute with time to the development of hyper-proliferative and apoptotic resistant clone of cells including pulmonary artery smooth muscle cells, fibroblasts, and even pulmonary artery endothelial cells allowing vascular remodeling and PAH development. Molecularly, these cells exhibit many features common to cancer cells offering the opportunity to exploit therapeutic strategies used in cancer to treat PAH. In this review, we outline the signaling pathways and mechanisms described in cancer that drive PAH cells’ survival and proliferation and discuss the therapeutic potential of antineoplastic drugs in PAH. PMID:28597757

The use of liquid chromatography-tandem mass spectrometry for therapeutic drug monitoring of antibiotics in cancer patients.

PubMed

El-Najjar, Nahed; Jantsch, Jonathan; Gessner, André

2017-08-28

Cancer remains a leading cause of mortality and morbidity worldwide. In addition to organ failure, the most frequent reasons for admission of cancer patients to intensive care units (ICU) are: infections and sepsis. As critically ill, the complexity of the health situation of cancer patients renders the standard antimicrobial regimen more complex and even inadequate which results in increased mortality rates. This is due to pathophysiological changes in the volume of distribution, increased clearance, as well as to organ dysfunction. While in the former cases a decrease in drug efficacy is observed, the hallmark of the latter one is overdosing leading to increased toxicity at the expense of efficacy. Furthermore, an additional risk factor is the potential drug-drug interaction between antibiotics and antineoplastic agents. Therefore, therapeutic drug monitoring (TDM) is a necessity to improve the clinical outcome of antimicrobial therapy in cancer patients. To be applied in routine analysis the method used for TDM should be cheap, fast and highly accurate/sensitive. Furthermore, as ICU patients are treated with a cocktail of antibiotics the method has to cover the simultaneous analysis of antibiotics used as a first/second line of treatment. The aim of the current review is to briefly survey the pitfalls in the current antimicrobial therapy and the central role of TDM in dose adjustment and drug-drug interaction's evaluation. A major section is dedicated to summarize the currently published analytical methods and to shed light on the difficulties and potential problems that can be encountered during method development.

A novel intracellular pH-responsive formulation for FTY720 based on PEGylated graphene oxide nano-sheets.

PubMed

Masoudipour, Elham; Kashanian, Soheila; Maleki, Nasim; Karamyan, Ali; Omidfar, Kobra

2018-01-01

This study was performed to investigate a novel pH-responsive nanocarrier based on modified nano graphene oxide (nGO) to promote the acid-triggered intracellular release of a poorly soluble drug, FTY720. To synthesize a drug conjugated to modified nGO, first the polyethylene glycol (PEG) was conjugated to nGO, then the produced PEG-nGO was functionalized with the anticancer drug, FTY720, through amide bonding. It was characterized by the scanning electron microscopy (SEM), the atomic force microscopy (AFM), the Fourier transform infrared (FTIR) spectroscopy and the UV-vis spectroscopy. In vitro drug release of the FTY720-conjugated PEG-nGO was evaluated at pH 7.4 and 4.6 PBS at 37 °C. Furthermore, the antineoplastic action of unloaded and drug-loaded carrier against the human breast adenocarcinoma cell line MCF7 was explored using MTT and BrdU assays. Characterization methods indicated successful drug deposition on the surface of nGO. In vitro, drug release results revealed a significantly faster release of FTY720 from PEG-nGO at acidic pH, compared with physiological pH. The proliferation assays proved that the unloaded nGO had no significant cytotoxicity against MCF7 cells, while free FTY720- and FTY720-loaded PEG-nGO had an approximately equal cytotoxic effect on the MCF7 cells. It was found that the extended release characteristic of FTY720 was well fitted to Korsmeyer-Peppas model and the release profile of FTY720 from PEG-nGO is diffusion controlled. PEGylated GO can act as a pH-responsive drug carrier to improve the efficacy of anticancer drug delivery.

The possible role of chemotherapy in antiangiogenic drug resistance.

PubMed

Bocci, Guido; Loupakis, Fotios

2012-05-01

The use of antiangiogenic drugs for cancer treatment was welcomed because of the hypothesis that they would be much less likely to lose their therapeutic activity as a result of tumor-acquired resistance over time. Unfortunately, the clinical experience has shown that acquired resistance to antiangiogenic therapeutic strategies is possible since many patients whose tumors initially respond to drugs such as bevacizumab (a monoclonal antibody against VEGF), sorafenib, or sunitinib (tyrosine kinase inhibitors targeting VEGF receptors and PDGF receptors) or metronomic chemotherapy (e.g. low dose cyclophosphamide) become nonresponsive, often within months of therapy initiation. Indeed, the role of associated antineoplastic chemotherapy in antiangiogenic resistance seems to be ignored by the previous studies and the real part played by these drugs has to be written yet. The studies undertaken on antiangiogenic resistance mainly involved mechanisms directly related to the antiangiogenic drugs alone and as such lead one to ask whether the acquired resistance to angiogenesis pathway-targeting might also be mediated by the chemotherapeutic drugs usually associated (at least into the clinic) with these types of drugs. The proposed hypothesis is concerning the possibility that the acquired resistance to antiangiogenic therapy could be actively and heavily modulated by the choice of the associated chemotherapeutic drug. The chemotherapeutic compounds may delay or accelerate the process through the induction, upregulation or downregulation of pro-angiogenic or anti-angiogenic factors or their receptors in the tumor, endothelial and other type of cells of the tumor microenvironment. In conclusion, the consequences of our hypothesis could be promptly translated into the preclinical studies and verified in clinical trials, involving cancer patients resistant to chemotherapy plus antiangiogenic drug schedules. Copyright © 2012 Elsevier Ltd. All rights reserved.

Taxanes: vesicants, irritants, or just irritating?

PubMed

Barbee, Meagan S; Owonikoko, Taofeek K; Harvey, R Donald

2014-01-01

Several classes of antineoplastic agents are universally referred to as vesicants with ample supporting literature. However, the literature surrounding the taxanes is controversial. While the American Society of Clinical Oncology and Oncology Nursing Society Chemotherapy Administration Safety Standards and the Chemotherapy and Biotherapy Guidelines and Recommendations for Practice identify the risks of extravasation and the parameters surrounding the infusion of known vesicants, recommend administration sites for known agents, and recommend antidotes for particular extravasation cases, they fail to provide specific recommendations for the administration of individual taxanes, or a classification system for antineoplastic agents as vesicants, irritants, or inert compounds. There is also a lack of prescribing information regarding such recommendations. The lack of a formal classification system further complicates the accurate delineation of vesicant antineoplastic agents and subsequent appropriate intravenous administration and extravasation management. There are several factors that make the classification of taxanes as vesicants or irritants challenging. Comprehensive preclinical data describing potential mechanisms of tissue damage or vesicant-like properties are lacking. Furthermore, most case reports of taxane extravasation fail to include the parameters surrounding administration, such as the concentration of medication and duration of infusion, making it difficult to set parameters for vesicant potential. Subsequently, many practitioners default to central venous administration of taxanes without evidence that such administration minimizes the risk of extravasation or improves outcomes thereof. Here, we review briefly the data surrounding taxane extravasation and potential vesicant or irritant properties, classify the taxanes, and propose a spectrum for antineoplastic agent potential to cause tissue injury that warrants clinical intervention if extravasation occurs.

Dosing of antirheumatic drugs in renal disease and dialysis.

PubMed

Swarup, Areena; Sachdeva, Namita; Schumacher, H Ralph

2004-08-01

Many patients with rheumatic diseases have their management complicated by renal problems. Renal failure modifies the metabolism of many drugs, especially by retention. Questions often arise about the effects of renal failure on the handling of drugs commonly used in rheumatology. For which drugs must we be especially concerned about increased toxicity? Patients on chronic dialysis may also need a variety of drugs for rheumatic disease. How are our drugs dialyzed, and which of these can be safety used and how best to use them?Decisions about dosing of rheumatic drugs are often required for the patients with chronic renal insufficiency or on long-term dialysis, although many drugs have not been formally studied in these settings. Patients with renal insufficiency are excluded from most drug trials. Data for some of these drugs have to be extrapolated based on the information available about the pharmacokinetics of the drug.This review addresses dosing of commonly used drugs in rheumatology in patients with chronic renal insufficiency or failure. It is compiled from a MEDLINE search of papers dealing with renal handling of antirheumatic drugs and suggestions for dose adjustments for these drugs. Drugs reviewed include commonly used disease-modifying antirheumatic drugs (DMARDS), drugs used for treatment of gout, commonly used nonsteroidal antnflammatory drugs (NSAIDS) and the newer COX-2 inhibitors.

Preliminary screening of some traditional Zulu medicinal plants for antineoplastic activities versus the HepG2 cell line.

PubMed

Opoku, A R; Geheeb-Keller, M; Lin, J; Terblanche, S E; Hutchings, A; Chuturgoon, A; Pillay, D

2000-11-01

Aqueous and methanol extracts of nine traditional Zulu medicinal plants, Cissus quandrangularis L., Cyphostemma flaviflorum (Sprague) Descoings, Cyphostemma lanigerum (Harv.) Descoings ex Wild & Drum, Cyphostemma natalitium (Szyszyl.) J. v. d. Merwe, Cyphostemma sp., Rhoicissus digitata (L. F.) Gilg & Brandt, Rhoicissus rhomboidea (E. Mey. Ex harv.) Planch, Rhoicissus tomentosa (Lam.) Wild & Drum, R. tridentata (L. F.) Wild & Drum and Rhoicissus tridentata (L. F.) Wild & Drum subsp. cuneifolia (Eckl. & Zeyh.) N. R. Urton, all belonging to the Vitaceae family, were evaluated to determine their therapeutic potentials as antineoplastic agents. The antiproliferative activity in vitro against HepG2 cells was determined. Twenty-two of the twenty-seven crude plant extracts showed activities ranging from 25% to 97% inhibition of proliferation when compared with the control which showed no inhibitory activity. Higher degrees of growth inhibition were found in aqueous root extracts in comparison with the methanol extracts of the same plant parts. The results show potential antineoplastic activity, indicating some scientific validation for traditional usage. Copyright 2000 John Wiley & Sons, Ltd.

How to Deal with the Drug Problem on Campus

ERIC Educational Resources Information Center

Hecklinger, Fred J.

1971-01-01

The author contends that an educational program is worth very little without an effective policy on handling illegal drug activity. Presented is a proposal for an institutional response toward dealing with the use of illegal drugs on campus. (Author)

Templates of patient brochures for the preparation, administration and safe-handling of oral chemotherapy.

PubMed

Siden, Rivka; Kem, Ravie; Ostrenga, Andrew; Nicksy, Darcy; Bernhardt, Brooke; Bartholomew, Joy

2014-06-01

The increased use of oral chemotherapy for the treatment of cancer introduces new challenges for patients and caregivers. Among them are the ability to swallow oral solid dosage forms, the proper administration of the agents and the safe-handling of chemotherapeutic drugs in the home. Since these drugs are hazardous, proper preparation, administration, and disposition introduces a variety of safety issues. The increased toxicity of these drugs coupled with complicated dosing regimens and the occasional need to dilute the drug or measure a liquid dosage form require careful instruction of the patient and/or caregivers. The purpose of this project was to create templates for writing patient instruction brochures. A group of clinicians specializing in oncology from several institutions in the United States and Canada met through a series of conference calls. The group included pharmacists with a specialty in pediatric oncology, investigational drug pharmacists, and an oncology nurse practitioner. National guidelines and practices at each institution were used for the creation of templates to be used in developing templates for medication and formulation-specific instruction brochures. The group developed six templates. The templates ranged in scope from instructions on the administration of intact tablets or capsules to directions on opening capsules or crushing tablets and mixing the content with foods or liquids. Thirty-three drug-specific brochures were developed using the templates. Templates of patient brochures and drug-specific brochures on the safe handling of chemotherapy in the home can be created using a collaborative, multi-institutional approach.

Natural variation in a single amino acid substitution underlies physiological responses to topoisomerase II poisons.

PubMed

Zdraljevic, Stefan; Strand, Christine; Seidel, Hannah S; Cook, Daniel E; Doench, John G; Andersen, Erik C

2017-07-01

Many chemotherapeutic drugs are differentially effective from one patient to the next. Understanding the causes of this variability is a critical step towards the development of personalized treatments and improvements to existing medications. Here, we investigate sensitivity to a group of anti-neoplastic drugs that target topoisomerase II using the model organism Caenorhabditis elegans. We show that wild strains of C. elegans vary in their sensitivity to these drugs, and we use an unbiased genetic approach to demonstrate that this natural variation is explained by a methionine-to-glutamine substitution in topoisomerase II (TOP-2). The presence of a non-polar methionine at this residue increases hydrophobic interactions between TOP-2 and its poison etoposide, as compared to a polar glutamine. We hypothesize that this stabilizing interaction results in increased genomic instability in strains that contain a methionine residue. The residue affected by this substitution is conserved from yeast to humans and is one of the few differences between the two human topoisomerase II isoforms (methionine in hTOPIIα and glutamine in hTOPIIβ). We go on to show that this amino acid difference between the two human topoisomerase isoforms influences cytotoxicity of topoisomerase II poisons in human cell lines. These results explain why hTOPIIα and hTOPIIβ are differentially affected by various poisons and demonstrate the utility of C. elegans in understanding the genetics of drug responses.

Drug Targeting and Biomarkers in Head and Neck Cancers: Insights from Systems Biology Analyses.

PubMed

Islam, Tania; Rahman, Rezanur; Gov, Esra; Turanli, Beste; Gulfidan, Gizem; Haque, Anwarul; Arga, Kazım Yalçın; Haque Mollah, Nurul

2018-06-01

The head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers in the world, but robust biomarkers and diagnostics are still not available. This study provides in-depth insights from systems biology analyses to identify molecular biomarker signatures to inform systematic drug targeting in HNSCC. Gene expression profiles from tumors and normal tissues of 22 patients with histological confirmation of nonmetastatic HNSCC were subjected to integrative analyses with genome-scale biomolecular networks (i.e., protein-protein interaction and transcriptional and post-transcriptional regulatory networks). We aimed to discover molecular signatures at RNA and protein levels, which could serve as potential drug targets for therapeutic innovation in the future. Eleven proteins, 5 transcription factors, and 20 microRNAs (miRNAs) came into prominence as potential drug targets. The differential expression profiles of these reporter biomolecules were cross-validated by independent RNA-Seq and miRNA-Seq datasets, and risk discrimination performance of the reporter biomolecules, BLNK, CCL2, E4F1, FOSL1, ISG15, MMP9, MYCN, MYH11, miR-1252, miR-29b, miR-29c, miR-3610, miR-431, and miR-523, was also evaluated. Using the transcriptome guided drug repositioning tool, geneXpharma, several candidate drugs were repurposed, including antineoplastic agents (e.g., gemcitabine and irinotecan), antidiabetics (e.g., rosiglitazone), dermatological agents (e.g., clocortolone and acitretin), and antipsychotics (e.g., risperidone), and binding affinities of the drugs to their potential targets were assessed using molecular docking analyses. The molecular signatures and repurposed drugs presented in this study warrant further attention for experimental studies since they offer significant potential as biomarkers and candidate therapeutics for precision medicine approaches to clinical management of HNSCC.

Curcumin loaded pH-sensitive hybrid lipid/block copolymer nanosized drug delivery systems.

PubMed

Jelezova, Ivelina; Drakalska, Elena; Momekova, Denitsa; Shalimova, Natalia; Momekov, Georgi; Konstantinov, Spiro; Rangelov, Stanislav; Pispas, Stergios

2015-10-12

Curcumin is a perspective drug candidate with pleiotropic antineoplastic activity, whose exceptionally low aqueous solubility and poor pharmacokinetic properties have hampered its development beyond the preclinical level. A possible approach to overcome these limitations is the encapsulation of curcumin into nano-carriers, incl. liposomes. The present contribution is focused on feasibility of using hybrid pH-sensitive liposomes, whereby curcumin is entrapped as a free drug and as a water soluble inclusion complex with PEGylated tert-butylcalix[4]arene, which allows the drug to occupy both the phospholipid membranes and the aqueous core of liposomes. The inclusion complexes were encapsulated in dipalmithoylphosphathydilcholine:cholesterol liposomes, whose membranes were grafted with a poly(isoprene-b-acrylic acid) diblock copolymer to confer pH-sensitivity. The liposomes were characterized by DLS, ζ-potential measurements, cryo-TEM, curcumin encapsulation efficacy, loading capacity, and in vitro release as a function of pH. Free and formulated curcumin were further investigated for cytotoxicity, apoptosis-induction and caspase-8, and 9 activation in chemosensitive HL-60 and its resistant sublines HL-60/Dox and HL-60/CDDP. Formulated curcumin was superior cytotoxic and apoptogenic agent vs. the free drug. The mechanistic assay demonstrated that the potent proapoptotic effects of pH-sensitive liposomal curcumin presumably mediated via recruitment of both extrinsic and intrinsic apoptotic pathways in both HL-60 and HL-60/CDDP cells. Copyright © 2015 Elsevier B.V. All rights reserved.

The Australian Managed Entry Scheme: Are We Getting it Right?

PubMed

Tuffaha, Haitham W; Scuffham, Paul A

2018-05-01

In 2010, the Australian Government introduced the managed entry scheme (MES) to improve patient access to subsidised drugs on the Pharmaceutical Benefits Scheme and enhance the quality of evidence provided to decision makers. The aim of this paper was to critically review the Australian MES experience. We performed a comprehensive review of publicly available Pharmaceutical Benefits Advisory Committee online documents from January 2010 to July 2017. Relevant information on each MES agreement was systematically extracted, including its rationale, the conditions that guided its implementation and its policy outcomes. We identified 11 drugs where an MES was considered. Most of the identified drugs (75%) were antineoplastic agents and the main uncertainty was the overall survival benefit. More than half of the MES proposals were made by sponsors and most of the schemes were considered after previous rejected/deferred submissions for reimbursement. An MES was not established in 8 of 11 drugs (73%) despite the high evidence uncertainty. Nevertheless, six of these eight drugs were listed after the sponsors reduced their prices. Three MESs were established and implemented by Deeds of Agreement. The three cases were concluded and the required data were submitted within the agreed time frames. The need for feasibility and value of an MES should be carefully considered by stakeholders before embarking on such an agreement. It is essential to engage major stakeholders, including patient representatives, in this process. The conditions governing MESs should be clear, transparent and balanced to address the expectations of various stakeholders.

Targeting ferritin receptors for the selective delivery of imaging and therapeutic agents to breast cancer cells

NASA Astrophysics Data System (ADS)

Geninatti Crich, S.; Cadenazzi, M.; Lanzardo, S.; Conti, L.; Ruiu, R.; Alberti, D.; Cavallo, F.; Cutrin, J. C.; Aime, S.

2015-04-01

In this work the selective uptake of native horse spleen ferritin and apoferritin loaded with MRI contrast agents has been assessed in human breast cancer cells (MCF-7 and MDA-MB-231). The higher expression of L-ferritin receptors (SCARA5) led to an enhanced uptake in MCF-7 as shown in T2 and T1 weighted MR images, respectively. The high efficiency of ferritin internalization in MCF-7 has been exploited for the simultaneous delivery of curcumin, a natural therapeutic molecule endowed with antineoplastic and anti-inflammatory action, and the MRI contrast agent Gd-HPDO3A. This theranostic system is able to treat selectively breast cancer cells over-expressing ferritin receptors. By entrapping in apoferritin both Gd-HPDO3A and curcumin, it was possible to deliver a therapeutic dose of 167 μg ml-1 (as calculated by MRI) of this natural drug to MCF-7 cells, thus obtaining a significant reduction of cell proliferation.In this work the selective uptake of native horse spleen ferritin and apoferritin loaded with MRI contrast agents has been assessed in human breast cancer cells (MCF-7 and MDA-MB-231). The higher expression of L-ferritin receptors (SCARA5) led to an enhanced uptake in MCF-7 as shown in T2 and T1 weighted MR images, respectively. The high efficiency of ferritin internalization in MCF-7 has been exploited for the simultaneous delivery of curcumin, a natural therapeutic molecule endowed with antineoplastic and anti-inflammatory action, and the MRI contrast agent Gd-HPDO3A. This theranostic system is able to treat selectively breast cancer cells over-expressing ferritin receptors. By entrapping in apoferritin both Gd-HPDO3A and curcumin, it was possible to deliver a therapeutic dose of 167 μg ml-1 (as calculated by MRI) of this natural drug to MCF-7 cells, thus obtaining a significant reduction of cell proliferation. Electronic supplementary information (ESI) available: Competition studies with free apoferritin, Fig. S1; APO-FITC intracellular distribution by immunofluorescence, Fig. S2. See DOI: 10.1039/c5nr00352k

Response of Human Prostate Cancer Cells to Mitoxantrone Treatment in Simulated Microgravity Environment

NASA Technical Reports Server (NTRS)

Zhang, Ye; Edwards, Christopher; Wu, Honglu

2011-01-01

This study explores the changes in growth of human prostate cancer cells (LNCaP) and their response to the treatment of antineoplastic agent, mitoxantrone, under the simulated microgravity condition. In comparison to static 1g, microgravity and simulated microgravity have been shown to alter global gene expression patterns and protein levels in various cultured cell models or animals. However, very little is known about the effect of altered gravity on the responses of cells to drugs, especially chemotherapy drugs. To test the hypothesis that zero gravity would result in altered regulation of cells in response to antineoplastic agents, we cultured LNCaP cells for 96 hr either in a High Aspect Ratio Vessel (HARV) bioreactor at the rotating condition to model microgravity in space or in the static condition as a control. 24 hr after the culture started, mitoxantrone was introduced to the cells at a final concentration of 1 M. The mitoxantrone treatment lasted 72 hr and then the cells were collected for various measurements. Compared to static 1g controls, the cells cultured in the simulated microgravity environment did not show significant differences in cell viability, growth rate, or cell cycle distribution. However, in response to mitoxantrone (1uM), a significant proportion of bioreactor cultured cells (30%) was arrested at G2 phase and a significant number of these cells were apoptotic in comparison to their static controls. The expressions of 84 oxidative stress related genes were analyzed using Qiagen PCR array to identify the possible mechanism underlying the altered responses of bioreactor culture cells to mitoxantrone. Nine out of 84 genes showed higher expression at four hour post mitoxantrone treatment in cells cultured at rotating condition compared to those at static. Taken together, the results reported here indicate that simulated microgravity may alter the responses of LNCaP cells to mitoxantrone treatment. The alteration of oxidative stress pathways in cells cultured under simulated microgravity conditions may be one of the mechanisms to cause such changes of sensitivity of LNCaP cells to mitoxantrone treatment.

A rationale for the use of proton pump inhibitors as antineoplastic agents.

PubMed

De Milito, Angelo; Marino, Maria Lucia; Fais, Stefano

2012-01-01

It is becoming increasingly acknowledged that tumorigenesis is not simply characterized by the accumulation of rapidly proliferating, genetically mutated cells. Microenvironmental biophysical factors like hypoxia and acidity dramatically condition cancer cells and act as selective forces for malignant cells, adapting through metabolic reprogramming towards aerobic glycolysis. Avoiding intracellular accumulation of lactic acid and protons, otherwise detrimental to cell survival is crucial for malignant cells to maintain cellular pH homeostasis. As a consequence of the upregulated expression and/or function of several pH-regulating systems, cancer cells display an alkaline intracellular pH (pHi) and an acidic extracellular pH (pHe). Among the pH-regulating proteins, proton pumps play an important role in both drug-resistance and metastatic spread, thus representing a suitable therapeutic target. Proton pump inhibitors (PPI) have been reported as cytotoxic drugs active against several human tumor cells and preclinical data have prompted the investigation of PPI as anticancer agents in humans. This review will update the current knowledge on the antitumor activities of PPI and their potential applications.

Artemisinin-derived dimer ART-838 potently inhibited human acute leukemias, persisted in vivo, and synergized with antileukemic drugs

PubMed Central

Fox, Jennifer M.; Moynihan, James R.; Mott, Bryan T.; Mazzone, Jennifer R.; Anders, Nicole M.; Brown, Patrick A.; Rudek, Michelle A.; Liu, Jun O.; Arav-Boger, Ravit; Posner, Gary H.

2016-01-01

Artemisinins, endoperoxide-containing molecules, best known as antimalarials, have potent antineoplastic activity. The established antimalarial, artesunate (AS), and the novel artemisinin-derived trioxane diphenylphosphate dimer 838 (ART-838) inhibited growth of all 23 tested acute leukemia cell lines, reduced cell proliferation and clonogenicity, induced apoptosis, and increased intracellular levels of reactive oxygen species (ROS). ART-838 was 88-fold more potent that AS in vitro, inhibiting all leukemia cell lines at submicromolar concentrations. Both ART-838 and AS cooperated with several established antileukemic drugs and newer kinase inhibitors to inhibit leukemia cell growth. ART-838 had a longer plasma half-life than AS in immunodeficient NOD-SCID-IL2Rgnull (NSG) mice, remaining at effective antileukemic concentrations for >8h. Intermittent cycles of ART-838 inhibited growth of acute leukemia xenografts and primagrafts in NSG mice, at higher potency than AS. Based on these preclinical data, we propose that AS, with its established low toxicity and low cost, and ART-838, with its higher potency and longer persistence in vivo, should be further developed toward integration into antileukemic regimens. PMID:26771236

Antiapoptotic and antigenotoxic effects of N-acetylcysteine in human cells of endothelial origin.

PubMed

Aluigi, M G; De Flora, S; D'Agostini, F; Albini, A; Fassina, G

2000-01-01

N-Acetylcysteine (NAC) is a drug bearing multiple preventive properties that can inhibit genotoxicity and carcinogenicity. NAC also inhibits invasion and metastasis of malignant cells, as well as tumor take. We recently demonstrated the effects of NAC on Kaposi's sarcoma cells supernatant-induced invasion in vitro and angiogenesis in vivo. Many anticancer agents act through cytotoxicity of rapidly proliferating cells and several antineoplastic drugs induce apoptosis of cancer cells. Since endothelial cells are the target for the inhibition of angiogenesis, we wanted to verify that NAC, while inhibiting tumor vascularization and endothelial cell invasion would not induce endothelial cell apoptosis. We tested the ability of NAC to modulate apoptosis and cytogenetic damage in vitro and to promote differentiation on a reconstituted basement membrane (matrigel) in two endothelial cell lines (EAhy926 and HUVE). Treatment with NAC protected endothelial cells from TGF-beta-induced apoptosis and paraquat-induced cytogenetic damage. Therefore, NAC acts as an antiangiogenic agent and, at the same time, appears to prevent apoptosis and oxygen-related genotoxicity in endothelial cells.

Drug Monographs: Atezolizumab and Everolimus.

PubMed

Green, Matthew A; Waddell, J Aubrey; Solimando, Dominic A

2016-11-01

The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparation, dispensing, and administration of antineoplastic therapy, and the agents, both commercially available and investigational, used to treat malignant diseases. Questions or suggestions for topics should be addressed to Dominic A. Solimando, Jr., President, Oncology Pharmacy Services, Inc., 4201 Wilson Blvd #110-545, Arlington, VA 22203, email: OncRxSvc@comcast.net; or J. Aubrey Waddell, Professor, University of Tennessee College of Pharmacy; Oncology Pharmacist, Pharmacy Department, Blount Memorial Hospital, 907 E. Lamar Alexander Parkway, Maryville, TN 37804, e-mail: waddfour@charter.net. The authors are not employees of, under contract to, recipients of funding to review products from, or in any other way affiliated with either Genentech, Inc. or Novartis Pharmaceuticals Corporation. The information presented in this review is based on published data and clinical expertise and includes information not included in the product labeling. Incorporation of such published data provides a more robust assessment of the drugs and assists pharmacists in evaluation of orders for off-label use of these agents.

Marizomib, a potent second generation proteasome inhibitor from natural origin.

PubMed

Ma, Long; Diao, Aipo

2015-01-01

The malignance of cancers reinforces the need to find potent antineoplastic agents. In the past decades, proteasome has been witnessed as a potential target to fulfil this purpose, as evidenced by the fact that the first-in-class proteasome inhibitor Bortezomib was marketed in 2003. Marizomib (Salinosporamide A, NPI-0052), as a marine natural product, promises to be of high efficacy against multiple myeloma (MM), relapsed/refractory MM and other types of solid tumours. Compared with Bortezomib, it arguably has fewer severe side effects. Marizomib has been termed as orphan drug against multiple myeloma by US Food and Drug Administration (FDA) in 2013 and by European Medicines Agency (EMA) in 2014. As one of the second generation proteasome inhibitors (PIs), Marizomib is expected to bring about a sustained and complete therapeutic to extend cancer patients' life span. In this article, we intended to briefly review the historical developments, mechanisms, pharmacology, biosynthesis and side effects of this agent, aiming to provide concise coverage for a broad readership. In the end, we proposed our perspective for its futuristic applications.

42 CFR 491.9 - Provision of services.

Code of Federal Regulations, 2010 CFR

2010-10-01

... center. (iii) Rules for the storage, handling, and administration of drugs and biologicals. (4) These... has available the drugs and biologicals commonly used in life saving procedures, such as analgesics...

42 CFR 491.9 - Provision of services.

Code of Federal Regulations, 2011 CFR

2011-10-01

... center. (iii) Rules for the storage, handling, and administration of drugs and biologicals. (4) These... has available the drugs and biologicals commonly used in life saving procedures, such as analgesics...

21 CFR 1301.71 - Security requirements generally.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 9 2011-04-01 2011-04-01 false Security requirements generally. 1301.71 Section 1301.71 Food and Drugs DRUG ENFORCEMENT ADMINISTRATION, DEPARTMENT OF JUSTICE REGISTRATION OF... dosage units, usable powders or nonusable powders); (3) The quantity of controlled substances handled; (4...

21 CFR 1301.71 - Security requirements generally.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 9 2013-04-01 2013-04-01 false Security requirements generally. 1301.71 Section 1301.71 Food and Drugs DRUG ENFORCEMENT ADMINISTRATION, DEPARTMENT OF JUSTICE REGISTRATION OF... dosage units, usable powders or nonusable powders); (3) The quantity of controlled substances handled; (4...

21 CFR 1301.71 - Security requirements generally.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 9 2012-04-01 2012-04-01 false Security requirements generally. 1301.71 Section 1301.71 Food and Drugs DRUG ENFORCEMENT ADMINISTRATION, DEPARTMENT OF JUSTICE REGISTRATION OF... dosage units, usable powders or nonusable powders); (3) The quantity of controlled substances handled; (4...

21 CFR 1301.71 - Security requirements generally.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 9 2014-04-01 2014-04-01 false Security requirements generally. 1301.71 Section 1301.71 Food and Drugs DRUG ENFORCEMENT ADMINISTRATION, DEPARTMENT OF JUSTICE REGISTRATION OF... dosage units, usable powders or nonusable powders); (3) The quantity of controlled substances handled; (4...

A potential non-invasive glioblastoma treatment: Nose-to-brain delivery of farnesylthiosalicylic acid incorporated hybrid nanoparticles.

PubMed

Sekerdag, Emine; Lüle, Sevda; Bozdağ Pehlivan, Sibel; Öztürk, Naile; Kara, Aslı; Kaffashi, Abbas; Vural, Imran; Işıkay, Ilkay; Yavuz, Burҫin; Oguz, Kader Karlı; Söylemezoğlu, Figen; Gürsoy-Özdemir, Yasemin; Mut, Melike

2017-09-10

New drug delivery systems are highly needed in research and clinical area to effectively treat gliomas by reaching a high antineoplastic drug concentration at the target site without damaging healthy tissues. Intranasal (IN) administration, an alternative route for non-invasive drug delivery to the brain, bypasses the blood-brain-barrier (BBB) and eliminates systemic side effects. This study evaluated the antitumor efficacy of farnesylthiosalicylic acid (FTA) loaded (lipid-cationic) lipid-PEG-PLGA hybrid nanoparticles (HNPs) after IN application in rats. FTA loaded HNPs were prepared, characterized and evaluated for cytotoxicity. Rat glioma 2 (RG2) cells were implanted unilaterally into the right striatum of female Wistar rats. 10days later, glioma bearing rats received either no treatment, or 5 repeated doses of 500μM freshly prepared FTA loaded HNPs via IN or intravenous (IV) application. Pre-treatment and post-treatment tumor sizes were determined with MRI. After a treatment period of 5days, IN applied FTA loaded HNPs achieved a significant decrease of 55.7% in tumor area, equal to IV applied FTA loaded HNPs. Herewith, we showed the potential utility of IN application of FTA loaded HNPs as a non-invasive approach in glioblastoma treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

Methotrexate diethyl ester-loaded lipid-core nanocapsules in aqueous solution increased antineoplastic effects in resistant breast cancer cell line.

PubMed

Yurgel, Virginia C; Oliveira, Catiuscia P; Begnini, Karine R; Schultze, Eduarda; Thurow, Helena S; Leon, Priscila M M; Dellagostin, Odir A; Campos, Vinicius F; Beck, Ruy C R; Guterres, Silvia S; Collares, Tiago; Pohlmann, Adriana R; Seixas, Fabiana K

2014-01-01

Breast cancer is the most frequent cancer affecting women. Methotrexate (MTX) is an antimetabolic drug that remains important in the treatment of breast cancer. Its efficacy is compromised by resistance in cancer cells that occurs through a variety of mechanisms. This study evaluated apoptotic cell death and cell cycle arrest induced by an MTX derivative (MTX diethyl ester [MTX(OEt)2]) and MTX(OEt)2-loaded lipid-core nanocapsules in two MTX-resistant breast adenocarcinoma cell lines, MCF-7 and MDA-MB-231. The formulations prepared presented adequate granulometric profile. The treatment responses were evaluated through flow cytometry. Relying on the mechanism of resistance, we observed different responses between cell lines. For MCF-7 cells, MTX(OEt)2 solution and MTX(OEt)2-loaded lipid-core nanocapsules presented significantly higher apoptotic rates than untreated cells and cells incubated with unloaded lipid-core nanocapsules. For MDA-MB-231 cells, MTX(OEt)2-loaded lipid-core nanocapsules were significantly more efficient in inducing apoptosis than the solution of the free drug. S-phase cell cycle arrest was induced only by MTX(OEt)2 solution. The drug nanoencapsulation improved apoptosis induction for the cell line that presents MTX resistance by lack of transport receptors.

Methotrexate diethyl ester-loaded lipid-core nanocapsules in aqueous solution increased antineoplastic effects in resistant breast cancer cell line

PubMed Central

Yurgel, Virginia C; Oliveira, Catiuscia P; Begnini, Karine R; Schultze, Eduarda; Thurow, Helena S; Leon, Priscila MM; Dellagostin, Odir A; Campos, Vinicius F; Beck, Ruy CR; Guterres, Silvia S; Collares, Tiago; Pohlmann, Adriana R; Seixas, Fabiana K

2014-01-01

Breast cancer is the most frequent cancer affecting women. Methotrexate (MTX) is an antimetabolic drug that remains important in the treatment of breast cancer. Its efficacy is compromised by resistance in cancer cells that occurs through a variety of mechanisms. This study evaluated apoptotic cell death and cell cycle arrest induced by an MTX derivative (MTX diethyl ester [MTX(OEt)2]) and MTX(OEt)2-loaded lipid-core nanocapsules in two MTX-resistant breast adenocarcinoma cell lines, MCF-7 and MDA-MB-231. The formulations prepared presented adequate granulometric profile. The treatment responses were evaluated through flow cytometry. Relying on the mechanism of resistance, we observed different responses between cell lines. For MCF-7 cells, MTX(OEt)2 solution and MTX(OEt)2-loaded lipid-core nanocapsules presented significantly higher apoptotic rates than untreated cells and cells incubated with unloaded lipid-core nanocapsules. For MDA-MB-231 cells, MTX(OEt)2-loaded lipid-core nanocapsules were significantly more efficient in inducing apoptosis than the solution of the free drug. S-phase cell cycle arrest was induced only by MTX(OEt)2 solution. The drug nanoencapsulation improved apoptosis induction for the cell line that presents MTX resistance by lack of transport receptors. PMID:24741306

Mesoporous silica nanoparticles as a promising skin delivery system for methotrexate.

PubMed

Sapino, Simona; Oliaro-Bosso, Simonetta; Zonari, Daniele; Zattoni, Andrea; Ugazio, Elena

2017-09-15

The systemic administration of methotrexate (MTX), a commonly used, antineoplastic drug which is also used in cutaneous disorders, is primarily associated with prolonged retention in the body and consequently with side effects. Innovative drug delivery techniques and alternative administration routes would therefore contribute to its safe and effective use. The general objective of this study is thus the development of MTX-based preparations for the topical treatment of skin disorders. MCM-41-like nanoparticles (MSN), are herein proposed as carriers which can improve the cutaneous absorption and hence the bioavailability and efficacy of MTX. The MTX/MSN complex, prepared via the impregnation procedure, has been physico-chemically characterized, while its cell cultures have had their biocompatibility and bioactivity tested. Furthermore, a series of stable MTX-based dermal formulations has been developed, some containing shea butter, a natural fat. Ex-vivo porcine skin absorption and the transepidermal permeation of MTX have also been monitored in a variety of media using Franz diffusion cells. Interestingly, the epidermal accumulation of the active molecule was increased by its inclusion into MSN, regardless of the surrounding medium. Furthermore, the presence of shea butter enhanced the skin uptake of the drug both in the free and in the loaded form. Copyright © 2017 Elsevier B.V. All rights reserved.

Selective CXCR4+ Cancer Cell Targeting and Potent Antineoplastic Effect by a Nanostructured Version of Recombinant Ricin.

PubMed

Díaz, Raquel; Pallarès, Victor; Cano-Garrido, Olivia; Serna, Naroa; Sánchez-García, Laura; Falgàs, Aïda; Pesarrodona, Mireia; Unzueta, Ugutz; Sánchez-Chardi, Alejandro; Sánchez, Julieta M; Casanova, Isolda; Vázquez, Esther; Mangues, Ramón; Villaverde, Antonio

2018-05-29

Under the unmet need of efficient tumor-targeting drugs for oncology, a recombinant version of the plant toxin ricin (the modular protein T22-mRTA-H6) is engineered to self-assemble as protein-only, CXCR4-targeted nanoparticles. The soluble version of the construct self-organizes as regular 11 nm planar entities that are highly cytotoxic in cultured CXCR4 + cancer cells upon short time exposure, with a determined IC50 in the nanomolar order of magnitude. The chemical inhibition of CXCR4 binding sites in exposed cells results in a dramatic reduction of the cytotoxic potency, proving the receptor-dependent mechanism of cytotoxicity. The insoluble version of T22-mRTA-H6 is, contrarily, moderately active, indicating that free, nanostructured protein is the optimal drug form. In animal models of acute myeloid leukemia, T22-mRTA-H6 nanoparticles show an impressive and highly selective therapeutic effect, dramatically reducing the leukemia cells affectation of clinically relevant organs. Functionalized T22-mRTA-H6 nanoparticles are then promising prototypes of chemically homogeneous, highly potent antitumor nanostructured toxins for precise oncotherapies based on self-mediated intracellular drug delivery. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Biotechnological engineering of heparin/heparan sulphate: a novel area of multi-target drug discovery.

PubMed

Rusnati, Marco; Oreste, Pasqua; Zoppetti, Giorgio; Presta, Marco

2005-01-01

Heparin is a sulphated glycosaminoglycan currently used as an anticoagulant and antithrombotic drug. It consists largely of 2-O-sulphated IdoA not l&r arrow N, 6-O-disulphated GlcN disaccharide units. Other disaccharides containing unsulphated IdoA or GlcA and N-sulphated or N-acetylated GlcN are also present as minor components. This heterogeneity is more pronounced in heparan sulphate (HS), where the low-sulphated disaccharides are the most abundant. Heparin/HS bind to a variety of biologically active polypeptides, including enzymes, growth factors and cytokines, and viral proteins. This capacity can be exploited to design multi-target heparin/HS-derived drugs for pharmacological interventions in a variety of pathologic conditions besides coagulation and thrombosis, including neoplasia and viral infection. The capsular K5 polysaccharide from Escherichia coli has the same structure as the heparin precursor N-acetyl heparosan. The possibility of producing K5 polysaccharide derivatives by chemical and enzymatic modifications, thus generating heparin/HS-like compounds, has been demonstrated. These K5 polysaccharide derivatives are endowed with different biological properties, including anticoagulant/antithrombotic, antineoplastic, and anti-AIDS activities. Here, the literature data are discussed and the possible therapeutic implications for this novel class of multi-target "biotechnological heparin/HS" molecules are outlined.

Chemotherapeutic potential of cow urine: A review

PubMed Central

Randhawa, Gurpreet Kaur; Sharma, Rajiv

2015-01-01

In the grim scenario where presently about 70% of pathogenic bacteria are resistant to at least one of the drugs for the treatment, cue is to be taken from traditional/indigenous medicine to tackle it urgently. The Indian traditional knowledge emanates from ayurveda, where Bos indicus is placed at a high pedestal for numerous uses of its various products. Urine is one of the products of a cow with many benefits and without toxicity. Various studies have found good antimicrobial activity of cow’s urine (CU) comparable with standard drugs such as ofloxacin, cefpodoxime, and gentamycin, against a vast number of pathogenic bacteria, more so against Gram-positive than negative bacteria. Interestingly antimicrobial activity has also been found against some resistant strains such as multidrug-resistant (MDR) Escherichia coli and Klebsiella pneumoniae. Antimicrobial action is enhanced still further by it being an immune-enhancer and bioenhancer of some antibiotic drugs. Antifungal activity was comparable to amphotericin B. CU also has anthelmintic and antineoplastic action. CU has, in addition, antioxidant properties, and it can prevent the damage to DNA caused by the environmental stress. In the management of infectious diseases, CU can be used alone or as an adjunctive to prevent the development of resistance and enhance the effect of standard antibiotics. PMID:26401404

21 CFR 1301.71 - Security requirements generally.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 9 2010-04-01 2010-04-01 false Security requirements generally. 1301.71 Section 1301.71 Food and Drugs DRUG ENFORCEMENT ADMINISTRATION, DEPARTMENT OF JUSTICE REGISTRATION OF..., cooperative buying, etc.); (2) The type and form of controlled substances handled (e.g., bulk liquids or...

The Pharmacological Mechanisms and Therapeutic Activities of Hydroxychloroquine in Rheumatic and Related Diseases.

PubMed

Hu, Changfeng; Lu, Lu; Wan, Jie-Ping; Wen, Chengping

2017-01-01

Hydroxychloroquine (HCQ) is known as one of the most fascinating synthetic antimalarial drugs during the last 50 years. It is currently among the most commonly employed medicines for the clinical treatment of rheumatic diseases, especially systemic lupus erythematosus and rheumatoid arthritis. In related mechanism studies, it has been found that HCQ possesses various immunomodulatory and anti-inflammatory activities. In addition, the effects of HCQ on anti-platelet, metabolic pathways, and antineoplasticity have also been disclosed in more recent studies. These significant findings on HCQ suggest the potential therapeutic applications of HCQ for treatment of many diseases, such as cancers, skin disease, antiphospholipid syndrome, etc. This review focuses on recent in vitro and clinical trials on its pharmacological mechanisms, therapeutic activities, and potential adverse effects. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Dexrazoxane for the prevention of cardiac toxicity and treatment of extravasation injury from the anthracycline antibiotics.

PubMed

Doroshow, James H

2012-08-01

The cumulative cardiac toxicity of the anthracycline antibiotics and their propensity to produce severe tissue injury following extravasation from a peripheral vein during intravenous administration remain significant problems in clinical oncologic practice. Understanding of the free radical metabolism of these drugs and their interactions with iron proteins led to the development of dexrazoxane, an analogue of EDTA with intrinsic antineoplastic activity as well as strong iron binding properties, as both a prospective cardioprotective therapy for patients receiving anthracyclines and as an effective treatment for anthracycline extravasations. In this review, the molecular mechanisms by which the anthracyclines generate reactive oxygen species and interact with intracellular iron are examined to understand the cardioprotective mechanism of action of dexrazoxane and its ability to protect the subcutaneous tissues from anthracycline-induced tissue necrosis.

The CDRH helix. A phase I clinical trial.

PubMed

Shimm, D S; Cetas, T C; Hynynen, K H; Buechler, D N; Anhalt, D P; Sykes, H F; Cassady, J R

1989-04-01

Seventeen patients have been given regional hyperthermia treatments using the Center for Devices and Radiologic Health (CDRH) Helix, a resonant helical coil unit. Most of these patients had large, clinically advanced tumors, whose mean volume exceeded 1000 cc. Mean maximum, minimum, and average temperatures were 40.6, 38.6, and 39.6 degrees C, respectively, for all sites combined. The pelvic heating capabilities of the CDRH Helix and the BSD-1000 annular phased array were compared, and generally were equivalent. Although the Helix could be used in a wider variety of locations, and was more comfortable and easier to use than the BSD-1000 annular phased array, neither device was particularly effective in generating clinically useful temperatures; the Helix is currently under investigation for use in regional-systemic hyperthermia in combination with antineoplastic drugs and biologic response modifiers.

The synthesis, structure-toxicity relationship of cisplatin derivatives for the mechanism research of cisplatin-induced nephrotoxicity.

PubMed

Hu, Jing; Wu, Tian-Ming; Li, Hong-Ze; Zuo, Ze-Ping; Zhao, Ying-Lan; Yang, Li

2017-08-01

Cisplatin is a widely used antineoplastic drug, while its nephrotoxicity limits the clinical application. Although several mechanisms contributing to nephrotoxicity have been reported, the direct protein targets are unclear. Herein we reported the synthesis of 29 cisplatin derivatives and the structure-toxicity relationship (STR) of these compounds with MTT assay in human renal proximal tubule cells (HK-2) and pig kidney epithelial cells (LLC-PK1). To the best of our knowledge, this study represented the first report regarding the structure-toxicity relationship (STR) of cisplatin derivatives. The potency of biotin-pyridine conjugated derivative 3 met the requirement for target identification, and the preliminary chemical proteomics results suggested that it is a promising tool for further target identification of cisplatin-induced nephrotoxicity. Copyright © 2017. Published by Elsevier Ltd.

Mechanisms of chitosan-coated poly(lactic-co-glycolic acid) nanoparticles for improving oral absorption of 7-ethyl-10-hydroxycamptothecin

NASA Astrophysics Data System (ADS)

Guo, Miao; Rong, Wen-Ting; Hou, Jie; Wang, Dong-Fang; Lu, Yu; Wang, Ying; Yu, Shu-Qin; Xu, Qian

2013-06-01

Chitosan-modified poly(lactic-co-glycolic acid) nanoparticles (CHI/PLGA NPs) loaded with 7-ethyl-10-hydroxycamptothecin (SN-38), named CHI/PLGA/SN-38 NPs, were successfully prepared using an oil-in-water (O/W) solvent evaporation method. The physicochemical properties of the novel NPs were characterized by DLS, Zeta potential, SEM, DSC, XRD, and FTIR. The encapsulation efficiency and drug loading content were 71.83 (±2.77)% and 6.79 (±0.26)%, respectively. In vitro drug release in the simulated gastric juice was lower than that in the intestinal juice. In situ single-pass intestinal perfusion (SPIP) studies indicated a dramatic improvement of drug absorption as a result of the synergistic effect between CHI and PLGA on P-glycoprotein (Pgp) inhibition. CHI/PLGA NPs showed high cellular uptake and low efflux for drugs in Caco-2 cells. The cytotoxicity studies revealed that CHI/PLGA NPs had a transient effect on the membrane integrity, but did not have an influence on cell viability. Based on the in vitro release studies, SPIP, and intracellular drug accumulation and transport investigations, we speculate rationally that CHI/PLGA NPs were mainly internalized in the form of intact NPs, thus escaping the recognition of enterocyte Pgp and avoiding efflux into the apical part of the enterocytes. After partial release of drugs inside the enterocytes, CHI/PLGA interfered with the microenvironment of Pgp and further weakened the Pgp-mediated efflux. Then, the drug-loaded NPs exited via the exocytose effect from the basal part of the enterocytes and entered the blood circulation. These results showed that CHI/PLGA NPs would be smart oral delivery carriers for antineoplastic agents that are also Pgp substrates.

Drug desensitization in the management of hypersensitivity reactions to monoclonal antibodies and chemotherapy.

PubMed

Mezzano, Veronica; Giavina-Bianchi, Pedro; Picard, Matthieu; Caiado, Joana; Castells, Mariana

2014-04-01

Hypersensitivity reactions to monoclonal antibodies and chemotherapy, which may vary in severity from mild to life-threatening, can lead to their discontinuation and replacement by alternative agents that are often less effective, more toxic, and/or more expensive. Drug desensitization has emerged as the best treatment modality capable of allowing re-introduction of the hypersensitivity reaction-inducing medication in highly sensitized patients in need of first line therapies. In recent years, the availability of new anti-neoplastic drugs and therapeutic monoclonal antibodies has increased, as has the potential for hypersensitivity reactions. Development of desensitization protocols for these new medications requires a careful assessment of the potential risks and benefits. The purposes of this review are to provide an overview of the presentation of hypersensitivity reactions amenable to desensitization and to increase awareness of the indications for and outcomes of desensitization protocols. Rapid drug desensitization has proven to be a safe and effective way of administering first line therapy to patients with hypersensitivity reactions, providing an extremely powerful treatment modality for patients for whom alternative drugs are deemed unacceptable. Rapid drug desensitization protocols should be administered only by highly trained allergists and nurses who have experience in determining which reactions are amenable to desensitization, and can identify high risk patients and provide them with appropriate care. Efforts should be made to increase awareness of the remarkable safety and efficacy of rapid drug desensitization among non-allergists, especially in the fields of oncology and rheumatology, so as to favor its universal application. Development of desensitization units to provide state-of-the-art care is possible only through coordinated teamwork.

Analysis of anti-neoplastic drug in bacterial ghost matrix, w/o/w double nanoemulsion and w/o nanoemulsion by a validated 'green' liquid chromatographic method.

PubMed

Youssof, Abdullah M E; Salem-Bekhit, Mounir M; Shakeel, Faiyaz; Alanazi, Fars K; Haq, Nazrul

2016-07-01

The objective of the present investigation was to develop and validate a 'green' reversed phase high-performance liquid chromatography (RP-HPLC) method for rapid analysis of a cytotoxic drug 5-fluorouracil (5-FU) in bulk drug, marketed injection, water-in-oil (w/o) nanoemulsion, double water-in-oil-in-water (w/o/w) nanoemulsion and bacterial ghost (BG) matrix. The chromatography study was carried out at room temperature (25±1°C) using an HPLC system with the help of ultraviolet (UV)-visible detector. The chromatographic performance was achieved with a Nucleodur 150mm×4.6mm RP C8 column filled with 5µm filler as a static phase. The mobile phase consisted of ethyl acetate: methanol (7:3% v/v) which was delivered at a flow rate of 1.0mLmin(-1) and the drug was detected in UV mode at 254nm. The developed method was validated in terms of linearity (r(2)=0.998), accuracy (98.19-102.09%), precision (% RSD=0.58-1.17), robustness (% RSD=0.12-0.53) and sensitivity with satisfactory results. The efficiency of the method was demonstrated by the assay of the drug in marketed injection, w/o nanoemulsion, w/o/w nanoemulsion and BG with satisfactory results. The successful resolution of the drug along with its degradation products clearly established the stability-indicating nature of the proposed method. Overall, these results suggested that the proposed analytical method could be effectively applied to the routine analysis of 5-FU in bulk drug, various pharmaceutical dosage forms and BG. Copyright © 2016 Elsevier B.V. All rights reserved.

The simcyp population based simulator: architecture, implementation, and quality assurance.

PubMed

Jamei, Masoud; Marciniak, Steve; Edwards, Duncan; Wragg, Kris; Feng, Kairui; Barnett, Adrian; Rostami-Hodjegan, Amin

2013-01-01

Developing a user-friendly platform that can handle a vast number of complex physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) models both for conventional small molecules and larger biologic drugs is a substantial challenge. Over the last decade the Simcyp Population Based Simulator has gained popularity in major pharmaceutical companies (70% of top 40 - in term of R&D spending). Under the Simcyp Consortium guidance, it has evolved from a simple drug-drug interaction tool to a sophisticated and comprehensive Model Based Drug Development (MBDD) platform that covers a broad range of applications spanning from early drug discovery to late drug development. This article provides an update on the latest architectural and implementation developments within the Simulator. Interconnection between peripheral modules, the dynamic model building process and compound and population data handling are all described. The Simcyp Data Management (SDM) system, which contains the system and drug databases, can help with implementing quality standards by seamless integration and tracking of any changes. This also helps with internal approval procedures, validation and auto-testing of the new implemented models and algorithms, an area of high interest to regulatory bodies.

Factors influencing oncology nurses' use of hazardous drug safe-handling precautions.

PubMed

Polovich, Martha; Clark, Patricia C

2012-05-01

To examine relationships among factors affecting nurses' use of hazardous drug (HD) safe-handling precautions, identify factors that promote or interfere with HD precaution use, and determine managers' perspectives on the use of HD safe-handling precautions. Cross-sectional, mixed methods; mailed survey to nurses who handle chemotherapy and telephone interviews with managers. Mailed invitation to oncology centers across the United States. 165 nurses who reported handling chemotherapy and 20 managers of nurses handling chemotherapy. Instruments measured the use of HD precautions and individual and organizational factors believed to influence precaution use. Data analysis included descriptive statistics and hierarchical regression. Manager interview data were analyzed using content analysis. Chemotherapy exposure knowledge, self-efficacy, perceived barriers, perceived risk, interpersonal influences, and workplace safety climate. Nurses were well educated, experienced, and certified in oncology nursing. The majority worked in outpatient settings and administered chemotherapy to an average of 6.8 patients per day. Exposure knowledge, self-efficacy for using personal protective equipment, and perceived risk of harm from HD exposure were high; total precaution use was low. Nurse characteristics did not predict HD precaution use. Fewer barriers, better workplace safety climate, and fewer patients per day were independent predictors of higher HD precaution use. HD handling policies were present, but many did not reflect current recommendations. Few managers formally monitored nurses' HD precaution use. Circumstances in the workplace interfere with nurses' use of HD precautions. Interventions should include fostering a positive workplace safety climate, reducing barriers, and providing appropriate nurse-patient ratios.

Oncogenic targets, magnitude of benefit, and market pricing of antineoplastic drugs.

PubMed

Amir, Eitan; Seruga, Bostjan; Martinez-Lopez, Joaquin; Kwong, Ryan; Pandiella, Atanasio; Tannock, Ian F; Ocaña, Alberto

2011-06-20

The relationship between market pricing of new anticancer drugs and the magnitude of clinical benefit caused by them has not been reported. Randomized clinical trials (RCTs) that evaluated approved new agents for solid tumors by the U.S. Food and Drug administration since the year 2000 were assessed. Hazard ratios (HRs) and 95% CIs were extracted for time-to-event end points described for each RCT. HRs were pooled for three groups: agents directed against a specific molecular target, for which the target population is selected by a biomarker (group A); less specific biologic targeted agents (group B); and chemotherapeutic agents (group C). Monthly market prices of these different drugs were compared. For overall survival (OS), the pooled HR was 0.69 (95% CI, 0.59 to 0.81) for group A (six drugs, six trials); it was 0.78 (95% CI, 0.74 to 0.83) for group B (seven drugs, 14 trials); and it was 0.84 (95% CI, 0.79 to 0.90) for group C (eight drugs, 12 trials). For progression-free survival (PFS), the pooled HR was 0.42 (95% CI, 0.36 to 0.49) for group A (six drugs, seven trials); it was 0.57 (95% CI, 0.51 to 0.64) for group B (seven drugs, 14 trials); and it was 0.75 (95% CI, 0.66 to 0.85) for group C (six drugs, 10 trials). Tests for heterogeneity between subgroups were highly significant for PFS (P < .001) and OS (P = .02). The median monthly prices for standard doses of drugs were $5375 for group A, $5644 for group B, and $6584 for group C (P = .87). New agents with specific molecular targets are clinically the most beneficial, but their monthly market prices are not significantly different from those of other anticancer agents.

Bortezomib induces apoptosis and suppresses cell growth and metastasis by inactivation of Stat3 signaling in chondrosarcoma.

PubMed

Bao, Xing; Ren, Tingting; Huang, Yi; Ren, Chongmin; Yang, Kang; Zhang, Hongliang; Guo, Wei

2017-02-01

Bortezomib, formerly known as PS341, is a novel proteasome inhibitor with in vitro and in vivo antineoplastic effects in many malignancies. However, diverse antitumor mechanisms of bortezomib have been identified in many investigations and preclinical studies. Understanding the molecular and cellular mechanisms through which bortezomib acts will improve the therapeutic utility of this drug in different cancer types. In the present study, we investigated the in vitro and in vivo effects of bortezomib on chondrosarcoma. Bortezomib selectively inhibited cell growth in chondrosarcoma cells but not in normal articular cartilage cells. In addition to growth inhibition, apoptosis and cell cycle arrest, bortezomib triggered alleviation of migratory and invasive properties of chondrosarcoma cells. Mechanistically, signal transducer and activator of transcription 3 (Stat3) and its downstream targets Bcl-2, cyclin D1 and c-Myc was inactivated by bortezomib treatment. Accordingly, small interfering RNA (siRNA)-mediated Stat3 knockdown enhanced bortezomib-induced apoptosis, and concomitantly enhanced the inhibitory effect of bortezomib on cell viability, migration and invasion. Moreover, while Slug, MMP9, MMP2, CD44, N-cadherin and vimentin, the mesenchymal cell markers, were repressed by bortezomib concomitant increased expression of E-cadherin was observed. In vivo, bortezomib downregulated Stat3 activity and mesenchymal cell marker expression, induced apoptosis and inhibition of metastasis and tumor growth. Together, inactivation of Stat3 signaling contributes to bortezomib-induced inhibition of tumor growth, migration and invation on chondrosarcoma. Bortezomib demonstrates an antineoplastic role on chondrosarcoma both in vitro and in vivo. These beneficial effects can be explained by bortezomib-mediated Stat3 supression. The present study suggests a promising therapeutics target in chondrosarcoma and probably in other kinds of metastatic malignant tumors.

Visible-light system for detecting doxorubicin contamination on skin and surfaces.

PubMed

Van Raalte, J; Rice, C; Moss, C E

1990-05-01

A portable system that uses fluorescence stimulated by visible light to identify doxorubicin contamination on skin and surfaces was studied. When activated by violet-blue light in the 465-nm range, doxorubicin fluoresces, emitting orange-red light in the 580-nm range. The light source to stimulate fluorescence was a slide projector with a filter to selectively pass short-wave (blue) visible light. Fluorescence was both observed visually with viewing spectacles and photographed. Solutions of doxorubicin in sterile 0.9% sodium chloride injection were prepared in nine standard concentrations ranging from 2 to 0.001 mg/mL. Droplets of each admixture were placed on stainless steel, laboratory coat cloth, pieces of latex examination glove, bench-top absorbent padding, and other materials on which antineoplastics might spill or leak. These materials then were stored for up to eight weeks and photographed weekly. The relative ability of water, household bleach, hydrogen peroxide solution, and soap solution to deactivate doxorubicin was also measured. Finally, this system was used to inspect the antineoplastic-drug preparation and administration areas of three outpatient cancer clinics for doxorubicin contamination. Doxorubicin fluorescence was easily detectable with viewing spectacles when a slide projector was used as the light source. The photographic method was sensitive for doxorubicin concentrations from 2.0 to 0.001 mg/mL. Immersion of study materials in bleach for one minute eliminated detectable fluorescence. Doxorubicin contamination is detectable for at least eight weeks in the ambient environment. Probable doxorubicin contamination was detected in two of the three clinics surveyed. A safe, portable system that uses fluorescence stimulated by visible light is a sensitive method for detecting doxorubicin on skin and surfaces.

The husk fiber of Cocos nucifera L. (Palmae) is a source of anti-neoplastic activity.

PubMed

Koschek, P R; Alviano, D S; Alviano, C S; Gattass, C R

2007-10-01

In the present study, we investigated the in vitro anti-tumoral activities of fractions from aqueous extracts of the husk fiber of the typical A and common varieties of Cocos nucifera (Palmae). Cytotoxicity against leukemia cells was determined by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. Cells (2 x 10(4)/well) were incubated with 0, 5, 50 or 500 microg/mL high- or low-molecular weight fractions for 48 h, treated with MTT and absorbance was measured with an ELISA reader. The results showed that both varieties have almost similar antitumoral activity against the leukemia cell line K562 (60.1 +/- 8.5 and 47.5 +/- 11.9% for the typical A and common varieties, respectively). Separation of the crude extracts with Amicon membranes yielded fractions with molecular weights ranging in size from 1-3 kDa (fraction A) to 3-10 kDa (fraction B) and to more than 10 kDa (fraction C). Cells were treated with 500 microg/mL of these fractions and cytotoxicity was evaluated by MTT. Fractions ranging in molecular weight from 1-10 kDa had higher cytotoxicity. Interestingly, C. nucifera extracts were also active against Lucena 1, a multidrug-resistant leukemia cell line. Their cytotoxicity against this cell line was about 50% (51.9 +/- 3.2 and 56.3 +/- 2.9 for varieties typical A and common, respectively). Since the common C. nucifera variety is extensively cultured in Brazil and the husk fiber is its industrial by-product, the results obtained in the present study suggest that it might be a very inexpensive source of new antineoplastic and anti-multidrug resistant drugs that warrants further investigation.

Alkylphosphocholines: influence of structural variation on biodistribution at antineoplastically active concentrations.

PubMed

Kötting, J; Berger, M R; Unger, C; Eibl, H

1992-01-01

Hexadecylphosphocholine (HPC) and octadecylphosphocholine (OPC) show very potent antitumor activity against autochthonous methylnitrosourea-induced mammary carcinomas in rats. The longer-chain and unsaturated homologue erucylphosphocholine (EPC) forms lamellar structures rather than micelles, but nonetheless exhibits antineoplastic activity. Methylnitrosourea was used in the present study to induce autochthonous mammary carcinomas in virgin Sprague-Dawley rats. At 6 and 11 days following oral therapy, the biodistribution of HPC, OPC and EPC was analyzed in the serum, tumor, liver, kidney, lung, small intestine, brain and spleen of rats by high-performance thin-layer chromatography. In contrast to the almost identical tumor response noted, the distribution of the three homologues differed markedly. The serum levels of 50 nmol/ml obtained for OPC and EPC were much lower than the value of 120 nmol/ml measured for HPC. Nevertheless, the quite different serum levels resulted in similar tumor concentrations of about 200 nmol/g for all three of the compounds. Whereas HPC preferably accumulated in the kidney (1 mumol/g), OPC was found at increased concentrations (400 nmol/g) in the spleen, kidney and lung. In spite of the high daily dose of 120 mumol/kg EPC as compared with 51 mumol/kg HPC or OPC, EPC concentrations (100-200 nmol/g) were low in most tissues. High EPC concentrations were found in the small intestine (628 nmol/g). Values of 170 nmol/g were found for HPC and OPC in the brain, whereas the EPC concentration was 120 nmol/g. Obviously, structural modifications in the alkyl chain strongly influence the distribution pattern of alkylphosphocholines in animals. Since EPC yielded the highest tissue-to-serum concentration ratio in tumor tissue (5.1) and the lowest levels in other organs, we conclude that EPC is the most promising candidate for drug development in cancer therapy.

Low oxygen tension reverses antineoplastic effect of iron chelator deferasirox in human glioblastoma cells.

PubMed

Legendre, Claire; Avril, Sylvie; Guillet, Catherine; Garcion, Emmanuel

2016-02-01

Overcoming resistance to treatment is an essential issue in many cancers including glioblastoma (GBM), the deadliest primary tumor of the central nervous system. As dependence on iron is a key feature of tumor cells, using chelators to reduce iron represents an opportunity to improve conventional GBM therapies. The aim of the present study was, therefore, to investigate the cytostatic and cytotoxic impact of the new iron chelator deferasirox (DFX) on human GBM cells in well-defined clinical situations represented by radiation therapy and mild-hypoxia. Under experimental normoxic condition (21% O2), deferasirox (DFX) used at 10 μM for 3 days reduced proliferation, led cell cycle arrest in S and G2-M phases and induced cytotoxicity and apoptosis in U251 and U87 GBM cells. The abolition of the antineoplastic DFX effects when cells were co-treated with ferric ammonium sulfate supports the hypothesis that its effects result from its ability to chelate iron. As radiotherapy is the main treatment for GBM, the combination of DFX and X-ray beam irradiation was also investigated. Irradiation at a dose of 16 Gy repressed proliferation, cytotoxicity and apoptosis, but only in U251 cells, while no synergy with DFX was observed in either cell line. Importantly, when the same experiment was conducted in mild-hypoxic conditions (3% O2), the antiproliferative and cytotoxic effects of DFX were abolished, and its ability to deplete iron was also impaired. Taken together, these in vitro results could raise the question of the benefit of using iron chelators in their native forms under the hypoxic conditions often encountered in solid tumors such as GBM. Developing new chemistry or a new drug delivery system that would keep DFX active in hypoxic cells may be the next step toward their application.

Gemcitabine-(5'-phosphoramidate)-[anti-IGF-1R]: molecular design, synthetic organic chemistry reactions, and antineoplastic cytotoxic potency in populations of pulmonary adenocarcinoma (A549).

PubMed

Coyne, Cody P; Narayanan, Lakshmi

2017-03-01

One molecular-based approach that increases potency and reduces dose-limited sequela is the implementation of selective 'targeted' delivery strategies for conventional small molecular weight chemotherapeutic agents. Descriptions of the molecular design and organic chemistry reactions that are applicable for synthesis of covalent gemcitabine-monophosphate immunochemotherapeutics have to date not been reported. The covalent immunopharmaceutical, gemcitabine-(5'-phosphoramidate)-[anti-IGF-1R] was synthesized by reacting gemcitabine with a carbodiimide reagent to form a gemcitabine carbodiimide phosphate ester intermediate which was subsequently reacted with imidazole to create amine-reactive gemcitabine-(5'-phosphorylimidazolide) intermediate. Monoclonal anti-IGF-1R immunoglobulin was combined with gemcitabine-(5'-phosphorylimidazolide) resulting in the synthetic formation of gemcitabine-(5'-phosphoramidate)-[anti-IGF-1R]. The gemcitabine molar incorporation index for gemcitabine-(5'-phosphoramidate)-[anti-IGF-R1] was 2.67:1. Cytotoxicity Analysis - dramatic increases in antineoplastic cytotoxicity were observed at and between the gemcitabine-equivalent concentrations of 10 -9  M and 10 -7  M where lethal cancer cell death increased from 0.0% to a 93.1% maximum (100.% to 6.93% residual survival), respectively. Advantages of the organic chemistry reactions in the multistage synthesis scheme for gemcitabine-(5'-phosphoramidate)-[anti-IGF-1R] include their capacity to achieve high chemotherapeutic molar incorporation ratios; option of producing an amine-reactive chemotherapeutic intermediate that can be preserved for future synthesis applications; and non-dedicated organic chemistry reaction scheme that allows substitutions of either or both therapeutic moieties, and molecular delivery platforms. © 2016 The Authors Chemical Biology & Drug Design Published by John Wiley & Sons Ltd.

Actin binding GFP allows 4D in vivo imaging of myofilament dynamics in the zebrafish heart and the identification of Erbb2 signaling as a remodeling factor of myofibril architecture.

PubMed

Reischauer, Sven; Arnaout, Rima; Ramadass, Radhan; Stainier, Didier Y R

2014-10-24

Dilated cardiomyopathy is a leading cause of congestive heart failure and a debilitating complication of antineoplastic therapies. Despite disparate causes for dilated cardiomyopathy, maladaptive cardiac remodeling and decreased systolic function are common clinical consequences, begging an investigation of in vivo contractile dynamics in development and disease, one that has been impossible to date. To image myocardial contractile filament dynamics in vivo and to assess potential causes of dilated cardiomyopathy in antineoplastic therapies targeting the epidermal growth factor receptor Erbb2. We generated a transgenic zebrafish line expressing an actin-binding green fluorescent protein in cardiomyocytes, allowing an in vivo imaging of myofilaments. Analysis of this line revealed architectural differences in myofibrils of the distinct cardiomyocyte subtypes. We used this model to investigate the effects of Erbb2 signaling on myofibrillar organization because drugs targeting ERBB2 (HER2/NEU) signaling, a mainstay of breast cancer chemotherapy, cause dilated cardiomyopathy in many patients. High-resolution in vivo imaging revealed that Erbb2 signaling regulates a switch between a dense apical network of filamentous myofibrils and the assembly of basally localized myofibrils in ventricular cardiomyocytes. Using this novel line, we compiled a reference for myofibrillar microarchitecture among myocardial subtypes in vivo and at different developmental stages, establishing this model as a tool to analyze in vivo cardiomyocyte contractility and remodeling for a broad range of cardiovascular questions. Furthermore, we applied this model to study Erbb2 signaling in cardiomyopathy. We show a direct link between Erbb2 activity and remodeling of myofibrils, revealing an unexpected mechanism with potentially important implications for prevention and treatment of cardiomyopathy. © 2014 American Heart Association, Inc.

Biological safety cabinetry.

PubMed Central

Kruse, R H; Puckett, W H; Richardson, J H

1991-01-01

The biological safety cabinet is the one piece of laboratory and pharmacy equipment that provides protection for personnel, the product, and the environment. Through the history of laboratory-acquired infections from the earliest published case to the emergence of hepatitis B and AIDS, the need for health care worker protection is described. A brief description with design, construction, function, and production capabilities is provided for class I and class III safety cabinets. The development of the high-efficiency particulate air filter provided the impetus for clean room technology, from which evolved the class II laminar flow biological safety cabinet. The clean room concept was advanced when the horizontal airflow clean bench was manufactured; it became popular in pharmacies for preparing intravenous solutions because the product was protected. However, as with infectious microorganisms and laboratory workers, individual sensitization to antibiotics and the advent of hazardous antineoplastic agents changed the thinking of pharmacists and nurses, and they began to use the class II safety cabinet to prevent adverse personnel reactions to the drugs. How the class II safety cabinet became the mainstay in laboratories and pharmacies is described, and insight is provided into the formulation of National Sanitation Foundation standard number 49 and its revisions. The working operations of a class II cabinet are described, as are the variations of the four types with regard to design, function, air velocity profiles, and the use of toxins. The main certification procedures are explained, with examples of improper or incorrect certifications. The required levels of containment for microorganisms are given. Instructions for decontaminating the class II biological safety cabinet of infectious agents are provided; unfortunately, there is no method for decontaminating the cabinet of antineoplastic agents. Images PMID:2070345

Use of oral antineoplastic in special situations in a third level hospital: real life results.

PubMed

Garcia-Muñoz, Carmen; Rodriguez-Quesada, Pedro Pablo; Ferrari-Piquero, José Miguel

2018-01-01

To analyse the effectiveness and safety of oral antineoplastic drugs  (ANEOs) that are authorized in special situations in a third-level hospital and to  compare the results obtained with the clinical evidence used for this  authorization. Descriptive observational and retrospective study. We included all  adult patients who started treatment with ANEO in special situations during the  year 2016. We collected demographic, treatment-related and clinical variables  (overall survival (OS), progression-free survival (PFS)). Adverse reactions and  detected interactions were collected. An unadjusted comparison was made  between the results of the available evidence and those of the study patients. 34 patients were treated, 50% were men, the median age was 58  years (38-80) and they presented ECOG 1 in 64.7%. Most of the treated  patients were diagnosed with advanced colorectal cancer, treated with  trifluridine-tipiracil, followed by palbociclib in breast cancer, obtaining results  similar to those of the evidence. The median PFS was 2.8 months (95% CI 0.8- 4.8) and the 8-month SG (95% CI 3.4-12.5) for all patients. 26% of patients  required dose reduction because of treatment toxicity. We found 13 interactions,  which affected 15 patients, only two of category X. The effectiveness of ANEO in special situations in our center is  similar to that of available evidence. The impact on survival is low and adverse  effects are common. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

[Cancer-vitamins-minerals: Complex relation].

PubMed

Adrianza de Baptista, Gertrudis; Murillo Melo, Carolain

2014-12-01

Since nutrition can influence the process of carcinogenesis, this study's objectives are to review the relationship between nutrition and cancer from the point of view of the role of micronutrients in the treatment of cancer patients, and to get to know the deficit relationship and the excess of micronutrients, with the etiology and cancer treatment. At the same time the patient's weight loss relates, among other things, to the type of cancerous tumor, its location, stage thereof, reason for which it may be associated with the deficiency of macro and micronutrients as from psychogenic, anorectics and mal-absorption effects or with mechanical effects as obstruction, among other toxic effects that are common in the treatment of cancer. Hence, the importance that the nutrition expert must have in making an adequate overall nutritional evaluation that allows the nutritional diagnosis, in studying the dietary patterns, to determine the toxic effects of the antineoplastic treatment in order to handle the treatment's timing excellence, symptoms and signs, and thus act effectively optiimizing the patient's life quality, and therewith his/her survival. There are controversies as to which specific dietary factors are related to cancer etiology and the results of studies on metabolic factors, and therefore, the relationship Cancer-Nutrition is quiet complex.

A novel fluoride anion modified gelatin nanogel system for ultrasound-triggered drug release.

PubMed

Wu, Daocheng; Wan, Mingxi

2008-01-01

Controlled drug release, especially tumor-targeted drug release, remains a great challenge. Here, we prepare a novel fluoride anion-modified gelatin nanogel system and investigate its characteristics of ultrasound-triggered drug release. Adriamycin gelatin nanogel modified with fluoride anion (ADM-GNMF) was prepared by a modified co-precipitation method with fluoride anion and sodium sulfate. The loading and encapsulation efficiency of the anti-neoplastic agent adriamycin (ADM) were measured by high performance liquid chromatography (HPLC). The size and shape of ADM-GNMF were determined by electron microscopy and photo-correlation spectroscopy. The size distribution and drug release efficiency of ADM-GNMF, before and after sonication, were measured by two designed measuring devices that consisted of either a submicron particle size analyzer and an ultrasound generator as well as an ultrasound generator, automatic sampler, and HPLC. The ADM-GNMF was stable in solution with an average diameter of 46+/-12 nm; the encapsulation and loading efficiency of adriamycin were 87.2% and 6.38%, respectively. The ultrasound-triggered drug release and size change were most efficient at a frequency of 20 kHz, power density of 0.4w/cm2, and a 1~2 min duration. Under this ultrasound-triggered condition, 51.5% of drug in ADM-GNMF was released within 1~2 min, while the size of ADM-GNMF changed from 46 +/- 12 nm to 1212 +/- 35 nm within 1~2 min of sonication and restored to its previous size in 2~3 min after the ultrasound stopped. In contrast, 8.2% of drug in ADM-GNMF was released within 2~3 min without sonication, and only negligible size changes were found. The ADM-GNMF system efficiently released the encompassed drug in response to ultrasound, offering a novel and promising controlled drug release system for targeted therapy for cancer or other diseases.

Management of malignancy-associated pleural effusion: current and future treatment strategies.

PubMed

Marchi, Evaldo; Teixeira, Lisete R; Vargas, Francisco S

2003-01-01

Management of recurrent malignant pleural effusion, a common complication of malignancy, poses a challenge to clinicians. Although almost one century has elapsed since the introduction of the pleurodesis procedure, the ideal approach and best agent are still to be defined. Optimally, pleurodesis should be done at the bedside with a minimally invasive procedure, and suitable agents to achieve pleural symphysis should be inexpensive, available worldwide and free of adverse effects. To date, no substance completely fulfills these requirements. Silver nitrate should be considered for pleurodesis because of its low cost and ease of handling. Although talc has been used most frequently to induce pleurodesis, reports of death due to acute respiratory failure have raised concerns about the safety of this agent. Tetracycline, an effective alternative used in the past, is no longer commercially available. This agent has been substituted with derivatives of tetracycline, such as minocycline and doxycycline with success rates similar to those with tetracycline. Several antineoplastic agents have been injected into the pleural space with the aim of producing pleural symphysis, the most representative of this group being bleomycin. Recent knowledge of the molecular mechanisms involved in pleural inflammation has brought into focus new substances, such as transforming growth factor beta and vascular endothelial growth factor, which may be used as pleurodesis agents in the future. Nevertheless, more studies are necessary to better define the potential of these substances in the induction of pleural symphysis.Ideally, a sclerosing agent should be cost-effective, available worldwide and easily administered. Talc will probably stand as the preferred agent to be used for pleurodesis in malignant pleural effusion because of its efficacy, easy manipulation and handling. However, further investigation is necessary to minimize adverse effects related to talc.

Early-life experience decreases drug-induced reinstatement of morphine CPP in adulthood via microglial-specific epigenetic programming of anti-inflammatory IL-10 expression.

PubMed

Schwarz, Jaclyn M; Hutchinson, Mark R; Bilbo, Staci D

2011-12-07

A critical component of drug addiction research involves identifying novel biological mechanisms and environmental predictors of risk or resilience to drug addiction and associated relapse. Increasing evidence suggests microglia and astrocytes can profoundly affect the physiological and addictive properties of drugs of abuse, including morphine. We report that glia within the rat nucleus accumbens (NAcc) respond to morphine with an increase in cytokine/chemokine expression, which predicts future reinstatement of morphine conditioned place preference (CPP) following a priming dose of morphine. This glial response to morphine is influenced by early-life experience. A neonatal handling paradigm that increases the quantity and quality of maternal care significantly increases baseline expression of the anti-inflammatory cytokine IL-10 within the NAcc, attenuates morphine-induced glial activation, and prevents the subsequent reinstatement of morphine CPP in adulthood. IL-10 expression within the NAcc and reinstatement of CPP are negatively correlated, suggesting a protective role for this specific cytokine against morphine-induced glial reactivity and drug-induced reinstatement of morphine CPP. Neonatal handling programs the expression of IL-10 within the NAcc early in development, and this is maintained into adulthood via decreased methylation of the IL-10 gene specifically within microglia. The effect of neonatal handling is mimicked by pharmacological modulation of glia in adulthood with ibudilast, which increases IL-10 expression, inhibits morphine-induced glial activation within the NAcc, and prevents reinstatement of morphine CPP. Taken together, we have identified a novel gene × early-life environment interaction on morphine-induced glial activation and a specific role for glial activation in drug-induced reinstatement of drug-seeking behavior.

Early-Life Experience Decreases Drug-Induced Reinstatement of Morphine CPP in Adulthood via Microglial-Specific Epigenetic Programming of Anti-Inflammatory IL-10 Expression

PubMed Central

Schwarz, Jaclyn M.; Hutchinson, Mark R.; Bilbo, Staci D.

2012-01-01

A critical component of drug addiction research involves identifying novel biological mechanisms and environmental predictors of risk or resilience to drug addiction and associated relapse. Increasing evidence suggests microglia and astrocytes can profoundly affect the physiological and addictive properties of drugs of abuse, including morphine. We report that glia within the rat Nucleus Accumbens (NAcc) respond to morphine with an increase in cytokine/chemokine expression, which predicts future reinstatement of morphine conditioned place preference (CPP) following a priming dose of morphine. This glial response to morphine is influenced by early-life experience. A neonatal handling paradigm that increases the quantity and quality of maternal care significantly increases baseline expression of the anti-inflammatory cytokine IL-10 within the NAcc, attenuates morphine-induced glial activation, and prevents the subsequent reinstatement of morphine CPP in adulthood. IL-10 expression within the NAcc and reinstatement of CPP are negatively correlated, suggesting a protective role for this specific cytokine against morphine-induced glial reactivity and drug-induced reinstatement of morphine CPP. Neonatal handling programs the expression of IL-10 within the NAcc early in development, and this is maintained into adulthood via decreased methylation of the IL-10 gene specifically within microglia. The effect of neonatal handling is mimicked by pharmacological modulation of glia in adulthood with Ibudilast, which increases IL-10 expression, inhibits morphine-induced glial activation within the NAcc, and prevents reinstatement of morphine CPP. Taken together, we have identified a novel gene X early-life environment interaction on morphine-induced glial activation, and a specific role for glial activation in drug-induced reinstatement of drug-seeking behavior. PMID:22159099

Measuring the Acoustic Release of a Chemotherapeutic Agent from Folate-Targeted Polymeric Micelles.

PubMed

Abusara, Ayah; Abdel-Hafez, Mamoun; Husseini, Ghaleb

2018-08-01

In this paper, we compare the use of Bayesian filters for the estimation of release and re-encapsulation rates of a chemotherapeutic agent (namely Doxorubicin) from nanocarriers in an acoustically activated drug release system. The study is implemented using an advanced kinetic model that takes into account cavitation events causing the antineoplastic agent's release from polymeric micelles upon exposure to ultrasound. This model is an improvement over the previous representations of acoustic release that used simple zero-, first- and second-order release and re-encapsulation kinetics to study acoustically triggered drug release from polymeric micelles. The new model incorporates drug release and micellar reassembly events caused by cavitation allowing for the controlled release of chemotherapeutics specially and temporally. Different Bayesian estimators are tested for this purpose including Kalman filters (KF), Extended Kalman filters (EKF), Particle filters (PF), and multi-model KF and EKF. Simulated and experimental results are used to verify the performance of the above-mentioned estimators. The proposed methods demonstrate the utility and high-accuracy of using estimation methods in modeling this drug delivery technique. The results show that, in both cases (linear and non-linear dynamics), the modeling errors are expensive but can be minimized using a multi-model approach. In addition, particle filters are more flexible filters that perform reasonably well compared to the other two filters. The study improved the accuracy of the kinetic models used to capture acoustically activated drug release from polymeric micelles, which may in turn help in designing hardware and software capable of precisely controlling the delivered amount of chemotherapeutics to cancerous tissue.

Cytotoxic drugs in drinking water: a prediction and risk assessment exercise for the thames catchment in the United kingdom.

PubMed

Rowney, Nicole C; Johnson, Andrew C; Williams, Richard J

2009-12-01

Cytotoxic, also known as antineoplastic, drugs remain an important weapon in the fight against cancer. This study considers the water quality implications for the Thames catchment (United Kingdom) arising from the routine discharge of these drugs after use, down the drain and into the river. The review focuses on 13 different cytotoxic drugs from the alkylating agent, antimetabolite, and anthracycline antibiotic families. A geographic-information-system-based water quality model was used in the present study. The model was informed by literature values on consumption, excretion, and fate data to predict raw drinking water concentrations at the River Thames abstraction points at Farmoor, near Oxford, and Walton, in West London. To discover the highest plausible values, upper boundary values for consumption and excretion together with lower removal values for sewage treatment were used. The raw drinking water cytotoxic drug maximum concentrations at Walton (the higher of the two) representative of mean and low flow conditions were predicted to be 11 and 20 ng/L for the five combined alkylating agents, 2 and 4 ng/L for the three combined antimetabolites, and 0.05 and 0.10 ng/L the for two combined anthracycline antibiotics, respectively. If they were to escape into tap water, then the highest predicted concentrations would still be a factor of between 25 and 40 below the current recommended daily doses of concern. Although the risks may be negligible for healthy adults, more concern may be associated with special subgroup populations, such as pregnant women, their fetuses, and breast-feeding infants, due to their developmental vulnerability.

21 CFR 1305.07 - Special procedure for filling certain orders.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 9 2010-04-01 2010-04-01 false Special procedure for filling certain orders. 1305.07 Section 1305.07 Food and Drugs DRUG ENFORCEMENT ADMINISTRATION, DEPARTMENT OF JUSTICE ORDERS FOR... management programs, or research, and is authorized by the Administrator to handle these substances, may fill...

21 CFR 225.35 - Use of work areas, equipment, and storage areas for other manufacturing and storage purpose.

Code of Federal Regulations, 2010 CFR

2010-04-01

... ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL CURRENT GOOD MANUFACTURING..., rodenticides, and other pesticides. Manufacturing, storage, or handling of nonfeed and feed products in the... pesticides unless such articles are approved drugs, indexed drugs, or approved food additives intended for...

21 CFR 225.35 - Use of work areas, equipment, and storage areas for other manufacturing and storage purpose.

Code of Federal Regulations, 2011 CFR

2011-04-01

... ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL CURRENT GOOD MANUFACTURING..., rodenticides, and other pesticides. Manufacturing, storage, or handling of nonfeed and feed products in the... pesticides unless such articles are approved drugs, indexed drugs, or approved food additives intended for...

21 CFR 225.35 - Use of work areas, equipment, and storage areas for other manufacturing and storage purpose.

Code of Federal Regulations, 2013 CFR

2013-04-01

... ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL CURRENT GOOD MANUFACTURING..., rodenticides, and other pesticides. Manufacturing, storage, or handling of nonfeed and feed products in the... pesticides unless such articles are approved drugs, indexed drugs, or approved food additives intended for...

21 CFR 225.35 - Use of work areas, equipment, and storage areas for other manufacturing and storage purpose.

Code of Federal Regulations, 2014 CFR

2014-04-01

... ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL CURRENT GOOD MANUFACTURING..., rodenticides, and other pesticides. Manufacturing, storage, or handling of nonfeed and feed products in the... pesticides unless such articles are approved drugs, indexed drugs, or approved food additives intended for...

21 CFR 225.35 - Use of work areas, equipment, and storage areas for other manufacturing and storage purpose.

Code of Federal Regulations, 2012 CFR

2012-04-01

... ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL CURRENT GOOD MANUFACTURING..., rodenticides, and other pesticides. Manufacturing, storage, or handling of nonfeed and feed products in the... pesticides unless such articles are approved drugs, indexed drugs, or approved food additives intended for...

21 CFR 179.41 - Pulsed light for the treatment of food.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Pulsed light for the treatment of food. 179.41 Section 179.41 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) IRRADIATION IN THE PRODUCTION, PROCESSING AND HANDLING OF FOOD Radiation and Radiation Sources...

21 CFR 179.43 - Carbon dioxide laser for etching food.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Carbon dioxide laser for etching food. 179.43 Section 179.43 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION (CONTINUED) IRRADIATION IN THE PRODUCTION, PROCESSING AND HANDLING OF...

21 CFR 179.41 - Pulsed light for the treatment of food.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Pulsed light for the treatment of food. 179.41 Section 179.41 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION (CONTINUED) IRRADIATION IN THE PRODUCTION, PROCESSING AND HANDLING OF...

21 CFR 179.39 - Ultraviolet radiation for the processing and treatment of food.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Ultraviolet radiation for the processing and treatment of food. 179.39 Section 179.39 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) IRRADIATION IN THE PRODUCTION, PROCESSING AND HANDLING OF FOOD...

21 CFR 179.41 - Pulsed light for the treatment of food.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Pulsed light for the treatment of food. 179.41 Section 179.41 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION (CONTINUED) IRRADIATION IN THE PRODUCTION, PROCESSING AND HANDLING OF...

21 CFR 179.30 - Radiofrequency radiation for the heating of food, including microwave frequencies.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Radiofrequency radiation for the heating of food, including microwave frequencies. 179.30 Section 179.30 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) IRRADIATION IN THE PRODUCTION, PROCESSING AND HANDLING OF...

21 CFR 179.41 - Pulsed light for the treatment of food.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Pulsed light for the treatment of food. 179.41 Section 179.41 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION (CONTINUED) IRRADIATION IN THE PRODUCTION, PROCESSING AND HANDLING OF...

21 CFR 179.41 - Pulsed light for the treatment of food.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Pulsed light for the treatment of food. 179.41 Section 179.41 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION (CONTINUED) IRRADIATION IN THE PRODUCTION, PROCESSING AND HANDLING OF...

21 CFR 179.43 - Carbon dioxide laser for etching food.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Carbon dioxide laser for etching food. 179.43 Section 179.43 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) IRRADIATION IN THE PRODUCTION, PROCESSING AND HANDLING OF FOOD Radiation and Radiation Sources...

Evaluating beneficial drug effects in a non‐interventional setting: a review of effectiveness studies based on Swedish Prescribed Drug Register data

PubMed Central

Hoffmann, Mikael

2017-01-01

Aims To describe and assess current effectiveness studies published up to 2014 using Swedish Prescribed Drug Register (SPDR) data. Methods Study characteristics were extracted. Each study was assessed concerning the clinical relevance of the research question, the risk of bias according to a structured checklist, and as to whether its findings contributed to new knowledge. The biases encountered and ways of handling these were retrieved. Results A total of 24 effectiveness studies were included in the review, the majority on cardiovascular or psychiatric disease (n = 17; 71%). The articles linked data from four (interquartile range: three to four) registers, and were published in 21 different journals with an impact factor ranging from 1.58 to 51.66. All articles had a clinically relevant research question. According to the systematic quality assessments, the overall risk of bias was low in one (4%), moderate in eight (33%) and high in 15 (62%) studies. Overall, two (8%) studies were assessed as contributing to new knowledge. Frequently occurring problems were selection bias making the comparison groups incomparable, treatment bias with suboptimal handling of drug exposure and an intention‐to‐treat approach, and assessment bias including immortal time bias. Good examples of how to handle bias problems included propensity score matching and sensitivity analyses. Conclusion Although this review illustrates that effectiveness studies based on dispensed drug register data can contribute to new evidence of intended effects of drug treatment in clinical practice, the expectations of such data to provide valuable information need to be tempered due to methodological issues. PMID:27928842

[Evaluation of two closed-system drug transfer device in the antineoplastic drug elaboration process].

PubMed

Gómez-Álvarez, Sandra; Porta-Oltra, Begoña; Hernandez-Griso, Marta; Pérez-Labaña, Francisca; Climente-Martí, Mónica

2016-01-01

to assess the impact of two closed-system drug transfer device on the local and environmental contamination and preparation times in the process of preparation of parenteral chemotherapy compared to the standard system. prospective observational study. Two different closed- systems providers, Care Fusion® and Icu Medical®, were compared to standard preparation. 15 nurses of Pharmacy Department prepared 5 preparations each one, one with the standard procedure and four using closed-systems. To evaluate the contamination, a fluorescein solution 0.5% was prepared. Two kind of contamination were evaluated, local (three points connection: closed-system connect vial, syringe and final infusion bags) and environmental (gloves and countertop). Percentage of contaminated preparations was obtained in each one. Time taken by each nurse in each preparation was recorded. 75 preparations were prepared. Local contamination was reduced 21% and 75% in closed-system Icu Medical® and Care Fusion® respectively. Care Fusion® closed system, local contamination was significantly lower than the standard system to the vial, syringe and final package, while Icu Medical® closed-systems only was significantly lower in the connection to the vial. Time of preparation was increased significantly with the use of closed-system between 23.4 and 30.5 seconds. both closed-systems drug transfer device have shown an improvement in contamination than the use of the standard system. However, preparation time has been significantly increased with the use of both systems. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

Pharmacokinetic variations in cancer patients with liver dysfunction: applications and challenges of pharmacometabolomics.

PubMed

Aboel Dahab, Ali; El-Hag, Dhia; Moutamed, Gamal M; Aboel Dahab, Sarah; Abuknesha, Ramadan; Smith, Norman W

2016-09-01

In cancer patients, pharmacokinetic variations between individuals and within individuals due to impairments in organs' function and other reasons such as genetic polymorphisms represent a major problem in disease management, which can result in unpredictable toxicity and variable antineoplastic effects. Addressing pharmacokinetic variations in cancer patients with liver dysfunction and their implications on anticancer and analgesic drugs, in addition to the use of advanced analytical techniques such as metabolomics and pharmacometabolomics, to monitor altered kinetic and discover metabolic biomarkers during therapeutic intervention will help in understanding and reducing pharmacokinetic variations of drugs in cancer patients as a step forward towards personalised medicine. Reviewing published literature addressing and/or related to complications resulting from altered pharmacokinetics (PKs) in cancer patients with liver dysfunction, anticancer and analgesic drugs, evaluating recent advances of pharmacokinetic detection using metabolomics/pharmacometabolomics and the challenges that are currently facing these techniques. The current situation presents a pressing need to reduce pharmacokinetic variations of drugs in cancer patients. Although most of the omics technologies are not entirely focussed on the study of pharmacokinetic variations and some studies are met with uncertainty, the use of pharmacometabolomics combined with other omics technology such as pharmacogenomics can provide clues to personalised cancer treatments by providing useful information about the cancer patient's response to medical interventions via identification of patients' dependent variables, understanding of correlations between individuals and population PKs, and therapy outcomes to achieve optimum therapeutic effects with minimum toxicity. We also propose an approach for PKs' evaluation using pharmacometabolomics.

Changes in Retail Prices of Prescription Dermatologic Drugs From 2009 to 2015.

PubMed

Rosenberg, Miranda E; Rosenberg, Steven P

2016-02-01

Physicians from many specialties as well as primary care prescribe dermatologic medications; as insurance formularies become increasingly restrictive and more patients are covered with high-deductible insurance plans, many patients are forced to pay high retail prices to obtain their medications. To determine the changes in the prices of commonly prescribed dermatologic medications since 2009 and to identify trends in price increases for different classes of drugs. Four national chain pharmacies received surveys requesting price data on commonly prescribed dermatologic drugs in 2009, 2011, 2014, and 2015. The initial survey requested information on 72 brand-name drugs. Subsequent surveys increased to eventually include 120 additional brand-name drugs and their generic alternatives when available. Owing to the frequency of prescription, diseases treated, or unusual price increases, 19 brand-name drugs surveyed in all 4 years were selected for final price trend analysis, which was conducted from August 1 to 15, 2015. Retail prices of topical and systemic drugs for the treatment of various dermatologic conditions. Prices of surveyed brand-name drugs increased rapidly between 2009 and 2015. Of the 19 brand-name drugs analyzed, the retail prices of 7 drugs more than quadrupled during the study period. Among these 19 drugs, the mean price increase was 401% during the 6-year survey period, with the majority of the price increases occurring after 2011. Prices of topical antineoplastic drugs had the greatest mean absolute and percentage increase ($10,926.58 [1240%]). Prices of drugs in the antiinfective class had the smallest mean absolute increase ($333.99); prices of psoriasis medications had the smallest mean percentage increase (180%). Prices of acne and rosacea medications increased a mean of 195%, and prices of topical corticosteroids increased a mean of 290% during the study period. Selected generic drugs surveyed in 2011 and 2014 also increased a mean of 279% during the 3-year period. The price of prescription dermatologic drugs rose considerably from 2009 to 2015, with the vast majority of price increases occurring after 2011. Percent increases for multiple, frequently prescribed medications greatly outpaced inflation, national health expenditure growth, and increases in reimbursements for physician services.

Biotechnological advancement in isolation of anti-neoplastic compounds from natural origin: a novel source of L-asparaginase.

PubMed

Shrivastava, Abhinav; Khan, Abdul Arif; Jain, Sudhir K; Singhal, P K; Jain, Shalini; Marotta, Francesco; Yadav, Hariom

2010-09-01

L-asparaginase catalyzes the hydrolysis of L-asparagine into aspartate and ammonia, which is used as an anti-neoplastic agent. Isolation of asparaginase from microorganisms may be cardinal for producing this anticancer agent at industrial level. A total of three hundred fungal isolates were screened for L-asparaginase production. These fungal isolates were growing on various fruits and vegetables. Among these, the Fusariumn sp. isolate that was growing on green chilly showed highest enzyme production. This study may give an outstanding contribution for finding organisms with high yielding L-asparaginase. Fungal L-asparaginase is superior in terms of its eukaryotic origin that may be responsible for its lesser toxicity.

Synthesis and biological properties of new 5-nitroindazole derivatives.

PubMed

Arán, Vicente J; Ochoa, Carmen; Boiani, Lucía; Buccino, Pablo; Cerecetto, Hugo; Gerpe, Alejandra; González, Mercedes; Montero, David; Nogal, Juan José; Gómez-Barrio, Alicia; Azqueta, Amaya; López de Ceráin, Adela; Piro, Oscar E; Castellano, Eduardo E

2005-05-02

A series of new 3-alkoxy- or 3-hydroxy-1-[omega-(dialkylamino)alkyl]-5-nitroindazoles have been synthesized and their trichomonacidal, antichagasic and antineoplastic properties studied. Five derivatives (5, 6, 8, 9 and 17) showed remarkable trichomonacidal activity against Trichomonas vaginalis at 10 microg/mL concentration. Three compounds (8, 10, 11) exhibited interesting antichagasic activity and these same compounds moderate antineoplastic activity against TK-10 and HT-29 cell lines. Unspecific cytotoxicity against macrophages has also been evaluated and only compounds 9, 10 and 11 resulted cytotoxic at the higher dose evaluated (100 microg/mL), loosing cytotoxicity at lower doses. QSAR studies have been carried out. X-ray crystallographic study of compound 8 has been performed.

SALL4 as an Epithelial-Mesenchymal Transition and Drug Resistance Inducer through the Regulation of c-Myc in Endometrial Cancer

PubMed Central

Yang, Xiaoming; Fang, Chi; Xu, Huali; Xi, Xiaowei

2015-01-01

SALL4 plays important roles in the development and progression of many cancers. However, the role and molecular mechanism of SALL4 in endometrial cancer remain elusive. In the present research, we have demonstrated that the expression of SALL4 was upregulated in endometrial cancer and correlated positively with tumor stage, metastases and poor survival of patients. The overexpression of SALL4 promoted the invasiveness in endometrial cancer cells, as indicated by the upregulation of mesenchymal cell marker N-cadherin and downregulation of the epithelial marker E-cadherin, and invasion assays in vitro. Additionally, there was also an increase in drug resistance in these cell models due to the upregulation of ATP-binding cassette multidrug transporter ABCB1 expression. Moreover, we also found that ABCB1 was critical for SALL4-induced drug resistance. In contrast, SALL4 knockdown restored drug sensitivity, reversed EMT, diminished cell metastasis and suppressed the downregulation of E-cadherin and the upregulation of N-cadherin and ABCB1. Furthermore, we showed that SALL4 upregulated c-Myc expression and c-Myc was a direct target for SALL4 by ChIP assay, depletion of c-Myc with siRNA abolished the SALL4-induced downregulation of E-cadherin, upregulation of N-cadherin and ABCB1, suggesting that c-Myc was a downstream target for SALL4 and required for SALL4-induced EMT, invasion and drugs resistance in endometrial cancer cells. These results indicated that SALL4 could induce EMT and resistance to antineoplastic drugs through the regulation of c-Myc. SALL4 and c-Myc may be novel therapeutic targets for endometrial cancer. PMID:26407074

Economic benefits of sponsored clinical trials on pharmaceutical expenditures at a medical center in Taiwan.

PubMed

Shen, Li-Jiuan; Chou, Hua; Huang, Chih-Fen; Chou, Guann-Miaw; Chan, Wing Kai; Wu, Fe-Lin Lin

2011-07-01

Concerns exist regarding the additional cost of patient care when patients are enrolled in clinical trials at hospitals. To assess the avoidance of drug costs by conducting sponsored clinical trials, a retrospective analysis evaluating drug cost avoidance in all sponsored clinical trials was conducted in 2008 at the most prominent medical center in Taiwan. The National Health Insurance (NHI) reimbursement prices of either the investigated drugs or the standardized drug therapy for each specific disease were used to calculate the cost avoidance. Drug cost avoidance from sponsored clinical trials per year, per trial, per patient, in different therapeutic areas, and in different phases was analyzed. Three quarters of the cost avoidance in drug expenditures from 194 sponsored clinical trials were estimated. All cost values are in US Dollars. Around $11.2 million was avoided at the center in 2008. The average value of cost avoidance was $58,000/trial-year or $3,900/participant-year. The early-phase trials and phase III trials accounted for 25% and 56% of all trials, respectively, while they constituted 32% and 49% of the total costs avoided, respectively. The most frequently conducted and highest cost-avoiding trials were those for antineoplastic agents, especially targeted therapy which accounted for 85% of the total cost avoidance of anti-cancer trials. This study demonstrates the profoundly positive economic impact on the healthcare system in Taiwan by sponsored clinical trials. To understand the trend of economic benefits of the trials on pharmaceutical expenditure, it would be important to analyze the cost avoidance of trials regularly in an institution. Copyright © 2011 Elsevier Inc. All rights reserved.

New Molecular Targets of Anticancer Therapy - Current Status and Perspectives.

PubMed

Zajac, Marianna; Muszalska, Izabela; Jelinska, Anna

2016-01-01

Molecularly targeted anticancer therapy involves the use of drugs or other substances affecting specific molecular targets that play a part in the development, progression and spread of a given neoplasm. By contrast, the majority of classical chemotherapeutics act on all rapidly proliferating cells, both healthy and cancerous ones. Target anticancer drugs are designed to achieve a particular aim and they usually act cytostatically, not cytotoxically like classical chemotherapeutics. At present, more than 300 biological molecular targets have been identified. The proteins involved in cellular metabolism include (among others) receptor proteins, signal transduction proteins, mRNA thread matrix synthesis proteins participating in neoplastic transformation, cell cycle control proteins, functional and structural proteins. The receptor proteins that are targeted by currently used anticancer drugs comprise the epithelial growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor(VEGFR). Target anticancer drugs may affect extracellular receptor domains (antibodies) or intracellular receptor domains (tyrosine kinase inhibitors). The blocking of the mRNA thread containing information about the structure of oncogenes (signal transduction proteins) is another molecular target of anticancer drugs. That type of treatment, referred to as antisense therapy, is in clinical trials. When the synthesis of genetic material is disturbed, in most cases the passage to the next cycle phase is blocked. The key proteins responsible for the blockage are cyclines and cycline- dependent kinases (CDK). Clinical trials are focused on natural and synthetic substances capable of blocking various CDKs. The paper discusses the molecular targets and chemical structure of target anticancer drugs that have been approved for and currently applied in antineoplastic therapy together with indications and contraindications for their application.

Anticancer drugs in surface waters: what can we say about the occurrence and environmental significance of cytotoxic, cytostatic and endocrine therapy drugs?

PubMed

Besse, Jean-Philippe; Latour, Jean-François; Garric, Jeanne

2012-02-01

This study considers the implications and research needs arising from anticancer (also referred to as antineoplastic) drugs being released into the aquatic environment, for the entire therapeutic classes used: cytotoxic, cytostatic and endocrine therapy drugs. A categorization approach, based on French consumption amounts, allowed to highlight parent molecules and several metabolites on which further occurrence and ecotoxicological studies should be conducted. Investigations of consumption trends at a national and a local scale show an increase in the use of anticancer drugs between 2004 and 2008, thus leading to increased levels released in the environment. It therefore appears necessary to continue surveying their presence in surface waters and in wastewater treatment plant (WWTP) effluents. Furthermore, due to the rise of anticancer home treatments, most of the prescribed molecules are now available in town pharmacies. Consequently, hospital effluents are no longer the main expected entry route of anticancer drugs into the aquatic environment. Concerning ecotoxicological risks, current knowledge remains insufficient to support a definitive conclusion. Risk posed by cytotoxic molecules is still not well documented and it is not possible to conclude on their long-term effects on non-target organisms. To date, ecotoxicological effects have been assessed using standardized or in vitro assays. Such tests however may not be suitable for anticancer drugs, and further work should focus on full-life cycle or even multigenerational tests. Environmental significance (i.e. occurrence and effects) of cytostatics (protein kinases inhibitors and monoclonal antibodies), if any, is not documented. Protein kinases inhibitors, in particular, deserve further investigation due to their universal mode of action. Finally, concerning endocrine therapy drugs, molecules such as antiestrogen Tamoxifen and its active metabolites, could be of concern. Overall, to accurately assess the ecotoxicological risk of anticancer drugs, we discuss the need to break away from tests on isolated molecules and to test effects of mixtures at the low ng.l(-1) range. Copyright © 2011 Elsevier Ltd. All rights reserved.

Stability of solutions of antineoplastic agents during preparation and storage for in vitro assays. General considerations, the nitrosoureas and alkylating agents.

PubMed

Bosanquet, A G

1985-01-01

In vitro drug sensitivity of tumour biopsies is currently being determined using a variety of methods. For these chemosensitivity assays many drugs are required at short notice, and this in turn means that the drugs must generally be stored in solution. There are, however, a number of potential problems associated with dissolving and storing drugs for in vitro use, which include (a) drug adsorption; (b) effects of freezing; (c) drug stability under the normal conditions of dilution and setting up of an in vitro assay; and (d) insolubility of drugs in normal saline (NS) or phosphate-buffered saline (PBS). These problems are considered in general, and some recommendations for use of solutions of drugs in in vitro assays are suggested. The nitrosoureas and alkylating agents are also investigated in greater detail in this respect. The nitrosoureas are found to be very labile in PBS at pH 7, with 5% degradation (t0.95) occurring in 10-50 min at room temperature. These values are increased about 10-fold on refrigeration and about 5- to 10-fold on reduction of the pH of the medium to pH 4-5. At pH 7 and room temperature, t0.95 is observed in under 1 h with the alkylating agents nitrogen mustard, chlorambucil, melphalan, 2,5-diaziridinyl-3,6-bis(2-hydroxyethylamino)-1,4-benzoquinone (BZQ), dibromodulcitol, dibromomannitol, treosulphan, and procarbazine. Of the other alkylating agents, 4-hydroperoxycylophosphamide (sometimes used in vitro in place of cyclophosphamide), busulphan, dianhydrogalactitol, aziridinylbenzoquinone (AZQ), and dacarbazine have a t0.95 of between 2 and 24 h, while ifosfamide and pentamethylmelamine are both stable in aqueous solution for greater than 7 days. About half the drugs studied in detail have been stored frozen in solution for in vitro use, although very little is known about their stability under these conditions.

Safe handling of cytotoxic compounds in a biopharmaceutical environment.

PubMed

Hensgen, Miriam I; Stump, Bernhard

2013-01-01

Handling cytotoxic drugs such as antibody-drug conjugates (ADCs) in a biopharmaceutical environment represents a challenge based on the potency of the compounds. These derivatives are dangerous to humans if they accidentally get in contact with the skin, are inhaled, or are ingested, either as pure compounds in their solid state or as a solution dissolved in a co-solvent. Any contamination of people involved in the manufacturing process has to be avoided. On the other hand, biopharmaceuticals need to be protected simultaneously against any contamination from the manufacturing personnel. Therefore, a tailor-made work environment is mandatory in order to manufacture ADCs. This asks for appropriate technical equipment to keep potential hazardous substances contained. In addition, clearly defined working procedures based on risk assessments as well as proper training for all personnel involved in the manufacturing process are needed to safely handle these highly potent pharmaceuticals.

Respiratory status determines the effect of emodin on cell viability.

PubMed

Dumit, Verónica I; Zerbes, Ralf M; Kaeser-Pebernard, Stephanie; Rackiewicz, Michal; Wall, Mona T; Gretzmeier, Christine; Küttner, Victoria; van der Laan, Martin; Braun, Ralf J; Dengjel, Jörn

2017-06-06

The anthraquinone emodin has been shown to have antineoplastic properties and a wealth of unconnected effects have been linked to its use, most of which are likely secondary outcomes of the drug treatment. The primary activity of emodin on cells has remained unknown. In the present study we demonstrate dramatic and extensive effects of emodin on the redox state of cells and on mitochondrial homeostasis, irrespectively of the cell type and organism, ranging from the yeast Saccharomyces cerevisiae to human cell lines and primary cells. Emodin binds to redox-active enzymes and its effectiveness depends on the oxidative and respiratory status of cells. We show that cells with efficient respiratory metabolism are less susceptible to emodin, whereas cells under glycolytic metabolism are more vulnerable to the compound. Our findings indicate that emodin acts in a similar way as known uncouplers of the mitochondrial electron transport chain and causes oxidative stress that particularly disturbs cancer cells.

Respiratory status determines the effect of emodin on cell viability

PubMed Central

Dumit, Verónica I; Zerbes, Ralf M; Kaeser-Pebernard, Stephanie; Rackiewicz, Michal; Wall, Mona T; Gretzmeier, Christine; Küttner, Victoria; van der Laan, Martin; Braun, Ralf J; Dengjel, Jörn

2017-01-01

The anthraquinone emodin has been shown to have antineoplastic properties and a wealth of unconnected effects have been linked to its use, most of which are likely secondary outcomes of the drug treatment. The primary activity of emodin on cells has remained unknown. In the present study we demonstrate dramatic and extensive effects of emodin on the redox state of cells and on mitochondrial homeostasis, irrespectively of the cell type and organism, ranging from the yeast Saccharomyces cerevisiae to human cell lines and primary cells. Emodin binds to redox-active enzymes and its effectiveness depends on the oxidative and respiratory status of cells. We show that cells with efficient respiratory metabolism are less susceptible to emodin, whereas cells under glycolytic metabolism are more vulnerable to the compound. Our findings indicate that emodin acts in a similar way as known uncouplers of the mitochondrial electron transport chain and causes oxidative stress that particularly disturbs cancer cells. PMID:28415582

Controlled release of mitomycin C from PHEMAH-Cu(II) cryogel membranes.

PubMed

Bakhshpour, Monireh; Yavuz, Handan; Denizli, Adil

2018-02-19

Molecular imprinting technique was used for the preparation of antibiotic and anti-neoplastic chemotherapy drug (mitomycin C) imprinted cryogel membranes (MMC-ICM). The membranes were synthezied by using metal ion coordination interactions with N-methacryloyl-(l)-histidine methyl ester (MAH) functional monomer and template molecules (i.e. MMC). The 2-hydroxyethyl methacrylate (HEMA) monomer and methylene bisacrylamide (MBAAm) crosslinker were used for the preparation of mitomycin C imprinted cryogel membranes by radical suspension polymerization technique. The imprinted cryogel membranes were characterized by scanning electron microscopy (SEM), Brunauer-Emmett-Teller (BET), Fourier transform infrared spectroscopy-attenuated total reflectance (FTIR-ATR) and swelling degree measurements. Cytotoxicity of MMC-ICMs was investigated using mouse fibroblast cell line L929. Time-dependent release of MMC was demonstrated within 150 h from cryogel membranes. Cryogels demonstrated very high MMC loading efficiency (70-80%) and sustained MMC release over hours.

Cannabis Use in Palliative Oncology: A Review of the Evidence for Popular Indications.

PubMed

Turgeman, Ilit; Bar-Sela, Gil

2017-02-01

A flowering plant of variegated ingredients and psychoactive qualities, cannabis has long been used for medicinal and recreational purposes. Currently, cannabis is approved in several countries for indications of symptomatic alleviation. However, limited knowledge on the benefits and risks precludes inclusion of cannabis in standard treatment guidelines. This review provides a summary of the available literature on the use of cannabis and cannabinoid-based medicines in palliative oncology. Favorable outcomes are demonstrated for chemotherapy-induced nausea and vomiting and cancer-related pain, with evidence of advantageous neurological interactions. Benefit in the treatment of anorexia, insomnia and anxiety is also suggested. Short- and long-term side effects appear to be manageable and to subside after discontinuation of the drug. Finally, cannabinoids have shown anti-neoplastic effects in preclinical studies in a wide range of cancer cells and some animal models. Further research is needed before cannabis can become a part of evidence-based oncology practice.

Fenbendazole as a Potential Anticancer Drug

PubMed Central

DUAN, QIWEN; LIU, YANFENG; ROCKWELL, SARA

2013-01-01

Background/Aims To evaluate the anticancer activity of fenbendazole, a widely used antihelminth with mechanisms of action that overlap with those of the hypoxia-selective nitroheterocyclic cytotoxins/radiosensitizers and the taxanes. Materials and Methods We used EMT6 mouse mammary tumor cells in cell culture and as solid tumors in mice to examine the cytotoxic and antitumor effects of fenbendazole as a single agent and in combination regimens. Results Intensive treatments with fenbendazole were toxic to EMT6 cells in vitro; toxicity increased with incubation time and under conditions of severe hypoxia. Fenbendazole did not alter the dose-response curves for radiation or docetaxel; instead, the agents produced additive cytotoxicities. Febendazole in maximally-intensive regimens did not alter the growth of EMT6 tumors, or increase the antineoplastic effects of radiation. Conclusion These studies provided no evidence that fenbendazole would have value in cancer therapy, but suggested that this general class of compounds merits further investigation. PMID:23393324

Fenbendazole as a potential anticancer drug.

PubMed

Duan, Qiwen; Liu, Yanfeng; Rockwell, Sara

2013-02-01

To evaluate the anticancer activity of fenbendazole, a widely used antihelminth with mechanisms of action that overlap with those of the hypoxia-selective nitroheterocyclic cytotoxins/radiosensitizers and the taxanes. We used EMT6 mouse mammary tumor cells in cell culture and as solid tumors in mice to examine the cytotoxic and antitumor effects of fenbendazole as a single agent and in combination regimens. Intensive treatments with fenbendazole were toxic to EMT6 cells in vitro; toxicity increased with incubation time and under conditions of severe hypoxia. Fenbendazole did not alter the dose-response curves for radiation or docetaxel; instead, the agents produced additive cytotoxicities. Febendazole in maximally-intensive regimens did not alter the growth of EMT6 tumors, or increase the antineoplastic effects of radiation. These studies provided no evidence that fenbendazole would have value in cancer therapy, but suggested that this general class of compounds merits further investigation.

Efficiency, costs and benefits of AOPs for removal of pharmaceuticals from the water cycle.

PubMed

Tuerk, J; Sayder, B; Boergers, A; Vitz, H; Kiffmeyer, T K; Kabasci, S

2010-01-01

Different advanced oxidation processes (AOP) were developed for the treatment of highly loaded wastewater streams. Optimisation of removal and improvement of efficiency were carried out on a laboratory, semiworks and pilot plant scale. The persistent cytostatic drug cyclophosphamide was selected as a reference substance regarding elimination and evaluation of the various oxidation processes because of its low degradability rate. The investigated processes are cost-efficient and suitable regarding the treatment of wastewater streams since they lead to efficient elimination of antibiotics and antineoplastics. A total reduction of toxicity was proven by means of the umuC-test. However, in order to reduce pharmaceuticals from the water cycle, it must be considered that the input of more than 80 % of the pharmaceuticals entering wastewater treatment systems results from private households. Therefore, advanced technologies should also be installed at wastewater treatment plants.

Clinical application of Chamomilla recutita in phlebitis: dose response curve study.

PubMed

Reis, Paula Elaine Diniz Dos; Carvalho, Emilia Campos de; Bueno, Paula Carolina Pires; Bastos, Jairo Kenupp

2011-01-01

This experimental and dose-response curve study aimed to carry out the quality control of the Chamomilla recutita sample, as well as to estimate the ideal dose, for anti-inflammatory effect, of the extract of its capitula, in patients with phlebitis due to peripheral intravenous infusion of antineoplastic chemotherapy and to evaluate the toxicity of this extract in human beings. The therapeutic efficacy, concerning the anti-inflammatory potential, of different doses of Chamomilla recutita extract were analyzed and compared in 25 patients. The time of regression of phlebitis was shorter for groups with 2.5% concentration (mean=29.2h, standard deviation = 8.98) and 5% concentration (mean = 38.8h, standard deviation = 17.47). Local toxicity was almost not observed. This research contributes to the innovation of the nursing clinical practice, since it suggests an alternative for the treatment of phlebitis through the clinical use of phytotherapeutic drugs.

Role of curcumin-dependent modulation of tumor microenvironment of a murine T cell lymphoma in altered regulation of tumor cell survival

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vishvakarma, Naveen Kumar; Kumar, Anjani; Singh, Sukh Mahendra, E-mail: sukhmahendrasingh@yahoo.com

2011-05-01

Using a murine model of a T cell lymphoma, in the present study, we report that tumor growth retarding action of curcumin involves modulation of some crucial parameters of tumor microenvironment regulating tumor progression. Curcumin-administration to tumor-bearing host caused an altered pH regulation in tumor cells associated with alteration in expression of cell survival and apoptosis regulatory proteins and genes. Nevertheless, an alteration was also observed in biophysical parameters of tumor microenvironment responsible for modulation of tumor growth pertaining to hypoxia, tumor acidosis, and glucose metabolism. The study thus sheds new light with respect to the antineoplastic action of curcuminmore » against a tumor-bearing host with progressively growing tumor of hematological origin. This will help in optimizing application of the drug and anticancer research and therapy. - Graphical Abstract: Display Omitted« less

[Influence of Cx26/Cx32 gap junction channel on antineoplastic effect of etoposide in Hela cells].

PubMed

Tong, Xu-Hui; Dong, Shu-Ying; Jiang, Guo-Jun; Fan, Gao-Fu

2012-03-01

To observe the influence of Cx26/Cx32 gap junction channel on the antineoplastic effect of etoposide in Hela cervical cancer cells. Fluorescence trace was used to assay the gap junction intercellular communication mediated by Cx26/Cx32 in Hela cells and its functional modulation by the pharmacological agents (oleamide, retinoid acid). A standard colony-forming assay was applied to determine the cell growth-inhibiting effect of etoposide in Hela cells with functional modulation of the gap junction. Hoechst 33258 staining was used to assess the changes in etoposide-induced apoptosis of Hela cells with altered gap junction functions. Oleamide markedly decreased while retinoid acid obviously increased the gap junction function in Hela cells. Standard colony-forming assay showed that etoposide produced a lowered antiproliferative effect in Hela cells with reduced gap junction and an increased antiproliferative effect in cells with enhanced gap junction function. In cells with a reduced gap junction function, etoposide induced a lowered apoptosis rate, which increased obviously in cells with an enhanced gap junction function. The antineoplastic effect of etoposide is reduced in Hela cells with a decreased gap junction intercellular communication mediated by Cx26/Cx32 and is enhanced in cells with an increased gap junction intercellular communication.

A Review of Analytical Methods for p-Coumaric Acid in Plant-Based Products, Beverages, and Biological Matrices.

PubMed

Ferreira, Paula Scanavez; Victorelli, Francesca Damiani; Fonseca-Santos, Bruno; Chorilli, Marlus

2018-05-14

p-Coumaric acid (p-CA), also known as 4-hydroxycinnamic acid, is a phenolic acid, which has been widely studied due to its beneficial effects against several diseases and its wide distribution in the plant kingdom. This phenolic compound can be found in the free form or conjugated with other molecules; therefore, its bioavailability and the pathways via which it is metabolized change according to its chemical structure. p-CA has potential pharmacological effects because it has high free radical scavenging, anti-inflammatory, antineoplastic, and antimicrobial activities, among other biological properties. It is therefore essential to choose the most appropriate and effective analytical method for qualitative and quantitative determination of p-CA in different matrices, such as plasma, urine, plant extracts, and drug delivery systems. The most-reported analytical method for this purpose is high-performance liquid chromatography, which is mostly coupled with some type of detectors, such as UV/Vis detector. However, other analytical techniques are also used to evaluate this compound. This review presents a summary of p-CA in terms of its chemical and pharmacokinetic properties, pharmacological effects, drug delivery systems, and the analytical methods described in the literature that are suitable for its quantification.

Dermatological adverse events with taxane chemotherapy

PubMed Central

Sibaud, Vincent; Lebœuf, Nicole R.; Roche, Henri; Belum, Viswanath R.; Gladieff, Laurence; Deslandres, Marion; Montastruc, Marion; Eche, Audrey; Vigarios, Emmanuelle; Dalenc, Florence; Lacouture, Mario E.

2017-01-01

Taxanes (docetaxel and paclitaxel) are among the most commonly prescribed anticancer drugs approved for the treatment of metastatic or locally advanced breast, non-small cell lung, prostate, gastric, head and neck, and ovarian cancers, as well as in the adjuvant setting for operable node-positive breast cancers. Although the true incidence of dermatological adverse events (AEs) in patients receiving taxanes is not known, and has never been prospectively analysed, they clearly represent one of the major AEs associated with these agents. With an increase in the occurrence of cutaneous AEs during treatment with novel targeted and immunological therapies when used in combination with taxanes, a thorough understanding of reactions attributable to this class is imperative. Moreover, identification and management of dermatological AEs is critical for maintaining the quality of life in cancer patients and for minimizing dose modifications of their antineoplastic regimen. This analysis represents a systematic review of the dermatological conditions reported with the use of these drugs, complemented by experience at comprehensive cancer centres. The conditions reported herein include skin, hair, and nail toxicities. Lastly, we describe the dermatological data available for the new, recently FDA-and EMA- approved, solvent-free nab-paclitaxel. PMID:27550571

Trial Watch

PubMed Central

Vacchelli, Erika; Aranda, Fernando; Eggermont, Alexander; Galon, Jérôme; Sautès-Fridman, Catherine; Cremer, Isabelle; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo

2014-01-01

Accumulating evidence suggests that the clinical efficacy of selected anticancer drugs, including conventional chemotherapeutics as well as targeted anticancer agents, originates (at least in part) from their ability to elicit a novel or reinstate a pre-existing tumor-specific immune response. One of the mechanisms whereby chemotherapy can stimulate the immune system to recognize and destroy malignant cells is commonly known as immunogenic cell death (ICD). Cancer cells succumbing to ICD are de facto converted into an anticancer vaccine and as such elicit an adaptive immune response. Several common chemotherapeutics share the ability of triggering ICD, as demonstrated in vaccination experiments relying on immunocompetent mice and syngeneic cancer cells. A large number of ongoing clinical trials involve such ICD inducers, often (but not always) as they are part of the gold standard therapeutic approach against specific neoplasms. In this Trial Watch, we summarize the latest advances on the use of cyclophosphamide, doxorubicin, epirubicin, oxaliplatin, and mitoxantrone in cancer patients, discussing high-impact studies that have been published during the last 13 months as well as clinical trials that have been initiated in the same period to assess the antineoplastic profile of these immunogenic drugs as off-label therapeutic interventions. PMID:24800173

F1174V mutation alters the ALK active conformation in response to Crizotinib in NSCLC: Insight from molecular simulations.

PubMed

Dehghanian, Fariba; Kay, Maryam; Vallian, Sadeq

2017-08-01

Crizotinib is an efficient antineoplastic drug for treatment of non-small cell lung carcinoma (NSCLC), which is identified as an anaplastic lymphoma kinase (ALK) inhibitor. F1174V is a recently identified acquired point mutation relating to the Crizotinib resistance in NSCLC patients. The mechanism of Crizotinib resistance relating to F1174V mutation as a non-active site mutation remains unclear. In this study, the molecular dynamic simulation was used to investigate the possible mechanisms by which F1174V mutation may affect the structure and activity of ALK kinase domain. The results suggested that F1174V mutation could cause two important secondary structure alterations, which led to the local conformational change in ALK kinase domain. This causes more positive free energy in the mutant complex in comparison with the wild-type one. In addition, our structural analyses illustrated that F1174V mutation could result in some important interactions, which represent the key characteristics of the ALK active conformation. This study provided a molecular mechanism for ALK Crizotinib resistance caused by F1174V mutation,which could facilitate designing more efficient drugs. Copyright © 2017 Elsevier Inc. All rights reserved.

Gold(III)-Dithiocarbamato Peptidomimetics in the Forefront of the Targeted Anticancer Therapy: Preclinical Studies against Human Breast Neoplasia

PubMed Central

Nardon, Chiara; Schmitt, Sara M.; Yang, Huanjie; Zuo, Jian

2014-01-01

Since the serendipitous discovery of cisplatin, platinum-based drugs have become well-established antitumor agents, despite the fact that their clinical use is limited by many severe side-effects. In order to both improve the chemotherapeutic index and broaden the therapeutic spectrum of current drugs, our most recent anti-neoplastic agents, Au(III) complexes, were designed as carrier-mediated delivery systems exploiting peptide transporters, which are up-regulated in some cancers. Among all, we focused on two compounds and tested them on human MDA-MB-231 (resistant to cisplatin) breast cancer cell cultures and xenografts, discovering the proteasome as a major target both in vitro and in vivo. 53% inhibition of breast tumor growth in mice was observed after 27 days of treatment at 1.0 mg kg−1 d−1, compared to control. Remarkably, if only the most responsive mice are taken into account, 85% growth inhibition, with some animals showing tumor shrinkage, was observed after 13 days. These results led us to file an international patent, recognizing this class of gold(III) peptidomimetics as suitable candidates for entering phase I clinical trials. PMID:24392119

Intravenous bisphosphonate-related osteonecrosis of the jaws: Influence of coadjuvant antineoplastic treatment and study of buccodental condition

PubMed Central

Bagán, José; Poveda-Roda, Rafael

2013-01-01

Objectives: To determine whether coadjuvant antineoplastic treatment can influence the number and size of bone exposures among patients with intravenous bisphosphonate-related osteonecrosis of the jaws (iBRONJ), and to analyze the buccodental condition of these patients. Material and methods: The study sample comprised 67 patients with iBRONJ, 53 patients without iBRONJ receiving treatment with intravenous bisphosphonates, and 36 healthy subjects. In all three groups, measurements were made of the CAO index and of resting whole saliva and stimulated whole saliva. In the patients with iBRONJ, the size (cm) and number of bone exposures were recorded. The data obtained were subjected to analysis of variance (ANOVA), the Mann-Whitney U-test, and multivariate logistic regression analysis. Results: A total of 57.6% of the patients presented single bone exposure, 25.4% presented two, and 17% more than two exposures. The mean exposure size was 2.3±1.9 cm. Neither the bivariate analysis nor the multivariate multiple regression analysis found coadjuvant antineoplastic treatment to exert a statistically significant effect upon the number and size of bone exposures. On the other hand, there were statistically significant differences among the three study groups in relation to the CAO index (p=0.02) and the number of missing teeth (p=0.00). The resting whole saliva and stimulated whole saliva levels were similar in the three groups, though the patients with osteonecrosis of the jaws showed comparatively lower SWS levels. Conclusions: Coadjuvant antineoplastic treatment alone appears to exert no influence upon the size and number of bone exposures in iBRONJ. The patients with this disease show a higher CAO index and a larger number of missing teeth. Key words:Osteonecrosis of the jaws, bisphosphonates, bone exposure, CAO index, resting whole saliva, stimulated whole saliva. PMID:23229272

MicroRNA-19a/b mediates grape seed procyanidin extract-induced anti-neoplastic effects against lung cancer.

PubMed

Mao, Jenny T; Xue, Bingye; Smoake, Jane; Lu, Qing-Yi; Park, Heesung; Henning, Susanne M; Burns, Windie; Bernabei, Alvise; Elashoff, David; Serio, Kenneth J; Massie, Larry

2016-08-01

Oncomirs are microRNAs (miRNA) associated with carcinogenesis and malignant transformation. They have emerged as potential molecular targets for anti-cancer therapy. We hypothesize that grape seed procyanidin extract (GSE) exerts antineoplastic effects through modulations of oncomirs and their downstream targets. We found that GSE significantly down-regulated oncomirs miR-19a and -19b in a variety of lung neoplastic cells. GSE also increased mRNA and protein levels of insulin-like growth factor II receptor (IGF-2R) and phosphatase and tensin homolog (PTEN), both predicted targets of miR-19a and -19b. Furthermore, GSE significantly increased PTEN activity and decreased AKT phosphorylation in A549 cells. Transfection of miR-19a and -19b mimics reversed the up-regulations of IGF2R and PTEN gene expression and abrogated the GSE induced anti-proliferative response. Additionally, oral administration of leucoselect phytosome, comprised of standardized grape seed oligomeric procyanidins complexed with soy phospholipids, to athymic nude mice via gavage, significantly down-regulated miR-19a, -19b and the miR-17-92 cluster host gene (MIR17HG) expressions, increased IGF-2R, PTEN, decreased phosphorylated-AKT in A549 xenograft tumors, and markedly inhibited tumor growth. To confirm the absorption of orally administered GSE, plasma procyanidin B1 levels, between 60 and 90 min after gavage of leucoselect phytosome (400 mg/kg), were measured by LC/MS at week 2 and 8 of treatment; the estimated concentration that was associated with 50% growth inhibition (IC50) (1.3 μg/mL) in vitro was much higher than the IC50 (0.032-0.13 μg/ml) observed in vivo. Our findings reveal novel antineoplastic mechanisms by GSE and support the clinical translation of leucoselect phytosome as an anti-neoplastic and chemopreventive agent for lung cancer. Published by Elsevier Inc.

21 CFR 500.45 - Use of polychlorinated biphenyls (PCB's) in the production, handling, and storage of animal feed.

Code of Federal Regulations, 2012 CFR

2012-04-01

... Food and Drug Administration have revealed that heat exchange fluids for certain pasteurization equipment used in processing animal feed contain PCB's. Although heat exchange fluids in such equipment are... animal feed shall: (i) Have the heat exchange fluid used in existing equipment or machinery for handling...

21 CFR 500.45 - Use of polychlorinated biphenyls (PCB's) in the production, handling, and storage of animal feed.

Code of Federal Regulations, 2013 CFR

2013-04-01

... Food and Drug Administration have revealed that heat exchange fluids for certain pasteurization equipment used in processing animal feed contain PCB's. Although heat exchange fluids in such equipment are... animal feed shall: (i) Have the heat exchange fluid used in existing equipment or machinery for handling...

21 CFR 1250.28 - Source and handling of ice.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Source and handling of ice. 1250.28 Section 1250... ice. Ice coming in contact with food or drink and not manufactured on the conveyance shall be obtained from sources approved by competent health authorities. All ice coming in contact with food or drink...

21 CFR 1250.28 - Source and handling of ice.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Source and handling of ice. 1250.28 Section 1250... ice. Ice coming in contact with food or drink and not manufactured on the conveyance shall be obtained from sources approved by competent health authorities. All ice coming in contact with food or drink...

21 CFR 1250.28 - Source and handling of ice.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Source and handling of ice. 1250.28 Section 1250... ice. Ice coming in contact with food or drink and not manufactured on the conveyance shall be obtained from sources approved by competent health authorities. All ice coming in contact with food or drink...

21 CFR 1250.28 - Source and handling of ice.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Source and handling of ice. 1250.28 Section 1250... ice. Ice coming in contact with food or drink and not manufactured on the conveyance shall be obtained from sources approved by competent health authorities. All ice coming in contact with food or drink...

77 FR 43842 - Agency Information Collection Activities; Submission for Office of Management and Budget Review...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-26

...; Irradiation in the Production, Processing, and Handling of Food AGENCY: Food and Drug Administration, HHS.... Irradiation in the Production, Processing, and Handling of Food--21 CFR Part 179 (OMB Control Number 0910-0186.... 321(s) and 348), food irradiation is subject to regulation under the food additive premarket approval...

Imaging of hepatic toxicity of systemic therapy in a tertiary cancer centre: chemotherapy, haematopoietic stem cell transplantation, molecular targeted therapies, and immune checkpoint inhibitors.

PubMed

Alessandrino, F; Tirumani, S H; Krajewski, K M; Shinagare, A B; Jagannathan, J P; Ramaiya, N H; Di Salvo, D N

2017-07-01

The purpose of this review is to familiarise radiologists with the spectrum of hepatic toxicity seen in the oncology setting, in view of the different systemic therapies used in cancer patients. Drug-induced liver injury can manifest in various forms, and anti-neoplastic agents are associated with different types of hepatotoxicity. Although chemotherapy-induced liver injury can present as hepatitis, steatosis, sinusoidal obstruction syndrome, and chronic parenchymal damages, molecular targeted therapy-associated liver toxicity ranges from mild liver function test elevation to fulminant life-threatening acute liver failure. The recent arrival of immune checkpoint inhibitors in oncology has introduced a new range of immune-related adverse events, with differing mechanisms of liver toxicity and varied imaging presentation of liver injury. High-dose chemotherapy regimens for haematopoietic stem cell transplantation are associated with sinusoidal obstruction syndrome. Management of hepatic toxicity depends on the clinical scenario, the drug in use, and the severity of the findings. In this article, we will (1) present the most common types of oncological drugs associated with hepatic toxicity and associated liver injuries; (2) illustrate imaging findings of hepatic toxicities and the possible differential diagnosis; and (3) provide a guide for management of these conditions. Copyright © 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Cabazitaxel and indocyanine green co-delivery tumor-targeting nanoparticle for improved antitumor efficacy and minimized drug toxicity.

PubMed

Tai, Xiaowei; Wang, Yang; Zhang, Li; Yang, Yuting; Shi, Kairong; Ruan, Shaobo; Liu, Yayuan; Gao, Huile; Zhang, Zhirong; He, Qin

2017-02-01

Cabazitaxel (CBX) is an effective antineoplastic agent for the treatment of many kinds of cancers. However, the poor water solubility remains a serious deterrent to the utilization of CBX as a commercial drug. In this study, we designed a strategy that integrated CBX into albumin nanoparticles (ANs) formed with human serum albumin (HSA) to improve the water solubility and targeting ability. Meanwhile, we utilized a photothermal agent-indocyanine green (ICG), which could cooperate with CBX to enhance the antitumor effect. The obtained ANs containing ICG and CBX (AN-ICG-CBX) exhibited good mono-dispersity. In vitro cytotoxicity study showed the effectiveness of CBX and ICG, respectively, whereas AN-ICG-CBX with irradiation exhibited the most efficient antiproliferative ability (83.7%). In vivo safety evaluation studies demonstrated the safety of AN-ICG-CBX. Furthermore, the in vivo antitumor study indicated that the AN-ICG-CBX with irradiation achieved higher tumor inhibition rate (91.3%) compared with CBX-encapsulated AN (AN-CBX) (83.3%) or ICG-encapsulated AN (AN-ICG) plus irradiation (60.1%) in 4T1 tumor-bearing mice. To sum up, a safety and effective formulation AN-ICG-CBX was developed in this study and successfully reduced the drug toxicity, improved the targeting efficiency and enhanced the therapeutic effects, becoming a promising candidate for clinical application.

Forecasting drug utilization and expenditure in a metropolitan health region.

PubMed

Wettermark, Björn; Persson, Marie E; Wilking, Nils; Kalin, Mats; Korkmaz, Seher; Hjemdahl, Paul; Godman, Brian; Petzold, Max; Gustafsson, Lars L

2010-05-17

New pharmacological therapies are challenging the healthcare systems, and there is an increasing need to assess their therapeutic value in relation to existing alternatives as well as their potential budget impact. Consequently, new models to introduce drugs in healthcare are urgently needed. In the metropolitan health region of Stockholm, Sweden, a model has been developed including early warning (horizon scanning), forecasting of drug utilization and expenditure, critical drug evaluation as well as structured programs for the introduction and follow-up of new drugs. The aim of this paper is to present the forecasting model and the predicted growth in all therapeutic areas in 2010 and 2011. Linear regression analysis was applied to aggregate sales data on hospital sales and dispensed drugs in ambulatory care, including both reimbursed expenditure and patient co-payment. The linear regression was applied on each pharmacological group based on four observations 2006-2009, and the crude predictions estimated for the coming two years 2010-2011. The crude predictions were then adjusted for factors likely to increase or decrease future utilization and expenditure, such as patent expiries, new drugs to be launched or new guidelines from national bodies or the regional Drug and Therapeutics Committee. The assessment included a close collaboration with clinical, clinical pharmacological and pharmaceutical experts from the regional Drug and Therapeutics Committee. The annual increase in total expenditure for prescription and hospital drugs was predicted to be 2.0% in 2010 and 4.0% in 2011. Expenditures will increase in most therapeutic areas, but most predominantly for antineoplastic and immune modulating agents as well as drugs for the nervous system, infectious diseases, and blood and blood-forming organs. The utilisation and expenditure of drugs is difficult to forecast due to uncertainties about the rate of adoption of new medicines and various ongoing healthcare reforms and activities to improve the quality and efficiency of prescribing. Nevertheless, we believe our model will be valuable as an early warning system to start developing guidance for new drugs including systems to monitor their effectiveness, safety and cost-effectiveness in clinical practice.

Forecasting drug utilization and expenditure in a metropolitan health region

PubMed Central

2010-01-01

Background New pharmacological therapies are challenging the healthcare systems, and there is an increasing need to assess their therapeutic value in relation to existing alternatives as well as their potential budget impact. Consequently, new models to introduce drugs in healthcare are urgently needed. In the metropolitan health region of Stockholm, Sweden, a model has been developed including early warning (horizon scanning), forecasting of drug utilization and expenditure, critical drug evaluation as well as structured programs for the introduction and follow-up of new drugs. The aim of this paper is to present the forecasting model and the predicted growth in all therapeutic areas in 2010 and 2011. Methods Linear regression analysis was applied to aggregate sales data on hospital sales and dispensed drugs in ambulatory care, including both reimbursed expenditure and patient co-payment. The linear regression was applied on each pharmacological group based on four observations 2006-2009, and the crude predictions estimated for the coming two years 2010-2011. The crude predictions were then adjusted for factors likely to increase or decrease future utilization and expenditure, such as patent expiries, new drugs to be launched or new guidelines from national bodies or the regional Drug and Therapeutics Committee. The assessment included a close collaboration with clinical, clinical pharmacological and pharmaceutical experts from the regional Drug and Therapeutics Committee. Results The annual increase in total expenditure for prescription and hospital drugs was predicted to be 2.0% in 2010 and 4.0% in 2011. Expenditures will increase in most therapeutic areas, but most predominantly for antineoplastic and immune modulating agents as well as drugs for the nervous system, infectious diseases, and blood and blood-forming organs. Conclusions The utilisation and expenditure of drugs is difficult to forecast due to uncertainties about the rate of adoption of new medicines and various ongoing healthcare reforms and activities to improve the quality and efficiency of prescribing. Nevertheless, we believe our model will be valuable as an early warning system to start developing guidance for new drugs including systems to monitor their effectiveness, safety and cost-effectiveness in clinical practice. PMID:20478043

Biodistribution of biodegradable polymeric nano-carriers loaded with busulphan and designed for multimodal imaging.

PubMed

Asem, Heba; Zhao, Ying; Ye, Fei; Barrefelt, Åsa; Abedi-Valugerdi, Manuchehr; El-Sayed, Ramy; El-Serafi, Ibrahim; Abu-Salah, Khalid M; Hamm, Jörg; Muhammed, Mamoun; Hassan, Moustapha

2016-12-19

Multifunctional nanocarriers for controlled drug delivery, imaging of disease development and follow-up of treatment efficacy are promising novel tools for disease diagnosis and treatment. In the current investigation, we present a multifunctional theranostic nanocarrier system for anticancer drug delivery and molecular imaging. Superparamagnetic iron oxide nanoparticles (SPIONs) as an MRI contrast agent and busulphan as a model for lipophilic antineoplastic drugs were encapsulated into poly (ethylene glycol)-co-poly (caprolactone) (PEG-PCL) micelles via the emulsion-evaporation method, and PEG-PCL was labelled with VivoTag 680XL fluorochrome for in vivo fluorescence imaging. Busulphan entrapment efficiency was 83% while the drug release showed a sustained pattern over 10 h. SPION loaded-PEG-PCL micelles showed contrast enhancement in T 2 *-weighted MRI with high r 2 * relaxivity. In vitro cellular uptake of PEG-PCL micelles labeled with fluorescein in J774A cells was found to be time-dependent. The maximum uptake was observed after 24 h of incubation. The biodistribution of PEG-PCL micelles functionalized with VivoTag 680XL was investigated in Balb/c mice over 48 h using in vivo fluorescence imaging. The results of real-time live imaging were then confirmed by ex vivo organ imaging and histological examination. Generally, PEG-PCL micelles were highly distributed into the lungs during the first 4 h post intravenous administration, then redistributed and accumulated in liver and spleen until 48 h post administration. No pathological impairment was found in the major organs studied. Thus, with loaded contrast agent and conjugated fluorochrome, PEG-PCL micelles as biodegradable and biocompatible nanocarriers are efficient multimodal imaging agents, offering high drug loading capacity, and sustained drug release. These might offer high treatment efficacy and real-time tracking of the drug delivery system in vivo, which is crucial for designing of an efficient drug delivery system.

The impact of religiosity and individual prayer activities on advanced cancer patients' health: is there any difference in function of whether or not receiving palliative anti-neoplastic therapy?

PubMed

Paiva, Carlos Eduardo; Paiva, Bianca Sakamoto Ribeiro; Yennurajalingam, Sriram; Hui, David

2014-12-01

Consecutive patients (n = 221) presenting for initial consultation at a palliative care outpatient clinic were prospectively interviewed and then followed until death. Individual prayer activity (IPA) and global religion scores were associated with quality of life, symptoms, inflammatory markers, and survival. Analyses were adjusted for whether patients were still receiving anti-neoplastic therapies (ANTs) or not. Higher religion scores were associated with lower levels of inflammation in advanced cancer patients still undergoing ANTs. Additionally, higher IPA was an independent good prognostic factor in patients on active ANTs. Further studies are necessary to confirm these findings and to investigate possible biological mechanisms involved.

QSPR modeling of octanol/water partition coefficient of antineoplastic agents by balance of correlations.

PubMed

Toropov, Andrey A; Toropova, Alla P; Raska, Ivan; Benfenati, Emilio

2010-04-01

Three different splits into the subtraining set (n = 22), the set of calibration (n = 21), and the test set (n = 12) of 55 antineoplastic agents have been examined. By the correlation balance of SMILES-based optimal descriptors quite satisfactory models for the octanol/water partition coefficient have been obtained on all three splits. The correlation balance is the optimization of a one-variable model with a target function that provides both the maximal values of the correlation coefficient for the subtraining and calibration set and the minimum of the difference between the above-mentioned correlation coefficients. Thus, the calibration set is a preliminary test set. Copyright (c) 2009 Elsevier Masson SAS. All rights reserved.

Comprehensive Analysis of miRNome Alterations in Response to Sorafenib Treatment in Colorectal Cancer Cells

PubMed Central

Pehserl, Anna-Maria; Ress, Anna Lena; Stanzer, Stefanie; Resel, Margit; Karbiener, Michael; Stadelmeyer, Elke; Stiegelbauer, Verena; Gerger, Armin; Mayr, Christian; Scheideler, Marcel; Hutterer, Georg C.; Bauernhofer, Thomas; Kiesslich, Tobias; Pichler, Martin

2016-01-01

MicroRNAs (miRNAs) are master regulators of drug resistance and have been previously proposed as potential biomarkers for the prediction of therapeutic response in colorectal cancer (CRC). Sorafenib, a multi-kinase inhibitor which has been approved for the treatment of liver, renal and thyroid cancer, is currently being studied as a monotherapy in selected molecular subtypes or in combination with other drugs in metastatic CRC. In this study, we explored sorafenib-induced cellular effects in Kirsten rat sarcoma viral oncogene homolog olog (KRAS) wild-type and KRAS-mutated CRC cell lines (Caco-2 and HRT-18), and finally profiled expression changes of specific miRNAs within the miRNome (>1000 human miRNAs) after exposure to sorafenib. Overall, sorafenib induced a time- and dose-dependent growth-inhibitory effect through S-phase cell cycle arrest in KRAS wild-type and KRAS-mutated CRC cells. In HRT-18 cells, two human miRNAs (hsa-miR-597 and hsa-miR-720) and two small RNAs (SNORD 13 and hsa-miR-3182) were identified as specifically sorafenib-induced. In Caco-2 cells, nine human miRNAs (hsa-miR-3142, hsa-miR-20a, hsa-miR-4301, hsa-miR-1290, hsa-miR-4286, hsa-miR-3182, hsa-miR-3142, hsa-miR-1246 and hsa-miR-720) were identified to be differentially regulated post sorafenib treatment. In conclusion, we confirmed sorafenib as a potential anti-neoplastic treatment strategy for CRC cells by demonstrating a growth-inhibitory and cell cycle–arresting effect of this drug. Changes in the miRNome indicate that some specific miRNAs might be relevant as indicators for sorafenib response, drug resistance and potential targets for combinatorial miRNA-based drug strategies. PMID:27916938

The effects of different antineoplastic agents and of pretreatment by modulators on three melanoma lines.

PubMed

Rodriguez-Vicente, J; Vicente-Ortega, V; Canteras-Jordana, M

1998-02-01

The chemotherapy of melanoma patients must be improved because of the naturally poor response and acquired resistance of this disease. The authors used mouse (B16F10) and human (SK-MEL-28 and SK-MEL-1) melanoma lines for in vitro treatment with melphalan, lomustine, fotemustine, and 4-hydroxyanisole (4-HA) alone, combined and after pretreatment with buthionine sulfoximine (BSO), ethacrynic acid (EA), and azelaic acid (AZA). Melphalan was the most effective individual drug, followed by lomustine, fotemustine, and 4-HA. The simultaneous administration of two agents was disappointing, although some combinations slightly improved the response compared with the individual treatments. Pretreatment with BSO enhanced the cytotoxicity of melphalan and lomustine 10-fold in B16F10 and 7.5-fold in SK-MEL-28, increasing the toxicity of fotemustine in all 3 lines. EA potentiated lomustine and fotemustine 9-fold and melphalan 5-fold in B16F10 and SK-MEL-28. AZA increased the effectiveness of lomustine and fotemustine in B16F10 and to a lower degree in the two human lines. 4-HA was the poorest drug for sensitization; only B16F10 BSO followed by 4-HA treatment demonstrated increased toxicity, and all other combinations with 4-HA were negative or antagonistic. There was a strong relationship between dopa oxidase activity and the toxicity of 4-HA. B16F10 was the most sensitive to all treatments and SK-MEL-1 the most resistant. Melphalan was the most active individual drug and 4-HA the least. Combinations of two drugs did not result in improved activity compared with drugs administered alone. Pretreatment with modulator seems to be a potential method for enhancing some treatments.

Implementing a new drug record system: a qualitative study of difficulties perceived by physicians and nurses.

PubMed

Andersen, S E

2002-03-01

To identify organisational difficulties faced by physicians and nurses when using drug prescribing sheets for recording both drug prescriptions and drug administration. Qualitative interview study. Two general internal medicine wards. Seven physicians and eight nurses. Difficulties explicitly identified by the participants during the interviews. The implementation of procedures conflicted with existing structure, culture, and routines. Insufficient competence within the system to use the drug prescribing sheets created resistance and made people down the line create their own interpretations and solutions to the problems they faced. A total of nine problems were identified: (1) insufficient knowledge and uncertainty about procedures, (2) ignorance of sources of error, (3) unclear responsibilities, (4) low community spirit, (5) insufficient communication, (6) clinician autonomy and low acceptance of change, (7) strong professional identity, (8) low priority task, and (9) logistical problems. Unawareness of procedures, insufficient dissemination of knowledge, and insufficient cooperation and skepticism among those who put drug handling into practice is likely to have an impact on the quality of health care. The identification of these obstacles may help managers to improve the quality of the drug handling process on internal medicine wards and make it possible to select a framework for changing the clinical behaviour of doctors and nurses.

Statins and Thyroid Carcinoma: a Meta-Analysis.

PubMed

Zhao, Junyu; Xu, Chunmei; Yao, Jinming; Yu, Changzhen; Liao, Lin; Dong, Jianjun

2018-06-19

Experimental studies have reported the antineoplastic effects of statins in thyroid carcinoma; however, observational studies suggested that statins might increase the risk of thyroid carcinoma. Therefore, this study evaluated the antineoplastic effects of statins in both in vitro studies and animal models, as well as the epidemiological evidence. Databases-PubMed, Cochrane Library, SinoMed, CNKI, Wanfang, and clinical trial registries- were searched. A meta-analysis was performed with sufficiently homogeneous studies. Eighteen articles were involved. In in vitro studies, statins showed a concentration-dependent inhibition of cell line growth (weighted mean difference -34.68, 95% confidence interval -36.53 to -32.83). A significant efficacy of statin-induced apoptosis was observed (weighted mean difference [95% confidence interval]: 24 h, 57.50 [55.98-59.03]; 48 h, 23.43 [22.19-24.66]; 72 h, 51.29 [47.52-55.07]). Early apoptosis was increased in a dose- and time-dependent manner. In in vivo antitumor studies, lovastatin inhibited tumor growth, as shown by a reduction in tumor volume. However, two clinical studies showed discordant results from the experimental studies. Experimental studies revealed the antineoplastic efficacy of statins but statins were associated with thyroid carcinoma in clinical studies. This discrepancy may be due to the different concentrations of statins used and the effects of hyperlipidemia interventions, and thus further study is required. © 2018 The Author(s). Published by S. Karger AG, Basel.

Antineoplastic agents extravasation from peripheral intravenous line in children: a simple strategy for a safer nursing care.

PubMed

Chanes, Daniella Cristina; da Luz Gonçalves Pedreira, Mavilde; de Gutiérrez, Maria Gaby Rivero

2012-02-01

The antineoplastic agents infusion through peripheral lines may lead to several adverse events such as extravasation that is one of the most severe acute reactions of this sort of treatment. The extravasation prevention and management must be part of a safe and evidence-based nursing care. Due to this fact, two algorithms were developed with the purpose of guiding nursing care to children who undergo chemotherapy through peripheral line. The objectives of this study were to determine the content validity of both algorithms with pediatric oncology nurses in Brazil and United States of America, and to verify the agreement between the evaluations of both groups. A descriptive validation study was carried out through the Delphi Technique that has the following steps: development of the data collection instrument, application to the specialists, data analysis, algorithms' review, re-evaluation by the specialists, final data analysis and content validity determination. The data analysis was descriptive and based on the specialists agreement consensus equal or higher than 80% in every step of the algorithms. The process showed that the agreement with both instruments ranged from 92.8% to 99.0%. The algorithms are valid for application in nursing care with the main purpose of preventing and managing the antineoplastic agents' extravasation. Copyright © 2011 Elsevier Ltd. All rights reserved.

Dichloroacetate and cancer: new home for an orphan drug?

PubMed

Kankotia, Shyam; Stacpoole, Peter W

2014-12-01

We reviewed the anti-cancer effects of DCA, an orphan drug long used as an investigational treatment for various acquired and congenital disorders of mitochondrial intermediary metabolism. Inhibition by DCA of mitochondrial pyruvate dehydrogenase kinases and subsequent reactivation of the pyruvate dehydrogenase complex and oxidative phosphorylation is the common mechanism accounting for the drug's anti-neoplastic effects. At least two fundamental changes in tumor metabolism are induced by DCA that antagonize tumor growth, metastases and survival: the first is the redirection of glucose metabolism from glycolysis to oxidation (reversal of the Warburg effect), leading to inhibition of proliferation and induction of caspase-mediated apoptosis. These effects have been replicated in both human cancer cell lines and in tumor implants of diverse germ line origin. The second fundamental change is the oxidative removal of lactate, via pyruvate, and the co-incident buffering of hydrogen ions by dehydrogenases located in the mitochondrial matrix. Preclinical studies demonstrate that DCA has additive or synergistic effects when used in combination with standard agents designed to modify tumor oxidative stress, vascular remodeling, DNA integrity or immunity. These findings and limited clinical results suggest that potentially fruitful areas for additional clinical trials include 1) adult and pediatric high grade astrocytomas; 2) BRAF-mutant cancers, such as melanoma, perhaps combined with other pro-oxidants; 3) tumors in which resistance to standard platinum-class drugs alone may be overcome with combination therapy; and 4) tumors of endodermal origin, in which extensive experimental research has demonstrated significant anti-proliferative, pro-apoptotic effects of DCA, leading to improved host survival. Copyright © 2014 Elsevier B.V. All rights reserved.

Effect of lithium chloride and antineoplastic drugs on survival and cell cycle of androgen-dependent prostate cancer LNCap cells

PubMed Central

Azimian-Zavareh, Vajihe; Hossein, Ghamartaj; Janzamin, Ehsan

2012-01-01

Objective: Glycogen synthase kinase-3β (GSK-3β) has been reported to be required for androgen receptor (AR) activity. This study sought to determine the usefulness of lithium chloride (LiCl) as a highly selective inhibitor of GSK-3β to increase the sensitivity of LNCap cells to doxorubicin (Dox), etoposide (Eto), and vinblastine (Vin) drugs. Materials and Methods: Thiazolyl Blue Tetrazolium Blue (MTT) assay was used to determine the cytotoxic effect to LiCl alone or in combination with low dose and IC50 doses of drugs. Subsequently, cell cycle analysis was performed by using flow cytometry. Results: LiCl showed cytotoxic effect in a dose- and time-dependent manner (P<0.001). Both Dox (100 or 280 nM) and Vin IC50 (5 nM) doses caused G2/M-phase arrest (P<0.001) compared with control. However, low dose (10 μM) or IC50 (70 μM) Eto doses showed G2/M or S-phase arrests, respectively (P<0.001). Combination of low dose or IC50 dose of Eto with LiCl showed increased apoptosis as revealed by high percent of cells in SubG1 (P<0.05, P<0.01, respectively). Moreover, Eto (10 μM) led to decreased percent of cells in G2/M phase when combined with LiCl (P<0.05). Conclusion: This study showed that LiCl increases apoptosis of (LNCap) Lymph Node Carcinoma of the Prostate cells in the presence of Eto, which is S- and G2-phase-specific drug. PMID:23248400

Progress in the pharmacological treatment of human cystic and alveolar echinococcosis: Compounds and therapeutic targets

PubMed Central

Siles-Lucas, Mar; Casulli, Adriano; Cirilli, Roberto

2018-01-01

Human cystic and alveolar echinococcosis are helmintic zoonotic diseases caused by infections with the larval stages of the cestode parasites Echinococcus granulosus and E. multilocularis, respectively. Both diseases are progressive and chronic, and often fatal if left unattended for E. multilocularis. As a treatment approach, chemotherapy against these orphan and neglected diseases has been available for more than 40 years. However, drug options were limited to the benzimidazoles albendazole and mebendazole, the only chemical compounds currently licensed for treatment in humans. To compensate this therapeutic shortfall, new treatment alternatives are urgently needed, including the identification, development, and assessment of novel compound classes and drug targets. Here is presented a thorough overview of the range of compounds that have been tested against E. granulosus and E. multilocularis in recent years, including in vitro and in vivo data on their mode of action, dosage, administration regimen, therapeutic outcomes, and associated clinical symptoms. Drugs covered included albendazole, mebendazole, and other members of the benzimidazole family and their derivatives, including improved formulations and combined therapies with other biocidal agents. Chemically synthetized molecules previously known to be effective against other infectious and non-infectious conditions such as anti-virals, antibiotics, anti-parasites, anti-mycotics, and anti-neoplastics are addressed. In view of their increasing relevance, natural occurring compounds derived from plant and fungal extracts are also discussed. Special attention has been paid to the recent application of genomic science on drug discovery and clinical medicine, particularly through the identification of small inhibitor molecules tackling key metabolic enzymes or signalling pathways. PMID:29677189

Quantification and study of the L-DOPA decarboxylase expression in gastric adenocarcinoma cells treated with chemotherapeutic substances.

PubMed

Korbakis, Dimitrios; Fragoulis, Emmanuel G; Scorilas, Andreas

2013-03-01

3,4-Dihydroxy-L-phenylalanine decarboxylase (DDC) is an enzyme implicated in the biosynthetic pathways of the neurotransmitters dopamine and probably serotonin. DDC gene expression has been studied in numerous malignancies and the corresponding data have shown remarkable alterations in the mRNA and/or protein levels encoded by the gene. The aim of this study was to examine any modulations in the DDC mRNA levels in gastric cancer cells after their treatment with the chemotherapeutic agents 5-fluorouracil, leucovorin, irinotecan, etoposide, cisplatin, and taxol. The sensitivity of the AGS gastric adenocarcinoma cells to the antineoplastic drugs was evaluated using the MTT assay. Total RNA was extracted and reverse transcribed into cDNA. A highly sensitive quantitative real-time PCR methodology was developed for the quantification of DDC mRNA. GAPDH was used as a housekeeping gene. Relative quantification analysis was carried out using the comparative C T method ((Equation is included in full-text article.)). The treatment of AGS cells with several concentrations of various broadly used anticancer drugs resulted in significant modulations of the DDC mRNA levels compared with those in the untreated cells in a time-specific and drug-specific manner. Generally, DDC expression levels appeared to decrease after three time periods of exposure to the selected chemotherapeutic agents, suggesting a characteristic DDC mRNA expression profile that is possibly related to the mechanism of each drug. Our experimental data show that the DDC gene might serve as a new potential molecular biomarker predicting treatment response in gastric cancer cells.

Current status and future prospects for enabling chemistry technology in the drug discovery process.

PubMed

Djuric, Stevan W; Hutchins, Charles W; Talaty, Nari N

2016-01-01

This review covers recent advances in the implementation of enabling chemistry technologies into the drug discovery process. Areas covered include parallel synthesis chemistry, high-throughput experimentation, automated synthesis and purification methods, flow chemistry methodology including photochemistry, electrochemistry, and the handling of "dangerous" reagents. Also featured are advances in the "computer-assisted drug design" area and the expanding application of novel mass spectrometry-based techniques to a wide range of drug discovery activities.

The Drug Question: The Constitution and Public Policy. Teacher's Guide.

ERIC Educational Resources Information Center

Constitutional Rights Foundation, Los Angeles, CA.

This teacher's guide complements the student text's presentation of lesson plans on the subject of illegal drug use. The booklet begins with an explanation of the benefits of law-related education (LRE) for democratic education. The guide then outlines suggestions for handling controversy; directing discussion; organizing cooperative and small…

21 CFR 58.90 - Animal care.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 1 2012-04-01 2012-04-01 false Animal care. 58.90 Section 58.90 Food and Drugs... FOR NONCLINICAL LABORATORY STUDIES Testing Facilities Operation § 58.90 Animal care. (a) There shall be standard operating procedures for the housing, feeding, handling, and care of animals. (b) All...

21 CFR 58.90 - Animal care.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 1 2011-04-01 2011-04-01 false Animal care. 58.90 Section 58.90 Food and Drugs... FOR NONCLINICAL LABORATORY STUDIES Testing Facilities Operation § 58.90 Animal care. (a) There shall be standard operating procedures for the housing, feeding, handling, and care of animals. (b) All...

21 CFR 58.90 - Animal care.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 1 2013-04-01 2013-04-01 false Animal care. 58.90 Section 58.90 Food and Drugs... FOR NONCLINICAL LABORATORY STUDIES Testing Facilities Operation § 58.90 Animal care. (a) There shall be standard operating procedures for the housing, feeding, handling, and care of animals. (b) All...

21 CFR 58.90 - Animal care.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 1 2014-04-01 2014-04-01 false Animal care. 58.90 Section 58.90 Food and Drugs... FOR NONCLINICAL LABORATORY STUDIES Testing Facilities Operation § 58.90 Animal care. (a) There shall be standard operating procedures for the housing, feeding, handling, and care of animals. (b) All...

21 CFR 58.90 - Animal care.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 1 2010-04-01 2010-04-01 false Animal care. 58.90 Section 58.90 Food and Drugs... FOR NONCLINICAL LABORATORY STUDIES Testing Facilities Operation § 58.90 Animal care. (a) There shall be standard operating procedures for the housing, feeding, handling, and care of animals. (b) All...

21 CFR 820.150 - Storage.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Storage. 820.150 Section 820.150 Food and Drugs... QUALITY SYSTEM REGULATION Handling, Storage, Distribution, and Installation § 820.150 Storage. (a) Each manufacturer shall establish and maintain procedures for the control of storage areas and stock rooms for...

21 CFR 820.150 - Storage.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Storage. 820.150 Section 820.150 Food and Drugs... QUALITY SYSTEM REGULATION Handling, Storage, Distribution, and Installation § 820.150 Storage. (a) Each manufacturer shall establish and maintain procedures for the control of storage areas and stock rooms for...

21 CFR 820.150 - Storage.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Storage. 820.150 Section 820.150 Food and Drugs... QUALITY SYSTEM REGULATION Handling, Storage, Distribution, and Installation § 820.150 Storage. (a) Each manufacturer shall establish and maintain procedures for the control of storage areas and stock rooms for...

21 CFR 820.150 - Storage.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Storage. 820.150 Section 820.150 Food and Drugs... QUALITY SYSTEM REGULATION Handling, Storage, Distribution, and Installation § 820.150 Storage. (a) Each manufacturer shall establish and maintain procedures for the control of storage areas and stock rooms for...