PDE5 inhibitors: considerations for preference and long-term adherence.

INTRODUCTION: Erectile dysfunction (ED) is a highly prevalent condition affecting nearly one in five men worldwide. The advent of phosphodiesterase type 5 inhibitors (PDE5i) has revolutionised the ED treatment landscape and provided effective, minimally invasive therapies to restore male sexual function. MATERIALS AND METHODS: A pubmed search was performed of all English language articles from 1996 to present reviewing PDE5i, including pharmacokinetics, efficacy profiles and comparisons, where available. RESULTS: Currently available PDE5i in the United States include sildenafil, vardenafil, tadalafil and avanafil, each of which has unique side effect, pharmacokinetic and outcome profiles. Sildenafil is associated with increased rate of visual changes, vardenafil with QT prolongation and tadalafil with lower back pain. Avanafil and vardenafil orodispersible tablet rapidly achieve peak plasma concentration, which results in faster onset of action, whereas tadalafil exhibits the longest half-life. First time response to PDE5i is approximately 60-70%, with no significant differences in efficacy noted among therapies. The literature does not clearly demonstrate a preference for one drug. High-treatment success rates (89%) were reported when patients were prescribed all available PDE5i. Daily dosing with tadalafil is associated with improved erectile function (EF) over time. Finally, novel modes of patient-provider interaction, including internet-based education, communication and prescribing, may also improve long-term adherence. CONCLUSIONS: PDE5i represent first line therapy for ED with excellent overall efficacy and satisfactory side effect profiles. Enhanced communciation, coupled with increased knowledge of drug characteristics, comparative treatment regimens and optimal prescribing patterns, offer compelling tools to improve long-term treatment success.

WAXS studies of the structural diversity of hemoglobin in solution.

Specific ligation states of hemoglobin are, when crystallized, capable of taking on multiple quaternary structures. The relationship between these structures, captured in crystal lattices, and hemoglobin structure in solution remains uncertain. Wide-angle X-ray solution scattering (WAXS) is a sensitive probe of protein structure in solution that can distinguish among similar structures and has the potential to contribute to these issues. We used WAXS to assess the relationships among the structures of human and bovine hemoglobins in different liganded forms in solution. WAXS data readily distinguished among the various forms of hemoglobins. WAXS patterns confirm some of the relationships among hemoglobin structures that have been defined through crystallography and NMR and extend others. For instance, methemoglobin A in solution is, as expected, nearly indistinguishable from HbCO A. Interestingly, for bovine hemoglobin, the differences between deoxy-Hb, methemoglobin and HbCO are smaller than the corresponding differences in human hemoglobin. WAXS data were also used to assess the spatial extent of structural fluctuations of various hemoglobins in solution. Dynamics has been implicated in allosteric control of hemoglobin, and increased dynamics has been associated with lowered oxygen affinity. Consistent with that notion, WAXS patterns indicate that deoxy-Hb A exhibits substantially larger structural fluctuations than HbCO A. Comparisons between the observed WAXS patterns and those predicted on the basis of atomic coordinate sets suggest that the structures of Hb in different liganded forms exhibit clear differences from known crystal structures.

Cardiopulmonary bypass through peripheral cannulation with percutaneous decompression of the left heart in a model of severe myocardial failure.

Prolonged closed chest cardiopulmonary bypass for severe total biventricular myocardial dysfunction requires invasive decompression of the left heart. The authors have developed an elongated helical coil that is permanently attached to the distal 8-10 cm of a flow directed Swan-Ganz catheter. When properly positioned, the helical coil kept the pulmonary artery (PA) and the tricuspid valves open, and allowed closed chest retrograde decompression of the left heart. The authors have evaluated the merits of closed chest cardiopulmonary bypass with decompression of the left heart in this manner in four sheep subjected to 30 min of warm global myocardial ischemia, along with induced ventricular fibrillation. All sheep developed severe global myocardial failure, with no left ventricular (LV) ejection. The authors have shown that pulmonary blood flow during cardiopulmonary bypass was reversed from the left heart, across the lungs, and into the right heart. The wedge pressure never exceeded 12 mmHg at any time, attesting to good decompression during periods of total ventricular failure, during partial recovery with some LV ejection, and after good recovery of LV function, followed by weaning from bypass after 44, 67, and 78 h of such support. One sheep could not be weaned from bypass, even after 5 days of CPBP. Lung function in all sheep remained unimpaired throughout, and there was no wound bleeding. The authors conclude that in this model of total myocardial failure, and while on closed chest CPBP, at all times and with all degrees of myocardial dysfunction, excellent LV decompression with the helical coil catheter was attained.

Respiratory impedances and acinar gas transfer in a canine model for emphysema.

We examined how the changes in the acini caused by emphysema affected gas transfer out of the acinus (Taci) and lung and chest wall mechanical properties. Measurements were taken from five dogs before and 3 mo after induction of severe bilateral emphysema by exposure to papain aerosol (170-350 mg/dose) for 4 consecutive wk. With the dogs anesthetized, paralyzed, and mechanically ventilated at 0.2 Hz and 20 ml/kg, we measured Taci by the rate of washout of 133Xe from an area of the lung with occluded blood flow. Measurements were repeated at positive end-expiratory pressures (PEEP) of 10, 5, 15, 0, and 20 cmH2O. We also measured dynamic elastances and resistances of the lungs (EL and RL, respectively) and chest wall at the different PEEP and during sinusoidal forcing in the normal range of breathing frequency and tidal volume. After final measurements, tissue sections from five randomly selected areas of the lung each showed indications of emphysema. Taci during emphysema was similar to that in control dogs. EL decreased by approximately 50% during emphysema (P < 0.05) but did not change its dependence on frequency or tidal volume. RL did not change (P > 0.05) at the lowest frequency studied (0.2 Hz), but in some dogs it increased compared with control at the higher frequencies. Chest wall properties were not changed by emphysema (P > 0.05). We suggest that although large changes in acinar structure and EL occur during uncomplicated bilateral emphysema, secondary complications must be present to cause several of the characteristic dysfunctions seen in patients with emphysema.

Intratracheal pulmonary ventilation (ITPV): control of positive end-expiratory pressure at the level of the carina through the use of a novel ITPV catheter design.

A new mode of pulmonary ventilation called intratracheal pulmonary ventilation (ITPV) was studied. Briefly, a continuous flow of air/oxygen is introduced through a small catheter, the tip of which is positioned at the carina, with a diffuser mounted at its distal end. A timed expiration valve, when closed, provides for inspiration; when open, it provides for expiration. The system as first described had a potential for significant back pressure at the level of the carina, which was more at rapid gas flows and with smaller endotracheal tubes. We have now mounted a venturi on the tip of the catheter (reverse thrust catheter [RTC]) that avoids back pressure, and which facilitates expiration. At respiratory rates from 10 to 120/min, the ITPV system with the RTC maintained end-expiratory pressure at the level of the carina at, or near 0 cm H2O. Compared to conventional mechanical ventilation, at identical respiratory rates, this system reduced tidal volume by one half at the lowest respiratory rates, and by as much as two thirds at the highest respiratory rates, with a proportional decrease in peak inspiratory pressure. ITPV has the smallest minute volume ventilation of any conventional or nonconventional mode of pulmonary ventilation.

An evaluation of clusters in the glaucomatous visual field.

We used a statistical cluster analysis to analyze patterns of loss in 76 visual fields with typical glaucomatous defects to identify natural groupings of test locations in the visual field. Eleven clusters in the Octopus Program G1 (Interzeag, Inc., Northboro, Massachusetts) visual field were thus defined. In a separate population of 70 early glaucomatous and 70 age-matched normal visual fields, the local mean defects within these clusters and the global mean defect were calculated to assess their relative abilities to discriminate between the two groups. The 11 clustered mean defects collectively had a sensitivity of 90% and a specificity of 93%; the global mean defect had a sensitivity of 81% and a specificity of 91%. Additionally, we examined the long-term fluctuation clusters of test locations compared to the long-term fluctuation of individual test locations. Four hundred ten visual fields of 93 clinically stable eyes of 67 patients with glaucoma, as well as 210 visual fields of 105 eyes of 105 normal subjects were studied. In the stable glaucoma group, mean fluctuation of clustered test locations was 3.5 dB2, and mean fluctuation of individual test locations was 7.0 dB2. In the normal group, the respective values were 0.6 dB2 and 1.8 dB2. Cluster analysis was effective in detecting localized loss and in dampening long-term fluctuation. We studied the use of clusters in distinguishing normal from glaucomatous as well as stable from deteriorating visual fields.

How to ventilate lungs as small as 12.5% of normal: the new technique of intratracheal pulmonary ventilation.

We wished to determine in a laboratory animal model how much residual lung was needed to sustain total gas exchange. In a series of young, healthy lambs weighing approximately 10 kg that were sedated and paralyzed, we progressively excluded from gas exchange all the left lung (a total of 43%), plus the right lower and cardiac lobes (81%), plus the right middle lobe (87.5%). In some studies, the respective lobes were surgically removed; in others, the bronchi and the pulmonary arteries to the respective lobes were ligated. We provided pulmonary ventilation using the pressure control mode (Servo 900 C) at a tidal volume of 20 mL/kg multiplied by the fraction of the remaining lungs, a respiratory rate up to 120/min, a peak inspiratory pressure of 12-15 cm H2O, and a positive end-expiratory pressure of 3 cm H2O. Those lambs with at least both the right upper lobe (RUL) and right middle lobe remaining (19% of total lungs) were weaned to room air on mechanical ventilation within 48 h. Ventilating RUL (12.5% of remaining lung) with the same ventilator required a substantially higher tidal volume and peak inspiratory pressure to result in adequate alveolar ventilation but led to respiratory failure and death within 8 h. We then applied a newly developed system of intratracheal pulmonary ventilation to ventilate the RUL (12.5% of remaining lung) alone. A continuous flow of humidified mixture of air and oxygen was directly passed into the trachea at the level of the carina through a diffuser at a tidal volume of 2.5 mL/kg. A single valve controlled expiration and respiratory rate.(ABSTRACT TRUNCATED AT 250 WORDS)

The use of agarose gels for quantitative determination of fluid saturations in porous media.

The use of agarose gel reference standards for quantifying petrophysical properties in porous media is described. The specific interest is to determine the values of fluid saturations and porosity in oil bearing rocks; the MRI methodology for estimating these properties is discussed. It is shown that the relaxation times of the gel reference standard and the relaxation times of the fluid contained in the porous media affect the estimation process. The determination of porosity and fluid saturations can be greatly simplified if the relaxation times of the reference standard and the relaxation times of the fluid are closely matched. Gel concentration of paramagnetic impurities in the form of copper ions is used to control the longitudinal relaxation properties. The relaxation properties of agarose gels, as a function of agarose and paramagnetic impurity concentrations, have been measured at 2.0 T. The data are well fitted by a simple polynomial in agarose concentration and paramagnetic impurity concentration. Finally, a one-dimensional imaging example of use of agarose gels as reference phantoms is discussed.

Long-term cardiopulmonary bypass by peripheral cannulation in a model of total heart failure. The decompression of the left heart through a percutaneous helical spring positioned within the lumen of the tricuspid and pulmonary artery valves.

We performed long-term closed-chest cardiopulmonary bypass in an animal model of total heart failure (induced ventricular fibrillation). The extracorporeal system included a venous reservoir, a roller pump, a membrane lung, and a blood pulsator system. We cannulated the right external jugular vein for venous drainage and the right subclavian artery for arterial return. To decompress the left heart we passed by percutaneous cannulation a special helical spring mounted on a Swan-Ganz catheter (Baxter Edwards Divisions, Irvine, Calif.) and positioned it to rest within the pulmonary artery and tricuspid valves, which rendered them partly incompetent. After induced ventricular fibrillation, blood flow was raised to keep the central venous pressure at baseline values. The lungs were ventilated with 5% carbon dioxide in room air. During bypass, mean pulmonary artery pressure was 10.0 +/- 1.7 mm Hg, mean wedge pressure 11.9 +/- 1.8 mm Hg, and mean blood pressure 95.2 +/- 5.6 mm Hg. After 2 days (four animals) and 3 days (two animals) the hearts were defibrillated. There was immediate ejection from both sides of the heart. All sheep were weaned from bypass within 29 +/- 11 minutes and their lungs were ventilated with room air within 42 +/- 34 minutes. At autopsy hearts and lungs grossly appeared normal. We conclude that the percutaneous helical spring resting within right heart valves provided excellent decompression throughout the study, with full recovery of heart and lung function on defibrillation.