1. ASB20123: A novel C-type natriuretic peptide derivative for treatment of growth failure and dwarfism
Hiroaki Maeda, Takafumi Yotsumoto, Toshimasa Jindo, Mayumi Furuya, Akira Yamaki, Ryuichi Nakamura, Kazunori Yoshikiyo, Sayaka Yoshida, Naomi Morozumi, Kenji Kangawa, Yoshiharu Minamitake PLoS One . 2019 Feb 22;14(2):e0212680. doi: 10.1371/journal.pone.0212680.
C-type natriuretic peptide (CNP) and its receptor natriuretic peptide receptor B (NPR-B) are physiological potent positive regulators of endochondral bone growth; therefore, the CNP/NPR-B signaling pathway is one of the most promising therapeutic targets for treating growth failure and dwarfism. In this article, we summarized the pharmacological properties of a novel CNP analog peptide ASB20123 as a therapeutic agent for short stature. ASB20123, one of the CNP/ghrelin chimeric peptides, is composed of CNP(1-22) and human ghrelin(12-28, E17D). Compared to CNP(1-22), ASB20123 showed similar agonist activity for NPR-B and improved biokinetics with a longer plasma half-life in rats. In addition, the distribution of ASB20123 to the cartilage was higher than that of CNP(1-22) after single subcutaneous (sc) injection to mice. These results suggested that the C-terminal part of ghrelin, which has clusters of basic amino acid residues and a BX7B motif, might contribute to the retention of ASB20123 in the extracellular matrix of the growth plate. Multiple sc doses of ASB20123 potently stimulated skeletal growth in rats in a dose-dependent manner, and sc infusion was more effective than bolus injection at the same dose. Our data indicated that high plasma levels of ASB20123 would not necessarily be required for bone growth acceleration. Thus, pharmaceutical formulation approaches for sustained-release dosage forms to allow chronic exposure to ASB20123 might be suitable to ensure drug effectiveness and safety.
2. C-type natriuretic peptide is associated with the severity of Crimean-Congo hemorrhagic fever
Mehmet Birhan Yilmaz, Fatma Mutlu Kukul Guven, Okan Onur Turgut, Ali Zorlu, Aynur Engin, Kenan Ahmet Turkdogan, Muhammed Mirhan Polat Int J Infect Dis . 2012 Aug;16(8):e616-20. doi: 10.1016/j.ijid.2012.04.009.
Background:Crimean-Congo hemorrhagic fever (CCHF) is characterized by vascular dysfunction, indicating the involvement of endothelial cells. C-type natriuretic peptide (CNP) plays a critical role in the coordination of vascular tone and is associated with the prognosis in critically ill patients such as those with sepsis and septic shock. We investigated whether CNP is related to the severity of CCHF.Methods:Forty-eight consecutive patients with a laboratory confirmed diagnosis of CCHF and 40 age-sex-matched healthy volunteers as the control group were prospectively enrolled into the study. CCHF patients were classified according to the disease severity into a non-severe group (n=28) and a severe group (n=20).Results:The CNP levels were detected to be 0.43 (0.4-0.7) ng/ml in the control group, 0.87 (0.7-1.0) ng/ml in the non-severe CCFH group, and 1.27 (0.8-1.7) ng/ml in the severe CCHF group. According to the receiver operating characteristics curve analysis, the optimal cut-off value of CNP to predict disease severity was >1.22 ng/ml, with 89.3% specificity and 55% sensitivity. CNP >1.22 ng/ml, lactate dehydrogenase >480 IU/l, and aspartate aminotransferase >202 IU/l were found to have prognostic significance in the univariate analysis. In the multivariate logistic regression analysis by forward stepwise method, CNP >1.22 ng/ml (odds ratio 8.336, p = 0.016) and lactate dehydrogenase >480 IU/l (odds ratio 16.206, p = 0.002) remained associated with disease severity after adjustment for confounding variables.Conclusions:CNP measurement could help in the risk stratification of patients with CCHF.
3. Circulating C-type natriuretic peptide is increased in orthotopic cardiac transplant recipients and associated with cardiac allograft vasculopathy
M G Buckley, D R Singer, A G Mitchell, G H Jenkins, M H Yacoub Clin Sci (Lond) . 2000 Nov;99(5):467-72.
C-type natriuretic peptide (CNP) is a potent, endothelial-derived relaxant and growth-inhibitory factor. Accelerated vascular disease is an important cause of morbidity in cardiac transplant recipients, and endothelial dysfunction is now well recognized in patients with cardiovascular disease. CNP has not previously been investigated following cardiac transplantation. We therefore studied plasma levels of immunoreactive CNP in patients early and late after heart transplantation, compared with levels in healthy subjects. We measured CNP in extracted human plasma using an antibody against human CNP-(1-22). CNP levels were significantly elevated in 13 cardiac recipients 2 weeks post-transplant [2.64+/-0.26 pmol/l (mean+/-S.E.M.)] compared with those in the normal healthy subjects (0.62+/-0.04 pmol/l; n=20, P<0.001). Plasma levels of CNP were also significantly elevated in a second group of established cardiac transplant recipients (1.15+/-0.07 pmol/l; n=46) studied 1-13 years post-transplant when compared with the healthy subjects (P<0.001). In the group studied later after transplantation, CNP levels were significantly associated with systolic blood pressure (P<0.05) and were higher in patients with angiographic post-transplant coronary artery disease (P=0.032). In conclusion, these findings clearly demonstrate that CNP is elevated soon after cardiac transplantation and remains raised in patients even several years post-transplant. CNP may be important as a circulating or local hormone involved in vascular contractile function and in the pathophysiology of cardiac allograft vasculopathy following heart transplantation.
