CDER Experience With Juvenile Animal Studies for CNS Drugs.

A survey was undertaken to evaluate juvenile animal studies conducted for drug applications reviewed by the Center for Drug Evaluation and Research between 2009 and 2014. Some conclusions about the nonclinical pediatric safety assessment based on studies performed in support of central nervous system-active compounds are presented here. A total of 44 completed studies from 32 New Drug Applications submitted to the Divisions of Psychiatry and Neurology Products were evaluated. Data on animal species and age range used, endpoints evaluated, and outcomes included in labeling were analyzed. Of the drugs evaluated, all but one had studies conducted in rats. In some cases, a second study in a nonrodent species (dog) was also conducted. Indices of growth and development and standard general toxicity parameters were included in all of the studies. Expanded neurohistopathology evaluations, bone mineral density measurements, and reproductive and neurobehavioral functional assessments were also generally carried out. A variety of neurological and neurobehavioral tests were employed. In the majority of rat studies, the potential for long-term cognitive impairment was evaluated using a complex water maze. Juvenile animal studies provided safety information considered relevant to drug use in children and that was included in labeling for 78% of the applications surveyed. The most commonly reported findings in labeling were for neurobehavioral effects, including changes in locomotor activity, auditory startle habituation, and learning and memory. Of the studies described in labeling with neurobehavioral effects, 54% found these effects to be persistent and to provide evidence of developmental neurotoxicity.

Health care experiences among women diagnosed with gestational breast cancer.

Gestational breast cancer (GBC) presents many challenges for women and the clinicians who care for them. The aim of this study was to explore the health care experiences of women diagnosed with GBC to inform and improve clinical care of women in this predicament. Semi-structured interviews were conducted with 17 women who had been diagnosed with GBC in the previous 5 years. The overarching themes for perceived quality of care were "communication" and "comprehensive care." "Communication" had two sub themes: "interdisciplinary communication" (the way health professionals from different disciplines communicated with each other about the management of the woman's care) and "patient communication" (how they communicated this to the woman). The "comprehensive care" theme incorporated three sub themes: "the spirit" (psychological care); "the mind" (information provision); and "the body" (management of treatment side effects). Women's own accounts of positive and negative experiences of GBC care provide unique and specific insights which improve understanding of their concerns and needs. The findings can inform advances in quality and efficacy of clinical care; offer guidance for obstetricians, oncologists and allied health professionals about the needs of women diagnosed with GBC and how care can be optimised; and inform the development of resources to assist women and their families.

Brain regions implicated in inhibitory control and appetite regulation are activated in response to food portion size and energy density in children.

OBJECTIVE: Large portions of energy-dense foods drive energy intake but the brain mechanisms underlying this effect are not clear. Our main objective was to investigate brain function in response to food images varied by portion size (PS) and energy density (ED) in children using functional magnetic resonance imaging (fMRI). METHODS AND DESIGN: Blood-oxygen-level-dependent (BOLD) fMRI was completed in 36 children (ages 7-10 years) after a 2-h fast while viewing food images at two levels of PS (Large PS, Small PS) and two levels of ED (High ED, Low ED). Children rated perceived fullness pre- and post-fMRI, as well as liking of images on visual analog scales post-fMRI. Anthropometrics were completed 4 weeks before the fMRI. Large PS vs Small PS and High ED vs Low ED were compared with region-of-interest analyses using Brain Voyager v 2.8. RESULTS: Region-of-interest analyses revealed that activation in the right inferior frontal gyrus (P=0.03) was greater for Large PS vs Small PS. Activation was reduced for High ED vs Low ED in the left hypothalamus (P=0.03). Main effects were no longer significant after adjustment for pre-fMRI fullness and liking ratings (PS, P=0.92; ED, P=0.58). CONCLUSION: This is the first fMRI study to report increased activation to large portions in a brain region that is involved in inhibitory control. These findings may contribute to understanding why some children overeat when presented with large portions of palatable food.

Attitudes and behaviours of maternal health care providers in interactions with clients: a systematic review.

BACKGROUND: High maternal mortality and morbidity persist, in large part due to inadequate access to timely and quality health care. Attitudes and behaviours of maternal health care providers (MHCPs) influence health care seeking and quality of care. METHODS: Five electronic databases were searched for studies from January 1990 to December 2014. Included studies report on types or impacts of MHCP attitudes and behaviours towards their clients, or the factors influencing these attitudes and behaviours. Attitudes and behaviours mentioned in relation to HIV infection, and studies of health providers outside the formal health system, such as traditional birth attendants, were excluded. FINDINGS: Of 967 titles and 412 abstracts screened, 125 full-text papers were reviewed and 81 included. Around two-thirds used qualitative methods and over half studied public-sector facilities. Most studies were in Africa (n = 55), followed by Asia and the Pacific (n = 17). Fifty-eight studies covered only negative attitudes or behaviours, with a minority describing positive provider behaviours, such as being caring, respectful, sympathetic and helpful. Negative attitudes and behaviours commonly entailed verbal abuse (n = 45), rudeness such as ignoring or ridiculing patients (n = 35), or neglect (n = 32). Studies also documented physical abuse towards women, absenteeism or unavailability of providers, corruption, lack of regard for privacy, poor communication, unwillingness to accommodate traditional practices, and authoritarian or frightening attitudes. These behaviours were influenced by provider workload, patients' attitudes and behaviours, provider beliefs and prejudices, and feelings of superiority among MHCPs. Overall, negative attitudes and behaviours undermined health care seeking and affected patient well-being. CONCLUSIONS: The review documented a broad range of negative MHCP attitudes and behaviours affecting patient well-being, satisfaction with care and care seeking. Reported negative patient interactions far outweigh positive ones. The nature of the factors which influence health worker attitudes and behaviours suggests that strengthening health systems, and workforce development, including in communication and counselling skills, are important. Greater attention is required to the attitudes and behaviours of MHCPs within efforts to improve maternal health, for the sake of both women and health care providers.

Breast cancer survivors' perspectives on whether clinical staff should ask breast cancer patients about childhood abuse.

INTRODUCTION: Recent studies have shown that women who recall childhood abuse are at increased risk of emotional problems following a breast cancer diagnosis. How services should respond is unclear given the risk of compounding the emotional trauma of cancer with questioning about abuse. Our aim was to present the research findings to women with experience of breast cancer so as to obtain their perspective on how this evidence should influence clinical practice. METHODS: Participants were women who had been treated for breast cancer at one of the study units and women with a history of breast cancer who were members of a local patient support group. Three focus groups were conducted (with six, five and three participants respectively). The interview transcripts were analysed qualitatively. RESULTS: Participants emphasised the importance of the research findings for cancer care. The consensus was that abuse and its consequences for patients being treated for cancer should not be a 'taboo' area, and that patients should be given the opportunity and choice to disclose abuse as part of a holistic programme of care. CONCLUSIONS: Services should examine how to include prompts about abuse as part of routine holistic assessment by clinical staff, who will need to be trained in eliciting and managing disclosures of abuse.

Sensory quality of meat from lambs fed garlic.

The objective of this study was to determine whether the inclusion of garlic in a ration would have a negative impact on the flavour of lamb. The study used meat from 31 Merino wether lambs fed diets with varying levels of garlic (0%, 1.8% and 3.6%) for 10 weeks. Cooked samples of meat from the lambs were assessed for flavour and acceptability as lamb by an untrained consumer panel. There was no difference (P>0.05) between the treatments in flavour score, but the 3.6% garlic treatment group scored significantly higher in terms of acceptability as lamb (P<0.05) and was commented on positively by the panellists more frequently than the meat from any other treatment (P<0.05). These results suggest that the inclusion of garlic into the animals' feed did not have a negative impact on the flavour of the lamb and, at the high rate (3.6%), made the meat more acceptable to the panellists.

Embryo-fetal developmental toxicity study design for pharmaceuticals.

Assessment of potential developmental and reproductive toxicity of human pharmaceuticals is currently guided by the International Conference on Harmonization (ICH) S5(R2) document (available at http://www.ich.org). The studies that assess developmental hazard are generally conducted in rodents and rabbits. Based on the authors' collective experience, adequate designs (including range-finding studies) and the presentation of data for these studies are described in detail. In addition, the suggested initiation and then total duration of these studies in relation to clinical studies that enroll women of childbearing potential are described. Optional parameters that may be included in the studies are discussed, as are study designs that combine assessments of fertility and developmental toxicity. New methods that may replace or enhance current procedures are outlined. The details described herein will assist all laboratories performing these studies, individuals who need to plan for the studies, and regulatory agencies that ultimately review these studies.

Juvenile animal toxicity study designs to support pediatric drug development.

The objective of juvenile animal toxicity studies of pharmaceuticals is to obtain safety data, including information on the potential for adverse effects on postnatal growth and development. Studies in juvenile animals may assist in identifying postnatal developmental toxicities or other adverse effects that are not adequately assessed in the routine toxicity evaluations and that cannot be safely or adequately measured in pediatric clinical trials. Unlike the traditional reproductive and developmental toxicology studies that have been discussed in the accompanying reports, the design requirements for toxicity studies in juvenile animals are not explicitly defined in regulatory guidance. However, studies in juvenile animals can be useful in providing safety information necessary to enable pediatric clinical trials in pediatric patients or when there are special concerns for toxicities that cannot be safely or adequately measured in clinical trials. These juvenile animal toxicity studies are designed on a case-by-case basis. General design considerations and examples of study designs for assessment of juvenile animal toxicity are discussed.

Chondroitin sulphate: an effective joint lubricant?

OBJECTIVE: The effect of chondroitin sulphate (CS) treatment on the friction and deformation characteristics of native and glycosaminoglycan (GAG) deficient articular cartilage was investigated. METHODS: Friction tests were conducted at 0.4 MPa load, in Static and Dynamic models, to determine the startup coefficient of friction (COF) and dynamic COF, respectively. Native cartilage: For each cartilage pin and plate couple, the COF was determined under three consecutive tests - (1) baseline COF in PBS (2) COF in CS lubricant and (3) COF again in PBS, after 24h CS treatment. GAG deficient cartilage: For each cartilage pin and plate couple, the baseline COF was determined in PBS initially and again following enzymatic treatment to deplete GAGs. The specimens were then soaked in CS solution for 24h and the COF determined again in PBS. In a similar manner, friction tests were replaced with indentation tests to study the deformation of the tissue. RESULTS: CS at 50mg/ml significantly lowered the startup COF of native cartilage both as a lubricant and a treatment solution. In the dynamic model, where the fluid load support is sustained at a high level, CS failed to have any effect on the COF of native cartilage. GAG depletion raised the friction and deformation levels of cartilage, and subsequent CS treatment failed to lower them to their native levels. CONCLUSION: CS proved to be an effective lubricant for cartilage under mixed-mode lubrication conditions. However, supplemental CS that diffused into the specimens had no influence on the fluid load support of cartilage.

Understanding the differences between the wear of metal-on-metal and ceramic-on-metal total hip replacements.

Hip simulator studies have been carried out extensively to understand and test artificial hip implants in vitro as an efficient alternative to obtaining long-term results in vivo. Recent studies have shown that a ceramic-on-metal material combination lowers the wear by up to 100 times in comparison with a typical metal-on-metal design. The reason for this reduction remains unclear and for this reason this study has undertaken simple tribometer tests to understand the fundamental material loss mechanisms in two material combinations: metal-on-metal and ceramic-on-ceramic. A simple-configuration reciprocating pin-on-plate wear study was performed under open-circuit potential (OCP) and with applied cathodic protection (CP) in a serum solution using two tribological couples: firstly, cobalt-chromium (Co-Cr) pins against Co-Cr plates; secondly, Co-Cr pins against alumina (Al2O3) plates. The pin and plate surfaces prior to and after testing were examined by profilometry and scanning electron microscopy. The results showed a marked reduction in wear when CP was applied, indicating that total material degradation under the OCP condition was attributed to corrosion processes. The substitution of the Co-Cr pin with an Al2O3 plate also resulted in a dramatic reduction in wear, probably due to the reduction in the corrosion-wear interactions between the tribological pair.

Interactive effects of nitrogen deposition and fire on plant and soil chemistry in an alpine heathland.

The response of alpine heathland vegetation and soil chemistry to N additions of 0, 10, 20 and 50 kg N ha(-1) year(-1) in combination with simulated accidental fire (+/-) was monitored over a 5-year period. N addition caused rapid and significant increases in plant tissue N content and N:P and N:K of Calluna vulgaris, suggesting increasing phosphorus and potassium limitation of growth. Soil C:N declined significantly with N addition, indicating N saturation and increasing likelihood of N leakage. Fire further decreased soil C:N and reduced potential for sequestration of additional N. This study shows that alpine heathlands, which occupy the headwaters of many rivers, have limited potential to retain deposited N and may rapidly become N saturated, leaking N into downstream communities and surface waters.

Determining normal variability in a developmental neurotoxicity test: a report from the ILSI Research Foundation/Risk Science Institute expert working group on neurodevelopmental endpoints.

With the implementation of the Food Quality Protection Act in 1996, more detailed evaluations of possible health effects of pesticides on developing organisms have been required. As a result, considerable developmental neurotoxicity (DNT) data have been generated on a variety of endpoints, including developmental changes in motor activity, auditory startle habituation, and various learning and memory parameters. One issue in interpreting these data is the level of variability for the measures used in these studies: excessive variability can obscure treatment-related effects, or conversely, small but statistically significant changes could be viewed as treatment related, when they might in fact be within the normal range. To aid laboratories in designing useful DNT studies for regulatory consideration, an operational framework for evaluating observed variability in study data has been developed. Elements of the framework suggest how an investigator might approach characterization of variability in the dataset; identification of appropriate datasets for comparison; evaluation of similarities and differences in variability between these datasets, and of possible sources of the variability, including those related to test conduct and test design. A case study using auditory startle habituation data is then presented, employing the elements of this proposed approach.

Sampling considerations for garden symphylans (Order: Cephalostigmata) in western Oregon.

Sampling recommendations were developed for a potato bait sampling method used to estimate garden symphylan (Scutigerella immaculata Newport) densities in western Oregon. Sample size requirements were developed using Taylor's power law to describe the relationship between sample means and variances. Developed sampling recommendations performed well at sample sizes of 30 and greater, when validated by resampling a cohort of 40 independent data sets. Sample size requirements for the bait sampling method were 1.5 times greater than the requirements for the soil sampling method over densities from 1 to 20 S. immaculata per sample unit. As S. immaculata densities increased from April to May, sample size requirements decreased by 36% for fixed precision levels. For sampling in April, decreasing the damage threshold from 20, to 10 and five S. immaculata per sample unit, required a 1.6 and 2.5 times greater sample size requirement, respectively, for a fixed precision level (c) appropriate for pest management (c = 0.25). The bait sampling method provides an efficient reliable alternative to the standard soil sampling method used to monitor garden symphylan populations.

Alumina-alumina artificial hip joints. Part I: a histological analysis and characterisation of wear debris by laser capture microdissection of tissues retrieved at revision.

The aims of this study were to investigate the tissues from uncemented Mittelmeier alumina ceramic-on-ceramic total hip replacements using histological methods and to isolate and characterise the ceramic wear debris using laser capture microdissection and electron microscopy. Tissues from around 10 non-cemented Mittelmeier alumina ceramic on ceramic THRs were obtained from patients undergoing revision surgery. Tissues were also obtained from six patients who were undergoing revisions for aseptic loosening of Charnley, metal-on-polyethylene prostheses. Tissue sections were analysed using light microscopy to determine histological reactions and also the location and content of alumina ceramic wear debris. Tissue samples were extracted from sections using laser capture microdissection and the characteristics of the particles subsequently analysed by TEM and SEM. The tissues from around the ceramic-on-ceramic prostheses all demonstrated the presence of particles, which could be seen as agglomerates inside cells or in distinct channels in the tissues. The tissues from the ceramic-on-ceramic retrievals had a mixed pathology with areas that had no obvious pathology, areas that were relatively rich in macrophages and over half of the tissues had in the region of 60% necrosis/necrobiosis. In comparison, the Charnley tissues showed a granulomatous cellular reaction involving a dense macrophage infiltrate and the presence of giant cells and < 30% necrosis/necrobiosis. The tissues from the ceramic prostheses also showed the presence of neutrophils and lymphocytes, which were not evident in the tissues from the Charnley retrievals. There were significantly more macrophages (p < 0.05), and giant cells (p < 0.01) in the Charnley tissues and significantly more neutrophils (p < 0.01) in the ceramic-on-ceramic tissues. TEM of the laser captured tissue revealed the presence of very small alumina wear debris in the size range 5-90 nm, mean size + SD of 24 +/- 19nm whereas SEM (lower resolution) revealed particles in the 0.05-3.2 microm size range. This is the first description of nanometre sized ceramic wear particles in retrieval tissues. The bi-modal size range of alumina ceramic wear debris overlapped with the size ranges commonly observed with metal particles (10-30 nm) and particles of ultra-high molecular weight polyethylene (0.1-1,000 microm). It is possible that the two size ranges of contributed to the mixed tissue pathology observed. It is speculated that the two types of ceramic wear debris are generated by two different wear mechanisms in vivo, under normal articulating conditions, relief polishing wear and very small wear debris is produced. while under conditions of microseparation of the head and cup and rim contact, intergranular and intragranular fracture and larger wear particles are generated.

Alumina-alumina artificial hip joints. Part II: characterisation of the wear debris from in vitro hip joint simulations.

Until recently it was not possible to reproduce clinically relevant wear rates and wear patterns in in vitro hip joint simulators for alumina ceramic-on-ceramic hip prostheses. The introduction of microseparation of the prosthesis components into in vitro wear simulations produced clinically relevant wear rates and wear patterns for the first time. The aim of this study was to characterise the wear particles generated from standard simulator testing and microseparation simulator testing of hot isostatically pressed (HIPed) and non-HIPed alumina ceramic-on-ceramic hip prostheses, and compare these particles to those generated in vivo. Standard simulation conditions produced wear rates of approximately 0.1 mm3 per million cycles for both material types. No change in surface roughness was detected and very few wear features were observed. In contrast, when microseparation was introduced into the wear simulation, wear rates of between 1.24 (HIPed) and 1.74 mm3 per million cycles (non-HIPed) were produced. Surface roughness increased and a wear stripe often observed clinically on retrieved femoral heads was also reproduced. Under standard simulation conditions only nanometre-sized wear particles (2-27.5 nm) were observed by TEM, and it was thought likely that these particles resulted from relief polishing of the alumina ceramic. However, when microseparation of the prosthesis components was introduced into the simulation, a bi-modal distribution of particle sizes was observed. The nanometre-sized particles produced by relief polishing were present (1-35nm). however, larger micrometre-sized particles were also observed by both transmission electron microscopy (TEM) (0.021 microm) and scanning electron microscopy (SEM) (0.05-->10 microm). These larger particles were thought to originate from the wear stripe and were produced by trans-granular fracture of the alumina ceramic. In Part I of this study, alumina ceramic wear particles were isolated from the periprosthetic tissues from around Mittelmeier ceramic-on-ceramic hip prostheses. Characterisation of the particles by TEM and SEM revealed a bi-modal size distribution. SEM analysis revealed particles in the 0.05-3.2 microm size range. and TEM revealed particles in the 5-90 nm size range, indicating that microseparation of the prosthesis components may be a common event in vivo. This study (Part II) has revealed that the introduction of microseparation of the prosthesis components during the swing phase of the wear simulation reproduced clinically relevant wear rates, wear patterns and wear particles in in vitro hip joint simulators.

Wear of HIPed and non-HIPed alumina-alumina hip joints under standard and severe simulator testing conditions.

Wear and the biological response to wear debris of artificial joints remain major concerns in total hip arthroplasty (THA). The long-term effects of UHMWPE wear debris are well documented and these have led to interest in alternate bearing materials for THA. Alumina ceramic-ceramic hip joints have been successfully used for more than 30 years with low wear and little incidence of osteolysis. The most common wear pattern observed on retrieved components is an elliptical wear 'stripe' on the heads and a corresponding worn area on the cup with an approximated wear rate of 1-5 mm3 pa. More severe wear has also occasionally occurred, usually in association with an abnormal clinical history. Modern alumina-alumina THAs use an improved HIPed (hot isostatically pressed) alumina ceramic-bearing material which may be more resistant to severe wear. Previous in vitro simulator studies have not replicated in vivo wear rates or mechanisms. The aim of this study was to compare previous generation non-HIPed alumina and modern HIPed alumina in a hip joint simulator under 'normal' and 'harsh' testing conditions. HIPed alumina was found to have a lower wear rate than non-HIPed alumina, although the difference was not statistically significant at the 95% confidence level. Testing in Gelofusine and water lubricants did not elevate the wear rates of either material. Elevated swing phase load testing also had no significant effect on the wear rates of either material. Testing in the absence of any lubricant produced very severe wear of the non-HIPed material in one specimen only.

Comparative analysis of two different types of alumina-alumina hip prosthesis retrieved for aseptic loosening.

We compared and quantified the modes of failure and patterns of wear of 11 Mittelmeier and 11 Ceraver-Ostal retrieved alumina-alumina hip prostheses with reference to the corresponding clinical and radiological histories. Macroscopic wear was assessed using a three-dimensional co-ordinate measuring machine. Talysurf contacting profilometry was used to measure surface roughness on a microscopic scale and SEM to determine mechanisms of wear at the submicron level. The components were classified into one of three categories of wear: low (no visible/measurable wear), stripe (elliptical wear stripe on the heads and larger worn areas on the cups) and severe (macroscopic wear, large volumes of material lost). Overall, the volumetric wear of the alumina-alumina prostheses was substantially less than the widely used metal and ceramic-on-polyethylene combinations. By identifying and eliminating the factors which accelerate wear, it is expected that the lifetime of these devices can be further increased.

Randomized phase III study comparing Best Supportive Care to Biafine as a prophylactic agent for radiation-induced skin toxicity for women undergoing breast irradiation: Radiation Therapy Oncology Group (RTOG) 97-13.

PURPOSE: To determine if Biafine compared to Best Supportive Care (BSC) is effective in minimizing or preventing radiation-induced dermatitis in women undergoing breast irradiation. METHODS AND MATERIALS: Patients were randomized between Biafine (n = 83) vs. BSC (n = 89). The institutions identified preference for BSC at the time of randomization. A no-treatment arm was allowed (16% received no treatment). Patients were instructed to apply randomized product three times a day, but not within 4 h of their daily RT session. Application began following their first radiation treatment and continued 2 weeks postradiation. Skin dermatitis was scored weekly utilizing the RTOG and ONS (Oncology Nursing Society) skin toxicity scales, a weekly patient satisfaction and quality-of-life questionnaire. RESULTS: Using the RTOG toxicity scale there was no overall difference for maximum dermatitis during RT between Biafine and BSC (p = 0.77). There was no difference in maximum toxicity by arm or breast size. There was an interaction between breast size and toxicity, with large-breasted women exhibiting more toxicity. Large-breasted women receiving Biafine were more likely to have no toxicity 6 weeks post RT. CONCLUSION: There was no overall difference between BSC and Biafine in the prevention, time to, or duration of radiation-induced dermatitis.

Do patients with rheumatoid arthritis established on methotrexate and folic acid 5 mg daily need to continue folic acid supplements long term?

BACKGROUND: It is postulated that some aspects of methotrexate toxicity may be related to its action as an anti-folate. Folic acid (FA) is often given as an adjunct to methotrexate therapy, but there is no conclusive proof that it decreases the toxicity of methotrexate and there is a theoretical risk that it may decrease the efficacy of methotrexate. OBJECTIVES: To look at the effect of stopping FA supplementation in UK rheumatoid arthritis (RA) patients established on methotrexate <20 mg weekly and FA 5 mg daily, to report all toxicity (including absolute changes in haematological and liver enzyme indices) and to report changes in the efficacy of methotrexate. METHODS: In a prospective, randomized, double-blind, placebo-controlled study, 75 patients who were established on methotrexate <20 mg weekly and FA 5 mg daily were asked to stop their FA and were randomized to one of two groups: placebo or FA 5 mg daily. Patients were evaluated for treatment toxicity and efficacy before entry and then at intervals of 3 months for 1 yr. RESULTS: Overall, 25 (33%) patients concluded the study early, eight (21%) in the group remaining on FA and 17 (46%) in the placebo group (P = 0.02). Two patients in the placebo group discontinued because of neutropenia. At 9 months there was an increased incidence of nausea in the placebo group (45 vs. 7%, P = 0.001). The placebo group had significantly lower disease activity on a few of the variables measured, but these were probably not of clinical significance. CONCLUSIONS: It is important to continue FA supplementation over the long term in patients on methotrexate and FA in order to prevent them discontinuing treatment because of mouth ulcers or nausea and vomiting. Our data suggest that FA supplementation is also helpful in preventing neutropenia, with very little loss of efficacy of methotrexate.