scholarly journals CDER Experience With Juvenile Animal Studies for CNS Drugs

2019 ◽  
Vol 38 (2) ◽  
pp. 88-95 ◽  
Author(s):  
J. Edward Fisher ◽  
Arippa Ravindran ◽  
Ikram Elayan
Keyword(s):  
Animal Studies ◽  
Drug Evaluation ◽  
Safety Information ◽  
Mineral Density ◽  
Juvenile Animal ◽  
Functional Assessments ◽  
Startle Habituation ◽  
Age Range ◽  
Neurobehavioral Effects

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.

scholarly journals Sclerostin depletion induces inflammation in the bone marrow of mice

2020 ◽  
Author(s):  
Cristine Donham ◽  
Betsabel Chicana ◽  
Alexander Robling ◽  
Asmaa Mohamed ◽  
Sonny Elizaldi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Animal Studies ◽  
Immune Cell ◽  
Extramedullary Hematopoiesis ◽  
Phase Iii ◽  
Bone Homeostasis ◽  
Mineral Density ◽  
Hematopoietic Stem ◽  
Phase Iii Clinical Trials

ABSTRACTRomosozumab, a humanized monoclonal antibody specific for sclerostin, has been approved for treatment of post-menopausal women with osteoporosis at high risk for fracture. In several Phase III clinical trials, romosozumab decreased the risk of vertebral fractures up to 73% and increased total hip area bone mineral density by 3.2%. Previous work in 12 to 15-week-old sclerostin-knockout (Sost-/-) mice indicated that changes in immune cell development occur in the bone marrow (BM), which could be a possible side effect to follow in human patients. Our overall goal was to define the mechanisms that guide behavior of long-term hematopoietic stem cells (LT-HSCs) after exposure to an irregular BM microenvironment. SOST plays an important role in maintaining bone homeostasis, as demonstrated by the increased ratio of bone volume to total volume observed in Sost-/- mice. Here, we examined the effects of short-term sclerostin depletion in the BM on hematopoiesis in young (8 week-old) mice receiving sclerostin-antibody (Scl-Ab) treatment for 6 weeks, and the effects of long-term Sost-deficiency on wild-type (WT) LT-HSCs transplanted into older (16-22 week-old) cohorts of Sost-/- mice. Our analyses revealed an increased frequency of granulocytes and decreased frequency of lymphocytes in the BM of Scl-Ab treated mice and WT→Sost-/- hematopoietic chimeras, indicating myeloid-biased differentiation in Sost-deficient BM microenvironments. This myeloid bias extended to extramedullary hematopoiesis in the spleen and was correlated with an increase in inflammatory cytokines TNFα, IL-1α and MCP-1 in the serum of the Sost-/- BM. Additionally, we observed alterations in erythrocyte differentiation in the BM and spleen of Sost-/- mice. Taken together, our current study indicates novel roles for Sost in the regulation of myelopoiesis and control of inflammation in the BM. Our animal studies strongly recommend tracking of hematopoietic function in patients treated with romosozumab.

Pharmacotherapy of Bone Loss in Postmenopausal Women: Focus on Denosumab

2009 ◽  
Vol 1 ◽  
pp. CMT.S1089
Author(s):  
Alejandro Roman-Gonzalez ◽  
Kathryn E. Ackerman
Keyword(s):  
Postmenopausal Women ◽  
Opportunistic Infections ◽  
Human Monoclonal Antibody ◽  
Safety Information ◽  
Study Groups ◽  
Mineral Density ◽  
Phase 3 ◽  
Turnover Markers ◽  
Near Future

Denosumab is a human monoclonal antibody against RANKL. This antibody decreases bone turnover markers and increases bone mineral density (BMD) in postmenopausal women. In phase 3 studies including more than 1100 women, denosumab achieved greater increases in lumbar spine, total hip, distal 1/3 radius, and total BMD than alendronate 70 mg weekly. Recent data suggest that denosumab also decreases vertebral and non-vertebral fractures. This drug seems to be safe, although the most frequent side effects are arthralgia, back pain, and nasopharyngitis. No increased incidence of neoplasia has been found compared to placebo or alendronate. However, infections requiring inpatient treatment were more frequent in study groups treated with denosumab. These were common community acquired infections and were treated with standard antibiotics. No opportunistic infections were reported. Denosumab is a very promising new drug for the treatment of osteopenia and osteoporosis, and hopefully more long-term safety information and further fracture data will support its commercial use in the near future.

Barriers to Physical Activity in Adolescents

2015 ◽  
Vol 23 (2) ◽  
pp. 47-59 ◽  
Author(s):  
Nadine Langguth ◽  
Tanja Könen ◽  
Simone Matulis ◽  
Regina Steil ◽  
Caterina Gawrilow ◽  
...  
Keyword(s):  
Physical Activity ◽  
Leisure Activities ◽  
Outcome Expectations ◽  
Multidimensional Approach ◽  
Factor Analyses ◽  
Physical And Mental Health ◽  
Tailored Interventions ◽  
Long Term Consequences ◽  
Age Range

During adolescence, physical activity (PA) decreases with potentially serious, long-term consequences for physical and mental health. Although barriers have been identified as an important PA correlate in adults, research on adolescents’ PA barriers is lacking. Thus reliable, valid scales to measure adolescents’ PA barriers are needed. We present two studies describing a broad range of PA barriers relevant to adolescents with a multidimensional approach. In Study 1, 124 adolescents (age range = 12 – 24 years) reported their most important PA barriers. Two independent coders categorized those barriers. The most frequent PA barriers were incorporated in a multidimensional questionnaire. In Study 2, 598 adolescents (age range = 13 – 21 years) completed this questionnaire and reported their current PA, intention, self-efficacy, and negative outcome expectations. Seven PA barrier dimensions (leisure activities, lack of motivation, screen-based sedentary behavior, depressed mood, physical health, school workload, and preconditions) were confirmed in factor analyses. A multidimensional approach to measuring PA barriers in adolescents is reliable and valid. The current studies provide the basis for developing individually tailored interventions to increase PA in adolescents.

Determinants of bone mineral density in long-term adult survivors of childhood cancer

2013 ◽  
Author(s):  
C Klap B ◽  
L te Winkel M ◽  
den Hoed M ◽  
van Waas M ◽  
J C M M Neggers S ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Childhood Cancer ◽  
Bone Mineral ◽  
Adult Survivors ◽  
Mineral Density ◽  
Survivors Of Childhood Cancer

Changes in bone metabolism associated with exposure to industrial vibration

2020 ◽  
pp. 766-766
Author(s):  
A. V. Sukhova ◽  
E. N. Kryuchkova
Keyword(s):  
Bone Mineral Density ◽  
Alkaline Phosphatase ◽  
Bone Resorption ◽  
Bone Formation ◽  
Bone Metabolism ◽  
Biochemical Markers ◽  
Mineral Density ◽  
Local Vibration ◽  
Markers Of Bone Formation

The influence of general and local vibration on bone remodeling processes is investigated. The interrelations between the long - term exposure of industrial vibration and indicators of bone mineral density (T-and Z-criteria), biochemical markers of bone formation (osteocalcin, alkaline phosphatase) and bone resorption (ionized calcium, calcium/creatinine) were established.

Primary Calvarial Ewing Sarcoma: A Case Series

2021 ◽  
Author(s):  
Sandeep Mohindra ◽  
Manjul Tripathi ◽  
Aman Batish ◽  
Ankur Kapoor ◽  
Ninad Ramesh Patil ◽  
...  
Keyword(s):  
Ewing Sarcoma ◽  
Tumor Resection ◽  
Case Series ◽  
Radical Excision ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Intradural Tumor ◽  
Age Range

Abstract Background Calvarial Ewing tumor is a relatively rare differential among bony neoplasms. We present our experience of managing primary calvarial Ewing sarcoma (EWS), highlighting their clinical and radiological findings. Method In a retrospective analysis, we evaluated our 12-year database for pathologically proven EWS. A literature search was conducted for the comparative presentation and update on the management and outcome. Result From January 2008 to December 2020, we managed eight patients (male:female = 5:3; age range 6 months to 19 years, mean 11.5 years) harboring primary calvarial EWS. All cases underwent wide local excision; two patients required intradural tumor resection, while one required rotation flap for scalp reconstruction. Mean hospital stay was 8 days. All patients received adjuvant chemo- and radiotherapy. Three patients remained asymptomatic at 5 years of follow-up, while two patients died. Conclusion Primary calvarial EWS is a rare entity. It usually affects patients in the first two decades of life. These tumors can be purely intracranial, causing raised intracranial pressure symptoms, which may exhibit rapidly enlarging subgaleal tumors with only cosmetic deformities or symptoms of both. Radical excision followed by adjuvant therapy may offer a favorable long-term outcome.

scholarly journals Bone mineral density and explanatory factors in children and adults with juvenile dermatomyositis at long term follow-up; a cross sectional study

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Henriette Schermacher Marstein ◽  
Kristin Godang ◽  
Berit Flatø ◽  
Ivar Sjaastad ◽  
Jens Bollerslev ◽  
...  
Keyword(s):  
Bone Turnover ◽  
Inflammatory Markers ◽  
Juvenile Dermatomyositis ◽  
Inflammatory Myopathy ◽  
Disease Onset ◽  
Whole Body ◽  
Mineral Density ◽  
Z Scores

Abstract Background Juvenile dermatomyositis (JDM) is the most common idiopathic inflammatory myopathy in children and adolescents. Both the disease and its treatment with glucocorticoids may negatively impact bone formation. In this study we compare BMD in patients (children/adolescence and adults) with long-standing JDM with matched controls; and in patients, explore how general/disease characteristics and bone turnover markers are associated with BMD. Methods JDM patients (n = 59) were examined median 16.8y (range 6.6–27.0y) after disease onset and compared with 59 age/sex-matched controls. Dual-energy X-ray absorptiometry (DXA) was used to measure BMD of the whole body and lumbar spine (spine) in all participants, and of ultra-distal radius, forearm and total hip in participants ≥20y only. Markers of bone turnover were analysed, and associations with outcomes explored. Results Reduced BMD Z-scores (<−1SD) were found in 19 and 29% of patients and 7 and 9% of controls in whole body and spine, respectively (p-values < 0.05). BMD and BMD Z-scores for whole body and spine were lower in all patients and for < 20y compared with their respective controls. In participants ≥20y, only BMD and BMD Z-score of forearm were lower in the patients versus controls. In patients, BMD Z-scores for whole body and/or spine were found to correlate negatively with prednisolone use at follow-up (yes/no) (age < 20y), inflammatory markers (age ≥ 20y) and levels of interferon gamma-induced protein 10 (IP-10) (both age groups). In all patients, prednisolone use at follow-up (yes/no) and age ≥ 20y were independent correlates of lower BMD Z-scores for whole body and spine, respectively. Conclusion In long-term JDM, children have more impairment of BMD than adults in spine and whole-body. Associations with BMD were found for both prednisolone and inflammatory markers, and a novel association was discovered with the biomarker of JDM activity, IP-10.

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