Modulation by antenatal therapies of cardiovascular and renal programming in male and female offspring of preeclamptic rats.

Morbidity and mortality risks are enhanced in preeclamptic (PE) mothers and their offspring. Here, we asked if sexual dimorphism exists in (i) cardiovascular and renal damage evolved in offspring of PE mothers, and (ii) offspring responsiveness to antenatal therapies. PE was induced by administering NG-nitro-L-arginine methyl ester (L-NAME, 50 mg/kg/day, oral gavage) to pregnant rats for 7 days starting from gestational day 14. Three therapies were co-administered orally with L-NAME, atrasentan (endothelin ETA receptor antagonist), terutroban (thromboxane A2 receptor antagonist, TXA2), or α-methyldopa (α-MD, central sympatholytic drug). Cardiovascular and renal profiles were assessed in 3-month-old offspring. Compared with offspring of non-PE rats, PE offspring exhibited elevated systolic blood pressure and proteinuria and reduced heart rate and creatinine clearance (CrCl). Apart from a greater bradycardia in male offspring, similar PE effects were noted in male and female offspring. While terutroban, atrasentan, or α-MD partially and similarly blunted the PE-evoked changes in CrCl and proteinuria, terutroban was the only drug that virtually abolished PE hypertension. Rises in cardiorenal inflammatory (tumor necrosis factor alpha, TNFα) and oxidative (isoprostane) markers were mostly and equally eliminated by all therapies in the two sexes, except for a greater dampening action of atrasentan, compared with α-MD, on tissue TNFα in female offspring only. Histopathologically, antenatal terutroban or atrasentan was more effective than α-MD in rectifying cardiac structural damage, myofiber separation, and cytoplasmic alterations, in PE offspring. The repair by antenatal terutroban or atrasentan of cardiovascular and renal anomalies in PE offspring is mostly sex-independent and surpasses the protection offered by α-MD, the conventional PE therapy.

Preventing Recurrent Preeclampsia by Tailored Treatment of Nonphysiologic Hemodynamic Adjustments to Pregnancy.

[Figure: see text].

The comparison of side effects of methyldopa, amlodipine, and metoprolol in pregnant women with chronic hypertension.

OBJECTIVE: The aim of the study was to compare the complication of Antihypertensive drug; in pregnant women with chronic hypertension. METHOD: This retrospective cohort study was performed on 300 pregnant women  with chronic hypertension. Results:  a relative risk of preeclampsia among methyldopa group was 3.45 times higher than the metoprolol, the relative risk of preterm labor was not significantly between methyldopa and metoprolol group, LBW, and IUGR in methyldopa and amlodipine groups . CONCLUSION: Methyldopa and amlodipine are associated with the least side effects in pregnant women treated for chronic hypertension.the incidence of preeclampsia was greater in methyldopa group.

Methyldopa as an inductor of postpartum depression and maternal blues: A review.

PURPOSE: Pregnancy and time period right after labour are connected with some dangerous states, such as: pregnancy-induced hypertension (PIH), which afflict 6-10 % of pregnant women and mood disorders where postpartum depression occurs among 10-15 % of women after labour and so-called baby blues afflicts around 43 % of them. Scientists tried to link those diseases which afflicts thousands of women per year, and the linking factor appears to be methyldopa which is the first choice treatment of PIH. Recent study showed that 778 % of pregnant women treated with methyldopa suffered to postpartum depression. Aim of this article is to delineate mechanisms through which methyldopa induce mood disorders. METHODS: Authors reviewed following databases for randomized controlled trials and review articles published up to February 2019: Pubmed, Scopus, Google Scholar, Cochrane Database and ClinicalKey. Keywords used to research were: postpartum depression, methyldopa, depression, baby blues, pregnancy-induced hypertension, gestational hypertension, VEGF, nitric oxide, prolactin, hyperprolactinaemia. Selection of studies was based on relevance, year of publication, and reliability of methodology. Authors included every study contributory to assessment of scale of the problem of postpartum depression and baby blues, along with connection of those diseases with usage of methyldopa. RESULTS: Methyldopa alterate neurotrophic factors levels, impairs cerebral blood flow, and through dopamine level reduction it impairs reward system and increase prolactin release. Moreover, methyldopa leads to catecholamines depletion which impairs neurons function and increase concentration of nitric oxide (NO) which have neurotoxic properties. CONCLUSIONS: Epidemiological, as well as pharmacological studies confirmed important role of methyldopa in induction of postpartum depression and baby blues through hormone alteration, reduced cerebral blood flow and neurons function impairment. This study proves how important for women's health is this problem and how complex is its mechanism.

Methyldopa versus nifedipine or no medication for treatment of chronic hypertension during pregnancy: A multicenter randomized clinical trial.

OBJECTIVE: To assess the maternal and fetal outcome in women with mild to moderate chronic hypertension on antihypertensive drug (methyldopa or nifedipine) therapy compared to no medication. METHODS: This multicenter randomized clinical trial was conducted at Menoufia University hospital, Shibin El-kom Teaching hospital and 11 Central hospitals at Menoufia governorate, Egypt.490 pregnant women with mild to moderate chronic hypertension were randomized into three groups; methyldopa group (n = 166), nifedipine group (n = 160) and control or no medication group (n = 164) who were followed from the beginning of pregnancy till the end of puerperium to record maternal and fetal outcome. RESULTS: Mothers in the control (no medication) group were more prone for the development of severe hypertension, preeclampsia, renal impairment, ECG changes, placental abruption and repeated hospital admissions (p < 0.001) when compared to mothers in both treatment groups (methyldopa and nifedipine). Neonates in the control (no medication) group were more prone for prematurity and admission to neonatal ICU (p < 0.001). CONCLUSION: Antihypertensive drug therapy is advisable in mild to moderate chronic hypertension during pregnancy to decrease maternal and fetal morbidity. When considering which agents to use for treatment, oral methyldopa and nifedipine are valid options.

Oral antihypertensive regimens (nifedipine retard, labetalol, and methyldopa) for management of severe hypertension in pregnancy: an open-label, randomised controlled trial.

BACKGROUND: Hypertension is the most common medical disorder in pregnancy, complicating one in ten pregnancies. Treatment of severely increased blood pressure is widely recommended to reduce the risk for maternal complications. Regimens for the acute treatment of severe hypertension typically include intravenous medications. Although effective, these drugs require venous access and careful fetal monitoring and might not be feasible in busy or low-resource environments. We therefore aimed to compare the efficacy and safety of three oral drugs, labetalol, nifedipine retard, and methyldopa for the management of severe hypertension in pregnancy. METHODS: In this multicentre, parallel-group, open-label, randomised controlled trial, we compared these oral antihypertensives in two public hospitals in Nagpur, India. Pregnant women were eligible for the trial if they were aged at least 18 years; they were pregnant with fetuses that had reached a gestational age of at least 28 weeks; they required pharmacological blood pressure control for severe hypertension (systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥110 mm Hg); and were able to swallow oral medications. Women were randomly assigned to receive 10 mg oral nifedipine, 200 mg oral labetalol (hourly, in both of which the dose could be escalated if hypertension was maintained), or 1000 mg methyldopa (a single dose, without dose escalation). Masking of participants, study investigators, and care providers to group allocation was not possible because of different escalation protocols in the study groups. The primary outcome was blood pressure control (defined as 120-150 mm Hg systolic blood pressure and 70-100 mm Hg diastolic blood pressure) within 6 h with no adverse outcomes. This study is registered with ClinicalTrials.gov, number NCT01912677, and the Clinical Trial Registry, India, number ctri/2013/08/003866. FINDINGS: Between April 1, 2015, and Aug 21, 2017, we screened 2307 women for their inclusion in the study. We excluded 1413 (61%) women who were ineligible, declined to participate, had impending eclampsia, were in active labour, or had a combination of these factors. 11 (4%) women in the nifedipine group, ten (3%) women in the labetalol group, and 11 (4%) women in the methyldopa group were ineligible for treatment (because they had only one qualifying blood pressure measurement) or had treatment stopped (because of delivery or transfer elsewhere). 894 (39%) women were randomly assigned to a treatment group and were included in the intention-to-treat analysis: 298 (33%) women were assigned to receive nifedipine, 295 (33%) women were assigned to receive labetalol, and 301 (33%) women were assigned to receive methyldopa. The primary outcome was significantly more common in women in the nifedipine group than in those in the methyldopa group (249 [84%] women vs 230 [76%] women; p=0·03). However, the primary outcome did not differ between the nifedipine and labetalol groups (249 [84%] women vs 228 [77%] women; p=0·05) or the labetalol and methyldopa groups (p=0·80). Seven serious adverse events (1% of births) were reported during the study: one (<1%) woman in the labetalol group had an intrapartum seizure and six (1%) neonates (one [<1%] neonate in the nifedipine group, two [1%] neonates in the labetalol group, and three [1%] neonates in the methyldopa group) were stillborn. No birth had more than one adverse event. INTERPRETATION: All oral antihypertensives reduced blood pressure to the reference range in most women. As single drugs, nifedipine retard use resulted in a greater frequency of primary outcome attainment than labetalol or methyldopa use. All three oral drugs-methyldopa, nifedipine, and labetalol-are viable initial options for treating severe hypertension in low-resource settings. FUNDING: PREEMPT (University of British Columbia, Vancouver, BC, Canada; grantee of Bill & Melinda Gates Foundation).

Maternal and perinatal outcomes associated with the use of renin-angiotensin system (RAS) blockers for chronic hypertension in early pregnancy.

OBJECTIVE: Previous research reported greater risk of adverse perinatal outcomes associated with first trimester exposure to angiotensin converting enzyme inhibitors (ACEIs) in comparison to unexposed pregnancies among non-hypertensive women. We examined the relationship between first trimester exposure to ACEIs and angiotensin receptor blockers (ARBs), and maternal and perinatal outcomes, whilst controlling for the underlying hypertension. STUDY DESIGN: We performed a population-based cohort study among 130,061 pregnancies resulting in birth in NSW, Australia between 2005 and 2012. Birth data were linked to hospital discharge and pharmaceutical dispensing records. After restricting to women with chronic hypertension, 67 and 73 pregnancies exposed to ACEIs and ARBs respectively during the first trimester were compared with 316 pregnancies exposed to methyldopa. STUDY OUTCOMES: Preterm delivery, caesarean section, low birth weight, small for gestational age and Apgar score <7. RESULTS: Compared to pregnancies exposed to methyldopa, the adjusted odds ratio (aOR) for ACEI exposure was 0.5 (95% CI: 0.2-1.1) for preterm delivery, 1.6 (0.8-3.1) for caesarean section, 0.6 (0.2-1.3) for LBW and 0.8 (0.4-1.9) for SGA. The corresponding aORs and confidence intervals for ARB exposure were 0.7 (0.3-1.5), 1.2 (0.6-2.6), 1.3 (0.7-2.6), and 1.2 (0.6-2.4). CONCLUSION: No association between early pregnancy exposure to ACEIs and ARBs and perinatal outcomes was observed, however, the possibility of an association cannot be ruled out due to limited power. Nonetheless, this study suggests that the magnitude of risk is smaller than that reported previously.

Pregnancy Outcome After First Trimester Use of Methyldopa: A Prospective Cohort Study.

Published experience on first trimester exposure to methyldopa is still limited, although it is recommended as first-line treatment for hypertensive disorders in pregnancy in most countries. The primary aim of this prospective observational cohort study was to analyze the rate of major birth defects and spontaneous abortions in women with methyldopa therapy for chronic hypertension. Outcomes of 261 pregnancies with first trimester exposure to methyldopa and 526 comparison pregnancies without chronic hypertension reported to the German Embryotox pharmacovigilance institute were evaluated. The rate of major birth defects in the exposed cohort was not significantly increased compared with the comparison cohort (3.7% versus 2.5%; adjusted odds ratio, 1.24; 95% confidence interval, 0.4-4.0). There was a tendency toward a higher rate of spontaneous abortions in exposed women. The risk of preterm birth was significantly higher, and adjusted birth weight scores were significantly lower in the methyldopa group. Head circumferences were significantly reduced in exposed boys only. There was neither evidence for an increased risk for birth defects or increase in early pregnancy loss nor evidence for growth restriction or a reduced head circumference in a sensitivity analysis comparing monotherapies with methyldopa to metoprolol. However, the significantly increased risk of preterm birth in methyldopa-treated pregnancies was confirmed. In conclusion, our study does not indicate a teratogenic risk of methyldopa. Further studies are needed to confirm its safety in the first trimester and clarify the influence of hypertension and methyldopa on preterm birth and intrauterine growth. CLINICAL TRIAL REGISTRATION: URL: https://drks-neu.uniklinik-freiburg.de/drks_web/. Unique identifier: DRKS00010502.

The CHIPS Randomized Controlled Trial (Control of Hypertension in Pregnancy Study): Is Severe Hypertension Just an Elevated Blood Pressure?

To determine whether clinical outcomes differed by occurrence of severe hypertension in the international CHIPS trial (Control of Hypertension in Pregnancy Study), adjusting for the interventions of "less tight" (target diastolic blood pressure [dBP] 100 mm Hg) versus "tight" control (target dBP 85 mm Hg). In this post-hoc analysis of CHIPS data from 987 women with nonsevere nonproteinuric preexisting or gestational hypertension, mixed effects logistic regression was used to compare the following outcomes according to occurrence of severe hypertension, adjusting for allocated group and the influence of baseline factors: CHIPS primary (perinatal loss or high-level neonatal care for >48 hours) and secondary outcomes (serious maternal complications), birth weight <10th percentile, preeclampsia, delivery at <34 or <37 weeks, platelets <100×109/L, elevated liver enzymes with symptoms, maternal length of stay ≥10 days, and maternal readmission before 6 weeks postpartum. Three hundred and thirty-four (34.1%) women in CHIPS developed severe hypertension that was associated with all outcomes examined except for maternal readmission (P=0.20): CHIPS primary outcome, birth weight <10th percentile, preeclampsia, preterm delivery, elevated liver enzymes (all P<0.001), platelets <100×109/L (P=0.006), and prolonged hospital stay (P=0.03). The association between severe hypertension and serious maternal complications was seen only in less tight control (P=0.02). Adjustment for preeclampsia (464, 47.3%) did not negate the relationship between severe hypertension and the CHIPS primary outcome (P<0.001), birth weight <10th percentile (P=0.005), delivery at <37 (P<0.001) or <34 weeks (P<0.001), or elevated liver enzymes with symptoms (P=0.02). Severe hypertension is a risk marker for adverse maternal and perinatal outcomes, independent of BP control or preeclampsia co-occurrence. CLINICAL TRIAL REGISTRATION: URL: http://pre-empt.cfri.ca/. Unique identifier: ISRCTN 71416914. URL: https://www.clinicaltrials.gov/. Unique identifier: NCT01192412.

Subclinical hypothyroidism causing hypertension in pregnancy.

This is a case of a 25-year-old primigravida who was referred to the hypertension specialist for elevated blood pressures. The patient had an elevated thyroid-stimulating hormone with normal free thyroxine (T4) levels and was positive for thyroid peroxidase antibodies resulting in a diagnosis of subclinical hypothyroidism. The patient was successfully treated with levothyroxine which normalized the blood pressure without the need for antihypertensive treatment. This case illustrates a cause of secondary hypertension that is not always considered in the differential diagnosis of a patient with hypertension in pregnancy.

Oral antihypertensive therapy for severe hypertension in pregnancy and postpartum: a systematic review.

BACKGROUND: Pregnant and postpartum women with severe hypertension are at increased risk of stroke and require blood pressure (BP) reduction. Parenteral antihypertensives have been most commonly studied, but oral agents would be ideal for use in busy and resource-constrained settings. OBJECTIVES: To review systematically, the effectiveness of oral antihypertensive agents for treatment of severe pregnancy/postpartum hypertension. SEARCH STRATEGY: A systematic search of MEDLINE, EMBASE and the Cochrane Library was performed. SELECTION CRITERIA: Randomised controlled trials in pregnancy and postpartum with at least one arm consisting of a single oral antihypertensive agent to treat systolic BP ≥ 160 mmHg and/or diastolic BP ≥ 110 mmHg. DATA COLLECTION AND ANALYSIS: Cochrane RevMan 5.1 was used to calculate relative risk (RR) and weighted mean difference by random effects. MAIN RESULTS: We identified 15 randomised controlled trials (915 women) in pregnancy and one postpartum trial. Most trials in pregnancy compared oral/sublingual nifedipine capsules (8-10 mg) with another agent, usually parenteral hydralazine or labetalol. Nifedipine achieved treatment success in most women, similar to hydralazine (84% with nifedipine; relative risk [RR] 1.07, 95% confidence interval [95% CI] 0.98-1.17) or labetalol (100% with nifedipine; RR 1.02, 95% CI 0.95-1.09). Less than 2% of women treated with nifedipine experienced hypotension. There were no differences in adverse maternal or fetal outcomes. Target BP was achieved ~ 50% of the time with oral labetalol (100 mg) or methyldopa (250 mg) (47% labetelol versus 56% methyldopa; RR 0.85 95% CI 0.54-1.33). CONCLUSIONS: Oral nifedipine, and possibly labetalol and methyldopa, are suitable options for treatment of severe hypertension in pregnancy/postpartum.

A single oral dose of fructose induces some features of metabolic syndrome in rats: role of oxidative stress.

BACKGROUND AND AIMS: To determine if a single oral dose of fructose to rats reproduces some features of metabolic syndrome observed after chronic administration and if so, to investigate its mechanisms. METHODS AND RESULTS: Systolic blood pressure was measured in rats before and after oral administration of fructose, and in animals pretreated with lipoic acid, methyldopa, losartan or streptozotocin. In other rats, glucose, insulin, uric acid, and insulin sensitivity index, were determined before and after fructose or lipoic acid plus fructose. Glutathione was measured in liver before and after fructose administration. In aortic rings from other rats, incubation with mannitol, fructose, or fructose plus lipoic acid was evaluated on the relaxation by acetylcholine. Fructose produced a moderate increase in blood pressure, which was prevented by lipoic acid or streptozotocin. Methyldopa and losartan decreased the pressor response minimally. Fructose increased oxidized glutathione, plasma glucose, insulin and uric acid, and diminished the insulin sensitivity index, and the reduced glutathione. Lipoic acid prevented hyperglycemia and hyperuricemia, and improved the insulin sensitivity index. Finally, endothelial dysfunction was prevented by lipoic acid. CONCLUSION: A single dose of fructose reproduces some of the features of metabolic syndrome, most changes were caused by oxidative stress and insulin resistance.

Rationale and design of the Newer Versus Older Antihypertensive Agents in African Hypertensive Patients (NOAAH) trial.

BACKGROUND: Sub-Saharan Africa experiences an epidemic surge in hypertension. Studies in African Americans led to the recommendation to initiate antihypertensive treatment in Blacks with a diuretic or a low-dose fixed combination including a diuretic. We mounted the Newer versus Older Antihypertensive Agents in African Hypertensive Patients (NOAAH) trial to compare in native African patients a fixed combination of newer drugs, not involving a diuretic, with a combination of older drugs including a diuretic. METHODS: Patients aged 30-69 years with uncomplicated hypertension (140-179/90-109 mmHg) and two or fewer associated risk factors are eligible. After a 4-week run-in period off treatment, 180 patients will be randomized to once daily bisoprolol/hydrochlorothiazide 5/6.25 mg or amlodipine/valsartan 5/160 mg. To attain and maintain blood pressure below 140/90 mmHg during 6 months of follow-up, the doses of bisoprolol and amlodipine in the combination tablets will be increased to 10 mg/day with the possible addition of α-methyldopa or hydralazine. NOAAH is powered to demonstrate a 5-mmHg between-group difference in sitting systolic pressure with a two-sided p-value of 0.01 and 90% power. NOAAH is investigator-led and complies with the Helsinki declaration. RESULTS: Six centers in four sub-Saharan countries started patient recruitment on September 1, 2010. On December 1, 195 patients were screened, 171 were enrolled, and 51 were randomized and followed up. The trial will be completed in the third quarter of 2011. CONCLUSIONS: NOAAH (NCT01030458) is the first randomized multicenter trial of antihypertensive medications in hypertensive patients born and living in sub-Saharan Africa.

Preparation and evaluation of a new nano pharmaceutical excipients and drug delivery system based in polyvinylpyrrolidone and silicate.

PURPOSE: This work describes the preparation of new nanocomposites based on lamellar silicates (AAM-alkyl ammonium montmorillonite) obtained by the intercalation of PVP K30 and glyceril monostearate. METHODS: By XRD, TGA and DSC analysis the AAM was characterized and its compactation characteristics, functionality and toxicity were also tested. The AAM/PVP K-30 and AAM/GME nanocomposite obtained were evaluated to identify the interlamellar spacing values by XRD diffratograms. Tablets were prepared using methyldopa and theophylline as model drugs and the dissolution tests were carried out in simulated gastric fluid and simulated enteric fluid. RESULTS: AAM showed a good compactability and compressibility characteristics for tablets preparation. The intercalation yields (approximately 25%) of the nanocomposites were efficient. The AAM/PVP K-30 nanocomposites were successfully tested as dissolution enhancers and sustained release matrixes. CONCLUSIONS: The results also suggested the promising use of AAM (viscogel B8) and the new nanocomposite prepared by clay/PVP K-30 intercalation as a new matrix for sustained release and the feasibility of using these new nanocomposites as dissolution enhancer.

Investigation of the effects of the chronic administration of some antihypertensive drugs on enzymatic and non-enzymatic oxidant/antioxidant parameters in rat ovarian tissue.

OBJECTIVE: In this study, effects of chronic antihypertensive drug (clonidine, methyldopa, amlodipine, ramipril, and rilmenidine) treatment on antioxidant-oxidant parameters were investigated in rat ovarian tissue. STUDY DESIGN: Chronic drug administration for 30 days and at the end, biochemical examinations (total glutathione (tGSH), glutathione peroxidase (GPO), glutathione reductase (GR), glutathione s-transferase (GST), superoxide dismutase (SOD), nitric oxide (NO), catalase (CAT), malondialdehyde (MDA), and myeloperoxidase (MPO) analyses) were performed. RESULTS: The levels of glutathione (GSH) and NO, and the activities of GPO, GR, GST, SOD, and CAT were measured the lowest in ramiprile group. Also in ramiprile group, the level of MDA and the activity of MPO was the highest. CONCLUSION: We divided the drugs into four groups according to their biochemical side effect potentials in ovarian tissue: (I) Drugs which have no clear negative effect on ovarian tissue: clonidine, rilmenidine; (II) Drugs which have mild negative effect on ovarian tissue: methyldopa; (III) Drugs which have moderate negative effect on ovarian tissue: amlodipine; (IV) Drugs which have severe negative effect on ovarian tissue: ramipril. These data might be useful in the selection of the least toxic antihypertensive drug in pregnant and/or normal females.

Single dose bioequivalence study of alpha-methyldopa tablet formulations using a modified HPLC method.

BACKGROUND AND OBJECTIVE: The purpose of the present study was to compare the bioavailability of a new methyldopa (CAS 555-30-6) tablet formulation with that of a reference formulation in 12 healthy male subjects using a modified HPLC method. METHODS: The study was designed as an open label, single-dose, randomized study with a cross-over design. Under fasting conditions, each subject received one 250-mg tablet orally as a single dose of a test or reference formulation on two treatment days. The treatment periods were separated by a one-week washout period. The blood samples were collected at different time points after each administration and determined using a rapid and reliable modified HPLC method. The method used was validated for specificity, accuracy, precision and sensitivity. The pharmacokinetic parameters (Cmax, AUC0-t, AUC0-infinity) were statistically compared by analysis of variance (ANOVA) for test and reference formulations. RESULTS AND DISCUSSION: All validation criteria for the developed HPLC method were in acceptable range. The maximum plasma concentration (Cmax) of alpha-methyldopa was 270.3-1864.9 ng/ml for the test and 224.5-1585.6 ng/ml for the reference formulation. The mean AUC0-infinity of alpha-methyldopa was 2002.1-10614.8 and 2076.8- 9056.3 ng x h/ml for the test and reference formulation, respectively. The calculated 90% confidence intervals for the mean test/reference ratios of mentioned parameters were 92.48-115.94, and 88.82-101.13 which are in the bioequivalence range. The statistical tests did not show any statistical differences between formulations suggesting that methyldopa tablet of test and reference can be considered as bioequivalent preparations. CONCLUSION: A rapid and reliable HPLC method with fluorescence detector was developed to analyze alpha-methyldopa in human plasma. Based on the obtained results the test formulation of alpha-methyldopa is bioequivalent to the reference formulation.

[Methyldopa-induced acute reactive hepatitis in pregnancy, drug-metabolizing capacity of the liver]. / Methyldopa által indukált akut reaktív hepatitis terhességben, a máj gyógyszer-metabolizáló képességének alakulása.

Alpha-methyldopa is a regularly used antihypertensive drug during pregnancy. Methyldopa, which decreases the sympathoadrenal system, is the first drug of choice since decades. The reactive hepatitis is not frequent, but known serious side effect of alpha-methyldopa. In non-pregnant women the estimated rate of manifest hepatotoxicity is 2.5-10%. In our case, gestation hypertension developed at the 21st gestation week of a 35 year-old pregnant woman. Oral methyldopa, a central alpha adrenergic blocker therapy was introduced. On the 23rd gestation week acute hepatitis developed. During differential diagnosis of hepatitis, the etiology of methyldopa was taken into account. Viral and autoimmune origin was rolled out. No fetal aberration was found during ultrasound examination. The function of drug metabolizing function from blood was measured by CYP phenotyping (CYP gene expression analysis). CYP3A4 enzyme plays a primary role in the metabolism of nifedipine. Antihypertensive therapy was changed from methyldopa to nifedipine. Nifedipine dosage was based on the value of CYP3A4 gene expression. With the reduced nifedipine therapy (30 mg daily), blood pressure was successfully under control. The diagnosis of alpha-methyldopa induced hepatitis was based on anamnesis, clinical picture and the results of chemical and radiological examination and confirmed by the level of drug-metabolizing capacity. The gestation hepatotoxicity of alpha-methyldopa was reported first in 1969 by Elkington Smith, who suggested the monitoring of serum aminotransferase during alpha-methyldopa therapy in pregnancy in their case report. Our case report confirms that monitoring of serum aminotransferase level is still valuable when treating a pregnant woman with alpha-methyldopa.

The timing of administration, dose dependence and efficacy of dopa decarboxylase inhibitors on the reversal of motor disability produced by L-DOPA in the MPTP-treated common marmoset.

Dopa decarboxylase inhibitors are routinely used to potentiate the effects of L-DOPA in the treatment of Parkinson's disease. However, neither in clinical use nor in experimental models of Parkinson's disease have the timing and dose of dopa decarboxylase inhibitors been thoroughly explored. We now report on the choice of dopa decarboxylase inhibitors, dose and the time of dosing relationships of carbidopa, benserazide and L-alpha-methyl dopa (L-AMD) in potentiating the effects of L-DOPA in the 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-treated common marmoset. Pre-treatment with benserazide for up to 3h did not alter the motor response to L-DOPA compared to simultaneous administration with L-DOPA. There was some evidence of a relationship between carbidopa and benserazide dose and increased locomotor activity and the reversal of motor disability. But in general, commonly used dose levels of dopa decarboxylase inhibitors appeared to produce a maximal motor response to L-DOPA. In contrast, dyskinesia intensity and duration continued to increase with both carbidopa and benserazide dose. The novel dopa decarboxylase inhibitor, L-AMD, increased locomotor activity and improved motor disability to the same extent as carbidopa or benserazide but importantly this was accompanied by significantly less dyskinesia. This study shows that currently, dopa decarboxylase inhibitors may be routinely employed in the MPTP-treated primate at doses which are higher than those necessary to produce a maximal potentiation of the anti-parkinsonian effect of L-DOPA. This may lead to excessive expression of dyskinesia in this model of Parkinson's disease and attention should be given to the dose regimens currently employed.

Is expectant management of early-onset severe preeclampsia worthwhile in low-resource settings?

OBJECTIVE: To evaluate the maternal and perinatal outcome following expectant management of early-onset severe preeclampsia (PE) at a tertiary hospital in Mansoura, Egypt. METHODS: This prospective, observational study included 211 patients with severe PE, occurring between 24 and 34 weeks of gestation. They were classified according to gestational age on admission into three groups. Group 1 included 61 patients with gestational ages between 24 and 28 weeks. Group 2 (28 to <32 weeks) included 66 patients and group 3 (32-34 weeks) included 84 patients. Outcome measures included prolongation of gestation, and maternal and perinatal complications. RESULTS: The median overall prolongation of gestation was 12 +/- 6 days. The rate of neonatal survival significantly increased (P < 0.001) from 12/61 (19.7%) in group 1 to 30/66 (45.5%) in group 2 and 67/84 (79.8%) in group 3. There were no maternal mortalities; however, 43 (20.4%) women developed significant morbidities. HELLP syndrome, renal impairment and placental abruption were the main complications. CONCLUSION: In low-resource settings, expectant management of early-onset severe PE is associated with relatively higher rates of perinatal mortality and maternal morbidity and should be limited to gestational ages between 28 and 34 weeks of gestation.