Construction of Drug–Polymer Thermodynamic Phase Diagrams Using Flory–Huggins Interaction Theory: Identifying the Relevance of Temperature and Drug Weight Fraction to Phase Separation within Solid Dispersions

Amorphous drug-polymer solid dispersions have the potential to enhance the dissolution performance and thus bioavailability of BCS class II drug compounds. The principle drawback of this approach is the limited physical stability of amorphous drug within the dispersion. Accurate determination of the solubility and miscibility of drug in the polymer matrix is the key to the successful design and development of such systems. In this paper, we propose a novel method, based on Flory-Huggins theory, to predict and compare the solubility and miscibility of drug in polymeric systems. The systems chosen for this study are (1) hydroxypropyl methylcellulose acetate succinate HF grade (HPMCAS-HF)-felodipine (FD) and (2) Soluplus (a graft copolymer of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol)-FD. Samples containing different drug compositions were mixed, ball milled, and then analyzed by differential scanning calorimetry (DSC). The value of the drug-polymer interaction parameter ? was calculated from the crystalline drug melting depression data and extrapolated to lower temperatures. The interaction parameter ? was also calculated at 25 °C for both systems using the van Krevelen solubility parameter method. The rank order of interaction parameters of the two systems obtained at this temperature was comparable. Diagrams of drug-polymer temperature-composition and free energy of mixing (?G mix) were constructed for both systems. The maximum crystalline drug solubility and amorphous drug miscibility may be predicted based on the phase diagrams. Hyper-DSC was used to assess the validity of constructed phase diagrams by annealing solid dispersions at specific drug loadings. Three different samples for each polymer were selected to represent different regions within the phase diagram

Dropping the weight stigma: Nostalgia improves attitudes toward persons who are overweight

Weight stigma, a negative attitude toward persons who are overweight, can lead to emotional detriment (increased vulnerability to depression and anxiety, decreased self-esteem) and discriminatory practices (denial of employment, lower wages, refusal of job promotion or college admission, healthcare deprivation), which have increased dramatically in the United States over the past decade. We report two experiments that implicate nostalgia as a resource or strategy for weight stigma reduction. We hypothesized and found that nostalgia about an encounter with a person who is overweight improves attitudes toward the group "overweight." Undergraduates who recalled a nostalgic (vs. ordinary) interaction with an overweight person subsequently showed more positive outgroup attitudes. The effect of nostalgia on outgroup attitudes was mediated by greater inclusion of the outgroup in the self and increased outgroup trust (Experiments 1 and 2), as well as reduced intergroup anxiety and greater perceptions of a common ingroup identity (Experiment 2). The findings have interventional potential. (C) 2011 Elsevier Inc. All rights reserved.

Adiponectin multimers, body weight and markers of cardiovascular risk in adolescence: Northern Ireland Young Hearts Project:Northern Ireland Young Hearts Project

Background:Research examining the relationship between adiponectin (AN) isoforms, body weight and cardiovascular (CV) risk factors is limited, particularly in younger populations. Objectives:To investigate the inter-relationships between AN isoforms and CV risk factors, and their dependence on body weight status, in adolescents. Design:Blood samples from 92 obese, 92 overweight and 92 normal weight age- and sex-matched adolescents were analysed for traditional cardiovascular disease (CVD) risk biomarkers and also total, high molecular weight (HMW), medium and low molecular weight (LMW) AN. Results:A significant inverse association was observed between total and HMW AN and waist-hip ratio (P=0.015, P=0.006, respectively), triglycerides (P=0.003, P=0.003, respectively) and systolic blood pressure (P=0.012, P=0.024, respectively) and a significant positive association with high-density lipoprotein (P<0.001, P<0.001, respectively) in multi-adjusted analyses. There was no evidence of a relationship between multimeric AN and high-sensitivity C-reactive protein. There was also little evidence of a relationship between LMW AN and CVD risk factors. There was a strong, body mass index (BMI)-independent, association between AN, CVD biomarkers and the hypertriglyceridemic waist phenotype. Conclusion:Prominent, BMI-independent associations between total and HMW AN, but not LMW AN, and CVD risk factors were already evident in this young population. This research in adolescents supports the contention that AN subfractions may have different biological actions. These associations in apparently healthy adolescents suggest an important role for AN and its subfractions in the pathogenesis of metabolic syndrome traits and indicate that the potential for total or HMW AN to act as early universal biomarkers of CV risk warrants further study.

Diclofenac disposition in Indian cow and goat with reference to Gyps vulture population declines

Gyps vultures across India are declining rapidly and the NSAID diclofenac has been shown to be the major cause. Vultures scavenge livestock carcasses that have been treated with diclofenac within the days preceding death. We present data on diclofenac disposition in Indian cow and goat, and field data on the prevalence of diclofenac in carcases in the environment. In the disposition experiment, animals were treated with a single intramuscular injection of diclofenac at 1000 microg kg-1 bw. In cow, diclofenac was detectable in liver, kidney and intestine up to 71 h post-treatment; in plasma, half-life was 12.2 h. In goat, tissue residues were undetectable after 26 h. Prevalence of diclofenac in liver from 36 dead livestock collected in the field was 13.9%. Data suggest that diclofenac residues in Indian cow and goat are short-lived, but diclofenac prevalence in carcasses available to vultures may still be very high.

School entry age outcomes for infants with birth weight ≤ 800 grams

To evaluate the mortality and long-term morbidity rates of extremely low birth weight (ELBW) infants admitted to neonatal intensive care units (NICUs).

Teenagers born at extremely low birth weight

Adolescence constitutes a major transition for extremely low birth weight (ELBW) teenagers. Recent studies of ELBW teenagers born in the 1980s have provided information about the growth and developmental characteristics of these individuals in adolescence and in early adulthood. ELBW teenagers are shorter and lighter than their full-term peers, and have a smaller head circumference. Cognitive and academic vulnerabilities documented during the school years, particularly difficulties with nonverbal intelligence and arithmetic, persist into late adolescence. Many ELBW children struggle in school and have lower academic achievement levels. The self-concept of ELBW teenagers is generally similar to that of their full-term peers, but their parents perceive them to be more vulnerable over a wide range of behavioural and psychosocial dimensions, particularly depression and attention. ELBW teenagers perceive themselves as needing more assistance in job seeking than do their peers. Physical activity levels and fitness in late adolescence are significantly lower in ELBW teenagers than in their full-term peers, constituting a potential additional health hazard in later life. The outcomes of ELBW teenagers are significantly influenced by socioeconomic, family and parenting factors.

Aerobic capacity, strength, flexibility, and activity level in unimpaired extremely low birth weight (

To compare aerobic capacity, strength, flexibility, and activity level in extremely low birth weight (ELBW) adolescents at 17 years of age with term-born control subjects.

Psychosocial and academic characteristics of extremely low birth weight (<or =800 g) adolescents who are free of major impairment compared with term-born control subjects

To compare academic and cognitive ability, attention, attitudes, and behavior of extremely low birth weight (ELBW) adolescents who are free of major impairments at 17 years of age with term-born control subjects.

Does parenchymal brain injury affect biobehavioral pain responses in very low birth weight infants at 32 weeks' postconceptional age?

Children with neurologic impairments have shown diminished pain response compared with control subjects; however, it remains unclear what mechanisms underlie this response or when it develops. If this were also true with premature infants who undergo neonatal intensive care, then infants with parenchymal brain injury (PBI) would be at increased risk of underrecognition and undertreatment of procedural pain. The purpose of this study was to determine whether infants with PBI display altered responses to acute procedural pain at 32 weeks' postconceptional age (PCA), compared with control subjects.

Pattern of learning disabilities in children with extremely low birth weight and broadly average intelligence

To examine the prevalence and pattern of specific areas of learning disability (LD) in neurologically normal children with extremely low birth weight (ELBW) (<or = 800 g) who have broadly average intelligence compared with full-term children with normal birth weight of comparable sociodemographic background, and to explore concurrent cognitive correlates of the specific LDs.

Developmental coordination disorder in extremely low birth weight children at nine years

Developmental coordination disorder (DCD) is defined as an impairment in the development of motor coordination that interferes with academic achievement or activities of daily living (DSM-IV). DCD has been reported to affect 5% to 9% of children in the normal population. This study describes the prevalence of DCD in a cohort of extremely low birth weight children (ELBW, <or = l800 g) at 8.9 years of age, from which were excluded children with major impairments. Seventy-three children were included in the study group, along with 18 term-born, socially matched controls. Of the 73 ELBW children, 37 (51%) were classified as having DCD. ELBW children with DCD also had significantly lower Performance IQ (PIQ) scores and were more likely (43%) to have a learning difficulty in arithmetic than ELBW children who did not have DCD. This study found that DCD is a common problem in school-aged ELBW children.

Demographic and therapeutic determinants of pain reactivity in very low birth weight neonates at 32 Weeks' postconceptional Age

Management of pain in very low birth weight infants is limited by a lack of empiric knowledge about the multiple determinants of biobehavioral reactivity in infants receiving neonatal intensive care.

Behavior, pain perception, and the extremely low-birth weight survivor

This article explores the literature concerning responses to pain of both premature and term-born newborn infants, the evidence for short-term and long-term effects of pain, and behavioral sequelae in individuals who have experienced repeated early pain in neonatal life as they mature. There is no doubt that pain causes stress in babies and this in turn may adversely affect long-term neurodevelopmental outcome. Although there are methods for assessing dimensions of acute reactivity to pain in an experimental setting, there are no very good measures available at the present time that can be used clinically. In the clinical setting repeated or chronic pain is more likely the norm rather than infrequent discrete noxious stimuli of the sort that can be readily studied. The wind-up phenomenon suggests that, exposed to a cascade of procedures as happens with clustering of care in the clinical setting in an attempt to provide periods of rest for stressed babies, an infant may in fact perceive procedures that are not normally viewed as noxious, as pain. Pain exposure during lifesaving intensive medical care of ELBW neonates may also affect subsequent reactivity to pain in the neonatal period, but behavioral differences are probably not likely to be clinically significant in the long term. Prolonged and repeated untreated pain in the newborn period, however, may produce a relatively permanent shift in basal autonomic arousal related to prior NICU pain experience, which may have long-term sequelae. In the long run, the most significant clinical effects of early pain exposure may be on neurodevelopment, contributing to later attention, learning, and behavior problems in these vulnerable children. Although there is considerable evidence to support a variety of adverse effects of early pain, there is less information about the long-term effects of opiates and benzodiazepines on the developing central nervous system. Current evidence reviewed suggests that judicious use of morphine for adjustment to mechanical ventilation may ameliorate the altered autonomic response. It may be very important, however, to distinguish stress from pain. Animal evidence suggests that the neonatal brain is affected differently when exposed to morphine administered in the absence of pain than in the presence of pain. Pain control may be important for many reasons but overuse of morphine or benzodiazepines may have undesirable long-term effects. This is a rapidly evolving area of knowledge of clear relevance to clinical management likely to affect long-term outcomes of high-risk children.