Exocyclic DNA adducts and oxidative stress parameters: useful tools for biomonitoring exposure to aldehydes in smokers.

CONTEXT: Exocyclic DNA adducts have been shown to be potential biomarkers of cancer risk related to oxidative stress and exposure to aldehydes in smokers. In fact, aldehydes potentially arise from tobacco combustion directly and endogenously through lipid peroxidation. OBJECTIVE: This study aims to investigate the relationship between a profile of nine aldehydes-induced DNA adducts and antioxidant activities, in order to evaluate new biomarkers of systemic exposure to aldehydes. METHODS: Using our previously published UPLC-MS/MS method, adducts levels were quantified in the blood DNA of 34 active smokers. The levels of antioxidant vitamins (A, C and E), coenzyme Q10, ß-carotene, superoxide dismutase (SOD) and autoantibodies against oxidized low-density lipoprotein were measured. RESULTS: Adducts induced by tobacco smoking-related aldehydes were quantified at levels reflecting an oxidative production from lipid peroxidation. A significant correlation between SOD and crotonaldehyde-induced adducts (p = 0.0251) was also observed. ß-Carotene was negatively correlated with the adducts of formaldehyde (p = 0.0351) and acetaldehyde (p = 0.0413). Vitamin C tended to inversely correlate with acetaldehyde-induced adducts (p = 0.0584). CONCLUSION: These results are promising, and the study is now being conducted on a larger cohort with the aim of evaluating the impact of smoking cessation programs on the evolution of adducts profile and antioxidants activities.

Changes in biomarkers of endothelial function, oxidative stress, inflammation and lipids after smoking cessation: A cohort study.

BACKGROUND: Tobacco use is known to be involved in the development of cardiovascular diseases, which leads to premature mortality. Endothelial dysfunction, the first step in this process, was shown induced by smoking. It is reported that quitting smoking could reduce the risk of diseases, but the implied mechanisms are still unclear. This study aimed to evaluate the biological markers of endothelial function in smokers when actively smoking and after cessation. METHODS: Quantification of several biomarkers reflecting inflammation, endothelium activation, oxidative stress, and lipids was performed in 65 smokers when actively smoking and after cessation (median abstinence duration of 70 days). RESULTS: A possible decrease of inflammation was observed through the concentration reduction of a proinflammatory cytokine (interleukine-6) on quitting. A decrease of endothelium activation was visible by the reduced level of the soluble intercellular adhesion molecule. Two antioxidants, uric acid and vitamin C, were found at higher concentration than before the cessation, potentially reflecting the decrease of oxidative stress on quitting. Lipid profile was improved post-quit since HDL level was increased and LDL level was decreased. All these effects were visible at short term with abstinence duration less than 70 days. No sex-specific difference was observed and no additional changes were observed for longer abstinence duration. CONCLUSION: These observations suggest that some adverse effects of smoking on endothelial function could be reversible on quitting smoking. It could encourage smokers to enter a cessation program to reduce the risk for cardiovascular diseases development.

Effect of the Nicotine Replacement Therapy on Biomarkers of Inflammation, Endothelial Dysfunction, Oxidative Stress, and Lipids in Smokers Who Quit Smoking.

INTRODUCTION: Our previous study showed major changes in biomarkers on quitting compared to the smoking state. They reflected a decrease in inflammation, endothelial activation, and oxidative stress, as well as an improved lipid profile. Nicotine replacement therapy (NRT) is effective to increase the rate of successful quitting, but healthcare professionals may have concerns to prescribe this first-line smoking cessation treatment because its effect on inflammation and related processes is controversial. AIMS AND METHODS: The present study assessed the influence of NRT on biomarkers of inflammation, endothelial function, oxidative stress, and lipids, in people who quit smoking. Sixty-five subjects who daily smoke cigarettes were recruited and followed on quitting. Thirty-five quit using NRT and thirty quit without NRT. Biomarkers of inflammation, endothelial function, oxidative stress, and lipids were quantified at baseline when actively smoking and after cessation in the presence of NRT or not. RESULTS: Changes in biomarkers on quitting did not differ according to the treatment used. No difference was found when comparing participants who were exposed to NRT and those who were not. CONCLUSIONS: These results may indicate that NRT has no effect on inflammation, endothelial function, oxidative stress, and lipids, when used as a medication aid for quitting smoking. IMPLICATIONS: This study provides new evidence to support the safety profile of NRT products regarding the biomarkers of endothelial function, oxidative stress, inflammation, and lipids.

Tacrolimus Prevents Mechanical and Humoral Alterations in Brain Death-induced Lung Injury in Pigs.

Rationale: Donor brain death-induced lung injury may compromise graft function after transplantation. Establishing strategies to attenuate lung damage remains a challenge because the underlying mechanisms remain uncertain. Objectives: The effects of tacrolimus pretreatment were evaluated in an experimental model of brain death-induced lung injury. Methods: Brain death was induced by slow intracranial infusion of blood in anesthetized pigs after randomization to tacrolimus (orally administered at 0.25 mg ⋅ kg-1 twice daily the day before the experiment and intravenously at 0.05 mg ⋅ kg-1 1 h before the experiment; n = 8) or placebo (n = 9) pretreatment. Hemodynamic measurements were performed 1, 3, 5, and 7 hours after brain death. After euthanasia of the animals, lung tissue was sampled for pathobiological and histological analysis, including lung injury score (LIS). Measurements and Main Results: Tacrolimus pretreatment prevented increases in pulmonary arterial pressure, pulmonary vascular resistance, and pulmonary capillary pressure and decreases in systemic arterial pressure and thermodilution cardiac output associated with brain death. After brain death, the ratio of PaO2 to FiO2 decreased, which was prevented by tacrolimus. Tacrolimus pretreatment prevented increases in the ratio of IL-6 to IL-10, VCAM1 (vascular cell adhesion molecule 1), circulating concentrations of IL-1ß, and glycocalyx-derived molecules. Tacrolimus partially decreased apoptosis (Bax [Bcl2-associated X apoptosis regulator]-to-Bcl2 [B-cell lymphoma-2] ratio [P = 0.07] and number of apoptotic cells in the lungs [P < 0.05]) but failed to improve LIS. Conclusions: Immunomodulation through tacrolimus pretreatment prevented pulmonary capillary hypertension as well as the activation of inflammatory and apoptotic processes in the lungs after brain death; however, LIS did not improve.

Long-term physicochemical stability of 5-fluorouracil at selected standardised rounded doses in polyolefin bags.

BACKGROUND: Chemotherapy doses are usually prescribed on the basis of body surface area but dose banding is emerging as an efficient alternative. Dose banding presents the possibility of in-advance preparation in a Centralized Intravenous Admixture Service. AIM OF THE STUDY: To evaluate the long-term stability of 5-fluorouracil at banded doses (700 mg and 800 mg) in polyolefin bags. MATERIALS AND METHODS: Ten polyolefin bags were prepared under aseptic conditions and stored at 23 ± 2°C for 24 days. Five of them were composed of 14 mL 5-fluorocuracil (700 g) in 100 mL 0.9% sodium chloride solution and the five other of 16 mL 5-fluorouracil (800 mg) in 100 mL 0.9% sodium chloride solution. At defined times, physical stability parameters were assessed: optical densities, pH measurements, visual and microscopical inspections. Solutions concentrations were measured using high-performance liquid chromatography coupled with a photodiode array detector. RESULTS: No change was observed on pH and optical density measurements during the study period. Visual and microscopical inspections remained free of colour change, precipitate, microagregate or crystal. The concentrations of 5-Fluorouracil in 800 mg bags remained stable for 24 days while the concentration in 700 mg bags showed a stability of at least 17 days. CONCLUSION: Five-fluorouracil at banded doses of 700 and 800 mg in polyolefin bags is physicochemically stable for at least 17 days at 23 ± 2°C. These results support the possibility of in advance centralised preparation.

Long term stability of an admixture of alizapride and ondansetron in 0.9% sodium chloride solution polyolefin bags stored at 5±3°C.

BACKGROUND: Patients undergoing chemotherapeutic treatment are currently treated by a concomittent infusion of alizapride and ondansetron. To optimise the procedure and to ensure patients' safety, the admixture could be prepared in advance by the Centralized Intravenous Additive Service (CIVAS) provided that the stability of the mixture has been proven beforhand to reduce nausea and vomiting.Aim of the study: to evaluate the long-term stability of an admixture of alizapride 0.926 mg/l and ondansetron 0.074 mg/ml in 0.9% sodium chloride polyolefin bags stored at 5 ± 3°C. MATERIAL AND METHODS: Five polyolefin bags containing 100 ml sodium chloride 0.9% added with 4 ml alizapride (100 mg) and 4 ml ondansetron (8 mg) were prepared in aseptic conditions and stored at 5 ± 3°C for 56 days. Periodically, physical stability tests were performed including: pH measurements, optical density measurements at 350, 410 and 550 nm to track turbidity appearance, visual and microscopical inspections to detect colour changes, precipitation, microaggregates or crystals. The concentrations of the solutions were measured by High Performance Liquid Chromatography coupled with an UV detector. RESULTS: There was no change in pH and optical densities during the study period. Visual and microscopical inspections didn't show any change of colour neither precipitation, microaggregate or crystal. The alizapride and ondansetron concentrations remained stable over the study. CONCLUSION: The admixture of alizapride and ondansetron in 0.9% sodium chloride solution polyolefin bags is physicochemically stable up to 56 days at 5 ± 3°C. These results support the possibility of preparing the solutions in advance by a CIVAS.

Elevation of biomarkers and long-term outcome after percutaneous coronary intervention.

BACKGROUND/OBJECTIVES: The impact of an elevation of cardiac biomarkers occurring after percutaneous coronary intervention (PCI) on long-term outcome remains controversial. Most available data are based on observational registries using multivariable analysis. In this study, a case-control approach was used to assess separately the impact of post-PCI elevation of CK-MB on the short-term in-hospital outcome and on the long-term outcome after hospital discharge. METHODS: Between 1 January 1996 and 31 December 2008, a postprocedural rise of CK-MB was observed in 363 among 8346 consecutive PCI procedures (4·3%). The overall in-hospital mortality for patients with or without CK-MB elevation after PCI was 8·5% and 1·5%, respectively (P < 0·001). For 245 hospital survivors with CK-MB elevation, we found 245 control cases matched for 9 relevant clinical parameters in our PCI database during the same period. The long-term survival of these patients was assessed by KM estimates. RESULTS: Despite an increased in-hospital mortality among patients with periprocedural elevation of CK-MB, the long-term outcome of patients who are discharged alive is independent of CK-MB release, curves of overall survival and of survival free of recurrence of myocardial infarction being similar up to 10 years after hospital discharge. CONCLUSIONS: In our population, the elevation of CK-MB after PCI identified a high-risk subgroup for in-hospital mortality but had no impact on the long-term prognosis, once the patient is discharged alive from the hospital.

Doxorubicin-loaded drug-eluting beads (DC Bead®) for use in transarterial chemoembolization: a stability assessment.

PURPOSE: Evaluation of doxorubicin stability over time when stored into the DC Bead embolic agent, in various containers, which are used for the delivery of the doxorubicin-loaded beads to the patients for up to 14 days under refrigerated conditions. METHODS: The doxorubicin was loaded through the ionic exchange mechanism into the calibrated polyvinyl alcohol-based hydrogel beads (DC Bead), with the loading process carried out either in the original DC Bead glass vials or within a polypropylene plastic syringe. The loaded samples were eluted at given time points and the extracted doxorubicin was analysed by high-performance liquid chromatography for concentration and chromatographic area response purity. RESULTS: The variance on the doxorubicin concentration of the samples stored in the syringes under refrigerated conditions was less than 10% over the 14 days period. The chromatographic purity of doxorubicin eluted from the DC Bead in their primary glass vial packaging was measured at 99.7%. The dissolution test showed that the elution rate and amount recovered from samples stored in vials were statistically similar between Day 0 and Day 14. The chromatographic purity of the doxorubicin loaded into DC Bead in presence of non-ionic contrast medium was >99.0% for 7 days under refrigerated conditions. CONCLUSIONS: Doxorubicin-loaded DC Bead® are shown to have adequate physicochemical stability over a period of 14 days when stored in syringes or vials under refrigerated conditions for up to 14 days. The admixtures of doxorubicin-loaded beads with contrast medium are stable for up to 7 days under refrigerated conditions.

Evaluation of 30-days stability of morphine hydrochloride and clonidine at high and low concentrations in polypropylene syringes.

OBJECTIVES: Clonidine is an alpha-2 adrenoreceptor agonist and is frequently combined with opioids (ie, morphine hydrochloride (HCl)) for the management of chronic pain. In palliative care, the administration of clonidine and morphine HCl is recommended in case of tolerance effect. This study aimed to evaluate the physical and chemical stability of this admixture at high and low concentrations in 14 and 48 mL polypropylene syringes. METHODS: The stability of a low concentration admixture of clonidine (Catapressan 0.15 mg/mL, Boehringer Ingelheim, Germany) and morphine (morphine HCl 40 mg/mL, Sterop, Belgium) at 0.003 and 0.417 mg/mL, respectively, was evaluated by using five polypropylene syringes of 48 mL. The high concentration admixture consisted of 0.032 mg/mL clonidine and 4.286 mg/mL morphine HCl and was evaluated by using five polypropylene syringes of 14 mL. All syringes were stored for 30 days at 5°C±3°C. Periodic samples were visually and microscopically examined to observe any particle appearance or colour change. pH and absorbance at three wavelengths (350, 410 and 550 nm) were monitored. The concentrations were measured by ultra-high performance liquid chromatography-photodiode array detection. RESULTS: During the 30 days, there was no change in colour or appearance of opacity, turbidity or precipitation, and pH remained stable. The low and high concentration admixtures were considered chemically stable since the lower limit of the 90% CI remained superior to 90% of the initial concentration. Concentration measurements showed that the degradation rate was less than 1% over 10 days for each component in both admixtures. CONCLUSIONS: The admixture of clonidine and morphine HCl at low and high concentrations in polypropylene syringes appeared to be physically and chemically stable throughout the study period of 30 days at 5°C±3°C. In conclusion, the admixture can be prepared in advance under aseptic conditions by a centralised intravenous additive service in the pharmacy department.

An ultra-high-performance chromatography method to study the long term stability of gemcitabine in dose banding conditions.

Gemcitabine is an analogue of cytidine arabinoside, used alone or in combination chemotherapy to treat various type of cancer. The dose-banding of gemcitabine provides the opportunity to anticipate the preparation of this anticancer drug on condition of carrying out stability studies. The aim of this study is to develop and validate a stability-indicating ultra-high-performance Liquid Chromatography (UHPLC) method for measuring the concentration of gemcitabine and to evaluate its stability at standardised rounded doses in polyolefin bags. The UHPLC with photodiode array (PDA) detector method was developed and validated (linearity, precision, accuracy, limits of detection and quantification, robustness and degradation test). Thirty polyolefin bags of gemcitabine (1600 mg/292 ml (n = 10), 1800 mg/297 ml (n = 10) and 2000 mg/303 ml (n = 10)) were prepared under aseptic conditions and stored at 5 ± 3 °C and 23 ± 2 °C for 49 days. Physical stability tests were periodically performed: visual and microscopic inspection and optical densities. The chemical stability was evaluated through pH monitoring and chromatographic assays. The results confirm the stability of Gemcitabine at selected standardised rounded doses of 1600 mg, 1800 mg and 2000 mg in NaCl 0.9% polyolefin bags for at least 49 days at 5 ± 3 °C and 23 ± 2 °C, allowing in-advance preparation.

Novel proposed cutoff values for anatabine and anabasine in differentiating smokers from non-smokers.

OBJECTIVES: Anatabine and anabasine are two tobacco alkaloids used to differentiate between tobacco users and abstainers, including users of nicotine replacement therapy. Cutoff values (>2 ng/mL for both alkaloids) have not been revised since their implementation in 2002. These values may be too high, leading to increased likelihood of misclassification between smokers and abstainers. This results in major consequences, especially adverse outcomes of transplantation when smokers were incorrectly identified as being abstinent. This study proposes that a lower threshold for anatabine and anabasine will better distinguish tobacco users from non-users and thereby improve patients' care. DESIGN AND METHODS: A new and more sensitive analytical method by liquid chromatography-mass detection was developed to allow the quantification of low concentrations. Anatabine and anabasine were measured in urine samples of 116 self-reported daily smokers and 47 long-term non-smokers (confirmed by the analysis of nicotine and its metabolites). The best compromise between sensitivity and specificity allowed us to determine new cutoff values. RESULTS: The thresholds >0.097 ng/mL for anatabine and >0.236 ng/mL for anabasine were associated with a sensitivity of 97% (anatabine) and 89% (anabasine) and a specificity of 98% for both alkaloids. These cutoff values greatly increased the sensitivity given that it dropped to 75% (anatabine) and 47% (anabasine) when using the reference value (>2 ng/mL). CONCLUSIONS: The cutoff values >0.097 ng/mL for anatabine and >0.236 ng/mL for anabasine appear to better differentiate tobacco users from abstainers than the current reference threshold (>2 ng/mL for both alkaloids). It may considerably impact patients' care, especially in transplantation settings in which smoking abstinence is essential to avoid adverse outcomes of transplantation.

Development of an Ultra-High Performance Liquid Chromatography method for the simultaneous mass detection of tobacco biomarkers in urine.

The quantification of tobacco exposure biomarkers is relevant to follow the patients' tobacco use. They allow to discriminate between tobacco users, non-users, passive smokers, and nicotine products users, such as in nicotine replacement therapy. The aim of this study was to develop and validate a quantification method of tobacco biomarkers of choice - nicotine, cotinine, trans-3'-hydroxycotinine, anatabine and anabasine - in urine. The challenge was to develop an easy and rapid liquid chromatography method requiring only one extraction step and allowing simultaneous detections. Some methods are described in the literature but need specific investment in terms of instrumentation and users training. Here, the developed method had to be carried out with instrumentation easily accessible for medical laboratories. The extraction of the analytes was performed by Supported Liquid Extraction (SLE), which consists in liquid-liquid extraction but supported by a sorbent. It allows to insure efficient neutrals extraction with less organic solvent and without any emulsion formation. 200 µl of basified urine - analytes of interest are neutral in this condition - were loaded on Novum SLE 96-Well Plates (Phenomenex) and analytes were eluted with 1 % formic acid in dichloromethane/propan-2-ol (95/5). After solvent evaporation, samples were reconstituted with 100 µl of water for injection. A mass detector (QDa, Waters) was used to detect analytes, this pre-optimised quadrupole mass analyser being less expensive and requiring less adjustments than traditional mass spectrometers while benefiting of the reliability of mass spectral data. This detector was integrated after an Ultra-high performance liquid chromatography (UHPLC) separation on a BEH C18 column (Waters) at a flow rate of 0.5 ml/min. A gradient elution of H2O (pH 10 with NH4OH) and CH3CN was used. Finally, the developed method was validated. This new method is conclusive to assess the patients' tobacco exposure and is easy to implement in medical laboratories.

Physical and Chemical Stability of Pharmaceutical Preparation of Bumetanide and Scopolamine.

Death rattle, which could often be associated with a pulmonary fluid overload, occurs in 25% to 90% of dying patients. The co-administration of scopolamine (anticholinergic drug) and bumetanide (loop diuretic) could be considered in order to avoid unnecessary fluid overload at end-stage of life. The objective of this study was to investigate the physical and chemical stabilities of the admixture bumetanide and scopolamine in order to prepare them in advance by a centralized intravenous additive service in-hospital pharmacy. The stability of the lowest (LOW) concentration was evaluated on five polypropylene syringes containing the admixture bumetanide (Burinex, 2 mg/4 mL) and scopolamine (0.25 mg/mL) at 41.67 µg/mL and 5.21 µg/mL. The highest (HIGH) concentration with 125 µg/mL of bumetanide and 31.25 µg/mL of scopolamine was evaluated on five polypropylene syringes. All syringes were stored for 18 days at 5°C ± 3°C. Periodic samples were visually and microscopically examined to observe any particle appearance or color change. The pH and absorbance at 3 wavelengths (350 nm, 410 nm, and 550 nm) were monitored. The concentrations were measured by ultra-high performance liquid chromatography-photodiode array detection, using a newly developed method. During the 18 days of test, there was no change in color or appearance of opacity, turbidity, or precipitation, and the pH remained stable. Mean concentrations of bumetanide and scopolamine at LOW and HIGH concentrations after 18 days remained statistically unchanged. The lower limits of the 95% confidence intervals of both molecules at LOW and HIGH concentrations remained higher than a 90% threshold of concentration, indicating the mixture was chemically stable. Degradation rates of bumetanide and scopolamine content at LOW and HIGH concentrations should not exceed a maximum of 0.70% every 10 days. This study was the first to show that the admixture of bumetanide and scopolamine is physically and chemically stable at two concentrations used in a palliative-care unit. This combination available in ready-to-use polypropylene syringes presents numerous advantages for patient's comfort and safety.

Microwave Freeze-thaw Technique for Injectable Drugs: A Review Updated from 1980 to 2021.

The objective of this review was to collect information and results about the method of the microwave freeze-thaw treatment of injectable drugs and whether the method can support the development of Centralized Intravenous Admixtures Services. A systematic review of the scientific literature about injectable drug stability studies was performed. The data are presented in a table, which describes the name of the drug, producer, final concentration, temperature and time of freezing storage, type of microwave oven, thawing power, method of dosage, and the results after treatment or final long-term storage at 5°C ± 3°C. From 1980 to 2021, 60 drugs were studied by the microwave freeze-thaw treatment, and the results were presented in 49 publications. Forty papers were presented by 8 teams (2 to 18 by team). The temperatures of freezing storage varied from -70°C to -10°C, the time storage from 4 hours to 12 months, and the thaw from low to full power. Drug concentrations were mainly determined by high-performance liquid chromatography. Most of the 59 drugs were stable during and after treatment. Only three teams tested the long-term stability after the microwave freeze-thaw treatment, the first for ganciclovir after 7 days, the second for ceftizoxime after 30 days, and the third for 20 drugs after 11 to 70 days. This review can help Centralized Intravenous Additive Services take charge of the productions of ready-to-use injectable drugs.

Long-term physico-chemical stability of 5-fluorouracile at standardised rounded doses (SRD) in MyFuser® portable infusion pump.

Management of chemotherapies is a strategic issue for european healthcare. Dose-banding enables to reduce waiting time of patients in day care units and drug wastage. The aim of this study was to assess the stability of 5-Fluorouracile (5-FU) at standardised rounded doses of 4 and 5 g in MyFuser® portable infusion pump for in-advance preparation. Ten MyFuser® (4 and 5 gr 5-FU added to NaCl 0.9%) were prepared under aseptic conditions and stored at room temperature (23 ± 2 °C) for 28 days then at 30 °C for three days. Physical stability tests were periodically performed: visual and microscopic inspection, pH measurements and optical densities. The concentration of solutions was measured by High Performance Liquid Chromatography/UV detector. Results confirm the stability of 5-FU at selected SRD of 4 g and 5 g with NaCl 0.9% in MyFuser® for at least 28 days at room temperature and three days at 30 °C, allowing in-advance preparation.

Genotoxicity of aldehyde mixtures: profile of exocyclic DNA-adducts as a biomarker of exposure to tobacco smoke.

Electrophilic compounds present in humans, originating from endogenous processes or pollutant exposures, pose a risk to health though their reaction with nucleophilic sites in protein and DNA. Among this chemical class, aldehydes are mainly present in indoor air and they can also be produced by endogenous lipid peroxidation arising from oxidative stress. Known to be very reactive, aldehydes have the ability to form exocyclic adducts to DNA that, for the most if not repaired correctly, are mutagenic and by consequence potential agents involved in carcinogenesis. The aim of this work was to establish profiles of exocyclic DNA adducts induced by aldehyde mixtures, which could ultimately be considered as a genotoxic marker of endogenous and environmental aldehyde exposure. Adducts were quantified by an accurate, sensitive and validated ultra high performance liquid chromatography-electrospray ionization analytical method coupled to mass spectrometry in the tandem mode (UHPLC-ESI-MS/MS). We simultaneously measured nine exocyclic DNA adducts generated during the exposure in vitro of calf thymus DNA to different concentrations of each aldehyde along, as well as, to an equimolar mixture of these aldehydes. This approach has enabled us to establish dose-response relationships that allowed displaying the specific reactivity of aldehydes towards corresponding adducts formation. Profiles of these adducts determined in DNA of current smokers and non-smokers blood samples supported these findings. These first results are encouraging to explore genotoxicity induced by aldehyde mixtures and can furthermore be used as future reference for adductomic approaches.

A validated UHPLC-MS/MS method for simultaneous quantification of 9 exocyclic DNA adducts induced by 8 aldehydes.

Human exposure to aldehydes is implicated in several diseases including cancer. These strong electrophilic compounds can react with nucleophilic sites in DNA to form reversible and irreversible modifications. These modifications, if not repaired, can contribute to pathogenesis. The aim of our study was to provide a mass spectrometry (MS)-based profiling method for identifying potential biomarkers of aldehydes exposure. We have developed and validated a highly sensitive method using ultra high performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UHPLC-ESI-MS/MS) for the simultaneous quantitation of 9 exocyclic DNA adducts derived from 8 main exogenous and endogenous aldehydes, namely formaldehyde, acetaldehyde, acrolein, crotonaldehyde, malondialdehyde, 4-hydroxy-2-nonenal, glyoxal and methylglyoxal. Finally, we applied the established method to quantify adducts in genomic DNA isolated from the blood of a smoker and a non-smoker blood samples in order to demonstrate its applicability.

Long-term stability of an infusion containing paracetamol, alizapride, ketorolac and tramadol in glass bottles at 5±3°C.

Background and objective: Infusion containing paracetamol, alizapride, ketorolac and tramadol is used after a general anaesthesia in order to limit pain, fever and nausea. Currently, these infusions are prepared according to demand in the anaesthesia unit, but the preparation in advance could improve quality of preparation and time management. The aim of this study was to investigate the long-term stability of this infusion in glass bottles at 5°C ± 3 °C. Method: Five bottles of infusion were stored at 5°C ± 3 °C for 60 days. A visual and microscope inspection were performed periodically to observe any particle appearance or colour change. pH and absorbance at three wavelengths were measured. The concentrations were measured by ultra-high performance liquid chromatography - diode array detection. Results: Multiple verifications were performed during the first 35 days and no crystal, impurity or colour change were observed. At the next time point (42nd day), crystals were visible to the naked eye. pH and absorbance at 350 nm and 550 nm were stable. A slight increase in the absorbance at 410 nm was observed during the study, suggesting that a degradation product could be formed and absorb at this wavelength. The infusion was considered chemically stable while the lower one-sided prediction limit at 95% remains superior to 90% of the initial concentration. Concentration measurements demonstrated that ketorolac and alizapride remained stable in the infusion for 35 days. The stability of tramadol was 28 days. However, degradation of paracetamol was much faster given that concentration has fallen below 90% of the initial concentration after 7 days. Conclusion: Infusion of paracetamol, alizapride, ketorolac and tramadol remains stable for 7 days in glass bottles at 5°C ± 3 °C and could be prepared in advance with these storage conditions.

Long-term Physicochemical Stability of Concentrated Solutions of Isosorbide Dinitrate in Polypropylene Syringes for Administration in the Intensive Care Unit.

In order to avoid fluid overload, more concentrated drug solutions in intensive care units are commonly used. This study evaluated the physicochemical stability of concentrated solution of isosorbide dinitrate in polypropylene syringes during 28 days at 5°C ± 3°C with protection from light. Five syringes of 50 mL, containing 0.60 mg/mL of isosorbide dinitrate in sodium chloride 0.9% were prepared and stored at 5°C ± 3°C with protection from light during 28 days. Immediately after preparation and periodically during the storage, isosorbide dinitrate concentration was measured by an ultra-performance liquid chromatography. Spectrophotometric absorbance at different wavelengths, pH measurements, and microscopic observations were also performed. All solutions were physicochemically stable during the whole period storage at 5°C ± 3°C. No color change, turbidity, precipitation or opacity, significant pH variations, or optic densities were observed in the solutions. Any crystals were seen by microscopic analysis. The concentration of isosorbide dinitrate remained above 90% of the initial concentration during the 28 days of storage. Solutions of isosorbide dinitrate 0.60 mg/mL in syringe of sodium chloride 0.9 % injection can be considered physically and chemically stable for 28 days when stored in syringes at 5°C ± 3°C with protection from light and may be prepared in advance by a centralized intravenous additive service.