Palosuran: clinical pharmacology of a urotensin-II receptor antagonist in type 2 diabetes mellitus

Type 2 Diabetes Mellitus (Type 2 DM) is a growing global public health threat, leading to a significant cost burden to society. Type 2 DM increases the risk of hypertension and associated macro- and microcardiovascular diseases, affecting the eyes, brain, kidneys, and cardiovasculature. Cardiovascular disease accounts for up to 80% of the deaths in individuals with Type 2 DM. The mechanistic background for the disease is an imbalance between increased insulin requirement (insulin resistance) versus insufficient insulin availability (insulin deficiency) resulting in hyperglycemia and increased circulatory fatty acids. Treatment of Type 2 DM is aimed at increasing pancreatic ß-cell function and lowering insulin resistance in order to lower blood glucose levels. While in first line life style changes such as weight loss and exercise should be implemented, various antidiabetic drugs are available that are can be used either as mono- or combination therapy. Overall, these agents are well tolerated. However, some risks remain which could affect patient's compliance and safety. Therefore, there is a need for better and safer antidiabetic drugs. Urotensin-II (U-II) has been described as one of the most potent vasoconstrictors up to date, though its function in humans is not fully understood. In humans, U-II receptors (UT receptor) have been identified in various tissues; amongst others the kidney and pancreas. These organs have a crucial role in glucose regulation and cardiovascular homeostasis, mechanisms which are disrupted in diabetic patients. Increases in U-II concentrations have also been observed in diabetic patients. Therefore, antagonism of U-II could be beneficial in treatment of this disease. Palosuran is a potent, selective, oral antagonist of the human UT receptor. In healthy subjects, palosuran was well tolerated after single- and multiple-dose administration over a wide dose range. The pharmacokinetics were indicative of a twice daily dosing regimen. Two absorption peaks could be detected at approximately 1 and 4 h after drug administration. Following peak plasma concentrations, elimination was biphasic with a faster and slower elimination phase resulting in low plasma concentrations at 12 h after drug administration. The intake of food had a minor effect on drug exposure when expressed in area under the curve, but is not considered to be of clinical relevance. Therefore palosuran can be administered with and without food. In an open-label study in patients with Type 2 diabetic nephropathy, 2-week treatment with palosuran significantly reduced the 24-hour urinary albumin excretion rate, an accepted clinical marker for cardiorenal disease progression. Surprisingly, in this study, no effects on other renal hemodynamic parameters (i.e., glomerular filtration rate, renal blood flow, filtration fraction) were observed, which hampered the understanding of the mechanism underlying the reduction of 24-h UAER. In a proof-of-concept, randomized, double-blind, placebo-controlled study, 4-week treatment with palosuran did not show any effect on insulin secretion or blood glucose levels in diet-treated patients with Type 2 DM. These studies suggest that palosuran is not efficacious in subjects with diabetic nephropathy and Type 2 DM. However, based on the expression of UT receptors in humans, there is enough reason to believe that UT receptor antagonists can have therapeutic value in various other cardiovascular, pulmonary, renal, and oncologic indications

Effect of Cyclosporine and Rifampin on the Pharmacokinetics of Macitentan, a Tissue-Targeting Dual Endothelin Receptor Antagonist

Macitentan is a dual endothelin receptor antagonist under phase 3 investigation in pulmonary arterial hypertension. We investigated the effect of cyclosporine (Cs) and rifampin on the pharmacokinetics of macitentan and its metabolites ACT-132577 and ACT-373898 in healthy male subjects. In addition, in vitro studies were performed to investigate interactions between macitentan and its active metabolite ACT-132577 with human organic anion-transporting polypeptides (OATPs). The clinical study (AC-055-111) was conducted as a two-part, one-sequence, crossover study. Ten subjects in each part received multiple-dose macitentan followed by multiple-dose co-administration of Cs (part A) or rifampin (part B). In the presence of Cs, steady-state area under the plasma concentration–time profiles during a dose interval (AUCτ) for macitentan and ACT-373898 increased 10% and 7%, respectively, and decreased 3% for ACT-132577. Steady-state AUCτ of macitentan and ACT-373898 in the presence of rifampin decreased 79% and 64%, respectively. For ACT-132577, no relevant difference in AUCτ between the two treatments was observed. Macitentan co-administered with Cs or rifampin was well tolerated. The complementary in vitro studies demonstrated no marked differences in uptake rates of macitentan and ACT-132577 between the wild-type and OATP over-expressing cells over the concentration range tested. Concomitant treatment with Cs did not have any clinically relevant effect on the exposure to macitentan or its metabolites, at steady-state. Concomitant treatment with rifampin reduced significantly the exposure to macitentan and its metabolite ACT-373898 at steady-state but did not affect the exposure to the active metabolite ACT-132577 to a clinically relevant extent

Ictiose Arlequim: Caso Clínico

Harlequin ichthyosis is a rare autosomal recessive congenital disease in which neonates present generalized hyperkeratotic plaques and deep fissures, ectropion, eclabium, malformation of the auricular pavilion and typical facies. Although several complications related to the skin restriction may occur, support in intensive care and early introduction of systemic retinoids, such as acitretin, have significantly contributed to patients' survival and improved prognosis. The purpose of this report is to present a rare case of harlequin ichthyosis and to discuss strategies for early diagnosis and first supportive care.Ictiose arlequim é uma doença congênita autossómica recessiva rara, na qual os recém-nascidos apresentam placas de hiperqueratose generalizadas e fissuras profundas, ectrópio, eclábio, malformação do pavilhão auricular e fácies típicas. Embora várias complicações relacionadas à restrição cutânea possam ocorrer, o suporte em terapia intensiva e a introdução precoce de retinóides sistémicos, como a acitretina, têm contribuído significativamente para a melhoria da sobrevida e do prognóstico dos doentes. O objetivo deste relato é apresentar um raro caso de ictiose arlequim e discutir estratégias para o diagnóstico precoce e o primeiro tratamento de suporte

Pharmacokinetic and pharmacodynamic evaluation of macitentan , a novel endothelin receptor antagonist for the treatment of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a chronic disorder of the pulmonary vasculature characterized by elevated mean pulmonary arterial pressure eventually leading to right-sided heart failure and premature death. Macitentan is an oral, once-daily, dual endothelin (ET)A and ETB receptor antagonist with high affinity and sustained receptor binding that was approved in the USA, Europe, Canada, and Switzerland for the treatment of PAH.; This review discusses the pharmacokinetics (PK) and pharmacodynamics (PD) of macitentan and its drug interaction potential based on preclinical and clinical data.; Up to date, macitentan is the only registered treatment for PAH that significantly reduced morbidity and mortality as a combined endpoint in a long-term event-driven study. The safety profile of macitentan is favorable with respect to hepatic safety and edema/fluid retention and may be better than that of other ET receptor antagonists such as bosentan and ambrisentan. The PK profile supports a once-a-day dosing regimen. Macitentan has limited interactions with other drugs. Based on these characteristics macitentan is an important new addition to the treatment of PAH

Effect of the urotensin-II receptor antagonist palosuran on secretion of and sensitivity to insulin in patients with Type 2 diabetes mellitus

AIMS: To investigate the effects of palosuran, a nonpeptidic, potent and selective antagonist of the urotensin-II receptor, on insulin and glucose regulation in 20 diet-treated patients with Type 2 diabetes mellitus in a double-blind, placebo-controlled, randomized, crossover, proof-of-concept study. METHODS: After 4 weeks' oral treatment with 125 mg palosuran or placebo b.i.d.,effects on insulin secretion and sensitivity and blood glucose levels were assessed by means of a hyperglycaemic glucose clamp, meal tolerance test, homeostasis model assessment-insulin resistance score, and daily self-monitoring of blood glucose. Plasma concentrations of palosuran were determined for 12 h on the last day of intake. RESULTS: Palosuran did not affect second-phase insulin response (primary end-point) during the hyperglycaemic glucose clamp in comparison with placebo [paired difference of -1.8 microU ml(-1), 95% confidence interval (CI) -7.8, 4.2]. Likewise, no effects of palosuran were detected on the first-phase insulin response, or on insulin secretion and blood glucose levels during the meal tolerance test or on homeostasis model assessment-insulin resistance score. No clinically significant effects on daily blood glucose profiles were observed during the study. Geometric mean C(max) and AUC(tau) (95% CI) and median t(max) (range) in this patient population were 180 ng ml(-1) (125, 260), 581 ng.h ml(-1) (422, 800) and 3.0 h (0.67, 4.3), respectively. CONCLUSIONS: The results of this study indicate that antagonism of the urotensin-II system does not influence insulin secretion or sensitivity or daily blood glucose levels in diet-treated patients with Type 2 diabetes