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2.
Br J Surg ; 107(1): 87-95, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31573084

RESUMO

BACKGROUND: When the blood supply ceases in a deceased organ donor, ischaemic injury starts. Kidneys are cooled to reduce cellular metabolism and minimize ischaemic injury. This cooling is slow and kidneys are lukewarm during nephrectomy. Smaller single-centre studies have shown that prolonged donor nephrectomy time decreases early kidney transplant function, but the effect on long-term outcome has never been investigated in large multicentre cohort studies. METHODS: The relationship between donor nephrectomy time and death-censored graft survival was evaluated in recipients of single adult-to-adult, first-time deceased-donor kidneys transplanted in the Eurotransplant region between 2004 and 2013. RESULTS: A total of 13 914 recipients were included. Median donor nephrectomy time was 51 (i.q.r. 39-65) min. Kidneys donated after circulatory death had longer nephrectomy times than those from brain-dead donors: median 57 (43-78) versus 50 (39-64) min respectively (P < 0·001). Donor nephrectomy time was independently associated with graft loss when kidneys were donated after circulatory death: adjusted hazard ratio (HR) 1·05 (95 per cent c.i. 1·01 to 1·09) per 10-min increase (P = 0·026). The magnitude of this effect was comparable to the effect of each hour of additional cold ischaemia: HR 1·04 (1·01 to 1·07) per h (P = 0·004). For kidneys donated after brain death, there was no effect of nephrectomy time on graft survival: adjusted HR 1·01 (0·98 to 1·04) per 10 min (P = 0·464). CONCLUSION: Prolonged donor nephrectomy time impairs graft outcome in kidneys donated after circulatory death. Keeping this short, together with efficient cooling during nephrectomy, might improve outcome.


ANTECEDENTES: La lesión por isquemia empieza en el momento que cesa la irrigación sanguínea del órgano donante. Para reducir el metabolismo celular y la lesión isquémica se reduce la temperatura de los riñones. Este enfriamiento es lento y los riñones se mantienen tibios durante la nefrectomía. Estudios unicéntricos con muestras pequeñas han demostrado que el tiempo de la nefrectomía del donante disminuye la función precoz del injerto renal, pero nunca se ha analizado su repercusión a largo plazo en grandes estudios multicéntricos. MÉTODOS: Se analizó la relación entre la duración de la nefrectomía del donante y la supervivencia del injerto en 13.914 adultos receptores de un primer riñón procedente de donante cadavérico adulto en la región de Eurotransplant entre los años 2004 y 2013. RESULTADOS: La mediana de duración de la nefrectomía del donante fue de 51 minutos (rango intercuartílico 39-65). En los riñones obtenidos en donantes a corazón parado la duración de la nefrectomía fue más prolongada que en los donantes en muerte cerebral (mediana 57 min (43-78 min) versus 50 min (39-64 min), P < 0,001). La duración de la nefrectomía en el donante se asoció de forma independiente con la pérdida del injerto (cociente de riesgos instantáneos, hazard ratio, HR, ajustado 1,05 por cada incremento de 10 minutos, i.c. del 95%: 1,01 a 1,09; P = 0,026) cuando los riñones se obtuvieron en donantes en parada cardíaca. La magnitud de este efecto fue comparable al efecto de cada hora adicional de isquemia fría (1,04, i.c. 95% 1,01-1,07, P = 0,004). En los riñones obtenidos de donantes en muerte cerebral, la duración de la nefrectomía no influyó en la supervivencia del injerto (HR ajustada 1,01 por aumento de 10 min, i.c. del 95%: 0,98 a 1,04). CONCLUSIÓN: La duración de la nefrectomía en donantes a corazón parado afecta la función de los injertos trasplantados. Reducir esta duración y disponer de un sistema de enfriamiento eficiente durante la nefrectomía podría mejorar los resultados.


Assuntos
Rejeição de Enxerto/etiologia , Transplante de Rim/métodos , Nefrectomia/estatística & dados numéricos , Doadores de Tecidos , Coleta de Tecidos e Órgãos/métodos , Idoso , Morte Encefálica/fisiopatologia , Isquemia Fria/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Tempo
3.
Am J Transplant ; 18(4): 881-889, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28980391

RESUMO

Circulatory death donor (DCD) kidney transplantations are steadily increasing. Consensus reports recommend limiting donor warm ischemia time (DWIT) in DCD donation, although an independent effect on graft outcome has not been demonstrated. We investigated death-censored graft survival in 18 065 recipients of deceased-donor kidney transplants in the Eurotransplant region: 1059 DCD and 17 006 brain-dead donor (DBD) kidney recipients. DWIT was defined as time from circulatory arrest until cold flush. DCD donation was an independent risk factor for graft failure (adjusted hazard ratio [HR] 1.28, 95% CI 1.10-1.46), due to an increased risk of primary nonfunction (62/1059 vs 560/17 006; P < .0001). With DWIT in the model, DCD donation was no longer a risk factor, demonstrating that DWIT explains the inferior graft survival of DCD kidneys. Indeed, DCD transplants with short DWIT have graft survival comparable to that of standard-criteria DBD transplants (P = .59). DWIT also associated with graft failure in DCDs (adjusted HR 1.20 per 10-minute increase, 95% CI 1.03-1.42). At 5 years after transplantation, graft failure occurred in 14 of 133 recipients (10.5%) with DWIT <10 minutes, 139 of 555 recipients (25.0%) with DWIT between 10 and 19 minutes, and 117 of 371 recipients (31.5%) with DWIT ≥20 minutes. These findings support the expert opinion-based guidelines to limit DWIT.


Assuntos
Morte Encefálica , Seleção do Doador , Rejeição de Enxerto/etiologia , Isquemia/fisiopatologia , Transplante de Rim/efeitos adversos , Doadores de Tecidos/provisão & distribuição , Isquemia Quente/efeitos adversos , Adulto , Idoso , Estudos de Coortes , Feminino , Seguimentos , Taxa de Filtração Glomerular , Sobrevivência de Enxerto , Humanos , Falência Renal Crônica/cirurgia , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Fatores de Tempo , Obtenção de Tecidos e Órgãos
4.
Am J Transplant ; 17(3): 724-732, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27593738

RESUMO

Recent studies raised the concern that warm ischemia during completion of vascular anastomoses in kidney implantation harms the transplant, but its precise impact on outcome and its interaction with other risk factors remain to be established. We investigated the relationship between anastomosis time and graft survival at 5 years after transplantation in 13 964 recipients of deceased donor solitary kidney transplants in the Eurotransplant region. Anastomosis time was independently associated with graft loss after adjusting for other risk factors (adjusted hazard ratio [HR] 1.10 for every 10-min increase, 95% confidence interval [CI] 1.06-1.14; p < 0.0001), whereas it did not influence recipient survival (HR 1.00, 95% CI 0.97-1.02). Kidneys from donation after circulatory death (DCD) were less tolerant of prolonged anastomosis time than kidneys from donation after brain death (p = 0.02 for interaction). The additive effect of anastomosis time with donor warm ischemia time (WIT) explains this observation because DCD status was no longer associated with graft survival when adjusted for this summed WIT, and there was no interaction between DCD status and summed WIT. Time to create the vascular anastomoses in kidney transplantation is associated with inferior transplant outcome, especially in recipients of DCD kidneys.


Assuntos
Anastomose Cirúrgica/efeitos adversos , Rejeição de Enxerto/etiologia , Falência Renal Crônica/cirurgia , Transplante de Rim/efeitos adversos , Obtenção de Tecidos e Órgãos/normas , Isquemia Quente/efeitos adversos , Adulto , Idoso , Morte Encefálica , Estudos de Coortes , Seleção do Doador , Europa (Continente) , Feminino , Seguimentos , Taxa de Filtração Glomerular , Sobrevivência de Enxerto , Humanos , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Doadores de Tecidos
5.
Am J Transplant ; 16(4): 1070-8, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26780242

RESUMO

Allograft outcome depends on a range of factors, including donor age, the allo-immune response, ischemia-reperfusion injury, and interstitial fibrosis of the allograft. Changes in the epigenome, and in DNA methylation in particular, have been implicated in each of these processes, in either the kidney or other organ systems. This review provides a primer for DNA methylation analyses and a discussion of the strengths and weaknesses of current studies, but it is also a perspective for future DNA methylation research in kidney transplantation. We present exciting prospects for leveraging DNA methylation analyses as a tool in kidney biology research, and as a diagnostic or prognostic marker for predicting allograft quality and success. Topics discussed include DNA methylation changes in aging and in response to hypoxia and oxidative stress upon ischemia-reperfusion injury. Moreover, emerging evidence suggests that DNA methylation contributes to organ fibrosis and that systemic DNA methylation alterations correlate with the rate of kidney function decline in patients with chronic kidney disease and end-stage renal failure. Monitoring or targeting the epigenome could therefore reveal novel therapeutic approaches in transplantation and open up paths to biomarker discovery and targeted therapy.


Assuntos
Metilação de DNA , Epigenômica , Nefropatias/genética , Nefropatias/prevenção & controle , Transplante de Rim , Animais , Humanos
6.
Am J Transplant ; 15(11): 2900-7, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26484837

RESUMO

Whether warm ischemia during the time to complete the vascular anastomoses determines renal allograft function has not been investigated systematically. We investigated the effect of anastomosis time on allograft outcome in 669 first, single kidney transplantations from brain-dead donors. Anastomosis time independently increased the risk of delayed graft function (odds ratio per minute [OR] 1.05, 95% confidence interval [CI] 1.02-1.07, p < 0.001) and independently impaired allograft function after transplantation (p = 0.009, mixed-models repeated-measures analysis). In a subgroup of transplant recipients, protocol-specified biopsies at 3 months (n = 186), 1 year (n = 189), and 2 years (n = 153) were blindly reviewed. Prolonged anastomosis time independently increased the risk of interstitial fibrosis and tubular atrophy on these protocol-specified biopsies posttransplant (p < 0.001, generalized linear models). In conclusion, prolonged anastomosis time is not only detrimental for renal allograft outcome immediately after transplantation, also longer-term allograft function and histology are affected by the duration of this warm ischemia.


Assuntos
Morte Encefálica , Função Retardada do Enxerto/patologia , Rejeição de Enxerto/patologia , Transplante de Rim/métodos , Duração da Cirurgia , Adulto , Anastomose Cirúrgica/métodos , Bélgica , Estudos de Coortes , Função Retardada do Enxerto/fisiopatologia , Feminino , Fibrose/etiologia , Fibrose/patologia , Rejeição de Enxerto/mortalidade , Sobrevivência de Enxerto , Humanos , Estimativa de Kaplan-Meier , Transplante de Rim/efeitos adversos , Transplante de Rim/mortalidade , Necrose Tubular Aguda/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Nefrectomia/métodos , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Doadores de Tecidos , Transplantados/estatística & dados numéricos , Transplante Homólogo , Resultado do Tratamento
7.
Acta Anaesthesiol Scand ; 57(3): 320-5, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23167550

RESUMO

BACKGROUND: Cyclic alveolar recruitment and derecruitment play a role in the pathomechanism of acute lung injury and may lead to arterial partial pressure of oxygen (PaO(2) ) oscillations within the respiratory cycle. It remains unknown, however, if these PaO(2) oscillations are transmitted to the microcirculation. The present study investigates if PaO(2) oscillations can be detected in the pig buccal mucosa microcirculation. METHODS: Respiratory failure was induced by surfactant depletion in seven pigs. PaO(2) oscillations caused by cyclic recruitment and derecruitment were measured in the thoracic aorta by fast fluorescence quenching of oxygen technology. Haemoglobin oxygen saturation, haemoglobin amount and blood flow in the buccal mucosa microcirculation were determined by combined fast white light spectrometry and laser Doppler flowmetry additionally to systolic arterial pressure. Measurements were performed during baseline conditions and during cyclic recruitment and derecruitment. RESULTS: Measurements remained stable during baseline. Respiratory-dependent oscillations occurred in the systemic circulation [PaO(2) oscillations 92 (69-172) mmHg; systolic arterial pressure oscillations 33 (13-35) %] and were related to the respiratory rate (5.0 ± 0.2/min) as confirmed by Fourier analysis. Synchronised oscillations were detected to the pig buccal mucosa microcirculation [haemoglobin oxygen saturation oscillations 3.4 (2.7-4.9) %; haemoglobin amount oscillations 8.5 (2.3-13.3) %; blood flow oscillations 66 (18-87) %]. The delay between PaO(2) -\ and microcirculatory oxygen oscillations was 7.2 ± 2.8 s. CONCLUSION: The present study suggests that PaO(2) oscillations caused by cyclic recruitment and derecruitment were transmitted to the buccal mucosa microcirculation. This non-invasive approach of measuring oxygen waves as a surrogate parameter of cyclic recruitment and derecruitment could be used to monitor PaO(2) oscillations at the bedside.


Assuntos
Bochecha/irrigação sanguínea , Oxigênio/sangue , Alvéolos Pulmonares/fisiologia , Animais , Aorta Torácica/fisiologia , Pressão Arterial , Lavagem Broncoalveolar , Análise de Fourier , Hemodinâmica/fisiologia , Fluxometria por Laser-Doppler , Microcirculação/fisiologia , Monitorização Fisiológica , Troca Gasosa Pulmonar , Fluxo Sanguíneo Regional/fisiologia , Insuficiência Respiratória/fisiopatologia , Suínos
8.
Br J Anaesth ; 110(2): 266-73, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23103776

RESUMO

BACKGROUND: Cyclic recruitment and derecruitment (R/D) play a key role in the pathomechanism of acute lung injury (ALI) leading to respiration-dependent oscillations of arterial partial pressure of oxygen (Pa(O(2))). These Pa(O(2)) oscillations could also be forwarded to the cerebral microcirculation. METHODS: In 12 pigs, partial pressure of oxygen was measured in the thoracic aorta (Pa(O(2))) and subcortical cerebral tissue (Pbr(O(2))). Cerebral cortical haemoglobin oxygen saturation (Sbr(O(2))), cerebral blood flow (CBF), and peripheral haemoglobin saturation (Sp(O(2))) were assessed by spectroscopy and laser Doppler flowmetry. Measurements at different fractions of inspired oxygen (F(I(O(2)))) were performed at baseline and during cyclic R/D. STATISTICS: frequency domain analysis, the Mann-Whitney test, linear models to test the influence of Pa(O(2)) and systolic arterial pressure (SAP) oscillations on cerebral measurements. RESULTS: Parameters [mean (SD)] remained stable during baseline. Pa(O(2)) oscillations [10.6 (8) kPa, phase(reference)], systemic arterial pressure (SAP) oscillations [20 (9) mm Hg, phase(Pa(O(2))-SAP) -33 (72)°], and Sp(O(2))oscillations [1.9 (1.7)%, phase(Pa(O(2))-Sp(O(2))) 264 (72)°] were detected during lung R/D at 1.0. Pa(O(2)) oscillations decreased [2.7 (3.5) kPa, P=0.0008] and Sp(O(2)) oscillations increased [6.8 (3.9)%, P=0.0014] at F(I(O(2))) 0.3. In the brain, synchronized Pbr(O(2)) oscillations [0.6 (0.4) kPa, phase(Pa(O(2))-Pbr(O(2))) 90 (39)°], Sbr(O(2)) oscillations [4.1 (1.5)%, phase(Pa(O(2))-Sbr(O(2))) 182 (54)°], and CBF oscillations [198 (176) AU, phase(Pa(O(2))-CBF) 201 (63)°] occurred that were dependent on Pa(O(2)) and SAP oscillations. CONCLUSIONS: Pa(O(2)) oscillations caused by cyclic R/D are transmitted to the cerebral microcirculation in a porcine model of ALI. These cyclic oxygen alterations could play a role in the crosstalk of acute lung and brain injury.


Assuntos
Lesão Pulmonar Aguda/complicações , Lesão Pulmonar Aguda/fisiopatologia , Circulação Cerebrovascular/fisiologia , Pulmão/fisiopatologia , Microcirculação/fisiologia , Oxigênio/sangue , Anestesia Geral , Animais , Monitorização Transcutânea dos Gases Sanguíneos , Pressão Sanguínea/efeitos dos fármacos , Líquido da Lavagem Broncoalveolar , Craniotomia , Hemodinâmica/fisiologia , Fluxometria por Laser-Doppler , Respiração Artificial , Suínos , Ventiladores Mecânicos
9.
J Voice ; 21(2): 151-6, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16504470

RESUMO

SUMMARY: Bilateral (quasi) symmetrical lesions of the anterior third of the vocal folds, commonly called vocal fold nodules (VFNs) are the most frequent vocal fold lesions in childhood caused by vocal abuse and hyperfunction. This study evaluates their long-term genesis with or without surgery and voice therapy. A group of 91 postmutational adolescents (mean age, 16 years), in whom VFNs were diagnosed in childhood, were questioned to analyze the evolution of their complaints. Thirty four of them could be clinically reexamined by means of the European Laryngological Society-protocol, including a complete laryngological investigation and voice assessment. A total of 21% of the questioned group (n=91) had voice complaints persisting into postpubescence with a statistically significant difference (P

Assuntos
Prega Vocal/patologia , Distúrbios da Voz/patologia , Distúrbios da Voz/fisiopatologia , Adolescente , Fatores Etários , Criança , Pré-Escolar , Progressão da Doença , Feminino , Humanos , Laringoscopia/métodos , Masculino , Índice de Gravidade de Doença , Distúrbios da Voz/diagnóstico , Qualidade da Voz
10.
Bioorg Med Chem ; 14(13): 4526-34, 2006 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-16517171

RESUMO

R107474, 2-methyl-3-[2-(1,2,3,4-tetrahydrobenzo[4,5]furo[3,2-c]pyridin-2-yl)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one, was investigated using in vitro and in vivo receptor assays and proved to be a potent and relatively selective alpha(2)-adrenoceptor antagonist. Performed assays in vitro were inhibition of binding to a large number of neurotransmitter receptor sites, drug receptor binding sites, ion channel binding sites, peptide receptor binding sites, and the monoamine transporters in membrane preparations of brain tissue or of cells expressing the cloned human receptors. The compound has subnanomolar affinity for halpha(2A)- and halpha(2C)-adrenoceptors (K(i) = 0.13 and 0.15 nM, respectively) and showed nanomolar affinity for the halpha(2B)-adrenoceptors and 5-hydroxytryptamine(7) (h5-HT(7)) receptors (K(i) = 1 and 5 nM, respectively). R107474 interacted weakly (K(i) values ranging between 81 and 920 nM) with dopamine-hD(2L), -hD(3) and -hD(4), h5-HT(1D)-, h5-HT(1F)-, h5-HT(2A)-, h5-HT(2C)-, and h5-HT(5A) receptors. The compound, tested up to 10 microM, interacted only at micromolar concentrations or not at all with any of the other receptor or transporter binding sites tested in this study. In vivo alpha(2A)- and alpha(2C)-adrenoceptor occupancy was measured by ex vivo autoradiography 1h after subcutaneous (sc) administration of R107474. It was found that R107474 occupies the alpha(2A)- and alpha(2C)-adrenoceptors with an ED(50) (95% confidence limits) of 0.014 mg/kg sc (0.009-0.019) and 0.026 mg/kg sc (0.022-0.030), respectively. Radiolabeled 2-methyl-3-[2-([1-(11)C]-1,2,3,4-tetrahydrobenzo[4,5]furo[3,2-c]pyridin-2-yl)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one ([(11)C]R107474) was prepared and evaluated as a potential positron emission tomography (PET) ligand for studying central alpha(2)-adrenoceptors. [(11)C]R107474 was obtained via a Pictet-Spengler reaction with [(11)C]formaldehyde in 33 +/- 4% overall decay-corrected radiochemical yield. The total synthesis time was 55 min and the specific activity was 24-28 GBq/micromol. The biodistribution of [(11)C]R107474 in rats revealed that the uptake of [(11)C]R107474 after in vivo intravenous administration is very rapid; in most tissues (including the brain) it reaches maximum concentration at 5 min after tracer injection. In agreement with the known distribution of alpha(2)-adrenoceptors in the brain, highest uptake of radioactivity was observed in septum (3.54 +/- 0.52 ID/g, 5 min pi) and entorhinal cortex (1.57 +/- 0.10 ID/g, 5 min pi). Tissue/cerebellum concentration ratios for septum (5.38 +/- 0.45, 30 min pi) and entorhinal cortex (3.43+/-0.24, 30 min pi) increased with time due to rapid uptake followed by a slow washout. In vivo blocking experiments using the non-selective alpha(2)-adrenoceptor antagonist mirtazapine demonstrated specific inhibition of [(11)C]R107474 binding in selective brain areas. The receptor binding profile of mirtazapine is reported and the selectivity of inhibition of binding is discussed. These results suggest that [(11)C]R107474 deserves further investigation as a potential radioligand for studying alpha(2)-adrenoceptors using PET.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 2 , Piridinas/farmacocinética , Pirimidinas/farmacocinética , Animais , Encéfalo/metabolismo , Clonagem Molecular , Humanos , Masculino , Piridinas/síntese química , Pirimidinas/síntese química , Ratos , Ratos Wistar , Receptores Adrenérgicos alfa 2/genética , Receptores Adrenérgicos alfa 2/metabolismo , Transdução de Sinais , Distribuição Tecidual
11.
J Pharmacol Exp Ther ; 302(2): 696-709, 2002 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12130734

RESUMO

In comparison with a series of reference compounds, (2R-trans)-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-acetamide (S)-Hydroxybutanedioate (R116301) was characterized as a specific, orally, and centrally active neurokinin-1 (NK(1)) receptor antagonist with subnanomolar affinity for the human NK(1) receptor (K(i): 0.45 nM) and over 200-fold selectivity toward NK(2) and NK(3) receptors. R116301 inhibited substance P (SP)-induced peripheral effects (skin reactions and plasma extravasation in guinea pigs) and a central effect (thumping in gerbils) at low doses (0.08-0.16 mg/kg, s.c. or i.p.), reflecting its high potency as an NK(1) receptor antagonist and excellent brain disposition. Higher doses blocked various emetic stimuli in ferrets, cats, and dogs (ED(50) values: 3.2 mg/kg, s.c.; 0.72-2.5 mg/kg, p.o.). Even higher doses (11-25 mg/kg, s.c.) were required in mice (capsaicin-induced ear edema) and rats (SP-induced extravasation and salivation), consistent with lower affinity for the rodent NK(1) receptor and known species differences in NK(1) receptor interactions. R116301 inhibited the ocular discharge (0.034 mg/kg) but not the dyspnoea, lethality, or cough (>40 mg/kg, s.c.) induced by [betaALA(8)]-neurokinin A (NKA) (4-10) in guinea pigs, attesting to NK(1) over NK(2) selectivity. R116301 did not affect senktide-induced miosis (>5 mg/kg, s.c.) in rabbits, confirming the absence of an interaction with the NK(3) receptor. R116301 was inactive in guinea pigs against skin reactions induced by histamine, platelet-aggregating factor, bradykinin, or Ascaris allergens (>10 mg/kg, s.c.). In all species, R116301 showed excellent oral over parenteral activity (ratio, 0.22-2.7) and a relatively long duration (6.5-16 h, p.o.). The data attest to the specificity and sensitivity of the animal models and support a role of NK(1) receptors in various diseases.


Assuntos
Butanóis/farmacologia , Antagonistas dos Receptores de Neurocinina-1 , Receptores da Neurocinina-1/administração & dosagem , Administração Oral , Alérgenos , Animais , Capsaicina/farmacologia , Gatos , Cães , Edema/induzido quimicamente , Edema/fisiopatologia , Furões , Gerbillinae , Cobaias , Histamina/farmacologia , Cinética , Malatos , Camundongos , Atividade Motora/efeitos dos fármacos , Piperidinas , Fator de Ativação de Plaquetas/farmacologia , Coelhos , Salivação/efeitos dos fármacos , Substância P/farmacologia , Fatores de Tempo
12.
J Voice ; 16(1): 1-7, 2002 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12002876

RESUMO

Normative voice range profiles (VRP) are calculated for a group of male and female teachers, based on 43 and 46 recordings, respectively. All individuals had healthy voices. These normative VRPs contain 95% prediction intervals for both frequency and intensity. They are based on a series of mathematical transformations of the original individual VRPs in order to maintain in the normative VRPs the typical oval VRP shape, including the dip between modal and falsetto register. The normative VRPs presented are directly applicable in the clinical practice of otolaryngologists and speech-language pathologists.


Assuntos
Qualidade da Voz , Voz/fisiologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valores de Referência , Treinamento da Voz
13.
Eur J Pharmacol ; 423(1): 71-83, 2001 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-11438309

RESUMO

Prucalopride is a novel enterokinetic compound and is the first representative of the benzofuran class. We set out to establish its pharmacological profile in various receptor binding and organ bath experiments. Receptor binding data have demonstrated prucalopride's high affinity to both investigated 5-HT(4) receptor isoforms, with mean pK(i) estimates of 8.60 and 8.10 for the human 5-HT(4a) and 5-HT(4b) receptor, respectively. From the 50 other binding assays investigated in this study only the human D(4) receptor (pK(i) 5.63), the mouse 5-HT(3) receptor (pK(i) 5.41) and the human sigma(1) (pK(i) 5.43) have shown measurable affinity, resulting in at least 290-fold selectivity for the 5-HT(4) receptor. Classical organ bath experiments were done using isolated tissues from the rat, guinea-pig and dog gastrointestinal tract, using various protocols. Prucalopride was a 5-HT(4) receptor agonist in the guinea-pig colon, as it induced contractions (pEC(50)=7.48+/-0.06; insensitive to a 5-HT(2A) or 5-HT(3) receptor antagonist, but inhibited by a 5-HT(4) receptor antagonist) as well as the facilitation of electrical stimulation-induced noncholinergic contractions (blocked by a 5-HT(4) receptor antagonist). Furthermore, it caused relaxation of a rat oesophagus preparation (pEC(50)=7.81+/-0.17), in a 5-HT(4) receptor antagonist sensitive manner. Prucalopride did not cause relevant inhibition of 5-HT(2A), 5-HT(2B), or 5-HT(3), motilin or cholecystokinin (CCK(1)) receptor-mediated contractions, nor nicotinic or muscarinic acetylcholine receptor-mediated contractions, up to 10 microM. It is concluded that prucalopride is a potent, selective and specific 5-HT(4) receptor agonist. As it is intended for treatment of intestinal motility disorders, it is important to note that prucalopride is devoid of anti-cholinergic, anticholinesterase or nonspecific inhibitory activity and does not antagonise 5-HT(2A), 5-HT(2B) and 5-HT(3) receptors or motilin or CCK(1) receptors.


Assuntos
Benzofuranos/farmacologia , Fármacos Gastrointestinais/farmacologia , Acetilcolina/farmacologia , Animais , Benzofuranos/metabolismo , Ligação Competitiva , Células CHO , Carbacol/farmacologia , Linhagem Celular , Colo/efeitos dos fármacos , Colo/fisiologia , Cricetinae , Dioxanos/farmacologia , Cães , Relação Dose-Resposta a Droga , Estimulação Elétrica , Esôfago/efeitos dos fármacos , Esôfago/fisiologia , Feminino , Vesícula Biliar/efeitos dos fármacos , Vesícula Biliar/fisiologia , Fármacos Gastrointestinais/metabolismo , Granisetron/farmacologia , Cobaias , Humanos , Íleo/efeitos dos fármacos , Íleo/fisiologia , Técnicas In Vitro , Indóis/farmacologia , Indometacina/farmacologia , Masculino , Motilina/análogos & derivados , Motilina/farmacologia , Contração Muscular/efeitos dos fármacos , Piperidinas/farmacologia , Coelhos , Ratos , Ratos Wistar , Receptores da Colecistocinina/antagonistas & inibidores , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D4 , Receptores dos Hormônios Gastrointestinais/antagonistas & inibidores , Receptores de Neuropeptídeos/antagonistas & inibidores , Receptores de Serotonina/metabolismo , Serotonina/farmacologia , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/farmacologia , Sincalida/farmacologia , Estômago/efeitos dos fármacos , Estômago/fisiologia , Sulfonamidas/farmacologia
14.
J Pept Res ; 57(4): 337-44, 2001 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11328491

RESUMO

The relationship between the conformation and biological activity of Leu-enkephalin was studied using (2S,6R,8S)-9-oxo-8-N-(Boc)amino-1-azabicyclo[4.3.0]nonane-2-carboxylic acid [(2S,6R,8S)-1, I(9)AA] as a constrained Gly(2)-Gly(3) dipeptide surrogate. [I(9)AA](2,3)-Leu-enkephalin 12 was assembled using solid-phase peptide synthesis on Merrifield resin with TBTU as the coupling reagent. The in vitro assays indicated that [I(9)AA](2,3)-Leu-enkephalin 12 exhibited affinities for the mu- and delta-opioid receptors that were three orders of magnitude lower than that of Leu-enkephalin, as well as partial agonist character for both receptors. In in vivo assays for spinal analgesia, the indolizidinone analog 12 showed significantly enhanced duration of action, indicating an increased metabolic stability. Conformational analysis was performed using NMR and CD spectroscopy. The amide temperature coefficients and 3J(NH-CalphaH) coupling constants for 12 could not support a hydrogen-bonded beta-turn structure; however, its CD spectrum indicated a turn conformation. Incorporation of indolizidinone amino acid 1 into Leu-enkephalin thus provided additional support for the importance of a turn conformation for the biological activity of the native peptide.


Assuntos
Dipeptídeos/síntese química , Encefalina Leucina/química , Indolizinas/síntese química , Receptores Opioides/metabolismo , Aminoácidos/química , Analgesia , Animais , Dicroísmo Circular , Dipeptídeos/química , Encefalina Leucina/metabolismo , Encefalina Leucina/farmacologia , Humanos , Indolizinas/química , Ligantes , Conformação Molecular , Estrutura Molecular , Ratos
15.
J Speech Lang Hear Res ; 43(3): 796-809, 2000 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-10877446

RESUMO

The vocal quality of a patient is modeled by means of a Dysphonia Severity Index (DSI), which is designed to establish an objective and quantitative correlate of the perceived vocal quality. The DSI is based on the weighted combination of the following selected set of voice measurements: highest frequency (F(0)-High in Hz), lowest intensity (I-Low in dB), maximum phonation time (MPT in s), and jitter (%). The DSI is derived from a multivariate analysis of 387 subjects with the goal of describing, purely based on objective measures, the perceived voice quality. It is constructed as DSI = 0.13 x MPT + 0.0053 x F(0)-High - 0.26 x I-Low - 1.18 x Jitter (%) + 12.4. The DSI for perceptually normal voices equals +5 and for severely dysphonic voices -5. The more negative the patient's index, the worse is his or her vocal quality. As such, the DSI is especially useful to evaluate therapeutic evolution of dysphonic patients. Additionally, there is a high correlation between the DSI and the Voice Handicap Index score.


Assuntos
Distúrbios da Voz/diagnóstico , Qualidade da Voz , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Acústica da Fala , Voz/fisiologia
16.
Br J Pharmacol ; 123(8): 1655-65, 1998 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-9605573

RESUMO

1. Alniditan, a novel migraine abortive agent, is a potent 5-HT1B/5-HT1D receptor agonist of nM affinity. We compared the agonistic properties of alniditan, sumatriptan and dihydroergotamine on the cloned human 5-HT1B receptor expressed at 200 fmol mg(-1) protein (Bmax) in non-induced L929sA cells, at 740 fmol mg(-1) protein in HEK 293 and at 2300 fmol mg(-1) protein in mIFNbeta-induced L929sA cells, and on the human cloned 5-HT1D receptor expressed in C6 glioma cells (Bmax 780 fmol mg(-1) protein). 2. Sodium butyrate treatment increased the expression level of human (h)5-HT1B receptors in HEK 293 cells and h5-HT1D receptors in C6 glioma cells approximately 3 fold, the binding affinities of [3H]-5-HT and [3H]-alniditan were unaffected. 3. Agonistic properties were evaluated based on inhibition of cyclic AMP accumulation in the cells after stimulation of adenylyl cyclase by forskolin or isoproterenol. Alniditan, sumatriptan and dihydroergotamine were full agonists at the hS-HT1B receptor (IC50 values were 1.7, 20 and 2 nM, respectively in HEK 293 cells) and hS-HT1D receptors (IC50 values of 1.3, 2.6 and 2.2 nM, respectively). At the h5-HT1B receptor the agonist potency of the compounds slightly increased with higher receptor density. The opposite was seen for antagonists (ocaperidone, risperidone and ritanserin). 4. This comparative study demonstrated that alniditan was 10 times more potent than sumatriptan at the h5-HT1B receptor, and twice as potent at the h5-HT1D receptor. Dihydroergotamine was more potent an agonist at the h5-HT1B receptor when expressed at high and low level in L929sA cells (but not in HEK 293 cells), and was less potent at the hS-HT1D receptor.


Assuntos
Benzopiranos/farmacologia , Di-Hidroergotamina/farmacologia , Propilaminas/farmacologia , Pirimidinas/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Agonistas do Receptor de Serotonina/farmacologia , Sumatriptana/farmacologia , Vasoconstritores/farmacologia , Adenilil Ciclases/metabolismo , Animais , Linhagem Celular , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Clonagem Molecular , Humanos , Ligantes , Camundongos , Ratos , Receptores de Serotonina/biossíntese , Transdução de Sinais/efeitos dos fármacos
17.
J Speech Lang Hear Res ; 41(2): 232-8, 1998 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-9570578

RESUMO

Voice range profiles (VRPs) were analyzed according to 11 frequency, intensity, and morphological characteristics for 94 normal children and 136 children with vocal fold pathologies (ages 6-11 years). Normative data are presented showing marked differences between the groups. Using a specific combination of the child's age, the highest vocal fundamental frequency, the lowest intensity, and the slope of the upper VRP contour, a Voice Range Profile Index for Children (VRPIc) may be constructed using discriminant analysis. It is shown how the VRPIc can be used to screen children for vocal disorder or to quantitatively assess the effectiveness of voice treatment. Since the group means of the VRPIc for healthy and dysphonic children are scaled to +10 and -10, respectively, the VRPIc enables the clinician to rate a child's vocal performance with reference to healthy and dysphonic children in general. The sensitivity and specificity of this method was found to be 90% and 83%, respectively.


Assuntos
Distúrbios da Voz/fisiopatologia , Qualidade da Voz , Análise de Variância , Criança , Feminino , Humanos , Laringoscopia/métodos , Masculino , Fonoterapia , Resultado do Tratamento , Prega Vocal/fisiopatologia , Distúrbios da Voz/terapia
18.
Mol Pharmacol ; 50(6): 1567-80, 1996 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-8967979

RESUMO

Alniditan is a new migraine-abortive agent. It is a benzopyran derivative and therefore structurally unrelated to sumatriptan and other indole-derivatives and to ergoline derivatives. The action of sumatriptan is thought to be mediated by 5-hydroxytryptamine (5-HT)1D-type receptors. We investigated the receptor-binding profile in vitro of alniditan compared with sumatriptan and dihydroergotamine for 28 neurotransmitter receptor subtypes, several receptors for peptides and lipid-derived factors, ion channel-binding sites, and monoamine transporters. Alniditan revealed nanomolar affinity for calf substantia nigra 5-HT1D and for cloned h5-HT1D alpha, h5-HT1D beta and h5-HT1A receptors (Ki = 0.8, 0.4, 1.1, and 3.8 nM, respectively). Alniditan was more potent than sumatriptan at 5-HT1D-type and 5-HT1A receptors. Alniditan showed moderate-to-low or no affinity for other investigated receptors; sumatriptan showed additional binding to 5-HT1F receptors. Dihydroergotamine had a much broader profile with high affinity for several 5-HT, adrenergic and dopaminergic receptors. In signal transduction assays using cells expressing recombinant h5-HT1D alpha, h5-HT1D beta, or h5-HT1A receptors, alniditan (like 5-HT) was a full agonist for inhibition of stimulated adenylyl cyclase (IC50 = 1.1, 1.3, and 74 nM, respectively, for alniditan). Therefore, in functional assays, the potency of alniditan was much higher at 5-HT1D receptors than at 5-HT1A receptors. We further compared the properties of [3H]alniditan, as a new radioligand for 5-HT1D-type receptors, with those of [3H]5-HT in membrane preparations of calf substantia nigra, C6 glioma cells expressing h5-HT1D alpha, and L929 cells expressing h5-HT1D beta receptors. [3H]Alniditan revealed very rapid association and dissociation binding kinetics and showed slightly higher affinity (Kd = 1-2 nM) than [3H]5-HT. We investigated 25 compounds for inhibition of [3H]alniditan and [3H]5-HT binding in the three membrane preparations; Ki values of the radioligands were largely similar, although some subtle differences appeared. Most compounds did not differentiate between 5-HT1D alpha and 5-HT1D beta receptors, except methysergide, ritanserin, ocaperidone, risperidone, and ketanserin, which showed 10-60-fold higher affinity for the 5-HT1D alpha receptor. The Ki values of the compounds obtained with 5-HT1D receptors in calf substantia nigra indicated that these receptors are of the 5-HT1D beta-type. We demonstrated that alniditan is a potent agonist at h5-HT1D alpha and h5-HT1D beta receptors; its properties probably underlie its cranial vasoconstrictive and antimigraine properties.


Assuntos
Benzopiranos/farmacologia , Transtornos de Enxaqueca/prevenção & controle , Propilaminas/farmacologia , Pirimidinas/farmacologia , Receptores de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/farmacologia , Vasoconstritores/farmacologia , Animais , Bovinos , Clonagem Molecular , Glioma/metabolismo , Células HeLa , Humanos , Camundongos , Ligação Proteica , Ensaio Radioligante , Receptores de Serotonina/genética , Agonistas do Receptor de Serotonina/metabolismo , Transdução de Sinais , Trítio , Células Tumorais Cultivadas
19.
Neuropsychopharmacology ; 15(2): 187-98, 1996 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-8840355

RESUMO

Recently, our laboratory has reported significant seasonal differences in [3H]paroxetine binding to platelets in depressed subjects. This study aimed to examine the seasonal variation in [3H]paroxetine binding to platelets and the relationships between [3H]paroxetine binding and climatic variables in healthy volunteers. We took monthly blood samples during one calendar year from 26 healthy volunteers for assay of [3H]paroxetine binding and analyzed the data by means of univariate and multivariate spectral and cosinor analyses. There was a statistically highly significant seasonal pattern in [3H]paroxetine binding to platelets with significant annual, 4-monthly, and bimonthly rhythms, which were expressed as a group phenomenon. [3H]Paroxetine binding to platelets was significantly lower in fall and summer than in winter and spring; lows occurred in summer and peaks in spring. The peak-trough difference in this yearly variation, expressed as a percentage of the mean, was as large as 83.7%. A large part of the variance, that is, 32.5%, in [3H]paroxetine binding could be explained by weather variables, such as ambient temperature, relative humidity, and air pressure. Highly significant common annual rhythms were expressed in [3H]paroxetine binding and ambient temperature or humidity (both inversely related) and changes in temperature the 2 weeks preceding blood samplings (positively related).


Assuntos
Antidepressivos de Segunda Geração/sangue , Plaquetas/metabolismo , Clima , Paroxetina/sangue , Estações do Ano , Adulto , Pressão do Ar , Antidepressivos de Segunda Geração/farmacocinética , Feminino , Humanos , Umidade , Masculino , Análise Multivariada , Paroxetina/farmacocinética , Valores de Referência , Análise de Regressão , Temperatura
20.
Acta Otorhinolaryngol Belg ; 50(4): 299-308, 1996.
Artigo em Inglês | MEDLINE | ID: mdl-9001639

RESUMO

Phonetography has been defined by SCHUTTE and SEIDNER in 1983. Nevertheless publications on phonetography go back to the thirties. Due to publications in the last decade and the development of computer phonetography this testing method has been used for various purposes in voice evaluation. This article gives a historical background, with the different ways of phonetogram recording and describes variables who have their effect on phonetogram results and interpretation. Secondly the range of application with normative and reference phonetograms is discussed.


Assuntos
Fonação/fisiologia , Medida da Produção da Fala/métodos , Distúrbios da Voz/fisiopatologia , Adulto , Criança , Feminino , Humanos , Masculino , Fonética , Processamento de Sinais Assistido por Computador , Distúrbios da Voz/diagnóstico
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