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1.
Graefes Arch Clin Exp Ophthalmol ; 260(4): 1083-1095, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34643793

RESUMO

PURPOSE: Although intraocular anti-vascular endothelial growth factors (anti-VEGFs) are effective as treatment of neovascular age-related macular degeneration (nAMD), the (economic) burden on the healthcare system is considerable. A treat-and-extend (T&E) regimen is associated with a lower number of injections without compromising the effectiveness and can therefore help optimise nAMD treatment. This study investigates the per-patient costs associated with nAMD treatment, when using aflibercept, bevacizumab, or ranibizumab with a T&E regimen. METHODS: In this cost-minimisation model, the per-patient costs in the Netherlands were modelled using a healthcare payers' perspective over a 3-year time horizon with the assumption that efficacy of treatments is similar. Additionally, the break-even price of the different anti-VEGFs was calculated relative to the cheapest option and injection frequency. RESULTS: The injection frequency varied from 14.2 for aflibercept to 27.4 for bevacizumab in 3 years. Nonetheless, bevacizumab remains the cheapest treatment option (€14,215), followed by aflibercept (€18,202) and ranibizumab (€31,048). The medication covers the majority of the per-patient costs for aflibercept and ranibizumab, while administration covers the majority of the per-patient costs for bevacizumab. The break-even prices of aflibercept and ranibizumab are respectively €507 and €60.58 per injection. Brolucizumab was included in the scenario analysis and was more expensive than aflibercept (€20,446). Brolucizumab should reduce to 13.8 injections over 3 years to be as costly as aflibercept. CONCLUSION: Bevacizumab is the cheapest anti-VEGF treatment. The list prices of all anti-VEGFs should reduce to be as costly as bevacizumab. Aflibercept is the second-choice treatment and so far brolucizumab is not.


Assuntos
Degeneração Macular , Receptores de Fatores de Crescimento do Endotélio Vascular , Inibidores da Angiogênese , Bevacizumab , Humanos , Injeções Intravítreas , Degeneração Macular/tratamento farmacológico , Ranibizumab , Proteínas Recombinantes de Fusão/uso terapêutico , Resultado do Tratamento , Acuidade Visual
2.
Eur J Health Econ ; 24(9): 1455-1472, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36633725

RESUMO

OBJECTIVES: The aim of this study was to evaluate the cost-effectiveness of ravulizumab compared with eculizumab for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH) in the Netherlands. METHODS: A cost-effectiveness analysis was conducted based on a Markov cohort model simulating the course of patients with PNH with clinical symptom(s) indicative of high disease activity, or who are clinically stable after having been treated with eculizumab for at least the past six months. Costs, quality of life, and the incremental cost-effectiveness ratio (ICER) were estimated over a lifetime horizon from a Dutch societal perspective. Several additional analyses were performed, including a one-way sensitivity analysis, a probabilistic sensitivity analysis, and scenario analysis. RESULTS: When compared with eculizumab, ravulizumab saves €266,833 and 1.57 quality adjusted life years (QALYs) are gained, resulting in a dominant ICER. Drug costs account for the majority of the total costs in both intervention groups. Cost savings were driven by the difference in total treatment costs of ravulizumab compared with eculizumab caused by the reduced administration frequency, accounting for 98% of the total cost savings. The QALY gain with ravulizumab is largely attributable to the improved quality of life associated with less frequent infusions and BTH events. At a willingness-to-pay threshold of €20,000/QALY, there is a 76.6% probability that ravulizumab would be cost-effective. CONCLUSIONS: The cost reduction and QALY gain associated with the lower rates of BTH and less frequent administration make ravulizumab a cost-saving and clinically beneficial substitute for eculizumab for adults with PNH in the Netherlands.


Assuntos
Hemoglobinúria Paroxística , Adulto , Humanos , Hemoglobinúria Paroxística/tratamento farmacológico , Análise Custo-Benefício , Qualidade de Vida , Países Baixos
3.
Pharmacoecon Open ; 7(6): 1007-1013, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37608071

RESUMO

INTRODUCTION: This review aims to critically appraise differences in methodology and quality of model-based and empirical-data-based cost-utility studies to address key limitations, opportunities, and challenges to inform future cost-utility analyses of continuous glucose monitoring (CGM) in type 1 diabetes. This protocol is registered at PROSPERO (CRD42023391284). METHODS: The review will be conducted in accordance with the PRISMA guideline for systematic reviews. Searches will be conducted in MEDLINE, Embase, Web of Science, Cochrane Library, and Econlit from 2000 to January 2023. Model and empirical data-based studies evaluating the cost-utility of any CGM system in type 1 diabetes will be considered for inclusion. Studies that only report on cost per life year or any other clinical outcome, or reporting only costs or only clinical outcomes studies in type 2 diabetes populations, and studies on bi-hormonal closed loops and do-it-yourself hybrid closed loop devices will be excluded. Two reviewers will independently screen each study for inclusion. Data on the intervention, population, model settings (such as perspective, time horizon), model type and structure, clinical outcomes used to populate the model, validation, and uncertainty will be extracted and qualitatively synthesised. Quality will be assessed using the Philips et al. 2006 (model-based studies) or Consensus Health Economic Criteria (empirical data-based studies) checklists. Model validation will be assessed using the AdViSHE checklist. DISCUSSION: Now that CGM is being used more broadly in practice, critical appraisal of existing cost-utility methodology and quality is important to inform future cost-utility analyses of CGM in type 1 diabetes in various settings.

4.
J Biomech ; 108: 109895, 2020 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-32636007

RESUMO

The Shank-to-Vertical Angle (SVA) is a commonly used parameter to describe orthotic alignment. 3D gait analysis (3DGA) or 2D video analysis are usually used to assess the SVA, but are not always feasible in clinical practice. As an alternative, an Inertial Measurement Unit (IMU) attached and aligned to the shank might be used. This study aimed to investigate the validity, inter-rater reliability and optimal location of a single IMU on the shank to assess the SVA. Thirteen healthy participants (7 m/6f, mean age: 45 ± 18 years) were recorded during quiet standing and barefoot walking using a 3D motion capture system and, simultaneously, with IMUs on the shank. The IMUs were anatomically placed and aligned at two different locations, i.e. anterior, in line with the tibial tuberosity and midline of the ankle (anterior IMU), and lateral, in line with the lateral epicondyle and lateral malleolus (lateral IMU). For each participant, the IMUs were placed by two different researchers. A paired t-test, Bland Altmann analysis (mean difference, repeatability coefficient) and intraclass correlation coefficient (ICC) between the 3DGA and both IMUs, and between raters, was performed. Although validity and reliability of the lateral IMU was low, good validity and inter-rater reliability was found for the anterior IMU (Rater1: mean difference: -0.7 ± 2.1, p = 0.27; ICC = 0.83 and Rater2: mean difference: -0.4 ± 1.9, p = 0.46; ICC = 0.86). Hence, a single IMU placed at the anterior side of the shank is a valid and reliable method to assess the SVA during standing and walking in healthy adults.


Assuntos
Marcha , Caminhada , Adulto , Análise da Marcha , Humanos , Perna (Membro) , Pessoa de Meia-Idade , Reprodutibilidade dos Testes
5.
Gait Posture ; 76: 92-97, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31743873

RESUMO

BACKGROUND: Improvement of balance control is an important rehabilitation goal for patients with motor and sensory impairments. To quantify balance control during walking, various stability outcome measures have described differences between healthy controls and patient groups with balance problems. To be useful for the evaluation of interventions or monitoring of individual patients, stability outcome measures need to be reliable. RESEARCH QUESTION: What is the test-retest reliability of six stability outcome measures during gait? METHODS: Patients with balance problems (n = 45) and healthy controls (n = 20) performed two times a two-minute walk test (2MWT). The intraclass correlation coefficient (ICC) and Bland-Altman analysis (coefficient of repeatability; CR) were used to evaluate the test-retest reliability of six stability outcome measures: dynamic stability margin (DSM), margin of stability (MoS), distance between the extrapolated centre of mass (XCoM) and centre of pressure (CoP) in anterior-posterior (XCoM-CoPAP) and medial-lateral (XCoM-CoPML) direction, and inclination angle between centre of mass (CoM) and CoP in anterior-posterior (CoM-CoPAP-angle) and medial-lateral (CoM-CoPML-angle) direction. A two way mixed ANOVA was performed to reveal measurement- and group-effects. RESULTS: The ICCs of all stability outcome measures ranged between 0.51 and 0.97. Significant differences between the measurements were found for the DSM (p = 0.017), XCoM-CoPAP (p = 0.008) and CoM-CoPAP-angle (p = 0.001). Significant differences between controls and patients were found for all stability outcome measures (p < 0.01) except for the MoS (p = 0.32). For the XCoM-CoP distances and CoM-CoP angles, the CRs were smaller than the difference between patients and controls. SIGNIFICANCE: Based on the ICCs, the reliability of all stability outcome measures was moderate to excellent. Since the XCoM-CoPML and CoM-CoPML-angle showed no differences between the measurements and smaller CRs than the differences between patients and controls, the XCoM-CoPML and CoM-CoPML-angle seem the most promising stability outcome measures to evaluate interventions and monitor individual patients.


Assuntos
Monitorização Fisiológica , Equilíbrio Postural , Caminhada , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Transtornos de Sensação/fisiopatologia
6.
BJS Open ; 4(2): 293-300, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31950702

RESUMO

BACKGROUND: Selected patients with colorectal peritoneal metastases are treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The concentration of intraperitoneal chemotherapy reflects the administered dose and perfusate volume. The aim of this study was to calculate intraperitoneal chemotherapy concentration during HIPEC and see whether this was related to clinical outcomes. METHODS: An observational multicentre study included consecutive patients with colorectal peritoneal metastases who were treated with CRS-HIPEC between 2010 and 2018 at three Dutch centres. Data were retrieved from prospectively developed databases. Chemotherapy dose and total circulating volumes of carrier solution were used to calculate chemotherapy concentrations. Postoperative complications, disease-free and overall survival were correlated with intraoperative chemotherapy concentrations. Univariable and multivariable logistic regression, Cox regression and survival analyses were performed. RESULTS: Of 320 patients, 220 received intraperitoneal mitomycin C (MMC) and 100 received oxaliplatin. Median perfusate volume for HIPEC was 5·0 (range 0·7-10·0) litres. Median intraperitoneal chemotherapy concentration was 13·3 (range 7·0-76·0) mg/l for MMC and 156·0 (91·9-377·6) mg/l in patients treated with oxaliplatin. Grade III or higher complications occurred in 75 patients (23·4 per cent). Median overall survival was 36·9 (i.q.r. 19·5-62·9) months. Intraperitoneal chemotherapy concentrations were not associated with postoperative complications or survival. CONCLUSION: CRS-HIPEC was performed with a wide variation in intraperitoneal chemotherapy concentrations that were not associated with complications or survival.


ANTECEDENTES: Ciertos pacientes seleccionados con metástasis peritoneales de cáncer colorrectal (peritoneal metastases, PM) se tratan con cirugía citorreductora (cytoreductive surgery, CRS) y quimioterapia intraperitoneal hipertérmica (hyperthermic intraperitoneal chemotherapy, HIPEC). La concentración de quimioterapia intraperitoneal refleja la dosis administrada y el volumen perfundido. El objetivo de este estudio fue calcular la concentración de quimioterapia intraperitoneal durante HIPEC y evaluar si ello se relacionaba con los resultados clínicos. MÉTODOS: Estudio observacional multicéntrico en el que se incluyeron pacientes consecutivos con PM de cáncer colorrectal que fueron tratados con CRS-HIPEC entre 2010 y 2018 en tres centros holandeses. Se obtuvieron los datos a partir de bases de datos mantenidas de forma prospectiva. La dosis de quimioterapia y los volúmenes circulantes totales de solución de perfusión se usaron para calcular las concentraciones de quimioterapia. Las complicaciones postoperatorias y las supervivencias libre de enfermedad y global se correlacionaron con las concentraciones de quimioterapia intraoperatoria. Se realizaron regresiones logísticas univariable y multivariable, regresión de Cox y análisis de supervivencia. RESULTADOS: De 320 pacientes, 220 recibieron mitomicina C intraperitoneal (MMC) y 100 oxaliplatino (OXA). El volumen medio de perfusión para HIPEC fue 5,0 L (rango 0,7-10,0). La mediana de concentración intraperitoneal del agente quimioterápico fue de 13,3 mg/L (rango 7,0-76,0) para MMC y 156,0 mg/L (rango 91,9 - 377,6) en pacientes tratados con OXA. Las complicaciones de grado 3 o mayores ocurrieron en 23,4% (n = 75). La mediana de supervivencia global fue de 36,9 meses (rango intercuartílico 19,5-62,9). Las concentraciones de quimioterapia intraperitoneal no se asociaron con las complicaciones postoperatorias ni con la supervivencia. CONCLUSIÓN: La CRS-HIPEC se realizó con una amplia variación en las concentraciones de quimioterapia intraperitoneal que no se asociaron con las complicaciones ni con la supervivencia.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Quimioterapia Intraperitoneal Hipertérmica/métodos , Mitomicina/administração & dosagem , Oxaliplatina/administração & dosagem , Neoplasias Peritoneais/tratamento farmacológico , Adulto , Idoso , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Terapia Combinada , Procedimentos Cirúrgicos de Citorredução/métodos , Bases de Dados Factuais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mitomicina/uso terapêutico , Morbidade , Países Baixos , Oxaliplatina/uso terapêutico , Neoplasias Peritoneais/secundário , Complicações Pós-Operatórias/epidemiologia , Estudos Prospectivos , Análise de Sobrevida
7.
J Appl Physiol (1985) ; 124(6): 1597-1604, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29543137

RESUMO

Impaired muscle relaxation is a feature of many neuromuscular disorders. However, few tests are available to quantify muscle relaxation. Transcranial magnetic stimulation (TMS) of the motor cortex can induce muscle relaxation by abruptly inhibiting corticospinal drive. The aim of our study was to investigate whether repeatability and reliability of TMS-induced relaxation are greater than voluntary relaxation. Furthermore, effects of sex, cooling, and fatigue on muscle relaxation properties were studied. Muscle relaxation of deep finger flexors was assessed in 25 healthy subjects (14 men and 11 women, age 39.1 ± 12.7 and 45.3 ± 8.7 yr, respectively) with handgrip dynamometry. All outcome measures showed greater repeatability and reliability in TMS-induced relaxation compared with voluntary relaxation. The within-subject coefficient of variability of normalized peak relaxation rate was lower in TMS-induced relaxation than in voluntary relaxation (3.0% vs. 19.7% in men and 6.1% vs. 14.3% in women). The repeatability coefficient was lower (1.3 vs. 6.1 s-1 in men and 2.3 vs. 3.1 s-1 in women) and the intraclass correlation coefficient was higher (0.95 vs. 0.53 in men and 0.78 vs. 0.69 in women) for TMS-induced relaxation compared with voluntary relaxation. TMS enabled demonstration of slowing effects of sex, muscle cooling, and muscle fatigue on relaxation properties that voluntary relaxation could not. In conclusion, repeatability and reliability of TMS-induced muscle relaxation were greater compared with voluntary muscle relaxation. TMS-induced muscle relaxation has the potential to be used in clinical practice for diagnostic purposes and therapy effect monitoring in patients with impaired muscle relaxation. NEW & NOTEWORTHY Transcranial magnetic stimulation (TMS)-induced muscle relaxation demonstrates greater repeatability and reliability compared with voluntary relaxation, represented by the ability to demonstrate typical effects of sex, cooling, and fatigue on muscle relaxation properties that were not seen in voluntary relaxation. In clinical practice, TMS-induced muscle relaxation could be used for diagnostic purposes and therapy effect monitoring. Furthermore, fewer subjects will be needed for future studies when using TMS to demonstrate differences in muscle relaxation properties.


Assuntos
Relaxamento Muscular , Estimulação Magnética Transcraniana , Adulto , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade
8.
Neth J Med ; 76(10): 426-430, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30569888

RESUMO

In 2012, the Dutch Health Council published a report addressing barriers for an early and broad introduction of direct oral anticoagulants (DOACs). The report raised concerns about the lack of an antidote, adherence, lack of monitoring in the case of overdose and the increased budget impact at DOAC introduction. In the past decade, international studies have shown that DOACs can provide healthcare benefits for a large number of patients. This has led to an increase in the prescription of DOACs, as they are an effective and user-friendly alternative to vitamin K antagonists (VKAs). Unlike VKAs, DOACs do not need monitoring of the international normalized ratio due to more predictable pharmacokinetics. However, the number of prescriptions of DOACs in the Netherlands is still lagging, compared to other European countries. This article highlights the potential health gains in the Netherlands if the use of DOACs were to increase, based on current international experience.


Assuntos
Fibrilação Atrial/tratamento farmacológico , Inibidores do Fator Xa , Acidente Vascular Cerebral/prevenção & controle , Tromboembolia Venosa/tratamento farmacológico , Inibidores do Fator Xa/classificação , Inibidores do Fator Xa/farmacologia , Humanos , Conduta do Tratamento Medicamentoso/organização & administração , Conduta do Tratamento Medicamentoso/tendências , Países Baixos , Preferência do Paciente , Medição de Risco
9.
Cancer Res ; 59(18): 4559-63, 1999 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-10493507

RESUMO

Topotecan- or mitoxantrone-selected cell lines (T8 and MX3, respectively), derived from the human IGROV1 ovarian cancer cell line, were resistant to the topoisomerase I inhibitors topotecan, SN-38 (the active metabolite of irinotecan), and 9-aminocamptothecin, as well as to the topoisomerase II drug mitoxantrone. In both resistant cell lines, decreased accumulation of topotecan and mitoxantrone was observed, caused by enhanced energy-dependent efflux of the drugs involved. In both cell lines, we found that the breast cancer resistance protein/mitoxantrone resistance/placenta-specific ATP binding cassette (BCRP/MXR/ABCP) gene was overexpressed. Furthermore, BCRP/MXR/ABCP expression levels in various partially revertant T8 cells correlated with the levels of resistance to topotecan, SN-38, and mitoxantrone, strongly suggesting BCRP/MXR/ABCP to be the transporter responsible for the enhanced efflux. Pharmacodynamic analysis demonstrated that BCRP/MXR/ABCP is a very efficient transporter of topotecan; in vitro, 70% of the intracellular topotecan pool was transported out of the T8 or MX3 cells within 30 s. In conclusion, we report for the first time that BCRP/MXR/ABCP can also be up-regulated upon exposure of tumor cells to the clinically important drug topotecan, and that BCRP-mediated efflux of topotecan is very efficient. This highly efficient efflux of topotecan by BCRP/MXR/ABCP may have clinical relevance for patients being treated with topotecan.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Antineoplásicos Fitogênicos/toxicidade , Resistência a Múltiplos Medicamentos , Regulação Neoplásica da Expressão Gênica , Mitoxantrona/toxicidade , Proteínas de Neoplasias , Topotecan/toxicidade , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Camptotecina/análogos & derivados , Camptotecina/toxicidade , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Irinotecano , Cinética , Neoplasias Ovarianas , Células Tumorais Cultivadas
10.
PLoS One ; 11(10): e0163550, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27776137

RESUMO

BACKGROUND: Dabigatran was proven to have similar effect on the prevention of recurrence of venous thromboembolism (VTE) and a lower risk of bleeding compared to vitamin K antagonists (VKA). The aim of this study is to assess the cost-effectiveness (CE) of dabigatran for the treatment and secondary prevention in patients with VTE compared to VKAs in the Dutch setting. METHODS: Previously published Markov model was modified and updated to assess the CE of dabigatran and VKAs for the treatment and secondary prevention in patients with VTE from a societal perspective in the base-case analysis. The model was populated with efficacy and safety data from major dabigatran trials (i.e. RE-COVER, RECOVER II, RE-MEDY and RE-SONATE), Dutch specific costs, and utilities derived from dabigatran trials or other published literature. Univariate, probabilistic sensitivity and a number of scenario analyses evaluating various decision-analytic settings (e.g. the perspective of analysis, use of anticoagulants only for treatment or only for secondary prevention, or comparison to no treatment) were tested on the incremental cost-effectiveness ratio (ICER). RESULTS: In the base-case scenario, patients on dabigatran gained an additional 0.034 quality adjusted life year (QALY) while saving €1,598. Results of univariate sensitivity analysis were quite robust. The probability that dabigatran is cost-effective at a willingness-to-pay threshold of €20,000/QALY was 98.1%. From the perspective of healthcare provider, extended anticoagulation with dabigatran compared to VKAs was estimated at €2,158 per QALY gained. The ICER for anticoagulation versus no treatment in patients with equipoise risk of recurrent VTE was estimated at €33,379 per QALY gained. Other scenarios showed dabigatran was cost-saving. CONCLUSION: From a societal perspective, dabigatran is likely to be a cost-effective or even cost-saving strategy for treatment and secondary prevention of VTE compared to VKAs in the Netherlands.


Assuntos
Antitrombinas/uso terapêutico , Análise Custo-Benefício , Dabigatrana/uso terapêutico , Tromboembolia Venosa/tratamento farmacológico , Tromboembolia Venosa/prevenção & controle , Humanos , Modelos Teóricos , Países Baixos , Probabilidade , Tromboembolia Venosa/economia
11.
Clin Cancer Res ; 7(4): 935-41, 2001 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11309344

RESUMO

This study was aimed at characterizing the role of BCRP/MXR/ABCP (BCRP) in resistance of the human ovarian tumor cell lines T8 and MX3 to camptothecins more extensively and investigating whether resistance can be reversed by inhibiting BCRP by GF120918. Camptothecins studied were topotecan, CPT-11, and its active metabolite SN-38, 9-aminocamptothecin, and the novel experimental camptothecins NX211, DX8951f, and BNP1350. Notably, DX8951f and BNP1350 appeared to be very poor substrates for BCRP, with much lower resistance factors observed both in T8 and MX3 cells than observed for the other camptothecins tested. In the presence of a nontoxic dose level of GF120918, the intracellular accumulation of topotecan in the T8 and MX3 cells was completely restored to the intracellular levels observed in the sensitive IGROV1 parental cell line. This resulted in almost complete reversal of drug resistance to topotecan and to most of the other topoisomerase I drugs tested in the T8 cell line and to complete reversal in the MX3 cells. However, coincubation of DX8951f or BNP1350 with GF120918 did not affect the cytotoxicity of either of these drugs significantly. From the combined data, we conclude that the affinities of topoisomerase I drugs for BCRP are, in decreasing order: SN-38 > topotecan > 9-aminocamptothecin approximately CPT-11 > NX211 > DX8951f > BNP1350. Furthermore, GF120918 appears to be a potent reversal agent of BCRP-mediated resistance to camptothecins, with almost complete reversal noted at 100 nM. Potential BCRP-mediated resistance to topoisomerase I inhibitors can also be avoided by using the BCRP-insensitive drugs DX8951f or BNP1350. This observation may have important clinical implications for future development of novel camptothecins.


Assuntos
Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Acridinas/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Camptotecina/farmacologia , Isoquinolinas/farmacologia , Proteínas de Neoplasias , Tetra-Hidroisoquinolinas , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Interações Medicamentosas , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células Tumorais Cultivadas
12.
J Neuroimmunol ; 119(1): 124-30, 2001 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-11525809

RESUMO

Experimental autoimmune encephalomyelitis (EAE) induced by immunization of mice with epitopes of the proteolipid protein (PLP), a major myelin constituent, forms a useful model for the study of multiple sclerosis (MS). In addition, MS patients display PLP-specific T- and B-cell responses, suggesting that PLP reactivity is relevant to pathogenesis.Here, the generation and characterization of a panel of mouse monoclonal antibodies (Mab) against PLP139-151, the prominent encephalitogenic sequence in SJL/J mice is described. Five Mab were generated by conventional immunization of an SJL/J mouse and hybridoma generation. These Mab reacted well with the PLP139-151 peptide in ELISA and belonged to the IgG2a and IgG2b subclasses, consistent with CD4+ T helper 1-cell-supported antibody formation. The Mab also efficiently detected PLP peptide-BSA conjugates in Western blot, confirming their multi-assay applicability. The Mab were subsequently used to determine the occurrence of demyelination in brains of MS patients and marmoset monkeys with EAE. Immunohistochemistry on both paraffin and frozen sections demonstrated a homogeneous expression of PLP139-151 in normal myelin, and a complete absence in lesions containing demyelinated areas, confirming that the Mab can be used as a general myelin marker. In active demyelinating MS lesions, the Mab visualized the peptide in the cytoplasm of macrophages containing phagocytosed myelin. In conclusion, this panel of Mab against the encephalitogenic PLP139-151 epitope forms a useful tool for further study of autoantigen expression, demyelination/remyelination and the staging of lesional activity in MS patients, as well as in EAE models in distinct animal species.


Assuntos
Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Proteína Proteolipídica de Mielina/metabolismo , Bainha de Mielina/metabolismo , Bainha de Mielina/patologia , Fragmentos de Peptídeos/metabolismo , Animais , Anticorpos Monoclonais , Callithrix , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/patologia , Feminino , Humanos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos , Valores de Referência
13.
Invest Ophthalmol Vis Sci ; 36(8): 1665-74, 1995 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-7601646

RESUMO

PURPOSE: Blue-on-yellow (B-on-Y) perimetry assesses the S-cone visual field under yellow adaptation. Glaucomatous field defects have been shown to appear earlier and to be larger in B-on-Y perimetry than in standard perimetry. An upper limit to the use of B-on-Y perimetry is set by the separation of the S-cones from the M- and L-cones. But, because the S-cones may also input to the luminance channel, the actual separation of the color and luminance channels is unknown. Here, the relative sensitivities of the color and luminance channels under B-on-Y test conditions are measured. METHODS: In 15 eyes with early glaucoma, 19 risk eyes, and 10 normal eyes, B-on-Y thresholds were measured from 0 degrees to 20 degrees eccentric and were compared to pure chromatic (B-in-Y) and achromatic (Y-on-Y) thresholds, obtained under identical yellow adaptation. RESULTS: In normals, B-on-Y thresholds were found to coincide with B-in-Y thresholds; Y-on-Y values were 0.5 log (at 20 degrees) to 0.9 log (at 0 degrees) higher. In the pathologic groups, the differences between B-in-Y and Y-on-Y thresholds were smaller. Pathologic threshold elevation is on average 1.8 times larger for chromatic than for achromatic stimuli. In some cases, the luminance channel takes over detection of the B-on-Y stimulus. CONCLUSIONS: In normals, the B-on-Y stimulus is mediated by the color channel. Takeover of detection by the luminance channel might impose limits on following color defects with B-on-Y perimetry. This takeover may occur before the S-cones become less sensitive than the M- and L-cones and might indicate S-cone input to the luminance channel.


Assuntos
Percepção de Cores/fisiologia , Glaucoma de Ângulo Aberto/fisiopatologia , Hipertensão Ocular/fisiopatologia , Células Fotorreceptoras Retinianas Cones/fisiologia , Limiar Sensorial/fisiologia , Testes de Campo Visual/métodos , Idoso , Feminino , Humanos , Pressão Intraocular , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Campos Visuais
14.
Ophthalmic Genet ; 15(2): 51-60, 1994 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-7850269

RESUMO

A mother and daughter with autosomal dominant retinitis pigmentosa (adRP) were found to carry a cytosine-to-adenine transversion mutation at codon 4 of the rhodopsin gene. This mutation predicts a substitution of lysine for threonine at one of the glycosylation sites in the rhodopsin molecule (Thr4Lys). Both patients presented with a similar phenotype including a tigroid pattern of the posterior pole and a regional predilection for degenerative pigmentary changes in the inferior retina with corresponding visual field defects. The electroretinographic pattern was suggestive of RP of the cone-rod type. This report documents the clinical findings associated with this defined mutation of the rhodopsin gene.


Assuntos
Códon/genética , Células Fotorreceptoras/patologia , Mutação Puntual , Retinose Pigmentar/genética , Rodopsina/genética , Adulto , Eletrorretinografia , Feminino , Fundo de Olho , Humanos , Lisina , Pessoa de Meia-Idade , Países Baixos , Linhagem , Retinose Pigmentar/patologia , Treonina , Testes Visuais , Campos Visuais
16.
Lasers Med Sci ; 20(1): 41-4, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-15864689

RESUMO

PURPOSE: To describe the localisation of the Ex-PRESS miniature glaucoma implant with an experimental setup for optical coherence tomography (OCT) of the anterior segment of the eye. METHODS: An OCT scanner, central wavelength 1,280 nm, bandwidth 60 nm, resolution of 12 microm, was built onto a slitlamp to scan the anterior segment of the eye. Five ex-vivo porcine eyes received an Ex-PRESS miniature glaucoma implant and were used as a model to visualise the position of the implant in the anterior segment. RESULTS: In the ex-vivo porcine eyes, the OCT images showed the anatomy of the anterior segment in great detail. The anterior segment OCT was able to visualise the whole outline and position of the implant. The abrupt change in reflectivity going from tissue to the implant resulted in a clear border along the circumference of the whole device. CONCLUSION: In this paper, we have shown that we were able to outline the Ex-PRESS miniature glaucoma implant in the anterior segment of the ex-vivo porcine eye by using an experimental OCT setup built onto a slitlamp. The acquisition time of 0.8 s is short enough to allow for the scanning of patients, and anterior segment OCT is expected to aid in providing answers to the question regarding which parameters will determine the success or failure of such a device.


Assuntos
Implantes para Drenagem de Glaucoma , Glaucoma/diagnóstico , Glaucoma/cirurgia , Tomografia de Coerência Óptica , Animais , Segmento Anterior do Olho , Modelos Animais de Doenças , Sensibilidade e Especificidade , Suínos
17.
Doc Ophthalmol ; 75(3-4): 303-14, 1990 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-2090405

RESUMO

A perimetric method using blue stimuli on a yellow background was compared with perimetry using white stimuli on a white background as a method of detecting glaucomatous damage. Meridian perimetry was used with an adapted Tübinger perimeter. The difference between the blue-on-yellow meridian and the white-on-white meridian was subdivided into two parts: the general blue sensitivity loss (GBSL), probably due to optical factors, and the corrected blue sensitivity loss (CBSL), probably due to glaucoma. Nine normals, fourteen primary open angle glaucoma (POAG) patients and nine ocular hypertensives (OHT) were tested. All POAG patients and some of the OHT group showed higher CBSL values than the controls. The blue-yellow meridian showed broader and deeper defects than the white-white meridian in all of the POAG group; some of the OHT group had defects in the blue-yellow meridian that were not present in the white-white meridian. In conclusion, blue on yellow perimetry shows promise as a method for more sensitive detection of early glaucomatous damage.


Assuntos
Testes de Percepção de Cores , Glaucoma de Ângulo Aberto/diagnóstico , Testes de Campo Visual/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Sensibilidades de Contraste , Feminino , Humanos , Pressão Intraocular , Masculino , Pessoa de Meia-Idade , Hipertensão Ocular/diagnóstico
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