Retrospective analysis of adverse drug reactions to anticancer drugs at a tertiary care hospital in South India

Background: Many newer drugs are approved every year for the treatment of cancers. With the limitation of clinical trials data on long-term safety, there is a need for constant monitoring of drugs use in various population. Occurrence of adverse drug reactions (ADRs) due to anticancer drugs is high due to their cytotoxic effects. Aims and Objectives: This study aims to analyze ADR reported due to anticancer drugs in relation to frequency of their occurrence, causality, severity, and preventability. Materials and Methods: This was a retrospective analysis of ADRs due to cancer chemotherapeutic agents that were spontaneously reported between January 2017 and June 2018. Data were collected from the suspected ADR notification forms submitted to ADR Monitoring Centre of the institute. Data were analyzed for type of cancers, medications used, type of ADRs, causality assessment, severity, and preventability. Results: A total of 545 ADRs were reported from 391 cases, with majority in females (65.1%). Breast was more commonly involved cancer (16.62%) and cisplatin was the common individual drug reported to cause ADRs (16.15%). The most common ADR reported was paresthesia (13.03%) followed by diarrhea (12.29%). Causality assessment revealed that most cases were probably related (61.65%). Most of the cases were moderately severe (61.28%) and most of the reported ADRs were not preventable (72.65%). Conclusion: Toxicities due to anticancer drugs can affect different organs. Most of the reported cases in this study are not preventable and of moderately severe. Appropriate use of preventive strategies helps in reduction in the occurrence and severity of ADRs.

Coconut oil nanoemulsion attenuates methotrexate-induced hepatotoxicity and nephrotoxicity in Ehrlich ascites carcinoma-bearing mice

Objective: To evaluate the protective effect of the coconut oil nanoemulsion against methotrexate-induced hepatotoxicity and nephrotoxicity in Ehrlich ascites carcinoma-bearing Swiss albino mice. Methods: Forty mice were divided into four groups. Group Ⅰ served as the untreated Ehrlich ascites carcinoma-bearing mice while Ehrlich ascites carcinoma-bearing mice in groups Ⅱ–Ⅳ received an intraperitoneal injection of 0.2 mL/kg coconut oil nanoemulsion, 20 mg/kg methotrexate as well as 0.2 mL/kg coconut oil nanoemulsion mixed with 20 mg/kg methotrexate, respectively. The toxicities of the treatments were assessed by determining the complete blood count, performing the serum analysis for liver and kidney functions, evaluating the oxidative status and visualizing histological changes in the liver and kidney tissues. Results: Treatment with methotrexate and coconut oil nanoemulsion markedly diminished the liver parameters including aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total protein, direct bilirubin and total bilirubin which were raised by methotrexate treatment (P < 0.05). Similarly, creatinine and blood urea nitrogen, as the indicators of kidney function, were dramatically lowered in the combination treatment group compared to the methotrexate group (P < 0.05). In addition, treatment with methotrexate and coconut oil nanoemulsion reduced the malondialdehyde and increased catalase, glutathione reductase and superoxide dismutase, in the liver and kidney tissues (P < 0.05). The treatment with methotrexate and coconut oil nanoemulsion reduced white blood cell count and increased the hemoglobin amount (P < 0.05), but did not cause any change in platelets and red blood cell count. Conclusions: Coconut oil nanoemulsion as a nanocarrier has great potential in reducing the adverse side effects induced by methotrexate.

Coconut oil nanoemulsion attenuates methotrexate-induced hepatotoxicity and nephrotoxicity in Ehrlich ascites carcinoma-bearing mice

Objective: To evaluate the protective effect of the coconut oil nanoemulsion against methotrexate-induced hepatotoxicity and nephrotoxicity in Ehrlich ascites carcinoma-bearing Swiss albino mice. Methods: Forty mice were divided into four groups. Group I served as the untreated Ehrlich ascites carcinoma-bearing mice while Ehrlich ascites carcinoma-bearing mice in groups II-IV received an intraperitoneal injection of 0.2 mL/kg coconut oil nanoemulsion, 20 mg/kg methotrexate as well as 0.2 mL/kg coconut oil nanoemulsion mixed with 20 mg/kg methotrexate, respectively. The toxicities of the treatments were assessed by determining the complete blood count, performing the serum analysis for liver and kidney functions, evaluating the oxidative status and visualizing histological changes in the liver and kidney tissues. Results: Treatment with methotrexate and coconut oil nanoemulsion markedly diminished the liver parameters including aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total protein, direct bilirubin and total bilirubin which were raised by methotrexate treatment (P < 0.05). Similarly, creatinine and blood urea nitrogen, as the indicators of kidney function, were dramatically lowered in the combination treatment group compared to the methotrexate group (P < 0.05). In addition, treatment with methotrexate and coconut oil nanoemulsion reduced the malondialdehyde and increased catalase, glutathione reductase and superoxide dismutase, in the liver and kidney tissues (P < 0.05). The treatment with methotrexate and coconut oil nanoemulsion reduced white blood cell count and increased the hemoglobin amount (P < 0.05), but did not cause any change in platelets and red blood cell count. Conclusions: Coconut oil nanoemulsion as a nanocarrier has great potential in reducing the adverse side effects induced by methotrexate.

A prospective observational study on drug safety monitoring and Pharmacoeconomics in patients with locally advanced unresectable NSCLC in a tertiary care hospital

Background: Lung cancer is the deadliest type of cancer for both men and women. The study was aimed at learning and comparing the toxicities of various chemotherapeutic regimens for the treatment of carcinoma lung, which will help in the implementation of counter measures to avoid development of toxicities, with a constant vigil on the patients during chemotherapeutic cycles. This study also aimed at searching into the added economic burden to the unfortunate patient, who is already suffering from a deadly disease. Study also targeted at evaluating the performance status of the patients receiving the chemotherapy.Methods: The Adverse Drug Reactions (ADR) data was collected from 40 patients receiving chemotherapy for locally advanced unresectable carcinoma lung from the cancer wards of a tertiary care hospital over a period of 2 months. ADRs were graded according to WHO guidelines and their performance statuses were assessed using the Zubrod抯 performance scale. Cost analysis of chemotherapeutic regimens was also carried out.Results: On comparison, alopecia and peripheral neuropathy were significantly more common with carboplatin-paclitaxel combination compared to other regimens (p value<0.005). Cost analysis reveals that the most commonly employed carboplatin-paclitaxel combination is more affordable when compared to the newer highly expensive agents but is costlier than cisplatin based chemotherapy. Also, carboplatin-paclitaxel combination offers a reasonably good performance status.Conclusions: Thus, carboplatin-paclitaxel combination is the preferred regimen for palliation in advanced NSCLC, especially in the older patients.

Cardiotoxicidade induzida por quimioterapia / Chemotherapy-induced cardiotoxicity

Introdução: A cardiotoxicidade resulta de efeitos diretos do tratamento do câncer na estrutura e função cardíaca, bem como na aceleração do desenvolvimento de doenças cardiovasculares em pacientes com fatores predisponentes. Isso tem levado a uma preocupação crescente no que concerne à morbidade prematura e óbito de pacientes sobreviventes ao câncer, uma vez que esse impacto negativo no prognóstico ocorre também em pacientes assintomáticos. Trata-se de um estudo de revisão da literatura com objetivo de explorar brevemente o tema sobre cardiotoxicidade. Métodos: Dados foram obtidos a partir de artigos e diretrizes atuais. Resultados: A sobrevida do câncer tem aumentado significativamente nas últimas décadas devido ao desenvolvimento de um maior número de agentes quimioterápicos. Entretanto, a área da Cardio-Oncologia carece ainda de protocolos bem estabelecidos que definam o manejo ideal no que tange à cardiotoxicidade induzida por terapia do câncer. Conclusões: A cardiotoxicidade permanece uma preocupação com impacto no prognóstico deste universo crescente de pacientes.

Introduction: Cardiotoxicity results from direct effects on cardiac structure and function in patients undergoing cancer treatment, as well as on accelerating the development of cardiovascular disease in patients with predisposing factors. This subject has led to a growing concern regarding the early morbidity and death of cancer survivors since there is negative impact on prognosis even in asymptomatic patients. This is a review of the literature which explores briefly the subject of cardiotoxicity. Methods: Our data were taken from current articles and guidelines. Results: Cancer survival has increased over time due to the development of a greater number of chemotherapeutic agents. However, Cardio-Oncology field still lacks of well-defined protocols to define the best management for cardiotoxicity. Conclusions: Cardiotoxicity remains a concern with an impact on the prognosis of this growing universe of patients.

Growth promoting use of antimicrobial agents in animals.

The antimicrobial growth promoter includes varieties of chemotherapeutics agent to be used for improving feed conversion efficiency, body weight gain and overall health. Now a day due to increased pressure of augmenting productivity, the animal husbandry industry is favorably inclined to professional use of antimicrobial growth promoters. AGP are administered at very low dose and they modify the bacterial quality and quantity in animal body towards favorable outcome with respect to reduced incidence of some diseases and infections. Today, non inophore group of compounds are being used widely for the purpose. These compounds alter the cell membrane permeability and causes death of bacterial cells. Wide varieties of compounds are available with specific purpose. The most ideal characteristic of AGP desired is minimum tissue residue and no cross resistance with human pathogens. The total amount of AGP used is difficult to estimate. The present review discusses the detail aspect of AGP at length.

Biomarkers for Colorectal Cancer Treatment / 대한소화기학회지

Individualized tailored therapy is a currently pursuing direction for improving the outcome of patients with colorectal cancer. Targeted therapy is the potential strategy to reach this goal by evaluating status of the presumed targets and their related effector molecules and by maximizing the efficacy of chemotherapeutic agents with less toxicity in individual patient. Numerous hurdles should be overcome, however, because therapeutic outcome can be affected by multiple components; tumor characteristics such as somatic mutations at the DNA, RNA, and protein levels; patient characteristics like germline genetic polymorphisms in enzymes linked to drug metabolism; and environmental factors that include diet and physical activity. Currently, large numbers of potential biomarkers have been proposed but have not yet accomplished supporting evidences for their routine usage in clinics. Therefore, clinical trials driven by molecular targets and relevant biomarkers for the understanding of the conflicting data are needed to make markers available in clinical practice.

Correlação entre uso de quimioterápicos antiinfecciosos e mortalidade / Correlation between antimicrobial chemotherapy and mortality

Objetivo: Correlacionar o consumo de quimioterápicos antiinfecciosos com mortes. Delineamento: Vigilância epidemiológica. População: Foram registradas todas as drogas quimioterápicas antiinfecciosas prescritas para tratar doenças infecciosas em um hospital. Os pacientes que as usaram foram seguidos desde a admissão até a alta ou o óbito hospitalar. Resultados: Foram estudados 4.968 pacientes que internaram 6.043 vezes. Das 2.305 internações nas quais os pacientes usaram quimioterápicos antiinfecciosos, 2.206 (95,7%) das vezes eles sobreviveram e 99 (4,29%) morreram. Os que sobreviveram usaram em média 1,55 (DP 1,09) quimioterápicos antiinfecciosos e os que morreram usaram em média 2,78 (DP 2,44) quimioterápicos antiinfecciosos, p<0.001. A correlação foi linear entre o número de quimioterápicos antiinfecciosos usados e a mortalidade. Os coeficientes obtidos foram: de correlação, 0.869 (p<0.001) e de determinação de Pearson de 0.755. O consumo de quimioterápicos antiinfecciosos por pacientes obteve correlação linear positiva de Spearman's rho de 0.905 (p=0.002). As relações entre as idades e a mortalidade obtiveram o coeficiente de correlação de Sperman's rho de 0.936, p<0.00. Conclusão: A quantidade de quimioterápicos antiinfecciosos usados para tratar pacientes se correlacionou positivamente com a morte e não parece ser uma boa estratégia para prevenila. Os autores sugerem desenvolver-se o conceito epidemiológico de suficiência de tratamento, considerando a cura e a morte como desfechos, como um índice de uso racional de quimioterápicos antiinfecciosos. Acredita-se que essa estratégia possa obter resultados de impacto no combate a crescente resistência antimicrobiana e na diminuição de gastos desnecessários em quimioterápicos antiinfecciosos (AU)

Aim: To correlate the consumption of antimicrobial chemotherapeutic agents with death figures. Research design: Epidemiological surveillance. Population: All antimicrobial chemotherapeutic agents prescribed to treat infectious diseases in a given hospital were registered. Patients were followed since admission until discharge or fatal outcome at the hospital. Results: Charts from 4968 patients, whose admissions totaled 6043 occasions, were analyzed. From a total of 2305 admissions in which patients were prescribed antimicrobial chemotherapeutic agents, in 2206 (95,7%) of the occasions patients survived, whereas in 99 occasions (4,29%) they died. Those who survived used in average 1,55 (SD 1,09) antimicrobial chemotherapeutic agents, while those who died used in average 2,78 (SD 2,44) antimicrobial chemotherapeutic agents (p<0.001). The observed correlation was linear between the number of antimicrobial chemotherapeutic agents prescribed and mortality. Two coefficients endorsed the observed correlation: a correlation coefficient of 0.869 (p<0.001) and a Pearson of 0.755. The consumption of antimicrobial chemotherapeutic displayed a linear and positive Spearman's correlation of 0.905 (p=0.002). The correlations between age and mortality yelled a Sperman's ρ of 0.936 (p<0.00). Conclusion: The quantity of prescribed antimicrobial chemotherapeutic was positively correlated with death. The development of a concept of epidemiological sufficiency of treatment is recommend by the authors. This concept, which considers cure and death as possible outcomes, would constitute a index of rational use of antimicrobial chemotherapeutic agents. It is believed that this strategy might help to curb the bacterial resistance to antimicrobial chemotherapeutic agents as well as to reduce dispensable expenditures with these pharmacological tools (AU)

Isolation and purification of breast cancer stem cells by suspension culture combined with chemotherapeutic agents / 中国癌症杂志

Background and purpose:The scarcity in quantity and continuous differentiation ability severely compromise the isolation and purification of cancer stem cells(CSCs).The existing sorting methods can only enrich CSCs as a heterogeneous population.However,more primitive CSCs closer to the source still have not been identified.Based on the CSC hypothesis,we hereby explored the possibility of isolation,culture,purification and identification of murine breast cancer stem cells in suspension culture combined with anticancer regimens. Methods :TM40D murine breast cancer cells were cultured in serum-free medium.The expression of CD44 + CD24-was measured by flow cytometry.Cells from the passage of TM40D cells with the highest expression of CD44 + CD24-were treated in combination with anticancer agents pacilitaxel and epirubicin at different peak plasma concentrations(PPC) for 24 hours,and then maintained under suspension culture.The rate of apoptosis was examined by flow cytometry with Annexin-V FITC/PI double staining method.Selected cells in different amounts were injected subcutaneously into BALB/C mice to observe tumor formation. Results :Cells of passage 10 in suspension culture had the highest percentage of CD44 + CD24-(about 77 percent).As few as 100 cells in 0.35 PPC could generate tumors in BALB/C mice. Conclusions :TM40D cell line contains breast cancer stem cells.This study suggested that suspension culture combined with anticancer regimens is a feasible approach for screening tumor stem cells.

Survey on the Side Effects of the Vesicant Chemotherapy / 기본간호학회지

The purpose of this study was to identify side effects of the vesicant chemotherapy. The study was designed to be a descriptive survey. The subjects of this study were 88 patients with various types of cancer, primary lung cancer(25.0%), advanced gastric cancer(25.0%), breast cancer(20.5%), etc. The mean age was 44.8 years old(range: 16-68). The questionnaire was completed by nurses of the outpatient unit and chemotherapy ward, and intravenous nurse specialist. The results of the study were as follows: 1) Chemotherapy was administered with a 23G scalp needle and 24G insyte. Injection site was dorsum of hands (64.7%), cephalic vein(19.3%). Successful rate for the first attempt was 88.6%. The first & second cycle chemotherapy was 29.5% each.. Mainly used drugs were Navelbine(34.1%), Adriamycin(20.5%). 2) Venous problems after chemotherapy were pain(13.6%) incurred by venous, mainly due to the administration of Navelbine; redness at the inravenous site(12.5%) and itching sense 2.3%. Non-venous problems were nausea (18.2%), dullness(14.8%), vomiting(8.0%), facial flushing(6.8%), anxiety(5.7%). Subjective discomforts after chemotherapy were generalized arm pain at the injection side(14.8%), dizziness(6.8%), weakness(5.7%) and general bodyache (5.7%). Systemic anaphylactic reaction and extravasation did not occur. 3) Non-venous problem after chemotherapy were nausea, vomiting & anorexia. Frequency of chemotherapy related to side effects were itching, facial flushing, and nausea(p<0.05). Day of chemothe-rapy related to side effects were nausea & vomiting(p<0.05). Site of chemothe- rapy related to side effects were redness(p<0.05). Frequency of venipuncture related to side effects were redness(p<0.05). Conclusively, cancer chemotherapy patients have had some venous problem. They need appropriate venous access devices for chemotherapy. And other non-venous problem will be managed appropriately. Further research was required to identify the rate of venous complication or side effects of vesicant chemotherapy.

Apoptosis Induced by Chemotherapeutic Agents in Differentiated HL-60 Human Leukemic Cell Line / 대한소아혈액종양학회지

PURPOSE: Chemotherapeutic agents are known to induce cell death in cancer cells by apoptotic mechanisms. This study was to investigate the influence of the differentiation on the apoptotic potential of chemotherapeutic agents. METHODS: Etoposide and cytosine arabinoside (Ara-C) were chosen as chemotherapeutic agents, and human promyelocytic leukemia cell line, HL-60, was used as target cells. RESULTS: Etoposide or Ara-C treated HL-60 cells showed cytoplasmic blebbing and nuclear condensation and fragmentation under fluorescence microscope when stained with acridine orange/ethidium bromide. In addition, the cellular DNA of HL-60 cells was found to cleave into internucleosomal fragments after treatment with chemotherapeutic agents. These findings were the characteristics of apoptosis and suggested the induction of apoptotic cell death of HL-60 cells by etoposide or Ara-C treatment. HL-60 cells are known to differentiate into myeloid or monocytic lineage by retinoic acid, phorbol 12-myristate acetate (PMA) and dimethyl sulfoxide (DMSO), and this differentiation itself can activate apoptosis program, so-called 'apoptosis by terminal differentiation'. The effect of terminal differentiation by PMA or DMSO on the apoptosis induced by etoposide or Ara-C was also investigated, utilizing qualitative and quantitative DNA fragmentation assay. HL-60 cells treated with PMA (100 nM) were adherent to culture dish and formed cellular processes. DMSO (1.25%) treated HL-60 cells instead recovered the ability to reduce nitroblue tetrazolium to blue-to-purple formazan, indicating its differentiation. After induction of differentiation by PMA or DMSO, differentiated HL-60 cells were treated with etoposide (10 muM) and Ara-C (50 muM) to compare its apoptotic potential with that of undifferentiated HL-60 cells. The ladder DNA induced by etoposide and Ara-C was decreased in differentiated HL-60 cells. On quantitative analysis of DNA fragmentation, PMA reduced DNA fragmentation induced by etoposide and Ara-C to 73% and 69%, respectively, and DMSO reduced it to 74% and 56%, respectively. In western blot analysis, the expression of Bcl-2, which is known to inhibit etoposide and Ara-C induced apoptosis, decreased significantly in HL-60 cells differentiated by PMA or DMSO. CONCLUSION: These results suggest that the differentiation of HL-60 cells by PMA or DMSO prevents apoptosis by etoposide and Ara-C, but bcl-2 proto-oncogene may have only minor role in inhibiting apoptosis by chemotherapeutic agents in differentiated HL-60 cell.

Synergistic Cytotoxicity of Chemotherapeutic Agents and Tumor Necrosis Factor ? against Hepatic Carcinoma Cells in vitro / 中国肿瘤生物治疗杂志

The synergistic cytotoxicity of rhTNF-? or/and six chemotherapeutic agents namely ADM, MMC, DDP, VP-16, GBP and IFO, against two human hepatic carcinoma cell lines, SMMC-7721 and BEL-7402, was examined by MTT assay. The results showed that the cytotoxic effects of six chemotherapeutic agents with rhTNF-? against two cell lines were significant. Examined cytotoxicity of rhTNF-? combined with chemotherapeutic agents, we found that rhTNF-? singnificantly enhanced cytotoxic efficacy of ADM, DDP, VP-16. The study suggested that rhTNF-? with some chemotherapeutic agents had synergistic effects. This and other preclinical studies with rhTNF-? will form the basis of clinical treatments for hepatic carcinoma patient.