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.

Antihypertensive treatment during pregnancy induces long-term changes in gut microbiota and the behaviors of the attention deficit hyperactivity disorder offspring.

The pathogenesis of attention-deficit/hyperactivity disorder (ADHD) has not been fully elucidated. Gestational hypertension could double the probability of ADHD in the offspring, while the initial bacterial communication between the mother and offspring has been associated with psychiatric disorders. Thus, we hypothesize that antihypertensive treatment during pregnancy may abate the impairments in neurodevelopment of the offspring. To test this hypothesis, we chose Captopril and Labetalol, to apply to pregnant spontaneously hypertensive rat (SHR) dams and examined the outcomes in the male offspring. Our data demonstrated that maternal treatment with Captopril and Labetalol had long-lasting changes in gut microbiota and behavioral alterations, including decreased hyperactivity and increased curiosity, spatial learning and memory in the male offspring. Increased diversity and composition were identified, and some ADHD related bacteria were found to have the same change in the gut microbiota of both the dam and offspring after the treatments. LC-MS/MS and immunohistochemistry assays suggested elevated expression of brain derived neurotrophic factor (BDNF) and dopamine in the prefrontal cortex and striatum of offspring exposed to Captopril/ Labetalol, which may account for the improvement of the offspring's psychiatric functions. Therefore, our results support the beneficial long-term effects of the intervention of gestational hypertension in the prevention of ADHD.

Cerebral Blood Flow Assessed with Phase-contrast Magnetic Resonance Imaging during Blood Pressure Changes with Noradrenaline and Labetalol: A Trial in Healthy Volunteers.

BACKGROUND: Adequate cerebral perfusion is central during general anesthesia. However, perfusion is not readily measured bedside. Clinicians currently rely mainly on mean arterial pressure (MAP) as a surrogate, even though the relationship between blood pressure and cerebral blood flow is not well understood. The aim of this study was to apply phase-contrast magnetic resonance imaging to characterize blood flow responses in healthy volunteers to commonly used pharmacologic agents that increase or decrease arterial blood pressure. METHODS: Eighteen healthy volunteers aged 30 to 50 yr were investigated with phase-contrast magnetic resonance imaging. Intra-arterial blood pressure monitoring was used. First, intravenous noradrenaline was administered to a target MAP of 20% above baseline. After a wash-out period, intravenous labetalol was given to a target MAP of 15% below baseline. Cerebral blood flow was measured using phase-contrast magnetic resonance imaging and defined as the sum of flow in the internal carotid arteries and vertebral arteries. Cardiac output (CO) was defined as the flow in the ascending aorta. RESULTS: Baseline median cerebral blood flow was 772 ml/min (interquartile range, 674 to 871), and CO was 5,874 ml/min (5,199 to 6,355). The median dose of noradrenaline was 0.17 µg · kg-1 · h-1 (0.14 to 0.22). During noradrenaline infusion, cerebral blood flow decreased to 705 ml/min (606 to 748; P = 0.001), and CO decreased to 4,995 ml/min (4,705 to 5,635; P = 0.01). A median dose of labetalol was 120 mg (118 to 150). After labetalol boluses, cerebral blood flow was unchanged at 769 ml/min (734 to 900; P = 0.68). CO increased to 6,413 ml/min (6,056 to 7,464; P = 0.03). CONCLUSIONS: In healthy, awake subjects, increasing MAP using intravenous noradrenaline decreased cerebral blood flow and CO. These data do not support inducing hypertension with noradrenaline to increase cerebral blood flow. Cerebral blood flow was unchanged when decreasing MAP using labetalol.

Haemodynamic effects of labetalol in isoflurane-anaesthetized dogs that received dexmedetomidine: A randomized clinical trial.

OBJECTIVE: To test whether labetalol improved cardiovascular function in anaesthetized dogs injected with dexmedetomidine. STUDY DESIGN: Prospective, randomized, blinded, clinical trial. ANIMALS: A group of 20 healthy client-owned dogs undergoing ovariohysterectomy. METHODS: Each dog received dexmedetomidine (5 µg kg-1) and methadone (0.2 mg kg-1) intramuscularly. General anaesthesia was induced with propofol and maintained with isoflurane in oxygen. All dogs were mechanically ventilated, and epidural anaesthesia with lidocaine was performed. Standard anaesthetic monitoring, invasive blood pressure, oesophageal Doppler and near-infrared tissue perfusion/oxygenation were applied. Peak velocity (PV), mean acceleration and stroke distance (SD) from the oesophageal Doppler were recorded. Arterial elastance (Ea) was calculated. Tissue oxygenation (rStO2) was also recorded. Prior to surgery, animals received either 0.1 mg kg-1 of labetalol intravenously (IV) over 60 seconds or the equivalent volume of saline. Data were recorded for 20 minutes. Age, weight and propofol dose were compared with a Wilcoxon rank-sum test. The effects of time, treatment and their interaction with haemodynamic and perfusion variables were analysed with mixed-effect models and Tukey's post hoc tests. RESULTS: Significant effects of the interaction between treatment and time were observed whereby heart rate (HR) was higher in dogs given labetalol (p = 0.01), whereas arterial blood pressure and Ea were lower (p < 0.01). Similarly, PV, SD and rStO2 were higher in the labetalol group, and significant effects were detected for the interaction between treatment and time (p < 0.01). CONCLUSIONS AND CLINICAL RELEVANCE: Labetalol at a dose of 0.1 mg kg-1 IV in dogs under general anaesthesia and administered a pre-anaesthetic medication of dexmedetomidine produced mild vasodilation (reduction of Ea), resulting in an increase in HR and left ventricular outflow. Although labetalol could be an effective option to achieve haemodynamic optimization after dexmedetomidine-induced vasoconstriction, future studies are needed to assess long-term effects.

Does Labetalol Trigger False Positive Drug Testing Results?

OBJECTIVES: Labetalol, an α- and ß-adrenergic antagonist used to treat hypertension in pregnancy has been blamed for causing false-positive amphetamine and methamphetamine results. In this study, we tested 3 concentrations of labetalol prepared with 4 specimen types (urine, plasma, meconium, and umbilical cord tissue), for amphetamine, methamphetamine, and several other drugs with screen and confirmation tests. METHODS: Residual drug-free specimens were pooled. Labetalol hydrochloride dissolved in methanol was used to prepare spikes in triplicate per specimen type (2.7, 50, and 100 µM), which were tested with 41 previously validated drug tests performed by immunoassay or liquid chromatography tandem mass spectrometry (LC-MS/MS). RESULTS: Labetalol triggered false-positive amphetamine and methamphetamine results by immunoassay in meconium but did not trigger positive results for any of the targeted drugs or drug metabolites tested by LC-MS/MS. No positive results were generated by any immunoassay or LC-MS/MS test included in the study, when challenged with high concentrations of labetalol in urine, plasma, or umbilical cord tissue. CONCLUSIONS: In summary, false-positive results can be generated by labetalol when tested by immunoassay, but false-positive results are not expected when testing is performed by highly specific analytical approaches such as LC-MS/MS.

Evaluation of intravenous infusion of labetalol versus magnesium sulfate on cerebral hemodynamics of preeclampsia patients with severe features using transcranial doppler.

PURPOSE: It is essential to understand the underlying pathophysiological mechanisms of preeclampsia cerebral complications. This study aimed to compare the cerebral hemodynamic effects of magnesium sulfate (MgSO4) and labetalol in pre-eclampsia patients with severe features. METHODS: Singleton pregnant women who suffered from late onset preeclampsia with severe features were enrolled and subjected to baseline Transcranial doppler (TCD) evaluation and then randomly assigned to either the magnesium sulfate group or labetalol group. TCD to measure middle cerebral artery (MCA) blood flow indices including mean flow velocity (cm/s), mean end-diastolic velocity (DIAS), and pulsatility index (PI) and to estimate CPP and MCA velocity were performed as basal measurements before study drug administration and at post-treatment one and six hours after administration. The occurrence of seizures and any adverse effects were recorded for each group. RESULTS: Sixty preeclampsia patients with severe features were included and randomly allocated into two equal groups. In group M the PI was 0.77 ± 0.04 at baseline versus 0.66 ± 0.05 at 1hour and 0.66 ± 0.05 at 6 hours after MgSO4 administration (p value < 0.001) also the calculated CPP was significantly decreased from 103.3 ± 12.7mmHg to 87.8 ± 10.6mmHg and 89.8 ± 10.9mmHg (p value < 0.001) at 1 and 6 hours respectively. Similarly, in group L the PI was significantly decreased from 0.77 ± 0.05 at baseline to 0.67 ± 0.05 and 0.67 ± 0.06 at 1 and 6 hours (p value < 0.001) after labetalol administration. Moreover, the calculated CPP was significantly decreased from 103.6 ± 12.6 mmHg to 86.2 ± 13.02mmHg at 1 hour and to 83.7 ± 14.6mmHg at 6 hours (p value < 0.001). In terms of changes in blood pressure and the heart rate, they were significantly lower in the labetalol group. CONCLUSION: Both magnesium sulfate and labetalol reduce CPP while maintaining cerebral blood flow (CBF) in preeclampsia patients with severe features. TRIAL REGISTRATION: The institutional review board of the Faculty of Medicine, Zagazig University approved this study with the reference number (ZU-IRB#: 6353-23-3-2020) and it was registered at clinicaltrials.gov (NCT04539379).

Identifying Targets to Improve the Management of Severe Hypertension in Pregnancy and Postpartum.

OBJECTIVES: To (1) define quality indicators, (2) describe care gaps, and (3) identify process issues in severe hypertension (sustained systolic blood pressure [BP] ≥160 mm Hg or diastolic BP ≥110 mm Hg) management at our tertiary care centre. METHODS: Pregnant and postpartum persons diagnosed with a hypertensive disorder of pregnancy from 2018 to 2019 were identified. A retrospective cohort of patients with severe hypertension was constructed, and data were collected through chart review. Severe hypertension management was assessed according to defined quality indicators. Clinical characteristics were compared between participants with and without time-to-target BP within 60 minutes. Process issues were examined for each severe hypertension occurrence. RESULTS: Of 608 participants with a hypertensive disorder of pregnancy, 90 (15%) experienced severe hypertension. Median time-to-target BP was 76 minutes (interquartile range 47-123 minutes), and target BP (<155/105 mm Hg) was achieved within 60 minutes in 31/90 (34%) participants. Appropriate antihypertensives for severe hypertension were used in 55/90 (61%), and time-to-treatment initiation was within 30 minutes in 42/54 (78%). Chronic hypertension and oral labetalol use were associated with delays in achieving target BP. Process issues related to severe hypertension management included inappropriate treatment (n = 35/90; 39%), failure to recognize severe hypertension as an emergency (n = 21/90; 23%), and delayed treatment initiation (n = 12/54; 22%). CONCLUSION: We defined quality indicators for severe hypertension management. Time-to-target BP within 60 minutes was achieved in a minority of patients, and chronic hypertension was associated with delayed severe hypertension resolution. Process issues in severe hypertension management were described.

Treatment of Post-Coarctectomy Hypertension With Labetalol-A 9-Year Single-Center Experience.

BACKGROUND: Although considering the pathophysiology of post-coarctectomy hypertension, ß-blockers should be effective, experience with labetalol for treatment is limited in the literature. METHODS: Retrospective collection and analysis of data in children aged ≤6 years following coarctectomy in our tertiary care university medical center between January 2009 and June 2018. RESULTS: 96 patients were included, 45 were treated with intravenous labetalol and 51 received no treatment. Median time to maximum dose received (median 1.1 mg/kg/h) was 2.7 h, and median time to the reduction of labetalol dose was 8.3 h. No antihypertensives had to be added. In one child, labetalol was switched to nitroprusside due to bronchoconstriction. Of patients receiving intravenous labetalol, 48% had been switched to oral labetalol at discharge. CONCLUSIONS: Intravenous labetalol is a fast, effective, and safe drug to treat hypertension following aortic coarctation repair. Labetalol is easily converted to oral therapy when the continuation of treatment is considered necessary.

In Vitro Toxicological Profile of Labetalol-Folic Acid/Folate Co-Administration in H9c2(2-1) and HepaRG Cells.

Background and Objectives: The consumption of dietary supplements has increased over the last decades among pregnant women, becoming an efficient resource of micronutrients able to satisfy their nutritional needs during pregnancy. Furthermore, gestational drug administration might be necessary to treat several pregnancy complications such as hypertension. Folic acid (FA) and folate (FT) supplementation is highly recommended by clinicians during pregnancy, especially for preventing neural tube birth defects, while labetalol (LB) is a ß-blocker commonly administered as a safe option for the treatment of pregnancy-related hypertension. Currently, the possible toxicity resulting from the co-administration of FA/FT and LB has not been fully evaluated. In light of these considerations, the current study was aimed at investigating the possible in vitro cardio- and hepato-toxicity of LB-FA and LB-FT associations. Materials and Methods: Five different concentrations of LB, FA, FT, and their combination were used in myoblasts and hepatocytes in order to assess cell viability, cell morphology, and wound regeneration. Results: The results indicate no significant alterations in terms of cell viability and morphology in myoblasts (H9c2(2-1)) and hepatocytes (HepaRG) following a 72-h treatment, apart from a decrease in the percentage of viable H9c2(2-1) cells (~67%) treated with LB 150 nM−FT 50 nM. Additionally, LB (50 and 150 nM)−FA (0.2 nM) exerted an efficient wound regenerating potential in H9c2(2-1) myoblasts (wound healing rates were >80%, compared to the control at 66%), while LB-FT (at all tested concentrations) induced no significant impairment to their migration. Conclusions: Overall, our findings indicate that LB-FA and LB-FT combinations lack cytotoxicity in vitro. Moreover, beneficial effects were noticed on H9c2(2-1) cell viability and migration from LB-FA/FT administration, which should be further explored.

Uterine Ultrasound Doppler Hemodynamics of Magnesium Sulfate Combined with Labetalol in the Treatment of Pregnancy-Induced Hypertension Using Empirical Wavelet Transform Algorithm.

The aim of this study was to explore the hemodynamic changes of magnesium sulfate combined with labetalol in the treatment of pregnancy-induced hypertension (PIH) under Doppler uterine ultrasound based on the empirical wavelet transform (EWT) algorithm. 500 patients with PIH in the hospital were selected and randomly divided into the control group (n = 250) and the observation group (n = 250). The control group was treated with conventional magnesium sulfate; the observation group was given labetalol based on magnesium sulfate drip in the control group. The uterine artery blood flow simulation model was established based on the EWT algorithm and compared with a short-time Fourier transform (STFT). The normalized root mean square error (NRMSE) of the STFT method was 0.19, and the NRMSE extracted by the EWT method was 0.13. After treatment, the blood pressure index, 24-hour urinary protein, and incidence of adverse birth outcomes in the observation group were lower than those in the control group; the effective rate of the control group (90.4%) was lower than that of the observation group (97.6%); the hemodynamic indexes of the uterine artery in the observation group were lower than those in the control group, and the differences were statistically significant (P < 0.05). The estimation accuracy of the EWT method was higher than that of the traditional STFT method; the combined treatment of magnesium sulfate and labetalol in patients with PIH had a remarkable effect, which could control the blood pressure index and reduce the 24-hour urinary protein; the uterine artery Doppler ultrasound examination could change hemodynamics and improve the adverse outcomes of mothers and infants.

A comparative study of intravenous labetalol VS intravenous nitroglycerin in the treatment of hypertensive crises.

Hypertensive crises is still a major public health problem, causing end organ damage like myocardial infarction, stroke, and renal failure. Labetalol and nitroglycerine are among the two most commonly used medicine to control the blood pressure, but there is no head to head comparison between these two medicines. This was a prospective randomized non-blinded study which included 50 patients of hypertensive crises, out which 25 patients received intravenous labetalol and 25 patients received intravenous nitroglycerine. We found that labetalol controlled the blood pressure more rapidly in comparison to nitroglycerine, without causing any extra side effect.

Initial antihypertensive agent effects on acute blood pressure after intracerebral haemorrhage.

INTRODUCTION: Current guidelines recommend blood pressure (BP) lowering in patients after acute intracerebral haemorrhage (ICH) without guidance on initial choice of antihypertensive class. This study sought to determine if initial antihypertensive class differentially effects acute BP lowering in a large multiethnic ICH cohort. METHODS: Subjects enrolled in the Ethnic/Racial Variations in ICH study between August 2010 and August 2017 with elevated admission BP and who received labetalol, nicardipine or hydralazine monotherapy as initial antihypertensive were analysed. Primary outcomes were systolic and diastolic BP changes from baseline to first BP measurement after initial antihypertensive treatment. Secondary outcomes included haematoma expansion (HE), hospital length of stay (LOS) and modified Rankin Score (mRS) up to 12 months after ICH. Exploratory outcomes assessed effects of race/ethnicity. Linear and logistic regression analyses, adjusted for relevant covariates, were performed to determine associations of antihypertensive class with outcomes. RESULTS: In total, 1156 cases were used in analyses. Antihypertensive class was associated with diastolic BP change (p=0.003), but not systolic BP change (p=0.419). Initial dosing with nicardipine lowered acute diastolic BP than labetalol (least square mean difference (labetalol-nicardipine)=5.47 (2.37, 8.57), p<0.001). Initial antihypertensive class was also found to be associated with LOS (p=0.028), but not with HE (p=0.406), mortality (p=0.118), discharge disposition (p=0.083) or mRS score at discharge, 3, 6 and 12 months follow-up (p=0.262, 0.276, 0.152 and 0.36, respectively). Race/ethnicity variably affected multivariable models. CONCLUSION: In this large acute ICH cohort, initial antihypertensive class was associated with acute diastolic, but not systolic, BP-lowering suggesting differential effects of antihypertensive agents. TRIAL REGISTRATION NUMBER: NCT01202864.

Comparison of Intravenous Antihypertensives on Blood Pressure Control in Acute Neurovascular Emergencies: A Systematic Review.

BACKGROUND: Acute blood pressure (BP) management in neurologic patients is paramount. Different neurologic emergencies dictate various BP goals. There remains a lack of literature determining the optimal BP regimen regarding safety and efficacy. The objective of this study was to identify which intravenous antihypertensive is the most effective and safest for acute BP management in neurologic emergencies. METHODS: Ovid EBM (Evidence Based Medicine) Reviews, Ovid Embase, Ovid Medline, Scopus, and Web of Science Core Collection were searched from inception to August 2020. Randomized controlled trials or comparative observational studies that evaluated clevidipine, nicardipine, labetalol, esmolol, or nitroprusside for acute neurologic emergencies were included. Outcomes of interest included mortality, functional outcome, BP variability, time to goal BP, time within goal BP, incidence of hypotension, and need for rescue antihypertensives. The Grading of Recommendations Assessment, Development, and Evaluation approach was used to evaluate the degree of certainty in the evidence available. RESULTS: A total of 3878 titles and abstracts were screened, and 183 articles were selected for full-text review. Ten studies met the inclusion criteria; however, the significant heterogeneity and very low quality of studies precluded a meta-analysis. All studies included nicardipine. Five studies compared nicardipine with labetalol, three studies compared nicardipine with clevidipine, and two studies compared nicardipine with nitroprusside. Compared with labetalol, nicardipine appears to reach goal BP faster, have less BP variability, and need less rescue antihypertensives. Compared with clevidipine, nicardipine appears to reach goal BP goal slower. Lastly, nicardipine appears to be similar for BP-related outcomes when compared with nitroprusside; however, nitroprusside may be associated with increased mortality. The confidence in the evidence available for all the outcomes was deemed very low. CONCLUSIONS: Because of the very low quality of evidence, an optimal BP agent for the treatment of patients with neurologic emergencies was unable to be determined. Future randomized controlled trials are needed to compare the most promising agents.

Comparison of the effects on maternal endothelial cell activation: an in vitro study of anti-hypertensive drugs clinically used in pre-eclampsia.

Endothelial cell dysfunction in pregnancy, which can be induced by placental factors, is the fundamental component of the pathogenesis of pre-eclampsia. The dysfunctional vascular endothelium disrupts the balance of vasodilatory and vasoconstrictive factors, resulting in increasing blood pressure. There is currently no effective treatment for pre-eclampsia and effective control of hypertension may reduce neonatal morbidity and mortality by prolonging gestation, especially in cases of early onset disease. To date methyldopa, labetalol, nifedipine and metoprolol are recommended for controlling blood pressure in pre-eclampsia. All of these drugs have different mechanisms of action. In this in vitro study we investigated whether different types of anti-hypertensive drugs could have different effects on improving maternal endothelial cell dysfunction. Endothelial cells (HMEC-1) were exposed to phorbol-12-myristate-13-acetate (PMA) or pre-eclamptic sera or extracellular vesicles (EVs) derived from pre-eclamptic placentae, in the presence of each of the studied anti-hypertensive drugs (methyldopa, labetalol, nifedipine and metoprolol) or placebo for 24 h. Endothelial cell-surface adhesion molecule (ICAM-1) and monocyte adhesion were measured. The expression of cell-face ICAM-1 by HMEC-1 cells and THP-1 monocyte adherent to HMEC-1 that were exposed to three separate well-known activators of endothelial cells in the presence of four anti-hypertensive drugs was significantly reduced regardless of the dose. However, the effect on the reduction of ICAM-1 expression and monocyte adhesion was not significantly different between the four medications. Our data suggest that the beneficial effect on improving endothelial cell function by these commonly prescribed anti-hypertensive drugs is seemingly independent of the anti-hypertensive mechanisms of the medication.

Application of comprehensive bioinformatics approaches to reconnoiter crucial genes and pathways underpinning hepatocellular carcinoma: a drug repurposing endeavor.

Hepatocellular carcinoma (HCC) is the fifth most common neoplasm in the world. Chronic inflammation of liver and associated wound healing processes collectively contribute to the development of cirrhosis which further progresses to dysplastic nodule and then to HCC. Etiological mediators and ongoing manipulations at cellular level in HCC are well established; however, key protein interactions and genetic alterations involved in stepwise hepatocarcinogenic pathways are seldom explored. This study aims to unravel novel targets of HCC and repurpose the FDA-approved drugs against the same. Genetic data pertinent to different stages of HCC were retrieved from GSE6764 dataset and analyzed via GEO2R. Subsequently, protein-protein interaction network analysis of differentially expressed genes was performed to identify the hub genes with significant interaction. Hub genes displaying higher interactions were considered as potential HCC targets and were validated thorough UALCAN and GEPIA databases. These targets were screened against FDA-approved drugs through molecular docking and dynamics simulation studies to capture the drugs with potential activity against HCC. Finally, cytotoxicity of the shortlisted drug was confirmed in vitro by MTT assay. CDC20 was identified as potential druggable target. Docking, binding energy calculations, and dynamic studies revealed significant interaction exhibited by Labetalol with CDC20. Further, in MTT assay, Labetalol demonstrated an IC50 of 200.29 µg/ml in inhibiting the cell growth of HepG2 cell line. In conclusion, this study discloses a series of key genetic underpinnings of HCC and recommends the pertinence of labetalol as a potential repurposable drug against HCC.

Metabolic Activation and Cytotoxicity of Labetalol Hydrochloride Mediated by Sulfotransferases.

Labetalol hydrochloride (LHCl), an α- and ß-adrenoreceptor blocker, is widely used for the treatment of hypertension as well as angina pectoris. Previous reports have demonstrated the adverse events during clinical application of LHCl, such as liver injury and acute renal failure. The present study aimed to investigate metabolic activation of LHCl to initiate the elucidation of the mechanisms of its liver toxicity. One glutathione (GSH) conjugate was detected in rat and human primary hepatocytes as well as bile of rats after exposure to LHCl. The GSH conjugate was chemically synthesized and characterized by Q-TOF and 1H NMR. Pretreatment of 2,6-dichloro-4-nitrophenol (DCNP), a broad-spectrum sulfotransferase (SULT) inhibitor, significantly attenuated the formation of the GSH conjugate in LHCl-treated hepatocytes and animals, indicating the participation of SULTs in metabolic activation of LHCl. Moreover, pretreatment with DCNP displayed significant protection against the observed cytotoxicity in rat primary hepatocytes, which suggests a correlation of the bioactivation of LHCl mediated by SULTs with LHCl-induced hepatotoxicity.

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.

Intravenous labetalol versus oral nifedipine for acute hypertension in pregnancy: effects on cerebral perfusion pressure.

BACKGROUND: Pregnant women with preeclampsia have been found to have elevated cerebral perfusion pressure and impaired cerebral autoregulation compared with normal pregnant women. Transcranial Doppler is a noninvasive technique used to estimate cerebral perfusion pressure. The effects of different antihypertensive medications on cerebral perfusion pressure in preeclampsia are unknown. OBJECTIVE: To compare the change in cerebral perfusion pressure before and after intravenous labetalol vs oral nifedipine in the setting of acute severe hypertension in pregnancy. STUDY DESIGN: This is a prospective cohort study of pregnant women between 24 and 42 weeks' gestation with severe hypertension (systolic blood pressure ≥160 mm Hg and/or diastolic blood pressure ≥110 mm Hg). Women who consented to the study and received either intravenous labetalol or oral nifedipine were included. Exclusion criteria included active labor or receipt of any antihypertensive medication within 2 hours of initial cerebral perfusion pressure measurement. Peripheral blood pressure and transcranial Doppler studies for middle cerebral artery hemodynamics were performed prior to the administration of antihypertensive medications and repeated 30 minutes after medication administration. RESULTS: A total of 16 women with acute severe hypertension were enrolled; 8 received intravenous labetalol and 8 received oral nifedipine. There were no significant differences between the labetalol and nifedipine groups in baseline characteristics such as maternal age, race and ethnicity, payment, hospital site, body mass index, nulliparity, gestational age, preexisting diabetes mellitus or chronic hypertension, fetal growth restriction, magnesium sulfate administration, and symptomatology (P>.05). When examined 30 minutes after the administration of either intravenous labetalol or oral nifedipine, there was a significantly greater decrease in systolic blood pressure (-9.8 mm Hg vs -39 mm Hg; P=.003), mean arterial pressure (-7.1 mm Hg vs -22.3 mm Hg; P=.02), and cerebral perfusion pressure (-2.5 mm Hg vs -27.7 mm Hg; P=.01) in the nifedipine group. There was no statistically significant decrease in diastolic blood pressure (-12.9 mm Hg vs -5.4 mm Hg; P=.15). The change in middle cerebral artery velocity by transcranial Doppler was compared between the groups and was not different (0.07 cm/s vs 0.16 cm/s; P=.64). CONCLUSION: Oral nifedipine resulted in a significant decrease in cerebral perfusion pressure, whereas labetalol did not, after administration for acute severe hypertension among women with preeclampsia. This decrease seems to be driven by a decrease in peripheral arterial blood pressure rather than a direct change in cerebral blood flow.

Regulation of magnesium sulfate combined with nifedipine and labetalol on disease-related molecules in serum and placenta in the treatment of preeclampsia.

OBJECTIVE: To explore the regulatory effect of magnesium sulfate combined with nifedipine and labetalol on disease-related molecules in serum and placenta in the treatment of preeclampsia. PATIENTS AND METHODS: Altogether 100 patients with preeclampsia admitted to the Children & Women's Healthcare of Laiwu City were selected. They were divided into control group and experimental group according to different treatment methods. Among them, 51 patients in the control group were treated with magnesium sulfate combined with nifedipine, and 49 patients in the experimental group were treated with labetalol on the basis of the treatment in the control group. The therapeutic effects of the two methods were compared. The levels of the following factors in the two groups were compared: kallikrein expression, pregnancy-associated plasma protein A (PAPP-A), pregnancy-specific ß1 glycoprotein (SPI), placental growth factor (PLGF), human placental prolactin (HPL), transforming growth factor ß1(TGF-ß1), vascular cell adhesion molecule 1 (VCAM-1) and E-selectin in serum and placenta tissues. RESULTS: After treatment, the blood pressure in the experimental group was lower than that in the control group (p<0.05). The expression of kallikrein in serum and placental tissue of the patients in the experimental group was higher than that of the patients in the control group (p<0.05); PAPP-A level was lower than that in the control group (p<0.05); TGF-ß1 level was higher than that in the control group (p<0.05); VCAM-1 and E-selectin were lower than those in the control group (p<0.05), and kallikrein and TGF-ß1 in serum and placenta in the non-occurrence group were higher than those in the occurrence group (p<0.05). The serum and placenta PAPP-A, VCAM-1, and E-selectin in the non-occurrence group were lower than those in the occurrence group (p<0.05). CONCLUSIONS: Magnesium sulfate combined with nifedipine and labetalol has good efficacy in the treatment of preeclampsia. They can promote the expression of endogenous kallikrein, reduce the level of pregnancy-related hypertension predictors, and weaken the infiltration ability of cytotrophoblasts.

Rational targeting of Wzb phosphatase and Wzc kinase interaction inhibits extracellular polysaccharides synthesis and biofilm formation in Acinetobacter baumannii.

Acinetobacter baumannii is an opportunistic nosocomial pathogen, and responsible for high mortality and morbidity. Biofilm formation is one of the resistance determinants, where extracellular polysaccharide (EPS) is an essential component. EPS synthesis and its export is regulated by the bacterial Wza-Wzb-Wzc system. Wzc exhibits auto-phosphorylation protein tyrosine kinase activity, while Wzb is a protein tyrosine phosphatase. Wzb mediates dephosphorylation of Wzc. Dephosphorylated Wzc is required for the export of the EPS through porin Wza-Wzc complex. It shows that the interaction of Wzb with Wzc is critical for the export of EPS. Therefore, if the Wzb-Wzc interaction is inhibited, then it might hinder the EPS transport and diminish the biofilm formation. In this study, we have modelled the Wzb, and Wzc proteins and further validated using PSVS, ProSA, RAMPAGE, and PDBsum. The modelled proteins were used for protein-protein docking. The docked protein-protein complex was minimized by Schrodinger software using OPLS_2005 force field. The binding site of the minimized Wzb-Wzc complex was identified by Sitemap. The high throughput virtual screening identified Labetalol hydrochloride and 4-{1-hydroxy-2-[(1-methyl-3-phenylpropyl) amino] propyl} phenol from FDA-approved drug library based on their interaction at the interface of Wzb-Wzc complex. The inhibitor-protein complex was further undergone molecular mechanics analysis using Generalized Born model and Solvent Accessibility (MMGBSA) to estimate the binding free energies. The lead was also used to generate the pharmacophore model and screening the molecule with antimicrobial scaffold. The identified lead was experimentally validated for its effect on EPS quantity and biofilm formation by A. baumannii. Wzb-Wzc interaction is essential for biofilm and EPS export; hence, the identified lead might be useful to regulate the biofilm formation by A. baumannii.