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1.
Nat Commun ; 15(1): 8903, 2024 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-39406706

RESUMO

Charge transfer between molecules lies at the heart of many chemical processes. Here, we focus on the ultrafast electron dynamics associated with the formation of charge-transfer-to-solvent (CTTS) states following X-ray absorption in aqueous solutions of Na+, Mg2+, and Al3+ ions. To explore the formation of such states in the aqueous phase, liquid-jet photoemission spectroscopy is employed. Using the core-hole-clock method, based on Auger-Meitner (AM) decay upon 1s excitation or ionization of the respective ions, upper limits are estimated for the metal-atom electron delocalization times to the neighboring water molecules. These delocalization processes represent the first steps in the formation of hydrated electrons, which are determined to take place on a timescale ranging from several hundred attoseconds (as) below the 1s ionization threshold to only 20 as far above the 1s ionization threshold. The decrease in the delocalization times as a function of the photon energy is continuous. This indicates that the excited electrons remain in the vicinity of the studied ions even above the ionization threshold, i.e., metal-ion electronic resonances associated with the CTTS state manifolds are formed. The three studied isoelectronic ions exhibit quantitative differences in their electron energetics and delocalization times, which are linked to the character of the respective excited states.

2.
Acta Orthop Belg ; 90(2): 311-318, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-39440508

RESUMO

Background and aims: Arthrofibrosis is a complication of intra-articular knee surgery which is caused by intra-articular fibrosis. To date, several preventive therapies for arthrofibrosis have been reported. This systematic review aims to summarize current knowledge about pharmacological arthrofibrosis prevention. Methods: A systematic literature search was conducted in Medline, Web of Science, and Cochrane library using the search term 'Arthrofibrosis AND prevention'. Subsequently, articles reporting the effects of a preventive pharmacological intervention against arthrofibrosis were included in this review. Results: 16 studies investigated the pharmacological prevention of arthrofibrosis of which 13 were conducted in animal models. Several drugs improved the range of motion (ROM) in animal models. Bevacizumab (ROM +39.4 degrees), nonsteroidal anti-inflammatory drugs (ROM +18.0-31.2 degrees), and rosiglitazone (ROM +19.5 degrees) significantly increased the ROM. Artesunate, mitomycin c, bevacizumab, hyaloglide, and botulinum toxin A significantly reduced adhesion scores. None of the drugs tested in humans improved the functional outcomes after joint arthroplasty. Methodological differences limited the ability to compare outcomes and, due to poor reporting of methodology, many studies had an unclear risk of bias. Conclusion: This review identified several drugs as potential candidates for arthrofibrosis prevention. These drugs modulate inflammation or alter the activity of fibroblasts. Most studies are conducted in experimental animal models and none of these results are currently translated into a clinical application. Moreover, the methodology and route of administration varied between studies. Nor were dose dependency studies conducted. Future studies should adopt a standardized approach to determine the effects of preventive pharmacological interventions on arthrofibrosis.


Assuntos
Fibrose , Fibrose/prevenção & controle , Humanos , Animais , Artropatias/prevenção & controle , Artropatias/etiologia , Articulação do Joelho/patologia , Amplitude de Movimento Articular/efeitos dos fármacos , Artroplastia do Joelho/efeitos adversos , Anti-Inflamatórios não Esteroides/uso terapêutico , Complicações Pós-Operatórias/prevenção & controle
4.
J Cyst Fibros ; 23(3): 563-565, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38281825

RESUMO

Lumacaftor/ivacaftor (Orkambi®, LUM/IVA) is indicated for the treatment of cystic fibrosis (CF) patients aged ≥ 2 years with homozygous F580del mutation in the CFTR gene. Triazole fungal agents are used to treat fungal disease in CF. The use of triazoles is limited by pharmacokinetic challenges, such as drug-drug interactions. The most notable drug-drug interaction between triazoles and LUM/IVA is due to strong induction of CYP3A4 and UGT by LUM. In this real-world retrospective observational study, we described the effect of LUM/IVA on the trough concentration of triazoles. Concomitant use of LUM/IVA with itraconazole, posaconazole or voriconazole resulted in subtherapeutic triazole levels in 76% of the plasma samples. In comparison, in patients with triazole agents without LUM/IVA only 30.6% of the plasma samples resulted in subtherapeutic concentrations. Subtherapeutic plasma concentrations of triazoles should be considered in CF patients on LUM/IVA and further research is warranted for other dosing strategies and alternative antifungal therapy.


Assuntos
Aminofenóis , Aminopiridinas , Antifúngicos , Benzodioxóis , Fibrose Cística , Combinação de Medicamentos , Interações Medicamentosas , Quinolonas , Triazóis , Humanos , Fibrose Cística/tratamento farmacológico , Fibrose Cística/microbiologia , Quinolonas/farmacocinética , Triazóis/farmacocinética , Triazóis/administração & dosagem , Estudos Retrospectivos , Benzodioxóis/farmacocinética , Masculino , Aminofenóis/farmacocinética , Feminino , Aminopiridinas/farmacocinética , Antifúngicos/farmacocinética , Antifúngicos/administração & dosagem , Criança , Adolescente , Adulto , Agonistas dos Canais de Cloreto/farmacocinética , Voriconazol/farmacocinética , Itraconazol/farmacocinética , Itraconazol/administração & dosagem
5.
Nat Chem ; 15(10): 1408-1414, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37620544

RESUMO

Biomolecular radiation damage is largely mediated by radicals and low-energy electrons formed by water ionization rather than by direct ionization of biomolecules. It was speculated that such an extensive, localized water ionization can be caused by ultrafast processes following excitation by core-level ionization of hydrated metal ions. In this model, ions relax via a cascade of local Auger-Meitner and, importantly, non-local charge- and energy-transfer processes involving the water environment. Here, we experimentally and theoretically show that, for solvated paradigmatic intermediate-mass Al3+ ions, electronic relaxation involves two sequential solute-solvent electron transfer-mediated decay processes. The electron transfer-mediated decay steps correspond to sequential relaxation from Al5+ to Al3+ accompanied by formation of four ionized water molecules and two low-energy electrons. Such charge multiplication and the generated highly reactive species are expected to initiate cascades of radical reactions.

6.
Phys Rev Lett ; 130(15): 156901, 2023 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-37115858

RESUMO

The determination of depth profiles across interfaces is of primary importance in many scientific and technological areas. Photoemission spectroscopy is in principle well suited for this purpose, yet a quantitative implementation for investigations of liquid-vapor interfaces is hindered by the lack of understanding of electron-scattering processes in liquids. Previous studies have shown, however, that core-level photoelectron angular distributions (PADs) are altered by depth-dependent elastic electron scattering and can, thus, reveal information on the depth distribution of species across the interface. Here, we explore this concept further and show that the experimental anisotropy parameter characterizing the PAD scales linearly with the average distance of atoms along the surface normal obtained by molecular dynamics simulations. This behavior can be accounted for in the low-collision-number regime. We also show that results for different atomic species can be compared on the same length scale. We demonstrate that atoms separated by about 1 Å along the surface normal can be clearly distinguished with this method, achieving excellent depth resolution.

7.
Acta Gastroenterol Belg ; 86(1): 17-25, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36842172

RESUMO

Background and aims: Irritable bowel syndrome (IBS) is a chronic disorder characterized by abdominal pain and an altered bowel habit. The aim of this study was to evaluate the characteristics of a population visiting a patient-centered informative website about IBS. Methods: Five digital surveys were used to assess the Rome IV criteria, red flag symptoms, healthcare use, psychological comorbidities, quality of life, symptom severity, diet, physical activity. Patients were divided into a Rome positive and negative population with the Rome positive population being further subtyped based on dominant stool pattern. Results: Red flag symptoms (42%) and comorbid psychological disorders (65% anxiety and 39% depression) were common. Despite consulting health care professionals and therapy, most patients (96%) still experienced moderate to severe symptoms with an average impact on quality of life. 73% performed regular physical exercise and 25% of the Rome positive population followed the FODMAP diet. Almost all participants consulted a health care professional at one point in time and used some form of therapy. 54% of the patients believed there is generally sufficient information available and 57% thinks that their physician takes IBS seriously. However, only 41% thinks that their physician has sufficient knowledge about IBS. Conclusions: This study underlines the importance of a thorough characterization of IBS patients. Furthermore, patients expressed an urgent need for high quality information and education for both health care professionals and patients.


Assuntos
Síndrome do Intestino Irritável , Humanos , Síndrome do Intestino Irritável/epidemiologia , Síndrome do Intestino Irritável/terapia , Síndrome do Intestino Irritável/diagnóstico , Qualidade de Vida , Inquéritos e Questionários , Dor Abdominal , Assistência Centrada no Paciente
8.
Eur Child Adolesc Psychiatry ; 32(8): 1427-1434, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35138475

RESUMO

OBJECTIVE: The Dutch law on youth care (the Youth Act) was implemented from 2015 onwards. One of the government's aims by implementing this new policy was de-medicalization of youths by separating youth mental healthcare from the rest of the healthcare system. A previous study conducted by our research group showed that prevalence rates of antipsychotic drug prescriptions stabilized among Dutch youth in the period 2005-2015, just before the introduction of the Youth Act. In our study, we aimed to describe antipsychotic drug use among Dutch children aged 0-19 years old before and after implementation of the Youth Act (2010-2019). METHODS: We analyzed prescription data of 7405 youths aged 0-19 years using antipsychotic drugs between 2010 and 2019, derived from a large Dutch community pharmacy-based prescription database (IADB.nl). RESULTS: Prevalence rates of antipsychotic drug use per thousand youths decreased significantly in youths aged 7-12 years old in 2019 compared to 2015 (7.9 vs 9.0 p < 0.05). By contrast, prevalence rates increased in adolescent females in 2019 compared to 2015 (11.8 vs 9.5 p < 0.05). Incidence rates increased significantly in adolescent youths in 2019 compared to 2015 (3.9 vs 3.0 p < 0.05), specifically among adolescent girls (4.2 per thousand in 2019 compared to 3.0 per thousand in 2015). Dosages in milligram declined for the most commonly prescribed antipsychotic drugs during the study period. The mean duration of antipsychotic drug use in the study period was 5.7 (95% CI 5.2-6.2) months. CONCLUSION: Despite the aim of the Youth Act to achieve de-medicalization of youths, no clear reduction was observed in prevalence rates of antipsychotic drugs or treatment duration in all subgroups. Prevalence rates even increased in adolescent females.


Assuntos
Antipsicóticos , Criança , Feminino , Humanos , Adolescente , Recém-Nascido , Lactente , Pré-Escolar , Adulto Jovem , Adulto , Antipsicóticos/uso terapêutico , Prescrições de Medicamentos , Incidência , Prevalência , Bases de Dados Factuais
9.
Eur J Clin Pharmacol ; 78(8): 1273-1287, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35567629

RESUMO

PURPOSE: A population pharmacokinetic (popPK) model may be used to improve tacrolimus dosing and minimize under- and overexposure in kidney transplant recipients. It is unknown how body composition parameters relate to tacrolimus pharmacokinetics and which parameter correlates best with tacrolimus exposure. The aims of this study were to investigate which body composition parameter has the best association with the pharmacokinetics of tacrolimus and to describe this relationship in a popPK model. METHODS: Body composition was assessed using bio-impedance spectroscopy (BIS). Pharmacokinetic analysis was performed using nonlinear mixed effects modeling (NONMEM). Lean tissue mass, adipose tissue mass, over-hydration, and phase angle were measured with BIS and then evaluated as covariates. The final popPK model was evaluated using goodness-of-fit plots, visual predictive checks, and a bootstrap analysis. RESULTS: In 46 kidney transplant recipients, 284 tacrolimus concentrations were measured. The base model without body composition parameters included age, plasma albumin, plasma creatinine, CYP3A4 and CYP3A5 genotypes, and hematocrit as covariates. After full forward inclusion and backward elimination, only the effect of the phase angle on clearance (dOFV = - 13.406; p < 0.01) was included in the final model. Phase angle was positively correlated with tacrolimus clearance. The inter-individual variability decreased from 41.7% in the base model to 34.2% in the final model. The model was successfully validated. CONCLUSION: The phase angle is the bio-impedance spectroscopic parameter that correlates best with tacrolimus pharmacokinetics. Incorporation of the phase angle in a popPK model can improve the prediction of an individual's tacrolimus dose requirement after transplantation.


Assuntos
Transplante de Rim , Tacrolimo , Composição Corporal , Citocromo P-450 CYP3A/genética , Genótipo , Humanos , Imunossupressores/farmacocinética , Modelos Biológicos , Tacrolimo/farmacocinética , Transplantados
10.
Drugs Aging ; 39(1): 83-95, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34918212

RESUMO

INTRODUCTION: Paracetamol pharmacokinetics (PK) is highly variable in older fit adults after intravenous administration. Frailty and oral administration likely result in additional variability. The aim was to determine oral paracetamol PK and variability in geriatric inpatients. METHODS: A population PK analysis, using NONMEM 7.2, was performed on 245 paracetamol samples in 40 geriatric inpatients (median age 87 [range 80-95] years, bodyweight 66.4 [49.3-110] kg, 92.5% frail [Edmonton Frail Scale]). All subjects received paracetamol 1000 mg as tablet (72.5%) or granulate (27.5%) three times daily. Simulations of dosing regimens (1000 mg every 6 hours [q6h] or q8h) were performed to determine target attainment, using mean steady-state concentration (Css-mean) of 10 mg/L as target. RESULTS: A one-compartment model with first order absorption and lag time best described the data. The inter-individual variability was high, with absorption rate constant containing the highest variability. The inter-individual variability could not be explained by covariates. Simulations of 1000 mg q6h and q8h resulted in a Css-mean of 10.8 [25-75th percentiles 8.2-12.7] and 8.13 [6.3-9.6] mg/L, respectively, for the average geriatric inpatient. The majority of the population remained off-target (22.2% [q6h] and 52.2% [q8h] <8 mg/L; 31.3 [q6h] and 7.6% [q8h] >12 mg/L). CONCLUSION: A population of average geriatric inpatients achieved target Css-mean with paracetamol 1000 mg q6h, while q8h resulted in underexposure for the majority of them. Due to high unexplained variability, a relevant proportion remained either above or below the target concentration of 10 mg/L. Research focusing on PK, efficacy and safety is needed to recommend dosing regimens.


Assuntos
Acetaminofen , Idoso Fragilizado , Idoso , Idoso de 80 Anos ou mais , Antibacterianos , Peso Corporal , Humanos , Infusões Intravenosas
12.
Neth J Med ; 78(6): 404-407, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33380548

RESUMO

Approximately 500 patients per year are admitted to the emergency department (ED) of the Erasmus University Medical Center presenting with intoxications with medication. For adequate treatment, it is sometimes important to know which drugs in which quantities were ingested. This can require laboratory analysis of blood or urine samples; however, these samples do not provide information about the possible effects that can still be expected. We performed toxicological screening on the gastric content of three patients admitted to our ED in January and February 2018. These patients underwent gastric lavage or received a gastric tube as part of routine care. The gastric fluid was analysed via UPLC-MS/MS using the Waters method for toxicological screening. In all three patients, we successfully determined drugs in the gastric content. In two patients, we identified more different drugs in the gastric content than in blood plasma. In the other patient, admitted approximately six hours after a severe autointoxication with the betablocker metoprolol, we found significant amounts of metoprolol in the gastric content acquired by gastric lavage. We therefore believe that analysis of gastric content after an intoxication can have multiple applications; for example, it may provide information about symptoms of intoxication that can be expected, it may aid patient care and may provide insight in the toxicokinetics of different drugs. In conclusion, we demonstrate that toxicological screening and quantification of drug levels in gastric content is possible and has potential as an adjunct in patient care, but limitations need to be addressed before implementation in clinical practice.


Assuntos
Preparações Farmacêuticas , Venenos , Cromatografia Líquida , Humanos , Espectrometria de Massas em Tandem , Irrigação Terapêutica
13.
Respir Med ; 171: 106101, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32799061

RESUMO

BACKGROUND: Bronchopulmonary dysplasia (BPD) remains a common complication of preterm birth. Both historically and in current practice, radiologic evaluation of the lungs has an important role in assessing disease severity and complications. AIM: To provide an overview of imaging techniques for detecting lung abnormalities in patients with BPD in all age ranges. METHODS: A systematic literature search was conducted in PubMed, Web of Science and the Cochrane Library. Records were screened by title and abstract and then by full text. A total of 37 records were selected and included in this qualitative literature overview. RESULTS: Computed tomography (CT) was the most commonly used imaging modality, followed by chest radiography and magnetic resonance imaging (MRI). Several qualitative and quantitative scoring systems were presented and most showed good correlation with BPD severity. The association with functional and clinical outcomes was only rarely reported, showing varying correlation with spirometry results and respiratory exacerbations. MRI is an upcoming imaging technique for BPD that is technically feasible, showing clear differences in the lung parenchyma of patients with BPD. CONCLUSION: Several imaging and scoring methods indicate that lung imaging continues to play a role in BPD care. Standardization and correlation with functional and clinical outcomes will become increasingly important for further research.


Assuntos
Displasia Broncopulmonar/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Progressão da Doença , Feminino , Humanos , Lactente , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Nascimento Prematuro , Radiografia Torácica , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X
14.
Int J Stroke ; 14(6): 620-629, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30875277

RESUMO

BACKGROUND: Time to reperfusion treatment is closely related to outcome in ischemic stroke. Prehospital stroke work-up in CT-equipped mobile stroke units is effective in reducing time to thrombolytic treatment. Current evidence predominantly comes from mobile stroke units staffed with neurologists but telemedicine-guided management may be acceptable for providing neurological expertise in ambulances. With unsatisfactory experiences in third-generation (3G)-based approaches, fourth-generation (4G) networks may provide adequate audio-visual quality but systematic comparisons of technological parameters and decision-making are lacking. METHODS: Trained actors presented stroke symptoms and paramedics assisted the remotely guided extended National Institutes of Health Stroke Scale (eNIHSS) assessment on the mobile stroke unit in Berlin, Germany. We compared technical parameters of 4G and 3G connections, assessed audio-visual quality of examination, and analyzed reliability of neurological assessment and treatment decisions made by the remote neurologist versus the mobile stroke unit neurologist. RESULTS: 4G and 3G connections were evaluated in 40 scenarios each. Connectivity was not available in 17% of 4G- and 15% of 3G-attempts with 6% simultaneous unavailability of both networks. The remote examiners graded audio and video quality in 4G better than in 3G with slightly shorter assessment duration in 4G (mean: 9 (SD:5) vs. mean 11 (SD:3) min, p = 0.10). Reliability of the eNIHSS sum scores was high with intraclass correlation coefficients of 0.99 (95% CI: 0.987-1.00) for 4G and 0.98 (95% CI: 0.96-0.99) for 3G. None of the remote treatment decisions differed from onsite decisions. CONCLUSIONS: 4G mobile communications provided higher quality of video-examination and allowed reliable remote assessment of stroke symptoms but coverage was still incomplete in both networks.


Assuntos
Tomada de Decisão Clínica , Serviços Médicos de Emergência/métodos , Exame Neurológico/métodos , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/diagnóstico , Telemedicina/métodos , Recursos Audiovisuais , Humanos , Simulação de Paciente , Reprodutibilidade dos Testes , Acidente Vascular Cerebral/terapia , Fatores de Tempo
15.
Br J Clin Pharmacol ; 85(1): 126-135, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30321459

RESUMO

AIMS: Paracetamol is the analgesic most used by older people. The physiological changes occurring with ageing influence the pharmacokinetics (PK) of paracetamol and its variability. We performed a population PK-analysis to describe the PK of intravenous (IV) paracetamol in fit older people. Simulations were performed to illustrate target attainment and variability of paracetamol exposure following current dosing regimens (1000 mg every 6 h, every 8 h) using steady-state concentration (Css-mean ) of 10 mg l-1 as target for effective analgesia. METHODS: A population PK-analysis, using NONMEM 7.2, was performed based on 601 concentrations of paracetamol from 30 fit older people (median age 77.3 years, range [61.8-88.5], body weight 79 kg [60-107]). All had received an IV paracetamol dose of 1000 mg (over 15 min) after elective knee surgery. RESULTS: A two-compartment PK-model best described the data. Volume of distribution of paracetamol increased exponentially with body weight. Clearance was not influenced by any covariate. Simulations of the standardized dosing regimens resulted in a Css of 9.2 mg l-1 and 7.2 mg l-1 , for every 6 h and every 8 h respectively. Variability in paracetamol PK resulted in Css above 5.4 and 4.1 mg l-1 , respectively, in 90% of the population and above 15.5 and 11.7, respectively, in 10% at these dosing regimens. CONCLUSIONS: The target concentration was achieved in the average patient with 1000 mg every 6 h, while every 8 h resulted in underdosing for the majority of the population. Furthermore, due to a large (unexplained) interindividual variability in paracetamol PK a relevant proportion of the fit older people remained either under- or over exposed.


Assuntos
Acetaminofen/farmacocinética , Analgésicos não Narcóticos/farmacocinética , Variação Biológica da População , Modelos Biológicos , Acetaminofen/administração & dosagem , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Analgesia/métodos , Analgésicos não Narcóticos/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade
16.
Br J Clin Pharmacol ; 85(3): 601-615, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30552703

RESUMO

AIMS: The aims of this study were to describe the pharmacokinetics of tacrolimus immediately after kidney transplantation, and to develop a clinical tool for selecting the best starting dose for each patient. METHODS: Data on tacrolimus exposure were collected for the first 3 months following renal transplantation. A population pharmacokinetic analysis was conducted using nonlinear mixed-effects modelling. Demographic, clinical and genetic parameters were evaluated as covariates. RESULTS: A total of 4527 tacrolimus blood samples collected from 337 kidney transplant recipients were available. Data were best described using a two-compartment model. The mean absorption rate was 3.6 h-1 , clearance was 23.0 l h-1 (39% interindividual variability, IIV), central volume of distribution was 692 l (49% IIV) and the peripheral volume of distribution 5340 l (53% IIV). Interoccasion variability was added to clearance (14%). Higher body surface area (BSA), lower serum creatinine, younger age, higher albumin and lower haematocrit levels were identified as covariates enhancing tacrolimus clearance. Cytochrome P450 (CYP) 3A5 expressers had a significantly higher tacrolimus clearance (160%), whereas CYP3A4*22 carriers had a significantly lower clearance (80%). From these significant covariates, age, BSA, CYP3A4 and CYP3A5 genotype were incorporated in a second model to individualize the tacrolimus starting dose: [Formula: see text] Both models were successfully internally and externally validated. A clinical trial was simulated to demonstrate the added value of the starting dose model. CONCLUSIONS: For a good prediction of tacrolimus pharmacokinetics, age, BSA, CYP3A4 and CYP3A5 genotype are important covariates. These covariates explained 30% of the variability in CL/F. The model proved effective in calculating the optimal tacrolimus dose based on these parameters and can be used to individualize the tacrolimus dose in the early period after transplantation.


Assuntos
Rejeição de Enxerto/prevenção & controle , Imunossupressores/farmacocinética , Transplante de Rim/efeitos adversos , Modelos Biológicos , Tacrolimo/farmacocinética , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Variação Biológica da População/fisiologia , Simulação por Computador , Citocromo P-450 CYP3A/genética , Relação Dose-Resposta a Droga , Feminino , Rejeição de Enxerto/imunologia , Humanos , Imunossupressores/administração & dosagem , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Tacrolimo/administração & dosagem , Transplantados , Adulto Jovem
17.
Pharmacol Res ; 130: 303-307, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29501679

RESUMO

The number of elderly people has increased considerably over the last decades, due to a rising life expectancy and ageing populations. As a result, an increased number of elderly with end-stage-renal-disease are diagnosed, for which the preferred treatment is renal transplantation. Over the past years the awareness of the elderly as a specific patient population has grown, which increases the importance of research in this group. Elderly patients often receive kidneys from elderly donors while younger donor kidneys are preferentially reserved for younger recipients. Although the rate of acute rejection after transplantation is lower in the elderly, these rejections may lead to graft loss more frequently, as kidneys from elderly donors have marginal reserve capacity. To prevent acute rejection, immunosuppressive therapy is needed. On the other hand, elderly patients have a higher risk to die from infectious complications, and thus less immunosuppression would be preferable. Immunosuppressive treatment in the elderly is complicated further by changes in the pharmacokinetics and pharmacodynamics, with increasing age. Adjustments in standard immunosuppressive regimes are therefore suggested for this population. An unmet need in transplantation medicine is a tool to guide a personalized approach to immunosuppression. Recently several promising biomarkers that identify injury to the graft at an early stage or predict acute rejection have been identified. Unfortunately, none of these biomarkers were tested specifically in the elderly. We believe there is an urgent need to perform clinical trials investigating novel immunosuppressive regimens in conjunction with biomarker studies in this specific population.


Assuntos
Imunossupressores/uso terapêutico , Transplante de Rim , Medicina de Precisão , Idoso , Animais , Biomarcadores , Fragilidade , Humanos , Terapia de Imunossupressão , Imunossupressores/farmacologia
18.
Urologe A ; 56(11): 1435-1439, 2017 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-29022046

RESUMO

Since November 2013, the alpha emitter radium-223 dichloride (Alpharadin/Xofigo®) has been approved for the treatment of men with castration-resistant prostate cancer (CRPC) with symptomatic bone metastases and no known visceral metastatic disease. In the ASYMPCA clinical trial, radium-223 was shown to improve overall survival and to reduce the time to the first symptomatic skeletal event. The use of radium-223 was associated with a reduction of pain and an improvement of health-related quality of life compared to the placebo arm. The efficacy of radium-223 dichloride was not inhibited by the use of chemotherapy with docetaxel. Studies have demonstrated a longer overall survival (OS) in patients with a combined treatment of abiraterone or enzalutamide; however, until this data is validated in larger clinical trials, the combination of radium-223 and abiraterone/enzalutamide cannot be recommended. Patients who have received concomitant medication with denosumab appeared to have a longer OS compared to patients who did not. A second treatment cycle of radium-223 was not associated with any adverse events when compared to the outcomes reported in the ASLYMPCA trial. Here the median radiographic progression-free survival was 9 months.


Assuntos
Neoplasias de Próstata Resistentes à Castração/radioterapia , Rádio (Elemento)/uso terapêutico , Androstenos/uso terapêutico , Benzamidas , Neoplasias Ósseas/patologia , Neoplasias Ósseas/radioterapia , Neoplasias Ósseas/secundário , Ensaios Clínicos como Assunto , Terapia Combinada , Denosumab/uso terapêutico , Humanos , Masculino , Estadiamento de Neoplasias , Nitrilas , Feniltioidantoína/análogos & derivados , Feniltioidantoína/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/patologia , Radioisótopos/uso terapêutico , Retratamento
19.
Eur J Clin Pharmacol ; 73(10): 1271-1277, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28681176

RESUMO

PURPOSE: Over 80% of the terminally ill patients experience delirium in their final days. In the treatment of delirium, haloperidol is the drug of choice. Very little is known about the pharmacokinetics of haloperidol in this patient population. We therefore designed a population pharmacokinetic study to gain more insight into the pharmacokinetics of haloperidol in terminally ill patients and to find clinically relevant covariates that may be used in developing an individualised dosing regimen. METHODS: Using non-linear mixed effects modelling (NONMEM 7.2), a population pharmacokinetic analysis was conducted with 87 samples from 28 terminally ill patients who received haloperidol either orally or subcutaneously. The covariates analysed were patient and disease characteristics as well as co-medication. RESULTS: The data were accurately described by a one-compartment model. The population mean estimates for oral bioavailability, clearance and volume of distribution for an average patient were 0.86 (IIV 55%), 29.3 L/h (IIV 43%) and 1260 L (IIV 70%), respectively. This resulted in an average terminal half-life of haloperidol of around 30 h. CONCLUSION: Our study showed that the pharmacokinetics of haloperidol could be adequately described by a one-compartment model. The pharmacokinetics in terminally ill patients was comparable to other patients. We were not able to explain the wide variability using covariates.


Assuntos
Antipsicóticos/farmacocinética , Delírio/tratamento farmacológico , Haloperidol/farmacocinética , Modelos Biológicos , Cuidados Paliativos , Doente Terminal , Adulto , Idoso , Idoso de 80 Anos ou mais , Antipsicóticos/administração & dosagem , Antipsicóticos/uso terapêutico , Simulação por Computador , Delírio/sangue , Feminino , Haloperidol/administração & dosagem , Haloperidol/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos
20.
J Vet Intern Med ; 31(4): 994-999, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28617995

RESUMO

BACKGROUND: N-terminal prohormone of brain natriuretic peptide (NT-proBNP) concentrations may be increased in cats with various cardiac disorders. The point-of-care (POC) ELISA assay uses the same biologic reagents as the quantitative NT-proBNP ELISA. Previous studies have evaluated the sensitivity and specificity of the POC ELISA in cats with cardiac disease. OBJECTIVES: To prospectively evaluate the diagnostic utility of the POC ELISA in a select population of cats. ANIMALS: Thirty-eight client-owned cats presented to the University of Florida Cardiology Service for cardiac evaluation. Fifteen apparently healthy cats recruited as part of another study. METHODS: Physical examination and echocardiography were performed in all cats. The POC ELISA was assessed visually as either positive or negative by a reader blinded to the echocardiographic findings, and results were analyzed relative to quantitative assay results. RESULTS: Twenty-six cats were diagnosed with underlying cardiac disease, and 27 cats were considered free of cardiac disease. Cats with cardiac disease included: 21 with hypertrophic cardiomyopathy, 2 with unclassified cardiomyopathy, 2 with restrictive cardiomyopathy, and 1 with 3rd degree atrioventricular (AV) block. The POC ELISA differentiated cats with cardiac disease with a sensitivity of 65.4% and specificity of 100%. CONCLUSIONS AND CLINICAL IMPORTANCE: The POC NT-proBNP ELISA performed moderately well in a selected population of cats. A negative test result cannot exclude the presence of underlying cardiac disease, and a positive test result indicates that cardiac disease likely is present, but further diagnostic investigation would be indicated for a definitive diagnosis.


Assuntos
Doenças do Gato/diagnóstico , Ensaio de Imunoadsorção Enzimática/veterinária , Cardiopatias/veterinária , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Animais , Bloqueio Atrioventricular/sangue , Bloqueio Atrioventricular/diagnóstico , Bloqueio Atrioventricular/veterinária , Cardiomiopatias/sangue , Cardiomiopatias/diagnóstico , Cardiomiopatias/veterinária , Cardiomiopatia Hipertrófica/sangue , Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/veterinária , Estudos de Casos e Controles , Doenças do Gato/sangue , Gatos , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Cardiopatias/sangue , Cardiopatias/diagnóstico , Masculino , Sistemas Automatizados de Assistência Junto ao Leito , Sensibilidade e Especificidade
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