Plasma Endothelin-1 Concentrations in Children With Cirrhosis and Their Relationship to Renal Function and the Severity of Portal Hypertension

Bakr, Asharf; Abdalla, Ahmed; Elmarsafawy, Hala; Abu-Hashem, I.; El-Regal, Mohammad Ezz; Amer, Talal; Abdel-Khalik, M. K.; Mostafa, H.; A-Kader, H. Hesham

doi:10.1097/00005176-200208000-00009

Cited by 11 publications

(10 citation statements)

References 26 publications

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“…SPP301 significantly increased plasma ET‐1 levels at the lowest dose of 5 mg. Plasma ET‐1 measurements are useful because plasma concentrations have been found to correlate well with the severity of certain diseases such as primary pulmonary hypertension, cirrhosis, and heart failure 9–11 . The observation that circulations of ET‐1 are increased by the ET A receptor selective antagonist SPP301 in this study is in line with recent observations by others 12 .…”

Section: Discussionsupporting

confidence: 90%

Pharmacokinetics and Pharmacodynamics of the ET_A‐Selective Endothelin Receptor Antagonist SPP301 in Healthy Human Subjects

Dieterle¹,

Mann²,

Kutz

2004

The Journal of Clinical Pharma

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SPP301 is a competitive antagonist of ET-1 with a high selectivity for the ETA receptor. A double-blind, placebo-controlled study was performed to investigate the tolerability, pharmacokinetics, and pharmacodynamics of SPP301 after single oral doses in male healthy subjects; doses of 5, 20, 50, 100, and 200 mg were given to different groups of 4 or 8 subjects each. The effect of food on the pharmacokinetics of SPP301 was assessed for the 50-mg dose according to a sequential design in the same subjects. At regular intervals, blood pressure and pulse rate, plasma levels of ET-1 and of SPP301 and its hydroxymethyl metabolite, and urinary excretion of the parent drug and its metabolite were determined. SPP301 was generally well tolerated. At doses >20 mg, adverse events that are typical for vasodilating agents-namely, headache, nausea and vomiting, dizziness, and postural hypotension-were observed. Maximum plasma levels of SPP301 were reached within 4.5 hours. Cmax and AUC values increased linearly with doses up to 100 mg. The apparent terminal half-life was quite constant over the whole dose range and ranged from 7.5 to 15.2 hours. Urinary excretion of SPP301 was below 0.1% of any dose. Cmax and AUC of the metabolite amounted only to about 5% of the values for SPP301. Concomitant food intake had no effect on the overall exposure but increased average peak plasma concentrations of SPP301 by around 50%. Plasma ET-1 increased nearly twofold at the 5-mg SPP301 dose, with no further relevant increase at higher doses. In conclusion, SPP301 is an active ET-1 antagonist and is well tolerated. The pharmacokinetics of the drug and its metabolite are linear up to 100 mg. Food does not affect overall exposure of SPP301 but increases Cmax. Urinary excretion of SPP301 is below 0.1% of the dose administered.

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Section: Discussionsupporting

confidence: 90%

Pharmacokinetics and Pharmacodynamics of the ET_A‐Selective Endothelin Receptor Antagonist SPP301 in Healthy Human Subjects

Dieterle¹,

Mann²,

Kutz

2004

The Journal of Clinical Pharma

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“…In addition, these studies found increased ET-1 synthesis in the renal papilla, which may contribute to renal dysfunction and predispose to acute renal failure during OJ (12). A clinical study of pediatric patients with cirrhosis showed a negative correlation between plasma ET-1 and creatinine clearance (22), which corroborates the link between renal dysfunction and OJ. In addition, it has been shown that ET-1 induces renal synthesis of PGE 2 , which exerts a vasodilatory effect on renal vascular tone (23).…”

Section: Discussionmentioning

confidence: 62%

Alteration of the renal regulatory hormonal pattern during experimental obstructive jaundice

Padillo

Cruz

Espejo

et al. 2009

Rev. esp. enferm. dig.

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Objective: the alteration of hormones regulating sodium and water status is related to renal failure in obstructive jaundice (OJ).Experimental design: OJ was induced by common bile duct ligation. Samples were obtained from the control (SO) and OJ groups at 24 and 72 hours, and at 7 days. Different parameters related to biliary obstruction, liver and renal injury, and vasoactive mediators such as renin, aldosterone, endothelin-1 (ET-1) and prostaglandin E 2 (PGE 2 ) were studied.Results: bile duct ligation caused an increase in total bilirubin (p < 0.001) and alkaline phosphatase (AP) (p < 0.001). The SO and OJ groups had the same values for diuresis, renin, and creatinine clearance at 24 h. However, animals with OJ had a lower sodium concentration in urine than SO animals (p < 0.01), as well as an increase in aldosterone levels (p < 0.03). ANP levels were moderately increased during OJ but did not reach statistical significance when compared to the SO group. In contrast, OJ animals showed a rise in serum ET-1 concentration (p < 0.001) and increased PGE 2 in urine (p < 0.001).Conclusions: biliary obstruction induced an increase in ET-1 release and PGE 2 urine excretion. These hormones might play a role during the renal complications associated with renal disturbances that occur during OJ. INTRODUCTIONCholestasis is a clinical and biochemical syndrome caused by the impaired bile flow often associated with extrahepatic complications (1). Acute renal failure is a major complication of obstructive jaundice (OJ), with 8% incidence in several series (2). Biliary obstruction was first linked to renal failure in the early study carried out by Clairmont and von Haberer (1910) (3). Several hypotheses have sought to explain the pathogenesis of renal dysfunction in OJ. The depletion of the extracellular compartment (4), myocardial dysfunction, and altered hemodynamic status (5) have been linked to renal failure in biliary obstruction. In addition, severe oxidative stress has been implicated in the renal dysfunction associated to experimental OJ (6,7) as well as other liver diseases (8). Other lines of research have looked at the involvement of vasoactive mediators such as endothelin-1 (ET-1). ET-1 is a powerful paracrine vasoconstrictor that acts by means of specific type-A and type-B receptors. In biochemical terms, it is a 21-amino acid peptide derived from what is known as big ET-1 by the action of the endothelin-converter enzyme. It is synthesized mainly by endothelial cells and to a lesser degree by stellate cells in the liver and biliary epithelium (9,10). ET-1 changes have been related to different human diseases (11). ET-1 both acts on the mesangial cells and causes vasoconstriction in the renal microcirculation, which may contribute -along- Enferm Dig 2009; 101: 408-412.

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“…A recent study found significantly elevated plasma endothelin-1 levels in patients with PPHTN compared to cirrhotic patients with portal hypertension but without pulmonary hypertension [8]. In addition, a large body of evidence suggests that endothelin-1 may also be involved in the pathogenesis of portal hypertension [24][25][26][27][28]. A recent case report of a patient with PPHTN (who was included in the present study) described normalisation of portal venous pressures with bosentan treatment [20].…”

Section: Discussionmentioning

confidence: 62%

Bosentan therapy for portopulmonary hypertension

Hoeper

Halank²,

Marx³

et al. 2005

Eur Respir J

185

109

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The dual endothelin receptor antagonist bosentan has been approved in several countries for pulmonary arterial hypertension, and patients with portopulmonary hypertension (PPHTN) have not specifically been excluded. However, no data have been published on the efficacy and safety of bosentan in this patient population. Here, the first clinical experiences with bosentan in patients with Child A cirrhosis and severe PPHTN are reported.In total, 11 consecutive patients with cirrhosis and severe PPHTN in New York Heart Association Functional Classes III and IV were treated for .1 yr with bosentan.After 1 yr of treatment with bosentan, all patients showed improved symptoms and exercise capacity. The 6-min walking distance increased from 310¡102 m at baseline to 388¡81 m at 1 yr. Cardiopulmonary exercise testing disclosed a significant increase in peak oxygen uptake, from 12.6¡3.5 to 16.6¡2.8 mL?min -1 ?kg -1 . Pulmonary vascular resistance fell from 944¡519 to 635¡321 dynes?s?L -1. The medication was well tolerated by all patients, and there was no evidence of drug-related liver injury.In conclusion, bosentan proved to be efficacious and safe in a small number of patients with portopulmonary hypertension.

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Plasma Endothelin-1 Concentrations in Children With Cirrhosis and Their Relationship to Renal Function and the Severity of Portal Hypertension

Cited by 11 publications

References 26 publications

Pharmacokinetics and Pharmacodynamics of the ET_A‐Selective Endothelin Receptor Antagonist SPP301 in Healthy Human Subjects

Pharmacokinetics and Pharmacodynamics of the ET_A‐Selective Endothelin Receptor Antagonist SPP301 in Healthy Human Subjects

Alteration of the renal regulatory hormonal pattern during experimental obstructive jaundice

Bosentan therapy for portopulmonary hypertension

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Plasma Endothelin-1 Concentrations in Children With Cirrhosis and Their Relationship to Renal Function and the Severity of Portal Hypertension

Cited by 11 publications

References 26 publications

Pharmacokinetics and Pharmacodynamics of the ETA‐Selective Endothelin Receptor Antagonist SPP301 in Healthy Human Subjects

Pharmacokinetics and Pharmacodynamics of the ETA‐Selective Endothelin Receptor Antagonist SPP301 in Healthy Human Subjects

Alteration of the renal regulatory hormonal pattern during experimental obstructive jaundice

Bosentan therapy for portopulmonary hypertension

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Pharmacokinetics and Pharmacodynamics of the ET_A‐Selective Endothelin Receptor Antagonist SPP301 in Healthy Human Subjects

Pharmacokinetics and Pharmacodynamics of the ET_A‐Selective Endothelin Receptor Antagonist SPP301 in Healthy Human Subjects