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In addition, improvement in exercise ability and delay in clinical worsening was demonstrated in adult patients who were already stabilized on background epoprostenol therapy 14 ; and.

c) the EMA product information specifically indicates sildenafil for the treatment of adult patients with pulmonary arterial hypertension classified as WHO functional class II and III, to improve exercise capacity 15 .

Efficacy has been shown in primary pulmonary hypertension and pulmonary hypertension associated with connective tissue disease 15 .

The EMA label also indicates sildenafil for the treatment of pediatric patients aged 1 year to 17 years old with pulmonary arterial hypertension 15 .

Efficacy in terms of improvement of exercise capacity or pulmonary hemodynamics has been shown in primary pulmonary hypertension and pulmonary hypertension associated with congenital heart disease 15 . Erectile Dysfunction NYHA Functional Class II-III Pulmonary arterial hypertension Pulmonary Arterial Hypertension (PAH) Contraindications & Blackbox Warnings. Learn about our commercial Contraindications & Blackbox Warnings data.

In vitro studies have shown that sildenafil is selective for phosphodiesterase-5 (PDE5) 11,12,13,14,15,16,8,9 . Its effect is more potent on PDE5 than on other known phosphodiesterases 11,12,13,14,15,16,8,9 .

In particular, there is a 10-times selectivity over PDE6 which is involved in the phototransduction pathway in the retina 11,12,13,14,15,16,8,9 . There is an 80-times selectivity over PDE1, and over 700-times over PDE 2, 3, 4, 7, 8, 9, 10 and 11 11,12,13,14,15,16,8,9 . And finally, sildenafil has greater than 4,000-times selectivity for PDE5 over PDE3, the cAMP-specific phosphodiesterase isoform involved in the control of cardiac contractility 11,12,13,14,15,16,8,9 . In eight double-blind, placebo-controlled crossover studies of patients with either organic or psychogenic erectile dysfunction, sexual stimulation resulted in improved erections, as assessed by an objective measurement of hardness and duration of erections (via the use of RigiScan®), after sildenafil administration compared with placebo 11,12,13,14,15,16,8,9 . Most studies assessed the efficacy of sildenafil approximately 60 minutes post-dose 11,12,13,14,15,16,8,9 . The erectile response, as assessed by RigiScan®, generally increased with increasing sildenafil dose and plasma concentration 11,12,13,14,15,16,8,9 .

The time course of effect was examined in one study, showing an effect for up to 4 hours but the response was diminished compared to 2 hours 11,12,13,14,15,16,8,9 . Sildenafil causes mild and transient decreases in systemic blood pressure which, in the majority of cases, do not translate into clinical effects 11,12,13,14,15,16,8,9 .

After chronic dosing of 80 mg, three times a day to patients with systemic hypertension the mean change from baseline in systolic and diastolic blood pressure was a decrease of 9.4 mmHg and 9.1 mmHg respectively 11,12,13,14,15,16,8,9 . After chronic dosing of 80 mg, three times a day to patients with pulmonary arterial hypertension lesser effects in blood pressure reduction were observed (a reduction in both systolic and diastolic pressure of 2 mmHg) 11,12,13,14,15,16,8,9 .

At the recommended dose of 20 mg three times a day no reductions in systolic or diastolic pressure were seen 11,12,13,14,15,16,8,9 .

Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG 11,12,13,14,15,16,8,9 . After chronic dosing of 80 mg three times a day to patients with pulmonary arterial hypertension no clinically relevant effects on the ECG were reported either 11,12,13,14,15,16,8,9 .

In a study of the hemodynamic effects of a single oral 100 mg dose of sildenafil in 14 patients with severe coronary artery disease (CAD) (> 70 % stenosis of at least one coronary artery), the mean resting systolic and diastolic blood pressures decreased by 7 % and 6 % respectively compared to baseline 11,12,13,14,15,16,8,9 . Mean pulmonary systolic blood pressure decreased by 9% 11,12,13,14,15,16,8,9 . Sildenafil showed no effect on cardiac output and did not impair blood flow through the stenosed coronary arteries 11,12,13,14,15,16,8,9 .

Mild and transient differences in color discrimination (blue/green) were detected in some subjects using the Farnsworth-Munsell 100 hue test at 1 hour following a 100 mg dose, with no effects evident after 2 hours post-dose 11,12,13,14,15,16,8,9 . The postulated mechanism for this change in color discrimination is related to inhibition of PDE6, which is involved in the phototransduction cascade of the retina 11,12,13,14,15,16,8,9 .

Sildenafil has no effect on visual acuity or contrast sensitivity. In a small size placebo-controlled study of patients with documented early age-related macular degeneration (n = 9), sildenafil (single dose, 100 mg) demonstrated no significant changes in visual tests conducted (which included visual acuity, Amsler grid, color discrimination simulated traffic light, and the Humphrey perimeter and photostress test) 11,12,13,14,15,16,8,9 . Sildenafil is an oral therapy for erectile dysfunction 5,12,13,16,8 . with sexual stimulation, it restores impaired erectile function by increasing blood flow to the penis 5,12,13,16,8 .

The physiological mechanism responsible for the erection of the penis involves the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation 5,12,13,16,8 . Nitric oxide then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood 5,12,13,16,8 .

Sildenafil is a potent and selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5) in the corpus cavernosum, where PDE5 is responsible for degradation of cGMP 5,12,13,16,8 .

Sildenafil has a peripheral site of action on erections 5,12,13,16,8 .

Sildenafil has no direct

relaxant

Moreover, apart from the presence of PDE5 in the corpus cavernosum of the penis, PDE5 is also present in the pulmonary vasculature 4,11,14,15,9 .

Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation 4,11,14,15,9 .

In patients with pulmonary arterial hypertension, this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation 4,11,14,15,9 .

Sildenafil is known to be quickly absorbed, with maximum plasma concentrations being observed within 30-120 minutes (with a median of 60 minutes) of oral administration in a fasting patient 11,12,13,14,15,16,8,9 . Moreover, the mean absolute bioavailability observed for sildenafil is about 41% (from a range of 25-63%) 11,12,13,14,15,16,8,9 .

In particular, after oral three times a day dosing of sildenafil, the AUC and Cmax increase in proportion with dose over the recommended dosage range of 25-100 mg 11,12,13,14,15,16,8,9 .

When used in pulmonary arterial hypertension patients, however, the oral bioavailability of sildenafil after a dosing regimen of 80 mg three times a day, was on average 43% greater than compared to the lower doses 11,12,13,14,15,16,8,9 . Finally, if sildenafil is administered orally with food, the rate of absorption is observed to be decreased with a mean delay in Tmax of about 60 minutes and a mean decrease in Cmax of approximately 29% 11,12,13,14,15,16,8,9 . Regardless, the extent of absorption is not observed to be significantly affected as the recorded AUC decreased by only about 11 % 11,12,13,14,15,16,8,9 . The mean steady-state volume of distribution documented for sildenafil is approximately 105 L - a value which suggests the medication undergoes distribution into the tissues 11,12,13,14,15,16,8,9 .

It is generally observed that sildenafil and its main circulating N-desmethyl metabolite are both estimated to be about 96% bound to plasma proteins 11,12,13,14,15,16,8,9 .

Nevertheless, it has been determined that protein binding for sildenafil is independent of total drug concentrations 11,12,13,14,15,16,8,9 . The metabolism of sildenafil is facilitated primarily by the CYP3A4 hepatic microsomal isoenzymes and to a minor extent, via the CYP2C9 hepatic isoenzymes 6,11,12,13,14,15,16,8,9 .

The predominant circulating metabolite results from the N-demethylation of sildenafil 6,11,12,13,14,15,16,8,9 . This particular resultant metabolite possesses a phosphodiesterase selectivity that is similar to the parent sildenafil molecule and a corresponding in vitro potency for PDE5 that is approximately 50% that of the parent drug 6,11,12,13,14,15,16,8,9 .

Moreover, plasma concentrations of the metabolite are about 40% of those recorded for sildenafil, a percentage that accounts for about 20% of sildenafil’s

pharmacologic

The total body clearance documented for sildenafil is 41 L/h 11,12,13,14,15,16,8,9 . In single-dose volunteer studies of doses up to 800 mg, adverse reactions were similar to those seen at lower doses, but the incidence rates and severities were increased 11,12,13,14,15,16,8,9 . Doses of 200 mg did not result in increased efficacy but the incidence of adverse reaction (headache, flushing, dizziness, dyspepsia, nasal congestion, altered vision) was increased 11,12,13,14,15,16,8,9 . Due to the lack of data on the effect of sildenafil indicated for the treatment of pulmonary arterial hypertension (PAH) in pregnant women, sildenafil is not recommended for women of childbearing potential unless also using appropriate contraceptive measures 11,14,15,9 . The safety and efficacy of sildenafil indicated for treating PAH in a woman during labor and delivery have not been studied 11,14,15,9 .

Caution should ultimately be exercised when sildenafil is administered to nursing women as it is not known if sildenafil or its metabolites are excreted in human breast milk 11,14,15,9 . The safety and efficacy of sildenafil for the treatment of PAH in children below 1 year of age has not been established as no data is available 15 .

Clinical experience with the elderly population in the use of sildenafil for the treatment of PAH has been varied. Some reports suggest that there are no identified differences in responses between elderly and younger patients 11 while others have documented that clinical efficacy as measured by 6-minute walk distance could be less in elderly patients 9 . In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy 11 .

Conversely, when sildenafil was used to treat erectile dysfunction in healthy elderly volunteers (65 years or over), a reduced clearance of sildenafil was observed 12,8 . This reduction resulted in about 90% higher plasma concentrations of sildenafil and the active N-desmethyl metabolite compared to those seen in healthy younger volunteers (18-45 years) 12,8 .

Due to age-differences in plasma protein binding, the corresponding increase in free sildenafil plasma concentration was approximately 40% 12,8 .

Sildenafil was not carcinogenic when administered to rats for 24 months at a dose resulting in total systemic drug exposure (AUCs) viagra pills without prescription for unbound sildenafil and its major metabolite of 29- and 42- times, for male and female rats, respectively, the exposures observed in human males given the Maximum Recommended Human Dose (MRHD) of 100 mg 11,12,13,14,15,16,8,9 .

Sildenafil was not carcinogenic when administered to mice for 18-21 months at dosages up to the Maximum Tolerated Dose (MTD) of 10 mg/kg/day, approximately 0.6 times the MRHD on a mg/m2 basis 11,12,13,14,15,16,8,9 . Sildenafil viagra pills without prescription was negative in in vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human lymphocytes and in vivo mouse micronucleus assays to detect clastogenicity 11,12,13,14,15,16,8,9 .

There was no impairment of fertility in rats given sildenafil up to 60 mg/kg/day for 36 days to females and 102 days to males, a dose producing an AUC value of more than 25 times the human male AUC 11,12,13,14,15,16,8,9 .

Affected organisms Humans and other mammals Pathways Not Available Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" href="javascript:void(0);"> Lilly's Cialis bites into Viagra's market share.

Article Diabetes and psoriasis drugs help Lilly beat forecasts. News Pricing pressure weighs on revenue at drugmaker Eli Lilly. Bayer Autifony Therapeutics SpringWorks Therapeutics.

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No-limits access to our site with up-to-the minute news Personalised news and email alerts Online discussion forums and Q&A section RSS news feeds that you can add to your favourite reader, or website Daily news email alert, with the breaking news stories and news roundup. Sildenafil (Viagra®) Classification: Phosphodiesterase Inhibitor.

About: Sildenafil (Viagra®) Sildenafil is a medication that is taken before sexual activity and allows men with erectile dysfunction (ED) to achieve and maintain an erection. ED or impotence is a condition viagra pills without prescription in which a man is unable viagra for sale without prescription to achieve or maintain an erection long enough for sexual intercourse.

This can be a result of medical conditions such as high blood pressure, diabetes, prostate problems, and heart disease, or a side effect of the medications typically taken for these conditions. Personal lifestyle factors such as stress, alcohol and/or tobacco use can also play a contributing role.

During surgery or radiation to the pelvic area (including prostate, bladder, and rectal procedures), damage can occur to the nerves that supply the penis.

This can result in either temporary or permanent impotence.

Some surgeons perform "nerve-sparing" surgeries in an attempt to preserve erectile function.

Even in these cases, however, the nerves will suffer some injury, and it can take 18-24 months or longer for erectile function to return. These men should be treated aggressively with oral or injectable medications for ED in order to speed recovery of the nerves and to prevent muscle wasting in the penis.

It should be taken around 60 minutes before sex, but can be taken as much as four hours or as few as 30 minutes before sex. Your doctor will determine the dose that is best for you. Some men require dose adjustments to find the dose that works best for them.

Men who take sildenafil will not have an erection without sexual stimulation. This drug is not an aphrodisiac and does not affect libido or desire.

Having multiple intercourse sessions with one dose has not been studied.

You should not adjust your dose without talking to your provider first. Men who take nitrates, such as nitroglycerin, Nitro-Bid, Isordil, or Deponit should not take sildenafil. Men who take Cardura, Flomax, or Hytrin for urinary symptoms should not take sildenafil. This medication can affect how other medications work.

Be sure your provider and pharmacist know all the medication (prescription and over-the-counter) and supplements you take.

Store your medication in the original, labeled container at room temperature and in a dry location (unless otherwise directed by your healthcare provider or

pharmacist

Do not take a higher dose of sildenafil than your provider orders for you. Headache, facial flushing, stuffy or runny nose, and upset stomach can occur.

Less frequent side effects

include

Chest, arm or neck pain, or nausea during sexual activity.

Sudden loss of vision in one or both eyes, loss of hearing, ringing in the ears or dizziness. Remember, sildenafil does not protect against sexually transmitted diseases, nor does it prevent pregnancy. Effective birth control is recommended during cancer treatment. Even if you are not producing sperm, you could still be fertile and conceive. Give guidance, not just Viagra, to men with diabetes and related impotence. Diabetic men with erectile dysfunction might consider a prescription for a drug like Viagra to be a permanent cure for a temporary issue: Take a pill, problem solved. But the truth, a leading urologist says, is entirely different. “If a diabetic patient has erectile dysfunction, it’s not enough to provide Viagra [sildenafil] or Cialis [tadalafil] and then send him on his merry way,” J. Francois Eid, MD, a New York City urologist, said at the annual meeting of the American Association of Diabetes Educators.

“It’s important to let individuals know the drug has not cured the erectile dysfunction. If patients don’t take care of the diabetes, the erectile dysfunction progresses.” In an interview, Dr.

Eid shared several messages for medical professionals who treat men with diabetes and related erectile dysfunction: • Diabetes has “devastating” effects on the penis, and may even cause it to shrink.

• Long-term uncontrolled diabetes can make ED permanent. • While ED drugs often fail in men with diabetes, several other options exist; and penis implants may provide significant relief.

An estimated 50%-75% of men with diabetes experience from some degree of ED, which is thought to be three times more common in diabetic men than other men, according to Dr. “Diabetes has a devastating effect on the muscle tissue inside the penis,” he said.

“All the tiny little arteries that feed blood to the muscle get occluded. Little by little, the muscle inside the penis shrinks.” Indeed, some diabetics with ED complain that their penises have shrunk, he said. Diabetic damage doesn’t stop with these small vessels, he said. “You really have two parallel situations: You need blood flow that feeds the muscle of the penis, and you need an artery dedicated to bringing blood rapidly when a man becomes aroused and wants to be sexually active,” he said. They’ll say ‘I can get a partial erection, viagra pills without prescription but I can’t maintain it.’ ” What comes after an ED diagnosis in diabetic patients?

Eid will instantly refer these men to a cardiologist.

“If a patient has diabetes and is newly diagnosed, a significant portion of these men are going to develop coronary artery disease in the next 2-3 years,” he said.

“One of the things we do is recommend is that they see a cardiologist

and

Eid also urges these patients to treat their diabetes in order to avoid developing ED for life.

“They need to manage their diabetes and make sure they control it so the ED will not progress and will stabilize, as a result,” he said.

“If the diabetes is controlled after the patient is first diagnosed, then the erections will come back.

But if the patient has diabetes for many years, and suddenly decides it’s time to control it, they cannot prevent the damage that’s already been done.” As for treatments, patients with diabetes and related ED should begin with medications like sildenafil and tadalafil, he recommended. But research findings suggest that the drugs will fail in half of men with type 2 diabetes, he said. Other options include viagra pills without prescription penile self-injections, vacuum devices, and penile implants.

The injections “can work well and are painless, but men detest having to inject themselves before sexual activity,” Dr.

And he said men rarely have success using vacuum devices, which are available over the counter.

By contrast, penis implants can successfully treat erectile dysfunction in many cases, Dr. Men trigger erections by squeezing a pump that is implanted into the scrotum. Fluid then flows from an implanted reservoir into a cylinder implanted in the penis. Men are often pleased by penis implants because they can have sex spontaneously without having to plan for it ahead of time, as required by medications. Eid receives or has received research support/grants from American Medical Systems, Coloplast, Lilly ICOS, Bayer, Vivus, Pharmacia-Upjohn, and Pfizer. He is or was a consultant and on the speakers bureau for Coloplast, American Medical Systems, Lilly ICOS, Bayer and Pfizer. How Viagra could boost a widely used blood cancer treatment.

Hematopoietic stem cells can save lives in the treatment of blood cancer, but hurdles remain to effectively harvest them for transplantation. A research team at the University of California, Santa Cruz has evidence that Pfizer’s popular erectile dysfunction drug Viagra can facilitate the release of stem cells from the bone marrow into the bloodstream, which could ease collection.

Transplantation practitioners traditionally mobilize stem cells using standard granulocyte-colony stimulating factor (G-CSF)—namely, Amgen’s Neupogen (filgrastim).

The UC Santa Cruz team found that pairing Viagra with Sanofi’s stem cell mobilizer Mozobil (plerixafor) worked almost as well in mice, the team reported in the journal Stem Cell Reports. “Given that both drugs are FDA approved, they could be relatively quickly tested in human volunteers,” the study’s senior author, Camilla Forsberg, said in a statement. If successful, it could provide a new strategy for stem cell transplant preparation, she argued.

Even though G-CSF agent works in most donors, it needs to be given for several days before the stem cells can be collected.

It’s costly and can cause side effects such as fatigue, nausea and bone pain. The Forsberg lab previously showed that increasing the ability of blood vessel walls to allow molecules through—known as vascular permeability—could help hematopoietic stem cells escape from bone marrow and into the blood. So Forsberg and her team hypothesized that Viagra, which relaxes blood vessel walls, might promote stem cell mobilization.

After all, the drug was originally designed to address cardiovascular diseases and is sometimes used to treat pulmonary hypertension.

In mice, a single oral dose of Viagra and an injection of Mozobil induced about 2,500 more hematopoietic stem cells to enter the bloodstream within just two hours, representing a 7.5-fold increase compared to control mice.

In contrast, Viagra alone wasn’t effective, and Mozobil monotherapy only showed about a threefold increase.