Upright T wave in precordial lead V1 indicates the presence of significant coronary artery disease in patients undergoing coronary angiography with otherwise unremarkable electrocardiogram.

OBJECTIVE: The goal of the current work was to assess the possible relationship between upright T wave in precordial lead V1 (TV1) and the occurrence of coronary artery disease (CAD) in patients undergoing coronary angiography with an otherwise unremarkable resting electrocardiogram (ECG). METHODS: Twelve-lead resting ECGs of 2,468 patients who underwent coronary angiography were analyzed by independent reviewers blinded to the patients' clinical data. Patients with any condition known to affect cardiac repolarization were not eligible for inclusion. RESULTS: Of 126 patients included in the study, 76 (60%) had at least one significant coronary artery stenosis. Significant CAD was more frequently found in patients with upright TV1 as compared to those with negative TV1 (74 vs. 43%, p = 0.001). Left circumflex (LCx) and left anterior descending (LAD) coronary artery lesions were more frequently observed in patients with upright TV1 than in those with inverted TV1. In univariate analysis, patients with upright TV1 were approx 4 times more likely to have significant CAD than those with inverted TV1 (odds ratio (OR) 3.7, 95% confidence interval (CI) 1.744-7.897). In addition, in the multivariate logistic regression model, upright TV1 was an independent predictor of significant CAD (OR 4.249, 95% CI 1.594-11.328), along with previous myocardial infarction (OR 17.533, 95% CI 3.338-92.091), male gender (OR 3.020; 95% CI 1.214-7.510), and age (OR 1.061; 95% CI 1.003-1.122). CONCLUSION: It might be worthwhile to routinely evaluate the polarity of the T wave in lead V1 in patients with suspected CAD, since it appears to have additional risk stratification potential.

Predicting no-reflow phenomenon prior to primary percutaneous coronary intervention using a novel probability risk score derived from clinical and angiographic parameters.

OBJECTIVE: We aimed to create a clinically usable probability risk score for prediction of no-reflow (NRF) phenomenon prior to primary percutaneous coronary intervention (PPCI). PATIENTS AND METHODS: This single-center and retrospective study included 1254 patients with acute ST-segment elevation myocardial infarction (STEMI) who underwent PPCI. Patients were randomly assigned into two groups in the ratio 2:1, the derivation dataset (n=840) and validation dataset (n=414). Independent predictors of NRF were identified and combined to create a prediction model using univariate and multivariate regression analysis in the derivation dataset. The risk score was tested and validated by calculating area under the receiver operating characteristic (ROC) curves in the derivation and validation datasets, respectively. RESULTS: Five significant, independent predictors of NRF were identified: age ≥ 65 years (odds ratio [OR]: 2.473, 95% confidence interval [CI]: 0.389-1.484, p < 0.01), heart rate ≥ 89 bpm (odds ratio [OR]: 1.622, 95% confidence interval [CI]: 0.024-0.945, p < 0.05), Killip class ≥ II (odds ratio [OR]: 1.914, 95% confidence interval [CI]: 0.024-1.306, p < 0.01), total ischemic time ≥ 268 min (odds ratio [OR]: 2.652, 95% confidence interval [CI]: 0.493-1.565, p < 0.01), and thrombus burden G≥4 (odds ratio [OR]: 8.351, 95% confidence interval [CI]: 0.344-15.901, p < 0.01). The risk score was created combining these predictors with assigned points. The overall score ranged from 0 to 17 points. The optimal cutoff value of the risk score was 11 points (area under curve [AUC]: 0.772, 95% confidence interval [CI]: 0.729-0.815, sensitivity 71.21%, specificity 70.34%, positive predictive value 30.92%, negative predictive value 92.91%, p < 0.001). The ROC curve for the validation group showed good discriminant power. CONCLUSIONS: We developed a novel risk score based on five clinical and angiographic parameters, which might be a useful clinical tool for prediction of NRF in STEMI patients prior to PPCI with an acceptable accuracy.

Normal Tissue Complication Probability (NTCP) Modelling of Severe Acute Mucositis using a Novel Oral Mucosal Surface Organ at Risk.

AIMS: A normal tissue complication probability (NTCP) model of severe acute mucositis would be highly useful to guide clinical decision making and inform radiotherapy planning. We aimed to improve upon our previous model by using a novel oral mucosal surface organ at risk (OAR) in place of an oral cavity OAR. MATERIALS AND METHODS: Predictive models of severe acute mucositis were generated using radiotherapy dose to the oral cavity OAR or mucosal surface OAR and clinical data. Penalised logistic regression and random forest classification (RFC) models were generated for both OARs and compared. Internal validation was carried out with 100-iteration stratified shuffle split cross-validation, using multiple metrics to assess different aspects of model performance. Associations between treatment covariates and severe mucositis were explored using RFC feature importance. RESULTS: Penalised logistic regression and RFC models using the oral cavity OAR performed at least as well as the models using mucosal surface OAR. Associations between dose metrics and severe mucositis were similar between the mucosal surface and oral cavity models. The volumes of oral cavity or mucosal surface receiving intermediate and high doses were most strongly associated with severe mucositis. CONCLUSIONS: The simpler oral cavity OAR should be preferred over the mucosal surface OAR for NTCP modelling of severe mucositis. We recommend minimising the volume of mucosa receiving intermediate and high doses, where possible.

The riboflavin-mediated photooxidation of doxorubicin.

PURPOSE: Previously, it was shown that exposing doxorubicin (ADR) to 365 nm light resulted in the loss of its cytotoxic activity as well as its absorbance at 480 nm. These processes were much enhanced when mediated by riboflavin. In the present study we investigated the quantitative and qualitative aspects of riboflavin-mediated photodegradation of ADR. METHODS: ADR solutions containing variable concentrations of riboflavin and other agents were exposed to 365 nm light for variable time periods and then the absorbance spectrum of ADR was measured by a double beam spectrophotometer. These measurements were used to calculate the half-time of the ADR degradation process. The degraded ADR solutions were analyzed by chromatography and mass spectrometry. RESULTS: Analysis of the riboflavin effect indicated that a maximal rate of photolytic degradation of ADR was obtained only after most of the ADR molecules had formed bimolecular complexes with riboflavin. The retardation of lumichrome formation by ADR and the inhibition of ADR bleaching by excess of ascorbic acid suggested that ADR was degraded by a photooxidation process. Similar spectral changes occurred when ADR was exposed to strong oxidizers such as sodium hypochlorite and dipotassium hexachloroiridate. Cyclic voltammetry revealed that the oxidation-reduction process of ADR was not electrochemically reversible and therefore the oxidation potential could not be determined accurately; however its value should be between 0.23 and 0.78 V. Analysis of the photooxidative process revealed that it was not mediated by the formation of singlet oxygen, superoxide anion radicals, hydrogen peroxide or hydroxyl radicals, and it is suggested that ADR was oxidized directly by the excited triplet riboflavin. The mass spectrograms and the HPLC chromatograms of photooxidized ADR indicate that the central ring of ADR was opened and that 3-methoxysalicylic acid was produced by this cleavage. CONCLUSIONS: The riboflavin-mediated photodegradation of ADR is an oxidative process resulting in the cleavage of the anthraquinone moiety. 3-Methoxysalicylic acid was identified as one of the resulting fragments. It is possible that some of the large fractions of the ADR metabolites that are non-fluorescent are the result of an in vivo oxidation of ADR and that 3-methoxysalicylic acid may play a role in the different biological activities of ADR.

The enhancement of riboflavin-mediated photo-oxidation of doxorubicin by histidine and urocanic acid.

PURPOSE: Previously we have shown that doxorubicin (Adriamycin, ADR) can be inactivated by light-excited riboflavin. The inactivation of the drug results from its direct oxidation by the excited triplet riboflavin in a type I photosensitization reaction, and 3-methoxysalicyclic acid is an ADR breakdown product. In the present study, we investigated the enhancement of this process by histidine and some other imidazole analogs. METHODS: ADR solutions containing various concentrations of riboflavin and other agents were exposed to 365 nm light for various time periods and then the absorbance spectrum of ADR was measured by a double beam spectrophotometer. These measurement were used to calculate the half-time of the ADR degradation process. The degraded ADR solutions were analyzed by HPLC. RESULTS: The rate of bleaching of ADR by light-excited riboflavin was enhanced in the presence of histidine in a concentration-dependent manner. This enhancement was more pronounced at higher riboflavin concentrations. Histidine also enhanced the riboflavin-mediated photobleaching of N,N-dimethyl-4-nitrosoaniline (RNO), a compound known to be resistant to oxidation by singlet oxygen but sensitive to oxidation by the trans-annular peroxide of histidine. RNO was found to block the histidine enhancement of the riboflavin-mediated photobleaching of ADR in a competitive manner. Among the imidazole analogs of histidine tested, urocanic acid was found to be the most efficient enhancer of the riboflavin-mediated photobleaching of ADR. Superoxide anion radicals which retard the oxidation of ADR were quenched by urocanic acid but not by histidine. It was shown that the oxidation of ADR by the trans-annular peroxide of histidine resulted in the formation of 3-methoxysalicylic acid. CONCLUSIONS: In contrast to singlet oxygen, the trans-annular peroxide, formed by the interaction of histidine and the singlet oxygen produced by photoexcited riboflavin, is an efficient oxidizer of ADR. The enhancement of the riboflavin-mediated photobleaching of ADR by histidine analogs depends on the rate of their conversion to a trans-annular peroxide and on the efficiency of these products in oxidizing ADR. However, for some analogs of histidine, as shown for urocanic acid, other mechanisms could also be involved. The presence of urocanic acid in the skin suggests that significant degradation of ADR could occur in the presence of biologically relevant concentrations of riboflavin if patients treated with ADR are exposed to sunlight. The finding that histidine also enhanced the degradation of ADR to 3-methoxysalicylic acid, suggests that the process of ADR oxidation by the trans-annular peroxides is similar to the direct oxidation of ADR by excited triplet riboflavin.

Pharmacokinetics and cerebrospinal fluid penetration of phenylacetate and phenylbutyrate in the nonhuman primate.

INTRODUCTION: Phenylbutyrate (PB) and its metabolite phenylacetate (PA) demonstrate anticancer activity in vitro through promotion of cell differentiation, induction of apoptosis through the p21 pathway, inhibition of histone deacetylase, and in the case of PB, direct cytotoxicity. We studied the pharmacokinetics, metabolism, and cerebrospinal fluid (CSF) penetration of PA and PB after intravenous (i.v.) administration in the nonhuman primate. METHODS: Three animals received 85 mg/kg PA and 130 mg/kg PB as a 30-min infusion. Blood and CSF samples were obtained at 15, 30, 35, 45, 60 or 75 min, and at 1.5, 2.5, 3.5, 5.5, 6.5, 8.5, 10.5 and 24.5 h after the start of the infusion. Plasma was separated immediately, and plasma and CSF were frozen until HPLC analysis was performed. RESULTS: After i.v. PA administration, the plasma area under the concentration-time curve (AUC) of PA (median +/- SD) was 82 +/- 16 mg/ml.min, the CSF AUC was 24 +/- 7 mg/ml.min, clearance (Cl) was 1 +/- 0.3 ml/min per kg, and the AUCCSF:AUCplasma ratio was 28 +/- 19%. After i.v. PB administration, the plasma PB AUC was 19 +/- 3 mg/ml.min, the CSF PB AUC was 8 +/- 11 mg/ml.min, the PB Cl was 7 +/- 1 ml/min per kg, and the AUCCSF:AUCplasma ratio was 41 +/- 47%. The PA plasma AUC after i.v. PB administration was 50 +/- 9 mg/ml.min, the CSF AUC was 31 +/- 24 mg/ml.min, and the AUCCSF:AUCplasma ratio was 53 +/- 46%. CONCLUSIONS: These data indicate that PA and PB penetrate well into the CSF after i.v. administration. There may be an advantage to administration of PB over PA, since the administration of PB results in significant exposure to both active compounds. Clinical trials to evaluate the activity of PA and PB in pediatric central nervous system tumors are in progress.

Plasma and cerebrospinal fluid pharmacokinetics of gemcitabine after intravenous administration in nonhuman primates.

PURPOSE: Gemcitabine (dFdC) is a difluorine-substituted deoxycytidine analogue that has demonstrated antitumor activity against both leukemias and solid tumors. Pharmacokinetic studies of gemcitabine have been performed in both adults and children but to date there have been no detailed studies of its penetration into cerebrospinal fluid (CSF). The current study was performed in nonhuman primates to determine the plasma and CSF pharmacokinetics of gemcitabine and its inactive metabolite, difluorodeoxyuridine (dFdU) following i.v. administration. METHODS: Gemcitabine, 200 mg/kg, was administered i.v. over 45 min to four nonhuman primates. Serial plasma and CSF samples were obtained prior to, during, and after completion of the infusion for determination of gemcitabine and dFdU concentrations. Gemcitabine and dFdU concentrations were measured using high-performance liquid chromatography (HPLC) and modeled with model-dependent and model-independent methods. RESULTS: Plasma elimination was rapid with a mean t1/2 of 8 +/- 4 min (mean +/- SD) for gemcitabine and 83 +/- 8 min for dFdU. Gemcitabine total body clearance (ClTB) was 177 +/- 40 ml/min per kg and the Vdss was 5.5 +/- 1.0 l/kg. The maximum concentrations (Cmax) and areas under the time concentration curves (AUC) for gemcitabine and dFdU in plasma were 194 +/- 64 microM and 63.8 +/- 14.6 microM.h, and 783 +/- 99 microM and 1725 +/- 186 microM.h, respectively. The peak CSF concentrations of gemcitabine and dFdU were 2.5 +/- 1.4 microM and 32 +/- 41 microM, respectively. The mean CSF:plasma ratio was 6.7% for gemcitabine and 23.8% for dFdU. CONCLUSIONS: There is only modest penetration of gemcitabine into the CSF after i.v. administration. The relatively low CSF exposure to gemcitabine after i.v. administration suggests that systemic administration of this agent is not optimal for the treatment of overt leptomeningeal disease. However, the clinical spectrum of antitumor activity and lack of neurotoxicity after systemic administration of gemcitabine make this agent an excellent candidate for further studies to assess the safety and feasibility of intrathecal administration.

[Membranous lesions and histochemical changes in cardiac muscle cells during hypoxia in white rats]. / Membranska ostecenja i histohemijske promene u misicnih celija srca belog pacova u hipoksiji.

The authors of this paper have explored the effects of intermittent hypoxia on the cell membrane and histochemical changes in the muscle cardiac tissue of the white rat. The animals have been exposed to the experimental conditions characteristic of 7.000 m of height above sea level and divided in three groups. The first one consisted of animals sacrificed immediately after the final exposition (first experimental group), in the second one there were animals sacrificed 24 hours after (the second experimental group), and the third group made animals sacrificed 7 days after the final exposition (the third experimental group). The hypoxial stress elicited the vacuolation in the cardiac muscle fibers of the subendocardial layer of miocard which persisted, and did not reduce its intensity and extensity in all the three groups of animals, while in fuxinorrhagia the intensity and extensity falls to the half of the animals sacrificed 24 hours after the experiment, and completely disappeared in those sacrificed 7 days after the final exposure. Glycogen as well as the activity of succinat-dehydrogenase were preserved in all the three experimental groups of animals. It could be concluded that hypoxia elicites ischemical changes in the sense of vacuolation of muscle tissue which does not disappear or its disappearance is slower than is the case with fuxinorrhagia which leaves a clear evidence, too, that the permeability of cytoplasmatic membrane affected by hypoxia was disturbed.

Meropenem pharmacokinetics in children and adolescents receiving hemodialysis.

The emergence of multi-drug-resistant bacteria is of great concern to the care of pediatric end-stage renal disease (ESRD) patients who receive either hemodialysis or peritoneal dialysis via a catheter. Infections with gram-negative organisms, especially Pseudomonas aeruginosa, are difficult to eradicate and often necessitate catheter removal. Meropenem, a broad-spectrum antibiotic of the carbapenem class of beta-lactams, is effective against most gram-positive and gram-negative bacteria and has enhanced activity against P. aeruginosa. We studied the pharmacokinetics of meropenem during and between hemodialysis treatments in seven pediatric patients. Meropenem was given as a single dose of 20 mg/kg (maximum 500 mg) before and after two separate hemodialysis treatments. Meropenem administration was tolerated without any adverse effects. Hemodialysis effectively cleared meropenem in a manner that correlated with percent urea reduction. Median drug half-life was 7.3 h off dialysis (range 4.9-11.7 h). The dose of 20 mg/kg was not sufficient to produce an acceptable interdialytic pharmacodynamic profile of 70% duration with a meropenem concentration >4 microg/ml, the MIC90 of meropenem for P. aeruginosa. Dosing simulations revealed that a daily dose of 25 mg/kg or an alternate day dose of 40 mg/kg would result in an acceptable pharmacodynamic profile. Both simulated doses achieved acceptable peak concentrations.