During Pregnancy the Comparison of Hydralazine and Nifedipine for Severe Hypertension

Objective: The research paper aims at the comparison of Nifedipine and Hydralazine safety and efficacy in the hypertension management during pregnancy. Study Design: The in-hand research design is RCT (Randomized Control Trial). Place and Duration: The venue of the in-hand research paper was Mother and Child Health Unit-II which is located in Pakistan Institute of Medical Sciences, Islamabad. The research commenced from 1st January, 2017 and concluded on 1st July, 2017. Methodology: The number of patients included in research paper was. These patients were diagnosed hypertension and their age was beyond twenty-eight weeks of gestation were enrolled as sample of the research paper after informed consent. Total number of patients was divided into two groups namely Nifedipine and Hydralazine groups. Patients were allocated groups randomly either Nifedipine or Hydralazine group. Before the start of treatment on the right side the blood pressure was checked in supine position, the same check was repeated at the interval of half hour continuously till two hours. Patients were also noticed for the presence of any side effect of the drugs. Results: Initial mean Blood Pressure reading was noted as 170/113 mmHg. One-hour time was effective for the control of systolic blood pressure of Nifedipine group; whereas, one and half hour was for the Hydralazine group. Both the groups were observed same time for the diastolic blood pressure that was one hour respectively for both the groups. Mean time of four and a half days was observed for the pregnancy prolongation in Nifedipine group; whereas, the same time for the Hydralazine group was two days. The p-value was significantly calculated as 0.02. Nifedipine group was treated with few doses of medication. Hydralazine group reflected association of palpitation, flushing, persistent Hypertension and tachycardia with the respective proportions of 56%, 56%, 16.7% and greater than 110 bpm (20%). No other significant difference was observed in the scaled variables of feto-maternal results with an exception of headache caused by Nifedipine in seventy-three percent of the cases after drug administration. Conclusion: In the scholastic research it is concluded that during pregnancy hypertension can best be controlled through Nifedipine in comparison with Hydralazine.

Development, in-vitro and ex-vivo evaluation of muco-adhesive buccal tablets of hydralazine hydrochloride

Abstract Hydralazine hydrochloride is an anti-hypertensive drug. The drug has poor oral bioavailability (BA) of about 30- 50% due to extensive first-pass metabolism. Hence, the buccal delivery was used to enhance the BA of hydralazine hydrochloride. Buccal muco-adhesive tablets were prepared by direct compression technique, using carbopol 934P, HPMC K4M, sodium alginate and sodium carboxy methyl cellulose (NaCMC) as muco-adhesive polymers. Prepared formulations were evaluated for physico-chemical characterization, ex-vivo residence time and in-vitro release studies. The some of the parameters viz hardness, thickness, weight variation are showing the values within the pharmacopeial limits. However, the swelling and bio-adhesive strength were increased with increasing polymer concentrations. From the in-vitro release studies, F9 buccal tablets prepared with NaCMC exhibited better release (96.56%, 6 h) profile than all other formulations and considerd as optimized. The release mechanism from kinetic methods suggests that, the drug release follows zero-order kinetics with diffusion mechanism. Thus, the buccal tablets of hydralazine hydrochloride showed enhanced BA and were further confirmed by in-vivo studies.

The alteration of neuronal activities of the cuneiform nucleus in non-hypovolemic and hypovolemic hypotensive conditions / Alterações da atividade neuronal no núcleo cuneiforme em condições hipovolêmicas e não hipovolêmicas

Abstract Background: The cuneiform nucleus is located in the center of the circuit that mediates autonomic responses to stress. Hemorrhagic hypotension leads to chemoreceptor anoxia, which consequently results in the reduction of baroreceptor discharge and stimulation of the chemoreceptor. Objective: Using the single-unit recording technique, the neuronal activities of the cuneiform nucleus were investigated in hypotensive states induced by hemorrhage and administration of an anti-hypertensive drug (hydralazine). Methods: Thirty male rats were divided into the control, hemorrhage, and hydralazine groups. The femoral artery was cannulated for the recording of cardiovascular responses, including systolic blood pressure, mean arterial pressure, and heart rate. Hydralazine was administered via tail vein. The single-unit recording was performed from the cuneiform nucleus. Results: The maximal systolic blood pressure and the mean arterial pressure significantly decreased and heart rate significantly increased after the application of hydralazine as well as the following hemorrhage compared to the control group. Hypotension significantly increased the firing rate of the cuneiform nucleus in both the hemorrhage and hydralazine groups compared to the control group. Conclusions: The present data indicate that the cuneiform nucleus activities following hypotension may play a crucial role in blood vessels and vasomotor tone.

RESUMO Antecedentes: O núcleo cuneiforme está localizado no centro do circuito que media as respostas autonômicas ao estresse. A hipotensão hemorrágica leva à anóxia dos quimiorreceptores, que, consequentemente, resulta na redução da descarga dos barorreceptores e estimulação do quimiorreceptor. Objetivo: Utilizando a técnica de registro em unidade única, as atividades neuronais do núcleo cuneiforme foram investigadas em estados de hipotensão induzida por hemorragia e administração de um anti-hipertensivo (hidralazina). Métodos: Trinta ratos machos foram divididos nos grupos controle, hemorragia e hidralazina. A artéria femoral foi canulada, para o registro de respostas cardiovasculares, incluindo pressão arterial sistólica, pressão arterial média e frequência cardíaca. A hidralazina foi administrada na veia da cauda. O registro de unidade única foi realizado a partir do núcleo cuneiforme. Resultados: A pressão arterial sistólica máxima e a pressão arterial média diminuíram significativamente, e a frequência cardíaca aumentou significativamente após a aplicação de hidralazina, bem como a hemorragia seguinte, em comparação com o grupo controle. A hipotensão aumentou significativamente a taxa de disparo da população do núcleo cuneiforme em ambos os grupos de hemorragia e hidralazina, em comparação com o grupo de controle. Conclusões: Os presentes dados indicam que as atividades do núcleo cuneiforme após hipotensão podem desempenhar um papel crucial nos vasos sanguíneos e no tônus vasomotor.

Synthesis and antileishmanial activity of naphthoquinone-based hybrids / Síntesis y actividad antileishmania de híbridos naftoquinónicos / Síntese e atividade antileishmania de híbridos naftoquinónicos

SUMMARY Introduction: Leishmaniasis is a disease caused by protozoa of the genus Leishmania and is considered endemic in 98 countries. Treatment with pentavalent antimonials has a high toxicity, which motivates the search for effective and less toxic drugs. α- and β-lapachones have shown different biological activities, including antiprotozoa. In recent studies, the isonicotinoylhydrazone and phthalazinylhydrazone groups were considered innovative in the development of antileishmania drugs. Molecular hybridization is a strategy for the rational development of new prototypes, where the main compound is produced through the appropriate binding of pharmacophoric subunits. Aims: To synthesize four hybrids of α- and β-lapachones, together with the isonicotinoylhydrazone and phthalazinylhydrazone groups and to determine the antileishmania activity against the promastigotic forms of L. amazonensis, L. infantum and L. major. Results: β-lapachone derivatives were more active against all tested leishmania species. βACIL (IC50 0.044μM) and βHDZ (IC50 0.023μM) showed 15-fold higher activity than amphotericin B. The high selectivity index exhibited by the compounds indicates greater safety for vertebrate host cells. Conclusion: The results of this work show that the hybrids βACIL and (3HDZ are promising molecules for the development of new antileishmania drugs.

RESUMEN Introducción: Leishmaniasis es una enfermedad causada por protozoos del género Leishmania y se considera endémica en 98 países. El tratamiento con antimoniales pentavalentes tiene una alta toxicidad, lo que motiva la búsqueda de fármacos eficaces y menos tóxico. α- y β-lapachones han mostrado diferentes actividades biológicas, incluido los antiprotozoarios. En estudios recientes, los grupos isonicotinoilhidra-zona y ftalazinilhidrazona se consideraron innovadores en el desarrollo de fármacos antileishmania. La hibridación molecular es una estrategia para el desarrollo racional de nuevos prototipos, donde el compuesto principal se produce a través de la unión apropiada de subunidades farmacofóricas. Objetivos: Sintetizar cuatro híbridos de α- y β-lapachones, junto con los grupos isonicotinoilhidrazona y ftalazinilhidrazona y determinar la actividad antileishmania frente a las formas promastigotas de L. amazonensis, L. infantum y L. major. Resultados: Los derivados de β-lapachone fueron más activos contra todas las especies de leishmania probadas. La βACIL (CI50 0,044μM) y βHDZ (CI50 0,023μM) mostraron actividad 15 veces mayor que la anfotericina B. El alto índice de selectividad que presentan los compuestos indica una mayor seguridad para las células huésped del vertebrado. Conclusión: Los resultados de este trabajo demuestran que los híbridos (ACIL y (HDZ son moléculas prometodoras para el desarrollo de nuevos fármacos antileishmania.

RESUMO Introdução: A leishmaniose é uma doença causada por protozoários do género Leishmania e é considerada endémica em 98 países. O tratamento com antimoniais pentavalentes apresenta alta toxicidade, o que motiva a pesquisa por medicamentos eficazes e menos tóxicos. α- e β-lapachones tém mostrado diferentes atividades biológicas, incluindo antiprotozoários. Em estudos recentes, os grupos isonicotinoilhi-drazona e ftalazinilhidrazona foram considerados inovadores no desenvolvimento de drogas antileishmania. A hibridização molecular é uma estratégia para o desenvolvimento racional de novos protótipos, onde o composto principal é produzido através da ligação apropriada de subunidades farmacofóricas. Objetivos: Sintetizar quatro híbridos de α- e β-lapachones, juntamente com os grupos isonicotinoil-hidra-zona e ftalazinilhidrazona e determinar a atividade antileishmania contra as formas promastigóticas de L. amazonensis, L. infantum e L. major. Resultados: Os derivados de β-lapachona foram mais ativos contra todas as espécies de leishmania testadas. BACIL (IC50 0,044 μM) e βHDZ (IC50 0,023 μM) apresentaram atividade 15 vezes maior do que a anfotericina B. O alto índice de seletividade dos compostos indica maior segurança para células hospedeiras de vertebrados. Conclusaõ: Os resultados deste trabalho mostram que os híbridos βACIL e βHDZ são moléculas promissoras para o desenvolvimento de novos fármacos antileishmania.

Evaluation of Antihypertensive Efficacy of Intravenous Hydralazine and Intravenous Labetalol in the Management of Severe Preeclampsia and Eclampsia..

Hypertensive disorders of pregnancy are one of the most common obstetrical problems and affect 5-10% of all pregnancies. Severe preeclampsia is a multi-system disorder and causes many complications like intracranial haemorrhage, hypertensive encephalopathy, abruptio placentae, heart failure, pulmonary oedema and eclampsia. Intravenous hydralazine and labetalol are considered as first line antihypertensive agents for management of hypertensive crisis. The objective of this study was to compare efficacy of intravenous hydralazine and labetalol in lowering blood pressure in severe pregnancy induced hypertension, as well as to find out frequency of maternal adverse reactions and foetal impacts.METHODSThe study was conducted at Calcutta National Medical College and Hospital over a period of one year. 100 women with severe preeclampsia were included in the study and randomly divided into two groups of 50 each. One group received intravenous hydralazine while the other group was treated with intravenous labetalol. The time and number of doses taken to achieve target blood pressure were noted. Number of patients having persistent severe hypertension after receiving maximum drug dosage were also taken into account.RESULTSThe pre-treatment systolic blood pressure was 168.80 mmHg in hydralazine group and 173.64 mmHg in labetalol group whereas the diastolic blood pressure was 143.92 mmHg and 142.6 mmHg in hydralazine and labetalol group respectively. Mean time to achieve blood pressure control was 22.20 minutes in hydralazine group and 26.04 minutes in labetalol group. There were 3 cases of persistent severe hypertension in hydralazine group and 2 cases in labetalol group. No statistically significant difference was found between the two groups in terms of efficacy, maternal adverse effects and perinatal outcome. However, maternal tachycardia and headache was found to be significantly higher in patients treated with hydralazine.CONCLUSIONSThus, both hydralazine and labetalol are effective and safe antihypertensive drugs which can be used to treat pregnancy induced hypertensive crisis. No significant difference is found between these two agents.

Comparative study of intravenous hydralazine and labetalol in severe hypertensive disorders of pregnancy

Background: Hypertensive disorders of pregnancy are among the most common medical complications of pregnancy and major cause of maternal, fetal and neonatal morbidity and mortality. The purpose of this study was to compare the efficacy and safety of intravenous hydralazine and labetalol for management of severe hypertensive disorders of pregnancy.Methods: This prospective study was conducted among 100 women admitted with SBP ≥ 160 or DBP ≥ 110 mmHg or both. Patients were divided into 2 groups randomly: labetalol and hydralazine group.Results: Majority of patients (38%) were in the age group of 21-25 years and primigravida (52%). There was more significant decrease in the systolic, diastolic and mean arterial blood pressure at the end of 15 and 30 minutes in labetalol group. Labetalol required fewer doses as compared to hydralazine to achieve the target blood pressure (average 1.95 versus 3.1). Total numbers of term deliveries were 19 (38%) in hydralazine group and 16 (32%) in labetalol group. Pre-term deliveries in hydralazine and labetalol group were 14 (28%) and 15 (30%) respectively. Headache was significantly more common in hydralazine treated patients than labetalol group.Conclusions: Both hydralazine and labetalol were effective and well-tolerated in the treatment of severe hypertensive disorders of pregnancy. Labetalol may be preferred because it was more effective in lowering the systolic blood pressure, diastolic blood pressure and mean arterial pressure to achieve target levels with less number of doses.

Hydralazine versus Labetalol for acute control of blood pressure in patients with severe pre-eclampsia: a randomized controlled trial

Background: Authors sought to compare the effectively of intravenous hydralazine and intravenous labetalol in controlling acute rise in blood pressure in patients with severe preeclampsia.Methods: In this double-blind randomized controlled trial, all pregnant women with sustained increase in blood pressure (BP) of 160 mmHg systolic or 110 mmHg diastolic or higher were randomized to receive intravenous (IV) hydralazine 5 mg (max. 4 doses) or IV labetalol in escalating doses of 20mg, 40mg, 80mg, 80mg to achieve target blood pressure of 150 mmHg systolic and 100 mmHg diastolic or lower. The primary objective of the study was to assess the time taken to control blood pressure. Secondary agendas were the number of repeat doses required and other side effect profile.Results: In the study duration of September 2015 to September 2017, authors enrolled 60 participants for our trial. The median time taken to achieve the target blood pressure was 22.4 minutes in both the groups. Close to half of the participants did not require repeat doses (46.66% with labetalol and 50% with hydralazine). No serious maternal or foetal side effects were noted during the study. Statistical tests were performed using SPSS for Windows version 22.Conclusions: As operated in the study, the efficacy of hydralazine and labetalol to control the acute rise in blood pressure is similar.

Synthesis of hydralazine-N-lactose and its metabolites in vitro / 中国药科大学学报

Hydralazine-N-lactose is a main impurity in hydralazine tablets.Hydralazine and lactose were used as raw materials,and silica gel column and preparation column of octadecylsilane bonded silica were selected to pre pare and purify hydralazine-N-lactose.Its in vitro metabolites were identified by utilizing SD rat liver microsomes.The results of samples in vitro were compared with blank group and the resulting metabolites structures were identified by LC-MS/MS.Hydrazine-N-lactose produced six main metabolites,including s-triazolo[3,4-a] phthalazine,3-methyl-s-triazolo [3,4-a] phthalazine,3-(1-hydroxy) methyl-s-triazolo [3,4-a] phthalazine,3-hydroxymethyl-s-triazolo[3,4-a] phthalazine,hydralazine and dehydro-hydralazine-N-lactose after in vitro metabolism.This study will be valuable in hydralazine-lactose conjunctions metabolism research and hydralazine formulation safety.

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.

Inhibición de la hipertrofia ventricular izquierda, normalización de la respuesta contráctil cardíaca y estrés oxidativo en hipertensión experimental / Inhibition of Left Ventricular Hypertrophy, Normalization of the Contractile Response and Oxidative Stress in Experimental Hypertension

Introducción y objetivos: La hipertrofia ventricular izquierda secundaria a hipertensión arterial se ha interpretado como un mecanismo de protección para reducir el estrés parietal y prevenir la insuficiencia cardíaca. Sin embargo, paradójicamente, su presencia se acompaña de un incremento de la morbimortalidad cardiovascular. El presente estudio se llevó a cabo con el propósito de evaluar si el tratamiento antihipertensivo crónico inhibe el desarrollo de hipertrofia ventricular izquierda y revierte el deterioro de la respuesta betaadrenérgica cardíaca y su posible relación con cambios en el metabolismo oxidativo del miocardio. Material y métodos: Ratas macho espontáneamente hipertensas (REH, 2 meses de edad) se distribuyeron en grupos (n grupo = 18) grupo según (mg/kg, v.o.): losartán 30 (L), hidralazina 11 (H), rosuvastatina 10 (R), carvedilol 20 (C), agua (control tratamiento). Control hipertensión: 18 ratas normotensas (Wistar-Kyoto, WKY). Periódicamente se registraron la presión arterial sistólica (PAS) (pletismografía, en animales despiertos) y el peso corporal (PC). Luego de 16 meses se practicó eutanasia. El 50% de los corazones se montaron en preparación de Langendorff para medir contractilidad preestímulo y posestímulo betaadrenérgico [isoproterenol (Iso): 10-9M, 10-7M, 10-5M]. En los corazones restantes se registró el peso del ventrículo izquierdo (PVI), que se normalizó por el PC. Se cuantificó la expresión inmunohistoquímica de tiorredoxina 1(Trx-1), peroxirredoxina 2 (Prx-2) y glutarredoxina 3 (Grx-3) (indicadores antioxidantes). Resultados: Peso corporal: similar en todos los grupos. PAS (mm Hg): 154 ± 3 (L), 137 ± 1 (H), 190 ± 3 (R)**, 206 ± 3 (REH)*, 183 ± 1 (C)**, 141 ± 1 (WKY) (*p < 0,05 vs. L, H, WKY; **p < 0,05 vs. L, H, WKY, REH). El PVI/PC de REH y R fue mayor (p < 0,05) respecto de L, H, C y WKY. En C no se observó correlación entre hipertensión e hipertrofia ventricular izquierda. Grupos REH, R y C: mostraron depresión de contractilidad basal vs. L, H y WKY. Respuesta a Iso 10-5 M: similar en WKY y L; disminuida en C, H, R y REH. Expresión de Trx-1, Prx-2 y Grx-3: aumentó en C, H, R y L (1,5-2 veces promedio; p < 0,01 vs. REH y WKY). Conclusiones: El tratamiento con losartán, hidralazina y carvedilol previno el desarrollo de hipertrofia ventricular izquierda. El losartán normalizó la respuesta al isoproterenol en REH. Factores adicionales participarían en el desarrollo de hipertrofia ventricular izquierda con deterioro de la respuesta inotrópica a la estimulación betaadrenérgica en hipertensión. El aumento en la expresión de tiorredoxinas por tratamientos antihipertensivos sugiere un beneficio asociado, aumentando la respuesta antioxidante frente al estrés oxidativo en hipertensión.

Background and objectives: Left ventricular hypertrophy secondary to hypertension has been perceived as a protective mechanism to reduce wall stress and prevent heart failure. However, its presence is paradoxically associated with increased cardiovascular morbidity and mortality The aim of this study was to evaluate whether chronic antihypertensive treatment inhibits the development of left ventricular hypertrophy and normalize the reverting impaired cardiac beta-adrenergic response, and its possible association with changes in myocardial oxidative metabolism. Methods: Spontaneously hypertensive male rats (SHR, 2 months old) were divided into groups (n grupo = 18) according to (mg/ group kg, p.o): losartan 30 (L), hydralazine-11 (H), rosuvastatin 10 (R), carvedilol 20 (C), and water (control treatment). The control hypertension group consisted of 18 normotensive rats (Wistar-Kyoto, WKY). Systolic blood pressure (SBP) (plethysmography in awake animals) and body weight (BW) were measured periodically. The animals were sacrificed at 16 months and 50% of the hearts were mounted in a Langendorff system to measure contractility before and after beta-adrenergic stimulation [isoproterenol (Iso): 10-9 M, 10-7 M, and 10-5 M]. In the remaining hearts left ventricular weight (LVW) was measured and normalized by B W. Immunohistochemical expression of thioredoxin 1 (Trx-1), peroxyredoxin 2 (Prx-2) and glutaredoxin 3 (Grx-3) (antioxidant indicators) was quantified. Results: Body weight was similar in all groups. Systolic blood pressure (mm Hg) was 154 ± 3 (L), 137 ± 1 (H), 190 ± 3 (R)**, 206 ± 3 (SHR)*, 183 ± 1 (C)**, and 141 ± 1 (WKY) (* p < 0.05 vs. L, H, WKY, ** p < 0.05 vs. L, H, WKY, SHR). LVW/BW was higher in SHR and R (p < 0.05) compared with L, H, C and WKY. In C, there was no correlation between hypertension and left ventricular hypertrophy. SHR, R and C evidenced baseline contractile depression vs. L, H and WKY. The response to 10-5 M Iso was similar in WKY and L, and reduced in C, H, R and SHR. The expression of Trx-1, Prx-2 and Grx-3 increased in C, H, R and L (average increase: 1.5-2 times; p < 0.01 vs. SHR and WKY). Conclusions: Treatment with losartan, hydralazine, and carvedilol prevented the development of left ventricular hypertrophy. Losartan normalized the response to isoproterenol in SHR. Additional factors might participate in the development of left ventricular hypertrophy with impaired inotropic response to beta-adrenergic stimulation in hypertension. The increased ex-pression of thioredoxins as a result of antihypertensive treatment suggests an additional benefit, increasing the antioxidant response against oxidative stress in hypertension.

Effects of Hydralazine and 5-Aza-CdR on cell proliferation of human osteosarcoma cell line MG-63 and expression of gene WW domain-containing oxidoreductase / 中华骨科杂志

Objective To investigate the growth inhibition of human osteosareoma cell line(MG-63) intervened by Hydralazine and 5'-aza-2'-deoxycytidine (5-Aza-CdR),and the effect on the mRNA expression of gene WW domain-containing oxidoreductase (WWOX).Methods Certain volume of 5 × 104/ml of human osteosarcoma cell line MG-63 in logarithmic growth phase were added into 96-well plate.There were Hydralazine group (drug concentration,0.1,1.0,10 μmol/L),5-Aza-CdR group (drug concentration,5,10,20 μmol/L),Hydralazine combined with 5-Aza-CdR group (drug concentration,0.1 μmo/L + 5 μmol/L,1.0 μmol/L + 10 μmol/L,10 μmol/L + 20 μmol/L) and control group (culture medium).Methyl thiazol tetrazolium(MTT) colorimetric methods were used to test the growth inhibition of MG-63 cells intervened by different concentrations of Hydralazine and 5'-aza -2'-deoxycytidine (5-Aza-CdR).Flow cytometry AnnexinV-FITC/PI methods were used to assay the effects of Hydralazine and 5-Aza-CdR inducing apoptosis in osteosarcoma cells in vitro.Real-time polymerase chain reaction (Real-Time PCR)methods were used to detect amplification of WWOX mRNA induced by Hydralazine combined with 5-Aza-CdR or alone.Western-blotting methods were used to examine the expression of WWOX in MG-63 cells.Results Hydralazine and 5-Aza-CdR effectively inhibited the growth of MG-63 cells in a concentration and time-dependent manner.Combined effect was more obvious.Further more the expression levels of WWOX mRNA and protein were increased significantly in combined groups as compared with other groups.Conclusion Hydralazine and 5-Aza-CdR could effectively inhibit the proliferation of MG-63 cells and induce apoptosis which is concurrent with the promotion of the expression of WWOX.The mechanism may be that Hydralazine/5-Aza-CdR effectively cause the demethylated of WWOX gene CpG-rich promoter regions,leading to the high expression of WWOX and inhibit the growth of MG-63 cells.The use of hydralazine in the treatment of osteosarcoma is worthy of further investigation.

Hipertrofia miocárdica induzida por consumo elevado de sal na dieta: avaliação do sistema renina-angiotensina e do efeito da N-acetilcisteína / Cardiac hypertrophy induced by high salt diet: renin-angiotensin system and N-acetylcysteine effect

As doenças cardiovasculares são a maior causa de morte no mundo e entre essas doenças, a hipertrofia cardíaca (HC) tem se destacado especialmente por ser um fator de risco de insuficiência cardíaca. A HC é um fenômeno que acompanha a hipertensão arterial e no qual se observa aumento de proteínas estruturais e contráteis dos cardiomiócitos, havendo muitas vezes concomitantemente aumento do colágeno intersticial. Fatores independentes da pressão arterial também podem contribuir para o desenvolvimento da hipertrofia cardíaca. Dentre estes fatores, a sobrecarga de sal na dieta tem se destacado. Diversos estudos comprovam o efeito hipertrófico do sal. Em modelos animais onde se estudou sobrecarga de sal, não foi detectado aumento da atividade de renina plasmática, sugerindo que o sistema renina-angiotensina aldosterona (SRA) circulante pode não estar envolvido no desenvolvimento da hipertrofia cardíaca. Apesar de alguns estudos tentarem elucidar o papel do sal no desenvolvimento da hipertrofia ventricular esquerda, os mecanismos pelo qual o sal atua ainda não estão totalmente esclarecidos. Neste contexto, o objetivo do presente estudo é observar os fenômenos que ocorrem no ventrículo esquerdo em resposta a sobrecarga de sal na dieta na tentativa de elucidar sua fisiopatologia. Para tanto, ratos Wistar machos foram divididos em cinco grupos de acordo com a dieta (normossódica 1,26% e hipersódica 8% de NaCl) e com o tratamento (losartan, cloridrato de hidralazina ou N-acetilcisteína). Foi avaliada a evolução ponderal, pressão arterial caudal, medida do diâmetro transverso do cardiomiócito, fibrose intersticial, expressão gênica e proteica dos componentes do SRA, dosagem de aldosterona sérica e cardíaca, dosagem de TBARS cardíaco, concentração de angiotensina II e estado conformacional dos receptores AT1 e AT2. Os principais resultados observados foram: o aumento do consumo de ração (com elevada concentração de NaCl) do grupo HS+NAC e consequente aumento na...

Cardiovascular diseases are the leading cause of death worldwide and among these diseases, the cardiac hypertrophy (CH) has been highlighted, especially as an important risk factor for developing heart failure. The CH is a phenomenon that accompanies hypertension and in which there is increased structural and contractile proteins in cardiomyocytes, with often concomitant increase of interstitial collagen. Blood pressure independent risk factors can also contribute to the development of cardiac hypertrophy. Among these factors, the high salt intake has been outstanding. Several studies confirm the hypertrophic effect of salt. In animal models submitted to salt overload, no increase in plasma renin activity was observed, suggesting that the renin-angiotensin (RAS) circulating system may not be involved in the development of cardiac hypertrophy. Although some studies attempting to elucidate the role of salt in the development of left ventricular hypertrophy, the mechanisms by which salt acts are not yet fully understood. In this context, the objective of this study is to observe the phenomena occurring in the left ventricle in response to dietary salt overload in an attempt to elucidate its pathophysiology.Male Wistar rats were divided into five groups according to their diet (1.26% and 8% NaCl) and treatment (losartan, hydralazine or N-acetylcysteine). We evaluated the body weight, tail-cuff blood pressure, the transverse diameter of the cardiomyocyte, interstitial fibrosis, gene and protein expression of RAAS components, serum and cardiac aldosterone dosage, cardiac TBARS, angiotensin II concentration and binding of conformation-specific anti-AT1 and anti-AT2 antibodies. The main results were: increased food intake (with high NaCl content) in the HS + NAC group and consequent increase in blood pressure and body weight; developing blood pressure-independent CH in the HS + HZ group partial or total prevention of such hypertrophy by treatment with losartan and...

Floating tablets of hydralazine hydrochloride: optimization and evaluation

Hydralazine hydrochloride has a half-life of 2 to 4 hours with an oral bioavailability of 26-50%. Since hydralazine has a demethylating effect on various suppressor genes, it can be used in various types of cancer to support chemotherapy. The purpose of this study was to optimize and evaluate floating tablets of hydralazine hydrochloride designed to prolong the gastric residence time and to provide controlled release of the drug for 14 h. The floating tablets of hydralazine hydrochloride were prepared by the wet granulation method. Semi-synthetic polymers of hydroxy propyl methyl cellulose (HPMC K100M) and ethyl cellulose were used as the release retarding agents. A 2² factorial design was applied to systematically optimize the drug release profile. The concentrations of HPMC K100M and ethyl cellulose were optimized to provide controlled release of hydralazine for 14h. Non-Fickian diffusion release transport was confirmed as the release mechanism for the optimized formulation and the predicted values agreed well with the experimental values. Drug excipient compatibility studies were investigated by FTIR, DSC and XRD. These data indicate that there were no chemical interactions between the drug and the polymer. In vivo X-ray imaging showed floating tablet performance in rabbits.

O cloridrato de hidralazina apresenta meia-vida de 2 a 4 horas, com biodisponibilidade oral de 26-50%. Uma vez que a hidralazina possui efeito desmetilante em vários genes supressores, ela pode ser utilizada para diversos tipos de câncer, em apoio à quimioterapia. O objetivo deste estudo foi o de avaliar e otimizar comprimidos flutuantes de cloridrato de hidralazina, planejados para prolongar o tempo de residência gástrica e proporcionar liberação controlada do fármaco por 14 h. Os comprimidos flutuantes de cloridrato de hidralazina foram preparados pelo método de granulação úmida. Polímeros semi-sintéticos de hidroxipropiletil celulose (HPMCK100M) e acetato de celulose foram utilizados como agente de retardamento de liberação. Aplicou-se planejamento fatorial 2² para otimizar sistematicamente o perfil de liberação do fármaco. As concentrações de HPMCK100M e de etilcelulose foram otimizadas para se obter liberação controlada de hidralazina durante 14 h. O transporte de liberação de difusão não-Fickiana foi confirmado como o mecanismo de liberação para a formulação otimizada e os valores previstos estiveram de acordo com os valores experimentais. Estudos de compatibilidade entre fármaco e excipiente foram realizados por FTIR, DSC e DRX. Estes dados indicaram que não havia interação química entre o fármaco e o polímero. Imagens de raios-X in vivo mostraram o desempenho dos comprimidos flutuantes em coelhos.

Effect of estrogen, hydralazine and ultraviolet ray on DNA methyltransferase-1 activity in patients with systemic lupus erythematosus / 中华皮肤科杂志

Objective To explore the mechanism underlying the induction of systemic lupus erythematosus (SLE) by estrogen, hydralazine and ultraviolet irradiation. Methods Peripheral blood mononuclear cells (PBMCs) were harvested from 10 patients with SLE and 9 normal human controls, and cultured with or without the intervention with estrogen, hydralazine or ultraviolet irradiation. The DNA methyltransferase-1 (DNMT1) activity of PBMCs was quantified by using DNMT activity/inhibition assay kit. Results No statistical difference was observed in DNMT1 activity between patients with SLE and normal controls (0.36 ± 0.24 vs 0.46 ± 0.17, P ＞ 0.05). A significant decrease was noted in DNMT1 activity in PBMCs from patients with SLE after intervention with estrogen (0.32 ± 0.18 vs 0.46 ± 0.17, t = 1.725, P ＜ 0.05), hydralazine (0.33 ±0.13 vs 0.46 ± 0.17, t = 1.739, P ＜ 0.05) and ultraviolet irradiation (0.30 ± 0.14 vs 0.46 ± 0.17, t = 1.739,P ＜ 0.05 ) compared with that from normal human controls. The treatment with hydralazine also induced an attenuation of DNMT1 activity in PBMCs from normal human controls (0.38 ± 0.12 vs 0.46 ± 0.17, P＜ 0.05).Conclusion Estrogen, hydralazine and ultraviolet irradiation can inhibit the DNMT1 activity of SLE patients,indicating that they may induce the initiation of SLE by altering the activity of DNMT1.

Estados hipertensivos del embarazo en adolescentes, hospital maternidad Enrique C. Sotomayor, año 2004 / Hypertensive states of pregnancy in adolescents at the maternity hospital Enrique C. Sotomayor in 2004

Estudio realizado en el hospital-maternidad “Enrique C. Sotomayor” en pacientes adolescentes que se diagnosticó hipertensión arterial, año 2004. Tipo de estudio: retrospectivo descriptivo. Objetivo: conocer la incidencia y resultantes materno-neonatales que nos lleve a controlar esta patología. Metodología: análisis de historias clínicas en pacientes adolescentes e hijos de las mismas, atendidos en el hospital-maternidad, año 2004. Resultados: hubo 146 casos (10,6 de embarazadas), con predominio de preeclampsia severa; promedio de edad: 16 años; la desproporción cefalopélvica y distocias de presentación fueron los defectos más comunes; al 96 se le realizó cesárea, las presiones arteriales se normalizaron 8 horas posparto. Neonatos: fue en 85 aptos para la edad gestacional; y fallecieron el 4. Conclusiones: a pesar de la gran cantidad de casos, se ha logrado controlarlos en casi su totalidad con rápido diagnóstico y eficaz terapéutica a través de cesáreas e hidralazinaStudy carried out at the maternity hospital “Enrique G. Sotomayor” in adolescent patients who were diagnosed arterial hypertension in 2004.

Study type: retrospective and descriptive. Objective: identify the incidence and maternal-neonatal results which could help us control this pathology. Methodology: analyses of clinical history in adolescent patients and their children attended at the maternity hospital in the year 2004. Results: there were 146 cases (10.6 of pregnant women), in whom severe preeclampsia was predominant; average age: 16 years old; cephalopelvic disproportion and presentation dystocias were the most common defects (96). They had a cesarean section. Arterial pressures were normalized 8 hours after delivery. Neonates: 85 were appropriate for gestational age; and 4 passed away. Conclusions: despite the big amount of cases, almost all of them were under control through fast diagnosis and efficient therapy of cesarean section and hydralazine.

Effects of hydralazine on NaIO3-induced rat retinal pigment epithelium degeneration / 国际眼科杂志(Guoji Yanke Zazhi)

·AIM: To study the effects of 10g/L hydralazine eye drops on 35mg/kg NaIO3-induced degeneration in rat eyes. · METHODS: Various doses of NalO3 and/or saline alone were injected into Brown Norway rats from hypoglossal vein. After 3, 7, 14 or 28 days of injection, ERG a-, b-, c- wave, fast oscillation (FO) and light peak (LP) were measured along with retinal colored pictures and fluorescein angiography taken. Some rats were chosen to study the histology of retinas by light microscopy and autofluorescence of retina flatmounts. Different concen- trations of NaIO3 were given to RPE-19 cells, and cell proliferation rate was measured. For hydralazine study, 35mg/kg NaIO3 was injected into Brown Norway rat from hypoglossal vein. NaIO3 group was treated with saline alone after NaIO3 injection, 10g/L hydralazine + NaIO3 group was treated with 10g/L hydralazine eyedrops after NaIO3 injection whereas normal group was treated with saline alone without NalO3 injection. All eyedrops were instilled locally 3 times a day for 4 weeks and ERG c-wave was measured at the end of 2 and 4 weeks.· RESULTS: After NaIO3 administration, the amplitude of all ERG waves fell markedly in large dose groups at 30, 40 or 60mg/kg NaIO3. Not many changes were observed in groups treated with < 30mg/kg NaIO3. Some retinal necrosis appeared from 3 days post-injection (PI) in 30mg/kg NaIO3 group, which became more serious in larger dose groups or longer treatment time, but no apparent change was found in smaller dose groups. Similarly, on the retina flatmount, RPE monolayer showed necrosis from 3 days PI in the 30mg/kg NaIO3 and larger dose groups. On histological examination, no significant change was seen in 30mg/kg NaIO3 and lower concentration groups. In cell culture experiment, changes were found in RPE-19 cells proliferation rate with a concentration of NaIO3 at 30mg/L or higher. In hydralazine experiments, 4 weeks after injection of NaIO3, ERG c-wave fell markedly in NaIO3 group to 31% of control group (P < 0.01). The ERG c-wave of hydra- lazine + NaIO3 group fell only to 50% of control group (P<0.05). This was a 61% reversal of the c-wave of NaIO3 treated group. · CONCLUSION: RPE degeneration induced by NaIO3 was both dose and time dependent. Around 30 to 40 mg/kg NaIO3 would be the optimal to be used as a non-exudative age-related macular degeneration rat model. Hydralazine may postpone the development of non-exudative age- related macular degeneration.

Effects of hydralazine on ocular blood flow and laser-induced choroidal neovascularization / 国际眼科杂志(Guoji Yanke Zazhi)

·AIM: To investigate the effect of hydralazine on choroidal blood flow in rabbits and laser-induced choroidal neovascularization (CNV) in rats and the effect of hydralazine on tube formation of human umbilical vein endothelial cells (HUVEC).used with raised intraocular pressure (IOP) of the left eye to 40mmHg.Hydralazine (10g/L) eye drops were instilled and ocular blood flow was measured with colored microspheres technique. Male Brown Norway rats were treated with Nd: YAG laser to break Bruch's membrane. Hydralazine (5, 10, 20g/L) eye drops or saline alone was instilled three times a day for 4 weeks after laser treatment. Fluorescein angiography (FA) and choroidal flat mount were used to measure the area of CNV. Tube formation of HUVEC was studied at different concen-trations of hydralazine.hydralazine eye drops enhanced the choroidal blood flow significantly at 30 and 60 minutes after drug instillation. After 4 week of drug treatment, 5, 10 and 20g/L hydralazine eye drops all reduced the CNV formation dramatically measured by fluorescein angiography and choroidal flat mount. When HUVEC was cultured on matrix gel for 48 hours, hydralazine at 3-30mg/L preven-ted the tube formation.vivo and HUVEC tube formation in vitro, and enhanced rabbits' choroidal blood flow after ischemia. It is hoped that hydralazine could be used to treat age-related ma-cular degeneration in the future.

Effect of Hydralazine on the methylation of APC in cervical carcinoma cell lines / 基础医学与临床

Objective To detect 5′CpG island methylation of APC(adenomatous polyposis coli) gene promoter region in cervical carcinoma cell lines (HeLa,CaSki,SiHa), and to investigate the possibility of Hydralazine in restoring the expression of APC gene through demethylation. Methods The CpG island methylation status of APC gene promoter region of the cervical carcinoma cell lines were analyzed using methylated specific polymerase chain reaction (MSP). The mRNA expression profile of APC gene was analyzed by using RT-PCR after Hydralazine treatment. Results The CpG island of APC gene was methylated in HeLa and hemimethylated in CaSki but not in SiHa. The mRNA expression of APC gene can be detected after hydralazine treatment. Conclusion The APC gene non-expression in cervical carcinoma is associated with CpG island methylation in APC gene promoter region. Hydralazine, served as a demethylating agent, enables to restore the expression of APC gene.

Effects of Hydralazine Pretreatment on Esmolol-induced Controlled Hypotension during Spine Surgery / 대한마취과학회지

BACKGROUND: Controlled hypotension improves surgical field and decreases transfusion requirement in surgical patients and can be induced with various kinds of drugs including esmolol and hydralazine. METHODS: This study examined the effect of a combination of esmolol and hydralazine as hypotensive agents in spine surgery. In the esmolol group (n = 15), after boluses of esmolol (0.5 mg/kg) injection, esmolol was infused to maintain the mean arterial pressure of 55-65 mmHg. In the hydralazine-esmolol group (n = 15), hydralazine (0.3 mg/kg) was administered 15 minutes before esmolol injection which was done in the same way as that of the esmolol group. RESULTS: The mean arterial pressure decreased to the target range more rapidly in the hydralazine-esmolol group. The heart rate was increased by hydralazine, but reduced by esmolol. The cardiac output remained elevated after hydralazine injection in the hydralazine-esmolol group, and decreased significantly by esmolol in the esmolol group. The administered dose of esmolol was much less in the hydralazine-esmolol group than in the esmolol group. CONCLUSIONS: Our data suggest that hydralazine can enhance the efficacy of esmolol-induced controlled hypotension. It can reduce the requirement of esmolol and maintain a higher cardiac output during hypotension.

Difference of Jugular Bulb Oxygen Saturation under Propofol, Enflurane and Isoflurane Anesthesia with Hydralazine-induced Deliberate Hypotension / 대한마취과학회지

BACKGROUND: Hydralazine produces cerebral vasodilation, which could appear differently according to which kind of anesthetics was used. SjO2, CBF and AJDO2 have been studied during general anesthesia with enflurane, isoflurane or propofol in 42 patients undergoing spinal surgery. METHODS: Forty-two healthy adult patients were divided into Group P (Propofol-N2O, n = 15), Group E (Enflurane-N2O, n = 15) and Group I (Isoflurane-N2O, n = 12). During the course of the study, the anesthetic concentration was constant. Induced hypotension was provided with hydralazine 20 mg in combination with a continuous infusion of esmolol within 50 - 100ng/kg/min. Arterial blood and jugular bulb blood were obtained and analyzed at normotensive and hypotensive period, respectively. SjO2, was compared within and between groups. RESULTS: SjO2 values of Group P were 66.2 +/- 7.7%, and 81.5 +/- 6.1%, those of Group E were 79.5 +/- 5.6%, and 78.9 +/- 4.9% and those of Group I were 82.0 +/- 6.2%, and 84.4 +/- 3.7% at normotension and hypotension, respectively (P < 0.05 between Group P and Group E, P < 0.05 between Group P and Group I, P < 0.05 within Group P). CONCLUSIONS: When the changes of CBF is assumed with that of SjO2, it may be concluded that CBF increased with hydralazine-induced hypotension in propofol-N2O anesthesia. It may be suggested that hydralazine reverses propofol induced cerebral vasoconstriction.