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16 pages, 740 KiB

Open AccessArticle

Monitoring of Levosimendan Administration in Patients with Pulmonary Hypertension Undergoing Cardiac Surgery and Effect of Two Different Dosing Schemes on Hemodynamic and Echocardiographic Parameters

by Panagiotis Ftikos, Areti Falara, Panagiota Rellia, Evangelos Leontiadis, George Samanidis, Natalia Kamperi, Artemios Piperakis, Constantin Tamvakopoulos, Theofani Antoniou and Kassiani Theodoraki

Pharmaceuticals 2023, 16(6), 815; https://doi.org/10.3390/ph16060815 - 30 May 2023

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Abstract

Introduction: The perioperative management of patients with pulmonary hypertension (PH) undergoing cardiac surgery represents one of the most challenging clinical scenarios. This fact mainly depends on the relationship existing between PH and right ventricular failure (RVF). Levosimendan (LS) is an inodilator that might [...] Read more.

Introduction: The perioperative management of patients with pulmonary hypertension (PH) undergoing cardiac surgery represents one of the most challenging clinical scenarios. This fact mainly depends on the relationship existing between PH and right ventricular failure (RVF). Levosimendan (LS) is an inodilator that might be an effective agent in the treatment of PH and RVF. The aim of this study was to examine the impact of the duration of cardiopulmonary bypass (CPB) on the therapeutic drug monitoring of LS and to evaluate the effect of preemptive administration of LS on perioperative hemodynamic and echocardiographic parameters in cardiac surgical patients with preexisting PH. Materials and Methods: In this study, LS was administered in adult patients undergoing cardiac surgery before CPB in order to prevent exacerbation of preexisting PH and subsequent right ventricular dysfunction. Thirty cardiac surgical patients with preoperatively confirmed PH were randomized to receive either 6 μg/kg or 12 μg/kg of LS after the induction of anesthesia. The plasma concentration of LS was measured after CPB. In this study, a low sample volume was used combined with a simple sample preparation protocol. The plasma sample was extracted by protein precipitation and evaporated; then, the analyte was reconstituted and detected using specific and sensitive bioanalytical liquid chromatography with mass spectrometry (LC-MS/MS) methodology. The clinical, hemodynamic, and echocardiographic parameters were registered and evaluated before and after the administration of the drug. Results: A fast bioanalytical LC-MS/MS methodology (a run time of 5.5 min) was developed for the simultaneous determination of LS and OR-1896, its main metabolite in human plasma. The LC-MS/MS method was linear over a range of 0.1–50 ng/mL for LS and 1–50 ng/mL for its metabolite OR-1896. Measured plasma concentrations of LS were inversely related to the duration of CPB. LS administration before CPB during cardiac surgery was effective in reducing pulmonary artery pressure and improving hemodynamic parameters after CPB, with a more pronounced and durable effect of the drug at the dose of 12 μg/kg. Additionally, administration of LS at a dose of 12 μg/kg in cardiac surgical patients with PH before CPB improved right ventricular function. Conclusion: LS administration decreases pulmonary artery pressure and may improve right ventricular function in patients with PH undergoing cardiac surgery. Full article

(This article belongs to the Special Issue Recent Advances in Pharmacology of Pulmonary Hypertension)

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12 pages, 1465 KiB

Open AccessArticle

Physiological and Psychological Response to Acute Mental Stress in Female Patients Affected by Chronic Pulmonary Arterial Hypertension: An Explorative Controlled Pilot Trial

by Alessandra Gorini, Beatrice De Maria, Patrycja Krasinska, Maurizio Bussotti, Francesca Perego and Laura Adelaide Dalla Vecchia

Pharmaceuticals 2023, 16(4), 493; https://doi.org/10.3390/ph16040493 - 27 Mar 2023

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Abstract

Little is known about physiological and psychological responses to mental stress in stable patients affected by pulmonary arterial hypertension (PAH). The current explorative controlled pilot study was conducted to investigate whether heart rate (HR) and perceived stress would differ during standardized mental stress [...] Read more.

Little is known about physiological and psychological responses to mental stress in stable patients affected by pulmonary arterial hypertension (PAH). The current explorative controlled pilot study was conducted to investigate whether heart rate (HR) and perceived stress would differ during standardized mental stress testing in PAH patients compared to healthy subjects. Correlation analysis between HR, perceived stress, participants’ psychological status and performance on the mental stress task was also performed. The study included 13 female PAH patients (average age: 44.38 ± 10.88 years; average education: 14 ± 3.07 years; mean duration of illness: 9.15 ± 5.37 years) and 13 female controls similar in age (mean age: 47.85 ± 6.36 years) and education (15.92 ± 1.55 years). Participants performed a standardized 9 min mental stress test (computer based, adaptive math task). HR and perceived stress during the task were compared to resting baseline and correlated with psychological state and task performance. Both HR and perceived stress significantly increased during mental stress in a similar way in both groups. A significant correlation was found between HR and perceived stress. Our data show that moderate mental stress has a comparable effect on HR and perceived stress increase in stable PAH patients and control subjects. Full article

(This article belongs to the Special Issue Recent Advances in Pharmacology of Pulmonary Hypertension)

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16 pages, 1378 KiB

Open AccessArticle

Monocrotaline-Induced Pulmonary Arterial Hypertension and Bosentan Treatment in Rats: Focus on Plasma and Erythrocyte Parameters

by Tomas Jasenovec, Dominika Radosinska, Marta Kollarova, Norbert Vrbjar, Peter Balis, Simona Trubacova, Ludovit Paulis, Lubomira Tothova, Ivana Shawkatova and Jana Radosinska

Pharmaceuticals 2022, 15(10), 1227; https://doi.org/10.3390/ph15101227 - 05 Oct 2022

Cited by 7 | Viewed by 2138

Abstract

The objective of our study was to contribute to the characterization of monocrotaline-induced pulmonary arterial hypertension (PAH) in a rat model, with emphasis on the renin–angiotensin–aldosterone system, parameters of oxidative stress, the activity of matrix metalloproteinases, and erythrocyte parameters. Moreover, we aimed to [...] Read more.

The objective of our study was to contribute to the characterization of monocrotaline-induced pulmonary arterial hypertension (PAH) in a rat model, with emphasis on the renin–angiotensin–aldosterone system, parameters of oxidative stress, the activity of matrix metalloproteinases, and erythrocyte parameters. Moreover, we aimed to analyze the effects of bosentan. Experiments were performed on 12-week-old male Wistar rats randomly assigned to 3 groups: control, monocrotaline-treated (60 mg/kg), and monocrotaline combined with bosentan (300 mg/kg/day). Our study confirmed the well-known effects of monocrotaline administration on lungs and the right ventricle, as well as pulmonary arterial pressure. In addition, we observed activation of the alternative pathway of the renin–angiotensin system, namely an increase in angiotensin (Ang) 1–7 and Ang 1-5 together with an increase in Ang I, but without any change in Ang II level, and downregulation of aldosterone 4 weeks after monocrotaline administration. For the first time, modifications of erythrocyte Na,K-ATPase enzyme kinetics were demonstrated as well. Our observations do not support data obtained in PAH patients showing an increase in Ang II levels, increase in oxidative stress, and deterioration in RBC deformability. Although bosentan primarily targets the vascular smooth muscle, our study confirmed its antioxidant effect. The obtained data suggest that besides the known action of bosentan, it decreases heart rate and increases erythrocyte deformability, and hence could have a beneficial hemodynamic effect in the PAH condition. Full article

(This article belongs to the Special Issue Recent Advances in Pharmacology of Pulmonary Hypertension)

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Review

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15 pages, 1840 KiB

Open AccessReview

Recent Advances in the Treatment of Pulmonary Arterial Hypertension Associated with Connective Tissue Diseases

by Anna Smukowska-Gorynia, Weronika Gościniak, Patrycja Woźniak, Sylwia Iwańczyk, Karolina Jaxa-Kwiatkowska, Sylwia Sławek-Szmyt, Magdalena Janus, Jerzy Paluszkiewicz and Tatiana Mularek-Kubzdela

Pharmaceuticals 2023, 16(9), 1252; https://doi.org/10.3390/ph16091252 - 05 Sep 2023

Viewed by 1839

Abstract

Pulmonary hypertension (PH) is a severe vascular complication of connective tissue diseases (CTD). Patients with CTD may develop PH belonging to diverse groups: (1) pulmonary arterial hypertension (PAH), (2) PH due to left heart disease, (3) secondary PH due to lung disease and/or [...] Read more.

Pulmonary hypertension (PH) is a severe vascular complication of connective tissue diseases (CTD). Patients with CTD may develop PH belonging to diverse groups: (1) pulmonary arterial hypertension (PAH), (2) PH due to left heart disease, (3) secondary PH due to lung disease and/or hypoxia and (4) chronic thromboembolic pulmonary hypertension (CTEPH). PAH most often develops in systemic scleroderma (SSc), mostly in its limited variant. PAH-CTD is a progressive disease characterized by poor prognosis. Therefore, early diagnosis should be established. A specific treatment for PAH-CTD is currently available and recommended: prostacyclin derivative (treprostinil, epoprostenol, iloprost, selexipag), nitric oxide and natriuretic pathway: stimulators of soluble guanylate cyclase (sGC: riociguat) and phosphodiesterase-five inhibitors (PDE5i: sildenafil, tadalafil), endothelin receptor antagonists (ERA: bosentan, macitentan, ambrisentan). Moreover, novel drugs, e.g., sotatercept, have been intensively investigated in clinical trials. We aim to review the literature on recent advances in the treatment strategy and prognosis of patients with PAH-CTD. In this manuscript, we discuss the mechanism of action of PAH-specific drugs and new agents and the latest research conducted on PAH-CTD patients. Full article

(This article belongs to the Special Issue Recent Advances in Pharmacology of Pulmonary Hypertension)

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22 pages, 785 KiB

Open AccessReview

Pharmacotherapy for Pulmonary Hypertension in Infants with Bronchopulmonary Dysplasia: Past, Present, and Future

by Candice D. Fike and Judy L. Aschner

Pharmaceuticals 2023, 16(4), 503; https://doi.org/10.3390/ph16040503 - 28 Mar 2023

Cited by 3 | Viewed by 2871

Abstract

Approximately 8–42% of premature infants with chronic lung disease of prematurity, bronchopulmonary dysplasia (BPD), develop pulmonary hypertension (PH). Infants with BPD-PH carry alarmingly high mortality rates of up to 47%. Effective PH-targeted pharmacotherapies are desperately needed for these infants. Although many PH-targeted pharmacotherapies [...] Read more.

Approximately 8–42% of premature infants with chronic lung disease of prematurity, bronchopulmonary dysplasia (BPD), develop pulmonary hypertension (PH). Infants with BPD-PH carry alarmingly high mortality rates of up to 47%. Effective PH-targeted pharmacotherapies are desperately needed for these infants. Although many PH-targeted pharmacotherapies are commonly used to treat BPD-PH, all current use is off-label. Moreover, all current recommendations for the use of any PH-targeted therapy in infants with BPD-PH are based on expert opinion and consensus statements. Randomized Control Trials (RCTs) are needed to determine the efficacy of PH-targeted treatments in premature infants with or at risk of BPD-PH. Prior to performing efficacy RCTs, studies need to be conducted to obtain pharmacokinetic, pharmacodynamic, and safety data for any pharmacotherapy used in this understudied and fragile patient population. This review will discuss current and needed treatment strategies, identify knowledge deficits, and delineate both challenges to be overcome and approaches to be taken to develop effective PH-targeted pharmacotherapies that will improve outcomes for premature infants with or at risk of developing BPD-PH. Full article

(This article belongs to the Special Issue Recent Advances in Pharmacology of Pulmonary Hypertension)

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20 pages, 1759 KiB

Open AccessReview

Pharmacology and Emerging Therapies for Group 3 Pulmonary Hypertension Due to Chronic Lung Disease

by Janae Gonzales and Dustin R. Fraidenburg

Pharmaceuticals 2023, 16(3), 418; https://doi.org/10.3390/ph16030418 - 09 Mar 2023

Cited by 1 | Viewed by 4064

Abstract

Pulmonary hypertension (PH) frequently complicates chronic lung disease and is associated with high morbidity and poor outcomes. Individuals with interstitial lung disease and chronic obstructive pulmonary disease develop PH due to structural changes associated with the destruction of lung parenchyma and vasculature with [...] Read more.

Pulmonary hypertension (PH) frequently complicates chronic lung disease and is associated with high morbidity and poor outcomes. Individuals with interstitial lung disease and chronic obstructive pulmonary disease develop PH due to structural changes associated with the destruction of lung parenchyma and vasculature with concurrent vasoconstriction and pulmonary vascular remodeling similar to what is observed in idiopathic pulmonary arterial hypertension (PAH). Treatment for PH due to chronic lung disease is largely supportive and therapies specific to PAH have had minimal success in this population with exception of the recently FDA-approved inhaled prostacyclin analogue treprostinil. Given the significant disease burden of PH due to chronic lung diseases and its associated mortality, a great need exists for improved understanding of molecular mechanisms leading to vascular remodeling in this population. This review will discuss the current understanding of pathophysiology and emerging therapeutic targets and potential pharmaceuticals. Full article

(This article belongs to the Special Issue Recent Advances in Pharmacology of Pulmonary Hypertension)

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19 pages, 763 KiB

Open AccessReview

Recent Advances in the Treatment of Pulmonary Arterial Hypertension

by Naoyuki Otani, Takashi Tomoe, Atsuhiko Kawabe, Takushi Sugiyama, Yasuto Horie, Hiroyuki Sugimura, Takanori Yasu and Takaaki Nakamoto

Pharmaceuticals 2022, 15(10), 1277; https://doi.org/10.3390/ph15101277 - 17 Oct 2022

Cited by 7 | Viewed by 2929

Abstract

Pulmonary arterial hypertension (PAH) is a disease in which stenosis or obstruction of the pulmonary arteries (PAs) causes an increase in PA pressure, leading to right-sided heart failure and death. Basic research has revealed a decrease in the levels of endogenous vasodilators, such [...] Read more.

Pulmonary arterial hypertension (PAH) is a disease in which stenosis or obstruction of the pulmonary arteries (PAs) causes an increase in PA pressure, leading to right-sided heart failure and death. Basic research has revealed a decrease in the levels of endogenous vasodilators, such as prostacyclin, and an increase in the levels of endogenous vasoconstrictors, such as endothelin, in patients with PAH, leading to the development of therapeutic agents. Currently, therapeutic agents for PAH target three pathways that are selective for PAs: the prostacyclin, endothelin, and nitric oxide pathways. These treatments improve the prognosis of PAH patients. In this review, we introduce new drug therapies and provide an overview of the current therapeutic agents. Full article

(This article belongs to the Special Issue Recent Advances in Pharmacology of Pulmonary Hypertension)

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29 pages, 2114 KiB

Open AccessReview

Strategizing Drug Therapies in Pulmonary Hypertension for Improved Outcomes

by Taylor Beckmann, Patrisha Shelley, Darshan Patel, Mounica Vorla and Dinesh K. Kalra

Pharmaceuticals 2022, 15(10), 1242; https://doi.org/10.3390/ph15101242 - 10 Oct 2022

Cited by 4 | Viewed by 6964

Abstract

Pulmonary hypertension (PH) is characterized by a resting mean pulmonary artery pressure (PAP) of 20 mmHg or more and is a disease of multiple etiologies. Of the various types of PH, pulmonary arterial hypertension (PAH) is characterized by elevated resistance in the pulmonary [...] Read more.

Pulmonary hypertension (PH) is characterized by a resting mean pulmonary artery pressure (PAP) of 20 mmHg or more and is a disease of multiple etiologies. Of the various types of PH, pulmonary arterial hypertension (PAH) is characterized by elevated resistance in the pulmonary arterial tree. It is a rare but deadly disease characterized by vascular remodeling of the distal pulmonary arteries. This paper focuses on PAH diagnosis and management including current and future treatment options. Over the last 15 years, our understanding of this progressive disease has expanded from the concept of vasoconstrictive/vasodilatory mismatch in the pulmonary arterioles to now a better appreciation of the role of genetic determinants, numerous cell signaling pathways, cell proliferation and apoptosis, fibrosis, thrombosis, and metabolic abnormalities. While knowledge of its pathophysiology has expanded, the majority of the treatments available today still modulate the same three vasodilatory pathways that have been targeted for over 30 years (endothelin, nitric oxide, and prostacyclin). While modifying these pathways may help improve symptoms and quality of life, none of these directly modify the underlying disease pathogenesis. However, there are now studies ongoing with new drugs that can prevent or reverse these underlying causes of PAH. This review discusses the evidence base for the current treatment algorithms for PAH, as well as discusses novel therapies in development. Full article

(This article belongs to the Special Issue Recent Advances in Pharmacology of Pulmonary Hypertension)

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