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BACKGROUND: Multimorbidity is a common phenomenon among patients treated in general practices. Key challenges within this group include functional difficulties, polypharmacy, treatment burden, fragmentation of care, reduced quality of life and increased health care utilization. These problems cannot be solved in the short consultation time of a general practitioner (GP) since there is an increasing shortage of GPs. In many countries, advanced practice nurses (APNs) are successfully integrated into primary health care for multimorbid patients. The objective of this study is to examine whether the integration of APNs in the primary care of multimorbid patients in Germany leads to optimized care of the target group and to a reduction in the workload of the GPs. METHODS: The intervention includes the integration of APNs into the care for multimorbid patients in general practice for twelve months. Qualifications for APNs include a master's level academic degree and 500 hours of project-specific training. Their tasks include in-depth assessment, preparation, implementation, monitoring and evaluation of a person-centred and evidence-based care plan. In this nonrandomized controlled trial, a prospective multicentre mixed methods study will be performed. The main inclusion criterion was the cooccurrence of three chronic diseases. For data collection in the intervention group (n = 817), routine data from health insurance companies and association of statutory health insurance physicians (ASHIP) will be used, as well as qualitative interviews. In addition, the intervention will be assessed through documentation of the care process and standardized questionnaires using a longitudinal design. The control group (n = 1634) will receive standard care. For the evaluation, routine data from health insurance companies are matched at a ratio of 1:2. Outcomes will be measured using emergency contacts and GP visits, treatment costs, health status of the patients and the satisfaction of parties involved. The statistical analyses will include Poisson regression to compare outcomes between the intervention and control groups. Descriptive and analytical statistical methods will be used in the longitudinal analysis of the intervention group data. Cost analysis will compare total costs and subgroup costs between the intervention and control groups. Qualitative data will be analysed using content analysis. DISCUSSION: Challenges to this protocol could include the political and strategic environment as well as the planned number of participants. TRIAL REGISTRATION: DRKS00026172 on DRKS.
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Medicina Geral , Qualidade de Vida , Humanos , Multimorbidade , Estudos Prospectivos , Custos de Cuidados de Saúde , Inquéritos e QuestionáriosRESUMO
PURPOSE: Post-operative outcome after total knee arthroplasty (TKA) in the treatment of end-stage osteoarthritis correlates strongly with pre-operative impairment-driven patient treatment goals. However, a clinical tool for measuring patient treatment goals in correlation to impairments is still missing, which impedes patient-oriented indication in TKA. METHODS: Patients scheduled for TKA were recruited in four German hospitals. All patients were handed the INDICATE Knee Score pre-operatively. The score contains 31 treatment goals with respective impairments, subdivided into seven categories. They were asked to rank all treatment goals and impairments on a 3-point scale. Treatment goals and impairments were then checked for frequency of occurrence. Correlation of goal and impairment was tested. Analysis for associations of treatment goals and different cohort characteristics (age, sex, BMI) was conducted. RESULTS: 1.298 patients were included in the study. Seven treatment goals were categorised as "main goal" from more than 90% of all patients ("knee pain", "range of motion", "walking distance", "overall physical function", "climbing stairs", "quality of life", "implant survival"). Comparing age groups, there were significant associations towards higher expectations regarding working, physical and sports related treatment goals in younger patients (< 65y) ("ability to work" (P ≤ .001), "sports activities" (P ≤ .001), "sex life" (P ≤ .001), "dependence on help of others" (P = .015), "preventing secondary impairment" (P = .03), "dependence on walking aids" (P = .005)). Higher BMI resulted in increasing relevance of "weight reduction" (P ≤ .001), "climbing stairs" (P = .039) "global health status" (P = .015) and "long standing" (P = .007) as a "main goal". Analysis for differences in treatment goals regarding sex showed women choosing more treatment goals as "main goals" than men. CONCLUSION: Seven treatment goals which were expected by > 90% in our collective can be classified as general treatment goals for TKA. Demographic factors (age, sex, BMI) were significantly associated with patients' expectations for TKA. We conclude physicians should clearly assess their patients' demands prior to TKA to maximise post-operative outcome. LEVEL OF EVIDENCE: Prognostic Level III.
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Artroplastia do Joelho , Osteoartrite do Joelho , Masculino , Humanos , Feminino , Artroplastia do Joelho/efeitos adversos , Objetivos , Osteoartrite do Joelho/cirurgia , Motivação , Satisfação do Paciente , Nível de Saúde , Resultado do TratamentoRESUMO
PURPOSE: We investigated the association between social inequality and participation in a mammography screening program (MSP). Since the German government offers mammography screening free of charge, any effect of social inequality on participation should be due to educational status and not due to the financial burden. METHODS: The 'Gutenberg Health Study' is a cohort study in the Rhine-Main-region, Germany. A health check-up was performed, and questions about medical history, health behavior, including secondary prevention such as use of mammography, and social status are included. Two indicators of social inequality (equivalence income and educational status), an interaction term of these two, and different covariables were used to explore an association in different logistic regression models. RESULTS: A total of 4,681 women meeting the inclusion criteria were included. Only 6.2% never participated in the MSP. A higher income was associated with higher chances of ever participating in a mammography screening (odds ratios (OR): 1.67 per 1000; 95%CI:1.26-2.25, model 3, adjusted for age, education and an interaction term of income and education). Compared to women with a low educational status, the odds ratios for ever participating in the MSP was lower for the intermediate educational status group (OR = 0.64, 95%CI:0.45-0.91) and for the high educational status group (0.53, 95%CI:0.37-0.76). Results persisted also after controlling for relevant confounders. CONCLUSIONS: Despite the absence of financial barriers for participation in the MSP, socioeconomic inequalities still influence participation. It would be interesting to examine whether the educational effect is due to an informed decision.
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Neoplasias da Mama , Mamografia , Neoplasias da Mama/diagnóstico por imagem , Estudos de Coortes , Estudos Transversais , Detecção Precoce de Câncer , Feminino , Humanos , Programas de Rastreamento , Fatores SocioeconômicosRESUMO
Background and Objectives: Tonsillar infections are a common reason to see a physician and lead to a reduction in the patients' health-related quality of life (HRQoL). HRQoL may be an important criterion in decision science and should be taken into account when deciding when to perform tonsillectomy, especially for chronic tonsillitis. The aim of this study was to determine the health utility for different states of tonsillar infections. Materials and Methods: Hospitalized patients with acute tonsillitis or a peritonsillar abscess were asked about their HRQoL with the 15D questionnaire. Patients who had undergone tonsillectomy were reassessed six months postoperatively. Results: In total, 65 patients participated in the study. The health states of acute tonsillitis and peritonsillar abscess had both a utility of 0.72. Six months after tonsillectomy, the mean health utility was 0.95. Conclusions: Our study confirms a substantial reduction in utility due to tonsillar infections. Tonsillectomy significantly improves the utility and therefore HRQoL six months after surgery.
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Abscesso Peritonsilar , Tonsilectomia , Tonsilite , Humanos , Abscesso Peritonsilar/cirurgia , Qualidade de Vida , Inquéritos e Questionários , Tonsilite/cirurgiaRESUMO
BACKGROUND: In the context of optimized treatment processes for knee and hip replacements, lengths of stay are given for Germany that clearly exceed the internationally published ones. In this context, the present analysis of data from the PROMISE study deals with the relationship between discharge readiness and discharge. METHODS: In the PROMISE study, a jointly developed, optimized standard of care was established in three hospitals of different levels of care and realized for a typical, largely unselected cohort of patients. Among others, data were collected on achievement of discharge criteria (DC) and actual discharge. Univariate comparisons were performed by chi-square tests or the Mann-WhitneyU tests. RESULTS: A total of 1782 patients were included, of whom a mean of 85.3% achieved all previously defined DCs at a mean of 2.4 (median 2) days postoperatively. Discharge for this group occurred after a mean of 5.4 (median 5) days. 14.7% of the participants did not achieve at least one DC. This group was discharged after a mean of 6.5 (median 6) days. Significant differences in outcomes were observed for different subgroups. CONCLUSION: The so-called DCs are used as relative criteria. Achievement generally does not result in timely discharge. If this were to happen, internationally established lengths of stay would also be a reality in Germany. What actually determines discharge from inpatient treatment remains open. A variety of medical, organizational, structural and financial factors could be of importance.
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Artroplastia de Quadril , Artroplastia do Joelho , Artroplastia de Quadril/métodos , Artroplastia do Joelho/métodos , Humanos , Articulação do Joelho , Tempo de Internação , Alta do PacienteRESUMO
CONTEXT: Hypoparathyroidism (hypoPT) is a rare endocrine disorder. Little is known about what factors are associated with potential quality of life (QOL) impairments. DESIGN: HypoPT patients at a minimum of 6 months' post diagnosis were invited to participate in an online survey through their treating physician or through self-help organisations METHODS: Impairments of clinical importance in QOL were considered present if the score of the respective functioning scale of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 exceeded a pre-defined threshold. Symptom burden was assessed using the HPQ-28. Multivariate logistic regression was used to identify factors associated with impairments in QOL. RESULTS: Data were available for 264 hypoPT patients. Impairments of clinical importance in QOL were reported for 40.4% in role functioning (RF), 40.6% in social functioning (SF), 60.8% in physical functioning (PF), 65.5% in cognitive functioning (CF) and 76.0% in emotional functioning (EF). Higher odds for reporting impaired QOL were seen for higher symptom burden (for almost all domains) and for being unable to work (for PF, RF and SF). Surgery for thyroid cancer being the cause of hypoPT was associated with lower odds in PF for patients and in PF and CF for patients with surgery for other thyroid-related diseases being the hypoPT cause. CONCLUSIONS: HypoPT needs to be recognised as a disease which might be associated with impaired QOL and affect daily living. Symptom management is crucial for improving QOL in hypoPT patients but socioeconomic factors like work-ability need to be considered when treating hypoPT patients.
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Hipoparatireoidismo , Neoplasias da Glândula Tireoide , Cognição , Humanos , Hipoparatireoidismo/etiologia , Qualidade de Vida/psicologia , Inquéritos e Questionários , Neoplasias da Glândula Tireoide/complicaçõesRESUMO
PURPOSE: Cancer patients have been shown to frequently suffer from financial burden before, during, and after treatment. However, the financial toxicity of patients with sarcoma has seldom been assessed. Therefore, the aim of this study was to evaluate whether financial toxicity is a problem for sarcoma patients in Germany and identify associated risk factors. METHODS: Patients for this analysis were obtained from a multicenter prospective cohort study conducted in Germany. Using the financial difficulties scale of the EORTC QLQ-C30, financial toxicity was considered to be present if the score exceeded a pre-defined threshold for clinical importance. Comparisons to an age- and sex-matched norm population were performed. A multivariate logistic regression using stepwise backward selection was used to identify factors associated with financial toxicity. RESULTS: We included 1103 sarcoma patients treated in 39 centers and clinics; 498 (44.7%) patients reported financial toxicity. Sarcoma patients had 2.5 times the odds of reporting financial difficulties compared to an age- and sex-matched norm population. Patient age < 40 and > 52.5 years, higher education status, higher income, and disease progression (compared to patients with complete remission) were associated with lower odds of reporting financial toxicity. Receiving a disability pension, being currently on sick leave, and having a disability pass were statistically significantly associated with higher odds of reporting financial toxicity. CONCLUSION: Financial toxicity is present in about half of German sarcoma patients, making it a relevant quality of life topic for patients and decision-makers.
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Estresse Financeiro , Sarcoma , Alemanha/epidemiologia , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Qualidade de Vida , Sarcoma/epidemiologia , Inquéritos e Questionários , SobreviventesRESUMO
OBJECTIVE: Various national and international guidelines for the management of thyroid cancer exist. The aim of this survey was to evaluate whether patients experience differences regarding the management of thyroid cancer in Germany and in France. METHODS: An online survey addressing diagnosis, treatment, aftercare, and information needs of thyroid cancer survivors was set up by the German and the French nationwide thyroid cancer self-help organizations. The survey consisted of up to 70 questions depending on the given answers. Descriptive statistics and univariate comparisons, if appropriate, for comparing thyroid cancer survivors in Germany and France were performed. RESULTS: In total, 1254 thyroid cancer survivors took part in the survey, of whom 1005 were included in the analysis, 618 from Germany and 387 from France. Remarkable differences between the two countries were observed regarding waiting times, diagnostics, surgical complications, radioiodine treatment, and aftercare of the patients. A high disease burden and lack of information regarding the condition and its treatment were reported in both countries. CONCLUSION: This large survey showed that despite various guidelines for the management of thyroid cancer, thyroid cancer survivors' experiences are noticeably different between two big European countries. Lack of information and unmet needs are still tasks to be addressed in order to optimize thyroid cancer care.
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Radioisótopos do Iodo , Neoplasias da Glândula Tireoide , Assistência ao Convalescente , Humanos , Inquéritos e Questionários , Sobreviventes , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/epidemiologia , Neoplasias da Glândula Tireoide/terapiaRESUMO
Background and purpose - Knee and hip replacement are common and increasing procedures, and an optimized care process that could be implemented in different settings would be useful. The PROMISE trial investigates whether a new care process works equally in different German settings and how the results compare with current non-standardized care.Patients and methods - This multi-center prospective mixed-method study includes 2,000 German patients receiving arthritis-related hip or knee endoprostheses. An interdisciplinary and cross-sectoral care process was developed and implemented in 3 German hospitals with different levels of care, and corresponding rehabilitation centers were included to bridge the gap after acute care.Duration and outcome - The PROMISE trial recruited patients between May 2018 and March 2020. Follow-up will end in February 2021. Assessments are performed at: examination on clinical indication, 1 week before surgery, on the day of surgery, at the end of hospitalization, end of the rehabilitation program, and 3 months, 6 months, and 12 months after surgery. Outcomes include patient-reported outcomes, medical examination findings, and routinely collected data regarding the surgery and complications. Guideline-based interviews are conducted with selected patients and care partners. The primary endpoint is the presence of chronic pain at 12 months after surgery. Secondary endpoints are the number of recognized pre-existing conditions, physical activity at 12 months after surgery, use of medical services, quality of life, and interactions between care partners.Trial registration - The trial is registered with the German Clinical Trials Register (https://www.drks.de; DRKS00013972; March 23, 2018).
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Artroplastia de Quadril , Artroplastia do Joelho , Equipe de Assistência ao Paciente , Próteses e Implantes , Avaliação da Deficiência , Alemanha , Humanos , Medição da Dor , Estudos Prospectivos , Qualidade de Vida , Inquéritos e Questionários , Resultado do TratamentoRESUMO
The disease and treatment of patients with head and neck cancer can lead to multiple late and long-term sequelae. Especially pain, psychosocial problems, and voice issues can have a high impact on patients' health-related quality of life. The aim was to show the feasibility of implementing an electronic Patient-Reported Outcome Measure (PROM) in patients with head and neck cancer (HNC). Driven by our department's intention to assess Patient-Reported Outcomes (PRO) based on the International Classification of Functioning during tumor aftercare, the program "OncoFunction" has been implemented and continuously refined in everyday practice. The new version of "OncoFunction" was evaluated by 20 head and neck surgeons and radiation oncologists in an interview. From 7/2013 until 7/2017, 846 patients completed the PROM during 2,833 of 3,610 total visits (78.5%). The latest software version implemented newly developed add-ins and increased the already high approval ratings in the evaluation as the number of errors and the time required decreased (6 vs. 0 errors, 1.35 vs. 0.95 min; p<0.01). Notably, patients had different requests using PRO in homecare use. An additional examination shows that only 59% of HNC patients use the world wide web. Using OncoFunction for online-recording and interpretation of PROM improved data acquisition in daily HNC patients' follow-up. An accessory timeline grants access to former consultations and their visualization supported and simplified structured examinations. This provides an easy-to-use representation of the patient's functional outcome supporting comprehensive aftercare, considering all aspects of the patient's life.
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PURPOSE: Surgical complications such as hypoparathyroidism (HPT) or vocal cord palsy are seldom assessed when the quality of life (QOL) in thyroid cancer patients is investigated. The aim of this study was to measure the QOL difference in thyroid cancer survivors with and without HPT. METHODS: Participants for this analysis were enrolled in 13 countries from a study that pilot-tested a thyroid cancer-specific QOL instrument. They were included if they had been diagnosed with thyroid cancer at least 9 months previously. QOL was measured using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core (EORTC QLQ-C30) and some items on HPT symptoms (eg, tingling in fingers or toes). HPT status and other clinical data were extracted from the patients' medical charts. Comparisons of QOL domains between patients with and without HPT were performed using Mann-Whitney U test. The occurrence of HPT-related symptoms was compared using chi-square tests. Multiple ordinal regression analysis was performed to evaluate factors that might affect QOL. RESULTS: Eighty-nine patients participated in this study, 17 of whom were considered to have HPT. Patients in the HPT group reported significantly reduced QOL in 9 of the 15 scales of the EORTC QLQ-C30 compared to patients without HPT. Regression analysis showed that HPT was independently negatively associated with various scales of the QLQ-C30. Both groups showed a high prevalence of typical HPT symptoms. CONCLUSION: Thyroid cancer patients with HPT report significantly impaired QOL compared to thyroid cancer survivors without HPT. The assessment of HPT should be considered when measuring QOL in thyroid cancer patients.
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Sobreviventes de Câncer , Hipoparatireoidismo , Complicações Pós-Operatórias , Qualidade de Vida , Neoplasias da Glândula Tireoide/cirurgia , Adulto , Idoso , Sobreviventes de Câncer/psicologia , Sobreviventes de Câncer/estatística & dados numéricos , Estudos Transversais , Feminino , Nível de Saúde , Humanos , Hipoparatireoidismo/epidemiologia , Hipoparatireoidismo/etiologia , Hipoparatireoidismo/psicologia , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/psicologia , Inquéritos e Questionários , Neoplasias da Glândula Tireoide/epidemiologiaRESUMO
PURPOSE: Patients with thyroid cancer are often assumed to have no quality of life (QOL) impairments after treatment because of thyroid cancer's good prognosis. However, the QOL implications of surgical complications and the necessity to take lifelong medication are seldom assessed. METHODS: Patients who had surgery due to thyroid cancer at the University Medical Center Mainz between 2010 and 2015 and who had calcium or parathyroid hormone levels below the reference values immediately following surgery were eligible for this study. QOL was assessed using the EORTC QLQ-C30 and the thyroid cancer module EORTC QLQ-THY34. Multiple logistic regression was used to determine factors associated with a worse QOL compared with a general population. RESULTS: A total of 75 (56%) of 134 eligible patients participated in the study. Patients with persistent/prolonged calcium or vitamin D intake reported worse QOL in the domains of global health, physical functioning, role functioning, emotional functioning, and insomnia than patients without current intake. Current calcium and vitamin D intake, higher education, living with a partner, and age had an effect on the odds of having worse QOL than the age- and sex-adjusted general population. CONCLUSION: Prolonged calcium and/or vitamin D intake are negatively associated with certain domains of QOL in thyroid cancer patients who are at least 1 year post surgery. Assessment of calcium and vitamin D and diagnosis of hypoparathyroidism are therefore important for the follow-up of thyroid cancer survivors since it may affect their QOL.
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Cálcio/administração & dosagem , Sobreviventes de Câncer , Hipoparatireoidismo/tratamento farmacológico , Qualidade de Vida , Neoplasias da Glândula Tireoide/cirurgia , Vitamina D/administração & dosagem , Adulto , Idoso , Feminino , Seguimentos , Nível de Saúde , Humanos , Hipoparatireoidismo/etiologia , Masculino , Pessoa de Meia-Idade , Neoplasias da Glândula Tireoide/complicações , Neoplasias da Glândula Tireoide/tratamento farmacológicoRESUMO
PURPOSE: The number of total hip (THA) and knee arthroplasties (TKA) grows constantly which causes enormously rising costs for healthcare systems. The aim of this systematic literature review was to evaluate whether a cost reduction can be achieved by THA or TKA fast-track protocols, which is a multidisciplinary approach aiming at faster recovery. METHODS: A systematic literature research was undertaken for the timeframe from 2007/01/01 to 2019/03/04 in PubMed. Abstracts and title of the identified records were checked for eligible criteria and afterward the full text was assessed. RESULTS: Seven studies were included in the review. All studies showed a reduction in the total cost for fast-track THA and TKA. Most studies based their cost calculations on the amount of days the patients spend in the hospital. CONCLUSION: Using a fast-track protocol can significantly reduce the overall costs of the treatment.
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Artroplastia de Quadril/economia , Artroplastia de Quadril/métodos , Artroplastia do Joelho/economia , Artroplastia do Joelho/métodos , Custos de Cuidados de Saúde , Tempo de Internação/economia , Idoso , Artroplastia de Quadril/efeitos adversos , Artroplastia do Joelho/efeitos adversos , Redução de Custos , Análise Custo-Benefício , Feminino , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite do Quadril/diagnóstico por imagem , Osteoartrite do Quadril/cirurgia , Osteoartrite do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/cirurgia , Complicações Pós-Operatórias/economia , Complicações Pós-Operatórias/fisiopatologia , Complicações Pós-Operatórias/cirurgiaRESUMO
PURPOSE: Cancer patients in Germany often face payments related to their disease or treatment which are not covered by their health insurance. The aim of this study was to analyze the amount of out-of-pocket payments (OOPPs) among cancer patients in Germany, to explore potential socioeconomic determinants of OOPPs, and to identify how cancer patients are burdened by these payments. METHODS: Cancer ptients were consecutively enrolled in 16 clinics in Leipzig, Germany. Data on OOPPs for the past 3 months and on socioeconomic status were obtained at the end of their hospital stay (t0) and 3 (t1) and 15 months (t2) after t0. Financial burden was calculated by dividing the monthly OOPPs by the midpoint of the income category, and the perceived burden was assessed by using the financial difficulties scale of the EORTC QLQ-C30. A two-part regression model was used to estimate the determinants of OOPPs. RESULTS: At baseline (t0), 502 cancer patients participated in the study and provided data on OOPPs and socioeconomic status. The mean 3-month OOPPs were the following: 205.8 at baseline, 179.2 at t1, and 148.1 at t2. Compared to the lowest income group (< 500 monthly), all other income groups (500-999, 1000-1499, and ≥ 1500) had higher 3-month OOPPs of 52.3 (p = 0.241), 90.2 (p = 0.059), or 62.2 (p = 0.176). Financial burden at t0 was 6.4% (SD 9.2%) on average, 5.4% (SD 9.9%) at t1, and to 3.9% (SD 7.0%) of monthly income at t2. CONCLUSION: German cancer patients face relatively high OOPPs during their cancer journey. These payments may burden cancer patients, especially certain subgroups like low-income groups.
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Gastos em Saúde/tendências , Seguro Saúde/economia , Neoplasias/economia , Adulto , Feminino , Alemanha , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Neoplasias/terapia , Adulto JovemRESUMO
OPINION STATEMENT: Quality of life measurements are well established in cancer clinical trials. In daily clinical practice, where cancer patients often suffer from disease-specific symptoms and report unmet needs regarding their treatment, these measurements are not systematically implemented. The systematic (often computer-based) assessment of quality of life in daily cancer care has shown to be beneficial for patient-physician communication, symptom management, shared decision-making, and in creating a learning health system. Unfortunately, to date, routine electronic quality of life assessments are usually limited to large cancer facilities. Patient and physician barriers as well as barriers from the administrative side in particular are currently hindering the implementation of these systems into the broad spectrum of clinical cancer care. Cost-effectiveness analyses of existing systems, the inclusion of all relevant stakeholders, and clear implementation guidelines are required to introduce quality of life measurements in clinical cancer practice to improve the treatment of cancer survivors and to create a health care system that addresses all their disease-related needs.
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Neoplasias/epidemiologia , Avaliação de Processos e Resultados em Cuidados de Saúde , Qualidade de Vida , Humanos , Avaliação de Processos e Resultados em Cuidados de Saúde/métodos , Medidas de Resultados Relatados pelo Paciente , Padrões de Prática Médica , Qualidade da Assistência à SaúdeRESUMO
AG-045572 (CMPD1, 1 a) is a nonpeptidic gonadotropin-releasing hormone (GnRH) antagonist that has been investigated for the treatment of sex hormone-related diseases. In the context of systematic studies on sila-substituted drugs, the silicon analogue disila-AG-045572 (1 b) and its derivative 2 were prepared in multi-step syntheses and characterized by elemental analyses (C, H, N), NMR spectroscopic studies (1H, 13C, 29Si), and single-crystal X-ray diffraction. The pharmacological properties of compounds 1 a, 1 b, and 2 were compared in terms of their in vitro potency at cloned human and rat GnRH receptors. Compounds 1 a and 2 were also examined in regard to their pharmacokinetics and in vivo efficacy in both castrated rat (luteinizing hormone (LH) suppression) and intact rat (testosterone suppression) models. The efficacy and pharmacokinetic profiles of 1 a and its silicon-containing analogue 2 appear similar, indicating that replacement of the 5,6,7,8-tetrahydronaphthalene ring system by the 1,3-disilaindane skeleton led to retention of efficacy. Therefore, the silicon compound 2 represents a novel drug prototype for the design of potent, orally available GnRH antagonists suitable for once-daily dosing.
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Furanos/química , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Antagonistas de Hormônios/química , Antagonistas de Hormônios/farmacologia , Tetra-Hidronaftalenos/química , Animais , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Furanos/farmacologia , Antagonistas de Hormônios/farmacocinética , Humanos , Hormônio Luteinizante/antagonistas & inibidores , Espectroscopia de Ressonância Magnética , Masculino , Estrutura Molecular , Orquiectomia , Ratos Wistar , Receptores LHRH/genética , Silício/química , Relação Estrutura-Atividade , Tetra-Hidronaftalenos/farmacologiaAssuntos
Antineoplásicos/química , Benzoatos/química , Compostos de Organossilício/síntese química , Ácidos Ftálicos/síntese química , Receptores do Ácido Retinoico/agonistas , Silício/química , Tetra-Hidronaftalenos/química , Antineoplásicos/farmacologia , Benzoatos/farmacologia , Células HeLa , Humanos , Compostos de Organossilício/química , Compostos de Organossilício/farmacologia , Ácidos Ftálicos/química , Ácidos Ftálicos/farmacologia , Receptores do Ácido Retinoico/metabolismo , Receptor alfa de Ácido Retinoico , Tetra-Hidronaftalenos/farmacologiaRESUMO
Twofold sila-substitution (C/Si exchange) in the saturated ring of the tetrahydronaphthalene skeleton of the retinoid agonists TTNPB (1 a) and 3-methyl-TTNPB (2 a) leads to disila-TTNPB (1 b) and disila-3-methyl-TTNPB (2 b), respectively. The silicon compounds 1 b and 2 b were synthesized in multiple steps, and their identities were established by elemental analyses, multinuclear NMR experiments, and single-crystal X-ray diffraction studies. Like TTNPB (1 a) and 3-methyl-TTNPB (2 a), the analogous silicon-based arotinoids 1 b and 2 b are strong pan-RAR agonists and display the same strong differentiation and apoptosis-inducing activity in NB4 promyelocytic leukemia cells as the parent carbon compounds. These results are in keeping with the nearly isomorphous structures of 1 a and 1 b bound to the complex of the RARbeta ligand-binding domain with the nuclear receptor (NR) box 2 peptide of the SRC-1 coactivator. The contacts within the ligand-binding pocket are identical except for helix H11, for which two turns are shifted in the disila-TTNPB (1 b) complex. This study represents the first comprehensive structure-function analysis of a carbon/silicon switch in a signaling molecule and demonstrates that silicon analogues can have the same biological functionalities and conserved structures as their parent carbon compounds, and it illustrates at the same time that silicon analogues of biologically active compounds have the potential to induce alternative allosteric effects, as in the case of helix H11, which might allow for novel options in drug design.