Relative to healthy subjects, patients with pulmonary arterial hypertension often present with decreased respiratory muscle strength, resulting in decreased maximum inspiratory pressure. Little is known about the impact of reduced respiratory muscle strength on the ability to achieve the peak inspiratory pressures needed for effective drug delivery when using portable dry powder inhalers (≥1.0 kPa). The objective of this study was to assess the impact of inhaler resistance and patient instruction on the inspiratory flow profiles of pulmonary arterial hypertension patients when using breath-actuated dry powder inhalers. The inspiratory flow profiles of 35 patients with pulmonary arterial hypertension were measured with variants of the RS01 dry powder inhaler. Profiles were determined with a custom inspiratory flow profile recorder. Results showed that going from the low resistance RS01 dry powder inhaler to the high resistance AOS® dry powder inhaler led to increases in mean peak inspiratory pressures for pulmonary arterial hypertension subjects from 3.7 kPa to 6.5 kPa. Instructions that ask pulmonary arterial hypertension subjects to inhale with maximal effort until their lungs are full led to a mean peak inspiratory pressures of 6.0 kPa versus 2.1 kPa when the same subjects are asked to inhale comfortably. Significant decreases in mean peak inspiratory pressures are also observed with decreases in lung function, with a mean peak inspiratory pressures of 7.2 kPa for subjects with FEV1 > 60% predicted, versus 3.3 kPa for those subjects with FEV1 < 50% predicted. In conclusion, despite having reduced respiratory muscle strength, subjects with pulmonary arterial hypertension can effectively use a breath-actuated dry powder inhaler. The probability of achieving effective dose delivery may be increased by using dry powder inhalers with increased device resistance, particularly when subjects do not follow the prescribed instructions and inhale comfortably.
Candida bloodstream infection (CBSI) accounted for 50% of bloodstream infections in our medical intensive care unit (MICU) in 2004. Our objective was to evaluate a risk-based fluconazole prophylaxis program. CBSI incidence, patient demographics, and unit metrics were retrospectively reviewed for 2004. Starting on January 2005, patients meeting pre-specified criteria were placed on risk-based fluconazole prophylaxis and their outcomes, adverse events, and unit metrics were prospectively collected. The inclusion criteria were based on a clinical prediction rule and included an MICU stay greater than 72 h, broad-spectrum antibiotics, and central venous catheter, along with at least two of the following: mechanical ventilation for at least 48 h, any type of dialysis, parenteral nutrition, pancreatitis, systemic steroids, or other systemic immunosuppressive agents. For 2004, the unit had nine CBSI, corresponding to a rate of 3.4 CBSI/1,000 line-days. Four cases were caused by C. albicans, four by C. glabrata, and one by C. tropicalis. The mean +/- standard deviation (SD) APACHE II score for these patients was 25 +/- 9. In 2005, a total of 36 patients (2.6% of all unit admissions) received prophylaxis and the unit had two CBSI, corresponding to a rate of 0.79 CBSI/1,000 line-days. One patient had C. albicans and the other had C. tropicalis. The mean +/- SD APACHE II score for these patients was 21 +/- 8. The mean +/- SD duration of fluconazole prophylaxis was 8 +/- 6 days. Fluconazole was discontinued in two patients due to non-severe adverse events (acute eosinophilia, elevated transaminases). The attributable cost of CBSI in the unit in 2004 was $63,000 per episode. The total cost for the 36 courses of fluconazole was $6,000. When comparing the 2004 CBSI patients and the 2005 prophylaxis patients, we found similar acuity, demographics, and risk factors, with no differences in MICU or hospital mortality or length of stay. Risk-based fluconazole prophylaxis in an MICU with a high incidence of CBSI was safe and cost-effective when applied to a limited number of patients and produced a significant decrease in the incidence of this disease.
Background: RT234 (vardenafil inhalation powder) is being developed for pulmonary administration ''as needed'', to acutely improve exercise tolerance and symptoms in patients with pulmonary arterial hypertension (PAH). Methods: This single-center, open-label, randomized study in 32 healthy adult subjects evaluated single and multiple inhalation doses of RT234, for safety, tolerability, and pharmacokinetics (PKs). Results: RT234 was generally safe and well tolerated at single doses of 0.2-2.4 mg and after repeated dose administration of up to 2.4 mg q4h for four doses daily for 9 days. The most common treatment-emergent adverse events were mild-to-moderate headaches. There was no evidence of pulmonary irritation or inflammation. Vardenafil was absorbed very rapidly after inhalation as RT234, independent of dose level and number of doses administered. The t max occurred at the time that the first blood sample following completion of dosing. After C max was achieved, plasma vardenafil concentrations declined rapidly in an exponential fashion that appeared to be parallel among dose levels. Vardenafil plasma concentrations and PK parameters increased in a dose-proportional manner. Vardenafil systemic exposure was notably greater after oral administration of 20 mg vardenafil tablets (Levitra Ò ) than after administration of any dose level of RT234. During repeated dose administration of RT234, C max was attained rapidly following each dose and in a pattern similar to that observed after single-dose administration. Minor accumulation, characterized by very low mean morning predose vardenafil concentrations (<0.5 ng/mL), occurred after q4h dosing of up to four doses per day for 9 days. Taken together, these findings show that no clinically important vardenafil accumulation is likely after repeated-dose administration of RT234. Mean vardenafil t 1/2 values were comparable after single-and repeated-dose administration. Conclusions: Comparative plasma vardenafil bioavailability data from this study provide scientific justification for reliance on Food and Drug Administration findings for Levitra tablets. These findings support further evaluation of RT234 for as-needed treatment of patients with PAH. The Clinical Trials Registration number is ACTRN12618001077257.
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