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The intravenous pharmacotherapy of critically ill patients is extremely challenging due to the high number of drugs administered. We therefore evaluated the physicochemical compatibility of combinations of clonidine with drugs frequently used in an intensive care unit setting. Amiodarone, dihydralazine, furosemide, levosimendan, metamizole, milrinone, urapidil, and verapamil were each prepared as binary combinations with clonidine at the standard low and high administration concentrations. Selected ternary combinations were also analyzed. Samples were examined for physical compatibility. To verify chemical compatibility in samples deemed either physically compatible or to exhibit uncertain results, the drug content was quantified using high-performance liquid chromatography. Admixtures of clonidine with amiodarone or furosemide proved to be physically incompatible, whereas mixtures with levosimendan and metamizole exhibited results, which were not clearly meeting the specification criteria for physical compatibility. Binary combinations of clonidine with dihydralazine, milrinone, urapidil, and verapamil were found to be physically compatible. Combinations with dihydralazine, levosimendan, metamizole, milrinon, urapidil, or verapamil were chemically compatible for the analyzed concentrations. Ternary admixtures of clonidine, metamizole, and urapidil, clonidine, metamizole, and verapamil, clonidine, urapidil, and verapamil were shown to be physicochemically compatible for the analyzed concentrations. These data suggest that clonidine can be coadministered with dihydralazine, levosimendan, metamizole, milrinone, urapidil, and verapamil. However, the concomitant administration of clonidine with amiodarone or furosemide is not recommended.

The pharmacotherapy of critically ill patients is challenging due to the variety of drugs that have to be applied. As the majority of pharmaceuticals must be administered intravenously because of the critical condition of the patients, the compatibility of co-applied intravenous drugs is crucial for a safe and successful infusion therapy. Antihypertensive therapy was reported by health care professionals to be ineffective in association with concomitant application of dihydralazine and metamizole (dipyrone). As both drugs are administered in German intensive care units, we analyzed their compatibility, examined the mechanisms of underlying dihydralazine degradation, and identified reaction products of dihydralazine and metamizole. Binary combinations were prepared at the high and the low end of the nominal administration concentration. Validated high performance liquid chromatography/ultraviolet absorption (HPLC-UV) analysis was conducted to quantify drug amount and high performance liquid chromatography/mass spectrometry (HPLC-MS) was used to analyze degradation products. The combinations of dihydralazine and metamizole proved to be incompatible as dihydralazine concentration decreased immediately and considerably. Metamizole also slightly decreased over time. Specific degradation products of dihydralazine were identified and a degradation pathway was postulated. Our findings demonstrate that the intravenous co-administration of dihydralazine and metamizole should be strictly avoided due to the incompatibility of these two drugs.

Aims Several antihypertensive drugs are used in the treatment of severe hypertension in pregnancy. The present study is a network meta-analysis comparing the efficacy and safety of these drugs. Methods Electronic databases were searched for randomized clinical trials comparing drugs used in the treatment of severe hypertension in pregnancy. The number of women achieving the target blood pressure (BP) was the primary outcome. Doses required and time taken for achieving the target BP, failure rate, and incidences of maternal tachycardia, palpitation, hypotension, headache, and neonatal death and stillbirth were the secondary outcomes. Mixed treatment comparison pooled estimates were generated using a random-effects model. Odds ratios for the categorical and mean difference for the numerical outcomes were the effect estimates. Results Fifty-one studies were included in the systematic review and 46 in the meta-analysis. No significant differences in the number of patients achieving target BP was observed between any of the drugs. Diazoxide [-15 (-20.6, -9.4)], nicardipine [-11.8 (-22.3, -1.2)], nifedipine/celastrol [-19.3 (-27.4, -11.1)], nifedipine/vitamin D [-17.1 (-25.7, -9.7)], nifedipine/resveratrol [-13.9 (-22.6, -5.2)] and glyceryl trinitrate [-33.8 (-36.7, -31)] were observed to achieve the target BP (in minutes) more rapidly than hydralazine. Nifedipine required fewer doses than hydralazine for achieving the target BP. Glyceryl trinitrate and labetalol were associated with fewer incidences of tachycardia and palpitation respectively than hydralazine. Trial sequential analysis concluded adequate evidence for hydralazine and nifedipine compared with labetalol. Moderate quality of evidence was observed for direct comparison estimate between labetalol and hydralazine but was either low or very low for other comparisons. Conclusion The present evidence suggests similar efficacy between nifedipine, hydralazine and labetalol in the treatment of severe hypertension in pregnancy. Subtle differences may exist in their safety profile. The evidence is inadequate for other drugs.

Drug–drug interactions (DDIs) can occur when one drug alters the metabolism of another drug. Drug metabolism mediated by cytochrome P450 enzymes (CYPs) is responsible for the majority of metabolism of known drugs and inhibition of CYP enzymes is a well-known cause of DDIs. In the current study, the use of various human liver microsomes (HLM)-based methods to determine occurrence of CYP-mediated metabolism-dependent inhibition (MDI) and possible follow-up studies were evaluated. Human CYP inhibition was studied using the following methodologies: direct inhibition and (non-diluted) IC50-shift assays, a ferricyanide-based reversibility assay, a spectrophotometric metabolic intermediate complex (MIC) assay, and recording of reduced carbon monoxide (CO)-difference spectra. HLM incubations in the presence and absence of NADPH and glutathione (GSH) were performed to study the possible formation of CYP-dependent GSH adducts. HLM incubations with the radiolabeled inhibitors mifepristone and paroxetine were performed to study CYP-mediated covalent binding. Dihydralazine and furafylline displayed irreversible MDI of CYP1A2. Paroxetine displayed both quasi-irreversible and irreversible MDI of CYP2D6, formation of CYP-dependent GSH adducts was observed, while CYP-mediated covalent binding occurred which was decreased in the presence of GSH. Mifepristone displayed irreversible MDI of CYP3A4, formation of CYP-dependent GSH adducts was observed, while CYP-mediated covalent binding occurred which was decreased in the presence of GSH. Troleandomycin and verapamil displayed quasi-irreversible MDI of CYP3A4; MIC formation was observed, while no formation of CYP-dependent GSH adducts occurred. This study gives a representative overview of current methodologies that can be used to study CYP inhibition. The here presented strategy can be applied as a tool during risk evaluation of CYP-mediated DDIs.

Indapamide and dihydralazine can be combined in fixed-dose formulations because of their complementary actions against hypertension. On the other hand, combined formulations present the problem of chemical interactions between the active ingredients, e.g. accelerated degradation of constituents or generation of quite new degradation products. Therefore, the main goal of the present study was to examine the chemical stability of indapamide and dihydralazine, as individuals and as a mixture, to detect potent interactions between both constituents, using FT-IR, HPLC and LC-MS methods. It was clearly shown that both drugs degraded more when they were in the mixture, i.e. indapamide was degraded more under high temperature/high humidity while dihydralazine was more sensitive to UV/VIS light. In solutions, indapamide was sensitive to strong acidic and strong alkaline conditions while dihydralazine degraded at pH ≥ 7. Generally, the process of degradation of indapamide and dihydralazine followed first order kinetics. The fastest degradation of both indapamide and dihydralazine was found at pH ≥ 10. Several degradation products of indapamide and dihydralazine were detected and identified by our LC-MS method. Interactions between both drugs were confirmed by detection of new degradation products of indapamide, i.e. 4-chloro-3-sulfamoylbenzamide and 4-chloro-3-(formylsulfamoyl)-N-(2-methyl-2,3-dihydro-1H-indol-1-yl)benzamide, only in the presence of dihydralazine.

The famous weak chemiluminescence (CL) system of potassium permanganate and sodium bisulfite (KMnO 4 -HSO 3 − ) was enhanced by the hollow fluorescent carbon nanodots (HCNs). The investigation of mechanism revealed that the enhanced CL was induced by the excited-state HCNs (HCNs ⁎ ), which could be produced from the electron-transfer annihilation of positively charged HCNs (HCNs + ) and negatively charged HCNs (HCNs − ) as well as by CL resonance energy transfer (CRET) from excited SO 2 (SO 2 ⁎ )/ 1 O 2 to HCNs. The dihydralazine sulfate (DHZS) had a diminishing effect on the CL of HCNs-KMnO 4 -HSO 3 − system due to the competitive consumption of O 2 − . Under the optimal conditions, the reduced CL signal with the concentration of DHZS was linear in the range of 1.0 × 10 − 7 –7.0 × 10 − 5 mol/L with a detection limit of 3.0 × 10 − 8 mol/L. The relative standard deviation for seven repeated determination of 5.0 × 10 − 6 mol/L DHZS was 2.1%. The established method was applied to the determination of DHZS in pharmaceutical preparations, human urine and plasma samples with good precision and accuracy.

Introduction: Severe preeclampsia is one of the most serious pathologies during pregnancy, with heavy morbidity and maternal-fetal mortality. The aim of our study was to help improve the management of severe preeclampsia. Methods: We conducted a cross-sectional analytical study from 1st September 2015 to 30th August 2016, at the Obstetrics and Gynecology Department of the Hopital communautaire of Bangui. The study population was pregnant and parturient patients with severe pre-eclampsia. Results: Out of 4021 registered cases, 41 met the inclusion criteria, with a prevalence of 1.0%. The primiparous were the most represented (48.8%). Magnesium sulfate was the most used as an anticonvulsant (70.7%) and dihydralazine was the most used for the High Blood Pressure (HBP). The main complications of pre-eclampsia were eclampsia (29.3%) and acute renal failure (19.5%). Overall, maternal mortality was 9.8% and perinatal mortality was 31.7%. Conclusion: The complications of severe preeclampsia are common in our study. The maternal and fetal prognosis remains a concern. Hence, we suggest early screening of pre-eclampsia symptoms during prenatal consultations to improve pregnancy outcome.

Dihydralazine and hydrochlorothiazide were stored at high temperature and humidity, under UV/Vis light and different pH, as individual drugs and the mixture. Then, a sensitive and selective HPLC-UV method was developed for simultaneous determination of dihydralazine and hydrochlorothiazide in presence of their degradation products. Finally, the degradation products were characterized through LC-DAD and LC–MS methods. Dihydralazine was sensitive to high temperature and humidity, UV/Vis light and pH ≥ 7. At the same time, it was resistant to acidic conditions. Hydrochlorothiazide was sensitive to high temperature and humidity, UV/Vis light and changes in pH. Its highest level of degradation was observed in 1 M HCl. Degradation of the drugs was higher when they were stressed in the mixture. In the case of dihydralazine, the percentage degradation was 5–15 times higher. What is more, dihydralazine became sensitive to acidic conditions. Hydrochlorothiazide was shown to be more sensitive to UV/Vis light and pH > 4. Degradation of dihydralazine and hydrochlorothiazide followed first-order kinetics. The quickest degradation of dihydralazine was found to be in 1 M NaOH while of hydrochlorothiazide was in 1 M HCl (individual hydrochlorothiazide) or at pH 7–10 (hydrochlorothiazide in the mixture). A number of new degradation products were detected and some of them were identified by our LC-DAD and LC–MS methods. In the stressed individual samples, (phenylmethyl)hydrazine and 1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide were observed for the first time. Interactions between dihydralazine and hydrochlorothiazide in the mixture were confirmed by additional degradation products, e.g., 2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1,4-trioxide.

Objective Determine the definitive position of ketanserin and dihydralazine for treatment of severe hypertension in pregnancy. Study design A single centre double blind randomized controlled trial was performed at the obstetrical tertiary high care unit of the University Medical Centre in Rotterdam, the Netherlands. Women with severe hypertension in pregnancy (diastolic blood pressure (DBP) ≥ 110 mmHg), and significant proteinuria (≥300 mg/24 h), and gestational age ≤ 32 weeks were eligible for the study. All patients ( n = 30) received two infusions (double dummy technique): one contained the active ingredient (ketanserin or dihydralazine), the other was used for placebo. Nicardipine was used as rescue medication. The main outcome measures were persistent severe hypertension (DBP > 100 mmHg > 120 min) despite maximum dosage of study medication and prolongation of pregnancy. Results Dihydralazine was significantly more effective in lowering blood pressure than ketanserin. No significant difference in prolongation of pregnancy was seen between the two groups. After 30 inclusions, the study was stopped because of the high rate of persistent hypertension using ketanserin and the high rate of maternal side effects using dihydralazine and the apparent succesful use of the rescue drug nicardipine. Conclusions Our results do not support the use of either dihydralazine or ketanserin for the treatment of severe hypertension in pregnancy. Future research is needed to compare nicardipine with other antihypertensive drugs currently in use for treatment of severe hypertension in pregnancy.

Progression of chronic kidney disease remains a principal problem in clinical nephrology and there is a pressing need for novel therapeutics and biomarkers. Aberrant promoter CpG island methylation and subsequent transcriptional silencing of specific genes have emerged as contributors to progression of chronic kidney disease. Here, we report that transcriptional silencing of the Ras-GTP suppressor RASAL1 contributes causally to progression of kidney fibrosis and we identified that circulating methylated RASAL1 promoter DNA fragments in peripheral blood correspond with levels of intrarenal levels of RASAL1 promoter methylation and degree of fibrosis in kidney biopsies, enabling non-invasive longitudinal analysis of intrarenal CpG island methylation. Retrospective analysis of patients with hypertensive nephrosclerosis revealed that circulating methylated RASAL1 promoter DNA fragments in peripheral blood decrease with Dihydralazine treatment in patients with hypertensive nephrosclerosis, and provided evidence that low-dose Dihydralazine delays decline of excretory kidney function, whereas Dihydralazine at standard doses had no protective effect. We demonstrate that the protective effect of Dihydralazine is due to induction of endogenous Tet3/Tdg-mediated DNA-de-methylation activity reversing aberrant promoter CpG island methylation, while HIF1α induction at standard doses counterbalances its protective activity. We conclude that RASAL1 promoter methylation is a therapeutic target and a biomarker of renal fibrosis. Our study suggests that therapeutic use of low-dose Dihydralazine in patients with chronic kidney disease and fibrosis deserves further consideration., Highlights • Aberrant RASAL1 promoter methylation contributes causally to progression of kidney fibrosis. • Degree of intrarenal RASAL1 methylation is reflected by levels of circulating methylated RASAL1 promoter fragments. • Low-dose Hydralazine induces endogenous Tet3-dependent de-methylation and inhibits progression of kidney fibrosis.

Introduction The measurement of cardiovascular endpoints in standard toxicology studies remains a challenge as the routinely used non-invasive methods require physical restraint, causing an increase of sympathetic neural activity, leading to excitement and potentially hypertension in the experimental animals. In this study, a miniature telemetry blood pressure transmitter was used to evaluate if the acute hyper- and hypotension could be detected in free moving cynomolgus monkeys as well as physically restrained animals using positive control drugs. Furthermore, as a comparator, routine high definition oscillometry (HDO) was performed in restrained animals. Methods: Hemodynamic parameters were monitored continuously from conscious, freely moving animals following oral administration of vehicle (water) or 1 and 10 mg/kg of etilefrine, and 1 and 4 mg/kg of dihydralazine as positive control articles. A second dose session was performed to confirm the reproducibility of results and a third dose session combined with physical restraint procedures for blood collection and HDO measurements. Results: There was a dose-dependent, statistically significant increase in the systolic blood pressure following oral doses of etilefrine at all 3 dose sessions. This effect was less apparent during session 3, probably due to the physical restraint applied for the blood sampling and HDO measurement. No differences in the blood pressure were measured using HDO. On all three dose sessions following oral doses of dihydralazine the expected statistically significant decrease in the diastolic pressure could be clearly measured even when the telemetric data recordings were combined with physical restraint. Discussion: Due to the advantages of the minimally invasive telemetry technique compared to HDO and the possibility of prolonged measurement periods, it is an invaluable tool for blood pressure measurement in freely moving animals in toxicology studies.

BACKGROUND An animal study reported that TGF-β1 maturation was linked to the homeostasis of blood pressure and elastogenesis of essential hypertension (EH). Recent advances require further research of TGF-β1 receptor in EH. METHODS A case-control study comprised of 2,012 adult hypertension case patients and 2,210 adult control subjects was conducted, and the association with blood pressure was further tested in children. Logistic regression and calculated genetic risk score were used to evaluate the effects of one single nucleotide polymorphism (SNP) and multiple SNPs on EH, respectively. RESULTS The genetic risk score of 10 SNPs showed a significant association with hypertension; the odds ratio of the upper quartile vs. the lower quartile was 1.282 (P = 4.67 × 10(-3)). rs7256241 in miR-518 was significantly associated with diastolic blood pressure (DBP) change in control subjects (P = 0.002), and this association was also observed in children (P = 0.04). The systolic blood pressure (SBP) and DBP of female patients taking reserpine were higher with the C and G alleles of rs3773661 (P = 0.004) and rs7256241 (P = 0.002), respectively. In patients taking Zhen Ju Jiang Ya tablets, SBP and DBP decreased linearly with rs749794 (P = 0.004 and P = 0.048, respectively). SBP decreased linearly with rs1155705 (P = 0.007) and rs11709624 (P = 0.04), but increased with rs1036096 (P = 0.03) in male patients. In male patients taking Jiang Ya tablets, SBP increased linearly with rs11709624 (P = 0.007), DBP increased linearly with rs1155705 (P = 0.03) whereas decreased with rs7256241 (P = 0.04). CONCLUSIONS Our results suggest that TGFBR2 and miR-518 harbor variants that increase the risk of EH and affect blood pressure homeostasis as well as efficacy of antihypertensive agents.

Background: Cardiovascular disease is the primary cause of mortality in patients with chronic kidney disease (CKD). Heart remodeling in CKD comprises mainly interstitial fibrosis and capillary loss. Beyond correcting renal anemia, erythropoietin (Epo) has potentially beneficial pleiotropic effects on heart remodeling. Methods: 12-week-old male Sprague-Dawley rats were randomized to 5/6 nephrectomy (NX) or sham operation (sham-op); subsequently, they received murine Epo (2.5 μg/kg/week), enalapril (12 mg/kg/day), Epo + enalapril, Epo + dihydralazine (25 mg/kg/day), or vehicle. Heart function and morphology was assessed after 16 weeks of treatment. Results: Compared with sham-op (81.2%), left ventricle fractional shortening was reduced in vehicle-treated NX (66.3%) and this was ameliorated by Epo (72.6%) and even prevented by enalapril (80.6%). Capillary length density was lower and the area of fibrosis more marked in vehicle-treated NX compared to sham-op. Capillary rarefaction and heart fibrosis were prevented in NX treated with Epo + enalapril and reduced in NX treated with enalapril and Epo + dihydralazine. Despite higher blood pressure, treatment with Epo reduced heart fibrosis but failed to prevent capillary loss. In parallel, expression of the p47phox NADPH oxidase was higher in untreated NX and was effectively reduced in NX treated with Epo + enalapril. Under basal conditions there was no difference between the groups regarding myocardial hypoxia as reflected by pimonidazole staining. Conclusion: Epo in combination with enalapril caused additive reduction of cardiac fibrosis and microvessel disease in 5/6 nephrectomized rats presumably by decreasing myocardial oxidative stress.

Diabetic nephropathy is the dominant cause of hypertension in insulin-dependent diabetics, and long-term rigid antihypertensive treatment inhibits the progression of nephropathy, probably even when there is renal insufficiency. In our clinical study 14 insulin-dependent diabetics with diabetic nephropathy and renal failure (glomerular filtration rate [GFR] 0.39 +/- 0.12 ml/sec) underwent rigid blood pressure treatment. Antihypertensive therapy included furosemide, propranolol, dihydralazine and nifedipine. The whole group showed a lowering in mean blood pressures from 150.1 +/- 2.3/91.3 +/- 1.4 mm Hg to 139.8 +/- 3.1/86.5 +/- 2.0 mm Hg (p less than 0.01). During the observation period the mean decline in glomerular filtration rate decreased from -0.022 +/- 0.003 ml/sec per month to -0.010 +/- 0.007 ml/sec per month. In 10 out of 14 patients with very advanced nephropathy the further decline of GFR halted markedly. Thus, vigorous blood pressure control is able to postpone endstage renal disease even in advanced diabetic nephropathy.

Emergency treatment of acute, severe hypertension was monitored prospectively during a period of nine months in a Danish multicenter trial. A total of 101 patients with supine diastolic blood pressures (DBP), phase V, ≥135 mmHg in three measurements at 5 min intervals entered the study. The emergency treatment was divided into three periods. In period I, lasting for the first hour, the patient was placed in the supine position and no drug treatment was given. If DBP did not fall below 135 mmHg, the patient entered period II, during which furosemide, 80 mg i.v., was given and observation continued for another hour. Patients with pronounced hypertensive encephalopathy (n = 15) and left venticular heart failure (n =2) started directly at period II. Provided DBP thereafter was still 135 mmHg or higher, the patients were randomized in period III (2nd-5th hour) to treatment with either chlorpromazine or dihydralazine in small refractory i.v. doses or diazoxide, 5 mg/kg b.wt. i.v., as a bolus injection. In period I, DBP fell below our “emergency limit” of 135 mmHg in 23 (27 %) of 84 patients whose mean arterial BP fell from 171 to 140 mmHg during the study. In period II, DBP fell below 135 mmHg in 23 (30%) of 78 patients and their mean arterial BP decreased from 174 to 135 mmHg during the study. In period III, 24 patients were treated with chlorpromazine, 16 with dihydralazine and 15 with diazoxide. In patients treated with chlorpromazine or dihydralazine, BP decreased gradually during the first hour, on average from 211/146 to 155/103 and from 219/147 to 162/89 mmHg, respectively. After diazoxide BP decreased abruptly in the first two minutes, on average from 211/144 to 166/100 mmHg. The complication rate was generally low and only a few patients were resistant to any of the treatments given. The study was not able to demonstrate that diazoxide is preferable to the other two drugs in emergency treatment.

Emergency treatment of acute, severe hypertension defined as diastolic blood pressure (DBP) greater than or equal to 135 mmHg combined with cerebral symptoms was prospectively monitored in a randomized multicenter study including 64 patients. Treatment was divided into two periods. In the first hour the patients were observed in the supine position after being given 40 mg furosemide intravenously. If DBP remained greater than 125 mmHg (n = 52), the patients were put on fractionated diazoxide administered intravenously (n = 28) or dihydralazine administered intramuscularly (n = 24). Blood pressure (BP) decreased with diazoxide from an average of 241/149 mmHg to 180/111 mmHg after 5 hours and with dihydralazine from 237/149 to 161/101 mmHg. The inter-individual BP response varied considerably. A clear and identical regression in neurological symptoms was observed on both drug regimens. No new neurological symptoms were seen to develop. It is concluded that a gradual fall in BP can be obtained after fractionated dosage of diazoxide (i.v.) as well as after dihydralazine (i.m.). The indication of acute parenteral therapy compared to less aggressive oral treatment is discussed.

Cerebral symptoms were registered in a multicenter study including 64 patients with severe hypertension, diastolic blood pressure (DBP) greater than or equal to 135 mmHg, and more or less pronounced hypertensive encephalopathy. The symptoms were: headache (70%), dizziness (35%), consciousness disturbances (28%), nausea (27%), paresis (23%), blurred vision (22%), paraesthesia (21%) and vomiting (14%). None had convulsions or coma. Initial treatment was furosemide i.v., and if DBP was greater than or equal to 125 mmHg after one hour, patients were randomized to treatment with either i.v. diazoxide (bolus injections of 75-150 mg) or i.m. dihydralazine (bolus injections of 6-12.5 mg). A gradual fall in blood pressure (BP) was obtained in all three groups. Along with BP reduction a substantial regression of neurological symptoms was registered. After 5 hours only minor cerebral symptoms were present without significant difference between diazoxide and dihydralazine. None developed cerebral complications. The study failed to show a significant correlation between BP reduction and regression of neurological symptoms graded semiquantitatively. Reduction of BP by titration using small repeated bolus injections is recommended, but oral treatment should be considered in the patients who are able to ingest peroral medication in spite of neurological symptoms.

The possibility of development of tolerance of treatment with vasodilators was investigated in 16 patients with severe chronic congestive cardiac failure. Independent of the primary site of action, the first application of a vasodilator resulted in lowering of pulmonary artery pressure by about 30% (isosorbide dinitrate 40 mg orally in delay-action form and 5 mg sublingually, prazosin 2 mg, dihydralazine 75 mg). Only dihydralazine reduced systemic resistance acutely by 42% and increased cardiac minute volume by 66%. After treatment for 12 days with isosorbide dinitrate delay-action (three times 20 mg), prazosin (three times 2 mg) or dihydralazine (three times 75 mg), there was persistent lowering of the pulmonary artery pressure 16 hours after cessation of treatment only after isosorbide dinitrate (-29%) and dihydralazine (-27%). A decrease of systemic resistance by 11% and an increase of cardiac minute volume by 20% were seen only after dihydralazine. An additional acute application of isosorbide dinitrate or dihydralazine resulted in a further decrease of pulmonary artery pressure (-25% and -11%, respectively). An additional decrease of systemic resistance (-23%) and increase of cardiac minute volume (+18%) were again only seen with dihydralazine. In contrast to the first medication there was no significant change of the pulmonary artery pressure after treatment with prazosin for 12 days.

The acute haemodynamic effects of 40 mg isosorbide dinitrate (10 subjects), 4 mg prazosin (20 subjects) and 50 mg dihydralazine (8 subjects) were compared in 24 patients with the clinical picture of chronic therapy-resistant cardiac failure (NY Heart Association stages III-IV). There was a fall in left-ventricular filling pressure of about 15% and right-atrial mean pressure of 21 and 24%, respectively, with isosorbide dinitrate and prazosin, while there was no change with dihydralazine. Cardiac output rose by 23% with dihydralazine and 20% with prazosin, but remained unchanged with isosorbide dinitrate. These data indicate that a reduction in pulmonary and systemic-venous congestion due to chronic decompensated cardiac failure can be achieved with isosorbide dinitrate and prazosin, while cardiac output can be improved only with prazosin and dihydralazine.

In 20 patients with essential arterial hypertension, grade II or III, the haemodynamic effect of a fixed combination of antihypertensive drugs (bemetizide, triamteren, bupranolol and dihydralazine) was studied by percutaneously-introduced flow-guided catheter in the pulmonary artery before, after three weeks and at the end of a six-month period of treatment; systemic arterial blood pressures were measured by the cuff method. Mean pressures, both at rest and on exercise were significantly and persistently lowered. Mean blood pressure at rest fell from 184/110 mmHg before treatment to 167/98 mmHg after three weeks, and to 158/93 mmHg after six months. The initial blood pressure on exercise was 226/129 mmHg, which fell after three weeks to 199/113 mmHg and after six months to 190/106 mmHg. At the same time, pulmonary artery pressure (as a measure of preload) fell by 23% at rest and 30% on exercise. Exercise tolerance of the patients rose by 28%. Pressure-heartrate product fell by 18%, as a pointer to an additional favourable effect on left ventricular oxygen consumption.

The validity of invasive preoperative diagnostic procedures in patients with unilateral renovascular hypertension was assessed. A significant lowering of blood pressure following reconstructive surgery can be predicted if following stimulation with Dihydralazine the renal-venous renin ratio of the involved to the noninvolved kidney is at least 2.0. Furthermore, it is of importance to determine the renal perfusion rate in the contralateral non-stenotic kidney which should be within normal limits. If these two criteria are met then in the majority of cases surgical intervention in unilateral hypertension is meaningful.

From our consecutive series of renal vein renin studies in 170 patients with kidney disorders and hypertension, we present those cured by surgical correction of a unilateral renal artery stenosis during the period 1973--75. The renin secretion patterns of these patients range between no demonstrable abnormality, even with a stimulating procedure using dihydralazine 7.5 i.v., and massive renin secretion already during basal conditions. Thus, the renin secretion may not be increased even after stimulation in some patients with durable unilateral renovascular hypertension. This fact may be explained by the rise of the systemic blood pressure, eventually maintained by sodium and water retention and accompanied by adaptive changes in the contralateral kidney. The perfusion pressure is thereby kept normal in the affected kidney, eliminating a stimulus for renin secretion. It is likely that many cases of renovascular hypertension pass through an early stage where no involvement of the renin-angiotensin system may be discovered. Of course, these patients will also benefit from surgery. The conclusion is that renin studies for diagnostic purposes should be performed when patients are on treatment and kept normotensive for some time, and that an additional challenge of the perfusion pressure, i.e., by use of dihydralazine, intravenously should be performed.

Background Drug treatment is imperative for pregnant women with pregnancy-induced hypertension (PIH) and pre-eclampsia. For more than 40 years, dihydralazine has been the drug of choice for this indication. Another particularly effective and better tolerable antihypertensive is urapidil. Yet only a few studies on limited patient collectives have been published on the clinical experience with urapidil in PIH. Methods Urapidil was interindividually compared to dihydralazine in a total of 42 patients, at six participating clinical centres. Patients were randomly assigned to the treatment groups. Urapidil was administered at an initial dose of 12.5–25 mg, dihydralazine was administered at a uniform initial dose of 5 mg. Patients were closely monitored for the initial 24 h of therapy. Until delivery and in the postpartal phase, mother and baby underwent four additional follow-up checks at regular intervals. Results Either drug was effective in lowering BP. Urapidil treatment proved to be better controllable. There were clear differences as to tolerability. In the urapidil group, one patient complained of headaches. In the dihydralazine group, six patients experienced adverse occurrences. Under dihydralazine treatment, some marked HR increases occurred, interpretable as reflectory tachycardia. Conclusions Urapidil proved to be equally effective as dihydralazine in lowering BP in patients with pre-eclampsia, but showed a better controllability and tolerability. Urapidil can hence be recommended as a promising alternative for patients with PIH.

A novel flow-injection chemiluminescence (CL) method for the determination of dihydralazine sulfate (DHZS) is described. The method is based on the reaction between DHZS and hexacyanoferrate(III) in alkaline solution to give weak CL signal, which is dramatically enhanced by eosin Y. The CL emission allows quantitation of DHZS concentration in the range 0.02-2.8mugml(-1) with a detection limit (3sigma) of 0.012mugml(-1). The experimental conditions for the CL reaction are optimized and the possible reaction mechanism is discussed. The method has been applied to the determination of DHZS in pharmaceutical preparations and compared well with the high performance liquid chromatography (HPLC) method.

Aim: To study the management and treatment of hypertensive disorders during pregnancy in Germany and compare the results with similar surveys. Methods: A multiple choice questionnaire was sent to 717 Departments of Obstetrics/Gynaecology in Germany, of which 34% responded. Results: Most German obstetricians treat women with moderate hypertension of more than 140/95 mmHg in the second trimester with anti-hypertensive drugs based on national protocols in outpatient clinics. First choice drug was methyldopa (46.7%). Thirty-seven percent of obstetricians use beta-blockers and 19.2% dihydralazine per os. 36.8% of obstetricians gave dihydralazine i.v. if blood pressure was 170/110 mmHg or higher. 38.1% of obstetricians prescribed aspirin to patients with moderate or severe hypertension. Many different views existed with respect to severe complications of hypertension such as HELLP syndrome or the treatment of eclamptic convulsions. Thirty-eight percent of obstetricians did not answer the question on how they would treat eclampsia. Conclusions: The management of anti-hypertensive disorders and preeclampsia varies greatly among German obstetricians. This survey indicates that information on individual experiences with treatment regimes together with educational programmes and new treatment modalities for preeclampsia and severe hypertensive complications should be more widely disseminated.

OBJECTIVES: To establish the effects of plasma volume expansion (PVE) followed by intravenous dihydralazine (DH) administration on maternal whole blood viscosity (WBV) and hematocrit, uteroplacental and fetoplacental downstream impedance and umbilical venous (UV) volume flow in pre-eclampsia. METHODS: In 13 pre-eclamptic women maternal and fetal hemodynamics were established by means of combined measurement of maternal arterial blood pressure (BP), WBV, hematocrit and uterine artery (UtA) resistance index (RI) in addition to umbilical artery (UA) pulsatility index (PI) and UV volume flow obtained from UV vessel area and UV time-averaged flow velocity. In each woman all parameters were measured four times at baseline, after PVE, after DH and 24 h after the start of treatment. RESULTS: Maternal diastolic BP, hematocrit and WBV display a significant reduction after PVE. In the fetus UA PI decreases significantly whereas a significant increase in UV cross-sectional area was detected. After maternal DH administration, arterial systolic and diastolic BP and UA PI show a significant decrease compared with the measurements following PVE. At 24 h, only maternal systolic and diastolic BP display a significant further decrease. No significant changes were established for the UtA RI, UV time-averaged velocity and UV volume flow during the entire study period. CONCLUSIONS: During pre-eclampsia, maternal PVE followed by DH administration results in a significant reduction in maternal diastolic BP, maternal hematocrit and WBV. Maternal PVE is associated with a significant increase in UV cross-sectional area and a non-significant rise of 11% in UV volume flow. Maternal DH administration does not result in any change in UV cross-sectional area. However, UA PI decreases significantly after both PVE and DH treatment.

Left ventricular hypertrophy (LVH) develops very early in experimental renovascular hypertension after clipping of one renal artery and is accompanied by a remodeling of cardiac structure which has not yet been investigated in detail. It was the aim of the present study to analyze changes in cardiomyocyte number and volume in LVH after 2 weeks of renovascular hypertension. Sprague-Dawley rats were subjected to clipping of the left renal artery (2K1C) or sham operation (sham). One group of 2K1C rats received antihypertensive treatment with dihydralazine. The experiment was terminated after 2 weeks. Hearts were investigated using stereological methods, electron microscopy, immunohistology for the proliferation marker proliferating cell nuclear antigen, the pro- and anti-apoptotic proteins Bax and Bcl-2 as well as the TUNEL technique. After 2 weeks, systolic blood pressure and relative left ventricular weight were significantly higher in untreated 2K1C animals than in sham and dihydralazine-treated 2K1C rats. Volume fraction of interstitial tissue and capillary length density were not different, whereas wall thickness of intramyocardial arteries was significantly higher in untreated 2K1C (5.12+/-0.7 micro m) than in sham (3.92+/-0.6 micro m) and in dihydralazine-treated 2K1C (3.91+/-0.7 micro m) rats. Cardiomyocyte diameter and volume were significantly higher in untreated 2K1C than in sham animals. The number of cardiomyocytes per left ventricle was significantly lower in untreated 2K1C rats (5.5+/-1.6 vs 3.9+/-6.9 x10(7)). Using immunohistochemistry, no direct evidence of apoptosis was found, but a relative higher expression of the anti-apoptotic protein bcl-2 expression was seen in untreated 2K1C than in sham animals. This may reflect a protective mechanism as a consequence of earlier occurring apoptosis. These observations document that experimental renovascular hypertension induces a rapidly developing LVH characterized by marked cardiac remodeling and substantial loss of cadiomyocytes.

In order to investigate the effects of antihypertensive drugs on blood pressure and gamma-amino butyric acid (GABA) content in the hypothalamus and the possible relationship between blood pressure decrease and GABA content changes, blood pressure and GABA contents after chronic (20 weeks) treatments of nitrendipine, atenolol, captopril, hydrochlorothiazide, dihydralazine and prazosin were studied in spontaneously-hypertensive rats (SHR). The acute and subacute (1 week) effects of nitrendipine on GABA contents was also observed in SHR. It was found that 20 week treatments with six different antihypertensive agents produced a decrease in systolic blood pressure and an increase in GABA content. The blood pressure level was significantly correlated with GABA content in the hypothalamus, but not with that in the cortex. Acute treatment with a single dose of nitrendipine, did not alter GABA content. Bicuculline, a GABA receptor antagonist, did not attenuate the hypotensive effect of nitrendipine. In conclusion, chronic treatments by different antihypertensive agents produced an increase of hypothalamic GABA content and a decrease of blood pressure. The increase of GABA content induced by nitrendipine seems likely to be secondary to blood pressure decrease.

Cerebral haemorrhage remains a major cause of hypertensive cerebral mortality. Lowering of raised blood pressure is therefore crucial in the clinical management of hypertensive disorders of pregnancy. This article reviews rapid-acting agents employed in life-threatening situations.

The influence of metabolic activation on the genotoxic activity of the antihypertensive drugs hydralazine and dihydralazine was investigated. An in vitro micronucleus test for estimating the genotoxic activity of these drugs was used. The results obtained indicated that hydralazine and dihydralazine induce micronuclei formation in L929 cells. When L929 cell cultures were treated with drugs together with liver membrane fraction (S9 fraction) from polychlorinated biphenyl (Aroclor 1254) induced rat liver, the number of micronucleated cells decrease, however, almost to the level found in control cultures. The experiments with modified S9 mix allow the conclusion that the antioxidant enzymes catalase and superoxide dismutase present in S9 liver fraction play a role in the protection of cells from the genotoxic action of hydralazine and dihydralazine.

Objective For the therapy of preeclamptic patients is Urapidil besides Dihydralazine another possible option for iv-therapy with good results in first clinical studies. Effects of both drugs on the newborns were observed. - Methods The maternal and fetal Urapidil plasma-concentrations and cardiovascular parameters of the newborns were observed in a randomised comparative therapy-study. - Results We found low fetal Urapidil plasma-concentrations as well as a less influence on cardiovascular parameters compared to dihydralazine. - Discussion With Urapaidil we have another therapeutic option in preeclampsia where we could not show any negative side-effects on the newborns.

Abstract —Hypertension with renal artery stenosis is associated with both an activated renin-angiotensin system and elevated sympathetic activity. Therefore, in this condition it may be favorable to use a therapeutic modality that does not reflexly increase heart rate, renin secretion, and sympathetic nervous activity. The purpose of the present study was to assess overall, renal, and muscle sympathetic activity after short-term administration of an angiotensin-converting enzyme inhibitor (enalaprilat) and a nonspecific vasodilator (dihydralazine) to hypertensive patients with renal artery stenosis. Forty-eight patients undergoing a clinical investigation for renovascular hypertension were included in the study. An isotope dilution technique for assessing norepinephrine spillover was used to estimate overall and bilateral renal sympathetic nerve activity. In 11 patients simultaneous intraneural recordings of efferent muscle sympathetic nerve activity were performed. Thirty minutes after dihydralazine administration, mean arterial pressure fell by 15%, whereas plasma angiotensin II, muscle sympathetic nerve activity, heart rate, and total body norepinephrine spillover increased ( P P

To evaluate the safety and outcome of women undergoing expectant management of early onset, severe pre-eclampsia.Prospective case series extending over a five-year period.Tygerberg Hospital, a tertiary referral centre.All women (n = 340) presenting with early onset, severe pre-eclampsia, where both the mother and the fetus were otherwise stable.Frequent clinical and biochemical monitoring of maternal status, together with careful blood pressure control, in a high care obstetric ward.Major maternal complications and prolongation of gestation.Multigravid women constituted 67% of the group. Antenatal biochemistry was reassuring with some expected, but not severe, deteriorations. Twenty-seven percent of women experienced a major complication, but few had poor outcomes. No maternal deaths occurred. Most major complications resolved quickly, necessitating only three admissions (0.8%) to the intensive care unit. One woman required dialysis. Pregnancies were prolonged by a mean (median) number of 11 days (9) before delivery, with more time being gained at earlier gestations. The postpartum inpatient stay (89%or =7 days, bearing in mind that 82% of women were delivered by caesarean section) was not extended.Careful noninvasive management of early onset, severe pre-eclampsia in a tertiary centre can diminish and limit the impact of serious maternal complications. Valuable time to prolong the pregnancy and improve neonatal outcome is thereby gained.

UNLABELLED Most agree that antihypertensive medication should be used to treat severe hypertension during pregnancy, but its role in patients with mild to moderate disease is debated. None of the regularly used drugs is completely safe for mother and fetus. Ketanserin decreases systolic and diastolic blood pressure in nonpregnant patients with acute and chronic hypertension. Its selective serotonin S2-receptor antagonist activity encouraged investigations into a possible role in pregnant women. These reports can be divided into four groups. Several studies confirmed that intravenous ketanserin decreases blood pressure significantly in patients with severe preeclampsia. There are indications that it may be at least as effective as dihydralazine, possibly with fewer side effects. Its role in chronic hypertension has not been studied adequately, but one randomized, controlled trial indicated efficacy comparable with that of alpha-methyldopa. Thirdly, it was concluded in a single descriptive study that the administration of ketanserin to patients with HELLP syndrome allowed delivery to be postponed for 5.3 days. Lastly, in a randomized, placebo-controlled trial, the addition of ketanserin to aspirin in patients with mild to moderate midtrimester hypertension was associated with a significant decrease in the number of cases of preeclampsia and severe hypertension, as well as a trend to less perinatal mortality, lower rates of abruptio placentae, and early-onset preeclampsia. Additional studies are needed to adequately assess a possible role for ketanserin with acute hypertension or moderate chronic hypertension. TARGET AUDIENCE Obstetricians & Gynecologists, Family Physicians LEARNING OBJECTIVES After completion of this article, the reader will be able to list the various drugs and their associated side effects that are used to treat hypertensive disorders during pregnancy; to describe the various effects of serotonin on the cardiovascular system; to summarize the literature concerning the use of ketanserin during pregnancy; and to list the potential uses of ketanserin in this setting.

Dihydralazine, given in small i.v. doses, has been of great value in diagnostic tests for unilateral renovascular hypertension, where it enhances renin release on the affected side. The acute hemodynamic effects of an i.v. dose of 0.1 mg/kg b.wt. were studied in 14 patients with essential hypertension, using a quantitative renographic technique for determination of effective renal plasma flow and radiocardiographic technique for determination of the parameters in systemic circulation. Cardiac index increased from 4.040 to 6.423 1/min.m2 (p less than 0.01), stroke index from 59 to 66 ml/beat.m2 (p less than 0.05), heart rate from 70.4 to 96.6 beats/min (p less than 0.01) and left ventricular work index from 1.04 to 1.49 W/m2 (p less than 0.01), while mean arterial B decreased from 125 to 110 mmHg (p less than 0.01) and total peripheral resistance index from 2927 to 1534 10(5).N.s.m(-3) (p less than 0.01). Effective renal plasma flow and pulmonary plasma volume were unchanged. Peripheral renin activity increased from 0.5 to 1.6 nmol A1/1.h (p less than 0.02). It is concluded that even a small test dose of 0.1 mg/kg of dihydralazine elicits a considerable additional work load on the heart, a circumstance that must be taken into consideration in studies of patients with coronary heart diseases.

There is little to suggest that the course of preeclamsia can be substantially affected by drug treatment. The vast majority of randomized studies do not indicate beneficial effects of antihypertensive treatment on proteinuria, fetal heart rate abnormalities, abruptio placentae and the incidence of preterm birth. There is also no definite effect on the development of superimposed preeclampsia, HELLP syndrome, renal failure or eclampsia. Moreover, blood pressure lowering agents fail to improve uteroplacental perfusion but may have adverse effects on fetal growth. Antihypertensive treatment is only indicated in severe hypertension ( > 170/110 mm Hg) to reduce the risk of cerebral hemorrhage. Dihydralazine injections may result in reduced placental blood flow and fetal distress. Oral nifedipine offers some advantages in view of more potent vasodilator actions on uterine and fetoplacental vessels and a lower incidence of fetal distress. Increasing evidence suggests that the mechanism of eclamptic seizure is cerebral vasoconstriction with resultant ischemia. Cerebral vessels are particularly sensitive to magnesium, which works by reversing cerebral vasoconstriction with resultant improvement in blood flow. Controlled trials have shown magnesium to be superior to both placebo and phenytoin for the prevention of eclampsia. Furthermore, magnesium has been found to be more effective than diazepam and phenytoin in preventing recurrence of seizures in women with eclampsia. Also the neonatal outcome favors magnesium, which is now generally accepted as the drug of choice for the prevention and treatment of eclampsia.

Objective: Nitroglycerin was used successfully in the second-line treatment of severe hypertension in two pregnant patients. Case report: One patient with preexisting hypertension developed severe hypertension at 27 weeks' gestation. Treatment with dihydralazine and methyldopa caused toxic liver damage. Another patient had severe hypertension unresponsive to dihydralazine an also had uterine contractions. Both patients received intravenous nitroglycerin at a rate of 0.5-4.0 mg/h over a period of 3 days. Maternal mean blood pressure returned to an almost normal level and uterine contractions ceased. There were no negative effects on mother or fetus. Conclusion: Nitroglycerin may be considered for short-term second-line treatment of severe hypertension in pregnancy.

The distinction between chronic hypertension, gestational hypertension, and preeclampsia is essential for the choice of the adequate pharmacotherapy. In chronic and gestional hypertension there is a positive prognosis for mother and child. Mostly, there is no need for pharmacotherapy in gestational hypertension and in chronic hypertension pharmacotherapy is only necessary in serious cases. Particularly in chronic hypertension the application of antihypertension drugs allows the woman to carry the child to full term. In contrast, preeclampsia represents potential danger for mother and fetus. In this case pharmacotherapy rarely shows satisfactory results. Only frequent clinical control and a premature delivery are considered adequate measures. Methyldopa is a well known antihypertensive drug for long-term therapy. Concerning adverse events in the mother modern antihypertensive drugs have disadvantages in relation to but there are advantages in terms of protection for the fetus. Of methyldopa ineffective is or cannot be tolerated of the β-blocker metoprolol can be alternatively applied. In case of emergency dihydralazine or – as as second choice – clonidine is appropiate.

Suitable hydrazines like phenylhydrazine (1), N,N-dimethyl hydrazine (4), and N,N-diphenyl hydrazine (5) can be oxidized by hydrogen peroxide at pH 7.4 and 37 degrees C to nitrosohydrogen and further to nitrite and nitrate. The extent of this property is correlated with platelet aggregation inhibiting and antithrombotic effects of these compounds, suggesting that an NO mediated mechanism might be involved. All hydrazines tested and two N-ethoxycarbonyl prodrugs exhibited antihypertensive effects which were not correlated to the above properties. This is especially pronounced in hydralazine (6) and dihydralazine (7) which induced a strong decrease in blood pressure but exhibit neither antiplatelet nor antithrombotic effects. This indicates that the mechanism of the antihypertensive activity is different from that of the antiplatelet activity.

Objective To compare the haemodynamic efficacy of ketanserin (a selective serotonin2-receptor blocker) with dihydralazine in the management of severe early-onset hypertension in pregnancy. Design Subgroup analysis within a randomised prospective multicentre trial to compare haemodynamic effects as measured by pulmonary artery catherization. Setting Departments of Obstetrics and Gynaecology and Intensive Care Medicine, Free University Hospital, Amsterdam and Sophia Hospital, Zwolle. Participants Thirty-one women with a diastolic blood pressure > 110 mmHg and a gestational age between 26 and 32 weeks. Results The antihypertensive efficacy of both drugs was comparable. Dihydralazine significantly increased cardiac output (P < 0.01), while ketanserin induced only minor changes in cardiac output. Systemic vascular resistance decreased in both groups, but the decrease was significantly more pronounced with dihydralazine compared with ketanserin. Ketanserin induced a significant but not clinically relevant increase in heart rate (P < 0.01, while dihydralazine caused marked tachycardia (P < 0.005). Left ventricular stroke work index was reduced to similar values in both groups. Conclusions The antihypertensive profile of ketanserin is characterised by an early and gradual reduction of blood pressure in combination with a moderate decrease in systemic vascular resistance and no significant change in cardiac output. Dihydralazine causes market tachycardia resulting in a considerable increase in cardiac output.

Background The primary objective of treatment in women with severe hypertension and pre-eclampsia is to prevent complications such as encephalopathy and haemorrhage. In many countries dihydralazine is considered the drug of choice for treating hypertension in pregnancy, because it now has been used safely for about 30 years, and the introduction of a new drug in pregnancy is a difficult task with partially unknown hazards. In some other countries combined alpha- and beta-blockers are also used. Taking into account that some patients with pre-eclampsia do not respond to dihydralazine and the drug has serious side-effects like headache and reflex tachycardia, there is some need for developing alternative treatment strategies using drugs that are more adequate for pregnancy than dihydralazine. Methods Urapidil is a post-synaptic alpha 1 adrenoceptor antagonist, which is widely used to control hypertensive crises unrelated to pregnancy. Since it is known that pre-eclampsia is associated with increased sympathetic activity, administration of an alpha 1 adrenoceptor antagonist provides a reasonable therapeutic basis. So far there is only one report describing the i.v. use of urapidil in the treatment of hypertension in pregnancy unresponsive to dihydralazine and one report which describes the oral use of urapidil. In an earlier pilot study we examined the dose range for i.v. application of urapidil necessary for adequate blood pressure control in patients with pre-eclampsia. In the present randomized controlled study 26 white women with pre-eclampsia and hypertension in pregnancy were included. Treatment was not blinded. During the initial period of intensive intravenous treatment all subjects were under constant surveillance by a physician and a nurse. Results Effective prolonged control of blood pressure (values below 150/100 mmHg) was achieved in all patients of the two groups. In one patient of the dihydralazine group signs of lightheadedness and near syncope were noted. After this side-effect of dihydralazine the patient was treated with urapidil. At the end of the observation period the maternal heart rate in the dihydralazine group was higher than in the urapidil group. Conclusions Since urapidil decreased the high blood pressure in patients with pre-eclampsia without serious side-effects urapidil appears preferable superior to dihydralazine. The haemodynamic effects of urapidil were more predictable than those of dihydralazine. The reduction of intracerebral pressure could be an additional advantage of urapidil in the treatment of patients with pre-eclampsia.

Objective: To compare the efficacy and safety of intravenous dihydralazine with ketanserin in the management of severe hypertension in the third trimester. Study design: A double blind randomised controlled trial, comparing 5 mg dihydralazine with 10 mg ketanserin after an intravenous infusion of 500 ml of a crystalloid solution. Medication was repeated every 20 min till the therapeutic goal of 90 mm Hg was reached, to a maximum of 4 dosages. Main outcome measures were treatment failures and emergency deliveries for fetal distress. Results: The therapeutic goal was met more often in patients receiving dihydralazine (36/38 compared to 27/42; P

Liver is a frequent target for drug-induced hepatitis. They can be classified in two categories: the hepatitis in which the drug or a metabolite reach a vital target in the cell and the hepatitis in which the drug triggers an adverse immune response directed against the liver. We will discuss essentially this second kind of disease. They have key clinical features such as the low frequency, the dose independence, the delay between the beginning of drug intake and the triggering of the disease, the shortening of the delay upon rechallenge and very often the presence of autoantibodies in the serum of the patients. Such signs were found in hepatitis triggered by drugs such as halothane, tienilic acid, dihydralazine, anticonvulsants. They will be taken as examples to show the recent progress in the understanding of the mechanisms leading to the disease. It has been postulated that the drug is metabolised into a reactive metabolite binding to the enzyme which generated it; therefore the neoantigen might trigger an immune response characterised by the production of antibodies recognising the native and or the modified protein. Most of these steps were proven in the cases of halothane, tienilic acid and dihydralazine. Several points seem important in the development of the disease; the equilibrium between toxication and detoxication pathways, the nature and amount of neoantigen, the individual immune response. However, many points remain unclear: for instance, the reason for the very low frequency of this kind of disease; the precise mechanism of the adverse immune response; the risk factors for developing such adverse reactions. Efforts should be made to better understand the mechanisms of this kind of disease: for instance, an animal model, tests to identify drugs at risk for such reactions, the role of these drugs in the processing of P450s and the processing of the neoantigens for their presentation to the immune system.

Objective: To compare the efficacy and safety of intravenous isradipine with dihydralazine in severe hypertension of pregnancy in Black patients.Methods: In this randomized study 40 Black patients with severe hypertension of pregnancy (DBP ≥ 110 mm Hg) at a tertiary referral hospital received intravenous isradipine [an initial dose of 0.15μ,g kg-1 min-1 for 15 min with increments of 0.0025 ixg kg-1 min-1 every 15 min until diastolic blood pressure (DBP) control (DBP < 95 mm Hg) was achieved, followed by a maintenance infusion of 0.15 μg kg-1 min-1 which was given for 15 min] or dihydralazine (6.25 mg given intravenously over 10 min; the dosage was repeated after 20 min if control was not achieved).Mean Outcome Measures: DBP < 95 mm Hg; fetal heart rate deceleration; fetal outcome.Results: Mean systolic blood pressure was reduced from 190.9 (95% CI 182.7-199.0) mm Hg to 137.6 (131.9-143.3) mm Hg in the isradipine group and from 187.9 (180.0-195.7) to 142.4 (133.0-151.7) mm Hg in the dihydralazine group. Th...