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Background: Estimation of glomerular filtration rate using equations based on creatinine is widely used to manage chronic kidney disease. In the UK, the Chronic Kidney Disease Epidemiology Collaboration creatinine equation is recommended. Other published equations using cystatin C, an alternative marker of kidney function, have not gained widespread clinical acceptance. Given higher cost of cystatin C, its clinical utility should be validated before widespread introduction into the NHS. Objectives: Primary objectives were to: (1) compare accuracy of glomerular filtration rate equations at baseline and longitudinally in people with stage 3 chronic kidney disease, and test whether accuracy is affected by ethnicity, diabetes, albuminuria and other characteristics; (2) establish the reference change value for significant glomerular filtration rate changes; (3) model disease progression; and (4) explore comparative cost-effectiveness of kidney disease monitoring strategies. Design: A longitudinal, prospective study was designed to: (1) assess accuracy of glomerular filtration rate equations at baseline (nâ =â 1167) and their ability to detect change over 3 years (nâ =â 875); (2) model disease progression predictors in 278 individuals who received additional measurements; (3) quantify glomerular filtration rate variability components (nâ =â 20); and (4) develop a measurement model analysis to compare different monitoring strategy costs (nâ =â 875). Setting: Primary, secondary and tertiary care. Participants: Adults (≥ 18 years) with stage 3 chronic kidney disease. Interventions: Estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration and Modification of Diet in Renal Disease equations. Main outcome measures: Measured glomerular filtration rate was the reference against which estimating equations were compared with accuracy being expressed as P30 (percentage of values within 30% of reference) and progression (variously defined) studied as sensitivity/specificity. A regression model of disease progression was developed and differences for risk factors estimated. Biological variation components were measured and the reference change value calculated. Comparative costs of monitoring with different estimating equations modelled over 10 years were calculated. Results: Accuracy (P30) of all equations was ≥ 89.5%: the combined creatinine-cystatin equation (94.9%) was superior (pâ <â 0.001) to other equations. Within each equation, no differences in P30 were seen across categories of age, gender, diabetes, albuminuria, body mass index, kidney function level and ethnicity. All equations showed poor (< 63%) sensitivity for detecting patients showing kidney function decline crossing clinically significant thresholds (e.g. a 25% decline in function). Consequently, the additional cost of monitoring kidney function annually using a cystatin C-based equation could not be justified (incremental cost per patient over 10 yearsâ =â £43.32). Modelling data showed association between higher albuminuria and faster decline in measured and creatinine-estimated glomerular filtration rate. Reference change values for measured glomerular filtration rate (%, positive/negative) were 21.5/-17.7, with lower reference change values for estimated glomerular filtration rate. Limitations: Recruitment of people from South Asian and African-Caribbean backgrounds was below the study target. Future work: Prospective studies of the value of cystatin C as a risk marker in chronic kidney disease should be undertaken. Conclusions: Inclusion of cystatin C in glomerular filtration rate-estimating equations marginally improved accuracy but not detection of disease progression. Our data do not support cystatin C use for monitoring of glomerular filtration rate in stage 3 chronic kidney disease. Trial registration: This trial is registered as ISRCTN42955626. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 11/103/01) and is published in full in Health Technology Assessment; Vol. 28, No. 35. See the NIHR Funding and Awards website for further award information.
Chronic kidney disease, which affects approximately 14% of the adult population, often has no symptoms but, in some people, may later develop into kidney failure. Kidney disease is most often detected using a blood test called creatinine. Creatinine does not identify everyone with kidney disease, or those most likely to develop more serious kidney disease. An alternative blood test called cystatin C may be more accurate, but it is more expensive than the creatinine test. We compared the accuracy of these two tests in more than 1000 people with moderate kidney disease. Participants were tested over 3 years to see if the tests differed in their ability to detect worsening kidney function. We also wanted to identify risk factors associated with loss of kidney function, and how much the tests normally vary to better understand what results mean. We compared the accuracy and costs of monitoring people with the two markers. Cystatin C was found slightly more accurate than the creatinine test at estimating kidney function when comparing the baseline single measurements (95% accurate compared to 90%), but not at detecting worsening function over time. This means that the additional cost of monitoring people over time with cystatin C to detect kidney disease progression could not be justified. Kidney test results could vary by up to 20% between tests without necessarily implying changes in underlying kidney function this is the normal level of individual variation. Cystatin C marginally improved accuracy of kidney function testing but not ability to detect worsening kidney function. Cystatin C improves identification of moderate chronic kidney disease, but our results do not support its use for routine monitoring of kidney function in such patients.
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Creatinina , Cistatina C , Progressão da Doença , Taxa de Filtração Glomerular , Insuficiência Renal Crônica , Humanos , Cistatina C/sangue , Creatinina/sangue , Masculino , Feminino , Insuficiência Renal Crônica/fisiopatologia , Pessoa de Meia-Idade , Idoso , Estudos Prospectivos , Estudos Longitudinais , Biomarcadores , Análise Custo-Benefício , Adulto , Reino Unido , AlbuminúriaRESUMO
Innovative models of medical and psychiatric care are necessary to address the complex needs of individuals with intellectual and developmental disabilities (IDD), including autism. This article describes a subspecialty medical home program that has provided accessible, comprehensive, coordinated, patient- and family-centered care for this high-needs, underserved patient population. For more than two decades, the University of Utah Huntsman Mental Health Institute Neurobehavior HOME Program (HOME) has provided primary and behavioral health care for individuals with IDD across their lifespan. Program highlights include integrated medical and behavioral health, a unique funding structure, innovative care delivery, and case management. HOME is a clinical setting as well as a Medicaid managed care plan that has blended medical and psychiatric funding streams. This unique funding structure has demonstrated the fiscal sustainability of focusing care on preventive and proactive management of health concerns and responding to crises using a coordinated and comprehensive approach. Rethinking health care delivery and adopting models that are both financially sustainable and provide quality care to this vulnerable population is greatly needed.
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The Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease (CKD) updates the KDIGO 2012 guideline and has been developed with patient partners, clinicians, and researchers around the world, using robust methodology. This update, based on a substantially broader base of evidence than has previously been available, reflects an exciting time in nephrology. New therapies and strategies have been tested in large and diverse populations that help to inform care; however, this guideline is not intended for people receiving dialysis nor those who have a kidney transplant. The document is sensitive to international considerations, CKD across the lifespan, and discusses special considerations in implementation. The scope includes chapters dedicated to the evaluation and risk assessment of people with CKD, management to delay CKD progression and its complications, medication management and drug stewardship in CKD, and optimal models of CKD care. Treatment approaches and actionable guideline recommendations are based on systematic reviews of relevant studies and appraisal of the quality of the evidence and the strength of recommendations which followed the "Grading of Recommendations Assessment, Development, and Evaluation" (GRADE) approach. The limitations of the evidence are discussed. The guideline also provides practice points, which serve to direct clinical care or activities for which a systematic review was not conducted, and it includes useful infographics and describes an important research agenda for the future. It targets a broad audience of people with CKD and their healthcare, while being mindful of implications for policy and payment.
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Transplante de Rim , Nefrologia , Insuficiência Renal Crônica , Humanos , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/terapia , Insuficiência Renal Crônica/complicações , Transplante de Rim/efeitos adversos , Diálise Renal/efeitos adversosRESUMO
Targeted protein degraders (TPDs), specifically the bifunctional protein degraders discussed in this manuscript, consist of two linked ligands for a protein of interest and an E3 ligase, resulting in molecules that largely violate accepted physicochemical limits (e.g., Lipinski's Rule of Five) for oral bioavailability. In 2021, the IQ Consortium Degrader DMPK/ADME Working Group undertook a survey of 18 IQ member and nonmember companies working on degraders to understand whether the characterization and optimization of these molecules were different from any other beyond the Rule of Five (bRo5) compounds. Additionally, the working group sought to identify pharmacokinetic (PK)/absorption, distribution, metabolism, and excretion (ADME) areas in need of further evaluation and where additional tools could aid in more rapid advancement of TPDs to patients. The survey revealed that although TPDs reside in a challenging bRo5 physicochemical space, most respondents focus their efforts on oral delivery. Physicochemical properties required for oral bioavailability were generally consistent across the companies surveyed. Many of the member companies used modified assays to address challenging degrader properties (e.g., solubility, nonspecific binding), but only half indicated that they modified their drug discovery workflows. The survey also suggested the need for further scientific investigation in the areas of central nervous system penetration, active transport, renal elimination, lymphatic absorption, in silico/machine learning, and human pharmacokinetic prediction. Based on the survey results, the Degrader DMPK/ADME Working Group concluded that TPD evaluation does not fundamentally differ from other bRo5 compounds but requires some modification compared with traditional small molecules and proposes a generic workflow for PK/ADME evaluation of bifunctional TPDs. SIGNIFICANCE STATEMENT: Based on an industry survey, this article provides an understanding of the current state of absorption, distribution, metabolism, and excretion science pertaining to characterizing and optimizing targeted protein degraders, specifically bifunctional protein degraders, based upon responses by 18 IQ consortium members and non-members developing targeted protein degraders. Additionally, this article puts into context the differences / similarities in methods and strategies utilized for heterobifunctional protein degraders compared to other beyond Rule of Five molecules and conventional small molecule drugs.
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Descoberta de Drogas , Ubiquitina-Proteína Ligases , Humanos , Disponibilidade Biológica , SolubilidadeRESUMO
BACKGROUND: Chronic kidney disease (CKD) is a very common long-term condition and powerful risk factor for cardiovascular disease (CVD). Low-dose aspirin is of proven benefit in the secondary prevention of myocardial infarction (MI) and stroke in people with pre-existing CVD. However, in people without CVD, the rates of MI and stroke are much lower, and the benefits of aspirin in the primary prevention of CVD are largely balanced by an increased risk of bleeding. People with CKD are at greatly increased risk of CVD and so the absolute benefits of aspirin are likely to be greater than in lower-risk groups, even if the relative benefits are the same. Post hoc evidence suggests the relative benefits may be greater in the CKD population but the risk of bleeding may also be higher. A definitive study of aspirin for primary prevention in this high-risk group, recommended by the National Institute for Health and Care Excellence (NICE) in 2014, has never been conducted. The question has global significance given the rising burden of CKD worldwide and the low cost of aspirin. METHODS: ATTACK is a pragmatic multicentre, prospective, randomised, open-label, blinded endpoint adjudication superiority trial of aspirin 75 mg daily vs. standard care for the primary prevention of CVD in 25,210 people aged 18 years and over with CKD recruited from UK Primary Care. Participants aged 18 years and over with CKD (GFR category G1-G4) will be identified in Primary Care and followed up using routinely collected data and annual questionnaires for an average of 5 years. The primary outcome is the time to first major vascular event (composite of non-fatal MI, non-fatal stroke and cardiovascular death [excluding confirmed intracranial haemorrhage and other fatal cardiovascular haemorrhage]). Deaths from other causes (including fatal bleeding) will be treated as competing events. The study will continue until 1827 major vascular events have occurred. The principal safety outcome is major intracranial and extracranial bleeding; this is hypothesised to be increased in those randomised to take aspirin. The key consideration is then whether and to what extent the benefits of aspirin from the expected reduction in CVD events exceed the risks of major bleeding. DISCUSSION: This will be the first definitive trial of aspirin for primary CVD prevention in CKD patients. The research will be of great interest to clinicians, guideline groups and policy-makers, in the UK and globally, particularly given the high and rising prevalence of CKD that is driven by population ageing and epidemics of obesity and diabetes. The low cost of aspirin means that a positive result would be of relevance to low- and middle-income countries and the impact in the developed world less diluted by any inequalities in health care access. TRIAL REGISTRATION: ISRCTN: ISRCTN40920200 . EudraCT: 2018-000644-26 . CLINICALTRIALS: gov: NCT03796156.
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Doenças Cardiovasculares , Infarto do Miocárdio , Insuficiência Renal Crônica , Acidente Vascular Cerebral , Adolescente , Adulto , Aspirina/efeitos adversos , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/prevenção & controle , Feminino , Hemorragia/induzido quimicamente , Hemorragia/tratamento farmacológico , Humanos , Masculino , Estudos Multicêntricos como Assunto , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/prevenção & controle , Inibidores da Agregação Plaquetária/efeitos adversos , Prevenção Primária/métodos , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/diagnóstico , Acidente Vascular Cerebral/tratamento farmacológicoRESUMO
Receptor-interacting serine/threonine protein kinase 2 (RIPK2) is an important kinase of the innate immune system. Herein, we describe the optimization of a series of RIPK2 PROTACs which recruit members of the inhibitor of apoptosis (IAP) family of E3 ligases. Our PROTAC optimization strategy focused on reducing the lipophilicity of the early lead which resulted in the identification of analogues with improved solubility and increased human and rat microsomal stability. We identified a range of IAP binders that were successfully incorporated into potent RIPK2 PROTACs with attractive pharmacokinetic profiles. Compound 20 possessed the best overall profile with good solubility, potent degradation of RIPK2, and associated inhibition of TNFα release. A proof-of-concept study utilizing a slow release matrix demonstrated the feasibility of a long-acting parenteral formulation with >1 month duration. This represents an attractive alternative dosing paradigm to oral delivery, especially for chronic diseases where compliance can be challenging.
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Proteína Serina-Treonina Quinase 2 de Interação com Receptor/metabolismo , Animais , Desenho de Fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Meia-Vida , Humanos , Masculino , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/genética , Células THP-1RESUMO
Focal adhesion kinase (FAK) is a key mediator of tumour progression and metastasis. To date, clinical trials of FAK inhibitors have reported disappointing efficacy for oncology indications. We report the design and characterisation of GSK215, a potent, selective, FAK-degrading Proteolysis Targeting Chimera (PROTAC) based on a binder for the VHL E3 ligase and the known FAK inhibitor VS-4718. X-ray crystallography revealed the molecular basis of the highly cooperative FAK-GSK215-VHL ternary complex, and GSK215 showed differentiated in-vitro pharmacology compared to VS-4718. In mice, a single dose of GSK215 induced rapid and prolonged FAK degradation, giving a long-lasting effect on FAK levels (≈96â h) and a marked PK/PD disconnect. This tool PROTAC molecule is expected to be useful for the study of FAK-degradation biology inâ vivo, and our results indicate that FAK degradation may be a differentiated clinical strategy versus FAK inhibition for the treatment of cancer.
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Antineoplásicos/farmacologia , Quinase 1 de Adesão Focal/antagonistas & inibidores , Proteólise/efeitos dos fármacos , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Benzamidas/química , Benzamidas/farmacocinética , Benzamidas/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Dipeptídeos/química , Dipeptídeos/farmacocinética , Dipeptídeos/farmacologia , Quinase 1 de Adesão Focal/metabolismo , Humanos , Camundongos , Estrutura Molecular , Ubiquitina-Proteína Ligases/metabolismoRESUMO
B-cell lymphoma 6 (BCL6) is a zinc finger transcriptional repressor possessing a BTB-POZ (BR-C, ttk, and bab for BTB; pox virus and zinc finger for POZ) domain, which is required for homodimerization and association with corepressors. BCL6 has multiple roles in normal immunity, autoimmunity, and some types of lymphoma. Mice bearing disrupted BCL6 loci demonstrate suppressed high-affinity antibody responses to T-dependent antigens. The corepressor binding groove in the BTB-POZ domain is a potential target for small compound-mediated therapy. Several inhibitors targeting this binding groove have been described, but these compounds have limited or absent in vivo activity. Biophysical studies of a novel compound, GSK137, showed an in vitro pIC50 of 8 and a cellular pIC50 of 7.3 for blocking binding of a peptide derived from the corepressor silencing mediator for retinoid or thyroid hormone receptors to the BCL6 BTB-POZ domain. The compound has good solubility (128 µg/ml) and permeability (86 nM/s). GSK137 caused little change in cell viability or proliferation in four BCL6-expressing B-cell lymphoma lines, although there was modest dose-dependent accumulation of G1 phase cells. Pharmacokinetic studies in mice showed a profile compatible with achieving good levels of target engagement. GSK137, administered orally, suppressed immunoglobulin G responses and reduced numbers of germinal centers and germinal center B cells following immunization of mice with the hapten trinitrophenol. Overall, we report a novel small-molecule BCL6 inhibitor with in vivo activity that inhibits the T-dependent antigen immune response.
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Proteínas Proto-Oncogênicas c-bcl-6 , Animais , Linfócitos B/metabolismo , Humanos , Camundongos , Transcrição Gênica , Dedos de ZincoRESUMO
Kidney disease is an important public health problem. Both acute kidney injury (AKI) and chronic kidney disease have been well defined and classified, leading to improved research efforts and subsequent management strategies and recommendations. For those patients with abnormalities in kidney function and/or structure who meet neither the definition of AKI nor chronic kidney disease, there remains a gap in research, care, and guidance. The term acute kidney diseases and disorders, abbreviated to acute kidney disease (AKD), has been introduced as an important construct to address this. To expand and harmonize existing definitions and to ultimately better inform research and clinical care, Kidney Disease: Improving Global Outcomes (KDIGO) organized a consensus workshop. Multiple invitees from around the globe, representing both acute and chronic kidney disease researchers and experts, met virtually to examine existing data, and discuss key concepts related to AKD. Despite some remaining unresolved questions, conference attendees reached general consensus on the definition and classification of AKD, management strategies, and research priorities. AKD is defined by abnormalities of kidney function and/or structure with implications for health and with a duration of ≤3 months. AKD may include AKI, but, more importantly, also includes abnormalities in kidney function that are not as severe as AKI or that develop over a period of >7 days. The cause(s) of AKD should be sought, and classification includes functional and structural parameters. Management of AKD is currently based on empirical considerations. A robust research agenda to enable refinement and validation of definitions and classification systems, and thus testing of interventions and strategies, is proposed.
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Injúria Renal Aguda , Insuficiência Renal Crônica , Doença Aguda , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/epidemiologia , Injúria Renal Aguda/terapia , Consenso , Humanos , Rim , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/terapiaRESUMO
Reducing the required frequence of drug dosing can improve the adherence of patients to chronic treatments. Hence, drugs with longer in vivo half-lives are highly desirable. One of the most promising approaches to extend the in vivo half-life of drugs is conjugation to human serum albumin (HSA). In this work, we describe the use of AlbuBinder 1, a small-molecule noncovalent HSA binder, to extend the in vivo half-life and pharmacology of small-molecule BMP1/TLL inhibitors in humanized mice (HSA KI/KI). A series of conjugates of AlbuBinder 1 with BMP1/TLL inhibitors were prepared. In particular, conjugate c showed good solubility and a half-life extension of >20-fold versus the parent molecule in the HSA KI/KI mice, reaching half-lives of >48 h with maintained maximal inhibition of plasma BMP1/TLL. The same conjugate showed a half-life of only 3 h in the wild-type mice, suggesting that the half-life extension was principally due to specific interactions with HSA. It is envisioned that conjugation to AlbuBinder 1 should be applicable to a wide range of small molecule or peptide drugs with short half-lives. In this context, AlbuBinders represent a viable alternative to existing half-life extension technologies.
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Metaloproteases/metabolismo , Inibidores de Proteases/farmacologia , Albumina Sérica Humana/metabolismo , Bibliotecas de Moléculas Pequenas/metabolismo , Animais , Proteína Morfogenética Óssea 1/metabolismo , Meia-Vida , Humanos , Camundongos , Estudo de Prova de Conceito , Inibidores de Proteases/farmacocinéticaRESUMO
Assessment of kidney function in oncology patients is a fundamental factor in profiling the survival risk, determining the appropriate dose of chemotherapeutic drugs, and defining a patient eligibility for clinical trials with novel agents. Both overestimation and underestimation of kidney function may affect the treatment efficacy and outcomes. Overestimation may lead to overdosing or inappropriate agent selection and the corresponding toxicity, whereas underestimation may be responsible for underdosing or inappropriate agent exclusion and subsequent treatment failure. This is of utmost importance in patients with cancer. Evaluation of kidney function is not only limited to the estimation of glomerular filtration rate or creatinine clearance. An accurate assessment of kidney function is advisable to reduce variability in decision making and ultimately the therapeutic outcomes of toxicity and clinical benefit. Therefore, additional studies are needed to investigate the validity of currently used formulas estimating kidney function in this population as well as their applicability to traditional chemotherapy, novel targeted therapies, and immunotherapies. Because of rapid discovery and development of new cancer agents, a reliable and comprehensive manner to screen for potential nephrotoxicity is critically important. As kidney function not only is limited to glomerular filtration rate changes but also involves tubular and even vascular dysfunction, urinalysis and kidney imaging studies should also be considered before therapeutic decisions are taken. However, several questions remain regarding these new technologies such as kidney-on-a-chip systems for the assessment of kidney function and injury, particularly in oncology, and it has yet to be implemented in clinical practice.
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Rim , Neoplasias , Creatinina , Taxa de Filtração Glomerular , Humanos , Testes de Função Renal , Neoplasias/tratamento farmacológicoRESUMO
Proteolysis-Targeting Chimeras (PROTACs) are heterobifunctional small-molecules that can promote the rapid and selective proteasome-mediated degradation of intracellular proteins through the recruitment of E3 ligase complexes to non-native protein substrates. The catalytic mechanism of action of PROTACs represents an exciting new modality in drug discovery that offers several potential advantages over traditional small-molecule inhibitors, including the potential to deliver pharmacodynamic (PD) efficacy which extends beyond the detectable pharmacokinetic (PK) presence of the PROTAC, driven by the synthesis rate of the protein. Herein we report the identification and development of PROTACs that selectively degrade Receptor-Interacting Serine/Threonine Protein Kinase 2 (RIPK2) and demonstrate in vivo degradation of endogenous RIPK2 in rats at low doses and extended PD that persists in the absence of detectable compound. This disconnect between PK and PD, when coupled with low nanomolar potency, offers the potential for low human doses and infrequent dosing regimens with PROTAC medicines.
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Anti-Inflamatórios/farmacologia , Desenho de Fármacos , Inflamação/prevenção & controle , Leucócitos Mononucleares/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacocinética , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/enzimologia , Doença de Crohn/tratamento farmacológico , Doença de Crohn/enzimologia , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Estabilidade Enzimática , Feminino , Humanos , Inflamação/enzimologia , Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Injeções Intravenosas , Leucócitos Mononucleares/enzimologia , Masculino , Proteólise , Ratos Sprague-Dawley , Ratos Wistar , Células THP-1 , Técnicas de Cultura de Tecidos , UbiquitinaçãoRESUMO
BACKGROUND: Health care costs and utilization for those with an intellectual or developmental disability (IDD) have been shown to be higher than the general population. OBJECTIVE: To investigate the services that contribute to higher costs and utilization among noninstitutionalized children with an IDD. DESIGN: Matched case-control secondary analysis of the 2000-2017 Medical Expenditure Panel Survey. Pediatric (age 0-21) patients with an IDD were matched to non-IDD subjects. Health care utilization and costs were evaluated with zero-inflated negative binomial regressions and generalized linear models, respectively. MEASURES: Outcome measures included high-acuity health care utilization [ie, emergency department (ED) visits and hospital admissions], and cost outcomes for total spending, ED use, hospitalization, medications, office visits, home health, and physical therapy. RESULTS: There was no statistical difference in utilization of EDs among the 2 groups though subjects with an IDD showed more hospitalizations than their matched cohort (incidence rate ratios=1.63, P=0.00). Total health care spending was higher among patients with an IDD (coefficient=$5831, P=0.00). Pediatric spending was higher in all measures except for ED. The biggest discrepancies in spending were seen in home health (coefficient=$2558, P=0.00) and outpatient visits (coefficient=$1180, P=0.00). CONCLUSIONS: Pediatric patients with an IDD had higher health care spending and utilization than non-IDD subjects in all categories except for ED use.
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Deficiências do Desenvolvimento/economia , Gastos em Saúde/estatística & dados numéricos , Deficiência Intelectual/economia , Assistência Ambulatorial/economia , Assistência Ambulatorial/estatística & dados numéricos , Estudos de Casos e Controles , Criança , Deficiências do Desenvolvimento/epidemiologia , Serviço Hospitalar de Emergência/economia , Serviço Hospitalar de Emergência/estatística & dados numéricos , Feminino , Inquéritos Epidemiológicos , Serviços de Assistência Domiciliar/economia , Serviços de Assistência Domiciliar/estatística & dados numéricos , Hospitalização/economia , Hospitalização/estatística & dados numéricos , Humanos , Deficiência Intelectual/epidemiologia , Masculino , Estados Unidos/epidemiologiaRESUMO
Proteolysis Targeting Chimeras (PROTACs) are a rapidly expanding new therapeutic modality inducing selective protein degradation and offering the potential of a differentiated pharmacological profile across multiple therapeutic areas. As the repertoire of protein targets and E3 ligases available for incorporation into PROTACs continues to grow, understanding the drug- and system-dependent parameters for PROTACs will be critical for achieving tissue/cell specific pharmacology. The review discusses the current knowledge and future direction of in vivo PROTAC study evaluation. The importance of establishing the quantitative relationship between loss of protein target and biological function in vivo, coupled with building mechanistic PK/PD and ultimately PBPK/PD models, is emphasised with the aim to aid translation from preclinical to clinical space.
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Proteólise , Animais , Avaliação Pré-Clínica de Medicamentos , Humanos , Modelos Biológicos , Pesquisa Translacional BiomédicaRESUMO
When assessing changes in glomerular filtration rate (GFR) it is important to differentiate pathological change from intrinsic biological and analytical variation. GFR is measured using complex reference methods (e.g., iohexol clearance). In clinical practice measurement of creatinine and cystatin C are used in the Modification of Diet in Renal Disease [MDRD] or Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equations to provide estimated GFR. Here we studied the biological variability of measured and estimated GFR in twenty nephrology outpatients (10 male, 10 female; median age 71, range 50-80 years) with moderate CKD (GFR 30-59 ml/min per 1.73 m2). Patients underwent weekly GFR measurement by iohexol clearance over four consecutive weeks. Simultaneously, GFR was estimated using the MDRD, CKD-EPIcreatinine, CKD-EPIcystatinC and CKD-EPIcreatinine+cystatinC equations. Within-subject biological variation expressed as a percentage [95% confidence interval] for the MDRD (5.0% [4.3-6.1]), CKD-EPIcreatinine (5.3% [4.5-6.4]), CKD-EPIcystatinC (5.3% [4.5-6.5]), and CKD-EPIcreatinine+cystatinC (5.0% [4.3-6.2]) equations were broadly equivalent. The within-subject biological variation for MDRD and CKD- EPIcreatinine+cystatinC estimated GFR were each significantly lower than that of the measured GFR (6.7% [5.6-8.2]). Reference change values, the point at which a true change in a biomarker in an individual can be inferred to have occurred with 95% probability were calculated. By the MDRD equation, positive and negative reference change values were 15.1% and 13.1% respectively. If an individual's baseline MDRD estimated GFR (ml/min per 1.73 m2) was 59, significant increases or decreases would be to values over 68 or under 51 respectively. Within-subject variability of estimated GFR was lower than measured GFR. Reference change values can be used to understand GFR changes in clinical practice. Thus, estimates of GFR are at least as reliable as measured GFR for monitoring patients over time.