Evaluation of non-invasive techniques to assess vasoconstriction in healthy volunteers using methoxamine as a probe drug

Non-invasive methods for assessment of the vascular effects of antimigraine drugs were evaluated with respect to their utility, variability and sensitivity in a double-blind, placebo-controlled, three-period crossover study in six healthy volunteers using an intravenous vasoconstrictor, methoxamine, as a probe drug. Changes in the internal diameter of the brachial and radial arteries were measured using ultrasound which had low between-day and within-day coefficients of variation. Peak systolic velocity (PSV), time-averaged velocity (TAV), total flow, resistance (RI) and pulsatility indices (PI) were measured by Doppler from one arterial wave form. Whilst PSV and TAV increased with methoxamine, because of bradycardia, changes in PI and RI were difficult to interpret. An automatic oscillametric cuff, a mercury-in-silastic strain gauge method and the "Finapres", finger arterial blood pressure monitor were used to follow changes in systolic blood pressure (SBP). The strain gauge technique underestimated arm SBP compared to the oscillometric method but clearly showed drug-related increases whilst the Finapres did not reflect changes in blood pressure detected by the other methods.     

External scintigraphy in monitoring the behavior of pharmaceutical formulations in vivo I: technique for acquiring high-resolution images of tablets

A new method for monitoring tablet disintegration in vivo was developed. In this method, the tablets were labeled with a short-lived radionuclide, technetium 99m, and monitored by a gamma camera. Several innovations were introduced with this method. First, computer reconstruction algorithms were used to enhance the scintigraphic images of the disintegrating tablet in vivo. Second, the use of a four-pinhole collimator to acquire multiple views of the tablet resulted in high count rates and reduced acquisition times of the scintigraphic images. Third, the magnification of the scintigraphic images achieved by pinhole collimation led to significant improvement in resolution. Fourth, the radioinuclide was incorporated into the granulation so that the whole mass of the tablet was uniformly labeled with high levels of activity. This technique allowed the continuous monitoring of the disintegration process of tablets in vivo in experimental animals. Multiple pinhole collimation and the labeling process permitted the acquisition of quality scintigraphic images of the labeled tablet every 30 sec. The resolution of the method was tested in vitro and in vivo.     

Comparative acute and combinative toxicity of aflatoxin B1 and T-2 toxin in animals and immortalized human cell lines

Aflatoxin B1 (AFB1) and T-2 toxin (T-2) are important food-borne mycotoxins that have been implicated in human health and as potential biochemical weapons threats. In this study the acute and combinative toxicity of AFB1 and T-2 were tested in F-344 rats, mosquitofish (Gambusia affinis), immortalized human hepatoma cells (HepG2) and human bronchial epithelial cells (BEAS-2B). Preliminary experiments were conducted in order to assess the acute toxicity and to obtain LD50, LC50 and IC50 values for individual toxins in each model, respectively. This was followed by testing combinations of AFB1 and T-2 to obtain LD50, LC50 and IC50 values for the combination in each model. All models demonstrated a significant dose response in the observed parameters to treatment. The potency of the mixture was gauged through the determination of the interaction index metric. The results of this study demonstrate that these two toxins interacted to produce alterations in the toxic responses generally classifiable as additive; however, a synergistic interaction was noted in the case of BEAS-2B. It can be gathered that this combination may pose a significant threat to public health and further research needs to be completed addressing alterations in metabolism and detoxification that may influence the toxic manifestations in combination.     

The thyroid endocrine disruptor perchlorate affects reproduction, growth, and survival of mosquitofish

The perchlorate anion--an oxidizer found in rockets, missiles, some ammunition, flares, airbags, and fireworks--occurs as a contaminant in ground and surface water in many parts of the United States. Its toxic effects include inhibition of thyroid hormone synthesis. To investigate its chronic toxicity, mosquitofish (Gambusia holbrooki) adults and fry were exposed to aqueous sodium perchlorate at 1, 10, and 100mg/L, and growth and reproductive performance (fecundity, eggs/embryos mass, and gonadosomatic index [GSI]) were determined. Five-day acute toxicity tests were also performed. Perchlorate had a stimulatory effect on fecundity, GSI, and egg/embryo mass, at least for some treatments. The LC50 of sodium perchlorate was 404 mg/L. Growth was enhanced at 1mg/L but inhibited at 10mg/L. These results suggest that, at environmentally relevant concentrations, perchlorate does not induce acutely toxic effects but may have mild stimulatory or hormetic effects on fitness parameters in this species.     

Long term effects of cardiac resynchronization therapy in non-ambulatory NYHA IV heart failure patients

Background: We aimed at evaluating the long‐term effects of cardiac resynchronization therapy (CRT) in nonambulatory New York Heart Association (NYHA) IV heart failure patients (NAIVHFP). Methods: Eighteen patients, 15 men and three women, eight with ischemic and 10 with nonischemic cardiomyopathy, who underwent biventricular pacemaker implantation while they were in nonambulatory NYHA IV class, were studied. Patients’ age was 58 ± 9 years and left ventricular ejection fraction (LVEF) 18 ± 3 %. Follow‐up data were obtained through review of follow‐up visits notes, stored echocardiographic studies, device interrogation data, and death certificates. Results: After a mean duration of 1223 ± 846 days, 11 patients were alive, including five patients who underwent heart transplantation (OCT) and seven dead. Three of 11 patients who received a CRT‐defibrillator, experienced at least one appropriate discharge, but eventually they either died or received an OCT during follow‐up. Sustained improvements in NYHA class (Z = 2.4, P = 0.015) and 6‐minute walk distance (0 vs 212 ± 95 m, P ? 0.001) were documented after a median duration of 855 days postimplantation. Cumulative proportion of death or OCT at 18 months—when full follow‐up data were available—was 18%, which compared favorably with historical controls. Full echocardiographic and clinical follow‐up data at 12‐months postimplantation were available for 10 patients, documenting a significant reduction in end‐systolic volume (248 ± 82 vs 269 ± 97 mL, P = 0.039). Conclusions: CRT can be safely applied in this subset of extreme severity heart failure patients, achieving encouraging survival rates and reverse remodeling effects. These observations can form an evidence‐based rationale for including NAIVHFP in randomized CRT trials. (PACE 2011; 34:1553–1560)     

Effects of ZnO nanomaterials on Xenopus laevis growth and development

The objectives of this study were to quantify uptake and developmental effects of zinc oxide nanomaterials (nano-ZnO) on Xenopus laevis throughout the metomormosis process. To accomplish this, X. laevis were exposed to aqueous suspensions of 40-100 nm nano-ZnO beginning in-ovo and proceeding through metamorphosis. Nanomaterials were dispersed via sonication methods into reconstituted moderately hard water test solutions. A flow-through system was utilized to decrease the likelihood of depletion in ZnO concentration. Exposure to 2 mg/L nano-ZnO significantly increased mortality incidence to 40% and negatively affected metamorphosis of X. laevis. Tadpoles exposed to 2 mg/L nano-ZnO developed slower as indicated by tadpoles with an average stage of 56 at the conclusion of the study which was significantly lower than the control tadpole stages. No tadpoles exposed to 2 mg/L of nano-ZnO completed metamorphosis by the conclusion of the study. Tadpoles exposed to 0.125 mg/L nano-ZnO experienced faster development along with larger body measurements indicating that low dose exposure to nano-ZnO can stimulate growth and metamorphosis of X. laevis.