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.

The significant improvement in ovarian PCOS syndrome using hydralazine and alendronate aromatase inhibitor FDA-approved drugs in Wistar rat models.

Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility. The aim of this study was to investigate the therapeutic potential of vitamin C, glutamine, mesalazine, hydralazine, and alendronate as new drug candidates for the treatment of letrozole-induced PCOS in female Wistar rats. PCOS was induced in rats by intramuscular injection of estradiol valerate (2 mg/kg body weight for 28 days). The rats then received normal saline (PCOS group), letrozole (0.5 mg/kg), vitamin C (100 mg/kg), glutamine (1000 mg/kg), mesalazine (200 mg/kg), hydralazine (30 mg/kg), and alendronate (17.5 mg/kg). Serum testosterone, LH, FSH, estradiol and progesterone levels were determined by ELISA method. H&E staining was used for histological analysis in the ovarian tissues. The groups treated with hydralazine and alendronate, show a significant decrease in testosterone, LH hormone, cystic and atretic follicles, and a significant increase in the number of single layer, multilayer, antral, graafian follicles and the volume of corpus luteum as compared to the PCOS group. Hydrolazine and alendronate appear to be effective in restoring folliculogenesis and increasing ovulation in PCOS rat. So that the natural process of ovulation and the improvement of the histology of polycystic ovaries and its shift towards healthy and active ovaries were observed. This finding supports the potential beneficial effect of hydrolazine and alendronate on improving PCOS complication.

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.

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)

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.

Iatrogenia farmacológica en el paciente cardiorrenal. A propósito de un caso / Pharmacological iatrogenesis in a cardiac-renal patient: Presentation of a case

Presentamos el caso de una paciente de 75 años, con insuficiencia renal crónica, fibrilación auricular, diabetes mellitus e hipertensión arterial, con ingresos hospitalarios repetidos para control de episodios de fibrilación auricular rápida, mal tolerados, con hipotensión y disnea. De la evolución clínica se deduce iatrogenia farmacológica y se discute la importancia de ésta en la práctica clínica general (AU)

A case is presented of a 75 year-old patient with chronic kidney failure, atrial fibrillation, diabetes mellitus, and hypertension. She had regularly been admitted to hospital due to episodes of rapid atrial fibrillation that were not well tolerated in relation to the concomitant hypotension and dyspnea. An adverse drug reaction was deduced from the clinical course, and the relative importance of this in daily medical practice is emphasized (AU)

Guía de práctica clínica de la Sociedad Europea de Cardiología (ESC) para el diagnóstico y tratamiento de la insuficiencia cardiaca aguda y crónica (2008) / No disponible

No disponible

Persistent hypertension and progressive renal injury induced by salt overload after short term nitric oxide inhibition

INTRODUCTION: Administration of the NO inhibitor Nwð-nitro-L-arginine methyl ester (NAME) and a high-salt diet (HS) promotes severe albuminuria and renal injury, which regresses upon discontinuation of treatments. OBJECTIVE: We investigated whether these changes reappear after reinstitution of HS, and whether they are prevented by treatment with the antilymphocyte agent mycophenolate mofetil (MMF) or the AT-1 receptor blocker losartan (L). Adult male Munich-Wistar rats received NAME and HS. A control Group (C) received only HS. After 20 days, rats receiving HS and NAME exhibited severe hypertension and albuminuria. After a 30-day recovery period, hypertension was attenuated and albuminuria had virtually disappeared. MATERIAL AND METHODS: Rats were then distributed among the following groups: HS, receiving HS; NS, receiving a normal salt (NS) diet; HS-MMF, receiving HS and MMF; HS-LOS, receiving HS and L; HS-HDZ, receiving HS and hydralazine (HDZ). Sixty days later, NS rats showed only slight albuminuria and renal damage or inflammation. In contrast, HS rats developed severe hypertension, marked glomerulosclerosis with interstitial expansion and renal infiltration by macrophages and angiotensin II-positive cells. The group treated with losartan had lowered blood pressure and a lack of albuminuria or renal injury. MMF provided similar protection without altering blood pressure, suggesting a nonhemodynamic effect, a hypothesis reinforced by the finding that HDZ lowered blood pressure without preventing renal injury. RESULTS: These results indicate that treatment with HS and NAME predisposes to the development of hypertension and renal injury upon salt overload, characterizing a new model of chronic nephropathy. CONCLUSION: The response to MMF or L, but not HDZ, suggests a key role for inflammatory rather than hemodynamic factors.

INTRODUÇÃO: A administração de Nômega-nitro-L-arginina metiléster (NAME), um inibidor da produção de NO, com dieta rica em sal (HS) promove albuminúria e dano renal graves, reversíveis ao interromperem-se os tratamentos. OBJETIVO: Investigamos se tais alterações recrudescem ao reinstituir-se a HS e se são prevenidas pelo micofenolato mofetil (MMF), um agente antilinfócito, ou losartan, um bloqueador do receptor AT-1. MATERIAL E MÉTODOS: Ratos Münich-Wistar machos adultos receberam NAME e HS. Um grupo controle (C) recebeu apenas HS. Após 20 dias, os ratos que receberam HS e NAME exibiam hipertensão e albuminúria graves. Após recuperação de 30 dias, a hipertensão atenuou-se e a albuminúria praticamente desapareceu. Formaram-se então os grupos: HS, recebendo HS; NS, recebendo dieta normal em sal (NS); HS-MMF, recebendo HS e MMF; HS-LOS, recebendo HS e losartan; HS-HDZ, recebendo HS e hidralazina. Após sessenta dias os ratos NS tinham albuminúria e dano/inflamação renal apenas discretos. Já os ratos HS desenvolveram hipertensão e glomerulosclerose acentuadas, expansão intersticial e infiltração renal por macrófagos e células positivas para angiotensina II. Losartan baixou a pressão arterial e preveniu albuminúria e lesão renal. MMF proporcionou proteção semelhante sem alteração pressórica, sugerindo a ação de mecanismos não hemodinâmicos, hipótese reforçada pelo achado de que a HDZ baixou a pressão arterial sem prevenir a nefropatia. RESULTADOS: Esses resultados indicam que o tratamento com HS e NAME predispõe ao desenvolvimento de hipertensão e lesão renal induzidos por excesso de sal, caracterizando um novo modelo de nefropatia crônica. CONCLUSÃO: A resposta ao MMF ou losartan, mas não à hidralazina, sugere o predomínio de fatores inflamatórios.

Efetividade do tratamento de gestantes hipertensas / Perinatal outcome in the different clinical forms of hypertension during pregnancy

OBJETIVO: Comparar as intercorrências clínicas materno-fetais e a efetividade do tratamento entre grupos das síndromes hipertensivas na gestação (SHG). MÉTODOS: Foram revisados 200 prontuários de gestantes com SHG, sendo avaliados as intercorrências fetais, a classificação da síndrome hipertensiva e o uso de anti-hipertensivos. RESULTADOS: Entre as intercorrências maternas, 85 (42,5 por cento) das pacientes foram classificadas no grupo controle; 32 (16 por cento) apresentaram hipertensão gestacional (HG); 67 (33,5 por cento) PE; 6 (3 por cento) hipertensão crônica; e 10 (5 por cento) pré-eclâmpsia sobreposta a hipertensão crônica (PSHC). Os menores valores para a idade gestacional, peso dos recém-nascidos e para o índice de Apgar foram observados nos grupos de pacientes com PE e PSHC. A utilização do tratamento não alterou os parâmetros perinatais em relação aos grupos com HG. O grupo de pacientes com PE apresentou a menor idade gestacional e o menor índice de Apgar quando comparado ao grupo controle. CONCLUSÃO: A introdução da terapia anti-hipertensiva durante a gestação foi de fundamental importância para o atendimento à gestante com SHG, embora tenha proporcionado poucos avanços em relação à prevenção das intercorrências perinatais, pois não houve alteração dos parâmetros gestacionais nos casos em que se comparou a utilização do tratamento. A medicação utilizada pouco interfere no fluxo sangüíneo materno-fetal, e conseqüentemente, nas condições de nascimento da criança.

OBJECTIVE: To compare the maternal-fetal clinical intercurrences and the effectiveness of treatment in the different clinical forms of hypertensive syndromes during pregnancy (HSP). METHODS: Medical records of 200 pregnant women with HSP were reviewed to appraise fetal intercurrences, classification of the hypertensive syndrome and use of antihypertensives. RESULTS: Of the 200 patients analyzed, 85 (42.5 percent) were controls; 32 (16 percent) presented gestational hypertension (GH), 67 (33.5 percent) had Pre-eclampsia (PE), 6 (3 percent) had chronic hypertension and 10 (5 percent) cases had PE superimposed chronic hypertension (PSCH). The lowest values for gestational age, weights of the newborn and for the Apgar index were observed in the patients with PE and PSCH. Treatment did not alter the Apgar index in relation to control and non-treated GH patients. Patients with PE presented the lowest gestational age and the smallest Apgar index when compared to controls. CONCLUSION: Introduction of an antihypertensive therapy during gestation was of fundamental importance for health improvement and pressure control of the pregnant woman with HSP. Nevertheless, it has been of little help for prevention of perinatal intercurrences. This was substantiated by the absence of improvement in the gestational conditions between the treated group when compared to the non-treated. Medication did not significantly improve the maternal-fetal blood flow and consequently in the birth condition of the child.

Tratamento da doença hipertensiva específica da gravidez, forma grave, com uso exclusivo de hipotensor / Treatment of pre-eclampsia, severe form, using only antihypertensive agents

É apresentado a conduçäo de 41 pacientes com DHEG (forma grave) com o uso de hipotensor exclusivamente, desde a internaçäo até o parto. Näo se utilizou nenhum tipo de anticonvulsivante. Os resultados mostram ausência de convulsöes embora tenha ocorrido, em alguns casos, agravamento clínico da doença. Näo ocorreram óbitos maternos e a mortalidade perinatal foi de 17 por cento

Emergência hipertensiva / Hypertensive emergencies

A emergência hipertensiva é uma condiçäo de risco iminente de vida caracterizada por elevaçäo súbita da pressäo arterial e comprometimento de órgäo-alvo. O cérebro, coraçäo, rins, retina e aorta säo alvos frequentes. Säo importantes a presteza diagnóstica e o tratamento precoce. Dá-se escolha aos anti-hipertensivos parenterais de açäo rápida e de curta duraçäo, evitando-se, porém, quedas pressóricas que comprometam a perfusäo de órgäos ou sistemas. O objetivo desta revisäo é mostrar como se diagnostica e se trata precocemente a emergência hipertensiva.

An open trial comparing usual care (hydralazine) with injectable Isradipine in severe pre-eclampsia

Pre-eclampsia is characterised by generalized vasospasm. When this affects the placental bed it causes foetal compromise. These placental bed vessels are under the control of locally acting agents such as electrolytes and are not influenced by neural acting vasodilators such as hydralazine. Calcium channel blockers such as isradipine should work on these vessels and therefore improve the outcome of these pregnancies compared with hydralazine. We did a randomized comparative trial with these two agents used parenterally, in 27 patients with severe pre-eclampsia. The main outcome variables examined were age, parity, bloodpressure before and after treatment, length of prolongation of the pregnancy after start of treatment, complications and foetal outcome. There were no significant differences between the two groups in pre-treatment or post-treatment variables. In conclusion we believe that isradipine offers no advantage over hydralazine in severe pre-eclampsia (AU)

Infarto renal con hipertensión arterial: informe de un caso pediátrico / Renal infarction with arterial hypertension: report of a pediatric case

El infarto renal puede definirse como la muerte de tejido renal debido a interferencia con su circulación sanguínea. Se presenta el caso de un paciente masculino, de nueve años de edad, con cefalea universal, vómitos de contenido gástrico y una tensión arterial (TA) de 140/100 mmHg. Su renina plasmática periférica fue de 7.4 ng/mL/h (normal hasta 2.5 ng/mL/h). La arteriografía renal indicó infarto parenquimatoso en polo superior de riñón derecho. Actualmente, está controlado con una tensión arterial de 110/70 mmHg, para lo cual recibe 1 mg/kg/día de captopril complementado con dieta hiposódica.