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1.
Dtsch Med Wochenschr ; 144(11): 710-714, 2019 06.
Artigo em Alemão | MEDLINE | ID: mdl-31163466

RESUMO

In diabetes, progression of cardio-renal disease is still the most important determinant of disease burden. Hence, the potential of glycaemic control is not the only measure any more to decide whether a new therapeutic approach is selected. Therapies with compelling cardiovascular and renal-protective effects are available. The two most promising new treatment concepts are sodium glucose co-transporter 2 (SGLT-2) inhibition and glucagon-like peptide-1 (GLP-1) receptor agonism. For both treatment concepts, prominent reductions in cardiovascular event rates and renal disease progression have been proven.To date, these beneficial effects appear to be more significant with SGLT-2 inhibitors than with GLP-1 receptor agonists, and further clinical trials with SGLT-2 inhibitors in patients with more advanced diabetic and non-diabetic kidney disease are currently underway. Furthermore, there are two new treatment concepts for attenuation of diabetic kidney disease progression close to finalization: selective antagonism of the mineralocorticoid receptor with finerenone and selective antagonism of the endothelin-1 receptor with atrasentan. Hence, in the near future, more treatment approaches might be available to face the major challenges in diabetes mellitus.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas , Atrasentana/uso terapêutico , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/prevenção & controle , Antagonistas do Receptor de Endotelina A/uso terapêutico , Humanos , Hipoglicemiantes/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
2.
Endocrinology ; 160(8): 1786-1796, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31173072

RESUMO

Bone metastasis is a painful complication of advanced prostate cancer. Endothelin-1 is a tumor-secreted factor that plays a central role in osteoblast activation and the osteosclerotic response of prostate cancer metastatic to bone. Antagonists that block the activation of the endothelin A receptor (ETAR), located on osteoblasts, reduce osteoblastic bone lesions in animal models of bone metastasis. However, ETAR antagonists demonstrated limited efficacy in clinical trials of men with advanced prostate cancer who also received standard androgen deprivation therapy (ADT). Previous data from our group suggested that, in a mouse model, ETAR antagonists might only be efficacious when androgen signaling in the osteoblast is lowered beyond the ability of standard ADT. This notion was tested in a mouse model of prostate cancer bone metastasis. Castrated and sham-operated male athymic nude mice underwent intracardiac inoculation of the ARCaPM castration-resistant prostate cancer cell line. The mice were then treated with either the ETAR antagonist zibotentan or a vehicle control to generate four experimental groups: vehicle+sham (Veh+Sham), vehicle+castrate (Veh+Castr), zibotentan+sham (Zibo+Sham), and zibotentan+castrate (Zibo+Castr). The mice were monitored radiographically for the development of skeletal lesions. The Zibo+Castr group had significantly longer survival and a single incidental lesion. Mice in the Zibo+Sham group had the shortest survival and the largest number of skeletal lesions. Survival and skeletal lesions of the Veh+Sham and Veh+Castr groups were intermediate compared with the zibotentan-treated groups. We report a complex interaction between ETAR and androgen signaling, whereby ETAR blockade was most efficacious when combined with complete androgen deprivation.


Assuntos
Neoplasias Ósseas/secundário , Antagonistas do Receptor de Endotelina A/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Pirrolidinas/uso terapêutico , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Endotelina-1/sangue , Masculino , Camundongos , Orquiectomia , Osteoblastos/efeitos dos fármacos , Osteoblastos/fisiologia , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Receptor de Endotelina A/metabolismo
3.
Hypertension ; 74(2): 323-330, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31177906

RESUMO

Dyslipidemia is common in chronic kidney disease (CKD). Despite statins, many patients fail to adequately lower lipids and remain at increased risk of cardiovascular disease. Selective ETA (endothelin-A) receptor antagonists reduce cardiovascular disease risk factors. Preclinical data suggest that ETA antagonism has beneficial effects on circulating lipids. We assessed the effects of selective ETA antagonism on circulating lipids and PCSK9 (proprotein convertase subtilisin/kexin type 9) in CKD. This was a secondary analysis of a fully randomized, double-blind, 3-phase crossover study. Twenty-seven subjects with predialysis CKD on optimal cardio- and renoprotective treatment were randomly assigned to receive 6 weeks dosing with placebo, the selective ETA receptor antagonist, sitaxentan, or long-acting nifedipine. We measured circulating lipids and PCSK9 at baseline and then after 3 and 6 weeks. Baseline lipids and PCSK9 did not differ before each study phase. Whereas placebo and nifedipine had no effect on lipids, 6 weeks of ETA antagonism significantly reduced total (-11±1%) and low-density lipoprotein-associated (-20±3%) cholesterol, lipoprotein (a) (-16±2%) and triglycerides (-20±4%); high-density lipoprotein-associated cholesterol increased (+14±2%), P<0.05 versus baseline for all. Additionally, ETA receptor antagonism, but neither placebo nor nifedipine, reduced circulating PCSK9 (-19±2%; P<0.001 versus baseline; P<0.05 versus nifedipine and placebo). These effects were independent of statin use and changes in blood pressure or proteinuria. Selective ETA antagonism improves lipid profiles in optimally-managed patients with CKD, effects that may occur through a reduction in circulating PCSK9. ETA receptor antagonism offers a potentially novel strategy to reduce cardiovascular disease risk in CKD. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT00810732.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Antagonistas do Receptor de Endotelina A/uso terapêutico , Nifedipino/administração & dosagem , Pró-Proteína Convertase 9/metabolismo , Insuficiência Renal Crônica/tratamento farmacológico , Adulto , Idoso , Análise de Variância , Doenças Cardiovasculares/etiologia , LDL-Colesterol/sangue , LDL-Colesterol/efeitos dos fármacos , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Seguimentos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Pessoa de Meia-Idade , Proteinúria/tratamento farmacológico , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/mortalidade , Medição de Risco , Resultado do Tratamento
4.
World Neurosurg ; 128: e639-e648, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31054336

RESUMO

BACKGROUND: Clazosentan, an endothelin-1 receptor antagonist, has been shown to prevent the development of large vessel angiographic vasospasm after aneurysmal subarachnoid hemorrhage (aSAH). It has been hypothesized that clazosentan can also reverse established angiographic vasospasm. METHODS: The REVERSE (resynchronization reverses remodeling in systolic left ventricular dysfunction) study was a prospective, multicenter, open-label, 2-stage pilot study of adult patients with aSAH who had received intravenous clazosentan (15 mg/hour) after developing moderate-to-severe angiographic vasospasm. The primary efficacy endpoint was the reversal of global cerebral vasospasm in large cerebral artery segments 3 hours after clazosentan initiation. The secondary endpoints included large artery vasospasm reversal at 24 hours and the maximum change in the angiographic cerebral circulation time. The change in vasospasm severity in the proximal and distal segments was investigated in an exploratory analysis. RESULTS: The primary efficacy endpoint was met in 3 of 11 evaluable patients (27.3%; 95% confidence interval, 6.0-61.0). However, recruitment was stopped after stage 1 in accordance with the predefined interim analysis criteria. In the exploratory analysis, 50.0% and 77.8% of the patients showed a significant reversal of vasospasm or improvement to the admission state in ≥2 distal segments at 3 and 24 hours and 28.6% and 77.8% in ≥2 proximal segments, respectively. CONCLUSIONS: Although the main analysis showed a reversal of large vessel vasospasm 3 hours after clazosentan initiation in a few patients, the exploratory analysis indicated a clear pharmacodynamic dilating effect on vasospastic cerebral vessels at 24 hours in most patients, in particular, in the distal arterial beds. This observation supported the inclusion of patients with established vasospasm in the ongoing REACT (prevention and treatment of vasospasm with clazosentan) trial.


Assuntos
Dioxanos/uso terapêutico , Antagonistas do Receptor de Endotelina A/uso terapêutico , Piridinas/uso terapêutico , Pirimidinas/uso terapêutico , Hemorragia Subaracnóidea/terapia , Sulfonamidas/uso terapêutico , Tetrazóis/uso terapêutico , Vasoespasmo Intracraniano/tratamento farmacológico , Adulto , Angiografia Digital , Angiografia Cerebral , Embolização Terapêutica , Procedimentos Endovasculares , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Procedimentos Neurocirúrgicos , Projetos Piloto , Hemorragia Subaracnóidea/complicações , Instrumentos Cirúrgicos , Vasoespasmo Intracraniano/etiologia , Adulto Jovem
5.
Lancet ; 393(10184): 1937-1947, 2019 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-30995972

RESUMO

BACKGROUND: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. METHODS: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18-85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR) 25-75 mL/min per 1·73 m2 of body surface area, and a urine albumin-to-creatinine ratio (UACR) of 300-5000 mg/g who had received maximum labelled or tolerated renin-angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders) were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days) or end-stage kidney disease (eGFR <15 mL/min per 1·73 m2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure) in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. FINDINGS: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325) or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4-2·9). 79 (6·0%) of 1325 patients in the atrasentan group and 105 (7·9%) of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR] 0·65 [95% CI 0·49-0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%) of 1325 patients in the atrasentan group and 34 (2·6%) of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85-2·07]; p=0·208). 58 (4·4%) patients in the atrasentan group and 52 (3·9%) in the placebo group died (HR 1·09 [95% CI 0·75-1·59]; p=0·65). INTERPRETATION: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. FUNDING: AbbVie.


Assuntos
Atrasentana/administração & dosagem , Creatinina/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Antagonistas do Receptor de Endotelina A/administração & dosagem , Insuficiência Renal Crônica/prevenção & controle , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Atrasentana/uso terapêutico , Creatinina/urina , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/urina , Método Duplo-Cego , Antagonistas do Receptor de Endotelina A/uso terapêutico , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/urina , Albumina Sérica Humana/urina , Resultado do Tratamento , Adulto Jovem
6.
J Int Med Res ; 47(5): 2177-2186, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30975046

RESUMO

OBJECTIVES: To assess whether switching patients with suboptimally controlled pulmonary arterial hypertension from bosentan or ambrisentan to macitentan would improve six-minute walk test (6MWT) distance and World Health Organization functional class. METHODS: This was a retrospective cohort analysis of 37 patients from a single center. Patients were separated into three heterogeneous treatment groups and followed for 18 months: switch group (n = 14): patients switched to macitentan from bosentan/ambrisentan; added group (n = 11): patients who began macitentan as de novo therapy (n = 5) or who added macitentan to an existing sildenafil regimen (n = 6); and control group (n = 12): patients for whom sildenafil and/or bosentan/ambrisentan therapy was unchanged. RESULTS: Mortality was observed in two patients (one each, switch and added groups). Patients in the control group had one hospital admission and 100% survival. There was significant improvement in functional class for the switch and added groups. Statistically significant improvement was observed in 6MWT distance in the added group alone. Overall, 92% of patients continued macitentan throughout the study. CONCLUSION: Macitentan was well tolerated. For bosentan/ambrisentan-treated patients with suboptimally controlled pulmonary arterial hypertension, switching to macitentan may facilitate an improvement in functional class.


Assuntos
Antagonistas do Receptor de Endotelina A/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Pirimidinas/uso terapêutico , Receptor de Endotelina A/metabolismo , Sulfonamidas/uso terapêutico , Idoso , Antagonistas do Receptor de Endotelina A/efeitos adversos , Feminino , Humanos , Hipertensão Pulmonar/diagnóstico por imagem , Hipertensão Pulmonar/fisiopatologia , Masculino , Pessoa de Meia-Idade , Pirimidinas/efeitos adversos , Sulfonamidas/efeitos adversos , Sístole/efeitos dos fármacos , Resultado do Tratamento , Função Ventricular/efeitos dos fármacos , Teste de Caminhada , Organização Mundial da Saúde
7.
Life Sci ; 222: 133-139, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30844374

RESUMO

BACKGROUND: Cigarette smoke is exogenous modifiable factors to changes the neurovascular complication. The chronic exposure of cigarette smoke enhances neurocognitive dysfunction. AIMS: The present study is focused on evaluating the role of ambrisentan (selective endothelin-A receptor antagonist) on cigarette smoke-induced cognitive impairment in Danio rerio. MAIN METHODS: The cognitive dysfunction was developed by cigarette smoke exposure (CSE; 10 min in 25 ml of CSE per day) for five days. The selective endothelin-A receptor antagonist i.e., ambrisentan (2.5 to 5 mg/kg; i.p. for five consecutive days) was used for testing of CSE induced cognitive dysfunction. In addition, treatment of reference drug i.e., donepezil (10 mg/kg; i.p. for five consecutive days) was used for this cognitive function study. The cognitive functions were assessed by light and dark chamber; color recognition; partition preference; horizontal compartment; and T-Maze tests. Further, the CSE induced biomarkers changes of the zebrafish brain samples were estimated. KEY FINDINGS: The treatment of ambrisentan showed a potential ameliorative effect against the CSE induced cognitive functions along with attenuation of biochemical changes. The results are comparable to donepezil-treated groups. SIGNIFICANCE: Therefore, ambrisentan can be considered for the attenuation of CSE induced impairment neurocognitive functions due to its reduction of free radical scavenging and neuroinflammatory actions as well as regulation of cholinergic neurotransmitter functions.


Assuntos
Fumar Cigarros/efeitos adversos , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Antagonistas do Receptor de Endotelina A/uso terapêutico , Fenilpropionatos/uso terapêutico , Piridazinas/uso terapêutico , Animais , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Fumar Cigarros/tendências , Disfunção Cognitiva/psicologia , Antagonistas do Receptor de Endotelina A/farmacologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Fenilpropionatos/farmacologia , Piridazinas/farmacologia , Fumaça/efeitos adversos , Peixe-Zebra
8.
J Am Soc Nephrol ; 29(11): 2745-2754, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30361325

RESUMO

BACKGROUND: We evaluated and compared the effects of sparsentan, a dual endothelin type A (ETA) and angiotensin II type 1 receptor antagonist, with those of the angiotensin II type 1 receptor antagonist irbesartan in patients with primary FSGS. METHODS: In this phase 2, randomized, double-blind, active-control Efficacy and Safety of Sparsentan (RE-021), a Dual Endothelin Receptor and Angiotensin Receptor Blocker, in Patients with Focal Segmental Glomerulosclerosis (FSGS): A Randomized, Double-blind, Active-Control, Dose-Escalation Study (DUET), patients aged 8-75 years with biopsy-proven FSGS, eGFR>30 ml/min per 1.73 m2, and urinary protein-to-creatinine ratio (UP/C) ≥1.0 g/g received sparsentan (200, 400, or 800 mg/d) or irbesartan (300 mg/d) for 8 weeks, followed by open-label sparsentan only. End points at week 8 were reduction from baseline in UP/C (primary) and proportion of patients achieving FSGS partial remission end point (FPRE) (UP/C: ≤1.5 g/g and >40% reduction [secondary]). RESULTS: Of 109 patients randomized, 96 received study drugs and had baseline and week 8 UP/C measurements. Sparsentan-treated patients had greater reductions in UP/C than irbesartan-treated patients did when all doses (45% versus 19%; P=0.006) or the 400 and 800 mg doses (47% versus 19%; P=0.01) were pooled for analysis. The FSGS partial remission end point was achieved in 28% of sparsentan-treated and 9% of irbesartan-treated patients (P=0.04). After 8 weeks of treatment, BP was reduced with sparsentan but not irbesartan, and eGFR was stable with both treatments. Overall, the incidence of adverse events was similar between groups. Hypotension and edema were more common among sparsentan-treated patients but did not result in study withdrawals. CONCLUSIONS: Patients with FSGS achieved significantly greater reductions in proteinuria after 8 weeks of sparsentan versus irbesartan. Sparsentan was safe and well tolerated.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Antagonistas do Receptor de Endotelina A/uso terapêutico , Glomerulosclerose Segmentar e Focal/tratamento farmacológico , Compostos de Espiro/uso terapêutico , Sulfonamidas/uso terapêutico , Adolescente , Adulto , Idoso , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/efeitos adversos , Criança , Creatinina/urina , Relação Dose-Resposta a Droga , Método Duplo-Cego , Antagonistas do Receptor de Endotelina A/administração & dosagem , Antagonistas do Receptor de Endotelina A/efeitos adversos , Feminino , Glomerulosclerose Segmentar e Focal/urina , Humanos , Irbesartana/administração & dosagem , Irbesartana/efeitos adversos , Irbesartana/uso terapêutico , Masculino , Pessoa de Meia-Idade , Proteinúria/tratamento farmacológico , Proteinúria/urina , Compostos de Espiro/administração & dosagem , Compostos de Espiro/efeitos adversos , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Adulto Jovem
9.
Eur J Pharmacol ; 834: 136-141, 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-30012496

RESUMO

HELLP (hemolysis elevated liver enzyme low platelet) syndrome is associated with hypertension, inflammation, oxidative stress and endothelial activation. The objective of this study was to determine if oxygen scavenging or endothelin A receptor antagonism improved hypertension and oxidative stress. sFlt-1 and sEndoglin were infused via mini-osmotic pump into normal pregnant rats (NP) on gestational day 12 to create HELLP syndrome. On gestational day 18 arterial catheters were inserted and on gestational day 19 mean arterial pressure was analyzed in rats; serum, urine and tissues were collected for molecular analysis. HELLP rats had significantly increased MAP compared to control normal pregnant rats (P < 0.0005). Endothelin A receptor antagonism via ABT-627 and Tempol, superoxide dismutase mimetic, were administered to a subset of normal pregnant and HELLP rats beginning on gestational day 13 and attenuated mean arterial pressure in HELLP rats (P < 0.05; P < 0.005). There were no statistically significant differences in mean arterial pressure between NP+ETA Receptor or NP+Tempol treated rats and NP rats (P = 0.22). Endothelin A receptor blockade significantly decreased HELLP induced isoprostane excretion (P < 0.0005), placental and hepatic reactive oxygen species (P < 0.05; P < 0.0005) and increased placental total antioxidant capacity (P < 0.005) compared to untreated HELLP rats. Similar results in isoprostane (P < 0.005), hepatic reactive oxygen species (P < 0.05) and placental total antioxidant capacity (P < 0.05) were seen in HELLP rats treated with Tempol or Endothelin A receptor antagonist vs. untreated HELLP rats. These data demonstrated a role for oxidative stress in contributing to the hypertension, placental and liver damage that is seen in HELLP syndrome.


Assuntos
Síndrome HELLP/metabolismo , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Pressão Arterial/efeitos dos fármacos , Óxidos N-Cíclicos/farmacologia , Óxidos N-Cíclicos/uso terapêutico , Modelos Animais de Doenças , Antagonistas do Receptor de Endotelina A/farmacologia , Antagonistas do Receptor de Endotelina A/uso terapêutico , Feminino , Hipertensão/metabolismo , Isoprostanos/metabolismo , Gravidez , Ratos , Ratos Sprague-Dawley , Receptor de Endotelina A/metabolismo , Marcadores de Spin
10.
Exp Eye Res ; 176: 1-9, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29944850

RESUMO

Hypertension is an independent risk factor for diabetic retinopathy, yet anti-hypertensive medications such as blockade of angiotensin II do not completely protect against vision-threatening vascular disease. We hypothesized that the potent vasoactive factor, endothelin (ET), is up-regulated in diabetic retinopathy and antagonism of the ET type A receptor (ETRA) or ET type B receptor (ETRB) ameliorates retinal vascular leakage independently of any blood pressure lowering effects. Spontaneously hypertensive rats (SHR) and their normotensive and genetic controls, Wistar Kyoto rats, were randomized to become diabetic or non-diabetic and studied for 8 weeks. Rats were further randomized to receive by intravitreal injection the ETRA antagonist, BQ123, the ETRB antagonist, BQ788, or vehicle, 5 days after the induction of streptozotocin diabetes and 4 weeks later. The treatments had no effect on systolic blood pressure which remained elevated in SHR. ET-1, ET-2, ETRA and ETRB were expressed in retina and retinal pigment epithelium (RPE)/choroid and increased by hypertension or diabetes. BQ123 reduced ET-1 and ET-2 expression in retina and RPE/choroid, while BQ788 had a similar effect but did not influence the mRNA levels of ET-1 in retina. Retinal vascular leakage and Müller cell stress as well as vascular endothelial growth factor (VEGF) expression in retina and RPE/choroid, were increased by hypertension or diabetes and there was an additive effect of these conditions. Treatment with BQ123 or BQ788 effectively reduced these events as well as the elevated levels of inflammatory factors in the retina. Our findings indicate that local ET systems exist in the retina and RPE/choroid that are up-regulated by hypertension and diabetes. The ability of locally delivered ET receptor antagonists to supress these overactive ET systems and reduce retinal vascular leakage and VEGF in the presence of hypertension indicate the potential of these approaches for the treatment of diabetic retinopathy.


Assuntos
Anti-Hipertensivos/uso terapêutico , Retinopatia Diabética/prevenção & controle , Antagonistas do Receptor de Endotelina A/uso terapêutico , Antagonistas do Receptor de Endotelina B/uso terapêutico , Hipertensão Ocular/prevenção & controle , Animais , Pressão Sanguínea/efeitos dos fármacos , Barreira Hematorretiniana/efeitos dos fármacos , Corioide/metabolismo , Diabetes Mellitus Experimental/prevenção & controle , Retinopatia Diabética/metabolismo , Antagonistas do Receptor de Endotelina A/metabolismo , Antagonistas do Receptor de Endotelina B/metabolismo , Endotelina-1/genética , Endotelina-1/metabolismo , Endotelina-2/genética , Endotelina-2/metabolismo , Ensaio de Imunoadsorção Enzimática , Técnica Indireta de Fluorescência para Anticorpo , Injeções Intravítreas , Hipertensão Ocular/metabolismo , Oligopeptídeos/uso terapêutico , Peptídeos Cíclicos/uso terapêutico , Piperidinas/uso terapêutico , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Reação em Cadeia da Polimerase em Tempo Real , Retina/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Estreptozocina
11.
Physiol Res ; 67(Suppl 1): S55-S67, 2018 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-29947528

RESUMO

Chronic kidney disease (CKD) is a life-threatening disease arising as a frequent complication of diabetes, obesity and hypertension. Since it is typically undetected for long periods, it often progresses to end-stage renal disease. CKD is characterized by the development of progressive glomerulosclerosis, interstitial fibrosis and tubular atrophy along with a decreased glomerular filtration rate. This is associated with podocyte injury and a progressive rise in proteinuria. As endothelin-1 (ET-1) through the activation of endothelin receptor type A (ET(A)) promotes renal cell injury, inflammation, and fibrosis which finally lead to proteinuria, it is not surprising that ET(A) receptors antagonists have been proven to have beneficial renoprotective effects in both experimental and clinical studies in diabetic and non-diabetic CKD. Unfortunately, fluid retention encountered in large clinical trials in diabetic CKD led to the termination of these studies. Therefore, several advances, including the synthesis of new antagonists with enhanced pharmacological activity, the use of lower doses of ET antagonists, the addition of diuretics, plus simply searching for distinct pathological states to be treated, are promising targets for future experimental studies. In support of these approaches, our group demonstrated in adult subtotally nephrectomized Ren-2 transgenic rats that the addition of a diuretic on top of renin-angiotensin and ET(A) blockade led to a further decrease of proteinuria. This effect was independent of blood pressure which was normalized in all treated groups. Recent data in non-diabetic CKD, therefore, indicate a new potential for ET(A) antagonists, at least under certain pathological conditions.


Assuntos
Diuréticos/uso terapêutico , Antagonistas do Receptor de Endotelina A/uso terapêutico , Receptor de Endotelina A/metabolismo , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/prevenção & controle , Animais , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Diuréticos/farmacologia , Antagonistas do Receptor de Endotelina A/farmacologia , Endotelina-1/antagonistas & inibidores , Endotelina-1/metabolismo , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia
12.
Physiol Res ; 67(Suppl 1): S167-S174, 2018 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-29947537

RESUMO

Hypertension in obesity is associated with increased insulin resistance, vascular mass and body mass index (BMI). The purpose of the study was to visualize endothelin-1 (ET-1) mediated constriction in arteries isolated from subcutaneous adipose tissue from obese hypertensive women previously operated by gastric bypass. Functional studies were conducted in a microvascular myograph. Expressed as percentage of contraction elicited by 124 mM KCl concentration-response curves for ET-1 were shifted leftward in arteries from obese hypertensive patients compared to healthy normotensive subjects. The vasodilator response to the ET-1 antagonist BQ123 (1 microM) was significantly higher in arteries from obese hypertensive patients (p<0.001). BQ123 induced relaxation was inhibited by NO synthase inhibitor L-NAME (0.1 nM). Preincubation with BQ123 enhanced the relaxation induced by acetylcholine (ACh; 0.1 nM - 0.1 mM) (p<0.001), but not that induced by NO donor sodium nitroprusside (SNP; 0.1 nM - 0.1 mM), in arteries from obese hypertensive patients. The present study show that hypertension yet prevail after gastric bypass surgery and the ET(A) receptor antagonist BQ123 may be a useful tool in reducing blood pressure in obese hypertensive patients.


Assuntos
Antagonistas do Receptor de Endotelina A/farmacologia , Endotélio Vascular/metabolismo , Obesidade/metabolismo , Receptor de Endotelina A/fisiologia , Vasodilatação/fisiologia , Tecido Adiposo/irrigação sanguínea , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Relação Dose-Resposta a Droga , Antagonistas do Receptor de Endotelina A/uso terapêutico , Endotélio Vascular/efeitos dos fármacos , Feminino , Derivação Gástrica/tendências , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Hipertensão/cirurgia , Pessoa de Meia-Idade , Obesidade/tratamento farmacológico , Obesidade/cirurgia , Técnicas de Cultura de Órgãos , Peptídeos Cíclicos/farmacologia , Peptídeos Cíclicos/uso terapêutico , Vasodilatação/efeitos dos fármacos
13.
Diabetes Obes Metab ; 20(8): 2019-2022, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29603851

RESUMO

This study aimed to identify the optimal dose of the endothelin-1 receptor antagonist atrasentan with maximal albuminuria reduction and minimal signs of sodium retention, as manifested by increase in bodyweight. Data from the RADAR-JAPAN studies were used, evaluating the effect of 0.75 or 1.25 mg/d of atrasentan in 161 patients with type 2 diabetes and kidney disease. Individual pharmacokinetic parameters were estimated using a population pharmacokinetic approach. Subsequently, changes in the urinary albumin-to-creatinine ratio (UACR) and bodyweight from baseline after 2 weeks' exposure were modelled as a function of the pharmacokinetic parameters. The 0.75 and 1.25 mg doses showed a mean UACR reduction of 34.0% and 40.1%, whereas mean bodyweight increased by 0.9 and 1.1 kg, respectively. A large variation between individuals was observed in the UACR and bodyweight responses. Individual pharmacokinetic parameters correlated significantly with both individual UACR and bodyweight responses (P < .01). The individual response curves for UACR and bodyweight crossed at approximately the mean trough concentration of 0.75 mg atrasentan, indicating that 0.75 mg/d of atrasentan is the optimal dose for kidney protection with maximal efficacy (albuminuria reduction) and safety (minimal sodium retention).


Assuntos
Atrasentana/administração & dosagem , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/tratamento farmacológico , Antagonistas do Receptor de Endotelina A/administração & dosagem , Insuficiência Renal/tratamento farmacológico , Albuminúria/prevenção & controle , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Atrasentana/efeitos adversos , Atrasentana/farmacocinética , Atrasentana/uso terapêutico , Variação Biológica da População , Biomarcadores/urina , Peso Corporal/efeitos dos fármacos , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/fisiopatologia , Nefropatias Diabéticas/urina , Relação Dose-Resposta a Droga , Método Duplo-Cego , Resistência a Medicamentos , Quimioterapia Combinada/efeitos adversos , Antagonistas do Receptor de Endotelina A/efeitos adversos , Antagonistas do Receptor de Endotelina A/farmacocinética , Antagonistas do Receptor de Endotelina A/uso terapêutico , Humanos , Taxa de Depuração Metabólica/efeitos dos fármacos , Eliminação Renal/efeitos dos fármacos , Insuficiência Renal/complicações , Insuficiência Renal/metabolismo , Insuficiência Renal/fisiopatologia , Índice de Gravidade de Doença , Sódio/metabolismo
14.
Diabetes Obes Metab ; 20(8): 1829-1835, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29604160

RESUMO

AIM: The SONAR trial uses an enrichment design based on the individual response to the selective endothelin receptor antagonist atrasentan on efficacy (the degree of the individual response in the urinary albumin-to-creatinine ratio [UACR]) and safety/tolerability (signs of sodium retention and acute increases in serum creatinine) to assess the effects of this agent on major renal outcomes. The patient population and enrichment results are described here. METHODS: Patients with type 2 diabetes with an estimated glomerular filtration rate (eGFR) within 25 to 75 mL/min/1.73 m2 and UACR between 300 and 5000 mg/g were enrolled. After a run-in period, eligible patients received 0.75 mg/d of atrasentan for 6 weeks. A total of 2648 responder patients in whom UACR decreased by ≥30% compared to baseline were enrolled, as were 1020 non-responders with a UACR decrease of <30%. Patients who experienced a weight gain of >3 kg and in whom brain natriuretic peptide exceeded ≥300 pg/mL, or who experienced an increase in serum creatinine >20% (0.5 mg/dL), were not randomized. RESULTS: Baseline characteristics were similar for atrasentan responders and non-responders. Upon entry to the study, median UACR was 802 mg/g in responders and 920 mg/g in non-responders. After 6 weeks of treatment with atrasentan, the UACR change in responders was -48.8% (95% CI, -49.8% to -47.9%) and in non-responders was -1.2% (95% CI, -6.4% to 3.9%). Changes in other renal risk markers were similar between responders and non-responders except for a marginally greater reduction in systolic blood pressure and eGFR in responders. CONCLUSIONS: The enrichment period has successfully identified a population with a profound UACR reduction without clinical signs of sodium retention in whom a large atrasentan effect on clinically important renal outcomes is possible. The SONAR trial aims to establish whether atrasentan confers renal protection.


Assuntos
Atrasentana/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Angiopatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Antagonistas do Receptor de Endotelina A/uso terapêutico , Hipertensão/tratamento farmacológico , Medicina de Precisão , Idoso , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Atrasentana/efeitos adversos , Angiopatias Diabéticas/complicações , Nefropatias Diabéticas/complicações , Nefropatias Diabéticas/epidemiologia , Diuréticos/uso terapêutico , Método Duplo-Cego , Resistência a Medicamentos , Quimioterapia Combinada/efeitos adversos , Antagonistas do Receptor de Endotelina A/efeitos adversos , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Hipertensão/complicações , Masculino , Pessoa de Meia-Idade , Insuficiência Renal/complicações , Insuficiência Renal/epidemiologia , Insuficiência Renal/prevenção & controle , Risco
15.
Kidney Int ; 94(1): 40-48, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29628139

RESUMO

Drug repurposing, is the re-tasking of known medications for new clinical indications. Advantages, compared to de novo drug development, include reduced cost and time to market plus the added benefit of a known pharmacokinetic and safety profiles. Suitable drug candidates are identified through serendipitous observations, data mining, or increased understanding of disease mechanisms. This review highlights drugs suited for repurposing in kidney disease. The main cause of mortality in patients with chronic kidney disease is cardiovascular disease. Hence, we have included CV endpoints for the drugs. This review begins with candidates in acute kidney injury: vasodilators levosimendan and vitamin D, followed by candidates in CKD, with particular focus on diabetic kidney disease, autosomal dominant polycystic kidney disease, and focal segmental glomerulosclerosis. Examples include glucose-lowering drugs (sodium glucose co-transporter 2 inhibitors, glucagon-like peptide 1 agonists, and metformin), which have mechanistic potential for cardiac and/or renal protection beyond glucose lowering, with broader applicability to the nondiabetic population; xanthine oxidase inhibitors (allopurinol, febuxostat), selective endothelin receptor A antagonist (atrasentan), Janus kinase inhibitor (baricitinib), selective costimulation modulator (abatacept), pentoxyfylline, and the DNA demethylating agent/vasodilator (hydralazine).


Assuntos
Doenças Cardiovasculares/prevenção & controle , Reposicionamento de Medicamentos , Insuficiência Renal Crônica/tratamento farmacológico , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/mortalidade , Ensaios Clínicos como Assunto , Antagonistas do Receptor de Endotelina A/uso terapêutico , Supressores da Gota/uso terapêutico , Humanos , Hipoglicemiantes/uso terapêutico , Imunossupressores/uso terapêutico , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/mortalidade , Vasodilatadores/uso terapêutico
16.
Diabetes Obes Metab ; 20(6): 1369-1376, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29405626

RESUMO

AIMS: Individuals with diabetes and chronic kidney disease (CKD) are at high risk for renal events. Recent trials of novel treatments have been negative, possibly because of variability in response to treatment of the target risk factor. Atrasentan is a selective endothelin A receptor antagonist that reduces urinary albumin-to-creatinine ratio (UACR), with a large variability between patients. We are assessing its effect on renal outcomes in the Study Of diabetic Nephropathy with AtRasentan (SONAR; NCT01858532) with an enrichment design (>30% lowering of albuminuria) to select patients most likely to benefit. MATERIALS AND METHODS: SONAR is a randomized, double-blind, placebo-controlled trial with approximately 3500 participants who have stage 2-4 CKD and macroalbuminuria and are receiving a maximum tolerated dose of a renin-angiotensin system inhibitor. RESULTS: After 6 weeks of exposure to atrasentan 0.75 mg once daily (enrichment period), participants with ≥30% UACR decrease and no tolerability issues (responders) were randomly assigned to placebo or atrasentan 0.75 mg/day. The responder group will be used for primary efficacy and safety analyses. Approximately 1000 participants with <30% UACR reduction (non-responders) were also randomized to placebo or atrasentan. The primary endpoint is a composite of a sustained doubling of serum creatinine or end-stage renal disease. The original power calculation indicated that a total of 425 primary renal events in the responder group provides 90% power to detect a 27% reduction in relative risk (alpha level of .05). CONCLUSION: SONAR aims to determine whether atrasentan added to guideline-recommended therapies safely reduces the risk of CKD progression and delays the onset of end-stage renal disease in patients with type 2 diabetes and nephropathy. SONAR also aims to establish whether the enrichment of patients based on their initial "surrogate" response to atrasentan will deliver a trial design in accord with personalized treatment of diabetic kidney disease.


Assuntos
Atrasentana/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/tratamento farmacológico , Antagonistas do Receptor de Endotelina A/uso terapêutico , Falência Renal Crônica/prevenção & controle , Medicina de Precisão , Insuficiência Renal Crônica/tratamento farmacológico , Adulto , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Atrasentana/efeitos adversos , Nefropatias Diabéticas/fisiopatologia , Progressão da Doença , Método Duplo-Cego , Resistência a Medicamentos , Quimioterapia Combinada/efeitos adversos , Antagonistas do Receptor de Endotelina A/efeitos adversos , Feminino , Humanos , Rim/efeitos dos fármacos , Rim/fisiopatologia , Falência Renal Crônica/complicações , Masculino , Ensaios Clínicos Controlados Aleatórios como Assunto , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/fisiopatologia , Projetos de Pesquisa , Índice de Gravidade de Doença
17.
Braz J Med Biol Res ; 51(2): e6373, 2017 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-29267497

RESUMO

Cyclosporin-A (CsA) is an immunosuppressant associated with acute kidney injury and chronic kidney disease. Nephrotoxicity associated with CsA involves the increase in afferent and efferent arteriole resistance, decreased renal blood flow (RBF) and glomerular filtration. The aim of this study was to evaluate the effect of Endothelin-1 (ET-1) receptor blockade with bosentan (BOS) and macitentan (MAC) antagonists on altered renal function induced by CsA in normotensive and hypertensive animals. Wistar and genetically hypertensive rats (SHR) were separated into control group, CsA group that received intraperitoneal injections of CsA (40 mg/kg) for 15 days, CsA+BOS and CsA+MAC that received CsA and BOS (5 mg/kg) or MAC (25 mg/kg) by gavage for 15 days. Plasma creatinine and urea, mean arterial pressure (MAP), RBF and renal vascular resistance (RVR), and immunohistochemistry for ET-1 in the kidney cortex were measured. CsA decreased renal function, as shown by increased creatinine and urea. There was a decrease in RBF and an increase in MAP and RVR in normotensive and hypertensive animals. These effects were partially reversed by ET-1 antagonists, especially in SHR where increased ET-1 production was observed in the kidney. Most MAC effects were similar to BOS, but BOS seemed to be better at reversing cyclosporine-induced changes in renal function in hypertensive animals. The results of this work suggested the direct participation of ET-1 in renal hemodynamics changes induced by cyclosporin in normotensive and hypertensive rats. The antagonists of ET-1 MAC and BOS reversed part of these effects.


Assuntos
Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/prevenção & controle , Ciclosporina/toxicidade , Antagonistas do Receptor de Endotelina A/farmacologia , Imunossupressores/toxicidade , Pirimidinas/farmacologia , Sulfonamidas/farmacologia , Lesão Renal Aguda/fisiopatologia , Animais , Bosentana , Creatinina/sangue , Antagonistas do Receptor de Endotelina A/uso terapêutico , Hemodinâmica , Immunoblotting , Imuno-Histoquímica , Rim/efeitos dos fármacos , Rim/fisiopatologia , Masculino , Estresse Oxidativo/fisiologia , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico , Pirimidinas/uso terapêutico , Ratos Endogâmicos SHR , Ratos Wistar , Reprodutibilidade dos Testes , Sulfonamidas/uso terapêutico , Resultado do Tratamento , Ureia/sangue
19.
BMC Nephrol ; 18(1): 323, 2017 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-29078759

RESUMO

BACKGROUND: We studied whether endothelin receptor antagonist and calcimimetic treatments influence renal damage and kidney renin-angiotensin (RA) components in adenine-induced chronic renal insufficiency (CRI). METHODS: Male Wistar rats (n = 80) were divided into 5 groups for 12 weeks: control (n = 12), 0.3% adenine (Ade; n = 20), Ade + 50 mg/kg/day sitaxentan (n = 16), Ade + 20 mg/kg/day cinacalcet (n = 16), and Ade + sitaxentan + cinacalcet (n = 16). Blood pressure (BP) was measured using tail-cuff, kidney histology was examined, and RA components measured using RT-qPCR. RESULTS: Adenine caused tubulointerstitial damage with severe CRI, anemia, hyperphosphatemia, 1.8-fold increase in urinary calcium excretion, and 3.5-fold and 18-fold increases in plasma creatinine and PTH, respectively. Sitaxentan alleviated tubular atrophy, while sitaxentan + cinacalcet combination reduced interstitial inflammation, tubular dilatation and atrophy in adenine-rats. Adenine diet did not influence kidney angiotensin converting enzyme (ACE) and AT4 receptor mRNA, but reduced mRNA of renin, AT1a, AT2, (pro)renin receptor and Mas to 40-60%, and suppressed ACE2 to 6% of that in controls. Sitaxentan reduced BP by 8 mmHg, creatinine, urea, and phosphate concentrations by 16-24%, and PTH by 42%. Cinacalcet did not influence BP or creatinine, but reduced PTH by 84%, and increased hemoglobin by 28% in adenine-rats. The treatments further reduced renin mRNA by 40%, while combined treatment normalized plasma PTH, urinary calcium, and increased ACE2 mRNA 2.5-fold versus the Ade group (p < 0.001). CONCLUSIONS: In adenine-induced interstitial nephritis, sitaxentan improved renal function and tubular atrophy. Sitaxentan and cinacalcet reduced kidney renin mRNA by 40%, while their combination alleviated tubulointerstitial damage and urinary calcium loss, and increased kidney tissue ACE2 mRNA.


Assuntos
Adenina/toxicidade , Calcimiméticos/uso terapêutico , Modelos Animais de Doenças , Antagonistas do Receptor de Endotelina A/uso terapêutico , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/tratamento farmacológico , Animais , Cinacalcete/uso terapêutico , Isoxazóis/uso terapêutico , Masculino , Ratos , Ratos Wistar , Insuficiência Renal Crônica/fisiopatologia , Tiofenos/uso terapêutico
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