BackgroundParenterally administered ascorbic acid modulates sepsis-induced inflammation and coagulation in experimental animal models. The objective of this randomized, double-blind, placebo-controlled, phase I trial was to determine the safety of intravenously infused ascorbic acid in patients with severe sepsis.MethodsTwenty-four patients with severe sepsis in the medical intensive care unit were randomized 1:1:1 to receive intravenous infusions every six hours for four days of ascorbic acid: Lo-AscA (50 mg/kg/24 h, n = 8), or Hi-AscA (200 mg/kg/24 h, n = 8), or Placebo (5% dextrose/water, n = 8). The primary end points were ascorbic acid safety and tolerability, assessed as treatment-related adverse-event frequency and severity. Patients were monitored for worsened arterial hypotension, tachycardia, hypernatremia, and nausea or vomiting. In addition Sequential Organ Failure Assessment (SOFA) scores and plasma levels of ascorbic acid, C-reactive protein, procalcitonin, and thrombomodulin were monitored.ResultsMean plasma ascorbic acid levels at entry for the entire cohort were 17.9 ± 2.4 μM (normal range 50-70 μM). Ascorbic acid infusion rapidly and significantly increased plasma ascorbic acid levels. No adverse safety events were observed in ascorbic acid-infused patients. Patients receiving ascorbic acid exhibited prompt reductions in SOFA scores while placebo patients exhibited no such reduction. Ascorbic acid significantly reduced the proinflammatory biomarkers C-reactive protein and procalcitonin. Unlike placebo patients, thrombomodulin in ascorbic acid infused patients exhibited no significant rise, suggesting attenuation of vascular endothelial injury.ConclusionsIntravenous ascorbic acid infusion was safe and well tolerated in this study and may positively impact the extent of multiple organ failure and biomarkers of inflammation and endothelial injury.Trial registrationClinicalTrials.gov identifier NCT01434121.

Cardiac ischemia associated with acute coronary syndrome and myocardial infarction is a leading cause of mortality and morbidity in the world. A rapid detection of the ischemic events is critically important for achieving timely diagnosis, treatment and improving the patient's survival and functional recovery. This minireview provides an overview on the current biomarker research for detection of acute cardiac ischemia. We primarily focus on inosine and hypoxanthine, two by-products of ATP catabolism. Based on our published findings of elevated plasma concentrations of inosine/hypoxanthine in animal laboratory and clinical settings, since 2006 we have originally proposed that these two purine molecules can be used as rapid and sensitive biomarkers for acute cardiac ischemia at its very early onset (within 15 min), hours prior to the release of heart tissue necrosis biomarkers such as cardiac troponins. We further developed a chemiluminescence technology, one of the most affordable and sensitive analytical techniques, and we were able to reproducibly quantify and differentiate total hypoxanthine concentrations in the plasma samples from healthy individuals versus patients suffering from ischemic heart disease. Additional rigorous clinical studies are needed to validate the plasma inosine/hypoxanthine concentrations, in conjunction with other current cardiac biomarkers, for a better revelation of their diagnostic potentials for early detection of acute cardiac ischemia.

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A simple and sensitive high-performance liquid chromatographic (HPLC) method utilizing fluorescence detection was developed for the determination of the phosphodiesterase type 5 inhibitor tadalafil in mouse plasma. This method utilizes a simple sample preparation (protein precipitation) with high recovery of tadalafil (∼98%), which eliminates the need for an internal standard. For constituent separation, the method utilized a monolithic C 18 column and a flow rate of 1.0 ml/min with a mobile phase gradient consisting of aqueous trifluoroacetic acid (0.1% TFA in deionized water pH 2.2, v/v) and acetonitrile. The method calibration was linear for tadalafil in mouse plasma from 100 to 2000 ng/mL (r > 0.999) with a detection limit of approximately 40 ng/ mL. Component fluorescence detection was achieved using an excitation wavelength of 275 nm with monitoring of the emission wavelength at 335 nm. The intra-and inter-day precision (relative standard deviation, RSD) values for tadalafil in mouse plasma were less than 14%, and the accuracy (percent error) was within -14% of the nominal concentration. The method was utilized on mouse plasma samples from research evaluating the potential cardioprotective effects of tadalafil on mouse heart tissue exposed to doxorubicin, a chemotherapeutic drug with reported cardiotoxic effects.

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