Analytical control of genotoxic impurities in the pazopanib hydrochloride manufacturing process

Pharmaceutical regulatory agencies are increasingly concerned with trace-level genotoxic impurities in drug substances, requiring manufacturers to deliver innovative approaches for their analysis and control. The need to control most genotoxic impurities in the low ppm level relative to the active pharmaceutical ingredient (API), combined with the often reactive and labile nature of genotoxic impurities, poses significant analytical challenges. Therefore, sophisticated analytical methodologies are often developed to test and control genotoxic impurities in drug substances. From a quality-by-design perspective, product quality (genotoxic impurity levels in this case) should be built into the manufacturing process. This necessitates a practical analysis and control strategy derived on the premise of in-depth process understanding. General guidance on how to develop strategies for the analysis and control of genotoxic impurities is currently lacking in the pharmaceutical industry. In this work, we demonstrate practical examples for the analytical control of five genotoxic impurities in the manufacturing process of pazopanib hydrochloride, an anticancer drug currently in Phase III clinical development, which may serve as a model for the other products in development. Through detailed process understanding, we implemented an analysis and control strategy that enables the control of the five genotoxic impurities upstream in the manufacturing process at the starting materials or intermediates rather than at the final API. This allows the control limits to be set at percent levels rather than ppm levels, thereby simplifying the analytical testing and the analytical toolkits to be used in quality control laboratories.     

High prevalence of chronic kidney disease in Iran: a large population-based study

Background  

Chronic kidney disease (CKD) is a global public health threat, associated with an alarming increase in morbidity and mortality. The importance is the worldwide increase in its incidence and prevalence.     

Temporal analysis of the incidence of meningitis in the Tehran metropolitan area, 1999-2005

Objectives  

The aim of this study was to describe the temporal determinants of meningitis incidence in the population living in the Tehran metropolis.     

Particle size design of PLGA microspheres for potential pulmonary drug delivery using response surface methodology

The large surface area, good vascularization, immense capacity for solute exchange and ultra-thinness of the alveolar epithelium are unique features of the lung facilitating systemic drug delivery via pulmonary administration. The efficacy and safety of many new and existing inhaled therapies may be enhanced through advanced controlled-release systems by using polymer particles. Poly (D,L-lactic-co-glycolic acid) (PLGA) is well known by its safety in biomedical preparations which has been approved for human use by the FDA. The optimum aerodynamic particle size distribution for most inhalation aerosols has generally been recognized to be in the range of 1-5 microns. PLGA microspheres, therefore, were prepared by a developed oil-in-oil solvent evaporation method and characterized. A four-factor, three levels Box-Behnken design was used for the optimization procedure with temperature, stirring speed, PLGA and surfactant concentration as independent variables. Particle size and polydispersity of microspheres were considered as dependent variables. PLGA microparticles were prepared successfully in desired size for pulmonary delivery by solvent evaporation method. It was found that the particle size of microspheres could be easily controlled. It was also proved that response surface methodology could efficiently be applied for size characterization and optimization of PLGA microparticles for pulmonary drug delivery.     

Frailty and its potential relevance to cardiovascular care

Frailty is characterized by vulnerability to acute stressors and is a consequence of decline in overall function and physiologic reserves. An estimated 7% of the US population older than 65 years and 30% of octogenarians are frail. The domains to define frailty include mobility, strength, balance, motor processing, cognition, nutrition, endurance, and physical activity. Pathophysiologic pathways leading to frailty involve a multisystem cascade that includes neuroendocrine dysfunction with lower insulin-like growth factor and dehydroepiandrosterone sulfate and an altered inflammatory milieu with increased levels of C-reactive protein, interleukins, tumor necrosis factor alpha, and abnormal coagulation. Frailty predicts death and heralds the transition to disability in general populations. As the population with coronary artery disease shifts toward older patients, physicians must consider the role of frailty in their patients. This review will enable clinicians to recognize frailty and consider its relevance in their daily practice. We also elaborate on reasons to consider frailty in older adults with cardiovascular disease and focus on its early identification, on referral to specialists, and on care after serious cardiac events.     

A prognostic index relating 24-hour ambulatory blood pressure to cardiac events in ischemic cardiomyopathy following defibrillator implantation

Background: We assessed the role of left ventricular ejection fraction and of ambulatory blood pressure monitoring (ABPM) to predict cardiac death and heart failure in patients with defibrillator fulfilling MADIT II criteria. ABPM variables assessed included: mean 24 hours diastolic and systolic blood pressure, mean 24 hours heart rate, and pulse pressure.
Methods: We studied 105 consecutive patients (age 67 ± 11), all with a defibrillator and ejection fraction ≤ 30%).
Results: At 1-year follow-up, there were 29 events (25%), three cardiac deaths, and 26 hospitalizations for heart failure. Age, creatinine, mean 24 hours diastolic blood pressure, and mean 24 hours systolic blood pressure (but not ejection fraction) were associated with events. A prognostic index (PI) was built by age and ABPM variables, according to the formula (120 – age) + (mean 24 hours diastolic blood pressure + mean 24 hours systolic blood pressure). Receiver operating characteristic curves showed the best cutoff for PI = 220 (sensitivity 81%, specificity 71%, positive predictive value 56%, negative predictive value 88%). Cox regression analysis confirmed the significant association between lower PI (< 220) and clinical events (HR 4.8, 95% CI 1.8–12.3, P = 0.0001 for PI). Overall, 12% of patients with high PI values (≥ 220 n = 71) had clinical events at 12-month follow-up, compared with 61% of patients with low PI (< 220 n = 34) (P < 0.0001).
Conclusion: The PI built by mean 24 hours diastolic and systolic blood pressure and age could be a simple method to stratify risk of cardiac death and acute heart failure in MADIT II patients, in whom ejection fraction, uniformly depressed, is not predictive.     

Adjustment process in Iranian women with breast cancer

Breast cancer is a devastating event for a woman. Physical changes and psychological problems, treatment to improve the patient's condition, and increased survival rates compared with other cancers manifest the importance of quality of life in these patients. This quality of life is affected by how the patients adjust to their situation. Hence, to understand adjustment to breast cancer, this research aimed to investigate the experience from the patients' perspective and how they interact with others and interpret their experiences in adjusting to the disease. A qualitative research approach based on grounded theory was used. The data were the result of 45 interviews with patients in different phases of their illness trajectory during 1 year, 6 interviews with families, and 10 observation sessions. The main categories that emerged were perceived threat to live, religious aspects, supportive dimensions, will to recover, increase in endurance, barriers to efforts leading to health, living with the disease with tolerance, and inhibitors and facilitators of tolerance. These main categories were understood as passages to reach evolutionary peaceful coexistence. Adjustment to breast cancer has positive evolutional process, and its direction is toward better adjustment. By positive mental reconstruction, the patients feel that they can live with their disease.     

Angiogenesis: a potentially critical part of remodelling in chronic airway diseases?

Angiogenesis is a prominent feature of the structural tissue remodelling that occurs in the chronic airway diseases of asthma, Bronchiolitis Obliterans Syndrome (BOS, post-lung transplantation), and in smoking-related Chronic Obstructive Pulmonary Disease (COPD). For each, we have explored the relationship between angiogenesis and underlying chronic inflammatory processes--are the hypervascular changes secondary to inflammation, or do they occur in parallel? What are the likely growth factors which stimulate the angiogenic process? We discuss the relationships that have been studied between angiogenesis and the physiological impairment of airflow obstruction. The pattern that emerges is complex and variable. In asthma, there is strong evidence to suggest that Vascular Endothelial Growth Factor (VEGF) and its receptor system is upregulated in the airway. Local production of VEGF has also been implicated as a major driver of angiogenesis in the airway component of COPD, though paradoxically emphysema seems to be due to lack of VEGF in the lung parenchyma. In BOS, the evidence suggests that VEGF is lacking in the airway: other mediators and especially C-X-C chemokines such as Interleukin (IL)-8, are likely to be more important in angiogenesis. The physiological consequences of angiogenesis are likely to be important in asthma (especially during acute episodes of deterioration), and probably also in COPD, although data is equivocal. In BOS, increased airway vascularity appears to occur early, but is not progressive. In terms of therapy, evidence for anti-angiogenic effectiveness is strongest for Inhaled Corticosteroid (ICS) and Long Acting Beta-Agonists (LABA) in asthma.