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The primary objective of the study was to demonstrate a dose response for 6MWD for 1, 5, and 20 mg TID oral sildenafil. The hypothesis was that there is a dose that is significantly less effective than sildenafil 20 mg TID.

Secondary objectives included assessment of the safety and tolerability of low-dose sildenafil during the 12 weeks of treatment in patients with PAH and evaluation of the effects of sildenafil on perceived PAH-progression biomarkers (B-type natriuretic peptide [BNP]/pro-BNP levels and cheap non prescription viagra tricuspid annular plane systolic excursion [TAPSE]).

The study protocol and amendments were reviewed and approved by the Institutional Review Board and/or Independent Ethics Committee at each participating center (Additional file 1); informed consent was obtained from all

patients

PAH, defined as mPAP ?25 mmHg and pulmonary artery wedge pressure ?15 mmHg at rest (or a left ventricular end diastolic pressure 3 and 6 h, and >6 and 8 h postdose), week 1 (immediately after BNP/pro-BNP sampling), weeks 4 and 8 (immediately before 6MWD), and week 12 (between 15 min and 3 h and between >3 and 6 h postdose, immediately before 6MWD, between >6 and 8 h postdose, and during RHC assessment).

Adverse events (AEs) were monitored throughout the study.

Laboratory testing and physical examinations were performed at screening, baseline, and weeks 4, 8, and 12. The relationship between

6MWD

Therefore, after receipt of 20 mg TID, sildenafil concentrations were anticipated to be > EC 90 for the entire 8-hour dosing interval; for 5 mg TID, above EC 50 for the entire 8-hour dosing interval but.

The study was conducted at 34 centers in Europe, Asia, Russia, the United States, and Brazil. Of the planned 219 patients, 169 were screened, 130 were randomized, and 129 were treated (1 patient [sildenafil 1 mg] did not meet entry criteria). Treated patients were mostly female and mostly Asian; baseline cardiac index was significantly higher in the sildenafil 20-mg group versus the 1- and 5-mg groups ( P = 0.0328 and 0.0030, respectively; Table 1). Two patients died during the double-blind phase (pneumonia [1 mg TID; death was the reason for discontinuation] and acute exacerbation of idiopathic pulmonary fibrosis [5 mg TID; patient was enrolled in error and received 4 days of treatment]), neither of which was considered to be treatment related; no deaths were reported in the open-label phase (Fig. Legend: TID = 3 times daily; SIL = sildenafil.*Right ventricular failure. † Drug hypersensitivity ( n = 1) and rash ( n = 1) Sildenafil concentration.

Overall, 129 patients provided 1068 sildenafil concentrations.

A 1-compartment pharmacokinetic model adequately described the sparse data.

From this model, the estimated apparent clearance was 43.9 (95% CI, 39.3–48.6) L/h, the apparent volume of distribution was 458 (95% CI, 393–523) L, and the absorption rate constant was 2.16 (95% CI, 1.48–2.84) h ?1 .

Coadministration of weak or moderate CYP3A4 inhibitors ( n = 12 patients/110 samples) reduced CL/F by 40.4% (95% CI, 19.2%–61.6%).

The model supported dose proportionality of exposures. The limit of quantification of the pharmacokinetic assay was 1 ng/mL; 134 samples were below the limit of quantification (BLQ).

The majority of BLQ samples (approximately 75%) were measured at the 1-mg TID sildenafil dose, but had little effect on the population pharmacokinetic parameter estimates.

Figure 3 represents the sildenafil concentration data.

Because a small accumulation existed between the first (at baseline visit) and subsequent doses, only concentrations after the second and subsequent doses are shown (for data including baseline visit, see Additional file 3). Concentrations after concomitant administration of CYP3A4 inhibitors were adjusted for the estimated effect.

Visual inspection of observed concentration distribution across each dose

indicated

The shaded area shows the concentration range between 3 ng/mL and 20 ng/mL, which are the average sildenafil plasma concentrations required to achieve 50% effect (EC 50 ) and 90% effect (EC90) on PVRI, respectively.

At week 12, compared with baseline, the increase in 6MWD was of a magnitude consistent with estimates of clinical significance [7, 8] in 5- and 20-mg TID groups and smaller although statistically significant in the 1-mg TID group. Among dose groups, the mean change in 6MWD from baseline was statistically significantly different only for the sildenafil 20- versus 1-mg group (Fig. Legend: Mean (SE) overall change from double-blind baseline in 6MWD in double-blind (week 12) and open-label (week 24) phases of the study ( a ), and change from baseline to week 12 in 6MWD by baseline 6MWD ( b ). All patients received sildenafil 20 mg TID in the open-label phase of the study (weeks 13–24). 6MWD = 6-minute walk distance; TID = 3 times daily. Analysis of change from baseline in 6MWD at week 12 showed a statistically significant ( P = 0.011) difference between sildenafil 1 mg and 20 mg, but not sildenafil 5 mg and 20 mg (Table 2). The results were confirmed by an analysis of variance; the mean treatment difference between sildenafil 20 mg and 1 mg was 23 (3–43) m and between 20 mg and 5 mg was –3 (–23 to 17) m ( P = 0.02 and 0.76, respectively). Mean change from baseline in 6MWD assessed by race.

Legend: Mean (SE) overall change from double-blind baseline in 6MWD in the double-blind (week 12) phase of the study ( a ) and change from baseline to week 12 in 6MWD by baseline 6MWD ( b ) assessed by race (Asian vs non-Asian). 6MWD = 6-minute walk distance; TID = 3 times daily.

During the open-label period (weeks 12 to 24), in which all patients received sildenafil 20 mg TID, patients who received sildenafil 1 mg TID during the double-blind phase (weeks 0 to 12) had a larger increase in 6MWD than patients who received sildenafil 5 mg TID (mean change, 31 vs 6 m, respectively); the magnitude of change was similar between patients who received sildenafil 1 mg and 20 mg TID in the double-blind phase (mean change, 31 vs 26 m; Fig.

Compared with baseline, there was a trend toward reduction in pulmonary vascular resistance (PVR) at week 12 in all groups; the mean reduction was statistically significantly different from 0 only in the 20-mg TID group (ie, 95% CIs do not include 0). There were no statistically significant differences among treatment groups for change in PVR (Table 3).

Changes at week 12 in the additional hemodynamic parameters were generally small and variable between groups. Most patients in each treatment group remained in the same functional class from baseline to week 12; the same was true through week 24 (Table 4). Odds ratios (ORs) showed no significant differences for functional class between sildenafil 20 mg and the 5-mg (OR, 1.08 [95% CI, 0.35–3.32]; P = 0.897) or 1-mg (OR, 1.55 [95% CI, 0.50–7.78]; P = 0.448) dose at week 12. Similarly, there were no differences between sildenafil 20 mg and the 5-mg (OR, 1.31 [95% CI, 0.42–4.05]; P = 0.639) or 1-mg (OR, 0.93 [95% CI, 0.30–2.91]; P = 0.899) dose at week 24. Four patients (sildenafil 1 mg and 5 mg, n = 1 each; sildenafil 20 mg, n = 2) reported events defined as clinical worsening (initiation of ETRA therapy [sildenafil 5-mg patient] and hospitalization due to PAH [all others]).

Decreases from baseline in BNP occurred in all groups at week 12; the response was dose related (Fig. The sildenafil 20-mg group was statistically significantly ( P = 0.005) different from the 1-mg but not the 5-mg group ( P = 0.496).

At week 24, changes from baseline for sildenafil 20 mg were not significantly different among groups. Changes from baseline in BNP ( a ) and pro-BNP ( b ) during double-blind (week 12) and open-label (week 24) phases of the study.

All patients received sildenafil 20 mg TID in the open-label phase of the study (weeks 13–24). BNP = B-type natriuretic peptide; TID = 3 times daily. Pro-BNP decreases occurred in all groups at week 12 and were dose related (Fig. Differences were significant when sildenafil 20 mg was compared with 1 but not 5 mg ( P = 0.009 and 0.414, respectively). At week 24, changes from baseline were not significantly different among groups. There was a trend toward a mean increase in TAPSE in all groups, but there were no statistically significant differences in mean TAPSE index among groups (mean [95% CI] increases of 0.14 [0.02–0.26], 0.17 [0.06–0.28], and 0.04 [–0.08 to 0.16] cm for sildenafil 1, 5, and 20 mg TID, respectively, at week 12 [LOCF] and 0.21 [0.06–0.37], 0.40 [0.19–0.61], and 0.15 [–0.09 to 0.39] at week 24 [LOCF]).

Borg dyspnea scores trended toward reduction in all groups (mean [95% CI] changes of –0.28 [–0.76 to 0.20], –0.89 [–1.35 to –0.43], and –0.43 [–0.94 to 0.08] for sildenafil 1, 5, and 20 mg TID, respectively, at week 12 [LOCF] and –1.10 [–1.75 to –0.46], –1.07 [–1.55 to –0.58], and –0.28 [–0.75 to 0.20] at week 24 [LOCF]), with no significant differences between sildenafil 1- and 5-mg TID groups compared with sildenafil 20 mg TID.

Baseline 6MWD was weakly correlated with BNP ( r = –0.19; P = 0.0393) and pro-BNP ( r = –0.22; P = 0.0145). The change in 6MWD at week 12 was also weakly correlated with changes at week 12 in BNP ( r = –0.18; P = 0.0499) and pro-BNP ( r = –0.22; P = 0.0193). The overall number of AEs and numbers of patients reporting AEs were similar between treatment groups in the double-blind and open-label portions of the study; treatment-related AEs (number of AEs and patients reporting AEs) increased with increasing dose (Table 5). Sildenafil was generally well tolerated, with most AEs being mild or moderate in severity. Dyspnea was the most common AE reported in both phases of the study; headache was the most common treatment-related AE (Table 5). No patients discontinued as a result of abnormal laboratory test results, and there was no evidence of dose-related increase in laboratory test abnormalities with increasing sildenafil dose. Sildenafil is one of the most widely used drugs in the treatment of PAH.

The dose of 20 mg TID was approved based on the results of the SUPER-1 study which demonstrated that Sildenafil 20 mg TID appeared to reach the plateau of the dose-response curve for

6MWD

These results raise the question as to whether a lower dosage could have a similar effect on 6MWD compared cheap non prescription viagra to the approved dose.

We found a significant increase from baseline in 6MWD at 12 weeks with all sildenafil doses; however, only at higher doses (5 and 20 mg TID) was the improvement of a magnitude considered to be clinically relevant ( 40 m) [7, 8].

In the absence of a placebo control arm, the small non-clinically significant increase in 6MWD in the 1 mg TID group in the double blind phase should be interpreted with caution as being a treatment effect as it is possible that this improvement could be seen as a “placebo effect” due to participation in an RCT. Among dose groups, the change in 6MWD from baseline was significant only with sildenafil 20 mg TID compared with sildenafil 1 mg TID. A Williams trend test confirmed that sildenafil 1 mg TID was the only dose statistically inferior to the approved dose of 20 mg TID. Generally, patients had greater improvements in hemodynamic parameters with sildenafil 20 mg TID versus 1 mg TID; however, these improvements were not statistically significantly different.

Significant differences were observed between sildenafil 1 mg TID and 20 mg TID for neurohormones at week 12.

There were no statistically significant differences between sildenafil 20 and 5 mg TID in 6MWD, hemodynamics, or changes in functional class. Results from pharmacokinetic modeling showed that the observed exposure with sildenafil 1 mg TID was slightly below EC 50 for maximal PVR change, the observed exposure with sildenafil 5 mg TID was above EC 50 and approaching EC 90 , and the observed exposure with sildenafil 20 mg TID was mainly above EC 90 .

The pharmacokinetic data justify the different clinical responses between sildenafil 1 and 20 mg TID and explain the small difference observed between sildenafil 20 and 5 mg TID because most of the patients on 5 mg TID had a sildenafil plasma level between 3 and 20 ng/mL.

A significant correlation among mean sildenafil plasma concentration and 6MWD could be observed, although the relationship between average sildenafil plasma concentration and PVR appeared to show only a shallow trend. Whether this was due to the missing placebo group or was a consequence of the smaller sample size and larger variability on PVR cannot be concluded but should be interpreted on the basis of the complex interplay between pharmacokinetics and pharmacodynamics. The vasodilator effect is the result of the interplay of several factors: tissue penetration of the drug, density and activity of PDE5 enzyme, and severity of vascular lesions.

Smaller improvement in 6MWD at week 12 with sildenafil 20 mg TID was observed in this study (38 m) compared with SUPER-1 (45 m); however, patient populations differed.

Both studies had similar baseline 6MWD, but a cheap non prescription viagra greater proportion of patients in this study had baseline functional class II status compared with those in SUPER-1 (57% vs 39%, respectively); therefore, patients in this study had lower-than-expected 6MWD at baseline. Patients in our study were also younger (45 vs 49 years), with a shorter time since diagnosis (median, 0.17 vs 0.85 years) and an increased percentage of Asian patients (67% vs 7%).

Geographic variation in 6MWD has been described for patients with PAH and was reported to be cheap non prescription viagra independent of anthropometric factors [9].

Although few non-Asian patients enrolled in this study, 6MWD did not appear to differ between groups, with the exception of sildenafil 1 mg TID (Fig. Interestingly, results from the open-label phase suggest the possibility of further improvement in 6MWD after the first 3 months of therapy with sildenafil 20 mg TID. The mean increase in 6MWD from baseline at the end of the double-blind phase (41 m) was maintained in the sildenafil 5-mg group uptitrated to sildenafil 20 mg TID in the extension study (50 m), yet larger increases were observed from the end of the double-blind study to the end of the open-label study in the sildenafil 1- and 20-mg groups (from 14–47 m and from 38–70 m, respectively).

Thus, sildenafil 20 mg TID maintains treatment effects regardless of prior low-dose treatment.

However, 6MWD did not increase to the same degree in patients previously treated with lower doses as in patients who continuously received 20 mg TID, suggesting that a longer duration of an adequate dose may confer a larger improvement in 6MWD.

Interestingly, the total improvement observed after 24 weeks in the 20-mg group (70 m) was larger than in the SUPER-1 study at 12 weeks (48 m) or 1 year (51 m) for all sildenafil doses combined. It may be possible that in a population of young and mainly incident cases, as in our study, further improvements in 6MWD may be observed with continued sildenafil treatment.

Decreases for BNP and pro-BNP versus baseline were significantly higher with sildenafil 20 mg versus 1 mg TID at week 12, paralleling findings with 6MWD. BNP levels similarly paralleled improvements (BNP levels decreased) or worsening (BNP levels increased) in pulmonary hemodynamics and functional parameters, including 6MWD, in patients with PAH in a previous study [10]. Elevated plasma BNP levels are associated with increased mortality in patients with PAH, and a decrease in BNP levels after therapy is associated with improved survival [11, 12]. Pro-BNP levels have recently been shown to identify poor outcome in patients with PAH [13, 14].

Longer-term follow-up of patients from our study is not ongoing, which prevents any correlation with mortality. The main limitation of the present study is its premature termination. The study was designed to assess the relative efficacy of sildenafil 20 mg TID and lower doses and powered for the primary endpoint but the sample size was not reached because of premature termination [4, 6]. Looking at the results, this does not seem a major issue, as the difference in the primary and secondary endpoints between 1 mgTID and 20 mg TID is statistically significant and coherent.

Regarding the comparison between the 5-mg and 20-mg groups, the differences were small enough that, even with the completion of the study, similar results may have been observed.

A

noninferiority

Sildenafil 5 mg TID appeared to have similar clinical and hemodynamic effects as 20 mg TID. Interestingly, 6MWD results from the open-label phase of the study suggest that patients on the approved sildenafil dose (20 mg TID) continued to show clinical improvement after the first 12 weeks of treatment. Hence, the question remains whether doses lower than 20 mg TID have therapeutic

value

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VIAGRA BLUNTS EFFECTS OF STRESS ON THE HUMAN HEART.

Sildenafil citrate (Viagra), a drug used to treat erectile dysfunction (ED) in millions of men, reduces the stimulatory effects of hormonal stress on the heart by half, according to results of a new study by researchers at Johns Hopkins. While sildenafil is

more

excess

David

“Sildenafil effectively puts a ‘brake’ on chemical stimulation of the heart,” says Kass.

The researchers’ findings, which appear in the journal Circulation online Oct.

24, are believed to be the first confirmation in humans that sildenafil has a direct effect on the heart.

Previous research by Kass and his team showed that sildenafil had such effects in mice, blocking the short-term effects of hormonal stress in the heart. Related studies by the group also showed that sildenafil prevents and reverses the long-term effects in the heart from chronic high blood pressure. Moreover, Kass adds, the latest Hopkins results confirm that sildenafil helps control heart function only when the heart is under duress, but has little impact under normal conditions.

Separate research from Kass and his team published earlier this year in the journal Nature Medicine showed that, in mice, sildenafil could reverse the negative effects on heart muscle weakened by heart failure and enlargement, a condition called hypertrophy. “But we had no firm evidence as to whether or how this therapy might work in the human heart.

Our latest research provides firm evidence this drug does indeed have an important impact on the heart.” Thirty-five healthy men and women, with an average age of 30 and no previous signs of coronary artery disease, participated in the six-month study. Within a three-hour timeframe, each participant received two separate injections of dobutamine (5 micrograms per kilogram for five minutes), a synthetic, adrenaline-like chemical that increases heart rate and pumping strength.

Between injections, study participants were randomly assigned to a group that was treated with sildenafil (100 milligrams taken orally) or to a group given a sugar pill placebo. All participants were then given the second dobutamine injection to see what effects sildenafil or placebo had on the heart.

Measurements of heart function were made before and after each injection. This included blood pressure readings, electrocardiograms and echocardiograms, as well as blood samples to confirm relatively equal levels of sildenafil and other enzymes.

Results showed that each dobutamine injection stimulated heart function, increasing heart rate and the force of each heartbeat used to pump blood throughout the body.

“This stimulation is similar to the way the nervous system normally increases heart function when triggered by emotional or exercise stress, or in diseases such as heart failure,” adds Kass.