Blue Sildenafil and Its Interaction with Food and Alcohol

The challenges involved in running trials with off-patent drugs is partly why ReDo exists. “I became involved because my son had osteosarcoma, and he didn’t respond to standard treatments,” says Pantziarka. “I found that there were people who were looking at non-cancer drugs which had some evidence of activity in cancer.” Sadly, Pantziarka was not able to find a treatment for his son, who died in 2011, but he ended up moving from a job in computer science to oncology research and now focuses on commercially neglected therapeutic areas, including repurposing. You can bypass the early stages of trials, so in theory the path should be clear to rapid adoption, should we have positive results “Our intention is to find treatments we can get to patients quickly and repurposing really fits the bill very well,” he explains. “You can bypass the early stages of trials, so in theory the path should be clear to rapid adoption, should we have positive results.” As part of the ReDo project, Pantziarka has built up a database of around 270 drugs with some potential to be repurposed as cancer therapies and this includes PDE-5 inhibitors. “Drugs like the PDE-5 inhibitors actually have a tremendous amount of existing evidence.

• The generic name "sildenafil" is less known than the brand name "Viagra."
• It can cause jaw pain or toothache as an uncommon side effect.
• The medication should be stored at temperatures between 15-30°C (59-86°F).
• It is not approved for use in combination with other ED treatments.
• The blue film coat may contain polyethylene glycol or titanium dioxide.
• It is essential to report any allergic reactions, such as hives or swelling.
• Patients with penile implants or prostheses should not use sildenafil.

Not just in vitro studies, but supporting data from extensive animal models, human data, case reports, and small clinical trials.” Pantziarka explains that PDE-5 inhibitors have an immunological effect in cancer (see Figure). “There is quite a wide range of evidence to show that actually these drugs can take the brakes off the immune response, so they help the anti-tumour immune response get into gear,” he says.

• The medication works best when the user is relaxed and not overly stressed.
• It can be affected by other medications that inhibit or induce CYP3A4.
• Can cause a stuffy nose or sinusitis due to its vasodilatory effects.
• The blue tablet is often round for standard doses and oval for higher ones.
• It is not a substitute for healthy lifestyle choices like exercise and diet.
• Patients with severe anemia or leukemia should use with medical guidance.
• The effects may be noticeable within 30 minutes for some individuals.

Figure 1: PDE-5 inhibitors and cancer One suggestion is to use PDE-5 inhibitors in cancer patients after surgery to try to reduce cancer reoccurrences[1] . “Because the PDE-5 inhibitors work on an immunological basis, and we think that the post-surgical reoccurrence is partly immune based, that is a really good fit,” says Pantziarka.

Does Viagra have side effects?

A phase I trial at the Ottawa Hospital Research Institute in Canada is trialling tadalafil use for five days before abdominal cancer surgery until ten days after, in combination with a protective influenza vaccine, to see if this impacts on cancer reoccurrence. PDE-5 inhibitors have really proven to be excellent drugs for repurposing in anti-cancer therapeutics PDE-5 inhibitors also seem to have a role in enhancing patients’ responses to existing chemotherapy drugs. There are the obvious vasodilating effects that may allow more of a drug to reach its tumour targets but there is also evidence that tumour cells over-express PDE-5 in breast, liver and lung cancers, so there may be other mechanisms at play. Paul Dent’s laboratory at Virginia Commonwealth University in the United States is dedicated to developmental cancer therapeutics and is involved in several collaborations to investigate the impact of PDE-5 inhibitors and cancer drugs. “PDE-5 inhibitors have really proven to be excellent drugs for repurposing in anti-cancer therapeutics,” says Dent.

How does sildenafil work (mechanism of action)?

“We were able to show that Viagra enhanced the lethality of breast cancer chemotherapy doxorubicin against prostate cancer cells[2] .” Dent’s group has also looked at combining PDE-5 inhibitors with the newer cancer-fighting kinase inhibitors. “We discovered that, for example, PDE-5 inhibitors can enhance the lethality of Bayer’s sorafenib (Nexavar) and regorafenib (Stivarga) in gastrointestinal tumours (including liver, pancreatic and bowel cancer)[3] .” “What we observed was that Viagra particularly — as that’s what we’ve tended to work with — was very good at enhancing the ability of these drugs to activate death receptor signalling. But it was also really good at inducing a toxic form of autophagy, so a couple of things were going on,” says Dent. Dent has also seen good results in the treatment of brain tumours. Getting cancer drugs into the brain is a problem, but PDE-5 inhibitors seem to help. A phase I trial at the Ottawa Hospital Research Institute in Canada is trialling tadalafil use for five days before abdominal cancer surgery until ten days after, in combination with a protective influenza vaccine, to see if this impacts on cancer reoccurrence. PDE-5 inhibitors have really proven to be excellent drugs for repurposing in anti-cancer therapeutics PDE-5 inhibitors also seem to have a role in enhancing patients’ responses to existing chemotherapy drugs. There are the obvious vasodilating effects that may allow more of a drug to reach its tumour targets but there is also evidence that tumour cells over-express PDE-5 in breast, liver and lung cancers, so there may be other mechanisms at play. Paul Dent’s laboratory at Virginia Commonwealth University in the United States is dedicated to developmental cancer therapeutics and is involved in several collaborations to investigate the impact of PDE-5 inhibitors and cancer drugs. “PDE-5 inhibitors have really proven to be excellent drugs for repurposing in anti-cancer therapeutics,” says Dent.

“We were able to show that Viagra enhanced the lethality of breast cancer chemotherapy doxorubicin against prostate cancer cells[2] .” Dent’s group has also looked at combining PDE-5 inhibitors with the newer cancer-fighting kinase inhibitors.

“We discovered that, for example, PDE-5 inhibitors can enhance the lethality of Bayer’s sorafenib (Nexavar) and regorafenib (Stivarga) in gastrointestinal tumours (including liver, pancreatic and bowel cancer)[3] .” “What we observed was that Viagra particularly — as that’s what we’ve tended to work with — was very good at enhancing the ability of these drugs to activate death receptor signalling. But it was also really good at inducing a toxic form of autophagy, so a couple of things were going on,” says Dent. Dent has also seen good results in the treatment of brain tumours. Getting cancer drugs into the brain is a problem, but PDE-5 inhibitors seem to help. “[PDE-5 inhibitors] are able to interfere with the pumps that are involved with the blood-brain barrier (BBB) and so you can also envisage using Viagra to try to further disrupt the BBB in patients with glioblastoma.” PDE-5 inhibitors also cause higher levels of nitric oxide and a greater free-radical load within cancer cells, which helps to kill them. Dent has started a phase II study on high-grade recurrent glioma using a combination of sorafenib, repurposed seizure medicine valproic acid, and sildenafil. “We have seen some quite nice six-month progression-free survival in some of these patients,” he says. Another important factor in PDE-5 inhibitors’ cancer fighting-properties is their ability to disrupt the effects of mutant K-RAS oncogenes. These cell signalling genes control cell proliferation, but when mutated lead to cancer, a mechanism involved in 90% of pancreatic cancers and 50% of bowel cancers.

MYTH #5: “This pill is only available through the GP”

Their role in dilating arteries and improving blood flow is already well known (see Panel), with sildenafil (Revatio; Pfizer) and tadalafil (Adcirca; Eli Lilly) approved for treating pulmonary arterial hypertension. “But newer lines of evidence are saying that they’re actually having a direct effect on the [heart] tissues,” says David Hutchings, honorary clinical lecturer in cardiovascular sciences at the University of Manchester, UK. Animal models show that PDE-5 inhibitors improve some abnormalities that occur in heart disease, which seem to be linked to the activation of PKG in cardiac cells and the vasculature — they improve contractile function in the heart[4] . But not all trials of PDE-5 inhibitors in cardiovascular disease have been successful. A large US trial — RELAX — looked at using PDE-5 inhibitors to treat heart failure with preserved ejection fraction or “diastolic HF”, which accounts for approximately half of heart failure cases and has a poor prognosis[5] .

Sildenafil: what you need to know

The trial showed no improvement in either contractile function or in the patient’s breathlessness or hospital admission rate. Hutchings admits the picture for heart failure is not clear and says PDE-5 inhibitors are certainly “not a panacea”. However, there does seem to be some cardioprotective effect, he says, particularly after a heart attack, when they could prevent further damage, and in heart failure with reduced ejection fraction, when the muscle of the left ventricle is not pumping normally. “But in the absence of large, randomised trials, it hasn’t been proven as such. So PDE-5 inhibitors are not routinely prescribed to protect the heart.” Hutchings believes that it is time for these trials to take place, but adds that they would be expensive and would need a large charity or public body to sponsor them. Newer lines of sildenafil film tablet evidence are saying that PDE-5 inhibitors actually having a direct effect on the heart tissues Working with John Hancock at the University of Texas, Dent has looked at combinations of drugs that could affect this cancer-causing mutant gene. The US Food and Drug Administration-approved kinase inhibitor neratinib (Nerlynx; Puma Biotechnology) removes mutant K-RAS proteins and another cancer-causing protein, N-RAS, from the surface of cancer cells, allowing them to be degraded inside the cell, thus halting their ability to cause cell proliferation and chemotherapy resistance. “John demonstrated that Viagra, through protein kinase G (PKG), would phosphorylate the [mutant] RAS [protein] and would take it off the plasma [cell] membrane and keep it stored at an intracellular site where it couldn’t act as an oncogene.” Using a combination of neratinib and sildenafil, Dent and Hancock found there was a larger effect on mutant K-RAS.

About the Company

The challenges involved in running trials with off-patent drugs is partly why ReDo exists. “I became involved because my son had osteosarcoma, and he didn’t respond to standard treatments,” says Pantziarka. “I found that there were people who were looking at non-cancer drugs which had some evidence of activity in cancer.” Sadly, Pantziarka was not able to find a treatment for his son, who died in 2011, but he ended up moving from a job in computer science to oncology research and now focuses on commercially neglected therapeutic areas, including repurposing. You can bypass the early stages of trials, so in theory the path should be clear to rapid adoption, should we have positive results “Our intention is to find treatments we can get to patients quickly and repurposing really fits the bill very well,” he explains. “You can bypass the early stages of trials, so in theory the path should be clear to rapid adoption, should we have positive results.” As part of the ReDo project, Pantziarka has built up a database of around 270 drugs with some potential to be repurposed as cancer therapies and this includes PDE-5 inhibitors.

Viagra and children

“Drugs like the PDE-5 inhibitors actually have a tremendous amount of existing evidence. Not just in vitro studies, but supporting data from extensive animal models, human data, case reports, and small clinical trials.” Pantziarka explains that PDE-5 inhibitors have an immunological effect in cancer (see Figure). “There is quite a wide range of evidence to show that actually these drugs can take the brakes off the immune response, so they help the anti-tumour immune response get into gear,” he says. Figure 1: PDE-5 inhibitors and cancer One suggestion is to use PDE-5 inhibitors in cancer patients after surgery to try to reduce cancer reoccurrences[1] . “Because the PDE-5 inhibitors work on an immunological basis, and we think that the post-surgical reoccurrence is partly immune based, that is a really good fit,” says Pantziarka. They are currently exploring the cellular mechanisms involved. Emerging evidence suggests that PDE-5 inhibitors have direct cardioprotective effects.

How to save on Viagra

The ability of PDE-5 inhibitors to open up the vasculature, as well as some being able to pass through the BBB, suggests they are good candidates for treating neurological diseases. Research has shown that sildenafil is successful in inhibiting neuro-inflammation and, in aged mouse models, lowering amyloid levels, the peptide plaques that are thought to clog the brain in Alzheimer’s disease[6] . Tadalafil was able to penetrate the BBB more effectively in mice than sildenafil but there have been no clinical trials for repurposing either drug in Alzheimer’s disease[7] . However, there has been some work on the use of PDE-5 inhibitors to treat vascular cognitive impairment, a form of dementia that receives less attention. “Often, it’s not quite dementia it’s a milder, earlier stage cognitive impairment,” says Atticus Hainsworth, a neuroscientist from the Neurosciences Research Centre at St George’s University of London.

Viagra for ED

The underlying problem is not enough blood flow to deep brain areas. “We have a huge brain and the deep bits rely on very thin arteries, about as thin as your eyelash, to carry blood. If they become stiff or narrow, or in some way not quite functional, the inner brain regions won’t get quite enough blood. It’s not that they’ll be blocked, they’ll perhaps get 50% to 70% of what they need,” explains Hainsworth. The theory is that a PDE-5 inhibitor may improve blood flow. Their role in dilating arteries and improving blood flow is already well known (see Panel), with sildenafil (Revatio; Pfizer) and tadalafil (Adcirca; Eli Lilly) approved for treating pulmonary arterial hypertension. “But newer lines of evidence are saying that they’re actually having a direct effect on the [heart] tissues,” says David Hutchings, honorary clinical lecturer in cardiovascular sciences at the University of Manchester, UK. Animal models show that PDE-5 inhibitors improve some abnormalities that occur in heart disease, which seem to be linked to the activation of PKG in cardiac cells and the vasculature — they improve contractile function in the heart[4] .

But not all trials of PDE-5 inhibitors in cardiovascular disease have been successful.

What is the difference between sildenafil and Viagra?

“[PDE-5 inhibitors] are able to interfere with the pumps that are involved with the blood-brain barrier (BBB) and so you can also envisage using Viagra to try to further disrupt the BBB in patients with glioblastoma.” PDE-5 inhibitors also cause higher levels of nitric oxide and a greater free-radical load within cancer cells, which helps to kill them. Dent has started a phase II study on high-grade recurrent glioma using a combination of sorafenib, repurposed seizure medicine valproic acid, and sildenafil. “We have seen some quite nice six-month progression-free survival in some of these patients,” he says. Another important factor in PDE-5 inhibitors’ cancer fighting-properties is their ability to disrupt the effects of mutant K-RAS oncogenes. These cell signalling genes control cell proliferation, but when mutated lead to cancer, a mechanism involved in 90% of pancreatic cancers and 50% of bowel cancers.

Can Viagra be crushed, split, or chewed?

Newer lines of sildenafil film tablet evidence are saying that PDE-5 inhibitors actually having a direct effect on the heart tissues Working with John Hancock at the University of Texas, Dent has looked at combinations of drugs that could affect this cancer-causing mutant gene. The US Food and Drug Administration-approved kinase inhibitor neratinib (Nerlynx; Puma Biotechnology) removes mutant K-RAS proteins and another cancer-causing protein, N-RAS, from the surface of cancer cells, allowing them to be degraded inside the cell, thus halting their ability to cause cell proliferation and chemotherapy resistance. “John demonstrated that Viagra, through protein kinase G (PKG), would phosphorylate the [mutant] RAS [protein] and would take it off the plasma [cell] membrane and keep it stored at an intracellular site where it couldn’t act as an oncogene.” Using a combination of neratinib and sildenafil, Dent and Hancock found there was a larger effect on mutant K-RAS. They are currently exploring the cellular mechanisms involved. Emerging evidence suggests that PDE-5 inhibitors have direct cardioprotective effects. A large US trial — RELAX — looked at using PDE-5 inhibitors to treat heart failure with preserved ejection fraction or “diastolic HF”, which accounts for approximately half of heart failure cases and has a poor prognosis[5] . The trial showed no improvement in either contractile function or in the patient’s breathlessness or hospital admission rate. Hutchings admits the picture for heart failure is not clear and says PDE-5 inhibitors are certainly “not a panacea”. However, there does seem to be some cardioprotective effect, he says, particularly after a heart attack, when they could prevent further damage, and in heart failure with reduced ejection fraction, when the muscle of the left ventricle is not pumping normally.

“But in the absence of large, randomised trials, it hasn’t been proven as such. So PDE-5 inhibitors are not routinely prescribed to protect the heart.” Hutchings believes that it is time for these trials to take place, but adds that they would be expensive and would need a large charity or public body to sponsor them. The ability of PDE-5 inhibitors to open up the vasculature, as well as some being able to pass through the BBB, suggests they are good candidates for treating neurological diseases. Research has shown that sildenafil is successful in inhibiting neuro-inflammation and, in aged mouse models, lowering amyloid levels, the peptide plaques that are thought to clog the brain in Alzheimer’s disease[6] .

• The pill's effectiveness can be influenced by psychological factors like depression.
• It can cause a temporary increase in heart rate or blood pressure changes.
• The medication is available in some online pharmacies with valid prescriptions.
• It is not recommended for men with certain eye conditions like NAION history.
• The blue color is used for patient compliance and easy identification.
• Patients should avoid grapefruit products as they can increase side effects.
• A healthcare provider can adjust the dose based on individual response and tolerance.

Tadalafil was able to penetrate the BBB more effectively in mice than sildenafil but there have been no clinical trials for repurposing either drug in Alzheimer’s disease[7] . However, there has been some work on the use of PDE-5 inhibitors to treat vascular cognitive impairment, a form of dementia that receives less attention. “Often, it’s not quite dementia it’s a milder, earlier stage cognitive impairment,” says Atticus Hainsworth, a neuroscientist from the Neurosciences Research Centre at St George’s University of London. The underlying problem is not enough blood flow to deep brain areas. “We have a huge brain and the deep bits rely on very thin arteries, about as thin as your eyelash, to carry blood. If they become stiff or narrow, or in some way not quite functional, the inner brain regions won’t get quite enough blood. It’s not that they’ll be blocked, they’ll perhaps get 50% to 70% of what they need,” explains Hainsworth. The theory is that a PDE-5 inhibitor may improve blood flow. Hainsworth, funded by the UK Alzheimer’s Society and the New York-based Alzheimer’s Drug Discovery Foundation, has just completed a phase II trial of tadalafil in 54 participants with brain vascular disease to see if it improves cognitive function[8] . A Boston University and University of Pennsylvania clinical trial is also looking at PDE-5 inhibitors, this time for treating traumatic microvascular injury in American football players[9] . The researchers are giving players with a history of mild traumatic brain injury a five-week course of sildenafil and hope to increase cerebrovascular reactivity — the capacity for cerebral blood vessels to dilate, which is a factor in assessing brain disorders and is often diminished by traumatic brain injuries. The potential for repurposing of PDE-5 inhibitors seems immense.

Pros and cons of Sildenafil (Viagra)

Hainsworth, funded by the UK Alzheimer’s Society and the New York-based Alzheimer’s Drug Discovery Foundation, has just completed a phase II trial of tadalafil in 54 participants with brain vascular disease to see if it improves cognitive function[8] . A Boston University and University of Pennsylvania clinical trial is also looking at PDE-5 inhibitors, this time for treating traumatic microvascular injury in American football players[9] . The researchers are giving players with a history of mild traumatic brain injury a five-week course of sildenafil and hope to increase cerebrovascular reactivity — the capacity for cerebral blood vessels to dilate, which is a factor in assessing brain disorders and is often diminished by traumatic brain injuries. The potential for repurposing of PDE-5 inhibitors seems immense.

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