Salicylic Acid and Risk of Colorectal Cancer: A Two-Sample Mendelian Randomization Study.

Salicylic acid (SA) has observationally been shown to decrease colorectal cancer (CRC) risk. Aspirin (acetylsalicylic acid, that rapidly deacetylates to SA) is an effective primary and secondary chemopreventive agent. Through a Mendelian randomization (MR) approach, we aimed to address whether levels of SA affected CRC risk, stratifying by aspirin use. A two-sample MR analysis was performed using GWAS summary statistics of SA (INTERVAL and EPIC-Norfolk, N = 14,149) and CRC (CCFR, CORECT, GECCO and UK Biobank, 55,168 cases and 65,160 controls). The DACHS study (4410 cases and 3441 controls) was used for replication and stratification of aspirin-use. SNPs proxying SA were selected via three methods: (1) functional SNPs that influence the activity of aspirin-metabolising enzymes; (2) pathway SNPs present in enzymes' coding regions; and (3) genome-wide significant SNPs. We found no association between functional SNPs and SA levels. The pathway and genome-wide SNPs showed no association between SA and CRC risk (OR: 1.03, 95% CI: 0.84-1.27 and OR: 1.08, 95% CI: 0.86-1.34, respectively). Results remained unchanged upon aspirin use stratification. We found little evidence to suggest that an SD increase in genetically predicted SA protects against CRC risk in the general population and upon stratification by aspirin use.

In-vitro and in-vivo metabolism of different aspirin formulations studied by a validated liquid chromatography tandem mass spectrometry method.

Low-dose aspirin (ASA) is used to prevent cardiovascular events. The most commonly used formulation is enteric-coated ASA (EC-ASA) that may be absorbed more slowly and less efficiently in some patients. To uncover these "non-responders" patients, the availability of proper analytical methods is pivotal in order to study the pharmacodynamics, the pharmacokinetics and the metabolic fate of ASA. We validated a high-throughput, isocratic reversed-phase, negative MRM, LC-MS/MS method useful for measuring circulating ASA and salicylic acid (SA) in blood and plasma. ASA-d4 and SA-d4 were used as internal standards. The method was applied to evaluate: (a) the "in vitro" ASA degradation by esterases in whole blood and plasma, as a function of time and concentration; (b) the "in vivo" kinetics of ASA and SA after 7 days of oral administration of EC-ASA or plain-ASA (100 mg) in healthy volunteers (three men and three women, 37-63 years). Parameters of esterases activity were Vmax 6.5 ± 1.9 and Km 147.5 ± 64.4 in plasma, and Vmax 108.1 ± 20.8 and Km 803.2 ± 170.7 in whole blood. After oral administration of the two formulations, tmax varied between 3 and 6 h for EC-ASA and between 0.5 and 1.0 h for plain-ASA. Higher between-subjects variability was seen after EC-ASA, and one subject had a delayed absorption over eight hours. Plasma AUC was 725.5 (89.8-1222) for EC-ASA, and 823.1(624-1196) ng h/mL (median, 25-75% CI) for plain ASA. After the weekly treatment, serum levels of TxB2 were very low (< 10 ng/mL at 24 h from the drug intake) in all the studied subjects, regardless of the formulation or the tmax. This method proved to be suitable for studies on aspirin responsiveness.

Role of aspirin-triggered lipoxin A4, aspirin, and salicylic acid in the modulation of the oxidative and inflammatory responses induced by plasma from women with pre-eclampsia.

PROBLEM: Oxidative stress and inflammation are key events leading to pre-eclampsia, involved in several maternal deaths. Low doses of acetylsalicylic acid (ASA) are used in the prevention and treatment of pre-eclampsia. The synthesis of aspirin-triggered lipoxin (ATL) by cyclooxygenase-2 acetylation is an alternative mechanism of ASA, which could explain the effectiveness of ASA treatments. The aim of this study was to evaluate the role of ASA, salicylates, and ATL in the modulation of the oxidative and inflammatory responses induced by plasma from women with pre-eclampsia. METHOD OF STUDY: Plasma from 14 women with pre-eclampsia and 17 normotensive pregnant women was probed for inducing oxidative and inflammatory responses on endothelial cells and U937 promonocytes. The role of ATL, ASA, and salicylic acid (SA) on these events was evaluated. RESULTS: Plasma from women with pre-eclampsia induced TBARS and nitrotyrosine production on endothelial and U937 cells. Pre-treatment with both ATL and ASA decreased the TBARS production, while ATL decreased the nitrotyrosine. Pre-eclamptic plasma augmented the translocation of NF-kB on U937 cells, which decreased by a high dose of ASA and SA. Finally, the pre-eclamptic plasma increased the adhesion of leukocytes-PMN and monocytes-to endothelium, and we were able to determine a state of resolution of inflammation, since ATL decreased the PMN adhesion, and conversely, it increased the monocytes adhesion to endothelium. CONCLUSION: Together, these results suggest that ATL could explain the beneficial actions of ASA and support further research on mechanisms, real efficacy, and rational use of ASA in pre-eclampsia.

Circulating Salicylic Acid and Metabolic Profile after 1-Year Nutritional⁻Behavioral Intervention in Children with Obesity.

Objectives and Study: Salicylic acid (SA), a phenolic compound produced by plants, may play a beneficial role on health. A pilot study showed that children with obesity had lower serum SA than normal-weight children. The aim of this trial was to evaluate the effect of a 1-year nutritional-behavioral intervention on serum SA levels and to study a possible association between SA levels and metabolic profile changes in children with obesity. METHODS: This was an interventional longitudinal observational uncontrolled cohort study. Forty-nine children with obesity, aged >6 years were evaluated. BMI (body mass index) z-scores were calculated. Fasting blood samples were analyzed for lipids, insulin, and glucose. The most significant metabolic variables were calculated. Serum SA was measured using a gas chromatography-mass spectrometry method. The 1-year intervention was based on the promotion of a balanced and normocaloric diet, in accordance with the national guidelines for treatment of childhood obesity. Additionally, behavioral education, based on the revised CALO-RE (Coventry, Aberdeen, and London-REfined) taxonomy, was performed. RESULTS: At the end of intervention, children showed an increase in serum SA levels (mean (Standard Deviation, SD) 0.06 (0.02) vs. 0.09 (0.05) µmol/L; p < 0.001), a reduction of BMI z-score (3.14 (0.79) vs. 3.02 (0.82); p < 0.001), TyG index (4.52 (0.20) vs. 4.48 (0.23); p < 0.001), AIP (atherogenic index of plasma) (0.36 (0.21) vs. 0.27 (0.25); p < 0.001), and triglycerides/HDL (high density lipoprotein) cholesterol (2.57 (1.28) vs. 2.18 (1.22); p < 0.001) ratio. No statistically significant change in HOMA-IR (homeostasis model assessment index) was observed (4.20 (3.29) vs. 4.03 (2.28)). An association between the longitudinal variation of serum SA and HOMA-IR was found (correlation coefficient: -0.338, p = 0.02). CONCLUSION: Nutritional-behavioral intervention may improve the circulating SA and the metabolic profile in children with obesity. Serum SA could influence mainly glucose metabolism. Further larger studies are needed to evaluate whether a nutritional intervention based on specific advice regarding the quantity and type of fruit and vegetables (FV) consumption could provide benefits in terms of metabolic syndrome.

Effect of Red Ginseng Extract on the Pharmacokinetics of Aspirin Metabolite in Sprague Dawley Rats.

Objective To investigate whether red ginseng extract can affect the pharmacokinetics of aspirin in Sprague Dawley (SD) rats.Methods Totally, 12 male SD rats were randomly and uniformly divided into the aspirin group (aspirin 10.42 mg·kg -1) and the combined group (red ginseng extraction 0.5 mg·g -1 + aspirin 10.42 mg·kg -1). After intragastric administration of drugs, blood samples (0.5 ml once) were drawn from orbit at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 10 and 12 hours after dosing. Plasma concentration of salicylic acid (metabolite of aspirin) was detected with ultraviolet-visible high performance liquid chromatography (HPLC). The reliability of the procedure was verified with respect to specificity, linearity, accuracy, precision, extraction recovery and matrix effect, and stability. Pharmacokinetics of salicylic acid was evaluated by using non-compartmental model. Results The method was proved to be validated. Compared with the aspirin group, area under the curve (AUC 0-t) and maximum concentration of salicylic acid in rats of the combined group increased obviously (P<0.01), while clearance rate (CLz/F) decreased clearly (P<0.05).Conclusion The in vivo study showed that red ginseng extract can help the internal absorption of aspirin, and delay the in vivo metabolism of aspirin.

A kinetic-based safety assessment of consumer exposure to salicylic acid from cosmetic products demonstrates no evidence of a health risk from developmental toxicity.

Salicylic acid (SA) has a long history of safe use as ingredient in topical cosmetic products. In 2016, the Committee for Risk Assessment of the European Chemicals Agency proposed to classify SA as a Category 2 reproductive toxicant based on adverse developmental effects in animal toxicity studies. This hazard-based classification (based on mg/kg doses) requires a reassessment of the safety of the current SA concentrations in cosmetic consumer products. Herein, a safety reassessment was performed in which margins of safety were calculated based on literature data on the NOAEL plasma exposure levels from animal reproductive toxicity studies with ASA (rapidly converts to SA in plasma), human SA plasma levels from oral exposure to ASA and human dermal exposure to SA-containing cosmetic products. In addition, a literature review was performed, which shows that there are no adverse developmental effects despite extensive human clinical oral use of ASA up to the maximum recommended therapeutic doses. The plasma exposure-based safety assessment for SA combined with an absence of any clinical health risk with oral ASA use in the literature supports that there is an acceptable margin of safety for the consumer exposure to SA as authorized in the current EU cosmetic regulation.

Determination of Acetaminophen, Dexchlorpheniramine, Caffeine, Cotinine and Salicylic acid in 100 µL of Whole Blood by UHPLC-MS/MS.

A sensitive and robust ultra-high-performance liquid chromatography-tandem mass spectrometry method has been developed and validated for the quantification of acetaminophen, dexchlorpheniramine, caffeine, cotinine and salicylic acid in postmortem blood samples from children younger than 4 years. The sample was prepared by a protein precipitation with ice-cold methanol/acetonitrile mixture (85:15, v/v). The organic phase was evaporated to dryness and the residue was dissolved in the mobile phase. Separation, with gradient elution and an acidic mobile phase, was achieved on an Acquity UPLC® HSS T3 column. The compounds were quantified using a multiple reaction-monitoring mode. Two transitions were monitored for each compound and one for the deuterated internal standards. The mass spectrometric detection in the positive ion mode was performed for all the compounds except salicylic acid which was detected in the negative ionization mode. The limits of quantification were as follows: acetaminophen 0.30 mg/L, dexchlorpheniramine 0.0050 mg/L, caffeine 0.099 mg/L, cotinine 0.00035 mg/L and salicylic acid 1.3 mg/L. Between-assay and within-assay precisions were ≤15% (biases: -10% to 26%) and ≤10%, respectively. Extraction recoveries varied from 93% to 137%. The matrix effects in blood, corrected with deuterated internal standards, were 100% ± 10% for all compounds except dexchlorpheniramine (111%) and caffeine (138%).

Synthesis of robust electrochemical substrate and fabrication of immobilization free biosensors for rapid sensing of salicylate and ß-hydroxybutyrate in whole blood.

An electrochemical latent redox probe, SAF 5 was designed, synthesized and characterized. A rapid and sensitive solution-based assay was demonstrated for salicylate hydroxylase (SHL). In presence of NADH at aerobic conditions, SHL catalyzed the decarboxylative hydroxylation of SAF and released a redox reporter amino ferrocene (AF 6). The release of AF 6 was monitored at interference free potential region (-50 mV vs. Ag|AgCl) using differential pulse voltammetry as signal read-out. The current signal generated by this process is highly specific, and insensitive to other biological interfering compounds. Next, the SAF incorporated SHL assay was extended to fabricate immobilization-free biosensors for rapid sensing of salicylic acid (SA) and ß-hydroxybutyrate (ß-HB) in whole blood. The described method rapidly detects SA in a linear range of 35-560 µM with detection limit of 5.0 µM. For ß-HB determination, the linear range was 10-600 µM and detection limit was 2.0 µM. Besides, the assay protocols are simple, fast, reliable, selective, sensitive and advantageous over existing methods. The whole blood assay did not required cumbersome steps such as, enzyme immobilization, pre-treatments and holds great practical potential in clinical diagnosis.

Pharmacokinetics and in vitro efficacy of salicylic acid after oral administration of acetylsalicylic acid in horses.

BACKGROUND: Although acetylsalicylic acid (ASA) is not frequently used as a therapeutic agent in horses, its metabolite SA is of special interest in equestrianism since it is a natural component of many plants used as horse feed. This led to the establishment of thresholds by horse sport organizations for SA in urine and plasma. The aim of this study was to investigate plasma and urine concentrations of salicylic acid (SA) after oral administration of three different single dosages (12.5 mg/kg, 25 mg/kg and 50 mg/kg) of acetylsalicylic acid (ASA) to eight horses in a cross-over designed study. RESULTS: In the 12.5 mg/kg group, SA concentrations in urine peaked 2 h after oral administration (2675 µg/mL); plasma concentrations peaked at 1.5 h (17 µg/mL). In the 25 mg/kg group, maximum concentrations were detected after 2 h (urine, 2785 µg/mL) and 1.5 h (plasma, 23 µg/mL). In the 50 mg/kg group, maximum concentrations were observed after 5 h (urine, 3915 µg/mL) and 1.5 h (plasma, 45 µg/mL). The plasma half-life calculated for SA varied between 5.0 and 5.7 h. The urine concentration of SA fell below the threshold of 750 µg/mL (set by the International Equestrian Federation FEI and most of the horseracing authorities) between 7 and 26 h after administration of 12.5 and 25 mg/kg ASA and between 24 and 36 h after administration of 50 mg/kg ASA. For ASA, IC50 were 0.50 µg/mL (COX-1) and 5.14 µg/mL (COX-2). For salicylic acid, it was not possible to calculate an IC50 for either COX due to insufficient inhibition of both cyclooxygenases. CONCLUSION: The established SA thresholds of 750 µg//mL urine and 6.5 µg/mL plasma appear too generous and are leaving space for misuse of the anti-inflammatory and analgetic compound ASA in horses.

Effect of Panax notoginseng saponins on the pharmacokinetics of aspirin in rats.

Aspirin (ASA) is widely used to treat fever, pain, inflammation and cerebral infarction in clinic. Panax Notoginseng Saponins (PNS) is the extracts of Panax Notoginseng (PN)-a traditional Chinese medicine extensively used in cardiovascular diseases. Panax notoginseng saponins and ASA are both widely used to treat cerebral infarction in China. Good results in clinical practice have been achieved when the two drugs were taken together. To investigate the effect of PNS on ASA in vivo, the concentrations of salicylic acid (SA) in blood were measured after oral administration of ASA or ASA combined with PNS by UPLC-MS/MS. Sample preparation was carried out by the protein precipitation technique with an internal Saikosaponin A standard. The separation of two components was achieved by using an ACQUITY UPLC ®BEH C18 Column (1.7µm 2.1×100mm) by gradient elution using water (containing 0.2% formic acid) and acetonitrile (containing 0.2% formic acid) as the mobile phase at a flow rate of 0.2mL/min. The pharmacokinetic parameters were determined by using non-compartmental analysis. The results suggested that drug-drug interaction in vivo existed between PNS and ASA. The concentration of the SA was increasing when the two drugs were administered together. The transport of ASA and SA in MDCK -MDR1 cell monolayer was used to verify this conclusion. The values of apparent permeability coefficients (Papp) were significantly increased when the two drugs were used together. This result suggested PNS could increase the gastrointestinal tract absorption of ASA and SA. These findings provide more insight for wise use of two drugs to treat or prevent cardiovascular diseases.

Salicylic acid retention impairs aspirin reactivity in type 2 diabetes.

High on-aspirin platelet reactivity (HAPR) has been associated with compromised aspirin efficacy in patients with diabetes suffering from acute cardiovascular events, but the key mechanisms remain elusive. The objective of this study was to uncover the potential link between pathogenic accumulation of salicylic acid (SA), the major metabolite of aspirin, and HAPR in diabetic state. Aspirin failed to inhibit platelet CD62P expression and thromboxane (TX) B2/6-keto-prostaglandin（PG）F1α ratio in a type 2 diabetes mellitus (T2DM) mice model, particularly in the female, which were unanimously accompanied by significantly higher plasma SA concentrations. Pre-administration with SA increased both platelet CD62P expression and TXB2/6-keto-PGF1α ratio in female T2DM mice, while pretreatment with NaHCO3 caused the opposite effect. On the in vitro human umbilical vein endothelial cells (HUVECs)-platelet interaction assay, SA suppressed inflammation-induced cyclooxygenase-2 upregulation on HUVECs and attenuated their inhibitory effect on platelet aggregation in a dose-dependent manner. The prolonged retention of SA in diabetes may be partially explained by the downregulation of various SA efflux transporters in the kidney and the decreased urine pH. Importantly, in female aspirin non-responsive patients, the trough plasma concentration of SA are markedly increased with T2DM treated with long-term aspirin, and TXB2/6-keto-PGF1α ratio and uric acid level in plasma are positively correlated with SA concentration. Our findings support that the accumulation of SA represents an important factor in causing HAPR in diabetes, and that targeting impaired SA excretion may become a novel intervention strategy to diabetes-associated HAPR.

Serum salicylic acid and fruit and vegetable consumption in obese and normal-weight children: a pilot-study.

Salicylic acid (SA), a phenolic compound produced by plants, may play a beneficial role on health. This pilot study evaluated whether there might be an association between serum SA and fruit and vegetable (FV) consumption in obese and normal-weight children. Thirty-four obese children (17 boys and 17 girls) and 34 normal-weight children were recruited. Dietary intake was evaluated by the 7-day dietary record. Serum SA was measured using gas chromatography-mass spectrometry method. FV intake in obese and normal-weight children was not different between groups (175.00 (97.66) g versus 192.29 (90.54) g, p = .455). Obese children had lower serum SA than normal-weight children [mean difference, -0.025; 95% CI (-0.044; -0.006) µmol/L]. Serum SA was not associated with daily intake of FV in obese (p = .111) and normal-weight (p = .092) children. Further studies are needed to evaluate the role of FV on serum SA, taking into account also the quantity and the type.

Bioavailability of aspirin in rats comparing the drug's uptake into gastrointestinal tissue and vascular and lymphatic systems: implications on aspirin's chemopreventive action.

Aspirin is an effective analgesic and antiplatelet drug that in addition to its ability to reduce pain, inflammation and fever, appears to have efficacy in the prevention/treatment of a range of diseases including heart disease, numerous cancers and Alzheimer's. It is important to understand the bioavailability of aspirin and its major metabolite, salicylic acid, since dosage and route of administration can vary for treating differing diseases, and the major side-effects of aspirin, upper gastrointestinal ulceration and bleeding, are dose-dependent. We examined the time course for gastroduodenal uptake of aspirin and the appearance of its major metabolite salicylic acid in blood and lymph after intragastric (to simulate oral) and intraduodenal (to simulate enteric-coating) dosing in rats. Results show that after intragastric dosing, intact aspirin is absorbed primarily by the gastric mucosa and to a lesser extent by the duodenal mucosa. When aspirin is dosed intragastrically or intraduodenally, a much greater concentration of aspirin enters the lymph than the blood. In contrast, the concentration of salicylic acid was higher in blood than in lymph. Lymph levels of both aspirin and salicylic acid were sufficiently high so as to perform a pharmacologic function there, possibly as a chemopreventive agent against colon cancer and potentially the metastatic spread of non-gastrointestinal cancers.

Analysis of Valproic Acid, Salicylic Acid and Ibuprofen in Whole Blood by GC-MS.

The Georgia Bureau of Investigation utilized a silylation method of analysis for low molecular weight carboxylic acids in the past. Due to the negative impact such derivatizations can have on gas chromatography-mass spectrometry (GC-MS) systems an alternative means of analysis was investigated. The described method is a whole blood solid phase extraction of valproic acid, salicylic acid and ibuprofen utilizing butylation for sensitivity and improved chromatography by GC-MS. The method produced a limit of detection and limit of quantitation at 1 mg/L for valproic acid, 2 mg/L for salicylic acid and 0.25 mg/L for ibuprofen. The variability based upon the middle of the calibration curve estimated to be 7% for valproic acid, 8% for salicylic acid and 11% for ibuprofen established upon a 95% confidence interval, with the highest percent coefficient of variation being 5.3% for ibuprofen.

Pharmacokinetic and pharmacodynamic interactions of aspirin with warfarin in beagle dogs.

1. Warfarin and aspirin are widely used in a wide spectrum of thromboembolic and atherothrombotic diseases. Despite the potential efficacy of warfarin-aspirin therapy, the safety and side effect of combined therapy remains unclear. 2. The aim of this study was to investigate the pharmacokinetic and pharmacodynamic interactions between warfarin and aspirin in beagles after single and multiple doses. 3. Coadministration of aspirin had no significant effects on the area under the plasma concentration time curve (AUC(0-t)) and maximum plasma concentration (Cmax) of R- and S-warfarin after a single dose of warfarin, but significantly increase the AUC(0-t) and Cmax and dramatically decrease the clearance (CL) of R- and S-warfarin after multiple dose of warfarin. Accordingly, there was a slight increase in the AUEC(0-t) and Emax of activated partial thromboplastin time (aPTT), prothrombin time (PT) and international normalized ratio (INR) after multiple dose of warfarin. 4. Coadministration of warfarin had no markedly effects on the AUC(0-t) and Cmax of aspirin and its metabolite salicylic acid after single or multiple dose of aspirin. Meanwhile, the AUEC(0-t) and Emax of inhibition of platelet aggregation (IPA) were not significantly affected by warfarin. 5. Our animal study indicated that coadministration of aspirin with warfarin can cause significant pharmacokinetic and pharmacodynamic drug-drug interactions in beagles. However, more studies are urgently needed to assess related information of warfarin-aspirin drug interactions in healthy volunteers or patients.

Personalized monitoring of therapeutic salicylic acid in dried blood spots using a three-layer setup and desorption electrospray ionization mass spectrometry.

Desorption electrospray ionization (DESI) mass spectrometry is an emerging technology for direct therapeutic drug monitoring in dried blood spots (DBS). Current DBS methods require manual application of small molecules as internal standards for absolute drug quantification. With industrial standardization in mind, we superseded the manual addition of standard and built a three-layer setup for robust quantification of salicylic acid directly from DBS. We combined a dioctyl sodium sulfosuccinate weave facilitating sample spreading with a cellulose layer for addition of isotope-labeled salicylic acid as internal standard and a filter paper for analysis of the standard-containing sample by DESI-MS. Using this setup, we developed a quantification method for salicylic acid from whole blood with a validated linear curve range from 10 to 2000 mg/L, a relative standard deviation (RSD%) ≤14%, and determination coefficients of 0.997. The limit of detection (LOD) was 8 mg/L and the lower limit of quantification (LLOQ) was 10 mg/L. Recovery rates in method verification by LC-MS/MS were 97 to 101% for blinded samples. Most importantly, a study in healthy volunteers after administration of a single dose of Aspirin provides evidence to suggest that the three-layer setup may enable individual pharmacokinetic and endpoint testing following blood collection by finger pricking by patients at home. Taken together, our data suggests that DBS-based quantification of drugs by DESI-MS on pre-manufactured three-layer cartridges may be a promising approach for future near-patient therapeutic drug monitoring.

Semi-physiologic model validation and bioequivalence trials simulation to select the best analyte for acetylsalicylic acid.

The objective of this paper is to apply a previously developed semi-physiologic pharmacokinetic model implemented in NONMEM to simulate bioequivalence trials (BE) of acetyl salicylic acid (ASA) in order to validate the model performance against ASA human experimental data. ASA is a drug with first-pass hepatic and intestinal metabolism following Michaelis-Menten kinetics that leads to the formation of two main metabolites in two generations (first and second generation metabolites). The first aim was to adapt the semi-physiological model for ASA in NOMMEN using ASA pharmacokinetic parameters from literature, showing its sequential metabolism. The second aim was to validate this model by comparing the results obtained in NONMEM simulations with published experimental data at a dose of 1000 mg. The validated model was used to simulate bioequivalence trials at 3 dose schemes (100, 1000 and 3000 mg) and with 6 test formulations with decreasing in vivo dissolution rate constants versus the reference formulation (kD 8-0.25 h (-1)). Finally, the third aim was to determine which analyte (parent drug, first generation or second generation metabolite) was more sensitive to changes in formulation performance. The validation results showed that the concentration-time curves obtained with the simulations reproduced closely the published experimental data, confirming model performance. The parent drug (ASA) was the analyte that showed to be more sensitive to the decrease in pharmaceutical quality, with the highest decrease in Cmax and AUC ratio between test and reference formulations.

Polysaccharide arabinogalactan from larch Larix sibirica as carrier for molecules of salicylic and acetylsalicylic acid: preparation, physicochemical and pharmacological study.

Inclusion complexes of salicylic acid (SA) and acetylsalicylic acid (aspirin, ASA) with polysaccharide arabinogalactan (AG) from larch wood Larix sibirica and Larix gmelinii were synthesized using mechanochemical technology. In the present study, we have investigated physicochemical properties of the synthesized complexes in solid state and in aqueous solutions as well as their anti-aggregation and ulcerogenic activity. The evidence of the complexes formation was obtained by nuclear magnetic resonance (NMR) relaxation technique. It was shown that in aqueous solution the molecules of SA and ASA are in fast exchange between the complex with AG macromolecules and solution. The stability constant of aspirin complex was calculated. It was shown that mechanochemically synthesized complexes are more stable when compared to the complex obtained by mixing solutions of the components. Complexes of ASA show two-fold increase of anti-platelet effect. It allows to reduce the dose of the antithrombotic drug and its ulcerogenic activity. These results substantiate the possibility to design new preparations on the basis of ASA with increased activity and safety.

Association of plasma concentrations of salicylic acid and high on ASA platelet reactivity in type 2 diabetes patients.

BACKGROUND: The objective of this study was to investigate the association between plasma concentrations of salicylic acid (SA) and other minor acetylsalicylic acid (ASA) metabolites and high on ASA platelet reactivity assessed with different methods in type 2 diabetic patients (T2DM). METHODS: Study cohort consisted of 293 T2DM patients on chronic ASA therapy. Platelet function inhibition was analyzed using measurements of serum thromboxane B2 (S-TxB2), VerifyNow Aspirin and Platelet Function Analyzer (PFA)-100 assays. The concentration of ASA metabolites in plasma was measured with a high-performance liquid chromatography (HPLC). RESULTS: In logistic regression analysis both ASA dose/kg of body weight and plasma SA concentration were found to be predictive of S-TxB2 concentrations above 0.72 ng/mL cut-off point (OR 16.9, 95% CI 2.29-125.8, p = 0.006 and OR 5.34, 95% CI 2.67-10.68, p < 0.001, respectively). When using the VerifyNow Aspirin Assay, the concentrations of SA were significantly lower (p = 0.007) in the group with high on ASA platelet reactivity when compared with the group with normal on ASA platelet reactivity. In logistic regression analysis plasma SA concentration was found to be predictive of VerifyNow Aspirin Reaction Units (ARU) ≥ 550 (OR 3.86, 95% CI 1.86-8.00, p < 0.001). CONCLUSIONS: Our study suggests that disturbances of pharmacokinetic mechanisms might contribute to lower plasma SA levels, and subsequently incomplete inhibition of thromboxane A2 synthesis as measured with S-TxB2 concentrations and increased platelet reactivity measured with VerifyNow in T2DM patients.

Determination of salicylic acid in human serum and urine samples by high-performance liquid chromatography with post-column Ru(bipy)3(2+)-Ce(SO4)2 chemiluminescence detection.

A sensitive, novel and rapid chemiluminescence (CL) method combined with high-performance liquid chromatography (HPLC) separation for the determination of salicylic acid (SA) is described in this work. The method was based on the fact that SA could significantly enhance the CL of the reaction of cerium sulfate and the tris(2,2-bipyridyl) ruthenium(II) CL system in the presence of acid. Under the optimal conditions, the CL intensity was linear over concentrations of SA in the range of 0.02-10 × 10(-6) g/mL, with a detection limit of 8 × 10(-9) g/mL (S/N = 3). Also, the relative standard detection was 2.2% for 1.0 × 10(-7) g/mL (n = 11). The proposed method has been successfully applied to the analysis of SA in human serum samples and urine samples with satisfactory results.