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1.
Lancet ; 394(10208): 1540-1550, 2019 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-31533906

RESUMO

BACKGROUND: Spironolactone is effective at reducing blood pressure in patients with uncontrolled resistant hypertension. However, the use of spironolactone in patients with chronic kidney disease can be restricted by hyperkalaemia. We evaluated use of the potassium binder patiromer to allow more persistent use of spironolactone in patients with chronic kidney disease and resistant hypertension. METHODS: In this phase 2 multicentre, randomised, double-blind, placebo-controlled study, we enrolled participants aged 18 years and older with chronic kidney disease (estimated glomerular filtration rate 25 to ≤45 mL/min per 1·73 m2) and uncontrolled resistant hypertension from 62 outpatient centres in ten countries (Bulgaria, Croatia, Georgia, Hungary, Ukraine, France, Germany, South Africa, the UK, and the USA). Patients meeting all eligibility criteria at the final screening visit were stratified by local serum potassium measurement (4·3 to <4·7 mmol/L vs 4·7 to 5·1 mmol/L) and history of diabetes. Participants were randomly assigned (1:1) with an interactive web response system to receive either placebo or patiromer (8·4 g once daily), in addition to open-label spironolactone (starting at 25 mg once daily) and their baseline blood pressure medications. Participants, the study team that administered treatments and measured blood pressure, and the investigators were masked to assigned treatment groups. Dose titrations were permitted after 1 week (patiromer) and 3 weeks (spironolactone). The primary endpoint was the between-group difference at week 12 in the proportion of patients on spironolactone. Efficacy endpoints and safety were assessed in all randomised patients (intention to treat). The study was registered with Clinicaltrials.gov, NCT03071263. FINDINGS: Between Feb 13, 2017, and Aug 20, 2018, we screened 574 patients. 295 (51%) of 574 patients met all inclusion criteria and were randomly assigned to spironolactone in addition to double-blind treatment with either placebo (n=148) or patiromer (n=147). At week 12, 98 (66%) of 148 patients in the placebo group and 126 (86%) of 147 patients in the patiromer group remained on spironolactone (between-group difference 19·5%, 95% CI 10·0-29·0; p<0·0001). Adverse events were mostly mild or moderate in severity and occurred in 79 (53%) of 148 patients in the placebo group and 82 (56%) of 147 patients in the patiromer group. INTERPRETATION: In patients with resistant hypertension and chronic kidney disease, patiromer enabled more patients to continue treatment with spironolactone with less hyperkalaemia. Persistent spironolactone enablement in this population of patients has clinical relevance for the treatment of resistant hypertension. FUNDING: Relypsa, a Vifor Pharma Group Company.


Assuntos
Diuréticos/administração & dosagem , Hipertensão/tratamento farmacológico , Polímeros/administração & dosagem , Espironolactona/administração & dosagem , Adulto , Idoso , Diuréticos/efeitos adversos , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Hiperpotassemia/prevenção & controle , Hipertensão/complicações , Masculino , Pessoa de Meia-Idade , Potássio/sangue , Insuficiência Renal Crônica/complicações , Espironolactona/efeitos adversos , Resultado do Tratamento
2.
Am J Case Rep ; 20: 1006-1010, 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31296836

RESUMO

BACKGROUND In the setting of acute decompensated heart failure (ADHF), tolvaptan, a selective V2 receptor antagonist, did not alter plasma renin activity or angiotensin II level, but significantly increased plasma aldosterone by the activation of V1ₐ receptor, suggesting that a high-dose mineralocorticoid receptor antagonist (MRA) combined with a V2 receptor antagonist might be of interest, especially in ADHF patients. However, in the setting of ADHF, the short-term and long-term efficacy of a high-dose MRA combined with tolvaptan remains unclear. CASE REPORT An 86-year-old woman with a history of chronic HF with a preserved ejection fraction due to obstructive hypertrophic cardiomyopathy and severe aortic stenosis was transferred to our hospital complaining of persistent dyspnea (New York Heart Association class IV). She did not respond to standard therapy with tolvaptan (15.0 mg/day). However, the present case demonstrated that adding high-dose spironolactone (100 mg/day) to low-dose tolvaptan (15.0 mg/day) is safe and well tolerated, resulting in an increase in urine output and improvement of the symptoms or signs of ADHF in a patient who was refractory to loop diuretics and tolvaptan. CONCLUSIONS The short- and long-term efficacy of high-dose spironolactone combined with low-dose tolvaptan may be associated with an attenuation of the aldosterone level, which is increased through V1ₐ activation by vasopressin during tolvaptan administration.


Assuntos
Estenose da Valva Aórtica/tratamento farmacológico , Cardiomiopatia Hipertrófica/tratamento farmacológico , Insuficiência Cardíaca/tratamento farmacológico , Espironolactona/administração & dosagem , Tolvaptan/administração & dosagem , Doença Aguda , Idoso de 80 Anos ou mais , Antagonistas dos Receptores de Hormônios Antidiuréticos/administração & dosagem , Estenose da Valva Aórtica/complicações , Cardiomiopatia Hipertrófica/complicações , Quimioterapia Combinada , Dispneia , Feminino , Insuficiência Cardíaca/etiologia , Humanos , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem
3.
Drug Des Devel Ther ; 13: 1487-1499, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31118582

RESUMO

Objective: To evaluate the safety and cardiovascular effect of low-dose spironolactone administration in end-stage renal failure patients undergoing hemodialysis coupled with conventional treatment. Methods: We conducted a systematic search for clinical trials on the safety and cardiovascular effect of additional low-dose spironolactone in hemodialysis patients. The search was performed on PubMed, EMBASE, Cochrane Library, and CBM databases. Relevant references (up to February 2016) were retrieved and subsequent results analyzed with a random-effects model or a fixed-effects model. Results: We identified nine trials with a total sample size of 765 patients. The results did not indicate significant differences regarding safety and serum potassium levels (mean difference [MD]=0.23, P=0.09) between the two treatment options. However, patients receiving low-dose spironolactone exhibited improvements in left venticular mass index (LVMI) (standardized mean difference= -0.58, P<0.00001) and left ventricular ejection fraction (LVEF) (MD=4.91, P<0.0001) with an additional decrease in systolic blood pressure (MD= -6.97, P=0.0001) and diastolic blood pressure (MD= -4.01, P=0.007). Furthermore, the clinical (OR=0.4, P=0.0003) or cardiovascular and cerebrovascular-related (OR=0.4, P=0.002) mortality was significantly lower among those patients. Conclusion: These results indicated that additional use of low-dose spironolactone associated with conventional treatment does not have a significant impact on serum potassium levels in hemodialysis patients. What's more, it might exert a protective effect on the cardiovascular system by optimizing LVMI, improving LVEF, decreasing arterial blood pressure and reducing events-related mortality. Further large sample size studies are needed to support these findings.


Assuntos
Sistema Cardiovascular/efeitos dos fármacos , Diálise Renal , Espironolactona/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Ensaios Clínicos como Assunto , Humanos , Potássio/sangue , Espironolactona/administração & dosagem , Espironolactona/efeitos adversos
4.
J Neurol ; 266(7): 1623-1632, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30937521

RESUMO

We report a young wheelchair-dependent patient with an unclear proximal myopathy and a heterozygous, de-novo Cav1.1-R1239G mutation suggesting hypokalemic periodic paralysis (HypoPP). Sonography showed a loss of the pennate pattern indicative of an edema, whereas fatty degeneration was excluded. Within 7 days of therapy with spironolactone, potassium and physical therapy, muscle strength almost completely normalized, a normal pennate pattern appeared and the edema was markedly reduced. She learned to walk without aid and to do sports and has continued to do so for 11 years until now. Over the years, we tested serum potassium values, muscle strength, muscle edema and muscular sodium content by 1.5 T, 3 T and 7 T 1H and 23Na magnetic resonance imaging. No fatty muscle degeneration developed. Muscular edema-like changes only occurred when she was pregnant and was set to reduced therapy. Because of the ability to do sports again, her mobility was further increased. Our observational study on this single patient may suggest that: (1) muscle imaging and molecular genetics are important diagnostic tools, (2) weakness in periodic paralysis may be reversible, and (3) continued adequate therapy may preserve muscle structure and strength on a longterm, whereas weakness due to fatty degeneration could be considered progressive and irreversible. Although HypoPP is a rare disease, it should be included in differential diagnosis not only if there is paroxysmal weakness, but also in cases of myopathy of unknown origin.


Assuntos
Canais de Cálcio Tipo L , Paralisia Periódica Hipopotassêmica/diagnóstico por imagem , Paralisia Periódica Hipopotassêmica/tratamento farmacológico , Força Muscular/efeitos dos fármacos , Músculo Esquelético/diagnóstico por imagem , Espironolactona/administração & dosagem , Adulto , Canais de Cálcio Tipo L/genética , Feminino , Humanos , Paralisia Periódica Hipopotassêmica/genética , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Força Muscular/fisiologia , Potássio/administração & dosagem , Fatores de Tempo
5.
JAMA Dermatol ; 155(6): 724-728, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30840033

RESUMO

Importance: Persistent alopecia occurs in a subset of patients undergoing chemotherapy, yet the quality of life (QOL) of these patients and their response to therapy have not been described in a large patient cohort. Objective: To characterize the clinical presentation of patients with persistent chemotherapy-induced alopecia (pCIA) or endocrine therapy-induced alopecia after chemotherapy (EIAC) and their QOL and treatment outcomes. Design, Setting, and Participants: A retrospective multicenter cohort of 192 women with cancer treated with cytotoxic agents who received a clinical diagnosis of persistent alopecia (98 with pCIA and 94 with EIAC) between January 1, 2009, and July 31, 2017, was analyzed. All patients were from the dermatology service in 2 comprehensive cancer centers and 1 tertiary-care hospital. Data on demographics, chemotherapy regimens, severity, clinical patterns, and response to hair-growth promoting agents were assessed. Data from the Hairdex questionnaire were used to assess the QOL of patients with alopecia. Main Outcomes and Measures: The clinical presentation, response to dermatologic therapy, and QOL of patients with pCIA were assessed and compared with those of patients with EIAC. Results: A total of 98 women with pCIA (median age, 56.5 years [range, 18-83 years]) and 94 women with EIAC (median age, 56 years [range, 29-84 years]) were included. The most common agents associated with pCIA were taxanes for 80 patients (82%); the most common agents associated with EIAC were aromatase inhibitors for 58 patients (62%). Diffuse alopecia was predominant in patients with pCIA compared with patients with EIAC (31 of 75 [41%] vs 23 of 92 [25%]; P = .04), with greater severity (Common Terminology Criteria for Adverse Events, version 4.0, grade 2) among patients with pCIA (29 of 75 [39%] vs 12 of 92 [13%]; P < .001). A negative emotional effect was reported by both groups. After treatment with topical minoxidil or spironolactone, moderate to significant improvement was observed for 36 of 54 patients with pCIA (67%) and for 32 of 42 patients with EIAC (76%). Conclusions and Relevance: Persistent chemotherapy-induced alopecia is frequently more severe and diffuse when compared with EIAC, and both groups of patients experienced a negative effect. A modest benefit was observed with dermatologic therapy. Additional studies are warranted to develop effective strategies for prevention and effective therapy for pCIA and EIAC.


Assuntos
Alopecia/induzido quimicamente , Antineoplásicos/efeitos adversos , Minoxidil/administração & dosagem , Qualidade de Vida , Espironolactona/administração & dosagem , Administração Tópica , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alopecia/tratamento farmacológico , Alopecia/epidemiologia , Antineoplásicos/administração & dosagem , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de Doença , Inquéritos e Questionários , Resultado do Tratamento , Adulto Jovem
6.
Medicine (Baltimore) ; 98(13): e15033, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30921227

RESUMO

RATIONALE: Cases of adrenocortical hyperfunction combined with primary aldosteronism have been reported in the literature, and the underlying mechanism involves the secretion of aldosterone and glucocorticoids by a tumor or an adenoma. However, adrenocortical hypofunction and coexisting primary aldosteronism have not been reported until now. Herein, we report a case of adrenocortical hypofunction combined with primary aldosteronism. PATIENT CONCERNS: A 66-year-old Chinese woman with rheumatoid arthritis who had been diagnosed with secondary adrenal insufficiency and was taking prednisone acetate tablets for replacement treatment presented to our department. She also had type 2 diabetes mellitus, osteoporosis, bilateral knee osteoarthritis, and lumbar vertebral compression fracture. She had previously developed tuberculosis, which had been cured. DIAGNOSIS: The cortisol and adrenocorticotropic hormone rhythm indicated cortisol dysfunction in the patient. A 64-slice computed tomography and magnetic resonance imaging both showed bilateral adrenal hyperplasia. A postural stimulation test indicated a high level of aldosteronism and a high aldosterone-to-renin ratio (ARR, supine position: aldosterone 1788.73 pg/mL, ARR 146.62; upright position: aldosterone 2916.21 pg/mL, ARR 92.29). The captopril test showed the aldosterone level decreased by 364.70 pg/mL 1 hour after administration of captopril (from 2153.28 to 1788.58 pg/mL). The decline in aldosterone level was approximately 16.90% (i.e., <30%), and the ARR was still >40. Based on the above-mentioned findings, we diagnosed the patient with adrenocortical hypofunction with primary aldosteronism. INTERVENTIONS: We administered spironolactone 20 mg twice daily and continued the glucocorticoid replacement therapy. OUTCOMES: One week after diagnosis, the patient had an aldosterone level of 2201.16 pg/mL, plasma renin activity of 3.88 ng/mL/h, and an ARR of 56.7 (upright position). Her blood pressure was maintained within the normal range. LESSONS: Although adrenocortical hypofunction with primary aldosteronism is rare, cases of primary aldosteronism complicated with hypercortisolism are occasionally encountered. Hence, whenever possible, we recommend testing both aldosterone and cortisol levels in all patients with adrenal dysfunction.


Assuntos
Insuficiência Adrenal/complicações , Síndrome de Cushing/complicações , Hiperaldosteronismo/complicações , Insuficiência Adrenal/metabolismo , Idoso , Aldosterona/análise , Síndrome de Cushing/metabolismo , Feminino , Humanos , Hidrocortisona/análise , Hiperaldosteronismo/tratamento farmacológico , Hiperaldosteronismo/metabolismo , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Espironolactona/administração & dosagem
8.
Kidney Int ; 95(4): 983-991, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30712923

RESUMO

Mineralocorticoid receptor antagonists have beneficial effects on left ventricular remodeling, cardiac fibrosis, and arrhythmia in heart failure, but efficacy and safety in dialysis patients is less clear. We evaluated the effect of spironolactone on left ventricular mass (LVM), an independent predictor of all-cause and cardiovascular mortality, in hemodialysis patients. In this placebo-controlled, parallel-group trial, 97 hemodialysis patients (23% female; mean age 60.3 years) were randomized to spironolactone 50 mg once daily (n=50) or placebo (n=47). The primary efficacy endpoint was change in LVM index (LVMi) from baseline to 40 weeks as determined by cardiac magnetic resonance imaging. Safety endpoints were development of hyperkalemia and change in residual renal function. There was no significant change in LVMi in participants randomized to spironolactone compared to placebo (-2.86±11.87 vs. 0.41±10.84 g/m2). There was also no difference in the secondary outcomes of mean 24-hour systolic or diastolic ambulatory blood pressure, left ventricular ejection fraction, 6-minute walk test distance, or New York Heart Association functional class. Moderate hyperkalemia (pre-dialysis potassium levels of 6.0-6.5 mmol/L) was more frequent with spironolactone treatment (155 vs. 80 events), but severe hyperkalemia (≥6.5 mmol/L) was not (14 vs. 24 events). Changes in residual urine volume and measured glomerular filtration rate did not differ between groups. There were no deaths in the spironolactone group and 4 deaths in the placebo group. Thus, treatment with 50 mg spironolactone did not change left ventricular mass index, cardiac function, or blood pressure in hemodialysis patients. Spironolactone increased the frequency of moderate hyperkalemia, but did not increase severe hyperkalemia.


Assuntos
Insuficiência Cardíaca/prevenção & controle , Ventrículos do Coração/patologia , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Espironolactona/administração & dosagem , Remodelação Ventricular/efeitos dos fármacos , Idoso , Método Duplo-Cego , Feminino , Insuficiência Cardíaca/etiologia , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/efeitos dos fármacos , Humanos , Hiperpotassemia/induzido quimicamente , Hiperpotassemia/epidemiologia , Falência Renal Crônica/complicações , Falência Renal Crônica/terapia , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Antagonistas de Receptores de Mineralocorticoides/efeitos adversos , Placebos/administração & dosagem , Placebos/efeitos adversos , Diálise Renal , Espironolactona/efeitos adversos , Volume Sistólico/efeitos dos fármacos , Resultado do Tratamento
9.
Pediatr Obes ; 14(5): e12500, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30653851

RESUMO

S100A4 is a marker of subcutaneous adipose tissue dysfunction. Polycystic ovary syndrome (PCOS) is often driven by hepato-visceral adiposity. PCOS phenotypes are normalized more by reduction of central fat with spironolactone/pioglitazone/metformin (SPIOMET) than by oral contraceptive (OC) treatment. We studied whether circulating S100A4 concentrations are high in adolescents with PCOS and, if so, whether they normalize more with OC or SPIOMET. Assessments included circulating S100A4, endocrine markers, body composition, abdominal fat partitioning in controls (n = 12) and girls with PCOS (n = 51; age 15.8 y; body mass index [BMI] 24.5 kg/m2 ), and 1-year changes in girls with PCOS randomized for OC (n = 27) or SPIOMET (n = 24) treatment. Mean S100A4 concentrations were 71% higher (P < 0.001) in girls with PCOS than in controls and associated with hepato-visceral adiposity (r = 0.47; P = 0.001); S100A4 concentrations decreased more (P < 0.01) with SPIOMET, those decreases associating to hepato-visceral fat loss (r = 0.50; P < 0.0001). S100A4 may become a circulating marker of hepato-visceral fat excess in adolescents with PCOS.


Assuntos
Anticoncepcionais Orais/uso terapêutico , Hipoglicemiantes/administração & dosagem , Gordura Intra-Abdominal/fisiopatologia , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Síndrome do Ovário Policístico/sangue , Proteína A4 de Ligação a Cálcio da Família S100/sangue , Adolescente , Adulto , Biomarcadores/sangue , Índice de Massa Corporal , Quimioterapia Combinada , Feminino , Humanos , Gordura Intra-Abdominal/efeitos dos fármacos , Metformina/administração & dosagem , Pioglitazona/administração & dosagem , Síndrome do Ovário Policístico/tratamento farmacológico , Síndrome do Ovário Policístico/fisiopatologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Espironolactona/administração & dosagem
10.
Oncogene ; 38(17): 3103-3118, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30622338

RESUMO

The cancer stem cell (CSC) model suggests that a subpopulation of cells within the tumor, the CSCs, is responsible for cancer relapse and metastasis formation. CSCs hold unique characteristics, such as self-renewal, differentiation abilities, and resistance to chemotherapy, raising the need for discovering drugs that target CSCs. Previously we have found that the antihypertensive drug spironolactone impairs DNA damage response in cancer cells. Here we show that spironolactone, apart from inhibiting cancerous cell growth, is also highly toxic to CSCs. Notably, we demonstrate that CSCs have high basal levels of DNA double-strand breaks (DSBs). Mechanistically, we reveal that spironolactone does not damage the DNA but impairs DSB repair and induces apoptosis in cancer cells and CSCs while sparing healthy cells. In vivo, spironolactone treatment reduced the size and CSC content of tumors. Overall, we suggest spironolactone as an anticancer reagent, toxic to both cancer cells and, particularly to, CSCs.


Assuntos
Antineoplásicos/administração & dosagem , Reparo do DNA/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Espironolactona/administração & dosagem , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular/efeitos dos fármacos , Reposicionamento de Medicamentos , Células HeLa , Humanos , Camundongos , Neoplasias/genética , Espironolactona/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Acta Cardiol ; 74(2): 100-107, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29587582

RESUMO

BACKGROUND: Signs and symptoms of volume overload are the most frequent reason for hospital admission in acute heart failure (AHF). Diuretics are mainstay treatment, but their optimal type and dose regimen remain unclear, especially in patients with cardiorenal syndrome. METHODS: This prospective study aimed to include 80 AHF patients with volume overload and cardiorenal syndrome. Through a 2 × 2 factorial design, patients were randomised towards (1) combinational treatment with acetazolamide and low-dose loop diuretics versus high-dose loop diuretics; and (2) open-label oral spironolactone 25 mg OD given upfront versus at discharge. Here reported are the results of the spironolactone treatment arm after complete follow-up of 34/80 patients (since the study was stopped because of slow recruitment). The primary study end-point was incident hypokalaemia (<3.5 mmol/L) or hyperkalaemia (>5.5 mmol/L). RESULTS: Serum potassium derangements were numerically less frequent in the upfront versus discharge spironolactone group, yet this result was underpowered due to incomplete study recruitment (hyperkalaemia: 6% vs. 11%; hypokalaemia: 13% vs. 28%, respectively; p-value = .270). Natriuresis after 24 h was higher in the upfront vs. discharge spironolactone group (314 ± 142 vs. 200 ± 91 mmol/L, respectively; p-value = .010). Relative change in plasma NT-proBNP level after 72 h was similar among both groups (-16 ± 29% vs. -5 ± 45%, respectively; p value = .393), with no difference in all-cause mortality (p-value = .682) or the combination of all-cause mortality and heart failure readmission (p-value = .799). DISCUSSION: Spironolactone use upfront in AHF patients at high risk for cardiorenal syndrome is safe and increases natriuresis.


Assuntos
Síndrome Cardiorrenal/tratamento farmacológico , Insuficiência Cardíaca Sistólica/tratamento farmacológico , Natriurese/efeitos dos fármacos , Espironolactona/administração & dosagem , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Síndrome Cardiorrenal/complicações , Síndrome Cardiorrenal/fisiopatologia , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Insuficiência Cardíaca Sistólica/complicações , Insuficiência Cardíaca Sistólica/fisiopatologia , Humanos , Masculino , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Estudos Prospectivos , Volume Sistólico/fisiologia , Resultado do Tratamento
12.
Br J Ophthalmol ; 103(8): 1184-1189, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30355720

RESUMO

AIMS: To evaluate the long-term oral mineralocorticoid receptor antagonist (MRa) treatment in chronic central serous chorioretinopathy (CSC). METHODS: Patients with chronic non-resolving CSC (defined as foveal subretinal fluid (SRF) lasting >4 months with retinal pigment epithelium (RPE) alterations) treated with MRa only (eplerenone or spironolactone) for at least 6 months were retrospectively included. Clinical and imaging characteristics were recorded during visits at baseline, 6, 12, 18 and 24 months. RESULTS: Sixteen eyes of 16 patients were included (mean age 53±11 years; 14 men, 2 women). Mean duration of SRF before treatment initiation was 11.2±19.7 months. MRa treatment was administered during 21.0±5.1 months (range, 10-24 months). There was a progressive improvement of visual acuity (p=0.05), a decrease of foveal SRF height (p=0.011), central macular thickness (p=0.004) and subfoveal choroidal thickness (p=0.002) over 24 months. Changes in SRF were correlated with subfoveal choroidal thickness at 24 months (p=0.006, Spearman r=065). The mean time to complete foveal SRF resolution was 10.5±8.0 months after treatment initiation. At 24 months, foveal SRF resolution was achieved in 13 eyes (81%). Minor side effects occurred in five patients (31%) and resolved after switching between MRa. CONCLUSION: The visual and anatomical benefit of MRa treatment prolonged for 6 months or more in chronic, non-resolving CSC appeared to be maintained over a 24-month period. These results suggest that MRa can be proposed as an alternative therapy in severe CSC with advanced RPE alterations.


Assuntos
Coriorretinopatia Serosa Central/tratamento farmacológico , Espironolactona/administração & dosagem , Acuidade Visual , Administração Oral , Adulto , Idoso , Coriorretinopatia Serosa Central/diagnóstico , Corioide/patologia , Doença Crônica , Feminino , Angiofluoresceinografia , Seguimentos , Fundo de Olho , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Retina/patologia , Estudos Retrospectivos , Fatores de Tempo , Tomografia de Coerência Óptica/métodos , Resultado do Tratamento
13.
Ann Vasc Surg ; 56: 103-107, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30342208

RESUMO

BACKGROUND: Postoperative fluid overload in cardiovascular surgery is associated with increased mortality and morbidity. Recently, tolvaptan (TLV), a selective vasopressin V2 antagonist, has been used for perioperative fluid management. This study aimed to validate the safety and effectiveness of TLV administration after total arch replacement (TAR) using selective cerebral perfusion. METHODS: From August 2016 to December 2016, 11 patients who had undergone TAR for thoracic aortic aneurysm were included in this study. In addition to the conventional diuretics furosemide (20 mg) and spironolactone (25 mg), TLV (7.5 mg) was administered orally. RESULTS: TLV increased urine output 1-3 days after administration. Body weight was gradually and steadily reduced until discharge. Neither renal nor liver dysfunction was recognized during the TLV administration. CONCLUSION: The concomitant use of TLV and conventional diuretics is safe and effective for fluid management after TAR using cardiopulmonary bypass, selective cerebral perfusion, and hypothermic circulatory arrest.


Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos/administração & dosagem , Aneurisma da Aorta Torácica/cirurgia , Implante de Prótese Vascular , Tolvaptan/administração & dosagem , Micção/efeitos dos fármacos , Equilíbrio Hidroeletrolítico/efeitos dos fármacos , Administração Oral , Idoso , Antagonistas dos Receptores de Hormônios Antidiuréticos/efeitos adversos , Aneurisma da Aorta Torácica/diagnóstico por imagem , Implante de Prótese Vascular/efeitos adversos , Esquema de Medicação , Quimioterapia Combinada , Feminino , Furosemida/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Estudos Retrospectivos , Inibidores de Simportadores de Cloreto de Sódio e Potássio/administração & dosagem , Espironolactona/administração & dosagem , Fatores de Tempo , Tolvaptan/efeitos adversos , Resultado do Tratamento , Perda de Peso/efeitos dos fármacos
14.
Br J Clin Pharmacol ; 85(1): 169-180, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30294825

RESUMO

AIMS: The aims of the present study were to explore whether a long-term intervention with dietary nitrate [(NO3 - ), a potential tolerance-free source of beneficial vasoactive nitric oxide] and spironolactone (to oppose aldosterone's potential deleterious cardiovascular effects) improve cardiac structure/function, independently of blood pressure (BP), in patients with/at risk of type 2 diabetes (a population at risk of heart failure). METHODS: A subsample of participants in our double-blind, randomized, factorial-design intervention (VaSera) trial of active beetroot juice as a nitrate source (≤11.2 mmol) or placebo (nitrate depleted) beetroot juice, and either ≤50 mg spironolactone or ≤16 mg doxazosin (control), had transthoracic cardiac ultrasounds at baseline (n = 105), and at 3 months and 6 months (n = 87) after the start of the intervention. Analysis was by modified intent-to-treat. RESULTS: Nitrate-containing juice (n = 40) decreased left ventricular (LV) end-diastolic volume {-6.3 [95% confidence interval (CI) -11.1, -1.6] ml} and end-systolic volume [-3.2 (95% CI -5.9, -0.5) ml], and increased end-diastolic mass/volume ratio [+0.04 (95% CI 0.00, 0.07)], relative to placebo juice (n = 47). Spironolactone (n = 44) reduced relative wall thickness compared with doxazosin (n = 43) [-0.01 (95% CI -0.02, -0.00)]. Although spironolactone reduced LV mass index relative to baseline [-1.48 (95% CI -2.08, -0.88) g m-2.7 ], there was no difference vs. doxazosin [-0.85 (95% CI -1.76, 0.05) g m-2.7 ]. Spironolactone also decreased the E/A ratio [-0.12 (95% CI -0.19, -0.04)] and increased S' (a tissue-Doppler systolic function index) by 0.52 (95% CI 0.05, 1.0) cm s-1 . BP did not differ between the juices, or between the drugs. CONCLUSIONS: Six months' dietary nitrate decreased LV volumes ~5%, representing new, sustained, BP-independent benefits on cardiac structure, extending mechanisms characterized in preclinical models of heart failure. Spironolactone's effects on cardiac remodelling and systolic-diastolic function, although confirmatory, were independent of BP.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Insuficiência Cardíaca/prevenção & controle , Coração/efeitos dos fármacos , Nitratos/administração & dosagem , Espironolactona/administração & dosagem , Adulto , Idoso , Beta vulgaris/química , Pressão Sanguínea/efeitos dos fármacos , Método Duplo-Cego , Doxazossina/administração & dosagem , Ecocardiografia , Feminino , Sucos de Frutas e Vegetais , Coração/diagnóstico por imagem , Insuficiência Cardíaca/etiologia , Humanos , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Análise de Onda de Pulso , Resultado do Tratamento , Rigidez Vascular/efeitos dos fármacos
15.
Kidney Int ; 95(4): 973-982, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30473139

RESUMO

The safety and efficacy of spironolactone is uncertain in end-stage renal disease. We randomized 129 maintenance hemodialysis patients to placebo (n=51) or spironolactone 12.5 mg (n=27), 25 mg (n=26), or 50 mg (n=25) daily for 36 weeks in a double-blind, placebo-controlled, multiple dosage trial to assess safety, tolerability and feasibility and to explore cardiovascular efficacy. The primary safety endpoints were hyperkalemia (potassium > 6.5 mEq/L) and hypotension requiring emergency department visit or hospitalization. Diastolic function was assessed by Doppler echocardiography. 125 participants (97%) completed dose escalation, with no significant difference in permanent study drug discontinuation between the groups (27.5% in placebo versus 16.7% in the combined spironolactone groups and 28% in the 50 mg group). Hyperkalemia frequency was similar between spironolactone and placebo (0.49 versus 0.50 events per patient-year) but demonstrated a significant linear trend due primarily to an increased event rate at the 50 mg dose (0.89 events per patient-year). The primary hypotension outcome was infrequent and similar with spironolactone and placebo (0.11 versus 0 events per patient-year). Gynecomastia was rare and did not differ significantly between groups. Change in diastolic function was similar with spironolactone and placebo. Spironolactone appears safe in carefully monitored maintenance hemodialysis patients, but did not affect cardiovascular parameters in this small study. Hyperkalemia occurs more frequently as dosage increases to 50 mg daily.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Hiperpotassemia/epidemiologia , Hipotensão/epidemiologia , Falência Renal Crônica/terapia , Antagonistas de Receptores de Mineralocorticoides/efeitos adversos , Espironolactona/efeitos adversos , Adulto , Idoso , Aldosterona/metabolismo , Doenças Cardiovasculares/diagnóstico por imagem , Diástole/efeitos dos fármacos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Ecocardiografia Doppler , Estudos de Viabilidade , Feminino , Ginecomastia/induzido quimicamente , Ginecomastia/epidemiologia , Humanos , Hiperpotassemia/sangue , Hiperpotassemia/induzido quimicamente , Hipotensão/induzido quimicamente , Falência Renal Crônica/complicações , Falência Renal Crônica/metabolismo , Masculino , Pessoa de Meia-Idade , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Placebos/administração & dosagem , Placebos/efeitos adversos , Potássio/sangue , Diálise Renal , Espironolactona/administração & dosagem
16.
Can J Physiol Pharmacol ; 97(1): 65-74, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30422674

RESUMO

Women have a lower incidence of cardiovascular diseases (CVD) than men at a similar age but the reverse is the case after menopause, indicating a possible protective effect of estrogen on cardiometabolic function. Although various hormonal therapies have been formulated to combat the CVD risks in postmenopausal state, the beneficial effects have not been consistent. Obesity with insulin resistance (IR) is closely linked to CVD risks while ovariectomized rodents have been shown to mimic a state of obesity and IR. We therefore hypothesized that low-dose spironolactone would ameliorate obesity and IR in estrogen-deprived rats by replenishing estrogen and suppressing elevated glycogen synthase kinase-3 (GSK-3). Ten-week-old female Wistar rats were divided into 4 groups: sham-operated (SHM), spironolactone (SPL; 0.25 mg/kg), and ovariectomized (OVX) rats treated with or without spironolactone daily for 8 weeks. Results showed that estrogen deprivation through ovariectomy caused increased body mass gain and visceral adiposity that are accompanied by increased HOMA-IR, HOMA-ß, 1-hour postload glucose, glucose intolerance, platelet/lymphocyte ratio, plasma insulin, atherogenic dyslipidemia, uric acid, GSK-3, corticosterone, and aldosterone and depressed 17ß-estradiol. However, treatment of OVX rats with spironolactone ameliorated all these effects. Taken together, the results demonstrate that treatment with low-dose spironolactone improves obesity and IR, which appears to involve replenishment of estrogen and suppression of GSK-3 along with circulating mineralocorticoid and glucocorticoid. The findings imply a positive cardiometabolic effect of low-dose spironolactone usage in estrogen-deprived conditions.


Assuntos
Estrogênios/sangue , Resistência à Insulina/fisiologia , Obesidade/sangue , Obesidade/tratamento farmacológico , Ovariectomia , Espironolactona/administração & dosagem , Animais , Relação Dose-Resposta a Droga , Feminino , Mediadores da Inflamação/sangue , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Ovariectomia/efeitos adversos , Ratos , Ratos Wistar , Resultado do Tratamento
17.
Vasc Health Risk Manag ; 15: 571-579, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31920323

RESUMO

Spironolactone, an antagonist of aldosterone, initially used as a potassium-sparing diuretic, was subsequently shown to be a very effective adjunctive agent in the treatment of patients with heart failure with reduced ejection fraction, by halting the disease progression, with significant beneficial effects on both morbidity and mortality. Other uses comprise resistant hypertension, edema in patients with cirrhosis, and other on- and off-label uses. Recent data indicate that spironolactone also may offer some symptomatic relief in patients with heart failure and preserved ejection fraction. However, a variable percentage of patients, particularly among the aged group, may have difficulty in swallowing or may be unable to swallow tablets and thus are deprived of the benefits of such therapy. In 2017, the FDA approved a liquid suspension formulation of spironolactone, CaroSpir®, which will enable more heart failure and other patients in need of aldosterone inhibition to avail themselves of the protective and beneficial effects of spironolactone. The new drug formulation comes as a banana-flavored oral suspension that contains 25 mg/5 mL of spironolactone, supplied in 4-ounce (118 mL) and 16-ounce (473 mL) bottles. The details of this drug formulation development and the benefits of spironolactone use in patients with heart failure with a focus on patient selection are herein reviewed.


Assuntos
Diuréticos/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Seleção de Pacientes , Espironolactona/administração & dosagem , Administração Oral , Tomada de Decisão Clínica , Diuréticos/efeitos adversos , Diuréticos/química , Diuréticos/farmacocinética , Formas de Dosagem , Composição de Medicamentos , Aromatizantes/administração & dosagem , Aromatizantes/química , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/fisiopatologia , Humanos , Antagonistas de Receptores de Mineralocorticoides/efeitos adversos , Antagonistas de Receptores de Mineralocorticoides/química , Antagonistas de Receptores de Mineralocorticoides/farmacocinética , Fatores de Risco , Espironolactona/efeitos adversos , Espironolactona/química , Espironolactona/farmacocinética , Resultado do Tratamento
18.
Hormones (Athens) ; 17(4): 573-579, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30467685

RESUMO

AIM: The evaluation of (a) noggin levels in patients with simple steatosis (SS) vs. nonalcoholic steatohepatitis (NASH) vs. controls, and (b) the effect of combined spironolactone plus vitamin E vs. vitamin E monotherapy on noggin levels in biopsy-proven patients with nonalcoholic fatty liver disease (NAFLD). METHODS: In the case-control study, 15 patients with SS, 16 with NASH, and 24 controls were included. In the randomized controlled trial, NAFLD patients were assigned to vitamin E (400 IU/d) or spironolactone (25 mg/d) plus vitamin E for 52 weeks. RESULTS: Noggin levels were lower in SS (5.8 ± 1.5 pmol/l) and NASH (8.7 ± 2.4 pmol/l) patients than in controls (13.7 ± 2.7 pmol/l; p for trend = 0.040), but were similar in SS and NASH patients. After adjustment for potential cofounders, log(noggin) remained different between groups. Log(noggin) levels similarly increased post-treatment in both groups: log(noggin) was not different between groups (p = 0.20), but increased within groups over time (p < 0.001), without a significant group × time interaction (p = 0.62). Log(noggin) significantly increased at month 2 post-treatment (p = 0.008 vs. baseline) and remained stable thereafter. CONCLUSIONS: Lower noggin levels were observed in NAFLD patients than in controls. Noggin levels increased similarly by either combined low-dose spironolactone plus vitamin E or vitamin E monotherapy. TRIAL REGISTRATION: NCT01147523.


Assuntos
Proteínas de Transporte/sangue , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Espironolactona/farmacologia , Vitamina E/farmacologia , Proteínas de Transporte/efeitos dos fármacos , Estudos de Casos e Controles , Quimioterapia Combinada , Humanos , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Espironolactona/administração & dosagem , Vitamina E/administração & dosagem
19.
Int J Pharm Compd ; 22(6): 516-526, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30384353

RESUMO

Compounded liquid medication is frequently required in children to allow easy dose adjustment and overcome swallowing difficulties. The objective of this study was to evaluate the stability of oral suspensions compounded with SyrSpend SF PH4 and the commonly used active pharmaceutical ingredients baclofen 2.0 mg/mL, carvedilol 5.0 mg/mL, hydrochlorothiazide 2.0 mg/mL, mercaptopurine 10.0 mg/mL, methadone hydrochloride 10.0 mg/mL, oseltamivir phosphate 6.0 mg/mL, phenobarbital 9.0 mg/mL and 15.0 mg/mL, propranolol hydrochloride 0.5 mg/mL and 5.0 mg/mL, pyrazinamide 100.0 mg/mL, spironolactone 2.0 mg/mL and 2.5 mg/mL, sotalol hydrochloride 5.0 mg/mL, tacrolimus monohydrate 0.5 mg/mL, ursodeoxycholic acid 20.0 mg/mL, and vancomycin hydrochloride 25.0 mg/mL. Suspensions were compounded with raw powders, except for mercaptopurine, pyrazinamide, and sotalol hydrochloride, which were made from commercial tablets. Stability was assessed by measuring the percentage recovery at 0 (baseline), 60 days, and 90 days after compounding for suspensions made with raw powders, which were stored at 2ÅãC to 8ÅãC. The stability of tablets, which were stored at 2ÅãC to 8ÅãC and 20ÅãC to 25ÅãC, was assessed by measuring the percentage recovery at 0 (baseline), 7 days, 14 days, 30 days, 60 days, and 90 days. Active pharmaceutical ingredients quantification was performed by ultraviolet high-performance liquid chromatography via a stability-indicating method. Given the percentage of recovery of the active pharmaceutical ingredients within the suspensions, the beyond-use date of the final products (active pharmaceutical ingredients + vehicle) was at least 90 days for all suspensions in the conditions tested. This suggests that SyrSpend SF PH4 is suitable for compounding active pharmaceutical ingredients from different pharmacological classes.


Assuntos
Baclofeno/química , Carvedilol/química , Hidroclorotiazida/química , Mercaptopurina/química , Metadona/química , Oseltamivir/química , Veículos Farmacêuticos/química , Fenobarbital/química , Propranolol/química , Sotalol/química , Espironolactona/química , Amido/química , Tacrolimo/química , Ácido Ursodesoxicólico/química , Vancomicina/química , Administração Oral , Baclofeno/administração & dosagem , Carvedilol/administração & dosagem , Composição de Medicamentos , Estabilidade de Medicamentos , Hidroclorotiazida/administração & dosagem , Concentração de Íons de Hidrogênio , Mercaptopurina/administração & dosagem , Metadona/administração & dosagem , Oseltamivir/administração & dosagem , Soluções Farmacêuticas , Fenobarbital/administração & dosagem , Propranolol/administração & dosagem , Pirazinamida/administração & dosagem , Sotalol/administração & dosagem , Espironolactona/administração & dosagem , Suspensões , Tacrolimo/administração & dosagem , Temperatura Ambiente , Fatores de Tempo , Ácido Ursodesoxicólico/administração & dosagem , Vancomicina/administração & dosagem
20.
Int J Pharm ; 553(1-2): 238-260, 2018 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-30359685

RESUMO

Most of the recent drug compounds coming out of the drug discovery pipeline are labile (multiple polymorphs), and need to be developed into robust marketed oral drug formulations. There are only 22 oral macroamorphous drug products approved by FDA and till date none approved oral nanoamorphous drug products. However, there are several oral nanoamorphous drug formulations (including both labile and non-labile drugs) being researched and a few of these are in the clinical trials. Due to the labile nature of these drug compounds, there is a need to utilize a controlled strategy for design and development of robust nanoamorphous drug formulations in order to prevent any physicochemical instability. The present research focuses on the use of a novel integrated critical process parameters and critical formulation parameters (iCPP-CFPs) DoE approach for the design and development of stable nanoamorphous spironolactone (BCS class II compound with eight polymorphic forms). There are possibilities of the interconversion of these polymorphic forms during processing (manufacturing nanoamorphous particles) and during storage. In the present study, polymorphic transitions (amorphous to crystalline and anhydrous to hydrate) were carefully monitored via orthogonal solid-state characterization tools. Significant polymorphic transitions were observed in the formulations stored at 40 °C/75% RH over six months, however the formulations stored at 4 °C were stable. The significant iCPP-CFPs (solvent-to-antisolvent ratio, drug concentration and inlet temperature of the spray dryer) were critically investigated for their influence on different CQAs (critical quality attributes). Solvent-to-antisolvent ratio and inlet temperature were identified to be the significant iCPP-CFPs. Particle size and total product yield were identified to be the significant CQAs. Lab-scale manufacturing of the spray dried nanoamorphous spironolactone resulted in a remarkably high total product yield (82.4 ±â€¯3.91% w/w) with a uniform and homogenous particle size (244.2 ±â€¯23.32 nm). Furthermore, the physicochemical attributes and the drug release criteria of the nanoamorphous spironolactone were compared with two marketed products (spironolactone tablets, USP 100 mg (Pfizer and Mylan)) and other in-house formulations. In addition, nanoamorphous spironolactone showed a significantly superior kinetic solubility/dissolution rate (10-fold) with a longer supersaturation time (∼6h) compared to the in-house formulations.


Assuntos
Química Farmacêutica/métodos , Desenho de Drogas , Nanopartículas , Espironolactona/administração & dosagem , Administração Oral , Cristalização , Diuréticos/administração & dosagem , Diuréticos/química , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Umidade , Tamanho da Partícula , Solubilidade , Solventes/química , Espironolactona/química , Temperatura Ambiente , Fatores de Tempo
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