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1.
J Stroke Cerebrovasc Dis ; 29(2): 104525, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31812455

RESUMO

BACKGROUND AND PURPOSE: A subset of ischemic stroke patients present with blood pressures above that considered safe for thrombolytic administration, requiring antihypertensive therapy. Guideline statements are ambivalent regarding which antihypertensive agent should be used to obtain a satisfactory blood pressure < 185/110 mm Hg prior to alteplase. METHODS: We reviewed data from consecutive patients at a single institution treated with alteplase from January 2014 to January 2019, collecting door-to-needle times, antihypertensive agent (if used), and antihypertensive-to-needle times. Patients were grouped by initial agent administered. We assessed for differences in door-to-needle times between those needing antihypertensive(s) and those who did not. Antihypertensive-to-needle times were compared across 3 antihypertensive groups (labetalol, nicardipine, and hydralazine). RESULTS: Analysis included 239 patients: 177 receiving no antihypertensive, 44 labetalol, 13 nicardipine, and 5 hydralazine. Those not administered an antihypertensive prior to alteplase had shorter door-to-needle times (52.6 minutes versus 62.1 minutes, P = .016). We found no statistical differences when comparing door-to-needle times across all groups (no med 52.6 minutes, labetalol 64.3 minutes, nicardipine 53.0 minutes, hydralazine 67.4 minutes, P = .052). No differences were found in antihypertensive-to-needle amongst the 3 antihypertensive groups (labetalol 18.75 minutes, nicardipine 12.15 minutes, hydralazine 25.40 minutes, P = .239). CONCLUSIONS: Patients requiring antihypertensives experienced slower door-to-needle times. No statistically significant changes were observed in door-to-needle times by antihypertensive used, however these results may have clinical importance. This study is limited by relatively small sample size. Pooling data from multiple institutions could provide more robust assessment and inform clinical practice.


Assuntos
Anti-Hipertensivos/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Fibrinolíticos/administração & dosagem , Hipertensão/tratamento farmacológico , Acidente Vascular Cerebral/tratamento farmacológico , Terapia Trombolítica , Tempo para o Tratamento , Ativador de Plasminogênio Tecidual/administração & dosagem , Idoso , Anti-Hipertensivos/efeitos adversos , Esquema de Medicação , Feminino , Fibrinolíticos/efeitos adversos , Humanos , Hidralazina/administração & dosagem , Hipertensão/diagnóstico , Hipertensão/fisiopatologia , Infusões Intravenosas , Labetalol/administração & dosagem , Masculino , Nicardipino/administração & dosagem , Estudos Retrospectivos , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/fisiopatologia , Terapia Trombolítica/efeitos adversos , Fatores de Tempo , Ativador de Plasminogênio Tecidual/efeitos adversos , Resultado do Tratamento
2.
Am J Cardiol ; 124(12): 1900-1906, 2019 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-31679641

RESUMO

Underuse of hydralazine/nitrate (HYD/NIT) in black patients with heart failure and reduced ejection fraction (HFrEF) has been previously described, but whether this important treatment gap persists in contemporary practice is unknown. Sacubitril/valsartan has become a part of guideline-directed medical therapy for HFrEF but data on utilization of this therapy in black patients is lacking. This study addressed these issues by assessing the frequency of HYD/NIT and sacubitril/valsartan use in black patients with HFrEF in the Change the Management of Patients with Heart Failure Registry, a multicenter cohort study. The association of race with utilization rates of these agents was also evaluated. Clinical and medication data at baseline and during 12 months of follow-up from black and nonblack registry patients without documented contraindications or intolerance to the medications of interest were analyzed. Data were available from December 2015 to October 2017, in 4,848 HFrEF patients, of whom 853 were black (18%) and 3995 were nonblack. Black patients were younger, more likely to be female, and had lower ejection fractions compared with nonblacks. Only 11% of black patients were receiving HYD/NIT therapy at baseline and 13% at 1 year. The percentage of black patients treated at baseline with sacubitril/valsartan was also low at 18% and remained unchanged at 1 year. After adjustment for covariates, race was independently associated with HYD/NIT use (odds ratio 8.32; 95% confidence interval 6.12 to 11.3; p < 0.0001), but not for sacubitril/valsartan. In conclusion, study findings demonstrate a marked persistent treatment gap for HYD/NIT and similar poor utilization of sacubitril/valsartan in black patients with HFrEF despite current guideline recommendations.


Assuntos
Afro-Americanos/estatística & dados numéricos , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/etnologia , Hidralazina/uso terapêutico , Neprilisina/uso terapêutico , Sistema de Registros , Idoso , Aminobutiratos/administração & dosagem , Antagonistas de Receptores de Angiotensina/uso terapêutico , Estudos de Coortes , Uso de Medicamentos , Feminino , Insuficiência Cardíaca/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Medição de Risco , Volume Sistólico/efeitos dos fármacos , Taxa de Sobrevida , Tetrazóis/administração & dosagem , Resultado do Tratamento
3.
Undersea Hyperb Med ; 46(5): 701-707, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31683370

RESUMO

Purpose: To report the successful treatment of postoperative posterior ischemic optic neuropathy (PION) with hyperbaric oxygen therapy and to review the current literature on the pathogenesis and treatment of PION. Observations: During an angiographic procedure at a community hospital, an elderly woman had a transient drop in blood pressure after receiving an intravenous dose of hydralazine. During recovery, the patient experienced bilateral vision loss. She was transferred to our specialty referral center for treatment with hyperbaric oxygen. We followed Table 5 in the U.S. Navy Diving Manual, the protocol for decompression sickness. Our patient's vision improved markedly immediately after the first session and continued to improve throughout the course of treatment to its completion. Follow-up ophthalmology visits found the patient's vision to be close to baseline. Conclusions and importance: PION is a rare condition. It has been difficult to determine a successful therapeutic approach because of the lack of large case-controlled studies. Hyperbaric oxygen has been used to treat other ischemic ophthalmic conditions, but there are only few reports of its use in patients with PION. Systemic steroids and antiplatelet therapy have also been used, with mixed success. In our patient, the combination of hyperbaric oxygen therapy and steroids was successful in restoring vision after postoperative PION.


Assuntos
Oxigenação Hiperbárica , Neuropatia Óptica Isquêmica/terapia , Complicações Pós-Operatórias/terapia , Idoso de 80 Anos ou mais , Anti-Hipertensivos/efeitos adversos , Feminino , Humanos , Hidralazina/efeitos adversos , Hipotensão/induzido quimicamente , Neuropatia Óptica Isquêmica/etiologia , Complicações Pós-Operatórias/etiologia , Recuperação de Função Fisiológica
4.
Nat Commun ; 10(1): 4905, 2019 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-31659167

RESUMO

Therapeutic activation of mitochondrial function has been suggested as an effective strategy to combat aging. Hydralazine is an FDA-approved drug used in the treatment of hypertension, heart failure and cancer. Hydralazine has been recently shown to promote lifespan in C. elegans, rotifer and yeast through a mechanism which has remained elusive. Here we report cAMP-dependent protein kinase (PKA) as the direct target of hydralazine. Using in vitro and in vivo models, we demonstrate a mechanism in which binding and stabilization of a catalytic subunit of PKA by hydralazine lead to improved mitochondrial function and metabolic homeostasis via the SIRT1/SIRT5 axis, which underlies hydralazine's prolongevity and stress resistance benefits. Hydralazine also protects mitochondrial metabolism and function resulting in restoration of health and lifespan in C. elegans under high glucose and other stress conditions. Our data also provide new insights into the mechanism(s) that explain various other known beneficial effects of hydralazine.


Assuntos
Envelhecimento/efeitos dos fármacos , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/efeitos dos fármacos , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Hidralazina/administração & dosagem , Sirtuína 1/metabolismo , Envelhecimento/genética , Envelhecimento/metabolismo , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/genética , Feminino , Humanos , Longevidade/efeitos dos fármacos , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Sirtuína 1/genética
5.
Am J Physiol Renal Physiol ; 317(3): F572-F583, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31241996

RESUMO

Many studies have suggested that renal T cell infiltration contributes to the pathogenesis of salt-sensitive hypertension. To investigate this mechanism further, we determined T cell profiles in the kidney and lymphoid tissues as a function of blood pressure in the female Envigo Dahl salt-sensitive (SS) rat maintained on low-Na+ (LS) diet. Mean arterial pressure and heart rate were measured by telemetry in SS rats from 1 mo old (juvenile) to 4 mo old. Normotensive salt-resistant (SR) rats were included as controls. Frequencies of T helper (CD4+) cells were greater in the kidney, lymph nodes, and spleen in 4-mo-old hypertensive SS rats compared with normotensive SR animals and SS juvenile rats, suggesting that renal T cell infiltration contributes to hypertension in the SS rat on a LS diet. At 1.5 mo, half of the SS rats were treated with vehicle (Veh), and the rest received hydralazine (HDZ; 25 mg·kg-1·day-1) for 11 wk. HDZ impeded the development of hypertension compared with Veh-treated control rats [mean arterial pressure: 157 ± 4 mmHg in the Veh-treated group (n = 6) vs. 133 ± 3 mmHg in the HDZ-treated group (n = 7), P < 0.001] without impacting T helper cell frequencies in the tissues, suggesting that HDZ can overcome mechanisms of hypertension driven by renal T cell infiltration under the LS diet. Renal frequencies of CD4+CD25+ and CD4+CD25+FoxP3+ regulatory T cells were significantly higher in 4-mo-old hypertensive rats compared with normotensive SR rats and SS juvenile rats, suggesting that these T cell subpopulations play a compensatory role in the development of hypertension. Greater understanding of these T cell populations could lead to new therapeutic targets for treating inflammatory diseases associated with hypertension.


Assuntos
Pressão Arterial , Dieta Hipossódica , Hipertensão/prevenção & controle , Rim/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Animais , Anti-Hipertensivos/farmacologia , Pressão Arterial/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Frequência Cardíaca , Hidralazina/farmacologia , Hipertensão/imunologia , Hipertensão/fisiopatologia , Rim/efeitos dos fármacos , Linfonodos/imunologia , Ratos Endogâmicos Dahl , Baço/imunologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Vasodilatadores/farmacologia
6.
Int J Oncol ; 55(1): 167-178, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31180533

RESUMO

Vascular endothelial growth inhibitor (VEGI; also referred to as TNFSF15 or TL1A) is involved in the modulation of vascular homeostasis. VEGI is known to operate via two receptors: Death receptor­3 (DR3) and decoy receptor­3 (DcR3). DR3, which is thus far the only known functional receptor for VEGI, contains a death domain and induces cell apoptosis. DcR3 is secreted as a soluble protein and antagonizes VEGI/DR3 interaction. Overexpression of DcR3 and downregulation of VEGI have been detected in a number of cancers. The aim of the present study was to investigate the effects of sodium valproate (VPA), a histone deacetylase inhibitor, in combination with hydralazine hydrochloride (Hy), a DNA methylation inhibitor, on the expression of VEGI and its related receptors in human osteosarcoma (OS) cell lines and human microvascular endothelial (HMVE) cells. Combination treatment with Hy and VPA synergistically induced the expression of VEGI and DR3 in both OS and HMVE cells, without inducing DcR3 secretion. In addition, it was observed that the combination of VPA and Hy significantly enhanced the inhibitory effect on vascular tube formation by VEGI/DR3 autocrine and paracrine pathways. Furthermore, the VEGI/VEGF­A immune complex was pulled down by immunoprecipitation. Taken together, these findings suggest that DNA methyltransferase and histone deacetylase inhibitors not only have the potential to induce the re­expression of tumor suppressor genes in cancer cells, but also exert anti­angiogenic effects, via enhancement of the VEGI/DR3 pathway and VEGI/VEGF­A interference.


Assuntos
Neoplasias Ósseas/tratamento farmacológico , Hidralazina/farmacologia , Osteossarcoma/tratamento farmacológico , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/biossíntese , Ácido Valproico/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Neoplasias Ósseas/irrigação sanguínea , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Sinergismo Farmacológico , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Inibidores Enzimáticos/farmacologia , Epigênese Genética , Humanos , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Osteossarcoma/irrigação sanguínea , Osteossarcoma/genética , Osteossarcoma/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Membro 25 de Receptores de Fatores de Necrose Tumoral/biossíntese , Membro 25 de Receptores de Fatores de Necrose Tumoral/genética , Transcrição Genética/efeitos dos fármacos , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética
7.
Clin Perinatol ; 46(2): 173-185, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31010554

RESUMO

This article reviews the pharmacology of the most commonly used antihypertensive medications during pregnancy; their mechanism of action; and the effects on the mother, the fetus, and lactation. Each class of antihypertensive pharmacologic agents have specific mechanisms of action by which they exert their antihypertensive effect. ß-Adrenoreceptor antagonists block these receptors in the peripheral circulation. Calcium channel blockers result in arterial vasodilation. α-Agonists inhibit vasoconstriction. Methyldopa is a centrally acting adrenoreceptor antagonist. Vasodilators have a direct effect on vascular smooth muscle. Diuretics decrease intravascular volume. Medications acting on the angiotensin pathway are avoided during pregnancy because of fetotoxic effects.


Assuntos
Anti-Hipertensivos/uso terapêutico , Hipertensão Induzida pela Gravidez/tratamento farmacológico , Hipertensão/tratamento farmacológico , Pré-Eclâmpsia/tratamento farmacológico , Antagonistas Adrenérgicos beta/uso terapêutico , Aspirina/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Doença Crônica , Clonidina/uso terapêutico , Inibidores de Ciclo-Oxigenase/uso terapêutico , Diuréticos/uso terapêutico , Feminino , Humanos , Hidralazina/uso terapêutico , Hipertensão Induzida pela Gravidez/prevenção & controle , Troca Materno-Fetal , Pré-Eclâmpsia/prevenção & controle , Gravidez , Complicações na Gravidez/tratamento farmacológico
8.
ESC Heart Fail ; 6(3): 487-498, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30892835

RESUMO

AIMS: Population data indicate that one in 25 persons of African ancestry has heart failure, a condition with relatively high mortality of around 50% in 5 years. Combined hydralazine and isosorbide dinitrate added to conventional therapy in African ancestry patients with heart failure and reduced ejection fraction improves quality of life and reduces the rate of first hospitalization for heart failure by 33% and annual mortality by 43%. The objectives of this study were to quantify the use of this guideline-recommended therapy in Europe and the potential effect of implementation gaps on mortality. METHODS AND RESULTS: Prescription drug registration and utilization databases and population statistics were analysed in a cross-European survey without language restriction. Main outcomes were the number of unique patients prescribed the fixed combination hydralazine-isosorbide dinitrate (primary) or both drugs (secondary) in Europe in 2015, and the excess mortality related to prescribing practices was estimated. The survey indicates that around 12 million persons of African ancestry live in Europe. It is estimated that 480 000 persons of this population group have heart failure, with 120 000 eligible for hydralazine and isosorbide dinitrate therapy. However, single-pill hydralazine-isosorbide dinitrate is not authorized and therefore not dispensed in Europe in 2015. Out of the 25 European nations surveyed, the UK and the Netherlands are the only countries with major African ancestry populations where both hydralazine and isosorbide dinitrate are available for oral use, aside Norway, Sweden, and Finland. Hydralazine and isosorbide dinitrate are prescribed to <500 European patients in 2015. Thus, despite the recommendations of the European Society of Cardiology, the large majority of African-European patients with heart failure do not receive this drug combination, potentially resulting in 4800 to 5800 excess deaths yearly. CONCLUSIONS: The life-saving, guideline-recommended, adjunctive therapy for heart failure in African ancestry patients with hydralazine and isosorbide dinitrate is rarely used in Europe. This major evidence-practice gap should urgently be overcome to reduce excess mortality in African-European patients with heart failure.


Assuntos
Grupo com Ancestrais do Continente Africano/estatística & dados numéricos , Fármacos Cardiovasculares/uso terapêutico , Prescrições de Medicamentos/estatística & dados numéricos , Insuficiência Cardíaca , Hidralazina/uso terapêutico , Dinitrato de Isossorbida/uso terapêutico , Estudos Transversais , Bases de Dados de Produtos Farmacêuticos , Combinação de Medicamentos , Europa (Continente)/epidemiologia , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/mortalidade , Humanos
9.
Ann Rheum Dis ; 78(4): 504-508, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30793701

RESUMO

OBJECTIVE: Drug-induced lupus (DIL) is an idiosyncratic side effect of treatments in which symptoms overlap with those of systemic lupus erythematosus (SLE). The spectrum of DIL constantly evolves with that of the pharmacopoeia. Here, we used VigiBase, the WHO global individual case safety reports (ICSRs) database, to identify the main drugs associated with DIL. METHODS: We analysed all ICSRs classified as 'systemic lupus erythematosus' according to the Medical Dictionary for Drug Regulatory Activities term (preferred term level) in VigiBase. The drugs considered in the analysis were those not used to treat SLE, with a positive lower end of the 95% credibility interval for the information component (IC025) ≥0, an indicator value for disproportionate Bayesian reporting. RESULTS: A total of 12 166 DIL ICSRs were identified using VigiBase. From those, 8163 ICSRs reporting on 118 suspected drugs with IC025 ≥0 were extracted. The median age at DIL onset was 49 years and the female to male sex ratio was 4.3. The median delay between start of suspected treatment and DIL occurrence was 172 days. DIL was reported as serious adverse event in 55.4%. Among the 118 suspected drugs, 42 had not been previously reported in association with DIL. The drugs associated with the highest number of DIL cases were infliximab, adalimumab, etanercept, procainamide and hydralazine. CONCLUSION: This study enables the identification of 118 drugs associated with DIL. The list of suspected drugs may prove useful to physicians when confronted with potential DIL cases. TRIAL REGISTRATION NUMBER: NCT03480529.


Assuntos
Lúpus Eritematoso Sistêmico/induzido quimicamente , Adalimumab/efeitos adversos , Adulto , Antirreumáticos/efeitos adversos , Bases de Dados Factuais , Etanercepte/efeitos adversos , Feminino , Humanos , Hidralazina/efeitos adversos , Infliximab/efeitos adversos , Masculino , Pessoa de Meia-Idade , Farmacovigilância , Procainamida/efeitos adversos , Estudos Retrospectivos , Organização Mundial da Saúde
10.
Drug Metab Dispos ; 47(5): 473-483, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30787100

RESUMO

Many promising drug candidates metabolized by aldehyde oxidase (AOX) fail during clinical trial owing to underestimation of their clearance. AOX is species-specific, which makes traditional allometric studies a poor choice for estimating human clearance. Other studies have suggested using half-life calculated by measuring substrate depletion to measure clearance. In this study, we proposed using numerical fitting to enzymatic pathways other than Michaelis-Menten (MM) to avoid missing the initial high turnover rate of product formation. Here, product formation over a 240-minute time course of six AOX substrates-O6-benzylguanine, N-(2-dimethylamino)ethyl)acridine-4-carboxamide, zaleplon, phthalazine, BIBX1382 [N8-(3-Chloro-4-fluorophenyl)-N2-(1-methyl-4-piperidinyl)-pyrimido[5,4-d]pyrimidine-2,8-diamine dihydrochloride], and zoniporide-have been provided to illustrate enzyme deactivation over time to help better understand why MM kinetics sometimes leads to underestimation of rate constants. Based on the data provided in this article, the total velocity for substrates becomes slower than the initial velocity by 3.1-, 6.5-, 2.9-, 32.2-, 2.7-, and 0.2-fold, respectively, in human expressed purified enzyme, whereas the K m remains constant. Also, our studies on the role of reactive oxygen species (ROS), such as superoxide and hydrogen peroxide, show that ROS did not significantly alter the change in enzyme activity over time. Providing a new electron acceptor, 5-nitroquinoline, did, however, alter the change in rate over time for mumerous compounds. The data also illustrate the difficulties in using substrate disappearance to estimate intrinsic clearance.


Assuntos
Aldeído Oxidase/metabolismo , Acetamidas/metabolismo , Acridinas/metabolismo , Guanidinas/metabolismo , Humanos , Hidralazina/metabolismo , Cinética , Fígado/metabolismo , Nitroquinolinas/metabolismo , Ftalazinas/metabolismo , Pirazóis/metabolismo , Pirimidinas/metabolismo , Espécies Reativas de Oxigênio/metabolismo
11.
Saudi J Kidney Dis Transpl ; 30(1): 226-230, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30804286

RESUMO

Hydralazine is a commonly used anti-hypertensive medication. It can, however, contribute to the development of autoimmunity, in the form of drug-induced lupus and anti-neutrophil cytoplasmic antibodies-associated vasculitis. We report a 45-year-old patient with hypertension managed with hydralazine for four years who presented with rapidly progressive glomerulonephritis (RPGN), requiring hemodialysis, and diffuse alveolar hemorrhage (DAH), requiring mechanical ventilation, and extracorporeal membrane oxygenation. The patient's autoantibody profile was consistent with a drug-induced autoimmune process and renal histology revealed focal necrotizing crescentic GN. She was treated with high-dose steroids, plasma exchange and rituximab. DAH resolved and her renal function improved, allowing discontinuation of hemodialysis. This case reveals that rituximab can be successfully used in the setting of hydralazine-induced vasculitis, including critically ill patients with severe DAH and acute kidney injury from RPGN.


Assuntos
Anti-Inflamatórios/uso terapêutico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Anti-Hipertensivos/efeitos adversos , Hidralazina/efeitos adversos , Rituximab/uso terapêutico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/induzido quimicamente , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Anti-Hipertensivos/uso terapêutico , Autoanticorpos/sangue , Feminino , Humanos , Hidralazina/uso terapêutico , Hipertensão/tratamento farmacológico , Pessoa de Meia-Idade , Esteroides/uso terapêutico
13.
Int J Gynaecol Obstet ; 144(1): 27-36, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30307609

RESUMO

OBJECTIVE: To estimate the effect of locally tailored clinical guidelines on intrapartum care and perinatal outcomes among women with severe hypertensive disorders in pregnancy (sHDP). METHODS: A pre-post study at Zanzibar's low-resource Mnazi Mmoja Hospital was conducted. All labouring women with sHDP were included at baseline (October 2014 to January 2015) and at 9-12 months after implementation of the ongoing intervention (October 2015 to January 2016). Background characteristics, clinical practice, and delivery outcomes were assessed by criterion-based case file reviews. RESULTS: Overall, 188 of 2761 (6.8%) women had sHDP at baseline, and 196 of 2398 (8.2%) did so during the intervention months. The median time between last blood pressure recording and delivery decreased during the intervention compared with baseline (P=0.015). Among women with severe hypertension, antihypertensive treatment increased during the intervention compared with baseline (relative risk [RR] 1.37, 95% confidence interval [CI] 1.14-1.66). Among the neonates delivered (birthweight ≥1000 g), stillbirths decreased (RR 0.56, 95% CI 0.35-0.90) and Apgar scores of seven or more increased during the intervention compared with baseline (RR 1.17, 95% CI 1.03-1.33). CONCLUSION: Although health system strengthening remains crucial, locally tailored clinical guidelines seemed to help work-overloaded birth attendants at a low-resource hospital to improve care for women with sHDP. CLINICALTRIALS.ORG: NCT02318420.


Assuntos
Anticonvulsivantes/administração & dosagem , Anti-Hipertensivos/administração & dosagem , Parto Obstétrico/estatística & dados numéricos , Hidralazina/administração & dosagem , Hipertensão Induzida pela Gravidez/tratamento farmacológico , Guias de Prática Clínica como Assunto , Índice de Apgar , Feminino , Humanos , Recém-Nascido , Tocologia/métodos , Pobreza , Gravidez , Resultado da Gravidez/epidemiologia , Melhoria de Qualidade , Estudos Retrospectivos , Índice de Gravidade de Doença , Natimorto/epidemiologia , Tanzânia/epidemiologia , Centros de Atenção Terciária/estatística & dados numéricos
14.
Pediatr Nephrol ; 34(5): 787-799, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-29808264

RESUMO

Neonatal hypertension is increasingly recognized as dramatic improvements in neonatal intensive care, advancements in our understanding of neonatal physiology, and implementation of new therapies have led to improved survival of premature infants. A variety of factors appear to be important in determining blood pressure in neonates, including gestational age, birth weight, and postmenstrual age. Normative data on neonatal blood pressure values remain limited. The cause of hypertension in an affected neonate is often identified with careful diagnostic evaluation, with the most common causes being umbilical catheter-associated thrombosis, renal parenchymal disease, and chronic lung disease. Clinical expertise may need to be relied upon to decide the best approach to treatment in such patients, as data on the use of antihypertensive medications in this age group are extremely limited. Available data suggest that long-term outcomes are usually good, with resolution of hypertension in most infants. In this review, we will take a case-based approach to illustrate these concepts and to point out important evidence gaps that need to be addressed so that management of neonatal hypertension may be improved.


Assuntos
Anti-Hipertensivos/administração & dosagem , Pressão Sanguínea/fisiologia , Hipertensão/diagnóstico , Doenças do Recém-Nascido/diagnóstico , Recém-Nascido Prematuro/fisiologia , Administração Intravenosa , Anti-Hipertensivos/efeitos adversos , Peso ao Nascer/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Determinação da Pressão Arterial/instrumentação , Determinação da Pressão Arterial/métodos , Tomada de Decisão Clínica , Idade Gestacional , Humanos , Hidralazina/administração & dosagem , Hidralazina/efeitos adversos , Hipertensão/epidemiologia , Hipertensão/etiologia , Hipertensão/terapia , Incidência , Recém-Nascido , Doenças do Recém-Nascido/epidemiologia , Doenças do Recém-Nascido/etiologia , Doenças do Recém-Nascido/terapia , Unidades de Terapia Intensiva Neonatal , Rim/fisiopatologia , Rim/cirurgia , Labetalol/administração & dosagem , Labetalol/efeitos adversos , Neuroblastoma/complicações , Neuroblastoma/cirurgia , Valores de Referência , Obstrução da Artéria Renal/complicações , Obstrução da Artéria Renal/cirurgia , Índice de Gravidade de Doença , Resultado do Tratamento
15.
Am J Physiol Heart Circ Physiol ; 316(3): H446-H458, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30499710

RESUMO

Although anticancer systemic therapy agents clearly lead to improved survival in patients with cancer, these can come at the cost of serious complications including cardiotoxicity. Two types of targeted systemic therapies currently in use for colorectal cancer (CRC) and renal cell cancer (RCC), respectively, include the vascular endothelial growth factor inhibitor bevacizumab (BVZ) and the tyrosine kinase inhibitor sunitinib (SNT). Despite the beneficial effects of BVZ and SNT in improving clinical outcomes in the settings of CRC and RCC, there is an increased risk of cardiac dysfunction. The aim of the present study was to determine whether prophylactic administration of renin-angiotensin system (RAS) inhibitors would attenuate the cardiotoxic side effects of BVZ or SNT in a chronic in vivo murine model. A total of 194 wild-type C57Bl/6 male mice received: 1) 0.9% saline, 2) BVZ (10 mg·kg-1·wk-1), or 3) SNT (40 mg·kg-1·day-1) for 4 wk. Within each arm, mice received daily prophylactic treatment with hydralazine (0.05 mg/ml), aliskiren (50 mg/kg), perindopril (4 mg/kg), or valsartan (2 mg/kg). Although hydralazine effectively lowered blood pressure in BVZ- or SNT-treated mice, it did not prevent left ventricular systolic dysfunction. Prophylactic administration of aliskiren, perindopril, or valsartan prevented adverse cardiovascular remodeling in mice treated with either BVZ or SNT. The addition of RAS antagonists also downregulated expression of phosphorylated p38 and Bcl-2-like 19-kDa interacting protein 3 in SNT-treated mice. In our chronic in vivo murine model, RAS antagonists partially attenuated the development of BVZ- or SNT-mediated cardiac dysfunction. Future clinical studies are warranted to investigate the cardioprotective effects of prophylactic treatment with RAS inhibitors in the settings of CRC and RCC. NEW & NOTEWORTHY In the evolving field of cardio-oncology, bevacizumab and sunitinib improve clinical outcomes in the settings of metastatic colorectal cancer and renal cell cancer, respectively. These anticancer drugs, however, are associated with an increased risk of cardiotoxicity. The prophylactic administration of renin-angiotensin system antagonists is partially cardioprotective against bevacizumab- and sunitinib-mediated cardiac dysfunction.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Antineoplásicos/toxicidade , Sistema Renina-Angiotensina , Disfunção Ventricular/prevenção & controle , Amidas/administração & dosagem , Amidas/uso terapêutico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Animais , Anti-Hipertensivos/administração & dosagem , Bevacizumab/toxicidade , Cardiotoxicidade , Fumaratos/administração & dosagem , Fumaratos/uso terapêutico , Hidralazina/administração & dosagem , Hidralazina/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Perindopril/administração & dosagem , Perindopril/uso terapêutico , Sunitinibe/toxicidade , Valsartana/administração & dosagem , Valsartana/uso terapêutico , Disfunção Ventricular/tratamento farmacológico , Disfunção Ventricular/etiologia
16.
Neurocrit Care ; 30(1): 118-125, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30051193

RESUMO

BACKGROUND: Blood pressure variability (BPV) is an independent predictor for early hematoma expansion, neurologic deterioration, and mortality. There are no studies on the effect of intravenous (IV) antihypertensive drugs on BPV. We sought to determine whether patients have more BPV with certain antihypertensive agents, in particular the effect of IV nicardipine. METHODS: We conducted a single-center, retrospective chart review of individuals diagnosed with spontaneous intracerebral hemorrhage (ICH) receiving labetalol, hydralazine, and/or nicardipine within 24 h of hospital admission to assess the primary endpoint of BPV, defined as the standard deviation of systolic BP, with labetalol and/or hydralazine compared to nicardipine ± labetalol and/or hydralazine. Repeated measures linear regression was performed to compare BPV over 24 h between regimens, and Cox proportional hazards regression was used to compare the time to goal SBP between regimens. RESULTS: Of the 1330 patients screened, 272 were included in our analysis; those included had a mean age of 69 years with 87.9% of Caucasian race. A total of 164 patients received IV bolus antihypertensives alone (labetalol, hydralazine or both), and 108 patients received IV nicardipine with or without additional IV boluses (labetalol, hydralazine, or both). Those who had IV nicardipine had significantly less BPV (p = 0.04) and was more likely to attain an SBP goal < 140 mmHg (p < 0.01). CONCLUSION: Our study suggests patients with ICH who do not receive a nicardipine-based antihypertensive regimen have more BPV, which has been associated with poor clinical outcomes. Prospective, randomized, controlled trials are needed to determine the impact of specific antihypertensive regimens on clinical outcomes.


Assuntos
Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Hemorragia Cerebral/tratamento farmacológico , Nicardipino/farmacologia , Administração Intravenosa , Adulto , Idoso , Anti-Hipertensivos/administração & dosagem , Feminino , Humanos , Hidralazina/farmacologia , Labetalol/farmacologia , Masculino , Pessoa de Meia-Idade , Nicardipino/administração & dosagem , Estudos Retrospectivos , Resultado do Tratamento
17.
Eur J Pharmacol ; 843: 199-209, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30472201

RESUMO

In this study, we investigated whether hydralazine could reduce renal ischemia and reperfusion (I/R) injury in rats. Renal I/R was induced by a 70-min occlusion of the bilateral renal arteries and a 24-h reperfusion, which was confirmed by the increased the mortality, the levels of blood urea nitrogen (BUN), blood creatinine (Cr), renal tissue NO and the visible histological damage of the kidneys. Apoptosis was evaluated by terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling (TUNEL) staining. Furthermore, the serum levels of malonaldehyde (MDA), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) were significantly elevated in renal I/R group, while the superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) levels were suppressed. However, intragastric pretreatment with hydralazine at doses of 7.5-30 mg/kg before renal I/R significantly limited the increase in mortality, BUN, Cr, oxidative stress, inflammatory factors, histological damage and apoptosis in the kidneys. In addition, hydralazine also increased p-AKT, Bcl-2 expression and decreased iNOS, Bax, cleaved caspase-3 expression in the kidneys. In conclusion, hydralazine reduced renal I/R injury probably via inhibiting NO production by iNOS/NO pathway, inhibiting oxidative stress, inflammatory response and apoptosis by a mitochondrial-dependent pathway.


Assuntos
Hidralazina/uso terapêutico , Rim/efeitos dos fármacos , Substâncias Protetoras/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular , Citocinas/sangue , Citocinas/genética , Hidralazina/farmacologia , Rim/metabolismo , Rim/patologia , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia
18.
Int J Radiat Oncol Biol Phys ; 103(5): 1212-1220, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30529374

RESUMO

PURPOSE: Radiation therapy (RT) offers an important and curative approach to treating prostate cancer, but it is associated with a high incidence of erectile dysfunction (ED). It is not clear whether the etiology of radiation-induced ED (RI-ED) is driven by RT-mediated injury to the vasculature, the nerves, or both. This pilot study sought to distinguish the effects of vascular and nerve injury in RI-ED by applying a vascular radioprotectant in a rat model of prostate RT. METHODS: A single dose of the thrombopoietin mimetic (TPOm; RWJ-800088), previously shown to mitigate radiation-induced vascular injury, was administered 10 minutes after single-fraction conformal prostate RT. Nine weeks after RT, rats were assessed for erectile and arterial function. Nerve markers were quantified with reverse transcriptase polymerase chain reaction. Immunofluorescent microscopy further characterized vascular effects of RT and TPOm. RESULTS: Sham animals and animals that received RT and TPOm showed significant arterial vasodilation in response to systemic hydralazine (24.1% ± 7.3% increase; P = .03 in paired t test). However, animals that received RT and vehicle were unable to mount a vasodilatory response (-7.4% ± 9.9% increase; P = .44 in paired t test). TPOm prevented RT-induced change in the penile artery cross-sectional area (P = .036), but it did not ameliorate cavernous nerve injury as evaluated by gene expression of neuronal injury markers. Despite significant structural and functional vascular protective effects and some trends for differences in nerve injury/recovery markers, TPOm did not prevent RI-ED at 9 weeks, as assessed by intracavernous pressure monitoring after cavernous nerve stimulation. CONCLUSIONS: These data suggest that vascular protection alone is not sufficient to prevent RI-ED and that cavernous nerve injury plays a key role in RI-ED. Further research is required to delineate the multifactorial nature of RI-ED and to determine if TPOm with modified dosing regimens can mitigate against nerve injury either through direct or vascular protective effects.


Assuntos
Disfunção Erétil/prevenção & controle , Pênis/efeitos da radiação , Peptídeos/administração & dosagem , Próstata/efeitos da radiação , Protetores contra Radiação/administração & dosagem , Vasodilatação/efeitos da radiação , Animais , Artérias/diagnóstico por imagem , Artérias/efeitos dos fármacos , Modelos Animais de Doenças , Disfunção Erétil/etiologia , Hidralazina/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular , Masculino , Manometria/métodos , Ereção Peniana/efeitos dos fármacos , Ereção Peniana/fisiologia , Ereção Peniana/efeitos da radiação , Pênis/irrigação sanguínea , Pênis/efeitos dos fármacos , Pênis/inervação , Projetos Piloto , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Tempo , Ultrassonografia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia
19.
BMJ Case Rep ; 20182018 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-30413463

RESUMO

Hydralazine, a vasodilator, is commonly used as an adjunctive treatment for moderate to severe hypertension, heart failure and hypertensive emergencies in pregnancy. Hydralazine-induced lupus was first described in 1953. Clinical presentation ranges from arthralgia, myalgia, petechiae, or rash to single or multiorgan involvement. An occurrence of systemic vasculitis is a rare complication. When presented as the pulmonary-renal syndrome, it could have a rapidly progressive course which can be fatal. Here, we describe a case of hydralazine-associated rapidly progressive glomerulonephritis and pulmonary haemorrhage. We use this case to review the current literature and discuss and highlight the importance of a high degree of clinical acumen, early diagnosis and prompt treatment for better clinical outcomes.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/induzido quimicamente , Glomerulonefrite/induzido quimicamente , Hemorragia/induzido quimicamente , Hidralazina/efeitos adversos , Pneumopatias/induzido quimicamente , Vasodilatadores/efeitos adversos , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/terapia , Biópsia , Eletroforese das Proteínas Sanguíneas , Diagnóstico Diferencial , Feminino , Hidratação , Glomerulonefrite/terapia , Glucocorticoides , Hemorragia/terapia , Humanos , Fatores Imunológicos , Glomérulos Renais/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Pneumopatias/terapia , Prednisolona , Diálise Renal , Rituximab , Síndrome
20.
Drug Des Devel Ther ; 12: 3753-3766, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30464406

RESUMO

Background: Hypertensive disorders are the most common complication in pregnancy which can even lead to maternal mortality. Hydralazine hydrochloride (HHC), a direct-acting vasodilator, is intravenously used as the first-line therapy in controlling hypertension in pregnancy (preeclampsia). It suffers poor oral bioavailability (26%-50%) due to first-pass metabolism. Objective: This work aims for the preparation of HHC rapidly disintegrating sublingual tablets of higher absorption rate, short onset of action, and higher bioavailability for rapid control on blood pressure (BP) in hypertensive emergencies especially preeclampsia. Methods: HHC sublingual tablet mixtures were prepared using starch sodium glycolate and Pharmaburst as super disintegrants at three different levels by direct compression and were subjected to full in vitro evaluation; the drug bioavailability from the optimized sublingual tablet formula was assessed in comparison to conventional oral tablets in rabbits, and the clinical efficacy on controlling BP in induced preeclampsia like mouse model was also studied. Results: The results indicated compatibility of the prepared tablet mixtures, good flow, and acceptable mechanical strength. Sublingual tablet formula containing Pharmaburst (7%) that showed fastest disintegration (21 seconds) and 100% drug release within 5 minutes was selected for further bioavailability and pharmacodynamic studies. The drug bioavailability was significantly increased with C max = 28.2767±4.61 µg/mL, AUC(0-α) = 52.85±3.18 µg.h/mL, and T max = 0.33±0.011 hour in comparison to 18.0633±23.2 µg/mL, 33.18±5.18 µg⋅h/mL, and 0.75±0.025 hour for conventional oral tablets. Results of pharmacodynamic studies proved significant rapid control on both systolic and diastolic BP to normal values within only 30 minutes without any significant difference from intravenous data. Conclusion: These results confirm the suitability of the prepared HHC sublingual tablets for use in rapid control on hypertensive crisis especially in pregnant women as an alternate to parenteral administration.


Assuntos
Hidralazina/farmacocinética , Hidralazina/uso terapêutico , Pré-Eclâmpsia/tratamento farmacológico , Vasodilatadores/farmacocinética , Vasodilatadores/uso terapêutico , Animais , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Feminino , Hidralazina/administração & dosagem , Masculino , Gravidez , Coelhos , Comprimidos/administração & dosagem , Comprimidos/farmacocinética , Comprimidos/farmacologia , Vasodilatadores/administração & dosagem
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