Synergistic effect of hydralazine associated with triazoles on Candida spp. in planktonic cells.

Objective: To evaluate the antifungal activity of hydralazine hydrochloride alone and in synergy with azoles against Candida spp. and the action mechanism. Methods: We used broth microdilution assays to determine the MIC, checkerboard assays to investigate synergism, and flow cytometry and molecular docking tests to ascertain action mechanism. Results: Hydralazine alone had antifungal activity in the range of 16-128 µg/ml and synergistic effect with itraconazole versus 100% of the fungal isolates, while there was synergy with fluconazole against 11.11% of the isolates. There was molecular interaction with the receptors exo-B(1,3)-glucanase and CYP51, causing reduced cell viability and DNA damage. Conclusion: Hydralazine is synergistic with itraconazole and triggers cell death of Candida spp. at low concentrations, demonstrating antifungal potential.

Intervenção coronária complexa com mínimo uso de contraste sob guia do ultrassom intracoronário em paciente com disfunção renal grave / Complex coronary intervention with minimal use of contrast under intracoronary ultrasound guidance in a patient with severe renal dysfunction

Apresentação Clínica • Paciente feminina, 39 anos; • Diabetes Mellitus tipo 1 complicada com retinopatia e nefropatia • TFG 13 mL/min/1.73m² • HbA1c 11,5% • HAS, DLP, Obesidade; • Medicamentos em uso crônico: AAS, atenolol, anlodipino, monocordil, hidralazina, furosemida, Insulina NPH • Apresenta-se com angina CCS III há 6 meses, motivo pelo qual foi submetida à cinecoronariografia em Dezembro/2021. • Por manter angina limitante, à despeito do tratamento medicamentoso, foi encaminhada para intervenção coronária percutânea, em caráter eletivo.

First-trimester miscarriage rate decreases with hydralazine therapy in pregnancies with early uterine vascular insufficiency: a cohort study.

BACKGROUND: Miscarriage is the most frequent cause of pregnancy loss, affecting 15-20% of clinically recognized pregnancies. Early uterine vascular insufficiency (EUVI), defined as abnormal uterine artery (UA) Doppler impedance indices in early pregnancy, is present in two-thirds of pregnancies ending in miscarriage after embryonic cardiac activity has been detected. There is currently no available therapy for reducing the risk of miscarriage in these cases. OBJECTIVE: To determine whether vasodilator therapy with hydralazine can reduce abnormally high UA impedance indices and miscarriage rates in pregnancies with EUVI when administered from before 9 weeks' gestation until completing 13 weeks' gestation. METHODS: A total of 253 consecutive singleton pregnancies with a live embryo and scanned before 9 weeks' gestation were included in the study. Ninety-two pregnancies (36.3%) were classified as having EUVI. Hydralazine was administered in daily doses of 50 mg, starting 24-36 h after the initial diagnosis of EUVI and continuing throughout the first trimester. The miscarriage rate in the hydralazine-treated EUVI group was compared with the one observed in our previously reported untreated cohort and the pregnancies with EUVI that declined treatment with hydralazine. RESULTS: The miscarriage rate among the hydralazine-treated EUVI group was significantly lower than the previously reported untreated cohort (7.8% versus 26.2%, p = .003; odds ratio (OR) = 4.3, 95% confidence interval (CI) = 1.6-11.9). In 15 untreated pregnancies with EUVI, the miscarriage rate was similar to that of the previously reported untreated cohort (26.7% versus 26.2%; p = .603) and higher than the hydralazine-treated group (26.7% versus 7.8%, p = .05; OR = 4.4, 95% CI = 1.1-18.2). CONCLUSIONS: Hydralazine therapy in pregnancies with EUVI was associated with a significant decrease in the rate of miscarriage. We suggest a sequence of events leading to a higher risk of miscarriage in pregnancies with EUVI and propose a potential mechanism through which hydralazine may reduce this risk.

Guía de práctica clínica para la prevención y manejo de la enfermedad hipertensiva del embarazo / Clinical practice guideline for the prevention and management of hypertensive disease in pregnancy

Proveer recomendaciones clínicas basadas en evidencia para la prevención y el manejo de la enfermedad hipertensiva del embarazo (EHE) en el Seguro Social de Salud (EsSalud) del Perú. En la presente GPC se formularon 11 recomendaciones (6 fuertes y 5 condicionales) que respondieron las preguntas clínicas definidas en el alcance de la GPC, acompañadas de 32 puntos de BPC y 3 flujogramas que abordan temas de prevención, tratamiento y seguimiento de la EHE.

The Therapeutic Value of Hydralazine in Reducing Inflammatory Response, Oxidative Stress, and Mortality in Animal Sepsis: Involvement of the PI3K/AKT Pathway.

ABSTRACT: Sepsis is an amplified systemic immune-inflammatory response produced by a microorganism, which involves activation of inflammatory cytokine signaling pathways and oxidative stress. A variety of studies have shown that hydralazine (HDZ) has potent antioxidant and anti-inflammatory proprieties. Therefore, we hypothesize that HDZ can improve the clinical outcome of sepsis. Thus, this work aimed to evaluate therapeutic value of HDZ in reducing inflammatory response, oxidative stress, and mortality in animal sepsis, and to investigate its possible mechanism of action. Sepsis was induced by the cecal ligation and puncture (CLP) method in Wistar rats. After surgery, the animals were randomly divided into three groups: sham, sepsis, and sepsis + HDZ (1 mg/kg, s.c.). All groups were monitored for 48 h to assess survival rate, and clinical, hemodynamic, biochemical, and cellular parameters. After euthanasia, blood, spleen, liver, and kidneys were collected for analysis. Blood serum cytokines, tissue myeloperoxidase (MPO) activity, and oxidative stress parameters were assessed. Involvement of the PI3K/Akt pathway was also investigated. Sepsis was successfully induced by the CLP technique. HDZ treatment increased the survival rate (from 50% to 90%), improved glycemia control, reduced the clinical severity sepsis and mean arterial pressure; and prevented increased MPO activity, TNF-α, IL-1ß, IL-10 levels, and oxidative damage markers. Additionally, HDZ significantly prevented the increase of Akt activation in the liver and kidney. HDZ largely mitigated the effects of sepsis by suppressing inflammatory and antioxidant responses via the PI3K/Akt pathway. These findings provide evidence that HDZ can be a new therapeutic alternative for treating sepsis.

Renal denervation reduces sympathetic overactivation, brain oxidative stress, and renal injury in rats with renovascular hypertension independent of its effects on reducing blood pressure.

The underlying mechanisms by which renal denervation (RD) decreases blood pressure (BP) remain incompletely understood. In this study, we investigated the effects of ischemic kidney denervation on different sympathetic outflows, brain and renal expression of angiotensin-II receptors, oxidative stress and renal function markers in the 2-kidney, 1-clip (2K-1C) rat model. Surgical RD was performed in Wistar male rats 4-5 weeks after clip implantation. After 10 days of RD, BP, and the activity of sympathetic nerves projecting to the contralateral kidney (rSNA) and splanchnic region were partially reduced in 2K-1C rats, with no change in systemic renin-angiotensin system (RAS). To distinguish the effects of RD from the reduction in BP, 2K-1C rats were treated with hydralazine by oral gavage (25 mg/kg/day for 1 week). RD, but not hydralazine, normalized oxidative stress in the sympathetic premotor brain regions and improved intrarenal RAS, renal injury, and proteinuria. Furthermore, different mechanisms led to renal injury and oxidative stress in the ischemic and contralateral kidneys of 2K-1C rats. Injury and oxidative stress in the ischemic kidney were driven by the renal nerves. Although RD attenuated rSNA, injury and oxidative stress persisted in the contralateral kidney, probably due to increased BP. Therefore, nerves from the ischemic kidney at least partially contribute to the increase in BP, sympathetic outflows, brain oxidative stress, and renal alterations in rats with renovascular hypertension. Based on these findings, the reduction in oxidative stress in the brain is a central mechanism that contributes to the effects of RD on Goldblatt hypertension.

Hydralazine-associated adverse events: a report of two cases of hydralazine-induced ANCA vasculitis / Eventos adversos associados à hidralazina: um relatório de dois casos de vasculite associada ao ANCA induzida por hidralazina

Abstract Hydralazine is a direct-acting vasodilator, which has been used in treatment for hypertension (HTN) since the 1950s. While it is well known to cause drug-induced lupus (DIL), recent reports are indicating the emergence of the drug-induced anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (DIV). Herein, we describe two patients (aged 57 and 87 years) who presented with severe acute kidney injury (AKI), proteinuria, and hematuria. Both were receiving hydralazine for the treatment of hypertension. ANCA serology was positive in both patients along with anti-histone antibodies (commonly seen in drug-induced vasculitis). Renal biopsy revealed classic crescentic (pauci-immune) glomerulonephritis in these patients and hydralazine was discontinued. During the hospital course, the 57-year-old patient required dialysis therapy and was treated with steroids and rituximab for the ANCA disease. Renal function improved and the patient was discharged (off dialysis) with a serum creatinine of 3.6 mg/dL (baseline = 0.9 mg/dL). At a follow-up of 2 years, the patient remained off dialysis with advanced chronic kidney disease (CKD) (stage IIIb). The 87-year-old patient had severe AKI with serum creatinine at 10.41 mg/dL (baseline = 2.27 mg/dL). The patient required hemodialysis and was treated with steroids, rituximab, and plasmapheresis. Unfortunately, the patient developed catheter-induced bacteremia and subsequently died of sepsis. Hydralazine can cause severe AKI resulting in CKD or death. Given this extremely unfavorable adverse-event profile and the widespread availability of alternative anti-hypertensive agents, the use of hydralazine should be carefully considered.

Resumo A hidralazina é um vasodilatador de ação direta, que vem sendo utilizado no tratamento da hipertensão arterial (HA) desde a década de 1950. Embora seja bem conhecido por causar lúpus induzido por drogas (LID), relatórios recentes estão indicando o surgimento da vasculite associada ao anticorpo citoplasmático anti-neutrófilo (ANCA), induzida por drogas (VID). Aqui, descrevemos dois pacientes (com idade entre 57 e 87 anos) que apresentaram lesão renal aguda grave (LRA), proteinúria e hematúria. Ambos estavam usando hidralazina para o tratamento da hipertensão. A sorologia para ANCA foi positiva em ambos os pacientes, juntamente com anticorpos anti-histona (comumente vistos na vasculite induzida por drogas). A biópsia renal revelou glomerulonefrite rapidamente progressiva clássica (pauci-imune) nestes pacientes e a hidralazina foi interrompida. Durante a internação hospitalar, o paciente de 57 anos necessitou de diálise e foi tratado com esteroides e rituximab para a doença do ANCA. A função renal melhorou e o paciente recebeu alta (fora da diálise) com creatinina sérica de 3,6 mg/dL (basal = 0,9 mg/dL). Em um seguimento de 2 anos, o paciente permaneceu fora da diálise com doença renal crônica avançada (DRC) (estágio IIIb). O paciente de 87 anos apresentava IRA grave com creatinina sérica em 10,41 mg/dL (valor basal de = 2,27 mg/dL). O paciente necessitou de hemodiálise e foi tratado com esteroides, rituximabe e plasmaferese. Infelizmente, o paciente desenvolveu bacteremia induzida por cateter e, posteriormente, evoluiu a óbito por sepse. A hidralazina pode causar IRA grave, resultando em DRC ou óbito. Dado este perfil de eventos adversos extremamente desfavorável e a disponibilidade generalizada de agentes anti-hipertensivos alternativos, o uso de hidralazina deve ser considerado com muita parcimônia.

Hydralazine-associated adverse events: a report of two cases of hydralazine-induced ANCA vasculitis.

Hydralazine is a direct-acting vasodilator, which has been used in treatment for hypertension (HTN) since the 1950s. While it is well known to cause drug-induced lupus (DIL), recent reports are indicating the emergence of the drug-induced anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (DIV). Herein, we describe two patients (aged 57 and 87 years) who presented with severe acute kidney injury (AKI), proteinuria, and hematuria. Both were receiving hydralazine for the treatment of hypertension. ANCA serology was positive in both patients along with anti-histone antibodies (commonly seen in drug-induced vasculitis). Renal biopsy revealed classic crescentic (pauci-immune) glomerulonephritis in these patients and hydralazine was discontinued. During the hospital course, the 57-year-old patient required dialysis therapy and was treated with steroids and rituximab for the ANCA disease. Renal function improved and the patient was discharged (off dialysis) with a serum creatinine of 3.6 mg/dL (baseline = 0.9 mg/dL). At a follow-up of 2 years, the patient remained off dialysis with advanced chronic kidney disease (CKD) (stage IIIb). The 87-year-old patient had severe AKI with serum creatinine at 10.41 mg/dL (baseline = 2.27 mg/dL). The patient required hemodialysis and was treated with steroids, rituximab, and plasmapheresis. Unfortunately, the patient developed catheter-induced bacteremia and subsequently died of sepsis. Hydralazine can cause severe AKI resulting in CKD or death. Given this extremely unfavorable adverse-event profile and the widespread availability of alternative anti-hypertensive agents, the use of hydralazine should be carefully considered.

Encouraging results with the compassionate use of hydralazine/valproate (TRANSKRIP™) as epigenetic treatment for myelodysplastic syndrome (MDS).

The hypomethylating agents azacytidine and decitabine are unaffordable for many patients with MDS. The combination of the DNA methyltransferase inhibitor hydralazine and the histone deacetylase inhibitor valproate has shown preliminary efficacy in MDS. The aim of this study is to evaluate the clinical efficacy and safety of hydralazine/valproate in a case series of MDS patients treated in a compassionate manner. Hydralazine was dosed according to the acetylation genotype of patients (slow acetylators 83 mg daily; fast acetylators 182 mg daily), and valproate was dosed at 30 mg/kg/day. Both drugs were given daily until disease progression. Response and toxicity were evaluated with the International Working Group criteria and CTCAE, version 4, respectively. Survival parameters were estimated with the Kaplan-Meier method. From 2009 to 2012, 14 patients were treated. The median age ± SD was 55.2 ± 19.52 (range 23-87) years. According to the IPSS, cases were graded as intermediate-1 (n = 8/14; 57.2%) or intermediate-2 (n = 6/14; 42.8%). Responses were as follows: five (35.7%) complete response, one (7.1%) partial response, and two (14.28%) became transfusion independent. The mean duration of response ± SD was 60 ± 35.28 months (range 5-94). Three patients progressed to AML. At a median follow-up of 57 months (range 1-106), the median OS was 27 months. At that point, five patients remained on the treatment, one with partial response and four with complete response. The median OS was not reached in the eight patients who saw a clinical benefit from the treatment, in comparison to an OS of 7 months in the six patients who had no treatment. The combination of hydralazine and valproate is safe and effective in MDS, and its further testing is highly desirable.

Efficacy of hydralazine and valproate in cutaneous T-cell lymphoma, a phase II study.

OBJECTIVES: To evaluate the activity and safety of hydralazine and valproate (Transkrip) in cutaneous T-cell lymphoma (CTCL). METHODS: Previously untreated and progressive/refractory CTCL patients received hydralazine at 83 mg or 182 mg/day for slow and rapid acetylators respectively plus magnesium valproate at a total dose of 30 mg/Kg t.i.d daily in continuous 28-day cycles in this phase II study. The primary objective was overall response rate (ORR) measured by the modified severity weighted assessment tool (m-SWAT), secondary end-points were time to response (TTR), time to progression (TTP), duration of response (DOR), progression-free survival (PFS), overall survival (OS) and safety. RESULTS: Fourteen patients were enrolled (7 untreated and 7 pretreated). ORR was 71% with 50% complete and 21% partial. Two had stable disease and two progressed. At a median follow-up of 36 months (5-52), median TTR was 2 months (1-4); median DOR was 28 months (5-45); median PFS 36 and not reached for OS. There were no differences in median TTR, DOR, and PFS between treated and pretreated patients. Pruritus relieve was complete in 13 out of 14 patients. No grade 3 or 4 toxicities were observed. CONCLUSION: The combination of hydralazine and valproate is safe, very well tolerated and effective in CTCL.

Isosorbide Dinitrate, With or Without Hydralazine, Does Not Reduce Wave Reflections, Left Ventricular Hypertrophy, or Myocardial Fibrosis in Patients With Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Wave reflections, which are increased in patients with heart failure with preserved ejection fraction, impair diastolic function and promote pathologic myocardial remodeling. Organic nitrates reduce wave reflections acutely, but whether this is sustained chronically or affected by hydralazine coadministration is unknown. METHODS AND RESULTS: We randomized 44 patients with heart failure with preserved ejection fraction in a double-blinded fashion to isosorbide dinitrate (ISDN; n=13), ISDN+hydralazine (ISDN+hydral; n=15), or placebo (n=16) for 6 months. The primary end point was the change in reflection magnitude (RM; assessed with arterial tonometry and Doppler echocardiography). Secondary end points included change in left ventricular mass and fibrosis, measured with cardiac magnetic resonance imaging, and the 6-minute walk distance. ISDN reduced aortic characteristic impedance (mean baseline=0.15 [95% CI, 0.14-0.17], 3 months=0.11 [95% CI, 0.10-0.13], 6 months=0.10 [95% CI, 0.08-0.12] mm Hg/mL per second; P=0.003) and forward wave amplitude (Pf, mean baseline=54.8 [95% CI, 47.6-62.0], 3 months=42.2 [95% CI, 33.2-51.3]; 6 months=37.0 [95% CI, 27.2-46.8] mm Hg, P=0.04), but had no effect on RM (P=0.64), left ventricular mass (P=0.33), or fibrosis (P=0.63). ISDN+hydral increased RM (mean baseline=0.39 [95% CI, 0.35-0.43]; 3 months=0.31 [95% CI, 0.25-0.36]; 6 months=0.44 [95% CI, 0.37-0.51], P=0.03), reduced 6-minute walk distance (mean baseline=343.3 [95% CI, 319.2-367.4]; 6 months=277.0 [95% CI, 242.7-311.4] meters, P=0.022), and increased native myocardial T1 (mean baseline=1016.2 [95% CI, 1002.7-1029.7]; 6 months=1054.5 [95% CI, 1036.5-1072.3], P=0.021). A high proportion of patients experienced adverse events with active therapy (ISDN=61.5%, ISDN+hydral=60.0%; placebo=12.5%; P=0.007). CONCLUSIONS: ISDN, with or without hydralazine, does not exert beneficial effects on RM, left ventricular remodeling, or submaximal exercise and is poorly tolerated. ISDN+hydral appears to have deleterious effects on RM, myocardial remodeling, and submaximal exercise. Our findings do not support the routine use of these vasodilators in patients with heart failure with preserved ejection fraction. CLINICAL TRIAL REGISTRATION: URL: www.clinicaltrials.gov. Unique identifier: NCT01516346.

Chronic enalapril treatment increases transient outward potassium current in cardiomyocytes isolated from right ventricle of spontaneously hypertensive rats.

It has been well established that chronic pressure overload resulting from hypertension leads to ventricular hypertrophy and electrophysiological remodeling. The transient outward potassium current (I to) reduction described in hypertensive animals delays ventricular repolarization, leading to complex ventricular arrhythmias and sudden death. Antihypertensive drugs, as angiotensin-converting enzyme inhibitors (ACEi), can restore I to and reduce the incidence of arrhythmic events. The purpose of this study was to evaluate the differential effects of long-term treatment with ACEi or direct-acting smooth muscle relaxant on the I to of left and right ventricle myocytes of spontaneously hypertensive rats (SHR). Animals were divided into four groups: normotensive Wistar-Kyoto rats (WKY), hypertensive (SHR), SHR treated for 6 weeks with enalapril 10 mg/kg/day (SHRE), or hydralazine 20 mg/kg/day (SHRH). Systolic blood pressure (SBP) and hypertrophy index (heart weight/body weight (HW/BW)) were determined at the end of treatment period. Cell membrane capacitance (C m) and I to were assessed in cardiomyocytes isolated from left and right ventricles. The SHR exhibited significantly increased SBP and HW/BW when compared to the WKY. The treated groups, SHRE and SHRH, restored normal SBP but not HW/BW. The SHR group exhibited a diminished I to in the left but not the right ventricle. Both the treated groups restored I to in the left ventricle. However, in the right ventricle, only enalapril treatment modified I to. The SHRE group exhibited a significant increase in I to compared to all the other groups. These findings suggest that enalapril may increase I to by a pressure overload independent mechanism.

Intravenous Hydralazine in Hospitalized Children and Adolescents with Hypertension.

OBJECTIVES: To explore the efficacy and safety of intravenous (IV) hydralazine in hospitalized children with hypertension. STUDY DESIGN: Data were retrospectively collected on hospitalized children treated with IV hydralazine. Percent changes in blood pressure (BP) were calculated, and linear regression was used to investigate associations between BP change and pertinent clinical and demographic variables. Bivariate logistic regression was used to investigate associations between the same covariates and the outcomes of ideal clinical response (ICR), a 10%-25% reduction in mean arterial pressure (MAP), and excess response (ER), a 25% reduction in MAP. RESULTS: A total of 141 initial doses of IV hydralazine (median dose, 0.10 mg/kg [IQR, 0.09-0.11; range, 0.02-0.37]) were analyzed. Median age was 8 years (IQR, 2-15; range, 0-24); most patients had renal disease, malignancy, or were organ transplant recipients. The mean MAP reduction was 19% ± 12%. An ICR occurred in 66 patients (47%). Higher initial MAP and increased hydralazine dose were associated with greater percentage decrease in MAP. No association was found between ICR and the covariates of interest; higher initial MAP was associated with greater odds of ICR. ER occurred in 44 children (31%). Among this group, higher initial MAP and higher hydralazine dose were associated with increased odds of ER, and administration of other antihypertensive drugs was associated with decreased odds of ER. Four adverse effects possibly related to IV hydralazine, including 2 episodes of hypotension, were recorded. CONCLUSIONS: IV hydralazine reduced BP in the majority of children. However, a substantial proportion of children experienced potentially excessive BP reduction.

Anti-TNF-α and hydralazine drug-induced lupus.

Drug-induced lupus is a rare drug reaction featuring the same symptoms as idiopathic lupus erythematosus. Recently, with the introduction of new medicines in clinical practice, an increase in the number of illness-triggering implicated drugs has been reported, with special emphasis on anti-TNF-α drugs. In the up-to-date list, almost one hundred medications have been associated with the occurrence of drug-induced lupus. The authors present two case reports of the illness induced respectively by hydralazine and infliximab, addressing the clinical and laboratorial characteristics, diagnosis, and treatment.

Anti-TNF-α and hydralazine drug-induced lupus

Drug-induced lupus is a rare drug reaction featuring the same symptoms as idiopathic lupus erythematosus. Recently, with the introduction of new medicines in clinical practice, an increase in the number of illness-triggering implicated drugs has been reported, with special emphasis on anti-TNF-α drugs. In the up-to-date list, almost one hundred medications have been associated with the occurrence of drug-induced lupus. The authors present two case reports of the illness induced respectively by hydralazine and infliximab, addressing the clinical and laboratorial characteristics, diagnosis, and treatment.

Hydralazine-valproate: a repositioned drug combination for the epigenetic therapy of cancer.

INTRODUCTION: DNA methylation (DNMTi) and histone deacetylase inhibitors (HDACi) are in development for cancer therapy. So far, four epigenetic drugs are approved for myelodysplastic syndrome (MDS) and cutaneous T-cell lymphoma (CTCL). The combination of hydralazine-valproate (TRANSKRIP(™)) is being repositioned as an oral DNMT and HDAC inhibitor. AREAS COVERED: Brief discussion on the current status of epigenetic drugs and studies published on the preclinical and clinical development of the hydralazine-valproate combination. EXPERT OPINION: Drug repositioning is a strategy for prompt and cost-efficient drug discovery. There is evidence that combining DNMTi with HDACi would be more efficacious than administering each agent on its own. Hydralazine-valproate is safe when used alone or in combination with chemotherapy or chemoradiation. The fact that both drugs are orally administered is another advantage over current epigenetic drugs. This combination is promising but larger studies are needed. Among these, the randomized Phase III trials in advanced and in locally advanced cervical cancer combined with chemotherapy and cisplatin-radiation respectively, would eventually confirm its efficacy. Studies on MDS and CTCL would also eventually prove the efficacy of hydralazine valproate so that in the coming years hydralazine-valproate could have a role in cancer epigenetic therapy.