Tadalafil for the Treatment of Pulmonary Arterial Hypertension A Double-Blind 52-Week Uncontrolled Extension Study

ObjectivesThe aim of this study was to evaluate the long-term safety and durability of efficacy of tadalafil for pulmonary arterial hypertension.BackgroundTadalafil is an oral phosphodiesterase-5 inhibitor approved for PAH treatment. In the multicenter, placebo-controlled, randomized, 16-week PHIRST (Pulmonary Arterial Hypertension and Response to Tadalafil) study, tadalafil 40 mg improved exercise capacity and delayed clinical worsening.MethodsEligible patients from PHIRST received once-daily tadalafil 20 mg (T20 mg) or 40 mg (T40 mg) (n = 357) in the double-blind, 52-week, uncontrolled extension study (PHIRST-2); 293 patients completed PHIRST-2. Durability of efficacy was explored using the 6-min walk distance (6MWD) test. Clinical worsening and changes in World Health Organization functional class were evaluated.ResultsThe safety profile of tadalafil in PHIRST-2 was similar to that in PHIRST, with typical phosphodiesterase-5 inhibitor adverse events. The 6MWDs achieved in PHIRST for the subset of patients receiving T20 mg and T40 mg in both PHIRST and PHIRST-2 (406 ± 67 m [n = 52] and 413 ± 81 m [n = 59] at PHIRST-2 enrollment, respectively) were maintained at PHIRST-2 completion (415 ± 80 m [n = 51] and 410 ± 78 m [n = 59], respectively). Numerically fewer patients who were on T40 mg in PHIRST and PHIRST-2 experienced World Health Organization functional class deterioration (6% [n = 5]) compared with those randomized to T20 mg (9% [n = 7]) across both studies. Post hoc analyses showed that background bosentan use and higher 6MWD at PHIRST baseline were associated with fewer clinical worsening events.ConclusionsLong-term treatment with tadalafil was well tolerated in patients with pulmonary arterial hypertension. In patients receiving either T20 mg or T40 mg, the improvements in 6MWD demonstrated in the 16-week PHIRST study appeared sustained for up to 52 additional weeks of treatment in PHIRST-2. (Pulmonary Arterial Hypertension and Response to Tadalafil Study; NCT00549302

Theoretical and statistical solutions to problems in physical mass spectrometry

The advent of ambient ionization mass spectrometry in the past decade has revolutionized the way direct analysis is performed. DESI mass spectrometry was the first of these techniques to be introduced, in 2004. Since that time an explosion in the number of ambient ionization techniques has occurred, a testament to the utility of performing analysis with mass spectrometry in open and native environments. The first part of this thesis develops a basic hydrodynamic theory of DESI via the methods of diffuse-interface capturing multiphase fluid dynamics. Results from these simulations confirm that a momentum-transfer event on a wetted surface is sufficient to replicate known progeny droplet properties. This is true even without incorporating the influence of electrostatics. The second part of this thesis develops a multivariate statistical method for unsupervised analysis of DESI in the imaging mode. This work is motivated by the need for a simple visualization method for morphological and chemical variation on a sample surface, as well as enabling a non-expert end-user to rapidly identify the state of an interrogated region of sample without a priori knowledge of the sample or complex, systematic analysis of full mass spectra. An approach based on the development of a uniform coordinate system for a given tissue type and disease state is developed via principal component analysis. It is shown that this method gives excellent agreement with false-color ion images of known biomarkers and histological stains. The final section of this thesis concerns the statistical and quantum mechanical treatment of serine clustering in the gas phase. These clusters are produced by a variety of atmospheric ionization methods, including sublimation/APCI, ESI, ESSI and SSI. They have been implicated in one possible mechanism leading to the origin of homochirality, as certain clusters exhibit remarkable chiral selectivity. A “structural landscape” is developed over a range of relevant cluster sizes, enantiomeric compositions, and ionizing charge states. Structures discovered via an approach based on basin-hopping molecular dynamics are used for further DFT-based optimization and analysis. It is shown that the behavior and stability of these systems is due to major structural rearrangements as a function of size and charge. The experimentally observed chiral selectivity may be understood in part by the unique network of hydrogen bonds facilitated by the serine hydroxyl side chain

Efficacy and safety of tadalafil in a Western European population of men with erectile dysfunction

OBJECTIVE: To evaluate, in a randomized, double-blind, placebo-controlled, multicentre trial, the safety and efficacy of on-demand tadalafil (an oral phosphodiesterase type-5 inhibitor approved in many countries for treating erectile dysfunction, ED) in a Western European population of men with mild-to-severe ED. PATIENTS AND METHODS: Patients were randomized according to baseline severity of ED in a ratio of 3 : 1 to receive either tadalafil 20 mg or placebo for 12 weeks. Primary efficacy endpoints were mean changes from baseline to endpoint (12 weeks) in the erectile function (EF) domain of the International Index of Erectile Function (IIEF) and percentages of 'Yes' responses to Sexual Encounter Profile (SEP) diary Question 2 ('Were you able to insert your penis into your partner's vagina?') and Question 3 ('Did your erection last long enough for you to have successful intercourse?'). Secondary endpoints included mean changes from baseline to endpoint in IIEF Intercourse Satisfaction and Overall Satisfaction domains, selected questions of the IIEF, and the percentage of 'Yes' responses to Global Assessment Questions (GAQ) at the last visit. Other analyses included the percentage of patients in each treatment group at endpoint with IIEF EF domain scores in the normal range (>26), the frequency of intercourse attempts and mean per-patient intercourse success rate at various times after dosing. RESULTS: The mean age of the patients was 53 years and 80% had a history of ED of > or = 1 year. The mean baseline EF domain score was 13.5, with 40.5% of patients in the severe category. Tadalafil improved mean EF domain scores by 11.1, vs 0.4 for placebo (P 2%) with tadalafil than placebo were headache, dyspepsia, flushing, back pain, pain in limb and myalgia. These adverse events were mostly mild to moderate. CONCLUSIONS: Tadalafil improved erectile function and was well tolerated when taken by men from Western Europe with mild-to-severe ED

Psychosocial outcomes and drug attributes affecting treatment choice in men receiving sildenafil citrate and tadalafil for the treatment of erectile dysfunction: Results of a multicenter, randomized, open-label, crossover study

Introduction. Although sildenafil citrate (sildenafil) and tadalafil are efficacious and well-tolerated treatments for erectile dysfunction (ED), preference studies have shown that patients may favor one medication over the other. Aim. To determine whether psychosocial outcomes differed when men with ED received tadalafil compared with sildenafil. Main Outcome Measures. Measures included a treatment preference question, Psychological and Interpersonal Relationship Scales (PAIRS), and Drug Attribute Questionnaire. Methods. Randomized, open-label, crossover study. After a 4-week baseline, men with ED (N = 367; mean age = 54 years; naive to type 5 phosphodiesterase inhibitor therapy) were randomized: tadalafil for 12 weeks then sildenafil for 12 weeks or vice versa (8-week dose optimization/4-week assessment phases). During dose optimization, patients started with 10 mg tadalafil, or 25 or 50 mg sildenafil and could titrate to their optimal dose (10 or 20 mg tadalafil; 25, 50, or 100 mg sildenafil). Medications were taken as needed. Patients completing both 12-week periods chose which medication to continue during an 8-week extension. Results. Of 291 men completing both treatment periods, 71% (N = 206) chose tadalafil and 29% (N = 85) chose sildenafil (P < 0.001) for the 8-week extension. When taking tadalafil compared with sildenafil men had higher mean endpoint scores on PAIRS Sexual Self-Confidence (tadalafil = 2.91 vs. sildenafil = 2.75; P < 0.001) and Spontaneity (tadalafil = 3.32 vs. sildenafil = 3.17; P < 0.001) Domains and a lower mean endpoint score on Time Concerns Domain (tadalafil = 2.2 vs. sildenafil = 2.59; P < 0.001). The two most frequently chosen drug attributes to explain treatment preference were ability to get an erection long after taking the medication and firmness of erections. Tadalafil and sildenafil were well tolerated with 12 (3.3%) patients discontinuing for an adverse event. Conclusions. As measured with PAIRS, men with ED had higher sexual self-confidence and spontaneity and less time concerns related to sexual encounters when treated with tadalafil compared with sildenafil. These psychosocial outcomes may help explain why more men (71%) preferred tadalafil for the treatment of ED in this clinical trial

Tadalafil monotherapy and as add-on to background bosentan in patients with pulmonary arterial hypertension

Background: Tadalafil 40 mg orally once daily, was shown to be well-tolerated and efficacious for pulmonary arterial hypertension in a 16-week, double-blind, placebo (PBO)-controlled trial. Inclusion criteria included the option for background bosentan. Analyses of tadalafil in treatment-naive patients and as add-on to bosentan were pre-specified. Objectives were to provide safety and efficacy data for both groups. Methods: Groups analyzed included: treatment-naive + PBO; treatment-naive + tadalafil; background bosentan + PBO; and background bosentan + tadalafil. Patients randomized to tadalafil or PBO (N = 405) were analyzed by bosentan use (yes = 216, no = 189). Treatment differences in 6-minute walk distance (6MWD, PBO-adjusted), functional class (FC), clinical worsening (CW) and adverse events were assessed. Hazard ratios (HRs) with 95% confidence intervals (CIs) are presented for FC and CW. Results: At Week 16, PBO-adjusted 6MWD increases were 44 m (CI: 20 to 69 m; n = 37) for tadalafil 40 mg in treatment-naive patients and 23 m (CI: -2 to 48 m; n = 42) for tadalafil 40 mg add-on to bosentan. The 6MWD for treatment-naive and background bosentan PBO patients decreased by 3 m and increased by 19 m, respectively, at Week 16 compared with baseline. Two (5%) treatment-naive patients had CW with tadalafil 40 mg vs 8 (22%) with PBO (HR = 3.3, CI: 1.1 to 10.0). Two (5%) background bosentan patients had CW with tadalafil 40 mg add-on vs 5 (11%) for PBO add-on (HR = 1.9, CI: 0.4 to 10.2). Adverse events for tadalafil monotherapy and as add-on were similar. Conclusion: Tadalafil 40 mg was well-tolerated and provided clinical benefit in patients as monotherapy. It was also well-tolerated when added to background bosentan, but data are insufficient to conclude additional benefit. © 2011 International Society for Heart and Lung Transplantation. All rights reserved