RESUMO
BACKGROUND: Clazosentan has been explored worldwide for the prophylaxis of cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH). In a dose-finding trial (CONSCIOUS-1) conducted in Israel, Europe, and North America, clazosentan (1, 5, and 15 mg/h) significantly reduced the incidence of cerebral vasospasm, but its efficacy in Japanese and Korean patients was unknown. We conducted a double-blind comparative study to evaluate the occurrence of cerebral vasospasm in Japanese and Korean patients with aSAH. METHODS: The aim of this multicenter, double-blind, randomized, placebo-controlled, dose-finding phase 2 clinical trial, was to evaluate the efficacy, pharmacokinetics, and safety of clazosentan (5 and 10 mg/h) against cerebral vasospasm after clipping surgery in Japanese and Korean patients with aSAH. Patients aged between 20 and 75 years were administered the study drug within 56 h after the aneurysm rupture and up to day 14 post-aSAH. The incidence of vasospasm, defined as an inner artery diameter reduction of major intracranial arteries ≥34% based on catheter angiography, was compared between each treatment group. Cerebral infarction due to vasospasm at 6 weeks and patients' outcome at 3 months was also compared. RESULTS: Among 181 enrolled patients, 158 completed the study and were analyzed. The incidence of vasospasm up to day 14 after aSAH onset was 80.0% in the placebo group (95% CI 67.0-89.6), 38.5% in the 5 mg/h clazosentan group (95% CI 25.3-53.0), and 35.3% in the 10 mg/h clazosentan group (95% CI 22.4-49.9), indicating that the incidence of vasospasm was significantly reduced by clazosentan treatment (placebo vs. 5 mg/h clazosentan, p < 0.0001; placebo vs. 10 mg/h clazosentan, p < 0.0001). The occurrence of cerebral infarction due to vasospasm was 20.8% in the placebo group (95% CI 10.8-34.1), 3.8% in the 5 mg/h clazosentan group (95% CI 0.5-13.2), and 4.2% in the 10 mg/h clazosentan group (95% CI 0.5-14.3), indicating that clazosentan significantly reduced the occurrence of cerebral infarctions caused by vasospasm (placebo vs. 5 mg/h clazosentan, p = 0.0151; placebo vs. 10 mg/h clazosentan, p = 0.0165). The overall incidence of all-cause death and/or vasospasm-related morbidity/mortality was significantly reduced in the 10 mg/h clazosentan group compared with the placebo group (p = 0.0003). CONCLUSION: These results suggest that clazosentan prevents cerebral vasospasm and subsequent cerebral infarction, and could thereby improve outcomes after performing a clipping surgery for aSAH in Japanese and Korean patients.
Assuntos
Infarto Cerebral/prevenção & controle , Dioxanos/uso terapêutico , Antagonistas do Receptor de Endotelina A/uso terapêutico , Procedimentos Neurocirúrgicos/efeitos adversos , Piridinas/uso terapêutico , Pirimidinas/uso terapêutico , Hemorragia Subaracnóidea/cirurgia , Sulfonamidas/uso terapêutico , Tetrazóis/uso terapêutico , Vasodilatadores/uso terapêutico , Vasoespasmo Intracraniano/prevenção & controle , Adulto , Idoso , Angiografia Digital , Angiografia Cerebral/métodos , Infarto Cerebral/diagnóstico por imagem , Infarto Cerebral/etiologia , Infarto Cerebral/fisiopatologia , Dioxanos/efeitos adversos , Dioxanos/farmacocinética , Método Duplo-Cego , Antagonistas do Receptor de Endotelina A/efeitos adversos , Antagonistas do Receptor de Endotelina A/farmacocinética , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Piridinas/efeitos adversos , Piridinas/farmacocinética , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , República da Coreia , Hemorragia Subaracnóidea/diagnóstico por imagem , Hemorragia Subaracnóidea/fisiopatologia , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacocinética , Tetrazóis/efeitos adversos , Tetrazóis/farmacocinética , Fatores de Tempo , Resultado do Tratamento , Vasodilatadores/efeitos adversos , Vasodilatadores/farmacocinética , Vasoespasmo Intracraniano/diagnóstico por imagem , Vasoespasmo Intracraniano/etiologia , Vasoespasmo Intracraniano/fisiopatologia , Adulto JovemRESUMO
We report the case of a 42-yearold woman diagnosed with heterozygous Fabry disease (FD) due to a novel α-galactosidase A Pro210Ser mutation and exhibiting a unique distribution of synaptopodin within podocytes. The patient was referred to our hospital with moderate proteinuria, and a renal biopsy was performed. Light microscopic examination of the specimen revealed diffuse global enlargement of podocytes, which also showed foamy changes. Electron microscopy revealed abundant myeloid bodies in podocytes and focal mitochondrial abnormalities within the tubules. The patient exhibited none of the characteristic symptoms of FD except hypohidrosis and had no obvious family history. Genetic analysis revealed a novel missense mutation (Pro210Ser) in the α-galactosidase A gene. She was ultimately diagnosed with FD based on immunohistochemical staining indicating large amounts of accumulated globotriaosylceramide in her podocytes, detection of urinary globotriaosylceramide secretion using high-performance thin-layer chromatography/ immunostaining, and structural modeling of the mutated α-galactosidase A (Pro210Ser). Immunostaining of the swollen and foamy podocytes using podocyte-associated antibodies (against podocalyxin, Wilms tumor-1, vimentin, and synaptopodin) revealed a unique distribution of synaptopodin surrounding globotriaosylceramide. To our knowledge, this is the first report of immunohistologically detected synaptopodin upregulation in foamy podocytes in a patient with FD.
Assuntos
Doença de Fabry/genética , Heterozigoto , Proteínas dos Microfilamentos/análise , Mutação de Sentido Incorreto , Podócitos/química , Vacúolos/química , alfa-Galactosidase/genética , Adulto , Biópsia , Análise Mutacional de DNA , Terapia de Reposição de Enzimas , Doença de Fabry/diagnóstico , Doença de Fabry/tratamento farmacológico , Doença de Fabry/enzimologia , Feminino , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Microscopia Eletrônica , Microscopia de Fluorescência , Modelos Moleculares , Fenótipo , Podócitos/ultraestrutura , Triexosilceramidas/análise , Vacúolos/ultraestrutura , alfa-Galactosidase/uso terapêuticoRESUMO
The present study aimed to characterize bladder endothelin-1 (ET-1) receptor binding of clinically used ET-1 receptor antagonists by using [(125)I]ET-1. The inhibition of specific [(125)I]ET-1 binding was measured in the presence of ET-1 and its receptor antagonists. Specific binding of [(125)I]ET-1 in rat bladder was saturable and of high affinity, which characterized selective labeling of bladder ET-1 receptors. ET-1, bosentan, ambrisentan, and CI-1020 inhibited specific [(125)I]ET-1 binding in a concentration-dependent manner at nanomolar ranges of IC50. Nonlinear least squares regression analysis revealed the presence of high- and low-affinity ET-1 receptor sites for ambrisentan and CI-1020. Bosentan and ambrisentan significantly increased the dissociation constant for bladder [(125)I]ET-1 binding without affecting maximal number of binding sites (Bmax). Thus, bosentan and ambrisentan seem to bind to bladder ET-1 receptor in a competitive and reversible manner. Oral administration of bosentan caused a dose-dependent decrease in Bmax for bladder [(125)I]ET-1 binding, suggesting significant binding of bladder ET-1 receptors in vivo. A significant amount of pharmacologically relevant ET-1 receptors may exist in the bladder. These receptors may be implicated in the pathogenesis of lower urinary tract symptoms and may also be promising targets for the development of therapeutic agents.
Assuntos
Anti-Hipertensivos/metabolismo , Fenilpropionatos/metabolismo , Piridazinas/metabolismo , Receptor de Endotelina A/metabolismo , Sulfonamidas/metabolismo , Bexiga Urinária/metabolismo , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/farmacologia , Sítios de Ligação/efeitos dos fármacos , Bosentana , Relação Dose-Resposta a Droga , Antagonistas do Receptor de Endotelina A , Endotelina-1/farmacologia , Masculino , Fenilpropionatos/farmacologia , Piridazinas/farmacologia , Ratos , Ratos Sprague-Dawley , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacologiaRESUMO
The present study aimed to characterize comparatively endothelin-1 (ET-1) receptors in rat tissues by radioligand binding assay using [(125)I]ET-1 and to examine receptor binding after oral administration of bosentan. Significant amount of specific [(125)I]ET-1 binding was detected in the lung, heart, kidney, bladder and cerebral cortex of rats. ET-1, bosentan, ambrisentan, and CI-1020 inhibited specific [(125)I]ET-1 binding in these tissues in a concentration-dependent manner. The Hill coefficients of each agent in the rat lung and cerebral cortex and those of bosentan and ET-1 in the heart, kidney and bladder were close to unity, while the Hill coefficients of ambrisentan and CI-1020 in the heart, kidney and bladder were less than one. The nonlinear least squares regression analysis revealed the presence of high- and low-affinity ET-1 receptor sites in these tissues for ambrisentan and CI-1020. Oral administration of bosentan caused a dose-dependent decrease in specific [(125)I]ET-1 binding in the rat lung, kidney and bladder, suggesting significant binding of the tissue ET-1 receptors in vivo. In conclusion, it has been shown that a significant amount of pharmacologically relevant ET-1 receptors may exist in rat tissues and that ET-1 receptor antagonists such as bosentan at pharmacological doses may exert some pharmacological effects by binding these ET-1 receptors.
Assuntos
Dioxóis/farmacologia , Endotelina-1/metabolismo , Fenilpropionatos/farmacologia , Piridazinas/farmacologia , Receptor de Endotelina A/metabolismo , Sulfonamidas/farmacologia , Animais , Bosentana , Córtex Cerebral/metabolismo , Antagonistas do Receptor de Endotelina A , Rim/metabolismo , Pulmão/metabolismo , Masculino , Miocárdio/metabolismo , Ratos , Ratos Sprague-Dawley , Bexiga Urinária/metabolismoRESUMO
Thioredoxin (TRX) is a redox-regulating protein, induced in response to oxidative stress. The function of TRX in the urine is unknown. We show here that urinary TRX begin to increase within one hour and peaks within two hours after ischemia reperfusion of mice. Serum levels of TRX are not changed by the ischemia/reperfusion. In a time-dependent study of immunohistochemistry, TRX appears diffusely in the tubular cytosol in sham-operated mice. On the other hand, immediately after renal ischemia/reperfusion, TRX become to eccentrically-locate in the apical side of the tubular cytosol, and then TRX is detected only in the urinary lumen. In contrast, when we examine the immunolocalization of glutaredoxin, which is a member of the TRX superfamily, we find that the immunoreactivity is unchanged after renal ischemia/reperfusion. Northern blotting and in situ hybridization show that epithelial cells constitutively express TRX mRNA but neither expression levels nor distribution are altered by ischemia-reperfusion. An overexpression of hTRX in transgenic mice attenuates the reperfusion injury. These data suggests that TRX is produced in tubular cells in a steady state. The increase in the urine after ischemia-reperfusion is not mediated by a de novo induction of TRX mRNA but by a discharge of TRX protein from tubular epithelial cells. TRX is useful for the diagnosis of AKI in association with oxidative stress.
Assuntos
Tiorredoxinas/metabolismo , Injúria Renal Aguda/diagnóstico , Animais , Biomarcadores , Camundongos , Estresse Oxidativo/fisiologia , Tiorredoxinas/análiseRESUMO
A 58-year-old woman was referred to our outpatient clinic for further examination of a mass detected in the right kidney on follow-up ultrasonography performed for active surveillance of right ovarian cancer. Ultrasonography and computed tomography showed a cyst (diameter, 30 mm) with an irregular wall in the middle of the right kidney. Right nephrectomy was performed since malignancy was suspected. Histological findings of the mass indicated cholesterol granuloma. Although cholesterol granulomas in the middle ear have been frequently reported, those in other organs have been reported in few studies. In this patient, the cholesterol granuloma could be barely distinguished from the cancer by using imaging techniques.
Assuntos
Colesterol/metabolismo , Granuloma/patologia , Nefropatias/patologia , Diagnóstico Diferencial , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
Prader-Willi Syndrome (PWS) is characterized by hyperphagia, severe obesity, and mental retardation from early childhood and occurs 1/10,000 to 1/15,000 live births in Japan. There is high prevalence of diabetes mellitus because of hyperphagia. The patient may sometimes face the necessity of renal replacement therapy (RRT) because of end-stage kidney disease (ESKD) caused by diabetes-associated kidney disease (DKD). Since mental retardation and extreme obesity usually prevent to introduce peritoneal dialysis (PD), hemodialysis (HD) has been the first choice of RRT. In this report, we experienced one case of patient with PWS suffering from ESKD due to DKD who started PD as an initial RRT and succeeded to continue for total of 40 months. The patient was 37-year-old man at the time of initiation of dialysis. PD was chosen for RRT because we suspected that he might have more technical difficulties for continuing HD. After several episodes of peritonitis, he successfully continues PD without peritonitis for next 27 months until the present time with good support by his family member. To our best knowledge, this is the first reported case of ESKD associated with PWS who was successfully treated with PD for long period.
Assuntos
Falência Renal Crônica/etiologia , Falência Renal Crônica/terapia , Diálise Peritoneal , Síndrome de Prader-Willi/complicações , Adulto , Humanos , MasculinoRESUMO
AIM: The target Geriatric Nutritional Risk Index (GNRI) for patients on chronic maintenance hemodialysis is unclear. We aimed to determine the relationship between the GNRI and independent walking ability in such patients. METHODS: In the present retrospective cohort study, 90 patients receiving chronic maintenance hemodialysis were included. Logistic regression analyses were carried out to evaluate the relationship between the GNRI and independent walking ability. Receiver operating characteristic curve analysis was carried out to determine the cut-off GNRI for predicting independent walking ability. RESULTS: Multivariate logistic regression analysis showed significant differences in age (odds ratio [OR] 0.8, 95% confidence interval [CI] 0.6-0.9), creatinine generation rate percentage (OR 1.1, 95% CI 1.0-1.2), GNRI (OR 1.4, 95% CI 1.1-1.8; P < 0.01) and urea removal rate (OR 0.3, 95% CI 0.1-0.9; P < 0.05). The cut-off GNRI for independent walking ability was 86.7 (area under the curve 0.80, sensitivity 92.1%, specificity 66.7%, positive hit ratio 86.6%, negative hit ratio 78.3%). The factors correlated with survival in the univariate analysis were the GNRI, equilibrated Kt/V, urea removal rate, clear space rate, salt intake amount (P < 0.01), number of days of hospitalization and %creatinine generation rate (P < 0.05). The Cox proportional hazard regression model showed an OR of 0.77 (95% CI 0.32-1.8) at a GNRI <86/GNRI ≥86. In the multivariate survival analysis, we observed no significant differences in any of the factors. CONCLUSIONS: GNRI was correlated with walking ability, which indicated that GNRI might predict future walking ability; also, a GNRI of 87 might be the target for maintaining walking ability. Geriatr Gerontol Int 2018; 18: 1556-1561.
Assuntos
Avaliação Nutricional , Diálise Renal , Insuficiência Renal/fisiopatologia , Caminhada/fisiologia , Idoso , Feminino , Avaliação Geriátrica , Humanos , Testes de Função Renal , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Curva ROC , Insuficiência Renal/complicações , Insuficiência Renal/terapia , Estudos Retrospectivos , Fatores de RiscoRESUMO
A simultaneous, selective, sensitive, and rapid liquid chromatography/tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantification of bosentan, ambrisentan, sildenafil, and tadalafil in 50µL of human blood plasma. Diluted plasma samples were extracted using a solid-phase extraction procedure with 2% formic acid and methanol. The four drugs were separated by high-performance liquid chromatography using a C18 column and an isocratic mobile phase running at a flow rate of 0.2mL/min for 5min. The drugs were detected by a tandem mass spectrometer with electrospray ionization using deuterated compounds as internal standards. Calibration curves were generated over the linear concentration range of 2-1000ng/mL in plasma with a lower limit of quantification of 2ng/mL for all compounds. Finally, this validated method was applied to a clinical pharmacokinetic study in pediatric patients with pulmonary arterial hypertension (PAH) following the oral administration of PAH drugs. These results indicate that this method is suitable for assessing the risk/benefit of combination therapy in the pediatric population and useful for therapeutic drug monitoring for PAH treatment.