Treatment Of Arterial Hypertension Research Articles

EFFECT OF RENAL DENERVATION ON THE PLASMA ADIPONECTIN CONCENTRATION IN PATIENTS WITH RESISTANT HYPERTENSION

Objective: Adiponectin is produced by white adipose tissue and has anti-diabetic, anti-atherosclerotic, anti-thrombotic, anti-inflammatory, and cardioprotective properties. In patients with arterial hypertension plasma concentration of adiponectin is lower than in healthy subjects. Renal denervation (RDN) i.e. percutaneous ablation of fibers from the sympathetic nervous system located in the wall of the renal arteries by radio frequency waves, is a method of resistant arterial hypertension treatment. The aim of this single center, interventional, clinical study was to assess the effect of RDN on the plasma adiponectin concentration in patients with resistant arterial hypertension. Design and method: Twenty-six patients (12 women, 14 men) aged 54.0±7.8 years with resistant hypertension who underwent RDN using Simplicity catheters (Medtronic, Inc., Northridge, CA) were enrolled in the study. Plasma adiponectin concentration was determined using the Human Adiponectin ELISA Kit (Otsuka Pharmaceutical Co, Tokyo, Japan) before the RDN and 6 and 12 months after this procedure. Results: Blood pressure (BP) values before RDN and 6 and 12 months after RDN were as follow: systolic BP - 190.4±24.5, 160.8±14.5, 155.7±17.9 mmHg (p<0.001) and diastolic BP - 111.7±18.9, 88.9±8.3, 91.2±10.2 mmHg (p<0.001), respectively. Body mass index (BMI) before RDN, 6 and 12 months after RDN were 31.5±4.2, 30.5 ±4.4, 30.2±4.0 kg/m2, (p = 0.057), respectively. Plasma adiponectin concentration before the RDN and 6 and 12 months after RDN were 6.93±4.85, 7.94±3.97, 8.83±6.12 [μg/ml] (p = 0.007), respectively. In the follow up i.e. 6 and 12 months after RDN plasma adiponectin concentration increases significantly in responders (systolic BP decrease higher or equal 25 mmHg) (7.93±6.14, 8.87±4.68, 10.57±7.51 [μg/mL]; respectively]; p = 0.03, and did not change significantly in low-responders to RDN (systolic BP decrease < 25 mmHg) (5.76±2.45, 6.86±2.76, 6.81±3.19 [μg/mL]; respectively; p = 0.2). Conclusions: 1. Plasma adiponectin concentration increases significantly after successful RDN in patients with resistant arterial hypertension. 2. Higher plasma adiponectin concentration may participate - beyond blood pressure reduction - in the cardiovascular benefits related to successful RDN, however clinical consequences of our results need further investigations.

Surrogate endpoints in pulmonary arterial hypertension trials

Why don't you just look at the pulmonary artery pressure? This question is frequently asked when we discuss endpoints in pulmonary arterial hypertension (PAH) trials with colleagues from other disease areas. Trials of antihypertensive drugs simply look at blood pressure changes, whereas pivotal trials in PAH use change in 6-min walk distance or time to clinical worsening as primary outcome measures. Why the difference? It is not just the invasiveness of right heart catheterisation but much more a question of validated surrogate endpoints. The US Food and Drug Administration (FDA) and other regulatory agencies approve drugs when they improve how patients feel, function, or survive. 1 Temple R Are surrogate markers adequate to assess cardiovascular disease drugs?. JAMA. 1999; 282: 790-795 Crossref PubMed Scopus (298) Google Scholar In systemic hypertension, lowering blood pressure predicts reductions in major adverse cardiovascular events including stroke, myocardial infarction, and cardiovascular death, and so authorities accept blood pressure reduction as a surrogate endpoint—ie, a substitute for a clinically meaningful endpoint that is expected to predict the effect of a therapy. 1 Temple R Are surrogate markers adequate to assess cardiovascular disease drugs?. JAMA. 1999; 282: 790-795 Crossref PubMed Scopus (298) Google Scholar In PAH, there is no convincing evidence that reductions in pulmonary artery pressure or pulmonary vascular resistance are directly linked to improved exercise capacity or better survival. Hence, change in 6-min walk distance is being frequently used as a primary endpoint assessing the function part of the FDA paradigm. Time to clinical worsening has been applied as well, a composite endpoint based on death, PAH-related worsening, and prespecified reductions in exercise capacity. However, these endpoints have limitations. Improvement in 6-min walk distance reflects better exercise capacity but is no surrogate of better outcomes. 2 Gabler NB French B Strom BL et al. Validation of 6-minute walk distance as a surrogate end point in pulmonary arterial hypertension trials. Circulation. 2012; 126: 349-356 Crossref PubMed Scopus (185) Google Scholar Time to clinical worsening does not capture clinical improvement, and reducing clinical worsening events does not necessarily lead to better survival. 3 Sitbon O Channick R Chin KM et al. Selexipag for the treatment of pulmonary arterial hypertension. N Engl J Med. 2015; 373: 2522-2533 Crossref PubMed Scopus (607) Google Scholar , 4 Galiè N Barberà JA Frost AE et al. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med. 2015; 373: 834-844 Crossref PubMed Scopus (750) Google Scholar , 5 Pulido T Adzerikho I Channick RN et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013; 369: 809-818 Crossref PubMed Scopus (981) Google Scholar In addition, studies designed to show improvement in time to clinical worsening require large sample sizes, a challenge in a rare disease like PAH. Hence, there is an ongoing search for surrogate endpoints. Is low-risk status a surrogate outcome in pulmonary arterial hypertension? An analysis of three randomised trialsMulticomponent risk scores have utility for the prediction of outcomes in patients with PAH. Clinical surrogacy for long-term outcomes cannot be inferred from observational studies of outcomes. Our analyses of three PAH trials with long-term follow-up suggest that further study is necessary before using these or other scores as surrogate outcomes in PAH RCTs or clinical care. Full-Text PDF

Features of the treatment of arterial hypertension in elderly patients

Arterial hypertension (AH) is one of the most common problems in the elderly and one of the most important cardiovascular risk factors. AH in the elderly has features with a high incidence of ISAH and is characterized by a high level of SBP and a low level of DBP, which creates certain problems for the safety of treatment. The need for antihypertensive therapy in elderly patients has received convincing evidence of the effectiveness of reducing mortality and cardiovascular complications. The purpose of this scientific review was to raise awareness of the problem of treating hypertension in elderly patients, including those with low DBP. The results of studies and meta-analyzes evaluating the efficacy and safety of standard and intensive SBP reduction in elderly patients, as well as the results of the effect of antihypertensive therapy on DBP levels, especially at baseline low DBP (<70 mmHg), are presented. The studies identified the main groups of antihypertensive drugs that provide an effective and safe reduction in blood pressure in elderly patients, have a cardioprotective effect and do not adversely affect comorbidities. These include: diuretics of the thiazide-like group, calcium channel blockers, as well as additional indications and concomitant conditions – ACE inhibitors and antigotensin II receptor blockers. Several meta-analyses have shown the benefit of intensively lowering SBP < 120 mmHg before the standard target level SBP < 140 mmHg. in elderly patients as a lower risk of fatal and non-fatal cardiovascular events and overall mortality. Thus, the impact of intensive SBP reduction was beneficial in preventing 1 case of MACE (NNT = 38) and in preventing 1 case of total mortality (NNT = 85); while the rate of harm in the form of arterial hypotension was significantly high (NNH = 778). With regard to the effect on the level of DBP in elderly patients with hypertension or ISAH, an inverse relationship between DBP and adverse coronary events was revealed and a J-curve was described, confirmed in a number of studies (INVEST, ARIC, SPRINT). Moreover, with an initially low DBP (<70 mmHg), a significant increase in the frequency of outcomes and the relative risk of outcomes was noted. It is not easy to decide on antihypertensive therapy in such situations. The evidence base of studies suggests the benefit of lowering SBP for the prevention of cardiovascular events in elderly patients, but with caution and individual approach. It is important to take into account individual patient characteristics such as cognition, autonomy, and frailty/frailty when setting target BP.

Небіволол – бета-адреноблокатор з вазодилатаційними властивостями: досягнення і перспективи застосування

Огляд присвячений клінічному застосуванню β-адреноблокатора з вазодилатаційними властивостями – небівололу. Розглянуто основні фармакологічні властивості та характеристики препарату, його кардіоселективність та механізми вазодилатаційної дії. Показано особливості застосування небівололу в лікуванні есенціальної артеріальної гіпертензії, ішемічної хвороби серця та серцевої недостатності. Препарат не має діабетогенної дії при тривалому застосуванні, сприятливо впливає на показники ліпідного та вуглеводного обмінів. У хворих з ішемічною хворобою серця продемонстровано його антиангінальну й антиішемічну дію та зниження частоти рецидивів після виконання операцій на коронарних артеріях. Препарат добре толерується та має високу ефективність у зниженні показників смертності в пацієнтів віком понад 70 років з хронічною серцевою недостатністю, незалежно від фракції викиду лівого шлуночка. У лікуванні ішемічної хвороби серця при цукровому діабеті 2-го типу перевагу надають β-адреноблокаторам з вазодилатаційними властивостями. При необструктивних ураженнях коронарних артерій з-поміж β-адреноблокаторів перевагу надають небівололу для лікування мікросудинної стенокардії. У пацієнтів з артеріальною гіпертензією небіволол, крім антигіпертензивного ефекту, має сприятливий вплив на функцію ендотелію, метаболічний профіль, центральну гемодинаміку, якість життя пацієнтів, а також кращий профіль побічних ефектів.

Pulmonary vascular disease as a complication of pediatric congenital heart diseases.

Congenital and acquired heart diseases can cause pulmonary hypertension (PH) in children, either by increasing pulmonary blood flow (PBF), left atrial pressure (LAp), and/or pulmonary vascular resistance (PVR). Pathophysiological process of pulmonary vascular disease (PVD) in different types of congenital heart diseases (CHDs) are reviewed hereafter. As with other types of PH, a rigorous diagnostic evaluation is mandatory to characterize the etiology of the PH, rule out other or additional causes of PH, and establish a risk profile. Cardiac catheterization remains the gold standard exam for PH diagnosis. Treatment of pulmonary arterial hypertension (PAH) associated with CHD (PAH-CHD) can then be started according to the recent guidelines recommendations, although most of the evidence is extrapolated from studies on other causes of PAH. PH in pediatric heart disease is often multifactorial, and sometimes unclassifiable, making the management of these patients complicated. The operability of patients with a prevalent left-to-right shunt and increase of PVR, the management of children with PH associated with left-sided heart disease, the challenges of pulmonary vascular disorders in children with univentricular heart physiology and the role of vasodilator therapy in failing Fontan patients are some of the hot topics discussed in this review.

Evaluating the effectiveness of an apelin analog as a potential treatment for pulmonary arterial hypertension using a sugen-hypoxia rat model

Background: Pulmonary arterial hypertension (PAH) is a debilitating syndrome characterized by heightened pulmonary arterial pressures, and adverse pulmonary vascular remodeling. Eventually, the right ventricle (RV) decompensates, and fatal right heart failure ensues. Existing treatments for PAH are ineffective at improving survival. Apelin is an endogenous cardioprotective peptide, and disruption of apelin signaling was associated with the development of PAH. Restoring the activity of the apelin pathway is a promising approach in reversing the arteriopathy underlying PAH to protect the RV. The salutary actions of apelin are limited by its short half-life; recently, apelin analogs designed with extended half-lives offer a novel therapeutic avenue requiring further testing. Objective: Our project aims to evaluate the effectiveness of an apelin analog as a potential treatment for PAH using a Sugen-Hypoxia (SuHx) rat model of PAH which recapitulates disease characteristics seen in humans. We hypothesize that the apelin analog treatment will improve pulmonary hemodynamics and preserve RV adaptation in rats exposed to SuHx and assuage the pulmonary arteriopathy seen in PAH rats. Experimental design: Male Sprague Dawley rats aged 9 weeks were randomly split into a placebo or treated PAH group. For 3 weeks, a control group was kept within normal room air while the placebo and treated PAH rats were kept in a hypoxia chamber (10% O 2 ). Placebo and treated rats were injected with SU5416 (20 mg/kg, SQ) once at the start of the 3 weeks to induce disease. The normoxic period lasted 5 weeks following the 3 weeks of hypoxia. Treated rats received apelin analog (0.5 μmol/kg, IV, b.i.d.) for the final 3 weeks of normoxia; the placebo group received the same dose of saline. Results: At endpoint, glomerular filtration rate (GFR) measurements showed that placebo treated (PAH-P) PAH rats had reduced GFR while apelin treated (PAH-A) PAH rats had recovered GFR. Echocardiography revealed that PAH-A rats had improved cardiac function compared to PAH-P rats. RV Pressure-volume loop surgeries showed that PAH-A rats had ameliorated RV hemodynamic pressures in contrast to PAH-P rats. Histological analysis demonstrated reduced cardiac fibrosis and hypertrophy, and fewer formations of pulmonary vascular lesions within PAH-A rats compared to PAH-P rats. Single nucleus RNA sequencing performed on RV and lung tissue delineated mitigation of disease progression within the PAH-A group compared to PAH-P rats. Electrocardiography recordings showed more severe electrical remodeling in the PAH-P group compared to the PAH-A rats. Conclusions & significance: Rats with PAH treated with apelin had overall improved cardiopulmonary health outcomes compared to placebo treated PAH rats. The results of this study provide insight into the beneficial role of the apelin pathway in the setting of PAH to propose a new treatment for patients with PAH to improve their duration and quality of life. Canadian Institutes of Health Research Grant This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Design and fabrication of a microfluidic system with embedded circular channels for rotary cell culture.

The development of functional blood vessels is today a fundamental pillar in the evaluation of new therapies and diagnostic agents. This article describes the manufacture and subsequent functionalization, by means of cell culture, of a microfluidic device with a circular section. Its purpose is to simulate a blood vessel in order to test new treatments for pulmonary arterial hypertension. The manufacture was carried out using a process in which a wire with a circular section determines the dimensions of the channel. To fabricate the blood vessel, cells were seeded under rotary cell culture to obtain a homogeneous cell seeding in the inner wall of the devices. This is a simple and reproducible method that allows the generation of blood vessel models in vitro.

Current achievements and prospects for the use of nebivolol in the treatment of patients with cardiovascular diseases

A literature review deals with the clinical use of nebivol as a beta-blocker (BB) with vasodilating properties. The principal pharmacological properties and characteristics of the drug, its cardioselectivity and mechanisms of vasodilation are presented. The special place of nebivolol in the treatment of essential arterial hypertension (AH), coronary heart disease (CHD) and heart failure (HF) is outlined. The drug does not possess a diabetogenic activity with a long-term use, and impacts favourably on the parameters of lipid and carbohydrate metabolism. In CHD patients, nebivolol demonstrates the anti-anginal and anti-ischemic activities, and reduces the frequency of angina recurrence after coronary artery interventions. The drug is well tolerated and characterized by a high effectiveness with respect to the reduction of mortality rates in patients with chronic HF over 70 years of age, regardless of the left ventricular ejection fraction. Vasodilating BB are preferred in the treatment of CHD patients with type 2 diabetes. In case of non-obstructive coronary lesions, nebivolol is chosen among existing BBs for the treatment of microvascular angina. The use of nebivolol in AH patients, in addition to the antihypertensive effect, is characterized by a favorable impact on the function of endothelium, the metabolic profile, central hemodynamics, health-related quality of life of patients, as well as more favorable profile of side effects.

Refined risk stratification, current treatment, and new therapeutic approaches in pulmonary arterial hypertension.

The 2022 European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines for pulmonary hypertension have introduced arefined risk stratification to guide both initial and subsequent treatment of pulmonary arterial hypertension (PAH). The risk stratification at PAH diagnosis still comprises three risk categories (low, intermediate, high) and lists some new parameters. As the estimated 1‑year mortality is more than 20% in high-risk patients after diagnosis, an initial triple-combination therapy including parenteral prostacyclin analogues is recommended for this group. All other patients should receive adual-combination therapy with an endothelin receptor antagonist and aphosphodiesterase‑5 inhibitor. However, this approach of initial combination therapy is only recommended for classic PAH, while monotherapy followed by regular follow-up and individualized therapy should be used for patients with cardiopulmonary comorbidities. For PAH patients without cardiopulmonary comorbidities, it is recommended to assess their risk at follow-up with anew 4‑strata classification, where the intermediate-risk group is split on the basis of three noninvasive parameters. Importantly, changes from intermediate-high to intermediate-low risk have been shown to be associated with abetter prognosis. In addition, the recommendations on treatment escalation became more precise with the addition of aprostacyclin receptor agonist or switching aphosphodiesterase‑5 inhibitor to asoluble guanylate cyclase stimulator for intermediate-low risk and proceeding to triple-combination therapy with parenteral prostacyclin analogues already for intermediate-high risk. With sotatercept, the first non-vasodilator PAH treatment will become available in the near future to further enrich our treatment options for this chronic and still severe disease.

Adherence, barriers, and facilitators for the treatment of systemic arterial hypertension: rapid review of evidenceAdhesión, obstáculos y elementos facilitadores en relación con el tratamiento de la hipertensión: revisión rápida de la evidencia

To identify strategies to increase adherence to systemic arterial hypertension (SAH) treatment and describe the barriers and facilitators for implementing these strategies in primary health care (PHC). A rapid evidence review was performed. We included systematic reviews with or without meta-analyses, published in English, Spanish or Portuguese, covering adults (age 18 to ≤ 60 years) with SAH followed in the PHC. Searches were performed in nine databases in December 2020 and updated in April 2022. The systematic reviews were assessed for methodological quality using the AMSTAR 2 tool. Fourteen systematic reviews on treatment adherence strategies and three on barriers and facilitators for implementation were included. Regarding methodological quality, one systematic review was classified as moderate, four as low, and the others as critically low. Four strategies were identified as options for health policies: actions performed by pharmacists; actions performed by non-pharmaceutical health professionals; self-monitoring, use of mobile apps, and text messages; and subsidies for the purchase of medicines. Low digital literacy, limited access to the internet, work process and incipient training were barriers for professionals. The users' educational and health literacy levels, accessibility to health services and good relationships with professionals were facilitators. Positive effects of strategies related to pharmaceutical care, self-monitoring, and the use of cell phone applications and text messages were identified to increase adherence to the treatment of SAH in the context of PHC. However, for implementation purposes, it is necessary to consider barriers and facilitators, in addition to the methodological limitations of the analyzed systematic reviews.

Novel Drugs for the Treatment of Pulmonary Arterial Hypertension: Where Are We Going?

Pulmonary arterial hypertension (PAH) is a progressive disease that despite advances in therapy is associated with a 7-year survival of approximately 50%. Several risk factors are associated with developing PAH, include methamphetamine use, scleroderma, human immunodeficiency virus, portal hypertension, and genetic predisposition. PAH can also be idiopathic. There are traditional pathways underlying the pathophysiology of PAH involving nitric oxide, prostacyclin, thromboxane A2, and endothelin-1, resulting in impaired vasodilation, enhanced vasoconstriction and proliferation in the pulmonary vasculature. Established PAH medications targets these pathways; however, this paper aims to discuss novel drugs for treating PAH by targeting new and alternative pathways.

Diet and Exercise Intervention in Pulmonary Hypertension

Current pharmacologic treatments for pulmonary arterial hypertension lead to vasodilation of the pulmonary arteries, increasing cardiac output and reducing pulmonary vascular resistance in patients with pulmonary arterial hypertension. Right ventricular failure is a leading cause of death in patients with pulmonary arterial hypertension, but there remain no promising leads in the treatment of right ventricular failure. Current research demonstrates that metabolic abnormalities, particularly regarding insulin resistance and glucose intolerance, may be pathologic in the development of right ventricular failure in patients with pulmonary arterial hypertension. In this review, we will address the potential role diet and exercise may play in improving right ventricular failure in patients with pulmonary arterial hypertension.

Clinical and LASCA preliminary data on selexipag efficacy for the treatment of digital vasculopathy in systemic sclerosis.

Systemic sclerosis (SSc) is burdened by Raynaud's phenomenon (RP) and digital ulcers (DUs) and sometimes standard vasoactive therapies are ineffective or contraindicated. Selexipag is an oral selective IP prostacyclin receptor agonist approved for the treatment of SSc-related pulmonary arterial hypertension. We aimed to evaluate clinical and instrumental efficacy of selexipag in SSc digital vasculopathy. SSc patients with severe digital vasculopathy refractory or with contraindication to all other vasoactive therapies were administered selexipag, evaluating at baseline and after 3 months clinical outcomes regarding RP and DUs and digital perfusion assessed by laser speckle contrast analysis (LASCA). Selexipag was administered to 9 SSc patients (66.6% female, mean age 52.3 ±16.6 years). One of them had to stop the drug for adverse effects. After three months selexipag determined a significant reduction of RP daily episodes (p=0.012) and RP mean duration (p=0.044). DUs decreased from 10 to 4 without reaching the statistical significance. A significant improvement in the mean perfusion of the fingers (p=0.016) was observed at LASCA. Selexipag showed good potential for the treatment of SSc-digital vasculopathy. Our results are certainly preliminary but yet quite encouraging. New trials for the evaluation of selexipag efficacy in SSc-digital vasculopathy are needed.

SATISFY-JP, a phase II multicenter open-label study on Satralizumab, an anti-IL-6 receptor antibody, use for the treatment of pulmonary arterial hypertension in patients with an immune-responsive-phenotype: Study protocol.

Pulmonary arterial hypertension (PAH), an intractable disease with a poor prognosis, is commonly treated using pulmonary vasodilators modulating the endothelin, cGMP, and prostacyclin pathway. Since the 2010s, drugs for treating pulmonary hypertension based on mechanisms other than pulmonary vasodilation have been actively developed. However, precision medicine is based on tailoring disease treatment to particular phenotypes by molecular-targeted drugs. Since interleukin-6 (IL-6) is involved in the development of PAH in animal models, and some patients with PAH have elevated IL-6 levels, the cytokine is expected to obtain potentials for therapeutic targeting. Accordingly, we identified a phenotype with elevated cytokine activity of the IL-6 family in the PAH population by combining case data extracted from the Japan Pulmonary Hypertension Registry with a comprehensive analysis of 48 cytokines using artificial intelligence clustering techniques. Including an IL-6 threshold ≥2.73 pg/mL as inclusion criteria for reducing the risk of insufficient efficacy, an investigator-initiated clinical study using satralizumab, a recycling anti-IL6 receptor monoclonal antibody, for patients with an immune-responsive phenotype is underway. This study is intended to test whether use of patient biomarker profile can identify a phenotype responsive to anti-IL6 therapy.

"It's that invisible illness":Patient and clinician perspectives on outcomes in pulmonary arterial hypertension treatment.

Knowledge of what outcomes are most meaningful to pulmonary arterial hypertension (PAH) stakeholders is limited. In this qualitative study, patients and clinicians endorsed personalized physical activity, symptoms, and psychosocial well-being as key outcomes to assess PAH treatment response, yet few are routinely measured in PAH clinical trials.

Impact of the new criteria for systemic arterial hypertension diagnosis and treatment suggested by the American College of Cardiology/American Heart Association

Impact of the new criteria for systemic arterial hypertension diagnosis and treatment suggested by the American College of Cardiology/American Heart Association

Redefying the therapeutic strategies against cardiorenal morbidity and mortality: Patient phenotypes.

Chronic kidney disease (CKD) patients face an unacceptably high morbidity and mortality, mainly from cardiovascular diseases. Diabetes mellitus, arterial hypertension and dyslipidemia are highly prevalent in CKD patients. Established therapeutic protocols for the treatment of diabetes mellitus, arterial hypertension, and dyslipidemia are not as effective in CKD patients as in the general population. The role of non-traditional risk factors (RF) has gained interest in the last decades. These entail the deranged clinical spectrum of secondary hyperparathyroidism involving vascular and valvular calcification, under the term "CKD-mineral and bone disorder" (CKD-MBD), uremia per se, inflammation and oxidative stress. Each one of these non-traditional RF have been addressed in various study designs, but the results do not exhibit any applied clinical benefit for CKD-patients. The "crusade" against cardiorenal morbidity and mortality in CKD-patients is in some instances, derailed. We propose a therapeutic paradigm advancing from isolated treatment targets, as practiced today, to precision medicine involving patient phenotypes with distinct underlying pathophysiology. In this regard we propose two steps, based on current stratification management of corona virus disease-19 and sepsis. First, select patients who are expected to have a high mortality, i.e., a prognostic enrichment. Second, select patients who are likely to respond to a specific therapy, i.e., a predictive enrichment.

Chemical Characterization and Multidirectional Biological Effects of Different Solvent Extracts of Arum elongatum: in Vitro and in Silico Approaches.

Arum elongatum (Araceae) is widely used traditionally for the treatment of abdominal pain, arterial hypertension, diabetes mellitus, rheumatism and hemorrhoids. This study investigated the antioxidant properties, individual phenolic compounds, total phenolic and total flavonoid contents (HPLC/MS analysis), reducing power and metal chelating effects of four extracts obtained from A. elongatum (ethyl acetate (EA), methanol (MeOH), methanol/water (MeOH/water) and infusion). The inhibitory activity of the extracts were also determined against acetylcholinesterase, butyrylcholinesterase, tyrosinase, amylase and glucosidase enzymes. The MeOH/water extracts contained the highest amount of phenolic contents (28.85 mg GAE/g) while the highest total flavonoid content was obtained with MeOH extract (36.77 mg RE/g). MeOH/water demonstrated highest antioxidant activity against DPPH⋅ radical at 38.90 mg Trolox equivalent per gram. The infusion extract was the most active against ABTS+ ⋅ (133.08 mg TE/g). MeOH/water extract showed the highest reducing abilities with the CUPRAC value of 102.22 mg TE/g and the FRAP value of 68.50 mg TE/g. A strong metal chelating effect was observed with MeOH/water extract (35.72 mg EDTAE/g). The PBD values of the extracts ranged from 1.01 to 2.17 mmol TE/g. EA extract displayed the highest inhibitory activity against AChE (2.32 mg GALAE/g), BChE (3.80 mg GALAE/g), α-amylase (0.56 mmol ACAE/g) and α-glucosidase (9.16 mmol ACAE/g) enzymes. Infusion extract was the most active against tyrosinase enzyme with a value of 83.33 mg KAE/g. A total of 28 compounds were identified from the different extracts. The compounds present in the highest concentration were chlorogenic acids, 4-hydroxybenzoic acid, caffeic acid, p-coumaric acid, ferulic acid, isoquercitrin, delphindin 3,5-diglucoside, kaempferol-3-glucoside and hyperoside. The biological activities of A. elongatum extracts could be due to the presence of compounds such as gallic acid, chlorogenic acids, ellagic acid, epicatechin, catechin, kaempferol, 4-hydroxybenzoic acid, caffeic acid, p-coumaric acid, ferulic acid, quercetin, isoquercitrin, and hyperoside. Extracts of A. elongatum showed promising biological activities which warrants further investigations in an endeavor to develop biopharmaceuticals.

Identification of Potent, Selective, and Peripherally Restricted Serotonin Receptor 2B Antagonists from a High-Throughput Screen.

Antagonists of the serotonin receptor 2B (5-HT2B) have shown great promise as therapeutics for the treatment of pulmonary arterial hypertension, valvular heart disease, and related cardiopathies. Herein, we describe a high-throughput screen campaign that led to the identification of highly potent and selective 5-HT2B antagonists. Furthermore, selected compounds were profiled for their predicted ability to cross the blood-brain barrier. Two exemplary compounds, VU0530244 and VU0631019, were predicted to have very limited potential for brain penetration in human subjects, a critical profile for the development of 5-HT2B antagonists devoid of centrally-mediated adverse effects.

PBPK-based dose finding for sildenafil in pregnant women for antenatal treatment of congenital diaphragmatic hernia.

Sildenafil is a potent vasodilator and phosphodiesterase type five inhibitor, commercially known as Revatio® and approved for the treatment of pulmonary arterial hypertension. Maternal administration of sildenafil during pregnancy is being evaluated for antenatal treatment of several conditions, including the prevention of pulmonary hypertension in fetuses with congenital diaphragmatic hernia. However, determination of a safe and effective maternal dose to achieve adequate fetal exposure to sildenafil remains challenging, as pregnancy almost always is an exclusion criterion in clinical studies. Physiologically-based pharmacokinetic (PBPK) modelling offers an attractive approach for dose finding in this specific population. The aim of this study is to exploit physiologically-based pharmacokinetic modelling to predict the required maternal dose to achieve therapeutic fetal exposure for the treatment congenital diaphragmatic hernia. A full-PBPK model was developed for sildenafil and N-desmethyl-sildenafil using the Simcyp simulator V21 platform, and verified in adult reference individuals, as well as in pregnant women, taking into account maternal and fetal physiology, along with factors known to determine hepatic disposition of sildenafil. Clinical pharmacokinetic data in mother and fetus were previously obtained in the RIDSTRESS study and were used for model verification purposes. Subsequent simulations were performed relying either on measured values for fetal fraction unbound (fu = 0.108) or on values predicted by the simulator (fu = 0.044). Adequate doses were predicted according to the efficacy target of 15ng/mL (or 38ng/mL) and safety target of 166ng/mL (or 409ng/mL), assuming measured (or predicted) fu values, respectively. Considering simulated median profiles for average steady state sildenafil concentrations, dosing regimens of 130mg/day or 150mg/day (administered as t.i.d.), were within the therapeutic window, assuming either measured or predicted fu values, respectively. For safety reasons, dosing should be initiated at 130mg/day, under therapeutic drug monitoring. Additional experimental measurements should be performed to confirm accurate fetal (and maternal) values for fu. Additional characterization of pharmacodynamics in this specific population is required and may lead to further optimization of the dosing regimen.