The "Preeclampsia and Hypertension Target Treatment" study: a multicenter prospective study to evaluate the effectiveness of the antihypertensive therapy based on maternal hemodynamic findings.

BACKGROUND: Despite major advances in the pharmacologic treatment of hypertension in the nonpregnant population, treatments for hypertension in pregnancy have remained largely unchanged over the years. There is recent evidence that a more adequate control of maternal blood pressure is achieved when the first given antihypertensive drug is able to correct the underlying hemodynamic disorder of the mother besides normalizing the blood pressure values. OBJECTIVE: This study aimed to compare the blood pressure control in women receiving an appropriate or inappropriate antihypertensive therapy following the baseline hemodynamic findings. STUDY DESIGN: This was a prospective multicenter study that included a population of women with de novo diagnosis of hypertensive disorders of pregnancy. A noninvasive assessment of the following maternal parameters was performed on hospital admission via Ultrasound Cardiac Output Monitor before any antihypertensive therapy was given: cardiac output, heart rate, systemic vascular resistance, and stroke volume. The clinician who prescribed the antihypertensive therapy was blinded to the hemodynamic evaluation and used as first-line treatment a vasodilator (nifedipine or alpha methyldopa) or a beta-blocker (labetalol) based on his preferences or on the local protocols. The first-line pharmacologic treatment was retrospectively considered hemodynamically appropriate in either of the following circumstances: (1) women with a hypodynamic profile (defined as low cardiac output [≤5 L/min] and/or high systemic vascular resistance [≥1300 dynes/second/cm2]) who were administered oral nifedipine or alpha methyldopa and (2) women with a hyperdynamic profile (defined as normal or high cardiac output [>5 L/min] and/or low systemic vascular resistances [<1300 dynes/second/cm2]) who were administered oral labetalol. The primary outcome of the study was to compare the occurrence of severe hypertension between women treated with a hemodynamically appropriate therapy and women treated with an inappropriate therapy. RESULTS: A total of 152 women with hypertensive disorders of pregnancy were included in the final analysis. Most women displayed a hypodynamic profile (114 [75.0%]) and received a hemodynamically appropriate treatment (116 [76.3%]). The occurrence of severe hypertension before delivery was significantly lower in the group receiving an appropriate therapy than in the group receiving an inappropriately treated (6.0% vs 19.4%, respectively; P=.02). Moreover, the number of women who achieved target values of blood pressure within 48 to 72 hours from the treatment start was higher in the group who received an appropriate treatment than in the group who received an inappropriate treatment (70.7% vs 50.0%, respectively; P=.02). CONCLUSION: In pregnant individuals with de novo hypertensive disorders of pregnancy, a lower occurrence of severe hypertension was observed when the first-line antihypertensive agent was tailored to the correct maternal hemodynamic profile.

Improvement of the cardiovascular effect of methyldopa by complexation with Zn(II): Synthesis, characterization and mechanism of action.

BACKGROUND: the antihypertensive drug α-methyldopa (MD) stands as one of the extensively used medications for managing hypertension during pregnancy. Zinc deprivation has been associated with many diseases. In this context, the synthesis of a Zn coordination complex [Zn(MD)(OH)(H2O)2]·H2O (ZnMD) provide a promising alternative pathway to improve the biological properties of MD. METHODS: ZnMD was synthesized and physicochemically characterized. Fluorescence spectral studies were conducted to examine the binding of both, the ligand and the metal with bovine serum albumin (BSA). MD, ZnMD, and ZnCl2 were administered to spontaneous hypertensive rats (SHR) rats during 8 weeks and blood pressure and echocardiographic parameters were determined. Ex vivo assays were conducted to evaluate levels of reactive oxygen species (ROS), thiobarbituric acid reactive substances (TBARS), and nitric oxide (NO). Cross-sectional area (CSA) and collagen levels of left ventricular cardiomyocytes were also assessed. Furthermore, the expression of NAD(P)H oxidase subunits (gp91phox and p47phox) and Superoxide Dismutase 1 (SOD1) was quantified through western blot analysis. RESULTS: The complex exhibited a moderate affinity for binding with BSA showing a spontaneous interaction (indicated by negative ΔG values) and moderate affinity (determined by affinity constant values). The binding process involved the formation of Van der Waals forces and hydrogen bonds. Upon treatment with MD and ZnMD, a reduction in the systolic blood pressure in SHR was observed, being ZnMD more effective than MD (122 ± 8.1 mmHg and 145 ± 5.6 mmHg, at 8th week of treatment, respectively). The ZnMD treatment prevented myocardial hypertrophy, improved the heart function and reduced the cardiac fibrosis, as evidenced by parameters such as left ventricular mass, fractional shortening, and histological studies. In contrast, MD did not show noticeable differences in these parameters. ZnMD regulates negatively the oxidative damage by reducing levels of ROS and lipid peroxidation, as well as the cardiac NAD(P)H oxidase, and increasing SOD1 expression, while MD did not show significant effect. Moreover, cardiac nitric oxide levels were greater in the ZnMD therapy compared to MD treatment. CONCLUSION: Both MD and ZnMD have the potential to be transported by albumin. Our findings provide important evidence suggesting that this complex could be a potential therapeutic drug for the treatment of hypertension and cardiac hypertrophy and dysfunction.

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.

Combined Effects of Methyldopa and Flavonoids on the Expression of Selected Factors Related to Inflammatory Processes and Vascular Diseases in Human Placenta Cells-An In Vitro Study.

The aim of the study was to investigate combined effects of flavonoids (apigenin, baicalein, chrysin, quercetin, and scutellarin) and methyldopa on the expression of selected proinflammatory and vascular factors in vitro for prediction of their action in pregnancy-induced hypertension. The research was conducted on a trophoblast-derived human choriocarcinoma cell line and a primary human umbilical vein endothelial cell line. Cytotoxicity of compounds in selected concentrations (20, 40, and 100 µmol) was measured using the MTT test and the concentration of 40 µmol was selected for further analysis. Subsequently, their effects with methyldopa on the expression of selected markers responsible for inflammation (TNF-α; IL-1ß; IL-6) and vascular effects (hypoxia-inducible factor 1α-HIF-1α; placental growth factor-PIGF; transforming growth factor ß-TGF-ß; vascular endothelial growth factor-VEGF) at the mRNA and protein levels were assessed. It was found that every combined administration of a flavonoid and methyldopa in these cells induced a down-regulating effect on all tested factors, except PIGF, especially at the mRNA expression level. As hypertension generally raises TNF-α, IL-1ß, IL-6, HIF-1α, TGF-ß, and VEGF mRNA expression and/or protein levels, the results obtained in the studied model may provide a positive prognostic factor for such activity in vivo.

[Pharmacological treatment of non-severe hypertension during pregnancy, postpartum and breastfeeding]. / Tratamiento farmacológico de la hipertensión arterial no severa durante el embarazo, el posparto y la lactancia.

Hypertension (HTN) in pregnancy is defined as systolic blood pressure ≥ 140 and/or diastolic blood pressure ≥ 90 mmHg. Based on the values, it is classified as non-severe (< 160/110 mmHg) and severe (≥ 160/110 mmHg). Before starting treatment in non-severe HTN, white- coat HTN should be ruled out. If outpatient management is possible, pharmacological initiation is suggested with sustained high values, avoiding < 120/80 mmHg. Safe drugs during pregnancy are methyldopa, labetalol, and nifedipine-retard. The use of nifedipine-XL or amlodipine can be considered with a lower level of evidence of safety. Diuretics, atenolol, and other beta-blockers for antihypertensive purposes is not recommended in this period. Renin-angiotensin-aldosterone system inhibitors are strictly contraindicated. In postpartum and breastfeeding, the same therapeutic regimen used during pregnancy can be maintained, trying early withdrawal of methyldopa. During puerperium, amlodipine and enalapril are safe, with minimal excretion in breast milk.

Methyldopa versus labetalol or no medication for treatment of mild and moderate chronic hypertension during pregnancy: a randomized clinical trial.

OBJECTIVE: to assess the maternal and fetal outcome in women with mild to moderate chronic hypertension on antihypertensive drug (methyldopa or labetalol) therapy compared to no medication. METHODS: This multicenter randomized clinical study was conducted at Menoufia University hospital, Shibin El-kom Teaching hospital at Menoufia governorate, Egypt.486 pregnant women with mild to moderate chronic hypertension were randomized into three groups; methyldopa group (n = 164), labetalol group (n = 160), and control or no medication group (n = 162) who were followed from the beginning of pregnancy till the end of puerperium to record maternal and fetal outcome. RESULTS: There was a highly significant difference between treatment groups (methyldopa and labetalol) and control group regarding the development of maternal severe hypertension, development of preeclampsia, renal impairment, presence of ECG changes, placental abruption, and repeated admission to hospital for blood pressure control (p < 0.001) with higher occurrence in the control (no treatment) group. Neonates in the labetalol group were more prone for the development of small for gestational age (SGA), neonatal hypotension, neonatal hyperbilirubinemia, and admission to NICU than their counterparts in the methyldopa and control groups (p < 0.001). The rate of prematurity was significantly higher in the control group than the treatment groups (p < 0.05). CONCLUSION: Treatment of mild to moderate chronic hypertension during pregnancy is beneficial in decreasing both maternal and fetal morbidity. The use of labetalol was associated with higher rates of SGA, neonatal hypotension, and neonatal hyperbilirubinemia compared to methyldopa or no medication.

Repurposed Drugs That Block the Gonococcus-Complement Receptor 3 Interaction Can Prevent and Cure Gonococcal Infection of Primary Human Cervical Epithelial Cells.

In the absence of a vaccine, multidrug-resistant Neisseria gonorrhoeae has emerged as a major human health threat, and new approaches to treat gonorrhea are urgently needed. N. gonorrhoeae pili are posttranslationally modified by a glycan that terminates in a galactose. The terminal galactose is critical for initial contact with the human cervical mucosa via an interaction with the I-domain of complement receptor 3 (CR3). We have now identified the I-domain galactose-binding epitope and characterized its galactose-specific lectin activity. Using surface plasmon resonance and cellular infection assays, we found that a peptide mimic of this galactose-binding region competitively inhibited the N. gonorrhoeae-CR3 interaction. A compound library was screened for potential drugs that could similarly prohibit the N. gonorrhoeae-CR3 interaction and be repurposed as novel host-targeted therapeutics for multidrug-resistant gonococcal infections in women. Two drugs, methyldopa and carbamazepine, prevented and cured cervical cell infection by multidrug-resistant gonococci by blocking the gonococcal-CR3 I-domain interaction.IMPORTANCE Novel therapies that avert the problem of Neisseria gonorrhoeae with acquired antibiotic resistance are urgently needed. Gonococcal infection of the human cervix is initiated by an interaction between a galactose modification made to its surface appendages, pili, and the I-domain region of (host) complement receptor 3 (CR3). By targeting this crucial gonococcal-I-domain interaction, it may be possible to prevent cervical infection in females. To this end, we identified the I-domain galactose-binding epitope of CR3 and characterized its galactose lectin activity. Moreover, we identified two drugs, carbamazepine and methyldopa, as effective host-targeted therapies for gonorrhea treatment. At doses below those currently used for their respective existing indications, both carbamazepine and methyldopa were more effective than ceftriaxone in curing cervical infection ex vivo This host-targeted approach would not be subject to N. gonorrhoeae drug resistance mechanisms. Thus, our data suggest a long-term solution to the growing problem of multidrug-resistant N. gonorrhoeae infections.

Multiple molecular targets mediated antioxidant activity, molecular docking, ADMET, QSAR and bioactivity studies of halo substituted urea derivatives of α-Methyl-l-DOPA.

A series of novel α-methyl-l-DOPA urea derivatives viz., 3-(3,4-dihydroxyphenyl)-2-methyl-2-(3-halo/trifluoromethyl substituted phenyl ureido)propanoic acids (6a-e) have been synthesized from the reaction of α-methyl-l-DOPA (3) with various aryl isocyanates (4a-e) by using triethylamine (5, TEA) as a base catalyst in THF at reflux conditions. The synthesized compounds are structurally characterized by spectral (IR, 1H &13C NMR and MASS) and elemental analysis studies and screened for their in-vitro antioxidant activity against DPPH, NO and H2O2 free radical scavenging assays and identified compounds 6c &6d as potential antioxidants. The acquired in vitro results were correlated with the results of molecular docking, ADMET, QSAR and bioactivity studies performed for them and predicted that the recorded in silico binding affinities are in good correlation with the in vitro antioxidant activity results. The molecular docking analysis has comprehended the strong hydrogen bonding interactions of 6a-e with 1CB4, 1N8Q, 3MNG, 1OG5, 1DNU, 3NRZ, 2CDU, 1HD2 and 2HCK proteins of their respective SOD, LO, PRXS5, CP450, MP, XO, NO, PRY5 and HCK enzymes. This has sustained the effective binding of 6a-e and resulted in functional inhibition of selective aminoacid residues to be pronounced as multiple molecular targets mediated antioxidant potent compounds. In addition, the evaluated toxicology risks of 6a-e are identified with in the potential limits of drug candidates. The conformational analysis of 6c & 6d prominently infers that urea moiety uniting α-methyl-l-DOPA with halo substituted aryl units into a distinctive orientation to comply good structure-activity to inhibit the proliferation of reactive oxygen species in vivo.

Rationally designed small molecules to prevent type 1 diabetes.

PURPOSE OF REVIEW: To review the recent findings that small 'drug-like' compounds block disease-specific human leukocyte antigen (HLA) molecules in type 1 diabetes (T1D). RECENT FINDINGS: The predominant genetic risk for developing T1D, the immune-mediated form of diabetes, is conferred through HLA genes. One such gene, termed HLA-DQ8, is present in 50-60% of patients with T1D and those at-risk. DQ8 presents disease-relevant peptides to T cells, which mediate tissue-specific destruction of pancreatic islets. Using a structure-based approach to evaluate the 'druggability' of the DQ8 molecule, methyldopa, a clinically well-established oral antihypertensive agent, was discovered to bind DQ8. Methyldopa blocked the activation of DQ8-specific T cells responding to self-antigens such as insulin but not influenza. In a proof-of-concept clinical trial (NCT01883804), methyldopa was administered to recent-onset T1D patients with the DQ8 gene that confirmed the mechanism of action and diminished inflammatory T cell responses toward insulin. SUMMARY: Methyldopa blocks the diabetes-specific function of HLA-DQ8, which represents a personalized medicine approach to treat the underlying autoimmunity in T1D. Clinical trials are warranted and underway to evaluate methyldopa in potentially preserving residual ß-cell function in those with new onset and at risk for T1D.

Methyldopa blocks MHC class II binding to disease-specific antigens in autoimmune diabetes.

Major histocompatibility (MHC) class II molecules are strongly associated with many autoimmune disorders. In type 1 diabetes (T1D), the DQ8 molecule is common, confers significant disease risk, and is involved in disease pathogenesis. We hypothesized that blocking DQ8 antigen presentation would provide therapeutic benefit by preventing recognition of self-peptides by pathogenic T cells. We used the crystal structure of DQ8 to select drug-like small molecules predicted to bind structural pockets in the MHC antigen-binding cleft. A limited number of the predicted compounds inhibited DQ8 antigen presentation in vitro, with 1 compound preventing insulin autoantibody production and delaying diabetes onset in an animal model of spontaneous autoimmune diabetes. An existing drug with a similar structure, methyldopa, specifically blocked DQ8 in patients with recent-onset T1D and reduced inflammatory T cell responses to insulin, highlighting the relevance of blocking disease-specific MHC class II antigen presentation to treat autoimmunity.

Increased oxidative stress and cytokinesis-block micronucleus cytome assay parameters in pregnant women with gestational diabetes mellitus and gestational arterial hypertension.

We investigated whether gestational diabetes mellitus (GDM) and gestational arterial hypertension (GH) are associated with increased oxidative stress and DNA damage. Study included 3 groups of pregnant women (GDM, GH and control). DNA damage biomarkers (micronuclei MNi, nucleoplasmic bridges NPBs and nuclear buds NBUDs) were assessed by cytokinesis-block micronucleus cytome assay. Oxidative stress levels were evaluated by analyzing malondialdehyde equivalents (TBARS) and 8-hydroxy-2'-deoxyguanosine (8-OHdG). Genotoxic effect of methyldopa, drug used to treat GH, was evaluated in in vitro experiment. TBARS levels, MNi, NPBs and NBUDs frequencies were significantly increased in both GDM and GH group. Concentrations of 8-OHdG were significantly higher in GDM than in other groups. Since methyldopa did not affect MNi, NPBs and NBUDs frequencies, nor TBARS and 8-OHdG levels, we concluded that methyldopa has no genotoxic effect. Thus, even when hyperglycemia or hypertension are present only during pregnancy they induce oxidative stress, DNA damage and chromosomal aberrations.

Antihypertensive methyldopa, labetalol, hydralazine, and clonidine reversed tumour necrosis factor-α inhibited endothelial nitric oxide synthase expression in endothelial-trophoblast cellular networks.

Medications used to control hypertension in pregnancy also improve trophoblast and endothelial cellular interaction in vitro. Tumour necrosis factor-α (TNF-α) inhibits trophoblast and endothelial cellular interactions and simultaneously decreases endothelial nitric oxide synthase (eNOS) expression. This study investigated whether antihypertensive medications improved these cellular interactions by modulating eNOS and inducible nitric oxide synthase (iNOS) expression. Human uterine myometrial microvascular endothelial cells (UtMVECs) were pre-incubated with (or without) low dose TNF-α (0.5 ng/mL) or TNF-α plus soluble fms-like tyrosine kinase-1 (sFlt-1) (100 ng/mL). The endothelial cells were cultured on Matrigel. After endothelial cellular networks appeared, trophoblast derived HTR-8/SVneo cells were co-cultured in the presence of clinically relevant doses of methyldopa, labetalol, hydralazine or clonidine for 24 hours. Cells were retrieved from the Matrigel to extract mRNA and eNOS and iNOS expression were examined by quantitative PCR. Methyldopa, labetalol, hydralazine and clonidine reversed the inhibitory effect of TNF-α on eNOS mRNA expression. After pre-incubating endothelial cells with TNF-α and sFlt-1, all the medications except methyldopa lost their effect on eNOS mRNA expression. In the absence of TNF-α, antihypertensive medications did not change eNOS expression. The mRNA expression of iNOS was not affected by TNF-α or any medications. This study shows that selected antihypertensive medications used in the treatment of hypertension in pregnancy increase eNOS expression in vitro when induced by the inflammatory TNF-α. The anti-angiogenic molecule sFlt-1 may antagonise the potential benefit of these medications by interfering with the NOS pathway.

[CHANGES IN THE BRAIN TESTOSTERONE METABOLISM AND SEXUAL BEHAVIOR IN MALE RATS PRENATALLY EXPOSED TO METHYLDOPA AND STRESS].

The changes of aromatase and 5α-reductase activities were studied in preoptic area (POA) and medial basal hypothalamus of 10-days-old and sexual behavior in 3-month-old male offsprings of rats exposed daily to noradrenaline antagonist methyldopa (400 mg/kg per os) 30 minutes prior to 1-hour immobilization during the last week of pregnancy (from 15th to 21st day). Prenatal stress caused aromatase activity lowering in the POA of developing brain and feminization (appearance of lordosis) and demasculinization of sexual behavior (prolongation of latent periods to the first mounting and first intromission as well as of the first ejaculation and postejaculation refractory period) in young male offspring. Oral methyldopa used prior to pregnant females stressing prevented early effect of prenatal stress on aromatase activity in the POA and normalized the male sexual behavior in young male rats by shortening both latent period to the first ejaculation and postejaculation refractory period, and an increase of numbers of ejaculation. The data obtained indicate that brain noradrenergic system plays significant role in the mechanisms of metabolic- and behavioral disturbances developing in male rats exposed to prenatal stress.

In-vitro study of the effect of anti-hypertensive drugs on placental hormones and angiogenic proteins synthesis in pre-eclampsia.

INTRODUCTION: Antihypertensive drugs lower the maternal blood pressure in pre-eclampsia (PE) by direct or central vasodilatory mechanisms but little is known about the direct effects of these drugs on placental functions. OBJECTIVE: The aim of our study is to evaluate the effect of labetolol, hydralazine, α-methyldopa and pravastatin on the synthesis of placental hormonal and angiogenic proteins know to be altered in PE. DESIGN: Placental villous explants from late onset PE (n = 3) and normotensive controls (n = 6) were cultured for 3 days at 10 and 20% oxygen (O2) with variable doses anti-hypertensive drugs. The levels of activin A, inhibin A, human Chorionic Gonadotrophin (hCG), soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng) were measured in explant culture media on day 1, 2 and 3 using standard immunoassays. Data at day 1 and day 3 were compared. RESULTS: Spontaneous secretion of sEndoglin and sFlt-1 were higher (p < 0.05) in villous explants from PE pregnancies compared to controls. There was a significant time dependent decrease in the secretion of sFlt-1 and sEndoglin in PE cases, which was seen only for sFlt-1 in controls. In both PE cases and controls the placental protein secretions were not affected by varying doses of anti-hypertensive drugs or the different O2 concentration cultures, except for Activin, A which was significantly (p < 0.05) higher in controls at 10% O2. INTERPRETATION: Our findings suggest that the changes previously observed in maternal serum hormones and angiogenic proteins level after anti-hypertensive treatment in PE could be due to a systemic effect of the drugs on maternal blood pressure and circulation rather than a direct effect of these drugs on placental biosynthesis and/or secretion.

Antihypertensive drugs methyldopa, labetalol, hydralazine, and clonidine improve trophoblast interaction with endothelial cellular networks in vitro.

OBJECTIVES: The interaction between trophoblasts and maternal endothelium is important for placental vascular modeling. Failure of uterine spiral artery transformation is linked to the etiopathology of preeclampsia. Antihypertensive medications used to control hypertension in early pregnancy can alter placental and circulating cytokines. This study investigated whether selected antihypertensive drugs can modulate the interaction between trophoblast and endothelial cells. METHODS: Human uterine myometrial microvascular endothelial cells were preincubated with (or without) low-dose tumor necrosis factor-α (TNF-α; 0.5 ng/ml) or TNF-α and soluble fms-like tyrosine kinase 1 (sFlt-1; 100 ng/ml). Red fluorescent-labeled endothelial cells were then cultured on Matrigel. After appearance of endothelial cellular networks, green fluorescent-labeled HTR-8/SVneo trophoblast cells were cocultured in the presence of pharmacological doses of methyldopa, labetalol, hydralazine, and clonidine. Images were captured after 24 h and drug effects on HTR-8/SVneo cell integration were quantified by Image Analysis software. The conditioned medium was collected to measure sFlt-1, vascular endothelial growth factor (VEGF), placental growth factor, interleukin-10, and interleukin-6 by ELISA. RESULTS: Methyldopa, labetalol, hydralazine, and clonidine increased trophoblast integration into TNF-α-preincubated endothelial cellular networks. In conditioned medium, sFlt-1 was reduced by methyldopa, hydralazine, and clonidine alone. VEGF was increased by methyldopa. A decrease in placental growth factor was seen by methyldopa and also in nontreated endothelial cell coculture of the other three drugs. CONCLUSION: Some antihypertensive drugs used in pregnancy may improve the cellular interaction between trophoblast and endothelial cells exposed to TNF-α. Methyldopa, hydralazine, and clonidine reduced sFlt-1 concentration in culture medium, whereas labetalol increased trophoblast integration independently of sFlt-1. Methyldopa increased VEGF concentration. Some pregnancy-related antihypertensives may affect placental vascularization.

Multi-spectroscopic and molecular modeling studies on the interaction of antihypertensive drug; methyldopa with calf thymus DNA.

The interaction of methyldopa [(S)-2-amino-3-(3,4-dihydroxyphenyl)-2-methyl propanoic acid] (MDP), antihypertensive drug, with calf thymus DNA (ct-DNA) was investigated by spectroscopic and viscometric techniques. According to the results arising from the fluorescence spectra, viscosity measurements and molecular modeling studies; we concluded that MDP is a minor groove binder of ct-DNA and preferentially binds to AT rich regions. Ethidium bromide (EB) displacement studies revealed that MDP did not have any effect on EB bound DNA which is indicative of groove binding. This was substantiated by displacement studies with Hoechst 33258, a known minor groove binder. In addition, the thermodynamic and docking parameters showed that hydrophobic interaction via drug aromatic rings inside the DNA minor groove plays a major role in this binding.

Effects of methyldopa and nifedipine on uteroplacental and fetal hemodynamics in gestational hypertension.

OBJECTIVE: Investigation of methyldopa and nifedipine effects on maternal and fetal hemodynamics in women with mild gestational hypertension during the third pregnancy trimester. METHODS: A prospective cohort study. Methyldopa effects were followed in 28 patients, and nifedipine effects in another 28 patients. There were also 28 healthy controls. RESULTS: Uterine artery blood velocity waveform indices were improved only by nifedipine. Neither of the drugs affected the indices in umbilical and fetal middle cerebral artery. Both drugs normalized maternal blood pressure and pulse. CONCLUSIONS: Methyldopa and nifedipine did not show clinically significant influence on umbilical artery and fetal cerebral blood flow.

Different culture media containing methyldopa for melanin production by Cryptococcus species.

INTRODUCTION: Melanin production by species of Cryptococcus is widely used to characterize C. neoformans complex in mycology laboratories. This study aims to test the efficacy of methyldopa from pharmaceutical tablet as a substrate for melanin production, to compare the production of melanin using different agar base added with methyldopa, and to compare the melanin produced in those media with that produced in Niger seed agar and sunflower seed agar by C. neoformans, C. laurentii, and C. albidus. Two isolates of each species, C. neoformans, C. laurentii, and C. albidus, and one of Candida albicans were used to experimentally detect conditions for melanin production. METHODS: The following media were tested: Mueller-Hinton agar (MHA), brain and heart infusion agar (BHIA), blood agar base (BAB), and minimal medium agar (MMA), all added with methyldopa, and the media Niger seed agar (NSA) and sunflower seed agar (SSA). RESULTS: All isolates grew in most of the culture media after 24h. Strains planted on media BAB and BHIA showed growth only after 48h. All isolates produced melanin in MMA, MHA, SSA, and NSA media. CONCLUSIONS: Methyldopa in the form pharmaceutical tablet can be used as a substrate for melanin production by Cryptococcus species; minimal medium plus methyldopa was more efficient than the BAB, MHA, and BHIA in the melanin production; and NSA and SSA, followed by MMA added with methyldopa, were more efficient than other media studied for melanin production by all strains studied.

Different culture media containing methyldopa for melanin production by Cryptococcus species / Avaliação de diferentes meios de cultura contendo metildopa para a produção de melanina por espécies de Cryptococcus

INTRODUCTION: Melanin production by species of Cryptococcus is widely used to characterize C. neoformans complex in mycology laboratories. This study aims to test the efficacy of methyldopa from pharmaceutical tablet as a substrate for melanin production, to compare the production of melanin using different agar base added with methyldopa, and to compare the melanin produced in those media with that produced in Niger seed agar and sunflower seed agar by C. neoformans, C. laurentii, and C. albidus. Two isolates of each species, C. neoformans, C. laurentii, and C. albidus, and one of Candida albicans were used to experimentally detect conditions for melanin production. METHODS: The following media were tested: Mueller-Hinton agar (MHA), brain and heart infusion agar (BHIA), blood agar base (BAB), and minimal medium agar (MMA), all added with methyldopa, and the media Niger seed agar (NSA) and sunflower seed agar (SSA). RESULTS: All isolates grew in most of the culture media after 24h. Strains planted on media BAB and BHIA showed growth only after 48h. All isolates produced melanin in MMA, MHA, SSA, and NSA media. CONCLUSIONS: Methyldopa in the form pharmaceutical tablet can be used as a substrate for melanin production by Cryptococcus species; minimal medium plus methyldopa was more efficient than the BAB, MHA, and BHIA in the melanin production; and NSA and SSA, followed by MMA added with methyldopa, were more efficient than other media studied for melanin production by all strains studied.

INTRODUÇÃO: A produção de melanina por espécies de Cryptococcus é uma característica amplamente utilizada em laboratórios de micologia para caracterização do complexoC. neoformans. O objetivo deste estudo foi verificar a eficácia da metildopa na forma farmacêutica de comprimido, como substrato para a produção de melanina por Cryptococcus, comparar diferentes bases de meios de cultura acrescidas de metildopa para produção de melanina e comparar o pigmento produzido nestes meios com o produzido em ágar Níger e ágar girassol por C. neoformans, C. laurentii e C. albidus. MÉTODOS: Foram testados dois isolados de cada uma das espécies, C. neoformans, C.laurentii e C.albidus, e um de C. albicans para avaliar a produção de melanina nos meios de cultura ágar Müeller-Hinton (MH), ágar brain heart infusion (BHI), ágar base sangue (BS), meio mínimo (MM), todos acrescidos de metildopa, e ainda ágar girassol e ágar Níger. RESULTADOS: Todos os isolados cresceram na maioria dos meios após 24h. O crescimento nos meios BS e BHI somente ocorreu após 48h. Todos os isolados produziram melanina nos meios MM, MH, girassol e Niger. CONCLUSÕES: A metildopa de origem farmacêutica pode ser utilizada como substrato para a produção de melanina por espécies de Cryptococcus; o MM acrescido de metildopa mostrou-se mais eficiente na produção de melanina do que os meios BS, MH e BHI; ágar girassol e ágar Níger seguidos de MM acrescido de metildopa foram os mais eficientes na produção de melanina pelos isolados estudados.

Older blood pressure medications-do they still have a place?

Hypertension is a major risk factor for cardiovascular disease, but control of hypertension remains inadequate, often because of poor patient adherence to prescribed medical regimens that are viewed as poorly tolerated and expensive. Physicians have largely stopped using some older blood pressure medications in favor of newer agents, mostly because of a presumed more favorable side effect profile. The investigators reviewed the pharmacologic properties and the evidence supporting the effectiveness and tolerability of several older blood pressure drugs: sympatholytic agents such as reserpine, methyldopa, and clonidine; diuretics such as chlorthalidone, ethacrynic acid and spironolactone; the vasodilators hydralazine and minoxidil; and others. In conclusion, some of these drugs are well studied and represent alternatives for patients who cannot afford or tolerate newer medications.