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Targeted protein degraders (TPDs), an emerging therapeutic modality, are attracting considerable interest with the promise to address disease-related proteins that are not druggable with conventional small molecule inhibitors. Despite their novel mechanism of action, the PK/PD relationship of degraders is still approached with a mindset deeply rooted in inhibitor drugs. Here, we establish how predictive mechanistic modeling specifically tailored to TPDs can significantly enhance the value of the available information during lead generation and optimization. By integrating the results from in vitro assays with routinely collected PK data, modeling accurately predicts degradation in vivo. These predictions transform the prioritization of compounds for in vivo studies as well as the selection of optimal dose schedules and most informative measurement time points with the least number of animals. Moreover, the comprehensive modeling framework (1) identifies the PK/PD driver of targeted protein degradation and subsequent downstream pharmacodynamic effects, and (2) uncovers the fundamental difference between degrader and inhibitor PK/PD relationships. The practical utility of our predictive modeling is demonstrated with relevant use cases. This framework will allow researchers to transition from current, mostly serendipity-based approaches to more sound model-informed decision making. Going forward, the presented predictive PK/PD modeling framework lays out a rational path to incorporate inter-species differences in the pharmacology and thus promises to help with getting the dose right in clinical trials.
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Modelos Biológicos , Proteólise , Humanos , Animais , Proteólise/efeitos dos fármacos , Descoberta de Drogas/métodos , Proteínas/metabolismoRESUMO
For oral drugs, medicinal chemists aim to design compounds with high oral bioavailability, of which permeability is a key determinant. Taking advantage of >2000 compounds tested in rat bioavailability studies and >20,000 compounds tested in Caco2 assays at Bayer, we have examined the molecular properties governing bioavailability and permeability. In addition to classical parameters such as logD and molecular weight, we also investigated the relationship between calculated pKa and permeability. We find that neutral compounds retain permeability up to a molecular weight limit of 700, while stronger acids and bases are restricted to weights of 400-500. We also investigate trends for common properties such as hydrogen bond donors and acceptors, polar surface area, aromatic ring count, and rotatable bonds, including compounds which exceed Lipinski's rule of five (Ro5). These property-structure relationships are combined to provide design guidelines for bioavailable drugs in both traditional and "beyond rule of 5" (bRo5) chemical space.
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Disponibilidade Biológica , Humanos , Ratos , Animais , Células CACO-2 , Permeabilidade , Ligação de Hidrogênio , Peso MolecularRESUMO
The field of targeted protein degradation is growing exponentially. Yet, there is an unmet need for pharmacokinetic/pharmacodynamic models that provide mechanistic insights, while also being practically useful in a drug discovery setting. Therefore, we have developed a comprehensive modeling framework which can be applied to experimental data from routine projects to: (1) assess PROTACs based on accurate degradation metrics, (2) guide compound optimization of the most critical parameters, and (3) link degradation to downstream pharmacodynamic effects. The presented framework contains a number of first-time features: (1) a mechanistic model to fit the hook effect in the PROTAC concentration-degradation profile, (2) quantification of the role of target occupancy in the PROTAC mechanism of action and (3) deconvolution of the effects of target degradation and target inhibition by PROTACs on the overall pharmacodynamic response. To illustrate applicability and to build confidence, we have employed these three models to analyze exemplary data on various compounds from different projects and targets. The presented framework allows researchers to tailor their experimental work and to arrive at a better understanding of their results, ultimately leading to more successful PROTAC discovery. While the focus here lies on in vitro pharmacology experiments, key implications for in vivo studies are also discussed.
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Accurate prediction of human clearance (CL) and volume of distribution at steady state (Vd,ss) for small molecule drug candidates is an essential component of assessing likely efficacious dose and clinical safety margins. In 2021, the IQ Consortium Human PK Prediction Working Group undertook a survey of IQ member companies to understand the current PK prediction methods being used to estimate these parameters across the pharmaceutical industry. The survey revealed a heterogeneity in approaches being used across the industry (e.g., the use of allometric approaches, differing incorporation of binding terms, and inconsistent use of empirical correction factors for in vitro-in vivo extrapolation, IVIVE), which could lead to different PK predictions with the same input data. Member companies expressed an interest in improving human PK predictions by identifying the most appropriate compound-class specific methods, as determined by physiochemical properties and knowledge of CL pathways. Furthermore, there was consensus that increased understanding of the uncertainty inherent to the compound class-dependent prediction would be invaluable in aiding communication of human PK and dose uncertainty at the time of candidate nomination for development. The human PK Prediction Working Group is utilizing these survey findings to help interrogate clinical IV datasets from across the IQ consortium member companies to understand PK prediction accuracy and uncertainty from preclinical datasets.
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Indústria Farmacêutica , Modelos Biológicos , Humanos , Cinética , Preparações FarmacêuticasRESUMO
PURPOSE: More than 15 years have passed since the first description of the unbound brain-to-plasma partition coefficient (Kp,uu,brain) by Prof. Margareta Hammarlund-Udenaes, which was enabled by advancements in experimental methodologies including cerebral microdialysis. Since then, growing knowledge and data continue to support the notion that the unbound (free) concentration of a drug at the site of action, such as the brain, is the driving force for pharmacological responses. Towards this end, Kp,uu,brain is the key parameter to obtain unbound brain concentrations from unbound plasma concentrations. METHODS: To understand the importance and impact of the Kp,uu,brain concept in contemporary drug discovery and development, a survey has been conducted amongst major pharmaceutical companies based in Europe and the USA. Here, we present the results from this survey which consisted of 47 questions addressing: 1) Background information of the companies, 2) Implementation, 3) Application areas, 4) Methodology, 5) Impact and 6) Future perspectives. RESULTS AND CONCLUSIONS: From the responses, it is clear that the majority of the companies (93%) has established a common understanding across disciplines of the concept and utility of Kp,uu,brain as compared to other parameters related to brain exposure. Adoption of the Kp,uu,brain concept has been mainly driven by individual scientists advocating its application in the various companies rather than by a top-down approach. Remarkably, 79% of all responders describe the portfolio impact of Kp,uu,brain implementation in their companies as 'game-changing'. Although most companies (74%) consider the current toolbox for Kp,uu,brain assessment and its validation satisfactory for drug discovery and early development, areas of improvement and future research to better understand human brain pharmacokinetics/pharmacodynamics translation have been identified.
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Barreira Hematoencefálica , Fármacos do Sistema Nervoso Central , Descoberta de Drogas , Encéfalo , Descoberta de Drogas/métodos , HumanosRESUMO
A large number of therapeutic drugs, herbal components and their metabolites are excreted by the kidneys. Therefore, generally applied models for estimating renal excretion, including freshly isolated rat proximal tubule cells, cultured tubule cells and immortalized kidney cell lines MDCKII, NRK-52E, IHKE-1 and Caki-1, were investigated regarding their predictive potential for active renal transport. Cultured proximal tubule cells showed an epithelial cell-like morphology and formed tight monolayers. However, mRNA expression analyses and immunohistochemical studies revealed patterns of tight junction proteins that were notably different from freshly isolated cells and distinct from those in vivo. High levels of mannitol permeation were found in NRK-52E, IHKE-1 and Caki-1 cells, suggesting that they are not suitable for bidirectional transport studies. Cultured cells and freshly isolated cells also differed in proximal tubule markers and transport proteins, indicating that cultured primary cells were in a state of dedifferentiation. Cell lines MDCKII, NRK-52E, IHKE-1 and Caki-1 did not accurately reflect the characteristics of proximal tubules. The expression patterns of marker and transport proteins differed from freshly isolated primary cells. In summary, each of these models has profound disadvantages to consider when adopting them reliable models for the in vivo situation. Thus, they should not be used alone but only in combination.
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Physiologically based pharmacokinetic modeling has become a standard tool to predict drug distribution in early stages of drug discovery; however, this does not currently encompass lysosomal trapping. For basic lipophilic compounds, lysosomal sequestration is known to potentially influence intracellular as well as tissue distribution. The aim of our research was to reliably predict the lysosomal drug content and ultimately integrate this mechanism into pharmacokinetic prediction models. First, we further validated our previously presented method to predict the lysosomal drug content (Schmitt et al., 2019) for a larger set of compounds (n = 41) showing a very good predictivity. Using the lysosomal marker lipid bis(monoacylglycero)phosphate, we estimated the lysosomal volume fraction for all major tissues in the rat, ranging from 0.03% for adipose up to 5.3% for spleen. The pH-driven lysosomal trapping was then estimated and fully integrated into the mechanistic distribution model published by Rodgers et al. (2005) Predictions of Kpu improved for all lysosome-rich tissues. For instance, Kpu increased for nicotine 4-fold (spleen) and 2-fold (lung and kidney) and for quinidine 1.8-fold (brain), although for most other drugs the effects were much less (≤7%). Overall, the effect was strongest for basic compounds with a lower lipophilicity, such as nicotine, for which the unbound volume of distribution at steady-state prediction changed from 1.34 to 1.58 l/kg. For more lipophilic (basic) compounds or those that already show strong interactions with acidic phospholipids, the additional contribution of lysosomal trapping was less pronounced. Nevertheless, lysosomal trapping will also affect intracellular distribution of such compounds. SIGNIFICANCE STATEMENT: The estimation of the lysosomal content in all body tissues facilitated the incorporation of lysosomal sequestration into a general physiologically based pharmacokinetic model, leading to improved predictions as well as elucidating its influence on tissue and subcellular distribution in the rat.
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Desenvolvimento de Medicamentos/métodos , Lisossomos , Preparações Farmacêuticas/metabolismo , Distribuição Tecidual/fisiologia , Animais , Lisossomos/química , Lisossomos/efeitos dos fármacos , Lisossomos/fisiologia , Lisossomos/ultraestrutura , Modelos Biológicos , Farmacocinética , Ratos , SolubilidadeRESUMO
The unbound partition coefficient (Kpuu) allows the estimation of intracellular target exposure from free extracellular drug concentrations. Although the active mechanisms controlling Kpuu are saturable, Kpuu is commonly determined at a single concentration, which may not be appropriate in cases in which drug concentrations can largely vary, e.g., in plasma in vivo or in vitro IC50 assays. We examined the concentration dependence of Kpuu in vitro using KAT6A inhibitors with varying potency drop-off in ZR75-1 breast cancer cells to account for exposure-related discrepancies between cellular and biochemical IC50 Considering saturability resulted in a better quantitative bridge between both IC50 values and gave way to a simplified method to determine Kpuu that is suitable for the prediction of unbound cytosolic drug concentrations without the need to generate fu,cell estimates from binding studies in cell homogenates. As opposed to the binding method, which destroys cellular integrity, this approach provides an alternative fu,cell estimate and directly reflects the fraction of unbound drug in the cell cytosol based on Kp saturation (fu,cyto) of intact cells. In contrast to the binding method, prediction of intracellular KAT6A exposure with this more physiologic approach was able to bridge the average exposure gap between biochemical and cellular IC50 values from 73-fold down to only 5.4-fold. The concept of concentration-dependent Kpuu provides a solid rationale for early drug discovery to discriminate between pharmacology and target exposure-related IC50 discrepancies. The attractiveness of the approach also lies in the use of the same assay format for cellular IC50, fu,cyto, and the unbound partition coefficient based on fu,cyto (Kpuu,cyto) determination. SIGNIFICANCE STATEMENT: Examination of the yet-unexplored concentration dependence of the unbound partition coefficient led to a new experimental approach that resulted in more reliable predictions of intracellular target exposure and is well suited for routine drug discovery projects.
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Inibidores Enzimáticos/farmacocinética , Histona Acetiltransferases/antagonistas & inibidores , Modelos Biológicos , Linhagem Celular Tumoral , Citosol/metabolismo , Histona Acetiltransferases/metabolismo , Humanos , Concentração Inibidora 50RESUMO
BACKGROUND: The ambulatory glucose profile (AGP) uses the wealth of data that are generated by continuous glucose monitoring, including flash glucose monitoring technologies, to provide a visual representation of glucose levels over a typical standard day of usually the most recent two weeks for a person with diabetes and helps to identify patterns and trends in glucose control. The AGP allows certain patterns of glucose levels to be identified and analyzed, such that treatment adjustments can be made, and new individual treatment goals can be defined. This helps to ensure increased treatment satisfaction and adherence, quality of life, and an improvement in metabolic management for people with diabetes. OBJECTIVE: To date, a range of approaches exists for interpreting the information contained in an AGP, with different priorities given to identifying and targeting patterns of hypoglycemia and the degree of variability and stability underlying the glucose levels. The objective of the present recommendation is to describe the steps for assessing an AGP in detail and to illustrate these steps using visual examples. CONCLUSION: This paper describes the consensus recommendations from a group of German expert diabetologists on the necessary steps for assessing an AGP in a structured and detailed way and to explain these steps using practical clinical examples.
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Automonitorização da Glicemia/normas , Glicemia/metabolismo , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 2/diagnóstico , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Consenso , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Medicina Baseada em Evidências/normas , Controle Glicêmico , Humanos , Hipoglicemiantes/uso terapêutico , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Resultado do TratamentoRESUMO
Bis(monoacylglycero)phosphate (BMP) and phosphatidylglycerol (PG) are structural isomeric phospholipids with very different properties and biological functions. Due to their isomeric nature, it has thus far been challenging to simultaneously quantify BMP and PG lipids in tissue samples by mass spectrometry. Therefore, we have developed a sensitive LC-MS/MS based approach with prior methylation derivatization that is able to handle large batches of samples. Using this high throughput platform, a simulated MS/MS database was established for confident lipid assignment. In this work, we have simultaneously identified and quantified BMP and PG lipid molecules in different body tissues of rats and mice. We report for the first time a quantitative molecular atlas of BMP and PG lipids for 14 different tissues and organs in Wistar rats, NMRI and CD1 mice. Organ- and species-specificity was analyzed and compared for both lipid molecule classes. A total of 34 BMP and 10â¯PG molecules were quantified, with PG concentrations being generally much higher across tissues than BMP, but BMP lipids showing a much higher molecular diversity between animal organs. The large diversity of the BMP lipids with regard to their abundance and molecular composition suggests distinct biological function(s) of the individual BMP molecules in different tissues and organs of body. Particularly high tissue levels of BMP were seen in spleen, lung, liver, kidney and small intestines, i.e. tissues that are known for their high abundance and/or activity level of lysosomes late and endosomes. Elevated BMP levels in brain tissue of APP/PSEN transgenic compared to age matched wild-type mice were also observed using this platform. This analytical methodology presented a high throughput LC-based approach incorporating simulated MS/MS database to identify and quantify BMP lipids as well as PG molecules.
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Lisofosfolipídeos/análise , Lipídeos de Membrana/química , Monoglicerídeos/análise , Fosfatidilgliceróis/análise , Animais , Cromatografia Líquida , Masculino , Lipídeos de Membrana/isolamento & purificação , Metilação , Camundongos , Camundongos Endogâmicos , Ratos , Ratos Wistar , Espectrometria de Massas em TandemRESUMO
Lysosomal sequestration may affect the pharmacokinetics, efficacy, and safety of new basic lipophilic drug candidates potentially impacting their intracellular concentrations and tissue distribution. It may also be involved in drug-drug interactions, drug resistance, and phospholipidosis. However, currently there are no assays to evaluate the lysosomotropic behavior of compounds in a setting fully meeting the needs of drug discovery. We have, therefore, integrated a set of methods to reliably rank order, quantify, and calculate the extent of lysosomal sequestration in rat hepatocytes. An indirect fluorescence-based assay monitors the displacement of the fluorescence probe LysoTracker Red by test compounds. Using a lysosomal-specific evaluation algorithm allows one to generate IC50 values at lower than previously reported concentrations. The concentration range directly agrees with the concentration dependency of the lysosomal drug content itself directly quantified by liquid chromatography-tandem mass spectrometry and thus permits a quantitative link between the indirect and the direct trapping assay. Furthermore, we have determined the full pH profile and corresponding volume fractions of the endo-/lysosomal system in plated rat hepatocytes, enabling a more accurate in silico prediction of the extent of lysosomal trapping based only on pK a values as input, allowing early predictions even prior to chemical synthesis. The concentration dependency-i.e., the saturability of the trapping-can then be determined by the IC50 values generated in vitro. Thereby, a more quantitative assessment of the susceptibility of basic lipophilic compounds for lysosomal trapping is possible.
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Bioensaio/métodos , Descoberta de Drogas/métodos , Hepatócitos/metabolismo , Lisossomos/metabolismo , Preparações Farmacêuticas/análise , Aminas/química , Animais , Células Cultivadas , Simulação por Computador , Hepatócitos/química , Hepatócitos/citologia , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Lisossomos/química , Microscopia de Fluorescência , Preparações Farmacêuticas/química , Preparações Farmacêuticas/metabolismo , Cultura Primária de Células , Ratos , Ratos Wistar , Espectrometria de Massas em Tandem/métodos , Distribuição TecidualRESUMO
Transplantation of pancreatic islets for treating type 1 diabetes is restricted to patients with critical metabolic lability resulting from the need for immunosuppression and the shortage of donor organs. To overcome these barriers, we developed a strategy to macroencapsulate islets from different sources that allow their survival and function without immunosuppression. Here we report successful and safe transplantation of porcine islets with a bioartificial pancreas device in diabetic primates without any immune suppression. This strategy should lead to pioneering clinical trials with xenotransplantation for treatment of diabetes and, thereby, represents a previously unidentified approach to efficient cell replacement for a broad spectrum of endocrine disorders and other organ dysfunctions.
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Diabetes Mellitus Experimental/cirurgia , Diabetes Mellitus Tipo 1/cirurgia , Diabetes Mellitus Tipo 1/terapia , Ilhotas Pancreáticas/cirurgia , Animais , Feminino , Terapia de Imunossupressão/métodos , Transplante das Ilhotas Pancreáticas/métodos , Primatas , Suínos , Transplante Heterólogo/métodosRESUMO
We report on the discovery of two new lead series for the development of glucocorticoid receptor agonists. Firstly, the discovery of tetrahydronaphthalenes led to metabolically stable and dissociated compounds. Their binding mode to the glucocorticoid receptor could be elucidated through an X-ray structure. Closer inspection into the reaction path and analyses of side products revealed a new amino alcohol series also addressing the glucocorticoid receptor and demonstrating strong anti-inflammatory activity in vitro.
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Anti-Inflamatórios/química , Receptores de Glucocorticoides/agonistas , Tetra-Hidronaftalenos/química , Amino Álcoois/química , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/farmacologia , Sítios de Ligação , Genes Reporter , Meia-Vida , Células HeLa , Humanos , Ligação de Hidrogênio , Concentração Inibidora 50 , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Monócitos/citologia , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Ligação Proteica , Receptores de Glucocorticoides/metabolismo , Relação Estrutura-Atividade , Tetra-Hidronaftalenos/farmacocinética , Tetra-Hidronaftalenos/farmacologia , Ativação Transcricional/efeitos dos fármacosRESUMO
BACKGROUND AND AIMS: Endoscopic management of post-Whipple pancreatic adverse events (AEs) with enteroscopy-assisted endoscopic retrograde pancreatography (e-ERP) is associated with high failure rates. EUS-guided pancreatic duct drainage (EUS-PDD) has shown promising results; however, no comparative data have been done for these 2 modalities. The goal of this study is to compare EUS-PDD with e-ERP in terms of technical success (PDD through dilation/stent), clinical success (improvement/resolution of pancreatic-type symptoms), and AE rates in patients with post-Whipple anatomy. METHODS: This is an international multicenter comparative retrospective study at 7 tertiary centers (2 United States, 2 European, 2 Asian, and 1 South American). All consecutive patients who underwent EUS-PDD or e-ERP between January 2010 and August 2015 were included. RESULTS: In total, 66 patients (mean age, 57 years; 48% women) and 75 procedures were identified with 40 in EUS-PDD and 35 in e-ERP. Technical success was achieved in 92.5% of procedures in the EUS-PDD group compared with 20% of procedures in the e-ERP group (OR, 49.3; P < .001). Clinical success (per patient) was attained in 87.5% of procedures in the EUS-PDD group compared with 23.1% in the e-ERP group (OR, 23.3; P < .001). AEs occurred more commonly in the EUS-PDD group (35% vs 2.9%, P < .001). However, all AEs were rated as mild or moderate. Procedure time and length of stay were not significantly different between the 2 groups. CONCLUSIONS: EUS-PDD is superior to e-ERP in post-Whipple anatomy in terms of efficacy with acceptable safety. As such, EUS-PDD should be considered as a potential first-line treatment in post-pancreaticoduodenectomy anatomy when necessary expertise is available.
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Colangiopancreatografia Retrógrada Endoscópica/métodos , Drenagem/métodos , Ductos Pancreáticos/patologia , Ductos Pancreáticos/cirurgia , Pancreaticoduodenectomia/efeitos adversos , Complicações Pós-Operatórias/terapia , Adulto , Idoso , Anastomose Cirúrgica/efeitos adversos , Colangiopancreatografia Retrógrada Endoscópica/efeitos adversos , Constrição Patológica/etiologia , Constrição Patológica/terapia , Dilatação , Drenagem/efeitos adversos , Endoscopia Gastrointestinal , Endossonografia , Feminino , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Stents , Resultado do Tratamento , Ultrassonografia de Intervenção/efeitos adversosRESUMO
The role of pharmacokinetics (PK) in drug discovery is to support the optimisation of the absorption, distribution, metabolism and excretion (ADME) properties of lead compounds with the ultimate goal to attain a clinical candidate which achieves a concentration-time profile in the body that is adequate for the desired efficacy and safety profile. A thorough characterisation of the lead compounds aiming at the identification of the inherent PK liabilities also includes an early generation of PK/PD relationships linking in vitro potency and target exposure/engagement with expression of pharmacological activity (mode-of-action) and efficacy in animal studies. The chapter describes an exposure-centred approach to lead generation, lead optimisation and candidate selection and profiling that focuses on a stepwise generation of an understanding between PK/exposure and PD/efficacy relationships by capturing target exposure or surrogates thereof and cellular mode-of-action readouts in vivo. Once robust PK/PD relationship in animal PD models has been constructed, it is translated to anticipate the pharmacologically active plasma concentrations in patients and the human therapeutic dose and dosing schedule which is also based on the prediction of the PK behaviour in human as described herein. The chapter outlines how the level of confidence in the predictions increases with the level of understanding of both the PK and the PK/PD of the new chemical entities (NCE) in relation to the disease hypothesis and the ability to propose safe and efficacious doses and dosing schedules in responsive patient populations. A sound identification of potential drug metabolism and pharmacokinetics (DMPK)-related development risks allows proposing of an effective de-risking strategy for the progression of the project that is able to reduce uncertainties and to increase the probability of success during preclinical and clinical development.
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Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Animais , Humanos , Modelos Biológicos , FarmacocinéticaRESUMO
AIM: To evaluate the use of translumenal pancreatography with placement of endoscopic ultrasonography (EUS)-guided drainage of the pancreatic duct. METHODS: This study enrolled all consecutive patients between June 2002 and April 2014 who underwent EUS-guided pancreatography and subsequent placement of a drain and had symptomatic retention of fluid in the pancreatic duct after one or more previous unsuccessful attempts at endoscopic retrograde cannulation of the pancreatic duct. In all, 94 patients underwent 111 interventions with one of three different approaches: (1) EUS-endoscopic retrograde drainage with a rendezvous technique; (2) EUS-guided drainage of the pancreatic duct; and (3) EUS-guided, internal, antegrade drainage of the pancreatic duct. RESULTS: The mean duration of the interventions was 21 min (range, 15-69 min). Mean patient age was 54 years (range, 28-87 years); the M:F sex ratio was 60:34. The technical success rate was 100%, achieving puncture of the pancreatic duct including pancreatography in 94/94 patients. In patients requiring drainage, initial placement of a drain was successful in 47/83 patients (56.6%). Of these, 26 patients underwent transgastric/transbulbar positioning of a stent for retrograde drainage; plastic prostheses were used in 11 and metal stents in 12. A ring drain (antegrade internal drainage) was placed in three of these 26 patients because of anastomotic stenosis after a previous surgical intervention. The remaining 21 patients with successful drain placement had transpapillary drains using the rendezvous technique; the majority (n = 19) received plastic prostheses, and only two received metal stents (covered self-expanding metal stents). The median follow-up time in the 21 patients with transpapillary drainage was 28 mo (range, 1-79 mo), while that of the 26 patients with successful transgastric/transduodenal drainage was 9.5 mo (range, 1-82 mo). Clinical success, as indicated by reduced or absence of further pain after the EUS-guided intervention was achieved in 68/83 patients (81.9%), including several who improved without drainage, but with manipulation of the access route. CONCLUSION: EUS-guided drainage of the pancreatic duct is a safe, feasible alternative to endoscopic retrograde drainage when the papilla cannot be reached endoscopically or catheterized.
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Drenagem/métodos , Endossonografia , Pancreatopatias/terapia , Ductos Pancreáticos , Ultrassonografia de Intervenção/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Colangiopancreatografia Retrógrada Endoscópica , Constrição Patológica , Drenagem/instrumentação , Endossonografia/instrumentação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pancreatopatias/diagnóstico por imagem , Ductos Pancreáticos/diagnóstico por imagem , Estudos Retrospectivos , Stents , Resultado do Tratamento , Ultrassonografia de Intervenção/instrumentaçãoRESUMO
Use of continuous subcutaneous insulin infusion (CSII) therapy improves glycemic control, reduces hypoglycemia and increases treatment satisfaction in individuals with diabetes. As a number of patient- and clinician-related factors can hinder the effectiveness and optimal usage of CSII therapy, new approaches are needed to address these obstacles. Ceriello and colleagues recently proposed a model of care that incorporates the collaborative use of structured SMBG into a formal approach to personalized diabetes management within all diabetes populations. We adapted this model for use in CSII-treated patients in order to enable the implementation of a workflow structure that enhances patient-physician communication and supports patients' diabetes self-management skills. We recognize that time constraints and current reimbursement policies pose significant challenges to healthcare providers integrating the Personalised Diabetes Management (PDM) process into clinical practice. We believe, however, that the time invested in modifying practice workflow and learning to apply the various steps of the PDM process will be offset by improved workflow and more effective patient consultations. This article describes how to implement PDM into clinical practice as a systematic, standardized process that can optimize CSII therapy.
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Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Hipoglicemia , Sistemas de Infusão de Insulina , Insulina , Autocuidado , Glicemia/análise , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/psicologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/psicologia , Gerenciamento Clínico , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemia/prevenção & controle , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Insulina/administração & dosagem , Insulina/efeitos adversos , Satisfação do Paciente , Relações Médico-Paciente , Autocuidado/métodos , Autocuidado/psicologiaRESUMO
Loss of pancreatic islet function and insulin-producing beta cell mass is a central hallmark in the pathogenesis of both type 1 and type 2 diabetes. While in type 1 diabetes this phenomenon is due to an extensive destruction of beta cells caused by an autoimmune process, the mechanisms resulting in beta cell failure in type 2 diabetes are different and less clear. Also, beta cell destruction in type 1 diabetes occurs early and is the initial step in the pathogenetic process, while beta cell loss in type 2 diabetes after an initial phase of hyperinsulinemia due to the underlying insulin resistance occurs relatively late and it is less pronounced. Since diabetes mellitus is the most frequent endocrine disease, with an increasing high prevalence worldwide, huge efforts have been made over the past many decades to identify predisposing genetic, environmental, and nutritional factors in order to develop effective strategies to prevent the disease. In parallel, extensive studies in different cell systems and animal models have helped to elucidate our understanding of the physiologic function of islets and to gain insight into the immunological and non-immunological mechanisms of beta cell destruction and failure. Furthermore, currently emerging concepts of beta cell regeneration (e.g., the restoration of the beta cell pool by regenerative, proliferative and antiapoptotic processes, and recovery of physiologic islet function) apparently is yielding the first promising results. Recent insights into the complex endocrine and paracrine mechanisms regulating the physiologic function of pancreatic islets, as well as beta cell life and death, constitute an essential part of this new and exciting area of diabetology. For example, understanding of the physiological role of glucagon-like peptide 1 has resulted in the successful clinical implementation of incretin-based therapies over the last years. Further, recent data suggesting paracrine effects of growth hormone-releasing hormone and corticotropin-releasing hormone on the regulation of pancreatic islet function, survival, and proliferation as well as on local glucocorticoid metabolism provide evidence for a potential role of the pancreatic islet-stress axis in the pathophysiology of diabetes mellitus. In this chapter, we provide a comprehensive overview of current preventive and regenerative concepts as a basis for the development of novel therapeutic approaches to the treatment of diabetes mellitus. A particular focus is given on the potential of the pancreatic islet-stress axis in the development of novel regenerative strategies.
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Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Ilhotas Pancreáticas/efeitos dos fármacos , Terapia de Alvo Molecular , Estresse Fisiológico , Estresse Psicológico/fisiopatologia , Animais , Diabetes Mellitus Tipo 1/etiologia , Diabetes Mellitus Tipo 1/fisiopatologia , Diabetes Mellitus Tipo 1/prevenção & controle , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Diabetes Mellitus Tipo 2/prevenção & controle , Humanos , Hipoglicemiantes/farmacologia , Insulina/metabolismo , Secreção de Insulina , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/fisiopatologiaRESUMO
Transplantation of pancreatic islets is emerging as a successful treatment for type-1 diabetes. Its current stringent restriction to patients with critical metabolic lability is justified by the long-term need for immunosuppression and a persistent shortage of donor organs. We developed an oxygenated chamber system composed of immune-isolating alginate and polymembrane covers that allows for survival and function of islets without immunosuppression. A patient with type-1 diabetes received a transplanted chamber and was followed for 10 mo. Persistent graft function in this chamber system was demonstrated, with regulated insulin secretion and preservation of islet morphology and function without any immunosuppressive therapy. This approach may allow for future widespread application of cell-based therapies.
Assuntos
Órgãos Bioartificiais , Diabetes Mellitus Tipo 1/terapia , Cultura em Câmaras de Difusão , Transplante das Ilhotas Pancreáticas/métodos , Peptídeo C/metabolismo , Teste de Tolerância a Glucose , Humanos , Imuno-Histoquímica , Terapia de Imunossupressão/métodos , Transplante das Ilhotas Pancreáticas/imunologia , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Impaired wound healing is a frequent and very severe problem in patients with diabetes mellitus, yet little is known about the underlying pathomechanisms. In this paper we review the biology of wound healing with particular attention to the pathophysiology of chronic wounds in diabetic patients. The standard treatment of diabetic ulcers includes measures to optimize glycemic control as well as extensive debridement, infection elimination by antibiotic therapy based on wound pathogen cultures, the use of moisture dressings, and offloading high pressure from the wound bed. In this paper we discuss novel adjuvant therapies with particular reference to the use of autologous skin transplants for the treatment of diabetic foot ulcers which do not respond to standard care.