Silver Complexes of Miconazole and Metronidazole: Potential Candidates for Melanoma Treatment.

Melanoma, arguably the deadliest form of skin cancer, is responsible for the majority of skin-cancer-related fatalities. Innovative strategies concentrate on new therapies that avoid the undesirable effects of pharmacological or medical treatment. This article discusses the chemical structures of [(MTZ)2AgNO3], [(MTZ)2Ag]2SO4, [Ag(MCZ)2NO3], [Ag(MCZ)2BF4], [Ag(MCZ)2SbF6] and [Ag(MCZ)2ClO4] (MTZ-metronidazole; MCZ-miconazole) silver(I) compounds and the possible relationship between the molecules and their cytostatic activity against melanoma cells. Molecular Hirshfeld surface analysis and computational methods were used to examine the possible association between the structure and anticancer activity of the silver(I) complexes and compare the cytotoxicity of the silver(I) complexes of metronidazole and miconazole with that of silver(I) nitrate, cisplatin, metronidazole and miconazole complexes against A375 and BJ cells. Additionally, these preliminary biological studies found the greatest IC50 values against the A375 line were demonstrated by [Ag(MCZ)2NO3] and [(MTZ)2AgNO3]. The compound [(MTZ)2AgNO3] was three-fold more toxic to the A375 cells than the reference (cisplatin) and 15 times more cytotoxic against the A375 cells than the normal BJ cells. Complexes of metronidazole with Ag(I) are considered biocompatible at a concentration below 50 µmol/L.

Silver, Its Salts and Application in Medicine and Pharmacy.

The healing properties of silver have been used since ancient times. The main aim of the study was to collect and review the literature on the clinical potential of silver, its salts and complex compounds. The second goal was to present an outline of the historical use of silver in medicine and pharmacy, taking into account the possibility of producing pharmaceutical drug forms on the premises of pharmacies. In the context of the growing resistance of microorganisms to available, widely used antibiotics, silver plays a key role. There is only one known case of bacterial resistance to silver-the Pseudomonas stutzeri strain, which naturally occurs in silver mines. The development of research in the field of coordination chemistry offers great opportunities in the design of new substances in which silver ions can be incorporated. These substances exhibit increased potency and often an extended antimicrobial spectrum. Silver-based compounds are, however, only limited to external applications, as opposed to their historic oral administration. Advanced studies of their physicochemical, microbiological, cytotoxic and genotoxic properties are ongoing and full of challenges. The improvement of the methods of synthesis gives the possibility of applying the newly synthesized compounds ex tempore, as was the case with the complex of metronidazole with silver (I) nitrate. Some of these experimental efforts performed in vitro are followed with clinical trials. The third and final goal of this study was to present the possibility of obtaining an ointment under the conditions of an actual pharmacy using silver (I) salts and a ligand, both of which are active substances with antimicrobial properties.

Multifunctional Silver(I) Complexes with Metronidazole Drug Reveal Antimicrobial Properties and Antitumor Activity against Human Hepatoma and Colorectal Adenocarcinoma Cells.

Silver salts and azole derivatives are well known for their antimicrobial properties. Recent evidence has demonstrated also their cytotoxic and genotoxic potential toward both normal and cancer cells. Still, little is known about the action of complexes of azoles with silver(I) salts. Thus, the goal of the study was to compare the chemical, cytotoxic and antimicrobial properties of metronidazole complexes with silver(I) nitrate and silver(I) sulfate to metronidazole and pure silver(I) salts. We synthetized a novel complex, [Ag(MTZ)2]2SO4, and confirmed its chemical structure and properties using 1H and 13C NMR spectroscopy and X-Ray, IR and elemental analysis. To establish the stability of complexes [Ag(MTZ)2NO3] and [Ag(MTZ)2]2SO4, they were exposed to daylight and UV-A rays and were visually assessed. Their cytotoxicity toward human cancer cells (HepG2, Caco-2) and mice normal fibroblasts (Balb/c 3T3 clone A31) was determined by MTT, NRU, TPC and LDH assays. The micro-dilution broth method was used to evaluate their antimicrobial properties against Gram-positive and Gram-negative bacteria. A biofilm eradication study was also performed using the crystal violet method and confocal laser scanning microscopy. The photo-stability of the complexes was higher than silver(I) salts. In human cancer cells, [Ag(MTZ)2]2SO4 was more cytotoxic than Ag2SO4 and, in turn, AgNO3 was more cytotoxic than [Ag(MTZ)2NO3]. For Balb/c 3T3 cells, Ag2SO4 was more cytotoxic than [Ag(MTZ)2]2SO4, while the cytotoxicity of AgNO3 and [Ag(MTZ)2NO3] was similar. Metronidazole in the tested concentration range was non-cytotoxic for both normal and cancer cells. The complexes showed increased bioactivity against aerobic and facultative anaerobic bacteria when compared to metronidazole. For the majority of the tested bacterial strains, the silver(I) salts and complexes showed a higher antibacterial activity than MTZ; however, some bacterial strains presented the reverse effect. Our results showed that silver(I) complexes present higher photo-stability, cytotoxicity and antimicrobial activity in comparison to MTZ and, to a certain extent, to silver(I) salts.

Stability of Metronidazole and Its Complexes with Silver(I) Salts under Various Stress Conditions.

Metronidazole is a drug widely used in the prevention and treatment of bacterial infections. Due to its possibility of the formation of stable metal complexes, it was decided to broaden its activity spectrum by introducing the silver(I) coordination compounds i.e., [Ag(MTZ)2NO3] and [(Ag(MTZ)2)2]SO4, which have significant antibacterial properties. The paper presents a description of a new qualitative and quantitative analysis of metronidazole in bulk and possible pharmaceutical preparations by thin-layer chromatography with densitometric detection. Optimal separation conditions were selected, and the analytical procedure was validated according to the ICH guidelines. The obtained data indicate that the method is sufficiently sensitive, precise, and accurate. The stability of the metronidazole solutions obtained from tablets, pure metronidazole, and its silver(I) complexes was tested. The research was carried out in various environments, at different temperatures, in H2O2 solution, and during exposure to radiation (UV, sunlight). The greatest degradation was found in the alkaline environment and at higher temperatures. The silver(I) complexes exhibited relatively high stability under analyzed conditions that are higher than standard metronidazole solutions and tablets. The observations were confirmed by the kinetic and thermodynamic analysis. The described studies of new metronidazole silver(I) complexes increase the potential for their application in infections both in humans and animals.

Clinical Application and Efficacy of Silver Drug in Ophthalmology: A Literature Review and New Formulation of EYE Drops with Drug Silver (I) Complex of Metronidazole with Improved Dosage Form.

The use of silver preparations in medicine is becoming increasingly popular. The basic aim of this evaluation was to review the literature on the clinical (in vivo) and antibacterial potential of silver preparations in ophthalmic diseases. The second goal was to summarize the results of experimental research on the use of silver preparations in ophthalmology. The third objective was to present a method for stabilizing eye drops containing silver (I) complex. Analysis of the pH stability of the silver (I) complex with metronidazole in the prepared dosage form (eye drops) was carried out. Most silver preparations are clinically used for topical application. Few experimental results indicate the usefulness of intraocular or systemic administration of silver (I) preparations as an alternative or additional therapy in infectious and angiogenic eye diseases. The development of a new formulation increases the stability of the dosage form. New forms of silver (I) products will certainly find application in the treatment of many ophthalmic diseases. One of the most important features of the silver (I) complex is its capacity to break down bacterial resistance. The new eye drops formula can significantly improve comfort of use. Due to their chemical nature, silver (I) compounds are difficult to stabilize, especially in the finished dosage form.

Effect of treatment with silver(I) complex of metronidazole on ocular rosacea: Design and formulation of new silver drug with potent antimicrobial activity.

BACKGROUND: Metronidazole with well-soluble silver nitrate forms a complex with potent activity (synergism) against bacterial strains and fungi with simultaneous lower side effect than in the case of the two agents administered separately. This study aimed to establish effectiveness in the treatment of ocular rosacea with new formulation of drops and ointment with silver(I) complex of metronidazole. METHODS: Three patients suffering from serious ophthalmic complications of acne rosacea were treated with drops and ointments applied 3 times a day for 3 months. The uncorrected visual acuity testing (UCVA), pachymetry as well as subjective and objective tear film assessment were evaluated. RESULTS: In all patients, we have improved UCVA as well as objective and subjective evaluation of the tear film parameters. No significant differences in corneal thickness were observed. CONCLUSION: Well soluble silver(I) complex of metronidazole might be an alternative method in ophthalmic complications of acne rosacea treatment.

Light Stability, Pro-Apoptotic and Genotoxic Properties of Silver (I) Complexes of Metronidazole and 4-Hydroxymethylpyridine against Pancreatic Cancer Cells In Vitro.

Antimicrobial properties of silver (I) ion and its complexes are well recognized. However, recent studies suggest that both silver (I) ion and its complexes possess anticancer activity associated with oxidative stress-induced apoptosis of various cancer cells. In this study, we aimed to investigate whether silver nitrate and its complexes with metronidazole and 4-hydroxymethylpyridine exert anticancer action against human pancreatic cancer cell lines (PANC-1 and 1.2B4). In the study, we compared decomposition speed for silver complexes under the influence of daylight and UV-A (ultraviolet-A) rays. We employed the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazonium bromide) assay to evaluate the cytotoxicity and the alkaline comet assay to determine genotoxicity of silver nitrate and its complexes. Flow cytometry and the Annexin V-FITC/PI apoptosis detection kit were used to detect the apoptosis of human pancreatic cancer cells. We found a dose dependent decrease of both pancreatic cancer cell line viability after exposure to silver nitrate and its complexes. The flow cytometry analysis confirmed that cell death occurred mainly via apoptosis. We also documented that the studied compounds induced DNA damage. Metronidazole and 4-hydroxymethylpyridine alone did not significantly affect viability and level of DNA damage of pancreatic cancer cell lines. Complex compounds showed better stability than AgNO3, which decomposed slower than when exposed to light. UV-A significantly influences the speed of silver salt decomposition reaction. To conclude, obtained data demonstrated that silver nitrate and its complexes exerted anticancer action against human pancreatic cancer cells.

Silver(I) Complexes of the Pharmaceutical Agents Metronidazole and 4-Hydroxymethylpyridine: Comparison of Cytotoxic Profile for Potential Clinical Application.

In previous papers, we have reported on the high antifungal and significant antibacterial activity against Gram-positive and Gram-negative bacteria of the water-soluble silver(I) complexes of metronidazole and derivatives of pyridine compared to silver nitrate. In the present study, the cytotoxic activity of the silver(I) complexes of metronidazole and 4-hydroxymethylpyridine was compared with that of silver nitrate. Metronidazole and 4-hydroxymethylpyridine were investigated using Balb/c 3T3 and HepG2 cell lines in order to evaluate the potential clinical application of silver(I) complexes. The cells were exposed for 72 h to compounds at eight concentrations. The cytotoxic concentrations (IC50) of the study compounds were assessed within four biochemical endpoints: mitochondrial activity, lysosomal activity, cellular membrane integrity, and total protein content. The investigated silver(I) complexes displayed comparable cytotoxicity to that of silver nitrate used in clinics. Mean cytotoxic concentrations calculated for investigated silver(I) complexes from concentration-response curves ranged from 2.13 to 26.5 µM. HepG2 cells were less sensitive to the tested complexes compared to fibroblasts (Balb/c 3T3). However, the most affected endpoint for HepG2 cells was cellular membrane damage. The cytotoxicity of both silver complexes was comparable for Balb/c 3T3 cells. The cytotoxic potential of the new silver(I) compounds compared to that of silver nitrate used in medicine indicates that they are safe and could be used in clinical practice. The presented results are yet more stimulating to further studies that evaluate the therapeutic use of silver complexes.