Hydralazine loaded nanodroplets combined with ultrasound-targeted microbubble destruction to induce pyroptosis for tumor treatment.

Pyroptosis, a novel type of programmed cell death (PCD), which provides a feasible therapeutic option for the treatment of tumors. However, due to the hypermethylation of the promoter, the critical protein Gasdermin E (GSDME) is lacking in the majority of cancer cells, which cannot start the pyroptosis process and leads to dissatisfactory therapeutic effects. Additionally, the quick clearance, systemic side effects, and low concentration at the tumor site of conventional pyroptosis reagents restrict their use in clinical cancer therapy. Here, we described a combination therapy that induces tumor cell pyroptosis via the use of ultrasound-targeted microbubble destruction (UTMD) in combination with DNA demethylation. The combined application of UTMD and hydralazine-loaded nanodroplets (HYD-NDs) can lead to the rapid release of HYD (a demethylation drug), which can cause the up-regulation of GSDME expression, and produce reactive oxygen species (ROS) by UTMD to cleave up-regulated GSDME, thereby inducing pyroptosis. HYD-NDs combined with ultrasound (US) group had the strongest tumor inhibition effect, and the tumor inhibition rate was 87.15% (HYD-NDs group: 51.41 ± 3.61%, NDs + US group: 32.73%±7.72%), indicating that the strategy had a more significant synergistic anti-tumor effect. In addition, as a new drug delivery carrier, HYD-NDs have great biosafety, tumor targeting, and ultrasound imaging performance. According to the results, the combined therapy reasonably regulated the process of tumor cell pyroptosis, which offered a new strategy for optimizing the therapy of GSDME-silenced solid tumors.

Beyond Quadruple Therapy and Current Therapeutic Strategies in Heart Failure with Reduced Ejection Fraction: Medical Therapies with Potential to Become Part of the Therapeutic Armamentarium.

Heart failure with reduced ejection fraction (HFrEF) is a complex clinical syndrome with significant morbidity and mortality and seems to be responsible for approximately 50% of heart failure cases and hospitalizations worldwide. First-line treatments of patients with HFrEF, according to the ESC and AHA guidelines, include ß-blockers, angiotensin receptor/neprilysin inhibitors, sodium-glucose cotransporter 2 inhibitors, and mineralocorticoid receptor antagonists. This quadruple therapy should be initiated during hospital stay and uptitrated to maximum doses within 6 weeks after discharge according to large multicenter controlled trials. Quadruple therapy improves survival by approximately 8 years for a 55-year-old heart failure patient. Additional therapeutic strategies targeting other signaling pathways such as ivabradine, digoxin, and isosorbide dinitrate and hydralazine combination for African Americans, as well as adjunctive symptomatic therapies, seem to be necessary in the management of HFrEF. Although second-line medications have not achieved improvements in mortality, they seem to decrease heart failure hospitalizations. There are novel medical therapies including vericiguat, omecamtiv mecarbil, genetic and cellular therapies, and mitochondria-targeted therapies. Moreover, mitraclip for significant mitral valve regurgitation, ablation in specific atrial fibrillation cases, omecamtiv mecarbil are options under evaluation in clinical trials. Finally, the HeartMate 3 magnetically levitated centrifugal left ventricular assist device (LVAD) has extended 5-year survival for stage D HF patients who are candidates for an LVAD.

Effects of vasodilators on beat-to-beat and every fifteen minutes blood pressure variability induced by noradrenaline infusion in rats.

Increased blood pressure variability (BPV) was shown to be associated with cardiovascular morbidities and/or mortalities. There are various types of BPV depending on time intervals of BP measurements, ranging from beat-to-beat to visit-to-visit or year-to-year. We previously found that continuous infusion of noradrenaline (NA) for 14 days increased short-term BPV every 15 min in rats. The aims of this study were to examine (1) whether NA infusion increases very short-term beat-to-beat BPV, (2) the effects of azelnidipine and hydralazine on NA-induced BPV, and (3) whether baroreceptor reflex sensitivity (BRS) is affected by NA or NA plus those vasodilators. Nine-week-old Wistar rats infused subcutaneously with 30 µg/h NA were orally treated with or without 9.7 mg/day azelnidipine or 5.9 mg/day hydralazine over 14 days. BP levels were continuously monitored via abdominal aortic catheter with a telemetry system in an unrestrained condition. Standard deviations (SDs) were used to evaluate beat-to-beat BPV and BPV every 15 min which was obtained by averaging BP levels for 10-s segment at each time point. BRS was determined by a sequence analysis. Continuous NA infusion over 14 days increased average BP, beat-to-beat BPV, and BPV every 15 min, lowering BRS. Comparing the two vasodilators, hydralazine reduced BP elevation by NA; meanwhile, azelnidipine alleviated BPV augmentation, preserving BRS, despite a smaller BP reduction. Thus, NA infusion increased both very short- and short-term BPV concomitantly with impaired BRS, while azelnidipine had an inhibitory effect, possibly independent of BP-lowering, on those types of BPV and impairment of BRS.

Hydralazine combined with conventional therapy improved outcomes in severe systolic dysfunction and mitral regurgitation.

AIMS: Patients with heart failure (HF) and reduced left ventricular ejection fraction (LVEF) accompanied by significant mitral regurgitation (MR) had poor outcome. Several vasodilator trials showed neutral results. We aimed to investigate the effect of early up-titration of hydralazine combined with conventional treatment in acute HF with severe systolic dysfunction and significant MR. METHODS AND RESULTS: The study was open-labelled, one-to-one ratio randomized designed. Consecutively hospitalized patients with decompensated HF symptoms, LVEF < 35%, and MR more than moderate severity were enrolled after exclusion. All participants with inadequate preload should have intake promotion with/without fluid supply. Patients receiving evidence-based medications (EBMs) as conventional treatment served as the control. Hydralazine + conventional treatment group received up-titration of hydralazine at Days 1-5 of the index admission combined with EBMs and throughout the course of follow-up. The endpoints included cardiovascular (CV) death and HF rehospitalization. Totally, 408 patients were enrolled (203 in conventional treatment and 205 in hydralazine + conventional treatment). The mean follow-up period was 3.5 years. The mean dose of hydralazine was 191 mg at index admission and 264 mg at study end in hydralazine + conventional treatment group. Both groups did not significantly differ in prescription rates and dosages of EBMs (all P > 0.05) at study end. Side effects did not differ between the two groups. Finally, 51% (104 out of 203 cases) reached endpoints in conventional group and 34.6% (71 out of 205 cases) in hydralazine + conventional treatment group, which had a significant reduction in CV events (hazard ratio 0.613, 95% confidence interval 0.427-0.877, P < 0.001). In-hospital death during the index admission was significantly higher in conventional group (5.4% vs. 0.5%, respectively; P = 0.001). CONCLUSIONS: When administered without inadequate preload, combining early up-titration of hydralazine with EBMs improves outcome in patients with severe systolic dysfunction and significant MR, and it is safe and well tolerated.

Matrine alleviates hypoxia-induced inflammation and pulmonary vascular remodelling via RPS5/NF-κB signalling pathway.

Hypoxia-induced vasoconstriction and vascular remodelling are the main pathological features of hypoxic pulmonary arterial hypertension (HPAH), and inflammation is participated in the occurrence of pulmonary vascular remodelling (PVR). Matrine is an alkaloid with the effects of anti-inflammation, antifibrosis and antitumour. But, few studies have explored the role of matrine in regulating PVR, and the related mechanisms are still unknown. In this study, we found that hypoxia-induced pulmonary artery smooth muscle cells (PASMCs) proliferation and inhibited its apoptosis, reduced the expression of ribosomal protein s5 and activated the nuclear factor kappa-B (NF-κB) signalling. Matrine, sildenafil and NF-κB inhibitor Bay 11-7082 could reverse these changes and impel the cell cycle in phase S retardation, and reduced the expression of p50, p65, proliferating cell nuclear antigen (PCNA), Bcl-2. In addition, matrine could lower right ventricular systolic pressure and mean pulmonary artery pressure of rats, α-smooth muscle actin and PCNA expression in pulmonary artery media, the levels of tumor necrosis factor-α and interleuki-1ß, thus improved hypoxia-induced PVR. This study indicated that matrine could alleviate inflammation and improve PVR through reversing the imbalance of proliferation and apoptosis of PASMCs, thus it had a therapeutic effect on HPAH.

Physiologic Treatment of Severe Hypertension in Pregnancy and Postpartum.

We aimed to evaluate physiologic treatment of severe hypertension. This was a retrospective cohort study of pregnant and postpartum patients with severe hypertension (systolic blood pressure [BP] 160 mm Hg or higher or diastolic BP 110 mm Hg or higher) treated with intravenous labetalol or hydralazine at a single tertiary care center between 2013 and 2018. Patients were classified as having physiologic treatment if they had hyperdynamic physiology (pulse pressure 65 mm Hg or higher) and received labetalol or had vasoconstrictive physiology (diastolic BP 100 mm Hg or higher) and received hydralazine. The primary outcome was number of antihypertensive doses to achieve nonsevere BP. Of 1,120 patients included in the analysis, 653 had physiologic treatment and 467 had nonphysiologic treatment, with 16 (1.4%) excluded for inability to classify physiology. Physiologic treatment was associated with fewer antihypertensive doses (1.4±0.9 doses vs 1.6±1.4 doses; adjusted ß -0.28, 95% CI, -0.42 to -0.14) and lower odds of medication conversion (2.5% vs 4.7%; adjusted odds ratio 0.48, 95% CI, 0.24-0.93) but no difference in time to nonsevere BP (31 minutes [interquartile range 16-66 minutes] vs 34 minutes [interquartile range 15-76 minutes]; adjusted hazard ratio 1.0, 95% CI, 0.9-1.2). Physiologic treatment of severe hypertension warrants further evaluation.

Single-Cell Imaging Maps Inflammatory Cell Subsets to Pulmonary Arterial Hypertension Vasculopathy.

Rationale: Unraveling immune-driven vascular pathology in pulmonary arterial hypertension (PAH) requires a comprehensive understanding of the immune cell landscape. Although patients with hereditary (H)PAH and bone morphogenetic protein receptor type 2 (BMPR2) mutations have more severe pulmonary vascular pathology, it is not known whether this is related to specific immune cell subsets. Objectives: This study aims to elucidate immune-driven vascular pathology by identifying immune cell subtypes linked to severity of pulmonary arterial lesions in PAH. Methods: We used cutting-edge multiplexed ion beam imaging by time of flight to compare pulmonary arteries (PAs) and adjacent tissue in PAH lungs (idiopathic [I]PAH and HPAH) with unused donor lungs, as controls. Measurements and Main Results: We quantified immune cells' proximity and abundance, focusing on those features linked to vascular pathology, and evaluated their impact on pulmonary arterial smooth muscle cells (SMCs) and endothelial cells. Distinct immune infiltration patterns emerged between PAH subtypes, with intramural involvement independently linked to PA occlusive changes. Notably, we identified monocyte-derived dendritic cells within PA subendothelial and adventitial regions, influencing vascular remodeling by promoting SMC proliferation and suppressing endothelial gene expression across PAH subtypes. In patients with HPAH, pronounced immune dysregulation encircled PA walls, characterized by heightened perivascular inflammation involving T cell immunoglobulin and mucin domain-3 (TIM-3)+ T cells. This correlated with an expanded DC subset expressing indoleamine 2,3-dioxygenase 1, TIM-3, and SAM and HD domain-containing deoxynucleoside triphosphate triphosphohydrolase 1, alongside increased neutrophils, SMCs, and alpha-smooth muscle actin (ACTA2)+ endothelial cells, reinforcing the heightened severity of pulmonary vascular lesions. Conclusions: This study presents the first architectural map of PAH lungs, connecting immune subsets not only with specific PA lesions but also with heightened severity in HPAH compared with IPAH. Our findings emphasize the therapeutic potential of targeting monocyte-derived dendritic cells, neutrophils, cellular interactions, and immune responses to alleviate severe vascular pathology in IPAH and HPAH.

The Role of Osteogenic Effect and Vascular Function in Bone Health in Hypertensive Rats: A Study of Anti-hypertensive and Hemorheologic Drugs.

Vascular dysfunction contributes to the development of osteopenia in hypertensive patients, as decreased blood supply to bones results in tissue damage and dysfunction. The effect of anti-hypertensive medicines on bone mass in hypertensive individuals is inconclusive because of the varied mechanism of their action, and suggests that reducing blood pressure (BP) alone is insufficient to enhance bone mass in hypertension. Pentoxifylline (PTX), a hemorheological drug, improves blood flow by reducing blood viscosity and angiogenesis, also has an osteogenic effect. We hypothesized that improving vascular function is critical to increasing bone mass in hypertension. To test this, we screened various anti-hypertensive drugs for their in vitro osteogenic effect, from which timolol and hydralazine were selected. In adult female spontaneously hypertensive rats (SHRs), timolol and hydralazine did not improve vascular function and bone mass, but PTX improved both. In female SHR animals, PTX restored bone mass, strength and mineralization, up to the level of normotensive control rats. In addition, we observed lower blood vasculature in the femur of adult SHR animals, and PTX restored them. PTX also restored the bone vascular and angiogenesis parameters that had been impaired in OVX SHR compared to sham SHR. This study demonstrates the importance of vascular function in addition to increased bone mass for improving bone health as achieved by PTX without affecting BP, and suggests a promising treatment option for osteoporosis in hypertensive patients, particularly at-risk postmenopausal women.

Early observations of Tier-3 drug shortages on purchasing trends across Canada: A cross-sectional analysis of 3 case-example drugs.

BACKGROUND: To curb the growing impact of drug shortages, Health Canada developed the Tiered Notification and Communication Framework which assigns potential shortages a corresponding tiered status. Tier-3 is assigned to shortages with the greatest potential impact on the healthcare system. This study aims to describe drug purchasing trends in response to Tier-3 shortages using three case-examples. METHODS: We conducted a time-series analysis of monthly purchasing data for three out of 17 Tier-3 drug shortages (hydralazine, sarilumab, and medroxyprogesterone acetate) with publicly available reports in July 2021 and available IQVIA MIDAS data from January 2016 to December 2021. We assessed percent changes in purchasing at 1-, 3-, and 6-months after the onset of each Tier-3 drug shortage and interventional ARIMA modelling was used to assess the statistical significance. RESULTS: Medroxyprogesterone acetate experienced a significant shift (p = 0.0370) in purchasing following its shortage, and the 1-, 3-, and 6-month percent changes were +14.9%, +6.8% and -3.1%, respectively. Hydralazine and sarilumab did not show a significant shift. The 1-, 3-, and 6-month percent changes for hydralazine were +15.5%, +10.2%, and +9.6% respectively and +25.2%, +45.1% and +39.2 for sarilumab. CONCLUSIONS: These results indicate that drugs assigned a Tier-3 status may not show declines in purchasing in the months following status assignment, which may be due to policy responses following the assignment. However, more insight is needed into the mechanisms through which these policy measures impact shortages and whether they are functioning as intended.

In vivo ameliorative effects of vitamin E against hydralazine-induced lupus.

OBJECTIVE: In this study, we investigated the in vivo ameliorative effects of vitamin E in a hydralazine-induced lupus model, which closely resembles SLE in humans. We aim to shed light on its potential as a therapeutic agent for managing SLE. METHODS: Forty BALB/c mice were used in this study. Hydralazine hydrochloride was orally administered in a concentration of 25 mg/kg to the five mice groups once weekly for a period of 5 weeks to induce a lupus-like condition. The untreated group was the normal control group. To confirm the development of lupus, an ANA test was conducted. After the mice tested positive for ANA, drug treatments commenced. The negative control group did not receive any drug treatment. The treatments included prednisolone, methotrexate and vitamin E, all administered at a concentration of 25 mg/kg, with a higher dose of vitamin E (50 mg/kg) also administered. RESULTS: Notably, on day 35, after drug treatment, we observed that mice that received vitamin E at a dosage of 50 mg/kg (3.01±0.100) had a slight decrease in lymphocyte hydrogen peroxide radicals when compared with the group receiving 25 mg/kg of vitamin E (3.30±0.100) (p<0.05). This finding suggests that the scavenging potential of vitamin E is dose dependent. CONCLUSION: This study suggests that vitamin E supplementation, especially at a higher dose (50 mg/kg), holds promise in ameliorating lupus-like conditions. These findings warrant further exploration and may offer a potential avenue for improving the disease status of patients experiencing SLE.

Treatment of acute-onset hypertension in pregnancy: A network meta-analysis of randomized controlled trials comparing anti-hypertensives and route of administration.

BACKGROUND: Consensus on the relative efficacy of available antihypertensive agents used in pregnancy is lacking. OBJECTIVE: To compare treatment success with antihypertensives and categorize by route of administration. SEARCH STRATEGY: MEDLINE, Embase, PubMed, Web of Science, Scopus, CINAHL, and clinicaltrials.gov were searched without date restriction. DATA COLLECTION: Peer-reviewed randomized controlled trials (RCTs) comparing pharmacologic agents used to treat hypertension in parturients were included. Evaluated treatment groups included IV-labetalol (BBIV), IV-hydralazine (DIV), oral-nifedipine (CCBPO), sublingual nifedipine (CCBSL), IV-calcium channel blocker (nonspecific)(CCBIV), IV-nitroglycerine (NTG), epoprostenol infusion (PRO), IV-ketanserin (5HT2B), IV-diazoxide (BZO), oral-nifedipine + methyldopa (CCBAG), oral-methyl-dopa (AAG), and oral prazosin (ABPO). ANALYSIS: Seventy-four studies (8324 patients) were eligible post PRISMA guidelines screening. Results were pooled using a Bayesian-approach for success of treatment (study defined target blood pressure), time to achieve target pressure, and neonatal intensive-care admissions. RESULTS: Treatment success (primary outcome, 55 trials with 5518 patients) was analyzed. Surface under the cumulative ranking curve (SUCRA) was categorized for 13 drugs, CCBPO (0.84) followed by CCBSL (0.78) were most likely to be effective in achieving target blood pressure. After sub-grouping by presence/absence of preeclampsia, CCB-PO ranked highest for both [(0.82) vs. (0.77), respectively]. Serotonin antagonists (0.99) and nitroglycerin (0.88) ranked highest for time to target pressure. NICU admissions were lowest for alpha-2 agonists (0.89), followed by BB PO (0.82) and hydralazine IV (0.49). CONCLUSION: Oral calcium-channel blockers ranked highest for treatment success. Ketanserin achieved target blood pressure fastest, warranting additional research. The results should be interpreted with caution as SUCRA values may not indicate whether the differences between interventions have clinically meaningful effect sizes.

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.

Hydralazine Promotes Central Nervous System Recovery after Spinal Cord Injury by Suppressing Oxidative Stress and Inflammation through Macrophage Regulation.

OBJECTIVE: This study aims to investigate the effects of hydralazine on inflammation induced by spinal cord injury (SCI) in the central nervous system (CNS) and its mechanism in promoting the structural and functional recovery of the injured CNS. METHODS: A compressive SCI mouse model was utilized for this investigation. Immunofluorescence and quantitative real-time polymerase chain reaction were employed to examine the levels of acrolein, acrolein-induced inflammation-related factors, and macrophages at the injury site and within the CNS. Western blotting was used to evaluate the activity of the phosphoinositide 3-kinase (PI3K)/AKT pathway to study macrophage regulation. The neuropathic pain and motor function recovery were evaluated by glutamic acid decarboxylase 65/67 (GAD65/67), vesicular glutamate transporter 1 (VGLUT1), paw withdrawal response, and Basso Mouse Scale score. Nissl staining and Luxol Fast Blue (LFB) staining were performed to investigate the structural recovery of the injured CNS. RESULTS: Hydralazine downregulated the levels of acrolein, IL-1ß, and TNF-α in the spinal cord. The downregulation of acrolein induced by hydralazine promoted the activation of the PI3K/AKT pathway, leading to M2 macrophage polarization, which protected neurons against SCI-induced inflammation. Additionally, hydralazine promoted the structural recovery of the injured spinal cord area. Mitigating inflammation and oxidative stress by hydralazine in the animal model alleviated neuropathic pain and altered neurotransmitter expression. Furthermore, hydralazine facilitated motor function recovery following SCI. Nissl staining and LFB staining indicated that hydralazine promoted the structural recovery of the injured CNS. CONCLUSION: Hydralazine, an acrolein scavenger, significantly mitigated SCI-induced inflammation and oxidative stress in vivo, modulated macrophage activation, and consequently promoted the structural and functional recovery of the injured CNS.

Comparison of efficacy of intravenous labetalol and intravenous hydralazine for management of pre-eclampsia in pregnant women.

Objectives: To compare the efficacy of intravenous Labetalol and intravenous Hydralazine in reduction of blood pressure in patients with severe pre-eclampsia. Methodology: This comparative study was conducted at the Department of Obstetrics and Gynecology at Ziauddin University Hospital, Karachi from1st June 2019 to 30th June 2020. Total 208 pregnant women having severe pre-eclampsia (systolic pressure ≥160 mmHg and diastolic pressure ≥110mmHg) were included in study. Group A received I/V Labetalol. Group B received I/V Hydralazine. Efficacy of drugs was observed by reduction in blood pressure and the number of doses administered. Data was analysed using SPSS version 26. Results: Systolic blood pressure reduction in Labetalol group was significantly lower than in hydralazine group (105.5 ±11.3 vs. 115.8 ±17.1, p≤ 0.001). Diastolic blood pressure reduction was also lower in labetalol group than in hydralazine group (p= 0.03). Number of dosage of drugs in Group A (Labetalol) was 3.2 ±1.2 vs. Group B (Hydralazine) was 4.4±1.4, p =0.006). Conclusion: The results of this study show that Labetalol is more effective as compared to Hydralazine in terms of reducing the systolic and diastolic blood pressure and number of doses (Drugs) for in patients with severe preeclampsia.

Diagnostic dilemma: drug-induced vasculitis versus systemic vasculitis.

Drug-induced vasculitis can rarely cause inflammation and necrosis of blood vessel walls of both kidney and lung tissue. Diagnosis is challenging because of the lack of difference between systemic and drug-induced vasculitis in clinical presentation, immunological workup and pathological findings. Tissue biopsy guides diagnosis and treatment. Pathological findings must be correlated with clinical information to arrive at a presumed diagnosis of drug-induced vasculitis. We present a patient with hydralazine-induced antineutrophil cytoplasmic antibodies-positive vasculitis with a pulmonary-renal syndrome manifesting as pauci-immune glomerulonephritis and alveolar haemorrhage.

Overlapping drug-induced vasculitis, ANCA-associated vasculitis, and lupus nephritis caused by low-dose hydralazine.

INTRODUCTION: We present a case of drug-induced vasculitis secondary to low-dose hydralazine with overlapping features of antineutrophil cytoplasmic antibody-associated vasculitis and drug-induced lupus nephritis. CASE PRESENTATION: A 52-year-old Hispanic woman with a medical history of resistant hypertension treated with hydralazine 10 mg twice daily for 1 year presented with generalized weakness, dizziness, nausea, vomiting, and gross hematuria. There was fever, tachycardia, leukocytosis, lactic acidosis, hyperkalemia, renal failure, and anemia. Chest computed tomography and bronchoscopy revealed a left lower lobe infiltrate and diffuse alveolar hemorrhage. Serologic testing was positive for anti-double-stranded DNA, anti-Smith, lupus anticoagulant, anti-histone, anti-cardiolipin IgM antibodies, and antineutrophil cytoplasmic antibodies (myeloperoxidase and proteinase 3). A kidney biopsy revealed crescentic glomerulonephritis with an overlapping finding of membranous nephropathy. Broad-spectrum antibiotics, immunosuppressants, corticosteroids, and plasmapheresis were initiated. The patient survived but required continuous hemodialysis. CONCLUSIONS: Although a few cases of simultaneous antibody-associated vasculitis and drug-induced lupus nephritis secondary to hydralazine use have been reported, this case is singular. Similar findings were previously reported with doses of 50-100 mg two to three times daily over 1-5 years. In our patient, a dose of only 10 mg twice daily for a year caused a severe disease presentation. This brings to light the combination of different vasculitides that can coexist and the potentially life-threatening adverse effects of low-dose hydralazine that should be kept in mind.

Xanthine oxidase/NADPH oxidase inhibition by hydralazine attenuates acute kidney injury and prevents the transition of acute kidney injury to chronic kidney disease.

AIMS: The enhancement of inflammation and reactive oxygen species leads to the damage of renal tubular cells in acute kidney injury (AKI), and the upregulation of inflammation increases the risk of AKI being converted into chronic kidney disease (CKD). Hydralazine has shown renoprotective effects in multiple kidney diseases and was shown to be a potent xanthine oxidase (XO) inhibitor. This study aimed to investigate the mechanisms of hydralazine in ischemia-reperfusion (I/R)-stimulated renal proximal tubular epithelial cells in vitro and in AKI animals in vivo. MAIN METHODS: The effects of hydralazine in AKI-to-CKD transition were also evaluated. Human renal proximal tubular epithelial cells were stimulated by I/R conditions in vitro. To generate a mouse model of AKI, a right nephrectomy was performed, followed by left renal pedicle I/R using a small atraumatic clamp. KEY FINDINGS: In the in vitro part, hydralazine could protect renal proximal tubular epithelial cells against insults from the I/R injury through XO/NADPH oxidase inhibition. In the in vivo part, hydralazine preserved renal function in AKI mice and improved the AKI-to-CKD transition by decreasing renal glomerulosclerosis and fibrosis independently of blood pressure lowering. Furthermore, hydralazine exerted antioxidant, anti-inflammatory, and anti-fibrotic effects both in vitro and in vivo. SIGNIFICANCE: Hydralazine, as a XO/NADPH oxidase inhibitor, could protect renal proximal tubular epithelial cells from the insults of I/R and prevent kidney damage in AKI and AKI-to-CKD. The above experimental studies strengthen the possibility of repurposing hydralazine as a potential renoprotective agent through its antioxidative mechanisms.

Mini review: The clinical avenues of combined hydralazine-nitrate in subjects with heart failure with reduced ejection fraction

Background: Combined hydralazine-nitrate has an avenue in the management of subjects with heart failure with reduced ejection fraction. Exploring the pharmacotherapy in this context will facilitate the clinical utility of the combined therapy. Objective: The main objective of this mini-review was to evaluate the role of combined hydralazine-nitrate in subjects with heart failure with reduced ejection fraction. Methods: We conducted a literature search on Google scholar, MEDLINE, and PubMed to identify the randomized clinical trials on combined hydralazine-nitrate, in subjects with heart failure with reduced ejection fraction. 2760 articles were returned initially out of which 10 trials were conforming to the inclusion criteria. However, three trails were the focus for the current mini-review. Key findings: The current mini-review lends support to the use of combined hydralazine-nitrate in subjects with heart failure with reduced ejection fraction (HFrEF). The combination may offer subjects who have remained symptomatic with HFrEF despite optimum dosing of standard therapy. Black subjects with HFrEF have proved to benefit from combined hydralazine-nitrate. The combination (e.g. small dose of hydralazine 12.5-25 mg twice a day and isosorbide mononitrate 10 mg twice a day) may provide alternative clinical utility in subjects with contraindications (renal artery stenosis, creatinine clearance less than 30 mL/minute, sustained hyperkalemia) to the use of ACEinh, ARBs, and/or ARNI. Subjects with HFrEF on combined hydralazine-nitrate should be assessed and monitored for systolic BP (keep >120 mmHg) and subjects with chronic kidney disease (keep eGFR > 30 mL/min/1.73 m2). Hydralazine-nitrate was inferior to ACEinh (higher all-cause mortality and cardiovascular mortality. Conclusion: The current mini- review provides the key points to support the use of hydralazine-nitrate in subjects with heart failure with reduced ejection fraction. (AU)

Reduction of Intravenous Antihypertensives through Clinical Decision Support in a Large Safety Net System.

BACKGROUND: Asymptomatic severe hypertension (also known as hypertensive urgency) is frequently encountered in the hospital. Previous evidence suggests that management with one-time doses of intravenous (IV) antihypertensives may increase adverse events. Despite this, single-dose treatment remains common in the emergency department and inpatient settings. METHODS: This quality initiative was launched at New York City Health + Hospitals, the largest safety net hospital system in the United States. The initiative involved two changes to electronic orders for IV hydralazine and IV labetalol: a nonintrusive advisory statement within the order instructions and a mandatory requirement to document the indication for IV antihypertensive use. RESULTS: This initiative took place from November 2021 to October 2022. Of the indications selected for IV antihypertensive orders, 60.7% were for hypertensive emergency, 15.3% were for patients who were strictly NPO, 21.2% were for other, and 2.8% selected more than one indication. For ED-only encounters, aggregate IV hydralazine and IV labetalol orders per 1,000 patient encounters were 2.53 preintervention and 1.55 postintervention (38.7% reduction, p < 0.001). For inpatient encounters, aggregate IV hydralazine and IV labetalol orders per 1,000 patient-days were 18.25 preintervention and 15.81 postintervention (13.4% reduction, p < 0.001). Similar trends were observed for individual orders of IV hydralazine and IV labetalol. There were significant reductions in 7 of the 11 hospitals in inpatient administration of aggregate IV hydralazine and labetalol orders per 1,000 patient-days. CONCLUSION: This quality improvement initiative successfully reduced unnecessary IV antihypertensive use in an 11-hospital safety net system.

Coordination of hydralazine with Cu2+ at acidic pH promotes its oxidative degradation at neutral pH.

Hydralazine (HL), a frequently prescribed oral antihypertensive drug, shows redox interactions with transition metals such as copper that are not fully understood. Copper may be present at high concentrations in the digestive tract and can affect oral drugs. An important parameter for such interactions is pH, which changes from acidic in the gastric juice to neutral pH in intestines. In this study, we examined interactions of HL with Cu2+ ions in conditions that mimic pH shift in the digestive tract using UV-Vis, Raman and EPR spectroscopy, cyclic voltammetry and oximetry. In the acidic solution, Cu2+ formed a stable mononuclear complex with two bidentate coordinated HL molecules. On the other hand, at neutral pH, Cu2+ initiated oxidation and degradation of HL. The degradation was more rapid in the HL-Cu2+ system that was initially prepared at acidic pH and then shifted to neutral pH. The formation of the complex at acidic pH increases the availability of Cu2+ for redox reactions after the shift to neutral pH at which Cu2+ is poorly soluble. These results imply that the change of pH along the digestive tract may promote HL degradation by allowing the formation of the complex at gastric pH which makes Cu2+ available for subsequent oxidation of HL at neutral pH.