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Pseudomonas aeruginosa is an opportunistic pathogen that can cause acute and severe infections. Increasing resistance to antibiotics has given rise to the urgent need for an alternative antimicrobial agent. A promising strategy is the inhibition of iron sequestration in the bacteria. The current work aimed to screen for inhibitors of pyoverdine-mediated iron sequestration in P. aeruginosa. As a drug target, we choose l-ornithine-N5-monooxygenase (PvdA), an enzyme involved in the biosynthesis of pyoverdine that catalyzes the FAD-dependent hydroxylation of the side chain amine of ornithine. As drug repurposing is a fast and cost-efficient way of discovering new applications for known drugs, the approach may help to solve emerging clinical problems. In this study, we use data about molecules from drug banks for screening. A total of 15 drugs that are similar in structure to l-ornithine, the substrate of PvdA, and 30 drugs that are sub-structures of l-ornithine were virtually docked against PvdA. N-2-succinyl ornithine and cilazapril were found to be the top binders with a binding energy of -12.8 and -9.1 kcal mol-1, respectively. As the drug-likeness and ADME properties of the drugs were also found to be promising, molecular dynamics studies were performed to further confirm the stability of the complexes. The results of this in silico study indicate that N-2-succinyl ornithine could potentially be explored as a drug for the treatment of P. aeruginosa infections.

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In this research, the selected drugs commonly used in diabetes and its comorbidities (gliclazide, cilazapril, atorvastatin, and acetylsalicylic acid) were studied for their interactions with bovine serum albumin-native and glycated. Two different spectroscopic methods, fluorescence quenching and circular dichroism, were utilized to elucidate the binding interactions of the investigational drugs. The glycation process was induced in BSA by glucose and was confirmed by the presence of advanced glycosylation end products (AGEs). The interaction between albumin and gliclazide, with the presence of another drug, was confirmed by calculation of association constants (0.11-1.07 × 104 M-1). The nature of changes in the secondary structure of a protein depends on the drug used and the degree of glycation. Therefore, these interactions may have an influence on pharmacokinetic parameters.

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For cilazapril (CLZ), analytical methods based on donor-acceptor phenomenon that are simple, rapid with broad linear dynamic range for the quantification of drug are not available in the literature. Considering the requirement for the methods, in this study, two economic, potent analytical methods based on the complexation of CLZ with π-acceptors, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and 2,5-dichloro-3,6-dihydroxy-p-benzoquinone (CA) were developed, validated, and studied spectrophotometrically. Various analytical data were discussed. The effects of experimental variables were optimized from the results of in silico technique, i.e. Box-Behnken design under response surface methodology. Linear dynamic range was significantly good in the range of 6-60 µg mL-1 and 20-260 µg mL-1 for DDQ and CA methods. Moreover, molecular docking studies corroborated the experimental results. Further, the methods were supplemented by the pharmaceutical and biological application for the quantitative assay of CLZ. Collectively, the results of the reported method of the analysis suggest that the developed approach is simple, sensitive, accurate and precise.

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Biopolymer-based spherical particles exhibit unique properties including narrow sizes and many functional groups on their surfaces. Therefore, they show great potential for application in many scientific and industrial processes. The main aim of this study was to prepare lignin-based spherical particles with the use of a cationic surfactant, hexadecyl(trimethyl)ammonium bromide (CTAB). In the first step, different preparation procedures were tested with varying parameters, including biopolymer and surfactant ratios, lignin filtration, and experimental time. The morphological and dispersion characteristics of the materials were determined to select the best samples with the most promising properties, which could then be tested for their acute toxicity. It was observed that almost all materials were characterized by spherical shapes in micro- and nanosizes. The sample with the best physicochemical properties was used for further analysis and then tested for medical applications: the improvement of the stability of a drug molecule, cilazapril (CIL). The formulated material (CIL@LC-2a 1:1 wt./wt.) exhibited outstanding properties and significantly improved the stability of cilazapril as tested in conditions of increased temperature and humidity. Lignin spherical particles may be employed as a promising material for shielding other active compounds from decomposition.

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In this study a solid dispersion and a physical mixture of cilazapril (CIL) with a biopolymer - polyvinylpyrrolidone (PVP) as a carrier were prepared so as to investigate the effect of PVP on the stability of CIL. CIL is unstable in solid state and decomposes rapidly under humid conditions. It requires stabilization to ensure safety of its use. The studied CIL/PVP formulations were prepared by milling and evaporation technique. Their identity was confirmed by FT-IR method. The stability of CIL in the CIL/PVP formulations was assessed by forced ageing test under isothermic conditions using RP-HPLC. The influence of temperature (experimental conditions: RH 76.4% and T = 70, 75, 80, 85, and 90 oC) and the effect of relative humidity (experimental conditions: RH 25.0%, 50.9%, 60.9%, 66.5%, 76.4%, T = 90 °C) on the rate of CIL degradation were examined. It was established that the process of CIL decay in the studied forms followed first-order kinetics with the formation of one degradation product - cilazaprilat. The degradation rate constant of this reaction was lower than that for pure CIL. The energy of activation of the CIL degradation in the presence of PVP was higher than that of pure CIL. Furthermore, CIL incorporated into PVP exhibited lower sensitivity to moisture. Based on these data PVP was considered as a potential stabilizing substance for CIL-containing dosage forms.

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Angiotensin-converting enzyme 2 (ACE2) is considered a potential therapeutic target of the renin-angiotensin system (RAS) for the treatment of cardiovascular diseases. We aimed to explore the effects of ACE2 overexpression on doxorubicin-induced cardiomyopathy in rats. Rats were randomly divided into treatment and control groups. The rats of treatment group were injected intraperitoneally with 6 doses of doxorubicin (2.5 mg/kg) within a period of two weeks. Two weeks after the initial injection of doxorubicin, these rats were randomly divided into Mock, Ad-EGFP, Ad-ACE2, and Cilazapril groups. The rats of Ad-EGFP and Ad-ACE2 groups received intramyocardial injection of Ad-EGFP and Ad-ACE2, respectively. The rats of Cilazapril group received cilazapril (10 mg/kg/day) via intragastric intubation. Apoptosis, inflammation, oxidative stress, cardiac function, the extent of myocardial fibrosis, and levels of ACE2, ACE, angiotensin II (AngII), and angiotensin (1-7) were evaluated. Four weeks after ACE2 gene transfer, the Ad-ACE2 group showed not only reduced apoptosis, inflammatory response, oxidative stress, left ventricular (LV) volume, extent of myocardial fibrosis and mortality of rats, but also increased LV ejection fraction and ACE2 expression level compared with the Mock and Ad-EGFP groups. ACE2 overexpression was superior to cilazapril in improving doxorubicin-induced cardiomyopathy. The putative mechanisms may involve activation of the AMPK and PI3K-AKT pathways, inhibition of the ERK pathway, decrease of TGF-ß1 expression, and interactions of shifting RAS components, such as decreased myocardium AngII levels, increased myocardium Ang (1-7) levels, and reduced ACE expression. Thus, ACE2 may be a novel therapeutic approach to prevent and treat doxorubicin-induced cardiomyopathy.

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Forced degradation studies on cilazapril were carried out according to ICH and WHO guidelines. Significant degradation of the drug was observed in acid and base conditions, resulting primarily in cilazaprilat. In neutral condition, five degradation products were formed, while under oxidative condition, two degradation products were generated. In total, seven degradation products were formed, which were separated on an Inertsil C-18 column using a stability-indicating HPLC method. Structure elucidation of the degradation products was done by using sophisticated and hyphenated tools like, LC-MS/TOF, LC-MS(n), on-line H/D exchange, LC-NMR and NMR. Initially, comprehensive mass fragmentation pathway of the drug was laid down. Critical comparison of mass fragmentation pathways of the drug and its hydrolytic degradation products allowed structure characterization of the latter. 1D and 2D proton LC-NMR studies further confirmed the proposed structures of hydrolytic degradation products. The oxidative degradation products could not be characterized using LC-MS and LC-NMR tools. Hence, these degradation products were isolated using preparative HPLC and extensive 1D ((1)H, (13)C, DEPT) and 2D (COSY, TOCSY, HETCOR and HMBC) NMR studies were performed to ascertain their structures. Finally, degradation pathways and mechanisms of degradation of the drug were outlined.

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PURPOSE: The aim of the present work is to study the thermal analysis of telmisartan and cilazapril. METHODS: Thermogravimetry (TGA), derivative thermogravimetry (DTG) and differential thermal analysis (DTA) were used through the work to achieve the thermal analysis study of some antihypertensive drugs, telmisartan and cilazapril. RESULTS: The results led to thermal stability data and also to the interpretation concerning the thermal decomposition. Thermogravimetry data allowed determination of the kinetic parameters such as, activation energy and frequency factor. CONCLUSION: The simplicity, speed and low operational costs of thermal analysis justify its application in the quality control of pharmaceutical compounds for medications.

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We describe an unusual case of lymphocytic pleural effusion associated with the use of cilazapril, a novel angiotensin-converting-enzyme inhibitor (ACEI). An 80-year-old male was prescribed cilazapril for hypertension. He subsequently presented with right chest pain and dry cough. He was found to have a lymphocytic pleural effusion on thoracentesis. Extensive workup, including open pleural biopsy, failed to reveal the etiology of the effusion. However, soon after the withdrawal of cilazapril, his clinical symptoms improved and the effusion disappeared. ACEI-induced pleural effusion has only been rarely reported. Drug-induced pleural effusion should be considered when formulating the differential diagnosis in a patient receiving ACEI.

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Objective To investigate the effects of cilazapril on heart rate corrected QT interval disoersion (QTcd) and ventricular arrhythmia (VA) in patients with essential hypertension. Methods 96 hypertensive patients with LVH were divided randomly into two groups. 48 patients in lercanidipine group were treated routinely plus lercanidipine. 48 patients in cilazapril group were treated with routine drugs plus cilazapril. QTcd of 12-lead sur-face ECC and VA malignant degree recorded by Holter were analyzed before therapy and 6 mgnths after therapy. Re-suits In the cilazapril group,the QTcd was different before and after the therapy ((76±12) ms vs (65±9) ms, P<0.05 ). In the lercanidipine group, the QTcd was not significantly different ((76±13 ) ms vs (74±12) ms, P > 0.05). QTed and the malignant degree of VA between the two groups were significantly different after the therapy. Conclusions Treatment with cilazapril can reduce the QTcd and the malignant degree of VA in hypertensive patients with LVH.

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Thirty seven patients with congestive heart failure (CHF) were divided into cilazapril group (n=19) and general treatment group (n=18). Serum levels of interleukin-6 (IL-6) ,interleukin-8 (IL-8) , interleukin-10(IL-10) and tumor necrosis factor-α(TNF-α) , left ventricular ejection fraction (LVEF) ,left ventricular end-diastolic diameter (LVEDD), cardiac output (CO) and fractional shortening (FS) were measured before and after treatment. Serum levels of cytokines were also measured in 40 healthy individuals (control group). Results: The serum levels of IL-6, IL-8, IL-10 and TNF-α in CHF patients were significantly higher than those in the control group ( all P<0.01 ) ; After treatment, the serum IL-6, IL-8 and TNF-α were significantly decreased (P<0.01 ,P<0.05 ) in the cilazapril group. The LVEF, FS, CO were significantly increased in the Cilazapril group ( P<0.01 ) ; And the serum levels of IL-6 were significantly decreased in the cilazapril group as compared with the general treatment group ( P<0.05 ), however, after treatment, the EF, LVEF, FS and CO had no statistical differences in the cilazapril group as compared with the general treatment group. In the control group only LVEF and FS improved(P<0.01) ; Cytokine levels showed no changes. It suggests that cilazapril can reduce the serum levels of pro-inflammatory cytokines, increased the serum levels of anti-inflammatory cytokine, protect and improved cardiac function in the patients with congestive heart failure.

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Objective To observe endothelial and fibrinolytic functions of clinical AF patients and effects of cilazapril on it and to investigate the mechanism and treatments of thrombogenesis in AF.Methods 63 AF patients were randomly divided into control group(n=30)and cilazapril group(n=33).All patients received general treatment according symptoms.In addition,the patients in cilazapril group received cilazapril(2.5mg/d,2 weeks).Plasma Ang Ⅱ, vWF,t-PA and PAI-1 level were measured before and after 2 weeks.There were 36 patients with sinus rhythm (SH)in non-AF control group.Results AF patients had higher plasma Angll level than SH patients that indicated RAS activated[(107.7?22.0)pg/mL vs(70.2?15.8)pg/mL,P

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Objective To observe endothelial and fibfinolytic functions of clinical AF patients and effects of cilazapril on it and to investigate the mechanism and treatments of thrombogenesis in AF.Methods 63 AF patients were randomly di- vided into control group (n=30) and cilazapril group (n=33).All patients received general treatment according symptoms.In addition,the patients in cilazapril group received cilazapril (2.5mg/d,2 weeks).Plasma Ang Ⅱ, vWF,t-PA and PAI-1 level were measured before and after 2 weeks.There were 36 patients with sinus rhythm (SH) in non-AF control group.Results AF patients had higher plasma AnglI level than SH patients that indicated RAS acti- vated[(107.7?22.0) ng/L vs (70.2?15.8) ng/L,P

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BACKGROUND: Although angiotensin-converting enzyme inhibitors (ACEIs) have been shown to prolong life in patients with congestive heart failure (CHF), the prognosis of these patients remains poor. OBJECTIVE: The purpose of the study was to reevaluate a cohort of patients with CHF after 7 years of follow-up with cilazapril therapy to assess the renin-angiotensin system (RAS), anatomic and functional capacity of the heart, and aldosterone escape. METHODS: Surviving patients from a cohort hospitalized for CHF between January 1994 and December 1994 who were treated with cilazapril in our center were included in this study. Exercise testing was carried out using the Kattus protocol, and breath-by-breath oxygen analysis, echocardiography, and hormonal analysis were done. RESULTS: Seven patients (5 men, 2 women; mean [SD] age, 70.6 [4.4]) were included in the study. Compared with the early effects (at 15 days) of cilazapril therapy, only mean (SD) peak exercise time decreased significantly at the 7-year follow-up (8.9 [2.4] minutes vs 5.1 [1.9] minutes; P = 0.02). Mean (SD) anaerobic threshold (AT) oxygen consumption and AT ratio increased slightly from 15 days, although these changes were not statistically significant (12.86 [3.5] mL/kg·min vs 13.57 [2.6] mL/kg·min; 70.3% [7.7%] vs 78.9% [9.8%], respectively). Compared with the early effect of therapy, patients had slightly lower mean (SD) ejection fractions (EFs), but the decrease did not reach statistical significance (52% [4%] vs 48% [4%]). Aldosterone levels were within normal limits in all patients, and 2 patients had increased RAS activity. CONCLUSIONS: In this study, the observed lack of aldosterone escape, as well as patient survival during ACEI therapy, may be due to selection bias of the surviving patients, who had better EFs and lack of aldosterone escape. Therefore, the remaining issue seems to be the selection of patients who will not show aldosterone escape during chronic ACEI treatment.

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AIM: To study the effect of cilazapril on pulmonary vascular endothelial dysfunction in hypoxic rats. METHODS: The structure and function of endothelium in hypoxic rats were studied by biochemical analysis, radioimmunoassay, transmission electron microscope and correlated with hemodynamic. RESULTS: 1) The change and damage of ultrastructure in endothelial cell (EC) were obsevered in hypoxic rats. 2) The contents of plasma nitric oxide (NO) and superoxide dismutase (SOD) activity in blood as well as endothelial nitric oxide synthase (eNOS) activity in the lung tissue were significantly lower in the hypoxic rat than those in contral animals. The concentrations of plasma endothelin-1(ET-1) and angiotensin converting enzyme(ACE) as well as malondialdehyde(MDA) were significantly higher in the hypoxic rat than these in contral animals. The relaxing and contracting factors had a significant positive/negative correlation with mean pulmonary artery pressure (mPAP). 3) Cilazapril significantly decreased the level of ET-1 and ACE and significantly increased the level of NO and activity of eNOS and SOD. At the same time, cilazapril extenuated hypoxia-induced injuries of EC. CONCLUSION: The results indicate that damaging structure and dysfunction of EC existes in hypoxic rats. The cilazapril effectively preventes and treates the chronic hypoxic PH by relieving the injury and improving secretion in EC.

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Objective To explore the effects of simvastatin and cilazapril on the expression of transforming growth factor-?_1 (TGF-?_1) and insulin-like growth factor-Ⅰ (IGF-Ⅰ) in the cultured human glomerular mesangial cells. Methods Human embryo glomerular mesangial cells were cultured in media with lower (5.6 mmol/L) or higher (30 mmol/L) glucose concentrations. Forty-eighthoursafteraddingsimvastatin(10 ?mol/L)and/or cilazapril (10 ?mol/L) to the cultured media, the concentrations of TGF-?_1, fibronection, laminin, type Ⅳ collagen proteins in the supernatant of cultured mesangial cells were determined by ELISA and radioimmunoassay and the expressions of TGF-?_1 and IGF-Ⅰ mRNA in cultured mesangial cells were also evaluated by RT-PCR. Results Compared with lower glucose control, the mesangial cells in the medium with higher glucose concentration showed excessive proliferation and higher expressions of TGF-?_1 and IGF-Ⅰ mRNA, and the levels of TGF-?_1, fibronection, laminin, and type Ⅳ collagen in the supernatant were also significantly increased. The expressions of TGF-?_1 and IGF-Ⅰ mRNA in the mesangial cells and the concentrations of TGF-?_1 and the extracellular matrix (ECM) proteins in the supernatant were all decreased after addition of simvastatin and cilazapril. Combination of simvastatin and cilazapril resulted in more profound suppressive effect on the expression of TGF-?_1 mRNA than either of them alone. Conclusion High concentration of glucose stimulates the cultured human mesangial cells excessively to express the TGF-?_1, IGF-Ⅰ and ECM proteins, and the high glucose-induced changes are suppressed by either simvastatin, cilazapril alone or combined treatment.

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0 05) Left ventricular (LV) end diastolic pressure (LVEDP), volume (LVV), weight (LVW) and septal thickness (STh) were all higher and left ventricular pressure maximal rate of rise and fall (?d p /d t ) were lower (all P

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group A by turns. (3) The concentrations of plasma endothelin-1 (ET-1) and angiotensin converting enzyme (ACE) were significantly higher in group B than that in group A. However, the ET-1 and ACE were significantly lower in group C than those in group B. (4) The ET-1 and ACE had a significant positive correlation with R/L+S, mPAP and PI, respectively. The multivariate linear regression analysis revealed that ET-1 and ACE were major factor affecting PI. CONCLUSION: The pulmonary vascular and myocardial structural remodeling are one of the pathogenesis accompanied with excessive cell proliferation in hypoxic pulmonary hypertension (PH). Cilazapril effectively prevents and treats the hypoxic PH by inhibiting cell proliferation and structural remodeling of pulmonary circulation, as induced by ET-1 and ACE.

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BACKGROUND AND OBJECTIVES: Angiotensin converting enzyme inhibitor (ACEI) is known to be effective in the prevention of left ventricular failure (LVF) after acute myocardial infarction. The aim of this study was to investigate the efficacy of an ACEI, Cilazapril, on left ventricular remodeling in patients with ischemic LVF, who underwent coronary interventions. MATERIALS AND METHODS: Cilazapril, 2.5 - 5.0 mg per day was administ-ered 12 weeks after coronary interventions in 25 patients (18 M, 7 F, 61.5+/-9 years) with impaired LV function (ejection fraction< or = 50%). Fifteen patients (9 M, 6 F, 59.4+/-7 years) without ACEI were compared by clinical examinations, blood chemistry, electrocardiogram and echocardiogram with Cilzapril group at 2, 4, 8 and 12 weeks after intervention. RESULTS: Blood pressure and heart rate were not changed after Cilazapril. LV end-diastolic volume (LVEDV) decreased from 153.1+/-38.7 to 135.6+/-25.5 ml and end-systolic volume from 84.9+/-34.7 to 72.6+/-25.1 ml after 12-week Cilazapril p=0.003, p=0.001. Ejection fraction (EF) was increased from 44.4+/-3.2 to 52.4+/-2.8% after 12 weeks of Cilazapril p=0.034. In control group, LVEDV was changed from 152.7+/-44.6 to 143.6+/-28.7 ml, which failed to show significant reduction. Side effects of Cilazapril were 3 dry cough (3/25, 12%) and 1 facial edema, 1 hypotension and 1 dizziness. CONCLUSION: Cilazapril is a beneficial adjunctive therapeutic agent in patients with ischemic left ventricular failure for the prevention of ventricular dilatation, especially after coronary intervention.

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