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1.
Regul Toxicol Pharmacol ; 144: 105483, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37640101

RESUMEN

Understanding and estimating the exposure to a substance is one of the fundamental requirements for safe manufacture and use. Many approaches are taken to determine exposure to substances, mainly driven by potential use and regulatory need. There are many opportunities to improve and optimise the use of exposure information for chemical safety. The European Partnership for Alternative Approaches to Animal Testing (EPAA) therefore convened a Partners' Forum (PF) to explore exposure considerations in human safety assessment of industrial products to agree key conclusions for the regulatory acceptance of exposure assessment approaches and priority areas for further research investment. The PF recognised the widescale use of exposure information across industrial sectors with the possibilities of creating synergies between different sectors. Further, the PF acknowledged that the EPAA could make a significant contribution to promote the use of exposure data in human safety assessment, with an aim to address specific regulatory needs. To achieve this, research needs, as well as synergies and areas for potential collaboration across sectors, were identified.


Asunto(s)
Alternativas a las Pruebas en Animales , Industrias , Animales , Humanos , Comercio , Medición de Riesgo
2.
J Palliat Med ; 26(5): 733, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-37130288
3.
Eur J Pediatr ; 182(4): 1847-1855, 2023 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-36795188

RESUMEN

Only a few acute hospital inpatient units dedicated to pediatric palliative care (PPC) patients exist today. Clinical data on the patients and care provided at specialized acute PPC inpatient units (PPCUs) are scarce. This study aims at describing patient and care characteristics on our PPCU to learn about the complexity and relevance of inpatient PPC. A retrospective chart analysis was performed on the 8-bed PPCU of the Center for Pediatric Palliative Care of the Munich University Hospital, including demographic, clinical, and treatment characteristics (487 consecutive cases; 201 individual patients; 2016-2020). Data were analyzed descriptively; the chi-square test was used for comparisons. Patients' age (1-35.5 years, median: 4.8 years) and length of stay (1-186 days, median 11 days) varied widely. Thirty-eight percent of patients were admitted repeatedly (range 2-20 times). Most patients suffered from neurological diseases (38%) or congenital abnormalities (34%); oncological diseases were rare (7%). Patients' predominant acute symptoms were dyspnea (61%), pain (54%), and gastrointestinal symptoms (46%). Twenty percent of patients suffered from > 6 acute symptoms, 30% had respiratory support incl. invasive ventilation, 71% had a feeding tube, and 40% had full resuscitation code. In 78% of cases, patients were discharged home; 11% died on the unit. CONCLUSION: This study shows the heterogeneity, high symptom burden, and medical complexity of the patients on the PPCU. The high dependency on life-sustaining medical technology points to the parallelism of life-prolonging and palliative treatments that is typical for PPC. Specialized PPCUs need to offer care at the intermediate care level in order to respond to the needs of patients and families. WHAT IS KNOWN: • Pediatric patients in outpatient PPC or hospices present with a variety of clinical syndromes and different levels of complexity and care intensity. • There are many children with life-limiting conditions (LLC) in hospitals, but specialized PPC hospital units for these patients are rare and poorly described. WHAT IS NEW: • Patients on a specialized PPC hospital unit show a high symptom burden and a high level of medical complexity, including dependency on medical technology and frequent full resuscitation code. • The PPC unit is mainly a place for pain and symptom management as well as crisis intervention, and needs to be able to offer treatment at the intermediate care level.


Asunto(s)
Cuidados Paliativos , Cuidado Terminal , Niño , Humanos , Lactante , Preescolar , Adolescente , Adulto Joven , Adulto , Pacientes Internos , Estudios Retrospectivos , Dolor
4.
Regul Toxicol Pharmacol ; 135: 105261, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-36103951

RESUMEN

New Approach Methodologies (NAMs) are considered to include any in vitro, in silico or chemistry-based method, as well as the strategies to implement them, that may provide information that could inform chemical safety assessment. Current chemical legislation in the European Union is limited in its acceptance of the widespread use of NAMs. The European Partnership for Alternative Approaches to Animal Testing (EPAA) therefore convened a 'Deep Dive Workshop' to explore the use of NAMs in chemical safety assessment, the aim of which was to support regulatory decisions, whilst intending to protect human health. The workshop recognised that NAMs are currently used in many industrial sectors, with some considered as fit for regulatory purpose. Moreover, the workshop identified key discussion points that can be addressed to increase the use and regulatory acceptance of NAMs. These are based on the changes needed in frameworks for regulatory requirements and the essential needs in education, training and greater stakeholder engagement as well the gaps in the scientific basis of NAMs.


Asunto(s)
Alternativas a las Pruebas en Animales , Pruebas de Toxicidad , Animales , Unión Europea , Humanos , Industrias , Medición de Riesgo , Pruebas de Toxicidad/métodos
5.
Regul Toxicol Pharmacol ; 134: 105244, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-35932886

RESUMEN

Considerable progress has been made in the design of New Approach Methodologies (NAMs) for the hazard identification of skin sensitising chemicals. However, effective risk assessment requires accurate measurement of sensitising potency, and this has proven more difficult to achieve without recourse to animal tests. One important requirement for the development and adoption of novel approaches for this purpose is the availability of reliable databases for determining the accuracy with which sensitising potency can be predicted. Some previous approaches have relied on comparisons with potency estimates based on either human or animal (local lymph node assay) data. In contrast, we here describe the development of a carefully curated Reference Chemical Potency List (RCPL) which is based on consideration of the best available human and animal data. The RCPL is comprised of 33 readily available chemicals that span a wide range of chemistry and sensitising potency, and contain examples of both direct and indirect (pre- and pro-) haptens. For each chemical a potency value (PV) was derived, and chemicals ranked according to PV without the use of potency categories. It is proposed that the RCPL provides an effective resource for assessment of the accuracy with which NAMs can measure skin sensitising potency.


Asunto(s)
Dermatitis Alérgica por Contacto , Alternativas a las Pruebas en Animales , Animales , Dermatitis Alérgica por Contacto/etiología , Dermatitis Alérgica por Contacto/patología , Haptenos , Humanos , Ensayo del Nódulo Linfático Local , Medición de Riesgo/métodos , Piel
6.
J Opioid Manag ; 17(2): 181-183, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33890281

RESUMEN

Methadone, or in Germany levomethadone, may be used for the treatment of iatrogenic opioid withdrawal syndrome in pediatric intensive care units. The limited literature on opioid rotation in children does not provide data for the switch from methadone to another opioid. We report switching a very ill preterm baby in an unstable condition from IV levomethadone to IV fentanyl identifying a possible conversion ratio of 6.0-4.5:1 emphasizing critical steps as equipotency appropriate for neonates and dose reduction for incomplete cross-tolerance. If clinical deterioration occurs in infants on opioid tapering with levomethadone, we hope that our observations may be helpful.


Asunto(s)
Analgésicos Opioides , Fentanilo , Analgésicos Opioides/efectos adversos , Niño , Fentanilo/efectos adversos , Alemania , Humanos , Lactante , Recién Nacido , Metadona , Narcóticos
7.
Regul Toxicol Pharmacol ; 108: 104470, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31479718

RESUMEN

The European Partnership for Alternative Approaches to Animal Testing (EPAA) convened a Partners' Forum on repeated dose toxicity (RDT) testing to identify synergies between industrial sectors and stakeholders along with opportunities to progress these in existing research frameworks. Although RTD testing is not performed across all industrial sectors, the OECD accepted tests can provide a rich source of information and play a pivotal role for safety decisions relating to the use of chemicals. Currently there are no validated alternatives to repeated dose testing and a direct one-to-one replacement is not appropriate. However, there are many projects and initiatives at the international level which aim to implement various aspects of replacement, reduction and refinement (the 3Rs) in RDT testing. Improved definition of use, through better problem formulation, aligned to harmonisation of regulations is a key area, as is the more rapid implementation of alternatives into the legislative framework. Existing test designs can be optimised to reduce animal use and increase information content. Greater use of exposure-led decisions and improvements in dose selection will be beneficial. In addition, EPAA facilitates sharing of case studies demonstrating the use of Next Generation Risk Assessment applying various New Approach Methodologies to assess RDT.


Asunto(s)
Alternativas a las Pruebas en Animales , Pruebas de Toxicidad/métodos , Animales , Humanos , Medición de Riesgo
10.
Regul Toxicol Pharmacol ; 99: 5-21, 2018 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-30144470

RESUMEN

The European Partnership for Alternative Approaches to Animal Testing (EPAA) convened a Partners' Forum Toxicokinetics and Read-Across to provide an overview on research activities to develop in vitro toxicokinetics methods and physiologically-based kinetic (PBK) models and to find synergies to enhance use of toxicokinetic data to strengthen read-across. Currently, lacking toxicokinetic data often prevent the application of read-across. Preferably, toxicokinetic data should be generated using in vitro and in silico tools and anchored towards human relevance. In certain sectors, PBK modelling is being used for risk assessment, but less so in others. Specific activities were identified to facilitate the use of in vitro and in silico toxicokinetic data to support read-across: The collation of available tools indicating the parameters and applicability domains covered; endpoint-specific guidance on toxicokinetics parameters required for read-across; case studies exemplifying how toxicokinetic data help support read-across. Activities to enhance the scientific robustness of read-across include the further user-friendly combination of read-across tools and formal guidance by the authorities specifying the minimum information requirements to justify read-across for a given toxicity endpoint. The EPAA was invited to continue dissemination activities and to explore possibilities to collate a contemporaneous list of open toxicokinetics tools that assist risk assessment.


Asunto(s)
Alternativas a las Pruebas en Animales/métodos , Animales , Simulación por Computador , Europa (Continente) , Humanos , Técnicas In Vitro/métodos , Modelos Biológicos , Medición de Riesgo/métodos , Toxicocinética
11.
J Pain Symptom Manage ; 54(2): 159-166, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-28602938

RESUMEN

CONTEXT: Specialized pediatric palliative home care (SPPHC) is the main pediatric palliative care structure in Germany. Detailed data on patient characteristics and care are sparse. Describing this population in terms of diagnoses and care needs is essential for further development of palliative care services for these patients. OBJECTIVES: We asked whether the population at our center 1) was representative compared with national mortality statistics; 2) showed differences in the clinical course among the four diagnostic categories established by the Association for Children with Terminal Conditions/Royal College of Paediatrics and Child Health; and 3) was different to published populations in pediatric palliative care regarding diagnoses, care, and place of death. METHODS: Retrospective single center chart analysis of 212 consecutive patients on SPPHC (2009-2015). RESULTS: Main International Statistical Classification of Diseases and Related Health Problems, 10th Revision groups were nervous system, congenital abnormalities, neoplasia, and metabolic disease, reflecting the mortality statistics for patients one to 20 years. Thirty-six percent of patients were assigned to ACT-3, 34% to ACT-4, 26% to ACT-1, and 4% to ACT-2. ACT-1 patients mostly needed high-intensity care for short durations, ACT-4 patients showed long survival times with mostly intermittent care. Seventy-five percent of patients showed nervous system involvement. Eighty-four percent died at home, 12% in hospital, and 4% in a hospice, with 96% dying at their preferred place. CONCLUSION: Our data on SPPHC show 1) significant differences between Association for Children with Terminal Conditions/Royal College of Paediatrics and Child Health groups in terms of care needs and survival; 2) a high prevalence of children with neurological problems; and 3) a large majority of children dying at home.


Asunto(s)
Servicios de Atención de Salud a Domicilio , Mortalidad , Cuidados Paliativos , Adolescente , Niño , Preescolar , Femenino , Alemania/epidemiología , Servicios de Atención de Salud a Domicilio/estadística & datos numéricos , Cuidados Paliativos al Final de la Vida/estadística & datos numéricos , Humanos , Lactante , Recién Nacido , Estimación de Kaplan-Meier , Masculino , Cuidados Paliativos/estadística & datos numéricos , Pediatría/estadística & datos numéricos , Estudios Retrospectivos , Adulto Joven
12.
Carbohydr Polym ; 168: 356-364, 2017 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-28457460

RESUMEN

Because the degree of substitution (DS) of chemically modified starches strongly affects their physicochemical properties and applications, rapid techniques for its determination are crucial. In the present work, ammonium starch phosphates carbamates (SPC) were obtained by reacting starch with urea-phosphoric acid. DS of phosphate (DSP), carbamate (DSC), and ammonium groups (DSNH4+) and contents of non-hydrolyzable amides (Nnh) of SPC were determined using the vanadomolybdophosphoric acid and saponification methods, respectively. It was the aim to investigate the extent to which Raman features of SPC relate to their DS values of different functional groups as obtained by wet chemistry. Strong linear correlations (R2=0.967…0.995) were found between DSP, DSNH4+, and the degree of substitution of urea (DSurea) and Raman signals at 820, 1710 and 1015cm-1. Thus, with appropriate calibration, Raman spectroscopy is a promising tool for the simultaneous and rapid determination of the level of phosphorylation and the ammonium and urea contents of SPC.

13.
Oncotarget ; 7(43): 70959-70968, 2016 Oct 25.
Artículo en Inglés | MEDLINE | ID: mdl-27486822

RESUMEN

PURPOSE: Advanced Ewing sarcomas have poor prognosis. They are defined by early relapse (<24 months after diagnosis) and/or by metastasis to multiple bones or bone marrow (BM). We analyzed risk factors, toxicity and survival in advanced Ewing sarcoma patients treated with the MetaEICESS vs. EICESS92 protocols. DESIGN: Of 44 patients, 18 patients were enrolled into two subsequent MetaEICESS protocols between 1992 and 2014, and compared to outcomes of 26 advanced Ewing sarcoma patients treated with EICESS 1992 between 1992 and 1996. MetaEICESS 1992 consisted of induction chemotherapy, whole body imaging directed radiotherapy to the primary tumor and metastases, tandem high-dose chemotherapy and autologous rescue. In MetaEICESS 2007 this treatment was complemented by allogeneic stem cell transplantation. EICESS 1992 comprised induction chemotherapy, local therapy to the primary tumor only followed by consolidation chemotherapy. RESULTS: In MetaEICESS 8/18 patients survived in complete remission vs. 2/26 in EICESS 1992 (p<0.05). Survival did not differ between MetaEICESS 2007 and MetaEICESS 1992. Three MetaEICESS patients died of complications, all in MetaEICESS 1992. After exclusion of patients succumbing to treatment related complications (n=3), 7/10 patients survived without BM involvement, in contrast to 0/5 patients with BM involvement. This was confirmed in a multivariate analysis. There was no correlation between BM involvement and the number of metastases at diagnosis. CONCLUSION: The MetaEICESS protocols yield long-term disease-free survival in patients with advanced Ewing sarcoma. Allogeneic stem cell transplantation was not associated with increased death of complications. Bone marrow involvement is a risk factor distinct from multiple bone metastases.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Médula Ósea/patología , Neoplasias Óseas/patología , Recurrencia Local de Neoplasia/patología , Sarcoma de Ewing/patología , Adolescente , Adulto , Neoplasias Óseas/mortalidad , Neoplasias Óseas/terapia , Niño , Terapia Combinada/métodos , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/terapia , Pronóstico , Estudios Prospectivos , Inducción de Remisión/métodos , Sarcoma de Ewing/mortalidad , Sarcoma de Ewing/terapia , Análisis de Supervivencia , Resultado del Tratamiento , Adulto Joven
14.
Dtsch Med Wochenschr ; 141(3): 215-7, 2016 Feb.
Artículo en Alemán | MEDLINE | ID: mdl-26841187

RESUMEN

MEDICAL HISTORY: An extensive thigh abscess was the reason for a hospital admission of a 66 year old woman. Apart from that there were no other known preexisting diseases. INVESTIGATIONS: The reason for the abscess was a perforated sigma carcinoma, which was incidentally found. Treatments and course: We treated the patient with a sigma resection and several debridements of the thigh. But for all that she died from septic shock. CONCLUSION: This case illustrates the importance of cancer screening programs and an accurate investigation of the medical history and clinical examination. This can be supported by a failure management, which does not sanction a failure but considers it as a chance for future improvement.


Asunto(s)
Absceso , Neoplasias del Colon Sigmoide , Muslo , Absceso/diagnóstico por imagen , Absceso/etiología , Absceso/patología , Anciano , Femenino , Humanos , Radiografía , Neoplasias del Colon Sigmoide/diagnóstico por imagen , Neoplasias del Colon Sigmoide/patología , Muslo/diagnóstico por imagen , Muslo/patología
18.
Biomed Res Int ; 2014: 637059, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25025064

RESUMEN

Central nervous system (CNS) involvement is a severe complication of BCR-ABL-positive leukemia after allogenic stem cell transplantation (alloSCT) associated with fatal outcome. Although second-generation tyrosine-kinase inhibitors (TKI) such as nilotinib have shown activity in systemic BCR-ABL(+) disease, little data exists on their penetration and efficacy within the CNS. Four patients (3 male, 1 female; age 15-49) with meningeal relapse after alloSCT and subsequent treatment with nilotinib were identified. A total of 17 cerebrospinal fluid (csf) and serum samples were assessed for nilotinib concentration and patient outcome was recorded. Nilotinib concentrations showed a low median csf/plasma ratio of 0.53% (range 0.23-1.5%), yet pronounced clinical efficacy was observed with long-lasting responses (>1 year) in three patients. Comparison with historical data showed a trend towards superior efficacy of nilotinib versus imatinib. Despite poor csf penetration, nilotinib showed significant clinical activity in CNS relapse of BCR-ABL(+) leukemias. As nilotinib has a high protein-binding affinity, the low-protein concentration in csf could translate into a relatively higher amount of free and therefore active nilotinib in csf as compared to blood, possibly explaining the observed efficacy. Thus, treatment with a 2nd generation TKI warrants further investigation and should be considered in cases of CNS relapse of BCR-ABL-positive leukemia after alloSCT.


Asunto(s)
Sistema Nervioso Central/patología , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Pirimidinas/administración & dosificación , Adolescente , Adulto , Benzamidas/administración & dosificación , Femenino , Proteínas de Fusión bcr-abl/genética , Humanos , Mesilato de Imatinib , Estimación de Kaplan-Meier , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Piperazinas/administración & dosificación , Trasplante de Células Madre/efectos adversos , Trasplante Homólogo/efectos adversos
19.
Langenbecks Arch Surg ; 399(3): 343-8, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24515267

RESUMEN

PURPOSE: This study was aimed to investigate incidence, circumstances and consequences of acute compartment syndrome (CS) of the lower extremity after gynecological operations in lithotomy position by collecting data from departments of Obstetrics and Gynecology in Germany. DESIGN: Retrospective observational study. SETTING: Departments of Obstetrics and Gynecology in the area of North Rhine (Germany) METHODS: A 24-item questionnaire was sent to 168 gynecological departments. In addition, cases anonymously reported to the Expert Committee for Medical Malpractice Claims of the Medical Association of North Rhine between 2002 and 2012 were analyzed. MAIN OUTCOME MEASURE: Incidence of acute CS after gynecological operations. RESULTS: A total of 59 questionnaires (35 %) were returned for analysis, reporting 21 cases of CS. Based on the collected data, we calculated an incidence of postoperative CS ranging between 0.067 % and 0.28 %. All reported cases of postoperative CS occurred after surgeries in lithotomy position, 57.1 % of cases occurred after laparoscopic procedures and 76.2 % after procedures longer than 4 h. Overall, 61.0 % of departments do not routinely inform about the risk of this complication when they get patients' informed consent. Reported prevention strategies were inconsistent and ranged from none to multiple measures. CONCLUSION: CS is a complication clearly associated with long lasting gynecological operations in Lithotomy position. Despite a relatively high incidence, so far no guidelines on perioperative management and medicolegal aspects exist and preventive measures are heterogeneous among institutions. The need for guidelines and recommendations by an expert committee has been identified.


Asunto(s)
Síndromes Compartimentales/epidemiología , Procedimientos Quirúrgicos Ginecológicos/efectos adversos , Extremidad Inferior , Enfermedad Aguda , Adulto , Anciano , Femenino , Alemania , Humanos , Incidencia , Laparoscopía/efectos adversos , Persona de Mediana Edad , Tempo Operativo , Posicionamiento del Paciente/efectos adversos , Estudios Retrospectivos , Factores de Riesgo , Adulto Joven
20.
Eur J Obstet Gynecol Reprod Biol ; 173: 7-12, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24290432

RESUMEN

Compartment syndrome (CS) of the lower leg is a rare but severe complication of operations in the lithotomy (LT) position after urologic, gynecologic and general surgery. A delay in diagnosis and treatment can lead to loss of function and even life-threatening complications. The pathophysiology is still not fully understood but it is believed that ischemia as a result of increased compartment pressure and decreased perfusion pressure may lead to CS. The type of leg support and the intraoperative hypotension have been discussed as risk factors but evidence is mainly based on case reports and expert opinion. Studies suggest that time spent in the LT position and the addition of head-down tilt are associated with CS. As these positions are routinely applied during various gynecologic procedures, forensically CS has to be considered as a specific complication of gynecologic surgery in the LT position. Despite the low incidence there is a need for prospective studies and guidelines for its prevention. Sixteen case reports describing 19 cases of CS following gynecologic surgery in lithotomy position were found during a literature search. This review is based on 14 of these case reports (17 cases), which describe a postoperative compartment syndrome in a previously healthy leg. We summarize the reported cases and literature on CS after gynecologic procedures in order to increase awareness among medical staff and to give careful recommendations regarding perioperative management based on available information.


Asunto(s)
Síndromes Compartimentales/etiología , Procedimientos Quirúrgicos Ginecológicos/efectos adversos , Posicionamiento del Paciente/efectos adversos , Femenino , Humanos
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