In silico and in vitro screening for carcinogenic potential of angiotensin-converting enzyme inhibitors and their degradation impurities.

According to some clinical observations, the use of angiotensin-converting enzyme inhibitors (ACEI) may be associated with an increased risk of cancer. The aim of the present study was to screen for the potential carcinogenicity, mutagenicity and genotoxicity of these drugs using in silico methodology. Delapril, enalapril, imidapril, lisinopril, moexipril, perindopril, ramipril, trandolapril, spirapril were thereby analyzed. In parallel, the corresponding degradation impurities, the diketopiperazine (DKP) derivatives, were also investigated. (Q)SAR computer software (VEGA-GUI and Lazar), available in the public domain, was employed. The obtained predictions suggested that none of the compounds tested (from the group of ACE-Is and DKPs) was mutagenic. Moreover, none of the ACE-Is was carcinogenic. The reliability of these predictions was high to moderate. In contrast, in the DKP group, ramipril-DKP and trandolapril-DKP were found to be potentially carcinogenic, but the reliability of this prediction was low. As for the genotoxicity screening, all compounds tested (ACE-I and DKP) were predicted to be active and genotoxic, with moexipril, ramipril, spirapril, and all DKP derivatives within the highest risk group. They were prioritized for experimental verification studies to confirm or exclude their toxic activity. On the other hand, the lowest risk of carcinogenicity was assigned to imidapril and its DKP. Then, a follow-up in vitro micronucleus assay for ramipril was performed. It showed that this drug was genotoxic via aneugenic activity, but only at concentrations exceeding real-life levels. At concentrations found in human blood after standard dose, ramipril was not genotoxic in vitro. Therefore, ramipril was considered safe for human use with a standard dosing regimen. The other compounds of concern (spirapril, moexipril and all DKP derivatives) should be subjected to analogous in vitro studies. We also concluded that the adopted in silico software was applicable for ACE-I toxicity prediction.

Lignin-Based Spherical Structures and Their Use for Improvement of Cilazapril Stability in Solid State.

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.

Stability of cilazapril in pediatric oral suspensions prepared from commercially available tablet dosage forms.

Abstract: Cilazapril is a drug commonly used in management of heart failure in pediatric population. On pharmaceutical market it is available only in inconvenient for pediatric use tablet dosage forms. Until now, no oral liquid formulation containing cilazapril has been evaluated. Therefore, the aim of this study was to prepare easy to made and palatable 1 mg/mL oral liquid formulation with cilazapril (with consideration of original and generic cilazapril tablet and different packages) and subsequent investigation of physicochemical stability of these suspensions. Formulations were compounded using cilazapril obtained from original or generic cilazapril marketed tablet formulations and Ora-Blend" suspending agent. Stability of prepared suspensions stored in closed amber glass or amber plastic PET bottles in the temperature of 298 K was estimated throughout 28 day shelf-life period. Chemical stability was assessed by HPLC cilazapril stability indicating method. Physical stability was evaluated by appearance, taste, smell, pH and theological assessments. Cilazapril oral suspensions at concentration of 1 mg/mL demonstrated satisfactory stability over 28 day long storage at room temperature. Cilazapril concentrations remained within acceptable limit (+/- 10%) stored in closed amber bottles made of glass or PET material. Moreover, suspensions physical properties remained unaffected. Cilazapril - Ora-Blend* pediatric oral liquid is easy to made, palatable and stable when stored at room temperature for 28 days. Stability of cilazapril oral liquid remains unchanged while using cilazapril tablets produced by different manufacturers and bottles made of amber glass or PET material.

Cilazapril stability in the presence of hydrochlorothiazide in model mixtures and fixed dose combination.

The presented study aimed at the evaluation of hydrochlorothiazide influence on cilazapril stability in model mixture and fixed dose tablet formulation. The degradation of cilazapril in the presence of hydrochlorothiazide took place according to autocatalytic reaction kinetic mechanism, described mathematically by Prout-Tompkins equation. Hydrochlorothiazide coexistence with cilazapril in model mixture and fixed dose tablet without blister package accelerated cilazapril degradation in comparison with degradation of cilazapril substance. Values of reaction induction time shortened, while those of observed reaction rate constant increased. Increasing values of relative humidity and temperature have negative impact on cilazapril stability. Determined semi-logarithmic relationships: In k = f(RH) and Arrhenius ln k = f(1/T) are linear and are cilazapril stability predictive. The blister (OPA/Alu/PVC//Alu) package of fixed dose tablets, constitutes absolute moisture protection and prevent cilazapril--hydrochlorothiazide interaction occurrence.

Photocatalytic degradation of sulfamethoxazole using TiO2-based materials - Perspectives for the development of a sustainable water treatment technology.

Heterogeneous photocatalysis using titanium dioxide-based materials is considered a promising and innovative solution to the water pollution problem. However, due to the limitations concerning the use of the developed materials and the applied photodegradation conditions, the research on photoremediation using TiO2 often stays behind the lab door. The challenge is to convert the basic research into a successful innovation, leading to the implementation of this process into wastewater treatment. For this purpose, the most active materials and optimal photodegradation conditions must be chosen. This article collects and compares the studies on photocatalytic degradation of an emerging pollutant - sulfamethoxazole, an antibacterial drug - and attempts to find the best approaches to be successfully applied on an industrial scale. Various types of TiO2-based photocatalysts are compared, including different nanoforms, doped or polymer-based composites, composites with graphene, activated carbon, dyes or natural compounds, as well as possible supporting materials for TiO2. The paper covers the impact of the irradiation source (natural sunlight, LED, mercury or xenon lamps) and water matrix on the photodegradation process, considering the ecological and economic sustainability of the process. Emphasis is put on the stability, ease of separation and reuse of the photocatalyst, power and safety of the irradiation source, identification of photodegradation intermediates and toxicity assays. The main approaches are critically discussed, main challenges and perspectives for an effective photocatalytic water treatment technology are pointed out.

Nanocomposites of Titanium Dioxide and Peripherally Substituted Phthalocyanines for the Photocatalytic Degradation of Sulfamethoxazole.

Phthalocyanines (Pcs) are often used in photosensitization of titanium(IV) oxide, a commonly employed photocatalyst, as such an approach holds the promise of obtaining highly stable and efficient visible light-harvesting materials. Herein, we report on the preparation, characterization and photoactivity of a series of composites based on TiO2 and peripherally modified metallophthalocyanines: either tetrasulfonated or 4,4',4'',4'''-tetraazaphthalocyanines, with either copper(II), nickel(II) or zinc(II) as the central metal ion. Physicochemical characterization was performed using UV-Vis diffuse reflectance spectroscopy, hydrodynamic particle-size analysis, surface-area analysis using N2 adsorption-desorption measurements and thermogravimetry combined with differential scanning calorimetry. The band-gap energy values were lower for the composites with peripherally modified phthalocyanines than for the commercial TiO2 P25 or the unsubstituted zinc(II) phthalocyanine-grafted TiO2. TG-DSC results confirmed that the chemical deposition, used for the preparation of Pc/TiO2 composites, is a simple and efficient method for TiO2 surface modification, as all the Pc load was successfully grafted on TiO2. The photocatalytic potential of the Pc/TiO2 materials was assessed in the photocatalytic removal of sulfamethoxazole-a commonly used antibacterial drug of emerging ecological concern. To compare the activity of the materials in different conditions, photodegradation tests were conducted both in water and in an organic medium.

Solid-State Stability Profiling of Ramipril to Optimize Its Quality Efficiency and Safety.

High global expenditure on out-of-label-date drugs, along with safety concerns associated with the accumulation of degradation impurities, justify the need for stability profiling. In this article, a comprehensive study on the solid-state stability of ramipril (RAM) was performed via isothermal methods under stress conditions. A validated stability-indicating HPLC protocol was used. The effects of various factors on the rate of RAM degradation were investigated, including: temperature, relative air humidity (RH), excipients (talc, starch, methylcellulose and hydroxypropyl methylcellulose), mode of tablet storage, and immediate packaging. The degradation impurities were also identified by HPLC-MS. It was found that RAM was unstable, and temperature accelerated its degradation. RAM was also vulnerable to RH changes, suggesting that it must be protected from moisture. The reaction followed first-order kinetics. The studied excipients stabilized RAM as a pure substance. The tableting process deteriorated its stability, explaining the need for appropriate immediate packaging. RAM in the form of tablets must be stored in blisters, and it cannot be crushed into two halves. The degradation impurities were ramiprilat and the diketopiperazine derivative.

Titanium Dioxide Nanoparticles in Food and Personal Care Products-What Do We Know about Their Safety?

Titanium dioxide (TiO2) is a material of diverse applications commonly used as a food additive or cosmetic ingredient. Its prevalence in products of everyday use, especially in nanosize, raises concerns about safety. Current findings on the safety of titanium dioxide nanoparticles (TiO2 NPs) used as a food additive or a sunscreen compound are reviewed and systematized in this publication. Although some studies state that TiO2 NPs are not harmful to humans through ingestion or via dermal exposure, there is a considerable number of data that demonstrated their toxic effects in animal models. The final agreement on the safety of this nanomaterial has not yet been reached among researchers. There is also a lack of official, standardized guidelines for thorough characterization of TiO2 NPs in food and cosmetic products, provided by international authorities. Recent advances in the application of 'green-synthesized' TiO2 NPs, as well as comparative studies of the properties of 'biogenic' and 'traditional' nanoparticles, are presented. To conclude, perspectives and directions for further studies on the toxicity of TiO2 NPs are proposed.

Unknown face of known drugs - what else can we expect from angiotensin converting enzyme inhibitors?

The renin-angiotensin system (RAS) is one of important systems among homeostatic mechanisms that control the function of cardiovascular, renal and adrenal systems. As RAS has a very complex nature, it has been also found as related to the control of cell migration and apoptosis. Angiotensin-converting enzyme inhibitors (ACEI) are drugs most commonly used in the modulation of RAS activity. ACEI have been extensively described as effective in the treatment of hypertension among adults, but also as drugs delaying progression in diabetic nephropathy and reducing mortality in left ventricular dysfunction and congestive heart failure. What is less obvious, ACEI are also widely used in pediatric nephrology and cardiology. Moreover, there are more and more reports showing evidence that ACEI can be beneficial in the treatment of many other diseases and the pleiotropic activity of ACEI is mainly based on their antioxidant properties. In this paper we focus on the less obvious possibilities of the clinical use of ACEI in neurological or oncological patients, discuss the role of ACE gene polymorphism and show the perspectives of potentially new applications of ACEI in contemporary pharmacotherapy.

Chemistry and pharmacology of Angiotensin-converting enzyme inhibitors.

The renin-angiotensin system has been established as an attractive target for pharmacological intervention since the discovery of first angiotensin-converting enzyme inhibitors (ACE-Is). In fact, these drugs are primarily used in the management of cardiovascular system-related diseases and renal insufficiency. Their mechanism of action involves the adjustment of balance between vasoconstrictive, hypertrophic and salt/water-retentive angiotensin II and vasodilatory and natriuretic bradykinin by the inhibition of angiotensin II biosynthesis and bradykinin degradation. Currently there are thirteen family members approved for use in humans. They differ in structure, chemistry and pharmacokinetic and pharmacodynamic properties yet they display a similar pharmacologic and toxicologic profile. All of them are effective in the treatment of hypertension as well as in cardiac insufficiency or diabetic nephropathy. Although they are generally well-tolerated several serious side-effects including life-threatening angioedema, renal failure and persistent dry cough could occur during the administration of ACE-Is, which may require the cessation of therapy. Furthermore, to provide maximum safety and efficiency of ACE-Is-based therapy, the knowledge of the related drug interactions and chronokinetics seems to be an absolute requirement. Here we discuss the above-mentioned issues regarding the pharmaceutical and chemical properties of the commercially- used ACE-Is.