Ketanserin versus dihydralazine for the treatment of severe hypertension in early-onset preeclampsia: a double blind randomized controlled trial.

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)≥110mmHg), and significant proteinuria (≥300mg/24h), 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>100mmHg>120min) 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.

Long-term efficacy and tolerability of a fixed-dose combination of antihypertensive agents: an open-label surveillance study in China.

BACKGROUND: A fixed-dose combination (FDC) of four compounds, hydrochlorothiazide 12.5 mg, triamterene 12.5 mg, dihydralazine 12.5 mg and reserpine 0.1 mg (HTDR), is widely used as an antihypertensive treatment in China. Although HTDR has been used in China for more than 30 years, there have been few comprehensive evaluations of this treatment. OBJECTIVE: The aim of this study was to investigate the long-term efficacy and tolerability of HTDR in Chinese patients with essential hypertension. METHODS: This was a 36-month, community-based, open-label surveillance study, conducted in the Huangpu District (Shanghai, China). The study was based in local primary healthcare settings. Subjects were recruited if they had essential hypertension, were aged ≥35 years at the time of enrolment, were expected to remain in the area for 3 years, and were able to provide informed consent. Patients who had secondary hypertension, myocardial infarction or stroke within 6 months of screening, impaired renal or hepatic function, history of cardiomyopathy or chronic heart failure, or were pregnant or lactating were excluded. HTDR was administered as one or two tablets per day in the morning. If necessary, additional hydrochlorothiazide was added. Blood pressure (BP) was measured at baseline and throughout the 36-month surveillance period every 3 months. Biochemical indicators (e.g. fasting blood glucose, plasma lipid parameters, plasma sodium and potassium, plasma uric acid and serum creatinine) were also measured, and adverse events were noted. BP reductions and the rate at which patients achieved BP targets (systolic BP [SBP] <140 mmHg and diastolic BP [DBP] <90 mmHg) throughout the period were determined. Subgroup analyses by sex and age were also conducted. RESULTS: A total of 1529 patients (550 male, 979 female; mean age 65.7 years) entered the study. After the 36-month treatment period, 93.1% of patients had achieved the SBP target, 97.9% had achieved the DBP target, and 92.1% had achieved both. The mean decreases in SBP and DBP were 15.3 mmHg and 9.9 mmHg, respectively. Overall, 127 adverse events in 119 patients (7.8%) occurred during the follow-up period, most of which were mild to moderate. Plasma lipid profiles were improved after 24 months of treatment. In addition, a significant increase in plasma potassium and a significant reduction in plasma uric acid were seen. CONCLUSION: HTDR was found to have good long-term efficacy and tolerability in Chinese patients with essential hypertension.

Antihypertensive therapy in patients with pre-eclampsia: A prospective randomised multicentre study comparing dihydralazine with urapidil.

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 12.5-25mg, dihydralazine was administered at a uniform initial dose of 5mg. Patients were closely monitored for the initial 24h 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.

Immune-mediated drug-induced liver disease.

Drug-induced immune-mediated hepatic injury is an adverse immune response against the liver that results in a disease with hepatitic, cholestatic, or mixed clinical features. Drugs such as halothane, tienilic acid, dihydralazine, and anticonvulsants trigger a hepatitic reaction, and drugs such as chlorpromazine, erythromycins, amoxicillin-calvulanic acid, sulfonamides and sulindac trigger a cholestatic or mixed reaction. Unstable metabolites derived from the metabolism of the drug may bind to cellular proteins or macromolecules, leading to a direct toxic effect on hepatocytes. Protein adducts formed in the metabolism of the drug may be recognized by the immune system as neoantigens. Immunocyte activation may then generate autoantibodies and cell-mediated immune responses, which in turn damage the hepatocytes. Cytochromes 450 are the major oxidative catalysts in drug metabolism, and they can form a neoantigen by covalently binding with the drug metabolite that they produce. Autoantibodies that develop are selectively directed against the particular cytochrome isoenzyme that metabolized the parent drug. The hapten hypothesis proposes that the drug metabolite can act as a hapten and can modify the self of the individual by covalently binding to proteins. The danger hypothesis proposes that the immune system only responds to a foreign antigen if the antigen is associated with a danger signal, such as cell stress or cell death. Most clinically overt adverse hepatic events associated with drugs are unpredictable, and they have intermediate (1 to 8 weeks) or long latency (up to 12 months) periods characteristic of hypersensitivity reactions. Immune-mediated drug-induced liver disease nearly always disappears or becomes quiescent when the drug is removed. Methyldopa, minocycline, and nitrofurantoin can produce a chronic hepatitis resembling AIH if the drug is continued.

Drug-induced lupus as a cause of relapsing inflammatory disease after renal transplantation.

We discuss the case of an 18-year-old-boy presenting with relapsing fever, arthralgia, myalgia and renal failure, 7 yr after renal transplantation. A thorough diagnostic work-up for infectious and inflammatory diseases revealed a mastoiditis and atypical mycobacteria, but symptoms persisted after treatment. Persistent antinuclear antibodies in combination with cardiolipin and myeloperoxidase antibodies, despite negative dsDNA antibodies, suggested a drug induced lupus-like syndrome. Six months after withdrawal of dihydralazine, all symptoms had disappeared. Drug-induced lupus should be considered as an important differential diagnosis in transplanted patients with recurrent inflammatory disease in conjunction with lupus-like symptoms and negative dsDNA antibodies. It may prevent a potentially hazardous reduction of immunosuppression in persistent inflammation.

Ketanserin for the treatment of preeclampsia.

OBJECTIVE: To compare maternal and perinatal outcome with the use of either intravenous ketanserin or dihydralazine in treatment of women with preeclampsia. METHODS: The records from January 1989 to January 1997 of all patients receiving intravenous ketanserin or dihydralazine as first line antihypertensive therapy were reviewed and standardized data forms were completed. 315 charts of patients were identified and evaluated for effects on blood pressure, laboratory parameters, maternal and perinatal outcome. RESULTS: During the study interval 169 patients received ketanserin and 146 dihydralazine. Significantly fewer antepartum (27% versus 38%, p = 0.04) and postpartum (25% versus 39%, p = 0.01) maternal complications were noted in patients receiving ketanserin. Occurrence of HELLP syndrome was significantly lower among patients who received ketanserin (20%) than among those who received dihydralazine (40%, p = 0.0001). Side-effects were reported with significantly higher frequency in patients receiving dihydralazine (60%) as compared to those receiving ketanserin (17%, p < 0.0001). Perinatal outcome was comparable, however, umbilical cord arterial pH values (mean +/- SD) were higher with ketanserin compared to dihydralazine (7.25 +/- 0.07 vs 7.23 +/- 0.09, p = 0.038). The incidence of placental abruption was higher in patients receiving dihydralazine (5.5%) versus those receiving ketanserin (0.6%, p = 0.014). CONCLUSION: Ketanserin appears to be a better option than dihydralazine for treatment of severe preeclampsia since fewer maternal complications and side-effects were observed in patients receiving ketanserin.

Target proteins in human autoimmunity: cytochromes P450 and UDP- glucuronosyltransferases.

Cytochromes P450 (CYPs) and UDP-glucuronosyltransferases (UGTs) are targets of autoantibodies in several hepatic and extrahepatic autoimmune diseases. Autoantibodies directed against hepatic CYPs and UGTs were first detected by indirect immunofluorescence as antiliver and/or kidney microsomal antibodies. In autoimmune hepatitis (AIH) type 2, liver and/or kidney microsomal (LKM) type 1 autoantibodies are detected and are directed against CYP2D6. About 10% of AIH-2 sera further contain LKM-3 autoantibodies directed against family 1 UGTs. Chronic infections by hepatitis C virus and hepatitis delta virus may induce several autoimmune phenomena, and multiple autoantibodies are detected. Anti-CYP2D6 autoantibodies are detected in up to 4% of patients with chronic hepatitis C, and anti-CYP2A6 autoantibodies are detected in about 2% of these patients. In contrast, 14% of patients with chronic hepatitis delta virus infections generate anti-UGT autoantibodies. In a small minority of patients, certain drugs are known to induce immune-mediated, idiosyncratic drug reactions, also known as 'druginduced hepatitis'. Drug-induced hepatitis is often associated with autoantibodies directed against hepatic CYPs or other hepatic proteins. Typical examples are tienilic acid-induced hepatitis with anti-CYP2C9, dihydralazine hepatitis with anti-CYP1A2, halothane hepatitis with anti-CYP2E1 and anticonvulsant hepatitis with anti-CYP3A. Recent data suggest that alcoholic liver disease may be induced by mechanisms similar to those that are active in drug-induced hepatitis. Autoantibodies directed against several CYPs are further detected in sera from patients with the autoimmune polyglandular syndrome type 1. Patients with autoimmune polyglandular syndrome type 1 with hepatitis often develop anti-CYP1A2; patients with adrenal failure develop anti-CYP21, anti- CYP11A1 or CYP17; and patients with gonadal failure develop anti-CYP11A1 or CYP17. In idiopathic Addison disease, CYP21 is the major autoantigen.

Ketanserin versus dihydralazine in the management of severe early-onset preeclampsia: maternal outcome.

OBJECTIVE: An open, randomized, prospective, multicenter trial was conducted to compare the efficacy and safety of intravenous ketanserin, a selective serotonin 2 receptor blocker, with that of intravenous dihydralazine in the management of severe early-onset (<32 weeks' gestation) preeclampsia. End points of this study were blood pressure control and maternal outcome. STUDY DESIGN: Patients with a diastolic blood pressure >110 mm Hg were randomly assigned to receive either ketanserin (n = 22) or dihydralazine (n = 22) as initial therapy. Plasma volume expansion preceded antihypertensive treatment, which was administered according to a fixed schedule. RESULTS: The reductions in blood pressure with the 2 drugs were similar; however, adequate blood pressure control was reached significantly earlier with ketanserin (84 +/_ 63 vs 171 +/- 142 minutes, P = .017). Occurrence of maternal complications was significantly lower among patients who received ketanserin than among patients who received dihydralazine (n = 6 vs n = 18, P =.0007). A significant difference in favor of ketanserin was noted in daily fluid balance. CONCLUSION: Antihypertensive efficacies of ketanserin and dihydralazine were comparable, but significantly fewer maternal complications were noted among the patients receiving ketanserin. Ketanserin is an attractive alternative in the management of severe early-onset preeclampsia.

[Current aspects of antihypertensive therapy in pregnant patients with pre-eclampsia]. / Aktuelle Aspekte in der antihypertensiven Therapie bei Schwangeren mit Präeklampsie.

Preeclampsia is a disease which occurs in Europe in about 6-8%, in the USA in about 7-10% and in Africa in about 18% of all pregnancies. A causal treatment of preeclampsia is, with the exception of delivery, not possible up to now. Since a prematurely delivery of the newborn has to be avoided because of the risks caused by immaturity of lungs, treatment and care of pregnant women having preeclampsia or any other kind of hypertensive diseases is restricted to the following approaches: antihypertensive treatment, volume expansion, and eclampsia prophylaxis with magnesium sulfate. Object of this treatment is to avoid complications on the mother's side caused by the disease and to postpone delivery, as far as possible from the child's side, in order to reduce the consequences of premature birth. During antihypertensive treatment of patients with serious hypertension, i.e. with diastolic blood pressure of 110 x mm Hg and higher, dihydralazine is in clinical use since 40 years, although many patients suffer from side-effects of dihydralazine such as distinctive tachycardia, headaches, fluid retention and nausea. With urapidil a well controllable antihypertensive is available, which prevents the effect of catecholamines at the vascular wall by a postsynaptic alpha-1 receptor blockade. Previous studies related to the application of urapidil in the treatment of hypertension during pregnancy certify the good controllability of urapidil following intravenous application as well as minor side-effects after start of treatment.

Drug-induced immunotoxicity.

Immune-related drug responses are one of the most common sources of idiosyncratic toxicity. A number of organs may be the target of such reactions; however, this review concentrates mostly on the liver. Drug-induced hepatitis is generally divided into two categories: acute hepatitis in which the drug or a metabolite destroys a vital target in the cell; immunoallergic hepatitis in which the drug triggers an adverse immune response directed against the liver. Their clinical features are: a) low frequency; b) dose independence; c) typical immune system manifestations such as fever, eosinophilia; d) delay between the initiation of treatment and onset of the disease; e) a shortened delay upon rechallenge; and f) occasional presence of autoantibodies in the serum of patients. Such signs have been found in cases of hepatitis triggered by drugs such as halothane, tienilic acid, dihydralazine and anticonvulsants. They will be taken as examples to demonstrate the recent progress made in determining the mechanisms responsible for the disease. The following mechanisms have been postulated: 1) the drug is first metabolized into a reactive metabolite which binds to the enzyme that generated it; 2) this produces a neoantigen which, once presented to the immune system, might trigger an immune response characterized by 3) the production of antibodies recognizing both the native and/or the modified protein; 4) rechallenge leads to increased neoantigen production, a situation in which the presence of antibodies may induce cytolysis. Toxicity is related to the nature and amount of neoantigen and also to other factors such as the individual immune system. An effort should be made to better understand the precise mechanisms underlying this kind of disease and thereby identify the drugs at risk; and also the neoantigen processes necessary for their introduction into the immune system. An animal model would be useful in this regard.

Epitope mapping of human CYP1A2 in dihydralazine-induced autoimmune hepatitis.

Dihydralazine-induced hepatitis is characterized by the presence of anti-liver microsomal (anti-LM) autoantibodies in the sera of patients. Cytochrome P450 1A2 (CYP1A2), involved in the metabolism of dihydralazine, was shown to be a target for autoantibodies. In order to investigate further the relationship between drug metabolism and the pathogenesis of this drug-induced autoimmune disease, and since the specificity of anti-LM autoantibodies towards CYP1A2 has been determined, the antigenic site was further localized. By constructing fragments derived from CYP1A2 cDNA and probing the corresponding proteins with several anti-LM sera, we were able to define a region (amino acid 335-471) which was immunoreactive with 100% of sera. An internal deletion in this region led to the loss of recognition by anti-LM autoantibodies, confirming that the epitope was conformational. Epitope mapping studies had previously been performed for CYP2D6, CYP17, CYP21A2, and recently for CYP3A1 and CYP2C9. Those data were compared with results obtained in the present study for CYP1A2.

Immunotoxicology of the liver: adverse reactions to drugs.

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.

Dihydralazine or ketanserin for severe hypertension in pregnancy? Preliminary results.

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 < 0.01). The need for delivery for fetal distress did not differ (3 after dihydralazine, 1 after ketanserin, P = 0.29) No therapy related perinatal loss occurred, but one mother with an undiagnosed phaechromocytoma died 24 h after receiving dihydralazine. CONCLUSION: Ketanserin in this dosage is less effective to lower diastolic blood pressure. The place of a fluid load prior to dihydralazine needs to be further investigated, as fetal heart rate decelerations were less common than previously reported.

Anti-cytochrome P450 autoantibodies in drug-induced disease.

Drugs may induce hepatitis through immune mechanisms. In this review we have used the examples of 2 drugs to elucidate the first steps leading to the triggering of such disease, namely tienilic acid (TA) and dihydralazine (DH). These drugs are transformed into reactive metabolite(s) by cytochrome P450 (2C9 for TA and 1A2 for DH) (step 1). The reactive metabolites produced are very short-lived and bind directly to the enzymes which generated them (step 2). A neoantigen is thus formed which triggers an immune response (step 3), characterized by the presence of autoantibodies in the patient's serum (step 4). The autoantibodies are directed against the cytochrome P450 which generated the metabolite(s). Although the process by which TA and DH induce-hepatitis has been elucidated, further studies are necessary to generalize this mechanism. In addition, an animal model will also be useful to fully understand the immune mechanism of this type of disease.

Nifedipine in acute hypertensive emergencies in pregnancy.

The effect of nifedipine (Adalat; Bayer-Miles)--a calcium channel blocker, which has a well-established place in nonobstetric hypertension--was compared with dihydralazine in 33 primigravidas with severe hypertension of pregnancy. Patients with a diastolic blood pressure greater than 110 mmHg before drug administration were randomly assigned to treatment with either nifedipine or dihydralazine. Both drugs were found to be equally efficacious. Nifedipine, however, showed an earlier onset of action in lowering systolic blood pressure and had the advantage of oral administration.

Kinetics of antipyrine and sulfamethazine in patients recovered from dihydralazine-hepatitis.

Pharmacokinetic studies with sulfamethazine (500 mg) and antipyrine (15 mg/kg) were performed in 27 hypertonic patients (16 females, 11 males, 37-78 years) who had recovered from a dihydralazine-induced hepatitis, and 21 patients with essential hypertension (13 females, 8 males, 18-74 years) treated with antihypertonics excluding dihydralazine. 20 patients of the hepatitis group (74%) and 12 patients of the control group (57%) were slow acetylators. With regard to the pharmacokinetic parameters no differences were found in both slow and rapid acetylators between the sulfamethazine group and the antipyrine group.

[Biotransformation in patients following Depressan-induced hepatitis]. / Biotransformation bei Patienten nach Depressan-Hepatitis.

In 17 patients who more than 1 year ago had suffered from a dihydralazine induced hepatitis the biotransformation velocity was investigated and compared with a healthy control group. 15 out of the 17 patients and 5 out of the 10 volunteers are slow acetylators. All slow acetylators eliminate sulfamethazine more slowly than rapid acetylators.--The elimination of caffeine and metamizol--test substances for oxidative biotransformation reactions--was retarded in patients after dihydralazine induced hepatitis in comparison to control persons. Slow acetylators have to be controlled carefully because of their higher risk of dihydralazine induced drug hepatitis.

[Drug-induced hepatitis after dihydralazine treatment with fatal consequences]. / Arzneimittelhepatitis nach Dihydralazin mit tödlichem Verlauf.

Adverse drug side effects of the antihypertensive substance dihydralazine have been increasingly observed in recent years. Damage is concentrated on the liver and is characterized by drug-induced hepatitis with confluent necrosis. Three cases (60 year old woman, 79 year old woman, 61 year old man) with lethal course after antihypertensive treatment, using dihydralazine are reported in this paper.

[Chronic drug-induced hepatitis caused by dihydralazine]. / Chronische Arzneimittelhepatitis durch Dihydralazin. Bericht über 2 Fälle.

Two cases are described, which revealed the picture of a dihydralazine-induced chronic aggressive hepatitis bioptically. One case was laparotomized under the clinical diagnosis of obstruction jaundice, the other exhibited no symptoms and was detected by elevated transaminases only. The time of exposure was 2-3 years. After withdrawal of dihydralazine the patients recovered within 2-3 months. Elevated transaminases (more than 1 mumol) should given occasion for withdrawing the drug or for performing of liver biopsy. In a total of 6,581 liver biopsies within five years an acute dihydralazine-hepatitis was seen more frequent than a chronic one (ratio 77:2).