Anthracycline-induced cardiotoxicity

The anthracyclines constitute a group of drugs widely used for the treatment of a variety of human tumors. However, the development of irreversible cardiotoxicity has limited their use. Anthracycline-induced cardiotoxicity can persist for years with no clinical symptoms. However, its prognosis becomes poor after the development of overt heart failure, possibly even worse than ischemic or idiopathic dilated cardiomyopathies. Due to the successful action of anthracyclines as chemotherapic agents, several strategies have been tried to prevent/ attenuate their side effects. Although anthracycline-induced injury appears to be multifactorial, a common denominator among most of the proposed mechanisms is cellular damage mediated by reactive oxygen species. However, it remains controversial as to whether antioxidants can prevent such side effects given that different mechanisms may be involved in acute versus chronic toxicity. The present review applies a multisided approach to the critical evaluation of various hypotheses proposed over the last decade on the role of oxidative stress in cardiotoxicity induced by doxorubicin, the most used anthracycline agent. The clinical diagnosis and treatment is also discussed. © 2008 Bentham Science Publishers Ltd.

Amifostine reduces the seminiferous epithelium damage in doxorubicin-treated prepubertal rats without improving the fertility status

Background: Amifostine is an efficient cytoprotector against toxicity caused by some chemotherapeutic drugs. Doxorubicin, a potent anticancer anthracycline, is known to produce spermatogenic damage even in low doses. Although some studies have suggested that amifostine does not confer protection to doxorubicin-induced testicular damage, schedules and age of treatment have different approach depending on the protocol. Thus, we proposed to investigate the potential cytoprotective action of amifostine against the damage provoked by doxorubicin to prepubertal rat testes (30-day-old) by assessing some macro and microscopic morphometric parameters 15, 30 and 60 days after the treatment; for fertility evaluation, quantitative analyses of sperm parameters and reproductive competence in the adult phase were also carried out.Methods: Thirty-day-old male rats were distributed into four groups: Doxorubicin (5 mg/kg), Amifostine (400 mg/kg), Amifostine/Doxorubicin (amifostine 15 minutes before doxorubicin) and Sham Control (0.9% saline solution). Standard One Way Anova parametric and Anova on Ranks non-parametric tests were applied according to the behavior of the obtained data; significant differences were considered when p < 0.05.Results: The rats killed 30 and 60 days after doxorubicin treatment showed diminution of seminiferous epithelium height and reduction on the frequency of tubular sections containing at least one type of differentiated spermatogonia; reduction of sperm concentration and motility and an increase of sperm anomalous forms where observed in doxorubicin-treated animals. All these parameters were improved in the Amifostine/Doxorubicin group only when compared to Doxorubicin group. Such reduction, however, still remained below the values obtained from the Sham Control group. Nevertheless, the reproductive competence of doxorubicin-treated rats was not improved by amifostine pre-administration.Conclusions: These results suggest that amifostine promotes a significant reduction of the doxorubicin long-term side effects on the seminiferous epithelium of prepubertal rats, which is reflected in the epidydimal fluid parameters in the adult phase. However, fertility status results suggest that such protection may not be effective against sperm DNA content damage. Further investigation of sperm DNA integrity must be carried out using amifostine and doxorubicin-treated experimental models. © 2010 Vendramini et al; licensee BioMed Central Ltd.

Ventricular systolic reserve in asymptomatic children previously treated with low doses of anthracyclines: A longitudinal, prospective exercise echocardiography study

Background: The time course of mild cardiotoxicity induced by anthracycline remains unknown. The aim of this study was to evaluate the long-term evolution of decreased myocardial reserve in children previously treated with a cumulative dose of anthracycline up to 100mg/m 2. Patients and Methods: Twenty-seven asymptomatic cancer survival patients (25 with lymphoblastic leukemia), in continuous remission and off treatment for >12 months with no alterations in conventional echocardiograms were evaluated by exercise echocardiography at 37±15.4 months (T1) and 101±24 months (T2) after finishing treatment (ADRIA group). This group was compared with 25 healthy individuals (control group) similar to the ADRIA group with respect to age and body surface area (BSA). All individuals underwent treadmill exercise testing according to Bruce protocol. Echocardiograms were performed before and immediately after exercise. Results: The groups were similar regarding cardiac structure and left ventricular (LV) systolic function at rest at T1 and T2. The growth of LV posterior wall thickness related to BSA was lower in the ADRIA group at T2. Post exercise, smaller LV ejection indexes and attenuated changes in the afterload in ADRIA group were observed at T1 and T2. Conclusion: The decreased systolic reserve induced by a low dose of anthracycline in asymptomatic children and adolescents remains unaffected over a 5-year period, suggesting that positive outcomes in chronic cardiotoxicity would be expected in patients with mild impairment after anthracycline treatment. © 2011 Wiley Periodicals, Inc.

Biocompatible microemulsion modifies the pharmacokinetic profile and cardiotoxicity of doxorubicin

Doxorubicin (DOX) is an anthracycline antibiotic with a broad antitumor spectrum. However, the clinical use of DOX is limited because of its cardiotoxicity, a dose-dependent effect. Colloidal drug delivery systems, such as microemulsions (MEs), allow the incorporation of drugs, modifying the pharmacokinetic (PK) profile and toxic effects. In this study, we evaluated the PK profile and cardiotoxicity of a new DOX ME (DOX-ME). The PK profile of DOX-ME was determined and compared with that of the conventional DOX after single-dose administration (6mg/kg, intravenous) in male Wistar rats (n = 12 per group). The cardiotoxicity of DOX formulations was evaluated by serum creatine kinase MB (CKMB) activity in both animal groups before and after drug administration. The plasma DOX measurements were performed by high-performance liquid chromatography with fluorescence detection, and the CKMB levels were assayed using the CKMB Labtest® kit. The ME system showed a significant increase in plasma DOX concentrations and lower distribution volume when compared with conventional DOX. Serum CKMB activity increased after conventional DOX administration but was unchanged in the DOX-ME group. These results demonstrate modifications in drug access to susceptible sites using DOX-ME. DOX-ME displayed features that make it a promising system for future therapeutic application. © 2012 Wiley Periodicals, Inc.

Validity and reliability of instruments designed to measure factors influencing the overuse of antibiotics

Background: Antibiotic overuse is a global public health issue that is influenced by several factors. The degree and prevalence of antibiotic overuse is difficult to measure directly. A more practical approach, such as the use of a psycho-social measurement instrument, might allow for the observation and assessment of patterns of antibiotic use. Study objective: The aim of this paper is to review the nature, validity, and reliability of measurement scales designed to measure factors associated with antibiotic misuse/overuse. Design: This study is descriptive and includes a systematic integration of the measurement scales used in the literature to measure factors associated with antibiotic misuse/overuse. The review included 70 international scientific publications from 1992 to 2010. Main results: Studies have presented scales to measure antibiotic misuse. However, the workup of these instruments is often not mentioned, or the scales are used with only early-phase validation, such as content or face validity. Other studies have discussed the reliability of these scales. However, the full validation process has not been discussed in any of the reviewed measurement scales. Conclusion: A reliable, fully validated measurement scale must be developed to assess the factors associated with the overuse of antibiotics. Identifying these factors will help to minimize the misuse of antibiotics.

Antibiotics overuse in children with upper respiratory tract infections in Saudi Arabia : risk factors and potential interventions

Background: Antibiotics misuse is currently one of the major public health issues worldwide. This misuse can lead to the development of bacterial resistance, increasing the burden of chronic diseases, rising costs of health services, and the development of side effects. Several factors may influence this pattern of overuse. Objectives:This article will review the pertinent factors contributing to the overuse of antibiotics worldwide, and to assess the intervention strategies to limit this overuse. Methods: studies about antibiotics use in children were reviewed from several electronic databases, such as MEDLINE and Pubmed. Results: Factors contributing to the overuse of antibiotics could include psychosocial factors, such as behaviors and attitudes (e.g. self-medication, over-the-counter medication, or patients/parents pressure), and demographic factors, such as socio-economic status and education level. Several intervention strategies were reported to be effective in reducing the overuse of antibiotics, such as health education, doctor-patient communication, and policies change. Multifaceted interventions were found to be the most effective in reducing the antibiotics overuse.

Assessing the overuse of antibiotics in children with URTIs in Saudi Arabia : development of the parental perception on antibiotics scale (PAPA scale)

Background: Antibiotic overuse is influenced by several factors that can only be measured using a valid and reliable psychosocial measurement instrument. This study aims to establish translation and early stage validation of an instrument recently developed by this research team to measure factors influencing the overuse of antibiotics in children with upper respiratory tract infections in Saudi Arabia. Method: The content evaluation panel was composed of area experts approached using the Delphi Technique. Experts were provided with the questionnaires iteratively, on a three-round basis until consensus on the relevance of items was reached independently. Translation was achieved by adapting Brislin’s model of translation. Results: After going through the iterative process with the experts, consensus was reached to 58 items (including demographics). Experts also pointed out some issues related to ambiguity and redundancy in some items. A final Arabic version was produced from the translation process. Conclusion: This study produced preliminary validation of the developed instrument from the experts’ contributions. Then, the instrument was translated from English to Arabic. The instrument will undergo further validation steps in the future, such as construct validity.

Assessing the overuse of antibiotics in children in Saudi Arabia : validation of the parental perception on antibiotics scale (PAPA scale)

Background Antibiotics overuse is a global public health issue influenced by several factors, of which some are parent-related psychosocial factors that can only be measured using valid and reliable psychosocial measurement instruments. The PAPA scale was developed to measure these factors and the content validity of this instrument was assessed. Aim This study further validated the recently developed instrument in terms of (1) face validity and (2) construct validity including: deciding the number and nature of factors, and item selection. Methods Questionnaires were self-administered to parents of children between the ages of 0 and 12 years old. Parents were conveniently recruited from schools’ parental meetings in the Eastern Province, Saudi Arabia. Face validity was assessed with regards to questionnaire clarity and unambiguity. Construct validity and item selection processes were conducted using Exploratory factor analysis. Results Parallel analysis and Exploratory factor analysis using principal axis factoring produced six factors in the developed instrument: knowledge and beliefs, behaviours, sources of information, adherence, awareness about antibiotics resistance, and parents’ perception regarding doctors’ prescribing behaviours. Reliability was assessed (Cronbach’s alpha = 0.78) which demonstrates the instrument as being reliable. Conclusion The ‘factors’ produced in this study coincide with the constructs contextually identified in the development phase of other instruments used to study antibiotic use. However, no other study considering perceptions of antibiotic use had gone beyond content validation of such instruments. This study is the first to constructively validate the factors underlying perceptions regarding antibiotic use in any population and in parents in particular.

Antibiotics for bronchiectasis exacerbations in children: rationale and study protocol for a randomised placebo-controlled trial

Background Despite bronchiectasis being increasingly recognised as an important cause of chronic respiratory morbidity in both indigenous and non-indigenous settings globally, high quality evidence to inform management is scarce. It is assumed that antibiotics are efficacious for all bronchiectasis exacerbations, but not all practitioners agree. Inadequately treated exacerbations may risk lung function deterioration. Our study tests the hypothesis that both oral azithromycin and amoxicillin-clavulanic acid are superior to placebo at improving resolution rates of respiratory exacerbations by day 14 in children with bronchiectasis unrelated to cystic fibrosis. Methods We are conducting a bronchiectasis exacerbation study (BEST), which is a multicentre, randomised, double-blind, double-dummy, placebo-controlled, parallel group trial, in five centres (Brisbane, Perth, Darwin, Melbourne, Auckland). In the component of BEST presented here, 189 children fulfilling inclusion criteria are randomised (allocation-concealed) to receive amoxicillin-clavulanic acid (22.5 mg/kg twice daily) with placebo-azithromycin; azithromycin (5 mg/kg daily) with placebo-amoxicillin-clavulanic acid; or placebo-azithromycin with placebo-amoxicillin-clavulanic acid for 14 days. Clinical data and a paediatric cough-specific quality of life score are obtained at baseline, at the start and resolution of exacerbations, and at day 14. In most children, blood and deep nasal swabs are also collected at the same time points. The primary outcome is the proportion of children whose exacerbations have resolved at day 14. The main secondary outcome is the paediatric cough-specific quality of life score. Other outcomes are time to next exacerbation; requirement for hospitalisation; duration of exacerbation; and spirometry data. Descriptive viral and bacteriological data from nasal samples and blood markers will also be reported. Discussion Effective, evidence-based management of exacerbations in people with bronchiectasis is clinically important. Yet, there are few randomised controlled trials (RCTs) in the neglected area of non-cystic fibrosis bronchiectasis. Indeed, no published RCTs addressing the treatment of bronchiectasis exacerbations in children exist. Our multicentre, double-blind RCT is designed to determine if azithromycin and amoxicillin-clavulanic acid, compared with placebo, improve symptom resolution on day 14 in children with acute respiratory exacerbations. Our planned assessment of the predictors of antibiotic response, the role of antibiotic-resistant respiratory pathogens, and whether early treatment with antibiotics affects duration and time to the next exacerbation, are also all novel.

Assessing the construct validity and reliability of the parental perception on antibiotics (PAPA) scales

Background: The overuse of antibiotics is becoming an increasing concern. Antibiotic resistance, which increases both the burden of disease, and the cost of health services, is perhaps the most profound impact of antibiotics overuse. Attempts have been made to develop instruments to measure the psychosocial constructs underlying antibiotics use, however, none of these instruments have undergone thorough psychometric validation. This study evaluates the psychometric properties of the Parental Perceptions on Antibiotics (PAPA) scales. The PAPA scales attempt to measure the factors influencing parental use of antibiotics in children. Methods: 1111 parents of children younger than 12 years old were recruited from primary schools’ parental meetings in the Eastern Province of Saudi Arabia from September 2012 to January 2013. The structure of the PAPA instrument was validated using Confirmatory Factor Analysis (CFA) with measurement model fit evaluated using the raw and scaled χ2, Goodness of Fit Index, and Root Mean Square Error of Approximation. Results: A five-factor model was confirmed with the model showing good fit. Constructs in the model include: Knowledge and Beliefs, Behaviors, Sources of information, Adherence, and Awareness about antibiotics resistance. The instrument was shown to have good internal consistency, and good discriminant and convergent validity. Conclusion: The availability of an instrument able to measure the psychosocial factors underlying antibiotics usage allows the risk factors underlying antibiotic use and overuse to now be investigated.

Does failed chronic wet cough response to antibiotics predict bronchiectasis?

Aim: To determine whether a child with chronic wet cough and poor response to at least 4 weeks of oral antibiotics is more likely to have bronchiectasis. Methods: All chest multi-detector computerised tomography (MDCT) scans at a single paediatric tertiary hospital from April 2010 to August 2012 were reviewed retrospectively so as to identify those ordered by respiratory physicians for assessment of children with a chronic wet cough. Information regarding age, sex, ethnicity, indication for imaging and the response to at least 4 weeks of antibiotics before having the scan were recorded from their charts. The data were analysed using simple and multiple logistic regression. Results: Of the 144 (87 males) eligible children, 106 (65 males, 30 Indigenous) aged 10–199 months had MDCT scan evidence of bronchiectasis. Antibiotic data were available for 129 children. Among the 105 children with persistent cough despite at least 4 weeks of antibiotics, 88 (83.8%) had bronchiectasis, while of the 24 children whose cough resolved after antibiotics, only six (25.0%) received this diagnosis (adjusted OR 20.9; 95% CI 5.36 to 81.8). Being Indigenous was also independently associated with radiographic evidence of bronchiectasis (adjusted OR 5.86; 95% CI 1.20 to 28.5). Conclusions: Further investigations including a MDCT scan should be considered in a child with a chronic wet cough that persists following 4 weeks of oral antibiotics. However, while reducing the likelihood of underlying bronchiectasis, responding well to a single prolonged course of antibiotics does not exclude this diagnosis completely.

Inhibition of Peroxidase-Catalyzed Iodination by Cephalosporins: Metallo-beta-Lactamase-Induced Antithyroid Activity of Antibiotics

Broad-spectrum antibiotics with heterocyclic side chains strongly inhibit peroxidase-catalyzed iodination in the presence of metallo--lactamase. This suggests that antibiotic resistance due to hydrolysis of the -lactam ring in antibiotics would have negative effects on thyroid activity.