Long-term experience with implantable treprostinil pumps in pulmonary arterial hypertension.

OBJECTIVES: To compare clinical parameters and quality of life in patients with pulmonary arterial hypertension (PAH) at the time of diagnosis, at the time of LenusPro pump implantation and during intravenous treptostinil treatment. METHODS: Seven patients with severe PAH treated with intravenous treptostinil via implantable LenusPro pumps were evaluated, including NYHA classification, six­minute walking test, BNP and quality of life assessment using the EQ-5D-5L questionnaire before and after pump implantation. RESULTS: No significant changes were observed in NYHA class and six­minute walking distance test. There was however a significant improvement in the quality of life and a decrease in BNP levels. The mean EQ-5D-5L index assessed during subcutaneous treptostinil treatment was significantly worse when compared to that assessed during its intravenous application (0.39 ± 0.24 vs 0.78 ± 0.28, p ˂ 0.05); the same is true about the pain/discomfort dimension. Complications occurred, namely one nonfatal pneumothorax, one nonfatal hemothorax, and one event of nonfatal treptostinil intoxication after refilling. CONCLUSIONS: In patients who do not tolerate subcutaneous treptostinil treatment, the use of the LenusPro implantable pump results in a significant improvement in quality of life with an acceptable safety profile (Tab. 2, Fig. 2, Ref. 19).

Predictors of survival in patients with pulmonary hypertension and acute right heart failure.

OBJECTIVES: The aim of this study was to analyse survival of patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) hospitalized due to an acute right heart failure (ARHF) with emphasis on risk factors and effectiveness of treatment following current guidelines. METHODS: We retrospectively analysed 117 hospitalizations of 70 patients (59 PAH patients; 11 CTEPH patients, mean age 53.1 ± 16.77 years, 54 % females) between 2004 and 2013. RESULTS: 96 cases were hospitalized at cardiology wards (CW) while 21 at intensive care unit (ICU). The overall hospital mortality was 12.8 %, CW mortality was 4 %, and ICU mortality was 52.4 %. Higher risk of in-hospital mortality was associated with younger age, lower sodium levels, severe forms of PAH (heritable PAH, CTD-PAH) and need of PAH combination treatment. The one-year survival from the first ARHF hospitalization was 67.6 % (95 % CI 57.1-80 %), the two-year survival was 41.9 % (95 % CI 30.8-56.9 %). The presence of ascites was a predictor of long-term mortality. CONCLUSIONS: Mortality in patients with PH and ARHF remains very high. Identification of its risk factors could be used as basis of risk-adapted therapy (Tab. 5, Fig. 2, Ref. 14).

Novel Zn(II) complexes with non-steroidal anti-inflammatory ligand, flufenamic acid: Characterization, topoisomerase I inhibition activity, DNA and HSA binding studies.

A series of new Zn(II) complexes with flufenamic acid (flu) has been synthesized, namely [Zn3(dmso)2(flu)6] (1), [Zn3(flu)6(py)2] (2), [Zn(flu)2(tmen)] (3), [ZnCl(flu)(neo)] (4), and [Zn(cyclam)(flu)2] (5), where py=pyridine, tmen=N,N,N',N'-Tetramethylethylene diamine, neo=2,9-Dimethyl-1,10-phenanthroline and cyclam=1,4,8,11-Tetraazacyclotetradecane. These complexes have been characterized by infrared spectroscopy, single-crystal X-ray structure analysis, elemental and thermal analysis. All complexes contain deprotonated flufenamic acid coordinated via carboxylato group to zinc atoms, but their structures differ in the carboxylato binding mode, the coordination number of the central atom, the shape of the coordination polyhedra and the resultant supramolecular structures. Furthermore, an interaction of complexes with calf-thymus DNA (CT DNA) and human serum albumin (HSA) has been investigated by spectroscopic techniques. Moreover, the complexes 1 and 2 inhibit the catalytic activity of topoisomerase I at 60µM.

Utilization of IR spectral detailed analysis for coordination mode determination in novel Zn-cyclen-aminoacid complexes.

The infrared spectra, elemental and thermal (TG/DTG and DTA) analyses of novel [Zn(cyclen-κ4N1,4,7,10)(HGly-κ2O,O')](ClO4)2 (1), and [Zn2(cyclen-κ4N1,4,7,10)2(µ-S-Ala-κ2N,O)](ClO4)(3)·2H2O (2) complexes (cyclen - 1,4,7,10-tetraazacyclododecane) were recorded and analyzed in the relation to their structural peculiarities. IR spectral data indicate both mono- or bidentate coordination mode of a carboxylate group in the prepared complexes (at pH≈9). The results indicate unusual bidentate carboxylate coordination mode (in complex (1)) toward to Zn2+-cyclen unit. Therefore the crystal structure determination of the crystalline complex [Zn(cyclen-κ4N1,4,7,10)(NO3-κ2O,O')](NO3) was attached in order to support the coordination mode assignment in complex (1).

Identification of the quinone cofactor in a lysyl oxidase from Pichia pastoris.

A copper amine oxidase from Pichia pastoris is the only known non-mammalian lysyl oxidase [Tur, S.S. and Lerch, K. (1988) FEBS Lett. 238, 74-76]. Recently, the cofactor in mammalian lysyl oxidase has been identified as a novel lysine tyrosylquinone moiety [Wang, S.X., Mure, M., Medzihradszky, K.F., Burlingame, A.L., Brown, D.E., Dooley, D.M., Smith, A.J., Kagan, H.M. and Klinman, J.P. (1996) Science 273, 1078-1084]. In order to identify the cofactor in P. pastoris lysyl oxidase, we have isolated the phenylhydrazone-derivative of the active-site peptide. This peptide has the active-site sequence conserved among topa quinone containing amine oxidases. The resonance Raman spectra of the phenylhydrazone derivatives of the enzyme, active-site peptide, and a topa quinone model compound are essentially identical. Collectively, these results establish that P. pastoris lysyl oxidase is a topa quinone enzyme.