Adriana Smarandache

Quinazoline derivatives are efficient chemosensitizers of antibiotic activity in Enterobacter aerogenes, Klebsiella pneumoniae and Pseudomonas aeruginosa resistant strains

Amongst the three series of quinazoline derivatives synthesised and studied in this work, some molecules increase the antibiotic susceptibility of Gram-negative bacteria presenting multidrug-resistant phenotypes. N-alkyl compounds induced an increase in the activity of chloramphenicol, nalidixic acid and sparfloxacin, which are substrates of the AcrAB-TolC and MexAB-OprM efflux pumps in clinical isolates. These molecules are able to increase the intracellular concentration of chloramphenicol in efflux pump-overproducing strains. Their activity depends on the antibiotic structure, suggesting that different sites may be involved for the recognition of substrates by a given efflux pump. Quinazoline molecules exhibiting a nitro functional group are more active, and structure-activity relationship studies may be undertaken to identify the pharmacophoric group involved in the AcrB and MexB affinity sites.

Direct modification of bioactive phenothiazines by exposure to laser radiation

Whereas exposure of combinations of a phenothiazine and bacterium to incoherent UV increases the activity of the phenothiazine, exposure of the phenothiazine alone does not yield an increase of its activity. Because the laser beam energy is greater than that produced by the incoherent UV sources, exposure of phenothiazines to specific lasers may yield molecules with altered activities over that of the unexposed parent. Chlorpromazine, thioridazine and promethazine active against bacteria were exposed to two distinct lasers for varying periods of time. Absorption and fluorescence spectra were conducted prior to and post-exposure and the products of laser exposure evaluated for activity against a Staphylococcus aureus ATCC strain via a disk susceptibility assay. Exposure to lasers alters the absorption/fluorescence spectra of the phenothiazines; reduces the activity of thioridazine against the test bacterium; produces a highly active chlorpromazine compound against the test organism. Exposure of phenothiazines to lasers alters their structure that results in altered activity against a bacterium. This is the first report that lasers can alter the physico-chemico characteristics to the extent that altered bioactivity results. Exposure to lasers is expected to yield compounds that are difficult to make via chemical manipulation methods. A survey of selected patents of interest, even co-lateral for the subject of this article is shortly made.

1064 nm Nd:YAG long pulse laser after polidocanol microfoam injection dramatically improves the result of leg vein treatment: A randomized controlled trial on 517 legs with a three-year follow-up

Objective To assess the efficacy and safety of a new method of clearing varicose veins in the long term. It consists of applying the long-pulsed Nd:YAG laser following the injection of polidocanol microfoam, in two consecutive sessions, treating both legs in full in each session. Method Randomized, Polidocanol-controlled, blind evaluation clinical trial comparing the results between 79 legs treated with Polidocanol and 517 treated with Polidocanol + Laser. Photographs were taken preoperatively and at three months, two years and three years after treatment, as well as patient self-assessments. Results Polidocanol + Laser is much more effective than polidocanol microfoam in clearing venulectasias with a diameter under 4 mm (p < 0.001). After three years, clearing percentages of 89% (Class I veins), 94% (Class II veins) and 95% (Class III veins) are observed, in comparison to 15%, 18% and 17%, respectively when only polidocanol was applied. No unexpected adverse effects were found and 86% of patients stated they were Satisfied or Very Satisfied. Conclusion The method leads to safe, fast and apparently permanent results. The treatment session lasts less than 1 h, and could become a first-choice treatment for the removal of all types of varicose veins with a diameter under 4 mm.

Toxicity study in blood and tumor cells of laser produced medicines for application in fabrics.

Phenothiazine derivatives are non-antibiotics with antimicrobial, fungistatic and fungicidal effects. We exposed to a high energy UV laser beam phenothiazines solutions in water at 20mg/mL concentration to increase antibacterial activity of resulting mixtures. Compared to previous results obtained on bacteria, more research is needed about UV laser irradiated phenothiazines applications on cancer cell cultures to evidence possible anticancerous properties. Evaluation of the safety of the newly obtained photoproducts in view of use on humans is also needed. Due to expensive animal testing in toxicology and pressure from general public and governments to develop alternatives to in vivo testing, in vitro cell-based models are attractive for preliminary testing of new materials. Cytotoxicity screening reported here shows that laser irradiated (4h exposure time length) chlorpromazine and promazine are more efficient against some cell cultures. Interaction of laser irradiated phenothiazines with fabrics show that promethazine and chlorpromazine have improved wetting properties. Correlation of these two groups of properties shows that chlorpromazine appears to be more recommended for applications on tissues using fabrics as transport vectors. The reported results concern stability study of phenothiazines water solutions to know the time limits within which they are stable and may be used.

Applications of Polidocanol in Varicose Vein Treatment Assisted by Exposure to Nd:YAG Laser Radiation

The understanding of the interaction between Polidocanol (POL) and the target veins tissues is important in utilizing it in varicose veins diseases treatment. Generally, the development of new drug delivery routes may represent methods to improve the efficacy and/or safety of the active pharmaceutical ingredients. With this respect, the treatment involving POL administration as foam has gained widespread use (Cavezzi and Tessari, 2009). Although the main approach in the treatment of small diameter veins, in venulectasias and reticular veins of less than 4 mm in diameter (class I/II and III) is sclerotherapy (Alos et al., 2006; Nijsten et. al., 2009; Parsi et al., 2007; Railan et al., 2006), lasers, especially the Nd:YAG laser, have shown interesting and non-negligible capabilities in treating these cases (Redondo and Cabrera, 2005; Santos et al., 2008; Trelles et al., 2005). Clinical experimental results prove that the exposure of the tissues impregnated with POL to laser radiation emitted at 1.06 ┤m improves the efficiency of the treatment (Moreno Moraga, n.d.).

Laser Optofluidics in Fighting Multiple Drug Resistance

The interaction of laser modified medicine solutions with hydrophilic and hydrophobic target surfaces has been investigated under the effect of simulated hypergravity conditions, employing the Large Diameter Centrifuge (LDC) facility, developed by the European Space Agency (ESA). Experiments have been performed within the HyperMed project under the aegis of the ESA “Spin Your Thesis!” 2015 programme. During centrifugation, real-time video files have been recorded regarding generation of ultrapure water, unexposed and laser exposed chlorpromazine aqueous pendant droplets, followed by their detachment due to the exerted high gravitational accelerations and finally by the formation of sessile droplets on target surfaces. In this way, information about the volume of the generated droplet, the degree of wetting and its time evolution at different hypergravity levels has been obtained. Phenothiazine solutions irradiated with UV laser radiation indicate reduced surface tension, thus presenting better wetting properties. Target surfaces impregnated with medicine solutions may constitute an unconventional tool and even vector in developing new drug delivery systems. Such a wetting process under high g-level conditions may be useful in space medicine applications. Microorganisms can survive, grow and even proliferate under the effect of increased gravity. Therefore, upon launching of a spacecraft, during a long-term mission in microgravity conditions, astronauts and spacecraft surfaces may require treatment and decontamination, respectively, against onboard infectious microbes. Since non-terrestrial gravity may alter drug properties, medicine droplets behaviour in interaction with target surfaces under hypergravity conditions is the aim of the present study.

Stability studies on Promethazine unexposed and exposed to UV laser radiation

As a phenothiazine derivative, Promethazine may undergo structural modifications when it is exposed to light. This process consists in the degradation of the initial compound and in the generation of new photoproducts with possible anti-infectious qualities. Stability studies are necessary in order to establish the proper use of drug solutions in different applications. At the same time, these investigations are important in the context of the generation of side-products induced by environmental conditions that bring new benefits to the compound. This study reports the stability of Promethazine aqueous solutions, based on their absorption spectra acquired before and after Nd:YAG laser irradiation sessions or under different temperature and illuminating storage conditions. Samples of Promethazine solutions in ultrapure water, at a concentration range between 10-6 M – 10-2 M, were kept in dark at 22°C, and 4°C as well as at 22°C in ambient light up to a time interval of three months. Absorption spectra were recorded periodically in order to determine any changes of the optical properties. Also, solutions of 20 mg/mL were exposed for different time intervals to laser radiation emitted at 266 nm by the Nd:YAG laser. The stability of the optical properties of irradiated Promethazine solutions for 4 h was investigated up to two months. The laser irradiated samples show similar but more rapid and intense changes compared to solutions exposed to ambient light, suggesting molecular modifications that could be due to the production of more polar phenothiazine derivatives.

Laser methods for pharmaceutical pollutants removal

The extensive use of pharmaceuticals became a worldwide environmental issue. Most of these compounds are not completely removed in wastewater treatment plants and, as a result, they are found in surface and ground water. In this report the behavior of two drugs, Thioridazine and BG1188 were investigated after their exposure in aqueous solutions to laser radiation. The degradation processes were monitored using spectroscopic techniques (Absorption Spectroscopy, Laser Induced Fluorescence, NMR Spectroscopy) and chromatographic methods (HPLC-MS). The Thioridazine 5x10-2 M solution was irradiated up to 11 min and, respectively, BG1188 10-3 M solution was irradiated up to 30 min, both with 355 nm Nd:YAG pulsed laser beam, with 30 mJ average pulse energy on the sample. The exposure of Thioridazine solution to laser radiation leads to the appearance of new VIS/NIR absorption peaks, while the 1H NMR spectrum of 11 min irradiated Thioridazine 5x10-2 M solution indicates modifications both in aliphatic and in aromatic protons regions. The HPLC-MS measurements highlight a change of Thioridazine in two metabolites: Mesoridazine in the first instance and Sulphoridazine finally. The behavior of the irradiated BG1188 10-3 M solution according to the evolution of the absorption and laser inducedfluorescence spectra highlights a photodecomposition of the initial solution and the appearance of new photoproducts. All the investigated solutions exhibit the photodegradation of the initial compounds, which allows us to consider that the exposure of solutions containing pharmaceutical products to laser beams may constitute a possible mean to remove these kinds of pollutants from different wastewater sources.

Stability Characterization of Quinazoline Derivative BG1188 by Optical Methods

3‐[2‐(dimethylamino)ethyl]‐6‐nitroquinazolin‐4(3H)‐one, labeled BG1188, is a new synthesized compound, out of a series of quinazoline derivatives developed to fight the multidrug resistance of antibiotics acquired by bacteria. A characterization of the BG1188 powder was made using FTIR spectra in order to evidence the functional groups in the medicine’s molecule. The ultraviolet‐visible (UV‐Vis) absorption spectra were used to study the stability of the BG1188 solutions in two solvents and at different temperatures. BG1188 concentration in ultrapure water was varied between 2×10−3 M (stock solution) and 10−6 M. The concentration recommended by higher activity on bacteria was 10−3 M. For the same reason, this was the utilized concentration of BG1188 in dimethyl sulfoxide (DMSO). Time stability was characterized by comparing the time evolution of the UV‐Vis absorption spectra of the BG1188 solutions in ultrapure de‐ionized water or in DMSO. The spectra were recorded daily for about 4 months after the prepar...

The modification of spectral characteristics of cytostatics by optical beams

Besides the biochemical action of methotrexate (MTX) and 5-fluorouracil (FU) their effect in destroying cancer tumours could be enhanced by exposure to light at different doses. Absorption, excitation and emission spectra of 10-4M - 10-5M MTX solutions in natural saline and sodium hydroxide at pH = 8.4 were measured, while their exposure to coherent and uncoherent light in the visible and near ultraviolet (UV) spectral ranges was made (Hg lamps and Nitrogen pulsed laser radiation were used). Absorption spectra exhibit spectral bands in the range 200 nm - 450 nm. The 200 - 450 nm excitation spectra were measured with emission centered on 470 nm; MTX fluorescence excitation was measured at 390 nm and the emission was detected between 400 nm and 600 nm showing a maximum at 470 nm. Spectra modifications, nonlinearly depending on exposure time (varying from 1 min to 20 min), evidenced MTX photo-dissociation to the fluorescent compound 2,4 diamino-formylpteridine. In the 5-FU case the absorption spectra exhibit bands between 200 nm and 450 nm. The emission fluorescence spectra were measured between 400 nm and 600 nm, with λex = 350 nm for UV Hg lamp and with λex = 360 nm for laser irradiated samples; at irradiation with N2 laser emitted radiation the excitation spectra were measured in the range of 200 nm - 400 nm, with λem = 440 nm. New vascularity rapid destruction was observed for conjunctive impregnated with 5-FU solution whilst exposed to incoherent UV and visible light.