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“I like to think of these as multi-targeted agents in contrast to the closely targeted agents, which are the more common thing in drug development now,” says Pantziarka.

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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.

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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. Dent says there are even indications that PDE-5 inhibitors sildenafil tablets lp 100 mg could have antiviral and antibiotic properties[10],[11] . “[Sildenafil is] a pretty unique drug,” adds Hutchings.

“I think the fact that it’s been so widely described and the uptake has been so big, has given us this opportunity to look at it from different angles.” Whether all of this research will culminate in new licensed indications remains to be seen.

Although repurposing promises cheap, effective drugs, there are problems associated with the process.

Infectious diseases and other possible uses

In combination with other drugs, they may be able to tackle hard-to-kill viruses, he says: “I mean, viruses like drug-resistant HIV, ebola, drug-resistant influenza, mumps, measles and rubella.” In addition, clinical trials or basic research have found PDE-5 inhibitors have a therapeutic effect in the recovery of peripheral neuropathy in mice with diabetes[12] , for treating age-related macular degeneration[13] , for male urogenital disease[14] and for cystic fibrosis[15] . I think the fact that sildenafil has been so widely described and the uptake has been so big, has given us this opportunity to look at it from different angles There are also a few studies suggesting PDE-5 inhibitors could be helpful in in vitro fertilisation treatment. Endometrial thickness is a strong predictor of implantation and ongoing pregnancy, and sufficient thickness is dependent on the uterine blood flow — something PDE-5 inhibitors could increase[16] . This enormous list to some degree reflects PDE-5 inhibitors’ ability to dilate the vasculature, and the therapeutic possibilities this offers. But it also reflects their multi-target properties. We have a situation where, yes the drugs are cheap, yes they may be effective, but there are financial disincentives to invest in the necessary research Dent says that when trying to combine new, expensive drugs with an older product, getting large pharmaceutical companies on board can be tough.

• 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.

“With small pharma, we’ve had a lot of success getting drugs,” but, he adds, “we deliberately think before we’ve even done an experiment: ‘How could we do this experiment more cheaply so that the cancer centre only has to buy one

expensive drug and not two?’.” Pantziarka explains that, since a lot of older drugs have been generic for decades, and in some cases there are dozens of manufacturers, it is difficult for a pharmaceutical company, or even a generics company, to invest.

• Research on blue sildenafil continues to evolve, focusing on safety and efficacy.
• Regulatory authorities, like the FDA, approve sildenafil for ED under strict guidelines.
• Online markets sell various brands of blue sildenafil, with variable quality.
• Always verify the source to avoid counterfeit or adulterated products.
• Use of blue sildenafil is generally safe when prescribed and used correctly.
• Patients should report any adverse effects to their healthcare provider immediately.
• Blue sildenafil is sometimes used in clinical studies for other medical conditions.
• The drug's patent expired, leading to generic versions being widely available.
• Proper medical assessment helps determine if sildenafil is suitable for a patient.
• Awareness campaigns promote safe use and inform about potential risks.

“We have a situation where, yes the drugs are cheap, yes they may be effective, but there are financial disincentives to invest in the necessary research.” Public funding is not easy to access either.

Warnings & Precautions

“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.

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“[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.

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Newer lines of 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. For example, Pantziarka says that EU Horizon 2020, a research and innovation programme with nearly €80bn of funding available between 2014 and 2020, requires applicants

Neurological disorders

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] .

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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 sildenafil chewable tablets 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.

Viagra and foods

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. to show they own the intellectual property — it is designed for innovations that provide an economic outcome, rather than value to patients and society.